MX2008008528A

MX2008008528A - Macrocyclic compounds useful as bace inhibitors

Info

Publication number: MX2008008528A
Application number: MXMX/A/2008/008528A
Authority: MX
Inventors: Mccarthy Clive; Betschart Claudia; Tintelnotblomley Marina; Jacob Veenstra Siem; Laumen Kurt; Machauer Rainer; Koller Manuel; Lerchner Andreas
Original assignee: Novartis Ag
Priority date: 2005-12-30
Filing date: 2008-06-27
Publication date: 2008-09-26

Abstract

The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.

Description

MACROCYCLIC COMPOUNDS USEFUL AS BACE INHIBITORS The present invention relates to novel macrocyclic compounds, to their preparation, to their use as medicaments, and to medicines comprising them. More particularly, the invention relates to a compound of the formula: wherein: R, is - (CH2) kN (Ra) Rb, wherein: k is 0, 1 or 2; Ra is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms) -alkyl (of 1 to 4 carbon atoms), aryl, aryl-alkyl (1 to 4 carbon atoms), hetero-aryl, hetero-aryl-alkyl (1 to 4 carbon atoms), chroman-4-yl, sochroman-4-yl, thiochroman-4 -yl, isothiochroman-4-yl, 1, 1-dioxo-1 lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2-lambda * 6 * -isothiochroman-4-yl, 1, 2,3, 4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo-1, 2,3,4-tetrahydro-1lambda * 6 * -benzo- [e] [1, 2] -thiazin-4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2lambda * 6 * -benzo- [c] [1,2] -thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda * 6 * -benzo- [c] [1,2] -oxatiin- 4-yl, 2,2-dioxo-3,4-dihydro-2H-2-lambda * 6 * -benzo- [e] [1, 2] -oxatiin-4-yl, 2,3,4,5-tetrahydro- benzo- [b] oxepin-5-yl or 1,4,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted; and R is a cycloalkyl group (of 3 to 8 carbon atoms), wherein: (a) one of the ring carbon members of the cycloalkyl fraction (of 3 to 8 carbon atoms), which are different from the carbon member of the ring, to which the nitrogen atom carrying Ra is attached, is optionally replaced by a hetero ring member, selected from the group consisting of -O-, -S-, -S (= O ) -, -S (= O) 2- and -N (RC) -, wherein: Rc is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl or hetero-aryl-alkyl (from 1 to 4 carbon atoms), optionally substituted, (b) the cycloalkyl fraction (of 3 to 8 carbon atoms) is substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, hyd roxyl, alkoxy (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) -alkoxyl (of 1 to 4 carbon atoms), thioalkyl (of 1 to 4 carbon atoms), alkyl (of 1) at 4 carbon atoms) -sulfinyl, alkyl (1 to 4 carbon atoms) -sulfonyl, alkyl (1 to 4 carbon atoms) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkoxy ( from 1 to 4 carbon atoms) -carbonyl, alkoxy (1 to 4 carbon atoms) -carbonyloxy, and an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, arylalkyl (from 1 to 4 carbon atoms), hetero-aryl, heteroaryl-alkyl (from 1 to 4 carbon atoms) carbon), non-aromatic heterocyclyl, non-aromatic heterocyclyl-alkyl (1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1, 1- dioxo-1 lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2lambda * 6 * -isothiochrom an-4-yl, 1, 2,3,4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth- 1-yl, 1, 1-dioxo-1, 2,3,4-tetrahydro-1-lambda * 6 * -benzo- [e] [1, 2] -thiazin-4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2lambda * 6 * -benzo- [c] [1, 2] -thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda * 6 * -benzo - [c] [1,2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo- [e] [1,2] -oxatiin-4- ilo, 2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl or 1, 3,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted, and (c ) the cycloalkyl fraction (of 3 to 8 carbon atoms) is optionally substituted on two adjacent carbon members of the ring by two substituents, which form, together with the two adjacent carbon members of the ring, with which they are attached, a cycloalkyl group (of 3 to 8 carbon atoms), wherein: (i) one of the carbon members of the ring of the cycloalkyl group (3 to 8 carbon atoms) fo rmed in this way, which are different from the two adjacent carbon members of the ring, with which these two substituents are optionally attached, is optionally replaced by a hetero member of the ring, selected from the group consisting of - O-, -S-, -S (= 0) -, -S (= 0) 2- and -N (Rd) -, where: Rd is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero- aryl or heteroaryl-1-alkyl (1 to 4 carbon atoms), optionally substituted, and (ii) the cycloalkyl group (3 to 8 carbon atoms) as formed, is optionally substituted by 1 to 4 substituents, in Dependently selected from the group consisting of halogen, cyano, oxo, hydroxyl, alkoxy lo (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alkoxyl (from 1 to 4 carbon atoms) carbon), thioalkyl (from 1 to 4 carbon atoms), alkyl (from 1 to 4 carbon atoms) -sulfinyl, alkyl (from 1 to 4 carbon atoms) -sulfonyl, alkyl (from 1 to 4 atoms) carbon) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkoxy lo (1 to 4 carbon atoms) -carbonyl, alkoxy (1 to 4 carbon atoms) -carbonyloxy, and one group alkyl (from 1 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl ( from 1 to 4 carbon atoms), hetero-aryl, hetero-aryl-alkyl (from 1 to 4 carbon atoms), non-aromatic heterocyclyl, non-aromatic heterocyclyl-alkyl (from 1 to 4 carbon atoms), chroman-4 -yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1-lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2-lambda * 6 * -isothiochroman-4-yl, 1,2, 3,4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo -1,2,3,4-tetrahydro-1lambda * 6 * -benzo- [e] [1, 2] -thiazin-4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2lambda * 6 * -benzo- [c] [1, 2] -thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda * 6 * -benzo- [c] [1, 2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo- [e] [1, 2] -oxatiin-4-yl, 2,3,4,5 -tetrahydro-benzo- [b] oxepin-5-yl or 1, 3,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted; R2 is hydrogen or alkyl (1 to 4 carbon atoms); R3 is hydrogen, alkyl (of 1 to 6 carbon atoms), or an alkyl group (of 1 to 6 carbon atoms) -OC (= O) NH, cycloalkyl (of 3 to 8 carbon atoms) -OC (= O) NH, cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms) -OC (= O) NH, aryl-alkyl (from 1 to 4 carbon atoms) -OC (= O) ) NH, heteroaryl-alkyl (of 1 to 4 carbon atoms) -OC (= O) NH, alkyl (of 1 to 4 carbon atoms) -C (= 0) NH, cycloalkyl (of 3 to 8 atoms) carbon) -C (= O) NH, aryl-C (= O) NH, aryl-alkyl (1 to 4 carbon atoms) -C (= O) NH, hetero-aryl-C (= O) NH , or hetero-aryl-alkyl (1 to 4 carbon atoms) -C (= O) NH, optionally substituted; Ar is an arylene or heteroarylene ring, the ring of which is optionally substituted with halogen, alkoxy (1 to 4 carbon atoms), hydroxyl or alkyl (1 to 4 carbon atoms), wherein U and Xi are the position ortho or meta one with respect to the other; U is a bond, O, CF2, CF2CF2, CHF, CHFCHF, cycloprop-1,2-ylene, alkyleneoxy (from 1 to 3 carbon atoms), alkylene (from 1 to 3 carbon atoms) -amino, alkylene (from 1 to 8 carbon atoms), or NRe, wherein: Re is hydrogen, alkyl (of 1 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms); any of: \ is hydrogen, and V2 is hydroxyl, or i and V2 are together oxo; W is CH = CH, cycloprop-1, 2-olene, phen-1,2-ylene, CH2CH (OH), CH (OH) CH2 or CR, R, CR, Rf, wherein: each Rf, independently, is hydrogen, fluorine or alkyl (of 1 to 4 carbon atoms); X is a alkanoylidene group (of 1 to 4 carbon atoms), alkylene (of 1 to 4 carbon atoms), cycloalkylene (of 3 to 8 carbon atoms), piperidin-diyl, pyrrolidin-diyl, benzothiazole-4,6 - diyl, benzoxazole-4,6-diyl, 1 H-benzo-triazole-4,6-diyl, imidazo- [1, 2-a] -pyridin-6,8-diyl, benzo- [1, 2,5 ] -oxadiazole-4,6-diyl, benzo- [1, 2,5] -thiadiazole-4,6-diyl, 1 H-indole-5,7-diyl, 1 H-indole-4,6-diyl, 1H-benzimidazole-4,6-diyl or 1 H-indazol-1,6-diyl, optionally substituted, or an optionally substituted arylene or heteroarylene ring, wherein Y and C (= 0) NR2 are in the position goal one with respect to the other; Xi is CRgRg, wherein: each Rg, independently, is hydrogen, fluorine or an alkyl group (of 1 to 8 carbon atoms), alkoxy (of 1 to 4 carbon atoms) -alkyl (of 1 to 4 carbon atoms) ), cycloalkyl (of 3 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms) -alkyl (of 1 to 4 carbon atoms), optionally substituted; Y is a link, O, S (= 0) 2, S (= 0) 2NRh, N (Rh) S (= 0) 2, NRh, C (Rh) OH, C (= 0) NRh, N (Rh) C (= O), C (= 0) N (Rh) O u ON (Rh) C (= 0), where: Rh is hydrogen , alkyl (of 1 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms); and Z is O, CH2, CF2, CHF, cycloprop-1, 2-ylene or a bond, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in the form of free base or in Acid addition salt form. More particularly, the invention relates to a compound of the formula I, wherein: R, is - (CH2) kN (Ra) Rb, wherein: k is 0, 1 or 2; Ra is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms) -alkyl (of 1 to 4 carbon atoms), aryl, aryl-alkyl (1 to 4 carbon atoms), hetero-aryl, hetero-aryl-alkyl (1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4 ilo, isothiochroman-4-yl, 1,1-dioxo-1-lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2-lambda * 6 * -isothiochroman-4-yl, 1, 2,3,4- tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo-1,2, 3,4-tetrahydro-1lambda * 6 * -benzo- [e] [1, 2] -thiazin-4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2lambda * 6 * -benzo - [c] [1,2] -thiazin-4-yl, 1, 1-dioxo-3,4-dihydro-1H-1lambda * 6 * -benzo- [c] [1,2] -oxatiin-4- ilo, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo- [e] [1, 2] -oxatiin-4-yl, 2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl or 1,4,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted; and Rb is a cycloalkyl group (of 3 to 8 carbon atoms), wherein: (a) one of the carbon members of the ring of the cycloalkyl fraction (of 3 to 8 carbon atoms), which are different from the carbon member of the ring, to which the nitrogen atom carrying Ra is attached, is optionally replaced by a hetero ring member, selected from the group consisting of -O-, -S-, -S (= O ) -, -S (= O) 2- and -N (RC) -, wherein: Rc is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl or hetero-aryl-alkyl (from 1 to 4 carbon atoms), optionally substituted, (b) the cycloalkyl fraction (of 3 to 8 carbon atoms) is substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, h idroxyl, alkoxy (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alkoxyl (from 1 to 4 carbon atoms), thioalkyl (from 1 to 4 carbon atoms), alkyl (from 1 at 4 carbon atoms) -sulfinyl, alkyl (1 to 4 carbon atoms) -sulfonyl, alkyl (1 to 4 carbon atoms) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkoxy ( 1 to 4 carbon atoms) -carbonyl, alkoxy (of 1 to 4 carbon atoms) -carbonyloxy, and an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms) - alkyl (from 1 to 4 carbon atoms), aryl, arylalkyl (from 1 to 4 carbon atoms), hetero-aryl, heteroaryl-alkyl (from 1 to 4 carbon atoms), non-aromatic heterocyclyl, non-aromatic heterocyclyl -alkyl (1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1, 1-dioxo-1-lambda * 6 * -thiochroman-4 -lilo, 2,2-dioxo-2lambda * 6 * - isothiochroman-4-yl, 1, 2,3,4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4 ilo, 1, 2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo-1, 2,3,4-tetrahydro-1-lambda * 6 * -benzo- [e] [1, 2] - thiazin-4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2-lambda * 6 * -benzo- [c] [1, 2] -thiazin-4-yl, 1,1-dioxo- 3,4-dihydro-1H-1lambda * 6 * -benzo- [c] [1,2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo - [e] [1, 2] -oxatiin-4-yl, 2,3,4,5-tetrahydro-benz o- [b] oxepin-5-yl or 1, 3,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted, and (c) the cycloalkyl fraction (from 3 to 8 carbon atoms) carbon) is optionally substituted on two adjacent carbon members of the ring by two substituents, which form, together with the two adjacent carbon members of the ring, with which they are attached, a cycloalkyl group (of 3 to 8 carbon atoms) , wherein: (i) one of the carbon members of the ring of the cycloalkyl group (of 3 to 8 carbon atoms) formed in this manner, which are different from the two adjacent carbon members of the ring, with which these are two optionally attached substituents, is optionally replaced by a hetero ring member, selected from the group consisting of -O-, -S-, -S (= O) -, -S (= O) 2- and -N (Rd) -, where: Rd is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms) ono) -alkyl (of 1 to 4 carbon atoms), aryl, aryl-alkyl (of 1 to 4 carbon atoms), hetero-aryl or hetero-aryl-alkyl (of 1 to 4 carbon atoms), optionally substituted , and (ii) the cycloalkyl group (3 to 8 carbon atoms) thus formed is optionally substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, hydroxyl, alkoxy (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alkoxyl (from 1 to 4 carbon atoms), thioalkyl (from 1 to 4 carbon atoms), alkyl (from 1 to 4 carbon atoms) - sulfinyl, alkyl (1 to 4 carbon atoms) -sulfonyl, alkyl (1 to 4 carbon atoms) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkoxy (1 to 4 carbon atoms) ) -carbonyl, alkoxy (of 1 to 4 carbon atoms) -carbonyloxy, and an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8) carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl, hetero-aryl-alkyl (from 1 to 4 carbon atoms), non-aromatic heterocyclyl, non-aromatic heterocyclyl-alkyl (1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1, 1-dioxo-1 lam bda * 6 * -thioc roman-4-yl, 2,2-dioxo-2-lambda * 6 * -isothiochroman-4-yl, 1, 2,3,4-tetrahydro-quinol-4-yl, 1, 2, 3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo-1,2,3,4-tetrahydro-1-lambda * 6 * -benzo - [e] [1, 2] -thiazin-4-yl, 2,2-dioxo-1,2,3,4-tetrahydro-2-lambda * 6 * -benzo- [c] [1,2] -thiazin- 4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda * 6 * -benzo- [c] [1, 2] -oxatiin-4-yl, 2,2-dioxo-3,4- dihydro-2H-2lambda * 6 * -benzo- [e] [1, 2] -oxatiin-4-yl, 2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl or 1, 3 , 4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted; R2 is hydrogen or alkyl (1 to 4 carbon atoms); R3 is hydrogen, alkyl (of 1 to 6 carbon atoms), or an alkyl group (of 1 to 6 carbon atoms) -OC (= O) NH, cycloalkyl (of 3 to 8 carbon atoms) -OC (= O) NH, cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms) -OC (= O) NH, aryl-alkyl (from 1 to 4 carbon atoms) -OC (= O) ) NH, hetero-aryl-alkyl (of 1 to 4 carbon atoms) -OC (= 0) NH, alkyl (of 1 to 4 carbon atoms) -C (= 0) NH, cycloalkyl (of 3 to 8 atoms) carbon) -C (= O) NH, aryl-C (= O) NH, aryl-alkyl (1 to 4 carbon atoms) -C (= O) NH, hetero-aryl-C (= 0) NH or hetero-aryl-alkyl (1 to 4 carbon atoms) -C (= O) NH, optionally substituted; Ar is an aromatic or heteroaromatic ring, the ring of which is optionally substituted with halogen, alkoxy (of 1 to 4 carbon atoms), hydroxyl or alkyl (of 1 to 4 carbon atoms), wherein U and X are in the position ortho or goal one with respect to the other; U is a bond, CF2, CF2CF2, CHF, CHFCHF, cycloprop-1, 2-ylene, alkyleneoxy (from 1 to 3 carbon atoms), alkylene (from 1 to 3 carbon atoms) -amino, alkylene (from 1 to 8 carbon atoms), or NRe, wherein: Re is hydrogen, alkyl (of 1 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms); Vi is hydrogen, and V2 is hydroxyl, or \ and V2 are oxo together; W is CH = CH, cycloprop-1, 2-ylene, CH2CH (OH), CH (OH) CH2 or CRfR, CR (R, wherein: each Rf, independently, is hydrogen, fluorine or alkyl (from 1 to 4 carbon atoms); X is an alkanoylidene group (from 1 to 4 carbon atoms), alkylene (from 1 to 4 carbon atoms), cycloalkylene (from 3 to 8 carbon atoms), piperidin-diyl, pi rrolidi n -diyl, benzothiazole-4,6-diyl, benzoxazole-4,6-diyl, 1 H-benzo-triazole-4,6-diyl, imidazo- [1, 2-a] -pyridin-6,8- diyl, benzo- [1, 2,5] -oxadiazol-4,6-diyl, benzo- [1, 2,5] -thiadiazole-4,6-diyl, 1 H-indole-5,7-diyl, H-indole-4,6-diyl, 1H-benzimidazole-4,6-diyl or 1 H-indazol-1,6-diyl, optionally substituted, or an optionally substituted aromatic or heteroaromatic ring, wherein Y and C (= 0) NR2 are in the meta position with respect to each other, Xi is CRgRg, wherein: each Rg, independently, is hydrogen, fluorine or an alkyl group (of 1 to 8 carbon atoms), alkoxy (from 1 to 4) carbon atoms) -alkyl (from 1 to 4 carbon atoms) arbono), cycloalkyl (of 3 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms) -alkyl (of 1 to 4 carbon atoms), optionally substituted; And it is a bond, O, S (= O) 2, S (= O) 2NRh, N (Rh) S (= O) 2, NRh, C (Rh) OH, C (= O) NRh, N (Rh) C (= O), C (= O) N (Rh) O or ON (Rh) C (= O), where: Rh is hydrogen , alkyl (of 1 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms); and Z is O, CH2, CF2, CHF, cycloprop-1, 2-ylene or a bond, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in the form of free base or in the form of acid addition salt. Taking into account the asymmetric carbon atoms present in the compounds of the formula I, the compounds can exist in a pure optically active form, or in the form of mixtures of optical isomers, for example, in the form of racemic mixtures. All optical isomers and their mixtures, including racemic mixtures, are part of the present invention. Halogen denotes fluorine, bromine, chlorine, or iodine. Optional substituents on the alkyl, alkoxyl or cycloalkyl groups or fractions may be, for example, one to three groups independently selected from hydroxyl, hydroxy-alkyl (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) -alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) -alkoxyl (of 1 to 4 carbon atoms), thioalkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) -carbonyl, alkyl (of 1 to 4 carbon atoms) -carbonyloxy, alkyl (of 1 to 4 carbon atoms) -carbonyl, alkyl (from 1 to 4 carbon atoms) -sulphonyl, cyano, oxo, and cycloalkyl (from 3 to 8 carbon atoms). Substituents on the rings or fractions of chroman-4-yl, isocroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1-lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2-lambda * 6 * -isothiochroman-4-yl, 1, 2,3,4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth-1-yl, 1, 1-dioxo-1, 2,3,4-tetrahydro-1 lambda * 6 * -benzo- [e] [1,2] -thiazin -4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2-lambda * 6 * -benzo- [c] [1, 2] -thiazin-4-yl, 1, 1-dioxo-3 , 4-dihydro-1 H-1 lambda * 6 * -benzo- [c] [1, 2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * - benzo- [e] [1,2] -oxatin-4-yl, 2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl, 1,3,4,5-tetrahydro-benzo- [c] oxepin-5-yl, benzothiazole-4,6-diyl, benzoxazole-4,6-diyl, 1H-benzo-triazole-4,6-diyl, imidazo- [1,2-a] -pyridin-6 , 8-diyl, benzo- [1, 2,5] -oxadiazol-4,6-diyl, benzo- [1, 2,5] -thiadiazol-4,6-diyl, 1 H-indole-5,7- diyl, 1 H-indol-4,6-diyl, 1H-benzimidazol-4,6-diyl, 1 H-indazol-1,6-diyl, non-aromatic heterocyclyl, aryl or hetero-aryl are, for example, one to four, in particular from one to three groups independently selected from hydroxyl, optionally substituted alkyl (from 1 to 8 carbon atoms), optionally substituted (C 1-6) alkoxy, S (= O) 2alkyl ( from 1 to 4 á carbon atoms), cycloalkyl (from 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), cyano, nitro, trifluoromethyl, halogen, aryl, hetero-aryl, and optionally substituted carbamoyl. An optionally substituted aryl or heteroaryl group can also carry, as optional substituents, for example, from one to three groups selected from benzyloxy, phenoxy, S (= O) 2 NH2, N (H) S (= O) 2alkyl (from 1 to 6 carbon atoms), N [(C 1-6 alkyl)] S (= O) 2alkyl (from 1 to 6 carbon atoms), 2-oxo-pyrrolidin-1-yl, 2 , 5-dioxa-cyclopent-1-yl, carboxyl, alkoxy (of 1 to 4 carbon atoms) -carbonyl, alkyl (of 1 to 4 carbon atoms) -carbamoyl, alkyl (of 1 to 4 carbon atoms) - sulfonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkyl (1 to 4 carbon atoms) -carbonyl, hydroxy-alkyl (1 to 4 carbon atoms), and optionally substituted amino. Optional substituents on the groups or fractions of alkanilidene, alkylene, cycloalkylene, piperidin-diyl or pyrrolidin-diyl may be, for example, from one to three groups independently selected from hydroxyl, hydroxyalkyl (from 1 to 4 carbon atoms) , alkoxy (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alkyl (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alcoxyl (from 1 to 4 carbon atoms), alkyl (1 to 4 carbon atoms) -sulfanyl, alkoxy (1 to 4 carbon atoms) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkyl (1 to 4) 4 carbon atoms) -carbonyl, alkyl (from 1 to 4 carbon atoms) -sulphonyl, cyano, oxo, carboxyl, carbamoyl and cycloalkyl (from 3 to 8 carbon atoms). Optional substituents on the amino groups may be, for example, one or two groups independently selected from alkyl (1 to 4 carbon atoms), alkoxy (1 to 4 carbon atoms) -alkyl (1 to 4) carbon atoms), alkoxy (1 to 4 carbon atoms) -carbonyl, aryl-alkoxy (1 to 4 carbon atoms) -carbonyl, and hetero-aryl-alkoxy (1 to 4 carbon atoms) -carbonyl . Optional substituents on carbamoyl may be, for example, one or two groups selected from alkyl (1 to 4 carbon atoms) and alkoxy (1 to 4 carbon atoms) -alkyl (1 to 4 carbon atoms) ). Aryl (and the aryl fraction in arylene) is, for example, naphthyl or preferably phenyl. Hetero-aryl (and the hetero-aryl moiety in heteroarylene) is, for example, a 5- or 6-membered aromatic ring, wherein 1, 2 or 3 ring atoms are heteroatoms independently selected from O, N and S, such as thiazolyl, oxazolyl, isoxazolyl, or preferably pyridyl. Non-aromatic heterocyclyl is, for example, a non-aromatic 5 or 6 membered ring, wherein 1, 2 or 3 ring atoms are heteroatoms independently selected from O, N and S, such as pyrrolidinyl, tetrahydro-furyl, tetrahydrothienyl or piperidyl. Any non-cyclic group or fraction containing carbon, with more than 1 carbon atom, is straight or branched chain. Unless defined otherwise, groups, fractions, or molecules containing carbon, contain, for example, from 1 to 8, preferably from 1 to 6, more preferably from 1 to 4, and most preferably from 1 or 2 carbon atoms. In preferred embodiments, the invention relates to a compound of formula I, in free base form or in acid addition salt form, wherein: (1) Ra is hydrogen; (2) k is 0; (3) R2 is hydrogen; (4) R3 is hydrogen; (5) W is CH2CH2, CH = CH or phen-1, 2-ylene; (6) Y is O or NH; (7) Z is a link; (8) the number of ring atoms included in the macrocyclic ring is 15 or 16; (9) Vf is hydrogen and V2 is hydroxyl; (10) X, is CH2; (11) Ar is a phen-1, 2-ylene ring or preferably phen-1,3-ylene ring, which ring is substituted by halogen or is preferably unsubstituted; (12) U is O, CH2 or CH20; (13) Rb is a cycloalkyl group (of 3 to 8 carbon atoms), preferably cyclopropyl, whose cycloalkyl group (of 3 to 8 carbon atoms) is substituted by 1 to 4 substituents, preferably by a substituent, independently selected from the group consisting of an aryl group and a hetero-aryl group, preferably consisting of a phenyl, pyridyl, and isoxazole group, whose aryl or hetero-aryl group is unsubstituted or substituted by 1 to 4 substituents, preferably by a substituent, independently selected from the group consisting of alkyl (1 to 8 carbon atoms) and hydroxy (1 to 8 carbon atoms); (14) X is an optionally substituted ar-1,3-ylene or heteroar-2,4-ylene ring, preferably a mono-substituted phen-1,3-ylene or pyrid-2,4-ylene ring, the substituent being selected from the group consisting of halogen, alkyl (from 1 to 8 carbon atoms), alkoxy (from 1 to 8 carbon atoms), N (H) S (= O) 2alkyl (from 1 to 6 carbon atoms), N-chloro (1-6 carbon atoms)] S (= O) 2-alkyl (of 1 to 6 carbon atoms), 2-oxo-pyrrolidin-1-yl, 2,5-dioxa-cyclopent- 1-yl, hetero-aryl, alkoxy (of 1 to 4 carbon atoms) -alkyl (of 1 to 4 carbon atoms), alkyl (of 1 to 8 carbon atoms) mono-substituted by oxo, alkoxy (of 1 at 8 carbon atoms) mono-substituted by oxo, and carbamoyl substituted by two groups independently selected from alkyl (from 1 to 4 carbon atoms). Preferred embodiments (1) to (14) are preferred in an independent, collective manner, or in any combination or sub-combination. In the especially preferred embodiments, the invention relates to one or more of one of the compounds of the formula I mentioned in the Examples hereinafter, in the form of the free base or in the form of the acid addition salt. In a further aspect, the invention relates to a process for the preparation of the compounds of the formula I, and their salts, which comprises the steps of: a) cyclization by metathesis of a compound of the formula: where R ,, R2, R3, Ar, U, V) p V2, X, X ,, Y and Z are as defined for formula I, in the presence of a catalyst, for example a ruthenium complex, tungsten , or molybdenum, optionally followed by reduction or functionalization of the resulting carbon-carbon double bond, or b) intramolecular cyclization of a compound of the formula: where R ,, R2, R3, Ar, U, Vi, V2, W, X, U and Z are as defined for formula I, Gf is a leaving group and G2 is hydrogen or a protecting group, in each case optionally followed by reduction, oxidation or functionalization of the resulting compound and / or by the cleavage of the optionally present protecting groups, and recovering the thus obtained compound of the formula I in the form of the free base or in the form of the acid addition salt. The reactions can be carried out according to conventional methods, for example as described in the Examples. The processing of the reaction mixtures, and the purification of the compounds obtainable in this manner, can be carried out according to known procedures. The acid addition salts can be produced from the free bases in a known manner, and vice versa. The compounds of the formula I can also be prepared by additional conventional processes, which processes are additional aspects of the invention, for example as described in the Examples. The starting materials of the formulas I I and 11 are known or can be prepared according to conventional processes starting from known compounds, for example as described in the Examples. The compounds of the formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as the "agents of the inventionX, exhibit valuable pharmacological properties when tested in vitro and in animals, and therefore, are useful as medicaments. The agents of the invention are inhibitors of aspartic proteases, and can be used for the treatment of disorders involving processing by these enzymes, In particular, they inhibit beta-secretase, and as such, inhibit beta-secretion generation. amyloid and subsequent accumulation in oligomers and fibrils Test 1: Inhibition of BACE HUmana Recombinant BACE (extracellular domain, expressed in baculovirus, and purified using conventional methods) in a concentration of 0.1 to 10 nM, incubated with the test compound in different concentrations for 1 hour at room temperature, in acetate buffer of 10 to 1 00 mM, pH 4.5, containing 0.1 percent CHAPS. The fluorescent quenched synthetic peptide substrate, derived from the APP sequence, and containing a pair of suitable fluorophore quenchers, is added to a final concentration of 1 to 5 μM, and the increase in fluorescence is recorded. a suitable excitation / emission wavelength, in a microplate spectrofluorimeter for 5 to 30 minutes at 1 minute intervals. The IC50 values are calculated from the percentage of inhibition of BACE activity as a function of the concentration of the test compound. Test 2: Inhibition of Human BACE-2. Recombinant BACE-2 (extracellular domain, expressed in baculovirus, and purified using conventional methods) in concentrations of 0.1 to 1 0 n M, is incubated with the test compound in different concentrations for 1 hour at room temperature, in acetate buffer from 1 0 to 1 00 mM, pH 4.5, containing CHAPS at 0.1 percent. The fluorescent-quenched synthetic peptide substrate, derived from the APP sequence, and containing a pair of suitable fluorophore quenchers, is added to a final concentration of 1 to 5 μM, and the increase in fl uorescence is recorded. at a suitable excitation / emission wavelength, in a microplate spectrofluorimeter for 5 to 30 minutes at 1 minute intervals. IC50 values are calculated from the percent inhibition of BACE-2 activity as a function of the concentration of the test compound. Test 3: Inhibition of Human Cathepsin D. Recombinant cathepsin D (expressed as procapsid D in baculovirus, purified using conventional methods, and activated by incubation in sodium format buffer, pH 3.7) is incubated with the test compound in different concentrations for 1 hour at room temperature, in Sodium acetate or sodium acetate regulator, at a suitable pH within the range of a pH of 3.0 to 5.0 .. The synthetic peptide substrate Mca-Gly-Lys-Pro-lle-Leu-Phe-Phe- Arg-Leu-Lys (DN P) -D-Arg-N H2 to a final concentration of 1 to 5 μM, and the increase in fluorescence is recorded at an excitation of 325 nanometers and an emission of 400 nanometers, in a microplate spectrofluorimeter for 5 to 30 minutes at 1 minute intervals. The IC50 values are calculated from the percent inhibition of cathepsin D activity as a function of the concentration of the test compound. Test 4: Inhibition of Cellular Release of Amiloid Peptide 1-40. The Chinese hamster ovary cells are transfected with the gene for the amyloid precursor protein. The cells are applied at a density of 8,000 cells / well, in a 96-well microtiter plate, and cultured for 24 hours in a DMEM cell culture medium containing 10 percent fetal calf serum. The test compound is added to the cells in different concentrations, and the cells are cultured for 24 hours in the presence of the test compound. The supernatants are harvested, and the concentration of amyloid peptide 1-40 is determined using a sandwich ELISA. The potency of the compound is calculated from the percentage inhibition of amyloid peptide release as a function of the concentration of the test compound. In at least one of the tests indicated above, the agents of the invention show activity in concentrations less than 50 μM. In a specific manner, the agent of the invention described in Example 5 shows an IC50 value of 0.25 μM in Test 1. The agents of the invention, therefore, are useful, for example, for the treatment and / or prevention of neurological and vascular disorders related to the generation and / or accumulation of beta-amyloid, such as neurodegenerative diseases such as Alzheimer's disease, Down syndrome, memory and cognitive impairment, dementia, amyloid neuropathies, cerebral inflammation, nerve and brain trauma, vascular amyloidosis, or cerebral hemorrhage with amyloidosis.

Some of the agents of the invention also inhibit the BACE-2 (APP 2 dissociation enzyme from the beta site) or the Cathepsin D, close homologs of the aspartyl proteases type pepsin, and beta-secretase. Due to the correlation of the expression of BACE-2 and CathD with a more tumorigenic and metastatic potential of tumor cells, these inhibitors are useful for the suppression of the process of metastasis associated with tumor cells. For the aforementioned indications, the appropriate dosage, of course, will vary depending on, for example, the compound employed, the host, the mode of administration, and the nature and severity of the condition being treated. However, it is generally indicated that satisfactory results are obtained in animals with a daily dosage of about 0.1 to about 100, preferably about 1 to about 50 milligrams / kilogram of animal body weight. In higher mammals, for example in humans, an indicated daily dosage is in the range of about 10 to about 2,000, preferably about 10 to about 200 milligrams of an agent of the invention, conveniently administered, by example, in divided doses up to four times a day, or in a sustained release form. The agent of the invention can be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions. In accordance with the foregoing, the present invention also provides an agent of the invention, for use as a medicament, for example for the treatment of neurological or vascular disorders related to the generation and / or accumulation of beta-amyloid. The present invention further provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. These compositions can be manufactured in a conventional manner. The unit dosage forms contain, for example, from about 1 to about 1,000, preferably from about 1 to about 500 milligrams of an agent of the invention. The agents of the invention can be administered alone or in combination with other pharmaceutical agents effective in the treatment of the conditions mentioned above. The pharmaceutical combination may be in the form of a unit dosage form, wherein each unit dosage will comprise a predetermined amount of the two components, mixed with suitable pharmaceutical carriers or diluents. Alternatively, the combination may be in the form of a package containing the two components separately, for example a package or dispensing device adapted for concomitant or separate administration of the two active agents, wherein these agents are arranged separately. Moreover, the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any neurological or vascular disorders related to the generation and / or accumulation of beta-amyloid. In yet a further aspect, the present invention provides a method for the treatment of any neurological or vascular disorders related to the generation and / or accumulation of beta-amyloid, in a subject in need of such treatment, which comprises administering to this subject, a therapeutically effective amount of an agent of the invention. The following Examples illustrate the invention, but do not limit it. Examples Abbreviations: AcOH Acetic acid, ac. Aqueous. 9-BBN 9-borabicyclo [3.3.1] nonane.

BF3 * Et20 Boron trifluoride diethyl-etherate. BINAP (+) - 1,1'-binaft-2,2'-diyl-bis- (diphenyl-phosphine).

CbzCl Benzyl chloroformate. DCM Dichloromethane. Reagent Dess-Martin 1, 1, 1-tris (acetoxy) -1, 1-dihydro-1,2-benzo dioxol-3 (1H9) -one. DMF Dimethyl-formamide. DMSO Dimethyl sulfoxide. EDC. HCl 1-Ethyl-3- [3- (dimethylamino) -propyl] -carbodi-imide hydrochloride. eq Equivalent (s). ES Spraying of electrons. EtMgBr Ethylmagnesium bromide. Et3N Triethylamine. EtOAc Ethyl acetate. EtOH Ethanol. Catalyst of Grubbs II [1, 3-bis- (2,4,6-trimethyl-phenyl) -2- imidazolidinylidene) -dichloro- (phenyl-methylene) - (triphenyl-phosphine) -ruthenium. h Time (s). HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate. HOBt Hydroxy-benzotriazole. HPLC High pressure liquid chromatography.

LC Liquid chromatography. LiOH * H2O Hydrate lithium hydroxide. MeCN Acetonitrile. Mel Iodine-methane. MeMgCI Methyl-magnesium chloride. MeOH Methanol. Min Minute (s) p.f. Melting point. MS Mass spectrometry. NH3 Aqueous ammonia 14 N. NMR Nuclear magnetic resonance spectrometry. Pd / C Palladium on carbon. Pd (OAc) 2 Palladium acetate (ll). Rf Retention factor (thin layer chromatography). rt Ambient temperature. sec Second (s). SK-CC02-A 2- (dimethylamino) -ferrocen-1-palladium (II) chloride / dinorbornyl phosphine complex.

SnCl2 * 2H20 Tin chloride hydrate. TBAI tetrabutyl ammonium iodide. TBME Terbutil-methyl-ether. THF Tetrahydrofuran.

Example 1: (S) -19-acetyl-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17) 19-hexaen-2-one a) [3-Acetyl-5 - ((1 S, 2R) -1 - (3-allyloxy-benzyl) -3-. {Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) - benzyl ester cyclopropyl] -amino.} -2-hydroxy-propyl-carbamoyl) -phenyl] -alyl-carbamic acid 500 milligrams (795 micromoles) of ((1S, 2R) -1- (3-allyloxy-benzyl) terbutyl ester ) -3- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propi I) -carbamic (building block C7) are dissolved in 4 milliliters of 4N HCl in dioxane, and the mixture is stirred for 1 hour, concentrated and co-evaporated with toluene. The residue is dissolved in dichloromethane (5 milliliters), and the solution is added to a solution of HOBt (183 milligrams, 1.19 millimoles, 1.5 equivalents), EDC * HCI (234 milligrams, 1.19 millimoles, 1.5 equivalents), Et3N ( 445 microliters, 3.18 mmol, 4 equivalents), and 3-acetyl-5- (allyl-benzyloxycarbonyl-amino) -benzoic acid (building block A5) in dichloromethane (10 milliliters). The reaction mixture is stirred at room temperature for 16 hours, and then quenched with 1N HCl in H20. The mixture is diluted with dichloromethane, and the organic layer is separated, washed with aqueous NaHCO3, and brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 3 to 7 to give the product. MS (ES +): 864 = [M + H] *.

HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 7.12 minutes. b) Benzyl ester of (Z) - (S) -19-acetyl-4 - ((R) -2-. {benzyloxycarbonyl] l- [1- (3-isopropyl-f-enyl) -cyclopropyl ester ] -amino.} -1-hydroxy-ethyl) -2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6.8 , 10 (22), 13,17,19-heptaen-16-carboxylic The Grubbs II catalyst (24.3 milligrams, 28.6 micromoles, 0.05 equivalents) is dissolved in dry dichloromethane under argon, and the solution is refluxed for 5 minutes. The benzyl ester of [3-acetyl-5 - ((1S, 2R) -1- (3-allyl-benzyl) -3-. {- benzyloxycarbonyl- [1- (3-isopropyl-phenyl) - cyclopropyl] -amino.} -2-hydroxy-propyl-carbamoyl) -phenyl] -alyl-carbamic acid (495 milligrams, 573 micromoles, 1 equivalent) is dissolved in dichloromethane (8 milliliters), and the solution is added by a syringe within 3 minutes. The reaction mixture is refluxed for 90 minutes and then cooled to room temperature. Coal is added (2 grams)The mixture is stirred for 30 minutes and filtered, and the filtrate is concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 2 to 3 to give the product. MS (ES +): 836 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 6.79 minutes. c) (S) -19-acetyl-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one The benzyl - (S) - (S) -19-acetyl-4 - ((R) -2-. {benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino ester. -1-hydroxy-ethyl) -2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa- (21), 6,8,10 (22), 13 , 17,19-heptaen-16-carboxylic acid (402 milligrams, 481 micromoles, 1 equivalent) is dissolved in tetrahydrofuran (6 milliliters), and the solution is added to a suspension of Pd / C (58.3 milligrams, 5 percent) in EtOH (30 milliliters). The reaction mixture is stirred under 1 atmosphere of hydrogen for 2 hours. The mixture is filtered, the filtrate is concentrated, the residue is dissolved in MeOH, and diethyl ether is added, until the product is precipitated. MS (ES +): 570 = [M + H] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time: 4.09 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.03 (d, 1H), 7.20-6.94 (m, 8H), 6.81-6.67 (m, 3H), 6.15 (t, 1H), 4.78 (d, 1H) , 4.26-4.17 (m, 1H), 3.95-3.82 (m, 2H), 3.55-3.35 (m, 2H), 3.09-2.92 (m, 2H), 2.86-2.75 (m, 1H), 2.71-2.45 ( m, 3H), 2.44 (s, 3H), 1.80-1.45 (m, 4H), 1.14 (d, 6H), 0. 95-0.75 (m, 4H). Example 2: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19- (2-oxo-propoxy) -11,16-dioxa-3-azatricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17 , 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) terbutyl ester ) -3- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (C7 building block) and 3-allyloxy acid -5- (2-Oxo-propoxy) -benzoic acid (building block A2). MS (ES +): 601 = [M + H] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.33 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.95 (d, 1H), 7.19-7.09 (m, 3H), 7.08-6.94 (m, 3H), 6.78 (d, 1H), 6.70 (d, 1H). , 6.64 (s, 1H), 6.55 (s, 1H), 6.44 (s, 1H), 4.86-4.74 (m, 1H), 4.75 (s, 2H), 4.39-4.27 (m, 1H), 4.26-4.16 (m, 1H), 4.11-3.83 (m, 3H), 3.55-3.44 (m, 1H), 2.94 (dd, 1H), 2.88-2.75 (m, 1H), 2.71-2.48 (m, 2H), 2.12 (s, 3H), 1.86-1.60 (m, 4H), 1.16 (d, 6H), 0.99-0.76 (m, 4H). Example 3: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclic propyl-my] -ethyl} -19-oxazol-2-i 1-11 -oxa-3,16-di aza-trici clone.3.1.1 * 6, 10 *] docosa-1 (21), 6, 8, 10 (22), 17 , 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1 - (3-allyloxy) tert-butyl ester. benzyl) -3- { benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (C7 building block) and 3- (allyl-benzyloxy-carbonyl-amino) -5-oxazol-2-yl-benzoic acid (building block A3).

MS (ES +): 595 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.16 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.15 (s, 1 H), 8.03 (d, 1 H), 7.32. (s, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.18-7.07 (m, 3H), 7.06-6.91 (m, 3H), 6.80-6.64 (m, 3H), 6.21 (t , 1H), 4.74 (d, 1H), 4.28-4.18 (m, 1H), 3.95-3.83 (m, 2H), 3.50-3.35 (m, 3H), 3.08-2.92 (m, 2H), 2.81-2.65 (m, 1H), 2.64-2.42 (m, 3H), 1.80-1.45 (m, 4H), 1.10 (d, 6H), 0.97-0.75 (m, 4H). Example 4: (S) -4- dimethyl-amide. { (R) -2- [3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -2-oxo-11, 16-dioxa-3-aza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-19 carboxylic acid The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3- { benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C6) and 5-allyloxy-N, N-dimethyl acid -isophthalmic (A4 building block). Rf (DCM / MeOH / NH3 = 90/9/1): 0.38. MS (ES +): 614 = [M + H] X 1 H-NMR (400 MHz, DMSO-d 6): 8.08 (d, 1H), 7.33 (s, 1H), 7.20-7.11 (m, 3H), 7.06- 6.90 (m, 5H), 6.79 (d, 1H), 6.73 (dd, 1H), 4.83 (d, 1H), 4.43-4.32 (m, 1H), 4.26-4.19 (m, 1H), 4.16-4.08 ( m 1H), 4.01- 3.84 (m, 2H), 3.55-3.47 (m, 1H), 3.01-2.80 (m, 7H), 2.69-2.57 (m, 2H), 1.88-1.62 (m, 5H), 1.24 (s, 9H), 1.02-0.79 (m, 5H). Example 5: (S) -18-acetyl-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -15-oxa-3-aza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen-2-one The compound is obtained of the title by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyl-benzyl) -3-. (benzyl) -l-butyl ester. carbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (C5 building block) and 3-acetyl-5-allyloxy-benzoic acid ( construction A6). MS (ES +): 555 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.59 minutes. 1 H-NMR (400 MHz, DMSO-d6): 8.20 (d, 1H), 7.68 (s, 1H), 7.44-7.37 (m, 2H), 7.21-6.91 (m, 8H), 4.81 (d, 1H), 4.42-4.33 (m , 1H), 4.22-4.07 (m, 2H), 3.56-3.50 (m, 1H), 3.15-3.08 (m, 1H), 2.89-2.78 (m, 1H), 2.76-2.52 (m, 8H), 2.00 -1.78 (m, 2H), 1.54-1.32 (m, 2H), 1.18 (d, 6H), 1.05-0.82 (m, 4H). Example 6: (S) -18-acetyl-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -etl} -3,15-diaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyl-benzyl) -3-. {benzyloxycarbonyl- [1 -] - terbutil ester (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (C5 building block) and 3-acetyl-5- (allyl-benzyloxycarbonyl-amino) -benzoic acid (building block A5). MS (ES +): 554 = [M + H] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time: 4.33 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.99 (d, 1H), 7.35 (s, 1H), 7.20-6.94 (m, 9H), 6.49 (s, 1H), 6.21 (t, 1H), 4.73 (d, 1H), 4.14-4.04 (m, 1H), 3.56-3.48 (m, 1H), 3.40-3.35 (m, 1H), 3.13-2.95 (m, 2H), 2.90-2.79 (m, 1H) , 2.72-2.55 (m, 5H), 2.45 (s, 3H), 1.96-1.87 (m, 1H), 1.85-1.72 (m, 1H), 1.52-1.38 (m, 1H), 1.18 (d, 6H) , 1.18-1.05 (m, 1H), 1.05-0.95 (m, 3H), 0.92-0.85 (m, 1H). Example 7: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclohexy-propyl] -ethyl} -18-methoxy-methi 1-3,15,17-triaza-t riciclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyl-benzyl) -3-tert-butyl ester. - { benzyloxycarbonyl- [1 - (3-isopropyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (C5 building block) and 2-allyl-amino- 6-methoxy-methyl-isonicotinic (building block A1). MS (ES +): 557 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.08 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.05 (d, 1H), 7.32 (s, 1H), 7.20- 7.07 (m, 3H), 7.06-6.94 (m, 4H), 6.66 (t, 1H) , 6.52 (s, 1H), 5.93 (s, 1H), 4.72 (d, 1H), 4.18 (s, 2H), 4.10-3.98 (m, 1H), 3.53-3.43 (m, 1H), 3. 30-3.20 (m, 1H), 3.27 (s, 3H), 3.13-2.94 (m, 2H), 2.90-2.77 (m, 1H), 2. 70-2.50 (m, 5H), 1.92-1.85 (m, 1H), 1.80-1.68 (m, 1H), 1.42-1.26 (m, 1H), 1.25-1.10 (m, 1H), 1.16 (d, 6H), 1.05-0.77 (m, 4H). Example 8: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-m-ethoxy-methi 1-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 -hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1 S, 2R) -1 - (3-allyloxy-benzyl) terbutyl ester -3- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic (C7 building block) and 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid (building block A7). MS (ES +): 572 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 3.91 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.86 (d, 1H), 7.18-6.95 (m, 6H), 6. 80-6.65 (m, 2H), 6.58-6.45 (m, 3H), 5.81 (t, 1H), 4.75-4.68 (m, 1H), 4.30-4.23 (m, 1H), 4.23 (s, 2H), 3.95-3.78 (m, 2H), 3.50-3.33 (m, 2H), 3.24 (s, 3H), 3.05-2.92 (m, 2H), 2.89-2.52 (m, 1H), 2.70-2.46 (, 3H) , 1.77-1.45 (m, 4H), 1.17 (d, 6H), 0.98-0.88 (m, 3H), 0.84-0.75 (m, 1H). Example 9: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-1-yl] -ethyl} -19-methyl-11 -oxa-3, 16,18-tr i aza-tr iciclo-tld.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17 , 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1 S, 2R) -1- (3-allyloxy) tertiary butyl ester. benzyl) -3- { benzyloxycarbonyl- [1 - (3-isopropyl I-phenyl I) -cyclopropyl] -am and no.} -2- hydroxypropyl I) -carbamic (C7 building block) and 2-allyl-amino-6-methyl-isonicotinic acid hydrochloride (building block A8). MS (ES +): 543 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.03 (d, 1H), 7.18-7.09 (m, 3H), 7.06-6.94 (m, 3H), 6.78-6.68 (m, 2H), 6.51 (t, 1H), 6.24 (s, 1H), 6.11 (s, 1H), 4.75 (d, 1H), 4.26-4.17 (m, 1H), 3.95-3.77 (m, 2H), 3.46-3.30 (m, 2H), 3.07-2.94 (m, 2H), 2.88 -2.77 (m, 1H), 2.65-2.45 (m, 3H), 2.20 (s, 3H), 1.82-1.58 (m, 3H), 1.57-1.45 (m, 1H), 1.17 (d, 6H), 0.98 -0.88 (m, 3H), 0.87-0.79 (m, 1H). Example 10: (S) -19-acetyl-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -11, 16-dioxa-3-aza-trici dolí 5.3.1.1 * 6,10 *] docosa-1 (21), 6, 8, 10 (22), 17,19- hexaen-2-on a the title compound by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3-. (benzyloxy-) terbutyl ester carbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (C7 building block) and 3-acetyl-5-allyloxy-benzoic acid ( construction A6). MS (ES +): 571 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.43 minutes. 'H-NMR (400 MHz, DMSO-d6): 8.14 (d, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.28 (s, 1H), 7.19-7.11 (m, 3H), 7.07 (d, 1H), 7.01-6.95 (m, 2H), 6.80 (d, 1H), 6.72 (dd, 1H), 4.84 (d, 1H), 4.47-4.37 (m, 1H), 4.27-4.12 ( m, 2H), 4.02-3.91 (m, 2H), 3.58-3.50 (m, 1H), 3.00-2.92 (m, 1H), 2.85-2.76 (m, 1H), 2.73-2.65 (m, 1H), 2.65-2.49 (m, 2H), 2.56 (s, 3H), 1.87-1.63 (m, 4H), 1.15 (d, 6H), 1.00-0.87 (m, 3H), 0.87-0.80 (m, 1H). Example 11: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methoxy-methyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17, 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) terbutyl ester) -3- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (C7 building block) and 2-allyl- amino-6-methoxy-methyl-isonicotinic (building block A1). MS (ES +): 573 = [M + H] *.

HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.02 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.10 (d, 1H), 7.20-7.10 (m, 3H), 7.09-6.98 (m, 3H), 6.80-6.70 (m, 2H), 6.64 (t, 1H), 6.51 (s, 1H), 6.24 (s, 1H), 4.78 (d, 1H), 4.29-4.24 (m, 1H), 4.24 (s, 2H), 3.96-3.80 (m, 2H), 3.50-3.30 (m, 2H), 3.31 (s) , 3H), 3.10-2.95 (m, 2H), 2.90-2.77 (m, 1H), 2.70-2.46 (m, 3H), 1.80-1.62 (m, 3H), 1.58-1.44 (m, 1H), 1.16 (d, 6H), 1.00-0.88 (m, 3H), 0.87-0.75 (m, 1H). Example 12: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -18-m ethoxy -met i 1-3,15-di aza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyl-benzyl) -3- tert-butyl ester. (benzyloxycarbonyl- [1- (3-isopropyl I-phenyl) -cyclopropyl] -am i no.} -2-h id roxi-propi I) -carbamic (building block C5) and the 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid (building block A7). MS (ES +): 556 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.39 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.81 (d, 1H), 7.34 (s, 1H), 7.19-7.10 (m, 3H), 7.08-6.95 (m, 4H), 6.57 (s, 1H). , 6.51 (s, 1H), 6.21 (s, 1H), 5.81 (t, 1H), 4.69 (d, 1H), 4.21 (s, 2H), 4.08-3.98 (, 1H), 3.52- 3.45 (m, 1H), 3.38-3.25 (m, 1H), 3.20 (s, 3H), 3.13-3.05 (m, 1H), 3.02-2.90 (m, 1H), 2.88-2.78 (m, 1H), 2.70-2.50 ( m, 5H), 1.95-1.85 (m, 1H), 1.83-1.70 (m, 1H), 1.53-1.38 (m, 1H), 1.19 (d, 6H), 1.18-1.03 (m, 1H), 1.06- 0.90 (m, 3H), 0.87-0.79 (m, 1H). Example 13: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -c-clopropi-am i no] -et i l} -18- (2-oxo-propoxy) -15-oxa-3-aza-tri-cyclote.3.1.1 * 6, 10 *] henicosa-1 (20), 6, 8, 10 (21), 16.18 -hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1 - (3-allyl-benzyl) - tert-butyl ester 3- { Benzyloxycarbonyl- [1 - (3-isopropyl I-phenyl) -cyclopropi I] -am i no.} -2-h id roxi-propi I) -carbamic (building block C5) and 3-allyloxy-5- (2-oxo-propoxy) -benzoic acid (building block A2). MS (ES +): 585 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.67 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.95 (d, 1H), 7.36 (s, 1H), 7.20-6.93 (m, 7H), 6.54 (s, 1H), 6.39 (s, 1H), 6.33. (s, 1H), 4.80-4.71 (m, 3H), 4.33-4.24 (m, 1H), 4.13-4.02 (m, 2H), 3.58-3.50 (m, 1H), 3.12- 3.06 (m, 1H) , 2.90-2.78 (m, 1H), 2.72-2.48 (m, 5H), 2.12 (s, 3H), 1.98-1.73 (m, 2H), 1.56-1.32 (m, 2H), 1.18 (d, 6H) , 1.05-0.80 (m, 4H). Example 14: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cycline propy I-a m] n -eti} -18-oxazole-2-1, 3, 15-diaza-tri-cy I o- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16, 18-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyl-benzyl) terbutyl ester -3- { Benzyloxycarbonyl- [1- (3-isopropyl I-phenyl) -cyclopropi I] -am i no.} -2-h id roxypropi I) -carbamic (building block C5 ) and 3- (allyl-benzyloxycarbonyl-amino) -5-oxazol-2-yl-benzoic acid (building block A3). MS (ES +): 579 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.54 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.13 (s, 1H), 7.98 (d, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.25-7.09 (m, 5H), 7.09 -6.94 (m, 4H), 6.37 (s, 1H), 6.28 (t, 1H), 4.70 (d, 1H), 4.11-3.99 (m, 1H), 3.54-3.44 (m, 1H), 3.41-3.29 (m, 1H), 3.11 (dd, 1H), 3.09-2.95 (m, 1H), 2.88-2.73 (m, 1H), 2.73-2.53 (m, 5H), 1.95-1.85 (m, 1H), 1.85-1.68 (m, 1H), 1.52-1.36 (m, 1H), 1.20-1.05 (m, 6H), 1.04-0.89 (m, 3H), 0.88-0.79 (m, 1H). Example 15: (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-ami] -1-hydroxy-ethyl} -19-methoxy-methi 1-11 -oxa-3,16-di aza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 -hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) - tert-butyl ester 3- (benzyloxycarbonyl- [1 - (3-te rbu ti lf in i I) -cyclop ropi l -am i no.} -2-hydroxypropyl I) -carbamic (building block C6 ) and 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid (building block A7). MS (ES +): 586 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.18 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.91 (d, 1H), 7.31 (s, 1H), 7.20-7.10 (m, 3H), 7.07-6.98 (m, 2H), 6.80-6.68 (m, 2H), 6.60-6.47 (m, 3H), 5.84 (t, 1H), 4.76 (d, 1H), 4.30-4.24 (m, 1H), 4.24 (s, 2H), 3.95-3.80 (m, 2H) , 3.53-3.35 (m, 2H), 3.24 (s, 3H), 3.05-2.94 (m, 2H), 2.71-2.45 (m, 3H), 1.81-1.45 (m, 4H), 1.25 (s, 9H) , 0.98-0.85 (m, 3H), 0.84-0.77 (m, 1H). Example 16: (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methoxymethyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17 , 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy) tert-butyl ester. benzyl) -3- { benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl-1-amino} -2-hydroxy-propyl) -carbamate (C6 building block) and 2-allyl-amino-6-methoxy-methyl-isonicotinic acid (building block A1). MS (ES +): 587 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 3.53 minutes. 'H-NMR (400 MHz, DMSO-d6): 8.11 (d, 1H), 7.30 (s, 1H), 7.20-7.10 (m, 3H), 7.05-6.98 (m, 2H), 6.77-6-70 (m, 2H), 6.63 (t, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 4.79 (d, 1H), 4.27-4.21 (m, 1H), 4.21 (s, 2H), 3.95-3.79 (m, 2H), 3.50-3.30 (m, 2H), 3.30 (s, 3H), 3.09-2.94 (m, 2H), 2.66-2.45 (m, H), 2.66-2.45 (m, 3H) ), 1.82-1.58 (m, 3H), 1.55-1.42 (m, 1H), 1.24 (s, 9H), 0.97-0.86 (m, 3H), 0.86-0.80 (m, 1H). Example 17: (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19- (2-oxo-propoxy) -11,16-dioxa-3-aza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17 , 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) terbutyl ester ) -3- { Benzyloxycarbonyl- [1 - (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C6) and 3-allyloxy acid -5- (2-Oxo-propoxy) -benzoic acid (building block A2). Rf (cydohexane / EtOAc = 50/50): 0.14. MS (ES +): 615 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.97 (d, 1 H), 7.33 (s, 1 H), 7.20- 7.11 (m, 3 H), 7.05-6.97 (m, 2 H), 6.78 (d, 1 H) , 6.72 (d, 1H), 6.65 (s, 1H), 6.46 (s, 1H), 4.84 (d, 1H), 4.78 (s, 2H), 4.39-4.29 (m, 1H), 4.26-4.18 (m , 1H), 4.11-4.01 (m 1H), 3.99-3.84 (m, 2H), 3.55-3.46 (m, 1H), 2.95 (d, 1H), 2.67 (t, 1H), 2.62-2.55 (m, 2H), 2.13 (s, 3H), 1.86-1.60 (m, 4H), 1.24 (s, 9H), 0.98-0.79 (m, 4H).

Example 18: (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-oxazol-2-yl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 -hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) - tert-butyl ester 3- ({benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C6) and 3- (alkylamide) benzyloxycarbonyl-amino) -5-oxazol-2-yl-benzoic acid (building block A3). Rf (DCM / MeOH = 95/5): 0.29. MS (ES +): 609 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.17 (s, 1H), 8.05 (d, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.21 (s) , 1H), 7.19-7.09 (m, 3H), 7.05-7.00 (m, 2H), 6.78 (d, 1H), 6.72 (dd, 1H), 6.68 (s, 1H), 6.22 (dd, 1H), 4.79 (d, 1H), 4.29-4.21 (m, 1H), 3.97-3.84 (m, 2H), 3.53-3.40 (m, 2H), 3.09-2.95 (m, 2H), 2.70-2.50 (m, 3H), 1.82-1.47 (m, 4H), 1.22 (s, 9H), 0.98-0.78 (m, 4H). Example 19: (S) -4-. { (R) -2- [1 - (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -18- (2-oxo-propoxy) -15-oxa-3-aza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (19), 6.8, 10 (21), 16 (20 ), 17-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the [(2R, 3S) -4- (3-allyl-phenyl) -3-terbutoxy-carbonyl- terbustyl ester. amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C8 building block) and 3-allyloxy-5- (2-oxo-propoxy) -benzoic (construction block A2). Rf (DCM / MeOH / NH3 = 90/10/1): 0.47. MS (LC / MS, ES +): 600 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.33 (d, 1H), 8.03 (d, 1H), 7.77 (s, 1H), 7.41 (s, 1H), 7.17-7.10 (m, 2H), 7.07. (d, 1H), 6.99 (d, 1H), 6. 56 (s, 1H), 6.41 (s, 1H), 6. 37 (s, 1H), 5.03 (d, 1H), 4.75 (s, 2H), 4.34-4.27 (m, 1H), 4.15-4.04 ( m, 2H), 3.64-3.60 (m, 1H), 3.14 (dd, 1H), 2.75-2.60 (m, 6H), 2.11 (s, 3H), 1.96-1.78 (m, 2H), 1.53-1.3 ( m, 2H), 1.27 (s, 9H), 1.26-1.17 (m, 2H), 1.06-0.98 (m, 2H). Example 20: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -18-oxazol-2-yl-3,15-diaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (19), 6,8,10 (21), 16 (20), 17- hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyl-phenyl) -3 acid -tertbutoxycarbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C8 building block) and 3- (allyl-benzyloxycarbonyl) -amino) -5-oxazol-2-yl-benzoic acid (building block A3). Rf (DCM / MeOH / NH3 = 90/10/1): 0.36. MS (LC / MS, ES +): 594 = [M + H] *. 1 H NMR (400 MHz, DMSO-d 6): 8.32 (d, 1 H), 8.16 (s, 1 H), 8.09 (d, 1H), 7.77 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.22 (s, 2H), 7.18 (t, 1H), 7.12-7.07 (m, 2H), 7.01 (d, 1H), 6.42 (s, 1H), 6.33 (t, 1H), 4.99 (d, 1H), 4.15-4.06 (m, 1H), 3.62-3.57 (m, 1H), 3.19-3.15 (m, 1H), 3.07-2.98 (m, 1H), 1.78-2.64 (m, 6H) , 1.97-1.74 (m, 2H), 1.50-1.40 (m, 1H), 1.30-1.09 (m, 3H), 1.23 (s, 9H), 1.08-0.98 (m, 2H). Example 21: ((S) -4- { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl.} -2-oxo-11- oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-19-yl) -methyl-amide of the propan-1-sulfonic acid The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1 - (3-allyloxy-benzyl) terbutyl ester ) -3- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C7) and the acid 3- ( allyl-benzyloxy-carbonyl-amino) -5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid (building block A13). MS (ES +): 663 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.43 minutes. H-NMR (400 MHz, DMSO-d6): 8.01 (d, 1H), 7.25-7.00 (m, 6H), 6. 83 (d, 1H), 6.77 (d, 1H), 6.67 (s, 2H), 6.55 (s, 1H), 6.07 (t, 1H), 4. 84 (d, 1H), 4.32-4.24 (m, 1H), 4.00-3.87 (m, 2H), 3.68-3.48 (m, 1H), 3.55-3.39 (m, 2H), 3.16 (s, 3H), 3.10-2.92 (m, 4H), 2.90-2.80 (m, 1H), 2.75-2.68 (m, 1H), 2.65-2.45 (m, 2H), 1.82-1.50 (m, 6H), 1.19 (d, 6H), 0.96 (t, 3H), 1.00-0.78 (m, 4H). Example 22: (S) -19-acetyl-4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -11, 16-dioxa-3-aza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one Obtained the title compound by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3-. (benzyloxycarbonyl) terbutyl ester. - [1 - (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C6) and 3-acetyl-5-allyloxy-benzoic acid (building block) A6). MS (ES +): 585 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.75 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.11 (d, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 7.20-7.09 (m, 3H), 7.04-6.94 (m, 2H), 6.79 (d, 1H), 6.72 (d, 1H), 4.84 (d, 1H), 4.46-4.30 (m, 1H), 4.25-4.11 (m , 2H), 4.00-3.88 (m, 2H), 3.52-3.49 (m, 1H), 3.00-2.90 (m, 1H), 2.70-2.45 (m, 3H), 2.49 (s, 3H), 1.86-1.60 (m, 4H), 1.22 (s, 9H), 0. 98-0.78 (m, 4H). Example 23: ((S) -4- { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -c-clopropi-amyl] -etyl. -2-oxo-11, 16-dioxa-3-aza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-19 Propan-1-sulfonic acid-1-methyl-amide The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- tert-butyl ester (3-allyloxy-benzyl) -3- { Benzyloxycarbonyl- [1- (3-te rbutyl-1-phen i) -cyclopropi I] -am and no.} -2-h id roxi -propi I) -carbamic (building block C7) and the allyl ester of 3-allyloxy-5- [methoxy- (propan-1-sulfonyl) -amino] -benzoic acid (building block A9). MS (ES +): 663 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 4.66 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.10 (d, 1H), 7.20-6.95 (m, 9H), 6. 81 (d, 1H), 6.75 (d, 1H), 4.89 (d, 1H), 4.39-4.32 (m, 1H), 4.28-4.20 (m, 1H), 4.12-4.08 (m, 1H), 4.00-3.88 (m, 2H), 3.68-3.48 (m, 1H), 3.55-3.50 (m, 1H), 3.21 (s, 3H), 3.10 -3.05 (m, 2H), 2.92 (d, 1H), 2. 84-2.74 (m, 1H), 2.69 (t, 1H), 2.57-2.50 (m, 2H), 1.85-1.60 (m, 6H), 1. 19 (d, 6H), 0.94 (t, 3H), 1.00-0.77 (m, 4H). Example 24: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methyl-11,16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one a) 2- [4- (3. {(2S, 3R) -2-terbutoxy-carbonyl-amino-4- [1- (4-tert-butyl-pyridin-2-methyl) -methyl ester il) -cyclopropyl-amino] -3-hydroxy-bu ti l.]. phenyl ox i) -butoxy] -6-m ethyl-i so nicotinic The product is prepared according to the method described in Example 43 (step a), starting from the terbutil-acid ester [(1S, 2R) -3- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -2-hydroxy-1- (3-hydroxy-benzyl) -propyl] -carbamic acid (block of C16 construction) and the 2- (4-methanesulfonyloxy-butoxy) -6-methyl-iso-nicotinic acid methyl ester (E1 building block). Rf: DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.24 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 50 -100 percent MeCN (3.25 minutes), 100 percent MeCN one hundred (0.75 minutes)): 2,775 minutes. MS (ES +): 691 = [M + H] * b) (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methyl-11, 16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one A solution of 60 milligrams (0.0868 millimoles) of 2- [4- (3- ({2S, 3R) -2-terbutoxy-carbonyl-amino-4- [1- ( 4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -3-hydroxy-butyl) -phenoxy) -butoxy] -6-methyl-isonicotinic acid is treated with 0.17 milliliters of 1N aqueous sodium hydroxide, and stirred for 18 hours. The mixture is acidified with 0.17 milliliters of 1N aqueous hydrochloric acid, and evaporated. The residue is taken up in 3 milliliters of 4N hydrochloric acid in dioxane, stirred for 2 hours, and evaporated. The product is absorbed in 20 milliliters of dichloromethane. To the stirred mixture at + 4 ° C is subsequently added 22.3 milligrams (0.13 millimoles) of HOBt, 25 milligrams (1.5 millimoles) of EDC, and 0.048 milliliters of N-methyl-morpholine. The mixture is heated slowly to room temperature and stirred for 18 hours. Water is added, and the organic phase is washed with 5 percent aqueous sodium bicarbonate and brine, dried over sodium sulfate, and chromatographed on silica gel using a gradient of dichloromethane and MeOH / 2 to 10. percent aqueous NH3 at 25 percent. The title compound is obtained as a colorless resin.

Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.35 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent of MeCN (0.75 minutes)): 2,264 minutes. MS (ES +): 559 = [M + H] * Example 25: Dimethyl-amide of (S) -4- acid. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-19 carboxylic acid The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3- { benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C7) and 5- (allyl-benzyloxycarbonyl- amino) -N, N-dimethyl-isophthalamic acid (building block A15). MS (ES +): 599 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.82 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.99 (d, 1H), 7.18-7.09 (m, 3H), 7. 08-6.96 (m, 3H), 6.80-6.70 (m, 2H), 6.59 (s, 2H), 6.51 (s, 1H), 6.02 (t, 1H), 4.76 (d, 1H), 4.30-4.20 ( m, 1H), 3.96-3.82 (m, 2H), 3.50-3.35 (m, 2H), 3.08-2.75 (m, 9H), 2.70-2.48 (m, 3H), 1.82-1.45 (m, 4H), 1.18 (d, 6H), 0.96-0.73 (m, 4H). Example 26: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methoxy-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2 -one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3- { benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C7) and 3- (allyl-benzyloxycarbonyl- amino) -5-methoxy-benzoic acid (building block A14). MS (ES +): 558 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.09 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.87 (d, 1H), 7.18-7.10 (m, 3H), 7.05 (d, 1H), 7.03-6.95 (m, 2H), 6.77 (d, 1H), 6.71 (d, 1H), 6.24 (s, 1H), 6.19 (s) , 2H), 5.82 (t, 1H), 4.77 (d, 1H), 4.28-4.20 (d, 1H), 3.95- 3.80 (m, 2H), 3.64 (s, 3H), 3.52-3.32 (m, 2H) ), 3.03-2.92 (m, 2H), 2.88-2.78 (m, 1H), 2.70-2.62 (m, 1H), 2.60-2.47 (m, 2H), 1.82-1.47 (m, 4H), 1.19 (d) , 6H), 0.97-0.82 (m, 4H). Example 27: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19- (2-oxo-propoxy) -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa- (21), 6,8,10 (22), 17, 19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) terbutyl ester -3- { Benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C7) and 3- (allyl) acid -benzyloxycarbonyl-amino) -5- (2-oxo-propoxy) -benzoic acid (building block A12). MS (ES +): 600 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.07 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.89 (d, 1H), 7.19-7.11 (m, 3H), 7.18-6.97 (m, 3H), 6.78 (d, 1H), 6.72 (d, 1H) , 6.26 (s, 1H), 6.17-6.11 (m, 2H), 5.82 (t, 1H), 4.78 (d, 1H), 4.63 (m, 2H), 4.29-4.20 (m, 1H), 3.96-3.81 (m, 2H), 3.53-3.32 (m, 2H), 3.04-2.92 (m, 2H), 2.89-2.79 (m, 1H), 2.71-2.61 (m, 1H), 2.61-2.48 (m, 2H) , 2.12 (s, 3H), 1.81-1.47 (m, 4H), 1.19 (d, 6H), 0.97-0.78 (m, 4H). Example 28: (S) -19-acetyl-4-. { (R) -2- [1- (3-tert-butyl-phenyl) -c-clopropi-1-yl] -1-hydroxy-ethyl} -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one Obtained the title compound by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3-. (benzyloxycarbonyl) terbutyl ester. - [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (building block C6) and 3-acetyl-5- (allyl-benzyloxycarbonyl) amino) -benzoic acid (building block A5). MS (ES +): 584 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.38 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.02 (d, 1H), 7.30 (s, 1H), 7.20-7.07 (s, 5H), 7.05-6.95 (m, 2H), 6.82-6.68 (m, 3H), 6.14 (t, 1H), 4.80 (d, 1H), 4.28-4.17 (m, 1H), 3.95-3.74 (m, 2H), 3.55-3.35 (m, 2H), 3.08-2.90 (m, 2H), 2.70-2.42 (m, 3H), 2.45 (s, 3H), 1.80-1.44 (m, 4H), 1.23 (s, 9H), 0.97-0.76 (m, 4H). Example 29: (S) -4-. { (R) -1-h id roxy-2- [1- (3-i sopropi l-f-enyl) -cyclopropyl-amino] -ethyl} -18-methoxy-methyl-11, 15-dioxa-3-aza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 50, starting from the [(2R, 3S) -4- (3-benzyloxy-phenyl) -3- tert-butyl ester. terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-isopropyl-phenyl) -cyclopropyl] -carbamic acid and the methyl ester of 3- (3-methanesulfonyloxy-propoxy) -5-methoxy -methyl-benzoic (E3 building block). MS (ES +): 559 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.37 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.95 (d, 1H), 7.21-7.12 (m, 4H), 7. 07 (d, 1H), 7.01 (d, 1H), 6.92-6.86 (m, 2H), 6.82-6.78 (m, 2H), 6.55 (s, 1H), 4.71 (d, 1H), 4.54 (ddd, 1H), 4.40 (ddd, 1H), 4.31 (s, 2H), 4.25-4.08 (m, 2H), 4.03-3.90 (m, 1H), 3.55-3.43 (m, 1H), 3.24 (s, 3H) , 3.12 (dd, 1H), 2.90-2.70 (m, 1H), 2.61-2.50 (m, 3H), 2.04-1.85 (m, 1H), 1.83-1.68 (m, 1H), 1.17 (d, 6H) , 1.05-0.80 (m, 4H).

Example 30: (S) -4-. { (R) -1-h id roxi-2- [1 - (3- i sopropi lf in incido propi l-am i no] -et i l.} -19-methoxy-meti 1-11, 16-dioxa -3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1 S, 2R) -1 - (3-allyloxy-benzyl) -3-. {benzyloxycarbonyl- [1-tert-butyl ester]. - (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (building block C7) and 2-allyloxy-6-methoxy-methyl-isonicotinic acid (building block A11) MS (ES +): 574 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) , retention time = 4.17 minutes Example 31: (S) -4 - ((R) -2- { 1 - [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl -amino] -ethyl.}. -1-hydroxy-ethyl) -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21) , 6,8,10 (22), 17,19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl- benzyl ester. amino-2-hydroxybutyl] -. { 1- [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl} - Carbamic (building block C19) and 3- (allyl-benzyloxycarbonylamino) -5-methoxy-methyl-benzoic acid (building block A7). MS (ES +): 591 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 3.85 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.95 (d, 1H), 7.15 (t, 1H), 7.03 (s, 1H), 6.79 (d, 1H), 6.71 (d, 1H), 6.60 (s) , 1H), 6.59 (s, 1H), 6.53 (s, 1H), 6.16 (s, 1H), 5.86 (t, 1H), 4.76 (d, 1H), 4.24 (s, 2H), 3.94-3.82 (m, 2H), 3.46-3.34 (m, 2H), 3.24 (s, 3H), 3.04-2.93 (m, 2H), 2.78-2.70 (m, 1H), 2.70-2.58 (m, 3H), 2.54 (s, 2H), 1.76-1.45 (m, 4H), 1.05 -0.76 (m, 4H), 0.87 (s, 9H). Example 32: (S) -4-. { (R) -1-hydroxy-2- [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl-amino] -ethyl} -18-m ethoxy-methi 1-3,15,17-triaza-tri-cid o- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18 -hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyl-phenyl) - 3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C12 building block) and 2-allyl-amino-6-acid -methoxy-methyl-isonicotinic (building block A1). MS (ES +): 558 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.27 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.28 (d, 1H), 8.11 (d, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.20-6.90 (m, 4H), 6.72-6.65 (m, 1H), 6.53 (s, 1H), 5.98 (s, 1H), 4.92 (d, 1H) ), 4.21 (s, 2H), 4.15-4.05 (m, 1H), 4.00-3.85 (m, 1H), 3.60-3.50 (m, 1H), 3.32 (s, 3H), 3.24-2.95 (m, 3H) ), 2. 92-2.78 (m, 1H), 2.75-2.60 (m, 4H), 2.00-1.88 (m, 1H), 1.82-1.70 (m, 1H), 1.43-1.10 (m, 8H), 1.09-0.82 (m, 4H). Example 33: (S) -4-. { (R) -1-hydroxy-2- [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl-amino] -ethyl} -19-methoxy-methyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 -hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) - 3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C11 building block) and 2-allyl-amino-6-methoxy-methyl-isonicotinic acid (building block A1). MS (ES +): 574 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.14 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.29 (d, 1H), 8.16 (d, 1H), 7.51 (s, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 6.64 (t, 1H), 6.51 ( s, 1H), 6.26 (s, 1H), 4.95 (d, 1H), 4.26- 4.22 (m, 1H), 4.22 (s, 2H), 3.96-3.85 (m, 2H), 3.58-3.50 (m, 1 HOUR), 3. 50-3.35 (m, 1H), 3.32 (s, 3H), 3.10-2.98 (m, 2H), 2.88-2.80 (m, 1H), 2. 73-2.58 (m, 4H), 1.80-1.62 (m, 3H), 1.58-1.44 (m, 1H), 1.28-1.04 (m, 4H), 1.17 (d, 6H). Example 34: (S) -18-acetyl-4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropi-l-amino] -1-h-idroxy-ethyl ester} -3,15-d iaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen-2-one The compound of the title by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyl-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy acid -butyl] - [1- (4-tert-butyl-pyrid-2-yl) -cyclopropyl] -carbamic acid (C8 building block) and 3-acetyl-5- (allyl-benzyloxy-carbonyl-amino) -benzoic acid ( building block A5). MS (ES +): 569 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 4.32 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.31 (d, 1H), 8.05 (d, 1H), 7.71. (s, 1H), 7.38 (s, 1H), 7.18-7.02 (m, 5H), 6.98 (d, 1H), 6.52 (s, 1H), 6.21 (t, 1H), 4.99 (d, 1H), 4.13-4.06 (m, 1H), 3.62-3.59 (s, 1H), 3.12 (d, 1H), 3.05-2.97 (m, 1H), 2.79-2.59 (m, 6H), 2.43 (s, 3H), 1.95-1.85 (m, 1H), 1.81-1.70 (m, 1H), 1.49-1.38 (m, 1H), 1.26 (s, 9H), 1.30-1.00 (m, 5H). Example 35: (S) -4 - [(R) -1-hydroxy-2- (2-phenyl-cyclopropyl-amino) -ethyl] -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo - [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one The title compound is obtained as a mixture of two epimers by a reaction sequence analogous to that of Example 1, starting from [(2R, 3S) -4- (3-allyloxy-f-enyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - (2-phenyl) benzyl ester - cyclopropyl) -carbamic acid (building block C20) and 3- (alkyloxycarbonyl-amine) -5-methoxymethyl-I-benzoic acid (building block A7). 1 H-NMR (400 MHz, DMSO-d 6): 8.02-7.90 (m, 1H), 7.22-6.99 (m, 7H), 6.81-6.69 (m, 2H), 6.62-6.49 (m, 3H), 5.91- 5.82 (m, 1H), 4.92-4.81 (m, 1H), 4.28-4.22 (m, 3H), 3.95-3.80 (m, 2H), 3.50-3.35 (m, 2H), 3.25 (s, 3H), 3.03-2.92 (m, 2H), 2.76-2.59 (m, 3H), 2.28-2.24 (m, 1H), 1.85-1.15 (m, 5H), 1.00-0.85 (m, 2H). Example 36: (S) -4-. { (R) -1-Hydroxy-2- [1- (3-propyl-isoxazol-5-yl) -cyclopropyl-amino] -ethyl} -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3- terbutoxycarbonyl-amino-2-hydroxybutyl] -. { 1- [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl} -carbamic (building block C19) and 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid (building block A7). MS (ES +): 563 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes), retention time = 3.27 minutes. Example 37: (S) -19-acetyl-4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 1, 19-hexaen-2-one Obtained the title compound by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino acid. 2-hydroxy-butyl] - [1 - (4-terbuyl-I-pyridin-2-yl) -cyclopropyl I] -carbamic acid (building block C18) and 3-acetyl-5- (allyl-benzyloxy- carbonyl-amino) -benzoic acid (building block A5). MS (ES +): 585 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.10 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.28 (d, 1H), 8.06 (d, 1H), 7.68 (s, 1H), 7.19 (s, 1H), 7.17-7.13 (m, 2H), 7.09 -7.05 (m, 2H), 6.84-6.78 (m, 2H), 6.72 (d, 1H), 6.14 (t, 1H), 4.99 (d, 1H), 4.30-4.21 (m, 1H), 3.96-3.87 (m, 2H), 3.61-3.54 (m, 1H), 3.51-3.40 (m, 1H), 3.07-2.97 (m, 2H), 2.74-2.55 (m, 4H), 2.44 (s, 3H), 1.80 -1.42 (m, 4H), 1.25-1.10 (m, 2H), 1.21 (s, 9H), 1.02-0.93 (m, 2H). Example 38: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methoxy-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2 -one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxi- carbonyl-amino-2-hydroxy-butyl] - [1 - (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (building block C18) and 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-benzoic acid (building block A14).

MS (ES +): 573 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.97 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.28 (d, 1 H), 7.90 (d, 1 H), 7.69 (s, 1H), 7.17-7.03 (m, 3H), 6.79 (d, 1H), 6.71 (d, 1H), 6.25 (s, 1H), 6.18-6.16 (m, 2H), 5.82 (t, 1H) ), 4.98 (d, 1H), 4.30-4.24 (m, 1H), 3.94-3.83 (m, 2H), 3.62 (s, 3H), 3.60-3.52 (m, 1H), 3.49-3.35 (m, 1H) ), 3.04-2.92 (m, 2H), 2.74-2.52 (m, 4H), 1.80-1.45 (m, 4H), 1.27 (s, 9H), 1.28-1.10 (m, 2H), 1.03-0.92 (m , 2H). Example 39: (E) - (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -9-fluoro-19-methyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13 , 17,19-heptaen-2-one a) [(R) -2 - ((E) - (S) -16-acetyl-9-fluoro-19-methyl-2-oxo-11] benzyl ester -oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13,17,19-heptaen-4-il ) -2-hydroxy-ethyl] - [1- (3-tert-butyl-phenyl) -cyclopropyl] -carbamic acid The title compound is obtained by an analogous reaction sequence (steps a and b) to that of Example 1, starting from [(2R, 3S) -4- (3-allyloxy-4-fluoro-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (2-tert-butyl-phenyl) benzyl ester ) -cyclopropyl] -carbamic acid (building block C10) and 2- (acetylallylamino) -6-methyl-isonicotinic acid (building block A17). Rf (EtOAc): 0.30.

MS (ES +): 749.3 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6, 121 ° C): 7.94 (d, 1H), 7.26-7.13 (m, 8H), 7.01 (d, 1H), 6.95 (dd, 1H), 6.88 (d, 1H), 6.81-6.77 (m, 1H), 5.90-5.84 (m, 1H), 5.70-5.63 (m, 1H), 5.09 (dd, 2H), 4.77-4.66 (, 2H), 4.53-4.46 (m , 1H), 4.13 (dd, 1H), 4.06-3.94 (m, 2H), 3.76 (dd, 1H), 3.32 (dd, 1H), 3.11-3.06 (m, 1H), 2.77-2.70 (m, 1H) ), 2.46 (s, 3H), 2.00 (s, 3H), 1.81-1.75 (m, 1H), 1.54-1.47 (m, 1H), 1.34-1.19 (m, 3H), 1.23 (s, 9H), 1.13-1.08 (m, 1H), 0.90-0.83 (m, 1H). b) (E) - (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -9-fluoro-19-methyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13 , 17,19-heptaen-2-one To a solution of the benzyl ester of the acid [(R) -2 - ((E) - (S) -16-acet i I -9-f luoro- 19-met i l-2-oxo-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13,17, 19-heptaen-4-yl) -2-hydroxy-ethyl] - [1- (3-tert-butyl-phenyl) -cyclopropyl] -carbamic acid (35 milligrams, 0.047 mmol) in 2 milliliters of dichloromethane, iodine is added -trimethylsilane (137 microliters, 0.935 mmol), and the mixture is stirred for 10 minutes. The excess iodo trimethylsilane is destroyed by the addition of 1 milliliter of MeOH, the reaction mixture is diluted with 10 milliliters of water, basified by the addition of 2 milliliters of 14N aqueous ammonia, and extracted with dichloromethane. methane. The combined organic layers are dried over sodium sulfate and evaporated. The residue is dissolved in 1 milliliter of EtOH, 2N sodium hydroxide (100 microliters, 0.2 mmol) is added, and the mixture is stirred for 20 hours. After heating at 60 ° C for 110 minutes, the reaction mixture is cooled to 0 ° C, and 500 microliters of 0.5M hydrochloric acid are added. The organic solvent is separated, the aqueous solution is made basic by the addition of 1 milliliter of 1M potassium hydrogen carbonate, and extracted with dichloromethane. The combined organic layers are dried over sodium sulfate and evaporated; The residue is purified by preparative thin layer chromatography (DCM / MeOH / NH3 = 95 / 4.5 / 0.5) to give the product as a colorless solid. HPLC (Waters SunFire C18, 5 microns, 4.6 x 150 millimeters, 30-100 percent MeCN (3 minutes), 100 percent MeCN (2.0 minutes), 1.5 milliliters / minute) retention time: 1.70 minutes. MS (ES +): 573 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.04 (d, 1H), 7.27 (s, 1H), 7.15-7.08 (m, 2H), 6.99-6.95 (m, 2H), 6.83 (d, 1H) , 6.77 (t, 1H), 6.72-6.69 (m, 1H), 6.51 (s, 1H), 6.32 (s, 1H), 5.81-5.76 (m, 1H), 5.58-5.50 (m, 1H), 4.83 (d, 1H), 4.76-4.62 (m, 2H), 4.01-3.93 (m, 1H), 3.81 (s, 2H), 3.52-3.46 (m, 1H), 3.04-2.99 (m, 1H), 2.62-2.52 (m, 2H), 2.21 (s) , 3H), 1.21 (s, 9H), 0.94-0.77 (m, 4H). Example 40: Dimethyl-amide of (E) - (S) -4- acid. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -9-fluoro-2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13,17 , 19-heptaen-19-carboxylic acid a) (E) - (S) -4 - ((R) -2- { Benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -1-hydroxy-ethyl) -19-dimethyl-carbamoyl-9-fluoro-2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa- 1 ( 21), 6,8,10 (22), 13,17,19-heptaen-16-carboxylic acid The title compound is obtained by an analogous reaction sequence (steps a and b) to that of Example 1, starting from the benzyl [(2R, 3S) -4- (3-allyloxy-4-fluoro-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1 - (2-tert-butyl-phenyl) acid ester -cyclopropyl] -carbamic acid (C10 building block) and 5- (allyl-benzyloxycarbonyl-amino). N, N-dimethyl-isophthalic acid (building block A15). Rf (EtOAc): 0.51. MS (ES +): 897 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6, 120 ° C): 7.82 (d, 1H), 7.46-7.41 (m, 3H), 7.32-7.12 (m, 10H), 7.05 (dd, 1H), 6.95 ( dd, 1H), 6.87-6.84 (m, 1H), 6.80-6.76 (m, 1H), 6.01-5.95 (m, 1H), 5.71-5.64 (m, 1H), 5.19-5.02 (m, 4H), 4.80-4.67 (m, 3H), 4.51-4.46 (m, 1H), 4.16-3.94 (m, 3H), 3.76 (dd, 1H), 3.32 (dd, 1H), 3.07 (dd, 1H), 2.87 ( s, 6H), 2.74 (dd, 1H), 1.81-1.75 (m, 1H), 1.53-1.47 (m, 1H), 1.32-1.18 (m, 3H), 1.23 (s, 9H), 1.12-1.06 ( m, 1H). b) Dimethyl-amide of (E) - (S) -4- acid. { (R) -2- [1 - (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -9-fluoro-2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13,17 , 19-heptaen-19-carboxylic acid To a solution of the benzyl ester of the acid (E) - (S) -4 - ((R) -2- { Benzyloxycarbon I- [1 - (3-te rbutyl-phenyl) -cyclopropyl] -amino.} -1-hydroxyethyl) -19-dimethyl-carbamoyl-9-f-Ioro-2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1 .r6.10 *] docosa-1 (21), 6,8,10 (22), 13,17,19-heptaen-16-carboxylic acid (67 milligrams, 0.075 millimoles) in 4 milliliters of dichloromethane, iodine is added -trimethylsilane (220 microliters, 1.5 mmol), and the mixture is stirred at room temperature. After an additional 25 minutes, iodo-trimethylsilane (33 microliters, 0.0225 mmol) is added, and stirring is continued for 20 minutes. The excess of iodide-trimethylsilane is destroyed by the addition of 1 milliliter of MeOH, and the solvents are evaporated. The residue is dissolved in 1.8 milliliters of methanol and purified by preparative HPLC (XTerra RP18, 5 microns, 19 x 150 millimeters, 10-100 percent MeCN (20 minutes), 20 milliliters / minute) to give the product as a grayish resin. Rf (DCM / MeOH / NH3 = 90/9/1): 0.21. MS (ES +): 629 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.96 (d, 1H), 7.28 (s, 1H), 7.14-7.08 (m, 2H), 7.00-6.94 (m, 2H), 6.89-6.86 (m, 1H), 6.76-6.67 (m, 4H), 6.34-6.31 (m, 1H), 5.87-5.80 (m, 1H), 5.58-5.50 (m, 1H), 4.82-4.63 (m, 3H), 4.02- 3.92 (m, 1H), 3.82 (br s, 2H), 3.52-3.46 (m, 1H), 3.04-2.99 (m, 1H), 2.91 (br s, 3H), 2.84 (br s, 3H), 2.66 -2.52 (m, 2H), 1.25-1.13 (m, 2H), 1.20 (s, 9H), 0.92-0.76 (m, 4H). Example 41: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -c i do propyl-amy] -ethyl} -18-m ethoxy-3, 15.17-t riaza-tr i cyclote.3.1.1 * 6, 10 *] henicosa-1 (19), 6, 8, 10 (21), 16 (20), 17 -hexaen-2-one The title compound can be obtained by a reaction sequence analogous to that of Example 1, starting from ((1 S, 2R) -1- (3-allyl-benzyl) terbutyl ester ) -3- {be nci loxi -carbon i l- [1 - (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic (building block C5) and the 2-allyl-amino-6-methoxy-isonicotinic acid (building block A18). Rf (DCM / MeOH = 95/5): 0.29. HPLC (Waters SunFire C18, 5 microns, 4.6 x 150 millimeters, 30-100 percent MeCN (3 minutes), 100 percent MeCN (2.0 minutes), 1.5 milliliters / minute) retention time: 2.48 minutes. MS (ES +): 543 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.94 (d, 1H), 7.32 (s, 1H), 7.18-7.12 (m, 3H), 7.06-6.97 (m, 4H), 6.57 (t, 1H), 5.83 (s, 1H), 5.59 (s, 1H), 4.73 (d, 1H), 4.06-3.98 (m, 1H), 3.68 (s, 3H), 3.52-3.46 (m, 1H), 3.29-3.19 (m, 1H), 3.09-2.95 (m, 2H), 2.87-2.80 (m, 1H), 2.68-2.61 (m, 2H), 2.58-2.53 (m, 1H), 1.95-1.87 (m, 1H), 1.77-1.69 (m, 1H), 1.45-1.39 (m , 1H), 1.26-1.15 (m, 3H), 1.18 (d, 6H), 1.00-0.89 (m, 3H), 0.86-0.81 (m, 1H). Example 42: (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methyl-11 -oxa-3, 16,18-triaza-tri-cid o- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 -hexaen-2-one a) (S) -16-acetyl-4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3- tert-butyl ester. (benzyloxycarbonyl- [1- (3-tert-butyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C6) and 2- (acetyl-allyl) acid amino) -6-methyl-isonicotinic (building block A17). Rf (DCM / MeOH = 95/5): 0.25. MS (LC / MS, ES +): 598.7 = [M + H] *. HPLC (Waters SunFire C18, 3.5 microns, 4.6 x 50 millimeters + 3.5 micron pre-column, 4.6 x 20 millimeters, 5-95 percent MeCN (7.5 minutes), 100 percent MeCN (2.5 minutes), 1.5 milliliters / minute) retention time: 3.61 minutes. b) (S) -4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-1-yl] -1-hydroxy-ethyl} -19-methyl-11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] - docosa-1 (21), 6,8,10 (22), 17,19- hexaen-2-one To a solution of (S) -16-acetyl-4-. { (R) -2- [1- (3-tert-butyl-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methyl-11-oxa-3,16,18-triaza-tricyc? - [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19- hexaen-2-one (25 milligrams, 0.042 millimoles) in 1.5 milliliters of EtOH at 0 ° C, 2N aqueous sodium hydroxide (84 microliters, 0.17 millimoles) is added, and the mixture is stirred for 5 hours at 60 ° C . The reaction mixture is cooled to 0CC, and 340 microliters of 0.5M aqueous hydrochloric acid are added. The organic solvent is evaporated, the aqueous solution is made basic by the addition of 1 milliliter of 1M aqueous potassium hydrogen carbonate, and extracted with dichloromethane. The combined organic layers are washed with water, dried over sodium sulfate, and evaporated. The residue is purified by preparative thin layer chromatography (DCM / MeOH = 95/5) to give the product as a colorless solid.

Rf (DCM / MeOH = 95/5): 0.24. MS (ES +): 557 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.03 (d, 1H), 7.31 (s, 1H), 7.16-7.11 (m, 3H), 7.01-6.97 (m, 2H), 6.76-6.70 (m, 2H), 6.52-6.48 (m, 1H), 6.23 (s, 1H), 6.12 (s, 1H), 4.78-4.75 (m, 1H), 4.24-4.19 (m, 1H), 3. 93-3.87 (m, 1H), 3.86-3.77 (m, 1H), 3.47-3.40 (m, 1H), 3.38-3.32 (m, 2H), 3.03-2.93 (m, 2H), 2.63-2.54 (m , 2H), 2.48-2.42 (m, 2H), 2.20 (s, 3H), 1.76-1.59 (m, 2H), 1.52-1.42 (m, 1H), 1.24 (s, 9H), 0.94-0.79 (m , 4H). Example 43: 13,14-benzo- (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methyl-11, 16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one a) Methyl-2-acid ester. { 2- [3 - ((2S, 3R) -4- { Benzyloxycarbonyl- [1- (3-isopropyl-l-enyl) -cyclopropyl] -amine no.} -2-ter-butoxy-carbon i I-amino-3-hydroxy-butyl) -phenoxy-methyl] -benzyloxy} -6-methyl-isonicotinic A suspension of 1 gram (2.72 millimoles) of 2- (2-methanesulfonyloxy-methyl-benzyloxy) -6-methyl-isonicotinic acid methyl ester (building block E2), 1.62 grams ( 2.72 mmol), [(2R, 3S) -3-terbutoxy-carbonyl-amino-2-hydroxy-4- (3-hydroxy-phenyl) -butyl] - [1- (3-isopropyl-phenyl) benzyl ester. ) -cyclopropyl] -carbamic (building block C17), 0.5 grams (1.368 millimoles) of tetrabutyl ammonium iodide, 0.44 grams (1.368 millimoles) of cesium carbonate, and 0.56 grams (4.10 millimoles) of potassium carbonate in N , N-dimethylformamide (10 milliliters), is stirred for 6 hours. The mixture is diluted with EtOAc and water. The organic layer is washed with water and brine, dried over sodium sulfate, and chromatographed on silica gel (hexane / EtOAc, 6: 1, 4: 1, 2: 1) to give a yellow resin. Rf: (EtOAc / hexane 1: 2): 0.3 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 70 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 3,862 minutes MS (ES +): 858 = [M + H] * b) Benzyl ester of 13,14-benzo - [(R) -2-hydroxy-2 - ((S) -19-methyl-2-oxo- 11,16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] - docosa-1 (21), 6,8,10 (22), 17,19-hexaen-4-yl ) -ethyl] - [1- (3-isopropyl-phenyl) -cyclopropyl] -carbamic 1.35 grams (1.57 mmol) of the methyl ester of 2- acid. { 2- [3- ((2S, 3R) -4- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -2-terbutoxy-carbonyl-amino-3- hydroxy-butyl) -phenoxy-methyl] -benzyloxy} -6-methyl-isonicotinic acid are dissolved in 10 milliliters of methanol and 4 milliliters of 1N aqueous sodium hydroxide, and stirred for 18 hours. The mixture is acidified with 5 milliliters of 1N aqueous hydrochloric acid, and extracted with EtOAc. The organic phase is washed with brine, dried over sodium sulfate, and concentrated. The residue is taken up in 10 milliliters of 4N hydrochloric acid in dioxane, stirred for 2 hours, and the solvent is evaporated at 25 ° C under reduced pressure. The residual product is dissolved in 100 milliliters of dichloromethane containing 1.05 milliliters of N-methylmorpholine, and added with the use of a syringe pump, to a stirred solution of 1.2 grams (3.15 millimoles) of HATU in 10 milliliters of dichloromethane over a period of 3 hours. Stirring is continued for 1 hour. The mixture is washed with 5 percent aqueous citric acid, water, 5 percent aqueous sodium bicarbonate, and water, dried over sodium sulfate, and chromatographed on silica gel (hexane / EtOAc, 5: 1, 3: 1, 2: 1, 1: 1, 1: 2) to obtain a colorless resin. Rf: (EtOAc / hexane 1: 1): 0.38 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 50 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 3,369 minutes. MS (ES +): 726 = [M + H] * c) 13,14-benzo- (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methyl-11, 16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-ona The benzyl-ester of 13,14-benzo - [(R) -2-hydroxy-2 - ((S) -19-m-ethyl-2-oxo-11,16-dioxa-3,18 -diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-4-yl) -ethyl] - [1- (3 -isopropyl-phenyl) -cyclopropyl] -carbamic acid (279 milligrams, 0.384 millimoles) is hydrogenated in tetrahydrofuran in the presence of 40 milligrams of Pt / C (Engelhard 4709) and 40 milligrams of Pd / C (Engelhard 4505) for 8 hours. The mixture is filtered and passed through chromatography on silica gel (EtOAc / hexanes, 3: 1, 1: 1 and 2: 1) to give a resin. Rf: (EtOAc / hexane 2: 1): 0.28 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 2,809 minutes MS (ES +): 592 = [M + H] + Example 44: (S) -19- [1, 3] -dioxolan-2-yl-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one Obtained the title compound by a reaction analogous to that of Example 1, starting from the ((1S, 2R) -1- (3-allyloxy-benzyl) -3-. {benzyloxycarbonyl- [(1S, 2R)] ester. 1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (C7 building block) and 3- (allyl-benzyloxycarbonyl-amino) -5- [ 1,3] -dioxolan-2-yl-benzoic acid (building block A21). Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.43 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 MeCN percent (0.75 minutes)): 2,509 minutes. MS (ES +): 600 = [M + H] * Example 45: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-thiazol-2-yl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (20), 6,8,10 (22), 17 (21 ), 18-hexaen-2-one a) Benzyl-ester of (Z) - (S) -4 - ((R) -2- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl)} -cyclopropyl] -amino.} -1-hydroxy-ethyl) -2-oxo-19-thiazol-2-yl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (20), 6, 8, 10 (22), 13.17 (21), 18-heptaen-16-carboxylic acid The title compound is obtained by a reaction sequence analogous to that of Example 1 (steps ab ), starting from the terbutil-ester of the acid ((1S, 2R) -1 - (3-allyloxy-benzyl) -3- { benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino.} -2-hydroxy-propyl) -carbamic acid (C7 building block) and 3- (allyl-benzyloxycarbonyl-amino) -5-thiazol-2-yl-benzoic acid (building block A20) . Rf: (hexane / EtOAc 1: 1): 0.37 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 70 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 2,454 minutes. MS (ES +): 877 = [M + H] * b) (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-thiazol-2-yl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (20), 6,8,10 (22), 17 (21 ), 18-hexaen-2-one The benzyl ester of the acid (Z) - (S) -4 - ((R) -2- { Benzyloxycarbonyl- [1- (3-isopropyl-phenyl) - cyclopropyl] -amino.] -1-hydroxy-ethyl) -2-oxo-19-thiazol-2-yl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa -1 (20), 6.8.10 (22), 13, 17 (21), 18-heptaen-16-carboxylic acid (163 milligrams, 0.187 mmol) is hydrogenated in tetrahydrofuran in the presence of 56 milligrams of Pd / C (Engelhard 4505) for 5 hours. The mixture is filtered over High-flow and concentrated. The residue is taken up in 6N aqueous hydrochloric acid, and heated at 60 ° C for 3 hours. The mixture is diluted with water and washed with hexane, basified with solid sodium carbonate, and extracted with tetrahydrofuran. The organic phase is dried over sodium sulphate and evaporated. The product is obtained as a colorless resin after chromatography on silica gel (DCM / MeOH / 25% aqueous NH3, 9/2 / 0.2). Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.23 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40 -100 percent MeCN (3.25 minutes), 100 percent of MeCN (0.75 minutes)): 1,893 minutes. MS (ES +): 611 = [M + H] * Example 46: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19- (2-oxo-pyrrolidin-1-yl) -11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 ( 22), 17,19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the terbutil-ester of the acid ((1S), 2R) -1- (3-allyloxy-benzyl) -3-. { benzyloxycarbonyl- [1- (3-isopropyl I-phenyl) -cyclopropi I] -am i no} -2-h id roxi-p ropi I) -carbamic (building block C7) and 3- (allyl-benzyloxycarbonyl-amino) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid ( building block A19). Rf: (DCM / MeOH / 25% aqueous NH3, 90/9/1): 0.20 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40 -100 percent MeCN (3.25 minutes), 100 MeCN percent (0.75 minutes)): 0.914 minutes.

MS (ES +): 611 = [M + H] * Example 47: (S) -8-fluoro-4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the terbutyl ester of the acid. { (1 S, 2 R) -1 - (3-allyloxy-5-fluoro-benzyl) -2-hydroxy-3- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -propyl} -carbamic (C14 building block) and 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid (building block A7). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 2,579 minutes. MS (ES +): 590 = [M + H] * 1 H-NMR (400 MHz, DMSO-d 6): 7.87 (d, 1H), 7.16 (t, 1H), 7.13 (s, 1H), 7.05 (d, 1H), 6.99 (d, 1H), 6.90 (s, 1H), 6.64-6.52 (m, 4H), 6. 44 (s, 1H), 5.85 (t, 1H), 4.79 (d, 1H,), 4.25-4.19 (m, 1H), 4.21 (s, 2H), 3.96-3.84 (m, 2H), 3.48-3.40 (m, 1H), 3.22 (s, 3H), 3.01-2.89 (m, 2H), 2.85-2.75 (m, 1H), 2.68- 2.59 (m, 1H), 2.57-2.40 (m, 2H), 1.74 - 1.45 (m, 4H), 1.14 (d, 6H), 0.95-0.75 (m, 4H). Example 48: (S) -18-c I gold-4-. { (R) -1-h id roxy-2- [1- (4-i sopropi I-pyridin-2-yl) -cyclopropyl-amino] -ethyl} -3,15,17-triaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 16,18-hexaen-2-one a) Benzyl- [(R) -2 - ((E) - (S) -15-acetyl-18-chloro-2-oxo-3,15,17-triaza-tricyclo [14.3.1.1 * 6,10 *] acid ester ] henicosa-1 (20), 6,8, 10 (21), 12,16,18-heptaen-4-yl) -2-hydroxy-ethyl] - [1- (4-isopropyl-pyridin-2-yl ) -cyclopropyl] -carbamic acid The title compound is obtained by a reaction sequence analogous to that of Example 1 (steps ab), starting from the benzyl ester of [(2R, 3S) -4- (3-allyl) acid phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (building block C12) and the acid 2- ( acetyl-allyl-amino) -6-chloro-isonicotinic acid (building block A16). Rf: (hexane / EtOAc 1: 2): 0.55 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 2,383 minutes. MS (ES +): 722, 724 = [M + H] * b) (S) -18-chloro-4-. { (R) -1-hydroxy-2- [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl-amino] -ethyl} -3,15,1-triaza-tricyclo- [14.3.1.1 * 6,10 *] - henicosa-1 (20), 6,8,10 (21), 16,18-hexaen-2-one A solution of 413 milligrams (0.572 millimoles) of the acid benzyl ester [(R) -2 - ((E) - (S) -15-acetyl-18-chloro-2-oxo-3,15,17-triaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (20), 6,8,10 (21), 12,16,18-heptaen-4-yl) -2-hydroxy-ethyl] - [1 - ( 4-isop ropi l-pyridin-2-i I) -cyclopropi I] -carbamic acid in 5 milliliters of EtOH, is hydrogenated in the presence of 80 milligrams of 5% Pt / C (Engelhard 4709) for 5 hours. The mixture is filtered over High-flow and evaporated. For complete deprotection of the protecting group, the residue is taken up in 6N aqueous hydrochloric acid and stirred at 60 ° C for 2 hours. The mixture is diluted with water and washed twice with hexane. The aqueous layer is basified with solid sodium carbonate, and extracted with tetrahydrofuran. The combined organic layers are dried over sodium sulfate and evaporated. Purification by chromatography on silica gel (gradient of dichloromethane and MeOH / aqueous 25% NH3, 9: 1, 2-10 percent) gives the product. Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.29 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40 -100 percent MeCN (3.25 minutes), 100 percent of MeCN (0.75 minutes)): 1,966 minutes. MS (ES +): 548, 550 = [M + H] * Example 49: (S) - 19-c I gold-4-. { (R) -1-h id roxy-2- [1- (4-i sopropi I-pyridin-2-yl) -cyclopropyl-amino] -ethyl} -11-oxa-3,16,18-triaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen-2-one You get the compound of! title by a reaction sequence analogous to that of Example 48, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy acid -butyl] - [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C11 building block) and 2- (acetylallylamino) -6-chlorosonicotinic acid (building block A16). Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.36 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40 -100 percent MeCN (3.25 minutes), 100 MeCN percent (0.75 minutes)): 1,273 minutes. MS (ES +): 564, 566 = [M + H] * Example 50: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methyl-11, 16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one a) Terbutil-acid ester. { (1S, 2R) -1- (3-benzyloxy-benzyl) -2-hydroxy-3- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -propyl} -carbamic The product is obtained by a reaction sequence analogous to that of the C5 building block (steps ad), starting from the methyl ester of (S) -3- (3-benzyloxy-phenyl) -2-terbutoxy acid -carbonyl-amino-propionic (building block C1) and 1- (3-isopropyl-phenyl) -cyclopropyl-amine (building block D1). MS (ES +): 545 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.35 minutes. b) [(2R, 3S) -4- (3-benzyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-isopropyl-phenyl) - tert-butyl ester cyclopropyl] -carbamic acid terbutil-ester. { (1 S, 2 R) -1 - (3-benzyloxy-benzyl) -2-hydroxy-3- [1 - (3-isopropyl-phenyl i) -cyclopropyl-1-yl] -propyl} -carbámico (1.60 grams, 2.94 millimoles, 1 equivalent) is dissolved in 20 milliliters of tetrahydrofuran. N, N-di-isopropyl-ethyl-amine (1.06 milliliters, 5.87 millimoles, 2 equivalents) and diterbutyl dicarbonate (838 milligrams, 3.82 millimoles, 1.3 equivalents) are added. The reaction is stirred for 65 hours at 60 ° C. The mixture is diluted with 10 milliliters of citric acid (10 percent in water) and EtOAc. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica (EtOAc / hexane, 3/7) to give the product. MS (ES +): 645 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 7.60 minutes. c) [(2R, 3S) -4- (3-hydroxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-isopropyl-phenyl) - tert-butyl ester cyclopropyl] -carbamic acid [(2R, 3S) -4- (3-benzyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-isopropyl- phenyl) -cyclopropyl] -carbamic acid (925 milligrams, 1.49 millimoles, 1 equivalent) is dissolved in 60 milliliters of EtOH, and added to Pd / C (181 milligrams) in 5 milliliters of EtOH under argon. The atmosphere is exchanged against hydrogen, and the reaction is stirred for 2 hours. The mixture is filtered through Hyflo and concentrated. The residue is purified by chromatography on silica (hexane / EtOAc, 7/3) to give the product. MS (ES +): 529 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time of retention = 6.21 minutes. d) Methyl ester of 2- acid. { 4- [3 ((2S, 3R) -2-terbutoxy-carbonyl-amino-4-. {Terbutoxy-carbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -3-hydroxy -butyl) -phenoxy] -butoxy} -6-methyl-isonicotinic acid [(2R, 3S) -4- (3-hydroxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3- isopropyl-phenyl) -cyclopropyl] -carbamic acid (400 milligrams, 721 micromoles, 1 equivalent) and 2- (4-methanesulfonyloxy-butoxy) -6-methyl-isonicotinic acid methyl ester (229 milligrams, 721 micromoles , 1 equivalent) (building block E1) are dissolved in 4 milliliters of N, N-dimethyl-formamide. Cesium carbonate (470 milligrams, 1.44 millimoles, 2 equivalents) and TBAI (53 milligrams, 144 micromoles, 0.2 equivalents) are added. The reaction mixture is stirred for 16 hours at room temperature. The mixture is diluted with water and EtOAc. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (EtOAc / hexane, 3/7) to give the product. MS (ES +): 776 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 65-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 6.61 minutes. e) (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19-methyl-11, 16-dioxa-3,18-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-ona The methyl-ester of acid 2-. { 4- [3 ((2S, 3R) -2-terbutoxy-carbonyl-amino-4-. {Tert-butoxy-carbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -3-hydroxy -butyl) -phenoxy] -butoxy} -6-methyl-isonicotinic (260 milligrams, 335 micromoles, 1 equivalent) is dissolved in 0.67 milliliters of 1N aqueous sodium hydroxide and 3 milliliters of methanol, and stirred at room temperature for 150 minutes. The mixture is concentrated and diluted with 8 milliliters of 4N hydrochloric acid in dioxane. The mixture is stirred at room temperature for 1 hour, and then concentrated. The white solid obtained is dissolved in dichloromethane (50 milliliters), N-methylmorpholine (209 microliters, 1.90 millimoles, 5.67 equivalents) and Et3N (210 microliters, 1.50 millimoles, 4.47 equivalents). This solution is added slowly to HOBt (206 milligrams, 1.51 millimoles, 4.5 equivalents) and EDC * HCI (295 milligrams, 1.51 millimoles, 4.5 equivalents) in 150 milliliters of dichloromethane within 6 hours. The reaction mixture is stirred for another 12 hours, and then diluted with citric acid (10 percent in water), followed by aqueous sodium bicarbonate and EtOAc. The organic layer is washed with water, dried over sodium sulfate, and concentrated. The residue is purified by chromatography on silica (DCM / MeOH / NH3480 / 20/1) to give the product. MS (ES +): 544 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 3.68 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.11 (d, 1H), 7.32-6.98 (m, 5H), 6.83 (s, 1H), 6.78-6.60 (m, 3H), 6.53 (s, 1H) , 4.88 (d, 1H), 4.45-4.39 (m, 1H), 4.27-4.20 (m, 1H), 4.18-4.12 (m, 1H), 4.00-3.92 (m, 1H), 3.92-3.83 (m, 1H), 3.53-3.46 (m, 1H), 2.99 (d, 1H), 2.87-2.78 (m, 1H), 2.63-2.45 (m, 3H), 2.37 (s, 3H), 1.82-1.50 (m, 4H), 1.18 (d, 6H), 0.95-0.79 (m, 4H). Example 51: (S) -4-. { (R) -1-hydroxy-2- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -ethyl} -19- (2-oxo-pyrrolidin-1-yl) -11,16-dioxa-3-aza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 ( 22), 17,19-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting with the terbutil-ester of the acid ((1 S, 2R) -1 - (3 -alloyloxybenzyl) -3- { benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino} -2-hydroxy-propyl) -carbamic acid (building block C7) and the 3-allyloxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (building block A22). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 2.68 minutes. MS (LC / MS, ES +): 612 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.01 (d, 1H), 7.31 (s, 1H), 7.18-7.13 (m, 3H), 7.05 (d, 1H), 7.0-6.98 (m, 2H). , 6.83 (s, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 4.82 (d, 1H), 4.44-4.33 (m, 1H), 4.24-4.19 (m, 1H), 4.10-4.04 (m, 1H), 3.98-3.86 (m, 2H), 3.75 (t, 2H), 3.54-3.47 (m, 1H), 2.93 (dd, 1H), 2.83-2.76 (m, 1H), 2.67 (dd) , 1H), 2.57 (dd, 1H), 2.51- 2.45 (m, 4H), 2.06-1.98 (m, 2H), 1.82-1.62 (m, 4H), 1.13 (d, 6H), 0.93-0.87 (m , 3H), 0.81-0.78 (m, 1H).

Example 52: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-ami] -1-hydroxy-ethyl} -18-meti 1-3,15,17-triaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (19), 6,8,10 (21), 16 (20), 17-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyl-phenyl) -3- terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyrid-2-yl) -cyclopropyl] -carbamic acid (C8 building block) and 2- (allyl-benzyloxycarbonyl- amino) -6-methyl-isonicotinic (building block A23). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 10-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 2.90 minutes. MS (LC / MS, ES +): 542 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.33 (d, 1H), 8.08 (d, 1H), 7.75 (s, 1H), 7.38 (s, 1H), 7.18 (t, 1H), 7.13 (dd) , 1H), 7.07 (d, 1H), 7.02 (d, 1H), 6.59 (t, 1H), 6.34 (s, 1H), 5.89 (s, 1H), 4.99 (d, 1H), 4.11-4.03 ( m, 1H), 3.60-3.59 (m, 1H), 3.43-3.38 (m, 1H), 3.37-3.24 (m, 1H), 3.16 (d, 1H), 3.05-2.95 (m, 1H), 2.75- 2.62 (m, 6H), 2.18 (s, 3H), 1.98-1.88 (m, 1H), 1.80-1.70 (m, 1H), 1.40-1.30 (m, 1H), 1.27 (s, 9H), 1.21- 1.16 (m, 2H), 1.06-0.98 (m, 2H). Example 53: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-ami] -1-hydroxy-ethyl} -19-meti 1-11 -oxa-3,16,18-triaza-tric iclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 hexane-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) - 3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (building block C18) and 2- (allyl-benzyloxy-) acid carbonyl-amino) -6-methyl-isonicotinic (building block A23). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 0-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 3.09 minutes. MS (LC / MS, ES +): 558 = [M + H] *. 'H-NMR (400 MHz, DMSO-d 6): 8.33 (d, 1H), 8.15 (d, 1H), 7.72 (s, 1H), 7.18 (t, 1H), 7.13 (dd, 1H), 7.08 ( s, 1H), 6.82 (d, 1H), 6.75 (dd, 1H), 6.56 (dd, 1H), 6.30 (s, 1H), 6.19 (s, 1H), 5.03 (d, 1H), 4.30-4.23 (m, 1H), 3.96-3.83 (m, 2H), 3.59-3.51 (m, 1H), 3.05 (d, 2H), 2.72-2.52 (m, 3H), 2.21 (s, 3H), 1.8-1.6 (m, 3H), 1.52-1.42 (m, 1H), 1.27 (s, 9H), 1.28-1.16 (m, 2H), 1.03-0.93 (m, 2H). Example 54: (S) -4-. { (R) -1-hydroxy-2- [1- (4-isopropyl-pyridin-2-yl) -c-clopropi-amy] -ethyl} -18-m-ethoxy-methi 1-3,15-diaza-tricyclo- [14.3.1.1 * 6,10 *] henicosa-1 (19), 6,8,10 (21), 16 (20), 17- hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyl-phenyl) -3 acid -tertbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C12 building block) and 3- (allyl-benzyloxycarbonyl) -amino) -5-methoxy-methyl-benzoic acid (building block A7). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 0-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 3.45 minutes. MS (LC / MS, ES +): 557 = [M + H] *. H-NMR (400 MHz, DMSO-d 6): 8.32 (d, 1H), 7.93 (d, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.18 (t, 1H), 7.06 (d , 1H), 7.08 (d, 1H), 7.02-7.00 (m, 2H), 6.60 (s, 1H), 6.54 (s, 1H), 6.25 (s, 1H), 5.96 (t, 1H), 4. 92 (d, 1H), 4.22 (s, 2H), 4.13-4.05 (m, 1H), 3.6-3.5 (m, 1H), 3.22 (s, 3H), 3.20-3.16 (m, 1H), 3.03- 2.63 (m, 8H), 1.97-1.87 (m, 1H), 1.82-1.72 (m, 1H), 1.52-1.42 (m, 1H), 1.30-1.27 (m, 1H), 1.20 (d, 6H), 1.21-0.99 (m, 4H). Example 55: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -18-methoxy-methi 1-3,15-diaza-tricyclo- [14.3.1.1 * 6,10 *] hßnicosa-1 (19), 6,8,10 (21), 16 (20), 17-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyl-phenyl) -3- terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyrid-2-yl) -cyclopropyl] -carbamic acid (C8 building block) and 3- (allyl-benzyloxycarbonyl- amino) -5-methoxy-methyl-benzoic acid (building block A7). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes), retention time: 2.69 minutes. MS (LC / MS, ES +): 571 = [M + H] *. 1 H NMR (400 MHz, DMSO-d 6): 8.33 (d, 1H), 7.92 (d, 1H), 7.77. (s, 1H), 7.41 (s, 1H), 7.17 (t, 1H), 7.11 (d, 1H), 7.08 (d, 1H), 7.01 (d, 1H), 8.58 (s,? H), 6.53 9s, 1H), 6.24 (s, 1H), 5.95 (t, 1H), 4.97 (d, 1H), 4.21 (s, 2H), 4.12-4.02 (m, 1H), 3.61-3.5 (m, 1H) , 3.43-3.47 (m, 1H), 3.21 (s, 3H), 3.16 (d, 1H), 3.03-2.90 (m, 1H), 2.74-2.65 (m, 5H), 1.97-1.87 (m, 1H) , 1.81-1.71 (m, 1H), 1.52-1.41 (m, 1H), 1.29-1.15 (m, 3H), 1.27 (s, 9H), 1.13-0.99 (m, 2H). Example 56: (S) -4-. { (R) -1-hydroxy-2- [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl-amino] -ethyl} -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3- terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-isopropyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (C11 building block) and 3- (allyl-benzyloxycarbonyl- amino) -5-methoxy-methyl-benzoic acid (building block A7). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 2.04 minutes. MS (LC / MS, ES +): 573 = [M + H] X 1 H-NMR (400 MHz, DMSO-d 6): 8.31 (d, 1H), 7.99 (d, 1H), 7.56 (s, 1H), 7.18 (t, 1H), 7.08 (s, 1H), 7.00 (d, 1H), 6.83 (d, 1H), 6.76 (d, 1H), 6.61 (s, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 5.89 (dd, 1H), 4.96 (d, 1H), 4.30-4.24 (m, 1H), 4.25 (s, 2H), 3.96-3.88 (m, 2H), 3.57-3.41 (m , 2H), 3.25 (s, 3H), 3.07-2.96 (m, 2H), 2.87-2.81 (m, 1H), 2.74-2.60 (m, 4H), 1.8-1.5 (m, 4H), 1.25 (dd) , 1H), 1.21-1.10 (m, 1H), 1.20 (d, 3H), 1.18 (d, 3H), 1.01-0.95 (m, 2H).

Example 57: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19-hexaen -2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3- terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (building block C18) and 3- (allyl-benzyloxycarbonyl- amino) -5-methoxy-methyl-benzoic acid (building block A7). HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 2.38 minutes. MS (LC / MS, ES +): 587 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.32 (d, 1H), 7.98 (d, 1H), 7.73 (s, 1H), 7.18 (t, 1H), 7.12-7.10 (m, 2H), 6.83. (d, 1H), 6.74 (dd, 1H), 6. 60 (s, 1H), 6.57 (s, 1H), 6.54 (s, 1H), 5.88 (dd, 1H), 5.00 (d, 1H), 4. 32-4.22 (m, 1H), 4.24 (s, 2H), 3.96-3.85 (m, 2H), 3.6-3.4 (m, 2H), 3. 25 (s, 3H), 3.07-2.95 (m, 2H), 2.73-2.56 (m, 3H), 1.8-1.4 (m, 4H), 1. 26 (s, 9H), 1.28-1.17 (m, 2H), 1.03-0.93 (m, 2H). Example 58: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-oxazol-2-yl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (20), 6,8,10 (22), 17 (21 ), 18-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy) acid. phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid (building block C18) and 3- (allyl) acid -benzyloxy-carbonyl-amino) -5-oxazol-2-yl-benzoic acid (building block A3). Rf (DCM / MeOH / NH3 = 90/10/1): 0.42. MS (LC / MS, ES +): 610 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.32 (d, 1H), 8.18 (s, 1H), 8.14 (d, 1H), 7.71 (s, 1H), 7.35 (s, 1H), 7.30 (s) , 1H), 7.21-7.16 (m, 2H), 7.11-7.08 (m, 2H), 6.83 (d, 1H), 6.75-6.70 (m, 2H), 6.26 (s, br, 1H), 5.05-5.00 (m, 1H), 4.30-4.25 (m, 1H), 3.97-3.87 (m, 2H), 3.62-3.44 (m, 2H), 3.10-3.00 (m, 2H), 2.75-2.55 (m, 4H) , 1.80-1.45 (m, 4H), 1.21 (s, 9H), 1.05-0.95 (m, 2H). Example 59: (S) -4-. { (R) -2- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19- (2-oxo-propoxy) -11,16-dioxa-3-aza-tricyclo- [15.3.1.1 * 6, 10 *] docosa-1 (20), 6,8,10 (22), 17 (21), 18-hexaen-2-one The title compound is obtained by a reaction sequence analogous to that of Example 1, starting from the benzyl ester of [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-tert-butyl-pyridine -2-yl) -cyclopropyl] -carbamic acid (C18 building block) and 3-allyloxy-5- (2-oxo-propoxy) -benzoic acid (building block A2). Rf (DCM / MeOH / NH3 = 90/10/1): 0.46. MS (LC / MS, ES +): 616 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.32 (d, 1H), 8.06 (d, 1H), 7.72 (s, 1H), 7.17 (t, 1H), 7.11 (d, 1H), 7.07 (s) , 1H), 6.83 (d, 1H), 6.74 (d, 1H), 6.70 (s, 1H), 6.58 (s, 1H), 6.49 (t, 1H), 5.06 (d, 1H), 4.79 (s, 2H), 4.44-4.34 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.05 (m, 1H), 4.00-3.90 (m, 1H), 3.62-3.56 (m, 1H), 3.02 ( dd, 1H), 2.75-2.69 (m, 2H), 2.62-2.58 (m, 1H), 2.13 (s, 3H), 1.85-1.63 (m, 4H), 1.29-1.15 (m, 3H), 1.26 ( s, 9H), 1.02-0.92 (m, 2H). Example 60: (S) -4 - ((R) -1-hydroxy-2-. {1- [3- (1-hydroxy-1-methyl-ethyl) -phenyl] -cyclopropyl-amino}. ethyl) -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 17,19 -hexaen-2-one a) (S) -4 - ((R) -2-. {benzyloxycarbonyl- [1- (3-bromo-phenyl) -cyclopropyl] -amino acid benzyl ester. . -1-hydroxy-ethyl) -19-methoxy-methyl-2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6, 8, 10 (22), 13,17,19-heptaen-16-carboxylic acid The title compound is obtained by a reaction sequence analogous to that of Example 1 (steps 1a-b), starting from the benzyl ester of the [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-bromo-phenyl) -cyclopropyl] -carbamic acid (block of construction C22) and 3- (allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid (building block A7). MS (ES +): 876 and 874 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes) ), retention time = 6.59 minutes. b) (S) -4-. { (R) -2- [1- (3-bromo-phen i) -cyclopropyl-1-yl] -1-hydroxy-ethyl} -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] - docosa-1 (21), 6,8,10 (22), 13,17, 19-heptaen-2-one The benzyl ester of (S) -4 - ((R) -2- { Benzyloxycarbonyl- [1- (3-bromo-phenyl) -cyclopropyl] -amino} . -1-hydroxy-ethyl) -19-methoxy-methyl-2-oxo-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6, 8.10 (22), 13,17,19-heptaen-16-carboxylic acid (250 milligrams, 283 micromoles, 1 equivalent) is dissolved in 4 milliliters of acetonitrile. TMSI (450 microliters, 3.24 millimoles, 11 equivalents) is added within 3 minutes at 0 ° C. The reaction mixture is stirred for 40 minutes at room temperature, and then poured into a solution of aqueous ammonia (7 milliliters, 25 percent in water) in methanol (30 milliliters). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is diluted with EtOAc and water. The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by chromatography on silica (MeOH / DCM / NH3, 20/380/1) to give the product. MS (ES +): 608 and 606 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) , retention time = 3.78 minutes. c) (S) -4 - ((R) -1-hydroxy-2- { 1- [3- (1-hydroxy-1-methyl-ethyl) -phenyl] -cyclopropyl-amino} -ethyl ) -19-methoxy-methyl-11-oxa-3,16-diazatricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22), 13,17, 19-heptaen-2-one La (S) -4-. { (R) -2- [1- (3-bromo-phenyl) -cyclopropyl-amino] -1-hydroxy-ethyl} -19-methoxy-methyl-11 -oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] - docosa-1 (21), 6,8,10 (22), 13,17, 19-heptaen-2-one (20 milligrams, 33 micromoles, 1 equivalent) is dissolved in 1 milliliter of tetrahydrofuran. Isopropyl magnesium chloride (2N in tetrahydrofuran, 140 microliters, 0.28 mmol, 8.75 equivalents) is added, and the reaction is cooled to -78 ° C, and stirred for 30 minutes at this temperature. Add tert-butyl lithium (1.7 N in pentane, 129 microliters, 0.20 mmol, 6.4 equivalents), the reaction is stirred for 60 seconds, and acetone (0.7 milliliters) is added within 10 seconds. The reaction is warmed to -60 ° C, and stirred for 10 minutes. The reaction is warmed to -30 ° C, 1.5 milliliters of acetone are added, followed by the addition of water and EtOAc. The organic layer is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica (EtOH / DCM / NH3, 4/96 / 0.7) to give the product. MS (ES +): 586 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.32 minutes. d) (S) -4 - ((R) -1-hydroxy-2- { 1- [3- (1-hydroxy-1-methyl-ethyl) -phenyl] -c-clopropi-am i not .}.-ethyl) -19-methoxy-methyl-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6,8,10 (22) , 1, 19-hexaen-2-one The (S) -4 - ((R) -1-hydroxy-2- { 1- [3- (1-hydroxy-1-methyl-ethyl) -phenyl] - cyclopropyl-amino.} - ethyl) -19-m-ethoxy-methi 1-11-oxa-3,16-diaza-tricyclo- [15.3.1.1 * 6,10 *] docosa-1 (21), 6, 8.10 (22), 13,17,19-heptaen-2-one (10 milligrams, 17 micromoles, 1 equivalent) is dissolved in 10 milliliters of EtOH, and added to Pd / C (10 milligrams) in 2 milliliters of EtOH under argon. The atmosphere is exchanged against hydrogen, and the reaction is stirred for 2 hours. The mixture is then filtered and concentrated. The product is purified by preparative HPLC (Sunfire Prep C180BD, 19 x 50 millimeters, 5 microns, 5-50 percent MeCN (17 minutes), 50-100 percent MeCN (50 seconds), 100 percent MeCN (70 seconds)). MS (ES +): 588 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.13 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 7.95 (d, 1H), 7.35-7.02 (m, 6H), 6. 80 (d, 1H), 6.74 (d, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 5.88 (t, 1H), 4.90 (s, 1H), 4.79 (s, 1H), 4.28-4.20 (m, 3H), 3.97-3.82 (m, 2H), 3.50-3.32 (m, 2H), 3.28 (s, 3H), 3.08-2.98 (m, 2H), 2.70 -2.30 (, 3H), 1.81-1.50 (m, 4H), 1.41 (s, 6H), 1.00-0.79 (m, 4H). Building block A1: 2-allyl-amino-6-methoxymethyl and nicotinic acid a) 2-Chloro-6-methyl-1-oxy-sonicotinic acid 2-Chloro-6-methyl-acid! sonicotinic (6.86 grams, 40 millimoles, 1 equivalent) is dissolved in AcOH (40 milliliters). 2 milliliters of H2O2 (35 percent in H2O) are added, and the reaction mixture is stirred for 76 hours at 95 ° C. During that time, 2 milliliters of H202 (35 percent in H2O) are added five times at regular intervals. The reaction mixture is concentrated and coevaporated with toluene to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 2.46 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.05 (d, 1H), 7.96 (d, 1H), 2.46 (s, 3H). b) 2-Chloro-6-hydroxy-methyl-isonicotinic acid 2-Chloro-6-methyl-1-oxy-isonicotinic acid (7.3 grams, 39 mmol, 1 equivalent) is dissolved in acetic acid anhydride, and the mixture of reaction is stirred at 100 ° C for 2 hours. The reaction mixture is then cooled to 40 ° C, and H2O (40 milliliters) is added for 2 hours. The mixture is concentrated, and the residue is purified by column chromatography using DCM / MeOH / AcOH in a ratio of 360 to 39 to 1, to give the acetylated product. The acetylated product is dissolved in methanol (50 milliliters), and NaOH (25 milliliters, 2N in H2O) is added The reaction mixture is stirred for 4 hours, and then diluted with HCl (2N in H20). and the residue is diluted with dichloromethane, the organic layer is separated, dried over sodium sulfate, filtered, and concentrated to give the product MS (ES-): 186 = [MH] ". HPLC (Nucleosil C18HD , 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes), retention time: 2.97 minutes c) 2-Chloro-6-methoxy acid methyl-isonicotinic acid 2-chloro-6-hydroxy-methyl-isonicotinic acid (4.6 grams, 24.5 millimoles, 1 equivalent) is dissolved in 100 milliliters of N, N-dimethyl formamide NaH is added (3.53 grams, 73.5 millimoles, 3 equivalents) at 0 ° C. The reaction mixture is stirred for 1 hour at 10 ° C. Mel (7.63 milliliters, 123 millimoles, 5 equivalents) is added within 15 minutes.The reaction mixture is ita at room temperature for 4 hours, and then quenched with 10 milliliters of NaOH (4N in H2O), diluted with 4N HCl in H2O and concentrated. The residue is diluted with DCM / MeOH, 9 to 1, and the organic layer is concentrated. The residue is purified by column chromatography using DCM / EtOH / AcOH in a ratio of 180 to 19 to 1 to give the product. MS (ES +): 202 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 3.80 minutes. d) 2-chloro-6-methoxy-methyl-isonicotinic acid terbutil-ester 2-Chloro-6-methoxy-methyl-isonicotinic acid (3.48 grams, 15.5 mmol, 1 equivalent) is dissolved in toluene (60 milliliters), and the solution is heated to 80 ° C. The N, N-dimethylformamide diterbutyl-acetal (7.53 milliliters, 31 millimoles, 2 equivalents) is added in portions over 8 hours. The reaction mixture is then diluted with tert-butyl methyl ether and washed with aqueous NaHCO3. The organic layer is dried over sodium sulfate, filtered, and concentrated to give the product. MS (ES +): 258 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 6.24 minutes. e) 2-allyl-amino-6-methoxy-methyl-isonicotinic acid terbutilyl ester Pd (OAc) 2 (97 milligrams, 0.42 millimoles, 0.05 equivalents), BINAP (269 milligrams, 0.42 millimoles, 0.05 equivalents), sodium terbutanolate (1.66 grams, 17 millimoles, 2 equivalents), and allylamine (784 milligrams, 12.7 millimoles, 1.5 equivalents), dissolve in toluene (80 milliliters), and the solution is stirred at 50 ° C for 20 minutes. The 2-chloro-6-methoxy-methyl-isonicotinic acid tertiary butyl ester (1.38 grams, 5.4 mmol, 1 equivalent) is dissolved in toluene (20 milliliters), and added to the reaction mixture at 50 ° C inside 20 minutes. The reaction mixture is stirred at 50 ° C for 1 hour, cooled to room temperature, and poured into ice and tert-butyl ether (200 milliliters). 4 grams of NH 4 Cl are added, and the mixture is stirred for 20 minutes. The organic layer is separated, dried over sodium sulfate, filtered, and concentrated to give the product. MS (ES +): 279 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.33 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.18 (s, 1 H), 6.87 (s, 1 H), 6.02-5.92 (m, 1H), 5.37-5.19 (m, 2H), 4.88-4.82 (m, 1H), 4.47 (s, 2H), 4.01-3.97 (m, 2H), 3.50 (s, 3H), 1.62 (s) , 9H). f) 2-allyl-amino-6-methoxy-methyl-isonicotinic acid The 2-allyl-amino-6-methoxy-methyl-isonicotinic acid terbutil ester (270 milligrams, 0.97 mmol, 1 equivalent) is dissolved in 4N HCl in dioxane (4.9 milliliters). The reaction mixture is stirred for 83 hours at room temperature, concentrated, and co-evaporated with toluene to give the product. MS (ES +): 223 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 2.59 minutes. Building block A2: 3-allyloxy-5- (2-oxo-propoxy) -benzoic acid a) 3-allyloxy-5- (2-oxo-propoxy) -benzoic acid methyl ester 300 milligrams (1.44 mmol, 1 equivalent) of the 3-allyloxy-5-hydroxy-benzoic acid methyl ester (Sórme et al., J. Am.

Chem. Soc., 2005, 1737-1743) are dissolved in acetone (10 milliliters). Add Kl (361 milligrams, 2.16 millimoles, 1.5 equivalents), K2CO3 (603 milligrams, 4.32 millimoles, 3 equivalents), and chloroacetone (192 micromoles, 2.16 millimoles, 1.5 equivalents). The reaction mixture is refluxed for 19 hours, and then cooled to room temperature. HCl (1N in H20) and diethyl ether are added. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.55 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.26 (t, 1H), 7.17 (t, 1H), 6.70 (t, 1H), 6.10-6.00 (m, 1H), 5.50-5.30 (m, 2H), 4.60 -4.57 (m, 4H), 3.93 (s, 3H), 2.32 (s, 3H). MS: 265 (M + 1), 263 (M-1). b) 3-Allyloxy-5- (2-oxo-propoxy) -benzoic acid 3-allyloxy-5- (2-oxo-propoxy) -benzoic acid is obtained by a hydrolysis reaction analogous to that for the building block A3, starting from the methyl ester of 3-alkyloxy-5- (2-oxo-propoxy) -benzoic acid. MS (ES-): 249 = [M-1] \ HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time: 3.57 minutes. Construction block A3: 3- (Allyl-benzyloxycarbonyl-amino) -5-oxazo acid I -2-i -benzoic acid a) N- (2,2-dimethoxy-ethyl) -5- methyl ester nitro-isophthalamic Under cooling with ice, a solution of 22.1 grams (90.7 millimoles) of the methyl ester of 3-chloro-carbonyl-5-nitro-benzoic acid (US Pat. No. US 4,120,891) in 200 milliliters of dichloromethane is added dropwise to a stirred suspension of 11.2 grams (181 millimoles) of K2CO3 and 11.7 millimeters (109 millimoles) of dimethyl acetal of amino acetaldehyde in 200 milliliters of dichloromethane. The mixture is stirred at room temperature for 2 days, diluted with ethyl acetate, and washed extensively with water. The organic phase is dried over sodium sulfate and evaporated to give the product in the form of a yellow oil. MS (ES-): 311 = [M-H] -. 1 H-NMR (400 MHz, CDCl 3): 9.00 (t, 1H), 8.88 (t, 1H), 8.75 (t, 1H), 6.60 (br s, NH), 4.56 (t, 1H), 4.04 (s, 3H), 3.69 (t, 2H), 3.48 (s, 6H). b) 5-Nitro-N- (2-oxo-ethyl) -isophthalamic acid methyl ester A mixture of 29.7 grams (95.1 millimoles) of the N- (2,2-dimethoxy-ethyl) -5 methyl ester -nitro-isophthalamic in 300 milliliters of tetrahydrofuran and 300 milliliters of 2N HCl, is stirred overnight. Ethyl acetate is added, and the mixture is washed twice with brine. The organic phase is dried over sodium sulfate and evaporated to give the product in the form of a yellow oil. MS (ES '): 265 = [MH] \ 1 H-NMR (400 MHz, CDCl 3): 9.82 (s, 1H), 9.03 (t, 1H), 8.91 (t, 1H), 8.80 (t, 1H), 7.20 (br s, NH), 4.54 (d, 1H), 4.03 (s, 3H). c) 3-Nitro-5-oxazol-2-yl-benzoic acid methyl ester A mixture of hexachloro-ethane (42.7 grams, 180 mmol) and 47.2 grams of triphenyl-phosphine (180 mmol) in 1 liter of acetonitrile, it is stirred for 20 minutes. A solution of 24 grams (90.2 mmol) of the 5-nitro-N- (2-oxo-ethyl) -isophthalamic acid methyl ester in 400 milliliters of acetonitrile, followed by 25.8 milliliters (361 mmol) of pyridine. After 18 hours at room temperature, the mixture is diluted with 500 milliliters of ethyl acetate and washed with brine. The organic phase is dried over sodium sulfate and concentrated, and the residue is purified by chromatography on silica gel (EtOAc / hexane, 1: 3) to give the product in the form of colorless crystals. MS (ES +): 249 = [M + H] *. 1 H-NMR (400 MHz, CDCl 3): 9.11 (t, 1H), 9.06 (t, 1H), 8.96 (t, 1H), 7.86 (s, 1H), 7.39 (s, 1H), 4.05 (s, 3H) ). d) 3-amino-5-oxazol-2-yl-benzoic acid methyl ester A solution of 11.7 grams (47.1 mmol) of 3-nitro-5-oxazol-2-yl-benzoic acid methyl ester in 1 liter of methanol and 200 milliliters of tetrahydrofuran, is stirred under a hydrogen atmosphere in the presence of 0.6 grams of Pd / C (10 percent) until the absorption of hydrogen ceases. The mixture is filtered over High-flow, and the filtrate is washed with tetrahydrofuran and evaporated to give the product.

MS (ES +): 219 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.22 (t, 1H), 7.86 (s, 1H), 7.47 (t, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 5.77 (br , 2H), 3.86 (s, 3H). e) 3-benzyloxycarbonyl-amino-5-oxazol-2-yl-benzoic acid methyl ester A mixture of 10.3 grams (47.2 mmol) of 3-amino-5-oxazol-2-yl methyl ester -benzoic acid, 25 grams of anhydrous sodium carbonate, and 7.69 milliliters (51.9 millimoles) of benzyl chloroformate, is stirred for 16 hours at room temperature, and filtered. The filtrate is concentrated, and the residue is chromatographed on silica gel (EtOAc / hexane, 1: 2) to give the product in the form of colorless crystals. MS (ES +): 353 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 10.30 (s, 1 H), 8.43 (s, 1 H), 8.30 (s, 1 H), 8.28 (s, 1 H), 8.18 (s, 1 H), 7.50-7.28. (m, 6H), 5.22 (s, 2H), 3. 90 (s, 3H). f) 3- (Allyl-benzyloxycarbonyl-amino) -5-oxazole-2-i-benzoic acid methyl ester 3-benzyloxycarbonyl-amino-5-oxazole-2-yl methyl ester -benzoic acid (330 milligrams, 0.927 millimoles, 1 equivalent) is dissolved in tetrahydrofuran (10 milliliters). NaH (48 milligrams, 60 percent, 1.21 millimoles, 1.3 equivalents) is added in portions, and the reaction mixture is stirred for 30 minutes at room temperature. Add TBAI (35 milligrams, 92.7 micromoles, 0.1 equivalents) and allyl bromide (119 microliters, 1.39 millimoles, 1.5 equivalents), and the reaction mixture is stirred for 20 hours, and then quenched with HCl (1N in H2O) . The aqueous phase is extracted with EtOAc. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated to give the product. MS (ES +): 393 = [M + H] *. 1 H-NMR (400 MHz, CDCl 3): 8.60-8.55 (m, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.32-7.24 (m, 6H), 6.0 -5.8 (m, 1H), 5.20 (s, 3H), 5.18-5.15 (m, 1H), 4.38 (d, 2H), 3.95 (s, 3H). g) 3- (Allyl-benzyloxycarbonyl-amino) -5-oxazol-2-yl-benzoic acid The methyl ester of 3- (allyl-benzyloxy-carbonyl-amino) -5-oxazole-2-yl- Benzoic acid (300 milligrams, 757 micromoles, 1 equivalent) is dissolved in methanol (10 milliliters) and H2O (4 milliliters). LiOH * H20 (100 milligrams, 2.37 millimoles, 3.13 equivalents) is added to the reaction mixture, which is stirred for 8 hours at room temperature, and then diluted with HCl (1N in H20) and dichloromethane. The combined organic solvents are separated and washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting crystals are washed with hexane, and dried in vacuo to give the product. MS (ES +): 379 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.30 (m, 1H), 8.24 (m, 1H), 8.10 (d, 1H), 7.95 (dd, 1H), 7.40 (s, 1H), 7.35-7.20. (m, 5H), 6.0-5.8 (m, 1H), 5.18-5.12 (m, 4H), 4.38 (d, 2H).

Building block A4: 5-allyloxy-N, N-dimethyl-isophthalamic acid a) Methyl ester of 5-allyloxy-isophthalic acid The product is obtained as described by Fang et al., J. Am. Chem. Soc, 1998 , 8543-8544. b) 5-allyloxy-N, N-dimethyl-isophthalic acid methyl ester A solution of 2.17 grams (9.18 mmol) of the 5-allyloxy-isophthalic acid monomethyl ester in 9.2 milliliters of thionyl chloride is heated to reflux for 1 hour. The excess thionyl chloride is removed under reduced pressure to give the methyl ester of 3-allyloxy-5-chloro-carbonyl-benzoic acid in the form of a colorless oil, which is used without further purification. To a solution of 2.36 grams (9.18 millimoles) of the 3-allyloxy-5-chloro-carbonyl-benzoic acid methyl ester in 9 milliliters of dichloromethane, 27.6 milliliters of a 1M solution of dimethylamine in tetrahydrofuran is added. (3 equivalents) at 0 ° C. The mixture is stirred at room temperature for 2 hours. 100 milliliters of a half-saturated aqueous solution of ammonium chloride are added. The mixture is extracted with tert-butyl ether (75 milliliters, 2 times), and the combined organic layers are washed with 50 milliliters of water, dried over sodium sulfate, and evaporated. The residue is purified by chromatography on silica gel (EtOAc) to give the product as a colorless oil. Rf (EtOAc): 0.48. MS (ES +): 364 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.49-7.46 (m, 2H), 7.24-7.20 (m, 1H), 6.08-5.97 (m, 1H), 5.40 (dd, 1H), 5.27 (dd, 1H), 4.68 (d, 1H), 3.85 (s, 3H), 2.99 (br s, 3H), 2.88 (br s, 3H). c) 5-allyloxy-N, N-dimethyl-isophthalamic acid To a solution of 2 grams (7.6 mmol) of the 5-allyloxy-N, N-dimethyl-isophthalamic acid methyl ester in 16.8 milliliters of tetrahydrofuran / methanol (1 : 1), 8.4 milliliters of 1M KOH (1.1 equivalents) are added at 0 ° C. The mixture is stirred at room temperature for 3 hours. The organic solvents are removed under reduced pressure, and the aqueous phase is acidified with HCl to a pH of 2 and extracted with dichloromethane / EtOH (80:20) (38 milliliters, 2 times). The combined organic layers are washed with 8 milliliters of water, dried over sodium sulfate, and evaporated, to give the product in the form of a colorless solid (m.p.:93-95 ° C). MS (ES +): 250 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 13.28 (br s, 1H), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 1H), 6.09-5.98 (m, 1H), 5.39 (dd , 1H), 5.26 (dd, 1H), 4.64 (d, 1H), 2.97 (br s, 3H), 2.88 (br s, 3H). Building block A5: 3-Acetyl-5- (allyl-benzyloxycarbonyl-amino) -benzoic acid a) 5-Benzyloxycarbonyl-ammonophthalic acid monomethyl ester 5-nitromethylamide monomethyl ester (50 grams, 220 millimoles, 1 equivalent) is dissolved in a mixture of 650 milliliters of methanol, and 350 milliliters of tetrahydrofuran. 3 grams of Pd / C are added, and the reaction mixture is hydrogenated overnight under 1 bar of H2 and then filtered. The filtrate is concentrated, and the residue is dissolved in a mixture of tetrahydrofuran (200 milliliters) and aqueous NaHCO3 (400 milliliters). CbzCl (62 milliliters, 50% in toluene, 184 mmol, 0.9 equivalents) is added, the reaction mixture is stirred for 1 hour, CbzCl (31 milliliters, 50% in toluene, 92 millimoles, 0.45 equivalents) is added. ), and the reaction mixture is stirred overnight. The white solid formed is washed with water and diethyl ether to give the product. MS (ES-): 328 = [MH] \ HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.36 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.40 (s, 1 H), 8.38 (s, 1 H), 8.17 (s, 1 H), 7.50-7.37 (m, 5 H), 5.21 (s, 2 H), 3.92. (s, 3H). b) 5-Benzyloxy-carbonyl-amino-5-hydroxy-methyl-benzoic acid methyl ester 5-benzyloxy-carbonyl-amino-isophthalic acid monomethyl ester (10 grams, 30.1 mmol, 1 equivalent) and Et3N ( 5 milliliters, 36.1 millimoles, 1.2 equivalents), are suspended in a mixture of tetrahydrofuran (200 milliliters) and N-methyl-pyrrolidone (200 milliliters). Isopropyl chloroformate (42 milliliters, 1 N in toluene, 42 mmol, 1.4 equivalents) is added, and the reaction mixture is stirred for 30 minutes at 0 ° C, and then diluted with diethyl ether and water. The organic layer is washed with 0.1 N HCl and brine. Dissolve NaBH4 (3.82 grams, 101 millimoles, 3.36 equivalents) in H20 (100 milliliters), and the solution is added to the reaction mixture, which is then stirred for 1 hour. Diethyl ether and H2O, and the organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 2 to give the product. MS (ES +): 333 = [M + NH 4] X 1 H-NMR (400 MHz, DMSO-d 6): 8.07 (s, 1 H), 7.68 (s, 1 H), 7.60 (s, 1 H), 7.50-7.37 ( m, 5H), 5.39 (t, 1H), 5.20 (s, 2H), 4.54 (d, 2H), 3.86 (s, 3H). c) 3-Benzyloxy-carbonyl-amino-5- (tert-butyl-dimethyl-silanyloxy-methyl) -benzoic acid methyl ester The 5-benzyloxy-carbonyl-amino-5-hydroxy-methyl-benzoic acid methyl ester ( 14.3 grams, 45.4 millimoles, 1 equivalent) is dissolved in N, N-dimethyl formamide (40 milliliters). Add tert-butyl-chloro-dimethylsilane (8.3 grams, 54.9 millimoles, 1.21 equivalents), imidazole (3.1 grams, 45.8 millimoles, 1.01 equivalents), and 4-dimethylaminopyridine (279 milligrams, 2.28 millimoles, 0.05 equivalents) . The reaction mixture is stirred for 8 hours at room temperature, and then diluted with diethyl ether and aqueous NaHCO 3. The organic layer is separated, dried over MgSO4, filtered, and concentrated. The residue is dissolved in diethyl ether, and hexane is added to precipitate the product, which is filtered and dried under vacuum.

MS (ES +): 447 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 7.09 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.96 (s, 1 H), 7.76 (s, 1 H), 7.67 (s, 1H), 7.47-7.37 (m, 5H), 6.82 (s, 1H), 5.26 (s, 2H), 4.80 (s, 2H), 3.93 (s, 3H), 0.99 (s, 9H), 0.18 (s, 6H). d) 3- (Allyl-benzyloxy-carbonyl-amino) -5- (tert-butyl-di-methyloxy-methyl-benzoic acid methyl ester) 3-benzyloxy-carbonyl-methyl-methyl ester amino-5- (tert-butyl-dimethyl-silanyloxy-methyl) -benzoic acid (14.0 grams, 29.8 mmol, 1 equivalent) is dissolved in 200 milliliters of N, N-dimethyl-formamide.

NaH (1.63 grams, 55 percent, 37.3 mmol, 1.25 equivalents) is added at 0 ° C, and the reaction mixture is stirred for 1 hour at 0 ° C. Allyl bromide (3.30 milliliters, 37.3 millimoles, 1. 25 equivalents), and the reaction mixture is stirred for 30 minutes at room temperature, poured into ice water, and diluted with EtOAc. The organic layer is separated, dried over MgSO 4, filtered, and concentrated to give the product. MS (ES +): 487 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 7.43 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.86 (s, 1 H), 7.82 (s, 1 H), 7.49 (s, 1 H), 7.40-7.30 (m, 5 H), 6.00-5.88 (m, 1 H), 5.26 -5.17 (s, 4H), 4.80 (s, 2H), 4.38 (d, 2H), 3.93 (s, 3H), 0.99 (s, 9H), 0.18 (s, 6H). e) 3- (Allyl-benzyloxycarbonyl-amino) -5-hydroxy-methyl-benzoic acid methyl ester 3- (allyl-benzyloxy-carbonyl-amino) -5- (tert-butyl-dimethyl) methyl ester -silyloxy-methyl) -benzoic acid (19.8 grams, 37.2 mmol, 1 equivalent) is dissolved in tetrahydrofuran (220 milliliters). TBAF in tetrahydrofuran (100 milliliters, 1 N in tetrahydrofuran, 100 mmol, 2.68 equivalents) is added, and the reaction mixture is stirred for 16 hours at room temperature, and then concentrated. The residue is purified by column chromatography using hexane / EtOAc in a ratio of 7 to 3, to give the product. MS (ES +): 373 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.63 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.92 (s, 1 H), 7.86 (s, 1 H), 7.49 (s, 1 H), 7.40-7.30 (m, 5 H), 6.00-5.88 (m, 1 H), 5.26 -5.17 (s, 4H), 4.76 (s, 2H), 4.38 (d, 2H), 3.92 (s, 3H). f) 3- (Allyl-benzyloxy-carbonyl-amino) -5-formyl-benzoic acid methyl ester 3- (allyl-benzyloxy-carbonyl-amino) -5-hydroxy-methyl-benzoic acid methyl ester ( 1.4 grams, 2.84 millimoles, 1 equivalent) is dissolved in dichloromethane. Dess-Martin reagent (1.49 grams, 3.40 mmol, 1.2 equivalents) is added, and the reaction mixture is stirred for 1 hour at room temperature. The organic layer is washed with 1N HCl, water and brine, dried over MgSO 4, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product. MS (ES +): 371 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 5.36 minutes. g) 3- (Allyl-benzyloxy-carbonyl-amino) -5- (1-hydroxyl-ethyl) -benzoic acid methyl ester 3- (allyl-benzyloxy-carbonyl-amino) -3-methyl-ester -formyl-benzoic acid (900 milligrams, 2.55 millimoles, 1 equivalent) is dissolved in tetrahydrofuran (12 milliliters). Methyl magnesium chloride (1.50 milliliters, 22 percent in tetrahydrofuran, 3.80 millimole, 1.5 equivalents) is added at -78 ° C, and the reaction mixture is stirred at -78 ° C for 1 hour, quenched with NH4CI aqueous (20 milliliters), warmed to room temperature, diluted with H20 and extracted with EtOAc. The organic layer is washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 2 to 3 to give the product. MS (ES +): 387 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.85 minutes. h) 3-Acetyl-5- (allyl-benzyloxycarbonyl-amino) -benzoic acid methyl ester 3- (allyl-benzyloxy-carbonyl-amino) -5- (1-hydroxy-ethyl) methyl ester ) -benzoic (661 milligrams, 1.70 millimoles, 1 equivalent) is dissolved in dichloromethane. Dess-Martin reagent (1.49 grams, 3.40 mmol, 1.2 equivalents) is added, and the reaction mixture is stirred for 1 hour at room temperature. The organic layer is washed with 1 N HCl, water and brine, dried over MgSO 4, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product. MS (ES +): 385 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 5.38 minutes. i) 3-Acetyl-5- (allyl-benzyloxycarbonyl-amino) -benzoic acid The methyl ester of 3-acetyl-5- (allyl-benzyloxycarbonyl-amino) -benzoic acid (572 milligrams, 1.56 mmol, 1 equivalent) is dissolved in methanol (20 milliliters). 3.1 milliliters of aqueous LiOH (1 N in H2O) are added, and the reaction mixture is stirred for 1 hour at room temperature, and diluted with dichloromethane and 2N HCl in H20. The organic layer is separated, dried over sodium sulfate, filtered, and concentrated to give the product. MS (ES-): 352 = [MH] \ HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.50 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.53 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.43-7.30 (m, 5H), 6.01-5.91 (m, 1H), 5.28 -5.19 (m, 4H), 4.41 (d, 2H), 2.67 (s, 3H). Construction block A6: 3-acetyl-5-allyloxy-benzoic acid a) 3-allyloxy-5-hydroxy-methyl-benzoic acid methyl ester The product is obtained using the reaction procedure described by Fang et al., J. Am. Chem. Soc, 1998, 8543-8544. b) 3-allyloxy-5-formyl-benzoic acid methyl ester The 3-allyloxy-5-hydroxy-methyl-benzoic acid methyl ester (1 gram, 4.45 mmol, 1 equivalent) is dissolved in dichloromethane ( 40 milliliters). The Dess-Martin reagent (2.34 grams, 5.35 mmol, 1.2 equivalents) is added, and the reaction mixture is stirred for 1 hour at room temperature, and then diluted with ether and water. The organic layer is washed with aqueous Na2CO3, dried over sodium sulfate, filtered, and concentrated to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.72 minutes. 1 H-NMR (400 MHz, CDCl 3): 10.0 (s, 1H), 8.17 (s, 1H), 7.86 (dd, 2H), 7.62 (dd, 1H), 7.40-7.20 (m, 5H), 6.16-6.02 (m, 1H), 5.50-5.32 (m, 2H), 4.72 (d, 2H), 3.99 (s, 3H). c) 3-Allyloxy-5- (1-hydroxy-ethyl) -benzoic acid methyl ester 3-allyloxy-5-formyl-benzoic acid methyl ester (800 milligrams, 3.63 mmol, 1 equivalent) dissolves in tetrahydrofuran. MeMgCI (1.85 milliliters, 22 percent in tetrahydrofuran, 5.45 mmol, 1.5 equivalents) is added at -78 ° C and the reaction mixture is stirred at -78 ° C for 1 hour, quenched with aqueous NH4CI, heated to Room temperature, and diluted with H20 and EtOAc. The organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 9 to give the product. MS (ES +): 254 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.07 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.66 (S, 1H), 7.50 (dd, 1H), 7.20 (dd, 1H), 6.17-6.02 (m, 1H), 5.50-5.33 (m, 2H), 4.94. (q, 1H), 4.62 (d, 2H), 3.94 (s, 3H), 1.93 (s, 1H), 1.55 (d, 3H). d) 3-Acetyl-5-allyloxy-benzoic acid methyl ester The 3-allyloxy-5- (1-hydroxyethyl) -benzoic acid methyl ester (570 milligrams, 2.41 mmol, 1 equivalent) is dissolved in dichloromethane (20 milliliters). The Dess-Martin reagent (1.23 grams, 2.89 mmol, 1.2 equivalents) is added, and the reaction mixture is stirred for 1 hour at room temperature, and washed with 1N HCl in H20, and then with brine. The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product. MS (ES +): 252 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.78 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.20 (s, 1H), 7.80 (dd, 1H), 7.69 (dd, 1H), 6.13-6.03 (m, 1H), 5.50-5.34 (m, 2H), 4.63 (d, 2H), 3.95 (s, 3H), 2.62 (s, 3H). e) 3-Acetyl-5-allyloxy-benzoic acid The product can be obtained by a hydrolysis reaction analogous to that for the A3 building block, starting from the 3-acetyl-5-allyloxy-benzoic acid methyl ester . MS (ES +): 238 - [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 3.74 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.04 (s, 1H), 7.72-7.67 (m, 2H), 6.13-6.02 (, 1H), 5.45-5.29 (m, 2H), 4.73 (d, 2H), 2.62 (s, 3H). A7 building block: 3- (allyl-benzyloxycarbonyl- to me not) -5-methoxy-methyl-1-benzoic acid a) 3-hydroxy-methyl-5-nitro-benzoic acid methyl ester 5-nitro -monomethyl isophthalate (22.5 grams, 100 millimoles, 1 equivalent) and Et3N (16.7 milliliters, 120 millimoles), 1.2 equivalents) are dissolved in tetrahydrofuran (200 milliliters). The solution is stirred at 0 ° C, and isopropyl chloroformate in toluene (140 milliliters, 1 N in toluene, 140 mmol, 1.4 equivalents) is added within 30 minutes. After stirring for 90 minutes at 0 ° C, the reaction mixture is poured onto ice and 50 milliliters of aqueous 0.1 N HCl, and then diluted with tert-butyl methyl ether. The organic layer is separated, dried over sodium sulfate, filtered, and concentrated. The residue is dissolved in 300 milliliters of tetrahydrofuran, and the solution is stirred at room temperature. A solution of NaBH (12.5 grams, 330 millimoles, 3.3 equivalents) in 100 milliliters of ice water is added within 15 minutes. The reaction mixture is stirred for 1 hour at room temperature, and then diluted with tert-butyl methyl ether and H2O. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 3.20 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.80 (s, 1 H), 8.48 (s, 1 H), 8.39 (s, 1 H), 4.93 (s, 2 H), 4.01 (s, 3 H). b) 3-methoxy-methyl-5-nitro-benzoic acid methyl ester 3-hydroxy-methyl-5-nitro-benzoic acid methyl ester (8.0 grams, 37.9 mmol, 1 equivalent) is dissolved in 80 milliliters of 13 N, N-dimethyl-formamide. NaH (2.15 grams, 49.3 millimoles, 1.3 equivalents) is added at 0 ° C. The suspension is stirred for 30 minutes at room temperature, and then methyl iodide (4.57 milliliters, 49.3 millimoles, 1.3 equivalents) is added. The reaction mixture is stirred for 3 hours at room temperature, and then quenched with 1 N HCl and tert-butyl methyl ether. The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 3, to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 4.45 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.80 (s, 1 H), 8.43 (s, 1 H), 8.38 (s, 1 H), 4.61 (s, 2 H), 4.00 (s, 3 H), 3.52 (s, 3 H) ). c) 3-Benzyloxycarbonyl-amino-5-methoxy-methyl-benzoic acid methyl ester 3-methoxy-methyl-5-nitro-benzoic acid methyl ester (3.80 grams, 16.9 millimoles, 1 equivalent) it is dissolved in EtOH (80 milliliters). SnCl2 * 2 H20 (1.58 grams, 7 mmol, 7 equivalents) is added, and the reaction mixture is heated at 75 ° C for 90 minutes, and then diluted with EtOAc and aqueous NaHCO3. The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is dissolved in tetrahydrofuran, and CbzCl (0.4 milliliters, 1.30 mmol, 1.2 equivalents) is added to the solution, followed by aqueous NaHCO3. The reaction mixture is stirred for 1 hour at room temperature, and then diluted with EtOAc. The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product. MS (ES-): 328 = [MH] \ HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 5.04 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.94 (s, 1 H), 7.84-7.70 (m, 2 H), 7.46-7.38 (m, 5 H), 6.82 (s, 1 H), 5.25 (s, 2 H), 4.52. (s, 2H), 3.93 (s, 3H), 3.42 (s, 3H). d) 3- (Allyl-benzyloxycarbonyl-amino) -5-methoxy-met-il-benzoic acid methyl ester 3-benzyloxy-carbonyl-amino-5-methoxy-methyl-benzoic acid methyl ester (1.98) grams, 6 millimoles, 1 equivalent) is dissolved in 25 milliliters of N, N-dimethyl-formamide. NaH (327 milligrams, 55 percent, 7.5 mmol, 1.25 equivalents) is added, and the reaction mixture is stirred for 40 minutes at 0 ° C. Allyl bromide (653 microliters, 7.5 mmol, 1.25 equivalents) is added, and the reaction mixture is stirred for 30 minutes at room temperature, then poured into ice water, and extracted with EtOAc. The organic layer is separated, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product.

MS (ES +): 387 = [M + NH4] X HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 5.55 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.92-7.88 (m, 2H), 7.48 (s, 1H), 7. 40-7.30 (m, 5H), 6.00-5.87 (m, 1H), 5.20-5.17 (m, 4H), 4.50 (s, 2H), 4. 34 (d, 2H), 3.94 (s, 3H), 3.40 (s, 3H). e) 3- (Allyl-benzyloxycarbonyl-amino) -5-methoxy-methyl-benzoic acid The product can be obtained by a hydrolysis reaction analogous to that for the A3 building block, starting from the methyl ester of the 3- (Allyl-benzyloxycarbon or l-amino) -5-m-ethoxy-methyl-benzoic acid. MS (ES-): 354 = [MH] \ HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention: 4.64 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.94 (s, 2 H), 7.55 (s, 1 H), 7.40-7.20. (m, 5H), 6.00-5.88 (m, 1H), 5.22-5.18 (m, 4H), 4.53 (s, 2H), 4.37 (d, 2H), 3.40 (s, 3H). Building block A8: 2-allyl-amino-6-methyl-isonicotinic acid hydrochloride a) 2-chloro-6-methyl-isonicotinic acid terbutil-ester A solution of 5.0 grams (29 mmol) of 2-chloro- 6- methyl-isonicotinic in 50 milliliters of chloroform, it is heated to reflux. 14 milliliters (58 mmol, 2 equivalents) of di-terbutoxy-methyl-dimethyl-amine are added dropwise over 30 minutes. After a reaction time of 1.5 hours and 3.5 hours, additional portions of di-terbutoxy-methyl-dimethylamine are added (each time 14 milliliters, 58 millimoles, 2 equivalents). After a reaction time of 4.5 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with aqueous sodium bicarbonate, and then with brine, dried over magnesium sulfate, filtered, and concentrated. The residue is purified by chromatography on silica (Flashmaster, hexane to hexane / EtOAc, 95/5), to give the product in the form of a white solid. Rf (DCM / methanol = 95: 5): 0.36. MS (LC / MS): 172/174 = [M + H - tertbutyl] *. 1 H-NMR (400 MHz, CDCl 3): 7.65 (s, 1 H), 7.60 (s, 1 H), 2.63 (s, 3H), 1.63 (s, 9H). b) 2-allyl-amino-6-methyl-isonicotinic acid terbutil-ester A mixture of 1.87 milliliters (24 millimoles, 1.1 equivalents) of allylamine, 0.254 grams (0.05 equivalents) of Pd (OAc) 2, 0.705 grams (0.05 equivalents) of BINAP, and 4.78 grams (48 millimoles, 2.2 equivalents) of sodium terbutylate in 110 milliliters of toluene, is heated at 60 ° C under a nitrogen atmosphere. A solution of 5.0 grams (22 millimoles) of 2-chloro-6-methyl-isonicotinic acid tertiary butyl ester in 40 milliliters of toluene is added dropwise over 30 minutes, and the reaction mixture is stirred at 60 ° C for 2.5 hours. hours and, after cooling to room temperature, diluted with EtOAc. The organic layer is washed with aqueous sodium bicarbonate, and then with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by chromatography on silica (Flashmaster, hexane to hexane / EtOAc, 80/20) to give the product. Rf (hexane / EtOAc = 70/30): 0.38. MS (LC / MS): 193 = [M + H - tertbutyl] *. 1 H-NMR (400 MHz, CDCl 3): 6.96 (s, 1 H), 6.76 (s, 1 H), 6.02-5.93 (m, 1 H), 5.31 (d, 1 H), 5.20 (d, 1 H), 4.81 (br s, 1H), 4.00-3.95 (m, 2H), 2.45 (s, 3H), 1.61 (s, 9H). c) 2-allyl-amino-6-methyl-isonicotinic acid hydrochloride A solution of 0.26 grams (1.0 mmol) of 2-allyl-amino-6-methyl-sonicotinic acid terbutyl ester in 9.2 milliliters (35 equivalents) of 4N HCl in dioxane, is heated for 2 hours to 60 ° C. The evaporation of the solvent gives the product in the form of a brown foam. Rf (DCM / MeOH = 70/30): 0.37. MS (LC / MS): 193 = [M + H] X 1 H-NMR (400 MHz, CDCl 3): 8.61 (br s, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 5.95-5.86 (m, 1H), 5.39 (d, 1H), 5.33 (d, 1H), 4.07 (br s, 2H), 2.68 (s, 3H). A9 building block: 3-allyloxy-5- [methoxy- (propan-1-sulfonyl) -amino] -benzoic acid allylester a) 3-allyloxy-5-nitro acid allylester benzoic acid 3-nitro-5-hydroxy-benzoic acid (500 milligrams, 2.73 millimoles, 1 equivalent) is dissolved in acetone (7 milliliters). Potassium carbonate (877 milligrams, 6.28 millimoles, 2.3 equivalents), allyl bromide (1.21 milliliters, 13.92 millimoles, 5.1 equivalents) and potassium iodide (907 milligrams, 5.46 millimoles, 2 equivalents) are added to the reaction mixture. The reaction mixture is heated for 40 hours at reflux temperature, and then diluted with water and EtOAc. The organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The product is purified by chromatography on silica (EtOAc / hexane, 1/9). MS (ES +): 281 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.85 minutes. b) 3-allyloxy-5-amino-benzoic acid allylester The 3-allyloxy-5-nitro-benzoic acid allylester (540 milligrams, 2.05 millimoles, 1 equivalent) is dissolved in EtOH (15 milliliters). SnCl2 * 2H2O (3.31 grams, 14.4 millimoles, 7 equivalents) is added, and the reaction is heated at 75 ° C for 1.5 hours. The reaction mixture is cooled to room temperature and diluted with 2N aqueous hydrochloric acid and EtOAc. The organic layer is separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The product is purified by chromatography on silica (EtOAc / hexane / NH3, 30/70 / 0.2). 19 MS (ES +): 234 [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.87 minutes. c) 3-Allyloxy-5- (propan-1-sulfonyl-amino) -benzoic acid allylester The 3-allyloxy-5-amino-benzoic acid allylester (300 milligrams, 1.29 mmol, 1 equivalent) is dissolve in dichloromethane (25 milliliters). Pyridine (737 microliters, 10.3 millimoles, 8 equivalents) and propan-sulfonyl chloride (634 microliters, 5.66 millimoles, 4.4 equivalents) are added, and the mixture is stirred for 4 hours at room temperature. The reaction is diluted with 1N aqueous hydrochloric acid and EtOAc. The organic layer is separated, wash with brine, dry over sodium sulfate, filter, and concentrate. The product is purified by chromatography on silica (EtOAc / hexane, 3/7). MS (ES +): 357 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.24 minutes. d) 3-allyloxy-5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid allylester Potassium carbonate (188 milligrams, 1.35 millimoles, 2.2 equivalents) and methyl iodide (85 microliters) , 1.35 mmol, 2.2 equivalents) to the solution of 3- allyloxy-5- (propan-1-sulfonyl-amino) -benzoic acid allylester (260 milligrams, 0.613 mmol, 1 equivalent) in 12 milliliters of acetonitrile. The reaction is stirred for 18 hours at room temperature. The mixture is filtered and concentrated. The product is purified by chromatography on silica (EtOAc / hexane, 1/4). MS (ES +): 371 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.62 minutes. e) 3-Allyloxy-5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid The allyl ester of 3-allyloxy-5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid (174 milligrams, 0.492 millimoles, 1 equivalent) is dissolved in 7 milliliters of methanol and 0.5 milliliters of hydroxide. aqueous sodium 4N. After stirring for 3 hours at room temperature, the reaction mixture is diluted with 2N aqueous hydrochloric acid and EtOAc. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated to give the product. MS (ES-): 312 [MH] "HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 4.22 minutes Construction block A10: 3- (3-methane-sulfonylloxy-propoxy) -5-methoxy-methyl-I-benzoic acid methyl ester a) 3-allyloxy-5-hydroxymethyl ester -methyl-benzoic acid The monomethyl ester of 5-allyloxy-isophthalic acid (Fang et al., J. Am. Chem. Soc. 1998, 8543-8544) (6.14 grams, 26 mmol, 1 equivalent) is dissolved in 200 milliliters of Tetrahydrofuran: Et3N (4.4 milliliters, 31.2 mmol, 1.2 equivalents) is added, and the reaction mixture is cooled to 0 ° C. After the addition of isopropyl chloroformate (1N in toluene, 36.4 milliliters, 36 mmol, 1.4 equivalents) , the reaction is stirred for 1 hour at 0 ° C. Water (50 milliliters) and tert-butyl ether (300 milliliters) are added.The organic layer is separated, washed with aqueous bicarbonate and brine, dried on sodium sulfate, filtered, and concentrated. The residue is dissolved in tetrahydrofuran (200 milliliters) at 0 ° C, and NaBH 4 (3.25 grams, 85.9 millimoles, 3.31 equivalents) are added in 25 milliliters of ice water within 10 minutes. The reaction is stirred for 1 hour at 0 ° C. 100 milliliters of water and 300 milliliters of terbutyl methyl ether are added, and the organic layer is separated, washed with aqueous bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The product is used in the next step without further purification. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 3.76 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.58 (s, 1 H), 7.42 (s, 1 H), 7.10 (s, 1 H), 6.05-5.92 (m, 1 H), 5.41-5.22 (m, 2 H), 4.66 (s, 2H), 4.53 (d, 2H), 3.86 (s, 3H). b) 3-allyloxy-5-methoxy-methyl-benzoic acid methyl ester NaH (1.19 grams, 29.8 mmol, 1.25 equivalents) is added to the solution of the 3-allyloxy-5-hydroxymethyl methyl ester benzoic acid (5.3 grams, 23.8 mmol, 1 equivalent) in N, N-dimethyl formamide (60 milliliters) at 0 ° C, and the reaction mixture is stirred for 30 minutes. After the addition of methyl iodide (3.32 milliliters, 35.8 millimoles, 1.5 equivalents), the reaction is stirred for 2 hours at room temperature. Aqueous 1N hydrochloric acid (20 milliliters) and tert-butyl methyl ether (200 milliliters) are added, the organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The product is used for the next step without further purification. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 4.99 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.52 (s, 1 H), 7.42 (s, 1 H), 7.05 (s, 1 H), 6.05-5.92 (m, 1 H), 5.40-5.19 (m, 2 H), 4.55 (d, 2H), 4.40 (s, 2H), 3. 85 (s, 3H), 3.32 (s, 3H). c) 3- (3-hydroxy-propoxy) -5-methoxy-methyl-benzoic acid methyl ester 9-BBN (0.5 N in tetrahydrofuran, 48.7 milliliters, 24.4 millimoles, 2.88 equivalents) is added to the methyl-methyl solution. 3-allyloxy-5-methoxy-methyl-benzoic acid ester (2.00 grams, 8.46 mmol, 1 equivalent) in tetrahydrofuran (60 milliliters) at 0 ° C, and the reaction mixture is stirred for 20 hours. After the addition of H202 (30 percent in water, 55 milliliters) and sodium carbonate (4 percent in water, 184 milliliters), the reaction is stirred for 1 hour. Terbutil-methyl-ether (250 milliliters) is addedThe organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The product is purified by chromatography on silica (EtOAc / hexane, 55/45). MS (ES +): 272 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.38 minutes. d) 3- (3-Methanesulfonyloxy-propoxy) -5-methoxy-methyl-benzoic acid methyl ester. Methanesulfonyl chloride (170 microliters, 2.2 mmol, 1.1 equivalents) and Et3N (334 microliters, 2.4) are added. millimoles, 1.2 equivalents) to the solution of 3- (3-hydroxy-propoxy) -5-methoxy-methyl-benzoic acid methyl ester (508 milligrams, 2.00 millimoles, 1 equivalent) in tetrahydrofuran (10 milliliters), and the The reaction is stirred for 22 hours. S added aqueous sodium bicarbonate (10 milliliters) and EtOAc (20 milliliters), the organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The product is purified by chromatography on silica (EtOAc / hexane, 1/1). MS (ES +): 350 [M + NH 4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time of retention = 4.26 minutes. Building block A11: 2-allyloxy-6-methoxy-methyl-isonicotinic acid 2-Chloro-6-methoxy-methyl-isonicotinic acid (building block A1b, 403 milligrams, 2 mmol, 1 equivalent) is dissolved in sulfoxide of dimethyl (3.4 milliliters) and allyl alcohol (1.7 milliliters). Sodium hydride (320 milligrams, 8 millimoles, 4 equivalents) is added, and the suspension is heated at 100 ° C for 3 hours. The reaction mixture is cooled to room temperature, and the pH is adjusted with 1N hydrochloric acid to pH = 3. The mixture is concentrated, and the product is purified by chromatography on silica (DCM / MeOH, 96/4). MS (ES +): 224 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 5-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 4.63 minutes. Construction block A12: 3- (Allyl-benzyloxycarbonyl-amino) -5- (2-oxo-propoxy) -benzoic acid The title compound is obtained following a published procedure (International Publication Number WO2006074950). MS (ES +): 401 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 4.38 minutes. Building block A13: 3- (Allyl-benzyloxycarbonyl-amino) -5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid a) 3-benzyloxycarbonyl-amino-5-nitro- benzoic To the solution of 3-amino-5-nitro-benzoic acid (25 grams, 135 millimoles, 1 equivalent) in tetrahydrofuran (150 milliliters), benzyl chloroformate (50 percent in toluene, 54 milliliters, millimoles, 1.2 equivalents) and aqueous sodium carbonate (150 milliliters). The reaction mixture is stirred for 90 minutes at room temperature, and then diluted with EtOAc and water. The organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The product is crystallized from diethyl ether and hexane. MS (ES +): 334 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time of retention = 2.67 minutes. b) 3- (Allyl-benzyloxy-carbonyl-amino) -5-nitro-benzoic acid allyles To the solution of 3-benzyloxy-carbonyl-amino-5-nitro-benzoic acid (34.5 grams, 106 mmol, 1 equivalent) in N, N-dimethylformamide (500 milliliters) at 0 ° C, sodium hydride (7.6 grams, 60 percent, 190 millimoles, 1.8 equivalents) is added, followed by TBAI (3.91 grams, 10.6 millimoles, 0.1 equivalents), and allyl bromide (16.9 milliliters, 190 millimoles, 1.8 equivalents). The reaction is stirred for 2 hours at room temperature, and then poured onto ice cold 0.5N hydrochloric acid. The mixture is extracted with diethyl ether. The combined organic layers are dried over sodium sulfate, they filter, and they concentrate. The product is purified by chromatography on silica (EtOAc / hexane, 1/4). MS (ES-): 355 [M-H] - HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 4.49 minutes. c) 3- (Allyl-benzyloxy-carbonyl-amino) -5-amino-benzoic acid allyl ester To the 3- (allyl-benzyloxy-carbonyl-amino) -5-nitro-benzoic acid allyl ester solution (8.8 grams, 22.2 mmol, 1 equivalent) in EtOH (180 milliliters), is added SnCl2 * 2H20 (35.8 grams, 155 millimoles, 7 equivalents). The reaction is heated at 75 ° C for 90 minutes, and then cooled to room temperature. The mixture is acidified with 2N aqueous hydrochloric acid, and diluted with EtOAc. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated. The product is purified by chromatography on silica (hexane / EtOAc / NH 3, 70/30 / 0.2). MS (ES +): 367 [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.04 minutes. d) Allyl ester of 3- (allyl-benzyloxycarbonyl-amino) -5- (propane-1-sulfonyl-amino) -benzoic acid To the solution of 3- (allyl-benzyloxycarbonyl) allylester amino) -5-amino-benzoic acid (8.4 grams, 20.8 millimoles, 1 equivalent) in dichloromethane (250 milliliters), pyridine (12 milliliters, 167 millimoles, 8 equivalents) and propan-sulfonyl chloride (13.1 grams) were added. , 91.7 millimoles, 4.4 equivalents). After stirring for 4 hours at room temperature, the reaction mixture is diluted with 1N aqueous hydrochloric acid and EtOAc. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated. The product is purified by chromatography on silica (EtOAc / hexane, 1/4). MS (ES +): 490 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.67 minutes. e) 3- (Allyl-benzyloxycarbonyl-amino) -5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid ester 3- to the allyl ester of 3- (allyl) acid benzyloxy-carbonyl-amino) -5- (propane-1-sulfonyl-amino) -benzoic acid (1.00 grams, 1.69 mmol, 1 equivalent) in acetonitrile (35 milliliters), potassium carbonate (520 milligrams, 3.72 mmol, 2.2 equivalents) and methyl iodide (234 microliters, 3.72 mmol, 2.2 equivalents). After stirring for 18 hours at room temperature, the reaction mixture is filtered and concentrated. The product is purified by chromatography on silica (EtOAc / hexane, 1/4). MS (ES +): 504 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 5.99 minutes. f) 3- (Allyl-benzyloxycarbonyl-amino) -5- [methyl- (propan-1-sulfonyl) -amino] -benzoic acid The solution of 3- (allyl-benzyloxycarbonyl-amino) allylester ) -5- [Methyl- (propan-1-sulfonyl) -amino] -benzoic acid (550 milligrams, 0.90 mmol, 1 equivalent) in methanol (15 milliliters) and 4N aqueous sodium hydroxide (0.9 milliliters, 3.62 mmol, 4 equivalents), is stirred for 3 hours at room temperature. The reaction mixture is diluted with EtOAc and 2N aqueous hydrochloric acid. The organic layer is separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the product. MS (ES-): 445 [MH] "HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 4.84 minutes Construction block A14: 3- (Allyl-benzyloxy-carbonyl-ami-no) -5-methoxy-benzoic acid a) 3- (allyl-benzyloxy-carbonyl-amino) -5-methoxy acid methyl ester -benzoic acid To a solution of 4.18 grams (12 mmol) of 3- (allyl-benzyloxy-carbonyl-amino) -5-methoxy-benzoic acid methyl ester [obtained following a published procedure (International Publication Number WO2006074950)] in 18 milliliters of dimethylformamide, 2.51 grams (18 millimoles) of powdered potassium carbonate are added. To this mixture is added 978 microliters (15.6 millimoles) of iodo-methane at 0 ° C. The mixture is allowed to warm to room temperature, and is stirred for 16 hours. The reaction mixture is diluted with 60 milliliters of water and extracted with toluene. The combined organic layers are washed with water, dried over sodium sulfate and evaporated, to give the product as a colorless oil. Rf (acetone / cyclohexane = 50/50): 0.63. MS (ES +): 356 = [M + H] *. 'H-NMR (400 MHz, DMSO-d6): 7.44 (s, 1H), 7.36-7.27 (m, 6H), 7.17 (t, 1H), 5.91-5.81 (m, 1H), 5.14-5.09 (m , 4H), 4.30 (d, 2H), 3.84 (S, 3H), 3.79 (S, 3H). b) 3- (Allyl-benzyloxycarbonyl-amino) -5-methoxy-benzoic acid To a solution of 4.09 grams (11.5 millimoles) of the methyl ester of 3- (allyl-benzyloxycarbonyl-amino) -5- methoxy-benzoic in 27.6 milliliters of THF / MeOH (50/50), 13.8 milliliters (13.8 millimoles) of 1M aqueous sodium hydroxide are added at 0 ° C. The mixture is allowed to warm to room temperature, and is stirred for 16 hours. The reaction mixture is acidified to a pH of 3 by the addition of milliliters of 1M aqueous hydrochloric acid. The organic solvents are evaporated, and the aqueous solution is extracted with dichloromethane. The combined organic layers are washed with half-saturated brine, dried over sodium sulfate, and evaporated, to give the product as a yellowish solid. p.f.98-99 ° C Rf (DCM / MeOH / NH3 = 95 / 4.5 / 0.5): 0.30. MS (ES +): 342.1 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 13.10 (br s, 1H), 7.42 (t, 1H), 7.35-7.26 (m, 6H), 7.12 (t, 1H), 5.91-5.81 (m, 1H ), 5.14-5.09 (m, 4H), 4.29 (d, 2H), 3.77 (s, 3H). Building block A15: 5- (Allyl-benzyloxycarbonyl-amyl) -N, N-methyl-isophthalamic acid a) 5-benzyloxy-carbonyl-amino-N, N-di-methyl-isophthalamic acid methyl ester A solution of 5-benzyloxy-carbonyl-amino-isophthalic acid monomethyl ester (3.29 grams, 10 mmol) [obtained according to the literature procedure, as described in International Publication Number WO2006074950] in thionyl chloride ( 10 milliliters, 140 mmol), is heated at reflux temperature for 1 hour. The excess thionyl chloride is evaporated, and the residue is dissolved in 20 milliliters of dichloromethane. At 0 ° C, a solution of dimethylamine in tetrahydrofuran (1.36 grams, 30 mmol) is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with 80 milliliters of dichloromethane and 100 milliliters of medium-saturated aqueous ammonium chloride. The layers are separated, the aqueous phase is extracted with dichloromethane, the combined organic layers are washed with water, dried over sodium sulfate, and evaporated. The residue is purified by chromatography on silica gel (cyclohexane / EtOAc, 80/20 to EtOAc), to give the product as a grayish solid. mp .: 155 - 158 ° C Rf (EtOAc / acetone = 80/20): 0.59. MS (ES +): 357 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 10.13 (s, 1H), 8.16 (s, 1H), 7.69 (t, 1H), 7.52 (t, 1H), 7.42-7.30 (m, 5H), 5.16 (s, 2H), 3.84 (s, 3H), 2.97 (s, 3H), 2.86 (s, 3H). b) 5- (Allyl-benzyloxycarbonyl-amino) -N, N-dimethylamine methylester To a solution of 5-benzyloxycarbonyl-amino-N, N-dimethyl methyl ester -isophthalamic (803 milligrams, 2.25 millimoles) in 4.5 milliliters of dimethyl formamide at 0 ° C, sodium hydride (177 milligrams, 4.06 millimoles, 60 percent in mineral oil) and allyl bromide (289 microliters, 3.38 mmol), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with 45 milliliters of toluene and 45 milliliters of a saturated solution of ammonium chloride. The layers are separated, the aqueous phase is extracted with toluene, the combined organic layers are washed with water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (cyclohexane / EtOAc, 90/10 to 50/50), which gives the product as a colorless resin. Rf (cyclohexane / EtOAc = 20/80): 0.39. MS (ES +): 397 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.89 (s, 1H), 7.73 (t, 1H), 7.59 (t, 1H), 7.34-7.26 (m, 5H), 5.91-5.81 (m, 1H) , 5.12-5.08 (m, 4H), 4.33 (d, 2H), 3.85 (s, 3H), 2.96 (s, 3H), 2.80 (s, 3H). c) 5- (Allyl-benzyloxycarbonyl-amino) -N, N-dimethyl-isophthalamic acid To a solution of 5- (allyl-benzyloxycarbonyl-amino) -N, N-dimethyl-isophthalamic acid methyl ester (712 milligrams, 1.8 millimoles) in 7.2 milliliters of THF / MeOH (50/50), 3.6 milliliters of 1M sodium hydroxide are added at 0 ° C. The solution is allowed to warm to room temperature, and is stirred for 3 hours. The reaction mixture is acidified to a pH of 3 by the addition of 6 milliliters of 0.5 M aqueous hydrochloric acid, and the organic solvents are evaporated. The aqueous solution is extracted with dichloromethane, the combined organic layers are washed with water, dried over sodium sulfate, and evaporated, to give a colorless foam. Rf (DCM / MeOH / NH3 = 90/9/1): 0.12. MS (ES +): 405 = [M + Na] *. 1 H-NMR (400 MHz, DMSO-d 6): 13.27 (br s, 1H), 7.86 (t, 1H), 7.72 (t, 1H), 7.55 (t, 1H), 7.33-7.26 (m, 5H), 5.91-5.81 (m, 1H), 5.13-5.08 (m, 4H), 4.32 (d, 2H ), 2.96 (s, 3H), 2.81 (s, 3H). A16 building block: 2- (Acetyl-allyl-amino) -6-chloro-isonicotinic acid a) 2-Acetyl-amino-6-chloro-isonicotinic acid ester A mixture of 14 grams of the acid ethyl ester 2-amino-6-chloro-isonicotinic (Temple et al., J. Heterocicl, Chem. 1970, 7, 451) (70 millimoles) in 150 milliliters of acetic anhydride (large excess) and 150 milliliters of pyridine (large excess), it is stirred at 60 ° C in the presence of 244 milligrams (2 millimoles) of DMAP for 16 hours. The mixture is concentrated in vacuo, taken up in EtOAc, and washed with 1N HCl, brine and 10 percent aqueous Na 2 CO 3 to give the title compound in the form of yellowish crystals (EtOH). Rf: (hexane / EtOAc = 2/1): 0.46 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 40-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) : 3.619 minutes MS (ES) [M + H] * = 243, 245 1 H-NMR (400 MHz, CDCl 3): 8.65 (s, 1 H), 7.97 (br s, 2 H), 7.65 (s, 1 H), 4.45 (q, 2H), 2.26 (s, 3H), 1.44 (t, 3H). b) 2- (Acetylallylamino) -6-chloro-isonicotinic acid ethyl ester A mixture of 6.0 grams (25 millimoles) of 2-acetyl-amino-6-chloro-isonicotinic acid ethyl ester, 10.36 grams (75 millimoles) of potassium carbonate, and 4.23 milliliters (50 millimoles) of allyl bromide in 25 milliliters of dimethylformamide, is stirred at 60 ° C for 24 hours. The cooled mixture is diluted with water and tert-butyl methyl ether. The organic phase is washed with water, dried over Na 2 SO 4 and evaporated. The product is purified by chromatography on silica gel (hexane / EtOAc, 9/1), to provide the title compound as a yellowish oil. Rf: (hexane / EtOAc = 2/1): 0.46 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 40-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) : 3.619 minutes MS (ES) [M + H] * = 283, 285; [MNa] * = 305, 307. 1 H-NMR (400 MHz, CDCl 3): 7.96 (br s, 1H), 7.74 (s, 1H), 5.98- 5.88 (m, 1H), 5.22-5.17 (m, 2H ), 4.59 (d, 2H), 4.45 (q, 2H), 2.26 (s, 3H), 1.44 (t, 3H). c) 2- (Acetylallylamino) -6-chloro-isonicotinic acid A solution of 1.08 grams of the 2- (acetylallylamino) -6-chloro-isonicotinic acid ethyl ester (3.82 millimoles) in 15 milliliters of methanol, treated with 5.5 milliliters of 1N NaOH (5.5 mmol), and stirred at 25 ° C for 30 minutes. The reaction is quenched with 6 milliliters of 1N HCl, and extracted with EtOAc. Crystallization from a small amount of EtOAc gives the title compound as yellow crystals. Rf: (2 percent EtOAc / AcOH): 0.60 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) : 3.475 minutes MS (ES) [M + H] * = 255, 257; [M + Na] * = 277, 279 1 H-NMR (400 MHz, CDCl 3): 8.04 (br s, 1H), 7.79 (s, 1H), 6.00-5.92 (m, 1H), 5.26-5.19 (m, 2H), 4.60 (d, 2H), 2.32 (s, 3H). A17 building block: 2- (Acetyl-allyl-amino) -6- m ethyl-i or nicotinic acid a) 2- (N'-isopropylidene-hydrazino) -6-methyl-isonicotinic acid ethyl ester A mixture of 7.35 grams 42.86 millimoles) of 2-chloro-6-methyl-isonicotinic acid, 10.75 grams (250 millimoles) hydrazine hydrate, and 10.7 milliliters of 4N NaOH, is stirred at 125 ° C for 24 hours. The mixture is evaporated to dryness, absorbed in 35 milliliters of water, 35 milliliters of ethanol, and 50 milliliters of acetone, and stirred for 1 hour. The mixture is concentrated once again, and refluxed in a solution of 20 milliliters of thionyl chloride in 200 milliliters of ethanol. After 1.5 hours, the mixture is cooled and filtered. The filtrate is diluted with ethyl acetate and washed with an aqueous solution of 10 percent NaHCO 3. The aqueous phase is extracted with EtOAc / acetone (4: 1) three times. The combined organic layers are dried over sodium sulfate, and chromatographed on silica gel ((EtOAc / hexanes = 1: 2), to give a tan oil, which is crystallized from EtOH / water.

P.f. 79-82 ° C Rf: (EtOAc / hexanes) = 1/1): 0.27 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 5 -100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)): 3,617 minutes. MS (ES +): 236 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.05 (br, 1H), 7.59 (s, 1H), 7.14 (s, 1H), 4.39 (q, 2H) , 2.46 (s, 3H), 2.07 (s, 3H), 1.93 (s, 3H), 1.41 (t, 3H). b) 2-amino-6-methyl-isonicotinic acid ethyl ester A solution of 8.37 grams (35.6 millimoles) of 2- (N'-isopropylidene-hydrazino) -6-methyl-isonicotinic acid ethyl ester in 150 milliliters of EtOH, hydrogenated for 11 hours at 80 ° C, and hydrogen at 6 bar in the presence of 25 grams of Raney Nickel. After cooling, the mixture is filtered on Celite and evaporated. The product is crystallized from EtOH / water, to give white crystals. Rf: (EtOAc / hexanes) = 1/1): 0.29 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20 -100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes) ): 1,355 minutes. MS (ES +): 181 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 7.08 (s, 1H), 6.93 (s, 1H), 4.61 (br, 2H), 4.19 (q, 2H) , 2.46 (s, 3H), 1.41 (t, 3H). c) 2- (Acetylallylamino) -6-methyl-isonicotinic acid The title compound is prepared in a manner similar to the A16 building block, starting from the ethyl ester of 2-amino-6-methyl -isonicotinic. The crude product is crystallized from EtOAc / hexanes, to obtain a white powder. HPLC (Zorbax SB-C18H, 3 x 30 millimeters, 1.8 microns, 10 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes), 100-10 percent MeCN (0.25 minutes)): 2,354 minutes.

MS (ES +): 235 = [M + H] * 1 H-NMR (400 MHz, d6-DMSO): 7.73 (s, 1H), 7.59 (s, 1H), 5.93- 5.82 (m, 1H), 5.16- 5.07 (m, 2H), 4.52-4.46 (m, 2H), 2.53 (s, 3H), 2.07 (s, 3H). Building block A18: 2-allyl-amino-6-methoxy-isonicotinic acid A mixture of 3.97 milliliters (52 millimoles, 10 equivalents) of allylamine, 0.97 grams (5.2 millimoles, 1 equivalent) of 2-chloro-6 acid -methoxy-isonicotinic acid (see A3 building block), and 1.29 grams (5.2 millimoles, 1 equivalent) of copper (II) sulphate pentahydrate in 10 milliliters of water, heated in a closed container for 2.5 hours, to a bath temperature of 160 ° C. After cooling to room temperature, the mixture is diluted with 400 milliliters of 10 percent aqueous citric acid, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, and the solvents are evaporated under reduced pressure. The residue is dissolved in approximately 20 milliliters of warm DCM / MeOH (2/1). After the addition of about 25 milliliters of hexane, partial evaporation of the solvents to a volume of about 20 milliliters, and holding at 4 ° C for 4 hours, the product is precipitated, and filtered and dried under vacuum. MS (LC / MS): 209 = [M + H] * 1 H-NMR (400 MHz, DMSO-d 6): 7.04 (t, 1H), 6.55 (s, 1H), 6.26 (s, 1H), 5.97- 5.88 (m, 1H), 5.21 (d, 1H), 5.09 (d, 1H), 3.92 (d, 2H), 3.80 (s, 3H). A19 building block: 3- (allyl-benzyloxycarbonyl-amino) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid a) 3-benzyloxycarbonyl-amino-5-methyl ester (2-oxo-pyrrolidin-1-yl) -benzoic acid To a stirred mixture of 3.74 grams (16.0 mmol) of the 3-amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester and 4.02 grams (48 millimoles) of sodium bicarbonate in 15 milliliters of MeCN, 8.0 milliliters (23.9 millimoles) of benzyl chloroformate (50 percent in toluene) are added dropwise. After 18 hours, the mixture is diluted with water and dichloromethane. A part of the sparingly soluble product is filtered. The organic layer is dried over sodium sulphate and evaporated. The crude product is crystallized from chloroform / MeOH / DMF / hexanes, to give a gray solid. Rf: (EtOAc / hexane, 2: 1): 0.60 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 10 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 3,389 minutes. MS (ES +): 369 = [M + H] * 1 H-NMR (400 MHz), DMSO-d6): 10.12 (s, NH), 8.01 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 5.19 (s, 2H), 3.85 (s, 3H), 3.82 ( t, 2H), 2.14-2.05 (m, 2H) b) 3- (Allyl-benzyloxycarbonyl-amino) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester A suspension of 3.69 grams (8.1 millimoles) of 3-benzyloxycarbonyl-amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester, 1.37 milliliters (16.2 millimoles) of allyl bromide, and 2.24 grams (16.2 mmol) of potassium carbonate in 8 milliliters dimethylformamide, is stirred at 50 ° C for 4 hours. The mixture is diluted with water and extracted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. The product is purified by chromatography on silica gel (EtOAc / hexanes, 1: 4, 1: 2, 1: 1, 2: 1). The title compound is isolated as a yellow resin. Rf: (EtOAc / hexane, 2: 1): 0.62 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 3.062 minutes MS (ES +): 409 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.09 (br s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.40-7.29 (m , 5H), 6.00-5.88 (m, 1H), 5.23-5.17 (m, 2H), 4.37-4.34 (m, 2H), 3.95 (s, 3H), 3.86 (t, 2H), 2.65 (t, 2H) ), 2.24-2.17 (m, 2H). c) 3- (Allyl-benzyloxycarbonyl-amino) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid A solution of 1.56 grams (3.82 mmol) of the methyl ester of 3- (allyl) acid benzyloxycarbonyl-amino) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid in 25 milliliters of methanol, treated with 8 milliliters of 1N aqueous sodium hydroxide. After 3 hours, the homogeneous mixture is acidified with 1N aqueous hydrochloric acid, and extracted with EtOAc. The organic phase is washed with water, dried over sodium sulfate and evaporated to give a yellowish foam. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (325 minutes), 100 percent MeCN (075 minutes)): 2475 minutes MS (ES +) 395 = [M + H ] * 1 H-NMR (400 MHz, CDCl 3): 8.17 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.40-731 (m, 5H), 6.01-590 (m, 1H) , 5.25-5.18 (m, 2H), 5.21 (s, 2H), 4.39-4.35 (m, 2H), 3.88 (t, 2H), 2.68 (t, 2H), 2.26-2.18 (m, 2H). A20 building block: 3- (allyl-benzyloxycarbonyl-amine) -5-t-azo I -2-M-benzoic acid a) 3-benzyloxycarbonyl-amino-5-iodo -benzoic acid To a stirred suspension of 4.66 grams (16.8 millimoles) of the 3-amino-5-iodo-benzoic acid methyl ester (J. Med. Chem 1973, 16, 684) in 16 milliliters of dichloro- methanol and 16 milliliters of 10 percent aqueous sodium bicarbonate, 84 milliliters of benzyl chloroformate (50 percent solution in toluene) are added dropwise. After 3 hours, the phases are separated, the organic phase is dried over sodium sulfate, and the solvent is evaporated. The product is crystallized from EtOAc / hexanes Rf: (hexane / EtOAc, 3: 1): 0.30 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 3,580 minutes. MS (ES +): 434 = [M + Na] * 1 H-NMR (400 MHz, CDCl 3) 8.20 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 747-738 (m, 5H) ), 680 (br s, NH), 525 (s, 2H), 394 (s, 3H) b) 3-benzyloxycarbonyl-amino-5-thiazol-2-yl-benzoic acid methyl ester A mixture of 1 gram (2.4 millimoles) of 3- (allyl-benzyloxycarbonyl-amino) -5-thiazole-2-yl-benzoic acid methyl ester, 1 gram (2.67 millimoles) of 2-tributyl-stanyl-thiazole, 84 milligrams (0.12 millimoles) of PdCI2 (PPh3) 2 and 20 milligrams of Cul in 10 milliliters of dioxane are refluxed until the reaction is stopped (according to the TLC analysis). The mixture is diluted with MeCN and washed twice with hexane. The polar phase is concentrated and stirred vigorously with a solution of 1 gram of potassium fluoride in 10 milliliters of water. The mixture is filtered over High-flow, and then heated to 60 ° C in the presence of 2 grams of sodium dithionite and 2 grams of carbon. The mixture is again filtered over High-flow, and further purified by chromatography on silica gel (hexane / EtOAc, 8: 1, 6: 1, 4: 1, 2: 1, 1: 2), to give a solid. yellow. Rf: (hexane / EtOAc, 3: 1): 0.18 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 3,254 minutes MS (ES +): 369 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.36 (s, 1H), 8.35 (s, 1H), 8.18 (S, 1H), 7.94 (d, 1H) , 7.49-7.40 (m, 6H), 6.95 (br s, NH), 5.28 (s, 2H), 3.98 (s, 3H). c) 3- (Allyl-benzyloxy-carbonyl-amino) -5-thiazole-2-yl-benzoic acid methyl ester A suspension of 257 milligrams (0.6981 mmol) of 3-benzyloxycarbonyl methyl ester -amino-5-thiazol-2-yl-benzoic acid, 0.12 milliliters (1.4 mmol) of allyl bromide, and 193 milligrams (1.4 mmol) of potassium carbonate in 4 milliliters of dimethyl formamide, is stirred for 4 hours . The mixture is diluted with water and extracted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. The product is purified by chromatography on silica gel (EtOAc / hexanes, 1: 6, 1: 4, 1: 2, 1: 1), to give a resin. Rf: (hexane / EtOAc, 1: 1): 0.41 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 2,499 minutes MS (ES +): 409 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.47 (s, 1H), 8.17 (br s, 1H), 8.02 (br s, 1H), 7.93 (d, 1H), 7.43 (d, 1H), 7.39-7.30 (m, 5H), 6.01-5.91 (m, 1H), 5.23 (s, 2H), 5.24-5.19 (m, 2H), 4.42-4.39 (m, 2H), 3.99 (s, 3H). d) 3- (Allyl-benzyloxy-carbonyl-amino) -5-thiazol-2-yl-benzoic acid A solution of 181 milligrams (0.444 mmol) of 3- (allyl-benzyloxycarbonyl-amino) methyl ester -5-thiazol-2-yl-benzoic acid in 1 milliliter of methanol is treated with 1 milliliter of 1N aqueous sodium hydroxide. After 18 hours, the mixture is acidified with 1 N aqueous hydrochloric acid to a pH of 2 to 3, and extracted with EtOAc. The organic phase is washed with water, dried over sodium sulfate, and evaporated to give a yellow resin. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent of MeCN (3.25 minutes), 100 percent of MeCN (0.75 minutes)): 2,916 minutes. MS (ES +): 395 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.62 (s, 1H), 8.20 (br s, 1H), 8.10 (s, 1H), 8.00 (d, 1H ), 7.47 (d, 1H), 7.40-7.31 (m, 5H), 6.04-5.92 (, 1H), 5.25-5.20 (m, 2H), 5.24 (s, 2H), 4.40-4.40 (m, 2H) . A21 building block: 3- (allyl-benzyloxycarbonyl-amino) -5- [1,3] -dioxolan-2-i-benzoic acid a) 3-nitro-5- (3-nitro-5-methyl ester tetrahydro-pyran-2-yloxy-methyl) -benzoic acid To a solution of 5.0 grams (23.68 mmol) of the methyl ester of 3-hydroxy-methyl-5-nitro-benzoic acid in 50 milliliters of dichloromethane, 2.38 milliliters are added. (26.0 mmol) of 3,4-dihydro-2H-pyran and 299 milligrams (1.28 mmol) of the (±) -canfor-1-sulfonic acid, and the mixture is stirred for 1 hour. After the reaction is complete, the mixture is washed with 5 percent aqueous sodium bicarbonate, dried over sodium sulfate, and chromatographed on silica gel (hexane / EtOAc, 3: 1) to give a solid white. Rf: (hexane / EtOAc 3: 1): 0.41 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20 -100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)): 5,408 minutes MS (ES +): 318 = [M + Na] * 1 H-NMR (400 MHz, CDCl 3): 8.80 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 4.97 (d, 1H, J = 15), 4.81-4.79 (m, 1H), 4.67 (d, 1H, J = 15), 4.02 (s, 3H), 3.98-3.89 (m, 1H), 3.65-3.59 (m, 1H), 1.99-1.58 (m, 6H). b) 3-amino-5- (tetrahydro-pyran-2-yloxy-methyl) -benzoic acid methyl ester A solution of 6.61 grams (22.38 mmol) of 3-nitro-5- (tetrahydro-) methyl ester pyran-2-yloxy-methyl) -benzoic acid, is hydrogenated in tetrahydrofuran in the presence of 0.66 grams of 5% Pt / C (Engelhard 4709) for 5 hours. The mixture is filtered over High-flow and concentrated to give a yellow material, which is used for the next step without further purification. Rf: (EtOAc / hexane, 1/3): 0.12 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20 -100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) : 3.012 minutes MS (ES +): 266 = [M + H] * c) 3-Benzyloxy-carbonyl-amino-5- (tetrahydro-pyran-2-yloxy-methyl) -benzoic acid methyl ester To a stirred mixture of 5.93 grams (22.35 mmol) of the 3-amino-5- (tetrahydro-pyran-2-yloxy-methyl) -benzoic acid methyl ester and 30 milliliters of 10 percent aqueous sodium bicarbonate in 30 milliliters tetrahydrofuran, are added by dripping 8.96 milliliters of benzyl chloroformate (50 percent in toluene). After 2 hours, the mixture is extracted with EtOAc. The organic phase is washed with water, dried over sodium sulfate, and the product is crystallized from EtOAc / hexane, to give white crystals. Rf: (EtOAc / hexane, 1/2): 0.47 HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20 -100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)) : 5,758 minutes. MS (ES +): 422 = [M + Na] * 1 H-NMR (400 MHz, CDCl 3): 7.99 (s, 1 H), 7.79 (s, 1 H), 7.72 (s, 1 H), 7.48-7.36 (m, 5H), 6.81 (br s, NH), 5.25 (s, 2H), 4.84 (d, 1H, J = 15), 4.76-4.73 (m, 1H), 4.54 (d, 1H, J = 15), 3.99 -3.90 (m, 1H), 3.94 (s, 3H), 3.62-3.53 (m, 1H), 1.95-1.58 (m, 6H). d) 3-benzyloxycarbonyl-amino-5-hydroxy-methyl-benzoic acid methyl ester A suspension of 4 grams (10 mmol) of 3-benzyloxycarbonyl-amino-5- (tetrahydroxy) methyl ester piran-2-yloxy-methyl) -benzoic acid and 200 milligrams (0.86 mmol) of the (±) -canfor-10-sulfonic acid in 50 milliliters of methanol and 5 milliliters of tetrahydrofuran, is stirred for 18 hours. The homogeneous solution is quenched with 10 percent aqueous sodium bicarbonate, and extracted with EtOAc. The organic phase is washed with brine, dried over sodium sulfate, and concentrated to give a white crystalline solid.

Rf: (EtOAc / hexane, 1/2): 0.16 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) 2,315 minutes MS (ES +): 298 = [M-OH] * '338 = [M + Na] * 1 H-NMR (400 MHz, CDCl 3): 7.94 (s, 1 H), 7.79 (s, 1 H), 7.77 (s, 1H), 7.47-7.36 (m, 5H), 7.05 (br s, NH), 5.24 (s, 2H), 4.75 (s, 2H), 3.92 (s, 3H). e) 3-benzyloxy-carbonyl-amino-5-formyl-benzoic acid methyl ester A suspension of 3.16 grams (10 mmol) of 3-benzyloxycarbonyl-amino-5-hydroxy-methyl-benzoic acid methyl ester and 8.71 grams (100 millimoles) of manganese oxide (IV), is stirred at 55 ° C for 3 hours. After cooling, the mixture is filtered over High-flow and evaporated, to provide a crystalline solid, which is used for the next step without further purification. Rf: (EtOAc / hexane, 1/2): 0.47 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 2.950 minutes MS (ES +): 298 = [M-OH] * '338 = [M + Na] * 1 H-NMR (400 MHz, CDCl 3): 10.09 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.27 (s, 1H), 7.77 (s, 1H), 7.48-7.39 (m, 5H), 7.05 (br s, NH), 5.28 (s, 2H), 3.98 (s, 3H). f) 3-benzyloxycarbonyl-amino-5- [1,3] -dioxolan-2-yl-benzoic acid methyl ester A 2.72 gram solution (8.68 millimoles) of 3-benzyloxycarbonyl methyl ester -amino-5-formyl-benzoic acid and 0.58 milliliters of ethylene glycol in 40 milliliters of toluene and 40 milliliters of cyclohexane, is heated to the reflux temperature in the presence of 54 milligrams of the (±) -canfor-10-sulphonic acid under removal continuous of water. After the reaction is completedThe mixture is diluted with tert-butyl methyl ether and washed with 10 percent aqueous sodium bicarbonate. The organic phase is washed with water, dried over sodium sulfate and evaporated. The product is used for the next step without further purification. HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20 -100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)): 5,040 minutes. MS (ES +): 358 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.05 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.48-7.38 (m, 5H), 6.94 (br S, NH), 5.87 (s, 1H), 5.25 (S, 2H), 4.19-4.05 (m, 4H), 3.93 (s, 3H). g) 3- (Allyl-benzyloxy-carbonyl-amino) -5- [1,3] -dioxolan-2-yl-benzoic acid methyl ester A suspension of 3.25 grams (9.09 mmol) of methyl 3-methyl ester -benzyloxy-carbonyl-amino-5- [1,3] -dioxolan-2-yl-benzoic acid, 1.54 milliliters (18.19 mmol) of allyl bromide, and 2.51 grams (18.19 mmol) of potassium carbonate in 7 milliliters of dimethyl - formamide, is stirred at 50 ° C for 4 hours. The mixture is diluted with water and extracted with EtOAc. The organic phase is washed three times with water and dried over sodium sulfate. The product is purified by chromatography on silica gel (EtOAc / hexanes, 1: 3, 1: 2, 1: 1) to give a yellow oil. Rf: (EtOAc / hexane, 1/3): 0.24 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 2.950 minutes MS (ES +): 298 = [M-OH] *: 338 = [M + Na] * 1 H-NMR (400 MHz, CDCl 3): 10.09 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.27 (s, 1H), 7.77 (s, 1H), 7.48-7.39 (m, 5H), 7.05 (br s, NH), . 28 (s, 2H), 3.98 (s, 3H). h) 3- (Allyl-benzyloxy-carbonyl-amino) -5- [1,3] -dioxolan-2-yl-benzoic acid A solution of 3.22 grams (8.1 mmol) of the methyl ester of 3- (allyl) acid benzyloxy-carbonyl-amino) -5- [1, 3] -dioxolan-2-i-benzoic acid in 15 milliliters of methanol, treated with 20 milliliters of 1N aqueous sodium hydroxide. After some time, the reaction mixture becomes homogeneous. After 2 hours, the mixture is acidified with 1N HCl and extracted with EtOAc. The organic phase is washed with water, dried over sodium sulfate, and evaporated to give a yellowish oil. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 2.674 minutes.

MS (ES +): 384 = [M + H] + 1 H-NMR (400 MHz, CDCl 3): 8.13 (s, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.40-7.31 (m, 5H), 6.01-5.89 (m, 1H), 5.89 (s, 1H), 5.27-5.18 (m, 2H), 5.22 (s, 2H), 4.40-4.34 (m, 2H), 4.20-4.05 (m, 4H). Building block A22: 3-allyloxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid a) 3-bromo-5-nitro-benzoic acid To the solution of 7.92 grams (43 mmol) of acid 3 -amino-5-nitro-benzoic acid in 4 milliliters of water in an ice bath, 48.8 milliliters (434 millimoles, 10 equivalents) of 48% aqueous HBr are added. A saturated aqueous solution of 4. 05 grams (59 millimoles, 1.35 equivalents) of sodium nitrite for 10 minutes. The solution obtained is added to the solution of 9. 36 grams (65 millimoles, 1.5 equivalents) of copper bromide in 48.8 milliliters (434 millimoles, 10 equivalents) of aqueous HBr at 48 percent at 70 ° C. The mixture is heated for 45 minutes at 70 ° C.

After cooling to room temperature, diethyl ether is added, and the organic layer is washed with water until a neutral pH is reached. Drying over sodium sulfate and evaporation of the solvent under reduced pressure give the product as a yellow solid.

MS (ES-): 245/247 = [M + H] * 1 H-NMR (400 MHz, d6-DMSO): 8.65 (s, 1H), 8.57 (s, 1H), 8.44 (s, 1H). b) 3-Nitro-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid The mixture of 3.37 grams (13.7 millimoles) of 3-bromo-5-nitro-benzoic acid, 1.74 grams (27.4 millimoles, 2 equivalents) of copper powder, 3.18 milliliters (41 millimoles, 3 equivalents) of 2-pyrrolidinone, and 1.89 grams (13.7 millimoles, 1 equivalent) of potassium carbonate, is stirred at 150 ° C for 16 hours. Add another 10 milliliters of 2-pyrrolidinone, 1.74 grams (27.4 millimoles, 2 equivalents) of copper powder, and 1.89 grams (13.7 millimoles, 1 equivalent) of potassium carbonate, and the mixture is again vigorously stirred for 5.5 hours at 150 ° C. After cooling to room temperature, the reaction is diluted with dichloromethane and 5 percent aqueous potassium carbonate. The solids are filtered, and the aqueous layer is acidified with a 10 percent aqueous potassium hydrogen sulfate solution. Extraction with dichloromethane, drying over sodium sulfate, and evaporation of the solvent under reduced pressure give some of the product. Upon standing, more product is precipitated from the aqueous layer, filtered, and dried under vacuum. MS (LC / MS): 273 = [M + H + Na] * 1 H-NMR (400 MHz, d 6 -DMSO): 8.83 (s, 1 H), 8.52 (s, 1 H), 8.37 (s, 1 H). 3.98 (t, 2H), 2.60 (t, 2H), 2.16-2.08 (m, 2H). c) 3-Amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid To the solution of 2.19 grams (8.75 mmol) of 3-nitro-5- (2-oxo-pyrrolidin-1-yl) ) -benzoic acid in 50 milliliters of MeOH / THF, 3/2, 0.2 grams of Pd / C (10 percent, Engelhard 4505) are added and the reaction is stirred at room temperature under hydrogen (1 atmosphere) for 18 hours . After filtering through Celite, the solvent is evaporated under reduced pressure to give the product. MS (ES-): 219 = [MH] "1 H-NMR (400 MHz, d6-DMSO): 7.34 (s, 1H), 7.18 (s, 1H), 6.98 (s, 1H) .5.46 (br s, 2H), 3.79 (t, 2H), 2.49 (t, 2H), 2.10-1.99 (m, 2H) d) 3-Hydroxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid solution of 1.33 grams (6.0 millimoles) of 3-amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid in 15 milliliters of water and 0.75 milliliters (13.3 millimoles, 2.2 equivalents) of concentrated sulfuric acid, a 0 ° C, 0.56 grams (8.2 millimoles, 1.35 equivalents) of sodium nitrite are added, after the addition of 10 milliliters of water, the reaction is heated to 90 ° C. After cooling to room temperature, the reaction is extract with EtOAc, the organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure to give the product MS (ES-): 220 = [MH] "1 H-NMR (400 MHz, d6-DMSO) : 9.86 (s, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.13 (s, 1H), 3.83 (t, 2H), 2.51 (t, 2H), 2.10-2.02 (m, 2H) ). e) 3-Allyloxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid To the solution of 1.57 grams (7.1 mmol) of 3-hydroxy-5- (2-oxo-pyrrolidin-1-yl) ) -benzoic acid in 5 milliliters of dimethylformamide, add 1.02 grams (21.3 millimoles, 3 equivalents) of 50 percent sodium hydride in oil. After the gas evolution is stopped, 2.53 milliliters (28.4 millimole, 4 equivalents) of allyl bromide are added, and the reaction mixture is stirred for 4 days at 60 ° C. The reaction is diluted with water and extracted with EtOAc. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The resulting ester is redissolved in 40 milliliters of methanol, and 0.347 grams (8.2 millimoles, 1.2 equivalents) of lithium hydroxide monohydrate are added. The reaction is stirred at room temperature for 48 hours. After evaporation of part of the solvent under reduced pressure, the reaction is taken up in water and washed with EtOAc. The aqueous layer is acidified with potassium acid sulfate and extracted with EtOAc. Drying over sodium sulfate and evaporation of the solvent under reduced pressure give the product. MS (LC / MS): 284 = [M + H + Na] * 1 H-NMR (400 MHz, CDCl 3): 7.91 (s, 1 H), 7.72 (s, 1 H), 7.47 (s, 1 H), 6.14- 6.05 (m, 1H), 5.49 (d, 1H), 5.35 (d, 1H), 4.65 (d, 2H), 3.95 (t, 2H), 2.69 (t, 2H), 2.26-2.17 (m, 2H) . Construction block A23: 2- (allyl-benzyloxycarbonyl-amino) -6-methyl-isonicotinic acid The title compound is obtained by a reaction sequence analogous to that described for the A3 building block (eg steps), starting from from the ethyl ester of 2-amino-6-methyl-isonicotinic acid (building block A17b). HPLC (Nucleosil C-18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 5.04 minutes. MS (LC / MS, ES +): 327 = [M + H] *. 1 H-NMR (400 MHz, CDCl 3): 8.15 (s, 1H), 7.54 (s, 1H), 7.44-7.30 (m, 5H), 6.03-5.93 (m, 1H), 5.30 (s, 2H), 5.20 (d, 1H), 5.14 (d, 1H), 4. 71 (d, 2H), 2.61 (s, 3H). Building Block C1: (S) -3- (3-Benzyloxy-phenyl) -2-terbutoxy-carbonyl-amino-propionic acid methyl ester The non-natural amino acid building block C1 is prepared, for example, as discloses in Tetrahedron, 2002, 58, 6951-6963, or in J. Am. Chem. Soc, 1993, 115, 10125-10138 (mp: 80-81 ° C). [a] D22: + 39.1 ° (c = 1.29, CHCI3). Rf (DCM / EtOAc = 90/10): 0.69. MS (ES +): 408 = [M + Na] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.45-7.29 (m, 5H), 7.27 (d, 1H), 7.18 (t, 1H), 6.89 (s, 1H), 6.87-6.81 (m, 1H) , 6.79 (d, 1H), 5.06 (s, 2H), 4.21-4.14 (m, 1H), 3.60 (s, 3H), 2.99-2.92 (m, 1H), 2.84-2.77 (m, 1H), 1.33 (s, 9H). Construction block C2: (S) -3- (3-bromo-phenyl) -2-terbutoxy-carbonyl-amino-propionic acid methyl ester The product is prepared analogously to the C1 building block, using 3- bromo-benzaldehyde in place of 3-benzyloxy-benzaldehyde (mp: 60-61 ° C). [a] D22: + 50.8 ° (c = 1.00, CHCI3). Rf (DCM / EtOAc = 90/10): 0.54. MS (ES +): 380 = [M + Na] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.44 (s, 1 H), 7.41-7.36 (m, 1 H), 7.30 (d, 1 H), 7.23 (d, 2 H), 4.23-4.15 (m, 1 H) , 3.62 (s, 3H), 3.04-2.98 (m, 1H), 2.87-2.79 (m, 1H), 1.32 (s, 9H). Construction block C3: (S) -3- (3-allyloxy-phenyl) -2-terbutox -carbonyl-l-am-non-propionic acid methyl ester a) Methyl ester of (S) -2 acid -tertbutoxy-carbonyl-amino-3- (3-hydroxy-phenyl) -propionic A solution of 5.81 grams (15 mmol) of the building block C1 in 150 milliliters of EtOH is stirred at room temperature in the presence of 1.5 grams of Pd / C (at 10 percent) under a hydrogen atmosphere for 2 hours. The catalyst is filtered, and the filtrate is evaporated, to give the product in the form of a colorless solid (m.p.:61-65CC). Rf (DCM / EtOAc = 80/20): 0.34. MS (ES +): 318 = [M + Na] X 1 H-NMR (400 MHz, DMSO-d 6): 9.27 (s, 1H), 7.22 (d, 1H), 7.04 (t, 1H), 6.63-6.56 ( m, 3H), 4.15-4.07 (m, 1H), 3.60 (s, 3H), 2.91-2.84 (m, 1H), 2.79-2.71 (m, 1H), 1.33 (s, 9H). b) (S) -3- (3-allyloxy-phenyl) -2-terbutoxycarbonyl-aminopropionic acid methyl ester To a solution of 2.34 grams (7.5 millimoles) of the methyl ester of the acid (S) ) -2-terbutoxy-carbonyl-amino-3- (3-hydroxy-phenyl) -proponic acid in 15 milliliters of acetone, 1.25 grams (9.75 millimoles) of K2C03 powder and 0.76 milliliters (9 millimoles) of bromide are added. alilo. The reaction mixture is stirred for 16 hours at 80 ° C, diluted with 15 milliliters of water, and extracted with dichloromethane (15 milliliters, 2 times). The combined organic layers are washed with 7.5 milliliters of 1M sodium hydroxide, and then 7.5 milliliters of half-saturated sodium chloride, dried over sodium sulfate and evaporated, to give the product in the form of a colorless solid (mp. : 50 - 51 ° C). [a] D22: + 40.9 ° (c = 1.18, CHCI3). Rf (DCM / EtOAc = 80/20): 0.70. MS (ES +): 358 = [M + Na] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.25 (d, 1H), 7.17 (t, 1H), 6.83-6.75 (m, 3H), 6.08-5.97 (m, 1H), 5.40-5.34 (m, 1H), 5.26-5.21 (m, 1H), 4.52 (d, 2H), 4.19-4.12 (m, 1H), 3.61 (s, 3H), 2.98-2.92 (m, 1H), 2. 84-2.77 (m, 1H), 1.33 (s, 9H). Construction block C4: (S) -3- (3-allyl-f in i I) -2-tert-butoxycarbon I-non-pro pion methyl ester A solution of 4.21 grams (11.75 millimoles) ) of the C2 building block, 5.58 milliliters (17.6 millimoles) of allyltributyl tin, and 1.51 grams (35.3 millimoles) of lithium chloride in 118 milliliters of N, N-dimethyl acetamide is degassed. Under an argon atmosphere, 367 milligrams (0.59 millimoles) of SK-CC02-A are added, and the reaction mixture is heated at 100 ° C for 17 hours. After the addition of 41 milliliters of a saturated solution of potassium fluoride at 0 ° C, the reaction mixture is stirred at room temperature for 30 minutes, and then filtered and washed with EtOAc (59 milliliters, 3 times). The filtrate layers are separated, the aqueous phase is extracted with 179 milliliters of EtOAc, and the combined organic layers are washed with water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (cyclohexane / EtOAc, 90/10), which gives the product in the form of a yellow oil. Rf (cyclohexane / EtOAc = 80/20): 0.31. MS (ES +): 342.1 = [M + Na] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.26 (d, 1H), 7.19 (t, 1H), 7.06-6.99 (m, 3H), 5.98-5.87 (m, 1H), 5.18-5.00 (m, 2H), 4.18-4.10 (m, 1H), 3.59 (s, 3H), 3.32 (d, 2H), 2.98-2.91 (m, 1H), 2.87-2.79 (m, 1H), 1.32 (s, 9H) .

C5 building block: ((1S.2R) -1- (3-Allyl-benzyl) -3-. {-benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] - tertiary butyl ester - amino.} -2-hydroxy-propyl) -carbamic a) [(S) -1- (3-allyl-benzyl) -3-chloro-2-oxo-propyl-carbamic acid terbutyl ester A solution of 1.95 grams (6.1 millimoles) of the C4 building block in 61 milliliters of tetrahydrofuran is cooled to -78 ° C and 1.8 milliliters (24.4 millimoles) of chloro-iodo-methane are added. 20.8 milliliters (30.5 millimoles) of a 1.47 M solution of lithium diisopropyl amide in tetrahydrofuran are added dropwise, while the temperature of the reaction mixture is kept below -73 ° C. The reaction mixture is stirred for 30 minutes and then carefully quenched with 9.1 milliliters (159 millimoles) of glacial acetic acid, while the temperature is maintained below -65 ° C. After stirring for 15 minutes at -78 ° C, the reaction mixture is allowed to warm to 0 ° C, diluted with 92 milliliters of medium-saturated aqueous sodium chloride, and extracted with tert-butyl-methyl ether (92 milliliters). , 2 times). The combined organic layers are washed with 92 milliliters of 1 M sodium sulfite, and then 92 milliliters of water, dried over sodium sulfate and evaporated, to give the product. Rf (cyclohexane / EtOAc = 80/20): 0.34. MS (LC / MS): 359.8 = [M + Na] *. b) [(1 S, 2S) -1- (3-allyl-benzyl) -3-chloro-2-hydroxy-propyl-carbamic acid terbutil-ester A solution of 471 milligrams (12.2 mmol) of sodium borohydride in 44 milliliters of EtOH is cooled to -78 ° C, and a solution of 3.2 grams (6.1 millimoles) of [(S) -1- (3-allyl-benzyl) -3-chloro acid] tert-butyl ester is added dropwise. -2-oxo-propyl] -carbamic acid in 90 milliliters of ethanol, while the temperature of the reaction mixture is maintained below -75 ° C. The reaction mixture is stirred at -78 ° C for 1 hour, and then allowed to warm to room temperature within 17 hours. At -78 ° C, 31 milliliters of 1M HCl are added dropwise. The reaction mixture is allowed to warm to room temperature, the ethanol is evaporated, and the residual aqueous solution is extracted with EtOAc (61 milliliters, 2 times). The combined organic layers are washed with 61 milliliters of a half-saturated solution of sodium chloride, dried over sodium sulfate, and evaporated. The residue is purified by chromatography on silica gel (cyclohexane / EtOAc, 90/10 to 80/20), and gives the product in the form of a pale brown solid (mp .: 123-126 ° C). Rf (cyclohexane / EtOAc = 80/20): 0.19. MS (ES +): 362.2 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.15 (t, 1H), 7.04-6.94 (m, 3H), 6.67 (d, 1H), 5.97-5.87 (m, 1H), 5.40 (d, 1H) , 5.09-4.99 (m, 2H), 3.68-3.52 (m, 3H), 3.49-3.43 (m, 1H), 3.00-2.94 (m, 1H), 2.58-2.52 (m, 1H), 1.28 (s, 9H). c) [(S) -2- (3-allyl-phenyl) -1- (S) -oxiranyl-ethyl] -carbamic acid terbutyl ester A solution of 3.20 grams (10.5 millimoles) of the acid terbutilus [ (1S, 2S) -1 - (3-allyl-benzyl) -3-chloro-2-hydroxy-propyl] -carbamic acid in a mixture of 19 milliliters of tetrahydrofuran, 19 milliliters of methanol, and 21 milliliters (21 millimoles, 2 equivalents) of 1N aqueous sodium hydroxide, is stirred at room temperature for 3 hours. The reaction mixture is diluted with 80 milliliters of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane. The organic layer is dried over sodium sulfate and evaporated to give the product. MS (LC / MS): 326 = [M + Na] *. 1 H-NMR (400 MHz, CDCl 3): 7.27 (d, 1H), 7.12-7.08 (m, 3H), 6. 05-5.94 (m, 1H), 5.13 (d, 1H), 5.09 (s, 1H), 4.47 (br s, 1H), 3.71 (br s, 1H), 3.41 (d, 2H), 3.01-2.78 ( m, 5H), 1.42 (s, 9H). d) Terbutil-acid ester. { (1S, 2R) -1- (3-allyl-benzyl) -2-hydroxy-3- [1- (3-isopropyl-phenyl I) -cyclopropi-1-yl] -propyl} -carbamic The [(S) -2- (3-allyl-f-enyl) -1 - (S) -oxiranyl-ethyl] -carbamic acid terbutil ester (2.4 grams, 7.04 mmol, 1 equivalent) is dissolved in 1- (3-isopropyl-phenyl) -cyclopropyl-amine (building block D1, 5.13 grams, 24.2 mmol, 3.44 equivalents). The reaction mixture is heated at 80 ° C for 15 hours, and purified by column chromatography using diethyl ether / NH3 (25 percent in H20) in a ratio of 200 to 1, to give the product. MS (ES +): 479 = [M + H] *. HPLC (Nucleosil C18HD, 20-100 percent MeCN) retention time: 5.11 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.28-7.03 (m, 8H), 6.03-5.92 (m, 1H), 5.13-5.02 (m, 2H), 4.52 (d, 1H), 3.80-3.68 (m, 1H), 3.40-3.34 (m, 3H), 3.02-2.77 (m, 3H), 2.72 (d, 2H), 1.33 (s, 9H), 1.26 (d, 6H), 1.03-0.90 (m, 4H). e) ((1S, 2R) -1- (3-Allyl-benzyl) -3- ({benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -amino) -butyl ester} -2-hydroxy-propyl) -carbamic acid terbutil-ester. { (1S, 2R) -1 - (3-Allyl-benzyl) -2-hydroxy-3- [1 - (3-isopropyl-phenyl) -cyclopropyl-1-yl] -propyl} carbonate (2.7 grams, 5.08 millimoles, 1 equivalent) is dissolved in dichloromethane (25 milliliters). Saturated aqueous Na2C03 is added, followed by CbzCl (50 percent in toluene, 2.04 milliliters, 6.1 mmol, 1.2 equivalents). The reaction mixture is stirred for 2 hours at room temperature, and then diluted with water (80 milliliters) and dichloromethane (160 milliliters). The organic layer is washed with water and then with brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using EtOAc / hexane in a ratio of 1 to 4 to give the product. MS (ES +): 613 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 7.41 minutes. Construction block C6: Terbutil-acid ester ((1S, 2R) - 1 - (3-al i lox i-be nci I) -3-. {Benci lox -carboni l- [1- (3- ter buti lf enyl) -cyclopropy l] -am and no.} -2-hydroxy-propyl) -carbamyl The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the block of C3 and 1 - (3-tert-butyl-phenyl) -cyclopropyl-amine construction (construction block D2). MS (ES +): 643 = [M + H] *. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 7.32 minutes. C7 building block: ((1S.2R) -1- (3-allyloxy-benzyl) -3-. {-benzyloxycarbonyl- [1- (3-isopropyl-phenyl) -cyclopropyl] -terbutyl ester - amino.} -2-hydroxy-propyl) -carbamic acid The product is obtained by a reaction sequence analogous to that of the building block C5, starting from the building block C3. MS (ES +): 629 = [M + H] *.

HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time: 7.23 minutes. Construction block C8: [(2R, 3S) -4- (3-allyl-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-terbutyl) acid benzyl ester l-pyrid-2-yl) -cyclopropyl] -carbamic The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the building block C4 and 1- (4-tert-butyl-pyrid- 2-yl) -cyclopropyl-amine (building block D3). Rf (hexane / EtOAc = 3/2): 0.45. MS (LC / MS, ES +): 628 = [M + H] *. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 3.36 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.39 (br s, 1 H), 7.41 (d, 1 H), 7.4-7.0 (m, 11 H), 6.92 (br s, 1 H), 6.03-5.90 (m, 1 H) , 5.15-5.05 (m, 4H), 4.74 (d, 1H), 3.9-3.75 (m, 2H), 3.4-3.3 (m, 2H), 3.1-2.85 (m, 2H), 1.6-1.2 (m, 4H, 1.35 (s, 9H), 1.32 / 1.26 (s, 9H) .Construction block C9: (S) -3- (3-alkyloxy-4-fluoro-phenyl) -2- terbutoxy-carbon Ia Ia non-propion co a) Methyl ester of 4-fluoro-3-hydroxy-benzoic acid The 4-fluoro-3-hydroxy-benzoic acid (24.7 grams, 112.8 mmol) is dissolved in methanol ( 300 milliliters) and cooled to 0 ° C. Thionyl chloride (15 milliliters) is added dropwise, and the mixture is then heated at 70 ° C for 60 minutes. The reaction mixture is concentrated in vacuo, taken up in EtOAc, and washed with a saturated solution of sodium bicarbonate, followed by saturated brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a white solid. HPLC / MS (SunFire C18 20 x 4.6 millimeters, 3.5 microns, reverse phase; column temperature of 40 ° C, 3 milliliters / minute, 05-100 percent MeCN containing 0.1 percent trifluoroacetic acid (4 minutes), retention time: 2.34 minutes. MS (LC / MS, ES +): 171 = [M + H] * 1 H-NMR (400 MHz, DMSO-d 6): 10.40 (s, 1 H), 7.65 (dd, 1 H), 7.40 (m, 1 H), 7.35 (m, 1H), 3.80 (s, 3H). b) 3-allyloxy-4-fluoro-benzoic acid methyl ester The 4-fluoro-3-hydroxy-benzoic acid methyl ester (26.3 grams, 154.5 mmol) is dissolved in acetone (300 milliliters). Potassium carbonate (42.7 grams, 305.8 millimoles) is added, followed 5 minutes later by the addition of allyl bromide (20 milliliters, 229 millimoles). The reaction mixture is stirred overnight at room temperature, concentrated in vacuo, and then diluted with ether and water. The organic layer is washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to give the product as a colorless oil. 1 H-NMR (400 MHz, DMSO-d 6): 7.67 (dd, 1H), 7.60 (m, 1H), 7.40 (dd, 1H), 6.1-6.0 (m, 1H), 5.45-5.30 (m, 2H) 4.72 (d, 2H), 3.85 (s, 3H). c) (3-allyloxy-4-fluoro-phenyl) -methanol The methyl ester of 3-allyloxy-4-fluoro-benzoic acid (5.0 grams, 23.5 mmol) is dissolved in tetrahydrofuran under an argon atmosphere. A solution of lithium aluminum hydride (17.7 milliliters, 1M in tetrahydrofuran, 17.7 millimoles) is added at room temperature, and the reaction mixture is stirred at room temperature for 55 minutes, quenched by the drip addition of water, and then solid sodium sulfate is added. The resulting aqueous paste is filtered through Celite, and the filter cake is washed with methanol. The filtrate is absorbed on silica and purified by chromatography on silica (EtOAc) to give the product as a colorless oil. HPLC / MS (SunFire C18 20 x 4.6 millimeters, 3.5 microns, reverse phase, column temperature of 40 ° C, 3 milliliters / minute, 05-100 percent MeCN containing 0.1 percent trifluoroacetic acid (4 minutes), retention time: 2.52 minutes MS (LC / MS, ES +): 205 = [M + Na] * 1 H-NMR (400 MHz, DMSO-d6): 7.15 (dd, 1H), 7.10 (dd, 1H), 6.87 (m, 1H), 6.1-6.0 (m, 1H), 5.45-5.30 (m, 2H), 4.60 (d, 2H), 4.42 (s, 2H), d) 2-allyloxy-4- clo ro-met il-1 -f luo ro-benzene A solution of (3-allyloxy-4-fluoro-phenyl) -methanol (3.76 grams, . 7 mmol) in thionyl chloride (3.04 milliliters, 41.3 mmol) is mixed at 0 ° C, and then stirred at room temperature for 2.5 hours. Excess thionyl chloride is evaporated, the residue is diluted with dichloromethane and 1M aqueous sodium carbonate. The layers are separated, the aqueous phase is extracted with dichloromethane, the combined organic layers are dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (hexane / Et20, 95/5) to give the product as a yellowish oil. Rf (hexane / Et20 = 80/20): 0.54. 1 H-NMR (400 MHz, DMSO-d 6): 7.25 (dd, 1H), 7.20 (dd, 1H), 7.03-6.99 (m, 1H), 6.09-5.99 (m, 1H), 5.41 (dd, 1H). , 5.28 (dd, 1H), 4.71 (s, 2H), 4.65-4.63 (m, 2H). e) 2-Acetyl-amino-2- (3-allyloxy-4-fluoro-benzyl) -malonic acid diethyl ester Sodium metal (324 milligrams, 14.0 mmol) in EtOH (18 milliliters) is slowly dissolved. To this solution are added the diethyl ester of 2-acetyl-amino-malonic acid (3.45 grams, 15.4 millimoles) and a solution of 2-allyloxy-4-chloro-methyl-1-fluoro-benzene (2.81 grams, 14.0 millimoles) in EtOH. The mixture is heated at 85 ° C for 18 hours. The solvent is removed under reduced pressure, and the residue is dissolved in DCM / EtOH (80:20) and washed with water. After retro-washing the aqueous layer with DCM / EtOH (80:20), the combined organic layers are dried over sodium sulfate and evaporated. The residue crystallizes on standing and is washed with hexane (3 times) to give the product as colorless crystals. p.f .: 53 - 57 ° C Rf (DCM / MeOH = 99/1): 0.21. MS (ES +): 382 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 8.13 (s, 1H), 7.08 (dd, 1H), 6.67 (dd, 1H), 6.55-6.51 (m, 1H), 6.08-5.99 (m, 1H) , 5.36 (dd, 1H), 5.25 (dd, 1H), 4.57 (d, 2H), 4.12 (q, 4H), 3.36 (s, 2H), 1.95 (s, 3H), 1.16 (t, 6H). f) Sodium salt of 2-acetyl-amino-2- (3-allyloxy-4-fluoryl-benzyl) malonic acid monoethyl ester To a solution of 2-acetyl-amino-2-diethyl ester (3-allyloxy-4-fluoro-benzyl) -malonic (5.15 grams, 13.5 mmol) in EtOH (65 milliliters) is added, at 0 ° C, 1N sodium hydroxide (18 milliliters, 18 mmol), and the The mixture is stirred at room temperature for 5 hours. The solvent is evaporated and the residue is used for the next step without further purification. R f (DCM / MeOH / NH 3 = 80/18/2): 0.27 MS (ES +): 354 = [M + H] *, 310 = [M-Ac] * 1 H-NMR (400 MHz, CDCl 3): 6.92 ( dd, 1H), 6.86 (s, 1H), 6.64 (dd, 1H), 6.59-6.55 (m, 1H), 6.07-5.97 (m, 1H), 5.39 (dd, 1H), 5.27 (dd, 1H) , 4.49 (d, 2H), 4.20 (t, 2H), 3.53 (q, 2H), 3.20 (br s, 1H), 1.97 (s, 3H), 1.26 (t, 3H). g) 2-Acetyl-amino-3- (3-allyloxy-4-fluoro-phenyl) -propionic acid ethyl ester A solution of the sodium salt of 2-acetyl-amino-2- (3-acetyl-2-acetyl ester) allyloxy-4-fluoro-benzyl) -malonic (5.46 grams, 13.3 millimoles) in 53 milliliters of dioxane, is heated at 120 ° C for 1.5 hours. The reaction mixture is diluted with 78 milliliters of dichloromethane and 78 milliliters of water, the layers are separated, and the aqueous phase is extracted with dichloromethane. The combined organic layers are washed with saturated brine, dried over sodium sulfate, and evaporated. The residue is precipitated from cyclohexane, and purified by chromatography on silica gel (cyclohexane / EtOAc, 95/5), which gives the product as a colorless residue that solidifies upon standing. P.f .: 73 - 76 ° C Rf (DCM / MeOH = 98/2): 0.27. MS (ES +): 310 = [M + H] *, 236 = [M-C02Et] X 1 H-NMR (400 MHz, DMSO-d 6): 7.07 (dd, 1H), 7.01 (dd, 1H), 6.76- 6.72 (m, 1H), 6.08-5.98 (m, 1H), 5.38 (dd, 1H), 5.25 (dd, 1H), 4.58 (d, 2H), 4.43-4.37 (m, 1H), 4.03 (q, 2H), 2.93 (dd, 1H), 2.82 (dd, 1H), 1.79 (s, 3H), 1.11 (t, 3H). h) (S) -3- (3-Allyloxy-4-fluoro-phenyl) -2-terbutoxy-carbo-methyl ester or the non-propionyl ester The title compound is obtained by a reaction sequence analogous to that of the building block C13 (steps ce), starting from the ethyl ester of 2-acetyl-amino-3- (3-allyloxy-4-fluoro-phenyl) -propionic acid. mp .: 65-70 ° C Rf (cyclohexane / EtOAc = 70/30): 0.41. MS (ES +): 376 = [M + Na] *, 254 = [M-Boc + H] *. 1 H-NMR (400 MHz, DMSO-d 6): 7.25 (d, 1H), 7.09-7.03 (m, 2H), 6.78-6.74 (m, 1H), 6.08-5.98 (m, 1H), 5.39 (dd, 1H), 5.26 (dd, 1H), 4.59 (d, 2H), 4.19-4.13 (m, 1H), 3.60 (s, 3H), 2.95 (dd, 1H), 2.78 (dd, 1H), 1.31 (s) , 9H). C10 building block: [(2R, 3S) -4- (3-allyloxy-4-fluoro-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- ( 2-tert-butyl-phenyl) -cyclopropyl] -carbamic acid The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the methyl ester of (S) -3- (3-allyloxy-4) -fluoro-phenyl) -2-terbutoxy-carbonyl-amino-propionic acid (C9) and 1- (3-tert-butyl-phenyl) -cyclopropyl-amine (D2). Rf (Cyclohexane / EtOAc = 80/20): 0.20. MS (ES +): 661 = [M + H] *. 1 H-NMR (400 MHz, DMSO-d 6, 120 ° C): 7.29-7.20 (m, 5H), 7.15-7.11 (m, 3H), 6.99-6.94 (m, 2H), 6.85-6.82 (m, 1H ), 6.76-6.72 (m, 1H), 6.15-6.09 (m, 1H), 6.08-5.98 (m, 1H), 5.37 (dd, 1H), 5.23 (dd, 1H), 5.07 (q, 1H), 4.63 (d, 1H), 4.56 (d, 2H), 3.83-3.77 (m, 1H), 3.68 (dd, 1H), 3.59-3.52 (m, 1H), 3.19 (dd, 1H), 2.96 (d, 1H), 2.53 (dd, 1H), 1.79-1.74 (m, 1H), 1.55-1.42 (m, 1H), 1.32-1.17 (m, 2H), 1.26 (s, 9H), 1.22 (s, 9H) , 1.10-1.04 (m, 1H). C11 building block: [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-isopropyl-) acid benzyl ester pyridin-2-yl) -cyclopropyl] -carbamic acid The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the building block C3 and 1- (4-isopropyl-pyridin-2-yl) ) -cyclopropyl-amine (building block D4). Rf (hexane / EtOAc = 1/1): 0.37. MS (LC / MS, ES +): 630 = [M + H] *. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 3.41 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.42 (br s, 1H), 7.36-7.08 (, 8H), 6.91-6.77 (m, 4H), 6.14-6.03 (m, 1H), 5.43 (d, 1H) , 5.30 (d, 1H), 5.15-5.06 (m, 2H), 4.57-4.49 (m, 2H), 3.87 (s, br, 1H), 3.08-2.8 (m, 3H), 1.55-1.15 (m, 6H), 1.36 (s, 9H), 1.29 (d, 3H), 1.21 (d, 3H). Construction block C12: [(2R, 3S) -4- (3-allyl-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (4-i sopropi) acid benzyl ester I-pi ri di n-2-i I) -cic lopropi l] -carbáic The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the building block C4 and 1 - ( 4-isopropyl-pyrid-2-yl) -cyclopropyl-amine (building block D4). Rf (hexane / EtOAc = 3/2): 0.41. MS (LC / MS, ES +): 614 = [M + H] *. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 40-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 3.24 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.37 (br s, 1 H), 7.36 -7.0 (m, 11 H), 6.77 (br s, 1 H), 6.02-5.90 (m, 1 H), 5.15-5.05 (m, 4H), 4.74 (s, br, 1H), 3.9-3.75 (m, 2H), 3.4-3.3 (m, 2H), 3.1-2.75 (m, 3H), 1.6-1.2 (m, 4H), 1.35 ( s, 9H), 1.27 (d, 3H), 1.22 (d, 3H). Construction block C13: (S) -3- (3-allyloxy-5-f luoro-f in i I) -2-terbutoxylcarbonyl-am i non-pro pion methyl ester (a) 3 -alloyloxy-5-fluoro-benzaldehyde A solution of 14.78 grams (64 millimoles) of the 1-allyloxy-3-bromo-5-fluoro-benzene (CAS 477956-04-0) in 500 milliliters tetrahydrofuran is cooled to -85 ° C . Drip buty I-1 and uncle (40 milliliters, 1.6 M solution in hexane) are added within 5 minutes. After 5 minutes, a solution of 10 milliliters (128 millimoles) of dimethyl formamide in 20 milliliters of tetrahydrofuran (T <) is added dropwise.; -65 ° C). After the addition, the mixture is stirred for 5 minutes, and then poured into a stirred mixture of 75 milliliters of 2N aqueous hydrochloric acid and ice. The mixture is extracted with tert-butyl methyl ether. The organic phase is washed extensively with water and concentrated. The crude aldehyde is used without purification in the next step. Rf: (hexane / EtOAc 6: 1): 0.48 1 H-NMR (400 MHz, CDCl 3): 9.94 (s, 1H), 7.25-7.18 (m, 2H), 6.95-6.90 (m, 1H), 6.13-6.02 (m, 1H), 5.50-5.34 (m, 2H), 4.64-4.61 (m, 2H). b) 4- [1- (3-allyloxy-5-f luoro-f-enyl) -met- (Z) -ylidene] -2-methyl-4H-oxazol-5-one A mixture of 3-allyloxy-5- crude fluoro-benzaldehyde (64 millimoles), 7.49 grams (64 millimoles) of acetic acid, 5.25 grams (64 millimoles) of sodium acetate, and 32.6 grams (320 millimoles) of acetic anhydride, is heated at 100 ° C for 3.5 hours . After cooling to 70 ° C, the mixture is poured into a mixture of water, EtOH, and ice, and stirred vigorously for 0.5 hour. The solid is filtered, washed with water and hexane, and dried under vacuum to produce a yellow powder. Rf: (hexane / EtOAc 6: 1): 0.44 'H-NMR (400 MHz, CDCl 3): 7.54 (d, 1H), 7.43 (s, 1H), 7.06 (s, 1H), 6.77-6.74 (m, 1H), 6.13-6.03 (m, 1H), 5.52-5.35 (m, 2H), 4.62-4.60 (m, 2H), 2.45 (s, 3H). c) 2-Acetyl-amino-3- (3-allyloxy-5-fluoro-phenyl) -propionic acid methyl ester To a solution of 14.7 grams (56.3 mmol) of 4- [1- (3-allyloxy-5 -fluoro-phenyl) -met- (Z) -ylidene] -2-methyl-4H-oxazol-5-one in 500 milliliters of methanol, add 1 gram of magnesium burrs. The mixture is heated to 40 ° C and after an induction period, an exothermic reaction is initiated. After the magnesium has been consumed, more burrs are added in portions, at a rate such that a temperature of 40-45 ° C is maintained. The total amount of magnesium added is 4.5 grams (187 millimoles). The reaction mixture is poured into a mixture of 200 milliliters of 2N aqueous hydrochloric acid and ice, and extracted with EtOAc. The organic phase is washed with water and 5 percent aqueous sodium bicarbonate, dried over sodium sulfate, and purified by chromatography on silica gel (hexane / EtOAc, 1: 1, 1: 2) followed by crystallization at from EtOAc / hexane, to give colorless crystals. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)): 2.137 minutes. MS (ES +): 296 = [M + H] * H-NMR (400 MHz, CDCl 3): 6.55 (d, 1H), 6.49 (s, 1H), 6.44 (d, 1H), 6.12-6.00 (m, 1H), 5.95 (br d, NH), 4.55 (q, 1H), 4.53 (d, 2H), 3.78 (s, 3H), 3.16-3.05 (m, 2H), 2.05 (s, 3H). d) (S) -3- (3-Allyloxy-5-fluoro-phenyl) -2-terbutoxy-carbonyl-amino-propionic acid The solution of 5.42 grams of the methyl ester of 2-acetyl-amino-3- ( 3-allyloxy-5-fluoro-phenyl) -propionic racemic in 2.4 milliliters of toluene, is added to 40 milliliters of phosphate buffer, pH 7.5. This mixture is treated with 300 microliters of Alcalase Typ DX (Lot: PMN0466) under static pH conditions. When the conversion reaches 48 percent, the reaction mixture is washed with dichloromethane [it is possible to isolate the methyl ester of (R) -3- (3-allyloxy-5-fluoro-phenyl) -2-terbutoxy acid -carbonyl-amino-propionic from organic extracts]. The aqueous phase is adjusted to a pH of 8, and cobalt (II) chloride is added to a final concentration of 0.1mM. After the addition of 400 milligrams of Acylase Amano (Lot: ACV12502), the mixture is stirred at room temperature. When the conversion is complete, 70 milliliters of tetrahydrofuran and 2.53 grams (18.35 millimoles) of sodium carbonate are added. At 0 ° C, 3.0 grams (18.35 mmol) of diterbutyl dicarbonate are added, and the reaction is stirred at room temperature for 5 hours. The organic solvent is evaporated under reduced pressure, and the remaining aqueous phase is acidified to a pH of 3, and extracted with EtOAc. The combined organic layers are dried over magnesium sulfate, and the solvent is evaporated under reduced pressure to give the yellow product. 1 H-NMR (CDCl 3): 6.50-6.54 (m, 3H), 5.97-6.06 (m, 1H), 5.39 (m, 1H), 5.28 (m, 1H), 4.99 (d, 1H), 4.49 (dt, 2H), 2.99-3.19 (m, 2H), 1.43 (s, 9H). e) Methyl ester of (S) -3- (3-allyloxy-5-fluoro-phenyl) -2-terbutoxycarbonyl-aminopropionic acid To a solution of the methyl ester of (S) -3- (3-Allyloxy-5-fluoro-phenyl) -2-terbutoxycarbonyl-amino-propionic acid in methanol, a solution of diazomethane in diethyl ether is added slowly until complete conversion. The excess diazomethane is destroyed by the addition of concentrated acetic acid (100 microliters), and the reaction mixture is then concentrated under reduced pressure.

The residue is dissolved in dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and the solvent is evaporated, to give the product as a colorless oil. 1 H-NMR (CDCl 3): 6.42-6.54 (m, 3H), 5.98-6.07 (m, 1H), 5.41 (dq, 1H), 5.30 (dq, 1H), 5.0 (d, 1H), 4.57 (q, 1H), 4.49 (dt, 2H), 3.68 (s, 3H), 2.97-3.1 (m, 2H), 1.43 (s, 9H). HPLC (Chiralpak AS-H 1205, 250 x 4.6 millimeters, 5 microliters, hexane / isopropanol, 95/5, 1 milliliter / minute), retention time: 10.75 minutes, > 99.9 percent enantiomeric excess, (retention time of the (R) enantiomer: 8.48 minutes) Construction block C14: Terbutil-acid ester. { (1S, 2R) -1- (3-allyloxy-5-fluoro-benzyl) -2-hydroxy-3- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -propyl} -carbamic The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the terbutil-ester of the acid. { (1S, 2R) -1- (3-allyloxy-5-fluoro-benzyl) -2-hydroxy-3- [1- (3-isopropyl-phenyl) -cyclopropyl-amino] -propyl} -carbamic (building block C13) and 1- (3-isopropyl-phenyl) -cyclopropyl-amine (building block D1). Rf: (hexane / EtOAc, 1: 1): 0.5 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) : 3,256 minutes. MS (ES +): 513 = [M + H] + 1 H-NMR (400 MHz, CDCl 3): 7.23-7.06 (m, 4H), 6.60-6.45 (m, 4H), 6.13-5.95 (m, 1H), 5.43-5.25 (m, 2H), 4.51-4.44 (m, 3H), 3.76-3.68 (m, 1H), 3.57-3.45 (m, 1H), 3.37-3.30 (m, 1H), 2.98-2.64 (m , 4H), 1.30 (s, 9H), 1.23 (d, 6H), 1.1-0.87 (m, 4H). Construction block C16: [(1S.2R) -3- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -2-hydroxy-1- (3-hydroxy) acid ester. benzyl) -propyl] -carbamic a) Terbutil-ester of the acid. { (1 S, 2 R) -1- (3-benzyloxy-benzyl) -3- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -2-hydroxy-propyl} -Carbamic A solution of 5.53 grams (15 millimoles) of the [(S) -2- (3-benzyloxy-phenyl) -1 - (S) -oxiranyl-ethyl] -carbamic acid terbutil ester (J. Med. Chem. 1996, 39, 1991) and 3.42 grams (18 mmol) of 1- (4-tert-butyl-pyrid-2-yl) -cyclopropyl-amine (building block D4) in 70 milliliters of EtOH, is stirred at 50 ° C. for 60 hours. The mixture is evaporated and passed through chromatography on silica gel (EtOAc / hexanes, 1: 8, 1: 5, 1: 3, 1: 1, 2: 1). Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.45 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes): 3323 minutes MS (ES +): 560 = [M + H] * 1 H-NMR (400 MHz, CDCl 3): 8.44 (d, 1H), 7.50-7.10 (m, 8H) , 6. 91-6.83 (m, 3H), 5.07 (s, 2H), 4.64 (d, 1H), 4.88-4.80 (m, 1H), 4.54-4.48 (m, 1H), 3.01-2.75 (m, 4H), 1.36 (br s, 9H), 1.32 (s, 9H), 1.28-1.18 (m, 4H). b) [(1S, 2R) -3- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-l-amino] -2-hydroxy-1- (3-hydroxy-benzyl) tert-butyl ester -propyl] - carbamic A solution of 4.9 grams (8.75 millimoles) of the terbutil-ester of the acid. { (1S, 2R) -1- (3-benzyloxy-benzyl) -3- [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl-amino] -2-hydroxy-propyl} -carbamic in 50 milliliters of EtOH, is hydrogenated in the presence of 0.49 grams of 10 percent Pd-C (Engelhardt 4505) for 12 hours. The mixture is filtered over High-flow and purified by chromatography on silica gel using a gradient of dichloromethane with 2 to 10 percent of 9/1 MeOH / 25 percent aqueous NH3. Rf: (DCM / MeOH / aqueous NH3 at 25 percent, 90/9/1): 0.23 HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30 -100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes): 2394 minutes MS (ES +): 470 = [M + H] + 1 H-NMR (400 MHz, CDCl 3): 8.44 (d, 1H), 7.20-7.11 (m, 3H ), 6. 80-6.70 (m, 3H), 4.74 (d, 1H), 3.89-3.80 (m, 1H), 3.57-3.50 (m, 1H), 2.95-2.73 (m, 4H), 1.35 (br s, 9H) , 1.30 (s, 9H), 1.28-1.18 (m, 4H). Construction block C17: [(2R, 3S) -3-terbutoxy-carbonyl-amino-2-hydroxy-4- (3-hydroxy-phenyl) -butyl] - [1- (3-isopropyl-) acid benzyl ester phenyl) -cyclopropyl] -carbamic acid Under a nitrogen atmosphere, a solution of 0.70 grams (1.11 mmol) of [(2R, 3S) -4- (3-allyloxy-phenyl) -3-te rbutoxy- benzyl ester] carboni l-am i non-2-hydroxybutyl] - [1- (3-iso propyl-f-enyl) -cyclopropyl] -carbamic acid (building block C7) and 12 milligrams (0.01 mmol) of Pd (PPh3) 4 in 7 milliliters of methanol, is stirred for 2.5 hours in the presence of 461 milligrams (3.34 millimoles) of potassium carbonate. The mixture is quenched with 5 milliliters of 1N aqueous hydrochloric acid, and extracted with EtOAc. The organic phase is washed with water, concentrated, and chromatographed on silica gel (EtOAc / hexane, 1: 2) Rf: (hexane / EtOAc = 1/1): 0.60 HPLC (Nucleosil C18-HD, 4 x 70 millimeters, 3 microns, 40-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)): 5.66 minutes. MS (ES) MH * = 589 C18 building block: [(2R.3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] -benzyl ester - [1- (4-tert-butyl-pyridin-2-yl) -cyclopropyl] -carbamic acid The product is obtained by a reaction sequence analogous to that of the building block C5, starting from the building block C4 and 1 - (4 -terbutyl-pyrid-2-yl) -cyclopropyl-amine (building block D3). Rf (hexane / EtOAc = 3/2): 0.38. MS (LC / MS, ES +): 644 = [M + H] *. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 3.52 minutes. 1 H-NMR (400 MHz, CDCl 3): 8.38 (br s, 1 H), 7.4 -6.77 (m, 12 H), 6. 12-6.00 (m, 1H), 5.43 (d, 1H), 5.30 (d, 1H), 5.15-5.05 (m, 2H), 4.78 (s, br, 1H), 4.55-4.45 (m, 2H), 3.95-3.75 (m, 2H), 3.1-2.85 (m, 2H), 1.5-1.2 (m, 4H), 1.35 (s, 9H), 1.32 / 1.26 (s, 9H). Construction block C19: [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - benzyl ester. { 1- [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl} -carbamic The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the C3 building block and 1 - [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl-amine (building block D5). MS (ES +): 648 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 6.95 minutes. Construction block C20: [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - (2-phenyl-cyclopropyl) acid benzyl ester -carbamic The product is obtained as a mixture of two diastereomers by a reaction sequence analogous to that of the C5 building block, starting from the building block C3 and the commercially available racemic trans-2-phenyl-cyclopropyl-amine. MS (ES +): 587 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 6.62 minutes. C21 building block: [(2R.3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-propyl-) acid benzyl ester isoxazol-5-yl) -cyclopropyl] -carbamic acid The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the C3 building block and 1- (3-propyl-isoxazol-5-yl) ) -cyclopropyl-amine (building block D6). MS (ES +): 620 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 6.52 minutes. Construction block C22: [(2R, 3S) -4- (3-allyloxy-phenyl) -3-terbutoxy-carbonyl-amino-2-hydroxy-butyl] - [1- (3-bromo- phenyl) -cyclopropyl] -carbamic acid The product is obtained by a reaction sequence analogous to that of the C5 building block, starting from the building block C3 and 1- (3-bromo-phenyl) -cyclopropyl-amine. The latter is obtained following a published procedure (International Publication Number WO2006074940). MS (ES +): 667 and 665 = [M + H] * 1 H-NMR (400 MHz, DMSO-d 6): 7.40-7.03 (m, 9H), 7.01-6.89 (m, 1H), 6.82-6.70 (m , 3H), 6.10-5.99 (m, 1H), 5.42-5.22 (m, 2H), 5.15 (s, 2H), 4.65-4.55 (s, 1H), 4.50 (d, 2H), 3.82-3.40 (m , 4H), 3.00-2.80 (m, 2H), 1.50-1.08 (m, 4H), 1.29 (s, 9H). Construction block D1: 1 - (3- i sopropi lf enyl) -ci do propi I-amine a) 3-isopropyl-benzonitrile 1-bromo-3-isopropyl-benzene (200 grams, 954 millimoles, 1 equivalent) Dissolve in 1 liter of 1-methyl-2-pyrrolidone. Zinc cyanide (114 grams, 954 millimoles, 1 equivalent) and Pd (PPh3) 4 (28.7 grams, 24.8 millimoles, 0.03 equivalents) are added under nitrogen. The reaction mixture is heated to 125 ° C, stirred at this temperature for 150 minutes, then cooled to room temperature, and filtered over Hyflo Super Gel, and the filtrate is diluted with H20 and EtOAc. The organic layer is washed with water, 1N HCl solution and brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using dichloromethane / hexane in a ratio of 1 to 3, to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (3 minutes)), retention time: 5.06 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.57 (s, 1H), 7.53-7.48 (m, 2H), 7.43 (t, 1H), 3.01-2.92 (m, 1H), 1.29 (d, 6H). b) 1- (3-isopropyl-phenyl) -cyclopropi I-amine The 3-isopropyl-benzonitrile (42 grams, 286 mmol, 1 equivalent) is dissolved in 670 milliliters of diethyl ether under argon. Titanium (IV) isopropoxide (90.4 grams, 315 mmol, 1.1 equivalents) is added. The reaction mixture is cooled to -70 ° C, and EtMgBr (3 M in diethyl ether, 210 milliliters, 630 mmol, 2.2 equivalents) is added within 60 minutes. The reaction mixture is heated to 10 ° C, and BF3 * Et20 (48 percent, 169 grams, 573 mmol, 2 equivalents) is added at this temperature. After 1 hour, the reaction mixture is quenched with 400 milliliters of 1N HCl, basified to a pH of 10 using 2N NaOH in H20, and filtered over Hyflo Super Gel. The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography using DCM / MeOH in a ratio of 19 to 1 to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (3 minutes)), retention time: 2.80 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.32-7.28 (t, 1H), 7.23 (s, 1H), 7.19-7.10 (m, 2H), 3.01-2.90 (m, 1H), 1.96 (s, 2H) , 1.33 (d, 6H), 1.12-1.09 (m, 2H), 1.09-1.02 (m, 2H). Construction block D2: 1- (3-tert-butyl-phenyl) -cyclopropyl-amine The product is obtained by a reaction sequence analogous to that of the D1 building block, starting from 1-bromo-3-terbuti I-benzene . Rf (Cyclohexane / EtOAc = 50/50): 0.19. MS (LC / MS): 190.1 = [M + H] *. 1 H-NMR (400 MHz, CDCl 3): 7.40-7.38 (m, 1H), 7.27-7.26 (, 2H), 7.15-7.12 (m, 1H), 1.91 (br s, 2H), 1.35 (s, 9H) , 1.09-1.05 (m, 2H), 1.03-0.99 (m, 2H). Construction block D3: 1- (4-tert-butyl-pyrid-2-yl) -cyclopropyl-amine The product is obtained by a reaction sequence analogous to that of the building block D1, starting from 4-tert-butyl-pyridine- 2-carbonitrile. The starting material can be prepared following published procedures (Z. R. Bell et al., Polihedron, 20 (15-16), 2045-2053, 2001). MS (LC / MS, ES +): 191 = [M + H] *. HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 10-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)), retention time: 2.35 minutes. 'H-NMR (400 MHz, CDCl 3): 8.43 (d, 1H), 7.41 (s, 1H), 7.10 (dd, 1H), 2.13 (brs, 2H), 1.41-1.27 (m, 2H), 1.35 (s, 9H), 1.16-1.13 (m, 2H). Construction block D4: 1- (4-isopropyl-pyridin-2-yl) -cyclopropyl-amine The product is obtained by a reaction sequence analogous to that of the building block D3, starting from 4-isopropyl-pyridine- 2-carbonitrile. The starting material can be prepared following published procedures (Publication International Number WO2006074950). Rf: (DCM / MeOH / NH3 = 90/9/1): 0.55 MS (LC / MS): 177 = [M + H] * 1 H-NMR (400 MHz, DMSO-d6): 8.23 (d, 1H) 7.61 (d, 1H), 6.95 (dd, 1H), 2.19-2.80 (m, 1H), 1.21 (d, 6H), 1.17 (q, 2H), 0.91 (q, 2H).

Construction block D5: 1- [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl-amine a) Ethyl-ester of (Z) -2-hydroxy-6,6-dimethyl acid -4-oxo-hept-2-enoic To an ice-cold solution of sodium ethanolate (128.5 grams, 1.79 moles) in EtOH (2500 milliliters) under a nitrogen atmosphere, 4,4-dimethyl-pentan-2- is added. ona (195.0 grams, 1.71 moles). Half an hour later, oxalic acid diethyl ester (231.5 grams, 1.71 moles) is added. After being stirred at room temperature for 24 hours, the reaction mixture is diluted with water, and acidified to a pH of 2.0 by 6N aqueous hydrochloric acid. The mixture is shrunk to approximately 1 liter, and extracted with dichloromethane. The combined extracts are washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide the product as a brown liquid. MS (LC / MS): 215 = [M + H] * 1 H-NMR (300 MHz, CDCl 3): 6.32 (s, 1 H), 4.35 (q, 2 H), 2.33 (s, 2 H), 1.60 (t, 3H), 1.04 (s, 9H). b) 5- (2,2-Dimethyl-propyl) -isoxazole-3-carboxylic acid To a solution of (Z) -2-hydroxy-6,6-dimethyl-4-oxo-hept-2-ethyl ester -neoic (298.5 grams, 1.39 moles) in EtOH (1600 milliliters), hydroxyl amine hydrochloride (106.5 grams, 1.53 moles) is added, and the resulting solution is stirred at room temperature for 24 hours. 2N aqueous sodium hydroxide (1740 milliliters, 3.48 moles) is added to the reaction, and the resulting solution is stirred at room temperature for 2 hours. The reaction mixture is acidified with 6N aqueous hydrochloric acid, concentrated to about 3 liters, and extracted with EtOAc (2000 milliliters). The combined organic layers are washed with brine, dried over magnesium sulfate, and concentrated. The resulting solid is washed with ether and dried to provide the product. 1 H-NMR (300 MHz, DMSO-dß): 6.61 (s, 1 H), 2.72 (s, 2 H), 0.94 (s, 9 H). c) 5- (2,2-Dimethyl-propyl) -isoxazole-3-carboxylic acid terbutyl-amide To a solution of 5- (2,2-dimethyl-propyl) -isoxazole-3-carboxylic acid (125.4 grams, 0.685 moles) in tetrahydrofuran (1500 milliliters) and MeCN (1500 milliliters), are added HOBT (101.75 grams, 0.753 moles) and EDCI (144.3 grams, 0.753 moles). After stirring for 30 minutes, tert-butylamine (86.7 milliliters, 0.821 moles) is added dropwise under a nitrogen atmosphere, and then the reaction is stirred at room temperature for 1.5 hours. The solvents are evaporated under reduced pressure, and the residue is taken up in dichloromethane (2000 milliliters). The mixture is washed with saturated aqueous sodium bicarbonate (500 milliliters, 2 times), the organic layer is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica (dichloromethane) to give the product as a white solid. MS (LC / MS): 239 = [M + H] * d) 5- (2,2-dimethyl-propyl) -isoxazole-3-carbonitrile A mixture of the 5- (2,2- dimethylpropyl) -isoxazole-3-carboxylic acid (58.0 grams, 0.243 moles) and phosphorus oxychloride (III) (156 milliliters, 1.70 moles) is heated under a nitrogen atmosphere at the reflux temperature for 2 hours. The reaction mixture is cooled to room temperature and concentrated to remove excess phosphorus oxychloride (III). The residue is diluted with dichloromethane (2000 milliliters) and washed with saturated aqueous sodium bicarbonate (500 milliliters)., 2 times). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by chromatography on silica (dichloromethane / hexanes, 1/1) to give the objective compound as a yellow liquid. 1 H-NMR (300 MHz, CDCl 3): 6.36 (s, 1 H), 2.74 (s, 2 H), 1.00 (s, 9 H). e) 1- [5- (2,2-dimethyl-propyl) -isoxazol-3-yl] -cyclopropyl-amine To a mixture of 5 grams (30.4 mmol) of 5- (2,2-dimethyl-propyl) - isoxazole-3-carbonitrile and 10.1 milliliters (34.1 millimoles) of titanium (IV) isopropoxide in 150 milliliters of dry diethyl ether, a solution of 22 milliliters of ethyl magnesium bromide (3M in diethyl ether, 66.0) is added. millimoles) at -70 ° C. The reaction mixture is allowed to reach room temperature within two hours, 7.6 milliliters (60.6 millimoles) of boron trifluoride diethyl etherate are added, and the stirring is continued for one hour. After the addition of 90 milliliters of 1M aqueous hydrochloric acid and 450 milliliters of diethyl ether, two transparent phases are obtained, which are treated with 300 milliliters of 10 percent aqueous sodium hydroxide. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated to give a dark orange oil. After filtration on a C18-bond elut column (Varian) with tetrahydrofuran / MeCN, the oil is purified by HPLC (dissolved in 6 milliliters of tetrahydrofuran, 25 injections, column XBridge C18, 19 x 150 millimeters, 5 microns, gradient from 95 percent MeCN in water up to 10 percent MeCN in water, which contains 0.02 percent ammonium hydroxide). The combined fractions of the product are concentrated, and the product is extracted with dichloromethane, to give the product as an orange solid. P.f .: 39 - 47 ° C MS (ES +): 195 = [M + H] *. 1 H-NMR (360 MHz, CDCl 3): 5.50 (s, 1 H), 2.50 (s, 2 H), 1.80 (br s, 2 H), 1.10-1.05 (m, 2 H), 0.95-0.90 (m, 2 H), 0.90 (s, 9H). Construction block D6: 1- (3-propyl-isoxazol-5-yl) -cyclopropyl-amine a) 3-Propyl-isoxazole-5-carboxylic acid Sodium (4.42 grams, 193 millimole, 1.05 equivalents) is added to 260 milliliters of EtOH at 0 ° C within 45 minutes, followed by the addition of 2-pentanone (15.8 grams, 184 mmol, 1 equivalent) and diethyl oxalate. The reaction mixture is heated to 60 ° C. After 3 hours, the mixture is concentrated, and the residue is dissolved in acetic acid (350 milliliters) and heated to 55 ° C. Hydroxyl amine hydrochloride (38.4 g) is dissolved in 150 milliliters of water, and added to the reaction mixture within 15 minutes. The reaction mixture is heated at 75 ° C for 20 hours. The mixture is concentrated, and the residue is diluted with dichloromethane (400 milliliters). The organic layer is dried over sodium sulfate and concentrated to give the product, which can be used for the next step without purification. MS (ES +): 156 = [M + H] * HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) , retention time = 0.66 minutes. b) 3-Propyl-isoxazole-5-carboxylic acid amide The 3-propyl-isoxazole-5-carboxylic acid (21 grams, 135 mmol, 1 equivalent) is dissolved in 400 milliliters of dichloromethane. Thionyl chloride (40 milliliters) and dimethylformamide (1 milliliter) are added. The reaction is heated to reflux temperature for 150 minutes, and then cooled to room temperature. The mixture is poured over 90 milliliters of aqueous ammonia (25 percent in water) at 0 ° C, and 600 milliliters of EtOAc are added. The organic layer is dried over sodium sulfate and concentrated. The product is crystallized from the residue solution in EtOAc and di-isopropyl ether. MS (ES +): 155 = [M + H] * HPLC (Zorbax SB-C18, 3 x 30 millimeters, 1.8 microns, 30-100 percent MeCN (3.25 minutes), 100 percent MeCN (0.75 minutes)) , retention time = 0.47 minutes. 1 H-NMR (600 MHz, DMSO-d6): 8.3 (s, 1H), 7.9 (s, 1H), 6.94 (s, 1H), 2.66-2.60 (m, 2H), 1.69-1.59 (m, 2H), 0.93-0.87 (m , 3H). c) 3-propyl-isoxazole-5-carbonitrile The 3-propyl-isoxazole-5-carboxylic acid amide (770 milligrams, 4.99 millimoles, 1 equivalent) is dissolved in 6 milliliters of phosphorus oxychloride (III), and heated at 110 ° C for 45 minutes. The reaction mixture is concentrated, the residue is dissolved in dichloromethane, washed with aqueous sodium bicarbonate, filtered, and concentrated to give the product. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 4.55 minutes. 1 H NMR (400 MHz, DMSO-d 6): 6.80 (s, 1 H), 2.72 (t, 2 H), 1.81-1.69 (m, 2 H), 1.01 (t, 3 H). d) 1- (3-propyl-isoxazol-5-yl) -cyclopropyl-amine The 3-propyl-isoxazole-5-carbonitrile (3 grams, 22 mmol, 1 equivalent) is dissolved in 15 milliliters of diethyl ether. titanium-IV isopropoxide (7.18 milliliters, 24.2 mmol, 1.1 equivalents) is added at room temperature, and the reaction is cooled to -65 ° C. Ethylmagnesium bromide (16 milliliters, 48 mmol, 2.2 equivalents) is added, and the reaction is warmed to room temperature within 2 hours. BF3 * Et20 (11.4 milliliters, 90.3 millimoles, 4.1 equivalents) is added at 0 ° C, and the reaction is stirred at 0 ° C for 1 hour. The reaction is quenched by the addition of 1N aqueous hydrochloric acid (4.9 milliliters), followed by the addition of 2N aqueous sodium hydroxide (11 milliliters). The mixture is diluted with tert-butyl methyl ether (80 milliliters) and water (50 milliliters). The organic layer is washed with brine, dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica (EtOAc / hexane, 95/5) to give the product. MS (ES +): 167 = [M + H] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), Retention time = 1.20 minutes. E3 building block: 3- (3-methane-sulfon-loxi-propoxy) -5-methoxy-methyl-1-benzoic acid methyl ester a) 3-allyloxy-5-hydroxy-methyl-benzoic acid methyl ester The monomethyl ester of 5-allyloxy-isophthalic acid (Fang et al., J. Am. Chem. Soc. 1998, 8543-8544) (6.14 grams, 26 mmol, 1 equivalent) is dissolved in tetrahydrofuran (200 milliliters). Et3N (4.4 milliliters, 31.2 mmol, 1.2 equivalents) is added, and the reaction mixture is cooled to 0 ° C. Isopropyl chloroformate (1N in toluene, 36.4 milliliters, 36 mmol, 1.4 equivalents) is added, and the reaction is stirred for 1 hour at 0 ° C. Water (50 milliliters) and tert-butyl methyl ether (300 milliliters) are added, and the organic layer is washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. The residue is dissolved in tetrahydrofuran (200 milliliters) at 0 ° C, and NaBH 4 (3.25 grams, 85.9 mmol, 3.31 equivalents) is added in 25 milliliters of ice water within 10 minutes. The reaction is stirred for 1 hour at 0 ° C. 100 milliliters of water and 300 milliliters of terbutyl methyl ether are added, the organic layer is washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. The product is used in the next step without further purification. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 3.76 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.58 (s, 1 H), 7.42 (s, 1 H), 7.10 (s, 1 H), 6.05-5.92 (m, 1 H), 5.41-5.22 (m, 2 H), 4.66 (s, 2H), 4.53 (d, 2H), 3.86 (s, 3H). b) 3-allyloxy-5-methoxy-methyl-benzoic acid methyl ester The 3-allyloxy-5-hydroxy-methyl-benzoic acid methyl ester (5.3 grams, 23.8 mmol, 1 equivalent) is dissolved in N, N-dimethyl formamide (60 milliliters). Sodium hydride (1.19 grams, 29.8 mmol, 1.25 equivalents) is added at 0 ° C, and the reaction mixture is stirred for 30 minutes. Mel (3.32 milliliters, 35.8 millimoles, 1.5 equivalents) is added, and the reaction mixture is stirred for 2 hours at room temperature. 20 milliliters of 1N aqueous hydrochloric acid and tertiary butyl ether (200 milliliters) are added, the organic layer is washed with brine, dried over sodium sulfate, and concentrated. The product is used in the next step without further purification. HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), retention time = 4.99 minutes. 1 H-NMR (400 MHz, CDCl 3): 7.52 (s, 1 H), 7.42 (s, 1 H), 7.05 (s, 1 H), 6.05-5.92 (m, 1 H), 5.40-5.19 (m, 2 H), 4.55 (d, 2H), 4.40 (s, 2H), 3. 85 (s, 3H), 3.32 (s, 3H). c) 3- (3-hydroxy-propoxy) -5-methoxy-methyl-benzoic acid methyl ester 3-allyloxy-5-methoxy-methyl-benzoic acid methyl ester (2.00 grams, 8.46 mmol, 1 equivalent) ) is dissolved in tetrahydrofuran (60 milliliters). 9-BBN (0.5 N in tetrahydrofuran, 48.7 milliliters, 24.4 millimoles, 2.88 equivalents) is added at 0 ° C, and the reaction mixture is stirred for 20 hours. H202 (30 percent in water, 55 milliliters) and aqueous sodium carbonate (4 percent in water, 184 milliliters) are added, and the reaction is stirred for 1 hour. Terbutil-methyl ether (250 milliliters) is added, the organic layer is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by chromatography on silica (EtOAc / hexane, 55/45) to give the product. MS (ES +): 272 [M + NH4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time Retention = 3.38 minutes. d) 3- (3-Methanesulfonyloxy-propoxy) -5-methoxy-methyl-benzoic acid methyl ester 3- (3-hydroxy-propoxy) -5-methoxy-methyl-benzoic acid methyl ester (508 milligrams, 2.00 millimoles, 1 equivalent) is dissolved in tetrahydrofuran (10 milliliters). Et3N (334 microliters, 2.4 mmol, 1.2 equivalents) and methan-sulfonyl chloride (170 microliters, 2.2 mmol, 1.1 equivalents) are added, and the reaction is stirred for 22 hours. Aqueous sodium bicarbonate (10 milliliters) and EtOAc (20 milliliters) are added, and the organic layer is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by chromatography on silica (EtOAc / hexane, 1/1) to give the product. MS (ES +): 350 [M + NH 4] * HPLC (Nucleosil C18HD, 4 x 70 millimeters, 3 microns, 20-100 percent MeCN (6 minutes), 100 percent MeCN (1.5 minutes)), time of retention = 4.26 minutes.

Claims

1. A compound of the formula: wherein: Rf is - (CH2) kN (Ra) Rb, wherein: k is 0, 1 or 2; Ra is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms) -alkyl (of 1 to 4 carbon atoms), aryl, aryl-alkyl (of 1 to 4 carbon atoms), heteroaryl, hetero-aryl-alkyl (of 1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, Sothiochroman-4-yl, 1,1-dioxo-1 lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2lam da * 6 * -isothiochroman-4-yl, 1, 2,3,4 -tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1,2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo-1, 2,3,4-tetrahydro-1-lambda * 6 * -benzo- [e] [1, 2] -thiazin -4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2-lambda * 6 * -benzo- [c] [1,2] -thiazin-4-yl, 1,1-d -oxo -3,4-dihydro-1 H-1 lambda * 6 * -benzo- [c] [1, 2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo- [e] [1,2] -oxatiin-4-yl, 2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl or 1, 3,4,5-tetrahydro- benzo- [c] oxepin-5-yl, optionally substituted; and R is a cycloalkyl group (of 3 to 8 carbon atoms), wherein: (a) one of the ring carbon members of the cycloalkyl fraction (of 3 to 8 carbon atoms), which are different from the carbon member of the ring, to which the nitrogen atom carrying Ra is attached, is optionally replaced by a hetero ring member, selected from the group consisting of -O-, -S-, -S (= 0 ) -, -S (= 0) 2- and -N (RC) -, wherein: Rc is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl or hetero-aryl-alkyl (from 1 to 4 carbon atoms), optionally substituted, (b) the cycloalkyl fraction (of 3 to 8 carbon atoms) is substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, hydroxyl, alkoxy (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alkoxyl (from 1 to 4 carbon atoms), thioalkyl (from 1 to 4 carbon atoms), alkyl (from 1 at 4 carbon atoms) -sulfinyl, alkyl (1 to 4 carbon atoms) -sulfonyl, alkyl (1 to 4 carbon atoms) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkoxy ( from 1 to 4 carbon atoms) -carbonyl, alkoxy (from 1 to 4 carbon atoms) -carbonyloxy and an alkyl group (from 1 to 8 carbon atoms), cycloalkyl (from 3 to 8 carbon atoms), cycloalkyl ( from 3 to 8 carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl, hetero-aryl-alkyl (from 1 to 4 atoms) carbon), non-aromatic heterocyclyl, non-aromatic heterocyclyl-alkyl (1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1, 1 -dioxo-1 lambda * 6 * -thiochroman-4-yl, 2,2-dioxo-2lambda * 6 * -isotioc roman-4-yl, 1, 2,3,4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth- 1-yl, 1, 1-dioxo-1, 2,3,4-tetrahydro-1-lambda * 6 * -benzo- [e] [1, 2] -thiazin-4-yl, 2,2-dioxo-1 , 2,3,4-tetrahydro-2lambda * 6 * -benzo- [c] [1,2] -thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda * 6 * - benzo- [c] [1,2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo- [e] [1,2] -oxatiin-4 -yl, 2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl or 1, 3,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted, and ( c) the cycloalkyl fraction (of 3 to 8 carbon atoms) is optionally substituted on two adjacent carbon members of the ring by two substituents, which form, together with the two adjacent carbon members of the ring, with which they are attached , a cycloalkyl group (of 3 to 8 carbon atoms), wherein: (i) one of the carbon ring members of the cycloalkyl group (3 to 8 carbon atoms) formed in this manner, which are different from those two adjacent carbon members of the ring, with which these two substituents are optionally attached, is optionally replaced by a hetero ring member, selected from the group consisting of -O-, -S-, -S (= 0) -, -S (= 0 ) 2- and -N (Rd) -, where: Rd is hydrogen or an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms) carbon) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl or hetero-aryl-alkyl (from 1 to 4 carbon atoms), optionally substituted , and (ii) the cycloalkyl group (3 to 8 carbon atoms) thus formed is optionally substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, hydroxyl, alkoxy (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms) -alkoxyl (from 1 to 4 carbon atoms), thioalkyl (from 1 to 4 carbon atoms), alkyl (from 1 to 4 carbon atoms) - sul finyl, alkyl (1 to 4 carbon atoms) -sulfonyl, alkyl (1 to 4 carbon atoms) -carbonyl, alkyl (1 to 4 carbon atoms) -carbonyloxy, alkoxy (1 to 4 carbon atoms) ) -carbonyl, alkoxy (of 1 to 4 carbon atoms) -carbonyloxy, and an alkyl group (of 1 to 8 carbon atoms), cycloalkyl (of 3 to 8 carbon atoms), cycloalkyl (of 3 to 8) carbon atoms) -alkyl (from 1 to 4 carbon atoms), aryl, aryl-alkyl (from 1 to 4 carbon atoms), hetero-aryl, hetero-aryl-alkyl (from 1 to 4 carbon atoms), non-aromatic heterocyclyl, non-aromatic heterocyclyl-alkyl (1 to 4 carbon atoms), chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isotioc roman -4-i lo, 1, 1-dioxo -1 lam bda * 6 * -thioc roman -4-yl, 2,2-dioxo-2-lambda * 6 * -isothiochroman-4-yl, 1, 2,3,4-tetrahydro-quinol-4-yl, 1, 2,3,4-tetrahydro-isoquinol-4-yl, 1, 2,3,4-tetrahydro-naphth-1-yl, 1,1-dioxo-1,2,3,4-tetrahydro-1 lam bda * 6 * -benzo- [e] [1,2] -thiazin-4-yl, 2,2-dioxo-1, 2,3,4-tetrahydro-2lambda * 6 * -benzo- [c] [1, 2] -thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda * 6 * -benzo - [c] [1, 2] -oxatiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda * 6 * -benzo- [e] [1, 2] -oxatiin-4- ilo,

2,3,4,5-tetrahydro-benzo- [b] oxepin-5-yl or 1, 3,4,5-tetrahydro-benzo- [c] oxepin-5-yl, optionally substituted; R2 is hydrogen or alkyl (1 to 4 carbon atoms); R3 is hydrogen, alkyl (of 1 to 6 carbon atoms), 0 an alkyl group (of 1 to 6 carbon atoms) -OC (= 0) NH, cycloalkyl (of 3 to 8 carbon atoms) -OC (= 0) NH, cycloalkyl (of 3 to 8 carbon atoms) - alkyl (from 1 to 4 carbon atoms) -OC (= 0) NH, aryl-alkyl (from 1 to 4 carbon atoms) -OC (= 0) NH, hetero-aryl-alkyl (from 1 to 4 carbon atoms) carbon) -OC (= 0) NH, alkyl (from 1 to 4 carbon atoms) -C (= 0) NH, cycloalkyl (from 3 to 8 carbon atoms) -C (= 0) NH, aryl-C ( = 0) NH, aryl-alkyl (from 1 to 4 carbon atoms) -C (= 0) NH, hetero-aryl-C (= 0) NH or hetero-aryl-alkyl (from 1 to 4 carbon atoms) -C (= 0) NH, optionally substituted; Ar is an arylene or heteroarylene ring, which ring is optionally substituted by halogen, alkoxy (of 1 to 4 carbon atoms), hydroxyl or alkyl (of 1 to 4 carbon atoms), wherein U and X, are in the ortho or meta position one with respect to the other; U is a bond, O, CF2, CF2CF2, CHF, CHFCHF, cycloprop-1, 2-ylene, alkyleneoxy (from 1 to 3 carbon atoms), alkylene (from 1 to 3 carbon atoms) -amino, alkylene (from 1 to 8 carbon atoms), or NRe, wherein: Re is hydrogen, alkyl (of 1 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms); any of: Vf is hydrogen, and V2 is hydroxyl, or Vf and V2 are together oxo; W is CH = CH, cycloprop-1, 2-ylene, phen-1, 2-ylene, CH2CH (OH), CH (OH) CH2 or CR, R, CR, R, where: each Rf, independently, is hydrogen, fluorine or alkyl (1 to 4 carbon atoms); X is a alkanoylidene group (of 1 to 4 carbon atoms), alkylene (of 1 to 4 carbon atoms), cycloalkylene (of 3 to 8 carbon atoms), piperidin-diyl, pyrrolidin-diyl, benzothiazole-4,6 -diyl, benzoxazole-4,6-diyl, 1 H-benzo-triazole-4,6-diyl, imidazo- [1, 2-a] -pyridin-6,8-diyl, benzo- [1, 2,5 ] -oxadiazole-4,6-diyl, benzo- [1,2,5] -thiadiazole-4,6-diyl, 1 H-indole-5,7-diyl, 1 H-indyl-4,6- diyl, 1H-benzimidazole-4,6-diyl or 1 H-indazol-1,6-diyl, optionally substituted, or an optionally substituted arylene or heteroarylene ring, wherein Y and C (= 0) NR2 are the goal position one with respect to the other; X is CRgRg, wherein: each Rg, independently, is hydrogen, fluorine or an alkyl group (of 1 to 8 carbon atoms), alkoxy (of 1 to 4 carbon atoms) -alkyl (of 1 to 4 carbon atoms) ), cycloalkyl (of 3 to 8 carbon atoms), or cycloalkyl (of 3 to 8 carbon atoms) -alkyl (of 1 to 4 carbon atoms), optionally substituted; And it is a link, O, S (= 0) 2, S (= 0) 2NRh, N (Rh) S (= 0) 2, NRh, C (Rh) OH, C (= 0) NRh, N (Rh) C (= 0), C (= 0) N (Rh) 0 or ON (Rh) C (= 0), where: Rh is hydrogen, alkyl (from 1 to 8 carbon atoms), or cycloalkyl (from 3 to 8 carbon atoms); and Z is O, CH2, CF2, CHF, cycloprop-1, 2-ylene or a bond, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in the form of free base or in the form of acid addition salt. 2. A process for the preparation of a compound as defined in claim 1 of the formula I, in the form of a free base or in the form of an acid addition salt, which comprises the steps of: a) cyclization by metathesis of a compound of the formula: wherein Rf, R 2, R 3, Ar, U, Vf, V 2, X, X 1 (Y and Z are as defined for formula I, in the presence of a catalyst, for example a ruthenium, tungsten, or molybdenum complex , optionally followed by reduction or functionalization of the resulting carbon-carbon double bond, or b) intramolecular cyclization of a compound of the formula: wherein R1f R2, R3, Ar, U, V1t V2, W, X, X1t Y and Z are as defined for formula I, Gf is a leaving group, and G2 is hydrogen or a protecting group, optionally each followed by reduction, oxidation or functionalization of the resulting compound and / or by dissociation of the optionally present protecting groups, and recovery of the compound thus obtained of the formula I in the form of the free base or in the form of the acid addition salt.

3. A compound according to claim 1, in free base form or in pharmaceutically acceptable acid addition salt form, for use as a medicament.

4. A compound according to claim 1, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, for use in the treatment of neurological or vascular disorders related to the generation and / or accumulation of beta-amyloid.

5. A pharmaceutical composition, which comprises a compound as claimed in claim 1, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, as an active ingredient, and a pharmaceutical carrier or diluent.

6. The use of a compound as claimed in claim 1, in free base form or in pharmaceutically acceptable acid addition salt form, as a medicament for the treatment of neurological or vascular disorders related to generation and / or accumulation of beta-amyloid.

7. The use of a compound as claimed in claim 1, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, for the manufacture of a medicament for the treatment of neurological or vascular disorders related to the generation and / or beta-amyloid accumulation.

8. A method for the treatment of neurological or vascular disorders related to the generation and / or accumulation of beta-amyloid in a subject in need of such treatment, which comprises administering to this subject a therapeutically effective amount of a compound as claimed in Claim 1, in free base form or in pharmaceutically acceptable acid addition salt form. A combination comprising a therapeutically effective amount of a compound as claimed in claim 1, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, and a second drug substance, for simultaneous administration or in sequence.