Macrocyclic compounds useful as BACE inhibitors

1. A compound of the formula

in which

R 1 is —(CH 2 ) k N(R a )R b , in which

k is 0, 1 or 2;

R a is hydrogen or an optionally substituted (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl-(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl, heteroaryl(C 1-4 )alkyl, chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*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]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group; and

R b is a (C 3-8 )cycloalkyl group, in which

(a) one of the carbon ring members of the (C 3-8 )cycloalkyl moiety, which are different from the carbon ring member, to which the nitrogen atom carrying R a 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(R c )—, in which

R c is hydrogen or an optionally substituted (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl or heteroaryl(C 1-4 )alkyl group,

(b) the (C 3-8 )cycloalkyl moiety is substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (C 1-4 )-alkoxy, (C 1-4 )alkoxy(C 1-4 )alkoxy, (C 1-4 )alkylthio, (C 1-4 )alkylsulfinyl, (C 1-4 )alkylsulfonyl, (C 1-4 )alkylcarbonyl, (C 1-4 )alkylcarbonyloxy, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkoxycarbonyloxy and an optionally substituted (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl-(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl, heteroaryl(C 1-4 )alkyl, non-aromatic heterocyclyl, non-aromatic heterocyclyl(C 1-4 )alkyl, chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*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]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, and

(c) the (C 3-8 )cycloalkyl moiety is optionally substituted at two adjacent carbon ring members by two substituents, which form, together with the two adjacent carbon ring members, to which they are attached, a (C 3-8 )cycloalkyl group, in which

(i) one of the carbon ring members of the (C 3-8 )cycloalkyl group thus formed, which are different from the said two adjacent carbon ring members, to which the said two substituents are optionally attached, is optionally replaced by a hetero ring member, selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 — and —N(R d )—, in which R d is hydrogen or an optionally substituted (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl or heteroaryl(C 1-4 )alkyl group, and

(ii) the (C 3-8 )cycloalkyl group thus formed is optionally substituted by 1 to 4 substituents, independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (C 1-4 )alkoxy, (C 1-4 )alkoxy(C 1-4 )alkoxy, (C 1-4 )alkylthio, (C 1-4 )alkylsulfinyl, (C 1-4 )alkylsulfonyl, (C 1-4 )alkylcarbonyl, (C 1-4 )alkylcarbonyloxy, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkoxycarbonyloxy and an optionally substituted (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-4 )alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl, heteroaryl(C 1-4 )alkyl, non-aromatic heterocyclyl, non-aromatic heterocyclyl(C 1-4 )alkyl, chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*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-2lambda*6*-benzo[c][1,2]thiazin-4-yl, 1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[c][1,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group;

R 2 is hydrogen or (C 1-4 )alkyl;

R 3 is hydrogen, (C 1-6 )alkyl or an optionally substituted (C 1-6 )alkylOC(═O)NH, (C 3-8 )cyclo-alkylOC(═O)NH, (C 3-8 )cycloalkyl(C 1-4 )alkylOC(═O)NH, aryl(C 1-4 )alkylOC(═O)NH, heteroaryl(C 1-4 )alkylOC(═O)NH, (C 1-4 )alkylC(═O)NH, (C 3-8 )cycloalkylC(═O)NH, arylC(═O)NH, aryl(C 1-4 )alkylC(═O)NH, heteroarylC(═O)NH or heteroaryl(C 1-4 )alkylC(═O)NH group;

Ar is a phenylene ring, which ring is optionally substituted with halogen, (C 1-4 )alkoxy, hydroxy or (C 1-4 )alkyl, whereby U and X 1 are in ortho- or meta-position to each other;

U is a bond, O, CF 2 , CF 2 CF 2 , CHF, CHFCHF, cycloprop-1,2-ylene, (C 1-3 )alkylenoxy, (C 1-3 )alkylenamino, (C 1-8 )alkylene or NR e , in which

R e is hydrogen, (C 1-8 )alkyl or (C 3-8 )cycloalkyl;

 either

V 1 is hydrogen and

V 2 is hydroxy

 or

V 1 and V 2 together are oxo;

W is CH═CH, cycloprop-1,2-ylene, phen-1,2-ylene, CH 2 CH(OH), CH(OH)CH 2 or CR f R f CR f R f , in which

each R f , independently, is hydrogen, fluorine or (C 1-4 )alkyl;

X is an optionally substituted phenylene or pyridinyl ring, whereby Y and C(═O)NR 2 are in meta-position to each other;

X 1 is CR g R g , in which

each R g , independently, is hydrogen, fluorine or an optionally substituted (C 1-8 )alkyl, (C 1-4 )alkoxy(C 1-4 )alkyl, (C 3-8 )cycloalkyl or (C 3-8 )cycloalkyl(C 1-4 )alkyl group;

Y is O or NH; and

Z is O, CH 2 , CF 2 , 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 free base form or in acid addition salt form;

wherein

the optional substituents on alkyl, alkoxy or cycloalkyl groups or moieties are one to three groups, independently selected from hydroxy, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )alkoxy(C 1-4 )alkyl, (C 1-4 )alkoxy(C 1-4 )alkoxy, (C 1-4 )alkylthio, (C 1-4 )alkoxycarbonyl, (C 1-4 )-alkylcarbonyloxy, (C 1-4 )alkylcarbonyl, (C 1-4 )alkylsulfonyl, cyano, oxo and (C 3-8 cycloalkyl;

the optional substituents on chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*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]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl, non-aromatic heterocyclyl, aryl or heteroaryl rings or moieties are one to three groups independently selected from hydroxy, optionally substituted (C 1-8 )alkyl, optionally substituted (C 1-6 )alkoxy, S(═O) 2 (C 1-4 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-4 )alkyl, cyano, nitro, trifluoromethyl, halogen, aryl, heteroaryl and optionally substituted carbamoyl;

an optionally substituted aryl or heteroaryl group may also carry, as optional substituents, one to three groups selected from benzyloxy, phenoxy, S(═O) 2 NH 2 , N(H)S(═O) 2 (C 1-6 )alkyl, N[(C 1-6 )alkyl]S(═O) 2 (C 1-6 )alkyl, 2-oxo-pyrrolidin-1-yl, 2,5-dioxa-cyclopent-1-yl, carboxy, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylcarbamoyl, (C 1-4 )alkylsulfonyl, (C 1-4 )alkylcarbonyloxy, (C 1-4 )alkylcarbonyl, hydroxy(C 1-4 )alkyl and optionally substituted amino;

optional substituents on amino groups can be one or two groups independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy(C 1-4 )alkyl, (C 1-4 )alkoxycarbonyl, aryl(C 1-4 )alkoxycarbonyl and heteroaryl(C 1-4 )alkoxycarbonyl;

optional substituents on carbamoyl can be one or two groups selected from (C 1-4 )alkyl and (C 1-4 )alkoxy(C 1-4 )alkyl;

aryl is naphthyl or phenyl;

a heteroaryl is an aromatic 5- or 6-membered ring, in which 1, 2 or 3 ring atoms are hetero atoms independently selected from O, N and S; and

a non-aromatic heterocyclyl is a non-aromatic 5- or 6-membered ring, in which 1, 2 or 3 ring atoms are hetero atoms independently selected from O, N and S.

2. A pharmaceutical composition, comprising:

the compound as claimed in claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, as active ingredient and

a pharmaceutical carrier or diluent.

3. A compound according to claim 1 , in free base form or in pharmaceutically acceptable acid addition salt form, selected from:

(S)-19-Acetyl-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[3-tert-Butyl-phenyl)-cyclopropylamino]-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-hexaene-19-carboxylic acid dimethylamide;

(S)-18-Acetyl-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-15-oxa-3-aza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-18-Acetyl-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-3,15-diaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-18-methoxymethyl-3,15,17-triaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-19-Acetyl-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-18-methoxymethyl-3,15-diaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-18-(2-oxo-propoxy)-15-oxa-3-aza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-18-oxazol-2-yl-3,15-diaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-1-hydroxy-ethyl}-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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;

Propane-1-sulfonic acid ((S)-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-19-Acetyl-4-{(R)-2-[1-(3-tert-butyl-phenyl)-cyclopropylamino]-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;

Propane-1-sulfonic acid((S)-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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-yl)-methyl-amide;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-2-oxo-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaene-19-carboxylic acid dimethylamide;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-19-Acetyl-4-{(R)-2-[1-(3-tert-butyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-18-methoxymethyl-11,15-dioxa-3-aza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-19-methoxymethyl-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;

(S)-4-{(R)-2-{1-[5-(2,2-Dimethyl-propyl)-isoxazol-3-yl]-cyclopropylamino}-ethyl}-1-hydroxy-ethyl)-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(4-isopropyl-pyridin-2-yl)-cyclopropylamino]-ethyl}-18-methoxymethyl-3,15,17-triaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(4-isopropyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-18-Acetyl-4-{(R)-2-[1-(4-tert-butyl-pyridin-2-yl)-cyclopropylamino]-1-hydroxy-ethyl}-3,15-diaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-4-[(R)-1-Hydroxy-2-(2-phenyl-cyclopropylamino)-ethyl]-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-propyl-isoxazol-5-yl)-cyclopropylamino]-ethyl}-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-19-Acetyl-4-{(R)-2-[1-(4-tert-butyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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;

(E)-(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-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;

(E)-(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-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-heptaene-19-carboxylic acid dimethylamide;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-18-methoxy-3,15,17-triaza-tricyclo[14.3.1.1*6,10*]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-one;

(S)-4-{(R)-2-[1-(3-tert-Butyl-phenyl)-cyclopropylamino]-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;

13,14-Benzo-(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclo-propylamino]-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;

(S)-19-[1,3]Dioxolan-2-yl-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-8-Fluoro-4-{(R)-1-hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-ethyl}-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-18-Chloro-4-{(R)-1-hydroxy-2-[1-(4-isopropyl-pyridin-2-yl)-cyclopropylamino]-ethyl}-3,15,17-triaza-tricyclo[14.3.1.1*6,10*]henicosa-1(20),6,8,10(21),16,18-hexaen-2-one;

(S)-19-Chloro-4-{(R)-1-hydroxy-2-[1-(4-isopropyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(3-isopropyl-phenyl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-1-hydroxy-ethyl}-18-methyl-3,15,17-triaza-tricyclo[14.3.1.1*6,10*]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-one;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-4-{(R)-1-Hydroxy-2-[1-(4-isopropyl-pyridin-2-yl)-cyclopropylamino]-ethyl}-18-methoxymethyl-3,15-diaza-tricyclo[14.3.1.1*6,10*]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-one;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-1-hydroxy-ethyl}-18-methoxymethyl-3,15-diaza-tricyclo[14.3.1.1*6,10*]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-one;

(S)-4-{(R)-1-Hydroxy-2-[1-(4-isopropyl-pyridin-2-yl)-cyclopropylamino]-ethyl}-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-1-hydroxy-ethyl}-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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;

(S)-4-{(R)-2-[1-(4-tert-Butyl-pyridin-2-yl)-cyclopropylamino]-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; and

(S)-4-((R)-1-Hydroxy-2-{1-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-cyclopropylamino}-ethyl)-19-methoxymethyl-11-oxa-3,16-diaza-tricyclo[15.3.1.1*6,10*]docosa-1(21),6,8,10(22),17,19-hexaen-2-one.