UA77768C2 - Cathepsin cysteine protease inhibitors, pharmaceutical composition based thereon and a process for preparation thereof - Google Patents

Abstract

This invention relates to a novel class of compounds that are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

Description

zcycloalkyl or heterocyclic ring, where the rhoatom is one to five substituents, the ring system independently indicated is optionally substituted with one or two substituents selected from C-alkyl, halogen, keto, cyano, halo, independently selected from alkyl, hydroxyalkyl, -OVU . -ZOpM(AZ(AU, 0 -ZOp (AZOV SS-

VAZ is hydrogen, C-valkyl or Cg-valkenyl svv M(А'AI -С(ВЕ(АТЛ)ОН, -СООН), - where the specified alkyl and alkenyl groups are optional- С(ВХАЗС(ОМ(ВУ РО), -СОХваХАе), - substituted by C3-ecycloalkyl or from one to M(А'ЗС(ВЕ(АТ (ВУ), -(А'ЗСО(ВУ), -МН(СНг2ОН), six halogen atoms; -MHC(FOOV!e, -5i(CHvz)z, heterocyclyl, aryl or

B" represents hydrogen, C1-alkyl or C1-2 alkenyl, heteroaryl; where the indicated alkyl and alkenyl groups are optional; B" represents hydrogen or C1-alkyl; substituted by C3-cycloalkyl or from one to or in and 28 or can be taken together with any six halogen atoms; which of the atoms to which they can be attached - or VZ Her B" can be taken together with a carbon atom, or are between them, with the formation of a 4-10- , to which they are attached with the formation of a C3-membered heterocyclic ring system, where the cycloalkyl ring, C3-vcycloalkenyl ring system, which can be a monocyclic ring or a five-seven-membered heterocyclic ring or bicyclic, optionally substituted by one radical, where cycloalkyl, cycloalkenin, or two substituents are indicated, independently, and heterocyclic groups are optionally substituted by C-alkyl, halogen, hydroxyalkyl, or by one or two substituents, regardless of hydroxy, keto, -ОВ"Е , -5819 or -M(B"9)"; early from C-alkyl, halogen, hydroxyalkyl, B? selected from the group consisting of hydrogen, hydroxy, alkoxy or keto; aryl, aryl(Ci-4)alkyl, heteroaryl, heteroa-

IN? selected from hydrogen or C-alkyl, substituted 1-aryl(Ci-4)alkyl, C3--zcycloalkyl, C3-zcycloalkyl(C3-b with halogen atoms; 4)alkyl and heterocyclyl(C1-4)alkyl, where the indicated groups

ANYA is oaryl, heteroaryl, C- can be optionally substituted by one, two halogenoalkyl, arylalkyl, or heteroarylalkyl, where or by three substituents independently selected from the indicated aryl, heteroaryl, arylalkyl, and halogen, alkoxy, or -5028!2; heteroarylalkyl groups are optionally substituted with B!? represents hydrogen or C-alkyl with one, two or three substituents, independently B" represents hydrogen or C-alkyl; selected Kk! halogen, C-alkyl, C-B!? represents hydrogen, C-alkyl, which az-haloalkyl, C3-cycloalkyl, haloalkyl, - covalently substituted by one, two or three substituents - 58, -58!2, -5ОВ8У, -50В8!2, -5028У, -5028!2, - independently selected from halogen . , Ci-alkyl, (Ci-alkyl)aryl, each O independently represents Ci-alkyl, Co- (Ci-alkyl)hydroxyl, -FO(Ci-alkyl), hydroxyl, halo-alkenyl; Co-alkynyl, oaryl, heteroaryl, C3- gen, aryl, heteroaryl, C3-ccycloalkyl, heterocyclo- ccycloalkyl or heterocyclyl, where each indicated is lyl, where indicated alkyl, aryl, heteroaryl, C3-aryl, heteroaryl, cycloalkyl and hetero- cscycloalkyl and heterocyclyl may be optional yaz is a cyclyl group that can be monocyclic when substituted eny either on a carbon atom, or on a hetero- or bicyclic, optionally substituted or on a rhoatom by one, two or three substituents, a carbon atom, or on a heteroatom by one to five independently selected from C-alkyl or halogen; by substituents independently selected from C-valkyl, A? represents hydrogen, C1-alkyl, (C1-alkyl)aryl, haloalkyl, halogen, keto, alkoxy, -582, -58"2, (C1-alkyl)hydroxyl, hydroxy, hydroxyl, halogen, -ОВ8, -ОВ! 2, M(B2)2", -50289 or -5028/9; aryl, heteroaryl, C3-zcycloalkyl, heterocyclyl, where

B" represents hydrogen, C3-alkyl, Co-is alkenyl, Co2-indicated alkyl, aryl, heteroaryl, C3-zvcycloalkyl and alkynyl, C1-alkyloxy, halogen, nitro, cyano, aryl, heterocyclyl can be optionally substituted heteroaryl, C3-cycloalkyl, heterocyclyl, "- either by the carbon atom, or by one heteroatom, svia, -С(Ф0О5СН(СН3)гии, -ОВУ, ОВ, - by two or three substituents, independently chosen

С(О)ВЯ, -ВЭ(ОО)А8Я, -С(О0)8З, -С(ОМ(В(В), - them from Si-valkyl or halogen; с(ом(вА'ХВ2), -С(О)М(АТ (А, -С(А'(АТОН), - or 2 and Р? can be taken together with a carbon atom-

ЗВв2, -58Я, -ВЭАЯ, -88, -С(ВЗ)з, -С(АО(АТ МВ)», to the plane to which they are attached, or are located -МАЯАС(О)МАО5(О) 2AU, -5О»НВ!2, -ВО(В2), -BO»НУ, - between them, with the formation of a C3-C cycloalkyl ring-

ЗОтп(В (ВУ), -ВОпсН(А (А), - this or C3-ageterocyclic ring, where 3-8-5ОМ(А СО), -505(В)С(ОМ(В2)) is indicated, - member ring system may be optional

OBO" (AB) 0 -M(А'ЗС(ОМА (VU), - replaced by one or two substitutes, independent

М(В')С(ОВЯ, -М(А'ЗС(ОВЯ, -МЩ(А'ЗС(ООВ) - but selected from Si-alkyl and halogen;

М(А35О(А 0 -С(А'Е(АТИМАТС(ВАТИВ, С- В: represents hydrogen or Si-alkyl), which is not

C(Veu(ATIM(AO) VU, "(AAU M(A (A)), - necessarily replaced by one, two or three prefixes C(A (AAU), vV'oB-, - substitutes, independently selected from halogen or - сС(veuvMAeС(Ве(АТСАУ), -С(ВеДАМ(ВеДАБ), - ОН; с(вдАЗС(В(АМ(ВУХА), - ВУ is hydrogen or Si-alkyl), which is not sosvg(vemvatsA), -С(В(vUMAZS(ОВ, - necessarily replaced by one, two or three substitutes) selected from halogen or -

B(OH)", -ОСНгО- or 4,4,5,5-tetramethyl-1,93,2- ОВУ; disoxoboran-2-yl; where the specified optional or 2nd BU groups can be taken together with the azo atom, substituted either by the carbon atom or by the het to which they are attached, or are located between

771168 6 them with the formation of a C3-β-heterocyclic ring, M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-) which is optionally substituted by one or two pyridines -4-ylphenyl)ethyl-leucinamide; substituents independently selected from C-alkyl, ha-M'!-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(4-C4- (2- hydroxyalkyl, hydroxy, alkoxy or keto; fluoroethyl)piperazin-1-ylcarbonylphenyl)ethyl/-- n independently selected from an integer from zero to leucinamide; three; M1-(cyanomethyl)-M2-(2,2 ,2-trifluoro-1-(4-C4-(2- each t independently selected from an integer from fluoroethyl)piperazin-1-yl|carbonyl and )phenyl)ethyl|/-- zero to two; leucinamide; and their pharmaceutical acceptable salts, stereoisomers and M2-(1-(1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl|-M!-

M-oxide derivatives. (cyanomethyl)! -leucinamide; 2. The compound according to item 1, where V! is hydrogen and B? M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(3-hydroxy- is hydrogen, or B"! and 22? can be taken as 3-methylbut-1-ynyl) phenyl|ethyl)!-leucinamide; together with the carbon atom to which they are attached, M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I|4-(3- with the formation of a C3-cycloalkyl ring, where hydroxy-3-methylbutyl)phenylethyl)!-leucinamide; this ring system is optionally substituted by Mm2-(15)-1(4-bromophenyl)-2,2,3,3, 3- one or two substituents selected from C-pentafluoropropyl|-M'-(cyanomethyl)!-leucinamide, alkyl or halogen, and its pharmaceutically acceptable M'!-(cyanomethyl)-M2-(15)-2,2, 3,3,3-pentafluoro-1- salts, stereoisomers and M-oxide derivatives.pyridin-4-ylphenyl)propyl-leucinamide; 3. The compound according to item 2, where EZ is C-alkyl, M!-(cyanomethyl )-M2-((15)-2,2,2-trifluoro-1-(4-fluoro- which is optionally substituted from one to six 1,1-diphenyl-4-yl)ethyl|I -leucinamide; atoms halogen, and B" is hydrogen, and its M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(1E)- is pharmaceutically acceptable these salts, stereoisomers and M-3-hydroxy-3-methylbut-1-enyl)| phenyl)ethyl)-- oxide derivatives. leucinamide; 4. The compound according to item 3, where BZ is n-propyl, M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-1-|4-isobutyl, 2- fluoro-2-methylpropyl, 2-(methylthio)-1,1-diphenyl-4-yl|ipropyl)i-leucinamide; trifluoromethylpropyl, 3-fluoro-2-(2-M'!-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-1-|(4-fluoromethyl)propyl, 2,2 -difluoroethyl, 2,2-(methylsulfonyl)-1,1-diphenyl-4-yl|propyl - difluoropropyl, 3,3,3-trifluoropropyl or 2,2-leucinamide; dichloroethyl and P" is hydrogen, and its - M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I4-(1- tically acceptable salts, stereoisomers and M-oxide oxidepyridin-3-yl)uphenyl|ethyl)!- leucinamide; derivatives. M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4- 5. The compound according to item 3, where P" represents hydrogen and Bo (morpholine-4 -ylcarbonyl)phenyl|ethyl)!-leucinamide; is aryl or heteroaryl, where the indicated aryl is M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- or heteroaryl neobo necessarily substituted by one, Cmethoxy(methyl)amino|carbonylphenyl)ethyl/-- two or three substituents selected from halo-leucinamide; gene or -5028!2; and its pharmaceutically acceptable M!-(cyanomethyl)-M2-(( 15)-2,2,2-trifluoro-1-(4-thien-3- salts, stereoisomers and M-oxide derivatives. ylphenyl)ethyl-leucinamide; 6. The compound according to item 3, where IS? is hydrogen and B M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-(4- is C-alkyl substituted by 1-6 methylpyridin-2-yl atoms )uphenyl|ethyl)! -leucinamide; halogen; and their pharmaceutically acceptable salts, methylpyridin-2-yl )uphenyl|ethyl)! -leucinamide; 7. The compound according to item 6, where BEZ represents hydrogen and 25 M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(2'-fluoro-) represents trifluoromethyl or 3 ,3,3,2,2- 1,1-diphenyl-4-yl)uethyl|I-leucinamide; pentafluoroethyl; and its pharmaceutically acceptable salts, M'-(cyanomethyl)-M2-41 5)-1-I4- (3,5- stereoisomers and M-oxide derivatives. dimethylisoxazol-4-yl)phenyl|-2,2,2-trifluoroethyliu - 8. The compound according to item b, where n equals two, each O is leucinamide; independently represents aryl or heteroaryl and B" M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4- represents -5ZOpCH(B'3(B) or -5O4( B8-X(VU), (hydroxymethyl)-1,1-diphenyl-4-yl|ethyl -

In Her VU, each independently represents hydrogen or leucinamide;

Si-valkyl; and its pharmaceutically acceptable salts, ste-Me-((15)-1-(4-cyano-1,1"-diphenyl-4-yl)-2,2,2- rheoisomers and M-oxide derivatives. trifluoroethyl|- M'-(cyanomethyl)!-leucinamide; 9. The compound according to item 1, selected from the group including: M'-(cyanomethyl)-M2-((15)-1-(34-difluoro-1,1 "-

N-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide; trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-methyl ether 4-1-P1-(cyanomethylcarbamoyl)-3-yl|styl)-leucinamide; methylbutylamino!-2,2,2-trifluoroethyldiphenyl-2-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-phenylethyl)|! - carboxylic acid; leucinamide; methyl ether 4-1-P1-(cyanomethylcarbamoyl)-3-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-fluoro-3-methylbutylamino|-2,2,2-trifluoroethyl)diphenyl-3-methylphenyl)ethyl-leucinamide; carboxylic acid;

M1-(cyanomethyl)-M2-K1B)-2,2,2-trifluoro-1-(4-M'1-(cyanomethyl)-M2-(15)-1-(3',4"- dimethoxy-1,1"-pyridin-3-ylphenyl)ethyl|-leucinamide; diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- |2'-pyridin-3-ylphenyl)ethyl|-leucinamide; (trifluoromethyl)-1,1"-diphenyl-4-yl|ethyl -

M1-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(4-leucinamide; pyridin-4-ylphenyl)ethyl|1-leucinamide; M1-(cyanomethyl)-M2-((15)-1-(3'4"-dichloro-1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(3'-Mm2-(15)-1-(2-benzoyl-1,1-diphenyl-4-yl) )-2,2,2-formyl-1,1"-diphenyl-4-yl)ethyl|1-leucinamide; trifluoroethyl|-N'-(cyanomethyl)!-leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(2-Me-((15)-1-(3'-acetyl-4"-hydroxy-1 ,1!-diphenyl-4-yl)-oxo-2,3-dihydro-1,3-benzothiazol-b-yl)uphenyl|ethyl-2,2,2-trifluoroethyl|-M'-(cyanomethyl)!- leucinamide; leucinamide; M1-(cyanomethyl)-M2-((15)-1-(2'-(cyanomethyl)-1,1"-

Mm2-((15)-1-I4-(5-bromopyridin-3-yl)uphenyl/|-2,2,2-diphenyl-4-yl|-2,2,2-trifluoroethyl)! -leucinamide; trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl-(trifluoromethoxy)-1,1 "-diphenyl-4-yl|Iethyl - leucinamide; leucinamide; M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4--

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I4-(1H-(methylsulfinyl)-1,1-diphenyl-4-yl|ethyl. - indole-4-iluphenyl |ethyl)! -leucinamide; leucinamide;

M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4- morpholine-pyrimidine-5-ylphenyl)ethyl|I--leucinamide; 4-ylphenyl)ethylI-leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M1-(cyanomethyl)-M2-(18)-2,2,2-trifluoro-1- 14-(6-quinolin-3-ylphenyl)ethyl-leucinamide; methylpyridin-3-yl)/phenyl(1-ethyl)-leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I(4-(1,3- M'1-(cyanomethyl)-M2-(15)-2,2, 2-trifluoro-1-(4-(6-thiazol-2-yl)/uphenyl|ethyl)-leucinamide; methylpyridin-3-yl)/phenyl|ethyl)-leucinamide; methyl ether 4-(11-(1--(cyanomethylcarbamoyl)-3-M!-(cyanomethyl)-M2-(12,2,2-trifluoro-1-phenylthien-2-methylbutylamino!-2,2,2- trifluoroethyldiphenyl-4-yl)ethyl|-leucinamide; carboxylic acid; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-quinoline-8-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-ylphenyl)ethyl|I-leucinamide; pyrimidine-2-ylphenyl)ethyl|I--leucinamide; M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-I4-(3-pyridin-2-ylphenyl)ethylI--leucinamide; methylpyridin-2-yl/uphenyl|ethyl) ! -leucinamide; M2-41-4-(aminosulfonyl)-1,1-diphenyl-4-yl|-2,2,2-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3-trifluoroethyl)-M1-(cyanomethyl)1-leucinamide; furyl)phenyl|ethyl)-leucinamide ; Me-(15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-yl|-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4-13-2,2,2-trifluoroethyl)-M1-(cyanomethyl)! -leucinamide; (trifluoromethyl)pyridin-2-yl|phenyl)ethyl)-- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-leucinamide; (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-|4-leucinamide; (trifluoromethyl)pyridin-2-yl|phenyl)ethyl)| - M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-leucinamide; (methylthio)-1,1-diphenyl-4-ylethyl)1-leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(5- Me-((15)-1-(4-bromophenyl)-2,2,2 -trifluoroethyl|-M!-(trifluoromethyl)pyridin-2-yl|phenyl)ethyl)|-(cyanomethyl)!-leucinamide; leucinamide; M'!-(cyanomethyl)-M2-(18)-2,2, 2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-K15)-2,2,2-trifluoro-1-(3'-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl. - methoxy-1,1 -diphenyl-4-yl)ethyl and -leucinamide; leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(3- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- |4- methoxy-1,1-diphenyl-4-yl)ethyl|i -leucinamide; (morpholin-4-ylsulfonyl)-1,1"-diphenyl-4-yl|iethyl -

Mm2-((15)-1-14-(acetylamino)-3'-fluoro-1,1"-diphenyl-4-leucinamide; 11-2,2,2-trifluoroethyl)-M1-(cyanomethyl)!. - M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-leucinamide; (isopropylsulfonyl)-1,1"-diphenyl-4-yl|ethyl -

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3-leucinamide; methylthien-2-iluphenyl|ethyl)!-leucinamide; Me-(15)-1 -I4-(aminosulfonyl)-1,1"-diphenyl-4-yl|-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(3'-fluoro-2,2,2-trifluoroethyl)-M1-(cyanomethyl)! -leucinamide; 1,1"-diphenyl-4-yl)ethyl|-leucinamide; m2-((15)-1--4-Kacetylamino)sulfonyl|-1,1"-

Mm2-((15)-1-I4-(5-acetylthien-2-yl)uphenyl/|-2,2,2-diphenyl-4-yl)-2,2,2-trifluoroethyl)-M!-trifluoroethyl )-M!-(cyanomethyl)! -leucinamide; (cyanomethyl)! -leucinamide;

Me-(15)-1-(3'-acetyl-1,1"-diphenyl-4-yl)-2,2.,2-M1-(cyanomethyl)-M2-(15)-2,2, 2-trifluoro-1-(2-trifluoroethyl(|-M'-(cyanomethyl)!-leucinamide; methyl-4-(methylsulfonyl)-1,1-diphenyl-4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-N9'-yl|ethyl)1-leucinamide; (trifluoromethyl)-1,1-diphenyl-4-yl|ethyl-Me-(1-(5-bromothien-2-yl)-2,2,2-trifluoroethyl/|-M!-leucinamide; (cyanomethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(5'-fluoro-Mm2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-M !- 2'-methoxy-1,1"-diphenyl-4-iluethyl|I-leucinamide; (cyanomethyl)!-leucinamide;

M1-(cyanomethyl)-M2-((15)-1-(3,5'-difluoro-1,1"-tert-butyl ether 4-(2-11-(11-diphenyl-4-yl)- 2,2,2-trifluoroethyl!--leucinamide; (cyanomethylcarbamoyl)-3-methyl-butylamino)|-2,2,2-

M1-(cyanomethyl)-M2-K15)-2,2,2-trifluoro-1-(2,3,5-trifluoroethyldiphenyl-4-yl)piperazine-1-carbon trifluoro-,1"-diphenyl-4 -yl)ethyl|I-leucinamide; acids; 3-(2-11-P-(cyanomethylcarbamoyl)-3-M'!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4- piperazine-methylbutylamino|-2,2,2-trifluoroethyl)diphenyl-3-1-yl-1,1"-diphenyl-4-yl)ethyl|i-leucinamide; yl)dacrylic acid; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(4-(2-

Mm2-((15)-1-I4-(9-anthryl)phenyl|-2,2,2-trifluoroethyl)-hydroxyethyl)piperazin-1-yl|-1,1-diphenyl-4-

M'-(cyanomethyl)! -leucinamide; il)iethyl)! -leucinamide;

9 771168 10

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-|4-(2- M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro -1-(4-hydroxy-2-methylpropyl)piperazin-1-yl|-1,1- methoxy-1,1"-diphenyl-4-yl)ethyl|I -leucinamide; diphenyl-4-yl)ethyl) !-leucinamide; M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-(1-(4-methoxyphenyl)ethyl-leucinamide; ((dimethylamino)carbonyl|phenyl)-2,2,2- M1-(cyanomethyl)-M2-((15)- 2,2,2-trifluoro-1-(4-trifluoroethyl)-leucinamide; pyridin-4-yl-1,1"-diphenyl-4-yl)ethyl-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-piperazine-M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-( 4-1-yl-1,1"-diphenyl-4-yl)ethyl-leucinamide; phenoxyphenyl)ethyl-leucinamide;

M1-(cyanomethyl)-M2-(1-(4-m2-((15)-1-(2-bromo-1,1"-diphenyl-4-yl)-2,2,2-(cyclopropylamino) carbonyl|phenyl)y-2,2,2-trifluoroethyl|-N'-(cyanomethyl)!-leucinamide; trifluoroethyl)!-leucinamide; Me-(15)-1-14-(4-chloropyridin-3-yl) phenyl|)|-2,2,2-4-1-P1-(cyanomethylcarbamoyl)-3-trifluoroethyl)-M!-(cyanomethyl)!-leucinamide; methylbutylamino|-2,2,2-trifluoroethylbenzoin Mm2-4( (15)-1-I(2-(acetylamino)-2'-methyl/|-1,1"-diphenyl-acid; 4-ylI-2,2,2-trifluoroethyl)-M!-(cyanomethyl)! -

M'-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(4-(2-leucinamide; fluoroethyl)piperazin-1-yl|-1,1-diphenyl-4-yl) ethyl)|- Mm2-(15)-1-(1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide; M'-(cyanomethyl)!-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-4-((4- M'1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- (4-(6-methylpiperazine-1-ylcarbonyl|phenyl)ethyl))!-methoxypyridin-3-ylphenyl|ethyl)!-leucinamide; leucinamide; M'!-(cyanomethyl)-M2-(15)-2,2 ,2-trifluoro-1-(4-(6-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-C4-(2-methoxypyridin-2-yl)uphenyl|ethyl)!-leucinamide; hydroxy-2-methylpropyl)piperazine- 1- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4"-ylcarbonylphenyl)ethyl|-leucinamide; (methylsulfonyl)-1,17:41"-terphenyl-4 -yl|ethyl -

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|14-(2-leucinamide; methyl-1,3-thiazol-4-iluphenyl|ethyl)!-leucinamide; Me-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-

M2-41-I4-(3-tert-butyl-1,2,4-triazin-5-yl)phenyl|-(cyanomethyl)-3-(1-methylcyclopropyl)! -alanine amide; 2,2,2-trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; M1-(cyanomethyl)-3-(1-methylcyclopropyl)-M2-(15)-

M1-(cyanomethyl)-M2-I(2,2,2-trifluoro-1-(4-(2-(3-2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl - (methylsulfonyl)phenyl|-1,3-thiazol-4-4-yl|ethyl)!-alaninamide; isophenyl)ethyl-leucinamide; M!-(cyanomethyl)-3-(1-methylcyclopropyl)-M2-(( 15)-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(2-(1H-2,2.2-trifluoro-1-(4-(methylthio)-1, 1"-diphenyl-4-pyrazol-4-yl)-1,3-thiazol-4-yl|phenyl)ethyl)|-yl|ethyl)!-alaninamide; leucinamide; M!-(cyanomethyl)-M2-( (15)-2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-|4-methyl-1,1"-diphenyl-4-yl)ethyl|i-leucinamide; (methylsulfonyl)piperazine- 1-yl|-1,1-diphenyl-4-Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2,2-yl)ethyl)I -leucinamide; trifluoroethyl|-M'-(cyanomethyl)! -leucinamide;

M2-(1-(3-bromophenyl)-2,2,2-trifluoroethyl|-M!- M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4- ( cyanomethyl)!-leucinamide; (hydroxymethyl)-1,1"-diphenyl-4-yl|ethyliu -

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(methylthio)-leucinamide; 1,1"-diphenyl-3-yl|ethyl)1-leucinamide; Mm2-(1 -(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(3-pyridine-4-(cyanomethyl)O-leucinamide; ylphenyl)ethyl|I-leucinamide; M1-(cyanomethyl)-M2 -(2,2,2-trifluoro-1-(4--

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-piperazine-(methylsulfonyl)-1,1-diphenyl-4-yl)ethyl-1-yl-1,1"- diphenyl-3-yl)ethyl-leucinamide; leucinamide;

M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4- M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(morpholine- methylsulfonyl)-1,1"-diphenyl-3-yl|ethyl. - 4-ylsulfonyl)-1,1"-diphenyl-4-yl)|ivetyl-leucinamide; leucinamide;

M-(cyanomethyl)-1-(2,2,2-trifluoro-1-M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-phenylethyl)amino)|cyclohexanecarboxamide; Kmethylamino )sulfonyl|-1,1"-diphenyl-4-yl)ethyl)O-1-1-(4-bromophenyl)-2,2,2-trifluoroethylamino)-M-leucinamide; (cyanomethyl)cyclohexanecarboxamide; M'- (cyanomethyl)-M2-(C18)-2,2,2-trifluoro-1-I4-(1-

M-(cyanomethyl)-1-(2,2,2-trifluoro-1-(4-piperazine-oxypyridin-4-yl)phenyl|ethyl)! -leucinamide; yl-1,1"-diphenyl-4-M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-14-(1-yl)ethyl|Iamino)cyclohexanecarboxamide; oxypyridin-4-yl) phenyl|ethyl)!-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-piperidine-M1-(cyanomethyl)-M-(2,2,2-trifluoro-1-4-(6- (1-4-ylphenyl)ethyl-leucinamide; hydroxy-1-methylethyl)-1-oxypyridine-3-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(4-pyridin-yl|phenyl)ethyl)! -leucinamide; 2-ylpiperazin-1-yl)phenyl|ethyl)! -leucinamide; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-I6-

M2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-(methylsulfonyl)pyridin-3-yl|phenyl)ethyl)! - (cyanomethyl)-3-cyclopropylalaninamide; leucinamide;

M1-(cyanomethyl)-3-cyclopropyl-M2-(2,2,2-trifluoro-M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(2-(4 - 1-(4-pyridin-4-ylphenyl)ethyl|alanine amide; methylpiperazin-1-yl)-1,3-thiazol-4-yl|Ifenyl)ethyl)--

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(2-pyridin-4-leucinamide; yl-1,1"-diphenyl-4-yl)ethyl I -leucinamide; M2-(1 -(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-(1-

M1-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(1,3-cyanocyclopropyl)! -leucinamide; thiazol-2-yl)ethyl|-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-piperazine-4-1-P1-(cyanomethylcarbamoyl)-3-methylbutylamine|-1-ylphenyl)ethyl|1-leucinamide; 2.2,2-trifluoroethyl)diphenyl-4-carboxylic acid;

M2-41-I3'(acetylamino)-1,1"-diphenyl-4-ylI|-2,2,2-methoxymethylamide 4"-(1-(1-(cyanomethylcarbamoyl)-trifluoroethyl)-M!- (cyanomethyl)!-leucinamide; 3-methylbutylamine|-2,2,2-trifluoroethyl)diphenyl-4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(4-carboxylic acid; propylpiperazin-1-yl)phenyl|ethyl)-leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I4-(C4-

M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|(4-(piperazine- (methylsulfonyl)benzyl| thio)methyl)phenyl|ethyl)| - 1-ylcarbonyl)phenyl|ethyl)! -leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-C4-(2-Me-C15)-1-14-(B-chloropyridin-2-yl)phenyl|)| -2,2,2- hydroxyethyl)piperazine-1-ylcarbonylphenyl)ethyl-- trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; leucinamide; Me-C15)-1-I3'(aminosulfonyl)-4-bromo-1,1"-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3-|3-diphenyl-4-yl|-2,2,2-trifluoroethyl)-M !- (trifluoromethyl)phenyl|)|-1,2,4-oxadiazole-5-(cyanomethyl)! -leucinamide; isophenyl)ethyl-leucinamide; Mm2-((15)-1-I2-bromo-3'-(methylsulfonyl)-1,1"- methyl ether 4-1-(11-(cyanomethylcarbamoyl)-3-diphenyl-4-ylI|-2,2 ,2-trifluoroethyl-M'-methylbutylamino!-2,2,2-trifluoroethyl)ybenzoic (cyanomethyl)!-leucinamide; acid; M'!-(cyanomethyl)-M2-((15)-2,2,2 -trifluoro-1-14-I(5-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4-KE)-2-methyl-b-(methylsulfonyl)pyridin-3-quinolin-2-ylethenylIfenyl)ethyl) ! -leucinamide; yl|phenyl)ethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3- M2-((15)-1-(4--5-chloro-3-|4 - methyl-1,2,4-oxadiazol-5-iluphenyl|ethyl.-(methylsulfonyl)phenyl|pyridin-2-iluphenyl)-2,2,2-leucinamide; trifluoroethyl|-M'-(cyanomethyl)!-leucinamide ; trifluoro-1-(4-oxadiazol-5-ylphenyl)-2,2,2-trifluoroethyl)-N'-phenylthio)methyl(phenyl)ethyl)-leucinamide; cyanomethyl)! -leucinamide; M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4-

Me-(15)-1-(4-benzoylphenyl)-2,2,2-trifluoroethyl|-M!-Ctrifluoromethyl)sulfonyl|-1,1-diphenyl-4-(cyanomethyl)! -leucinamide; il)iethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(thien-2-M'1-(cyanomethyl)-M2-(15)-2,2,2 -trifluoro-1-(4-(4-ylcarbonyl/phenyl|ethyl)!-leucinamide; fluorobenzoyl)I(amino|methyluphenyl)ethyl|Y--

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-I4-(1,3-leucinamide; thiazol-2-ylcarbonyl)phenyl|ethyl)! -leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(2)-2-(methylsulfonyl)phenyl|ethyl)-leucinamide; 4-(methylsulfonyl)phenyl| Ethenylphenyl)ethyl-N-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-leucinamide; (2-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl. -

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(E)-2-leucinamide; (4-(methylsulfonyl)phenyl|ethenylphenyl)ethyl|-- M'1-(cyanomethyl)-M2-(15)-1-14-(ethylsulfonyl)-1,1"-leucinamide; diphenyl-4-yl|-2,2,2-trifluoroethyl)!-leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- m2-((15)-1-(4-(CI3-(2-chloro-6-fluorophenyl) )-5-isobutyrylphenyl)ethyl|-leucinamide; methylisoxazol-4-ylcarbonylamino)methyl|phenyl)y-

Mm2-4((15)-1-I4-(4-bromo-1,3-thiazol-2-iluphenyl)-2,2,2-2,2,2-trifluoroethyl)-M-(cyanomethyl) !-leucinamide; trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; m2-((15)-1-4-((9-chloro-3-methyl-4-oxoisoxazole4,3-

M1-(cyanomethyl)-M2-K15)-1-(4-cyanophenyl)-2,2,2-siquinolin-5(4H)-yl)umethyl|phenyl)-2,2,2-trifluoroethyl! -leucinamide; trifluoroethyl)-M!-(cyanomethyl)! -leucinamide;

M!-(cyanomethyl)-M2-K1 5)-1-(4-ethynylphenyl)-2,2,2- M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- |4- trifluoroethyl--leucinamide; methoxy-3-(methylsulfonyl)-1,1"-diphenyl-4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(2'-fluoro-yl|styl)1-leucinamide; 1,1"-diphenyl-4-yl)ethyl|-leucinamide; Mm2-4((15)-1-I4"-chloro-4-(methylsulfonyl)-1,172,1"7-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-I4-(1,3-terphenyl-4-ylI|-2,2,2-trifluoroethyl)-M1- thiazol-2-yl/phenylethyl)-leucinamide; (cyanomethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(methylthio)- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- (2-1,1"-diphenyl-4-yl|Hethyl)l-leucinamide; methoxy-4-(methylsulfonyl)-1,1"-diphenyl-4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(2-yl|ethyl)i-leucinamide; methylquinolin-7-yl)uphenyl|ethyl)-leucinamide; Me-C15)-1-|I2'-chloro-4-(methylsulfonyl)-1,1"-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(1H-indole-diphenyl-4-yl|-2,2,2-trifluoroethyl)i-M1- 5- yl)phenyl|ethyl)! -leucinamide; (cyanomethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(1-|4-(dimethylamino)-1,1"- M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4- ((2-diphenyl-4-yl|-2,2,2-trifluoroethyl|-leucinamide; hydroxyethyl)thio|-1,1-diphenyl-4-yl)ethyl)| -

M1-(cyanomethyl)-M2-((15)-1-(4-leucinamide; (Ccyanomethyl)amino|carbonylphenyl)-2,2,2- M'1-(cyanomethyl)-M2-(15)- 2,2,2-trifluoro-1-13'-fluoro-trifluoroethyl!-leucinamide; 4-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl -

M!-(cyanomethyl)-M2-K1 B)-1-(4-leucinamide; ((cyanomethyl)amino|carbonylphenyl)-2,2,2- M!-(cyanomethyl)-M2-((15)-2 -

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-1|9'-leucinamide; (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-19'- M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1- (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - 14-(2-methyl-1,3-oxazol-4-yl)phenyl|ethyl)u. - leucinamide; leucinamide;

M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-((2- M!-(cyanomethyl)-M2-((15)-2,2,2- trifluoro-1-(4-

Imethoxy(methyl)amino|-2-oxoethylsulfonyl)-1,1-pyrazin-2-ylphenyl)ethyl|I-leucinamide; diphenyl-4-yl|ethyl)-leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-(2-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4-((2-methylpyridin-4-yl)phenyl|ethyl)-leucinamide; hydroxy-2-methylpropyl)sulfonyl |-1,1"-diphenyl-4-M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-(4-yl)ethyl)I-leucinamide; methylpyridine- 3-yl)/phenyl|ethyl)-leucinamide;

M2-(15)-1-4-(aminosulfonyl)-1,1"-diphenyl-4-yl|- M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1- 2,2,2-trifluoroethyl)-M1-(1-cyanocyclopropyl)|.- I4-(1H-pyrazol-4-yl)uphenyl|ethyl)-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2 -((15)-2,2,2-trifluoro-1-m2-(4-bromophenyl)(2,4,6-trifluorophenyl)methyl|-M!- (4-pyridin-4-ylphenyl)ethyl|- leucinamide; (cyanomethyl)!--leucinamide; M2-(15)-1-(3'-acetyl-1,1"-diphenyl-4-yl)-2,2,2-

M1-(cyanomethyl)-M2-(4-pyridin-4-ylphenyl)(2,4,6-trifluoroethyl|-M1-(1-cyanocyclopropyl)!.-trifluorophenyl)methyl! -leucinamide; leucinamide;

M1-(cyanomethyl)-M2-I|(4-(4-M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-fluorobenzyl)phenyl)|(phenyl) methyl!--leucinamide; (3'-fluoro-4-methyl-1,1"-diphenyl-4-yl)ethyl|//--

M1-(cyanomethyl)-M2-(phenyl|4-(pyridin-3-leucinamide; ylmethyl)phenyl|methyl)! -leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

Mm2-(4-bromophenyl)|4-15-14-(1-hydroxy-1-methylethyl)phenyl|pyridine-2-(methylsulfonyl)phenyl|methyl)-M!-(cyanomethyl)! - il)iethyl)! -leucinamide; leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-1-|4-

M1-(cyanomethyl)-M2-(|4-(methylsulfonyl)phenyl|(4"-(1-hydroxy-1-methylethyl)-1,1-diphenyl-4-(methylthio)-1,1-diphenyl- 4-yl|methyl)yl-leucinamide; yl|propyl)yl-leucinamide;

M1-(cyanomethyl)-M2-DCA-(methylsulfonyl)-1,1"- M1-(1-cyanocyclopropyl)-M2-((15)-2,2,3,3,3-diphenyl-4- yl|(4-"methylsulfonyl)phenyl|methyliu - pentafluoro-1-(2-methyl-1,1-diphenyl-4-yl)propyl|-- leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trichloro-1-(4-M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-1- |4- glycoloylphenyl)ethyl|-leucinamide;

M1-(cyanomethyl)-M2-(2-fluoro-1-(fluoromethyl)-1- M1-(cyanomethyl)-M2-((15)-2,2,3,3,3-pentafluoro-1- (2/- phenylethyl-leucinamide; fluoro-1,1-diphenyl-4-yl)propyl|I-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|(4-(pyrrolidine-M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1 - 1-ylacetyl)phenyl|ethyl)! -leucinamide; (2-methoxy-3-(methylsulfonyl)-1,1-diphenyl-4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(piperazin-yl|ethyl)1-leucinamide; 1-ylcarbonyl/phenyl|ethyl)11-leucinamide; Me-C15 )-1-I3'"aminosulfonyl)-4"-methoxy-1,1"-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-14-(2-(4-diphenyl-4-yl|-2,2,2-trifluoroethyl)-M1-(1- methylpiperazin-1-yl)-1,3-thiazol-4-yl|phenyl)ethyl)/ - cyanocyclopropyl)! -leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

M1-(1-cyanocyclopropyl)-3-(1-methylcyclopropyl)-I4-(b-methoxypyridin-3-iluphenyl|ethyl)u. - m2-(2,2,2-trifluoro-1-(4-(1-(2-leucinamide; hydroxyethyl)propyl|Iphenyl)ethyl)!-alaninamide; M'!-(cyanomethyl)-M2(15)- 2,2,3,3,3-pentafluoro-1-|4-

Me-((4-(4-tert-butylpiperazin-1-B-methylpyridin-2-yl)uphenyl|propyl)-leucinamide; yl)/phenyl|(pentafluorophenyl)methyl|-M!- M!-(1- cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-(cyanomethyl)!--leucinamide; (4-(5-(methylsulfonyl)pyridin-2-yl|phenyl)ethyl) --

M-(cyanomethyl)-1-(11-14-(4-methylpiperazine-1-leucinamide; yl)phenyl|ethyl)piperidine-2-carboxamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-m2-((4-(4-tert-butylpiperazin-1-yl)uphenyl|(pyridin-I4-( 5-methylpyridin-2-yl)/phenyl|ethyl)-leucinamide; 2-yl)umethyl|-N'-(cyanomethyl)!-leucinamide; M!-(cyanomethyl)-4-fluoro-M2-(15)- 2,2,2-trifluoro-1-

M2-4I4-(4-tert-butylpiperazin-1-yl)uphenyl-(2-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl - (trifluoromethyl)pyridin-2-yl|methyl)-M! - leucinamide; (cyanomethyl)! -leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-(45)-M-(cyanomethyl)-4-methyl-1-|(15)-1-( 4-trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-piperazin-1-ylphenyl)ethyl|-prolinamide; yl|styl)-leucinamide; (45)-M-(cyanomethyl)-4-methyl-1-M18)-1-(4-M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- piperazin-1-ylphenyl)ethyl|-prolinamide; trifluoro-1-(2'-methyl-4-(methylsulfonyl)-1,1-

M-(cyanomethyl)-1-((15)-1-(4-piperazin-1-diphenyl-4-yl|ethyl)-leucinamide; ylphenyl)ethyl|-prolinamide; M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-

M-(cyanomethyl)-1-(1 A)-1-(4-piperazin-1-(5-O1H-pyrazol-3-yl)pyridin-2-yl|ethyl)-leucinamide; ylphenyl)ethyl|-prolinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

M-(cyanomethyl)-4,4-difluoro-1-((15)-1-(4-piperazine- (b-quinolin-5-ylpyridin-2-yl)ethyl|-leucinamide; 1-ylphenyl)ethyl- -prolinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-(b-quinolin-6-ylpyridin-2-yl)ethyl|-leucinamide; (4-methylphenyl)ethyl- -leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2-difluoro-1-|I4-

M1-(1-cyanocyclopropyl)-M2-(15)2,2,2-trifluoro-1-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl. -

I4-(1H-pyrazol-3-yl)uphenyl|ethyl)-leucinamide; leucinamide;

Me-(15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2.,3,3,3- Me-((15)-1-(3'-acetyl) -1,1"-diphenyl-4-yl)-2,2,2-pentafluoropropyl|-M!-(1-cyanocyclopropyl) I - trifluoroethyl /|-M!-(1-cyanocyclopropyl)-4-fluoro - leucinamide leucinamide;

Me-(15)-1-(1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl|- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2 ,2,2-

M1-(1-cyanocyclopropyl)! -leucinamide; trifluoro-1-I4-(1H-pyrazol-3-yl)phenyl|ethyl -

Mm2-((15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-yl|-leucinamide; 2,2,3,3,3-pentafluoropropyl)-M!-(1- M' -(15)-1-cyanoethyl|-M2-C15)-2,2,2-trifluoro-1-|4-cyanocyclopropyl)!-leucinamide; (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(1- leucinamide; ethoxyvinyl)phenyl|-2,2,2-trifluoroethyl)- M!-(15)-1-cyano -3-(methylthio)propyl/|-M2-((15)-2,2,2- leucinamide; trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-

Me-(15)-1-(4-acetylphenyl)-2,2,2-trifluoroethyl|-M!-yl|ethyl)i-leucinamide; (1-cyanocyclopropyl)! -leucinamide; M'-(15)-1-cyano-3-(methylsulfonyl)propyl|-Me-

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1" - (4-isopropylphenyl)ethyl|-leucinamide; diphenyl-4-yl|ethyl)!-leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-Mm2-(15)-1-(4-bromophenyl)-2,2,3,3,3-phenylethyl -leucinamide; pentafluoropropyl|-M1-(1-cyanocyclopropyl)| -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-leucinamide;

14-(1-hydroxy-1-methylethyl)phenyl|ethyl. - M'-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-1-I|4-leucinamide; (b-methoxypyridine-2-iluphenyl|propyl) and -leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1- M2-(15)-1-(5-bromopyridin-2-yl)-2,2,2-

14-(1-methylcyclopropyl)phenyl|ethyl)-leucinamide; trifluoroethyl|-M'-(cyanomethyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-( 5-(4-(2,4,6'-trimethyl-1,1-diphenyl-4-yl)ethyl|--(methylsulfonyl)phenyl|pyridin-2-yl)ethyl) - leucinamide; leucinamide;

Me-((15)-1-(b-chloropyridin-3-yl)-2,2,2-trifluoroethyl-M!-(-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1 -

M!-(1-cyanocyclopropyl)! -leucinamide; I2-(1-hydroxy-1-methylethyl)-1,1"-diphenyl-4-

M2-4(15)-1-I5-(4-acetylphenyl)pyridin-2-ylI-2,2,2-yl|styl)-leucinamide; trifluoroethyl)-M!-(1-cyanocyclopropyl)! - M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(6'-leucinamide; methyl-3,3'-dipyridin-b-yl)ethyl|1-leucinamide;

Mm2-((15)-1-I6-(4-acetylphenyl)pyridin-3-yl|-2,2,2- M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2- trifluoro-1-trifluoroethyl)-N-(1-cyanocyclopropyl)-N4-(b-methoxypyridin-2-yl)uphenyl|ethyl)u. - leucinamide; leucinamide;

M2-4(15)-1-15-(3-acetylphenyl)pyridin-2-yl1-2,2,2-M'1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro- 1-(4-(6-trifluoroethyl)-N-(1-cyanocyclopropyl)-oxo-1,6-dihydropyridin-2-yl)uphenyl|ethyl. - leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-(45)-M'1-(cyanomethyl)-5,5,5-trifluoro-Me-(15 )-2,2,2- (5-4-(1-hydroxyethyl)phenyl|pyridin-2-yl)ethyl)--trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-leucinamide; il|styl) -leucinamide; m2-I(15)-1-(1,1"-diphenyl-4-yl)-2,2,3,3,3-(45)-M-(1-cyanocyclopropyl)-5,5,5 -trifluoro-Me-pentafluoropropyl|-M'-"(cyanomethyl)!-leucinamide; (15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-

Me-(15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2.,3,3,3-diphenyl-4-yl|ethyl)-leucinamide; pentafluoropropyl|- M'-(cyanomethyl)!-leucinamide; (45)-M'!-(cyanomethyl)-5,5,5-trifluoro-Me-(15)-2,2,2-

Me-(15)-1-(1,1"-diphenyl-4-yl)-2,2,3,3,3-trifluoro-1-I4-(methylthio)-1,1"-diphenyl-4- il|ethyl. - pentafluoropropyl|-M!-(1-cyanocyclopropyl) I - leucinamide; leucinamide; (45)-M!-(1-cyanocyclopropyl)-5,5,5-trifluoro-Me-

M2-(1-benzyl-2,2,2-trifluoroethyl)-M!-(1-(15)-2,2,2-trifluoro-1-(4-(methylthio)-1,1-diphenyl-4 - cyanocyclopropyl)-leucinamide; yl|styl)-leucinamide; m2-((15)-1-(4-tert-butylphenyl)-2,2,2-trifluoroethyl- (45)-M2-((15U-1-(4-bromophenyl)-2,2,2-trifluoroethyl) -

M!-(1-cyanocyclopropyl)! -leucinamide; M1-(cyanomethyl)-5,5,5-trifluoro-I-leucinamide;

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M'- (45)-M2-((15)-1-(4-bromophenyl)-2,2,2 -trifluoroethyl|-(cyanomethyl)-4-methyl-1-leucinamide; M1-(1-cyanocyclopropyl)-5,5,5-trifluoro-

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl/|-M!-(1-leucinamide; cyanocyclopropyl)-4-methyl-i-leucinamide; Mm2-((15)-1-(4-(6-aminopyridin-3-iluphenyl|-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; (4--2-(1H-pyrazol-4-yl)-1,3-thiazol-4-ylIfenyl)ethyl)-- Mm2-(15)-1-(4-bromophenyl)-2,2,2- trifluoroethyl|-M-(1-leucinamide; cyanocyclopropyl)-4-fluoro-I-leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1- M'-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro- 1-I|4-

I4-(2-methyl-1,3-thiazol-4-iluphenyl|ethyl. - (b-methylpyridin-3-yl)phenyl|propyl)-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-pentafluoro-1-(4-(b-methylpyridine-3-

14-(2-methylpyridin-4-yl)uphenyl|ethyl)-leucinamide; yl)phenyl|propyl)i -leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1- M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

14-(2-methylpyridin-3-yl)/phenyl|ethyl)-leucinamide; 14-(b-methylpyridin-3-yl)/phenyl|ethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4- (1-

14-(b-methylpyridin-2-yl)/phenyl|ethyl)-leucinamide; hydroxyethyl)-1,1-diphenyl-4-yl|ethyl)-leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(2,2,2- M'-(cyanomethyl)-M2-((15)-2,2 ... ; diphenyl-4-yl)ipropyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3-M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4 - pentafluoro-1-(4-(methylthio)-1,1"-diphenyl-4-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl-yl|ipropyl)i-leucinamide; alanine amide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,3,3,3- M!-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro- 1-|4-pentafluoro-1-(4-(1-hydroxy-1-methylethyl)-1,1"-(isopropylsulfonyl)-1,1"-diphenyl-4-yl|propyl - diphenyl-4-yl| Ipropyl)-leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3- M1-(1-cyano-1-methylethyl)-M2-((15)-2,2,2 -trifluoro-1-pentafluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4- (2-(methylsulfonyl)-1,1-diphenyl-4-yl|Iethyl. - yl|Ipropyl)i - leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,3,3,3- M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1- pentafluoro-1-(4-(6b-methoxypyridin-2-(42-K2-hydroxy-2-methylpropyl)sulfonyl|-1,1"-yl/uphenyl|propyl)-leucinamide; diphenyl-4-yl)ethyl) !-leucinamide; (48)-M'-(cyanomethyl)-5,5,5-trifluoro-M2-C15)-2,2,2- M1-(1-cyanocyclopropyl)-M2-((15)-2 ,2,2-trifluoro-1-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-(2-methyl-4-(methylsulfonyl)-1,1-diphenyl-4-yl) )-leucinamide; yl|stil)-leucinamide; (48)-M1-(1-cyanocyclopropyl)-5,5,5-trifluoro-Me-M1-(1-cyanocyclopropyl)-M2-C15)-1- I4-(C15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-(ethylsulfonyl)-1,1-diphenyl-4-yl|-2,2,2-diphenyl -4-yl|ethyl)-leucinamide; trifluoroethyl)! -leucinamide;

M!-(cyanomethyl)-M2-((15)-2,2,33,3-pentafluoro-1-(4- Mm2-4((15)-1-(-(aminosulfonyl)-1,1"- diphenyl-4-yl]-methyl-1,1"-diphenyl-4-yl)propyl]-leucinamide; 2,2,2-trifluoroethyl)-N-(1-cyanocyclopropyl)-4-

M1-(cyanomethyl)-M2-((15)-2,2,3,3,3-pentafluoro-1-|4-fluoro-I-leucinamide; (1,3-thiazol-2-iluphenyl|propyl) and -leucinamide; M'-(cyanomethyl)-M2-(5)-I4-(methylsulfonyl)-1,1"-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-ethynylphenyl)-diphenyl-4-yl|4-(trifluoromethoxy)phenyl|methyliu. - 2,2,3,3,3 -pentafluoropropyl)I -leucinamide; leucinamide;

M!-(cyanomethyl)-M2-(15)-1-|4- M!-(cyanomethyl)-M2-|(5)-(2-(methylsulfonyl)-1,1"- (cyclopropylethynyl)phenyl|- 2,2,2-trifluoroethyl)!-diphenyl-4-yl(thien-2-yl)umethyl|-leucinamide; leucinamide; M!-(cyanomethyl)-M2-((5)-(4"-piperazine-4 -yl-1-yl-1,1"-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-diphenyl-4-yl(thien-2-yl)umethyl)- (cyclopropylethynyl)phenyl|-2,2,2-trifluoroethyl )! - leucinamide methanesulfonate; leucinamide; M'-(cyanomethyl)-M2-((5)-(4-fluorophenyl)|4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(5-(methylsulfonyl)-1,1-diphenyl-4-yl|methyl. - methyl-1, 3-thiazol-2-iluphenyl(ethyl)-leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-M'-(cyanomethyl)-M2-(5)-I4-(methylsulfonyl)-1,1"-

I4-(1,3-thiazol-2-iluphenyl|ethyl)! -leucinamide; diphenyl-4-yl--trifluoromethyl)phenyl|methyl) -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-leucinamide;

I4-(5-methyl-1,3-thiazol-2-iluphenyl|ethyl. - Mm2-((5)-(4-chlorophenyl)|4"-(methylsulfonyl)-1,1"-leucinamide; diphenyl-4 -yl(Imethyl)-N-(cyanomethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-(cyclopropylethynyl) phenyl|-2,2,3,3,3-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl.-pentafluoropropyl)!-leucinamide; norvalinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-Me-((5)-(4-bromophenyl)(thien-2-yl)umethyl|-M1-

I4-(4-methyl-1,3-thiazol-2-iluphenyl|ethyl.-(cyanomethyl)!-leucinamide; leucinamide; M!-(cyanomethyl)-M2-|(5)-I4-(4,4, 5,5-tetramethyl-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4-(4-1,3,2-dioxaborolan-2-iluphenyl(thien-2-yl)methyl) -- methyl-1,3-thiazol-2-iluphenyl|ethyl)!-leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(15)-1-I(4-(4,5-dimethyl-1,3-Mm2-(A)-(4-bromophenyl)|(4-thiazol-2-yl )uphenyl|-2,2,2-trifluoroethyl - (trifluoromethoxy)phenyl|methyl)-M!-(cyanomethyl)|!- leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-((1 5)-1-|(4- M-(cyanomethyl)-M2-((1 5)-I4-(4,4,5,5-tetramethyl- ( ethylsulfonyl)-1,1-diphenyl-4-yl|-2,2,2- 1,2,3-dioxaborolan-2-yl)phenyl-trifluoroethyl)-4-fluoro-I-leucinamide; (trifluoromethoxy)phenyl| methyl)!-leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- Mm2-(5)-(4-bromophenyl)(2-furyl)methyl|-M!- trifluoro-1- (4-pyridin-3-ylphenyl)ethyl--(cyanomethyl)! -leucinamide; leucinamide; M1-(cyanomethyl)-M2-((5)-2-furyl/(g"-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-(methylsulfonyl)-1,1-diphenyl-4-yl|methyl. - trifluoro-1-(4-methoxy-3-(methylsulfonyl)-1,1-leucinamide; diphenyl-4-yl|ethyl)! -leucinamide; M2-(11-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M'-6-(cyanomethyl)! -norvalinamide; (cyanomethyl)! -alanine amide; m2-(B8)-(4-bromophenyl) |4-

Mm2-((15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-yl|-(trifluoromethyl)phenyl|methyl)-M!-(cyanomethyl)| - 2,2,3,3 ,3-pentafluoropropyl)-N-(cyanomethyl)-leucinamide, leucinamide;

M1-(cyanomethyl)-M2-11-I4-(4-cyclopropylpiperazine-M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-1-yl)-1,1 "-diphenyl-4-yl|-2,2,2-trifluoroethyl - 14-(2-methylpyridin-4-yl)uphenyl|ethyliu - norvalinamide; norvalinamide;

Me-(A)-(4-bromophenyl)(4-chlorophenyl)methyl|-M!- M!-(1-cyanocyclopropyl)-5,5,5-trifluoro-M2-((15)-(cyanomethyl)! -leucinamide; 2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-4-yl|ethyl)! -norvalinamide; (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-norvalinamide; I4-(1H-pyrazole -3-yl)uphenyl|ethyl)-norvalinamide;

Me-(5)-(4-bromophenyl) (3-methylthien-2-ylylmethyl)-M1-M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1- ( cyanomethyl)! -leucinamide; I2-(1-hydroxy-1-methylethyl)-1,1"-diphenyl-4-

Me-(5)-(4-bromophenyl)(thien-3-yl)umethyl|-M!-yl|ethyl)i-norvalinamide; (cyanomethyl)! -leucinamide; M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-

M1-(cyanomethyl)-M2-((5)-(2,4-difluorophenyl(4"- 14-(5-methylpyridin-2-yl)phenyl|ethyliu - (methylsulfonyl)-1,1"-diphenyl- 4-yl|methyl - norvalinamide; leucinamide; cyanomethylamide 2-((4-bromophenyl)pyridine-4-

M1-(cyanomethyl)-M2-((5)-(4-(methylsulfonyl)-1,1"-ylmethyliamin)pentanoic acid; diphenyl-4-yl|«thien-3-yl)methylyl--leucinamide; cyanomethylamide 2-I(4-bromophenyl)thiazole-2-

M1-(cyanomethyl)-M2-((5)-(4-(methylsulfonyl)-1,1"-ylmethyliamino)pentanoic acid; diphenyl-4-yl|(3-methylthien-2-yl)methyl/-- (1-cyanocyclopropyl)amide (25)-2-I(5)-1-(42-leucinamide; acetyldiphenyl-4-yl)-2,2,2-

M1-(cyanomethyl)-M2-((5)-(4"-(4-trifluoroethylamine|pentanoic acid; cyclopropylpiperazin-1-yl)-1,1-diphenyl-4-yl)(3- (1-cyanocyclopropyl )amide (25)-2-I(5)-1-(2,4-methylthien-2-yl)umethyl-leucinamide; difluorodiphenyl-4-yl)-2,2,2-

M!-(cyanomethyl)-M2-((5)-(4"-(4-trifluoroethylamino|pentanoic acid; cyclopropylpiperazin-1-yl)-1,1"-diphenyl-4-yl)|(thien- (1 -cyanocyclopropyl)amide (25)-2-I(5)-1-(34-

3-yl)-methyl-leucinamide; difluorodiphenyl-4-yl)-2,2,2-

M2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-trifluoroethylamino|pentanoic acid; (cyanomethyl)-5,5,5-trifluoro-I-norvalinamide; (1-cyanocyclopropyl)amide (25)-2-|(5)-1-(3'-chloro-4-

M1-(cyanomethyl)-5,5,5-trifluoro-M2-(15)-2,2,2-fluorodiphenyl-4-yl)-2,2,2-trifluoro-1-(4-(methylsulfonyl) -1,1-diphenyl-4-trifluoroethylamino|pentanoic acid; yl|styl)-norvalinamide; (1-Cyanocyclopropyl)amide (25)-2-((5)-2,2.2-m2-I((5)-(4-bromophenyl)(3-methylthien-2-yl)umethyl|-M!-trifluoro -1-(4-methanesulfonylaminodiphenyl-4-(1-cyanocyclopropyl)!-leucinamide; yl)ethylamino|ipentanoic acid;

M1-(1-cyanocyclopropyl)-M2-((5)-|4-cyanomethylamide (25)-2-((5)-I(4-bromophenyl)thiazole-2-(methylsulfonyl)-1,1"-diphenyl -4-yl|(3-methylthien-2-ylmethylamino)-4-methylpentanoic acid; ylylmethyl-leucinamide; M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-

M1-(cyanomethyl)-M2-((5)-3-furyl(r"-|-chloro-1,1"-diphenyl-4-yl|ethyl)-norvalinamide; (methylsulfonyl)-1,1"- diphenyl-4-yl|methyl - M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-leucinamide; |2-chloro-3'-methyl-1,1"- diphenyl-4-yl|ethyl. -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-norvalinamide; -(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl. - M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-norvalinamide; |2-chloro-2-methyl-1,1"-diphenyl-4-yl|ethyl. -

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl/|-M!-(1-norvalinamide; cyanocyclopropyl)! -norvalinamide; (1-cyanocyclopropyl)amide (25)-2-((5)-2,2,2-

Me-(5)-(4-bromophenyl) (4-bromothien-2-ylylmethyl/|-M!-trifluoro-1-I4-(1H-indole-5-(cyanomethyl)!-leucinamide; yl)phenyl|ethylamine )pentanoic acid; m2-I((5)-(4-bromophenyl)(thien-3-ylylmethyl/|-M1-(1-(1-cyanocyclopropyl)amide (25)-2-((5)-2,2.2- cyanocyclopropyl) !-leucinamide; trifluoro-1-(3'-methanesulfonylaminodiphenyl-4-

M1-(cyanomethyl)-M2-((5)-(4-(methylsulfonyl)-1,1"-yl)ethylamine|pentanoic acid; diphenyl-4-yl|(4--4--methylsulfonyl)phenyl/ thien-2-M-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-ylylmethyl)-leucinamide; 12-fluoro-1,1"-diphenyl-4-yl|ethyl ) -norvalinamide;

M1-(1-cyanocyclopropyl)-M2-((5)-(4-M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1-(methylsulfonyl)-1,1 "-diphenyl-4-yl|(thien-3-I2-fluoro-3'-methyl-1,1-diphenyl-4-yl|Iethyl. - IlumethylI-leucinamide; norvalinamide;

Mm2-((15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-yl|- M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro- 1- 2,2,2-trifluoroethyl)-N-(1-cyanocyclopropyl)|!- - 13-fluoro-2-methyl-1,1-diphenyl-4-yl|ethyl)-norvalinamide; norvalinamide;

Me-(5)-(4-bromophenyl) (4-bromothien-2-ylylmethyl)-M1-(1-M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro- 1- cyanocyclopropyl)! -leucinamide; (2-trifluoromethoxy-1,1-diphenyl-4-yl|ethyl. -

Me-(5)-(2-(aminosulfonyl)-1,1"-diphenyl-4-yl|(thiennorvalinamide;

Z-Ilumethyl/|-M'-(1-cyanocyclopropyl)! -leucinamide; (1-Cyanocyclopropyl)amide (25)-2-I(5)-2,2,2-m2-((5)-(2-(aminosulfonyl)-1,1"-diphenyl-4-yl|(thien - trifluoro-1-(4-methyldiphenyl-4-

3-yl)methyl|-M!-(cyanomethyl)! -leucinamide; yl)ethylamine|ipentanoic acid;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-(1-cyanocyclopropyl)amide (25)-2-I(5)-1-(42--methoxy-3 -(methylsulfonyl)-1,1-diphenyl-4-cyanodiphenyl-4-yl)-2,2,2-yl|styl)-norvalinamide; trifluoroethylamine|pentanoic acid;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-(25)-M-(1-cyanocyclopropyl)-4,4-difluoro-2-((15)- -methoxy-1,1-diphenyl-4-yl|ethyl)-norvalinamide; 2,2,2-trifluoro-1-(4!-(methylsulfonyl)-1,1"-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-diphenyl-4-yl|styl)amino)butanamide;

I4-(benzo|(1,3|dioxol-5-iluphenyl|ethyl)! - (25)-M-(1-cyanocyclopropyl)-4,4-difluoro-2-((15)-norvalinamide; 2,2.2 -trichloro-1-(4-(methylsulfonyl)-1,1-diphenyl-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-4-yl|ethyl)amino)butanamide;

12-(methoxycarbonyl)-1,1"-diphenyl-4-yl|ethyl - (25)-M-(cyanomethyl)-4,4-difluoro-2-((15)-2,2,2-norvalinamide; trichloro-1-(-(methylsulfonyl)-1,1-diphenyl-4-(1-cyanocyclopropyl)amide (25)-2-(5)-K(4-yl|ethyl)amino)butanamide; bromophenyl)thiazol- 2-ylmethyl|amino)-4-(25)-4,4-dichloro-M-(cyanomethyl)-2-((15)-2,2,2- methylpentanoic acid; trifluoro-1-(-(methylsulfonyl) -1,1-diphenyl-4-cyanomethylamide (25)-2-(5)-C2-yl|ethyl)amino)butanamide; methanesulfonyldiphenyl-4-yl)thiazol-2-(25)-4,4-dichloro- M-(1-cyanocyclopropyl)-2-((15)-ylmethylamino-4-methylpentanoic acid; 2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-(1-cyanocyclopropyl)amide ( 25)-2-I(5)-2,2,2-4-yl|stil)amino)butanamide; trifluoro-1-(4-trifluoromethyldiphenyl-4-(25)-4,4-dichloro-M-( 1-Cyanocyclopropyl)-2-((15)-yl)/ethylamino|Ipentanoic acid; 2,2.2-trichloro-1-(4-(methylsulfonyl)-1,1-diphenyl-(1-cyanocyclopropyl)amide (25) -2-I(5)-2,2,2-4-yl|stil)amino)butanamide; trifluoro-1-(2-trifluoromethyldiphenyl-4-(25)-4,4-dichloro-M-(cyanomethyl) -2-((15)-2,2,2-yl)/ethylam in|Ipentanoic acid; trichloro-1-(-(methylsulfonyl)-1,1-diphenyl-4-(1-cyanocyclopropyl)amide (25)-2-(5)-C224-yl|ethyl)amino)butanamide; difluorodiphenyl-4-yl)thiazol-2-ylmethyl|amino)-4-Mm2-(15)-1-(1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl-methylpentanoic acid; M1 -(1-cyanocyclopropyl)-4-I-leucinamide; (1-cyanocyclopropyl)amide (25)-2-(5)-(4-M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)- 2,2,2-methanesulfonyldiphenyl-4-yl)thiazol-2-trifluoro-1-13'-(1-hydroxyethyl)-1,1"-diphenyl-4-ylmethyl|amino)-4-methylpentanoic acid; il|ethyl)! -leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)2,2,2- M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- trifluoro-1-I(I4(1-oxido-2,3-dihydro-1-benzothien-5-trifluoro-1-(4-methyl-1,1"-diphenyl-4-yl)ethyl|-- yl) (phenyl|ethyl)!-leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-dioxido-M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2, 2-2,3-dihydro-1-benzothien-5-yl)uphenyl|-2,2,2-trifluoro-1-I3'-(1-hydroxy-1-methylethyl)-1,1-trifluoroethyl)-4 -fluoro-I -leucinamide; diphenyl-4-yl|ethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-M2-4((15)-1-(4-(1,1-dioxido-Mm2-(15)-1-(2-acetyl-1,1"-diphenyl-4 -yl)-2,2,2- 2,3-dihydro-1,2-benzisothiazol-5-yl)uphenyl|-2,2,2-trifluoroethyl/|-M!-(1-cyanocyclopropyl)-4- fluoro-trifluoroethyl)-4-fluoro-I-leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-Me-((15)-1-(2'-acetyl-1,1"-diphenyl-4-yl )-2,2,2-trifluoro-1-(4-(methylsulfinyl)-1,1"-diphenyl-4-trifluoroethyl)-N-(1-cyanocyclopropyl)-4-fluoro-yl-yl ) -leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-dioxido-M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2, 2-

3-oxo-2,3-dihydro-1,2-benzisothiazole-5-iluphenyl|-trifluoro-1-12-(1-hydroxyethyl)-1,1"-diphenyl-4-2,2,2-trifluoroethyl) -4-fluoro-II-leucinamide; yl|stil)-leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- trifluoro-1-(2'-(1-hydroxy-1-methylethyl)-1,1"- trifluoro-1-(2'-(1-hydroxyethyl)-1,1"-diphenyl-4-diphenyl-4- yl|ethyl)!-leucinamide; yl|styl)-leucinamide;

M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2, 2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-trifluoro-1-12-(1-hydroxy-1-methylethyl)-1,1-yl|stil)-norvalinamide; diphenyl-4-yl|ethyl)-leucinamide;

M1-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-trifluoro -1-(4-(methylsulfonyl)-1,1-diphenyl-4-trifluoro-1-(2'-(1-hydroxy-1-methylethyl)-1,1-yl|styl)-norvalinamide; diphenyl-4 -yl|ethyl)-leucinamide;

M1-(cyanomethyl)-4-fluoro-Me-(15)-2,2,2-trichloro-1-M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2 ,2- -(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl.-trifluoro-1-5-(4-(methylsulfonyl)phenyl|pyridin-2-leucinamide; yl)ethyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15))-2,2,2 - trichloro-1-(4-(methylsulfonyl)-1,1"-diphenyl-4-trifluoro-1-6-(4-(methylsulfonyl)phenyl|pyridin-3-yl|styl)-leucinamide; yl)ethyl) !-leucinamide;

M1-(1-cyanocyclopropyl)-4,4-difluoro-M2-(15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2 - trichloro-1-(4-(methylsulfonyl)-1,1"-diphenyl-4-trifluoro-1-(4-6-(methylsulfonyl)amino|pyridin-3-yl|styl)-norvalinamide; ylphenyl)ethyl -leucinamide;

M1-(cyanomethyl)-4,4-difluoro-Me-C15)-2,2,2- M1-(cyanomethyl)-4-fluoro-M2-((15)-2,2,2-trifluoro- 1-trichloro-1-(4-(methylsulfonyl)-1,1"-diphenyl-4-(4--6-Kmethylsulfonyl)amino|pyridin-3-yl|styl)-norvalinamide; isophenyl)ethyl|-leucinamide; (25)-M-(cyanomethyl)-4,4-difluoro-2-((15)-2,2,2- M1-(1-cyanobutyl)-4-fluoro-M2-(15)-2,2 ,2-trifluoro-1-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4- (2-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl) amine) butanamide; leucinamide;

M1-(1-cyano-2-cyclopropylethyl)-4-fluoro-M2-(15)- M1-(1-cyanocyclopropyl)-M2-((1 5)-1-I4-(5,5-diethyl-2 - 2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-oxo-2,5-dihydrofuran-3-iluphenyl)-2,2,2-4-ylethyl) 1-leucinamide; trifluoroethyl)-4-fluoro-1-leucinamide;

M1-(1-cyano-2-pyridin-3-ylethyl)-4-fluoro-Me-C15)-M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2 - 2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-trifluoro-1-I4-(5-oxo-4-oxaspiro|(2.4)hept-6-en-7- 4-yl|ethyl)l -leucinamide; yl)phenyl|ethyl)! -leucinamide;

M1-(1-cyano-3-hydroxy-3-methylbutyl)-4-fluoro-M2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- (C15)- 2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-trifluoro-1-I4-(6-oxo-5-oxaspiro|3.Oct-7-en-8-diphenyl-4 -yl(ethyl)-leucinamide; yl)phenyl|ethyl)!-leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- trifluoro-1-(4-(1-oxo-1,3-dihydro-2-benzofuran-5-trifluoro-1-I4-(5-oxo-4-oxaspiro|(2.4)hept-6-en-6- yl(uphenyl|ethyl)l -leucinamide; yl)phenyl|ethyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-|4-(3,3-dimethyl-M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2 ,2- 1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl|-2,2,2-trifluoro-1-I4-(6-oxo-5-oxaspiro|3.Oct-7 -en-7-trifluoroethyl)-4-fluoro-I-leucinamide; yl)phenyl|ethyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(3,3-diethyl-1-M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2 ,2,2-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl|-2,2,2-trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide; trifluoroethyl) -4-fluoro-I-leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4- trifluoro-1-(4- (3-oxo-1,3-dihydro-2-benzofuran-5-yl|ethyl)-leucinamide; yl)/phenyl|ethyl)! -leucinamide; M2-(15)-1-(2-acetyl-1,1"-diphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(1,1-dimethyl-trifluoroethyl|-M!-(1-cyanocyclopropyl)!. -

Z-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl|-2,2,2-leucinamide; trifluoroethyl)-4-fluoro-I-leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-diethyl-3-(4-quinolin-6-ylphenyl)ethyl|-leucinamide; oxo-1,3-dihydro- 2-benzofuran-5-yl)phenyl|-2,2,2-Me-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-(1- trifluoroethyl)- 4-fluoro-I-leucinamide; cyanocyclopropyl)-4,4-difluoro-I-norvalinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-C15)-2,2,2 - trifluoro-1-(2-(3-oxo-1,3-dihydro-2-benzofuran-5-trifluoro-1-14-(methylthio)-1,1"-diphenyl-4-yl|ethyl). - yl )-1,1"--diphenyl-4-yl|ethyl)! -leucinamide; norvalinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-2,2, 2-dimethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4- 1,1"-diphenyl-4- yl|-2,2,2-trifluoroethyl)-4-fluoro-yl-yl|ethyl)-norvalinamide; leucinamide; M!-(15)-1-cyano-3-(methylsulfonyl)propyl|-Me-

M1-(1-cyanocyclopropyl)-M2-15)-1-|4-(1,1-diethyl-(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1 "-

(Z-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1"-diphenyl-4-yl|ethyl)-leucinamide; diphenyl-4-yl|-2,2,2-trifluoroethyl) -4-fluoro-1 - M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-leucinamide; trifluoro-1(4-quinoline-b-ylphenyl)ethyl)-- leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-trifluoro -1-(2-(1-oxo-1,3-dihydro-2-benzofuran-5-trifluoro-1-(4-(methylsulfinyl)-1,1-diphenyl-4-yl)-1,1"- -diphenyl-4-yl|ethyl)!-leucinamide; yl|styl)-leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-|4-(3,3- M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1- dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-12-(1-hydroxyethyl)-1,1-diphenyl-4-yl|ethyl. - 1,1"-diphenyl-4-yl|-2,2,2-trifluoroethyl)-4-fluoro-y - leucinamide; leucinamide; Me-((15)-1-(4-acetyl-1,1" -diphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-1-|4-(3,3-diethyl-trifluoroethyl|-M!-(1-cyanocyclopropyl)!. - 1-oxo-1,3-dihydro -2-benzofuran-5-yl)-1,1"-leucinamide; diphenyl-4-yl|-2,2,2-trifluoroethyl)-4-fluoro-y - M1-(1-cyanocyclopropyl)-M2-( (15)-2,2,2-trifluoro-1-leucinamide;(4-quinolin-6-ylphenyl)ethyl-leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-Me-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M !-(1-trifluoro-1-(4-(5-oxo-2,5-dihydrofuran-3-cyanocyclopropyl)-4,4-difluoro-1-norvalinamide; yl/phenyl|ethyl)1-leucinamide; M! -(1-cyanocyclopropyl)-4,4-difluoro-Me-C15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-4(15)-1-I4-(2,2-dimethyl-trifluoro-1-I4-(methylthio)-1,1"-diphenyl-4-yl|ethyl. -

B-oxo-2,5-dihydrofuran-3-yl)phenyl|-2,2,2-norvalinamide; trifluoroethyl)-4-fluoro-I-leucinamide; M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(2,2-diethyl-5B-trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-oxo- 2,5-dihydrofuran-3-yl)uphenyl (2,2,2-yl)-ethyl)-norvalinamide; trifluoroethyl)-4-fluoro-1-leucinamide; N-(1-cyanocyclopropyl)-4-fluoro- M2-((15)-2,2,2-

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-trifluoro-1-4-(5-methyl-6-(methylsulfonyl)pyridine-trifluoro-1-(4- (2-oxo-2,5-dihydrofuran-3-3-yl|phenyl)ethyl)!-leucinamide; yl)/phenyl|ethyl)!III -leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-(15)-1-|I4-(5,5-dimethyl-trifluoro-1-14-(6-(1-hydroxy-1-methylethyl)-5-2 -oxo-2,5-dihydrofuran-3-yl)phenyl (2,2,2-methylpyridin-3-ylphenyl)ethyl)-leucinamide; trifluoroethyl)-4-fluoro-I-leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-trifluoro-1-(4-fluoro-1,1"-diphenyl-4-yl)ethyl--leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- trifluoro-1-(3'-methyl-4-(methylsulfonyl)-1,1"-trifluoro-1-3'-(1-hydroxyethyl)-1,1"-diphenyl-4-diphenyl-4-yl|Iethyl ) -leucinamide; il|styl) -leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl) -2,2-trifluoro-1-(4-(b-methylpyridin-3-iluphenyl|ethyl. - difluoroethyl|-M!-(1-cyanocyclopropyl)| - leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- M1-(1-cyanocyclopropyl)-M2-((15)-1-I4-(3,5 - trifluoro-1-(4-(methylthio)-1,1-diphenyl-4-yl|Iethyl. - dimethylisoxazol-4-yl)phenyl|-2,2,2-trifluoroethyl)-leucinamide; 4-fluoro-I -leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- M!-(15)-1-cyano-3-(methylsulfonyl)propyl|-Me- trifluoro-1- (4-(1-hydroxy-1-methylethyl)-1,1"- (15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"- diphenyl-4-yl| (ethyl)-leucinamide; diphenyl-4-yl|ethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- trifluoro-1-(4-(2-methylquinolin-7-yl)phenyl|ethyl. - trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-4 -fluoro-M2-(15)-2,2,2-

Mm2-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M'-trifluoro-1-(4-(methylsulfinyl)-1,1-diphenyl-4-(cyanomethyl)- 4,4-difluoro-I-norvalinamide; yl|stil)-leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-trifluoro-1- trifluoro-1-4-((15)-1-hydroxyethyl|-1,1-diphenyl-4-I2-(1-hydroxyethyl)-1,1-diphenyl-4-yl|Iethyl.-yl)ethyl)I -leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2- M2-(15)-1-(2-acetyl-1,1"-diphenyl-4-yl)-2, 2,2-trifluoro-1-4-((18)-1-hydroxyethyl|-1,1"-diphenyl-4-trifluoroethyl|-M!-(1-cyanocyclopropyl)!.-yl)ethyl)I-leucinamide ; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1- M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-

E-trifluoroacetyl)-1,1"-diphenyl-4-yl|ethyl. - (4-quinolin-6-ylphenyl)ethyl--leucinamide; leucinamide; Me-((15)-1-(4-bromophenyl)- 2,2,2-trifluoroethyl|-M!-(1-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-cyanocyclopropyl)-4-difluoro-I-norvalinamide;

N5-(2-Naphthyl)pyridin-2-yl|ethyl)N-leucinamide; M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-C15)-2,2,2-

M1-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2-trifluoro-1-14-(methylthio)-1,1"-diphenyl-4-yl|ethyl. - trifluoro -1-(4-(methylthio)-1,1-diphenyl-4-yl|ethyl. - norvalinamide; norvalinamide; M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-2,2 ,2-

M1-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2- trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4- trifluoro-1-(4- (methylsulfonyl)-1,1-diphenyl-4-ylethyl)norvalinamide; ylethyl)norvalinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-trifluoro-1-4-(5-methyl-6-(methylsulfonyl)pyridine-trifluoro-1-(4- (5-methyl-1,3-thiazol-2-3-yl|phenyl)ethyl)!-leucinamide; yl)/phenyl|ethyl)!III -leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-dioxide-trifluoro-1-14-(6-(1-hydroxy-1-methylethyl)-5-

(3-oxo-2,3-dihydro-1,2-benzisothiazol-5-ylphenyl)-methylpyridine-3-ylphenyl)ethyl)!-leucinamide; 2,2,2-trifluoroethyl)-4-fluoro-II-leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- m2-(4-bromophenyl)(phenyl)methyl|-M-(1-trifluoro-1-(4- fluoro-1,1"-diphenyl-4-yl)ethyl--cyanocyclopropyl)!-leucinamide; leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2 - trifluoro-1-(4-methyl-1,1"-diphenyl-4-yl)ethyl|-- trifluoro-1-133'-methyl-4-(methylsulfonyl)-1,1-leucinamide; diphenyl-4- yl|ethyl)-leucinamide; m2-I(15)-1-(1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl- M1-(1-cyanocyclopropyl)-4-fluoro-M2 -(15)-2,2,2-

M1-(1-cyanocyclopropyl)-4-I-leucinamide; trifluoro-1-I4-(b-methylpyridin-3-iluphenyl|ethyl. -

Mm2-4((15)-1-I4-(5-chloropyridin-2-yl)phenyl|-2,2,2-leucinamide; trifluoroethyl)-M!-(1-cyanocyclopropyl)-4-1 - M1- (1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-14-(methylthio)-1,1"-diphenyl-4-yl|ethyl. -

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-leucinamide; trifluoro-1-(4-pyridin-4-ylphenyl)ethyl-- M1-(1- cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-I2-(1-hydroxy-1-methylethyl)-1,1-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2-diphenyl-4-yl|ethyl)! -leucinamide; trifluoro-1-4-Mmethylsulfonyl)amino|-1,1- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-diphenyl-4-yl)ethyl)! -leucinamide; trifluoro-1-I4-(2-methylquinoline-7-iluphenyl|ethyl. -

Mm2-((15)-1-(4-bromophenyl)-2,2-difluoroethyl|-M-(1-leucinamide; cyanocyclopropyl)!-leucinamide; Me-((15)-1-(4-bromophenyl)- 2,2,2-trifluoroethyl|-M!-

M'-(1-cyanocyclopropyl)-M2-(15)-2,2-difluoro-1-I4-(cyanomethyl)-4,4-difluoro-I-norvalinamide; (methylthio)-1,1-diphenyl-4-yl|ethyl)-leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-trifluoro-1-24-((15)-1-hydroxyethyl|-1,1-diphenyl-4- trifluoro-1-(4-pyrimidin-5-ylphenyl)ethyl|--yl)ethyl)I-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-m2-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl) -2,2,2-trifluoro-1-4-((18)-1-hydroxyethyl|-1,1-diphenyl-4-trifluoroethyl|-M!-(1-cyanocyclopropyl)-4-I - yl) (ethyl)!-leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-12. The compound according to item 9, which is M1-

12-"trifluoroacetyl)-1,1-diphenyl-4-yl|ethyl. - (cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4-leucinamide; (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-leucinamide or its pharmaceutically acceptable

N5-(2-Naphthyl)pyridin-2-yl|ethyl)N-leucinamide; salt

M1-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2- 13. The compound according to item 9, which is M2-(15)-1-|4-trifluoro-1 -(4-(methylthio)-1,1-diphenyl-4-yl|ethyl.-(aminosulfonyl)-1,1-diphenyl-4-yl|-2,2,2- norvalinamide; trifluoroethyl)-M!- (cyanomethyl)! -leucinamide or

M!-(cyanomethyl)-4,4-difluoro-Me-C15)-2,2,2- its pharmaceutically acceptable salts. trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4- 14. Pharmaceutical composition containing spol-yl|stil)-norvalinamide; according to item 1 and a pharmaceutically acceptable carrier.

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- 15. Pharmaceutical composition according to item 14, obtained trifluoro-1-(4-(5-methyl-1,3 -thiazole-2- by combining the compound according to item 1 and pharmaceutic-yl/phenyl|ethyl)-leucinamide; a suitable carrier.

M1-(1-cyanocyclopropyl)-M2-((1 5)-1-(4-(1,1-dioxydo- 16. Pharmaceutical composition according to item 14, which additionally

3-oxo-2,3-dihydro-1,2-benzisothiazol-5-iluphenyl|- contains another agent selected from organic 2,2,2-trifluoroethyl)-4-fluoro-yl-leucinamide; bisphosphonate, an estrogen receptor modulator,

Me-(4-bromophenyl)u(phenyl)methyl/|-M!-(1- estrogen receptor beta modulator, modulato-cyanocyclopropyl)! -leucinamide; ra of the androgen receptor, an inhibitor of proton AT-

M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- Osteoclast phases, HMO-CoA reductase inhibitor, trifluoro-1-(4-methyl-1,1"-diphenyl -4-yl)ethyl||-- an antagonist of the integrin receptor or anabolic leucinamides; an agent of osteoblasts, and their pharmaceutically acceptable m2-I(15)-1-(1,1"-diphenyl-4-yl)-2,2 ,2-trifluoroethylene salts and mixtures.

M1-(1-cyanocyclopropyl)-4-I-leucinamide; 17. The method of obtaining a pharmaceutical composition,

M2-4(15)-1-14-(5-chloropyridin-2-yl)phenyl|-2,2,2-, which includes the combination of the compound according to item 1 and pharmaceutical-trifluoroethyl)-M!-(1 -cyanocyclopropyl)-4-I - topically acceptable carrier. leucinamide; 18. The method of inhibiting cathepsin activity in ssa-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-acetate, requiring this, comprising the introduction of trifluoro-1-(4-pyridin-4-ylphenyl)ethyl- to the indicated mammal therapeutically effective cell-leucinamide; bones of the compound according to item 1.

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2- 19. The method according to item 18, where the cathepsin activity is represented by trifluoro-1-4-MKmethylsulfonyl)amino|-1,1- is the activity of cathepsin K. diphenyl-4-yl)ethyl)! -leucinamide; 20. The method according to item 19, where the disease in which

Me-(15)-1-(4-bromophenyl)-2,2-difluoroethyl|-M-(1- shown inhibition of cathepsin, is a cyanocyclopropyl)! -leucinamide; osteoporosis.

M1-(1-cyanocyclopropyl)-M2-(15)-2,2-difluoro-1-|4- 21. Method of treatment of cathepsin-dependent diseases- (methylthio)-1,1-diphenyl-4-yl|ethyl) -leucinamide; vans or conditions in a mammal in need of this, which

M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- involves administering to the indicated mammal a therapeutically effective amount of trifluoro-1-(4-pyrimidin-5-ylphenyl)ethyl compounds according to item 1. leucinamide; 22. The method according to item 21, where the disease is selected from: m2-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2,2- osteoporosis, osteoporosis induced glucocor-trifluoroethyl/|-M!-(1-cyanocyclopropyl)-4-fluoro-y - ticoids, Paget's disease, abnormally elevated leucinamide; bone metabolism, periodontal disease,

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- tooth loss, bone fractures, rheumatoid trifluoro-1-I3-(1-hydroxyethyl)-1,1"-diphenyl -4- arthritis, osteoarthritis, periprosthetic osteo-yl|stil)-leucinamide; lysis, osteogenesis defect, metastatic z-m2-I(15)-1-(4-acetyl-1,1"-diphenyl-4-yl) -2,2- bone disease, hypercalcemia of malignant tumor - difluoroethyl|-M!-(1-cyanocyclopropyl)| - lin or multiple myeloma in a mammal, leucinamide; in need of it.

M1-(1-cyanocyclopropyl)-M2-((1 5)-1-(4-(3,5- 23. The method according to item 22, where the disease is dimethylisoxazol-4-yl)phenyl|-2,2 ,2-trifluoroethyl)- osteoporosis. 4-fluoro-I-leucinamide; 24. The method of inhibiting bone resorption in a mammal, and their pharmaceutically acceptable salts, stereoiso- needing it, which includes the introduction of casemers and M-oxide derivatives. therapeutically effective amount 10. The compound according to item 9, which is M1-(1- compound according to item 1. cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-trifluoro- 25. Method increasing the mineral density of 1-(4-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl) cysts in a mammal in need of it, which includes veleucinamide or its pharmaceutically acceptable salts, therapeutically effective for said mammal 26. Method of reducing the risk of fractures in a mammal, cyanocyclopropyl)-4-fluoro-Me-C15)-2 ,2,2-trifluoro- requiring this, which includes the introduction of 1-(4-(methylsulfinyl)-1,1-diphene yl-4-yl|Iethylinum to a mammal of a therapeutically effective amount of leucinamide or its pharmaceutically acceptable compounds according to item 1. salt.

A number of disorders of cysteine proteases in humans and other mammals. These proteases function in abnormal bone resorption or in association with normal physiological as well as with pathological bone resorption. Such violations include, hyic degradation of connective tissue. Cathepsins, but not only, osteoporosis, osteoporosis, induced- play a major role in the destruction of internal glucocorticoids, Paget's disease (defunct cellular proteins and their renewal and remodeling. rupturing osteodystrophy), abnormally increased At this time, a number of bone metabolism was identified and sequenced , periodontal disease, cathepsins from various sources. These cathepsins are usually tooth loss, bone fractures, rheumatoid are found in various tissues For example, arthritis, osteoarthritis, coloprosthetic osteolysis, de- was cloned cathepsin B, E, H, I, K, 5, UM, and 7. effect of osteogenesis, metastatic disease Cathepsin K (which is also known by the acronym bone, hypercalcemia of malignancy, and multi-cat K) is also known as cathepsin O and cathepsin 02. multiple myeloma. One of the most common ways to see The application of PCT UMO 96/13523, Kpergyi rusheni is osteoporosis, the highest frequency of manifestation of RPaptaseshisisI!5, Ips., published on May 9, which occurs in women in the period after menopause. 1996, which is incorporated herein by reference in its own right

Osteoporosis is a systemic disease in its entirety. Cathepsin I. is involved in the normal skeleton, characterized by low bone lysosomal proteolysis, as well as in separate mass and destruction of bone microarchitectonic disease states that include, but not tissues with further increase in bone fragility only, melanoma metastasis. Cathepsin 5 and susceptibility to fracture. Osteoporotic fractures are equal to Alzheimer's disease and some autoimmune disorders, the main cause of morbidity and mortality, including, but not limited to, the young and old population. At least 5,095 women and those with diabetes, multiple sclerosis, and an average third of men have an osteoporotic fracture. In pemphigus, Gravis's disease, myasthenia gravis, sys- a large part of the elderly population already has filiform lupus erythematosus, rheumatoid arthritis, bone density and a high risk of fractures. and Hoshimoto's thyroiditis; allergic disorders, c

There is a high need for both prevention and treatment, including, but not limited to, asthma; and allogeneic immunization for osteoporosis and other conditions associated with them, including, but not limited to, bone resorption. Since osteoporosis, as well as rotting of organ transplants or tissue tran- other disorders associated with bone destruction, in grafts. Elevated levels found in tumors are mainly chronic conditions, it is believed that Cathepsin B and the redistribution of this enzyme, which will require constant treatment for appropriate therapy, confirms the role in tumor invasion and metastasis. bathroom In addition, the activity of Cathepsin B, which rejects

Osteoporosis is characterized by a progressive deviation from the norm, involved in such painful destruction of bone architecture and mineralization that conditions such as rheumatoid arthritis, osteoarthritis, leads to a loss of bone strength and an increase in the rate of sagipia, acute pancreatitis, inflammatory fractures. The skeleton is constantly reconstructed - diseases of the respiratory tract and bone and adjusts by establishing a balance between osteobial disorders. fins that lay down new bone, and osteoclasts are known to cysteine protease inhibitors, such as those that destroy or resorb bone. With E-64 (trans-epoxysuccinyl-I-leucylamide-(4-guanidino)butane in some disease states and in old age) is effective in inhibiting the balance between bone formation and bone resorption. (See Oeiaii5ze, U. M. ei ai., 1987, Vope shenyi; bone is eliminated at a higher rate. 8: 305-313, incorporated herein by reference in his

Such a long-term imbalance of the predominance of resobration to the full extent. Cathep- over the formation leads to a weaker struxin K was recently cloned, and a specific expression in bone osteocture and to an increased risk of fractures was found. flippers | See Teika, K. ei ai., 1994, In Vioi Spet

Bone resorption is initially carried out by osteo- 269:1106-1109; pi, (3. R. eyi ai., 1995, REV5 I eyi clasts, which are multinucleated giant- 357:129-134; Vgotte, 0. and Okatoio, K., 1995, Vio! cells. Osteoclasts resorb bone . 1996, U Viol Speth 271:12511-12516, are included here. These lacunae are retained as a reference in their entirety. Concomitant with clo- at low pH by proton ATP, an autosomal recessive disorder , peak pump. The acidic environment in lacunodysostosis, characterized by the phenotype of prini, initiates bone demineralization followed by degenerate systemic osteoporosis with reduced gradation of bone proteins or collagen under the action of bone resorption, was mapped to mutation, proteases such as cysteine proteases. See Oeiaizve, present in the Cathepsin K gene. At this time, it became known

U. M. ei ai., 1980, Viospet 9 192:365-368; YuOeiaivve, domo that all mutations detected in the cathepsin K gene in

U. ei ai., 1984, Viospet Viorpuz Kez5 Sottype: 441 - as a result lead to protein inactivation. (See 447; Re|aisze, 9. M. ei ai!., 1987, Vope 8:305-313, which Sir, W. 0. ei ai.,, 1996, Zsiepse 273: 1236-1238; included here as a reference in its entirety Choppzop, M. V. Yeyi, 1996, bepote Nev5 6:1050- zion, Collagen constitutes 9595 of the organic matrix 1055, are incorporated herein by reference in their entirety. Therefore, proteases that take participation in the destruction of collagen. Thus, it can be predicted that collagen cathepsins are the most important components involved in osteoclast-mediated bone metabolism, and as a result, bone development and resorption. The progression of osteoporosis. Cathepsin K is synthesized in the form of ZKda pop-

Cathepsins belong to the papain superfamily of proenzymes localized in lysosomes

lin department and where it approximately self-activates | Ve Ved VZN m in a mature enzyme of 27 kDa at low pH. (See in M. p

MsOtsepeu, M. 5. ei a, 1997, . Vioi Spet vysh HC 2 7M2:13955-13960; IishShemzhoi-Emap5, A. Yei Ai., p in OV 1997, Vope 20: 51-86, are incorporated herein by reference in their entirety. Cathepsin K is the closest to cathepsin 5, having 5,695 sequences of identity. where K' represents hydrogen, Sivalkyl or Co. of amino acids. 52P2 substrate spealkenyl, where alkyl and alkenyl groups are indicated, the specificity of Cathepsin K is similar to that of Cathepsin 5, necessarily substituted from one to six atoms with an advantage in positions RI and P2 of positively charged halogen, C3-ecycloalkyl, -ZAU, -5H?, -ZONB, - generated residues, such as arginine, and hydrophobic ZOV", -5O2NAe, -5O2B", -BO2CH(АСА), - Ov", 7 residues, such as phenylalanine or leucine, corresponding to Ov, ShKA", aryl, heteroaryl or heterocyclyl, resp. IDiv., Vgotte, O. ei ai., 1996, In Vioi Spet where aryl, heteroaryl and heterocyclic compounds are indicated - 271: 2126-2132; Vovvaga, M. .). Yei AI., 1996, In Vi! per group are not necessarily replaced by one or two

Spec 271:12517-12524, incorporated herein by reference with substituents independently selected from C-valkyl, in their entirety. Cathepsin K is active in the wide-halogen, hydroxyalkyl, hydroxy, alkoxy, or com pH range and is significantly active at pH 4-8, keto, which, thus, allows the detection of good ca- B" is hydrogen, Sivalky, or talytic activity in resorption lacunae os- Sgvalkenyl, where the alkyl and alkenyl groups of tebclasts, where the pH is about 4-5, are indicated, optionally substituted from one to six atoms

Type I human collagen, the main collagen with halogen, C3-ecycloalkyl, -ZN", -ZA!?, -VONU, tci, is a good substrate for Cathepsin K. |See -z3ov", -5O2Ne, -BO2H, -VOSN(В'А"), "OH, -

Kayepai, MU., et al., 1998, Biospet./ 331:727-732, OH", -MSH(A")", aryl, heteroaryl or heterocyclyl, is incorporated herein by reference in its entirety. where aryl, heteroaryl and heterocyclic

Experiments of ip migo using antisense groups optionally substituted with one or two catch oligonucleotides for Cathepsin K showed with substituents independently selected from C-alkyl, reduced resorption of ip migo bone, which is possible halogen, hydroxyalkyl, hydroxy, alkoxy or due to a decrease in translation Cathepsin K. keto mRNA; (See Ipii, T., et al., 1997, U Viol Speth 272:8109- or ki P? can be taken together with atom 8112, incorporated herein by reference in its full carbon to which they are attached, forming the The crystal structure of the Czeacycloalkyl or heterocyclic ring was established,

Katepsin K. IDiv. Meogagyi, M.E., ei a, 1997, May where the indicated ring system is not necessarily replaced by

Kill Vio! 4: 105-109; 7pao, V., ei a!., 1997, Mai schena by one or two substitutes, independently

Kill Vio! 4: 109-11, which are incorporated herein by reference as selected from C1-alkyl, hydroxyalkyl, halogen- in their entirety. Selec-alkyl or halogen were also developed; tive inhibitors of Cathepsin K based on pepti- A is hydrogen, C-alkyl or roof. IDiv. Vgotte, O., ei ai., 1996, Viospet / Cg-valkenyl where alkyl and alkenyl groups are specified 315:85-89; Tpotrzgop, 5. K., Yei a!., 1997, Rgos may be optionally substituted with C3-cycloalkyl or from

Asai 5si OA 94: 14249-14254, which are incorporated herein as one to six halogen atoms, are referenced in their entirety. Thus, ingi-B" represents hydrogen, Ct-alkyl or Cathepsin K bitors can reduce the resorption of Cg-valkenyl, where the alkyl and alkenyl groups of the bone are indicated. optionally substituted with Csescycloalkyl or from

Such inhibitors would be useful when treated with one to six halogen atoms; movements involving bone resorption, such as P" and K" can be taken together with the atom of osteoporosis. carbon, to which they are attached with the formation of can be used for the treatment and/or pro-ring or five-seven-membered heterocyclic prophylaxis of cathepsin-dependent states or diseases of the radical, where cycloalkyl, cycloalkene- mammals in need of this are indicated. One variant of a functional and optionally substituted heterocyclic group of this invention is illustrated by a compound with no one or two substituents, regardless of the choice of

Formula I, and its pharmaceutically acceptable salts with Stvalkyl, halogen, hydroxyalkyl, we, stereoisomers and M-oxide derivatives; hydroxy, alkoxy or keto;

IN? selected from hydrogen or Si-alkyl, substituted-

Not BA VZN K with 1-6 halogen atoms; c" fe b "c: A? represents aryl, heteroaryl, u. p M ve! Cishaloalkyl, arylalkyl or heteroarylalkyl, where the specified aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted

I. with one, two or three substituents, regardless of whether they are selected from halogen, C 1 -alkyl, or

NOI CHEMICAL formulas: -585, -58, -ОВ5, -5ОВ"2, -50285, -5028!2, - вбесн(В2(В), "ОВ, "МВВ, cyano, or aryl, optionally substituted - 5028"2. each O is independently a C-alkyl,

C2-alkenyl; C-alkynyl, aryl, heteroaryl,

C3-ccycloalkyl or heterocyclyl, where each is indicated by cycloalkyl, heterocyclyl, where indicated is alkyl, aryl, heteroaryl, cycloalkyl and heteroaryl, heteroaryl, C3-ccycloalkyl and heterocyclyl cyclyl groups, which may be monocyclic, may be optionally substituted or atomically or bicyclic, optionally substituted either on carbon or on the heteroatom by one, two or carbon atoms or on the heteroatom by one to five three substituents, independently selected from C-- substituents, independently selected from C-alkyl, alkyl or halogen; haloalkyl, halogen, keto, alkoxy, -582, -5872, B? represents hydrogen, Si-valkyl, -ОВ2, -ОВ!2, M(В2)", -5028U, or -5028'9; (Ci-alkyl)aryl, (Ci-alkyl)hydroxyl, alkyl,

B" represents hydrogen, C1-alkyl, C1-alkenyl, hydroxyl, halogen, aryl, heteroaryl, C3-

Co-valkynyl, C 1-alkyloxy, halogen, nitro, cyano, z-cycloalkyl, heterocyclyl, where indicated is alkyl, aryl, heteroaryl, C 3-bcycloalkyl, heterocyclyl, - aryl, heteroaryl, C 3-bcycloalkyl and heterocyclyl

СВ, -С(ОО5ЦСН(СН3)гИ, -ОВУ, -ОВО,- can be optionally substituted either by atom

С(О)ВЯ, -ВЭЕЕ(ОО)А8Я, -С(О0)8З, -С(ОМ(В(В), - carbon, or by one, two or so heteroatoms) -С(ОМ(А (B, -C(A'Z(ATZON, - three substitutes, independently chosen from

ЗА", -58У, -В'О5AU, -83, -С(ВЗ)з, -С(АЗ(АТЗМ(ВУ)"), Si-alkyl or halogen; -MA'С(О)МА (0283 , -50282, -BO(B2), -8028U, - or Pg and P? can be taken together with the atom

ЗОтп(В (ВУ), -ВОпсН(А (А), - the carbon to which they are attached or found-

ЗО2М(А СО), -З05(В2)С(ОМ(В2)», between them, with the formation of C3-zcycloalkyl

OBO", -M(BA(A"), -MSH(AZS(OM(ATO(AU, - ring or C3-heterocyclic ring, where indicated

М(А')С(О)Вя, -М(А)С(О)8О, -М(А)С(ОООО,- 3-8 membered ring system can be optional

М(В35О(А 0 -С(А'Е(АТИМАТС(ВА В, С- is substituted by one or two substituents, non-

С(АЭ(АТИМ(АТАЯ, 00 -С(А'Е(АТИМ(АТАС) - depending on selected from C-alkyl and halogen; с(А'Э(АТИВС(А (ААУ), Vo. - B: represents is hydrogen or Si-valkyl, which does not have s(vahvMAasS(vVa(v(A -C(VvaAUM(VaCA)), - necessarily substituted by one, two or three s(vdAZS(V(AM(VUKHA)), - substituents , independently selected from halogen or c(o)c(vehAM(NeCDA), -C(VeKAM(HC(OVYA, - -Onr8; c(o)cS(Vneu(vBev(Ve), 0 C(Ve(AS( ОМ(В(А, СС-ВЗ is hydrogen or C|i-alkyl, which is not

B(OH)", -OSHg2O- or 4,4,5,5-tetramethyl-1,3,2- necessarily substituted by one, two or three dioxoborolan-2-yl; where the indicated groups are optional substituents, independently selected from halogen or substituted either by a carbon atom or by heteroa- -ОБ5; therefore, by one to five substituents, regardless of whether or not the VUs can be taken together with the early atom from C-alkyl, halogen, keto, cyano, nitrogen, to which they are attached, or are haloalkyl, hydroxyalkyl, -OVU, -MO", -MNU, - between them with the formation of a C3-heterocyclic ring-

МНО(О288, -АЗ50О»2В!2, -5О2В2, -BO(В2), -5872, - this one, which is optionally replaced by one or two

ЗА, -5ОпМ(Бе(АЯУ, 0 -5ОпМ(А)С(О(А2) СС- substituents, independently selected from C-valkyl, в'ЗМ(А(А)") -С(АЕ'Е(AlL )OH, -СООН, - halogen of hydroxyalkyl, hydroxy, alkoxy or keto; "сС(ВеХАС(ОМ(В2) (Р), -С(оу(Ве(А), - п is independently selected from an integer from zero m( в'Зс(вув'(ВУ), -Х(В'ЗСО(ВУ), -МН(СНг)2ГОН, up to three; -МНСТсувёе, -5и(CH3)з, heterocyclyl, aryl or each t independently chosen from an integer number of heteroaryl; from zero to two;

VZ is hydrogen or Si-alkyl; and their pharmaceutically acceptable salts, stereoiso- or P and E8 or can be taken together with any-mers and M-oxide derivatives. which of the atoms to which they can be attached - Preferably, this invention relates to no, or are between them, with the formation of 4-10 compounds of the following chemical formula: membered heterocyclic ring system, where the ring system, which can be monocyclic - Av. Р5 В It is monocyclic or bicyclic, optionally substituted. du with him or two substitutes, regardless of 1 p! Wow! selected from C1-alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OB!E, -5819 or -M(B"9)"; and I

BZ is selected from the group consisting of hydrogen, where K is hydrogen, C1-alkyl or aryl, aryl(C1-alkyl, heteroaryl, heteroa-C8-valkenyl, where alkyl and alkenyl groups are indicated, aryl(C:i-4) alkyl, Czacycloalkyl, Czacycloalkyl optionally substituted from one to six atoms: (Ci-d)alkyl and heterocyclyl(Ci-4)alkyl, where halogen atoms are indicated, Czacycloalkyl, "ZA, -ZA 7, "ZON, 12 9 12 12 11 12 groups can be optionally substituted by one, called with "ВО "-ЗОгН, -ЗО2сН(АТА), ОБ, - two or three substituents, independently chosen - ОН", -МШЧА У", aryl, heteroaryl or heterocyclyl , they are from halogen, alkoxy or -5028!2; where indicated aryl, heteroaryl and heterocy-

Vo represents hydrogen or C-alkyl clinal groups optionally substituted by one or

B"! represents hydrogen or C 1 alkyl; by two independently selected substituents Z

you is hydrogen, C1-alkyl, which is not C1-alkyl, halogen, hydroxyalkyl, hydroxy, alco- necessarily substituted with one, two or three Xy or keto, substituents independently selected from halogen, H" is hydrogen, C1-alkyl or alkoxy, cyano, "MAO or -5879; Cg-valkenyl, where alkyl and alkenyl groups are indicated

VN? is hydrogen, C-alkyl, (Ci-alkyl)aryl, (Ci-alkyl)hydroxyl, /-O(Ci-alkyl), halogen atoms, Oz--cycloalkyl, with, - 7, edrokoy halogen wet and heteroarite with -VON, VONA, OH, "ZOsHn(A(A")), OH, -

Ov, -M(B!2)2, aryl, heteroaryl or heterocyclyl, С(А'(АВо)ЗС(А (А (ВУ), в'ов-, - where aryl, heteroaryl and heterocyclyl are indicated) (вМААС(ВауААУ) -С(ВУАУМ(В(А), С- lyl groups are optionally substituted by one or с(вгАС(Вг (ВМ) (Р)), - by two substituents independently selected from Сч-сос(ve( vUMm(VeuA), -C(V(AM(NUS(OVYA, - alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy C(C(VU(vUB(H), 0 cS(veAZS(OMVUHVU), - or keto; in (OH)", -OSHg2O- or 4,4,5,5-tetramethyl-1,3,2- or B! and B" can be taken together with a dioxaborolan-2-yl atom; where the indicated groups are not necessarily carbon , to which they are attached, with the formation substituted either by a carbon atom or by a heteroatom

of a C3-cycloalkyl or heterocyclic ring with one to five substituents, independently selected ring system optionally substituted with C-alkyl, halogen, keto, cyano, halogenated with one or two substituents, regardless of alkyl, hydroxyalkyl, -ОВУ, -МО", -МН2, -МНО(О2Б88, selected from 1-6 alkyl, hydroxyalkyl, halogen- -835028!2, -5028!?, -5О(Б2), -58!?, - 585, - alkyl or halogen;

BZ is hydrogen, C-alkyl or cC(А(Во)м(в'ЕАИ, -С(А'(AT)OH, -СООН, -

Cg-valkenyl, where alkyl and alkenyl groups C(ВХАЗС(ОМ(ВУ РО), -СОХваХАе) are indicated, - optionally substituted by C3-zcycloalkyl or from M(А'ЗС(ВЕ(АТ (ВУ), - (А'ЗСО(ВУ), -МН(СНг2ОН), one to six halogen atoms; -МНС(ФОВ!e, -5и(СНвз)з, heterocyclyl, aryl or

IN? is hydrogen, Siwalkil or C". heteroaryl; valkenyl, where alkyl and alkenyl groups B are indicated? is hydrogen or Si-alkyl; optionally substituted by C3"cycloalkyl or from or P" and E3 or can be taken together with any one to six halogen atoms; which of the atoms to which they can be attached or C and B" can be taken together with an atom no, or are between them with the formation of 4-10 carbons, to which they are attached with the formation of a C3-membered heterocyclic ring system, where the ring system, which can be a monocyclic ring or five- of a seven-membered heterocyclic group with a non- or bicyclic, optionally substituted radical, where cycloalkyl, cycloalkenine, or two substituents are indicated, independent and heterocyclyl groups are optionally substituted with C-alkyl, halogen, hydroxyalkyl, substituted with one or two substituents , regardless of hydroxy, keto, -OV"E, -5819 or -M(B"9)"; selected from C-alkyl, halogen, hydroxyalkyl, B? selected from the group consisting of hydrogen, hydroxy, alkoxy or keto; aryl, aryl(Ci-4)alkyl, heteroaryl, heteroa-

IN? selected from hydrogen or C1-alkyl, substituted (C1-4)alkyl, C3-6cycloalkyl, C3-6cycloalkyl with 1-6 halogen atoms; (Ci-4) alkyl and heterocyclyl (Ci-4) alkyl, where indicated

AND? is aryl, heteroaryl, the groups may be optionally substituted by one,

C-vehaloalkyl, arylalkyl or heteroarylalkyl, with two or three substituents, independently selected from aryl, heteroaryl, arylalkyl and them from halogen, alkoxy or -5028'2; heteroarylalkyl groups are optionally substituted with B!? represents hydrogen or C-alkyl with one, two or three substituents, regardless of whether B" represents hydrogen or C-alkyl; chosen Kk! halogen, C-alkyl, C-B'?g represents hydrogen or C-alkyl, which is haloalkyl , C3-ecycloalkyl, haloalkoxy, - optionally substituted by one, two or three substituents independently selected from halogen, 5ОСН(В (А), -ОВ!, -М(В(В"), cyano or alkoxy, cyano, -MA"O or -5819; aryl, optionally substituted -502872; Ba represents hydrogen, Si- alkyl, (Ci-alkyl) each O is independently C-alkyl, aryl, (Ci-alkyl) hydroxyl, -O(Ci-alkyl), hydroxyl,

Co-alkenyl; C3-alkynyl, aryl, heteroaryl, halogen, aryl, heteroaryl, C3-zcycloalkyl, hetero-

C3-ccycloalkyl or heterocyclyl, where each indicated cyclyl, where indicated alkyl, aryl, heteroaryl, aryl, heteroaryl, cycloalkyl and hetero- C3-ccycloalkyl and heterocyclyl can be substituted cyclyl groups, which can be monocyclic either on the carbon atom or on the heteroatom one, or bicyclic, optionally substituted by two or three substituents, regardless of the choice of a carbon atom, or by one to five C-alkyl or halogen heteroatoms; by substituents independently selected from C-valkyl, A? represents hydrogen, C1-alkyl, (C1-haloalkyl, halogen, keto, alkoxy, -582, -58"2, alkyl)aryl, (Ci-alkyl) hydroxyl, alkoxy, hydro- -ОВ8, -ВО!2 , M(B2)2, -5О2НВУ, or -5028/9; sil, halogen, aryl, heteroaryl, Czacycloalkyl,

E represents hydrogen, C1-6 alkyl, C1-6 alkenyl, heterocyclyl, where alkyl, aryl, heteroaryl,

C3-valkynyl, C3-valkyloxy, halogen, nitro, cyano, C3-vcycloalkyl, and heterocyclyl can be optional - aryl, heteroaryl, C3-vcycloalkyl, heterocyclyl, - necessarily substituted either on the carbon atom or on the hesium, -C (Ф0О5ЦСН(СН3)гии, -ОВУ, -ОВ'О, - teratom with one, two or three substituents,

С(О)ВЯ, -ВЭ(ОО)А8Я, -С(О0)8З, -С(ОМ(В(В), - independently selected from C-alkyl or halogen; с(ом(вА'ХВ2) .

ЗВв2, -58Я, -ВЭАЯ, -88, -С(ВЗ)з, -С(АО(АТ МВ)», the carbon to which they are attached, or find- -МАЯАС(О)МАО5(О )2AU, -5О»НВ!2, -ВО(В2), -BO»НУ, - sia between them, with the formation of C3-vcycloalkyl

ЗОтп(В (ВУ), -ВОпсН(А (А), - ring or C3-heterocyclic ring, where 5ОМ(А СО), -505(В)С(ОМ(В2)), - 3-8 membered ring system may be optional

OBO" (АВ) 0 -М(А'ЗС(ОМА (VU), - is substituted by one or two substituents, non-

М(Б')С(ОВЯ, -М(А'ЗС(ОВЯ, -М(А'ЗС(ООВ, - depending on selected from C-alkyl and halogen);

М(В)5О4(ВУ), -«С(ВЕ(АТИМАТС(В (Аа) ВУ, В: represents hydrogen or Si-alkyl, which is not

С(Веу(АТИМ(АО) ВУ, -С(А(АпМ(А (А) - necessarily substituted with one, two or three substituents independently selected from halogen or substituted with one or more substituents as described by -ОВ5 ; above: cyclopropyl, cyclobutyl, cyclopentyl, cyclo-

HO is hydrogen or C-alkyl, which is not loghexyl and cycloheptyl. In one category, cyclohexyl is formed when substituted by one, two or three elements of the invention. substituents independently selected from halogen or In one variant of the implementation of this invention -OVU; IN? is a C-alkyl substituted by 1-6 atoms or in: And RU can be taken together with a halogen atom and EZ is a C-alkyl substituted by 1-6 nitrogens to which they are attached or are halogen atoms. In another variant, the implementation between them with the formation of a C3-heterocyclic ring of the invention E? represents hydrogen and BEZ represents this, which is optionally substituted by one or two C-in C-alkyl, substituted by 1-6 halogen atoms. In the substituents independently selected from C-alkyl, in the following embodiment, B? is a halogen of hydroxyalkyl, hydroxy, alkoxy or keto; hydrogen and RU is a Si-alkyl, substituted 1-6 p independently selected from an integer from zero with fluorine atoms. In the following embodiment, up to three; IN? is hydrogen and P? is a C-alkyl, each t independently selected from an integer substituted with fluorine atoms. In another version, from zero to two; exercise, eh? is hydrogen and BE is co- and their pharmaceutically acceptable salts, trifluoromethyl or 3,3,3,2,2-pentafluoroethyl, mers and M-oxide derivatives. more preferably P: is trifluoromethyl.

In one embodiment of the present invention In another embodiment of the present invention,

IN! and c2, each, represent hydrogen. Otherwise, VAZ is hydrogen and RZ is aryl or, in the embodiment of this invention, B" and P, in the case of heteroaryl, where the indicated aryl and heteroaryl are optional

Finding at the same carbon atom, necessarily replaced by halogen or -5028'2. must be taken together with the carbon atom to which, in another embodiment of the present invention, they are attached, with the formation of a 3-9 membered cycloa- B! and 2, taken together with the carbon atom to which the alkyl ring system, where they are attached, form a cyclopropyl, cyclobus system optionally substituted with C-alkyl, hydyl, cyclopentyl, cyclohexyl and cycloheptyl, oxyalkyl and halogen. Examples of ring systems are mainly cyclopropyl; BZ represents n-terms that can be formed include propyl, isobutyl, 2-fluoro-2-methylpropyl, /--2-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexatrifluoromethylpropyl, 3-fluoro-2-(2 - sil and cycloheptyl In the preferred version, cyclopropyl is formed from the reaction of difluoromethyl)propyl, 2,2-difluoroethyl, 2,2-nation. difluoropropyl, 3,3,3-trifluoropropyl, or 2,2-

In another embodiment of the present invention, dichloroethyl; BV? and VZ represent hydrogen; and B?

IN! and 2 are taken together with a carbon atom, to which is a C-alkyl, substituted by 1-6 atoms, are attached, with the formation of a 3-8 membered heterocyclic halogen; mainly BU is a Si-alkyl of a single ring system, where ring sys- substituted with fluorine atoms is indicated; more preferably, 25 is optionally substituted with C 1 -alkyl, is trifluoromethyl or 3,3,3,2,2-hydroxyalkyl or haloalkyl. Examples of pentafluoroethyl, most preferably trifluorocarbon ring systems that can be formed, til. Within this variant of implementation, especially include piperidinyl, pyrrolidinyl or the preferred variant of implementation is the variant where n is tetrahydropyranyl. is equal to 1. The second particularly preferred variant

In one variant of the implementation of this invention, that implementation is a variant where n is equal to 2. Another

VZ and B? each, independently, represent Si. a particularly preferred embodiment is 4-alkyl or H. In the following embodiment, the variant where n is 3. Preferably, n is 1, KZ of this invention is isobutyl or n- in those cases where O is heteroaryl, propyl and B" is H, more preferably, C, which is optionally substituted by halogen or phenyl, is n-propyl. nyl, substituted by hydroxyalkyl, -SOV'O (where B'O

In the next variant of the implementation of this invention, - is C-alkyl) or -5028!2 or O is C-alkyl, BZ is C-alkyl, where the indicated alkyl is phenyl, which is optionally substituted by halo-substituted by C3-zcycloalkyl or halogen. Regenome, -"СОМВ2В? (where 2 is hydrogen or important, C is 2-fluoro-2-methylpropyl, 2-Ci-alkyl, and 2? is hydrogen, C-alkyl, cyclotrifluoromethylpropyl, 3-fluoro-2-(2- loalkyl or C1-alkoxy or B: and PE? together with the atom of fluoromethyl)propyl, 2,2-difluoroethyl, 2,2-nitrogen, to which they are attached, form hetero-difluoropropyl, 3,3,3-trifluoropropyl or 2, 2- cyclyl, where the specified heterocyclyl is not necessarily dichloroethyl, and P" is hydrogen. More substituted by alkyl, hydroxyalkyl, or halo- important C is 2-fluoro-2-methyl propyl. alkyl), -"Z028! 2 (where B!2 is a C-alkyl), -

In another variant of the implementation of this invention SOOV", alkynyl, optionally substituted hyd-

BZ and BU, taken together with the carbon atom to which they are attached by oxy or cycloalkyl, substituted alkenyl, form C3-zcycloalkyl ky-hydroxy, alkyl, optionally substituted hydro-ring, Czacycloalkenyl ring or five-seven , -OVOZ (where BU is aryl), -OVO, - a membered heterocyclic radical, where the indicated cycle is CBA'B5C9B0 VU (where P? is aryl), -CH2g5 loalkyl, cycloalkenyl and heterocyclic (aryl), cyano, - SOVZ? or heteroaryl. the groups are optionally substituted by C-alkyl, halo- Preferably, n is 2 and each O is a mono, hydroxyalkyl, hydroxy, alkoxy or keto. battle phenyl, where the second phenyl is attached in position

Examples of ring systems that can be formed by 4 of the first phenyl ring (phenyl attached, including, but not limited to, the following, attached to the carbohydrate atom, bearing the EZ group and 9) considering that the heterocycle is not necessarily in addition, each phenyl is optionally substituted by one or two substituents independently chosen from the 4-position of the first phenyl, and heterocyclyl is represented by C1-alkyl, halogen, hydroxy, alkoxy, halo, morpholin-4-yl, pyrrolidin-1-yl, piperidine -1- genalkyl, haloalkoxy or -5028"2 (where B is yl, piperidin-4-yl or piperazin-1-yl, substituted by C-alkyl), and the second phenyl is additionally dikal B". Preferably КЕ" is hydrogen substituted by the radical B". More preferably, each is alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, and O is phenyl, where the second phenyl is added - СООВ' or -5028!2 (where B" is a in position 4 of the first phenyl ring and C-alkyl). the second phenyl is optionally substituted with a radical In another embodiment of the present invention,

B" which is located in position 4 of the phenyl B! and 2 are taken together with the carbon atom to which the ring is -5028!2 (where K!2 is the attached, with the formation of cyclopropyl, cyclo-

C-alkyl is optionally substituted by a hydroxyl group of butyl, cyclopentyl, cyclohexyl, and cyclohepty group or a halogen), -"502МВ:2ВУ (where ВЕ: and РУ are not, more preferably, cyclopropyl; БЕЗ and В are taken depending on whether hydrogen or Si -alkyl or VE: and together with the carbon atom to which they are attached,

VU together with the nitrogen atom to which they are attached, with the formation of a C3-C cycloalkyl ring, Св-В. цЦИ- form a heterocyclic ring), -5B'2 (where B" of a cloalkenyl ring or a five- to seven-membered ring is a C-alkyl), -ZOV"? (where B? represents a co-heterocyclic radical, where cycloalkyl, C-alkyl are indicated), --ЧНСОВ'Z (where B!? represents flax, cycloalkenyl and heterocyclyl groups

Si-alkyl), -MA'OD" (where B" and B! are optionally substituted by Si-vsalalkyl, halogen,

Si-alkyl), -Z0O2MNHSO'O, heteroaryl, halogen, - hydroxyalkyl, hydroxy, alkoxy or keto. App-

SOOV! (where B!? represents hydrogen or Si-alkyl), the rings of ring systems that can be formed, -ОВ? (where P? represents hydrogen or aryl), -OB'O include, but are not limited to, the following, including - (where B"O represents C1-alkyl), aryl, substituted - vuing that the heterocycle is not necessarily substituted 5028: (where B! is C1-alkyl), cyano, halo- with one or more substituents as described above: genalkyl, -C(B'(BpL)OH, C1-alkyl optionally cyclopropyl, cyclobutyl, cyclopentyl , cyclohex- substituted -ОВ'О and halogen, СО? (where BEZ represents sil, cycloheptyl, tetrahydrofuran-4-yl, pipery- with aryl), -СОВ'O, or -МНЗО2В!? (where VO represents dyn-4 -il. Preferably, EZ and B", taken together with the C-alkyl atom) and additionally the second phenyl ring of the carbon to which they are attached, form a cyclo- optionally substituted by another substituent, vibra- propyl, cyclobutyl, cyclopentyl, cyclohexyl , nim 3 Sivalkylu, -SNO, -SOOV!O, -SOVO, - or cycloheptyl. A more preferred option

МНСОВ'", halogen, haloalkyl, -ОВ!? (where in the implementation of the invention there is a variant when РЕЗ and РУ, taken represents hydrogen or C-alkyl, where indicated along with the carbon atom to which they are attached, alkyl is optional substituted by halogen), - form cyclohexyl. In this variant, the

ZO2MN", - MNSOV! (where E!O is C-alkyl), but, a particularly preferred variant is the variant, or -5O2B!2 (where B? is C-alkyl). Where are the E radicals? are hydrogen; and B: represents mainly, the second phenyl substituted by the radical B" is a C-alkyl, substituted by 1-6 halogen atoms; in position 4, where B" is -508!2, -5O28!2 mainly EZ is a C-alkyl, replaced by Z where K!? is C-alkyl (mainly methyl) with fluorine atoms; more preferably, RU is either -BOtpMVgVU, where RE: and VU independently represent trifluoromethyl or 3,3,3,2,2-pentafluoroethyl, or hydrogen or alkyl or P: and BU together form more preferably trifluoromethyl. In this variant, heterocyclyl, and t is an integer from zero to zero, a particularly preferred variant is up to two. Preferably, B' is a methylsulfonyl variant, where n is equal to 1. The second is especially per-phenyl, M-methylaminosulfonyl, aminosulfonyl, an important variant is the variant where n is equal to 2. Also or morpholin-4-ylsulfonyl. one particularly preferred option is to carry out

Preferably, n is equal to 2, in the case when there is no option where n is equal to 3. Preferably, n is the first O (O is attached to the carbon atom representing 1 in the case when O is the heterogeneity of the EZ group and RU) is phenyl, and the second Y is aryl, optionally substituted with halogen or is heterocyclyl (preferably morpholine-4-phenyl, substituted with hydroxyalkyl, -SOV'O (deyl, piperazin-1-yl or piperidin-4- il), optionally - B!? represents C1-alkyl) or -5028!2, or O is explicitly substituted by cycloalkyl, heteroaryl, It is phenyl, optionally substituted by haloalkyl or hydroxyalkyl, more preferably , genome, -SOMNA2B? (where Ba is hydrogen or cyclopropyl, methyl, ethyl or hydroxyethyl-Ci-alkyl, and 2? is hydrogen, C-alkyl, cyclo and the specified heterocyclic ring is attached to loalkyl or C-alkyl, or 2 and P? together with the nitrogen atom at position 4 of the phenyl ring, to which they are attached, form

Preferably, n is equal to 2, in the case when the heterocyclic radical, where the specified heterocycle - the first O (O attached to a carbon atom, which is optionally substituted by an alkyl or halogen group EZ and RU) is phenyl, and the second is Y nalalkyl), -5028"2 (where EK is a C-alkyl), - is a heteroaryl substituted by one or SOOK, alkynyl, substituted by hydroxy, alkenyl, substituted by two substituents independently selected from hydrogenated hydroxy, alkyl, neobo necessarily substituted xyalkyl, -5028!2 (where "2 is C-alkyl), hydroxy, -OV!O, -SV'YED"5STOVIVO (where RU represents

C-alkyl, halogen, haloalkyl, amino or -self aryl), -СНа5(aryl)-СОВЗ or heteroaryl.

ОВ, Preferably, n equals 2 and each О represents a so-

Preferably, n is 3, where the first and second rings are phenyl, where the second phenyl is attached in position

O is phenyl, and the third O is a 4-membered ring of the first phenyl ring (phenyl is attached to a heterocyclyl and optionally substituted as defined to the carbon atom bearing the РЕ? and Р groups) and, but above. More preferably, the first and second O are optionally substituted, where each phenyl is optionally substituted with a phenyl, where the second phenyl is attached to the ring by one or two substituents independently selected from C-alkyl, halogen, hydroxy, alkoxy substituents independently selected from halogen, si, haloalkyl, haloalkyl, and the second phenyl of Ci-alkyl, Ci-haloalkyl, C3-cycloalkyl, ha- is additionally substituted by radical B". , -50285, - it is important, each O is a phenyl, where the second is ZO»2v!g, -BOSN(В!2(В), «ОВ, -МЩЧА (В), cyano-phenyl is attached in position 4 of the first phenyl- or an optionally substituted aryl of the ring, and the second phenyl optionally substituted 5О02В":, More preferably, the phenyl is substituted by the radical В", which is located in the position of C-alkyl, halogen, haloalkyl or halo- 4 of the phenyl ring, and represents -5028!2 (where B! genalkoxy. In this embodiment, the other represents a C-alkyl, optionally substituted by the predominant in an ariant is when B' and 2 are each a halogen), -ZO2MAUVYA (where Be and ВО are independently hydrogen. In this embodiment, .represent hydrogen or C 1-6 alkyl, or 2: and VU, another preferred option is when PE! and B2 taken together with the nitrogen atom to which they are attached, together with the carbon atom to which they are attached, form a heterocyclic ring), -5B'2 (where B" to form a 3-8 membered cycloalkyl or he- is Si -valkyl), -CHUNSOVZ (where EZ represents a heterocyclic ring system, where the number of Si-valkyl is indicated), -MV'YAVy (where KO and B"! represent this system optionally substituted by Si-valkyl,

Ci-alkyl), heteroaryl, halogen, -"COOV'O (where BO is hydroxyalkyl or halogen. The preferred ring is hydrogen or Ci-alkyl 1), -OBZ (where BZ systems that can be formed include in represents hydrogen or aryl), aryl, substituted - itself cyclopropyl, cyclobutyl, cyclopentyl, cyclo-

ZO2B!:2 (where B: represents C-alkyl), cyano, halohexyl and cycloheptyl, more preferably cyclop- genalkyl, -"CHO, -C(B'3(AT)OH, C-alkyl, neobo" - ropyl. In these preferred and more preferred variants, it is necessarily substituted by the radical -ОВ'"О and halogen, - antah is implemented by an even more preferred option

СОВ'О, or -МН5ОО»2Б'О (where В? represents the implementation of there is a variant where EZ represents Ci-alkyl and

C-alkyl) and, additionally, the second phenyl ring is not - B? represents H. Preferably, 23 represents n- necessarily substituted by another substituent, selected propyl or isobutyl, and B" represents H. B of these pe- from halogen, haloalkyl, -OB. (where B!2 represents the respective and in more preferred options, hydrogen or C-alkyl, where the indicated alkyl is optional, in another, even more preferred option, it is effectively substituted by halogen) or -5028"!2 (where in": nen, there is an option where VZ is 2- fluoro-2- is C-alkyl). ,2-difluoroethyl, 2,2-

B" represents -5028'"2, where B? is difluoropropyl, 3,3,3-trifluoropropyl or 2,2-

C-alkyl (mainly methyl) or -5HOtpMAgVe, where B: dichloroethyl; and P" represents hydrogen. In these transitions, and B independently represent hydrogen or alkyl, important and more preferred variants of implementation, or in: and KU together form a heterocyclyl, and t, in another, even more preferred variant, realizes an integer from zero to two. Preferably, there is an option where R3 and B" can be taken together with no, B" represents methylsulfonyl, /-M- the carbon atom to which they are attached from utvo- methylaminosulfonyl, aminosulfonyl, or by moring of a C3-C cycloalkyl ring, a C3-1 cycloalphon-4-ylsulfonyl kenyl ring or a five- to seven-membered hetero-

Preferably, n is equal to 2 in the case when the first O of the cyclic radical, where cycloalkyl is indicated (O is attached to a carbon atom, which cycloalkenyl and heterocyclyl groups do not require EZ and RU groups) is phenyl, and the second O is substituted C-alkyl, halogen, hydroxyl- is a heterocyclic radical (mostly alkyl, hydroxy, alkoxy or ketone. Examples are piperazin-1-yl or piperidin-4-yl) substituted by cyclo- ring systems that can be formed, including alkyl, C 1 -alkyl or hydroxyalkyl, including, but not limited to, the following, preferably cyclopropyl, methyl, ethyl, or that this heterocycle is optionally substituted with hydroxyethyl, and said heterocyclic ring with one or more substituents as indicated above: attached at position 4 of the phenyl ring. cyclopropyl, cyclobutyl, cyclopentyl, cyclohex-

Preferably, n is 2 in those cases where sil and cycloheptyl. In a preferred variant of implementation, the first O (O attached to a carbon atom, which when cyclohexyl is formed, bears the groups ЕЗ and РУ) is phenyl, and the second U is a heteroaryl substituted by one or in the preferred variant, where n is equal to 1. Another by two substituents independently chosen from hydro- the preferred option when n is 2. Another xyalkyl, -5028!2 (where B! is a C-alkyl), the preferred option when n is equal to 3. Prefer-

Si-valkyl, halogen, or -OV!Yu. Preferably, n is even, n is equal to 1 in the case when O is 3, where the first and second O are phenyl, or heteroaryl, which is optionally substituted and the third O is a heterocyclic radical, and halogen or phenyl substituted with hydroxyalkyl - optionally substituted as defined above. More SOV'" (where B? is a C-alkyl) or 5028", preferably, the first and second O are phe- or O is a phenyl optionally substituted, where the second phenyl is attached in the 4th position by a halogen, -SOMV2B? (where 2 is the first phenyl and the heterocyclic radical is di or C-alkyl, and PE? is hydrogen, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-Ci-alkyl, cycloalkyl, or C-alkyl or 2 and 5 yl, piperidin-4-yl or piperazin-1-yl, substituted together with the nitrogen atom to which they are attached, dikal B". Preferably, B" is hydrogen, form a heterocyclic radical, where the indicated alkyl , hydroxyalkyl, haloalkyl or cycloalkyl, heterocyclyl is optionally substituted with alkyl

In another embodiment of the present invention, or haloalkyl), -5028!2 (where B? represents

E represents hydrogen and K represents aryl, non-Sivalkyl), -"COOV'"E, alkynyl, substituted hydroxy, necessarily substituted by one, two or three alkenyl, substituted hydroxy, alkyl, optionally substituted hydroxy, - OV!O, -SV'YED"5STod'VZU (where the second O is phenyl, where the second phenyl

VZ? is aryl), -СНеа5(aryl) -СОВ? or he- is attached at position 4 of the first phenyl, and hetero- is heteroaryl. rocyclic radical is morpholin-4-yl,

Preferably, n is 2, and each O is pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, or phenyl itself, where the second phenyl is attached to polo-piperazin-1-yl, optionally substituted by group B ". 4 of the first phenyl ring (phenyl is attached. Predominantly PE" is hydrogen, alkyl, hydroxyned to the carbon atom bearing groups PE? and P) and, alkyl, haloalkyl or cycloalkyl. additionally, where each phenyl is optionally substituted in one embodiment of the present invention with one or two substituents independently A: represents hydrogen, and B: represents heteroselected from C-alkyl, halogen, hydroxy, alkocryl, neobo is necessarily substituted by C-alkyl, halohex, haloalkyl, haloalkyl, and the second by phenyl, haloalkyl or haloalkyl. Preferably, additionally substituted by radical B". More preferably, VU is thiazolyl, pyridinyl, importantly, each OO is phenyl, where the second tetrazolyl, thienyl or furanyl, optionally substituted phenyl is attached in position 4 of the first phenyl-substituted C1-4 alkyl or halogen. In this embodiment, the ring, and the second phenyl is optionally substituted, the preferred embodiment is the radical B", which is located in the position where B! and 2? each is hydrogen. In 4 of this phenyl ring and is -502H12 in this version of implementation, another preferred va- (where Kig2 is a C-alkyl, an optional variant is where B! and Pg, taken together with an atom placed by a halogen), 5О2МВ:В (where ВЕ: and ВУ are independent of the carbon to which they are attached, form 3-8, they represent hydrogen or C.alkyl, or EC: and a membered cycloalkyl or heterocyclic ring

VU together with the nitrogen atom to which they are attached, the system where the specified ring system does not necessarily form a heterocyclic ring), -5B'2 (where B" is substituted by C-alkyl, hydroxyalkyl and halo- is C-alkyl ), -CHUNSOVZ (where EZ is a so-genome. Predominant ring systems that can be C-valkyl), -"MV'YAV!! (where EE" and В!!! represent cells formed, include contains cyclopropyl, C-alkyl), heteroaryl, halogen, -SOOV!O (where cyclobutyl, cyclopentyl, cyclohexyl and cyclohep-

IN!? represents hydrogen or C-alkyl), -ОВ?Я (where BZ is til, more preferably cyclopropyl. In these predominance- represents hydrogen or aryl), aryl, substituted in other and more preferred variants of implementation by the radical -5028!2 (where B!? is a Ci-alkyl), a more preferred option is the option where BZ is cyano, haloalkyl, -CHO, -C(B'Z(B')ZON, cC- is a Ci-alkyl and 27 is N. Peralkyl, optionally substituted by the group-OB'O and importantly, BZ is n-propyl or isobutyl and B" is a halogen, -SOV'O, or -MNOO»B!? (where BO represents H In these preferred and more preferably C-alkyl) and additionally the second Feyl ring in other variants, it is even more optionally substituted by another substituent. , haloalkyl, -ОВ!? (where BO represents fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-isohydrogen or C-alkyl, where the indicated alkyl is fluoro-2-(2-fluoromethyl)propyl, 2,2-difluoroethyl, 2,2- optionally substituted by halogen) or -50 28!2 difluoropropyl, 3,3,3--rifluoropropyl or 2,2- (where B? is a C-valkyl). More preferably, dichloroethyl; and B" represents hydrogen. In these, the second phenyl is replaced by the radical B" in the most important and more preferred variants of implementation of No. 4, where B represents -5028!2, where B": represents another, even more preferred an option is a C-alkyl (predominantly methyl) or -5HOpMvevU where R3 and B" can be taken together with a carbon atom of B: and B3 independently represent hydrogen or the one to which they are attached, with the formation of C3-alkyl . Per-ring or five- to seven-membered heterocyclic important B" is methylsulfonyl, M- radical, where cycloalkyl, cycloalkeny-methylaminosulfonyl, aminosulfonyl or mor- and heterocyclic groups are optionally substituted folin-4-ylsulfonyl. no Si -alkyl, halogen, hydroxyalkyl, hydro-

Preferably, n is equal to 2, in the case where sy is an alkoxy or a ketone. Examples of rings, the first O (O attached to a carbon atom, which systems that can be formed include ЕZ and РУ groups) is phenyl, and the second is itself, but not only, the following, given that it is a heterocyclic radical ( preferably heterocycle optionally substituted with one or piperazin-1-yl or piperidin-4-yl) substituted with cyclo- more substituents as described above: cyclopro-loalkyl, C1-alkyl or hydroxyalkyl, more pil, cyclobutyl, cyclopentyl, cyclohexyl and cyclo - preferably cyclopropyl, methyl, ethyl or heptyl. The preferred option is when hydroxyethyl is formed, and the specified heterocyclic ring is cyclohexyl. attached at position 4 of the phenyl ring. In this embodiment, it is particularly advantageous

Preferably, n is equal to 2, in the case when the variant is the variant where n is equal to 1. The second O (O attached to a carbon atom, which, in a particularly preferred embodiment, carries EZ and RU groups) is phenyl, and the second Y is a variant where n is 2. Another particularly representative heteroaryl is substituted by one or a preferred embodiment is a variant where n is 3 by two substituents independently selected from hydroxy. Preferably, n is 1 in that polyalkyl, -502E (where EK is a C-alkyl), so when O is a heteroaryl, it is optional

Si-alkyl, halogen or -OH" substituted by halogen or phenyl substituted

Preferably n equals 3, when the first and second hydroxyalkyl, -SOV!? (where VZ is

O is phenyl, and the third O is C1-alkyl)u or -5028!2, or O is phenyl, a heterocyclic radical and optionally substituted, optionally substituted with halogen, -SOMV2B? as defined above. More preferably, the first and (where 2 represents hydrogen or Si-alkyl, and B?

is hydrogen, C1-alkyl, cycloalkyl or is heteroaryl, optionally substituted

C-valcox, or 2 and B? together with a nitrogen atom, to one or two substituents, regardless of the choice of which they are attached, form a heterocyclic ring from hydroxyalkyl, -5028!2 (where B!? is a radical, where the specified heterocyclyl is not necessarily C-alkyl), C- is alkyl, halogen or -ОВ'Э, substituted by alkyl or haloalkyl), -5028!2 Preferably, n is equal to 3, where the first and second (where BE!"? is a C-alkyl), -SOOV'O, alkyne- O are phenyl, and the third O is a radical substituted by hydroxy, alkenyl, substituted by a heterocyclic radical, and optionally substituted hydroxy, alkyl, optionally substituted by hydroxy, as described above. More preferably, the first and second oxy, -OB "O, -SVYAED" SODA (where E? represents the first and O represent phenyl, where the second phenyl is aryl), -"SNeb(aryl) -SOVZ or heteroaryl. connected in position 4 of the first phenyl, and hetero-

Preferably, M is 2 and each O is a co-cyclic radical is morpholin-4-yl, or phenyl, where the second phenyl is attached to polo-pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, or 4 of the first phenyl ring (phenyl, piperazin-1-yl, substituted by group B". Preferably, B is attached to the carbon atom bearing the groups РЕ? and Р) and represents hydrogen, alkyl, hydroxyalkyl, halogen, additionally, where each phenyl is optionally substituted alkyl or cycloalkyl independently substituted with one or two substituents In one embodiment of the present invention selected from C1-alkyl, halogen, hydroxy, alkoc-B and 28 or may be taken together with any of C1-haloalkyl , haloalkoxy, and the second phenyl of the atoms to which they may be attached, or additionally substituted by group B". They are more predominant between them, with the formation of 4-10 membered rings, each O is a phenyl, where the second phenyl is a heterocyclic ring system, where the ring is attached in position 4 of the first phenyl ring system, which can be a monocyclic ring, and the second phenyl is non-cyclic "necessarily substituted or bicyclic, optionally substituted by group B", which is located in position 4 of a phenyl-Ci-alkyl, halogen, hydroxyalkyl, hydroxy, ring and is -502ВІ2 (where Ві2 is a keto group, -ОВ'!Э, -58!? or -M(B'O)". In the following C-alkyl, optionally substituted with a halogen in the embodiment of this invention by EK and K wine), -5О2МВ2ВУ (where EE: apa ВУ independently are defined in such a way that they can be taken as hydrogen or C-alkyl, or B: and BU together with together with the nitrogen atom to which they are attached, the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocyclic ring ), -5B"2 (where K!2 is a heterocycle with 5-7 members in the co harvest ring and non-

C-alkyl), -ЧНСОВЗ (where ЕР? represents C3-alkyl), necessarily contain, in addition to the nitrogen atom, -МВЭЕВ"! (where ВЭЭ and вВы represent C-alkyl) , 1 or 2 additional heteroatoms selected from M, O and heteroaryl, halogen, -"COOV'"Z (where B? represents 5, the specified heterocycle is optionally substituted hydrogen or C-alkyl), -OB? (where BE? is one or more substituents selected from hydrogen or aryl), aryl substituted with a group -5028!2 C 1 -alkyl, halogen, hydroxyalkyl, hydroxy, keto- (where B? is C 1 -alkyl), cyano , haloalkyl, rupi, -OB'!E, -5819 or -M(B'O)". In the following application, -bHO, -F(B'Z(AT)OH, Si-alkyl, not necessarily rad, B" and 28 are defined in such a way that they can be substituted by the group-OB!:? and halogen, - SOV", or - must be taken together with the nitrogen atom, to which

МНЗО2В!: (where B" is a C-alkyl), and, additionally, they are attached to form a 5- or b-membered ring, the second phenyl ring does not necessarily have to be a heterocyclic ring system. Examples of such heterocycles with another substituent selected from halogen, which can thus be utologenalkyl, -ОВ'!? (where VO is hydrogen or rhenium, including but not limited to five or

Si-alkyl, where the indicated alkyl is optionally substituted by a six-membered ring containing at least one halogen) or -5028!2 (where B!? is a nitrogen atom, optionally substituted by one or

Si-valkyl). More preferably, the second phenyl is substituted with more substituents as described above. Preferred by the EK" group in position 4, where B" is a variant of implementation when the optional 5028" is formed, where B"? represents a C-alkyl (preferably substituted pyrrolidinyl. methyl) or -5OtpiMVeVU, where B: and VU independently appear- In one embodiment of the present invention, they are hydrogen or alkyl, or EC: and KE together Ba and 2? are defined in such a way that they can form a heterocyclic radical, and t means to be taken with a carbon or nitrogen atom, to which is an integer from zero to two. Mostly B" they are attached, for the formation of a monocyclic is a methylsulfonyl, M- or bicyclic carbocycle or heterocycle with 5-7 methylaminosulfonyl, aminosulfonyl or mor-members in each ring. This heterocycle can optionally contain folin-4-ylsulfonyl. addition to the atom

Preferably, n is equal to 2 in the case when nitrogen, 1 or 2 additional heteroatoms, selected first O (O is attached to a carbon atom with M, O and 5. The indicated carbocycle and heterocycle can carry groups ЕЗ and РУ) is phenyl , and the second U is not necessarily substituted by one or more is a heterocyclic radical (mostly by substituents selected from C-alkyl and halogen. piperazin-1-yl or piperidin-4-yl), substituted cycl- Reference to the above-mentioned preferred vari- loalkyl, C1-alkyl or hydroxyalkyl, more anti implementation means the inclusion of all combina- preferably cyclopropyl, methyl, ethyl or this specific and preferred groups, unless hydroxyethyl is specified, and specified heterocyclic ring of another. attached at position 4 of the phenyl ring. Another variant of the implementation of this invention

Preferably, n is equal to 2 in the case when the first O (O attached to a carbon atom, which according to the invention, which includes: carries EZ and RU groups) is phenyl, and the second Y () interaction compounds of formula (a):

The present embodiment includes methods of treating osteoporosis. t pi viv! Characteristic compounds of the present invention are shown in Tables I-IM below: (c) Compounds of formula I, where B, B, B, B, and 28 are hydrogen, shown in Table I, led-

I and it below: where B!-B5 and O are defined above, p' is an integer from 1-3, and X is a halogen, from the compound ІІ in

And what is formula (b): ven san a Пп в'- (0) ah she ВШ МИ В зла и зп:

PAZA Ivo LE NDI PAN A A min) POD 0 zzenenweih 05

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AND THE COUNCIL FROM U AH NI ov U o V

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I ; ON ; and ЖЖ и З-methylpratsia и SE и Constipation - paquokidny (m) optional separation of the mixture of stereo-dry isomers of the compound of the formula (I) obtained above - UNTIL AGAIN food of Ileneks S. There. reemeritny hryverayanviki- and the mentioned stages (i), (ii), (iii), (m), or (m), with obtained renewals! 17! There is no separate stereoisomer. Gaia | yameanyuvh 6507 Crash

This invention relates to methods of treatment | Manifestation of violations associated with anomalous RESPONSE OF DRAINAGE; ; ; NO Pehlal oh! SE | Ziphomnomnih: btsia bone. Such disorders include, but are not limited to, osteoporosis, osteoporosis induced by glucocorticoids, Paget's disease ), abnormally elevated OB 1 vlemnevvnny OB DVvelyu i du : ; ; I V iopmekhahoramk i Se: OKOM o KI bone metabolism, periodontal disease, GLEBA 001 oneknyaerenia 000000. uKKN Ki ! tooth loss, bone fractures, rheumatoid arthritis lnEonnunyy 50 NN a osteva aukoloprosthetic osteoli N ya ro geracheromy SB. wow! rheumatism, rheumatism, peri-prosthetic teoli- THE GRANTED GOES VC BUT TOD OTHER MIND OF THE DAY Tess: "IN sis, osteogenesis insufficiency, cyst disease- Tov | pmErasnryMh | ke Z shin current associated with metastases, hypercalcemia of the sciatica, and malignant tumor tumors and multiple myeloma. Prefer- N B, |obkkayarmnya | SVOO YAM layetyt Me and . Ah N! N 0 megaxismimekisvmvi current version of the implementation includes the methods ' EB5, 5 1 Жено кихе | Treatment of osteoporosis and bone diseases associated with metastasis. Preferable nn not nn ZSH 77168 : х ROMMOTODOMOH AND TETU mir Me, shi : I S, au prat hydra KHEVMNK NINI as

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53 777168 5a thien-3-ylphenyl)ethyl|I--leucinamide; in t v am M'!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(4-brevure|methylpyridin-2-yl)uphenyl|ethyl)i-leucinamide; min Av M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-1|4-(5-buttitu methylpyridin-2-yl)phenyl|ethyl)!1 -leucinamide; o NN PON M'-(cyanomethyl)-M2-(18)-2,2,2-trifluoro-1-(2--

ЖАВ жа 00 МЖК в, took fluoro-1,1"-diphenyl-4-yl)ethyl--leucinamide; nie nn nn wn M'-(cyanomethyl)-M?-(15)-1-I4-(3, 5- pon nn nn se dimethylisoxazol-4-yl)phenyl|-2,2,2-trifluoroethyl)|.- ko ' i tnakuny Pozheyts se Y metvzulfikaavniai | leucinamide;

OMNKYNNN INA Mina KAN NANKNNNN M'-(cyanomethyl)-M?-(15)-2,2,2-trifluoro-1-|4-(hydroxymethyl)-1,1"-diphenyl-4-yl|ethyl -

Specific variants of implementation of this vinacholeucinamide; include, but are not limited to: Mm2-(15)-1-(2-cyano-1,1"-diphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-trifluoroethyl|-M'-(cyanomethyl)! -leucinamide; trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-M!-(cyanomethyl)-M2-((15)-1-(34-difluoro-1,1"-yl|stil) - leucinamide; diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide;

M'-(cyanomethyl)-M2-(2,2,2-trifluoro-1-4-1-P-phenylethyl methyl ether)! -leucinamide; (cyanomethylcarbamoyl)-3-methylbutylamino|-2,2,2-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-fluoro-3-trifluoroethyl)diphenyl-2-carboxylic acid; methylphenyl)ethyl-leucinamide; Methyl ether 4-1-P-

M1-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(4-(cyanomethylcarbamoyl)-3-methylbutylamino|-2,2,2-pyridin-3-ylphenyl)ethyl| -leucinamide; trifluoroethyldiphenyl-3-carboxylic acid;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-M1-(cyanomethyl)-M2-((15)-1-(3'4-dimethoxy-pyridine) -3-ylphenyl)ethyl|-leucinamide; 1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl/--

M'-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(4-leucinamide; pyridin-4-ylphenyl)ethyl|-leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(2-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(trifluoromethyl)-1,1-diphenyl-4-yl|ethyl-pyridin-4-ylphenyl)ethyl |I-leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(4-M1-(cyanomethyl)-M2-C15)-1-(3',4-dichloro-1 ,1"- (C4-(2-fluoroethyl)piperazin-1-diphenyl-4-yl)-2,2,2-trifluoroethyl-1-leucinamide; yl|carbonylphenyl)ethyl|1-leucinamide; M1-(cyanomethyl)- M2-((15)-2,2,2-trifluoro-1-(3'-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-C4-(2-formyl-1,1-diphenyl-4-yl)ethyl-leucinamide; fluoroethyl)piperazine-1- ilycarbonylphenyl)ethyl||/-- M'!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(2-leucinamide; oxo-2,3-dihydro-1, 3-benzothiazol-b-yl)phenyl|ethyliu -

M2-11-(1,1"-diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide;

M!-(cyanomethyl)! -leucinamide; Mm2-((15)-1-(4-(5-bromopyridin-3-yl)phenyl|-2,2,2-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(3-trifluoroethyl)-M1-(cyanomethyl)!-leucinamide; hydroxy-3-methylbut-1-ynyl)/ phenyl|ethyl - M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-leucinamide; (trifluoromethoxy)-1,1"-diphenyl-4-yl|ethyliu -

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3-leucinamide; hydroxy-3-methylbutyl)phenyl|ethyl)! -leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

Me-(15)-1-(4-bromophenyl)-2,2,3,3,3-(1H-indol-4-yl)phenyl|ethyl)! -leucinamide; pentafluoropropyl|-M'-(cyanomethyl)! -leucinamide; M'1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-pyrimidin-5-ylphenyl)ethyl-leucinamide; 1-(4-pyridin-4-ylphenyl)propyl|i-leucinamide; M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-quinolin-3-ylphenyl)ethyl-leucinamide; fluoro-1,1-diphenyl-4-yl)ethyl |-leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-K15)-2,2,2-trifluoro-1-(4-(1,93-thiazol-2-yl)uphenyl|ethyl)! -leucinamide;

(1E)-3-hydroxy-3-methylbut-1-enyl|phenyl)ethyl))! - Methyl ether 4-1-P-leucinamide; (cyanomethylcarbamoyl)-3Z-methylbutylamino|-2,2,2-

M1-(cyanomethyl)-M2-((15)-2,2,3,3,3-pentafluoro-trifluoroethyl)idiphenyl-4-carboxylic acid; 1-(-("methylthio)-1,1-diphenyl-4-yl|Ipropyl--M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-leucinamide); pyrimidine-2-ylphenyl)ethyl-leucinamide;

M1-(cyanomethyl)-1-M2-(15)-2,2,3,3,3-pentafluoro- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- 114-(3-1-(2-(methylsulfonyl)-1,1-diphenyl-4-yl)-propyl-methylpyridin-2-yl)uphenyl|ethyl)-leucinamide; leucinamide; M'1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(1-furyl)phenyl|ethyl)! -leucinamide; oxypyridin-3-yl)uphenyl|ethyl)-leucinamide; M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(3-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(trifluoromethyl)pyridin-2-ylIfenyl)ethyl)| - (morpholin-4-ylcarbonyl)phenyl|ethyl)! -leucinamide; leucinamide;

M!-(cyanomethyl)-M2-(1 5)-2,2,2-trifluoro-1-(4- M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1 -(4-I4-

Cmethoxy(methyl)amino|carbonylphenyl)ethyl/-- (trifluoromethyl)pyridin-2-ylIfenyl)ethyl)| - leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-M'1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro- 1-14-I(5-

771168 56 (trifluoromethyl)pyridin-2-yl|phenyl)ethyl)| - leucinamide; leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-K15)-2,2,2-trifluoro-1-(3'-(methylthio)-1,1-diphenyl-4-ylethyl)-leucinamide; methoxy-1,1"-diphenyl-4-yl)ethyl|I-leucinamide; Me-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(3-M1-(cyanomethyl)1-leucinamide; methoxy-1,1-diphenyl-4-yl)ethyl and -leucinamide; M1-(cyanomethyl)-M2-(18)-2,2,2-trifluoro-1-(I-

Mm2-((15)-1-I4-(acetylamino)-3'-fluoro-1,1"-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl. - diphenyl-4-yl|- 2,2,2-trifluoroethyl)-M!-leucinamide; (cyanomethyl)! -leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(3-(morpholin-4-ylsulfonyl)-1,1-diphenyl-4-yl|ethyl) - methylthiene -2-yl)uphenyl|ethyl)-leucinamide; leucinamide;

M1-(cyanomethyl)-M2-K15)-2,2,2-trifluoro-1-(3'- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1- |4-fluoro-1,1-diphenyl-4-yl)ethyl| -leucinamide; (isopropylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - m2-4(15)-1-(4-(5-acetylthien-2-iluphenyl)|-2,2,2- leucinamide; trifluoroethyl) -M!-(cyanomethyl)!-leucinamide; m2-4((15)-1-(-(aminosulfonyl)-1,1"-diphenyl-4-m2-((15)-1-(3'-acetyl -1,1"-diphenyl-4-yl)-2,2,2-yl|-2,2,2-trifluoroethyl)-M!-(cyanomethyl)!-trifluoroethyl(|-M'-(cyanomethyl)! -leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-19'- Me-((15)-1-4-((acetylamino)sulfonyl|-1,1"- ( trifluoromethyl)-1,1"-diphenyl-4-yl|ethyl-diphenyl-4-yl)-2,2,2-trifluoroethyl)-N-leucinamide; (cyanomethyl)! -leucinamide;

M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(5 "- M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1 -|2'- fluoro-2'-methoxy-1,1"-diphenyl-4-yl)ethyl-- methyl-4-(methylsulfonyl)-1,1-diphenyl-4-leucinamide; yl|styl)-leucinamide ;

M1-(cyanomethyl)-M2-((15)-1-(3,5'-difluoro-1,1"- Mm2-(1-(5-bromothien-2-yl)-2,2,2- trifluoroethyl (N-diphenyl-4-yl)-2,2,2-trifluoroethyl-leucinamide (cyanomethyl)-leucinamide;

M1-(cyanomethyl)-M2-K15)-2,2,2-trifluoro-1-M2-(11-(4-bromophenyl)-2,2,2-trifluoroethyl|-M1- (2,3 ,5'-trifluoro-1,1"-diphenyl-4-yl)ethyl--(cyanomethyl)!-leucinamide; leucinamide; Tert-butyl ether 4-(4241-1- 3-(2-11-P-( cyanomethylcarbamoyl)-3-(cyanomethylcarbamoyl)-3-methyl-butylamino)|-2,2,2- methylbutylamino|-2,2,2-trifluoroethyl)diphenyl-3-trifluoroethyl)idiphenyl-4-yl)piperazine-1- carboxylic illuacrylic acid; acids;

Mm2-((15)-1-I4-(9-anthryl)phenyl|-2,2,2-M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(2-trifluoroethyl) -N-(cyanomethyl)!-leucinamide;piperazin-1-yl-1,1-diphenyl-4-yl)ethyl //--

Me-(15)-1-(4-benzothyl-1,1"-diphenyl-4-yl)-2,2,2-leucinamide; trifluoroethyl (|-M'-(cyanomethyl)!-leucinamide; M!- (cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-I4-(2-

Me-(15)-1-(3'-acetyl-4-hydroxy-1,1"-diphenyl-hydroxyethyl)piperazin-1-yl|-1,1-diphenyl-4-4-yl)-2,2 ,2-trifluoroethyl (|-M-(cyanomethyl))!-yl)ethyl)!-leucinamide; leucinamide; M-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-( 4-(2-

M1-(cyanomethyl)-M2-((15)-1-(2-(cyanomethyl)-hydroxy-2-methylpropyl)piperazin-1-yl|-1,1"-1,1"-diphenyl-4- yl|-2,2,2-trifluoroethyl-diphenyl-4-yl)ethyl)! -leucinamide; leucinamide; M!-(cyanomethyl)-M2-(1-(4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-Kdimethylamino)carbonyl|phenyl)-2,2,2-(methylsulfonyl)-1,1"-diphenyl-4-yl |ethyl - trifluoroethyl)!-leucinamide; leucinamide; M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-piperazin-1-yl-1,1-diphenyl-4-yl)ethyl//--(methylsulfinyl)-1, 1"-diphenyl-4-yl|ethyl - leucinamide; leucinamide; M!-(cyanomethyl)-M2-(1-(4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-Ccyclopropylamino)carbonyl|phenyl)-2,2,2-morpholin-4-ylphenyl)ethyl|I -leucinamide; trifluoroethyl)! -leucinamide;

M1-(cyanomethyl)-M2-C18)-2,2,2-trifluoro-1-(4-(6-4-1-11--(cyanomethylcarbamoyl)-3-methylpyridin-3-yl)/phenyl |ethyl)-leucinamide; methylbutylamino!|-2,2,2-trifluoroethyl) benzoin

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(6-acid; methylpyridin-3-yl)/phenyl|ethyl)-leucinamide; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-I4-(2-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(5-fluoroethyl)piperazin-1-yl|-1,1-diphenyl-4-yl)ethyl)| - phenylthien-2-yl)ethyl|I-leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-quinoline-M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(4 - 8-ylphenyl)ethyl|--leucinamide; methylpiperazin-1-yl)carbonyl|Ifenyl)ethyl)| -

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-leucinamide; pyridin-2-ylphenyl)ethyl|-leucinamide; M'1-(cyanomethyl)-M2-I2,2,2-trifluoro-1-(4-C4-(2-

M2-411-142-(aminosulfonyl)-1,1-diphenyl-4-yl|-hydroxy-2-methylpropyl)piperazine-1-2,2,2-trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; yl|carbonylphenyl)ethyl|-leucinamide;

Mm2-((15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-M1-(cyanomethyl)-H2-(15)-2,2,2-trifluoro-1-|4- (2-yl1-2,2,2-trifluoroethyl)-M'-(cyanomethyl)|-methyl-1,3-thiazol-4-yl/phenyl|ethyl)!-leucinamide; leucinamide; Mm2-41-14- (3-tert-butyl-1,2,4-triazine-5-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1- |- iluphenyl-26262-trifluoroethyl)-M'-(cyanomethyl)| - (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - leucinamide;

57 771168 58

M1-(cyanomethyl)-M2-I(2,2,2-trifluoro-1-(4-(2-(3- M'-(cyanomethyl)-3-(1-methylcyclopropyl)|. - (methylsulfonyl) phenyl|-1,3-thiazol-4-alaninamide; isophenyl)ethyl-1-leucinamide; M'-(cyanomethyl)-3-(1-methylcyclopropyl)-Me-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-(2-(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl) -1,1"- (1H-pyrazol-4-yl)-1,3-thiazol-4-yl(phenyl)ethyl)--diphenyl-4-yl|ethyl)!-alaninamide; leucinamide; M'-(cyanomethyl) -3-(1-methylcyclopropyl)-Me-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-|4-(15)-2,2,2-trifluoro-1-(4-(methylthio)-1,1 -diphenyl-4-(methylsulfonyl)piperazin-1-yl|-1,1"-diphenyl-4-yl|ethyl)!-alaninamide; yl)ethyl)!-leucinamide; M!-(cyanomethyl)-M2-( (15)-2,2,2-trifluoro-1-(4-

M2-(1-(3-bromophenyl)-2,2,2-trifluoroethyl|-N-methyl-1,1"-diphenyl-4-yl)ethyl]-leucinamide; (cyanomethyl)-leucinamide; Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2,2-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-trifluoroethyl|-M'-(cyanomethyl)!-leucinamide; (methylthio)-1,1-diphenyl-3-yl| acetyl) leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(3-(hydroxymethyl)-1,1"-diphenyl-4-yl|ethylui.-pyridin-4-ylphenyl)ethyl|I -leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(2- Mm2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M'- piperazine-1- yl-1,1-diphenyl-3-yl)ethyl|-- (cyanomethyl)O-leucinamide; leucinamide; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4--

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(methylsulfonyl)-1,1-diphenyl-4-yl|ethylyl-(methylsulfonyl)-1,1"-diphenyl- 3-yl|ethyl.-leucinamide; leucinamide; M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-

M-(cyanomethyl)-1-(2,2,2-trifluoro-1-(morpholin-4-ylsulfonyl)-1,1-diphenyl-4-phenylethyl)amino|cyclohexanecarboxamide; ilph|stylU-leucinamide; 1-41-(4-bromophenyl)-2,2,2-trifluoroethylamino)-M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-

M-(cyanomethyl)cyclohexanecarboxamide; Cmethylamino)sulfonyl|-1,1"-diphenyl-4-yl)ethyl)O-

M-(cyanomethyl)-1-(2,2,2-trifluoro-1-(4-leucinamide; piperazin-1-yl-1,1"-diphenyl-4-M'!-(cyanomethyl)-M2-( C18)-2,2,2-trifluoro-1-N4-(1-yl)ethylamino)cyclohexanecarboxamide; oxypyridin-4-yl)phenyl(ethyl)!-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4- M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(1-piperidine) -4-ylphenyl)ethyl|1-leucinamide; oxypyridin-4-yl)phenyl|ethyl)!-leucinamide;

M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(4- M!-(cyanomethyl)-M-(2,2,2-trifluoro-1-4-(6 -(1-pyridin-2-ylpiperazin-1-yl)phenyl|ethyl)y - hydroxy-1-methylethyl)-1-oxypyridin-3-leucinamide; yl|phenyl)ethyl)! -leucinamide;

M2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M1- M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-I6- (cyanomethyl )-3-cyclopropylalanine amide; (methylsulfonyl)pyridine-3-yl|phenyl)ethyl)!-

M1-(cyanomethyl)-3-cyclopropyl-Me-(2,2,2-leucinamide; trifluoro-1-(4-pyridin-4-ylphenyl)ethyl|alaninamide; M1-(cyanomethyl)-M2-(2 ,2,2-trifluoro-1-(4-(2-(4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(2-methylpiperazin-1-yl)-1,3-thiazol-4-yl|Ifenyl)ethyl)--pyridin-4- yl-1,1"-diphenyl-4-yl)ethyl-leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(1B)-2,2,2-trifluoro-1-(1,3-M2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-M !-(1-thiazol-2-yl)ethyl|-leucinamide; cyanocyclopropyl)!-leucinamide;

M!-(cyanomethyl)-M2-K1 5)-2,2,2-trifluoro-1-(42- M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4- methoxy) -1,1-diphenyl-4-yl)ethyl-leucinamide, piperazin-1-ylphenyl)ethyl-leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-M2-(1-13'acetylamino)-1,1-diphenyl-4-yl1-2, 2,2- methoxyphenyl)ethyl-leucinamide; trifluoroethyl)-M!-(cyanomethyl)! -leucinamide;

M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4- (4-pyridin-4-yl-1,1"-diphenyl-4-yl)ethyl-leucinamide; propylpiperazin-1-yl/uphenyl|ethyl)!-leucinamide;

M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4- phenoxyphenyl)ethyl|-leucinamide;(piperazin-1-ylcarbonyl)phenyl|ethyl)!-leucinamide;

Me-(15)-1-(4-bromo-1,1"-diphenyl-4-yl)-2,2,2-M'1-(cyanomethyl)-M2-12,2,2-trifluoro-1 -(4-C4-(2-trifluoroethyl(|-M'-(cyanomethyl)!-leucinamide; hydroxyethyl)piperazin-1-ylcarbonylphenyl)ethyl--

M2-4(15)-1-4-(4-chloropyridin-3-yl)uphenyl|-2,2,2-leucinamide; trifluoroethyl)-M!-(cyanomethyl)! -leucinamide; M'!-(cyanomethyl)-M2-|((15)-2,2,2-trifluoro-1-(4-(3-

Mm2-((15)-1-14-(acetylamino)-2'-methylyl|-1,1"-3-trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-diphenyl-4-yl |-2,2,2-trifluoroethyl)-M!-iluphenyl)ethyl|-leucinamide; (cyanomethyl)!-leucinamide; Methyl ether 4-1-11-m2-I(15)-1-(1,1" -diphenyl-4-yl)-2,2,2-(cyanomethylcarbamoyl)-3-methylbutylamino|-2,2,2-trifluoroethyl|-N'-(cyanomethyl)! -leucinamide; trifluoroethyl)benzoic acid;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(6- M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro -1-(4-Methoxypyridin-3-yl)/phenyl|ethyl)!-leucinamide; KE)-2-quinolin-2-ylethenyl|phenyl)ethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(6- M'1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro -1-(4-(3-Methoxypyridin-2-yl)phenyl|ethyl)-leucinamide; methyl-1,2,4-oxadiazol-5-yl)phenyl|ethyl)y. -

M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4"-leucinamide; (methylsulfonyl)-1,17:21"-terphenyl-4-yl|ethyl - Mm2 -((15)-1-(4-I3-(5-bromopyridin-3-yl)-1,2,4-leucinamide; oxadiazol-5-yl|phenyl)-2,2,2-trifluoroethyl)-M '-

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-cyanomethyl)! -leucinamide;

59 771168 60

Me-(15)-1-(4-benzoylphenyl)-2,2,2-trifluoroethyl|-M'-(cyanomethyl)! -leucinamide; trifluoroethyl|-M'-(cyanomethyl)! -leucinamide; M'1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-Cphenylthio)methyl|phenyl)ethyl)! -leucinamide; (thien-2-ylcarbonyl)phenyl|ethyl)! -leucinamide; M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4-Ctrifluoromethyl)sulfonyl|-1,1"-diphenyl-4-(1,3-thiazol-2- ylcarbonyl)phenyl(ethyl)!-leucinamide; yl)ethyl)!-leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1 -(4- (2)-2-I4- (4-fluorobenzoyl)(amino|methyluphenyl)ethyl||/-- (methylsulfonyl)phenyl|ethenylphenyl)ethylI-- leucinamide; leucinamide; M!-(cyanomethyl)-M2 -(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)phenyl|ethyl)-leucinamide;

KE)-2-I4- M'-(1-cyanocyclopropyl)-M2-((15)-2,2,2- (methylsulfonyl)phenyl|ethenylphenyl)ethyl-- trifluoro-1-(-(methylsulfonyl)-1 ,1-diphenyl-4-leucinamide; yl|stil)-leucinamide;

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- M1-(cyanomethyl)-M2-(15)-1-(4-(ethylsulfonyl)- isobutyrylphenyl )ethyl|-leucinamide; 1,1"-diphenyl-4-yl|-2,2,2-trifluoroethyliu -

Mm2-((15)-1-N4-(4-bromo-1,3-thiazol-2-yl)phenyl|-leucinamide; 2,2,2-trifluoroethyl)-N-(cyanomethyl)! -leucinamide; M2-((15)-1-4-((Y3-(2-chloro-6-fluorophenyl)-5-

M1-(cyanomethyl)-M2-K15)-1-(4-cyanophenyl)-methylisoxazol-4-yl|carbonylamino)methyl|phenyl)y-2,2,2-trifluoroethyl! -leucinamide; 2,2,2-trifluoroethyl)-M!-(cyanomethyl)! -leucinamide;

M1-(cyanomethyl)-M2-(15)-1-(4-ethynylphenyl)-m2-((15)-1-4-Y(9-chloro-3-methyl-4-2,2,2 -trifluoroethyl!-leucinamide; oxoisoxazoli4,3-c|quinoline-5(4H)-yl)umethyl|phenyl)-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(2'-2,2,2-trifluoroethyl)-M'-(cyanomethyl)!-leucinamide; fluoro-1 ,1-diphenyl-4-yl)ethyl|-leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-methoxy-3-(methylsulfonyl)-1,1"-diphenyl-4-(1,3-thiazol- 2-yl)phenyl(ethyl)-leucinamide; yl(styl)-leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4- Me-(15)-1-14"-chloro-4-(methylsulfonyl)-(methylthio)-1,1- diphenyl-4-yl|ethyl)1-leucinamide; 1,172,1"-terphenyl-4-yl|-2,2,2-trifluoroethyl)-M!-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4-(2-(cyanomethyl)1-leucinamide; methylquinolin-7-yl)uphenyl|ethyl)-leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|2'-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-I4-(1H-methoxy-4-(methylsulfonyl)-1,1"-diphenyl-4-indol-5-yl)/phenyl |ethyl)!-leucinamide; yl|styl)-leucinamide;

M1-(cyanomethyl)-M2-/1-I4-(dimethylamino)-1,1"-Me-C15)-1-|I2'-chloro-4-(methylsulfonyl)-1,1"-diphenyl-4 -yl|-2,2,2-trifluoroethyl|-leucinamide; diphenyl-4-yl|-2,2,2-trifluoroethyl)-M!-

M!-(cyanomethyl)-M2-K1 5)-1-(4-(cyanomethyl)!-leucinamide; ((cyanomethyl)amino|carbonylphenyl)-2,2,2- M!-(cyanomethyl)-M2-( (15)-2,2,2-trifluoro-1-4-trifluoroethyl!-leucinamide; K-hydroxyethyl)thio|-1,1-diphenyl-4-yl)ethyl)--

M1-(cyanomethyl)-M2-(1 B)-1-(4-leucinamide; (Cyanomethyl)amino|carbonylphenyl)-2,2,2- M1-(cyanomethyl)-M2-(15)-2, 2,2-trifluoro-1-|3'- trifluoroethyl! -leucinamide; fluoro-42-(methylsulfonyl)-1,1-diphenyl-4-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-1|9'-yl|ethyl)1-leucinamide; (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-4-leucinamide; Ke2-hydroxyethyl)sulfonyl |-1,1-diphenyl-4-4-A1-P1-(cyanomethylcarbamoyl)-3-yl)ethyl)I-leucinamide; methylbutylamino-2,2,2-trifluoroethyl)diphenyl-4-M!-(cyanomethyl) -M2-(15)-2,2,2-trifluoro-1-19'-carboxylic acid; (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

Methoxymethylamide 4-1-11-leucinamide; (cyanomethylcarbamoyl)-3-methylbutylamine|-2,2,2-M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-trifluoroethyldiphenyl-4-carboxylic acid; (2-(methoxy(methyl)amino|-2-oxoethylsulfonyl)-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-1,1"-diphenyl-4-yl|ethyl)1 -leucinamide; (D4-M1-( cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4- (methylsulfonyl)benzylhigioumethyl)phenyl|ethyl) !- Ke2e-hydroxy-2-methylpropyl)sulfonyl|-1,1- leucinamide (diphenyl-4-yl)ethyl)-leucinamide;

Mm2-4((15)-1-I4-(5-chloropyridin-2-yl)phenyl|-2,2,2- m2-((15)-1-(-(amiposulfonyl)-1,1"- diphenyl-4-trifluoroethyl)-N-(cyanomethyl)-leucinamide; yl|-2,2,2-trifluoroethyl)-N-(1-cyanocyclopropyl)|-

Mm2-((15)-1-3-(aminosulfonyl)-4-bromo-1,1"-leucinamide; diphenyl-4-yl|-2,2,2-trifluoroethyl)-Ml- Mm2-(4- bromophenyl)(2,4,6-trifluorophenyl)methyl-(cyanomethyl)!-leucinamide; M'-(cyanomethyl)!-leucinamide;

Me-4(15)-1-14-bromo-3-(methylsulfonyl)-1,1"-M!-(Cyanomethyl)-M2-((4-pyridin-4-diphenyl-4-yl|-2, 2,2-trifluoroethyl)-M'-ylphenyl)(2,4,6-trifluorophenyl)methylI-leucinamide; (cyanomethyl)!-leucinamide; M!-(cyanomethyl)-M2-I(4-(4-

M!-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(4-|5-fluorobenzyl)phenyl|(phenyl)methyl-leucinamide; methyl-6-(methylsulfonyl)pyridine- 3- M1-(cyanomethyl)-M2-phenyl(|4-(pyridin-3-ylphenyl)ethyl)!-leucinamide; ylmethyl)phenyl|methyl)!-leucinamide;

Mm2-((15)-1-(4-(B5-chloro-3-|4- m2-(4-bromophenyl)|4- (methylsulfonyl)phenyl|pyridin-2-iluphenyl)-2,2,2- (methylsulfonyl)phenyl|methyl)-M!-(cyanomethyl)yl!-

leucinamide; yl)ethyl|-leucinamide;

M!-(cyanomethyl)-M2-/|4- M!-(1-cyanocyclopropt)-M2-((1 5)-2,2,2- (methylsuli fonyl)phenyl|(4-(methylthio)-1 ,1"- trifluoro-1-15-14-(1-hydroxy-1-diphenyl-4-yl|methyl)!-leucinamide; methylethyl)phenyl|pyridin-2-yl)ethyl)!-leucinamide;

M1-(cyanomethyl)-M2-C4-(methylsulfonyl)-1,1"-M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-diphenyl-4- yl|(4-(methylsulfonyl)phenyl|methyl) - 1-(4-(1-hydroxy-1-methylethyl)-1,1-diphenyl-4-leucinamide; yl|Ipropyl)i -leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trichloro-1-(4-M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3- glycoloylphenyl)ethyl -leucinamide; pentafluoro-1-(2-methyl-1,1-diphenyl-4-yl)propyl|--

M1-(cyanomethyl)-M2-(2-fluoro-1-(fluoromethyl)-1-leucinamide; phenylethyl-leucinamide; M'-(cyanomethyl)-M2-(15)-2,2,3,3,3 -pentafluoro-

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-I4-1-(4-(b6-methoxypyridin-3-yl)uphenyl|propyl. - (pyrrolidin-1-ylacetyl)phenylethyl) !-leucinamide; leucinamide;

M!-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4- M!-(cyanomethyl)-M2-((15)-2,2,3,3,3-pentafluoro- ( piperazin-1-ylcarbonyl)/phenyl|ethyl)!-leucinamide; 1-(2'-Fluoro-1,1"-diphenyl-4-yl)propyl|--leucinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-(4-(2-(4- M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2- methylpiperazine -1-yl)-1,3-thiazol-4-yl|phenyl)ethyl)-- trifluoro-1-(4-methoxy-3-(methylsulfonyl)-1,1"- leucinamide; diphenyl-4-yl| ethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-3-(1-Me-C15)-1-I3'-aminosulfonyl)-4"-methoxy-1,1"-methylcyclopropyl)-M2-(2,2,2-trifluoro -1-(4-|11-(2-diphenyl-4-yl|-2,2,2-trifluoroethyl)-M!-(1- hydroxyethyl)propylIfenyl)ethyl)! -alanine amide; cyanocyclopropyl)! -leucinamide; m2-((4-(4-tert-butylpiperazine-1-M!-(1-cyanocyclopropyl)-M2-((15)-2,2,2-yl)phenyl|(pentafluorophenyl)methyl|-M!- trifluoro-1-N4-(b-methoxypyridin-3-yl)phenyl|ethyl-(cyanomethyl)!-leucinamide; leucinamide;

M-(cyanomethyl)-1-(11-14-(4-methylpiperazin-1-M'1-(cyanomethyl)-M2(15)-2,2,3,3,3,-pentafluoro-yl)phenyl| ethyl)piperidine-2-carboxamide; 1-4-5-methylpyridin-2-yl)phenyl|propyl. -

Me-((4-(4-tert-butylpiperazine-1-leucinamide; yl)phenyl|(pyridin-2-ylmethyl|-M!-(cyanomethyl)yl! - M!-(1-cyanocyclopropyl)-M2-( (15)-2,2,2-leucinamide; trifluoro-1-4-(5-(methylsulfonyl)pyridin-2-m2-44-(4-tert-butylpiperazin-1-yl)uphenyl-yl|phenyl) ethyl)!-leucinamide; (trifluoromethyl)pyridin-2-yl|methyl)-M!- M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-(cyanomethyl)!--leucinamide; trifluoro -1-I4-(5-methylpyridin-2-iluphenyl|ethyl. - (45)-M-(cyanomethyl)-4-methyl-1-((1 5)-1-(4- leucinamide; piperazine-1- ylphenyl)ethyl|-prolinamide; M1-(cyanomethyl)-4-fluoro-M2-C15)-2,2,2-(45)-M-(cyanomethyl)-4-methyl-1-((1 8) -1-(4-trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-piperazin-1-ylphenyl)ethyl|-prolinamide; yl|styl)-leucinamide;

M-(cyanomethyl)-1-((15)-1-(4-piperazine-1-M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-ylphenyl) ethyl!-prolinamide; trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-

M-(cyanomethyl)-1-(1A)-1-(4-piperazin-1-yl)-leucinamide; ylphenyl)ethyl--prolinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M-(cyanomethyl)-4,4-difluoro-1-((15)-1-(4-trifluoro-1-(2'-methyl-4-(methylsulfonyl)-1,1-piperazin-1-ylphenyl) ethyl|-prolinamide; diphenyl-4-yl|ethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2.2- M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-(4-methylphenyl)ethyl |-leucinamide; trifluoro-1-15-(1H-pyrazol-3-yl)pyridin-2-yl|ethyl.-

M1-(1-cyanocyclopropyl)-M2-C15)2,2,2-trifluoroleucinamide; 1-(4-(1H-pyrazol-3-yl/uphenyl|ethyl)!-leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-(5-quinolin-5-ylpyridin-2-yl)ethyl-- trifluoro-1-(4-(2- methyl-1,3-oxazol-4-leucinamide; isophenyl|ethyl)-leucinamide; M1-(1-cyanocyclopropyl)-M2-K15)-2,2,2-

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-trifluoro-1-(5-quinolin-6-ylpyridin-2-yl)ethyl|-- pyrazin- 2-ylphenyl)ethyl|I -leucinamide; leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(2-M1-(1-cyanocyclopropyl)-M2-C15)-2,2-difluoro-1 - methylpyridin-4-chlorophenylethyl)-leucinamide; (2-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl. -

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4-(4-leucinamide; methylpyridin-3-yl)/phenyl|ethyl)-leucinamide; Mm2-(15)-1-(2-acetyl-1,1"-diphenyl-4-yl)-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-2,2,3,3,3-pentafluoropropyl|-M'-(1-trifluoro-1-I4-(1H-pyrazole- 4-yl)uphenyl|ethyl.-cyanocyclopropyl)! -leucinamide; leucinamide; Me-((15)-1-(1,1"-diphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-trifluoroethyl/|-M1-(1-cyanocyclopropyl)!-trifluoro-1-(4-pyridin-4-ylphenyl) ethyl-- leucinamide; leucinamide; M2-C15)-1-(I4-(aminosulfonyl)-1,1"-diphenyl-4-m2-((15)-1-(3'-acetyl-1,1"- diphenyl-4-yl)-2,2,2-yl|-2,2,3,3,3-pentafluoropropyl)-M!-(1-trifluoroethyl|-M!-(1-cyanocyclopropyl))!-cyanocyclopropyl )! -leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-1-I4-(1-

M1-(1-cyanocyclopropyl)-M2-K(15)-2,2,2-ethoxyvinyl)uphenyl|-2,2,2-trifluoroethyl)-trifluoro-1-(3'-fluoro-4-methyl-1 ,1-diphenyl-4-leucinamide;

63 777168 64

Me-(15)-1-(4-acetylphenyl)-2,2,2-trifluoroethyl|-trifluoro-1-I4-(1H-pyrazol-3-yl)phenyl|ethyl -

M!-(1-cyanocyclopropyl)! -leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2.2-Mm!-(15)-1-cyanoethyl|-M2-((15)-2,2,2-trifluoro-1-trifluoro -1-(4-isopropylphenyl)ethyl|I--leucinamide; (2-(methylsulfonyl)-1,1-diphenyl-4-yl|Iethyl. -

M1-(1-cyanocyclopropyl)-M2-K(15)-2,2,2-leucinamide; trifluoro-1-phenylethyl|-leucinamide; M'-(15)-1-cyano-3-(methylthio)propyl/|-Me-(15)-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-trifluoro-1-I4-(1- hydroxy-1-4-yl|ethyl)l -leucinamide; methylethyl)phenyl|ethyl)! -leucinamide; M!-(15)-1-cyano-3-(methylsulfonyl)propyl|-Me-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"- trifluoro-1 -(4-(1-methylcyclopropyl)phenyl|ethyliu.-diphenyl-4-yl|ethyl)!-leucinamide; leucinamide; Me-((15)-1-(4-bromophenyl)-2.,2,3, 3,3-

M1-(1-cyanocyclopropyl)-M2-K(15)-2,2,2-pentafluoropropyl|-M'-(1-cyanocyclopropyl)! - trifluoro-1-(2'4,6'-trimethyl-1,1"-diphenyl-4-leucinamide; yl)ethyl|1-leucinamide; M1-(cyanomethyl)-M2-((15)-2 ,2,3,3,3-pentafluoro-m2-((15)-1-(b-chloropyridin-3-yl)-2,2,2- 1-(4-(6-methoxypyridin-2-yl) uphenyl|propyl.-trifluoroethyl/|-M!-(1-cyanocyclopropyl))!-leucinamide; leucinamide; Me-((15)-1-(B-bromopyridin-2-yl)-2,2,2-

M2-4(15)-1-N5-(4-acetylphenyl)pyridin-2-yl|-trifluoroethyl|-M'-(cyanomethyl)! -leucinamide; 2,2,2-trifluoroethyl)-N-(1-cyanocyclopropyl)|. - M'1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-(5-|4-leucinamide; (methylsulfonyl)phenyl|pyridin-2-yl)ethyl) -

Mm2-((15)-1-I6-(4-acetylphenyl)pyridin-3Z-yl|-leucinamide; 2,2.2-trifluoroethyl)-M1-(1-cyanocyclopropyl)|!- - M1-(-cyanocyclopropyl) -M2-(15)-2,2,2-trifluoro-leucinamide; 1-(4-(1-hydroxy-1-methylethyl)-1,1-diphenyl-4-

M2-4(15)-1-I5-(3-acetylphenyl)pyridin-2-yl|-yl|styl)-leucinamide; 2,2,2-trifluoroethyl)-N-(1-cyanocyclopropyl)|. - M1-(cyanomethyl)-B2-((15)-2,2,2-trifluoro-1-(6-leucinamide; methyl-3,3'-dipyridin-b-yl)ethyl|1-leucinamide;

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2- trifluoro-1-15-4-( 1-hydroxyethyl)phenyl|pyridin-2-trifluoro-1-4-(b-methoxypyridin-2-yl)phenyl|ethyliu.-yl)ethyl)! -leucinamide; leucinamide; m2-I(15)-1-(1,1"-diphenyl-4-yl)-2,2,3,3,3-M1-(cyanomethyl)-M2-(15)-2,2,2 -trifluoro-1-14-(6-pentafluoropropyl|-N'!-(cyanomethyl)!-leucinamide; oxo-1,6-dihydrotridin-2-yl)uphenyl|ethyliu. -

Me-(15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-leucinamide; 2,2,3,3,3-pentafluoropropyl|-M'-(cyanomethyl)) - (45 )-M1-(cyanomethyl)-5,5,5-trifluoro-M2-(15)-leucinamide; 2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-

Me-(15)-1-(1,1"-diphenyl-4-yl)-2,2,3,3,3-4-yl|ethyl)-leucinamide; pentafluoropropyl|-M!-(1- cyanocyclopropyl) I - (45)-M!-(1-cyanocyclopropyl)-5,5,5-trifluoro-Meleucinamide; (15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)- 1.1"-

M2-(1-benzyl-2,2,2-trifluoroethyl)-M1-(1-diphenyl-4-yl|ethyl)i-leucinamide; cyanocyclopropyl)! -leucinamide; (45)-M'-(cyanomethyl)-5,5,5-trifluoro-M2-(15)-m2-((15)-1-(4-tert-butylphenyl)-2,2,2-2, 2.2-trifluoro-1-(4-(methylthio)-1,1"-diphenyl-4-trifluoroethyl/|-M!-(1-cyanocyclopropyl))!-yl|styl)-leucinamide; leucinamide; (45)- M!-(1-cyanocyclopropyl)-5,5,5-trifluoro-Me-

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl- (15)-2,2,2-trifluoro-1-(4-(methylthio)-1,1-diphenyl-4 -

M'-(cyanomethyl)-4-methyl-leucinamide; il|styl) -leucinamide;

Mm2-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl- (45)-M2-((15)-1-(4-bromophenyl)-2,2,2-

M1-(1-cyanocyclopropyl)-4-methyl-1-leucinamide; trifluoroethyl|-M'-(cyanomethyl)-5,5,5-trifluoro-i -

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-leucinamide; trifluoro-1-4-(2-(1H-pyrazol-4-yl)-1,3-thiazol-4- (45)-M2-((15)-1-(4-bromophenyl)-2,2,2-ylphenyl)ethyl)!-leucinamide; trifluoroethyl|-M!-(1-cyanocyclopropyl)-5,5,5 -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2-trifluoro-I-leucinamide; trifluoro-1-(4-(2-methyl-1,3-thiazol-4-Mm2-4(15)-1-(4-(6-aminopyridin-3-iluphenyl|-2,2,2-yl) uphenyl(ethyl)1-leucinamide, trifluoroethyl)-N-(cyanomethyl)-leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2- M2-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-trifluoro-1-(4-( 2-methylpyridin-4-iluphenyl|ethyl. - M1-(1-cyanocyclopropyl)-4-fluoro-1-leucinamide; leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,3,3, 3-pentafluoro-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-1-(4-(b-methylpyridin-3-yl)uphenyl|propyl. - trifluoro-1-(4-(2-methylpyridine) -3-iluphenyl|ethyl.-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2-pentafluoro-1-(4-(b-methylpyridin-3-trifluoro-1-(4-(b-methylpyridin-2-iluphenyl|ethyl) - yl)phenyl|propyl)i-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-m2-((15)-1-(3'-acetyl-1 ,1"-diphenyl-4-yl)-2,2,2-trifluoro-1-I4-(b-methylpyridin-3-iluphenyl|ethyl. - trifluoroethyl|-M!-(1-cyanocyclopropyl)-4-fluoro - leucinamide; leucinamide; M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-(1-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-hydroxyethyl)-1,1"-diphenyl-4-yl(1-ethyl)-leucinamide;

65 771168 66

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|(4-leucinamide; (2,2,2-trifluoro-1-hydroxyethyl)-1,1-diphenyl-4 - M'-(cyanomethyl)-M2-((15)-2,2,3,3,3-pentafluoro-yl|styl)-leucinamide; 1-4-((2-hydroxy-2-methylpropyl)sulfoyl| -1,1-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3-diphenyl-4-yl)ipropyl)I-leucinamide; pentafluoro-1-(4-(methylthio)-1,1"-diphenyl-4-M!-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-yl|Ipropyl) and -leucinamide; (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,3,3,3- alaninamide; pentafluoro-1-(4-(1-hydroxy-1-methylethyl)-1,1"- M !-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-diphenyl-4-yl|Ipropyl)-leucinamide; 1-4-(isopropylsulfonyl)-1,1"-diphenyl- 4-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,3,3,3-yl|Ipropyl)i-leucinamide; pentafluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-M!-(1-cyano-1-methylethyl)-M2-((15)-2,2,2-yl|Ipropyl)i -leucinamide; trifluoro-1-(-(methylsulfonyl)-1,1-diphenyl-4-

M1-(1-cyanocyclopropyl)-M2-((15)-2,2,3,3,3-yl|styl)1-leucinamide; pentafluoro-1-(4-(b-methoxypyridine-2-M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-yl/uphenyl|propyl)-leucinamide; trifluoro-1-4- ((2-hydroxy-2-(48)-M'-(cyanomethyl)-5,5,5-trifluoro-M2-C15)-methylpropyl)sulfonyl|-1,1-diphenyl-4-yl)ethyl)I -- 2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-leucinamide; 4-yl|styl)! -leucinamide; M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-(48)-M1-(1-cyanocyclopropyl)-5,5,5-trifluoro-Me-trifluoro-1-(2' -methyl-4-(methylsulfonyl)-1,1-(C15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl)-leucinamide; diphenyl-4-yl|ethyl)i -leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-1-I2-

M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-(ethylsulfonyl)-1,1-diphenyl-4-yl|-2,2,2- 1-(4 -methyl-1,1"-diphenyl-4-yl)propyl|I-leucinamide; trifluoroethyl)!-leucinamide;

M1-(cyanomethyl)-M2-(15)-2,2,3,3,3-pentafluoro-Mm2-4((15)-1-(-(aminosulfonyl)-1,1"-diphenyl-4- 1-I4-(1,3-thiazol-2-iluphenyl|propyl)-leucinamide; yl|I-2,2,2-trifluoroethyl)-M!-(1-cyanocyclopropyl)-4-

M1-(1-cyanocyclopropyl)-M2-(15)-1-(4-fluoro-I-leucinamide; ethynylphenyl)-2,2,3,3,3-pentafluoropropyl|-- M1-(cyanomethyl) -M2-(5)-I42-(methylsulfonyl)-leucinamide; 1,1"-diphenyl-4-yl|4-

M1-(cyanomethyl)-M2-((15)-1-(4-(trifluoromethoxy)phenyl|methyl)!-leucinamide; (cyclopropylethynyl)phenyl|-2,2,2-trifluoroethyl)! - M1-(cyanomethyl)-M2-((5)-(42-(methylsulfonyl)-leucinamide; 1,1"-diphenyl-4-yl|thien-2-ylmethylyl-leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-|4- M1-(cyanomethyl)-M2-|((5)-(42-piperazin-4-ium-1-(cyclopropylethynyl) phenyl|-2,2,2-trifluoroethyl)!-yl-1,1"-diphenyl-4-yl) (thien-2-ylmethyl)|I -leucinamide leucinamide; methanesulfonate;

M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-(4-(5- M'-(cyanomethyl)-M2-((5)-(4-fluorophenyl)|4 - methyl-1,3-thiazol-2-iluphenyl|ethyl)!-leucinamide; (methylsulfonyl)-1,1-diphenyl-4-yl|methyl -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2-leucinamide; trifluoro-1-I(4-(1,3-thiazol-2-iluphenyl|ethyliu. - M1-(cyanomethyl)-M2-((5)-I4-(methylsulfonyl)-leucinamide; 1,1"-diphenyl -4-yl--trifluoromethyl)phenyl|methyliu -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-leucinamide; trifluoro-1-(4-(5-methyl-1,3-thiazol-2-Mm2-((5)-(4-chlorophenyl)|4"-(methylsulfonyl)-1,1"-yl/uphenyl|ethyl )1 -leucinamide; diphenyl-4-yl|methyl)-N-(cyanomethyl)!-leucinamide;

M1-(1-cyanocyclopropyl)-M2-15)-1-|4- M1-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-(cyclopropylethynyl)phenyl |-2,2,3,3,3-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl. - pentafluoropropyl)! -leucinamide; norvalinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2- Mm2-((5)-(4-bromophenyl)(thien-2-yl)umethyl|-M!- trifluoro-1-( 4-(4-methyl-1,3-thiazol-2-(cyanomethyl)!-leucinamide; isophenyl|ethyl)!i-leucinamide; M!-(cyanomethyl)-M2-|(5)-I4-(4, 4,5,5-tetramethyl-

M1-(cyanomethyl)-M2-((15)-2,2,2-trifluoro-1-|4-(4-1,3,2-dioxaborolan-2-iluphenyl(thien-2-yl)methyl) -- methyl-1,3-thiazol-2-iluphenyl|ethyl)!-leucinamide; leucinamide;

M1-(cyanomethyl)-M2-((15)-1-(4-(4,5-dimethyl-1,3-m2-(A)-(4-bromophenyl)|4-thiazol-2-yl) )uphenyl|-2,2,2-trifluoroethyl - (trifluoromethoxy)phenyl|methyl)-M!-(cyanomethyl)|!- leucinamide; leucinamide;

M1-(1-cyanocyclopropyl)-M2-(15)-1-|I4- M1-(cyanomethyl)-M2-((5)-I4-(4,4,5,5-tetramethyl-(ethylsulfonyl) -1,1-diphenyl-4-yl|-2,2,2-1,3,2-dioxaborolan-2-yl)phenyl-trifluoroethyl)-4-fluoro-1-leucinamide; (trifluoromethoxysp)phenyl|methyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- Mm2-(5)-(4-bromophenyl)(2-furyl)methyl|-M!- trifluoro-1- (4-pyridin-3-ylphenyl)ethyl--(cyanomethyl)! -leucinamide; leucinamide; M'1-(cyanomethyl)-M2-(5)-2-furyl(g-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-(methylsulfonyl)-1,1-diphenyl-4-yl|methyl. - trifluoro-1-(4-methoxy-3-(methylsulfonyl)-1,1-leucinamide; diphenyl-4-yl|ethyl)i-leucinamide; Mm2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-

Mm2-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-(cyanomethyl)!-norvalinamide;

M!-in (cyanomethyl)! -alanine amide; m2-(B8)-(4-bromophenyl) |4-

Mm2-((15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-(trifluoromethyl)phenyl|methyl)-M!-(cyanomethyl)|-ilI|-2,2,3,3 ,3-pentafluoropropyl)-M!-(cyanomethyl)|.- leucinamide,

67 771168 68

M1-(cyanomethyl)-M2-(1-|4'-(4-trifluoro-1-(4-methoxy-3-(methylsulfonyl)-1,1"- thioiopropylpiperazin-1-yl)-1,1" -diphenyl-4-yl|-2,2,2-diphenyl-4-yl|ethyl)!-norvalinamide; trifluoroethyl)! -norvalinamide; M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-

Me-(A)-(4-bromophenyl)(4-chlorophenyl)methyl|-M!-trifluoro-1-14-(2-methylpyridin-4-iluphenyl|ethyl.-(cyanomethyl)!-leucinamide; norvalinamide;

M1-(cyanomethyl)-M2-(2,2,2-trifluoro-1-|4- M1-(1-cyanocyclopropyl)-5,5,5-trifluoro-Me-(methylsulfonyl)-1,1"- diphenyl-4-yl|ethyl - (15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-norvalinamide; diphenyl-4-yl|ethyl)!-norvalinamide;

Me-(5)-(4-bromophenyl) (3-methylthien-2-yl)methyl|- M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-

M'-(cyanomethyl)! -leucinamide; trifluoro-1-I4-(1H-pyrazol-3-yl)phenyl|ethyl -

Me-(5)-(4-bromophenyl)(thien-3-yl)umethyl|-Norvalinamide; (cyanomethyl)! -leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-

M1-(cyanomethyl)-M2-((5)-(2,4-difluorophenyl)|44-trifluoro-1-12-(1-hydroxy-1-methylethyl)-1,1-(methylsulfonyl)-1, 1"-diphenyl-4-yl|methyl-diphenyl-4-yl|ethyl)!-norvalinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-

M1-(cyanomethyl)-M2-((5)-(4-(methylsulfonyl)-trifluoro-1-14-(5-methylpyridin-2-iluphenyl|ethyl. - 1,1"-diphenyl-4-yl( thien-3-ylmethyl|-leucinamide; norvalinamide;

M1-(cyanomethyl)-M2-((5)-(4-(methylsulfonyl)-2-I(4-bromophenyl)pyridin-4-1,1"-diphenyl-4-yl|(3-methylthien-2 -yl)umethyl//-- ylmethyl|amino)upentanoic acid cyanomethylamide; leucinamide; 2-(M(4-Bromophenyl)thiazol-2-

M1-(cyanomethyl)-M2-((5)-(4"-(4-ylmethylylamino)pentanoic acid cyanomethyl-cyclopropylpiperazin-1-yl)-1,1-diphenyl-4-yl)(3-mid; methylthiene -2-yl)umethylyl-leucinamide; (1-Cyanocyclopropyl)ylMid(25)-2-I(5)-1-(42-

M1-(cyanomethyl)-M2-((5)-(4"-(4-acetyldiphenyl-4-yl)-2,2,2-cyclopropylpiperazin-1-yl)-1,1"-diphenyl-4- yl)|(thien-trifluoroethylamine|peptanoic acid;

3-yl)-methyl-leucinamide; (1-Cyanocyclopropyl)amide (25)-2-|(5)-1-(24-

M2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-difluorodiphenyl-4-yl)-2,2,2-(cyanomethyl)-5,5,5-trifluoro-I - norvalinamide; trifluoroethylamino|pentanoic acid;

M1-(cyanomethyl)-5,5,5-trifluoro-M2-(15)-2,2,2-(1-cyanocyclopropyl)amide (25)-2-I(5)-1-(34- trifluoro -1-(4-(methylsulfonyl)-1,1-diphenyl-4-difluorodiphenyl-4-yl)-2,2,2-yl|styl)-norvalinamide; trifluoroethylamino|pentanoic acid; m2-I((5)-(4-bromophenyl)(3-methylthien-2-yl)methyl- (1-Cyanocyclopropyl)amide (25)-2-I(5)-1-(3-

M!-(1-cyanocyclopropyl)! -leucinamide; chloro-4-fluorodiphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((5)-(4-trifluoroethylamino|pentanoic acid; (methylsulfonyl)-1,1"-diphenyl-4-yl|(3-methylthien-2-(1-Cyanocyclopropyl )amide(25)-2-Y((5)-2,2,2-ylylmethyl-leucinamide; trifluoro-1-(4-methanesulfonylaminodiphenyl-4-

M1-(cyanomethyl)-M2-((5)-3-furyl"-yl)ethylamine|pentanoic acid; (methylsulfonyl)-1,1"-diphenyl-4-yl|methyl - Cyanomethylamide (25)-2- 4(5)-((4-leucinamide; bromophenyl)thiazol-2-ylmethylamino)-4-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-methylpentanoic acid; trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-yl|styl)-norvalinamide; trifluoro-1-(4-chloro-1,1-diphenyl-4-yl|ethyl. -

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethylene-norvalinamide;

M!-(1-cyanocyclopropyl)! -norvalinamide; M1-(1-cyanocyclopropyl)-M2-C15)-2,2,2-

Me-(5)-(4-bromophenyl)(4-bromothien-2-yl)methyl|-trifluoro-1-(4-chloro-3'-methyl-1,1-diphenyl-4-

M'-(cyanomethyl)! -leucinamide; il|estyl)-norvalinamide; m2-I((5)-(4-bromophenyl)u(thien-3-yl)umethyl|-M!-(1- M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2- cyanocyclopropyl)!-leucinamide; trifluoro-1-14-chloro-2'-methyl-1,1"-diphenyl-4-

M1-(cyanomethyl)-M2-((5)-(14-(methylsulfonyl)-yl|ethyl)-norvalinamide; 1,1"-diphenyl-4-yl1(4,-14-(1-cyanocyclopropyl)amide (25)-2-((5)-2,2.2- (methylsulfonyl)phenyl|hyen-2-yl)methyl)|-trifluoro-1-I4-(1H-indole-5-leucinamide; yl)phenyl|ethylamine )pentanoic acid;

M1-(1-Cyanocyclopropyl)-M2-((5)-(4-(1-Cyanocyclopropyl)amide(25)-2-Y((5)-2,2,2-(methylsulfonyl)-1,1 "-diphenyl-4-yl|(thien-3-trifluoro-1-(3'-methanesulfonylaminediphenyl-4-ylylmethyl-leucinamide; yl)ethylamine|ipentanoic acid;

Mm2-((15)-1-I4-(aminosulfonyl)-1,1"-diphenyl-4-M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-ylI-2,2, 2-trifluoroethyl)-N-(1-cyanocyclopropyl)|- trifluoro-1-I(4-fluoro-1,1-diphenyl-4-yl|ethyl. - norvalinamide; norvalinamide;

Me-(5)-(4-bromophenyl)(4-bromothien-2-yl)methyl|- M1-(1-cyanopropyl)-M2-(15)-2,2,2-

M!-(1-cyanocyclopropyl)! -leucinamide; trifluoro-1-I(4-fluoro-3'-methyl-1,1"-diphenyl-4-

Me-(5)-(2-(aminosulfonyl)-1,1"-diphenyl-4-yl|ethyl)-norvalinamide; yl(thien-3-ylylmethyl|-M!-(1-cyanocyclopropyl)!. - M1 -(1-cyanocyclopropyl)-M2-(15)-2,2,2-leucinamide; trifluoro-1-3'-fluoro-4-methyl-1,1"-diphenyl-4-m2-I((5) -(-(aminosulfonyl)-1,1"-diphenyl-4-yl|ethyl)-norvalinamide; yl(thien-3-ylmethyl|-M'-(cyanomethyl)!-leucinamide; M1-(1-cyanocyclopropyl)- M2-(15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2-trifluoro-1-I4-trifluoromethoxy-1,1-diphenyl-4-

69 771168 70 il|styl)-norvalinamide; 2,2.2-trichloro-1-(4-(methylsulfonyl)-1,1-diphenyl-(1-cyanocyclopropyl)amide(25)-2-Y(5)-2,2,2-4-yl|Hyethyl) -norvalinamide; trifluoro-1-(4-methyldiphenyl-4-M1-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2-yl)/ethylamine|Ipentanoic acid; trichloro-1-(-(methylsulfonyl)-1,1-diphenyl-4-(1-Cyanocyclopropyl)amide(25)-2-I(5)-1-(42-yl|ethyl)-norvalinamide; cyanodiphenyl-4 -yl)-2,2,2- (25)-M-(cyanomethyl)-4,4-difluoro-2-((15)-2,2,2-trifluoroethylamine|pentanoic acid; trifluoro-1-(- (methylsulfonyl)-1,1-diphenyl-4-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-yl|ethyl)amino)butanamide; trifluoro-1-(4-methoxy-1,1-diphenyl-4-yl|ethyl. - (25)-M-(1-cyanocyclopropyl)-4,4-difluoro-2-norvalinamide; ((15)-2 ,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2-diphenyl-4-yl|ethyl)amino)butanamide; trifluoro-1-(4-(benzo(1,3|dioxol-5-yl)uphenyl|ethyl) I - (25)-M-(1-cyanocyclopropyl)-4,4-difluoro-2-norvalinamide; (( 15)-2,2,2-trichloro-1-I4-(methylsulfonyl)-1,1'-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-diphenyl-4-yl|ethyl)amino)butanamide; trifluoro-1-(4-(methoxycarbonyl)-1,1"-diphenyl-4-(25)-M-(cyanomethyl)-4,4-difluoro-2-((15)-2,2,2-yl) |styl)-norvalinamide; trichloro-1-(-(methylsulfonyl)-1,1-diphenyl-4-(1-Cyanocyclopropyl)amide (25)-2-((5)-C4-yl|ethyl)amino)butanamide ; bromophenyl)thiazol-2-ylmethyl|amino)-4-(25)-4,4-dichloro-M-(cyanomethyl)-2-((15)-2,2,2- methylpentanoic acid; trifluoro-1- (-(methylsulfonyl)-1,1-diphenyl-4-

Cyanomethylamide (25)-2-(5)-(4-yl|ethyl)amino)butanamide; methanesulfonyldiphenyl-4-yl)thiazol-2-(25)-4,4-dichloro-N-(1-cyanocyclopropyl)-2-ylmethyliamin)-4-methylpentanoic acid; ((15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-(1-cyanocyclopropyl)amide(25)-2-Y(5)-2,2,2- diphenyl-4-yl|styl)amino)butanamide;trifluoro-1-(4-trifluoromethyldiphenyl-4-(25)-4,4-dichloro-N-(1-cyanocyclopropyl)-2-yl)ethylamino|pentanoic acid; ((15)-2,2,2-trichloro-1-I4-(methylsulfonyl)-1,1'-(cyanocyclopropyl)amide(25)-2-((5)-2,2.2-diphenyl-4-yl |styl)amino)butanamide; trifluoro-1-(2-trifluoromethyldiphenyl-4-(25)-4,4-dichloro-M-(cyanomethyl)-2-((15)-2,2,2-yl)/ Ethylamine|Ipentanoic acid, trichloro-1-(-(methylsulfonyl)-1,1-diphenyl-4-(1-Cyanocyclopropyl)amide (25)-2-(5)-(24-yl|ethyl)amino)butanamide; difluorodiphenyl-4-yl)thiazol-2-ylmethylylamino)-4-Mm2-(15)-1-(1,1"-diphenyl-4-yl)-2,2,2-methylpentanoic acid; trifluoroethyl|-M!-(1-cyanocyclopropyl)-4-1 - (1-cyanocyclopropyl)amide(25)-2-(5)-(2-leucinamide; methanesulfonyldiphenyl-4-yl)thiazol-2-M!- (1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-ylmethyliamino)-4-methylpentanoic acid; trifluoro-1-13'-(1-hydroxyethyl)-1,1"-diphenyl-4-

M1-(1-Cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-yl|ethyl)! -leucinamide; trifluoro-1-(4-(1-oxido-2,3-dihydro-1-benzothien-5-M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- yl(uphenyl|ethyl)!-leucinamide; trifluoro-1-(4-methyl-1,1"-diphenyl-4-yl)ethyl|--

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-leucinamide; dioxido-2,3-dihydro-1-benzothien-5-iluphenyl)-2,2,2 - M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-trifluoroethyl),-4-fluoro-I-leucinamide; trifluoro-1-I3'-(1-hydroxy-1-methylethyl)-1,1-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(1,1-diphenyl-4-yl|ethyl)-leucinamide; dioxido-2,3-dihydro-1,2-benzisothiazole -5-yl)uphenyl-Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2,2- 2,2,2-trifluoroethyl)-4- fluoro-II-leucinamide; trifluoroethyl (|-M)-(1-cyanocyclopropyl)-4-fluoro-

M1-(1-Cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-(4-(methylsulfinyl)-1,1"-diphenyl-4-Me-((15)-1-(2'-acetyl-1,1"-diphenyl-4-yl)-2,2 ,2-yl[stil)-leucinamide; trifluoroethyl|-M-(1-cyanocyclopropyl)-4-fluoro-

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-leucinamide; dioxido-3-oxo-2,3-dihydro-1,2-benzisothiazole-5-M1-( 1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-yl)/uphenyl|-2,2,2-trifluoroethyl)-4-fluoro-y-trifluoro-1-12-(1 -hydroxyethyl)-1,1"-diphenyl-4-leucinamide; yl|stil)-leucinamide;

M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- M!-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- trifluoro-1-(2'-(1-hydroxy-1-methylethyl)-1,1"- trifluoro-1-(2'-(1-hydroxyethyl)-1,1"-diphenyl-4-diphenyl-4- yl|ethyl)!-leucinamide; yl|styl)-leucinamide;

M1-(1-Cyanocyclopropyl)-4,4-difluoro-M2-(15)- M1-(1-Cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2- 2,2,2- trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-trifluoro-1-12-(1-hydroxy-1-methylethyl)-1,1-4-yl|ethyl)1-norvalinamide; diphenyl-4-yl|ethyl)-leucinamide;

M1-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-trifluoro -1-(4-(methylsulfonyl)-1,1-diphenyl-4-trifluoro-1-(2'-(1-hydroxy-1-methylethyl)-1,1-yl|styl)-norvalinamide; diphenyl-4 -yl|ethyl)-leucinamide;

M1-(cyanomethyl)-4-fluoro-M2-(15)-2,2,2-trichloro-M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2 - 1-(4-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl. - trifluoro-1-5-(4-(methylsulfonyl)phenyl|pyridin-2-leucinamide; yl)ethyl)!-leucinamide ;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- trichloro-1-(4-(methylsulfonyl)-1,1"-diphenyl-4-trifluoro-1-6-(4-(methylsulfonyl)phenyl|pyridin-3-yl|styl)-leucinamide; yl)ethyl)! -leucinamide;

M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)- M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-

trifluoro-1-(4--6-(methylsulfonyl)amino|pyridine-3-2,2.,2--trifluoroethyl)-4-fluoro-I-leucinamide; isophenyl)ethyl-leucinamide; M1-(1-cyanocyclopropyl)-M2-C15)-1-I4-(2,2-

M1-(cyanomethyl)-4-fluoro-M2-((15)-2,2,2-diethyl-5-oxo-2,5-dihydrofuran-3-iluphenyl|-2,2,2-trifluoro-1 -(4--6-(methylsulfonyl)amino|pyridine-3-trifluoroethyl)-4-fluoro-I-leucinamide; isophenyl)ethylI-leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M1-(1-cyanobutyl)-4-fluoro-Me-(15)-2,2,2-trifluoro-1-I4-(2-oxo-2,5-dihydrofuran-3-trifluoro-1-(4- (methylsulfonyl)-1,1-diphenyl-4-yl)phenyl|ethyl)! -leucinamide; il|styl)i -leucinamide; M1-(1-cyanocyclopropyl)-M2-((1 5)-1-I4-(5,5-

M1-(1-cyano-2-cyclopropylethyl)-4-fluoro-Me2-dimethyl-2-oxo-2,5-dihydrofuran-3-yl)phenyl|-(C15)-2,2,2-trifluoro- 1-(4-(methylsulfonyl)-1,1"-2,2,2-trifluoroethyl)-4-fluoro-1-leucinamide; diphenyl-4-yl|1ethyl)-leucinamide; M1-(1-cyanocyclopropyl) -M2-C1 5)-1-I4-(5,5-

M!-(1-cyano-2-pyridin-3-ylethyl)-4-fluoro-Mediethyl-2-oxo-2,5-dihydrofuran-3-iluphenyl|-2,2,2- (C15)- 2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-trifluoroethyl)-4-fluoro-1 -leucinamide; diphenyl-4-yl|ethyl)1 -leucinamide; M1-(1- cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M1-(1-cyano-3-hydroxy-3-methylbutyl)-4-fluoro-trifluoro-1-I4-(5-oxo-4-oxaspiro|(2.4)hept-6-ene-7-

Mm2-((15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-yl)phenyl|ethyl)!-leucinamide; diphenyl-4-yl|ethyl)!-leucinamide M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M1-(1-cyanocycloprolyl)-4-fluoro-M2-C15)-2,2,2-trifluoro-1-(4-(6b-ocoo-5-oxaspiro|3.Acto-7-ene-5- trifluoro-1-(4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)/phenyl|ethyl)!-leucinamide; yl)/phenyl|ethyl)!III -leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(3,3-trifluoro-1-I4-(5-oxo-4-oxaspiro|(2.4)hept-6-ene- 6- dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)/phenyl|ethyl)!-leucinamide; yl)/uphenyl|-2,2,2-trifluoroethyl)-4-fluoro- i - M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-I4-(6-oxo-5-oxaspiro|3.Oct-7-en-7-

M1-(1-cyanocyclopropyl)-M2-415)-1-14-(3,3-yl)/phenyl|ethyl)! -leucinamide; diethyl-1-oxo-1,3-dihydro-2-benzofuran-5-M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-yl/uphenyl|-2 ,2,2-trifluoroethyl)-4-fluoro-1-trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(115)-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- 2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-trifluoro-1- (4-(3-oxo-1,3-dihydro-2-benzofuran-5-4-yl|ethyl)-leucinamide; yl)/phenyl|ethyl)!-leucinamide; M2-(15)-1-(2 -acetyl-1,1"-diphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-1-I(4-(1,1-trifluoroethyl|-M!-(1-cyanocyclopropyl)!. - dimethyl-3-oxo-1,3 -dihydro-2-benzofuran-5-leucinamide; yl)[uphenyl]-2,2,2-trifluoroethyl)-4-fluoro-yl-M-(1-cyanocyclopropyl)-M2-(15)-2, 2,2-leucinamide; trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide;

M1-(1-cyanocyclopropyl)-M2-415)-1-I4-(1,1-Me-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-diethyl-3- oxo-1,3-dihydro-2-benzofuran-5-N-(1-difluorocyclopropyl)-4,4-difluoro-yl)[uphenyl]-2,2,2-trifluoroethyl)-4-fluoro- i - norvalinamide; leucinamide; M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-2,2.2-trifluoro-1-(4-(methylthio)-1,1"-diphenyl-4-trifluoro -1-(4(3-oxo-1,3-dihydro-2-benzofuran-5-yl|ethyl)-norvalinamide; yl)-1,1"--diphenyl-4-yl|ethyl)!-leucinamide; M1-(1-cyanocycloprophal)-4,4-difluoro-M2-(15)-

M1-(1-cyanocyclopropyl)-M2-(15)-1-I4-(1,1-2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-dimethyl-3-oxo) -1,3-dihydro-2-benzofuran-5-yl)-4-yl(ethyl)-norvalinamide; 1,1"-diphenyl-4-yl|-2,2,2-trifluoroethyl)-4-fluoro-yl-M'-(15)-1-cyano-3-(methylsulfonyl)propyl|-Me-leucinamide; (15)-2,2,2-trifluoro-1-I4-(methylsulfonyl)-1,1"-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(1,1-diphenyl-4-yl|ethyl)-leucinamide; diethyl-3-oxo-1,3-dihydro-2 -benzofuran-5-yl)-1,1"- M1-(1-Cyanocyclopropyl)-4-fluoro-Me-((15)-2,2,2-diphenyl-4-yl|-2,2,2 -trifluoroethyl)-4-fluoro-1 - trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2 ,2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-trifluoro-1-(4-(methylsulfinyl)-1,1-diphenyl-4-trifluoro-1-(4 (1-oxo-1,3-dihydro-2-benzofuran-5-yl|ethyl)-leucinamide; yl)-1,1"--diphenyl-4-yl|ethyl)!-leucinamide; M!-(1 -cyanocyclopropyl)-M2-C15)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(3,3-trifluoro-1-I2-(1-hydroxyethyl)-1,1"-diphenyl-4-dimethyl-1 -oxo-1,3-dihydro-2-benzofuran-5-yl)-yl|ethyl)-leucinamide; 1,1"-diphenyl-4-yl|-2,2,2-trifluoroethyl)-4-fluoro- i - M2-(15)-1-(2-acetyl-1,1"-diphenyl-4-yl)-2,2,2-leucinamide; trifluoroethyl|-M!-(1-cyanocyclopropyl)| -

M1-(1-cyanocyclopropyl)-M2-((15)-I-I4-(3,3-leucinamide; diethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-1, 1"- M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-diphenyl-4-yl|-2,2,2-trifluoroethyl)-4-fluoro-1-trifluoro-1 -(4-quinoline-b6-ylphenyl)ethyl|-leucinamide; leucinamide; Me-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- M1-(1-cyanocyclopropyl)-4,4-difluoro-i - trifluoro-1-(4-(5 -oxo-2,5-dihydrofuran-3-norvalinamide; isophenyl|ethyl)-leucinamide; M1-(1-cyanocyclopropyl)-4,4-difluoro-M2-(15)-

M1-(1-cyanocyclopropyl)-M2-((15)-1-(4-(2,2-2,2.2-trifluoro-1-(4-(methylthio)-1,1"-diphenyl-4- dimethyl-5-oxo-2,5-dihydrofuran-3-iluphenyl|-yl|ethyl)-norvalinamide;

M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-trifluoro-1-(4-tridin-4-ylphenyl)ethyl|-leucinamide; 2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- 4 -yl|ethyl)N-norvalinamide; trifluoro-1-4-(methylsulfonyl)amino|-1,1"-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-diphenyl-4-yl)ethyl)! -leucinamide; trifluoro-1-4-(5-methyl-6-(methylsulfonyl)pyridine-Mm2-(15)-1-(4-bromophenyl)-2,2-difluoroethyl|-M!-

Z-yl|phenyl)ethyl)! -leucinamide; (1-cyanocyclopropyl)!I -leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2- M1-(1-cyanocyclopropyl)-M2-((15)-2,2-difluoro-1-trifluoro-1 -14-(6-(1-hydroxy-1-methylethyl)-5-(2-(methylthio)-1,1"-diphenyl-4-yl|ethyl)-leucinamide; methylpyridin-3-yl|phenyl)ethyl )!-leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- trifluoro-1-(4-pyrimidin-5-ylphenyl)ethyl/-- trifluoro-1-(4- fluoro-1,1-diphenyl-4-yl)ethyl|Y-- leucinamide; leucinamide; Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2 ,2-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-trifluoroethyl|-M1-(1-cyanocyclopropyl)-4-1-trifluoro-1-(3'- methyl-4-(methylsulfonyl)-1,1"-leucinamide; diphenyl-4-yl|ethyl)i -leucinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2 -

M1-(1-cyanocyanopropyl)-4-fluoro-M2-(15)-2,2,2-trifluoro-1-I3'-(1-hydroxyethyl)-1,1"-diphenyl-4-trifluoro-1- (4-(b-methylpyridin-3-iluphenyl|ethyl.-yl|ethyl)-leucinamide; leucinamide; Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)- 2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-difluoroethyl|-M1-(1-cyanocyclopropyl)|-trifluoro-1-(4-(methylthio)- 1,1-diphenyl-4-yl|ethyl.-leucinamide; leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-1-I4-(3,5-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- dimethylisoxazol-4-iluphenyl)|-2,2,2-trifluoroethyl)-trifluoro-1-(4- (1-hydroxy-1-methylethyl)-1,1"-4-fluoro-1-leucinamide; diphenyl-4-yl|1-ethyl)-leucinamide; M'-(15)-1-cyano-3-(methylsulfonyl) propyl|-Me-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2-(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1" - trifluoro-1-(4-(2-methylquinolin-7-yl)phenyl|ethyl. - diphenyl-4-yl|ethyl)-leucinamide; leucinamide; M!-(1-cyanocyclopropyl)-4-fluoro-M2- ((15)-2,2,2-

Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide;

M'-(cyanomethyl)-4,4-difluoro-I-norvalinamide; M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2-trifluoro-1-(4-(methylsulfinyl)-1,1-diphenyl-4-trifluoro-1-4-( (15)-1-hydroxyethyl (1,1-diphenyl-4-yl)-leucinamide; yl)ethyl)-1-leucinamide; M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-trifluoro-1-I2-(1-hydroxyethyl)-1,1"-diphenyl-4-trifluoro-1 -4-((18)-1-hydroxyethyl|-1,1"-diphenyl-4-yl|styl)-leucinamide; yl)ethyl)I-leucinamide; Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2,2-

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2-trifluoroethyl/|-M1-(1-cyanocyclopropyl)! - trifluoro-1-(4-trifluoroacetyl)-1,1"-diphenyl-4-leucinamide; yl|styl)i-leucinamide; M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2 -

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-(4-quinolin-b6-ylphenyl)ethyl|-leucinamide; trifluoro-1-(5-(2-naphthyl)pyridin-2-yl|ethyl.- M2-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-leucinamide; M1-(1- cyanocyclopropyl)-4,4-difluoro-i -

M1-(cyanomethyl)-4,4-difluoro-Me-C15)-2,2,2-norvalinamide; trifluoro-1-(4-(methylthio)-1,1-diphenyl-4-yl|ethyl.-M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-C15)-norvalinamide; 2,2.2-trifluoro-1-(4-(methylthio)-1,1"-diphenyl-4-

M1-(cyanomethyl)-4,4-difluoro-Me-C15)-2,2,2-yl|ethyl)! -norvalinamide; trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-M1-(1-cyanocyclopropyl)-4,4-difluoro-Me-(15)-yl|styl)-norvalinamide; 2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-4-yl|ethyl)! -norvalinamide; trifluoro-1-(4-(5-methyl-1,3-thiazol-2-M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-yl)/phenyl| ethyl)!-leucinamide; trifluoro-1-4-(5-methyl-6-(methylsulfonyl)pyridine-

M1-(1-cyanocyclopropyl)-M2-415)-1-14-(1,1-3-yl|phenyl)ethyl)! -leucinamide; Dioxide-3-oxo-2,3-dihydro-1,2-benzisothiazole-5-M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-yl/uphenyl| -2,2,2-trifluoroethyl)-4-fluoro-i-trifluoro-1-14-I(6-(1-hydroxy-1-methylethyl)-5-leucinamide; methylpyridin-3-ylphenyl)ethyl)!- leucinamide; m2-(4-bromophenyl)(phenyl)methyl|-M-(1- M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- cyanocyclopropyl)!-leucinamide; trifluoro -1-(4-fluoro-1,1"-diphenyl-4-yl)ethyl--

M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-(4-methyl-1,1"-diphenyl-4-yl)ethyl|-- M1-(1-Cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide ; trifluoro-1-133'-methyl-4-(methylsulfonyl)-1,1-

Me-(15)-1-(1,1"-diphenyl-4-yl)-2,2,2-diphenyl-4-yl|ethyl)-leucinamide; trifluoroethyl/|-M!-(1-cyanocyclopropyl) -4-I - M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-I4-(b-methylpyridin-3-iluphenyl|ethyl. -

Mm2-4((15)-1-I4-(5-chloropyridin-2-yl)phenyl|-2,2,2-leucinamide; trifluoroethyl)-M!-(1-cyanocyclopropyl)-4-1 - M1- (1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-leucinamide; trifluoro-1-14-(methylthio)-1,1"-diphenyl-4-yl|ethyl. -

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2- M1-(1-cyanocyclopropyl)-M2-4((1 5)-1-I(4-(3,5 - trifluoro-1-(4-(1-hydroxy-1-methylethyl)-1,1"-dimethylisoxazol-4-yl)phenyl|-2,2,2-trifluoroethyl)- diphenyl-4-yl|Iethyl) - 4-fluoro-I-leucinamide;

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- and their pharmaceutically acceptable salts, stereoisotrifluoro-1-(4-(2-methylquinolin-7-yl)phenyl |ethyl. -mers and M-oxide derivatives. leucinamide; The scope of this invention also includes fa-

Mm2-((15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl- a pharmaceutical composition containing a compound of

M'-(cyanomethyl)-4,4-difluoro-I-norvalinamide; mules And, as described above, and pharmaceutically acceptable

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-tene carrier. This invention also includes trifluoro-1-4-((15)-1-hydroxyethyl|-1 ,1-diphenyl-4- production of a pharmaceutical composition including yl)ethyl)I-leucinamide; contains a pharmaceutically acceptable carrier and

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- any of the compounds specifically described herein trifluoro-1-4-((18)-1-hydroxyethyl |-1,1"-diphenyl-4- invention. These and other aspects of this invention will be yl)ethyl)I -leucinamide; apparent from the information contained herein.

M1-(1-cyanocyclopropyl)-M2-(15)-2,2,2- Compounds according to the present invention are inhibitors of trifluoro-1-(2-(trifluoroacetyl)-1,1-diphenyl-4-ram cathepsins and , therefore, are useful for the treatment of il|stil)-leucinamide; or prevention of cathepsin-dependent diseases

M1-(1-cyanocyclopropyl)-M2-(15)-2,2.2- or states of mammals, mainly humans. In particular, the trifluoro-1-(5-(2-naphthyl)pyridin-2-yl|ethyl.- compounds according to the present invention are inhibitors of leucinamides; Cathepsin K and, therefore, are useful for the treatment or

M!-(cyanomethyl)-4,4-difluoro-M2-(15)-2,2,2- prevention of diseases or conditions dependent on trifluoro-1-(4-(methylthio)-1,1-diphenyl-4- il|Iethyl. - from Cathepsin K, in mammals, mainly in humans. norvalinamide; "Cathepsin-dependent diseases or conditions"

M!-(cyanomethyl)-4,4-difluoro-Me-(15)-2,2,2- refer to pathological conditions that depend on trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4 - from the activity of one or more cathepsins. diseases or conditions dependent on Cathepsin K"

M!-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- refer to pathological conditions that depend on trifluoro-1-(4-(5-methyl-1,3-thiazol- 2- from the activity of Cathepsin K. Diseases associated with the action of Cathepsin K include

M1-(1-cyanocyclopropyl)-M2-((1 5)-1-(4-(1,1- osteoporosis, osteoporosis, induced glucocorti- dioxdo-3-oxo-2,3-dihydro-1,2-benzisothiazole -5- coids, Paget's disease, abnormally elevated yl)/uphenyl|-2,2,2-trifluoroethyl)-4-fluoro-i - bone metabolism, periodontal disease, leucinamide; tooth loss, bone fractures, rheumatoid arthritis

Me-(4-bromophenyl)u(phenyl)methyl/|-M!-(1- arthritis, osteoarthritis, periprosthetic osteolysis, cyanocyclopropyl)! -leucinamide; violation of osteogenesis, metastasizing disease

M!-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2-) bone formation, hypercalcemia of malignant tumors and trifluoro-1-(4-methyl-1,1"-diphenyl-4 -yl)ethyl||-- multiple myeloma. In the treatment of such conditions, with leucinamide; the compounds presented here, a therapeutic

M2-(IV)-1-(1,1"-diphenyl-4-yl)-2,2,2- amount will vary according to the specific trifluoroethyl|-M!-(1-cyanocyclopropyl)-4-I - disease , and it can easily be determined by leucinamide; a specialist in this field. Although both treatment and prophylaxis

M2-4(15)-1-14-(5-chloropyridin-2-yl)phenyl|-2,2,2-ctic are considered within the scope of this invention, trifluoroethyl)-M!-(1-cyanocyclopropyl)-4- And - the predominant application is the treatment of these conditions. leucinamide; A variant of the implementation of this invention is

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2,2- sib inhibition of cathepsin activity in mammals, pot-trifluoro-1-(4-pyridin-4-ylphenyl)ethyl- - taking this, which includes the introduction of the specified leucinamide; to a mammal a therapeutically effective amount of any

M1-(1-cyanocyclopropyl)-4-fluoro-M2-((15)-2,2.2- any of the compounds or any of the pharmaceutical trifluoro-1-4-MKmethylsulfonyl)amino|-1,1- compositions described above. diphenyl-4-yl)ethyl)! -leucinamide; One group of implementations is the way in which ac-

Me-(15)-1-(4-bromophenyl)-2,2-difluoroethyl|-M!- activity of cathepsin is the activity of cathep- (1-cyanocyclopropyl)! -leucinamide; son K.

M1-(1-cyanocyclopropyl)-M2-(15)-2,2-difluoro-1- Another embodiment of this invention is -(methylthio)-1,1"-diphenyl-4-yl|Hyethyl)-leucinamide; method of treatment or prevention of cathepsin-

M1-(1-cyanocyclopropyl)-4-fluoro-M2-(15)-2,2,2-dependent states in a mammal in need of this, which trifluoro-1-(4-pyrimidin-5-ylphenyl)ethyl|-- includes administering to said mammal therapeutically leucinamide; an effective amount of any of the compounds, or

Me-((15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2.,2- any of the pharmaceutical compositions described trifluoroethyl/|-M!-(1 -cyanocyclopropyl)-4-- above. leucinamide; The group of this implementation is the method in which ac-

M1-(1-cyanocyclopropyl)-4-fluoro-Me-(15)-2,2,2- activity of cathepsin is Cathep-trifluoro-1-I3-(1-hydroxyethyl)-1,1"-diphenyl -4- synu K. yl|stil)-leucinamide; Another variant of implementation of this invention is m2-I(15)-1-(4-acetyl-1,1"-diphenyl-4-yl)-2,2- method inhibition of bone destruction in a mammal, pot-difluoroethyl|-M!-(1-cyanocyclopropyl)| - taking this, which includes the introduction of the indicated leucinamide; a mammalian therapeutically effective amount of any

which of the compounds, or any of the pharmaceutical 9|. Usefulness of Cathepsin K inhibitors in the treatment of the compositions described above. Another option for the effect or prevention of resorption in subarticular ossification of this invention is a method of reducing the destruction and generalized destruction of the bone. rheumatoid arthritis. an effective amount of any of the compounds, or Another variant of the implementation of this invention is any of the pharmaceutical compositions described above. The usefulness of Cathepsin K inhibitors in oarthritis in a mammal in need of it, including suppression of bone resorption, is known from the literature, and therapeutically administered to the indicated mammal see (Zigoyr, .V., Iagk, M.M/, Mebreg, OB., an effective amount of any of the compounds or any

Vpatsasnaggtua, A., Viake, 5., Oage, G.S., Egpaga, K-E., which of the pharmaceutical compositions described by

Noytap, 5.9U., Datev, I.E., Magdyi5, A.M/., You, U., etc. It is known from the literature that osteoarthritis (OA) is

MazKko-Mozeg, 9.A., Tiy, V.A., Tota57eK, T. | is carried out by quite certain changes in the synglobomep, M. Strong and selective inhibition of Katebakh, including erosion of the surface of the human articular synovium leads to the suppression of bone cartilage resorption by periaticular intracartilaginous ki ip mimo in non-human primates. (U. Vope with ossification/osteophytosis and subchondral cyst

Mipeg. Res., 16:1739-1746; 2001; and Mona, V.9., And emu, tissue sclerosis and cyst formation, (see

M.A., Waiddeg, A. Oodaz, K.A., date5, I.E., Oeeiteieg E, Arepagoii, K, "O5ieoatypgiyi5 apa rope:

Tpotrzop, 5., Vozzaga, M.9., Sait, T., Soppog, 9.K., ozieoodis iure5 oi o5ieoatppgyi5 oi Pe Pir". ZKkeieiai

Totav2gek, T.A., 52emusgyk, I., Ogake, E.N., Mereg, Vadioi. 1989; 18: 165-74. Recently, the expression

O., and Somzhep, M.I). Peptide-aldehyde inhibitors are speculated about the possible contribution of subchondriasin K suppressing bone resorption and ip mimo and ip lny sclerosis of bone in the occurrence and development of OA. miigo U. Vope Mipeg. Nev. 12:1396-1406; 1997). Hardened subchondral bone, as a reaction to sug-

Another variant of this invention is a method of lilob for impulse repetitive loading, forging or prevention of osteoporosis in a mammal, which is less capable of softening and distributing the effort of the person in need of it, which includes the introduction of the joint, subjecting it to a more significant mechanical mammalian therapeutically effective the amount of pressure on the surface of the articular cartilage. This, in any of the compounds, or any of the aforementioned in turn, accelerates the wear of the cartilage and fiber- pharmaceutical compositions described above. Collation, see Kaidipy, EI and Kobze KM, "What is the effect of cathepsin K inhibitors in the treatment of zirspopag! rope ip (Pe ipiyayop apa rgodgevviop oi prevention of osteoporosis is known from the literature, sapiniade aatade", Siip. Oppor. 1986; 213: 34-40).

Go Zatzid, R., Nyplikeg, E., MMepteuieg, O., Uopev, Suppression of excessive subarticular resorption 5., Woude, A., Kotteg»zkKigsp, MM., Mogiig, 9U.0., Zspy, bones by the action of an antiresorptive agent, such as English

R., and Mopiidioga, K.. Weakened bone resorption bitor Cathepsin K, will lead to suppression by subcho- osteoclasts leads to osteoporosis in mice, dendritic bone metabolism, therefore, may be phytic for cathepsin K. (Rgos. May). aside 5 BOTH have a beneficial effect on the progression of OA. In 95:13453-13458; 1998I. addition to the above hypothesis, expression

Another variant of the implementation of this invention is Cathepsin K was recently discovered in synovial fibroblasts, macrophage-like cells and arthritis in a mammal in need of it, which includes chondrocytes of the synovial layer and in ligaments. of frontal cartilage obtained from patients with OA, tive amount of any of the compounds or any of the cf. Noy, MU-5, Ii, MU, Keuzgeg, S, UMereg, E, I emu, pharmaceutical compositions described above. Z A, Kieip, MU, StamaIese, EM, Soiagipd, ZA, Vgotte, the literature knows that the progressive destruction of O, "Sotragizop oi SaShervzip K apa 5 ehrzhezviop of a separate bone is the main cause of dysfunction of the m/ypip te Kpeshtayoiid apa O5ieoagpygjys Zupomiyt", joint and disability of patients with rheumatoid - Ap Apeytaiyivt 2002; 46: 663-74; and kindred, KA, by him arthritis (RA), Yediv. Soiigipd ZK, Soppog, UK, Ogake, EN, bSoulep, M, "Ehrgezziop oi "Raipodepeziz oi bBope egosiop5 ip peshitaiioia Sasherzip K tezzepdeg EMA ip diapi seiii5 apa Ipeig app". Sig. Orip. Kpeshtaiyo!. 2002; 14: 406-10). rgesygzog5 ip pitap o5ieoagpygyis zupomia! iiz5tsev".

Analysis of joint tissues from patients with RA provided evidence, Ap Apeytaiyyvet 1999; 42: 1588-93; and Kopcypep, that cathepsin K positive osteoclasts represent so- HT, Mapaveiip, U, PI, T-E, baiya, y, Gavziv, etc., cell types that mediate focal "Acidis suzyvipe epdorgoivipase cypervzip K ip te bone resorption , associated with rheumatoid side- depegayop oi She zirepisiai apisshiag Puaiiipe novial damage, see Noah, MU-5, GII, M, sapiade ip o5ieoatigyiz", Appgy5 KPpeitaii5t

Keuzgeg, A, UUereg, E, I emu, V, Kivip, MU, szgamaiPese, 2002; 46: 953-60). These recent studies, such

EM, Soidgipu, ZK, Vgotte, O.

Satsherzip K apa 5 ehrgezviop m/ypip (te KPPeshtaioiy of type II collagen in articular cartilage, associyo- apa O5ieoapiijyis Zupomisht", Appgyi5 EPpestaiivt with the development of osteoarthritis. Usefulness of engineering 2002; 46: 663-74|. In addition, generalized destruction - Cathepsin K inhibitors in the treatment or prevention of bone resorption is the main cause of osteoarthritis as described herein, thus those associated with severe RA. patient-self inhibition of osteoclast-driven tives with chronic RA, see Socid A, zatyugook, P, subchondral bone metabolism, and two

Oemias. and others. the implementation of this invention is a method of treating cancer in a mammal requiring sodium thio- or alginate, carboxymethyl cellulose, pogo, which includes the introduction of ethylene glycol, waxes and the like into said mammal. Lubricants in a therapeutically effective amount of any of the used in these dosed onions or any of the pharmaceutical compositions, forms, include sodium oleate, stearate described above. It is known from the literature that sodium cathepsin, magnesium stearate, sodium benzoate, acetate

K is expressed in carcinoma of the mammary gland lu- sodium, sodium chloride and the like. Dina disintegrators (see GiShemzhmooi-Emap5e Au, Viire sa, Vomeg include, without limitation, starch, me-

M/V, Rapeu 0, UModageki V, Kokiro T, Ipaoka T, cellulose, agar, bentonite, xanthan gum and

Zioape U, Emap5 OV, SaPadneg UA, "Te o5ieosiavi- similar. In those cases when aqueous suspensions are required for oral azosiatei rgoiease saShervip K i5 ehrgezei ip use, active

Ppitap Bgeazi sagsipot." Sapseg Ke5z 1997 Oes component is combined with an emulsifier and suspend- 15:57 (23):5386-90). than agents. They can be added if desired

Confirmation of this invention by way of example certain sweeteners and/or flavoring agents. For the use of any of the compounds described above, intramuscularly, intraperitoneally, in the preparation of a medicinal product for the treatment of skin and intravenous use, or the prevention of osteoporosis in mammals, sterile solutions of the active compound are routinely prepared. Another confirmation of this nent, and the pH of the solutions should be stable invention on the example is the use of any of the established and buffered. For the intravenous compounds described above, in the preparation of medicinal use, it is necessary to control the total amount of means for treatment and/or prevention: destruction- the concentration of dissolved substances to provide bone resorption, bone resorption, bone fractures, isotonicity of the drug. metastasizing bone disease and/or disorders related to Cathepsin functioning. to enter in the form of liposomal delivery systems

The compounds according to the present invention can be administered in the eyes, such as small unilamellar vesicles, large ones to mammals, preferably humans, either individually, or multilamellar vesicles and multilamellar vesicles. preferably, in combination with pharmaceutically acceptable Liposomes can be formed with various phospholytic carriers or diluents, optionally, such as cholesterol, stearylamine or phos- with known adjuvants, for example, aluminum, phatidylcholine. in a pharmaceutical composition, according to standard pharmaceutical practice. These compounds can be delivered using monoclonal orally or parenterally, including antibodies as individual carriers, with which the molecules of the compound bind, including intravenously, intramuscularly. Compounds according to this intraperitoneal, subcutaneous, rectal and invention can also be associated with solution - local routes of administration. by them polymers as carriers of medicines that

In the case of oral tablets, they are prescribed. Such polymers can include slips, commonly used carriers, polyvinylpyrrolidone, pyran copolymer, polyhydroxy- include lactose and corn cro- cypropylmethacrylamidephenol, polyhydroxyethyl-mal, and usually added lubricating agents, spartamidephenol or polyethylene oxide polylysine, such as magnesium stearate. For oral use, it is substituted with palmitoyl residues. In addition, in the form of a capsule, the diluents that the applications according to the present invention can be combined include lactose and dried corn starch with a class of biodegradable polymers. For oral- are used to achieve a controlled state, the therapeutic compound, according to the release of the drug, for example, poly- nad, the selected compound can be administered, lactic acid, polyglycolic acid, for example, in the form of tablets or capsules, or in polyacrylic and polyglycol oxide copolymers in the form of an aqueous solution or suspension. For perlota, polyepsilon with caprolactone, polyhydroxymaral administration in the form of a tablet or capsule, hydrochloric acid, polyorthoesters, polyacetal - the active medicinal component can be combined with oral, non-toxic, cross-linked pharmaceuticals or an amphipathically blocking acceptable, inert carrier, such as lacto-copolymers of hydrogels. for, starch, sucrose, glucose, methylcellulose, These compounds are also applicable in combination with magnesium stearate, calcium diphosphate, cal- sulfate known agents used for tion, mannitol, sorbitol and the like; for the oral treatment or prevention of osteoporosis, osteopo- application in liquid form, oral medicinal rose, induced by glucocorticoids, disease components can be combined with any Paget, abnormal increased metabolism oral, non-toxic, pharma- bone, periodontal disease, loss distinct inert carrier, such as ethanol, glyce- teeth, bone fractures, rheumatoid arthritis, rin, water and the like. Moreover, in the case of osteoarthritis, near-prosthetic osteolysis, defec- when it is desirable or necessary, in the mixture also the mother of osteogenesis, metastasizing disease, appropriate binders, bone lubricants, hyperkalemia of a malignant tumor and multiple, should be included in the mixture. disintegrating agents and coloring agents. multiple myeloma. Combinations of compounds disclosed herein

Suitable binders include starch, gelatin, natural sugars, such as in the treatment or prevention of osteoporosis, or glucose or beta-lactose, corn starch, and other bone disorders are present in chewing gum, natural and synthetic adhesives of this invention. One of ordinary skill in the art can understand what combinations of agents would be

81 777168 82 useful, based on the specific characteristics of the drug - lithium, magnesium and ammonium. Salt remedies and the caused disease are more preferable. Such sodium. Non-limiting examples of derivatives include agents include the following: an organic derivative selected from the group consisting of bisphosphonates; estrogen receptor modulator; ester, hydrates and amides. androgen receptor modulator; inhibitor of proton- It should be noted that the term "bisphosphonate" ATPfase of osteoclasts; inhibitor of HMO-CoA reductase and "birosphonate" used here, odnoctase; integrin receptor antagonist; anabolic therapeutic agents of this invention, also a personal agent of osteoblasts, such as PTH (PTH); and they are intended to cover diphosphonates, biphos- pharmaceutically acceptable salts and mixtures. Predominance of phonic acids and diphosphonic acids, as well as the combination is a compound according to the given salts and derivatives of these substances. The use of spe- the invention and an organic bisphosphonate. Another over-specific nomenclature in relation to the bisphosphonate combination is a compound according to da- or bisphosphonates is not intended to be limited by the invention and an estrogen receptor modulator. the scope of this invention, unless specifically indicated

Another preferred combination is a compound of As a result of the use at this time of conventional according to this invention and receptor modulator specialists in this field of mixed nomenclature, androgen. Another preferred combination is the ratio of the specific gravity or percentage composition of the compound according to the present invention and the anabolic phosphonate compound of the present invention to the primary osteoblast agent. new masses of active acid, if not stipulated here - "Organic bisphosphonate" includes, but it is especially. For example, the phrase "about 5 mg not only, compounds of the chemical formula bisphosphonate, which inhibits bone resorption, selected from the group consisting of alendronate, its

RON, a pharmaceutically acceptable salt, based on the mass of active alendronic acid" means that several

A-CH) CH value of the selected birosphonate compound is calculated on the basis of 5 mg of alendronic acid.

Non-limiting examples of bisphosphonates used herein include the following:

Alendronic acid, 4-amino-1- where n is equal to the whole number of vido to 7, goes A Its hydroxybutylidene-1,1-bisphosphonic acid.

X are independently selected from the group consisting of H, Alendronate (also known as alendronate na-

OH, halogen, MNeg, ZN, phenyl, C-Czo alkyl, C3- sodium or alendronate monosodium trihydrate), 4-

Czo branched or cyclic alkyl, bicyclic-amino-1-hydroxybutylidene-1,1-bisphosphonic/oxygen ring structure containing two or three M, lots of monosodium trihydrate.

C1-Czo substituted alkyl, C1-Cio alkyl, substituted- Alendronic acid and alendronate (described in the MH, C3-C0 branched or cyclic alkyl- US patents 4922007, Kiesgukomuvki et al., publ., substituted MH", C1- Sio dialkyl substituted treated May 1, 1990; 5019651, Kiesgukomu»ki and

MNa, C1-C0 Alkoxy, C1-Sthio Alkyl, Thio Substituted, etc., published May 28, 1991; 5510517, thiophenyl, halophenylthio, C1-Cio alkyl, substituted Oatseg et al., published April 23, 1996; nogo with phenyl, pyridyl, furanyl, pyrrolidin- 5648491, Juaceg et al., published Jul 15 lom, imidazolyl, imidazopyridinyl, and benzyl, 1997, each of which is incorporated herein by reference in such that both A and X are not selected from H or ON, when n to its full extent. is equal to 0; or A and X, taken together with the cycloheptylaminomethylene-1,1-birosphonic carbon atom to which they are attached, formed C3-C10 acid, UM 175, Matapoispi (incadronate, formerly

Ring. Mon | known as cimadronate), (described in US Pat

In the above chemical formula of alkylene 4970335, Izotiga et al., published 13 leaf groups can be straight, branched or pada 1990, incorporated herein by reference in its cyclic, provided that for a given chemical for- full volume. mules choose enough atoms. C1-C2 substituted 1,1-dichloromethylene-1,1-diphosphonic acid alkyl can include a wide range of substituents (clodronic acid), disodium salt (clodronate, kiv, non-limiting examples of which include Rgosieg apa Satrbije), (described in Belgian Patent No. 672205 (1966) and 9. Oga. Spec 32, 4111 (1967), phenyl, pyridyl, furanyl, pyrrolidinyl, imidazo- incorporated herein by reference in their entirety). nil, MH", C1-C1o alkyl or dialkyl substituted 1-hydroxy-3-(1-pyrrolidinyl)propylidene-1, 1-

МН», ОН, ЗН, and С1-С:о Alkoxy. bisphosphonate acid (EB-1053).

The above chemical formula also includes 1-hydroxyethane-1,1-diphosphonic acid (ethylates complex carbocyclic, aromatic, and heterodronic acids). atomic structures for A and/or X substituents, non-limiting 1-hydroxy-3-(M-methyl-M- examples of which include naphthyl, pentylamine)propylidene-1,1-pyrosphonic acid, quinolyl, isoquinolyl, adamantyl and chlorophenylthio. also known as VM-210955, Voepiipdeg-Mapppeit

Pharmaceutically acceptable salts and derivatives of bifo- (ibandronate), (described in US Pat. No. 4,927,814, sphonates are also used herein. Non-limit- published May 22, 1990, included herein as general examples of salts include salts, references in their entirety selected from the group. , containing alkali metal, ammonium and 1-hydroxy-2-imidazo-(1,2-a)pyridine-3-mono-, di-, tri-or tetra-C1-C2-alkyl-substituted yl(?)ethylidene (minodronate).ammonium Preferred salts are salts selected from the β-amino-1-hydroxyhexylidene-1,1-bisphosphonate group consisting of sodium, potassium, potassium salts (neridronate).

83 771168 84

3-(dimethylamino)-1-hydroxypropylidene-1,1- bisphosphonic acid (olpadronate) in alternative dosing regimens. phonate can be administered at intervals other than what-

C-amino-1-hydroxypropylidene-1,1-day, for example dosing once a week, bisphosphonic acid (pamidronate). dosing twice a week, biweekly dosing and (2-(2-pyridinyl)ethylidene|-1,1-birosphonic ky- dosing twice a month. With the slot dosing regimen (pyridronate) (described in US patent once a week alendronate monosodium trihydrate 4761406 , included as a reference in its report, can be administered in a dose of 10 mg/week or 7 mg/week. 1-Hydroxy-2-(3-pyridinyl)ethylidene-1,1- "Selective modulators of the estrogen receptor - bisphosphonic acid (risedronate ). well" refer to compounds that interfere or (4-chlorophenyl)thiomethane-1,1-disphosphinic acid suppress the binding of estrogen to the receptor, lota (tiludronate), (described in US patent regardless of the mechanism. Examples of modulators 4876248 , VgeIPege et al., October 24, 1989, which estrogen receptors include, but are not included in this reference in its entirety, estrogen, progestogen, estradiol, drolox, sifen, raloxifene, lasofoxifene, T5E-424, and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1- moxifene, idoxifene, I 353381, I 117081, torebisphosphonic acid (zoledronate). mifene, fulvestrant, 4-(7-(2,2-dimethyl-1-

Non-limiting examples of oxopropoxy-4-methyl-2-I4-I(2-(1- include aledronate, cimadronate, clo-piperidinyl)ethoxy|phenyl|-2H-1-benzopyran-3-dronate, etidronate, ibandronate, incadronate, minod-yl|phenyl-2,2-dimethylpropanoate, 4-4-dronate, neridronate, olpadronate, pamidronate, pyridihydroxybenzophenone-2,4-dinitrophenyl-hydrazone and dronate, risedronate, tiludronate and zolendronate and their ZHnb4b are pharmaceutically acceptable. salts and esters. "Estrogen receptor beta modulator" is

A particularly preferred bisphosphonate is an alendro compound that selectively acts as an agonist or antagonist, especially sodium, potassium, calcium, magnesium estrogen receptor beta (ERD). Agonizing va or ammonium salt of alendronic acid. Illus- ERPD increases tryptophan gene transcription, a hydrotoxic example of a preferred bisphosphonate is xylase (TRN, a key enzyme in the synthesis of the serosodium salt of alendronic acid, especially hydtonin) through an ERD-mediated event. Priclarate sodium salt of alendronic acid. This estrogen receptor beta agonist can be salt can be hydrated with whole number of moles Found in the publication of the international application PCT UMO of water or with non-whole number of moles of water. In addi- 01/82923, published Nov. 8, 2001, and UMO illustrative example of a preferred biphos- 02/41835, published May 20, 2002, both phonate is the hydrate sodium salt of alendronic acid- are incorporated herein by reference in their entirety). lots, mainly when this hydrate salt "Androgen receptor modulator" belongs to - is alendronate monosodium trihydrate. to compounds that interfere or inhibit

Obviously, a mixture of binding of androgens to the receptor can be used, regardless of the mechanism of two or more bisphosphonate active substances. Examples of wine receptor modulators. | | estrogen include finasteride and other inhibitors

Exact dosage of organic bisphosphonate, 5o-reductase inhibitor, nilutamide, flutamide, bicaluation, specifically selected bisphosphonate, age, "Proton ATPase inhibitor of osteoclasts" size, sex and condition of the mammal or person, nature and is related to the proton ATPase inhibitor, what is the severity of the disease that can be treated, and is carried out on the apical membrane of the osteoclast and other important medical and physical factors. was reported to play an important role in the process

Hence, the exact pharmaceutically effective amount of bone resorption. This proton pump is attrac- can be identified early and may be an easy target for the development of resorption inhibitors when identified by the caregiver or clinician. Corresponding bones that are potentially useful for treatment and quantity can be determined in the usual ex- prevention of osteoporosis and family metabolic experiment in animal models and clinical cause of diseases. (See S. Ragip et al., "BeIesiime studies on humans. In general, the appropriate amount of bi-ippyriug" oi She ovieosiavi masisiag roiop ATRAvse av phosphonate is chosen to obtain inhibitory pome! rope apiigezogryime adepiv", 0OT, 4: 163-172 actions on bone resorption, that is, the amount of bi- (1999), included here as a reference in its total phosphonate inhibiting bone resorption. is approximately to inhibitors of 3-hydroxy-3-methylglutaryl-CoA re- from approximately 1.5 to approximately b0bOmkg/kg of body weight and, reductase. .the NMO-CoA reductase relationship can be easily

For alendronate monosodium trihydrate, generally identified using assays, well-accepted human administered doses are generally known in the art. For example, see assays, but are in the range from about 2mg/day to (described or cited in US patent 4231938 in 40mg/day, preferably from about 5mg/day to column. 6, and UMO 84/02131 on pp. 30-33). Terms 40mg/day. In the USA, the currently tested doses for "NMO-CoA reductase inhibitor" and "NMO-alendronate monosodium trihydrate inhibitor are CoA reductases" when used here have the same mg/day for the prevention of osteoporosis, which is significant.

TOmg/day for the treatment of osteoporosis and 40mg/day Examples of NMO-CoA reductase inhibitors for the treatment of Paget's disease. can be used, include, but are not limited to, lovastatin IMEMASOKF;); see patents citrate, dihydrochloride, edetate, edisilate, estolate,

US 4231938, 4294926 and 4319039), Simvastatin Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, (2OSONF), see US patents 4444784, 4820850 and glycolylarsanilate, hexyl resorcinate, hydrabamine, 4916239|, pravastatin |REVAMASNOI F); see pate- hydrobromide, hydrochloride, hydroxynaphthoate, iodide, nti US 4346227, 4537859, 4410629, 5030447 and isothionate, lactate, lactobionate, laurate, malate, ma- 51805891, fluvastatin (EBSOI F; see patents leate, mandelate, mesylate, methyl sulfate, pain,

US 5354772, 4911165, 4929437, napsylate, nitrate, oleate, oxalate, pamoate, palm!- 5189164, 5118853, 5290946 and 5356896), atorvastatin, pantothenate, phosphate/diphosphate, polygalactutin (SHIRITOVF; see US patents 39527 , ronate, salicylate, stearate, subacetate, succinate, 4681893, 5489691 and 5342952) and cerivastatin (also tannate, tartrate, theoclate, tosylate, triethiodide ! va: known as rivastatin and VAUSNOI F; see patent lerat. c, o, godu

US 5177080). The structural formulas of these and additionally "Ester derivatives of the described compounds of inhibitory inhibitors of NMO-CoA reductase, which can act as inhibitors of NMO-CoA reductase can act as powders used in these methods, (described on the basis of medicinal products, which, when absorbed in the blood stream of a warm-blooded animal, can split

Spetivmu 8. Ipaizig, pp. 85-89 (February 5, 1996) and in pouring in such a way as to release the drug in US patents 4,782,084 and 4,885,314). The concept of "inhibition of NMO-Sod reductase" is used to improve therapeutic efficacy. here, includes all pharmaceutically acceptable As used above, "antagonists of the form of lactones and open acids (that is, where the kiltegrin receptor" refers to compounds that this lactone is open in the form of a free acid), and selectively exert an antagonistic effect , inhibit both the forms of salts and esters of compounds that either counteract the binding of a physiological ligand, have an inhibitory effect on NMO-CoA with surZ integrin, to compounds that provide antagonism to reductases, and, therefore, the use of such salts, contact effect, inhibit or counteract the binding of esters, forms of lactones and open acids of the physiological ligand with our5 integrin, included in the scope of this invention. Images of bows that have an antagonistic effect, inhibit either the lactone part and its corresponding open form, counteract the binding of the physiological ligand and from the acid are given below in the form of structures | and And! ouVZ integrin and with sur5 integrin and to compounds that have an antagonistic effect, inhibit or counteract the activity of a separate integrin(s) that ex-

Fe fr are pressed on the endothelial cells of the capillaries.

This term also refers to antagonists

I ; ob, our8, oari, sari, o5ri, ozri and sera, integrins. y y This term also refers to antagonists lactone Open of any combination of orz, or, ore, osv, sari, 1 acid sari, ovi, ovri and sera integrins. (N.M. Gode and co-authors in RMAB BA 96:1591-1596 (1999) | triggered and triggered synergistic effects between the antagonist to antagonize the form of the open acid, the form of the fields of angiogenic integrin and tumor-specific esters mainly can be formed into young uiinnyh Mstastaya Tx de, open acid, and all such forms are included in the results say that this combination of drawing the term "NMO-CoA reductase inhibitor" acting as potential opportunities for the treatment of soy vd i drugs from Moasiyaniu imya 0C00 1 of metastatic tumor growth. Antoni tatin, and, most preferably, simvastatin. Here, the integrin receptor inhibits the resorption of the term "pharmaceutically acceptable salts" in relation to the NMO-Sod reductase inhibitor. should mean non-toxic salts of the compounds used in the present invention, which are mainly membranous. tors of adhesion, which mediate are obtained by the interaction of free acid with organic SUBOLINES cell-cell! matrix cell. or an inorganic base, in particular those that interact non-covalently in the integrin unit and are formed from cations, for example sodium, potassium, aluzapen from divalent cations. Most. (minium, calcium, lithium, magnesium, zinc) tetramethylammonium, as well as those salts formed from amines, is the most abundant integrin on osteoclasts. An example is ammonia, ethylenediamine, M-methylglucamine, (o/osteoclast ), which probably plays a limiting role in the organization of lysine, arginine, ornithine, choline, M, M'- speed! cytoskeleton, important dibenzylethylenediamine, chlorprocaine, diethanol - for cell migration and polarization. The antagonistic mine, procaine, M-benzylphenethylamine, /1-p- action of surz is selected from inhibition of bone resorption, chlorobenzyl-2-pyrrolidin-1"-ylmethylbenzimidazole, suppression of restenosis, delay of degeneration of pla-diethylamine, piperazine and tris(hydroxymethyl)ami- we, inhibition of arthritis! suppression of the growth of ranomethane. The following examples of salt forms of inky tumor and metastases. NMO-COoA bitors may include, but not "Anabolic agent of osteoblasts" refers only, acetate, benzenesulfonate, benzoate, bicar- to bone-building agents such as PTH.Bonate, bisulfate, bitartrate, borate, bromide, edetate have been shown to spike parathyroid-calcium, camsylate, carbonate, chloride, clavulanate, eating hormone (PTH) or its amino-terminal fra-

gments and analogs prevents, delays, partially components in certain quantities. reverses bone destruction and stimulates the formation of The term "therapeutically effective amount", bone in animals and humans. For discussion, the reference used here means that the amount of (OM. Oetrzegeg et al., "Aparoiis asiopv5oi active compound or pharmaceutical agent, ragamnugoii pPoptope op rope", Epdosg Chem 14: 690- which elicits a biological or medical response at 709 (1993).The study demonstrated a clinical tissue, system, animal, or human to which the benefit of parathyroid hormone in stimulating the researcher, veterinarian, physician, or other cli- bone formation and thus increased bone mass and strength. The results were reported to the EM The terms "treatment" or "therapy" of the disease-

Meeg et al., in Mem Epd U Mea 344 1434-1441, the method used here includes se- (2001)). be: disease prevention, i.e. it is not allowed

In addition, fragments of the protein, familial paraly- to develop clinical symptoms of reoid hormone or analogs such as RTNgR-(1- disease in a mammal that can undergo this- 36) have demonstrated strong anticalciuric go disease or be prone to it, but, effects | see MA. Zuei et al., “Symptom-less or symptom-free asthmatics

Pogtope-geiyaey rgoyeip-(1-36) viytsiagev tgepai of this disease; delay of the disease, bug saisisht geareogriop ip popta! pitap means stopping or reducing the development of the disease or its clinical symptoms; or weaken

Pppytoga! puregsaisetia oi taiidpapsu", USEM 86: disease, i.e. causing regression of the disease- 1525-1531 (2001)) and may also have potential itching or its clinical symptoms. possibility as anabolic agents for the treatment The term "bone resorption" using- osteoporosis. here refers to the process, with the help of which

As part of a fixed dose, such combinations of long osteoclasts destroy bone. kts use compounds according to the present invention. The present invention also covers a pharmaceutical course in the dose range described below and another composition applicable for the treatment of osteoporosis pharmaceutically active agent(s) in its establishment or other bone disorders, which includes the administered dose range . Compounds according to this version of a therapeutically effective amount of compounds of the invention can be used alternatively with according to the present invention, with pharmaceutically acceptable carriers or diluents, or without (agents), in the case when the assembly of combinations . Corresponding compositions according to this invention are inappropriate. dom include aqueous solutions containing

The term "administration" and its variants (e.g. compounds according to the present invention and pharmaceutical- "purpose" of the compound) with respect to the compound according to but acceptable carriers, for example physiological saline solution of the present invention means the introduction of the given compound at a pH level of, for example, 7.4. These solutions can be introduced into the bloodstream of the patient or the precursor of the medicinal product of this compound with the help of the system of the animal in need of treatment. In volume of local bolus injection. in the case when the compound according to the present invention In the case when the compound according to the present invention or its prodrugs are provided in combination with one or bi- the invention is administered to a person, the daily dosage of only other active agents (e.g. cytotoxic- will usually be determined by the order of the therapeutic agent etc.), under the "introduction" and his doctor with changes, mainly, respectively, the riants under each mean parallel and to the age, mass and reaction of a particular patient, and the sequential introduction of a given compound or its prodrugs and the skin and severity of the patient's symptoms. other agents. The present invention includes, in one characteristic application, prodrugs of the compounds of the present invention. well, the amount of the compound is administered to a mammal in which the pro-

Usually, such prodrugs will be functional in the treatment of a cathepsin-dependent condition. The conversion derivatives of the compounds according to the present invention, which are ral dosages according to the present invention, are easily converted into the desired compound. used to obtain the specified effects,

Therefore, in the methods of treatment according to this wine- will be in the range approximately between course, the term "prescription" will cover 0.01 mg per KG of body weight per day for the treatment of the various conditions described with the compound, dis- (mg/kg/day) approximately up to 100mg/kg/day, preferably covered alone or with a compound that may not be from 0.01 to 10mn/kg/day, and most preferably covered alone, but which converts to some 0.1 to 5.O0mg /kg/day. For oral administration, the compound is administered ip immediately after administration to the patient. The usual days of the composition are mainly supplied in the form of the method of selection and preparation of the corresponding pochi-tablets containing 0.01, 0.05, 01, 0.5, 1.0, 2.5, days of prodrugs (described, for example, in "Oevidp 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active

Rgodhyd5", under the editorship. N. Vypadaaga, Eisemieg, 1985, a component for symptomatic correction is incorporated herein by reference in its entirety in the patient receiving treatment. Medicines. Metabolites of these compounds include the agent typically contains from about 0.01 mg of active species produced when the compound is administered to about 500 mg of the active component, converted according to the present invention into the biological environment, from about 1 mg to about 100 mg of ac - higher tive component. Intravenously the most

The term "composition" used, preferred doses will be in the range herein, is intended to cover a product that mis- from about 0.1 to about 10mg/kg/minute tying certain components in certain amounts, as well as at a constant rate of infusion. Preferably, the co- and any resulting product according to the present invention can be administered directly or indirectly, from a combination of certain in a single daily dose or the total daily dose can be administered in divided doses of two, three or In that case, when any variable (for example, four times a day. Moreover, the preferred compounds РК1, К2, Ка, etc.) occurs more than once for this invention, it can be entered intraran- once in any component, its determination in an intranasal form with the help of a local use case is independent in every other occurrence of suitable intranasal carriers, or dku. Also, combinations of substitutes and variables are allowed by transdermal routes, using those only if such combinations result in the form of transdermal skin pieces plastic-stable compounds. Lines drawn inside the kilter, well known to those of ordinary skill in the art of these systems from substitutes, indicate that the branches When administered in the form of a transdermal bond can be attached to any atoms of the delivery system, the dosage administered will be , carbon rings that are replaced. If the ring is certainly continuous, and not a jump-like system is polycyclic, it means that the connection during the dosing regime. attaches to any carbon atoms that

Compounds according to the present invention can be substituted only on the proximal ring. are used in combination with other agents that It is understood that substituents and replacement structures are used to treat cathepsin- in compounds according to the present invention may be mediated conditions. The individual components selected by one of ordinary skill in the art for such combinations can be introduced separately to obtain compounds that are chemically stable and that different times during the course of treatment or parallel can be easily synthesized by means of a separate or single combination of forms. therefore, known in this field, as well as those

It is clear that the present invention, thus, including those set forth below, from readily available all such modes of simultaneous or althetic substances. If the surrogate is itself the surrogate of the rnative treatment and the term "assignment" is interpreted by more than one group, it is clear that these different rprets accordingly. It will be understood that the volume of the group can be located on the same carbon atom of combinations of the compounds of this invention with other agents or on different carbon atoms, as long as the results used for the treatment of cathepty result in a stable structure. The phrase "optionally substituted by one or more substituents" includes in principle any combination with any pharmaceutical should be taken as equivalent to the phrase "optionally substituted by at least one substitute" and treatment of disorders related to the effect of estrogen. in such cases, the preferred implementation option

The scope of the present invention, therefore, includes zero to three substituents. bringing the presently claimed compounds into com- The term "alkyl" as used herein binations with another agent selected from organic includes both branched and straight lan- bisphosphonate; estrogen receptor modulator; yoke saturated aliphatic hydrocarbon groups that modulate the androgen receptor; the inhibitor has from one to ten carbon atoms, if a ton ATPase of osteoclasts; and the NMO-CoA inhibitor is not specifically determined. For example, C1-C0, as in reductase; integrin receptor antagonist; ana- "C 1 -C 10 alkyl" is defined to include groups having 1,2, 3,4, 5, 6, 7, 68, 9 or 10 carbon atoms (PTH); and their pharmaceutically acceptable salts and derivatives in a linear, branched or cyclic mixture. tossing For example, "C1-C10 alkyl" in particular

These and other aspects of the present invention will be apparent from the information contained herein. hexyl, heptyl, octyl, nonyl, decyl, etc.

Compounds according to the present invention can be ma- "Alkoxy" or "alkyloxy" represents alkyl asymmetric centers, chiral axis and chiral group, as defined above, if not specified - planes (described in: E.S. EmpeiI and 5. N. Umieep, especially where the alkyl group attached

Ziegeospetivhigu oi Sagtrop Sotroypavz, add. UMieu nana through the oxygen bridge. 8 Bop5, Mem/ ХОогК, 1994, pages 1119-11901, and zu- The term "cycloalkyl" or "carbocycle" will be found in the form of racemates, mixtures of racemates - mean cyclic rings of alkanes with total purity and in the form of individual diastereoisomers, with scrap of carbon atoms from three to eight, if not all possible isomers and their mixtures, in that is determined especially, or any number including optical isomers, included in the present invention. this interval (ie, cyclopropyl, cyclobutyl,

In addition, the compounds disclosed herein can exist in the cyclopentyl, cyclohexyl, cycloheptyl, or cycloform tautomers and both (looctyl) tautomeric forms. are included within the scope of this invention, even if If the number of carbon atoms is not specified, only one tautomeric structure is depicted. The term "alkenyl" refers to a non-aromatic example, it is clear that any reference to a hydrocarbon radical, direct or branched - compound A, given below, includes a fused one containing from 2 to 10 carbon atoms and a tomeric structure In, and vice versa, as well as their mixtures. at least 1 carbon carbon double bond. Predominantly 1 carbon carbon is present in it; double bond and up to 4 hec BAS of non-aromatic carbon-carbon double bonds may be present

Her A drinks X A connections. Thus, "Co-Cv alkenyl" means an M alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ether-

And nil, propenyl, butenyl and cyclohexenyl. As described above in relation to alkyl, the straight, branched or cyclic portions of the alkenyl group may contain double bonds and may be substituted if permitted by this definition. a substituted alkenyl group is indicated. Specialists in this field understand that "the atom

The term "cycloalkenyl" shall mean cyclic halogen" or "halogen" used rings of 3 to 10 carbon atoms, unless otherwise specified, includes chlorine, fluorine, bromine and iodine. especially those containing at least 1 carbon The term "keto" means carbonyl (C-O). The term lac is a carbon double bond (ie, cyclohexenyl, cyclohexenyl, cycloheptenyl, or cyclooctenyl) as used herein, wherein alkyl is as defined above. well, with the rest of the molecule through the oxygen atom. App-

The term "alkynyl" refers to the hydrocarbon group alkoxy, including methoxy, ethoxy, and the like radical, straight or branched. ty from 2 to 10 carbon atoms, unless specified The term "haloalkyl" means an alkyl raleno especially containing at least 1 carbon dical, as defined above, unless a carbon triple bond is specified. It may be present, especially, which is substituted by one to five, preferably up to 3 carbon-carbon triple bonds. by one to three halogen atoms.

Thus, "C 2 -C 2 alkynyl" means alkynyl radi- Typical examples include but cal having from 2 to 6 carbon atoms. Not only alkynyl, trifluoromethyl, dichloroethyl and the like. groups include ethynyl, propynyl and butynyl. The term "haloalkyl" is a radi-

As described above in relation to alkyl, straight line, split-ORE, where ЕВ. represents an alkyl, as a defined branched or cyclic part of an alkynyl group, which is substituted by one to five, preferably can contain triple bonds and can be substituted by one to three halogen atoms. They are characteristic if a substituted alkynyl group is indicated. methods include, but are not limited to, trifluorome-

In some cases, the substituents can be vytyloxy, dichloroethyloxy and the like. means a carbon chain that includes The term "arylalkyl" includes alkyl zero, for example (Co-Cv)alkylenaryl. If we take the part where alkyl is defined above and includes in aryl is phenyl, this definition includes the aryl part where aryl is defined above. phenyl itself, as well as -SNaRPY, -SNa.SNeRY, Examples of arylalkyl include, but not sn(SnHz3Snesn(СНЗ РИ, etc.) only, benzyl, fluorobenzyl, chlorobenzyl, phenyl- "Aryl" , as used herein, means tyl, phenylpropyl, fluorophenylethyl, and chlorophenylethyl. any stable monocyclic or bicyclic Examples of alkylaryl include, but are not limited to, a carbon ring of up to 12 atoms in each ring, where only, toluene, ethylphenyl, and propylphenyl. at least one ring is aromatic. The term "heteroarylalkyl" as used herein will refer to a system that includes phenyl, naphthyl, tetrahydronaphthyl, indanyl, bife- a heteroaryl moiety, where the heteroaryl nil , phenanthryl, anthryl, or acenaphthyl. In the case defined above and contains an alkyl moiety. In cases where the aryl substituent is bicyclic and one of the heteroaryl alkyl groups includes, but not the ring is non-aromatic, it is clear that only thienylmethyl, thienylmethyl, thienylethyl, thienylpropyl, pyrene occurs through an aromatic ring. dilmethyl, pyridylethyl and imidazoylmethyl.

The term "heteroaryl" used The term "cycloalkylalkyl" includes an alt, represents a stable monocyclic, bicyclic moiety, where alkyl is defined above, and also a single or tricyclic ring of up to 10 atoms each includes a cycloalkyl moiety, where cycloalkyl is a ring where at least one ring is an aromatic alkyl as defined above. Examples of cycloalkylalkyl and containing from 1 to 4 heteroatoms selected from the group include, but are not limited to, cyclopropyl, consisting of 0, M, and 5. Heteroaryl groups in til, cyclopentylmethyl, cyclohexylmethyl, cyclo- within the scope of this definition include , but propylethyl, and the like. not only: benzoimidazolyl, benzofuranyl, benzo- The term "hydroxyalkyl" means a linear monofurazanyl, benzopyrazolyl, benzotriazolyl, benzo- valent hydrocarbon radical from one to thiophenyl, benzoxazolyl, carbazolyl, carbolinyl, six carbon atoms or a branched mono- cinnolinyl, furanyl, indolinyl, indolyl, an indolasylent hydrocarbon radical from three to shesnyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinones of carbon atoms, substituted by one or two lyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadihydroxy groups, provided that in the case the presence of azolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, two hydroxy groups, both of which are not on pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, one carbon atom. Typical examples include pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, including, but not limited to, hydroxymethyl, 2-quinoxalinyl, tetrazolyl, tetrazolpyridyl, thiadiahydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and zolyl, thiazolyl, thienyl , triazolyl, dihydrobenzoimi- similar. dazolyl, dihydrobenzofuranyl, dihydrobenzothiophe- The term "heterocycle" or "heterocyclyl", which nil, dihydrobenzoxazolyl, dihydroindolyl, as used herein, means a 5-10 membered nonaro- dihydroquinolinyl, methylenedioxybenzene, benzothia- matic ring, unless specifically stated that zolyl, benzothienyl , quinolinyl, isoquinolinyl, oxazolyl contains from 1 to 4 heteroatoms selected from the group, and tetrahydroquinoline. In the case when the heteroaryl consisting of 0, M, 5, 50, or 50" and including a substituent is bicyclic and one ring is non-aro, it is a bicyclic group. "Heterocyclyl", such a chimatic or does not contain heteroatoms, of course, nom, includes, but is not limited to, the following: in which attachment occurs through an aromatic perazinyl, piperidinyl, pyrrolidinyl, morpholinyl, ring or through a ring that contains a heteroatom , thiomorpholinyl, tetrahydropyranyl, dihydropipery- respectively. If the heteroaryl contains nitrogen atoms, dienyl, tetrahydrothiophenyl, and the like. If hetero- it is clear that their corresponding M-oxides also cover the cycle contains nitrogen, it is clear that its corresponding M-

oxides are also covered by this definition. AcOonH - acetic acid

This invention also includes M-oxide BEz x boron trifluoride derivatives and protected derivatives of compounds of Formula I/. Na- Bos - tert-butyloxycarbonyl example, in the case when compounds of the formula | VosgO - di-tert-butyl dicarbonate contain an oxidizable nitrogen atom, the nitrogen atom of 5 butyllithium can be converted to M-oxide by methods well known in the art. Also, in that high-SNOsSi" - methylene chloride of padku, when the compounds of the formula I! contain groups such as СН3СМ - acetonitrile as hydroxy, carboxy, thiol or any group containing nitrogen atom(s), these groups can be protected by appropriate protecting groups. You are complete! is copper iodide, a list of the corresponding protecting groups can be found rABT - diethylaminosulfur trifluoride in (T.MU. OSgeepe, "Rgoyesime Sgotspr5 ip Ogdapis PIREA : diisopropylethylamine zupipeviz", Uopp UMieu 8 5op5, Ips. 1981, disclosure of OMA - M,M-dimethylacetamide which is incorporated herein by reference in its entirety OMAR - 4-(dimethylamino)pyridine. Protected derivatives of the compounds of the formula | can be prepared by methods well known in the art.

When the term "alkyl" or "aryl" or any - EOSI E 1-"Z-dimethylaminopropyl)-3- which of them, standing before the root, appear - ethyl carbodiimide hydrochloride in the name of the substituent (for example, aryl Co-v alkyl) EBO : diethyl ether it should be interpreted as including EvMm - triethylamine in itself the restrictions that are given above for "alkyl - EUAs - ethyl acetate lu" and "aryl". The indicated number of carbon atoms EN : ethanol (for example Si- 1o) will refer independently to NATO - o-(7-azabenzotriazol-1-yl)-M,M,M'M'- the number of carbon atoms in the alkyl or cyclic tetramethyluronium hexafluorophosphate alkyl part of the molecule or to the alkyl part - HOAc - acetic acid of a larger substituent in which the alkyl appears KSO" - potassium carbonate as its leading radical. КНМОЗ5 - potassium hexamethyldisilazane

Pharmaceutically acceptable salts of compounds according to KOVy! - potassium tert-butoxide according to this invention include non-toxic salts of compounds according to this PON - lithium hydroxide of the invention, formed by inorganic or organic acids. For example, commonly accepted meon : methanol non-toxic salts include salts obtained from inorganic acids, such as hydrochloric, sulfuric, sulfamic, phosphoric, M5 - methanesulfonyl - mesyl nitric and the like, as well as salts obtained from organic М5СИ - methanesulfonyl chloride of nocturnal acids, such as acetic, propionic, succinic - Mavna - sodium borohydride na, glycolic, stearic, lactic, malic, vin-man - sodium hydride na, citric, ascorbic, pamova, maleinova, Ma! - sodium iodide hydroxymaleic, phenylacetate, glutamic, be- MmastmVnH" - sodium cyanoborohydride nzoic, salicylic, sulfanil, 2- MagSO" - sodium carbonate acetoxybenzoic, fumaric, toluenesulfonic - Manso»z - sodium hydrogencarbonate lota, methanesulfonic, ethanedisulfonic, ox-ammonium - sodium hydroxide of lion, isethion, trifluoroacetate and the like. Otry- Mag25O»4 - sodium sulfate, manna of pharmaceutically acceptable salts is described Mv5 - M-bromosuccinimide above and other typical pharmaceutically acceptable salts of МН3: ammonia are more fully described by Ivegou ei ai., "Rpaptaseksshiisai MNASI " ammonium chloride zaiivb", u. Rpagt. zsi., 1977:66:1-19, included here Ra/C - palladium on coal as a reference). Pharmaceutically acceptable salts of Rasi" - dichloropalladium(II) in accordance with the present invention can be synthesized from compounds according to the present invention, which contain bis-diphenylphosphino) ferrocenedichloropalladium (II) and the oxidizing part of the Ragz(ava)z molecule - by traditional chemical methods. As a rule, tris(idibenzylideneacetone)dipalladium(O) salts of basic compounds are prepared either by ion exchange PO - a protecting group by chromatography, or by the interaction of a free base with stoichiometric amounts of РРІІ3 - triphenylphosphine, or with an excess of (РPO)ІЗРМей - methyltriphenoxyphospho iodide - the desired salt-forming inorganic or organic - ionic acid in the appropriate solvent or in various PPRTZ - pyridinium p-toluenesulfonate solvent combinations. Similarly, salts of IrgoMium 2 lithium diisopropylamide of acidic compounds are formed by means of reactions of benzotriazole-1- with the corresponding inorganic or organic yloxytris(pyrrolidine)phosphonium-hexafluorophosphate base. Kt. - room temperature

For the purposes of this description, the specified values are Nasych. - saturated aqueous solution of foot contractions: TEA "trifluoroacetic acid

THF - tetrahydrofuran

TiSiI-x titanium chloride (IM) Compounds according to the present invention can also be

Ps - thin-layer chromatography must be obtained in accordance with Scheme 2,

TM5SIII - chlorotrimethylsilane shown below. Ketone or aldehyde can be

Me - methyl is condensed with an amino alcohol to obtain a cyclo-

Ege ethyl aminal. Treatment with 3 equivalents of the reagent p-Pg x normal propyl Grignard or an organolithium reagent gives the reaction i-Pg - isopropyl and an alkylated amino alcohol. Oxidation of alcohol p-Vy xx normal butyl by the chromium system, for example oxidation by i-Vy - isobutyl Jones (Chopez5) or with the help of NeIov/StgOz, or, 5-Vy - secondary butyl alternatively, by two-stage oxidation

And-Vy - tertiary butyl (for example, oxalyl chloride/DMSO/EVM, then

The new compounds of this invention can be massi) will give the corresponding carboxylic acid. Pep- obtained in accordance with the following general interaction and the Suzuki reaction, described in the scheme of accepted methods using the corresponding 1, will give the compounds according to the present invention. substances, and are additionally illustrated by separate examples. The compounds illustrated in the examples, SCHEME 2, however, are not interpreted as creating only a genus, which nev? considered as the present invention. The following examples of ЯООВАООАКОА?О0diastrk yam Хhalogen-(ХНМОВ additionally illustrate the details of obtaining the data of Я ДНО тля веше compounds according to the present invention. A specialist in this field will easily understand that there are known variations of the conditions and processes of the following preparative processes of mo-YARA Certain combinations of compounds must be used to obtain these compounds.

All temperatures are given in degrees Celsius unless n is specified separately.

Schemes of sg di

Compounds according to the present invention can be obtained according to Scheme 1, given in vv | See below. Thus, a complex α-amino ether can be added to a haloalkyl ketone to obtain an aminal, which can be dehydrated into an imine Thorodiol in the presence of a dehydrating agent , such as Tisia, o and I

Ma5o" or isopropyl trifluoroacetate. Reduction of the imine with a reducing agent, such as sodium borohydride or sodium borohydride, gives the amine. Hydrolysis of the ester and formation of the amide bno, respectively, with substituted aminoacetonitrile gives the compound according to the present invention. If the substituted Compounds according to the present invention are also halogen on the O system, palladium-catalyzed must be obtained in accordance with Scheme 3, linking by the Suzuki method (5y!y2yKi) from the answer given below. Ketone or aldehyde can be boronic acid gives additional compounds condensed with aminoalcohol to obtain cyclo- according to the present invention. of the aminal. Treatment with a large amount of equivalents of Grignard reagent or organolithium reagent

SCHEME 1 gent gives the corresponding alkylated aminoalcohol. This

And | alcohol can be converted into compounds according to the present invention by the method described in Scheme 2. i : vue 2, i : m - in nn svo u i v se M meon o on ve Y z na v Vo pt u" -i i iy Halogen. I i, he I v, ku VES RUVOR, OME, iya u halogens) My

EM 5 vya pn is CHI agyady re vy--V(On) yari x TIKI yun pyadytkva ad. MNa2СОз, OME, (9) mon

ROS (arrO), A

Compounds of the present invention may also be prepared in accordance with Scheme 4. An appropriately substituted phenylacetate may be polyenolized with an appropriate base (including, but not limited to, GOA, KNMO5, Man or pVy ! her) and ob-

made with paraformaldehyde with the formation of dio- shown below. Peptide compound alpha-al. This diol can be converted into diphto-amino acids described in Schemes 1, 2 or 5, with alides using a fluorinating reagent such as fa-aminoamide followed by dehydrogenation as SABT. Hydrolysis of the complex ester followed by the resulting primary amide (Moedei, rearrangement of Kurtis (Sygpitsy5) then gives the amine. Weppeg", 5. A. German Spet. Asia 1996, 79, 1863) gives

This amine can replace an appropriately substituted compound according to the present invention. complex alpha-bromo ether giving complex alpha-amino ester. It can be transformed into SCHEME 6 of the compound according to the present invention by the method described in Scheme 1. shiyu nik ? " z - chn, "di

Salon D. tkhv Halogn | i M scheme KK svat ru on on E E som viv zhov, firewood OAt ov TEDA, IPyridin 7 p 0 nsno o tA

Ge) by 1) water base 2) ORRA, IVCHON 3) TA | , ate I in-vo" halo Ya.

B Eov n A vodn. Makhsov, OME, Nya dv vya Rosiorov, and pn Its basis is according to Mne The synthesis of some amino alcohols, which are used as starting products according to schemes 2, 3 and 5, is presented in schemes 7 -11. For example, the synthesis of (25)-2-amino-4-fluoro-4-methylpentan-yl-ol, where Kk-Me, is presented in Scheme 7 below. Starting with shk from the corresponding deprotected aspartic acid,

The carbon group and the carboxyl group can be reduced to the alcohol by using standard literary methods (for example, the formation of a mixed anhydride with

And the subsequent restoration of MavVNe). Protected va-

The compounds according to the present invention, as well as the 2-amino-4-methylpentane-1,4-diol (B-Me) morphant, will be obtained in accordance with scheme 5, and can therefore be formed with the help of the following. The hemiacetal can be condensed under the influence of the Grignard reagent or organolithium. combined with an aminoalcohol in which the alcohol part Finally, the hydroxyl part of the molecule can molecule is protected by an appropriate protecting group. to be transformed into the desired fluorosubstituent from the

Treatment of the resulting imine with a Grignard reagent using a fluorinating agent such as CA5T. or an organolithium reagent will give the corresponding Protected or unprotected version of this amyl-alkylated amino alcohol. The alcohol protecting group of the no-alcohol can then be converted into the compounds can then be removed and the alcohol can be converted into compounds according to the present invention according to Schemes 1, 2, or ZiB. by the method described in Scheme 2, or by first carrying out the Suzuki reaction, followed by oxidation of the Scheme 7 alcohol under the influence of H»viOv/SgOz, and then by peptide binding. o her va o ro o Restoration (in) sla b

SCHEME 5 RO. and vv -e-- oon no on 7 bn Red vo in tr tovku 1uHalogen-(O) ii noga 2 lova Ome 00 odu oRa "

Us 2uRemoval | had a protective group

In d vno vd

Ho pn Removing the protection of rAVT sg ya'-v(on Ra. tre, in RUVOR, OME, 29. o om, NM on NO ore NO oRa yav" em ROSI(drr), And vaz Y 4-Fluoroleucinol can also be synthetic - the appearance of NeOv/StOz, prepared according to scheme 8. 4,5-Dehydroleucine pe-

Chet -ШШШШШШ8ШЙО8ЕЦШЧЮЗ- voru it is converted into (45)-4-(2-methylprop-2-enyl)-1,3-"no mn oxazolidin-2-one, as presented in the scheme below.

This intermediate is then treated with hydropho-

Compounds according to the present invention can also be obtained with a mordant reagent, such as HE-pyridine, according to scheme 6, (45)-4-(2-fluoro-2-methylpropyl)-1,3-

oxazolidin-2-one. Hydrolysis by a base (i.e., solvents such as EN and THF. Aminoprotective

Ba(On)»: or Maon) then gives (25)-2-amino-4-fluoro- the group is then removed in an appropriate manner from- 4-methylpentane 1-ol. according to the nature of the protective group.

SCHEME 5 SCHEME 10 ra o i ! U Btrication, x v v | ve vi

Hv |U S doka i nn V, n "Mu se ny SM No n 2 u-o 9 o

Me E Deprotection in v mm ---- on -7OH "Me nm V oyu H "Kon Synthesis of (25,45)-2-amino-5,5,5-trifluoro-4- and methylpentan-1- ole used in this

D8) of the invention, represented in Scheme 11. M-Benzoyl-5,5,5-trifluoroleucine |O)iiiita, ei. AI. U. Ogd. Spet.,

Synthesis of 4,4-difluoro-I-norvaline, de Kk-Me, 1989, 54, 4511-4522| can be hydrolyzed is presented in scheme 9 below. Starting with an acid solution, such as 6M NH, with suitably deprotected serine, iodination can be heated under reflux. The intermediate is carried out using a reagent, such a compound NCI salt of an amino acid, then it is converted into (RPO)zZR"Me!. The introduction of zinc into the resulting M-acetyl-5,5,5-trifluoroleucine, and the amino group of the resulting iodide can be carried out 2p-Si pairs and TM5Si are decomposed from the vycochiral center by enzymatic melting of 2p-Si pairs and TM5Si. Obtained in the resul method (Zupipeiis Sottipisaiop5, 1996, 26, these zincates are then subjected to the combination reaction that 1109-1115). The isolated 5,5,5-trifluoro- II -leucine is catalyzed by palladium, with an alkanoyl chloride to then protect with a protecting group, obtaining a ketone. As a result, this ketone time- such as benzyl carbamate, and the esterifying group of the molecule can be converted into the desired carboxylic acid. Two diastereoisomers in polo- difluoro derivative with using a fluorinating agent, 4 is then separated by a thin-layer column such as OAB5T. Protected or unprotected by chromatography. One of the enantiomers, (25, a variant of this amino acid or amino alcohol then 45) protective amino acid, then converted into can be converted into compounds according to this amino alcohol, as represented in Scheme 10. invention according to Schemes 1, 2, C and 5.

SCHEME 11

ECHEMA 5 1. As", MaON and 2. Acylase!

On Xia 1) Si mi av a bM pen av i SON 3, sys, MON o Iodination RO... she ko me MN, 4. SM, iy dn tyunnnnknya NU 2IRa Sa, Me MNnSOR . 5. Separation

Ra. i no ovRa | NSI salt

M o mon

N Oova Zh po SEZ o kash I. Vi Yia

In "257. restoration 1 acid connection of protection ra rAET E in sr: ОМе 52, removal of protection s Menor o on 2) Restoration It" -О Na

TIA ore nora n - 25.4K-enantiomer

Not d Compounds according to the present invention, where P? Yavra emits hydrogen, and ER? is aryl or he-

KE 0 dihguhlakhist EE theroaryl, can also be obtained in the corresponding

Correspondence to Scheme 12 as shown below. Condensation

Re nn aryl or heteroaryl aldehyde with amino alcohol, in non ? in which the alcohol part of the molecule is protected by an appropriate protective group, followed by further processing

Amino alcohols used in this invention by the resulting imine reagent can also be synthesized in the Grignard reaction or by an organolithium reagent of the formula according to scheme 10. -MoH (where O is recognized as a reducing agent, such as the one above), with subsequent removal of oxygen-

Mavna, in the presence or absence of GISI, in the leaving group, gives an alkylated amino alcohol. This factor, such as EION, or in the system of mixed alkylated aminoalcohol is then converted into compounds according to the present invention either by the method presented in scheme 2, or in conjunction with the explosives by carrying out the Suzuki reaction with boron base. the potential of a halogen with a complex ester of the formula B"-B(OH)", then oxidation. B and 1 by the corresponding oxidizing agent, such as НеИО6/СгОз, with obtaining an acid and, at the end , by treating this aminoacetonitrile acid with the conditions of peptide binding described by J I: vv N m Ved: Leads to before.

SCHEME 12 SINA, no

ME in vn ve de e vod MANSO. UOME, n p di i-o Ve ia 1) halogen popei Shen and nairoRa 77 OR haloe (YULIMOH) - bno and no protection The following examples describe the synthesis of selected compounds of this invention.

Example 1

Ah, Her | Synthesis of /M'(cyanomethyl)-M2-(2,2,2-trifluoro-1-; in vn cm Not where in phenylethyl)! -leucinamide in pools Scheme 2 tester mon is o pon KAK G

NATI, OIREA, VYAKOn)" and | Oh my

OME water, MANSO» OME, GG SHY tr - rOSio(drriІСсН,сI, р Го! ; in 0 nysusyu; Leads in I water ----- i in Molon To the solution of hydrochloride of methyl ether 1 - pn I and leucine ( 975mg, 5.37mmol) in dichloromethane (30ml) was added 2,2,2-trifluoroacetophenone (0.75ml,

Compounds according to the present invention can also be obtained in accordance with scheme 13, lamin (3.5 ml, 20 mmol), tissia (0.55 ml, 5.0 mmol) in shown below. Interaction appropriately M- 0.45 ml dichloromethane and this mixture was stirred protected amino acid derivative from oxetane overnight. Then TisSia (0.4 ml, with tosylate in the presence of sodium iodide in the amount of 3.5 mmol) was added and the mixture was stirred according to Added to an organic solvent such as dimethylformamide (1050 mg, 16.7 mmol) in methylformamide gave the corresponding complex ester oc- (2 mmol) and the mixture was stirred for 2 h. Poured into 1N satan, which when treated with diborane gives complex maon and extracted with ethyl acetate (2x). Organic ortho ether. Removal of the amino-protecting group gives the phase washed with amine and saturated salt amine, which upon condensation with the aldehyde of the formula solution, then dried over MozO" and evaporated

VeSHO (where P is aryl or heteroaryl) lys. Purification with the help of column chromo- or hemiacetal of the formula BeC(OHHOV) (where P matography (gradient from 3095 to 9090 ethylace- represents an alkyl group) under reaction conditions, tat/hexane) gave methyl M(2,2,2-trifluoro -1- described above gives an imine. Treatment of this imine is phenylethyl)! -leucinate , Grignard reagent or organolithium reagent. At room temperature, methyl solution under the reaction conditions described above gives M-alkylated M-(2,2,2-trifluoro-1-phenylethyl)! -leucinate (150 mg, derivative. Removal of the orthoether gives the corresponding car- 0.50 mmol) in 271 THF/MeOH was added 1 M CHON. bonic acid, which is then converted into compounds The mixture was stirred overnight and concentrated according to the present invention by condensation from aminol. The residue was partitioned between ethyl acetate and pho-acetonitrile under the conditions of peptide binding with sphatic buffer with pH 3.5. The organic phase is further processed by the Suzuki reaction as described above. washed with saturated saline solution, dried over Mdzoh and concentrated to obtain M-(2,2,2-

SCHEME with trifluoro-1-phenylethyl)! - leucine

A mixture of M-(2,2,2-trifluoro-1-phenylethyl)|-- leucine (149 mg, 0.50 mmol), aminoacetonitrile hydrochloride (102 mg, 1.11 mmol) and RUVOR (260 mg,

Ramosone p yucca (0.500 mmol) was dissolved in DMF (5 ml). OME was added to the plate and triethylamine (0.3 mL, 2.1 mmol) was added, and the mixture was stirred.

It was left overnight, then poured into phosphate buffer pH 3.0 and extracted with ethyl acetate in rum/ethyl acetate. The organic phase was then washed again with saturated aqueous Mansoze and saturated sodium bicarbonate. left solution, dried over MdbOx and - evaporated. Purification with the help of ISO codmelon column chromatography (gradient from 2095 to 5095 ethyl acetate/hexane) gave M'-(cyanomethyl)-Me2- Example 4 (2,2,2-trifluoro-1-phenylethyl)! -leucinamide in appearance- Synthesis of M!-(Cyanomethyl)-M2-CA- and a 1:11 mixture of diastereomers. M5 (iARSCI): 313.9 (methylsulfonyl)-1,1-diphenyl-4-yl|(4-

IMNTI (methylsulfonyl)phenyl|methyl)! - leucinamide

Example 2

Synthesis of m2-P1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M'-(cyanomethyl)! -leucinamide 05550 s

Nz

E (A sn

E. Yae S n Y same M

Her -m M My sb sg

X le (9) about FI

Vg - TV - ЖКЖ и

Using the method of Example 1, MA-11-(4-bromophenyl)-2,2,2-trifluoroethyl/|-M!- Stage 1:00 Methyl / M-(4-bromophenyl)|4-(cyanomethyl)! -leucinamide. M5 (-EBI): 403.9, 405.9 (methylsulfonyl)phenyl|methylene)-leucinate

IMA1T. Solution (4-bromophenyl)|4-

Example C (methylsulfonyl)phenyl|methanone (202mg,

Synthesis / M'-(cyanomethyl)-M"-(2,2,2-trifluoro-1- 0.59 mmol), methyl ether hydrochloride I1-(4-piperazin-1-yl-1,1-diphenyl-4- yl)ethyl-leucine (328 mg, 2.0 mmol) and camphorsulfonic acid leucinamide (52 mg, 0.22 mmol) in toluene was heated under reflux for 18 hours and under CH using a Dean-Stark nozzle. The solvent was removed in vacuo, and the resulting freezing residue was purified using chromatography,

Its Y M using Es and hexane as an eluent to obtain a 1:11 mixture of the title compound and (I starting (4-bromophenyl)|4-

Hm (methylsulfonyl)phenyl|methanone. my Stage 2: Methyl M-(4-bromophenyl)y|4-(methylsulfonyl)phenyl|methyl)! -leucinate

To M2-I1-(4-bromophenyl)-2,2,2-trifluoroethyl-M!- To a solution of 1:1 mixture of methyl M-(bromophenyl)|(4-(cyanomethyl)!-leucinamide (242mg, 0.bOmmol ) and 4- (methylsulfonyl)phenyl|methyleneleucinate and (4- 4-(tert-butoxycarbonyl)-1- bromophenyl)|(4-(methylsulfonyl)phenyl)|methanone from piperazinyl|phenylboronic acid /(220mg, stage 1 (185mg, 0.2 mmol) in acetic acid - 0.72 mmol) in OME (3ml) in a stream of dry nitrogen to toluene (1:3, 4ml) sodium borohydride was added, 2M aqueous sodium carbonate (0.9ml, (7400mg) was added in parts every ZOkhv . for 2 days 1.8mmol) and then the catalyst PaSi"(drri). (bZmg, (the addition was stopped overnight) using a 0.077mmol funnel). The reaction mixture was heated to 857 to add solids. The reaction mixture for 18 hours. Water was added and the extracted product was partitioned between EOAc and water, the organic layer was treated with EOAc, the organic layer was dried over Mag505 and concentrated.

Ma»5O and concentrated in a vacuum. The crude product resulting from the mixture was purified by means of chromatography and purified by means of vicorography chromatography using EtOAc and hexane as an eluent of BEOAc in hexane to obtain the tert. Methyl M-(4-bromophenyl) |

3-methylbutyl)amino|-2,2,2-trifluoroethyl)-1,1"- muval in the form of a colorless resin, and (4-diphenyl-4-yl)-1-piperazinecarboxylate. bromophenyl)|(4-(methylsulfonyl )phenyl|methanol

To tert-butyl(4-(1-К15Х(-1- was obtained as a white solid. (cyanomethyl)(amino|carbonyl)-3- Stage C: M-(4-bromophenyl)-4-methylbutyl)amine) (-2,2,2-trifluoroethyl)-1,1"- (methylsulfonyl)phenyl|methyl. --leucine diphenyl-4-yl)-1-piperazinecarboxylate (275 mg, to the solution methyl o M-(4-bromophenyl) |4- 0.47mmol) in dry THF (1ml) in dry nitrogen do-(methylsulfonyl)phenyl|methyl)!-leucinate was added dropwise with MebOozN (125μl, 1.9mmol) action 2 (8mg, 0.17mmol ) in THF (ml) and meon (0.5 ml) for 15 min. and the reaction was allowed to proceed during which Tn SPON (0.3 ml, 0.3 mmol) was added. Obtained at 18 hours. The reaction mixture was distributed between EOAc and the resulting mixture was stirred at room temperature with Mansoz saturated with water for 18 hours, and then distributed to 7.5. The organic layer was dried over Mag50Ox and concentrated between EOAc and water with Tn HC (0.5 ml). The organic was digested under vacuum. The crude product was purified dried over Mag50 for two layers, filtered and concentrated with the help of chromatography was silicated in a vacuum to obtain the compound in the form of a colorless resin, eluted with MNAOH/conc.//Meon/cSnesi. (110/89) to obtain M1-(cyanomethyl)-M2-(2,2,2- Stage 4: MA-(4-bromophenylua-trifluoro-1-(2-piperazin-1-yl-1,1" -diphenyl-4-(methylsulfonyl)phenyl|methyl)-M'-(cyanomethyl))-yl)/ethyl|-leucinamide in the form of a light yellow foam. leucinamide

M5 (shEBI): 488.3 (MA11". To a solution of M-(4-bromophenyl)|4-

(methylsulfonyl)phenyl|methyl)!i -leucine from stage C (7/bmg, 0.17mmol), NATO (146bmg, Using the method described for app-

O,Zvmmol), aminoacetonitrile hydrochloride (52mgHg, ladu 8, where M2-(11-(4-bromophenyl)-2,2,2-trifluoroethyl-

0.5 mmol) in DMF (1.1 ml) cooled to - M'-(cyanomethyl)I -leucinamide was substituted at 107"C, M,M-diisopropylethylamine (0.1 ml, Mm2-(11-(3-bromophenyl) was added )-2,2,2-trifluoroethyl|-M1- 0.75 mmol). EtOAc and water.The organic layer was dried over M5 (4E51): 482.2 MAG.

Mag25O4, filtered and concentrated in a vacuum. Example 6

The crude product was purified by chromatography using EtOAc and hexane as eluent of pyridin-4-ylphenyl)ethyl-leucinamide with obtaining the title compound in the form of a colorless resin

Stage 5: M'-(cyanomethyl)-M2-(4- i sn (methylsulfonyl)phenyl|(4-(methylthio)-1,1-diphenyl-su HZ 4-yl|methyl)Y -leucinamide with M M see

Heterogeneous mixture M2-(4-bromophenyl)|4- na (methylsulphonyl)phenyl|methyl)-M!-(cyanomethyl)|! - leucines from stage 4 (72mg, 0.15mmol), 4-(methylated phenylboronic acid svi) -trifluoroethyl- 2 gmmol) in dimethyl ether of ethylene glycol M!-( ianomethyl)i! -ley ynamide was replaced by Me- (ml) and 2M aqueous sodium carbonate was degassed in ) 36 at oo dou M vacuum | purged with nitrogen. To this mixture is added I (cyanometite leucinamide, indicated in the title of 1. and She. bis(diphenylphosphino)ferrocene|dichloropalladium (I), the compound was obtained in the form of a colorless resin. dichloromethane complex (19 mg, 0.023 mmol), with M5 ( EI): 4051 (MAG. by subsequent degassing and nitrogen purging. The reaction mixture was heated at 852C for 16 hours to synthesize M "(cyanomethyl)-e.2,2g-trifluoro-1- with effective stirring The reaction mixture (I-piperazin-1-yl-1,1"-diphenyl-3-yl)ethyl|-- was distributed between EtOAc and aqueous MH:aOdS of leucinamide 2595 wt./vol. The organic layer was dried over Mag5Om, and the solution was filtered and concentrated in vacuo. The crude product was purified by column chromatography using EtOAc and hexane as eluent to give the title compound as a colorless resin.

Stage 6: M1-(Cyanomethyl)-M2-C4-(methylsulfonyl)-1,1-diphenyl-4-yl|(4- | Using the method described for the preparation of (methylsulfonyl)phenyl|methyl--leucinamide and 3, where M2-11-(4-bromophenyl)-2,2,2-trifluoroethyl|-

To the solution M ""cyanomethyl)-Mm -- M'-(cyanomethyl)!--leucinamide was replaced by Me-methylsulfonyl)phenyl(4-(methylthio)-1,1"-diphenyl-P-(3-bromophenyl) -2,2,2-trifluoroethyl|-M1-4-yl|methyl--leucinamide (b3mg, 0.12mmol), na-(cyanomethyl)!-leucinamide, the indicated tritungstate dihydrate (2mg, 0.00bmmol) was obtained , the title compound in the form of a colorless resin, rabutylammonium hydrosulfate (4 mg, 0.01 mmol) M5 (ChEBI): 488.3 (MAG. added a solution of 30% w/v aqueous peroxide Example 8 of hydrogen (100 μl, 0.9 mmol) and the resulting Synthesis M'(cyanomethyl)-MU(15)-2,2,2-trifluoro- mixture was stirred "at room temperature 144-(methylsulfonyl)-1,1"-diphenyl-4-yl)ethyl) and - within 10 minutes The reaction mixture was distributed between leucinamide

ETAs and water - 1M Manzoz (-3:1). The organic layer was dried over Ma25O, filtered and concentrated under vacuum. The crude product was purified by chromatography using ESUAS and Hexor CH as an eluent to obtain the title compound indicated in , M in the form of a colorless resin. and M. Z

M5 (ЧЕ51И): 568.2 (MAG. Zh d- o u

Example 5 about | in M

Synthesis of /M'-(cyanomethyl)-M2-(2,2,2-trifluoro-1- o -(methylsulfonyl)-1,1-diphenyl-3-yl|ethyl) - Synthesis of leucinamide

Stage 1: Preparation of (25)-1-tert-butyl(dimethyl)silyl|oxy)-4-methylpentan-2-amine mevo» sn At room temperature to a solution of I1-

Ff SE H of leucinol (6.0 g) in dichloromethane (100 ml) was added

M Mo iSM triethylamine (1 ml) LOBSTER (01) and tpt-

Phenobutyldimethylsilyl chloride (8.5g). This mixture was stirred at room temperature for 2 hours, and then water was added. The organic layer of il|styliamino)pentan-1-ol was separated, and the aqueous layer was additionally extracted with dichloromethane. The combined organic layers were washed with (27.7), 4-(methylthio)phenylboronic acid saturated saline solution, dried with sulfa- (15.77), 2M MazSO:z (100ml) and n-propanol (500ml), volume magnesium and the solvent was removed under vacuum from the solution and a stream of nitrogen was passed for 15 minutes. Then, a 1:3 mixture (3.5 g) of RA(OAS)" and PP" was added to the precipitate of the title compound, and the reaction was used as such in the next reaction. this mixture was heated to 70"C and stirred in

IN NMR (СО3СОС0Оз) 6 3.48 (m, 2Н), 3.32 (m, nitrogen atmosphere for 8 hours. The mixture was cooled- 1Н), 2.76 (m, 1Н), 1.78 (m, 1) , 1.22-1.02 (m, 2H), chewed to room temperature, diluted 0.88 (m, 15H), 0.06 (s, 6H). ethyl acetate (500 ml) and poured into water (2 l) and ice

Stage 2: Obtaining (25)-1-TsChtret- (500g). The ethyl acetate layer was separated and the aqueous layer of butyl(dimethyl)silyl|oxy)-4-methyl-M-(1 E)-2,2,2- was additionally extracted with ethyl acetate (200 ml). trifluoroethylidene|pentan-2-amine The combined ethyl acetate extracts were washed with 0.5N

A solution of (25)-1-CChtret-Mmaon (2x200ml), aqueous MNACI, saturated so-butyl(dimethyl)silyl|oxy)-4-methylpentan-2-aminol solution and dried with magnesium sulfate. After removing the solvent from stage 1 (50g) in toluene (300ml) and trifluoroacetal, a residue remained, aldehyde methyl hemiacetal (35ml) was heated to which was purified by chromatography at 50%, refluxing for 16 using a gradient of ethyl acetate and hexane (1:4 up to hours, during this time water was collected according to 1:3), and again with acetone and toluene (1:10). The rest of my Dean-Stark nozzle. The solvent was evaporated and dissolved in hot hexane (200 ml), and the solution was concentrated under vacuum and the residue was purified at 5 °C, allowed to cool to 0 °C with stirring, using hexane and ethyl acetate (91) as an eluent from The solid obtained was filtered and dried to obtain the title compound.to obtain the title compound.

IN NMR (COzSOSOSO) 5 7.88 (m, 1H), 3.76-3.45 IN NMR (COzZSOSO) 5 7.7 (2H, d), 7.65 (2H, d), (m, ЗН ), 1.60-1.25 (m, ЗН), 0.88 (m, 15Н), 0.06 (с, 7.6 (2Н, d), 7.35 (2Н, d), 4, 5-46 (IN, m), 3.7

ZN), 0.04 (c, ZN). (IN(OH), m), 3.5-3.6 (1Н, m), 3.3-3.4 (1Н, m), 2.7 (IN,

Stage 3: Obtaining /(25)-2-((15)-1-(4- M), 2.5 (ЗН, с), 2.3-2.4 (1Н(МН), m), 1 ,65-1.75 (1H, bromophenyl)-2,2,2-m), 1.2-1.4 (ZH, m), 0.8-0.9 (6H, dd). trifluoroethylamino)methylpentan-1-ol. Stage 5: Preparation of (25)-4-methyl-2-((15)-

H-Vii (2.5 M in hexane, 42 ml) was added at - 2,2.2-trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-70"Сb to a THF (400 ml) solution of 1,4 - 4-yl|ethyl)amino)pentan-1-ol dibromobenzene (25.8g) and the mixture was stirred at 0"C to the sulfide solution (19Hg) from stage 4 in draft for 25 minutes. Then, THF was added dropwise, toluene (400 ml) was added Magu/O4-2H2gO (0.16 g) and a (30 ml) solution of (25)-1-CChteret-Vy"MNBO" (0.81 g). Then 3095 butyl(dimethyl)silyl|ioxy)-4-methyl-M-(1 E)-2,2,2- hydrogen peroxide (12.2 ml) was slowly added, the mixture was stirred with trifluoroethylidene|Ipentane-2-amine (31 g ) and the mixture at room temperature for 4.5 hours. The mixture was stirred for 1.5 hours. Then it was slowly poured onto a mixture of ice, diluted and poured into a mixture of ethyl acetate (500 ml), water (2 l), aqueous sodium thiosulfate and ethyl acetate. Organi-ice (300 g) and ammonium chloride (100 g) with an intensive layer was separated and the aqueous layer was additionally extracted by mixing. The organic layer was separated and washed with ethyl acetate (2 x 100 ml). The combined organic and aqueous layers were additionally extracted with ethyl acetate and washed with saturated saline (2x500 ml). The combined organic layers were washed, dried with magnesium sulfate, and the solvent was removed in a saturated saline solution, dried in a sulfa vacuum to obtain a residue, which was purified to magnesium volume and the solvent was removed in a vacuum with 5IO" using ethyl acetate and hexane (11) of the remainder, which was used as such. Use as an eluent to obtain this product. the above-mentioned residue was dissolved in THF (250 ml) and IN NMR (SOZSOSO) 5 8.05 (2H, d), 8.0 (2H, d), the solution was cooled to 0"C. It was added dropwise- 7.85 (2H, d), 7.7 (2Н, d), 4.6-4.7 (1Н, m), 3.75 (IN, 1M TTF solution of fluoride /- tert-m), 3.6 (1Н , m), 3.35-3.45 (1H, m), 3.2 (ZH, s), 2.7-2.8 butylammonium (110 ml), the mixture interacted during -2.45 (1N, m), 1.7-1.8 (1N, m), 1.2-1.5 4 hours. The mixture was poured into ethyl acetate (30 Oml), (2N, m), 0.8 -0.95 (6H, dd). water (2L) and ammonium chloride (100g) with intensive stirring. The organic layer was separated, and the aqueous (2-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl. - additionally extracted with ethyl acetate (2x100 ml). leucine

The combined organic layers were washed with a saturated suspension of NeIov/SgOz (529 ml of 0.44 M in CH3SM; saline solution, dried with magnesium sulfate and see Note below), cooled to 0"C, and the solvent was removed in vacuo to obtain a precipitate dropwise alcohol solution from stage 5 (20g) in the excess, which was purified to 5µO2 using gra-CH3SM (230ml).The mixture was stirred at 0-57 dient of ethyl acetate and hexane (1:5 to 1:4) as eluent for 3.5 hours. The mixture was poured into MagHPO4 to obtain the title compound at pH 4 (1.5 L) with vigorous stirring, and

IN NMR (CO3SOSO») 5 7.6 (2H, d), 7.45 (2H, d), the mixture was extracted with diethyl ether (3x250 ml). 4.55 (1H, m), 3.65-3.7 (1H, m), 3.5-3.55 (1H, m), 3.25- The combined ether extracts were washed with water and 3.35 (1Н, m), 2.6-2.7 (1Н, m), 2.25-2.35 (1Н, m), 1.65- saturated saline solution (1:1), diluted 1.75 ( 1H, m), 1.3-1.4 (1H, m), 1.2-1.3 (1H, m), 0.75-0.9 aqueous Manzose and saturated saline solution. (6H, dd). The organic extract was dried with sodium sulfate,

Step 4: Preparation of (25)-4-methyl-2-((15)- was filtered and the solvents were evaporated to dryness from 2,2,2-trifluoro-1-(4-(methylthio)-1,1-diphenyl-4 - obtaining the remainder, which was divided into two parts-

for further cleaning. SNiISM (1500 ml). The mixture was stirred at 0-57C

The above-mentioned crude acid (10g) for 3.5 hours. The mixture was poured into MagNHROX, pH 4, taken up in isopropyl acetate (2500ml) and extracted with (2.5l) with intensive stirring and cold 0.1N Maon extract (3x250ml). The combined extracts were extracted with diethyl ether (3x50 ml). The combined effects were washed with diethyl ether (250 ml), and then the pure extracts were washed with water and saturated sodium chloride was slowly acidified to pH 4. saline solution. The organic (2x250 ml) and isopropyl acetate layer were dried and the final extract was dried with sodium sulfate, filtered to obtain a high-quality product and concentrated in a vacuum to obtain M-purification, and used as such in the next I15)-1-4 -bromophenyl)-2,2,2-trifluoroethyl/-- stage. leucine, which is used as such in the

Note: the oxidizing reagent (NviOv/SgOz) is a ready combination with aminoacetonitrile. were as described in Teigapedgop I etseg5 39 (1998), Benzotriazole-1-benzotriazole-1-

HPLC (contains 0.595 water); no water was added. yloxytris(dimethylamine)phosphonium hexafluoropho-

IN NMR (CO3СОС0Оз) 5 8.05 (2H, d), 7.95 (2H, sphate (71.5g), aminoacetonitrile hydrochloride d), 7.8 (2H, d), 7.65 (2H, d) , 4.45-4.55 (1H, m), 3.55- (25.4) and the mixture was cooled to 0"С. 2.8-3.0 (sh. m, MH/OH), (60, vml) was added dropwise and the mixture was heated to 1.95-2.05 (1H, m), 1.55-1.6 ( 2Н, m), 0.9-1.0 (6Н, m). at room temperature, and stirred for

Stage 7: Obtaining M'(cyanomethyl) - 16 hours. The mixture was poured onto ice and saturated water

Me(15))2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"- sodium bicarbonate, and extracted with diethyl diphenyl-4-yl|ethyl M-leucinamide ether (33x30Oml). the combined extracts were washed

Magnesium sulfa-7 (93) was added to a DMF (200 ml) solution of the acid from the stage saturated with a saturated saline solution, and the solvent was removed under vacuum. phosphate (11.6g), amine acetonitrile hydrochloride (3.94g) were added with a gradient of ethyl acetate and hexane (1:3 to 1:2) and the mixture was cooled to 0°C. Triethylamine (9.9ml) to obtain the title compound, enough was added dropwise and the mixture was heated to room temperature for use in the next stage and stirred for 16 h. poured onto ice and saturated aqueous (2H, d), 7.45 (2H, d), 4.4 (IN, m), 4.1 4.2 (2H, m), 3,4- sodium bicarbonate, and extracted with diethyl ether-3.5 (1N, m, 2.6-2.7 (1N, m), 1.8-1.95 (1N, m), 1.4-1.6 rum (3x100ml). The combined extracts were washed with (2N, m), 85-0.95 (6N, m) saturated saline solution, dried with sulfa- anomethyl)-M2(15)- tom magnesium and the solvent was removed in vacuo. Zal-2,2.2-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-shock) was purified by chromatography on 5iO", using dioxaborolan-2-yl)phenyl|ethyl)! -leucinamide in ethyl acetate and hexane (1:1). The specified title compound was passed through DMF under a stream of nitrogen, then mixed in a diethyl (700 ml) suspension of M2(15)-1-(4-bromophenyl)-2,2-ether for 16 hours, filtered and dried. -M'(cyanomethyl)! -leucinamide with Ly (m.p. 140.575). stage 1 (28.5g), bis(pinacolato)diboron (23g) and

IN NMR (COzSOSO») 5 8.0 (2H, d), 7.95 (2H, d), potassium acetate (24g) for 15 minutes from a distance - 7.8 (2H, d), 7.65 (2H , d), 4.35-5 4.45 (1H, m), 4.1-4.2 by the addition of (1,1"-bisidiphenylphosphino)ferrocene (2H, m), 3.45-3.55 ( 1Н, m), 3.15 (ЗН, с), 2.65-2.7 (1Н, dichloropalladium(II!), complex (1:1) with dichlorometa-

M), 1.85-1.95 (1H, m), 1.4-1.6. (2H, m), 0.85-0.95 nom (2.9g). The mixture was heated to 65-7C and stirred in a nitrogen atmosphere for 2.5 hours. The mixture

Example 9 was cooled to room temperature, diluted

Synthesis of M2(15)-1-(4(aminosulfonyl)-1,1"- was treated with ethyl acetate and hexane (1:1, 300 ml) and lydiphenyl-4-ylI|-2,2,2-trifluoroethyl)-M (cyanomethyl)|!- was poured into water (2 L) and ice (500 g). The organic layer of leucinamide was separated and the aqueous layer was further extracted with ethyl acetate and hexane (1:11, 3x200 Oml). The combined

Sleep the extracts were washed with saturated saline

E E E vn nom and dried with magnesium sulfate. After removal

After 1 h of the solvent, a residue remained, which was purified by chromatography on 5% using ethyl

I cetate and hexane (1:2) to obtain boronate. yo: o IN NMR (COzSOSO) 6 7.95-8.05 (shs, MN), 7.7- o, | pH 7.8 (2H, d), 7.45-7.55 (2H, d), 4.3-4.4 (1H, m), 4.05-

Go 4.15 (2H, m), 3.4-3.5 (1H, m), 2.55-2.65 (1H, m), 1.85- 1.95 (1H, m), 1.45-1.55 (2Н, m), 1.15-1.4 (12Н, m; some pinacol is also present as an impurity),

Stage 1: Obtaining M2(15)|-1-(4-bromophenyl)- 0.85-0.95 (ВН, m). 2,2,2-trifluoroethyl-M'(cyanomethyl)!--leucinamide Stage 3: Preparation of M2(158)-1-I14-

A suspension of NeIov/SgOz (1925 ml of 0.44 M in CH2SM; (aminosulfonyl)-1,1"-diphenyl-4-yl|-2,2,2- see Note on stage 6, example 8) cooled trifluoroethyl)-K (cyanomethyl)!-leucinamide was brought to 0"C and a solution of (25)-2- was added dropwise. A stream of nitrogen was passed through the suspension, ((15)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino) -4- obtained from the defense from stage 2 (4g), 4- methylpentan-1-ol from stage 4, example 8, (60g) in bromobenzenesulfonamide (3.3g), 2M MaCO3

(20ml) and n-propanol (100ml) for 15 minutes. es E E

Then a 1:3 mixture (0.25 g) of RI(OAS)" and PP" was added, and with M the reaction mixture was heated to 857C and stirred in a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and poured onto water (500 ml) and ice (100 g). The ethyl acetate layer was separated, and the aqueous layer was further extracted with ethyl acetate. Step 1. Preparation of (45)-4-isobutyl-2-(100ml). The combined ethyl acetate extracts of promy-(pentafluoroethyl)-1,3-oxazolidine were washed with diluted aqueous MansoOz, saturated pentafluoropropanal methyl hemiacetal salt solution and dried with magnesium sulfate. (14.9g, 82.8mmol) and I-leucinol (9.7g, 82.8mmol) which was purified by chromatography at 5". used 0 was dissolved in OH benzop and heated on the reverse, melting the radic ulyl acetate, heck dichlorome" with a baked Dean-Stark nozzle. The resulting solution was washed in diethyl ether for 16 hours, cooled, concentrated to obtain vka: filtered and dried to obtain the indicated B zana in the title compound in the form of oil, which was used directly in the next stage. ), 7.65 (H, d), 6.6-6.7 (2H, m), 4.4 (1H, bromophenyl with fluoropropylmn m), 4.1-4.2 (2H, m), 3.5 (1N, m), 2.6-2.7 (1N, m), 1.9 To -78С dibromobenzene solution (9.85G, (TN, m), 1.45-1.6 (2N . .2 mmol) obtaining a thick suspension or cyanocyclopropyl-me(18)2,25- suspension. After stirring for 10 min., a solution of (45)-4-isobutyl-2-(pentafluoroethyl)-1 was added, 3-trifluoro-1-14-(methylsulfonyl)-1,1"-diphenyl-4-oxazolidine (3, 3 g, 13 mmol) in 3 ml of THF gives ethyl leucinamide or a dark brown solution. The solution was allowed to warm to room temperature, then poured

E C in saturated aqueous ammonium chloride and extracted

I. There is a dream with ether. Purification by means of chromatography on -M silica gel (1095 to 4090 ethyl acetate/hexane gradient) gave the named compound in the form of one diastere-

I Ha! rheomer o f Stage 3: Preparation of M2-((15)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl|-5!-(cyanomethyl)!-ne Keleucinamide

Total sample (25)-2-((15)-1-(4-spi' bromophenyl)-2,2,3,3,3-pentafluoropropyl|amine)-4- o mixture M-(15)-2, 2,2-trifluoro-1-(4-(methypsulfacyl)-1-dipheny-1-ethyl P methylpentan-1-ol (1.6 g, 4.0 mmol) converted to leucine from Example 8 (0.83 g), O-( 7- into the compound specified in the title using azabenzotriazol-1-yl)-M,M,M',M'-tetramethyluronium by the method of example 8, stages 6 and 7. Purification with dopohexafluorophosphate (0.78g), cyclopropylamine hydro- Chromatography on silica gel (1590-8095 ethyl chloride (0.466 g) in DMF (18 ml) at 0"C was added with an acetate/hexane gradient) gave the named compound triethylamine (0.9 ml). The mixture was kept at room temperature. In the form of a solid. room temperature for 48 hours, and then H NMR (CO3SOSOO, 500 MHz) 5 7.8 (1H, width), was poured into diluted aqueous ammonium chloride and 1.55 (2H, m), 7.40 (2H , m), 4.4-4.5 (1H, m) 3.95 (2H, diethyl ether. The ether layer was separated, and the aqueous m), 3.33 (1H, m), 2.75 (1H, m ), 1.82 (1Н, m), 1.5 (1Н, additionally extracted with diethyl ether m. Volume, m), 1.38 20 (TN, m), 0.88 (6Н, dd). and obtained ether extracts were washed with saturated saline solution, dried with magnesium sulfate and 2,2,3,3,3-pentafluoro-1-(4 The -pyridine-4- agent was removed in vacuo. The residue was purified in iphenyl)propyl-leucinamide 5IO" using ethyl acetate and hexanes (1:1) as To solution M T015)71-(4-bromophenyl)-2,2,3 ,3,3- eluent, with further dilution in diethyl-pentafluoropropyl|-M'-(cyanomethyl)--leucinamide ether to obtain the spo- (B2 mg, 0.18 mmol), 4-pyridylboronic acid indicated in the title. (Zomg, 0.24 mmol) and RasSighharri) (14 mg, 0.02 mmol) in

IN NMR (COzSOSO») 5 8.15 (1H, sho), 8.05 (2H, 2.5 ml dmMf added 2M MagOz (0.25 ml). Mixture d), 8.0 (2H, d), 7, 8 (?H, d), 7.65 (2H, d), 4.35-4.45. heated to 95 s for 2.5 hours, then cooled (In, m), 3.35-3.45 (In, mM), 3.2 (ZH, s), 2.65-2.7 (In , chewed and distributed BETWEEN water Ma?goO»z and efim), 0.85-0.95 (VN, m). solution and dried over Mazo". Cleaning chrome-

Example 11 by tography on silica gel (6595-9595 ethyl acet-

Synthesis of M1-(cyanomethyl)-M2-((15)-2,2,3,3,3-tat/hexane gradient) afforded the title compound. pentafluoro-1-(4-pyridin-4-ylphenyl)propyl||-- H NMR (СО3СОСО:з, 500MHz) 5 8.66 (2Н, m), leucinamide 7.85 (1Н, ext.), 7, 81 (2H, m), 7.70 (2H, m), 7.62 (2H,

M), 4.5-4.6 (1Н, m), 3.95 (2Н, m), 3.4 (1Н, m), 2.81

(1H, m), 1.88 (1H, m), 1.55 (1H, m), 1.42 (1H, m), 0.92 were washed with ethyl acetate (2x50ml). Combined organic (6H, dd). the layers were washed with a saturated saline solution,

Example 12 was dried with magnesium sulfate and the solvent was removed

Synthesis of /M1-(1-cyanocyclopropyl)-M2-((15)-2,2- in vacuum to obtain a residue that was purified on difluoro-1-4-(methylsulfonyl)-1,1-diphenyl-4-5IO» using a gradient of hexane and ethylacetyl)-leucinamide (80:20-60:40) as eluent to give the title compound. in IN NMR (СозСОСОО) 5 7.6 (2Н, d), 7.45 (2Н, d),

BE and Zone 6.0 (1H, dt), 4.25 (1H, m), 3.65 (1H, t), 3.5-3.55 (1H,

X A m), 3.3-3.35 (1Н, m), 2.55-2.65 (1Н, m), 2.15-2.25 (1Н, g ЗЖ ох m), 1.6 -1.7 (1Н, m), 1.3-1.4 (1Н, m), 1.2-1.3 (1Н, m),

OD and 0.9 (ZN, d), 0.8 (ZN, d). o r M Stage 4: Preparation of M-(15)-1-(4-bromophenyl)- in 4 2,2-difluoroethyl|--leucine

Sn The NeiIov/StOz suspension (5.5 ml of 0.40 M in SNzOM; see Note below) was cooled to 0"C and added

Stage 1: Preparation of (25)-1-(Tretyl solution of alcohol from stage C (250 mg) in butyl(dimethyl)silyl|oxy)-4-methylpentan-2-amine CHzCM (3.7 ml) was added dropwise. The mixture was stirred at 0-57

Obtained as in stage 1 of Example 8. within 3.5 hours. After this period was added

Stage 2: Obtaining (25)-1-Chret-2.Oml oxidant. After 1.5 hours, the mixture was poured into butyl(dimethyl)silyl|oxy)-M-(1 E)-2,2-Mag2HPOX buffer (0.4 g in 1 Oml) with intensive difluoroethylidene|-4-methylpentan-2-amine stirring , and the mixture was extracted with diethyl

A mixture of (25)-1-TsChret- with ether (3x20ml). The combined ether layers were washed with butyl(dimethyl)silyl|oxy)-4-methylpentan-2-amino ly water and saturated saline solution (11), (8.5 g, 36 dmol) and difluoroacetaldehyde ethyl hemia-diluted aqueous Manzose and saturated salt cetal (5.0 g, 39.7 mmol) in benzene was heated with this solution. The organic extract was dried in a reflux condenser with a Dean-Stark nozzle with magnesium foil, filtered, and the solvent was evaporated overnight. The solvent was removed in vacuo. The solids to dryness, obtaining the excess specified in the title, were passed through a short column of silica compound, which was used without additional co-gel and eluted with hexane-EuAc (1071) to obtain. of the compound specified in the title in the form of bDdo- Note: oxidizing reagent (NviOv/SgOz) ready- yellow oil. shafts as described in |Teigapeidgop Getseg5 39 (1998)

IN NMR (COzSOS0O»z) 6 7.72 (m, 1H), 6.12 (dt, 5323-5326), but using CH2SM of purity 1H), 3.70 (dd, 1H), 3.54 (dd, 1H), 3.36 (m, 1H), 1.48 HPLC (contains 0.595 water); no water was added. (m, 2H), 1.32 (m, 1H), 0.95-0.78 (m, 15H), 0.06 (s, IN NMR (SOZZSOSO) 5 7.55 (2H, d), 7 ,4 (2H, d),

ZN), 0.02 (c, ZN). 6.05 (1H, dt), 3.95-4.05 (1H, m), 3.45 (1H, t), 2.7-3.0

Stage 3: Obtaining /(25)-2-C(15)-1-(4- (sm, MH/OH), 1.85-1.95 (1H, m), 1.5 (2H, t) , 0.95 bromophenyl)-2,2-difluoroethylamine)-4-methylpentane- (ZH, d), 0.9 10 (ZH, d). 1-ol Stage 5: Preparation of M2-(15)-1-(4-bromophenyl)-

H-Vycy (2.5 M in hexane, 1.4 ml) was added to - 2,2-difluoroethyl|-M!-(1-cyanocyclopropyl)| - 70"C TgF (8.5 ml) solution of 1,4-dibromobenzene leucinamide (884 mg) and the mixture was stirred for 15 minutes. To DMF (2 ml) acid solution from Stage 4

Then THF (8.5 ml) was added dropwise, the solution (258 mg) was added /O-(7-azabenzotriazolyl)-(25)-1-CH tert-butyl(dimethyl)silyl|oxy)-4-methyl- | M,M,M',M'-tetramethyluronium hexafluorophosphate

A mixture of M-(1TE)-2,2-difluoroethylidene|pentan-2-amine (1.0 g) and (337 mg) and 1-aminocyclopropanecarbonitrile was stirred for 1.5 hours. Danu su- chloride (175mg). After stirring for a while, the mixture was then slowly poured into ice-saturated water for 1 minute, an aqueous solution of ammonium chloride (0.45 ml) was added dropwise, and the mixture was stirred for 16 hours. stirring and extracted with parts The resulting mixture was poured into saturated ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate and extracted with ethyl saturated saline, dried with sulfaacetate (33x5ml). The combined extracts were washed with magnesium and the solvent was removed in a vacuum with a saturated saline solution, the residue was dried under vacuum, which was purified at 510°C using magnesium sulfate, and the solvent was removed in a vacuum. using a gradient of hexane and ethyl acetate (90:10- The residue was purified by chromatography on 5 g of 75:25) as an eluent to obtain (25)-M-(15)-1-(4) using hexane and ethyl acetate (80:20-50 :50) bromophenyl)-2,2-difluoroethyl|-1-Ctret- to give the title compound. butyl(dimethyl)silyl|oxy)-4-methylpentan-2-amine. IN NMR (СО3СОСО») 5 8.05 (1Н, m), 7.55 (2Н, (25)-М-(15)-1-(4-Bromophenyl)-2,2-difluoroethyl|-1- Dd ), 7.4 (2H, d), 6.05 (1H, dt), 3.95-4.05 (1H, m), 3.25-

Tert-butyl(dimethyl)silyl|oxy)-4-methylpentane-2- 3.3 (1H, m), 2.4-2.45 (1H, m), 1.8-1.9 (1H, m ), 1.4-1.55 amine (200 mg) was dissolved in CH3CM (4 ml) and a solution (2N, m), 0.95-1.1 (2N, m), 0.95 (6N, t). was cooled to 0"C. HE was added dropwise. Stage 6: Preparation of M!-(1-cyanocyclopropyl)-pyridine (40 μl) and the mixture was reacted for 16 m2-((18)-2,2-difluoro-1-(4 -(methylthio)-1,1"-diphenyl-4-hour. The mixture was poured into a saturated solution of bicaryl|stil)-leucinamide sodium bonate, ethyl acetate was added, and the resulting suspension was passed through a stream of nitrogen, and the resulting mixture was vigorously shaken. Organic aryl bromide from stage 5 (b5mg), the 4th layer was separated, and the aqueous layer was additionally extracted with (methylthio)phenylboronic acid (40mg), 2M

MagSo" (0.22 ml) and DMF (1.0 ml) for 5 minutes. saturated aqueous MNASI was added to the mixture

Rasizharri) was then added and the reaction mixture was extracted twice with EAs. The combined organics were heated to 80"C and stirred in a nitrogen atmosphere, and the extracts were washed with saturated saline for 4 hours. The mixture was cooled to room temperature, dried over anhydrous MdzaOx and concentrated at a temperature, diluted with ethyl acetate (20 ml) and poured into oil (5.3g). The crude oil (2.0g) was then poured into a saturated solution of sodium bicarbonate. treated with (Vy) AME (bml, 1M in THF). The mixture was re-

The ethyl acetate layer was separated and the aqueous layer was additionally stirred at room temperature during extraction with ethyl acetate (2 x 5 ml). Combined for 1 hour, saturated aqueous MNACI was added, and the mixture of ethyl acetate extracts was washed with saturated sodium chloride and extracted with EIOAc twice. The organic compounds were combined with an aqueous solution and dried with magnesium sulfate. The samples were washed with a saturated saline solution, removal of the solvent left a residue, which was dried over anhydrous Md5Ox and concentrated until purified by chromatography on 5 µOg using oils. Chromatography (2095 EtOAc/hexane) with a gradient of hexane and ethyl acetate (90:10-50:50) gave the title compound. washing the named compound. Stage 2: Obtaining M-K15)-1-(b-chloropyridine-

IN NMR (COz3СОС0Oz) 6 8.1 (1Н, m), 7.6-7.65 (4Н, 3-yl)-2,2,2-trifluoroethyl! - leucine

M), 7.45 (2Н, d), 7.35 (2Н, d), 6.05 (1Н, dt), 3.9-4.0 A matrix solution of NeIov/SgOz solution was prepared (ТН, m) . 138mgH, 1.8-1.9 (1H, m), 1.3-1.5 (AN, m), 0.85-1.0 (8H, m). 1.2moloo) in SNIzSM (684 ml) with the receipt of 0.44M

Stage 7: Preparation of M!-(1-cyanocyclopropyl) solution. To a solution of HviOv/SgOz (1bmmol, Zbml, m2-(15)-2,2-difluoro-1-I4-(methylsulfonyl)-1,1"- 0.44M in THF) at -57C (ice and salt bath) diphenyl-4-yl|ethyl)-leucinamide was added to a solution of (25)-2-4(15)-1-(b-chloropyridin-3-

To a solution of the sulfide (5 mg) from stage 6 in toluene-yl)-2,2,2-trifluoroethylamine-4-methylpentan-1-ol (1.0 ml) and ethyl acetate (0.1 ml) was added Mother O4 (1 g ) in Zml THF drop by drop. Monitored internal 2NgoO (mg) and Via4MNBO" (2mg). Then 3095 hydrogen peroxide (ZOmcl) was slowly added to the temperature and the reaction temperature was not given, and the mixture was ground to rise above 0"C. The reaction was monitored with a sieve at room temperature for 1.5 hours using thin-layer chromatography until the end. The mixture was poured into a diluted aqueous reaction solution (3-4 hours). Sodium thiosulfate and ethyl acetate were added to the reaction mixture. The organic was washed with MagzhHPO4 (8 Oml), which was then extracted, the layer was separated, and the aqueous was additionally extracted with EtOAc. The organic extract was washed with saturated ethyl acetate (2 x 10 ml). The combined organic layers were washed with saline, ManzoOz (120 ml) and again saturated with saturated saline, dried with saline, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo - MBO" and concentrated to an oil. The oil was washed again to obtain a residue, which was purified on SiO», dissolved in EAc and filtered through a thin layer of silica gel using hexane and ethyl acetate (50:50-0:100), eluted with EtOAc and The filtrate was then concentrated with dichloromethane and diethyl ether (90:10) to obtain the title compound as an eluent to obtain the title compound. meadows Stage: 3: Obtaining Mm2-((15)-1-(6-

IN NMR (COZSOSO) 5 8.15 (1H, m), 8.0 (2H, d), chloropyridin-3-yl)-2,2,2-trifluoroethyl|-M-(1- 7.95 (2H , d), 7.75 (2H, d), 7.55 (2H, d), 6.1 (1H, dt), cyanocyclopropyl)! -leucinamide 4.0-4.1 (1H, m), 3.25-3.35 (1H, m), 3.15 (ЗН, с), 2.А- To a solution of crude acid (0.73 Hg, 2.5 (1N, m), 1.8-1.9 (1N, m), 1.4-1.55 (AN, m), 0.85- 2.25mMmMol) from stage 2 in DMF (12ml ) added 1-1.05 (8Н, m). aminocyclopropanecarbonitrile hydrochloride (0.4g,

Example 13 3.37 mmol) and NATY (0.86 g, 2.25 mmol). They added

Synthesis of /M2-(15)-1-(6-chloropyridin-3-yl)-2,2,2-diisopropylethylamine (1.96ml, 11.24mmol), a mixture of trifluoroethyl|-M!-(1-cyanocyclopropyl)| - stirred at room temperature for leucinamide for 20 hours. E(Ac) and water were added. The mixture was separated after stirring, and the organic extract was washed

SNU was filled with water and a saturated saline solution, and

E E E were washed over anhydrous Md5O4. Concentration of or

From the aqueous extract followed by chromatography with M (30-5095 EOAc/hexane) gave the indicated in the title

M x nm compound. cm o t M5 (CHE51I): 389.3 (M-11U.

MIN NMR (СОз3СОСОз, 500MHz): b 0.92 (d, ZN,

And uU-6.6Hz), 0.93 (d, ZN, 9U-6.6Hz), 1.00 (m, 1H), 1.09

Stage 1: Obtaining / (25)-2-(Ш15)-1-(6-(m, ТН), 1.45 (m, 4Н), 1.90 (m, 1Н), 2.81 (m, 1H), 3.43 chloropyridin-3-yl)-2,2,2-trifluoroethylamine)-4-(m, 1NH, 4.47 (m, 1H), 7.54 (d, 1H, 9-8, 3Hz), 7.98 (d, methylpentan-1-ol, 1TH 0-6.2Hz), 8.1 (s, 1H), 8.5 (s, 1H).

To a solution of 5-bromo-2-chloropyridine (2.5 g, Example 14

n-Synthesis of M2-C15)-1-I6-(4-acetylphenyl)pyridine-3-butyllithium (13mmol, 2.5M in hexane). A mixture of per-yl|-2,2,2-trifluoroethyl)-M-(1-cyanocyclopropyl)!. - stirred at -78"C for 1 hour. Added (25)-leucinamide 1-tert-butyl(dimethyl)silyl|oxy)-4-methyl-M-

ITE)-2,2,2-trifluoroethylidene|Ipentane-2-amine (3.64g, 11.7mmol, see Step 2, Example 8). The mixture was stirred at -78"C for 2 hours. Before the reactions

E Chiral (2H, m), 2.55-2.75 (2H, m), 1.4 (9H, s).

E. E Stage 2: Preparation of benzyl(45)|-2-oxo-1,3- sn, oxazolidin-4-ilyacetate with di To a solution of alcohol (95.77) from stage 7 in dichloro-! (925 ml) was added pyridine (625 ml) and the mixture was cooled to 0-57. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added, and the mixture was warmed to room temperature and stirred for 1 hour, and then heated to 907C for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 ml) and washed with N.O

To the solution /MA-(15)-1-(b-chloropyridin-3-yl)- (300 ml). The organic layer was washed with saturated 2,2,2-trifluoroethyl|-M!-(1-cyanocyclopropyl)-salt solution, dried with sodium sulfate and leucinamide (100 mg, 0.2 mmol) in toluene (1.5 ml) and the solvents were removed in vacuo . The residue was purified n-propanol (0.4 ml) was added in a stream of nitrogen 4-chromatography on 5iO2 using ethylacetate (acetyl)phenylboronic acid (55mg, 0.3Zmmol), tat and hexane in a ratio of 1:1, then ethylacetate-

RF(RRNZ3)a (15mg, 0.01Zmmol) and Mag6CO3 (2M, 0.5ml). volume 3 by obtaining // benzyl(45)|-2-oxo-1,3-

The mixture was degassed with a rapid flow of nitrogen, barbo-oxazolidin-4-yl|acetate. passing through the mixture, and the mixture was heated to 150"7C in an IN NMR (СО350С0Оз) 5 7.8 (1Н, МН), 7.3-7.45 microwave reactor 5 type Sgeayog (Reggopai (BN, m), 5.05- 5.15 (2H, m), 4.4-4.5 (1H, m), 41-42

Spetizigu AV, Orrzaia, Zuluedep) during 8b0Osec. (1H, m), 4.0-4.05 (1H, m), 3.6-3.8 (2H, m).

The mixture was cooled, diluted with E(OAc and washed with water. Chromatography (50956 EtOAc/hexane) methylpropyl)-1,3-oxazolidin-2-one gave the compound indicated in the title.

M5 (TE5I): 473.2 (MAG. til ether) was added to the toluene mixture

IN NMR (500 MHz, COzSOSO:"): 6 0.93 (d, ZN, (Z340ml) and THF (340ml) at -207C. Then y-6.6Hz was added), 0.94 (d, ZN, U- 6.6 Hz), 1.07 (m, 1H), 1.40 dropwise warm THF solution (170 ml) ether (m, 2H), 1.49 (m, 1H), 1.55 (m, 1H ), 1.92 (m, 1H), 2.66 from stage 2 (40g), keeping the temperature below - (c, ЗН), 2.83 (m, 2H), 3.45 (m, 1H), 4 .50 (m, 1H), 8.15 102C. The mixture was kept for 2 hours, and after (m, 5H), 8.30 (d, 2H, U-8.5Hz), 8.79 (s, 1H). then water (1000 ml) was slowly added to the mixture and

Example 15 of acetic acid (200ml) and the resulting

Synthesis of M!-(1-cyanocyclopropyl)-4-fluoro-Me- the mixture was stirred for 2 hours at room

C15)-2,2,2-trifluoro-1-14-(methylsulfonyl)-1,1- at the temperature. The aqueous layer was separated, and the organic diphenyl-4-yl|ethyl Y--leucinamide layer was extracted with water (2 x 200 ml). The product was extracted from the combined aqueous layers using

Adding dichloromethane and the extraction apparatus without

SE N m of intermittent action. The dichloromethane extract was evaporated to dryness using heptane as a co-solvent for the azeotropic distillation of acetic acid. The residue was purified by column chromatography using ethanol and dichloromethane (1:30) to give (45)-4 -(2-hydroxy-2-methylpropyl)- by 11,3-oxazolidin-2-one. 1

Stage 1: Obtaining benzyl(35)-3-(tert-4 55 pn btdon muz UNO M) From butoxycarbonyl)amino|-4-hydroxybutanoate (in c) 165-185 (2n m), 1 25 (vn m). shi

M-(tert-butoxycarbonyl)! -aspartic /acid- "Stage u. Preparation of (48)-4-(2-fluoro-2-lot 4-benzyl ether (30g) was dissolved in dimethyl-methylpropyl)-1,3-oxazolidin-2-one xyetane (FOml ) and the solution was cooled to -576 Dichloromethane solution (100 ml) of alcohol

M-methylmorpholine (10.32 ml) was added from the (47.8 g) from stage C was added to the solution of tryptose by the slow addition of isobutyl chloroformate ridi(diethylamine)sulfur (48.97) in dichloromethane (12 6 bml) so that the reaction temperature is maintained (500 ml) at -70260. The mixture was heated to room temperature below -10 °C. The mixture was kept at room temperature and stirred for 1 hour. 0.5 hours. The solids were quickly filtered and then the mixture was carefully added to the mixture at 0" washed with dimethoxyethane (30 ml). The filtrate was saturated aqueous MansoOz (800 ml). The organic was cooled to -50°C. The solution was slowly added. The layer was separated and washed with saturated aqueous sodium borohydride (4 ,47) in water (45 ml), so that Mansoz. The aqueous layer was additionally extracted with dichloromethane (100 ml) and combined dichloromethane 1570. Then water (500 ml) was added, so that tem - the layers were dried and concentrated. The residue was purified, the temperature of the reaction mixture was kept below - by chromatography at 5iOg using ethyl acetate. (45)-4-(2-fluoro-2-methylpropyl)-1,3-benzyl(38)-3-(tert-butoxycarbonyl)amino|-4-oxazolidin-2-one" hydroxybutanoate. IN NMR (COz50С03) 5 7.6 (1Н, МН), 4.4-4.5 "N-NMR (СО3СОС0О») 6 7.3-7.45 (5Н, m), 5.85- (1Н , m), 3.95-4.05 (1Н, m), 3.9-3.95 (1Н, m), 1.8-1.95 5.95 (1Н, МН), 5.15 ( 2H, c), 3.95-41 (2H, m), 35-87... (on, m), 1.25-1.4 (VN, 26).

Stage 5: Preparation of (25)-2-amino-4-fluoro-4-methylpentan-1-ol The same procedure was repeated on a larger scale using 1,4-dibromobenzene (1.2 g),

To the solution of the fluorine derivative (21.0 g) from stage 4 in H-Via (1.4 ml) and imine (1.38 g) and the reaction mixture in aqueous ethyl alcohol (21 b ml) were added and the procedure was as indicated above. Combined residues of two potassium hydroxides (21.9g). The mixture was heated to reflux, dissolved in THF (10 ml) and cooled in a refrigerator for 4 hours and cooled to 0. Fluoride was added and brought to room temperature. Then, the mixture of tetrabutylammonium (bml with 1M THF solution) was centrifuged and co-evaporated with toluene, stirred at 5°C for 16 hours. stirred for 0.5 hour. Su- (1g) and crushed ice and separated the organic layer. The suspension was filtered through Celite and the Celite was washed. The aqueous layer was additionally extracted with ethyl acetate-dichloromethane (3x100ml). The filtrate was concentrated (2x15ml) and the combined organic the layers were dried and concentrated to dryness to obtain (25)-2-amino-4-fluoro-4-. The residue was purified on 5O2 using methylpentan-1-ol.

IN NMR (COzO0) 5 3.4-3.5 (1H, m), 3.2-3.3 (1H, (25)-2-4(15)-1-(4-bromophenyl)-2, 2.2- m), 3.0-3.1 (1Н, m), 1.5-1.7 (2Н, m), 1.95 (ЗН, с), 1.3 trifluoroethylamine)-4- fluoro-4-methylpentan-1-ol. (ZN, p.). IN NMR (COzSOSO:) b 7.65 (2Н, m), 7.5 (2Н, m),

Stage 6: Obtaining (25)-1-Quarter- 4.5-4.6 (1H, m), 3.8 (1H, m), 3.6 (1H, m), 3.3-3.4 (1H, butyl(dimethyl)silyl|oxy)-4-fluoro-4-methylpentane-m), 2.85-2.0 (1H, m), 2.55 (1H, m), 1.7-1 ,9 (2H, c), 1,3-2-amine 1,4 (6H, m).

The amino alcohol (21.0g) from stage 5 was dissolved in dichloromethane (300ml) and the solution was cooled to 0°C. 2,2,2- trifluoroethyl|-M!-(1-cyanocyclopropyl)-4-I -

4-(Dimethylamine)pyridine (0.051g) and tert-butyldimethylsilyl chloride (21g) were added, then triethylamine was added. to 0"C and added at temperature during the night. The reaction mixture was added dropwise to the solution of alcohol from stage 8 (1.55g) in CH3ZSM and saturated aqueous chloride (ml) was slowly poured into 0"C. The mixture was stirred at 0-57C for 3.5 ammonium and extracted with dichloromethane (3x30Oml). hours The mixture was poured into Mag2HRO»h: rnai (200 ml)

The organic layer was washed with saturated saline with intensive stirring and the mixture was extracted with a solution, dried with sodium sulfate, and dissolved in diethyl ether (3x5Oml). The combined ethers were removed in a vacuum to obtain (25)-1-Ct. ), then with diluted aqueous 2-amine. Manzose and saturated saline solution. Mixture

IN NMR (COzO0) 5 3.6-3.65 (1Н, m), 3.4-3.5 (1Н, dried with sodium sulfate, filtered and solution-m), 3.1-3.2 (1Н, m), 1.6-1.8 (2Н, m), 1.35-1.45 (6Н, m), were evaporated to dryness to obtain М-|(1 5)-1- 0.93 (9Н, c), 0.1 (6H, c). (4-bromophenyl)-2,2,2-trifluoroethyl|-4-fluoro-i -

Stage t: Preparation of (25)-1-Tret-leucine, which was used as such in the next butyl(dimethyl)silyl|oxy)-4-fluoro-4-methyl-M- stage.

IT E)-2,2,2-trifluoroethylidene|pentan-2-amine Note: oxidizing reagent (NeIov/SgOz)

Trifluoroacetaldehyde me- (1998) 5323-5326) was added to a solution of the amine (31.5 g) from stage 6 in benzene as described in (Heijgapedop Heineg 5 39 (126 ml), but using CHzSM tilhemiacetal (21.bml). The solution was heated with HPLC grade (contains 0.595 water); water was not used in the refrigerator during the night. using a Dean-Stark nozzle to collect water. Diisopropylethylamine (4.2 ml) was added to 0"C

The reaction mixture was cooled to room temperature, the acid suspension (1.5 g) indicated above, 1-amino-1- temperature and concentrated to dryness. The residue of cyclopropanecarbonitrile hydrochloride (1.18 g) was oxidized to 5 µg using 495 g of ethyl acetate in (7-azabenzotriazol-1-yl)-M,M,M'M'-hexane to give (25)-1-CChteret - tetramethyluronium hexafluorophosphate (1.94 g) and dibutyl(idimethyl)silyl|ioxy)-4-fluoro-4-methylpentane-methylformamide (5 ml) and the mixture interacted with 2-amine. at room temperature for 48 hours. Then the mixture

IN NMR (СОз3СОСОз) b 7.9-7.95 (1Н, m), 3.75- poured on ice and diluted aqueous chloride 3.85 (1Н, m), 3.7-3.75 (1Н, m ), 3.53-3.6 (1H, m), 1.9-ammonium. The mixture was extracted with ethyl acetate and ether 2.0 (2Н, m), 1.3-1.4 (6Н, m), 0.9 (9Н, с), 01 (ЗН, с), rum (1:1) and the combined organic layers were washed with 0.05 (ZH, c). diluted MagHRO» pH 3 and saturated saline

Stage 8: Preparation of /(25)-2-((15)-1-(4- solution. Solvents were evaporated to dryness and bromophenyl)-2,2,2-trifluoroethyl|amine)-4-fluoro-4- residue was purified by chromatography on 51O2 using methylpentan-1-ol, ethyl acetate and hexane (1:2) to obtain

A solution of 1,4-dibromobenzene (0.26 g) in Me-(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|-M!-(1-

THFf (4 ml) was added to H-Vygi (0.42 ml of a 2.5 M solution of cyanocyclopropyl)-4-fluoro-I-leucinamide in dosat-hexane) and the mixture was kept for 20 minutes. nth degree of purity for the next stage.

Imine (0.329 Hg) from stage 7 was added in THF (2 ml) and su- IN NMR (SOZZSOSO:) 5 8.15 (1H, MH), 7.6 (2H, the mixture was kept for 2 hours. Then the mixture was added m), 7.45 (2H, m), 4.35-4.45 (1H, m), 3.45-3.55 (1H, m), to a mixture of water (5Oml), MNASI (1g) and crushed 1, 9-2.1 (2Н, m), 1.75-1.85 (1Н, МН), 1.35-1.55 (8Н, ice. The mixture was extracted with ethyl acetate (2x25 l) m), 1.1- 1.15 (1N, m), 0.95-1.05 (1N m). and the combined ethyl acetate layers were dried and evaporated to dryness. 4-fluoro-M2-(18)-2,2,2-trifluoro-1-(4-(methylthio)-1,1"-

diphenyl-4-yl|ethyl)-leucinamide hydrochloride

A stream of nitrogen was passed through a suspension of bromoracemic diastereomeric mixture of ethyl M-mid from stage 9 (0.338 ), 4-benzoyl-5,5,5-trifluoroleucianate (10.Og, (methylthio)phenylboronic acid (0.252g), 2M 31, 5 mmol), obtained according to the method of aqueous MagSO3 (0.8 ml) and DMF (4 ml) within 15 hours. a!y (U. Ogd. Spet., 1989, 54, 4511-4522, minutes. Then Rasi" arri (0. g) was added and the reaction was heated under reflux in 6M; the aqueous mixture was heated to 85"7C and stirred at - of NCI (100 ml) for 16 hours. After cooling in a nitrogen atmosphere for 5 hours. The cooling mixture was washed with ESO and concentrated in a column to room temperature, diluted under vacuum to obtain racemic diastereomer ethyl acetate (1 ml) and poured into water (5 ml ) and an aqueous mixture of 5,5,5-trifluoroleucine NH salts, ice. The ethyl acetate layer was separated, and the aqueous layer was NMR (Methanol-34) 6 4.10 (m, 1H), 2.65 (m, additionally extracted with ethyl acetate. Combined 1H), 2.35-1.80 (m, 2H), 1.25 (m, 3H). ethyl acetate extracts were dried and solvents of the form Stage 2: Methyl(45)-M-K(benzyloxy)carbonyl |- was poured in vacuo. The residue was purified by chromatography of 5,5,5-trifluoro-I-leucinate and methyl(4Kk)-M-Kbenzyl on 5iO" using ethyl acetate and hexane (1:2) with oxy)carbonyl|-5,5 ,5-trifluoro-I-leucinate by obtaining M1-(1-cyanocyclopropyl)-4-ft or-M2- To a cold (072) salt solution of 5,5,5- (15)-2,2,2-trifluoro-1-(4-(methylthio)-1,1-diphenyl-4- trifluoroleucine NS (with stage 17 above) in H2«E il|Stil )E-leucinamide. (ZOml) was added 1M aqueous Mahon (boml,

IN NMR (COzSOSO»z) 6 8.15 (1H, MH), 7.1-7.2 bomol), then acetic anhydride (3.5ml, (AN, m), 7.5-7.55 (2H , m), 7.35-7.4 (2H, m), 4.3-44 36.7 mmol). The mixture was stirred at room (IN, m), 3.45-3.55 (IN, m), 2.75-2.8 (IN, MH), 2.5 temperature for 3 min-1 h. After acidification (ZH, s), 1.9-2.05 (2Н, m), 1.3-1.5 (8Н, m), 1.0-1.1 (IN, b6M aqueous NSI (bml) , the mixture was extracted with EtOAc m), 0.85-0.95 (1H, m). (6x). The combined EIOAc extracts were washed with saturated

Stage 11: Preparation of M1-(1-cyanocyclopropyl)- with salt solution, dried (Ma5O") and concentrated 4-fluoro-M2-(15)-2,2,2-trifluoro-1-|4-. The residue was diluted with hexane: ESO (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl - (17) To obtain trifluoroleucine M-acetyl-5,5,5-leucinamide in the form of a white solid.

To a 0"C sulfide solution (0.265 g) from stage 10. To a suspension of M-acetyl-5,5,5-trifluoroleucine in toluene (5Xml) and dichloromethane (5ml) was added (4.2g, 18.5mmol) in HgO (35ml ) added 1M water

MaguMO4-2H2O (0.002g) and H-Vy«MNZOH (0.01g). Then Mahon (18.5 ml, 18.5 mmol) mixture was stirred and slowly added 3095 hydrogen peroxide (0.137 ml) and stirred for 15-30 minutes. to obtain a homogeneous mixture, the solution was stirred at room temperature. Acylase I EU 3.5.1.14 was added, from within 3 hours. The mixture was slowly poured over Zidt, Sai. Zh A 3010; 55 mg the mixture was stirred with a mixture of ice, diluted aqueous thiosulfate at room temperature overnight. NMR of non-sodium and ethyl acetate. The organic layer was separated, and a large aliquot (evaporated in vacuum) of crude aqueous was additionally extracted with ethyl acetate. substances showed a ratio of 53:47 for the beginning

The combined organic layers were washed with saturated solvent and product. Then the mixture was acidified with a saline solution, dried with magnesium sulfate and 6M aqueous HCl (43.5 ml) and extracted. ). Combined EIUAs extracts in ethyl acetate, hexane and dichloromethane (1:1:0.1) as eluent. filled with a saturated saline solution, dried

The residue was triturated in diethyl ether (M95054) and concentrated to obtain crude M1-(1-cyanocyclopropyl)-4-fluoro-Me2- M-acetyl-5,5,5-trifluoro-O-leucine in in the form of (C15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"- a pale yellow solid (cCho-i 27.67 (c 1.5, diphenyl-4-yl ((ethyl)-leucinamide. EYN). The aqueous layer was concentrated in a vacuum and dried

IN NMR (COzSOSO»z) 6 8.2 (1Н, МН), 8.05-8.1 was carried out in a vacuum overnight to obtain 5.5.5- (2Н, m), 7.95-8.0 (2H, m), 7.8 (2H, m), 7.65 (2H, m), trifluoro-I-leucine, possibly contaminated by Masi and 4.35-4.45 (1H, m), 3.5 -3.6 (1H, m), 3.2 (ZN, s), 2.8-2.9 NOI salts, TsOCh--4.17 (s 0.77, NgO). (IN, МН), 1.9-21 (2Н, m), 1.3-1.5 (8Н, m), 1.05-1.15 To the mixed solution of 5,5, 5-trifluoro-і1 - (1 N, m), 0.9-1.0 (1 N, m). leucine (12g) in HgOo (150ml) at 0"С was added

Example 16 benzyl chloroformate (4.6 ml, 34 mol), followed by

Synthesis of (45)-M'-(1-cyanocyclopropyl)-5,5,5- by dropwise addition of 1M aqueous Mmaon (120 ml, trifluoro-M2-((15)-2,2,2-trifluoro-1-|4 - 120 mmol). Benzyl chlorophospho-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl dimethyl (4.8 ml, 34 mmol) was additionally added. The mixture was additionally stirred with leucinamide at 0"C and the pH of the mixture became - 7. The mixture was washed with ESO (2x) and acidified with aqueous HCl.

The SEZ bottom layer was extracted with EUAs (3x), dried

Eh huh. (Ma»5Oy) and concentrated in a vacuum to obtain

M M-I-Kbenzyloxy)carbonyl|-5,5,5-trifluoro-i - yar o t m i. of leucine. The crude acid was dissolved in ESO

They and A were treated with a solution of diazomethane in ESO. Chromatova d-o, ; Graphing through silica gel and elution with hexane (7:3) gave methyl (45)-M-(benzyloxy)carbonyl 5,5,5-trifluoro-I-leucinate in the form of a less polar fraction .

Stage 1: Obtaining the salt 5,5,5-trifluoroleucine IN NMR (Acetone-dv) 5 7.45-7.25 (m, 5H), 6.86 (d,

1H), 5.10 (m, 2H), 4.38 (m, 1H), 3.70 (s, ЗН), 2.45 (m, salt solution, dried (Mdzoz) and concentrated - 1H), 2 .05 (m, 1H), 1.85 (m, 1H), 1.16 (d, ЗН). shafts Chromatography through silica gel and elution

Additional elution gave (4k)-M-hexane'E(OAc (4:11) gave the title compound (benzyloxy)carbonyl|-5,5,5-trifluoro-1-leucinate as a pale yellow oil. more polar fraction contaminated with a small amount of benzyl alcohol 4.58 (m, 1H), 7.60 (d, 2H), 7.48 (d, 2H) (t, 1H), 3.45 20 (m, 2H), 2.90 (m,

IN NMR (Acetone-av) 5 7.40-7.25 (m, 5H), 6.86 (d, 1H), 2.70 (m, 1H), 2.25 (m, 1H), 1, 75 (m, 1H), 1.45 (m, 1H), 5.08 (s, 2H), 4.35 (m, 1H), 3.70 (s, ЗН), 2.54 (m, 1H )U, 1.14 (d, ZN). 1H), 2.20 (m, 1H), 1.75 (m, 1H), 1.16 (d, ЗН). Stage 6: (45)-M-((15)-1-(4-bromophenyl)-2,2,2-

Stage 3: (25, 45)-2-amino-5,5,5-trifluoro-4-trifluoroethyl)|-5,5,5-trifluoro-I -leucine methylpentan-1-ol The title compound was obtained as

To the methyl(45)-M- solution described in step 9, Example 15 with (25,45)-2-C(15)-(benzyloxy)carbonyl/|-5,5,5-trifluoro-Y-leucinate 1- (4-bromophenyl)-2,2,2-trifluoroethylamine)-5,5,5- (5.4 g, 16.2 mmol) in EYN (150 ml) at room temperature trifluoro-4-methylpentan-1-ol. temperature, GG SI (2.8 g, bbmol) and a mixture of IN NMR (Acetone-adbv) 5 7.58 (d, 2H), 7.46 (d, 2H) were added, stirred for 10-15 min., followed by 4, 46 (m, 1H), 3.58 (dd, 1H), 2.80 (m, 1H), 1.92 (m, 1H), with the addition of Mavna (2.5 g, bbmmol). The mixture alternates with 1.72 (m, 1H), 1.20 (d, ZN). incubated at room temperature for 2 hours. Stage 7: (45)-M2-((18)-1-(4-bromophenyl)-2,2,2-

After diluting HgO (bOml), the mixture was quenched with 6M trifluoroethyl|-M!-(1-cyanocyclopropyl)-5,5,5- aqueous HCl (13ml). An additional amount of trifluoro-I-leucinamide was added

H2O and the mixture was extracted with EtOAc (2x). Combined The title compound was obtained as

EtOAc extracts were washed with saturated saline described in step 9, Example 15 with (45)-M-((15)-1- solution, dried (Mag25O4) and concentrated with (4-bromophenyl)-2,2,2-trifluoroethyl|d |-5,5,5-trifluoro- by obtaining crude benzyl(15,35)-4,4,4-Y leucine. shir.s, 1H), 7.59 (d, methylbutylcarbamate. 2H), 7.43 (d, 2H), 4.34 (m, 1H), 3.48 (m, 1H), 2.78 (m ,

The above-mentioned alcohol was dissolved in EYN 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.39 (m, 2H), 1.14 (d, (15O0ml) and added 1095 РО/С ("500 mg). Mixture of PE-ZN), 1.15-0.90 (m, 2H). stirred in the atmosphere of Ne (balloon) during the night. M5 (CHEBI): 486488 (MAG.

The catalyst was filtered through celite and the filter Stage 8: (45)-M!-(1-cyanocyclopropyl)-5,5,5-rate was concentrated to obtain the indicated -trifluoro-1-|4- trap compound in the form of a colorless oil. (methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl -

IN YAME (Methanol-az) 6 3.48 (dd, 1H), 3.38 (dd, leucinamide 1H), 2.85 (m, 1H), 2.50 (m, 1H), 25 1.62- 1.40 (m, 2H). The named compound was obtained as described for 1.12 (d, ЗН). In stages 10 and 11 of Example 15 with (45)-M2-((15)-1-(4-

Stage 4: (25,45)-1-Ct-bromophenyl)-2,2,2-trifluoroethyl|-M'-(1-butyl(dimethyl)silyl|oxy)-5,5,5-trifluoro-4- methyl-cyanocyclopropyl)-5,5,5-trifluoro-I-leucinamide.

M-(1E)-2,2,2-trifluoroethylidene|pentan-2-amine IsCho--662 (with 0.5, acetone). (25,45)-2-Amine-5,5,5-trifluoro-4-methylpentane- IN NMR (Acetone-dv) 5 8.20 (sh.s, 1H), 8.03 (d, 1-ol (2.6 g, 15.2 mmol) was converted to the indicated in 2H), 7.94 (d, 2H), 7.78 (d, 2H), 7.62 (d, 2H), 4.41 (m, title compound as described in stages 1 and 2, app. 1H), 3.52 (m, 1H), 3.17 (s, ЗН), 2.88 (m, 1H), 1.98 (m, order 8. 1H), 1.58 (m, 1H), 1.35 (m, 2H), 1.16 (d, ЗН), 1.15-

IN NMR (Acetone-dv) δ 7.98 (m, 1H), 3.80 (m, 1H), 0.85 (m, 2H). 3.60 (m, 2H), 2.18 (m, 1H), 1.98 (m, 1H), 1.65 (m, 1H), M5 (-E51): 562 (Ma11". 1.12 (d, ЗН), 0.88 (с, 9Н), 0.06 (с, ЗН), 0.02 (с, ЗН). Example 17

Stage 5: (25,45)-2-C(15)-1-(4-bromophenyl)- Synthesis of M-benzyl-1-(benzyloxy)-4-fluoro-4-2,2,2-trifluoroethylamino)-5, 5,5-trifluoro-4-methylpentan-2-amino methylpentan-1-ol Stage 1: Preparation of M-(tert-butoxycarbonyl)-

To a cold (-78"C) solution of /-1,4-4-methylenenorvaline dibromobenzene (7.0g, 29.7mmol) in EBO (75ml) To a solution of dehydro-I-leucine (2.00g, solution 2 was added dropwise .5M n-Vii in hexane 15.48mmol) and di-tert-butyldicarbonate (10.14g, (7.0ml, 17.5mmol) and the mixture was stirred for 46.4mmol) in THF (about 100ml) and water (about 2h . at -78"C. A solution of (25.45)-1-Ctret-5 Oml) was added, triethylamine (12.94 ml, butyl(dimethyl)silyl|oxy)-5,5,5-trifluoro-4-methyl- 92 .8 mmol). The reaction mixture was stirred at

M-CTE)-2,2,2-trifluoroethylidene|pentan-2-amine at ambient temperature for (3.7g, 10.1mmol) in a small amount of EBO and the mixture overnight. Citric acid was added (about 100 ml was additionally stirred at -78°C for a 1 M aqueous solution) and the product was extracted with additional Th. Then the mixture was quenched with NegO, extracted in 400 ml of methylene chloride. The organic phase was poured with E(OAc, dried (MazO ) and concentrated, dried with sodium sulfate, filtered and concentrated

The above-mentioned crude product was dissolved in THF and subjected to rotary evaporation. Purification (20ml) and HOAc (0.3ml) were added. After addition by chromatography on silica gel using 0- solution of 1M tetrabutylammonium fluoride in THF 10965 methanol in dichloromethane as eluent gave (20ml, 20mmol), the mixture was stirred at room temperature - the title compound. temperature during the night. The solvent was removed in vacuo, the residue was diluted with H2O and extracted with (hydroxymethyl)-3-methylbul-3-enylcarbamate with EUDAs. EAs extract was washed with a saturated solution of Bos-dehydro-i-leucine (2.84 g,

12 4 mmol) and 4-methylmorpholine (1.3 bml, 12.4 mmol) in dry THF (40 ml), equilibrated at 2- to -10"C, isobutylchloropho- benzyloxycarbonylamino-5,5,5 -trifluoro-pent-2-remate (1.6 mL, 12.4 mmol). The reaction mixture of daenoic acid was stirred for 30 minutes, and the precipitate was M-(Benzyloxycarbonyl)trimethyl ether removed by filtration. The filtrate was equilibrated with phosphoglycine and OBO were dissolved in dry methyl

while stirring, dichloromethane (5 mL) was added dropwise, and the reaction mixture was cooled with sodium borohydride (0.938 g, 24, mmol) to approximately -30°C. 3,3,3-Trifluoropropanal (1 equiv) was added to 10 ml of water. The reaction mixture was added dropwise to the cooled and stirred solution to ambient temperature, and the reaction mixture was left in the stirring medium and stirred for an additional hour at -30"C, and for an hour. The reaction was quenched with saturated aqueous bicarbonate overnight at ambient temperature with sodium bonate, and the product was extracted into ethyl acetate. Methylene chloride was added (about tat. The organic layer was dried with magnesium sulfate, 100 ml) and the organic phase was washed with InHCI (about 100 ml, filtered and concentrated using a rotor), then with a saturated saline solution of the evaporator to obtain the product indicated in the title (about 10 Oml). The organic phase was dried over compounds. M9Bo", filtered and concentrated using

M5 (4-E5I): 216.1 |M-bos--1Г1" of the rotary evaporator. This crude product is

Stage 3: Preparation of tert-butyl benzyl 41-sthal using chromatography on silica gel with

Benzyl oxy)methyl|-3-methylbut-3-enyl)/carbamate with a gradient of 10-3095 ethyl acetate in hexane with tri-

To a solution of Bos-dehydro-i-leucinol (2.56 g, 2-11.91 mmol of methyl ether) and benzyl bromide (3.54 ml, 29.8 mmol) benzyloxycarbonylamine-5,5,5-trifluoro-pent-2-in Sodium hydride (1.19 g of 6095 enoic acid in the form of a white crystalline solid dispersion in mineral oil, 29.8 mmol) and the resulting substance were added to DMF (50 ml). The mixture was left to stir for 3 hours. M5 (1E51): 318.0 (M--11").

An additional amount of benzyl bromide was added Stage 2: Preparation of methyl ether (5)-2- (3.54 ml) and dispersion of sodium hydride (1.19 g) and the reaction mixture of benzyloxycarbonylamine-5,5,5-trifluoropentane acid was left to stir for additional 16 hours. Water was added (about 2-Benzyloxycarbonylamino methyl ether-100ml) and the product was extracted twice into dichlorometa-5,5,5-riftorpent-2-enoic acid (15.37g, no (00ml). The organic phases were combined and washed with 48.5 mmol) was dissolved in absolute ethanol or twice approximately 100 ml of water. Organic phases (100 ml) in a Parr hydrogenation vessel. The solution was dried with magnesium sulfate, filtered and concentrated, bubbled with a stream of nitrogen, and then ruval was added using a rotary evaporator. Purification of (45UOirpos (350 mg). The reaction mixture was placed in a Parr hydrogenation apparatus using chromatography on silica gel and pumped out using a gradient of 0-595 ethyl acetate per hectare from the free space above the mixture, and then the sled gave the title compound. created a pressure of 50 pounds per square inch of hydrogen

Stage 4: Preparation of M-benzyl-1-(benzyloxy)- the process was repeated seven times and then the vessel of 4-fluoro-4-methylpentan-2-amine was pressurized to 50 psi hydrogen and re-

A solution of 7095 hydrofluoride in pyridine (3.75 mL) was stirred in a Parr apparatus overnight. The reaction mixture was re-equilibrated to 0"C in polypropylene, then concentrated using a rvoir. A solution of benzyl ether M was added by rotary evaporation, dissolved in 1:1 ethyl-benzyl-Bos-(I)-leucinol (1.52 g, 3 .85 mmol) and the reactant: hexanes and filtered through a layer of dioxide. (5)- for 5 days. The reaction was quenched by the addition of ice-water 2-benzyloxycarbonylamino-5,5,5- and the product was extracted into methylene chloride. Purified trifluoropentanoic acid, which was transferred without it by chromatography on silica gel using additional purification. gradient 0-1095 methanol in dichloromethane dialylo Stage 3: Preparation of benzyl ether (5) - the title compound.(4,4,4-trifluoro-1-hydroxymethylbutyl)carbamino

M5 (-Е51): 316.0 | MA11". acid

Example 18 Methyl ether (25)-2-

Synthesis of cyanomethyl amide (25)-5,5,5-trifluoro-2-Benzyloxycarbonylamino-5,5,5- (C(15)-2,2,2-trifluoro-1-(2-(methylsulfonyl)-1, 1"-trifluoropentanoic acid from stage 2 was dissolved in diphenyl-4-yl|ethyl)amino)pentanoic acid in dry THF (400 ml). A solution of GiIVNa (2.11 g in 100 ml of dry THF) was added dropwise with stirring.

The bath and the solution were left to mix at room temperature.

Environmental temperature during the night. The reaction mixture was concentrated using

M. SM turned on the rotary evaporator and added 400 ml of water. and M and Then the pH was adjusted to pH 2 by adding concentrated HCl, and then the product was extracted into ethyl acetate. (I tat. The organic phase was washed twice with water, dried with Mo95O:4, filtered and concentrated using a rotary evaporator to obtain crude benzyl ether (5)-trifluoropentan-1-ol (4,4,4-trifluoro -1-hydroxymethylbutyl)carbamine H-Hys (2.5M in hexane, 21.4ml) was added dropwise to the stirred solution of 1,4-

M5 (-EBI): 290.2 (MA1G. of dibromobenzene (12.6g) in dry diethyl ether

Stage 4: Preparation of benzyl ether (1- (8 VOml) at -30"C and the reaction mixture was stirred (tert-butyldimethylsilanyloxymethyl)-4,4,4- for 30 minutes. Then trifluorobutylcarbamic acid solution (25)-1- was added dropwise tert-butyl(dimethyl)silyl|oxy)-

To a solution of benzyl ether (5)-(4,4,4-5,5,5-trifluoro-M-C1E)-2,2,2-trifluoro-1-hydroxymethylbutyl)carbamino /-oxy-trifluoroethylidene|pentane-2 -amine (3.75g, lots (13.89g, 47.7mmol) and triethylamine (7.32ml, 10.7mmol) in dry diethyl ether (30ml) and 52.5mmol) in DMF (bOml) were added dropwise, the reaction the mixture was left to warm up to temperature, while stirring, the solution of butyldimethylsilyl chloride (7.91 g in 40 ml of DMF) was stirred for 16 hours. The reaction mixture was then heated at ambient temperature. washed using 100 ml of water. Organic

The solution was left to stir during the phase was washed with saturated saline overnight at ambient temperature. dried with magnesium sulfate and filtered. Filt-

The reaction mixture was then concentrated using rotary evaporation, and ethylation was added to obtain the crude product, cetate. The organic phase was washed twice with water, which was purified by means of chromatography on dryness using MazoO»x, filtered and the lycagel using 190 ethyl acetate in hexane was concentrated by means of rotary evaporation as an eluent to obtain (5)-(1-(4-bromophenyl) The crude product was purified by chromatography on silica gel using 10905 ethylbutyldimethylsilanyloxymethyl)-4,4,4-acetate in hexane as an eluent to obtain trifluorobutyl|iamine ( 1.8g). (5)-11-(4-Bromophenyl)-benzyl ether (1-(tert-2.2,2-trifluoroethyl-|1-(tert-butyldimethyl-butyldimethylsilanyloxymethyl)-4,4,4-trifluoro- silanyloxymethyl)-4,4,4-trifluorobutylamine dibutyl|-carbamic acid in the form of white crystals was dissolved in THF (5 Oml) and cooled to 0"С and the solid substance was added. tert-butylammonium fluoride was added dropwise

M5 (4E51): 406.2 (MAH (10.bml, 1M THF solution). The reaction mixture

Stage 5: Preparation of (25)-1-Tret- was left to warm to ambient temperature- butyl(dimethyl)silyl|oxy)-5,5,5-trifluoropentane-2- medium and stirred for 4 h- amine dyne. The reaction mixture was quenched with saturated water

Benzyl ether PI -(tertiary solution of ammonium chloride, and then added

Butyldimethylsilanyloxymethyl)-4,4,4-ethyl acetate and the mixture was vigorously shaken. Organotrifluorobutyl Iicarbamic acid was dissolved in the overnight layer, separated and washed twice with saturated absolute ethanol (100 ml) in a hydrogenation saline solution, dried with magnesium sulfate and a Parr vessel, and the solution was bubbled with nitrogen. It was filtered. The solvent was removed with the help of a 1095 Ra on coal (1.8 g) and a vessel containing a rotary evaporator with a residue was poured into a Parr hydrogenation apparatus. The pumped-which was purified at 5iO2 using a gradient of 20-li air from the headspace of the vessel and then 2595 ethyl acetate in hexane as eluent from the obtain- created a pressure of 5O0lbs/sq. inch of hydrogen. This process was repeated seven times and then a vessel of trifluoroethyl|amino)-5,5,5-trifluoropentan-1-ol. pressurized to 50 psig of hydrogen and stirred overnight in a Parr apparatus. -trifluoro-2- mash was removed by filtration through Seyleph and then ((15)-2,2,2-trifluoro-1-(4-(methylsulfonide)-1,1"- the reaction mixture was concentrated using rhodiphenyl-4- yl|ethyl ) amino)pentan-1-ol toric evaporation to obtain (25)-1- A stream of nitrogen was passed through the suspension of (25)-2-

Tert-butyl(dimethyl)silyl|oxy)-5,5,5- (S(15)-1-(4-bromophenyl)-2,2,2-trifluoroethyl|amino)-trifluoropentane-2-amine. 5,5,5-trifluoropentan-1-ol (0.55g), 2-(4-

M5 (4E51I): 2721 (MH methanesulfonylphenyl)-4,4,5,5-tetramethyl-

Stage 6: Preparation of (25)-1-Tret-I1,3,2|dioxaborolane (0.59g) 2.5M KgSOOz (2.75mL) and butyl(dimethyl)silyl|oxy)-5,5,5-trifluoro -M-C1E)- DMF (0.91 ml) for 20 minutes. Then added 2,2,2-trifluoroethylidene|pentan-2-amine chloride M,T-

A solution of (25)-1-CChtert-Bis(idiphenylphosphino)ferrocene|palladium (I) (11-butyl(dimethyl)silyl|oxy)-5,5,5-trifluoropentane-2- complex with dichloromethane, Za4mg), the capacity of herme- amine (3.00 g, 11.06 mmol) and trifluoroacetaldehyde were added and the reaction mixture was heated to 85°7C, and ethyl hemiacetal (1.6 g, 11.0 mmol) in benzene was stirred under a nitrogen atmosphere for 5 h. (20 ml) was heated under reflux for - dyne. The reaction mixture was cooled to room temperature for 2 hours, during which time the water was collected at temperature, diluted with ethyl acetate (50ml) and a Dean-Stark nozzle. The solvent was removed in vacuo with water (5Oml) and vigorously shaken. The umi was separated to obtain crude ( 25)-1-triethyl acetate layer and washed 3 times with water, dried with butyl(dimethyl)silyl|oxy)-5,5,5-trifluoro-M-(1 E)-ly magnesium sulfate and filtered. Removal 2, 2,2-trifluoroethylidene|pentan-2-amine. solvent left a residue, which was purified by

M5 (ЧЕ51): 352.2 (МА1|" by means of chromatography on 5iO" using

Stage 7: Preparation of /(25)-2-((15)-1-(4- gradient 10-30956 ethyl acetate in hexane. Rotary bromophenyl)-2,2,2-trifluoroethylamino)-5,5,5- evaporation of the corresponding fractions gave (25)-

5,5,5-trifluoro-2-((15)-2,2,2-trifluoro-1-|I8- (ZE, d). (methylsulfonyl)-1,1"-diphenyl-4- Example 19 il |ethyl)amino)pentan-1-ol Synthesis of M'-(cyanomethyl)-M2-(5)-(4-fluorophenyl)-

Stage 9: Preparation of (25)-5,5,5-trifluoro-2-(2-(methylsulfonyl)-1,1"-diphenyl-4-yl|methyl. - (C(15)-2,2,2 -trifluoro-1-(4-(methylsulfonyl)-1,1- leucinamide of diphenyl-4-ylph|ethylamiso)pentanoic acid

The matrix suspension of the oxidant was obtained by mixing periodic acid (2.28 g) and chromium trioxide (4.6 mg) in wet acetonitrile (0.75 g and water) to form a suspension with a total volume of 22.8 ml. The oxidant suspension (4.22 ml) was then added dropwise to the stirred solution of (25)-o and no 5,5,5-trifluoro-2-((15)-2,2,2-trifluoro- 1-|I8- 8 (methylsulfonyl)-1,1-diphenyl-4-yl|Styliamino)pentan-i-ol (0.35 g, 0.74 mmol) in moist acetonitrile (3.7 ml) while maintaining the temperature. Stage 1 : Obtaining (5)-2-C4-rature at 0-5"C. The reaction mixture was allowed to heat up to ambient temperature. 9.67mmol) and 4- after an hour, and then stirred during do-fluorobenzaldehyde (1.20g, 9.67mmol) was dissolved in tax 4 hours. The reaction was quenched with aqueous benzene (30ml) and heated with reflux sodium hydrogen phosphate (6g/ 100 ml) and added with a solvent for 1 hour, using the ol apparatus, and the mixture was intensively shaken. Dean-Stark organic phase to remove water. (5)-2-((4-) was washed with 1:1 salt solution: water, then with aqueous fluorobenzylidene )amino|-4-methylpentan-1-ol is isolated with sodium bisulfite (2.2g/50ml), then n saturated with concentration in a vacuum, and immediately used with saline solution. The organic layer was then dried without further purification. with sodium sulfate, filtered, and concentrated. Stage: Preparation of (25)-2-((M)-I((4-) by rotary evaporation. The crude bromophenyl)-(4-fluorophenyl)methyl|amino)-4- product was purified by by chromatography on methylpentan-1-ol silica gel using 5-1095 methanol in methyl- To a solution of 1,4-dibromobenzene / (11.4 g, lene chloride as an eluent to obtain (25)-5.5.5- 48.35 mmol) in trifluoro-2-((15)-2,2,2-trifluoro-1-I-n-butyllithium (24.2 ml, 2.0 M cyclohexane solution) (methylsulfonyl)-1 was added to ether (120 ml) at -30"C ,1-diphenyl-4- for 10 minutes. The reaction mixture of yl|ethylamino)pentanoic acid was stirred for 45 minutes, after which it was added

M5 (-EB5I): 482.0 (M-1G. drops of solution (5)2-I(4-fluorobenzylidene)amino|-4-

Stage 10: Preparation of cyanomethylamide (25)-methylpentan-1-ol (maximum 2.16g, 9.67mmol from 5,5,5-trifluoro-2-((15)-2,2,2-trifluoro-1-| 18- previous stage) in ether (30 ml). After 2 hours, (methylsulfonyl)-1,1-diphenyl-4-yl| during which the reaction mixture was allowed to heat up to 0"C, water was added ( The product was extracted with (25)-5,5,5-Trifluoro-2-((15)-2,2,2-trifluoro-1) ethyl acetate (150 ml), washed with saturated 2-(methylsulfonyl)- 1,1-diphenyl-4-nim salt solution (100ml), dried over il|iStyliamino)pentanoic acid (0.55g, M9BoO", filtered, concentrated in vacuum and 0.114mmol), aminoacetonitrile hydrochloride (21mg, purified on a thin layer silica gel (2095 ethyl - 0.228 mmol) and NATI (4 mg, 0.114 mmol) were dissolved in acetate/hexane elution) to obtain (25)-2-(H)-(4- in DMF (2 ml) and the reaction mixture was cooled to - bromophenyl) -(4-fluorophenyl)methyl|amino)-4- 20"С. Diisopropylethylamine (0.1 Oml, methylpentan-1-ol. 0.57 mmol) was added and the reaction mixture was stirred at - M5 (TARSI): 380, 382 (М-А1|x. 20"C for three hours, and then at the temperature of IN NMR (SOSIZz) 6 0.91 (d, 6H), 1.22 (m, 1H), tures of the environment during 16 h- 1.43 (m, 1H), 1.61 (m, 1H), 2 .62 (m, 1H), 3.28 (m, 1H), dyn. Ethyl acetate (about 30 ml) and water were added 3.63 (m, 1H), 4.95 (s, 1H); 7.00 (m , 2H), 7.22 (d, 2H), (about 30 ml) and the mixture was vigorously shaken. 7.2 (m, 2H), 7.44 (d, 2H).

The organic layer was washed with water, dried with sulfur, and filtered. The filtrate was concentrated bromophenyl)-(4-fluorophenyl)methyl|amino)-4- shafts using rotary evaporation and methylpentanoic acid, the residue was purified by chromatography on K solution / (25)-2-(B8)-(4-bromophenyl)-(4- silica gel using 3095 ethyl acetate in hec-fluorophenyl)methylamino)-4- methylpentan-1-ol sani as eluent to obtain cyanomethylamide (3.28g, 8.65mmol) in acetonitrile (50ml), which mis- (25)-5,5,5-trifluoro-2-((15)-2, 2,2-trifluoro-1-(4-diethyl) water (0.5375 ml) at 0-52C was added, over 20 minutes, to (methylsulfonide)-1,1"-diphenyl-4-, a solution of periodic acid and yl|ethyl chromium oxide )amino)pentanoic acid in the form of white IMI in acetonitrile (Homl: the prepared dissolved solid substance.

M (TEB5I): 522.3 (MAH stirring for 2 hours at room temperature

IN NMR (SOCI3) 5 8.0-8.053 (2H, d), 7.74-7.78 temperature according to the 3 method described in (2H, d), 7.63-7.66 (2H, d), 7.48-7.51 (2H, d), 6.94- Teimapedgtop Gekegv5, 1998, my. 39, pp. 5323-5326). 7.00 (IN, Bi, MN), 4.06-4.22 (ZH, m), 3.36-3.43 (1H, The reaction mixture was stirred overnight at-m), 2.21-2, 37 (ZN, m), 1.88-2.03 (2Н, m). "E NMR heating to room temperature. Disodium phosphate (1.8g/100ml of water) was added (SOCIz) 6 -66.74- -66.83 (ZE, t), -74.14- -7417). The reaction mixture was extracted with toluene (150ml), washed with difluorophenyl)-(4--methanesulfonyldiphenyl-4-11 saturated saline solution/water (50ml), yl)umethylamino)-4-methylpentanoic acid with freshly prepared sodium bisulfite solution (27/50ml water), saturated saline solution E (5 Oml), dried over Md5O5", filtered, concentrated in a vacuum and purified on a thin layer of silica gel (3095 ethyl acetate/hexane elution to remove non-polar impurities, then BO M we ethyl acetate/dichloromethane elution ) with obtaining (A on (25)-2-CA)-(4-bromophenyl)-(4-fluorophenyl)methyl|amino)-4-methylpentanoic /-acid--8 lota.

Stage 4: Preparation of cyanomethylamide (25)-2- (P)-((4-bromophenyl)-(4-fluorophenyl)methyl|amino)-4- Stage 1: Preparation of (25)-2-((2,4- methylpentanoic acid difluorobenzylidene)amino|-4-methylpentan-1-ol

To o solution / (25)-2-(B)-((4-bromophenyl)-(4- Solution of (5)-(-)-leucineol (2.47g, 21mmol) and fluorophenyl)methyl|amino)-4 -methylpentanoic /-kis- 2,A4-difluorobenzaldehyde (3g, 21 mmol) in benzene (1.17 g, 2.8 mmol) in THF (20 ml) at -107C (5 Oml) was heated under reflux, 4-methylmorpholine ( 0.315ml, 2.86mmol) and a draft of 4 hours, during which time the water was collected in isobutyl chloroformate (0.371ml, 2.86mmol). Dean-Stark reaction nozzle. The solvent was evaporated and the mixture was stirred for 10 minutes under vacuum to obtain (25)-2-((2,4- after which aminoacetonitrile hydrochloride difluorobenzylidene)amino|-4-methylpentan-1-ol was added. (0.318g, 3.4Zmmol ), followed by 4-methylmorpholine IN NMR (СО350С0О) 6 8.18 (s, 1H), 7.51 (d, 1H), (0.315ml, 2.8bmmol). The solution was stirred pro- 6.81 (d, 2H), 4.6 (width c, 1H), 3.8-3.2 (m, ЗН), 1.6-1.2 with a draft of 90 minutes. Ethyl acetate (ZOml) and (m, ЗН) were added. 0.9-0.8 (m, 6H) aqueous disodium phosphate (ZOml). The organic phase Stage 02: Obtaining //(25)-2-(5)-(4- was separated, washed with saturated saline bromophenyl)- (2,4-difluorophenyl)methylamino)-4-nom, dried over Ma5O5" and evaporated to dryness. methylpentan-1-ol

The product was purified on a thin layer of silica gel (10-K solution of 1,4-dibromobenzene /(24.5 g, 5090 ethyl acetate/hexane gradient elution) with 100 mmol, 5 eq) in dry ether (200 ml) in an atmosphere of cyanomethylamide (25) -2-(8)-(4- nitrogen ferric at -30"С) was added nVii (64.75 ml, bromophenyl)-(4-fluorophenyl)methylamino)-4- 1.6M solution in hexane, Bekv) and the reaction mixture of methylpentane acid, stirred for 1 hour, slowly added

Stage 5: Preparation of M1-(cyanomethyl)-M2-((5)- solution of 2-(2,4-difluorobenzylidene)amino|-4-(4-fluorophenyl)|(4-(methylsulfonyl)-1,1" -diphenyl-4-methylpentan-1-ol (5 g, 20 mmol) in dry yl|methyl)-leucinamide ether at -302 C. After stirring for 4 hours,

The reaction was quenched with water. , 0.63 mmol), 2-(4-Ma5ox. The solvent was removed under reduced pressure, and the crude product methanesulfonylphenyl)-4,4,5,5-tetramethyl was subjected to flash chromatography on

1,3,2Idioxaborolane (0.177g, 0.62bmmol) and car- BOOsmZ osilica gel using 8:2 potassium hexobonate (0.703ml of a 2.0M solution) in DMF (5ml) san"EUAs as an eluent to obtain (25 )-2-(5)-((4- was degassed. M,T-bromophenyl)-(2,4-difluorophenyl)methyl|amino)-4- bisidiphenylphosphino)ferrocene|dichloropalladium (I), methylpentan-1-ol was added dichloromethane complex (27mg, 0.038mmol). NMR reaction (СО350С0Оз) 5 7.31 (dd, 2Н), 7.05 (d, the reaction mixture was heated in a sealed tube at 80-1Н), 6.94, ( dd, 2H), 6.63 (d, 1H), 6.54 (d, 1H), 5.02 85"C for 3 hours and cooled to room temperature - (c, 1H), 4.45 (t, 1H ), 3.5-3.3 (m, 2H), 2.3 (s, 1H), 2.15 at the same temperature. Ethyl acetate (15 ml) was added. (c, 1H), 1.85 (m, 1H), 1.18-1.4 (m, 2H), 0.9-0.8 (m,

The reaction mixture was washed with saturated saline. solution (1Oml), saturated aqueous Mansoz Stage 3: Preparation of (25)-2-(8)-((4- (1Oml), saturated saline solution (1Oml), bromophenyl)-(2,4-difluorophenyl)methyliamino)- 4- filtered through a layer of M950O/0AKSO activated methylpentanoic acid not coal/silica gel, concentrated in a vacuum and using the method given at the stage purified by preparative thin-layer chromatography- From Example 19, oxidized 2-I((4-bromophenyl)-(2, 4- raffia (TS) (SphotaioiogpF using 595 difluorophenyl)methyl|amino)-4-methylpentan-1-ol eluting with ethyl acetate/dichloromethane to give (25)-2-(5)-(4-bromophenyl)- (2,4-

M1-(cyanomethyl)-M2-((5)-(4-fluorophenyl)1-difluorophenyl)methyl|amino)-4-methylpentanoic (methylsulfonyl)-1,1"-diphenyl-4-yl|methyl/i - acid in the form of a solid substance of creamy cholecinamide.

IN NMR (SOSIz): 6 0.77 (d, ZN), 0.9 (d, ZN); 1.38 Stage 4: Preparation of cyanomethylamide (25)-2- (m, 1H), 1.57 (m, 1H), 1.71 (m, 1H), 2.01 (shr.s, 1H), ( (5)-K4-bromophenyl)-(2.4- 3.09 (s, 3H), 3.09 (m, 1H), 4.07 (m, 2H), 4.89 (1H, s), difluorophenyl)methylamino)-4-methylpentanoic acid 7.03 (m, 2H), 7.21 (m, 1H), 7.33 (m, 2H), 7.42 (d, 2H), acid 7.53 (m , 2H), 7.68 (d, 2H), 7.97 (d, 2H). Using the methodology given in sta-

Example 20 of action 4 of Example 19, (25)-2-((5)-((4-bromophenyl)-(2,4-

Synthesis of cyanomethylamide /(25)-2-(5)-((2,4-difluorophenyl)methylamino)-4-methylpentanoic acid

lot was combined with aminoacetonitrile to obtain water (200 ml). The organic phase was separated, the cyanomethylamide (25)-2-(5)-I(4-bromophenyl)- was washed with a saturated saline solution (200 ml), (2,4-difluorophenyl)methyl|amino)-4-methylpentanoic acid was dried over Md5oO", was filtered, and the acid was evaporated in the form of a white solid. to dryness to obtain (25)-(5)-(1-(4-bromophenyl)-

NMR (CO350С03) 6 7.31 (dd, 2H), 7.05 (d, 2,2.2-trifluoroethyl-|1-(tert- 1H), 6.94 (dd, 2H), 6.63 (d , 1H), 6.54 (d, 1H), 4.92 (s, butyldimethylsilanyloxymethyl)butylamine, which is 1H), 4.14 (t, 2H), 3.32 (m, 1H), 3.19 (m, 1H), 2.98 (m, used directly in the next stage 1H), 1.85 (m, 1H), 1.46 (m, 1H), 0.9-0.8 (m, 6H) . without additional cleaning.

Stage 5: Preparation of cyanomethylamide (25)-2- Stage C: Preparation of (25)-2-((5)-1-(4-(5)-(2.4-difluorophenyl)-(4-bromophenyl)-2,2 ,2-trifluoroethylamino|pentan-1-ol methanesulfonyldiphenyl-4-yl)umethylamino)-4- To a solution of /(25)-(5)-I1-(4-bromophenyl)-2,2,2- methylpentanoic acid trifluoroethyl- |1-(third-

Using the method given for the stable dimethylsilanyloxymethyl)butyl|amine of action 5 of example 19, the Suzuki interaction (49.58 g, 109 mmol) was carried out in THF (200 ml) and pho- (bBy2iki) was added with cyanomethylamide /(25)-2-(5) -(4-tetrabutylammonium hydride (11 Oml of 1.0M solution). The rheobromophenyl)-(2,4-difluorophenyl)methyl|amino)-4- cationic mixture was stirred overnight with chem-methylpentanoic acid to obtain cyanomenate temperature. After concentration of the reactive thylamide ((25)-2-(5)-(2,4-difluorophenyl)-(4-) ether (300 ml) was added to the mixture. The reaction mixture methanesulfonyldiphenyl-4-yl)umethyl|amino)-4- was washed with water (2x100ml), saturated salt of methylpentanoic acid in the form of a white solid solution (100ml), evaporated to dryness, and then the substance. purified by flash chromatography (395

1N NMR (СО350С0Оз) 5 8.01 (dd, 2H), 7.8 (dd, ethyl acetate/hexane elution of highly nonpolar re- 2Н), 7.35 (dd, 2Н), 7.11 (dd, 2Н), 7.03 (d, 1H), 6.93 chovin, then 4095 ethyl acetate/hexane for elution (d, 2H), 6.62 (d, 1H), 6.55 (d, 1H), 5.0 (s , 1H), 4.13 (t, product). The fractions containing the product were combined - 2H), 3.35 (m, 1H), 3.0 (m, 1H), 2.99 (m, 1H), 2.85 (c, ly, concentrated to with a volume of 300 ml, washed

ЗН), 1.84 (m, 1Н), 1.45 (m, 1Н), 0.9-0.8 (m, 6Н). 025M citric acid (200 ml), saturated

Example 21 with saline solution (100 ml), dried over Mdboa,

The synthesis of M-(15)-1-(4-bromophenyl)-2,2,2- was filtered and evaporated to obtain (25)-2-trifluoroethyl|-M-(1-cyanocyclopropyl)-I - 5)-1 -(4-bromophenyl)-2,2,2-norvalinamide trifluoroethylamino|pentan-y-ol. This substance was used directly in the next stage without additional purification. TS (3095 ethyl acetate/hexane) K-0.28.

And M. iSM Stage 4; Preparation of (25)-2-((5)-1-(4-su i b x bromophenyl)-2,2,2-trifluoroethylamino|pentanoic

Hg acids

To a solution of crude (25)-2-|(5)-1-(4-

Stage 1: Preparation of (5)-I1-(tert-bromophenyl)-2,2,2-trifluoroethylamino|pentan-1-ol butyldimethylsilanyloxymethyl)butyl|-(2,2,2- (37.1g, Tb9mmol in dry acetonitrile) (500 ml) of trifluoroethylidene)amine at -78"С, a solution of periodic acid was added

A mixture of (5)-1-(tert- (71.7) and chromium trioxide (144mg) in dry acetone-butyldimethylsilanyloxymethyl)butylamine (27tg, trilyl (b3Oml) for 1 hour. The reaction mixture 126bmmol) and trifluoroacetaldehyde methylhemiace- was allowed to heat to room temperature thallium (17.2g, 132mmol) in benzene (250ml) was heated with stirring overnight. The reaction mixture was refluxed using na- was concentrated under reduced pressure to a common Dean-Dean-Stark cage to remove water. The volume is approximately 500 ml. A solution of lemon juice was added for 2 hours and no more water was collected. The reaction solution of acid (22 g in 25 ml of NaOH) and the mixture was extracted, the mixture was cooled and concentrated with ethyl acetate (800 ml). The solution was washed with fresh (5)-I1-"tert-prepared Manzose (2 x 200 ml, 25 g of solid re-butyldimethylsilanyloxymethyl)butyl|-(2,2,2- iron, dissolved to 200 ml of water), saturated with trifluoroethylidene)amine, which was used on a saline solution (300 ml), dried over Ma5Oa, the first stage without additional purification or filtered, and evaporated to obtain a pale- prolonged drying due to its volatility. orange solid, which was powdered 590

Stage 2: Preparation of (25)-(5)-P1-(4-bromophenyl)-ethyl acetate/hexane to obtain ((25)-2-(5)-X1-2,2,2-trifluoroethyl-|1-( tert-(4-bromophenyl)-2,2,2-trifluoroethylamino|pentanoic butyldimethylsilanyloxymethyl)butyl|amino acid. An additional amount of acid was obtained

To a solution of dibromobenzene (63.7g, 270mmol) with the concentration of the mother solutions, distribution in ether (bO0Oml) at -30"C was added H-Vy and (108ml of the residue between ether and aqueous Manso, acidification of a 2.5M hexane solution) according to 15 minutes through the aqueous layer with citric acid, liquid funnel extraction. The solution was allowed to heat up to -1070 with ethyl acetate, dried over Md5o", filtered for 35 minutes, and cooled again to -30"C. Addition and evaporation of the solvent. shafts (5)-11- Stage 5: Preparation of M2-(15)-1-(4-bromophenyl)- (Butyldimethylsilanyloxymethyl)butyl|-(2,2,2- 2,2,2-trifluoroethyl|-M'- (1-cyanocyclopropyl)|-trifluoroethylidene)amine (35.12g, 108mmol) into norvalinamide ether (200ml) over 20 minutes. The reaction mixture was stirred for 1 hour while heating to 0°C. Trifluoroethylamino|pentanoic acid (19.0 g) was added. ,

135 777168 136 53.b6mmol), 1-aminocyclopropanecarbonitrile hydrochloride Example 23 (12.71g, 107mmol, synthesized from hydrogen) Synthesis of M2-(1-(4-bromophenyl)-2,2,2-no from Oboppei, M. and trifluoroethyl-M'-(cyanomethyl)-norvalinamide

NATO (22.42g, 59.0mmol) was dissolved in DMF (200ml) and cooled to -78°C. Diisopropylethylamine (37.35ml, 214mmol) was added, and after stirring for 1 hour, cooling M M. AsM The bath was removed. The reaction mixture was allowed to stir for an additional 1 hour, after which saturated MnSO 3 (300 mL) was added. (500ml), washed with saturated saline solution (100ml), (cyanomethyl)urvalinamide was obtained similarly with 0.25M citric acid (200ml), saturated in the same way:

Mansoz (200 ml), saturated with a saline solution of tryptov Chi(methylsulfonyl)-1, 1 diphenyl-Y- (200 ml), was dried over Ma5O5/0ABSO, filtered with yl|ethyl)-norvalinamide using amino- through silicon dioxide and evaporated to dryness. Pis-acetonitrile at the stage of interaction with (25)-2-I((5)-1-(4- by elution of the residue through another thin layer of dioxybromophenyl)-2,2,2-trifluoroethylamino|Ipentane du silicon 1095 ethyl acetate/ with dichloromethane as KO ME (chEVI . 392 394 I(MA1T- mobile phase, the product was concentrated and recrystallized from ether/hexane to obtain Me-- Synthesis of M'-(this mg. Y. Y. 1 cyanomethyl)-M2-((15)-2,2,2-trifluoro

M5 (-E5I): 416, 418 | M-1T. norvalinamide

IN NMR (SOSIz): 5 0.97 (ZN, t), 0.98 (m, 1), 1.07 (m, 1H), 1.41 (m, 2H), 1.49 (m, 2H ), 1.62 (m, 1H), es 1.72 (m, 1H), 3.27 (1H, m), 1.04 (m, 1H), 7.1 (sh.s, M. cm 1H), 1.24 (d, 25 2H), 7.75 (d, 2H). sauce in

Example 22 Another FI

Synthesis of M1-(1-cyanocyclopropyl)-M2-((15)-2,2,2-MeO»8 trifluoro-1-(4-(methylsulfonyl)-1,1-diphenyl-4-ylethyl-norvalinamide M! -(Cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I4--(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -norvalinamide was obtained in a similar way from M!-(1 -

SEZ Hn cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-I4-

M M. CM (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl - (i n b AH norvalinamide using M2-(1-(4-

Ф bromophenyl)-2,2,2-trifluoroethyl|-M'-(cyanomethyl)! -

Meb»5 norvalinamide, described above, in the Suzuki reaction with 4-methanesulfonylphenylboronic acid or

A mixture of m2-(188)-1-(4-bromophenyl)-2,2,2-pinacolboronate; Alternatively, this trifluoroethyl-M!-(1-cyanocyclopropyl) compound could be obtained as a result of corvalinamide binding (wt, TB 44 mmol), 4-0 bouzouki between // (25)45)11Abromphenyl)-2,2,2 - methanesulfonylphenyl boronic acid (3.40 g, trifluoroethyl/-/1-(third 16.98 mmol), and 2M CoCOz (19.3 ml) were dissolved in butyldimethylsilanyloxymethyl) butylamine and 4-

DMF (75 ml) in a thick-walled flask. The reaction mixture was degassed with methanesulfonylphenylboronic acid in the presence of: degassed, and M, - essence, 1 bis(idiphenylphosphino)ferrocene|dichloropalladium (1), / bisidiphenylphosphino)ferrocenedichloropalladium (1), dichloromethane complex (0.678g, 0.926bmmol) was added. dichloromethane complex in accordance with

The flask was sealed, heated at 80-852C using the method described above, followed by cleavage for 3 hours, cooled and diluted by ethylating the silyl ether with tetrabutyl acetate fluoride (300ml). The solution was washed with 1:1 ammonia, oxidation using NviOv/SgOz milk/saturated saline solution / (200 ml), (see above) 3 obtaining (25)-2-(5)-2,2,2- saturated saline solution (200 ml), trifluoro-1-(4-methanesulfonyldiphenyl-4-ethyl)ethylamino|pentanoic acid filtered through a three-layer plug of silicon dioxide, and a combination of this (bottom) OARSO, and M95O" (top), concentrated into substances with aminoacetonitrile hydrochloride in vacuo, and purified on a layer of silica gel (50-7095 in the presence of NATOi/diisopropylethylamine/DMF triethyl acetate/hexane elution). The product was then purified by recrystallization from M (TE) by adding the named compound. 468 (MAG. ethyl acetate/hexane to obtain the compound specified in the title Example 25, il. ; M5 (zE51I): 494 MAG. Synthesis of M'"cyanomethyl)-M'A-CI A) 22.2. 1H NMR (SOCIv): 5 0.97 (t, 3H), 0.98 (m, 1H), 1 trifluoro-1-|(4(methylsulfonyl)-1,1-diphenyl-4- (m, TN) , 1.42 (m, 2H), 1.29 (m, 2H), 1.63 (m, 1H), 1.77 l|ethyl norvalinamide (m, 1H), 3.13 (s, 3 . 78 (d, 2H), 8.02 (d, 2H).

AND

SEZ with 0 Hn x M. CM direct OM

Mes5 g what

Yam A

Stage 1: Preparation of (45)-4-propyl-2-M trifluoromethyloxazolidine (-Norvalinol hydrochloride (5.25 g, The compound indicated in the title was obtained by 37.6 mol) and trifluoroacetaldehyde by methyl hemiacepper coupling according to the method of Suzuki 4-tal (ml, 37 mmol) was heated in benzene (100 ml) of cyclopropylpiperazinephenyl bromide from cyanometh- in the presence of triethylamine (5.26 ml, 37 mmol) with amide (25)-2-(2,2,2-Trifluoro-1-14 -(4,4,5,5- refluxed using apa-tetramethyl-/1,3,2|dioxaborolan-2-yl)-phenyl|- Dean-Stark reagent to collect water. After 3 hours ethylamino)-pentane acid in the presence of M,T- the reaction mixture was cooled, diluted with ephibisi(diphenylphosphino)ferrocene|dichloropalliadium (I), rum (100ml), filtered and evaporated to dryness, dichloromethane complex, as described above, with obtaining (45)-4- propyl-2- by further purification with the help of the drug trifluoromethyloxazolidine, which was used without TI-C (Spgotagiop"). additional purification. M5 (te): 514 |IMATG.

Stage 2: Preparation of (25)-2-|1-(4-bromophenyl)-Example 27 and 2,2,2-trifluoroethylamino|pentan-1-ol Synthesis of M--(15)-1--2-(aminosulfonyl) -1.1"-

Butyllithium (41 ml of 2.0M cyclohexane diphenyl-4-yl-2,2,2-trifluoroethyl)-M'-(1-chin) was added at -302C to a solution of 1,4-cyanocyclopropyl)! -norvalinamide of dibromobenzene (19.3g, 81.89mmol) in ether (25Oml) in 10 minutes. After 1 hour, a solution of (45)-4-propyl-2-t-rifluoromethyloxazolidine (3.00g, SEZ n 16.38mmol) was added to ether (50ml) for 30 minutes via a drop funnel. After stirring for 90 minutes, water (100 ml) was added. The organic phase was washed with saturated saline NM. F (100 ml), dried over Md5o", filtered, and evaporated to dryness. The residue was purified on a layer of silica gel (10-3095 ethyl acetate/hexane elution). Approx. The compound indicated in the title was obtained from a 2:11 mixture of diastomers /(25)-2-1-(4- by a method similar to that described for //-M'-bromo)rotor ot (anocyclopropyl) e-( 15) 22 o trifluoro-bromophenyl)-2,2,2-trifluoroethylamino|pentan-1-ol. oval (Saw ilIethyl

Stage 3: Preparation of M'-(cyanomethyl)-M2-(15)-M5 (tEBI): 495 |MYH" AND 2.2.2-trifluoro-1-(4-(methylsulfonyl)-1,1"-diphenyl-1 ; , I x o 4-ylethyl-norvalinamide and M'-(cyanomethyl-M"- 108 (mn pi Nu taya (m nut (m

There is an afenita leti nova 1 AN), 3.28 (m, 1H), 4.16 (4, 1H), 4.9 (shyr.s", 18), 7.2

Synthesis of (25)-2-(1-(4-bromophenyl)-2,2,2- (c, TN), 7.43 (d, 29), 7.6 (d, 2H), 7.72 ( d, 2H), 7.99 of trifluoroethylamino|pentanoic acid and (d, "Example 28 conversion into an aminoacetonitrile addition product . . . was carried out in a method identical to the described result C planodiclo rhodium amide (25) 2- more, for M2 -(1-(4-bromophenyl)-2,2,2-trifluoroethyl|- here acetyldiphenylyl) that

M'-(cyanomethyl)! - norvalinamide. Suzuki interaction of trifluoroethylamino|pentanoic acid of this product, by a method identical to that described for /M'-(cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-I-CE (methylsulfonyl)-1,1"- diphenyl-4-yl|ethyl - r c cm of norvalinamide with obtaining a 2:11 mixture of M!-С M X (cyanomethyl)-M2-(15)-2,2,2-trifluoro-1-|4-tno ( methylsulfonyl)-1,1-diphenyl-4-yl|ethyliu-o norvalinamide and /M'«(cyanomethyl)-M2-(1 8)-2,2,2-trifluoro-1-(4-(methylsulfonyl)- 1,1-diphenyl-4-yl|ethyl)i-norvalinamide, which was isolated by the method The compound indicated in the title was obtained by preparative TS (Sphotaiohyopfd).

M5 (1E5I): 468 |IMA1)". cyanocyclopropyl)-M2-(15)-2,2,2-trifluoro-1-I2-

Example 26 (methylsulfonyl)-1,1-diphenyl-4-ylethyl -

Synthesis of M'-(cyanomethyl)-Me-(1-|2-(4- norvalinamide using cross-coupling-cyclopropylpiperazin-1-yl)-1,1"-diphenyl-4-yl|- by the Suzuki method between 4-2.2.2-trifluoroethyl)i-norvalinamide acetylphenylboronic acid and M2-|((15)-1-(4- bromophenyl)-2,2,2-trifluoroethyl|-M-(1- cyanocyclopropyl)i-norvalinamide in the presence

I1,1"-bisidiphenylphosphino)ferrocene- (q, 1H), 7.21 (sh.s, 1H), 7.13-7.3 (m, 2H), 7.38 (m, dichloropalladium (II), dichloromethane complex (1H), 7.42 (d, 2H), 7.57 (d, 2H).

M5 (-Е51): 458 Mat", 480 |M--1-Mau". Example 31

IN NMR (SOCI3): 6 0.97 (t, ЗН), 0.98 (m, 1Н), 1, - Preparation of (i-cyano-cyclopropyl)amide (25)-2- 7 (m, 1), 1.42 (m, 2H), 1.57 (s, 2H), 1.63 (m, 1), I(15)-1-(3'-chloro-4-fluorodiphenyl-4-yl)-2 ... .s, 1H), 7.43 (d, 2H), 7.65-7.69 (2хd,

AN), 8.03 (d, 2H).

Example 29 SE, n

Preparation of (1-cyanocyclopropyl)amide (25)-2-cho M SM

К18)-1-(24-difluorodiphenyl-4-yl)-2,2,2- trifluoroethylamino|pentanoic acid od od od.

SEZ n i t y cm

Х The compound indicated in the title was obtained according to the following procedure

FI itself, SIMILAR to that described for M!-(1-

E E cyanocyclopropyl)-M2-((15)-2,2,2-trifluoro-1-I4-(methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

The title compound was synthesized by sponorvalinamide using a cross-coupling method similar to that described for /-M'-(1) by the Suzuki method between /3-chloro-4-cyanocyclopropyl)-M2-(15)- 2,2,2-trifluoro-1-|4-fluorophenylboronic acid and /M?-(15)-1-(4-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl-bromophenyl)-2 ,2,2-trifluoroethyl/|-M'-(1-norvalinamide with the help of crosslinking with cyanocyclopropyl)!--norvalinamide in the presence of vana by the method // Suzuki between /2,4- P,1-bisyidiphenylphosphino)ferrocene - difluorophenylboronic acid and M2-((15)-1-(4-dichloropalladium (II), dichloromethane complex. bromophenyl)-2,2,2-trifluoroethyl|-M!-(1- M5 (TE5I): 468 (Mat) ).cyanocyclopropyl)!-norvalinamide in the presence of 1H NMR (SOCI3): 5 0.99 (t, 3H), 1.00 (m, 1H),

I1,1-bisidiphenylphosphino)ferrocene- 1.08 (m, 1H), 1.42 (m, 2H), 1.51 (m, 2H), 1.62 (m, 1H), dichloropalladium (II), dichloromethane of the complex 1.79 (m, 1H), 2.19 (width, 1H), 3.33 (dd, 1H), 4.17

M5 (zE51): 452 |Ma-117474 |M--1--Mag. (sq., NU, 7.21 (m, 2H), 7.42 (m, ЗН), 7.57 (d, 2H), 7.62

IN NMR (SOSIz): 5 0.90 (m, 1), 0.97 (t, ZN), (m, 1Hn). 1.04 (m, 1H), 1.41-1.5 (m, 4H), 1.62 (m, 1H), 1.78 (m, Example 32 1H), 2.19 (width, 1H), 3.32 (dd, 1H), 4.13 (dd, 1H), Synthesis of /(1-cyanocyclopropyl)-amide /(25)-2- 6.95 (m, 2H), 7.19 ( shir.s, 1H), 7.41 (m, 3H), 7.53 (d, (15)-2,2,2-trifluoro-1-(4-methyldiphenyl-4-yl)-2Hn). ethylamino|pentanoic acid

Example 30

Synthesis of (1-cyanocyclopropyl)-amide ((25)-2-)

I(15)-1-(34-difluorodiphenyl-4-yl)-2,2,2-Sgz n trifluoroethylamino|pentanoic acid xx M Mu cm (Y on p EE

The compound specified in the title was synthesized by a method similar to that described for /M/-(1-

Also cyanocyclopropyl)-M-(15)-2,2,2-trifluoro-1-|4-

E (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl -

E of norvalinamide with the help of cross-linking by the Suzuki method between p-tolylboron

The title compound was obtained by acidification and M2-(18)-1-(4-bromophenyl)-2,2,2- sob, similar to 3 described for /M'Y(1-trifluoroethyl|-M!-(1 -cyanocyclopropyl)!-cyanocyclopropyl)-M"-(15)-2,2,2-trifluoro-1-|4-norvalinamide in the presence of M-(methylsulfonyl)-1,1"-diphenyl-4-yl|ethyl. - bisidiphenylphosphino)ferrocene|dichloropalladium (I), norvalinamide with the help of a crosslink - dichloromethane complex. by the Suzuki method between 3,4- M5 (TE): 430 (MANI. difluorophenylboronic acid and M'-(15)-1-(4- IN NMR (SOS33): 5 0.90 (m, 1H), 0 .98 (t, 3H), bromophenyl)-2,2,2-trifluoroethylI-M'-(1- 1.02 (m, 1H) 1.4-1.5 (m, 4H), 1.62 ( m, 1H), 1.69 (m, cyanocyclopropyl)I -norvalinamide in the presence of 1H), 2.19 (shr.s, 1H), 2.41 (s, 3H), 3.35 (dd, 1H), 4.1

P,1-bisidiphenylphosphino)ferrocene|dichloropalladium (q, 1H)U, 7.21 (s, 1H) 7.24 (d, 2H), 7.38 (d, 2H), 7.46 (I), dichloromethane of the complex (d, 2H), 7.60 (d, 2H).

M5 (TE51): 452 MAT", 474 |М-А-1--Mag". Example 33 H NMR (SOCI3): 6 0.97 (t, 3H), 0.98 (m, 1H), Synthesis of /(1-cyanocyclopropyl)-amide /(25)-2- 1.07 (m, 1H), 1.42 (m, 2H), 1.5 (m, 2H), 1.62 (m, 1H), I(15)-1-(2-cyanodiphenyl-4-yl)-2,2 ,2- 1.77 (m, 1H), 2.18 (width, 1H), 3.29 (dd, 1H), 4.17 trifluoroethylamino/pentanoic acid

(10ml) and dried over Md5O»4. The solvent was also removed under reduced pressure to obtain a yellow oil, which

CEa Y n was subjected to flash column chromatography on cXE as MOM 200cmZ silica gel using 3:1 hec-

GUM TI and saneyuAc as an eluent to obtain /3-side o methyloxetan-3-ylmethyl ether (25)-2-

What else is benzyloxycarbonylamino-4-methyl pentanoic acid

My loti (Sb2-I ey oxetane ester) in the form of a thick yellow oil. sovaane was synthesized according to the above description, 1N NMR (СО350С0) 7.75 (d, 1Н), 7.26-7.38 (m, ТТ 5Н), 5.05 (s, 2Н), 4.0- 4.4 (m, 8H), 1.45-1.7 (m, ЗН), cyanocyclopropyl-Mm2-C5)-2,2,2-trifluoro-1-I4-t (s, again (m , vn) ) | ) (methylsulfonyl)-1,1-diphenyl-4-yl|ethyl.- Stage 3: Preparation of benzyl ether (3- ation according to the method of sum 3-methyl-1-(4-methyl-2 ,6,7-trioxa-bicyclo|(2.2.2|oct-y,y Y 1-yl)butylcarbamic acid pyenopheniaboronoyl Iolate (MAU. (25)-2-Benzyloxycarbonylamino-4-methyl-

God's POD of pentanoic acid with 3-methyloxetan-3-ylmethyl cyanocyclopropyl)i- -norvalinamide in the presence of ether (Cr2-ieooxetane ester) (2g, tm "-bisyidiphenylphosphino)ferrocene|dichloropalladium 5.7 mmol) was dissolved in dry SnCl" (10 ml ) in (I, dichloromethane complex, under a nitrogen atmosphere. VEzEBO (40 μl, 0.3 mmol, mes EBI ZHI IMT". 0.054 eq) was diluted in dry SNES" (1 ml) and synthesized, , 26)-2-(53- (4 was placed in a reaction vessel. The reaction mixture of 6 syntheses of polymethitanium with )-2-(5)-Caz- was allowed to warm to room temperature and per-ormphenyl)-thiazol-2-yl-methyl-amino)-4- was mixed within 12 hours Methylpentanoic acid triethylamine (335 μl, 3.5 mmol, 0.58 eq) was added and the reaction mixture was stirred for additional 30 h. before concentration into a thick oil. The crude product was re-dissolved in EtOAc (15 mL), washed with 395 ml of NaCl

Moi (10 ml), and saturated Masi (10 ml), dried (Md5O"),

M and evaporated to dryness. The reaction was colorless

A thick oil, which crystallized on standing to give benzyl ether (|3-methyl-1-(4-methyl-2,6,7-

Stage ': Preparation of 3-methyl-3-trioxa-bicyclo(|2.2.2|oct-1-yl)butylcarbamic (toluenesulfonyloxymethyl)oxetane acid, (complex ester Сб2-И-ей-ОВО). p-Toluenesulfonyl chloride (57.2 g, 30 mmol) NMR (CO350С0:z) 7.25-7.35 (width m, 5H), dissolved in dry pyridine (400 ml) in an atmosphere 6.88 (d, 1H) , 5.05 (s, 2H), 3.80 (s, 6H), 3.7 (m, 1H) of nitrogen. Z-methyl-3-T2g-1.6 (m, ZN), 075-0.85 (m, BN), 0.70 (c, ZN) was slowly added. (hydroxymethyl)oxetane (20.A4g, 200 mmol) and the solution were stirred for 1.5 hours. Then trioxa-bicyclo (2.2.2| of oct-1-yl)butylamine, crushed ice (400 g) to intensively stirred To benzyl ether (3-methyl-1-(4-methyl) mixture, which was allowed to stir during the addition of 2.6,7-trioxa-bicyclo|2.2.2| oct-1-date 0.5h. Then, the white precipitate was collected on phyllobutyl Iicarbamic acid (3.2g, 9.2mmol) in filter paper M/paitap 41 and washed with absolute EUN (30ml) and 1096 Pa was added to the water. The product was dried under high activated carbon (32 mg, 1096) in a vacuum atmosphere to obtain 3-methyl-3-nitrogen. The reaction mixture was hydrogenated at 5°C (toluenesulfonyloxymethyl) oxetane (oxetantho- for 2 hours. The reaction was monitored with the help of sylate) in the form white powder of oxanthosylate. pure TC and the reaction mixture was filtered through 1H NMR (SOCI3); 5 7.81 (d, 2H), 7.37 (d, 2H) Seille. The solvent was removed to give 3-methyl- 4.37 (m, 4H), 411 (s, 2H), 246 (s, ЗН), 1.31 (03). 0 emethylvv, t trioxa bidiclog a loc

Stage 2: Preparation of (3-methypoxetan-3-yl)butylamine as a white solid. ylmethyl and ether (25)-2-IN NMR (СО350С0О3) 3.80 (s, 6Н), 3.2-3.4 benzyloxycarbonylamino-4-methyl-pentanoic acid (shr.s, ЗН), 1.75 (m, 1H), 1.0-1.4 (m, 2H), 0.75-0.90 lots (m, 6H), 0.75 (s, ЗН).

Cg-i-leucine (2 g, 7.5 mmol) and. C52CO3 (1.4Aug, Stage 5: Preparation of (|3-methyl-1-(4-methyl-4, Bmmol, 0.beq)) was dissolved in water (20ml). Then 2.,6,7-trioxa-bicyclo| 2.2.2|oct-1-yl)butyl/uhiazol- and schi ne |: 2-ylmethyleneamine water was removed in vacuo, and the resulting oil was lyophilized for 12 hours with the obtained solution of 3-methyl-1-(4- white solid with methyl-2,6,7-trioxane. To this solid bicyclo(2.2.2|oct-1-yl)butylamine (1.9 g, 8.9 mmol) and wine was added I 3-methyl- 3-thiazole-2-carboxaldehyde (998mg, 8.8mmol) in bet-(toluenesulfonyloxymethyl)oxetane (oxetanthones were heated under reflux with prozipate) (1.8g, 4.5mmol), and Ma! (224mg, 1 ,5mmol, THROUGH Agree using a Dean-Stark nozzle,

0.2 eq) were taken in DMF (35 ml) and left to stir; during this time, water was collected and the residue was boiled in a nitrogen atmosphere for 48 hours. Then the residue was evaporated under reduced pressure and DMF was removed under vacuum, resulting in bicyclo 2 o metal se methy 76, trioxa: the solid was dissolved in EOAc (boml) and pro-bicyclo(2.2.2|oct-1-yl)butylthiazole -2- washed with 1096 MansCO3 (20 ml) and saturated Masylmethyleneamine in the form of an orange solid

yellow color

IN NMR (СО350С0О5) 8.4 (s, 1Н), 7.97 (d, 1Н), dk 7.84 (d, 1Н), 3.82 (s, 6Н), 3.4 (m, 1Н) , 1.7 (m, 1H), 1.5 Mam n (m, 1H), 1.3 (m, 1H), 0.9 (m, 6H), 0.75 (s, ЗН). M. OsM

Stage 6: Preparation of (4-bromophenyl)|thiazol-2-NO 0 Xylmethyl-|13-methyl-1-(4-methyl-2,6,7-trioxa-Bg bicyclo(2.2.2|oct-1- yl)butyl|amine

To a solution of dibromobenzene (700 mg, 3.2 mmol) The title compound was obtained by adding a 2.5 M solution of pVIII in dry ether to the compound (25)-2-(5)-(4-bromophenyl)-thiazole-2- ilsan (1.3 mL, 3.2 mmol) at -30°C. After mixing methyl|amino)-4-methylpentanoic acid with stirring for 1 hour, a solution of aminocyclopropanecarbonitrile was slowly added in the presence

13-methyl-1-(4-methyl-2,6,7-trioxa-NATI and diisopropylamine, in a manner similar to epibicyclo((2.2.2|oct-1-yl)butyl|-thiazol-2-ylmethylene) - sanim to obtain Example 34. Synthesis of (25)-2-amine (500 mg, 1.6 mmol) in 5 ml of dry ether. Reaction mixture of (5)-K4-bromophenyl)thiazol-2-ylmethyl|amino)-4- were left to stir at the same methylpentanoic acid was carried out with the help of temperature for 2 hours, and then the reaction was carried out by the addition of bromophenyllithium (formed by adding 5y with water and extracted with ethyl acetate. Organ- 1,4-dibromobenzene and n-butyllithium) to the product overnight the layer was washed with saturated Mashi and dried by imine condensation between thiazole 2- over Md95O4. The solvent was evaporated under vacuum. carboxyaldehyde and / 3-methyl-1-(4-methyl-2,6,7-

The crude product was subjected to column flash-trioxa-bicyclo(2.2.2|oct-1-yl)butylamine (glass chromatography using 2:1 hexane:EAc as the ester of G-leucine OBO, obtained in the corresponding eluent with obtaining (4- bromophenyl)thiazole-2-st to the method described for Example 34), with polymethyl-13-methyl-1-(4-methyl-2,6,7-trioxa) further orthoester deprotection. bicyclo(2.2.2 |oct-1-yl) butyl|amine in the form of pale-IN NMR (SOSI"): 6 0.82 (d, ЗН), 0.95 (d, ЗН), a yellow solid. 1.04 (m, 2H), 1.46-1.62 (m, 4H), 1.80 (m, 1H), 3.12

IN NMR (СО350С05) 7.64 (d, 1Н), 7.59 (d, 1Н), (dd, 1Н), 4.95 (s, 1Н), 7.22 (s, 1Н), 7.23 -7.25 (d, 2H), 7.5 (d, 2H), 7.28 (d, 2H), 5.68 (c, 1H), 3.82 (c, 6H), 7.31 ( m, 2H), 7.47 (d, 2H), 7.74 (m, 1H). 3.3 (m, 1H), 2.65 (m, 1H), 1.95 (m, 1H), 1.4 (m, 1H), Example 36 1.2 (m, 1H), 0.9 (d, ZN), 0.75 (c, ZN), 0.7 (d, ZN). Synthesis of (1-cyanocyclopropyl)amide (25)-2-4(5)-

Stage 7. Preparation of (25)-2-((5)-C4-24-difluorodiphenyl-4-yl)thiazol-2-ylmethylylamino)bromophenyl)thiazol-2-ylmethylamino)-4-4-methylpentanoic methylpentanoic acid

To a solution of K4-bromophenyl)thiazol-2-yl-methyli-t

13-methyl-1-(4-methyl-2,6,7-trioxa-5.em|.bicyclo(2.2.2|oct-1-yl)butyl|amine (500 mg, Its g c cm 1.06 mmol) in THFf (20 ml) and water (18 ml), n IY A 1Tn NS (3.5 ml) was added. The reaction mixture was stirred at room temperature for 2 hours. After comparing the TI C to the disappearance of the initial substance, (M(OH).NgO ev) was added : (280.2mg, 6b, Seq.) and stirred at room temperature for 2h. Then 1N HCl was added. OAC and the organic layer were dried over Suzuki (1-cyanocyclopropyl)amide (25)-2-((5)-((4-

Ma5O". The solvent was evaporated to obtain bromophenyl)thiazol-2-ylmethyl|amino)-4-(25)-2-(5)-((4-bromophenyl)-thiazol-2-ylmethyl|amino)-methylpentanoic acid Kk 2.A- of 4-methylpentanoic acid in the form of a yellow solid by difluorobenzeneboronic acid, in the presence of this substance. P,1-bisidiphenylphosphino)ferrocene-

Stage 8: Preparation of cyanomethylamide (25)-2- dichloropadadium (II), dichloromethane complex. (5)-(4-bromophenyl)thiazol-2-ylmethyl|amino)-4- M5 (-EBI): 479 |MA1T. of methylpentanoic acid IN NMR (SOCI"): 6 0.84 (d, ЗН), 0.97 (d, ЗН),

In the presence of NATI (eq) and diisopropylethyl - 1.03 (m, 2H), 1.47 (m, 2H), 1.57-1.62 (m, 4H), 1.95 (m, min (4eq) , connected (25)-2-4(5)-I(4-bromophenyl)-1H), 3.27 (dd, 1H), 5.02 (s, 1H), 6.93 (m, 2H ), 7.32 (m, thiazol-2-ylmethylamino)-4-methylpentanoic acid 1H), 7.39 (m, 1), 7.42 (m, 3H), 7.48 (d, 2H), 7 .77 (d, with aminoacetonitrile (2eq, Teq excess) with 1nH). obtaining cyanomethylamide (25)-2-((5)-(4- Example 37 bromophenyl)thiazol-2-ylmethylamino)-4- Synthesis of (i-cyanocyclopropyl)-amide (25)-2-4(5)- methylpentanoic acid in the form of a cream-colored solid ((4-methanesulfonyldiphenyl-4-yl)thiazol-2-wine). ylmethylamino)-4-methylpentanoic acid

IN NMR (СО350С0О5) 8.73 (t, 1Н), 7.66 (d, 1Н), 7.64 (d, 1), 7.5 (dd, 2Н), 7.25 (dd, 10 2Н) 4.92 (d, t 1H), 4.14 (t, 2H), 3.32 (s, 1H), 3.19 (m, 1H), 2.98 (m, 5 dm n 1H), 1 .85 (m, 1H), 1.46 (m, 1H), 0.9-0.85 (m, 6H). M m. s

Example 35 (I am not A

Synthesis of (i-cyanocyclopropyl)-amide (25)2-(5)- ((4-bromophenyl)thiazol-2-ylmethyl|amino)-4-methylpentanoic acid 05 was washed with a saturated solution of ammonium chloride,

The title compound was obtained with a saturated salt solution (2xX), dried over a solution similar to that described for (1-magnesium sulfate, filtered, and the solvent of cyanocyclopropyl)amide (25)-2-(5)-C224- was dissolved in vacuum The residue was purified by means of difluorodiphenyl-4-yl)thiazol-2-ylmethyliamino)-4-chromatography on silica gel using methylpentanoic acid, with the help of cross-ethyl acetate and hexane to obtain methyl M-bonding according to the Suzuki method ((i - ((benzyloxy)carbonyl)-4-oxo-I-norvalinate. cyanocyclopropyl)amide (25)-2-((5)-C4- Stage 3: Preparation of methyl M-bromophenyl)thiazol-2-ylmethylI|amino)- 4- ((benzyloxy)carbonyl)-4,4-difluoro-I-norvalinate of methylpentanoic acid With 4- to a solution of methyl M-((benzyloxy)carbonyl)-4-methanesulfonylphenylboronic acid in oxo-I-norvalinate (1, 3g, 4.65mmol) in dichloromethane (20ml) and methanol (0.019ml) at 0"С slowly bisidiphenylphosphino)ferrocene|dichloropalladium (II), CA5T (2.46ml) was added. The ice bath was removed dichloromethane complex and replaced with a bath with hot water (57"C).

M5 (-EB5I): 521 (M-1T. The bath with hot water was changed three times, then the mixture

Example 38 was stirred overnight at room temperature

Synthesis of //M!-(1-cyanocyclopropyl)-4,4-difluororaturium. The mixture was slowly poured onto a cold

Me-4(15)-2,2,2-trifluoro-1-(4-(methylsulfonyl)-1,1"-sulfonated MansCoOz, extracted with ethyl acetate, diphenyl-4-yl|Hyethyl)-norvalinamide was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was filtered

E E was evaporated in a vacuum. The residue was purified by

E EE n with the help of chromatography on silica gel using ethyl acetate and hexane to obtain methyl M-sor M. ((benzyloxy)carbonyl)-4,4-difluoro-I-norvalinate.

Y and Y Stage 4: Preparation of benzyl (15)-3,3-difluoro-y shk o I 1-(hydroxymethyl) butylcarbamate o | - M To a solution of methyl M-((benzyloxy)carbonyl)- o 4,4 difluoro-I-norvalinate (1.59 g, 5.29 mmol) in

Lithium chloride (919mgHg) was added to CH ethanol (5Xbml) and the mixture was stirred for 10 minutes. Slow

Stage 1: Preparation of methyl M- sodium boron hydride (820 mg) was added, the mixture of per-((benzyloxy)carbonyl)-3-iodo-I-alaninate was stirred for 2 hours. Then another was added

To a solution of carbobenzyloxy-I-serine (25 g, a portion of sodium borohydride (100 mg) and stirring, 104 mmol) in ethyl acetate (200 ml) was added and the solution was continued for 30 minutes. of diazomethane in ether until pale yellow. The mixture was diluted with water (20 ml) and slowly colored. The solvent was evaporated under vacuum. It was neutralized with 1N HCl, and M, M-dimethylformamide (400 ml) was added to the residue with the addition of another aliquot of water. The mixture was extracted with methyltriphenoxyphosphonium iodide (5O0g, ethyl acetate (2x), washed with saturated saline - 110 mmol). The mixture was stirred for 15 minutes with the solution, dried over magnesium sulfate, lye, then methanol (15 ml) was added, and the mixture was then filtered and the solvent was evaporated in a vacuum with sodium thiosulfate poured into 2095 and extracted to obtain benzyl (15)-3,3-difluoro -1- with a mixture of 1:1 ethylacetate hexane (2 l). Organic (hydroxymethyl)butylcarbamate. the layer was washed with water, saturated saline. stirred and the solvent was evaporated under vacuum. Zalamine shock was purified by chromatography on To a solution of benzyl (15)-3,3-difluoro-1-silica gel using ethyl acetate and hexane. (hydroxymethyl)butylcarbamate (from stage 4) in ether

The obtained compound was powdered in diethyl ether (25 ml), palladium on charcoal (1095, ether/hexane, filtered and dried in air with 150 mg) was added, and the mixture was stirred in an atmosphere of H»g (ba- to obtain methyl M-((benzyloxy)carbonyl)- 3- lon) within 2 hours. Dichloromethane and a mixture of iodo-alaninate were added. filtered on celite. The solvent was evaporated in

Stage 2: Preparation of methyl M- under vacuum The residue was dissolved in dichloromethane ((benzyloxy)carbonyl)-4-oxo-I-norvalinate (15 ml) and triethylamine (ml), M,M-

A mixture of methyl M-((benzyloxy)carbonyl)-3-iodo-dimethylaminopyridine (TOmg) and chloro-t-

Y-alanine (10g, 27.5mmol), from stage 1, zinc-butyldimethylsilane (844mg). The mixture was stirred with copper vapor (3.3 g) in benzene (11 Oml) and M, M- during the night, then water was added and dimethylacetamide salt (7.4 ml) was subjected to ultrasound. The mixture was extracted with ethyl acetate (2x), heated in an ultrasonic bath for 2 hours. It was washed with a saturated saline solution, dried under draft during this period, 3 portions of 1,2- over magnesium sulfate were added, filtered, and the solvent of dibromoethane (0.24 ml) and chlorotrimethylsilane was evaporated in a vacuum to obtain (25)-1- (0.17 ml). (tert-butyl(dimethyl)silyl)oxy)-4,4-bis(triphenylphosphine)palladium chloride (0.958g, 1.4mmol) and difluoropentan-2-amine were then added to this mixture. acetyl chloride (2.5 ml, 35.2 mmol) and the mixture is heated. 4-difluoro-M-(1E)- to room temperature, the mixture was filtered 2,2,2-trifluoroethylidene)pentan-2-amine on celite with ethyl acetate, then the organic layer Solution (25)-1-(tert-

butyl(dimethyl)silyl)oxy)-4,4-difluoropentane-2-shi: NE ss . . sh-. . . KMyazvymoi mi Mdra po i Yaeiletetsi be OM ENCHM U ZK ENN: amine from stage 5, and trifluoroacetaldehyde methylhemiorla Zori en and E acetal (80965, 0.9ml) in benzene (20ml) were heated with | coivenevevy A jam cha IMBSEME M 1 : PA reflux refrigerator during still using GB dnomenya and Zlyv NBN Vel ZEMNI i toving the Dean-Stark apparatus. The evaporation solvent is KSO on nn utii sten nn 6. KVN NN no o MB KREM N vals in a vacuum and the residue was purified with the help of nen and ANNA NA chromatography on silica gel using eth-ium vezekev PET Lola ro . and puvdin mk uyu VI ZNM N H lacacetate and hexanes to obtain (25)-1-(tert- Kv OH nn keV i - - -M- - I pyr mi star peviyuyia N I piz What I 2 butyl(dimethyl)silyl) oxy)-4,4-difluoro-M-(1E) in 2,2,2-trifluoroethylidene)pentan-2-amine. And prdtenet on lnesru vti" I ! and : -2- -1-(4- Gneknroonid nene KUM IRYNA ii it

Stage t: Obtaining (25) 2 (g Z) 1 a PA. 1-olu GNrch in the book of MES KYM

To -78"С of a solution of 1,4-dibromobenzene (33Omg) in ee NN EN VN

THF (Boml) was added to 2.5 M p-Vshi in hexane reno koe (0.52 ml) and the solution was kept for 30 minutes: ZBK NI; 1. I Гм люжеажци и ZNU tsonutyr il ime SE an ime, lin. Then solution (25) was added. 1-(tert pe in Not MNN butyl(dimethyl)silyl)oxy)-4,4-difluoro-M-((1E)- PEK Korinoniyuvanyaim OVA A ABOVE JUICE NOT 2,2,2-trifluoroethylidene)pentan-2-amine (333 MmMg) in the NC

THF (5.2 ml). The mixture was stirred at -787C for 45 minutes, then poured onto a cold surface. When all the saturated ammonium chloride was added, it was extracted with ethyl acetate (2xX), washed with a saturated saline solution, dried over magnesium sulfate, filtered and purified. Ш КК century | KENE EMO was stirred and the solvent was evaporated under vacuum. Zalyp ev Z shi en shock was dissolved in tHgF (1 Oml) cooled in a bath and drunk outside Xia | I N. . . and decimoscheh and | : ice/water and added n-tetrabutylammonium fluoride C Kdivnemet PV KVvne I KV KN I MySHI (1M in THF, 1.5ml). The mixture was stirred at 0" PE about NN NN

Nv B No NN NM! for 1 hour, poured into cold water, extra-pen i ia ia Kot ef NI PN PN

EC VU Z V N was washed with ethyl acetate (2x), washed with saturated GAY ianVti mar red" NAME OF THE NAMES DOWN saline solution, dried over magnesium sulfate, filtered, and the solvent was evaporated under vacuum. HB I umi with obtaining (25) 2 (y Z) 1 (4 bromophenyl) TK Yadavoment and I VKI duv iv ZT MM : 2.,2.2-trifluoroethyl)amino)-4,4-difluoropentan-1 -ol. Kon NN

Stage 8: Preparation of M2-((15)-1-(4-bromophenyl)-! Men 0000 NKT VM VN difluoro-I -norvalinamide I earth nskovkya a creAYAYA: I and IEM NVMYTMO MM d.sinsntttntttinttnttttttt epithets (25)-2-((15)-1-(4-Bromophenyl)-2,2,2 - ЭЕИАДИБКсяно t one AS EMEGENK I MOVI trifluoroethyl)amino)-4,4-difluoropentan-1-ol perern z Kn Z Ov was created into the compound indicated in the title using | eV NEK PV 00 infe vk ; you te and mettsotseiv efe Io dnemetya krovi MOVBY ZM N toving the method described in stage 9 of Example 15. ruled Iv I ZY tnnaketk so a! . . .

Stage 9: Obtaining M!-(1-cyanocyclopropyl)- by IN POM 2; : Moyuyuyuky ether of KZ inometvlyudilauilyuya. 1 MBO YAKA MM : 4,4-difluoro-M schu 5)-2,2,g-trifluoro-1-14(methylthio)- and methylpbbutlky noi du a trifluoroethylyluene. 1,1"-diphenyl-4-yl|ethyl)i -norvalinamide o p PI : RM PPokhomesvy and TSO ZVI Zo jams MENE and BMI N

M'-(15)-1-(4-Bromophenyl)-2,2,2-trifluoroethylene nn I MLN

M'- 1-cyanocyclopropyl -4,4-di tor-i- EMdivnometna M VK V tuya PASKI i IM i zhk pa | And norvalinamide was converted into the compound specified in the title using the method described in the RHYTHM of DME spykhayuth OMS t-idyuryunen ni umtifony on nnA Dsh stage 10 When clade 15. and ZY lprne and row NE Pa i VANI 1

Stage 10: Preparation of M1-1-(cyanocyclopropyl)-VENU o IN 'PA VKA olumtrynya mia FMM loBYA MA and 4,4-difluoro-M'-(15)-2,2,2-trifluoro-1-14- HOKfTeU M late MEN otr (methylsulfonyl)-1 NO -diphenyl-4-yl|ethyl)u - ! But an um prave E MIV la UA E : : p itrafUkhnetatih and lira visti I N ! norvalinamide Tlenvinemya 00000000

M1-(1-Cyanocyclopropyl)--4,4-difluoro-M2-ЦИ1 58)- and a en VD Y | MSE Mr: 2,2,2-trifluoro-1-(4-(methylthio)-1,1-diphenyl-4- T value svefn О1 ММ ВН Я TM Ж. Й : . And pyrimidine-Zlafonz myo zve aamih : : il|ethyl-norvalinamide was converted into the title compound indicated in the column using the method described in step 11 of Example 15.

Using experimental methods similar to those listed above, the following compounds were synthesized:

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