RS96203A - Novel compounds and compositions as cathepsin inhibitors - Google Patents

Novel compounds and compositions as cathepsin inhibitors

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Publication number
RS96203A
RS96203A YU96203A YUP96203A RS96203A RS 96203 A RS96203 A RS 96203A YU 96203 A YU96203 A YU 96203A YU P96203 A YUP96203 A YU P96203A RS 96203 A RS96203 A RS 96203A
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Serbia
Prior art keywords
phenylmethanesulfonylmethyl
cyclohexylmethyl
cyanomethyl
alkyl
malonamide
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YU96203A
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Serbian (sr)
Inventor
Sheila Zipfel
John Patterson
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Axys Pharmaceuticals Inc.
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Publication date
Application filed by Axys Pharmaceuticals Inc. filed Critical Axys Pharmaceuticals Inc.
Publication of RS96203A publication Critical patent/RS96203A/en

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Abstract

The present invention relates to novel selective cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

Description

NOVA JEDINJENJA I KOMPOZICIJE KOJA SE KORISTE KAO INHIBITORI KATEPSINA NEW COMPOUNDS AND COMPOSITIONS USED AS CATHEPSIN INHIBITORS

Pronalazak Invention

Dati prijava odnosi se na jedinjenja i kompozicije za lečenje oboljenja u vezi sa aktivnošću cistein proteaze, naročito oboljenja u vezi sa aktivnošću katepsina S. The present application relates to compounds and compositions for the treatment of diseases related to cysteine protease activity, particularly diseases related to cathepsin S activity.

OPIS PRONALASKA DESCRIPTION OF THE INVENTION

< <

Cisteinske proteaze predstavljaju klasu peptidaza koje se karakterišu prisustvom cisteinskog ostatka u katalitičkom mestu enzima. Cisteinske proteaze povezane su sa normalnom degradacijom i dobijanjem proteina. Neubičajena aktivnost cisteinskih proteaza, na primer, kao rezultat povećane ekspresije ili pojačane aktivnosti, može imati patološke posledice. U ovom pogledu, izvesne cisteinske proteaze povezane su sa brojnim bolesnim stanjima koja imaju veze sa artritisom, mišićnom distrofijom, inflamacijom, invazijom tumora, glomerulonefritisom, malarijom, periodontalnom bolešću, metahromatskom leukodistrofijom i ostallim oboljenjima. Povećana aktivnost catepsina S doprinosi patologiji i/ ili simptomatologiji brojnih oboljenja. Shodno tome, molekuli koji inhibiraju aktivnost katepsin S proteaze korisna su terapeutska sredstva u lečenju takvih oboljenja. Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with normal protein degradation and recovery. Abnormal activity of cysteine proteases, for example, as a result of increased expression or increased activity, can have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states related to arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and other diseases. Increased cathepsin S activity contributes to the pathology and/or symptomatology of numerous diseases. Accordingly, molecules that inhibit cathepsin S protease activity are useful therapeutic agents in the treatment of such diseases.

Data prijava odnosi se na jedinjenja formule I: The present application relates to compounds of formula I:

u kojoj in which

X' predstavlja -NHC(R')(R2)X2 ili -NHX3 X<2>je<y>cijano, -C(R7)(R8)X3, . X' represents -NHC(R')(R2)X2 or -NHX3 X<2>is<y>cyano, -C(R7)(R8)X3, .

C(R<7>)(R<8>)CF3, -C(R7)(R<8>)CF2CF2R9 -CH=CHS(0)2R<5>, -C(0)CF2C(0)NR5r5, . C(R<7>)(R<8>)CF3, -C(R7)(R<8>)CF2CF2R9 -CH=CHS(0)2R<5>, -C(0)CF2C(0)NR5r5, .

C(0)C(0)NR<5>r6, -C(0)C(0)OR5, -CtCOCr^OR<S>, -C(0)CH2N(R6)SC>2R5 ili - C(0)C(0)NR<5>r6, -C(0)C(0)OR5, -CtCOCr^OR<S>, -C(0)CH2N(R6)SC>2R5 or -

C(0)C(0)R<5>; gde je R<5>(Ci-4)alkil, (C5-1 o)aril(Co-6)alkil ili (C5-io)heteroaril(Cn-6)alkil; gde je R<6>vodonik ili (C-|-6)alkil; R<7>je vodonik ili (C-j -4)alkil i R<8>je hidroksi ili R<7>i R<8>zajedno grade okso; R<9>je vodonik, halo, (Ci-4)alkil, (C5-10)aril(Co-6)alkil ili (C5-1 o)heteroaril(Co-6)a'kil; X<3>obuhvata heteromonociklični prsten sa 4 do 6 atoma u prstenu ili spojeni heterociklični prstenasti sistem sa 8 do C(0)C(0)R<5>; where R<5> is (C 1-4 )alkyl, (C 5-1 o )aryl(C 1-6 )alkyl or (C 5-10 )heteroaryl(C 1-6 )alkyl; where R<6> is hydrogen or (C-1-6)alkyl; R<7> is hydrogen or (C-1-4)alkyl and R<8> is hydroxy or R<7> and R<8> together form oxo; R<9> is hydrogen, halo, (C 1-4 )alkyl, (C 5-10 )aryl(C 0-6 )alkyl or (C 5-1 o )heteroaryl(C 0-6 )alkyl; X<3>comprises a heteromonocyclic ring with 4 to 6 ring atoms or a fused heterocyclic ring system with 8 to

14 atoma u prstenu i bilo koji derivat karbocikličnog ketona, iminoketona ili tioketona; u kojem unutar R<5>, X<2>ili X<3>bilo koji aliciklični ili aromatični prstenasti sistem može biti dalje supstituisan sa 1 do 5 radikala koji su nezavisno odabrani od (C-|-6)alkil, (C-|-6)alkiliden, cijano , halo, halo-supstitusani (Ci-4)alkil, nitro, - 14 ring atoms and any carbocyclic ketone, imino ketone or thioketone derivative; wherein within R<5>, X<2> or X<3> any alicyclic or aromatic ring system may be further substituted with 1 to 5 radicals independently selected from (C-|-6)alkyl, (C-|-6)alkylidene, cyano, halo, halo-substituted (Ci-4)alkyl, nitro, -

x4nr<12>R<12>)x<4>NR<12>C(0)R<1>2i.x4nr<1>2c(0)OR12i. x4nr<12>R<12>)x<4>NR<12>C(0)R<1>2i.x4nr<1>2c(0)OR12i.

x4nr12c(0)NR12r12,X4nr12c(NR"I2)nr12r12ix4or12|x4sr12i. x4nr12c(0)NR12r12,X4nr12c(NR"I2)nr12r12ix4or12|x4sr12i.

X4C(0)0R12,-X4C(0)R12>-X40C(0)R12,X4C(0)NR12r12i-X4S(0)2NR12r12iX4NR1 2s(0)2R1 2,-X4p(0)(OR1 2)OR1 2,-x4oP(0)(OR1 2)0R1 2,. X4C(0)0R12,-X4C(0)R12>-X40C(0)R12,X4C(0)NR12r12i-X4S(0)2NR12r12iX4NR1 2s(0)2R1 2,-X4p(0)(OR1 2)OR1 2,-x4oP(0)(OR1 2)0R1 2,.

X4NR12c(0)R13, -X4S(0)R13 i -x4s(0)2R<13>i / ili 1 radikal odabran od -R14, - X4NR12c(0)R13, -X4S(0)R13 and -x4s(0)2R<13>and / or 1 radical selected from -R14, -

X4OR14, -X4SR14, -X4S(0)R14, -X4s(0)2R14, -X4C(0)R14,-X4C(0)OR14,-X4OR14, -X4SR14, -X4S(0)R14, -X4s(0)2R14, -X4C(0)R14,-X4C(0)OR14,-

x<4>0C(0)R<14>i-x<4>NR<l>4R12).x4fsjR12c(0)R<1>4,-x4NR<12>C(0)0R'|4I-x<4>c(0)NR<12>r<12>i.X<4>s(0)2NR14r12,.x4Nr1<2>s(0)2R14,-x4nr<12>C(0)NR14R12j.X4NR12C(NR12)NR1 4r1 2f gde jeX4 veza ili (C-|-6)alkil; R<12>prj svakom pojavljivanju svaki za sebe vodonik, (Ci-6)alkil ili halo-supstituisani (Ci-6)alkil; R<13>je (Ci-6)alkil il halo-supstituisani(C-1-6)alkil; i R<14>je (C3-10)cikloakil(Co-6)alkil, x<4>0C(0)R<14>i-x<4>NR<l>4R12).x4fsjR12c(0)R<1>4,-x4NR<12>C(0)0R'|4I-x<4>c(0)NR<1 2>r<12>i.X<4>s(0)2NR14r12,.x4Nr1<2>s(0)2R14,-x4nr<12>C(0)NR14R12j.X4NR12C(NR12)NR1 4r1 2f where X4 is a bond or (C-1-6)alkyl; R<12> before each occurrence is each hydrogen, (Ci-6)alkyl or halo-substituted (Ci-6)alkyl; R<13> is (C1-6)alkyl or halo-substituted (C1-6)alkyl; and R<14>is (C3-10)cycloalkyl(C0-6)alkyl,

hetero(C3-l o)cikloalkil(Co-6)alkil, (C6-10)aril(Co-6)alkil, hetero(Cs-i rj)aril(Co-6)alkil, (Cg-io)bicik!oaril(Co-6)alkil ili hetero(C8-lo)bicikloaril(Co-6)alkil; hetero(C3-10)cycloalkyl(Co-6)alkyl, (C6-10)aryl(Co-6)alkyl, hetero(C8-10)aryl(Co-6)alkyl, (C8-10)bicycloaryl(Co-6)alkyl or hetero(C8-10)bicycloaryl(Co-6)alkyl;

R<1>je vodonik, halo ili (Ci-6)alkil i R<2>je odabran iz grupe koju čine vodonik, cijano, R<1>is hydrogen, halo or (Ci-6)alkyl and R<2>is selected from the group consisting of hydrogen, cyano,

hal0,-X4NR12R12,-X4NR12C(O)R12,-X4NR<12>C(0)OR<12>,-X4NR<12>C(O)NR12R<12>,-X4NR12C(NR12)NR12R1 2,-X4OR12,X4SR12,-X4C(0)OR1 2,-X4C(0)R12,-X4OC(0)R1 2, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR<12>R<1>2,X<4>NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR<12>, hal0,-X4NR12R12,-X4NR12C(O)R12,-X4NR<12>C(0)OR<12>,-X4NR<12>C(O)NR12R<12>,-X4NR12C(NR12)NR12R1 2,-X4OR12,X4SR12,-X4C(0)OR1 2,-X4C(0)R12,-X4OC(0)R1 2, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR<12>R<1>2,X<4>NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR<12>,

X<4>OP(0)(OR<12>)OR12,-X4NR<12>C(0)R<13>, -X<4>S(0)R<13>i-X4S(0)2R<13>, -R<14>, -X4OR14, -X4SR<14>, X<4>OP(0)(OR<12>)OR12,-X4NR<12>C(0)R<13>, -X<4>S(0)R<13>and-X4S(0)2R<13>, -R<14>, -X4OR14, -X4SR<14>,

-X<4>S(0)R14,-X<4>S(0)2R<14>, -X4C(0)R14 -X<4>C(0)OR<14>, -X<4>OC(0)R<14>,-X<4>NR14R12,--X<4>S(0)R14,-X<4>S(0)2R<14>, -X4C(0)R14 -X<4>C(0)OR<14>, -X<4>OC(0)R<14>,-X<4>NR14R12,-

,X<4>NR<12>C(0)R<1>4,-X4NR<12>C(0)OR<14>,-X<4>C(0)NR<12>R12,-X<4>S(0)2NR<14>R12,-X4NR<12>S(0)2R<14>,-x4nr1<2>C(0)NR<14>r12 i-x<4>NR<i2>C(NRi<2>)NRi4Ri2, gde su X<4>, r12, r13 j r14kao što je ranije definisano; ili R<1>i R<2>zajedno sa atomom ugljenika za koji su vezani i R<1>i R<2>grade (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; gde je unutar pomenutog R<2>bilo koji heteroaril, aril, cikloalkil, heterocikloalkil, cikloalkilen ili heterocikloalkilen po slobodnom izboru supstituisan sa 1 do 3 radikala koji su nezavisno odabrani od C(i-6)alkil, (C-|-6)alkiliden, cijano , halo, halo-supstitusani (Ci-4)alkil, nitro, -x<4>nr12r12,x4nr<12>c(0)R12,-x<4>nr12c(0)OR12,-x<4>nr12c(0)nr12r12.-X<4>NR<12>C(NR<12>)NR<1>2R12,-X<4>OR<1>2,-X<4>SR<12>,-X<4>C(0)OR<12>,-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X4C(0)NR12R12 -X<4>S(0)2NR12R12,X4NR1<2>S(0)2R<12>,-X<4>P(0)(OR<12>)OR<12>,-X<4>OP(0)(OR12)OR12,-X4NR1<2>C(0)R13, -X4S(0)R13, -X<4>S(0)2R<13>iX<4>C(0)R<13>, gdeSUX<4>, . i-x<4>NR<i2>C(NRi<2>)NRi4Ri2, where X<4>, r12, r13 and r14 are as previously defined; or R<1> and R<2> together with the carbon atom to which both R<1> and R<2> are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; wherein within said R<2> any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from C(i-6)alkyl, (C-|-6)alkylidene, cyano, halo, halo-substituted (Ci-4)alkyl, nitro, -x<4>nr12r12,x4nr<12>c(0)R12,-x<4>nr12c(0)OR12,-x<4>nr12c(0)nr12r12.-X<4>NR< 12>C(NR<12>)NR<1>2R12,-X<4>OR<1>2,-X<4>SR<12>,-X<4>C(0)OR<12>,-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X4C(0)NR12R12 -X<4>S(0)2NR12R12,X4NR1<2>S(0)2R<12>,-X<4>P(0)(OR<12>)OR<12>,-X<4>OP(0)(OR12)OR12,-X4NR1<2>C(0)R13, -X4S(0)R13, -X<4>S(0)2R<13>iX<4>C(0)R<13>, whereSUX<4>,

r12jr13 g0re definisani; R<3>je -C(R<6>)(R<6>)X<5>, gde je R<6>gore definisan i gde je X<5>odabrana od -x<4>nr12r12,-x4nr12C(0)R<12>,-x<4>nr12C(0)OR12,x4nr12C(0)NR12r12,-X<4>NR<12>C(NR<12>)NR<12>R<12>,-X<4>OR<1>2,-X<4>SR<12>,-X<4>C(0)OR<12>>-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR12R<12>, X<4>NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR12,-X4R<12>,-X<4>OP(0)(OR<12>)OR12,-X4C(0)R<13>,-X4NR<12>C(0)R<13>, -X<4>S(0)R<13>i-X4S(0)2R<13>, -R14, - r12jr13 defined above; R<3>is -C(R<6>)(R<6>)X<5>, where R<6>is as defined above and X<5>is selected from -x<4>nr12r12,-x4nr12C(0)R<12>,-x<4>nr12C(0)OR12,x4nr12C(0)NR12r12,-X<4>NR<12 >C(NR<12>)NR<12>R<12>,-X<4>OR<1>2,-X<4>SR<12>,-X<4>C(0)OR<12>>-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR12R<12>, X<4>NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR12,-X4R<12>,-X<4>OP(0)(OR<12>)OR12,-X4C(0)R<13>,-X4NR<12>C(0)R<13>, -X<4>S(0)R<13>i-X4S(0)2R<13>, -R14, -

X<4>OR<14>, -X<4>SR<14>, -X<4>S(0)R<14>, -X<4>S(0)2R14, -X<4>C(0)R14,-X<4>C(0)OR<14>, -X<4>OC(0)R<14>,-X<4>NR<1>4R12,-X<4>NR<12>C(0)R<14>,-X4NR<12>C(0)OR<14>,-X<4>C(0)NR14R12,-X<4>S(0)2NR<14>R12,-X<4>OR<14>, -X<4>SR<14>, -X<4>S(0)R<14>, -X<4>S(0)2R14, -X<4>C(0)R14,-X<4>C(0)OR<14>, -X<4>OC(0)R<14>,-X<4>NR<1>4R12,-X<4>NR<12>C(0)R<14>,-X4NR<12>C(0)OR<14>,-X<4>C(0)NR14R12,-X<4>S(0)2NR<14>R12,-

X4NR12S(0)2R14-X4NR12C(0)NR14R12i -X4NR12C(NR12)NR<14>R<12>, gdeSUX<4>,R12,R13 X4NR12S(0)2R14-X4NR12C(0)NR14R12i -X4NR12C(NR12)NR<14>R<12>, whereSUX<4>,R12,R13

iR14 kao što je ranije definisano; X<4>je -NR6R6, -NR<6>R14,-NR6R15 ili -NR6X<5>C(0)R14 iR14 as previously defined; X<4>is -NR6R6, -NR<6>R14, -NR6R15 or -NR6X<5>C(0)R14

gde su R6,X5 iR14kao što je ranije opisano i R<15>je vodonik, -(Ci -6)alkil ili - where R6, X5 and R14 are as previously described and R<15> is hydrogen, -(C1-6)alkyl or -

X<5>OR6 gde je X<5>gore opisan; ili R6 i R<1>5 zajedno sa atomom azota za koji su vezani i R<6>i R<15>grade hetero(C3-io)cikloalkil ili hetero(C5--|o)aril ili hetero(Cs-10)bicikloaril; gde se u okviru R<3>i R<4>bilo koji aliciklični ili aromatični prstenasti sistem može dalje supstituisati sa 1-5 radikala koji su nezavisno odabrani od (C-|-6)alkil, (Ci-6)alkiliden, cijano, halo, halo-supstituisani(Ci-4)alkil, nitro, - X<5>OR6 where X<5> is as described above; or R6 and R<1>5 together with the nitrogen atom to which both R<6> and R<15> are attached form hetero(C3-io)cycloalkyl or hetero(C5--|o)aryl or hetero(Cs-10)bicycloaryl; where within R<3> and R<4> any alicyclic or aromatic ring system can be further substituted with 1-5 radicals independently selected from (C-|-6)alkyl, (Ci-6)alkylidene, cyano, halo, halo-substituted (Ci-4)alkyl, nitro, -

X<4>NR<12>R<1>2).x4NR<12>C(0)R<12>,-X<4>nr<12>C(0)OR<12>). X<4>NR<12>R<1>2).x4NR<12>C(0)R<12>,-X<4>nr<12>C(0)OR<12>).

x<4>nr<12>C(0)NR<12>R12,x4NR12c(NR12)NR12R12ix4or12iX4sr12i. x<4>nr<12>C(0)NR<12>R12,x4NR12c(NR12)NR12R12ix4or12iX4sr12i.

X<4>C(0)OR<12>,-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X<4>C(0)NR<12>R<12>, -X4S(0)2NR12R12 X<4>C(0)OR<12>,-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X<4>C(0)NR<12>R<12>, -X4S(0)2NR12R12

X4NR1 2S(0)2R1 2,-X4p(0)(OR1 2)OR1 2,-X4OP(0)(ORl 2)or1 2,. X4NR1 2S(0)2R1 2,-X4p(0)(OR1 2)OR1 2,-X4OP(0)(OR1 2)or1 2,.

x4nr1<2>C(0)R13,-X<4>S(0)R13 i -X<4>S(0)2R<13>i / ili 1 radikal odabran od -R<14>, - x4nr1<2>C(0)R13,-X<4>S(0)R13 and -X<4>S(0)2R<13>and / or 1 radical selected from -R<14>, -

X4OR<1>4, -X4SR<14>, -X<4>S(0)R<14>, -X<4>S(0)2R<14>, -X<4>C(0)R<14>, -X<4>C(0)0R<14>, - X4OR<1>4, -X4SR<14>, -X<4>S(0)R<14>, -X<4>S(0)2R<14>, -X<4>C(0)R<14>, -X<4>C(0)0R<14>, -

X<4>OC(0)R<14>,-X<4>NR<14>R<12>,-X<4>NR<12>c(0)R<1>4,-X4NR<12>C(0)OR<14>,-x<4>c(0)NR<1>4R12,-X<4>S(0)2NR<14>r<1>2,.x4nr<12>s(0)2R<14>,-X4NR12c(0)NR14r12 j -X4NR12C(NR12)nr14r<12>]i gde u granicama R3 i R<4>bilo koji alifatični prsten može dalje biti supstituisan sa 1-5 radikala nezavisno supstituisani od cijano, halo, nitro, -NR<12>r12, -NR12C(0)R12, -NR12C(0)OR12, - X<4>OC(0)R<14>,-X<4>NR<14>R<12>,-X<4>NR<12>c(0)R<1>4,-X4NR<12>C(0)OR<14>,-x< 4>c(0)NR<1>4R12,-X<4>S(0)2NR<14>r<1>2,.x4nr<12>s(0)2R<14>,-X4NR12c(0)NR14r12 j -X4NR12C(NR12)nr14r<12>]i where within R3 and R<4>any aliphatic ring can be further substituted with 1-5 radicals independently substituted by cyano, halo, nitro, -NR<12>r12, -NR12C(0)R12, -NR12C(0)OR12, -

NR<12>C(0)NR<12>R<12->NR<1>2C(NR<12>)NR<12>R<12>,-0R<12>,-SR<12>,-C(0)0R<12>1. NR<12>C(0)NR<12>R<12->NR<1>2C(NR<12>)NR<12>R<12>,-0R<12>,-SR<12>,-C(0)0R<12>1.

C(0)R12,-OC(0)R12i-C(0)NR12R12i.S(0)2NR12R12,-NR12s(0)2R<12>,-P(0)(OR12)OR12i.oP(0)(OR12)OR12i.NR12C(0)R13,-S(0)R"I3 i -S(0)2R<13>; C(0)R12,-OC(0)R12i-C(0)NR12R12i.S(0)2NR12R12,-NR12s(0)2R<12>,-P(0)(OR12)OR12i.oP(0)(OR12)OR12i.NR12C(0)R13,-S(0)R13 i -S(0)2R<13>;

gdesu X4, R<12>j R<14>ranije definisani; pod uslovom da je samo jedna biciklična prstenasta struktura prisutna u okviru R<3>ili R<4>; i derivati N-oksida, derivati proleka, derivati sa zaštitnom grupom, pojedinačni izomeri i smeše tih izomera; i farmaceutski prihvatljive soli i solvati (na primer, hidrati) tih jedinjenja i derivati N-oksida; derivati proleka, derivati sa zaštitnim grupama, pojedinačni izomeri i smeše tih izomera. Drugi aspekt pronalaska predstavlja farmaceutsku kompoziciju koja sadrži jedinjenje formule I ili derivata N-oksida, pojedinačni izomeri ili smeše tih izomera, ili njena farmaceutski prihvatljiva so, u u smesi sa jednim ili više odgovarajućih ekscipijenata. Treći aspekt pronalaska odnosi se na postupak za lečenje oboljenja kod životinja gde inhibicija katepsina S može da spreči where X4, R<12>j R<14> are previously defined; provided that only one bicyclic ring structure is present within R<3> or R<4>; and N-oxide derivatives, prodrug derivatives, derivatives with a protective group, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvates (eg, hydrates) of those compounds and N-oxide derivatives; prodrug derivatives, derivatives with protective groups, individual isomers and mixtures of these isomers. Another aspect of the invention is a pharmaceutical composition containing a compound of formula I or an N-oxide derivative, individual isomers or mixtures of these isomers, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients. A third aspect of the invention relates to a method for treating diseases in animals where inhibition of cathepsin S can prevent

inhibira ili poboljša patologiju i/ ili simptomatologiju oboljenja, gde pomenuti postupak obuhvata primenu na životinje terapeutski efikasne količine jedinjenja formule I ili derivata N-oksida, pojedinačnog izomera il smeše tih izomera; ili njene farmaceutski prihvatljive soli. inhibits or improves the pathology and/or symptomatology of the disease, where the said procedure includes the application to animals of a therapeutically effective amount of a compound of formula I or an N-oxide derivative, an individual isomer or a mixture of these isomers; or pharmaceutically acceptable salts thereof.

Četvrti aspekt pronalaska predstavlja postupak za pripremanje jedinjenja formule I i derivata N-oksida, derivata proleka, zaštićenih derivata, pojedinačnih izomera il smeše tih izomera; ili njene farmaceutski prihvatljive soli. The fourth aspect of the invention is a process for preparing compounds of formula I and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers or mixtures of these isomers; or pharmaceutically acceptable salts thereof.

DETALJAN OPIS PRONALASKA DETAILED DESCRIPTION OF THE INVENTION

Definicije: Definitions:

Osim ako drugačije nije navedeno , sledeći nazivi, upotrebljeni u Opisu i Zahtevima u okviru ove Prijave imaju značenja, data u ovom Odeljku : "Alicikličan" označava prsten sa karakterističnim rasporedom atoma ugljenika u zatvorenim nearomatičnim prstenastim strukturama, s osobinama, koje podsećaju na osobine alifatičnih struktura i mogu biti zasićeni ili nezasićeni i sa dve ili vise dvostrukih ili trostrukih veza. Unless otherwise stated, the following names used in the Description and Claims within this Application have the meanings given in this Section: "Alicyclic" means a ring with a characteristic arrangement of carbon atoms in closed non-aromatic ring structures, with properties that resemble the properties of aliphatic structures and can be saturated or unsaturated and with two or more double or triple bonds.

"Alifatičan" označava deo sa karakterističnim nerazgranatim ili razgranatim rasporedom sastavnih atoma ugljenika i može biti zasićen ili delimično zasićen i sa dve ili više dvostrukih ili trostrukih veza. "Aliphatic" means a moiety with a characteristic unbranched or branched arrangement of the constituent carbon atoms and may be saturated or partially saturated and with two or more double or triple bonds.

"Alkil" predstavlja sam po sebi nerazgranati ili razgranati, zasićeni ili nezasićeni radikal sa naznačenim brojem atoma ugljenika (na pr. (C-|-6)alkil znači metil, etil, propil, izopropil, butil, sek-butil, izobutil, terc.-butil, vinil, alil, 1-propenil, izopropenil, 1-butenil, 2-butenil, 3-butenil, 2-metilalil, etinil, 1-propinil, 2-propinil i si.). Alkil, naznačen kao deo većeg radikala (na pr. kao u arilalkilu) označava nerazgranati ili razgranati, zasićeni ili nezasićeni dvovalentni radikal, sa brojem atoma naznačenih ili kada je naznačeno 0 atoma, to znači vezu (na pr. (C6--]0)aril(Co-3)alkil obuhvata fenil, benzil, fenetil, 1-feniletil, 3-feniletil i njima slično). "Alkyl" per se represents an unbranched or branched, saturated or unsaturated radical with the indicated number of carbon atoms (eg (C-|-6)alkyl means methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc.). Alkyl, indicated as part of a larger radical (e.g. as in arylalkyl) means an unbranched or branched, saturated or unsaturated divalent radical, with the number of atoms indicated or when 0 atoms are indicated, it means a bond (e.g. (C6--]0)aryl(Co-3)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylethyl and the like).

"Alkilen", osim ako je naznačeno drugačije, označava nerazgranati (pravi) ili razgranati, alifatični, dvovalentni radikal sa naznačenim brojem atoma ugljenika (na pr.(Ci-6)alkilen označava metilen (-CH2-), etilen (-CH2CH2-), trimetilen (-CH2CH2CH2-), tetrametilen (-CH2CH2CH2CH2-), 2-butenilen (- "Alkylene", unless otherwise indicated, means an unbranched (straight) or branched, aliphatic, divalent radical with the indicated number of carbon atoms (eg (Ci-6)alkylene means methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-), 2-butenylene (-

CH2CH=CHCH2-), 2-metiltetrametilen (-CH2-CH(CH3)CH2CH2-)>pentametilen (-CH2CH2CH2CH2CH2-) i si.) CH2CH=CHCH2-), 2-methyltetramethylene (-CH2-CH(CH3)CH2CH2-)>pentamethylene (-CH2CH2CH2CH2CH2-) and si.)

"Alkiliden" označava nerazgranati ili razgranati, zasićeni ili nezasićeni alifatični, dvovalentni radikal sa naznačenim broja atoma ugljenika (na pr. (C-|-6)-alkiliden uključuje metiliden (=CH2), etiliden (=CHCH2), izopropiliden (=C(CH3)3), "Alkylidene" means a straight or branched, saturated or unsaturated aliphatic, divalent radical having the indicated number of carbon atoms (eg (C-|-6)-alkylidene includes methylidene (=CH2), ethylidene (=CHCH2), isopropylidene (=C(CH3)3),

propiliden (=CHCH2CH2), alkiliden (=CHCH=CH2) i si.). propylidene (=CHCH2CH2), alkylidene (=CHCH=CH2) etc.).

"Amino" označava radikal -NH2. Osim ako je naznačeno dugačije, "Amino" means the radical -NH2. Unless stated longer,

jedinjenja prema pronalasku sa sadržajem amino polovina sadrže njihove zaštićene derivate. Pogodne zaštitne grupe za amino polovine uključuju acetil, terc.-butoksikarbonil, benziloksikarbonil i si. compounds according to the invention containing amino moieties contain protected derivatives thereof. Suitable protecting groups for the amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

"Životinje" uključuju i ljude, neljudske sisare (na pr., pse, mačke, goveda, konje,ovce, koze, svinje, jelene, itd.) i nesisare (na pr. ptice, itd.). "Animals" include humans, non-human mammals (eg, dogs, cats, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.).

"Aromatičan" označava polovinu, gde sastavni atomi čine nezasićeni sistem prstena, pri čemu svaki je sp2 hibridizovan i ukupan broj pi elektrona jednak je 4n + 2. "Aromatic" means a half, where the constituent atoms form an unsaturated ring system, each sp2 hybridized and the total number of pi electrons equals 4n + 2.

"Aril" označava sklop monocikličnog ili bicikličnog prstena sa sadržajem ukupnog broja naznačenih atoma ugljenika, pri čemu se svaki prsten sastoji od 6 atoma ugljenika u prstenu i aromatičan je ili kada je vezan za drugi prsten formira sklop aromatičnog prstena. Na pr., (C6-I2)aril kao što se upotrebljava u ovoj prijavi uključuje obuhvata bez ograničenja, bifenil-2-il, 2-bromofenil, 2-bromokarbonilfenil,, 2-bromo-5-fluorofenil, 4-terc-butilfenil, 4-karbamoilfenil, 4-karboksi-2-nitrofenil, 2-hlorofenil, 4-hlorofenil, 3-hlorokarbonilfenil, 4-hlorokarbonilfenil, 2-hloro-4-fluorofenil, 2-hloro-6-fluorofenil, 4-hloro-2-nitrofenil, 6-hloro-2-nitrofenil, 2,6-dibromofenil, 2,3-dihlorofenil, 2,5-dihlorofenil, 3,4-dihlorofenil, 2-difluorometoksifenil, 3,5-dimetilfenil, -2-etoksikarbonilfenil, 2-fluorofenil, 2-jodofenil, 4-izopropilfenil, 2-metoksifenil, 4-metoksifenil, 2-metilfenil, 3-metilfenil, 4-metilfenil, 5-metil-2-nitrofenil, 4-metilsulfonilfenil, naft-2-il, 2-nitrofenil, 3-nitrofenil, 4-nitrofenil, 2,3,4,5,6-pentafluorofenil, fenil, 2-trifluorometoksifenil, 3-fluorometoksifenil, 4-trifluorometoksifenil, 2-trifluorometoksifenil, 3-trifluorometilfenil, 4-trifluorometilfenil, 2-trifluorometilsulfanilfenil, 4-trifluorometilsulfanilfenil i slično. "Aryl" means a monocyclic or bicyclic ring assembly containing the total number of carbon atoms indicated, wherein each ring consists of 6 ring carbon atoms and is aromatic or when attached to another ring forms an aromatic ring assembly. For example, (C 6 -I 2 )aryl as used herein includes but is not limited to biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo-5-fluorophenyl, 4-tert-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl, 2-ethoxycarbonyl, 2-fluorophenyl, 2-iodophenyl, 4-isopropylphenyl, 2-Methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, 2-trifluoromethoxyphenyl, 4-methylsulfonylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl and the like.

Po slobodnom izboru supstituisani (C6-lo)aril kao što se koristi u ovoj prijavi obuhvata 3-acetilfenil, 3-terc-butoksikarbonilaminometilfenil, biofenil-4-il, 3-hidroksifenil, 4-hidroksifenil, 3-metoksifenil, naft-2-il, 3-fenoksifenil, fenil i slično. Optionally substituted (C6-10)aryl as used herein includes 3-acetylphenyl, 3-tert-butoxycarbonylaminomethylphenyl, biophenyl-4-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, naphth-2-yl, 3-phenoxyphenyl, phenyl, and the like.

„ Bicikloaril „ označava bicikličnu prstenastu strukturu sa naznačenim brojem atoma ugljenika, gde su prstenovi vezani preko jednostruke veze ili su spojeni i gde je barem jedan od prstenova u okviru strukture aromatičan, i bilo koji karbociklični ketonski, tioketonski ili iminoketonski derivat (na primeer, (Cg-io)bicikloaril obuhvata cikloheksilfenil, 1,2-dihidronaftil, 2,4-diokso-1,2,3,4-tetrahidronaftil, indanil, indenil, 1,2,3,4-tetrahidronaftil i slično). "Bicycloaryl" means a bicyclic ring structure having the indicated number of carbon atoms, where the rings are single-bonded or fused and where at least one of the rings within the structure is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative (for example, (C8-10)bicycloaryl includes cyclohexylphenyl, 1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like).

„Karbamoil" označava radikal -C(0)NH2- Ukoliko drugačije nije naznačeno, "Carbamoyl" means the radical -C(0)NH2- Unless otherwise indicated,

jedinjenja prema pronalasku koja sadrže karbamoilne ostatke uključuju njihove zaštićene derivate. Odgovarajuće grupe za zaštitu za karbamoilne ostatke uključuju acetil, terc-butoksikarbonil, benziloksikarbonil, i njima slične grupe, kao i nezaštićene i zaštićene derivate koji ulaze u opseg pronalaska. compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and similar groups, as well as unprotected and protected derivatives falling within the scope of the invention.

„ Derivat karboksilnog ketona „ označava derivat koji sadrži ostatak -C(O)-. "Carboxylic ketone derivative" means a derivative containing a -C(O)- residue.

„Karboksi" označava radikal -C(0)OH. Ukoliko drugačije nije naznačeno, jedinjenja iz pronalaska koja sadrže karboksilne ostatke obuhvataju njihove zaštićene derivate. Odgovarajuće grupe za zaštitu za karbooksilne ostatke uključuju benzil, terc-butil i njima slične grupe. "Carboxy" means the radical -C(0)OH. Unless otherwise indicated, compounds of the invention containing carboxyl moieties include protected derivatives thereof. Suitable protecting groups for carboxyl residues include benzyl, tert-butyl and similar groups.

„Cikloalkil" onačava zasićeni ili delimično nezasićeni monociklični, spojeni biciklični ili premošćeni policiklični prstenasti sklop koji sadrži naznačene atome ugljenika, i bilo koji karbociklični ketonski, tioketonski ili iminoketonski derivat (na primer, (C3-1 o)cikloalkil obuhvata ciklopropil, ciklobutil, "Cycloalkyl" means a saturated or partially unsaturated monocyclic, fused bicyclic or bridged polycyclic ring structure containing the indicated carbon atoms, and any carbocyclic ketone, thioketone or iminoketone derivative (for example, (C3-1 o)cycloalkyl includes cyclopropyl, cyclobutyl,

ciklopentil,cikloheksil,cikloheksenil,2,5-cikloheksadienil, bicikloheksilil, biciklo[2.2.2]oktil,adamantan-1 -il, dekahidronaftil, oksocikloheksil, dioksocikloheksil, tiocikloheksil, 2-oksobiciklo[2.2.1]hept-1-il, i njima slične derivate). cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, bicyclo[2.2.2]octyl,adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and similar derivatives).

„Cikloalkilen" označava zasićeni ili delimično nezasićeni monociklični prsten ili premošćeni policiklični prstenasti sklop koji sadrži naznačene ugljenikove atomime, i bilo koji karbociklični ketonski, tioketonski ili iminoketonski derivat. Na "Cycloalkylene" means a saturated or partially unsaturated monocyclic ring or bridged polycyclic ring assembly containing the indicated carbon atoms, and any carbocyclic ketone, thioketone or iminoketone derivative. At

primer, slučaj daP<J>i R<2>zajedno sa ugljenikovim atomom na koji su i R<1>i R2 prikačeni grade (C3-8)cikloalkilen" obuhvata bez ograničenja sledeće: for example, the case that P<J>and R<2>together with the carbon atom to which both R<1>and R2 are attached form a "(C3-8)cycloalkylene" includes without limitation the following:

„Oboljenje" specifično označava bilo koje bolesno stanje životinje ili dela njenog tela i obuhvata nezdravo stanje koje bi moglo biti uzrokovano, ili koje nastaje kao posledica medicinske ili veterinarske terapije koja se primenjuje na životinji, tj. „sporedni efekti" terapije. "Disease" specifically means any diseased condition of an animal or part of its body and includes an unhealthy condition that could be caused by, or that occurs as a consequence of medical or veterinary therapy applied to the animal, i.e. "side effects" of therapy.

„ Halo" označava fluoro, hloro, bromo ili jodo. "Halo" means fluoro, chloro, bromo or iodo.

„ Halo-supstituisana alkil ,„ kao izolovana grupa ili deo neke veće grupe, označava „ alkil „ supstituisan sa jednim ili više „ halo „ atoma, na način na koji su ti pojmovi definisani u ovoj prijavi. Halo-supstituisani alkil uključuje haloalkil, dihaloalkil, trihaloalkil, perhaloalkil i si. (na pr. halo-supstituisani (Ci-3)alkil uključuje hlorometil, dihlorometil, difluorometil, trifluorometil, 2,2,2-trifluoroetil, perfluoroetil, 2,2,2-trifluoro-1,1 -dihloroetil i si.). "Halo-substituted alkyl," as an isolated group or part of a larger group, means "alkyl" substituted with one or more "halo" atoms, as those terms are defined in this application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like. (e.g., halo-substituted (Ci-3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, etc.).

„ Heteroatomski ostatak „ obuhvata -N=, -NR-, -O-, -S- ili -S(0)2, gde je R vodonik, "Heteroatomic residue" includes -N=, -NR-, -O-, -S- or -S(O)2, where R is hydrogen,

(C-|-6)alkil ili zaštitna grupa (C-1-6)alkyl or a protecting group

„ Heterocikloalkilen „ označava cikloalkilen, kako je definisano u ovoj prijavi, pod uslovom da se jedan ili više od naznačenih atoma ugljenika u prstenu zameni heteroatomskim ostatkom iz grupe koju čine od -N-, -NR-, -O-, ili -S(0)2-, gde je R "Heterocycloalkylene" means cycloalkylene, as defined in this application, provided that one or more of the indicated ring carbon atoms is replaced by a heteroatomic residue selected from the group consisting of -N-, -NR-, -O-, or -S(0)2-, where R is

vodonik ili (Ci-6)alkil. Na pr., u slučaju da R<1>i R<2>zajedno sa atomom ugljenika za koji su vezani oba formiraju hetero(C3-8)cikloalkilen" uključuju, ali bez ograničenja, sledeće : hydrogen or (C 1-6 )alkyl. For example, in the event that R<1> and R<2> together with the carbon atom to which they are attached both form a hetero(C3-8)cycloalkylene" include, but are not limited to, the following:

u kojima je R vodonik, (Ci-6)alkil ili jedna zaštitna grupa. wherein R is hydrogen, (C 1-6 )alkyl or a protecting group.

kao što je u ovom tekstu definisano, „Heteroaril" označava aril, pod uslovom da je jedan ili više označenih ugljenikovih atoma iz prstena, zamenjen sa heteroatomskim ostatkom odabranim iz -N, -NR, -O- ili -S-, u kojem je R vodonik, (Ci-6)alkil ili grupa za zaštitu, ili predstavlja slobodnu valencu koja služi kao tačka spajanja za atom azota u prstenu i gde svaki prsten obuhvata od 5 do 6 atoma u prstenu. Na primer, po slobodnom izboru supstituisana hetero(C5-i2)aril kao što se koristi u ovoj prijavi, obuhvata bez ograničenja, 4-amino-2-hidroksipirimidin-5-il, benzotiazol-2-il, 1H-benzoimidazol-2-il, 2-bromopirid-5-il, 5-bromopirid-2-il, 4-karbamoiltiazol-2-il, 3-karboksipirid-4-il, 5-karboksi-2,6-dimetilpirid-3-il, 3,5-dimetilizoksazol-4-il, 5-etoksi-2,6-dimetilpirid-3-il, 5-fluoro-6-hidroksipirimidin-4-il, fur-2-il, fur-3-il, 5-hidroksi-4,6-dimetilpirid-3-il, 8-hidroksi-5,7-dimetilhinolin--2-il, 5-hidroksimetilizoksazol-3-il, 3-hidroksi-6-metilpirid-2-il, 3-hidroksipirid-2-il, 1H-imidazol-2-il, 1 H-imidazol-4-il, 1 H-indol-3-il, izotiazol-4-il, izoksazol-4-il, 2-metilfur-3-il, 5-metilfur-2-il, 1 -metil-1 H-imidazol-2-il, 5-metil-3H-imidazol-4-il, 5-metoksiizoksazol-3-iol, 5-metil-2H-pirazol-3-il, 3-metilpirid-2-il, 4-metilpirid-2-il,5-metilpirid-2-il, 6-metilpirid-2-il, 2-metilpirid-3-il, 2-metiltiazol-4-il, 5-nitropirid-2-il, 2H-pirazol-3-il, 3H-pirazol-4-il, piridazin-3-il, pirid-2-il, pirid-3-il, pirid-4-il, 5-pirid-3-il-2H-[1,2,4]triazol-3-il, pirimidin-4-il, pirimidin-5-il, 1 H-pirol-3-il, hinolin-2-il, 1H-tetrazol-5-il, tiazol-2-il, tiazol-5-il, tien-2-il, tien-3-il, 2H-[1,2,4]triazol-3-il, 3H-[1,2,3]triazol-4-il, 5-trifluorometilpirid-2-il i slično. as defined herein, "Heteroaryl" means aryl, provided that one or more of the designated ring carbon atoms is replaced by a heteroatomic residue selected from -N, -NR, -O- or -S-, wherein R is hydrogen, (Ci-6)alkyl or a protecting group, or represents a free valence that serves as a point of attachment for a ring nitrogen atom and where each ring comprises from 5 to 6 ring atoms. For example, optionally substituted hetero(C5-12)aryl as used herein includes, without limitation, 4-amino-2-hydroxypyrimidin-5-yl, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl, 4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl, 5-carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydroxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl, 8-hydroxy-5,7-dimethylquinolin-2-yl, 5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, 1H-imidazol-2-yl, 1 H-imidazol-4-yl, 1 H-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl, 1 H-imidazol-2-yl, 5-methyl-3H-imidazol-4-yl, 5-methoxyisoxazol-3-yl, 5-methyl-2H-pyrazol-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl,5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylthiazol-4-yl, 5-nitropyrid-2-yl, 2H-pyrazol-3-yl, 3H-pyrazol-4-yl, pyridazin-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H-[1,2,4]triazol-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1 H-pyrrol-3-yl, quinolin-2-yl, 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl, thien-2-yl, thien-3-yl, 2H-[1,2,4]triazol-3-yl, 3H-[1,2,3]triazol-4-yl, 5-trifluoromethylpyrid-2-yl and the like.

Kao što je definisano u samoj prijavi, „ Heterobicikloaril „ ozačava bicikloaril, pod uslovom da je jedan ili više označenih ugljenikovih atoma iz prstena, zamenjen sa heteroatomskim ostatkom odabranim iz -N, -NR, -O- ili -S-, u kojem je R vodonik, (Ci-6)alkil ili grupa za zaštitu, ili predstavlja slobodnu valencu koja služi kao tačka spajanja za atom azota u prstenu i gde svaki prsten obuhvata od 5 do 6 atoma u prstenu i bilo koji derivat karbocikličnog ketona, tioketona ili iminoketona. kao što se koristi u ovoj prijavi, po slobodnom izboru supstituisana hetero(C8-10)bicikloaril , obuhvata bez ograničenja 2- amino-4-okso-3,4-dihidropteridin-6-il i slično. Generalno, pojam heterobicikloaril na način kako se koristi u ovoj prijavi, predstavlja benzo[1,3]-dioksol-5-il-3,4-dihidro-2H-[1,8]naftiridinil, 3,4-dihidro-2H-hinolinil, 2,4-diokso-3,4-dihidro-2H-hinazolinil,1,2,3,4,5,6-heksahidro[2,2']bipiridinil, As defined in the application itself, "Heterobicycloaryl" means bicycloaryl, provided that one or more of the designated ring carbon atoms is replaced by a heteroatomic residue selected from -N, -NR, -O- or -S-, wherein R is hydrogen, (Ci-6)alkyl or a protecting group, or represents a free valence that serves as a point of attachment for a ring nitrogen atom and where each ring comprises from 5 to 6 ring atom and any carbocyclic ketone, thioketone or iminoketone derivative as used herein, optionally substituted hetero(C8-10)bicycloaryl, includes without limitation 2-amino-4-oxo-3,4-dihydropteridin-6-yl and the like. In general, the term heterobicycloaryl as used herein benzo[1,3]-dioxol-5-yl-3,4-dihydro-2H-[1,8]naphthyridinyl, 3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl,1,2,3,4,5,6-hexahydro[2,2'']bipyridinyl,

3- okso-2,3-dihidrobenzo[1,4]oksazinil, 5,6,7,8-tetrahidrohinolinil i slično. „Heterocikloalkil" označava cikloalkil, kao što je ovde definisano, pod uslovom da jedan ili više navedenih ugljenikovih atoma u prstenu, zamenjen sa heteroatomskim ostatkom koji može biti -N, -NR, -O- ili -S-, gde je R vodonik, (C-|-6)alkil ili grupa za zaštitu, ili predstavlja slobodnu valencu koja služi kao tačka spajanja za atom azota u prstenu i gde svaki prsten obuhvata od 5 do 6 atoma u prstenu i bilo koji derivat karbocikličnog ketona, tioketona ili iminoketona (na primer, pojam hetero(C5-i2)cikloalkil obuhvata imidazolinil, morfolinil, piperazinil, 3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl and the like. "Heterocycloalkyl" means cycloalkyl, as defined herein, provided that one or more of said ring carbon atoms is replaced by a heteroatomic residue which may be -N, -NR, -O- or -S-, where R is hydrogen, (C-|-6)alkyl or a protecting group, or represents a free valence that serves as a point of attachment for a ring nitrogen atom and where each ring comprises from 5 to 6 ring atoms and any derivative carbocyclic ketone, thioketone or iminoketone (for example, the term hetero(C5-12)cycloalkyl includes imidazolinyl, morpholinyl, piperazinyl,

piperidil, pirolidinil, pirolinil, hinuklidinil i slično). piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl and the like).

Odgovarajuće zaštitne grupe obuhvataju terc-butoksikarbonil, benziloksikarbonil, benzil, 4-metoksibenzil, 2-nitrobenzil, i njima slične grupe. Ukoliko drugačije nije naznačeno derivati koji su nezaštićeni ili koji su zaštićeni ulaze u opseg pronalaska. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and similar groups. Unless otherwise indicated, derivatives that are unprotected or that are protected are included in the scope of the invention.

"Hidroksi" označava radikal -OH. Osim ako je naznačeno drugačije, jedinjenja prema pronalasku sa sadržajem hidroksi radikala uključuju njihove zaštićene derivate. Pogodne zaštitne grupe za hidroksi polovine uključuju benzil i si. "Derivat iminoketona" označava derivat koji sadrži grupu -C(NR)-, gde je R vodonik ili (C-|-6)alkil. "Hydroxy" means the radical -OH. Unless otherwise indicated, compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for the hydroxy moieties include benzyl and si. "Iminoketone derivative" means a derivative containing the group -C(NR)-, where R is hydrogen or (C-|-6)alkyl.

"Izomeri" označavaju jedinjenja formule I identične molekulske formule, ali se razlikuju po prirodi ili sekvenci vezivanja njihovih atoma ili po rasporedu njihovih atoma u prostoru. Izomeri koji se razlikuju po rasporedu njihovih atoma u prostoru nazivaju se „ stereoizomeri „. Stereoizomeri, koji se ne odnose kao predmet i njegov lik u ogledalu nazivaju se „ diastereoizomeri „ a stereoizomeri, koji se odnose kao predmet i njegov lik u ogledalu nazivaju se "enantiomeri", ili nekiput "optički izomeri". Atom ugljenika vezan za četiri različita supstituenta naziva se „ hiralni cetar „. Jedinjenje sa jednim hiralnim centrom poseduje dva enantiomerna oblika suprotne hiralnosti i naziva se „ racematska smeša „. Jedinjenje sa više od jednog hiralnog centra poseduje 2<n>~^ parova enantiomera , gde je n broj hiralnih centara. Jedinjenja sa više od jednog hiralnog centra mogu postojati bilo kao pojedinačni diastereomeri bilo kao smeše diastereomera, nazvani "diastereomerna smeša". Kada postoji jedan hiralni centar, stereoizomer se može odrediti pomoću "Isomers" mean compounds of formula I of identical molecular formula, but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers, which are not related as an object and its mirror image, are called "diastereoisomers", and stereoisomers, which are related as an object and its mirror image, are called "enantiomers", or, as it were, "optical isomers". A carbon atom attached to four different substituents is called a "chiral ceter". A compound with one chiral center has two enantiomeric forms of opposite chirality and is called a "racematic mixture". A compound with more than one chiral center has 2<n>~^ pairs of enantiomers, where n is the number of chiral centers. Compounds with more than one chiral center can exist either as individual diastereomers or as mixtures of diastereomers, called a "diastereomer mixture". When a single chiral center is present, the stereoisomer can be determined by

apsolutne konfiguracije tog hiralnog centra. absolute configuration of that chiral center.

Apsolutna konfiguracija se odnosi na prostorni raspored supstituenata, vezanih za taj hiralni centar. Enantiomere karakteriše apsolutna konfiguracija njihovih hiralnih centara koja je opisana pravilima R- i S- redosleda po Cahn-u, Ingold-u i Prelog-u. Konvencije u pogledu stereohemijske nomenklature, stereohemijski postupci odredjivanja i razdvajanja stereoizomera su dobro poznati u struci (na pr., v. "Advanced Organic Chemistrv", 4.izd., March, Jerry, John Wiley & Sons, Nju Jork, 1992). Podrazumeva se da su nazivi i ilustracije u ovoj prijavi upotrebljeni za opisivanje jedinjenja formule I i namenjene su obuhvatanju svih mogućih stereoizomera. Tako, na pr., naziv N-[1-(1-Benzilkarbamoil-metanoil)-propil-4-morfolin-4-il-4-okso-2-fenilmetansulfonilmetil-butiramid treba da obuhvati N-[(S)-1-(1-Benzilkarbamoil-metanoil)-propil]-4-morfolin-4-il-4-okso-2-fenilmetansulfonilmetil-butiramid i svaku njihovu smešu, racemsku ili drugačiju od racemske. The absolute configuration refers to the spatial arrangement of the substituents attached to that chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers, which is described by the rules of R- and S-order according to Cahn, Ingold and Prelog. Stereochemical nomenclature conventions, stereochemical procedures for determining and separating stereoisomers are well known in the art (eg, see "Advanced Organic Chemistry", 4th ed., March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustrations used in this application to describe the compounds of formula I are intended to encompass all possible stereoisomers. Thus, for example, the name N-[1-(1-Benzylcarbamoyl-methaneyl)-propyl-4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyramide should include N-[(S)-1-(1-Benzylcarbamoyl-methaneyl)-propyl]-4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyramide and any mixture thereof, racemic or otherwise. racemic.

" ketonski derivat " označava derivat koji sadrži grupu -C(O)-. Na primer u ovoj prijavi X<3>može da bude 2-acetoksi-azetidin-3-il. „ Karbociklični derivat ketona „ u ovom primeru za X<3>može da bude 2-acetoksi-4-okso-azetidin-3-il (videti tabelu 3, C32). "ketone derivative" means a derivative containing the group -C(O)-. For example in this application X<3> can be 2-acetoxy-azetidin-3-yl. The "carbocyclic ketone derivative" in this example for X<3> can be 2-acetoxy-4-oxo-azetidin-3-yl (see Table 3, C32).

„Nitro" označava radikal -NO2. "Nitro" means the radical -NO2.

„Opciono" ili „po slobodnom izboru" znači i da opisano stanje ili okolnost na koju se odnosi ne mora da se pojavi i da opis obuhvata slučajeve kod kojih se stanje ili okolnost pojavljuje. Na primer, fraza „ u kojoj u okviru R<3>i R<4>bilo koji aliciklični il aromatični prstenasti sistem može da bude dalje supstituisan sa 1-5 radikala ", "Optional" or "optional" means both that the described condition or circumstance to which it refers need not occur and that the description includes cases where the condition or circumstance does occur. For example, the phrase "wherein R<3>and R<4>any alicyclic or aromatic ring system may be further substituted with 1-5 radicals",

označava da R<3>i R<4>mogu ili nemoraju biti supstituisani da bi ušli u opseg pronalaska. means that R<3> and R<4> may or may not be substituted to fall within the scope of the invention.

„ Oksoalkil" označava alkil, kako je ranije definisano, gde je jedan od velikog broja naznačenih atoma ugljenika zamenjen sa kiseoničnom grupom (-0-), na primer, okso(C2-6)a'kil obuhvata metoksimetil, itd. "Oxoalkyl" means alkyl, as previously defined, where one of the plurality of indicated carbon atoms is replaced by an oxygen group (-O-), for example, oxo(C2-6)alkyl includes methoxymethyl, etc.

Pojam „Derivati N-oksida" označava derivate jedinjenja sa formulom I u kojima su atomi azota u oksidovanom stanju (tj., O-N) i koji poseduje željenu farmakološku aktivnost. The term "N-oxide derivatives" means derivatives of compounds of formula I in which the nitrogen atoms are in the oxidized state (ie, O-N) and which possess the desired pharmacological activity.

„Patologija" bolesti označava osnovnu prirodu, uzroke i razvoj bolesti kao i strukturne i funkcionalne promene koje potiču od oboljenja. "Pathology" of a disease means the basic nature, causes and development of the disease as well as the structural and functional changes resulting from the disease.

„Farmaceutski prihvatljiv" označava da je pomenuti proizvod koristan za pripremanje farmaceutskih preparata koja su uopšteno bezbedni, netoksični i koji nisu ni sa biološkog niti sa bilo kog drugog aspekta nepoželjni i koji obuhata one koju su prihvatljivi za veterinarsku primenu a isto tako i za humanu farmaceutsku primenu. "Pharmaceutically acceptable" means that the mentioned product is useful for the preparation of pharmaceutical preparations which are generally safe, non-toxic and which are neither biologically nor from any other aspect undesirable and which includes those which are acceptable for veterinary use as well as for human pharmaceutical use.

„Farmaceutski prihvatljiva so" označava soli jedinjenja formule I koja su farmaceutski prihvatljiva, kako je gore definisano, i koja poseduju željeno farmakološku aktivnost. Takve soli obuhvatajusoli dobijene adicijomneorganske kiseline kao što je hlorovodonična kiselina, bromovodonična kiselina, sumporna kiselina, azotna kiselina, fosforna kiselina, i njima slične kiseline; ili sa organskim kiselinama kao što su sirćetna kiaelina, propionska kiselina, heksanska kiselina, heptanska kiselina, ciklopentanpropionska kiselina, glikolna kiselina, pirogroždjana kiselina, mlečna kiselina, malonska kiselina, ćilibarna kiselina, jabučna kiselina, maleinska kiselina, fumarna kiselina, vinska kisellina, limunska kiselina, benzoeva kiselina, o-(4-hidrokibenzoil)benzoeva kisleina, cimetna kiselina, madelinska kiselina, metansulfonska kiselina, etansulfonska kiselina, 1,2-etandisulfonska kiselina, 2-hidroksietansulfonska kiselina, benzensulfonska kiselina, p-hlorobenzensulfonska kiselina, 2-naftalensulfonska kiselina, p-toluensulfonska kiselina, kamforsulfonska kiselina, 4-metilbiciklo[2.2.2]okt-2-en-1-karboksilna kiselina, glukoheptonska(enatna) kiselina, 4,4'-metilenbis(3-hidroksi-2-en-1-karboksilna kiselina), 3-fenilpropionska kiselina, trimetilsirćetna kiselina, tercijalna butirsirćetna kiselina, lauril sumporna kisleina, glukonska kiselina, glutaminska kiselina, hidroksinaftonska kiselina, salicilna kiselina, stearinska kiselina, mukonska kiselina i njima slične kiseline. "Pharmaceutically acceptable salt" means salts of compounds of formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include salts obtained by the addition of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and similar acids; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydrokibenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid. acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butyric acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthonic acid, salicylic acid, stearic acid, muconic acid and similar acids.

Farmaceutski prihvatljive soli takodje obuhvataju i soli dobijene adicijom baze kada prisutni kiselinski protoni imaju sposobnost da reaguju sa neorganskim ili organskim bazama. Prihvatljive neorganske baze obuhvataju natrijum hidroksid, natrijum karbonat, kalijum hidroksid, amonijum hidroksid, aluminijum hidroksid i kalcijum hidroksid. Prihvatljive organske baze uključuju etanolamin, dietanolamin, trietanolamin, trometamin, N-metilglukamin i njima slične baze. Pharmaceutically acceptable salts also include base addition salts when the acid protons present have the ability to react with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and similar bases.

„ Prolek" označava jedinjenje koje se konvertovati in vivo metaboličkim putem (na primer hidrolizom) u jedinjenje sa formulom (I). Na primer estar jedinjenja formule (I) koji sadrži hidroksi grupu, može se prevesti hidrolizom in vivo u polazni molekul. "Prodrug" means a compound that is converted in vivo by a metabolic pathway (eg, hydrolysis) to a compound of formula (I). For example, an ester of a compound of formula (I) containing a hydroxy group can be converted by hydrolysis in vivo into the starting molecule.

Alternativno estar jedinjenja formule (I) koji sadrži karboksi grupu može se prevesti in vivo u polazni molekul. Odgovarajući estri jedinjenja formule (I) koji sadrže hidroksi grupu, su na primer, acetati, citrati, laktati, tartarati, malonati, oksalati, salicilati, propionati, sukcinati, fumarati, maleati, metilen-bis-b-hidroksinaftoati,soli gentizinske kiseline,izotionati, di-p-toluoiltartarati, metansulfonati, etansulfonati, benzensulfonati, p-toluensulfonati, cikloheksilsulfamati i hinatati. Odgovarajući estri od jedinjenja (t) koji sadrže karboksi grupu su na primer oni opisani od F.J. Leinweber, Drug, Metab. Res., 1987, 18, strana 379. Posebno korisna klasa estara jedinjenja formulvv (I) koji sadrže hidroksi grupu, može se formirati iz kiselinskih ostataka odabranih od onih koji su opisani od strane Bundgaard et al., J. Med. Chem., 1989, 32, trana 2503-2507, i koji uključuju (aminometil)-benzoate, na primer, dialkilamino-benzoate u kojima dve alkil Alternatively, an ester of a compound of formula (I) containing a carboxy group can be converted in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisic acid salts, isothionates, di-p-toluoyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and hinate. Suitable esters of compound (t) containing a carboxy group are for example those described by F.J. Leinweber, Friend, Metab. Res., 1987, 18, page 379. A particularly useful class of esters of compounds of formula (I) containing a hydroxy group can be formed from acid residues selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, pp. 2503-2507, and which include (aminomethyl)-benzoates, for example, dialkylamino-benzoates in which two alkyl

grupe mogu spojene zajedno i/ ili zaklonjene sa atomom kiseonika ili po slobodnom izboru supstituisane sa atomom azota, na primer sa alkilovanim atomom azota, još više sa (morflolino-metil)benzoatima, na primer, 3- ili 4-(morfolinometil)-benzoatima, i (4-alkiIpiperazin-1-il)benzoatima, na primer 3- ili 4-(4-alkilpiperazin-1-il)benzoatima. groups can be joined together and/or shielded with an oxygen atom or optionally substituted with a nitrogen atom, for example with an alkylated nitrogen atom, even more with (morpholino-methyl)benzoates, for example, 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, for example 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

„ Zaštićeni derivat " označava derivate jedinjenja I u kojima su reaktivno(a) mesta(o) blokirana sa zaštitnim grupama. Zaštićeni derivati jedinjenja formule I korisni su za dobijanje jedinjenja sa formulom I ili sami mogu biti aktivni inhibitiori catepsina S. Opširna lista odgovarajućih grupa za zaštitu može se naći kod T.W. Greene, Protecting Groups in Organic Svnhtesis, Jonh Wiley & Sons, Inc. 1981). "Protected derivative" means derivatives of compound I in which the reactive site(s) are blocked with protecting groups. Protected derivatives of compounds of formula I are useful for preparing compounds of formula I or may themselves be active cathepsin S inhibitors. An extensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).

„ Terapeutski efikasna količina „ označava količinu koja je, kada se daje životinji radi tretmana neke bolesti, dovoljna sa delotvoran tretman iste bolesti. "Therapeutically effective amount" means an amount which, when administered to an animal for the treatment of a disease, is sufficient to effectively treat the same disease.

„ Derivat tioketona „ označava derivat sa sadržajem polovine -C(S)-. " Thioketone derivative " means a derivative with half -C(S)- content.

„ Tretman „ ili „ tretiranje „ označava bilokakvo davanje jedinjenja prema ovom pronalasku i obuhvata : "Treatment" or "treatment" means any administration of a compound of the present invention and includes:

(1) Sprečavanje bolesti da se pojavi kod neke životinje, koja bi mogla imati predispoziciju za tu bolest, ali još ne oseća ili ne pokazuje patologiju ili simptomatologiju bolesti. (2) Inhibiciju bolesti kod neke životinje, koja doživljava ili pokazuje patologiju ili simptomatologiju te bolesti na, na pr., zaustavljanje daljeg razvoja patologije i/ili simptomatologije), ili (3) Poboljšanje bolesnog stanja kod neke životinje, koja doživljava ili pokazuje patologiju ili simptomatologiju kod bolesnika (na pr., menjanje smera razvoja patologije i/ili simptomatologije) (1) Preventing a disease from appearing in an animal, which may have a predisposition to that disease, but does not yet feel or show the pathology or symptomatology of the disease. (2) Inhibition of a disease in an animal, which experiences or exhibits the pathology or symptomatology of that disease to, e.g., stop the further development of the pathology and/or symptomatology), or (3) Improvement of the disease state in an animal, which experiences or exhibits the pathology or symptomatology in the patient (e.g., changing the direction of the development of the pathology and/or symptomatology)

Nomenklatura: Nomenclature:

JEdinjenja formule I i intermedijeri i polazni materijali korišćeni za njihovo dobijanje dobili su imena prema pravilima lUPAK-ove nomenklature u kojem karakteristične grupe imaju opadajući prioritet prilikom navodjenja kao osnovne grupe na sledeći način: kiseline, estri, amidi itd. Alternativno, jedinjenja su dobila nazive pomoću AutoNom 4.0 (Beilstein Information Svstems, Inc.). Na primer, jedinjenje formule I u kojem je X<1>-NHC(R1)(R2)X2 (R1 i R2 su svaki za sebe vodonik), X<2>je cijano, R<3>je cikloheksilmetil, i R<4>je fenilamino;kao što je jedinjenje sledeće strukture: Compounds of formula I and intermediates and starting materials used to obtain them were named according to the rules of lUPAK nomenclature in which characteristic groups have decreasing priority when listing as basic groups as follows: acids, esters, amides, etc. Alternatively, compounds were named using AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of formula I wherein X<1> is -NHC(R1)(R2)X2 (R1 and R2 are each hydrogen), X<2> is cyano, R<3> is cyclohexylmethyl, and R<4> is phenylamino; such as a compound of the following structure:

dobilo je naziv N-cijanometil-2-cikloheksilmetil-N'-fenil-malonamid. it was named N-cyanomethyl-2-cyclohexylmethyl-N'-phenyl-malonamide.

Poželjna izvodjenja datog pronalaska: Preferred embodiments of the present invention:

Pošto je najšira definicija pronalaska navedena u kratkom opisu pronalaska, Since the broadest definition of the invention is set forth in the brief description of the invention,

poželjni su izvesni aspekti pronalaska. Na primer, X<1>je -NHC(R<1>)(R<2>)X2 ili - certain aspects of the invention are preferred. For example, X<1>is -NHC(R<1>)(R<2>)X2 or -

NHX3; X<2>je cijano; -C(0)X<3>, -C(0)F3, -C(0)CF2CF2R<9>, -CH=CHS(0)2R<5>, - NHX3; X<2> is cyano; -C(0)X<3>, -C(0)F3, -C(0)CF2CF2R<9>, -CH=CHS(0)2R<5>, -

C(0)CF2C(0)NR5r5, -C(0)C(0)NR<5>r6, -C^C^ORS, -C(0)CH20R<5>, - C(0)CF2C(0)NR5r5, -C(0)C(0)NR<5>r6, -C^C^ORS, -C(0)CH20R<5>, -

C(0)CH2N(R<6>)S02R<5>ili -C(0)C(0)R<5>; gde su R<5>i r<6>gore opisani C(O)CH2N(R<6>)SO2R<5> or -C(0)C(0)R<5>; where R<5> and r<6> are as described above

X<3>obuhvata heterociklični prsten sa 4 do 6 atoma u prstenu ili spojeni heterociklični PRSTENASTI sistem sa 8 do 14 atoma u prstenu i bilo koji derivat karbocikličnog ketona, iminoketona ili tioketona; gde u okviru R<5>, X<2>ili X<3>bilo koji aliciklični il aromatični prstenasti sistem može biti dalje supstituisan sa 1 do 5 X<3>includes a heterocyclic ring with 4 to 6 ring atoms or a fused heterocyclic RING system with 8 to 14 ring atoms and any derivative of a carbocyclic ketone, iminoketone or thioketone; where within R<5>, X<2> or X<3> any alicyclic or aromatic ring system may be further substituted with 1 to 5

radikala odabranih od (C-|-6)alkil ili -X<4>OC(0)R<12>i/ili 1 radikal odabran od -R<14>, - radicals selected from (C-|-6)alkyl or -X<4>OC(0)R<12> and/or 1 radical selected from -R<14>, -

X4C(0)R14 ili -X4OC(0)R14; gdesuX4, R<12>i R<14>gore opisani; R<1>je vodonik ili (C-|-6)alkil i R2 je vodonik, -X<4>OR1<2>, (C5-io)heteroaril(Co-6)alkil, (C5--|o)aril(Crj-6)alkil, (C5-io)cikloalkil(Co-6)alkil, (C5-io)heterocikloalkil(Co-6)alkil ili (Ci-6)alkil; X4C(0)R14 or -X4OC(0)R14; where X4, R<12> and R<14> are as described above; R<1>is hydrogen or (C-|-6)alkyl and R2 is hydrogen, -X<4>OR1<2>, (C5-io)heteroaryl(Co-6)alkyl, (C5--|o)aryl(Crj-6)alkyl, (C5-io)cycloalkyl(Co-6)alkyl, (C5-io)heterocycloalkyl(Co-6)alkyl or (Ci-6)alkyl;

ili R<1>i R<2>zajedno sa atomom ugljenika za koji su vezani i R<1>i R<2>grade (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; gde je unutar pomenutog R<2>bilo koji heteroaril, aril, cikloalkil, heterocikloalkil, cikloalkilen ili heterocikloalkilen po slobodnom izboru supstituisan sa 1 do 3 radikala koji su nezavisno odabrani od (Ci-6)alkil i hidroksi; R<3>je -CH2X<5>, gde je X^ pri svakom pojavljivanju odabran od -X<4>SR<12>, -X<4>C(0)NR<12>R<12>, -X<4>S(0)2R<13>, -X<4>C(0)R13, -X4SR14, -X4R12, -R<14>, -X<4>S(0)2R<14>, -x4C(0)R14 -x<4>C(0)NR14R1<2>, gde su x4,R12,R13 iR14 gore definisani; R<4>je -NR6R6, - nr6r14 -nr6r15 ili -NR6x<5>C(0)R14 gde su R<6>, x<5>iR14 ranije definisani i r15je vodonik, -C(i-6)alkil ili -X^OR<6>gde je X^ opisan ranije; ili R^ i R<l5>zajedno sa atomom azota za koji su vezani i R<6>i R<15>grade hetero(C3-io)cikloalkil, or R<1> and R<2> together with the carbon atom to which both R<1> and R<2> are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; wherein within said R<2> any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (Ci-6)alkyl and hydroxy; R<3>is -CH2X<5>, where X^ at each occurrence is selected from -X<4>SR<12>, -X<4>C(0)NR<12>R<12>, -X<4>S(0)2R<13>, -X<4>C(0)R13, -X4SR14, -X4R12, -R<14>, -X<4>S(0)2R<14>, -x4C(0)R14 -x<4>C(0)NR14R1<2>, where x4,R12,R13 and R14 are as defined above; R<4> is -NR6R6, - nr6r14 -nr6r15 or -NR6x<5>C(O)R14 where R<6>, x<5> and R14 are previously defined and r15 is hydrogen, -C(i-6)alkyl or -X^OR<6>where X^ is previously described; or R^ and R<15> together with the nitrogen atom to which both R<6> and R<15> are attached form hetero(C3-io)cycloalkyl,

hetero(C5-io)aril ili hetero(C8-10)bicikloaril; gde u u okviru R<3>i R<4>bilo koji aliciklični ili aromatični prsten može po slobodnom izboru biti dalje supstituisan sa 1 do 5 radikala koji su nezavisno odabrani od (Ci-6)alkil, cijano, halo, nitro, halo-supstituisani(Ci-4)alkil,-x<4>OR12,-x4c(O)0R12,-x4C(0)R13,-x4C(O)NR12R12-hetero(C5-10)aryl or hetero(C8-10)bicycloaryl; where within R<3> and R<4> any alicyclic or aromatic ring can optionally be further substituted with 1 to 5 radicals independently selected from (Ci-6)alkyl, cyano, halo, nitro, halo-substituted (Ci-4)alkyl,-x<4>OR12,-x4c(O)0R12,-x4C(0)R13,-x4C(O)NR12R12-

x<4>nr<12>S(0)2R<12>i/ ili 1 radikal odabran od -R14, -X4OR14 i -x4C(0)NR14r12;gde u okviru R<3>i R<4>bilo koji alifatični deo prstena može dalje da bude supstituisan sa 1-5 radikala nezavisno odabranih od cijano; gde su X4, R1<2>, R<1>3 i R14 gore opisani; x<4>nr<12>S(0)2R<12>i/ or 1 radical selected from -R14, -X4OR14 and -x4C(0)NR14r12;where within R<3>and R<4>any aliphatic portion of the ring may be further substituted with 1-5 radicals independently selected from cyano; where X4, R1<2>, R<1>3 and R14 are as described above;

pod uslovom da je samo jedna biciklična prstenasta struktura prisutna u okviru R<3>provided that only one bicyclic ring structure is present within R<3>

iliR4.Posebno je x<1>-NHC(R1)(R2)X2 ili-nhx<3>;x<2>je cijano, -C(0)X3, -CF<3>, -CF2CF3, (E)-2-benzensulfonil-vinil, 2-dimetilkarbamoil-2,2-difluoro-acetil, 1 -benzilkarbamoil-metanoil, 1 -neziloksi(oksalil), 2-benziloksi-acetil, 2-benzensulfonilamino-etanoil ili or R4. In particular, x<1> is -NHC(R1)(R2)X2 or -nhx<3>; x<2> is cyano, -C(0)X3, -CF<3>, -CF2CF3, (E)-2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 1-benzylcarbamoyl-methanol, 1-nesyloxy(oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanol or

2-okso-2-fenil-etanoil; X3 je 1 H-benzoimidazol-2-il, pirimidin-2-il, benzooksazol-2-il, benzotiazol-2-il, piridazin-3-il, 3-fenil-[1,2,4]oksadiazol-5-il, 3-etil-[1,2,4]oksadiazol-5-il, 2-metil-4-okso-tetrahidro-furan-3-il, 2-etil-4-okso-tetrahidrofuran-3-il, 4-okso-1-(1-fenil-metanoil)-pirolidin-3-il ili (S)-2-Acetoksi-4-okso-azetidin-3-il; R<1>je vodonik ili metil i R<2>je vodonik, metoksimetil, (C-|-6)alkil, fenetil, 2-oxo-2-phenyl-ethanoyl; X3 is 1 H-benzoimidazol-2-yl, pyrimidin-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]oxadiazol-5-yl, 3-ethyl-[1,2,4]oxadiazol-5-yl, 2-methyl-4-oxo-tetrahydrofuran-3-yl, 2-ethyl-4-oxo-tetrahydrofuran-3-yl, 4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or (S)-2-Acetoxy-4-oxo-azetidin-3-yl; R<1>is hydrogen or methyl and R<2>is hydrogen, methoxymethyl, (C-|-6)alkyl, phenethyl,

tiofen-2-il ili 5-metil-furan-2-il ili (ii) R<1>i R<2>zajedno sa atomom ugljenika za koji su vezani i R<1>i R<2>grade ciklopropilen, tetrahidro-piran-4-ilen ili metil-piperidin-4-ilen. thiophen-2-yl or 5-methyl-furan-2-yl or (ii) R<1> and R<2> together with the carbon atom to which both R<1> and R<2> are attached form cyclopropylene, tetrahydro-pyran-4-ylene or methyl-piperidin-4-ylene.

R<3>je još poželjnije tiofen-2-sulfonilmetil, 3-hloro-2-fluoro-fenilmetansulfonilmetil, benzensulfonilmetil, fenilmetansulfonilmetil, 2-(1,1-difluorometoksi)fenilmetansulfonilmetil, 2-benzensulfonil-etil, 2-(piridin-2-sulfonil)-etil, 2-(piridin-4-sulfonil)-etil, 2-fenilmetansulfonil-etil, oksi-piridin-2-ilmetansulfonilmetil, prop-2-en-1 -sulfonilmetil, 4-metoksi-fenilmetansulfonilmetil, p-tolilmetansulfonilmetil, 4-hloro-fenilmetansulfonilmetil, o-tolilenmetansulfonilmetil, 3,5-dimetil-fenilmetansulfonilmetil, 4-trifluorometil-fenilmetan sulfonilmetil, 4-trifluorometoksi-fenilmetansulfonilmetil, 2-bromo-fenilmetansulfonilmetil, piridin-2-ilmetnasulfonilmetil, piridin-3-ilmetansulfonilmetil, piridin-4-ilmetansulfonilmetil, naftalen-2-ilmetansulfonilmetil, 3-metil-fenilmetansulfonilmetil, 3-trifluorometil-fenilmetansulfonilmetil, 3-trifluorometoksi-fenilmetansulfonilmetil, 4-fluoro-2-trifluorometoksi-fenilmetansulfonilmetil, 2-fluoro-6-trifluorometil-fenilmetansulfonilmetil, 3-hloro-fenilmetansulfonilmetil, 2-fluoro-fenilmetansulfonilmetil, 2-trifluoro-fenilmetansulfonilmetil, 2-cijano-fenilmetansulfonilmetil, 4-terc-butil-fenilmetansulfonilmetil, 2-fluoro-3-metil-fenilmetansulfonilmetil, 3-fluoro-fenilmetansulfonilmetil, 4-fluoro-fenilmetansulfonilmetil, 2-hloro-fenilmetansulfonilmetil, 2,5-difluoro-fenilmetansulfonilmetil, 2,6-difluoro-fenilmetansulfonilmetil, 2,5-dihloro-fenilmetansulfonilmetil, 3,4-dihloro-fenilmetansulfonilmetil, 2-(1,1 -difluoro-metoksi)-fenilmetansulfonilmetil, 2-cijano-fenilmetansulfonilmetil, 3-cijano-fenilmetansulfonilmetil, 2-trifluorometoksi-fenilmetansulfonilmetil, 2,3-difluoro-fenilmetansulfonilmetil, 2.5-dilfuoro-fenilmetansulfonilmetil, bifenil-2-ilmetansulfonilmetil, cikloheksilmetil, 3-fluoro-fenilmetansulfonilmetil, 3,4-difluoro-fenilmetansulfonilmetil, 2,4-difluoro-fenilmetansulfonilmetil, 2,4,6-trifluoro-fenilmetansulfonilmetil, 2,4,5-trifluoro-fenilmetansulfonilmetil, 2,3,4-trifluoro-fenilmetansulfonilmetil, 2,3,5-trifluoro-fenilmetansulfonilmetil, 2,5,6-trifluoro-fenilmetansulfonilmetil, 2-hloro-5-trifluorometilfenilmetansulfonilmetil, 2-metil-propan-1 -sulfonil, 2-fluoro-3-trifluorometilfenilmetansulfonilmetil, 2-fluoro-4-trifluorometilfenilmetansulfonilmetil, 2-fluoro-5-trifluorometilfenilmetansulfonilmetil, 4-fluoro-3-trifluorometilfenilmetansulfonilmetil, 2-metoksi-fenilmetansulfonilmetil, bis-trifluorometil-fenilmetansulfonilmetil, 4-difluorometoksi-fenilmetansulfonilmetil, 2-difluorometoksi-fenilmetansulfonilmetil, 3-difluorometoksi-fenilmetansulfonilmetil, 2,6-dihloro-fenilmetansulfonilmetil, bifenil-4-ilmetansulfonilmetil, 3,5-dimetil-izoksazol-4-ilmetansulfonilmetil, 5-hloro-tiofen-2-ilmetansulfonilmetil, 2-[4-(1,1 - Difluoro-metoksi)-benzensulfonil]-etil, 2-[2-(1,1 -Difluoro-metoksi)-benzensulfonil]-etil, 2-[3-(1,1 -Difluoro-metoksi)-benzensulfonil]-etil, 2-(4-trifluorometoksi-benzensulfonil)-etil, 2-(3-trifluorometoksi-benzensulfonil)-etil, 2-(2-trifluorometoksi-benzensulfonii)-etil, (cijanometil-metil-karbamoil)-metil, butil, bifenil-3-ilmetil, 2-okso-2-pirolidin-1 -il-etil, 2-benzensulfonil-etil, izobutilsulfanilmetil, 2-fenilsulfanil-etil, cikloheksilmetansulfonilmetil, 2-cikloheksil-etansulfonil, benzil, naftalen-2-il, benzilsulfanilmetil, 2-trifluorometil-benzilsulfanilmetil, 5-bromo-tiofen-2-ilmet.il, fenilsulfanil-etil i ciklopropilmetansulfonilmetil. R<3> is even more preferably thiophene-2-sulfonylmethyl, 3-chloro-2-fluoro-phenylmethanesulfonylmethyl, benzenesulfonylmethyl, phenylmethanesulfonylmethyl, 2-(1,1-difluoromethoxy)phenylmethanesulfonylmethyl, 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl, oxy-pyridin-2-ylmethanesulfonylmethyl, prop-2-en-1 -sulfonylmethyl, 4-methoxy-phenylmethanesulfonylmethyl, p-tolylmethanesulfonylmethyl, 4-chloro-phenylmethanesulfonylmethyl, o-tolylenemethanesulfonylmethyl, 3,5-dimethyl-phenylmethanesulfonylmethyl, 4-trifluoromethyl-phenylmethanesulfonylmethyl, 2-bromo-phenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, naphthalen-2-ylmethanesulfonylmethyl, 3-methyl-phenylmethanesulfonylmethyl, 3-trifluoromethyl-phenylmethanesulfonylmethyl, 3-trifluoromethoxy-phenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxy-phenylmethanesulfonylmethyl, 2-fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-trifluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 4-tert-butyl-phenylmethanesulfonylmethyl, 2-fluoro-3-methyl-phenylmethanesulfonylmethyl, 3-fluoro-phenylmethanesulfonylmethyl, 4-fluoro-phenylmethanesulfonylmethyl, 2-chloro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethanesulfonylmethyl, 2,6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenylmethanesulfonylmethyl, 3,4-dichloro-phenylmethanesulfonylmethyl, 2-(1,1 -difluoro-methoxy)-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 3-cyano-phenylmethanesulfonylmethyl, 2-trifluoromethoxy-phenylmethanesulfonylmethyl, 2,3-difluoro-phenylmethanesulfonylmethyl, 2,5-difluoro-phenylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl, 3-fluoro-phenylmethanesulfonylmethyl, 3,4-difluoro-phenylmethanesulfonylmethyl, 2,4-difluoro-phenylmethanesulfonylmethyl, 2,4,6-trifluoro-phenylmethanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2,3,4-trifluoro-phenylmethanesulfonylmethyl, 2,3,5-trifluoro-phenylmethanesulfonylmethyl, 2,5,6-trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2-methyl-propane-1 -sulfonyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-Methoxy-phenylmethanesulfonylmethyl, bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4-difluoromethoxy-phenylmethanesulfonylmethyl, 2-difluoromethoxy-phenylmethanesulfonylmethyl, 3-difluoromethoxy-phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl, 5-chloro-thiophen-2-ylmethanesulfonylmethyl, 2-[4-(1,1 - Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[2-(1,1 -Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[3-(1,1 -Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(3-trifluoromethoxy)-benzenesulfonyl]-ethyl, (cyanomethyl-methyl-carbamoyl)-methyl, butyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1 -yl-ethyl, 2-benzenesulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, 2-trifluoromethyl-benzylsulfanylmethyl, 5-bromo-thiophen-2-ylmethyl, phenylsulfanyl-ethyl and cyclopropylmethanesulfonylmethyl.

Najpoželjnije je da je R<4>fenilamino, benzilamino, 4-fenoksi-fenilamino, fenetilamino, 3-fenil-propilamino, morfolin-4-il, cikloheksilamino, naftalen-1 -ilmetil-amino, piridin-3-ilamino, 6-metoksi-piridin-3-ilamino, diizobutilamino, 4-nitro-benzilamino, 2-tiofen-2-il-etilamino, 3-fenoksi-fenilamino, cijanometil-amino, (piridin-3-ilmetil)-amino, 5,6,7,8-tetrahidronaftalen-1 -ilamino, 2-piridin-2-iletilamino, 2,3-dihidro-indol-1-il, 3,4-dihidro-1H-izohinolin-2-il, cikloheksilmetil-amino, 2-metoksi-benzilamino, 1-fenil-etilamino, (piridin-4-ilmetil)-amino, benzil-metil-amino, 3-nitro-benzilamino, 4-metoksi-fenilamino, 3-karbamoil-fenilamino, 4-karbamoil-fenilamino, (tetrahidro-furan-2-ilmetil)-amino, 3,4-dihidro-2H-hinolin-1-il, dimetilamino, butilmetilamino, diizopropilamino, propilmetilamino, 1-(benzooksazol-2-karbonil)-propilamino i izobutilmetilamino. Most preferably R<4> is phenylamino, benzylamino, 4-phenoxy-phenylamino, phenethylamino, 3-phenyl-propylamino, morpholin-4-yl, cyclohexylamino, naphthalen-1 -ylmethyl-amino, pyridin-3-ylamino, 6-methoxy-pyridin-3-ylamino, diisobutylamino, 4-nitro-benzylamino, 2-thiophen-2-yl-ethylamino, 3-phenoxy-phenylamino, cyanomethyl-amino, (pyridin-3-ylmethyl)-amino, 5,6,7,8-tetrahydronaphthalen-1 -ylamino, 2-pyridin-2-ylethylamino, 2,3-dihydro-indol-1-yl, 3,4-dihydro-1H-isoquinolin-2-yl, cyclohexylmethyl-amino, 2-methoxy-benzylamino, 1-phenyl-ethylamino, (pyridin-4-ylmethyl)-amino, benzyl-methyl-amino, 3-nitro-benzylamino, 4-methoxy-phenylamino, 3-carbamoyl-phenylamino, 4-carbamoyl-phenylamino, (tetrahydro-furan-2-ylmethyl)-amino, 3,4-dihydro-2H-quinolin-1-yl, dimethylamino, butylmethylamino, diisopropylamino, propylmethylamino, 1-(benzoxazole-2-carbonyl)-propylamino and isobutylmethylamino.

Gore navedena poželjna izvodjenja obuhvataju sve značajne kombinacije sa poželjnim grupama. The above preferred embodiments include all significant combinations with the preferred groups.

Posebna jedinjenja iz datog pronalaska odabrana su od jedinjenja koja se dobijaju spajanjem acil atoma ugljenika (C<*>) jednog od fragmenata (A1 do A37) pokazanim u tabeli 1, za metinski atom ugljenika (<*>CH<*>) jednog od fragmenata (B1 do B88) pokazanim u tabeli 2, i spajanjem metinskog atoma ugljenika (<*>CH<*>) jednog od fragmenata (B1 do B88) pokazanim u tabeli 2 za acil atom ugljenika (C<*>) jednog od fragmenata (C1 do C36) navedenim u tabeli 3. Particular compounds of the present invention are selected from compounds obtained by coupling the acyl carbon atom (C<*>) of one of the fragments (A1 to A37) shown in Table 1, to the methine carbon atom (<*>CH<*>) of one of the fragments (B1 to B88) shown in Table 2, and by coupling the methine carbon atom (<*>CH<*>) of one of the fragments (B1 to B88) shown in Table 2 to acyl carbon atom (C<*>) of one of the fragments (C1 to C36) listed in Table 3.

Sledeće tabele predstavljaju vodič za izvodjenje datog pronalaska. MEdjutim, one ne ograničavaju opim datog pronalaska. Stručnjaci mogu selektivno da pripreme odredjena jedinjenja spajanjem jednog od fragmenata pokazanim u tabeli 1 za bilo koji od fragmenata pokazanim u tabeli 2, i nakon toga povezivanjem fragmenata pokazanim u tabeli 2 za bilo koji od fragmenata iz tabele 3. The following tables are a guide to the practice of the present invention. HOWEVER, they do not limit the scope of the present invention. Those skilled in the art can selectively prepare certain compounds by coupling one of the fragments shown in Table 1 to any of the fragments shown in Table 2, and then coupling the fragments shown in Table 2 to any of the fragments in Table 3.

Tako, na primer, u tabeli 4 jedinjenje označeno kao A2-B45-C35 predstavlja proizvod kombinovanja grupe A2 u tabeli 1 i B45 u tabeli 2 i C35 u tabeli 3, naime So, for example, in Table 4, the compound marked as A2-B45-C35 represents the product of combining the group A2 in Table 1 and B45 in Table 2 and C35 in Table 3, namely

N-[ 1-( 1- benzooks azol- 2- il- meta noil)- 3- ffenil-propil]- N'- benzil - 2- cikl oheksil meti I-malonamid: N-[ 1-(1- benzoxazol-2-yl-methanoyl)-3-phenyl-propyl]-N'-benzyl-2-cyclohexyl methyl I-malonamide:

Ostala poželjna jedinjenja formule I odabrana su od grupe koju čine: 2- butil- N- cijanometil- N'- fenil- malonamid (Jedinjenje 1; označeno kao A1-B88-C1); Other preferred compounds of formula I are selected from the group consisting of: 2-butyl-N-cyanomethyl-N'-phenyl-malonamide (Compound 1; designated as A1-B88-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- fenil- malonamid (Jedinjenje 2; označeno kao A1-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-phenyl-malonamide (Compound 2; designated as A1-B45-C1);

N- Ciianometil- 2- cikloheksilmetil- N'- fenetil- malonamid (Jedinjenje 3; označeno kao A4-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-phenethyl-malonamide (Compound 3; designated as A4-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- piridin- 4ilmetil- malonamid (Jedinjenje 4; označeno kao A24-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-pyridin-4ylmethyl-malonamide (Compound 4; designated as A24-B45-C1);

N-[1 -(Benzooksazol-2-karbonil)-3-fenil-pr opi I]-N'-benzil-2-ci klone ksil metil - N-[1-(Benzoxazole-2-carbonyl)-3-phenyl-propyl]-N'-benzyl-2-cyclone xyl methyl -

malonamid (Jedinjenje 5; označeno kao A2-B45-C35); malonamide (Compound 5; designated as A2-B45-C35);

N- Cijanometil- N'- cikloheksil- 2- cikloheksilmetil- malonamid (Jedinjenje 6; označeno kao A7-B45-C1); N-Cyanomethyl-N'-cyclohexyl-2-cyclohexylmethyl-malonamide (Compound 6; designated as A7-B45-C1);

N- Benzil- N'- cijanometil- 2- cikloheksilmetil- malonamid (Jedinjenje 7; označeno kao A2-B45-C1); N-Benzyl-N'-cyanomethyl-2-cyclohexylmethyl-malonamide (Compound 7; designated as A2-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 4- fenoksi- fenil)- malonamid ( Jedinjenje 8lN-Cyanomethyl-2-cyclohexylmethyl-N'-(4-phenoxy-phenyl)-malonamide (Compound 8l

označeno kao A3- B45- C1); marked as A3- B45- C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 3- fenil- propil)- malonamid (Jedinjenje 9; označeno kao A5-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(3-phenyl-propyl)-malonamide (Compound 9; designated as A5-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- 3- mon' olin- 4- il- 3- okso- propionamid (Jedinjenje 10; označeno kao A6-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-3-mon'olin-4-yl-3-oxo-propionamide (Compound 10; designated as A6-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- naftalen- 1- ilmetil- malonamid (Jedinjenje 11; označeno kao A8-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-naphthalen-1-ylmethyl-malonamide (Compound 11; designated as A8-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- piridin- 3- il- malonamid (Jedinjenje 12; označeno kao A9-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-pyridin-3-yl-malonamide (Compound 12; designated as A9-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N', N'- diizobutil- malonamid (Jedinjenje 13; označeno kao A11-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N',N'-diisobutyl-malonamide (Compound 13; designated as A11-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N', N'- diizopropil- malonamid (Jedinjenje 14; označeno kao A36-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N',N'-diisopropyl-malonamide (Compound 14; designated as A36-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 6- metoksi- piridin- 3- il)- malonamid (Jedinjenje 15; označeno kao A10-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(6-methoxy-pyridin-3-yl)-malonamide (Compound 15; designated as A10-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 2- tiofen- 2- il- etil)- malonamid (Jedinjenje 16; označeno kao A13-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(2-thiophen-2-yl-ethyl)-malonamide (Compound 16; designated as A13-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 3- fenoksi- fenil)- malonamid (Jedinjenje 17; označeno kao A14-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(3-phenoxy-phenyl)-malonamide (Compound 17; designated as A14-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 4- nitro- benzih- malonamid (Jedinjenje 18; označeno kao A12-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(4-nitro-benzyl-malonamide (Compound 18; designated as A12-B45-C1);

N, N'- Bis- cijanometil- 2- cikloheksilmetil- malonamid (Jedinjenje 19; označeno kao N,N'-Bis-cyanomethyl-2-cyclohexylmethyl-malonamide (Compound 19; designated as

A15-B45-C1); A15-B45-C1);

N-C ijanometil-2-cikl oheksil metil- N'-( 5.6, 7. 8- tetrahidro- naftalen- 1 - ih- malonamid N-C cyanomethyl-2-cyclohexyl methyl-N'-(5.6,7.8-tetrahydro-naphthalene-1-yl-malonamide)

(Jedinjenje 20; označeno kao A17-B45-C1); (Compound 20; designated as A17-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 2- piridin- 2- il- etil)- malonamid (Jedinjenje 21; označeno kao A18-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(2-pyridin-2-yl-ethyl)-malonamide (Compound 21; designated as A18-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- 3-( 2, 3- dihidro- indol- 1- il)- malonamid (Jedinjenje 22; označeno kao A19-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-3-(2,3-dihydro-indol-1-yl)-malonamide (Compound 22; designated as A19-B45-C1);

N-Cijanometil-2-cikloheksilmetil-3-(3.4-dihidro-1 H-izohinollin^-ilj-g^okfirv propionamid (Jedinjenje 23; označeno kao A20-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-3-(3,4-dihydro-1H-isoquinolline-yl-g-hydroxypropionamide (Compound 23; designated as A20-B45-C1);

N- Cijanometil- 2- N'- bis- cikloheksilmetil- malonamid (Jedinjenje 24; označeno kao A21-B45-C1); N-Cyanomethyl-2-N'-bis-cyclohexylmethyl-malonamide (Compound 24; designated as A21-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 2- metoksi- benzil)- malonamid (Jedinjenje 25; označeno kao A22-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(2-methoxy-benzyl)-malonamide (Compound 25; designated as A22-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 1- fenil- etil)- malonamid (Jedinjenje 26; označeno kao A23-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(1-phenyl-ethyl)-malonamide (Compound 26; designated as A23-B45-C1);

N- Benzil- N'- cijanometil- 2- cikloheksilmetil- N- metil- malonamid (Jedinjenje 27; označeno kao A25-B45-C1); N-Benzyl-N'-cyanomethyl-2-cyclohexylmethyl-N-methyl-malonamide (Compound 27; designated as A25-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- f3- nitro- benzil)- malonamid (Jedinjenje 28; označeno kao A26-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(3-nitro-benzyl)-malonamide (Compound 28; designated as A26-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'-( 4- metoksi- benzil)- malonamid (Jedinjenje 29; označeno kao A27-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-(4-methoxy-benzyl)-malonamide (Compound 29; designated as A27-B45-C1);

N-( 3- Karbamoil- fenil)- N'- ciianometil- 2- cikloheksilmetil- malonamid (Jedinjenje 30; označeno kao A28-B45-C1); N-(3-Carbamoyl-phenyl)-N'-cyanomethyl-2-cyclohexylmethyl-malonamide (Compound 30; designated as A28-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- piridin- 3- ilmetil- malonamid (Jedinjenje 31; označeno kao A16-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-pyridin-3-ylmethyl-malonamide (Compound 31; designated as A16-B45-C1);

N-( 4- karbamoilfenil)- N'- ciianometil- 2- cikloheksilmetil- malonamid (Jedinjenje 32; označeno kao A29-B45-C1); N-(4-carbamoylphenyl)-N'-cyanomethyl-2-cyclohexylmethyl-malonamide (Compound 32; designated as A29-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- N'- tetrahidrofur- 2- ilmetilmalonamid (Jedinjenje 33; označeno kao A30-B45-C1); N-Cyanomethyl-2-cyclohexylmethyl-N'-tetrahydrofur-2-ylmethylmalonamide (Compound 33; designated as A30-B45-C1);

N- Cijanometil- 2- cikloheksilmetil- 3-( 3. 4- dihidro- 2H- hinolin- 1- il)- 3- oksopropionamid N- Cyanomethyl- 2- cyclohexylmethyl- 3-( 3. 4- dihydro- 2H- quinolin- 1- yl)- 3- oxopropionamide

(Jedinjenje 34; označeno kao A31-B45-C1); (Compound 34; designated as A31-B45-C1);

N4erc- butil- N'- cijanometil- 2- cikloheksilmetil- N- metilmalonamicl (Jedinjenje 35; označeno kao A35-B45-C1); N4-tert-butyl-N'-cyanomethyl-2-cyclohexylmethyl-N-methylmalonamicl (Compound 35; designated as A35-B45-C1);

N- cijanometil- 2- cikloheksilmetil- N'- metil- N'- propilmalonamid (Jedinjenje 36; označeno kao A34-B45-C1); N-cyanomethyl-2-cyclohexylmethyl-N'-methyl-N'-propylmalonamide (Compound 36; designated as A34-B45-C1);

N- butil- N'- cijanometil- 2- cikloheksilmetil- N- metilmalonamid (Jedinjenje 37; označeno kao A33-B45-C1); N-butyl-N'-cyanomethyl-2-cyclohexylmethyl-N-methylmalonamide (Compound 37; designated as A33-B45-C1);

N- cijanometil- 2- cikloheksilmetil- N', N'- dimetilmalonamid (Jedinjenje 38; označeno kao A32-B45-C1); N-cyanomethyl-2-cyclohexylmethyl-N',N'-dimethylmalonamide (Compound 38; designated as A32-B45-C1);

N- Benzil- N'- cijanometil- 2-( 2- fenilsulfaniletil)- malonamid (Jedinjenje 39; označeno kao A2-B80-C1); N-Benzyl-N'-cyanomethyl-2-(2-phenylsulfanylethyl)-malonamide (Compound 39; designated as A2-B80-C1);

2-( 2- fenilsulfoniletil)- N- benzil- N'- cijanometilmalonamid (Jedinjenje 40; označeno kao A2-B6-C1); 2-(2-phenylsulfonylethyl)-N-benzyl-N'-cyanomethylmalonamide (Compound 40; designated as A2-B6-C1);

2-( 2- Benzensulfonil- etil)- N-[( S)- 1-( 1 - benzooksazol- 2- il- metanoil)- pentil]- N'- benzilmalonamid (Jedinjenje 41; označeno kao A2-B6-C12); 2-(2-Benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzooxazol-2-yl-methanol)-pentyl]-N'-benzylmalonamide (Compound 41; designated as A2-B6-C12);

N, N'- Bis-[( S)- 1-( 1- benzooksazol- 2- il- metanoil)- propilj- 2- cikloheksilmetil- malonamid N, N'- Bis-[( S)- 1-( 1- Benzoxazol-2- yl- methanoyl)- propyl- 2- cyclohexylmethyl- malonamide

(Jedinjenje 42; označeno kao A37-B45-C13); (Compound 42; designated as A37-B45-C13);

i derivati N-oksida, derivati proleka, derivati sa zaštitnom grupom, pojedinačni izomeri i smeše tih izomera; i farmaceutski prihvatljive soli i solvati (na primer, hidrati) tih jedinjenja i derivati N-oksida; derivati proleka, derivati sa zaštitnim grupama, pojedinačni izomeri i smeše tih izomera. and N-oxide derivatives, prodrug derivatives, derivatives with a protective group, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvates (eg, hydrates) of those compounds and N-oxide derivatives; prodrug derivatives, derivatives with protective groups, individual isomers and mixtures of these isomers.

Farmakolgija i primena: Pharmacology and application:

JEdinjenja prema pronalasku predstavljaju selektivne inhibitore katepsina S, i korisna su u lečenju oboljenja u kojima aktivnost catepsina S doprinosi patologiji i/ ili simptomatologiji oboljenja. Na primer, jedinjenja iz pronalaska korisna su u lečenju autoimunih poremećaja, koji obuhvataju bez ograničenja početni juvenilni diabetes, multipl sklerozu, pemfigus vulgaris, Graveovu bolest, miastenia gravis, sistemski lupus eritematozus, reumatoidni artritis i Hašimotov tiroiditis; alergijske poremećaje, koji uključuju ali nisu ograničeni na astmu; i alogenične imune odgovore, koji uključuju ali nisu ograničeni na reakciju na transplatanta organa ili presadjenog tkiva. The compounds of the invention are selective inhibitors of cathepsin S, and are useful in the treatment of diseases in which cathepsin S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in the treatment of autoimmune disorders, including but not limited to incipient juvenile diabetes, multiple sclerosis, pemphigus vulgaris, Grave's disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto's thyroiditis; allergic disorders, including but not limited to asthma; and allogeneic immune responses, which include but are not limited to reactions to organ transplants or transplanted tissue.

Katepsin S uključen je u poremećaje koji obuhvataju ekscesivnu elastolizu, kao što su hronična opstruktivna bolest pluća (na primer, emfizem), bronhiolitis, ekcesivnu elastoliza disajnih puteva kod astme i bronhitisa, pneumonitis i kardiovaskularna oboljenja kao što su ruptura plaka, aterom. Katepsin S je uključen u fibrilnu formaciju i stoga su inhibitori katepsina S korisni u lečenju sistemskog amiloiditisa. Inhibitorska aktivnost jedinjenja iz ovog pronalaska za cisteinsku proteazu može biti odredjena metodama poznatim onima koji su upućeni u stanje tehnike. Pogodni in vivo ogledi za odredjivanje aktivnosti proteaze i njene inhibicije sa probnim jedinjenjima su poznati. Uobičajeno, test meri hidrolizu peptidnog supstrata indukovanog proteazom. Detalji o testovima za merenje inhibicije aktivnosti proteaze su dati dalje u primerima 6-9, koji slede. Cathepsin S is involved in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonitis, and cardiovascular diseases such as plaque rupture, atheroma. Cathepsin S is involved in fibril formation and therefore cathepsin S inhibitors are useful in the treatment of systemic amyloiditis. Cysteine protease inhibitory activity of the compounds of the present invention can be determined by methods known to those skilled in the art. Suitable in vivo assays for determining protease activity and its inhibition with test compounds are known. Typically, the assay measures protease-induced hydrolysis of a peptide substrate. Details of assays for measuring inhibition of protease activity are provided further in Examples 6-9, which follow.

Primena i farmaceutske kompozicije: Application and pharmaceutical compositions:

U opštem slučaju, jedinjenja formule I će se davati u terapeutski delotvornim dozama pomoću bilokojeg uobičajenog i prihvatljivog načina poznatog u struci, bilo pojedinačno bilo u kombinaciji sa nekim drugim terapeutskim sredstvom. Terapeutski delotvorna količina se može menjati u širokom opsegu, zavisno od težine bolesti, uzrasta i relativnog zdravlja pacijenta, jačine jedinjenja koje se koristi i drugih činilaca. Na pr., terapeutski delotvorne količine jedinjenja formule I mogu se menjati od 1 mikrograma po kg telesne težine (jxg/kg) do oko 10 mikrograma po kg telesne težine (mg/kg) dnevno, tipično od oko 1o u,g/kg do 0.1 mg/kg dnevno. Stoga se terapeutski delotvorna količina kod ljudskog pacijenta težine 80 kg može menjati od 100 u.g/kg do 100 mg/kg dnevno, tipično 1 (ig/kg do 10 mg/kg dnevno. U opštem slučaju, uobičajeno vešt u struci, koji radi oslanjajući se na lično iskustvo i objave u ovoj prijavi, biće u stanju da odredi terapeutski delotvornu količinu jedinjenja formule I za tretman odredjene bolesti. In general, the compounds of formula I will be administered in therapeutically effective doses by any conventional and acceptable means known in the art, either alone or in combination with another therapeutic agent. The therapeutically effective amount can vary widely, depending on the severity of the disease, the age and relative health of the patient, the strength of the compound used, and other factors. For example, therapeutically effective amounts of a compound of formula I may vary from 1 microgram per kg body weight (jxg/kg) to about 10 micrograms per kg body weight (mg/kg) per day, typically from about 10 u.g/kg to 0.1 mg/kg per day. Therefore, a therapeutically effective amount in a human patient weighing 80 kg may vary from 100 µg/kg to 100 mg/kg per day, typically 1 µg/kg to 10 mg/kg per day. In general, one of ordinary skill in the art, working in reliance on personal experience and the disclosures herein, will be able to determine a therapeutically effective amount of a compound of formula I for the treatment of a particular disease.

Jedinjenja formule I mogu se davati kao farmaceutske kompozicije jednim od sledećih načina : oralno, sistemski (na pr., transdermalno, intranazalno ili supozitorijama) ili parenteralno (na pr., intramuskularno, intravenozno ili potkožno). Kompozicije mogu biti u obliku tableta, pilula, kapsula, polutvrdih pakovanja, praškova, formulacija sa produženim ispuštanjem, rastvora, suspenzija, eliksira, aerosola, ili bilokoje druge odgovarajuće kompozicije i sastoje se, obično, od jedinjenja formule I u kombinaciji . Compounds of formula I may be administered as pharmaceutical compositions by one of the following routes: orally, systemically (eg, transdermally, intranasally, or suppositories), or parenterally (eg, intramuscularly, intravenously, or subcutaneously). The compositions may be in the form of tablets, pills, capsules, semi-hard packs, powders, extended release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition and typically consist of compounds of formula I in combination.

sa bar jednim farmaceutski prihvatljivim dodatkom. Prihvatljivi ekscipijenti su netoksični, pomažu davanju i ne deluju negativno na korisno dejstvo aktivnog sastojka. Ovakvi ekscipijenti mogu biti čvrsti, tečni, polučvrsti ili, u slučaju kompozicija aerosola, gasoviti ekscipijenti , koji su uopšteno uzev, dostupni stručnim licima. with at least one pharmaceutically acceptable additive. Acceptable excipients are non-toxic, aid in administration and do not adversely affect the beneficial effect of the active ingredient. Such excipients can be solid, liquid, semi-solid or, in the case of aerosol compositions, gaseous excipients, which are generally available to those skilled in the art.

Čvrsti farmaceutski dodaci uključuju štirak, celulozu, talk, glikozu, laktozu, sukrozu, želatin, slad, pirinač, brašno, kredu, silika žel, magnezijum stearat, natrijum stearat, glicerol monostearat, natrijum hlorid, obrano mleko u prahu, i si. Tečni i polučvrsti dodaci se mogu birati od vode, etanola, glicerola, propilen glikola i različitih ulja, uključujući onih od nafte, životinjskih, biljnih ili sintetičkog porekla (na pr., ulja kikirikija, ulja soje, mineralnog ulja, sezamovog ulja, itd.). Preporučljivi tečni nosači, posebno za rastvore za injekcije, uključuju vodu, fiziološki rastvor, vodeni rastvor glikoze i glikole. Solid pharmaceutical additives include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skimmed milk powder, etc. Liquid and semi-solid additives may be selected from water, ethanol, glycerol, propylene glycol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin (eg, peanut oil, soybean oil, mineral oil, sesame oil, etc.). Recommended liquid carriers, especially for injectable solutions, include water, saline, aqueous glucose solution, and glycols.

Količina jedinjenja formule I u kompozicija može se menjati zavisno od tipa formulacije, veličine jedinične doze, vrste dodatka i drugih činilaca, poznatih veštima u struci farmaceutske nauke. Obično, kompozicija jedinjenja formule I za tretman neke date bolesti sadržavaće od 0,01 tež.% do 10 tež.%, preporučljivo 0,3 do 1 tež.% aktivnog sastojka, pri čemu je ostatak dodatak ili dodaci. Preporučljivo, farmaceutska kompozicija će se davati u pojedinačnim dozama za stalni tretman ili u obliku pojedinačne dozead libitumkada se specifično traži smanjenje simptoma. Reprezentativne farmacutske kompozicije sa sadržajem jedinjenja formule I opisane su u Primeru 10. The amount of the compound of formula I in the composition can be changed depending on the type of formulation, the size of the unit dose, the type of additive and other factors known to those skilled in the pharmaceutical science. Typically, a composition of a compound of formula I for the treatment of a given disease will contain from 0.01 wt.% to 10 wt.%, preferably 0.3 to 1 wt.% of the active ingredient, with the remainder being an additive or additives. Preferably, the pharmaceutical composition will be administered in single doses for continuous treatment or in single dosead libitum form when symptom reduction is specifically sought. Representative pharmaceutical compositions containing compounds of formula I are described in Example 10.

Hernija: Hernia:

Postupci za pravljenje jedinjenja formule I: Procedures for making compounds of formula I:

Jedinjenja prema pronalasku mogu se pripremiti primenom ili adaptacijom poznaih postupaka pod kojim se podrazumevaju postupci koji su korišćeni u ovom tekstu ili su opisani u literaturi na primer oni koji su opisani od R.C. Larock u Comprehensive Organic Transformations, VCH publishers, 1989. The compounds according to the invention can be prepared by applying or adapting known procedures, by which is meant the procedures used in this text or described in the literature, for example those described by R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

U reakcijama koje su ovde opisane neophodno je da se izvrši zaštita reaktivnih funkcionalnih grupa kao što su na primer, hidroksi, amino, imino, tio ili karboksi grupe, jer je poželjno da se pomenute grupe nadju u krajnjem proizvodu, da bi se izbegla njihovo neželjeno učešće u reakcijama. Konvencionalne zaštitne grupe mogu da se koriste prema standardnoj praksi, na primer, videti T.W. Greene and P.G.M. Wuts in „ Protecitve Groups in Organic Chemistrv „ John Wiley and Sons, 1991. In the reactions described here, it is necessary to protect reactive functional groups such as, for example, hydroxy, amino, imino, thio or carboxy groups, because it is desirable that the mentioned groups are found in the final product, in order to avoid their unwanted participation in the reactions. Conventional protecting groups can be used according to standard practice, for example, see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Jedinjenja formule I, gde X"! predstavlja -NHC(R"I(R2) mogu se dobiti prema postupku koji je opisan na sledećoj reakcionoj šemi: Compounds of formula I, where X"! represents -NHC(R"I(R2) can be obtained according to the procedure described in the following reaction scheme:

i and

u kojoj su X<2>, R<1>, R<2>, R<3>i R<4>definisani u kratkom pregledu pronalaska. Jedinjenja formule I mogu se dobiti spajanjem kiseline formule 2 sa jedinjenjem formule NH2CR<1>R<2>X<2>. Reakcija kondenzacije može se izvesti sa odgovarajućim agensom za kuplovanje (na primer, benzotriazol-1-iloksitrispirolidinofosfonijum heksafluorofosfat (PyBOP(reg. žig), 1-(3-dimetilaminopropil)-3-etilkarbodiimid hidrohlorid (EDCI), O-benzotriazol-1-il-N,N,N',N'-tetrametiluronijum heksafluorofosfat (HBTU), 1,3-dicikloheksilkarbodiimid (DCC) ili slično) i po slobodnom izboru odgovarajućeg katalizatora (na primer, 1-hidroksibenzotriazol (HOBt), 1-hidroksi-7-azabenotriazola (HOAt) ili slično) i ne-nukleofilne baze ( na primer, N-metilmorfolin, trietilamin, ili slično ili bilo koja odgovarajuća kombinacija) u odgovarajućem rastvaraču (N-metilpirolidinon , ili njemu slični rastvarač) na okolnoj temepraturi i potrebno je 3 do 10 sati da bi se reakcija završila. Detaljniji wherein X<2>, R<1>, R<2>, R<3> and R<4> are defined in the Summary of the Invention. Compounds of formula I can be obtained by coupling the acid of formula 2 with the compound of formula NH2CR<1>R<2>X<2>. The condensation reaction can be performed with a suitable coupling agent (for example, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP(trademark), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) or the like) and a free choice of a suitable catalyst (for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenotriazole (HOAt) or the like) and a non-nucleophilic base (for example, N-methylmorpholine, triethylamine, or the like or any suitable combination) in a suitable solvent (N-methylpyrrolidinone, or a similar solvent) at ambient temperature and it takes 3 to 10 hours to complete the reaction more detailed

opis sinteze jedinjenja formule I pomoću postupka iz reakcione šeme 1 naveden je u primerima niže. a description of the synthesis of compounds of formula I by the procedure of reaction scheme 1 is given in the examples below.

Jedinjenja formule I, gde X<1>predstavlja -NHX<3>mogu se dobiti prema postupku koji je opisan na sledećoj reakcionoj šem 2i: Compounds of formula I, where X<1>represents -NHX<3> can be obtained according to the procedure described in the following reaction scheme 2i:

i and

u kojoj su X<2>, , R<3>i R<4>definisani u kratkom pregledu pronalaska. wherein X<2>, , R<3> and R<4> are defined in the Summary of the Invention.

Jedinjenja formule I mogu se dobiti spajanjem kiseline formule 2 sa jedinjenjem formule NH2X<3>. Reakcija kondenzacije može se izvesti sa odgovarajućim agensom za kuplovanje (na primer, benzotriazol-1-iloksitrispirolidinofosfonijum heksafluorofosfat (PyBOP(reg. žig), 1-(3-dimetilaminopropil)-3-etilkarbodiimid hidrohlorid (EDCI), O-benzotriazol-1 -il-N,N,N',N'-tetrametiluronijum heksafluorofosfat (HBTU), 1,3-dicikloheksilkarbodiimid (DCC) ili slično) i po slobodnom izboru odgovarajućeg katalizatora (na primer, 1-hidroksibenzotriazol (HOBt), 1-hidroksi-7-azabenotriazola (HOAt) ili slično) i ne-nukleofilne baze ( na primer, N-metilmorfolin, trietilamin, ili slično ili bilo koja odgovarajuća kombinacija) u odgovarajućem rastvaraču (N-metilpirolidinon , ili njemu slični rastvarač) na okolnoj temepraturi i potrebno je 3 do 10 sati da bi se reakcija završila. Detaljniji opis sinteze jedinjenja formule I pomoću postupka iz reakcione šeme 1 naveden je u primerima niže. Compounds of formula I can be obtained by coupling the acid of formula 2 with the compound of formula NH2X<3>. The condensation reaction can be performed with a suitable coupling agent (for example, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP(trademark), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) or the like) and a free choice of a suitable catalyst (for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenotriazole (HOAt) or the like) and a non-nucleophilic base (for example, N-methylmorpholine, triethylamine, or the like or any suitable combination) in a suitable solvent (N-methylpyrrolidinone, or a similar solvent) at ambient temperature and it takes 3 to 10 hours to complete the reaction A more detailed description of the synthesis compounds of formula I by the procedure of reaction scheme 1 is set forth in the examples below.

Dopunski postupci za pripremu jedinjenja formule I Additional procedures for the preparation of compounds of formula I

Jedinjenje formule I može se pripremati kao farmaceutski prihvatljiva adiciona so kiselina reakcijom jedinjenja u obliku slobodne baze sa farmaceutski prihvatljivom neorganskom ili organskom kiselinom. Alternativno, farmaceutski prihvatljiva adicione soli baze jedinjenja formule I se može pripremati reakcijom jedinjenja u obliku slobodne kiseline sa farmaceutski prihvatljivom neorganskom ili organskom bazom. Neorganske i organske kiseline i baze su pogodne za pripremanje farmaceutski prihvatljivih soli jedinjenja formule I i objašnjene su u odeljku koji se odnosi na definicije ove prijave. Alternativno, oblici soli jedinjenja formule I se mogu pripremati korišćenjem soli polaznih materijala ili medjuproizvoda. A compound of formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the compound in free base form with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of formula I can be prepared by reacting the compound in free acid form with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases are suitable for the preparation of pharmaceutically acceptable salts of compounds of formula I and are explained in the definition section of this application. Alternatively, salt forms of compounds of formula I can be prepared using salts of starting materials or intermediates.

Slobodni kiselinski oblici i bazni oblici jedinjenja formule I mogu se dobiti iz odgovarajućih oblika adicionih soli baza i adicionih soli kiselina. Na pr., jedinjenje formule I u obliku adicione soli kiseline može se prevesti u odgovarajuću slobodnu bazu obradom sa odgovarajućom bazom (na pr., rastvorom amonijum hidroksida, natrijum hidroksidom, itd.). Jedinjenje formule I u obliku adicione soli baze se može prevesti u odgovarajuću slobodnu kiselinu pomoću odgovarajuće kiseline (na pr., hlorovodonične kiseline, itd.). The free acid forms and base forms of the compounds of formula I can be obtained from the corresponding forms of addition salts of bases and addition salts of acids. For example, a compound of formula I in acid addition salt form can be converted to the corresponding free base by treatment with an appropriate base (eg, ammonium hydroxide solution, sodium hydroxide, etc.). A compound of formula I in the form of a base addition salt can be converted to the corresponding free acid using a suitable acid (eg, hydrochloric acid, etc.).

A/-oksidi jedinjenja formule I mogu se pripremati postupcima poznatim uobičajeno veštima u struci. Na pr., A/-oksidi se mogu pripremati obradom neoksidovanog oblika jedinjenja formule I sredstvom za oksidaciju (na pr., trifluoropersirćetnom kiselinom, permaleinskom kiselinom, perbenzoevom kiselinom, persirćetnom kiselinom, mefa-hloroperoksibenzoevom kiselinom, itd.) u odgovarajućem inertnom organskom rastvaraču (na pr., halogenisanom ugljovodiku, kao metilen hloridu) na oko 0°C. Alternativno, A/-oksidi jedinjenja formule I se mogu pripremati od /V-oksida odgovarajućeg polaznog materijala. The N-oxides of compounds of formula I can be prepared by methods known to those of ordinary skill in the art. For example, A/-oxides can be prepared by treating the unoxidized form of a compound of formula I with an oxidizing agent (eg, trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, mepha-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (eg, a halogenated hydrocarbon such as methylene chloride) at about 0°C. Alternatively, the A/-oxides of compounds of formula I can be prepared from the /V-oxides of the appropriate starting material.

Jedinjenja formule I u neoksidovanom obliku mogu se pripremati odN-oksida jedinjenja formule I obradom sredstvom za redukciju (na pr., sumporom, sumpor dioksidom, trifenil fosfinom, litijum borohidridom, natrijum borohidridom, fosfor trihloridom, tribromidom, itd.) u pogodnom inertnom organskom rastvaraču (na pr., acetonitrilu, etanolu, vodenom rastvoru dioksana, itd.) na 0 do 80°C. Compounds of formula I in unoxidized form may be prepared from the N-oxide of a compound of formula I by treatment with a reducing agent (eg, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80°C.

Derivati proleka jedinjenja formule I u obliku jedinjenja mogu se pripremati postupcima poznatim onima koji su upućeni u u stanje tehnike (na pr., za više detalja v. Saulnieret al.,(1994),Bioorganic and Medicina! Chemistn/Letters,4 : 1985). Na pr., odgovarajući derivati proleka mogu se propremiti reakcijom nederivatisanim jedinjenjem formule I sa pogodnim sredstvom za karbamilisanje (na pr., 1,1-aciloksialkilkarbonohloridatom, para-nitrofenil karbonatom, itd.). Prodrug derivatives of compounds of formula I in compound form can be prepared by methods known to those skilled in the art (eg, for more details, see Saulnieret al., (1994), Bioorganic and Medicina! Chemistn/Letters, 4 : 1985). For example, suitable prodrug derivatives can be modified by reacting a non-derivatized compound of formula I with a suitable carbamylating agent (eg, 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.).

Zaštićeni derivati jedinjenja formule I se mogu pripremati na načine koji su poznati onima koji su upućeni u stanje tehnike. Detaljan opis primenljivih postupaka za stvaranje zaštitnih grupa i njihovo skidanje se može naći u T.VV.Green,Protecting Groups in Organic Synthesis,John Wiley & Sons, Ine, 1999. Protected derivatives of compounds of formula I can be prepared by methods known to those skilled in the art. A detailed description of applicable procedures for creating and removing protecting groups can be found in T.V.V. Green, Protecting Groups in Organic Synthesis, John Wiley & Sons, Ine, 1999.

Jedinjenja iz datog pronalaska formule I se mogu pripremati ili formirati na uobičajeni način tokom postupka prema datom pronalasku, u vidu solvata (na primer, hidrati). Hidrati jedinjenja iz datog pronalaska mogu se dobiti na uobičajeni način rekristalizacijom iz smeše vodenog/ organskog rastvarača. korišćenjem organskih rastvarača kao što su dioksin, tetrahidrofuran ili metanol. Jedinjenja formule I se mogu pripremati kao njihovi individualni stereoizomeri reakcijom racemske smeše jedinjenja sa optički aktivnim sredstvom za rastvaranje radi formiranja diastereoizomernih jedinjenja, odvajanjem diastereomera i skupljanjem optički čistih enantiomera. Dok se razdvajanje enantiomera može vršiti upotrebom kovalentnih diasteromernih derivata jedinjenja formule I, disocijabilni kompleksi se radije upotrebljavaju (na pr., kristalne diastereoizometrne soli). Diastereomeri poseduju odredjene fizičke osobine (na pr. tačke topljenja -t.t.-, tačke ključanja -t.k.-, rastvorljivost, reaktivnost, itd.) i mogu se lako odvojiti koristeći ove različitosti. Diastereomeri se mogu razdvojiti hromatografijom ili, preporučljivo, postupcima razdvajanja/rezolucije na osnovi razlika u rastvorljivosti. Zatim se izdvaja optički čist enantiomer, zajedno sa sredstvom za rastvaranje, bilokojim praktičnim načinom, koji ne bi doveo do racemizacije. Detaljniji opis primenljivih postupaka rezolucije stereoizomera jedinjenja iz njihove racematske smeše se može naći u: Jean Jacques Collet, Samuel H. VVilen, Enantiomeri, racemati i rezolucije (Enantiomers, Racemats and Resolutions), John Wiley & Sons,Inc.,(1981). Compounds of the present invention of formula I may be prepared or formed in a conventional manner during the process of the present invention, in the form of solvates (for example, hydrates). The hydrates of the compounds of the present invention can be obtained in the usual way by recrystallization from an aqueous/organic solvent mixture. using organic solvents such as dioxin, tetrahydrofuran or methanol. Compounds of formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active solvent to form diastereoisomeric compounds, separating the diastereomers, and collecting the optically pure enantiomers. While separation of enantiomers can be accomplished using covalent diastereomeric derivatives of compounds of formula I, dissociable complexes are preferably used (eg, crystalline diastereoisomeric salts). Diastereomers have certain physical properties (eg melting points -m.p.-, boiling points -b.p.-, solubility, reactivity, etc.) and can be easily separated using these differences. Diastereomers can be separated by chromatography or, preferably, separation/resolution procedures based on differences in solubility. The optically pure enantiomer is then separated, together with a solvent, by any practical means which would not lead to racemization. A more detailed description of applicable procedures for the resolution of stereoisomers of compounds from their racemic mixture can be found in: Jean Jacques Collet, Samuel H. Wileyn, Enantiomers, Racemates and Resolutions (Enantiomers, Racemats and Resolutions), John Wiley & Sons, Inc., (1981).

U zaključku, jedan aspekt pronalaska je postupak za pripremanje jedinjenja formule I, pri čemu taj postupak obuhvata : In conclusion, one aspect of the invention is a process for preparing a compound of formula I, wherein the process includes:

(A) reakciju jedinjenja formule 2 : (A) reaction of compounds of formula 2:

sa jedinjenjem formule NH2CR1R2X<2>, u kojem suR1, R2, R<3>i R<4>definisani u with a compound of the formula NH2CR1R2X<2>, in which R1, R2, R<3>and R<4> are defined in

kratkom opisu pronalaska za jedinjenje formule I; ili a brief description of the invention for the compound of formula I; or

(B) reakciju jedinjenja formule 2 sa jedinjenjem formule NH2X<3>u kojem su R<3>, (B) reaction of the compound of formula 2 with the compound of formula NH2X<3> in which R<3>,

R<4>i X<3>definisani u kratkom opisu pronalaska za jedinjenje formule I; i R<4> and X<3> defined in the brief description of the invention for the compound of formula I; and

(C) po slobodnom izboru prevodjenje jedinjenja formule I u farmaceutski prihvatljivu so; (D) po želji prevodjenje soli jedinjenja formule I u oblik, koji nije so ; (E) po želji prevodjenje neoksidovanog oblika jedinjenja formule I u farmaceutski prihvatljiv /V-oksid ; (F) po želji prevodjenje oblika A/-oksida jedinjenja formule I u njegov neoksidovani oblik ; (G) po želji razdvajanje pojedinačnog izomera jedinjenja formule I iz smeše izomera; (H) po želji prevodjenje ne-derivatizovanih derivata jedinjenja I u farmaceutski derivat proleka (I) po slobodnom izvodjenju prevodjenje derivata proleka jedinjenja formule I u njegov ne-derivatizovani oblik. (C) optionally converting the compound of formula I into a pharmaceutically acceptable salt; (D) optionally converting a salt of a compound of formula I into a non-salt form; (E) optionally converting the unoxidized form of the compound of formula I into a pharmaceutically acceptable β-oxide; (F) optionally converting the A/-oxide form of the compound of formula I into its non-oxidized form; (G) optionally separating an individual isomer of a compound of formula I from a mixture of isomers; (H) optionally converting the non-derivatized derivatives of compound I into a pharmaceutical derivative of the prodrug (I) optionally converting the prodrug derivative of the compound of formula I into its non-derivatized form.

Primeri: Examples:

Dati pronalazak je dalje predstavljen kroz primere, bez da je ograničen na primere koji ilustruju dobijanje jedinjenja formule I (Primeri) i intermedijera (Reference) prema pronalasku. The present invention is further presented by way of examples, without being limited to examples illustrating the preparation of compounds of formula I (Examples) and intermediates (References) according to the invention.

REFERENCA 1 REFERENCE 1

2- Fenilkarbamoil- kapronska kiselina 2- Phenylcarbamoyl- caproic acid

Rastvor anilina (5.47 ml, 60 mmol) i trietilamina (8.36 ml, 60 mmol) u metilen hloridu (150 ml) hladi se na -20°C i obradjuje sa metilmalonilhloridom (8.36 ml, 60 mmol) u metilen hloridu (20 ml). Reakciona smeša se ostavlja da se zagreje do okolne temeprature 3 h i nakon toga se sipa u hladni 1N HCI. organski sloj se odvaja i ispire sa vodenim rastvorom natrijum bikarbonata, nakon toga sa koncetrovanim rastvorom soli i suši na magnezijum sulfatu i isparava da bise dobio metil 2-fenilkarbamoilacetat. A solution of aniline (5.47 ml, 60 mmol) and triethylamine (8.36 ml, 60 mmol) in methylene chloride (150 ml) was cooled to -20°C and treated with methylmalonyl chloride (8.36 ml, 60 mmol) in methylene chloride (20 ml). The reaction mixture was allowed to warm to ambient temperature for 3 h and then poured into cold 1N HCl. the organic layer was separated and washed with aqueous sodium bicarbonate, then with brine and dried over magnesium sulfate and evaporated to give methyl 2-phenylcarbamoylacetate.

Smeša metil 2-fenilkarbamoilacetata (1.159 g, 6 mmol) litijum hidroksida (0.43 g, 0.18 mmol) i 1-jodobutana (0.91 ml, 8 mmol) u N-metilpirolidinonu (10 ml) meša se na okolnoj temepraturi 1.5 sat. Reakciona smeša se sipa u ledenu vodu, ekstrahuje sa etilacetatom (dva puta, svaka sa po 50 ml), kombinovani organski ekstrakti se ispiraju sa koncentrovanim rastvorom soli, suše na magenzijum sulfatu i isparavaju. Ostatak se prečišćava fleš hromatografijom na silika gelu eluiranjem sa 20%-tnim etilacetat/ heksan da bi se dobio metil 2-fenilkarbamoilheksanoat (0.715 g, prinos 48%). A mixture of methyl 2-phenylcarbamoylacetate (1.159 g, 6 mmol), lithium hydroxide (0.43 g, 0.18 mmol) and 1-iodobutane (0.91 ml, 8 mmol) in N-methylpyrrolidinone (10 ml) was stirred at ambient temperature for 1.5 h. The reaction mixture is poured into ice water, extracted with ethyl acetate (twice, each with 50 ml), the combined organic extracts are washed with concentrated salt solution, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to give methyl 2-phenylcarbamoylhexanoate (0.715 g, 48% yield).

Rastvor metil 2-fenilkarbamoilheksanoat 90.98 g, 3.9 mmol) u metanolu (10 ml) obradjuje se sa natrijum hidroksidom (4ml, 4 mmol) na okolnoj temerpaturi u vremenu od 17 h. Metanol se uklanja pod sni/enim pritiskom i ostatak se obradjuje sa 1N HCI i ekstrahuje sa etilacetatom (dva puta, svaki sa po 50 ml). Organski slojevi se ispiraju sa koncentrovanim rastvorom soli, supe na magnezijum sulfatu i isparavaju da bi se dobio 2-fenilkarbamoilkapronska kiselina (0.68 g, 2.9 mmol, prinos 74%). A solution of methyl 2-phenylcarbamoylhexanoate (90.98 g, 3.9 mmol) in methanol (10 ml) was treated with sodium hydroxide (4 ml, 4 mmol) at ambient temperature for 17 h. The methanol is removed under reduced pressure and the residue is treated with 1N HCl and extracted with ethyl acetate (twice, 50 ml each). The organic layers were washed with brine, saturated with magnesium sulfate, and evaporated to give 2-phenylcarbamoylcaproic acid (0.68 g, 2.9 mmol, 74% yield).

REFERENCA 2 REFERENCE 2

poluamid 2- Cikloheksilmetil- N- fenil- malonske kiseline semiamide of 2-Cyclohexylmethyl-N-phenyl-malonic acid

Smeša metil 2-fenilkarbamoilacetata (dobijena kao u referentnom primeru 1) A mixture of methyl 2-phenylcarbamoylacetate (obtained as in reference example 1)

(4.39 g, 2.27 mmol), litijum hidroksia (1.08 g, 45 mmol) i bromometilcikloheksana (3.756 ml, 27 mmol) u N-metilpirolidonu (25 ml) meša se na okolnoj temepraturi u vremenu od 17 h (4.39 g, 2.27 mmol), lithium hydroxy (1.08 g, 45 mmol) and bromomethylcyclohexane (3.756 ml, 27 mmol) in N-methylpyrrolidone (25 ml) was stirred at ambient temperature for 17 h

Reakciona smeša se sipa u ledenu vodu, ekstrahuje sa etrom (tri puta, svaka sa po 100 ml). Ekstrakti se ispiraju sa vodom i nakon toga sa koncentrovanim rastvorom soli, suše na magenzijum sulfatu i isparavaju. Ostatak se prečišćava fleš hromatografijom na silika gelu eluiranjem sa 10%-tnim etilacetatom ( heksan) da bi se dobio metil 2-cikloheksilmetil-N-fenil malonamat (1.89 g, 6.5 mmol, prinos 20%). Gornji vodeni sloj se haldi na ledu i zakišeljava do pH 2 sa 1N HCI. Vodeni sloj se ekstrahuje sa etrom (3 puta, svaki sa 100 ml) i ekstrakti se ispiraju sa vodom, nakon toga sa koncentrovanim rastvorom soli, suše na magnezijum sulfatu i isparavaju da bi se dobio poluamid 2-cikloheksilmetil-N-fenil-malonske kiseline (1.12 g, pronos 18%). The reaction mixture is poured into ice water, extracted with ether (three times, each with 100 ml). The extracts are washed with water and then with concentrated salt solution, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate (hexane) to give methyl 2-cyclohexylmethyl-N-phenyl malonate (1.89 g, 6.5 mmol, 20% yield). The upper aqueous layer is cooled on ice and acidified to pH 2 with 1N HCl. The aqueous layer was extracted with ether (3 times, 100 ml each) and the extracts were washed with water, then with brine, dried over magnesium sulfate and evaporated to give 2-cyclohexylmethyl-N-phenyl-malonic acid semiamide (1.12 g, 18% yield).

REFERENCA 3 REFERENCE 3

poluamid 2- Cikloheksilmetil- N- fenetil- malonske kiseline semiamide of 2-Cyclohexylmethyl-N-phenethyl-malonic acid

Dodaje se natrijum (6.9 g, 0.3 mol) rastvoren u etanolu (300 ml_) i nakon toga dietilmalonat (50.3 ml, 0.3 mol). Dodaje se bromometilcikloheksan (46 mL, 0.33 Sodium (6.9 g, 0.3 mol) dissolved in ethanol (300 mL) was added followed by diethylmalonate (50.3 mL, 0.3 mol). Add bromomethylcyclohexane (46 mL, 0.33

mol) i reakciona smeša se zagreva na 70°C, 14 h. REakciona smeša se hladi i etanol se uklanja isparavanjem. Rezultujući ostatak se rastvara u ledenoj vodi i nakon toga se ekstrahuje sa etil acetatom. Organski slojevi se ispiraju sa vodom, nakon toga se koncentrovanim rastvorom soli i suše na magenzijum sulfatu. Rastvaraći se uklanjaju pod sniženim pritiskom da bi se dobio dietilcikloheksil malonat. mol) and the reaction mixture is heated to 70°C for 14 h. The reaction mixture is cooled and the ethanol is removed by evaporation. The resulting residue was dissolved in ice water and then extracted with ethyl acetate. The organic layers are washed with water, then with a concentrated salt solution and dried over magnesium sulfate. The solvents are removed under reduced pressure to give diethylcyclohexyl malonate.

Rastvor dietilcikoheksilmalonata (12.8 g, 0.05 mol) u etanolu (100 mL) se obradjuje sa rastvorom litijum hidroksida (1.2 g, 0.05 mola) u vodi (50 mL) i nakon toga se meša na okolnoj temperaturi 15 sati. Etanol se uklanja na sniženom pritisku i dodaje se voda (50 mL) u ostatak. REakciona smeša se ekstrahuje sa etrom, hladi na ledu i zakišeljava do pH 1.5 sa HCI. Vodeni sloj se zasićuje sa NaCI i ekstrahuje sa etilacetatom (dva puta, svaka sa po 150 ml). Sušenjem na magenzijum sulfatu i isparavanjem rastvarača dobija se 2-cikloheksilmalonat (8.52 g, 37 mmol), prinos 74%). A solution of diethylcyclohexylmalonate (12.8 g, 0.05 mol) in ethanol (100 mL) was treated with a solution of lithium hydroxide (1.2 g, 0.05 mol) in water (50 mL) and then stirred at ambient temperature for 15 h. The ethanol is removed under reduced pressure and water (50 mL) is added to the residue. The reaction mixture is extracted with ether, cooled on ice and acidified to pH 1.5 with HCl. The aqueous layer is saturated with NaCl and extracted with ethyl acetate (twice, each with 150 ml). Drying over magnesium sulfate and evaporation of the solvent gives 2-cyclohexylmalonate (8.52 g, 37 mmol), yield 74%).

Etil 2-cikloheksilmalonat (8.52 g, 37 mmol) u etilacetatu (80 ml) se hladi do 0°C i obradjuje sa dimetilformamidom (50 j.iL) i nakon toga sa oksalilhloridom (3.93 ml, 45 mmol). REakciona temepratura se podiže do sobne temeprature i posle 2 sata rastvarači se uklanjaju na sniženom pritisku da bi se dobio 2-cikloheksilmalonil hlorid. Ethyl 2-cyclohexylmalonate (8.52 g, 37 mmol) in ethyl acetate (80 mL) was cooled to 0°C and treated with dimethylformamide (50 µL) followed by oxalyl chloride (3.93 mL, 45 mmol). The reaction temperature is raised to room temperature and after 2 hours the solvents are removed under reduced pressure to give 2-cyclohexylmalonyl chloride.

Gorepomenuti Malonilhlorid rastvara se do zapremine od 28 ml sa etilacetatom i 2 ml tog rastvora dodajese u rastvor feniletilamina (0.376 ml, 3 mmol) i Nmetilmorfolina (0.40 g, 4 mmol) u etilacetatu (4 ml) na -20°C. Posle 15 minuta reakciona smeša se ostavlja da se zagreje do okolne temperature. Reakciona smeša se rastvara sa etil acetatom (5 ml) i ledenom ovodom (5 ml). Organski sloj se odvaja i ispire sa hladnom 0.05 N HCI, nakon tgoa sa vodenim rastvorom naHC03, nakon toga sa koncentrovanim rastvorom soli, suši na magnezijum su Ifatu i isparava na sniženom pritisku. Ostatak se prečišćava radijalnom hromatografijom da bi se dobio etil-2-cikloheksilmetil-N-fenetil malonamat (0.366 g, 1.10 mmol, prinos 42%). The aforementioned Malonyl chloride is dissolved to a volume of 28 ml with ethyl acetate and 2 ml of this solution is added to a solution of phenylethylamine (0.376 ml, 3 mmol) and Nmethylmorpholine (0.40 g, 4 mmol) in ethyl acetate (4 ml) at -20°C. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was dissolved in ethyl acetate (5 ml) and ice water (5 ml). The organic layer is separated and washed with cold 0.05 N HCl, then with aqueous NaHCO 3 , then with concentrated brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by radial chromatography to give ethyl-2-cyclohexylmethyl-N-phenethyl malonate (0.366 g, 1.10 mmol, 42% yield).

Pomenuti estar (0.366 g, 1.10 mmol) u etanolu (10 ml) obradjuje se na okolnoj temepraturi sa vodenim rastvorom natrijum hidroksida (1.3 ml IN) u vremenu od 2.5 h. REakciona smeša se rastvara u vodi (30 ml) i ispire sa etrom (3 puta, 30 ml svakaO. Vodeni sloj se hladi , zakišeljava sa 1N HCI (2 ml) i ekstrahuje sa etilacetatom (3 puta, 30 ml svaka). Ekstrakti etilacetata se ispiraju sa koncentrovanim rastvorom soli, suše na magenzijum sulfatu i ispravaju da bi se dobio poluamid 2-Cikloheksilmetil-N-fenetil- malonske kiseline (0.138 g, 0.46 mmol, prinos 42%). The mentioned ester (0.366 g, 1.10 mmol) in ethanol (10 ml) was treated at ambient temperature with an aqueous solution of sodium hydroxide (1.3 ml IN) for 2.5 h. The reaction mixture was dissolved in water (30 mL) and washed with ether (3 times, 30 mL each). The aqueous layer was cooled, acidified with 1N HCl (2 mL) and extracted with ethyl acetate (3 times, 30 mL each). malonic acid (0.138 g, 0.46 mmol, yield 42%).

REFERENCA 4 REFERENCE 4

poluamid 2- Cikloheksilmetil- N- piridin- 4- ilmetil- malonske kiseline 2-Cyclohexylmethyl-N-pyridin-4-ylmethyl-malonic acid semiamide

Etil 2-cikloheksilmetilmalonil hlorid, dobijen kao u referenci 3 (0.307 g, 1.25 mmol) kondezuje se sa 4-aminometil piridinom korišćenjem postupka iz reference 3 da bi se dobio poluamid 2-Cikloheksilmetil-N-piridin-4-ilmetil- malonske kiseline (0.237 g, 0.74 mmol, prinos 58%). Ethyl 2-cyclohexylmethylmalonyl chloride, obtained as in reference 3 (0.307 g, 1.25 mmol) was condensed with 4-aminomethyl pyridine using the procedure of reference 3 to give 2-Cyclohexylmethyl-N-pyridin-4-ylmethyl-malonic acid semiamide (0.237 g, 0.74 mmol, 58% yield).

Ovaj estar se hidrolizuje sa natrijum hidroksidom korišćenjem postupka iz reference 3 da bi se dobio poluamid 2-cikloheksilmetil-N-piridin-4-ilmetil-malonske kiseline (0.041 g, 0.14 mml, prinos 19%). This ester is hydrolyzed with sodium hydroxide using the procedure of reference 3 to give 2-cyclohexylmethyl-N-pyridin-4-ylmethyl-malonic acid semiamide (0.041 g, 0.14 mmol, 19% yield).

Postupukom koji je naveden u gore pomenutim primerima dobijaju se sledeća jedinjenja: poluamid N-Benzil-2-cikloheksilmetil-malonske kiseline; The following compounds are obtained by the procedure mentioned in the above-mentioned examples: N-Benzyl-2-cyclohexylmethyl-malonic acid half-amide;

poluamid 2-Cikloheksilmetil-N-(4-fenoksi-fenil)-malonske kiseline; 2-Cyclohexylmethyl-N-(4-phenoxy-phenyl)-malonic acid semiamide;

poluamid 2-Cikloheksilmetil-N-(3-fenil-propil)-malonske kiseline; 2-Cyclohexylmethyl-N-(3-phenyl-propyl)-malonic acid semiamide;

poluamid 2-Cikloheksilmetil-3-morfolin-4-il-3-okso-propionske kiseline; poluamid N-Cikloheksil-2-cikloheksilmetil-malonske kiseline; 2-Cyclohexylmethyl-3-morpholin-4-yl-3-oxo-propionic acid semiamide; N-Cyclohexyl-2-cyclohexylmethyl-malonic acid semiamide;

poluamid 2-Cikloheksilmetil-N-naftalen-1 -ilmetil-malonske kiseline; poluamid-N-piridin-3-il-malonske kiseline; 2-Cyclohexylmethyl-N-naphthalen-1-ylmethyl-malonic acid semiamide; N-pyridin-3-yl-malonic acid semiamide;

poluamid N,N-diizobutil-malonske kiseline; N,N-diisobutylmalonic acid semiamide;

poluamid N-(6-metoksi-piridin-3-il)-malonske kiseline; N-(6-methoxy-pyridin-3-yl)-malonic acid semiamide;

poluamid N-(3-fenoksi-fenil)-malonske kiseline; N-(3-phenoxy-phenyl)-malonic acid semiamide;

poluamid N-(4-nitro-benzil)-malonske kiseline; N-(4-nitro-benzyl)-malonic acid semiamide;

poluamid N-Cijanometil-2-cikloheksilmetil-malonske kiseline; N-Cyanomethyl-2-cyclohexylmethyl-malonic acid semiamide;

poluamid 2-Cikloheksilmetil-N-(5,6,7,8-tetrahidro-naftalen-1 -il)-malonske kiseline; poluamid 2-Cikloheksilmetil-N-(2-piridin-2-il-etil)-malonske kiseline; 2-Cikloheksilmetil-3-(2,3-dihidro-indol-1-il)-3-okso-propionske kiseline; 2,N-Bis-cikloheksilmetil-3-okso-butiramid; 2-Cyclohexylmethyl-N-(5,6,7,8-tetrahydro-naphthalen-1-yl)-malonic acid semiamide; 2-Cyclohexylmethyl-N-(2-pyridin-2-yl-ethyl)-malonic acid semiamide; 2-Cyclohexylmethyl-3-(2,3-dihydro-indol-1-yl)-3-oxo-propionic acid; 2,N-Bis-cyclohexylmethyl-3-oxo-butyramide;

2-Cikloheksilmetil-N-(2-metoksi-benzil)-3-okso-butiramid; 2-Cyclohexylmethyl-N-(2-methoxy-benzyl)-3-oxo-butyramide;

poluamid 2-Cikloheksilmetil-N-(1-fenil-etil)-malonske kiseline; 2-Cyclohexylmethyl-N-(1-phenyl-ethyl)-malonic acid semiamide;

poluamid N-Benzil-2-cikloheksilmetil-N-metil-malonske kiseline; 2- Cikloheksilmetil-N-(3-nitro-benzil)-3-okso-butiramid; N-Benzyl-2-cyclohexylmethyl-N-methyl-malonic acid semiamide; 2- Cyclohexylmethyl-N-(3-nitro-benzyl)-3-oxo-butyramide;

poluamid 2-Cikloheksilmetil-N-(4-metoksi-benzil)-malonske kiseline; poluamid N-(3-Karbamoil-fenil)-2-cikloheksilmetil-maIonske kiseline; poluamid 2-Cikloheksilmetil-N-piridin-3-ilmetil-malonske kiseline; 2-Cyclohexylmethyl-N-(4-methoxy-benzyl)-malonic acid semiamide; N-(3-Carbamoyl-phenyl)-2-cyclohexylmethyl-maionic acid semiamide; 2-Cyclohexylmethyl-N-pyridin-3-ylmethyl-malonic acid semiamide;

poluamid N-(4-Karbamoil-fenil)-2-cikloheksilmetil-malonske kiseline; poluamid 2-Cikloheksilmetil-N-(tetrahidro-furan-2-il-metil)-malonske kiseline; 3- (3,4-dihidro-2H-hinolin-1 -il)-3-okso-propionska kiselina; N-(4-Carbamoyl-phenyl)-2-cyclohexylmethyl-malonic acid semiamide; 2-Cyclohexylmethyl-N-(tetrahydro-furan-2-yl-methyl)-malonic acid semiamide; 3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propionic acid;

poluamid N-terc-Butil-2-cikloheksilmetil-N-metil-malonske kiseline; N-tert-Butyl-2-cyclohexylmethyl-N-methyl-malonic acid semiamide;

poluamid 2-cikloheksilmetil-N-metil-N-propil-malonske kiseline; 2-cyclohexylmethyl-N-methyl-N-propyl-malonic acid semiamide;

poluamid 2-cikloheksilmetil-N-metil-malonske kiseline; 2-cyclohexylmethyl-N-methyl-malonic acid semiamide;

poluamid N,N-Cikloheksilmetil-N,N-dimetil-malonske kiseline; (R)-2-Benzilkarbamoil-4-fenilsulfanil- buterna kiselina; i N,N-Cyclohexylmethyl-N,N-dimethylmalonic acid semiamide; (R)-2-Benzylcarbamoyl-4-phenylsulfanyl-butyric acid; and

4-Benzensulfonil-2-benzilkarbamoil- buterna kiselina. 4-Benzenesulfonyl-2-benzylcarbamoyl-butyric acid.

PRIMER 1 EXAMPLE 1

2-butil-N-cijanometil-N'-fenilmalonamid 2-butyl-N-cyanomethyl-N'-phenylmalonamide

(Jedinjenje 1) (Compound 1)

Rastvor koji čine 2-Fenilkarbamoil-heksanska kiselina (188 g, 0.8 mmol), dobijen u referenci 1, u DMF (5.0 mL) obradjuje se sa PyBOP (reg. žig) (425 0.8 mmol). aminoacetonitril bisulfatom (140 mg, 0.9 mmol) i trietilaminom (600 mL, 4.3 mmol). Smeša se meša 3 sata i nakon toga razdvaja izmedju vode ( (20 ml) i etil acetata (50 mL). Organski sloj se razdvaja i ispire sa 1M zasićenim vodenim rastvorom natrijum bikarbonata, 1M rastvorom hlorovodonične kiseline i vode, zatim se suši (MgS04) i koncentruje. Proizvod se prečišćava od ostataka fleš hromatografijom na silika gelu (60°A) sa 50%-tnim etil acetatom u heksanu da bi se dobio 2-butil-N-cijanometil-N'-fenilmalonami (125 mg, prinos 57%).<1>H NMR (DMSO) 10.01 (s, 1H), 7.59 (d, J=8Hz, 2H), 7.31 (t, J= 7Hz, 2H), 7.06 (t, J= 7Hz, 1H),4.13(d, J= 6Hz, 2H), 3.32 (t, J= 8Hz, 1H), 1.80 (m, 2H), 1.25 (m, 4H), 0.86 (t, J= 7Hz, 3H). MS: m/e 273.9. A solution of 2-Phenylcarbamoyl-hexanoic acid (188 g, 0.8 mmol), obtained in reference 1, in DMF (5.0 mL) was treated with PyBOP (reg. trademark) (425 0.8 mmol). aminoacetonitrile bisulfate (140 mg, 0.9 mmol) and triethylamine (600 mL, 4.3 mmol). The mixture is stirred for 3 hours and then partitioned between water ((20 mL) and ethyl acetate (50 mL). The organic layer is separated and washed with 1M saturated aqueous sodium bicarbonate solution, 1M hydrochloric acid and water, then dried (MgSO4) and concentrated. The product is purified from residues by flash chromatography on silica gel (60°A) with 50% ethyl acetate in hexane. to give 2-butyl-N-cyanomethyl-N'-phenylmalonami (125 mg, 57% yield).<1>H NMR (DMSO) 10.01 (s, 1H), 7.59 (d, J=8Hz, 2H), 7.31 (t, J= 7Hz, 2H), 7.06 (t, J= 7Hz, 1H), 4.13 (d, J= 6Hz, 2H), 3.32 (t, J= 8Hz, 1H), 1.80 (m, 2H), 1.25 (m, 4H), 0.86 (t, J= 7Hz, 3H). MS: m/e 273.9.

PRIMER 2 EXAMPLE 2

N-Cijanometil-2-cikloheksilmetil-N'-fenil-N'-fenilmalonamid N-Cyanomethyl-2-cyclohexylmethyl-N'-phenyl-N'-phenylmalonamide

(Jedinjenje 2); (Compound 2);

Rastvor koji čine poluamid 2-Cikloheksilmetil-N-metil-malonske kiseline (350 mg, 1.2 mmol) dobijen kao u referenci 2, EDCI (250 mg, 1.3 mmol), HOBt hidrat (199 mg, 1.3 mmol), amino acetonitril bisulfat (200 mg, 1.3 mmol) i N-metilmorfolin (0.30 ml, 2.7 mmol) u N,N-dimetilpirolidonu (5 ml) meša se na okolnoj temepraturi 15 sati. REakciona smeša se sipa u hladni 1N HCI i ekstrahuje sa etilacetatom, Organska faza se ispire sa vodenim zasićenim rastvorom natrijum bikarbonata i nakon toga sa koncentrovanim rastvorom soli (50 ml svaki) suši na magnezijum sulfatu i isparava. Ostatak se prečišćava radijalnom hromatografijom korišćenjem 50% etil acetat/heksan kao eluenta da bi se dobio N-Cijanometil-2-cikloheksilmetil-N'-fenil-N'-fenilmalonamid (179 mg, prinos 48%).<1>H NMR (DMSO) 10.01 (s, 1H), 8.47 (t, J= 5Hz, 1H), 7.59 (t, J= 7Hz, 2H), 7.31 (t, J= 8Hz, 2H), 7.07 (d, J= 1 Hz, 1H), 4.13 (d, J=5Hz, 2H), 3.47 (t, J= 7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H). MS: m/e 313.2. A solution of 2-Cyclohexylmethyl-N-methyl-malonic acid semiamide (350 mg, 1.2 mmol) obtained as in reference 2, EDCI (250 mg, 1.3 mmol), HOBt hydrate (199 mg, 1.3 mmol), amino acetonitrile bisulfate (200 mg, 1.3 mmol) and N-methylmorpholine (0.30 ml, 2.7 mmol) in N,N-dimethylpyrrolidone (5 ml) was stirred at ambient temperature for 15 hours. The reaction mixture is poured into cold 1N HCl and extracted with ethyl acetate. The organic phase is washed with aqueous saturated sodium bicarbonate solution and then with concentrated salt solution (50 ml each), dried over magnesium sulfate and evaporated. The residue was purified by radial chromatography using 50% ethyl acetate/hexane as eluent to give N-Cyanomethyl-2-cyclohexylmethyl-N'-phenyl-N'-phenylmalonamide (179 mg, 48% yield). <1>H NMR (DMSO) 10.01 (s, 1H), 8.47 (t, J= 5Hz, 1H), 7.59 (t, J= 7Hz, 2H), 7.31 (t, J= 8Hz, 2H), 7.07 (d, J= 1 Hz, 1H), 4.13 (d, J=5Hz, 2H), 3.47 (t, J= 7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H). MS: m/e 313.2.

PRIMER 3 EXAMPLE 3

N-Cijanometil-2-cikloheksilmetil-N'-feniletilmalonamid N-Cyanomethyl-2-cyclohexylmethyl-N'-phenylethylmalonamide

(Jedinjenje 3) (Compound 3)

Rastvor koji čine poluamid 2-Cikloheksilmetil-N-fenetil-malonske kiseline (138 mg, 0.46 mmol) dobijen kao u referenci 3, EDCI (115 mg, 0.60 mmol), HOBt hidrat (92 mg, 0.60 mmol), N-metilmorfolin (0.115 ml, 1.38 mmol) u N,N-dimetilpirolidonu (4 ml) meša se na okolnoj temepraturi 10 min. Dodaje se aminoacetonitril bisulfat (106 mg, 0.69 mmol). Reakciona smeša se meša na okolnoj temperaturi 2 sata, zatim se sipa u hladni 1N HCI i ekstrahuje dva puta sa etilacetatom (50 ml svaki). Organska faza se ispire sa vodenim rastvorom natrijum bikarbonata (50 ml svaka) i nakon toga sa koncentrovanim rastvorom soli (50 ml svaki) suši na magnezijum sulfatu i isparava. A solution of 2-Cyclohexylmethyl-N-phenethylmalonic acid semiamide (138 mg, 0.46 mmol) obtained as in reference 3, EDCI (115 mg, 0.60 mmol), HOBt hydrate (92 mg, 0.60 mmol), N-methylmorpholine (0.115 ml, 1.38 mmol) in N,N-dimethylpyrrolidone (4 ml) was stirred at ambient temperature. 10 min. Add aminoacetonitrile bisulfate (106 mg, 0.69 mmol). The reaction mixture was stirred at ambient temperature for 2 h, then poured into cold 1N HCl and extracted twice with ethyl acetate (50 mL each). The organic phase is washed with aqueous sodium bicarbonate (50 ml each) and then with brine (50 ml each), dried over magnesium sulfate and evaporated.

Ostatak se prečišćava radijalnom hromatografijom korišćenjem 50% etil acetat/heksan kao eluenta da bi se dobio N-Cijanometil-2-cikloheksilmetil-N'-fenilmalonamid (56 mg, prinos 36%).<1>H NMR (DMSO) 8.38 (t, J= 5Hz, 1H), 7.98 (t, J= 6Hz, 1H), 7.25 (m, 5H), 4.10 (d, J= 6Hz, 2H), 2.71 (t, J= 7Hz, 2H), 1.6 (m, 4H), 0.85 (m, 2H). MS: m/e 342.10. The residue was purified by radial chromatography using 50% ethyl acetate/hexane as eluent to give N-Cyanomethyl-2-cyclohexylmethyl-N'-phenylmalonamide (56 mg, 36% yield).<1>H NMR (DMSO) 8.38 (t, J= 5Hz, 1H), 7.98 (t, J= 6Hz, 1H), 7.25 (m, 5H), 4.10 (d, J= 6Hz, 2H), 2.71 (t, J= 7Hz, 2H), 1.6 (m, 4H), 0.85 (m, 2H). MS: m/e 342.10.

PRIMER 4 EXAMPLE 4

N-Cijanometil-2-cikloheksilmetil-N'-pirid-4-ilmetilmalonamid N-Cyanomethyl-2-cyclohexylmethyl-N'-pyrid-4-ylmethylmalonamide

(Jedinjenje 4) (Compound 4)

Rastvor koju čine 2-Cikloheksilmetil-N-piridin-4-ilmetil-malonske kiseline (41 mg, 0.14 mmol), dobijen kao u referenci 4, spaja se sa acetonitrilom kako što je opisano u primeru 3 da bi se dobio N-cijanometil-2-cikloheksilmetil-N'-pirid-4-ilmetilmalonamid (13 mg, prinos 28%).<1>H NMR (DMSO) 8.5 (m, 4H), 7.20 (d, J= 6Hz, 2H), 4.3 (m, 2H), 4.13 (d, J= 5Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.83 (m, 2H). MS: m/e 329.08. A solution of 2-Cyclohexylmethyl-N-pyridin-4-ylmethyl-malonic acid (41 mg, 0.14 mmol) obtained as in reference 4 was combined with acetonitrile as described in example 3 to give N-cyanomethyl-2-cyclohexylmethyl-N'-pyrid-4-ylmethylmalonamide (13 mg, 28% yield).<1>H NMR (DMSO) 8.5 (m, 4H), 7.20 (d, J= 6Hz, 2H), 4.3 (m, 2H), 4.13 (d, J= 5Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.83 (m, 2H). MS: m/e 329.08.

PRIMER 5 EXAMPLE 5

N-[1-(1-Benzooksazol-2-il-metanoil)-3-fenil-propil)-N'-benzil-2-cikloheksilmetil malonamid N-[1-(1-Benzoxazol-2-yl-methanoyl)-3-phenyl-propyl)-N'-benzyl-2-cyclohexylmethyl malonamide

(Jedinjenje 5) (Compound 5)

Smeša poluamida N-benzil-2-cikloheksilmetil-malonske kiseline (200 mg, 0.69 mmol), HOBt (159 mg, 1.04 mmol), EDC (146 mg, 0.76 mmol), 2-amino-1-benzooksazol-2-il4-fenil-butan-1-on (195 mg, 0.69 mg), dihlormatana (3 mL) i trietilamina (106 uL, 0.76 mmol) meša se 2 sata. Proizvod se ekstrahuje u etil acetatu (60 mL) i ispire sa dve porcije od 15 mL 1N HCI, i dve porcije od 15 mL zasićenog NaHS03, suši na MgS04i koncentruje. Dodaje se etil acetat (5 mL) i dobijeni beli precipitat se sakuplja da bi se dobio N-[1-(1-benzooksazol-2-il-1-hidroksi-metil)-3-fenil-propil]-N'-benzil-2-cikloheksilmetil malonamid (81 mg, 01.2 mmol, prinos 21%). A mixture of N-benzyl-2-cyclohexylmethyl-malonic acid semiamide (200 mg, 0.69 mmol), HOBt (159 mg, 1.04 mmol), EDC (146 mg, 0.76 mmol), 2-amino-1-benzooxazol-2-yl4-phenyl-butan-1-one (195 mg, 0.69 mg), dichloromethane (3 mL) and triethylamine (106 uL, 0.76 mmol) was stirred for 2 hours. The product was extracted into ethyl acetate (60 mL) and washed with two 15 mL portions of 1N HCl, and two 15 mL portions of saturated NaHSO 3 , dried over MgSO 4 , and concentrated. Ethyl acetate (5 mL) was added and the resulting white precipitate was collected to give N-[1-(1-benzooxazol-2-yl-1-hydroxy-methyl)-3-phenyl-propyl]-N'-benzyl-2-cyclohexylmethyl malonamide (81 mg, 01.2 mmol, 21% yield).

N-[1 - (1 -benzooksazol-2 -il-1 -hidroksi -me ti I)-3-fen i l-propil]-N'-b enzil-2-cikloheksilmetil malonamid (70 mg, 0.126 mmol) i rastvara u 0.6 mL dihlormetana i obradjuje sa Des Martinovim perjodinanom (107 mg, 0.253 mmol). Smeša se meša 2 sata, nakon toga se dodaje 8 mL 0.26 M Na2S203u zasićenom NaHS03i smeša se ekstrahuje sa dva porcije od 15 mL etil acetata i sipire sa dva pouta po 4 mL zasićenog NaHS03. Organski sloj se suši na MgS04i koncentruje. Proizvod se rekristalizuje iz etil acetata i heksana da bi se dobio N-[ 1 -( 1- Benzooksazol- 2- il-metanoil)- 3- fenil- propil)- N'- benzil- 2- cikloheksilmetil malonamid (40 mg, 0.072 mmol, prinos 57%);<1>H NMR (DMSO) 7.88 (m, 1H), 7.68-7.40 (m, 3H), 7.35-7.10 (m, 10H), 6.90 (m, 1H), 5.65 (m, 1H), 4.43 (d, J= 5.7Hz, 2H), 3.25 (m, 1H), 2.74 (t, J= 8.0Hz, 1H), 2.46 (m, 1H),2.17(m, 1H), 1.77 (t, J= 7.4 Hz, 1H), 1.64 (m, 7H), 1.22 (m, N-[1-(1-benzooxazol-2-yl-1-hydroxy-methyl)-3-phen and l-propyl]-N'-benzyl-2-cyclohexylmethyl malonamide (70 mg, 0.126 mmol) and dissolved in 0.6 mL of dichloromethane and treated with Des Martin's periodinan (107 mg, 0.253 mmol). The mixture was stirred for 2 hours, after which 8 mL of 0.26 M Na2S203 in saturated NaHSO3 was added and the mixture was extracted with two portions of 15 mL of ethyl acetate and filtered with two portions of 4 mL of saturated NaHSO3. The organic layer is dried over MgSO4 and concentrated. The product is recrystallized from ethyl acetate and hexane to give N-[ 1 -( 1- Benzoxazol-2-yl-methanoyl)- 3- phenyl- propyl)- N'- benzyl- 2- cyclohexylmethyl malonamide (40 mg, 0.072 mmol, yield 57%); <1>H NMR (DMSO) 7.88 (m, 1H), 7.68-7.40 (m, 3H), 7.35-7.10 (m, 10H), 6.90 (m, 1H), 5.65 (m, 1H), 4.43 (d, J= 5.7Hz, 2H), 3.25 (m, 1H), 2.74 (t, J= 8.0Hz, 1H), 2.46 (m, 1H), 2.17(m, 1H), 1.77 (t, J= 7.4 Hz, 1H), 1.64 (m, 7H), 1.22 (m,

4H), 0.87 (m, 2H). MS: (M<+>+1) 552.8; 551.68. 4H), 0.87 (m, 2H). MS: (M<+>+1) 552.8; 551.68.

Sledeća jedinjenja formule I dobijaju se prema gorenavedenim postupcima: The following compounds of formula I are obtained according to the above procedures:

N- Cijanometil- 2- cikloheksil- 2- cikloheksilmetilmalonarnid (Jedinjenje 6);<1>H NMR (DMSO) 8.31 (t, J= 6Hz, 1H), 7.82 (d, J= 8Hz, 1H), 4.10 (d, J= 8Hz, 2H), 3.52 (m, 1H), 3.20 (t, J= 7Hz, 1H), 1.6 (m, 12H), 1.1 (m, 9H), 0.83 (m, 2H). MS (m/e) 320.11; N- benzil- N'- cijanometil- 2- cikloheksilmetilmalonamid (Jedinjenje 7);<1>H NMR (DMSO) 8.45 (m, 2H), 7.3 (m, 5H), 4.33 (dd, J= 6.15Hz, 1H), 4.23 (dd, J= 6,15Hz, 1H), 4.12 (d, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS ( m/e) 328.15, M. Wt. = 327.43; N- cijanometil- 2- cikloheksilmetil- N'-( 4- fenoksimetil) malonamid (Jedinjenje 8);<1>H NMR (DMSO) 10.1 (s, 1H), 8.50 (t, J= 5Hz, 1H), 7.61 (d, J= 7Hz, 2H), 7.37 (t, J= 7Hz, 2H), 7.11 (t, J= 7Hz, 1H), 7.0 (m, 4H), 4.14 (d, J= 5 Hz, 2H), 3.47 (t, J= 7Hz, 1H), 1.7(m,7H), 1.1 (m,4H), 0.92 (m, 2H). MS (m/e) 406.10, M. Wt. = 405.49. N- cijanometil- 2- cikloheksilmetil- N'-( 3- fenilpropil) malonamid (Jedinjenje 9);<1>H NMR (DMSO) 8.38 (t, J= 6Hz,1 H), 8.00 (t, J= 6Hz, 1H), 7.2 (m, 5H), 4.10 (t, J= 5Hz, 2H), 3.23 (t, J= 7Hz, 1H), 3.1 (m, 2H), 2.5 (m, 2H), 1.6 9m, 9H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) 356.02. N- cijanometil- 2- cikloheksilmetil- 3- morfolin- 4- il- 3- oksopropionamid (Jedinjenje 10);<1>H NMR (DMSO) 8.54 (t, J= 4Hz, 1H), 4.12 (d, J= 5 Hz, 2H), 3.5 (m, 8H), 1.65 (m, 8H), 1.15 (m, 4H) 0.85 (m, 2H). MS (m/e) = 308.05; N- cijanometil- 2- cikloheksilmetil- N'- naft- 1 - ilmetilmalonamid (Jedinjenjel 1);<1>H NMR (DMSO) 8.53 (t, J= 5Hz, 1H), 8.43 (d, J= 6Hz, 1H), 8.04 (m, 1H), 7.94 (m, 1H), 7.86 (d, J= 8Hz, 1H), 7.5 (m, 4H), 4.85 (dd, J= 6,15Hz, 1H), 4.65 (dd, J= 5,15Hz, 1H), 4.12 (d, J- 3Hz, 2H), 3.3 (m, 1H), 1.6 (m, 8H), 1.0 (m, 5H); MS (m/e) 378.18, M. Wt. = 377.18; N- cijanometil- 2- cikloheksilmetil- N'- piridin- 3- ilmalonamid (Jedinjenje 12);<1>H NMR (DMSO) 10.24 (s, 1H), 8.75 (s, 1H), 8.54 (t, J= 5Hz, 1H), 8.29(d, J= 5Hz, 1H), 8.04 (d, J= 7Hz, 2H), 7.36 (m, 1H), 4.13 (d, J= 5 Hz, 2H), 3.49 (t, J= 7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H). MS (m/e) = 314.91; N- cijanometil- 2- cikloheksilmetil- N', N'- diizobutilmalonamid (Jedinjenje 13);<1>H NMR (DMSO) 8.50 (t, J= 4Hz, 1H), 4.09 (m, 2H), 3.63 (t, J= 7 Hz, 1H), 3.2 (m, 2H), 3.05 (m, 2H), 1.9 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 14H). MS (m/e) 350.08, M. Wt. = 349.51; N- cijanometil- 2- cikloheksilmetil- N', N'- diizopropilmalonamid (Jedinjenje 14);<1>H NMR (DMSO) 8.45 (t, J= 5Hz, 1H), 4.1 (m, 3H), 3.55 (t, J= 7 Hz, 1H), 3.46 (m, 1H), 1.6 (m, 7H), 1.27 (d, J= 7H, 6H), 1.1 (m, 10H), 0.85 (m, 2H). MS (m/e) = 321.99, M. Wt. = 321.24; N- cijanometil- 2- cikloheksilmetil- N'-( 6- metoksipirid- 3- il) malonamid (Jedinjenje 15);<1>H NMR (DMSO) 10.04 (s, 1H), 8.50 (t, J= 5 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J= 9 Hz, 1H), 6.80 (d, J= 9Hz, 1H), 4.13 (m, 2H), 3.81 (s, 3H), 3.44 (t, J= 8Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H). MS (m/e) = 345.01, M. Wt. = 344.18; N- cijanometil- 2- cikloheksilmetil- N'-( 2- tien- 2- iletil) malonamid (Jedinjenje 16);<1>H NMR (DMSO) 8.40 (t, J= 5 Hz, 1H), 8.07 (t, J= 5Hz, 12H), 7.33 (d, J= 5Hz, 1H), 6.91 (m, 1H),6.87 (m, 1H), 4.10 (d, J= 5 Hz, 2H), 3.3 (m, 3H), 3.21 (t, J= 7Hz, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) = 348.09, M. Wt. = 347.48; N- cijanometil- 2- cikloheksilmetil- N'-( 3- fenoksifenil) malonamid (Jedinjenje 17);<1>H NMR (DMSO) 10.1 (s, 1H), 8.45 (t, J= 5 Hz, 1H), 7.41 (t, J= 8Hz, 2H), 7.33 (m, 3H), 7.16 (t, J= 7 Hz, 1H), 7.03 (d, J= 8Hz, 2H), 6.73 (m, 1H), 4.1 (m, 2H), 3.42 (t, J= 7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) - 406.04, M. Wt. = 405.49; N- cijanometil- 2- cikloheksilmetil- N'-( 4- nitrobenzil) malonamid (Jedinjenje 18);<1>H NMR (DMSO) 8.61 (t, J= 6 Hz, 1H), 8.53 (t, J= 6Hz, 1H), 8.17 (d, J= 9 Hz, 2H), 7.47 (d, J=9Hz, 2H), 4.41 (d, J= 6Hz, 2H), 4.14 (d, J= 6Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.87 (m, 2H). MS (m/e) = 373.02, M. Wt. = 372.42. N, N'- biscijanometil- 2- cikloheksilmetilmalonamid (Jedinjenje 19);<1>H NMR (DMSO) 8.59 (t, J= 5 Hz, 2H), 4.14 (d, J= 6Hz, 4H), 3.28 (t, J= 8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.86 (m, 2H). MS (m/e) = 276.99, M. Wt. = 276.34; N-cijanometil-2-cikloheksilmetil-N'-(5,6.7,8-tetrahidronaft-1 - i I) malonamid (Jedinjenje 20);<1>H NMR (DMSO) 9.28 (s, 1H), 8.57 (t, J= 6 Hz, 1H), 7.21 (t, J= 8Hz, 1H), 7.05 (t, J= 8 Hz, 1H), 6.90 (d, J= 7Hz, 1H), 4.16 (d, J= 6Hz, 2H), 3.49 (t, J= 7Hz, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 1.7 (m, 11H), 1.1 (m, 4H), 0.91 (m, 2H). MS (m/e) = 368.04, M. Wt. = 367.48. N- cijanometil- 2- cikloheksilmetil- N'-( 2- pirid- 2- ilmetil) malonamid (Jedinjenje 21);<1>H NMR (DMSO) 8.49 (m, 1H), 8.40 (t, J= 6 Hz, 1H), 8.00 (t, J= 5Hz, 1H), 7.68 (dt, J=2.8 Hz, 1H), 7.2 (m, 2H), 4.09 (d, J= 6Hz, 2H), 3.42 (m, 2H), 3.17 (t, J= 8Hz, 1H), 2.85 (t, J= 7Hz, 2H), 1.6 (m, 7H), 1.07 (m, 4H), 0.83 (m, 2H). MS (m/e) = 343.04, M. Wt. = 342.44; N-cijanometil-2-cikloheksilmetJi-3-(2,3-dihi.droindo (Jedinjenje 22);<1>H NMR (DMSO) 8.73 (t, J= 5 Hz, 1H), 8.06 (t, J= 8Hz, 1H), 7.24 (d, J=7Hz, 1H), 7.15 (t, J= 7Hz, 1H), 7.00 (t, J= 7Hz, 1H), 4.15 (d, J= 5Hz, 2H), 4.1 (m, 2H), 3.66 (t, J= 7Hz, 1H), 3.14 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H). MS (m/e) = 340.02, M. Wt. = 339.19; N;Cijan 001611122icjkioheksi]metili(3^4^dihidro^lH^izohinoMfvEHl)^- oksopropionamid (Jedinjenje 23);<1>H NMR (DMSO) 8.64 (t, J= 5 Hz, 1H), 7.15 (s, 4H), 4.65 (m, 2H), 4.11 (t, J= 6Hz, 2H), 3.77 (m, 2H), 2.8 (m, 2H), 1.7 (m, 7H), 1.1 (m, 4H), 0.89 (m, 2H), 3.54 (m, 1H); MS (m/e) = 354.02, M. Wt. = 353.46; N- Cyanomethyl- 2- cyclohexyl- 2- cyclohexylmethylmalonamide (Compound 6); <1>H NMR (DMSO) 8.31 (t, J= 6Hz, 1H), 7.82 (d, J= 8Hz, 1H), 4.10 (d, J= 8Hz, 2H), 3.52 (m, 1H), 3.20 (t, J= 7Hz, 1H), 1.6 (m, 12H), 1.1 (m, 9H), 0.83 (m, 2H). MS (m/e) 320.11; N- benzyl- N'- cyanomethyl- 2- cyclohexylmethylmalonamide (Compound 7);<1>H NMR (DMSO) 8.45 (m, 2H), 7.3 (m, 5H), 4.33 (dd, J= 6.15Hz, 1H), 4.23 (dd, J= 6.15Hz, 1H), 4.12 (d, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) 328.15, M. Wt. = 327.43; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 4- phenoxymethyl) malonamide (Compound 8); <1>H NMR (DMSO) 10.1 (s, 1H), 8.50 (t, J= 5Hz, 1H), 7.61 (d, J= 7Hz, 2H), 7.37 (t, J= 7Hz, 2H), 7.11 (t, J= 7Hz, 1H), 7.0 (m, 4H), 4.14 (d, J= 5 Hz, 2H), 3.47 (t, J= 7Hz, 1H), 1.7(m, 7H), 1.1 (m, 4H), 0.92 (m, 2H). MS (m/e) 406.10, M. Wt. = 405.49. N- cyanomethyl- 2- cyclohexylmethyl- N'-( 3- phenylpropyl) malonamide (Compound 9); <1>H NMR (DMSO) 8.38 (t, J= 6Hz, 1H), 8.00 (t, J= 6Hz, 1H), 7.2 (m, 5H), 4.10 (t, J= 5Hz, 2H), 3.23 (t, J= 7Hz, 1H), 3.1 (m, 2H), 2.5 (m, 2H), 1.6 9m, 9H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) 356.02. N- cyanomethyl- 2- cyclohexylmethyl- 3- morpholin- 4- yl- 3- oxopropionamide (Compound 10); <1>H NMR (DMSO) 8.54 (t, J= 4Hz, 1H), 4.12 (d, J= 5 Hz, 2H), 3.5 (m, 8H), 1.65 (m, 8H), 1.15 (m, 4H) 0.85 (m, 2H). MS (m/e) = 308.05; N-cyanomethyl-2-cyclohexylmethyl-N'-naphth-1-ylmethylmalonamide (Compound 1); <1>H NMR (DMSO) 8.53 (t, J= 5Hz, 1H), 8.43 (d, J= 6Hz, 1H), 8.04 (m, 1H), 7.94 (m, 1H), 7.86 (d, J= 8Hz, 1H), 7.5 (m, 4H), 4.85 (dd, J= 6.15Hz, 1H), 4.65 (dd, J= 5.15Hz, 1H), 4.12 (d, J- 3Hz, 2H), 3.3 (m, 1H), 1.6 (m, 8H), 1.0 (m, 5H); MS (m/e) 378.18, M. Wt. = 377.18; N- cyanomethyl- 2- cyclohexylmethyl- N'- pyridin- 3- ylmalonamide (Compound 12);<1>H NMR (DMSO) 10.24 (s, 1H), 8.75 (s, 1H), 8.54 (t, J= 5Hz, 1H), 8.29(d, J= 5Hz, 1H), 8.04 (d, J= 7Hz, 2H), 7.36 (m, 1H), 4.13 (d, J= 5 Hz, 2H), 3.49 (t, J= 7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H). MS (m/e) = 314.91; N- cyanomethyl- 2- cyclohexylmethyl- N', N'- diisobutylmalonamide (Compound 13); <1>H NMR (DMSO) 8.50 (t, J= 4Hz, 1H), 4.09 (m, 2H), 3.63 (t, J= 7 Hz, 1H), 3.2 (m, 2H), 3.05 (m, 2H), 1.9 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 14H). MS (m/e) 350.08, M. Wt. = 349.51; N- cyanomethyl- 2- cyclohexylmethyl- N', N'- diisopropylmalonamide (Compound 14); <1>H NMR (DMSO) 8.45 (t, J= 5Hz, 1H), 4.1 (m, 3H), 3.55 (t, J= 7 Hz, 1H), 3.46 (m, 1H), 1.6 (m, 7H), 1.27 (d, J = 7H, 6H), 1.1 (m, 10H), 0.85 (m, 2H). MS (m/e) = 321.99, M. Wt. = 321.24; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 6- methoxypyrid-3- yl) malonamide (Compound 15);<1>H NMR (DMSO) 10.04 (s, 1H), 8.50 (t, J= 5 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J= 9 Hz, 1H), 6.80 (d, J= 9Hz, 1H), 4.13 (m, 2H), 3.81 (s, 3H), 3.44 (t, J= 8Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H). MS (m/e) = 345.01, M. Wt. = 344.18; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 2- thien- 2- ylethyl) malonamide (Compound 16);<1>H NMR (DMSO) 8.40 (t, J= 5 Hz, 1H), 8.07 (t, J= 5Hz, 12H), 7.33 (d, J= 5Hz, 1H), 6.91 (m, 1H), 6.87 (m, 1H), 4.10 (d, J= 5 Hz, 2H), 3.3 (m, 3H), 3.21 (t, J= 7Hz, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) = 348.09, M. Wt. = 347.48; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 3- phenoxyphenyl) malonamide (Compound 17); <1>H NMR (DMSO) 10.1 (s, 1H), 8.45 (t, J= 5 Hz, 1H), 7.41 (t, J= 8Hz, 2H), 7.33 (m, 3H), 7.16 (t, J= 7 Hz, 1H), 7.03 (d, J= 8Hz, 2H), 6.73 (m, 1H), 4.1 (m, 2H), 3.42 (t, J= 7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H). MS (m/e) - 406.04, M. Wt. = 405.49; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 4- nitrobenzyl) malonamide (Compound 18); <1>H NMR (DMSO) 8.61 (t, J= 6 Hz, 1H), 8.53 (t, J= 6Hz, 1H), 8.17 (d, J= 9 Hz, 2H), 7.47 (d, J= 9Hz, 2H). 4.41 (d, J= 6Hz, 2H), 4.14 (d, J= 6Hz, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.87 (m, 2H). MS (m/e) = 373.02, M. Wt. = 372.42. N,N'-biscyanomethyl-2-cyclohexylmethylmalonamide (Compound 19);<1>H NMR (DMSO) 8.59 (t, J= 5 Hz, 2H), 4.14 (d, J= 6Hz, 4H), 3.28 (t, J= 8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H). 0.86 (m, 2H). MS (m/e) = 276.99, M. Wt. = 276.34; N-cyanomethyl-2-cyclohexylmethyl-N'-(5,6.7,8-tetrahydronaphth-1 - i I)malonamide (Compound 20);<1>H NMR (DMSO) 9.28 (s, 1H), 8.57 (t, J= 6 Hz, 1H), 7.21 (t, J= 8Hz, 1H), 7.05 (t, J= 8 Hz, 1H), 6.90 (d, J= 7Hz, 1H), 4.16 (d, J= 6Hz, 2H), 3.49 (t, J= 7Hz, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 1.7 (m, 11H), 1.1 (m, 4H), 0.91 (m, 2H). MS (m/e) = 368.04, M. Wt. = 367.48. N- cyanomethyl- 2- cyclohexylmethyl- N'-( 2- pyrid- 2- ylmethyl) malonamide (Compound 21);<1>H NMR (DMSO) 8.49 (m, 1H), 8.40 (t, J= 6 Hz, 1H), 8.00 (t, J= 5Hz, 1H), 7.68 (dt, J=2.8 Hz, 1H), 7.2 (m, 2H), 4.09 (d, J= 6Hz, 2H), 3.42 (m, 2H), 3.17 (t, J= 8Hz, 1H), 2.85 (t, J= 7Hz, 2H), 1.6 (m, 7H), 1.07 (m, 4H), 0.83 (m, 2H). MS (m/e) = 343.04, M. Wt. = 342.44; N-cyanomethyl-2-cyclohexylmethyl-3-(2,3-dihydroindo (Compound 22);<1>H NMR (DMSO) 8.73 (t, J= 5 Hz, 1H), 8.06 (t, J= 8Hz, 1H), 7.24 (d, J= 7Hz, 1H), 7.15 (t, J= 7Hz, 1H). 7.00 (t, J= 7Hz, 1H), 4.15 (d, J= 5Hz, 2H), 4.1 (m, 2H), 3.66 (t, J= 7Hz, 1H), 3.14 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H). 340.02, M. Wt. = 339.19; N;Cyan 001611122icjkyohexy]methyl(3^4^dihydro^1H^isoquinoMfvEHl)^- oxopropionamide (Compound 23); <1>H NMR (DMSO) 8.64 (t, J= 5 Hz, 1H), 7.15 (s, 4H), 4.65 (m, 2H), 4.11 (t, J= 6Hz, 2H), 3.77 (m, 2H), 2.8 (m, 2H), 1.7 (m, 7H), 1.1 (m, 4H), 0.89 (m, 2H), 3.54 (m, 1H); MS (m/e) = 354.02, M. Wt. = 353.46;

N- cijanometil- 2- N'- biscikloheksilmetilmalonamid (Jedinjenje 24);<1>H NMR (DMSO) 8.34 (t, J= 5 Hz, 1H), 7.93 (t, J= 5Hz, 1H), 4.09 (d, J= 6Hz, 2H), 3.23 (dd, J= 7.9 Hz, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 1.6 (m, 12H), 1.4 (m, 1H), 1.1 (m, 7H), 0.86 (m, 4H); MS (m/e) = 334.00, M. Wt. = 333.47. N- cyanomethyl- 2- N'- biscyclohexylmethylmalonamide (Compound 24);<1>H NMR (DMSO) 8.34 (t, J= 5 Hz, 1H), 7.93 (t, J= 5Hz, 1H), 4.09 (d, J= 6Hz, 2H), 3.23 (dd, J= 7.9 Hz, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 1.6 (m, 12H), 1.4 (m, 1H), 1.1 (m, 7H), 0.86 (m, 4H); MS (m/e) = 334.00, M. Wt. = 333.47.

N- cijanometil- 2- cikloheksilmetil- N-) 2- metoksibenzil) malonamid (Jedinjenje 25);<1>H NMR (DMSO) 8.44 (t, J= 5 Hz, 1H), 8.27 (t, J= 6Hz, 1H), 7.24 (dt, J=2,7Hz,1H), 7.10 (dd, J=2,7Hz,1H), 6.96 (d, J= 7Hz, 1HH), 6.88 (dt, J= 7,1Hz, 1H), 4.30 (dd, J=6.16Hz, 1H), 4.20 (dd, J= 5.16Hz, 1H), 4.12 (d, J= 6Hz, 2H), 3.79 (s, 3H), 3.3 (m, 1H) , 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 358.03, M. Wt. = 357.45. N- cyanomethyl- 2- cyclohexylmethyl- N-) 2- methoxybenzyl) malonamide (Compound 25); <1>H NMR (DMSO) 8.44 (t, J= 5 Hz, 1H), 8.27 (t, J= 6Hz, 1H), 7.24 (dt, J=2,7Hz, 1H), 7.10 (dd, J=2.7Hz,1H), 6.96 (d, J= 7Hz, 1HH), 6.88 (dt, J= 7.1Hz, 1H), 4.30 (dd, J=6.16Hz, 1H), 4.20 (dd, J= 5.16Hz, 1H), 4.12 (d, J= 6Hz, 2H), 3.79 (s, 3H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 358.03, M. Wt. = 357.45.

N- cijanometil- 2- cikloheksilmetil- N'-( 1- feniietil) malonamid (Jedinjenje 26);<1>H NMR (DMSO) 8.25 (m, 1H), 7.4 (m, 5H), 4.02 (m, 2H), 3.18 (s, 3H), 3.25 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.7 (m, 2H); MS (m/e) = 328.08, M. Wt. = 327.42; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 1- phenylethyl) malonamide (Compound 26);<1>H NMR (DMSO) 8.25 (m, 1H), 7.4 (m, 5H), 4.02 (m, 2H), 3.18 (s, 3H), 3.25 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.7 (m, 2H); MS (m/e) = 328.08, M. Wt. = 327.42;

N- benzil- N'- cijanometil- 2- cikloheksilmetil- N- metilmalonamid (Jedinjenje 27);<1>H NMR (DMSO) 8.62 (m, 1H), 7.3 (m, 5H), 4.5 (m, 2H), 4.13 (d, J= 6Hz, 2H), 3.7 (m, 1H), 2.93 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.88 (m, 2H); MS (m/e) = 342.09, M. Wt. = 341.45; N- benzyl- N'- cyanomethyl- 2- cyclohexylmethyl- N- methylmalonamide (Compound 27); <1>H NMR (DMSO) 8.62 (m, 1H), 7.3 (m, 5H), 4.5 (m, 2H), 4.13 (d, J= 6Hz, 2H), 3.7 (m, 1H), 2.93 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.88 (m, 2H); MS (m/e) = 342.09, M. Wt. = 341.45;

N- cijanometil- 2- cikloheksilmetil- N'-( 3- nitrobenzil)- malonamid (Jedinjenje 28);<1>H NMR (DMSO) 8.6 (t, 1H), 8.5 (t, 1H), 8.1 (m, 2H), 7.6 (m, 2H), 4.1 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 373.07, M. Wt. = 372.42; N- cyanomethyl- 2- cyclohexylmethyl- N'-( 3- nitrobenzyl)- malonamide (Compound 28); <1>H NMR (DMSO) 8.6 (t, 1H), 8.5 (t, 1H), 8.1 (m, 2H), 7.6 (m, 2H), 4.1 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 373.07, M. Wt. = 372.42;

N- cijanometil- 2- cikloheksilmetil- N'-( 4- metoksibenzil)- malonamid N- cyanomethyl- 2- cyclohexylmethyl- N'-( 4- methoxybenzyl)- malonamide

(Jedinjenje 29);<1>H NMR (DMSO) 8.42 (t, J= 5Hz, 1H), 8.38 (t, J= 6Hz, 1H), 7.14 (d, J= 9Hz, 2H), 6.86 (d, J= 9Hz, 2H), 4.25 (dd, J= 6.15Hz, 1H), 4.15 (dd, J= 7,16Hz, 1H), 3.71 (s, 3H), 3.27 (t, J= 8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.84 (m, 2H), 4.11 (d, J= 6Hz, 2H); MS (m/e) = 356.97, M. Wt. = 357.45; (Compound 29);<1>H NMR (DMSO) 8.42 (t, J= 5Hz, 1H), 8.38 (t, J= 6Hz, 1H), 7.14 (d, J= 9Hz, 2H), 6.86 (d, J= 9Hz, 2H), 4.25 (dd, J= 6.15Hz, 1H), 4.15 (dd, J= 7.16Hz, 1H), 3.71 (s, 3H), 3.27 (t, J= 8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.84 (m, 2H), 4.11 (d, J= 6Hz, 2H); MS (m/e) = 356.97, M. Wt. = 357.45;

N-( 3- karbamoilfenil)- N'- cijanometil- 2- cikloheksilmetilmalonamid (Jedinjenje 30);<1>H NMR (DMSO) 10.14 (s, 1H), 8.48 (t, 1H), 8.03 (s, 1H), 7.75 (d, 1H), 7.54 (d,1H), 7.35 (m, 2H), 4.12 (d, 2H), 3.4 (t, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H), 3.29 (s, 3H); MS (m/e) = 357.11, M. Wt. = 356.42; N-(3-carbamoylphenyl)-N'-cyanomethyl-2-cyclohexylmethylmalonamide (Compound 30); 2H), 4.12 (d, 2H), 3.4 (t, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H), 3.29 (s, 3H); MS (m/e) = 357.11, M. Wt. = 356.42;

N- cijanometil- 2- cikioheksilmetil- N'- pirid- 3- ilmetilmalonamid (Jedinjenje 31);<1>H NMR (DMSO) 8.4 (m, 4H), 7.55 (d, 1H), 7.25 (dd, 1H), 4.28 (dd, 1H), 4.18 (dd,1H), 4.05 (d, 2H), 3.2 (m, 1H), 1.6 (m, 7H), 1.01 (m, 4H), 0.78 (m, 2H); MS (m/e) = 329.03, M. Wt. = 328.41; N-( 4- karbamoilfenil)- N'- cijanometil- 2- cikloheksilmetilmalonamid (Jedinjenje 32);<1>H NMR (DMSO) 10.22 (s, 2H), 8.50 (t, J= 6Hz, 1 H), 7.83 (d, J= 9Hz, 2H), 7.64 (d, J= 9Hz, 2H), 7.52 (s, 1H), 4.13 (d, J= 6Hz, 2H), 3.48 (t, J= 7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H); MS (m/e) = 357.04, M. Wt. = 356.42; N- cijanometil- 2- cikloheksilmetil- N'- tetrahidrofur- 2- ilmetilmalonamid (Jedinjenje 33);<1>H NMR (DMSO) 8.38 (t, J= 5Hz, 1H), 7.98 (t, J= 4Hz, 1H), 4.10 (d, J= 6Hz, 2H), 3.8 (m, 2H), 3.6 (m, 1H), 3.2 (m, 4H), 1.8 (m, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 322.02, M. Wt. = 321.41; N- cyanomethyl- 2- cyclohexylmethyl- N'- pyrid- 3- ylmethylmalonamide (Compound 31); <1>H NMR (DMSO) 8.4 (m, 4H), 7.55 (d, 1H), 7.25 (dd, 1H), 4.28 (dd, 1H), 4.18 (dd, 1H), 4.05 (d, 2H), 3.2 (m, 1H), 1.6 (m, 7H), 1.01 (m, 4H), 0.78 (m, 2H); MS (m/e) = 329.03, M. Wt. = 328.41; N-(4-carbamoylphenyl)-N'-cyanomethyl-2-cyclohexylmethylmalonamide (Compound 32);<1>H NMR (DMSO) 10.22 (s, 2H), 8.50 (t, J= 6Hz, 1H), 7.83 (d, J= 9Hz, 2H), 7.64 (d, J= 9Hz, 2H), 7.52 (s, 1H), 4.13 (d, J= 6Hz, 2H), 3.48 (t, J= 7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H); MS (m/e) = 357.04, M. Wt. = 356.42; N- cyanomethyl- 2- cyclohexylmethyl- N'- tetrahydrofur- 2- ylmethylmalonamide (Compound 33);<1>H NMR (DMSO) 8.38 (t, J= 5Hz, 1H), 7.98 (t, J= 4Hz, 1H), 4.10 (d, J= 6Hz, 2H), 3.8 (m, 2H), 3.6 (m, 1H), 3.2 (m, 4H), 1.8 (m, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 322.02, M. Wt. = 321.41;

N- cijanometil- 2- cikloheksilmetil- 3-( 3. 4- dihidro- 2H- hinolin- 1- il)- 3- oksopropionamid N- cyanomethyl- 2- cyclohexylmethyl- 3-( 3. 4- dihydro- 2H- quinolin- 1- yl)- 3- oxopropionamide

(Jedinjenje 34);<1>H NMR (DMSO) 8.5 (m, 1H), 7.35 (m, 1H), 7.2 (m, 4H), 4.1 (m,2H), 3.82 (dd, 1H), 2.78 (t, 1H), 2.72 (t, 1H), 2.72 (t, 1H), 2.59 (m, 1H), 1.8 (m, 2H), 1.5 (m, 7H), 1.0 (m, 4H), 0.7 (m, 2H); MS (m/e) = 354.02, M. Wt. = 353.46; (Compound 34);<1>H NMR (DMSO) 8.5 (m, 1H), 7.35 (m, 1H), 7.2 (m, 4H), 4.1 (m, 2H), 3.82 (dd, 1H), 2.78 (t, 1H), 2.72 (t, 1H), 2.72 (t, 1H), 2.59 (m, 1H), 1.8 (m, 2H), 1.5 (m, 7H), 1.0 (m, 4H), 0.7 (m, 2H); MS (m/e) = 354.02, M. Wt. = 353.46;

N- terc- butil- N'- cijanometil- 2- cikloheksilmetil- N- metilmalonamid (Jedinjenje 35);<1>H NMR (DMSO) 8.41 (t, J= 5Hz, 1H), 4.09 (d, J= 5Hz, 1H), 3.56 (t, J= 7Hz, 1H), 2.86 (s, 3H), 1.6 (m, 7H), 1.31 (s, 9H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 308.04, M. Wt. = 307.43; N- tert-butyl- N'- cyanomethyl- 2- cyclohexylmethyl- N- methylmalonamide (Compound 35);<1>H NMR (DMSO) 8.41 (t, J= 5Hz, 1H), 4.09 (d, J= 5Hz, 1H), 3.56 (t, J= 7Hz, 1H), 2.86 (s, 3H), 1.6 (m, 7H), 1.31 (s, 9H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e) = 308.04, M. Wt. = 307.43;

N- cijanometil- 2- cikloheksilmetil- N'- metil- N- propilmalonamid (Jedinjenje 36);<1>H NMR (DMSO) 8.5 (m, 1H), 4.10 (m, 2H), 3.60 (d, J= 7Hz, 1H), 3.2 (m, 2H), 2.96 (s, 3H), 1.65 (m, 7H), 1.45 (m, 2H), 1.1 (m, 4H), 0.8 (m, 5H); MS (m/e) = 294.02, M. Wt. = 293.40; N- cyanomethyl- 2- cyclohexylmethyl- N'- methyl- N- propylmalonamide (Compound 36); <1>H NMR (DMSO) 8.5 (m, 1H), 4.10 (m, 2H), 3.60 (d, J= 7Hz, 1H), 3.2 (m, 2H), 2.96 (s, 3H), 1.65 (m, 7H), 1.45 (m, 2H), 1.1 (m, 4H), 0.8 (m, 5H); MS (m/e) = 294.02, M. Wt. = 293.40;

N- butil- N'- cijanometil- 2- cikloheksilmetil- N'- metilmalonamid (Jedinjenje 37);<1>H NMR (DMSO) 8.5 (m, 1H), 4.10 (m, J = 5Hz, 2H), 3.60 (t, 1H), 3.3 (m, 2H), 2.95 (s, 3H), 1.6 (m, 7H), 1.4 (m, 2H), 1.1 (m, 6H), 0.8 (m, 5H); MS (m/e) = 308.01, M. Wt. = 307.43; N- butyl- N'- cyanomethyl- 2- cyclohexylmethyl- N'- methylmalonamide (Compound 37); <1>H NMR (DMSO) 8.5 (m, 1H), 4.10 (m, J = 5Hz, 2H), 3.60 (t, 1H), 3.3 (m, 2H), 2.95 (s, 3H), 1.6 (m, 7H), 1.4 (m, 2H), 1.1 (m, 6H), 0.8 (m, 5H); MS (m/e) = 308.01, M. Wt. = 307.43;

N- cijanometil- 2- cikloheksilmetil- N', N'- dimetilmalonamid (Jedinjenje 38);<1>H NMR (DMSO) 8.55 (t, J=5Hz, 1H), 4.10 (m, J = 7Hz, 2H), 3.62 (t, J= 8Hz, 1H), 2.99 (s, 3H), 2.81 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 266.01, M. Wt. = 265.18; N- cyanomethyl- 2- cyclohexylmethyl- N', N'- dimethylmalonamide (Compound 38); <1>H NMR (DMSO) 8.55 (t, J=5Hz, 1H), 4.10 (m, J = 7Hz, 2H), 3.62 (t, J= 8Hz, 1H), 2.99 (s, 3H), 2.81 (s, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e) = 266.01, M. Wt. = 265.18;

N- benzil- N'- cijanometil- 2-( 2- fenilsulfaniletil)- malonamid (Jedinjenje 39);<1>H NMR (DMSO) 8.56 (t, J= 6Hz, 1H), 8.49 (t, J = 6Hz, 1H), 7.2 (m, 10H), 4.29 (d, J= 6Hz, 2H), 4.14 (d, J= 6Hz, 2H), 3.40 (t, J= 7Hz, 1H), 2.86 (t, J = 8Hz, 2H), 2.05 (m, 2H); MS (m/e) = 368.02, M. Wt. = 367.14; i N- benzyl- N'- cyanomethyl- 2-( 2- phenylsulfanylethyl)- malonamide (Compound 39); <1>H NMR (DMSO) 8.56 (t, J= 6Hz, 1H), 8.49 (t, J = 6Hz, 1H), 7.2 (m, 10H), 4.29 (d, J= 6Hz, 2H), 4.14 (d, J = 6Hz, 2H), 3.40 (t, J = 7Hz, 1H), 2.86 (t, J = 8Hz, 2H), 2.05 (m, 2H); MS (m/e) = 368.02, M. Wt. = 367.14; and

2-( 2- fenilsulfoniletil)- N- benzil- N'- cijanometilmalonamid (Jedinjenje 40);<1>H NMR (DMSO) 8.56 (t, J= 6Hz, 1H), 8.43 (t, J = 6Hz, 1H), 7.86 (d, J - 7Hz, 2H), 7.79 (t, J= 5Hz, 1H), 7.68 (t, J= 8Hz, 2H), 7.25 (m, 5H), 4.26 (d, J= 6Hz, 2H), 4.13 (d, J = 6Hz, 2H), 3.36 (m, 1H), 3.19 (m, 2H), 2.00 (m, 2H); MS (m/e) = 400.04, M. Wt. = 399.47; 2-( 2- Phenylsulfonylethyl)- N- benzyl- N'- cyanomethylmalonamide (Compound 40); <1>H NMR (DMSO) 8.56 (t, J= 6Hz, 1H), 8.43 (t, J = 6Hz, 1H), 7.86 (d, J - 7Hz, 2H), 7.79 (t, J= 5Hz, 1H), 7.68 (t, J= 8Hz, 2H), 7.25 (m, 5H), 4.26 (d, J= 6Hz, 2H), 4.13 (d, J = 6Hz, 2H), 3.36 (m, 1H), 3.19 (m, 2H), 2.00 (m, 2H); MS (m/e) = 400.04, M. Wt. = 399.47;

SiiE-BenzjlsuJfonihetiU-N^US^ SiiE-BenzjlsuJfonihetiU-N^US^

benzilmalonamid (Jedinjenje 41);<1>H NMR (DMSO) 8.56 (t, J= 6Hz, 1H), 8.2(m, 1H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J= 6Hz, 2H), 3.41 (t, J = 7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H), 0.82 (m, 3H); MS (m/e) = 576.27, M. Wt. = 575.21; i benzylmalonamide (Compound 41);<1>H NMR (DMSO) 8.56 (t, J= 6Hz, 1H), 8.2(m, 1H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J= 6Hz, 2H), 3.41 (t, J = 7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H), 0.82 (m, 3H); MS (m/e) = 576.27, M. Wt. = 575.21; and

N. N'- Bis-[( S)- 1-( benzooksazol- 2- ilmetanoil)- propil1- 2- cikloheksilmetil- malonamid N. N'- Bis-[( S)- 1-( Benzoxazol-2- ylmethanoyl)- propyl1- 2- cyclohexylmethyl- malonamide

(Jedinjenje 42);<1>H NMR (DMSO) 8.41 (td J= 6Hz, 2H), 8.00 (d, J= 8Hz, 2H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J= 6Hz, 2H), 3.41 (t, J = 7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H), 0.82 (m, 3H); MS (m/e) = 576.27, M. Wt. = 573.21. (Compound 42);<1>H NMR (DMSO) 8.41 (td J= 6Hz, 2H), 8.00 (d, J= 8Hz, 2H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J= 6Hz, 2H), 3.41 (t, J = 7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H), 0.82 (m, 3H); MS (m/e) = 576.27, M. Wt. = 573.21.

PRIMER 6 EXAMPLE 6

Ogled sa katepsinom S Cathepsin S assay

Rastvori probnih jedinjenja u različitim koncentracijama napravljeni su u 10 uA. dimetil sulfoksida (DMSO) i nakon toga se rastvaraju u oglednom puferu (40 ul, koji obuhvata: MES, 50 mM (pH 6.5); EDTA, 2.5 mL i NaCI, 100 mM). Humani katepsin S (0.158 pMola u 25 ul oglednog pufera) se dodaje u razblažene rastvore. Ogledni rastvori semešaju 5-10 sekundi na posudi za mešanje, prekrivaju se i inkubiraju 30 minuta na sobnoj temperaturi. Z-Val-Val-Arg-AMC (9 nMmola u 25 u.L oglednog pufera) dodaje se u ogledni rastvor i hidroliza je praćena spektrofotometrijski na( k460 nm) 5 minuta. Prividne konstante inhibicije (Ki) izračunate su iz krive enzima korišćenjem standadnih matematičkih modela. Solutions of test compounds at various concentrations were made in 10 µA. dimethyl sulfoxide (DMSO) and then dissolved in sample buffer (40 µl, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mL and NaCl, 100 mM). Human cathepsin S (0.158 pMole in 25 µl assay buffer) was added to the diluted solutions. Sample solutions are mixed for 5-10 seconds on a mixing bowl, covered and incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC (9 nMmol in 25 µL assay buffer) was added to the assay solution and hydrolysis was monitored spectrophotometrically at (x460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the enzyme curve using standard mathematical models.

PRIMER 7 EXAMPLE 7

Ogled sa katepsinom B Cathepsin B assay

Rastvori probnih jedinjenja u različitim koncentracijama napravljeni su u 10 nL dimetil sulfoksida (DMSO) i onda se rastvaraju u oglednom puferu (40 uL, koji obuhvata: N,N-bis-(2-hidroksietil)-2-aminoetansulfonsku kiselinu (BES), 50 mM (pH 6); polioksietilensorbitan monolaurat, 0.05%; i ditiotreitol (DTT), 2.5mM). Humani katepsin B (0.025 pMola u 25 u.L oglednog pufera) se dodaje u razblažene rastvore. Ogledni rastvori mešaju se 5-10 sekundi na posudi za mešanje, prekrivaju se i inkubiraju 30 minuta na sobnoj temperaturi. Z-FR-AMC (20 nMmola u 25 ul oglednog pufera) dodaje se u ogledni rastvor i hidroliza je praćena spektrofotometrijski na( X460 nm) 5 minuta. Prividne konstante inhibicije (Ki) izračunate su iz krive enzima korišćenjem standardnih matematičkih modela. Solutions of test compounds at various concentrations were made in 10 nL of dimethyl sulfoxide (DMSO) and then dissolved in assay buffer (40 uL, comprising: N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMole in 25 µL assay buffer) was added to the diluted solutions. Sample solutions are mixed for 5-10 seconds on a mixing bowl, covered and incubated for 30 minutes at room temperature. Z-FR-AMC (20 nMmol in 25 µl assay buffer) was added to the assay solution and hydrolysis was monitored spectrophotometrically at (X460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from enzyme curves using standard mathematical models.

PRIMER 8 EXAMPLE 8

Ogled sa katepsinom K Cathepsin K assay

Rastvori probnih jedinjenja u različitim koncentracijama napravljeni su u 10 |iL dimetil sulfoksida (DMSO) i onda se rastvaraju u oglednom puferu (40 u.L, koji obuhvata: MES, 50 mM (pH 5.5); EDTA, 2.5 mL; i DTT, 2.5 mM). Humani katepsin K (0.0906 pMola u 25 u.L oglednog pufera) se dodaje u razblažene rastvore. Ogledni rastvori mešaju se 5-10 sekundi na posudi za mešanje, prekrivaju se i inkubiraju 30 minuta na sobnoj temperaturi. Z-Phe-Arg-AMC (4 nMmola u 25 u.L oglednog pufera) se dodaje u ogledni rastvor i hidroliza se prati spektrofotometrijski na( X460 nm) 5 minuta. Prividne konstante inhibicije (Ki) izračunate su iz krive enzima korišćenjem standadnih matematičkih modela. Solutions of test compounds at various concentrations were made in 10 µL dimethyl sulfoxide (DMSO) and then dissolved in assay buffer (40 µL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mL; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMole in 25 µL assay buffer) was added to the diluted solutions. Sample solutions are mixed for 5-10 seconds on a mixing bowl, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (4 nMmol in 25 µL assay buffer) is added to the assay solution and hydrolysis is monitored spectrophotometrically at (X460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the enzyme curve using standard mathematical models.

PRIMER 9 EXAMPLE 9

Ogled sa katepsinom L Cathepsin L assay

Rastvori probnih jedinjenja u različitim koncentracijama napravljeni su u 10 nL dimetil sulfoksida (DMSO) i onda se rastvaraju u oglednom puferu (40 [ iL, koji obuhvata: MES, 50 mM (pH 5.5); EDTA, 2.5 mL i DDT, 2.5 mM). Humani katepsin L (0.158 pMola u 25 [ iL oglednog pufera) se dodaje u razblažene rastvore. Ogledni rastvori mešaju se 5-10 sekundi na posudi za mešanje, prekrivaju se i inkubiraju 30 minuta na sobnoj temperaturi. Z-Phe-Arg-AMC (9 nMmola u 25 ul oglednog pufera) dodaje se u ogledni rastvor i hidroliza je praćena spektrofotometrijski na( k460 nm) 5 minuta. Prividne konstante inhibicije (Ki) izračunate su iz krive enzima korišćenjem standadnih matematičkih modela. Solutions of test compounds at various concentrations were made in 10 nL of dimethyl sulfoxide (DMSO) and then dissolved in assay buffer (40 µL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mL and DDT, 2.5 mM). Human cathepsin L (0.158 pMole in 25 µL assay buffer) was added to the diluted solutions. Sample solutions are mixed for 5-10 seconds on a mixing bowl, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (9 nMmol in 25 µl assay buffer) was added to the assay solution and hydrolysis was monitored spectrophotometrically at (x460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the enzyme curve using standard mathematical models.

Jedinjenja iz pronalaska testirana su pomoću gore opisanog ogleda i primećeno je da pokazuju inhibitorsku aktivnost za katepsin S. Na primer, pronadjeno je da jedinjenja iz datog pronalaska pokazuju inhibitorsku aktivnost za katepsin S proteazu u koncentracijama koje su najmanje 50 puta manje od onih koncentracija koje su potrebne da bi se proizvela ekviaktivna inhibicija aktivnosti proteaze katepsina K. Prividne konstante inhibicije (Ki) za jedinjenja iz datog pronalaska za katepsin S u opsegu su od oko 10"<10>M do oko 10"<7>M. Compounds of the invention were tested using the assay described above and were found to exhibit inhibitory activity for cathepsin S. For example, compounds of the invention were found to exhibit inhibitory activity for cathepsin S protease at concentrations at least 50 times less than those concentrations required to produce equiactive inhibition of cathepsin K protease activity. Apparent inhibition constants (Ki) for compounds of the invention for cathepsin S ranged from about 10"<10>M to about 10"<7>M.

PRIMER 10 EXAMPLE 10

Farmaceutske formulacije koje sadrže jedinjenje sa formulom I Pharmaceutical formulations containing a compound of formula I

INTRAVENOZNA FORMULACIJA INTRAVENOUS FORMULATION

Claims (1)

1. Jedinjenja formule I: u kojoj X"! predstavlja -NHC(R1)(R2)X2 ili -NHX3,X2 je cijano, -C(R7)(R8)X<3>, - C(R<7>)(R<8>)CF3, -C(R7)(R<8>)CF2CF2R9 -CH=CHS(0)2R<5>, -C(0)CF2C(0)NR5r<5>i. C(0)C(0)NR<5>r6, -C(0)C(0)OR5, -C(0)CH20R<5>, -C(0)CH2N(R6)SC>2R5 ili - C(0)C(0)R<5>; gde je R<5>(Ci-4)alkil, (C5-1 o)ari!(Co-6)alkil ili (C5-1 o)heteroaril(Cn-6)alkil; gde je R<6>vodonik ili (C-|-6)alkil; r<7>je vodonik ili (C-|-4)alkil i R<8>je hidroksi ili R<7>i R<8>zajedno grade okso; R<9>je vodonik, halo, (Ci-4)alkil, (C5-10)an'l(Co-6)alkil ili (C5-1 o)heteroaril(Co-6)alkil; X<3>obuhvata heteromonociklični prsten sa 4 do 6 atoma u prstenu ili spojeni heterociklični prstenasti sistem sa 8 do 14 atoma u prstenu i bilo koji derivat karbocikličnog ketona, iminoketona ili tioketona; gde unutar R<5>, X<2>ili X<3>bilo koji aliciklični ili aromatični prstenasti sistem može biti dalje supstituisan sa 1 do 5 radikala koji su nezavisno odabrani od (Ci-6)a Ikil ,(Ci -6)a Ikil iden ,cijano, halo ,hal o-su psti tusani(Ci - 4)a Ikil ,nitro, x4NR12R12iX4NR12C(o)Rl2 .x4NR12C(o)OR12,-X4NR12C(0)NR12R12.X4NR12C(NR12)NR12R12,X4OR12,X4SR12,-X4C(0)OR12,-X4C(0)R12, - X<4>OC(0)R12, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR<12>R<1>2,X<4>NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR<12>,-x4OP(0)(OR12)OR12-x4NR12C(0)R13,-X<4>S(0)R13 i -X<4>S(0)2R<13>i / ili 1 radikal odabran Od -R<1>4, -X<4>OR<14>, -X<4>SR<1>4, -X<4>S(0)R14,-X<4>S(0)2R14,-X<4>C(0)R14,-X<4>C(0)OR<14>, - X4OC(0)R14,-X4NR1 4R1 2,-X4NR1 2C(0)R1 4,-X4NR1 2C(0)OR1 4,-X4C(0)N R1 2R1 2X<4>S(0)2NR14R1<2.->X4NR1<2>S(0)2R14,-X<4>NR<12>C(0)NR14R12i -X4NR12C(NR12)NR14R12, gde je X<4>veza ili (Ci-6)alkil; R^<2>pri svakom pojavljivanju svaki za sebe vodonik, (C-|-6)alkif ili halo-supstituisani (Ci-6)alkil; R13 je (Ci-6)alkil il halo-supstituisani(C-1-6)alkil; i R<14>je (C3-io)cikloakil(Co-6)alkil, hetero(C3-1 o)cikloalkil(Co-6)alkil, (C6-10)aril(Co-6)alkil, hetero(C5-i o)aril(Co-6)alkil, (Cg-io)bicikloaril(Co-6)alkil ili hetero(Cs--|o)bicikloaril(Co-6)aH<'l;R1 Je vodonik, halo ili (Ci-6)alkil i R<2>je odabran iz grupe koju čine vodonik, cijano, halO,-X4NR1 2R1 2,-X4NR1 2C(0)R12,-X4NR1 2C(0)OR1 2,-X4NR1 2C(0)NR1 2R1 2,-X4NR12C(NR1 2)NR12R12,-X4OR12,X4SR12,-X4C(0)OR1 2,-X4C(0)R12,-X4OC(0)R12, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR<1>2R12,X4NR1<2>S(0)2R<12>,-X<4>P(0)(OR<12>)OR<12>, X<4>OP(0)(OR<12>)OR<12>,-X<4>NR<12>C(0)R13, -X4S(0)R<13>i-X4S(0)2R<13>, -R<14>, -X4OR<14>, -X<4>SR<14>, -X<4>S(0)R<14>, -X<4>S(0)2R<14>, -X<4>C(0)R<14>, -X<4>C(0)OR<14>, -X<4>OC(0)R14,-X4NR14R12,-X4NR1<2>C(0)R<1>4,-X4NR<12>C(O)OR<14>,-X<4>C(0)NR<12>R12,-X<4>S(0)2NR<14>R12,-X<4>NR12S(O)2R<14>,-x4nr12C(0)NR14r12 i-X4NR12C(NR12)NR14R12, gde su X<4>,R12,R13 iR14 kao što je ranije definisano; ili R<1>i R<2>zajedno sa atomom ugljenika za koji su vezani i R<1>i R<2>grade (C3-8)cikloalkilen ili (C3-8)heterocikloalkilen; gde je unutar pomenutog R<2>bilo koji heteroaril, aril, cikloalkil, heterocikloalkil, cikloalkilen ili heterocikloalkilen po slobodnom izboru supstituisan sa 1 do 3 radikala koji su nezavisno odabrani od C(-|-6)alkil, (Ci-6)alkiliden, cijano , halo, halo-supstitusani (C-|-4)alkil, nitro, -x4nr12r12,x4nr<12>c(0)r12,-x4nr1<2>c(0)OR12,-x4nr12c(0)NR12r12'-X4NR1<2>C(NR<12>)NR<12>R<12>,-X<4>OR<12>,-X<4>SR<12>,-X<4>C(O)OR12,-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X<4>C(0)NR<1>2R1<2>, -X<4>S(0)2NR<1>2R12,X4NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR<12>,-x<4>o<p>(0)(or12)OR12,-x4nr12c(0)R13, -X4S(0)R13,-x<4>s(0)2R13 i x4C(0)R13 gde su X<4>, r12 i r<1>3 g0re definisani; R<3>je -C(R<6>)(R6)X5, gde je R<6>gore definisan i gde je X<5>odabrana od -x<4>nr12r12,-x4nr12C(0)R12,-x4nr12C(0)OR12,x4nr1<2>C(0)NR12r12,-X<4>NR<12>C(NR<12>)NR12R<12>,-X<4>OR<1>2,-X<4>SR12,-X<4>C(0)OR<12>,-X<4>C(0)R12, -X4OC(0)R<12>,-X<4>R12, X<4>C(0)NR<12>R<12>, -X<4>S(0)2NR12R<1>2,X<4>NR<12>S(0)2R12-X<4>P(0)(OR<12>)OR<12>,-X<4>OP(0)(OR12)OR12,-X<4>C(0)R13,-X4NR<12>C(0)R<13>, -X<4>S(0)R<13>i -X<4>S(0)2R<13>, -R<14>, -X4OR<1>4, -X<4>SR<1>4, -X<4>S(0)R14, -X<4>S(0)2R<14>, -X<4>C(0)R<14>, -X<4>C(O)0R<14>, -X<4>OC(0)R<14>,-X<4>NR<14>R<12>,-X<4>NR1<2>C(0)R<14>,-X4NR<12>C(0)OR<14>,-X<4>C(0)NR14R12,-X<4>S(0)2NR14R12,-X4NR1<2>S(0)2R<14>,-X4NR1<2>C(0)NR14R12i-X4NR12C(NR12)NR14R12, gde SU X4,R12,R13 i R<14>kao što je ranije definisano; X<4>je -nr<6>r6, -nr6R14, -nr6r15\\\-nr6X5C(0)R<14>gde su R6,X5 iR<14>kao što je ranije opisano i R<15>je vodonik, -(C-|-6)alkil ili - X5OR6 gde je X<5>gore opisan; ili R<6>i R"15 zajedno sa atomom azota za koji su vezani i R6 i R<15>grade hetero(C3-io)cikloalkil ili hetero(Cs-io)aril ili hetero(Cs-10)bicikloaril; gde se u okviru R<3>i R<4>bilo koji aliciklični ili aromatični prstenasti sistem može dalje supstituisati sa 1-5 radikala koji su nezavisno odabrani od (C-j.1. Compounds of formula I: in which X"! represents -NHC(R1)(R2)X2 or -NHX3,X2 is cyano, -C(R7)(R8)X<3>, - C(R<7>)(R<8>)CF3, -C(R7)(R<8>)CF2CF2R9 -CH=CHS(0)2R<5>, -C(0)CF2C(0)NR5r<5>i. C(O)C(0)NR<5>r6, -C(0)C(0)OR5, -C(0)CH20R<5>, -C(0)CH2N(R6)SC>2R5 or - C(0)C(0)R<5>; where R<5> is (C 1-4 )alkyl, (C 5-1 o )aryl(C 1-6 )alkyl or (C 5-1 o )heteroaryl(C 1-6 )alkyl; where is it R<6> is hydrogen or (C-1-6)alkyl; r<7> is hydrogen or (C-|-4)alkyl and R<8> is hydroxy or R<7> and R<8> together form oxo; R<9> is hydrogen, halo, (C1-4)alkyl, (C5-10)an'1(C0-6)alkyl or (C5-1o)heteroaryl(C0-6)alkyl; X<3> includes a heteromonocyclic ring with 4 to 6 ring atoms or a fused heterocyclic ring system with 8 to 14 ring atoms and any derivative of a carbocyclic ketone, iminoketone or thioketone; where within R<5>, X<2> or X<3> any alicyclic or aromatic ring system may be further substituted with 1 to 5 radicals independently selected from (Ci-6)a alkyl, (Ci-6)a alkylidene, cyano, halo, halo o-su psti tusani(Ci - 4)a Ikyl,nitro, x4NR12R12iX4NR12C(o)Rl2 .x4NR12C(o)OR12,-X4NR12C(0)NR12R12.X4NR12C(NR12)NR12R12,X4OR12,X4SR12,-X4C(0)OR12,-X4C(0)R12, - X<4>OC(0)R12, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR<12>R<1>2,X<4>NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR<12>,-x4OP(0)(OR12)OR12-x4NR12C(0)R13,-X<4>S(0)R13 and -X<4>S(0)2R<13>and / or 1 radical selected from -R<1>4, -X<4>OR<14>, -X<4>SR<1>4, -X<4>S(0)R14,-X<4>S(0)2R14,-X<4>C(0)R14,-X<4>C(0)OR<14>, - X4OC(0)R14,-X4NR1 4R1 2,-X4NR1 2C(0)R1 4,-X4NR1 2C(0)OR1 4,-X4C(0)N R1 2R1 2X<4>S(0)2NR14R1<2.->X4NR1<2>S(0)2R14,-X<4>NR<12>C(0)NR14R12i -X4NR12C(NR12)NR14R12, where X<4> is a bond or (C1-6)alkyl; R^<2> at each occurrence is each hydrogen, (C-1-6)alkyl or halo-substituted (C1-6)alkyl; R 13 is (C 1-6 )alkyl or halo-substituted (C 1-6 )alkyl; and R<14> is (C3-10)cycloalkyl(C0-6)alkyl, hetero(C3-1 o)cycloalkyl(Co-6)alkyl, (C6-10)aryl(Co-6)alkyl, hetero(C5-i o)aryl(Co-6)alkyl, (C8-io)bicycloaryl(Co-6)alkyl or hetero(Cs--|o)bicycloaryl(Co-6)aH<'l;R1 is hydrogen, halo or (Ci-6)alkyl and R<2> is selected from the group consisting of hydrogen, cyano, halo, -X4NR1 2R1 2,-X4NR1 2C(0)R12,-X4NR1 2C(0)OR1 2,-X4NR1 2C(0)NR1 2R1 2,-X4NR12C(NR1 2)NR12R12,-X4OR12,X4SR12,-X4C(0)OR1 2,-X4C(0)R12,-X4OC(0)R12, X<4>C(0)NR<1>2R12,-X<4>S(0)2NR<1>2R12,X4NR1<2>S(0)2R<12>,-X<4>P(0)(OR<12>)OR<12>, X<4>OP(0)(OR<12>)OR<12>,-X<4>NR<12>C(0)R13, -X4S(0)R<13>and-X4S(0)2R<13>, -R<14>, -X4OR<14>, -X<4>SR<14>, -X<4>S(0)R<14>, -X<4>S(0)2R<14>, -X<4>C(0)R<14>, -X<4>C(0)OR<14>, -X<4>OC(0)R14,-X4NR14R12,-X4NR1<2>C(0)R<1>4,-X4NR<12>C(O)OR<14>,-X<4>C (0)NR<12>R12,-X<4>S(0)2NR<14>R12,-X<4>NR12S(O)2R<14>,-x4nr12C(0)NR14r12 and -X4NR12C(NR12)NR14R12, wherein X<4>, R12, R13 and R14 are as previously defined; or R<1> and R<2> together with the carbon atom to which both R<1> and R<2> are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene; where it is within the mentioned R<2>any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkylene optionally substituted with 1 to 3 radicals independently selected from C(-|-6)alkyl, (Ci-6)alkylidene, cyano, halo, halo-substituted (C-|-4)alkyl, nitro, -x4nr12r12,x4nr<12>c(0)r12,-x4nr1<2>c(0)OR12,-x4nr12c(0)NR12r12'-X4NR1<2> C(NR<12>)NR<12>R<12>,-X<4>OR<12>,-X<4>SR<12>,-X<4>C(O)OR12,-X<4>C(0)R<12>, -X<4>OC(0)R<12>, X<4>C(0)NR<1>2R1<2>, -X<4>S(0)2NR<1>2R12,X4NR<12>S(0)2R12,-X<4>P(0)(OR<12>)OR<12>,-x<4>o<p>(0)(or12)OR12,-x4nr12c(0)R13, -X4S(0)R13,-x<4>s(0)2R13 and x4C(0)R13 where X<4>, r12 and r<1>3 are defined above; R<3>is -C(R<6>)(R6)X5, where R<6>is as defined above and X<5>is selected from -x<4>nr12r12,-x4nr12C(0)R12,-x4nr12C(0)OR12,x4nr1<2>C(0)NR12r12,-X<4>NR< 12>C(NR<12>)NR12R<12>,-X<4>OR<1>2,-X<4>SR12,-X<4>C(0)OR<12>,-X<4>C(0)R12, -X4OC(0)R<12>,-X<4>R12, X<4>C(0)NR<12>R<12>, -X<4>S(0)2NR12R<1>2,X<4>NR<12>S(0)2R12-X<4>P(0)(OR<12>)OR<12>,-X<4>OP(0)(OR12)OR12,-X<4>C(0)R13,-X4NR<12>C(0)R<13>, -X<4>S(0)R<13>and -X<4>S(0)2R<13>, -R<14>, -X4OR<1>4, -X<4>SR<1>4, -X<4>S(0)R14, -X<4>S(0)2R<14>, -X<4>C(0)R<14>, -X<4>C(O)0R<14>, -X<4>OC(0)R<14>,-X<4>NR<14>R<12>,-X<4>NR1<2>C(0)R<14>,-X4NR<12>C(0)OR<14>,-X<4>C(0)NR1 4R12,-X<4>S(0)2NR14R12,-X4NR1<2>S(0)2R<14>,-X4NR1<2>C(0)NR14R12i-X4NR12C(NR12)NR14R12, where X4, R12, R13 and R<14> ARE as previously defined; X<4>is -nr<6>r6, -nr6R14, -nr6r15\\\-nr6X5C(0)R<14>where R6,X5 and R<14>are as before described and R<15> is hydrogen, -(C-|-6)alkyl or - X5OR6 where X<5> is described above; or R<6> and R"15 together with the nitrogen atom to which both R6 and R<15> are attached form hetero(C3-io)cycloalkyl or hetero(Cs-io)aryl or hetero(Cs-10)bicycloaryl; where within R<3>and R<4> any alicyclic or aromatic ring system can be further substituted with 1-5 radicals that are independently selected from (C-j. 6)alkil, (C-|-6)alkiliden, cijano, halo, halo-supstituisani(C-|-4)alkil, nitro, -x<4>nr<12>r<12>,-X<4>NR<12>C(0)R<12>,-X4NR<12>C(0)OR<12>,-X4NR12C(O)NR12R12-X4NR12C(NR12)NR12R12,X4OR12,X4SR12,-X4C(0)OR12,-X4C(O)R12, - X<4>OC(0)R<12>, X<4>C(0)NR12R12, -X<4>S(0)2NR<12>R12,X<4>NR<12>S(O)2R<12>,-X<4>P(O)(OR<12>)0R12,-X<4>OP(0)(OR12)OR12,-X<4>NR<12>C(0)R13,-X<4>S(0)R13, -X<4>C(0)R13, i-X<4>S(0)2R<13>i / ili 1 radikal odabran od -R14, -X4OR14 -X<4>SR<14>, -X4S(0)R<14>, -X4S(0)2R<14>, -X4C(0)R14, -X4C(0)OR14, - X4OC(0)R14,-X4NR14R1 2,-X4NR1 2C(0)R1 4,-X4NR1 2C(0)OR1 4,-X4C(0)NR1 4R1 2,-X<4>S(0)2NR<14>R<12>-X4NR1<2>S(O)2R<14>,-X<4>NR<12>C(O)NR<14>R12i-X<4>NR<12>C(NR12)NR14R12, i gde u granicama R<3>i R<4>bilo koji alifatični prsten može dalje biti supstituisan sa 1-5 radikala nezavisno supstituisani od cijano, halo, nitro, -nr<12>r<12>, -nr<12>C(0)R<12>, -NR12C(0)OR<12>, -NR12C(0)NR<12>R12,-NR12C(NR<1>2)NR12R12i-OR12,-SR12,-C(0)OR<12>,-C(0)R<12>,-OC(0)R<12>,-C(0)NR12R<12>,-S(0)2NR<12>R12,-NR12S(O)2R<12>,-P(O)(0R12)0R12,-op(0)(or12)OR12,-nr12c(0)r13,-S(0)R13 i-S(0)2R13; gde su X4,R12,R13i R14 ranije definisani; pod uslovom da je samo jedna biciklična prstenasta struktura prisutna u okviru R<3>ili R<4>; i derivati N-oksida, derivati proleka, derivati sa zaštitnom grupom, pojedinačni izomeri i smeše tih izomera; i farmaceutski prihvatljive soli i solvati (na primer, hidrati) tih jedinjenja i derivati N-oksida; derivati proleka, derivati sa zaštitnim grupama, pojedinačni izomeri i smeše tih izomera.6)alkyl, (C-|-6)alkylidene, cyano, halo, halo-substituted (C-|-4)alkyl, nitro, -x<4>nr<12>r<12>,-X<4>NR<12>C(0)R<12>,-X4NR<12>C(0)OR<12>,-X4NR12C( O)NR12R12-X4NR12C(NR12)NR12R12,X4OR12,X4SR12,-X4C(0)OR12,-X4C(O)R12, - X<4>OC(0)R<12>, X<4>C(0)NR12R12, -X<4>S(0)2NR<12>R12,X<4>NR<12>S(O)2R<12>,-X<4>P(O)(OR<12>)0R12,-X<4>OP(0)(OR12)OR12,-X<4>NR<12>C(0)R13,-X<4>S(0)R13, -X<4>C(0)R13, and-X<4>S(0)2R<13>and / or 1 radical selected from -R14, -X4OR14 -X<4>SR<14>, -X4S(0)R<14>, -X4S(0)2R<14>, -X4C(0)R14, -X4C(0)OR14, - X4OC(0)R14,-X4NR14R1 2,-X4NR1 2C(0)R1 4,-X4NR1 2C(0)OR1 4,-X4C(0)NR1 4R1 2,-X<4>S(0)2NR<14>R<12>-X4NR1<2>S(O)2R<14>,-X<4>NR<12>C(O)NR<14>R12i-X<4>NR<12>C(NR12)NR14R12, and where within R<3>and R<4>any aliphatic ring may be further substituted with 1-5 radicals independently substituted by cyano, halo, nitro, -nr<12>r<12>, -nr<12>C(0)R<12>, -NR12C(0)OR<12>, -NR12C(0)NR<12>R12,-NR12C(NR<1>2)NR12R12i-OR12,-SR12,-C(0)OR<12>,-C(0)R<12>,-OC(0)R<12>,-C(0)N R12R<12>,-S(0)2NR<12>R12,-NR12S(O)2R<12>,-P(O)(0R12)0R12,-op(0)(or12)OR12,-nr12c(0)r13,-S(0)R13 i-S(0)2R13; where X 4 , R 12 , R 13 and R 14 are as previously defined; provided that only one bicyclic ring structure is present within R<3> or R<4>; and N-oxide derivatives, prodrug derivatives, derivatives with a protective group, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvates (eg, hydrates) of those compounds and N-oxide derivatives; prodrug derivatives, derivatives with protective groups, individual isomers and mixtures of these isomers. 2. Jedinjenje prema patentnom zahtevu 1, u kojem je X<1>je -NHC(R1)(R2)X2 ili -NHX<3>;X2 je cijano; -C(0)X3, -C(0)CF"3, - C(0)CF2CF2R<9>, -CH=CHS(0)2R5, -C(0)CF2C(0)NR<5>r<5>i-C(0)C(0)NR<5>r<6>, . C(0)C(0)OR<5>, -C(0)CH20R<5>, -C(0)CH2N(R<6>)S02R<5>ili -C(0)C(0)R<5>; gde su R<5>i r<6>gore opisani; X<3>obuhvata heterociklični prsten sa 4 do 6 atoma u prstenu ili spojeni heterociklični prstenasti sistem sa 8 do 14 atoma u prstenu i bilo koji derivat karbocikličnog ketona, iminoketona ili tioketona; gde u okviru R<5>, X<2>ili X<3>bilo koji aliciklični il aromatični prstenasti sistem može biti dalje supstituisan sa 1 do 5 radikala odabranih od (C-|-6)alkil ili -X<4>OC(0)R<12>i/ili 1 radikal odabran od -R14 -X<4>C(0)R14 ili -X4OC(0)R<14>; gde suX4,R12 i R"14 gore opisani; R<1>je vodonik ili (Ci-6)alkil i R2 je vodonik, -X40R1<2>, (C5-io)heteroaril(Co-6)alkil, (C5-io)aril(Co-6)alkil, (C5-io)cikloalkil(Co-6)alkil, (C5-io)heterocikloalkil(Co-6)alkil ili (C-|-6)alkil; ili R<1>i R<2>zajedno sa atomom ugljenika za koji su vezani i R"<1>i R<2>grade (C3.2. The compound according to claim 1, wherein X<1> is -NHC(R1)(R2)X2 or -NHX<3>; X2 is cyano; -C(0)X3, -C(0)CF"3, - C(0)CF2CF2R<9>, -CH=CHS(0)2R5, -C(0)CF2C(0)NR<5>r<5>i-C(0)C(0)NR<5>r<6>, . C(0)C(0)OR<5>, -C(0)CH20R<5>, -C(0)CH2N(R<6>) or -C(0)C(0)R<5>; where R<5> and r<6> include a heterocyclic ring with 4 to 6 ring atoms or a fused heterocyclic ring system with 8 to 14 ring atoms; where in R<5>, X<2> or X<3> is any alicyclic or aromatic the ring system may be further substituted with 1 to 5 radicals selected from (C-|-6)alkyl or -X<4>OC(0)R<12> and/or 1 radical selected from -R14 -X<4>C(0)R14 or -X4OC(0)R<14>; where X4, R12 and R"14 are as described above; R<1> is hydrogen or (C1-6)alkyl and R2 is hydrogen, -X40R1<2>, (C5-io)heteroaryl(Co-6)alkyl, (C5-io)aryl(Co-6)alkyl, (C5-io)cycloalkyl(Co-6)alkyl, (C5-io)heterocycloalkyl(Co-6)alkyl or (C-1-6)alkyl; or R<1>and R<2> together with the carbon atom to which both R"<1>and R<2> are attached (C3. 8)cikloalkilen ili (C3-8)heterocikloalkilen; gde je unutar pomenutog R<2>bilo koji heteroaril, aril, cikloalkil, heterocikloalkil, cikloalkilen ili heterocikloalkilen po slobodnom izboru supstituisan sa 1 do 3 radikala koji su nezavisno odabrani od (C-|-6)alkil i hidroksi; R<3>je -CH2X<5>, gde je X<5>pri svakom pojavljivanju odabran od -X<4>SR12,-X<4>C(0)NR<12>R<12>, -X4S(0)2R<13>, -X<4>C(0)R<13>, -X4SR14 -X4R<12>, -R14,-X<4>S(0)2R<14>, -x<4>C(0)R14, -x<4>C(0)NR14R1<2>, gde su X<4>,R12, r13 iR14 gore definisani; R<4>je -NR6R6, - nr6r14, -nr6r15 ili -nr6x<5>C(0)R14 gde su r6,x5ir1<4>ranije definisani iR15 je vodonik, -C(i-6)alkil ili -X<5>OR<6>gde je X<5>opisan ranije; ili R<6>i R15zajedno sa atomom azota za koji su vezani i R<6>j R<15>grade hetero(C3-io)cikloalkil, hetero(C5-io)aril ili hetero(C8-lo)bicikloaril; gde u u okviru R<3>i R<4>bilo koji aliciklični ili aromatični prsten može po slobodnom izboru biti dalje supstituisan sa 1 do 5 radikala koji su nezavisno odabrani od (Ci-6)alkil, cijano, halo, nitro, halo-supstituisani(Ci-4)alkil,-x<4>OR<12>,-x<4>C(0)OR12,-x4C(0)R13,-x4C(0)NR12R12. x<4>nr<12>S(0)2R12 i/ ili 1 radikal odabran od -R14, -x4OR14 i -x4C(0)NR14r12;gde u okviru R<3>i R<4>bilo koji alifatični deo prstena može dalje da bude supstituisan sa 1-5 radikala nezavisno odabranih od cijano; gde su X<4>, R12,R13iR14 gore opisani; pod uslovom da je samo jedna biciklična prstenasta struktura prisutna u okviru R<3>ili R<4>; i derivati N-oksida, derivati proleka, derivati sa zaštitnom grupom, pojedinačni izomeri i smeše tih izomera; i farmaceutski prihvatljive soli i solvati (na primer, hidrati) tih jedinjenja i derivati N-oksida; derivati proleka, derivati sa zaštitnim grupama, pojedinačni izomeri i smeše tih izomera.8) cycloalkylene or (C3-8) heterocycloalkylene; wherein within said R<2> any heteroaryl, aryl, cycloalkyl, heterocycloalkyl, cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C-|-6)alkyl and hydroxy; R<3>is -CH2X<5>, where X<5>at each occurrence is selected from -X<4>SR12, -X<4>C(0)NR<12>R<12>, -X4S(0)2R<13>, -X<4>C(0)R<13>, -X4SR14 -X4R<12>, -R14,-X<4>S(0)2R<14>, -x<4>C(0)R14, -x<4>C(0)NR14R1<2>, where X<4>, R12, r13 and R14 are as defined above; R<4>is -NR6R6, -nr6r14, -nr6r15 or -nr6x<5>C(O)R14 where r6,x5ir1<4>are as previously defined and R15 is hydrogen, -C(i-6)alkyl or -X<5>OR<6>where X<5>is as previously described; or R<6> and R15 together with the nitrogen atom to which R<6> and R<15> are attached form hetero(C3-10)cycloalkyl, hetero(C5-10)aryl or hetero(C8-10)bicycloaryl; where within R<3> and R<4> any alicyclic or aromatic ring can optionally be further substituted with 1 to 5 radicals independently selected from (Ci-6)alkyl, cyano, halo, nitro, halo-substituted (Ci-4)alkyl,-x<4>OR<12>,-x<4>C(O)OR12,-x4C(0)R13,-x4C(0)NR12R12. x<4>nr<12>S(0)2R12 and/or 1 radical selected from -R14, -x4OR14 and -x4C(0)NR14r12; where within R<3>and R<4>any aliphatic portion of the ring may be further substituted with 1-5 radicals independently selected from cyano; where X<4>, R12, R13 and R14 are as described above; provided that only one bicyclic ring structure is present within R<3> or R<4>; and N-oxide derivatives, prodrug derivatives, derivatives with a protective group, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvates (eg, hydrates) of those compounds and N-oxide derivatives; prodrug derivatives, derivatives with protective groups, individual isomers and mixtures of these isomers. 3. Jedinjenja prema patentnom zahtevu 2 u kojem: jeX"!-NHC(R1)(R2)X2 ili -NHX3; X<2>je cijano, -C(0)X<3>, -CF<3>, -CF2CF3, (E)-2-benzensulfonil-vinil, 2-dimetilkarbamoil-2,2-difluoro-acetil, 1 -benzilkarbamoil-metanoil, 1 - benziloksi(oksalil), 2-benziloksi-acetil, 2-benzensulfonilamino-etanoil ili 2-okso-2-fenil-etanoil; X<3>je 1H-benzoimidazol-2-il, pirimidin-2-il, benzooksazol-2-il, benzotiazol-2-il, piridazin-3-il, 3-fenil-[1,2,4]oksadiazol-5-il, 3-etil-[1,2,4]oksadiazol-5-il, 2-metil-4-okso-tetrahidro-furan-3-il, 2-etil-4-okso-tetrahidro-furan-3-il, 4-okso-1 -(1 -fenil-metanoil)-pirolidin-3-il ili (S)-2-Acetoksi-4-okso-azetidin-3-il; R<1>je vodonik ili metil i R<2>je vodonik, metoksimetil, (Ci-6)alkil, fenetil, tiofen-2-il ili 5-metil-furan-2-il ili (ii) R"i i R<2>zajedno sa atomom ugljenika za koji su vezani i R^ i R<2>grade ciklopropilen, tetrahidro-piran-4-ilen ili metil-piperidin-4-ilen.3. Compounds according to claim 2 in which: is X"!-NHC(R1)(R2)X2 or -NHX3; X<2>is cyano, -C(0)X<3>, -CF<3>, -CF2CF3, (E)-2-benzenesulfonyl-vinyl, 2-dimethylcarbamoyl-2,2-difluoro-acetyl, 1-benzylcarbamoyl-methanol, 1- benzyloxy(oxalyl), 2-benzyloxy-acetyl, 2-benzenesulfonylamino-ethanoyl or 2-oxo-2-phenyl-ethanoyl; 3-ethyl-[1,2,4]oxadiazol-5-yl, 2-methyl-4-oxo-tetrahydro-furan-3-yl, 2-ethyl-4-oxo-tetrahydro-furan-3-yl, 4-oxo-1-(1-phenyl-methanoyl)-pyrrolidin-3-yl or (S)-2-Acetoxy-4-oxo-azetidin-3-yl; R<1> is hydrogen or methyl and R<2> is hydrogen, methoxymethyl, (Ci-6)alkyl, phenethyl, thiophen-2-yl or 5-methyl-furan-2-yl or (ii) R"i and R<2> together with the carbon atom to which both R^ and R<2> are attached form cyclopropylene, tetrahydro-pyran-4-ylene or methyl-piperidin-4-ylene. 4. Jedinjenje prema patentnom zahtevu 3, u kojem je R<3>odabran od tiofen-2-sulfonilmetil, 3-hloro-2-fluoro-fenilmetansulfonilmetil, benzensulfonilmetil, fenilmetansulfonilmetil, 2-(1,1 -difluoro-metoksi)fenilmetansulfonilmetil, 2-benzensulfonil-etil, 2-(piridin-2-sulfonil)-etil, 2-(piridin-4-sulfoniI)-etil, 2-fenilmetansulfonil-etil, oksi-piridin-2-ilmetansulfonilmetil, prop--2-en-1 -sulfonilmetil, 4-metoksi-fenilmetansulfonilmetil, p-tolilmetansulfonilmetil, 4-hloro-fenilmetansulfonilmetil, o-tolilmetansulfonilmetil, 3,5-dimetil-fenilmetansulfonilmetil, 4-trifluorometil-fenilmetan sulfonilmetil, 4-trifluorometoksi-fenilmetansulfonilmetil, 2-bromo-fenilmetansulfonilmetil, piridin-2-ilmetnasulfonilmetil, piridin-3-ilmetansulfonilmetil, piridin-4-ilmetansulfonilmetil, naftalen-2-ilmetansulfonilmetil, 3-metil-fenilmetansulfonilmetil, 3-trifluorometil-fenilmetansulfonilmetil, 3-trifluorometoksi-fenilmetansulfonilmetil, 4-fluoro-2-trifluorometoksi-fenilmetansulfonilmetil,4. A compound according to claim 3, wherein R<3> is selected from thiophene-2-sulfonylmethyl, 3-chloro-2-fluoro-phenylmethanesulfonylmethyl, benzenesulfonylmethyl, phenylmethanesulfonylmethyl, 2-(1,1-difluoro-methoxy)phenylmethanesulfonylmethyl, 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfonyl)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl, 2-phenylmethanesulfonyl-ethyl, oxy-pyridin-2-ylmethanesulfonylmethyl, prop--2-ene-1 -sulfonylmethyl, 4-methoxy-phenylmethanesulfonylmethyl, p-tolylmethanesulfonylmethyl, 4-chloro-phenylmethanesulfonylmethyl, o-tolylmethanesulfonylmethyl, 3,5-dimethyl-phenylmethanesulfonylmethyl, 4-trifluoromethyl-phenylmethanesulfonylmethyl. sulfonylmethyl, 4-trifluoromethoxy-phenylmethanesulfonylmethyl, 2-bromo-phenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, naphthalen-2-ylmethanesulfonylmethyl, 3-methyl-phenylmethanesulfonylmethyl, 3-trifluoromethyl-phenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxy-phenylmethanesulfonylmethyl, 2- fluoro-6-trifluorometil-fenilmetansulfonilmetil,2-fluoro-6-trifluoromethyl-phenylmethanesulfonylmethyl, 3- hloro-fenilmetansulfonilmetil, 2-fluoro-fenilmetansulfonilmetil, 2-trifluoro-fenilmetansulfonilmetil, 2-cijano-fenilmetansulfonilmetil,3-chloro-phenylmethanesulfonylmethyl, 2-fluoro-phenylmethanesulfonylmethyl, 2-trifluoro-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 4- terc-butil-fenilmetansulfonilmetil,4-tert-butyl-phenylmethanesulfonylmethyl, 2- fluoro-3-metil-fenilmetansulfonilmetil,2-fluoro-3-methyl-phenylmethanesulfonylmethyl, 3- fluoro-fenilmetansulfonilmetil, 4-fluoro-fenilmetansulfonilmetil, 2-hloro-fenilmetansulfonilmetil,3-fluoro-phenylmethanesulfonylmethyl, 4-fluoro-phenylmethanesulfonylmethyl, 2-chloro-phenylmethanesulfonylmethyl, 2.5- difluoro-fenilmetansulfonilmetil,2.5-difluoro-phenylmethanesulfonylmethyl, 2.6- difluoro-fenilmetansulfonilmetil, 2,5-dihloro-fenilmetansulfonilmetil,2.6-difluoro-phenylmethanesulfonylmethyl, 2,5-dichloro-phenylmethanesulfonylmethyl, 3.4- dihloro-fenilmetansulfonilmetil, 2-(1,1-difluoro-metoksi)-fenilmetansulfonilmetil, 2-cijano-fenilmetansulfonilmetil, 3-cijano-fenilmetansulfonilmetil, 2-trifluorometoksi-fenilmetansulfonilmetil,3.4-dichloro-phenylmethanesulfonylmethyl, 2-(1,1-difluoro-methoxy)-phenylmethanesulfonylmethyl, 2-cyano-phenylmethanesulfonylmethyl, 3-cyano-phenylmethanesulfonylmethyl, 2-trifluoromethoxy-phenylmethanesulfonylmethyl, 2.3- difluoro-fenilmetansulfonilmetil,2.3-difluoro-phenylmethanesulfonylmethyl, 2.5- dilfuoro-fenilmetansulfonilmetil, bifenil-2-ilmetansulfonilmetil, cikloheksilmetil, 3-fluoro-fenilmetansulfonilmetil,2.5- dilfluoro-phenylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, cyclohexylmethyl, 3-fluoro-phenylmethanesulfonylmethyl, 3.4- difluoro-fenilmetansulfonilmetil, 2,4-difluoro-fenilmetansulfonilmetil, 2,4,6-trifluoro-fenilmetansulfonilmetil, 2,4,5-trifluoro-fenilmetansulfonilmetil,3.4-difluoro-phenylmethanesulfonylmethyl, 2,4-difluoro-phenylmethanesulfonylmethyl, 2,4,6-trifluoro-phenylmethanesulfonylmethyl, 2,4,5-trifluoro-phenylmethanesulfonylmethyl, 2.3.4- trifluoro-fenilmetansulfonilmetil,2.3.4- trifluoro-phenylmethanesulfonylmethyl, 2.3.5- trifluoro-fenilmetansulfonilmetil,2.3.5- trifluoro-phenylmethanesulfonylmethyl, 2.5.6- trifluoro-fenilmetansulfonilmetil, 2-hloro-5-trifluorometilfenilmetansulfonilmetil, 2-metil-propan-1 -sulfonil, 2-fluoro-3-trifluorometilfenilmetansulfonilmetil, 2-fluoro-4-trifluorometi[fenilmetansulfonilmetil, 2-fluoro-5-trifluorometilfenilmetansuIfonilmetil,2.5.6- trifluoro-phenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2-methyl-propane-1 -sulfonyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-4-trifluoromethyl[phenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl, 4- fluoro-3-trifluorometilfenilmetansulfonilmetil, 2-metoksi-fenilmetansulfonilmetil, bis-trifluorometil-fenilmetansulfonilmetil,4-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-methoxy-phenylmethanesulfonylmethyl, bis-trifluoromethyl-phenylmethanesulfonylmethyl, 4- difluorometoksi-fenilmetansulfonilmetil,4- difluoromethoxy-phenylmethanesulfonylmethyl, 2- difluorometoksi-fenilmetansulfonilmetil,2- difluoromethoxy-phenylmethanesulfonylmethyl, 3- difluorometoksi-fenilmetansulfonilmetil, 2,6-dihloro-fenilmetansulfonilmetil, bifenil-4-ilmetansulfonilmetil, 3,5-dimetil-izoksazol-4-ilmetansulfonilmetil,3- difluoromethoxy-phenylmethanesulfonylmethyl, 2,6-dichloro-phenylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, 3,5-dimethyl-isoxazol-4-ylmethanesulfonylmethyl, 5- hloro-tiofen-2-ilmetansulfonilmetil,5-chloro-thiophen-2-ylmethanesulfonylmethyl, 2-[4-(1,1 -Difluoro-metoksi)-benzensulfonil]-etil,2-[4-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[2-(1,1 -Difluoro-metoksi)-benzensulfonil]-etil, 2-[3-(1,1-Difluoro-metoksi)-benzensulfonil]-etil, 2-(4-trifluorometoksi-benzensulfonil)-etiI, 2-(3-trifluorometoksi-benzensulfonil)-etil, 2-(2-trifluorometoksi-benzensulfonil)-etil, (cijanometil-metil-karbamoil)-metil, butil, bifenil-3-ilmetil, 2-okso-2-pirolidin-1 -il-etii, 2-benzensulfonil-etil, izobutilsulfanilmetil, 2-fenilsulfanil-etil, cikloheksilmetansulfonilmetil, 2-cikloheksil-etansulfonil, benzil, naftalen-2-il, benzilsulfanilmetil, 2-trifiuorometil-benzilsulfanilmetil, 5-bromo-tiofen-2-ilmetil, fenilsulfanil-etil i ciklopropilmetansulfonilmetil.2-[2-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-[3-(1,1-Difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl, (cyanomethyl-methyl-carbamoyl)-methyl, butyl, biphenyl-3-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-benzenesulfonyl-ethyl, isobutylsulfanylmethyl, 2-phenylsulfanyl-ethyl, cyclohexylmethanesulfonylmethyl, 2-cyclohexyl-ethanesulfonyl, benzyl, naphthalen-2-yl, benzylsulfanylmethyl, 2-trifluoromethyl-benzylsulfanylmethyl, 5-bromo-thiophen-2-ylmethyl, phenylsulfanyl-ethyl and cyclopropylmethanesulfonylmethyl. 5. Jedinjenje prema patentnom zahtevu 4, u kojem je R<4>odabran od fenilamino, benzilamino, 4-fenoksi-fenilamino, fenetilamino, 3--fenil-propilamino, morfolin-4-il, cikloheksilamino, naftalen-1-ilmetil-amino, piridin-3-ilamino, 6-metoksi-piridin-3-ilamino, diizobutilamino, 4-nitro-benzilamino, 2-tiofen-2-il-etilamino, 3-fenoksi-fenilamino, cijanometil-amino, (piridin-3-ilmetil)-amino, 5,6,7,8-tetrahidronaftalen-1-ilamino, 2-piridin-2-iletilamino, 2,3-dihidro-indol-1-il, 3,4-dihidro-1 H-izohinolin-2-il, cikloheksilmetil-amino, 2-metoksi-benzilamino, 1-fenil-etilamino, (piridin-4-ilmetil)-amino, benzil-metil-amino, 3-nitro-benzilamino, 4-metoksi-fenilamino, 3-karbamoil-fenilamino, 4-karbamoil-fenilamino, (tetrahidrofuran-2-ilmetil)-amino, 3,4-dihidro-2H-hinolin-1-il, dimetilamino, butilmetilamino, diizopropilamino, propilmetilamino, 1-(benzooksazol-2-karbonil)-propilamino i izobutilmetilamino.5. A compound according to claim 4, wherein R<4> is selected from phenylamino, benzylamino, 4-phenoxy-phenylamino, phenethylamino, 3--phenyl-propylamino, morpholin-4-yl, cyclohexylamino, naphthalen-1-ylmethyl-amino, pyridin-3-ylamino, 6-methoxy-pyridin-3-ylamino, diisobutylamino, 4-nitro-benzylamino, 2-thiophen-2-yl-ethylamino, 3-phenoxy-phenylamino, cyanomethyl-amino, (pyridin-3-ylmethyl)-amino, 5,6,7,8-tetrahydronaphthalen-1-ylamino, 2-pyridin-2-ylethylamino, 2,3-dihydro-indol-1-yl, 3,4-dihydro-1H-isoquinolin-2-yl, cyclohexylmethyl-amino, 2-methoxy-benzylamino, 1-phenyl-ethylamino, (pyridin-4-ylmethyl)-amino, benzyl-methyl-amino, 3-nitro-benzylamino, 4-methoxy-phenylamino, 3-carbamoyl-phenylamino, 4-carbamoyl-phenylamino, (tetrahydrofuran-2-ylmethyl)-amino, 3,4-dihydro-2H-quinolin-1-yl, dimethylamino, butylmethylamino, diisopropylamino, propylmethylamino, 1-(benzoxazole-2-carbonyl)-propylamino and isobutylmethylamino. 6. Jedinjenje prema patentnom zahtevu 5 odabrano je iz grupe koju čine: 2-butil-N-cijanometil-N'-fenil-malonamid; N-Cijanometil-2-cikloheksilmetil-N'-fenil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-fenetil-malonamid ;N-Cijanometil-2-cikloheksilmetil-N'-piridin-4ilmetil-malonamid; N-[1-(Benzooksazol-2-karbonil)-3-fenil-propil]-N'-benzil-2-cikloheksilmetil-malonamid ; N-Cijanometil-N'-cikloheksil-2-cikloheksilmetil-malonamid; N-Benzil-N'-cijanometil-2-cikloheksilmetil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(4-fenoksi-fenil)-malonamid; N-Cijanometil-2-cikloheksilmetil-N'-(3-fenil-propil)-malonamid ; N-Cijanometil-2-cikloheksilmetil-3-morfolin-4-il-3-okso-propionamid ; N-Cijanometil-2-cikloheksilmetil-N'-naftalen-1-ilmetil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-piridin-3-il-malonamid ; N-Cijanometil-2-cikloheksilmetil-N',N'-diizobutil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N',N'-diizopropil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(6-metoksi-piridin-3-il)-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(2-tiofen-2-il-etil)-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(3-fenoksi-fenil)-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(4-nitro-benzil)-malonamid ; N, N'-Bis-cijanometil-2-cikloheksilmetil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(5,6,7,8-tetrahidro-naftalen-1-il)-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(2-piridin-2-il-etil)-malonamid ; N-Cijanometil-2-cikloheksilmetil-3-(2,3-dihidro-indol-1-il)-3-okso-propionamid; N-Cijanometil-2-cikloheksilmetil-3-(3,4-dihidro-1 H-izohinollin-2-il)-3-oksopropionamid ; N-Cijanometil-2-N'-bis-cikloheksilmetil-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(2-metoksi-benzil)-malonamid ; N-Cijanometil-2-cikloheksilmetil-N'-(1-fenil-etil)-malonamid; N-Benzil-N'-cijanometil-2-cikloheksilmetil-N-metil-malonamid; N-Cijanometil-2-cikloheksilmetil-N'-(3-nitro-benzil)-malonamid; N-Cijanometil-2-cikloheksilmetil-N'-(4-metoksi-benzil)-malonamid; N-(3-Karbamoil-fenil)-N'-cijanometil-2-cikloheksilmetil-malonamid; N-Cijanometil-2-cikloheksilmetil-N'-piridin-3-ilmetil-malonamid; N-(4-karbamoilfenil)-N'-cijanometil-2-cikloheksilmetil-malonamid; N-Cijanometil-2-cikloheksilmetil-N'-tetrahidrofur-2-ilmetilmalonamid ; N-Cijanometil-2-cikloheksilmetil-3-(3,4-dihidro-2H-hinolin-1-il)-3-oksopropionam N-terc-butil-N'-cijanometil-2-cikloheksilmetil-N-metilmalonamid ; N-cijanometil-2-cikloheksilmetil-N'-metil-N'-propilmalonamid ; N-butil-N'-cijanometil-2-cikloheksilmetil-N-metilmalonamid; N-cijanometil-2-cikloheksilmetil-N\N'-dimetilmalonamid ; N-Benzil-N'-cijanometi!-2-(2-fenilsulfaniletil)-malonamid ; 2-(2-fenilsulfoniletil)--N-benzil-N'-cijanometilmalonamid ; 2-(2-Benzensulfonil-etil)-N-[(S)-1-(1 -benzooksazol-2-il-metanoil)-pentil]-N'-benzilmalonamid ; N,N'-Bis-[(S)-1 -(1 -benzooksazol-2-il-metanoil)-propil]-2-cikloheksilmetilmalonamid; i derivati N-oksida, derivati proleka, derivati sa zaštitnom grupom, pojedinačni izomeri i smeše tih izomera; i farmaceutski prihvatljive soli i solvati tog jedinjenja i derivati N-oksida; derivati proleka, derivati sa zaštitnim grupama, pojedinačni izomeri i smeše tih izomera.6. The compound according to claim 5 is selected from the group consisting of: 2-butyl-N-cyanomethyl-N'-phenyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-phenyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-phenethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-pyridin-4ylmethyl-malonamide; N-[1-(Benzoxazole-2-carbonyl)-3-phenyl-propyl]-N'-benzyl-2-cyclohexylmethyl-malonamide; N-Cyanomethyl-N'-cyclohexyl-2-cyclohexylmethyl-malonamide; N-Benzyl-N'-cyanomethyl-2-cyclohexylmethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(4-phenoxy-phenyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(3-phenyl-propyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-3-morpholin-4-yl-3-oxo-propionamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-naphthalen-1-ylmethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-pyridin-3-yl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N',N'-diisobutyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N',N'-diisopropyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(6-methoxy-pyridin-3-yl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(2-thiophen-2-yl-ethyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(3-phenoxy-phenyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(4-nitro-benzyl)-malonamide; N, N'-Bis-cyanomethyl-2-cyclohexylmethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(5,6,7,8-tetrahydro-naphthalen-1-yl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(2-pyridin-2-yl-ethyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-3-(2,3-dihydro-indol-1-yl)-3-oxo-propionamide; N-Cyanomethyl-2-cyclohexylmethyl-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropionamide; N-Cyanomethyl-2-N'-bis-cyclohexylmethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(2-methoxy-benzyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(1-phenyl-ethyl)-malonamide; N-Benzyl-N'-cyanomethyl-2-cyclohexylmethyl-N-methyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(3-nitro-benzyl)-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-(4-methoxy-benzyl)-malonamide; N-(3-Carbamoyl-phenyl)-N'-cyanomethyl-2-cyclohexylmethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-pyridin-3-ylmethyl-malonamide; N-(4-carbamoylphenyl)-N'-cyanomethyl-2-cyclohexylmethyl-malonamide; N-Cyanomethyl-2-cyclohexylmethyl-N'-tetrahydrofur-2-ylmethylmalonamide; N-Cyanomethyl-2-cyclohexylmethyl-3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropionam N-tert-butyl-N'-cyanomethyl-2-cyclohexylmethyl-N-methylmalonamide; N-cyanomethyl-2-cyclohexylmethyl-N'-methyl-N'-propylmalonamide; N-butyl-N'-cyanomethyl-2-cyclohexylmethyl-N-methylmalonamide; N-cyanomethyl-2-cyclohexylmethyl-N\N'-dimethylmalonamide; N-Benzyl-N'-cyanomethyl-2-(2-phenylsulfanylethyl)-malonamide; 2-(2-phenylsulfonylethyl)-N-benzyl-N'-cyanomethylmalonamide; 2-(2-Benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-pentyl]-N'-benzylmalonamide; N,N'-Bis-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-propyl]-2-cyclohexylmethylmalonamide; and N-oxide derivatives, prodrug derivatives, derivatives with a protective group, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvates of that compound and N-oxide derivatives; prodrug derivatives, derivatives with protective groups, individual isomers and mixtures of these isomers. 7. Farmaceutska kompozicija koja obuhvata terapeutski efikasnu količinu jedinjenja formule 1 u kombinaciji sa farmaceutski prihvatljivim ekscipijentom.7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 in combination with a pharmaceutically acceptable excipient. 8. Upotreba terapeutski efikasne količine jedinjenja prema patentnom zahtevu 1 ili derivata N-oksida ili pojedinačnog izomera, ili farmaceutski prihvatljive soli ili solvata tih jedinjenja i derivata N-oksida,, derivata proleka, derivata sa zaštitnim grupama, pojedinačnih izomera i smeše tih izmomera, za proizvodnju leka za lečenje oboljenja kod životinja gde se inhibicijom katepsina S može sprečiti, inhibirati ili poboljšati patologija i/ ili simptomatologija oboljenja.8. The use of a therapeutically effective amount of a compound according to patent claim 1 or an N-oxide derivative or an individual isomer, or a pharmaceutically acceptable salt or solvate of those compounds and N-oxide derivatives, prodrug derivatives, derivatives with protective groups, individual isomers and a mixture of those isomers, for the production of a drug for the treatment of diseases in animals where by inhibiting cathepsin S the pathology and/or symptomatology of the disease can be prevented, inhibited or improved. 9. Postupak za dobijanje jedinjenja formule I: obuhvata (A) reakciju jedinjenja formule 2 : sa jedinjenjem formule NH2CR1R2X<2>, u kojem suR1,R<2>, R3 i r<4>definisani u kratkom opisu pronalaska za jedinjenje formule I; ili (B) reakciju jedinjenja formule 2 sa jedinjenjem formule NH2X<3>u kojem su R<3>i R<4>i X<3>opisani u kratkom opisu pronalaska za jedinjenje formule I; i (C) po slobodnom izboru prevodjenje jedinjenja formule I u farmaceutski prihvatljivu so; (D) po želji prevodjenje soli jedinjenja formule I u oblik koji nije so ; (E) po želji prevodjenje neoksidovanog oblika jedinjenja formule I u farmaceutski prihvatljiv A/-oksid ; (F) po želji prevodjenje oblika A/-oksida jedinjenja formule I u njegov neoksidovani oblik ; (G) po želji razdvajanje pojedinačnog izomera jedinjenja formule I iz smeše izomera; (H) po želji prevodjenje ne-derivatizovanih derivata jedinjenja I u farmaceutski derivat proleka; i (I) po slobodnom izvodjenju prevodjenje derivata proleka jedinjenja formule I u njegov ne-derivatizovani oblik.9. The process for obtaining the compound of formula I: includes (A) the reaction of the compound of formula 2: with the compound of formula NH2CR1R2X<2>, in which R1, R<2>, R3 and r<4> are defined in the brief description of the invention for the compound of formula I; or (B) reacting a compound of formula 2 with a compound of formula NH2X<3> in which R<3> and R<4> and X<3> are described in the brief description of the invention for a compound of formula I; and (C) optionally converting the compound of formula I into a pharmaceutically acceptable salt; (D) optionally converting a salt of a compound of formula I into a non-salt form; (E) optionally converting the non-oxidized form of the compound of formula I into a pharmaceutically acceptable A/-oxide; (F) optionally converting the A/-oxide form of the compound of formula I into its non-oxidized form; (G) optionally separating an individual isomer of a compound of formula I from a mixture of isomers; (H) optionally converting non-derivatized derivatives of compound I into a pharmaceutical prodrug derivative; and (I) in a free embodiment converting the prodrug derivative of the compound of formula I into its non-derivatized form.
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