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RS20050666A - Substituted n- arylheterocycles, method for production and use thereof as medicaments - Google Patents

Substituted n- arylheterocycles, method for production and use thereof as medicaments

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Publication number
RS20050666A
RS20050666A YUP-2005/0666A YUP20050666A RS20050666A RS 20050666 A RS20050666 A RS 20050666A YU P20050666 A YUP20050666 A YU P20050666A RS 20050666 A RS20050666 A RS 20050666A
Authority
RS
Serbia
Prior art keywords
alkyl
independently
group
phenyl
aryl
Prior art date
Application number
YUP-2005/0666A
Other languages
Serbian (sr)
Inventor
Lothar Schwink
Siegfried Stengelin
Matthias Gossel
Thomas Bohme
Gerhard Hessler
Petra Stahl
Dirk Gretzke
Original Assignee
Sanofi Aventis Deutschland Gmbh.,
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Application filed by Sanofi Aventis Deutschland Gmbh., filed Critical Sanofi Aventis Deutschland Gmbh.,
Publication of RS20050666A publication Critical patent/RS20050666A/en

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

Pronalazak se odnosi na supstituisane N-aril-heterocikle, kao i na njihove fiziološki prihvatljive soli i fiziološki funkcionalne derivate. Opisuju se jedinjenja formule (I) u kojoj ostaci imaju data značenja, njihovi N-oksidi, kao i njihove fiziološki prihvatljive soli i postupci za njihovu proizvodnju. Jedinjenja su pogodna, na pr. kao anorektici.The invention relates to substituted N-aryl heterocycles, as well as to their physiologically acceptable salts and physiologically functional derivatives. Described are compounds of formula (I) in which the residues have the meanings given, their N-oxides, as well as their physiologically acceptable salts and processes for their production. The compounds are suitable, e.g. as anorexics.

Description

SUPSTITUISANI N-ARIL-HETEROCIKLI, POSTUPCI NJIHOVESUBSTITUTED N-ARYL-HETEROCYCLES, THEIR PROCESSES

PROIZVODNJE I NJIHOVA UPOTREBA KAO LEKOVAPRODUCTION AND THEIR USE AS MEDICINES

Pronalazak se odnosi na supstituisane N-aril-heterocikle i nihove fiziološki The invention relates to substituted N-aryl heterocycles and their physiological properties

prihvatljive soli i fiziološki funkcionalne derivate. acceptable salts and physiologically functional derivatives.

Jedinjenja koja imaju farmakološko dejstvo i slična su po svojoj opštoj Compounds that have a pharmacological effect and are similar in general

strukturi N-aril-heterociklima opisanim u ovom tekstu bila su već opisana u ranijem delu. Tako, na primer, WO 00/35454 opisuje ureido - supstituisane fenil-piperidine i -pirilidine kao aktivne supstance za kočenje zapaljenskih i autoimunih oboljenja. Acil-amido supstituisani fenil-pirolidini se predlažu u WO 02/042271 za lečenje šećerne bolesti, gojaznosti i poremećaja u structures of N-aryl-heterocycles described in this text were already described in an earlier part. Thus, for example, WO 00/35454 describes ureido-substituted phenyl-piperidines and -pyrylidines as active substances for inhibiting inflammatory and autoimmune diseases. Acyl-amido substituted phenyl-pyrrolidines are proposed in WO 02/042271 for the treatment of diabetes, obesity and disorders in

metabolizmu masti. fat metabolism.

Pronalazak je proizašao iz zadatka da se stave na raspolaganje jedinjenja The invention arose from the task of making compounds available

koja izazivaju smanjenje težine kod sisara i pogodna su za sprečavanje i lečenje gojaznosti i šećerne bolesti. which cause weight loss in mammals and are suitable for the prevention and treatment of obesity and diabetes.

Pronalazak se, s toga, odnosi na jedinjenja formule I The invention therefore relates to compounds of formula I

u kojoj oznake znače in which the labels mean

R1, R2 nezavisno jedan od drugog, H, (d-C8)-alkil, - R1, R2 independently of each other, H, (d-C8)-alkyl, -

(CR78R79)0-R12, (CrC4)-alkoksi-(CrC4)-alkil, aril-oksi-(Ci-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, CO-(CrC8)-alkil, -CO-(CH2)0-R12, CO-aril-oksi-(d-C4)-alkil, CO-(C2-C8)-alkenil, CO-(C2-C8)-alkinil, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkil-S(0)p-(C,-C4)-alkil, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 4 dodatnih hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može biti dodatno (CR78R79)0-R12, (CrC4)-Alkoxy-(CrC4)-Alkyl, Aryl-Oxy-(Ci-C4)-Alkyl, (C3-C8)-Alkenyl, (C3-C8)-Alkynyl, CO-(CrC8)-Alkyl, -CO-(CH2)0-R12, CO-Aryl-oxy-(C4)-Alkenyl, (C3-C8)-Alkenyl, CO-(C2-C8)-alkynyl, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkyl-S(0)p-(C,-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))SO(R25); or R1 and R2 together with the nitrogen atom, to which they are attached, form a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may contain 0 to 4 additional hetero-atoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring system may be additionally

supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(CrC8)-alkil, (d-C4)-alkoksi-(d-C4)-alkil, hidroksi-(Cr C4)-alkil, (C0-C8)-alkilen-ahl, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(CrC6)-alkil, N(R31)(R32) ili S02CH3; substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, O-(CrC8)-alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, hydroxy-(Cr C4)-alkyl, (C0-C8)-alkylene-ahl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29). N(R30)CO(C1C6)-alkyl, N(R31)(R32) or SO2CH3;

o 0,1,2,3,4,5,6; about 0,1,2,3,4,5,6;

P 0,1,2 P 0,1,2

q, r, s nezavisno jedan od drugog, 0,1,2,3,4; q, r, s independently of each other, 0,1,2,3,4;

R13, R14 nezavisno jedan od drugog, jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 druga hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(CrC8)-alkil; R13, R14 independently of each other, a 5 - 10-membered aromatic ring system which can contain 0-2 other heteroatoms from the group of nitrogen, oxygen and sulfur and can be substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, 0-(CrC8)-alkyl;

R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32

nezavisno jedan od drugog, H, (C-i-C6)-alkil; independently of each other, H, (C 1 -C 6 )-alkyl;

R18 H, (CrC6)-alkil, CO(Ci-C6)-alkil, CO(R33); R18 H, (C1C6)-alkyl, CO(C1-C6)-alkyl, CO(R33);

ili or

R17 i R18, R21 i R22, R27 i R28, R31 i R32 R17 and R18, R21 and R22, R27 and R28, R31 and R32

nezavisno jedan od drugoga, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0-1 dalji hetero-atom iz grupe N-(C-i-C6)-alkil, kiseonik i sumpor; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(C-i-C6)-alkyl, oxygen and sulfur;

R33 jedan 5 - 10-člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(CrC8)-alkil; R33 a 5-10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, O-(CrC8)-alkyl;

R12 OH, 0-(Ci-C6)-alkil, O(C0-C8)-alkilen-aril, CN, S-(CrC6)-alkil, COO(R80), CON(R81)(R93), N(R82)(R83), 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, I, OH, CF3, N02, CN, OCF3, okso, 0-(Ci-Ce)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(d-C6)-alkil, (Ci-Ce)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-cicloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C5)-alkinil, O-(C0-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38)),(R39), CO(C(R37)(R38))t(R39), CO(CrC6)-alkil, COCOO(CrC6)-alkil, COO(R40), S(0)U(R41) i COOH; R12 OH, 0-(Ci-C6)-alkyl, O(C0-C8)-alkylene-aryl, CN, S-(CrC6)-alkyl, COO(R80), CON(R81)(R93), N(R82)(R83), 3 - 12-membered mono-, bi- or spirocyclic ring which may contain one or more hetero-atoms from the group N, O and S, and 3 - 12-membered The ring members may contain further substituents, such as F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O-(Ci-Ce)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, S-(d-C6)-alkyl, (Ci-Ce)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C5)-alkynyl, O-(C0-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38),(R39), CO(C(R37)(R38))t(R39), CO(C1C6)-alkyl, COCOO(C1C6)-alkyl, COO(R40), S(O)U(R41) and COOH;

t 0,1,2,3,4,5,6; t 0,1,2,3,4,5,6;

u 0,1,2; in 0,1,2;

R34, R35, R37, R38 R34, R35, R37, R38

nezavisno jedan od drugog, H, (C-i-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

ili or

R34 i R35 R34 and R35

najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(CrC6)-alkil, kiseonika, i sumpora i može, najpovoljnije, da bude supstituisan sa 1 - 2 okso grupe; most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(CrC6)-alkyl, oxygen, and sulfur and can, most advantageously, be substituted with 1 - 2 oxo groups;

R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0 -2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(Ci-C8)-alkil; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5-10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, 0-(Ci-C8)-alkyl;

R40 H, (Ci-C8)-alkil, (C2-C6)-alkenil, (C0-C8)-alkilen-aril; R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl;

R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (C1-C6)-alkil, 0-(Ci-C8)-alkil; R41 (Ci-C6)-alkyl, 5-10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, 0-(Ci-C8)-alkyl;

R78, R79 nezavisno jedan od drugog, H, (C-i-C8)-alkil, hidroksi-(Cr R78, R79 independently of each other, H, (C-i-C8)-alkyl, hydroxy-(Cr

C4)-alkil, OH, (Ci-C4)-alkoksi-(CrC4)-alkil; C 4 )-alkyl, OH, (C 1 -C 4 )-Alkoxy-(C 1 -C 4 )-Alkyl;

R80, R81 R80, R81

R93 nezavisno jedan od drugog, H, (d-C8)-alkil, (C2-C6)-alkenil, (C0-C8)-alkilen-aril; R 93 independently of each other, H, (C 1 -C 8 )-alkyl, (C 2 -C 6 )-alkenyl, (C 0 -C 8 )-alkylene-aryl;

R82, R83 nezavisno jedan od drugog, H, (d-C6)-alkil; R82, R83 independently of each other, H, (C6)-alkyl;

ili or

R82 i R83 R82 and R83

najpovoljnije zajedno sa azotovim atomom za koji su vezani, jedan 5 -6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(d-Ce)-alkil, kiseonika i sumpora i može, napovoljnije, da bude supstituisan sa 1 - 2 okso grupe; most advantageously together with the nitrogen atom to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, may also contain 0-1 further hetero-atoms from the group N-(d-Ce)-alkyl, oxygen and sulfur and may, more favorably, be substituted with 1-2 oxo groups;

R3 H, (Ci-C6)-alkil; R3 H, (C1-C6)-alkyl;

R4, R5 nezavisno jedan od drugog, H, (d-C6)-alkil, OH, R4, R5 independently of each other, H, (d-C6)-alkyl, OH,

0-(CrC6)-alkil, 0-CO(CrC6)-alkil, S-(d-C6)-alkil; O-(C 1 -C 6 )-alkyl, O-CO(C 1 -C 6 )-alkyl, S-(d -C 6 )-alkyl;

R6, R7, R8, R9 R6, R7, R8, R9

nezavisno jedan od drugog, H, (d-C8)-alkil; independently of each other, H, (C 8 )-alkyl;

ili or

R6 i R7, R8 i R9 R6 and R7, R8 and R9

nezavisno jedan od drugog, najpovoljnije okso; independently of each other, most advantageously oxo;

n, m nezavisno jedan od drugog, 0, 1, 2; n, m independent of each other, 0, 1, 2;

A, B, D, G nezavisno jedan od drugog, N, C(R42); A, B, D, G independently of each other, N, C(R42);

ili or

grupe A i B ili grupe D i G su svaka C(R42) i zajedno grade jedan 5 - 6-to člani karbociklični ili heterciklični radikal da bi sve u svemu dali jedan biciklični sistem; groups A and B or groups D and G are each C(R42) and together they form a 5 - 6-membered carbocyclic or hetercyclic radical to give a single bicyclic system;

R42 H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(CrC6)-alkil, 0-(Ci-C4)-alkoksi-(CrC4)-alkil, S-(Ci-C6)-alkil, (CrC6)-aikil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (C0-C8)-alkilen-aril, O-(C0-C8)-alkilen-aril, S-aril, N(R43)(R44), S02-CH3, COOH, COO-(CrC6)-alkil, CON(R45)(R46), N(R47)CO(R48), R42 H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(CrC6)-alkyl, 0-(Ci-C4)-Alkoxy-(CrC4)-alkyl, S-(Ci-C6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O-(C0-C8)-alkylene-aryl, S-aryl, N(R43)(R44), S02-CH3, COOH, COO-(CrC6)-alkyl, CON(R45)(R46), N(R47)CO(R48),

N(R49)SO2(R50), CO(R51), -(CR84R85)X-0(R86); N(R49)SO2(R50), CO(R51), -(CR84R85)X-0(R86);

R43, R44, R45, R46, R47, R49 R43, R44, R45, R46, R47, R49

nezavisno jedan od drugog, H, (d-C8)-alkil; ili independently of each other, H, (C 8 )-alkyl; or

R43 i R44, R45 i R46 R43 and R44, R45 and R46

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(CrC6)-alkil, kiseonik i sumpor; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(CrC6)-alkyl, oxygen and sulfur;

R48, R50, R51 R48, R50, R51

nezavisno jedan od drugog, H, (Ci-C8)-alkil, aril; independently of each other, H, (C 1 -C 8 )-alkyl, aryl;

R84, R85 nezavisno jedan od drugog, H, (d-C8)-alkil; R84, R85 independently of each other, H, (C8)-alkyl;

R86 H, (Ci-C6)-alkil, aril; R86 H, (C1-C6)-alkyl, aryl;

x 1,2,3,4,5,6; x 1,2,3,4,5,6;

R10 H, (CrC8)-alkil, (C3-C6)-alkenil, (C3-C6)-alkinil; R 10 H, (C 1 -C 8 )-alkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl;

X N(R52), O, jedna veza, C=C, C(R53)(R54), X N(R52), O, single bond, C=C, C(R53)(R54),

C(R55)(R56)0, CO, C^C, jednu grupu formule - C(R55)(R56)0, CO, C^C, one group of the formula -

(CR87R88)Y- u kojoj jedna ili više -(CR87R88)- grupa (CR87R88)Y- in which one or more -(CR87R88)- groups

može da bude zamenjena sa Y da bi se dobio hemijski prihvatljivi radikal; may be replaced by Y to give a chemically acceptable radical;

Z O, S, N(R89); Z O, S, N(R89);

R52, R53, R54, R55, R56 R52, R53, R54, R55, R56

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R87, R88 nezavisno jedan od drugog, H, (C1-C4)-alkil, pri čemu R87 i R88 u y grupi mogu u svakom slučaju da imaju isto ili različito značenje; R87, R88 independently of each other, H, (C1-C4)-alkyl, whereby R87 and R88 in the y group can in any case have the same or different meaning;

y 2, 3, 4, 5, 6; and 2, 3, 4, 5, 6;

R89 H, (CrC8)-alkil; R89 H, (C1-C8)-alkyl;

E 3 - 14-to članu bivalentnu karbo- ili heterocikličnu strukturu prstena sa 0 - 4 hetero-atoma iz grupe N, O i S, koja najpovoljnije može da ima supstituente iz grupe H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, okso, O-(CrC6)-alkil, 0-(C1-C4)-alkoksi-(Ci-C4)-alkil, S-(CrC6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, O-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (C0-C8)-alkilen-aril, O-(C0-C8)-alkilen-aril, S-aril, N(R57)(R58), S02-CH3, COOH, COO-(CrC6)-alkil, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) i može biti mono- ili biciklična; E 3 - 14-membered bivalent carbo- or heterocyclic ring structure with 0 - 4 hetero-atoms from the group N, O and S, which most advantageously can have substituents from the group H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O-(CrC6)-alkyl, 0-(C1-C4)-Alkoxy-(Ci-C4)-alkyl, S-(CrC6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O-(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, COOH, COO-(CrC6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic;

R57, R58, R59, R60, R61, R63 R57, R58, R59, R60, R61, R63

nezavisno jedan od drugog, H, (CrC8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

ili or

R57 i R58, R59 i R60 R57 and R58, R59 and R60

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(C-i-C6)-alkil, kiseonik i sumpor; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(C-i-C6)-alkyl, oxygen and sulfur;

R62, R64, R65 R62, R64, R65

nezavisno jedan og drugog H, (CrC8)-alkil, aril; independently of each other H, (C 1 -C 8 )-alkyl, aryl;

K jednu vezu, O, OCH2, CH20, S, SO, S02, N(R66), K single bond, O, OCH2, CH20, S, SO, SO2, N(R66),

N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, jednu grupu formule -(CR90R91)Z- u kojoj jedan ili više - N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, one group of the formula -(CR90R91)Z- in which one or more -

(CR90R91)- grupa može da se zameni sa Z da bi se dobio neki hemijski prihvatljivi radikal; (CR90R91)- group can be replaced by Z to obtain some chemically acceptable radical;

v 1,2,3,4 v 1,2,3,4

R66, R67, R68, R69, R70 R66, R67, R68, R69, R70

nezavisno jedan od drugog, H, (d-C8)-alkil; independently of each other, H, (C 8 )-alkyl;

Z O, S, N(R92), CO, SO, S02; Z O, S, N(R92), CO, SO, SO2;

R90, R91 nezavisno jedan od drugog, H, (d-C8)-alkil, hidroksi-(d-C4)-alkil, hidroksi, (Ci-C4)-alkoksi-(Ci-C4)-alkil, pri čemu R90 i R91 u z grupi mogu u svakom slučaju da imaju ista i različita značenja; R90, R91 independently of each other, H, (d-C8)-alkyl, hydroxy-(d-C4)-alkyl, hydroxy, (C1-C4)-alkoxy-(C1-C4)-alkyl, wherein R90 and R91 in the z group can in any case have the same or different meanings;

z 2, 3, 4, 5, 6; with 2, 3, 4, 5, 6;

R92 H, (d-Ca)-alkil; R92 H, (C1-C8)-alkyl;

R11 H, (CrC8)-alkil, (d-C4)-alkoksi-(d-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi-ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno R11 H, (C1C8)-alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may contain 0 to 4 hetero-atoms selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may be additionally

supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, O-(d-C8)-alkil, (d-C4)-alkoksi-(d-C4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, hidroksi-(CrC4)-alkil, COO(R74), N(R75)CO(d-C6)-alkil, substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, O-(d-C8)-alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy-(CrC4)-alkyl, CO(R74), N(R75)CO(d-C6)-alkyl,

N(R76)(R77) ili S02CH3, SCF3; N(R76)(R77) or SO2CH3, SCF3;

R71, R72, R73, R74, R75, R76, R77 R71, R72, R73, R74, R75, R76, R77

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

ili or

R72 i R73, R76 i R77 R72 and R73, R76 and R77

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(d-C6)-alkil, kiseonika i sumpora; ili independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(d-C6)-alkyl, oxygen and sulphur; or

E, K i R11 zajedno grade jedan triciklični sistem u kome prsteni mogu, nezavisno jedan od drugog, [lacuna] da budu zasićeni, delimično zasićeni ili nezasićeni i svaki može da sadrži 3-8 atoma u prstenu; E, K and R 11 together form a tricyclic system in which the rings may, independently of each other, [lacuna] be saturated, partially saturated or unsaturated and each may contain 3-8 ring atoms;

i njihovi N-oksidi i njihove fiziološki prihvatlčjive soli. and their N-oxides and their physiologically acceptable salts.

R1, R2 nezavisno jedan od drugog, H, (CrC8)-alkil, -(CH2)0-R12, R1, R2 independently of each other, H, (C1C8)-alkyl, -(CH2)O-R12,

(d-C4)-alkoksi-(Ci-C4)-alkil, aril-oksi-(d-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, CO-(d-C8)-alkil, -CO-(CH2)0-R12, (d-C4)-Alkoxy-(C1-C4)-Alkyl, Aryl-Oxy-(d-C4)-Alkyl, (C3-C8)-Alkenyl, (C3-C8)-Alkynyl, CO-(d-C8)-Alkyl, -CO-(CH2)0-R12,

CO-aril-oksi-(Ci-C4)-alkil, CO-(C2-C8)-alkenil, CO-(C2-C8)-alkinil, C0CH=CH(R13), C0CC(R14), CO-(CrC4)-alkil-S(0)p-(CrC4)-alkil, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa atomom azota sa kojim su vezani neki 4 do 10-to člani mono-, bi- ili spiro-ciklični prsten koji, osim od azotovog atoma, može da sadrži 0 do 4 dodata hetero-atoma uzetih iz grupe kiseonika, azota i sumpora, pri čemu heterociklični prsten može biti dodatno supstituisan sa CO-aryl-oxy-(Ci-C4)-alkyl, CO-(C2-C8)-alkenyl, CO-(C2-C8)-alkynyl, C0CH=CH(R13), C0CC(R14), CO-(CrC4)-alkyl-S(0)p-(CrC4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which some 4 to 10-membered mono-, bi- or spiro-cyclic ring is attached which, apart from the nitrogen atom, may contain 0 to 4 additional hetero-atoms taken from the group of oxygen, nitrogen and sulfur, wherein the heterocyclic ring may be additionally substituted with

F, Cl, Br, CF3, N02, CN, (Ci-Ce)-alkil, 0-(CrC8)-alkil, (d-C4)-alkoksi-(CrC4)-alkil, (Co-C8)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(CrC6)-alkil, N(R31)(R32) ili S02CH3; F, Cl, Br, CF3, NO2, CN, (Ci-Ce)-alkyl, O-(CrC8)-alkyl, (d-C4)-Alkoxy-(CrC4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(CrC6)-alkyl, N(R31)(R32). or SO 2 CH 3 ;

o 0,1,2,3,4,5,6; about 0,1,2,3,4,5,6;

P 0,1,2 P 0,1,2

q, r, s nezavisno jedan od drugog 0, 1, 2, 3, 4; q, r, s independently of each other 0, 1, 2, 3, 4;

R13, R14 nezavisno jedan od drugog, jedan 5 do 10-to člani aromatski sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa R13, R14 independently of each other, a 5- to 10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with

F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil; F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O-(C1-C8)-alkyl;

R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32

nezavisni jedan od drugog H, (Ci-C6)-alkil; independent of each other H, (C 1 -C 6 )-alkyl;

R18 H, (CrC6)-alkil, CO(CrC6)-alkil, CO(R33); R18 H, (C1C6)-alkyl, CO(C1C6)-alkyl, CO(R33);

R17 i R18, R21 i R22, R27 i R28, R31 i R32 R17 and R18, R21 and R22, R27 and R28, R31 and R32

nezavisno jedan od drugog, najpovoljnije zajedno sa atomom azota za koji su vezani, jedan 5 - 6-to člani prsten koji osim azotovog atoma može da sadrži 0 - 1 od drugih hetero-atoma iz grupe N-(Ci-C6)-alkil, kiseonik i sumpor. independently of each other, most advantageously together with the nitrogen atom to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, may contain 0-1 of other hetero-atoms from the group N-(Ci-C6)-alkyl, oxygen and sulfur.

R33 jedan 5 -10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, R33 is a 5-10 membered aromatic ring system which may contain 0-2 further hetero-atoms from the nitrogen group,

kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(Ci-C8)-alkil, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, O-(Ci-C8)-alkyl,

R12 OH, 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S i 3 - 12-to člani prsten može da sadrži dalje supstituente kao što su F, Cl, Br, I, OH, CF3, N02, CN, OCF3, okso, 0-(CrC6)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(C1-C6)-alkil, (CrC6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-ciklo alkenil, 0-(C3-C8)-ciklo alkenil, (C2-C6)-alkinil, O-(C0-C8)-alkilen-aril, N(R34)(R35), R12 OH, a 3-12-membered mono-, bi- or spirocyclic ring which may contain one or more hetero-atoms from the group N, O and S and the 3-12-membered ring may contain further substituents such as F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, 0-(CrC6)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, S-(C1-C6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cyclo alkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C8)-cycloalkyl, O-(C0-C8)-alkylene-aryl, N(R34)(R35),

COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(CrC6)-alkil, COCOO(CrC6)-alkil, COO(R40), S(0)U(R41) i COOH; COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1C6)-alkyl, COCOO(C1C6)-alkyl, COO(R40), S(O)U(R41) and COOH;

t 0,1,2,3,4,5,6; t 0,1,2,3,4,5,6;

u 0,1,2; in 0,1,2;

R34, R35, R37, R38 R34, R35, R37, R38

nezavisno jedan od drugog, H, (C1-C8)-alkil; independently of each other, H, (C1-C8)-alkyl;

R34 and R35 R34 and R35

najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(CrC6)-alkil, kiseonika i sumpora i može da bude, najpovoljnije, supstituisan sa 1 - 2 okso-grupe; most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(CrC6)-alkyl, oxygen and sulfur and can be, most advantageously, substituted with 1 - 2 oxo-groups;

R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(CrC8)-alkil; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5-10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, 0-(CrC8)-alkyl;

R40 H, (CrC8)-alkil, (C2-C6)-alkenil, (C0-C8)-alkilen-aril; R 40 H, (C 1 -C 8 )-alkyl, (C 2 -C 6 )-alkenyl, (C 0 -C 8 )-alkylene-aryl;

R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (d-Cej-alkil, 0-(CrC8)-alkil; R41 (Ci-C6)-alkyl, 5-10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (d-C6-alkyl, O-(CrC8)-alkyl;

R3 H, (CrC6)-alkil; R3 H, (C1-C6)-alkyl;

R4, R5 nezavisno jedan od drugog, H, (Ci-C6)-alkil, OH, R4, R5 independently of each other, H, (Ci-C6)-alkyl, OH,

0-(CrC6)-alkil, 0-CO(Ci-C6)-alkil, S-(CrC6)-alkil; O-(C1-C6)-alkyl, O-CO(C1-C6)-alkyl, S-(C1-C6)-alkyl;

R6, R7, R8, R9 R6, R7, R8, R9

nezavisno jedan od drugog, H, (CrC8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R6 i R7, R8 i R9 R6 and R7, R8 and R9

nezavisno jedan od drugog, najpovoljnije okso; independently of each other, most advantageously oxo;

n, m nezavisno jedan od drugog, 0, 1, 2; n, m independent of each other, 0, 1, 2;

A, B, D, G nezavisno jedan od drugog, N, C(R42); A, B, D, G independently of each other, N, C(R42);

R42 H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(CrC6)-alkil, O-(d-C^-alkoksi-CCrC^-alkil, S-(CrC6)-alkil, (C1-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-ciklo alkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (C0-C8)-alkilen-aril, O-(C0-C8)-alkilen-aril, S-aril, N(R43)(R44), S02-CH3, COOH, COO-(CrC6)-alkil, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) R42 H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(CrC6)-alkyl, O-(d-C^-Alkoxy-CCrC^-alkyl, S-(CrC6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl. (C3-C8)-cyclo alkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O-(C0-C8)-alkylene-aryl, S-aryl, N(R43)(R44), S02-CH3, COOH, COO-(CrC6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51)

R43, R44, R45, R46, R47, R49 R43, R44, R45, R46, R47, R49

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R43 i R44, R45 i R46 R43 and R44, R45 and R46

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-Ce)-alkil, kiseonika i sumpora; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-Ce)-alkyl, oxygen and sulphur;

R48, R50, R51 R48, R50, R51

nezavisno jedan od drugog, H, (CrC8)-alkil, aril; independently of each other, H, (C 1 -C 8 )-alkyl, aryl;

R10 H, (Ci-C8)-alkil, (C3-C6)-alkenil, (C3-C6)-alkinil; R 10 H, (C 1 -C 8 )-alkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl;

X N(R52), O, jedna veza, C=C, C(R53)(R54), C(R55)(R56)0; X N(R52), O, single bond, C=C, C(R53)(R54), C(R55)(R56)0;

R52, R53, R54, R55, R56 R52, R53, R54, R55, R56

nazavisno jedan od drugog H, (CrC8)-alkil; independently of each other H, (C 1 -C 8 )-alkyl;

E 3 - 8-mo člani bivalentni karbo- ili heterocikličnu strukturu prstena sa 0 - 4 hetero-atoma iz grupe N, O i S, koji mogu, najpovoljnije, da imaju supstituente iz grupe H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(CrC6)-alkil, 0-(CrC4)-alkoksi-(Ci-C4)-alkil, S-(CrC6)-alkil, (d-C^-alki!, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (C0-C8)-alkilen-aril, O-(C0-C8)-alkilen-aril, S-aril, N(R57)(R58), S02-CH3, COOH, COO-Cd^-alkil, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) i mogu biti mono- ili biciklični; E 3 - 8-membered bivalent carbo- or heterocyclic ring structure with 0 - 4 hetero-atoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(CrC6)-alkyl, 0-(CrC4)-Alkoxy-(Ci-C4)-alkyl, S-(CrC6)-alkyl, (d-C^-alkyl!, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O-(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, COOH, COO-Cd^-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic;

R57, R58, R59, R60, R61, R63 R57, R58, R59, R60, R61, R63

nezavisno jedan od drugog, H, (d-C8)-alkil; independently of each other, H, (C 8 )-alkyl;

R57 i R58, R59 i R60 R57 and R58, R59 and R60

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(C-i-C6)-alkil, kiseonika i sumpora; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(C-i-C6)-alkyl, oxygen and sulphur;

R62, R64, R65 R62, R64, R65

nezavisno jedan od drugog, H, (Ci-Ca)-alkil, aril; independently of each other, H, (C1-C6)-alkyl, aryl;

K jednu vezu, O, OCH2, CH20, S, SO, S02, N(R66), K single bond, O, OCH2, CH20, S, SO, SO2, N(R66),

N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C; N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C;

v 1,2,3,4; v 1,2,3,4;

R66, R67, R68, R69, R70 R66, R67, R68, R69, R70

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R11 H, (d-C8)-alkil, (CrC4)-alkoksi-(CrC4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, jedan 3- 12-to člani mono-, bi- ili spiro-ciklični prsten koji može da sadrži 0 do 4 hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(CrC8)-alkil, (d-C^-alkoksHCrC^-alkil, (C0-C8)-alkilen-aril, okso, R11 H, (d-C8)-alkyl, (CrC4)-Alkoxy-(CrC4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3- to 12-membered mono-, bi- or spiro-cyclic ring which may contain 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may be additionally substituted with F, Cl, Br, CF3, NO2, CN, (C1C6)-alkyl, O-(C1C8)-alkyl, (d-C4-AlkoxyHCrC4-alkyl, (C0-C8)-alkylene-aryl, oxo,

CO(R71), CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(CrC6)-alkil, N(R76)(R77) ili S02CH3; CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1C6)-alkyl, N(R76)(R77) or SO2CH3;

R71, R72, R73, R74, R75, R76, R77 R71, R72, R73, R74, R75, R76, R77

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R72 i R73, R76 i R77 R72 and R73, R76 and R77

nezavisno jedan od drugog, najpovoljnije zajedno sa atomom azota za koji su vezani, jedan prsten sa 5 do 6 članova koji, osim atoma azota, može da ima još i 0 - 1 drugih hetero-atoma iz grupe N-(Ci-C6)-alkil, kiseonik i sumpor; ili independently of each other, preferably together with the nitrogen atom to which they are attached, one ring with 5 to 6 members which, in addition to the nitrogen atom, can also have 0 - 1 other heteroatoms from the group N-(Ci-C6)-alkyl, oxygen and sulfur; or

E, K i R11 E, K and R11

zajedno grade jedan triciklični sistem prstena, pri čemu prsteni mogu da budu nezavisni jedan od drugog [lacuna] zasićeni, delimično zasićeni ili nezasićeni i svaki može da sadrži 3-8 atoma u prstenu; together they form a tricyclic ring system, where the rings can be independent of each other [lacuna] saturated, partially saturated or unsaturated and each can contain 3-8 ring atoms;

i njihove fiziološki prihvatljive soli. and their physiologically acceptable salts.

Pronalazak se odnosi na jedinjenja formule I u obliku njihovih racemata, smeša obogaćenih enantiomerom i čistih enantiomera i na njihove diastereoizomere i njihove smeše. The invention relates to compounds of formula I in the form of their racemates, enantiomer-enriched mixtures and pure enantiomers and to their diastereoisomers and mixtures thereof.

alkil, alkenil i alkinil radikali u supstituentima R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92 i R93 mogu da budu ili sa normalnim ili sa razgranatim nizom ili, najpovoljnnije, halogenovani. alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R 89 , R 90 , R 91 , R 92 and R 93 may be either straight or branched or, most preferably, halogenated.

Izraz "aril" znači pre svega fenil- ili naftil-grupu. The term "aryl" means primarily a phenyl or naphthyl group.

Jedan "triciklični sistem" predstavlja strukture koje imaju 3 prstena koji su povezani zajedno sa više nego jednom vezom. Primeri takvih sistema su kondezovani sistemi sa 3 prstena i spirocikli sa kondenzovanim sistemom prstena. A "tricyclic system" represents structures that have 3 rings joined together by more than one bond. Examples of such systems are 3-ring fused systems and fused ring system spirocycles.

U slučaju kada R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan prsten, taj prsten može da bude supstituisan sa jednim ili više od pomenutih supstituenata. In the case when R1 and R2 together with the nitrogen atom, to which they are attached, form one ring, that ring can be substituted with one or more of the mentioned substituents.

Bivalentna struktura E karbo- ili heterocikličnog prstena uključuje strukture koje su povezane sa jednim i to istim atomom za dve susedne grupe K i X. Framaceutski prihvatljive soli su zbog njihove veće rastvorljivosti u vodi, u odnosu na polazna ili osnovna jedinjenja, posebno pogodna za medicinske primene. The bivalent structure E of the carbo- or heterocyclic ring includes structures that are connected to one and the same atom for two adjacent groups K and X. Pharmaceutically acceptable salts are, due to their greater solubility in water, compared to the starting or basic compounds, particularly suitable for medical applications.

Ove soli moraju da imaju farmaceutski prihvatljiv anjon ili katjon. Pogodne farmaceutski prihvatljive adicione soli kiselina jedinjenja prema pronalasku su soli neorganskih kiselina kao što su hlorovodonična kiselina, bromovodonična, fosforna, metafosforna, azotna sulfonska i sumporna kiselina i organske kiseline, kao što su, na primer, sirćetna kiselina, benzo-sulfonska, benzoeva, limunska, etan-sulfonska, fumarna, glukonska, glikolna, izetionska, mlečna, laktobionska, maleinska, malinska, metan-sulfonska, ćilibarna, p-toluol-sulfonska, vinska i trifluor-sirćetna kiselina. U medicinske svrhe naročito se pretpostavlja hlorna so. Pogodne farmaceutski prihvatljive bazne soli su amonijumove soli, soli alkalnih metala (takve kao što su soli natrijuma i kalijuma), soli zemno-alkalnih metala (takve kao što su soli magnezijuma i kalcijuma). These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric sulphonic and sulfuric acids and organic acids such as, for example, acetic, benzosulphonic, benzoic, citric, ethanesulphonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malinic, methanesulphonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. Chlorine salt is especially assumed for medicinal purposes. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts).

Soli sa farmaceutski neprihvatljivim anjonom spadaju, isto tako, u okvir pronalaska, kao korisni intermedijari za spravljanje ili prečišćavanje faramceutski prihvatljivih soli i / ili za upotrebu u neterapeutske, na primer, in vitro svrhe. Salts with a pharmaceutically unacceptable anion also fall within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro purposes.

Izraz "fiziološki funkcionalni derivati" upotrebljen ovde odnosi se na svaki fiziološki prihvatljivi derivat nekog jedinjenja, prema pronalasku, formule I, na primer nekog estra koji je prilikom davanja nekom sisaru, kao što je , na primer, čovek sposoban da nagradi (direktno ili indirektno) neko jedinjenje formule I ili neki njegov aktivni metabolit. The term "physiologically functional derivatives" used here refers to any physiologically acceptable derivative of a compound, according to the invention, of formula I, for example an ester which, when administered to a mammal, such as, for example, a human, is capable of rewarding (directly or indirectly) a compound of formula I or an active metabolite thereof.

Fiziološki funkcionalni derivati uključuju prolekove jedinjenja prema pronalasku. Takvi prolekovi mogu da metaboliziraju in vivo u jedinjenje prema pronalasku. Ovi prolekovi mogu, a ne moraju i sami da budu aktivni. Physiologically functional derivatives include prodrugs of the compounds of the invention. Such prodrugs may metabolize in vivo to a compound of the invention. These prodrugs may or may not be active themselves.

Jedinjenja prema pronalsku mogu da postoje i u raznim polimorfnim oblicima, na primer, kao amorfni i kristalni polimorfni oblici. Svi polimorfni oblici jedinjenja prema pronalasku spadaju u okvir pronalaska i oni su jedan dalji aspekt pronalaska. Compounds according to Pronalsk can also exist in various polymorphic forms, for example, as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention fall within the scope of the invention and are a further aspect of the invention.

Sve reference u vezi jedinjenja "compound(s) of formula (I)", ovde i nadalje, odnose se na jedinjenja formule I, kako je ranije opisano i na njihove soli, solvate i fiziološki funkcionalne derivate, kako je ovde opisano. All references to "compound(s) of formula (I)", herein and hereinafter, refer to compounds of formula I, as previously described, and their salts, solvates, and physiologically functional derivatives, as described herein.

Ako radikali ili supstituenti mogu da se pojave u jedinjenjima formule I više nego jedanput, oni svi mogu da imaju, nezavisno jedan od drugog, značenja koja se ovde tvrde i mogu da budu identični ili različiti. If radicals or substituents may appear in compounds of formula I more than once, they may all have, independently of one another, the meanings claimed herein and may be identical or different.

U jednoj naročito pretpostavljenoj celini sadašnji pronalazak se odnosi na jedinjenja formule I u kojima oznake znače: R1, R2 nezavisno jedan od drugog, H, (Ct-C8)-alkil, -(CH2)0 -R12, In one particularly assumed aspect, the present invention relates to compounds of formula I in which the designations mean: R1, R2 independently of each other, H, (Ct-C8)-alkyl, -(CH2)0 -R12,

(C1-C4)-alkoksi-(Ci-C4)-alkil, CO-(Ci-C8)-alkil, -CO-(CH2)0- R12, COCH=CH(R13), COCC(R14), CO-(CrC4)-alkil-S(0)p-(CrC4)-alkil, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može da bude dodatno supstituisan sa F, (Ci-C6)-alkil, 0-(CrC8)-alkil, (C0-C8)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(CrC6)-alkil, N(R31)(R32) ili S02CH3, pri čemu se pretpostavlja da R1 i R2 nisu oba H (C1-C4)-Alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0- R12, COCH=CH(R13), COCC(R14), CO-(CrC4)-alkyl-S(0)p-(CrC4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 together with the nitrogen atom, to which they are attached, form a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system may be additionally substituted with F, (Ci-C6)-alkyl, O-(CrC8)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1C6)-alkyl, N(R31)(R32) or SO2CH3, wherein R1 and R2 are assumed not to be both H

i, dalje se pretpostavlja, da R1 i R2, zajedno sa azotovim atomom, nisu radikal morfolina; and, it is further assumed that R1 and R2, together with the nitrogen atom, are not a morpholine radical;

o 0,1,2,3,4; about 0,1,2,3,4;

P 0,1,2; P 0,1,2;

q, r, s nezavisno jedan od drugog, 0, 1,2, 3, da su po mogućnosti q, s nezavisno jedan od drugog, 1, 2, 3, a r je 0, 1, 2, 3; q, r, s independent of each other, 0, 1,2, 3, that preferably q, s are independent of each other, 1, 2, 3, and r is 0, 1, 2, 3;

R13, R14 nezavisno jedan od drugog, jedan 5 do 10-to člani aromatski sistem prstena koji može da sadrži jedan dalji hetero-atom iz grupe azota, kiseonika i sumpora i može biti supstituisan sa R13, R14 independently of each other, a 5 to 10-membered aromatic ring system which may contain one further hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with

F, Cl, (CrCej-alkil, 0-(CrC8)-alkil; F, Cl, (C1C6-alkyl, O-(C1C8)-alkyl;

R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32

nezavisno jedan od drugog, H, (CrC6)-alkil; independently of each other, H, (C 1 -C 6 )-alkyl;

R18 H, (CrC6)-alkil, CO(Ci-C6)-alkil, CO(R33); R18 H, (C1C6)-alkyl, CO(C1-C6)-alkyl, CO(R33);

R17 i R18, R21 i R22, R27 i R28, R31 i R32 R17 and R18, R21 and R22, R27 and R28, R31 and R32

nezavisno jedan od drugog,, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(CrC6)-alkil, kiseonika i sumpora. independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(CrC6)-alkyl, oxygen and sulfur.

R33 jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži jedan dalji hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (CrC6)-alkil, 0-(CrC8)-alkil; R33 is a 5- to 10-membered aromatic ring system which may contain one further hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (CrC6)-alkyl, O-(CrC8)-alkyl;

R12 OH, 3 - 12-to člani-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupa N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente kao što su F, Cl, CF3, CN, okso, 0-(CrC6)-alkil, (Ci-C6)-alkil, O-(C0-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38)),(R39), CO(CrC6)-alkil, COCOO(Ci-C6)-alkil, COO(R40) i S(0)U(R41), pri čemu u jednoj pretpostavljenoj celini supstituent 0-(CrC6)-alkil je isključen u slučaju da je 3 -12-to člani prsten fenil; R12 OH, a 3-12-membered, bi- or spirocyclic ring which may contain one or more hetero-atoms from the groups N, O and S, and the 3-12-membered ring may contain further substituents such as F, Cl, CF3, CN, oxo, 0-(CrC6)-alkyl, (Ci-C6)-alkyl, O-(C0-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38)),(R39), CO(CrC6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40) and S(0)U(R41), whereby in one assumed unit the substituent 0-(CrC6)-alkyl is excluded in the case that there are 3 - 12 members phenyl ring;

t 0,1,2,3,4; t 0,1,2,3,4;

u 0,1,2; in 0,1,2;

R34, R35, R37, R38 R34, R35, R37, R38

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R34 i R35 R34 and R35

najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonik i sumpor i može, najpovoljnije, da bude supstituisan sa 1 - 2 oksi-grupe; most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur and can, most advantageously, be substituted with 1 - 2 oxy-groups;

R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži jedan dalji hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (CrC6)-alkil, 0-(Cr R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5 - 10-membered aromatic ring system which may contain one further hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (CrC6)-alkyl, 0-(Cr

C8)-alkil; C8-alkyl;

R40 H, (CrC8)-alkil, (C2-C6)-alkenil, (C0-C8)-alkilen-aril; R 40 H, (C 1 -C 8 )-alkyl, (C 2 -C 6 )-alkenyl, (C 0 -C 8 )-alkylene-aryl;

R41 (CrC6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i koji može da bude supstituisan sa F, Cl, (Ci-Ce)-alkil, 0-(Ci-C8)-alkil; R41 (CrC6)-alkyl, 5-10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and which may be substituted with F, Cl, (Ci-Ce)-alkyl, O-(Ci-C8)-alkyl;

R3 H, (CrCe)-alkil; R3 H, (C1-C6)-alkyl;

R4, R5 nezavisno jedan od drugog, H, (Ci-Ce)-alkil, OH, R4, R5 independently of each other, H, (Ci-Ce)-alkyl, OH,

0-(CrC6)-alkil, O-COfC-rCeJ-alkil; O-(C1C6)-alkyl, O-COfC-1C6-alkyl;

R6, R7, R8, R9 R6, R7, R8, R9

nezavisno jedan od drugog, H, (CrC8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R6 i R7, R8 i R9 R6 and R7, R8 and R9

nezavisno jedan od drugog,, najpovoljnije okso; independently of each other, the most favorable oxo;

n, m nezavisno jedan od drugog, 0, 1,2, po mogućstvu m je 0, n, m independently of each other, 0, 1,2, preferably m is 0,

1, 2 i nje 1; 1, 2 and n 1;

A, B, D, G nezavisni jedan od drugog N, C(R42); A, B, D, G independent of each other N, C(R42);

R42 je H, F, Cl, Br, CF3, CN, 0-{ C^ C6)- alW\\, (Ci-C6)-alkil, (C3- R42 is H, F, Cl, Br, CF3, CN, O-{C1-C6)-AlW\\, (C1-C6)-alkyl, (C3-

C8)-cikloalkil, (C0-C2)-alkilen-aril, O-(C0 - C2)-alkilen-aril, N(R43)(R44), S02-CH3, COO-(Ci-C5)-alkil, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) C8)-cycloalkyl, (C0-C2)-alkylene-aryl, O-(C0 - C2)-alkylene-aryl, N(R43)(R44), SO2-CH3, COO-(Ci-C5)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51)

R43, R44, R45, R46, R47, R49 nezavisno jedan od drugog, H, (Ci-C8)-alkil; R43, R44, R45, R46, R47, R49 independently of each other, H, (C1-C8)-alkyl;

R43 j R44, R45 i R46 R43 and R44, R45 and R46

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulphur;

R48, R50, R51 R48, R50, R51

nezavisnoi jedan od drugog H, (Ci-C8)-alkil, aril; independently of each other H, (C 1 -C 8 )-alkyl, aryl;

R10 H, (CrC8)-alkil; R10 H, (C1-C8)-alkyl;

X N(R52), O, jedna veza, C=C, C(R53)(R54), C(R55)(R56)0; X N(R52), O, single bond, C=C, C(R53)(R54), C(R55)(R56)0;

R52, R53, R54, R55, R56 R52, R53, R54, R55, R56

nezavisno jedan od drugog, H, (Ci-C8)-alkil independently of each other, H, (C 1 -C 8 )-alkyl

E 3 - 8-mo člani bivalentni karbo- ili heterociklični sistem prstena sa 0 - 4 hetero-atoma iz grupe N, O i S, koji mogu, najpovoljnije, da imaju susptituente iz grupe H, F, Cl, CF3, N02, OH, CN, 0-(CrC6)-alkil, (CrC6)-alkil, (C0-C8)-alkilen-aril, O-(C0 - C8)-alkilen-aril, N(R57)(R58), S02-CH3, COO-(Ci-C6)-alkil, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) i mogu biti mono- ili biciklični, po mogućstvu grupa E nema supstituenta iz grupe (C0-C8)-alkilen-aril, O-(C0-C8)-alkilen-aril i N(R57)(R58), u kojoj R57 i R58 grade zajedno sa azotovim atomom jedan 5-6-to član prsten u orto - položaju u odnosu na mesto vezivanja X; naročito se pretpostavlja da je E monociklično; E 3 - 8-member bivalent carbo- or heterocyclic ring system with 0 - 4 hetero-atoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, CF3, NO2, OH, CN, 0-(CrC6)-alkyl, (CrC6)-alkyl, (C0-C8)-alkylene-aryl, O-(C0 - C8)-alkylene-aryl, N(R57)(R58), SO2-CH3, COO-(Ci-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and can be mono- or bicyclic, preferably group E has no substituent from the group (C0-C8)-alkylene-aryl, O-(C0-C8)-alkylene-aryl and N(R57)(R58), in which R57 and R58 build together with the nitrogen atom a 5-6-membered ring in the ortho - position in relation to the binding site of X; in particular, E is assumed to be monocyclic;

R57, R58, R59, R60, R61, R63 R57, R58, R59, R60, R61, R63

nezavisno jedan od drugog, H, (CrC8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R57 i R58, R59 i R60 R57 and R58, R59 and R60

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom za koji su vezani jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(CrC6)-alkil, kiseonik i independently of each other, preferably together with a nitrogen atom to which a 5-6-membered ring is attached, which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(CrC6)-alkyl, oxygen and

sumpor, pri čemu po mogućnosti R59 i R60 nisu oboje H; sulfur, wherein preferably R59 and R60 are not both H;

R62, R64, R65 R62, R64, R65

nezavisno jedan od drugog, H, (CrC8)-alkil, aril; independently of each other, H, (C 1 -C 8 )-alkyl, aryl;

K jedna veza, O, CH20, N(R66), (C(R69)(R70))V, C=C, K single bond, O, CH20, N(R66), (C(R69)(R70))V, C=C,

OCH2, CON(R68), najbolje jedna veza, O, CH20, ((CR69)(R70))V, C<=>C, N(R66); OCH2, CON(R68), preferably one bond, O, CH20, ((CR69)(R70))V, C<=>C, N(R66);

v 1, 2; v 1, 2;

R66, R68, R69, R70 R66, R68, R69, R70

nezavisno jedan od drugog, H, (CrC8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R11 H, (CrC8)-alkil, (CrC^-alkoksKCrC^-alkil, (C3-C8)-alkenil, jedan 3 do 10-to-člani mono-, bi- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, N02, CN, (CrC6)-alkil, 0-(CrC8)-alkil, (CrC4)-alkoksi-(Ci-C4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(CrC6)-alkil, N(R76)(R77) ili S02CH3, a najbolje da R11 nije COO(R74); R11 H, (CrC8)-alkyl, (CrC3-AlkOxKCrC3-alkyl, (C3-C8)-alkenyl, one 3 to 10-membered mono-, bi- or spirocyclic ring which may contain 0 to 4 hetero-atoms selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may be additionally substituted with F, Cl, Br, CF3, NO2, CN, (CrC6)-alkyl, O-(CrC8)-alkyl, (CrC4)-Alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(CrC6)-alkyl, N(R76)(R77) or SO2CH3, and preferably R11 is not COO(R74);

R71, R72, R73, R74, R75, R76, R77 R71, R72, R73, R74, R75, R76, R77

nezavisno jedan od drugog, H, (CrC8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

R72 i R73, R76 i R77 R72 and R73, R76 and R77

nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group

N-(Ci-C6)-alkil, kiseonika i sumpora. N-(Ci-C6)-alkyl, oxygen and sulfur.

Naročito se pretpostavljaju jedinjenja formule I u kojima Compounds of formula I in which

A, B, D, G su nezavisno jedan od drugog, N ili C(R42), a ukupan broj A, B, D, G are independent of each other, N or C(R42), and the total no

azotovih atoma u ovom prstenu je 0 - 2, a najbolje 0 ili 1. of nitrogen atoms in this ring is 0 - 2, and preferably 0 or 1.

Posebno naročito se pretpostavljaju jedinjenja formule I u kojima Compounds of formula I in which

n je 1 i n is 1 and

m je 1 ili 2. m is 1 or 2.

Naročito se pretpostavljaju jedinjenja formula I u kojima Compounds of formula I in which

A, B, D, G su nezavisno jedan od drugog, N ili C(R42), a ukupan broj azotovih atoma u ovom prstenu je 0 - 2, a najbolje 0 ilu 1; A, B, D, G are independent of each other, N or C(R42), and the total number of nitrogen atoms in this ring is 0 - 2, preferably 0 or 1;

n je 1 i n is 1 and

m je 1 ili 2. m is 1 or 2.

U jednom daljem pretpostavljenom delu sadašnji pronalazak se odnosi na jedinjenja formule I u kojima oznake znače: R1, R2 nezavisno jedan od drugog, su H, (CrC8)-alkil, - (CR78R79)0 -R12, (Ci-C4)-alkoksi-(CrC4)-alkil, (C3-C8)-alken.il, CO-(d-C8)-alkil, -CO-(CH2)0-R12, CO-aril-oksi-(CrC4)-alkil, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21 )(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 - 10-to člani mono-, bi- ili spirociklični prsten koji, sem azotovog atoma, može da sadrži 0-2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može dodatno da bude supstituisan sa F, Cl, CF3, (Ci-C6)-alkil, 0-(CrC4)-alkil, (d-C4)-alkoksi-(d-C4)-alkil, hidroksi-(CrC4)-alkil, (C0-C2)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(CrC6)-alkil, N(R31)(R32) ili S02CH3; najbolje nezavisno jedan od drugog, H, (d-C8)-alkil, -(CR78R79)0 -R12, (Ci-C4)-alkoksi-(d-C4)-alkil, CO-(d-C8)-alkil, -CO-(CH2)0-R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono- ili biciklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može dodatno da bude supstituisan sa F, Cl, CF3, (CrC6)-alkil, 0-(Ci-C4)-alkil, (CrC4)-alkoksi-(d.C4)-alkil, In a further assumed part, the present invention relates to compounds of formula I in which the designations mean: R1, R2 independently of each other, are H, (CrC8)-alkyl, - (CR78R79)0 -R12, (C1-C4)-Alkoxy-(CrC4)-alkyl, (C3-C8)-alken.yl, CO-(d-C8)-alkyl, -CO-(CH2)0-R12, CO-aryl-oxy-(CrC4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21 )(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 build together with the nitrogen atom, to which they are attached, a 4-10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, can contain 0-2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring system can be additionally substituted with F, Cl, CF3, (Ci-C6)-alkyl, 0-(CrC4)-alkyl, (d-C4)-Alkoxy-(d-C4)-alkyl, hydroxy-(CrC4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(CrC6)-alkyl, N(R31)(R32) or SO2CH3; preferably independently of each other, H, (d-C8)-alkyl, -(CR78R79)0 -R12, (Ci-C4)-Alkoxy-(d-C4)-alkyl, CO-(d-C8)-alkyl, -CO-(CH2)0-R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))SO(R25); or R1 and R2 together with the nitrogen atom, to which they are attached, form a 4 to 10-membered mono- or bicyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring system may be additionally substituted with F, Cl, CF3, (CrC6)-alkyl, 0-(Ci-C4)-alkyl, (C1C4)-Alkoxy-(C1-C4)-Alkyl,

(C0-C2)-alkilen-aril, okso, CO(R26), hidroksi, N(R31)(R32) ili S02CH3; (C0-C2)-alkylene-aryl, oxo, CO(R26), hydroxy, N(R31)(R32) or SO2CH3;

naročito se pretpostavlja,nezavisno jedan od drugog, H, (CrC8)-alkil, -(CR78R79)0 -R12, (d-C^-alkoksKd^)-alkil, CO-(CrC8)-alkil, -CO-(CH2)0 -R12, CO(C(R15)(R16))qN(R17)(R18), ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono - ili biciklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika i azota, pri čemu heterociklični svstem prstena može da bude dodatno supstituisan sa F, (C1-C6)-alkil, (Ci-C4)-alkoksi-(CrC4)-alkil, okso, CO(R26), hidroksi, N(R31)(R32); in particular it is assumed, independently of each other, H, (CrC8)-alkyl, -(CR78R79)0 -R12, (d-C^-alkoxyKd^)-alkyl, CO-(CrC8)-alkyl, -CO-(CH2)0 -R12, CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form together with the nitrogen atom to which they are attached. 4 to 10-membered mono- or bicyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional hetero-atoms selected from the group of oxygen and nitrogen, whereby the heterocyclic ring system may be additionally substituted with F, (C1-C6)-alkyl, (Ci-C4)-alkoxy-(CrC4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32);

00, 1, 2, 3, 4, 5, 6; najbolje 0, 1, 2, 3, 4; posebno najbolje 0, 00, 1, 2, 3, 4, 5, 6; best 0, 1, 2, 3, 4; especially best 0,

1,2, 3; 1,2,3;

q, r nezavisno jedan od drugog, 1, 2, 3; najbolje q je 1 ili 2; q, r independently of each other, 1, 2, 3; best q is 1 or 2;

s 0, 1, 2, 3, 4; najbolje 0, 1, 2, 3; posebno najbolje 0, 1, 2; with 0, 1, 2, 3, 4; best 0, 1, 2, 3; especially best 0, 1, 2;

R13, R14 nezavisno jedan od drugog, su jedan fenil - prsten koji R13, R14 independently of each other, are one phenyl ring which

može da sadrži 0-1 azotov atom; may contain 0-1 nitrogen atom;

R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32

nezavisno jedan od drugog, H, (C1-C6)-alkil; independently of each other, H, (C1-C6)-alkyl;

R18 H, (CrC6)-alkil, CO(CrC6)-alkil, CO(R33); najbolje H, (Cr C6)-alkil, CO(CrC6)-alkil; naročito se pretpostavlja H, R18 H, (C1C6)-alkyl, CO(C1C6)-alkyl, CO(R33); preferably H, (C 1 -C 6 )-alkyl, CO(C 1 -C 6 )-alkyl; in particular, H is assumed,

(Ci-Ce)-alkil; (C1-C6)-alkyl;

ili or

R17 i R18, R21 i R22, R27 i R28, R31 i R32 R17 and R18, R21 and R22, R27 and R28, R31 and R32

nezavisno jedan od drugog, grade najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; najbolje je daje prsten pirolidon, piperidin, N-metil-piperazin, morfolin; independently of each other, they most advantageously form together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulphur; it is best if the ring is pyrrolidone, piperidine, N-methyl-piperazine, morpholine;

R33 jedan 5 - 10.to člani aromatični sistem prstena koji može da sadrži jedan dalji hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa; R33 is a 5 - 10 membered aromatic ring system which may contain one further hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with;

R12 OH, 0-(CrC6)-alkil, O-(C0-C8)-alkilen-aril, CN, S-(Ci-C6)-alkil, COO(R80), CON(R81)(R82), jedan 3 - 12-to člani mono-, bi- ili spiro-ciklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S i 3 - 12-to člani prsten može da sadrži, dalje, supstituente kao što F, Cl, Br, OH, CF3, CN, okso, 0-(CrC6)-alkil, (Ci-C4)-alkoksi-(d-C4)-alkil, (Ci-C6)-alkil, O-(C0-C8)-alkilen-aril, (C0-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(CrC6)-alkil, COCOO(Ci-C6)-alkil, COO(R40), S(0)U(R41); R12 OH, O-(CrC6)-alkyl, O-(C0-C8)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, COO(R80), CON(R81)(R82), one 3-12-membered mono-, bi- or spiro-cyclic ring which may contain one or more hetero-atoms from the group N, O and S and the 3-12-membered ring may contain, further, substituents such as F, Cl, Br, OH, CF3, CN, oxo, O-(CrC6)-alkyl, (Ci-C4)-Alkoxy-(d-C4)-alkyl, (Ci-C6)-alkyl, O-(C0-C8)-alkylene-aryl, (C0-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)U(R41);

najbolje OH, 0-(CrC6)-alkil, O-(C0-C8)-alkilen-aril, CN, 3 - 10-to člani mono- ili biciklični prsten koji moža da sadrži 1 - 3 hetero-atoma iz grupe N, O and S, i 3 - 10-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, OH, CF3, CN, okso, 0-(CrC6)-alkil, (CrC4)-alkoksi-(Cr C4)-alkil, (Ci-Ce)-alkil, (C0-C2)-alkilen-aril, N(R34)(R35), CO(CrCe)-alkil; best OH, 0-(CrC6)-alkyl, O-(C0-C8)-alkylene-aryl, CN, 3-10-membered mono- or bicyclic ring which can contain 1-3 hetero-atoms from the group N, O and S, and the 3-10-membered ring can contain further substituents, such as F, Cl, Br, OH, CF3, CN, oxo, 0-(CrC6)-alkyl, (C 1 -C 4 )-Alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 0 -C 2 )-alkylene-aryl, N(R 34 )(R 35 ), CO(C 1 -C 6 )-alkyl;

naročito se pretpostavlja OH, 0-(CrC6)-alkil, 3 - 10-to člani mono- ili biciklični prsten koji može da sadrži 1 - 2 hetero-atoma iz grupe N, O i S, a 3 - 10-to člani prsten može da sadrži dalje supstituente, kao što su F, OH, okso, (CrC6)-alkil, CO(Ci-C6)-alkil; in particular, OH, 0-(CrC6)-alkyl, 3-10-membered mono- or bicyclic ring which can contain 1-2 hetero-atoms from the group N, O and S is assumed, and the 3-10-membered ring can contain further substituents, such as F, OH, oxo, (CrC6)-alkyl, CO(Ci-C6)-alkyl;

t 0,1,2,3,4,5,6; t 0,1,2,3,4,5,6;

u 0, 1, 2; najbolje 0 ili 2; naročito se pretpostavlja 2; in 0, 1, 2; best 0 or 2; in particular, 2 is assumed;

R34, R35, R37, R38 R34, R35, R37, R38

nezavisno jedan od drugog, H, (Ci-C8)-alkil; independently of each other, H, (C 1 -C 8 )-alkyl;

ili or

R34 i R35 R34 and R35

najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora i može, najpovoljnije, da bude susptituisan sa 1 - 2 okso - grupe; most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur and can, most advantageously, be substituted with 1 - 2 oxo - groups;

R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5- 10-to člani aromatični sistem prstena koji može da sadrži 1 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (C1-C6)-alkil, 0-(Ci-C8)-alkil; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5-10-membered aromatic ring system which may contain 1-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (C1-C6)-alkyl, O-(Ci-C8)-alkyl;

R40 H, (CrC8)-alkil, (C2-C6)-alkenil, (C0-C3)-alkilen-aril; R 40 H, (C 1 -C 8 )-alkyl, (C 2 -C 6 )-alkenyl, (C 0 -C 3 )-alkylene-aryl;

R41 (CrC6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, R41 (CrC6)-alkyl, 5 - 10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl,

(Ci-C6)-alkil, 0-(Ci-C8)-alkil; (C 1 -C 6 )-alkyl, O-(C 1 -C 8 )-alkyl;

R78, R79 nezavisno jedan od drugog, H, (CrC8)-alkil, hidroksi-(CrC4)-alkil, OH, (CrC4)-alkoksi-(Ci-C4)-alkil; R 78 , R 79 independently of each other, H, (C 1 -C 8 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;

R80, R81 nezavisno jedan od drugog, H, (CrC8)-alkil; R80, R81 independently of each other, H, (C1C8)-alkyl;

R3 H, (Ći-Ce)-alkil; najbolje H; R 3 H, (C 1 -C 6 )-alkyl; best H;

R4, R5 nezavisno jedan od drugog, H, (Ci-C6)-alkil, OH, R4, R5 independently of each other, H, (Ci-C6)-alkyl, OH,

0-(Ci-C6)-alkil, 0-CO-(CrC6)-alkil, S-(CrC6)-alkil; najbolje nezavisno jedan od drugog, H, (Ci-C6)-alkil, OH, 0-(Ci-C6)-alkil, 0-CO-(CrC6)-alkil; naročito se pretpostavlja, nezavisno jedan od drugog, H, OH, 0-(Ci-C6)-alkil; O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, S-(C1-C6)-alkyl; preferably independently of each other, H, (C 1 -C 6 )-alkyl, OH, O-(C 1 -C 6 )-alkyl, O-CO-(C 1 -C 6 )-alkyl; in particular, independently of each other, H, OH, O-(Ci-C6)-alkyl are assumed;

R6, R7, R8, R9 R6, R7, R8, R9

H; H;

ili or

R6 i R7, R8 i R9 R6 and R7, R8 and R9

nezavisno jedan od drugog, najbolje okso; independent of each other, preferably oxo;

najbolje da su R6, R7, R8, R9 H; preferably R6, R7, R8, R9 are H;

n 1 n1

m 1 ili 2; najbolje 1; m 1 or 2; preferably 1;

A, B, D, G nezavisno jedan od drugog, N, C(R42); A, B, D, G independently of each other, N, C(R42);

ili or

grupe A i B ili D i G su svaka C(R42) i zajedno grade jednu orto - fenilensku jedinicu da bi se sve u svemu dobio jedan 1,4-disupstituisan naftalinski sistem ; groups A and B or D and G are each C(R42) and together they build one ortho-phenylene unit in order to obtain one 1,4-disubstituted naphthalene system;

najbolje best

BjeN, C(R42); i A, D, G C(R42); BjeN, C(R42); and A, D, G C(R42);

naročito se pretpostavlja it is especially assumed

A, B, D, G su C(R42); A, B, D, G are C(R42);

R42 H, F, Cl, Br, CF3, CN, CHd-CeJ-alkil, 0-(CrC4)-alkoksi-(Ci-C4)-alkil, S-(CrC6)-alkil, (CrC6)-alkil, (C0- C8)-alkilen-aril, O-(C0-C8)-alkilen-aril, N(R43)(R44), S02-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)*-0(R86); ;najbolje H, F, Cl, Br, CF3, CN, 0-(d-CQ)-alkil, (d-C6)-alkil, S02-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), ;-(CR84R85)X-0(R86); naročito se pretpostavlja H, F, Cl, CF3, CN, (CrC6)-alkil, -(CR84R85)X-0(R86); ;R43, R44, R45, R46, R47 ;nezavisno jedan od drugog, H, (CrC8)-alkil; ;ili ;R43 i R44, R45 i R46 ;nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0-1 dalji hetero-atom iz grupe N-(C1-C6)-alkil, kiseonik i sumpor; ;R48, R50, R51 ;nezavisno jedan od drugog, H, (CrC8)-alkil, aril; najbolje ;nezavisno jedan od drugog, H, (d-C8)-alkil; ;R84, R85 H; ;R86 H, (CrC6)-alkil; ;x 0, 1, 2; najbolje 0, 1; posebno se pretpostavlja 1; ;R10 H, (CrC8)-alkil; ;X N(R52), jedna veza, C=C, C(R53)(R54), C(R55)(R56)0, ;C^C, CH2-CH2, YCH2; najbolje N(R52), jedna veza, C=C, C(R53)(R54), CH2-CH2; naročito se pretpostavlja jedna ;veza, C=C, C(R53)(R54), CH2-CH2; ;Y O, S, N(R89); ;R89 H, (CrC8)-alkil; ;R52, R53, R54, R55, R56 ;nezavisno jedan od drugog, H, (Ci-C8)-alkil; ;E 3 - 8-mo člani bivalentni karbo- ili heterociklični sistem prstena sa 0 - 4 hetero-atoma iz grupe N, O i S, koji mogu, najpovoljnije, da imaju susptituente iz grupe H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(CrC6)-alkil, 0-(Cr C4)-alkoksi-(Ci-C4)-alkil, S-(CrC6)-alkil, (d-C6)-alkil, (C2-Ce)-alkenil, 0-(C3-C8)-cikloalkil, (C3 - C8)-cikloalkenil, (C2 -C6)-alkinil, (CO-C8)-alkilen-aril, O-(C0 - C8)-alkilen-aril, S-aril, N(R57)(R58), S02-CH3, N(R61)CO(R62), ;N(R63)S02(R64), CO(R65) i mogu biti mono- ili biciklični; ;najbolje 5 - 7-mo člani bivalentni karbo- ili heterociklični sistem prstena sa 0 - 3 hetero-atoma iz grupe N, O i S, koji mogu, najpovoljnije, da imaju susptituente iz grupe H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkil, ;S-(CrC6)-alkil, (d-C6)-alkil, (C2-C6)-alkenil, O-(C0 - C8)-alkilen-aril, S-aril, N(R57)(R58), S02-CH3, N(R61)CO(R62), CO(R65) i mogu da budu mono- ili biciklični; ;naročito se pretpostavlja 5 - 7-mo člani bivalentni karbo- ili heterociklični sistem prstena sa 0 - 2 hetero-atoma iz ;grupe N, O i S, koji može, najpovoljnije, da ima supstituente iz grupe H, F, Cl, Br, OH, CF3, N02, OCF3, 0-(CrC6)-alkil, (CrC6)-alkil, (C2-C6)-alkenil, N(R57)(R58), S02-CH3, CO(R65) ;npr., je E izabrano iz grupe koja se sastoji od ; ;koja može, najpovoljnije, da ima supstituente iz grupe H, F, Cl, Br, OH, CF3, N02, OCF3, O-Cd-CeJ-alkil, (CrC6)-alkil, (C2-C6)-alkenil, N(R57)(R58), S02-CH3, CO(R65); ;najbolje ; ;koji mogu, najpovoljnije, da imaju ranije navedene supstituente; ;R57, R58, R61, R63 ;nezavisno jedan od drugog, H, (CrC3)-alkil; ;R62, R64, R65 ;nezavisno jedan od drugog, H, (C1-Cs)-alkil, aril; najbolje nezavisno jedan od drugog, H, (CrC8)-alkil; ;K jednu vezu, O, OCH2, CH20, S, SO, S02, N(R66), ;N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, S02CH2; ;najbolje jednu vezu, O, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))V, CO, C=C, SCH2; naročito se pretpostavlja jedna veza, O, OCH2, CH20, C0N(R68), (C(R69)(R70))V, CO, C=C; ;v 1, 2, 3, 4; najbolje 1, 2, 3; naročito se petpostavlja 1,2; ;R66, R67, R68, R69, R70 ;nezavisno jedan od drugog, H, (CrC8)-alkil; ;R11 H, (CrC8)-alkil, (Ci-C4)-alkoksi-(CrC4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten, koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (CrC6)-alkil, 0-(Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, hidroksi-(CrC4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(CrC6)-alkil, N(R76)(R77) ili S02CH3; ;najbolje (CrC8)-alkil, (CrC4)-alkoksi-(Ci-C4)-alkil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten koji ;može da sadrži 0 do 3 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (CrC6)-alkil, 0-(CrC8)-alkil, (C0-C2)-alkilene-aril, okso, CO(R71), CON(R72)(R73), hidroksi, N(R75)CO(CrC6)-alkil, N(R76)(R77) ili S02CH3; ;naročito se pretpostavlja (Ci-C8)-alkil, (CrC4)-alkoksi-(CrC4)-alkil, jedan 3 do 10-to člani mono- ili biciklični prsten koji može da sadrži 0-2 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može dodatno da bude supstituisan sa F, Cl, Br, CF3, CN, (d-Ce^alkil, 0-(Ci-C8)-alkil, okso, CO(R71), CON(R72)(R73), N(R75)CO(Ci-C6)-alkil, ili S02CH3; ;R71, R72, R73, R74, R75, R76, R77 ;nezavisno jedan od drugog, H, (Ci-C8)-alkil; ili ;R72 i R73, R76 i R77 ;nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, moža da sadrži 0 - 1 ;dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; ili ;njihovi N-oksidi i njihove fiziološki prihvatljive soli. ;U jednoj daljoj pretpostavljenoj celini, A, B, G i D u formuli I su CH ili: ako je E 1,4-fenilen, pretpostavljena značenja za A, B, G i D su, dalje, ona navedena dole u tabeli I: Ako je E pretpostavljena značenja za A, B, G i D su, dalje, ona navedena dole u tabeli II: Ako je E pretpostavljena značenja za A, B, G i D su, dalje, ona nevedena dole u tabeli III: ;Dalje pretpostavljene kombinacije za E i A, B, G i D navedene su u tabeli ;IV. ; ;Radikali R11, K, X i E u formuli I poseduju u jednoj naročito pretpostavljenoj celini jedno od sledećih značenja: ;R11 je najbolje izabrati iz grupe koja se sastoji od: ;n-propil, n-butil, izo-butil, izo-pentil, ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheks-(1)-enil, fenil, p-fluoro-fenil, p-hloro-fenil, p-bromo-fenil, p-tolil, p-metoksi-fenil, p-trifluoro-metil-fenil p-metil-tio-fenil, o-fluoro-fenil, o-hloro-fenil, o-cijano-fenil, m-fluoro-fenil, 2,4-difluoro-fenil, 3-fluoro-4-metil-fenil, 2-nitro-4-metil--fenil, 2-amino-4-metil-fenil, ;K je najbolje da se izabere uz grupe koja se sastoji od. -O-, veza, C=C, CH2, CH20, CONH, OCH2, CO, SCH2i (CH2)20. ;X je najbolje da se izabere iz grupe koja se sastoji od veze, NH i CH2. ;E je najbolje da se izabere iz grupe koja se sastoji od: ;Pretpostavljene kombinacije od R11, K, X i E su dole navedene: ;Ako su K i X svaki jedna veza onda se naročito pretpostavljaju značenja za E i R11 kao što sledi: ■ Ako je E 1,4-fenilen, R11 se bira iz grupe koja se sastoji od: cikloheksil, p-tolil, p-fluoro-fenil, o-fluoro-fenil, p-metoksi-fenil, p-hloro-fenil, o-hloro-fenil, 2,4-difluoro-fenil, 3-fluoro-4-metil-fenil, o-cijano-fenill, ■ Ako je E ;R11 je izabrano iz grupe koja se sastoji od: ;p-hloro-fenil, p-tolil, p-fluoro-fenil, p-metoksi-fenil, p-trifluoro-metil-fenil, o-fluoro-fenil, fenil i ;Dalje kombinacije od E i R11, za slučaj kada su K i X svaki jedna veza, navedene su u tabeli V: ;Ako je K -O- i X je jedna veza, NH ili CH2, naročito pretpostavljena značenja za E i R11 su sledeća: 5 ;■ Ako je E 1,4-fenilen, R11 se bira iz grupe koja se sastoji od: ;fenil, ciklopentil, n-butil, izo-butil, izo-pentil, 2,4-difluoro-fenil i p-fluoro-fenil. 10 Dalje kombinacije od E i R11 za slučaj kada je K -O- i X je jedna veza, NH ili CH2su navedene u tabeli VI: ;Ako je K C<=>C i X je jedna veza, naročito pretpostavljena značenja E i R11 su sledeća: ;5■Ako je E ;R11 se bira iz grupe koja se sastoji od: ;fenil, p-fluoro-fenil i p-hloro-fenil. ;Ako je K CH2i X je jedna veza, naročito pretpostavljena značenja E i R11 10 su navedena dole u tabeli VII: 15 Ako je K CH20 i X je jedna veza, naročito pretpostavljena značenja za E i R11 su sledeća: ;■ Ako je E 1,4-fenilen, R11 se bira iz grupe koja se sastoji od: ;fenil, ciklopropil i cikloheksil. ;20 ;Ako je K CONH i X je jedna veza, naročito pretpostavljena značenja za E i R11 su navedena dole u tabeli VIII: ;Ako je K OCH2i X je jedna veza, naročito se pretpostavljaju značenja za E i R11 koja su navedena dole u tabeli IX ispod: ;Kombinacije R11, K i E navedene dole u tabeli X se, dalje, naročito pretpostavljaju dodatno prethodno pomenutim kombinaciajma, sa X posebno naročito pretpostavljajući u obliku jedne veze: Jedinjenja formule I su naročito pretpostavljena celina u obliku jedinjenja formule la ;u kojoj radikali R1, R2, R10, R11, R42, i grupe X, E, K imaju prethodno pomenuta značenja, a R42' je definisan kao R42, pri čemu R42 i R42' u jedinjenjima formule la mogu da budu identični ili različiti, ili N-oksidi i njihove fiziološki prihvatljive soli. ;U jednoj pretpostavljenoj celini pronalaska radikali R1, R2, R10, R11, R42, R42' i grupe X, E, K imaju sledeća značenja: R1, R2 nezavisno jedan od drugog, H, (Ci-C8)-alkil, -(CR78R79)0 - ;R12, (C1-C4)-alkoksi-(Ci-C4)-alkil, ili R1 i R2 grade zajedno sa azotom, za koji su vezani, jedan 4 - 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 -2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može da bude dodatno supstituisan sa F, (Ci-C6)-alkil, 0-(Ci-C4)-alkil, (C1-C4)-alkoksi-(CrC4)-alkil, hidroksi-(CrC4)-alkil, (C0-C2)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, N(R31)(R32) ili S02CH3; pri čemu R<1>i R<2>nisu oba CO(R26), a najbolje H, (d-CsJ-alkil, - ;(CR78R79)0-R12, (CrC^-alkoksKd-OO-alkil, ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 - 10-to člani mono- ili biciklični prsten koji, osim azotovog atoma, može da sadrži 0-2 dodatna hetero-atoma izabrana iz grupe kiseonika i azota, pri čemu heterociklični sistem prstena može da bude dodatno supstituisan sa F, (d-Ce^alkil, (Ci-C4)-alkoksi-(C1-C4)-alkil, okso, CO(R26), hidroksi, N(R31)(R32); ;o 0, 1, 2, 3, 4, a najbolje ;0, 1,2, 3; ;q 1, 2, 3, a najbolje ;1 ili 2; ;s 0,1,2; ;R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 ;nezavisno jedan od drugog, H, (CrC6)-alkil; ;ili ;R17iR18, R27iR28, R31 i R32 ;nezavisno jedan od drugog, najpovoljnijje zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(d-C6)-alkil, kiseonika i sumpora, a najbolje da je prsten pirolidin, piperidin, N-metil-piperazin, morfolin; ;R12 OH, 0-(CrC6)-alkil, O-(C0-C2)-alkilen-aril, CN, S-(Ci-C6)-alkil, 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži 1 do 3 hetero-atoma iz grupe N, O i S, a 3 ;- 12-to člani prsten može da sadrži dalje supstituente, kao što su F, OH, CF3, CN, okso, (Ci-C6)-alkil, (C0-C2)-alkilen-aril, N(R34)(R35), COO(R40), CO(CrC6)-alkil, a najbolje ;OH, 0-(C-i-C6)-alkil, 3 -10-to člani mono- ili biciklični prsten koji može da sadrži 1 - 2 hetero-atoma iz grupe N, O i S, i 3 - 10-to člani prsten može da sadrži dalje supstituente, kao F, OH, okso, (d-CeJ-alkil, CO(Ci-C6)-alkil; ;R34,R35 nezavisno jedan od drugog, H, (Ci-C4)-alkil; ;R40 H, (Ci-C6)-alkil, (C0-C2)-alkilen-aril; ;R78, R79 nezavisno jedan od drugog, H, (CrCsJ-alkil, hidroksi-(Ci-C4)-alkil, OH, (CrC4)-alkoksi-(CrC4)-alkil; ;R42, R42' nezavisno jedan od drugog, H, F, Cl, Br, CF3, CN, (CrC6)-alkil; ;R10 H, (Ci-C8)-alkil; ;X N(R52), jednu vezu, C=C, C(R53)(R54), CH2CH2; ;R52, R53, R54 ;nezavisno jedan od drugog, H, (Ci-Ca)-alkil; ;E 5 - 7-mo članu bivalentnu karbo- ili heterocikličnu strukturu prstena sa 0 - 3 hetero-atoma iz grupe N, O i S, koji mogu, najpovoljnije, da imaju supstituente iz grupe H, F, Cl, Br, CF3, OH, CN, OCF3, N02, O-Cd-CeJ-alkil, (Ci-C6)-alkil, S02-CH3, CO(R65); ;najbolje 5 -7-mo članu bivalentnu karbo- ili heterocikličnu strukturu prstena sa 0 - 2 hetero-atoma iz grupe N, O i S, koji mogu, najpovoljnije, da imaju supstituente iz grupe H, F, Cl, Br, OH, CF3, N02, OCF3, 0-(Ci-C6)-alkil, (CrC6)-alkil, (C2-C6)-alkenil, N(R57)(R58), S02-CH3, CO(R65) ;npr. E je izabrano iz grupe koja se sastoji od ; ;koji, najpovoljnije, mogu da imaju supstituente iz grupe H, F, Cl, Br, OH, ;5 CF3, N02, OCF3, 0-(CrC6)-alkil, (CrC6)-alkil, (C2-C6)-alkenil, N(R57)(R58), SO2-CH3, CO(R65); ;a najbolje ; ;koji može, najpovoljnije, da ima već pomenute supstituente; ;R65 H, (d-C8)-alkil; ;15 ;K jedna veza, O, OCH2, CH20, S, S02, N(R66), N(R67)CO, ;CON(R68), (C(R69)(R70))V, CO, C=C, SCH2, S02CH2; a najbolje jedna veza, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, izuzetno najpovoljnije CH2, CO, C=C; ;v 1, 2, 3, a najbolje ;5 1,2; ;R66, R67, R68, R69, R70 ;nezavisno jedan od drugog, H, (Ci-C8)-alkil; ;10 R11 (CrC8)-alkil, (Ci-C4)-alkoksi-(CrC4)-alkil, jedan 3 do 10-to-člani mono-, bi-, tri- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonik.azot i sumpor , pri čemu sistem prstena može da bude dodatno supstituisan ;sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, 0-(CrC8)-alkil, okso, ;15 CO(R71), hidroksi, N(R75)CO(CrC6)-alkil, ili S02CH3; a najbolje (Ci-Cs)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, jedan 3 do 10-člani mono- ili biciklični prsten koji može da sadrži 0 do 2 hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može dodatno da bude supstitusan 20 sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, okso, CO(R71), CON(R72)(R73), N(R75)CO(Ci-C6)-alkil, ili S02CH3; R71, R72, R73, R74, R75, R76, R77 25 nezavisno jedan od drugog, H, (d-C8)-alkil; ;ili ;R72 i R73, R76 i R77 ;nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim ;atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, 30 osim azota, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora. ;U jednoj pretpostavljenoj realizaciji odnosi se predstavljeni pronalazak na jedinjenjna formule la, ;U kojoj su ;X je CH2CH2, N(R52), CH2, OCH2, SCH2, CH=CH, a najbolje CH2CH2, ;CH=CH; ;E je ; ;K je jedna veza, O ili C(R69)(R70); ;a drugi simboli R1, R2, R10, R11, R42, R42', R52, R69 i R70 imaju značenja data gore, povezano sa definicijom radikala jedinjenja formula la. ;U jednoj daljoj pretpostavljenoj realizaciji odnosi se predstavljen pronalazak na jedinjenjenja formule la, ;U kojoj su ;X je N(R52), a najbolje NH, ili C(R53)(R54); ; najbolje ;K je jedna veza, O ili C(R69)(R70), a najbolje 0; ;najbolje O ;i drugi simboli R1, R2, R10, R11, R42, R42',R52, R53, R54, R69 i R70 imaju značenja data gore, povezano sa definicijom radikala jedinjenja formule la. ;U jednoj daljoj naročito pretpostavljenoj realizacijij jedinjenja formule la nalave se jedinjenja formule lb ; ;u kojoj radikali R1, R2, R10 i R11 i grupe E i D imaju gore navedena značenja, ili su N-oksidi i njihove fiziološki prihvatljive soli. ;U jednoj pretpostavljnoj realizaciji radikali R1, R2, R10 i R11 i grupe E i D imaju sledeća značenja: R1, R2 nezavisno jedan od drugog, H, (CrC8)-alkil, - ;(CR78R79)0-R12, (d-d)-alkoksi-(d-d)-alkil, (C3-C8)- ;alkenil, CO-(CrC8)-alkil, -CO-(CH2)0-R12, CO-ariloksi-(Cr C4)-alkil, C0CH=CH(R13), C0CC(R14), C0(C(R15)(R16))qN(R17)(R18), ;C0(C(R19)(R20))rCON(R21 )(R22), ;CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može da bude dodatno supstituisan sa F, Cl, CF3, (CrC6)-alkil, 0-(CrC4)-alkil, (C1-C4)-alkoksi-(CrC4)-alkil, hidroksi-(Ci-C4)-alkil, (C0-C2)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(CrC6)-alkil, N(R31)(R32) ili S02CH3, gde R1 i R2 oba nisu CO(R26); najbolje, nezavisno jedan od drugog, H, (CrCsJ-alkil, -(CR78R79)0 -R12, (CrC4)-alkoksi-(Ci-C4)-alkil, CO-(CrC8)-alkil, -CO-(CH2)0 -R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono- ili biciklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični prsten može biti dodatno supstituisan sa F, Cl, CF3, (CrC6)-alkil, 0-(CrC4)-alkil, (CrC4)-alkoksi-(Ci-C4)-alkil, (C0-C2)-alkilen-aril, okso, hidroksi, N(R31)(R32) ili S02CH3, gde R1 i R2 nisu oba CO-(Ci-C8)-alkil; ;naročito se pretpostavlja, nezavisno jedan od drugog, H, (Ci-C8)-alkil, -(CR78R79)0-R12, (CrC^-alkoksHd-OO-alkil, CO-(Ci-C8)-alkil, -CO-(CH2)0-R12, ;CO(C(R15)(R16))qN(R17)(R18), ili R1, a R2 gradi zajedno sa azotovim atomom, za koji je vezan, jedan 4 do 10-člani mono- ili biciklični prsten koji,osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika,i azota, pri čemu heterociklični sisitem prstena može da bude dodatno supstituisan sa F, (Ci-C6)-alkil, (cr C4)-alkoksi-(CrC4)-alkil, okso, CO(Ci-C8)-alkil, hidroksi, N(R31)(R32), gde R1 i R2 nisu oba CO(Ci-C8)-alkil; ;o 0, 1, 2, 3, 4, 5, 6; najbolje 0, 1, 2, 3, 4; naročito se ;pretpostavlja 0,1,2, 3; ;q, r nezavisno jedan od drugog, 1, 2, 3; najbolje q je 1 ili 2; ;s 0, 1, 2, 3, 4; najbolje 0, 1, 2, 3; naročito se pretpostavlja 0, 1, ;2; ;R13, R14 nezavisno jedan od drugog, jedan fenil - prsten koji može da ;sadrži 0 -1 azotov atom; ;R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, ;R30, R31, R32 ;nezavisno jedan od drugog, H, (CrC6)-alkil; ;R18 H, (Ci-Ce)-alkil, CCKd-CeJ-alkil, CO(R33); najbolje H, (d-d.)-alkil, CO(d-C6)-alkil; naročito se pretpostavlja H, (Ci-C6)-alkil; ili ;R17 i R18, R21 i R22, R27 i R28, R31 i R32 ;nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; najbolje da je prsten pirolidin, piperidin, N-metil-piperazin, morfolin; ;R33 jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži još jedan hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (CrC6)-alkil, 0-(CrC8)-alkil; ;R12 je OH, 0-(Ci-C6)-alkil, O-(C0-C8)-alkilen-aril, CN, S-(Ci-C6)-alkil, COO(R80), CON(R81)(R82), 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, OH, CF3, CN, okso, 0-(CrC6)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (CrCe)-alkil, O-(C0-C8)-alkilen-aril, (C0-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38)),(R39), CO(C(R37)(R38))t(R39), CO(CrC6)-alkil, COCOO(CrC6)-alkil, COO(R40), S(0)U(R41); ;najbolje OH, 0-(CrC6)-alkil, O-(C0-C8)-alkilen-aril, CN, 3 - 10-to člani mono- ili biciklični prsten koji može da sadrži 1 - 3 hetero-atoma iz grupe N, O i S, a 3 - 10-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, OH, CF3, CN, okso, 0-(CrC6)-alkil, (CrC4)-alkoksi-(Ci-C4)-alkil, (Ci-C6)-alkil, (C0-C2)-alkilen-aril, N(R34)(R35), CO(Ci-C6)-alkil; ;naročito se pretpostavljaju OH, 0-(Ci-C6)-alkil, 3 - 10-to člani mono- ili biciklični prsteni koji mogu da sadrže 1-2 hetero-atoma iz grupe N, O i S, a 3 - 10-to člani prsten može da sadrži dalje supstituente, kao što su F, OH, okso, (C-i-Ce)-alkil, COfCrCeJ-alkil; ;t 0,1,2,3,4,5,6; ;u 0, 1, 2; najbolje 0 ili 2; naročito se pretpostavlja 2; ;R34, R35, R37, R38 nezavisno jedan od drugog, H, (CrC8)-alkil; ;ili ;R34 i R35 ;najprihvatljivije zajedno sa azotovim atomom, za koji su vezani, jedan 5 -6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupre N-(Ci-Ce)-alkil, kiseonika i sumpora i može, najpovoljnije, da bude supstituisan sa 1 - 2 okso grupe; ;R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (CrC6)-alkil, 0-(CrC8)-alkil; ;R40 H, (Ci-C8)-alkil, (C2-C6)-alkenil, (C0-C8)-alkilen-aril; ;R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0 -2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa F, Cl, (CrC6)-alkil, 0-(d-C8)-alkil; ;R78, R79 nezavisno jedan od drugog, H, (CrC8)-alkil, hidroksi-(C-i-C4)-alkil, OH, (d^-alkoksKC^J-alkil; ;R80, R81 nezavisno jedan od drugog, H, (d-CsV-alkil; ;R10 H, (Ci-C8)-alkil; ;E 3 - 8-mo člane bivalentne karbo- ili heterociklične strukture prstena sa 0 -4 hetero-atoma iz grupe N, O i S, koje mogu da imaju supstituente, najpovoljnije iz grupe H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkil, 0-(CrC4)-alkoksi-(Ci-C4)-alkil, S-(CrC6)-alkil, (CrC6)-alkil, (C2-C6)-alkenil, N(R57)(R58), S02-CH3, N(R61 )CO(R62), N(R63)S02(R64), CO(R65) i mogu da budu mono- ili biciklični; ;najbolje 5 - 7-mo člane bivalentne karbo- ili heterociklične strukture prstena sa 0 - 3 hetero-atoma iz grupe N, O i S, koji mogu da imaju, najpovoljnije, supstituente iz grupe H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, -N(R57)(R58), S02-CH3, N(R61)CO(R62), CO(R65) i mogu da budu mono- ili biciklični; naročito se pretpostavljaju 5 - 7-mo člane bivalente karbo- ili heterociklične strukture prstena sa 0 - 2 hetero-atoma iz grupe N, O i S, koje mogu da imaju, najpovoljnije supstituente iz grupe H, F, Cl, Br, OH, CF3, N02, OCF3, O-(CrC6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil,-N(R57)(R58), S02-CH3, CO(R65) ;npr., E je izabrano iz grupe koja se sastoji od ; ;koji mogu da imaju supstituente, najpovoljnije, iz grupe H, F, Cl, Br, OH, CF3, N02, OCF3, 0-(CrC6)-alkil, (d-CeJ-alkil, (C2-C6)-alkenil, N(R57)(R58), S02-CH3, CO(R65); ;najbolje ; ;koji mogu da imaju, najpovoljnije, ranije pomenute supstituente; ;R57, R58, R61, R63 ;nezavisno jedan od drugog, H, (Ci-Cs)-alkil; ;R62, R64, R65 ;nezavisno jedan od drugog, H, (Ci-Ce)-alkil, aril; najbolje nezavisno jedan od drugog, H, (Ci-C8)-alkil; ;K jedna veza, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, ;CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, S02CH2; ;najbolje jedna veza, O, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))V, CO, C=C, SCH2; naročito se pretpostavlja jedna veza, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, CO, ;C=C; ;v 1, 2, 3, 4; najbolje 1, 2, 3; naročito se pretpostavlja 1,2; ;R66, R67, R68, R69, R70 ;nezavisno jedan od drugog, H, (Ci-C8)-alkil; ;R11 H, (Ci-C8)-alkil, (Ci-C4)-alkoksi-(C1-C4)-alkil, (C3-C8)-alkenil, ;(C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (CrC4)-alkoksi-(Ci-C4)-alkil, hidroksi-(CrC4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R71), ;CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(C1-C6)-alkil, N(R76)(R77) or S02CH3SCF3; ;najbolje (Ci-C8)-alkil, (C1-C4)-alkoksi-(Ci-C4)-alkil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten koji može da ;sadrži 0 do 3 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (C0-C2)-alkilen-aril, okso, C0(R71), CON(R72)(R73), hidroksi, N(R75)CO(Ci-C6)-alkil, N(R76)(R77) ili S02CH3; ;naročito se pretpostavlja (Ci-C8)-alkil, (CrC4)-alkoksi-(Ci-C4)-alkil, jedan 3 do 10-to člani mono- ili biciklični prsten koji može da sadrži 0 do 2 hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (CrC6)-alkil, O-(Ci-C8)-alkil, okso, C0(R71), CON(R72)(R73), N(R75)CO(Cr C6)-alkil, or S02CH3; ;R71, R72, R73, R74, R75, R76, R77 ;nezavisno jedan od drugog, H, (CrC8)-alkil; ;ili ;R72 i R73, R76 i R77 ;nezavisno jedan od drugog, najpovoljnije zajedno sa jednim azotovim atomom, za koji su vezanijedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atoma iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora. ;U jednoj pretpostavljenoj realizaciji sadašnji pronalazak se odnosi na jedinjenja formule lb ;u kojoj ;X je jedna veza, ;E je ; ;gde ranije pomenute grupe mogu, najpovoljnije, da imaju suspstituente iz grupe H, F, Cl, Br, OH, CF3, N02, OCF3, 0-(CrC6)-alkil, (CrC6)-alkil, (C2-C6)-alkenil, N(R57)(R58), S02-CH3, CO(R65); ;najbolje, daje E ; ;u kojima grupe mogu da imaju ranije pomenute supstituente; ;K je jedna veza; i ;drugi radikali R1, R2, R10 i R11 i grupa D imaju značenja data gore u vezi sa definicijom radikala jedinjenja formule lb. ;R11 u ranije pomenutim jedinjenjima formule lb je, naročito se pretpostavlja, jedan supstituisan mono- ili biciklični sistem prstena sa 5 - 10 članova, koji mogu imati 0-3 hetero-atoma, naročito N, O i/ili S, posebno se pretpostavlja fenil sa 0 -1 N atomom, cikloheksil ili jedan biciklični sistem sa 8 -10 članova i 1 - 2 hetero-atoma, naročito N, O i/ili S. ;Kod jednog daljeg pretpostavljenog vida realizacije odnosi se predstavljen pronalazak na jedinjenja formule lb ;u kojoj ;X je jedna veza; ;Eje ; ;gde ranije pomente grupe mogu, najbolje, da imaju supstituente iz grupe H, F, Cl, Br, OH, CF3) N02, OCF3, 0-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenyl, N(R57)(R58), S02CH3i CO(R65); ;najbolje ; ;u kojima grupe mogu da imjau ranije pomenute supstituente; ;K je CH2, CH2CH2, O, CH20, OCH2, CON(R68), N(R67)CO, S, S02, ;SCH2, S02, S02CH2, CO ili jedna trostruka veza; ;najbolje CH2, O, CH20, OCH2, CON(R68), SCH2, CO ili jedna trostruka veza; i ;drugi radikali R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R67 i R68 i gupa D imaju značenja koja su gora navedena, u vezi sa definicijom radikala jedinjenja formule lb. ;Količina jedinjenja formula(l) potrebna da se postigne željeni biološki efekat zavisi od brojnih činilaca, na primer, od specifičnog jedinjenja koje je izabrano, nameravane upotrebe, načina davanja i kliničkih uslova pacijenta. Dnevna doza je uglavnom od 0.3 mg do 100 mg (tipično od 3 mg do 50 mg) dnevno i po kilogramu telesne težine, na primer, 3-10 mg/kg/danu. Jedna intravenozna doza može da bude, na primer, u oblasti od 0.3 mg do 1.0 mg/kg, koja se može na pogodan način davati kao infuzija od 10 ng do 100 ng po kilogramu i po minutu. Pogodni rastvori za infuzije za ove svrhe sadrže, na primer, od 0.1 ng do 10 mg, tipično od 1 ng do 10 mg, po mililitru. Pojedinačne doze mogu da sadrže, na primer, od 1 mg do 10 g aktivne supstance. Ampule za injekcije, tako, mogu da sadrže, na primer, od 1 mg do 100 mg, a preparati za jedinične doze koje se mogu davati orlano, kao na primer, tablete ili kapsule, mogu da sadrže, na primer, od 1.0 do 1000 mg, najčešće od 10 do 600 mg. U slučaju farmaceutski prihvatljivih soli ranije pomenuti podaci o težini zasnivaju se na težini slobodnog jedinjenja iz koga je so izvedena. Za profilaksu i terapiju pri gore pomenutim uslovima, jedinjenja formule (I) mogu da se upotrebe kao čista, pretpostavlja se, međutim, da su u obliku jednog farmaceutskog preparata sa jednim prihvatljivim nosačem. Nosač mora, naravno, da bude prihvatljiv u smislu da je kompatibilan sa drugim sastojcima preparata i da nije štetan po zdravlje pacijenta. Nosač mora da je čvrst ili tečan ili i jedno i drugo i pretpostavlja se da je formulisan sa jedinjenjem u obliku jedinične doze, na primer, kao tableta, koja može da sadrži od 0.05% do 95% masenih aktivne supstance. Druge aktivne farmaceutske supstance mogu, takođe, da budu prisutne, uključujući druga jedinjenja formule (I). Framaceutski preparati pronalaska mogu da se proizvedu nekom od poznatih farmaceutskih metoda, koje se u osnovi sastoje od mešanja komponenata sa farmaceutski prihvatljivim nosačem i / ili pomoćnom supstancom. ;Framaceutski preparati pronalaska su oni koji su pogodni za orlano, rektalo, topično, peroralno (na primer podjezično) i parenteralno (na primer subkutano, intramuskulaturno, intradermalno ili intravenozno) davanje, mada najpogodniji način davanja zavisi u svakom pojedinačnom slučaju od prirode i jačine stanja koje treba da se tertira i od prirode jedinjenja formule (I) koje se u pojedinom slučaju koristi. Obloženi preparati i obloženi preparati koji lagano otpuštaju aktivnu suspstancu spadaju, takođe, u okvir pronalaska. Pretpostavljaju se preparati koji su otporni na kiseline i želudačne sokove. Pogodne prevlake otporne na želudačne sokove obuhvataju acetat ftalata celuloze, polivinil-acetat-ftalat, ftalat hidroksi-propil-metil-celuloze i anjonske polimere metakrilne kiseline i metil-metakrilata. ;Pogodna farmaceutska jedinjenja za oralnu upotrebu mogu da budu u obliku posebne jedinice kao što su, na primer, kapsule, obložene kapsule, ;tablete za sisanje ili tablete od kojih svaka sadrži određenu količinu jedinjenja formule(1); kao prahove ili granule; kao rastvor ili suspenziju u nekoj vodenoj ili nevodenoj sredini; ili kao emulzija ulje - u - vodi ili emulzija voda - u - ulju. Ovi preparati mogu, kao što je već pomenuto, da se proizvedu pomoću nekog pogodnog postupka koji uključuje i fazu u kojoj se aktivna supstanca i nosač (koji može da se sastoji od jedne ili više dodatnih komponenti) dovode u kontakt. Preparati su uglavnom proizvedeni ujednačenim i homogenim mešanjem aktivnih komponenti sa tečnim i / ili fino usitnjenim čvrstim nosačem, posle čega se proizvod oblikuje, ako je potrebno. Tako, na primer, jedna tableta može da se proizvede presovanjem ili livenjem nekog praha ili granula jedinjenja, ako je potrebno sa jednom ili više dodatnih komponenata. Presovane tablete mogu da se proizvedu tabletiranjem jedinjenja u obliku u kome slobodno teku, kao na primer kada su prah ili granule i gde se na odgovarajući način mešaju sa vezivom, sredstvom za klizanje, inertnim razblaživačem i / ili sa jedom ili više površinski aktivnih - dispergujućih supstanci u nekom odgovarajućem aparatu. Livene tablete se mogu proizvesti livenjem jedinjenja koje je u obliku praha i navlaženo je pomoću nekog inertnog tečnog razblaživača, u nekom pogodnom aparatu. ;Farmaceutski preparati koji su pogodni za perialno (podjezično) davanje obuhvataju tablete za sisanje koje sadrže neko jedinjenje formule (I) sa nekim sredstvom za ukus, po pravilu sa saharozom i gumi arabikom ili tragantom i pasitile koje sadrže jedinjenje u nekoj inertnoj osnovi, kao što su želatin i glicerin ili saharoza i gumi arabika. ;Farmaceutski preparati pogodni za parenteralno davanje sadrže, najbolje, strerilne vodene preparate jedinjenja formule (I), koji su, po moućnosti, izitoni sa krvlju potencijalnog primaoca. Ovi preparati se najbolje daju intravenozno, ma da se davanje može da izvede subkutanom, intarmuskularnom ili intradermalnom injekcijom. Ovi preparati mogu se, najbolje, proizvesti mešanjem jedinjenja sa vodom i sterilisanjem dobivenog rastvora i podešavanjem da bude izoton sa krvlju. Preparati pronalaska, koji mogu da se injektiraju, sadrže uglavnom od 0.1 do 5% masenih aktivnog jedinjenja. ;Farmaceutski preparati pogodni za rektalno davanje su, najbolje, u obliku čepića sa pojedinačnim dozama. Oni mogu da se proizvedu mešanjem nekog jedinjenja formule (I) sa jednim ili više uobičajenih čvrstih nosača, na primer, kakao - buterom i oblikovanjem dobivene mešavine. ;Farmaceutski preparati pogodni za topičnu upotrebu na koži je najbolje da su obliku masti, krema, losiona, pasta, spreja, aerozola ili ulja. Nosači koji se mogu upotrebiti su vazelin, lanolin, polietilen-glikol, alkoholi i kombinacije dveju ili više ovih supstanci. Aktivna supstanca je uglavnom prisutna u nekoj koncentraciji od 0.1 do 15% masenih preparata, na primer od 0.5 do 2%. ;Moguće je, takođe i trandermalno davanje. Farmaceutski preparati pogodni za trandermalnu upotrebu mogu da budu u obliku pojedinačnih flastera koji su pogodni za dugotrajan intiman kontakt sa epidermom pacijenta. Takvi flasteri na odgovarajući način sadrže aktivnu susptancu u nekom vodenom rastvoru koji je puferisan, ako odgovara, rastvoren i / ili dispergovan u nekom adhezivnom sredstvu, ili dispergovan u nekom polimeru. Jedna pogodna koncentracija aktivne supstance je oko 1% do 35%, najbolje oko 3% do 15%. Jedna posebna mogućnost je da aktivna supstanca bude oslobođena pomoću elektrotransporta ili jontoforeze, kako je opisano, na primer u Pharmaceutical Research, 2(6): 318 (1986). ;Jedinjenja formule (I) okarakterisana su svojim povoljnim dejstvima na metabolizam masti i ona su naročito pogodna kod sisara za smanjenje težine i za održavanje smanjene težine, pošto je smanjenje težine izvršeno i kao anoreksijsko sredstvo. Jedinjenja su okarakterisana svojom niskom toksičnošću i retkim sporednim efektima. Jedinjenja mogu da se upotrebe sama ili u kombinaciji sa drugim aktivnim supstancama za smanjenje težine ili sa onim koji su anoreksijski aktivni. Dalji anoreksijski aktivni sastojci ove vrste su pomenuti, na primer, u Crvenoj listi, poglavlje 01, pod: sredstva sa smanjenje težine / supresanti apetita i oni, takođe, uključuju aktivne komponente koje povećavaju razmenu energije u organizmu i tako dovode do smanjenja težine, ili one koje uglavnom utiču na opšti metabolizam organizma na takav način da jedno povećanje unošenja kalorija ne dovodi do povećanja rezerve masti, a jedno normalno unošenje kalorija dovodi do smanjenja rezerve masti organizma. Jedinjenja su pogodna za profilaksu i, naročiro, za tertiranje suvišne težine ili gojaznosti. Jedinjenja su, dalje, pogodna za profilaksu i, naročito, za lečenje šećerne bolesti tipa II, arterioskleroze i za normalizovanje metabolizma masti i za lečenje visokog krvnog pritiska. Jedinjenja deluju kao MCH antagonisten i, takođe, pogodni su za lečenje poremećaja osećanja zadovoljstva i psihijatrijskih bolesti, kao što su, na primer, depresije, stanja straha, neuroze izazvane strahom, šizofrenija i za lečenje bolesti koje su vezane za cirkadianski ritmus i za lečenje od zloupotrebe lekova. ;Kod jednog drugog aspekta pronalaska jedinjenja formule I se mogu davati u kombinaciji sa jednom ili više drugih farmakološki aktivnih supstanci koje su izabrane, na primer, iz grupe anti-diabetika, sredstava protiv gojaznosti, aktivnih sastojaka koji smanjuju krvni pritisak, sredstava za smanjenje masnoća i aktivnih sastojaka za lečenje i / ili sprečavanje komplikacija izazvanih šećernom bolešću ili povezanih sa šećernom bolešću.. ;Kao dalje farmakološki aktvine supstance su naročiro pogodni: ;svi anti-dijabetici pomenuti u Crvenoj listi 2001, poglavlje 12. Oni mogu da se kombinuju sa jedinjenjima formule I ovog pronalaska, naročito za sinergetska poboljšanja dejstva. Davanje kombinacija aktivnih supstanci može da se izvede ili odvojenim davanjem pacijentu aktivnih supstanci ili u obliku kombinovanih proizvoda u kojima je u farmaceutskom preparatu prisutno mnoštvo aktivnih komponenti. Najveći broj aktivnih supstanci koje su navedene dole su obelodanjene u USP Dictionarv of USAN i International Drug Names, US Pharmacopeia, Rockville 2001. ;Pogodni anti-dijabetici uključuju insulin i derivate insulina, kao što su, na primer, Lantus<®>ili HMR 1964, brzo-delujući insulini (vidi US 6,221,633), amilin, GLP-1 i GLP-2 derivati, kao što su, na primer, oni obelodanjeni u WO 98/08871 of Novo Nordisk A/S, i hipoglikemijski aktivne supstance koje su oralno efikasne. ;Oralno efikasni hipoglikemijski aktivni sastojci uključuju, najbolje, sulfonil-karbamide, biguanidine, meglitinide, oksa-dazolidin-dione, tiazolidin-dione, inhibitore glukozidaze, glukagon-receptor-antagonisten, GLP-1 agonisten, sredstva za proširenje sudova za eliminaciju kalijuma, kao što su, na primer, oni obelodanjeni u WO 97/26265 i WO 99/03861 of Novo Nordisk A/S, insulin-senzitizere, aktivatore insulin-receptore kinaze, inhibitore enzima jetre koji igraju ulogu u stimulaciji glukoneogeneze i / ili glikogenolize.na primer inhibitori glikogen fofsforilaze, modulatori uzimanja glukoze i eliminacije glukoze, jedinjenja koja menjaju metabolizam masti, kao što su anti-hiper-lipidemijske aktivne supstance i anti-lipidemijske aktivne supstance, npr., HMGCoA-reduktaze-inhibitor, inhibitori transporta holesterola / uzimanja holesterola, inhibitori resorpcije žučnih kiselina ili inhibitori mikrozomal-triglicerid-transfer-proteina (MTP), jedinjenja koja smanjuju uzimanje hrane, PPAR i RXR agonisten i aktivne supstance koje deluju na kalijum kanale beta - ćelija, koji su zavisni od ATP-a. ;U jednom vidu realizacije pronalaska predstavljena jedinjenja se daju u kombinaciji sa insulinom. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim HMGCoA-reduktaze-inhibitorom, kao što su simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim inhibitorom apsorpcije holesterola, kao što su, na primer, ecetimib, tikuezid, pamakvezid. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim PPAR gamma agonistom, kao što su, na primer, roziglitazon, pioglitazon, JTT-501, Gl 262570. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa PPAR alpha agonistom, kao što su, na primer, GW 9578, GW 7647. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim mešanim PPAR alpha/gamma agonistom, kao što su, na primer, GW 1536, AVE 8042, AVE 8134, AVE 0847, ili kao što je opisano u PCT/US 11833, PCT/US 11490, DE10142734.4. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim fibratom, kao što je, na primer, fenofibrat, klofibrat, bezafibrat. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim MTP inhibitorom, kao što su, na primer, implitapid, BMS-201038, R-103757. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa inhibitorom apsorpcije žučnih kiselina (vidi, na primer, US 6,245,744 ili US 6,221,897), kao što je , na primer, HMR 1741. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim CETP inhibitorom, kao što je, na primer, JTT-705. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim adsorbesom polimernih žučnih kiselina, kao što su, na primer, holestir-amin, kolesevelam. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim LDL receptor- induktorom (vidi US 6,342,512), kao što su, na primer, HMR1171, HMR1586. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim ACAT inhibitorom, kao što je, na primer, avasimib. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim antioksidansom, kao što je, na primer, OPC-14117. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim lipoprotein-lipaza-inhibitorom, kao što je, na primer, NO-1886. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim ATP-citrat-liaza-inhibitorom, kao što je, na primer, SB-204990. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim inhibitorom sinteze skvalena, kao što je, na primer, BMS-188494. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim lipoprotein(a)-antagonistom, kao što su, na primer, CI-1027 ili nikotinska kiselina. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim lipaza-inhibitorom, kao što je, na primer, orlistat. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa insulinom. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim sulfonil-karbamidom, kao što su, na primer, tolbutamid, glibenklamid, glipizid ili glimepirid. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim biguanidinom, kao što je, na primer, metformin. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim meglitinidom, kao što je, na primer, repaglinid. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim tiazolidin-dionom, kao što su, na primer, troglitazon, ciglitazon, pioglitazon, rosiglitazon ili jedinjenja obelodanjena u ;W0 97/41097 of Dr. Reddv's Research Foundation, naročito 5-[[4-[(3,4-dihidro-3-metiyl-4-okso-2-kuinazolinil-metoksi]fenil]metil]-2,4-tiazolidin-dion. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednim inhibitorom a-glukozidaze, kao što su, na primer, miglitol ili akarboza. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa jednom aktivnom supstancom koja deluje na ATP - zavisne kalijumove kanale beta ćelija, kao što su, na primer, tolbutamid, glibenklamid, glipizid, glimepirid ilir repaglinid. ;U jednom vidu realizacije pronalaska jedinjenja formule I se daju u kombinaciji sa više nego jednim ranije pomenutim jedinjenjem, na primer, u kombinaciji sa nekim sulfonil-karbamidom i metforminom, sa sufonil-karbamidom i akarbozom, repaglinid i metformin, insulin i neki sulfonil-karbamid, insulin i metformin, insulin i troglitazon, insulin i lovastatin, itd. Jedinjenja prema pronalasku mogu, šta više, da se daju u kombinaciji sa jednim ili više sredstava protiv gojaznosti, ili aktivnom supstancom za kontrolu apetita. ;U jednoj daljoj realizaciji jedinjenja formule I se daju u kombinaciji sa CART modulatorima (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety i gastric emptying in mice" Asakawa, A, et al., M.: Hormone i Metabolic Research (2001), 33(9), 554-558), NPY antagonisten, npr., naftalin-1-sulfonska kiselina {4-[(4-aminokuinazolin-2-il-amino)metil]cikloheksil-metil}amid; hidro-hlorid (CGP 71683A)), MC4 agonisten (npr. 1-amino-1,2,3,4-tetrahidronaftalin-2-karboksi-kiselina [2-(3a-benzil-2-metil-3-okso-2,3,3a,4,6,7-heksahidro-pirazolo[4,3-c]piridin-5-il)-1-(4-hloro-fenil)-2-okso-etil]-amid; (WO 01/91752)), oreksin antagonisten (npr. 1-(2-metil-benz-oksazol-6-il)-3-[1,5]naft-hiridin-4-il-kirbamid; hidro-hlorid (SB-334867-A)), H3 agonisten (3-cikloheksil-1-(4,4-dimetil-1,4,6,7-tetrahidro-imidazo[4,5-c]piridin-5-il)propan-1-on so oksalne kiseline (WO 00/63208)); TNF agonisten, CRF antagonisten (npr., [2-metil-9-(2,4,6-trimetilfenil)-9H-1,3,9-triazafluoren-4-il]dipropil-amine (WO 00/66585)), CRF BP antagonisten (npr., urokortin), urokortin agonisten, p3 agonisten (npr., 1- (4-hloro-3-metan-sulfonil-metil-fenil)-2-[2-(2,3-dimetil-1H-indol-6-il-oksi)etil-amino]-etanol-hidro-hlorid (WO 01/83451)), MSH (melanocit-stimulišući hormoni) agonisten, CCK-A agonisten (npr., {2-[4-(4-hloro-2,5-dimetoksi-fenil)-5-(2-cikloheksil-etil)tiazol-2-il4<abamoil]-5,7-dimetil-indol-1-il} sirćetna kiselina so trifluoro-sirćetne kiseline (WO 99/15525)), serotonin ;-obnavljajući inhibitori (npr., deksfen-fluor-amin), mešana sertoninergiska i noradrenergiska jedinjenja (npr., WO 00/71549), 5HT agonisten, npr., so 1 -(3-etil-benzofuran-7-il)piperazin-oksalne kiseline (WO 01/09111), bombesin agonisten, galanin antagonisten, hormoni rasta (npr., humani ;hormoni rasta), jedinjenja koja otpuštaju hormone rasta terc.-butil-estar (6-benzi-loksi-1-(2-diizopropil-amino-etil-karbamoil)-3,4-dihidro-1H-izohinolin-2- karboksilne kiseline (WO 01/85695)), TRH agonisten (vidi, na primer, EP 0 462 884), dekuplujući protein 2 ili 3 modulatori, leptin agonisten (vidi, na primer, Lee, Daniel W.; Leinung, MatthevvC; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonisten kao jedan potencijalni prilaz za lečenje gojaznosti. Drugs ofthe Future (2001), 26(9), 873-881), DA agonisten (bromokriptin, dopreksin), lipaza/amilaza inhibitori (npr., WO 00/40569), PPAR modulatori (npr., WO 00/78312), RXR modulatori ili TR-p agonisten. ;Kod jednog vida realizacije pronalaska druga aktivna supstanca je leptin; vidi, na primer, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622. ;Kod jednog vida realizacije druga aktivna supstanca je deksamfatamin ili amfetamin. ;Kod jednog vida realizacije druga aktivna supstanca je fenfluramin ili deksfenfluramin. ;Kod jednog drugog vida realizacije druga aktivna supstanca je sibutramin ili mono- i bis-demetilovani aktivni metaboliti sibutramina. ;Kod jednog vida realizacije druga aktivna supstanca je orlistat. ;Kod jednog vida realizacije druga aktivna supstanca je mazindol ili fentermin. ;Kod jednog vida realizacije jedinjenja formule I se daju u kombinaciji sa balast - supstancama, najbolje nerastvornim balast - supstancama (vidi, na primer, carob/Caromax<®>(Zunft H J; et al., Carob pulp preparation for treatment of hvpercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.). Caromax je jedan proizvod koji sadrži karob od firme Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main)). kombinacija sa Caromax<®>moguća je u jednom pripremanju ili pomoću odvojenog davanja jedinjenja formule I i Caromax<®->a. Caromax<®>se može u vezi sa ovim, takođe davati u obliku proizvoda hrane, kao što su peciva ili musle. ;Predstavljena jedinjenja mogu se dodatno davati u kombinaciji sa jednom ili više anti-hiper-tenzivnih aktivnih supstanci. Primeri anti-hiper-tenzivnih aktivnih supstanci su beta blokeri, kao što su alprenolol, atenol, timolol, pindolol, propanolol i metoprolol, ACE (angiotensin konvertujući enzim) inhibitori, kao što su, na primer, benazepril, kaptopril, enalapril, fosinopril, lisinopril, kuinapril i rampril, blokeri kalcijum- - kanala, kao sto su nifedipin, felodipin, nikardipin, izradipin, nimodipin, diltiazem i verapamil, i alfa blokeri, kao što su doksazosin, urapidil, prazosin i terazosin. Dalje se upućuje na literaturu Remington: The Science i Practice of Pharmacv, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, 1995. ;Podrazumeva se da se svaka pogodna kombinacija jedinjenja prema pronalasku sa, najpovoljnije, jednom ili više ranije pomenutih farmakološki aktivnih supstanci i, po izboru, sa jednom ili više drugih farmakološki aktivnih supstanci, smatra pokrivenom zahtevom za zaštitu predstavljenog pronalaska.. ;Primeri;Dejstvo jedinjenja je ispitivano na sledeći način: ;Model biološkog testa: ;Anoreksijski efekat je ispitivan na ženkama NMRI miševima. Posle obustavljanja hrane za 17 sati supstanca za ispitivanje je davana prinudno. Životinje su držane pojedinačno sa slobodnim pristupom pijaćoj vodi i nuđeno im je kondenzovano mleko 30 minuta posle davanje supstance. Potrošnja kondenzovanog mleka određivana je svakih pola sata u toku 7 sati i posmatrano je opšte raspoloženje životinja. Izmerena potrošnja mleka upoređena je sa kontrolnim životinjama.. ;Tabela 1: anoreksijski efekat meren kao smanjenje kumulovane potrošnje mleka tretiranih životinja u poređenju sa kontrolnim životinjama ;OPIS EKSPERIMENATA ;Funkcionalna merenja za odeređivanje IC50 vrednosti ;Kloniranje cDNK za humani MCH receptor, spravljanje jednog ;rekombinanta HEK293 ćelijske linije koja izražava humani MCH receptor i funkcionalna merenja sa rekombinantnim ćelijskim linijama odigravalo se na isti način kako je opisano od starne Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). Razlika od ove reference bila je, međutim, upotreba plasmida pEAK8 iz EDGE Biosistems (USA), da bi se konstruisao ekspresioni vektor. Domaćin koji je koršćen za tranfekciju bila je jedna transformisana HEK ćelijska linija imenovana kao "PEAK Stable Cells" ;(slično iz EDGE Biosistems). Funkcionalna merenja ćelijskog kalcijum - fluksa posle dodavanja agonistena (MCH) u prisustvu liganda ovog pronalaska izvođena su uz pomoć FLIPR aparata od Molecular Devices (USA), koristeći protokole proizvođača aparature. ;Primeri i metode spravljanja, date dole u detaljima, služe da ilustruju pronalazak bez da ga, međutim, ograničavaju. ;Jedinjenja formule I prema pronalasku mogu da se sintetizuju uz pomoć reakcija koje su, u principu, poznate. Na primer, jedinjenja su bila dobivena u skladu sa sledećim opštim reakcionim shemama. ;Druga jedinjenja pronalaska mogu da se dobiju drugim putevima sinteze, koji su vidljivi kroz primer dat u sledećoj shemi. ;Ima i više primera kako se vidi iz sledeće sheme. ;Opisi opštih korišćenih postupaka vidljivi su kroz primere opisane na sledećim mestima: postupci A, B i C u primeru 1; ;postupak D u primeru 2; ;postupak E u primeru 3; ;postupak E-a u primeru 275; ;postupak E-b u primeru 286; ;postupak F u primeru 4; ;postupak F-a u primeru 264; ;postupak F-a u primeru 264; ;postupak G u primeru 15; ;posrupak H u primeru 237; ;postupak H-a u primeru 298; ;postupak I u primeru 238; ;postupak J u primeru 245; ;postupak J-a u primeru 297; ;postupak K u primeru 250; ;postupak L u primeru 254; ;postupak M u primeru 274; ;postupak N u primeru 277; ;postupak O u primeru 279; ;postupak O-a u primeru 292; ;postupak O-b u primeru 280; ;postupak P u primeru 285; ;postupak Q u primeru 290; ;postupak R u primeru 309. ;Opšta objašnjenja ;a) Način crtanja strukturnih formula ;Zbog jasnoće, u strukturnim formulama kod datih primera, prikazani su ;samo atomi koji nisu vodonik. ;U tabelama 6-13, jedinjenja obogaćena enantiomerom se identifikuju preko obeleženog vodonikovog atoma na stereogenskom centru. Ako nije izričito rečeno prikazani primeri obogaćeni enentiomerom imaju (R) konfiguraciju na 3-amino-pirolidin-stereo-centru. ;b) Oblici soli ;Mnoga od jedinjenja prema pronalasku su baze i mogu da grade soli sa ;odgovarajuće jakim kiselinama. Naročito posle prečišćavanja jedinjenja pomoću HPLC- hromatografije, koristeći mobilnu fazu koja sadrži hidro-tirfluor-sirćetnu kiselinu, oni mogu biti u obliku hidro-trifluor-acetata. Ovi se mogu prevesti u ovde prikazane slobodne baze pomoću jednostavnog tretiranja nekog rastvora soli sa, na primer, rastvorom natrijum-karbonata ;c) Jedinice karakterističnih veličina ;Jedinica date molekulske težine je "g/mol". Pikovi koji se pojavljuju u ;masenom spektru naznačeni su kao odnos molekulske težine jona i električnog naboja molekuskog jona (m/z). ;Primer 1 ;N-Metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)acet-amid ; ;Postupak A ;Rastvor 4-fenoksi-anilina (3.33 g) u DMF - u (10 ml) dodat je, kap po kap, u jedan rastvor karbonil-diimidazola (2.92 g) u DMF - u (12 ml) i, zatim, je smeša ohlađena na 0°C. Posle 30 minuta dodat je, kap po kap N-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acetamid (3.80 g) u DMF-u (10 ml). Reakcioni rastvor je držan, prvo na sobnoj temperaturi tokom 2 sata, a zatim 30 minuta na 80°C. Smeša je dodata, kap po kap, u vodu (600 ml) i dobiveni talog je proceđen uz pomoć vakuuma i opran vodom. Na drugi način, proizvod može i da se ekstrahuje pomoću etil-acetata i da se prečisti, posle uparavanj, pomoću hromatografije. Na kraju je dobiven proizvod molekulske težine 444.54 (C26H28N403); MS (ESI): 445 (M+H+). ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid ;Postupak B ;Suspenzija N-metil-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amida (3.5 g) i paladijum(ll)-hidroksida (20% na uglju; 0.9 g) u etanolu (150 ml) i etil-acetatu (300 ml) mešana je snažno 3 sata u atmosferi vodonika (atmosferski pritisak). Uklonjen je katalizator ceđenjem i filtrat je uparen. Na kraju je dobiven proizvod molekulske težine 233.32 (C13H19N30); MS (ESI): 234 (M+H+). ;N-Metil-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid ;Postupak C ;4-Fluor-nitro-benzol (25.0 g) dodat je polako u jednu suspenziju N-metil-N-pirolidin-3-il-acet-amida (25.2 g) i cezijum-karbonata (57.6 g) u DMF - u (300 ml). Reakciona smeša se posle 2 sata sipa u vodu i nastali talog se procedi uz pomoć vakuuma. Na drugi način, proizvod može da se ekstrahuje pomoću etil-acetata i posle uparavanja prečisti pomoću hromatografije. Na kraju se dobiva proizvod molekulske težine 263.30 (C13H17N303): MS (ESI): 264 (M+H+). ;Primer 2 ;1-[4-(3-Metil-amino-pirolidin-1-il)fenil]-3-(4-fenoksi-fenil)karbamid ; ;Postupak D ;Smeša N-metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)acet-amida (6.0 g), etanola (250 ml), vode (60 ml) i rastvora natrijum-hidroksida (10 M; 80 ml) grejano je sa povratnim hladnjakom 12 sati. Alkohol je odestilisan i nastali talog je oceđen uz pomoć vakuuma i opran pomoću dihlor-metana. Dodatna količina proizvoda dobivena je uparavanjem organskog sloja i hromatografisanjem (silika-gel, dihlor-metan / metanol 9:1 sa 1% trietil-amina). Na kraju je dobiven proizvod molekulske težine 402.50 (C24H26N402); MS (ESI): 403 (M+H+). ;Primer 3 ;N-Metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)-2-fenil-acet-amid ; ;Postupak E ;TOTU (327 mg) je dodat u rastvor 1-[4-(3-metil-amino-pirolidin-1-il)fenil]-3-(4-fenoksi-fenil)karbamida (402 mg) u DMF -u (3 ml) na 0°C. Posle 10 minuta dodati su Huenig-ova baza (130 mg) i, zatim, jedan rastvor fenil-sirćetne kiseline (136 mg) u DMF - u (1 ml). Posle 12-to časovnog reagovanja na sobnoj temperaturi u smešu je dodata voda i sve je ekstrahovano pomoću etil-acetata. Organski sloj je osušen iznad magenzijum-sulfata i uparen. Ostatak je prečišćen pomoću preparativne HPLC. Na kraju je dobiven proizvod molekulske težine 520.64 (C32H32N403); MS (ESI): 521 (M+H+) kao hidro-trifluor-acetat. ;Primer 4 ;ff?J-N-Metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)acetamid ; ;f/:?/)-N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 4-fenoksi-anilinom po postupku A. Na kraju je dobiven proizvod molekulske težine 444.54 (C26H28N403); MS (ESI): 445 (M+H+). ;ff?J-N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid fRJ-N-Metil-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid je higrogenizovan po posupku B. Na kraju je dobiven proizvod molekulske težine 233.32 (C13H19N30); MS (ESI): 234 (M+H+). ;(Ry)-N-Metil-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid ;postupak F ;(7?j-N-[1-(4-Nitro-fenil)pirolidin-3-il]acet-amid (1.3 g) je dodat u porcijama u suspenziju natrijum-hidrida (50% u ulju; 0.25 g) u DMF - u (50 ml). Po prestanku izdvajanja gasa dodat je jod-metan (0.82 g). Posle jednog sata rekciona smeša je pažljivo hidrolizovana vodom i ekstrahovana pomoću etil-acetata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Na kraju je dobiven proizvod molekulske 263.30 (C13H17N303); MS (ESI): 264 (M+H+). ;(R>N-[1-(4-Nitro-fenil)pirolidin-3-il]acet-amid ;(RJ-N-pirolidin-3-il-acet-amid je reagovao sa 4-fluor-nitro-benzolom po postupku C. Na kraju je dobiven proizvod molekulske težine 249.27 (C12H15N303); MS (ESI): 250 (M+H+). ;Primer 5 ;(S>N-Metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)acet-amid ; ;Redosled opisan u primeru 4 primenjen je na (Sj-N-pirolidin-3-il-acet-amid. Na kraju je dobiven proizvod molekulske težine 444.54 (C26H28N403); MS (ESI): 445 (M+H+). ;Primer 6 ;('f?/)-1-[4-(3-Metil-amino-pirolidin-1-il)fenil]-3-(4-fenoksi-fenil)karbamid ; (Rj-N-Metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)acet-amid je reagovao po postupku D. Na kraju je dobiven proizvod molekulske težine 402.50 (C24H26N402); MS (ESI): 403 (M+H+). Primer 7 (^Sj-1-[4-(3-Metil-amino-pirolidin-1-il)fenil]-3-(4-fenoksi-fenil)karbamid ;CS/)-N-Metil-N-(1-{4-[3-(4-fenoksi-fenil)ureido]fenil}pirolidin-3-il)acet-amid je reagovao po postupku D. Na kraju je dobiven proizvod molekulske težine 402.50 (C24H26N402); MS (ESI): 403 (M+H+). ;Primer 8 ;(R)-N-(1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)-N-metil--acet-amid ; ;(R)-N-[1-(4-Amino-fenil)pirolidin-3-il)-N-metil-acet-amid je reagovao sa 4-ciklopentil-oksi-anilinom po postupku A. Na kraju je dobiven proizvod molekulske težine 436.56 (C25H32N403); MS (ESI): 437 (M+H+). ;(S)-N-(1-{4-[3-(4-ciklopentil-oksi-fenil)-ureido]-fenil}-pirolidin-3-il)-N-metil-acet-amid je dobiven na isti način iz (S)-N-[1-(4-amino-fenil)-pirolidin-3-il]-N-metil-acet-amid. ;4-Ciklopentil-oksi-anilin ;Smeša 4-nitro-fenola (63.7 g), brom-ciklopentana (68.2 g), kalijum-karbonata (63.3 g) i DMF - a (300 ml) grejana je na 80°C 24 sata. Po ohlađenju smeša je razblažena vodom i ekstrahovana pomoću etil-acetata. Organski sloj je opran vodom, osušen iznad magnezijum-sulfata i uparen. Ostatak je hidrogenizovan po postupku B. Na kraju je dobiven proizvod molekulske težine 177.25 (C11H15NO); MS (ESI): 178 (M+H+). ;Primer 9 ;1-(4-Ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)fenil]karbamid ; ;N-(1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)-N-metil-acet-amid je reagovao po postupku D. Na kraju je dobiven proizvod molekulske težine 394.52 (C23H30N4O2); MS (ESI): 395 (M+H+). ;(R)- i (S)-1-(4-ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)-fenil]-karbamid je dobiven na ist način iz (R)- i (S)-N-(1-{4-[3-(4-ciklopentil-oksi-fenil)-ureido]-fenil}-pirolidin-3-il)-N-metil-acet-amid. ;Primer 10 ;Etil-estar (1-{4-[3-(4-ciklopentil-oksi-ifenil)ureido]fenil}pirolidin-3-il)metil-karb-aminske kiseline ;Etil-hlor-format (8 u.1) je dodat, kap po kap, u rastvor 1-(4-ciklopentil-oksi-fenil)-3-[4-(3-rnetil-amino-pirolidin-1-il)fenil]karbamida (20 mg) i Huenig-ove baze (10 mg) u dihlor-metanu (3 ml), posle 12 sati je reakciona smeša uparena i ostatak je prečišćen pomoću preparativne HPLC. Na kraju je dobiven proizvod molekulske težine 466.59 (C26H34N404); MS (ESI): 467 (M+H+) u obliku hidro-trifluor-acetata. ;Primer 11 ;1-(1-{4-[3-(4-ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)-3-etil-1-metil-karbamid ; ;Etil-izocijanat (7 jul) je dodat, kap po kap, u rastvor 1-(4-ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)fenil]karbamida (20 mg) i Huenig-ove baze (10 mg) u dihlor-metanu (3 ml). Posle 12 sati rekciona smeša je uparena i ostatak je prečišćen pomoću preparativne HPLC. Na kraju je dobiven proizvod molekulske težine 465.60 (C26H35N503); MS (ESI): 466 (M+H+) u obliku hidro-trifluor-acetata. ;Primer 12 1-(4-Ciklopentil-oksi-fenil)-3-(4-{3-[metil-((R)-5-okso-pirolidin-2-il-metil)amino]pirolidin-1-il}fenil)karbamid ;(RJ-5-Brom-metil-pirolidin-2-one (15 mg) je dodat u suspenzuju 1-(4-ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)fenil]karbamida (30 mg) i kalijum-karbonata (20 mg) u DMF - u (3 ml). Posle 2 sata reakciona smeša je proceđena i uparena i ostatak je prečišćen pomoću preparativne HPLC. Na kraju je dobiven proizvod molekulske težine 491.64 (C28H37N503); MS (ESI): 492 (M+H+) u obliku hidro-trifluor-acetata. ;Primer 13 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 4-(4-hlor-fenil)piperidin-1-karboksilne kiseline ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa karbonil-diimidazolom i, zatim, sa 4-(4-chlor-fenil)piperidinom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 455.00 (C25H31CIN402); MS (ESI): 455 (M+H+). ;( R)- i(S;-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 4-(4-hlor-fenil)piperidin-1-karboksilne kiseline dobiven je na isti način iz( R)- i ( S)- H-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acetamida. ;Primer 14 ;terc.-Butil( R)-[\-(4-{[4-(4-hlor-fenil)piperidin-1 -karbonil]amino}fenil)pirolidin-3-il]metil-karbamat ; ;terc.-Butil ('/?j-[1-(4-amino-fenil)pirolidin-3-il]metil-karbamat je reagovao sa karbonil-diimidazolome i, zatim sa 4-(4-hlor-fenil)piperidinom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 513.09 (C28H37CIN403); MS (ESI): 513 (M+H+). ;terc.-Butil (RJ-[1-(4-amino-fenil)pirolidin-3-il]metil-karbamat ;terc.-Butil (RJ-metil-fl -(4-nitro-fenil)pirolidin-3-il]karbamat je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 291.40 (C16H25N302); MS (ESI): 292 (M+H+). ;terc.-Butil (Rj-metil-[1-(4-nitro-fenil)pirolidin-3-il]karbamat ;terc.-Butil (RJ-[1-(4-nitro-fenil)pirolidin-3-il]karbamat je alkilovan sa jod-metanom po postupku F. Kao rezultat dobiven je proizvod molekulske težine 321.38 (C16H23N304); MS (ESI): 322 (M+H+). ;terc.-Butil( R)-[\ -(4-nitro-fenil)pirolidin-3-il]karbamat;terc.-Butil (RJ-pirolidin-3-il-karbamat je reagovao sa 4-fluor-nitro-benzolom prema postupku C. Kao rezultat dobiven je proizvod molekulske težine 307.35 (C15H21N304); MS (ESI): 308 (M+H+). ;Primer 15 ;[4-(3-Metil-amino-pirolidin-1 -il)fenil]amid (R)-4-(4-hloro-fenil)piperidin-1 - karbonske kiseline ; ;postupak G ;Trifluor-sirćetna kiselina (6.67 g)je dodata ujedan rastvor terc.-Butil (RJ-[1-(4-{[4-(4-hlor-fenil)piperidin-1-karbonil]amino}fenil)pirolidin-3-il]metil-karbamata (1.5 g) u dihlor-metanu (50 ml). Posle 3 sata uklonjene su isparljive supstance i ostatak je rastvoren u dihlor-metanu. Posle pranja sa rastvorom natrijum-karbonata organski sloj je osušen iznad magnezijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine 412.97 (C23H29CIN40); MS (ESI): 413 (M+H+). ;Primer 16 ;(4-{('Rj-3-[Metil-(1-metil-piperidin-3-il-karbonil)amino]pirolidin-1-il}fenil)amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; [4-(3-Metil-amino-pirolidin-1 -il)fenil]amid (R>4-(4-hlor-fenil)piperidin1-karbonske kiseline je reagovao sa1-metil-piperidin-3-karboksilnom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 538.14 (C30H40CIN5O2); MS (ESI): 538 (M+H+). Primer 17 (4-ff?j-{3-[Metil-(2-piperidin-1-il-acetil)amino]pirolidin-1-il}fenil)amid 4-(4-hlor-fenil)piperidin-1 -karbonske kiseline [4-(3-Metil-amino-pirolidin-1-il)fenil]amid (f?)-4-(4-hlor-fenil)piperidin-1-karbonske kiseline reagovao je sa piperidin-1-il-sirćetnom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 538.14 (C30H40CIN5O2); MS (ESI): 538 (M+H+). Primer 18 (4-(RH3-[Meti|-(2-okso-tiazolidin-4-karbonil)amino]pirolidin-1-il}fenil)amid 4-(4-hlor-fenil)piperidin-1 -karbonske kiseine ;[4-(3-Metil-amino-pirolidin-1 -il)fenil]amid (Rj-4-(4-hlor-fenil)piperidin-1 - karbonske kisleine reagovao je sa 2-okso-tiazolidin-4-karbonskom ;kiselinom po postupku E. Kao rezultat dobiven je proizvod molekulske težine 542.10 (C27H32CIN503S); MS (ESI): 542 (M+H+). ;Primer 19 ;(4-{3-[Metil-(2,2,2-trifluor-acetil)amino]pirolidin-1-il}fenil)amid( R)- 4-( 4- h\ or-fenil)piperidin-1-karbonske kiseline ; ;ff?HN-[1-(4-Amino-fenil)pirolidin-3-il]-2,2,2-trifluor-N-metil-acet-amid resgovaoje sa karbonil-diimidazolom i, zatim, sa 4-(4-hlor-fenil)-piperidinom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 508.98 (C25H28CIF3N402); MS (ESI): 509 (M+H+). ;f/?/)-[N-[1-(4-Amino-fenil)pirolidin-3-il]-2,2,2-trifluor-N-metil-acet-amid ;(RJ-2,2,2-Trifluor-N-metil-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid hidrogenizovan je po postupku B. Kao rezultat dobiven je proizvod molekulske težine 287.29 (C13H16F3N30); MS (ESI): 288 (M+H+). ;(R;-2,2,2-Trifluor-N-metil-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid ;Anhidrid trifluor-sirćetne kiseline (0.5 ml) dodat je, kap po kap, ujedan rastvor ff?j-metil-[1-(4-nitro-fenil)pirolidin-3-il]amina (0.48 g) u piridinu (2 ml). Posle 3 sata reakciona smeša je razblažena vodom i ekstrahovana pomoću etil-acetata. Organski sloj je opran rastvorom limunske kiseline, sušen je iznad magnezijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine 317.27 (C13H14F3N303); MS (ESI): 318 ;(M+H+). ;(R/)-Metil-[1-(4-nitro-fenil)pirolidin-3-il]amin ;Rastvor terc.-butil (R/)-metil-[1-(4-nitro-fenil)pirolidin-3-il]kcarbamata (0.7 g) u dihlor-metanu (5 ml) tretiranje sa trifluor-sirćetmom kiselinom (3 ml) u toku jednog sata. Rekcioni rastvor je upareni ostatak je rastvoren u dihlor-metanu. posle pranja sa rastvorom natrijum-karbonata organski sloj je oeušen iznad magnezijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine of 221.26 (C11H15N302); MS (ESI): 222 ;(M+H+). ;Primer 20 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}metil-amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; ;{4-[3-(Acetil-metil-amino)pirolidin-1 iyl]fenil}amid 4-(4-hlor-fenil)piperidin-1 - karbonske kiseline tretitan je sa jodo-metanom prema postupku F. Kao rezultat dobiven je proizvod molekulske težine 469.03 (C26H33CIN402); MS (ESI):469(M+H+). ;Primer 21 ;(4-{3-[Acetil-(2-dietil-amino-etil)amino]pirolidin-1-il}fenil)amid(ft)-4-(4-hlor-fenil)piperidin-1-karbonske kisleline ; ff?>N-[1-(4-Amino-fenil)pirolidin-3-il]-N-(2-dietil-amino-etill)acet-amid reagovao je sa 4-(4-hlor-fenil)piperidinom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 540.15 (C30H42CIN5O2); MS (ESI): 540 (M+H+). (RJ-N-[1-(4-Aminofenil)pirolidin-3-il]-N-(2-dietil-amino-etil)acet-amid (f?>N-(2-Dietil-amino-etil)-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid hidrogenizovan je prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 318.47 (C18H30N4O); MS (ESI): 319 (M+H+). ('f?j-N-(2-Dieti-lamino-etil)-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid (RJ-N-[1-(4-nitro-fenil)pirolidin-3-il]acet-amid reagovao je sa 2-hlor-etil-dietil-aminom prema postupku F. Kao rezultat dobiven je proizvod molekulske težine 348.45 (C18H28N403); MS (ESI): 349 (M+H+). Primer 22 1-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-3-(4-fenoksi-fenil)karbamid ;Dimetil-pirolidin-3-il-amin reagovo je sa 4-fluor-nitro-benzolom, dobiveno nitro - jedinjenje redukovano je pomoću vodonika i, na kraju je anilin reagovao sa CDI i 4-fenoksi-anilinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 416.53 (C25H28N402); MS (ESI):417(M+H+). ;Primer 23 ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-izobutoksi-fenil)propion-amid ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid reagovao je sa 2-(4-izobutoksi-fenil)propionskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 437.59 (C26H35N303); MS (ESI): 438 (M+H+). ;Primer 24 ;N-(1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)acet-amid ;N-Pirolidin-3-il-acet-amid je reagovao sa 4-fluor-nitro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-ciklopentil-oksi-anilinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 422.53 (C24H30N4O3); MS (ESI): 423 (M+H+). ;( R)-i (SJ-N-(1 -{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)acet-amid su dobiveni na isti način polazeći od( R)-i (SJ-N-pirolidin-3-il-acet-amida. ;Primer 25 ;N-(1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)-N-etil-acet-amid ; ;N-Etil-N-pirolidin-3-il-acet-amid je reagovao sa 4-fluor-nitro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-ciklopentil-oksi-anilinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 450.59 (C26H34N403); MS (ESI): 451 (M+H+). ;Primer 26 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]-3-metil-fenil}amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; ;N-Metil-N-pirolidin-3-il-acet-amid je ragovao sa 1-fluor-2-metil-4-nir.ro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-(4-hlor-fenil)piperidinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 469.03 (C26H33CIN402); MS (ESI): 469 (M+H+). ;Primer 27 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il)-3-fluor-fenil}amid 4-(4-hlor-fenil)piperidin-1 -karbonske kiseline ; ;N-Metil-N-pirolidin-3-il-acet-amid reagovao je sa 1,2-difluor-4-nitro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-(4-hlor-fenil)piperidinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 472.99 (C25H30CIFN4O2); MS (ESI): 473 (M+H+). ;Primer 28 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]-2,6-difluor-fenil}amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; ;N-Metil-N-pirolidin-3-il-acet-amid reagovao je sa 1,3,5-trifluor-2-nitro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-(4-hlor-fenil)piperidinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 490.99 (C25H29CIF2N402); MS (ESI): 491 (M+H+). ;Primer 29 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]-2-metil-fenil}amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; ;N-Metil-N-pirolidin-3-il-acet-amid je reagovao sa 4-fluor-2-metil-1-nitrobenzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-(4-hlor-fenil)piperidinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 469.03 (C26H33CIN402); MS (ESI): 469 (M+H+). ;Primer 30 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]-2-fluor-fenil}amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; ;N-Metil-N-pirolidin-3-il-acet-amide je reagovao sa 2,4-difluor-1 -nitro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-(4-hlor-fenil)piperidinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 472.99 (C25H30CIFN4O2); MS (ESI): 473 (M+H+). ;Primer 31 ;terc.-Butil (RJ-[1-(5-{[4-(4-hlor-fenil)piperidin-1-karbonil]amino}pyridin-2-il)pirolidin-3-il]metil-karbamat ; ;Tok sinteze za dobivanje terc.-butil (f?>[1-(4-{[4-(4-hlor-fenil)piperidin-1-karbonil]amino}fenil)pirolidin-3-il]metil-karbamata izvođen je tako što je započeo od 2-chlor-5-nitro-piridina umesto od 4-fluor-nitrobenzola. Rezultat toga je dobivanje proizvoda molekulske težine 514.07 (C27H36CIN503); MS (ESI): 514(M+H+). ;Primer 32 ;[6-(3-Metil-amino-pirolidin-1-il)pyridin-3-il]amid (R)-[4-(4-hlor-fenil)piperidin-1-karbonske kiseline ;terc.-Butil ('f?j-[1-(5-{[4-(4-hlor-fenil)piperidin-1-karbonil]amino}pyridin-2-il)pirolidin-3-il]metil-karbamat tertiran je sa trifluor-sirćetnom kiselinom po postupku G. Rezultat toga je dobivanje proizvoda molekulske težine 413.95 (C22H28CIN50); MS (ESI): 414 (M+H+). ;Na sličan način bilo je moguće da se dobije racemski [6-(3-metil-amino-pirolidin-il)pyridin-3-il]amid [4-(4-hlor-fenil)piperidin-1 -karbonske kiseline. ;Primer 33 ;{6-[3-(Acetil-metil-amino)pirolidin-1-il]piridin-3-il}amid 4-(4-hlor-fenil)piperidin-1 -karbonske kiseline ; ;N-Metil-N-pirolidin-3-il-acet-amid je reagovao sa 2-hlor-5-nitro-piridinom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-(4-hlor-fenil)piperidinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 490.99 (C25H29CIF2N402); MS (ESI): 491 (M+H+). ;Primer 34 1-[4-(4-Dimetil-amino-piperidin-1-il)fenil]-3-(4-fenoksi-fenil)karbamid ;Dimetil-piperidin-4-il-amin je reagovao sa 4-fluor-nitro-benzolom, dobiveno nitro - jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin ([1-(4-amino-fenil)piperidin-4-il]dimetil-amin) reagovao sa CDI i 4-fenoksi-anilinom prema postupcima A, B i C. Kao rezultat dobiven je proizvod molekulske težine 430.55 (C26H30N4O2); MS (ESI): 431 (M+H+). ;Primer 35 ;1-(4-Ciklopentil-oksi-fenil)-3-[4-(4-morfolin-4-il-iiperidin-1-yl)fenil]karbamid ; ;4-Piperidin-4-il-morfolin je reagovao sa 4-fluor-nitro-benzolom, dobiveno nitro-jedinjenje je redukovano pomoću vodonika i, na kraju, je anilin reagovao sa CDI i 4-ciklopentil-oksi-anilinom A, B i C. Kao rezultat dobiven je proizvod molekulske težine 464.61 (C27H36N403); MS (ESI): 465 ;(M+H+). ;Primer 36 ;4-Butoksi-N-[4-(4-dimetil-amino-piperidin-1-il)fenil]benzamid ; ;([1-(4-Amino-fenii)piperidin-4-il]dimetil-amin) je reagovao sa 4-4-butoksi-benzoevom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 395.55 (C24H33N302); MS (ESI): 396 ;(M+H+). ;Primer 37 ;{4-[3-(Acetil-metil-amino)azetidin-1-il]fenil}amid 4-(4-hlor-fenil)piperidin-1-karbonske kiseline ; ;N-[1-(4-Amino-fenil)azetidin-3-il]-N-metil-acet-amid je reagovao sa karbonil-diimidazolom i 4-(4-hlor-fenil)piperidinom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 440.98 (C24H29CIN402); MS (ESI): 441 (M+H+). ;N-[1-(4-Amino-fenil)azetidin-3-il]-N-metil-acet-amid ;N-Metil-N-[1-(4-nitro-fenil)azetidin-3-il]acet-amid je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 219.29 (C12H17N30); MS (ESI): 220 (M+H+). ;N-Metil-N-[1-(4-nitro-fenil)azetidin-3-il]acet-amid ;N-[1-(4-nitro-fenil)azetidin-3-il]acet-amid je alkilovan sa jod-metanom prema postupku F. Kao rezultat dobiven je proizvod molekulske težine 249.27 (C12H15N303); MS (ESI): 250 (M+H+). ;N-[1-(4-Nitro-fenil)azetidin-3-il]acet-amid ;Anhidrid sirćetne kiseline (0.6 ml) dodat je u rastvor 1-(4-nitro-fenil)azetidin-3-il-amina (0.5 g ) u piridinu (1.2 ml). Posle jednog sata uklonjene su isparljive frakcije. Kao rezultat dobiven je proizvod molekulske težine 235.24 (C11H13N303); MS (ESI): 236 (M+H+). ;1-(4-Nitro-fenil)azetidin-3-il-amin ;terc.-Butil [1-(4-nitro-fenil)azetidin-3-il]karbamat je tertian sa trifluor-sirćetnom kiselinom prema postupku G. Kao rezultat dobiven je proizvod molekulske težine 193.21 (C9H11N302); MS (ESI): 194(M+H+). ;terc.-Butil [1 -(4-nitro-fenil)azetidin-3-il]karbamat ;terc.-Butil azetidin-3-il-karbamat je reagovao sa 4-fluor-nitro-benzolom prema postupku C. Kao rezultat dobiven je proizvod molekulske težine 293.33 (C14H19N304); MS (ESI): 294 (M+H+). ;Primer 38 ;terc.-Butil [1 -(4-{[4-(4-hior-fenil)piperidin-1 -karbonil]amino}fenil)azetidin-3-iljmetil-karbamat ; ;terc.-Butil [1-(4-amino-fenil)azetidin-3-il]metil-karbamat je reagovao sa karbonil-diimidazolom i 4-(4-hlor-fenil)piperidinom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 499.06 (C27H35CIN403; MS (ESI): 499 (M+H+). ;terc.-Butil [1 -(4-amino-fenil)azetidin-3-il]metil-karbamat terc.-Butil metil-[1-(4-nitro-fenil)azetidin-3-il]karbamat je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 277.37 (C15H23N302); MS (ESI): 278 (M+H+). ;terc.-Butil metil-[1-(4-nitro-fenil)azetidin-3-il]karbamat terc.-Butil [1-(4-nitro-fenil)azetidin-3-il]carbamat alkilovan je pomoću jod-metana prema postupku F. Kao rezultat dobiven je proizvod molekulske težine 307.35 (C15H21N304); MS (ESI): 308 (M+H+). ;Primer 39 ;[4-(3-Metil-amino-azetidin-1 -il)fenil]amid 4-(4-hlor-fenil)piperidin-1 - karbonske kiseline ; terc.-Butil [1-(4-{[4-(4-hlor-fenil)piperidin-1-karbonil]amino}fenil)azetidin-3-iljmetil-karbamat je reagovao sa trifluor-sirćetnom kiselinom prema postupku G. Kao rezultat dobiven je proizvod molekulske težine 398.94 (C22H27CIN40); MS (ESI): 399 (M+H+). Primer 40 N-Metil-N-[1-(4-{3-[4-(piridin-3-il-oksi)fenil]ureido}fenil)pirolidin-3-il]acet-amid ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa karbonil-diimidazolom i, zatim, sa 4-(piridin-3-il-oksi)fenil-aminom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 445.53 (C25H27N503); MS (ESI): 446 (M+H+). ;Primer 41 ;N-Metil-N-(1-{4-[3-(4-piperidin-1-il-fenil)ureido]fenil}pirolidin-3-il)acet-amid ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa karbonil-diimidazolome i, zatim, sa 4-piperidin-1 -il-fenil-aminom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 435.57 (C25H33N502); MS (ESI): 436 (M+H+). ;Primer 42 ;N-{4-[3-(Acetil-meti-amino)pirolidin-1-il]fenil}-4-fenoksi-benz-amid ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao 4-fenoksi-benzoevom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 429.52 (C26H27N303); MS (ESI): 430 (M+H+). ;Primer 43 ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-4-butoksi-benz-amid ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 4-butoksi-benzoevom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 409.53 (C24H31N303); MS (ESI): 410 ;(M+H+). ;Primer 44 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 4-(4-hlor-fenil)cikloheksan-karbonske kiseline ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 4-(4-hlor-fenil)cikloheksan-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 454.02 (C26H32CIN302); MS (ESI): 454 (M+H+). ;Primer 45 ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-3-(4-izopropil-fenil)akril-amid ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 3-(4-izopropil-fenil)akrilnom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 405.54 (C25H31N302); MS (ESI): 406 ;(M+H+). ;Primer 46 ;(1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)metil-amid tetrahidro-furan-2-karbonske kiseline ; 1-(4-Ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)fenil]karbamid je reagovao sa tetrahidro-furan-2-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 492.62 (C28H36N404); MS (ESI): 493 (M+H+). Primer 47 (1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)metil-amid 1-acetil-pirolidin-2-karbonske kiseline 1-(4-Ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)fenil]karbamid je reagovao sa 1-acetil-pirolidin-2-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 533.68 (C30H39N5O4); MS (ESI): 534 (M+H+). Primer 48 (1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)metil-amid 5-okso-pirolidin-2-karbonska kiselina 1-(4-Ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1-il)fenil]karbamid je reagovao sa 5-okso-pirolidin-2-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 505.62 (C28H35N504); MS (ESI): 506 (M+H+). Primer 49 (1-{4-[3-(4-Ciklopentil-oksi-fenil)ureido]fenil}pirolidin-3-il)metil-amid 2-okso-tiazolidin-4-karbonske kiseline 1 -(4-Ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1 -il)fenil]karbamid je reagovao sa 2-okso-tiazolidin-4-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 523.66 (C27H33N504S); MS (ESI): 524 (M+H+). Postupak 50 {1 -[4-(4-Cikloheksil-benzoil-amino)fenil]pirolidin-3-il}metil-amid (R)-1 -metil-piperidin-3-karbonske kiseline (R)-4-Cikloheksil-N-[4-(3-metil-amino-pirolidin-1-il)fenil]benz-amid je reagovao sa 1-metil-piperidin-3-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 502.71 (C31H42N402); MS (ESI): 503 (M+H+). Primer 51 N-(1-{4-[3-(6-Ciklopentil-oksi-piridin-3-il)ureido]fenil}pirolidin-3-il)-N-metil-acet-amid ;N-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa karbonil-diimidazolom i, zatin, sa 6-ciklopentil-oksi-piridin-3-il-aminom prema postupku A. Kao rezultat dobiven je proizvod molekulske težine 437.55 (C24H31N503); MS (ESI): 438 (M+H+). ;6-Ciklopentil-oksi-piridin-3-il-amin ;Smeša 5-nitro-piridin-2-ola (14.0 g), brom-ciklopentana (8.0 g), kalijum-karbonata (14 g) i DMF (200 ml) je grejana na 80°C 6 sati. Po ohlađenju reakciona smeša je razblažena vodom i ekstrahovana etil-acetatom. Organski sloj je opran vodom, osušen iznad magnezijum-sulfata i uparen. Ostatak je prečišćen pomoću hromatografije na silika - gelu. Nastali proizvod (2-ciklopentil-oksi-5-nitro-piridin) je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 178.24 (C10H14N2O); MS (ESI): 179 (M+H+). ;Primer 52 ;1-(6-Ciklo-pentil-oksi-piridin-3-il)-3-[4-(3-metil-amino-pirolidin-1-il)-feniljkarbamid ; ;N-(1-{4-[3-(6-Ciklopentil-oksi-piridin-3-il)ureido]fenil}pirolidin-3-il)-N-metil-acet-amid je tertian sa rastvorom natrijum-hidroksida prema postupku D. Kao rezultat dobiven je proizvod molekulske težine 395.51 (C22H29N502); MS (ESI): 395 (M+H+). ;Primer 53 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 4'-fluor-bifenil-4-karbonska kiselina ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amide je reagovao sa 4'-fluor-bifenil-4-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 431.51 (C26H26FN302); MS (ESI): 432 (M+H+). ;Primer 54 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 4'-trifluor-metil-bifenil-4-karbonska kiselina ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 4'-trifluor-metil-bifenil-4-karbonskom kiselinom prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 481.52 (C27H26F3N302); MS (ESI): 482 (M+H+). ;Primeri 55-103 ;1 -(4-Fenoksi-fenil)-3-[4-(3-metil-amino-pirolidin-1 -il)fenil]karbamid je reagovao sa raznim karbonskim kiselinama prema postupku E. Proizvodi su prikazani u tabeli 2. Primeri 104-144 1 -(4-Ciklopentil-oksi-fenil)-3-[4-(3-metil-amino-pirolidin-1 -il)fenil]karbamid je reagovao sa raznim karbonskim kiselinama prema postupku E. Proizvodi su prikazani u tabeli 3. ;Primeri 145-185 ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa raznim karbonskim kiselinama prema postupku E. Proizvodi su prikazani u tabeli 4. ;Primeri 186-234 ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa karbonil-diimidazolom i, zatim, sa raznim aminima prema postupku A. Proizvodi su prikazani u tabeli 5. ; ;Nach Methode F-a vvurde {1-[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]-pyrrolidin-3-yl}-methyl-carbaminsaure tert-butylester mit 2-Ethylbutylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargevvicht 548,78 (C33H48N403); MS (ESI): 549 (M+H+). ;Beispiel 266 ;(1-{5-[(4-Cyclohexyl-benzoyl)-(3-methyl-but-2-enyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl-carbaminsaure tert-butylester ; ;Nach Methode F-a vvurde {1-[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]-pyrrolidin-3-yl}-methyl-carbaminsaure tert-butylester mit 3-Methyl-2-butenylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargevvicht 546,76 (C33H46N403); MS (ESI): 547 (M+H+). ;Beispiel 267 ;(1-{5-[(4-Cyclohexyl-benzoyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl-carbaminsaure tert-butylester ; ;Postupak H ;Cezijum-karbonat (36 mg) i n-butil-bromid (15 mg) dodati su rastvoru N-{4-[3-(acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-hidroksi-fenil)propion-amida (27 mg) u DMF (1 ml). Posle reakcionog vremena od 2 časa na sobnoj temperaturi, smeši je dodata voda i izvršena je ekstrakcija etil-acetatom. Organski sloj je osušen iznad natrijum-sulfata i uparen je. Ostatak je kristalizovan iz smeše dietil- etar/metanol. Dobiven je proizvod molekulske težine 437.59 (C26H35N303); MS(ESI): 438 (M+H+). ;N-{4-[3-(Acetil-metil-fenil)pirolidin-1-il]fenil}-2-(4-hidroksi-fenil)propion-amid N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 2-(4-hidroksi-fenil)propionskom kiselinom po postupku I. Dobiven je proizvod molekulske težine 381.48 (C22H27N303); MS(ESI): 382 (M+H+). ;Primer 238 ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenii}-2-(4-izo-butoksi-fenil)acet-amid ; ;N-{4-[3-(Acetil-metil-fenil)pirolidin-1-il]fenil}-2-(4-hidroksi-fenil)acet-amid je reagovao sa izobutil-bromidom po postupku H. Dobiven je proizvod molekulske težine 423.56 (C25H33N303); MS(ESI): 424 (M+H+). ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-hidroksi-fenil)acet-amid Postupak I 4-Hidroksi-fenil-sirćetna kiselina (305 mg), 1-hidroksi-benzo-triazol (300 mg) i 1-(3-dimetil-amino-propil)-3-etil-karbo-diimid-hidro-hlorid (480 mg) u DMF (5 ml) su mešani sa N-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acet-amidom (470 mg) na sobnoj temperaturi u toku 3 sata. Smeši je tada dodata voda, i izvršena je ekstrakcija etil-acetatom. Organski sloj je ispran zasićenim rastvorom natrijum-hlorida, osušen iznad natrijum-sulfata, uparen i kristalisan iz dietil-etra. Dobiven je proizvod molekulske težine 367.45 (C21H25N303); MS(ESI): 368 (M+H+). ;Primer 239 ;(f?)-N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-butoksi-fenil)acet-amid ; (f?)-N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 4-butoksi-fenil-sirćetnom kiselinom po postupku E. Dobiven je proizvod molekulske težine 423.56 (025H33N3O3); MS(ESI): 424 (M+H+). Primer 240 N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-ciklopropil-metoksi-fenil)-propion-amid ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-hidroksi-fenil)propion-amid je reagovao sa brom-metil-ciklopropanom po postupku H. Dobiven je proizvod molekulske težine 435.57 (C26H33N303); MS(ESI): 436 (M+H+). ;Primer 241 ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-ciklobutil-metoksi-fenil)-propion-amid ; ;N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-(4-hidroksi-fenil)propion-amid je reagovao sa brom-metil-ciklobutanom po postupku H. Dobiven je proizvod molekulske težine 449.60 (C27H35N303); MS(ESI): 450 (M+H+). ;Primer 242 ;{4-[3-(Acetil-metil-amino)pirolidin-1 -il]fenil}amid 1 -(4-metoksi-fenil)-1 - ciklopropan-karbonske kiseline ; ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 1-(4-metoksi-fenil)-1-ciklopropan-karbonskom kiselinom po postupku E. Dobiven je proizvod molekulske težine 407.52 (C24H29N303); MS(ESI): 408 ;(M+H+). ;Primer 243 ;{4-[3-(Acetil-metil-amino)pirolidin-1 -N]fenil}amid 1 -(4-butoksi-fenil)ciklopropan-karbonske kiseline ; ;{4-[3-( Acetil-metil-amino)pirolidin-1 -il]fenil}amid 1 -(4-hidroksi-fenil)ciklopropan-karbonske kiseline je reagovao sa n-butil-bromidom prema postupku H. Dobiven je proizvod molekulske težine 449.60 (C27H35N303); MS(ESI): 450 (M+H+). ;{4-[3-(Acetil-metil-amino)pirolidin-1 -il]fenil}amid 1 -(4-hidroksi-fenil)ciklopropan-karbonske kiseline ;Bor-tribromid-dimetil-sulfid (460 mg) je dodat rastvoru {4-[3-(acetil-metil-amino)pirolidin-1 -il]fenil}amida 1 -(4-metoksi-fenil)ciklopropan-karbonske kiseline (540 mg) u dihlor-metanu (5.5 ml) na 0°C. Posle odvijanja reakcije u toku 12 sati na sobnoj temperaturi, smeši je dodata voda, slojevi su razdvojeni i izvršena je ekstrakcija vodenog sloja dihlor-metanom. Pomešani organski slojevi su osušeni iznad natrijum-sulfata, upareni i prečišćeni hromatografski (silika-gel, toluol/etanol/etil-acetat 8:1:1 uz dodatak 0.1% trietil-amina). Dobiven je proizvod molekulske težine 393.49 (C23H27N303); MS(ESI): 394 (M+H+). ;Primer 244 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-N-metil-amid (f?)-4-(4-fluor-fenil)piperidin-1 -karbonske kiseline ; ;{4-[3-( Acetil-metil-amino)pirolidin-1 -il]fenil}amid (R)-4-(4-fluor-fenil)piperidin-1-karbonske kiseline (22 mg) je dodat suspenziji natrijum-hidrida (95% u ulju; 0.005 g) u DMF (1 ml). Kada je prestalo izdvajanje ;gasa, dodat je jod-metan (0.02 ml). Posle tri sata, reakciona smeša je pažljivo hidrolizovana vodom i izvršena je ekstrakcija dihlor-metanom. Organski sloj je osušen iznad magnezijum-sulfata i uparen, a ostatak je kristalizovan iz pentana. Dobiven je proizvod molekulske težine 452,58 (C26H33FN402); MS (ESI): 453 (M+H+). ;Primer 245 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 5-2-[(2-fluor-fenil)etinil]furan-2-karbonske kiseline ; ;Postupak J ;Najpre diizopropil-amin (14.9 mg), a zatim rastvor {4-[3-(acetil-metil-amino)pirolidin-1-il]fenil}amida 5-brom-furan-2-karbonske kiseline (50.0 mg) i 1-etinil-2-fluor-benzol (17.7 mg) u dioksanu (0.5 ml) i DMF (0.2 ml) dodati su pod inertnim uslovima suspenziji paladijum bis(tri-terc-butil-fosfin)dihlorida (3.8 mg) i bakar(l)-jodida (0.9 mg) u DMF (0.5 ml). Posle reakcionog vremena od 12 sati na sobnoj temperaturi, smeša je razblažena etil-acetatom i proceđena kroz silika-gel, filtrat je uparen i prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 445.18 (C26H24FN303); MS(ESI): 446 (M+H+) kao hidro-trifluor-acetat. ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 5-brom-furan-2-karbonske kiseline ;N-[1-(4-Amino-fenil)pirolidin-3-il]-N-metil-acet-amid je reagovao sa 5-brom-2-furan-karbonskom kiselinom po postupku E. Dobiven je proizvod molekulske težine 406.28 (C18H20BrN3O3); MS(ESI): 407 (M+H+). ;Primer 246 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 5-2-[(4-fluor-fenil)etinil]furan-2-karbonske kiseline ; ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 5-brom-furan-2-karbonske kiseline je reagovao sa 1-etinil-4-fluor-benzolom po postupku J. Dobiven je proizvod molekulske težine 445.18 (C26H24FN303); MS(ESI): 446 (M+H+) kao hidro-trifluor-acetat. ;Primer 247 ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 5-2-[(2-hlor-fenil)etinil]furan-2-karbonske kiseline ; ;{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 5-brom-furan-2-karbonske kiseline je reagovao sa 1-etinil-2-hlor-benzolom po postupku J. Dobiven je proizvod molekulske težine 461.15 (C26H24CIN303); MS(ESI): 462 (M+H+) kao hidro-trifluor-acetat. ;Primer 248 ;R-4-Butoksi-N-(3-fluor-4-{3-[(2-hidroksi-2-metil-propil)metil-amino]pirolidin-1-il}-fenil)benz-amid ;Rastvor (R)-4-butoksi-N-[3-fluor-4-(3-metil-amino-pirolidin-1-il)fenil]benz-amida (0,03 g) i izobutilen-oksida u etanolu (5 ml) zagrevan je uz refluks u toku 3 sata. Tada je izvršeno uparavanje u vakuumu. Dobiven je proizvod molekulske težine 457.59 (C26H36FN303); MS (ESI): 458 (M+H+). ;Primer 249 ;R-4-Butoksi-N-(3-fluor-4-{3-[(3-hidroksi-3-metil-butil)metil-amino]pirolidin-1-il}-fenil)-N-metil-benz-amid ; ;Rastvor (R)-4-butoksi-N-[3-fluor-4-(3-metil-amino-pirolidin-1-il)fenil]benz-amida (0.03 g), trietil-amina (0.02 g) i 4-brom-2-metil-butan-2-ola (0.03 g) u DMF (2 ml) grejan je na 80°C u toku 16 časova. Posle hlađenja, dodat je etil-acetat (100 ml), smeša je isprana vodom (2 x 50 ml), i organski sloj je osušen iznad natrijum-sulfata, proceđen i uparen. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 471.62 (C27H38FN303); MS (ESI): 472 (M+H+). ;4-Brom-2-metil-butan-2-ol ;Metil-magnezijum-bromid (3M u dietil-etru, 46 ml)je dodat rastvoru etil-3-brom-propionata (10 g) u dietil-etru (100 ml), na sobnoj temperaturi, u argonu. U toku ovg postupka, temperatura smeše je održavana između 20°C i 35°C. Posle 2 sata, smeša je usuta u zasićeni rastvor amonijum-hlorida. Nakon toga, izvršena je ekstrakcija dietil-etrom, a zatim sušenje iznad natrijum-sulfata, ceđenje i uparavanje. Dobiven je željeni proizvod. ;Primer 250 ;R-4-Butoksi-N-[6-(3-diciklopropil-amino-pirolidin-1-il)piridin-3-il]benz-amid ; Postupak K Rastvor (R)-N-[6-(3-amino-pirolidin-1-il)piridin-3-il]-4-butoksi-benz-amida (0.065 g) u metanolu (2 ml) je pomešan sa glacijalnom sirćetnom kiselinom (0.11 ml) i [(1-etoksi-ciklopropil)oksi]trimetil-silanom (0.19 g). Tada je dodat natrijum-cijano-bor-hidrid (0.051 g) i smeša je zagrevana uz refluks u toku 16 časova. Smeša je zatim proceđena, uparena, apsorbovana u dihlor-metanu, isprana natrijum-hidroksidom (2N; 20 ml) i rastvorom natrijum-hlorida (20 ml), osušena iznad magnezijum-sulfata i uparena. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 434.59 (C26H34N402); MS (ESI): 435 (M+H+). Primer 251 R-4-Butoksi-N-[6-(3-diciklopropil-amino-pirolidin-1-il)piridin-3-il]-N-metil-benz-amid (R)-4-Butoksi-N-[6-(3-diciklopropil-amino-pirolidin-1-il)piridin-3-il]benz-amid je metilovan prema postupku F. Dobiven je proizvod molekulske težine 448.61 (C27H36N402); MS (ESI): 449 (M+H+). Primer 252 R-4-butoksi-N-{6-[3-(ciklopropil-metil-amino)pirolidin-1-il]piridin-3-il}benz-amid (R)-4-Butoksi-N-[6-(3-metil-amino-pirolidin-1-il)piridin-3-il]benz-amid je ciklopropilovan prema postupku K. Dobiven je proizvod molekulske težine 408.551 (C24H32N402); MS (ESI): 409 (M+H+). Primer 253 terc-Butil-{1-[4-(2-amino-4-butoksi-benzoil-amino)-3-fluor-fenil]pirolidin-3-il}metil-karbamat ;terc-Butil-[1 -(4-amino-3-fluor-fenil)pirolidin-3-il]metil-karbamat je reagovao sa 4-butoksi-2-nitro-benzojevom kiselinom prema postupku E, nakon čega je izvršena hidrogenacija. Dobiven je proizvod molekulske težine 500.62 (C27H37FN404); MS (ESI): 501 (M+H+). ;4-Butoksi-2-nitro-benzojeva kiselina ;Rastvor 4-fluor-2-nitro-benzojeve kiseline (1.81 g) u butanolu (20 ml) pomešan je sa sumpornom kiselinom (3 ml) i mešan na 110°C u toku 4 sata. Dodat je etil-acetat (100 ml) i smeša je isprana zasićenim rastvorom natrijum-bikarbonata (3 x 50 ml), osušena iznad natrij um-sulfata, proceđena i uparena u vakuumu. Ostatak (2.2 g) je na -10°C u kapima dodat rastvoru natrijum-butoksilata, napravljenom od butanola (20 ml) i natrijum-hidrida (2.18 g) na -10°C u argonu, i zatim mešan u toku 20 sati. Dodat je etil-acetat (100 ml) i smeša je isprana vodom (2 x 50 ml), osušena iznad natrijum-sulfata, proceđena i uparena u vakuumu. Ostatak je prečišćen preparativnom HPLC metodom. Butil-4-butoksi-2-nitro-benzoat je hidrolizovan natrijum-hidroksidom (5N; 100 ml) u etanolu na sobnoj temperaturi u toku 3 časa. Smeša je zakišeljena hlorovodoničnom kiselinom (10 N; 100 ml), izvršena je ekstrakcija dihlor-metanom i organski sloj je osušen iznad natrijum-sulfata, proceđen i uparen. Dobiven je proizvod molekulske težine 239.23 (C11H13N05); MS (ESI): 240 (M+H+). ;Primer 254 ;N-{4-[3-(7-Aza-biciklo[2.2.1]hept-7-il)-2-okso-pirolidin-1-il]fenil}-4-cikloheksil-N-metil-benz-amid ; ;Postupak L ;Smeša N-[4-(3-brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amida (100 mg), kalijum-karbonata (60 mg), 7-aza-biciklo[2.2.1]heptana (44 mg) i DMF (2 ml) održavana je na 50°C u toku 6 sati. Smeša je razblažena vodom i ekstrahovana etil-acetatom. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 471.65 (C30H37N3O2); MS (ESI): 472 (M+H+). ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amid N-(4-Amino-fenil)-4-cikloheksil-N-metil-benz-amid (3.0 g) u aceto-nitrilu (30 ml) je pomešan je sa trinatrijum-fosfatom (0.95 g) i, dodat je, na 0°C, 2-brom-4-hlor-butiril-bromid (2.9 g). Posle jednog sata, dodat je rastvor natrijum-hidroksida (0.85 g) u vodi (10 ml) i smeša je snažno mešana na sobnoj temperaturi u toku 6 sati. Tada je dodata ista količina rastvora natrijum-hidroksida i mešanje je nastavljeno još 48 sati. Rastvor je razblažen vodom i ekstrahovan etil-acetatom. Organski sloj je osušen iznad magnezijum-sulfata i uparen je. Ostatak je prečišćen hromatografski na silika-gelu (pokretna faza etil-acetat/heptan 1:2). Dobiven je proizvod molekulske težine 455.40 (C24H27BrN202); MS (ESI): 456 (M+H+). ;N-(4-Amino-fenil)-4-cikloheksil-N-metil-benz-amid ;4-Cikloheksil-karbonska kiselina (5.0 g) i 4-nitro-fenil-izocijanat (4.0 g) mešani su u toluolu (150 ml) u toku 3 sata a zatim ostavljeni preko noći. Talog je proceđen uz pomoć vakuuma i ispran dietil-etrom. Dobiveni amid je etilovan po postupku F i hidrogenovan po postupku B. Dobiven je proizvod molekulske težine 308.43 (C20H24N2O); MS (ESI): 309 (M+H+). ;Primer 255 ;4-Cikloheksil-N-metil-N-[4-(3-morfolin-4-il-2-okso-pirolidin-1-il)fenil]benz-amid ; ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amid je reagovao sa morfolinom po postupku L. Dobiven je proizvod molekulske težine 461.61 (C28H35N303); MS (ESI): 462 (M+H+). ;Primer 256 ;4-Cikloheksil-N-metil-N-[4-(2-okso-3-piperidin-1-il-pirolidin-1-il)fenil]benz-amid ; ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amid je reagovao sa piperidinom po postupku L. Dobiven je proizvod molekulske težine 459.64 (C29H37N302); MS (ESI): 460 (M+H+). ;Primer 257 ;4-Cikloheksill-N-metil-N-[4-(2'-okso[1,3']bipirolidinil-1'-il)fenil]benz-amid ; ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amid je reagovao sa pirolidinom po postupku L. Dobiven je proizvod molekulske težine 445.61 (C28H35N302); MS (ESI): 446 (M+H+). ;Primer 258 ;4-Cikloheksil-N-metil-N-[4-(3-metil-amino-2-okso-pirolidin-1-il)fenil]benz-amid ; ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amid je reagovao sa metil-aminom po postupku L. Dobiven je proizvod molekulske težine 405.54 (C25H31N302); MS (ESI): 406 (M+H+). ;Primer 259 ;4-Cikloheksil-N-[4-(3-cikloheksil-amino-2-okso-pirolidin-1-il)fenil]-N-metil-benz-amid ; ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-amid je reagovao sa cikloheksil-aminom po postupku L. Dobiven je proizvod molekulske težine 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+). ;Primer 260 ;4-Cikloheksil-N-{4-[3-(ciklopropil-metil-amino)-2-okso-pirolidin-1-il]fenil}-N-metil-benz-amid ; ;N-[4-(3-Brom-2-okso-pirolidin-1-il)fenil]-4-cikloheksil-N-metil-benz-arnid je reagovao sa ciklopropil-metil-aminom po postupku L. Dobiven je proizvod molekulske težine 445.61 (C28H35N302); MS (ESI): 446 (M+H+). ;Primer 261 ;N-{4-[3-(Acetil-metil-amino)-2-okso-pirolidin-1-il]fenil}-4-cikloheksil-N-metil-benz-amid ; 4-Cikloheksil-N-metil-N-[4-(3-metil-amino-2-okso-pirolidin-1-il)fenil]benz-amid (52 mg) pomešan je sa piridinom (0.5 ml) i anhidridom sirćetne kiseline (130 mg) i, posle 3 sata, isparljive frakcije uklonjene su uz pomoć vakuuma. Dobiven je proizvod molekulske težine 447.58 (C27H33N303); MS (ESI): 448 (M+H+). Primer 262 4-Cikloheksil-N-metil-N-[4-(4-metil-amino-2-okso-pirolidin-1-il)fenil]benz-amid ;terc-Butanol (8 ml), trietil-amin (350 mg) i na kraju difenil-fosforil-azid (1.18 g) dodati su 1-{4-[(4-cikloheksil-benzoil)metil-amino]fenil}-5-okso-pirolidin-3-karbonskoj kiselini (1.5 g), i smeša je tada zagrevana na 95°C u toku 48 sati. Rastvor je razblažen etil-acetatom i ispran dva puta vodom. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Sirovi proizvod je reagovao dalje po postupku G. Dobiven je proizvod molekulske težine 405.54 (C25H31N302); MS (ESI): 406 (M+H+). ;1-{4-[(4-Cikloheksil-benzoil)metil-amino]fenil}-5-okso-pirolidin-3-karbonska kiselina ;N-(4-Amino-fenil)-4-cikloheksil-N-metil-benz-amid (3.0 g) je zagrevan sa itakonskom kiselinom (1.27 g) na 100°C u toku 3 sata. Prečišćavanje je izvršeno ceđenjem kroz silika-gel (pokretna faza etil-acetat/metanol 5:1). Dobiven je proizvod molekulske težine 420.51 (C25H28N204); MS (ESI): 421 (M+H+). ;Primer 263 ;N-{4-[4-(Acetil-metil-amino)-2-okso-pirolidin-1-il]fenil}-4-cikloheksil-N-metil-benz-amid ; ;4-Cikloheksil-N-metil-N-[4-(4-metil-amino-2-okso-pirolidin-1-il)fenil]benz-amid (101 mg) je pomešan sa piridinom (20 mg) i anhidridom sirćetne ;kiseline (25 mg) i, posle 3 sata, isparljive frakcije su uklonjene uz pomoć vakuuma. Dobiven je proizvod molekulske težine 447.58 (C27H33N303); MS (ESI): 448 (M+H+). ;Primer 264 ;terc-Butil-(1-{5-[(4-cikloheksil-benzoil)propil-amino]piridin-2-il}pirolidin-3-il)metil-karbamat ; Postupak F-a terc-Butil-{1-[5-(4-cikloheksil-benzoil-amino)piridin-2-il]pirolidin-3-il}metil-karbamat (50 mg), cezijum-karbonat (249 mg), kalijum-jodid (17 mg), N-metil-pirolidon (1.5 ml) i propil-jodid (40 mg) mešani su na 60°C u toku 5 sati. Ukoliko je konverzija bila nekompletna, smeša je zagrejana na 100°C i, posle dodatka još propil-jodida (40 mg), grejana na 140°C u toku 12 sati. Reakciona smeša je razblažena etil-acetatom, isprana vodom i rastvorom natrijum-bikarbonata, osušena iznad Chromabond XTR i uparena. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 520.72 (C31H44N403); MS (ESI): 521 (M+H+). Primer 265 terc-Butil-(1-{5-[(4-cikloheksil-benzoil)-(1-etil-propil)amino]piridin-2-il}pirolidin-3-il)-metil-karbamat ;terc-Butil-{1 -[5-(4-cikloheksil-benzoU-amino)piridin-2-it]piro]idin-3-il}metil-karbamat je reagovao sa 2-etil-butil-bromidom po postupku F-a. Dobiven je proizvod molekulske težine 548.78 (C33H48N403); MS (ESI): 549 ;(M+H+). ;Primer 266 ;terc-Butil-(1-{5-[(4-cikloheksil-benzoil)-(3-metil-but-2-en-il)amino]piridin-2-il}pirolidin-3-il)metil-karbamat ; terc-Butil-{1-[5-(4-cikloheksil-benzoil-amino)piridin-2-il]pirolidin-3-il}metil-karbamat je reagovao sa 3-metil-2-butenil-bromidom po postupku F-a. Dobiven je proizvod molekulske težine 546.76 (C33H46N403); MS (ESI): 547 (M+H+). Primer 267 terc-Butil-(1-{5-[(4-cikloheksil-benzoil)metil-amino]piridin-2-il}pirolidin-3-il)metil-karbamat ;terc-Butil-{1-[5-(4-cikloheksil-benzoil-amino)piridin-2-il]pirolidin-3-il}metil-karbamat je reagovao sa metil-jodidom po postupku F-a. Dobiven je proizvod molekulske težine 492.67 (C29H40N4O3); MS (ESI): 493 (M+H+). ;Po postupku F-a dobivena su i sledeća jedinjenja iz terc-butil-{1-[5-(4-cikloheksil-benzoil-amino)piridin-2-il]pirolidin-3-il}metil-karbamata i odgovarajućeg sredstva za alkilovanje: terc-Butil-(1-{5-[sec-butil-(4-cikloheksil-benzoil)amino]piridin-2-il}pirolidin-3-il)metil-karbamat ;terc-Butil-(1-{5-[(4-cikloheksil-benzoil) izopropil-amino]piridin-2-il}pirolidin-3-il)metil-karbamat ;terc-Butil-(1-{5-[(4-cikloheksil-benzoil)prop-2-in-il-amino]piridin-2-il}pirolidin-3-il)-metil-karbamat ;Primer 268 ;[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-p-tolil-etinil-furan-2-karbonske kiseline ; ;0.042 ml diizopropil-amina dodato je, u atmosferi argona, u 3.8 mg Pd(tBu)2CI2i 0.95 mg CuJ u 0.2 ml DMF. Rastvor 94.6 mg [4-(3-dimetil- ;amino-pirolidin-1 -il)fenil]amida 5-brom-furan-2-karbonske kiseline u 0.3 ml DMF i rastvor 4-etinil-toluola u 0.3 ml DMF su tada dodavani u kapima. Rastvor je mešan na sobnoj temperaturi preko noći. Talog koji je izdvojen proceđen je uz pomoć vakuuma i filtrat je prečišćen preparativnom HPLC metodom. Željeni proizvod molekulske težine 413.52; MS (ESI): 414 dobiven je kao hidro-trifluor-acetat. ;[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-brom-furan-2-karbonske kiseline ;[1-(4-Amino-fenil)pirolidin-3-il]dimetil-amin je reagovao sa 5-brom-2-furan-karbonskom kiselinom po postupku E. Proizvod molekulske težine 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) dobiven je kao hidro-trifluor-acetat. ;Primeri 269-273 dobiveni su na isti način: ; ;Primer 274 ;[6-(3-Dimetil-amino-pirolidin-1-il)piridin-3-il]-amid (R)-4'-fluor-bifenil-4-karbonske kiseline ; ;Postupak M ;[6-(3-Metil-amino-pirolidin-1-il)piridin-3-il]-amid (R)-4'-fluor-bifenil-4-karbonske kiseline (390 mg), rastvoren u mravljoj kiselini (230 mg), pomešan je sa rastvorom formaldehida (37% aq.; 0.4 ml) i smeša je grejana na 80°C u toku 3 sata. Ohlađeni rastvor je uparen i raspodeljen između etil-acetata i zasićenog rastvora natrijum-karbonata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Sirovi proizvod je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 404.49 (C24H25FN40); MS (ESI): 405 (M+H+). ;Primer 275 ;{4-[3-(Acetil-metil-amino)pirolidin-1 -il]fenil}amid 1 -(4-fluor-fenil)piperidin-4-karbonske kiseline ; ;Postupak E-a ;Smeša od 0.048 g 1-(4-fluor-fenil)piperidin-4-karbonske kiseline, 0.5 ml SOCI2 i jedne kapi DMF mešana je na sobnoj temperaturi u toku 2 sata. Višak SOCI2 je tada uklonjen uz pomoć vakuuma. Ostatak je rastvoren u 0.4 ml DMF pa je dodato 0.033 ml trietil-amina i 0.048 g N-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acet-amida. Rastvor je mešan na sobnoj temperaturi preko noći. Tada je rastvor proceđen i prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 438.20 (C25H31FN402); MS (ESI): 439 (M+H+) kao hidro-trifluor-acetat. ;1 -(4-Fluor-fenil)piperidin-4-karbonska kiselina ;0.875 g 4-brom-fluor-benzola, 0.016 g Pd(dba)3<*>CHCI3, 0.022 g 2-(dicikloheksil-fosfino)bifenila i 2.28 g cezijum-karbonata stavljeni su u toplotom osušen i argonom ispran balon, pa je dodato 0.943 g etil-4-piperidin-karboksilata u 5 ml degaziranog toluola. Rastvor je grejan na 100°C preko noći. Smeša je ohlađena i zatim uparena u vakuumu. Ostatak je apsorbovan u smeši acetat/voda. Organski sloj je ispran 10% rastvorom NaHC03, osušen iznad natrijum-sulfata i uparen uz pomoć vakuuma. Ostatak je prečišćen preparativnom HPLC metodom. R42 H, F, Cl, Br, CF3, CN, CHd-CeJ-alkyl, O-(CrC4)-Alkoxy-(Ci-C4)-alkyl, S-(CrC6)-alkyl, (CrC6)-alkyl, (C0- C8)-alkylene-aryl, O-(C0-C8)-alkylene-aryl, N(R43)(R44), SO2-CH3, CON(R45)(R46). N(R47)CO(R48), CO(R51), -(CR84R85)*-O(R86); ;preferably H, F, Cl, Br, CF3, CN, 0-(d-CQ)-alkyl, (d-C6)-alkyl, SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), ;-(CR84R85)X-0(R86); in particular, H, F, Cl, CF3, CN, (CrC6)-alkyl, -(CR84R85)X-O(R86) are assumed; R43, R44, R45, R46, R47 independently of each other, H, (C1C8)-alkyl; ; or ; R43 and R44, R45 and R46 ; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(C1-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of each other, H, (C1C8)-alkyl, aryl; preferably; independently of each other, H, (d-C8)-alkyl; ;R84, R85 H; ;R86 H, (C1C6)-alkyl; ;x 0, 1, 2; best 0, 1; in particular, 1 is assumed; ;R10 H, (C1C8)-alkyl; ;X N(R52), single bond, C=C, C(R53)(R54), C(R55)(R56)0, ;C^C, CH2-CH2, YCH2; preferably N(R52), single bond, C=C, C(R53)(R54), CH2-CH2; in particular, one bond is assumed, C=C, C(R53)(R54), CH2-CH2; ; Y O, S, N(R89); ;R89 H, (C1C8)-alkyl; R52, R53, R54, R55, R56 independently of each other, H, (C1-C8)-alkyl; ;E 3 - 8-membered bivalent carbo- or heterocyclic ring system with 0 - 4 hetero-atoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(CrC6)-alkyl, 0-(Cr C4)-Alkoxy-(Ci-C4)-alkyl, S-(CrC6)-alkyl, (d-C6)-alkyl, (C2-Ce)-alkenyl, O-(C3-C8)-cycloalkyl, (C3 - C8)-cycloalkenyl, (C2 -C6)-alkynyl, (CO-C8)-alkylene-aryl, O-(C0 - C8)-alkylene-aryl, S-aryl, N(R57)(R58), S02-CH3, N(R61)CO(R62), ;N(R63)SO2(R64), CO(R65) and can be mono- or bicyclic; ; preferably 5 - 7-membered bivalent carbo- or heterocyclic ring system with 0 - 3 hetero-atoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkyl, ;S-(CrC6)-alkyl, (d-C6)-alkyl, (C2-C6)-alkenyl, O-(C0-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), CO(R65) and may be mono- or bicyclic; in particular, a 5 - 7-membered bivalent carbo- or heterocyclic ring system with 0 - 2 hetero-atoms from the group N, O and S is assumed, which can, most advantageously, have substituents from the group H, F, Cl, Br, OH, CF3, NO2, OCF3, 0-(CrC6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); eg, E is selected from the group consisting of; which can, most advantageously, have substituents from the group H, F, Cl, Br, OH, CF3, NO2, OCF3, O-Cd-CeJ-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); ; the best ; which can, most advantageously, have the previously mentioned substituents; R57, R58, R61, R63, independently of each other, H, (C1C3)-alkyl; R62, R64, R65 independently of each other, H, (C1-C8)-alkyl, aryl; preferably independently of each other, H, (C 1 -C 8 )-alkyl; ;K single bond, O, OCH2, CH2O, S, SO, SO2, N(R66), ;N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, SO2CH2; ;preferably one bond, O, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))V, CO, C=C, SCH2; in particular one bond is assumed, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, CO, C=C; ;v 1, 2, 3, 4; best 1, 2, 3; 1.2 is especially important; R66, R67, R68, R69, R70, independently of each other, H, (C1C8)-alkyl; ;R11 H, (CrC8)-alkyl, (Ci-C4)-Alkoxy-(CrC4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, one 3 to 10-membered mono-, bi-, tri- or spirocyclic ring, which may contain 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the ring system may be additionally substituted with F, Cl, Br, CF3, CN, (CrC6)-alkyl, O-(Ci-C8)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, hydroxy-(CrC4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74). N(R75)CO(CrC6)-alkyl, N(R76)(R77) or SO2CH3; ;preferably (CrC8)-alkyl, (CrC4)-Alkoxy-(Ci-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which ;may contain 0 to 3 hetero-atoms selected from the group of oxygen, nitrogen and sulfur, whereby the ring system may be additionally substituted with F, Cl, Br, CF3, CN, (CrC6)-alkyl, O-(C1C8)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1C6)-alkyl, N(R76)(R77) or SO2CH3; (Ci-C8)-alkyl, (CrC4)-Alkoxy-(CrC4)-alkyl, a 3- to 10-membered mono- or bicyclic ring which may contain 0-2 hetero-atoms selected from the group of oxygen, nitrogen and sulfur is especially assumed, whereby the ring system may be additionally substituted with F, Cl, Br, CF3, CN, (d-Ce^alkyl, 0-(Ci-C8)-alkyl, oxo, CO(R72)(R73), N(R75)CO(C1-C6)-alkyl, or SO2CH3;; R71, R72, R73, R74, R75, R76, R77; independently of each other, H, (Ci-C8)-alkyl; or; best together with nitrogen by the atom to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, may contain 0 - 1; another heteroatom from the group N-(Ci-C6)-alkyl, oxygen and sulphur; or their N-oxides and their physiologically acceptable salts. ;In a further preferred embodiment, A, B, G and D in formula I are CH or: if E is 1,4-phenylene, the preferred meanings for A, B, G and D are further those listed below in Table I: If E the assumed meanings of A, B, G and D are further those listed below in Table II: If E the assumed meanings for A, B, G and D are, further, those not listed below in Table III: ;Further assumed combinations of E and A, B, G and D are listed in Table ;IV. ; The radicals R11, K, X and E in formula I possess in particular one to the assumed unit one of the following meanings: ;R11 is best chosen from the group consisting of: ;n-propyl, n-butyl, iso-butyl, iso-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex-(1)-enyl, phenyl, p-fluoro-phenyl, p-chloro-phenyl, p-bromo-phenyl, p-tolyl, p-methoxy-phenyl, p-trifluoro-methyl-phenyl p-methyl-thio-phenyl, o-fluoro-phenyl, o-chloro-phenyl, o-cyano-phenyl, m-fluoro-phenyl, 2,4-difluoro-phenyl, 3-fluoro-4-methyl-phenyl, 2-nitro-4-methyl--phenyl, 2-amino-4-methyl-phenyl, ;K is best selected from the group consisting of. -O-, bond, C=C, CH2, CH2O, CONH, OCH2, CO, SCH2i (CH2)20. ;X is preferably selected from the group consisting of a bond, NH and CH2. ;E is preferably selected from the group consisting of: ;Assumed combinations of R11, K, X and E are listed below: ;If K and X are each a single bond then particularly assumed meanings for E and R11 are as follows: ■ If E is 1,4-phenylene, R11 is selected from the group consisting of: cyclohexyl, p-tolyl, p-fluoro-phenyl, o-fluoro-phenyl, p-methoxy-phenyl, p-chloro-phenyl, o-chloro-phenyl, 2,4-difluoro-phenyl, 3-fluoro-4-methyl-phenyl, o-cyano-phenyl, ■ If E ;R11 is selected from the group consisting of: ;p-chloro-phenyl, p-tolyl, p-fluoro-phenyl, p-methoxy-phenyl, p-trifluoro-methyl-phenyl, o-fluoro-phenyl, phenyl and ;Further combinations of E and R 11 , for the case where K and X are each a single bond, are listed in Table V: ;If K is -O- and X is a single bond, NH or CH 2 , particularly assumed meanings for E and R 11 are as follows: 5 ;■ If E is 1,4-phenylene, R 11 is selected from the group consisting of: ;phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluoro-phenyl and p-fluoro-phenyl. 10 Further combinations of E and R11 for the case where K is -O- and X is a single bond, NH or CH2 are listed in Table VI: ;If K is C <=>C and X is a single bond, particularly assumed meanings of E and R 11 are as follows: ;5■If E ;R 11 is selected from the group consisting of: ;phenyl, p-fluoro-phenyl and p-chloro-phenyl. If K is CH2 and X is a single bond, particularly assumed meanings of E and R 11 10 are listed below in Table VII: 15 If K is CH 20 and X is a single bond, particularly assumed meanings of E and R 11 are as follows: ;■ If E is 1,4-phenylene, R 11 is selected from the group consisting of: ;phenyl, cyclopropyl and cyclohexyl. ;20 ;If K is CONH and X is a single bond, particularly assumed meanings for E and R11 are set forth below in Table VIII: ;If K is OCH2 and X is a single bond, particularly assumed meanings for E and R11 are set forth below in Table IX below: ;Combinations of R11, K, and E set forth below in Table X are further particularly assumed in addition to the aforementioned combinations, with X particularly particularly assumed to be in the form of a single bond: Compounds of Formula I are in particular, an assumed entity in the form of a compound of the formula Ia; in which the radicals R1, R2, R10, R11, R42, and groups X, E, K have the previously mentioned meanings, and R42' is defined as R42, whereby R42 and R42' in the compounds of the formula Ia can be identical or different, or N-oxides and their physiologically acceptable salts. ;In an assumed entity of the invention, the radicals R1, R2, R10, R11, R42, R42' and the groups X, E, K have the following meanings: R1, R2 independently of each other, H, (Ci-C8)-alkyl, -(CR78R79)0 - ;R12, (C1-C4)-Alkoxy-(Ci-C4)-alkyl, or R1 and R2 build together with nitrogen, to which they are attached, a 4-10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, can contain 0-2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring system can be additionally substituted with F, (Ci-C6)-alkyl, 0-(Ci-C4)-alkyl, (C1-C4)-Alkoxy-(C1-C4)-Alkyl, hydroxy-(C 1 -C 4 )-alkyl, (C 0 -C 2 )-alkylene-aryl, oxo, CO(R 26 ), CON(R 27 )(R 28 ), hydroxy, N(R 31 )(R 32 ) or SO 2 CH 3 ; whereby R <1>and R <2> are not both CO(R26), and preferably H, (d-CsJ-alkyl, - ;(CR78R79)0-R12, (CrC^-alkoxyKd-OO-alkyl, or R1 and R2 build together with the nitrogen atom, to which they are attached, a 4 - 10-membered mono- or bicyclic ring which, apart from the nitrogen atom, can contain 0-2 additional hetero-atoms selected from the group oxygen and nitrogen, whereby the heterocyclic ring system can be additionally substituted with F, (d-Ce-alkyl, (Ci-C4)-Alkoxy-(C1-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32); ;o 0, 1, 2, 3, 4, and best of all; best ;1 or 2; ;s 0,1,2; ;R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32; independently of each other, H, (C1C6)-alkyl; ; or ; R17 and R18, R27 and R28, R31 and R32 ; independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(d-C6)-alkyl, oxygen and sulfur, and preferably the ring is pyrrolidine, piperidine, N-methyl-piperazine, morpholine; ;R12 OH, O-(CrC6)-alkyl, O-(C0-C2)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, 3 - 12-membered mono-, bi- or spirocyclic ring which can contain 1 to 3 hetero-atoms from the group N, O and S, and the 3; - 12-membered ring can contain further substituents, such as F, OH, CF3, CN, oxo, (Ci-C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(CrC6)-alkyl, and best; OH, 0-(C-i-C6)-alkyl, a 3-10-membered mono- or bicyclic ring which may contain 1-2 hetero-atoms from the group N, O and S, and the 3-10-membered ring may contain further substituents, such as F, OH, oxo, (d-CeJ-alkyl, CO(C 1 -C 6 )-alkyl; R34, R35 independently of each other, H, (C1-C4)-alkyl; ;R40 H, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl; ;R78, R79 independently of each other, H, (CrC5J-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (CrC4)-alkoxy-(CrC4)-alkyl; ;R42, R42' independently of each other, H, F, Cl, Br, CF3, CN, (CrC6)-alkyl; ;R10 H, (Ci-C8)-alkyl; ;X N(R52), one bond, C=C, C(R54), CH2CH2; R52, R53, R54; independently of each other, H, (Ci-Ca)-alkyl; heterocyclic ring structure with 0 - 3 heteroatoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, Br, CF3, OH, CN, OCF3, NO2, O-Cd-CeJ-alkyl, (Ci-C6)-alkyl, SO2-CH3, CO(R65); ; preferably a 5-7-membered bivalent carbo- or heterocyclic ring structure with 0-2 hetero-atoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, Br, OH, CF3, N02, OCF3, 0-(Ci-C6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); eg. E is selected from the group consisting of ; ;which, most advantageously, can have substituents from the group H, F, Cl, Br, OH, ;5 CF3, NO2, OCF3, O-(CrC6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); and the best which can, most advantageously, have the already mentioned substituents; ;R65 H, (d-C8)-alkyl; ;15 ;K single bond, O, OCH2, CH20, S, SO2, N(R66), N(R67)CO, ;CON(R68), (C(R69)(R70))V, CO, C=C, SCH2, SO2CH2; and preferably one bond, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, extremely favorable CH2, CO, C=C; ;v 1, 2, 3, and the best ;5 1,2; R66, R67, R68, R69, R70, independently of each other, H, (C1-C8)-alkyl; ;10 R11 (CrC8)-alkyl, (Ci-C4)-Alkoxy-(CrC4)-alkyl, one 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which can contain 0 to 4 hetero-atoms selected from the group of oxygen, nitrogen and sulfur, whereby the ring system can be additionally substituted; with F, Cl, Br, CF3, CN, (C 1 -C 6 )-alkyl, O-(C 1 -C 8 )-alkyl, oxo, ;15 CO(R 71 ), hydroxy, N(R 75 )CO(C 1 -C 6 )-alkyl, or SO 2 CH 3 ; and best (Ci-Cs)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, one 3 to 10-membered mono- or bicyclic ring which may contain 0 to 2 hetero-atoms selected from the group of oxygen, nitrogen and sulfur, whereby the ring system may be additionally substituted 20 with F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, O-(C 1 -C 8 )-alkyl, oxo, CO(R 71 ), CON(R 72 )(R 73 ), N(R 75 )CO(C 1 -C 6 )-alkyl, or SO 2 CH 3 ; R71, R72, R73, R74, R75, R76, R77 independently of each other, H, (d-C8)-alkyl; or R72 and R73, R76 and R77 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, in addition to nitrogen, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur. In an assumed embodiment, the presented invention relates to compounds of formula Ia, in which X is CH2CH2, N(R52), CH2, OCH2, SCH2, CH=CH, and preferably CH2CH2, CH=CH; ;E is ; ;K is a single bond, O or C(R69)(R70); and the other symbols R 1 , R 2 , R 10 , R 11 , R 42 , R 42 ′, R 52 , R 69 and R 70 have the meanings given above in connection with the definition of the radical of the compound of formula la. In a further putative embodiment, the presented invention relates to compounds of formula Ia, wherein X is N(R52), preferably NH, or C(R53)(R54); ; best ;K is a single bond, O or C(R69)(R70), and best 0; preferably O and other symbols R 1 , R 2 , R 10 , R 11 , R 42 , R 42 , R 52 , R 53 , R 54 , R 69 and R 70 have the meanings given above in connection with the definition of the radical of the compound of formula Ia. In a further particularly assumed embodiment of compounds of formula la, compounds of formula lb are obtained; ; in which radicals R1, R2, R10 and R11 and groups E and D have the above meanings, or are N-oxides and their physiologically acceptable salts. In one hypothetical embodiment, the radicals R1, R2, R10 and R11 and groups E and D have the following meanings: R1, R2 independently of each other, H, (CrC8)-alkyl, - ;(CR78R79)0-R12, (d-d)-Alkoxy-(d-d)-alkyl, (C3-C8)- ;alkenyl, CO-(CrC8)-alkyl, -CO-(CH2)0-R12, CO-aryloxy-(Cr C4)-alkyl, C0CH=CH(R13), C0CC(R14), C0(C(R15)(R16))qN(R17)(R18), ;C0(C(R19)(R20))rCON(R21 )(R22), ;CO(C(R23)(R24))sO(R25); or R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system may be further substituted with F, Cl, CF3, (CrC6)-alkyl, 0-(CrC4)-alkyl, (C1-C4)-Alkoxy-(CrC4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(CrC6)-alkyl, N(R31)(R32) or SO2CH3, where R1 and R2 are both not CO(R26); preferably, independently of each other, H, (CrCsJ-alkyl, -(CR78R79)0 -R12, (CrC4)-Alkoxy-(Ci-C4)-alkyl, CO-(CrC8)-alkyl, -CO-(CH2)0 -R12, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom, to which they are attached, a 4- to 10-membered mono- or bicyclic ring which, in addition to the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the heterocyclic ring may be additionally substituted with F, Cl, CF3, (CrC6)-alkyl, O-(C1C4)-alkyl, (C 1 -C 4 )-Alkoxy-(C 1 -C 4 )-alkyl, (C 0 -C 2 )-alkylene-aryl, oxo, hydroxy, N(R 31 )(R 32 ) or SO 2 CH 3 , wherein R 1 and R 2 are not both CO-(C 1 -C 8 )-alkyl; ;in particular it is assumed, independently of each other, H, (Ci-C8)-alkyl, -(CR78R79)0-R12, (CrC^-alkoxHd-OO-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0-R12, ;CO(C(R15)(R16))qN(R17)(R18), or R1, and R2 builds together with a nitrogen atom, to which it is attached, one 4- to 10-membered mono- or bicyclic ring which, in addition to the nitrogen atom, may contain 0 to 2 additional hetero-atoms selected from the oxygen group, and nitrogen, wherein the heterocyclic ring system may be further substituted with F, (C 1 -C 6 )-alkyl, (c 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, oxo, CO(C 1 -C 8 )-alkyl, hydroxy, N(R 31 )(R 32 ), where R 1 and R 2 are not both CO(C 1 -C 8 )-alkyl; ;o 0, 1, 2, 3, 4, 5, 6; best 0, 1, 2, 3, 4; in particular, 0,1,2, 3 are assumed; ;q, r independently of each other, 1, 2, 3; best q is 1 or 2; ; with 0, 1, 2, 3, 4; best 0, 1, 2, 3; in particular, 0, 1, ;2 are assumed; ;R13, R14 independently of each other, one phenyl ring which can ;contains 0 -1 nitrogen atom; ;R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, ;R30, R31, R32; independently of each other, H, (CrC6)-alkyl; ;R18 H, (C1-C6)-alkyl, CCKd-C6-alkyl, CO(R33); preferably H, (d-d)-alkyl, CO(d-C6)-alkyl; in particular, H, (C 1 -C 6 )-alkyl is assumed; or; R17 and R18, R21 and R22, R27 and R28, R31 and R32; independently of each other, preferably together with the nitrogen atom, to which they are attached, one 5 - 6-membered ring which, apart from the nitrogen atom, can also contains 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine, N-methyl-piperazine, morpholine; ;R33 a 5 - 10-membered aromatic ring system which may contain another hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (CrC6)-alkyl, O-(CrC8)-alkyl; ;R12 is OH, 0-(Ci-C6)-alkyl, O-(C0-C8)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, COO(R80), CON(R81)(R82), 3-12-membered mono-, bi- or spirocyclic ring which may contain one or more hetero-atoms from the group N, O and S, and the 3-12-membered ring may contain further substituents, such as F, Cl, Br, OH, CF3, CN, oxo, O-(CrC6)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (CrCe)-alkyl, O-(C0-C8)-alkylene-aryl, (C0-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36). (C(R37)(R38)),(R39), CO(C(R37)(R38))t(R39), CO(C1C6)-alkyl, COCOO(C1C6)-alkyl, COO(R40), S(O)U(R41); ; preferably OH, 0-(CrC6)-alkyl, O-(C0-C8)-alkylene-aryl, CN, 3 - 10-membered mono- or bicyclic ring which may contain 1 - 3 hetero-atoms from the group N, O and S, and the 3- to 10-membered ring may contain further substituents, such as F, Cl, Br, OH, CF3, CN, oxo, O-(CrC6)-alkyl, (CrC4)-Alkoxy-(Ci-C4)-alkyl, (Ci-C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), CO(C 1 -C 6 )-alkyl; ; especially OH, 0-(Ci-C6)-alkyl, 3-10-membered mono- or bicyclic rings which may contain 1-2 hetero-atoms from the group N, O and S are assumed, and the 3-10-membered ring may contain further substituents, such as F, OH, oxo, (C-i-Ce)-alkyl, COfCrCeJ-alkyl; ;t 0,1,2,3,4,5,6; ;in 0, 1, 2; best 0 or 2; in particular, 2 is assumed; R34, R35, R37, R38 independently of each other, H, (C1C8)-alkyl; ; or ; R34 and R35 ; most acceptable together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-Ce)-alkyl, oxygen and sulfur and can, most advantageously, be substituted with 1 - 2 oxo groups; ;R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5 - 10-membered aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (CrC6)-alkyl, O-(C1C8)-alkyl; ;R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl; ;R41 (Ci-C6)-alkyl, 5-10-membered aromatic ring system which can contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and can be substituted with F, Cl, (CrC6)-alkyl, 0-(d-C8)-alkyl; ;R78, R79 independently of each other, H, (C1C8)-alkyl, hydroxy-(C-1-C4)-alkyl, OH, (d^-alkoxyKC^J-alkyl; ;R80, R81 independently of each other, H, (d-C8)-alkyl; ;R10 H, (C1-C8)-alkyl; ;E 3 - 8th members bivalent carbo- or heterocyclic ring structures with 0-4 hetero-atoms from the group N, O and S, which can have substituents, most preferably from the group H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, 0-(CrC4)-Alkoxy-(Ci-C4)-alkyl, S-(CrC6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic; ; the best 5 - 7th members of a bivalent carbo- or heterocyclic ring structure with 0 - 3 hetero-atoms from the group N, O and S, which can have, most advantageously, substituents from the group H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, -N(R57)(R58), SO2-CH3, N(R61)CO(R62), CO(R65) and may be mono- or bicyclic; in particular, 5 - 7 members of the bivalent carbo- or heterocyclic ring structure with 0 - 2 hetero-atoms from the group N, O and S are assumed, which can have the most favorable substituents from the group H, F, Cl, Br, OH, CF3, N02, OCF3, O-(CrC6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, -N(R57)(R58), SO2-CH3, CO(R65); eg, E is selected from the group consisting of ; ;which can have substituents, most advantageously, from the group H, F, Cl, Br, OH, CF3, NO2, OCF3, 0-(CrC6)-alkyl, (d-CeJ-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); ;best ; ;which can have, most advantageously, the previously mentioned substituents; ;R57, R58, R63; independently of each other, (Ci-C8)-alkyl; ;R62, R64, R65; independently of each other, H, (Ci-C8)-alkyl; ;K single bond, OCH2, S, SO2, N(R66), N(R67)CO, ;CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, SO2CH2; ;preferably one bond, O, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))V, CO, C=C, SCH2; in particular one bond is assumed, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, CO, ;C=C; ;v 1, 2, 3, 4; best 1, 2, 3; in particular, 1.2 is assumed; R66, R67, R68, R69, R70, independently of each other, H, (C1-C8)-alkyl; R11 H, (C1-C8)-alkyl, (Ci-C4)-Alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may contain 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the ring system may be additionally substituted with F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl, (CrC4)-Alkoxy-(Ci-C4)-alkyl, hydroxy-(CrC4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), ;CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3SCF3; preferably (Ci-C8)-alkyl, (C1-C4)-Alkoxy-(Ci-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may contain 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may be additionally substituted with F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(C1-C8)-alkyl, (C0-C2)-alkylene-aryl, oxo, C0(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3; (Ci-C8)-alkyl is especially assumed, (CrC4)-Alkoxy-(Ci-C4)-alkyl, a 3- to 10-membered mono- or bicyclic ring which may contain 0 to 2 hetero-atoms selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may be additionally substituted with F, Cl, Br, CF3, CN, (CrC6)-alkyl, O-(Ci-C8)-alkyl, oxo, C0(R71), CON(R72)(R73), N(R75)CO(CrC6)-alkyl, or SO2CH3; ;R71, R72, R73, R74, R75, R76, R77; independently of each other, H, (C1C8)-alkyl; ; or ; R72 and R73, R76 and R77 ; independently of each other, preferably together with one nitrogen atom, to which one 5 - A 6-membered ring which, apart from the nitrogen atom, can also contain 0-1 further hetero-atoms from the group N-(Ci-C6)-alkyl, oxygen and sulphur. In one putative embodiment, the present invention relates to compounds of formula lb wherein X is a single bond, E is where the previously mentioned groups can, most advantageously, have substituents from the group H, F, Cl, Br, OH, CF3, NO2, OCF3, O-(CrC6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); ;best, gives E ; ;in which the groups may have the previously mentioned substituents; ;K is one connection; and ;the other radicals R1, R2, R10 and R11 and the group D have the meanings given above in connection with the definition of the radical of the compound formulas lb. R11 in the previously mentioned compounds of formula lb is, in particular, a substituted mono- or bicyclic ring system with 5-10 members, which may have 0-3 hetero-atoms, especially N, O and/or S, it is especially assumed to be phenyl with 0-1 N atoms, cyclohexyl or a bicyclic system with 8-10 members and 1-2 hetero-atoms, especially N, O and/or S. in a further assumed embodiment, the presented invention refers to compounds of the formula lb; in which; X is one bond; ; Eje ; where the previously mentioned groups can preferably have substituents from the group H, F, Cl, Br, OH, CF3) NO2, OCF3, O-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2CH3i CO(R65); ; the best ; ; in which groups can have the previously mentioned substituents; ;K is CH2, CH2CH2, O, CH2O, OCH2, CON(R68), N(R67)CO, S, SO2, ;SCH2, SO2, SO2CH2, CO or one triple bond; ;preferably CH2, O, CH2O, OCH2, CON(R68), SCH2, CO or one triple bond; and; the other radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R67 and R68 and group D have the meanings given above, in connection with the definition of the radical of the compound of formula lb. The amount of a compound of formula (I) required to achieve the desired biological effect depends on a number of factors, for example, the specific compound selected, the intended use, the route of administration and the clinical conditions of the patient. The daily dose is mostly from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example, 3-10 mg/kg/day. A single intravenous dose may be, for example, in the range of 0.3 mg to 1.0 mg/kg, which may conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Individual doses may contain, for example, from 1 mg to 10 g of active substance. Ampoules for injections can thus contain, for example, from 1 mg to 100 mg, and unit dose preparations that can be administered orally, such as tablets or capsules, can contain, for example, from 1.0 to 1000 mg, most often from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the previously mentioned weight data are based on the weight of the free compound from which the salt is derived. For prophylaxis and therapy under the above-mentioned conditions, the compounds of formula (I) may be used as pure, provided, however, that they are in the form of a pharmaceutical preparation with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the preparation and that it is not harmful to the patient's health. The carrier must be solid or liquid or both and is assumed to be formulated with the compound in unit dose form, for example as a tablet, which may contain from 0.05% to 95% by weight of the active substance. Other active pharmaceutical substances may also be present, including other compounds of formula (I). The pharmaceutical preparations of the invention can be produced by any of the known pharmaceutical methods, which basically consist of mixing the components with a pharmaceutically acceptable carrier and/or auxiliary substance. Pharmaceutical preparations of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable way of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated preparations and coated preparations that slowly release the active substance also fall within the scope of the invention. Preparations that are resistant to acids and gastric juices are assumed. Suitable gastric acid resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical compounds for oral use may be in the form of a separate unit such as, for example, capsules, coated capsules, lozenges or tablets each containing a specific amount of a compound of formula (1); as powders or granules; as a solution or suspension in an aqueous or non-aqueous environment; or as an oil-in-water emulsion or a water-in-oil emulsion. These preparations can, as already mentioned, be produced by means of a suitable process which includes a phase in which the active substance and the carrier (which may consist of one or more additional components) are brought into contact. Preparations are generally produced by uniform and homogeneous mixing of active components with a liquid and/or finely divided solid carrier, after which the product is shaped, if necessary. Thus, for example, a tablet can be produced by pressing or casting some powder or granules of the compound, if necessary with one or more additional components. Compressed tablets may be produced by tableting the compounds in a free-flowing form, such as when they are powders or granules, and mixing them appropriately with a binder, glidant, inert diluent, and/or one or more surface-active-dispersing agents in some suitable apparatus. Molded tablets may be produced by molding the compound which is in powder form and moistened with an inert liquid diluent, in a suitable apparatus. Pharmaceutical preparations suitable for perial (sublingual) administration include lozenges containing a compound of formula (I) with a flavoring agent, typically sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base, such as gelatin and glycerin or sucrose and gum arabic. Pharmaceutical preparations suitable for parenteral administration contain, preferably, sterile aqueous preparations of the compounds of formula (I), which are preferably mixed with the blood of the potential recipient. These preparations are best administered intravenously, although administration may be by subcutaneous, intramuscular, or intradermal injection. These preparations can best be produced by mixing the compound with water and sterilizing the resulting solution and adjusting it to be isotonic with blood. The preparations of the invention, which can be injected, generally contain from 0.1 to 5% by mass of active compounds. Pharmaceutical preparations suitable for rectal administration are preferably in the form of suppositories with individual doses. They can be produced by mixing a compound of formula (I) with one or more conventional solid carriers, for example cocoa butter, and molding the resulting mixture. Pharmaceutical preparations suitable for topical use on the skin are best in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers that can be used are petroleum jelly, lanolin, polyethylene glycol, alcohols, and combinations of two or more of these substances. The active substance is generally present in a concentration of 0.1 to 15% by mass of preparations, for example from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical preparations suitable for transdermal use may be in the form of individual patches suitable for long-term intimate contact with the patient's epidermis. Such patches appropriately contain an active substance in an aqueous solution that is buffered, if appropriate, dissolved and/or dispersed in an adhesive agent, or dispersed in a polymer. A suitable concentration of the active substance is about 1% to 35%, preferably about 3% to 15%. One particular possibility is that the active substance is released by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). The compounds of formula (I) are characterized by their favorable effects on fat metabolism and they are particularly suitable in mammals for weight reduction and maintenance of reduced weight, since weight reduction is also performed as an anorexic agent. The compounds are characterized by their low toxicity and rare side effects. The compounds can be used alone or in combination with other weight-reducing active substances or with anorexic active substances. Further anorexic active ingredients of this type are mentioned, for example, in the Red List, chapter 01, under: weight loss agents / appetite suppressants and they also include active components that increase the energy exchange in the body and thus lead to weight loss, or those that mainly affect the general metabolism of the body in such a way that an increase in calorie intake does not lead to an increase in fat reserves, and a normal intake of calories leads to a decrease in body fat reserves. The compounds are suitable for prophylaxis and, in particular, for the treatment of excess weight or obesity. The compounds are furthermore suitable for prophylaxis and, in particular, for the treatment of type II diabetes, arteriosclerosis and for normalizing fat metabolism and for the treatment of high blood pressure. The compounds act as MCH antagonists and are also suitable for the treatment of hedonic disorders and psychiatric diseases, such as, for example, depression, fear states, fear-induced neuroses, schizophrenia, and for the treatment of diseases related to circadian rhythms and for the treatment of drug abuse. In another aspect of the invention, the compounds of formula I can be administered in combination with one or more other pharmacologically active substances selected, for example, from the group of anti-diabetic agents, anti-obesity agents, blood pressure-lowering active ingredients, fat-lowering agents and active ingredients for the treatment and/or prevention of complications caused by diabetes or related to diabetes. in the Red List 2001, Chapter 12. They can be combined with the compounds of formula I of the present invention, especially for synergistic enhancement of action. Administration of combinations of active substances can be carried out either by separate administration of the active substances to the patient or in the form of combination products in which a plurality of active components are present in the pharmaceutical preparation. The largest number of active substances listed below are disclosed in the USP Dictionarv of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Suitable anti-diabetics include insulin and insulin derivatives, such as, for example, Lantus <®>or HMR 1964, rapid-acting insulins (see US 6,221,633), amylin, GLP-1 and GLP-2 derivatives, such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and hypoglycemic active substances that are orally effective. Orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxa-dazolidine-diones, thiazolidine-diones, glucosidase inhibitors, glucagon-receptor-antagonists, GLP-1 agonists, vasodilators for the elimination of potassium, such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, insulin receptor kinase activators, inhibitors of liver enzymes that play a role in the stimulation of gluconeogenesis and/or glycogenolysis. for example glycogen phosphorylase inhibitors, modulators of glucose uptake and glucose elimination, compounds that alter fat metabolism, such as anti-hyper-lipidemic active substances and anti-lipidemic active substances, e.g., HMGCoA-reductase-inhibitor, cholesterol transport / cholesterol uptake inhibitors, bile acid resorption inhibitors or inhibitors microsomal-triglyceride-transfer-protein (MTP), compounds that reduce food intake, PPAR and RXR agonists and active substances that act on beta-cell potassium channels, which are dependent on ATP. In one embodiment of the invention, the presented compounds are administered in combination with insulin. In one embodiment of the invention, compounds of formula I are given in combination with one HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin. In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol absorption inhibitor, such as, for example, ecetimid, tiquezide, pamaquezide. ;In one embodiment of the invention, the compounds of formula I are administered in combination with one PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570. ;In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW 9578, GW 7647. ;In one embodiment of the invention, the compounds of formula I are administered in combination with one mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 11833, PCT/US 11490, DE10142734.4. In one embodiment of the invention, the compounds of formula I are administered in combination with one fibrate, such as, for example, fenofibrate, clofibrate, bezafibrate. In one embodiment of the invention, compounds of formula I are administered in combination with an MTP inhibitor, such as, for example, implitapide, BMS-201038, R-103757. ;In one embodiment of the invention, the compounds of formula I are administered in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), such as, for example, HMR 1741. ;In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705. In one embodiment of the invention, the compounds of formula I are given in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesevelam. In one embodiment of the invention, compounds of formula I are administered in combination with an LDL receptor inducer (see US 6,342,512), such as, for example, HMR1171, HMR1586. In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimib. In one embodiment of the invention, the compounds of formula I are administered in combination with an antioxidant, such as, for example, OPC-14117. In one embodiment of the invention, compounds of formula I are administered in combination with a lipoprotein-lipase-inhibitor, such as, for example, NO-1886. In one embodiment of the invention, compounds of formula I are administered in combination with an ATP-citrate-lyase inhibitor, such as, for example, SB-204990. In one embodiment of the invention, the compounds of formula I are administered in combination with an inhibitor of squalene synthesis, such as, for example, BMS-188494. In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein(a)-antagonist, such as, for example, CI-1027 or nicotinic acid. In one embodiment of the invention, compounds of formula I are administered in combination with a lipase inhibitor, such as, for example, orlistat. In one embodiment of the invention, compounds of formula I are administered in combination with insulin. In one embodiment of the invention, the compounds of formula I are administered in combination with a sulphonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment of the invention, compounds of formula I are administered in combination with a biguanidine, such as, for example, metformin. In one embodiment of the invention, the compounds of formula I are administered in combination with one meglitinide, such as, for example, repaglinide. In one embodiment of the invention, compounds of formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddv's Research Foundation, especially 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl-methoxy]phenyl]methyl]-2,4-thiazolidine-dione. ;In one embodiment of the invention, the compounds of formula I are administered in combination with one α-glucosidase inhibitor, such as, for example, miglitol or acarbose. ;In one embodiment of the invention, the compounds of formula I are administered in combination with one active a substance that acts on ATP-dependent potassium channels of beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride, or repaglinide; In one embodiment of the invention, the compounds of formula I are administered in combination with more than one previously mentioned compound, for example, in combination with some sulfonylurea and metformin, with sulfonylurea and acarbose, repaglinide and metformin, and some insulin sulfonyl urea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. The compounds of the invention may, moreover, be administered in combination with one or more anti-obesity agents, or an appetite control active substance. In a further embodiment, compounds of formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g., naphthalene-1-sulfonic acid. {4-[(4-Aminoquinazolin-2-yl-amino)methyl]cyclohexyl-methyl}amide; hydrochloride (CGP 71683A)), MC4 agonistic (eg 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chloro-phenyl)-2-oxo-ethyl]-amide; (WO 01/91752)), orexin antagonist (eg 1-(2-methyl-benz-oxazol-6-yl)-3-[1,5]naphth-pyridin-4-yl-carbamide; hydrochloride (SB-334867-A)), H3 agonist (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonist, CRF antagonist (eg, [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropyl-amine (WO 00/66585)), CRF BP antagonist (eg, urocortin), urocortin agonist, p3 agonist (eg, 1- (4-chloro-3-methane-sulfonyl-methyl-phenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yl-oxy)ethyl-amino]-ethanol-hydro-chloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonist, CCK-A agonist (eg, {2-[4-(4-chloro-2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)thiazol-2-yl4 <abamoyl]-5,7-dimethyl-indol-1-yl} acetic acid with trifluoroacetic acid (WO 99/15525)), serotonin;-reuptake inhibitors (eg, dexphene-fluoro-amine), mixed sertoninergic and noradrenergic compounds (eg, WO 00/71549), 5HT agonists, eg, salt 1 -(3-ethyl-benzofuran-7-yl)piperazine-oxalic acid (WO 01/09111), bombesin agonist, galanin antagonist, growth hormones (eg, human; growth hormones), growth hormone-releasing compounds tert-butyl (6-benzyl-loxy-1-(2-diisopropyl-amino-ethyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ester (WO 01/85695)), TRH agonist (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, MatthewC; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to obesity treatment. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors (eg, WO 00/40569), PPAR modulators (eg, WO 00/78312), RXR modulators or TR-β agonists. In one embodiment of the invention, the second active substance is leptin; see, for example, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gemma, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622. In one embodiment, the second active substance is dexamfetamine or amphetamine. In one embodiment, the second active substance is fenfluramine or dexfenfluramine. In another embodiment, the second active substance is sibutramine or mono- and bis-demethylated active metabolites of sibutramine. In one embodiment, the second active substance is orlistat. In one embodiment, the second active substance is mazindol or phentermine. In one embodiment, the compounds of formula I are administered in combination with ballast substances, preferably insoluble ballast substances (see, for example, carob/Caromax <®>(Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.). Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main)). combination with Caromax <®>is possible in a single preparation or by separate administration of compounds of formula I and Caromax <®->a. Caromax <®>can in connection with this also be given in the form of food products, such as pastries or muesli. The presented compounds can be additionally administered in combination with one or more anti-hypertensive active substances. Examples of anti-hypertensive active substances are beta blockers, such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors, such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers, such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alpha blockers, such as doxazosin, urapidil, prazosin, and terazosin. Further reference is made to the literature Remington: The Science and Practice of Pharmacv, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, 1995. ;It is understood that any suitable combination of a compound according to the invention with, most advantageously, one or more of the previously mentioned pharmacologically active substances and, optionally, with one or more other pharmacologically active substances, is considered covered by the claim of the protection of the presented invention.. ;Examples;The effect of the compound was tested on the following method: ;Biological test model: ;Anorexic effect was investigated on female NMRI mice. After stopping food for 17 hours, the test substance was administered forcibly. Animals were housed individually with free access to drinking water and were offered condensed milk 30 minutes after substance administration. Condensed milk consumption was determined every half hour for 7 hours and the general mood of the animals was observed. Measured milk consumption was compared with control animals.. ;Table 1: anorexic effect measured as reduction in cumulative milk consumption of treated animals compared to control animals ;DESCRIPTION OF EXPERIMENTS ;Functional measurements to determine IC50 values ;Cloning of cDNA for the human MCH receptor, creation of a ;recombinant HEK293 cell line expressing the human MCH receptor and functional measurements with recombinant cell lines played out in the same way as described by old Audinot et al. (J. Biol. Chem. 276, 13554-13562, 2001). The difference from this reference, however, was the use of plasmid pEAK8 from EDGE Biosystems (USA) to construct the expression vector. The host used for transfection was a transformed HEK cell line named "PEAK Stable Cells" (similarly from EDGE Biosystems). Functional measurements of cellular calcium flux after addition of agonistene (MCH) in the presence of the ligand of the present invention were performed with the FLIPR apparatus from Molecular Devices (USA), using the protocols of the apparatus manufacturer. The examples and methods of manufacture detailed below serve to illustrate the invention without, however, limiting it. The compounds of formula I according to the invention can be synthesized with the help of reactions that are, in principle, known. For example, the compounds were prepared according to the following general reaction schemes. Other compounds of the invention may be obtained by other synthetic routes, which are exemplified in the following scheme. ;There are more examples as can be seen from the following diagram. ;Descriptions of the general procedures used are visible through the examples described in the following places: procedures A, B and C in example 1; ;procedure D in example 2; ;procedure E in example 3; ;action of E in example 275; ;procedure E-b in example 286; ;procedure F in example 4; ;procedure of F in example 264; ;procedure of F in example 264; ;procedure G in example 15; ;building H in example 237; ;procedure of H in example 298; ;procedure I in example 238; ;procedure J in example 245; ;procedure of J in example 297; ;procedure K in example 250; ;procedure L in example 254; ;procedure M in example 274; ;procedure N in example 277; ;procedure O in example 279; ;the procedure of O in example 292; ;procedure O-b in example 280; ;procedure P in example 285; ;procedure Q in example 290; ;procedure R in example 309. ;General explanations ;a) How to draw structural formulas ;For the sake of clarity, in the structural formulas of the given examples, only atoms other than hydrogen are shown. ;In Tables 6-13, enantiomerically enriched compounds are identified by the labeled hydrogen atom at the stereogenic center. Unless otherwise stated, the enantiomer-enriched examples shown have the (R) configuration at the 3-amino-pyrrolidine stereo-center. b) Salt Forms Many of the compounds according to the invention are bases and can form salts with correspondingly strong acids. Especially after purification of the compounds by means of HPLC-chromatography, using a mobile phase containing hydro-trifluoro-acetic acid, they can be in the form of hydro-trifluoro-acetate. These can be converted into the free bases shown here by simply treating a salt solution with, for example, a sodium carbonate solution; c) Units of characteristic sizes; The unit of a given molecular weight is "g/mol". The peaks that appear in the mass spectrum are indicated as the ratio of the molecular weight of the ion to the electric charge of the molecular ion (m/z). Example 1 N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide; Procedure A A solution of 4-phenoxy-aniline (3.33 g) in DMF (10 ml) was added dropwise to a solution of carbonyl-diimidazole (2.92 g) in DMF (12 ml) and the mixture was then cooled to 0°C. After 30 minutes, N-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acetamide (3.80 g) in DMF (10 ml) was added dropwise. The reaction solution was kept, first at room temperature for 2 hours, and then at 80°C for 30 minutes. The mixture was added, drop by drop, to water (600 ml) and the resulting precipitate was vacuum filtered and washed with water. Alternatively, the product can be extracted with ethyl acetate and purified, after preparation, by chromatography. In the end, a product with a molecular weight of 444.54 (C26H28N403) was obtained; MS (ESI): 445 (M+H+). ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide ;Procedure B ;Suspension of N-methyl-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide (3.5 g) and palladium(II)-hydroxide (20% on carbon; 0.9 g) in ethanol (150 ml) and ethyl acetate (300 ml) was stirred vigorously for 3 hours in a hydrogen atmosphere (atmospheric pressure). The catalyst was removed by filtration and the filtrate was evaporated. In the end, a product with a molecular weight of 233.32 (C13H19N30) was obtained; MS (ESI): 234 (M+H+). ;N-Methyl-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide ;Procedure C ;4-Fluoro-nitro-benzene (25.0 g) was added slowly to a suspension of N-methyl-N-pyrrolidin-3-yl-acet-amide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture is poured into water and the resulting precipitate is filtered off with the help of a vacuum. Alternatively, the product can be extracted with ethyl acetate and purified by chromatography after evaporation. Finally, a product with a molecular weight of 263.30 (C13H17N303) is obtained: MS (ESI): 264 (M+H+). Example 2 1-[4-(3-Methyl-amino-pyrrolidin-1-yl)phenyl]-3-(4-phenoxy-phenyl)urea; ;Procedure D ;A mixture of N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide (6.0 g), ethanol (250 ml), water (60 ml) and sodium hydroxide solution (10 M; 80 ml) was heated under reflux for 12 hours. The alcohol was distilled off and the resulting precipitate was filtered off under vacuum and washed with dichloromethane. An additional amount of product was obtained by evaporation of the organic layer and chromatography (silica gel, dichloromethane / methanol 9:1 with 1% triethylamine). In the end, a product with a molecular weight of 402.50 (C24H26N402) was obtained; MS (ESI): 403 (M+H+). Example 3: N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-2-phenyl-acet-amide; Procedure E TOTU (327 mg) was added to a solution of 1-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]-3-(4-phenoxy-phenyl)urea (402 mg) in DMF (3 ml) at 0°C. After 10 minutes, Huenig's base (130 mg) was added, followed by a solution of phenylacetic acid (136 mg) in DMF (1 ml). After 12 hours of reaction at room temperature, water was added to the mixture and everything was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by preparative HPLC. In the end, a product with a molecular weight of 520.64 (C32H32N403) was obtained; MS (ESI): 521 (M+H+) as hydrotrifluoroacetate. ;Example 4 ;ff? N-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide; ;f/:? /)-N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4-phenoxy-aniline according to procedure A. In the end, a product with a molecular weight of 444.54 (C26H28N403) was obtained; MS (ESI): 445 (M+H+). ;ff? J-N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide fRJ-N-Methyl-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide was hydrogenated according to procedure B. Finally, a product with a molecular weight of 233.32 (C13H19N30) was obtained; MS (ESI): 234 (M+H+). ;(Ry)-N-Methyl-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide ;Procedure F ;(7?j-N-[1-(4-Nitro-phenyl)pyrrolidin-3-yl]acet-amide (1.3 g) was added portionwise to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased iodomethane (0.82 g) was added. After one hour, the reaction mixture was carefully hydrolyzed with ethyl acetate. The organic layer was dried over magnesium sulfate. Finally, the product of molecular weight 263.30 (ESI) was obtained. ;(R>N-[1-(4-Nitro-phenyl)pyrrolidin-3-yl]acet-amide ;(RJ-N-pyrrolidin-3-yl-acet-amide was reacted with 4-fluoro-nitro-benzene according to procedure C. In the end, a product with a molecular weight of 249.27 (C12H15N303); MS (ESI): 250 (M+H+) was obtained. ;Example 5 ;(S>N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide ; ;The sequence described in example 4 was applied to (Sj-N-pyrrolidin-3-yl-acet-amide). In the end, a product with a molecular weight of 444.54 (C26H28N403); MS (ESI): 445 was obtained (M+H+). ;Example 6 ;('f? /)-1-[4-(3-Methyl-amino-pyrrolidin-1-yl)phenyl]-3-(4-phenoxy-phenyl)urea; (Rj-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide was reacted according to procedure D. Finally, a product with a molecular weight of 402.50 (C24H26N402); MS (ESI): 403 (M+H+) was obtained. Example 7 (^Sj-1-[4-(3-Methyl-amino-pyrrolidin-1-yl)phenyl]-3-(4-phenoxy-phenyl)carbamide; CS/)-N-Methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide was reacted according to procedure D. In the end, a product with a molecular weight of 402.50 was obtained. (C24H26N402); MS (ESI): 403 (M+H+). Example 8 (R)-N-(1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl--acet-amide; (R)-N-[1-(4-Amino-phenyl)pyrrolidin-3-yl)-N-methyl-acet-amide was reacted with 4-cyclopentyl-oxy-aniline according to procedure A. In the end, a product with a molecular weight of 436.56 (C25H32N403) was obtained; MS (ESI): 437 (M+H+). ;(S)-N-(1-{4-[3-(4-cyclopentyl-oxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acet-amide was obtained in the same way from (S)-N-[1-(4-amino-phenyl)-pyrrolidin-3-yl]-N-methyl-acet-amide. ;4-Cyclopentyl-oxy-aniline ;A mixture of 4-nitro-phenol (63.7 g), bromo-cyclopentane (68.2 g), potassium carbonate (63.3 g) and DMF (300 ml) was heated at 80°C for 24 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was hydrogenated according to procedure B. In the end, a product with a molecular weight of 177.25 (C11H15NO) was obtained; MS (ESI): 178 (M+H+). Example 9 ;1-(4-Cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]urea; ;N-(1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-acet-amide was reacted according to procedure D. In the end, a product with a molecular weight of 394.52 (C23H30N4O2) was obtained; MS (ESI): 395 (M+H+). (R)- and (S)-1-(4-cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)-phenyl]-urea was obtained in the same way from (R)- and (S)-N-(1-{4-[3-(4-cyclopentyl-oxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acet-amide. Example 10 (1-{4-[3-(4-cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-carbamic acid ethyl ester; Ethyl chloroformate (8 u.1) was added dropwise to a solution of 1-(4-cyclopentyl-oxy-phenyl)-3-[4-(3-rmethyl-amino-pyrrolidin-1-yl)phenyl]carbamide. (20 mg) and Huenig's base (10 mg) in dichloromethane (3 ml), after 12 hours the reaction mixture was evaporated and the residue was purified by preparative HPLC. In the end, a product with a molecular weight of 466.59 (C26H34N404) was obtained; MS (ESI): 467 (M+H+) as hydrotrifluoroacetate. Example 11 1-(1-{4-[3-(4-cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-3-ethyl-1-methyl-urea; ;Ethyl isocyanate (July 7) was added dropwise to a solution of 1-(4-cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]carbamide (20 mg) and Huenig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was evaporated and the residue was purified by preparative HPLC. In the end, a product with a molecular weight of 465.60 (C26H35N503) was obtained; MS (ESI): 466 (M+H+) as hydrotrifluoroacetate. ;Example 12 1-(4-Cyclopentyl-oxy-phenyl)-3-(4-{3-[methyl-((R)-5-oxo-pyrrolidin-2-yl-methyl)amino]pyrrolidin-1-yl}phenyl)carbamide;(RJ-5-Bromo-methyl-pyrrolidin-2-one) (15 mg) was added to the suspension. 1-(4-cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-pyrrolidin-1-yl)urea (20 mg) in DMF (3 ml). After 2 hours the reaction mixture was filtered and the residue was purified by preparative HPLC. 492 (M+H+) in the form of hydro-trifluoroacetate; Example 13 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with carbonyl-diimidazole and then with 4-(4-chloro-phenyl)piperidine according to procedure A. As a result, a product with a molecular weight of 455.00 (C25H31CIN402) was obtained; MS (ESI): 455 (M+H+). (R)- and (S)-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid was obtained in the same way from (R)- and (S)-H-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acetamide. Example 14 tert-Butyl (R)-[\-(4-{[4-(4-chloro-phenyl)piperidine-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methyl-carbamate; ;tert.-Butyl ('/? j-[1-(4-amino-phenyl)pyrrolidin-3-yl]methyl-carbamate was reacted with carbonyl-diimidazoles and then with 4-(4-chloro-phenyl)piperidine according to procedure A. As a result, a product of molecular weight 513.09 (C28H37CIN403); MS (ESI): 513 (M+H+) was obtained. ;tert.-Butyl (RJ-[1-(4-amino-phenyl)pyrrolidin-3-yl]methyl-carbamate; tert.-Butyl (RJ-methyl-fl -(4-nitro-phenyl)pyrrolidin-3-yl]carbamate was hydrogenated according to procedure B. As a result obtained is a product of molecular weight 291.40 (C16H25N302); MS (ESI): 292 (M+H+). ;tert.-Butyl (Rj-methyl-[1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate ;tert.-Butyl (RJ-[1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate was alkylated with iodomethane according to procedure F. As a result, a product with a molecular weight of 321.38 (C16H23N304); MS (ESI): 322 (M+H+). ;tert.-Butyl( R )-[\ -(4-nitro-phenyl)pyrrolidin-3-yl]carbamate; (C15H21N304); MS (ESI): 308 (M+H+). Example 15 [4-(3-Methyl-amino-pyrrolidin-1-yl)phenyl]amide (R)-4-(4-chloro-phenyl)piperidine-1-carboxylic acid; Procedure G Trifluoroacetic acid (6.67 g) was added to a solution of tert-butyl (RJ-[1-(4-{[4-(4-chloro-phenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methyl-carbamate (1.5 g) in dichloromethane (50 ml). After 3 hours, the volatile substances were removed and the residue was dissolved in After washing with sodium carbonate solution, the organic layer was dried over magnesium sulfate, resulting in a product with a molecular weight of 412.97 (C23H29CIN40); MS (ESI): 413 (M+H+). ;Example 16 ;(4-{('Rj-3-[Methyl-(1-methyl-piperidin-3-yl-carbonyl)amino]pyrrolidin-1-yl}phenyl)amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid ; with 1-methyl-piperidine-3-carboxylic acid according to procedure E. As a result, a product of molecular weight 538.14 (C30H40CIN5O2) was obtained; MS (ESI): 538 (M+H+). 4-(4-Chloro-phenyl)piperidin-1-carboxylic acid [4-(3-Methyl-amino-pyrrolidin-1-yl)phenyl]amide (f?)-4-(4-chloro-phenyl)piperidin-1-carboxylic acid was reacted with piperidin-1-yl-acetic acid according to procedure E. molecular weight 538.14 (C30H40CIN5O2); MS (ESI): 538 (M+H+). Example 18 (4-(RH3-[Methyl|-(2-oxo-thiazolidin-4-carbonyl)amino]pyrrolidin-1-yl}phenyl)amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; with 2-oxo-thiazolidine-4-carboxylic acid according to procedure E. As a result, a product of molecular weight 542.10 (C27H32CIN503S); MS (ESI): 542 (M+H+) was obtained. or-phenyl)piperidine-1-carboxylic acids ; ;ff? HN-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methyl-acet-amide was reacted with carbonyl-diimidazole and then with 4-(4-chloro-phenyl)-piperidine according to procedure A. As a result, a product with a molecular weight of 508.98 (C25H28CIF3N402) was obtained; MS (ESI): 509 (M+H+). ;f/? /)-[N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methyl-acet-amide; (RJ-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide was hydrogenated according to procedure B. As a result, a product with a molecular weight of 287.29 (C13H16F3N30) was obtained; MS (ESI): 288 (M+H+). ;(R;-2,2,2-Trifluoro-N-methyl-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide; Trifluoroacetic anhydride (0.5 ml) was added dropwise to a solution of ff?j-methyl-[1-(4-nitro-phenyl)pyrrolidin-3-yl]amine (0.48 g) in pyridine (2 ml). After 3 hours, the reaction mixture was diluted with water and extracted with citric acid, dried over magnesium sulfate to give a product of molecular weight 317.27 (ESI): ;(R/)-Methyl-[1-(4-nitro-phenyl)]amine. Tert-butyl (R/)-methyl-[1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) for one hour. The reaction solution was evaporated and the residue was dissolved in dichloromethane. after washing with sodium carbonate solution, the organic layer was dried over magnesium sulfate and evaporated. As a result, a product with a molecular weight of 221.26 (C11H15N302) was obtained; MS (ESI): 222; (M+H+). Example 20 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}methyl-amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; ;{4-[3-(Acetyl-methyl-amino)pyrrolidin-1 yl]phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid was treated with iodomethane according to procedure F. As a result, a product with a molecular weight of 469.03 (C26H33CIN402) was obtained; MS (ESI): 469 (M+H+). Example 21 (4-{3-[Acetyl-(2-diethyl-amino-ethyl)amino]pyrrolidin-1-yl}phenyl)amide (ft)-4-(4-chloro-phenyl)piperidine-1-carboxylic acids; ff? >N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-(2-diethyl-amino-ethyl)acet-amide was reacted with 4-(4-chloro-phenyl)piperidine according to procedure A. As a result, a product with a molecular weight of 540.15 (C30H42CIN5O2) was obtained; MS (ESI): 540 (M+H+). (RJ-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethyl-amino-ethyl)acet-amide (f?>N-(2-Diethyl-amino-ethyl)-N-[1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide was hydrogenated according to procedure B. As a result, a product with a molecular weight of 318.47 (C18H30N4O); MS (ESI): 319 was obtained. (M+H+). (C18H28N403); MS (ESI): 349 (M+H+). Example 22 1-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-3-(4-phenoxy-phenyl)urea; Dimethyl-pyrrolidin-3-yl-amine was reacted with 4-fluoro-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline was reacted with CDI and 4-phenoxy-aniline according to procedures A, B and C. As a result, a product of molecular weight was obtained 416.53 (C25H28N402); MS (ESI): 417 (M+H+). Example 23: N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-isobutoxy-phenyl)propion-amide; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide reacted is with 2-(4-isobutoxy-phenyl)propionic acid according to procedure E. As a result, a product with a molecular weight of 437.59 (C26H35N303) was obtained; MS (ESI): 438 (M+H+). ;Example 24 ;N-(1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide ;N-Pyrrolidin-3-yl-acet-amide was reacted with 4-fluoro-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline was reacted with CDI and 4-cyclopentyl-oxy-aniline according to procedures A, B and C. As a result, a product with a molecular weight of 422.53 (C24H30N4O3) was obtained; MS (ESI): 423 (M+H+). ;( R)-i (SJ-N-(1 -{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide were obtained in the same way starting from (R)-i (SJ-N-pyrrolidin-3-yl-acet-amide. ; Example 25 ;N-(1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)-N-ethyl-acet-amide ; ;N-Ethyl-N-pyrrolidin-3-yl-acet-amide was reacted with 4-fluoro-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline was reacted with CDI and 4-cyclopentyl-oxy-aniline according to procedures A, B and C. As a result, a product with a molecular weight of 450.59 (C26H34N403) was obtained; MS (ESI): 451 (M+H+). Example 26 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]-3-methyl-phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; ;N-Methyl-N-pyrrolidin-3-yl-acet-amide was reacted with 1-fluoro-2-methyl-4-niro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, the aniline was reacted with CDI and 4-(4-chloro-phenyl)piperidine according to procedures A, B and C. As a result, a product with a molecular weight of 469.03 (C26H33CIN402) was obtained; MS (ESI): 469 (M+H+). Example 27 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl)-3-fluoro-phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; ;N-Methyl-N-pyrrolidin-3-yl-acet-amide was reacted with 1,2-difluoro-4-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline was reacted with CDI and 4-(4-chloro-phenyl)piperidine according to procedures A, B and C. As a result, a product with a molecular weight of 472.99 (C25H30CIFN4O2) was obtained; MS (ESI): 473 (M+H+). Example 28 4-(4-chloro-phenyl)piperidine-1-carboxylic acid {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]-2,6-difluoro-phenyl}amide; ;N-Methyl-N-pyrrolidin-3-yl-acet-amide was reacted with 1,3,5-trifluoro-2-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, at finally, aniline was reacted with CDI and 4-(4-chloro-phenyl)piperidine according to procedures A, B and C. As a result, a product with a molecular weight of 490.99 (C25H29CIF2N402) was obtained; MS (ESI): 491 (M+H+). Example 29 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]-2-methyl-phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; ;N-Methyl-N-pyrrolidin-3-yl-acet-amide was reacted with 4-fluoro-2-methyl-1-nitrobenzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline was reacted with CDI and 4-(4-chloro-phenyl)piperidine according to procedures A, B and C. As a result, a product with a molecular weight of 469.03 (C26H33CIN402) was obtained; MS (ESI): 469 (M+H+). Example 30 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]-2-fluoro-phenyl}amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acid; ;N-Methyl-N-pyrrolidin-3-yl-acet-amide was reacted with 2,4-difluoro-1-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline was reacted with CDI and 4-(4-chloro-phenyl)piperidine according to procedures A, B and C. As a result, a product with a molecular weight of 472.99 (C25H30CIFN4O2) was obtained; MS (ESI): 473 (M+H+). ;Example 31 ;tert.-Butyl (RJ-[1-(5-{[4-(4-chloro-phenyl)piperidin-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate ; The synthesis flow for obtaining tert.-butyl (f? >[1-(4-{[4-(4-chloro-phenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methyl-carbamate was carried out starting from 2-chloro-5-nitro-pyridine instead of 4-fluoro-nitrobenzene gives a product of molecular weight 514.07 (ESI): 514 (M+H+). ;tert.-Butyl ('f?j-[1-(5-{[4-(4-chloro-phenyl)piperidin-1-carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate was tertiated with trifluoroacetic acid according to procedure G. This resulted in a product of molecular weight 413.95 (C22H28CIN50); MS (ESI): 414 (M+H+). Similarly, it was possible to obtain obtained racemic [6-(3-methyl-amino-pyrrolidin-yl)pyridin-3-yl]amide [4-(4-chloro-phenyl)piperidine-1-carboxylic acid. ;N-Methyl-N-pyrrolidin-3-yl-acet-amide reacted with 2-chloro-5-nitro-pyridine, the resulting nitro compound was reduced with hydrogen and, finally, the aniline was reacted with CDI and 4-(4-chloro-phenyl)piperidine according to procedures A, B and C. As a result, a product of molecular weight 490.99 (C25H29CIF2N402) was obtained; MS (ESI): 491 (M+H+). ;Example 34 1-[4-(4-Dimethyl-amino-piperidin-1-yl)phenyl]-3-(4-phenoxy-phenyl)urea ;Dimethyl-piperidin-4-yl-amine was reacted with 4-fluoro-nitro-benzene, the resulting nitro compound was reduced with hydrogen and, finally, aniline ([1-(4-amino-phenyl)piperidin-4-yl]dimethyl-amine) was reacted with CDI and 4-phenoxy-aniline according to procedures A, B and C. As a result, a molecular weight product was obtained 430.55 (C26H30N4O2); MS (ESI): 431 (M+H+). Example 35 1-(4-Cyclopentyl-oxy-phenyl)-3-[4-(4-morpholin-4-yl-iiperidin-1-yl)phenyl]urea; ;4-Piperidin-4-yl-morpholine was reacted with 4-fluoro-nitro-benzene, the resulting nitro-compound was reduced with hydrogen and, finally, the aniline was reacted with CDI and 4-cyclopentyl-oxy-aniline A, B and C. As a result, a product of molecular weight 464.61 (C27H36N403) was obtained; MS (ESI): 465; (M+H+). Example 36 4-Butoxy-N-[4-(4-dimethyl-amino-piperidin-1-yl)phenyl]benzamide; ;([1-(4-Amino-phenyl)piperidin-4-yl]dimethyl-amine) was reacted with 4-4-butoxy-benzoic acid according to procedure E. As a result, a product with a molecular weight of 395.55 (C24H33N302) was obtained; MS (ESI): 396; (M+H+). Example 37 4-(4-chloro-phenyl)piperidine-1-carboxylic acid {4-[3-(Acetyl-methyl-amino)azetidin-1-yl]phenyl}amide; ;N-[1-(4-Amino-phenyl)azetidin-3-yl]-N-methyl-acet-amide was reacted with carbonyl-diimidazole and 4-(4-chloro-phenyl)piperidine according to procedure A. As a result, a product with a molecular weight of 440.98 (C24H29CIN402) was obtained; MS (ESI): 441 (M+H+). ;N-[1-(4-Amino-phenyl)azetidin-3-yl]-N-methyl-acet-amide ;N-Methyl-N-[1-(4-nitro-phenyl)azetidin-3-yl]acet-amide was hydrogenated according to procedure B. As a result, a product with a molecular weight of 219.29 (C12H17N30) was obtained; MS (ESI): 220 (M+H+). ;N-Methyl-N-[1-(4-nitro-phenyl)azetidin-3-yl]acet-amide ;N-[1-(4-nitro-phenyl)azetidin-3-yl]acet-amide was alkylated with iodomethane according to procedure F. As a result, a product with a molecular weight of 249.27 (C12H15N303) was obtained; MS (ESI): 250 (M+H+). ;N-[1-(4-Nitro-phenyl)azetidin-3-yl]acet-amide Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitro-phenyl)azetidin-3-yl-amine (0.5 g) in pyridine (1.2 ml). After one hour, the volatile fractions were removed. As a result, a product with a molecular weight of 235.24 (C11H13N303) was obtained; MS (ESI): 236 (M+H+). ;1-(4-Nitro-phenyl)azetidin-3-yl-amine ;tert.-Butyl [1-(4-nitro-phenyl)azetidin-3-yl]carbamate is a tertium with trifluoroacetic acid according to procedure G. As a result, a product of molecular weight 193.21 (C9H11N302) was obtained; MS (ESI): 194 (M+H+). tert-Butyl [1-(4-nitro-phenyl)azetidin-3-yl]carbamate ;tert.-Butyl azetidin-3-yl-carbamate was reacted with 4-fluoro-nitro-benzene according to procedure C. As a result, a product of molecular weight 293.33 (C14H19N304) was obtained; MS (ESI): 294 (M+H+). Example 38 tert-Butyl [1-(4-{[4-(4-chloro-phenyl)piperidine-1-carbonyl]amino}phenyl)azetidin-3-ylmethyl-carbamate; ;tert.-Butyl [1-(4-amino-phenyl)azetidin-3-yl]methyl-carbamate was reacted with carbonyl-diimidazole and 4-(4-chloro-phenyl)piperidine according to procedure A. As a result, a product with a molecular weight of 499.06 (C27H35CIN403; MS (ESI): 499 (M+H+)) was obtained. ;tert.-Butyl [1 -(4-amino-phenyl)azetidin-3-yl]methyl-carbamate tert.-Butyl methyl-[1-(4-nitro-phenyl)azetidin-3-yl]carbamate was hydrogenated according to procedure B. As a result, a product with a molecular weight of 277.37 (C15H23N302) was obtained; MS (ESI): 278 (M+H+). ; tert.-Butyl methyl-[1-(4-nitro-phenyl)azetidin-3-yl]carbamate tert.-Butyl [1-(4-nitro-phenyl)azetidin-3-yl]carbamate was alkylated using iodomethane according to procedure F. As a result, a product with a molecular weight of 307.35 (C15H21N304) was obtained; MS (ESI): 308 (M+H+). Example 39 [4-(3-Methyl-amino-azetidin-1-yl)phenyl]amide 4-(4-chloro-phenyl)piperidine-1-carboxylic acids; tert-Butyl [1-(4-{[4-(4-chloro-phenyl)piperidin-1-carbonyl]amino}phenyl)azetidin-3-ylmethyl-carbamate was reacted with trifluoroacetic acid according to procedure G. As a result, a product with a molecular weight of 398.94 (C22H27CIN40) was obtained; MS (ESI): 399 (M+H+). Example 40 N-Methyl-N-[1-(4-{3-[4-(pyridin-3-yl-oxy)phenyl]ureido}phenyl)pyrrolidin-3-yl]acet-amide; N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with carbonyl-diimidazole and then with 4-(pyridin-3-yl-oxy)phenyl-amine according to procedure A. As a result, product molecular weight 445.53 (C25H27N503); MS (ESI): 446 (M+H+). Example 41 N-Methyl-N-(1-{4-[3-(4-piperidin-1-yl-phenyl)ureido]phenyl}pyrrolidin-3-yl)acet-amide; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with carbonyl-diimidazoles and, then, with 4-piperidin-1-yl-phenyl-amine according to procedure A. As a result, a product with a molecular weight of 435.57 (C25H33N502) was obtained; MS (ESI): 436 (M+H+). Example 42: N-{4-[3-(Acetyl-methy-amino)pyrrolidin-1-yl]phenyl}-4-phenoxy-benz-amide; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4-phenoxy-benzoic acid according to procedure E. As a result, a product of molecular weight 429.52 (C26H27N303) was obtained; MS (ESI): 430 (M+H+). Example 43: N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-4-butoxy-benz-amide; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4-butoxy-benzoic acid according to procedure E. As a result, a product of molecular weight 409.53 (C24H31N303) was obtained; MS (ESI): 410; (M+H+). Example 44 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 4-(4-chloro-phenyl)cyclohexane-carboxylic acid; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4-(4-chloro-phenyl)cyclohexane-carboxylic acid according to procedure E. As a result, a product of molecular weight 454.02 (C26H32CIN302) was obtained; MS (ESI): 454 (M+H+). Example 45: N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-3-(4-isopropyl-phenyl)acrylamide; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide reacted with 3-(4-isopropyl-phenyl)acrylic with acid according to procedure E. As a result, a product with a molecular weight of 405.54 (C25H31N302) was obtained; MS (ESI): 406; (M+H+). Example 46 (1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-amide of tetrahydro-furan-2-carboxylic acid; 1-(4-Cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]urea was reacted with tetrahydro-furan-2-carboxylic acid according to procedure E. As a result, a product with a molecular weight of 492.62 (C28H36N404) was obtained; MS (ESI): 493 (M+H+). Example 47 (1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-amide 1-acetyl-pyrrolidine-2-carboxylic acid 1-(4-Cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]urea was reacted with 1-acetyl-pyrrolidine-2-carboxylic acid according to procedure E. As a result, the product molecular weight 533.68 (C30H39N5O4); MS (ESI): 534 (M+H+). Example 48 (1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-amide 5-oxo-pyrrolidine-2-carboxylic acid 1-(4-Cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]urea was reacted with 5-oxo-pyrrolidine-2-carboxylic acid according to procedure E. As a result, a product with a molecular weight of 505.62 (C28H35N504) was obtained; MS (ESI): 506 (M+H+). Example 49 (1-{4-[3-(4-Cyclopentyl-oxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-amide 2-oxo-thiazolidine-4-carboxylic acid 1 -(4-Cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1 -yl)phenyl]carbamide was reacted with 2-oxo-thiazolidine-4-carboxylic acid according to the procedure E. As a result, a product with a molecular weight of 523.66 (C27H33N504S) was obtained; MS (ESI): 524 (M+H+). Procedure 50 {1-[4-(4-Cyclohexyl-benzoyl-amino)phenyl]pyrrolidin-3-yl}methyl-amide (R)-1-methyl-piperidine-3-carboxylic acid (R)-4-Cyclohexyl-N-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]benz-amide was reacted with 1-methyl-piperidine-3-carboxylic acid according to procedure E. As a result, a product of molecular weight 502.71 (C31H42N402); MS (ESI): 503 (M+H+). Example 51 N-(1-{4-[3-(6-Cyclopentyl-oxy-pyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-acet-amide; N-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with carbonyl-diimidazole and 6-cyclopentyl-oxy-pyridin-3-yl-amine according to the procedure A. As a result, a product with a molecular weight of 437.55 (C24H31N503) was obtained; MS (ESI): 438 (M+H+). ;6-Cyclopentyl-oxy-pyridin-3-yl-amine ;A mixture of 5-nitro-pyridin-2-ol (14.0 g), bromo-cyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 ml) was heated at 80°C for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyl-oxy-5-nitro-pyridine) was hydrogenated according to procedure B. As a result, a product with a molecular weight of 178.24 (C10H14N2O) was obtained; MS (ESI): 179 (M+H+). Example 52 1-(6-Cyclo-pentyl-oxy-pyridin-3-yl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)-phenylurea; ;N-(1-{4-[3-(6-Cyclopentyl-oxy-pyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-acet-amide is tertinated with sodium hydroxide solution according to procedure D. As a result, a product with a molecular weight of 395.51 (C22H29N502) was obtained; MS (ESI): 395 (M+H+). Example 53 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 4'-fluoro-biphenyl-4-carboxylic acid; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4'-fluoro-biphenyl-4-carboxylic acid according to procedure E. As a result, a product of molecular weight 431.51 (C26H26FN302) was obtained; MS (ESI): 432 (M+H+). Example 54 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 4'-trifluoro-methyl-biphenyl-4-carboxylic acid; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4'-trifluoro-methyl-biphenyl-4-carboxylic acid according to procedure E. As a result, a product of molecular weight 481.52 (C27H26F3N302) was obtained; MS (ESI): 482 (M+H+). ;Examples 55-103 ;1 -(4-Phenoxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1 -yl)phenyl]carbamide was reacted with various carboxylic acids according to procedure E. The products are shown in Table 2. Examples 104-144 1 -(4-Cyclopentyl-oxy-phenyl)-3-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]urea -yl)phenyl]urea was reacted with various carboxylic acids according to procedure E. The products are shown in Table 3. ;Examples 145-185 ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with various carboxylic acids according to procedure E. The products are shown in Table 4. ;Examples 186-234 ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with carbonyl-diimidazole and then with various amines according to procedure A. The products are shown in Table 5. ; ;Nach Methode F-a vvurde {1-[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]-pyrrolidin-3-yl}-methyl-carbaminsaure tert-butylester mit 2-Ethylbutylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargevvicht 548.78 (C33H48N403); MS (ESI): 549 (M+H+). ;Beispiel 266 ;(1-{5-[(4-Cyclohexyl-benzoyl)-(3-methyl-but-2-enyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl-carbaminsaure tert-butylester ; ;Nach Methode F-a vvurde {1-[5-(4-Cyclohexyl-benzoylamino)-pyridin-2-yl]-pyrrolidin-3-yl}-methyl-carbaminsaure tert-butylester mit 3-Methyl-2-butenylbromid umgesetzt. Man erhielt so das Produkt mit dem Molekulargevvicht 546.76 (C33H46N403); MS (ESI): 547 (M+H+). ;Beispiel 267 ;(1-{5-[(4-Cyclohexyl-benzoyl)-methyl-amino]-pyridin-2-yl}-pyrrolidin-3-yl)-methyl-carbaminsaure tert-butylester ; ;Procedure H ;Cesium carbonate (36 mg) and n-butyl bromide (15 mg) were added to a solution of N-{4-[3-(acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxy-phenyl)propionamide (27 mg) in DMF (1 ml). After a reaction time of 2 hours at room temperature, water was added to the mixture and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate and evaporated. The residue was crystallized from a diethyl ether/methanol mixture. A product with a molecular weight of 437.59 (C26H35N303) was obtained; MS(ESI): 438 (M+H+). ;N-{4-[3-(Acetyl-methyl-phenyl)pyrrolidin-1-yl]phenyl}-2-(4-hydroxy-phenyl)propion-amide N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 2-(4-hydroxy-phenyl)propionic acid according to procedure I. A product of molecular weight 381.48 (C22H27N303) was obtained; MS(ESI): 382 (M+H+). Example 238: N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-iso-butoxy-phenyl)acet-amide; ;N-{4-[3-(Acetyl-methyl-phenyl)pyrrolidin-1-yl]phenyl}-2-(4-hydroxy-phenyl)acet-amide was reacted with isobutyl bromide according to procedure H. A product of molecular weight 423.56 (C25H33N303) was obtained; MS(ESI): 424 (M+H+). ;N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxy-phenyl)acet-amide Procedure I 4-Hydroxy-phenyl-acetic acid (305 mg), 1-hydroxy-benzo-triazole (300 mg) and 1-(3-dimethyl-amino-propyl)-3-ethyl-carbo-diimide-hydrochloride (480 mg) were mixed in DMF (5 ml). with N-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide (470 mg) at room temperature for 3 hours. Water was then added to the mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated and crystallized from diethyl ether. A product with a molecular weight of 367.45 (C21H25N303) was obtained; MS(ESI): 368 (M+H+). Example 239 (f)-N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-butoxy-phenyl)acet-amide; (f?)-N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 4-butoxy-phenyl-acetic acid according to procedure E. A product with a molecular weight of 423.56 (025H33N3O3) was obtained; MS(ESI): 424 (M+H+). Example 240 N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-cyclopropyl-methoxy-phenyl)-propion-amide; N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxy-phenyl)propion-amide was reacted with bromo-methyl-cyclopropane according to procedure H. A product with a molecular weight of 435.57 was obtained. (C26H33N303); MS(ESI): 436 (M+H+). Example 241: N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-cyclobutyl-methoxy-phenyl)-propion-amide; ;N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxy-phenyl)propion-amide was reacted with bromo-methyl-cyclobutane according to procedure H. A product of molecular weight 449.60 (C27H35N303) was obtained; MS(ESI): 450 (M+H+). Example 242 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 1-(4-methoxy-phenyl)-1-cyclopropane-carboxylic acid; ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 1-(4-methoxy-phenyl)-1-cyclopropane-carboxylic acid according to procedure E. A product with a molecular weight of 407.52 (C24H29N303) was obtained; MS(ESI): 408; (M+H+). Example 243 {4-[3-(Acetyl-methyl-amino)pyrrolidine-1-N]phenyl}amide 1-(4-butoxy-phenyl)cyclopropane-carboxylic acid; ;{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 1-(4-hydroxy-phenyl)cyclopropane-carboxylic acid was reacted with n-butyl bromide according to procedure H. A product of molecular weight 449.60 (C27H35N303) was obtained; MS(ESI): 450 (M+H+). ;{4-[3-(Acetyl-methyl-amino)pyrrolidin-1 -yl]phenyl}amide 1 -(4-hydroxy-phenyl)cyclopropane-carboxylic acid ;Boron-tribromide-dimethyl-sulfide (460 mg) was added to a solution of {4-[3-(acetyl-methyl-amino)pyrrolidin-1 -yl]phenyl}amide 1 -(4-methoxy-phenyl)cyclopropane-carboxylic acid (540 mg) in dichloromethane. (5.5 ml) at 0°C. After the reaction took place for 12 hours at room temperature, water was added to the mixture, the layers were separated and the aqueous layer was extracted with dichloromethane. The mixed organic layers were dried over sodium sulfate, evaporated and purified by chromatography (silica gel, toluene/ethanol/ethyl acetate 8:1:1 with the addition of 0.1% triethylamine). A product with a molecular weight of 393.49 (C23H27N303) was obtained; MS(ESI): 394 (M+H+). Example 244 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-N-methyl-amide (f?)-4-(4-fluoro-phenyl)piperidine-1-carboxylic acid; {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide (R)-4-(4-fluoro-phenyl)piperidine-1-carboxylic acid (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). When gas evolution stopped, iodomethane (0.02 ml) was added. After three hours, the reaction mixture was carefully hydrolyzed with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated, and the residue was crystallized from pentane. A product with a molecular weight of 452.58 (C26H33FN402) was obtained; MS (ESI): 453 (M+H+). Example 245 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 5-2-[(2-fluoro-phenyl)ethynyl]furan-2-carboxylic acid; ;Procedure J ;First diisopropyl-amine (14.9 mg), then a solution of {4-[3-(acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 5-bromo-furan-2-carboxylic acid (50.0 mg) and 1-ethynyl-2-fluoro-benzene (17.7 mg) in dioxane (0.5 ml) and DMF (0.2 ml) were added under inert conditions to the suspension of palladium bis(tri-tert-butyl-phosphine)dichloride (3.8 mg) and copper(l)-iodide (0.9 mg) in DMF (0.5 ml). After a reaction time of 12 hours at room temperature, the mixture was diluted with ethyl acetate and filtered through silica gel, the filtrate was evaporated and purified by the preparative HPLC method. A product with a molecular weight of 445.18 (C26H24FN303) was obtained; MS(ESI): 446 (M+H+) as hydrotrifluoroacetate. ;{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide of 5-bromo-furan-2-carboxylic acid ;N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide was reacted with 5-bromo-2-furan-carboxylic acid according to procedure E. A product with a molecular weight of 406.28 was obtained. (C18H20BrN3O3); MS(ESI): 407 (M+H+). Example 246 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 5-2-[(4-fluoro-phenyl)ethynyl]furan-2-carboxylic acid; ;{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide of 5-bromo-furan-2-carboxylic acid was reacted with 1-ethynyl-4-fluoro-benzene according to procedure J. A product of molecular weight 445.18 (C26H24FN303) was obtained; MS(ESI): 446 (M+H+) as hydrotrifluoroacetate. Example 247 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 5-2-[(2-chloro-phenyl)ethynyl]furan-2-carboxylic acid; ;{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide of 5-bromo-furan-2-carboxylic acid was reacted with 1-ethynyl-2-chloro-benzene according to procedure J. A product of molecular weight 461.15 (C26H24CIN303) was obtained; MS(ESI): 462 (M+H+) as hydrotrifluoroacetate. ;Example 248 ;R-4-Butoxy-N-(3-fluoro-4-{3-[(2-hydroxy-2-methyl-propyl)methyl-amino]pyrrolidin-1-yl}-phenyl)benz-amide ;Solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]benz-amide (0.03 g) and isobutylene oxide (5 ml) in ethanol was heated under reflux for 3 hours. The pairing was then carried out in a vacuum. A product with a molecular weight of 457.59 (C26H36FN303) was obtained; MS (ESI): 458 (M+H+). Example 249 R-4-Butoxy-N-(3-fluoro-4-{3-[(3-hydroxy-3-methyl-butyl)methyl-amino]pyrrolidin-1-yl}-phenyl)-N-methyl-benz-amide; A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]benz-amide (0.03 g), triethylamine (0.02 g) and 4-bromo-2-methyl-butan-2-ol (0.03 g) in DMF (2 ml) was heated at 80°C for 16 hours. After cooling, ethyl acetate (100 mL) was added, the mixture was washed with water (2 x 50 mL), and the organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was purified by the preparative HPLC method. A product with a molecular weight of 471.62 (C27H38FN303) was obtained; MS (ESI): 472 (M+H+). 4-Bromo-2-methyl-butan-2-ol Methyl magnesium bromide (3M in diethyl ether, 46 ml) was added to a solution of ethyl 3-bromopropionate (10 g) in diethyl ether (100 ml) at room temperature under argon. During this procedure, the temperature of the mixture was maintained between 20°C and 35°C. After 2 hours, the mixture was poured into saturated ammonium chloride solution. After that, extraction with diethyl ether was performed, followed by drying over sodium sulfate, straining and evaporation. The desired product was obtained. Example 250 R-4-Butoxy-N-[6-(3-dicyclopropyl-amino-pyrrolidin-1-yl)pyridin-3-yl]benz-amide; Procedure K A solution of (R)-N-[6-(3-amino-pyrrolidin-1-yl)pyridin-3-yl]-4-butoxy-benz-amide (0.065 g) in methanol (2 ml) was mixed with glacial acetic acid (0.11 ml) and [(1-ethoxy-cyclopropyl)oxy]trimethyl-silane (0.19 g). Sodium cyanoborohydride (0.051 g) was then added and the mixture was heated under reflux for 16 hours. The mixture was then filtered, evaporated, absorbed in dichloromethane, washed with sodium hydroxide (2N; 20 ml) and sodium chloride solution (20 ml), dried over magnesium sulfate and evaporated. The residue was purified by the preparative HPLC method. A product with a molecular weight of 434.59 (C26H34N402) was obtained; MS (ESI): 435 (M+H+). Example 251 R-4-Butoxy-N-[6-(3-dicyclopropyl-amino-pyrrolidin-1-yl)pyridin-3-yl]-N-methyl-benz-amide (R)-4-Butoxy-N-[6-(3-dicyclopropyl-amino-pyrrolidin-1-yl)pyridin-3-yl]benz-amide was methylated according to procedure F. A product with a molecular weight of 448.61 was obtained. (C27H36N402); MS (ESI): 449 (M+H+). Example 252 R-4-butoxy-N-{6-[3-(cyclopropyl-methyl-amino)pyrrolidin-1-yl]pyridin-3-yl}benz-amide (R)-4-Butoxy-N-[6-(3-methyl-amino-pyrrolidin-1-yl)pyridin-3-yl]benz-amide was cyclopropylated according to procedure K. A product with a molecular weight of 408,551 (C24H32N402) was obtained. MS (ESI): 409 (M+H+). Example 253 tert-Butyl-{1-[4-(2-amino-4-butoxy-benzoyl-amino)-3-fluoro-phenyl]pyrrolidin-3-yl}methyl-carbamate; tert-Butyl-[1 -(4-amino-3-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate was reacted with 4-butoxy-2-nitro-benzoic acid according to procedure E, after which hydrogenation was carried out. A product with a molecular weight of 500.62 (C27H37FN404) was obtained; MS (ESI): 501 (M+H+). 4-Butoxy-2-nitro-benzoic acid A solution of 4-fluoro-2-nitro-benzoic acid (1.81 g) in butanol (20 ml) was mixed with sulfuric acid (3 ml) and stirred at 110°C for 4 hours. Ethyl acetate (100 mL) was added and the mixture was washed with saturated sodium bicarbonate solution (3 x 50 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue (2.2 g) was added dropwise at -10°C to a solution of sodium butoxylate made from butanol (20 ml) and sodium hydride (2.18 g) at -10°C under argon, and then stirred for 20 hours. Ethyl acetate (100 mL) was added and the mixture was washed with water (2 x 50 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by the preparative HPLC method. Butyl-4-butoxy-2-nitro-benzoate was hydrolyzed with sodium hydroxide (5N; 100 ml) in ethanol at room temperature for 3 hours. The mixture was acidified with hydrochloric acid (10 N; 100 ml), extracted with dichloromethane and the organic layer was dried over sodium sulfate, filtered and evaporated. A product with a molecular weight of 239.23 (C11H13N05) was obtained; MS (ESI): 240 (M+H+). Example 254: N-{4-[3-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-oxo-pyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methyl-benz-amide; ;Procedure L ;A mixture of N-[4-(3-bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide (100 mg), potassium carbonate (60 mg), 7-aza-bicyclo[2.2.1]heptane (44 mg) and DMF (2 ml) was maintained at 50°C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by the preparative HPLC method. A product with a molecular weight of 471.65 (C30H37N3O2) was obtained; MS (ESI): 472 (M+H+). N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide N-(4-Amino-phenyl)-4-cyclohexyl-N-methyl-benz-amide (3.0 g) in acetonitrile (30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0°C, was added. 2-Bromo-4-chloro-butyryl-bromide (2.9 g). After one hour, a solution of sodium hydroxide (0.85 g) in water (10 ml) was added and the mixture was stirred vigorously at room temperature for 6 hours. Then the same amount of sodium hydroxide solution was added and stirring was continued for another 48 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). A product with a molecular weight of 455.40 (C24H27BrN202) was obtained; MS (ESI): 456 (M+H+). ;N-(4-Amino-phenyl)-4-cyclohexyl-N-methyl-benz-amide ;4-Cyclohexyl-carboxylic acid (5.0 g) and 4-nitro-phenyl-isocyanate (4.0 g) were stirred in toluene (150 ml) for 3 hours and then left overnight. The precipitate was vacuum filtered and washed with diethyl ether. The obtained amide was ethylated according to procedure F and hydrogenated according to procedure B. A product with a molecular weight of 308.43 (C20H24N2O) was obtained; MS (ESI): 309 (M+H+). Example 255 4-Cyclohexyl-N-methyl-N-[4-(3-morpholin-4-yl-2-oxo-pyrrolidin-1-yl)phenyl]benz-amide; ;N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide was reacted with morpholine according to procedure L. A product of molecular weight 461.61 (C28H35N303) was obtained; MS (ESI): 462 (M+H+). Example 256 4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin-1-yl-pyrrolidin-1-yl)phenyl]benz-amide; ;N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide was reacted with piperidine according to procedure L. A product of molecular weight 459.64 (C29H37N302) was obtained; MS (ESI): 460 (M+H+). Example 257 4-Cyclohexyl-N-methyl-N-[4-(2'-oxo[1,3']bipyrrolidinyl-1'-yl)phenyl]benz-amide; ;N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide was reacted with pyrrolidine according to procedure L. A product of molecular weight 445.61 (C28H35N302) was obtained; MS (ESI): 446 (M+H+). Example 258 4-Cyclohexyl-N-methyl-N-[4-(3-methyl-amino-2-oxo-pyrrolidin-1-yl)phenyl]benz-amide; ;N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide was reacted with methyl-amine according to procedure L. A product of molecular weight 405.54 (C25H31N302) was obtained; MS (ESI): 406 (M+H+). Example 259 4-Cyclohexyl-N-[4-(3-cyclohexyl-amino-2-oxo-pyrrolidin-1-yl)phenyl]-N-methyl-benz-amide; ;N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-amide was reacted with cyclohexyl-amine according to procedure L. A product with a molecular weight of 473.66 (C30H39N3O2) was obtained; MS (ESI): 474 (M+H+). Example 260 4-Cyclohexyl-N-{4-[3-(cyclopropyl-methyl-amino)-2-oxo-pyrrolidin-1-yl]phenyl}-N-methyl-benz-amide; ;N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methyl-benz-arnide was reacted with cyclopropyl-methyl-amine according to procedure L. A product of molecular weight 445.61 (C28H35N302) was obtained; MS (ESI): 446 (M+H+). Example 261 N-{4-[3-(Acetyl-methyl-amino)-2-oxo-pyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methyl-benz-amide; 4-Cyclohexyl-N-methyl-N-[4-(3-methyl-amino-2-oxo-pyrrolidin-1-yl)phenyl]benz-amide (52 mg) was mixed with pyridine (0.5 ml) and acetic anhydride (130 mg) and, after 3 hours, the volatile fractions were removed under vacuum. A product with a molecular weight of 447.58 (C27H33N303) was obtained; MS (ESI): 448 (M+H+). Example 262 4-Cyclohexyl-N-methyl-N-[4-(4-methyl-amino-2-oxo-pyrrolidin-1-yl)phenyl]benz-amide; tert-Butanol (8 ml), triethyl-amine (350 mg) and finally diphenyl-phosphoryl-azide (1.18 g) were added. 1-{4-[(4-cyclohexyl-benzoyl)methyl-amino]phenyl}-5-oxo-pyrrolidine-3-carboxylic acid (1.5 g), and the mixture was then heated at 95°C for 48 hours. The solution was diluted with ethyl acetate and washed twice with water. The organic layer was dried over magnesium sulfate and evaporated. The crude product was further reacted according to procedure G. A product with a molecular weight of 405.54 (C25H31N302) was obtained; MS (ESI): 406 (M+H+). ;1-{4-[(4-Cyclohexyl-benzoyl)methyl-amino]phenyl}-5-oxo-pyrrolidine-3-carboxylic acid ;N-(4-Amino-phenyl)-4-cyclohexyl-N-methyl-benz-amide (3.0 g) was heated with itaconic acid (1.27 g) at 100°C for 3 hours. Purification was performed by filtration through silica gel (mobile phase ethyl acetate/methanol 5:1). A product with a molecular weight of 420.51 (C25H28N204) was obtained; MS (ESI): 421 (M+H+). Example 263: N-{4-[4-(Acetyl-methyl-amino)-2-oxo-pyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methyl-benz-amide; 4-Cyclohexyl-N-methyl-N-[4-(4-methyl-amino-2-oxo-pyrrolidin-1-yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic anhydride (25 mg) and, after 3 hours, the volatile fractions were removed under vacuum. A product with a molecular weight of 447.58 (C27H33N303) was obtained; MS (ESI): 448 (M+H+). Example 264 tert-Butyl-(1-{5-[(4-cyclohexyl-benzoyl)propyl-amino]pyridin-2-yl}pyrrolidin-3-yl)methyl-carbamate; Procedure F tert-Butyl-{1-[5-(4-cyclohexyl-benzoyl-amino)pyridin-2-yl]pyrrolidin-3-yl}methyl-carbamate (50 mg), cesium carbonate (249 mg), potassium iodide (17 mg), N-methyl-pyrrolidone (1.5 ml) and propyl iodide (40 mg) were mixed at 60°C for 5 hours. If the conversion was incomplete, the mixture was heated to 100°C and, after the addition of more propyl iodide (40 mg), heated to 140°C for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and sodium bicarbonate solution, dried over Chromabond XTR and evaporated. The residue was purified by the preparative HPLC method. A product with a molecular weight of 520.72 (C31H44N403) was obtained; MS (ESI): 521 (M+H+). Example 265 tert-Butyl-(1-{5-[(4-cyclohexyl-benzoyl)-(1-ethyl-propyl)amino]pyridin-2-yl}pyrrolidin-3-yl)-methyl-carbamate; tert-Butyl-{1 -[5-(4-cyclohexyl-benzoU-amino)pyridin-2-it]pyro]idin-3-yl}methyl-carbamate was reacted with 2-ethyl-butyl bromide according to the procedure F. A product with a molecular weight of 548.78 (C33H48N403) was obtained; MS (ESI): 549; (M+H+). Example 266 tert-Butyl-(1-{5-[(4-cyclohexyl-benzoyl)-(3-methyl-but-2-en-yl)amino]pyridin-2-yl}pyrrolidin-3-yl)methyl-carbamate; tert-Butyl-{1-[5-(4-cyclohexyl-benzoyl-amino)pyridin-2-yl]pyrrolidin-3-yl}methyl-carbamate was reacted with 3-methyl-2-butenyl bromide according to procedure Fa. A product with a molecular weight of 546.76 (C33H46N403) was obtained; MS (ESI): 547 (M+H+). Example 267 tert-Butyl-(1-{5-[(4-cyclohexyl-benzoyl)methyl-amino]pyridin-2-yl}pyrrolidin-3-yl)methyl-carbamate; tert-Butyl-{1-[5-(4-cyclohexyl-benzoyl-amino)pyridin-2-yl]pyrrolidin-3-yl}methyl-carbamate was reacted with methyl iodide according to procedure F. A product with a molecular weight of 492.67 (C29H40N4O3) was obtained; MS (ESI): 493 (M+H+). According to procedure F, the following compounds were obtained from tert-butyl-{1-[5-(4-cyclohexyl-benzoyl-amino)pyridin-2-yl]pyrrolidin-3-yl}methyl-carbamate and a suitable alkylating agent: tert-Butyl-(1-{5-[sec-butyl-(4-cyclohexyl-benzoyl)amino]pyridin-2-yl}pyrrolidin-3-yl)methyl-carbamate ;tert-Butyl-(1-{5-[(4-cyclohexyl-benzoyl)isopropyl-amino]pyridin-2-yl}pyrrolidin-3-yl)methyl-carbamate ;tert-Butyl-(1-{5-[(4-cyclohexyl-benzoyl)prop-2-yn-yl-amino]pyridin-2-yl}pyrrolidin-3-yl)-methyl-carbamate ;Example 268 5-p-tolyl-ethynyl-furan-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide; 0.042 ml of diisopropylamine was added, under argon, to 3.8 mg of Pd(tBu) 2 Cl 2 and 0.95 mg of CuJ in 0.2 ml of DMF. A solution of 94.6 mg of 5-bromo-furan-2-carboxylic acid [4-(3-dimethyl-;amino-pyrrolidin-1-yl)phenyl]amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate that was separated was filtered with the help of vacuum and the filtrate was purified by the preparative HPLC method. Desired product molecular weight 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate. ;[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide of 5-bromo-furan-2-carboxylic acid ;[1-(4-Amino-phenyl)pyrrolidin-3-yl]dimethyl-amine reacted with 5-bromo-2-furan-carboxylic acid according to procedure E. Product molecular weight 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate. ;Examples 269-273 were obtained in the same way: ; Example 274 [6-(3-Dimethyl-amino-pyrrolidin-1-yl)pyridin-3-yl]-amide (R)-4'-fluoro-biphenyl-4-carboxylic acid; ;Procedure M ;[6-(3-Methyl-amino-pyrrolidin-1-yl)pyridin-3-yl]-amide (R)-4'-fluoro-biphenyl-4-carboxylic acid (390 mg), dissolved in formic acid (230 mg), was mixed with formaldehyde solution (37% aq.; 0.4 ml) and the mixture was heated at 80°C for 3 hours. The cooled solution was evaporated and partitioned between ethyl acetate and saturated sodium carbonate solution. The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC. A product with a molecular weight of 404.49 (C24H25FN40) was obtained; MS (ESI): 405 (M+H+). Example 275 {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide 1-(4-fluoro-phenyl)piperidine-4-carboxylic acid; ;Procedure E ;A mixture of 0.048 g of 1-(4-fluoro-phenyl)piperidine-4-carboxylic acid, 0.5 ml of SOCl2 and one drop of DMF was stirred at room temperature for 2 hours. Excess SOCI2 was then removed under vacuum. The residue was dissolved in 0.4 ml of DMF and 0.033 ml of triethylamine and 0.048 g of N-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide were added. The solution was stirred at room temperature overnight. Then the solution was filtered and purified by the preparative HPLC method. A product with a molecular weight of 438.20 (C25H31FN402) was obtained; MS (ESI): 439 (M+H+) as hydrotrifluoroacetate. ;1 -(4-Fluoro-phenyl)piperidine-4-carboxylic acid; 0.875 g of 4-bromo-fluoro-benzene, 0.016 g of Pd(dba)3 <*>CHCl3, 0.022 g of 2-(dicyclohexyl-phosphino)biphenyl and 2.28 g of cesium carbonate were placed in a heat-dried and argon-flushed flask, and 0.943 g of ethyl-4-piperidinecarboxylate in 5 ml of degassed toluene was added. The solution was heated to 100°C overnight. The mixture was cooled and then evaporated in vacuo. The residue was absorbed in an acetate/water mixture. The organic layer was washed with 10% NaHCO 3 solution, dried over sodium sulfate and evaporated under vacuum. The residue was purified by the preparative HPLC method.

4.4 ml 2N rastvora kalijum-hidroksida dodato je rastvoru 1.1 g etil-1-(4-fluor-fenil)piperidin-4-karboksilata u 100 ml metanola. Smeša je mešana preko noći na sobnoj temperaturi. Tada je pH podešen na 6 sa 5% hlorovodoničnom kiselinom, i rastvor je uparen uz pomoć vakuuma. Ostatak je prečišćen preparativnom HPLC metodom. 4.4 ml of 2N potassium hydroxide solution was added to a solution of 1.1 g of ethyl 1-(4-fluoro-phenyl)piperidine-4-carboxylate in 100 ml of methanol. The mixture was stirred overnight at room temperature. The pH was then adjusted to 6 with 5% hydrochloric acid, and the solution was evaporated under vacuum. The residue was purified by the preparative HPLC method.

Primer 276 Example 276

{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}amid 4-fenoksi-cikloheksan-karbonske kiseline 4-phenoxy-cyclohexane-carboxylic acid {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}amide

0.251 g PyBOP i 0.135 ml trietil-amina dodati su rastvoru 0.106 g 4-fenoksi-cikloheksan-karbonske kiseline i 0.113 g N-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acet-amida u 9 ml DMF na 0°C. Posle 10 minuta, rastvor je izložen sobnoj temperaturi i ostavljen uz mešanje preko noći. Rastvarač je ukljonjen uz pomoć vakuuma i ostatak je apsorbovan u smeši voda/etil-acetat. Etil-acetatna faza je isprana 10% limunskom kiselinom i 10% rastvorom NaHC03 i osušena iznad natrijum-sulfata, a rastvarač je uklonjen uz pomoć vakuuma. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je željeni proizvod. Molekulska težina 435.25 (C26H33N303), MS: 436 (M+H+). 0.251 g of PyBOP and 0.135 ml of triethylamine were added to a solution of 0.106 g of 4-phenoxy-cyclohexane-carboxylic acid and 0.113 g of N-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide in 9 ml of DMF at 0°C. After 10 minutes, the solution was exposed to room temperature and left with stirring overnight. The solvent was removed under vacuum and the residue was absorbed in water/ethyl acetate. The ethyl acetate phase was washed with 10% citric acid and 10% NaHCO 3 solution and dried over sodium sulfate, and the solvent was removed under vacuum. The residue was purified by the preparative HPLC method. The desired product was obtained. Molecular weight 435.25 (C26H33N303), MS: 436 (M+H+).

4-Fenoksi-cikloheksan-karbonska kiselina 4-Phenoxy-cyclohexane-carboxylic acid

0.63 g p-toluol-sulfonil-hlorida dodato je rastvoru 0.522 g etil-4-hidroksi-cikloheksan-karboksilata u 5.0 ml piridina. Reakcija se odvijala 3 sata na sobnoj temperaturi uz mešanje. Reakciona smeša je uparena u vakuumu. Dobivena čvrsta supstanca je apsorbovana u vodi i etil-acetatu i organski sloj je ispran tri puta 2N hlorovodoničnom kiselinom i jedanput zasićenim rastvorom NaCI. Organski sloj je osušen iznad natrijum sulfata i uparen uz pomoć vakuuma. Dobiveni proizvod korišćen je dalje bez prečišćavanja. Dobiveni proizvod (0.55 g) je rastvoren u 11.2 ml DMF pa je dodato 0.159 g fenola i 0.549 g cezijum-karbonata. Rastvor je zatim grejan na 80°C u toku 0.63 g of p-toluene-sulfonyl-chloride was added to a solution of 0.522 g of ethyl-4-hydroxy-cyclohexane-carboxylate in 5.0 ml of pyridine. The reaction took place for 3 hours at room temperature with stirring. The reaction mixture was evaporated in vacuo. The resulting solid was absorbed in water and ethyl acetate and the organic layer was washed three times with 2N hydrochloric acid and once with saturated NaCl solution. The organic layer was dried over sodium sulfate and evaporated in vacuo. The obtained product was used further without purification. The obtained product (0.55 g) was dissolved in 11.2 ml of DMF and 0.159 g of phenol and 0.549 g of cesium carbonate were added. The solution was then heated to 80°C in the flow

6 sati. Posle hlađenja, smeša je uparena uz pomoć vakuuma i prečišćena hromatografijom u koloni, na silika-gelu (eluent: etil-acetat/n-heptan 1:1). Dobiven je željeni proizvod. Molekulska težina 248.32 (C15H20O3), MS: 249 (M+H+). 0.06 ml 2N rastvora kalijum-hidroksida dodato je rastvoru 0.12 g etil-4-fenoksi-cikloheksan-karboksilata u 8 ml smeše voda/THF (1:1). Rastvor je grejan na 60°C u toku 3 sata. U smešu je dodat etil-acetat i 10% limunska kiselina. Vodeni sloj je ekstrahovan tri puta etil-acetatom, osušen iznad natrijum-sulfata i uparen uz pomoć vakuuma. Dobiveno jedinjenje je korišćeno, bez daljeg prečišćavanja, u sledećem stadijumu. Primer 277 N-[4-(3-Cikloheksil-amino-pirolidin-1-il)fenil]-4-izobutoksi-benz-amid 6 hours. After cooling, the mixture was evaporated under vacuum and purified by column chromatography on silica gel (eluent: ethyl acetate/n-heptane 1:1). The desired product was obtained. Molecular weight 248.32 (C15H20O3), MS: 249 (M+H+). 0.06 ml of 2N potassium hydroxide solution was added to a solution of 0.12 g of ethyl-4-phenoxy-cyclohexane-carboxylate in 8 ml of a water/THF (1:1) mixture. The solution was heated to 60°C for 3 hours. Ethyl acetate and 10% citric acid were added to the mixture. The aqueous layer was extracted three times with ethyl acetate, dried over sodium sulfate and evaporated under vacuum. The resulting compound was used, without further purification, in the next step. Example 277 N-[4-(3-Cyclohexyl-amino-pyrrolidin-1-yl)phenyl]-4-isobutoxy-benz-amide

Postupak N Procedure N

(4-lzobutoksi-N-[4-(3-okso-pirolidin-1-il)fenil]benz-amid (50 mg) u metanolu (2 ml) pomešan je sa amino-cikloheksanom (28 mg) i glacijalnom sirćetnom kiselinom (10 mg), i dodat je rastvor natrijum-cijano-bor-hidrida (1M u (4-Isobutoxy-N-[4-(3-oxo-pyrrolidin-1-yl)phenyl]benz-amide (50 mg) in methanol (2 ml) was mixed with amino-cyclohexane (28 mg) and glacial acetic acid (10 mg), and a solution of sodium cyanoborohydride (1M in

toluolu; 0.17 ml). Posle 8 časova, rastvor je uparen i razdeljen u smeši etil-acetata i vode. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Sirovi proizvod je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 435.61 (C27H37N302); MS (ESI): 436 (M+H+). toluene; 0.17 ml). After 8 hours, the solution was evaporated and partitioned in a mixture of ethyl acetate and water. The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC. A product with a molecular weight of 435.61 (C27H37N302) was obtained; MS (ESI): 436 (M+H+).

4-lzobutoksi-N-[4-(3-okso-pirolidin-1-il)fenil]benz-amid 4-lzobutoksi-benzojeva kiselina reagovala je sa 4-(1,4-dioksa-7-aza-spiro[4.4]non-7-il)fenil-aminom po postupku E-a. Dobiveni amid (0.25 g) u acetonu (10 ml) je pomešan sa para-toluol-sulfonskom kiselinom (monohidrat, 109 mg), i smeša je ključala uz refluks u toku 8 sati. Pošto je dodat trietil-amin (0.5 ml), smeša je razblažena vodom i ekstrahovana etil-acetatom. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Dobiven je proizvod molekulske težine 352.44 (C21H24N203); MS (ESI): 353 (M+H+). 4-Isobutoxy-N-[4-(3-oxo-pyrrolidin-1-yl)phenyl]benz-amide 4-Isobutoxy-benzoic acid was reacted with 4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)phenyl-amine according to procedure E-a. The resulting amide (0.25 g) in acetone (10 mL) was mixed with para-toluenesulfonic acid (monohydrate, 109 mg), and the mixture was refluxed for 8 hours. After triethylamine (0.5 ml) was added, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. A product with a molecular weight of 352.44 (C21H24N203) was obtained; MS (ESI): 353 (M+H+).

4-Butoksi-N-[4-(3-okso-pirolidin-1-il)-fenil]benz-amid je dobiven korišćenjem 4-butoksi-benzojeve kiseline na isti način. Na isti način, iz 4-butoksi-benzojeve kiseline i 4-(1,4-dioksa-7-aza-spiro[4.4]non-7-il)-3-fluor-fenil-amina dobiven je 4-butoksi-N-[4-(1,4-dioksa-7-aza-spiro[4.4]non-7-il)-3-fluor-fenil]benz-amid od kojeg je, posle metilovanja prema postupku F i tretiranja sa para-toluol-sulfonskom kiselinom kao što je već opisano, dobiven 4-butoksi-N-[3-fluor-4-(3-okso-pirolidin-1-il)fenil]benz-amid. 4-Butoxy-N-[4-(3-oxo-pyrrolidin-1-yl)-phenyl]benz-amide was obtained using 4-butoxy-benzoic acid in the same manner. In the same way, 4-butoxy-N-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluoro-phenyl]benz-amide was obtained from 4-butoxy-benzoic acid and 4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluoro-phenyl-amine, from which, after methylation according to procedure F and treatment with para-toluene-sulfonic acid as already described, obtained 4-butoxy-N-[3-fluoro-4-(3-oxo-pyrrolidin-1-yl)phenyl]benz-amide.

4-(1,4-Dioksa-7-aza-spiro[4.4]non-7-il)fenil-amin 4-(1,4-Dioxa-7-aza-spiro[4.4]non-7-yl)phenyl-amine

Trimetil-hlor-silan (9.3 g) je polako dodavan rastvoru 1-benzil-3-pirolidinona (5.0 g) u dihlor-metanu (30 ml) i etilen-glikolu (2.67 g). Nakon 18 časova, smeša je usuta u rastvor natrijum-hidroksida (1N). Organski sloj je odvojen, osušen iznad magnezijum-sulfata i uparen. Ostatak je rastvoren u metanolu (30 ml) i amonijum- formijatu (5.2 g) i dodat je paladijum-hidroksid (10% na uglju, 300 mg). Smeša je ključala uz refluks u toku 8 sati, proceđena i uparena. Dobiveni ostatak je reagovao sa 4-fluor-nitro-benzolom po postupku C. Hidrogenovanje je na kraju izvedeno prema postupku B. Dobiven je proizvod molekulske težine 220.27 (C12H16N202); MS (ESI): 221 (M+H+). Trimethylchlorosilane (9.3 g) was slowly added to a solution of 1-benzyl-3-pyrrolidinone (5.0 g) in dichloromethane (30 ml) and ethylene glycol (2.67 g). After 18 hours, the mixture was poured into sodium hydroxide solution (1N). The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (30 ml) and ammonium formate (5.2 g) and palladium hydroxide (10% on charcoal, 300 mg) was added. The mixture was refluxed for 8 hours, filtered and evaporated. The obtained residue was reacted with 4-fluoro-nitro-benzene according to procedure C. Hydrogenation was finally carried out according to procedure B. A product with a molecular weight of 220.27 (C12H16N202) was obtained; MS (ESI): 221 (M+H+).

4-(1,4-Dioksa-7-aza-spiro[4.4]non-7-il)-3-fluor-fenil-amin je dobiven na isti način, korišćenjem 3,4-difluor-nitro-benzola. 4-(1,4-Dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluoro-phenyl-amine was obtained in the same way, using 3,4-difluoro-nitro-benzene.

Primer 278 Example 278

{4-[3-(Metil-pirimidin-2-il-amino)pirolidin-1-il]-fenil}amid (R)-4-(4-hlor-fenil)piperidin-1-karbonske kiseline {4-[3-(Methyl-pyrimidin-2-yl-amino)pyrrolidin-1-yl]-phenyl}amide (R)-4-(4-chloro-phenyl)piperidine-1-carboxylic acid

[4-(3-Metil-amino-pirolidin-1 -il)fenil]amid (R)-4-(4-hlor-fenil)piperidin-1 - karbonske kiseline (100 mg) je reagovao sa kalijum-karbonatom (100 mg) i 2-brom-pirimidinom (50 mg) u N-metil-pirolidonu (3 ml) na 100°C u toku 4 sata. Rastvor je tada razdeljen između etil-acetata i vode. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Sirovi proizvod je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine [4-(3-Methyl-amino-pyrrolidin-1-yl)phenyl]amide (R)-4-(4-chloro-phenyl)piperidine-1-carboxylic acid (100 mg) was reacted with potassium carbonate (100 mg) and 2-bromo-pyrimidine (50 mg) in N-methyl-pyrrolidone (3 ml) at 100°C for 4 hours. The solution was then partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC. A molecular weight product was obtained

491.04 (C27H31CIN60); MS (ESI): 491 (M+H+). 491.04 (C27H31CIN60); MS (ESI): 491 (M+H+).

Primer 279 Example 279

terc-Butil [1-(4-{[5-(2-fluor-fenil)furan-2-karbonil]amino}fenil)pirolidin-3-il]metil-karbamat tert-Butyl [1-(4-{[5-(2-fluoro-phenyl)furan-2-carbonyl]amino}phenyl)pyrrolidin-3-yl]methyl-carbamate

Postupak O Procedure O

Tetrakis(trifenil-fosfin)paladijum(0) (20 mg) je dodat rastvoru terc-butil(1-{4-[(5-brom-furan-2-karbonil)amino]fenil}pirolidin-3-il)metil-karbamata (252 mg) u degaziranom toluolu (4 ml), u argonu, u balonu od 10 ml sa dva grla, i mešan na sobnoj temperaturi u toku 10 minuta. Tada je dodat rastvor 2-fluor-benzol-borne kiseline (73 mg u 1 ml etanola) i 0.35 ml 2M rastvora natrijum-karbonata i smeša je mešana na 100°C u toku 24 časa. Tetrakis(triphenyl-phosphine)palladium(0) (20 mg) was added to a solution of tert-butyl(1-{4-[(5-bromo-furan-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methyl-carbamate (252 mg) in degassed toluene (4 ml), under argon, in a 10 ml two-necked flask, and stirred at room temperature for 10 minutes. Then a solution of 2-fluoro-benzene-boronic acid (73 mg in 1 ml of ethanol) and 0.35 ml of 2M sodium carbonate solution were added and the mixture was stirred at 100°C for 24 hours.

Tada su reakcionoj smeši dodata voda (5 ml) i etil-acetat (5 ml), organski sloj je odvojen a vodeni sloj je ekstrahovan 2 x etil-acetatom (10 ml). Spojeni organski slojevi su upareni i ostatak je prečišćen preparativnom HPLC metodom. Željeni proizvod molekulske težine 479.56 (C27H30FN3O4); MS (ESI): 480 (M+H+) dobiven je kao hidro-trifluor-acetat. Moguće je i koristiti cezijum-karbonat kao bazu i zagrevati rekcionu smešu na 150°C u mikrotalasnom aparatu u toku 3 minuta. Then water (5 ml) and ethyl acetate (5 ml) were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted 2 x with ethyl acetate (10 ml). The combined organic layers were evaporated and the residue was purified by preparative HPLC. Desired product molecular weight 479.56 (C27H30FN3O4); MS (ESI): 480 (M+H+) was obtained as hydrotrifluoroacetate. It is also possible to use cesium carbonate as a base and heat the reaction mixture to 150°C in a microwave oven for 3 minutes.

terc-Butil(1-{4-[(5-brom-furan-2-karbonil)amino]fenil}pirolidin-3-il)metil-karbamat tert-Butyl(1-{4-[(5-bromo-furan-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methyl-carbamate

5-Brom-furan-2-karbonska kiselina reagovala je sa terc-butil-[1-(4-amino-fenil)pirolidin-3-il]metil-karbamatom po postupku E. Dobiven je proizvod molekulske težine 464.36 (C21H26BrN304); MS (ESI): 464 (M+H+). 5-Bromo-furan-2-carboxylic acid was reacted with tert-butyl-[1-(4-amino-phenyl)pyrrolidin-3-yl]methyl-carbamate according to procedure E. A product with a molecular weight of 464.36 (C21H26BrN304) was obtained; MS (ESI): 464 (M+H+).

Na isti način dobivena su sledeća jedinjenja: [4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-brom-furan-2-karbonske kiseline The following compounds were obtained in the same way: [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide of 5-bromo-furan-2-carboxylic acid

terc-Butil(1-{4-[(5-brom-tiofen-2-karbonil)amino]fenil}pirolidin-3-il)metil-karbamat tert-Butyl(1-{4-[(5-bromo-thiophene-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methyl-carbamate

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 2-brom-tiazol-4-karbonske kiseline 2-Bromo-thiazole-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide

4-Jod-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]benz-amid (R)-N-[4-(3-Dimetil-amino-pirolidin-1-il)-3-fluor-fenil]-4-jod-benz-amid 4-Brom-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]-3-fluor-benz-amid 4-Iodo-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]benz-amide (R)-N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)-3-fluoro-phenyl]-4-iodo-benz-amide 4-Bromo-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]-3-fluoro-benz-amide

Primer 280 Example 280

[4-(3-Dimetil-amino-pirolidin-1-il)-3-fluor-fenil]amid (3R)-3'-cijano-bifenil-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-3-fluoro-phenyl]amide (3R)-3'-cyano-biphenyl-4-carboxylic acid

Postupak O-b Procedure O-b

0.002 mg Pd(PPh3)4 dodato je u rastvor 0.022 g (R)-N-[4-(3-dimetil-amino-pirolidin-1-il)-3-fluor-fenil]-4-jod-benz-amida u 0.45 ml degaziranog DMF i mešan na sobnoj temperaturi u toku 10 minuta. Tada je rastvoru dodato 0.035 ml vode, 0.021 g K3P04 i 0.008 g 3-cijano-fenil-borne kiseline. Rastvor je grejan na 80°C preko noći. Tada je rastvor proceđen i prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 428.20 (C26H25FIN40); MS (ESI): 429 (M+H+) kao hidro-trifluor-acetat. 0.002 mg of Pd(PPh3)4 was added to a solution of 0.022 g of (R)-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)-3-fluoro-phenyl]-4-iodo-benz-amide in 0.45 ml of degassed DMF and stirred at room temperature for 10 minutes. Then 0.035 ml of water, 0.021 g of K3P04 and 0.008 g of 3-cyano-phenyl-boronic acid were added to the solution. The solution was heated to 80°C overnight. Then the solution was filtered and purified by the preparative HPLC method. A product with a molecular weight of 428.20 (C26H25FIN40) was obtained; MS (ESI): 429 (M+H+) as hydrotrifluoroacetate.

Primer 281 Example 281

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-amid 3,2',4'-trifluor-bifenil-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-amide of 3,2',4'-trifluoro-biphenyl-4-carboxylic acid

1-Brom-2,4-difluor-benzol je reagovao sa benz-amidom N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]-2-fluor-4-borne kiseline po postupku O-b. Dobiven je proizvod molekulske težine 439.19 (C25H24F3N30); MS (ESI): 440 (M+H+) kao hidro-trifluor-acetat. 1-Bromo-2,4-difluoro-benzene was reacted with N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benzamide according to procedure O-b. A product with a molecular weight of 439.19 (C25H24F3N30) was obtained; MS (ESI): 440 (M+H+) as hydrotrifluoroacetate.

Benz-amid N-[4-(3-dimetil-amino-pirolidin-1 -il)fenil]-2-fluor-4-borne kiseline 4-Karboksi-3-fluor-fenil-borna kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-il]dimetil-aminom po postupku E-b. Dobiven je proizvod molekulske težine 371.18 (C19H23BFN303); MS (ESI): 372 (M+H+) kao hidro-trifluor-acetat. N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benz-amide 4-Carboxy-3-fluoro-phenyl-boronic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethyl-amine according to procedure E-b. A product with a molecular weight of 371.18 (C19H23BFN303) was obtained; MS (ESI): 372 (M+H+) as hydrotrifluoroacetate.

Primer 282 Example 282

[4-(3-Dimetil-amino-pirolidin-1-il)-fenil]amid 5-(2,4-difluor-fenil)tiofen-2-karbonske kiseline 5-(2,4-difluoro-phenyl)thiophene-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenyl]amide

1-Brom-2,4-difluor-benzol je reagovao sa [4-(3-dimetil-amino-pirolidin-1-il)fenil]amidom 2-borna kiselina-tiofen-5-karbonske kiseline po postupku O- 1-Bromo-2,4-difluoro-benzene was reacted with [4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 2-boronic acid-thiophene-5-carboxylic acid according to the O-

b. Dobiven je proizvod molekulske težine 427.52 (C23H23F2N30S); MS (ESI): 428 (M+H+) kao hidro-trifluor-acetat. b. A product with a molecular weight of 427.52 (C23H23F2N30S) was obtained; MS (ESI): 428 (M+H+) as hydrotrifluoroacetate.

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 2-borna kiselina-tiofen-5-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 2-boronic acid-thiophene-5-carboxylic acids

5-Karboksi-2-tiofen-borna kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-il]-dimetil-aminom po postupku E-b. Dobiven je proizvod molekulske težine 359.15 (C17H22BN303S); MS (ESI): 360 (M+H+) kao hidro-trifluor-acetat. 5-Carboxy-2-thiophene-boronic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]-dimethyl-amine according to procedure E-b. A product with a molecular weight of 359.15 (C17H22BN303S) was obtained; MS (ESI): 360 (M+H+) as hydrotrifluoroacetate.

Primer 283 Example 283

N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-6-(4-fluor-fenil)nikotin-amid N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-6-(4-fluoro-phenyl)nicotinamide

5-[4-(3-Dimetil-amino-pirolidin-1-il)fenil-karbamoil]piridin-2-il]trifluor-metan-sulfonat je reagovao sa 4-fluor-benzol-bornom kiselinom pod uslovima datim u postupku O-b. (Zagrevanje na 140°C u mikrotalasnom aparatu u toku 15 minuta). Dobiven je proizvod molekulske težine 404.20 (C24H25FN40); MS (ESI): 405 (M+H+) kao hidro-trifluor-acetat. 5-[4-(3-Dimetil-amino-pirolidin-1-il)fenil-karbamoil]piridin-2-il]trifluor- metan-sulfonat 5-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl-carbamoyl]pyridin-2-yl]trifluoro-methane-sulfonate was reacted with 4-fluoro-benzene-boronic acid under the conditions given in procedure O-b. (Heating at 140°C in the microwave for 15 minutes). A product with a molecular weight of 404.20 (C24H25FN40) was obtained; MS (ESI): 405 (M+H+) as hydrotrifluoroacetate. 5-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl-carbamoyl]pyridin-2-yl]trifluoro-methane-sulfonate

Suspenzija 0.0.5 g N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]-6-hidroksi-nikotin-amida u 0.4 ml DME dodata je rastvoru 0.084 ml rastvora LDA (2M) 0.4 ml u DME na 0°C. Smeša je mešana na 0°C u toku 2 sata. Tada je smeši dodat rastvor 0.055 g N-fenil-trifluor-metan-sulfon-imida u 0.2 ml DME. Rastvor je ostavljen da dostigne sobnu temperaturu, a zatim je grejan na 80°C u toku 3 sata. Posle hlađenja, rastvor je koncentrovan uz pomoć vakuuma. Ostatak je apsorbovan u smeši etil-acetat/voda, i vodeni sloj je ekstrahovan tri puta etil-acetatom. Organski slojevi su spojeni, osušeni iznad natrijum-sulfata, upareni uz pomoć vakuuma i prečišćeni preparativnom HPLC metodom. A suspension of 0.0.5 g of N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]-6-hydroxy-nicotinamide in 0.4 ml of DME was added to a solution of 0.084 ml of a solution of LDA (2M) 0.4 ml in DME at 0°C. The mixture was stirred at 0°C for 2 hours. Then a solution of 0.055 g of N-phenyl-trifluoro-methane-sulfon-imide in 0.2 ml of DME was added to the mixture. The solution was allowed to reach room temperature and then heated to 80°C for 3 hours. After cooling, the solution was concentrated under vacuum. The residue was taken up in ethyl acetate/water, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, evaporated under vacuum and purified by preparative HPLC.

N-[4-(3-Dimetil-amino-pirolidin-1-il)-fenil]-6-hidroksi-nikotin-amid 6-Hidroksi-nikotinska kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-iljdimetil-aminom po postupku E-b. Dobiven je proizvod molekulske težine 326.17 (C18H22N402); MS (ESI): 327 (M+H+) kao hidro-trifluor-acetat. N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamide 6-Hydroxy-nicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yldimethyl-amine according to procedure E-b. A product with a molecular weight of 326.17 (C18H22N402) was obtained; MS (ESI): 327 (M+H+) as hydrotrifluoroacetate.

Primer 284 Example 284

N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-6-(2,4-difluor-fenil)nikotin-amid N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-6-(2,4-difluoro-phenyl)nicotinamide

2,4-Difluor-fenil-borna kiselina je reagovala sa 5-[4-(3-dimetil-amino-pirolidin-1-il)-fenil-karbamoil]piridin-2-il]trifluor-metan-sulfonatom po postupku O-b. Dobiven je proizvod molekulske težine 422.00 (C24H24F2N40); MS (ESI): 423 (M+H+) kao hidro-trifluor-acetat. 2,4-Difluoro-phenyl-boronic acid was reacted with 5-[4-(3-dimethyl-amino-pyrrolidin-1-yl)-phenyl-carbamoyl]pyridin-2-yl]trifluoro-methane-sulfonate according to procedure O-b. A product of molecular weight 422.00 (C24H24F2N40) was obtained; MS (ESI): 423 (M+H+) as hydrotrifluoroacetate.

Primer 285 Example 285

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 2',4'-difluor-bifenil-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 2',4'-difluoro-biphenyl-4-carboxylic acid

2',4'-Difluor-bifenil-4-karbonska kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-il]dimetil-aminom po postupku E-a. Dobiven je proizvod molekulske težine 421.20 (C25H25F2N30); MS (ESI): 422 (M+H+) kao hidro-trifluor-acetat. 2',4'-Difluoro-biphenyl-4-carboxylic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethyl-amine according to procedure E. A product with a molecular weight of 421.20 (C25H25F2N30) was obtained; MS (ESI): 422 (M+H+) as hydrotrifluoroacetate.

2\4'-Difluorbifenil-4-karbonska kiselina 2\4'-Difluorobiphenyl-4-carboxylic acid

Postupak P Procedure P

0.098 ml 1 N rastvora litijum-hidroksida dodato je u rastvor 0.051 g etil-2',4'-difluor-bifenil-4-karboksilata u 1 ml smeše THF/voda (1:1), i smeša je mešana na sobnoj temperaturi preko noći. 5% hlorovodonična kiselina korišćena je za neutralizaciju rastvora, koji je uparen uz pomoć vakuuma, a ostatak je prečišćen preparativnom HPLC metodom. 0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051 g of ethyl-2',4'-difluoro-biphenyl-4-carboxylate in 1 ml of THF/water (1:1), and the mixture was stirred at room temperature overnight. 5% hydrochloric acid was used to neutralize the solution, which was evaporated with the help of vacuum, and the rest was purified by preparative HPLC method.

Etil-2',4'-difluor-bifenil-4-karboksilat Ethyl 2',4'-difluoro-biphenyl-4-carboxylate

0.009 g Pd(PPh3)4 dodato je rastvoru 0.091 g etil-4-jod-benzoata u 0.96 ml degaziranog toluola i mešano u toku 10 minuta. Tada su dodati rastvor 0.047 g 2,4-difluor-fenil-borne kiseline u 0.114 ml etanola i 0.201 ml 2N rastvora Na2C03. Rastvor je grejan na 100°C preko noći. Reakciona smeša je tada uparena u vakuumu i ostatku je dodata smeša voda/etil-acetat. Vodeni sloj je ekstrahovan tri puta etil-acetatom i osušen iznad natrijum-sulfata, a rastvarač je uklonjen uz pomoć vakuuma i prečišćen preparativnom HPLC metodom. 0.009 g of Pd(PPh3)4 was added to a solution of 0.091 g of ethyl-4-iodo-benzoate in 0.96 ml of degassed toluene and stirred for 10 minutes. Then a solution of 0.047 g of 2,4-difluoro-phenyl-boronic acid in 0.114 ml of ethanol and 0.201 ml of 2N Na2CO3 solution were added. The solution was heated at 100°C overnight. The reaction mixture was then evaporated in vacuo and water/ethyl acetate was added to the residue. The aqueous layer was extracted three times with ethyl acetate and dried over sodium sulfate, and the solvent was removed under vacuum and purified by preparative HPLC.

Primer 286 Example 286

{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-amid 2\4'-difluor-bifenil-4-karbonske kiseline {4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-amide 2\4'-difluoro-biphenyl-4-carboxylic acid

Postupak E-b Procedure E-b

0.095 g HATU, 0.068 g HOBT i 0.035 ml trietil-amina dodati su rastvoru 0.047 g of 2',4'-difluor-bifenil-4-karbonske kiseline i 0.058 g N-[1-(4-amino-fenil)pirolidin-3-il]-N-metil-acet-amida u 2 ml DMF na 0°C. Posle 10 minuta, rastvor je ostavljen da dostigne sobnu temperatutu i mešan je na toj temperaturi preko noći. Tada je rastvarač uklonjen uz pomoć vakuuma a ostatak je apsorbovan u smeši voda/etil-acetat. Eitl-acetatni sloj je ispran 10% rastvorom NaHC03 i vodom. Etil-acetatni sloj je osušen iznad natrijum-sulfata i rastvarač je uklonjen uz pomoć vakuuma. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je željeni proizvod. Molekulska težina 449.19 (C26H25F2N302), MS: 450 (M+H+). 0.095 g of HATU, 0.068 g of HOBT and 0.035 ml of triethylamine were added to a solution of 0.047 g of 2',4'-difluoro-biphenyl-4-carboxylic acid and 0.058 g of N-[1-(4-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide in 2 ml of DMF at 0°C. After 10 minutes, the solution was allowed to reach room temperature and stirred at that temperature overnight. The solvent was then removed under vacuum and the residue was absorbed in a water/ethyl acetate mixture. The ethyl acetate layer was washed with 10% NaHCO 3 solution and water. The ethyl acetate layer was dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by the preparative HPLC method. The desired product was obtained. Molecular weight 449.19 (C26H25F2N302), MS: 450 (M+H+).

Primer 287 Example 287

N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-3-fluor-4-(4-metil-piperidin-1-il)-benz-amid N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-3-fluoro-4-(4-methyl-piperidin-1-yl)-benz-amide

3-Fluor-4-(4-metil-piperidin-1-il)benzojeva kiselina je reagovala sa [1-(4-amino-fenil)-pirolidin-3-il]dimetil-aminom po postupku E-a. Dobiven je proizvod molekulske težine 424.00 (C25H33FN40); MS (ESI): 425 (M+H+) kao hidro-trifluor-acetat. 3-Fluoro-4-(4-methyl-piperidin-1-yl)benzoic acid was reacted with [1-(4-amino-phenyl)-pyrrolidin-3-yl]dimethyl-amine according to procedure E. A product of molecular weight 424.00 (C25H33FN40) was obtained; MS (ESI): 425 (M+H+) as hydrotrifluoroacetate.

3- Fluor-4-(4-metil-piperidin-1 -il)benzojeva kiselina 3- Fluoro-4-(4-methyl-piperidin-1-yl)benzoic acid

Metil-3-fluor-4-(4-metil-piperidin-1-il)benzoat je tretiran litijum-hidroksidom po postupku P. Dobiven je proizvod molekulske težine 237.28 (C13H16FN02); MS (ESI): 238 (M+H+). Methyl-3-fluoro-4-(4-methyl-piperidin-1-yl)benzoate was treated with lithium hydroxide according to procedure P. A product with a molecular weight of 237.28 (C13H16FN02) was obtained; MS (ESI): 238 (M+H+).

Metil-3-fluor-4-(4-metil-piperidin-1-il)benzoat Methyl-3-fluoro-4-(4-methyl-piperidin-1-yl)benzoate

0.076 g kalijum-karbonata dodato je rastvoru 0.086 g metil-3,4-difluor-benzoata i 0.050 g 4-metil-piperidina u 0.5 ml DMF. Reakciona smeša je grejana na 60°C u toku 2 dana, proceđena i prečišćena preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 251.3 (C14H18FN02); MS (ESI): 252 (M+H+) kao hidro-trifluor-acetat. 0.076 g of potassium carbonate was added to a solution of 0.086 g of methyl-3,4-difluoro-benzoate and 0.050 g of 4-methyl-piperidine in 0.5 ml of DMF. The reaction mixture was heated to 60°C for 2 days, filtered and purified by the preparative HPLC method. A product with a molecular weight of 251.3 (C14H18FN02) was obtained; MS (ESI): 252 (M+H+) as hydrotrifluoroacetate.

Primer 288 Example 288

4- Butoksi-N-(4-{3-[(2-dimetil-amino-acetil)metil-amino]pirolidin-1-il}fenil)-N-metil-benz-amid 4-Butoxy-N-(4-{3-[(2-dimethyl-amino-acetyl)methyl-amino]pyrrolidin-1-yl}phenyl)-N-methyl-benz-amide

4-Butoksi-N-metil-N-[4-(3-metil-amino-pirolidin-1-il)fenil]benz-amid je reagovao sa N,N-dimetil-glicinom po postupku E. Dobiven je proizvod molekulske težine 466.63 (C27H38N403); MS (ESI): 467 (M+H+). (R)-4-Butoksi-N-(4-{3-[(2-dimetil-aminoacetil)metil-amino]pirolidin-1-il}fenil)-N-metil-benz-amid je dobiven na isti način. Primer 289 N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-4-butoksi-N-metil-benz-amid 4-Butoksi-N-metil-N-[4-(3-metil-amino-pirolidin-1-il)fenil]benz-amid pomešan je sa piridinom i anhidridom sirćetne kiseline. Isparljive frakcije su uklonjene posle 2 sata. Dobiven je proizvod molekulske težine 423.56 (C25H33N303); MS (ESI): 424 (M+H+). Primer 290 4-Butiril-amino-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]benz-amid 4-Butoxy-N-methyl-N-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]benz-amide was reacted with N,N-dimethyl-glycine according to procedure E. A product of molecular weight 466.63 (C27H38N403) was obtained; MS (ESI): 467 (M+H+). (R)-4-Butoxy-N-(4-{3-[(2-dimethyl-aminoacetyl)methyl-amino]pyrrolidin-1-yl}phenyl)-N-methyl-benz-amide was obtained in the same way. Example 289 N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-4-butoxy-N-methyl-benz-amide 4-Butoxy-N-methyl-N-[4-(3-methyl-amino-pyrrolidin-1-yl)phenyl]benz-amide was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. A product with a molecular weight of 423.56 (C25H33N303) was obtained; MS (ESI): 424 (M+H+). Example 290 4-Butyryl-amino-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]benz-amide

Postupak Q Procedure Q

4-Amino-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]benz-amid (32 mg) u dihlor-metanu (2 ml) pomešan je sa kalijum-karbonatom (50 mg) i butiril-hloridom (11 mg). Smeša je proceđena i uparena posle 12 časova. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 394.52 (C23H30N4O3); MS (ESI): 395 (M+H+). 4-Amino-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]benzamide (32 mg) in dichloromethane (2 ml) was mixed with potassium carbonate (50 mg) and butyryl chloride (11 mg). The mixture was filtered and evaporated after 12 hours. The residue was purified by the preparative HPLC method. A product with a molecular weight of 394.52 (C23H30N4O3) was obtained; MS (ESI): 395 (M+H+).

Druga mogućnost je da reaguje 4-amino-N-[4-(3-dimetil-amino-pirolidin-1-il)-fenil]benz-amid sa buternom kiselinom po postupku E. Another possibility is to react 4-amino-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)-phenyl]benz-amide with butyric acid according to procedure E.

4-Amino-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]benz-amid 4-terc-Butoksi-karbonil-amino-benzojeva kiselina je reagovala sa 1-(4-amino-fenil)pirolidin-3-il]dimetil-aminom po postupku E, i proizvod je tretiran po postupku G. Dobiven je proizvod molekulske težine 324.43 (C19H24N40); MS (ESI): 325 (M+H+). 4-Amino-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]benz-amide 4-tert-Butoxy-carbonyl-amino-benzoic acid was reacted with 1-(4-amino-phenyl)pyrrolidin-3-yl]dimethyl-amine according to procedure E, and the product was treated according to procedure G. A product of molecular weight 324.43 (C19H24N40) was obtained; MS (ESI): 325 (M+H+).

Primer 291 Example 291

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-amid 2-fenil-etinil-tiazol-4-karbonske kiseline 2-Phenyl-ethynyl-thiazole-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-amide

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 2-brom-tiazol-4-karbonske kiseline (100 mg) rastvoren je u tetrahidro-furanu (2 ml), pa su dodati fenil-acetilen (52 mg), trietil-amin (52 mg), trifenil-fosfin (17 mg), bis(trifenil-fosfin)paladijum-dihlorid (89 mg) i bakar(l)-jodid (9.6 mg). Reakciona smeša je grejana na 150°C u mikrotalasnom aparatu u toku 3 minuta i zatim je uparena. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 416.55 (C24H24N40S); MS (ESI): 417 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide of 2-bromo-thiazole-4-carboxylic acid (100 mg) was dissolved in tetrahydrofuran (2 ml), then phenyl-acetylene (52 mg), triethyl-amine (52 mg), triphenyl-phosphine (17 mg), bis(triphenyl-phosphine)palladium dichloride (89 mg) and copper(l)-iodide were added. (9.6 mg). The reaction mixture was heated at 150°C in a microwave oven for 3 minutes and then evaporated. The residue was purified by the preparative HPLC method. A product with a molecular weight of 416.55 (C24H24N40S) was obtained; MS (ESI): 417 (M+H+).

Primer 292 Example 292

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-amid 5-(4-fluor-fenil)piridin-2-karbonske kiseline 5-(4-Fluoro-phenyl)pyridine-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-amide

Postupak O-a O's procedure

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-hlor-piridin-2-karbonske kiseline (100 mg) rastvoren u toluolu pomešan je sa 4-fluor-fenil-bornom kiselinom (81 mg), POPD (15 mg) i cezijum-karbonatom (2M aq.; 0.5 ml). Reakciona smeša je grejana na 150°C u mikrotalasnom aparatu u toku 10 minuta i zatim je uparena. Ostatak je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 404.49 (C24H25FN40); MS (ESI): 405 (M+H+). 5-Chloro-pyridine-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide (100 mg) dissolved in toluene was mixed with 4-fluoro-phenyl-boronic acid (81 mg), POPD (15 mg) and cesium carbonate (2M aq.; 0.5 ml). The reaction mixture was heated at 150°C in a microwave oven for 10 minutes and then evaporated. The residue was purified by the preparative HPLC method. A product with a molecular weight of 404.49 (C24H25FN40) was obtained; MS (ESI): 405 (M+H+).

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-hlor-piridin-2-karbonske kiseline 5-Chloro-pyridine-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide

[1-(4-Amino-fenil)pirolidin-3-il]dimetil-amin je reagovao sa 5-hlor-piridin-2-karbonskom kiselinom po postupku E. Dobiven je proizvod molekulske težine 344.85 (C18H21CIN40); MS (ESI): 345 (M+H+). [1-(4-Amino-phenyl)pyrrolidin-3-yl]dimethyl-amine was reacted with 5-chloro-pyridine-2-carboxylic acid according to procedure E. A product with a molecular weight of 344.85 (C18H21CIN40) was obtained; MS (ESI): 345 (M+H+).

Primer 293 Example 293

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-amid 5-(4-fluor-fenil)piridin-2-karbonske kiseline 5-(4-Fluoro-phenyl)pyridine-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-amide

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-hlor-piridin-2-karbonske kiseline je reagovao sa 4-metil-fenil-bornom kiselinom po postupku O-a. Dobiven je proizvod molekulske težine 400.53 (C25H28N40); MS (ESI): 401 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide of 5-chloro-pyridine-2-carboxylic acid was reacted with 4-methyl-phenyl-boronic acid according to procedure O-a. A product with a molecular weight of 400.53 (C25H28N40) was obtained; MS (ESI): 401 (M+H+).

Primer 294 Example 294

[4-(3-Dimetil-amino-pirolidin-1 -il)-fenil]amid 1 -benzol-sulfonil-piperidin-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenyl]amide 1-benzene-sulfonyl-piperidine-4-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid piperidin-4-karbonske kiseline (70 mg) rastvoren u N-metil-pirolidonu (2 ml) pomešan je sa kalijum-karbonatom (45 mg) i benzol-sulfonil-hloridom (35 mg). Posle 12 sati, smeša je proceđena i filtratje prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 456.61 (C24H32N403S); MS (ESI): 457 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]piperidine-4-carboxylic acid amide (70 mg) dissolved in N-methyl-pyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC method. A product with a molecular weight of 456.61 (C24H32N403S) was obtained; MS (ESI): 457 (M+H+).

Primer 295 Example 295

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid 1 -(4-fluor-benzol-sulfonil)piperidin-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 1-(4-fluoro-benzenesulfonyl)piperidine-4-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid piperidin-4-karbonske kiseline (70 mg) rastvoren u N-metil-pirolidonu (2 ml) pomešan je sa kalijum-karbonatom (45 mg) i 4-fluor-benzol-sulfonil-hloridom (40 mg). Posle 12 sati, smeša je proceđena i filtrat je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 474.60 (C24H31FN403S); MS (ESI): 475 (M+H+). Piperidine-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methyl-pyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and 4-fluoro-benzenesulfonyl chloride (40 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. A product with a molecular weight of 474.60 (C24H31FN403S) was obtained; MS (ESI): 475 (M+H+).

Primer 296 Example 296

[4-(3-Dimetil-amino-pirolidin-1-il)-fenil]amid 1-(butan-1-sulfonil)piperidin-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenyl]amide 1-(butane-1-sulfonyl)piperidine-4-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid piperidin-4-karbonske kiseline (70 mg) rastvoren u N-metil-pirolidonu (2 ml), pomešan je sa kalijum-karbonatom (45 mg) i butil-sulfonil-hloridom (30 mg). Posle 12 sati, smeša je proceđena i filtrat je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 436.62 (C22H36N403S); MS (ESI): 437 Piperidine-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methyl-pyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and butyl sulfonyl chloride (30 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. A product with a molecular weight of 436.62 (C22H36N403S) was obtained; MS (ESI): 437

(M+H+). (M+H+).

Primer 297 Example 297

[4-(3-Dimetil-amino-pirolidin-1-il)-fenil]amid 5-(4-butoksi-fenil-etinil)furan-2-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenyl]amide 5-(4-butoxy-phenyl-ethynyl)furan-2-carboxylic acid

Postupak J-a J's procedure

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 5-brom-furan-2-karbonske kiseline (75 mg) rastvoren je zajedno sa 1-butoksi-4-etinil-benzolom (35 mg) u N,N-dimetil-form-amidu (1 ml) i, pod argonom, dodat u kapima suspenziji Pd(tBu3P)2CI2 (4 mg), bakar(l)-jodida (75 mg) i N,N-diizopropil-amina (20 mg) u bezvodnom tetrahidro-furanu (3 ml). Smeša je mešana na sobnoj temperaturi u toku 8 sati. Izvršeno je ceđenje kroz filter od sinterovanog stakla i uparavanje, a sirovi proizvod je prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 471.6 (C29H33N303); MS (ESI): 472 (M+H+) kao hidro-trifluor-acetat. 5-Bromo-furan-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4-ethynyl-benzene (35 mg) in N,N-dimethyl-form-amide (1 ml) and, under argon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper(l)-iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 8 hours. Straining through a sintered glass filter and evaporation were performed, and the crude product was purified by preparative HPLC. A product of molecular weight 471.6 (C29H33N303) was obtained; MS (ESI): 472 (M+H+) as hydrotrifluoroacetate.

Primer 298 Example 298

6-Butoksi-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]nikotin-amid 6-Butoxy-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]nicotinamide

Postupak H-a H's procedure

Rastvor 0.1 g kalijum-hidroksida u 1 ml DMSO mešanje na sobnoj temperaturi u toku 10 minuta i tada je dodato 0.1 g N-[4-(3-dimetil-amino-pirolidin-1-il)-fenil]-6-hidroksi-nikotin-amida. Rastvor je mešan u toku 10 minuta, pa je dodato 0.084 g 1-brom-butana. Smeša je mešana na sobnoj temperaturi preko noći. Posle dodatka vode i etil-acetata, vodeni sloj je ekstrahovan tri puta etil-acetatom. Organski slojevi su spojeni, osušeni iznad natrijum-sulfata, upareni u vakuumu i prečišćeni preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) kao hidro-trifluor-acetat. A solution of 0.1 g of potassium hydroxide in 1 ml of DMSO was stirred at room temperature for 10 minutes and then 0.1 g of N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamide was added. The solution was stirred for 10 minutes, then 0.084 g of 1-bromo-butane was added. The mixture was stirred at room temperature overnight. After addition of water and ethyl acetate, the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, evaporated in vacuo and purified by preparative HPLC. A product with a molecular weight of 382.24 (C22H30N4O2) was obtained; MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.

Primer 299 Example 299

6-Ciklopropil-metoksi-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]nikotin-amid 6-Cyclopropyl-methoxy-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]nicotinamide

Brom-metil-ciklopropan je reagovao sa N-[4-(3-dimetil-amino-pirolidin-1-il)-fenil]-6-hidroksi-nikotin-amidom po postupku H-a. Dobiven je proizvod molekulske težine 380.22 (C22H28N402); MS (ESI): 381 (M+H+) kao hidro-trifluor-acetat. Bromo-methyl-cyclopropane was reacted with N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamide according to procedure H. A product with a molecular weight of 380.22 (C22H28N402) was obtained; MS (ESI): 381 (M+H+) as hydrotrifluoroacetate.

Primer 300 Example 300

N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-6-izobutoksi-nikotin-amid N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-6-isobutoxy-nicotinamide

1-Brom-2-meti!-propan je reagovao sa N-[4-(3-dimetil-amino-pirolidin-1-il)-fenil]-6-hidroksi-nikotin-amidom po postupku H-a. Dobiven je proizvod molekulske težine 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) kao hidro-trifluor-acetat. 1-Bromo-2-methyl-propane was reacted with N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)-phenyl]-6-hydroxy-nicotinamide according to procedure H. A product with a molecular weight of 382.24 (C22H30N4O2) was obtained; MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.

Primer 301 Example 301

N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-6-(4-fluor-fenoksi)nikotin-amid 49 mg kalijum-karbonata dodato je rastvoru 0.041 g 6-hlor-N-[4-(3-dimetil-amino-piroiidin-1-il)fenil]nikotin-amida i 4-fluor-fenola (30 mg) u 0.8 ml DMF, i smeša je grejana na 140°C u mikrotalasnom aparatu u toku 90 minuta. Posle dodatka vode i etil-acetata, vodeni sloj je ekstrahovan tri puta etil-acetatom. Organski slojevi su spojeni, osušeni iznad natrijum-sulfata, upareni u vakuumu i prečišćeni preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 420.2 (C24H25FN402); MS (ESI): 421 (M+H+) kao hidro-trifluor-acetat. N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-6-(4-fluoro-phenoxy)nicotinamide 49 mg of potassium carbonate was added to a solution of 0.041 g of 6-chloro-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]nicotinamide and 4-fluorophenol (30 mg) in 0.8 ml of DMF, and the mixture was heated at 140°C in the microwave for 90 minutes. After addition of water and ethyl acetate, the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, evaporated in vacuo and purified by preparative HPLC. A product of molecular weight 420.2 (C24H25FN402) was obtained; MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.

6-Hlor-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]nicotinamid 6-Hlor-nikotinska kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-iljdimetil-aminom po postupku E-b. Dobiven je proizvod molekulske težine 344.14 (C18H21CIN40); MS (ESI): 345 (M+H+) kao hidro-trifluor-acetat. 6-Chloro-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]nicotinamide 6-Chloro-nicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yldimethyl-amine according to procedure E-b. A product with a molecular weight of 344.14 (C18H21CIN40) was obtained; MS (ESI): 345 (M+H+) as hydrotrifluoroacetate.

Sledeći primeri pripravljeni su na isti način. The following examples are prepared in the same way.

Primer 305 N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-2-fluor-4-fenoksi-benz-amid Example 305 N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-2-fluoro-4-phenoxy-benz-amide

Sprašena molekulska (4 A), 0.01 g bakar-acetata i 0.02 g benz-amida N-[4-(3-dimetil-amino-pirolidin-1-ii)fenil]-2-fluor-4-borne kiseline dodata su rastvoru 0.008 g fenola u 0.5 ml metilen-hlorida i mešana na 40°C u toku 24 sata. Rastvarač je tada uklonjen uz pomoć vakuuma, ostatak je apsorbovan u smeši voda/etil-acetat, vodeni sloj je ekstrahovan tri puta etil-acetatom. Organski slojevi su spojeni, osušeni iznad natrijum-sulfata, upareni u vakuumu i prečišćeni preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 419.2 (C25H26FN302); MS (ESI): 420 (M+H+) kao hidro-trifluor-acetat. Powdered molecular weight (4 A), 0.01 g of copper acetate and 0.02 g of benzamide N-[4-(3-dimethyl-amino-pyrrolidin-1-ii)phenyl]-2-fluoro-4-boronic acid were added to a solution of 0.008 g of phenol in 0.5 ml of methylene chloride and stirred at 40°C for 24 hours. The solvent was then removed under vacuum, the residue was absorbed in water/ethyl acetate, the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, evaporated in vacuo and purified by preparative HPLC. A product with a molecular weight of 419.2 (C25H26FN302) was obtained; MS (ESI): 420 (M+H+) as hydrotrifluoroacetate.

Benz-amid N-[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]-2-fluor-4-borne kiseline 4-Karboksi-3-fluor-fenil-borna kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-il]dimetil-aminom po postupku E-b. Dobiven je proizvod molekulske težine 371.18 (C19H23BFN303); MS (ESI): 372 (M+H+) kao hidro-trifluor-acetat. N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-2-fluoro-4-boronic acid benz-amide 4-Carboxy-3-fluoro-phenyl-boronic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethyl-amine according to procedure E-b. A product with a molecular weight of 371.18 (C19H23BFN303) was obtained; MS (ESI): 372 (M+H+) as hydrotrifluoroacetate.

Primer 306 Example 306

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 4-(3-Cijanofenil)-3,6-dihidro-2H-piridin-1-karbonske kiseline 4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]arnid 4-(4,4,5,5-tetrametil-[1,3,2]dioksa-borolan-2-il)-3,6-dihidro-2H-piridin-1-karbonske kiseline je reagovao sa 3-brombenzo-nitrilom po postupku O-a. Dobiven je proizvod molekulske težine 415.54 (C25H29N50); MS (ESI): 416 (M+H+) [4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 4-(4,4,5,5-tetrametil-[1,3,2]dioksa-borolan-2-il)-3,6-dihidro-2H-piridin-1 karbonske kiseline 4-(4,4,5,5-Tetrametil-[1,3,2]dioksa-borolan-2-il)-1,2,3,6-tetrahidro-piridin je reagovao sa [1-(4-amino-fenil)pirolidin-3-il]dimetil-aminom po postupku A. Dobiven je proizvod molekulske težine 440.40 (C24H37BN403); MS (ESI): 441 (M+H+) Primer 307 [4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 4-(2-cijano-fenil)-3,6-dihidro-2H-piridin-1 -karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]anide 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid was reacted with 3-bromobenzonitrile according to the procedure of O-a. A product with a molecular weight of 415.54 (C25H29N50) was obtained; MS (ESI): 416 (M+H+) [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxa-borolan-2-yl)-1,2,3,6-tetrahydro-pyridine was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethyl-amine according to procedure A. A product of molecular weight 440.40 (C24H37BN403) was obtained; MS (ESI): 441 (M+H+) Example 307 [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 4-(2-cyano-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

[4-(3-dimetil-amino-pirolidin-1-il)fenil]amid 4-(4,4,5,5-tetrametil-[1,3,2]dioksa-borolan-2-il)-3,6-dihidro-2H-piridin-1 karbonske kiseline je reagovao sa 2-brombenzo-nitrilom po postupku O-a. Dobiven je proizvod molekulske težine 415.54 (C25H29N50); MS (ESI): 416 (M+H+) [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid was reacted with 2-bromobenzonitrile according to the procedure of O-a. A product with a molecular weight of 415.54 (C25H29N50) was obtained; MS (ESI): 416 (M+H+)

Primer 308 Example 308

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 4-(3-metil-sulfanil-fenil)-3,6-dihidro-2H-piridin-1 -karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 4-(3-methyl-sulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 4-(4,4,5,5-tetrametil-[1,3,2]dioksa-borolan-2-il)-3,6-dihidro-2H-piridin-1 karbonske kiseline je reagovao sa 3-brom-tio-anizolom po postupku O-a. Dobiven je proizvod molekulske težine 436.62 (C25H32N40S); MS (ESI): 437 (M+H+) Primer 309 4-(5-Hlor-piridin-2-il-oksi)-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]benz-amid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridin-1 carboxylic acid was reacted with 3-bromo-thio-anisole according to the procedure of O. A product with a molecular weight of 436.62 (C25H32N40S) was obtained; MS (ESI): 437 (M+H+) Example 309 4-(5-Chloro-pyridin-2-yl-oxy)-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]benz-amide

0.143 g kalijum-karbonata dodato je rastvoru 0.19 g 4-[4-(3-dimetil-amino-pirolidin-1-il)fenil-karbamoil]fenil-acetata u 2 ml DMF, i rastvor je grejan na 130°C u mikrotalasnom aparatu u toku 15 minuta. Rastvor je tada pomešan sa vodom i etil-acetatom, vodeni sloj je zamrznut, a ostatak je korišćen u sledećoj fazi bez daljeg prečišćavanja. 0.143 g of potassium carbonate was added to a solution of 0.19 g of 4-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl-carbamoyl]phenyl-acetate in 2 ml of DMF, and the solution was heated at 130°C in a microwave oven for 15 minutes. The solution was then mixed with water and ethyl acetate, the aqueous layer was frozen, and the residue was used in the next step without further purification.

Postupak R Procedure R

Rastvor 0.05 g N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]-4-hidroksi-benz-amida, 0.017 g 2,5-dihlor-piridina i 0.064 g kalijum-karbonata u 0.8 ml DMF je grejan na 230°C u mikrotalasnom aparatu u toku 30 minuta. Rastvor je proceđen i prečišćen preparativnom HPLC metodom. Dobiven je proizvod molekulske težine 436.17 (C24H25CIN402); MS (ESI): 437 (M+H+) kao hidro-trifluor-acetat. A solution of 0.05 g of N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]-4-hydroxy-benz-amide, 0.017 g of 2,5-dichloro-pyridine and 0.064 g of potassium carbonate in 0.8 ml of DMF was heated to 230°C in a microwave oven for 30 minutes. The solution was filtered and purified by the preparative HPLC method. A product with a molecular weight of 436.17 (C24H25CIN402) was obtained; MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.

4-[4-(3-Dimetil-amino-pirolidin-1-il)fenil-karbamoil]fenil-acetat 4-Acetoksi-benzojeva kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-iljdimetil-aminom po postupku E-b. Dobiven je proizvod molekulske težine 367.19 (C21H25N303); MS (ESI): 368 (M+H+) kao hidro-trifluor-acetat. 4-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl-carbamoyl]phenyl-acetate 4-Acetoxy-benzoic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yldimethyl-amine according to procedure E-b. A product with a molecular weight of 367.19 (C21H25N303) was obtained; MS (ESI): 368 (M+H+) as hydrotrifluoroacetate.

Primer 310 Example 310

N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-4-(5-fluor-piridin-2-il-oksi)benz-amid N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-4-(5-fluoro-pyridin-2-yl-oxy)benz-amide

2-Hlor-5-fluor-piridin je reagovao sa N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]-4-hidroksi-benz-amid po postupku R. Dobiven je proizvod molekulske težine 420.2 (C24H25FN402); MS (ESI): 421 (M+H+) kao hidro-trifluor-acetat. Primer 311 4-(6-Hlor-piridin-3-il-oksi)-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]benz-amid 2-Chloro-5-fluoro-pyridine was reacted with N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]-4-hydroxy-benz-amide according to procedure R. A product of molecular weight 420.2 (C24H25FN402) was obtained; MS (ESI): 421 (M+H+) as hydrotrifluoroacetate. Example 311 4-(6-Chloro-pyridin-3-yl-oxy)-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]benz-amide

je dobiven kao nusproizvod reakcije u primeru 310. Dobiven je proizvod molekulske težine 436.95 (C24H25CIN402); MS (ESI): 437 (M+H+) kao hidro-trifluor-acetat. was obtained as a byproduct of the reaction in example 310. A product with a molecular weight of 436.95 (C24H25CIN402) was obtained; MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.

Primer 312 Example 312

[4-(3-Dimetil-amino- pirolidin-1 -il)fenil]amid 5-hlor-3',6'-dihidro-2'H-[2,4']bipiridinil-1 '-karbonske kiseline 5-Chloro-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide

[1-(4-Amino-fenil)pirolidin-3-il]dimetil-annin (32 mg) i karbonil-diimidazol (27.1 mg) su rastvoreni u aceto-nitrilu (1.5 ml), i smeša je mešana u toku 3 sata. Trietil-amin (63.4 ul) je dodat rastvoru 5-hlor-1',2',3',6'- tetrahidro-[2,4']bipiridina (40.7 mg) u THF (1 ml) i hloroformu (0.5 ml). Posle 15 minuta, smeša je u kapima dodata u prvi rastvor i mešana preko noći. Smeša je uparena i ostatak je raspodeljen između dihlor-metana i vode. Organski sloj je osušen iznad natrijum-sulfata, proceđen i uparen. Onečišćenje primarnim i/ili sekundarnim aminom je uklonjeno rastvaranjem ostatka u dihlor-metanu (1.5 ml) i dodavanjem rastvora u suspenziju polimerno-vezanog p-toluol-sulfonil-hlorida (0.5 g) u dihlor-metanu (6 ml) i trietil-aminu (128 pl), uz mešanje. Posle 3 sata, smola je proceđena i isprana nekoliko puta dihlor-metanom. Spojeni organski slojevi su upareni. Ostatak je prečišćen hromatografski (silika-gel, pokretna faza: etil-acetat/dihlor-metan (5%), amonijak (7N u metanolu, 2%), kasnije etil-acetat/dihlor-metan (5%), amonijak (7N u metanolu, 3%)). Dobiven je proizvod molekulske težine 425.97 (C23H28CIN50); MS (ESI): 426 [1-(4-Amino-phenyl)pyrrolidin-3-yl]dimethyl-annine (32 mg) and carbonyl-diimidazole (27.1 mg) were dissolved in acetonitrile (1.5 ml), and the mixture was stirred for 3 hours. Triethylamine (63.4 µl) was added to a solution of 5-chloro-1',2',3',6'-tetrahydro-[2,4']bipyridine (40.7 mg) in THF (1 ml) and chloroform (0.5 ml). After 15 minutes, the mixture was added dropwise to the first solution and stirred overnight. The mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and evaporated. Primary and/or secondary amine contamination was removed by dissolving the residue in dichloromethane (1.5 ml) and adding the solution to a suspension of polymer-bound p-toluenesulfonyl chloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 µl), with stirring. After 3 hours, the resin was filtered and washed several times with dichloromethane. The combined organic layers are paired. The residue was purified by chromatography (silica gel, mobile phase: ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 2%), later ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 3%)). A product with a molecular weight of 425.97 (C23H28CIN50) was obtained; MS (ESI): 426

(M+H+). (M+H+).

5-Hlor-1 \2\3\6'- tetrahidro-[2,4']bipiridin 5-Chloro-1\2\3\6'-tetrahydro-[2,4']bipyridine

Rastvor terc-butil-S-hlor-S'.e'-dihidro^'H-^^'jbipiridin-l'-karboksilata (50 mg) u hloroformu (2.4 ml) pomešan je sa hlorovodonikom (4N u dioksanu; 0.8 ml) i smeša je uparena posle 13 sati. Dobiven je proizvod molekulske težine 194.67 (C10H11CIN2); MS (ESI): 195 (M+H+). A solution of tert-butyl-S-chloro-S'.e'-dihydro^'H-^^'bipyridine-1'-carboxylate (50 mg) in chloroform (2.4 ml) was mixed with hydrogen chloride (4N in dioxane; 0.8 ml) and the mixture was evaporated after 13 hours. A product with a molecular weight of 194.67 (C10H11CIN2) was obtained; MS (ESI): 195 (M+H+).

terc-Butil-S-hlor-S'.e'-dihidro^'H-^^'jbipiridin-l'-karbamat Rastvor 2-brom-5-hlor-piridina (131 mg) u DMF (degaziran azotom; 4.5 ml) je dodat smeši terc-butil-4-(4,4,5,5-tetrametil-[1,3,2]dioksa-borolan-2-il)-3,6- tert-Butyl-S-chloro-S'.e'-dihydro^'H-^^'jbipyridine-1'-carbamate A solution of 2-bromo-5-chloro-pyridine (131 mg) in DMF (degassed with nitrogen; 4.5 ml) was added to a mixture of tert-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-3,6-

đihidro-2H-piridin-1 -karbamata (Eastwood, Paul R., Tetrahedron Lett, 41, 19, 2000, 3705-3708; 200 mg), kalijum-karbonata (0.265 g) i Pd(dppf)CI2 (50 mg). Smeša je grejana na 80°C u toku 8 sati. Posle hlađenja, smeša je razblažena dihlor-metanom i isprana rastvorom natrijum-karbonata i vodom. Organski sloj je osušen iznad natrijum-sulfata, proceđen i uparen. Ostatak je prečišćen hromatografski (silika-gel, pokretna faza: heptan/etil-acetat (2%)/dihlor-metan (5%), kasnije heptan/etil-acetat (5%)/dihlor-metan (5%)). dihydro-2H-pyridine-1-carbamate (Eastwood, Paul R., Tetrahedron Lett, 41, 19, 2000, 3705-3708; 200 mg), potassium carbonate (0.265 g) and Pd(dppf)Cl2 (50 mg). The mixture was heated to 80°C for 8 hours. After cooling, the mixture was diluted with dichloromethane and washed with sodium carbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography (silica gel, mobile phase: heptane/ethyl acetate (2%)/dichloromethane (5%), later heptane/ethyl acetate (5%)/dichloromethane (5%)).

Primer 313 Example 313

[4-(3-Dimetil-amino-pirolidin-1 -il)- feniljamid 5-(2-amino-4-metil-fenil)furan-2-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenylamide 5-(2-amino-4-methyl-phenyl)furan-2-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1 -il)- feniljamid 5-(2-nitro-4-metil-fenil)furan-2-karbonske kiseline je hidrogenovan po postupku B. Dobiven je proizvod molekulske težine 404.22 (C24H28N402); MS (ESI): 405 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenylamide 5-(2-nitro-4-methyl-phenyl)furan-2-carboxylic acid was hydrogenated according to procedure B. A product with a molecular weight of 404.22 (C24H28N402) was obtained; MS (ESI): 405 (M+H+).

Primer 314 Example 314

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid 5-(2-acetll-amino-4-metil-fenil)furan-2-karbonske kiseline 5-(2-Acetyl-amino-4-methyl-phenyl)furan-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide

[4-(3-Dimetil-amino-pirolidin-1 -il)- feniljamid 5-(2-amino-4-metil-fenil)furan-2-karbonske kiseline je reagovao sa acetil-hloridom po postupku Q. 5-(2-Amino-4-methyl-phenyl)furan-2-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenylamide was reacted with acetyl chloride according to procedure Q.

Dobiven je proizvod molekulske težine 446.23 (C26H30N4O3); MS (ESI): 447 (M+H+). A product with a molecular weight of 446.23 (C26H30N4O3) was obtained; MS (ESI): 447 (M+H+).

Primer 315 Example 315

[4-(3-Dimetil-amino- pirolidin-1 -il)fenil]amid 5-(2-izobutiril-amino-4-metil-fenil)furan-2-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 5-(2-isobutyryl-amino-4-methyl-phenyl)furan-2-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1 -il)- feniljamid 5-(2-amino-4-metil-fenil)furan-2-karbonske kiseline je reagovao sa izobutiril-hloridom po postupku Q. Dobiven je proizvod molekulske težine 474.26 (C28H34N403); MS (ESI): 475 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)-phenylamide 5-(2-amino-4-methyl-phenyl)furan-2-carboxylic acid was reacted with isobutyryl chloride according to procedure Q. A product of molecular weight 474.26 (C28H34N403) was obtained; MS (ESI): 475 (M+H+).

Primer 316 Example 316

[4-(3-Dimetil-amino- pirolidin-1 -il)fenil]metil-amid 5'-hlor-3,4,5,6-tetrahidro-2H-[1,2']bipiridinil-4-karbonske kiseline 5'-chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl-amide

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]metil-amid piperidin-4-karbonske kiseline (44.4 mg) i 2,5-dihlor-piridin (60 mg) grejani su na 160°C u toku 15 minuta. Dodat je o-ksilol (0.5 ml) i grejanje na 160°C nastavljeno je u toku 2 časa. Ohlađena sirova smeša je prečišćena hromatografski (silika-gel, eluent: etil-acetat/amonijak (7N u metanolu)). Dobiven je proizvod molekulske težine 442.01 (C24H32CIN50); MS (ESI): 442 (M+H+). Piperidine-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl-amide (44.4 mg) and 2,5-dichloro-pyridine (60 mg) were heated at 160°C for 15 minutes. O-xylene (0.5 ml) was added and heating at 160°C was continued for 2 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). A product of molecular weight 442.01 (C24H32CIN50) was obtained; MS (ESI): 442 (M+H+).

Piperidin-4-karbonske kiseline[4-(3-dimetil-amino-pirolidin-1-il)fenil]metil-amid Piperidine-4-carboxylic acid[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl-amide

terc-Butil-4-{[4-(3-dimetil-amino-pirolidin-1-il)fenil]metil4<arbamoil}piperidin-1-karboksilat je tretiran trifluor-acetatom po postupku G. Dobiven je proizvod molekulske težine 330.48 (C19H30N4O); MS (ESI): 331 (M+H+). tert-Butyl-4-{[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl4<arbamoyl}piperidine-1-carboxylate was treated with trifluoroacetate according to procedure G. A product with a molecular weight of 330.48 (C19H30N4O) was obtained; MS (ESI): 331 (M+H+).

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid piperidin-4-karbonske kiseline može se pripremiti na isti način. Piperidine-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide can be prepared in the same way.

terc-Butil-4-{[4-(3-dimetil-amino-pirolidin-1-il)fenil]metil-karbamoil}piperidin-1-karboksilat tert-Butyl-4-{[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl-carbamoyl}piperidine-1-carboxylate

Rastvor N-Boc-piperidin-4-karbonske kiseline (550 mg) i piridina (0.47 ml) u dihlor-metanu (15 ml) je pomešan sa tionil-hloridom (0.21 ml) i posle 30 minuta rastvor dimetil[1-(4-metil-amino-fenil)pirolidin-3-il]amina (0.5 g), trietil-amina (1.17 ml), DMAP (0.44 g) i dihlor-metana (10 ml) je dodat u kapima. Posle 16 sati, smeša je razblažena dihlor-metanom, isprana vodom i zasićenim rastvorom soli, osušena iznad natrijum-sulfata i uparena. Ostatak je prečišćen hromatografski (silika-gel, eluent: etil-acetat/amonijak (7N u metanolu)). Dobiven je proizvod molekulske težine 430.60 (C24H38N403); MS (ESI): 431 (M+H+). terc-Butil-4-{[4-(3-dimetil-amino-pirolidin-1-il)fenil]karbamoil}piperidin-1-karboksilat može se pripremiti na isti način. A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with thionyl chloride (0.21 ml) and after 30 minutes a solution of dimethyl[1-(4-methyl-amino-phenyl)pyrrolidin-3-yl]amine (0.5 g), triethylamine (1.17 ml), DMAP (0.44 g) and dichloromethane (10 ml) was added dropwise. After 16 hours, the mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). A product with a molecular weight of 430.60 (C24H38N403) was obtained; MS (ESI): 431 (M+H+). tert-Butyl-4-{[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]carbamoyl}piperidine-1-carboxylate can be prepared in the same way.

Sledeći primeri pripremljeni su na isti način: The following examples were prepared in the same way:

Primer 320 Example 320

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid 3,4,5,6-tetrahidro-2H-[1,2']bipiridinil-4-karbonske kiseline 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid piperidin-4-karbonske kiseline (30 mg) i 2-hlor-piridin (90 mg) zagrevani su na 160°C u toku 2 sata. Dodat je 2-hlor-piridin (0.2 ml) i smeša je ponovo zagrevana na 160°C u toku 4 sata. Ohlađena sirova smeša je prečišćena hromatografski (silika-gel, eluent: etil-acetat/amonijak (3N u metanolu)). Dobiven je proizvod molekulske težine 393.54(C23H31N50); MS (ESI): 394 (M+H+). Piperidine-4-carboxylic acid [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide (30 mg) and 2-chloro-pyridine (90 mg) were heated at 160°C for 2 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was reheated to 160°C for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). A product with a molecular weight of 393.54(C23H31N50) was obtained; MS (ESI): 394 (M+H+).

Sledeći primeri pripremljeni su na isti način: The following examples were prepared in the same way:

Primer 323 Example 323

[4-(3-Dimetil-amino- pirolidin-1 -il)fenil]amid 5'-hlor-3,4,5,6-tetrahidro-2H-[1,2']bipiridinil-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 5'-chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid

[4-(3-dimetil-amino-pirolidin-1-l)fenil]amid piperidin-4-karbonske kiseline (30 mg), 2,5-dihlor-piridin (30 mg) i tributil-amin (0.2 ml) grejani su na 160°C u toku 2 sata. Ohlađena sirova smeša je isprana heptanom i prečišćena hromatografski (silika-gel, eluent: etil-acetat/amonijak (3N u metanolu)). Dobiven je proizvod molekulske težine 427.98 (C23H30CIN5O); MS (ESI): 428 (M+H+). Piperidine-4-carboxylic acid [4-(3-dimethyl-amino-pyrrolidin-1-1)phenyl]amide (30 mg), 2,5-dichloro-pyridine (30 mg) and tributylamine (0.2 ml) were heated at 160°C for 2 hours. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). A product with a molecular weight of 427.98 (C23H30CIN5O) was obtained; MS (ESI): 428 (M+H+).

Primer 324 Example 324

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid 1 -(4-hlor-2-cijano-fenil)piperidin-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide 1-(4-chloro-2-cyano-phenyl)piperidine-4-carboxylic acid

[4-(3-Dimetil-amino-pirolidin-1-il)fenil]amid piperidin-4-karbonske kiseline je reagovao sa 2,5-dihlor-benzo-nitrilom kao što je opisano u primeru 323. Dobiven je proizvod molekulske težine 452.00 (C25H30CIN5O); MS (ESI): 452 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]piperidine-4-carboxylic acid amide was reacted with 2,5-dichloro-benzonitrile as described in Example 323. A product of molecular weight 452.00 (C25H30CIN5O) was obtained; MS (ESI): 452 (M+H+).

Primer 325 Example 325

[4-(3-Dimetil-amino- pirolidin-1 -il)fenil]metil-amid 1 -(2-acetil-amino-4-hlorfenil)piperidin-4-karbonske kiseline [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl-amide 1-(2-acetyl-amino-4-chlorophenyl)piperidine-4-carboxylic acid

Paladijum na uglju (10%; 10 mg) je dodat rastvoru [4-(3-dimetil-amino-pirolidin-1- il)fenil]metil-amida 1-(4-hlor-2-nitro-fenil)piperidin-4-karbonske kiseline (50 mg) u glacijalnoj sirćetnoj kiselini (5 ml). Rastvor je mešan u atmosferi vodonika (1 bar) i dodat je anhidrid sirćetne kiseline (14 ul). Posle jednog sata, dodato je još anhidrida sirćetne kiseline (6 pl) i smeša je mešana 15 minuta. Suspenzija je proceđena i filtrat je uparen. Ostatak je prečišćen hromatografski (silika-gel, eluent: etil-acetat/amonijak (7N u metanolu)). Dobiven je proizvod molekulske težine 498.07 (C27H36CIN502); MS (ESI): 498 (M+H+). Palladium on charcoal (10%; 10 mg) was added to a solution of 1-(4-chloro-2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]methyl-amide (50 mg) in glacial acetic acid (5 ml). The solution was stirred under a hydrogen atmosphere (1 bar) and acetic anhydride (14 µl) was added. After one hour, more acetic anhydride (6 µl) was added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was evaporated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). A product of molecular weight 498.07 (C27H36CIN502) was obtained; MS (ESI): 498 (M+H+).

Sledeći primeri pripremljeni su na isti način: The following examples were prepared in the same way:

Primer 329 (R)-N-[4-(3-Dimetil-amino-pirolidin-1-il)fenil]-2-(4-fenil-piperidin-1-il)acet-amid Example 329 (R)-N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]-2-(4-phenyl-piperidin-1-yl)acet-amide

Cezijum-karbonat (100 mg) i 4-fenil-piperidin (48 mg) dodati su rastvoru (R)-2-hlor-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]acet-amida (80 mg) u aceto-nitrilu (5 ml) i DMF (1 ml), i smeša je držana na 65°C u toku 12 časova. Smeša je oslobođena isparljivih frakcija i ostatak je raspodeljen između vode i dihlor-metana. Organski sloj je osušen iznad natrijum-sulfata, proceđen i uparen. Ostatak je prečišćen hromatografski (silika-gel, eluent: metanol/dihlor-metan). Dobiven je proizvod molekulske težine 406.58 (C25H34N40); MS (ESI): 407 (M+H+). Cesium carbonate (100 mg) and 4-phenyl-piperidine (48 mg) were added to a solution of (R)-2-chloro-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the mixture was kept at 65°C for 12 hours. The mixture was freed from volatile fractions and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). A product with a molecular weight of 406.58 (C25H34N40) was obtained; MS (ESI): 407 (M+H+).

Takođe je moguće koristiti kalijum-karbonat ili piridin kao pomoćne baze, dodati kalijum-jodid kao katalizator ili izvesti reakciju na 150°C u mikrotalasnim aparatima. It is also possible to use potassium carbonate or pyridine as auxiliary bases, add potassium iodide as a catalyst or carry out the reaction at 150°C in microwaves.

(R)-2-Hlor-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]acet-amid Trietil-amin (2.03 g)je dodat rastvoru (R)-[1-(4-amino-fenil)pirolidin-3-il]-dimetil-amina (3.15 g) u dihlor-metanu (120 ml), a zatim je u kapima dodat hlor-acetil-hlorid (2.26 g). Posle 3 sata, smeša je razblažena dihlor-metanom i isprana vodom i rastvorom soli. Organski sloj je osušen iznad natrijum-sulfata, proceđen i uparen. Ostatak je prečišćen hromatografski (R)-2-Chloro-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]acet-amide Triethylamine (2.03 g) was added to a solution of (R)-[1-(4-amino-phenyl)pyrrolidin-3-yl]-dimethyl-amine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography

(silika-gel, eluent: metanol/dihlor-metan). Dobiven je proizvod molekulske težine 281.79 (C14H20CIN3O); MS (ESI): 282 (M+H+). (silica gel, eluent: methanol/dichloromethane). A product with a molecular weight of 281.79 (C14H20CIN3O) was obtained; MS (ESI): 282 (M+H+).

Na isti način pripremljeni su: N-{4-[3-(Acetil-metil-amino)pirolidin-1-il]fenil}-2-hlor-acet-amid 2-Hlor-N-[4-(3-dimetil-amino-pirolidin-1-il)fenil]acet-amid (R)-2-Hlor-N-[6-(3-dimetil-amino-pirolidin-1-il)piridin-3-il]acet-amid The following were prepared in the same way: N-{4-[3-(Acetyl-methyl-amino)pyrrolidin-1-yl]phenyl}-2-chloro-acet-amide 2-Chloro-N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]acet-amide (R)-2-Chloro-N-[6-(3-dimethyl-amino-pyrrolidin-1-yl)pyridin-3-yl]acet-amide

Sledeći primeri pripremljeni su analogno postupku prikazanom u primeru 329: The following examples were prepared analogously to the procedure shown in example 329:

Primer 340 Example 340

[6-(3-Dimetil-amino-pirolidin-1-il)piridin-3-il]-amid (R)-4-benzil-piperidin-1-karbonske kiseline [6-(3-Dimethyl-amino-pyrrolidin-1-yl)pyridin-3-yl]-amide (R)-4-benzyl-piperidine-1-carboxylic acid

(R)-6-(3-Dimetil-amino-pirolidin-1-il)piridin-3-il-amin je dodat rastvoru karbonil-diimidazola (53 mg) u DMF (0.5 ml) na 0°C. Posle 15 minuta dodat je 4-benzil-piperidin (57 mg) i smeša je grejana na 90°C sat vremena. Ohlađena smeša je oslobođena isparljivih frakcija. Ostatak je prečišćen hromatografski (silika-gel, eluent: metanol/dihlor-metan). Dobiven je proizvod molekulske težine 407.56 (C24H33N50); MS (ESI): 408 (M+H+). (R)-6-(3-Dimethyl-amino-pyrrolidin-1-yl)pyridin-3-yl-amine was added to a solution of carbonyl-diimidazole (53 mg) in DMF (0.5 ml) at 0°C. After 15 minutes, 4-benzyl-piperidine (57 mg) was added and the mixture was heated at 90°C for one hour. The cooled mixture is freed from volatile fractions. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). A product with a molecular weight of 407.56 (C24H33N50) was obtained; MS (ESI): 408 (M+H+).

Sledeći primeri pripremljeni su na isti način: The following examples were prepared in the same way:

Sledeći primeri pripremljeni su na isti način po posrupku H: The following examples were prepared in the same way according to procedure H:

Primer 352 (R)-N-[4-(3-Dimetilaminopirolidin-1-il)-3-fluorogenyl]-4-(piridin-2-iloksi)benzamid Example 352 (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorogenyl]-4-(pyridin-2-yloxy)benzamide

(R)-N-[4-(3-Dimetilaminopirolidin-1-il)-3-fluorofenll]-4-hidroksibenzamid je reagovao sa 2-chloropiridinom prema postupku R. Ovo je dalo proizvod molekulske težine od 434.52 (C25H27N402); MS (ESI): 435 (M+H+). (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was reacted with 2-chloropyridine according to procedure R. This gave a product with a molecular weight of 434.52 (C25H27N402); MS (ESI): 435 (M+H+).

Primer 353 - Primer 507 Example 353 - Example 507

Različiti pirolidinilanilini su reagovali sa različitim aminima prema postupku A. Dobijeni proizvodi su sumarno dati u tabeli 6. Different pyrrolidinylanilines were reacted with different amines according to procedure A. The products obtained are summarized in Table 6.

Primer 508- Primer 1130 Example 508- Example 1130

Različiti pirolidinilanilini su reagovali sa različitim kiselinama prema postupku E. Dobijeni proizvodi su sumarno dati u tabeli 7. Different pyrrolidinylanilines were reacted with different acids according to procedure E. The products obtained are summarized in Table 7.

Primer 1131 - Primer 1232 Example 1131 - Example 1232

Različtit (hetero)aril halidi (halogenidi) su reagovali sa različitim boronskim kiselimanaprema postupku O. Dobijeni proizvodi su sumarno dati u tabeli 8. Various (hetero)aryl halides (halides) were reacted with various boronic acids according to procedure O. The obtained products are summarized in Table 8.

Primer 1233 - Primer 1237 Example 1233 - Example 1237

Različiti aril halid reagovali su sa različitim acetelenima prema postupku J. Dobijeni proizvodi su sumarno dati u tabeli 9. Different aryl halides were reacted with different acetylenes according to procedure J. The products obtained are summarized in Table 9.

Primer 1238-primer 1403 Example 1238-example 1403

Različiti aminopirolidini and N-arilpirolidinoni su reagovali sa različitim aldehidima, etonima i aminima prema postupku N. Dobijeni proizvodi su sumarno dati u tabeli 10. Various aminopyrrolidines and N-arylpyrrolidinones were reacted with various aldehydes, etones and amines according to procedure N. The obtained products are summarized in Table 10.

Primer 1404 - primer 1423 Example 1404 - example 1423

Različiti aminopirolidini su reducktivno methilovani formaldehidom Dobijeni proizvodi su sumarno dati u Tabeli 11. Various aminopyrrolidines were reductively methylated with formaldehyde. The resulting products are summarized in Table 11.

Primer 1424 - primer 1443 Example 1424 - example 1443

Različiti amidi su alkilovani prema postupku F. Dobijeni proizvodi su sumarno dati u Tabeli 12. Various amides were alkylated according to procedure F. The products obtained are summarized in Table 12.

Primer 1444 - Primer 1618 Example 1444 - Example 1618

Različiti terc-butil karbamati su dobijeni prema postupku G Dobijeni proizvodi su sumarno dati u Tabeli 13. Various tert-butyl carbamates were obtained according to procedure G. The obtained products are summarized in Table 13.

Sinteze pirolidin- anilina koji su potrebni kao međuproizvodi Syntheses of pyrrolidine-anilines which are required as intermediates

[1-(4-Amino-2-hlor-fenil)pirolidin-3-il]dimetilamin [1-(4-Amino-2-chloro-phenyl)pyrrolidin-3-yl]dimethylamine

Postupak C-a Procedure C

U rastvor 2-hlor-1-fluor-4-nitro-benzola (0.52 g) u DMF - u (5 ml) dodat je polako rastvor 3-dimetil-amino-pirolidona (0.34 g). Posle jednog sata u reakcionu smešu je dodat etil-acetat i rastvor je ekstrahovan sa 10% hlorovodoničnom kiselinom (2 x 20 ml). Vodeni sloj je opran pomoću etil-acetata (2 x 20 ml), podešen onda na pH > 10 pomoću 10%-og amonijaka i ekstrahovan pomoću etil-acetata. Žuti rastvor je osušen pomoću natrijum-sulfata, zatim proceđen i uparen pomoću rotacionog uparivača. Ostatak je rastvoren u dihlor-metanu (50 ml), dodat je zink (10 g) i glacijalna sirćetna kiselina je (5 ml) dodata polako, kap po kap, uz hlađenje ledom. Suspenzija je mešana 15 minuta, zatim proceđena i oprana pomoću 10%-nog amonijaka (2 x 20 ml) i uparena. Kao rezultat dobiven je proizvod molekulske težine 239.75 (C12H18CIN3); MS (ESI): 239 (M+H+), 240 A solution of 3-dimethyl-amino-pyrrolidone (0.34 g) was slowly added to a solution of 2-chloro-1-fluoro-4-nitro-benzene (0.52 g) in DMF (5 ml). After one hour, ethyl acetate was added to the reaction mixture and the solution was extracted with 10% hydrochloric acid (2 x 20 ml). The aqueous layer was washed with ethyl acetate (2 x 20 ml), then adjusted to pH > 10 with 10% ammonia and extracted with ethyl acetate. The yellow solution was dried using sodium sulfate, then filtered and evaporated using a rotary evaporator. The residue was dissolved in dichloromethane (50 ml), zinc (10 g) was added and glacial acetic acid (5 ml) was added slowly dropwise under ice cooling. The suspension was stirred for 15 minutes, then filtered and washed with 10% ammonia (2 x 20 ml) and evaporated. As a result, a product with a molecular weight of 239.75 (C12H18CIN3) was obtained; MS (ESI): 239 (M+H + ), 240

(M+H+), (M+H+),

5-Amino-2-(3-dimetil-amino-pirolidin-1-il)benzo-nitril Dimetil-amino-pirolidin je tretiran sa 2-fluor-5-nitro-benzo-nitril i, posle toga, redukovan prema postupku C-a. Kao rezultat dobiven je proizvod molekulske težine 230.32 (C13H18N4); MS (ESI): 231 (M+H+), 5-Amino-2-(3-dimethyl-amino-pyrrolidin-1-yl)benzo-nitrile Dimethyl-amino-pyrrolidine was treated with 2-fluoro-5-nitro-benzo-nitrile and then reduced according to procedure C-a. As a result, a product with a molecular weight of 230.32 (C13H18N4) was obtained; MS (ESI): 231 (M+H+),

[1-(4-Amino-3-hlor-fenil)pirolidin-3-il]dimetilamin [1-(4-Amino-3-chloro-phenyl)pyrrolidin-3-yl]dimethylamine

Dimetil-amino-pirolidin je tretiran sa 3-hlor-1-fluor-4-nitro-benzolom i, posle toga redukovan prema postupku C-a. Kao rezultat dobiven je proizvod molekulske težine 239.75 (C12H18CIN3); MS (ESI): 239 (M+H+), 240 Dimethyl-amino-pyrrolidine was treated with 3-chloro-1-fluoro-4-nitro-benzene and then reduced according to procedure C. As a result, a product with a molecular weight of 239.75 (C12H18CIN3) was obtained; MS (ESI): 239 (M+H + ), 240

(M+H+), (M+H+),

[1-(4-Amino-3-metil-fenil)pirolidin-3-il]dimetil-amin [1-(4-Amino-3-methyl-phenyl)pyrrolidin-3-yl]dimethyl-amine

Dimetil-amino-pirolidin je tretiran sa 4-fluor-2-metil-1-nitro-benzolom i, posle toga redukovan prema postupku C-a. Kao rezultat dobiven je proizvod molekulske težine 219.33 (C13H21N3); MS (ESI): 220 (M+H+). Dimethyl-amino-pyrrolidine was treated with 4-fluoro-2-methyl-1-nitro-benzene and then reduced according to procedure C-a. As a result, a product with a molecular weight of 219.33 (C13H21N3) was obtained; MS (ESI): 220 (M+H+).

terc.-Butil-(R)-[1-(4-amino-2-fluor-fenil)pirolidin-3-il]metil-karbamat Postupak C-b tert.-Butyl-(R)-[1-(4-amino-2-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate Method C-b

terc.-Butil-(R)-(+)-pirolidin-3-il-karbamat (1.86 g) polako je dodavan u jednu suspenziju 3,4-difluor-nitro-benzola (1.59 g) i kalijum-karbonata (2.8 g) u DMF - u (10 ml). Posle 10 minuta dodat je etil-acetat (50 ml) i smeša je oprana vodom (3 x 50 ml) u levku za odvajanje, osušena je pomoću natrijum-sulfata, proceđena i uparena. Ostatak je rastvoren u DMF - u (10 ml) i dodat je natrijum-hidrid (0.48 g). Posle 15 minuta dodat je metil-jodid (1.41 g) uz hlađenje ledom. Posle 30 minuta dodat je etil-acetat (50 ml) i smeša je oprana vodom (3 x 50 ml) u levku za odvajanje, osušena je pomoću natrijum-sulfata, proceđena i uparena. Supstanca je, zatim, tretirana kao što je opisano za postupak B. Kao rezultat dobiven je proizvod molekulske težine 309.39 (C16H24FN302); MS (ESI): 310 (M+H+). tert-Butyl-(R)-(+)-pyrrolidin-3-yl-carbamate (1.86 g) was slowly added to a suspension of 3,4-difluoro-nitro-benzene (1.59 g) and potassium carbonate (2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml) was added and the mixture was washed with water (3 x 50 ml) in a separatory funnel, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in DMF (10 ml) and sodium hydride (0.48 g) was added. After 15 minutes, methyl iodide (1.41 g) was added under ice cooling. After 30 min, ethyl acetate (50 ml) was added and the mixture was washed with water (3 x 50 ml) in a separatory funnel, dried over sodium sulfate, filtered and evaporated. The substance was then treated as described for procedure B. As a result, a product of molecular weight 309.39 (C16H24FN302) was obtained; MS (ESI): 310 (M+H+).

terc.-Butil-(S)-[1-(4-amino-2-fluor-fenil)pirolidin-3-il]metil-karbamat je dobiven na isti način. tert-Butyl-(S)-[1-(4-amino-2-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate was obtained in the same way.

terc.-Butil-(R)-[1-(2-fluor-4-izopropil-amino-fenil)pirolidin-3-il]metil-karbamat terc.-Butil-(R)-[1-(4-amino-2-fluor-fenil)pirolidin-3-il]metil4<arbamat alkilovan je acetonom koristeći triacetoksi-bor-hidrid kao sredstvo za redukciju, prema postupku N. Kao rezultat dobiven je proizvod molekulske težine 351.47 (C19H30FN3O2); MS (ESI): 352 (M+H+). tert.-Butyl-(R)-[1-(2-fluoro-4-isopropyl-amino-phenyl)pyrrolidin-3-yl]methyl-carbamate tert.-Butyl-(R)-[1-(4-amino-2-fluoro-phenyl)pyrrolidin-3-yl]methyl4<arbamate was alkylated with acetone using triacetoxy-borohydride as a reducing agent, according to procedure N. As a result, a product with a molecular weight of 351.47 was obtained. (C19H30FN3O2); MS (ESI): 352 (M+H+).

terc.-Butil-(R)-[1-(2-fluor-4-ciklo-butil-amino-fenil)pirolidin-3-il]metil-karbamat tert-Butyl-(R)-[1-(2-fluoro-4-cyclo-butyl-amino-phenyl)pyrrolidin-3-yl]methyl-carbamate

terc.-Butil-(R)-[1-(4-amino-2-fluor-fenil)pirolidin-3-il]metil-karbamat alkilovan je pomoću ciklo-butanona koristeći triacetoksi-bor-hidrid kao sredstvo za redukciju, prema postupku N. Kao rezultat dobiven je proizvod molekulske težine 363.48 (C20H30FN3O2); MS (ESI): 364 (M+H+). tert-Butyl-(R)-[1-(4-amino-2-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate was alkylated with cyclo-butanone using triacetoxy-borohydride as a reducing agent, according to procedure N. As a result, a product with a molecular weight of 363.48 (C20H30FN3O2) was obtained; MS (ESI): 364 (M+H+).

terc.-Butil-(R)-[1-(2-fluor-4-metil-amino-fenil)pirolidin-3-il]meti-lkarbamat tert-Butyl-(R)-[1-(2-fluoro-4-methyl-amino-phenyl)pyrrolidin-3-yl]methyl-lcarbamate

terc.-Butil-(R)-{1-[4-(benzil-oksi-karbonil-metil-amino)-2-fluor-fenil]pirolidin-3-il}-metil-karbamat tretiran je kako je opisano za postupak B. Kao rezultat dobiven je proizvod molekulske težine 323.41 (C17H26FN302); MS (ESI): 324 (M+H+). tert-Butyl-(R)-{1-[4-(benzyl-oxy-carbonyl-methyl-amino)-2-fluoro-phenyl]pyrrolidin-3-yl}-methyl-carbamate was treated as described for procedure B. As a result, a product of molecular weight 323.41 (C17H26FN302) was obtained; MS (ESI): 324 (M+H+).

terc.-Butil-(R)-{1-[4-(benzil-oksi-karbonil-metil-amino)-2-fluor-fenil]pirolidin-3-il}-metil-karbamat tert-Butyl-(R)-{1-[4-(benzyl-oxy-carbonyl-methyl-amino)-2-fluoro-phenyl]pyrrolidin-3-yl}-methyl-carbamate

terc.-Butil-(R)-(+)-[1-(4-amino-2-fluor-fenil)pirolidin-3-il]metil-karbamat (0.93 g) je dodat u jedan rastvor N-(benzil-oksi-karbonil-oksi)sukcinimida (2.49 g) u dihlor-metanu (30 ml). Posle 12 sati smeša je oprana vodom (2 x 30 ml), tert-Butyl-(R)-(+)-[1-(4-amino-2-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate (0.93 g) was added to a solution of N-(benzyl-oxy-carbonyl-oxy)succinimide (2.49 g) in dichloromethane (30 ml). After 12 hours, the mixture was washed with water (2 x 30 ml),

osušena natrijum-sulfatom, proceđena i uparena. Ostatak je prekristalisan iz aceto-nitrila. Proizvod koji je na ovaj način dobiven rastvoren je u DMF- u (10 ml) i, zatim, je dodat natrijum-hidrid (0.24 g). Posle 15 minuta dodat je metil-jodid (0.71 g) uz hlađenje ledom. Posle 15 minuta dodat je etil-acetat (50 ml) i smeša je oprana vodom (3 x 30 ml), osušena natrijum-sulfatom, proceđena i uparena. Kao rezultat dobiven je proizvod molekulske težine 457.55 (C25H32FN304); MS (ESI): 458 (M+H+). dried with sodium sulfate, filtered and evaporated. The residue was recrystallized from acetonitrile. The product thus obtained was dissolved in DMF (10 ml) and then sodium hydride (0.24 g) was added. After 15 minutes, methyl iodide (0.71 g) was added under ice cooling. After 15 min, ethyl acetate (50 ml) was added and the mixture was washed with water (3 x 30 ml), dried over sodium sulfate, filtered and evaporated. As a result, a product with a molecular weight of 457.55 (C25H32FN304) was obtained; MS (ESI): 458 (M+H+).

(R)-[1-(2-Fluor-4-metil-amino-fenil)pirolidin-3-il]dimetil-amin Trecijarni butil-estar (R)-{1 -[4-(benzil-oksi-karbonil-metil-amino)-2-fluor-fenil]pirolidin-3-il}metil-karbaminske kiseline je tretiran prema postupku G, a nastali amin je metilovan prema postupku M. Hidrogenizacija je izvedena, na kraju, prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 237.32 (C13H20FN3); MS (ESI): 238 (M+H+). Dimetil-[1-(4-metil-amino-fenil)pirolidin-3-il]amin se može sintetizovati na isti način. (R)-[1-(2-Fluoro-4-methyl-amino-phenyl)pyrrolidin-3-yl]dimethyl-amine Tertiary butyl ester (R)-{1-[4-(benzyl-oxy-carbonyl-methyl-amino)-2-fluoro-phenyl]pyrrolidin-3-yl}methyl-carbamic acid was treated according to procedure G, and the resulting amine was methylated according to procedure M. Hydrogenation was carried out, finally, according to procedure B. As a result, the product molecular weight 237.32 (C13H20FN3); MS (ESI): 238 (M+H+). Dimethyl-[1-(4-methyl-amino-phenyl)pyrrolidin-3-yl]amine can be synthesized in the same way.

2-Dimetil-amino-N-[1-(2-fluor-4-metil-amino-fenil)pirolidin-3-il]-N-metil-acet-amid 2-Dimethyl-amino-N-[1-(2-fluoro-4-methyl-amino-phenyl)pyrrolidin-3-yl]-N-methyl-acet-amide

Tercijarni butil-estar (R)-{1 -[4-(benzil-oksi-karbonil-metil-amino)-2-fluor-fenil]pirolidin-3-il}metil-karbaminske kiseline je tretiran prema postupku G i nastali amin je reagovao sa N,N-dimetil-glicinom prema postupku E. Hidrogenizacija je izvedena, na kraju, prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 308.40 (C16H25FN40); MS (ESI): 309 (M+H+). Tertiary butyl ester (R)-{1-[4-(benzyl-oxy-carbonyl-methyl-amino)-2-fluoro-phenyl]pyrrolidin-3-yl}methyl-carbamic acid was treated according to procedure G and the resulting amine was reacted with N,N-dimethyl-glycine according to procedure E. Hydrogenation was performed, finally, according to procedure B. As a result, a product with a molecular weight of 308.40 (C16H25FN40) was obtained; MS (ESI): 309 (M+H+).

terc.-Butil-(R)-[1-(4-amino-3-fluor-fenil)pirolidin-3-il]metil-karbamat 2,4-Difluor-nitro-benzol je tretiran sa terc-butil- (R)-(+)-pirolidin-3-il-karbamatom, zatim metilovan i, na kraju, hidrigenizovan prema postupku C-b. Kao rezultat dobiven je proizvod molekulske težine 309.39 (C16H24FN302); MS (ESI): 310 (M+H+). tert-Butyl-(R)-[1-(4-amino-3-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate 2,4-Difluoro-nitro-benzene was treated with tert-butyl-(R)-(+)-pyrrolidin-3-yl-carbamate, then methylated and, finally, hydrogenated according to procedure C-b. As a result, a product with a molecular weight of 309.39 (C16H24FN302) was obtained; MS (ESI): 310 (M+H+).

terc.-Butil-[1-(4-amino-naftalen-1-il)pirolidin-3-iljmetil-karbamat Postupak tert-Butyl-[1-(4-amino-naphthalen-1-yl)pyrrolidin-3-ylmethyl-carbamate Procedure

terc.-Butil-metil-pirolidin-3-il-karbamat (1.86 g) je dodat polako u jednu suspenziju 4-fluor-1-nitro-naftalina (1.91 g) i kalijum-karbonata (2.8 g) u DMF - u (10 ml), posle 10 minuta dodat je etil-acetat (50 ml) i smeša je oprana u levku za odvajanje vodom (3 x 50 ml), osušena pomoću natrijum-sulfata, proceđena i uparena. Supstanca je tretirana, dalje, kako je opisano u postupku B. Kao rezultat dobiven je proizvod molekulske težine 341.46 (C20H27N3O2); MS (ESI): 342 (M+H+). tert-Butyl-methyl-pyrrolidin-3-yl-carbamate (1.86 g) was added slowly to a suspension of 4-fluoro-1-nitro-naphthalene (1.91 g) and potassium carbonate (2.8 g) in DMF (10 ml), after 10 min ethyl acetate (50 ml) was added and the mixture was washed in a separatory funnel with water (3 x 50 ml), dried with of sodium sulfate, filtered and evaporated. The substance was further treated as described in procedure B. As a result, a product of molecular weight 341.46 (C20H27N3O2) was obtained; MS (ESI): 342 (M+H+).

terc.-Butil-[1-(4-amino-3-brom-fenil)pirolidin-3-il]metil-karbamat 2-Brom-4-fluor-1-nitro-benzol je tretiran sa terc.-butil- metil-pirolidin-3-il-karbamatom i, posle toga, redukovan prema postupku C-a. Kao rezultat dobiven je proizvod molekulske težine 370.29 (C16H24BrN302); MS (ESI): 370 (M+H+), 372 (M+H+). tert.-Butyl-[1-(4-amino-3-bromo-phenyl)pyrrolidin-3-yl]methyl-carbamate 2-Bromo-4-fluoro-1-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and then reduced according to procedure Ca. As a result, a product with a molecular weight of 370.29 (C16H24BrN302) was obtained; MS (ESI): 370 (M+H + ), 372 (M + H + ).

terc.-Butil-[1-(4-amino-3-cijano-fenil)pirolidin-3-il]metil-karbamat 2-Cijano-4-fluor-1-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga redukovan prema postupku C-a. Kao rezultat dobiven je proizvod molekulske težine 316.41 (C17H24N402); MS (ESI): 317(M+H+). tert.-Butyl-[1-(4-amino-3-cyano-phenyl)pyrrolidin-3-yl]methyl-carbamate 2-Cyano-4-fluoro-1-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and then reduced according to procedure C a. As a result, a product with a molecular weight of 316.41 (C17H24N402) was obtained; MS (ESI): 317 (M+H+).

terc.-Butil-[1-(5-amino-6-hlorpiridin-2-il)pirolidin-3-il]metil-karbamat 2- Hlor-6-fluor-3-nitropiridin je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamat i, posle toga, redukovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 326.83 (C15H23CIN402); MS (ESI): 326 (M+H+), 327 (M+H+). tert.-Butyl-[1-(5-amino-6-chloropyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-6-fluoro-3-nitropyridine was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, reduced according to procedure C-c. As a result, a product with a molecular weight of 326.83 (C15H23CIN402) was obtained; MS (ESI): 326 (M+H+), 327 (M+H+).

terc.-Butil-[1-(4-amino-2,3-difluorfenil)pirolidin-3-il]metil-karbamat 2.3.4- Trifluornitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, redukovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 327.38 (C16H23F2N302); MS (ESI): 328 (M+H+). tert.-Butyl-[1-(4-amino-2,3-difluorophenyl)pyrrolidin-3-yl]methyl-carbamate 2.3.4-Trifluoronitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, reduced according to procedure C-c. As a result, a product with a molecular weight of 327.38 (C16H23F2N302) was obtained; MS (ESI): 328 (M+H+).

terc.-Butil-[1-(4-amino-2-brom-fenil)pirolidin-3-il]metil-karbamat 3- Bromo-4-fluor-1-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, redukovan prema postupku C-a. Kao rezultat dobiven je proizvod molekulske težine 370.29 (C16H24BrN302); MS (ESI): 370 (M+H+), 372 (M+H+). tert.-Butyl-[1-(4-amino-2-bromo-phenyl)pyrrolidin-3-yl]methyl-carbamate 3-Bromo-4-fluoro-1-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and then reduced according to procedure C-a. As a result, a product with a molecular weight of 370.29 (C16H24BrN302) was obtained; MS (ESI): 370 (M+H + ), 372 (M + H + ).

terc.-Butil-[1-(4-amino-2,6-difluofrenil)pirolidin-3-il]metil-karbamat 3.4.5- Trifluor-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il- tert.-Butyl-[1-(4-amino-2,6-difluorophrenyl)pyrrolidin-3-yl]methyl-carbamate 3.4.5- Trifluoro-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-

karbamatom i, posle toga je hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 327.38 (C16H23F2N302); MS (ESI): 328 (M+H+). carbamate and, after that, it is hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 327.38 (C16H23F2N302) was obtained; MS (ESI): 328 (M+H+).

terc.-Butil-(R)-[1-(4-amino-2-hidroksi-metil-fenil)pirolidin-3-il]karbamat (2-Fluor-5-nitro-fenil)metanol je tretiran sa terc.-butil- (R)-(+)-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 307.40 (C16H25N303); MS (ESI): 308 (M+H+). tert-Butyl-(R)-[1-(4-amino-2-hydroxy-methyl-phenyl)pyrrolidin-3-yl]carbamate (2-Fluoro-5-nitro-phenyl)methanol was treated with tert-butyl-(R)-(+)-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 307.40 (C16H25N303) was obtained; MS (ESI): 308 (M+H+).

terc.-Butil-[1-(4-amino-2-hlor-fenil)pirolidin-3-il]metil-karbamat 2- Hlor-1-fluor-4-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 311.81 (C15H22CIN302); MS (ESI): 311 (M+H+), 312 (M+H+). tert.-Butyl-[1-(4-amino-2-chloro-phenyl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-1-fluoro-4-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 311.81 (C15H22CIN302) was obtained; MS (ESI): 311 (M+H + ), 312 (M + H + ).

terc.-Butil-[1-(4-amino-2,5-difluor-fenil)pirolidin-3-il]metil-karbamat 3,4,6-Trifluor-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 327.38 (C16H23F2N302); MS (ESI): 328 (M+H+). tert.-Butyl-[1-(4-amino-2,5-difluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate 3,4,6-Trifluoro-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 327.38 (C16H23F2N302) was obtained; MS (ESI): 328 (M+H+).

terc.-Butil-[1-(4-amino-2-metil-fenil)pirolidin-3-il]metil-karbamat terc.-Butil-4-fluor-3-metil-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3- il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 291.40 (C16H25N302); MS (ESI): 292 (M+H+). tert.-Butyl-[1-(4-amino-2-methyl-phenyl)pyrrolidin-3-yl]methyl-carbamate tert.-Butyl-4-fluoro-3-methyl-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 291.40 (C16H25N302) was obtained; MS (ESI): 292 (M+H+).

terc.-Butil-[1-(4-amino-3-trifluor-metil-fenil)pirolidin-3-il]metil-karbamat 4- Fluor-2-trifluor-metil-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 345.37 (C16H22F3N302); MS (ESI): 346 (M+H+). tert.-Butyl-[1-(4-amino-3-trifluoro-methyl-phenyl)pyrrolidin-3-yl]methyl-carbamate 4-Fluoro-2-trifluoro-methyl-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 345.37 (C16H22F3N302) was obtained; MS (ESI): 346 (M+H+).

terc.-Butil-[1-(4-amino-2-hlor-3-fluor-fenil)pirolidin-3-il]metil-karbamat 2,4-Difluor-3-hlor-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 329.80 (C15H21CIN302); MS (ESI): 329 (M+H+), 330 (M+H+). tert.-Butyl-[1-(4-amino-2-chloro-3-fluoro-phenyl)pyrrolidin-3-yl]methyl-carbamate 2,4-Difluoro-3-chloro-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 329.80 (C15H21CIN302) was obtained; MS (ESI): 329 (M+H+), 330 (M+H+).

terc.-Butil-[1-(4-amino-2-cijano-fenil)pirolidin-3-il]metil-karbamat 3- Cijano-4-fluor-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 302.38 (C16H22N402); MS (ESI): 303 (M+H+). tert.-Butyl-[1-(4-amino-2-cyano-phenyl)pyrrolidin-3-yl]methyl-carbamate 3-Cyano-4-fluoro-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 302.38 (C16H22N402) was obtained; MS (ESI): 303 (M+H+).

terc.-Butil-[1-(4-amino-5-hlor-2-metil-fenil)pirolidin-3-il]metil-karbamat 1- Hlor-5-fluor-4-metil-2-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 325.84 (C16H24CIN302); MS (ESI): 325 (M+H+), 326 (M+H+). tert.-Butyl-[1-(4-amino-5-chloro-2-methyl-phenyl)pyrrolidin-3-yl]methyl-carbamate 1-Chloro-5-fluoro-4-methyl-2-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 325.84 (C16H24CIN302) was obtained; MS (ESI): 325 (M+H + ), 326 (M + H + ).

terc.-Butil-(R)-[1-(5-amino-piridin-2-il)pirolidin-3-il]metil-karbamat 2- Hlor-5-nitro-piridin je tretiran sa terc.-butil- (R)-(+)-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-b. Kao rezultat dobiven je proizvod molekulske težine 322.37 (C16H24FN302); MS (ESI): 323 (M+H+). tert.-Butyl-(R)-[1-(5-amino-pyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-5-nitro-pyridine was treated with tert.-butyl-(R)-(+)-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-b. As a result, a product with a molecular weight of 322.37 (C16H24FN302) was obtained; MS (ESI): 323 (M+H+).

terc.-Butil-[1-(5-amino-piridin-2-il)pirolidin-3-il]metil-karbamat 2-Hlor-5-nitro-piridin je tretiran sa terc.-butil- metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 322.37 (C16H24FN302); MS (ESI): 323 tert.-Butyl-[1-(5-amino-pyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-5-nitro-pyridine was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 322.37 (C16H24FN302) was obtained; MS (ESI): 323

(M+H+). (M+H+).

terc.-Butil-(R)-[1-(4-amino-fenil)pirolidin-3-il]metil-karbamat 4- Fluor-nitro-benzol je tretiran sa terc.-butil- (R)-(+)-pirolidin-3-il- tert.-Butyl-(R)-[1-(4-amino-phenyl)pyrrolidin-3-yl]methyl-carbamate 4-Fluoro-nitro-benzene was treated with tert.-butyl-(R)-(+)-pyrrolidin-3-yl-

karbamatom i, posle toga, hidrogenizovan prema postupku C-b. Kao rezultat dobiven je proizvod molekulske težine 291.40 (C16H25N302); MS (ESI): 292 (M+H+). carbamate and, subsequently, hydrogenated according to procedure C-b. As a result, a product with a molecular weight of 291.40 (C16H25N302) was obtained; MS (ESI): 292 (M+H+).

terc.-Butil-[1-(4-amino-2-trifluor-metil-fenil)pirolidin-3-il]metil-karbamat 4-Fluor-3-trifluor-metil-nitro-benzol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 345.37 (C16H22F3N302); MS (ESI): 346 (M+H+). tert.-Butyl-[1-(4-amino-2-trifluoro-methyl-phenyl)pyrrolidin-3-yl]methyl-carbamate 4-Fluoro-3-trifluoro-methyl-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 345.37 (C16H22F3N302) was obtained; MS (ESI): 346 (M+H+).

terc.-Butil-[1-(5-amino-4-metilpiridin-2-il)pirolidin-3-il]metil-karbamat 2-Hlor-4-metil-5-nitro-piridin je tretiran sa terc.-butil- metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 306.419 (C16H26N402); MS (ESI): 306 (M+H+), 307 (M+H+). tert.-Butyl-[1-(5-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-4-methyl-5-nitro-pyridine was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 306,419 (C16H26N402) was obtained; MS (ESI): 306 (M+H + ), 307 (M + H + ).

terc.-Butil-[1-(5-amino-3-metil-piridin-2-il)pirolidin-3-il]metil-karbamat 2-Hlor-3-metil-5-nitro-piridin je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 306.419 (C16H26N402); MS (ESI): 306 (M+H+), 307 (M+H+). tert.-Butyl-[1-(5-amino-3-methyl-pyridin-2-yl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-3-methyl-5-nitro-pyridine was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 306,419 (C16H26N402) was obtained; MS (ESI): 306 (M+H + ), 307 (M + H + ).

terc.-Butil-[1-(4-amino-2-hidroksi-metil-fenil)pirolidin-3-il]metil-karbamat (2-Fluor-5-nitro-fenil)metanol je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 321.42 (C17H27N303); MS (ESI): 322 (M+H+). tert-Butyl-[1-(4-amino-2-hydroxy-methyl-phenyl)pyrrolidin-3-yl]methyl-carbamate (2-Fluoro-5-nitro-phenyl)methanol was treated with tert-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 321.42 (C17H27N303) was obtained; MS (ESI): 322 (M+H+).

terc.-Butil-[1-(4-amino-3-hlor-2-cijano-fenil)pirolidin-3-il]metil-karbamat 2-Hlor-6-fluor-3-nitro-benzo-nitril je tretiran sa terc.-butil-metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 350.5 (C17H23CIN402); MS (ESI): 350 (M+H+), 351 (M+H+). tert.-Butyl-[1-(4-amino-3-chloro-2-cyano-phenyl)pyrrolidin-3-yl]methyl-carbamate 2-Chloro-6-fluoro-3-nitro-benzo-nitrile was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 350.5 (C17H23CIN402) was obtained; MS (ESI): 350 (M+H + ), 351 (M + H + ).

terc.-Butil-[1-(4-amino-3-metil-fenil)pirolidin-3-il]rnetil-karbamat 4- Fluor-2-metil-nitro-benzol je tretiran sa terc.-butil- metil-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 291.40 (C16H25N302); MS (ESI): 292 (M+H+). tert.-Butyl-[1-(4-amino-3-methyl-phenyl)pyrrolidin-3-yl]rmethyl-carbamate 4-Fluoro-2-methyl-nitro-benzene was treated with tert.-butyl-methyl-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 291.40 (C16H25N302) was obtained; MS (ESI): 292 (M+H+).

terc.-Butil-[1-(5-amino-piridin-2-il)pirolidin-3-iljkarbamat 2-Hlor-5-nitro-piridin je tretiran sa terc.-butil- (R)-(+)-pirolidin-3-il-karbamatom i, posle toga, hidrogenizovan prema postupku C-c. Kao rezultat dobiven je proizvod molekulske težine 278.36 (C14H22N402); MS (ESI): 279 (M+H+). tert.-Butyl-[1-(5-amino-pyridin-2-yl)pyrrolidin-3-ylcarbamate 2-Chloro-5-nitro-pyridine was treated with tert.-butyl-(R)-(+)-pyrrolidin-3-yl-carbamate and, subsequently, hydrogenated according to procedure C-c. As a result, a product with a molecular weight of 278.36 (C14H22N402) was obtained; MS (ESI): 279 (M+H+).

5- (3-Dimetil-amino-pirolidin-1-il)piridin-2-il-amin 5-(3-Dimethyl-amino-pyrrolidin-1-yl)pyridin-2-yl-amine

Suspenzija 5-brom-2-nitro-piridina (2 g), 3-(dimetil-amino)pirolidina (1.149). (R)-(+)2,2'-bis(difenil-fosfino)-1,1'-binaftil (0.5 g), paladijum(ll) acetata (0.09 g), cezijum-karbonata (4.5 g) u toluolu (20 ml) je grejana na100°C 3 sata. Posle hlađenja na sobnu temperaturu izvršena je ekstrakcija sa 1N hlorovodoničnom kiselinom (2 x 100 ml). Vodeni sloj je podešen na pH > 10 pomoću amonijaka, ekstrahovan pomoću etil-acetata (2 x 100 ml), osušen pomoću natrijum-sulfata, proceđen i uparen. Supstanca je, zatim, tretirana prema opisu za postupak B. Kao rezultat dobiven je proizvod molekulske težine 206.29 (C11H18FN4); MS (ESI): 207 (M+H+). Suspension of 5-bromo-2-nitro-pyridine (2 g), 3-(dimethyl-amino)pyrrolidine (1.149). (R)-(+)2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl (0.5 g), palladium(II) acetate (0.09 g), cesium carbonate (4.5 g) in toluene (20 ml) was heated at 100°C for 3 hours. After cooling to room temperature, extraction was performed with 1N hydrochloric acid (2 x 100 ml). The aqueous layer was adjusted to pH > 10 with ammonia, extracted with ethyl acetate (2 x 100 ml), dried with sodium sulfate, filtered and evaporated. The substance was then treated according to the description for procedure B. As a result, a product with a molecular weight of 206.29 (C11H18FN4) was obtained; MS (ESI): 207 (M+H+).

N-[1-(4-Amino-fenil)-4-hidroksi-pirolidin-3-il]-N-metil-acet-amid trans-N-(4-Hidroksi-pirolidin-3-il)-N-metil-acet-amid je reagovao sa 4-fluor-nitro-benzolom prema postupku C i rpoizvod je, zatim, hidrogenizovan prema metodi B. Kao rezultat dobiven je proizvod molekulske težine 249.32 (C13H19N302); MS (ESI): 250 (M+H+). N-[1-(4-Amino-phenyl)-4-hydroxy-pyrrolidin-3-yl]-N-methyl-acet-amide trans-N-(4-Hydroxy-pyrrolidin-3-yl)-N-methyl-acet-amide was reacted with 4-fluoro-nitro-benzene according to method C and the product was then hydrogenated according to method B. As a result, a product with a molecular weight of 249.32 was obtained. (C13H19N302); MS (ESI): 250 (M+H+).

trans-N-(4-Hidroksi-pirolidin-3-il)-N-metil-acet-amid trans-N-(4-Hydroxy-pyrrolidin-3-yl)-N-methyl-acet-amide

terc.-Butil-trans-3-hidroksi-4-metil-amino-pirolidin-1 -karboksilat (1.0 g, tetrahedron: Asymmetry 2001, 12, 2989) je pomešan sa piridinom (1.5 g) i tert-Butyl-trans-3-hydroxy-4-methyl-amino-pyrrolidine-1-carboxylate (1.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was mixed with pyridine (1.5 g) and

anhidridom sirćetne kieline (0.567 g). Posle 3 sata uklonjene su isparljive komponente u visokom vakuumu. Ostatak je tretiran prema postupku G. Kao rezultat dobiven je proizvod molekulske težine 158.20 (C7H14N202); MS (ESI): 159(M+H+). acetic anhydride (0.567 g). After 3 hours, volatile components were removed under high vacuum. The residue was treated according to procedure G. As a result, a product with a molecular weight of 158.20 (C7H14N202) was obtained; MS (ESI): 159 (M+H+).

trans-1-(4-Amino-fenil)-4-dimetil-amino-pirolidin-3-ol terc.-Butil-6-oxa-3-aza-biciklo[3.1,0]heksan-3-karboksilat (2.0 g, tetrahedron: Asymmetry 2001,12, 2989) je mešan sa dimetil-aminom (40% aq., 10 ml) 12 sati. Smeša je uparena i raspoređena između vode i etil-acetata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Sirovi proizvod je tretiran po postupku G. Nastali amin je reagovao sa 4-fluor-nitro-benzolom po postupku C. Nastalo nitro-jedinjenje je hidrogenizovano prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 221 (C12H19N30); MS (ESI): 222 (M+H+). trans-1-(4-Amino-phenyl)-4-dimethyl-amino-pyrrolidin-3-ol tert.-Butyl-6-oxa-3-aza-bicyclo[3.1,0]hexane-3-carboxylate (2.0 g, Tetrahedron: Asymmetry 2001,12, 2989) was stirred with dimethylamine (40% aq., 10 ml) for 12 h. The mixture was evaporated and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The crude product was treated according to procedure G. The resulting amine was reacted with 4-fluoro-nitro-benzene according to procedure C. The resulting nitro compound was hydrogenated according to procedure B. As a result, a product of molecular weight 221 (C12H19N30) was obtained; MS (ESI): 222 (M+H+).

[1-(4-Amino-fenil)-4-metoksi-pirolidin-3-il]dimetil-amin Jedna druga mogućnost za nitro jedinjenje, sintetizovano u prethodnom postupku, je da se alkiluje pomoću metil-jodida prema postupku F i, zatim, hidrogenizuje prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 235 (C13H21N30); MS (ESI): 236 (M+H+). [1-(4-Amino-phenyl)-4-methoxy-pyrrolidin-3-yl]dimethyl-amine Another possibility for the nitro compound, synthesized in the previous procedure, is to alkylate with methyl iodide according to procedure F and, then, hydrogenate according to procedure B. As a result, a product with a molecular weight of 235 (C13H21N30) was obtained; MS (ESI): 236 (M+H+).

[1-(4-Amino-fenil)pirolidin-3-il]dimetil-amin [1-(4-Amino-phenyl)pyrrolidin-3-yl]dimethyl-amine

Dimetil-pirolidin-3-il-amin je reagovao sa 4-fluor-nitro-benzolom prema postupku C iproizvod je,posle toga, hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 205.31 (C12H19N3); MS (ESI): 206 (M+H+). Dimethyl-pyrrolidin-3-yl-amine was reacted with 4-fluoro-nitro-benzene according to procedure C and the product was then hydrogenated according to procedure B. As a result, a product with a molecular weight of 205.31 (C12H19N3) was obtained; MS (ESI): 206 (M+H+).

1-(4-Amino-fenil)-3-dimetil-amino-pirolidin-2-on 1-(4-Amino-phenyl)-3-dimethyl-amino-pyrrolidin-2-one

Trinatrijum-fosfat (3.56 g)je dodat u rastvor 4-nitro-anilina (5.0 g) u aceto-nitrilu (30 ml) i, na 0°C je dodat 2-brom-4-hlor-butiril-bromid (11 g). Posle jednog sata dodat je rastvor natrijum-hidroksida (3.2 g) u vodi (10 ml) i smeša je snažno mešana na sobnoj temperaturi. Posle 6 sati ponovo je dodata ista količina rastvora natrijum-hidroksida i smeša je ostavljena da stoji preko noći. Reakciona smeša je razblažena vodom i ekstrahovana pomoću etil-acetata. Organski sloj je osušen iznad magnezijum sulfata i uparen. Sirovi proizvod (0.5 g) je grejan sa dimetil-aminom (160 mg) u toluolu (20 ml) na 80°C u toku 3 sata. Reakcioni rastvor je razblažen vodom i ekstrahovan pomoću etil-acetata. Organski sloj je osušen iznad magenzijum-sulfata i uparen. Sirovi proizvod je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 219.29 (C12H17N30); MS (ESI): 220 (M+H+). Trisodium phosphate (3.56 g) was added to a solution of 4-nitro-aniline (5.0 g) in acetonitrile (30 ml) and, at 0°C, 2-bromo-4-chloro-butyryl-bromide (11 g) was added. After one hour, a solution of sodium hydroxide (3.2 g) in water (10 ml) was added and the mixture was vigorously stirred at room temperature. After 6 hours, the same amount of sodium hydroxide solution was added again and the mixture was left to stand overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The crude product (0.5 g) was heated with dimethylamine (160 mg) in toluene (20 ml) at 80°C for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The crude product was hydrogenated according to procedure B. As a result, a product with a molecular weight of 219.29 (C12H17N30) was obtained; MS (ESI): 220 (M+H+).

1-(4-Amino-fenil)-3-(7-aza-biciklo[2.2.1]hept-7-il)pirolidin-2-on je dobiven na isti način. 1-(4-Amino-phenyl)-3-(7-aza-bicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one was obtained in the same way.

4-[3-(7-Aza-biciklo[2.2.1]hept-7-il)pirolidin-1-il]fenil-amin 1-(4-Nitro-fenil)-3-(7-aza-biciklo[2.2.1]hept-7-il)pirolidin-2-on (0.25 g) u THF - u (10 ml) pomešano je sa bor - THF kompleksom (1M u THF, 0.83 ml) i zagrevano uz ključanje sa povratnim hladnjakom 3 sata. Pošto se reakcija završila smeša je razblažena vodom i podešena na pH 9-10 pomoću hlorovodonične kiseline (4N). Ekstrakcija pomoću etil-acetta, sušenje i uparavanje organskog sloja dali su jedan sirovi proizvod koji je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 257.38 (C16H23N3); MS (ESI): 258 (M+H+). 4-[3-(7-Aza-bicyclo[2.2.1]hept-7-yl)pyrrolidin-1-yl]phenyl-amine 1-(4-Nitro-phenyl)-3-(7-aza-bicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) in THF (10 ml) was mixed with the boron complex (1M in THF, 0.83 ml) and heated to reflux for 3 hours. After the reaction was completed, the mixture was diluted with water and adjusted to pH 9-10 using hydrochloric acid (4N). Extraction with ethyl acetate, drying and evaporation of the organic layer gave a crude product which was hydrogenated according to procedure B. As a result, a product with a molecular weight of 257.38 (C16H23N3) was obtained; MS (ESI): 258 (M+H+).

(R)-1 '-(4-Amino-fenil)-[1,3']bipirolidin-il-2-on (R)-1'-(4-Amino-phenyl)-[1,3']bipyrrolidin-yl-2-one

terc.-Butil-[1-(4-nitro-fenil)pirolidin-3-il]karbamat je tretiran prema postupku G. Sirovi proizvod (1.4 g)je rastvoren u aceto-nitrilu (20 ml) i pomešan sa trinatrijum - foffatom (0.67 g) i 4-hlor-butiril-hloridom (1.1 g). Posle 2 sata dodat je natrijum hidroksid (0.6 g) u vodi (10 ml) i smeša je snažno mešana. Posle 12 sati ponovo je dodata ista količina rastvora natrijum-hidroksida i smeša je mešana dalje, još 24 sata. Upareni reakcioni rastvor podeljen je između vode i etil-acetata i organski sloj je osušen i uparen. Ostatak je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 245.33 (C14H19N30); MS (ESI): 246 (M+H+). tert-Butyl-[1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate was treated according to procedure G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chloro-butyryl-chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was added again and the mixture was stirred for another 24 hours. The evaporated reaction solution was partitioned between water and ethyl acetate and the organic layer was dried and evaporated. The residue was hydrogenated according to procedure B. As a result, a product with a molecular weight of 245.33 (C14H19N30) was obtained; MS (ESI): 246 (M+H+).

[(R)-1 -(4-Amino-fenil)pirolidin-3-il]metil-amid 1 -metil-piperidin-3- [(R)-1-(4-Amino-phenyl)pyrrolidin-3-yl]methyl-amide 1-methyl-piperidin-3-

karboksilne kiseline carboxylic acids

terc.-Butil-(R)-[1-(4-nitro-fenil)pirolidin-3-il]metil-karbamat je tretiran prema postupku G i reagovan sa 1-metil-piperidin-3-karboksilnom kiselinom prema postupku E. Na kraju je izvršeno i hidrogenizovanje prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 316.45 (C18H28N40); MS (ESI): 317 (M+H+). tert.-Butyl-(R)-[1-(4-nitro-phenyl)pyrrolidin-3-yl]methyl-carbamate was treated according to procedure G and reacted with 1-methyl-piperidine-3-carboxylic acid according to procedure E. Finally, hydrogenation was performed according to procedure E. As a result, a product with a molecular weight of 316.45 (C18H28N40) was obtained; MS (ESI): 317 (M+H+).

(R)-N-[1-(4-Amino-fenil)pirolidin-3-il]-2-dimetil-amino-N-metil-acet-amid je dobiven na isti način koristeći N,N-dimetil-glicin. (R)-N-[1-(4-Amino-phenyl)pyrrolidin-3-yl]-2-dimethyl-amino-N-methyl-acet-amide was obtained in the same way using N,N-dimethyl-glycine.

N-[(R)-1-(4-Amino-fenil)pirolidin-3-il]-N-(2-dietil-amino-etil)acetamid N-(2-Dietil-amino-etil)-N-[(R)-1-(4-nitro-fenil)pirolidin-3-il]acet-amid je hidrogenizovan prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 318.47 (C18H30N4O); MS (ESI): 319 (M+H+). N-[(R)-1-(4-Amino-phenyl)pyrrolidin-3-yl]-N-(2-diethyl-amino-ethyl)acetamide N-(2-Diethyl-amino-ethyl)-N-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]acet-amide was hydrogenated according to procedure B. As a result, a product with a molecular weight of 318.47 (C18H30N4O) was obtained; MS (ESI): 319 (M+H+).

N-(2-Dietil-amino-etil)-N-[(R)-1-(4-nitro-fenil)pirolidin-3-il]acet-amid Acetil-hlorid (2.9 g) je rastvoren u 50 ml suvog dihlor-metana, pomešan je, zatim, sa 5.3 ml trietil-amina i, posle dodavanja N,N-dietil-N'-[(R)-1-(4-nitro-fenil)pirolidin-3-il]-etan-1,2-diamina (5.8 g), reakciona smeša je mešana na sobnoj temperaturi 30 minuta. Posle toga, (LCMS kontrola), u reakcionu smešu je dodata voda (10 ml) i smeša je ekstrahovana pomoću dihlor-metana (2x10 ml). Spojeni organski slojevi su osušeni iznad magnezijum sulfata, rastvarač je uklonjen i sirovi proizvod je razdvojen hromatografijom na stubu silika - gela (dihlor-metan / metanol 10:1). Kao rezultat dobiven je proizvod molekulske težine 348.45 (C18H28N403); MS (ESI): 349 (M+H+). N-(2-Diethyl-amino-ethyl)-N-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]acetamide Acetyl chloride (2.9 g) was dissolved in 50 ml of dry dichloromethane, then mixed with 5.3 ml of triethylamine and, after adding N,N-diethyl-N'-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]-ethane-1,2-diamine (5.8 g), the reaction mixture was stirred at room temperature for 30 minutes. After that, (LCMS control), water (10 ml) was added to the reaction mixture and the mixture was extracted with dichloromethane (2x10 ml). The combined organic layers were dried over magnesium sulfate, the solvent was removed and the crude product was separated by silica gel column chromatography (dichloromethane/methanol 10:1). As a result, a product with a molecular weight of 348.45 (C18H28N403) was obtained; MS (ESI): 349 (M+H+).

N,N-Dietil-N'-[(R)-1-(4-nitro-fenil)pirolidin-3-il]etan-1,2-diamin terc.-Butil-(2-dietil-amino-etil)-[(R)-1-(4-nitro-fenil)pirolidin-3-il]karbamat (7.9 N,N-Diethyl-N'-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]ethane-1,2-diamine tert.-Butyl-(2-diethyl-amino-ethyl)-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate (7.9

g) je reagovao sa trifluor-sirćetnom kiselinom prema metodi G. Kao rezultat dobiven je proizvod molekulske težine 306.41 (C16H26N402); MS (ESI): 307 (M+H+). g) was reacted with trifluoroacetic acid according to method G. As a result, a product with a molecular weight of 306.41 (C16H26N402) was obtained; MS (ESI): 307 (M+H+).

terc.-Butil-(2-dietil-amino-etil)-[(R)-1-(4-nitro-fenil)pirolidin-3-il]karbamat tert-Butyl-(2-diethyl-amino-ethyl)-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate

terc.-Butil-[(R)-1-(4-nitro-fenil)pirolidin-3-il]karbamat (6.0 g) je rastvoren u 50 ml N,N-dimetil-formamida i, posle dodavanja natrijum-hidrida (1.1 g), mešano je na sobnoj temperaturi 30 minuta i, na kraju, dodat je hidro-hlorid hlor-etil-dietil-amin (4.1 g). Smeša je, potom, mešana na sobnoj temperaturi, uz isključivanje prisutva vlage, 4 sata. Reakcija je zaustavljena dodavanjem vode (50 ml) i smeša je, zatim, ekstrahovana pomoću etil-acetata (3 x 50 ml) i organski slojevi su osušeni iznad magnezijum-sulfata i uklonjen je rastvarač. Kao rezultat dobiven je proizvod molekulske težine 406.53 (C21H34N404); MS (ESI): 407 (M+H+). tert-Butyl-[(R)-1-(4-nitro-phenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethyl-formamide and, after addition of sodium hydride (1.1 g), stirred at room temperature for 30 minutes and, finally, chloro-ethyl-diethyl-amine hydrochloride (4.1 g) was added. The mixture was then stirred at room temperature, excluding the presence of moisture, for 4 hours. The reaction was quenched by the addition of water (50 mL) and the mixture was then extracted with ethyl acetate (3 x 50 mL) and the organic layers were dried over magnesium sulfate and the solvent was removed. As a result, a product with a molecular weight of 406.53 (C21H34N404) was obtained; MS (ESI): 407 (M+H+).

[4-(3-Dimetil-amino-pirolidin-1 -il)fenil]amid piperidin-4-karbonske kiseline mono-terc.-Butil-estar piperidin-1,4-dikarbonske kiseline je reagovao sa [1-(4-amino-fenil)pirolidin-3-il]dimeti-aminom prema postupku E i proizvod je, zatim, tretiran prema metodi G. Kao rezultat dobiven je proizvod molekulske težine 316.45 (C18H28N40); MS (ESI): 317 (M+H+). [4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenyl]amide of piperidine-4-carboxylic acid mono-tert.-Butyl ester of piperidine-1,4-dicarboxylic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethylamine according to method E and the product was then treated according to method G. As a result, a product with a molecular weight of 316.45 (C18H28N40) was obtained; MS (ESI): 317 (M+H+).

Sinteze amina potrebnih kao međuproizvodi Synthesis of amines required as intermediates

Spiro[1,3-benzo-dioksol-2,1 '-ciklopentanj-5-amin Spiro[1,3-benzo-dioxol-2,1'-cyclopentane-5-amine

Rastvor spiro[5-nitro-1,3-benzo-dioksol-2,1'-ciklopentan] - a (8.8 g) u metanolu (90 ml) je hidrogenizovano po pritiskom od 6 bara, uz prisustvo paladijuma na uglju (10%, 0.1 g). Posle 30 minuta na sobnoj temperaturi smeša je proceđena i uparena. Kao rezultat dobiven je proizvod molekulske težine 191.23 (C11H13N02); MS(ESI): 192 (M+H+). A solution of spiro[5-nitro-1,3-benzo-dioxole-2,1'-cyclopentane]-a (8.8 g) in methanol (90 ml) was hydrogenated at 6 bar in the presence of palladium on charcoal (10%, 0.1 g). After 30 minutes at room temperature, the mixture was filtered and evaporated. As a result, a product with a molecular weight of 191.23 (C11H13N02) was obtained; MS(ESI): 192 (M+H+).

Spiro[5-nitro-1,3-benzo-dioksol-2,1'-ciklopentan] Spiro[5-nitro-1,3-benzo-dioxole-2,1'-cyclopentane]

Rastvor spiro[1,3-benzodioksol-2,1'-ciklopentan] - a (8.5 g) u 20 ml dihlor-metana dodato je, kap po kap, na 10°C u azotnu kiselinu jačine 65% (65 ml). Posle 2 sata na 5-10°C, smeša je razblažena vodom, organski sloj je odvojen i vodeni sloj je ekstrahovan dva puta pomoću dihlor-metana. Spojeni organski slojevi oprani su vodom do neutralne reakcije, osušeni su iznad natrijum-sulfata, upareni i kristalisani iz heptana. Kao rezultat dobiven je proizvod molekulske težine 221.21 (C11H11N04); MS(ESI): 222 A solution of spiro[1,3-benzodioxole-2,1'-cyclopentane]-a (8.5 g) in 20 ml of dichloromethane was added dropwise at 10°C to 65% strength nitric acid (65 ml). After 2 hours at 5-10°C, the mixture was diluted with water, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water until neutral, dried over sodium sulfate, evaporated and crystallized from heptane. As a result, a product with a molecular weight of 221.21 (C11H11N04) was obtained; MS(ESI): 222

(M+H+). (M+H+).

Spiro[1,3-benzo-dioksol-2,1 '-ciklopentan] Spiro[1,3-benzo-dioxole-2,1 '-cyclopentane]

Katehol (11 g) i ciklopentanon (9 ml) zagrevani su, uz povratni hladnjak i sa jednim nastavkom za hvatanje vode, u toluolu (150 ml) sa p-toluol-sulfonskom kiselinom (0.18 g). Posle 18 sati smeša se upari i prečisti pomoću hromarografije (silika - gel, heptan / etil-acetat 4:1). Kao rezultat dobiven je proizvod molekulske težine 176.22 (C11H1202); MS(ESI): 177 Catechol (11 g) and cyclopentanone (9 ml) were heated, with a reflux condenser and a water trap, in toluene (150 ml) with p-toluenesulfonic acid (0.18 g). After 18 hours, the mixture is evaporated and purified by chromatography (silica gel, heptane/ethyl acetate 4:1). As a result, a product with a molecular weight of 176.22 (C11H1202) was obtained; MS(ESI): 177

(M+H+). (M+H+).

S-Hlor-ž'.a'.S'.e'-tetrahidro-l'H-P^lbipiridin-iM'-ol S-Chloro-x'.a'.S'.e'-Tetrahydro-1'H-P^lbipyridin-iM'-ol

Butil-litijum (15% u heksanu; 7.6 ml)je dodat, kap po kap, ujedan rastvor 2-brom-5-hlor-piridina (2.0 g) u dietil-etru (50 ml) na -78°C i, posle jednog sata, ukapanje rastvor N-terc.-butoksi-karbonil-4-piperidinona (2.1 g) u dietil-etru (10 ml). Posle 30 minuta pažljivo je dodata voda i smeša je ekstrahovana etil-acetatom. Organski sloj je osušen iznad natrijum-sulfata, oceđen i uparen. Ostatak je tretiran prema postupku G. Kao rezultat dobiven je proizvod molekulske težine 212.68 (C10H13CIN2O); MS(ESI): 213(M+H+). Butyllithium (15% in hexane; 7.6 ml) was added dropwise, a solution of 2-bromo-5-chloro-pyridine (2.0 g) in diethyl ether (50 ml) at -78°C and, after one hour, a solution of N-tert.-butoxy-carbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was carefully added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, drained and evaporated. The residue was treated according to procedure G. As a result, a product with a molecular weight of 212.68 (C10H13CIN2O) was obtained; MS(ESI): 213(M+H+).

Sledeća jedinjenja su dobivena na isti način: 5- Fluor-2,,3,,5',6,-tetrahidro-1'H-[2,4,Jbipiridinil-4,-ol The following compounds were obtained in the same way: 5-Fluoro-2,,3,,5',6,-tetrahydro-1'H-[2,4,Jbipyridinyl-4,-ol

6- Hlor-2,,3,l5,,6,-tetrahidro-1,H-[3,4,]bipiriclinil-4,-ol. 6-Chloro-2,,3,15,,6,-tetrahydro-1,H-[3,4,]bipyriclinyl-4,-ol.

6-Ciklo-pentil-oksi-piridin-3-il-amin 6-Cyclo-pentyl-oxy-pyridin-3-yl-amine

Smeša 2-hidroksi-5-nitro-piridina (1.4 g), ciklopentil-bromida (1.5 g) i kalijum-karbonata (3 g) grejana je u DMF - u (20 ml) na 80°C 6 sati. Smeša je razblažena vodom i ekstrahovana pomoću etil-acetata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Ostatak je prečišćen pomoću hromatografije na silika-gelu (mobilna faza: etil-acetat / heptan 1:2). Nitro - jedinjenje koje je dobiveno na ovaj način hidrogenozovano je prema postupku B. Kao rezultat dobiven je proizvod molekulske težine 178.24 (C10H14N2O2); MS(ESI): 179 (M+H+). A mixture of 2-hydroxy-5-nitro-pyridine (1.4 g), cyclopentyl bromide (1.5 g) and potassium carbonate (3 g) was heated in DMF (20 ml) at 80°C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (mobile phase: ethyl acetate / heptane 1:2). The nitro compound obtained in this way was hydrogenated according to procedure B. As a result, a product with a molecular weight of 178.24 (C10H14N2O2) was obtained; MS(ESI): 179 (M+H+).

6-(4-Fluor-fenil)-3-aza-biciklo[4.1.0]heptan 6-(4-Fluoro-phenyl)-3-aza-bicyclo[4.1.0]heptane

Dietil-zink (1M u heksanu, 19 ml) u dihlor-metanu (100 ml) mešanoje sa trifluor-sirćetnom kiselinom (3 ml) na 0°C. Posle 20 minuta dodat je dijod-metan (3 ml) u dihlor-metanu (10 ml). Dodat je, zatim, 4-(4-fluor-fenil)-1,2,3,6-tetrahidro-piridin (3.0 g) u dihlor-metanu (10 ml) i smeša je mešana na sobnoj temperaturi preko noći. Posle dodavanja hlorovodonične kiseline (1N) odvojeni su slojevi i organski sloj je opran vodom, osušen iznad magnezijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine 191.25 (C12H14FN); MS(ESI): 192 (M+H+). Diethylzinc (1M in hexane, 19ml) in dichloromethane (100ml) was stirred with trifluoroacetic acid (3ml) at 0°C. After 20 min, diiodo-methane (3 ml) in dichloromethane (10 ml) was added. 4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (3.0 g) in dichloromethane (10 ml) was then added and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1N), the layers were separated and the organic layer was washed with water, dried over magnesium sulfate and evaporated. As a result, a product with a molecular weight of 191.25 (C12H14FN) was obtained; MS(ESI): 192 (M+H+).

Sinteze karbonskih kiselina potrebnih kao međurproizvodi Synthesis of carboxylic acids needed as intermediate products

4-(4-Metil-piperidin-1 -il)benzoeva kiselina 4-(4-Methyl-piperidin-1-yl)benzoic acid

4-(4-Metil-piperidin1-il)benzo-nitril (1.2 g)je zagrevan sa povratnim hladnjakom 3 sata u prisustvu kalijum-hidroksida (0.7 g) u vodi (2 ml) i etilen-glikola (8 ml). Smeša je razblažena vodom, oprana etil-acetatom i zakišeljena pomoću 2N hlorovodonične kiseline. Istaloženi proizvod je oceđen uz pomoć vakuuma, rastvoren u dihlor-metanu i osušen iznad natrijum-sulfata, uparen i kristalisan iz dietil-etra. Kao rezultat dobiven je proizvod molekulske težine 219.29 (C13H17N02); MS(ESI): 220 (M+H+). 4-(4-Methyl-piperidin-1-yl)benzonitrile (1.2 g) was heated under reflux for 3 hours in the presence of potassium hydroxide (0.7 g) in water (2 ml) and ethylene glycol (8 ml). The mixture was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitated product was drained under vacuum, dissolved in dichloromethane and dried over sodium sulfate, evaporated and crystallized from diethyl ether. As a result, a product with a molecular weight of 219.29 (C13H17N02) was obtained; MS(ESI): 220 (M+H+).

4-(4-Metilpiperidin1-il)benzo-nitril 4-(4-Methylpiperidin-1-yl)benzonitrile

4-Fluor-benzo-nitril (1.21 g) je zagrevan sa 4-metil-piperidinom (1.00 g) na 180°C jedan sat. Smeša je rastvorena u etil-acetatu, oprana vodom, zatim, pomoću 2N rastvora natrijum-hidroksida i zasićenog rastvora natrijum-bikarbonata, osušena, potom, iznad natrijum-sulfata i uparena i kristalisana iz n-pentana. Kao rezultat dobiven je proizvod molekulske težine 200.29 (C13H16N2); MS(ESI): 201 (M+H+). 4-Fluoro-benzo-nitrile (1.21 g) was heated with 4-methyl-piperidine (1.00 g) at 180°C for one hour. The mixture was dissolved in ethyl acetate, washed with water, then with 2N sodium hydroxide solution and saturated sodium bicarbonate solution, then dried over sodium sulfate and evaporated and crystallized from n-pentane. As a result, a product with a molecular weight of 200.29 (C13H16N2) was obtained; MS(ESI): 201 (M+H+).

4-Butoksi-cikloheksan-karbonska kiselina 4-Butoxy-cyclohexane-carboxylic acid

Natrijum-hidrid (2.78 g) je dodat uz hlađenje ledom i pod argonom u jedan rastvor etil-4-hidroksi-ciklokarboksilata (10 g) i butil-jodida (10.6 g) u DMF - u. Posle 12 sati smeša je izlivena na led (200 g), ekstrahovana pomoću etil-acetata (100 ml) i oprana, zatim, vodom (3 x 50 ml). Organski sloj je uparen i pomešan sa etanolom (50 ml) i 5N natrijum-hidroksidom (30 ml). Rastvor je grejan na 60°C 4 sata. Posle hlađenja na sobnu temperaturu pomoću 2N hlorovodonične kiseline podešeno je pH < 2, zatim je ekstrahovano pomoću etil-acetata (3 x 50 ml), osušeno pomoću magnezijum-sulfata, oceđeno i upareno. Kao rezultat dobiven je proizvod molekulske težine 200.28 (C11H20O3); MS (ESI): 201 (M+H+). Sodium hydride (2.78 g) was added under ice-cooling and under argon to a solution of ethyl 4-hydroxycyclocarboxylate (10 g) and butyl iodide (10.6 g) in DMF. After 12 hours, the mixture was poured onto ice (200 g), extracted with ethyl acetate (100 ml) and then washed with water (3 x 50 ml). The organic layer was evaporated and mixed with ethanol (50 ml) and 5N sodium hydroxide (30 ml). The solution was heated at 60°C for 4 hours. After cooling to room temperature with 2N hydrochloric acid, pH < 2 was adjusted, then extracted with ethyl acetate (3 x 50 ml), dried with magnesium sulfate, drained and evaporated. As a result, a product with a molecular weight of 200.28 (C11H20O3) was obtained; MS (ESI): 201 (M+H+).

1 -Benzil-1 H-[1,2,3]triazol-4-karbonska kiselina 1 -Benzyl-1H-[1,2,3]triazole-4-carboxylic acid

Metil-1-benzil-1H-[1,2,3]triazol-4-karboksilat (217 mg) je rastvoren u 4 ml metanola i hidrolizovan pomoću 2 ml 2N rastvora natrijum-hidroksida. Posle zakišeljavanja pomoću 4 ml 2N hlorovodonične kiseline nastali talog je oceđen,rastvoren u 5 ml etil-acetata i prečišćen pomoću preparativne HPLC. Kao rezultat dobiven je proizvod molekulske težine 203.2 (C10H9N3O2); MS (ESI): 204 (M+H+). Methyl 1-benzyl-1H-[1,2,3]triazole-4-carboxylate (217 mg) was dissolved in 4 ml of methanol and hydrolyzed with 2 ml of 2N sodium hydroxide solution. After acidification with 4 ml of 2N hydrochloric acid, the resulting precipitate was drained, dissolved in 5 ml of ethyl acetate and purified by preparative HPLC. As a result, a product with a molecular weight of 203.2 (C10H9N3O2) was obtained; MS (ESI): 204 (M+H+).

Metil-1 -benzil-1 H-[1,2,3]triazol-4-karboksilat Methyl-1-benzyl-1H-[1,2,3]triazole-4-carboxylate

Benzil-azid (266 mg) je rastvoren zajedno sa natrijumom-askorbatom (20 Benzyl azide (266 mg) was dissolved together with sodium ascorbate (20

mg) i bakar-sulfatom (5 mg) u 8 ml jedne smeše rastvarača (terc.-butanol / voda 3:1), i dodat je metil-propionat (336 mg). Rastor je mešan na sobnoj temperaturi dva sata. Pri tome se izdvojio beli talog koji je oceđen na jednoj friti uz pomoć vakuuma i, na kraju osušen. Kao rezultat dobiven je proizvod molekulske težine 217.23 (C11H11N302); MS (ESI): 218 (M+H+). 1-Bifenil-4-il-1H-[1,2,3]triazol-4-karbonska kiselina sintetizovana je na isti način iz 4-etinil-bifenila i etil-azido-acetata. mg) and copper sulfate (5 mg) in 8 ml of a solvent mixture (tert.-butanol / water 3:1), and methyl propionate (336 mg) was added. The slurry was stirred at room temperature for two hours. In doing so, a white precipitate was separated, which was drained on a frit with the help of a vacuum and finally dried. As a result, a product with a molecular weight of 217.23 (C11H11N302) was obtained; MS (ESI): 218 (M+H+). 1-Biphenyl-4-yl-1H-[1,2,3]triazole-4-carboxylic acid was synthesized in the same way from 4-ethynyl-biphenyl and ethyl-azido-acetate.

1 -Butil-1 H-indol-5-karbonska kiselina 1 -Butyl-1H-indole-5-carboxylic acid

Natrijum-hidrid (50% u ulju, 1.4 g) je dodat u metil-1 H-indol-5-karboksilat (5.0 g) u DMF - u (100 ml) i, posle prestanka razvijanja gasa, dodat je brom-butan (3.9 g). Posle 12 sati reakcioni rastvor je razblažen pomoću etil-acetata i opran tri puta vodom. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Ostatak je prečišćen pomoću hromatografije na stubu silika-gela (mobilna faza: etil-acetat / heptane 1:6). Nastali estar je rastvoren u metanolu (10 ml) i zagrevan, uz ključanje sa povratnim hladnjakom, sa natrijum-hidroksidom (0.6 g ) u vodi (10 ml) 12 sati. Smeša je razblažena vodom i zakišeljena pomoću hlorovodonične kiseline, a onda ekstrahovana pomoću etil-acetata. Organski sloj je osušen iznad magenzijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine 217.27 (C13H15N02); MS (ESI): 218 (M+H+). Sodium hydride (50% in oil, 1.4 g) was added to methyl 1 H -indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution had ceased, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / heptanes 1:6). The resulting ester was dissolved in methanol (10 ml) and heated under reflux with sodium hydroxide (0.6 g) in water (10 ml) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. As a result, a product with a molecular weight of 217.27 (C13H15N02) was obtained; MS (ESI): 218 (M+H+).

3'-Acetil-amino-bifenil-4-karbonska kiselina 3'-Acetyl-amino-biphenyl-4-carboxylic acid

3'-Amino-bifenil-4-karbonska kiselina (0.2 g)je pomešana sa piridinom (0.7 3'-Amino-biphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7

g) i anhidridom sirćetne kiseline (180 mg) i, posle 14 sati, uklonjene su isparljive frakcije. Ostatak je rastvoren u rastvoru natrijum-hidroksida (2N) i g) and acetic anhydride (180 mg) and, after 14 hours, the volatile fractions were removed. The residue was dissolved in sodium hydroxide solution (2N) and

opran pomoću dietil-etra. Vodeni sloj je zakišeljen pomoću hlorovodonične kiseline i ekstrahovan etil-acetatom. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine 255.28 (C15H13N03); MS (ESI): 256 (M+H+). washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. As a result, a product with a molecular weight of 255.28 (C15H13N03) was obtained; MS (ESI): 256 (M+H+).

3'-lzobutiril-amino-bifenil-4-karbonska kiselina 3'-isobutyryl-amino-biphenyl-4-carboxylic acid

3'-Amino-bifenil-4-karbonska kiselina (0.2 g) pomešana je u dihlor-metanu sa kalijum-karbonatom (121 mg) i izobutiril-hloridom (94 mg). Posle 12 sati smeša je razblažena pomoću rastvora natrijum-hidroksida i oprana dietil-etrom. Vodeni sloj je zakišeljen pomoću hlorovodonične kiseline i ekstrahovan pomoću etil-acetata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Kao rezultat dobiven je proizvod molekulske težine 283.33 (C17H17N03); MS (ESI): 284 (M+H+). 3'-Amino-biphenyl-4-carboxylic acid (0.2 g) was mixed in dichloromethane with potassium carbonate (121 mg) and isobutyryl chloride (94 mg). After 12 hours, the mixture was diluted with sodium hydroxide solution and washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. As a result, a product with a molecular weight of 283.33 (C17H17N03) was obtained; MS (ESI): 284 (M+H+).

5-Butoksi-piridin-2-karbonska kiselina 5-Butoxy-pyridine-2-carboxylic acid

Natrijum-hidrid (50% u ulju, 250 mg) je dodat u benz-hidril-5-hidroksi-piridin-2-karboksilat (2.0 g) u DMF - u (20 ml) i, posle prestanka razvijanja gasa, dodat je 1-brom-butan (0,72 g). Smeša je grejana na 90° C 6 sati. Smeša je, zatim, razblažena vodom i ekstrahovana pomoću etil-acetata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Ostatak je hidrogenizovan na isti način kao u postupku B. Kao rezultat dobiven je proizvod molekulske težine 195.22 (C10H13NO3); MS (ESI): 196 (M+H+). Sodium hydride (50% in oil, 250 mg) was added to benz-hydryl-5-hydroxy-pyridine-2-carboxylate (2.0 g) in DMF (20 ml) and, after gas evolution had ceased, 1-bromo-butane (0.72 g) was added. The mixture was heated at 90°C for 6 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was hydrogenated in the same way as in procedure B. As a result, a product with a molecular weight of 195.22 (C10H13NO3) was obtained; MS (ESI): 196 (M+H+).

4-Metil-3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-6,-karbonska kiselina Benzhidril-5-trifluor-metan-sulfonil-oksi-piridin-2-karboksilat (3.0 g) je grejan sa 4-metil-piperidinom (1.4 g) na 80°C jedan sat. Reakciona smeša je odmah prečišćena pomoću preparativne HPLC i, zatim, hidrogenizovana na isti našin kao u postupku B. Kao rezultat dobiven je proizvod molekulske težine 220.27 (C12H16N202); MS (ESI): 221 (M+H+). 4-Methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6,-carboxylic acid Benzhydryl-5-trifluoromethanesulfonyl-oxy-pyridine-2-carboxylate (3.0 g) was heated with 4-methyl-piperidine (1.4 g) at 80°C for one hour. The reaction mixture was immediately purified by preparative HPLC and then hydrogenated in the same manner as in procedure B. As a result, a product with a molecular weight of 220.27 (C12H16N202) was obtained; MS (ESI): 221 (M+H+).

N-[4-(3-Dimetil-amino-pirolidin-1-il)feniljtereftalaminska kiselina N-[4-(3-Dimethyl-amino-pyrrolidin-1-yl)phenylterephthalamic acid

Postupak P-a P's procedure

Metil-estar N-[4-(3-dimetil-amino-pirolidin-1 -il)fenil]tereftalaminske kiseline (1.7 g) rastvoren je u metanolu (20 ml) i sve je mešano sa rastvorom natrijum-hidriksida (2N, 15 ml) na sobnoj temperaturi u toku 24 sata. Ako konverzija nije potpuna moguće je smešu zagrevati sa povratnim hladnjakom. Organski rastvarač je odestilisan i smeša je zakišeljena pomoću hlorovodonične kiseline. Talog koji se izdvojio je oceđen uz pomoć vakuuma i osušen. Kao rezultat dobiven je proizvod molekulske težine 353.42 (C20H23N3O3); MS (ESI): 354 (M+H+). N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester (1.7 g) was dissolved in methanol (20 ml) and mixed with sodium hydroxide solution (2N, 15 ml) at room temperature for 24 hours. If the conversion is not complete, it is possible to heat the mixture with a reflux condenser. The organic solvent was distilled off and the mixture was acidified with hydrochloric acid. The precipitate that separated was drained under vacuum and dried. As a result, a product with a molecular weight of 353.42 (C20H23N3O3) was obtained; MS (ESI): 354 (M+H+).

Metil-estar N-[4-(3-dimetil-amino-pirolidin-1 -il)fenil]tereftalaminske kiseline [1-(4-Amino-fenil)pirolidin-3-il]dimetil-amin je reagovao sa mono-metil-estrom tereftalne kiseline prema postupku E. Kao rezultat dobiven je proizvod molekulske težine 367.45 (C21H25N303); MS (ESI): 368 (M+H+). N-[4-(3-dimethyl-amino-pyrrolidin-1-yl)phenyl]terephthalamic acid methyl ester [1-(4-Amino-phenyl)pyrrolidin-3-yl]dimethyl-amine was reacted with terephthalic acid mono-methyl ester according to procedure E. As a result, a product with a molecular weight of 367.45 (C21H25N303) was obtained; MS (ESI): 368 (M+H+).

4-(Ciklopentan-karbonil-metil-amino)benzoeva kiselina Metil-4-metil-amino-benzoat je reagovao sa ciklopentan-karbonskom kiselinom prema postupku E i, onda je hidrolizovan prema postupku P-a. Kao rezultat dobiven je proizvod molekulske težine 247.30 (C14H17N03); MS (ESI): 248 (M+H+). 4-(Cyclopentane-carbonyl-methyl-amino)benzoic acid Methyl-4-methyl-amino-benzoate was reacted with cyclopentane-carboxylic acid according to procedure E and then hydrolyzed according to procedure P-a. As a result, a product with a molecular weight of 247.30 (C14H17N03) was obtained; MS (ESI): 248 (M+H+).

Sledeća jedinjenja dobivena su na isti način: 4-(Ciklopentan-karbonil-amino)-3-metoksi-benzoeva kiselina 2-Hlor-4-(ciklopentan-karbonil-amino)benzoeva kiselina 2- Fluor-4-(ciklopentan-karbonil-amino)benzoeva kiselina 4-(Ciklopentan-karbonil-amino)-3-metil-benzoeva kiselina 4-(Ciklopentan-karbonil-amino)benzoeva kiselina The following compounds were obtained in the same way: 4-(Cyclopentane-carbonyl-amino)-3-methoxy-benzoic acid 2-Chloro-4-(cyclopentane-carbonyl-amino)benzoic acid 2-Fluoro-4-(cyclopentane-carbonyl-amino)benzoic acid 4-(Cyclopentane-carbonyl-amino)-3-methyl-benzoic acid 4-(Cyclopentane-carbonyl-amino)benzoic acid

4- (Ciklopentan-karbonil-amino)-3-trifluor-metoksi-benzoeva kiselina 3- Hlor-4-(ciklopentan-karbonil-amino)benzoeva kiselina 5- Hlor-4-(ciklopentan-karbonil-amino)-2-metoksi-benzoeva kiselina 4- [(Cikloheks-1 -en-karbonil)amino]benzoeva kiselina 4-[(Ciklopent-1 -en-karbonil)amino]benzoeva kiselina 4- (Cyclopentane-carbonyl-amino)-3-trifluoro-methoxy-benzoic acid 3- Chloro-4-(cyclopentane-carbonyl-amino)benzoic acid 5- Chloro-4-(cyclopentane-carbonyl-amino)-2-methoxy-benzoic acid 4- [(Cyclohex-1-ene-carbonyl)amino]benzoic acid 4-[(Cyclopent-1-ene-carbonyl)amino]benzoic acid

3-Fluor-4-(1-metil/butoksi)benzoeva kiselina 3-Fluoro-4-(1-methyl/butoxy)benzoic acid

Rastvor 0.449 g 1-[3-fluor-4-(1-metil-butoksi)fenil]etanona u 6.8 ml dioksana dodato je kap po kap u 1.36 g NaOH, 1.6 g broma u 6.8 ml vode. Smeša je mešana na sobnoj temperaturi 30 minuta i, zatim, grejana na 50°C u toku jednog sata. Višak broma je razložen dodavanjem rastvora natrijum-disulfida i rastvor je, posle toga, sipan u hlorovodoničnu kiselinu jačine 25 % mešan u toku 20 minuta. Rastvor je ekstrahovan pomoću etil-acetata. Spojeni organski slojevi su osušeni iznad natrijum-sulfata, upareni u vakuumu i prečišćeni pomoću preparativne HPLC. Kao rezultat dobiven je proizvod molekulske težine 226.1 (C12H15F03); MS (ESI): 227 (M+H+). A solution of 0.449 g of 1-[3-fluoro-4-(1-methyl-butoxy)phenyl]ethanone in 6.8 ml of dioxane was added dropwise to 1.36 g of NaOH, 1.6 g of bromine in 6.8 ml of water. The mixture was stirred at room temperature for 30 minutes and then heated to 50°C for one hour. The excess bromine was decomposed by adding sodium disulfide solution and the solution was then poured into 25% hydrochloric acid and stirred for 20 minutes. The solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated in vacuo and purified by preparative HPLC. As a result, a product with a molecular weight of 226.1 (C12H15F03) was obtained; MS (ESI): 227 (M+H+).

1 -[3-Fluor-4-(1 -metil-butoksi)fenil]etanon 1-[3-Fluoro-4-(1-methyl-butoxy)phenyl]ethanone

0.058 g NaH je dodato u jedan rastvor 0.176 g 2-pentanola u 2 ml DMF - a, i rastvor je mešan na sobnoj temperaturi u toku jednog sata. Onda je dodato 0.312 g 3,4-difluor-acetofenona i smeša je mešana na sobnoj temperaturi preko noći. Reakcioni rastvor je rastvoren u etil-acetatu i opran dva puta vodom. Organski sloj je osušen iznad natrijum-sulfata i uparen u vakuumu. Nastalo jedinjenje je učestvovalo u reakcijama bez daljeg prečišćavanja. 0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml of DMF, and the solution was stirred at room temperature for one hour. Then 0.312 g of 3,4-difluoro-acetophenone was added and the mixture was stirred at room temperature overnight. The reaction solution was dissolved in ethyl acetate and washed twice with water. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting compound participated in the reactions without further purification.

Sledeća jedinjenja su dobivena na isti način: 4-Cyclobutoksi-3-fluorbenzoeva kiselina 3- Fluor-4-(2-metil-ciklo-propil-metoksi)benzoeva kiselina 4- (2-Ciklopropil-etoksi)-3-fluor-benzoeva kiselina The following compounds were obtained in the same way: 4-Cyclobutoxy-3-fluorobenzoic acid 3-Fluoro-4-(2-methyl-cyclo-propyl-methoxy)benzoic acid 4-(2-Cyclopropyl-ethoxy)-3-fluoro-benzoic acid

3- Fluor-4-(1 -metil-piperidin-3-il-oksi)benzoeva kiselina 4- (1-Acetil-piperidin-3-il-oksi)-3-fluor-benzoeva kiselina 3- Fluor-4-(1-metil-pirolidin-3-il-oksi)benzoeva kiselina 4- (1-Acetil-pirolidin-3-il-oksi)-3-fluor-benzoeva kiselina 3- Fluor-4-(1 -metil-piperidin-3-il-metoksi)benzoeva kiselina 3- Fluoro-4-(1 -methyl-piperidin-3-yl-oxy)benzoic acid 4- (1-Acetyl-piperidin-3-yl-oxy)-3-fluoro-benzoic acid 3- Fluoro-4-(1-methyl-pyrrolidin-3-yl-oxy)benzoic acid 4- (1-Acetyl-pyrrolidin-3-yl-oxy)-3-fluoro-benzoic acid 3- Fluoro-4-(1 -methyl-piperidin-3-yl-methoxy)benzoic acid

4- (2,4-Difluor-fenoksi)benzoeva kiselina 4-(2,4-Difluoro-phenoxy)benzoic acid

U jedan rastvor od 0.428 g etil-4-(2,4-difluor-fenoksi)benzoata u 2 ml THF / voda (1:1) dodato je 0.518 g kalijum-hidroksida. Rastvor je grejan na 110°C u toku 6 sati. U vakuumu je, onda, uklonjen THF i vodeni sloj je osušen u smrznutom stanju i prečišćen pomoću preparativne HPLC. Kao rezultat dobiven je proizvod molekulske težine 250.04 (C13H8F203); MS (ESI): 251 (M+H+). 0.518 g of potassium hydroxide was added to a solution of 0.428 g of ethyl-4-(2,4-difluoro-phenoxy)benzoate in 2 ml of THF/water (1:1). The solution was heated to 110°C for 6 hours. THF was then removed in vacuo and the aqueous layer was freeze-dried and purified by preparative HPLC. As a result, a product with a molecular weight of 250.04 (C13H8F203) was obtained; MS (ESI): 251 (M+H+).

Etil-4-(2,4-difluor-fenoksi)benzoat Ethyl 4-(2,4-difluorophenoxy)benzoate

U rastvor 0.1 g 2,4-difluor-fenola u 0.5 ml DMF - a dodato je 0.018 g NaH. Reakciona smeša je mešana na sobnoj temperaturi u toku 45 minuta. Onda je ukapano 0.129 g etil-4-fluor-benzoata u 0.5 ml DMF - a. Reakcijona smeša je grejana na 110°C preko noći. Posle hlađenja upareno je u vakuumu i ostatak je rastvoren u smeši etil-acetat / voda. Etil-acetatni sloj je opran tri puta vodom, osušen iznad natrijum-sulfata, uparen u vakuumu i prečišćen pomoću preparativne HPLC. Kao rezultat dobiven je proizvod molekulske težine 278.08 (C15H12F203); MS (ESI): 279 (M+H+) 0.018 g of NaH was added to a solution of 0.1 g of 2,4-difluorophenol in 0.5 ml of DMF. The reaction mixture was stirred at room temperature for 45 minutes. Then 0.129 g of ethyl-4-fluoro-benzoate was added dropwise in 0.5 ml of DMF. The reaction mixture was heated at 110°C overnight. After cooling, it was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate/water. The ethyl acetate layer was washed three times with water, dried over sodium sulfate, evaporated in vacuo and purified by preparative HPLC. As a result, a product with a molecular weight of 278.08 (C15H12F203) was obtained; MS (ESI): 279 (M+H+)

4-(2,4-Difluor-fenoksi)benzoeva kiselina je reagovala sa [1-(4-amino-fenil)pirolidin-3-il]-dimetil-aminom prema postupku E-b. Kao rezultat dobiven je proizvod molekulske težine 437.19 (C25H25F2N302); MS (ESI): 438 (M+H+) kao hidro-trifluor-acetat. 4-(2,4-Difluoro-phenoxy)benzoic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]-dimethyl-amine according to procedure E-b. As a result, a product with a molecular weight of 437.19 (C25H25F2N302) was obtained; MS (ESI): 438 (M+H+) as hydrotrifluoroacetate.

4-Butoksi-3-metoksi-benzoeva kiselina 4-Butoxy-3-methoxy-benzoic acid

Metil-4-hidroksi-3-metoksi-benzoat je alkilovan pomoću brom-butana prema postupku H i, zatim, hidrolizovan prema postupku P-a. Kao rezultat dobiven je proizvod molekulske težine 224.26 (C12H1604); MS (ESI): 225 Methyl-4-hydroxy-3-methoxy-benzoate was alkylated with bromobutane according to procedure H and then hydrolyzed according to procedure P-a. As a result, a product with a molecular weight of 224.26 (C12H1604) was obtained; MS (ESI): 225

(M+H+). (M+H+).

Sledeća jedinjenja su dobivena na isti način: 4-Butoksi-3,5-dihlorbenzoeva kiselina The following compounds were obtained in the same way: 4-Butoxy-3,5-dichlorobenzoic acid

4-Butoksi-3-nitro-benzoeva kiselina 4-Butoxy-3-nitro-benzoic acid

4-Butoksi-3-hlor-benzoeva kiselina 4-Butoxy-3-chloro-benzoic acid

4-Butoksi-3,5-dimetil-benzoeva kiselina 4-Butoxy-3,5-dimethyl-benzoic acid

4-Butoksi-2,3-dihlor-5-metoksi-benzoeva kiselina 4-Butoxy-2,3-dichloro-5-methoxy-benzoic acid

4-Butoksi-2,3,5,6-tetrafluor-benzoeva kiselina 4-Butoxy-2,3,5,6-tetrafluoro-benzoic acid

4-Butoksi-3-fluor-benzoeva kiselina 4-Butoxy-3-fluoro-benzoic acid

3- Acetil-4-butoksi-benzoeva kiselina 3- Acetyl-4-butoxy-benzoic acid

2,4-Di-butoksi-benzoeva kiselina 2,4-Di-butoxy-benzoic acid

4- Butoksi-2-hlor-benzoeva kiselina 4- Butoxy-2-chloro-benzoic acid

4-Propoksi-metil-benzoeva kiselina 4-Propoxy-methyl-benzoic acid

Natrijum hidrid (50% u ulju; 0.42 g) je pažljivo dodan u jedan rastvor propanola (0.6 g) u DMF - u (8 ml). Posle završetka razvijanja gasa dodat je metil-4-brom-metil-benzoat (1.0 g). Posle 4 sata smeša je razdeljena između vode i etil-acetata. Organski sloj je osušen iznad magnezijum-sulfata i uparen. Ostatak je hidrolizovan prema postupku P-a. Kao rezultat dobiven je proizvod molekulske težine 194.23 (C11H1403); MS (ESI): 195 Sodium hydride (50% in oil; 0.42 g) was carefully added to a solution of propanol (0.6 g) in DMF (8 ml). After gas evolution was complete, methyl-4-bromo-methyl-benzoate (1.0 g) was added. After 4 hours the mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was hydrolyzed according to the procedure of P. As a result, a product with a molecular weight of 194.23 (C11H1403) was obtained; MS (ESI): 195

(M+H+). (M+H+).

Sledeća jedinjenja su dobivena na isti način: 4-Ethoksi-metil-benzoeva kiselina The following compounds were obtained in the same way: 4-Ethoxy-methyl-benzoic acid

4-Butoksi-metil-benzoeva kiselina 4-Butoxy-methyl-benzoic acid

4-lzo-Butoksi-metil-benzoeva kiselina 4-liso-Butoxy-methyl-benzoic acid

4-Fenoksi-metil-benzoeva kiselina 4-Phenoxy-methyl-benzoic acid

4-(Piridin-3-il-oksi-metil)benzoeva kiselina 4-(Pyridin-3-yl-oxy-methyl)benzoic acid

4-(Piridin-2-il-oksi-metil)benzoeva kiselina 4-(Pyridin-2-yl-oxy-methyl)benzoic acid

4-Benzo-imidazol-1 -il-metil-benzoeva kiselina 4-Benzo-imidazol-1-yl-methyl-benzoic acid

4-lndol-1 -il-metil-benzoeva kiselina 4-lndol-1-yl-methyl-benzoic acid

4-Fenil-sulfanil-metil-benzoeva kiselina 4-Phenyl-sulfanyl-methyl-benzoic acid

4-(Pirimidin-2-il-sulfanil-metil)benzoeva kiselina 4-(Pyrimidine-2-yl-sulfanyl-methyl)benzoic acid

4-(Piridin-2-il-sulfanil-metil)benzoeva kiselina 4-(Pyridin-2-yl-sulfanyl-methyl)benzoic acid

4-(2-Cijano-fenoksi-metil)benzoeva kiselina 4-(2-Cyano-phenoxy-methyl)benzoic acid

4-(2-Hlor-fenoksi-metil)benzoeva kiselina 4-(2-Chloro-phenoxy-methyl)benzoic acid

4-Ciklo-butoksi-metil-benzoeva kiselina 4-Cyclo-butoxy-methyl-benzoic acid

4-Ciklo-pentil-oksi-metil-benzoeva kiselina 4-Cyclo-pentyl-oxy-methyl-benzoic acid

4-Ciklo-heksil-oksi-metil-benzoeva kiselina 4-Cyclo-hexyl-oxy-methyl-benzoic acid

4-sec-Butoksi-metil-benzoeva kiselina 4-sec-Butoxy-methyl-benzoic acid

4-Pentoksi-metil-benzoeva kiselina 4-Pentoxy-methyl-benzoic acid

4-(3-Oks-3a,4,5,6-tetrahidro-3H-ciklopenta-pirazol-2-il)benzoeva kiselina Rastvor 4-hidrazino-benzoeve kiseline (0.3 g), etil-2-okso-ciklopentan-karboksilata (0.31 g) i p-toluol-sulfonske kiseline (340 mg) u etanolu (12 ml) zagrevan je uz ključanje sa povratnim hladnjakom u toku 12 sati. Upareni reakcioni rastvor je prečišćen pomoću preparativne HPLC. Izolovani reakcioni proizvod (kao etil-estar) hidrolizovan je prema postupku P-a. Kao rezultat dobiven je proizvod molekulske težine 244.25 (C13H12N203); MS (ESI): 245 (M+H+). 4-(3-Ox-3a,4,5,6-tetrahydro-3H-cyclopenta-pyrazol-2-yl)benzoic acid A solution of 4-hydrazino-benzoic acid (0.3 g), ethyl-2-oxo-cyclopentane-carboxylate (0.31 g) and p-toluene-sulfonic acid (340 mg) in ethanol (12 ml) was heated under reflux for 12 hours. The evaporated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was hydrolyzed according to procedure P. As a result, a product with a molecular weight of 244.25 (C13H12N203) was obtained; MS (ESI): 245 (M+H+).

4-Butoksi-2-metoksi-benzoeva kiselina 4-Butoxy-2-methoxy-benzoic acid

4-Hidroksi-2-metoksi-benzaldehid je alkilovan pomoću 1-brom-butana prema postupku H. Nastali aldehid (6.4 g), u dioksanu (100 ml), mešan je sa natrijum-dihidrogen-fosfatom (14.4 g) i sumpornom kiselinom (2.4 ml) i 4-Hydroxy-2-methoxy-benzaldehyde was alkylated with 1-bromo-butane according to procedure H. The resulting aldehyde (6.4 g), in dioxane (100 ml), was mixed with sodium dihydrogen phosphate (14.4 g) and sulfuric acid (2.4 ml) and

rastvor je, zatim, ohlađen na 10°C. Jedan rastvor natrijum-hlorita (3.61 g) u vodi (100 ml) je dodat na takav način da temperatura ne pređe 10°C. Pošto je prošlo 15 minuta od završetka dodavanja, dodat je natrijum-sulfit (4.6 g). Posle daljnih 15 minuta podesi se pH na vrednost 2, pomoću the solution was then cooled to 10°C. One solution of sodium chlorite (3.61 g) in water (100 ml) was added in such a way that the temperature did not exceed 10°C. After 15 minutes had passed since the addition was complete, sodium sulfite (4.6 g) was added. After another 15 minutes, adjust the pH to a value of 2, using

hlorovodonične kiseline i dioksan se ukloni u rotacionom uparivaču. Vodeni sloj se ekstrahuje pomoću etil-actata. Organski sloj se suši iznad magnezijum-sulfata, procedi se i upari. Ostatak se prečisti pomoću of hydrochloric acid and the dioxane is removed in a rotary evaporator. The aqueous layer is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The residue is purified using

preparativne HPLC. Kao rezultat dobiven je proizvod molekulske težine 224.26 (C12H1604); MS (ESI): 225 (M+H+). preparative HPLC. As a result, a product with a molecular weight of 224.26 (C12H1604) was obtained; MS (ESI): 225 (M+H+).

4-Butoksi-5-hlor-2-metoksi-benzoeva kiselina je dobivena kao sporedni proizod. 4-Butoxy-5-chloro-2-methoxy-benzoic acid was obtained as a side product.

4-(1-Propoksi-etil)benzoeva kiselina 4-(1-Propoxy-ethyl)benzoic acid

Metil-4-(1-hidroksi-etil)benzoat (2.0 g) rastvoren u DMF - u (30 ml) je mešan sa propil-jodidom (3.8 g) i dodat je, zatim, natrijum-hidrid (50% u ulju, 0.53 g). Po završetku ekzotermne reakcije smeša se meša u toku jednog sata i, zatim, se doda pažljivo voda. Sve se ekstrahuje pomoću etil-acetata i organski sloj se suši iznad natrijum-sulfata, procedi i upari. Ostatak se hidrolizuje prema postupku P-a. Kao rezultat dobiven je proizvod molekulske težine 208.26 (C12H1603); MS (ESI): 209 (M+H+). Methyl 4-(1-hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) was mixed with propyl iodide (3.8 g) and then sodium hydride (50% in oil, 0.53 g) was added. After the end of the exothermic reaction, the mixture is stirred for one hour and then water is carefully added. Everything is extracted with ethyl acetate and the organic layer is dried over sodium sulfate, filtered and evaporated. The residue is hydrolyzed according to the procedure of P. As a result, a product with a molecular weight of 208.26 (C12H1603) was obtained; MS (ESI): 209 (M+H+).

Claims (20)

1. Jedinjenja formule I u kojoj oznake znače R1, R2 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, -(CR78R79)0-R12, -(CH2)0-R12, (Ci-C4)-alkoksi-(Ci-C4)-alkil, ariloksi-(Ci-C4)-alkil, (C3-C8)-alkenil, (C3-Cs)-alkinil, CO-(Ci-C8)-alkil, -CO-(CH2)0-R12, CO-ariloksi-(Ci-C4)-alkil, CO-(C2-C8)-alkenil, CO-(C2-C8)-alkinil, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkil-S(0)p-(Ci-C4)-alkil, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa atomom azota, sa kojim su vezani, neki 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, odvojeno od azotovog atoma, može da sadrži 0 do 4 dodata hetero-atoma uzetih iz grupe kiseonika, azota i sumpora, gde heterociklični prsten može biti dodatno supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(C1-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, hidroksi-(Ci-C4)-alkil, (Co-Ca)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(Ci-C6)-alkil, N(R31)(R32) ili S02CH3; o 0,1,2,3,4,5,6; p 0,1,2 q, r, s nezavisno jedan od drugog 0, 1, 2, 3, 4; R13, R14 nezavisno jedan od drugog, jedan 5 -10-to člani aromatični sistem prstena koji može da sadrži 0 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisani sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 nezavisno jedan od drugog, H, (Ci-C6)-alkil; R18 H, (Ci-C6)-alkil, CO(Ci-C6)-alkil, CO(R33); ili R17 i R18, R21 i R22, R27 i R28, R31 i R32 nezavisno jedan od drugog, najpovoljnije zajedno sa atomom azota, za koji su vezani, jedan prsten sa 5 do 6 članova koji, osim atoma azota, može da ima još i 0 - 1 drugih hetero-atoma iz grupe N-(C-|-C6)-alkil, kiseonik i sumpor; R33 jedan prsten sa 5 do 6 članova koji, osim atoma azota, može da ima još i 0 - 2 drugih hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa F, Cl, Br, CF3, N02, CN, (C-|-C6)-alkil, 0-(Ci-C8)-alkil; R12 OH, 0-(Ci-C6)-alkil, 0(Crj-C8)-alkilen-aril, CN, S-(Ci-C6)-alkil, COO(R80), CON(R81)(R93), N(R82)(R83), 3 - 12-to člani mono, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S i 3 - 12-to člani prsten može da sadrži, dalje, supstituente kao što su F, Cl, Br, I, OH, CF3, N02, CN, OCF3, okso, 0-(Ci-C6)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkii, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, O-(C0-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkil, COCOO(Ci-C6)-alkil, COO(R40), S(0)U(R41) i COOH; t 0,1,2,3,4,5,6; u 0,1,2; ili R34, R35, R37, R38 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R34 i R35 najpovoljnije zajedno sa atomom azota, za koji su vezani, 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 od drugih hetero-atoma iz grupe N-(Ci-C6)-alkil, kiseonik i sumpor i može, najpovoljnije, da bude supstituisan sa 1 - 2 okso-grupe; R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5- 10-to člani aromatični sistem prstena koji može da sadrži 0-2 druga hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa F, Cl, Br, CF3, NO2, CN, (Ci-Ce)-alkil, 0-(Ci-Cs)-alkil; R40 H, (Ci-C8)-alkil, (C2-C6)-alkenil, (Co-Cs)-alkilen-aril; R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 druga hetero-atoma iz grupe azota, kiseonika i sumpora i može biti supstituisan sa F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil; R78, R79 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, hidroksi-(C-|-C4)- alkil, OH, (Ci-C4)-alkoksi-(Ci-C4)-alkil| R80, R81 R93 nezavisno jedan od drugog, H, (C-|-C8)-alkil, (C2-C6)-alkenil, (Crj- C8)-alkilen-aril; R82, R83 nezavisno jedan od drugog, H, (C-|-C6)-alkil; ili R82 i R83 najbolje zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hereo - atom iz grupe N-(C-|-C6)-alkil, kiseonik i sumpor i može da bude, najbolje, supstituisan sa 1 - 2 okso-grupe; R3 H, (Ci-C6)-alkil; R4, R5 nezavisno jedan od drugog, H, (C-|-C6)-alkil, OH, 0-(Ci-C6)-alkil, 0-CO(Ci-C6)-alkil, S-(Ci-C6)-alkil; R6, R7, R8, R9 nezavisno jedan od drugog, H, (Ci-C8)-alkil; ili R6 i R7, R8 i R9 nezavisno jedan od drugog, najpovoljnije okso; n, m nezavisno jedan od drugog, 0,1,2; A, B, D, G nezavisno jedan od drugog, N, C(R42); ili grupe A i B ili D i G su svaka C(R42) i zajedno obrazuju jedan 5 -6-to člani karbociklični ili heterociklični radikal dajući kao krajnji rezultat jedan biciklični sistem R42 H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkil, 0-(Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(C-|-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (Co-Ca)-alkilen-aril, 0-(Co-C8)-alkilen-aril, S-aril, N(R43)(R44), SO2-CH3, COOH, COO-(Ci-C6)-alkil, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51), -(CR84R85)X-0(R86); R43, R44, R45, R46, R47, R49 nazavisno jedan od drugog, H, (C-i-Cs)-alkil; ili R43 i R44, R45 i R46 nezavisno jedan od drugog, najpovoljnije zajedno sa atomom azota, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim atoma azota, može da sadrži 0 -1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonik i sumpor; R48, R50, R51 nezavisno jedan od drugog, H, (C-|-C8)-alkil, aril; R84, R85 nezavisno jedan od drugog, H, (C-|-C8)-alkil; R86 H, (Ci-C6)-alkil, aril; X 1,2,3,4,5,6; R10 H, (Ci-C8)-alkil, (C3-C6)-alkenil, (C3-C6)-alkinil; X N(R52), O, jedna veza, C=C, C(R53)(R54), C(R55)(R56)0, CO, C=C, jedna grupa formule -(CR87R88)y- u kojoj jedan ili više -(CR87R88)- grupa može da se zameni sa Y, da bi se dobio jedan hemijski racionalan radikal; Y O, S, N(R98); R52, R53, R54, R55, R56 nezavisno jedan od drugog, H, (Ci-C8)-alkil; R87, R88 nezavisno jedan od drugog, H, (Ci-C4)-alkil, gde R87 i R88 u grupama y mogu u svakom slučaju da imaju isto ili drugačije značenje; y 2, 3, 4, 5, 6; R89 H, (Ci-C8)-alkil; E 3 -14 - to člani bivalentni karbo- ili heterociklični sistem prstena sa 0 - 4 hetero-atoma iz grupe N, O i S koji mogu, najpovoljnije, da imaju supstituente iz grupe H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, okso, 0-(Ci-C6)-alkil, 0-(Ci-C4)-alkoksi-(C1-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, O-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (Co-C8)-alkilen-aril, 0-(Co-C8)-alkilen-aril, S-aril, N(R57)(R58), SO2-CH3, COOH, COO-(Ci-C6)-alkil, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) i mogu biti mono- ili biciklični; R57, R58, R59, R60, R61, R63 nezavisno jedan od drugog, H, (C-|-C8)-alkil; ili R57 i R58, R59 i R60 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sedrži 0 -1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonik i sumpor; R62, R64, R65 nezavisno jedan od drugog, H, (Ci-C8)-alkil, aril; K jedna veza, O, OCH2, CH2O, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^C, C=C, jedna grupa formule -(CR90R91)2- u kojoj jedna ili više -(CR90R91)- grupa može da se zameni sa Z dajući jedan hemijski racionalan radikal; v 1,2,3,4 R66, R67, R68, R69, R70 nezavisno jedan od drugog, H, (C-|-C8)-alkil; Z 0, S, N(R92), CO, SO, S02; R90, R91 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, hidroksi-(Ci-C4)- alkil, hidroksi, (Ci-C4)-alkoksi-(Ci-C4)-alkil, gde R90 i R91 u z grupama mogu u svakom slučaju da imaju isto ili različito značenje; z 2,3,4,5,6; R92 H, (Ci-C8)-alkil; R11 H, (Ci-Cs)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-Cs)-alkenil, (C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi-, ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, gde prsten može da bude dodatno supstituisan sa F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, hidroksi-(CrC4)-alkil, COO(R74), N(R75)CO(Ci-C6)-alkil, N(R76)(R77) ili S02CH3; R71, R72, R73, R74, R75, R76, R77 nezavisno jedan od drugog, H, (C-|-C8)-alkil; ili R72 i R73, R76 i R77 nezavisno jedan od drugog, najpovoljnije zajedno sa atomom azota, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 drugi hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonik i sumpor; ili E, K i R11 zajedno grade jedan triciklični sistem gde prsteni mogu, nezavisno jedan od drugog [lakuna], da budu zasićeni, delimično zasićeni ili nezasićeni i svaki može da sadrži 3-8 atoma u prstenu; i N-okside i njihove fiziološki prihvatljive soli.1. Compounds of formula I in which the labels mean R1, R2 independently of each other, H, (Ci-Cs)-alkyl, -(CR78R79)0-R12, -(CH2)0-R12, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, aryloxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, (C3-Cs)-alkynyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0-R12, CO-aryloxy-(Ci-C4)-alkyl, CO-(C2-C8)-alkenyl, CO-(C2-C8)-alkynyl, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkyl-S(0)p-(Ci-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 build together with the nitrogen atom to which they are attached, some 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may contain 0 to 4 additional heteroatoms taken from the oxygen, nitrogen and sulfur groups, where the heterocyclic ring may be additionally substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(C1-C8)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-Ca)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or SO2CH3; about 0,1,2,3,4,5,6; p 0,1,2 q, r, s independently of each other 0, 1, 2, 3, 4; R13, R14 independently of each other, one 5-10th member aromatic a ring system which may contain 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of each other, H, (C 1 -C 6 )-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of each other, preferably together with the nitrogen atom, to which they are attached, one ring with 5 to 6 members which, in addition to the nitrogen atom, can also have 0 - 1 other heteroatoms from the group N-(C-|-C6)-alkyl, oxygen and sulfur; R33 is a 5- to 6-membered ring which, apart from the nitrogen atom, can it also has 0-2 other heteroatoms from the group of nitrogen, oxygen and sulfur and can be substituted with F, Cl, Br, CF3, NO2, CN, (C-|-C6)-alkyl, O-(Ci-C8)-alkyl; R12 OH, O-(C1-C6)-alkyl, O(C1-C8)-alkylene-aryl, CN, S-(C1-C6)-alkyl, COO(R80), CON(R81)(R93), N(R82)(R83), a 3-12-membered mono, bi- or spirocyclic ring which may contain one or more hetero-atoms from the group N, O and S and the 3-12-membered ring may further contain substituents such as F, Cl, Br, I, OH, CF3, N02, CN, OCF3, oxo, O-(Ci-C6)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-Alkyl, S-(Ci-C6)-Alkyl, (Ci-C6)-Alkyl, (C2-C6)-Alkenyl, (C3-C8)-Cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, O-(C0-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)U(R41) and COOH; t 0,1,2,3,4,5,6; in 0,1,2; or R34, R35, R37, R38 independently of each other, H, (C 1 -C 8 )-alkyl; R34 and R35 most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 of other heteroatoms from the group N-(Ci-C6)-alkyl, oxygen and sulfur and can, most advantageously, be substituted with 1 - 2 oxo groups; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5-10 members aromatic ring system which may contain 0-2 other hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (Ci-Ce)-alkyl, O-(C 1 -C 8 )-alkyl; R 40 H, (C 1 -C 8 )-alkyl, (C 2 -C 6 )-alkenyl, (C 0 -C 8 )-alkylene-aryl; R41 (Ci-C6)-alkyl, 5 - 10-membered aromatic ring system that can to contain 0-2 other heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R78, R79 independently of each other, H, (C1-C8)-alkyl, hydroxy-(C-|-C4)- alkyl, OH, (C1-C4)-Alkoxy-(C1-C4)-alkyl| R80, R81 R93 independently of each other, H, (C-1-C8)-alkyl, (C2-C6)-alkenyl, (C1- C8)-alkylene-aryl; R82, R83 independently of each other, H, (C-1-C6)-alkyl; or R82 and R83 preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero atom from the group N-(C-|-C6)-alkyl, oxygen and sulfur and can be, best, substituted with 1 - 2 oxo-groups; R 3 H, (C 1 -C 6 )-alkyl; R4, R5 independently of each other, H, (C-|-C6)-alkyl, OH, O-(C1-C6)-alkyl, O-CO(C1-C6)-alkyl, S-(C1-C6)-alkyl; R6, R7, R8, R9 independently of each other, H, (C 1 -C 8 )-alkyl; or R6 and R7, R8 and R9 independently of each other, most advantageously oxo; n, m independent of each other, 0,1,2; A, B, D, G independently of each other, N, C(R42); or groups A and B or D and G are each C(R42) and together form a 5-6-membered carbocyclic or heterocyclic radical giving as the final the result is a bicycle system R42 H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-alkyl, 0-(Ci-C4)-Alkoxy-(Ci-C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-Ca)-alkylene-aryl, O-(Co-C8)-alkylene-aryl, S-aryl, N(R43)(R44), SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51), -(CR84R85)X-0(R86); R43, R44, R45, R46, R47, R49 independently of one another, H, (C 1 -C 8 )-alkyl; or R43 and R44, R45 and R46 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of each other, H, (C-1-C8)-alkyl, aryl; R84, R85 independently of each other, H, (C-1-C8)-alkyl; R86 H, (C1-C6)-alkyl, aryl; X 1,2,3,4,5,6; R 10 H, (C 1 -C 8 )-alkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl; X N(R52), O, single bond, C=C, C(R53)(R54), C(R55)(R56)0, CO, C=C, one group of the formula -(CR87R88)y- in which one or more -(CR87R88)- groups can be replaced by Y, to give a chemically rational radical; Y O, S, N(R98); R52, R53, R54, R55, R56 independently of each other, H, (C 1 -C 8 )-alkyl; R87, R88 independently of each other, H, (C1-C4)-alkyl, where R87 and R88 in groups y can in any case have the same or different meaning; y 2, 3, 4, 5, 6; R89 H, (C1-C8)-alkyl; E 3 -14 - members of the bivalent carbo- or heterocyclic ring system with 0 - 4 hetero-atoms from the group N, O and S which can, most advantageously, have substituents from the group H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, 0-(Ci-C6)-alkyl, 0-(Ci-C4)-alkoxy-(C1-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic; R57, R58, R59, R60, R61, R63 independently of each other, H, (C-1-C8)-alkyl; or R57 and R58, R59 and R60 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulfur; R62, R64, R65 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; K single bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^C, C=C, one group of the formula -(CR90R91)2- in which one or more -(CR90R91)- groups can is replaced by Z giving a chemically rational radical; in 1,2,3,4 R66, R67, R68, R69, R70 independently of each other, H, (C-1-C8)-alkyl; Z 0, S, N(R92), CO, SO, SO2; R90, R91 independently of each other, H, (C1-C8)-alkyl, hydroxy-(C1-C4)- alkyl, hydroxy, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, where R 90 and R 91 in the z groups can in any case have the same or different meanings; z 2,3,4,5,6; R92 H, (C1-C8)-alkyl; R11 H, (Ci-Cs)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (C3-Cs)-alkenyl, (C3-C8)-alkynyl, a 3- to 10-membered mono-, bi-, or spirocyclic ring that may contain 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the ring may be further substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy-(CrC4)-alkyl, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of each other, H, (C-1-C8)-alkyl; or R72 and R73, R76 and R77 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 other hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulphur; or E, K and R11 together form a tricyclic system where the rings can, independently of each other [lacuna], to be saturated, partially saturated or unsaturated and each may contain 3-8 ring atoms; and N-oxides and their physiologically acceptable salts. 2. Jedinjenja formule I prema zahtevul, u kojoj oznake znače: R1, R2 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, -(CH2)0-R12, (Ci-C4)-alkoksi-(Ci-C4)-alkil, ariloksi-(Ci-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, CO-(Ci-C8)-alkil, -CO-(CH2)0-R12, CO-ariloksi-(Ci-C4)-alkil, CO-(C2-C8)-alkenil, CO-(C2-C8)-alkinil, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkil-S(0)p-(C1-C4)-alkil, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4- do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 4 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može dodatno da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (C1-C4)-alkoksi-(C1-C4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(Ci-C6)-alkil, N(R31)(R32) ili SO2CH3;2. Compounds of formula I as claimed, in which the symbols mean: R1, R2 independently of each other, H, (Ci-Cs)-alkyl, -(CH2)O-R12, (Ci-C4)-Alkoxy-(Ci-C4)-Alkyl, Aryloxy-(Ci-C4)-Alkyl, (C3-C8)-Alkenyl, (C3-C8)-Alkynyl, CO-(Ci-C8)-Alkyl, -CO-(CH2)0-R12, CO-Aryloxy-(Ci-C4)-Alkyl, CO-(C2-C8)-Alkenyl, COCH=CH(R13), COCC(R14), CO-(Ci-C4)-alkyl-S(0)p-(C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 build together with the nitrogen atom, to which they are attached, a 4- to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, can contain 0 to 4 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring system can be additionally substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl, (C1-C4)-Alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or SO2CH3; 00,1,2,3,4,5,6; P 0,1,2 q, r, s nezavisno jedan od drugog, 0, 1, 2, 3, 4; R13, R14 nezavisno jedan od drugog, jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(C-|-C8)-alkil; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 nezavisno jedan od drugog, H, (Ci-C6)-alkil; R18 H, (Ci-C6)-alkil, CO(Ci-C6)-alkil, CO(R33); R17 i R18, R21 i R22, R27 i R28, R31 i R32 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonik i sumpor; R33 jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(Ci-Ca)-alkil; R12 OH, 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, I, OH, CF3, N02, CN, OCF3, okso, 0-(C1-C6)-alkil, (C1-C4)-alkoksi-(Ci-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-C8)-cikloalkenil. (C2-C6)-alkinil. O-(Co-Cs)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkil, COCOO(Ci-C6)-alkil, COO(R40), S(0)U(R41) i COOH; t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R34 i R35 najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(C-i-Cs)-alkil, kiseonika i sumpora i može da bude, najpovoljnije, supstituisan sa 1 - 2 okso-gurpe; R36, R39 nezavisno jedan od drugog, (C3-Cs)-cikloalkil, 5- 10-to člani aromatični sistem prstena koji može da sadrži 0 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, O-(Ci-Cs)-alkil; R40 H, (Ci-Cs)-alkil, (C2-C6).-alkenil, (Crj-C8)-alkilen-aril; R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, Br, CF3, N02, CN, (Ci-C6)-alkil, 0-(Ci-Ca)-alkil; R3 H, (Ci-C6)-alkil; R4, R5 nezavisno jedan od drugog, (Ci-C6)-alkil, OH, 0-(Ci-C6)-alkil, O- CO(Ci-C6)-alkil, S-(Ci-C6)-alkil; R6, R7, R8, R9 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R6 i R7, R8 i R9 nezavisno jedan od drugog, najpovoljnije okso; n, m nezavisno jedan od drugog, 0, 1, 2; A, B, D, G nezavisno jedan od drugog, N, C(R42); R42 H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkil, 0-(Ci- C4)-alkoksi-(Ci-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C8)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-Cs)-cikloalkenil, 0-(C3-C8)-cikloalkenil, (C2-C6)-alkinil, (Co-Cs)-alkilen-aril, 0-(Co-C8)-alkilen-aril, S-aril, N(R43)(R44), SO2-CH3, COOH, COO-(Ci-C6)-alkil, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) R43, R44, R45, R46, R47, R49 nezavisno jedan od drugog, H, (C1-Cs)-alkil; R43 i R44, R45 i R46 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 -1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonik i sumpor; R48, R50, R51 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, aril; R10 H, (Ci-C8)-alkil, (C3-C6)-alkenil, (C3-C6)-alkinil; X N(R52), O, jednu vezu, C=C, C(R53)(R54), C(R55)(R56)0; R52, R53, R54, R55, R56 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; E 3 - 8-mo članu bivalentnu karbo- ili heterocikličnu strukturu prstena sa 0 - 4 hetero-atoma iz grupe N, O i S koji mogu, najpovoljnije, da imaju supstituente iz grupe H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(Ci-C6)-alkil, 0-(Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, (C3-C3)-cikloalkil, 0-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, 0-(C3-Cs)-cikloalkenil, (C2-C6)-alkinil, (Co-C8)-alkilen-aril, O-(Co-Cs)-alkilen-aril, S-aril, N(R57)(R58), S02-CH3, COOH, COO-(Ci-C6)-alkil, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) i mogu da budu mono- ili biciklični; R57, R58, R59, R60, R61, R63 nezavisno jedan od drugog, H, (Ci-C8)-alkil; R57 i R58, R59 i R60 nezavisno jedan od drugog, najpovoljnije zajedno sa aztovim atomom, za koji si vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, mogu da sadrže 0 - 1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonika i sumpora; R62, R64, R65 nezavisno jedan od drugog, H, (Ci-C8)-alkil, aril; K jedna veza, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^C; v 1,2,3,4; R66, R67, R68, R69, R70 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R11 H, (Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkil, 0-(Ci-C3)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (Co-Ca)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(Ci-C6)-alkil, N(R76)(R77) iliS02CH3; R71, R72, R73, R74, R75, R76, R77 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R72 i R73, R76 i R77 nezavisno jedan od drugog, najpoviljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 -1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; ili E, Ki R11 zajedno grade jedan triciklični sistem, pri čemu prsteni mogu, nezavisno jedan od drugog [lakunaj, da budu zasićeni, delimično zasićeni ili nezasićeni i svaki može da sadrži 3 - 8 atoma u prstenu, i njihove fiziološki prihvatljive soli.00,1,2,3,4,5,6; P 0,1,2 q, r, s independently of each other, 0, 1, 2, 3, 4; R13, R14 independently of each other, one 5 - 10th member aromatic a ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O-(C-|-C 8 )-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of each other, H, (C 1 -C 6 )-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulphur; R33 is a 5- to 10-membered aromatic ring system that can contains 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-Ca)-alkyl; R12 OH, 3 - 12-membered mono-, bi- or spirocyclic ring which can contains one or more hetero-atoms from the group N, O and S, and the 3 - 12-membered ring may contain further substituents, such as F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O-(C1-C6)-alkyl, (C1-C4)-alkoxy-(Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O-(C3-C8)-cycloalkenyl. (C2-C6)-alkynyl. O-(Co-Cs)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40), S(0)U(R41) and COOH; t 0,1,2,3,4,5,6; in 0,1,2; R34, R35, R37, R38 independently of each other, H, (C 1 -C 8 )-alkyl; R34 and R35 most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(C-i-Cs)-alkyl, oxygen and sulfur and can be, most advantageously, substituted with 1 - 2 oxo-groups; R36, R39 independently of each other, (C3-Cs)-cycloalkyl, 5-10 members an aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O-(C 1 -C 5 )-alkyl; R 40 H, (C 1 -C 8 )-alkyl, (C 2 -C 6 ).-alkenyl, (C 1 -C 8 )-alkylene-aryl; R41 (Ci-C6)-alkyl, 5 - 10-membered aromatic ring system that can to contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-Ca)-alkyl; R 3 H, (C 1 -C 6 )-alkyl; R4, R5 independently of each other, (Ci-C6)-alkyl, OH, O-(Ci-C6)-alkyl, O- CO(C1-C6)-alkyl, S-(C1-C6)-alkyl; R6, R7, R8, R9 independently of each other, H, (C 1 -C 8 )-alkyl; R6 and R7, R8 and R9 independently of each other, most advantageously oxo; n, m independent of each other, 0, 1, 2; A, B, D, G independently of each other, N, C(R42); R42 H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, 0-(Ci- C4)-Alkoxy-(Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-Cs)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C8)-cycloalkyl, (Co-Cs)-alkylene-aryl, O-(Co-C8)-alkylene-aryl, S-aryl, N(R43)(R44), SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) R43, R44, R45, R46, R47, R49 independently of one another, H, (C 1 -C 8 )-alkyl; R43 and R44, R45 and R46 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; R 10 H, (C 1 -C 8 )-alkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl; X N(R52), O, single bond, C=C, C(R53)(R54), C(R55)(R56)0; R52, R53, R54, R55, R56 independently of each other, H, (C 1 -C 8 )-alkyl; E 3 - 8-membered bivalent carbo- or heterocyclic structure rings with 0 - 4 heteroatoms from the group N, O and S which can, most advantageously, have substituents from the group H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, 0-(Ci-C4)-Alkoxy-(Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, (C3-C3)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-Cs)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, O-(Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, COOH, COO-(Ci-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and can be mono- or bicyclic; R57, R58, R59, R60, R61, R63 independently of each other, H, (C 1 -C 8 )-alkyl; R57 and R58, R59 and R60 independently of each other, preferably together with the nitrogen atom, to which you are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulphur; R62, R64, R65 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; K single bond, O, OCH2, CH2O, S, SO, SO2, N(R66), N(R67)CO, CON(R 68 ), (C(R 69 )(R 70 )) V , CO, C 2 C ; c 1,2,3,4; R66, R67, R68, R69, R70 independently of each other, H, (C 1 -C 8 )-alkyl; R 11 H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C3-C8)-alkynyl, a 3- to 10-membered mono-, bi-, or spirocyclic ring that may contain 0 to 4 heteroatoms selected from the group of oxygen, nitrogen, and sulfur, wherein the ring system may be additionally substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, 0-(Ci-C3)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (Co-Ca)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO 2 CH 3 ; R71, R72, R73, R74, R75, R76, R77 independently of each other, H, (C 1 -C 8 )-alkyl; R72 and R73, R76 and R77 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atoms from the group N-(Ci-C6)-alkyl, oxygen and sulfur; or E, Ki R11 together form a tricyclic system, whereby the rings can, independently of each other [lacunae, to be saturated, partially saturated or unsaturated and each may contain 3 - 8 ring atoms, and their physiologically acceptable salts. 3. Jedinjenje formule I prema zahtevu 1 ili 2 u kojima oznake znače: R1, R2 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, -(CH2)0-R12, (Ci-C4)-alkoksi-(Ci-C4)-alkil, CO-(Ci-C8)-alkil, -CO-(CH2)0-R12, COCH=CH(R13), COCC(R14), CO-(C1-C4)-alkil-S(0)p-(Ci-C4)-alkil, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koi su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseoika, azota i sumpora, pri čemu heterociklični sistem prstena može dodatno da bude supstituisan sa F, (Ci-C6)-alkil, 0-(Ci-Cs)-alkil, (Co-Cs)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(Ci-C6)-alkil, N(R31)(R32) ili SO2CH3;3. Compound of formula I according to claim 1 or 2 in which the symbols mean: R1, R2 independently of each other, H, (Ci-Cs)-alkyl, -(CH2)0-R12, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0-R12, COCH=CH(R13), COCC(R14), CO-(C1-C4)-alkyl-S(0)p-(Ci-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring system may be additionally substituted with F, (Ci-C6)-alkyl, 0-(Ci-Cs)-alkyl, (Co-Cs)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3; 00,1,2,3,4; P 0,1,2; q, r, s nezavisno jedan od drugog, 0, 1,2, 3; R13, R14 nezavisno jedan od drugog, jedan 5- 10-to člani aromatični sistem prstena koji može da sadrži jedan dalji hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (Ci-C6)-alkil, 0-(C1-C8)-alkil; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29. R30, R31, R32 nezavisno jedan od drugog, H, (Ci-C6)-alkil; R18 H, (Ci-C6)-alkil, CO(Ci-C6)-alkil, CO(R33); R17 i R18, R21 i R22, R27 i R28, R31 i R32 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonika i sumpora; R33 jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži još jedan hetero-atom iz grupe azota, kiseonika i sumpora i može da budu supstituisani sa F, Cl, (C-|-C6)-alkil, O-(Ci-Cs)-alkil; R12 OH, 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može d sadrži jedan ili više hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, CF3, CN, okso, 0-(Ci-C6)-alkil, (Ci-C6)-alkil, 0-(Cn-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkil, COCOO(Ci-C6)-alkil, COO(R40) i S(0)U(R41); t 0,1,2,3,4; u 0,1,2; R34, R35, R37, R38 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R34 i R35 najpovoljnije zajedno sa azotovim atomom, zakoji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora i može da bude supstituisan, najpovoljnije sa 1 - 2 okso - grupe; R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži još jedan hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (Ci-Cs)-alkil, O^Ci-Cs^alkil; R40 H, (Ci-Ca)-alkil, (C2-C6)-alkenil, (Co-Cs)-alkilen-aril; R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (Ci-C6)-alkil, O-(d-C8)-alkil; R3 H, (Ci-C6)-alkil; R4, R5 nezavisno jedan od drugog, H, (Ci-C6)-alkil, OH, 0-(Ci-C6)-alkil, 0-CO(Ci-C6)-alkil; R6, R7, R8, R9 nezavisno jedan od drugog, H, (C-|-C8)-alkil; R6 i R7, R8 i R9 nezavisno jedan od drugog, okso; n, m nezavisno jedan od drugog, 0,1,2; A, B, D, G nezavisno jedan od drugog, N, C(R42); R42 H, F, Cl, Br, CF3, CN, 0-(Ci-C6)-alkil, (d^-alkil, (C3-C8)- cikloalkil, (Co-C2)-alkilen-aril, 0-(Co-C2)-alkilen-aril, N(R43)(R44), SO2-CH3, COO-(Ci-C6)-alkil, C0N(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) R43 R44 R4fi R4fi R47 R49 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R43 i R44, R45 i R46 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonika i sumpora; R48, R50, R51 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, aril; R10 H, (Ci-C8)-alkil; X N(R52), O, jedna veza, C=C, C(R53)(R54), C(R55)(R56)0; R52, R53, R54, R55, R56 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; E 3 - 8-mo članu bivalentnu karbo- ili heterocikličnu strukturu prstena sa 0 - 4 hetero-atoma iz grupe N, O i S, koja može, najpovoljnije, da ima supstituente iz grupe H, F, Cl, CF3, NO2, OH, CN, 0-(Ci-C6)-alkil, (Ci-C6)-alkil, (C0-C8)-alkilen-aril, 0-(Crj-C8)-alkilen-aril, N(R57)(R58), SO2-CH3, COO-(Ci-C6)-alkil, CON(R59)(R60), N(R61)CO(R62), N(R63)S02(R64), CO(R65) i može da bude mono- ili biciklična; R57, R58, R59, R60, R61, R63 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R57 i R58, R59 i R60 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 -1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; R62, R64, R65 nezavisno jedan od drugog, H, (Ci-C8)-alkil, aril; K jedna veza, O, CH2O, N(R66), (C(R69)(R70))V, C=C; v 1,2; R66, R67, R68, R69, R70 nezavisno jedan od drugog, H, (C-|-C8)-alkil; R11 H, (Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-Cs)-alkenil, jedan 3 do 10-to člani mono-, bi- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C0-C8)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(Ci-C6)-alkil, N(R76)(R77) ili S02CH3; R71, R72, R73, R74, R75, R76, R77 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R72 i R73, R76 i R77 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, zakoji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupe N-(C-]-C6)-alkil, kiseonika i sumpora.00,1,2,3,4; P 0,1,2; q, r, s independently of each other, 0, 1,2, 3; R13, R14 independently of each other, each of the 5-10 members is aromatic a ring system which may contain one further hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (Ci-C6)-alkyl, O-(C1-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29. R30, R31, R32 independently of each other, H, (C 1 -C 6 )-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulphur; R33 is a 5- to 10-membered aromatic ring system that can contains another hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (C-|-C6)-alkyl, O-(Ci-C8)-alkyl; R12 OH, 3 - 12-membered mono-, bi- or spirocyclic ring which can d contains one or more hetero-atoms from the group N, O and S, and the 3 - 12-membered ring may contain further substituents, such as F, Cl, CF3, CN, oxo, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, 0-(Cn-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40) and S(O)U(R41); t 0,1,2,3,4; in 0,1,2; R34, R35, R37, R38 independently of each other, H, (C 1 -C 8 )-alkyl; R34 and R35 most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur and can be substituted, most advantageously with 1 - 2 oxo - groups; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5 - 10 members an aromatic ring system which may contain another hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (Ci-Cs)-alkyl, O^Ci-Cs^alkyl; R40 H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (Co-C5)-alkylene-aryl; R41 (Ci-C6)-alkyl, 5 - 10-membered aromatic ring system that can to contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (Ci-C6)-alkyl, O-(d-C8)-alkyl; R 3 H, (C 1 -C 6 )-alkyl; R4, R5 independently of each other, H, (Ci-C6)-alkyl, OH, O-(Ci-C6)-alkyl, O-CO(C1-C6)-alkyl; R6, R7, R8, R9 independently of each other, H, (C-1-C8)-alkyl; R6 and R7, R8 and R9 independent of each other, oxo; n, m independent of each other, 0,1,2; A, B, D, G independently of each other, N, C(R42); R42 H, F, Cl, Br, CF3, CN, O-(Ci-C6)-alkyl, (di-alkyl, (C3-C8)- cycloalkyl, (Co-C2)-alkylene-aryl, O-(Co-C2)-alkylene-aryl, N(R43)(R44), SO2-CH3, COO-(Ci-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO2(R50), CO(R51) R43 R44 R4fi R4fi R47 R49 independently of each other, H, (C 1 -C 8 )-alkyl; R43 and R44, R45 and R46 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 -1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; R 10 H, (C 1 -C 8 )-alkyl; X N(R52), O, single bond, C=C, C(R53)(R54), C(R55)(R56)0; R52, R53, R54, R55, R56 independently of each other, H, (C 1 -C 8 )-alkyl; E 3 - 8-membered bivalent carbo- or heterocyclic structure ring with 0 - 4 heteroatoms from the group N, O and S, which can, most advantageously, have substituents from the group H, F, Cl, CF3, NO2, OH, CN, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C0-C8)-alkylene-aryl, O-(Crj-C8)-alkylene-aryl, N(R57)(R58), SO2-CH3, COO-(Ci-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and can be mono- or bicyclic; R57, R58, R59, R60, R61, R63 independently of each other, H, (C 1 -C 8 )-alkyl; R57 and R58, R59 and R60 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can contain 0-1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur; R62, R64, R65 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; K single bond, O, CH2O, N(R66), (C(R69)(R70))V, C=C; v 1.2; R66, R67, R68, R69, R70 independently of each other, H, (C-1-C8)-alkyl; R 11 H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may contain 0 to 4 hetero-atoms selected from the group of oxygen, nitrogen and sulphur, whereby the ring system may be additionally substituted with F, Cl, Br, CF3, NO2, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another, H, (C 1 -C 8 )-alkyl; R72 and R73, R76 and R77 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(C-]-C6)-alkyl, oxygen and sulfur. 4. Jedinjenje formule 1 prema zahtevima od 1 do 3, pri čemu su A, B, D, G nezavisno jedan od drugog, N ili C(R42), a ukupan broj azotovih atoma u ovom prstenu je 0-2.4. The compound of formula 1 according to claims 1 to 3, wherein A, B, D, G independently of each other, N or C(R42), and the total number of nitrogen of atoms in this ring is 0-2. 5. Jedinjenje formule 1 prema zahtevima od 1 do 4, pri čemu n je 1 i m je 1 ili 2.5. The compound of formula 1 according to claims 1 to 4, wherein n is 1 and m is 1 or 2. 6. Jedinjenje formule 1 prema zahtevu 1, u kojoj oznake znače: R1, R2 nezavisno jedan od drugog, H, (Ci-CsJ-alkil, -(CR78R79)0-R12, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-C8)-alkenil, CO-(Ci-C8)-alkil, -CO-(CH2)0-R12, CO-ariloksi-(Ci-C4)-alkil, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); ili R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični sistem prstena može da bude dodatno supstituisan sa F, Cl, CF3, (Ci-C6)-alkil, 0-(C1-C4)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, hidroksi-(C-i-C4)-alkil, (Cn-C2)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(Ci-C6)-alkil, N(R31)(R32) ili SO2CH3; o 0,1,2,3,4,5,6; q, r nezavisno jedan od drugog, 1, 2, 3; s 0,1,2,3,4; R13, R14 nezavisno jedan od drugog, jedan fenil - prsten koji može da sadrži 0-1 azotov atom; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 nezavisno jedan od drugog, H, (Ci-Ce)-alkil; R18 H, (Ci-C6)-alkil, CO(Ci-C6)-alkil, CO(R33); ili R17 i R18, R21 i R22, R27 i R28, R31 i R32 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 -1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; R33 jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži još jedan hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (Ci-C6)-alkil, 0-(C-|-C8)-alkil; R12 OH, 0-(Ci-C6)-alkil, 0-(Co-C8)-alkilen-aril, CN, S-(Ci-C6)-alkil, COO(R80), CON(R81)(R82), 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, OH, CF3, CN, okso, 0-(Ci-C6)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (Ci-C6)-alkil, O-(Co-Cs)-alkilen-anl, (Co-Cs)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkil, COCOO(Ci-C6)-alkil, COO(R40), S(0)U(R41); t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 nezavisno jedan od drugog, H, (Ci-C8)-alkil; ili R34 i R35 najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonika i sumpoa i može da bude supstituisan, najpovoljnije, sa 1 - 2 okso-grupe; R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5- 10-to člani aromatični sistem prstena koji može da sadrži 0 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (C-|-C6)-alkil, 0-(Ci-Ca)-alkil; R40 H, (Ci-C8)-alkil, (C2-C6)-alkenil, (Co-C8)-alkilen-aril; R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0-2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (Ci-C6)-alkil, O-(Ci-C8)-alkil; R78, R79 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, hidroksi-(C-|-C4)- alkil, OH, (Ci-C4)-alkoksi-(Ci-C4)-alkil; R80, R81 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R3 H, (Ci-C6)-alkil; R4, R5 nezavisno jedan od drugog, H, (C-|-C6)-alkil, OH, 0-(C-|-C6)-alkil, 0-CO(Ci-C6)-alkil, S-(Ci-C6)-alkil; R6, R7, R8, R9 H; ili R6 i R7, R8 i R9 nezavisno jedan od drugog, najpovoljnije okso; n 1; m 1 ili 2; A, B, D, G nezavisno jedan od drugog, N, C(R42); ili Grupe A i B ili D i G su svaka C(R42) i zajedno grade jednu orto-fenilensku jedinicu, sveukupno dajući jedan 1,4-disupstituisani naftalinski sistem; R42 H, F, Cl, Br, CF3, CN, 0-(Ci-C6)-alkil, 0-(Ci-C4)-alkoksi-(Ci- C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (Co-CsJ-alkilen-aril, O-(Co-C8)-alkilen-aril, N(R43)(R44), SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)X-0(R86); R43, R44, R45, R46, R47 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; ili R43 j R44, R45 j R46 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-CeJ-alkil, kiseonika i sumpora; R48, R50, R51 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, aril; R84, R85 H; R86 H, (Ci-C6)-alkil; x 0,1,2; R10 H, (Ci-C8)-alkil; X N(R52), jedna veza, C=C, C(R53)(R54), C(R55)(R56)0, C^C, CH2-CH2, YCH2; Y O, S, N(R89); R89 H, (Ci-Ca)-alkil; R52, R53, R54, R55, R56 nezavisno jedan od drugog, H, (Ci-C8)-alkil; E 3 - 8-mo člani bivalentni karbo- ili heterociklični sistem prstena sa 0 - 4 hetero-atoma iz grupe N, O i S, koji mogu da maju, najpovoljnije, supstituente iz grupe H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkil, 0-(Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, 0-(C3-C8)-cikloalkil, (C3-C8)-cikloalkenil, (C2-C6)-alkinil, (Co-C8)-alkilen-aril, 0-(Co-C8)-alkilen-aril, S-aril, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)S02(R64), CO(R65) i mogu da budu mono- ili biciklični; R57, R58, R61, R63 nezavisno jedan od drugog, H, (C-|-C8)-alkil; R62, R64, R65 nezavisno jedan od drugog, H, (Ci-C8)-alkil, aril; K jedna veza, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, S02CH2; v 1,2,3,4; R66, R67, R68, R69, R70 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R11 H, (Ci-Ca)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, hidroksi-(Ci-C4)-alkil, (Crj-C8)-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, C00(R74), N(R75)CO(Ci-C6)-alkil, N(R76)(R77) ili SO2CH3; R71, R72, R73, R74, R75, R76, R77 nezavisno jedan od drugog, H, (C-|-C8)-alkil; ili R72 i R73, R76 i R77 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonik i sumpor; ili N-oksidi i njihove fiziološki prihvatljive soli.6. The compound of formula 1 according to claim 1, in which the symbols mean: R1, R2 independently of each other, H, (Ci-CsJ-alkyl, -(CR78R79)0-R12, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0-R12, CO-aryloxy-(Ci-C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 build together with the nitrogen atom, to which they are attached, one 4 to 10-membered mono-, bi- or spirocyclic ring which, in addition to the nitrogen atom, may contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system may be further substituted with F, Cl, CF3, (Ci-C6)-alkyl, O-(C1-C4)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(C-i-C4)-alkyl, (Cn-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH3; about 0,1,2,3,4,5,6; q, r independently of each other, 1, 2, 3; with 0,1,2,3,4; R13, R14 independently of each other, one phenyl ring which can contains 0-1 nitrogen atom; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of each other, H, (C 1 -C 6 )-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulfur; R33 is a 5- to 10-membered aromatic ring system that can contains another hetero-atom from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (C1-C6)-alkyl, O-(C-|-C8)-alkyl; R12 OH, O-(Ci-C6)-alkyl, O-(Co-C8)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, COO(R80), CON(R81)(R82), a 3- to 12-membered mono-, bi- or spirocyclic ring which may contain one or more hetero-atoms from the group N, O and S, and the 3- to 12-membered ring may contain further substituents, such as F, Cl, Br, OH, CF3, CN, oxo, 0-(Ci-C6)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (Ci-C6)-alkyl, O-(Co-Cs)-alkylene-anl, (Co-Cs)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39). CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)U(R41); t 0,1,2,3,4,5,6; in 0,1,2; R34, R35, R37, R38 independently of each other, H, (C 1 -C 8 )-alkyl; or R34 and R35 most advantageously, together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, it can also contain 0-1 further hetero-atoms from the group N-(C-|-C6)-alkyl, oxygen and sulfur and can be substituted, most advantageously, with 1-2 oxo-groups; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5-10 members an aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (C-|-C 6 )-alkyl, O-(C 1-C 6 )-alkyl; R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C0-C8)-alkylene-aryl; R41 (Ci-C6)-alkyl, 5 - 10-membered aromatic ring system that can to contain 0-2 further hetero-atoms from the nitrogen group, oxygen and sulfur and may be substituted with F, Cl, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl; R78, R79 independently of each other, H, (C1-C8)-alkyl, hydroxy-(C-|-C4)- alkyl, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl; R 80 , R 81 independently of each other, H, (C 1 -C 8 )-alkyl; R 3 H, (C 1 -C 6 )-alkyl; R4, R5 independently of each other, H, (C-|-C6)-alkyl, OH, O-(C-|-C6)-alkyl, O-CO(C1-C6)-alkyl, S-(C1-C6)-alkyl; R6, R7, R8, R9 H; or R6 and R7, R8 and R9 independently of each other, most advantageously oxo; n 1; m 1 or 2; A, B, D, G independently of each other, N, C(R42); or Groups A and B or D and G are each C(R 42 ) and together form one ortho-phenylene unit, altogether giving one 1,4-disubstituted naphthalene system; R42 H, F, Cl, Br, CF3, CN, O-(Ci-C6)-alkyl, O-(Ci-C4)-Alkoxy-(Ci- C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (Co-CsJ-alkylene-aryl, O-(Co-C8)-alkylene-aryl, N(R43)(R44), SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)X-0(R86); R44, R45, R46, R47 independently of each other, H, (C 1 -C 8 )-alkyl; or R43 j R44, R45 j R46 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-CeJ-alkyl, oxygen and sulfur; R48, R50, R51 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; R84, R85 H; R86 H, (C1-C6)-alkyl; x 0,1,2; R 10 H, (C 1 -C 8 )-alkyl; X N(R52), single bond, C=C, C(R53)(R54), C(R55)(R56)0, C^C, CH2-CH2, YCH2; Y O, S, N(R89); R89 H, (C1-C6)-alkyl; R52, R53, R54, R55, R56 independently of each other, H, (C 1 -C 8 )-alkyl; E 3 - 8-member bivalent carbo- or heterocyclic ring system with 0 - 4 hetero-atoms from the group N, O and S, which can have, most advantageously, substituents from the group H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, 0-(Ci-C4)-alkoxy-(Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, O-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, O-(Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and may be mono- or bicyclic; R57, R58, R61, R63 independently of each other, H, (C-1-C8)-alkyl; R62, R64, R65 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; K single bond, O, OCH2, CH20, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, SO2CH2; c 1,2,3,4; R66, R67, R68, R69, R70 independently of each other, H, (C 1 -C 8 )-alkyl; R11 H, (C1-C6)-alkyl, (C1-C4)-Alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3- to 10-membered mono-, bi-, tri- or spirocyclic ring which may contain 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the system may be additionally substituted with F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl, (C1-C4)-Alkoxy-(C1-C4)-Alkyl, Hydroxy-(C1-C4)-Alkyl, (C1-C8)-Alkylene-Aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, CO0(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of each other, H, (C-1-C8)-alkyl; or R72 and R73, R76 and R77 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulphur; or N-oxides and their physiologically acceptable salts. 7. Jedinjenje prema zahtevima od 1 do 6, naznačeno time, da ima formulu la u kojoj oznake znače: R1, R2 nezavisno jedan od drugog, H, (Ci-C8)-alkil, -(CR78R79)0 -R12, (C-|-C4)-alkoksi-(C-|-C4)-alkil, R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični prsten može da bude dodatno supstituisan sa F, (Ci-Ce)-alkil, 0-(Ci-C4)-alkil, (C-|-C4)-alkoksi-(Ci-C4)-alkil, hidroksi-(Ci-C4)-alkil, (Crj-C2)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, N(R31)(R32) iliS02CH3; gde R<1>i R<2>nisu oba CO(R26); o 0,1,2,3,4; q 1,2,3; s 0,1,2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 nezavisno jedan od drugog, H, (Ci-C6)-alkil; ili R17 i R18, R27 i R28, R31 i R32 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; R12 OH, 0-(Ci-C6)-alkil, 0-(Crj-C2)-alkilen-aril, CN, S-(Ci-C6)- alkil, 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži 1 do 3 hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, OH, CF3, CN, okso, (Ci-C6)-alkil, (Co-C2)-alkilen-aril, N(R34)(R35), COO(R40), CO(Ci-C6)-alkil; R34, R35 nezavisno jedan od drugog, H, (Ci-C4)-alkil; R40 H, (Ci-C6)-alkil, (C0-C2)-alkilen-aril; R78, R79 nezavisno jedan od drugog, H, (C<|-C8)-alkil, hidroksi-(C-|-C4)- alkil, OH, (Ci-C4)-alkoksi-(Ci-C4)-alkil; R42, R42' nezavisno jedan od drugog, H, F, Cl, Br, CF3, CN, (C1-C6)- alkil; R10 H, (Ci-Cs)-alkil; X N(R52), jedna veza, C=C, C(R53)(R54), CH2CH2; R52, R53, R54 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; E 5 - 7-mo članu bivalentnu karbo- ili heterocikličnu strukturu prstena sa 0-3 hetero-atoma iz grupe N, O i S, koja može da ima suspstituente, najpovoljnije, iz grupe H, F, Cl, Br, CF3, OH, CN, OCF3, N02, 0-(Ci-C6)-alkil, (Ci-C6)-alkil, SO2-CH3, CO(R65); R65 H, (Ci-C8)-alkil; K jedna veza, O, OCH2, CH20, S, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^ C, SCH2, S02CH2; v 1,2,3, R66, R67, R68, R69, R70 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R11 (Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatano supstituisan sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, O-(Ci-Cs)-alkil, okso, C0(R71), hidroksi, N(R75)CO(Ci-C6)-alkil, ili SO2CH3; R71, R72, R73, R74, R75, R76, R77 nezavisno jedan od drugog, H, (C-|-C8)-alkil; ili R72 i R73, R76 i R77 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; ili N-okside ili njihove fiziološki prihvatljive soli.7. A compound according to claims 1 to 6, characterized in that it has the formula la in which the symbols mean: R1, R2 independently of each other, H, (Ci-C8)-alkyl, -(CR78R79)0 -R12, (C-|-C4)-Alkoxy-(C-|-C4)-alkyl, R1 and R2 together with the nitrogen atom, to which they are attached, form a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, can contain 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, whereby the heterocyclic ring can be additionally substituted with F, (C1-C6)-alkyl, O-(C1-C4)-alkyl, (C-|-C4)-Alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C 1 -C 2 )-alkylene-aryl, oxo, CO(R 26 ), CON(R 27 )(R 28 ), hydroxy, N(R 31 )(R 32 ) or SO 2 CH 3 ; where R<1> and R<2> are not both CO(R26); about 0,1,2,3,4; q 1,2,3; with 0,1,2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 independently of each other, H, (C 1 -C 6 )-alkyl; or R17 and R18, R27 and R28, R31 and R32 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulphur; R12 OH, O-(C1-C6)-alkyl, O-(C1-C2)-alkylene-aryl, CN, S-(C1-C6)- alkyl, 3-12-membered mono-, bi- or spirocyclic ring which can contain 1 to 3 hetero-atoms from the group N, O and S, and the 3-12-membered ring can contain further substituents, such as F, OH, CF3, CN, oxo, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(C1-C6)-alkyl; R34, R35 independently of each other, H, (C 1 -C 4 )-alkyl; R40 H, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl; R78, R79 independently of each other, H, (C<|-C8)-alkyl, hydroxy-(C-|-C4)- alkyl, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl; R42, R42' independently of each other, H, F, Cl, Br, CF3, CN, (C1-C6)- alkyl; R 10 H, (C 1 -C 8 )-alkyl; X N(R52), single bond, C=C, C(R53)(R54), CH2CH2; R52, R53, R54 independently of each other, H, (C 1 -C 8 )-alkyl; E 5 - 7th member bivalent carbo- or heterocyclic structure rings with 0-3 heteroatoms from the group N, O and S, which can have substituents, most advantageously, from the group H, F, Cl, Br, CF3, OH, CN, OCF3, NO2, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, SO2-CH3, CO(R65); R 65 H, (C 1 -C 8 )-alkyl; K single bond, O, OCH2, CH20, S, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C, C, SCH2, SO2CH2; v 1,2,3, R66, R67, R68, R69, R70 independently of each other, H, (C 1 -C 8 )-alkyl; R11 (C1-C8)-alkyl, (C1-C4)-Alkoxy-(C1-C4)-alkyl, one 3 to 10 mono-, bi-, tri- or spirocyclic ring members which may contain 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, wherein the ring system may be further substituted with F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, O-(Ci-Cs)-alkyl, oxo, C0(R71), hydroxy, N(R75)CO(Ci-C6)-alkyl, or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of each other, H, (C-1-C8)-alkyl; or R72 and R73, R76 and R77 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can also contain 0 - 1 further hetero-atom from the group N-(Ci-C6)-alkyl, oxygen and sulphur; or N-oxides or their physiologically acceptable salts. 8. Jedinjenja prema zahtevima od 1 do 6, naznačena time, da imaju formulu lb u kojoj oznake znače: R1, R2 nezavisno jedan od drugog, H, (Ci-CsJ-alkiI, -(CR78R79)0 - R12, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-C8)-alkenil, CO-(Ci-Cs)-alkil, -CO-(CH2)0 -R12, CO-ariloksi-(Ci-C4)-alkil, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); R1 i R2 grade zajedno sa azotovim atomom, za koji su vezani, jedan 4 do 10-to člani mono-, bi- ili spirociklični prsten koji, osim azotovog atoma, može da sadrži 0 do 2 dodatna hetero-atoma izabrana iz grupe kiseonika, azota i sumpora, pri čemu heterociklični prsten može da bude dodatno supstituisan sa F, Cl, CF3, (C-|-C6)-alkil, 0-(Ci-C4)-alkil, (C1 -C4)-alkoksi-(C 1 -C4)-alkil, hidroksi-(Ci-C4)-alkil, (Co-C2)-alkilen-aril, okso, CO(R26), CON(R27)(R28), hidroksi, COO(R29), N(R30)CO(Ci-C6)-alkil, N(R31)(R32) iliS02CH3, gde R1 i R2 nisu oba CO(R26);8. Compounds according to claims 1 to 6, characterized in that they have the formula lb in which the symbols mean: R1, R2 independently of each other, H, (Ci-CsJ-alkyl, -(CR78R79)0 - R12, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO-(Ci-Cs)-alkyl, -CO-(CH2)0 -R12, CO-aryloxy-(Ci-C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); R1 and R2 together with the nitrogen atom, to which they are attached, form one 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may contain 0 to 2 additional hetero-atoms selected from the group of oxygen, nitrogen and sulphur, wherein the heterocyclic ring may be additionally substituted with F, Cl, CF3, (C-|-C6)-alkyl, O-(Ci-C4)-alkyl, (C1 -C4)-Alkoxy-(C 1 -C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or SO2CH3, where R1 and R2 are not both CO(R26); 00,1,2,3,4,5,6; q, r nezavisno jedan od drugog, 1, 2, 3; s 0,1,2,3,4; R13, R14 nezavisno jedan od drugog, jedan fenil - prsten koji može da sadrži 0-1 azotovatom; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 nezavisno jedan od drugog, H, (Ci-C6)-alkil; R18 H, (Ci-C6)-alkil, CO(C-|-C6)-alkil, CO(R33);; ili R17 i R18, R21 i R22, R27 i R28, R31 i R32 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 -1 dalji hetero-atom iz grupe N-(Ci-C6)-alkil, kiseonika i sumpora; R33 jedan 5 - 10-to člani aromatični sistem prstena koji može da sadrži još jedan hetero-atom iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (Ci-C6)-alkil, 0-(Ci-C8)-alkil; R12 je OH, 0-(Ci-C6)-alkil, 0-(Cn-C8)-alkilen-aril, CN, S-(Ci-C6)- alkil, COO(R80), CON(R81)(R82), 3 - 12-to člani mono-, bi- ili spirociklični prsten koji može da sadrži jedan ili više hetero-atoma iz grupe N, O i S, a 3 - 12-to člani prsten može da sadrži dalje supstituente, kao što su F, Cl, Br, OH, CF3, CN, okso, 0-(Ci-C6)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C1-C6)-alkil, 0-(Co-C8)-alkilen-aril, (C0-C8)-alkilen-aril, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(Ci-C6)-alkil, COCOO(C-|-C6)-alkil, COO(R40), S(0)U(R41); t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 nezavisno jedan od drugog, H, (Ci-C8)-alkil; ili R34 i R35 najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži 0 - 1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonika i sumpora i može da bude supstituisan, najpovoljnije, sa 1 - 2 okso-grupe; R36, R39 nezavisno jedan od drugog, (C3-C8)-cikloalkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supstituisan sa F, Cl, (C-|-C6)-alkil, 0-(Ci-Cs)-alkil; R40 H, (Ci-C8)-alkil, (C2-C6)-alkenil, (Crj-CsJ-alkilen-aril; R41 (Ci-C6)-alkil, 5 - 10-to člani aromatični sistem prstena koji može da sadrži 0 - 2 dalja hetero-atoma iz grupe azota, kiseonika i sumpora i može da bude supsdtituisan sa F, Cl, (Ci-C6)-alkil, 0-(Ci-C8)-alkil; R78, R79 nezavisno jedan od drugog, H, (C-|-C8)-alkil, hidroksi-(C-|- C4)-alkil, OH, (Ci-C4)-alkoksi-(Ci-C4)-alkil; R80, R81 nezavisno jedan od drugog, H, (Ci-C8)-alkil; R10 H, (Ci-C8)-alkil; E 3 - 8-mo članu bivalentnu karbo- ili hetero-cikličnu strukturu prstena sa 0 - 4 hetero-atoma iz gruoe N, O i S, koja može da ima supstituente, najpovoljnije, iz grupe H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkil, 0-(Ci-C4)-alkoksi-(Ci-C4)-alkil, S-(Ci-C6)-alkil, (Ci-C6)-alkil, (C2-C6)-alkenil, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)S02(R64), CO(R65) i može da bude mono- ili biciklična; R57, R58, R61, R63 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; R62, R64, R65 nezavisno jedan od drugog, H, (Ci-Cs)-alkil, aril; K jedna veza, O, OCH2, CH20, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, SO2CH2; v 1,2,3,4; R66, R67, R68, R69, R70 nezavisno jedan od drugog, H, (C-|-C8)-alkil; R11 H, (Ci-Cs)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, (C3-C8)-alkenil, (C3-C8)-alkinil, jedan 3 do 10-to člani mono-, bi-, tri- ili spirociklični prsten koji može da sadrži 0 do 4 hetero-atoma izabranih iz grupe kiseonika, azota i sumpora, pri čemu sistem prstena može da bude dodatno supstituisan sa F, Cl, Br, CF3, CN, (Ci-C6)-alkil, 0-(Ci-C8)-alkil, (Ci-C4)-alkoksi-(Ci-C4)-alkil, hidroksi-(Ci-C4)-alkil, (Co-CsJ-alkilen-aril, okso, CO(R71), CON(R72)(R73), hidroksi, COO(R74), N(R75)CO(Ci-C6)-alkil, N(R76)(R77) ili S02CH3SCF3; R71, R72, R73, R74, R75, R76, R77 nezavisno jedan od drugog, H, (Ci-Cs)-alkil; ili R72 i R73, R76 i R77 nezavisno jedan od drugog, najpovoljnije zajedno sa azotovim atomom, za koji su vezani, jedan 5 - 6-to člani prsten koji, osim azotovog atoma, može da sadrži i 0 - 1 dalji hetero-atom iz grupe N-(C-|-C6)-alkil, kiseonika i sumpora; N-okside i njihove fiziološki prihvatljive soli.00,1,2,3,4,5,6; q, r independently of each other, 1, 2, 3; with 0,1,2,3,4; R13, R14 independently of each other, one phenyl ring which can contains 0-1 nitrogen; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of each other, H, (C 1 -C 6 )-alkyl; R18 H, (C1-C6)-alkyl, CO(C-1-C6)-alkyl, CO(R33);; or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of each other, preferably together with the nitrogen atom, to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can also contain 0-1 further hetero-atoms from the group N-(Ci-C6)-alkyl, oxygen and sulphur; R33 is a 5- to 10-membered aromatic ring system that can contains another hetero-atom from the group of nitrogen, oxygen and sulfur and can be substituted with F, Cl, (Ci-C6)-alkyl, O-(C1-C8)-alkyl; R12 is OH, O-(C1-C6)-alkyl, O-(Cn-C8)-alkylene-aryl, CN, S-(C1-C6)- alkyl, COO(R80), CON(R81)(R82), a 3-12-membered mono-, bi- or spirocyclic ring which may contain one or more hetero-atoms from the group N, O and S, and the 3-12-membered ring may contain further substituents, such as F, Cl, Br, OH, CF3, CN, oxo, 0-(Ci-C6)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, (C1-C6)-alkyl, O-(Co-C8)-alkylene-aryl, (C0-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C-|-C6)-alkyl, COO(R40), S(O)U(R41); t 0,1,2,3,4,5,6; in 0,1,2; R34, R35, R37, R38 independently of each other, H, (C 1 -C 8 )-alkyl; or R34 and R35 most advantageously together with the nitrogen atom, to which they are attached, a 5 - 6-membered ring which, apart from the nitrogen atom, can contain 0 - 1 further hetero-atom from the group N-(C-|-C6)-alkyl, oxygen and sulfur and can be substituted, most advantageously, with 1 - 2 oxo-groups; R36, R39 independently of each other, (C3-C8)-cycloalkyl, 5 - 10 members an aromatic ring system which may contain 0-2 further hetero-atoms from the group of nitrogen, oxygen and sulfur and may be substituted with F, Cl, (C-|-C6)-alkyl, O-(C1-C8)-alkyl; R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (C1-C8)-alkylene-aryl; R41 (Ci-C6)-alkyl, 5 - 10-membered aromatic ring system which may contain 0 - 2 further hetero-atoms from the nitrogen group, oxygen and sulfur and may be substituted with F, Cl, (C 1 -C 6 )-alkyl, O-(C 1 -C 8 )-alkyl; R78, R79 independently of each other, H, (C-|-C8)-alkyl, hydroxy-(C-|- C 4 )-alkyl, OH, (C 1 -C 4 )-Alkoxy-(C 1 -C 4 )-Alkyl; R80, R81 independently of each other, H, (C1-C8)-alkyl; R 10 H, (C 1 -C 8 )-alkyl; E 3 - 8th member bivalent carbo- or hetero-cyclic structure ring with 0 - 4 heteroatoms from the group N, O and S, which can have substituents, most advantageously, from the group H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Ci-C6)-alkyl, 0-(Ci-C4)-alkoxy-(Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, N(R61)CO(R62), N(R63)SO2(R64), CO(R65) and can be mono- or bicyclic; R57, R58, R61, R63 independently of each other, H, (C 1 -C 8 )-alkyl; R62, R64, R65 independently of each other, H, (C 1 -C 8 )-alkyl, aryl; K single bond, O, OCH2, CH20, S, SO, SO2, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, SO2CH2; c 1,2,3,4; R66, R67, R68, R69, R70 independently of each other, H, (C-1-C8)-alkyl; R11 H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3 to 10 membered mono-, bi-, tri- or spirocyclic ring which may contain 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur groups, whereby the ring system can be additionally substituted with F, Cl, Br, CF3, CN, (Ci-C6)-alkyl, O-(Ci-C8)-alkyl, (Ci-C4)-Alkoxy-(Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-CsJ-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH3SCF3; R71, R72, R73, R74, R75, R76, R77 independently of each other, H, (C 1 -C 8 )-alkyl; or R72 and R73, R76 and R77 independently of each other, preferably together with nitrogen by the atom to which they are attached, a 5-6-membered ring which, apart from the nitrogen atom, can also contain 0-1 further hetero-atoms from the group N-(C-|-C6)-alkyl, oxygen and sulphur; N-oxides and their physiologically acceptable salts. 9. Lek koji sadrži jedno ili više jedinjenja prema zahtevima od 1 do 8.9. Medicine containing one or more compounds according to claims 1 to 8. 10. Lek koji sadrži jedno ili više jedinjenja prema zahtevima od 1 do 8 i jedan ili više anoreksijski aktivnih sastojaka.10. Medicine containing one or more compounds according to claims 1 to 8 and one or more anorexic active ingredients. 11. Jedinjenje formule I prema zahtevima od 1 do 8, za upotrebu kao leka za profilaksu ili lečenje gojaznosti.11. A compound of formula I according to claims 1 to 8, for use as a medicament for the prophylaxis or treatment of obesity. 12. Jedinjenje formule I prema zahtevima od 1 do 8, za upotrebu kao leka za profilaksu ili lečenje šećerne bolesti tipa II.12. A compound of formula I according to claims 1 to 8, for use as a drug for the prophylaxis or treatment of type II diabetes. 13. Jedinjenje formule I prema zahtevima od 1 do 8 u kombinaciji sa najmanje jednim daljim anoreksijski aktivnim sastojkom, za upotrebu kao leka za profilaksu ili lečenje gojaznosti.13. A compound of formula I according to claims 1 to 8 in combination with at least one further anorexic active ingredient, for use as a medicine for the prophylaxis or treatment of obesity. 14. Jedinjenje formule I prema zahtevima od 1 do 8 u kombinaciji sa najmanje jednim daljim anoreksijski aktivnim sastojkom, za upotrebu kao leka za profilaksu ili lečenje šećerne bolesti tipa II.14. The compound of formula I according to claims 1 to 8 in combination with at least one further anorexic active ingredient, for use as a medicine for the prophylaxis or treatment of type II diabetes. 15. Postupak za proizvodnju leka koji sadrži jedno ili više jedinjenja formule I, prema zahtevima od 1 do 8, koji se sastoji od mešanja aktivnih sastojaka sa nekim farmaceutski prihvatljivim nosačem i prevođenja ove smeše u oblik pogodan za davanje.15. A method for the production of a drug containing one or more compounds of formula I, according to claims 1 to 8, which consists of mixing the active ingredients with a pharmaceutically acceptable carrier and converting this mixture into a form suitable for administration. 16. Korišćenje jedinjenja formule I prema zahtevima od 1 do 8 za proizvodnju leka za smanjenje težine kod sisara.16. Use of a compound of formula I according to claims 1 to 8 for the manufacture of a medicament for weight reduction in mammals. 17. Korišćenje jedinjenja formule I prema zahtevima od 1 do 8 za proizvodnju leka za profilaksu ili lečenje gojaznosti.17. Use of the compound of formula I according to claims 1 to 8 for the production of a drug for the prophylaxis or treatment of obesity. 18. Korišćenje jedinjenja formule I prema zahtevima od 1 do 8 za proizvodnju leka za profilaksu ili lečenje šećerne bolesti tipa II.18. Use of the compound of formula I according to claims 1 to 8 for the production of a drug for the prophylaxis or treatment of type II diabetes. 19. Korišćenje jedinjenja formule I prema zahtevima od 1 do 8 za proizvodnju leka za lečenje poremećaja raspoloženja i drugih psihijatriskih indikacija, i za lečenje oboljenja vezanih sa cirkadianskim ritmusom, i za lečenje zloupotrebe lekova.19. Use of the compound of formula I according to claims 1 to 8 for the production of a drug for the treatment of mood disorders and other psychiatric indications, and for the treatment of diseases related to the circadian rhythm, and for the treatment of drug abuse. 20. Korišćenje jedinjenja formule I prema zahtevima od 1 do 8 kao MCH antagonista.20. Use of a compound of formula I according to claims 1 to 8 as an MCH antagonist.
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