NO320912B1 - Thiooxindole derivatives, pharmaceutical compositions comprising these and their use in the manufacture of medicaments. - Google Patents

Thiooxindole derivatives, pharmaceutical compositions comprising these and their use in the manufacture of medicaments. Download PDF

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Publication number
NO320912B1
NO320912B1 NO20015380A NO20015380A NO320912B1 NO 320912 B1 NO320912 B1 NO 320912B1 NO 20015380 A NO20015380 A NO 20015380A NO 20015380 A NO20015380 A NO 20015380A NO 320912 B1 NO320912 B1 NO 320912B1
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Norway
Prior art keywords
cyclohexane
spiro
indole
alkyl
indol
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NO20015380A
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Norwegian (no)
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NO20015380L (en
NO20015380D0 (en
Inventor
James P Edwards
Puwen Zhang
Andrew Fensome
Jay E Wrobel
Christopher M Tegley
Marci C Koko
Edward G Melenski
Todd Kevin Jones
Lin Zhi
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Ligand Pharm Inc
Wyeth Corp
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Priority claimed from US09/552,033 external-priority patent/US6355648B1/en
Application filed by Ligand Pharm Inc, Wyeth Corp filed Critical Ligand Pharm Inc
Publication of NO20015380D0 publication Critical patent/NO20015380D0/en
Publication of NO20015380L publication Critical patent/NO20015380L/en
Publication of NO320912B1 publication Critical patent/NO320912B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring

Description

Foreliggende oppfinnelse angår forbindelser som er agonister for progesteronreseptoren, deres anvendelse og farmasøytiske preparater omfattende disse. The present invention relates to compounds which are agonists for the progesterone receptor, their use and pharmaceutical preparations comprising these.

Intracellulære reseptorer (IR) danner en klasse strukturelt relaterte genregulatorer som er kjent som "ligandavhengige transkripsjonsfaktorer" (R.M. Evans, Science, 240, 889, 1988). Steroidreseptorfamilien er et undersett av IR-familien og inkluderer progesteronreseptoren (PR), østrogenreseptoren (ER), androgenreseptoren (AR), glukokotrikoidre-septoren (GR), og mineralokortikoidreseptoren (MR). Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand-dependent transcription factors" (R.M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family and includes the progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).

Det naturlige hormon, eller ligand, for PR er steroide progesteron, men syntetiske forbindelser som medroksyprogesteronacetat eller levonergestrel er fremstilt og tjener også som ligander. Når først en slik ligand er tilstede i fluidet som omgir en celle passerer den gjennom membranet ved passiv diffusjon og binder til IR og kreerer et resep-tor/ligandkompleks. Dette kompleks binder til spesifikke genpromotere som er tilstede i cellens DNA. Når det først er bundet til DNA modulerer komplekset produksjonen av mRNA og protein som kodes av genet. The natural hormone, or ligand, for PR is the steroid progesterone, but synthetic compounds such as medroxyprogesterone acetate or levonergestrel have been prepared and also serve as ligands. Once such a ligand is present in the fluid that surrounds a cell, it passes through the membrane by passive diffusion and binds to IR and creates a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to DNA, the complex modulates the production of mRNA and protein encoded by the gene.

En forbindelse som binder til en IR og etterligner virkningen av det naturlige hormon kalles en agonist, mens en forbindelse som inhiberer virkningen av hormonet er en antagonist. A compound that binds to an IR and mimics the action of the natural hormone is called an agonist, while a compound that inhibits the action of the hormone is an antagonist.

PR-agonister (naturlige og syntetiske) er kjent for å spille en viktig rolle hos kvinners helse. PR-agonister benyttes ved fødselskontrollformuleringer, karakteristisk i nærvær av en en ER-agonist, alternativt kan de benyttes i forbindelse med en PR-antagonist. ER-agonister er benyttet for å behandle menopausesymptom, men har vært assosiert med en proliferativ virkning på uterus som kan føre til en øket risiko for uterincancere. Koadministrering av en PR-agonist reduserer/bøter på denne risiko. PR agonists (natural and synthetic) are known to play an important role in women's health. PR agonists are used in birth control formulations, characteristically in the presence of an ER agonist, alternatively they can be used in connection with a PR antagonist. ER agonists are used to treat menopause symptoms, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancer. Co-administration of a PR agonist reduces/compensates this risk.

Forbindelsene ifølge oppfinnelsen har vist seg å virke som kompetitive inhibitorer for progesteronbinding til PR og virker som agonister. Disse forbindelser kan benyttes for kontrasepsjon og postmenopausal hormonerstatningsterapi. The compounds according to the invention have been shown to act as competitive inhibitors of progesterone binding to PR and act as agonists. These compounds can be used for contraception and postmenopausal hormone replacement therapy.

Jones, et al., beskriver i U.S. patent nr. 5,688,810 PR-antagonisten dihydroquinolin A. Jones, et al., describe in the U.S. patent No. 5,688,810 the PR antagonist dihydroquinoline A.

Jones, et al., beskriver enoleteren B (U.S. patent nr. 5,693,646) som en PR-ligand. Jones, et al., describe the enoleter B (U.S. Patent No. 5,693,646) as a PR ligand.

Jones, et al, beskriver forbindelsen C (U.S. patent nr. 5,696,127) som en PR-ligand. Jones, et al., describe compound C (U.S. Patent No. 5,696,127) as a PR ligand.

Zhi, et al., beskriver laktonene D, E og F som PR-antagonister (J. Med. Chem., 41,291, 1998). Zhi, et al., describe lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998).

Zhi, et aL, beskriver eteren G som en PR-agonist (J. Med. Chem., 41,291,1998). Zhi, et al, describes the ether G as a PR agonist (J. Med. Chem., 41,291,1998).

Combs, et al., beskriver amidet H som Ugand for PR (J. Med. Chem., 38,4880,1995). Combs, et al., describe the amide H as Uganda for PR (J. Med. Chem., 38, 4880, 1995).

Perlman, et al., beskriver vitamin D analogen I som PR-ligand (Tet. Letters, 35,2295, 1994). Perlman, et al., describe the vitamin D analog I as PR ligand (Tet. Letters, 35, 2295, 1994).

Hamann, et al, beskriver PR-antagonisten J (Ann. N.Y. Acad. Sei., 761,383,1995). Hamann, et al., describe the PR antagonist J (Ann. N.Y. Acad. Sci., 761,383,1995).

Chen et al. beskriver PR-antagonisten K (Chen et al., "POI-37", 16,h Int. Cong. Het. Chem., Montana, 1997). Chen et al. describes the PR antagonist K (Chen et al., "POI-37", 16,h Int. Cong. Het. Chem., Montana, 1997).

Kurihari et al. beskriver PR-ligand L (J. Antibiotics, 50,360,1997). Kurihari et al. describes PR ligand L (J. Antibiotics, 50,360,1997).

Kuhla et al., beskriver oksindolet M som et kardiotonikum (WO 86/03749). Kuhla et al., describe the oxindole M as a cardiotonic (WO 86/03749).

Weber beskriver oksindolet N for kardiovaskulære indikasjoner (WO 91/06545). Weber describes the oxindole N for cardiovascular indications (WO 91/06545).

Fischer et al. krever en fremstillingsmåte for fremstilling av forbindelser som inkluderer den generiske struktur O (US 5 453 516). Fischer et al. claims a method of preparation for the preparation of compounds that include the generic structure O (US 5,453,516).

R = diverse R = miscellaneous

Singh et al. beskriver PDE Ill-inbibitoren P (J. Med. Chem, 37,248,1994). Singh et al. describes the PDE II inhibitor P (J. Med. Chem, 37,248,1994).

Andreani et al. beskriver det cytotoksiske middel Q (Acta. Pharn. Nord., 2,407,1990). Andreani et al. describes the cytotoxic agent Q (Acta. Pharn. Nord., 2,407,1990).

Binder et al. beskriver strukturen R som er et mellomprodukt for fremstilling av COX II-inhibitorer (WO 97/13767). Binder et al. describes the structure R which is an intermediate for the production of COX II inhibitors (WO 97/13767).

Waish (A. H. Robins) beskriver oksindolet S som et mellomprodukt (US patent nr. 4,440,785, US patent nr. 4,670,566). Waish (A.H. Robins) describes the oxindole S as an intermediate (US Patent No. 4,440,785, US Patent No. 4,670,566).

Bohm et al. krever oksindolet T som kardiovaskulært middel (WO 91/06545). Bohm et al. claims oxindole T as a cardiovascular agent (WO 91/06545).

Bohm et al. inkluderte den generiske struktur U (WO 91/04974). Bohm et al. included the generic structure U (WO 91/04974).

JP 63112584 A inneholder den generiske struktur V: JP 63112584 A contains the generic structure V:

Boar et al. beskriver dioksolanet W som et mellomprodukt for fremstilling av acetyl-cholinesterase-inhibitorer (WO 93/12085 Al). Boar et al. describes the dioxolane W as an intermediate for the production of acetyl-cholinesterase inhibitors (WO 93/12085 A1).

Kende et al. beskriver metodologier for fremstilling av 3,3-substituerte oksindoler, for eksempel X, som ble benyttet i foreliggende oppfinnelse (Synth. Commun., 12,1, 1982). Kende et al. describes methodologies for the preparation of 3,3-substituted oxindoles, for example X, which were used in the present invention (Synth. Commun., 12,1, 1982).

Foreliggende oppfinnelse tilveiebringer forbindelser med formelen: The present invention provides compounds with the formula:

der: there:

Ri og R2uavhengig er valgt fra gruppen bestående av H, Ct-6-alkyl, C|-6-alkyl substituert med fenyl, R 1 and R 2 are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl substituted with phenyl,

eller Ri og R2er forenet for å danne en ring omfattende -CH2(CH2)nCH2-, or R1 and R2 are joined to form a ring comprising -CH2(CH2)nCH2-,

ner et heltall fra 1 til 5; ner an integer from 1 to 5;

R3er valgt fra gruppen bestående av H, OH og CORA; R 3 is selected from the group consisting of H, OH and CORA;

R<A>erC].3alkoksy; R<A>erC].3Alkoxy;

RterH; RterH;

R<5>er valgt fra gruppene a) og b); R<5>is selected from groups a) and b);

a) en substituert benzenring inneholdende substituentene X, Y og Z som vist nedenfor: a) a substituted benzene ring containing the substituents X, Y and Z as shown below:

X er valgt fra gruppen omfattende H halogen, OH, CN, Ci-3alkoksy, NO2, X is selected from the group consisting of H halogen, OH, CN, C 1-3 alkoxy, NO 2 ,

Ci-3perfluoralkyl, og C(=N-OH)-NH2; C 1-3 perfluoroalkyl, and C(=N-OH)-NH 2 ;

Y og Z uavhengig er valgt fra gruppen bestående av H, halogen, CN, N02og Cioalkoksy; Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 and C 10 alkoxy;

der ikke alle X, Y og Z er H; b) tienyl, pyrrolyl, pyrimidinyl, furanyl eller pyridinyl inneholdende en eller to uavhengige substituenter valgt fra gruppen bestående av H, halogen, CN og CMalkyl, wherein not all X, Y and Z are H; b) thienyl, pyrrolyl, pyrimidinyl, furanyl or pyridinyl containing one or two independent substituents selected from the group consisting of H, halogen, CN and C-M alkyl,

C(S)NH2og C(=N-OH)-NH2; C(S)NH2 and C(=N-OH)-NH2;

hvor pyrrolringen eventuelt er substituert på N-atomet med H, Ci-3-alkyl, C(0)OCm-alkyl eller Ci-4-alkyl; where the pyrrole ring is optionally substituted on the N atom with H, C1-3 alkyl, C(0)OCm alkyl or C1-4 alkyl;

Q<1>er S, NR7, eller CRgRg; Q<1> is S, NR7, or CRgRg;

R<7>er valgt fra gruppen omfattende CN, H og OR<11>; R<7> is selected from the group consisting of CN, H and OR<11>;

Rs og R9er uavhengige substituenter valgt fra gruppen bestående av N02, CN eller CO2R10, R s and R 9 are independent substituents selected from the group consisting of NO 2 , CN or CO 2 R 10 ,

Rio er CMalkyl; R 10 is C 1 -C alkyl;

R<11>er H eller C(0)Ci.3-alkyl; R<11> is H or C(O)C1-3 alkyl;

eller or

et farmasøytisk akseptabelt salt derav. a pharmaceutically acceptable salt thereof.

To foretrukne sett av forbindelser ifølge oppfinnelsen er angitt ved strukturene: Two preferred sets of compounds according to the invention are indicated by the structures:

der: there:

R3er valgt fra gruppen bestående av H, OH og CORA; R 3 is selected from the group consisting of H, OH and CORA;

RA er Ci.3alkoksy; R A is C 1-3 alkoxy;

RierH; RierH;

R5er a) eller b); R 5 is a) or b);

a) en substituert benzenring med formelen: a) a substituted benzene ring of the formula:

X er valgt fra gruppen bestående av H, halogen, CN, NO2eller Ci-3perfluoralkyl; X is selected from the group consisting of H, halogen, CN, NO 2 or C 1-3 perfluoroalkyl;

Y er på 4'- eller 5'-posisjon og valgt fra gruppen bestående av H, halogen, CN, NO2, djalkoksy og CMalkyl; Y is in the 4' or 5' position and selected from the group consisting of H, halogen, CN, NO 2 , dialkyloxy and C 1 -C alkyl;

der X og Y ikke begge er H; eller where X and Y are not both H; or

b) en seksleddet ring med strukturen: b) a six-membered ring with the structure:

der: there:

X<1>er N eller CX<2>;X<1> is N or CX<2>;

X<2>er halogen, CN eller CSNH2; X<2>is halogen, CN or CSNH2;

Q<1>er S, NR7eller CRgRg; Q<1> is S, NR7 or CRgRg;

R7er CN; R 7 is CN;

Rg og R9er uavhengige substituenter valgt fra gruppen bestående av NO2, CN og CO2R10; Rg and R9 are independent substituents selected from the group consisting of NO2, CN and CO2R10;

Rio er Cioalkyl; R 10 is C 10 alkyl;

eller or

et farmasøytisk akseptabelt salt derav. a pharmaceutically acceptable salt thereof.

Andre foretrukne forbindelser har formelen: Other preferred compounds have the formula:

der there

Rh er valgt fra gruppen bestående av H eller C(0)Ci-3-alkyl; Rh is selected from the group consisting of H or C(O)C 1-3 alkyl;

R5er a), b) eller c): R5 is a), b) or c):

a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: a) a substituted benzene ring containing the substituents X and Y as shown below:

der: there:

X er valgt fra gruppen bestående av H, halogen, CN, CNH2COH, Ci^alkoksy, Ci^alkyl, NO2, Cioperfluoralkyl; X is selected from the group consisting of H, halogen, CN, CNH 2 COH, C 1-4 alkoxy, C 1-4 alkyl, NO 2 , Cioperfluoroalkyl;

Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci-3alkoksy og Ci^alkyl; Y is in the 4' or 5' position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1-3 alkoxy and C 1-3 alkyl;

der X og Y ikke begge er H; where X and Y are not both H;

b) en femleddet ring med strukturen: b) a five-membered ring with the structure:

der: there:

UerO, SellerNRe; UerO, SellerNRe;

Re er H, Ci.3alkyl eller Ci.4C02alkyl; R e is H, C 1-3 alkyl or C 1-4 CO 2 alkyl;

X' er valgt fra gruppen bestående av halogen, CN, N02, CSNH2og Ci^alkyl; X' is selected from the group consisting of halogen, CN, NO 2 , CSNH 2 and C 1-6 alkyl;

Y' er valgt fra gruppen bestående av H, halogen, og Ci-4alkyl; Y' is selected from the group consisting of H, halogen, and C 1-4 alkyl;

der nevnte halogen er F; eller wherein said halogen is F; or

c) en seksleddet med strukturen: c) a six-membered one with the structure:

der: there:

Xi er N eller CX<2>; Xi is N or CX<2>;

X<2>er halogen, CN eller CONH2; X<2> is halogen, CN or CONH2;

eller or

et farmasøytisk akseptabelt salt derav. a pharmaceutically acceptable salt thereof.

En ytterligere foretrukken undergruppe av forbindelser har formelen: A further preferred subset of compounds has the formula:

der: there:

R5er a), b) eller c): R5 is a), b) or c):

a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: a) a substituted benzene ring containing the substituents X and Y as shown below:

der: there:

X er valgt fra gruppen bestående av H, halogen, CN, CNHNOH, Ci^alkoksy, Cualkyl, NO2og Ci.3perfluoralkyl; X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-6 alkoxy, Cualkyl, NO2 and C1-3 perfluoroalkyl;

Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci-3alkoksy og Cijalkyl; Y is in the 4' or 5' position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1-3 alkoxy and C 1-3 alkyl;

der X og Y ikke begge er H; where X and Y are not both H;

b) en femleddet ring med strukturen: b) a five-membered ring with the structure:

der: there:

Uer O, Seller NR*; Uer O, Seller NR*;

Réer H, Ci-3alkyl eller Ci-4C02alkyl; Is H, C 1-3 alkyl or C 1-4 CO 2 alkyl;

X' er valgt fra gruppen bestående av halogen, CN, CSNH2og Ci^alkyl; X' is selected from the group consisting of halogen, CN, CSNH 2 and C 1-6 alkyl;

Y' er valgt fra gruppen bestående av H, halogen, og CMalkyl; Y' is selected from the group consisting of H, halogen, and C 1 -C alkyl;

der nevnte halogen er F; eller wherein said halogen is F; or

c) en seksleddet ring med strukturen: c) a six-membered ring with the structure:

der: there:

X, er N eller CX<2>; X, is N or CX<2>;

X<2>er halogen, CN eller CONH2; X<2> is halogen, CN or CONH2;

eller or

et farmasøytisk akseptabelt salt derav. a pharmaceutically acceptable salt thereof.

Nok en foretrukken gruppe av disse forbindelser inkluderer de som har den generelle formel: Another preferred group of these compounds includes those having the general formula:

der: there:

Ri 5 er valgt fra gruppen bestående av CO2R10og CN; Ri 5 is selected from the group consisting of CO 2 R 10 and CN;

Ri0erCi.3alkyl; R 10 -C 1-3 alkyl;

R5er a), b) eller c): R5 is a), b) or c):

a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: a) a substituted benzene ring containing the substituents X and Y as shown below:

der: there:

X er valgt fra gruppen bestående av H, halogen, CN, CNHNOH, Ci-3alkoksy, Ci.3alkyl, NO2, Ci-3perfluoralkyl; X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-3 alkoxy, C1-3 alkyl, NO2, C1-3 perfluoroalkyl;

Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci^alkoksy og CMalkyl; Y is at the 4'- or 5'-position and is selected from the group consisting of H, halogen, CN, NO2, C1-6 alkoxy and C1-6 alkyl;

der X og Y ikke begge er H; where X and Y are not both H;

b) en femleddet ring med strukturen: b) a five-membered ring with the structure:

der: there:

UerO, SellerNRe; UerO, SellerNRe;

Re er H, Ci.3alkyl eller CMC02alkyl; Re is H, C1-3 alkyl or CMC02 alkyl;

X' er valgt fra gruppen bestående av halogen, CN, NO2, CSNH2og Cualkyl; X' is selected from the group consisting of halogen, CN, NO2, CSNH2 and Cualkyl;

Y' er valgt fra gruppen bestående av H, halogen, og Ci^alkyl; Y' is selected from the group consisting of H, halogen, and C 1-6 alkyl;

eller or

c) en seksleddet ring med strukturen: c) a six-membered ring with the structure:

der: there:

X, er N eller CX<2>;X, is N or CX<2>;

X<2>er halogen, CN eller CSNH2; X<2>is halogen, CN or CSNH2;

eller or

et farmasøytisk akseptabelt salt derav. a pharmaceutically acceptable salt thereof.

En ytterligere foretrukken subgruppe av forbindelser har formelen: A further preferred subgroup of compounds has the formula:

der: there:

R5er a), b) eller c): R5 is a), b) or c):

a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: a) a substituted benzene ring containing the substituents X and Y as shown below:

der: there:

X er valgt fra gruppen bestående av H, halogen, CN, CNHNOH, Ci.3alkoksy, Ci.3alkyl, NO2og C].3perfluoralkyl; X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-3 alkoxy, C1-3 alkyl, NO2 and C1-3 perfluoroalkyl;

Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci.3alkoksy og Ci.3alkyl; Y is in the 4'- or 5'-position and is selected from the group consisting of H, halogen, CN, NO2, C1-3 alkoxy and C1-3 alkyl;

der X og Y ikke begge er H; where X and Y are not both H;

b) en femleddet ring med strukturen: b) a five-membered ring with the structure:

der: there:

UerO, SellerNRe; UerO, SellerNRe;

Re er H, Ci.3alkyl eller CMC02alkyl; Re is H, C1-3 alkyl or CMC02 alkyl;

X' er valgt fra gruppen bestående av halogen, CN, CSNH2og C1.3alk.yl; X' is selected from the group consisting of halogen, CN, CSNH 2 and C 1-3 alk.yl;

Y' er valgt fra gruppen bestående av H, halogen, og Ci^alkyl; Y' is selected from the group consisting of H, halogen, and C 1-6 alkyl;

der nevnte halogen er F; eller wherein said halogen is F; or

c) en seksleddet ring med strukturen: c) a six-membered ring with the structure:

der: there:

Xi er N eller CX<2>;Xi is N or CX<2>;

X<2>er halogen, CN eller CONH2; X<2> is halogen, CN or CONH2;

eller or

et farmasøytisk akseptabelt salt derav. a pharmaceutically acceptable salt thereof.

En ytterligere foretrukken gruppe forbindelser ifølge oppfinnelsen er valgt blant: 5"-(3-fluorfenyl)spiro[cykloheksan-l ,3 '-[3H]indol]-2'(l 'H)-on oksim, 5 '-(2-fluorfenyl)spiro[cykloheksan-1,3 '-[3H]indol]-2'(l 'H)-on oksim, 5 '-(4-fluorfenyl)spiro[cykloheksan-1,3 '-[3H]indol]-2'(l 'H)-on oksim, 5'-(3,4-difluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on oksim, 5' -(3 -metoksyfenyl)-spiro [cykloheksan-1,3'- [3H]indol] -2' (1 'H)-on oksim, 5' -(3 -nitrofenyl)spiro [cykloheksan-1,3' - [3H]indol] -2' (1 'H)-on oksim, og 5 '-(3-cyanofenyl)-spiro[cykloheksan-1,3 '-[3H]indol]-2'(l 'H)-on oksim, A further preferred group of compounds according to the invention is selected from: 5"-(3-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one oxime, 5'-(2 -fluorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-one oxime, 5'-(4-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indole ]-2'(1'H)-one oxime, 5'-(3,4-difluorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-one oxime, 5 ' -(3 -Methoxyphenyl)-spiro [cyclohexane-1,3'- [3H]indole] -2' (1 'H)-one oxime, 5' -(3 -nitrophenyl)spiro [cyclohexane-1,3' - [3H]indole]-2' (1'H)-one oxime, and 5'-(3-cyanophenyl)-spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H) -on oxime,

eller et farmasøytisk akseptabelt salt derav. or a pharmaceutically acceptable salt thereof.

En ytterligere foretrukken gruppe har strukturen: A further preferred group has the structure:

der: there:

R5er den substituerte benzenring med formelen: R5 is the substituted benzene ring of the formula:

X er valgt fra gruppen bestående av H, halogen, CN, Ci^alkoksy, Cualkyl, N02og Ci-3perfluoralkyl; X is selected from the group consisting of H, halogen, CN, C 1-3 alkoxy, C 1-3 alkyl, NO 2 and C 1-3 perfluoroalkyl;

Y er på 4'- eller 5'-posisjon og er valgt blant gruppen bestående av H, halogen, CN, NO2, Ci^alkoksy og Ci^alkyl; Y is in the 4'- or 5'-position and is selected from the group consisting of H, halogen, CN, NO2, C1-6 alkoxy and C1-6 alkyl;

der X og Y ikke begge er H. where X and Y are not both H.

En ytterligere foretrukken undergruppe av forbindelser har formelen: A further preferred subset of compounds has the formula:

der: there:

R5er den femleddede ring med strukturen: R5 is the five-membered ring with the structure:

der: there:

U er O, Seller NR*; U is O, Seller NR*;

ReerHellerCi-aalkyl; R 1 -Heller C 1-6 alkyl;

X' er valgt blant gruppen bestående av halogen, CN, CSNH2, Cioalkyl, og Cualkoksy; X' is selected from the group consisting of halogen, CN, CSNH2, C10alkyl, and C10alkyl;

Y' er valgt blant gruppen bestående av H, halogen og Cualkyl; Y' is selected from the group consisting of H, halogen and Cualkyl;

der nevnte halogen er F. wherein said halogen is F.

En ytterligere foretrukken undergruppe av forbindelser har formelen: A further preferred subset of compounds has the formula:

der: there:

R5er den seksleddede ring med strukturen: R5 is the six-membered ring with the structure:

X<1>er N eller CX<2>; X<1> is N or CX<2>;

X<2>er halogen, CN eller CSNH2. X<2>is halogen, CN or CSNH2.

En ytterligere foretrukken gruppe forbindelser ifølge oppfinnelsen er valgt fra gruppen bestående av: S^CS-klorfenylJspirotcykloheksan-l.S^tSHlindoll^XrHHion, 3- (r,2'-dihydro-2'-tioksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)benzonitril, 4- (^2^dihydro-2'-tioksospiro[cyklohe^ 3- (l ,2-dihydro-2-tioksospiro[cykloheksan-1,3-[3H]indol]-5-yl)-5-fluorbenzonitril, 4- metyl-5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]-indol]-5-yl)-2-tiofen tioamid, A further preferred group of compounds according to the invention is selected from the group consisting of: S^CS-chlorophenylJspirotcyclohexane-1.S^tSHlindoll^XrHHion, 3-(r,2'-dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H ]indol]-5'-yl)benzonitrile, 4-(^2^dihydro-2'-thioxospiro[cyclohe^ 3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indole] -5-yl)-5-fluorobenzonitrile, 4-methyl-5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]-indol]-5-yl)-2-thiophene thioamide,

5- (l,2-dihydro-2-tioksospiro[cyklopentan-l,3-[3H]indol]-5'-yl)-lH-pyrrol-2-karbonitril, 5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrole-2-carbonitrile,

5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-lH-pym)l-2-karbonitril, 5-(2'-tioksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-l-metyl-pyrrol-2-karbonitril, 5-(l,2-dihydro-2-tioksospiro[cyklopentan-l,3-[3H]indol]-5-yl)-3-tiofenkarbonitril, 5-(l,2-dihydro-tioksospiro(cyklopentan-l,3-[3H]indol)-5-yl)-2-tiofenkarbonitril, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-pym)1-2-carbonitrile, 5-(2'-thioxospiro[cyclohexane- 1,3'-[3H]indol]-5'-yl)-1-methyl-pyrrole-2-carbonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indole ]-5-yl)-3-thiophenecarbonitrile, 5-(1,2-dihydro-thioxospiro(cyclopentan-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile,

5-(3-fluor-4-metoksyf(myl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5-(2-amino-5-pyrimidinyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 3-(l,2-dihydro-2-tioksospiro[cyklopentan-l,3-[3H]indol]-5-yl)-5-fluorbenzonitril, 3- (l ,2-dihydro-2-tioksospiro[cykloheksan-1,3-[3H]indol]-2-yl)-4-fluorbenzonitril, 5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-2-yl)-3-pyirdinkarbom 5-(3,4-difluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5-(5-klor-2-tienyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5 -(1,2-dihydro-2-tioksospiro [cykloheksan-1,3- [3H]indol] -5-yl)-3 -furankarbonitril, 5-(3-klor-4-fluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5-(3-klor-5-fluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5-(3,5-difluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH9-tion, 5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-4-propyl-2-tiofenkarbonitril, 5 -(3-fluor-4-nitrofenyl)spiro [cykloheksan-1,3- [3H]indol] -2(1 H)-tion, 4- (l ,2-dihydro-2-tioksospiro[cykloheksan-1,3-[3H]indol]-5-yl)-2-furankarbonitril, 5"-(2-klorfenyl)spiro[cyklobutan-1,3"-[3H]indol]-2"(l "H)-tion, 5"-(2-klorfenyl)spiro[cykloheksan-l,3"-[3H]indol]-2"(l"H)-tion, 5"-(4-klorfenyl)spiro[cykloheksan-l,3"-[3H]indol]-2"(l"H)-tion, 5- (l",2"-dihydro-2"-tioksospiro[cykloheksan-l,3"-[3H]indol]-5"-yl)-4-metyl-2-tiofenkarbonitril, 5 '-(l",2"-dihydro-2"-tioksospiro[cykloheksan-1,3"-[3H]indol]-5"-yl)-2-tiofenkarbonitril, 5-(3-Fluoro-4-methoxy(myl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5-(2-amino-5-pyrimidinyl)spiro[cyclohexane-1 ,3-[3H]indol]-2(1H)-thione, 3-(1,2-dihydro-2-thioxospiro[cyclopentan-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile, 3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-4-fluorobenzonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1 ,3-[3H]indol]-2-yl)-3-pyridinecarbome 5-(3,4-difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-thione, 5-( 5-chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3- [3H ]indol]-5-yl)-3-furancarbonitrile, 5-(3-chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5-(3- chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5-(3,5-difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]- 2(1H9-thione, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile, 5-(3-fluoro -4-nitrophenyl)spiro [cyclohexane-1,3- [3H]indole]-2(1H)-thione, 4-(1,2-dihydro-2-thioxospiro[c cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile, 5"-(2-chlorophenyl)spiro[cyclobutane-1,3"-[3H]indole]-2"(l "H )-thione, 5"-(2-chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione, 5"-(4-chlorophenyl)spiro[cyclohexane-1 ,3"-[3H]indole]-2"(1"H)-thione, 5-(1",2"-dihydro-2"-thioxospiro[cyclohexane-1,3"-[3H]indole]-5 "-yl)-4-methyl-2-thiophenecarbonitrile, 5'-(1",2"-dihydro-2"-thioxospiro[cyclohexane-1,3"-[3H]indol]-5"-yl)-2 -thiophene carbonitrile,

5"-(3-fluorfenyl)spiro[cykloheksan-l,3"-[3H]indol]-2"(l"H)-tion, 5-(3-hydroksyfenyl)spiro [cykloheksan-1,3-[3H]indol-2(lH)-tion, 5-[4-fluor-3-(trifluormetyl)fenyl]spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 4- (l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-2-fluorbenzonitril, 5 -(3 -fluor-5-metoksyfenyl)spiro [cykloheksan-1,3 -[3H] indol] -2(1 H)-tion, 3- [<l>\2'-dihydro-2'-(hydroksyimino)spiro[cykloheksan-l,3'-[3H]indol]-5'-yl]-5-fluorbenzonitril, 5"-(3-fluorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione, 5-(3-hydroxyphenyl)spiro[cyclohexane-1,3-[3H ]indole-2(1H)-thione, 5-[4-fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 4-(1, 2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile, 5 -(3 -fluoro-5-methoxyphenyl)spiro [cyclohexane-1,3 -[3H ] indole] -2(1 H )-thione, 3- [<l>\2'-dihydro-2'-(hydroxyimino)spiro[cyclohexane-1,3'-[3 H ]indol]-5'-yl] -5-fluorobenzonitrile,

5- (spiro[cykloheksan-l,3'-[3H]indol]-2'-(hydroksyimino)-5'-yl)-metyl-2-tiofenkarbonitril, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-methyl-2-thiophenecarbonitrile,

5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(hyd^oksyimino)-5'-yl-2-tiofenkarbonitril^4- (spiro[cykloheksan-1,3 '-[3H]indol]-2'-(hydroksyimino)-5 '-yl)-2-tiofenkarbonitril, 5- (spiro[cykloheksan-l,3'-[3H]indol]-2'-(hyd^oksyimino)-5'-yl)-lH-pyrrol-l-metyl-2-karbonitril, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl-2-thiophenecarbonitrile^4- (spiro[cyclohexane-1,3'-[3H ]indole]-2'-(hydroxyimino)-5'-yl)-2-thiophenecarbonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5' -yl)-1H-pyrrole-1-methyl-2-carbonitrile,

5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(hy(h'oksyimino)-5'-yl)-lH-pyrrol-2-karbonitril, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hy(h'oxyimino)-5'-yl)-1H-pyrrole-2-carbonitrile,

4- (spiro [cykloheksan-1,3 '-[3H] indol]-2'-(acetoksyimino)-5' -yl)-2-tiofenkarbonitril, 3-fluor-N'-hydroksy-5-[2'-(hydroksyimino)spiro[cykIoheksan-l ,3 '-[3H]indol]-5 '-yl]benzenkarboksimidamid, 4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(acetoxyimino)-5'-yl)-2-thiophenecarbonitrile, 3-fluoro-N'-hydroxy-5-[2'- (hydroxyimino)spiro[cyclohexane-1,3'-[3H]indol]-5'-yl]benzenecarboximidamide,

N' -hydroksy-5 -(spiro [cykloheksan-1,3 '-[3H] indol] -2 '-(hydroksyimino)-5 * -yl)-4-metyl-2- tiofenkarboksimidamid, N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5*-yl)-4-methyl-2-thiophenecarboximidamide,

N'-hydroksy-4-(spiro[cykloheksan-1,3' -[3H]indol]-2' -(hydroksyimino)-5 *-yl-2-tiofenkarboksimidamid, N'-hydroxy-4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5*-yl-2-thiophenecarboximidamide,

N,-hydroksy-5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(hydroksyimino)-5'-yl)-2-tiofenkarboksimidamid, N,-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-2-thiophenecarboximidamide,

5- {3-klorfenyl)-3,3-dimetyl-1,3-dihydro-2H-indol-2-tion, 5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-thione,

3- benzyl-5-(3-klorfenyl)-3-metyl-l,3-dihydro-2H-indol-2-tion, 4- (3,3-dimetyl-2-tiokso-2,3-dihydro-lH-indol-5-yl)-2-r^onitril, 5- (3-metoksyfenyI)-3,3-dimetyl-l,3-dihydro-2H-indol-2-tion, 3- benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione, 4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H -indol-5-yl)-2-ronitrile, 5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-thione,

5-(3-klorfenyl)-3,3-dietyl-l,3-dihydro-2H-indol-2-tion, 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione,

5'-(3-klorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2,-ylidencyanamid, 5'-(3-cyano-5-fluorfenyl)spiro[cykIoheksan-1,3 *-[3H]indol]-2*-ylidencyanamid, 5'-(5-cyano-l H-pyrrol-2-yl)spiro[cykloheksan-l ,3 '-[SHlindoll^^ylidencyanamid, 5' -(5 -cyano-tiofen-2-yl)spiro[cykloheksan-1,3' -[3H] indol]-2 *-ylidencyanamid, 5 '-(5-cyano-3-metyl-tiofen-2-yl)spiro[cykloheksan-l ,3 '-[3H]indol]-2'-ylidencyanamid, 5'-(5-cyano-tiofen-3-yl)spirotcykloheksan-l,3,-[3H]indol]-2'-ylidencyanamid, 3- (spiro[cykloheksan-l ,3 '-[3H]indol]-5 '-yl)-5-fluor-benzonitril, 5-(spiro[cykloheksan-l ,3 '-[3H]indol]-2'-cyanometylen-5 *-yl> 1 H-pyrrol-2-karbonitril, 5-(spiro[cykloheksan-l ,3 '-[3H]indol]-2'-cyanometylen-5 '-yl)-1 -metyl-1 H-pyrrol-2-karbonitril, 5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2,-ylidenecyanamide, 5'-(3-cyano-5-fluorophenyl)spiro[cyclohexane-1,3 *-[ 3H]indol]-2*-ylidenecyanamide, 5'-(5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[SHlindoll^^ylidenecyanamide, 5'-(5-cyano- thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indol]-2*-ylidenecyanamide, 5'-(5-cyano-3-methyl-thiophen-2-yl)spiro[cyclohexane-1, 3'-[3H]indole]-2'-ylidenecyanamide, 5'-(5-cyano-thiophen-3-yl)spirocyclohexane-1,3,-[3H]indole]-2'-ylidenecyanamide, 3-(spiro [cyclohexane-1,3'-[3H]indole]-5'-yl)-5-fluoro-benzonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-cyanomethylene-5 *-yl>1H-pyrrole-2-carbonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanomethylene-5'-yl)-1-methyl-1H-pyrrole -2-carbonitrile,

5-(2'-cyanometylen-spiro[cykloheksan-1,3 *-[3H]indol]-5*-yl)-tiofen-2-karbonitril, 5-(spiro[cykloheksan-l ,3 *-[3H]indol]-2*-cyanometylen-5 '-yl)-4-metyl-tiofen-2-karbonitril, og 5-(2'-cyanomethylene-spiro[cyclohexane-1,3*-[3H]indol]-5*-yl)-thiophene-2-carbonitrile, 5-(spiro[cyclohexane-1,3*-[3H] indol]-2*-cyanomethylene-5'-yl)-4-methyl-thiophene-2-carbonitrile, and

4- (spiro[cykloheksan-l,3'-[3H]indol]-2'-cyanomety]en-5'-yl)-tiofen-2-karbonitril, eller et farmasøytisk akseptabelt salt derav. 4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-cyanomethylene-5'-yl)-thiophene-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

En annen foretrukken gruppe er: 5- (l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-l-(tert-butoksykarbonyl)-pyrrol-2-karbonitril eller 5-( 1,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-4-n-butyl-2-tiofenkarbonitril, eller et farmasøytisk akseptabelt salt derav. Another preferred group is: 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile or 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile, or a pharmaceutically acceptable salt thereof.

En ytterligere foretrukken undergruppe av forbindelser er de der R5er tiofen eller furan. A further preferred subset of compounds are those in which R 5 is thiophene or furan.

Forbindelsene ifølge oppfinnelsen kan inneholde et asymmetrisk karbonatom og noen av forbindelsene ifølge oppfinnelsen kan inneholde ett eller flere asymmetrisentre og således gi opphav til optiske isomerer og diastereomerer. Mens det er vist uten henblikk på stereokjemien i formlene, inkluderer oppfinnelsen slike optiske isomerer og diastereomerer så vel som de racemiske og oppløste, enantiomert rene R- og S-stereo-isomerer; så vel som andre blandinger av R- og S-stereoisomerene og farmasøytisk akseptable salter derav. The compounds according to the invention may contain an asymmetric carbon atom and some of the compounds according to the invention may contain one or more centers of asymmetry and thus give rise to optical isomers and diastereomers. While shown without reference to the stereochemistry of the formulas, the invention includes such optical isomers and diastereomers as well as the racemic and resolved, enantiomerically pure R- and S-stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.

Uttrykket "alkyl" benyttes her for å henvise til både rette og forgrenede alifatiske hy-drokarbongrupper med 1 til 8 og fortrinnsvis 1 til 6 karbonatomer. The term "alkyl" is used here to refer to both straight and branched aliphatic hydrocarbon groups with 1 to 8 and preferably 1 to 6 carbon atoms.

Uttrykkene "substituert alkyl" henviser til alkyl, alkenyl og alkynyl som nettopp beskrevet og med en eller flere substituenter. Disse substituenter kan være festet til et hvilket som helst karbonatom i alkylgruppen forutsatt at bindingen gir en stabil kjemisk del. The terms "substituted alkyl" refer to alkyl, alkenyl and alkynyl as just described and with one or more substituents. These substituents may be attached to any carbon atom in the alkyl group provided that the bond provides a stable chemical moiety.

Uttrykket "aryl" benyttes her for å henvise til et aromatisk system som kan være en en-keltring eller flere aromatiske ringer fusert eller bundet sammen slik at minst en del av de fuserte eller sammenbundede ringer danner det konjugerte aromatiske system. Aryl-grupper er uten begrensning fenyl, naftyl, bifenyl, antryl, tetrahydronaftyl, fenantryl. The term "aryl" is used here to refer to an aromatic system which can be a single ring or several aromatic rings fused or bonded together so that at least part of the fused or bonded rings form the conjugated aromatic system. Aryl groups are without limitation phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.

Uttrykket "alkoksy" benyttes for å henvise til OR-gruppen der R er eventuelt substituert alkyl inneholdende 1 til 8 og fortrinnsvis 1 til 6 karbonatomer. Uttrykket "halogen" henviser til Cl, Br, F eller I. The term "alkoxy" is used to refer to the OR group where R is optionally substituted alkyl containing 1 to 8 and preferably 1 to 6 carbon atoms. The term "halogen" refers to Cl, Br, F or I.

Forbindelsene ifølge oppfinnelsen kan fremstilles i henhold til de nedenfor beskrevne metoder: The compounds according to the invention can be prepared according to the methods described below:

I henhold til skjema 1, blir kommersielt tilgjengelig oksindol 3 behandlet med en sterk metallorganisk base (for eksempel butyllitium, litiumdiisopropylamid, kaliumheksame-tyldisilazid) i et inert oppløsningsmiddel (som THF eller dietyleter) under nitrogen ved redusert temperatur (ca. -20°C) (Kende, et al. Synth. Commun. 12,1, 1982) i nærvær av litiumklorid eller N,N,N',N'-tetrametyletylen-diamin. Det resulterende dianion behandles så med overskudd av en elektrofil som et alkylhalogenid, fortrinnsvis et -jodid. Hvis Ri og R2skal forenes slik at produktet 4 inneholder en spirocykel i 3-posisjon, bør elektrofilen være bifunksjonell, det vil si et dijodid. Etterfølgende bromering av 4 skjer glatt med brom i eddiksyre (et organisk medoppløsningsmiddel som diklormetan kan tilsettes etter behov) i nærvær av natriumacetat, for å gi arylbromidet 5. Bromidet 5 omsettes med et palladiumsalt (for eksempel tetrakis(trifenylfosfln)palladium (0) eller palladiumacetat), i et egnet oppløsningsmiddel (som THf, dimetoksyetan, aceton, etanol eller toluen) ved romtemperatur og under en inert atmosfære som argon eller nitrogen. Blandingen behandles så med en aryl- eller heteroarylborsyre leier -borsyreester og en base som natriumkarbonat, trietylamin eller kaliumfosfat, i vann eller en fluoridkilde som cesiumfluorid, under vannfrie betingelser. Produktet 6 kan så isoleres og renses i henhold til standardmetoder. According to Scheme 1, commercially available oxindole 3 is treated with a strong organometallic base (eg, butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (such as THF or diethyl ether) under nitrogen at reduced temperature (about -20°C ) (Kende, et al. Synth. Commun. 12,1, 1982) in the presence of lithium chloride or N,N,N',N'-tetramethylethylenediamine. The resulting dianion is then treated with an excess of an electrophile such as an alkyl halide, preferably an -iodide. If Ri and R2 are to be united so that the product 4 contains a spirocycle in the 3-position, the electrophile should be bifunctional, i.e. a diiodide. Subsequent bromination of 4 occurs smoothly with bromine in acetic acid (an organic cosolvent such as dichloromethane can be added as needed) in the presence of sodium acetate, to give the aryl bromide 5. The bromide 5 is reacted with a palladium salt (for example, tetrakis(triphenylphosphln)palladium (0) or palladium acetate), in a suitable solvent (such as THf, dimethoxyethane, acetone, ethanol or toluene) at room temperature and under an inert atmosphere such as argon or nitrogen. The mixture is then treated with an aryl or heteroaryl boronic acid bearing boronic acid ester and a base such as sodium carbonate, triethylamine or potassium phosphate, in water or a fluoride source such as cesium fluoride, under anhydrous conditions. The product 6 can then be isolated and purified according to standard methods.

Omsetningen av indolin-2-on-derivatet 6 med enten Lawessen's reagens eller fosforpentasulfid i et egnet organisk oppløsningsmiddel (pyridin, THF, dioksan, dimetoksyetan, diklormetan, benzen, toluen, zylen) ved en temperatur mellom romtemperatur og opp- løsningsmidlets tilbakeløpstemperatur gir tilgang til tiokarbonylderivatet 7. Et additiv som natriumhydrogenkarbonat kan også være brukbart. The reaction of the indolin-2-one derivative 6 with either Lawessen's reagent or phosphorus pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent gives access to the thiocarbonyl derivative 7. An additive such as sodium bicarbonate may also be useful.

Hvis Ri og R2er forskjellige, fremstilles mellomproduktet 4 ved å omsette dianionet av 3 med en ekvivalent av elektrofilen Ri-X (der X er en avspaltbar gruppe som jod). Den resulterende mono-alkylerte forbindelse kan så isoleres og på ny underkastes reaksjons-betingelsene ved bruk av R2-X, eller alternativt benyttes in situ for den andre alkylering med R2-X. Hvis alternativt det ønskede produkt 7 skal inneholde R2= H blir det isolerte monoalkylerte mellomprodukt ført gjennom de etterfølgende trinn. If Ri and R2 are different, intermediate 4 is prepared by reacting the dianion of 3 with one equivalent of the electrophile Ri-X (where X is a leaving group such as iodine). The resulting mono-alkylated compound can then be isolated and again subjected to the reaction conditions using R2-X, or alternatively used in situ for the second alkylation with R2-X. If, alternatively, the desired product 7 is to contain R 2 = H, the isolated monoalkylated intermediate is passed through the following steps.

Andre metodologier er også tilgjengelige for kobling av den pendante aryl- eller hete-roarylgruppe, Ar, til oksindolplattformen, f.eks. omsetning av forbindelse 5 med et aryl-eller heteroarylstannan, aryl- eller heteroarylsink, eller aryl- eller heteroarylmagnesium-halogenid i nærvær av en palladium- eller nikkelkatalysator (skjema 2). De ønskede aryl- eller heteroarylmetalliske spesier som beskrevet ovenfor dannes ved standardtek-nikker. Other methodologies are also available for coupling the pendant aryl or heteroaryl group, Ar, to the oxindole platform, e.g. reaction of compound 5 with an aryl or heteroaryl stannane, aryl or heteroaryl zinc, or aryl or heteroaryl magnesium halide in the presence of a palladium or nickel catalyst (Scheme 2). The desired aryl or heteroaryl metallic species as described above are formed by standard techniques.

Andre funksjonaliteter kan også installeres i 3-posisjonen av indolinplattformen i henhold til skjema 3. Oksidasjon av det ikke-substituerte indolin 8, fortrinnsvis under nøyt-rale eller sure betingelser (for eksempel selendioksyd i tørr dioksan under tilbakeløp) gir isatin 9. Forbindelsen 9 kan funksjonaliseres videre for å gi et ketal 11 ved behandling med en alkohol og sur katalysator under dehydratiseringsbetingelser. Alternativt gir omsetningen av 9 med et andre keton under egnede betingelser (piperidin i toluen ved tilbakeløp; eller TiClVZn i THF ved tilbakeløp) alkylidenderivater 11. Omsetning av isatin 9 med en Grignard-reagens eller organolitium gir tertiære alkoholer 12 (R = H). Disse alkoholer kan så funksjonaliseres videre ved alkylerings- eller acyleringsprosedy-rer. Other functionalities can also be installed in the 3-position of the indoline platform according to Scheme 3. Oxidation of the unsubstituted indoline 8, preferably under neutral or acidic conditions (for example, selenium dioxide in dry dioxane under reflux) gives isatin 9. The compound 9 can be further functionalized to give a ketal 11 by treatment with an alcohol and acid catalyst under dehydration conditions. Alternatively, the reaction of 9 with a second ketone under suitable conditions (piperidine in toluene at reflux; or TiClVZn in THF at reflux) gives alkylidene derivatives 11. Reaction of isatin 9 with a Grignard reagent or organolithium gives tertiary alcohols 12 (R = H). These alcohols can then be further functionalized by alkylation or acylation procedures.

Omsetning av indolin-2-on-derivater 6 med enten Lawessen's reagens eller fosforpentasulfid i et egnet organisk oppløsningsmiddel (som pyridin, THF, dioksan, dimetoksyetan, diklormetan, benzen, toluen eller xylen) ved en temperatur mellom romtemperatur og oppløsningsmidlets tilbakeløpstemperatur gir tilgang til tiokarbonylderivatet 7. Et additiv som natriumhydrogenkarbonat kan også være brukbart. Reaction of indolin-2-one derivatives 6 with either Lawessen's reagent or phosphorus pentasulfide in a suitable organic solvent (such as pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene or xylene) at a temperature between room temperature and the reflux temperature of the solvent provides access to the thiocarbonyl derivative 7. An additive such as sodium bicarbonate may also be useful.

En alternativ måte for fremstilling er å omsette forbindelsen 5 med enten Lawessen's reagens eller fosforpentasulfid i et egnet organisk oppløsningsmiddel (pyridin, THF, An alternative way of preparation is to react compound 5 with either Lawessen's reagent or phosphorus pentasulphide in a suitable organic solvent (pyridine, THF,

dioksan, dimetoksyetan, diklormetan, benzen, toluen, xylen) ved en temperatur mellom romtemperatur og oppløsningsmidlets tilbakeløpstemperatur, under en inert atmosfære som nitrogen eller argon, gir tilgang til tiokarbonylderivatet 13. Deretter gir omsetning av bromidet 13 i et vannfritt oppløsningsmiddel som THF eller EtC«2 med en sterk base (som fortrinnsvis natriumhydrid, natriumheksametyldisilazid eller kaliumhydrid) fulgt av omsetning ved redusert temperatur (-50 til -20°C) med n-butyllitium og N, N, N', N'-tetrametyletylendiamin etter et egnet tidsrom fulgt av et trialkylborat (trimetyl- eller triisopropylborat) gir etter sur opparbeiding borsyren 14 (skjema 4). Forbindelsen 14 kan så omsettes under palladiumkatalyserte betingelser (tetra-kis(trifenylfosfln)palladium(0) eller palladiumacetat), base (NaHC03, Na2C03, K2CO3, trietylamin, CsF), oppløsningsmiddel (toluen/EtOH/vann, THF/vann, dimetoksyetan/vann, vannfri dimetoksyetan) med et aryl- eller heteroarylbromid, aryl- eller heteroaryljodid, aryl- eller heteroaryltrifluormetansulfonat eller aryl- eller heteroarylfluorsulfonat, for å gi de ønskede forbindelser 7. dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent, under an inert atmosphere such as nitrogen or argon, gives access to the thiocarbonyl derivative 13. Then reaction of the bromide 13 in an anhydrous solvent such as THF or EtC "2 with a strong base (such as preferably sodium hydride, sodium hexamethyldisilazide or potassium hydride) followed by reaction at reduced temperature (-50 to -20°C) with n-butyllithium and N,N,N',N'-tetramethylethylenediamine after a suitable time followed by a trialkyl borate (trimethyl or triisopropyl borate) gives, after acid work-up, the boric acid 14 (Scheme 4). Compound 14 can then be reacted under palladium-catalyzed conditions (tetrakis(triphenylphosphln)palladium(0) or palladium acetate), base (NaHC03, Na2CO3, K2CO3, triethylamine, CsF), solvent (toluene/EtOH/water, THF/water, dimethoxyethane/ water, anhydrous dimethoxyethane) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate, to give the desired compounds 7.

Alternativt kan man omsette forbindelse 13 under palladiumkatalyserte betingelser (te-trakis(tirfenylfosfin)palladium(0) eller palladiumacetat), base (NaHCCh, Na2CC>3, K2CO3, trietylamin, CsF), oppløsningsmiddel (toluen/EtOH/vann, THF/vann, dimetoksyetan/vann, vannfri dimetoksyetan)) med et aryl- eller heteroarylbromid, aryl- eller heteroaryljodid, aryl- eller heteroaryltrifluormetansulfonat eller aryl- eller heteroarylfluorsulfonat, for å oppnå de ønskede forbindelser 7. Alternatively, one can react compound 13 under palladium-catalyzed conditions (tetrakis(tyrphenylphosphine)palladium(0) or palladium acetate), base (NaHCCh, Na2CC>3, K2CO3, triethylamine, CsF), solvent (toluene/EtOH/water, THF/water , dimethoxyethane/water, anhydrous dimethoxyethane)) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate, to obtain the desired compounds 7.

Behandling av bromidet 5 i et vannfritt oppløsningsmiddel (som THF eller Et20) med en sterk base (fortrinnsvis natriumhydrid, natriumheksametyldisilazid, kaliumhydrid) fulgt av omsetning under redusert temperatur (-50 til -20°C) med n-butyllitum og AWAT.AT-tetrametyletylendiamin fulgt, efter et egnet tidsrom av et trialkylborat (trimetyl- eller triisopropylborat) gir efter sur opparbeiding borsyren 15 (skjema 5). Forbindelse 15 kan så omsettes under palladiumkatalyserte betingelser (tetra-kis(trifenylfosfin)palladium(0)), base (NaHC03, Na2C03, K2C03, trietylamin, CsF), oppløsningsmiddel (toluen/EtOH/vann, THF/vann, dimetoksyetan/vann, vannfri dimetoksyetan)) med et aryl- eller heteroarylbromid, aryl- eller heteroaryljodid, aryl- eller heteroaryltrifluormetansulfonat eller aryl- eller heteroarylfluorsulfonat, for å tilveie-bringe de ønskede forbindelser 6. Treatment of the bromide 5 in an anhydrous solvent (such as THF or Et2O) with a strong base (preferably sodium hydride, sodium hexamethyldisilazide, potassium hydride) followed by reaction under reduced temperature (-50 to -20°C) with n-butyllithium and AWAT.AT- tetramethylethylenediamine followed, after a suitable period of time, by a trialkyl borate (trimethyl or triisopropyl borate) gives, after acid work-up, the boric acid 15 (scheme 5). Compound 15 can then be reacted under palladium-catalyzed conditions (tetrakis(triphenylphosphine)palladium(0)), base (NaHCO3, Na2CO3, K2CO3, triethylamine, CsF), solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired compounds 6.

En alternativ strategi vil være å fremstille et sink- eller magnesiumorganisk reagens fra forbindelse 5 og omsette dette in situ med et aryl- eller heteroarylbromid, aryl- eller heteroaryljodid, aryl- eller heteroaryltrifluormetansulfonat eller aryl- eller heteroarylfluorsulfonat under palladiumkatalyserte betingelser for å gi forbindelse 6. Slike or-ganosink- eller -magnesiumspesier kan fremstilles ved behandling av bromidet 57 i et vannfritt oppløsningsmiddel (som THF eller Et20) med en sterk base (som fortrinnsvis natriumhydrid, natriumheksametyldisilazid, kaliumhydrid) fulgt av omsetning ved redusert temperatur (-50 til -20°C) med n-butyllitium og N, N, N', AT-tetrametyletylendiamin, efter et egnet tidsrom fulgt av omsetning med vannfri sinkklorid eller magnesiumbro-mid. An alternative strategy would be to prepare an organozinc or magnesium reagent from compound 5 and react this in situ with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate under palladium-catalyzed conditions to give compound 6 Such organozinc or -magnesium species can be prepared by treating the bromide 57 in an anhydrous solvent (such as THF or Et2O) with a strong base (such as preferably sodium hydride, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (-50 to - 20°C) with n-butyllithium and N,N,N',AT-tetramethylethylenediamine, after a suitable period of time followed by reaction with anhydrous zinc chloride or magnesium bromide.

Omsetning av indolin-2-on-derivater 6 med enten Lawessen's reagens eller fosforpentasulfid i et egnet oppløsningsmiddel (pyridin, THF, dioksan, dimetoksyetan, diklormetan, benzen, toluen, xylen) ved en temperatur mellom romtemperatur og oppløsnings-midlets tilbakeløpstemperatur gir under en inert atmosfære (som nitrogen eller argon), tilgang til tiokarbonylderivatet 15. Et additiv som natriumhydrogenkarbonat kan også være brukbart. Reaction of indolin-2-one derivatives 6 with either Lawessen's reagent or phosphorus pentasulfide in a suitable solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent gives under a inert atmosphere (such as nitrogen or argon), access to the thiocarbonyl derivative 15. An additive such as sodium bicarbonate may also be useful.

I henhold til skjema 6 kan tioamidderivatene 7 omdannes til enaminderivatene 16 (Wrobel, et al., J. Med. Chem., 1989,2493). According to scheme 6, the thioamide derivatives 7 can be converted to the enamine derivatives 16 (Wrobel, et al., J. Med. Chem., 1989, 2493).

Således gir omsetningen av tioamidet 7 (Pg = H, 2-(trimetylsilyl)-etoksymetyl, benzyl, osv.) med trietyloksoniumtetrafluorborat fulgt av omsetning med en nukleofil (nitrom-etan, cyanamid, trifluormetansulfonamid, Meldrum's syre, osv.), fulgt av fjerning av den beskyttende gruppe under egnede betingelser (for eksempel tetrabutylammoniumfluorid i THF for Pg = 2-(trimetylsilyl)-etoksymetyl) enaminderivatene 16. Egnede oppløsningsmidler for de to trinn er valgt blant diklormetan, THF, dioksan, 1,2-dikloretan, og omsetningen gjennomføres ved en temperatur fra -78°C til opptøsnings-midlets kokepunkt under en inert atmosfære (som nitrogen eller argon). Thus, the reaction of the thioamide 7 (Pg = H, 2-(trimethylsilyl)-ethoxymethyl, benzyl, etc.) with triethyloxonium tetrafluoroborate, followed by reaction with a nucleophile (nitromethane, cyanamide, trifluoromethanesulfonamide, Meldrum's acid, etc.), gives removal of the protecting group under suitable conditions (for example tetrabutylammonium fluoride in THF for Pg = 2-(trimethylsilyl)-ethoxymethyl) enamine derivatives 16. Suitable solvents for the two steps are selected from dichloromethane, THF, dioxane, 1,2-dichloroethane, and the reaction is carried out at a temperature from -78°C to the boiling point of the solvent under an inert atmosphere (such as nitrogen or argon).

I henhold til skjema 7, vil behandling av mellomproduktet 7 med et alkyleringsmiddel som metyljodid, etyljodid, 2,4-dinitrofluorbenzen, eller 4-nitrofluorbenzen, i nærvær av en egnet base (for eksempel en aminbase som pyridin, trietylamin eller diisopropyletylamin eller litium-, natrium-, kalium- eller cesiumkarbonat) i et egnet oppløsningsmid-del (som DMF, THF, DMSO, dioksan eller acetonitril) ved en temperatur mellom -78°C og oppløsningsmidlets kokepunkt, så gi tioamineterene 17. Etterfølgende omsetning av mellomproduktene 17 med hydroksylamin eller et surt salt av hydroksylamin (for eksempel hydrokloridet) i et egnet oppløsningsmiddel (for eksempel, men ikke begrenset til pyridin, metanol, etanol, iso-propanol, DMF, THF eller DMSO og eventuelt i nærvær av et additiv som en tertiær aminbase eller natrium- eller kaliumacetat) ved en temperatur mellom -78°C og oppløsningsmidlets kokepunkt, så gi N-hydroksyamidinene 18. According to Scheme 7, treatment of intermediate 7 with an alkylating agent such as methyl iodide, ethyl iodide, 2,4-dinitrofluorobenzene, or 4-nitrofluorobenzene, in the presence of a suitable base (for example, an amine base such as pyridine, triethylamine or diisopropylethylamine or lithium- , sodium, potassium or cesium carbonate) in a suitable solvent (such as DMF, THF, DMSO, dioxane or acetonitrile) at a temperature between -78°C and the boiling point of the solvent, then give the thioamine ethers 17. Subsequent reaction of the intermediates 17 with hydroxylamine or an acid salt of hydroxylamine (for example the hydrochloride) in a suitable solvent (for example but not limited to pyridine, methanol, ethanol, iso-propanol, DMF, THF or DMSO and optionally in the presence of an additive such as a tertiary amine base or sodium or potassium acetate) at a temperature between -78°C and the boiling point of the solvent, then give the N-hydroxyamidines 18.

Tilsvarende behandling av mellomproduktene 17 med en karbonnukleofil som et malo-natderivat (for eksempel malononitril, en cyanoacetatester, en nitroacetatester eller et malonat) i nærvær av en egnet base (for eksempel en aminbase som pyridin, trietylamin eller di-iso-propyletylamin eller litium-, natrium-, kalium- eller cesiumkarbonat) eller en Lewis-syre (for eksempel et bortrifluoirdeterat, et bly II salt, titantetraklorid, et magnesium II salt, eller et sølvsalt) i et oppløsningsmiddel som er kompatibelt med den valgte base eller Lewis-syre (for eksempel DMF, THF, DMSO, dioksan eller acetonitril, kloroform, benzen, toluen eller diklormetan) så gi adduktet 19. Hvis gruppen R3i adduktet 19 er en ester av en karboksylsyre, kan den dekarboksyleres direkte for å gi en-aminderivatet 20 ved behandling med for eksempel natriumjodid i DMSO ved en temperatur mellom romtemperatur og oppløsningsmidlets koketemperatur. Alternativt kan esteren først hydrolyseres til karboksylsyren (ved behandling med en vandig base (som litium-, natrium- eller kaliumhydroksyd) i et egnet oppløsningsmiddel (som THF, dioksan, acetonitril, metanol eller etanol)), fulgt av dekarboksylering i nærvær av en syre (for eksempel salt- eller svovelsyre) i et egnet oppløsningsmiddel (som acetonitril, THF eller dioksan) for å gi derivatene 20. Alternativt kan xantatesteren av karboksylsyren fremstilles ved omsetning med en base som natrium- eller kaliumhydrid i THF, fulgt av behandling med karbondisulfid. Etterfølgende omsetning med tributyltinnhydrid ved forhøyet temperatur i et oppløsningsmiddel som benzen eller toluen under en inert nitrogen- eller argonatmosfære og i nærvær av en radikalinitiator som benzoylperoksyd eller azo-bis-iso-butyronitril vil så gi produktet 20. Similarly, treatment of the intermediates 17 with a carbon nucleophile such as a malonate derivative (for example malononitrile, a cyanoacetate ester, a nitroacetate ester or a malonate) in the presence of a suitable base (for example an amine base such as pyridine, triethylamine or di-isopropylethylamine or lithium -, sodium, potassium, or cesium carbonate) or a Lewis acid (for example, a boron trifluoride etherate, a lead II salt, titanium tetrachloride, a magnesium II salt, or a silver salt) in a solvent compatible with the selected base or Lewis acid (for example DMF, THF, DMSO, dioxane or acetonitrile, chloroform, benzene, toluene or dichloromethane) then give adduct 19. If the group R3 in adduct 19 is an ester of a carboxylic acid, it can be decarboxylated directly to give the en-amine derivative 20 by treatment with, for example, sodium iodide in DMSO at a temperature between room temperature and the solvent's boiling temperature. Alternatively, the ester may first be hydrolyzed to the carboxylic acid (by treatment with an aqueous base (such as lithium, sodium or potassium hydroxide) in a suitable solvent (such as THF, dioxane, acetonitrile, methanol or ethanol)), followed by decarboxylation in the presence of an acid (for example, hydrochloric or sulfuric acid) in a suitable solvent (such as acetonitrile, THF or dioxane) to give the derivatives 20. Alternatively, the xanthate ester of the carboxylic acid can be prepared by reaction with a base such as sodium or potassium hydride in THF, followed by treatment with carbon disulfide . Subsequent reaction with tributyltin hydride at elevated temperature in a solvent such as benzene or toluene under an inert nitrogen or argon atmosphere and in the presence of a radical initiator such as benzoyl peroxide or azo-bis-iso-butyronitrile will then give the product 20.

En alternativ strategi for syntetisering av produktet 18 er vist i skjema 8. Således behandles bromidet 13 (det tilsvarende klorid, jodid, triflatester kan også benyttes) med et alkyleringsmiddel som metyl- eller etyljodid, 2,4-dinitrofluorbenzen eller 4-nitrofluorbenzen, i nærvær av en egnet base (for eksempel en aminbase som pyridin, trietylamin eller diisopropyletylamin eller litium-, natirum-, kalium- eller cesiumkarbonat) i et egnet oppløsningsmiddel (som DMF, THF, DMSO, dioksan eller acetonitril) ved en temperatur mellom -78°C og oppløsningsmidlets koketemperatur, så gi tioimi-noeterene 21. Etterfølgende reduksjon av mellomproduktet 21 med hydroksylamin eller et syresalt av hydroksylamin (for eksempel hydroklorid eller hydrobromid) i et egnet oppløsningsmiddel (for eksempel, men ikke begrenset til pyridin, metanol, etanol, iso-propanol, DMF, THF eller DMSO og eventuelt i nærvær av et additiv som en tertiær aminbase eller natrium- eller kaliumacetat) ved en temperatur mellom -78°C og oppløs-ningsmidlets koketemperatur, så gi N-hydroksyamidinet 22. Mellomproduktet 22 kan så beskyttes med en kompatibel gruppe (for eksempel benzyleter, acylderivat, tetrahydro-pyranyleter, metoksymetyleter, silyleter) for å gi derivatet 23. Alternativt kan forbindelsen 21 omsettes direkte med et beskyttet hydroksylaminderivat (valgt blant, men ikke begrenset til de beskyttende grupper som er beskrevet ovenfor) for direkte å gi derivatet 23. Forbindelsen 23 kan så omsettes med et palladiumsalt (for eksempel tetra-kis(trifenylfosfin)palladium(0) eller palladiumacetat), i et egnet oppløsningsmiddel (som THF, dimetoksyetan, aceton, etanol eller toluen) ved romtemperatur og under en inert atmosfære (som nitrogen eller argon). Blandingen behandles så med en aryl- eller heteroarylborsyre eller -borsyreester og en base (natriumkarbonat, trietylamin, kaliumfosfat) i vann eller en fluoridkilde (som cesiumfluorid), under vannfrie betingelser, og reaksjonsblandingen kan så oppvarmes til oppløsningsmidlets koketemperatur. Det ønskede produkt 24 blir så isolert og renset ved standard teknikker. An alternative strategy for synthesizing the product 18 is shown in Scheme 8. Thus, the bromide 13 (the corresponding chloride, iodide, triflate ester can also be used) is treated with an alkylating agent such as methyl or ethyl iodide, 2,4-dinitrofluorobenzene or 4-nitrofluorobenzene, in the presence of a suitable base (for example an amine base such as pyridine, triethylamine or diisopropylethylamine or lithium, sodium, potassium or cesium carbonate) in a suitable solvent (such as DMF, THF, DMSO, dioxane or acetonitrile) at a temperature between -78 °C and the boiling temperature of the solvent, then give the thioiminoethers 21. Subsequent reduction of the intermediate 21 with hydroxylamine or an acid salt of hydroxylamine (for example, hydrochloride or hydrobromide) in a suitable solvent (for example, but not limited to pyridine, methanol, ethanol, iso-propanol, DMF, THF or DMSO and optionally in the presence of an additive such as a tertiary amine base or sodium or potassium acetate) at a temperature between -78°C and the boiling temperature of the solvent, then give the N-hydroxyamidine 22. The intermediate 22 can then be protected with a compatible group (for example, benzyl ether, acyl derivative, tetrahydro-pyranyl ether, methoxymethyl ether, silyl ether) to give the derivative 23. Alternatively, the compound 21 can be reacted directly with a protected hydroxylamine derivative (selected from, but not limited to, the protecting groups described above) to directly give derivative 23. Compound 23 can then be reacted with a palladium salt (for example, tetrakis(triphenylphosphine)palladium(0) or palladium acetate) , in a suitable solvent (such as THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature and under an inert atmosphere (such as nitrogen or argon). The mixture is then treated with an aryl or heteroaryl boronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or a fluoride source (such as cesium fluoride), under anhydrous conditions, and the reaction mixture can then be heated to the boiling temperature of the solvent. The desired product 24 is then isolated and purified by standard techniques.

Forbindelsen 24 kan så debeskyttes under betingelser som dikteres av arten av den beskyttende gruppe. Hvis for eksempel den beskyttende gruppe er en benzyleter, vil behandling med bortribromid eller trimetylsilyljodid i et egnet oppløsningsmiddel (som diklormetan) gi forbindelsen 18. Andre metoder for fjerning av benzyleteren vil invol-vere hydrogenering (hydrogengass eller en annen hydrogenkild som cykloheksadien eller ammoniumformat) i nærvær av en palladiumkatalysator. Oppløsningsmidler egnet for en slik prosess er metanol, etanol, THF, etylacetat og dioksan, ved en temperatur mellom romtemperatur og oppløsningsmidlets koketemperatur. Hvis den beskyttende gruppe er et acetalderivat (tetrahydropyranyl eller metoksymetyletere) kan hydrolysen gjennomføres under sure betingelser (salt-, svovel-, p-toluensulfonsyre eller sur ionebyt-teharpiks) i et oppløsningsmiddel som metanol, etanol, THF, dioksan eller acetonitril. Hvis den beskyttende gruppe er et acetylderivat (acetat eller benzoat) kan hydrolysen gjennomføres under sure betingelser som beskrevet ovenfor eller under basiske betingelser (litium-, natrium- eller kaliumhydroksyd) i et oppløsningsmiddel som en alkohol, THF, dioksan eller acetonitril, ved en temperatur mellom romtemperatur og oppløs-ningsmidlets koketemperatur. Hvis den beskyttende gruppe er en silyleter, kan forbindelse 18 fremstilles ved hydrolysering av mellomproduktet 24 under de sure betingelser som er beskrevet ovenfor eller alternativt ved å eksponere forbindelse 24 til en fluoridkilde (for eksempel natrium-, cesium- eller tetrabutylammoniumfluorid) i et oppløs-ningsmiddel som en alkohol, THF, dioksan eller acetonitril, ved en temperatur mellom romtemperatur og oppløsningsmidlets koketemperatur. En inert atmosfære av nitrogen eller argon kan være nødvendig. Compound 24 can then be deprotected under conditions dictated by the nature of the protecting group. For example, if the protecting group is a benzyl ether, treatment with boron tribromide or trimethylsilyl iodide in a suitable solvent (such as dichloromethane) will give compound 18. Other methods of removing the benzyl ether will involve hydrogenation (hydrogen gas or another hydrogen source such as cyclohexadiene or ammonium formate) in the presence of a palladium catalyst. Solvents suitable for such a process are methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature between room temperature and the boiling temperature of the solvent. If the protecting group is an acetal derivative (tetrahydropyranyl or methoxymethyl ethers), the hydrolysis can be carried out under acidic conditions (hydrochloric, sulfuric, p-toluenesulfonic acid or acidic ion exchange resin) in a solvent such as methanol, ethanol, THF, dioxane or acetonitrile. If the protecting group is an acetyl derivative (acetate or benzoate) the hydrolysis can be carried out under acidic conditions as described above or under basic conditions (lithium, sodium or potassium hydroxide) in a solvent such as an alcohol, THF, dioxane or acetonitrile, at a temperature between room temperature and the boiling temperature of the solvent. If the protecting group is a silyl ether, compound 18 can be prepared by hydrolyzing intermediate 24 under the acidic conditions described above or alternatively by exposing compound 24 to a fluoride source (for example, sodium, cesium, or tetrabutylammonium fluoride) in a soln. solvent such as an alcohol, THF, dioxane or acetonitrile, at a temperature between room temperature and the boiling temperature of the solvent. An inert atmosphere of nitrogen or argon may be required.

En annen metode for syntetisering av forbindelse 18 vil være å omdanne det beskyttede N-hydroksyamidin 23 til en borsyre eller boresyreester (med litiumhalogenbytting fulgt av quenching med triisopropylborat, eller palladiumkatalysert kobling med diborpinako-lat) og så å koble dette borsyre- eller -esterderivat med et arylklorid, -bromid, -jodid eller -triflat under et egnet palladiumkatalysesystem som beskrevet tidligere. Etterføl-gende debeskyttelse som beskrevet for skjema 8 vil så gi de ønskede forbindelser 18. Another method for synthesizing compound 18 would be to convert the protected N-hydroxyamidine 23 into a boric acid or boric acid ester (with lithium halogen exchange followed by quenching with triisopropyl borate, or palladium-catalyzed coupling with diborpinacolate) and then to couple this boric acid or -ester derivative with an aryl chloride, bromide, iodide or triflate under a suitable palladium catalyst system as described previously. Subsequent deprotection as described for scheme 8 will then give the desired compounds 18.

I henhold til skjema 9, vil behandling av N-hydroksyamidin 18 under reduserende betingelser (for eksempel katalytisk hydrogenering, jern i eddiksyre eller hydrazin-Raney-nikkel) så gi mellomproduktet 25. Opp løsningsmidler egnet for en slik prosess omfatter metanol, etanol, THF, etylacetat og dioksan, ved temperaturer mellom romtemperatur og oppløsningsmidlets koketemperatur. Beskyttelsen av det sekundære nitrogen (et ter-tiært butylkarbamid er vist som ikke-begrensende eksempel) under standardbetingelser vil så gi forbindelse 26. Omsetning av forbindelse 26 med et elektrofUt cyaneringsmid-del (for eksempel cyanogenbromid, N-cyanobenzotriazol eller cyanogenbromid/4-dimetylaminopyirdinkompleks) i et egnet oppløsningsmiddel (THF, acetonitril eller DMF, eventuelt i nærvær av en base som pyridin eller natriumhydrid eller kalium tert-butoksyd) kan så gi den ønskede forbindelse 27.1 enkelte tilfeller kan cyaneringstrinnet inntre med samtidig fjerning av den sekundære nitrogenbeskyttende gruppe, hvis denne debeskyttelse ikke inntrer in situ vil et ytterligere hydrolysetrinn være nødvendig. According to Scheme 9, treatment of N-hydroxyamidine 18 under reducing conditions (for example, catalytic hydrogenation, iron in acetic acid or hydrazine-Raney-nickel) will then give intermediate 25. Solvents suitable for such a process include methanol, ethanol, THF , ethyl acetate and dioxane, at temperatures between room temperature and the solvent's boiling point. The protection of the secondary nitrogen (a tertiary butylurea is shown as a non-limiting example) under standard conditions will then give compound 26. Reaction of compound 26 with an electrophilic cyanating agent (for example cyanogen bromide, N-cyanobenzotriazole or cyanogen bromide/4- dimethylaminopyridine complex) in a suitable solvent (THF, acetonitrile or DMF, optionally in the presence of a base such as pyridine or sodium hydride or potassium tert-butoxide) can then give the desired compound 27.1 in some cases the cyanation step can occur with simultaneous removal of the secondary nitrogen protecting group, if this deprotection does not occur in situ, a further hydrolysis step will be necessary.

En alternativ syntese av forbindelse 27 kan følge den av forbindelse 18, skjema 8, der et N-cyanoamidinbromid 28, fremstilt fra forbindelse 22 ved tilpasning av en tilsvarende strategi til reaksjonene som er vist i skjema 9, kunne kobles med en egnet funksjonali sert arylborsyre eller en borsyreester for å gi forbindelse 27.1 en annen strategi kan mellomproduktet 28 omdannes til den tilsvarende borsyre eller borsyreester og koblet i en Suzuki- eller Suzuki-typepalladiurnkobling med et egnet funksjonalisert arylbromid. An alternative synthesis of compound 27 can follow that of compound 18, Scheme 8, where an N-cyanoamidine bromide 28, prepared from compound 22 by adapting a similar strategy to the reactions shown in Scheme 9, could be coupled with a suitable functionalized arylboronic acid or a boric acid ester to give compound 27.1 another strategy, the intermediate 28 can be converted to the corresponding boric acid or boric acid ester and coupled in a Suzuki or Suzuki-type palladiurne coupling with a suitable functionalized aryl bromide.

Forbindelsene ifølge oppfinnelsen kan benyttes i form av salter avledet fra farmasøytisk eller fysiologisk godtagbare syrer eller baser. Disse salter inkluderer, men er ikke begrenset til de følgende salter med uorganiske syrer som salt-, svovel-, salpeter- eller fosforsyre, eller eventuelt organiske syrer som eddik-, oksal-, rav- og maleinsyre. Andre salter er salter med alkalimetaller eller jordalkalimetaller som natrium, kalium, kalsium eller magnesium i form av estere, karbamater og andre konvensjonelle "prodrug"-former, som, når de administreres i slik form, omdanner den aktive del in vivo. The compounds according to the invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric, sulfuric, nitric or phosphoric acid, or possibly organic acids such as acetic, oxalic, succinic and maleic acids. Other salts are salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "prodrug" forms, which, when administered in such form, convert the active moiety in vivo.

Foreliggende oppfinnelse inkluderer farmasøytiske preparater omfattende en forbindelse ifølge oppfinnelsen eller et farmasøytisk akseptabelt salt derav og en farmasøytisk ak-septabel bærer eller eksipient. Oppfinnelsen inkluderer også anvendelse av en forbindelse ifølge oppfinnelsen eller nevnte akseptable salter derav for fremstilling av et medikament. The present invention includes pharmaceutical preparations comprising a compound according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The invention also includes the use of a compound according to the invention or said acceptable salts thereof for the preparation of a medicament.

Videre inkluderer oppfinnelsen anvendelse av en forbindelse ifølge oppfinnelsen eller et akseptabelt salt derav for fremstilling av et medikament brukbart for administrering til et pattedyr som trenger behandling for dysfunksjonen blødning. Oppfinnelsen angår videre anvendelse av en forbindelse ifølge oppfinnelsen eller et akseptabelt salt derav for fremstilling av et medikament brukbart for administrering til et pattedyr for behandling av kasinomer og adenokasinomer av endometrium, ovarie, bryst, colon eller prostata. Videre inkluderer oppfinnelsen anvendelse av en forbindelse ifølge oppfinnelsen eller et farmasøytisk akseptabelt salt derav for fremstilling av et medikament brukbart for administrering til et pattedyr som kontraseptiv. I tillegg angår oppfinnelsen anvendelse av en forbindelse ifølge oppfinnelsen eller et farmasøytisk akseptabelt salt derav for fremstilling av et medikament brukbart for hormonerstatningsterapi. Progesteronreseptorantagonistene ifølge oppfinnelsen, benyttet alene eller i kombinasjon, kan benyttes i metoder for kontrasepsjon og terapi og/eller prevensjon av benigne og malignante neoplastiske sykdommer. Spesifikke anvendelser for forbindelsene og de farmasøytiske preparater ifølge oppfinnelsen inkluderer terapi og/eller prevensjon av uterinmyometriale fibroider, endometriose, benign prostatahypertrofi; karsinomer og adenokarsinomer av endometrium, ovarie-, bryst-, colon-, prostata-, pituitær-, menin-giom- og andre hormon-avhengige tumorer. Ytterligere anvendelse av de herværende progesteronreseptorantagonister inkluderer synkronisering av østrus hos kveg. Furthermore, the invention includes the use of a compound according to the invention or an acceptable salt thereof for the preparation of a medicament useful for administration to a mammal in need of treatment for the bleeding dysfunction. The invention further relates to the use of a compound according to the invention or an acceptable salt thereof for the preparation of a medicament usable for administration to a mammal for the treatment of carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon or prostate. Furthermore, the invention includes the use of a compound according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful for administration to a mammal as a contraceptive. In addition, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof for the production of a drug usable for hormone replacement therapy. The progesterone receptor antagonists according to the invention, used alone or in combination, can be used in methods for contraception and therapy and/or prevention of benign and malignant neoplastic diseases. Specific uses for the compounds and pharmaceutical preparations according to the invention include therapy and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors. Additional uses of the present progesterone receptor antagonists include synchronization of estrus in cattle.

Når forbindelsene anvendes innenfor de ovenfor anvendte områder, kan de kombineres med en eller flere farmasøytisk akseptable bærere eller drøyemidler, for eksempel opp-løsningsmidler, fortynnere og lignende, og kan administreres oralt i former som tabletter, kapsler, dispergerbare pulvere, granuler eller suspensjoner inneholdende for eksempel fra 0,05 til 5% suspensjonsmiddel, siruper inneholdende for eksempel fra rundt 10 til 50% sukker og eliksirer inneholdende for eksempel fra 20 til 50% etanol og lignende, eller i form av sterile, injiserbare oppløsninger eller suspensjoner inneholdende fra 0,05 til 5% suspensjonsmiddel i et isotonisk medium. Slike farmasøytiske preparater kan for eksempel inneholde fra rundt 25 til rundt 90% av den aktive bestanddel i kombinasjon med bæreren, vanligvis mellom rundt 5 og 60 vekt-%. When the compounds are used within the above-mentioned ranges, they can be combined with one or more pharmaceutically acceptable carriers or excipients, for example solvents, diluents and the like, and can be administered orally in forms such as tablets, capsules, dispersible powders, granules or suspensions containing for example from 0.05 to 5% suspending agent, syrups containing for example from around 10 to 50% sugar and elixirs containing for example from 20 to 50% ethanol and the like, or in the form of sterile, injectable solutions or suspensions containing from 0, 05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may for example contain from about 25 to about 90% of the active ingredient in combination with the carrier, usually between about 5 and 60% by weight.

Den effektive dose av aktiv bestanddel som benyttes, kan variere avhengig av den be-nyttede forbindelse, administreirngsmodus og alvoret ved den tilstand som behandles. Imidlertid oppnås generelt tilfredsstillende resultater når forbindelsene ifølge oppfinnelsen administreres ved en daglig dose fra rundt 0,5 til rundt 500 mg/kg dyrekroppsvekt, fortrinnsvis gitt i individuelle doser 2 til 4 ganger daglig, eller i en form med opprettholdt frigivning. For de fleste store dyr er den totale daglige dose fra rundt 1 til 100 mg og fortrinnsvis fra rundt 2 til 80 mg. Doseformer som er egnet for intern bruk omfatter fra rundt 0,5 til 500 mg av den aktive forbindelse i grundig blanding med faste eller flytende, farmasøytisk akseptable bærere. Doseregimet kan justeres for å gi den opti-male terapeutiske respons. For eksempel kan flere oppdelte doser administreres daglig eller dosen kan reduseres proporsjonalt som antydet ved den terapeutiske situasjon. The effective dose of active ingredient used may vary depending on the compound used, the mode of administration and the severity of the condition being treated. However, generally satisfactory results are obtained when the compounds of the invention are administered at a daily dose of from about 0.5 to about 500 mg/kg animal body weight, preferably given in individual doses 2 to 4 times daily, or in a sustained release form. For most large animals the total daily dose is from about 1 to 100 mg and preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in thorough admixture with solid or liquid pharmaceutically acceptable carriers. The dosage regimen can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be reduced proportionally as indicated by the therapeutic situation.

Disse aktive forbindelser kan administreres oralt og intravenøst, intramuskulært eller subkutant. Faste bærere er stivelse, lactose, dikalsiumfosfat, mikrokrystallinsk cellulose, sucrose og kaolin, mens flytende bærere er sterilt vann, polyetylenglycoler, ikke-ioniske surfaktanter og spiselige oljer som mais-, jordnøtt- og sesamolje, alt efter arten av den aktive bestanddel og den spesielle administreringsform. Drøyemidler som vanligvis benyttes ved fremstilling av farmasøytiske preparater kan med fordel inkluderes, for eksempel smaks- og farvemidler, preservativer og antioksydanter, for eksempel vitamin E, askorbinsyre, BHT og BHA. These active compounds can be administered orally and intravenously, intramuscularly or subcutaneously. Solid carriers are starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers are sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oil, depending on the nature of the active ingredient and the special form of administration. Emulsifiers that are usually used in the manufacture of pharmaceutical preparations can advantageously be included, for example flavoring and coloring agents, preservatives and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.

De foretrukne farmasøytiske preparater fra et fremstillings- og administreringssyns-punkt er faste preparater og særlig tabletter og faststoffylte eller væskefylte kapsler. Oral administrering av forbindelsene er foretrukket. The preferred pharmaceutical preparations from a manufacturing and administration point of view are solid preparations and in particular tablets and solid-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

Disse aktive forbindelser kan også administreres parenteralt eller intrapeirtonealt. Opp-løsninger eller suspensjoner av disse aktive forbindelser som fri base eller farmako-logisk akseptabelt salt kan fremstilles i vann, hensiktsmessig blandet med en surfaktant som hydroksypropylcellulose. Dispersjoner kan også fremstilles i glycerol, væske, polyetylenglycoler og blandinger derav i oljer. Under vanlige betingelser for lagring og bruk inneholder disse preparater et preserveirngsmiddel for å forhindre mikroorganisme-vekst. These active compounds can also be administered parenterally or intrapeirtoneally. Solutions or suspensions of these active compounds as free base or pharmacologically acceptable salt can be prepared in water, suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent microorganism growth.

De farmasøytiske former som er egnet for injeksjon inkluderer sterile, vandige oppløs-ninger eller dispersjoner og sterile pulvere for ekstemporan fremstilling av sterile, injiserbare oppløsninger eller dispersjoner. I alle tilfelle må formen være steril og må være fluid i den grad lett sprøytebruk foreligger. Den må være stabil under fremstillings- og lagringsbetingelser og må bevare mot kontamineringsinnvirkning av mikroorganismer som bakterier og fungi. Bæreren kan være et oppløsningsmiddel eller et dispergerende medium, for eksempel vann, etanol (for eksempel glycerol, propylenglycol og flytende polyetylenglycol), egnede blandinger derav og vegetabilsk olje. The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that light syringe use is available. It must be stable under manufacturing and storage conditions and must protect against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersing medium, for example water, ethanol (for example glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oil.

Oppfinnelsen skal forklares nærmere ved hjelp av de følgende, ikke-begrensende ek-sempler. The invention shall be explained in more detail by means of the following, non-limiting examples.

EKSEMPEL 1 EXAMPLE 1

S^- G- klorfenvhsDirotcvkloheksan- lJ^- fSHlindoll^ YrHVtion Spirorcvkloheksan- 13'- f 3H1indon- 2'- f rHton S^- G- chlorophenvhsDirotcvchlorohexane- lJ^- fSHlindoll^ YrHVtion Spirorcvchlorohexane- 13'- f 3H1indon- 2'- f rHton

En oppløsning av oksindol (25 g, 0,19 mol) i 800 cm<3>vannfri tetrahydrofuran ble av-kjølt til -20°C og deretter ble n-butyllitium (2,5M i heksaner, 152 cm<3>,0,38 mol) langsomt tilsatt fulgt av N, N, N', N -tetrametyletylendiamin (51 cm<3>,0,38 mol). Efter 15 mi- minutter ble 1,5-dijodpentan (174 g, 0,54 mol) tilsatt langsomt og blandingen tillatt oppvarming til romtemperatur. Efter omrøring i 16 timer ble 11 mettet vandig ammonium-kloridoppløsning og 11 EtOAc tilsatt. Efter 15 minutter ble sjiktene separert og den vandige fase ble ekstrahert to ganger med EtOAc. De kombinerte organiske sjikt ble ekstrahert med IN saltsyre og så vasket med 500 cm saltoppløsning, tørket over MgSC>4 og konsentrert for å oppnå en olje. Oljen ble tnturert med 200 cm heksan og 20 cm3 benzen. Presipitatet ble samlet og tørket under vakuum og man oppnådde subtittelforbindelsen (26,3 g, 69,6%) som farveløse krystaller med smeltepunkt 110-114°C. A solution of oxindole (25 g, 0.19 mol) in 800 cm<3>anhydrous tetrahydrofuran was cooled to -20°C and then n-butyllithium (2.5M in hexanes, 152 cm<3>.0 .38 mol) slowly added followed by N,N,N',N-tetramethylethylenediamine (51 cm<3>,0.38 mol). After 15 min, 1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture allowed to warm to room temperature. After stirring for 16 hours, 11 of saturated aqueous ammonium chloride solution and 11 of EtOAc were added. After 15 minutes, the layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic layers were extracted with 1N hydrochloric acid and then washed with 500 cm brine, dried over MgSO4 and concentrated to give an oil. The oil was titrated with 200 cm3 of hexane and 20 cm3 of benzene. The precipitate was collected and dried under vacuum to give the sub-title compound (26.3 g, 69.6%) as colorless crystals with melting point 110-114°C.

'H NMR (DMSO-d6) 5 1,67 (m, 10H), 6,84 (d, 1H, J=8Hz), 6,94 (t, 1H, J=8Hz), 7,17 (t, 1H, J=8Hz), 7,44 (d, 1H, J=8Hz), 10,3 (S, 1H). 1 H NMR (DMSO-d 6 ) δ 1.67 (m, 10H), 6.84 (d, 1H, J=8Hz), 6.94 (t, 1H, J=8Hz), 7.17 (t, 1H, J=8Hz), 7.44 (d, 1H, J=8Hz), 10.3 (S, 1H).

5'- bromspirorcvkloheksan- 1. 3'- r3Hlindoll- 2'( l' HVone 5'- bromospirorcvchlorohexane- 1. 3'- r3Hlindoll- 2'( l' HVone

Til en oppløsning av spiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on(17,6 g, 0,09 mol) i 300 cm<3>eddiksyre ble det satt natriumacetat (8,0 g, 0,1 mol) og brom (14,6 g, 0,091 mol) under omrøring. Efter 30 minutter ved romtemperatur ble reaksjonsblandingen fordelt mellom vann og EtOAc. Den vandige fase ble ekstrahert to ganger med EtOAc. De kombinerte organiske sjikt ble vasket med vann, tørket over MgS04og fordampet og resten ble triturert med heksan. Presipitatet ble samlet og tørket under vakuum for å oppnå subtittelforbindelsen (16,5 g, 67%) som hvitaktige krystaller med smeltepunkt 196-199°C. Sodium acetate (8 .0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30 minutes at room temperature, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water, dried over MgSO 4 and evaporated and the residue was triturated with hexane. The precipitate was collected and dried under vacuum to afford the sub-title compound (16.5 g, 67%) as whitish crystals mp 196-199°C.

'H NMR (DMSO-d6) 8 1,62 (m, 10H), 6,8 (d, 1H, J=6,8Hz), 7,36 (d, 1H, J=8,2,1,8Hz), 1H NMR (DMSO-d6) δ 1.62 (m, 10H), 6.8 (d, 1H, J=6.8Hz), 7.36 (d, 1H, J=8.2, 1.8Hz ),

7,58 (dd, 1H, J=8,2,1,8Hz), 10,44 (S, 1H). 7.58 (dd, 1H, J=8.2,1.8Hz), 10.44 (S, 1H).

5-( 3- klorfenvnspiro[ cvkloheksan- 1. 3-|" 3Hlindoll- 2( lHVone 5-( 3- chlorophenvnspiro[ cvchlorohexane- 1. 3-|" 3Hlindoll- 2( lHVone

En oppløsning av 5'-bromspiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on(0,32 g, 1,14 mmol) og tetralds(trifenylfosfln)palladium(0) (0,14 g, 0,12 mmol) i dimetoksyetan (6 cm ) ble omrørt under N2i 20 minutter. Til denne blanding ble det så satt 3-klorfenylborsyre (0,21 g, 1,37 mmol) og natriumkarbonat (0,36 g, 3,4 mmol) i vann (3 cm<3>). Oppløsningen ble bragt til tilbakeløp i 6 timer og så avkjølt til romtemperatur, heilt i vann og ekstrahert tre ganger med EtOAc. De kombinerte organiske ekstrakter ble vasket med vann, og saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med etylacetat:heksan 1:3 for å gi subtittelforbindelsen (0,28 g, 0,89 mmol, 80%) som et gult faststoff med smeltepunkt 164-165°C. A solution of 5'-bromospiro[cyclohexane-1,3'-[3H]indole]-2'(rH)-one (0.32 g, 1.14 mmol) and tetralds(triphenylphosphln)palladium(0) (0 .14 g, 0.12 mmol) in dimethoxyethane (6 cm ) was stirred under N 2 for 20 min. To this mixture was then added 3-chlorophenylboronic acid (0.21 g, 1.37 mmol) and sodium carbonate (0.36 g, 3.4 mmol) in water (3 cm<3>). The solution was refluxed for 6 hours and then cooled to room temperature, poured into water and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 with ethyl acetate:hexane 1:3 to give the sub-title compound (0.28 g, 0.89 mmol, 80%) as a yellow solid, mp 164-165°C.

'H NMR (CDCI3) 8 1,60-1,78 (m, 6H), 1,81-1,99 (m, 4H), 7,04 (d, J=8,lHz, 1H), 7,22-7,47 (m, 4H), 7,53 (s, 1H), 7,61 (s, 1H), 9,28 (br s, 1H).<13>C-NMR(CDC13) 20,17, 24,12, 31,92 (t), 47,22 (s), 109,21, 121,94, 124,06, 125,50, 1 H NMR (CDCl 3 ) δ 1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J=8.1Hz, 1H), 7, 22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H).<13>C-NMR(CDC13) 20, 17, 24.12, 31.92 (h), 47.22 (s), 109.21, 121.94, 124.06, 125.50,

125,79,125,97, 126,38,128,96 (d), 132,88,133,59,135,60,139,14, 125,79,125,97, 126,38,128,96 (d), 132,88,133,59,135,60,139,14,

142,17,182,89 (s). 142,17,182,89 (s).

MS (EI) m/z 310,312(M-H)<+>. MS (EI) m/z 310.312(M-H)<+>.

Analyse (Ci9H,8ClNO) C, H, N. Analysis (Ci9H,8ClNO) C, H, N.

Til en oppløsning av 5'-(3-klorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on(0,63 g, 2,00 mmol) i 20 cm3 tørr xylen ble det under nitrogen satt 2,4-bis(4-metoksyfenyl)-l,3-ditia-2,4-difosfetan-2,4-disulfid (0,89 g, 2,2 mmol) hvorefter blandingen ble oppvarmet under tilbakeløp. Efter 72 timer ble blandingen fordampet og resten underkastet kolonnekromatografi over SiC«2 med gradienteluering EtOAcrheksan, for å gi et faststoff som ble omkrystallisert fra diisopropyleter/heksan for å gi tittelforbindelsen som gule krystaller (0,17 g, 0,51 mmol, 26%): smp. 223-227°C. To a solution of 5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'(rH)-one (0.63 g, 2.00 mmol) in 20 cm3 of dry xylene 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.89 g, 2.2 mmol) was added under nitrogen, after which the mixture was heated under reflux . After 72 h, the mixture was evaporated and the residue subjected to column chromatography over SiCl2 eluting with a gradient of EtOAc-hexane to give a solid which was recrystallized from diisopropyl ether/hexane to give the title compound as yellow crystals (0.17 g, 0.51 mmol, 26% ): m.p. 223-227°C.

1H NMR (CDCI3) 8 1,53-1,66 (m, 8H), 1,83-2,05 (m, 4H), 2,07-2,17 (m, 2H), 7,11 (d, 1H NMR (CDCl 3 ) δ 1.53-1.66 (m, 8H), 1.83-2.05 (m, 4H), 2.07-2.17 (m, 2H), 7.11 (d ,

1H, J=8,0Hz), 7,31-7,53 (m, 3H), 7,54 (s, 1H), 7,86 (S, 1H), 9,93 (s, 1H, 1H, J=8.0Hz), 7.31-7.53 (m, 3H), 7.54 (s, 1H), 7.86 (S, 1H), 9.93 (s, 1H,

br). br).

MS ((+APCI) m/z 328 (M+H)<+>. MS ((+APCI) m/z 328 (M+H)<+>).

EKSEMPEL 2 EXAMPLE 2

S- fr^^ dihydro- Z^ tioksospirolcvkloheksan- l^^ fSHl- indoll- S^ vnbenzonitril S- fr^^ dihydro- Z^ thioxospirolcvchlorohexane- l^^ fSHl- indoll- S^ vnbenzonitrile

Til en løsning av 5'-bromspiro[cykloheksan-l,3-[3H]indol]-2'(l'H)-on(l,00 g, 3,57 mmol) i dimetoksyetan i 20 cm3 dimetoksyetan ble det satt tetra-kis(trifenylfosfin)palladium (0,20 g, 0,17 mmol). Efter 15 minutter ble 3-formylfenylborsyre (1,00 g, 6,93 g) tilsatt, fulgt av kaliumkarbonat (2,90 g, 21 mmol) i vann i 10 cm<3>vann. Efter 20 timer under tilbakeløp ble blandingen avkjølt og heilt i vann og ekstrahert tre ganger med EtOAc. De kombinerte organiske ekstrakter ble vasket med mettet saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med gradienteluering EtOAcrheksan, for å gi tittelforbindelsen (0,66 g, 2,15 mmol, 60%) som et hvitt faststoff. To a solution of 5'-bromospiro[cyclohexane-1,3-[3H]indole]-2'(1'H)-one (1.00 g, 3.57 mmol) in dimethoxyethane in 20 cm3 of dimethoxyethane was added tetra-kis(triphenylphosphine)palladium (0.20 g, 0.17 mmol). After 15 minutes, 3-formylphenylboronic acid (1.00 g, 6.93 g) was added, followed by potassium carbonate (2.90 g, 21 mmol) in water in 10 cm<3>water. After 20 hours under reflux, the mixture was cooled and poured into water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 eluting with a gradient of EtOAc-hexane to give the title compound (0.66 g, 2.15 mmol, 60%) as a white solid.

<*>H NMR (CDCI3) 8 1,65-1,85 (m, 6H), 1,86-2,08 (m, 4H), 7,22 (d, 1H, J=8Hz), 7,48 (dd, 1H, J=8,2Hz), 7,61 (t, 1H, J=8Hz), 7,66 (d, 1H, J=2Hz), 7,81-7,88 (m, 2H), 8,06 (t, 1H, J=2Hz), 8,30 (s, 1H, br). <*>H NMR (CDCl3) δ 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8Hz), 7, 48 (dd, 1H, J=8.2Hz), 7.61 (t, 1H, J=8Hz), 7.66 (d, 1H, J=2Hz), 7.81-7.88 (m, 2H ), 8.06 (t, 1H, J=2Hz), 8.30 (s, 1H, br).

MS ((+)ESI) m/z 306 (M+H)<+>. MS ((+)ESI) m/z 306 (M+H)<+>.

3- f r . 2' - dihvdro- 2' - oksospirof cykloheksan- 1. 3 '- f 3H1 indol] - 5 '- yflbenzaldehydoksim Til en oppløsning av 3-(r,2'-dihydro-2'-oksospirocykloheksan-l,3'-[3H]indol-5'-yl)benzaldehyd (0,59 g, 1,95 mmol) i 10 cm<3>EtOH:H20:8:2) ble det satt hydroksylamin hydroklorid (0,17 g, 2,5 mmol) og natriumacetat (0,20 g, 2,5 mmol). Efter 20 minutter ble blandingen konsentrert, vann ble tilsatt og produktet ekstrahert to ganger med EtOAc. De kombinerte organiske sjikt ble vasket med mettet natriumhydrogenkarbonat-oppløsning, vann, mettet saltoppløsning, tørket over MgSC*4 og fordampet for å gi sub-titteloksimet (0,63 g, 1,95 mmol, 100%) som ble benyttet uten ytterligere rensing. 3- f r . 2' - dihydro- 2' - oxospiroph cyclohexane- 1. 3 '- f 3H1 indole] - 5 '- ylbenzaldehyde oxime To a solution of 3-(r,2'-dihydro-2'-oxospirocyclohexane-1,3'-[ 3H]indol-5'-yl)benzaldehyde (0.59 g, 1.95 mmol) in 10 cm<3>EtOH:H2O:8:2) was added hydroxylamine hydrochloride (0.17 g, 2.5 mmol ) and sodium acetate (0.20 g, 2.5 mmol). After 20 minutes the mixture was concentrated, water was added and the product was extracted twice with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate solution, water, brine, dried over MgSC*4 and evaporated to give the sub-title oxime (0.63 g, 1.95 mmol, 100%) which was used without further purification .

,<3>C-NMR (CDC13) 8 1,60-1,84 (m, 6H), 1,85-2,00 (m, 4H), 6,86 (d, 1H, J=8Hz), 7,36 ,<3>C-NMR (CDCl 3 ) δ 1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H), 6.86 (d, 1H, J=8Hz), 7.36

(dd, 1H, J=8,2Hz), 7,43-7,50 (m, 1H), 7,57-7,67 (m, 2H), 7,85 (s, 1H, (dd, 1H, J=8.2Hz), 7.43-7.50 (m, 1H), 7.57-7.67 (m, 2H), 7.85 (s, 1H,

br), 8,25 (s, 1H), 8,68 (s, 1H, br), 8,94 (s, 1H, br). MS((-)ESI)m/z319(M-H)\ br), 8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br). MS((-)ESI)m/z319(M-H)\

3- fr. 2,- dihvdro- 2,- oksosDirorcvkloheksan- 1. 3'- r3H1indon- 5,- vnbenzonitril En oppløsning av S^r^^dihydro^^oksospirofcykloheksan-ljS^fSHlindoll-S'-yl)benzaldehydoksim (0,48 g, 1,49 mmol) i 10 cm<3>kloroform ble behandlet med selen-dioksid (0,38 g, 3,50 mmol) og oppvarmet under tilbakeløp. Efter 16 timer ble blandingen konsentrert og resten renset ved kolonnekromatografi over Si02med EtOAc:heksan 1:4 og produktet omkrystallisert fra EtOAc:heksan for å gi subtittelforbindelsen (0,161 g, 0,53 mmol, 35%) som et hvitt faststoff med smeltepunkt 190-191oC. 3- Fr. 2,- dihvdro- 2,- oxosDirorcvclohexane- 1. 3'- r3H1indon- 5,- vnbenzonitrile A solution of S^r^^dihydro^^oxospirofcyclohexane-ljS^fSHlindoll-S'-yl)benzaldehyde oxime (0.48 g, 1.49 mmol) in 10 cm<3>chloroform was treated with selenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16 h, the mixture was concentrated and the residue purified by column chromatography over SiO 2 with EtOAc:hexane 1:4 and the product recrystallized from EtOAc:hexane to give the subtitle compound (0.161 g, 0.53 mmol, 35%) as a white solid, mp 190- 191oC.

<l>H NMR (CDCI3) 8 1,59-1,87 (m, 6H), 1,88-2,09 (m, 4H), 7,03 (d, 1H, J=8Hz), 7,42 <1>H NMR (CDCl3) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8Hz), 7, 42

(dd, 1H, J=8,2Hz), 7,54 (t, 1H, J=8Hz), 7,58-7,65 (m, 2H), 7,78 (dt, 1H, (dd, 1H, J=8.2Hz), 7.54 (t, 1H, J=8Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H,

J=7,2Hz), 7,83 (m, 1H), 8,26 (s, 1H, br). J=7.2Hz), 7.83 (m, 1H), 8.26 (s, 1H, br).

MS ((+) ESI) m/z 303 (M+H)<+>. MS ((+) ESI) m/z 303 (M+H)<+>.

Omsetning av 3-(l \2'-dihydro-2'-oksospiro[cykloheksan-l ,3'[3H]indol]-5'-yl)benzonitril og Lawesson<*>s reagens i henhold til prosedyren i eksempel 1 gir tittelforbindelsen med smeltepunkt >231°C (dekomp.). Reaction of 3-(1\2'-dihydro-2'-oxospiro[cyclohexane-1,3'[3H]indol]-5'-yl)benzonitrile and Lawesson<*>'s reagent according to the procedure in Example 1 gives the title compound with m.p. >231°C (decomp.).

'HNMR (DMSO-de) 8 1,38-1,55 (m, 3H), 1,82-1,99 (m, 7H), 7,16 (d, 1H, J=8,lHz), 'HNMR (DMSO-de) δ 1.38-1.55 (m, 3H), 1.82-1.99 (m, 7H), 7.16 (d, 1H, J=8.1Hz),

7,63-7,69 (m, 2H), 7,80 (d, 1H, J=7,7Hz), 8,01 (d, 1H, J=8Hz) og 12,76 7.63-7.69 (m, 2H), 7.80 (d, 1H, J=7.7Hz), 8.01 (d, 1H, J=8Hz) and 12.76

(s, 1H). (p, 1H).

MS ((-)-APCI) m/z 317 [M-H]\ MS ((-)-APCI) m/z 317 [M-H]\

EKSEMPEL 3 EXAMPLE 3

4- fl,. 2,- dihvdro- 2,- tioksospirorcvkloheksan- 1. 3,- r3Hlindoll- 5,- vn- 2-tiofenkarbonitril 4- fl,. 2,- dihydro- 2,- thioxospirorcvchlorohexane- 1. 3,- r3Hlindoll- 5,- vn- 2-thiophenecarbonitrile

3- ( trimetvlstannvlV2- tiofenkarbonitril 3- (trimethylstannylV2-thiophenecarbonitrile

En oppløsning av 3-brom-2-tiofenkarbonitril (0,8 g, 4,3 mmol), tetra-kis(trifenylfosfin)palladium(0) (0,25 g, 0,2 mmol) og heksametylditinn (1,4 g, 4,3 mmol) i 5 cm3 dimetoksyetan ble oppvarmet under tilbakeløp i 14 timer og så avkjølt til romtemperatur. Reaksjonsblandingen ble absorbert på fluorisil og renset ved kolonnekromatografi over Si02med metylenkloirdiheksan 1:9 for å gi subtittelforbindelsen (1,04 g, 3,8 mmol, 90%) som et klar, viskøs olje. A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2 mmol) and hexamethylditinne (1.4 g , 4.3 mmol) in 5 cm3 of dimethoxyethane was heated under reflux for 14 hours and then cooled to room temperature. The reaction mixture was absorbed onto Fluorisil and purified by column chromatography over SiO 2 with methylene chloride hexane 1:9 to give the subtitle compound (1.04 g, 3.8 mmol, 90%) as a clear, viscous oil.

'H NMR (CDC13) 8 0,35 (s, 9H), 7,56 (d, J=0,9Hz, 1H), 7,66 (d, J=0,9Hz, 1H). 1 H NMR (CDCl 3 ) δ 0.35 (s, 9H), 7.56 (d, J=0.9Hz, 1H), 7.66 (d, J=0.9Hz, 1H).

4- ( 1. 2- dihvdro- 2- oksospirorcvkloheksan- 1. 3- f 3Hlindol- 5- vl)- 2- tiofenkarborutril En oppløsning av 5'-bromspiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on(0,53 g, 1,9 mmol), diklorbis(trifenylfosfin)palladium(n) (0,1 g, 0,14 mmol) og trifenylarsin (0,14 g, 0,47 mmol) i 8 cm3 dimetoksyetan ble omrørt under N2i 20 minutter. Til denne blanding ble det så satt 3-(trimetylstannyl)-2-tiofenkarbonitril (0,64 g, 2,35 mmol). Oppløs-ningen ble bragt til tilbakeløp i 32 timer. Efter avkjøling til romtemperatur ble reaksjonsblandingen absorbert på fluorisil og renset ved kolonnekromatografi over Si02med etylacetat:heksan 2:3 for å gi subtittelforbindelsen (0,43 g, 1,39 mmol, 74%) som et hvitaktig faststoff. 4- ( 1. 2- dihydro- 2- oxospirocyclohexane- 1. 3- f 3Hlindole- 5- vl)- 2- thiophenecarborutril A solution of 5'-bromospiro[cyclohexane-1,3'-[3H]indole]-2 '(rH)-one (0.53 g, 1.9 mmol), dichlorobis(triphenylphosphine)palladium(n) (0.1 g, 0.14 mmol) and triphenylarsine (0.14 g, 0.47 mmol) in 8 cm3 of dimethoxyethane was stirred under N2 for 20 min. To this mixture was then added 3-(trimethylstannyl)-2-thiophenecarbonitrile (0.64 g, 2.35 mmol). The solution was refluxed for 32 hours. After cooling to room temperature, the reaction mixture was absorbed on Fluorisil and purified by column chromatography over SiO 2 with ethyl acetate:hexane 2:3 to give the sub-title compound (0.43 g, 1.39 mmol, 74%) as an off-white solid.

<!>H NMR (CDCI3) 8 1,56-2,1 (m, 10H), 6,97 (d, J=8,0Hz, 1H), 7,39 (dd, J=8,03,1,45Hz, <!>H NMR (CDCl3) δ 1.56-2.1 (m, 10H), 6.97 (d, J=8.0Hz, 1H), 7.39 (dd, J=8.03.1 ,45Hz,

1H), 7,57 (d, J=l,45Hz, 1H), 7,59 (d, J=l,4Hz, 1H), 7,84 (d, J=l,4Hz, 1H), 7.57 (d, J=1.45Hz, 1H), 7.59 (d, J=1.4Hz, 1H), 7.84 (d, J=1.4Hz,

1H), 8,32 (br s, 1H). 1H), 8.32 (br s, 1H).

<13>C-NMR (CDCI3) 8 22,07, 26,56, 34,4 (t), 48,13 (s), 110,18 (d), 111,3, 114,75 (s), <13>C-NMR (CDCl3) 8 22.07, 26.56, 34.4 (t), 48.13 (s), 110.18 (d), 111.3, 114.75 (s),

122,92, 126,76 (d), 128,44 (s), 137,55 (d), 138,11, 142,71, 144,49, 122.92, 126.76 (d), 128.44 (s), 137.55 (d), 138.11, 142.71, 144.49,

182,13 (s). 182.13 (s).

MS (EI) m/z 307(M-H)<+>. MS (EI) m/z 307(M-H)<+>.

Analyse (Ci8H16N2OS) C, H, N. Analysis (Ci8H16N2OS) C, H, N.

En oppløsning av 4-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-2-tiofenkarbonitril (1,0 g, 3,2 mmol) og Lawesson's reagens (1,3 g, 3,2 mmol) i 20 ml o-xylen ble oppvarmet i 2,5 time. Reaksjonsblandingen ble vasket med 5 x 100 ml destil lert vann, tørket over MgSC<4 og fordampet. Produktet ble renset ved kolonnekromatografi over SiC<2 med EtOAc:heksan 1:5 for å gi tittelforbindelsen (0,2 g, 20%) som et blekgult faststoff med et smeltepunkt 230-232°C. A solution of 4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile (1.0 g, 3.2 mmol) and Lawesson's reagent (1.3 g, 3.2 mmol) in 20 mL of o-xylene was heated for 2.5 h. The reaction mixture was washed with 5 x 100 ml of distilled water, dried over MgSO4 and evaporated. The product was purified by column chromatography over SiC<2 with EtOAc:hexane 1:5 to give the title compound (0.2 g, 20%) as a pale yellow solid, mp 230-232°C.

<!>H NMR (DMSO-de) 8 12,72 (s, 1H), 8,52 (d, 1H, J=l,5Hz), 8,36 (d, 1H, J=l,5Hz), <!>H NMR (DMSO-de) δ 12.72 (s, 1H), 8.52 (d, 1H, J=1.5Hz), 8.36 (d, 1H, J=1.5Hz),

8,00 (d, 1H, J=l,5Hz), 7,69 (dd, 1H, J=6,4,1,8Hz), 7,10 (d, 1H, 8.00 (d, 1H, J=1.5Hz), 7.69 (dd, 1H, J=6.4,1.8Hz), 7.10 (d, 1H,

J=8,3Hz), 1,98-1,77 (m, 7H), 1,43-1,33 (m, 3H). J=8.3Hz), 1.98-1.77 (m, 7H), 1.43-1.33 (m, 3H).

MS (EI) M<+>@ m/z 324. MS (EI) M<+>@ m/z 324.

EKSEMPEL 4 EXAMPLE 4

3-( l, 2- dihvdro- 2- tioksospirofcykloheksan- l, 3-[ 3H1indoll- 5- vn- 5- fluorbenzonitril Til en oppløsning av 5'-bromspiro[cykloheksan-l,3'-[3H]indol]-2'-(rH)-on(ll g, 0,04 mol) i 200 cm3 tørr tetrahydrofuran ble det satt natriumhydrid (60% dispersjon i mine-ralolje, 1,6 g, 0,04 mol). Efter 30 minutters omrøring ved romtemperatur ble blandingen avkjølt til -78°C og butyllitium (1,7M i heksaner, 23,2 cm<3>, 0,04 mol) ble langsomt tilsatt. Efter 30 minutter ble diisopropylborat (25 cm , 0,11 mol) tilsatt og blandingen tillatt oppvarming til romtemperatur. Efter 2 timer ble 500 cm IN saltsyre og 500 cm etylacetat tilsatt. Den vandige fase ble ekstrahert med etylacetat, og de kombinerte organiske sjikt så vasket med vann, saltoppløsning, tørket over MgSC>4og fordampet. Resten ble triturert med heksan og presipitatet tørket under vakuum for å oppnå (2'-okso-2,3-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)borsyre (8,3 g, 86%) som et hvitaktig faststoff som ble benyttet uten ytterligere rensing. En prøve som ble triturert ytterligere med etylacetat hadde et smeltepunkt 255-260°C (dekomp.). 3-(1,2-dihydro-2-thioxospirophcyclohexane-1,3-[3H1indoll-5-vn-5-fluorobenzonitrile To a solution of 5'-bromospiro[cyclohexane-1,3'-[3H]indole]-2 '-(rH)-one (11 g, 0.04 mol) in 200 cm 3 of dry tetrahydrofuran was added sodium hydride (60% dispersion in mineral oil, 1.6 g, 0.04 mol). After 30 minutes of stirring at room temperature, the mixture was cooled to -78°C and butyllithium (1.7M in hexanes, 23.2 cm<3>, 0.04 mol) was slowly added.After 30 minutes, diisopropyl borate (25 cm , 0.11 mol) was added and the mixture allowed to warm to room temperature. After 2 hours, 500 cm of 1N hydrochloric acid and 500 cm of ethyl acetate were added. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were then washed with water, brine, dried over MgSO4 and evaporated. The residue was triturated with hexane and the precipitate dried under vacuum to afford (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boric acid (8.3 g, 86% ) as a whitish solid which was used without further cleansing. A sample which was further triturated with ethyl acetate had a melting point of 255-260°C (decomp.).

'H NMR (DMSO-de) 6 1,50 (m, 2H), 1,73 (m, 8H), 6,82 (d, 1H, J=7,72Hz), 7,66 (d, 1 H NMR (DMSO-de) δ 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J=7.72Hz), 7.66 (d,

1H, J=7,72Hz), 7,91 (s, 3H, br), 10,36 (s, 1H). 1H, J=7.72Hz), 7.91 (s, 3H, br), 10.36 (s, 1H).

MS ((-)ESI) m/z 244 [M-H]. MS ((-)ESI) m/z 244 [M-H].

3-( 1. 2- dihvdro- 2- oksospiro|" cvkloheksan- 1. 3- r3H1indoll- 5- vl)- 5- fluorbenzonitril Til en oppløsning av 3,5-dibromfluorbenzen i 100 cm3 dietyleter ble det ved -78°C dråpevis tilsatt n-butyllitium (2,5M, 8 cm<3>,20 mmol). Efter 30 minutter ble blandingen behandlet med 20 cm3 DMF i 10 cm<3>dietyleter og omrøringen ble fortsatt ved -78°C. Efter 30 minutter ble blandingen quenchet med fortynnet vandig HC1, separert og det vandige sjikt ekstrahert med EtOAc. De kombinerte organiske sjikt ble kombinert, vas- 3-( 1. 2- dihydro- 2- oxospiro|" cvclohexane- 1. 3- r3H1indol- 5- vl)- 5- fluorobenzonitrile To a solution of 3,5-dibromofluorobenzene in 100 cm3 of diethyl ether at -78°C n-butyllithium (2.5M, 8 cm<3>,20 mmol) was added dropwise. After 30 minutes, the mixture was treated with 20 cm3 DMF in 10 cm<3>diethyl ether and stirring was continued at -78°C. After 30 minutes the mixture was quenched with dilute aqueous HCl, separated and the aqueous layer extracted with EtOAc.The combined organic layers were combined, washed

ket med vann, saltoppløsning, tørket over MgS04og fordampet for å gi 3-fluor-5-brombenzaldehyd (4,0 g, 19,7 mmol, 100%) som en olje. Tried with water, brine, dried over MgSO 4 and evaporated to give 3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil.

'H NMR (CDC13) 8 inter alia 7,50-7,53 (m, 2H), 7,82 (s, 1H) og 9,93 (m, 1H). 1 H NMR (CDCl 3 ) δ inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H).

MS (EI) m/z 202,204 [M<*>]. MS (EI) m/z 202.204 [M<*>].

Til en oppløsning av den sistnevnte forbindelse (4,0 g, 19,7 mmol) i 50 cm<3>etanohvann 8:2 ble det satt natriumacetat (1,72 g, 21 mmol) og hydroksylamin hydroklorid (1,45 g, 21 mmol) og blandingen ble oppvarmet under tilbakeløp. Efter 30 minutter ble blandingen avkjølt, fordampet og resten fordelt mellom vann og EtOAc. Det vandige sjikt ble reekstrahert med EtOAc og de kombinerte organiske sjikt vaskt med vann, mettet natriumhydrogenkarbonatoppløsning, saltoppløsning, tørket over MgS04og fordampet for å gi 3-fluor-5-brombenzaldehydoksim (3,76 g, 17,24 mmol, 87%) som ble benyttet uten ytterligere rensing. Sodium acetate (1.72 g, 21 mmol) and hydroxylamine hydrochloride (1.45 g, 21 mmol) and the mixture was heated under reflux. After 30 minutes, the mixture was cooled, evaporated and the residue partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc and the combined organic layers washed with water, saturated sodium bicarbonate solution, brine, dried over MgSO 4 and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76 g, 17.24 mmol, 87%) as was used without further purification.

'H NMR (CDCI3) 8 7,24-7,27 (m, 2H), 7,50 (s, 1H), 7,68 (s, 1H) og 8,04 (s, 1H). 1 H NMR (CDCl 3 ) δ 7.24-7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s, 1H).

MS (EI) m/z 217 [M<+>]. MS (EI) m/z 217 [M<+>].

Oksimet ovenfor (3,76 g, 17,24 mmol) og 370 mg kobber(II)acetat ble oppløst i 100 cm3 acetonitril under nitrogen og oppvarmet under tilbakeløp. Efter 5 timer ble blandingen fordampet, resten tatt opp i EtOAc, vasket med IN svovelsyre, vann, saltoppløs-ning, tørket over MgS04og fordampet for å gi 3-fluor-5-brombenzonitril (3,08 g, 15,39 mmol, 89%) som ble benyttet uten ytterligere rensing. The above oxime (3.76 g, 17.24 mmol) and 370 mg of copper (II) acetate were dissolved in 100 cm 3 of acetonitrile under nitrogen and heated under reflux. After 5 h the mixture was evaporated, the residue taken up in EtOAc, washed with 1N sulfuric acid, water, brine, dried over MgSO 4 and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89 %) which was used without further purification.

Bromidet ovenfor (3,0 g, 15 mmol) og tetrakis(trifenylfosfin)palladium(0) (0,86 g, 0,75 mmol) ble oppløst i 130 cm3 dimetoksyetan under nitrogen. Efter 15 minutter ble (2'-okso-2,3-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)borsyre (2,82 g, 11,5 mmol) og natriumkarbonat (3,1 g, 29,3 mmol) oppløst i 40 cm3 vann, tilsatt, og blandingen oppvarmet under tilbakeløp. Efter 8 timer ble blandingen avkjølt, heilt i vann og ekstrahert med 3 x EtOAc. De kombinerte organiske sjikt ble så vasket med vann, tørket over MgS04og fordampet. Resten ble så renset ved kolonnekromatografi med gradienteluering EtOAc:heksan og produktet omkrystallisert fra metanol for å gi 3-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-5-fluorbenzonitril (1,78 g, 5,55 mmol, 48%), smeltepunkt 199-205°C. The above bromide (3.0 g, 15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.75 mmol) were dissolved in 130 cm 3 of dimethoxyethane under nitrogen. After 15 minutes, (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boric acid (2.82 g, 11.5 mmol) and sodium carbonate (3 .1 g, 29.3 mmol) dissolved in 40 cm 3 of water, added, and the mixture heated under reflux. After 8 hours, the mixture was cooled, poured into water and extracted with 3 x EtOAc. The combined organic layers were then washed with water, dried over MgSO 4 and evaporated. The residue was then purified by column chromatography eluting with gradient EtOAc:hexane and the product recrystallized from methanol to give 3-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5 -fluorobenzonitrile (1.78 g, 5.55 mmol, 48%), mp 199-205°C.

!H NMR (CDCI3) 8 1,64-2,03 (m, 10H), 7,03 (d, 1H, J=8Hz), 7,31 (dt, 1H, J=7,7 og 1,6Hz), 7,41 (dd, 1H, J=8,17Hz), 7,49 (dt, 1H, J=9,6,2Hz), 7,58 (d, 1H, 1H NMR (CDCl3) δ 1.64-2.03 (m, 10H), 7.03 (d, 1H, J=8Hz), 7.31 (dt, 1H, J=7.7 and 1.6Hz ), 7.41 (dd, 1H, J=8.17Hz), 7.49 (dt, 1H, J=9.6.2Hz), 7.58 (d, 1H,

J=2Hz), 7,64 (s, 1H) og 8,37 (s, 1H). J=2Hz), 7.64 (s, 1H) and 8.37 (s, 1H).

MS (EI) m/z 320 [M<4>]. MS (EI) m/z 320 [M<4>].

Til en oppløsning av 3-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-5-fluorbenzonitril (0,32 g, 1,0 mmol) i 10 cm<3>xylener ble det under nitrogen satt Lawes-son's reagens (0,89 g, 2,22 mmol) og reaksjonsblandingen ble oppvarmet under tilbake-løp. Efter 4 timer ble blandingen avkjølt, fordampet og resten underkastet kolonnekromatografi over Si02med gradienteluering EtOAc:heksan for å gi (0,143 g, 0,42 mmol, 42%) som et hvitt faststoff med smeltepunkt 236-250°C. To a solution of 3-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile (0.32 g, 1.0 mmol) in 10 cm<3>xylenes, Laweson's reagent (0.89 g, 2.22 mmol) was added under nitrogen and the reaction mixture was heated at reflux. After 4 h the mixture was cooled, evaporated and the residue subjected to column chromatography over SiO 2 eluting with gradient EtOAc:hexane to give (0.143 g, 0.42 mmol, 42%) as a white solid, mp 236-250°C.

<!>H NMR (CDCI3) 8 1,54-1,66 (m, 3H), 1,86-2,18 (m, 7H), 7,16 (d, 1H, J=8,lHz), 7,33-7,36 (m, 1H), 7,46-7,52 (m, 2H), 7,65 (s, 1H), 7,85 (d, 1H, J=lHz), 10,05 <!>H NMR (CDCl 3 ) δ 1.54-1.66 (m, 3H), 1.86-2.18 (m, 7H), 7.16 (d, 1H, J=8.1Hz), 7.33-7.36 (m, 1H), 7.46-7.52 (m, 2H), 7.65 (s, 1H), 7.85 (d, 1H, J=lHz), 10, 05

(s, 1H). (p, 1H).

MS ((+)-APCI) m/z 337 [M+H]<+>. MS ((+)-APCI) m/z 337 [M+H]<+>.

EKSEMPEL 5 EXAMPLE 5

4- metvl- 5-( l, 2- dihvdro- 2- tioksospirofcykloheksan- l, 3- f3Hl- indoll- 5- vn- 2- tiofen tioamid 4- metvl- 5-(l, 2- dihydro- 2- thioxospirofcyclohexane-l, 3- f3Hl- indoll- 5- vn- 2- thiophene thioamide

2'-okso-2',3'-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)borsyre (2,45 g, 10 mmol), 2-brom-5-cyano-3-metyltiofen (2,4 g, 12 mmol), kalium (4 g, 29 mmol) og te-trakis(tirfenylfosfin)palladium(0) (0,6 g, 0,5 mmol) i 130 cm3 dimetoksyetan:vann:etanol 10:2:1, ble oppvarmet til 80°C i 16 timer og så heilt i 1 liter vann og ekstrahert med EtOAc. De organiske sjikt ble vasket med saltoppløsning, tørket over MgS04og konsentrert. Råproduktet ble underkastet kolonnekromatografi over Si02med EtOAc:heksan, 1:1, for å oppnå tittelforbindelsen (0,9 g, 28%), med smeltepunkt 200-203°C. 2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boronic acid (2.45 g, 10 mmol), 2-bromo-5-cyano- 3-Methylthiophene (2.4 g, 12 mmol), potassium (4 g, 29 mmol) and tetrakis(tyrphenylphosphine)palladium(0) (0.6 g, 0.5 mmol) in 130 cm3 of dimethoxyethane:water: ethanol 10:2:1, was heated to 80°C for 16 hours and then whole in 1 liter of water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO 4 and concentrated. The crude product was subjected to column chromatography over SiO 2 with EtOAc:hexane, 1:1, to afford the title compound (0.9 g, 28%), mp 200-203°C.

<*>H NMR (DMSO-d6) 8 1,63 (m, 8H), 1,87 (m, 2H), 2,27 (s, 3H), 6,95 (d, 1H, J=8,13Hz), 7,34 (dd, 1H, J=8,13,1,98Hz), 7,54 (d, 1H, J=l,98Hz), 7,82 <*>H NMR (DMSO-d6) δ 1.63 (m, 8H), 1.87 (m, 2H), 2.27 (s, 3H), 6.95 (d, 1H, J=8, 13Hz), 7.34 (dd, 1H, J=8.13,1.98Hz), 7.54 (d, 1H, J=1.98Hz), 7.82

(S, 1H), 10,50 (S, 1H). (S, 1H), 10.50 (S, 1H).

MS ((+)APCI) m/z 323 [M+H]<+>. MS ((+)APCI) m/z 323 [M+H]<+>.

En oppløsning av 4-metyl-5-[2'-okso-2',3'-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-2-tiofenkarbonitril (0,61 g, 1,9 mmol) og fosforpentasulfid (0,92 g, 2,1 mmol) i 17 ml dioksan ble oppvarmet til 85°C i 30 minutter. Reaksjonsblandingen ble heilt i destillert vann og vasket med vandig NaHC03, destillert vann, tørket over MgS04og fordampet til tørr tilstand. Resten ble renset ved kolonnekromatografi med 2,5% Me-OH:CH2Cl2for å gi tittelforbindelsen (0,05 g, 8%) som et orangebrunt faststoff med smeltepunkt 244-249°C. A solution of 4-methyl-5-[2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-2-thiophenecarbonitrile (0.61 g , 1.9 mmol) and phosphorus pentasulfide (0.92 g, 2.1 mmol) in 17 mL of dioxane was heated to 85°C for 30 minutes. The reaction mixture was poured into distilled water and washed with aqueous NaHCO 3 , distilled water, dried over MgSO 4 and evaporated to dryness. The residue was purified by column chromatography with 2.5% Me-OH:CH 2 Cl 2 to give the title compound (0.05 g, 8%) as an orange-brown solid, mp 244-249°C.

<]>H NMR (DMSO-d6) 8 12,75 (s, 1H), 9,54 (s, 1H), 9,34 (s, 1H), 7,76 (d, 1H, J=l,5Hz), <]>H NMR (DMSO-d 6 ) δ 12.75 (s, 1H), 9.54 (s, 1H), 9.34 (s, 1H), 7.76 (d, 1H, J=1, 5 Hz),

7,58 (s, 1H), 7,45 (dd, 1H, J=6,4,1,8Hz), 7,14 (d, 1H, J=7,9Hz), 2,26 (s, 7.58 (s, 1H), 7.45 (dd, 1H, J=6.4,1.8Hz), 7.14 (d, 1H, J=7.9Hz), 2.26 (s,

3H), 1,98-1,89 (m, 7H), 1,83-1,81 (m, 3H). 3H), 1.98-1.89 (m, 7H), 1.83-1.81 (m, 3H).

MS ((+)APCI) [M+H]<+>@ m/z 373. MS ((+)APCI) [M+H]<+>@ m/z 373.

EKSEMPEL 6 - Farmakologi EXAMPLE 6 - Pharmacology

Den progestasjonelle aktivitet for forbindelsene ifølge oppfinnelsen ble evaluert i in vitro- og in vivo-analysene som beskrevet nedenfor. In vitro-potensene ligger i området 0. 01 nM til 10 000 nM og in vivo-potensene i området 1 ug/kg til 30 mg/kg. The progestational activity of the compounds according to the invention was evaluated in the in vitro and in vivo assays as described below. The in vitro potencies range from 0.01 nM to 10,000 nM and the in vivo potencies range from 1 µg/kg to 30 mg/kg.

A. In vitro-biologi A. In vitro biology

In vitro-biologien bestemmes ved The in vitro biology is determined by

(1) kompetitiv radioligand-binding: Anvendelse av A-formen av den humane progeste-ronreseptor med progesteron som radioligand; (2) ko-transfeksjonsanalyse som gir funksjonell aktivitet uttrykt som agonist EC50- og antagonist ICso-verdiene; (3) En T47D-celleproliferering som er en ytterligere funksjonell analyse som også tilveiebringer agonist- og antagonistdata; og (4) T47D-cellealkaliske fosfataseanalyse som er en ytterligere funksjonell analyse som også gir agonist- og antagonistdata. (1) competitive radioligand binding: Use of the A form of the human progesterone receptor with progesterone as radioligand; (2) co-transfection assay yielding functional activity expressed as agonist EC 50 and antagonist IC 50 values; (3) A T47D cell proliferation which is an additional functional assay that also provides agonist and antagonist data; and (4) T47D cell alkaline phosphatase assay which is an additional functional assay that also provides agonist and antagonist data.

1. hPR- bindingsanalyse 1. hPR binding assay

Denne analyse gjennomføres i henhold til C. Pathirana, R.B. Stein, T.S. Berger, W. Fe-nical, T. Ianiro, D.E. Mais, A. Torres, M.E. Glodman, "Nonsteroidal human proge-steronreceptor modulators from the marine alga cymoplia barbata",, "J. Steroid Bio-chem. Mol. Biol.", 1992,41, 733-738. This analysis is carried out according to C. Pathirana, R.B. Stein, T.S. Berger, W. Fenical, T. Ianiro, D.E. Mais, A. Torres, M.E. Glodman, "Nonsteroidal human progesterone receptor modulators from the marine alga cymoplia barbata",, "J. Steroid Bio-chem. Mol. Biol.", 1992,41, 733-738.

2. PRE- luciferaseanalvse i CV- 1- celler 2. PRE-luciferase assay in CV-1 cells

Formålet med denne analyse er å bestemme en forbindelses progestasjonale og anti-progestasjonale potens basert på dens virkning på PRE-luciferase reporteraktiviteten i CV-1-celler som er ko-transfektert med human PR- og PRE-luciferaseplasmider. Mate-rialer og metoder som benyttes i analysen er som følger. The purpose of this assay is to determine the progestational and anti-progestational potency of a compound based on its effect on the PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. Materials and methods used in the analysis are as follows.

a. Medium: a. Medium:

Vekstmediet var som følger: DMEM (Bio Whittaker) inneholdende 10% (volum/volum) føtalt bovinserum (varme-inaktivert), 0,1 mM MEM ikke-essensielle aminosyrer, 100 U/ml penicillin, 100 mg/ml streptomycin og 2 mM GlutaMax (GIBCO, BRL). Forsøks-mediet var som følger: DMEM (Bio Whittaker), fenolrød-fri, inneholdende 10% (vo-lum/volum) trekullstrippet føtalt bovinserum (varme-inaktivert), 0,1 mM MEM ikke-essensielle aminosyrer, 100 U/ml penicillin, 100 mg/ml streptomycin og 2 mM GlutaMax (GIBCO, BRL). The growth medium was as follows: DMEM (Bio Whittaker) containing 10% (vol/vol) fetal bovine serum (heat-inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows: DMEM (Bio Whittaker), phenol red-free, containing 10% (vol/vol) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin and 2 mM GlutaMax (GIBCO, BRL).

b. Cellekultur, transfeksion. behandling og luciferaseanalyse b. Cell culture, transfection. treatment and luciferase assay

Forråds-CV-1-celler holdes i vekstmedium. Ko-transfeksjon skjer ved bruk av 1,2 x IO7 celler, 5 mg pLEM-plasmid med hPR-B innskutt ved Sphl- og BamHl-setene, 10 mg pGL3-plasmid med to PRE'er oppstrøms luciferasesekvensen, og 50 mg sonikert kalve-thymus DNA som bærer-DNA i 250 ml. Elektroporeringen gjennomføres ved 260 V og 1 000 mF i en Biorad Gene Pulser II. Efter elektroporeringen resuspenderes cellene i vekstmedium og bringes på plater i 96-brønners plater ved 40 000 celler/brønn i 200 ul. Efter inkubering over natten blir mediet endret til forsøksmedium. Cellene behandles derefter med referanse- eller testforbindelser i forsøksmedium. Forbindelsene testes på antiprogestasjonell aktivitet i nærvær av 3 nM progesteron. 24 timer efter behandling kasseres mediet, cellene vaskes tre ganger med D-PBS (GIBCO, BRL). 50 ul celle-lyseringsbuffer (Promega, Madison, WI) settes til hver brønn og platene rystes i 15 minutter i en Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase-aktiviteten måles ved bruk av luciferasereagenser fra Promega. Stock CV-1 cells are maintained in growth medium. Co-transfection is done using 1.2 x 107 cells, 5 mg of pLEM plasmid with hPR-B inserted at the Sphl and BamHl sites, 10 mg of pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg of sonicated calf - thymus DNA as carrier DNA in 250 ml. The electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II. After electroporation, the cells are resuspended in growth medium and plated in 96-well plates at 40,000 cells/well in 200 ul. After overnight incubation, the medium is changed to experimental medium. The cells are then treated with reference or test compounds in test medium. The compounds are tested for antiprogestational activity in the presence of 3 nM progesterone. 24 hours after treatment, the medium is discarded, the cells are washed three times with D-PBS (GIBCO, BRL). 50 µl of cell lysis buffer (Promega, Madison, WI) is added to each well and the plates are shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity is measured using luciferase reagents from Promega.

c. Analyse av resultater: c. Analysis of results:

Hver behandling består av minst 4 replikater. Log-transformerte data benyttes for analyse av varians og ikke-lineær dosisresponskurve-tilpasning for både agonist- og anta-gonistmodellene. Huber-vekting ben<y>ttes for å vekte ned effekten av utenforliggende. EC50- eller ICso-verdiene beregnes fra de retransformerte verdier. JMP-programmer (SAS Institute, Inc.) benyttes for både enveis-analyse av varians og ikke-lineære responsanalyser. Each treatment consists of at least 4 replicates. Log-transformed data are used for analysis of variance and non-linear dose-response curve fitting for both the agonist and antagonist models. Huber weighting is used to reduce the effect of outliers. The EC50 or ICso values are calculated from the retransformed values. JMP programs (SAS Institute, Inc.) are used for both one-way analysis of variance and non-linear response analyses.

d. Referanseforbindelser: d. Reference connections:

Progesteron og trimegeston er referanseprogestiner og RU486 er referanse-antiprogestinet. Alle referanseforbindelser kjøres i fulldose-responskurver og EC50- eller IC50-verdiene beregnes. Progesterone and trimegestone are the reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50 or IC50 values are calculated.

Progestasjonell aktivitet: Forbindelser som øver PRE-luciferase-aktiviteten signifikant (p < 0,05) sammenlignet med vehikkelkontrollen ansees som aktive. Progestational activity: Compounds that exert PRE-luciferase activity significantly (p < 0.05) compared to the vehicle control are considered active.

Antiprogestasjonell aktivitet: Forbindelser som reduserer 3 nM progesteron indusert PRE-luciferase-aktivitet signifikant (p < 0,05). Antiprogestational activity: Compounds that significantly reduce 3 nM progesterone induced PRE-luciferase activity (p < 0.05).

EC50: Konsentrasjon av en forbindelse som gir halv-maksimal økning av PRE-lucife-raseaktiviteten (default-nM) med SE. EC50: Concentration of a compound that gives half-maximal increase of PRE-lucife race activity (default-nM) with SE.

IC50: Konsentrasjon av en forbindelse som gir halv-maksimal reduksjon i 3nM proge-ston-indusert PRE-luciferase-aktivitet (default-nM) med SE. IC50: Concentration of a compound that produces half-maximal reduction in 3nM progestin-induced PRE-luciferase activity (default-nM) with SE.

3. T47D- celleprolifereringsanalvse 3. T47D cell proliferation assay

Formålet med denne analyse er bestemmelsen av den progestasjonelle og antiprogesta-sjonelle potens ved bruk av en celleprolifereringsanalyse i T47D-celler. En forbindelses effekt på DNA-syntesen i T47D-celler måles. Materiell og metoder som benyttes i denne analyse er som følger. The purpose of this analysis is the determination of the progestational and antiprogestational potency using a cell proliferation assay in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured. Material and methods used in this analysis are as follows.

a. Vekstmedium: a. Growth medium:

DMEM:F12 (1) (GIBCO, BRL) supplert med 10% (volum/volum) føtalbovinserum (ikke-varmeinaktivert), 100 U/ml penicillin, 100 mg/ml streptomycin og 2 mm GlutaMax (GIBCO, BRL). DMEM:F12 (1) (GIBCO, BRL) supplemented with 10% (vol/vol) fetal bovine serum (non-heat inactivated), 100 U/ml penicillin, 100 mg/ml streptomycin and 2 mm GlutaMax (GIBCO, BRL).

b. Behandlingsmedium: b. Treatment medium:

Minimum essensielt medium (MEM) (#51299.038GIBCO, BRL) fenolrød-fritt supplert med 0,5% trekull strippet føtalbovinserum, 100 U/ml penicillin, 200 mg/ml streptomycin og 2 mM GlutaMax (GIBCO, BRL). Minimum essential medium (MEM) (#51299.038GIBCO, BRL) phenol red-free supplemented with 0.5% charcoal-stripped fetal bovine serum, 100 U/ml penicillin, 200 mg/ml streptomycin and 2 mM GlutaMax (GIBCO, BRL).

c. Cellekultur c. Cell culture

T47D-forrådsceller holdes i vekstmedium. For BrdU-innarbeidingsanalysen bringes cellene på plate i 96-brønners plater (Falcon, Becton Dicikinson Labware) ved 10 000 celler/brønn i vekstmedium. Efter inkubering over natten endres mediet til behandlingsmedium og cellene dyrkes i ytterligere 24 timer før behandling. Forrådsforbindelsene oppløses i en egnet vehikkel (100% etanol eller 50% etanol:50% DMSO), deretter fortynnet i behandlingsmedium og satt til cellene. Progestin- og antiprogestinreferanse-forbindelser kjøres i fulldose-responskurver. Sluttkonsentrasjonen av vehikkel er 0,1%. I kontrollbrønner får cellene kun vehikkel. Antiprogestiner behandles i nærvær av 0,03 nM trimegeston, referanseprogestinagonisten. 24 timer efter behandling kasseres mediet og cellene merkes med 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) i behandlingsmedium i 4 timer. T47D stock cells are maintained in growth medium. For the BrdU incorporation assay, the cells are plated in 96-well plates (Falcon, Becton Dicikinson Labware) at 10,000 cells/well in growth medium. After overnight incubation, the medium is changed to treatment medium and the cells are cultured for a further 24 hours before treatment. The stock compounds are dissolved in a suitable vehicle (100% ethanol or 50% ethanol:50% DMSO), then diluted in treatment medium and added to the cells. Progestin and antiprogestin reference compounds are run in full dose response curves. The final concentration of vehicle is 0.1%. In control wells, the cells only receive vehicle. Antiprogestins are treated in the presence of 0.03 nM trimegestone, the reference progestin agonist. 24 hours after treatment, the medium is discarded and the cells are labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) in treatment medium for 4 hours.

d. Celleprolifereringsanalyse d. Cell proliferation assay

Ved slutten av BrdU-merkingen, fjernes mediet og BrdU-innarbeiding måles ved bruk av en celleprolifereirngs-ELISA-kitt (#RPN 250, Amersham Life Science) i henhold til produsentens instruksjoner. Kort sagt blir cellene fiksert i et etanolholdig fiksativ i 30 minutter, fulgt av inkubering i en blokkeringsbuffer i 30 minutter for å redusere bak- grunnen. Peroksydase-merket anti-BrdU-antistoff settes til brønnene og inkuberes i 60 minutter. Cellene skylles tre ganger med PBS og inkuberes med 3,3',5,5'-tetrametyl-benzimid(TMB)substrat i 10-20 minutter avhengig av potensen for de testede forbindelser. At the end of BrdU labeling, the medium is removed and BrdU incorporation is measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to the manufacturer's instructions. Briefly, the cells are fixed in an ethanol-containing fixative for 30 minutes, followed by incubation in a blocking buffer for 30 minutes to reduce the background. Peroxidase-labeled anti-BrdU antibody is added to the wells and incubated for 60 minutes. The cells are rinsed three times with PBS and incubated with 3,3',5,5'-tetramethyl-benzimide (TMB) substrate for 10-20 minutes depending on the potency of the tested compounds.

Deretter blir 25 ul IM svovelsyre satt til hver brønn for å stanse farvereaksjonen og optisk densitet avleses i en plateleser ved 450 nm innen 5 minutter. Then 25 ul IM sulfuric acid is added to each well to stop the color reaction and optical density is read in a plate reader at 450 nm within 5 minutes.

e. Analyse av resultater: e. Analysis of results:

Kvadratrot-transformerte data benyttes for analyse av varians og ikke-lineær dosisresponskurve-tilpastning bpde for agonist- og antagonistmodus. Huber-vekting benyttes for å vekte ned effektene av utenforliggende. EC50- eller ICso-verdier beregnes fra de retransformerte verdier. JMP-programvare (SAS Institute, Inc.) benyttes for både enveis-analyse av variant og ikke-lineære dosisresponsanalyser i både enkeltdose- og dosisresponsstudier. Square-root transformed data are used for analysis of variance and non-linear dose-response curve fitting bpde for agonist and antagonist modes. Huber weighting is used to reduce the effects of extraneous factors. EC50 or ICso values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and nonlinear dose-response analyzes in both single-dose and dose-response studies.

f. Referanseforbindelser: f. Reference connections:

Trimegeston og medroksyprogesteronacetat (MPA) er referanseprogestiner og RU486 er referanse-antiprogestinet. Alle referanseforbindelser kjøres i fulldose-responskurver og EC50- eller IC50-verdiene beregnes. Trimegestone and medroxyprogesterone acetate (MPA) are the reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50 or IC50 values are calculated.

EC50: Konsentrasjon av en forbindelse som gir halv-maksimal økning i BrdU-inkorpo-rering med SE; EC50: Concentration of a compound that gives a half-maximal increase in BrdU incorporation with SE;

IC50: Konsentrasjon av en forbindelse som gir halv-maksimal reduksjon i 0,1 trimegeston-indusert BrdU-innarbeiding med SE. IC50: Concentration of a compound that produces half-maximal reduction in 0.1 trimegestone-induced BrdU incorporation with SE.

4. T47D- cellealkalisk fosfataseanalvse 4. T47D- cell alkaline phosphatase assay

Formålet med denne analyse er å identifisere progestiner eller antiprogestiner ved å bestemme en forbindelses effekt på alkalisk fosfatase-aktivitet i T47D-celler. Materiell og metoder som benyttes i denne analyse er som følger. The purpose of this assay is to identify progestins or antiprogestins by determining a compound's effect on alkaline phosphatase activity in T47D cells. Material and methods used in this analysis are as follows.

a. Kulturmedium: a. Culture medium:

DMEM:F12 (1:1) (GIBCO, BRL) supplert med 5% (volum/volum) trekull-strippet fø-talbovinserum (ikke varme-inaktivert), 100 U/ml penicillin, 100 ug/ml streptomycin og 2 mM GlutaMax (GIBCO, BRL). DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5% (vol/vol) charcoal-stripped fetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100 µg/ml streptomycin and 2 mM GlutaMax (GIBCO, BRL).

b. Alkalisk fosfatase- bufferanalvse: b. Alkaline phosphatase buffer assay:

I. 0,1M Tris-HCl, pH 9,8, inneholdende 0,2% Triton X-100 I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100

II. 0,1M Tris-HCl, pH 9,8, inneholdende 4 mM p-nitrofenylfosfat (Sigma). II. 0.1 M Tris-HCl, pH 9.8, containing 4 mM p-nitrophenyl phosphate (Sigma).

c. Cellekultur og behandling: c. Cell culture and treatment:

Dypfryste T47D-celler ble tint i et 37°C vannbad og fortynnet til 280 000 celler/ml i kulturmedium. Til hver brønn i en 96-brønners plate (Falcon, Becton Dickinson Labware) ble det satt 180 ul fortynnet cellesuspensjon. 20 ul referanse- eller testforbindelser, fortynnet i kulturmediet, ble så satt til hver brønn. Ved testing på progestin-anta-gonistaktiviteten ble referanse-antiprogestiner eller testforbindelser tilsatt i nærvær av 1 nM progesteron. Cellene ble inkubert ved 37°C i en 5% C02/fuktet atmosfære i 24 timer. Deep-frozen T47D cells were thawed in a 37°C water bath and diluted to 280,000 cells/ml in culture medium. To each well in a 96-well plate (Falcon, Becton Dickinson Labware) was added 180 µl of diluted cell suspension. 20 µl of reference or test compounds, diluted in the culture medium, were then added to each well. When testing for progestin antagonist activity, reference antiprogestins or test compounds were added in the presence of 1 nM progesterone. The cells were incubated at 37°C in a 5% CO 2 /humidified atmosphere for 24 hours.

d. Alkalisk fosfatase- enzymanalyse: d. Alkaline phosphatase enzyme assay:

Ved slutten av behandlingen ble mediet fjernet fra platen og 50 ul analysebuffer I ble satt til hver brønn. Platene ble rystet på en titerplateryster i 15 minutter. Derefter ble 150 ul analysebuffer II satt til hver brønn. Optiske densitetsmålinger ble gjennomført i 5 minutters intervaller i 30 minutter ved en testbølgelengde på 405 nM. At the end of the treatment, the medium was removed from the plate and 50 µl of assay buffer I was added to each well. The plates were shaken on a titer plate shaker for 15 minutes. Then 150 µl of assay buffer II was added to each well. Optical density measurements were carried out at 5 minute intervals for 30 minutes at a test wavelength of 405 nM.

e. Analyse av resultater: Analyse av dose- responsdata e. Analysis of results: Analysis of dose-response data

For referanse- og testforbindelser genereres det en dosisresponskurve for dose (X-aksen) mot hastigheten for enzymreaksjon (helning (Y-aksen). Kvadratrot-transfor-mert data benyttes for analyse av varians og ikke-lineær dosisresponskurve-tilpasning for både agonist- og antagonistmodus. Huber-vekting benyttes for å vekte ned effektene av utenforliggende. EC50- eller ICso-verdier beregnes fra retransformerte verdier. JMP-programvare (SAS Institute, Inc.) benyttes for både enveis-analyse av varians og ikke-lineær dosisresponsanalyser både i enkeltdose- og dosisresponsstudier. For reference and test compounds, a dose-response curve is generated for dose (X-axis) versus rate of enzyme reaction (slope (Y-axis). Square-root-transformed data is used for analysis of variance and non-linear dose-response curve fitting for both agonist- and antagonist mode. Huber weighting is used to weight down the effects of outliers. EC50 or ICso values are calculated from retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose-response analyzes both in single-dose and dose-response studies.

f. Referanseforbindelser: f. Reference connections:

Progesteron og trimegeston er referanseprogestiner og RU486 er referanse-antiprogestinet. Alle referanseforbindelser kjøres i fulldose-responskurver og EC50- og IC50-verdiene beregnes. Progesterone and trimegestone are the reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50 and IC50 values are calculated.

B. In vivo-biologi B. In vivo biology

Den primære in vivo-analyse er rotte-dicidualiseringsmodellen som kan benyttes for å bestemme progestasjonelle effekter av både agonister og antagonister. Den sekundære in vivo-analyse er rotte-ovuleringsinhiberingsmodellen som er under utvikling og derfor er protokollen ikke tilgjengelig. The primary in vivo assay is the rat decidualization model that can be used to determine progestational effects of both agonists and antagonists. The secondary in vivo assay is the rat ovulation inhibition model which is under development and therefore the protocol is not available.

1. Rotte- ducidualiseringsanalyse 1. Rat ductualization assay

Formålet med denne prosedyre er å evaluere effekten av progestiner og antiprogestiner på rotteuterin-decidualisering og å sammenligne de relative potenser for forskjellige testforbindelser. Materiell og metoder som benyttes ved denne analyse er som følger. The purpose of this procedure is to evaluate the effect of progestins and antiprogestins on rat uterine decidualization and to compare the relative potencies of different test compounds. Material and methods used in this analysis are as follows.

a. Metoder: a. Methods:

Testforbindelsene oppløses i 100% etanol og blandes med maisolje (vehikkel). Forråds-oppløsninger av testforbindelsene i olje (Mazola™) prepareres så ved oppvarming (~80°C) av blandingen for å fordampe etanol. Testforbindelser blir derefter fortynnet med 100% maisolje eller 10% etanol i maisolje før behandling av dyrene. Ingen diffe-ranse i dicidualrespons ble funnet når disse to vehikler ble sammenlignet. The test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle). Stock solutions of the test compounds in oil (Mazola™) are then prepared by heating (~80°C) the mixture to evaporate ethanol. Test compounds are then diluted with 100% corn oil or 10% ethanol in corn oil before treating the animals. No difference in decidual response was found when these two vehicles were compared.

b. Dvr ( RACUC protokoll # 5002) b. Dvr (RACUC protocol # 5002)

Ovarie-ektomiserte mature Sprague-Dawley hunnrotter (~ 60 dager gamle med kroppsvekt 230 g) oppnås fra Taconic (Taconic Farms, NY) efter kirurgi. Ovarie-ektomi gjen-nomføres minst 10 dager før behandling for å redusere sirkulerende sexsteroider. Dyrene huses under 12 timer lys/mørke-cykler og gis standard rottefor og vann ad libitum. Ovariectomized mature female Sprague-Dawley rats (~60 days old with body weight 230 g) are obtained from Taconic (Taconic Farms, NY) after surgery. Ovariectomy is performed at least 10 days before treatment to reduce circulating sex steroids. The animals are housed under 12-hour light/dark cycles and given standard rat chow and water ad libitum.

c. Behandling c. Processing

Rottene veies og tilskrives vilkårlig grupper på 4 eller 5 før behandling. Testforbindelsene i 0,2 ml vehikkel administreres ved subkutan injeksjon ved nakkeroten eller ved tvangsforing ved bruk av 0,5 ml. Dyrene behandles en gang daglig i 7 dager. For prø-ving av antiprogestiner, gis dyrene testforbindelsene og en EC50dose av progesteron (5,6 mg/kg) under de første tre behandlingsdager. Efter decidualstimulering fortsetter dyrene å motta progesteron inntil nekropsi 4 dager senere. The rats are weighed and randomly assigned to groups of 4 or 5 before treatment. The test compounds in 0.2 ml vehicle are administered by subcutaneous injection at the nape of the neck or by forced gavage using 0.5 ml. The animals are treated once a day for 7 days. For testing antiprogestins, the animals are given the test compounds and an EC50 dose of progesterone (5.6 mg/kg) during the first three days of treatment. After decidual stimulation, the animals continue to receive progesterone until necropsy 4 days later.

d. Dosering d. Dosage

Dosene prepareres basert på midlere mg/kg gruppe kroppsvekt. I alle studier er en kont-rollgruppe som kun mottok vehikkel, inkludert. Bestemmelsen av dosisresponskurvene gjennomføres ved bruk av doser med halv-log-økninger (for eksempel 0,1, 0,3,1,0,3,0 mg/kg). The doses are prepared based on average mg/kg group body weight. In all studies, a control group that only received vehicle is included. The determination of the dose-response curves is carried out using doses in half-log increments (eg 0.1, 0.3, 1, 0, 3, 0 mg/kg).

e. Dicidual induksjon e. Decidual induction

Ca. 24 timer efter den tredje injeksjon induseres decidualisering i ett av uterinhornene ved skraping av det antimesometriale luminalepitelium med en stump 21 G-nål. Det kontralaterale horn skrapes ikke og tjener som ikke-stimulert kontroll. Ca. 24 timer efter den siste behandling, avlives rottene ved asfyksasjon og kroppsvekten måles. Uteri fjernes og trimmes for fett. Decidualisering (D-horn) og kontroll (C-horn) uterinhornene veies separat. About. 24 hours after the third injection, decidualization is induced in one of the uterine horns by scraping the antimesometrial luminal epithelium with a blunt 21 G needle. The contralateral horn is not scratched and serves as a non-stimulated control. About. 24 hours after the last treatment, the rats are killed by asphyxiation and the body weight is measured. Uterus is removed and trimmed for fat. Decidualization (D-horn) and control (C-horn) uterine horns are weighed separately.

f. Analyse av resultater: f. Analysis of results:

Økningen i vekt av det decidualiserte uterinhorn beregnes ved D-horn:C-horn og loga-ritmisk transformasjon benyttes for å maksimalisere normaliteten og homogeniteten av varians. Huber-M-estimatoren benyttes for å vekte ned de utenforliggende transformerte observasjoner for både dosis-responskurvetilpasningen og enveis-analysen av variansen. JMP programvare (SAS Institute, Inc.) ben<y>ttes for både enveis ANOVA og for ikke-lineære dosis-responsanalyser. The increase in weight of the decidualized uterine horn is calculated by D-horn:C-horn and logarithmic transformation is used to maximize normality and homogeneity of variance. The Huber-M estimator is used to weight down the outlying transformed observations for both the dose-response curve fitting and the one-way analysis of variance. JMP software (SAS Institute, Inc.) was used for both one-way ANOVA and for non-linear dose-response analyses.

g. Referanseforbindelser g. Referral links

Alle progestin-referanseforbindelser ble kjørt i fulle dosis-responskurver og EC50for uterinvekten ble beregnet. All progestin reference compounds were run in full dose-response curves and the EC50 for uterine weight was calculated.

EKSEMPEL 7 EXAMPLE 7

S- a^- dihvdro- l- tioksosDirofcvkloDentan- lJ- raHlindoll- S^ vlVlH- Dvrrol- l-karbonitril S- a^- dihvdro- l- thioxosDirofcvkloDentan- lJ- raHlindoll- S^ vlVlH- Dvrrol- l-carbonitrile

S-( 2,- okso- 2\ 3,- dihvdrospirorcvklopentan- 1. 3'- r3H1indon- 5'- vl- 2- cvanopvrrol S-( 2,- oxo- 2\ 3,- dihydrospirorcvclopentane- 1. 3'- r3H1indon- 5'- vl- 2- cvanopvrrol

En oppløsning av 5'-bromspiro[cyklopentan-l,3<*->[3H]indol]-2'(rH)-on(2>0 g, 7,5 mmol) og tetrakis(trifenylfosfin)palladium(0) (430 mg, 0,3 mmol) i 50 ml etylenglykol dimetyleter ble omrørt under en nitrogenstrøm i 15 minutter. Til oppløsningen ble det efter hverandre satt l-t-butoksykarbonylpyrrol-2-borsyre (2,1 g, 9,7 mmol) og kaliumkarbonat (2,4 g, 17 mmol) i 10 ml vann. Blandingen ble oppvarmet til 80°C i 3 timer og tillatt avkjøling. Reaksjonsblandingen ble heilt i 50 ml vann og ekstrahert med 3x50 ml etylacetat. De organiske sjikt ble kombinert, vasket med 50 ml saltoppløsning og tørket over magnesiumsulfat. Oppløsningen ble renset og konsentrert under vakuum. Krystallisering fra 20% etylacetat :heksan ga 2-(r-2'-dihydro-2,-oksospiro[cyklopentan-l,3'-[3H]indol]-5<*->yl)-5'-yl)-lH-pyrrol-l-karboksylsyre, tert-butylester (2,2 g, 83%) som et hvitt pulver med smeltepunkt 179-180,5°C. A solution of 5'-bromospiro[cyclopentane-1,3<*->[3H]indole]-2'(rH)-one (2>0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in 50 mL of ethylene glycol dimethyl ether was stirred under a stream of nitrogen for 15 minutes. 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in 10 ml of water were added to the solution one after the other. The mixture was heated to 80°C for 3 hours and allowed to cool. The reaction mixture was poured into 50 ml of water and extracted with 3x50 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of brine and dried over magnesium sulfate. The solution was purified and concentrated under vacuum. Crystallization from 20% ethyl acetate:hexane gave 2-(r-2'-dihydro-2,-oxospiro[cyclopentane-1,3'-[3H]indol]-5<*->yl)-5'-yl)- 1H-Pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as a white powder, mp 179-180.5°C.

'H NMR (DMSO-dé, 400 MHz) 8 1,30 (s, 9H), 1,75-1,98 (m, 8H), 6,16 (dd, 1H, J=*l,8, 1 H NMR (DMSO-dé, 400 MHz) δ 1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H, J=*1.8,

3,3Hz), 6,22 (T, 1H, J=3,3,3,3Hz), 6,79 (d, 1H, J=7,9Hz), 7,08 (dd, 1H, J=l,8,7,9Hz), 7,14 ('d', 1H, J=l,5Hz), 7,28 (dd, J=l,9,3,3Hz), 10,30 (s, 3.3Hz), 6.22 (T, 1H, J=3.3,3.3Hz), 6.79 (d, 1H, J=7.9Hz), 7.08 (dd, 1H, J=l ,8,7,9Hz), 7.14 ('d', 1H, J=l,5Hz), 7.28 (dd, J=l,9,3,3Hz), 10.30 (s,

1H). 1H).

MS (EI) m/z 352 [M<4>]. MS (EI) m/z 352 [M<4>].

Analyse for C21H24N2O3: Analysis for C21H24N2O3:

Beregnet: C, 71,57; H, 6,86; N, 7,95. Calculated: C, 71.57; H, 6.86; N, 7.95.

Funnet: C, 71,08; H, 6,83; N, 7,74. Found: C, 71.08; H, 6.83; N, 7.74.

Til en oppløsning av 2-(l ',2'-dihydro-2'-oksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-lH-pyrrol-l-karboksylsyre, tert-butylester (2,2 g, 6,0 mmol) i 25 ml vannfri THF ble det ved -78°C satt klorsulfonylisocyanat (0,63 ml, 7,0 mmol). Efter 90 minutter ble di-metylformamid (11 ml, 140 mmol) tilsatt og reaksjonsblandingen tillatt oppvarming til romtemperatur. Reaksjonsblandingen ble heilt i 50 ml vann og ekstrahert med 2x50 ml etylacetat. De organiske sjikt ble kombinert, vasket med 50 ml saltoppløsning, tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Rensing via flashkolonnekromatografi over silikagel med 30% etylacetat:heksan ga 5-(2'-okso-2',3<*->dihychospiro[cyklopentan-l,3'-[3H]indol]-5'-yl-2-cyanop tert-butylester (1,7 g, 75%) som hvite krystaller med smeltepunkt 167-9°C. To a solution of 2-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 6.0 mmol) in 25 ml of anhydrous THF was added chlorosulfonyl isocyanate (0.63 ml, 7.0 mmol) at -78°C. After 90 minutes, dimethylformamide (11 mL, 140 mmol) was added and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into 50 ml of water and extracted with 2x50 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification via flash column chromatography over silica gel with 30% ethyl acetate:hexane gave 5-(2'-oxo-2',3<*->dihychospiro[cyclopentan-1,3'-[3H]indole]-5'-yl-2- cyanop tert-butyl ester (1.7 g, 75%) as white crystals m.p. 167-9°C.

<*>H NMR (DMSO-d6,400 MHz) 5 1,34 (s, 9H), 1,75-1,98 (m, 8H), 6,39 (d, 1H, J=3,7Hz), 6,84 (d, 1H, J=7,9Hz), 7,17 (dd, 1H, J=l,8, 7,9Hz), 7,28 (*t\ <*>H NMR (DMSO-d6,400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H, J=3.7Hz) , 6.84 (d, 1H, J=7.9Hz), 7.17 (dd, 1H, J=1.8, 7.9Hz), 7.28 (*t\

2H), 10,41 (s, 1H). 2H), 10.41 (s, 1H).

MS (ESI) m/z 376 [M-H]\ MS (ESI) m/z 376 [M-H]\

Analyse for C22H23N3O3: Analysis for C22H23N3O3:

Beregnet: C, 70,01; H, 6,14; N, 11,13. Calculated: C, 70.01; H, 6.14; N, 11,13.

Funnet: C, 69,67; H, 6,38; N, 11,04. Found: C, 69.67; H, 6.38; N, 11.04.

5-(2'-okso-2',3'-dihydrospiro[cyklopentan-l,3'-[3H]indol]-5'-yl-2-cyanopyrrol-l-karboksylsyre, tert-butylester (lg, 2,7 mmol) ble anbragt i 25 ml rundkolbe med gum-miseptum og utstyrt med nitrogeninnløp og nål for å tillate gassutløp. En heftig strøm av nitrogen ble opprettholdt da flasken ble anbragt i et oljebad og oppvarmet til 165°C. Efter 20 minutter ved denne temperatur ble kolben fjernet fra oljebadet og tillatt avkjø-ling. Krystallisering fra etyleter ga tittelforbindelsen (600 mg, 79%) som et gult pulver med smeltepunkt 285-286°C. 5-(2'-oxo-2',3'-dihydrospiro[cyclopentane-1,3'-[3H]indole]-5'-yl-2-cyanopyrrole-1-carboxylic acid, tert-butyl ester (lg, 2, 7 mmol) was placed in a 25 ml round bottom flask with a rubber septum and fitted with a nitrogen inlet and needle to allow gas escape. A vigorous stream of nitrogen was maintained as the flask was placed in an oil bath and heated to 165°C. After 20 minutes at this temperature, the flask was removed from the oil bath and allowed to cool Crystallization from ethyl ether gave the title compound (600 mg, 79%) as a yellow powder, mp 285-286°C.

'H NMR (DMSO-d6,400 MHz) 8 1,75-2,03 (m, 8H), 6,60 (dd, 1H, J=2,4, 3,7Hz), 6,84 1 H NMR (DMSO-d6,400 MHz) δ 1.75-2.03 (m, 8H), 6.60 (dd, 1H, J=2.4, 3.7Hz), 6.84

(d, 1H, J=8,lHz), 6,94 (dd, 1H, J=2,4, 3,7Hz), 7,52 (dd, 1H, J=l,8, (d, 1H, J=8.1Hz), 6.94 (dd, 1H, J=2.4, 3.7Hz), 7.52 (dd, 1H, J=1.8,

8,1Hz), 7,60 (d, 1H, J=l,8Hz), 10,38 (s, 1H), 12,45 (s, 1H). 8.1Hz), 7.60 (d, 1H, J=1.8Hz), 10.38 (s, 1H), 12.45 (s, 1H).

MS (ESI) m/z 276 [M-H]\ MS (ESI) m/z 276 [M-H]\

Analyse for C17H15N3O: Analysis for C17H15N3O:

Beregnet: C, 73,63; H, 5,45; N, 15,15. Calculated: C, 73.63; H, 5.45; N, 15.15.

Funnet: C, 73,24; H, 5,34; N, 14,96. Found: C, 73.24; H, 5.34; N, 14.96.

Til 5-(l,2-dihydro-2-oksospiro[cyklopentan-l,3-[3H]indol]-5'-yl)-lH-pyrrol-2-karbonitril (0,18 g, 0,7 mmol, 1 ekv.) i 20 ml p-xylen ble det satt Lawesson's reagens (0,14 g, 0,36 mmol, 0,5 ekv.) og reaksjonsblandingen ble oppvarmet til tilbakeløp i 1 time. Reaksjonsblandingen ble avkjølt til romtemperatur og absorbert på silikagel. Rensing ved flashkolonnekromatografi over 20% etylacetat:heksan på silikagel ga produktet som et orangefarvet faststoff. Ytterligere rensing ved HPCL ga tittelforbindelsen som et grønt faststoff (0,144 g, 70%) med smeltepunkt 275-276°C (dekomp.). To 5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrole-2-carbonitrile (0.18 g, 0.7 mmol, 1 eq.) in 20 ml p-xylene was added Lawesson's reagent (0.14 g, 0.36 mmol, 0.5 eq.) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and absorbed onto silica gel. Purification by flash column chromatography over 20% ethyl acetate:hexane on silica gel gave the product as an orange solid. Further purification by HPCL gave the title compound as a green solid (0.144 g, 70%) mp 275-276°C (decomp.).

<*>H NMR (DMSO-d6, 300 MHz) 5 1,81-2,16 (m, 8H), 6,69 (dd, 1H, J=2,3, 3,7Hz), 6,98 (dd, 1H, J=l,8, 3,7Hz), 7,04 (d, 1H, J=8,2Hz), 7,63 (dd, 1H, J=l,6, <*>H NMR (DMSO-d6, 300 MHz) δ 1.81-2.16 (m, 8H), 6.69 (dd, 1H, J=2.3, 3.7Hz), 6.98 ( dd, 1H, J=1.8, 3.7Hz), 7.04 (d, 1H, J=8.2Hz), 7.63 (dd, 1H, J=1.6,

8,2Hz), 7,72 (d, 1H, J=l,3Hz), 12,57 (s, 1H), 12,65 (s, 1H). 8.2Hz), 7.72 (d, 1H, J=1.3Hz), 12.57 (s, 1H), 12.65 (s, 1H).

MS (ESI) [M-H]" = 292. MS (ESI) [M-H]" = 292.

Analyse for C17H15N3S: Analysis for C17H15N3S:

Beregnet: C, 69,6; H, 5,15; N, 14,32. Calculated: C, 69.6; H, 5.15; N, 14.32.

Funnet: C, 69; H, 5,31; N, 13,81. Found: C, 69; H, 5.31; N, 13.81.

EKSEMPEL 8 EXAMPLE 8

5- fl. 2- dihvdro- 2- tioksospiro-[ cvkloheksan- 1. 3-[ 3Hlindoll- 5- vn- l- ftert-butoksvkarbonvD- pvrrol- 2- karbonitril 5- fl. 2- dihydro- 2- thioxospiro-[ cyclohexane- 1. 3-[ 3Hlindoll- 5- vn- 1- pter-butoxycarbonvD- pyrrole- 2- carbonitrile

Til en oppløsning av 5'-brom-spiro[cykloheksan-l,3'-indolin]-2'-on(3,4 g, 12 mmol) i 100 ml 1,2-DME ble det under en nitrogenatmosfære satt tetra-kis(trifenylfosfin)palladium(0) (70 mg, 5 mol-%). Efter 15 minutter ble 2-boron-lH-pyrrol-l-karboksylsyre, 1-tert-butylester (1,3 ekv., 3,31 g, 15,6 mmol) og en oppløsning av K2CO3(2,3 ekv., 3,83 g, 27,6 mmol) i 5 ml vann tilsatt efter hverandre. Oppløsning-en ble oppvarmet til 80°C i 3 timer og tillatt avkjøling. Reaksjonsblandingen ble heilt i 200 ml vann og ekstrahert med 2x100 ml EtOAc. De organiske sjikt ble slått sammen, vasket med 150 ml saltoppløsning og tørket over MgSO-j. Oppløsningen ble filtrert, konsentrert under vakuum og resten renset ved flashkolonnekromatografi over silikagel og eluert med 30% EtOAc:heksan for å gi 2-(l\2'-dihydro-2'-oksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-lH-pyrrol-l-karboksylsyre, tert-butylester (3,4 g, 76%) som et hvitt pulver med smeltepunkt 177°C. Under a nitrogen atmosphere, tetra- kis(triphenylphosphine)palladium(0) (70 mg, 5 mol%). After 15 minutes, 2-boron-1H-pyrrole-1-carboxylic acid, 1-tert-butyl ester (1.3 equiv., 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 equiv., 3.83 g, 27.6 mmol) in 5 ml of water added one after the other. The solution was heated to 80°C for 3 hours and allowed to cool. The reaction mixture was poured into 200 ml of water and extracted with 2x100 ml of EtOAc. The organic layers were combined, washed with 150 ml of brine and dried over MgSO 4 . The solution was filtered, concentrated under vacuum and the residue purified by flash column chromatography over silica gel eluting with 30% EtOAc:hexane to give 2-(1\2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H] indol]-5'-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177°C.

'H NMR (CDCI3, 300 MHz) 5 1,38 (s, 9H), 1,59-1,93 (m, 10H), 6,18 (m, 1H), 6,23 ('f, 1 H NMR (CDCl 3 , 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m, 10H), 6.18 (m, 1H), 6.23 ('f,

1H, 3H), 6,91 (d, 1H, J=8Hz), 7,21 (d, 1H, J=8Hz), 7,34 (m, 1H), 7,44 (s, 1H, 3H), 6.91 (d, 1H, J=8Hz), 7.21 (d, 1H, J=8Hz), 7.34 (m, 1H), 7.44 (s,

1H), 8,33 (br s, 1H, D2Oex.). 1H), 8.33 (br s, 1H, D 2 Oex.).

MS((+)-APCI) m/z 367 [(M+H)<+>]. MS((+)-APCI) m/z 367 [(M+H)<+>].

Analyse for C22H26N2O3: Analysis for C22H26N2O3:

Beregnet: C, 72,11; H, 7,15; N, 7,64. Calculated: C, 72.11; H, 7.15; N, 7.64.

Funnet: C, 71,7; H, 7,16; N, 7,5. Found: C, 71.7; H, 7.16; N, 7.5.

Til en oppløsning av 2-(r,2,-dihydro-2'-oksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-lH-pyrrol-l-karboksylsyre, tert-butylester (0,75 g, 2 mmol) i 20 ml vannfri THF ble det ved -78°C satt klorsulfonylisocyanat (1,15 ekv., 0,23 ml, 2,3 mmol). Efter 90 minutter To a solution of 2-(r,2,-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester ( 0.75 g, 2 mmol) in 20 ml of anhydrous THF was added at -78°C with chlorosulfonyl isocyanate (1.15 eq., 0.23 ml, 2.3 mmol). After 90 minutes

ble DMF (20 ekv., 3,6 ml, 46 mmol) tilsatt og reaksjonsblandingen tillatt oppvarming til romtemperatur. Reaksjonsblandingen ble heilt i 50 ml vann og ekstrahert med 2x50 ml etylacetat. De organiske sjikt ble slått sammen, vasket med 50 ml saltoppløsning, tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Rensing via flashkolonnekromatografi på silikagel med 30% etylacetat:heksan ga 5-(2'-okso-2',3'-dihydrospiro [cykloheksan-1,3 '-[3H]indol]-5 '-yl-2-cyanopyrrol-1 -karboksylsyre, tert-butylester (0,5 g, 63%) som en olje som krystalliserte fra aceton for å gi hvite krystaller med smeltepunkt 156°C. DMF (20 eq., 3.6 mL, 46 mmol) was added and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into 50 ml of water and extracted with 2x50 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification via flash column chromatography on silica gel with 30% ethyl acetate:hexane gave 5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indole]-5'-yl-2-cyanopyrrole- 1 -carboxylic acid, tert -butyl ester (0.5 g, 63%) as an oil which crystallized from acetone to give white crystals, mp 156°C.

'H NMR (DMSO-d6, 400 MHz) 8 1,32 (s, 9H), 1,50 (m, 3H), 1,60-1,70 (m, 5H), 1,75-1,85 (m, 2H), 6,38 (d, 1H, J=3,7Hz), 6,87 (d, 1H, J=7,9Hz), 7,18 (dd, 1H, J=l,5, 7,9Hz), 7,27 (d, 1H, J=3,7Hz), 7,48 (d, 1H, J=l,8Hz), 10,42 (bs, 1 H NMR (DMSO-d 6 , 400 MHz) δ 1.32 (s, 9H), 1.50 (m, 3H), 1.60-1.70 (m, 5H), 1.75-1.85 (m, 2H), 6.38 (d, 1H, J=3.7Hz), 6.87 (d, 1H, J=7.9Hz), 7.18 (dd, 1H, J=1.5, 7.9Hz), 7.27 (d, 1H, J=3.7Hz), 7.48 (d, 1H, J=1.8Hz), 10.42 (bs,

1H). 1H).

MS (EI) m/z 391 (M<4>). MS (EI) m/z 391 (M<4>).

Analyse for C23H25N3O3: Analysis for C23H25N3O3:

Beregnet: C, 70,57, H, 6,44; N, 10,73. Calcd: C, 70.57, H, 6.44; N, 10.73.

Funnet: C, 69,82; H, 6,46; N, 10,43 Found: C, 69.82; H, 6.46; N, 10.43

Til en oppløsning av 2-cyano-5-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-lH-pyrrol-1-karboksylsyre, tert-butylester (0,7 g, 1,8 mmol, 1 ekv.) i 70 ml toluen ble det satt Lawesson's reagens (0,47 g, 1,1 mmol, 0,65 ekv.) og reaksjonsblandingen ble oppvarmet til tilbakeløp i 1 time. Reaksjonsblandingen ble avkjølt til romtemperatur, heilt i 100 ml vann og ekstrahert med 2x100 ml etylacetat. De organiske sjikt ble kombinert, vasket med 50 ml saltoppløsning, tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Rensing ved flashkolonnekromatografi over 20-30% etylacetat:heksan på silikagel ga tittelforbindelsen som et gult faststoff (0,7 g, 96%). To a solution of 2-cyano-5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester ( 0.7 g, 1.8 mmol, 1 eq.) in 70 mL toluene was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq.) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into 100 ml of water and extracted with 2x100 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by flash column chromatography over 20-30% ethyl acetate:hexane on silica gel afforded the title compound as a yellow solid (0.7 g, 96%).

'H NMR (DMSO-de, 500 MHz) 8 1,30-1,98 (m, 19H), 6,45 (d, 1H, J=3,7Hz), 7,09 (d, 1 H NMR (DMSO-de, 500 MHz) δ 1.30-1.98 (m, 19H), 6.45 (d, 1H, J=3.7Hz), 7.09 (d,

1H, J=7,9Hz), 7,31-7,34 (m, 2H), 7,81 (d, 1H, J=l,4Hz), 12,74 (s, 1H). MS (ESI) [M-H]- = 406. 1H, J=7.9Hz), 7.31-7.34 (m, 2H), 7.81 (d, 1H, J=1.4Hz), 12.74 (s, 1H). MS (ESI) [M-H]- = 406.

Analyse for C23H25N302S: Analysis for C23H25N302S:

Beregnet: C, 67,79; H, 6,18; N, 10,31. Calcd: C, 67.79; H, 6.18; N, 10.31.

Funnet: C, 67,86; H, 5,99; N, 10,25. Found: C, 67.86; H, 5.99; N, 10.25.

EKSEMPEL 9 EXAMPLE 9

5- fl. 2- dihvdro- 2- tioksospirorcvkloheksan- 1. 3- r3H1indoll- 5- vn- lH- Dvrrol- 2-karbonitril 5- fl. 2- dihydro- 2- thioxospirorcvchlorohexane- 1. 3- r3H1indoll- 5- vn- 1H- Dvrrol- 2-carbonitrile

Til en oppløsning av 5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-l-(tert-butoksykarbonyl)-pyrrol-2-karbonitril (0,5 g, 1,2 mmol, 1 ekv.) i 5 ml THF ble det tilsatt NaOEt (0,25 g, 3,6 mmol, 3 ekv.) i 5 ml EtOH og reaksjonsblandingen ble oppvarmet til 80°C i 24 timer. Oppløsningsmidlene ble fjernet under vakuum og resten fordelt mellom 50 ml etylacetat og 50 ml vann. Sjiktene ble separert og det vandige sjikt ekstrahert med 50 ml etylacetat. De organiske sjikt ble slått sammen, vasket med 50 ml saltoppløsning, tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Rensing ved flashkolonnekromatografi over 30% etylacetat:heksan på silikagel ga tittelforbindelsen (0,27 g, 68%) som et gult pulver. To a solution of 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2-carbonitrile (0, 5 g, 1.2 mmol, 1 equiv) in 5 mL THF was added NaOEt (0.25 g, 3.6 mmol, 3 equiv) in 5 mL EtOH and the reaction mixture was heated to 80 °C for 24 h . The solvents were removed under vacuum and the residue partitioned between 50 ml of ethyl acetate and 50 ml of water. The layers were separated and the aqueous layer extracted with 50 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by flash column chromatography over 30% ethyl acetate:hexane on silica gel afforded the title compound (0.27 g, 68%) as a yellow powder.

'H NMR (DMSO-d6, 500 MHz) 5 1,32-1,99 (m, 10H), 6,71 (d, 1H, J=3,7Hz), 7,00 (d, 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.32-1.99 (m, 10H), 6.71 (d, 1H, J=3.7Hz), 7.00 (d,

1H, J=3,7Hz), 7,09 (d, 1H, J=8,4Hz), 7,70 (dd, 1H, J=l,6, 8,4Hz), 8,05 1H, J=3.7Hz), 7.09 (d, 1H, J=8.4Hz), 7.70 (dd, 1H, J=1.6, 8.4Hz), 8.05

(d, 1H, J=l,lHz), 12,67 (s, 1H), 12,73 (s, 1H). (d, 1H, J=1,1Hz), 12.67 (s, 1H), 12.73 (s, 1H).

MS (ESI) [M-H]- = 306. MS (ESI) [M-H]- = 306.

Analyse for C18H17N3S: Analysis for C18H17N3S:

Beregnet: C, 70,33; H, 5,57; N, 13,67. Calculated: C, 70.33; H, 5.57; N, 13.67.

Funnet: C, 69,64; H, 5,79; N, 13,04. Found: C, 69.64; H, 5.79; N, 13.04.

EKSEMPEL 10 EXAMPLE 10

5-( 2,- tioksospiro[ cvkloheksan- l, 3,-[ 3Hlindoll- 5'- vl)- l- metvl- pvrrol- 2- karbonitril Til en oppløsning av 5-(2'-oksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-l-metyl-pyrrol-2-karbonitril (0,55 g, 1,8 mmol, 1 ekv.) i 50 ml toluen ble det satt Lawesson's reagens (0,47 g, 1,1 mmol, 0,65 ekv.) og reaksjonsblandingen ble oppvarmet til 80°C i 1 time. Reaksjonsblandingen ble avkjølt til romtemperatur, heilt i 100 ml van og ekstrahert med 2x100 ml etylacetat. De organiske sjikt ble kombinert, vasket med 50 ml salt-oppløsning, tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Rensing ved flashkolonnekromatografi over silikagel ga produktet som et hvitt faststoff (0,32 g, 55%). 5-(2,- thioxospiro[cyclohexane-1,3,-[ 3Hlindoll-5'-vl)-1-methyl- pyrrole-2-carbonitrile To a solution of 5-(2'-oxospiro[cyclohexane-1,3 '-[3H]indol]-5'-yl)-1-methyl-pyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 equiv.) in 50 ml of toluene was added Lawesson's reagent (0, 47 g, 1.1 mmol, 0.65 eq.) and the reaction mixture was heated to 80°C for 1 hour. The reaction mixture was cooled to room temperature, poured into 100 ml of water and extracted with 2x100 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by flash column chromatography over silica gel afforded the product as a white solid (0.32 g, 55%).

<*>H NMR (DMSO-de, 500 MHz) 8 1,36-1,99 (m, 10H), 3,7 (s, 3H), 6,35 (d, 1H, J=4,2Hz), 7,05 (d, 1H, J=4,2Hz), 7,16 (d, 1H, J=7,9Hz), 7,44 (dd, 1H, <*>H NMR (DMSO-de, 500 MHz) δ 1.36-1.99 (m, 10H), 3.7 (s, 3H), 6.35 (d, 1H, J=4.2Hz) , 7.05 (d, 1H, J=4.2Hz), 7.16 (d, 1H, J=7.9Hz), 7.44 (dd, 1H,

J=l,6, 8,1Hz), 7,83 (d, 1H, J=l,6Hz), 12,75 (s, 1H). J=1.6, 8.1Hz), 7.83 (d, 1H, J=1.6Hz), 12.75 (s, 1H).

MS (ESI) [M-H]- = 320. MS (ESI) [M-H]- = 320.

Analyse for C19H19N3S: Analysis for C19H19N3S:

Beregnet: C, 70,99; H, 5,96; N, 13,07. Calculated: C, 70.99; H, 5.96; N, 13.07.

Funnet: C, 68,69; H, 5,36; N, 12,27. Found: C, 68.69; H, 5.36; N, 12.27.

EKSEMPEL 11 EXAMPLE 11

5-( l, 2- dihvdro- 2- tioksospiro[ cvklopentan- l, 3-[ 3Hlindoll- 5- vl)- 3- tiofenkarbonitril 5- brom- 2- tiofenkarbonitril 5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3Hlindoll-5-vl)-3-thiophenecarbonitrile 5-bromo-2-thiophenecarbonitrile

En blanding av 5-brom-2-tiofenkarboksaldehyd (96,0 g, 500 mmol), hydroksylamin hydroklorid (111,9 g, 500 mmol), pyridin (500 ml) og etanol (500 ml) ble oppvarmet under nitrogen til tilbakeløp i 2 timer. Reaksjonsblandingen ble avkjølt til omgivelsestemperatur og konsentrert under vakuum for å gi en olje. Råproduktet ble triturert to ganger med isvann og det oppnådde faststoff samlet på et filter. En blanding av en del av faststoffet ovenfor og mengde, kobber (II) acetat monohydrat (4,2 g, 21 mmol) i 1,41 acetonitril ble oppvarmet til tilbakeløp i 3 timer. Oppløsningsmidlet ble fjernet under våkum og resten oppløst i etylacetat. Oppløsningen ble behandlet med 2x30 ml 5% vandig svovelsyre, 2x30 ml vann, 20 ml saltoppløsning og tørket over MgS04. Oppløs-ningsmidlet ble fjernet under vakuum og resten oppløst i en minimummengde kloroform (11) og tillatt utkrystallisering. De oppnådde krystaller ble samlet på et filter og filtratet konsentrert og renset ved kromatografi over silikagel med kloroform for å oppnå subtittelforbindelsen som et hvitaktig faststoff (til sammen 31,5 g, 58%). A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL) and ethanol (500 mL) was heated under nitrogen to reflux in 2 hours. The reaction mixture was cooled to ambient temperature and concentrated under vacuum to give an oil. The crude product was triturated twice with ice water and the resulting solid collected on a filter. A mixture of a portion of the above solid and amount of copper (II) acetate monohydrate (4.2 g, 21 mmol) in 1.4 L of acetonitrile was heated to reflux for 3 h. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The solution was treated with 2x30 ml 5% aqueous sulfuric acid, 2x30 ml water, 20 ml brine and dried over MgSO 4 . The solvent was removed under vacuum and the residue dissolved in a minimum amount of chloroform (11) and allowed to crystallize. The crystals obtained were collected on a filter and the filtrate concentrated and purified by chromatography over silica gel with chloroform to obtain the subtitle compound as an off-white solid (total 31.5 g, 58%).

IR (film) cm-<1>2200. IR (film) cm-<1>2200.

'H NMR (CDCI3) 8 7,39-7,38 (d, 1H, J=4,lHz), 7,10 (d, 1H, J=4,0Hz). 1 H NMR (CDCl 3 ) δ 7.39-7.38 (d, 1H, J=4.1Hz), 7.10 (d, 1H, J=4.0Hz).

MS (EI) m/z 187 (M1-, 98%), 189 (M*.100%). MS (EI) m/z 187 (M1-, 98%), 189 (M*.100%).

5-(l ,2-dihydro-2-oksospiro[cyklopentan-1,3-[3H]indol]-5-yl)-3-tiofenkarbonitril ble fremstilt i henhold til prosedyren i eksempel 5 ved bruk av 5-brom-2-tiofenkarbonitril og (2'-okso-2',3'-dihydrospiro[cykloheksan-1,3'-[3H]indol]-5'-yl)borsyre; smeltepunkt 225-228°C. 5-(1,2-dihydro-2-oxospiro[cyclopentan-1,3-[3H]indol]-5-yl)-3-thiophenecarbonitrile was prepared according to the procedure of Example 5 using 5-bromo-2 -thiophenecarbonitrile and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boric acid; melting point 225-228°C.

'H NMR (DMSO-de) 8 1,63 (m, 8H), 1,90 (m, 2H), 6,91 (d, 1H, J=8,13Hz), 7,55 (dd, 1 H NMR (DMSO-de) δ 1.63 (m, 8H), 1.90 (m, 2H), 6.91 (d, 1H, J=8.13Hz), 7.55 (dd,

1H, J=8,13,1,76Hz), 7,60 (d, 1H, J=4,17Hz), 7,75 (d, 1H, J=l,76Hz), 1H, J=8.13,1.76Hz), 7.60 (d, 1H, J=4.17Hz), 7.75 (d, 1H, J=1.76Hz),

7,93 (d, 1H, J=4,17Hz), 10,51 (s, 1H). 7.93 (d, 1H, J=4.17Hz), 10.51 (s, 1H).

MS ((+)APCI) m/z 309 [M+H]<+>. MS ((+)APCI) m/z 309 [M+H]<+>.

En oppløsning av 5-(l,2-dihydro-2-oksospiro[cyklopentan-l,3-[3H]-indol]-5-yl)-3-tiofenkarbonitril (0,66 g, 2,4 mmol) og 2,4-bis (4-metoksyfenyl)-l,3-ditia-2,4-difosfetan-2,4-disulfid (0,97 g, 2,4 mmol) i 250 ml toluen ble omrørt ved 80°C i 2 timer. Oppløsningen ble konsentrert under vakuum. Resten ble ekstrahert med etylacetat og etylacetatoppløsningen vasket med vann, tørket over magnesiumsulfat og konsentrert. Resten ble renset ved kolonnekromatografi over silikagel med etylacetat:heksan 20:80 for å gi tittelforbindelsen (0,24 g, 32%), med smeltepunkt 269-272°C. A solution of 5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]-indol]-5-yl)-3-thiophenecarbonitrile (0.66 g, 2.4 mmol) and 2 ,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.97 g, 2.4 mmol) in 250 mL of toluene was stirred at 80°C for 2 hours. The solution was concentrated under vacuum. The residue was extracted with ethyl acetate and the ethyl acetate solution washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography over silica gel with ethyl acetate:hexane 20:80 to give the title compound (0.24 g, 32%), mp 269-272°C.

'H NMR (DMSO-d6) 8 2,09 (m, 8H), 7,05 (d, J=8,lHz, 1H), 7,55 (dd, J=8,l, 1,7Hz, 1 H NMR (DMSO-d 6 ) δ 2.09 (m, 8H), 7.05 (d, J=8.1Hz, 1H), 7.55 (dd, J=8.1, 1.7Hz,

1H), 7,7 (d, J=l,7Hz, 1H), 7,95 (d, J=l,3Hz, 1H), 8,49 (d, J=l,3Hz, 1H), 1H), 7.7 (d, J=1.7Hz, 1H), 7.95 (d, J=1.3Hz, 1H), 8.49 (d, J=1.3Hz, 1H),

8,49 (d, J=l,3Hz, 1H), 12,68 (s, 1H). 8.49 (d, J=1.3Hz, 1H), 12.68 (s, 1H).

MS (EI NEG) m/z 309 (M-H)\ MS (EI NEG) m/z 309 (M-H)\

EKSEMPEL 12 EXAMPLE 12

5-( l , 2- dih vdro- tioksospiro( cvklopentan- l . 3- f 3H1 indol)- 5- vl)- 2- tiofenkarbonitril Tittelforbindelsen ble fremstilt fra 5-(l,2-dihydro-oksospiro(cyklopentan-l,3-[3H]indol)-5-yl)-2-tiofenkarbonitril (2,6 g, 6,8 mmol) og Lawesson's reagens (3,32 g, 8,2 mmol) ved oppvarming til tilbakeløp i 150 ml toluen i 3 timer i et utbytte på 1,5 g (48,3%) og med smeltepunkt 250-253°C. 5-(1,2-dihvdro-thioxospiro(cyclopentane-1.3-f3H1 indole)-5-v1)-2-thiophenecarbonitrile The title compound was prepared from 5-(1,2-dihydro-oxospiro(cyclopentane-1, 3-[3H]indol)-5-yl)-2-thiophenecarbonitrile (2.6 g, 6.8 mmol) and Lawesson's reagent (3.32 g, 8.2 mmol) by heating to reflux in 150 mL of toluene in 3 hours in a yield of 1.5 g (48.3%) and with a melting point of 250-253°C.

'H NMR (DMSO-de) 8 12,75 (s, 1H), 7,98-7,97 (d, 1H, J=3,9Hz), 7,71-7,70 (d, 1H, 1 H NMR (DMSO-de) δ 12.75 (s, 1H), 7.98-7.97 (d, 1H, J=3.9Hz), 7.71-7.70 (d, 1H,

J=5,2Hz), 7,65-7,62 (d, 1H, J=8,lHz), 7,09-7,07 (d, 1H, J=8,lHz), 2,13, J=5.2Hz), 7.65-7.62 (d, 1H, J=8.1Hz), 7.09-7.07 (d, 1H, J=8.1Hz), 2.13,

2,08 (m, 6H), 1,99-1,85 (m, 2H). 2.08 (m, 6H), 1.99-1.85 (m, 2H).

MS [M-H]- = 309. MS [M-H]- = 309.

IR (SP ATR) 1430,1620, 2220 cm<1>. IR (SP ATR) 1430, 1620, 2220 cm<1>.

Analyse for C17H14N2S2. Analysis for C17H14N2S2.

Beregnet: C, 65,77; H, 4,55; N, 9,02. Calcd: C, 65.77; H, 4.55; N, 9.02.

Funnet: C, 65,27; H, 4,41; N, 8,84. Found: C, 65.27; H, 4.41; N, 8.84.

EKSEMPEL 13 EXAMPLE 13

5-( 3- fluor- 4- metoksvfenyl) spiro[ cvkloheksan- l, 3[ 3Hlindol- 2( lH)- tion 5-( 3- fluor- 4- metoksyfenvnspiro|" cvkloheksan- l, 3- r3Hlindol1- 2( lHVone Fremstilt fra 4-brom-2-fluoranisol og (2'-okso-2\3'-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)borsyre i henhold til prosedyren i eksempel 5 for å gi subtittelforbindelsen som et hvitt faststoff med et smeltepunkt 178-180°C. 5-( 3- fluoro- 4- methoxyphenyl) spiro[ cyclohexane- 1, 3[ 3Hlindol- 2( 1H)- thione 5-( 3- fluoro- 4- methoxyphenvn spiro|" ccyclohexane- 1, 3- r3Hlindol- 1- 2( lHVone Prepared from 4-bromo-2-fluoroanisole and (2'-oxo-2\3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boric acid according to the procedure in Example 5 for to give the sub-title compound as a white solid, mp 178-180°C.

<J>H NMR (DMSO-de) 6 10,4 (s, 1H), 7,65 (d, 1H, J=l,lHz), 7,5-7,4 (m, 3H), 7,2 (t, 1H, <J>H NMR (DMSO-de) 6 10.4 (s, 1H), 7.65 (d, 1H, J=1,1Hz), 7.5-7.4 (m, 3H), 7, 2 (t, 1H,

J=d J=8,8 Hz), 3,9 (s, 3H), 1,9 (m, 2H), 1,7-1,6 (m, 8H). J=d J=8.8 Hz), 3.9 (s, 3H), 1.9 (m, 2H), 1.7-1.6 (m, 8H).

MS (APCI (-)) m/z 324 [M-H]'. MS (APCI (-)) m/z 324 [M-H]'.

Analyse for C20H20FNO2: Analysis for C20H20FNO2:

Beregnet: C, 73,83; H, 6,20; N, 4,30. Calculated: C, 73.83; H, 6.20; N, 4.30.

Funnet: C, 73,55; H, 6,23; N, 4,40. Found: C, 73.55; H, 6.23; N, 4.40.

Tittelforbindelsen ble fremstilt ved tilbakeløp over natten av en blanding av 5-(3-fluor-4- metoksyfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-onog en lik mengde fosforpentasulfid i pyridin. Fjerning av pyridinet under vakuum fulgt av behandling av resten med 5N saltsyreoppløsning og etterfølgende omkrystallisering fra etanol ga et grått faststoff med smeltepunkt 228-229°C. The title compound was prepared by refluxing overnight a mixture of 5-(3-fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-one and an equal amount of phosphorus pentasulfide in pyridine. Removal of the pyridine under vacuum followed by treatment of the residue with 5N hydrochloric acid solution and subsequent recrystallization from ethanol gave a gray solid, mp 228-229°C.

<!>H NMR (DMSO-d6) 8 12,7 (s, 1H), 7,9 (s, 1H), 7,6-7,5 (m, 2H), 7,5-7,4 (m, 1H), 7,2 <!>H NMR (DMSO-d6) δ 12.7 (s, 1H), 7.9 (s, 1H), 7.6-7.5 (m, 2H), 7.5-7.4 ( m, 1H), 7.2

(t, 1H, J=8,8Hz), 7,1 (d, 1H, J=8,lHz), 3,9 (s, 3H), 1,9-1,8 (m, 7H), 1,4-1,3 (m, 3H). (t, 1H, J=8.8Hz), 7.1 (d, 1H, J=8.1Hz), 3.9 (s, 3H), 1.9-1.8 (m, 7H), 1 .4-1.3 (m, 3H).

MS (APCI (-)) [M-H]- m/z 324. MS (APCI (-)) [M-H]- m/z 324.

Analyse for C2oH2oFNOS-0,25 H20. Analysis for C2oH2oFNOS-0.25 H2O.

Beregnet: C, 69,44; H, 5,97; N, 4,05. Calcd: C, 69.44; H, 5.97; N, 4.05.

Funnet: C, 69,43; H, 5,75; N, 4,32. Found: C, 69.43; H, 5.75; N, 4.32.

EKSEMPEL 14 EXAMPLE 14

5- ( 2- amino- 5- pyridimidinvnspirolcvkloheksan- l, 3- f3Hlindoll- 2( lHltion Fremstilt ved tilbakeløp over natten av en blanding av 5-(2-amino-5-pyrimidinyl)spiro[cykloheksan-l,3-[3H]-indol]-2(lH)-on og en lik mengde fosforpentasulfid i pyridin. Fjerning av pyridinet under vakuum fulgt av behandling av resten med 5- ( 2- amino- 5- pyridimidinvspirolccyclohexane-1, 3- f3Hlindol- 2( lHltion Prepared by refluxing overnight from a mixture of 5-(2-amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H ]-indol]-2(lH)-one and an equal amount of phosphorus pentasulfide in pyridine, removal of the pyridine under vacuum followed by treatment of the residue with

5N saltsyreoppløsning og etterfølgende omkrystallisering fra etanol ga et grått faststoff med smeltepunkt 274-277°C (dekomp.). 5N hydrochloric acid solution and subsequent recrystallization from ethanol gave a gray solid with melting point 274-277°C (decomp.).

'H NMR (DMSO-de) 5 12,7 (s, 1H), 8,6 (s, 2H), 7,9 (s, 1H), 7,5 (d, 1H, J=8,lHz), 7,1 1 H NMR (DMSO-de) δ 12.7 (s, 1H), 8.6 (s, 2H), 7.9 (s, 1H), 7.5 (d, 1H, J=8.1Hz) , 7.1

(d, 1H, J~8,lHz), 6,8 (s, 2H), 1,9-1,8 (m, 7H), 1,4-1,3 (m, 3H). (d, 1H, J~8.1Hz), 6.8 (s, 2H), 1.9-1.8 (m, 7H), 1.4-1.3 (m, 3H).

MS (APCI (-)) [M-H]- m/z 309. MS (APCI (-)) [M-H]- m/z 309.

EKSEMPEL 15 EXAMPLE 15

3- fl. 2- dihvdro- 2- tioksospirofcvklopentan- U- f3Hlindoll- 5- vlV5- fluorbenzonitril Spirolcvklopentan- 1. 3 '- KHI indoll^ O ' HVone 3- fl. 2- dihydro- 2- thioxospirofcvklopentane- U- f3Hlindoll- 5- vlV5- fluorobenzonitrile Spirolcvclopentane- 1. 3 '- KHI indoll^ O ' HVone

Til en til -25°C avkjølt oppløsning av oksindol (2,0 g, 15,0 mmol) i 40 cm<3>vannfri THF ble det under N2dråpevis satt n-butyllitium (1,6M i heksaner, 19,7 cm<3>,31,5 mmol). Til den resulterende melkeaktige oppløsning ble det satt N,N)N',N'-tetrametyletylendiamin (4,75 cm<3>,31,5 mmol). Efter 30 minutter ble en oppløsning av 1,4-dijodbutan (21,9 g, To a solution of oxindole (2.0 g, 15.0 mmol) cooled to -25°C in 40 cm<3>anhydrous THF was added dropwise under N2 n-butyllithium (1.6M in hexanes, 19.7 cm< 3>.31.5 mmol). To the resulting milky solution was added N,N)N',N'-tetramethylethylenediamine (4.75 cm<3>, 31.5 mmol). After 30 minutes, a solution of 1,4-diiodobutane (21.9 g,

70,6 mmol) i 3 cm<3>THF tilsatt og reaksjonsblandingen tillatt oppvarming til romtemperatur og omrørt i 14 timer. Reaksjonsblandingen ble heilt i vann, ekstrahert to ganger med EtOAc hvoretter de kombinerte organiske sjikt ble vasket med fortynnet HC1 (pH 1) og 2 ganger med vann, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med EtOAc:heksan 1:4 for å gi subtittelforbindelsen (1,4 g, 7,5 mmol, 50%) som et gyldent faststoff. 70.6 mmol) in 3 cm<3>THF added and the reaction mixture allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was poured into water, extracted twice with EtOAc after which the combined organic layers were washed with dilute HCl (pH 1) and twice with water, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 with EtOAc:hexane 1:4 to give the subtitle compound (1.4 g, 7.5 mmol, 50%) as a golden solid.

<!>H NMR (CDCb) 5 1,8-2,2 (m, 8H), 6,94 (dd, J=7,5,1,0Hz, 1H9, 7,01 (dd, J=7,5, <!>H NMR (CDCb) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0Hz, 1H9, 7.01 (dd, J=7, 5,

1,0Hz, 1H), 7,14-7,25 (m, 2H), 9,30 (br s, 1H). 1.0Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).

S- brom- spirorcvklopentan- l. S^- rSHIindon^ TrH^- one S- bromo- spirorcvklopentan- l. S^- rSHIindon^ TrH^- one

En oppløsning av spiro[cyklopentan-l,3'-[3H]indol]-2'(rH)-on(0,27 g, 1,4 mmol) og natriumacetat (0,12 g, 1,46 mmol) 110 cm3 eddiksyre ble behandlet med brom (0,24 g, 1,51 mmol) i 2 cm<3>eddiksyre. Efter 30 minutter ble blandingen heilt i mettet natrium-hydrogenkarbonatoppløsning og ekstrahert to ganger med EtOAc, hvoretter de kombinerte organiske sjikt ble vasket med vann, mettet natriumhydrogenkarbonatoppløsning, vann, tørket over MgS04og fordampet for å gi subtittelforbindelsen (0,37 g, 1,47 mmol, 96%) som et hvitaktig faststoff som så ble benyttet uten ytterligere rensing. A solution of spiro[cyclopentane-1,3'-[3H]indole]-2'(rH)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) 110 cm3 of acetic acid was treated with bromine (0.24 g, 1.51 mmol) in 2 cm<3>acetic acid. After 30 minutes, the mixture was poured into saturated sodium hydrogen carbonate solution and extracted twice with EtOAc, after which the combined organic layers were washed with water, saturated sodium hydrogen carbonate solution, water, dried over MgSO 4 and evaporated to give the subtitle compound (0.37 g, 1.47 mmol, 96%) as a whitish solid which was then used without further purification.

'H NMR (CDCI3) 8 1,8-2,27 (m, 8H), 6,79 (d, J=8,Hz, 1H), 7,30-7,39 (m, 2H), 8,63 (br s, 1H). 1 H NMR (CDCl 3 ) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8.Hz, 1H), 7.30-7.39 (m, 2H), 8, 63 (br p, 1H).

S^- O- cvano- S- fluorfenvlVspirorcvklopentan- l . 3 '- r3H1indofl- 2*( 1 ' HVone S^- O- cvano- S- fluorophenvlVspirorcvclopentan- l. 3 '- r3H1indofl- 2*( 1 ' HVone

En oppløsning av 3-cyano-5-fluor-brombenzen (0,5 g, 2,6 mmol) og 0,2 g tetra-kis(trifenylfosifn)palladium(0) i 20 cm3 etylenglykol dimetyleter ble omrørt under N2i 20 minutter. Til denne blanding ble det så satt (spiro[cyklopentan-l,3'-[3H]indol]-2<*->A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol) and 0.2 g of tetra-kis(triphenylphosphine)palladium(0) in 20 cm 3 of ethylene glycol dimethyl ether was stirred under N 2 for 20 min. To this mixture was then added (spiro[cyclopentane-1,3'-[3H]indole]-2<*->

(1 'H)-one-5-yl)borsyre (0,9 g, 3,9 mmol) og natriumkarbonat (0,8 g, 7,8 mmol) i 5 cm<3>vann. Oppløsningen ble bragt til tilbakeløp i 18 timer og så avkjølt til romtemperatur, heilt i 2N NaOH og ekstrahert tre ganger med EtOAc. De kombinerte ekstrakter ble vasket med vann, saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med EtOAc:heksan for å gi subtittelforbindelsen (0,35 g, 44%) som hvite nåler med smeltepunkt 235-237'C. (1'H)-one-5-yl)boric acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in 5 cm<3>water. The solution was refluxed for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted three times with EtOAc. The combined extracts were washed with water, brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 with EtOAc:hexane to give the sub-title compound (0.35 g, 44%) as white needles, mp 235-237°C.

<!>H NMR (DMSO-d6) 5 10,5 (s, 1H), 8,1 (s, 1H), 8,0 (dt, 1H, J=l,7,2,0,7,0Hz), 7,8-7,7 <!>H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7.2.0.7.0Hz ), 7.8-7.7

(m, 2H), 7,6 (dd, 1H, J=l,8,6,4Hz), 6,9 (d, 1H, J=8,lHz), 2,0-1,9 (m, (m, 2H), 7.6 (dd, 1H, J=1,8,6,4Hz), 6.9 (d, 1H, J=8,1Hz), 2.0-1.9 (m,

8H). 8H).

MS (EI) M<+>@ m/z 306. MS (EI) M<+>@ m/z 306.

Generell prosedyre A General procedure A

Tittelforbindelsen ble fremstilt fra 40 mg 5'-(3-cyano-5-fluorfenyl)-spiro[cyklopentan-l,3'-[3H]indol]-2'-(rH)-onog 50 mg Lawesson's reagens i 10 ml toluen under tilbake-løp i et forseglet rør i 16 timer. Blandingen ble konsentrert og resten oppløst i en mini-mal mengde THF og så renset ved HPLC over Si02med kolonne 30 cmx2,5, og med EtOAc:heksan 2:8 i en hastighet av 20 ml/min. for å derved å gi 0,022 g tittelforbindelse som et hvitaktig faststoff med smeltepunkt 236-238°C. The title compound was prepared from 40 mg of 5'-(3-cyano-5-fluorophenyl)-spiro[cyclopentane-1,3'-[3H]indole]-2'-(rH)-one and 50 mg of Lawesson's reagent in 10 ml of toluene under reflux in a sealed tube for 16 hours. The mixture was concentrated and the residue dissolved in a minimal amount of THF and then purified by HPLC over SiO 2 with a 30 cm x 2.5 column, and with EtOAc:hexane 2:8 at a rate of 20 ml/min. to thereby give 0.022 g of the title compound as a whitish solid m.p. 236-238°C.

'H NMR (DMSO-dé) 6 12,66 (br s, 1H), 8,11 (s, 1H), 7,97 (dt, 1H, J=10,l og 2,2Hz), 7,79-7,76 (m, 2H), 7,68 (dd, 1H, J=8,l og 1,7Hz), 7,07 (d, 1H, J=8,lHz), 2,10-2,05 (m, 6H)og 1,97-1,88 (m,2H). 1 H NMR (DMSO-dé) δ 12.66 (br s, 1H), 8.11 (s, 1H), 7.97 (dt, 1H, J=10.1 and 2.2Hz), 7.79 -7.76 (m, 2H), 7.68 (dd, 1H, J=8.1 and 1.7Hz), 7.07 (d, 1H, J=8.1Hz), 2.10-2, 05 (m, 6H) and 1.97-1.88 (m, 2H).

MS (EI) m/z 322 [Mf. MS (EI) m/z 322 [Mf.

EKSEMPEL 16 EXAMPLE 16

5-( 3- klorfenvn- 3. 3- dimetvl- L3- dihvdro- 2H- indol- 2- tion 5-( 3- chlorophenvn- 3. 3- dimethyl- L3- dihydro- 2H- indol- 2- thione

5- f 3 - klor- fenvlV3. 3- dimetvl- 1. 3- dihvdro- indol- 2- one 5- f 3 - chloro- phenvlV3. 3- dimetvl- 1. 3- dihydro- indol- 2- one

5-brom-l,3-dihydro-3,3-dimetyl-2H-indol-2-on(0,98 g, 4,07 mol) og 0,239 g tetra-kis(trifenylfosfin)palladium(0) ble omrørt under en atmosfære av nitrogen i 35 cm<3>dimetoksyetan. Efter 15 minutter ble 3-klorfenylborsyre (1,27 g, 8,13 mmol) tilsatt, fulgt av kaliumkarbonat (3,40 g, 45 mmol) i 15 cm<3>vann. Reaksjonsblandingen ble oppvar- 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) and 0.239 g of tetrakis(triphenylphosphine)palladium(0) were stirred under an atmosphere of nitrogen in 35 cm<3>dimethoxyethane. After 15 minutes, 3-chlorophenylboronic acid (1.27 g, 8.13 mmol) was added, followed by potassium carbonate (3.40 g, 45 mmol) in 15 cm<3>water. The reaction mixture was heated

met til tilbakeløp i 2 timer og så omrørt ved romtemperatur over natten. Blandingen ble fortynnet med mettet ammoniumklorid og ekstrahert tre ganger med EtOAc. De kombinerte organiske sjikt ble tørket over MgS04, filtrert og fordampet. Resten ble renset ved kolonnekromatografi over Si02med EtOAcrheksan 1:3 for å gi subtittelforbindelsen refluxed for 2 hours and then stirred at room temperature overnight. The mixture was diluted with saturated ammonium chloride and extracted three times with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and evaporated. The residue was purified by column chromatography over SiO2 with EtOAcrhexane 1:3 to give the sub-title compound

(0,284 g, 25%) med smeltepunkt 188-189°C. (0.284 g, 25%) with melting point 188-189°C.

'H NMR (DMSO-de) 8 3,34 (6H), 6,93 (d, 1H, J=8,04Hz), 7,38-7,35 (m, 1H), 7,53-7,43 1 H NMR (DMSO-de) δ 3.34 (6H), 6.93 (d, 1H, J=8.04Hz), 7.38-7.35 (m, 1H), 7.53-7, 43

(m, 2H), 7,61 (d, 1H, J=7,68Hz), 7,70 (s, 2H), 10,40 (s, 1H). (m, 2H), 7.61 (d, 1H, J=7.68Hz), 7.70 (s, 2H), 10.40 (s, 1H).

IR (KBr): 3420,3150, 3050,1700 ot1. IR (KBr): 3420, 3150, 3050, 1700 ot1.

MS (EI) m/z 270 (M-H)-. MS (EI) m/z 270 (M-H)-.

CHN for Ci6Hi4ClNO + 0,1 C4H802. CHN for Ci6Hi4ClNO + 0.1 C4H8O2.

Beregnet: C, 70,21; H, 5,32; N, 4,99. Calculated: C, 70.21; H, 5.32; N, 4.99.

Funnet: C, 70,3; H, 5,44; N, 4,93. Found: C, 70.3; H, 5.44; N, 4.93.

Tittelforbindelsen ble fremstilt fra 100 mg 5-(3-klor-fenyl)-3,3-dimetyl-l,3-dihydro-indol-2-onog 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A for å gi 0,031 g tittelforbindelse som et hvitaktig faststoff med smeltepunkt 158-160°C. The title compound was prepared from 100 mg of 5-(3-chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene according to the general procedure A to give 0.031 g of the title compound as an off-white solid m.p. 158-160°C.

'H NMR (CDCU) 8 9,67 (br s, 1H), 7,55 (s, 1H), 7,47-7,43 (m, 3H), 7,40-7,30 (m, 2H), 1 H NMR (CDCU) δ 9.67 (br s, 1H), 7.55 (s, 1H), 7.47-7.43 (m, 3H), 7.40-7.30 (m, 2H ),

7.08 (d, 1H, J=8,7Hz) og 1,50 (s, 6H). 7.08 (d, 1H, J=8.7Hz) and 1.50 (s, 6H).

MS (EI) m/z 287/289 [M]<+>. MS (EI) m/z 287/289 [M]<+>.

EKSEMPEL 17 EXAMPLE 17

3- benzvl- 5- f3- klorfenvn- 3- metvl- 1. 3- dihvdro- 2H- indol- 2- tion Tittelforbindelsen ble fremstilt fra 100 mg 3-benzyl-5-(3-klor-fenyl)-3-metyl-l,3-dihydro-indol-2-on og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A for å gi 0,022 g tittelforbindelse som et hvitaktig faststoff med smeltepunkt 168-170°C. 3- benzyl- 5- f3- chlorophenyl- 3- methyl- 1. 3- dihydro- 2H- indol- 2- thione The title compound was prepared from 100 mg of 3-benzyl-5-(3-chloro-phenyl)-3-methyl -1,3-dihydro-indol-2-one and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene according to General Procedure A to give 0.022 g of the title compound as an off-white solid, mp 168-170°C.

<!>H NMR (CDCI3) 8 9,23 (br s, 1H), 7,49 (s, 1H), 7,49-7,30 (m, 4H), 7,21 (s, 1H), 7,15-7.09 (m, 3H), 6,96-6,94 (m, 2H), 6,89 (d, 1H, J=8,0Hz), 3,19 (dd, 2H, <!>H NMR (CDCl 3 ) δ 9.23 (br s, 1H), 7.49 (s, 1H), 7.49-7.30 (m, 4H), 7.21 (s, 1H), 7.15-7.09 (m, 3H), 6.96-6.94 (m, 2H), 6.89 (d, 1H, J=8.0Hz), 3.19 (dd, 2H,

J=40,5 og 13Hz) og 1,57 (s, 3H). J=40.5 and 13Hz) and 1.57 (s, 3H).

MS (EI) m/z 363/365 [M]<+>. MS (EI) m/z 363/365 [M]<+>.

EKSEMPEL 18 EXAMPLE 18

4- 0. 3- dimetvl- 2- tiQkso- 2. 3- dihvdro- lH- indol- 5- vh- 2- furoiiitril 4- D3- dimetyl- 2- okso- 23- dihvdro4H- indol- 5- vlVruran- 2- karboruM 4- 0. 3- dimethyl- 2- thiQxo- 2. 3- dihydro- 1H- indole- 5- vh- 2- furoiiitrile 4- D3- dimethyl- 2- oxo- 23- dihydro4H- indole- 5- vlVruran- 2 - carboruM

Fremstilt i henhold til prosedyren i eksempel 5 ved bruk av (2'-okso-[2,3-dihydro-3,3-dimetyl-l,3<*->[3H]indol]-5'-yl)borsyre (354 mg, 1,7 mmol) og 4-brom-furan-2-karbonitril (200 mg, 1,2 mmol) for å gi subtittelforbindelsen (76 mg, 0,3 mmol, 26%) som et hvitt faststoff med smeltepunkt 199,6-201,4°C. Prepared according to the procedure of Example 5 using (2'-oxo-[2,3-dihydro-3,3-dimethyl-1,3<*->[3H]indol]-5'-yl)boric acid ( 354 mg, 1.7 mmol) and 4-bromo-furan-2-carbonitrile (200 mg, 1.2 mmol) to give the subtitle compound (76 mg, 0.3 mmol, 26%) as a white solid, mp 199 .6-201.4°C.

<l>H NMR (DMSO-do) 5 1,28 (s, 6H), 6,89 (d, J=8,0Hz, 1H), 7,48 (dd, J=8,0,1,8Hz, 1H), <1>H NMR (DMSO-do) δ 1.28 (s, 6H), 6.89 (d, J=8.0Hz, 1H), 7.48 (dd, J=8.0,1.8Hz , 1H),

7,65 (d, J=l,5Hz, 1H), 8,1 (s, 1H), 8,5 (s, 1H), 10,46 (s, 1H). MS (ESI) m/z 251 (M-HV. 7.65 (d, J=1.5Hz, 1H), 8.1 (s, 1H), 8.5 (s, 1H), 10.46 (s, 1H). MS (ESI) m/z 251 (M-HV.

Analyse for C]5Hi2N2O2*0,6 H2. Analysis for C] 5 Hi 2 N 2 O 2 * 0.6 H 2 .

Tittelforbindelsen ble fremstilt fra 73 mg 4-(3,3-dimetyl-2-okso-2,3-dihydro-lH-indol-5- yl)-furan-2-karbonitril og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A for å gi 0,003 g tittelforbindelse som et hvitaktig faststoff med smeltepunkt 188-191'C. The title compound was prepared from 73 mg of 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene according to General Procedure A to give 0.003 g of the title compound as an off-white solid, mp 188-191°C.

<!>H NMR (CDC13) 8 9,63 (br s, 1H), 7,83 (s, 1H), 7,36-7,33 (m, 3H), 7,06 (d, 1H, <!>H NMR (CDCl 3 ) δ 9.63 (br s, 1H), 7.83 (s, 1H), 7.36-7.33 (m, 3H), 7.06 (d, 1H,

J=7,9Hz)ogl,48(s,6H). J=7.9Hz) and g1,48(s,6H).

MS (EI) m/z 268 [M]<+>. MS (EI) m/z 268 [M]<+>.

EKSEMPEL 19 EXAMPLE 19

5-( 3- metoksvfenvn- 3. 3- dimetvl- 1. 3- dihvdro- 2H- indol- 2- tion 5- brom- 1. 3- dihvdro- 3. 3- dimetvl- 2H- indol- 2- one 5-( 3- methoxyphenyl- 3. 3- dimethyl- 1. 3- dihydro- 2H- indol- 2- thione 5- bromo- 1. 3- dihydro- 3. 3- dimethyl- 2H- indol- 2- one

3,3-dimetyl-indol-2-on (0,65 g, 4,03 mmol) og natriumacetat (0,33 g, 4,07 mmol) ble omrørt i 5 cm3 eddiksyre og deretter ble brom (0,66 g, 4,13 mmol) i 5 cm3 eddiksyre dråpevis satt til reaksjonsblandingen. Reaksjonsblandingen ble omrørt i 15 minutter og så heilt i vann. Blandingen ble gjort basisk med natriumkarbonat, ekstrahert tre ganger med etylacetat, tørket over MgSCu, filtrert og fordampet for å gi subtittelforbindelsen (0,89 g, 92%). 3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g, 4.07 mmol) were stirred in 5 cm 3 of acetic acid and then bromine (0.66 g , 4.13 mmol) in 5 cm3 acetic acid added dropwise to the reaction mixture. The reaction mixture was stirred for 15 minutes and then completely poured into water. The mixture was basified with sodium carbonate, extracted three times with ethyl acetate, dried over MgSCu, filtered and evaporated to give the subtitle compound (0.89 g, 92%).

'H NMR (DMSO-de) 8 1,21 (s, 6H), 6,76 (d, 1H, J=8,22Hz), 7,29 (dd, 1H, J=2,12Hz, 1H NMR (DMSO-de) δ 1.21 (s, 6H), 6.76 (d, 1H, J=8.22Hz), 7.29 (dd, 1H, J=2.12Hz,

8,23 Hz), 7,49 (d, 1H, J=2,03Hz), 10,4 (s, 1H). 8.23 Hz), 7.49 (d, 1H, J=2.03Hz), 10.4 (s, 1H).

5-brom-l,3-dihydro-3,3-dimetyl-2H-indol-2-on (0,33 g, 1,38 mmol) og 0,094 g tetra-kis(trifenylfosfin)palladium(0) ble omrørt under en atmosfære av nitrogen i 12 cm<3>dimetoksyetan. Efter 15 minutter ble 3-metoksyfenylborsyre (0,42 g, 2,76 mmol) tilsatt, fulgt av kaliumkarbonat (1,15 g, 8,34 mmol) i 5 cm<3>vann. Reaksjonsblandingen ble oppvarmet til tilbakeløp i 5 timer og så avkjølt til romtemperatur. Mettet vandig ammoniumklorid og EtOAc ble tilsatt og blandingen ble filtrert. Det vandige sjikt ble ekstrahert to ganger med EtOAc og de kombinerte organiske sjikt ble tørket over MgSO<t, filtrert og fordampet. Resten ble renset ved kolonnekromatografi over Si02med EtOAc:heksan 1:3 for å gi 5-(3-metoksy-fenyl)-3,3-dimetyl-l,3-dihydro-indol-2-on(0,ll g, 31%) med smeltepunkt 157-158'C. 5-Bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and 0.094 g of tetrakis(triphenylphosphine)palladium(0) were stirred under an atmosphere of nitrogen in 12 cm<3>dimethoxyethane. After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by potassium carbonate (1.15 g, 8.34 mmol) in 5 cm<3>water. The reaction mixture was heated to reflux for 5 hours and then cooled to room temperature. Saturated aqueous ammonium chloride and EtOAc were added and the mixture was filtered. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography over SiO 2 with EtOAc:hexane 1:3 to give 5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (0.11 g, 31 %) with melting point 157-158'C.

■H NMR (DMSO-d6) 5 3,34 (s, 6H), 3,82 (s, 3H), 6,87-6,93 (m, 2H), 7,20-7,15 (m, 2H), 7,37-7,32 (m, 1H), 7,49-7,46 (m, 1H), 7,63 (d, 1H, J=l,14Hz), 10,4 (s, ■H NMR (DMSO-d 6 ) δ 3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m, 2H), 7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14Hz), 10.4 (s,

1H). 1H).

MS (EI) m/z 266 (M-H)'. MS (EI) m/z 266 (M-H)'.

CHN for Ci7H17Nd2. CHN for Ci7H17Nd2.

Beregnet: C, 76,38; H, 6,41; N; 5,24. Calculated: C, 76.38; H, 6.41; N; 5.24.

Funnet: C, 76,02; H, 6,49; N, 5,02. Found: C, 76.02; H, 6.49; N, 5.02.

Tittelforbindelsen ble fremstilt fra 100 mg 5-(3-metoksy-fenyl)-3,3-dimetyl-l,3-dihydro-indol-2-on og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A for å gi tittelforbindelsen i en mengde av 0,022 g som et hvitaktig faststoff med smeltepunkt 149-150°C. The title compound was prepared from 100 mg of 5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene according to the general procedure A to give the title compound in an amount of 0.022 g as an off-white solid, mp 149-150°C.

<l>H NMR (CDC13) 5 9,69 (br s, 1H), 7,49-7,46 (m, 2H), 7,37 (t, 1H, J=8,0Hz), 7,16 (d, <1>H NMR (CDCl 3 ) δ 9.69 (br s, 1H), 7.49-7.46 (m, 2H), 7.37 (t, 1H, J=8.0Hz), 7.16 (d,

1H, J=7,7Hz), 7,09-7,06 (m, 2H), 6,90 (dd, 1H, J=8,2 og 2,3 Hz), 3,88 (s, 1H, J=7.7Hz), 7.09-7.06 (m, 2H), 6.90 (dd, 1H, J=8.2 and 2.3 Hz), 3.88 (s,

3H)ogl,50(s,6H). 3H) and g1,50 (s,6H).

MS (EI) m/z 283 [Mf. MS (EI) m/z 283 [Mf.

EKSEMPEL 20 EXAMPLE 20

3-( l<2- dihvdro- 2- tioksosplrofcvkloheksan- 1. 3-[ 3Hlindon- 5- vn- 4- fluorbenzonitril 3- n. 2- dihvdro- 2- oksospiro[ cvkloheksan- 1. 3-[ 3H1indol1- 5- vlV4- fluorbenzonitril Forbindelsen ble fremstilt i henhold til prosedyren i eksempel 5 og ble oppnådd med smeltepunkt 205-206°C. 3-( l<2- dihydro- 2- thioxosplrofcvchlorohexane- 1. 3-[ 3Hlindone- 5- vn- 4- fluorobenzonitrile 3- n. 2- dihydro- 2- oxospiro[ cvchlorohexane- 1. 3-[ 3H1indol1- 5- v1V4-Fluorobenzonitrile The compound was prepared according to the procedure in Example 5 and was obtained with a melting point of 205-206°C.

'H NMR (DMSO-d6) 5 10,47 (s, 1H), 8,08-8,06 (dd, 1H), 7,89-7,85 (m, 1H), 7,65 (s, 1 H NMR (DMSO-d 6 ) δ 10.47 (s, 1H), 8.08-8.06 (dd, 1H), 7.89-7.85 (m, 1H), 7.65 (s,

1H), 7,54-7,49 (m, 1H), 7,43-7,40 (tt, 1H), 6,95-6,93 (d, 1H, J=7,9Hz), 1H), 7.54-7.49 (m, 1H), 7.43-7.40 (tt, 1H), 6.95-6.93 (d, 1H, J=7.9Hz),

1,97-1,83 (m, 2H), 1,69-1,55 (m, 8H). 1.97-1.83 (m, 2H), 1.69-1.55 (m, 8H).

MS (EI) m/z 320 (M<1>"). MS (EI) m/z 320 (M<1>”).

Tittelforbindelsen ble fremstilt fra 100 mg 3-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-4-fluorbenzonitril og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A, for å gi 0,037 g tittelforbindelsen som et hvitaktig faststoff med smeltepunkt 230-233°C. The title compound was prepared from 100 mg of 3-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene according to General Procedure A, to give 0.037 g of the title compound as an off-white solid, m.p. 230-233°C.

'H NMR (CDC13) 8 9,82 (br s, 1H), 7,86 (s, 1H), 7,77 (d, 1H, J=7,0 og 1,8Hz), 7,68-7,63 (m, 1H), 7,45 (d, 1H, J=8,0Hz), 7,31 (d, 1H, J=9,0Hz), 7,15 (d, 1H, 1 H NMR (CDCl 3 ) δ 9.82 (br s, 1H), 7.86 (s, 1H), 7.77 (d, 1H, J=7.0 and 1.8Hz), 7.68-7 .63 (m, 1H), 7.45 (d, 1H, J=8.0Hz), 7.31 (d, 1H, J=9.0Hz), 7.15 (d, 1H,

J=8,lHz), 2,17-1,84 (m, 7H) og 1,60-1,54 (m, 3H). J=8.1Hz), 2.17-1.84 (m, 7H) and 1.60-1.54 (m, 3H).

MS (EI) m/z 336 [M<+>]. MS (EI) m/z 336 [M<+>].

EKSEMPEL 21 EXAMPLE 21

5-( L2- dihvdro- 2- tioksospirofcvkloheksan- l, 3-[ 3Hlindoll- 5- vn- 3- pyridinkarbonitril En oppløsning av 3-brompyridin-5-karbonitril (2,79 g, 15,26 mmol), heksametylditinn (5,00 g, 15,26 mmol) og tetrakis(trifenylfosfin)palladium(0) (0,20 g, 0,17 mmol) i 30 cm<3>vannfri dimetoksyetan ble oppvarmet til tilbakeløp under N2. Efter 16 timer ble blandingen konsentrert og renset ved kolonnekromatografi over Si02med EtOAc:heksan 5:95 for å gi 3-cyanopyridin-5-trimetylstannan (2,82 g, 10,55 mmol, 69%). 5-( L2- dihydro- 2- thioxospirofcvchlorohexane- 1, 3-[ 3Hlindoll- 5- vn- 3- pyridinecarbonitrile A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol), hexamethyl ditin (5 .00 g, 15.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) in 30 cm<3>anhydrous dimethoxyethane were heated to reflux under N2. After 16 h the mixture was concentrated and purified by column chromatography over SiO 2 with EtOAc:hexane 5:95 to give 3-cyanopyridine-5-trimethylstannane (2.82 g, 10.55 mmol, 69%).

<*>H NMR (CDCI3) 8 0,40 (s, 9H), 8,01 (m, 1H), 8,80 (m, 2H). <*>H NMR (CDCl 3 ) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H).

MS ((+) APCI) m/z 269 (M+H)<+>. MS ((+) APCI) m/z 269 (M+H)<+>.

En oppløsning av 5'-bromspiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on (1,97 g, 7,05 mmol), 3-cyanopyridin-5-trimetylstannan (2,26 g, 8,46 mmol), A solution of 5'-bromospiro[cyclohexane-1,3'-[3H]indol]-2'(rH)-one (1.97 g, 7.05 mmol), 3-cyanopyridine-5-trimethylstannane (2, 26 g, 8.46 mmol),

bis(trifenylfosfin)palladium(II)klorid (0,33 g, 0,47 mmol) og litiumklorid (1,48 g, 35 mmol) i 30 cm3 vannfri toluen ble oppvarmet under tilbakeløp. Efter 16 timer ble reaksjonsblandingen avkjølt, fordelt mellom EtOAc og vann, og det vandige sjikt reekstrahert to ganger med EtOAc hvoretter de kombinerte organiske ekstrakter ble vasket med vann, tørket over MgS04og fordampet. Resten ble underkastet kolonnekromatografi over Si02med EtOAc:heksan 1:2 og så renset ytterligere ved preparativ LC (Pri-mesphere C18, 10 mikron, 50 x 250 mm, MeCN:H20 1:1, 100 cm<3>/min., RT 7,92 min.) bis(triphenylphosphine)palladium(II) chloride (0.33 g, 0.47 mmol) and lithium chloride (1.48 g, 35 mmol) in 30 cm3 of anhydrous toluene were heated under reflux. After 16 hours, the reaction mixture was cooled, partitioned between EtOAc and water, and the aqueous layer re-extracted twice with EtOAc after which the combined organic extracts were washed with water, dried over MgSO 4 and evaporated. The residue was subjected to column chromatography over SiO 2 with EtOAc:hexane 1:2 and then further purified by preparative LC (Primesphere C18, 10 micron, 50 x 250 mm, MeCN:H 2 O 1:1, 100 cm<3>/min., RT 7.92 min.)

for å gi 3-(l\2'-mhydro-2'-oksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)py^ karbonitril som hvite krystaller (0,56 g, 1,84 mmol, 26%) med smeltepunkt 232-234°C. to give 3-(1\2'-mhydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)pyr^carbonitrile as white crystals (0.56 g, 1, 84 mmol, 26%) with melting point 232-234°C.

<!>H NMR (CDC13) 8 1,68-1,89 (m, 6H), 1,93-2,13 (m, 4H), 7,12 (d, 1H, J=8Hz), 7,49 <!>H NMR (CDCl 3 ) δ 1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, J=8Hz), 7, 49

(dd, 1H, J=8,2Hz), 7,66 (d, 1H, 2Hz), 8,15 (t, 1H, J=2Hz), 8,39 (s, 1H, (dd, 1H, J=8.2Hz), 7.66 (d, 1H, 2Hz), 8.15 (t, 1H, J=2Hz), 8.39 (s, 1H,

br), 8,89 (d, 1H, J=2Hz), 9,06 (d, 1H, J=2Hz). br), 8.89 (d, 1H, J=2Hz), 9.06 (d, 1H, J=2Hz).

MS ((+)-ESI) m/z 304 (M+H)<+>. MS ((+)-ESI) m/z 304 (M+H)<+>.

Analyse for C19H17N3O CHN. Analysis for C19H17N3O CHN.

Tittelforbindelsen ble fremstilt fra 100 mg 3-(l ',2'-dihydro-2'-oksospiro[cykloheksan-l,3'-[3H]indol-5'-yl)pyridin karbonitril og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A for å gi 0,004 g tittelforbindelse som et gult faststoff med smeltepunkt 237-238°C. The title compound was prepared from 100 mg of 3-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl)pyridine carbonitrile and 120 mg of Lawesson's reagent in 10 ml of toluene under reflux according to General Procedure A to give 0.004 g of the title compound as a yellow solid m.p. 237-238°C.

'H NMR (CDCI3) 8 9,56 (br s, 1H), 9,03 (d, 1H, J=l,9Hz), 8,87 (d, 1H, J=l,4Hz), 8,12 1 H NMR (CDCl 3 ) δ 9.56 (br s, 1H), 9.03 (d, 1H, J=1.9Hz), 8.87 (d, 1H, J=1.4Hz), 8.12

(s, 1H), 7,87 (s, 1H), 7,50 (d, 1H, J=8,lHz), 7,17 (d, 1H, J=8,lHz), 2,19-1,85 (m, 7H) og 1,59-1,54 (m, 3H). (s, 1H), 7.87 (s, 1H), 7.50 (d, 1H, J=8.1Hz), 7.17 (d, 1H, J=8.1Hz), 2.19-1 .85 (m, 7H) and 1.59-1.54 (m, 3H).

MS ((-)-APCI) m/z 318 [M-H]-. MS ((-)-APCI) m/z 318 [M-H]-.

EKSEMPEL 22 EXAMPLE 22

5-( 3. 4- difluorfenvnsPiro[ cvkloheksan- L3-[ 3Hlindoll- 2( lH)- tion 5 '-( 3. 5- difluorfenvnspirorcvkloheksan- 1. 3 '- r3Hlindoll- 2'( l ' HVon Fremstilt i henhold til prosedyren i eksempel 5 med smeltepunkt 180-183°C. 5-( 3. 4- difluorophenvnsPiro[ cvchlorohexane- L3-[ 3Hlindoll- 2( lH)- thione 5 '-( 3. 5- difluorophenvnspirorcvchlorohexane- 1. 3 '- r3Hlindoll- 2'( l ' HVon Prepared according to the procedure in example 5 with melting point 180-183°C.

<*>H NMR (CDCI3) 8 8,35 (s, 1H), 7,59 (d, 1H, J=2,0Hz), 7,40 (dd, 1H, J=6,2,2,0Hz), 7,10-7,03 (m, 2H), 6,99 (d, 1H, J=8,lHz), 7,76 (tt, 1H, J=4,3, 2,3Hz), <*>H NMR (CDCl3) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=6.2,2.0Hz ), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J=8.1Hz), 7.76 (tt, 1H, J=4.3, 2.3Hz),

2,05-1,62 (m, 10H). 2.05-1.62 (m, 10H).

MS ((+)APCI) m/z 314 [M+H]<+>. MS ((+)APCI) m/z 314 [M+H]<+>.

Tittelforbindelsen ble fremstilt fra 100 mg 5'-(3,5-difluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A, for å gi 0,020 g produkt som et gult faststoff med smeltepunkt 232-233°C. The title compound was prepared from 100 mg of 5'-(3,5-difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(rH)-one and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene in according to General Procedure A, to give 0.020 g of product as a yellow solid, mp 232-233°C.

'H NMR (CDCI3) 8 10,05 (br s, 1H), 7,83 (s, 1H), 7,44 (dd, 1H, J=8,l og 1,4Hz), 7,38-7,30 (m, 1H), 7,26-7,19 (m, 3H), 7,11 (d, 1H, J=8,lHz), 2,17-1,82 (m, 1 H NMR (CDCl 3 ) δ 10.05 (br s, 1H), 7.83 (s, 1H), 7.44 (dd, 1H, J=8.1 and 1.4Hz), 7.38-7 .30 (m, 1H), 7.26-7.19 (m, 3H), 7.11 (d, 1H, J=8.1Hz), 2.17-1.82 (m,

7H) og 1,66-1,53 (m, 3H). 7H) and 1.66-1.53 (m, 3H).

MS ((-)-APCI) m/z 328 [M-H]\ MS ((-)-APCI) m/z 328 [M-H]\

EKSEMPEL 23 EXAMPLE 23

5- f5- klor- 2- tienvnspirofcvkloheksan- 1. 3-[ 3Hlindoll- 2( lBn- tion 5- f5- klor- 2- tienvnspirorcvkloheksan- 1. 3- r3Hlindoll- 2flHVon 5- f5- chloro- 2- thienvnspirofcvchlorohexane- 1. 3-[ 3Hlindoll- 2( lBn- thione 5- f5- chloro- 2- thienvnspirofcvchlorohexane- 1. 3- r3Hlindoll- 2flHVon

Fremstilt i henhold til prosedyren i eksempel 5 med smeltepunkt 191-192°C. Prepared according to the procedure in example 5 with melting point 191-192°C.

'HNMRtCDCb) 8 1,6-2,1 (m, 10H), 6,85-6,95 (m, 2H), 6,98 (d, J=4,0Hz, 1H), 7,36 (HNMRtCDCb) 8 1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, J=4.0Hz, 1H), 7.36

(dd, J=7,5,1,6Hz, 1H), 7,53 (d, J=0,9Hz, 1H), 7,80 (br s, 1H).<13>C-NMR (THF-dg) 8 21,35, 25,33,33,12 (t), 48,32 (s), 110,40,121,66,121,96,125,44, (dd, J=7.5,1.6Hz, 1H), 7.53 (d, J=0.9Hz, 1H), 7.80 (br s, 1H).<13>C-NMR (THF- dg) 8 21,35, 25,33,33,12 (h), 48,32 (s), 110,40,121,66,121,96,125,44,

127,25 (d), 128,17,128,43,136,92,140,20,143,43, 183,72 (s). MS (EI) m/z 318(M+H)<+>. 127.25 (d), 128.17,128.43,136.92,140.20,143.43, 183.72 (s). MS (EI) m/z 318(M+H)<+>.

Analyse for (C17Hi6ClNOS) C, H, N. Analysis for (C17Hi6ClNOS) C, H, N.

Tittelforbindelsen ble fremstilt fra 100 mg 5-(5 -klor-2-tienyl)spiro [cykloheksan-1,3-[3H]indol]-2(lH)-on og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A, for å gi 0,041 g produkt som et gulaktig faststoff med smeltepunkt 231-232°C. The title compound was prepared from 100 mg of 5-(5-chloro-2-thienyl)spiro [cyclohexane-1,3-[3H]indol]-2(1H)-one and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene, in according to General Procedure A, to give 0.041 g of product as a yellowish solid, mp 231-232°C.

'H NMR (CDCI3) 8 9,75 (br s, 1H), 7,82 (d, 1H, J=l,2Hz), 7,43 (dd, 1H, J=8,l og 1,6Hz), 7,04-7,02 (m, 2H), 6,89 (d, 1H, J=3,8), 2,15-1,84 (m, 7H) og 1 H NMR (CDCl 3 ) δ 9.75 (br s, 1H), 7.82 (d, 1H, J=1.2Hz), 7.43 (dd, 1H, J=8.1 and 1.6Hz) , 7.04-7.02 (m, 2H), 6.89 (d, 1H, J=3.8), 2.15-1.84 (m, 7H) and

1,59-1,52 (m, 3H). 1.59-1.52 (m, 3H).

MS ((-)-APCI) m/z 332/334 [M-H]-. MS ((-)-APCI) m/z 332/334 [M-H]-.

EKSEMPEL 24 EXAMPLE 24

5-( l, 2- dihvdro- 2- tioksospirofcvkloheksan- L3-[ 3Hlindoll- 5- vl)- 3- furankarbonitril 5- 0 ,. 2'- dihvdro- 2,- oksospiro[ cykloheksan- l , 3 '-[ 3H] indol"|- 5 '- vn- 3- furankarbonitril Fremstilt i henhold til prosedyren i eksempel 5 med smeltepunkt 243-245°C. 5-(1,2-dihydro-2-thioxospirochlorohexane-L3-[3Hlindoll-5-vl)-3-furancarbonitrile 5-0,. 2'-dihydro-2,-oxospiro[cyclohexane-1,3'-[3H]indole"|-5'-vn-3-furancarbonitrile Prepared according to the procedure in example 5 with melting point 243-245°C.

'H NMR (DMSO-d<s) 5 10,48 (s, 1H), 8,62 (d, 1H, J=0,7Hz), 7,76 (d, 1H, J=l,5Hz), 1H NMR (DMSO-d<s) δ 10.48 (s, 1H), 8.62 (d, 1H, J=0.7Hz), 7.76 (d, 1H, J=1.5Hz),

7,58-7,55 (d, 1H), 7,33 (d, 1H, J=0,7Hz), 6,92-6,90 (d, 1H, J=8,lHz), 7.58-7.55 (d, 1H), 7.33 (d, 1H, J=0.7Hz), 6.92-6.90 (d, 1H, J=8.1Hz),

1,87-1,83 (m, 2H), 1,73-1,53 (m, 8H). 1.87-1.83 (m, 2H), 1.73-1.53 (m, 8H).

MS ((+)EI) m/z 292 (M+). MS ((+)EI) m/z 292 (M+).

Tittelforbindelsen ble fremstilt fra 100 mg S^^^dihydro^-oksospirotcykloheksan-l,3'-[3H]indol]-5'-yl)-3-furankarbonitril og 120 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, ifølge den generelle prosedyre A, for å gi 0,020 g produkt som et gult faststoff med smeltepunkt 264-268°C. The title compound was prepared from 100 mg of S^^^dihydro^-oxospirocyclohexane-1,3'-[3H]indol]-5'-yl)-3-furancarbonitrile and 120 mg of Lawesson's reagent in 10 ml of refluxing toluene, according to the general procedure A, to give 0.020 g of product as a yellow solid, mp 264-268°C.

<!>H NMR (CDC13) 8 9,66 (br s, 1H), 7,98 (s, 2H), 7,59 (dd, 1H, J=8,2 og 1,5Hz), 7,08 (d, <!>H NMR (CDCl 3 ) δ 9.66 (br s, 1H), 7.98 (s, 2H), 7.59 (dd, 1H, J=8.2 and 1.5Hz), 7.08 (d,

1H, J=8,2Hz), 6,78 (s, 1H), 2,16-1,85 (m, 7H) og 1,56-1,52 (m, 2H). MS ((-)-APCI) m/z 307 [M-H]". 1H, J=8.2Hz), 6.78 (s, 1H), 2.16-1.85 (m, 7H) and 1.56-1.52 (m, 2H). MS ((-)-APCI) m/z 307 [M-H]".

EKSEMPEL 25 EXAMPLE 25

5-( 3- klor- 4- fluorfenvnspirorcvkloheksan- 1. 3- 13Hlindoll- 2( lHVtion S'- f 3- klor- 4- fluorfenvnspirorcvkloheksan- l . 3 '- r3H1indoll- 2' f 1 ' HVon 5-( 3- chloro- 4- fluorophenvspirorcvchlorohexane- 1. 3- 13Hlindoll- 2( lHVtion S'- f 3- chloro- 4- fluorophenvspirorcvchlorohexane- 1. 3 '- r3H1indoll- 2' f 1 ' HVon

Fremstilt i henhold til prosedyren i eksempel 5, med smeltepunkt 188-189°C. Prepared according to the procedure in example 5, with melting point 188-189°C.

'H NMR (CDC13) 8 7,57-7,54 (m, 2H), 7,41-7,34 (m, 2H), 7,20 (t, 1H, J=8,7Hz), 9,96 1 H NMR (CDCl 3 ) δ 7.57-7.54 (m, 2H), 7.41-7.34 (m, 2H), 7.20 (t, 1H, J=8.7Hz), 9, 96

(d, 1H, J=8,lHz), 2,04-1,65 (m, 10H). (d, 1H, J=8.1Hz), 2.04-1.65 (m, 10H).

MS ((+)APCI) m/z 330 [M+Hf. MS ((+)APCI) m/z 330 [M+Hf.

Tittelforbindelsen ble fremstilt fra 100 mg 5'-(3-klor-4-fluorfenyl)-spiro[cykloheksan-1,3*-[3H]indol]-2'(l 'H)-on og 100 mg Lawesson's reagens i 10 ml toluen under tilbake-løp ifølge generell prosedyre A, for å gi 0,036 g produkt som et hvitt faststoff. The title compound was prepared from 100 mg of 5'-(3-chloro-4-fluorophenyl)-spiro[cyclohexane-1,3*-[3H]indol]-2'(1'H)-one and 100 mg of Lawesson's reagent in 10 ml of toluene under reflux according to general procedure A, to give 0.036 g of product as a white solid.

'H NMR (DMSO-de) 8 12,74 (br s, 1H), 7,92 (d, 1H, J=l,4Hz), 7,87 (dd, 1H, J=7,l og 2,3Hz), 7,70-7,65 (m, 1H), 7,61 (dd, 1H, J=7,l og 1,5Hz), 7,49 (t, 1H, J=8,9Hz), 7,14 (d, 1H, J=8,lHz), 1,99-1,82 (m, 7H) og 1,40-1,37 (m, 1H NMR (DMSO-de) δ 12.74 (br s, 1H), 7.92 (d, 1H, J=1.4Hz), 7.87 (dd, 1H, J=7.1 and 2, 3Hz), 7.70-7.65 (m, 1H), 7.61 (dd, 1H, J=7.1 and 1.5Hz), 7.49 (t, 1H, J=8.9Hz), 7.14 (d, 1H, J=8.1Hz), 1.99-1.82 (m, 7H) and 1.40-1.37 (m,

3H). 3H).

MS ((-)-APCI) m/z 344/346 [M-H]<*>. MS ((-)-APCI) m/z 344/346 [M-H]<*>.

EKSEMPEL 26 EXAMPLE 26

5- f3- klor- 5- fluorfenvnspirofcvkloheksan- 1. 3-[ 3Hlindoll- 2( lH)- tion S^- G- klor- S- fluorfenvnspirorcvkloheksan- lJ^ rSHIindoll^ YrHVori 5- f3- chloro- 5- fluorophenvnspirofcvchlorohexane- 1. 3-[ 3Hlindoll- 2( lH)- thione S^- G- chloro- S- fluorophenvnspirorcvchlorohexane- lJ^ rSHIindoll^ YrHVori

Fremstilt i henhold til prosedyren i eksempel 5 med smeltepunkt 178-180°C. Prepared according to the procedure in example 5 with melting point 178-180°C.

'H NMR (CDCI3) 5 8,50 (s, 1H), 7,57 (d, 1H, J=l,8Hz), 7,39 (dd, 1H, J=6,2,1,9Hz), 1 H NMR (CDCl 3 ) δ 8.50 (s, 1H), 7.57 (d, 1H, J=1.8Hz), 7.39 (dd, 1H, J=6.2,1.9Hz),

7,33-7,32 (m, 1H), 7,15 (dq, 1H, J=5,7,1,7, 0,7Hz), 7,06 (dq, 1H, J=4,2, 7.33-7.32 (m, 1H), 7.15 (dq, 1H, J=5.7,1.7, 0.7Hz), 7.06 (dq, 1H, J=4.2,

1,9, 0,4Hz), 7,00 (d, 1H, J=8,lHz), 2,05-1,64 (m, 10H). 1.9, 0.4Hz), 7.00 (d, 1H, J=8.1Hz), 2.05-1.64 (m, 10H).

MS ((-)ESI) [M-H]- @ m/z 328. MS ((-)ESI) [M-H]- @ m/z 328.

Tittelforbindelsen ble fremstilt fra 100 mg 5'-(3-klor-5-fluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on og 100 mg Lawesson's reagens i 10 ml toluen ved tilbake-løp, ifølge generell prosedyre A, for å gi 0,039 g produkt som et hvitaktig faststoff. The title compound was prepared from 100 mg of 5'-(3-chloro-5-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one and 100 mg of Lawesson's reagent in 10 ml toluene at reflux, according to general procedure A, to give 0.039 g of product as an off-white solid.

<*>H NMR (DMSO-d6) 8 12,76 (br s, 1H), 7,97 (d, 1H, J=l,lHz), 7,67 (dd, 1H, J=8,l og 1,4Hz), 7,60-7,54 (m, 2H), 7,40 (dt, 1H, J=8,65 og 2,0Hz), 7,14 (d, 1H, <*>H NMR (DMSO-d6) δ 12.76 (br s, 1H), 7.97 (d, 1H, J=1,1Hz), 7.67 (dd, 1H, J=8,1 and 1.4Hz), 7.60-7.54 (m, 2H), 7.40 (dt, 1H, J=8.65 and 2.0Hz), 7.14 (d, 1H,

J=8,lHz), 1,99-1,83 (m, 7H) og 1,41-1,38 (m, 3H). J=8.1Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m, 3H).

MS ((-)-APCI) m/z 344/346 [M-H]". MS ((-)-APCI) m/z 344/346 [M-H]".

EKSEMPEL 27 EXAMPLE 27

5-( 3, 5- difluorfenvDspiro f cvkloheksan- 1, 3- f 3H1 indoll- 2( l H)- tion S^ rS. S- difluorfenvnspirorcvkloheksan- lJ^ rSHlindon^ YrHVon 5-( 3, 5- difluorophenvDspiro f cvclohexane- 1, 3- f 3H1 indoll- 2( l H)- tion S^ rS. S- difluorophenvspirorcvclohexane- lJ^ rSHlindone^ YrHVon

Fremstilt ifølge prosedyren i eksempel 5 med smeltepunkt 180-183°C. Prepared according to the procedure in example 5 with a melting point of 180-183°C.

<!>H NMR (CDCI3) 8 8,35 (s, 1H), 7,59 (d, 1H, J=2,0Hz), 7,40 (dd, 1H, J=6,2, 2,0Hz), <!>H NMR (CDCl 3 ) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=6.2, 2.0Hz ),

7,10-7,03 (m, 2H), 6,99 (d, 1H, J=8,lHz), 7,76 (tt, 1H, J=4,3, 2,3Hz), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J=8.1Hz), 7.76 (tt, 1H, J=4.3, 2.3Hz),

2,05-1,62 (m, 10H). 2.05-1.62 (m, 10H).

MS ((+)APCI) m/z 314 [M+H]<+>. MS ((+)APCI) m/z 314 [M+H]<+>.

Tittelforbindelsen ble fremstilt fra 100 mg 5'-(3,5'-difluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on og 100 mg Lawesson's reagens i 10 ml toluen ved tilbakeløp, ifølge generell prosedyre A, for å gi 0,029 g av tittelforbindelsen som et hvitaktig faststoff. The title compound was prepared from 100 mg of 5'-(3,5'-difluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one and 100 mg of Lawesson's reagent in 10 ml of toluene at reflux, according to general procedure A, to give 0.029 g of the title compound as an off-white solid.

<*>H NMR (DMSO-d6) 8 12,76 (br s, 1H), 7,84 (s, 1H), 7,64-7,56 (m, 1H), 7,46 (d, 1H, J=8,lHz), 7,40-7,32 (m, 1H), 7,22-7,15 (m, 2H), 1,99-1,80 (m, 7H) og <*>H NMR (DMSO-d6) δ 12.76 (br s, 1H), 7.84 (s, 1H), 7.64-7.56 (m, 1H), 7.46 (d, 1H , J=8.1Hz), 7.40-7.32 (m, 1H), 7.22-7.15 (m, 2H), 1.99-1.80 (m, 7H) and

1,38-1,35 (m, 3H). 1.38-1.35 (m, 3H).

MS ((-)-APCI) m/z 328 [M-H]'. MS ((-)-APCI) m/z 328 [M-H]'.

EKSEMPEL 28 EXAMPLE 28

5- f 1, 2- dih ydro- 2- tioksospiro [ cvkloheksan- 1, 3- [ 3H1 indoll- 5- vD- 4- propyl- 2-tiofenkarbonitril 5- f 1, 2- dihydro- 2- thioxospiro [ cvclohexane- 1, 3- [ 3H1 indoll- 5- vD- 4- propyl- 2-thiophenecarbonitrile

5- fl. 2- dihvdro- 2- oksospiro[ cvkloheksan- 1. 3-[ 3H1indol]- 5- vl')- 4- propyl- 2-tiofenkarbonitril. 5- fl. 2-dihydro-2-oxospiro[cyclohexane-1.3-[3H1indole]-5-vl')-4-propyl-2-thiophenecarbonitrile.

Tittelforbindelsen ble fremstilt på en måte tilsvarende eksempel 5 fra 5-brom-4-n-propyltiofen-2-karbonitril (1,17 g, 5 mmol), (l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-borsyre (1,24 g, 5 mmol), tetrakis(trifenylfosfin)palladium, kaliurnkar-bonat (2,75 g, 21 mmol), 10 ml vann og 50 ml dimetoksyetan, oppvarmet til tilbakeløp over natten, for å gi produktet (0,7 g, 40%) med smeltepunkt 168-171°C. The title compound was prepared in a manner similar to Example 5 from 5-bromo-4-n-propylthiophene-2-carbonitrile (1.17 g, 5 mmol), (1,2-dihydro-2-oxospiro[cyclohexane-1,3- [3H]indole]-5-boronic acid (1.24 g, 5 mmol), tetrakis(triphenylphosphine)palladium, potassium bicarbonate (2.75 g, 21 mmol), 10 mL of water, and 50 mL of dimethoxyethane, heated to reflux over overnight to give the product (0.7 g, 40%) mp 168-171°C.

<*>H NMR (DMSO-de) 8 10,56 (s, 1H), 7,93 (s, 1H), 7,52-7,51 (d, 1H, J=l,5Hz), 7,33-7,29 (dd, 1H, J=l,6Hz), 7,00-6,96 (d, 1H, J=8,0Hz), 2,62-2,57 (t, 2H), <*>H NMR (DMSO-de) δ 10.56 (s, 1H), 7.93 (s, 1H), 7.52-7.51 (d, 1H, J=1.5Hz), 7, 33-7.29 (dd, 1H, J=1.6Hz), 7.00-6.96 (d, 1H, J=8.0Hz), 2.62-2.57 (t, 2H),

1,86 (m, 2H), 1,70-1,56 (m, 11H), 0,88-0,84 (t, H). 1.86 (m, 2H), 1.70-1.56 (m, 11H), 0.88-0.84 (t, H).

MS m/z (APCI (+)) 351 [M+H]<+.>MS m/z (APCI (+)) 351 [M+H]<+.>

IR (KBr) 1620,1700,2200 cm'<1>. IR (KBr) 1620, 1700, 2200 cm'<1>.

Analyse for C2iH22N2OS»l/2 H20: Analysis for C2iH22N2OS»l/2 H20:

Beregnet: C, 70,2; H, 6,39; N, 7,79. Calculated: C, 70.2; H, 6.39; N, 7.79.

Observert: C, 70,67; H, 6,34; N, 7,62. Observed: C, 70.67; H, 6.34; N, 7.62.

Tittelforbindelsen ble fremstilt fra 90 mg 5-(l,3-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-4-propyl-2-tiofenkarbonitril og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A for å gi 0,037 g tittelforbindelse som et orangefarvet faststoff. •H NMR (DMSO-d6) 8 12,83 (br s, 1H), 7,96 (s, 1H), 7,77 (s, 1H), 7,44 (d, 1H, J=7,7Hz), 7,19 (d, 1H, J=8,0Hz), 2,60 (t, 2H, J=8,0Hz), 1,98-1,79 (m, The title compound was prepared from 90 mg of 5-(1,3-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile and 90 mg of Lawesson's reagent in 10 ml of toluene under reflux according to General Procedure A to give 0.037 g of the title compound as an orange solid. •H NMR (DMSO-d6) δ 12.83 (br s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, J=7.7Hz ), 7.19 (d, 1H, J=8.0Hz), 2.60 (t, 2H, J=8.0Hz), 1.98-1.79 (m,

7H), 1,64-1,56 (m, 2H), 1,39-1,35 (m, 2H) og 0,87 (t, 3H, J=7,3Hz). MS ((-)-APCI) m/z 365 [M-H]'. 7H), 1.64-1.56 (m, 2H), 1.39-1.35 (m, 2H) and 0.87 (t, 3H, J=7.3Hz). MS ((-)-APCI) m/z 365 [M-H]'.

EKSEMPEL 29 EXAMPLE 29

5-( 3- fluor- 4- nitrofenvl) spiro[ cykloheksan- l, 3-[ 3Hlindol- 2flH) tioii 5- n- fluor- 4- nitrofenvl) spiro[ cykloheksan- 1. 3- r3Hlindol]- 2( lH)- one Forbindelsen ble fremstilt fra (2'-okso-2,3-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)borsyre (3,2 g, 12,5 mmol) og 4-brom-4-fluornitrobenzen (3 g, 13,6 mmol) som beskrevet for eksempel 5 for å gi tittelforbindelsen (0,7 g, 16%) som et gult faststoff med smeltepunkt 213-215°C. 5-( 3- fluoro- 4- nitrophenyl) spiro[ cyclohexane- 1, 3-[ 3Hlindol- 2flH) thioii 5- n- fluoro- 4- nitrophenyl) spiro[ cyclohexane- 1. 3- r3Hlindole]- 2( 1H) - one The compound was prepared from (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boric acid (3.2 g, 12.5 mmol) and 4 -bromo-4-fluoronitrobenzene (3 g, 13.6 mmol) as described for Example 5 to give the title compound (0.7 g, 16%) as a yellow solid, mp 213-215°C.

<!>H NMR (DMSO-d6) 8 1,5-1,8 (m, 8H), 1,8-2,0 (m, 2H), 6,96 (d, 1H, J=8,13Hz), 7,68 <!>H NMR (DMSO-d6) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H, J=8.13Hz ), 7.68

(dd, 1H, J=8,13,1,76Hz), 7,74 (dd, 1H, J=8,68,1,76Hz), 7,86 (d, 1H, J=l,98Hz), 7,92 (dd, 1H, J=13,4,1,76Hz), 8,18 (t, 1H, J=8,46Hz) og (dd, 1H, J=8.13,1.76Hz), 7.74 (dd, 1H, J=8.68,1.76Hz), 7.86 (d, 1H, J=1.98Hz), 7.92 (dd, 1H, J=13.4,1.76Hz), 8.18 (t, 1H, J=8.46Hz) and

10,52 (s, 1H). 10.52 (p, 1H).

MS (EI) m/z = 340 (M<*>). MS (EI) m/z = 340 (M<*>).

Tittelforbindelsen ble fremstilt fra 90 mg 5-(3-fluor-4-nitrofenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-on og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A for å gi 0,021 av produktet som et gult faststoff. The title compound was prepared from 90 mg of 5-(3-fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one and 90 mg of Lawesson's reagent in 10 ml of refluxing toluene, in according to General Procedure A to give 0.021 of the product as a yellow solid.

<!>H NMR (DMSO-d6) 8 12,82 (br s, 1H), 8,21 (t, 1H, J=8,4Hz), 8,07 (d, 1H, J=lHz), <!>H NMR (DMSO-d6) δ 12.82 (br s, 1H), 8.21 (t, 1H, J=8.4Hz), 8.07 (d, 1H, J=1Hz),

7,98 (dd, 1H, J=13,lHz), 7,79 (dt, 1H, J=8,l og 2,6Hz), 7,19 (1H, 7.98 (dd, 1H, J=13.1Hz), 7.79 (dt, 1H, J=8.1 and 2.6Hz), 7.19 (1H,

J=8,2Hz), 1,99-1,83 (m, 7H) og 1,42-1,39 (m, 3H). J=8.2Hz), 1.99-1.83 (m, 7H) and 1.42-1.39 (m, 3H).

MS ((-)-APCI) m/z 355 [M-H]-. MS ((-)-APCI) m/z 355 [M-H]-.

EKSEMPEL 30 EXAMPLE 30

4- fl, 2- dihvdro- 2- tioksospiro[ cykloheksan- l, 3- f3Hlindoll- 5- vn- 2- furankarbonitril 4-( l . 2- dihvdro- 2- oksospiro|" cvkloheksan- 1. 3-[ 3Hlindol]- 5- vl)- 2- furankarbonitril En oppløsning av 3-brom-5-cyano-furan (0,75 g, 4,4 mmol) og tetrakis(trifenylfosfin)-palladium(O) (0,4 g) i 20 cm3 etylenglykol dimetyleter ble omrørt under N2i 20 minutter. Til denne blanding ble det så satt (spiro[cykloheksan-l,3'-[3H]indol]-2'-(rH)-on-5-yl)borsyre (1,6 g, 6,5 mmol) og natriumacetat (1,4 g, 13,1 mmol) i 5 cm3 vann. Oppløs-ningen ble bragt til tilbakeløp i 18 timer og så avkjølt til romtemperatur, heilt i 2N Na-OH og ekstrahert tre ganger med EtOAc. De kombinerte ekstrakter ble vasket med vann, saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med EtOAc:heksan for å gi produktet (0,45 g, 36%) som et hvitaktig faststoff med smeltepunkt 240-242°C. 4- fl, 2- dihydro- 2- thioxospiro[ cyclohexane- 1, 3- f3Hlindol- 5- vn- 2- furancarbonitrile 4-( l . 2- dihydro- 2- oxospiro|" cyclohexane- 1. 3-[ 3Hlindol] - 5- vl)- 2- furancarbonitrile A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol) and tetrakis(triphenylphosphine)-palladium(O) (0.4 g) in 20 cm3 of ethylene glycol dimethyl ether was stirred under N2 for 20 minutes.To this mixture was then added (spiro[cyclohexane-1,3'-[3H]indol]-2'-(rH)-on-5-yl)boric acid (1, 6 g, 6.5 mmol) and sodium acetate (1.4 g, 13.1 mmol) in 5 cm3 of water. The solution was refluxed for 18 hours and then cooled to room temperature, poured into 2N Na-OH and extracted three times with EtOAc. The combined extracts were washed with water, brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 with EtOAc:hexane to give the product (0.45 g, 36%) as an off-white solid, mp 240 -242°C.

'H NMR (DMSO-de) 8 10,4 (s, 1H), 8,5 (s, 1H), 8,2 (s, 1H), 7,7 (s, 1H), 7,5 (dd, 1H, 1 H NMR (DMSO-de) δ 10.4 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd , 1H,

J=l,5, 6,5Hz), 6,9 (d, 1H, J=8,0Hz), 2,0-1,6 (m, 10H). J=1.5, 6.5Hz), 6.9 (d, 1H, J=8.0Hz), 2.0-1.6 (m, 10H).

MS (EI) M<+>@ m/z 292. MS (EI) M<+>@ m/z 292.

Tittelforbindelsen ble fremstilt fra 67 mg 4-(l,2-dihydro-2-oksospiro [cykloheksan-1,3-[3H]indol]-5-yl)-2-furankarbonitril og 67 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A, for å gi 0,018 g av tittelforbindelsen som et gult faststoff. The title compound was prepared from 67 mg of 4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile and 67 mg of Lawesson's reagent in 10 ml of refluxing toluene according to General Procedure A, to give 0.018 g of the title compound as a yellow solid.

<!>H NMR (DMSO-de) 8 12,74 (s, 1H), 8,68 (s, 1H), 8,26 (s, 1H), 7,96 (s, 1H), 7,62 (dd, <!>H NMR (DMSO-de) δ 12.74 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.62 (dd,

1H, J=8,0 og 1,0Hz), 7,10 (s, 1H, J=8,lHz), 1,94-1,78 (m, 7H) og 1,35-1,32 (m, 3H). 1H, J=8.0 and 1.0Hz), 7.10 (s, 1H, J=8.1Hz), 1.94-1.78 (m, 7H) and 1.35-1.32 (m , 3H).

MS ((-)-APCI) m/z 307 [M-H]-. MS ((-)-APCI) m/z 307 [M-H]-.

EKSEMPEL 31 EXAMPLE 31

5"- f3- klorfenvnspirorcvklobutan- L3M-[ 3Hlindon- 2M( lwH)- tion 5- bromspirorcvklobutan- 1, 3-[ 3H" lindol]- 2( lH)- on 5"- f3- chlorophenvnspirorcclobutane- L3M-[ 3Hlindone- 2M( lH)- thione 5- bromospirorcclobutane- 1, 3-[ 3H" lindol]- 2( lH)- one

Til en omrørt oppløsning av spiro[cyklobutan-l,3'-[3H]indol]-2'(l'H)-on (J. Med. Chem. 1987, 824-9) (1,0 g, 6 mmol) i 10 ml iseddik ble det dråpevis og ved romtemperatur satt en oppløsning av brom (0,30 ml, 6 mmol) i 6 ml iseddik. Efter omrøring i 10 minutter ble vannfri natriumacetat (0,47 g, 6 mmol) tilsatt og oppløsningen konsentrert under vakuum. Resten ble oppløst i 50 ml etyleter og vasket sekvensielt med 50 ml vann, 50 ml mettet vandig bikarbonatoppløsning, 50 ml vann og 30 ml saltoppløsning. De organiske sjikt ble tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Krystallisering fra etyleter ga produktet som et hvitt fluffet faststoff (1,1 g, 73%) med smeltepunkt 235-7°C. To a stirred solution of spiro[cyclobutane-1,3'-[3H]indole]-2'(1'H)-one (J. Med. Chem. 1987, 824-9) (1.0 g, 6 mmol ) in 10 ml of glacial acetic acid, a solution of bromine (0.30 ml, 6 mmol) in 6 ml of glacial acetic acid was added dropwise at room temperature. After stirring for 10 minutes, anhydrous sodium acetate (0.47 g, 6 mmol) was added and the solution concentrated under vacuum. The residue was dissolved in 50 ml of ethyl ether and washed sequentially with 50 ml of water, 50 ml of saturated aqueous bicarbonate solution, 50 ml of water and 30 ml of saline. The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. Crystallization from ethyl ether gave the product as a white fluffy solid (1.1 g, 73%) mp 235-7°C.

'H NMR (DMSO-d6, 300 MHz) 8 2,15-2,41 (m, 6H), 6,74 (d, 1H, J=8,2Hz) 7,33 (d, 1H, 1H NMR (DMSO-d6, 300 MHz) δ 2.15-2.41 (m, 6H), 6.74 (d, 1H, J=8.2Hz) 7.33 (d, 1H,

J=2, 82Hz), 7,75 (d, 1H, J=2Hz), 10,36 (bs, 1H). J=2, 82Hz), 7.75 (d, 1H, J=2Hz), 10.36 (bs, 1H).

MS (EI) m/z 251 [M<*>]. MS (EI) m/z 251 [M<*>].

Analyse for CnHioBrNO: Analysis for CnHioBrNO:

Beregnet: C, 52,41; H, 4,00; N, 5,56. Calculated: C, 52.41; H, 4.00; N, 5.56.

Funnet: C, 51,98; H, 4,24; N, 5,42. Found: C, 51.98; H, 4.24; N, 5.42.

Til en oppløsning av 5-bromspiro[cyklobutan-l,3-[3H]indol]-2(lH)-on (0,6 g, 2 mmol) i 50 ml etylenglykol dimetyleter ble det under en nitrogenatmosfære satt tetra-kis(trifenylfosfin)palladium(0) (140 mg, 0,1 mmol). Til oppløsningen ble det sekvensielt satt 3-klorfenylborsyre (0,48 g, 3 mmol) og kaliumkarbonat (0,76 g, 5 mmol) i 5 ml vann. Blandingen ble oppvarmet til 80°C i 3 timer og tillatt avkjøling. Reaksjonsblandingen ble heilt i 100 ml vann og ekstrahert med 3x100 ml etylacetat. De organiske sjikt ble slått sammen, vasket med 50 ml saltoppløsning og tørket over magnesiumsulfat. Oppløsningen ble filtrert, konsentrert under vakuum og resten renset ved HPLC (Zorbax PRO, C18,10u, 15A, 50mm x 250 mm; 35% vann/65% AcCN; 254 NM; AMB. temp.) for å gi 5-(3-klorfenyl)spiro[cyklobutan-l,3-[3H]indol]-2(lH)-on (200 mg, 35%) som et hvitt pulver med smeltepunkt 199,5-201°C. Under a nitrogen atmosphere, tetrakis triphenylphosphine)palladium(0) (140 mg, 0.1 mmol). To the solution was sequentially added 3-chlorophenylboronic acid (0.48 g, 3 mmol) and potassium carbonate (0.76 g, 5 mmol) in 5 ml of water. The mixture was heated to 80°C for 3 hours and allowed to cool. The reaction mixture was poured into 100 ml of water and extracted with 3x100 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of saline and dried over magnesium sulfate. The solution was filtered, concentrated under vacuum and the residue purified by HPLC (Zorbax PRO, C18,10u, 15A, 50mm x 250mm; 35% water/65% AcCN; 254 NM; AMB. temp.) to give 5-(3 -chlorophenyl)spiro[cyclobutan-1,3-[3H]indol]-2(1H)-one (200 mg, 35%) as a white powder m.p. 199.5-201°C.

'H NMR (DMSO-de, 300 MHz) 8 2,21-2,28 (m, 2H), 2,40-2,45 (m, 4H), 6,87 (d, 1H, 1 H NMR (DMSO-de, 300 MHz) δ 2.21-2.28 (m, 2H), 2.40-2.45 (m, 4H), 6.87 (d, 1H,

J=8,lHz), 7,37 ('d', 1H), 7,44-7,52 (m, 2H), 7,65 (bd, 1H, J=7,8Hz), 7,76 J=8.1Hz), 7.37 ('d', 1H), 7.44-7.52 (m, 2H), 7.65 (bd, 1H, J=7.8Hz), 7.76

(bs, 1H), 7,92 (bs, 1H), 10,35 (s, 1H). (bs, 1H), 7.92 (bs, 1H), 10.35 (s, 1H).

MS (EI) m/z 283 [M<4>]. MS (EI) m/z 283 [M<4>].

Analyse for C17H14CINO: Analysis for C17H14CINO:

Beregnet: C, 71,96; H, 4,97; N, 4,94. Calculated: C, 71.96; H, 4.97; N, 4.94.

Funnet: C, 70,75; H, 5,07; N, 4,68. Found: C, 70.75; H, 5.07; N, 4.68.

Tittelforbindelsen ble fremstilt fra 55 mg 5-(3-klorfenyl)spiro[cyklobutan-l,3-[3H]indol]-2(lH)-on og 55 mg Lawesson's reagens i 10 ml toluen, i henhold til den generelle prosedyre A for å gi 0,016 g av tittelforbindelsen som et orangefarvet faststoff. The title compound was prepared from 55 mg of 5-(3-chlorophenyl)spiro[cyclobutan-1,3-[3H]indol]-2(1H)-one and 55 mg of Lawesson's reagent in 10 ml of toluene, according to the general procedure A to give 0.016 g of the title compound as an orange solid.

<l>H NMR (DMSO-d6) 8 12,58 (br s, 1H), 8,07 (d, 1H, J=l,5Hz), 7,82 (t, 1H, J=l,7Hz), <1>H NMR (DMSO-d6) δ 12.58 (br s, 1H), 8.07 (d, 1H, J=1.5Hz), 7.82 (t, 1H, J=1.7Hz) ,

7,70 (d, 1H, J=7,74Hz), 7,60 (dd, 1H, J=8,12 og 1,71 Hz), 7,49 (t, 1H, 7,9Hz), 7,41 (d, 1H, J=8,32Hz), 7,05 (d, 1H, J=8,14Hz) og 2,57-2,27 (m, 7.70 (d, 1H, J=7.74Hz), 7.60 (dd, 1H, J=8.12 and 1.71 Hz), 7.49 (t, 1H, 7.9Hz), 7, 41 (d, 1H, J=8.32Hz), 7.05 (d, 1H, J=8.14Hz) and 2.57-2.27 (m,

6H). 6H).

MS ((-)-APCI) m/z 298/300 [M-H]-. MS ((-)-APCI) m/z 298/300 [M-H]-.

EKSEMPEL 32 EXAMPLE 32

5w- f2- klorfenvnspiro[ cvkloheksan- 1. 3"- r3Hlindoll- 2,, ri" HVtion Tittelforbindelsen ble fremstilt fra 90 mg 5 "-(2-klorfenyl)spiro [cykloheksan-1,3 "-[3H]indol]-2"(l"H)-tion og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, 5w- f2- chlorophenvnspiro[ cvcyclohexane- 1. 3"- r3Hlindoll- 2,, ri" HVtion The title compound was prepared from 90 mg of 5 "-(2-chlorophenyl)spiro[cyclohexane-1,3 "-[3H]indole]- 2"(l"H)-thione and 90 mg of Lawesson's reagent in 10 ml of refluxing toluene,

i henhold til den generelle prosedyre A, for å gi 0,042 g av produktet som et hvitaktig faststoff. according to General Procedure A, to give 0.042 g of the product as an off-white solid.

'H NMR (DMSO-d6) 5 12,75 (br s, 1H), 7,80 (d, 1H, J=l,lHz), 7,58-7,55 (m, 1H), 1 H NMR (DMSO-d 6 ) δ 12.75 (br s, 1H), 7.80 (d, 1H, J=1,1Hz), 7.58-7.55 (m, 1H),

7,48-7,36 (m, 4H), 7,16 (d, 1H, J=8,0Hz). 7.48-7.36 (m, 4H), 7.16 (d, 1H, J=8.0Hz).

MS ((-)-APCI) m/z 326/328 [M-H]\ MS ((-)-APCI) m/z 326/328 [M-H]\

EKSEMPEL 33 EXAMPLE 33

5w-( 4- klorfenvUspiro[ cvkloheksan- L3w-[ 3Hlindol- 2M( l" HVtion Tittelforbindelsen ble fremstilt fra 90 mg 5-(4-klorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-on og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A, for å gi 0,035 g av produktet som et hvitaktig faststoff. 5w-(4-ChlorophenvUspiro[cyclohexane-L3w-[3Hlindole-2M(l"HVtion) The title compound was prepared from 90 mg of 5-(4-chlorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(lH) -on and 90 mg of Lawesson's reagent in 10 ml of refluxing toluene, according to general procedure A, to give 0.035 g of the product as an off-white solid.

<X>H NMR (DMSO-d6) 5 12,74 (br s, 1H), 7,91 (d, 1H, J=l,3Hz), 7,69 (d, 2H, J=5,5Hz), <X>H NMR (DMSO-d6) δ 12.74 (br s, 1H), 7.91 (d, 1H, J=1.3Hz), 7.69 (d, 2H, J=5.5Hz) ,

7,60 (dd, 1H, J=8,l og 1,4Hz), 7,50 (d, 2H, J=8,5Hz), 7,15 (d, 1H, 7.60 (dd, 1H, J=8.1 and 1.4Hz), 7.50 (d, 2H, J=8.5Hz), 7.15 (d, 1H,

J=8,lHz), 1,99-1,83 (m, 7H) og 1,50-1,36 (m, 3H). J=8.1Hz), 1.99-1.83 (m, 7H) and 1.50-1.36 (m, 3H).

MS ((-)-APCI) m/z 326/328 [M-H]". MS ((-)-APCI) m/z 326/328 [M-H]".

EKSEMPEL 34 EXAMPLE 34

S- d^ l^- dihvdro- l^- tioksospirofcvkloheksan- lJ^ rSHl- indol- S^- vlM- metvl- Z-tiofenkarbonitril S- d^ l^- dihydro- l^- thioxospirofcvchlorohexane- lJ^ rSHl- indole- S^- vlM- metvl- Z-thiophenecarbonitrile

5- brom- 4- metvl- 2- tiofenkarboksaldehvd 5- bromo- 4- methyl- 2- thiophenecarboxaldehvd

Til en oppløsning av dietyleamin (28 g, 0,383 mol) i 400 ml vannfri THF ble det ved -40°C og under nitrogen satt en oppløsning av n-BuLi (2,5M, 153 ml, 0,383 mol) i heksan. Efter tilsetningen ble oppløsningen omrørt ved -40°C i nitrogen i 30 minutter, av-kjølt til -78°C og behandlet dråpevis med en oppløsning av 2-brom-3-metyltiofen (45 g, 0,254 mol) i 450 ml vannfri THF. Reaksjonsoppløsningen ble omrørt ved -78°C i 30 minutter og behandlet med 100 ml vannfri DMF. Blandingen ble tillatt oppvarming til omgivelsestemperatur og quenchet med 11 IN vandig saltsyreoppløsning. Oppløsning-en ble ekstrahert med 3x450 ml etylacetat og ekstraktene vasket med vann, saltoppløs-ning og tørket over MgS04. Efter fjerning av oppløsningsmidlet under vakuum ble tittelforbindelsen oppnådd som et hvitt faststoff (46 g, 88,3%). En prøve av dette produkt ble krystallisert fra heksan og hadde smeltepunkt 63-65°C. To a solution of diethylamine (28 g, 0.383 mol) in 400 ml of anhydrous THF was added at -40°C and under nitrogen a solution of n-BuLi (2.5M, 153 ml, 0.383 mol) in hexane. After the addition, the solution was stirred at -40°C under nitrogen for 30 minutes, cooled to -78°C and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in 450 ml anhydrous THF . The reaction solution was stirred at -78°C for 30 minutes and treated with 100 ml of anhydrous DMF. The mixture was allowed to warm to ambient temperature and quenched with 11 IN aqueous hydrochloric acid solution. The solution was extracted with 3x450 ml ethyl acetate and the extracts washed with water, brine and dried over MgSO 4 . After removal of the solvent under vacuum, the title compound was obtained as a white solid (46 g, 88.3%). A sample of this product was crystallized from hexane and had a melting point of 63-65°C.

IR(KBr) 1654 cm1. IR(KBr) 1654 cm 1 .

'H NMR (CDCI3) 8 9,75 (s, 1H), 7,45 (s, 1H), 2,26 (s, 3H). 1 H NMR (CDCl 3 ) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H).

MS (EI) m/z 204/206^). MS (EI) m/z 204/206^).

Analyse for C6H5BrOS: Analysis for C6H5BrOS:

Beregnet: C, 35,14; H, 2,46. Calculated: C, 35.14; H, 2.46.

Funnet: C, 35,00; H, 2,44. Found: C, 35.00; H, 2.44.

5- brom- 4- metvl- 2- tiofenkarbonitril 5-bromo-4-methyl-2-thiophenecarbonitrile

Fremstilt fra 5-brom-4-metyl-2-tiofen karboksaldehyd ved bruk av prosedyren i eksempel 5, som hvitt faststoff med smeltepunkt 40-42°C. Prepared from 5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure of Example 5, as a white solid, mp 40-42°C.

IR(KBr) 220 cm-<1>. IR(KBr) 220 cm-<1>.

'H NMR (CDCI3) 8 7,29 (s, 1H), 2,21 (s, 3H). 1 H NMR (CDCl 3 ) δ 7.29 (s, 1H), 2.21 (s, 3H).

MS (EI) m/z 201/203 (M<+>, 98%/100%). MS (EI) m/z 201/203 (M<+>, 98%/100%).

Analyse for C6H4BrNS: Analysis for C6H4BrNS:

Beregnet: C, 35,66; H, 1,99; N, 6,93. Calculated: C, 35.66; H, 1.99; N, 6.93.

Funnet: C, 36,00; H, 2,14; N, 6,76. Found: C, 36.00; H, 2.14; N, 6.76.

Fremstilt i henhold til prosedyren i eksempel 5 ved bruk av (2'-okso-[2,3-dihydro-3,3-dimetyl-l,3'-[3H]indol]-5'-yl)borsyre (357 mg, 1,7 mmol) og 5-brom-4-metyltiofen-2-karbonitril (295 mg, 1,5 mmol) for å gi 5-(3,3-dimetyl-2-okso-2,3-dihydro-lH-indol-5-yl)-4-metyltiofen-2-karbonitril (227 mg, 0,8 mmol, 55%) som et hvitt faststoff med smeltepunkt 192,3-193°C. Prepared according to the procedure of Example 5 using (2'-oxo-[2,3-dihydro-3,3-dimethyl-1,3'-[3H]indol]-5'-yl)boric acid (357 mg , 1.7 mmol) and 5-bromo-4-methylthiophene-2-carbonitrile (295 mg, 1.5 mmol) to give 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H -indol-5-yl)-4-methylthiophene-2-carbonitrile (227 mg, 0.8 mmol, 55%) as a white solid, mp 192.3-193°C.

'H NMR (DMSO-de) 8 1,29 (s, 6H), 2,29 (s, 3H), 6,97 (d, J=8,0Hz, 1H), 7,34 (dd, 1 H NMR (DMSO-de) δ 1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d, J=8.0Hz, 1H), 7.34 (dd,

J=8,0,1,8Hz, 1H), 7,49 (d, J=l,7Hz, 1H), 7,84 (s, 1H), 10,57 (s, 1H). MS (EI) m/z 282 (M)<+>. J=8.0,1.8Hz, 1H), 7.49 (d, J=1.7Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H). MS (EI) m/z 282 (M)<+>.

Analyse for Ci6Hi4N2OS. Analysis for Ci6Hi4N2OS.

Tittelforbindelsen ble fremstilt fra 5-(3,3-dimetyl-2-okso-2,3-dihydro-lH-indol-5-yl)-4-metyltiofen-2-karbonitril (0,77 g, 2,39 mmol) og fosforpentasulfid (0,42 g, 0,96 mmol) i 20 ml toluen under tilbakeløp. Efter 3 timer ble reaksjonsblandingen avkjølt og fordelt mellom vann og EtOAc, hvorefter det organiske sjikt ble separert, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med gradientelue ring EtOAcrheksan for å gi produktet (0,25 g, 0,73 mmol, 30%) som et orangefarvet faststoff. The title compound was prepared from 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile (0.77 g, 2.39 mmol) and phosphorus pentasulfide (0.42 g, 0.96 mmol) in 20 mL toluene under reflux. After 3 hours, the reaction mixture was cooled and partitioned between water and EtOAc, after which the organic layer was separated, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 eluting with a gradient of EtOAc-hexane to give the product (0.25 g, 0.73 mmol, 30%) as an orange solid.

'H NMR (DMSO-dfi) 5 12,82 (br s, 1H), 7,88 (s, 1H), 7,82 (d, 1H, 2Hz), 7,49 (dd, 1H, 1 H NMR (DMSO-dfi) δ 12.82 (br s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, 2Hz), 7.49 (dd, 1H,

J=8,l, 1,6Hz), 7,18 (d, 1H, J=8,lHz), 1,99-1,80 (m, 7H) og 1,40-1,36 (m, J=8.1, 1.6Hz), 7.18 (d, 1H, J=8.1Hz), 1.99-1.80 (m, 7H) and 1.40-1.36 (m,

3H). 3H).

MS ((-)-APCI) m/z 321 [M-H]<*>. MS ((-)-APCI) m/z 321 [M-H]<*>.

EKSEMPEL 35 EXAMPLE 35

5- n". 2"- dihvdro- 2"- tioksosDirolcvkloheksaD- 1. 3"-[ 3Hlindoll- 5"- vn- 2-tiofenkarbonitril 5- n". 2"- dihydro- 2"- thioxosDirolcvclohexaD- 1. 3"-[ 3Hlindoll- 5"- vn- 2-thiophenecarbonitrile

5- brom- 2- tiofenkarbonitril 5-bromo-2-thiophenecarbonitrile

En blanding av 5-brom-2-tiofenkarboksaldehyd (96,0 g, 500 mmol), hydroksylamin A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine

hydroklorid (111,9 g, 500 mmol), 500 ml pyridin og 500 ml etanol ble oppvarmet under nitrogen under tilbakeløp i 2 timer. Reaksjonsblandingen ble avkjølt til omgivelsestemperatur og konsentrert under vakuum for å gi en olje. Råproduktet ble triturert to ganger med isvann og det oppnådde faststoff samlet på et filter. En blanding av en del av faststoffet ovenfor (44,31 g, 215 mmol), kobber(I])acetat monohydrat (4,2 g, 21 mmol) i 1,41 acetonitril ble oppvarmet til tilbakeløp i 3 timer. Oppløsningsmidlet ble fjernet hydrochloride (111.9 g, 500 mmol), 500 mL pyridine and 500 mL ethanol were heated under nitrogen under reflux for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under vacuum to give an oil. The crude product was triturated twice with ice water and the resulting solid collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper(I) acetate monohydrate (4.2 g, 21 mmol) in 1.4 L of acetonitrile was heated to reflux for 3 h. The solvent was removed

under vakuum og resten oppløst i etylacetat. Oppløsningen ble vasket med 2x30 ml 5%-ig vandig svovelsyre, 2x30 ml vann, 20 ml saltoppløsning og tørket over MgSOj*. Opp-løsningsmidlet ble fjernet under vakuum og resten oppløst i en minimum mengde kloroform (11) for å tillate krystallisering. De oppnådde krystaller ble samlet på et filter og filtratet konsentrert og renset ved kromatografi over silikagel med kloroform for å gi subtittelforbindelsen som et hvitaktig faststoff (til sammen 31,5 g, 58%). under vacuum and the residue dissolved in ethyl acetate. The solution was washed with 2x30 ml of 5% aqueous sulfuric acid, 2x30 ml of water, 20 ml of saline and dried over MgSO 4 . The solvent was removed under vacuum and the residue dissolved in a minimum amount of chloroform (11) to allow crystallization. The crystals obtained were collected on a filter and the filtrate concentrated and purified by chromatography over silica gel with chloroform to give the subtitle compound as an off-white solid (total 31.5 g, 58%).

IR (film) cm*<1>2200. IR (film) cm*<1>2200.

<l>H NMR (CDC13) 5 7,39-7,38 (d, 1H, J=4,lHz), 7,10 (d, 1H, J=4,0Hz). 1 H NMR (CDCl 3 ) δ 7.39-7.38 (d, 1H, J=4.1Hz), 7.10 (d, 1H, J=4.0Hz).

MS (EI) m/z 187 (M<+>, 98%), 189 (M<*>, 100%). MS (EI) m/z 187 (M<+>, 98%), 189 (M<*>, 100%).

5-(2'-okso-2 ',3 '-dihydrospiro[cykloheksan-l ,3 '-[3H]indol]-5 '-yl-2-tiofenkarbonitril ble fremstilt i henhold til prosedyren i eksempel 5 ved bruk av 5-brom-2-tiofenkarbonitril og (2<*->okso-2\3'-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5<*->yl)borsyre, med smeltepunkt 225-228°C. 5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indole]-5'-yl-2-thiophenecarbonitrile was prepared according to the procedure of Example 5 using 5 -bromo-2-thiophenecarbonitrile and (2<*->oxo-2\3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5<*->yl)boric acid, with melting point 225-228° C.

'HNMR(DMSO-de)8 1,63 (m, 8H), 1,90 (m,2H), 6,91 (d, 1H, J=8,13Hz), 7,55 (dd, 'HNMR(DMSO-de)8 1.63 (m, 8H), 1.90 (m,2H), 6.91 (d, 1H, J=8.13Hz), 7.55 (dd,

1H, J=8,14,1,76Hz), 7,60 (d, 1H, J=4,17Hz), 7,75 (d, 1H, J=l,76Hz), 1H, J=8.14,1.76Hz), 7.60 (d, 1H, J=4.17Hz), 7.75 (d, 1H, J=1.76Hz),

7,93 (d, 1H, J=4,17Hz), 10,51 (s, 1H). 7.93 (d, 1H, J=4.17Hz), 10.51 (s, 1H).

MS ((+)APCI) m/z 309 [M+Hf. MS ((+)APCI) m/z 309 [M+Hf.

Tittelforbindelsen ble fremstilt fra 0,69 g 5-(2'-okso-2',3<*->dihydrospiro[cykloheksan-l,3,-[3H]indol]-5<*->yl-2-tiofenkarbonitril og 0,4 g fosforpentasulfid i 20 ml toluen under tilbakeløp. Efter 3 timer ble reaksjonsblandingen avkjølt, heilt i mettet vandig natrium-hydrogenkarbonatoppløsning og ekstrahert med EtOAc. De organiske sjikt ble separert, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med gradienteluering EtOActheksan for å gi tittelforbindelsen (0,215 g) som et orangefarvet faststoff. The title compound was prepared from 0.69 g of 5-(2'-oxo-2',3<*->dihydrospiro[cyclohexane-1,3,-[3H]indole]-5<*->yl-2-thiophenecarbonitrile and 0.4 g phosphorus pentasulfide in 20 ml toluene under reflux. After 3 hours, the reaction mixture was cooled, poured into saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layers were separated, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 with gradient elution EtOAc hexane to give the title compound (0.215 g) as an orange solid.

<*>H NMR (DMSO-de) 8 12,82 (br s, 1H), 8,00-7,98 (m, 2H), 7,74 (d, 1H, J=4,lHz), 7,69 (dd, 1H, J=8,2 og 1,6Hz), 7,14 (d, 1H, J=8,lHz), 1,99-1,83 (m, 7H) og <*>H NMR (DMSO-de) δ 12.82 (br s, 1H), 8.00-7.98 (m, 2H), 7.74 (d, 1H, J=4.1Hz), 7 .69 (dd, 1H, J=8.2 and 1.6Hz), 7.14 (d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and

1,40-1,37 (m, 3H). 1.40-1.37 (m, 3H).

MS ((-)-APCI) m/z 323 [M-H]-. MS ((-)-APCI) m/z 323 [M-H]-.

EKSEMPEL 36 EXAMPLE 36

5*'-( 3- fluorfenvnspirotcvkloheksan- 1. 3w- f3HliDdoll- 2wnMm- tfon 5,- f3- fluorfenvnspirorcvkloheksan- L3,- r3Hlindon- 2- frmon 5*'-( 3- fluorophenvnspirocvchlorohexane- 1. 3w- f3HliDdoll- 2wnMm- tfon 5,- f3- fluorophenvnspirocvclohexane- L3,- r3Hlindone- 2- frmon

Fremstilt i henhold til prosedyren i eksempel 5 med smeltepunkt 171-172°C. Prepared according to the procedure in example 5 with melting point 171-172°C.

'H NMR (CDC13) 8 8,43 (s, 1H), 7,62 (d, 1H, J=l,8Hz), 7,42 (dt, 1H, J=6,2,2,0Hz), 1 H NMR (CDCl 3 ) δ 8.43 (s, 1H), 7.62 (d, 1H, J=1.8Hz), 7.42 (dt, 1H, J=6.2,2.0Hz),

7,39-7,37 (m, 1H), 7,33 (dt, 1H, J=5,l, 1,3Hz), 7,26 (dq, 1H, J=5,9, 7.39-7.37 (m, 1H), 7.33 (dt, 1H, J=5.1, 1.3Hz), 7.26 (dq, 1H, J=5.9,

2,1Hz), 7,05-6,99 (m, 2H), 2,03-1,64 (m, 10H). 2.1Hz), 7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H).

MS ((+)APCI) m/z 296 [M+H]<+>. MS ((+)APCI) m/z 296 [M+H]<+>.

Tittelforbindelsen ble fremstilt fra 0,70 g 5M3-fluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l 'H)-on og 0,4 g fosforpentasulfid i 20 ml toluen under tilbakeløp. Efter 3 timer ble reaksjonsblandingen avkjølt, heilt i mettet vandig natriumhydrogenkarbo-natoppløsning og ekstrahert med EtOAc, hvoretter det organiske sjikt ble separert, tør-ket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med gradienteluering EtOAc :heksan for å gi produktet (0,42 g) som et hvitaktig faststoff. The title compound was prepared from 0.70 g of 5M3-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one and 0.4 g of phosphorus pentasulfide in 20 ml of refluxing toluene. After 3 hours, the reaction mixture was cooled, poured into saturated aqueous sodium bicarbonate solution and extracted with EtOAc, after which the organic layer was separated, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO2 with gradient elution EtOAc:hexane to give the product (0.42 g) as an off-white solid.

'H NMR (DMSO-de) 8 12,75 (br s, 1H), 7,95 (d, 1H, J=l,5Hz), 7,64 (dd, 1H, J=8,13 og 1,5Hz), 7,53-7,48 (m, 3H), 7,21-7,14 (m, 2H), 1,99-1,83 (m, 7H) og 1H NMR (DMSO-de) δ 12.75 (br s, 1H), 7.95 (d, 1H, J=1.5Hz), 7.64 (dd, 1H, J=8.13 and 1, 5Hz), 7.53-7.48 (m, 3H), 7.21-7.14 (m, 2H), 1.99-1.83 (m, 7H) and

1,40-1,37 (m, 3H). 1.40-1.37 (m, 3H).

MS ((-)-APCI) m/z 310 [M-H]". MS ((-)-APCI) m/z 310 [M-H]".

EKSEMPEL 37 EXAMPLE 37

5-( 3- h vdroksvfen vOspiro [ cykloheksan- 1, 3- [ 3H1 indoll - 2( 1 H)- tion S^- fS- hvdroksvfenvnspirorcvkloheksan- l. S^ rSHlindoll^ YriD- on 5-( 3- h vdroksvphen vOspiro [ cyclohexane- 1, 3- [ 3H1 indoll - 2( 1 H)- tion S^- fS- hvdroksvphenvnspirorcvclohexan- l. S^ rSHlindoll^ YriD- on

Fremstilt i henhold til prosedyren for eksempel 5 med smeltepunkt 213-216°C. Prepared according to the procedure of example 5 with melting point 213-216°C.

*H NMR (CDCI3) 8 1,60-1,96 (m, 10H), 6,78-6,82 (m, 1H), 6,94 (d, 1H, J=8Hz), 7,01-7.04 (m, 2H), 7,23 (t, 1H, J=7,7Hz), 7,38 (d, 1H, J=8Hz), 7,61 (s, 1H), *H NMR (CDCl3) δ 1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J=8Hz), 7.01- 7.04 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 7.38 (d, 1H, J=8Hz), 7.61 (s, 1H),

8,91 (s, 1H) og 9,73 (s, lH,br). 8.91 (s, 1H) and 9.73 (s, 1H, br).

MS ((+)-APCI) m/z 294 [M+H]<+>. MS ((+)-APCI) m/z 294 [M+H]<+>.

Tittelforbindelsen ble fremstilt fra 100 mg 5'-(3-hydroksyfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on og 110 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A for å gi 0,0045 g av tittelforbindelsen som et hvitaktig faststoff. The title compound was prepared from 100 mg of 5'-(3-hydroxyphenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one and 110 mg of Lawesson's reagent in 10 ml of refluxing toluene, according to General Procedure A to give 0.0045 g of the title compound as an off-white solid.

'H NMR (CDCI3) 8 9,59 (br s, 1H), 7,89 (s, 1H), 7,49 (dd, 1H, J=8,l og 1,5Hz), 7,33 (t, 1 H NMR (CDCl 3 ) δ 9.59 (br s, 1H), 7.89 (s, 1H), 7.49 (dd, 1H, J=8.1 and 1.5Hz), 7.33 (t ,

1H, J=7,9Hz), 7,15-7,10 (m, 3H), 6,84 (dd, 1H, J=8,0 og 2,2Hz), 2,17-2.05 (m, 2H), 1,98-1,88 (m, 5H) og 1,57-1,53 (m, 3H). 1H, J=7.9Hz), 7.15-7.10 (m, 3H), 6.84 (dd, 1H, J=8.0 and 2.2Hz), 2.17-2.05 (m, 2H ), 1.98-1.88 (m, 5H) and 1.57-1.53 (m, 3H).

MS ((-)-APCI) m/z 308 [M-H]-. MS ((-)-APCI) m/z 308 [M-H]-.

EKSEMPEL 38 EXAMPLE 38

5- f3- klorfenvn- 3. 3- dietvl- 1. 3- dihvdro- 2H- indol- 2- tion 5- f3- chlorophenvn- 3. 3- diethyl- 1. 3- dihydro- 2H- indol- 2- thione

En oppløsning av oksindol (40 g, 0,3 mol) i 400 ml tørr THF ble under N2avkjølt til A solution of oxindole (40 g, 0.3 mol) in 400 mL of dry THF was cooled under N2 to

-25°C og behandlet dråpevis med n-butyllitium (2,5M i heksaner, 240 ml, 0,6 mol). Til den resulterende oppløsning ble det satt N,N,N',N'-tetrametyletylendiamin (90,4 ml, 0,6 mol). Efter 30 minutter ble jodetan (48 ml, 0,6 mol) tilsatt og blandingen tillatt oppvarming til romtemperatur og omrørt over natten. Reaksjonsblandingen ble heilt i vandig NRjCl-oppløsning, ekstrahert to ganger med EtOAc hvorefter de kombinerte organiske sjikt ble vasket med fortynnet HC1, vann, saltoppløsning, tørket over MgS04og konsentrert. Restoljen ble triturert med heksan for å gi råproduktet (24,5 g, 51%). En prøve -25°C and treated dropwise with n-butyllithium (2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was added N,N,N',N'-tetramethylethylenediamine (90.4 mL, 0.6 mol). After 30 minutes, iodoethane (48 mL, 0.6 mol) was added and the mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into aqueous NR 2 Cl solution, extracted twice with EtOAc, then the combined organic layers were washed with dilute HCl, water, brine, dried over MgSO 4 and concentrated. The residual oil was triturated with hexane to give the crude product (24.5 g, 51%). A sample

på 3 g ble omkrystallisert fra EtOAc:heksan for å gi 3-etyl-indol-2-on (1,4 g), med smeltepunkt 100-101°C. of 3 g was recrystallized from EtOAc:hexane to give 3-ethyl-indol-2-one (1.4 g), mp 100-101°C.

'H NMR (DMSO-de) 5 0,76 (t, 3H, J=7,5Hz), 1,8-2,0 (m, 2H), 3,38 (t, 3H, J=5,7Hz), 1H NMR (DMSO-de) δ 0.76 (t, 3H, J=7.5Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J=5.7Hz ),

6,8 (dt, 1H, J=7,69,0,45Hz), 6,93 (dt, 1H, J=7,45,1,10Hz), 7,15 (m, 1H), 6.8 (dt, 1H, J=7.69,0.45Hz), 6.93 (dt, 1H, J=7.45,1.10Hz), 7.15 (m, 1H),

7,22 (m, 1H), 10,3 (s, 1H). 7.22 (m, 1H), 10.3 (s, 1H).

MS (ESI) m/z 270 [M+H]<+>. MS (ESI) m/z 270 [M+H]<+>.

En oppløsning av 3-etyl-indol-2-on (16 g, 0,1 mol) i 200 ml tørr THF ble under N2av-kjølt til -25°C og behandlet dråpevis med n-butyllitium (2,5M i heksaner, 80 ml, 0,2 mol). Til den resulterende oppløsning ble det satt N,N,N',N'-tetrametyletylendiamin (30 ml, 0,2 mol). Efter 30 minutter ble jodetan (8 ml, 0,1 mol) tilsatt og reaksjonsblandingen tillatt oppvarming til romtemperatur og omrørt over natten. Reaksjonsblandingen ble heilt i vandig NH^Cl-oppløsning, ekstrahert to ganger med EtOAc, hvorefter de kombinerte organiske sjikt ble vasket med fortynnet HC1, vann, saltoppløsning, tørket over MgS04og konsentrert. Restoljen ble triturert med heksan for å gi 3,3-dietylindol-2-on (9 g, 45%), med smeltepunkt 156-159°C. A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in 200 mL of dry THF was cooled to -25°C under N2 and treated dropwise with n-butyllithium (2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was added N,N,N',N'-tetramethylethylenediamine (30 mL, 0.2 mol). After 30 minutes, iodoethane (8 mL, 0.1 mol) was added and the reaction mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into aqueous NH 4 Cl solution, extracted twice with EtOAc, then the combined organic layers were washed with dilute HCl, water, brine, dried over MgSO 4 and concentrated. The residual oil was triturated with hexane to give 3,3-diethylindol-2-one (9 g, 45%), mp 156-159°C.

'H NMR (DMSO-d6) 8 10,44 (s, 1H), 7,70-7,69 (t, 1H), 7,62-7,59 (m, 1H), 7,58 (d, 1H, 1 H NMR (DMSO-d 6 ) δ 10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H), 7.58 (d, 1H,

J=l,7Hz), 7,53-7,50 (m, 1H), 7,45-7,41 (t, 1H), 7,36-7,35 (m, 1H), 7,34-7,33 (m, 1H), 6,91-6,89 (d, 1H, J=8,2Hz), 1,87-1,80 (m, 2H), 1,77-1,70 J=1.7Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34- 7.33 (m, 1H), 6.91-6.89 (d, 1H, J=8.2Hz), 1.87-1.80 (m, 2H), 1.77-1.70

(m, 2H), 0,54-0,50 (t, 6H). (m, 2H), 0.54-0.50 (t, 6H).

MS (+ESI) m/z 190 (M+H)<+>. MS (+ESI) m/z 190 (M+H)<+>.

En oppløsning av 3,3-dietylindol-2-on (8 g, 40 mmol) og natriumacetat (4 g, 48 mmol) i 100 ml eddiksyre ble behandlet med brom (6,4 g, 40 mmol). Efter 30 minutter ble blandingen fortynnet med vann og ekstrahert to ganger med EtOAc. De kombinerte organiske sjikt ble vasket med vann, mettet natriumhydrogenkarbonatoppløsning, så saltopp-løsning, tørket over MgS04og fordampet for å gi råproduktet (7,6 g, 75%). En prøve ble omkrystallisert fra EtOAc:heksan for å gi 5-brom-l,3-dihydro-3,3-dietyl-[2H]-indol-2-on, med smeltepunkt 164-165°C. A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in 100 mL of acetic acid was treated with bromine (6.4 g, 40 mmol). After 30 minutes, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with water, saturated sodium bicarbonate solution, then brine, dried over MgSO 4 and evaporated to give the crude product (7.6 g, 75%). A sample was recrystallized from EtOAc:hexane to give 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one, mp 164-165°C.

<*>H NMR (DMSO-de) 5 10,45 (s, 1H), 7,41-7,40 (d, 1H), J=2,2Hz), 7,34-7,31 (m, 1H), 6,78-6,76 (d, 1H, J=8,2Hz), 1,78-1,65 (m, 4H), 0,50-0,46 (m, 6H). <*>H NMR (DMSO-de) δ 10.45 (s, 1H), 7.41-7.40 (d, 1H), J=2.2Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H, J=8.2Hz), 1.78-1.65 (m, 4H), 0.50-0.46 (m, 6H).

MS (-ESI) m/z 266/268 (M-H)-. MS (-ESI) m/z 266/268 (M-H)-.

En oppløsning av brom-l,3-dihydro-3,3-dietyl-[2H]-indol-2-on (2,7 g, 10 mmol), 3-klorfenylborsyre (1,6 g, 10 mmol), kaliumkarbonat (4 g, 30 mmol) og tetra-kis(trifenylfosfin)palladium(0) (0,5 g, 0,4 mmol) i 100 ml dimetoksyetan, 25 ml etanol og 25 ml vann ble oppvarmet til tilbakeløp i 6 timer. Efter avkjøling til romtemperatur ble blandingen fortynnet med vann og ekstrahert to ganger med EtOAc. De kombinerte organiske ekstrakter ble vasket med vann og så saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02med EtOAc:heksan 1:3 for å gi 5-(3-klor-fenyl)-3,3-dietyl-l,3-dihydro-indol-2-on-forbindelsen (0,8 g, 27%) med smeltepunkt 195-197°C. A solution of bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 g, 10 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmol) in 100 mL dimethoxyethane, 25 mL ethanol, and 25 mL water were heated to reflux for 6 h. After cooling to room temperature, the mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with water and then brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 with EtOAc:hexane 1:3 to give the 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (0.8 g , 27%) with melting point 195-197°C.

<J>H NMR (DMSO-d6) 8 7,70 (t, 1H, J=2Hz), 7,62-7,60 (m, 1H), 7,58 (d, 1H, J=l,7Hz), <J>H NMR (DMSO-d6) δ 7.70 (t, 1H, J=2Hz), 7.62-7.60 (m, 1H), 7.58 (d, 1H, J=1.7Hz ),

7,52 (dd, 1H, J=8,l, 2Hz), 7,43 (t, 1H, 7,9Hz), 7,36-7,33 (m, 1H), 6,90 7.52 (dd, 1H, J=8.1, 2Hz), 7.43 (t, 1H, 7.9Hz), 7.36-7.33 (m, 1H), 6.90

(d, 1H, J=8,lHz), 1,87-1,70 (m, 4H) og 0,52 (t, 6H, J=7,4Hz). (d, 1H, J=8.1Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, J=7.4Hz).

MS (+APCI) m/z 300/302 (M-H)-. MS (+APCI) m/z 300/302 (M-H)-.

Tittelforbindelsen ble fremstilt fra 100 mg 5-(3-klor-fenyl)-3,3-dietyl-l,3-dihydro-indol-2-on-forbindelsen og 100 mg Lawesson's reagens i 10 ml toluen under tilbakeløp i henhold til den generelle prosedyre A, for å gi 0,023 g produkt som et gult faststoff. The title compound was prepared from 100 mg of the 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound and 100 mg of Lawesson's reagent in 10 ml of refluxing toluene according to the general procedure A, to give 0.023 g of product as a yellow solid.

<!>H NMR (DMSO-de) 8 12,73 (br s, 1H), 7,77 (t, 1H, J=l,8Hz), 7,75 (d, 1H, J=l,6Hz), <!>H NMR (DMSO-de) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8Hz), 7.75 (d, 1H, J=1.6Hz) ,

7,68-7,62 (m, 2H), 7,48 (t, 1H, J=7,9Hz), 7,40 (d, 1H, J=8,3Hz), 7,09 (d, 1H, J=8,lHz), 2,07-2,00 (m, 2H), 1,86-1,79 (m, 2H) og 0,37 (t, 6H, 7.68-7.62 (m, 2H), 7.48 (t, 1H, J=7.9Hz), 7.40 (d, 1H, J=8.3Hz), 7.09 (d, 1H , J=8.1Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H,

J=7,3Hz). J=7.3Hz).

MS ((-)-APCI) m/z 314/316 [M-H]-. MS ((-)-APCI) m/z 314/316 [M-H]-.

EKSEMPEL 39 EXAMPLE 39

5- f4- fluor- 3-( trifluormetvnfenvllspirorcvkloheksan- 1. 3- r3Hlindoll- 2( lH)- tion 5- f4- fluoro- 3-( trifluoromethvnphenvllspirorcvclohexane- 1. 3- r3Hlindoll- 2( 1H)- thione

5-[4-fluor-3-(trilfuormetyl)fenyl]spiro[cykloheksan-l,3-[3H]indol]-2(lH)-on ble fremstilt fra(2,-okso-2,3-dihydrospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)borsyre (2,5 g, 10 mmol) og 5-brom-2-fluor-tirfluormetylbenzen (2 g, 8 mmol) som beskrevet i eksempel 5, for å gi tittelforbindelsen (0,87 g, 30%) som et faststoff med smeltepunkt 222°C. 5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one was prepared from (2,-oxo-2,3-dihydrospiro[cyclohexane -1,3'-[3H]indol]-5'-yl)boric acid (2.5 g, 10 mmol) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 g, 8 mmol) as described in Example 5, to give the title compound (0.87 g, 30%) as a solid, m.p. 222°C.

<*>H NMR (DMSO-de) 8 1,5-1,8 (m, 8H), 1,8-2,0 (m, 2H), 6,92 (d, 1H, J=8,13Hz), 7,51 (dd, 1H, J=8,13,1,76Hz), 7,55 (dd, 1H, J=10,54, 9,01Hz), 7,72 (d, 1H, <*>H NMR (DMSO-de) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.92 (d, 1H, J=8.13Hz ), 7.51 (dd, 1H, J=8.13,1.76Hz), 7.55 (dd, 1H, J=10.54, 9.01Hz), 7.72 (d, 1H,

J=l,76Hz), 7,90 (dd, 1H, J=7,03,2,20Hz), 7,98 (m, 1H) og 10,39 (s, 1H). MS (EI) m/z 363 (M*). J=1.76Hz), 7.90 (dd, 1H, J=7.03,2.20Hz), 7.98 (m, 1H) and 10.39 (s, 1H). MS (EI) m/z 363 (M*).

Tittelforbindelsen ble fremstilt fra 90 mg 5-[4-fluor-3-(trifluormetyl)fenyl]spiro[cykloheksan-l,3-[3H]indol]-2(lH)on og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A, for å gi 0,016 g produkt som et gult faststoff. The title compound was prepared from 90 mg of 5-[4-fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)one and 90 mg of Lawesson's reagent in 10 ml of refluxing toluene , according to General Procedure A, to give 0.016 g of product as a yellow solid.

'H NMR (DMSO-de) 5 12,75 (br s, 1H), 8,06-8,00 (m, 1H), 7,96-7,92 (m, 2H), 7,66-7,56 (m, 2H), 7,16 (d, 1H, J=8,lHz), 1,99-1,83 (m, 7H) og 1,41-1,38 (m, 1 H NMR (DMSO-de) δ 12.75 (br s, 1H), 8.06-8.00 (m, 1H), 7.96-7.92 (m, 2H), 7.66-7 .56 (m, 2H), 7.16 (d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m,

3H). 3H).

MS ((-)-APCI) m/z 378 [M-H]-. MS ((-)-APCI) m/z 378 [M-H]-.

EKSEMPEL 40 EXAMPLE 40

4- ( 1. 2- dihvdro- 2- tioksospirofcvkloheksan- l, 3- f3Hlindoll- 5- vl)- 2- fluorbenzonitril Tittelforbindelsen ble fremstilt fra 90 mg 4-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-2-fluorbenzonitril og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A, for å gi 0,050 g tittelforbindelse som et orangefarvet faststoff. 4-(1.2-Dihydro-2-thioxospiro-cyclohexane-1,3-f3Hlindoll-5-v1)-2-fluorobenzonitrile The title compound was prepared from 90 mg of 4-(1,2-dihydro-2-oxospiro[cyclohexane-1, 3-[3H]indol]-5-yl)-2-fluorobenzonitrile and 90 mg of Lawesson's reagent in 10 ml of refluxing toluene, according to General Procedure A, to give 0.050 g of the title compound as an orange solid.

<!>H NMR (DMSO-d6) 8 12,80 (br s, 1H), 8,04 (d, 1H, J=l,3Hz), 7,98 (t, 1H, J=7,5Hz), <!>H NMR (DMSO-d6) δ 12.80 (br s, 1H), 8.04 (d, 1H, J=1.3Hz), 7.98 (t, 1H, J=7.5Hz) ,

7,92 (dd, 1H, J=ll,3 og 1,3Hz), 7,76 (d, 2H, J=8,0Hz), 7,18 (d, 1H, 7.92 (dd, 1H, J=11.3 and 1.3Hz), 7.76 (d, 2H, J=8.0Hz), 7.18 (d, 1H,

J=8,2Hz), 1,99-1,82 (m, 7H) og 1,40-1,38 (m, 3H). J=8.2Hz), 1.99-1.82 (m, 7H) and 1.40-1.38 (m, 3H).

MS ((-)-APCI) m/z 335 [M-H]\ MS ((-)-APCI) m/z 335 [M-H]\

EKSEMPEL 41 EXAMPLE 41

5- ( l, 2- dihvdro- 2- tioksospiro[ cvkloheksan- l, 3-[ 3Hlindoll- 5- vl)- 4- n- butyl- 2-tiofenkarbonitril 5-(l,2-dihydro-2-thioxospiro[cyclohexane-l,3-[3Hlindoll-5-vl)-4-n-butyl-2-thiophenecarbonitrile

Tittelforbindelsen ble fremstilt på en måte tilsvarende eksempel 5 fra 5-brom-4-n-butyltiofenkarbonitril (1,24 g, 5,1 mmol), (l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-borsyre (1,24 g, 5,05 mmol), tetrakis(trifenylfosfin)palladium (0,25 g), kaliumkarbonat (2,75 g, 21 mmol), 10 ml vann og 50 ml dimetoksyetan, oppvarmet til tilbakeløp i 5 timer for å gi 5-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl) 4-n-butyl-2-tiofenkarbonitrol (1 g, 54%), med smeltepunkt 130-132°C. The title compound was prepared in a manner analogous to Example 5 from 5-bromo-4-n-butylthiophenecarbonitrile (1.24 g, 5.1 mmol), (1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H ]indole]-5-boronic acid (1.24 g, 5.05 mmol), tetrakis(triphenylphosphine)palladium (0.25 g), potassium carbonate (2.75 g, 21 mmol), 10 ml water and 50 ml dimethoxyethane, heated to reflux for 5 h to give 5-(1,2-dihydro-2-oxospiro[cyclohexan-1,3-[3H]indol]-5-yl) 4-n-butyl-2-thiophenecarbonitrol (1 g , 54%), with melting point 130-132°C.

'HNMR (DMSO-de) 8 10,56 (s, 1H), 7,92 (s, 1H), 7,52-7,51 (d, 1H, J=l,2Hz), 7,32-7,29 (dd, 1H, J=l,5Hz), 6,98-6,96 (d, 1H, J=8,0Hz), 2,64-2,59 (t, 2H), HNMR (DMSO-de) δ 10.56 (s, 1H), 7.92 (s, 1H), 7.52-7.51 (d, 1H, J=1.2Hz), 7.32-7 .29 (dd, 1H, J=1.5Hz), 6.98-6.96 (d, 1H, J=8.0Hz), 2.64-2.59 (t, 2H),

1,99-1,86 (m, 2H), 1,70-1,50 (m, 11H), 1,32-1,22 (m, 2H), 0,86-0,82 (t, 1.99-1.86 (m, 2H), 1.70-1.50 (m, 11H), 1.32-1.22 (m, 2H), 0.86-0.82 (t,

3H). 3H).

MS (APCI(+)) m/z 365 [M+H]<+>. MS (APCI(+)) m/z 365 [M+H]<+>.

IR (KBr) 1620,1700, 2200 cm"<1>. IR (KBr) 1620,1700, 2200 cm"<1>.

Analyse for C22H24N2OS«l,4 H20: Analysis for C22H24N2OS«1,4 H20:

Beregnet: C, 71,61; H,6,69; N, 7,59. Calculated: C, 71.61; H, 6.69; N, 7.59.

Observert: C, 71,13; H, 6,61; N, 6,91. Observed: C, 71.13; H, 6.61; N, 6.91.

Tittelforbindelsen ble fremstilt fra 90 mg 5-(l,2-dihydro-2-oksospiro[cykloheksan-l,3-[3H]indol]-5-yl) 4-n-butyl-2-tiofenkarbonitril og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A, for å gi 0,050 g produkt som et orangefarvet faststoff. The title compound was prepared from 90 mg of 5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl) 4-n-butyl-2-thiophenecarbonitrile and 90 mg of Lawesson's reagent in 10 ml of toluene under reflux, according to general procedure A, to give 0.050 g of product as an orange solid.

'H NMR (DMSO-de) 5 12,83 (br s, 1H), 7,95 (s, 1H), 7,77 (s, 1H), 7,44 (d, 1H, 1 H NMR (DMSO-de) δ 12.83 (br s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H,

J=8,lHz), 7,18 (d, 1H, J=8,lHz), 2,63 (t, 1H, J.79=8,0Hz), 1,99-1,77 (m, 7H), 1,60-1,50 (m, 2H), 1,39-1,35 (m, 3H), 1,29-1,22 (m, 2H) og 0,81 (t, J=8.1Hz), 7.18 (d, 1H, J=8.1Hz), 2.63 (t, 1H, J.79=8.0Hz), 1.99-1.77 (m, 7H ), 1.60-1.50 (m, 2H), 1.39-1.35 (m, 3H), 1.29-1.22 (m, 2H) and 0.81 (t,

3H, 7,3Hz). 3H, 7.3Hz).

MS ((-)-APCI) m/z 379 [M-H]". MS ((-)-APCI) m/z 379 [M-H]".

EKSEMPEL 42 EXAMPLE 42

5-( 3- fluor- 5- metoksvfenvl) spiro[ cvkloheksan- l, 3-[ 3Hlindoll- 2-( lH)- tion Tittelforbindelsen ble fremstilt fra 90 mg 5-(3-fluor-5-metoksyfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-on og 90 mg Lawesson's reagens i 10 ml toluen under tilbakeløp, i henhold til den generelle prosedyre A, for å gi 0,043 g produkt som et hvitaktig faststoff. 5-(3-fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3Hlindol-2-(1H)-thione The title compound was prepared from 90 mg of 5-(3-fluoro-5-methoxyphenyl)spiro[cyclohexane- 1,3-[3H]indol]-2(1H)-one and 90 mg of Lawesson's reagent in 10 ml of refluxing toluene, according to General Procedure A, to give 0.043 g of product as an off-white solid.

<l>H NMR (DMSO-de) 8 12,74 (br s, 1H), 7,90 (s, 1H), 7,63 (dd, 1H, J=8,l og 1,2Hz), <1>H NMR (DMSO-de) δ 12.74 (br s, 1H), 7.90 (s, 1H), 7.63 (dd, 1H, J=8.1 and 1.2Hz),

7,13 (d, 1H, J=8,lHz), 7,08 (d, 1H, J=10Hz), 7,01 (s, 1H), 6,83 (dt, 1H, 7.13 (d, 1H, J=8.1Hz), 7.08 (d, 1H, J=10Hz), 7.01 (s, 1H), 6.83 (dt, 1H,

J=ll og 2,0Hz), 1,99-1,83 (m, 7H) og 1,40-1,37 (m, 3H). J=11 and 2.0Hz), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H).

MS ((-)-APCI) m/z 340 [M-H]". MS ((-)-APCI) m/z 340 [M-H]".

EKSEMPEL 43 EXAMPLE 43

5-( 3- klorfen vD- N- h vdroksvspiro f cvkloheksan- 1, 3 *- f 3H1 indoll- 2- amin Til en oppløsning av 5'-(3-klorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-tion (0,74 g, 2,25 mmol) i 15 ml THF ble det tilsatt natriumhydrid (60% i olje, 0,1 g 2,5 mmol) ved romtemperatur. Efter 15 minutter ble metyljodid (0,18 ml, 2,88 mmol) tilsatt. Efter 1 time ble reaksjonsblandingen fordelt mellom vann og EtOAc, de organiske sjikt vasket med saltoppløsning, tørket over MgS04og fordampet for å gi 5-(3-klorfenyl)-2-(metyltio)spiro[cyklohekasn-l,3'-[3H]indol] (0,80 g, 100%) som ble benyttet uten ytterligere rensing. 5-( 3- chlorophen vD- N- h vdroxvspiro f cvclohexane- 1, 3 *- f 3H1 indoll- 2- amine To a solution of 5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H ]indole]-2'(rH)-thione (0.74 g, 2.25 mmol) in 15 mL THF was added sodium hydride (60% in oil, 0.1 g 2.5 mmol) at room temperature. After 15 minutes, methyl iodide (0.18 mL, 2.88 mmol) was added. After 1 h, the reaction mixture was partitioned between water and EtOAc, the organic layers washed with brine, dried over MgSO 4 , and evaporated to give 5-(3-chlorophenyl)-2 -(methylthio)spiro[cyclohexan-1,3'-[3H]indole] (0.80 g, 100%) which was used without further purification.

Til en oppløsning av den sistnevnte forbindelse (1,96 g, 5,73 mmol) i 20 ml DMSO ble det satt hydroksylamin (60% i vann, 5 ml) og blandingen ble oppvarmet til 120°C. Efter 1 time ble reaksjonsblandingen avkjølt, fordelt mellom dietyleter og mettet vandig am-moniumkloridoppløsning. Det organiske sjikt ble vasket med vann og saltoppløsning og så tørket over MgS04 og fordampet. Råproduktet ble så krystallisert fra MeOH for å gi tittelforbindelsen (1,67 g, 5,08 mmol, 89%) som et hvitt faststoff. To a solution of the latter compound (1.96 g, 5.73 mmol) in 20 ml of DMSO was added hydroxylamine (60% in water, 5 ml) and the mixture was heated to 120°C. After 1 hour, the reaction mixture was cooled, partitioned between diethyl ether and saturated aqueous ammonium chloride solution. The organic layer was washed with water and brine and then dried over MgSO 4 and evaporated. The crude product was then crystallized from MeOH to give the title compound (1.67 g, 5.08 mmol, 89%) as a white solid.

<!>H NMR (CDC13) 5 7,52 (t, 1H, J=l,7Hz), 7,43-7,28 (m, 7H), 6,83 (d, 1H, J=8Hz) og <!>H NMR (CDCl 3 ) δ 7.52 (t, 1H, J=1.7Hz), 7.43-7.28 (m, 7H), 6.83 (d, 1H, J=8Hz) and

1,98-1,51 (m, 10H). 1.98-1.51 (m, 10H).

MS (ESI) (+)) m/z 327/329 [M+H]<+>. MS (ESI) (+)) m/z 327/329 [M+H]<+>.

EKSEMPEL 44 EXAMPLE 44

N-( acetvloksv)- 5'-( 3- klorfenvl) spiro[ cvkloheksan- L3'-[ 3Hlindoll- 2w- amin N-(acetyloxy)-5'-(3-chlorophenyl)spiro[cyclohexane-L3'-[3Hlindol-2w-amine

Til en oppløsning av 5-(3-klorfenyl)-N-hydroksyspiro[cykloheksan-l,3'-[3H]indol]-2-amin (0,23 g, 0,71 mmol) i 10 ml metylenkloird:metanol 9:1 ble det satt eddiksyreanhydrid (0,08 ml, 0,8 mmol) og en katalytisk mengde 4-dimetylaminopyridin under en nitrogenatmosfære. Efter 20 minutter ble reaksjonsblandingen fordampet og produktet renset ved kolonnekromatografi over Si02 med metanol:metylenklorid 5:95. Produktet ble så triturert med diisopropyleter for å gi tittelforbindelsen (0,12 g, 0,32 mmol, 45%). To a solution of 5-(3-chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3'-[3H]indole]-2-amine (0.23 g, 0.71 mmol) in 10 mL of methylene chloride:methanol 9 :1 was added acetic anhydride (0.08 ml, 0.8 mmol) and a catalytic amount of 4-dimethylaminopyridine under a nitrogen atmosphere. After 20 minutes, the reaction mixture was evaporated and the product purified by column chromatography over SiO2 with methanol:methylene chloride 5:95. The product was then triturated with diisopropyl ether to give the title compound (0.12 g, 0.32 mmol, 45%).

<*>H NMR (CDCI3) 8 7,52-7,51 (m, 2H), 7,43-7,27 (m, 5H), 6,88 (d, 1H, J=8Hz), 2,27 (s, 3H), 2,04-1,92 (m, 4H), 1,84-1,74 (m, 4H) og 1,72-1,57 (m, 2H). <*>H NMR (CDCl 3 ) δ 7.52-7.51 (m, 2H), 7.43-7.27 (m, 5H), 6.88 (d, 1H, J=8Hz), 2, 27 (s, 3H), 2.04-1.92 (m, 4H), 1.84-1.74 (m, 4H) and 1.72-1.57 (m, 2H).

MS (ESI (+)) m/z 369/371 [M+H]<+>. MS (ESI (+)) m/z 369/371 [M+H]<+>.

Analyse for C2iH2iClN2O2«0,5H2O: Analysis for C2iH2iClN2O2«0.5H2O:

Beregnet: C, 66,98; H, 5,64; N, 7,34. Calcd: C, 66.98; H, 5.64; N, 7.34.

Funnet: C, 66,74; H, 5,86; N, 7,41. Found: C, 66.74; H, 5.86; N, 7.41.

EKSEMPEL 45 EXAMPLE 45

5,-( 3- fluorfenvnspirorcvkloheksan- 1. 3,- f3Hlindoll- 2,( l, H)- on oksim Fremstilt i henhold til metoden ifølge eksempel 43 fra 5'-(3-fluorfenyOspirotcykloheksan-l^^-tSHlindoll^Xl 'H)-tion (0,59 g, 1,90 mmol) for å gi tittelforbindelsen (0,053 g, 0,17 mmol, 10%). 5,-(3-Fluorophenylspirocyclohexane-1.3,-f3Hlindoll-2,(1,H)-one oxime Prepared according to the method according to example 43 from 5'-(3-FluorophenyOspirocyclohexane-1^^-tSHlindoll^Xl ' H)-thione (0.59 g, 1.90 mmol) to give the title compound (0.053 g, 0.17 mmol, 10%).

'H NMR (DMSO-de) 8 9,59 (s, 1H), 9,40 (s, 1H), 7,57 (d, 1H, J=l,5Hz), 7,46-7,39 (m, 1H NMR (DMSO-de) δ 9.59 (s, 1H), 9.40 (s, 1H), 7.57 (d, 1H, J=1.5Hz), 7.46-7.39 ( m,

4H), 7,11-7,05 (m, 1H), 6,80 (d, 1H, J=8,lHz), 2,04-1,97 (m, 2H), 1,82-1,74 (m, 2H) og 1,66-1,42 (m, 6H). 4H), 7.11-7.05 (m, 1H), 6.80 (d, 1H, J=8.1Hz), 2.04-1.97 (m, 2H), 1.82-1, 74 (m, 2H) and 1.66-1.42 (m, 6H).

MS (ESI (-)) m/z 309 [M-H]\ MS (ESI (-)) m/z 309 [M-H]\

Analyse for C19H19FN2O: Analysis for C19H19FN2O:

Beregnet: C, 73,53; H, 6,17; N, 9,03. Calculated: C, 73.53; H, 6.17; N, 9.03.

Funnet: C, 73,33; H, 6,07; N, 8,83. Found: C, 73.33; H, 6.07; N, 8.83.

EKSEMPEL 46 EXAMPLE 46

S-^- fluorfenynsDirofcvkloheksan- lJ^-^ Hlindoll- Z^ rHVon oksim 5'- bromspirorcvkloheksan- 1. 3' r3H1indoll- 2'( rHVon2, fO- benzvloksim>). 5'-brom-2'-(metyltio)spiro[cykloheksan-l,3'-[3H]indol] (9,0 g, 28,98 mmol) og O-benzylhydroksylamin hydroklorid (13,8 g, 86,9 mmol) ble kombinert i 150 ml metanol og oppvarmet til 45°C i 6 timer. Metanol ble fordampet under vakuum. Etylacetat ble satt til resten og blandingen ble vasket med ammoniumkloirdoppløsning. Etylacetat ble tørket over magnesiumsulfat, etylacetatet samlet fordampet under vakuum og resten flashkromatografert på alumina 90 med heksan:EtOAc 9:1 til det ønskede produkt (6,5 g,60%). S-^- fluorophenynsDirofcvclohexane- lJ^-^ Hlindoll- Z^ rHVon oxime 5'- bromospirorcvclohexane- 1. 3' r3H1indoll- 2'( rHVon2, fO- benzvloxim>). 5'-bromo-2'-(methylthio)spiro[cyclohexane-1,3'-[3H]indole] (9.0 g, 28.98 mmol) and O-benzylhydroxylamine hydrochloride (13.8 g, 86.9 mmol) were combined in 150 mL of methanol and heated to 45°C for 6 hours. Methanol was evaporated under vacuum. Ethyl acetate was added to the residue and the mixture was washed with ammonium chloride solution. Ethyl acetate was dried over magnesium sulfate, the ethyl acetate was collectively evaporated under vacuum and the residue flash chromatographed on alumina 90 with hexane:EtOAc 9:1 to the desired product (6.5 g, 60%).

<J>H NMR (DMSO-de, 300 MHz) 8 1,38-1,70 (m, 8H), 1,92-2,06 (m, 2H), 5,06 (s, 2H), <J>H NMR (DMSO-de, 300 MHz) δ 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H),

6,71 (d, 1H, J=8,26Hz), 7,22-7,43 (m, 7H), 9,62 (s, 1H). 6.71 (d, 1H, J=8.26Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1H).

Prosedyre A Procedure A

5,-( 2- fluorfenvn- spirofcvkloheksan- 1. 3'- r3Hlindoll- 2'( lHVon 2( Q- benzvloksimV 5'-bromspiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on 2'(0)-benzyloksim) (1,0 g, 2,6 mmol) og tetrakistrifenylfosfin Pd (0) (0,14 g, 0,12 mmol) ble omrørt under en atmosfære av nitrogen i 23 ml etylenglykoldimetyleter. Efter 15 minutter ble 2-fluorfenylborsyre (0,72 mg, 5,2 mmol) tilsatt, fulgt av natriumkarbonat (1,6 g, 15,6 mmol) i 6,0 ml vann. Reaksjonsblandingen ble oppvarmet til tilbakeløp over natten, avkjølt til romtemperatur og filtrert gjennom en celittplugg. Mettet ammoniumklorid ble tilsatt. Vannsjiktet ble ekstrahert med 3x100 ml etylacetat. De kombinerte organiske sjikt ble tørket over MgS04, filtrert og oppløsningsmidlet fjernet under vakuum. Produktet ble renset ved flashsilikagelkromatografi og eluert med heksan:etylacetat 10:0,5 for å gi den ønskede forbindelsen (0,75 g, 1,8 mmol, 72%) som en viskøs olje. 5,-( 2- fluorophenvn- spirofccyclohexane- 1. 3'- r3Hlindoll- 2'( lHVon 2( Q- benzvloximV 5'-bromospiro[cyclohexane-1,3'-[3H]indole)-2'(rH)- on 2'(0)-benzyloxime) (1.0 g, 2.6 mmol) and tetrakistriphenylphosphine Pd(0) (0.14 g, 0.12 mmol) were stirred under an atmosphere of nitrogen in 23 mL of ethylene glycol dimethyl ether. After 15 min, 2-fluorophenylboronic acid (0.72 mg, 5.2 mmol) was added, followed by sodium carbonate (1.6 g, 15.6 mmol) in 6.0 mL water.The reaction mixture was heated to reflux overnight, cooled to room temperature and filtered through a plug of celite. Saturated ammonium chloride was added. The aqueous layer was extracted with 3x100 mL ethyl acetate. The combined organic layers were dried over MgSO 4 , filtered and the solvent removed under vacuum. The product was purified by flash silica gel chromatography and eluted with hexane:ethyl acetate 10:0 .5 to give the desired compound (0.75 g, 1.8 mmol, 72%) as a viscous oil.

<*>H NMR (DMSO-de, 500 MHz) 5 1,44-1,73 (8H, m), 1,93-2,06 (2H, q), 5,00 (2H, s), 6,88 (1H, d, J=8,lHz), 7,24-7,38 (6H, m), 7,44-7,56 (5H, m), 9,64 (1H, <*>H NMR (DMSO-de, 500 MHz) δ 1.44-1.73 (8H, m), 1.93-2.06 (2H, q), 5.00 (2H, s), 6 .88 (1H, d, J=8.1Hz), 7.24-7.38 (6H, m), 7.44-7.56 (5H, m), 9.64 (1H,

s). s).

MS (ESI(+ve)) m/z 399 [M-H]-. MS (ESI(+ve)) m/z 399 [M-H]-.

Prosedyre B Procedure B

En oppløsning av 5'-(2-fluorfenyl)-spiro[cykloheksan-l,3'-[3H]indol]-2'(lH)-on 2(0-benzyloksim) (0,55 g, 1,37 mmol) i 15 ml etanol ble satt til 0,11 g 10% palladium på karbon i 10 ml etanol. Blandingen ble omrørt under en atmosfære av hydrogen (ballong) i 24 timer ved romtemperatur. Reaksjonsblandingen ble filtrert gjennom en celittplugg og filtratet konsentrert under vakuum. Produktet ble renset ved flashsilikagelkromatografi med gradienteluering med heksan:etylacetat for å gi tittelforbindelsen (0,45 g, 1,12 mmol, 82%), med smeltepunkt 200-203°C. A solution of 5'-(2-fluorophenyl)-spiro[cyclohexane-1,3'-[3H]indole]-2'(1H)-one 2(O-benzyloxime) (0.55 g, 1.37 mmol ) in 15 ml of ethanol was added to 0.11 g of 10% palladium on carbon in 10 ml of ethanol. The mixture was stirred under an atmosphere of hydrogen (balloon) for 24 hours at room temperature. The reaction mixture was filtered through a plug of celite and the filtrate concentrated under vacuum. The product was purified by flash silica gel chromatography eluting with a gradient of hexane:ethyl acetate to give the title compound (0.45 g, 1.12 mmol, 82%), mp 200-203°C.

'H NMR (DMSO-de, 500 MHz) 8 1,45-1,73 (8H, m), 1,96-2,00 (2H, q), 6,83 (1H, d, 1 H NMR (DMSO-de, 500 MHz) δ 1.45-1.73 (8H, m), 1.96-2.00 (2H, q), 6.83 (1H, d,

J=7,9), 7,23-7,50 (6H, m), 9,42 (1H, s), 9,58 (1H, s). J=7.9), 7.23-7.50 (6H, m), 9.42 (1H, s), 9.58 (1H, s).

MS (ESI(+ve)) m/z 311 (M+H)<+>. MS (ESI(+ve)) m/z 311 (M+H)<+>.

EKSEMPEL 47 EXAMPLE 47

5,- f4- fluorfenvnspiro[ cvklohekasn- 1. 3,- f3Hlindol- 2,( l, HVon oksim 5 •-( 4- fluorfenvl)- spirorcvkloheksan- 1. 3 '- r3Hlindoll- 2 Yl ' HVon 2 YO- benzvloksim) Forbindelsen ble fremstilt fra 5'-bromspiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on 2'(0-benzyloksim) (1,0 g, 2,6 mmol) og 4-fluorfenylborsyre (0,72 g, 5,2 mmol) i hen- 5,- f4- fluorophenvnspiro[ cvclohexan- 1. 3,- f3Hlindol- 2,( l, HVon oxime 5 •-( 4- fluorophenvl)- spirorcvcclohexane- 1. 3 '- r3Hlindoll- 2 Yl ' HVon 2 YO- benzvloxime) The compound was prepared from 5'-bromospiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-one 2'(O-benzyloxime) (1.0 g, 2.6 mmol) and 4-Fluorophenylboronic acid (0.72 g, 5.2 mmol) in hen-

hold til eksempel 46, prosedyre A. Produktet ble renset ved flashsilikagelkromatografi og eluert med heksan:etylacetat 10:0,5 for å oppnå den ønskede forbindelse (0,70 g, 1,7 mmol, 67%) som en viskøs olje. refer to Example 46, procedure A. The product was purified by flash silica gel chromatography eluting with hexane:ethyl acetate 10:0.5 to afford the desired compound (0.70 g, 1.7 mmol, 67%) as a viscous oil.

'H NMR (DMSO-d6,500 MHz) 8 1,42-1,77 (8H, m), 1,95-1,99 (2H, q), 5,00 (2H, s), 1 H NMR (DMSO-d6,500 MHz) δ 1.42-1.77 (8H, m), 1.95-1.99 (2H, q), 5.00 (2H, s),

6,84 (1H, d, J=8,lHz), 7,21-7,63 (1H, m), 9,58 (1H, s). 6.84 (1H, d, J=8.1Hz), 7.21-7.63 (1H, m), 9.58 (1H, s).

MS (ESI(-ve)) m/z 399 (M-H)-. MS (ESI(-ve)) m/z 399 (M-H)-.

Produktet ble syntetisert ved bruk av 5<*->(4-fluofrenyl)-spiro[cykloheksan-l,3'-[3H]indol]-2<*>(rH)-on 2'{0-benzyloksim) (0,70 g, 1,74 mmol), i henhold til eksempel 45, prosedyre B. Produktet ble renset ved flashsilikagelkromatografi og gradienteluering heksan:etylacetat for å oppnå tittelforbindelsen (0,44 g, 1,4 mmol, 81%), med smeltepunkt 205-208°C. The product was synthesized using 5<*>(4-fluophrenyl)-spiro[cyclohexane-1,3'-[3H]indole]-2<*>(rH)-one 2'{O-benzyloxime) (0 .70 g, 1.74 mmol), according to Example 45, procedure B. The product was purified by flash silica gel chromatography and gradient elution hexane:ethyl acetate to afford the title compound (0.44 g, 1.4 mmol, 81%), m.p. 205-208°C.

'H NMR (DMSO-dé, 500 MHz) 8 1,43-1,77 (8H, m), 2,00-2,05 (2H, q), 6,80 (1H, d, 1 H NMR (DMSO-dé, 500 MHz) δ 1.43-1.77 (8H, m), 2.00-2.05 (2H, q), 6.80 (1H, d,

J=8,2Hz), 7,21-7,24 (2H, m), 7,33-7,35 (1H, dd, J=l,9Hz), 7,49 (1H, s), J=8.2Hz), 7.21-7.24 (2H, m), 7.33-7.35 (1H, dd, J=1.9Hz), 7.49 (1H, s),

7,60-7,63 (2H, m), 9,35 (1H, s), 9,56 (1H, s). 7.60-7.63 (2H, m), 9.35 (1H, s), 9.56 (1H, s).

MS (ESI(+ve)) m/z 311 (M+H)<+.>MS (ESI(+ve)) m/z 311 (M+H)<+.>

EKSEMPEL 48 EXAMPLE 48

S>-( 3. 4- difluorfenvnspirofcvkloheksaii- 1. 3'- r3Hlmdon- 2' fim- on oksim 5,- G. 4- difluorfenvn- spirorcvkloheksan- L3'- r3H1indon- 2YrHVon rfO- benzvloksimV Forbindelsen ble fremstilt fra 5<*->bromspiro{cykloheksan-l,3'-[3H]indol}-2<*>(rH)-on 2'(0-benzyloksim) (1,0 g, 2,6 mmol) og 3,4-difluorfenylborsyre (1,6 g, 5,2 mmol av en 50%-ig oppløsning av syre i THF:vann) i henhold til eksempel 46, prosedyre A. Produktet ble renset ved flashsilikagelkromatografi og eluert med heksan:etylacetat 10:0,5 for å gi det ønskede produkt (0,75 g, 1,7 mmol, 69%) som en viskøs olje. S>-( 3. 4- difluorophenvspirofcvclohexaii- 1. 3'- r3Hlmdon- 2' fim- one oxime 5,- G. 4- difluorophenvn- spirorcvclohexane- L3'- r3H1indone- 2YrHVon rfO- benzvloximV The compound was prepared from 5<* ->bromospiro{cyclohexane-1,3'-[3H]indole}-2<*>(rH)-one 2'(0-benzyloxime) (1.0 g, 2.6 mmol) and 3,4-difluorophenylboronic acid (1.6 g, 5.2 mmol of a 50% solution of acid in THF:water) according to Example 46, Procedure A. The product was purified by flash silica gel chromatography and eluted with hexane:ethyl acetate 10:0.5 for to give the desired product (0.75 g, 1.7 mmol, 69%) as a viscous oil.

'H NMR (DMSO-d6, 500 MHz) 8 1,41-1,78 (8H, m), 1,95-1,99 (2H, q), 5,00 (2H, s), 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.41-1.78 (8H, m), 1.95-1.99 (2H, q), 5.00 (2H, s),

6,82 (1H, d), 7,28-7,46 (8H, m), 7,58 (1H, q), 7,67-7,71 (1H, m), 9,61 6.82 (1H, d), 7.28-7.46 (8H, m), 7.58 (1H, q), 7.67-7.71 (1H, m), 9.61

(1H, s). (1H, p).

MS (ESI(-ve)) m/z 417 (M-H)\ MS (ESI(-ve)) m/z 417 (M-H)\

Omsetning av den sistnevnte forbindelse (0,70 g, 1,6 mmol) i henhold til eksempel 45, prosedyre B, ga tittelforbindelsen (0,44 g, 1,3 mmol, 80%). Reaction of the latter compound (0.70 g, 1.6 mmol) according to Example 45, procedure B, gave the title compound (0.44 g, 1.3 mmol, 80%).

'H NMR (DMSO-de, 500 MHz) 8 1,42-1,79 (8H, m), 2,01-2,05 (2H, q), 6,78-6,80 (1H, d), 7,39-7,46 (3H, m), 7,55 (1H, s), 7,70 (1H, m), 9,10 (1H, s), 9,59 (1H, 1 H NMR (DMSO-de, 500 MHz) δ 1.42-1.79 (8H, m), 2.01-2.05 (2H, q), 6.78-6.80 (1H, d) , 7.39-7.46 (3H, m), 7.55 (1H, s), 7.70 (1H, m), 9.10 (1H, s), 9.59 (1H,

s). s).

MS (ESI(+ve)) m/z 329 (M+H)<+>. MS (ESI(+ve)) m/z 329 (M+H)<+>.

EKSEMPEL 49 EXAMPLE 49

5'- f3- metoksvfenvnspirorcvkloheksan- 1. 3'-[ 3Hlindoll- 2'( l' H)- on oksim 5'-( 3- metoksvfenvlVspirorcvM^ Forbindelsen ble fremstilt fra 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(rH)-on 2'(0-benzyloksim) (1,0 g, 2,6 mmol) og 3-metoksyfenyl borsyre (0,79 g, 5,2 mmol) i henhold til eksempel 46, prosedyre A. Produktet ble renset ved flashsilikagelkromatografi og eluert med heksametylacetat 10:0,5 for å gi det ønskede produkt (0,80 g, 1,9 mmol, 75%) som en viskøs olje. 5'- f3- methoxysphenvspirorcvcyclohexane- 1. 3'-[ 3Hlindoll- 2'( 1' H)- one oxime 5'-( 3- methoxysphenvspirorcvM^ The compound was prepared from 5'-bromospiro{cyclohexane-1,3'-[ 3H]indol}-2'(rH)-one 2'(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-methoxyphenyl boric acid (0.79 g, 5.2 mmol) according to Example 46, procedure A. The product was purified by flash silica gel chromatography eluting with hexamethyl acetate 10:0.5 to give the desired product (0.80 g, 1.9 mmol, 75%) as a viscous oil.

'H NMR (DMSO-d6, 500 MHz) 8 1,43-1,78 (8H, m), 1,95-2,00 (2H, q), 3,80 (3H, s), 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.43-1.78 (8H, m), 1.95-2.00 (2H, q), 3.80 (3H, s),

5,00 (2H, s), 6,82-6,86 (2H, m), 7,10-7,16 (2H, m), 7,28-7,53 (10H, m), 5.00 (2H, s), 6.82-6.86 (2H, m), 7.10-7.16 (2H, m), 7.28-7.53 (10H, m),

9,57 (1H, s). 9.57 (1H, p).

MS (ESI(-ve)) m/z 411 (M-H)-. MS (ESI(-ve)) m/z 411 (M-H)-.

Omsetning av den sistnevnte forbindelse (0,80 g, 1,9 mmol) i henhold til eksempel 46, prosedyre B, ga tittelforbindelsen (0,48 g, 1,4 mmol, 77%), som et hvitt faststoff med smeltepunkt 101-104°C. Reaction of the latter compound (0.80 g, 1.9 mmol) according to Example 46, Procedure B, gave the title compound (0.48 g, 1.4 mmol, 77%) as a white solid, mp 101- 104°C.

'H NMR (DMSO-d6, 500 MHz) 8 1,44-1,78 (8H, m), 1,99-2,03 (2H, q), 3,81 (3H, s), 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.44-1.78 (8H, m), 1.99-2.03 (2H, q), 3.81 (3H, s),

6,78 (1H, d), 6,85 (1H, d), 7,10-7,16 (2H, m), 7,30-7,38 (2H, m), 7,50 6.78 (1H, d), 6.85 (1H, d), 7.10-7.16 (2H, m), 7.30-7.38 (2H, m), 7.50

(1H, d), 9,35 (1H, s), 9,56 (1H, s). (1H, d), 9.35 (1H, s), 9.56 (1H, s).

MS (ESI(+ve)) m/z 323 (M+H)<+>. MS (ESI(+ve)) m/z 323 (M+H)<+>.

EKSEMPEL 50 EXAMPLE 50

5*-( 3- nitrofen vDspiro f cykloheksan- 1, 3"- [ 3H1 indoll - 2 * ( 1 " Hl- on oksim 5'- f3- nitrofenvlVspirorcvkloheksan- 1. 3,- r3Hlindol1- 2'( l' H)- on2,( OVbenzvloksim Forbindelsen ble fremstilt fra 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(rH)-on 2'(0-benzyloksim) (1,0 g, 2,6 mmol) og 3-nitrofenyl borsyre (0,86 g, 5,2 mmol) i henhold til eksempel 46, prosedyre A. Rensing ved flashsilikagelkromatografi og eluert 5*-( 3- nitrophen vDspiro f cyclohexane- 1, 3"- [ 3H1 indoll - 2 * ( 1 " Hl- on oxime 5'- f3- nitrophenvlVspirorcvclohexane- 1. 3,- r3Hlindol1- 2'( l' H) - on2,( OVbenzvloxime The compound was prepared from 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(rH)-one 2'(0-benzyloxime) (1.0 g, 2.6 mmol) and 3-nitrophenyl boric acid (0.86 g, 5.2 mmol) according to Example 46, Procedure A. Purification by flash silica gel chromatography and eluted

med heksametylacetat 10:0,5 ga det ønskede produkt (0,60 g, 1,4 mmol, 55%) som en viskøs olje. with hexamethyl acetate 10:0.5 gave the desired product (0.60 g, 1.4 mmol, 55%) as a viscous oil.

'H NMR (DMSO-d6, 500 MHz) 8 1,42-1,82 (8H, m), 2,02-2,04 (2H, q), 5,01 (2H, s), 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.42-1.82 (8H, m), 2.02-2.04 (2H, q), 5.01 (2H, s),

6,88 (1H, d), 7,28-7,71 (8H, m), 8,08-8,13 (2H, m), 8,38 (1H, d), 9,69 6.88 (1H, d), 7.28-7.71 (8H, m), 8.08-8.13 (2H, m), 8.38 (1H, d), 9.69

(1H, s). (1H, p).

MS (ESI(-ve)) m/z 426 (M-H)\ MS (ESI(-ve)) m/z 426 (M-H)\

Prosedyre C Procedure C

Den sistnevnte forbindelse (0,54 g, 1,26 mmol) ble oppløst i 25 ml tørr metylenklorid og avkjølt til -78°C under nitrogen. Bortribromid (3,8 ml, 3,8 mmol, 1,0M i metylenklorid) ble dråpevis tilsatt i løpet av 5 minutter. Efter 30 minutter ble reaksjonsblandingen quenchet med 5 ml mettet natriumbikarbonat. Reaksjonsblandingen ble tillatt oppvarming til romtemperatur og sjiktene separert og det vandige sjikt ekstrahert med metylenklorid. De kombinerte organiske sjikt ble tørket over Na2SC«4, filtrert og oppløs-ningsmidlet fjernet under vakuum. Produktet ble renset ved flashsilikagelkromatografi og eluert med heksan:etylacetat 8:1 for å gi tittelforbindelsen (0,33 g, 0,9 mmol, 78%), med smeltepunkt 221-224°C. The latter compound (0.54 g, 1.26 mmol) was dissolved in 25 mL of dry methylene chloride and cooled to -78°C under nitrogen. Boron tribromide (3.8 mL, 3.8 mmol, 1.0 M in methylene chloride) was added dropwise over 5 minutes. After 30 minutes, the reaction mixture was quenched with 5 ml of saturated sodium bicarbonate. The reaction mixture was allowed to warm to room temperature and the layers separated and the aqueous layer extracted with methylene chloride. The combined organic layers were dried over Na2SO4, filtered and the solvent removed under vacuum. The product was purified by flash silica gel chromatography eluting with hexane:ethyl acetate 8:1 to give the title compound (0.33 g, 0.9 mmol, 78%), mp 221-224°C.

<*>H NMR (DMSO-de, 500 MHz) 8 1,42-1,83 (8H, m), 1,99-2,07 (2H, q), 6,84-6,85 (1H, dd), 7,50-7,52 (1H, m), 7,67-7,71 (2H, m), 8,08-8,12 (2H, m), 8,37-8,38 <*>H NMR (DMSO-de, 500 MHz) δ 1.42-1.83 (8H, m), 1.99-2.07 (2H, q), 6.84-6.85 (1H, dd), 7.50-7.52 (1H, m), 7.67-7.71 (2H, m), 8.08-8.12 (2H, m), 8.37-8.38

(1H, d), 9,48 (1H, s), 9,64 (1H, s). (1H, d), 9.48 (1H, s), 9.64 (1H, s).

MS (ESI(+ve)) m/z 338 (M+H)<+>. MS (ESI(+ve)) m/z 338 (M+H)<+>.

EKSEMPEL 51 EXAMPLE 51

5,- f3- cvanofenvnspiro[ cvkloheksan- 1. 3,-[ 3Hlindoll- 2, fl, H)- on oksim 3- rspirorcvkloheksan- lJ*- r3Hlindoll- a' HVon- 2'- fO- benzvloksim) lbenzonitrin r3Hlindoll- 5- vllbenzonitril 5,- f3- cvanophenvnspiro[ cvclohexane- 1. 3,-[ 3Hlindoll- 2, fl, H)- on oxime 3- rspirorcvclohexan- lJ*- r3Hlindoll- a' HVon- 2'- fO- benzvloxim) lbenzonitrin r3Hlindoll- 5 - villibenzonitrile

Forbindelsen ble fremstilt fra 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(rH)-on 2'(0-benzyloksim) (1,0 g, 2,6 mmol) og 3-cyanofenyl borsyre (0,76 g, 5,2 mmol) i henhold til eksempel 46, prosedyre A. Produktet ble renset ved flashsilikagelkromatografi med elueringsmiddel heksan:etylacetat 10:0,5 for å gi det ønskede produkt (0,75 g, 1,8 mmol, 71%) som en viskøs olje. The compound was prepared from 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(rH)-one 2'(O-benzyloxime) (1.0 g, 2.6 mmol) and 3- cyanophenyl boric acid (0.76 g, 5.2 mmol) according to Example 46, Procedure A. The product was purified by flash silica gel chromatography eluting with hexane:ethyl acetate 10:0.5 to give the desired product (0.75 g, 1 .8 mmol, 71%) as a viscous oil.

'H NMR (DMSO-d6, 500 MHz) 8 1,41-1,81 (8H, m), 1,96-2,03 (2H, q), 5,01 (2H, s), 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.41-1.81 (8H, m), 1.96-2.03 (2H, q), 5.01 (2H, s),

6,86 (1H, d), 7,28-7,33 (9H, m), 7,95-7,97 (1H, d), 8,12 (1H, s), 9,65 6.86 (1H, d), 7.28-7.33 (9H, m), 7.95-7.97 (1H, d), 8.12 (1H, s), 9.65

(1H, s). (1H, p).

MS (ESI(-ve)) m/z 406 (M-H)-. MS (ESI(-ve)) m/z 406 (M-H)-.

Omsetning av den sistnevnte forbindelsen (0,17 g, 0,43 mmol) og bortribromid (1,2 ml, 1,2 mmol) i henhold til eksempel 50, prosedyre C, ga tittelforbindelsen (0,06 g, 0,2 mmol, 47%) som et hvitt faststoff, med smeltepunkt 198-200°C. Reaction of the latter compound (0.17 g, 0.43 mmol) and boron tribromide (1.2 mL, 1.2 mmol) according to Example 50, Procedure C, gave the title compound (0.06 g, 0.2 mmol , 47%) as a white solid, melting point 198-200°C.

'H NMR (DMSO-de, 500 MHz) 8 1,41-1,80 (8H, m), 1,97-2,04 (2H, q), 6,80 (1H, q), 1 H NMR (DMSO-de, 500 MHz) δ 1.41-1.80 (8H, m), 1.97-2.04 (2H, q), 6.80 (1H, q),

7,45-7,69 (4H, m), 7,93-7,95 (1H, dd), 8,10 (1H, s), 9,42 (1H, s), 9,59 7.45-7.69 (4H, m), 7.93-7.95 (1H, dd), 8.10 (1H, s), 9.42 (1H, s), 9.59

(1H, s). (1H, p).

(ESI(+ve)) m/z 318 (M+H)<+>. (ESI(+ve)) m/z 318 (M+H)<+>.

EKSEMPEL 52 EXAMPLE 52

S- rr^^- dihvro^^- fhvdroksviminolspirorcvkloheksan- lJ^- PHlindon- S^- vn- S-fluorbenzonitril S- rr^^- dihvro^^- fhvdroxviminolspirorcvchlorohexane- lJ^- PHlindone- S^- vn- S-fluorobenzonitrile

Til en oppløsning av 3-fluor-5-cyano-brombenzen (0,4 g, 2,0 mmol) i 10 ml tørr DMF ble det satt diborpinakolatester (0,63 g, 2,5 mmol), kaliumkarbonat (0,65 g, 6,7 mmol) og 0,2 g PdCl2 (dppf) og reaksjonsblandingen oppvarmet til 80°C under nitrogen. Efter 8 timer ble 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(l 'H)-on 2'(0-benzyloksim) To a solution of 3-fluoro-5-cyano-bromobenzene (0.4 g, 2.0 mmol) in 10 mL of dry DMF was added diborpinacolate ester (0.63 g, 2.5 mmol), potassium carbonate (0.65 g, 6.7 mmol) and 0.2 g of PdCl2 (dppf) and the reaction mixture heated to 80°C under nitrogen. After 8 hours, 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(1'H)-one 2'(O-benzyloxime)

(0,2 g, 0,5 mmol), 0,05 g PdCl2(dppf) og natriumkarbonat (1,30 g, 12,5 mmol) tilsatt og oppvarmingen til 80°C ble fortsatt. Efter 8 timer ble reaksjonsblandingen avkjølt og fordelt mellom vann og etylacetat, det organiske sjikt vasket med saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02og eluert med EtOAc:heksan 1:20 for å gi det ønskede produkt (0,14 g, 0,33 mmol, 66%). (0.2 g, 0.5 mmol), 0.05 g of PdCl 2 (dppf) and sodium carbonate (1.30 g, 12.5 mmol) were added and heating to 80°C was continued. After 8 hours, the reaction mixture was cooled and partitioned between water and ethyl acetate, the organic layer washed with brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 eluting with EtOAc:hexane 1:20 to give the desired product (0.14 g, 0.33 mmol, 66%).

Omsetning av den sistnevnte forbindelse (0,14 g, 0,33 mmol) og bortribromid (1,0 ml, 1,0 mmol) ifølge eksempel 50, prosedyre C ga tittelforbindelsen (0,019 g, 0,05 mmol, 17%). Reaction of the latter compound (0.14 g, 0.33 mmol) and boron tribromide (1.0 mL, 1.0 mmol) according to Example 50, procedure C gave the title compound (0.019 g, 0.05 mmol, 17%).

'H NMR (DMSO-d6, 300 MHz) 8 9,65 (s, 1H), 9,49 (s, 1H), 8,04 (m, 1H), 7,89 (dt, 1H, 1 H NMR (DMSO-d 6 , 300 MHz) δ 9.65 (s, 1H), 9.49 (s, 1H), 8.04 (m, 1H), 7.89 (dt, 1H,

J=10,5 og 2Hz), 7,72-7,68 (m, 2H), 7,54 (d, 1H, J=8,lHz), 6,80 (d, 1H, J=10.5 and 2Hz), 7.72-7.68 (m, 2H), 7.54 (d, 1H, J=8.1Hz), 6.80 (d, 1H,

J=8,lHz), 2,05-1,99 (m, 2H), 1,84-1,76 (m, 2H) og 1,65-1,44 (m, 6H). MS (ESI(+ve)) m/z 336 (M+H)<+>. J=8.1Hz), 2.05-1.99 (m, 2H), 1.84-1.76 (m, 2H) and 1.65-1.44 (m, 6H). MS (ESI(+ve)) m/z 336 (M+H)<+>.

EKSEMPEL 53 EXAMPLE 53

5- f5Dirolcvkloheksaii- 1. 3>- r3HliDdoll- 2'- fbvroksvimiDoV5,- vn- 4- mervl- 2-tiofenkarbonitril 5- f5Dirolcvklohexaii- 1. 3>- r3HliDdoll- 2'- fbvroksvimiDoV5,- vn- 4- mervl- 2-thiophenecarbonitrile

4- metvl- S- tirmetvlsaraivl- tiofen- 2- karbonitril 4-Methyl-S-trimethylsarayl-thiophene-2-carbonitrile

Forbindelsen ble fremstilt fra 5-brom-4-metyl-tiofen-2-karbonitril (3,08 g, 15,2 mmol), tetrakisfenylfosfin Pd (0) (0,82 g, 0,71 mmol), heksametylditinn (5,0 g, 15,2 mmol) og 20 ml etylenglykol dimetyleter under nitrogen. Blandingen ble oppvarmet til tilbakeløp i 14 timer. Reaksjonsblandingen ble konsentrert under vakuum og renset ved bruk av flashsilikagelkromatografi og eluert med 2% MeOH:metylenklorid for å gi det ønskede produkt (2,8 g, 0,01 mmol, 67%) som en olje. The compound was prepared from 5-bromo-4-methyl-thiophene-2-carbonitrile (3.08 g, 15.2 mmol), tetrakisphenylphosphine Pd(0) (0.82 g, 0.71 mmol), hexamethylditinne (5, 0 g, 15.2 mmol) and 20 ml of ethylene glycol dimethyl ether under nitrogen. The mixture was heated to reflux for 14 hours. The reaction mixture was concentrated in vacuo and purified using flash silica gel chromatography eluting with 2% MeOH:methylene chloride to give the desired product (2.8 g, 0.01 mmol, 67%) as an oil.

'H NMR (DMSO-de, 300 MHz) 8 0,41 (9H, s), 2,28 (3H, s), 7,83 (1H, s). 1 H NMR (DMSO-de, 300 MHz) δ 0.41 (9H, s), 2.28 (3H, s), 7.83 (1H, s).

Den sistnevnte forbindelse (0,20 g, 0,50 mmol), diklorbis(trifenylfosfin)palladium(II) The latter compound (0.20 g, 0.50 mmol), dichlorobis(triphenylphosphine)palladium(II)

(0,02 g, 0,03 mmol) og trifenylarsin (0,03 g, 0,13 mmol) i 8,0 ml DME ble omrørt under nitrogen i 20 minutter. S^bromspirolcykloheksan-l^^tS^indolJ^XrHi-on 2'(0-benzyloksim) (0,18 g, 0,64 mmol) ble tilsatt i en oppløsning av 2,0 ml DME. Oppløs-ningen ble oppvarmet til tilbakeløp over natten, Reaksjonsoppløsningen ble konsentrert under vakuum og renset ved flashsilikagelkromatografi og eluert med heksan :etylacetat 12:1 for å gi det urene produkt (0,10 g, 0,25 mmol, 50%) som en benyttet uten ytterligere rensing. (0.02 g, 0.03 mmol) and triphenylarsine (0.03 g, 0.13 mmol) in 8.0 mL DME was stirred under nitrogen for 20 min. S^Bromospirolecyclohexane-1^^tS^indolJ^XrHi-one 2'(O-benzyloxime) (0.18 g, 0.64 mmol) was added in a solution of 2.0 mL DME. The solution was heated to reflux overnight. The reaction solution was concentrated under vacuum and purified by flash silica gel chromatography eluting with hexane:ethyl acetate 12:1 to give the crude product (0.10 g, 0.25 mmol, 50%) as a used without further purification.

Bortrimbromid (2,6 ml, 2,6 mmol av en 1,0M opplsøning i metylenklorid) ble satt til en oppløsning av det sistnevnte produkt (0,37 g, 0,86 mmol) i 1,7 ml tørr metylenklorid ved -78°C. Oppløsningen ble omrørt i 30 minutter og quenchet med 10 ml mettet natriumbikarbonat. Blandingen ble tillatt oppvarming til romtemperatur og sjiktene separert. Det organiske sjikt ble tørket over Na2S04, filtrert og konsentrert under vakuum for å gi råproduktet som ble renset ved flashsilikagelkromatografi og eluert med 6:1 heksan:etylacetat for å gi tittelforbindelsen (0,02 g, 24%) med smeltepunkt 173-176°C. Borontrim bromide (2.6 mL, 2.6 mmol of a 1.0 M solution in methylene chloride) was added to a solution of the latter product (0.37 g, 0.86 mmol) in 1.7 mL of dry methylene chloride at -78 °C. The solution was stirred for 30 minutes and quenched with 10 ml of saturated sodium bicarbonate. The mixture was allowed to warm to room temperature and the layers separated. The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product which was purified by flash silica gel chromatography and eluted with 6:1 hexane:ethyl acetate to give the title compound (0.02 g, 24%) mp 173-176° C.

<*>H NMR (DMSO-de, 500 MHz) 8 1,44-1,73 (8H, m), 1,96-2,00 (2H, m), 2,28 (3H, s), 6,82-6,84 (1H, m), 7,24-7,26 (1H, dd, J=l,7Hz), 7,38 (1H, m), 7,82 (1H, <*>H NMR (DMSO-de, 500 MHz) 8 1.44-1.73 (8H, m), 1.96-2.00 (2H, m), 2.28 (3H, s), 6 .82-6.84 (1H, m), 7.24-7.26 (1H, dd, J=1.7Hz), 7.38 (1H, m), 7.82 (1H,

m), 9,51 (lH,m), 9,66 (lH,m). m), 9.51 (lH,m), 9.66 (lH,m).

MS (ESI(+ve)) m/z 338 (M+H)<+>. MS (ESI(+ve)) m/z 338 (M+H)<+>.

EKSEMPEL 54 EXAMPLE 54

5-( spiro[ cvkloheksan- l, 3*-[ 3Hlindoll- 2'( hvdroksvimino)- 5*- vl)- 2- tiofenkarbonitril Til en oppløsning av 2-cyanotiofen (1,0 g, 9,16 mmol) og tri-iso-propylborat (2,3 ml, 10 mmol) i 30 ml tørr THF ble det under nitrogen og ved -78°C dråpevis satt litiumheksa-metyldisilazid (IM i THF, 10 ml, 10 mmol). Efter 30 minutter ble reaksjonsblandingen quenchet med IN HC1, og så ekstrahert med etylacetat, hvorefter det organiske sjikt ble vasket med vann, tørket over Na2SC>4og fordampet for å oppnå produktet (1,25 g, 8,17 mmol, 89%) som ble benyttet uten ytterligere rensing. 5-(spiro[cyclohexane-1,3*-[3Hlindoll-2'(hydroxvimino)-5*-vl)-2-thiophenecarbonitrile To a solution of 2-cyanothiophene (1.0 g, 9.16 mmol) and tri -iso-propylborate (2.3 ml, 10 mmol) in 30 ml of dry THF, lithium hexamethyldisilazide (1M in THF, 10 ml, 10 mmol) was added dropwise under nitrogen and at -78°C. After 30 minutes, the reaction mixture was quenched with 1N HCl, then extracted with ethyl acetate, after which the organic layer was washed with water, dried over Na 2 SO 4 and evaporated to give the product (1.25 g, 8.17 mmol, 89%) as was used without further purification.

'H NMR (DMSO-d6, 500 MHz) 8 8,75 (br s, 2H), 7,97 (d, 1H, J=8Hz) og 7,73 (d, 1H, 1H NMR (DMSO-d6, 500 MHz) δ 8.75 (br s, 2H), 7.97 (d, 1H, J=8Hz) and 7.73 (d, 1H,

J=8,Hz). J=8.Hz).

MS (ESI(-ve)) m/z 152 [M-H]". MS (ESI(-ve)) m/z 152 [M-H]".

Man arbeider videre med det sistnevnte produkt (0,91 g, 5,95 mmol) og 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(l'H)-on2'(0-benzyloksim) (1,53 g, 3,97 mmol) i henhold til eksempel 46, prosedyre A og rensing ved flashsilikagelkromatografi og eluering med heksan:THF 5:1 ga det ønskede produkt (0,66 g, 1,59 mmol) som ble benyttet uten ytterligere rensing. Work is continued with the latter product (0.91 g, 5.95 mmol) and 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(1'H)-one2'(0- benzyl oxime) (1.53 g, 3.97 mmol) according to Example 46, Procedure A and purification by flash silica gel chromatography eluting with hexane:THF 5:1 gave the desired product (0.66 g, 1.59 mmol) as was used without further purification.

MS (ESI(-ve)) m/z 421 (M-H)-. MS (ESI(-ve)) m/z 421 (M-H)-.

Omsetning av den sistnevnte forbindelse (0,60 g, 1,45 mmol) og bortribromid (IM i diklormetan, 5 ml, 5 mmol) i henhold til eksempel 50, prosedyre C, ga tittelforbindelsen (0,036 g, 0,11 mmol, 8%). Reaction of the latter compound (0.60 g, 1.45 mmol) and boron tribromide (1 M in dichloromethane, 5 mL, 5 mmol) according to Example 50, Procedure C, gave the title compound (0.036 g, 0.11 mmol, 8 %).

'H NMR (DMSO-de, 300 MHz) 8 9,71 (s, 1H), 9,62 (s, 1H), 7,92 (d, 1H, J=3,9Hz), 7,63 1 H NMR (DMSO-de, 300 MHz) δ 9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, J=3.9Hz), 7.63

(d, 1H, J=l,5Hz), 7,54 (d, 1H, J=3,9Hz), 7,47 (dd, 1H, J=8,l og 1,6Hz), (d, 1H, J=1.5Hz), 7.54 (d, 1H, J=3.9Hz), 7.47 (dd, 1H, J=8.1 and 1.6Hz),

6,78 (d, 1H, J=8,lHz), 2,13-1,90 (m, 2H) og 1,78-1,60 (m, 6H). 6.78 (d, 1H, J=8.1Hz), 2.13-1.90 (m, 2H) and 1.78-1.60 (m, 6H).

MS (ESI(+ve)) m/z 324 (M+H)<+>. MS (ESI(+ve)) m/z 324 (M+H)<+>.

EKSEMPEL 55 EXAMPLE 55

4-( spirofcvkloheksan- l, 3,- f3Hlindoll- 2"( hydroksvimino)- 5'- vl)- 2- tiofenkarbonitril 4-( trimetylstannvl)- 2- tiofenkarbonitril 4-(spirochlorohexane-1,3,-f3Hlindoll-2"(hydroxyimino)-5'-vl)-2-thiophenecarbonitrile 4-(trimethylstannvl)-2-thiophenecarbonitrile

En oppløsning av 3-brom-2-tiofenkarbonitril (0,8 g, 4,3 mmol), tetrakis(trifenylfosfin)-palladium(O) (0,25 g, 0,2 mmol) og heksametylditinn (1,4 g, 4,3 mmol) i 5 cm<3>dime toksyetan ble oppvarmet under tilbakeløp i 14 timer og så avkjølt til romtemperatur. Reaksjonsblandingen ble absorbert på florisil og renset ved kromatografi over SiC>2 med metylenklorid:heksan 1:9 for å gi subtittelforbindelsen (1,4 g, 3,8 mmol, 90%) som et klar, viskøs olje. A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis(triphenylphosphine)palladium(O) (0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) in 5 cm<3>dime toxyetane was heated under reflux for 14 hours and then cooled to room temperature. The reaction mixture was absorbed onto florisil and purified by chromatography over SiC>2 with methylene chloride:hexane 1:9 to give the sub-title compound (1.4 g, 3.8 mmol, 90%) as a clear, viscous oil.

'H NMR (CDC13) 5 0,35 (s, 9H), 7,56 (d, J=0,9Hz, 1H), 7,66 (d, J=0,9Hz, 1H). 1 H NMR (CDCl 3 ) δ 0.35 (s, 9H), 7.56 (d, J=0.9Hz, 1H), 7.66 (d, J=0.9Hz, 1H).

Til en oppløsning av 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(rH)-on 2'(0-benzyloksim) (1,65 g, 4,28 mmol), 4-(trimetylstannyl)-2-tiofenkarbonitril (1,48 g, 5,44 mmol), 330 mg trifenylarsin i 20 ml tørr dimetoksyetan ble det under nitrogen satt bis(trifenylfosfin)palladium(H)klorid, og blandingen ble oppvarmet under tilbakeløp i 16 timer. Efter avkjøling til romtemperatur ble blandingen fordampet og resten renset ved kolonnekromatografi over SiC>2 og radienteluert med EtOAc :heksan for å gi det ønskede produkt (0,61 g, 1,47 mmol, 56%). To a solution of 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(rH)-one 2'(O-benzyloxime) (1.65 g, 4.28 mmol), 4- (trimethylstannyl)-2-thiophenecarbonitrile (1.48 g, 5.44 mmol), 330 mg of triphenylarsine in 20 ml of dry dimethoxyethane, bis(triphenylphosphine)palladium(H)chloride was added under nitrogen, and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the mixture was evaporated and the residue purified by column chromatography over SiC>2 and radially eluted with EtOAc:hexane to give the desired product (0.61 g, 1.47 mmol, 56%).

Omsetning av den sistnevnte forbindelsen (0,61 g, 1,47 mmol) og bortribromid (IM i diklormetan, 4,5 ml, 4,5 mmol) ifølge eksempel 50, prosedyre C ga tittelforbindelsen (0,084 g, 0,26 mmol, 18%). Reaction of the latter compound (0.61 g, 1.47 mmol) and boron tribromide (1 M in dichloromethane, 4.5 mL, 4.5 mmol) according to Example 50, procedure C gave the title compound (0.084 g, 0.26 mmol, 18%).

'H NMR (DMSO-d6, 300 MHz) 8 9,61 (s, 1H), 9,42 (s, 1H), 8,41 (s, 1H), 8,18 (s, 1H), 1 H NMR (DMSO-d 6 , 300 MHz) δ 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H),

7,65 (s, 1H), 7,48 (dd, 1H, J=8,0 og 0,9Hz), 6,76 (d, 1H, J=8,lHz), 2,03-1,96 (m, 2H) og 1,78-1,42 (m, 6H). 7.65 (s, 1H), 7.48 (dd, 1H, J=8.0 and 0.9Hz), 6.76 (d, 1H, J=8.1Hz), 2.03-1.96 (m, 2H) and 1.78-1.42 (m, 6H).

MS (ESI(+ ve)) m/z 324 (M+H)<+>. MS (ESI(+ve)) m/z 324 (M+H)<+>.

EKSEMPEL 56 EXAMPLE 56

5-( spiro [ cvkloheksan- 1, 3 *- [ 3H1 indoll - 2 * ( hvdroksyimino)- 5*- vD- l H- pyrrol- 1 -metvl-2- karbonitril 5-( spiro [ cvchlorohexane- 1, 3 *- [ 3H1 indoll - 2 * ( hvdroxyimino)- 5*- vD- 1 H- pyrrole- 1 - metvl-2- carbonitrile

2- ( 5' rspirofcvkloheksan- 1. 3 '- fSHlindoll- d • HVon- 2,( Q- benzvloksim) l 1- lH- pvrrol- 1 - karboksylsyre, tert- butylester 2- ( 5' rspirofcvclohexane- 1. 3 '- fSHlindoll- d • HVon- 2,( Q- benzvloxime) l 1- lH- pvrrole- 1 - carboxylic acid, tert- butyl ester

En oppløsning av 5'-bromspiro{cykloheksan-l,3'-[3H]indol}-2'(lH)-on 2'(0-benzyloksim) (7,4 g, 19,17 mmol) og tetrakis(trifenylfosfin)palladium(0) (2,5 g, 2,00 mmol) i 100 ml DME ble omrørt under nitrogen i 15 minutter. Til oppløsningen ble det satt 1-tert-butoksykarbonylpyrrolborsyre (5,5 g, 26 mmol) og 50 ml IM natriumkarbonat. Blandingen ble oppvarmet til 80°C i 6 timer og tillatt avkjøling. Reaksjonsblandingen ble heilt i vann og ekstrahert med 3 x 100 ml etylacetat. De organiske sjikt ble kombinert og tørket over magnesiumsulfat. Oppløsningen ble filtrert, konsentrert under vakuum og resten renset ved flashkromatografi på silikagel med heksan:etylacetat 4,5:1 for å gi produktet (7,7 g, 88%) som et hvitt faststoff. A solution of 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(1H)-one 2'(O-benzyloxime) (7.4 g, 19.17 mmol) and tetrakis(triphenylphosphine )palladium(0) (2.5 g, 2.00 mmol) in 100 mL DME was stirred under nitrogen for 15 min. To the solution was added 1-tert-butoxycarbonylpyrroleboronic acid (5.5 g, 26 mmol) and 50 ml of 1M sodium carbonate. The mixture was heated to 80°C for 6 hours and allowed to cool. The reaction mixture was poured into water and extracted with 3 x 100 ml of ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo and the residue purified by flash chromatography on silica gel with hexane:ethyl acetate 4.5:1 to give the product (7.7 g, 88%) as a white solid.

'H NMR (DMSO-de, 300 MHz) 8 1,28 (s, 9H), 1,55-1,66 (m, 8H), 1,83-1,98 (m, 2H), 1 H NMR (DMSO-de, 300 MHz) δ 1.28 (s, 9H), 1.55-1.66 (m, 8H), 1.83-1.98 (m, 2H),

4,99 (s, 2H), 6,12-6,14 (m, 1H), 6,22 (t, 1H, J=3,26Hz), 6,76 (d, 1H, J=7,9Hz), 7,02 (dd, 1H, J=7,98,1,4Hz), 7,19 (s, 1H), 7,27-7,31 (m, 2H), 7,35 (t, 1H, J=6,8Hz), 7,43 (d, 1H, J=8Hx), 9,55 (s, 1H). 5 '-( 1 - tetr- butoksvkarbonvl- lH- pvrrol- 2- vnspirorcvkloheksan- 1. 3 '- r3H1indoll- 2'-( 1 * H) on- 2'-( Q- benzvloksimM '- karboksylsyre. tert- butylester. 4.99 (s, 2H), 6.12-6.14 (m, 1H), 6.22 (t, 1H, J=3.26Hz), 6.76 (d, 1H, J=7.9Hz ), 7.02 (dd, 1H, J=7.98,1.4Hz), 7.19 (s, 1H), 7.27-7.31 (m, 2H), 7.35 (t, 1H , J=6.8Hz), 7.43 (d, 1H, J=8Hx), 9.55 (s, 1H). 5 '-( 1 - tetr- butoxxcarbonvl- 1H- pvrrol- 2- vnspirorcvclohexane- 1. 3 '- r3H1indoll- 2'-( 1 * H)one- 2'-( Q- benzvloximM '- carboxylic acid. tert- butyl ester.

Til en oppløsning av 2-{5'[spiro[cykloheksan-l,3'-[3H]indol]-(l'H)-on-2'(0-benzyloksim)]}-lH-pyrrol-l -karboksylsyre, tert-butylester (7,7 g, 16,38 mmol) i 100 ml vannfri THF ble det satt natriumhydrid (0,665 g, 17 mmol). Efter at hydrogenoppløs-ningen ga seg ble di-tert-butyldikarbonat (10,9 g, 50 mmol) i 0,20 g DMAP tilsatt og reaksjonsblandingen omrørt ved 65°C i 18 timer. Reaksjonsblandingen ble heilt i vann og ekstrahert med etylacetat. De organiske sjikt ble kombinert og tørket over magnesiumsulfat. Oppløsningen ble filtrert, konsentrert under vakuum for å gi produktet (9,0 g, 15,76 mmol) som ble benyttet direkte i det neste trinn. To a solution of 2-{5'[spiro[cyclohexane-1,3'-[3H]indole]-(1'H)-one-2'(0-benzyloxime)]}-1H-pyrrole-1-carboxylic acid , tert-butyl ester (7.7 g, 16.38 mmol) in 100 ml of anhydrous THF was added sodium hydride (0.665 g, 17 mmol). After the hydrogen solution gave way, di-tert-butyl dicarbonate (10.9 g, 50 mmol) in 0.20 g of DMAP was added and the reaction mixture was stirred at 65°C for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The solution was filtered, concentrated under vacuum to give the product (9.0 g, 15.76 mmol) which was used directly in the next step.

Til en oppløsning av 5'-(l-tert-butoksykarbonyl-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-(l'H)on-2'-(0-benzyloksim)-l'-karboksylsyre, tert-butylester (9,0 g, 15,76 mmol) i 75 ml vannfri THF ble det ved -78°C satt klorsulfonylisocyanat (1,55 ml, 17,54 mmol). Efter 90 minutter ble DMF (21 ml, 275 mmol) tilsatt og reaksjonsblandingen tillatt oppvarming til romtemperatur. Reaksjonsblandingen ble heilt i 200 ml vann og ekstrahert med 2x100 ml etylacetat. De organiske sjikt ble kombinert og tørket over magnesiumsulfat, filtrert og konsentrert under vakuum. Rensing ved flashkolonnekromatografi over silikagel og eluering med 10% etylacetat:heksan ga 5'-(5-cyano-l-tert-butoksykarbonyl-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'(rH)on-2'(0-benzyloksim)-l '-karboksylsyre, tert-butylester (7,6 g, 82%) som et hvitt pulver. To a solution of 5'-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'-(1'H)one-2'- (0-Benzyl oxime)-1'-carboxylic acid, tert-butyl ester (9.0 g, 15.76 mmol) in 75 ml of anhydrous THF was added at -78°C chlorosulfonyl isocyanate (1.55 ml, 17.54 mmol) . After 90 minutes, DMF (21 mL, 275 mmol) was added and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into 200 ml of water and extracted with 2x100 ml of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by flash column chromatography over silica gel and elution with 10% ethyl acetate:hexane gave 5'-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole] -2'(rH)one-2'(O-benzyloxime)-1'-carboxylic acid, tert-butyl ester (7.6 g, 82%) as a white powder.

<*>H NMR (DMSO-d6, 300 MHz) 8 1,30 (s, 9H), 1,38 (s, 9H), 1,58-1,83 (m, 8H), 1,72-1,73 (m, 2H), 5,0 (s, 2H), 6,44-6,45 (d, 1H, J=3,76), 7,25-1,46 (m, 10H). <*>H NMR (DMSO-d6, 300 MHz) δ 1.30 (s, 9H), 1.38 (s, 9H), 1.58-1.83 (m, 8H), 1.72-1 .73 (m, 2H), 5.0 (s, 2H), 6.44-6.45 (d, 1H, J=3.76), 7.25-1.46 (m, 10H).

S^ rS- cvano- lH- pyrrol^- vnspirorcvkloheksan- l. S^ rSHIindoll^ Triffon^^ CO-benzyloksimVl '- karboksylsyre. tert- butylester S^ rS- cvano- lH- pyrrole^- vnspirorcvclohexane- l. S^ rSHIindoll^ Triffon^^ CO-benzyloximVl '- carboxylic acid. tert-butyl ester

Til en oppløsning av 5'-(5-cyano-l-tert-butoksykarbonyl-lH-pyrrol-2-yl)spiro[cykloheksan-l ,3 '-[3H]indol]-2'(l 'H)on-2'(0-benzyloksim)-l'-karboksylsyre, tert-butylester (7,6 g, 3,25 g, 48 mmol) i 30 ml vannfri THF ble det satt en oppløsning av natriumetoksyd i 120 ml etanol. Reaksjonsblandingen ble oppvarmet til 80°C og om-rørt over natten. Blandingen ble avkjølt til romtemperatur og konsentrert under vakuum. Resten ble oppløst i etylacetat og vasket med vann, saltoppløsning og tørket over magnesiumsulfat. Oppløsningsmidlet ble fordampet under vakuum for å gi produktet (6,1 g, 95%). To a solution of 5'-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)one- 2'(O-Benzyloxime)-1'-carboxylic acid, tert-butyl ester (7.6 g, 3.25 g, 48 mmol) in 30 ml of anhydrous THF was added a solution of sodium ethoxide in 120 ml of ethanol. The reaction mixture was heated to 80°C and stirred overnight. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with water, saline and dried over magnesium sulfate. The solvent was evaporated under vacuum to give the product (6.1 g, 95%).

'H NMR (DMSO, 500 MHz) 8 1,38 (s, 9H), 1,63-1,74 (m, 8H), 1,88-1,97 (m, 2H), 5,08 1 H NMR (DMSO, 500 MHz) δ 1.38 (s, 9H), 1.63-1.74 (m, 8H), 1.88-1.97 (m, 2H), 5.08

(s, 2H), 6,69-6,7 (d, 1H, J=0,8Hz), 6,98-6,99 (d, 1H, J=0,7Hz), 7,29-7,37 (m, 1H), 7,35 (m, 2H), 7,42 (m, 3H), 7,63 (dd, 1H, J=l,8, 0,3Hz), 7,76 (d, 1H, J=0,4Hz). (s, 2H), 6.69-6.7 (d, 1H, J=0.8Hz), 6.98-6.99 (d, 1H, J=0.7Hz), 7.29-7, 37 (m, 1H), 7.35 (m, 2H), 7.42 (m, 3H), 7.63 (dd, 1H, J=1.8, 0.3Hz), 7.76 (d, 1H, J=0.4Hz).

5 '-( 5- cvano- 1 - metyl- lH- pvrrol- 2- vnspiro fe vkloheksan- 1. 3 '- r3H1indoll- 2'-( O-benzyloksiml- l '- karboksylsyre. tert- butylester 5 '-( 5- cvano- 1 - methyl- 1H- pyrrole- 2- vnspirofe vclohexane- 1. 3 '- r3H1indoll- 2'-( O-benzyloximl- 1 '- carboxylic acid. tert- butyl ester

Til5"-(5-cyano-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)on-2'-(0-benzyloksim)-1'-karboksylsyre, tert-butylester (6,1 g, 12,29 mmol) i 75 ml DMF ble det tilsatt kaliumkarbonat (6,5 g, 47 mmol) og Mel (1 ml, 15,4 mmol), hvoretter reaksjonsblandingen ble omrørt ved romtemperatur i 2,5 time. Reaksjonsblandingen ble heilt i vann og ekstrahert med etylacetat. Det organiske sjikt ble vasket med saltoppløsning og oppløsningsmidlet konsentrert under vakuum for å gi det ønskede produkt (6,1 g, 12,29 mmol) som ble bragt videre til det neste trinn uten<y>tterligere rensing. •h NMR (DMSO, 300 MHz) 8 1,38 (s, 9H), 1,62-1,98 (m, 10H), 3,71 (s, 3H), 5,08 (s, 2H), 6,34 (d, 1H, J=4,l), 7,03 (d, 1H, J=3,99), 7,30-7,53 (m, 8H). Til5"-(5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)one-2'-(O-benzyloxime)-1 '-carboxylic acid, tert-butyl ester (6.1 g, 12.29 mmol) in 75 mL of DMF was added potassium carbonate (6.5 g, 47 mmol) and Mel (1 mL, 15.4 mmol), after which the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and the solvent concentrated under vacuum to give the desired product (6.1 g, 12.29 mmol) which was carried on to the next step without further purification.•h NMR (DMSO, 300 MHz) δ 1.38 (s, 9H), 1.62-1.98 (m, 10H), 3.71 (s , 3H), 5.08 (s, 2H), 6.34 (d, 1H, J=4.1), 7.03 (d, 1H, J=3.99), 7.30-7.53 (m, 8H).

S- IS^- spirorcvkloheksan- lJ^ rSHlindoll- a^ HVon^^- ør- benzvloksimll- lH- pvrrol- l-metyl- 2- karbonitril S- IS^- spirorcvchlorohexane- lJ^ rSHlindoll- a^ HVon^^- ør- benzvloximll- lH- pvrrol- 1-methyl- 2- carbonitrile

5-'(5-cyano-l-metyl-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-(0-benzyloksim)-l '-karboksylsyre, tert-butylester (6,1 g, 12,29 mmol) ble oppløst i 5 ml dioksan og 4M HC1 i 10 ml dioksan ble tilsatt og reaksjonsblandingen oppvarmet til 45°C i 3,5 timer. Blandingen ble forsiktig nøytralisert med mettet natriumbikarbonat. Reaksjonsblandingen ble heilt i vann og ekstrahert med etylacetat. Det organiske sjikt ble vasket med saltoppløsning og tørket over magnesiumsulfat. Oppløsningsmidlet ble fordampet under vakuum. Rensing ved kolonnekromatografi over silikagel med 5% etylacetat:heksan ga produktet (4,36 g, 94%). 5-'(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'-(O-benzyloxime)-1'-carboxylic acid, tert -butyl ester (6.1 g, 12.29 mmol) was dissolved in 5 mL dioxane and 4M HCl in 10 mL dioxane was added and the reaction heated to 45°C for 3.5 hours. The mixture was carefully neutralized with saturated sodium bicarbonate. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under vacuum. Purification by column chromatography over silica gel with 5% ethyl acetate:hexane gave the product (4.36 g, 94%).

<l>H NMR (DMSO-d6,300 MHz) 6 1,57-1,7 (m, 8H), 1,9-2,05 (m, 2H), 3,68 (s, 3H), 5,00 <1>H NMR (DMSO-d6,300 MHz) 6 1.57-1.7 (m, 8H), 1.9-2.05 (m, 2H), 3.68 (s, 3H), 5 ,00

(s, 2H), 6,25 (d, 1H, J=3,92), 6,85 (d, 1H, J=8,03), 7,00 (d, 1H, J=4,08), 7,2-7,44 (m, 7H), 9,7 (s, 1H). (s, 2H), 6.25 (d, 1H, J=3.92), 6.85 (d, 1H, J=8.03), 7.00 (d, 1H, J=4.08) , 7.2-7.44 (m, 7H), 9.7 (s, 1H).

Til 5-{5'-spiro[cykloheksan-l,3'-[3H]indol]-(l'H)-on-2'-(0-benzyloksim)}-m 1-metyl-karbonitril (4,36 g, 10,6 mmol) i 50 ml metylenklorid ble det satt 35 ml IM bortribromid i metylenklorid ved -78°C. Reaksjonsblandingen ble tillatt oppvarming til romtemperatur. Efter 4 timer ble reaksjonsblandingen quenchet med 10 ml mettet natriumbikarbonat. Det organiske sjikt ble samlet og det vandige sjikt ekstrahert med 2x100 ml etylacetat, de organiske sjikt kombinert, vasket med saltoppløsning, tørket over magnesiumsulfat og oppløsningsmidlet fordampet under vakuum. Resten ble renset ved flashkromatografi over silikagel med heksan:etylacetat 7:3 for å gi tittelforbindelse^ 1,3 5 g, 40%) som et hvitt faststoff. To 5-{5'-spiro[cyclohexane-1,3'-[3H]indole]-(1'H)-one-2'-(0-benzyloxime)}-m 1-methylcarbonitrile (4.36 g, 10.6 mmol) in 50 ml of methylene chloride, 35 ml of IM boron tribromide in methylene chloride were added at -78°C. The reaction mixture was allowed to warm to room temperature. After 4 hours, the reaction mixture was quenched with 10 ml of saturated sodium bicarbonate. The organic layer was collected and the aqueous layer extracted with 2x100 ml ethyl acetate, the organic layers combined, washed with brine, dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash chromatography over silica gel with hexane:ethyl acetate 7:3 to give the title compound (1.35 g, 40%) as a white solid.

'H NMR (DMSO-de, 300 MHz) 8 1,58-1,71 (m, 8H), 1,99-2,00 (m, 2H), 3,69 (s, 3H), 1 H NMR (DMSO-de, 300 MHz) δ 1.58-1.71 (m, 8H), 1.99-2.00 (m, 2H), 3.69 (s, 3H),

6,24 (d, 1H, J=4,07Hz), 6,8 (d, 1H, J=8,05Hz), 6,99 (d, 1H, J=4,01Hz), 7,20 (dd, 1H, J=8,04, 1,57Hz), 7,36 (d, 1H, J=l,12Hz), 9,48 (s, 1H), 9,62 (s, 1H). 6.24 (d, 1H, J=4.07Hz), 6.8 (d, 1H, J=8.05Hz), 6.99 (d, 1H, J=4.01Hz), 7.20 (dd , 1H, J=8.04, 1.57Hz), 7.36 (d, 1H, J=1.12Hz), 9.48 (s, 1H), 9.62 (s, 1H).

EKSEMPEL 57 EXAMPLE 57

5- fspiro[ cvkloheksan- L3,- f3Hlindoll- 2,-( hvdroksviminoV5,- vn- lH- pvrrol- 2-karbonitril 5 -( spiro [ cykloheksan- 1, 3' -[ 3] - indoll - 2 * ( 1 HV( O- benzvloksim)')- 1 H- p vrrol- 2- karbonitril Forbindelsen ble fremstilt fra 5'-(5-cyano-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)on-2'-(0-benzyloksim)-l'-karboksylsyre, tert-butylester (0,395 g, 0,796 mmol) oppløst i 2 ml THF og 10 ml 4M HC1 dioksan:vann ved å følge prosedyren som ble benyttet for å fremstille 5-{5'-spiro[cykloheksan-l,3'-[3H]indol]-(l'H)-on-2'-(0-benzyloksim)}-lH-pyrrol-l-metyl-2-karbonitril idet det ønskede produkt ble oppnådd (0,220 g, 0,745 mmol, 95%). 5- fspiro[ cvclohexane- L3,- f3Hlindoll- 2,-( hvdroxviminoV5,- vn- lH- pvrrole- 2-carbonitrile 5 -( spiro [ cyclohexane- 1, 3' -[ 3] - indoll - 2 * ( 1 HV (O-benzvoloxim)')-1H-p pyrrole-2-carbonitrile The compound was prepared from 5'-(5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole ]-2'(1'H)one-2'-(0-benzyloxime)-1'-carboxylic acid, tert -butyl ester (0.395 g, 0.796 mmol) dissolved in 2 mL THF and 10 mL 4M HCl dioxane:water by following the procedure used to prepare 5-{5'-spiro[cyclohexane-1,3'-[3H]indole]-(1'H)-one-2'-(0-benzyloxime)}-1H-pyrrole -1-methyl-2-carbonitrile to give the desired product (0.220 g, 0.745 mmol, 95%).

<*>H NMR (DMSO-d6, 500 MHz) 8 1,44-1,50 (m, 1H), 1,61-1,70 (m, 7H), 1,94-1,99 (m, 2H), 5,0 (s, 2H), 6,55 (d, 1H, J=4Hz), 6,79 (d, 1H, J=8,0Hz), 6,95 (d, 1H, J=4Hz), 7,27-7,31 (m, 1H), 7,34-7,37 (m, 2H), 7,42-7,43 (m, 2H), 7,47 (dd, 1H, J=8,0, 1,4Hz), 7,65 (d, 1H, J=l,5Hz), 9,65 (s, 1H), 12,4 (s, 1H). <*>H NMR (DMSO-d6, 500 MHz) δ 1.44-1.50 (m, 1H), 1.61-1.70 (m, 7H), 1.94-1.99 (m, 2H), 5.0 (s, 2H), 6.55 (d, 1H, J=4Hz), 6.79 (d, 1H, J=8.0Hz), 6.95 (d, 1H, J= 4Hz), 7.27-7.31 (m, 1H), 7.34-7.37 (m, 2H), 7.42-7.43 (m, 2H), 7.47 (dd, 1H, J=8.0, 1.4Hz), 7.65 (d, 1H, J=1.5Hz), 9.65 (s, 1H), 12.4 (s, 1H).

Tittelforbindelsen ble fremstilt fra 5-(spiro[cykloheksan-l,3'-[3]indol]-2'(lH)-(0-benzyloksim))-lH-pyrrol-2-karbonitril (0,325 g, 0,82 mmol) og 6 ml IM bortribromid i metylenklorid ved å følge prosedyren for fremstilling av 5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(hydroksyimino)-5'-yl)-lH-pyrrol-l-metyl-2-karbonitril, for å oppnå produktet som et hvitaktig faststoff (0,110 g, 0,326 mmol, 44%). The title compound was prepared from 5-(spiro[cyclohexane-1,3'-[3]indole]-2'(1H)-(O-benzyloxime))-1H-pyrrole-2-carbonitrile (0.325 g, 0.82 mmol ) and 6 ml 1M boron tribromide in methylene chloride by following the procedure for the preparation of 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-1H-pyrrol- 1-methyl-2-carbonitrile, to obtain the product as an off-white solid (0.110 g, 0.326 mmol, 44%).

'H NMR (DMSO-d6, 500 MHz) 6 1,46-1,5 (m, 1H), 1,62-1,71 (m, 7H), 1,95-2,05 (m, 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.46-1.5 (m, 1H), 1.62-1.71 (m, 7H), 1.95-2.05 (m,

2H), 6,55 (d, 1H, J=4,0Hz), 6,75 (d, 1H, J=8,0Hz), 6,94 (d, 1H, J=3,47Hz), 7,45 (dd, 1H, J=8,l, 1,73Hz), 7,63 (d, 1H, J=l,73), 9,42 (s, 1H), 9,59 (s, 1H), 12,39 (s, 1H). 2H), 6.55 (d, 1H, J=4.0Hz), 6.75 (d, 1H, J=8.0Hz), 6.94 (d, 1H, J=3.47Hz), 7, 45 (dd, 1H, J=8.1, 1.73Hz), 7.63 (d, 1H, J=1.73), 9.42 (s, 1H), 9.59 (s, 1H), 12.39 (p, 1H).

EKSEMPEL 58 EXAMPLE 58

4-( spirorcvkloheksan- l, 3*- f3HlindoH- 2'( acetoksvimino)- 5*- vl)- 2- tiofenkarbonitril Til en oppløsning av 4-(spiro[cykloheksan-l,3'-[3H]indol]-2'(hydroksyimino)-5'-yl)-2-tiofenkarbonitril (2,21 g, 6,83 mmol) og 1 ml eddiksyreanhydrid i 30 ml diklormetan:pyridin 9:1 ble det satt 250 mg 4-dimetylaminopyridin ved romtemperatur. Efter 3 4-(spirocyclohexane-1,3*-f3HlindoH-2'(acetoxvimino)-5*-vl)-2-thiophenecarbonitrile To a solution of 4-(spiro[cyclohexane-1,3'-[3H]indole]-2 (hydroxyimino)-5'-yl)-2-thiophenecarbonitrile (2.21 g, 6.83 mmol) and 1 ml of acetic anhydride in 30 ml of dichloromethane:pyridine 9:1, 250 mg of 4-dimethylaminopyridine was added at room temperature. After 3

timer ble blandingen fortynnet med diklormetan, vasket med vann, fortynnet saltsyre og vann, tørket over MgSC>4 og fordampet. Resten ble renset ved kolonnekromatografi med gradienteluering EtOAc:heksan for å gi tittelforbindelsen (0,84 g, 2,29 mmol, 33%) som et hvitt faststoff. hours, the mixture was diluted with dichloromethane, washed with water, dilute hydrochloric acid and water, dried over MgSO4 and evaporated. The residue was purified by column chromatography eluting with EtOAc:hexane gradient to give the title compound (0.84 g, 2.29 mmol, 33%) as a white solid.

MS (ESI(+ve)) m/z 366 [M+H]<+>. MS (ESI(+ve)) m/z 366 [M+H]<+>.

EKSEMPEL 59 EXAMPLE 59

3- fluor- N'- hvdroksv- 5- f2'-( hvdroksvamino) spirofcvkloheksan- l, 3*-[ 3H1indoll- 5'-<y>llbenzenkarboksimidamid 3-fluoro-N'-hydroxy-5-f2'-(hydroxyamino)spirochlorohexane-1,3*-[3H1indol-5'-<y>llbenzenecarboximidamide

5'-( 3- cvano- 5- fluorfenvl)- 2-( metvltio) spiro|" cvkloheksan- 1, 3 *-|" 3H1indol] 5'-(3-Cvano-5-fluorophenyl)-2-(methylthio)spiro|"cyclohexane-1,3*-|" 3H1indole]

Forbindelsen ble fremstilt fra 3-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-5-fluorbenzonitril (0,451 g, 1,34 mmol) i henhold til prosedyren som beskrevet i eksempel 43 for å gi det ønskede produkt (0,316 g, 0,90 mmol, 67%). The compound was prepared from 3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-5-fluorobenzonitrile (0.451 g, 1.34 mmol) according to to the procedure as described in Example 43 to give the desired product (0.316 g, 0.90 mmol, 67%).

'H NMR (DMSO-de, 300 MHz) 6 7,74 (d, 1H, J=l,7Hz), 7,68 (t, 1H, J=l,4Hz), 7,58 (d, 1 H NMR (DMSO-de, 300 MHz) δ 7.74 (d, 1H, J=1.7Hz), 7.68 (t, 1H, J=1.4Hz), 7.58 (d,

1H, J=8,0Hz), 7,54 (t, 1H, J=2,3Hz), 7,50 (dd, 1H, J=8,0 og 1,9Hz), 1H, J=8.0Hz), 7.54 (t, 1H, J=2.3Hz), 7.50 (dd, 1H, J=8.0 and 1.9Hz),

7,33-7,29 (m, 1H), 2,67 (s, 3H), 2,04-1,78 (m, 7H) og 1,58-1,50 (m, 3H). MS (ESI(+ve)) m/z 351 (M+H)<+>. 7.33-7.29 (m, 1H), 2.67 (s, 3H), 2.04-1.78 (m, 7H) and 1.58-1.50 (m, 3H). MS (ESI(+ve)) m/z 351 (M+H)<+>.

Til en oppløsning av den sistnevnte forbindelse (0,30 g, 0,88 mmol) i 10 ml DMSO ble det satt 1 ml 50% vandig oppløsning av hydroksylamin og reaksjonsblandingen oppvarmet til 120°C. Efter 1 time ble blandingen avkjølt, fordelt mellom mettet vandig ammoniumklorid og etylacetat. Det organiske sjikt ble vasket med vann, saltoppløsning, tørket over MgS04og fordampet. Resten ble renset ved kolonnekromatografi over Si02, med 5% MeOH i diklormetan for å gi tittelforbindelsen (0,079 g, 0,23 mmol, 26%) som et hvitt skum. To a solution of the latter compound (0.30 g, 0.88 mmol) in 10 ml of DMSO was added 1 ml of a 50% aqueous solution of hydroxylamine and the reaction mixture was heated to 120°C. After 1 hour, the mixture was cooled, partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with water, brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 , with 5% MeOH in dichloromethane to give the title compound (0.079 g, 0.23 mmol, 26%) as a white foam.

<*>H NMR (DMSO-dfi, 300 MHz) 8 9,79 (s, 1H), 9,61 (s, 1H), 9,42 (s, 1H), 7,73 (s, 1H), 7,61 (d, 1H, J=l,3Hz), 7,46 (dd, 1H, J=8,3 og 1,5Hz), 7,34 (d, 1H, J=10Hz), 6,81 (d, 1H, J=8,0Hz), 6,01 (s, 2H), 2,11-2,02 (m, 2H) og 1,81-1,56 (m, 8H). <*>H NMR (DMSO-dfi, 300 MHz) δ 9.79 (s, 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.73 (s, 1H), 7.61 (d, 1H, J=1.3Hz), 7.46 (dd, 1H, J=8.3 and 1.5Hz), 7.34 (d, 1H, J=10Hz), 6.81 (d, 1H, J=8.0Hz), 6.01 (s, 2H), 2.11-2.02 (m, 2H) and 1.81-1.56 (m, 8H).

MS (ESI(+ve)) m/z 369 (M+H)<+>. MS (ESI(+ve)) m/z 369 (M+H)<+>.

EKSEMPEL 60 EXAMPLE 60

N*- hvdroksv- 5-( spiro[ cvkloheksan- l, 3'-[ 3Hlindon- 2'( hvdroksyimino)- 5'- vl)- 4-metvl- 2- tiofenkarboksimidamid N*-hydroxy-5-(spiro[cyclohexane-1,3'-[3Hlindone-2'(hydroxyimino)-5'-vl)-4-methyl-2-thiophenecarboximidamide

4- metvl- 5-( spiro' cvkloheksan- 1, 3' [ 3H] indoll- 2'-( metvltio>5 '- vl)- 2- tiofenkarbonitril Til kalium tert-butoksyd (0,32 g, 2,6 mmol) i THF ble det satt 5-(l',2'-dihydro-2'-tioksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-4-metyl-2-tiofenkarbonitril (0,84 g, 2,5 mmol). Efter 15 minutter ble metyljodid (0,50 g, 3,48 mmol) tilsatt. Efter 3 timer ble reaksjonsblandingen heilt i mettet ammoniumklorid og ekstrahert med etylacetat. De organiske sjikt ble kombinert og tørket over magnesiumsulfat. Oppløsningen ble filtrert, konsentrert under vakuum og resten renset ved flashkromatografi over silikagel med heksan:etylacetat 4:1 for å gi det ønskede produkt (0,530 g, 85%). 4- methyl-5-(spiro'cyclohexane-1,3'[3H]indol-2'-(methylthio>5'-vl)-2-thiophenecarbonitrile To potassium tert-butoxide (0.32 g, 2.6 mmol ) in THF was added 5-(1',2'-dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-4-methyl-2-thiophenecarbonitrile (0 .84 g, 2.5 mmol). After 15 minutes, methyl iodide (0.50 g, 3.48 mmol) was added. After 3 hours, the reaction mixture was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate The solution was filtered, concentrated under vacuum and the residue purified by flash chromatography over silica gel with hexane:ethyl acetate 4:1 to give the desired product (0.530 g, 85%).

<*>H NMR (DMSO-d6,300 MHz) 8 1,48 (m, 3H), 1,70 (m, 2H), 1,81 (m, 5H), 2,32 (s, 3H), 2,62 (s, 3H), 7,48 (dd, 1H, J=7,87Hz, 1,46Hz), 7,5 (d, 1H, J=8,05Hz), 7,77 (d, 1H, J=l,46Hz), 7,88 (s, 1H). <*>H NMR (DMSO-d6,300 MHz) δ 1.48 (m, 3H), 1.70 (m, 2H), 1.81 (m, 5H), 2.32 (s, 3H), 2.62 (s, 3H), 7.48 (dd, 1H, J=7.87Hz, 1.46Hz), 7.5 (d, 1H, J=8.05Hz), 7.77 (d, 1H , J=1.46Hz), 7.88 (s, 1H).

Til 4-metyl-5-(spiro[cykloheksan-1,3 '-[3H]indol]-2'-(metyltio)-5 '-yl]-2-tiofenkarbonitril (0,450 g, 1,3 mmol) i 1 ml DMSO ble det satt 2 ml 50% hydroksyl-aminhydrokloirdoppløsning i vann og det hele oppvarmet til 100°C i 2,5 timer. Vann ble tilsatt inntil oppløsningen ble lett turbid og derefter ble blanding tillatt avkjøling til romtemperatur. Det hvite faststoff ble filtrert og samlet og oppløst i etylacetat og tørket over magnesiumsulfat. Oppløsningen ble filtrert, konsentrert under vakuum for å gi 0,320 g, 69%. To 4-methyl-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(methylthio)-5'-yl]-2-thiophenecarbonitrile (0.450 g, 1.3 mmol) in 1 ml of DMSO was added 2 ml of 50% hydroxylamine hydrochloride solution in water and the whole was heated to 100°C for 2.5 hours. Water was added until the solution became slightly turbid and then the mixture was allowed to cool to room temperature. The white solid was filtered and collected and dissolved in ethyl acetate and dried over magnesium sulfate.The solution was filtered, concentrated under vacuum to give 0.320 g, 69%.

'H NMR (DMSO-d6, 500 MHz) 5 1,4-1,74 (m, 8H), 1,94-2,4, (m, 2H), 2,54 (s, 3H), 5,8 1 H NMR (DMSO-d 6 , 500 MHz) δ 1.4-1.74 (m, 8H), 1.94-2.4, (m, 2H), 2.54 (s, 3H), 5, 8

(s, 1H), 6,79 (d, 1H, J=8,0), 7,16 (dd, 1H, J=8,12,1,83), 7,39 (m, 2H), 9,42 (s, 1H), 9,56 (s, 1H), 9,58 (s, 1H). (s, 1H), 6.79 (d, 1H, J=8.0), 7.16 (dd, 1H, J=8.12,1.83), 7.39 (m, 2H), 9 .42 (p, 1H), 9.56 (p, 1H), 9.58 (p, 1H).

EKSEMPEL 61 EXAMPLE 61

N'- hvdroksv- 4'-( spiro[ cvkloheksan- l, 3*-[ 3Hlindoll- 2'-( livdroksvimipo)- 5'- vl- 2-tiofenkarboksimidamid N'-hydroxiv-4'-(spiro[cyclohexane-1,3*-[ 3Hlindoll-2'-(livdroxvimipo)-5'-vl-2-thiophenecarboximidamide

4-(spiro[cykloheksan-1,3 '-[3H]indol]-2'-(metyltio)-5 '-yl]-2-tiofenkarbonitril (0,077 g, 0,237 mmol) ble omsatt med en 50% oppløsning av lml hydroksylamin ved å følge prosedyren i eksempel 60 for å gi tittelforbindelsen (0,016 g, 0,044 mmol, 20%). 4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(methylthio)-5'-yl]-2-thiophenecarbonitrile (0.077 g, 0.237 mmol) was reacted with a 50% solution of lml hydroxylamine following the procedure of Example 60 to give the title compound (0.016 g, 0.044 mmol, 20%).

MS (ESI, (+ve)) m/z 357 [M+H]<+>. MS (ESI, (+ve)) m/z 357 [M+H]<+>.

EKSEMPEL 62 EXAMPLE 62

N"- hvdroksv- 5-( spirofcvkloheksan- l, 3*- f3Hlindoll- 2"-( hvdroksvimino)- 5*- vl)- 2-tiofenkarboksimidamid N"- hydroxy- 5-(spirochlorohexane-1,3*- 3Hlindoll- 2"-( hydroxyimino)- 5*- vl)- 2-thiophenecarboximidamide

Tittelforbindelsen ble fremstilt fra 5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(metyltio)-5'-yl]-2-tiofenkarbonitril (0,500 g, 1,5 mmol) og en 50% oppløsning av et overskudd på 2 ml hydroksylamin, ved å følge prosedyren i eksempel 60 for å gi produktet (0,200 g, 0,56 mmol, 56%). The title compound was prepared from 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(methylthio)-5'-yl]-2-thiophenecarbonitrile (0.500 g, 1.5 mmol) and a 50 % solution of an excess of 2 mL of hydroxylamine, following the procedure of Example 60 to give the product (0.200 g, 0.56 mmol, 56%).

'H NMR (DMSO-de, 500 MHz) 8 1,45-1,75 (m, 8H), 1,97-2,06 (m, 2H), 5,89 (s, 1H), 1 H NMR (DMSO-de, 500 MHz) δ 1.45-1.75 (m, 8H), 1.97-2.06 (m, 2H), 5.89 (s, 1H),

6,74 (d, 1H, J=8Hz), 7,3 (d, 1H, J=3,9Hz), 7,34 (dd, 1H, J=8,06, 1,46Hz), 7,4 (d, 1H, J=8,0Hz), 7,5 (d, 1H, 1,95Hz), 9,44 (s, 1H), 9,58 (s, 1H), 9,6 (s, 1H). 6.74 (d, 1H, J=8Hz), 7.3 (d, 1H, J=3.9Hz), 7.34 (dd, 1H, J=8.06, 1.46Hz), 7.4 (d, 1H, J=8.0Hz), 7.5 (d, 1H, 1.95Hz), 9.44 (s, 1H), 9.58 (s, 1H), 9.6 (s, 1H ).

EKSEMPEL 63 EXAMPLE 63

5'-( 3- klorfenvnspirofcvkloheksan- l, 3*- r3Hlindoll- 2*- vliden- cyanamid 5*- f3- klorfenvl) spiro|" cvkloheksan- 1. 3'-[ 3Hlindol1- 2'- amin 5'-( 3- chlorophenvspirofccyclohexane- 1, 3*- r3Hlindol- 2*- vlidene- cyanamide 5*- f3- chlorophenvl) spiro|" cchlorohexane- 1. 3'-[ 3Hlindol1- 2'- amine

Til en turbid oppløsning av 5'-(3-klorfenyl)-N-hydroksyspiro[cykloheksan-l,3-[3H]indol-2-amin (0,500 g, 1,53 mmol) i 25 ml etanol ble det satt hydrazinhydrat (0,600 ml, 12,24 mmol). Oppløsningen ble oppvarmet til 55°C der 50% Raney-nikkel i vann ble satt til reaksjonsblandingen for å opprettholde en konstant gassutvikling. Efter 45 minutter ble den varme reaksjonsblanding filtrert gjennom en celitplugg og skylt med en rikelig mengde varm metanol. Filtratet ble konsentrert under vakuum for å gi 0,890 g av et opakt faststoff. Produktet ble renset ved flashsilikagelkromatografi og eluert med 2% -> 8% metanol metylenklorid med 0,1% ammoniumhydroksyd for å gi 0,310 g (65%) av det ønskede produkt som et hvitt faststoff med smeltepunkt 118-120°C. •h NMR (DMSO-de, 300 MHz) 5 1,31-1,46 (m, 2H), 1,70-1,93 (m, 8H), 7,0 (d, 1H), 7,1 (br, 2H, 2NH), 7,31-7,34 (dt, 1H, J=8Hz), 7,41-7,46 (t, 2H), 7,55-7,58 (d, 1H), 7,62 (s, 1H), 7,72 (s, 1H). Hydrazine hydrate ( 0.600 mL, 12.24 mmol). The solution was heated to 55°C where 50% Raney nickel in water was added to the reaction mixture to maintain constant gas evolution. After 45 minutes, the hot reaction mixture was filtered through a celite plug and rinsed with copious amounts of hot methanol. The filtrate was concentrated in vacuo to give 0.890 g of an opaque solid. The product was purified by flash silica gel chromatography eluting with 2% -> 8% methanol methylene chloride with 0.1% ammonium hydroxide to give 0.310 g (65%) of the desired product as a white solid mp 118-120°C. h NMR (DMSO-de, 300 MHz) δ 1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H), 7.1 (br, 2H, 2NH), 7.31-7.34 (dt, 1H, J=8Hz), 7.41-7.46 (t, 2H), 7.55-7.58 (d, 1H) , 7.62 (p, 1H), 7.72 (p, 1H).

MS (ECI(+ve)) m/z 311 (M+H)<+>. MS (ECI(+ve)) m/z 311 (M+H)<+>.

1 - tert- butoks vkarbonvl- 5' -( 3 - klorfen vDspiro [ cykloheksan- 1, 3' -|" 3H] indoll - 2' - amin Til en oppløsning av 5'-(3-klorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2'-amin (0,310 g, 0,96 mmol) i tørr metylenklorid ble det ved 0°C satt di-tert-butyldikarbonat (0,252 g, 1,15 mmol) og 4-dimetylaminopyridin (0,117 g, 0,96 mmol). Oppløsningen ble tillatt 1 - tert-butox vcarbonvl- 5' -( 3 - chlorophen vDspiro [cyclohexane- 1, 3' -|" 3H] indoll - 2' - amine To a solution of 5'-(3-chlorophenyl)spiro[cyclohexane-l ,3-[3H]indol]-2'-amine (0.310 g, 0.96 mmol) in dry methylene chloride was added at 0°C di-tert-butyldicarbonate (0.252 g, 1.15 mmol) and 4-dimethylaminopyridine (0.117 g, 0.96 mmol) The solution was allowed

oppvarming til romtemperatur og omrørt i 24 timer. Reaksjonsoppløsningen ble fortynnet med 50 ml vann og sjiktene ble separert. De organiske sjikt ble tørket over Na2S04, filtrert og konsentrert under vakuum for å gi 0,355 g av en gul olje. Produktet ble renset ved flashsilikagelkromatografi og eluert med 1% -> 3% metanolrmetylenklorid for å gi det ønskede produkt (0,081 g, 20%) som et hvitt faststoff. warming to room temperature and stirring for 24 hours. The reaction solution was diluted with 50 ml of water and the layers were separated. The organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 0.355 g of a yellow oil. The product was purified by flash silica gel chromatography eluting with 1% -> 3% methanol-methylene chloride to give the desired product (0.081 g, 20%) as a white solid.

lU NMR (DMSO-de, 300 MHz) 8 1,58 (m, 2H), 1,63 (s, 9H, Boe), 1,77-1,79 (m, 8H), 1U NMR (DMSO-de, 300 MHz) δ 1.58 (m, 2H), 1.63 (s, 9H, Boe), 1.77-1.79 (m, 8H),

7,42-7,48 (m, 2H), 7,64-7,68 (m, 3H), 7,70-7,80 (m, 2H), 9,72 (s, 1H, 7.42-7.48 (m, 2H), 7.64-7.68 (m, 3H), 7.70-7.80 (m, 2H), 9.72 (s, 1H,

NH). NH).

MS (ECI(ve)) m/z 411 (M+H)<+>. MS (ECI(ve)) m/z 411 (M+H)<+>.

1' -tert-butoksykarbonyl-5' -(3 -klorfenyl)spiro [cykloheksan-1,3' -[3H] indol] -2' -amin (0,120 g, 0,29 mmol) i 2,0 ml tørr DMF ble satt til en oppløsning av 4-dimetylaminopyridin (0,089 g, 0,73 mmol) og cyanogenbromid (0,077 g, 0,73 mmol) i 4,0 ml tørr DMF ved 0°C. Den gule oppløsning ble oppvarmet til 40°C i 16 timer. Opparbeiding inkluderte å helle reaksjonsblandingen i 50 ml 0,IN NaHC03med etterføl-gende ekstrahering med 3x50 ml etylacetat. De kombinerte organiske sjikt ble tørket over vannfri Na2S04, filtrert og konsentrert under vakuum for å gi 0,091 g av en gul rest. Produktet ble renset ved flashsilikagelkromatografi og eluert med en trinnvis gra- 1'-tert-butoxycarbonyl-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'-amine (0.120 g, 0.29 mmol) in 2.0 mL dry DMF was added to a solution of 4-dimethylaminopyridine (0.089 g, 0.73 mmol) and cyanogen bromide (0.077 g, 0.73 mmol) in 4.0 mL of dry DMF at 0°C. The yellow solution was heated to 40°C for 16 hours. Workup included pouring the reaction mixture into 50 mL of 0.1N NaHCO 3 followed by extraction with 3x50 mL of ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give 0.091 g of a yellow residue. The product was purified by flash silica gel chromatography and eluted with a stepwise gra-

dient 5:1 —> 3:1 heksan:etylacetat for å gi 0,031 g (32%) av produktet som et lysegult faststoff med smeltepunkt 225°C (dekomp.). dient 5:1 —> 3:1 hexane:ethyl acetate to give 0.031 g (32%) of the product as a light yellow solid m.p. 225°C (decomp.).

<!>H NMR (DMSO-d6, 500 MHz) 8 1,46-1,73 (m, 8H), 1,89-1,90 (m, 2H), 7,13-7,16 (d, <!>H NMR (DMSO-d6, 500 MHz) δ 1.46-1.73 (m, 8H), 1.89-1.90 (m, 2H), 7.13-7.16 (d,

1H), 7,38-7,41 (dt, 1H, J=8Hz), 7,45-7,50 (m, 1H), 7,60-7,63 (dd, 2H, 1H), 7.38-7.41 (dt, 1H, J=8Hz), 7.45-7.50 (m, 1H), 7.60-7.63 (dd, 2H,

J=6,4Hz), 7,71 (s, 1H), 7,85 (s, 1H), 12,1 (s, 1H, NH). J=6.4Hz), 7.71 (s, 1H), 7.85 (s, 1H), 12.1 (s, 1H, NH).

MS (ECI(-ve)) m/z 336 (M-H)-. MS (ECI(-ve)) m/z 336 (M-H)-.

Andre ønskelige forbindelser som kan fremstilles i henhold til de her beskrevne metoder omfatter 5 '-(3-cyano-5-fluorfenyl)spiro[cykloheksan-l ,3 '-[3H]indol]-2'-ylidencyanamid, 5'-(5-cyano-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2-ylidencyanamid, 5'-(5-cyano-l-metyl-lHpyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-yliden-cyanamid, 5'-(5-cyano-tiofen-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2-ylidencyanamid, 5'-(5'cyano-3-metyl-tiofen-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-cyanamid, 5'-(5-cyano-tiofen-3-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-ylidencyanamid, 3-(2'-cyanometylen-spiro[cykloheksan-1,3'-[3H]indol]-5'yl)-5-fluorbenzonitril, 5-(2'-cyanometylen-spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-lH-pyrrol-2-karbonitril, 5-(2'-cyanometylen-spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-l-metyl-lH-pyrrol-2-karbonitril, 5-(2'-cyanometylen-spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-tiofen-2-karbonitril, 5-(2'-cyanometylen-spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-4-metyl-tiofen-2-karbonitril, 4-(2'-cyanometylen-spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-tiofen-2-karbonitril. Other desirable compounds which can be prepared according to the methods described here include 5'-(3-cyano-5-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'-ylidene cyanamide, 5'-( 5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2-ylidenecyanamide, 5'-(5-cyano-1-methyl-1Hpyrrol-2-yl)spiro [cyclohexane-1,3'-[3H]indole]-2'-ylidene cyanamide, 5'-(5-cyano-thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indole]- 2-ylidene cyanamide, 5'-(5'cyano-3-methyl-thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'-cyanamide, 5'-(5-cyano- thiophen-3-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'-ylidenecyanamide, 3-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H]indole]-5 'yl)-5-fluorobenzonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1H-pyrrole-2-carbonitrile, 5-(2' -cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-1-methyl-1H-pyrrole-2-carbonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1, 3'-[3H]indol]-5'-yl)-thiophen-2-carbonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol]-5'-yl)- 4-methyl-thiophene-2-carboni tril, 4-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-thiophene-2-carbonitrile.

Claims (19)

1. Forbindelse,karakterisert vedformelen: 1. Compound characterized by the formula: der: R]og R2uavhengig er valgt fra gruppen bestående av H, Cj^-alkyl, Ci^-alkyl substituert med fenyl, eller R]og R2er forenet for å danne en ring omfattende -CH2(CH2)nCH2-, n er et heltall fra 1 til 5; R3er valgt fra gruppen bestående av H, OH og CORA; RA er Ci.3alkoksy; R4erH; R<5>er valgt fra gruppene a) og b); a) en substituert benzenring inneholdende substituentene X, Y og Z som vist nedenfor: where: R] and R 2 are independently selected from the group consisting of H, C 1 -alkyl, C 1 -alkyl substituted with phenyl, or R] and R 2 are joined to form a ring comprising -CH 2 (CH 2 )nCH 2 -, n is an integer from 1 to 5; R 3 is selected from the group consisting of H, OH and CORA; R A is C 1-3 alkoxy; R 4 is H; R<5>is selected from groups a) and b); a) a substituted benzene ring containing the substituents X, Y and Z as shown below: X er valgt fra gruppen omfattende H halogen, OH, CN, Ci-3alkoksy, NO2, Ci-3perfluoralkyl, og C(=N-OH)-NH2; Y og Z uavhengig er valgt fra gruppen bestående av H, halogen, CN, NO2og Ci-3alkoksy; der ikke alle X, Y og Z er H; b) tienyl, pyrrolyl, pyrimidinyl, furanyl eller pyridinyl inneholdende en eller to uavhengige substituenter valgt fra gruppen bestående av H, halogen, CN og CMalkyl, C(S)NH2og C(=N-OH)-NH2; hvor pyrrolringen eventuelt er substituert på N-atomet med H, Ci-3-alkyl, C(0)OCm-alkyl eller Ci-4-alkyl; Q<1>er S, NR7, eller CR8R9; R<7>er valgt fra gruppen omfattende CN, H og OR<11>; Rg og R9er uavhengige substituenter valgt fra gruppen bestående av NO2, CN eller CO2R10, Rio er Ci.3alkyl; R<11>er H eller C(0)Ci-3-alkyl; eller et farmasøytisk akseptabelt salt derav.X is selected from the group consisting of H halogen, OH, CN, C 1-3 alkoxy, NO 2 , C 1-3 perfluoroalkyl, and C(=N-OH)-NH 2 ; Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 and C 1-3 alkoxy; wherein not all X, Y and Z are H; b) thienyl, pyrrolyl, pyrimidinyl, furanyl or pyridinyl containing one or two independent substituents selected from the group consisting of H, halogen, CN and C-1 alkyl, C(S)NH 2 and C(=N-OH)-NH 2 ; where the pyrrole ring is optionally substituted on the N atom with H, C1-3 alkyl, C(0)OCm alkyl or C1-4 alkyl; Q<1> is S, NR7, or CR8R9; R<7> is selected from the group consisting of CN, H and OR<11>; Rg and R9 are independent substituents selected from the group consisting of NO2, CN or CO2R10, R 10 is C 1-3 alkyl; R<11> is H or C(O)C1-3 alkyl; or a pharmaceutically acceptable salt thereof. 2. Forbindelse,karakterisert vedformelen der: R3er valgt fra gruppen bestående av H, OH og CORA; RA er Ci.3alkoksy; RterH; R5er a) eller b); a) en substituert benzenring med formelen: 2. Compound characterized by the formula where: R 3 is selected from the group consisting of H, OH and CORA; R A is C 1-3 alkoxy; RterH; R 5 is a) or b); a) a substituted benzene ring of the formula: X er valgt fra gruppen bestående av H, halogen, CN, NO2eller Cioperfluoralkyl; Y er på 4'- eller 5'-posisjon og valgt fra gruppen bestående av H, halogen, CN, NO2, Ci-3alkoksy og CMalkyl; der X og Y ikke begge er H; eller b) en seksleddet ring med strukturen: X is selected from the group consisting of H, halogen, CN, NO 2 or Cioperfluoroalkyl; Y is at the 4' or 5' position and selected from the group consisting of H, halogen, CN, NO 2 , C 1-3 alkoxy and C 1-3 alkyl; where X and Y are not both H; or b) a six-membered ring with the structure: der: X<1>er N eller CX<2>; X<2>er halogen, CN eller CSNH2; Q<1>er S, NR-7 eller CR8R9; R7erCN; Rg og R9er uavhengige substituenter valgt fra gruppen bestående av NO2, CN og CO2R10; Rio er CMalkyl; eller et farmasøytisk akseptabelt salt derav.there: X<1> is N or CX<2>; X<2>is halogen, CN or CSNH2; Q<1> is S, NR-7 or CR8R9; R7 is CN; Rg and R9 are independent substituents selected from the group consisting of NO2, CN and CO2R10; R 10 is C 1 -C alkyl; or a pharmaceutically acceptable salt thereof. 3. Forbindelse,karakterisert vedformelen 3. Compound characterized by the formula der Rh er valgt fra gruppen bestående av H eller C(0)Ci-3-alkyl; R5er a), b) eller c): a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: there Rh is selected from the group consisting of H or C(O)C 1-3 alkyl; R5 is a), b) or c): a) a substituted benzene ring containing the substituents X and Y as shown below: der: X er valgt fra gruppen bestående av H, halogen, CN, CNH2COH, Ci-3alkoksy, CMalkyl, NO2, Ci-3perfluoralkyl; Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci^alkoksy og CMalkyl; der X og Y ikke begge er H; b) en femleddet ring med strukturen: der: UerO, SellerNRe; Re er H, CMalkyl eller CMC02alkyl; X' er valgt fra gruppen bestående av halogen, CN, N02, CSNH2og CMalkyl; Y' er valgt fra gruppen bestående av H, halogen, og Ci^alkyl; der nevnte halogen er F; eller c) en seksleddet med strukturen: where: X is selected from the group consisting of H, halogen, CN, CNH 2 COH, C 1-3 alkoxy, C 1-3 alkyl, NO 2 , C 1-3 perfluoroalkyl; Y is at the 4'- or 5'-position and is selected from the group consisting of H, halogen, CN, NO2, C1-6 alkoxy and C1-6 alkyl; where X and Y are not both H; b) a five-membered ring with the structure: where: UerO, SellerNRe; R e is H, C1 alkyl or CMC02 alkyl; X' is selected from the group consisting of halogen, CN, NO 2 , CSNH 2 and C 1 -C alkyl; Y' is selected from the group consisting of H, halogen, and C 1-6 alkyl; wherein said halogen is F; or c) a six-membered with the structure: der: Xi er N eller CX<2>; X<2>er halogen, CN eller CONH2; eller et farmasøytisk akseptabelt salt derav.where: Xi is N or CX<2>; X<2> is halogen, CN or CONH2; or a pharmaceutically acceptable salt thereof. 4. Forbindelse,karakterisert vedformelen: 4. Compound characterized by the formula: der:there: R.5er a), b) eller c): a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: R.5 is a), b) or c): a) a substituted benzene ring containing the substituents X and Y as shown below: der: X er valgt fra gruppen bestående av H, halogen, CN, CNHNOH, Ci^alkoksy, CMalkyl, N02og Ci-3perfluoralkyl; Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci-3alkoksy og CMalkyl; der X og Y ikke begge er H; b) en femleddet ring med strukturen: where: X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-3 alkoxy, C1-3 alkyl, NO2 and C1-3 perfluoroalkyl; Y is in the 4' or 5' position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1-3 alkoxy and C 1-3 alkyl; where X and Y are not both H; b) a five-membered ring with the structure: der: UerO, SellerNRe; Re er H, Ci-3alkyl eller Ci^CCbalkyl; X' er valgt fra gruppen bestående av halogen, CN, CSNH2og CMalkyl; Y' er valgt fra gruppen bestående av H, halogen, og Cj^alkyl; der nevnte halogen er F; eller c) en seksleddet ring med strukturen: there: UerO, SellerNRe; Re is H, C 1-3 alkyl or C 1-6 alkyl; X' is selected from the group consisting of halogen, CN, CSNH2 and CMalkyl; Y' is selected from the group consisting of H, halogen, and C 1-6 alkyl; wherein said halogen is F; or c) a six-membered ring with the structure: der: X, er N eller CX<2>; X<2>er halogen, CN eller CONH2; eller et farmasøytisk akseptabelt salt derav.where: X, is N or CX<2>; X<2> is halogen, CN or CONH2; or a pharmaceutically acceptable salt thereof. 5. Forbindelse,karakterisert vedformelen: 5. Compound characterized by the formula: der: Ru er valgt fra gruppen bestående av CO2R10og CN; Rio er Ci_3alkyl; R5er a), b) eller c): a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: there: Ru is selected from the group consisting of CO 2 R 10 and CN; R 10 is C 1-3 alkyl; R5 is a), b) or c): a) a substituted benzene ring containing the substituents X and Y as shown below: der: X er valgt fra gruppen bestående av H, halogen, CN, CNHNOH, Cioalkoksy, CMalkyl, NO2, Ci-3perfluoralkyl; Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, Ci-3alkoksy og Ci^alkyl; der X og Y ikke begge er H; b) en femleddet ring med strukturen: der: U er O, S eller NRe; Re er H, d-3alkyl eller CMC02alkyl; X' er valgt fra gruppen bestående av halogen, CN, N02, CSNH2og CMalkyl; Y' er valgt fra gruppen bestående av H, halogen, og CMalkyl; eller c) en seksleddet ring med strukturen: where: X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-3alkyl, C1-3alkyl, NO2, C1-3perfluoroalkyl; Y is in the 4' or 5' position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1-3 alkoxy and C 1-3 alkyl; where X and Y are not both H; b) a five-membered ring with the structure: where: U is O, S or NRe; R e is H, C 1-3 alkyl or CMC0 2 alkyl; X' is selected from the group consisting of halogen, CN, NO 2 , CSNH 2 and C 1 -C alkyl; Y' is selected from the group consisting of H, halogen, and C 1 -C alkyl; or c) a six-membered ring with the structure: der: Xjer N eller CX<2>;X<2>er halogen, CN eller CSNH2; eller et farmasøytisk akseptabelt salt derav.where: X is N or CX<2>; X<2> is halogen, CN or CSNH2; or a pharmaceutically acceptable salt thereof. 6. Forbindelse,karakterisert vedformelen: 6. Compound characterized by the formula: der: Rs er a), b) eller c): a) en substituert benzenring inneholdende substituentene X og Y som vist nedenfor: there: Rs is a), b) or c): a) a substituted benzene ring containing the substituents X and Y as shown below: der: X er valgt fra gruppen bestående av H, halogen, CN, CNHNOH, Ci^alkoksy, CMalkyl, NO2og Ci-3perfluoralkyl; Y er på 4'- eller 5'-posisjon og er valgt fra gruppen bestående av H, halogen, CN, NO2, C1,3alkoksy og C1 ^alkyl; der X og Y ikke begge er H; b) en femleddet ring med strukturen: der: UerO, SellerNRfi; Re er H, Ci.3alkyl eller CMC02alkyl; X' er valgt fra gruppen bestående av halogen, CN, CSNH2og Ci-3alkyl; Y' er valgt fra gruppen bestående av H, halogen, og Ci^alkyl; der nevnte halogen er F; eller c) en seksleddet ring med strukturen: where: X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-3 alkoxy, C1-3 alkyl, NO2 and C1-3 perfluoroalkyl; Y is in the 4'- or 5'-position and is selected from the group consisting of H, halogen, CN, NO2, C1,3 alkoxy and C1-3 alkyl; where X and Y are not both H; b) a five-membered ring with the structure: where: UerO, SellerNRfi; Re is H, C1-3 alkyl or CMC02 alkyl; X' is selected from the group consisting of halogen, CN, CSNH 2 and C 1-3 alkyl; Y' is selected from the group consisting of H, halogen, and C 1-6 alkyl; wherein said halogen is F; or c) a six-membered ring with the structure: der: Xi er N eller CX<2>; X<2>er halogen, CN eller CONH2; eller et farmasøytisk akseptabelt salt derav.where: Xi is N or CX<2>; X<2> is halogen, CN or CONH2; or a pharmaceutically acceptable salt thereof. 7. Forbindelse,karakterisert vedat den er valgt blant: 5"-(3-fluorfenyl)spiro[cykloheksan-1,3 '-[3H]indol]-2'(l 'H)-on oksim, 5'-(2-fluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on oksim, 5'-(4-fluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on oksim, 5'-(3,4-difluorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on oksim, 5'-(3-metoksyfenyl)-spiro[cykloheksan-l,3'-[3H]indol]-2'(rH)-on oksim, 5'-(3-nitrofenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-on oksim, og 5 '-(3-cyanofenyl)-spiro[cykloheksan-1,3 '-[3H]indol]-2'(l 'H)-on oksim, eller et farmasøytisk akseptabelt salt derav.7. Compound characterized in that it is selected from: 5'-(3-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one oxime, 5'-(2-fluorophenyl) )spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-one oxime, 5'-(4-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indole]- 2'(1'H)-one oxime, 5'-(3,4-difluorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-one oxime, 5'- (3-Methoxyphenyl)-spiro[cyclohexane-1,3'-[3H]indole]-2'(rH)-one oxime, 5'-(3-nitrophenyl)spiro[cyclohexane-1,3'-[3H] indol]-2'(1'H)-one oxime, and 5'-(3-cyanophenyl)-spiro[cyclohexane-1,3'-[3H]indol]-2'(1'H)-one oxime, or a pharmaceutically acceptable salt thereof. 8. Forbindelse ifølge et hvilket som helst av kravene 1 eller 2,karakterisert vedformelen: 8. Compound according to any one of claims 1 or 2, characterized by the formula: der: R5er den substituerte benzenring med formelen: there: R5 is the substituted benzene ring of the formula: X er valgt fra gruppen bestående av H, halogen, CN, Ci-3alkoksy, CMalkyl, NO2og C1 -3perfluoralkyl; Y er på 4'- eller 5'-posisjon og er valgt blant gruppen bestående av H, halogen, CN, N02, Cijalkoksy og Ci^alkyl; der X og Y ikke begge er H.X is selected from the group consisting of H, halogen, CN, C1-3 alkoxy, C1-3 alkyl, NO2 and C1-3 perfluoroalkyl; Y is in the 4'- or 5'-position and is selected from the group consisting of H, halogen, CN, NO 2 , C 1-6 oxy and C 1-6 alkyl; where X and Y are not both H. 9. Forbindelse ifølge et hvilket som helst av kravene 1 eller 2,karakterisert vedformelen: 9. Compound according to any one of claims 1 or 2, characterized by the formula: der:there: R.5er den femleddede ring med strukturen: R.5 is the five-membered ring with the structure: der: U er O, Seller NR*; Re er H eller Ci.3alkyl; X' er valgt blant gruppen bestående av halogen, CN, CSNH2, CMalkyl, og Ci^alkoksy; Y' er valgt blant gruppen bestående av H, halogen og CMalkyl; der nevnte halogen er F.where: U is O, Seller NR*; Re is H or C 1-3 alkyl; X' is selected from the group consisting of halogen, CN, CSNH 2 , C 1-6 alkyl, and C 1-6 alkoxy; Y' is selected from the group consisting of H, halogen and C 1 -C alkyl; wherein said halogen is F. 10. Forbindelse ifølge et hvilket som helst av kravene 1 eller 2,karakterisert vedformelen: 10. Compound according to any one of claims 1 or 2, characterized by the formula: der: Rs er den seksleddede ring med strukturen: there: Rs is the six-membered ring with the structure: X<1>er N eller CX2; X<2>er halogen, CN eller CSNH2.X<1>is N or CX2; X<2>is halogen, CN or CSNH2. 11. Forbindelse ifølge krav 1,karakterisert vedat den er valgt fra gruppen bestående av 5'-(3-klorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'(l'H)-tion,11. Compound according to claim 1, characterized in that it is selected from the group consisting of 5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'(1'H)-thione, 3- ( 1 ',2 '-dihydro-2 '-tioksospiro[cykloheksan-1,3 '-[3H]indol]-5 '-yl)benzonitril,3-(1',2'-dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)benzonitrile, 4- (l\2'-dihydro-2'-tioksospiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-2-tiofenkarboniri 3- (l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-5-fluorbenzonitril, 4- metyl-5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]-indol]-5-yl)-2-tiofen tioamid,4-(1\2'-dihydro-2'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-2-thiophenecarboniri 3-(1,2-dihydro-2-thioxospiro[ cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile, 4-methyl-5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]-indole] -5-yl)-2-thiophene thioamide, 5- (l ,2-dihydro-2-tioksospiro[cyklopentan-l ,3-[3H]indol]-5 '-yl)- lH-pyrrol-2-karbomtril, 5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-y^^ 5-(2'-tioksospiro[cykloheksan-1,3 '-[3H]indol]-5 '-yl)-1 -metyl-pyrrol-2-karbonitril, 5-(l,2-dihydro-2-tioksospiro[cyklopentan-l,3-[3H]indol]-5-yl)-3-tiofenkarbonitril, 5-(l ,2-dihydro-tioksospiro(cyklopentan-1,3-[3H]indol)-5-yl)-2-tiofenkarbonitril, 5-(3-fluor-4-metoksyfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion,5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrole-2-carbomtrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indole]-5-y^^ 5-(2'-thioxospiro[cyclohexane-1,3'-[3H]indole) -5'-yl)-1-methyl-pyrrole-2-carbonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclopentan-1,3-[3H]indol]-5-yl)-3-thiophenecarbonitrile , 5-(1,2-dihydro-thioxospiro(cyclopentan-1,3-[3H]indol)-5-yl)-2-thiophenecarbonitrile, 5-(3-fluoro-4-methoxyphenyl)spiro[cyclohexane-1, 3-[3H]indole]-2(1H)-thione, 5 -(2-amino-5 -pyrimidinyl)spiro [cykloheksan-1,3 - [3H] indol] -2(1 H)-tion, 3-(l,2-dihydro-2-tioksospiro[cyklopentan-l,3-[3H]indol]-5-yl)-5-fluorbenzonitril,5-(2-amino-5-pyrimidinyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 3-(1,2-dihydro-2-thioxospiro[cyclopentane-1, 3-[3H]indol]-5-yl)-5-fluorobenzonitrile, 3- (l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-2-yl)-4-fluorbenzonitril, 5 -(1,2-dihydro-2-tioksospiro [cykloheksan-1,3 - [3H] indol] -2-yl)-3 -pyridinkarbonitril, 5-(3,4-difluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5-(5-klor-2-tienyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 5-(l ,2-dihydro-2-tioksospiro[cykloheksan-1,3-[3H]indol]-5-yl)-3-furankarbonitril, 5-(3-klor-4-fluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion,3-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-2-yl)-4-fluorobenzonitrile, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1 ,3 - [3H]indol]-2-yl)-3-pyridinecarbonitrile, 5-(3,4-difluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5- (5-chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[ 3H]indol]-5-yl)-3-furancarbonitrile, 5-(3-chloro-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5 -(3 -klor-5 -fluorfenyl)spiro [cykloheksan-1,3 -[3H] indol] -2(1 H)-tion, 5-(3,5-difluorfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH9-tion, 5-(l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-4-propyl-2-tiofenkarbonitril, 5-(3-fluor-4-nitrofenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion,5-(3-chloro-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 5-(3,5-difluorophenyl)spiro[cyclohexane-1,3- [3H]indole]-2(1H9-thione, 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile, 5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 4- (l ,2-dihydro-2-tioksospiro[cykloheksan-1,3-[3H]indol]-5-yl)-2-furankarbonitril, 5"-(2-klorfenyl)spiro[cyklobutan-l,3"-[3H]indol]-2"(l"H)-tion, 5"-(2-klorfenyl)spiro[cykloheksan-l,3"-[3H]indol]-2"(l"H)-tion, 5"-(4-klorfenyl)spiro[cykloheksan-l>3"-[3H]indol]-2"(l"H)-tion,4-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile, 5"-(2-chlorophenyl)spiro[cyclobutane-1,3" -[3H]indole]-2"(1"H)-thione, 5"-(2-chlorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1"H)-thione, 5"-(4-Chlorophenyl)spiro[cyclohexane-1>3"-[3H]indole]-2"(1"H)-thione, 5- (l",2"-dihydro-2"-tioksospiro[cykloheksan-lJ3"-[3H]indol]-5"-yl)-4-metyl-2-tiofenkarbonitril, 5'-(l'',2''-dihydro-2''-tioksospiro[cykloheksan-l,3''-[3H]indol]-5"-yl)-2-tiofenkarbonitril, 5''-(3-fluorfenyl)spiro[cykloheksan-l,3"-[3H]indol]-2"(l''H)-tion, 5-(3-hydroksyfenyl)spiro[cykloheksan-1,3-[3H]indol-2(lH)-tion, 5-[4-fluor-3-(trifluorrnetyl)fenyl]spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion,5-(1",2"-dihydro-2"-thioxospiro[cyclohexane-1J3"-[3H]indol]-5"-yl)-4-methyl-2-thiophenecarbonitrile, 5'-(1'',2 ``-dihydro-2''-thioxospiro[cyclohexane-1,3''-[3H]indol]-5'-yl)-2-thiophenecarbonitrile, 5''-(3-fluorophenyl)spiro[cyclohexane-1,3"-[3H]indole]-2"(1''H)-thione, 5-(3-hydroxyphenyl)spiro[cyclohexane-1,3- [3H]indole-2(1H)-thione, 5-[4-fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 4- (l,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-2-fluorbenzonitril,4-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzonitrile, 5- (3-fluor-5-metoksyfenyl)spiro[cykloheksan-l,3-[3H]indol]-2(lH)-tion, 3- [l',2'-dihydro-2'-(hy(iroksyimino)spiro[cykloheksan-l,3'-[3H]indol]-5'-yl]-5-fluorbenzonitril, 5-(spiro[cykloheksan-1,3 '-[3H]indol]-2'-(hydroksyimino)-5 '-yl)-metyl-2-tiofenkarbonitril, 5-(spiro[cykloheksan-1,3 '-[3H]indol]-2 '-(hydroksyimino)-5 '-yl-2-tiofenkarbonitril,5-(3-Fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 3-[1',2'-dihydro-2'-(hy(iroxyimino )spiro[cyclohexane-1,3'-[3H]indol]-5'-yl]-5-fluorobenzonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino) -5'-yl)-methyl-2-thiophenecarbonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl-2-thiophenecarbonitrile, 4- (spiro[cykloheksan-l,3'-[3H]indol]-2'-(hydroksyimino)-5'-yl)-2-tiofenkarbonitril, 5-(spiro[cykloheksan-1,3' -[3H] indol] -2' -(hydroksyimino)-5' -yl)-1 H-pyrrol-1 -metyl-2-karbonitril, 5-(spiro[cykloheksan-1,3' -[3H] indol] -2' -(hydroksyimino)-5' -yl)-1 H-pyrrol-2-karbonitril,4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-2-thiophenecarbonitrile, 5-(spiro[cyclohexane-1,3'-[3H] indole]-2'-(hydroxyimino)-5'-yl)-1H-pyrrole-1-methyl-2-carbonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'- (hydroxyimino)-5'-yl)-1H-pyrrole-2-carbonitrile, 4- (spiro [cykloheksan-1,3 '-[3H]indol]-2'-(acetoksyimino)-5 '-yl)-2-tiofenkarbonitril, 3-fluor-N'-hydroksy-5-[2'-(hydroksyimino)spiro[cykloheksan-l,3'-[3H]indol]-5'-yl]benzenkarboksimidamid, N'-hydroksy-5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(hydroksyimino)-5'-yl)-4-metyl-2- tiofenkarboksimidamid, N' -hydroksy-4-(spiro [cykloheksan-1,3' - [3H] indol] -2' -(hydroksyimino)-5' -yl-2-tiofenkarboksimidamid, N'-hydroksy-5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-(hydroksyimino)-5'-yl)-2-tiofenkarboksimidamid,4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(acetoxyimino)-5'-yl)-2-thiophenecarbonitrile, 3-fluoro-N'-hydroxy-5-[2'- (hydroxyimino)spiro[cyclohexane-1,3'-[3H]indol]-5'-yl]benzenecarboximidamide, N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2' -(hydroxyimino)-5'-yl)-4-methyl-2-thiophenecarboximidamide, N'-hydroxy-4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5 ' -yl-2-thiophenecarboximidamide, N'-hydroxy-5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-(hydroxyimino)-5'-yl)-2-thiophenecarboximidamide, 5- (3-klorfenyl)-3,3-dimetyl-l,3-dihydro-2H-indol-2-tion,5-(3-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione, 3- benzyl-5-(3-klorfenyl)-3-metyl-1,3-dihydro-2H-indol-2-tion,3- benzyl-5-(3-chlorophenyl)-3-methyl-1,3-dihydro-2H-indole-2-thione, 4- (3,3-dimetyl-2-tiokso-2,3-dihydro-lH-indol-5-yl)-2-furonitril,4-(3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl)-2-furonitrile, 5- (3-metoksyfenyl)-3,3-dimetyl-l,3-dihydro-2H-indol-2-tion, 5-(3-klorfenyl)-3,3-dietyl-l,3-dihydro-2H-indol-2-tion, 5'-(3-klorfenyl)spiro[cykloheksan-l,3'-[3H]indol]-2'-ylidencyanamid,5-(3-methoxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione, 5-(3-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H- indol-2-thione, 5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3H]indole]-2'-ylidene cyanamide, 5' -(3 -cyano-5 -fluorfenyl)spiro[cykloheksan-1,3'- [3H] indol] -2' -ylidencyanamid, 5'-(5-cyano-lH-pyrrol-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-ylidencyanamid, 5'-(5-cyano-tiofen-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-ylidencyanamid, 5'-(5-cyano-3-metyl-tiofen-2-yl)spiro[cykloheksan-l,3'-[3H]indol]-2'-ylidencyanamid,5'-(3-cyano-5-fluorophenyl)spiro[cyclohexane-1,3'- [3H]indole]-2'-ylidene cyanamide, 5'-(5-cyano-1H-pyrrol-2-yl)spiro[ cyclohexane-1,3'-[3H]indole]-2'-ylidenecyanamide, 5'-(5-cyano-thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'- ylidene cyanamide, 5'-(5-cyano-3-methyl-thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'-ylidene cyanamide, 5' -(5 -cyano-tiofen-3 -yl)spiro[cykloheksan-1,3'- [3H]indol] -2' -ylidencyanamid, 3- (spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-5-fluor-benzonitril, 5-(spiro[cykloheksan-l,3'-[3H]indol]-2'-cyanometylen-5'-yl)-lH-pyrrol-2-karbonitril, 5-(spiro[cykloheksan-l ,3 '-[3H]indol]-2'-cyanometylen-5'-yl)-1 -metyl-lH-pyrrol-2-karbonitril, 5-(2'-cyanometylen-spiro[cykloheksan-l,3'-[3H]indol]-5'-yl)-tiofen-2-karbonitril, 5-(spiro[cykloheksan-l ,3 '-[3H]indol]-2'-cyanometylen-5 '-yl)-4-metyl-tiofen-2-karbonitril, og5' -(5-cyano-thiophen-3-yl)spiro[cyclohexane-1,3'-[3H]indole]-2'-ylidene cyanamide, 3-(spiro[cyclohexane-1,3'-[3H]indole ]-5'-yl)-5-fluoro-benzonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanomethylene-5'-yl)-1H-pyrrole-2-carbonitrile , 5-(spiro[cyclohexane-1,3'-[3H]indol]-2'-cyanomethylene-5'-yl)-1-methyl-1H-pyrrole-2-carbonitrile, 5-(2'-cyanomethylene- spiro[cyclohexane-1,3'-[3H]indol]-5'-yl)-thiophene-2-carbonitrile, 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-cyanomethylene- 5'-yl)-4-methyl-thiophene-2-carbonitrile, and 4- (spiro[cykloheksan-1,3' - [3H] indol] -2' -cyanometylen-5' -yl)-tiofen-2-karbonitril, eller et farmasøytisk akseptabelt salt derav.4-(spiro[cyclohexane-1,3'-[3H]indole]-2'-cyanomethylene-5'-yl)-thiophene-2-carbonitrile, or a pharmaceutically acceptable salt thereof. 12. Forbindelse ifølge krav 2,karakterisert vedat den er 5- (l ,2-dihydro-2-tioksospiro[cykloheksan-l ,3-[3H]indol]-5-yl)-1 -(tert- butoksykarbonyl)-pyrrol-2-karbonitril eller 5-(l ,2-dihydro-2-tioksospiro[cykloheksan-l,3-[3H]indol]-5-yl)-4-n-butyl-2-tiofenkarbonitril, eller et farmasøytisk akseptabelt salt derav.12. Compound according to claim 2, characterized in that it is 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-(tert-butoxycarbonyl)-pyrrole-2 -carbonitrile or 5-(1,2-dihydro-2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile, or a pharmaceutically acceptable salt thereof. 13. Forbindelse ifølge et hvilket som helst av kravene 3 til 6,karakterisert vedat R5er tiofen eller furan.13. Compound according to any one of claims 3 to 6, characterized in that R 5 is thiophene or furan. 14. Farmasøytisk preparat,karakterisert vedat det omfatter en forbindelse ifølge et hvilket som helst av kravene 1 til 13, eller et farmasøytisk akseptabelt salt derav, og en farmasøytisk akseptabelt bærer eller eksipient.14. Pharmaceutical preparation, characterized in that it comprises a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 15. Anvendelse av en forbindelse ifølge et hvilket som helst av kravene 1 til 13, eller nevnte akseptable salt derav, for fremstilling av et medikament.15. Use of a compound according to any one of claims 1 to 13, or said acceptable salt thereof, for the manufacture of a medicament. 16. Anvendelse av forbindelsen ifølge et hvilket som helst av kravene 1 til 13, eller et akseptabelt salt derav, for fremstilling av et medikament brukbart for administrering til et pattedyr som trenger behandling for dysfunksjonen blødning.16. Use of the compound according to any one of claims 1 to 13, or an acceptable salt thereof, for the preparation of a medicament useful for administration to a mammal in need of treatment for the bleeding dysfunction. 17. Anvendelse av en forbindelse ifølge et hvilket som helst av kravene 1 til 13, eller et akseptabelt salt derav for fremstilling av et medikament brukbart for administrering til et pattedyr for behandling av karsinomer og adenokarsinomer av endometrium, ovarie, bryst, kolon eller prostata.17. Use of a compound according to any one of claims 1 to 13, or an acceptable salt thereof, for the manufacture of a medicament useful for administration to a mammal for the treatment of carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon or prostate. 18. Anvendelse av en forbindelse ifølge et hvilket som helst av kravene 1 til 13, eller et farmasøytisk akseptabelt salt derav, for fremstilling av et medikament brukbart for administrering til et pattedyr som kontraseptiv.18. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for administration to a mammal as a contraceptive. 19. Anvendelse av en forbindelse ifølge et hvilket som helst av kravene 1 til 3, eller et farmasøytisk akseptabelt salt derav, for fremstilling av et medikament brukbart for hormonerstatningsterapi.19. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for hormone replacement therapy.
NO20015380A 1999-05-04 2001-11-02 Thiooxindole derivatives, pharmaceutical compositions comprising these and their use in the manufacture of medicaments. NO320912B1 (en)

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