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

Description

The present invention relates to compounds which are agonists for the progesterone receptor, their use and pharmaceutical preparations comprising these.

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).

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.

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 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.

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., describe in the U.S. patent No. 5,688,810 the PR antagonist dihydroquinoline A.

Jones, et al., describe the enoleter B (U.S. Patent No. 5,693,646) as a PR ligand.

Jones, et al., describe compound C (U.S. Patent No. 5,696,127) as a PR ligand.

Zhi, et al., describe lactones D, E and F as PR antagonists (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., describe the amide H as Uganda for PR (J. Med. Chem., 38, 4880, 1995).

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

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

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

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

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

Weber describes the oxindole N for cardiovascular indications (WO 91/06545).

Fischer et al. claims a method of preparation for the preparation of compounds that include the generic structure O (US 5,453,516).

R = miscellaneous

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

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

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) describes the oxindole S as an intermediate (US Patent No. 4,440,785, US Patent No. 4,670,566).

Bohm et al. claims oxindole T as a cardiovascular agent (WO 91/06545).

Bohm et al. included the generic structure U (WO 91/04974).

JP 63112584 A contains the generic structure V:

Boar et al. describes the dioxolane W as an intermediate for the production of acetyl-cholinesterase inhibitors (WO 93/12085 A1).

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).

The present invention provides compounds with the formula:

there:

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,

or R1 and R2 are joined to form a ring comprising -CH2(CH2)nCH2-,

ner an integer from 1 to 5;

R 3 is selected from the group consisting of H, OH and CORA;

R<A>erC].3Alkoxy;

RterH;

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 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 10 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-M alkyl,

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

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 CRgRg;

R<7> is selected from the group consisting of CN, H and OR<11>;

R s and R 9 are independent substituents selected from the group consisting of NO 2 , CN or CO 2 R 10 ,

R 10 is C 1 -C alkyl;

R<11> is H or C(O)C1-3 alkyl;

or

a pharmaceutically acceptable salt thereof.

Two preferred sets of compounds according to the invention are indicated by the structures:

there:

R 3 is selected from the group consisting of H, OH and CORA;

R A is C 1-3 alkoxy;

RierH;

R 5 is a) or b);

a) a substituted benzene ring of the formula:

X is selected from the group consisting of H, halogen, CN, NO 2 or C 1-3 perfluoroalkyl;

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;

where X and Y are not both H; or

b) a six-membered ring with the structure:

there:

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

X<2>is halogen, CN or CSNH2;

Q<1> is S, NR7 or CRgRg;

R 7 is CN;

Rg and R9 are independent substituents selected from the group consisting of NO2, CN and CO2R10;

R 10 is C 10 alkyl;

or

a pharmaceutically acceptable salt thereof.

Other preferred compounds have the formula:

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:

there:

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 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:

there:

UerO, SellerNRe;

R e is H, C 1-3 alkyl or C 1-4 CO 2 alkyl;

X' is selected from the group consisting of halogen, CN, NO 2 , CSNH 2 and C 1-6 alkyl;

Y' is selected from the group consisting of H, halogen, and C 1-4 alkyl;

wherein said halogen is F; or

c) a six-membered one with the structure:

there:

Xi is N or CX<2>;

X<2> is halogen, CN or CONH2;

or

a pharmaceutically acceptable salt thereof.

A further preferred subset of compounds has the formula:

there:

R5 is a), b) or c):

a) a substituted benzene ring containing the substituents X and Y as shown below:

there:

X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-6 alkoxy, Cualkyl, 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:

there:

Uer O, Seller NR*;

Is H, C 1-3 alkyl or C 1-4 CO 2 alkyl;

X' is selected from the group consisting of halogen, CN, CSNH 2 and C 1-6 alkyl;

Y' is selected from the group consisting of H, halogen, and C 1 -C alkyl;

wherein said halogen is F; or

c) a six-membered ring with the structure:

there:

X, is N or CX<2>;

X<2> is halogen, CN or CONH2;

or

a pharmaceutically acceptable salt thereof.

Another preferred group of these compounds includes those having the general formula:

there:

Ri 5 is selected from the group consisting of CO 2 R 10 and CN;

R 10 -C 1-3 alkyl;

R5 is a), b) or c):

a) a substituted benzene ring containing the substituents X and Y as shown below:

there:

X is selected from the group consisting of H, halogen, CN, CNHNOH, C1-3 alkoxy, C1-3 alkyl, NO2, C1-3 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:

there:

UerO, SellerNRe;

Re is H, C1-3 alkyl or CMC02 alkyl;

X' is selected from the group consisting of halogen, CN, NO2, CSNH2 and Cualkyl;

Y' is selected from the group consisting of H, halogen, and C 1-6 alkyl;

or

c) a six-membered ring with the structure:

there:

X, is N or CX<2>;

X<2>is halogen, CN or CSNH2;

or

a pharmaceutically acceptable salt thereof.

A further preferred subgroup of compounds has the formula:

there:

R5 is a), b) or c):

a) a substituted benzene ring containing the substituents X and Y as shown below:

there:

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:

there:

UerO, SellerNRe;

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 alk.yl;

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:

there:

Xi is N or CX<2>;

X<2> is halogen, CN or CONH2;

or

a pharmaceutically acceptable salt thereof.

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,

or a pharmaceutically acceptable salt thereof.

A further preferred group has the structure:

there:

R5 is the substituted benzene ring of the formula:

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 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;

where X and Y are not both H.

A further preferred subset of compounds has the formula:

there:

R5 is the five-membered ring with the structure:

there:

U is O, Seller NR*;

R 1 -Heller C 1-6 alkyl;

X' is selected from the group consisting of halogen, CN, CSNH2, C10alkyl, and C10alkyl;

Y' is selected from the group consisting of H, halogen and Cualkyl;

wherein said halogen is F.

A further preferred subset of compounds has the formula:

there:

R5 is the six-membered ring with the structure:

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

X<2>is halogen, CN or CSNH2.

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-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3H]indol]-5'-yl)-1H-pyrrole-2-carbonitrile,

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-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-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[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[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'-(hy(h'oxyimino)-5'-yl)-1H-pyrrole-2-carbonitrile,

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-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-thione,

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-chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione,

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'-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[cyclohexane-1,3'-[3H]indole]-2'-cyanomethylene-5'-yl)-thiophene-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

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.

A further preferred subset of compounds are those in which R 5 is thiophene or furan.

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.

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.

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.

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.

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.

The compounds according to the invention can be prepared according to the methods described below:

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.

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.

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.

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.

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.

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.

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,

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.

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.

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.

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.

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.

According to scheme 6, the thioamide derivatives 7 can be converted to the enamine derivatives 16 (Wrobel, et al., J. Med. Chem., 1989, 2493).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The invention shall be explained in more detail by means of the following, non-limiting examples.

EXAMPLE 1

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

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.

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

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.

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).

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

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.

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,

142,17,182,89 (s).

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

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

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 (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,

br).

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

EXAMPLE 2

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

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 (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)<+>.

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 (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,

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,- 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.

<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,

J=7.2Hz), 7.83 (m, 1H), 8.26 (s, 1H, br).

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

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) 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) and 12.76

(p, 1H).

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

EXAMPLE 3

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

3- (trimethylstannylV2-thiophenecarbonitrile

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.

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- 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 (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=1.45Hz, 1H), 7.59 (d, J=1.4Hz, 1H), 7.84 (d, J=1.4Hz,

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

<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,

182.13 (s).

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

Analysis (Ci8H16N2OS) C, H, N.

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) δ 12.72 (s, 1H), 8.52 (d, 1H, J=1.5Hz), 8.36 (d, 1H, J=1.5Hz),

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).

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

EXAMPLE 4

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.).

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).

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

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

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.

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<*>].

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.

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<+>].

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.

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.

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) and 8.37 (s, 1H).

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

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 (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

(p, 1H).

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

EXAMPLE 5

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

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) 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).

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

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-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,

3H), 1.98-1.89 (m, 7H), 1.83-1.81 (m, 3H).

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

EXAMPLE 6 - Pharmacology

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 biology

The in vitro biology is determined by

(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 binding assay

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-luciferase assay in CV-1 cells

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:

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. Cell culture, transfection. treatment and luciferase assay

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. Analysis of results:

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. Reference connections:

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.

Progestational activity: Compounds that exert PRE-luciferase activity significantly (p < 0.05) compared to the vehicle control are considered active.

Antiprogestational activity: Compounds that significantly reduce 3 nM progesterone induced PRE-luciferase activity (p < 0.05).

EC50: Concentration of a compound that gives half-maximal increase of PRE-lucife race activity (default-nM) with SE.

IC50: Concentration of a compound that produces half-maximal reduction in 3nM progestin-induced PRE-luciferase activity (default-nM) with SE.

3. T47D cell proliferation assay

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. Growth medium:

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. Treatment medium:

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. Cell culture

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. Cell proliferation assay

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.

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. Analysis of results:

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. Reference connections:

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: Concentration of a compound that gives a half-maximal increase in BrdU incorporation with SE;

IC50: Concentration of a compound that produces half-maximal reduction in 0.1 trimegestone-induced BrdU incorporation with SE.

4. T47D- cell alkaline phosphatase assay

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. Culture medium:

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. Alkaline phosphatase buffer assay:

I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100

II. 0.1 M Tris-HCl, pH 9.8, containing 4 mM p-nitrophenyl phosphate (Sigma).

c. Cell culture and treatment:

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. Alkaline phosphatase enzyme assay:

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. Analysis of results: Analysis of dose-response data

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. Reference connections:

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 biology

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. Rat ductualization assay

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. Methods:

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 protocol # 5002)

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. Processing

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. Dosage

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. Decidual induction

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. Analysis of results:

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. Referral links

All progestin reference compounds were run in full dose-response curves and the EC50 for uterine weight was calculated.

EXAMPLE 7

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

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

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.

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,

1H).

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

Analysis for C21H24N2O3:

Calculated: C, 71.57; H, 6.86; N, 7.95.

Found: C, 71.08; H, 6.83; N, 7.74.

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) 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).

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

Analysis for C22H23N3O3:

Calculated: C, 70.01; H, 6.14; N, 11,13.

Found: C, 69.67; H, 6.38; N, 11.04.

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.

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=8.1Hz), 6.94 (dd, 1H, J=2.4, 3.7Hz), 7.52 (dd, 1H, J=1.8,

8.1Hz), 7.60 (d, 1H, J=1.8Hz), 10.38 (s, 1H), 12.45 (s, 1H).

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

Analysis for C17H15N3O:

Calculated: C, 73.63; H, 5.45; N, 15.15.

Found: C, 73.24; H, 5.34; N, 14.96.

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) 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=1.3Hz), 12.57 (s, 1H), 12.65 (s, 1H).

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

Analysis for C17H15N3S:

Calculated: C, 69.6; H, 5.15; N, 14.32.

Found: C, 69; H, 5.31; N, 13.81.

EXAMPLE 8

5- fl. 2- dihydro- 2- thioxospiro-[ cyclohexane- 1. 3-[ 3Hlindoll- 5- vn- 1- pter-butoxycarbonvD- pyrrole- 2- carbonitrile

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.

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

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

Analysis for C22H26N2O3:

Calculated: C, 72.11; H, 7.15; N, 7.64.

Found: C, 71.7; H, 7.16; N, 7.5.

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

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.

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).

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

Analysis for C23H25N3O3:

Calcd: C, 70.57, H, 6.44; N, 10.73.

Found: C, 69.82; H, 6.46; N, 10.43

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%).

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=1.4Hz), 12.74 (s, 1H). MS (ESI) [M-H]- = 406.

Analysis for C23H25N302S:

Calcd: C, 67.79; H, 6.18; N, 10.31.

Found: C, 67.86; H, 5.99; N, 10.25.

EXAMPLE 9

5- fl. 2- dihydro- 2- thioxospirorcvchlorohexane- 1. 3- r3H1indoll- 5- vn- 1H- Dvrrol- 2-carbonitrile

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.

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=1.6, 8.4Hz), 8.05

(d, 1H, J=1,1Hz), 12.67 (s, 1H), 12.73 (s, 1H).

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

Analysis for C18H17N3S:

Calculated: C, 70.33; H, 5.57; N, 13.67.

Found: C, 69.64; H, 5.79; N, 13.04.

EXAMPLE 10

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) 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=1.6, 8.1Hz), 7.83 (d, 1H, J=1.6Hz), 12.75 (s, 1H).

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

Analysis for C19H19N3S:

Calculated: C, 70.99; H, 5.96; N, 13.07.

Found: C, 68.69; H, 5.36; N, 12.27.

EXAMPLE 11

5-(1,2-dihydro-2-thioxospiro[cyclopentane-1,3-[3Hlindoll-5-vl)-3-thiophenecarbonitrile 5-bromo-2-thiophenecarbonitrile

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.

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%).

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.

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=1.76Hz),

7.93 (d, 1H, J=4.17Hz), 10.51 (s, 1H).

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

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.

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=1.7Hz, 1H), 7.95 (d, J=1.3Hz, 1H), 8.49 (d, J=1.3Hz, 1H),

8.49 (d, J=1.3Hz, 1H), 12.68 (s, 1H).

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

EXAMPLE 12

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.

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=8.1Hz), 7.09-7.07 (d, 1H, J=8.1Hz), 2.13,

2.08 (m, 6H), 1.99-1.85 (m, 2H).

MS [M-H]- = 309.

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

Analysis for C17H14N2S2.

Calcd: C, 65.77; H, 4.55; N, 9.02.

Found: C, 65.27; H, 4.41; N, 8.84.

EXAMPLE 13

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=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).

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

Analysis for C20H20FNO2:

Calculated: C, 73.83; H, 6.20; N, 4.30.

Found: C, 73.55; H, 6.23; N, 4.40.

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) 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=8.1Hz), 3.9 (s, 3H), 1.9-1.8 (m, 7H), 1 .4-1.3 (m, 3H).

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

Analysis for C2oH2oFNOS-0.25 H2O.

Calcd: C, 69.44; H, 5.97; N, 4.05.

Found: C, 69.43; H, 5.75; N, 4.32.

EXAMPLE 14

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 hydrochloric acid solution and subsequent recrystallization from ethanol gave a gray solid with melting point 274-277°C (decomp.).

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~8.1Hz), 6.8 (s, 2H), 1.9-1.8 (m, 7H), 1.4-1.3 (m, 3H).

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

EXAMPLE 15

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

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) 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) 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).

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

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.

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- fluorophenvlVspirorcvclopentan- l. 3 '- r3H1indofl- 2*( 1 ' HVone

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)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) 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=1,8,6,4Hz), 6.9 (d, 1H, J=8,1Hz), 2.0-1.9 (m,

8H).

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

General procedure A

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.

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.

EXAMPLE 16

5-( 3- chlorophenvn- 3. 3- dimethyl- L3- dihydro- 2H- indol- 2- thione

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

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

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%) with melting point 188-189°C.

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).

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

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

CHN for Ci6Hi4ClNO + 0.1 C4H8O2.

Calculated: C, 70.21; H, 5.32; N, 4.99.

Found: C, 70.3; H, 5.44; N, 4.93.

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.

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) and 1.50 (s, 6H).

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

EXAMPLE 17

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 (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 and 13Hz) and 1.57 (s, 3H).

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

EXAMPLE 18

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

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.

<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=1.5Hz, 1H), 8.1 (s, 1H), 8.5 (s, 1H), 10.46 (s, 1H). MS (ESI) m/z 251 (M-HV.

Analysis for C] 5 Hi 2 N 2 O 2 * 0.6 H 2 .

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 (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) and g1,48(s,6H).

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

EXAMPLE 19

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-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%).

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).

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-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).

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

CHN for Ci7H17Nd2.

Calculated: C, 76.38; H, 6.41; N; 5.24.

Found: C, 76.02; H, 6.49; N, 5.02.

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.

<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 and 2.3 Hz), 3.88 (s,

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

MS (EI) m/z 283 [Mf.

EXAMPLE 20

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.

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),

1.97-1.83 (m, 2H), 1.69-1.55 (m, 8H).

MS (EI) m/z 320 (M<1>”).

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.

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=8.1Hz), 2.17-1.84 (m, 7H) and 1.60-1.54 (m, 3H).

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

EXAMPLE 21

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 (CDCl 3 ) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H).

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

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(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.)

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 (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,

br), 8.89 (d, 1H, J=2Hz), 9.06 (d, 1H, J=2Hz).

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

Analysis for C19H17N3O CHN.

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.

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=8.1Hz), 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]-.

EXAMPLE 22

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 (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).

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

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.

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) and 1.66-1.53 (m, 3H).

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

EXAMPLE 23

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

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

(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)<+>.

Analysis for (C17Hi6ClNOS) C, H, N.

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.

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).

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

EXAMPLE 24

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.

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=8.1Hz),

1.87-1.83 (m, 2H), 1.73-1.53 (m, 8H).

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

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 (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) and 1.56-1.52 (m, 2H). MS ((-)-APCI) m/z 307 [M-H]".

EXAMPLE 25

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

Prepared according to the procedure in example 5, with melting point 188-189°C.

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=8.1Hz), 2.04-1.65 (m, 10H).

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

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.

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).

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

EXAMPLE 26

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

Prepared according to the procedure in example 5 with melting point 178-180°C.

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,

1.9, 0.4Hz), 7.00 (d, 1H, J=8.1Hz), 2.05-1.64 (m, 10H).

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

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) 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=8.1Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m, 3H).

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

EXAMPLE 27

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

Prepared according to the procedure in example 5 with a melting point of 180-183°C.

<!>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=8.1Hz), 7.76 (tt, 1H, J=4.3, 2.3Hz),

2.05-1.62 (m, 10H).

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

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) 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).

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

EXAMPLE 28

5- f 1, 2- dihydro- 2- thioxospiro [ cvclohexane- 1, 3- [ 3H1 indoll- 5- vD- 4- propyl- 2-thiophenecarbonitrile

5- fl. 2-dihydro-2-oxospiro[cyclohexane-1.3-[3H1indole]-5-vl')-4-propyl-2-thiophenecarbonitrile.

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) 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).

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

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

Analysis for C2iH22N2OS»l/2 H20:

Calculated: C, 70.2; H, 6.39; N, 7.79.

Observed: C, 70.67; H, 6.34; N, 7.62.

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) and 0.87 (t, 3H, J=7.3Hz). MS ((-)-APCI) m/z 365 [M-H]'.

EXAMPLE 29

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) 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=1.98Hz), 7.92 (dd, 1H, J=13.4,1.76Hz), 8.18 (t, 1H, J=8.46Hz) and

10.52 (p, 1H).

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

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) δ 12.82 (br s, 1H), 8.21 (t, 1H, J=8.4Hz), 8.07 (d, 1H, J=1Hz),

7.98 (dd, 1H, J=13.1Hz), 7.79 (dt, 1H, J=8.1 and 2.6Hz), 7.19 (1H,

J=8.2Hz), 1.99-1.83 (m, 7H) and 1.42-1.39 (m, 3H).

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

EXAMPLE 30

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.

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=1.5, 6.5Hz), 6.9 (d, 1H, J=8.0Hz), 2.0-1.6 (m, 10H).

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

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) δ 12.74 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.62 (dd,

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]-.

EXAMPLE 31

5"- f3- chlorophenvnspirorcclobutane- L3M-[ 3Hlindone- 2M( lH)- thione 5- bromospirorcclobutane- 1, 3-[ 3H" lindol]- 2( lH)- one

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.

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).

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

Analysis for CnHioBrNO:

Calculated: C, 52.41; H, 4.00; N, 5.56.

Found: C, 51.98; H, 4.24; N, 5.42.

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.

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=8.1Hz), 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).

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

Analysis for C17H14CINO:

Calculated: C, 71.96; H, 4.97; N, 4.94.

Found: C, 70.75; H, 5.07; N, 4.68.

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.

<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 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).

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

EXAMPLE 32

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,

according to General Procedure A, to give 0.042 g of the product as an off-white solid.

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).

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

EXAMPLE 33

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) 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=8.1 and 1.4Hz), 7.50 (d, 2H, J=8.5Hz), 7.15 (d, 1H,

J=8.1Hz), 1.99-1.83 (m, 7H) and 1.50-1.36 (m, 3H).

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

EXAMPLE 34

S- d^ l^- dihydro- l^- thioxospirofcvchlorohexane- lJ^ rSHl- indole- S^- vlM- metvl- Z-thiophenecarbonitrile

5- bromo- 4- methyl- 2- thiophenecarboxaldehvd

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 cm 1 .

1 H NMR (CDCl 3 ) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H).

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

Analysis for C6H5BrOS:

Calculated: C, 35.14; H, 2.46.

Found: C, 35.00; H, 2.44.

5-bromo-4-methyl-2-thiophenecarbonitrile

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>.

1 H NMR (CDCl 3 ) δ 7.29 (s, 1H), 2.21 (s, 3H).

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

Analysis for C6H4BrNS:

Calculated: C, 35.66; H, 1.99; N, 6.93.

Found: C, 36.00; H, 2.14; N, 6.76.

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.

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=1.7Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H). MS (EI) m/z 282 (M)<+>.

Analysis for Ci6Hi4N2OS.

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.

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=8.1, 1.6Hz), 7.18 (d, 1H, J=8.1Hz), 1.99-1.80 (m, 7H) and 1.40-1.36 (m,

3H).

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

EXAMPLE 35

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

5-bromo-2-thiophenecarbonitrile

A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine

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 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.

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%).

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,

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).

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

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) 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).

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

EXAMPLE 36

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

Prepared according to the procedure in example 5 with melting point 171-172°C.

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=5.1, 1.3Hz), 7.26 (dq, 1H, J=5.9,

2.1Hz), 7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H).

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

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.

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).

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

EXAMPLE 37

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

Prepared according to the procedure of example 5 with melting point 213-216°C.

*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) and 9.73 (s, 1H, br).

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

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.

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 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]-.

EXAMPLE 38

5- f3- chlorophenvn- 3. 3- diethyl- 1. 3- dihydro- 2H- indol- 2- thione

A solution of oxindole (40 g, 0.3 mol) in 400 mL of dry THF was cooled under N2 to

-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

of 3 g was recrystallized from EtOAc:hexane to give 3-ethyl-indol-2-one (1.4 g), mp 100-101°C.

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),

7.22 (m, 1H), 10.3 (s, 1H).

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

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.

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=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).

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

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) 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)-.

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) 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=8.1, 2Hz), 7.43 (t, 1H, 7.9Hz), 7.36-7.33 (m, 1H), 6.90

(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)-.

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) 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=8.1Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H,

J=7.3Hz).

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

EXAMPLE 39

5- f4- fluoro- 3-( trifluoromethvnphenvllspirorcvclohexane- 1. 3- r3Hlindoll- 2( 1H)- thione

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) 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=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*).

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.

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).

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

EXAMPLE 40

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) 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=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) and 1.40-1.38 (m, 3H).

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

EXAMPLE 41

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

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) 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,

3H).

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

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

Analysis for C22H24N2OS«1,4 H20:

Calculated: C, 71.61; H, 6.69; N, 7.59.

Observed: C, 71.13; H, 6.61; N, 6.91.

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.

1 H NMR (DMSO-de) δ 12.83 (br s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H,

J=8.1Hz), 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).

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

EXAMPLE 42

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.

<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=8.1Hz), 7.08 (d, 1H, J=10Hz), 7.01 (s, 1H), 6.83 (dt, 1H,

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]".

EXAMPLE 43

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.

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 (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).

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

EXAMPLE 44

N-(acetyloxy)-5'-(3-chlorophenyl)spiro[cyclohexane-L3'-[3Hlindol-2w-amine

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 (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]<+>.

Analysis for C2iH2iClN2O2«0.5H2O:

Calcd: C, 66.98; H, 5.64; N, 7.34.

Found: C, 66.74; H, 5.86; N, 7.41.

EXAMPLE 45

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%).

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=8.1Hz), 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]\

Analysis for C19H19FN2O:

Calculated: C, 73.53; H, 6.17; N, 9.03.

Found: C, 73.33; H, 6.07; N, 8.83.

EXAMPLE 46

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) 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).

Procedure A

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) 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).

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

Procedure B

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.

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).

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

EXAMPLE 47

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-

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.

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=8.1Hz), 7.21-7.63 (1H, m), 9.58 (1H, s).

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

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.

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=1.9Hz), 7.49 (1H, s),

7.60-7.63 (2H, m), 9.35 (1H, s), 9.56 (1H, s).

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

EXAMPLE 48

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.

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

(1H, p).

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

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%).

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).

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

EXAMPLE 49

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.

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),

9.57 (1H, p).

MS (ESI(-ve)) m/z 411 (M-H)-.

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.

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

(1H, d), 9.35 (1H, s), 9.56 (1H, s).

MS (ESI(+ve)) m/z 323 (M+H)<+>.

EXAMPLE 50

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

with hexamethyl acetate 10:0.5 gave the desired product (0.60 g, 1.4 mmol, 55%) as a viscous oil.

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

(1H, p).

MS (ESI(-ve)) m/z 426 (M-H)\

Procedure 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) 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).

MS (ESI(+ve)) m/z 338 (M+H)<+>.

EXAMPLE 51

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

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.

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

(1H, p).

MS (ESI(-ve)) m/z 406 (M-H)-.

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.

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

(1H, p).

(ESI(+ve)) m/z 318 (M+H)<+>.

EXAMPLE 52

S- rr^^- dihvro^^- fhvdroxviminolspirorcvchlorohexane- lJ^- PHlindone- S^- vn- S-fluorobenzonitrile

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 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%).

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%).

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 and 2Hz), 7.72-7.68 (m, 2H), 7.54 (d, 1H, J=8.1Hz), 6.80 (d, 1H,

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)<+>.

EXAMPLE 53

5- f5Dirolcvklohexaii- 1. 3>- r3HliDdoll- 2'- fbvroksvimiDoV5,- vn- 4- mervl- 2-thiophenecarbonitrile

4-Methyl-S-trimethylsarayl-thiophene-2-carbonitrile

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.

1 H NMR (DMSO-de, 300 MHz) δ 0.41 (9H, s), 2.28 (3H, s), 7.83 (1H, s).

The latter compound (0.20 g, 0.50 mmol), dichlorobis(triphenylphosphine)palladium(II)

(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.

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=1.7Hz), 7.38 (1H, m), 7.82 (1H,

m), 9.51 (lH,m), 9.66 (lH,m).

MS (ESI(+ve)) m/z 338 (M+H)<+>.

EXAMPLE 54

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.

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).

MS (ESI(-ve)) m/z 152 [M-H]".

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)-.

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 %).

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=1.5Hz), 7.54 (d, 1H, J=3.9Hz), 7.47 (dd, 1H, J=8.1 and 1.6Hz),

6.78 (d, 1H, J=8.1Hz), 2.13-1.90 (m, 2H) and 1.78-1.60 (m, 6H).

MS (ESI(+ve)) m/z 324 (M+H)<+>.

EXAMPLE 55

4-(spirochlorohexane-1,3,-f3Hlindoll-2"(hydroxyimino)-5'-vl)-2-thiophenecarbonitrile 4-(trimethylstannvl)-2-thiophenecarbonitrile

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.

1 H NMR (CDCl 3 ) δ 0.35 (s, 9H), 7.56 (d, J=0.9Hz, 1H), 7.66 (d, J=0.9Hz, 1H).

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%).

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%).

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 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)<+>.

EXAMPLE 56

5-( spiro [ cvchlorohexane- 1, 3 *- [ 3H1 indoll - 2 * ( hvdroxyimino)- 5*- vD- 1 H- pyrrole- 1 - metvl-2- carbonitrile

2- ( 5' rspirofcvclohexane- 1. 3 '- fSHlindoll- d • HVon- 2,( Q- benzvloxime) l 1- lH- pvrrole- 1 - carboxylic acid, tert- butyl ester

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.

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- butoxxcarbonvl- 1H- pvrrol- 2- vnspirorcvclohexane- 1. 3 '- r3H1indoll- 2'-( 1 * H)one- 2'-( Q- benzvloximM '- carboxylic acid. tert- butyl ester.

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.

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) 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- pyrrole^- vnspirorcvclohexane- l. S^ rSHIindoll^ Triffon^^ CO-benzyloximVl '- carboxylic acid. tert-butyl ester

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%).

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=1.8, 0.3Hz), 7.76 (d, 1H, J=0.4Hz).

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-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^- spirorcvchlorohexane- lJ^ rSHlindoll- a^ HVon^^- ør- benzvloximll- lH- pvrrol- 1-methyl- 2- carbonitrile

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%).

<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).

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.

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=1.12Hz), 9.48 (s, 1H), 9.62 (s, 1H).

EXAMPLE 57

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) 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).

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%).

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=8.1, 1.73Hz), 7.63 (d, 1H, J=1.73), 9.42 (s, 1H), 9.59 (s, 1H), 12.39 (p, 1H).

EXAMPLE 58

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

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]<+>.

EXAMPLE 59

3-fluoro-N'-hydroxy-5-f2'-(hydroxyamino)spirochlorohexane-1,3*-[3H1indol-5'-<y>llbenzenecarboximidamide

5'-(3-Cvano-5-fluorophenyl)-2-(methylthio)spiro|"cyclohexane-1,3*-|" 3H1indole]

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%).

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 and 1.9Hz),

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)<+>.

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) 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)<+>.

EXAMPLE 60

N*-hydroxy-5-(spiro[cyclohexane-1,3'-[3Hlindone-2'(hydroxyimino)-5'-vl)-4-methyl-2-thiophenecarboximidamide

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) 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).

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%.

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 (p, 1H), 9.56 (p, 1H), 9.58 (p, 1H).

EXAMPLE 61

N'-hydroxiv-4'-(spiro[cyclohexane-1,3*-[ 3Hlindoll-2'-(livdroxvimipo)-5'-vl-2-thiophenecarboximidamide

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]<+>.

EXAMPLE 62

N"- hydroxy- 5-(spirochlorohexane-1,3*- 3Hlindoll- 2"-( hydroxyimino)- 5*- vl)- 2-thiophenecarboximidamide

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%).

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 ).

EXAMPLE 63

5'-( 3- chlorophenvspirofccyclohexane- 1, 3*- r3Hlindol- 2*- vlidene- cyanamide 5*- f3- chlorophenvl) spiro|" cchlorohexane- 1. 3'-[ 3Hlindol1- 2'- amine

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)<+>.

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

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.

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,

NH).

MS (ECI(ve)) m/z 411 (M+H)<+>.

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 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) 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,

J=6.4Hz), 7.71 (s, 1H), 7.85 (s, 1H), 12.1 (s, 1H, NH).

MS (ECI(-ve)) m/z 336 (M-H)-.

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. Compound characterized by the formula: 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 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. 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 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: 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. Compound characterized by the formula 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: 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: where: Xi is N or CX<2>; X<2> is halogen, CN or CONH2; or a pharmaceutically acceptable salt thereof. 4. Compound characterized by the formula: there: R.5 is a), b) or c): a) a substituted benzene ring containing the substituents X and Y as shown below: 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: 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: where: X, is N or CX<2>; X<2> is halogen, CN or CONH2; or a pharmaceutically acceptable salt thereof. 5. Compound characterized by the formula: 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: 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: where: X is N or CX<2>; X<2> is halogen, CN or CSNH2; or a pharmaceutically acceptable salt thereof. 6. Compound characterized by the formula: there: Rs is a), b) or c): a) a substituted benzene ring containing the substituents X and Y as shown below: 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: where: Xi is N or CX<2>; X<2> is halogen, CN or CONH2; or a pharmaceutically acceptable salt thereof. 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. Compound according to any one of claims 1 or 2, characterized by the formula: there: R5 is the substituted benzene ring of the formula: 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. Compound according to any one of claims 1 or 2, characterized by the formula: there: R.5 is the five-membered ring with the structure: 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. Compound according to any one of claims 1 or 2, characterized by the formula: there: Rs is the six-membered ring with the structure: X<1>is N or CX2; X<2>is halogen, CN or CSNH2. 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'-thioxospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)benzonitrile, 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-(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[cyclohexane-1,3-[3H]indole]-2(1H)-thione, 3-(1,2-dihydro-2-thioxospiro[cyclopentane-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-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-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[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-(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-(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(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[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[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-chlorophenyl)-3,3-dimethyl-1,3-dihydro-2H-indole-2-thione, 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-furonitrile, 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-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-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[cyclohexane-1,3'-[3H]indole]-2'-cyanomethylene-5'-yl)-thiophene-2-carbonitrile, or a pharmaceutically acceptable salt thereof. 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. Compound according to any one of claims 3 to 6, characterized in that R 5 is thiophene or furan. 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. 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. 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. 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. 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. 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.