KR20020000636A - Thio-oxindole derivatives - Google Patents

Abstract

The present invention relates to compounds which are agonists of progesterone receptors having formula (1) or formula (2) or pharmaceutically acceptable salts thereof, as well as methods of using these compounds in the induction of contraception or treatment of progesterone-related carcinomas and adenocarcinomas will be.

(Formula 1)

(Formula 2)

Wherein the substituents are as defined.

Description

Thio-oxindole derivatives {THIO-OXINDOLE DERIVATIVES}

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 progesterone receptors (PR), estrogen receptors (ER), androgen receptors (AR), glucocorticoid receptors (GR), and inorganic corticosteroid receptors (MR).

Natural hormones or ligands for PR are steroid progesterone, but synthetic compounds such as methoxyprogesterone acetate or levonorgestrel are also used as ligands. Once the ligand is in the fluid surrounding the cell, it passes through the membrane by passive diffusion and binds to the IR to form a receptor / ligand complex. This complex binds to a specific gene promoter present in the DNA of the cell. Once bound to DNA, the complex regulates the production of mRNA and the protein encoded by the gene.

Compounds that bind to IR and mimic the action of natural hormones are named agonists, and compounds that inhibit the effects of hormones are termed antagonists.

PR agonists (natural and synthetic) are known to play an important role in women's health. PR agonists are typically used in birth control agents in the presence of ER agonists, or alternatively they may be used with PR antagonists. ER agonists are used to treat the symptoms of menopause, but are also associated with a proliferative effect on the uterus, which can increase the risk of uterine cancer. Co-administration of PR agonists reduces / eliminates such risks.

Compounds of the present invention have been shown to act as competitive inhibitors for progesterone binding to PR and act as agonists. These compounds can be used for contraception and postmenopausal hormone replacement therapy.

Jones et al. Describe the PR antagonist dihydroquinoline A in US Pat. No. 5,688,810.

Jones et al. Described Enol Ether B (US Pat. No. 5,693,646) as a PR ligand.

Jones et al. Described Compound C (US Pat. No. 5,696,127) as a PR ligand.

Zhi et al. Described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998).

Zhi et al. Described ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998).

Combs et al. Described amide H as a ligand for PR (J. Med. Chem., 38, 4880, 1995).

Perlman et al. Described vitamin D analogue I as a PR ligand (Tet. Letters, 35, 2295, 1994).

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

Chen et al. Described PR antagonist K (Chen, et al, POI-37, 16 ^th Int. Cong. Het. Chem., Montana, 1997).

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

Kuhla et al. Described oxindole M as having strong heart activity (WO 86/03749).

Weber et al teach oxindole N for cardiovascular indicators (WO 91/06545).

Fischer et al. Claim a recipe for preparing compounds comprising the general formula O (US Pat. No. 5,453,516).

R = various

Singh et al. Described PDE III inhibitor P (J. Med. Chem., 37, 248, 1994).

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

Binder et al. Described Structural Formula R, an intermediate for preparing COX II inhibitors (WO 97/13767).

Walsh (A. H. Robins) described Oxidol S as an intermediate (US Pat. No. 4,440,785, US Pat. No. 4,670,566).

R 1 = F, Cl, Br, alkyl, NH ₂

R2 = alkyl, alkoxy, F, Cl, NH ₂ , CF ₃

Bohm et al. Claimed Oxidol T as a cardiovascular preparation (WO 91/06545).

Bohm et al. Comprise the general structural formula U (WO 91/04974).

JP 63112584 A contains the general formula V.

Boar et al. Described Dioxolane W as an intermediate for the preparation of acetylcholinesterase inhibitors (WO 93/12085 A1).

Kende et al. Described a method for preparing 3,3-substituted auxindol, for example X, for use in the present invention (Synth. Commun., 12, 1, 1982).

The present invention relates to compounds which are agonists of progesterone receptors, their preparation and use.

The present invention provides compounds of Formula 1 or Formula 2, or pharmaceutically acceptable salts thereof.

Where

R ₁ and R ₂ are H, alkyl, substituted alkyl; OH; O (alkyl); O (substituted alkyl); OAc; Aryl; Optionally substituted aryl; Heteroaryl; Optionally substituted heteroaryl; Alkylaryl; Alkylheteroaryl; 1-propynyl; Or independently selected from 3-propynyl: or

R ₁ and R ₂ are combined to

_{-CH 2 (CH 2) nCH 2} -, -CH 2 CH 2 CMe 2 CH 2 CH 2 -, -O (CH 2) mCH 2 -, O (CH 2) pO-, -CH 2 CH 2 OCH 2 CH _2- , or -CH ₂ CH ₂ N (H or alkyl) CH ₂ CH _2-

To form a ring comprising one of;

m is an integer from 1 to 4;

n is an integer from 1 to 5;

p is an integer from 1 to 4; or

R ₁ and R ₂ together comprise a double bond with one of CMe ₂ , C (cycloalkyl), O, C (cycloether);

R ₃ is selected from H, OH, NH ₂ , C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₆ alkenyl, alkynyl or substituted alkynyl, or COR ^A ;

R ^A is H, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ aminoalkyl, or substituted C ₁ To C ₃ aminoalkyl;

R ₄ is H, halogen, CN, NH ₂ , C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, substituted C ₁ to C ₆ alkoxy, C ₁ to C ₆ amino Alkyl, or substituted C ₁ to C ₆ aminoalkyl;

R ⁵ is selected from the group a), b) or c);

a) R ⁵ is a trisubstituted benzene ring containing substituents X, Y and Z as shown below;

X is halogen, OH, CN, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ thioalkyl, substituted C ₁ to C ₃ thioalkyl, S (O) alkyl, S (O) ₂ alkyl, C ₁ to C ₃ aminoalkyl, substituted C ₁ to C ₃ aminoalkyl, NO ₂ , C ₁ to C ₃ perfluoro Alkyl, 5 or 6 membered heterocycle containing 1 to 3 heteroatoms, CONH ₂ , CSNH ₂ , CONHalkyl, CSNHalkyl, CON (alkyl) ₂ , CSN (alkyl) ₂ , COR ^B , OCOR ^B , NR ^C COR ^B is selected from;

R ^B is H, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, aryl, substituted aryl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ aminoalkyl Or substituted C ₁ to C ₃ aminoalkyl;

R ^C is H, C ₁ to C ₃ alkyl, or substituted C ₁ to C ₃ alkyl;

Y and Z are independently selected from H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, or C ₁ to C ₃ thioalkyl; or

b) R ⁵ has 1, 2 or 3 heteroatoms selected from O, S, SO, SO ₂ or NR ⁶ and H, halogen, CN, NO ₂ and C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, 5 or 6 membered heterocycle containing 1 or 2 independent substituents from the group of C ₁ to C ₃ aminoalkyl, COR ^D or NR ^E COR ^D ;

R ^D is H, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, aryl, substituted aryl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ aminoalkyl Or substituted C ₁ to C ₃ aminoalkyl;

R ^E is H, C ₁ to C ₃ alkyl, or substituted C ₁ to C ₃ alkyl;

R ⁶ is H, or C ₁ to C ₃ alkyl; or

c) R ⁵ is indol-4-yl, indol-7-yl or benzo-2, optionally substituted by 1 to 3 substituents selected from halogen, lower alkyl, CN, NO ₂ , lower alkoxy or CF ₃ A thiophene moiety;

Q ¹ is S, NR ₇ , CR ₈ R ₉ ;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, acyl, substituted acyl, aroyl, substituted aroyl, SO ₂ CF ₃ , OR ¹¹ or NR ¹¹ R ¹² ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , A substituted heterocycle, NO ₂ , CN, or an independent substituent selected from the group of CO ₂ R ₁₀ ;

R ₁₀ is C ₁ to C ₃ alkyl; or

CR ₈ R ₉ has the following structure

A six-membered ring as represented by;

Q ² is part

Is selected from;

R ¹¹ , R ¹² and R ¹³ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl or Independently from substituted aroyl or sulfonyl.

Preferred lists of substituents represented by R ¹¹ , R ¹² and R ¹³ in the group of compounds described herein include H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, —C (O) — (C ₁ to C ₆ alkyl), -S (O) _2- (C ₁ to C ₆ alkyl), phenyl or benzyl.

It will be understood that the invention includes all tautomeric forms of the compounds, formulas and substituents described herein.

Two preferred sets of compounds of the invention are depicted by structures 2 and 3, or pharmaceutically acceptable salts thereof, respectively.

Wherein each R ⁵ is a disubstituted benzene ring containing substituents X and Y as shown below;

X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ perfluor Roalkyl, a 5-membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy;

Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl.

Another preferred group of formula 2 are those in which R ⁵ is a 5-membered ring having the structure shown below, or pharmaceutically acceptable salts thereof.

From here,

U is O, S, or NR ⁶ ;

R ⁶ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy;

Y 'is selected from H, F or C ₁ to C ₄ alkyl.

More preferred subgroups of such compounds are those in which R ₅ is a thiophene or furan ring substituted by X 'and Y' as described above.

More preferred subgroups of structures 2 and 3 are those in which R ₅ is a 6 membered ring having the following structure, or a pharmaceutically acceptable salt thereof.

From here,

X ¹ is N or CX ² ;

X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and;

Q ¹ is S, NR ₇ , CR ₈ R ₉ ;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ,

R ₁₀ is C ₁ to C ₃ alkyl;

CR ₈ R ₉ has the following structure

It is within the range of the six-membered ring as indicated by.

Even more preferred groups of these compounds are those having the following structural formulae, or pharmaceutically acceptable salts thereof.

Wherein each R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below;

X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ perfluor Roalkyl, a 5-membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy;

Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl.

constitutional formula

More preferred subgroups of compounds of are those wherein R ₅ is a 6 membered ring having the structure: or pharmaceutically acceptable salts thereof.

From here,

X ¹ is N or CX ² ;

X ² is halogen, CN, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, or NO _2, and;

Q ² is as defined above;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ;

R ₁₀ is C ₁ to C ₃ alkyl;

CR ₈ R ₉ has the following structure

It is within the range of the six-membered ring as indicated by.

A more preferred set of compounds of the present invention are depicted by Structural Formula 4, or a pharmaceutically acceptable salt thereof.

Wherein R ₁₄ is selected from the group of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, substituted sulfonyl.

Wherein R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below,

X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON (alkyl) ₂ , CSN (alkyl) ₂ , CNHNHOH, CNH ₂ NOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ perfluoroalkyl, 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy;

Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl.

Another preferred group of formula 4 are those in which R ₅ is a 5-membered ring having the structure shown below, or pharmaceutically acceptable salts thereof.

From here,

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is halogen, CN, NO _2, CONH _2, CNHNHOH, CNH ₂ NOH, CSNH _2, CONH-alkyl, CSNH-alkyl, CON ilkil _2, CSN alkyl _2, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy Is selected from;

Y 'is selected from H, F or C ₁ to C ₄ alkyl.

More preferred subgroups of such compounds are those in which R ₅ is a thiophene or furan ring substituted by X 'and Y' as described above.

More preferred subgroups of compounds of formula 4 are those in which R ₅ is a 6 membered ring having the structure: or pharmaceutically acceptable salts thereof.

From here,

X ¹ is N or CX ² ;

X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, alkyl, CNO _2, CSN alkyl ₂ or NO _2, and;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ;

R ₁₀ is C ₁ to C ₃ alkyl.

A more preferred set of compounds of the invention is depicted by formula 5, or a pharmaceutically acceptable salt thereof.

Where

R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below;

X is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl _2, CNHNOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, N0 _2, C ₁ to C ₃ Perfluoroalkyl, a 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy;

Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl.

Another preferred group of formula 5 are those in which R ₅ is a 5-membered ring having the structure shown below, or a pharmaceutically acceptable salt thereof.

From here,

U is 0, S, or NR ₆ ;

R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy;

Y 'is selected from H, F or C ₁ to C ₄ alkyl.

More preferred subgroups of such compounds are those in which R ₅ is a thiophene or furan ring substituted by X 'and Y' as described above, or pharmaceutically acceptable salts thereof.

More preferred subgroups of compounds of formula 5 are those in which R ₅ is a 6 membered ring having the structure: or pharmaceutically acceptable salts thereof.

From here,

X ¹ is N or CX ² ;

X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ;

R ₁₀ is C ₁ to C ₃ alkyl.

A more preferred set of compounds of the invention is depicted by formula 6, or a pharmaceutically acceptable salt thereof.

Wherein R ₁₅ is selected from the group of H, Me, CO ₂ R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, CN.

Wherein R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below;

X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , CNHNOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ Perfluoroalkyl, a 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy;

Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl.

Another preferred group of formula 6 are those in which R ₅ is a 5-membered ring having the structure shown below, or pharmaceutically acceptable salts thereof.

From here,

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy;

Y 'is selected from the group of H, F or C ₁ to C ₄ alkyl.

More preferred subgroups of such compounds are those in which R ₅ is a thiophene or furan ring substituted by X 'and Y' as described above, or pharmaceutically acceptable salts thereof.

More preferred subgroups of compounds of formula 6 are those in which R ₅ is a 6 membered ring having the structure: or pharmaceutically acceptable salts thereof.

From here,

X ¹ is N or CX ² ;

X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ;

R ₁₀ is C ₁ to C ₃ alkyl.

A more preferred set of compounds of the present invention are depicted by the formula 7, or pharmaceutically acceptable salts thereof.

Where

R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below;

X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , CNHNOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ Perfluoroalkyl, a 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy;

Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl.

Another preferred group of formula 7 are those wherein R ₅ is a 5-membered ring having the structure shown below, or pharmaceutically acceptable salts thereof.

From here,

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy;

Y 'is selected from H, F or C ₁ to C ₄ alkyl.

More preferred subgroups of such compounds are those in which R ₅ is a thiophene or furan ring substituted by X 'and Y' as described above.

More preferred subgroups of compounds of formula 7 are those in which R ₅ is a 6 membered ring having the structure: or pharmaceutically acceptable salts thereof.

From here,

X ¹ is N or CX ² ;

X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and;

R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ;

R ₁₀ is C ₁ to C ₃ alkyl.

The compounds of the present invention may contain asymmetric carbon atoms, and some of the compounds of the present invention may contain one or more asymmetric centers, thus resulting in optical isomers and diastereomers. In the general formula (1) and (2), the stereochemistry is ignored and shown, but the present invention is directed to such optical isomers and diastereomers; Racemic and separated enantiomerically pure R and S stereoisomers; Other mixtures of R and S stereoisomers, and pharmaceutically acceptable salts thereof.

As used herein, the term "alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms; "Alkenyl" is intended to include straight and branched chain alkyl groups having 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms; "Alkynyl" groups are intended to include straight and branched chain alkyl groups having at least one or two carbon-carbon triple bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms.

The term "acyl" refers to carbonyl substituents comprising straight and branched chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term "substituted acyl" refers to halogen, CN, OH and Consider the acyl group just described, optionally substituted with 1 to 6 groups selected from NO ₂ .

The term "aroyl" also refers to a carbonyl substituent having a phenyl or heteroaromatic group. Its heteroaromatic groups include 2-, 3- or 4-pyridinyl, 2- and 3-furanyl, 2- or 3-thiophenyl, or 2- or 4-pyrimidinal. The term "substituted aroyl" also refers to the aroyl group just described, optionally substituted with 1 to 6 groups selected from halogen, CN, OH and NO ₂ .

The terms "substituted alkyl", "substituted alkenyl" and "substituted alkynyl" refer to halogen, CN, OH, NO ₂ , amino, aryl, heterocycle, substituted aryl, substituted heterocycle, alkoxy, aryloxy , Alkyl, alkenyl and alkynyl as just described with one or more substituents from the group comprising substituted alkyloxy, alkylcarbonyl, alkylamino, arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl or alkynyl group, provided that their attachment constitutes a stable chemical moiety.

As used herein, the term “aryl” refers to an aromatic system that may be a single ring or multiple aromatic rings that are fused or linked together, such that at least one portion of the fused or linked ring forms a conjugated aromatic system. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.

The term "substituted aryl" refers to halogen, CN, OH, NO ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or aryl Considered aryl as just defined with 1-4 substituents from the group containing thio.

As used herein, the term “heterocycle” refers to a stable 4- to 7-membered one that is saturated, partially unsaturated or unsaturated, consisting of 1 to 4 heteroatoms selected from the group comprising carbon atoms and N, O and S atoms. Describe ring or stable multicyclic heterocycles. N and S atoms can be oxidized. Heterocycles also include any polycycle in which any of the heterocycles defined above are fused to an aryl ring. Heterocycles may be attached to any heteroatom or carbon atom provided that the resulting structure is chemically stable. Such heterocyclic groups include, but are not limited to, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azifinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyri Midinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide and Isoquinolinyl.

As used herein, the term “substituted heterocycle” refers to halogen, CN, OH, NO ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted The just-defined heterocycle having 1 to 4 substituents selected from the group comprising alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio is described.

As used herein, the term "thioalkyl" refers to an SR group, where R is alkyl or substituted alkyl containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. As used herein, the term "alkoxy" refers to an OR group, where R is alkyl or substituted alkyl containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. As used herein, the term “aryloxy” refers to an OR group, where R is aryl or substituted aryl as defined above. As used herein, the term "alkylcarbonyl" refers to an RCO group, where R is alkyl or substituted alkyl containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. As used herein, the term "alkylcarboxy" refers to a COOR group, where R is alkyl or substituted alkyl containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term "aminoalkyl" refers to secondary and tertiary amines, wherein alkyl or substituted alkyl groups containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, may be the same or different and the attachment position is It is a nitrogen atom. The term "halogen" refers to Cl, Br, F, or I.

Compounds of the invention can be prepared according to the procedures described below.

According to Scheme 1, commercially available oxindoles (3) in the presence of lithium chloride or N, N, N ', N'-tetramethylethylenediamine are reacted with an inert solvent (e.g. , THF, diethyl ether) with strong organometallic bases (e.g., butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide) (Kende, et al, Synth. Commun., 12, 1 , 1982). The resulting di-anion is then treated with excess electrophile such as alkyl halide, preferably iodide. If R ₁ and R ₂ are to be combined such that product (4) contains spirogly at the 3-position, the electrophile must be difunctional, i.e. iodide. The bromination of (4) then proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as needed) in the presence of sodium acetate to give aryl bromide (5). This bromide (5) is a palladium salt (e.g., tetrakis (triphenylphos) in a suitable solvent (e.g. THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature under an inert atmosphere (argon, nitrogen). Pin) palladium (0) or palladium acetate). The mixture is then treated with aryl or heteroaryl boronic acid or boronic esters and bases in water (sodium acetate, triethylamine, potassium phosphate) or with a fluoride source (cesium fluoride) under anhydrous conditions.

Indolin-2-one derivative (6) and Laweson reagent (6) 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 Lawessen's reagent) or phosphorus pentasulfide provides the thiocarbonyl derivative (7). Additives such as sodium bicarbonate may also be useful.

If R ₁ and R ₂ are different, intermediate (4) is prepared by reaction of the anion of (3) with one equivalent of electrophile R ₁ -X (X = leaving group, for example iodine), in one of the results, or alkylated compound is separated is reacted again with reaction conditions using R ₂ -X, or used in situ for the second alkylation with R ₂ -X. Alternatively, if the desired product 7 should contain R ₂ = H, a separate mono-alkylated intermediate is obtained through the following steps.

Other methods also provide for the coupling of the pendant aryl or heteroaryl group Ar with an auxindol platform, for example compound (7) in the presence of a palladium or nickel catalyst or a halogenated aryl or heteroaryl stannane, aryl or heteroaryl zinc, Or react with aryl or heteroaryl magnesium (Scheme 2). The necessary aryl or heteroaryl metal species described above are formed through standard techniques.

According to Scheme 3, other functional groups can be easily installed in the 3-position of the indolin platform. Preferably, oxidation of unsubstituted indolin 8 under neutral or acidic conditions (eg, selenium dioxide in dry dioxane at reflux) provides isatin 9. Under dehydration conditions compound 9 can be further functionalized by treatment with an alcohol and an acidic catalyst to provide ketal 11. Alternatively, the reaction of the secondary ketone under stable conditions (piperidine in reflux toluene; or TiCl ₄ / Zn in reflux THF) (9) gives an alkylidene derivative (11). Reaction of isatin (9) with Grignard reagent or organolithium provides tertiary alcohol (12) (R = H). These alcohols may then be further functionalized by an alkylation or acylation process.

Indolin-2-one derivative (6) and Laweson reagent 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 or The reaction of phosphorus pentasulfide gives the thiocarbonyl derivative (7). Additives such as sodium bicarbonate may also be useful.

Another method of preparation is the compound (in pyrodine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent under an inert atmosphere (nitrogen or argon). 5) to react with Laweson reagent or phosphorus penta sulfide to provide a thiocarbonyl derivative (13). The bromide (13) is reacted with a strong base (preferably sodium hydride, sodium hexamethyldisilazide, potassium hydride) in anhydrous solvents (e.g. THF, Et ₂ O), followed by reduction temperature (-50 to- At 20 ° C.) and n-butyllithium and N, N, N, N′-tetramethylethylenediamine, followed by a suitable time after reaction with trialkylborate (trimethyl or triisopropylborate) and acid workup. Acid 14 is obtained (Scheme 4). Next, compound (14) was treated with palladium catalyst conditions (tetrakis (triphenylphosphine) palladium (0), base (NaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, CsF), solvent (toluene Aryl or heteroaryl trifluoro of aryl bromide or heteroaryl, aryl iodide or heteroaryl, aryl or heteroaryl fluorosulfonate under (EtOH / water, THF / water, dimethoxyethane / water, dimethoxyethane anhydride)) It can be reacted with methanesulfonate to give the desired compound (7).

Palladium catalyst conditions (tetrakis (triphenylphosphine) palladium (0), base (NaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, CsF), solvent (toluene / EtOH / water, THF / water Aryl or heteroaryl trifluoromethanesulfo of compound (13) with aryl bromide or aryl or heteroaryl, aryl iodide or heteroaryl, or aryl or heteroaryl fluorosulfonate Another reaction of the nate gives the desired compound (7).

The bromide (5) is treated with a strong base (preferably sodium hydride, sodium hexamethyldisilazide, potassium hydride) in anhydrous solvents (e.g. THF, Et ₂ O), followed by reduction temperature (-50 to- At 20 ° C.) and n-butyllithium and N, N, N, N′-tetramethylethylenediamine, and then after a suitable time, react with trialkylborate (trimethyl or triisopropylborate) and work up Acid 15 is obtained (Scheme 5). Next, palladium catalyst conditions (tetrakis (triphenylphosphine) palladium (0), base (NaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, CsF), solvent (toluene / EtOH / water, Aryl or heteroaryl trifluoro of aryl bromide or heteroaryl, aryl iodide or heteroaryl, aryl or heteroaryl fluorosulfonate under compound (15) under THF / water, dimethoxyethane / water, anhydrous dimethoxyethane) It can be reacted with methanesulfonate to give the desired compound (6).

Another strategy is to prepare an organic zinc or magnesium reagent from compound (5), which is aryl or heteroaryl trifluoro of aryl bromide or heteroaryl, aryl iodide or heteroaryl, aryl or heteroaryl fluorosulfonate under palladium catalytic conditions In situ reaction with methanesulfonate to provide compound (6). Such organic zinc or magnesium species is treated with bromide 57 with a strong base (preferably sodium hydride, sodium hexamethyldisilazide, potassium hydride) in anhydrous solvents (e.g. THF, Et ₂ O), followed by By reacting with n-butyllithium and N, N, N ', N'-tetradimethylethylenediamine at a reduction temperature (-50 to -20 ° C) and then after a suitable time with anhydrous zinc chloride or magnesium bromide Can be prepared.

Indolin-2-one derivative 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 (nitrogen or argon) Reaction of (6) with Laweson reagent or phosphorus pentasulfide provides thiocarbonyl derivative (15). Additives such as sodium bicarbonate may also be useful.

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

Thus, thioamide (7) (Pg = H, 2- (thiomethylsilyl) -ethoxymethyl, benzyl, etc.) is reacted with thioethyloxonium tetrafluoroborate, followed by nucleophiles (nitromethane, cyanamide, Trifluoromethanesulfonamide, meldrum's acid, etc.), followed by removal of the protecting group under suitable conditions (e.g., tetrabutylammonium fluoride in THF for suitable Pg = 2- (trimethylsilyl) -ethoxymethyl) The lower surface enamine derivative 16 is obtained. Suitable solvents for the second stage are selected from chloromethane, THF, dioxane, 1,2-dichloroethane, and the reaction is carried out at -78 ° C. at a temperature up to the boiling point of the solvent under an inert atmosphere (nitrogen or argon).

According to Scheme 7, suitable bases (e.g. pyridine, triethylamine or in a suitable organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a temperature between the boiling point of the solvent at -78 ° C or In the presence of an amine base such as diisopropylethylamine or lithium carbonate, sodium, potassium or cesium), the intermediate (7) is alkylated, for example methyl iodide, ethyl iodide, 2,4-dinitrofluorobenzene or 4- Treatment with nitrofluorobenzene affords thiimino ether (17). Then, a suitable solvent (eg, but not limited to pyridine, methanol, ethanol, isopropanol, DMF, THF or DMSO, and optionally tertiary amine base or sodium acetate at a temperature between −78 ° C. and the boiling point of the solvent) Or in the presence of an additive such as potassium), reacting intermediate 17 with hydroxylamine or an acid salt of hydroxylamine (eg hydrochloride) to obtain N-hydroxylamine 18.

Similarly, suitable bases (e.g., amine bases such as pyridine, triethylamine or diisopropylethylamine or lithium carbonate, sodium, potassium or cesium) or Lewis acids (e.g. boron trifluoride etherate, lead (II) salts, titanium tetrachloride, magnesium (II) salts, or silver salts, are compatible with the base or Lewis acid selected (e.g., DMF, THF, DMSO, dioxane or acetonitrile, chloroform, benzene, toluene Or dichloromethane), intermediate 17 is treated with a carbon nucleophile such as a malonate derivative (e.g., malononitrile, cyano acetate ester, nitro acetate ester or malonate) to obtain adduct 19. If the R 3 group in the adduct 19 is an ester of a carboxylic acid, it is then directly decarboxylated, for example by treatment with sodium iodide in DMSO at room temperature between the boiling point of the solvent and the enamine derivative ( 20). Or alternatively, the ester is first reacted with a carboxylic acid by treatment with an aqueous base (eg lithium hydroxide, sodium or potassium) in a suitable solvent (eg acetonitrile, THF, dioxane acetonitrile, methanol or ethanol). Hydrolyzed and then decarboxylated in the presence of an acid (eg hydrochloric acid or sulfuric acid) in a suitable solvent (eg acetonitrile, THF, dioxane) to provide the derivative 20. Alternatively, xanthate esters of carboxylic acids can be prepared by reaction with a base such as sodium hydride or potassium in THF, followed by treatment with disulphide. Subsequently, the reaction with hydrogenated tributyltin at elevated temperature in a solvent such as benzene or toluene under inert nitrogen or argon in the presence of a radical initiator such as benzoyl peroxide or azo-bis-iso-butyronitrile provides the product (20). .

Another strategy for synthesizing product 18 is illustrated by Scheme 8. Thus, bromide 13 (corresponding chloride, iodide or triflate esters may also be used) is suitable organic solvent (eg, DMF, THF, DMSO, at a temperature between −78 ° C. and the boiling point of the solvent). Alkylating agents, for example methyl iodide, in the presence of a suitable base (e.g., an amine base such as pyridine, triethylamine or diisopropylethylamine, or lithium carbonate, sodium, potassium or cesium) in dioxane or acetonitrile) Treated with ethyl iodide, 2,4-dinitrofluorobenzene, or 4-nitrofluorobenzene to give the thiimino ester (21). Then, a suitable solvent (eg, but not limited to pyridine methanol, ethanol, isopropanol, DMF, THF or DMSO and optionally tertiary amine base or sodium acetate or potassium at a temperature between −78 ° C. and the boiling point of the solvent) Intermediate 21 in the presence of an additive such as hydroxylamine or an acid salt of hydroxylamine (eg hydrochloride, hydrobromide) to obtain N-hydroxyamidine 22. Intermediate 22 may then be protected with compatible groups (eg, benzylether, acyl derivatives, tetrahydropyranyl ether, methoxy methyl ether, silyl ether) to provide derivative 23. Alternatively, compound 21 may be reacted directly with a protected hydroxylamine derivative (selected without being limited to the protecting groups described above) to provide derivative 23 directly. Next, at room temperature under an inert atmosphere (argon, nitrogen), the compound (23) is added with a palladium salt (eg, tetrakis (triphenyl) in a suitable solvent (eg, THF, dimethoxyethane, acetone, ethanol or toluene). Phosphine) palladium (0) or palladium acetate). This mixture is then treated with aryl or heteroaryl boronic acid or boronic esters and bases in water (sodium carbonate, triethylamine, potassium phosphate), or with a fluoride source (cesium fluoride) under anhydrous conditions, and then the reactant is It may be heated to the boiling point of the solvent. The required product 24 is then separated and purified by standard means.

Compound (24) can then be deprotected under conditions defined by the nature of the protecting group. For example, if the protecting group is benzyl ether, then compound (18) can be obtained by treatment with boron tribromide or trimethylsilyl iodide in a suitable solvent (eg dichloromethane). Other methods for removing benzyl ethers include hydrogenation in the presence of a palladium catalyst (hydrogen gas or other hydrogen source such as cyclohexadiene or ammonium formate). Suitable solvents for such processes at room temperature and between the boiling point of the solvents include methanol, ethanol, THF, ethyl acetate and dioxane. If the protecting group is an acetal derivative (tetrahydropyranyl or methoxymethyl ether), the hydrolysis is then carried out in acidic conditions (hydrochloric acid, sulfuric acid, p-toluene sulfonic acid or in a solvent such as methanol, ethanol, THF, dioxane or acetonitrile). Acidic ion exchange resin). If the protecting group is an acyl derivative (e.g. acetate or benzoate), then hydrolysis is carried out as described above in a solvent such as alcohol, THF, dioxane or acetonitrile at room temperature and between the boiling point of the solvent. It can be done under acidic conditions or basic conditions (lithium hydroxide, sodium or potassium). If the protecting group is a silyl ether, then compound (18) is then subjected to hydrolysis of intermediate (24) under acidic conditions described above in a solvent such as alcohol, THF, dioxane or acetonitrile at room temperature and between the boiling point of the solvent Or by exposing compound 24 to a fluoride source (eg, potassium fluoride, cesium fluoride or tetrabutylammonium fluoride). Inert atmosphere of nitrogen or argon may be required.

Another method of synthesizing compound (18) converts the protected N-hydroxyamidine (23) to boronic acid or boronic acid esters (lithium halide exchange followed by quenching with triisopropylborate, or diborinated pinacholic acid). By palladium catalyzed coupling) and then coupling this boronic acid or ester derivative with aryl chloride, aryl bromide, aryl iodide or aryl triflate under a suitable palladium catalyst system as previously described. The desired compound (18) will then be provided by deprotection as described in Scheme 8.

According to Scheme 9, treatment of N-hydroxyamidine 18 under reducing conditions (eg, catalytic hydrogenation, iron in acetic acid or hydrazine-lanney nickel) provides intermediate 25. Suitable solvents for such processes at room temperature and between the boiling point of the solvents include methanol, ethanol, THF, ethyl acetate and dioxane. Next, protection of secondary nitrogen (quaternary butyl carbamate is shown as a non-limiting example) under standard conditions provides compound (26). Cyanating agents (e.g., cyanobromide, which are electrophiles with compound 26 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) The reaction of N-cyanobenzotriazole or cyanogenide / 4-dimethylaminopyridine complex) can provide the desired compound (27). In some cases, if deprotection does not occur in situ and then a further hydrolysis step is needed, the cyanation step may occur concurrently with the removal of the secondary nitrogen protecting group.

Other syntheses of compound (27) can be followed for compound (18) in Scheme 8, and brominated N-cyanoamidine (28) prepared from compound (22) employing a strategy similar to that shown in Scheme 9. This may be coupled with a suitably functionalized aryl boronic acid or boronic acid ester to provide compound (27). Alternatively, compound 28 may be converted to the corresponding boronic acid or boronic ester and coupled with a suitably functionalized aryl bromide with Suzuki or Suzuki type palladium coupling.

The compounds of the present 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, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and optionally organic acids such as acetic acid, oxalic acid, succinic acid and malic acid. Other salts include salts with alkali or alkaline earth metals, such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates and other conventional "prodrugs", which when administered in such form Converted to the active moiety in vivo.

The present invention encompasses pharmaceutical compositions and treatments comprising administering to a mammal a pharmaceutically effective amount of one or more of the compounds or pharmaceutically acceptable salts thereof described above as agonists for progesterone receptors.

Progesterone receptor agonists of the present invention, used alone or in combination, include methods of contraception and dysfunctional bleeding, uterine leiomyoma, endometriosis; Polycystic ovary syndrome, endometrium, ovary, breast, colon, prostate carcinoma and adenocarcinoma. Additional uses of the present invention include stimulation of food intake.

When the present compounds are used for such utility, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example solvents, diluents and the like, and may be used in tablets, capsules, dispersible flours, granules, or for example Orally in the form of suspensions containing from 0.05 to 5% suspending agent, for example syrups containing from about 10 to 50% sugars, and for example elisir containing from about 20 to 50% ethanol and the like. Or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to 90%, more usually from about 5 to 60% by weight of active ingredient in combination with a carrier.

The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration and the severity of the condition to be treated. However, generally satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of about 0.5 to about 500 mg / kg of animal body weight, preferably in divided doses of 2 to 4 times per day, or in sustained release form. Is provided. For the largest mammals, the total daily dose is about 1 to 100 mg, preferably about 2 to 80 mg. Dosage forms suitable for the context comprise about 0.5 to 500 mg of the active compound in a familiar mixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adapted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or these doses may be reduced in proportion to the requirements required for the therapeutic condition.

These active compounds can be administered orally as well as by the intravenous, intramuscular or subcutaneous route. Depending on the nature of the active ingredient and whether it is suitable for the particular dosage form desired, the solid carrier comprises starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and the liquid carrier is a sterile water, polyethylene glycol, nonionic interface Active agents and cooking oils such as corn, peanuts and sesame oil. Advantageously, flavoring agents, coloring agents, preservatives and antioxidants can be included, such as auxiliaries customarily used in the preparation of pharmaceutical compositions such as vitamin E, ascorbic acid, BHT and BHA.

In view of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, preferably tablets, and hard filled or liquid filled capsules. Oral administration of the compound is preferred.

These active compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as free bases or pharmaceutically acceptable salts can be prepared in water suitably mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the instant preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that the injectable solution readily exits. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol (eg glycerol, propylene glycol and liquid propylene glycol), suitable mixtures thereof, and vegetable oils.

The invention will be further understood by the following non-limiting examples.

Example 1

5 '-(3-chlorophenyl) spiro (cyclohexane-1,3'-[3H] indole] -2 '(1'H) -thione

Spiro [cyclohexane-1,3 '-[3H] indole] -2'-(1'H) -one

After cooling anhydrous tetrahydrofuran (800 cm ³ ) solution of auxindol (25 g, 0.19 mol) to −20 ° C., n-butyllithium (2.5 M in hexane, 152 cm ³ , 0.38 mol) was slowly added and N, N , N ', N'-tetramethylethylenediamine (51cm ³ , 0.38mol) was added. After 15 minutes, 1,5-diyodopentane (174 g, 0.54 mol) was slowly added and the mixture was allowed to warm to room temperature. After stirring for 6 hours, saturated aqueous ammonium chloride solution (1 L) and EtOAc (1 L) were added. After 15 minutes, the layers were separated and the aqueous phase extracted with EtOAc (x2). The combined organic layers were extracted with hydrochloric acid (1N), washed with brine (500 cm ³ ), dried (MgSO ₄ ) and concentrated to yield an oil. The oil was triturated with hexane (200 cm ³ ) and benzene (20 cm ³ ). The precipitate was collected and dried in vacuo to yield the title compound (26.3 g, 69.6%) as colorless crystals: mp 110-114 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.67 (m, 10H), 6.84 (d, 1H, J = 8 Hz) 6.94 (t, 1H, J = 8 Hz), 7.17 (t, 1H, J = 8 Hz), 7.44 (d, 1H, J = 8 Hz), 10.3 (S, 1H).

5'-bromosspiro [cyclohexane-1,3 '-[3H] indole] -2' (1'H) -one

Sodium acetate (8.0 g, 0.1 mol) in a solution of spiro [cyclohexane-1,3 '-[3H] indole] -2'(1'H) -one (17.6 g, 0.09 mol) in acetic acid (300 cm ³ ) and Bromine (14.6 g, 0.091 mol) was added 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. Layers were washed with water, dried (MgSO ₄ ), evaporated and the residue was triturated with hexane. The precipitate was collected and dried in vacuo to yield the title compound (16.5 g, 67%) as grayish white crystals: mp 196-199 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.62 (m, 10H), 6.8 (d, 1H, J = 6.8 Hz), 7.36 (d, 1H, J = 8.2, 1.8 Hz), 7.58 (dd, 1H, J = 8.2, 1.8 Hz), 10.44 (S, 1H).

5- (3-chlorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one

5'-bromospiro [cyclohexane-1,3 '-[3H] indole] -2'(1'H) -one (0.32 g, 1.14 mmol) and tetrakis (triphenylphosphine) palladium (0) A solution of (0.14 g, 0.12 mmol) in dimethoxyethane (6 cm ³ ) was stirred for 20 minutes under nitrogen. To the mixture was 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, then cooled to room temperature and extracted with EtOAc (x3). The combined organic extracts were washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (Si0 ₂ , ethyl acetate: hexane 1: 3) to give the 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 = 8.1 Hz, 1H), 7.22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1 H), 9.28 (br s, 1 H); ¹³ C NMR ((CDCl ₃ ) 20.17, 24.12, 31.92 (t), 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 (MH) ⁺ ; Assay (C ₁₉ H ₁₈ ClNO) C, H, N.

To a dry xylene (20 cm ³ ) solution of 5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (0.63 g, 2.0 mmol) 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.89 g, 2.2 mmol) was added and the mixture was heated to reflux. did. After 72 hours, the mixture was evaporated and the residue was column chromatographed (SiO ₂ , EtOAc: hexanes, gradient eluting) to give a solid, which was recrystallized from diisopropylether / hexanes to give yellow crystals (0.17 g, 0.51 mmol, 26 %) To give the title compound: mp 223-227 ° C; d (CDCl ₃ ) 1.53-1.66 (m, 8H), 1.83-2.05 (m, 4H), 2.07-2.17 (m, 2H), 7.11 (d, 1H, J = 8.0 Hz) 7.31-7.53 (m, 3H ), 7.54 (s, 1 H), 7.86 (S, 1 H), 9.93 (s, 1 H, br): MS ((+ APCI) m / z 328 (M + H) ⁺ .

Example 2

3- (1 ', 2'-dihydro-2'-thioxospiro [cyclohexane-1,3'-[3H] indol] -5'-yl) benzonitrile

5'-bromo moss fatigue [cyclohexane -1,3 '- [3H] indol] -2'(1'H) - one-dimethoxyethane kiss tetra (20cm ³⁾ a solution of (1.00g, 3.57mmol) ( Triphenylphosphine) palladium (0.20 g, 0.17 mmol) was added. After 15 minutes, 3-formylphenylboronic acid (1.00 g, 6.93 g) was added and potassium carbonate (2.90 g, 21 mmol) in water (10 cm ³ ) was added. After refluxing for 20 hours, the mixture was cooled and poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with saturated brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexanes, gradient elution) to give the title compound (0.66 g, 2.15 mmol, 60%) as a white solid: ¹ H NMR (CDCl ₃ ) δ 1.65-1.85 ( m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J = 8 Hz), 7.48 (dd, 1H, J = 8.2 Hz), 7.61 (t, 1H, J = 8 Hz), 7.66 ( d, 1H, J = 2 Hz, 7.81-7.88 (m, 2H), 8.06 (t, 1H, J = 2 Hz), 8. 30 (s, 1H, br); MS ((+) ESI) m / z 306 (M + H) ⁺ .

3- (1 ', 2'-dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol-5'-yl) benzoaldehyde oxime

Hydroxylamine hydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5 mmol) were added to 3- (1 ', 2'-dihydro-2' in EtOH: H ₂ 0 (10 cm ³ , 8: 2). -Oxospyrocyclohexane-1,3 '-[3H] indol-5'-yl) benzoaldehyde (0.59 g, 1.95 mmol) was added to the solution. After 20 minutes, the mixture was concentrated, water was added and the product extracted with EtOAc (x2). The combined organic layers were washed with saturated sodium bicarbonate solution, water, saturated brine, dried (MgSO ₄ ) and evaporated to afford the oxime (0.63 g, 1.95 mmol, 100%) of the subtitle which was used without further purification: ¹ H NMR (CDCl ₃ ) δ 1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H), 6.86 (d, 1H, J = 8 Hz), 7.36 (dd, 1H, J = 8,2 Hz), 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 / z 319 (MH).

3- (1 ', 2'-dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol-5'-yl) benzonitrile

Chloroform (10 cm) of 3- (1 ', 2'-dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol-5'-yl) benzoaldehyde oxime (0.48 g, 1.49 mmol) ³ ) The solution was treated with selenium dioxide (0.38 g, 3.50 mmol) and heated while refluxing. After 16 h, the mixture was concentrated and the residue was purified by column chromatography (SiO ₂ , EtOAc: hexanes 1: 4) and the product was recrystallized from EtOAc-hexanes to give the title compound (0.161 g, 0.53 mmol, as a white solid). 35%) was obtained: mp 190-191 ° C; ¹ H NMR (CDCl ₃ ) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J = 8 Hz), 7.42 (dd, 1H, J = 8, 2 Hz), 7.54 (t, 1H, J = 8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J = 7,2 Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m / z 303 (M + H) ⁺ .

According to Example 1, reacting 3- (1 ', 2'-dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol-5'-yl) benzonitrile and Laweson reagent To give the title compound: mp> 231 ° C. (decomposed); ¹ H NMR (DMSO-d ₆ ) δ 1.38-1.55 (m, 3H), 1.82-1.99 (m, 7H), 7.16 (d, 1H, J = 8.1 Hz), 7.63-7.69 (m, 2H), 7.80 (d, 1H, J = 7.7 Hz), 8.01 (d, 1H, J = 8 Hz) and 12.76 (s, 1H); MS ((−)-APCI) m / z 317 [M ⁻ H] ⁻ .

Example 3

4- (1 ', 2'-dihydro-2'-thioxospiro [cyclohexane-1,3'-[3H] indol] -5'-yl) -2-thiophencarbonitrile

3- (trimethylstannyl) -2-thiophencarbonitrile

Of 3-bromo-2-thiophencarbonitrile (0.8 g, 4.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) The dimethoxyethane (5 cm ³ ) solution was heated to reflux for 14 hours and then cooled to room temperature. The reaction mixture was adsorbed on Florisil and purified by column chromatography (SiO ₂ , methylene chloride: hexane 1: 9) to give the title 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 = 0.9 Hz, 1H), 7.66 (d, J = 0.9 Hz, 1H).

4- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -2-thiophencarbonitrile

5'-bromospiro [cyclohexane-1,3 '-[3H] indole] -2'(1'H) -one (0.53 g, 1.9 mmol), dichlorobis (triphenylphosphine) palladium (II) A solution of dimethoxyethane (8 cm ³ ) of (0.1 g, 0.14 mmol) and triphenylarcine (0.14 g, 0.47 mmol) was stirred under N ₂ for 20 minutes. 3- (trimethylstannyl) -2-thiophencarbonitrile (0.64 g, 2.35 mmol) was added to this mixture. The solution was refluxed for 32 hours. After cooling to room temperature, the reaction mixture was adsorbed on Florisil and purified by column chromatography (SiO ₂ , ethyl acetate: hexanes 2: 3) to give the title compound as a grayish white solid (0.43 g, 1.39 mmol, 74%). ) Was obtained: ¹ H NMR (CDCl ₃ ) δ 1.56-2.1 (m, 10H), 6.97 (d, J = 8.0 Hz, lH), 7.39 (dd, J = 8.03, 1.45 Hz, 1H), 7.57 (d , J = 1.45 Hz, 1H), 7.59 (d, J = 1.4 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 8.32 (br s, 1H); ¹³ C NMR (CDCl ₃ ) δ 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 (MH) ⁺ ; Assay (C ₁₈ H ₁₆ N ₂ OS) C, H, N.

4- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -2-thiophencarbonitrile (1.0 g, 3.2 mmol) and Laweson reagent (1.3 g, 3.2 mmol) of o-xylene (20 mL) solution was heated for 2.5 hours. The reaction mixture was washed with distilled water (5 × 100 mL), dried over MgSO ₄ and evaporated. The product was purified by column chromatography (Si0 ₂ , EtOAc: hexanes 1: 5) to give the title compound (0.2 g, 20%) as a pale yellow solid: mp 230-232 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 12.72 (s, 1H), 8.52 (d, 1H, J = 1.5Hz), 8.36 (d, 1H, J = 1.5Hz), 8.00 (d, 1H, J = 1.5 Hz), 7.69 (dd, 1H, J = 6.4, 1.8 Hz), 7.10 (d, 1H, J = 8.3 Hz), 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-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile

Sodium hydride in a 5'-bromosspiro [cyclohexane-1,3 '-[3H] indole] -2'-(1'H) -one (11 g, 0.04 mol) dry tetrahydrofuran (200 cm ³ ) solution 60% dispersion in mineral oil, 1.6 g, 0.04 mol) was added. After stirring at room temperature for 30 minutes, the mixture was cooled to -78 ° C and butyllithium (1.7 M in hexane, 23.2 cm ³ , 0.04 mol) was added slowly. After 30 minutes, diisopropylborate (25 cm ³ , 0.11 mol) was added and the mixture was allowed to warm to room temperature. After 2 hours, hydrochloric acid (1N, 500cm ³ ) and ethyl acetate (500cm ³ ) were added. After the aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was triturated with hexane and the precipitate was dried in vacuo to give (2'-oxo-2,3-dihydrospiro [cyclohexane-1,3 '-[3H] indole] -5' as a grayish white solid. -Yl) boronic acid (8.3 g, 86%) was obtained and used without further purification. The sample further polished with ethyl acetate had the following characteristics: mp 255-260 ° C. (decomposed); ¹ H NMR (DMSO-d ₆ ) δ 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J = 7.72 Hz) 7.66 (d, 1H, J = 7.72 Hz) 7.91 (s, 3H, br), 10.36 (s, 1 H); MS ((−) ESI) m / z 244 [M−H].

3- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile

N-butyllithium (2.5 M, 8 cm ³ , 20 mmol) was added dropwise to a 3,5-dibromofluorobenzene diethyl ether (100 cm ³ ) solution at -78 ° C. After 30 minutes, the mixture was treated with DMF (20 cm ³ ) in diethyl ether (10 cm ³ ) and stirring continued at −78 ° C. After 30 minutes, the mixture was quenched with dilute aqueous HCl solution and separated to extract the aqueous layer with EtOAc. The combined organic layers were washed with water, brine, dried (MgSO ₄ ) and evaporated to afford 3-fluoro-5-bromobenzoaldehyde (4.0 g, 19.7 mmol, 100%) as oil: ¹ H NMR (CDCl) ₃ ) δ in particular 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS (EI) m / z 202, 204 [M ⁺ ].

To a solution of ethanol: water (8: 2, 50cm ³ ) of the last described compound (4.0 g, 19.7 mmol) was added sodium acetate (1.72 g, 21 mmol) and hydroxylamine hydrochloride (1.45 g, 21 mmol) and the mixture was refluxed. Heated. After 30 minutes, the mixture was cooled, evaporated and the residue partitioned between water and EtOAc. The aqueous layer was reextracted with EtOAc and the combined organic layers were washed with water, saturated sodium bicarbonate solution, brine, dried (MgSO ₄ ) and evaporated to 3-fluoro-5-bromobenzoaldehyde oxime (3.76 g, 17.24). mmol, 87%), which 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 oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg) were dissolved in acetonitrile (100 cm ³ ) under nitrogen and heated while refluxing. After 5 h the mixture was evaporated and the residue was taken up in EtOAc and washed with sulfuric acid (1N), water, brine, dried (MgSO ₄ ) and evaporated to 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89%), which was used without further purification. The bromide (3.0 g, 15 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.86 g, 0.75 mmol) were dissolved in dimethoxyethane (130 cm ³ ) under nitrogen. After 15 minutes, (2'-oxo-2,3-dihydrospiro [cyclohexane-1,3 '-[3H] indol] -5'-yl) boronic acid (2.82 g, 11.5 mmol) and water (40 cm Sodium carbonate (3.1 g, 29.3 mmol) dissolved in ³ ) was added, and the mixture was heated to reflux. After 8 h the mixture was cooled and poured into water and extracted with EtOAc (x3). Layers were washed with water, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (EtOAc: hexane, gradient elution) and the product was recrystallized from methanol to give 3- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indole ] -5-yl) -5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%) was obtained: mp 199-205 ° C; ¹ H NMR (CDCl ₃ ) δ 1.64-2.03 (m, 10H), 7.03 (d, 1H, J = 8 Hz), 7.31 (dt, 1H, J = 7.7 and 1.6 Hz), 7.41 (dd, 1H, J = 8, 1.7 Hz), 7.49 (dt, 1H, J = 9.6, 2 Hz), 7.58 (d, 1H, J = 2 Hz), 7.64 (s, 1H) and 8.37 (s, 1H): MS (EI) m / z 320 [M ⁺ ].

3- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile (0.32 g, 1.0 mmol) xylene under nitrogen Laweson reagent (0.89 g, 2.22 mmol) was added to the 10 cm ³ ) solution, and the reaction was heated while refluxing. After 4 h, the mixture was cooled and evaporated and the residue was column chromatographed (SiO ₂ , EtOAc: hexanes, gradient eluting) to give a solid (0.143 g, 0.42 mmol, 42%): mp 236-250 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.54-1.66 (m, 3H), 1.86-2.18 (m, 7H), 7.16 (d, 1H, J = 8.1 Hz), 7.33-7.36 (m, 1H), 7.46-7.52 (m, 2H), 7.65 (s, 1H), 7.85 (d, 1H, J = 1 Hz), 10.05 (s, 1H); MS ((+)-APCI) m / z 337 [M + H] ⁺ .

Example 5

4-methyl-5- (1,2-dihydro-2-thioxospyro (cyclohexane-1,3- [3H] -indol] -5-yl) -2-thiophene thioamide

Dimethoxyethane: water: ethanol (130 cm ³ , 10: 2: 1) 2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3'-[3H] indole] -5'- I) 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 (triphenylphosphine) palladium ( 0) (0.6 g, 0.5 mmol) was heated at 80 ° C. for 16 hours, then poured into 1 L of water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated. The crude product was column chromatography (SiO ₂ , EtOAc: hexanes, 1: 1) to give the title compound (0.9 g, 28%): mp 200-203 ° C .; ¹ H NMR (DMSO-d ₆ ) 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, 1.98 Hz) 7.54 (d, 1H, J = 1.98 Hz), 7.82 (S, 1H), 10.50 (S, 1H); MS ((+) APC1) m / z 323 [M + H] ⁺ .

4-methyl-5- [2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3'-[3H] indol] -5'-yl) -2-thiophencarbonitrile (0.61 g, 1.9 mmol) and a solution of dioxane (17 mL) of phosphorus pentasulfide (0.92 g, 2.1 mmol) were heated at 85 ° C for 30 minutes. The reaction mixture was poured into distilled water, washed with NaHCO ₃ aqueous solution, distilled water, dried over MgSO ₄ and evaporated without moisture. The residue was purified by column chromatography (2.5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.05 g, 8%) as an orange-brown solid: mp 244-249 ° C .; ^{1 H-NMR (DMSO-d} 6) δ 12.75 (s, 1H), 9.54 (s, 1H), 9.34 (s, 1H), 7.76 (d, 1H, J = 1.5Hz), 7.58 (s, 1H) , 7.45 (dd, 1H, J = 6.4, 1.8 Hz), 7.14 (d, 1H, J = 7.9 Hz), 2.26 (s, 3H), 1.981.89 (m, 7H), 1.83-1.81 (m, 3H ); MS ((+) APCI) [M + H] ⁺ @ m / z 373.

Example 6-Pharmacy

Premenstrual activity of the compounds of the invention was evaluated by in vitro and in vivo assays described below. In vitro efficacy ranges from 0.01 nM to 10,000 nM and in vivo ranges from 1 μg / kg to 100 mg / kg.

A. In Vitro Ecology

In vitro ecology includes: (1) competitive radioligand binding using a type A human progesterone receptor with progesterone as the radioligand; (2) co-transfection assays that provide functional activity expressed as agonist EC50 and antagonist IC50 values; (3) T47D cell proliferation, a further functional assay providing agonist and antagonist data; And (4) T47D cell alkaline phosphatase assay, a further functional assay providing agonist and antagonist data.

1. hPR binding assay

This analysis is done by Pathirana, C .; Stein, R. B .; Berger, T. S .; Fenical, W .; Ianiro, T .; Mais, D. E .; Torres, A .; glodman, M. E., Nonsteroidal Human Progesterone Receptor Regulators from Sea Algae Simoplia Barbata, J. Steroid Biochem. Mol. Biol., 1992, 41, 733-738.

2. PRE-Luciferase Assay in CV-1 Cells

The purpose of this assay is to premenstrual or anti-menstrual efficacy of compounds based on the effect of the compound on PRE-luciferase receptor activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. To decide. Materials and methods used in the analysis are as follows.

a. Growth medium : DMEM containing 10% (v / v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acid, 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM glutaMax (GIBCO, BRL) BioWhittaker). Experimental medium: containing 10% (v / v) chalcol-free fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acid, 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM glutaMax (GIBCO, BRL) DMEM (BioWhittaker) without phenol red.

b. Cell Culture, Transfection, Treatment and Luciferase Assay

Stock CV-1 cells were maintained in growth medium. Co-transfection was sonicated as 1.2 × 10 ⁷ cells in 250 mL, 5 mg of pLEM plasmid with hPR-B inserted at the Sph1 and BamH1 sites, 10 mg of pGL3 plasmid with two PRE upstream of luciferase sequence and carrier DNA Calf thymus DNA was used using 50 mg. Electroporation was performed at 260 V and 1,000 mF in Bioradgene Pulser II. After electroporation, cells were resuspended in growth medium and plated in 96-well plates at 40,000 cells / well in 200 ul. After incubation overnight, the medium was replaced with experimental medium. Next, cells were treated with reference material or test compound in experimental medium. Compounds were tested for anti-menstrual activity in the presence of 3 nM progesterone. Media was discarded 24 hours after treatment and cells were washed three times with D-PBS (GIBCO, BRL). 50 μl of cell lysis buffer (Promega, Madison, Wis.) Was added to each well and the plate was shaken for 15 minutes on a Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity was measured using Luciferase Reagent from Promega.

c. Result analysis:

Each treatment was repeated at least four times. Data converted to Log was used for the analysis of nonlinear dose response curves fitted for variance and agonist and antagonist modes. Huber weights are used to downweight the influence of the outer points. EC ₅₀ or IC ₅₀ values were calculated from the reconverted values. JMP software (SAS Institute, Inc.) was used for unidimensional variance analysis and nonlinear response analysis.

d. Reference compound:

Progesterone and trimegestone are reference progestins and RU486 is reference antiprogestin. Full dose response curves were generated for all reference compounds and EC ₅₀ or IC ₅₀ values were calculated.

Premenstrual activity: Compounds which significantly increase the PRE-luciferase activity (p <0.05) compared to the excipient control are considered to be active.

Anti-menstrual activity: compounds that significantly (p <0.05) reduce 3 nM progesterone induced PRE-luciferase activity.

EC ₅₀ : concentration of compound (default-nM) which results in a semi-maximal increase in 3 nM progesterone induced PRE-luciferase activity with SE.

IC ₅₀ : concentration of compound (default-nM) which results in a semi-maximal decrease in 3 nM progesterone induced PRE-luciferase activity with SE.

3. T47D Cell Proliferation Assay

The purpose of this assay is to measure premenstrual and antimenstrual efficacy using cell proliferation assays in T47D cells. The effect of the compound on DNA synthesis in T47D cells is measured. Materials and methods used in this analysis are as follows.

a. Growth medium : DMEM: F12 (1: 1) supplemented with 10% (v / v) fetal bovine serum (not heat inactivated), 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM glutaMax (GIBCO, BRL) (GIBCO, BRL).

b. Treatment Medium : Minimum Essential Medium (MEM) without phenol red supplemented with 0.5% CHARCHOL-REMOTED fetal bovine serum, 100 U / ml penicillin, 200 mg / ml streptomycin and 2 mM glutaMax (GIBCO, BRL) (# 51200-038GIBCO, BRL).

c. Cell culture :

Stock T47D cells were maintained in growth medium. For BrdU binding assays, cells were plated in 10,000 cells / well 96-well plates (Falcon, Becton Dickinson Labware) in growth medium. After incubation overnight, the medium was changed to treatment medium and the cells were further incubated for 24 hours before being treated. The stock compound was dissolved in a suitable excipient (100% ethanol or 50% ethanol / 50% DMSO), then diluted in treatment medium and added to the cells. Full dose-response curves were prepared for progestin and antiprogestin reference compounds. The final concentration of excipient is 0.1%. In control wells, cells received only excipients. Antiprogestin is tested in the presence of 0.03 nM trimegston, a reference progestin agonist. At 24 hours post treatment, the medium was discarded and cells were 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 was removed and BrdU binding was measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to the manufacturer's instructions. In brief, cells are fixed in ethanol containing fixative for 30 minutes and then incubated in blocking buffer for 30 minutes to reduce background. Peroxidase-labeled anti-BrdU antibody was added to the wells and incubated for 60 minutes. Cells were rinsed three times with PBS and incubated with 3,3 ', 5,5'-tetramethylbenzidine (TMB) substrate for 10-20 minutes depending on the efficacy of the compounds tested. Next, 25 μl of 1 M sulfuric acid is added to each well to stop the color reaction, and the optical density is read in a plate reader at 450 nm within 5 minutes.

e. Analyzing the results :

Data converted to square roots are used for analysis of nonlinear dose response curves fitted for variance and agonist and antagonist modes. Huber weights are used to downweight the influence of an outer point. EC ₅₀ or IC ₅₀ values are calculated from the reconverted values. In single dose and dose response studies, JMP software (SAS Institute, Inc.) is used for single-dimensional analysis of variance and nonlinear dose response analysis.

f. Reference compound :

Trimegeston and methoxyprogesterone acetate (MPA) are reference progestins and RU486 is reference antiprogestin. Full-capacity response curves for all reference compounds are prepared and EC ₅₀ or IC ₅₀ values are calculated.

EC ₅₀ : concentration of compound resulting in a semi-maximal increase in BrdU bond with SE.

IC ₅₀ : Concentration of compounds resulting in anti-maximal reduction of 0.1 trimegeston induced BrdU bond with SE.

4. T47D Cell Alkaline Phosphatase Assay

The purpose of this assay is to identify progestin or antiprogestin by measuring the effect of the compound on alkaline phosphatase activity in T47D cells. Materials and methods used in this analysis are as follows.

a. Culture medium : DMEM: F12 supplemented with 5% (v / v) chalcol-free fetal bovine serum (not heat inactivated), 100 U / ml penicillin, 100 μl / ml streptomycin and 2 mM glutaMax (GIBCO, BRL) 1: 1) (GIBCO, BRL).

b. Alkaline Phosphatase Assay Buffer :

I. 1M Tris-HCl with 0.2% Triton X-1000, pH 9.8.

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

c. Cell culture and treatment :

Frozen T47D cells were thawed in a 37 ° C. water bath and diluted to 280,000 cells / ml in culture medium. 180 μl of diluted cell suspension was added to each well of a 96-well plate (Falcon, Becton Dickinson Labware). Next, 20 μl of the reference substance or test compound diluted in the culture medium was added to each well. When tested for progestin antagonistic activity, reference antiprogestin or test compound was added in the presence of 1 nM progesterone. Cells were incubated for 24 hours at 37 ° C. in 5% CO ₂ / humidified atmosphere.

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 plate was shaken on a titer plater shaker for 15 minutes. Next, 150 μl of Assay Buffer II was added to each well. Optical density was measured at 5 minute intervals for 30 minutes at a test wavelength of 405 nM.

e. Outcome Analysis: Analysis of Dose Response Data

For reference materials and test compounds, dose response curves were made of dose (X-axis) to enzyme reaction ratio (tilt) (Y-axis). Data converted to square roots are used for analysis of nonlinear dose response curves fitted for variance and agonist and antagonist modes. Huber weights are used to downweight the influence of an outer point. EC ₅₀ or IC ₅₀ values are calculated from the reconverted values. In single dose and dose response studies, JMP software (SAS Institute, Inc.) was used for single-dimensional analysis of variance and nonlinear dose response analysis.

f. Reference compound :

Progesterone and trimegestone are reference progestins and RU486 is reference antiprogestin. Full-capacity response curves for all reference compounds are prepared and EC ₅₀ or IC ₅₀ values are calculated.

B. In vivo Ecology

The first in vivo assay is a rat decidualization model that can be used to measure the premenstrual effects of agonists and antagonists. A second in vivo assay is under development as a rat ovulation inhibition model and therefore this protocol cannot be used.

1. Rat decidualization assay

This procedure is used to evaluate the effects of progestin and antiprogestin on rat uterine decidualization and to compare the relative efficacy of various test compounds. The materials and methods used in this analysis are as follows.

a. Method : Test compound was dissolved in 100% ethanol and mixed with corn oil (excipient). Next, a stock solution of the test compound in oil (Mazola ^™ ) was prepared by heating the mixture (˜80 ° C.) to evaporate ethanol. The test compound was then diluted with 100% corn oil or 10% ethanol in corn oil prior to animal treatment. When comparing these two excipients, no difference was found in the decidual reaction.

b. Animals (RACUC Protocol # 5002)

Ovarian adult female Sprague-Dawley rats (˜60 days old, 230 g) are obtained postoperatively from Taconic (Taconic Farms, NY). Ovariectomy is performed at least 10 days before treatment to reduce blood steroids. Animals were allowed to live under a 12 hour light / dark cycle and optionally provided with standard rat food and water.

c. process

Rats were weighed and randomly assigned to 4 or 5 groups prior to treatment. Test compounds in 0.2 ml excipients are administered by subcutaneous injection in the nape of the neck or by gavage using 0.5 ml. Animals are treated once daily for 7 days. For the antiprogestin test, animals are given test compound and EC ₅₀ dose (5.6 mg / kg) of progesterone during the first 3 days of treatment. After decidual stimulation, animals continue to receive progesterone until necropsy 4 days later.

d. Capacity

Doses were prepared based on mg / kg average group weight. In all studies, the control group received an excipient. Measurement of the dose response curve was performed using doses with half log increase (eg, 0.1, 0.3, 1.0, 3.0 mg / kg ...).

e. Decidual induction

Approximately 24 after the third infusion, decidualization is induced in one of the uterine angles by scraping the antimethomeric luminal epithelium with a thick 21G needle. The opposite angle is not scraped and used as a non-irritating control. At about 24 hours after the last treatment, the rats were suffocated and C0 _2, and measure the weight. Squeeze the uterus to get rid of fat Decidalization (D-angle) and control (C-angle) uterine angles are weighed respectively.

f. Result analysis

The increase in weight of the deciduitized uterine angle is calculated by D-angle / C-angle, and logarithmic conversion is used to maximize the degree of definition and homogeneity of variance. Huber M-evaluators are used to downweight the outer points of the converted observations in the one-dimensional analysis of dose response curve fitting and variance. JMP software (SAS Institute, Inc.) is used for single-dimensional ANOVA and nonlinear dose response analysis.

g. Reference compound

Full dose response curves were generated for all progestin reference compounds and EC ₅₀ versus uterine wet weight was calculated.

Concentration: Compound concentration in the assay (default-mg / kg body weight)

Route of administration: The route by which the compound is administered to the animal

Body weight: Average total animal weight (default-kg)

D-angle: wet weight of decidual uterine angle (default-mg)

C-angle: wet weight of control uterine angle (default-mg)

Dropout reaction: [(D-C) / C] x100%

Premenstrual activity: Compounds which significantly induce decidualization (p <0.05) compared to excipient controls are considered to be active.

Anti-menstrual activity: Compounds that significantly reduce (p <0.05) EC ₅₀ progesterone induced decidualization.

EC ₅₀ relative to uterine weight: concentration of compound which results in a semi-maximal increase in decidual response (default-mg / kg).

IC ₅₀ : Concentration of compound (default-mg / kg) resulting in anti-maximal reduction of EC ₅₀ progesterone induced decidual response to uterine weight.

Example 7

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

5- (2'-oxo-2 ', 3'-dihydrospiro [cyclopentane-1,3'-[3H] indole] -5'-yl-2-cyanopyrrole

5'-bromospiro [cyclopentane-1,3 '-[3H] indole] -2'(1'H) -one (2.0 g, 7.5 mmol) and tetrakis (triphenylphosphine) palladium (0) A solution of (430 mg, 0.3 mmol) of ethylene glycol dimethyl ether (50 mL) was stirred under nitrogen for 15 minutes. To this solution were added 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and aqueous potassium carbonate (2.4 g, 17 mmol) solution (10 mL). The mixture was heated at 80 ° C. for 3 hours and cooled. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallized from 20% ethyl acetate / hexanes, 2- (1 ', 2'-dihydro-2'oxospyro [cyclopentane-1,3'-[3H] indol] -5'-yl) -1H as a white powder Pyrrole-1-carboxylic acid tert-butyl ester (2.2 g, 83%) was obtained: mp 179-180.5 ° C. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H, J = 1.8, 3.3 Hz), 6.22 ('t', 1H, J = 3.3, 3.3 Hz), 6.79 (d, 1H, J = 7.9 Hz), 7.08 (dd, 1H, J = 1.8, 7.9 Hz), 7.14 ('d', 1H, J = 1.5 Hz), 7.28 ( dd, J = 1.9, 3.3 Hz), 10.30 (s, 1H). MS (EI) m / z 352 [M ⁺ ]. Analytical theory of C ₂₁ H ₂₄ N ₂ O ₃ : C 71.57; H 6.86; N 7.95. Found: C 71.08; H 6.83; N 7.74.

2- (1 ', 2'-dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol] -5'-yl) -1H-pyrrole-1-carboxylic acid tert-butyl To the ester (2.2 g, 6.0 mmol) THF (anhydrous, 25 mL) solution 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 was allowed to warm to room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (30% ethyl acetate / hexanes) gave 5- (2'-oxo-2 ', 3'-dihydrospiro [cyclopentane-1,3'-[3H] indole as white crystals. ] -5'-yl-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (1.7 g, 75%) was obtained: mp 167-169 ° C. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H, J = 3.7 Hz), 6.84 (d, 1H, J = 7.9 Hz), 7.17 (dd, 1H, J = 1.8, 7.9 Hz), 7.28 ('t', 2H), 10.41 (s, 1H) MS (ESI) m / z 376 [M ⁻ H] ⁻ .C ₂₂ H ₂₃ N ₃ 0 ₃ Analytical theory: 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 (1 g, 2.7 mmol) was placed in a 25 mL round bottom flask, sealed with a rubber stopper, and equipped with a needle to allow nitrogen inlet and gas to escape, and the flask was placed in an oil bath and heated to 165 ° C. with vigorous flowing of nitrogen. After 20 minutes, the flask was removed from the oil bath and cooled, crystallized from ethyl ether to give the title compound (600 mg, 79%) as a yellow powder: mp 285-286 ° C. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.75-2.03 (m, 8H), 6.60 (dd, 1H, J = 2.4, 3.7 Hz), 6.84 (d, 1H, J = 8.1 Hz), 6.94 (dd, 1H, J = 2.4, 3.7 Hz), 7.52 (dd, 1H, J = 1.8, 8.1 Hz), 7.60 (d, 1H, J = 1.8 Hz), 10.38 (s, 1H), 12.45 (s, 1H) .MS (ESI) m / z 276 [MH] ^- C ₁₇ H ₁₅ N ₃ O of analysis theoretical:.. C 73.63; H 5.45 ; N 15.15 found: C 73.24; H 5.34; N 14.96.

5- (1,2-dihydro-2-oxospyro [cyclopentan-1,3- [3H] indol] -5'-yl) -1H-pyrrole-2-carbonitrile in p-xylene (20 mL) 0.18 g, 0.7 mmol, 1 equivalent) of Laweson reagent (0.14 g, 0.36 mmol, 0.5 equivalent) was added, and the reaction was heated under reflux for 1 hour. The reaction was cooled to room temperature and adsorbed onto silica gel. Purification by flash column chromatography on silica gel (20% ethyl acetate / hexanes) afforded the product of an orange powder. Further purification by HPLC gave the title compound (0.144 g, 70%) as a green solid: mp 275-276 ° C. (decomposed). ¹ H NMR (d ₆ -DMSO, 300 MHz) δ 1.81-2.16 (m, 8H), 6.69 (dd, 1H, J = 2.3,3.7 Hz), 6.98 (dd, 1H, J = 1.8, 3.7 Hz), 7.04 (d, 1H, J = 8.2 Hz), 7.63 (dd, 1H, J = 1.6, 8.2 Hz), 7.72 (d, 1H, J = 1.3 Hz), 12.57 (s, 1H), 12.65 (s, 1H) . MS (ESI) [M ⁻ H] ⁻ = 292. Analytical theory of C ₁₇ H ₁₅ N ₃ S: C 69.6; H 5.15; N 14.32. Found: C 69; H 5.31; N 13.81.

Example 8

5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -1- (tert-butoxycarbonyl) -pyrrole-2-carboni Trill

Tetrakis (triphenylphosphine) in 5'-bromo-spiro [cyclohexane-1,3'-indoline] -2'-one (3.4 g, 12 mmol) 1,2-DME (100 mL) solution under nitrogen atmosphere Palladium (0) (70 mg, 5 mol%) was added. After 15 minutes, an aqueous solution of _2- borono-1H-pyrrole-1-carboxylic acid 1-tert butyl ester (1.3 equiv., 3.31 g, 15.6 mmol) and K ₂ CO ₃ (2.3 equiv., 3.83 g, 27.6 mmol) 5 mL) was added continuously. The solution was heated to 80 ° C. for 3 hours and cooled. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layer was washed with brine (150 mL) and dried over MgSO ₄ . The solution was filtered and concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluted with 30% EtOAc / hexanes) to give 2- (1 ', 2'-dihydro-2'-oxosepyro as a white powder. [Cyclohexane-1,3 '-[3H] indole] -5'-yl) -1H-pyrrole-1-carboxylic acid tert-butyl ester (3.4 g, 76%) was obtained: 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 ('t', 1H, 3 Hz), 6.91 (d, 1H, J = 8Hz), 7.21 (d, 1H, J = 8Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex), MS ((+)-APCI) m / z 367 [(M + H) ⁺ ]. Analytical theory of C ₂₂ H ₂₆ N ₂ O ₃ : C 72.11; H 7.15; N 7.64. Found: C 71.7; H 7.16; N 7.5.

2- (1 ', 2'-Dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol] -5'-yl) -1H-pyrrole-1-carboxyl at -78 ° C To a solution of acid tert-butyl ester (0.75 g, 2 mmol) THF (anhydrous, 20 mL) was added chlorosulfonyl isocyanate (1.15 equiv, 0.23 mL, 2.3 mmol). After 90 minutes, DMF (20 equiv, 3.6 mL, 46 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purified by flash column chromatography on silica gel (30% ethyl acetate / hexanes) to give 5- (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3'-[3H] indole] as oil. -5'-yl-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (0.5 g, 63%) was obtained, which was crystallized from acetone to give white crystals: mp 156 ° C. ¹ H NMR (d _6- DMSO, 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 = 3.7 Hz) , 6.87 (d, 1H, J = 7.9 Hz), 7.18 (dd, 1H, J = 1.5, 7.9 Hz), 7.27 (d, 1H, J = 3.7 Hz), 7.48 (d, 1H, J = 1.8 Hz) MS (EI) m / z 391 (M ⁺ ) Anal. Calcd. For C ₂₃ H ₂₅ N ₃ 0 ₃ : C 70.57; H 6.44; N 10.73. Found: C 69.82; H 6.46; N 10.43.

2-cyano-5- (1,2-dihydro-2-oxospyro [cyclohexane-1,3 [3H] indol] -5-yl) -1H-pyrrole-1-carboxylic acid tert-butyl ester (0.7 g, 1.8 mmol, 1 equiv) To a solution of toluene (70 mL), Laweson reagent (0.47 g, 1.1 mmol, 0.65 equiv) was added, and the reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and poured into water (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (20-30% ethyl acetate / hexanes) gave the title compound (0.7 g, 96%) as a yellow solid: ¹ H NMR (d ₆ -DMSO, 500 MHz) δ 1.30-1.98 ( m, 19H), 6.45 (d, 1H, J = 3.7 Hz), 7.09 (d, 1H, J = 7.9 Hz), 7.31-7.34 (m, 2H), 7.81 (d, 1H, J = 1.4 Hz), 12.74 (s, 1 H). MS (ESI) [M ⁻ H] ⁻ = 406. Analytical theory of C ₂₃ H ₂₅ N ₃ 0 ₂ S: C 67.79; H 6.18; N 10.31. Found: C 67.86; H 5.99; N 10.25.

Example 9

5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -1H-pyrrole-2-carbonitrile

5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -1- (tert-butoxycarbonyl) -pyrrole-2-carboni NaOEt (0.25 g, 3.6 mmol, 3 equiv) in EtOH (5 mL) was added to a THF (5 mL) solution of tril (0.5 g, 1.2 mmol, 1 equiv), and the reaction was heated at 80 ° C. for 24 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (30% ethyl acetate / hexanes) gave the title compound (0.27 g, 68%) as a yellow powder: ¹ H NMR (d ₆ -DMSO, 500 MHz) δ 1.32-1.99 (m, 10H), 6.71 (d, 1H, J = 3.7 Hz), 7.00 (d, 1H, J = 3.7 Hz), 7.09 (d, 1H, J = 8.4 Hz), 7.70 (dd, 1H, J = 1.6, 8.4 Hz), 8.05 (d, 1H, J = 1.1 Hz), 12.67 (s, 1H), 12.73 (s, 1H). MS (ESI) [M ⁻ H] ⁻ = 306. Analytical theory of C ₁₈ H ₁₇ N ₃ S: C 70.33; H 5.57; N 13.67. Found: C 69.64; H 5.79; N 13.04.

Example 10

5- (2'-Tioxospyro [cyclohexane-1,3 '-[3H] indol] -5'-yl) -1-methyl-pyrrole-2-carbonitrile

5- (2'-Oxospyro [cyclohexane-1,3 '-[3H] indol] -5'-yl) -1-methyl-pyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 equiv) toluene Laweson reagent (0.47 g, 1.1 mmol, 0.65 equiv) was added to the (50 mL) solution, and the reaction was heated at 80 ° C. for 1 hour. The reaction was cooled to room temperature and poured into water (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel provided the product as a white solid (0.32 g, 55%): ¹ H NMR (d ₆ -DMSO, 500 MHz) δ 1.36-1.99 (m, 10H), 3.7 (s, 3H) , 6.35 (d, 1H, J = 4.2 Hz), 7.05 (d, 1H, J = 4.2 Hz), 7.16 (d, 1H, J = 7.9 Hz), 7.44 (dd, 1H, J = 1.6, 8.1 Hz) , 7.83 (d, 1H, J = 1.6 Hz), 12.75 (s, 1H). MS (ESI) [M ⁻ H] ⁻ = 320. Analytical theory of C ₁₉ H ₁₉ N ₃ S: 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-thioxospyro [cyclopentane-1,3- [3H] indol] -5-yl) -3-thiophencarbonitrile

5-bromo-2-thiophencarbonitrile

A mixture of 5-bromo-2-thiophenecarboxyaldehyde (96.0 g, 500 mmol), pyridine (500 mL), hydroxylamine hydrochloride (111.9 g, 500 mmol) and ethanol (500 mL) was heated under reflux for 2 hours under nitrogen. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford an oil. The solid obtained by polishing the crude product twice with ice water was collected on a filter. A mixture of some of the solid (44.31 g, 215 mmol) and monohydrate copper (II) acetate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid solution (2X30 mL), water (2X30 mL), brine (20 mL) and dried (MgSO ₄ ). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1 L) to crystallize. The obtained crystals were collected on a filter, the filtrate was concentrated and purified by chromatography (silica gel, chloroform) to give the title compound (31.5 g combined, 58%) as a white solid. IR (Film) 2200 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ 7.39-7.38 (d, 1H, J = 4.1 Hz), 7.10 (d, 1H, J = 4.0 Hz); MS (EI) m / z 187 (M &lt; + &gt;, 98%) 189 (M ⁺ , 100%).

5- (1,2-dihydro-2-oxospyro [cyclopentane-1,3- [3H] indol] -5-yl) -3-thiophencarbonitrile to 5-bromo-2-thiophencarboni Prepared according to the procedure of Example 5 using tril and (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3' [3H] indol] -5'-yl) boronic acid mp 225-228 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J = 8.13 Hz), 7.55 (dd, 1H, J = 8.13, 1.76 Hz), 7.60 (d, 1H, J = 4.17 Hz), 7.75 (d, 1H, J = 1.76 Hz), 7.93 (d, 1H, J = 4. 17 Hz), 10.51 (s, 1H); MS ((+) APCI) m / z 309 [M + H] ⁺ .

5- (1,2-dihydro-2-oxospyro [cyclopentane-1,3- [3H] indol] -5-yl) -3-thiophencarbonitrile (0.66 g, 2.4 mmol) and 2,4 Toluene (250 mL) solution of bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphane-2,4-disulfide (0.97 g, 2.4 mmol) at 80 ° C. for 2 hours Stirred. The solution was concentrated in vacuo. The residue was extracted with ethyl acetate, the ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / hexane 20/80) to give the title compound: mp 269-272 ° C. (0.24 g, 32%). ¹ H NMR (DMSO-d ₆ ) δ 2.09 (m, 8H), 7.05 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 8.1, 1.7 Hz, 1H), 7.7 (d, J = 1.7 Hz, 1H), 7.95 (d, J = 1.3 Hz, 1H), 8.49 (d, J = 1.3 Hz, 1H), 8.49 (d, J = 1.3 Hz, 1H), 12.68 (s, 1H); MS (EI NEG) m / z 309 (M ⁻ H) ⁻ .

Example 12

5- (1,2-dihydro-thioxospyro (cyclopentane-1,3- [3H] indol) -5-yl) -2-thiophencarbonitrile

5- (1,2-dihydro-oxospyro (cyclopentane-1,3- [3H] indol] -5-yl) -2-thiophencarboni heated with reflux of the title compound in toluene (150 mL) for 3 hours. Prepared from tril (2 g, 6.8 mmol) and Laweson reagent (3.32 g, 8.3 mmol) Yield 1.5 g (48.3%); mp 250-253 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 12.75 (S, 1H), 7.98-7.97 (d, 1H, J = 3.9 Hz), 7.71-7.70 (d, 1H, J = 5.2 Hz), 7.65-7.62 (d, 1H, J = 8.1 Hz), 7.09-7.07 (d , 1H, J = 8.1Hz), 2.13-2.08 (m, 6H), 1.99-1.85 (m, 2H); MS [MH] - 309; IR (SP ATR) 1430, 1620, 2220cm -1, C 17 H Analytical Theory of ₁₄ N ₂ S ₂ : 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- [3H] indole] -2 (1H) -thione

5- (3-fluoro-4-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one

4-bromo-2-fluoroanisole and (2′-oxo-2 ′, 3′-dihydrospiro [cyclohexane-1,3 ′-[3H] indole] -5 according to the procedure of Example 5 Prepared from '-yl) boronic acid to give the title compound as a white solid: mp 178-180 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 10.4 (s, 1H), 7.65 (d, 1H, J = 1.1 Hz), 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]; Analytical theory of C ₂₀ H ₂₀ FNO ₂ : C 73.83, H 6.20, N 4.30. Found: C 73.55, H 6.23, N 4.40.

The title compound was mixed with 5- (3-fluoro-4-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one in a mixture of phosphorus pentasulphide overnight in pyridine. Prepared by reflux. After removal of pyridine in vacuo, the residue was treated with 5N hydrochloric acid solution and recrystallized in ethanol to give a gray solid: mp 228-229 ° C .; ¹ H NMR (DMSO-d ₆ ) 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 = 8.8 Hz), 7.1 (d, 1H, J = 8.1 Hz), 3.9 (s, 3H), 1.9-1.8 (m, 7H), 1.4-1.3 (m, 3H); MS (APCI (−)) [M ⁻ H] ⁻ m / z 324 C ₂₀ H ₂₀ Analytical theory of FNOS.0.25H ₂ O 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-pyrimidinyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione

Phosphorous pentasulphide having the same weight as 5- (2-amino-5-pyrimidinyl) spiro [cyclohexane-1,3- [3H] -indole] -2 (1H) -one was prepared by refluxing in pyridine overnight. After removal of pyridine in vacuo, the residue was treated with 5N hydrochloric acid solution and then recrystallized in ethanol to give a gray solid: mp 274-277 ° C. (decomposed); ¹ H NMR (DMSO-d ₆ ) 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 = 8.1 Hz), 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- (1,2-Dihydro-2-thioxospyro [cyclopentane-1,3- [3H] indol] -5-yl) -fluorobenzonitrile

Spiro [cyclopentan-1,3 '-[3H] indole] -2' (1'H) -one

N-butyllithium (1.6 M in hexane, 19.7 cm ³ , 31.5 mmol) was added dropwise to an auxindol (2.0 g, 15.0 mmol) anhydrous THF (40 cm ³ ) solution at -25 ° C. under N ² . N, N, N ', N'-tetramethylethylenediamine (4.75 cm ³ , 31.5 mmol) was added to the resulting milky white solution. After 30 minutes, a 1,4-diiodobutane (21.9 g, 70.6 mmol) THF (3 cm ³ ) solution was added, and the reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was poured into water and extracted with EtOAc (x2) and the combined organic layers were washed with dilute HCl (pH 1) and water (x2), dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexanes 1: 4) to give the title compound (1.4 g, 7.5 mmol, 50%) as a tan solid: ¹ H NMR (CDCl ₃ ) δ 1.8-2.2 (m, 8H), 6.94 (dd, J = 7.5, 1.0 Hz, 1H), 7.01 (dd, J = 7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H) .

5-Bromo-spiro [cyclopentan-1,3 '-[3H] indole] -2' (1'H) -one

A solution of acetic acid (10 cm ³ ) of spiro [cyclopentane-1,3 '-[3H] indole] -2'(1'H) -one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) Treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm ³ ). After 30 minutes, the mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc (x2), and the combined organic layers were washed with water, saturated sodium bicarbonate solution, water, dried (MgSO ₄ ) and evaporated to a grayish white solid. As a title compound (0.37 g, 1.47 mmol, 96%) was obtained, which was 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 s, 1H).

5 '-(3-cyano-5-fluorophenyl) -spiro [cyclopentane-1,3'-[3H] indole] -2 '(1'H) -one

Ethylene glycol dimethyl ether (20 cm ³ ) solution of ³ -cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 g) was mixed for 20 minutes. Stirred under N ₂ . To this mixture was added (spiro [cyclopentan-1,3 '-[3H] indole] -2'(1'H) -one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) aqueous solution (5 cm ³ ) was added. The solution was refluxed for 18 hours, then cooled to room temperature and poured into 2N NaOH and extracted with EtOAc (x3). The combined extracts were washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc, hexanes) to give white needled subtitle compound (0.35 g, 44%): mp 235-237 ° C .; ¹ H NMR (DMSO-d ₆ ) 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, 6.4 Hz), 6.9 (d, 1H, J = 8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M ⁺ @ m / z 306.

General course A

The title compound was purified by 5 '-(3-cyano-5-fluorophenyl) spiro [cyclopentane-1,3'-[3H] indole] -2 '(1'H) -one (40 mg) in toluene (10 ml). ) And Laweson reagent (50 mg) were prepared by refluxing for 16 hours in a sealed tube. The mixture was concentrated and the residue dissolved in a minimum amount of THF and purified by HPLC (SiO ₂ , 30 cm × 2.5 cm, EtOAc-hexane 2: 8, 20 mL / min) to afford the title compound (0.022 g) as a grayish white solid. Obtained: mp 236-238 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 12.66 (br s, 1H), 8.11 (s, 1H), 7.97 (dt, 1H, J = 10.1 and 2.2 Hz), 7.79-7.76 (m, 2H), 7.68 ( dd, 1H, J = 8.1 and 1.7 Hz), 7.07 (d, 1H, J = 8.1 Hz), 2.10-2.05 (m, 6H) and 1.97-1.88 (m, 2H); MS (EI) m / z 322 [M] ⁺ .

Example 16

5- (3-chlorophenyl) -3,3-dimethyl-1,3-dihydro-2H-indole-2-thione

5- (3-chlorophenyl) -3,3-dimethyl-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 tetrakis (triphenylphosphine) palladium (0) (0.239 g) It stirred in dimethoxyethane (35cm <^3> ) in nitrogen atmosphere. After 15 minutes, 3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added followed by an aqueous solution of potassium carbonate (3.40 g, 45 mmol) (15 cm ³ ). The reaction was heated to reflux for 2 hours and then stirred at room temperature overnight. The mixture was diluted with saturated ammonium chloride and extracted with EtOAc (x3). Layers were dried (MgSO ₄ ), filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexane, 1: 3) to give the title compound (0.284 g, 25%): mp 188-189 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 3.34 (s, 6H), 6.93 (d, 1H, J = 8.04 Hz), 7.38-7.35 (m, 1H), 7.53-7.43 (m, 2H), 7.61 (d , 1H, J = 7.68 Hz), 7.70 (s, 2H), 10.40 (s, 1H); IR (KBr) 3420, 3150, 3050, 1700 cm ⁻¹ ; MS (EI) m / z 270 (MH) ⁻ ; CHN theoretic of C ₁₆ H ₁₄ ClNO + O.1C ₄ H ₈ 0 ₂ : C 70.21; H 5.32; N 4.99; Found: C 70.3; H 5.44; N 4.93.

According to general procedure A, 5- (3-chlorophenyl) -3,3-dimethyl-1,3-dihydro-indol-2-one (100 mg) and Laweson reagent (120 mg) were refluxed in toluene (10 mL). The title compound (0.031 g) was obtained as a grayish white solid: mp 158-160 ° C .; ¹ H NMR (CDCl ₃ ) 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 = 8.7 Hz) and 1.50 (s, 6 H); MS (EI) m / z 287/289 [M] ⁺ .

Example 17

3-benzyl-5- (3-chlorophenyl) -3-methyl-1,3-dihydro-2H-indole-2-thione

According to General Procedure A, 3-benzyl-5- (3-chlorophenyl) -3-methyl-1,3-dihydro-indol-2-one (100 mg) and Laweson reagent (120 mg) were added to toluene (10 mL). At reflux, the title compound (0.022 g) was obtained as a grayish white solid: mp 168-170 ° C .; ¹ 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 = 8.0 Hz), 3.19 (dd, 2H, J = 40.5 and 13 Hz) and 1.57 (s, 3H); MS (EI) m / z 363/365 [M] ⁺ .

Example 18

4- (3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl) -2-furonithrin

4- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl-furan-2-carbonitrile

According to the procedure of Example 5, (2'-oxo- [2,3-dihydro-3,3-dimethyl-1,3 '-[3H] indol] -5'-yl) boronic acid (354 mg, 1.7 mmol) and 4-bromofuran-2-carbonitrile (200 mg, 1.2 mmol) to give the title compound (76 mg, 0.3 mmol, 26%) as a white solid: mp 199.6-201.4 ° C., ¹ H NMR (DMSO-d ₆ ) δ 1.28 (s, 6H), 6.89 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.0, 1.8 Hz, 1H), 7.65 (d, J = 1.5 Hz , 1H), 8.1 (s, 1H), 8.5 (s, 1H), 10.46 (s, 1H); MS (ESI) m / z 251 (MH) ^- ; Analysis _{C 15 H 12 N 2 0 2} · 0.6H 2 0

According to general procedure A, 4- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -furan-2-carbonitrile (73 mg) and Laweson reagent (120 mg) ) Was refluxed in toluene (10 mL) to give the title compound (0.003 g) as a grayish white solid: mp 188-191 ° C .; ¹ 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 = 7.9 Hz) and 1.48 (s, 6H) ; MS (EI) m / z 268 [M] ⁺ .

Example 19

5- (3-methoxyphenyl) -3,3-dimethyl-1,3-dihydro-2H-indole-2-thione

5-Bromo-1.3-dihydro-3,3-dimethyl-2H-indol-2-one

3,3-dimethyl-indol-2-one (0.65g, 4.03mmol) and sodium acetate (0.33g, 4.07mmol) acetic acid (5cm ³⁾ was stirred in and then, acetic acid (5cm ³⁾ of bromine (0.66g, 4.13 mmol) was added dropwise to the reaction mixture. The reaction was stirred for 50 minutes and then poured into water. The mixture was basified with sodium carbonate, extracted with ethyl acetate (x3), dried (MgSO ₄ ), filtered and evaporated to yield the subtitle compound (0.89 g, 92%): ¹ H NMR (DMSO-d ₆ ) δ 1.21 (s, 6H), 6.76 (d, 1H, J = 8.22 Hz), 7.29 (dd, 1H, J = 2.12 Hz, 8.23 Hz), 7.49 (d, 1H, J = 2.03 Hz), 10.4 (s, 1H ).

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.094 g) It stirred in dimethoxyethane (12cm <^3> ) in nitrogen atmosphere. After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by aqueous potassium carbonate (1.15 g, 8.34 mmol) solution (5 cm ³ ). The reaction was heated to reflux for 5 hours and then cooled to room temperature. Saturated aqueous ammonium chloride solution and EtOAc were added and the mixture was filtered. The aqueous layer was extracted with EtOAc (x2) and the combined organic layers were dried (MgSO ₄ ), filtered and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexane 1: 3) to give 5- (3-methoxyphenyl) -3,3-dimethyl-1,3-dihydro-indol-2-one (0.11 g, 31%) was obtained: mp 157-158 ° C; ¹ 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 = 1.14 Hz), 10.4 (s, 1H); MS (EI) m / z 266 (MH) ⁻ ; CHN theory of C ₁₇ H ₁₇ NO ₂ : C 76.38; H 6.41; N 5.24. Found: C 76.02; H 6.49; N 5.02.

According to general procedure A, 5- (3-methoxyphenyl) -3,3-dimethyl-1,3-dihydro-indol-2-one (100 mg) and Laweson reagent (120 mg) in toluene (10 mL) At reflux, the title compound (0.022 g) was obtained as a grayish 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 = 8.0 Hz), 7.16 (d, 1H, J = 7.7 Hz), 7.09 -7.06 (m, 2H), 6.90 (dd, 1H, J = 8.2 and 2.3 Hz), 3.88 (s, 3H) and 1.50 (s, 6H); MS (EI) m / z 283 [M] ⁺ .

Example 20

3- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -4-fluorobenzonitrile

3- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -4-fluorobenzonitrile

Prepared according to the procedure of Example 5: mp 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 = 7.9 Hz), 1.97-1.83 (m, 2H), 1.69-1.55 (m, 8H); MS (EI) m / z 320 (M ⁺ ).

According to General Procedure A, 3- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -4-fluorobenzonitrile (100 mg) Wesson reagent (120 mg) was refluxed in toluene (10 mL) to give the title compound (0.037 g) as a grayish white solid: mp 230-233 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.82 (br s, 1H), 7.86 (s, 1H), 7.77 (dd, 1H, J = 7.0, 1.8 Hz), 7.68-7.63 (m, 1H), 7.45 (d, 1H, J = 8.0 Hz, 7.31 (d, 1H, J = 9.0 Hz), 7.15 (d, 1H, J = 8.1 Hz), 2.17-1.84 (m, 7H) and 1.60-1.54 (m, 3H); MS (EI) m / z 336 [M] ⁺ .

Example 21

5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -3-pyridinecarbonitrile

Anhydrous of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol), hexamethylditin (5.00 g, 15.26 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.20 g, 0.17 mmol) The dimethoxyethane (30 cm ³ ) solution was heated to reflux under N ₂ . After 16 h, the mixture was concentrated and purified by column chromatography (SiO ₂ , EtOAc: hexanes 5:95) to give 3-cyanopyridine-5-trimethylstannan (2.82 g, 10.55 mmol, 69%): ¹ H NMR (CDCl ₃ ) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); MS ((+) APCI) m / z 269 (M + H) ⁺ .

5'-bromospiro [cyclohexane-1,3 '-[3H] indole] -2'(1'H) -one (1.97 g, 7.05 mmol), 3-cyanopyridin-5-trimethylstannan ( Anhydrous toluene (30 cm ³ ) solution of 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) was heated while refluxing. After 16 h, the mixture was cooled and partitioned between EtOAc and water and the aqueous layer was reextracted with EtOAc (x2) and the combined organic extracts washed with water, dried (MgSO ₄ ) and evaporated. The residue was column chromatographed (SiO ₂ , EtOAc: hexane, 1: 2) followed by preparative LC (Primesphere C18, 10 microns, 50 × 250 mm, MeCN: H ₂ 0 1: 1, 100 cm ³ / min, RT 7.92 min) Further purified as white crystals (0.56 g, 1.84 mmol, 26%) as 3- (1 ', 2'-dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indole-5 ' -Yl) pyridine carbonitrile was obtained: mp 232-234 ° C., ¹ H NMR (CDCl ₃ ) δ 1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, IH, J = 8 Hz ), 7.49 (dd, 1H, J = 8,2 Hz), 7.66 (d, 1H, 2 Hz), 8.15 (t, 1H, J = 2 Hz), 8.39 (s, 1H, br), 8.89 (d, 1H, J = 2 Hz), 9.06 (d, 1H, J = 2 Hz); MS ((+)-ESI) m / z 304 (M + H) ⁺ ; Anal C ₁₉ H ₁₇ N ₃ 0 CHN.

In accordance with General Procedure A, 3- (1 ', 2'-dihydro-2'ox-sourcepyro [cyclohexane-1,3'-[3H] indol-5'-yl) pyridine carbonitrile (100 mg) and Laweson reagent (120 mg) was refluxed in toluene (10 mL) to give the title compound (0.004 g) as a yellow solid: mp 237-238 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.56 (br s, 1H), 9.03 (d, 1H, J = 1.9 Hz), 8.87 (d, 1H, J = 1.4 Hz), 8.12 (s, 1H), 7.87 (s , 1H), 7.50 (d, 1H, J = 8.1 Hz), 7.17 (d, 1H, J = 8.1 Hz), 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-difluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5 '-(3,5-difluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one

Prepared according to the procedure of Example 5: mp 180-183 ° C .; ¹ H NMR (CDCl ₃ ) δ 8.35 (s, 1H), 7.59 (d, 1H, J = 2.0 Hz), 7.40 (dd, 1H, J = 6.2, 2.0 Hz), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J = 8.1 Hz), 7.76 (tt, 1H, J = 4.3, 2.3 Hz), 2.05-1.62 (m, 10H); MS ((+) APCI) m / z 314 [M + H] ⁺ .

According to general procedure A, 5 '-(3,5-difluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (100 mg) and Laweson Reagent (120 mg) was refluxed in toluene (10 mL) to give the title compound, which gave the product (0.020 g) 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 1.4 Hz), 7.38-7.30 (m, 1H), 7.26-7.19 ( m, 3H), 7.11 (d, 1H, J = 8.1 Hz), 2.17-1.82 (m, 7H) and 1.66-1.53 (m, 3H); MS ((−)-APCI) m / z 328 [M ⁻ H] ⁻ .

Example 23

5- (5-chloro-2-thienyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5- (5-chloro-2-thienyl) spiro [cyclohexane-1,3- [3H] indole) -2 (1H) -one

Prepared according to the procedure of Example 5: mp 191-192 ° C., ¹ H NMR (CDCl ₃ ) δ 1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, J = 4.0 Hz , 1H), 7.36 (dd, J = 7.5, 1.6 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.80 (br s, 1H); ¹³ C NMR (THF-d ₈ ) δ 21.35, 25.33, 33.12 (t), 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) ⁺ ; Anal (C ₁₇ H ₁₆ ClNOS) C, H, N.

According to general procedure A, 5- (5-chloro-2-thienyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (100 mg) and Laweson reagent (120 mg) Reflux in toluene (10 mL) to give the title compound, which yielded the product (0.041 g) as a yellow solid: mp 231-232 ° C .; ¹ HNMR (CDCl ₃ ) δ 9.75 (br s, 1H), 7.82 (d, 1H, J = 1.2 Hz), 7.43 (dd, 1H, J = 8.1 and 1.6 Hz), 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-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -3-furancarbonitrile

5- (1 ', 2'-Dihydro-2'-oxospyro [cyclohexane-1,3'-[3H] indol] -5'-yl) -3-furancarbonitrile:

Prepared according to the procedure of Example 5: mp 243-245 ° C. ¹ H NMR (DMSO-d ₆ ) δ 10.48 (s, 1H), 8.62 (d, 1H, J = 0.7 Hz), 7.76 (d, 1H, J = 1.5 Hz), 7.58-7.55 (dd, 1H), 7.33 (d, 1H, J = 0.7 Hz), 6.92-6.90 (d, 1H, J = 8.1 Hz), 1.87-1.83 (m, 2H), 1.73-1.53 (m, 8H). MS ((+) EI) m / z 292 (M ⁺ ).

According to general procedure A, 5- (1 ', 2'-dihydro-2'oxospyro [cyclohexane-1,3'-[3H] indol] -5'-yl) -3-furancarbonitrile (100 mg) ) And Laweson reagent (120 mg) were refluxed in toluene (10 mL) to give the title compound, which gave the product (0.020 g) as a yellow solid: mp 264-268 ° C .; ¹ H NMR (CDCl ₃ ) δ 9.66 (br s, 1H), 7.98 (s, 2H), 7.59 (dd, 1H, J = 8.2 and 1.5 Hz), 7.08 (d, 1H, J = 8.2 Hz), 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-fluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5 '-(3-chloro-4-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one

Prepared according to the procedure of Example 5: mp 188-189 ° C .; ¹ H NMR (CDCl ₃ ) δ 7.97 (s, 1H), 7.57-7.54 (m, 2H), 7.41-7.34 (m, 2H), 7.20 (t, 1H, J = 8.7 Hz), 9.96 (d, 1H , J = 8.1 Hz), 2.04-1.65 (m, 10H); MS ((+) APCI) m / z 330 [M + H] ⁺ .

According to general procedure A, 5 '-(3-chloro-4-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (100 mg) and Wesson's reagent (100 mg) was refluxed in toluene (10 mL) to give the title compound, which gave the product (0.036 g) as a grayish white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.74 (br s, 1H) , 7.92 (d, 1H, J = 1.4 Hz), 7.87 (dd, 1 H, J = 7.1 and 2.3 Hz), 7.70-7.65 (m, 1H), 7.61 (dd, 1H, J = 7.1 and 1.5 Hz) , 7.49 (t, 1H, J = 8.9 Hz), 7.14 (d, 1H, J = 8.1 Hz), 1.99-1.82 (m, 7H) and 1.40-1.37 (m, 3H): MS ((-)-APCI ) m / z 344/346 [MH] ^-

Example 26

5- (3-Chloro-5-fluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5 '-(3-chloro-5-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one

Prepared according to the procedure of Example 5: mp 178-180 ° C .; ¹ H-NMR (CDCl ₃ ) δ 8.50 (s, 1H), 7.57 (d, 1H, J = 1.8 Hz), 7.39 (dd, 1H, J = 6.2, 1.9 Hz), 7.33-7.32 (m, 1H) , 7.15 (dq, 1H, J = 5.7, 1.7, 0.7 Hz), 7.06 (dq, 1H, J = 4.2, 1.9, 0.4 Hz), 7.00 (d, 1H, J = 8.1 Hz), 2.05-1.64 (m , 10H); MS ((−) ESI) [M ⁻ H] ⁻ @ m / z 328.

According to general procedure A, 5 '-(3-chloro-5-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (100 mg) and Wesson's reagent (100 mg) was refluxed in toluene (10 mL) to give the title compound, which gave the product (0.039 g) as a grayish white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.76 (br s, 1H) , 7.97 (d, 1H, J = 1.1 Hz), 7.67 (dd, 1H, J = 8.1 and 1.4 Hz), 7.60-7.54 (m, 2H), 7.40 (dt, 1H, J = 8.65 and 2.0 Hz), 7.14 (d, 1H, J = 8.1 Hz), 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-difluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5 '-(3,5-difluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one

Prepared according to the procedure of Example 5: mp 180-183 ° C .; ¹ H-NMR (CDCl ₃ ) δ 8.35 (s, 1H), 7.59 (d, 1H, J = 2.0 Hz), 7.40 (dd, 1H, J = 6.2, 2.0 Hz), 7.10-7.03 (m, 2H) , 6.99 (d, 1H, J = 8.1 Hz), 7.76 (tt, 1H, J = 4.3, 2.3 Hz), 2.05-1.65 (m, 10H); MS ((+) APCI) m / z 314 [M + H] ⁺ .

According to general procedure A, 5 '-(3,5-difluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (100 mg) and Laweson Reagent (100 mg) was refluxed in toluene (10 mL) to give the title compound (0.029 g) as a grayish white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.76 (br s, 1H), 7.84 (s, 1H), 7.64-7.56 (m, 1H), 7.46 (d, 1H, J = 8.1 Hz), 7.40-7.32 (m, 1H), 7.22-7.15 (m, 2H), 1.99-1.80 (m, 7H) And 1.38-1.35 (m, 3 H); MS ((−)-APCI) m / z 328 [M ⁻ H] ⁻ .

Example 28

5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -4-propyl-2-thiophencarbonitrile

5- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -4-propyl-2-thiophencarbonitrile

5-bromo-4-n-propylthiophene-2-carbonitrile (1.17 g, 5 mmol) heated to reflux the title compound overnight, (1,2-dihydro-2-oxospyro [cyclohexane-1, From 3- [3H] indole) -5-boronic acid (1.24 g, 5 mmol), tetrakis (triphenylphosphine) palladium, potassium carbonate (2.75 g, 21 mmol), water (10 mL) and dimethoxyethane (50 mL) Prepared to give the product (0.7 g, 40%): mp 168-171 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 10.56 (s, 1H), 7.93 (s, 1H) 7.52-7.51 (d, 1H, J = 1.5 Hz), 7.33-7.29 (dd, 1H, J = 1.6 Hz) , 7.006.96 (d, 1H, J = 8.0 Hz), 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 . Analytical theory of C ₂₁ H ₂₂ N ₂ OS · ½H ₂ O: C 70.2; H 6.93; N 7.79. Found: C 70.67; H 6.34; N 7.62.

According to general procedure A, 5- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -4-propyl-2-thiophene carbonitrile ( 90 mg) and Laweson reagent (90 mg) were refluxed in toluene (10 mL) to give the title compound (0.037 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.83 (br s, 1H), 7.96 ( s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, J = 7.7 Hz), 7.19 (d, 1H, J = 8.0 Hz), 2.60 (t, 2H, J = 8.0 Hz), 1.98- 1.79 (m, 7H), 1.64-1.56 (m, 2H), 1.39-1.35 (m, 2H) and 0.87 (t, 3H, J = 7.3 Hz); MS ((−) APCI) m / z 365 [M ⁻ H] ⁻ .

Example 29

5- (3-fluoro-4-nitrophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5- (3-fluoro-4-nitrophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (H) -one

According to the procedure of Example 5, (2'-oxo-2,3-dihydrospiro [cyclohexane-1,3 '-[3H] indol] -5'-yl) boronic acid (3.2 g, 12.5 mmol) And 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) gave the title compound (0.7 g, 16%) as a yellow solid: mp 213-215 ° C; ¹ H NMR (DMSO-d ₆ ) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H, J = 8.13 Hz), 7.68 (dd, 1H, J = 8.13, 1.76 Hz), 7.74 (dd, 1H, J = 8.68, 1.76 Hz), 7.86 (d, 1H, J = 1.98 Hz), 7.92 (dd, 1H, J = 13.4, 1.76 Hz), 8.18 (t, 1H, J = 8.46 Hz) and 10.52 (s, 1 H); MS (EI) m / z = 340 (M ⁺ ).

According to General Procedure A, 5- (3-fluoro-4-nitrophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Laweson reagent (90 mg) Was refluxed in toluene (10 mL) to give the title compound, which gave the product (0.021 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ 12.82 (br s, 1H), 8.21 (t, 1H, J = 8.4 Hz), 8.07 (d, 1H, J = 1 Hz), 7.98 (dd, 1H, J = 13.1 Hz), 7.79 (dt, 1H, J = 8.1 and 2.6 Hz), 7.19 (1H, J = 8.2 Hz ), 1.99-1.83 (m, 7H) and 1.42-1.39 (m, 3H): MS ((-) APCI) m / z 355 [M ⁻ H] ⁻ .

Example 30

4-2-dihydro-2-thioxopyrocyclohexane-1,3- [3H] indol] -5-yl) -2-furancarbonitrile

4- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -2-furancarbonitrile

Ethylene glycol dimethyl ether (20 cm ³ ) solution of ³ -bromo-5-cyano-furan (0.75 g, 4.4 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.4 g) was added to N ₂ for 20 minutes. It was stirred under. To this mixture (spiro [cyclohexane-1,3 '-[3H] indole] -2'(1'H) -one-5-yl) boronic acid (1.6 g, 6.5 mmol) and sodium acetate (1.4 g, 13.1 mmol) was added (5 cm ³ ). The solution was refluxed for 18 hours and then cooled to room temperature and poured into 2N NaOH and extracted with EtOAc (x3). Layers were washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc, hexanes) to give the product (0.45 g, 36%) as a grayish white solid: mp 240-242 ° C .; 1 H NMR (DMSO-d ₆ ) 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 = 8.0 Hz), (m, 10H); MS (EI) M ⁺ @ m / z 292.

4- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -2-furancarbonitrile (67 mg) and Laweson according to General Procedure A Reagent (67 mg) was refluxed in toluene (10 mL) to give the title compound (0.018 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) 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 1.0 Hz), 7.10 (s, 1H, J = 8.1 Hz), 1.94-1.78 (m, 7H) and 1.35- 1.32 (m, 3H): MS ((−)-APCI) m / z 307 [M ⁻ H] ⁻ .

Example 31

5 "-(3-chlorophenyl) spirocyclobutane-1,3"-[3H] indole] -2 "(1" H) -thione

5-Bromospiro [cyclobutan-1,3- [3H] indole] -2 (1H) -one

Cold acetic acid of stirred spiro [cyclobutan-1,3 '-[3H] indole] -2'(1'H) -one (J. Med. Chem. 1987,824-9) (1.0 g, 6 mmol) A bromine (0.30 mL, 6 mmol) cold acetic acid (6 mL) solution was added dropwise to the 10 mL solution at room temperature. After stirring for 10 minutes, anhydrous sodium acetate (0.47 g, 6 mmol) was added and the solution was concentrated in vacuo. The residue was dissolved in ethyl ether (50 mL) and washed successively with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization from ethyl ether gave the product as a white powder (1.1 g, 73%). Mp 235-7 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) 2.15-2.41 (m, 6H), 6.74 (d, 1H, J = 8.2 Hz), 7.33 (dd, 1H, J = 2, 8.2 Hz), 7.75 (d , 1H, J = 2 Hz), 10.36 (bs, 1H). MS (EI) m / z 251 [M ⁺ ]. Analytical theory of C ₁₁ H ₁₀ BrNO: C 52.41; H 4.00; N 5.56. Found: C 51.98; H 4.24; N 5.42.

To a solution of 5-bromospiro [cyclobutane-1,3- [3H] indole] -2 (1H) -one (0.6 g, 2 mmol) in ethylene glycol dimethyl ether (50 mL) under nitrogen atmosphere, tetrakis (triphenylforce) Pin) palladium (0) (140 mg, 0.1 mmol) was added. 3-chlorophenylboronic acid (0.48 g, 3 mmol) and aqueous potassium carbonate (0.76 g, 5 mmol) solution (5 mL) were successively added to this solution. The mixture was heated to 80 ° C. for 3 hours and cooled. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. The residue was purified by HPLC (Zorbax PRO, C18, 10u, 15A, 50x250mm; 35% water / 65% AcCN; 254NM; AMB. Temperature) to give 5- (3-chlorophenyl) spiro [cyclobutane-1 as white powder. , 3- [3H] indole] -2 (1H) -one (200 mg, 35%) was obtained: mp 199.5-201 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) 2.21-2.28 (m, 2H), 2.40-2.45 (m, 4H), 6.87 (d, 1H, J = 8.1 Hz), 7.37 ('d', 1H), 7.44-7.52 (m, 2H), 7.65 (bd, 1H, J = 7.8 Hz), 7.76 (bs, 1H), 7.92 (bs, 1H), 10.35 (s, 1H). MS (EI) m / z 283 [M ⁺ ]. Analytical theory of C ₁₇ H ₁₄ ClNO: C 71.96; H 4.97; N 4.94. Found: C 70.75; H 5.07; N 4.68.

According to General Procedure A, 5- (3-chlorophenyl) spiro [cyclobutane-1,3- [3H] indole] -2 (1H) -one (55 mg) and Laweson reagent (55 mg) were added to toluene (10 mL). At reflux, the title compound (0.016 g) was obtained as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.58 (br s, 1H), 8.07 (d, 1H, J = 1.5 Hz), 7.82 (t, 1H, J = 1.7 Hz, 7.70 (d, 1H, J = 7.74 Hz), 7.60 (dd, 1H, J = 8.12 and 1.71 Hz), 7.49 (t, 1H, 7.9 Hz), 7.41 (d, 1H, J = 8.32 Hz), 7.05 (d, 1H, J = 8.14 Hz) and 2.57-2.27 (m, 6H); MS ((−)-APCI) m / z 298/300 [M ⁻ H] ⁻ .

Example 32

5 "-(2-chlorophenyl) spiro [cyclohexane-1,3"-[3H] indole] -2 "(1" H) -thione

According to general procedure A, 5 "-(2-chlorophenyl) spiro [cyclohexane-1,3"-[3H] indole] -2 "(1" H) -thione (90 mg) and Laweson reagent (90 mg) Was refluxed in toluene (10 mL) to give the title compound, which gave the product as a grayish white solid (0.042 g): ¹ H NMR (DMSO-d ₆ ) δ 12.75 (br s, 1H), 7.80 (d, 1H, J = 1.1 Hz) 7.58-7.55 (m, 1H), 7.48-7.36 (m, 4H), 7.16 (d, 1H, J = 8.0 Hz); MS ((−)-APCI) m / z 326/328 [M ⁻ H] ⁻ .

Example 33

5 "-(4-chlorophenyl) spiro [cyclohexane-1,3"-[3H] indole-2 "(1" H) -thione

According to General Procedure A, 5- (4-chlorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Laweson reagent (90 mg) were added to toluene (10 mL). The title compound was prepared by refluxing to give the product (0.035 g) as a grayish white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.74 (br s, 1H), 7.91 (d, 1H, J = 1.3 Hz), 7.69 (d, 2H, J = 5.5 Hz), 7.60 (dd, 1H, J = 8.1 and 1.4 Hz), 7.50 (d, 2H, J = 8.5 Hz), 7.15 (d, 1H, J = 8.1 Hz), 1.99-1.83 (m, 7H) and 1.50-1.36 (m, 3H); MS ((−)-APCI) [M ⁻ H] ⁻ m / z 326/328.

Example 34

5- (1 ", 2" -dihydro-2 "-thioxopyro [cyclohexane-1,3"-[3H] indol] -5 "-yl) -4-methyl-2-thiophencarbonitrile

5-bromo-4-methyl-2-thiophene carboxyaldehyde

To a solution of diethylamine (28 g, 0.383 mol) in THF (400 mL) was added n-BuLi (2.5 M, 153 mL, 0.383 mol) hexane solution at -40 ° C. under nitrogen. After addition, the solution was stirred at −40 ° C. under nitrogen for 30 minutes, cooled to −78 ° C. and added dropwise with 2-bromo-3-methylthiophene (45 g, 0.254 mol) anhydrous THF (450 mL) solution. The reaction solution was stirred for 30 min at -78 &lt; 0 &gt; C and treated with anhydrous DMF (100 mL). The mixture was warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid solution (1 L). The solution was extracted with ethyl acetate (3 × 450 mL), washed with water, brine and dried (MgSO ₄ ). After removal of solvent in vacuo, the title compound was obtained as a white solid (46 g, 88.3%). Samples of the product were crystallized from hexanes: mp 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 (M &lt; + &gt;). Analytical theory of C ₆ H ₅ BrOS: C 35.14; H 2.46. Found: C 35.00; H 2.44.

5-bromo-4-methyl-2-thiophencarbonitrile

Prepared from 5-bromo-4-methyl-2-thiophene carboxyaldehyde using the procedure of Example 5. White solid: mp 40-42 ° C .; IR (KBr) 2200 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) δ 7.29 (S, 1H), 2.21 (S, 3H). MS (EI) m / z 201/203 (M &lt; + &gt;, 98% / 100%); Analytical theory of C ₆ H ₄ BrNS: C 35.66; H 1.99; N, 6.93. Found: C 36.00; H 2.14; N 6.76.

(2'-oxo- [2,3-dihydro-3,3-dimethyl-1,3 '-[3H] indol] -5'-yl) boronic acid (357 mg, 1.7 mmol) and 5-bromo- Prepared according to the procedure of Example 5 using 4-methylthiophene-2-carbonitrile (295 mg, 1.5 mmol) to give 5- (3,3-dimethyl-2-oxo-2,3-di as a white solid. Hydro-1H-indol-5-yl) -4-methylthiophen-2-carbonitrile (227 mg, 0.8 mmol, 55%) was obtained: mp 192.3-193 ° C., ¹ H NMR (DMSO-d ₆ ) δ 1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.0, 1.8 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H) , 7.84 (s, 1 H), 10.57 (s, 1 H); MS (EI) m / z 282 (m) ⁺ ; Anal C ₁₆ H ₁₄ N20S.

5- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -4-methylthiophen-2-carbonitrile (0.77 g, 2.39 mmol) and phosphorus penta sulfide (0.42 g, 0.96 mmol) was refluxed in toluene (20 mL) to prepare the title compound. After 3 hours, the reaction was cooled, partitioned between water and EtOAc, the organic layer was separated, dried (MgSO ₄ ) and evaporated. Purify the residue by column chromatography (SiO ₂ , EtOAc: hexanes, gradient elution) to give the product as an orange solid (0.25 g, 0.73 mmol, 30%): ¹ H NMR (DMSO-d ₆ ) δ 12.82 (br s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, 2 Hz), 7.49 (dd, 1H, J = 8.1, 1.6 Hz), 7.18 (d, 1H, J = 8.1 Hz), 1.99-1.80 (m, 7H) and 1.40-1.36 (m, 3H); MS ((−)-APCI) m / z 321 [M ⁻ H] ⁻ .

Example 35

5- (1 ", 2" -dihydro-2 "-thioxopyro [cyclohexane-1,3"-[3H] indol] -5 "-yl) -2-thiophencarbonitrile

5-bromo-2-thiophencarbonitrile

A mixture of 5-bromo-2-thiophenecarboxyaldehyde (96.0 g, 500 mmol), pyridine (500 mL), hydroxylamine hydrochloride (111.9 g, 500 mmol) and ethanol (500 mL) was heated under reflux for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford an oil. The solid obtained by polishing the crude product twice with ice water was collected on a filter. A portion of the solid (44.31 g, 215 mmol) and acetonitrile (1.4 L) solution of monohydrate copper acetate (II) (4.2 g, 21 mmol) was heated under reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid solution (2 × 30 mL), water (2 × 30 mL), brine (20 mL) and dried (MgSO ₄ ). The solvent was removed in vacuo and the residue was crystallized by dissolving in a minimum amount of chloroform (1 L). The obtained crystals were collected on a filter, the filtrate was concentrated and purified by chromatography (silica gel, chloroform) to yield the title compound as a grayish white solid (31.5 g combined, 58%). IR (Film) 2200 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ 7.39-7.38 (d, 1H, J = 4.1 Hz), 7.10 (d, 1H, J = 4.0 Hz); MS (EI) m / z 187 (M ⁺ , 98%) 189 (M ⁺ , 100%).

5- (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3'-[3H] indol] -5'-yl-2-thiophencarbonitrile was replaced with 5-bromo-2 Example 5 procedure using -thiophencarbonitrile and (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3' [3H] indol] -5'-yl) boronic acid Prepared according to: mp 225-228 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.63 (m, 8H), 1.90 (m, 2H), 6.91 (d, 1H, J = 8.13 Hz), 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 ((+) APC1) m / z 309 [M + H] ⁺ .

5- (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3'-[3H] indol] -5'-yl-2-thiophencarbonitrile (0.69 g) and pentasulfide Phosphorus (0.4 g) was refluxed in toluene (20 mL) to give the title compound After 3 hours, the reaction was cooled and poured into saturated aqueous sodium hydrogen carbonate solution and extracted with EtOAc The organic layer was separated, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexanes, gradient elution) to give the title compound (0.215 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.82 (br s, 1H ), 8.00-7.98 (m, 2H), 7.74 (d, 1H, J = 4.1 Hz), 7.69 (dd, 1H, J = 8.2 and 1.6 Hz), 7.14 (d, 1H, J = 8.1 Hz), 1.99 -1.83 (m, 7H) and 1.40-1.37 (m, 3H); MS ((-)-APCI) m / z 323 [M ⁻ H] ⁻ .

Example 36

5 "-(3-fluorophenyl) spiro [cyclohexane-1,3"-[3H] indole] -2 "(1" H) -thione

5 '-(3-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one

Prepared according to the procedure of Example 5: mp 171-172 ° C .; ¹ H-NMR (CDCl ₃ ) δ 8.43 (s, 1H), 7.62 (d, 1H, J = 1.8 Hz), 7.42 (dt, 1H, J = 6.2, 2.0 Hz), 7.39-7. 37 (m, 1H), 7.33 (dt, 1H, J = 5.1, 1.3 Hz), 7.26 (dq, 1H, J = 5.9, 2.1 Hz), 7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H); MS ((+) APCI) m / z 296 [M + H] ⁺ .

5 '-(3-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (0.70 g) and phosphorus penta sulfide (0.4 g) were added to toluene ( 20 mL) to afford the title compound. After 3 hours, the reaction was cooled, poured into saturated aqueous sodium hydrogen carbonate, extracted with EtOAc, the organic layer was separated, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexanes, gradient elution) to give the product as a grayish white solid (0.42 g): ¹ H NMR (DMSO-d ₆ ) δ 12.75 (br s, 1H ), 7.95 (d, 1H, J = 1.5 Hz), 7.64 (dd, 1H, J = 8.13 and 1.5 Hz), 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-hydroxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5 '-(3-hydroxyphenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one

Prepared according to the procedure of Example 5: mp 213-216 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J = 8 Hz), 7.01-7.04 (m, 2H), 7.23 (t, 1H, J = 7.7 Hz, 7.38 (d, 1H, J = 8 Hz), 7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (s, 1H, br); MS ((+)-APCI) 294 [M + H] ⁺ .

According to general procedure A, 5 '-(3-hydroxyphenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one (100 mg) and Laweson reagent (110 mg) ) Was refluxed in toluene (10 mL) to give the title compound (0.0045 g) as a grayish 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 1.5 Hz), 7.33 (t, 1H, J = 7.9 Hz), 7.15-7.10 (m, 3H), 6.84 (dd, 1H, J = 8.0 and 2.2 Hz), 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- (3-chlorophenyl) -3,3-diethyl-1,3-dihydro-2H-indole-2-thione

The oxindole (40 g, 0.3 mol) dry THF (400 mL) solution was cooled to -25 ° C under N ₂ and treated dropwise with n-butyllithium (2.5 M in hexane, 240 mL, 0.6 mol). N, N, N ', N'-tetramethylethylenediamine (90.4 mL, 0.6 mol) was added to the resulting solution. After 30 minutes, urethane ethane (48 mL, 0.6 mol) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into NH ₄ Cl solution and extracted with EtOAc (2 ×), and the combined organic layers were washed with dilute HCl, water, brine, dried (MgSO ₄ ) and concentrated. The remaining oil was triturated with hexane to give crude product (24.5 g, 51%). Sample (3 g) was recrystallized from EtOAc / hexanes to give 3-ethyl-indol-2-one (1.4 g): mp 100-101 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 0.76 (t, 3H, J = 7.5 Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J = 5.7 Hz), 6.8 (dt, 1H, J = 7.69, 0.45 Hz), 6.93 (dt, 1H, J = 7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m / z 270 [M + H].

The 3-ethyl-indol-2-one (16 g, 0.1 mol) dry THF (200 mL) solution under N ₂ was cooled to -25 ° C and dropwise treated with n-butyllithium (2.5 M in hexane, 80 mL, 0.2 mol). . N, N, N ', N'-tetramethylethylenediamine (30 mL, 0.2 mol) was added to the resulting solution. After 30 minutes, yodoethane (8 mL, 0.1 mol) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into aqueous NH ₄ Cl solution and extracted with EtOAc (2 ×), and the combined organic layers were washed with dilute HCl, water, brine, dried (MgSO ₄ ) and concentrated. The remaining 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 = 1.7 Hz), 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 = 8.2 Hz), 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).

An acetic acid (100 mL) solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) was treated with bromine (6.4 g, 40 mmol). After 30 minutes, the mixture was diluted with water and extracted with EtOAc (2 ×). The combined organic layers were washed with water, saturated sodium bicarbonate solution, brine, dried (MgSO ₄ ) and evaporated to afford crude product (7.6 g, 75%). The sample was recrystallized from EtOAc / hexanes to give 5-bromo-1,3-dihydro-3,3-diethyl- [2H] -indol-2-one: mp 164-165 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 10.45 (s, IH), 7.41-7.40 (d, 1H, J = 2.2 Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J = 8.2 Hz), 1.78-1.65 (m, 4H), 0.50-0.46 (m, 6H); MS (-ESI) m / z 266/268 (MH).

5-Bromo-1,3-dihydro-3,3-diethyl- [2H] -indol-2-one (2.7 g, 10 mmol) in dimethoxyethane (100 mL), ethanol (25 mL) and water (25 mL) ), 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) were heated under reflux for 6 hours. . After cooling to rt, the mixture was diluted with water and extracted with EtOAc (2 ×). The combined organic extracts were washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (SiO ₂ , EtOAc: hexane 1: 3) to give 5- (3-chloro-phenyl) -3,3-diethyl-1,3-dihydro-indol-2-one compound. (0.8 g, 27%) was obtained: mp 195-197 ° C; ¹ H NMR (DMSO-d ₆ ) δ 7.70 (t, 1H, J = 2 Hz), 7.62-7.60 (m, 1H), 7.58 (d, 1H, J = 1.7 Hz), 7.52, (dd, 1H, J = 8.1, 2 Hz), 7.43 (t, 1H, 7.9 Hz), 7.36-7.33 (m, 1H), 6.90 (d, 1H, J = 8.1 Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, J = 7.4 Hz); MS (+ APCI) m / z 300/302 (MH).

According to General Procedure A, toluene (10 mL) with 5- (3-chloro-phenyl) -3,3-diethyl-1,3-dihydro-indol-2-one compound (100 mg) and Laweson reagent (100 mg) Reflux in) afforded the title compound to give the product (0.023 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ 12.73 (br s, 1H), 7.77 (t, 1H, J = 1.8 Hz) , 7.75 (d, 1H, J = 1.6 Hz), 7.68-7.62 (m, 2H), 7.48 (t, 1H, J = 7.9 Hz), 7.40 (d, 1H, J = 8.3 Hz), 7.09 (d, 1H, J = 8.1 Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H), and 0.37 (t, 6H, J = 7.3 Hz): MS ((-)-APCI) m / z 314 / 316 [M ⁻ H] ⁻ .

Example 39

5- [4-fluoro-3- (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

5- [4-fluoro-3- (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3H] indole] -2- (1H) -one was prepared as described in Example 5 ( 2'-oxo-2,3-dihydrospiro [cyclohexane-1,3 '-[3H] indol] -5'-yl) boronic acid (2.5 g, 10 mmol) and 5-bromo-2-fluoro Prepared from trifluoromethylbenzene (2 g, 8 mmol) to give the title compound (0.87 g, 30%) as a solid: mp 222 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.92 (d, 1H, J = 8.13 Hz), 7.51 (dd, 1H, J = 8.13, 1.76 Hz), 7.55 (dd, 1H, J = 10.54, 9.01 Hz), 7.72 (d, 1H, J = 1.76 Hz), 7.90 (dd, 1H, J = 7.03, 2.20 Hz), 7.98 (m, 1H) And 10.39 (s, 1 H); MS (EI) m / z 363 (M ⁺ ).

According to general procedure A, 5- [4-fluoro-3- (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Wesson's reagent (90 mg) was refluxed in toluene (10 mL) to give the title compound, which gave the product (0.016 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ 12.75 (br s, 1H), 8.068. 00 (m, 1H), 7.96-7.92 (m, 2H), 7.66-7.56 (m, 2H), 7.16 (d, 1H, J = 8.1 Hz), 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-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -2-fluorobenzonitrile

According to General Procedure A, 4- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) -2-fluorobenzonitrile (90 mg) and Wesson reagent (90 mg) was refluxed in toluene (10 mL) to give the title compound (0.050 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.80 (br s, 1H), 8.04 (d, 1H, J = 1.3 Hz), 7.98 (t, 1H, J = 7.5 Hz), 7.92 (dd, 1H, J = 11.3 and 1.3 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.2 Hz), 1.99-1.82 (m, 7H) and 1.40-1.38 (m, 3H); MS ((−)-APCI) m / z 335 [M ⁻ H] ⁻ .

Example 41

5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] indol] -5-yl) 4-n-butyl-2-thiophencarbonitrile

In a manner similar to Example 5, 5-bromo-4-n-butyl thiophencarbonitrile (1.24 g, 5.1 mmol), (1,2-dihydro-2 oxofyrrole, heated at reflux for 5 hours, was heated. [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), water (10 mL) and dimethoxyethane (50 mL) to prepare 5- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) 4-n- Butyl-2-thiophencarbonitrile (1 g, 54%) was obtained: mp 130-132 ° C. ¹ H NMR (DMSO-d ₆ ) δ 10.56 (s, 1H), 7.92 (s, 1H), 7.52-7.51 (d, 1H, J = 1.2 Hz), 7.32-7.29 (dd, 1H, J = 1.5 Hz ), 6.98-6.96 (d, 1H, J = 8.0 Hz), 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 ; Analytical theory of C ₂₂ H ₂₄ N ₂ OS. 1 / 4H ₂ 0: C71.61; H 6.69; N 7.59. Found: C 71.13; H 6.61; N 6.91.

5- (1,2-dihydro-2-oxospyro [cyclohexane-1,3- [3H] indol] -5-yl) 4-n-butyl-2-thiophencarbonitrile, according to general procedure A (90 mg) and Laweson reagent (90 mg) were refluxed in toluene (10 mL) to give the title compound (0.050 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) 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, 7.3 Hz): MS ( (−)-APCI) m / z 379 [M ⁻ H] ⁻ .

Example 42

5- (3-Fluoro-5-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione

According to general procedure A, 5- (3-fluoro-5-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Laweson reagent (90 mg) ) Was refluxed in toluene (10 mL) to give the title compound, which gave the product (0.043 g) as a grayish white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.74 (br s, 1H), 7.90 (s , 1H), 7.63 (dd, 1H, J = 8.1 and 1.2 Hz), 7.13 (d, 1H, J = 8.1 Hz), 7.08 (d, 1H, J = 10 Hz), 7.01 (s, 1H), 6.83 ( dt, 1H, J = 11 and 2.0 Hz), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H): MS ((−)-APCI) m / z 340 [M ⁻ H] ⁻ .

Example 43

5- (3-chlorophenyl) -N-hydroxyspiro [cyclohexane-1,3 '-[3H] indol] -2-amine

5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -thione (0.74 g, 2.25 mmol) in dry THF (15 mL) solution at room temperature Sodium hydride (60% in oil, 0.1 g, 2.5 mmol) was added. After 15 minutes, methyl iodide (0.18 mL, 2.88 mmol) was added. After 1 h, the reaction mixture is partitioned between water and EtOAc, the organic layer is washed with brine, dried (MgSO ₄ ) and evaporated to 5- (3-chlorophenyl) -2- (methylthio) spiro [cyclohexane- 1,3 '-[3H] indole] (0.80 g, 100%) was obtained and used without further purification.

To a solution of DMSO (20 mL) of the last described compound (1.96 g, 5.73 mmol) was added hydroxylamine (60% in water, 5 mL) and the mixture was heated to 120 ° C. After 1 hour, the mixture was cooled and partitioned between diethyl ether and saturated aqueous ammonium chloride solution. The organic layer was washed with water, brine, dried (MgSO ₄ ) and evaporated. The crude product was crystallized from MeOH to give the title compound (1.67 g, 5.08 mmol, 89%) as a white solid: ¹ H NMR (CDCl ₃ ) δ 7.52 (t, 1H, J = 1.7 Hz), 7.43-7.28 ( m, 7H), 6.83 (d, 1H, J = 8 Hz) and 1.98-1.51 (m, 10H); MS (ESI (+)) m / z 327/329 [M + H] ⁺ .

Example 44

N- (acetyloxy) -5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indol] -2 "-amine

Methylene chloride-methanol (9: 1, 10 mL) of 5- (3-chlorophenyl) -N-hydroxyspiro [cyclohexane-1,3 '-[3H] indole] -2-amine (0.23 g, 0.71 mmol) The solution was added acetic anhydride (0.08 mL, 0.8 mmol) and 4-dimethylaminopyridine (catalyst amount) under a nitrogen atmosphere. After 20 minutes, the reaction was evaporated to purify the product by column chromatography (Si0 ₂ , methanol: methylene chloride 5:95). The product was triturated with diisopropylether to give the title compound (0.12 g, 0.32 mmol, 45%): ¹ H NMR (CDCl ₃ ) δ 7.52-7.51 (m, 2H), 7.43-7.27 (m, 5H), 6.88 (d, 1H, J = 8 Hz), 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] ⁺ ; C ₂₁ H ₂₁ ClN ₂ 0 ₂ .Hores of 0.5H ₂ 0: C 66.98; H 5.64; N 7.34. Found: C 66.74; H 5.86; N 7.41.

Example 45

5 '-(3-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole-2 '(1'H) -one oxime

5 '-(3-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -thione (0.59 g, 1.90 mmol) according to the method of Example 43 Prepared to give the title compound (0.053 g, 0.17 mmol, 10%): ¹ H NMR (DMSO-d ₆ ) δ 9.59 (s, 1H), 9.40 (s, 1H), 7.57 (d, 1H, J = 1.5 Hz), 7.46-7.39 (m, 4H), 7.11-7.05 (m, 1H), 6.80 (d, 1H, J = 8.1 Hz), 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] ⁻ , C ₁₉ H ₁₉ FN ₂ 0 requires: C 73.53, H 6.17, N 9.03. Found C 73.33, H 6.07, N 8.83.

Example 46

5 '-(2-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole-2 '(1'H) -one oxime

5'-bromospiro {cyclohexane-1,3 '-[3H] indole-2' (1'H) -one 2 '(O-benzyloxime)

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) Was combined in methanol and heated at 45 ° C. for 6 hours. Methanol was evaporated in vacuo, ethyl acetate was added to the residue, and the mixture was washed with ammonium chloride solution. Ethyl acetate was dried over magnesium sulfate, the collected ethyl acetate was evaporated in vacuo and the residue was flash chromatographed on alumina 90 (9: 1 hexanes / EtOAc) to give the desired product (6.5 g, 60%): ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H), 6.71 (d, 1H, J = 8.26 Hz), 7.22- 7.43 (m, 7 H), 9.62 (s, 1 H).

Course A

5 '-(2-fluorophenyl) -spiro [cyclohexane-1,3' [3H] indole] -2 '(1H) -one 2 (O-benzyloxime)

Tetrakis (triphenylphosphine) Pd (0) (0.14g, 0.12mmol) and 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one 2 '(0-benzyl oxime) (1.0 g, 2.6 mmol) was stirred in ethylene glycol dimethyl ether (23 mL) under nitrogen atmosphere. After 15 minutes, 2-fluorophenylboronic acid (0.72 mg, 5.2 mmol) was added followed by an aqueous sodium carbonate (1.6 g, 15.6 mmol) solution. The reaction was heated to reflux overnight, cooled to room temperature and filtered through a plug of celite. Saturated ammonium chloride was added. The water layer was extracted with ethyl acetate (3x100 mL). Layers were dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The product was purified by flash silica gel chromatography (eluent: 10: 0.5 hexane: ethyl acetate) to give the desired target compound (0.75 g, 1.8 mmol, 72%) as viscous oil: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.44-1.73 (8H, m), 1.93-2.06 (2H, q), 5.00 (2H, s), 6.88 (1H, d, J = 8.1 Hz), 7.24-7.38 (6H, m), 7.44-7.56 (5H, m), 9.64 (1H, s); MS (ESI (+ ve)) m / z 399 (MH) ^- .

Course B

5 '-(2-fluorophenyl) -spiro [cyclohexane-1,3'-[3H] indole] -2 '(1H) -one 2 (O-benzyloxime) (0.55 g, 1.37 mmol) (15 mL) solution was added to palladium on carbon (10%, 0.11 g) in ethanol (10 mL). The mixture was stirred at room temperature under hydrogen (balloon flask) atmosphere for 24 hours. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated in vacuo. The product was purified by flash silica gel chromatography (hexane: ethyl acetate, gradient elution) to give the title compound (0.45 g, 1.12 mmol, 82%): mp 200-203 ° C .; ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (1 H, s), 9.58 (1 H, s); MS (ESI (+ ve)) m / z 311 (M + H) ⁺ .

Example 47

5 '-(4-fluorophenyl) spirocyclohexane-1,3'-[3H] indole-2 '(1'H) -one oxime

5 '-(4-fluorophenyl) -spiro [cyclohexane-1,3'-[3H] indole-2 '(1'H) -one 2' (0-benzyloxime)

According to process A of example 46, 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one 2 '(0-benzyloxime) (1.0 g , 2.6 mmol) and 4-fluorophenylboronic acid (0.72 g, 5.2 mmol). The product was purified by flash silica gel chromatography (eluent: 10: 0.5 hexanes: ethyl acetate) to give the desired product as a viscous oil (0.70 g, 1.7 mmol, 67%): ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.42-1.77 (8H, m), 1.95-1.99 (2H, q), 5.00 (2H, s), 6.84 (1H, d, J = 8.1 Hz), 7.21-7.63 (1H, m), 9.58 (1H, s); MS (ESI (−ve)) m / z 399 (M ⁻ H) ⁻ .

Example 48

5 '-(3,4-difluorophenyl) 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 2' (O-benzyloxime)

According to process A of example 46, 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one 2 '(0-benzyloxime) (1.0 g , 2.6 mmol) and 3,4-difluorophenylboronic acid (1.6 g, 5.2 mmol of a 50% acid solution in THF / water). The product was purified by flash silica gel chromatography (eluent: 10: 0.5 hexane: ethyl acetate) to give the desired product as a viscous oil (0.75 g, 1.7 mmol, 69%): ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (1 H, m), 9.61 (1 H, s); MS (ESI (−ve)) m / z 417 (M ⁻ H) ⁻ .

According to procedure B of Example 45, the last described compound (0.70 g, 1.6 mmol) was reacted to give the title compound (0.44 g, 1.3 mmol, 80%): ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 '-(3-methoxyphenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one oxime

5 '-(3-methoxyphenyl) -spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one 2' (O-benzyloxime)

According to process A of example 46, 5'-bromosspiro [cyclohexane-1,3 '-[3H] indole-2'(1'H) -one 2 '(0-benzyloxime) (1.0 g, 2.6 mmol) and 3-methoxyphenylboronic acid (0.79 g, 5.2 mmol). The product was purified by flash silica gel chromatography (eluent: 10: 0.5 hexanes: ethyl acetate) to give the desired product as a viscous oil (0.80 g, 1.9 mmol, 75%): ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (10 H, m), 9.57 (1 H, s); MS (ESI (−ve)) m / z 411 (M ⁻ H) ⁻ .

According to procedure B of Example 46, the last described compound (0.80 g, 1.9 mmol) was reacted to give the title compound (0.48 g, 1.4 mmol, 77%) as a white solid: mp 101-104 ° C .; ¹ H NMR (500 MHz, DMSO-d ₆ ) 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-nitrophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one oxime

5 '-(3-nitrophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one 2' (O-benzyloxime)

According to process A of example 46, 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one 2 '(O-benzyloxime) (1.0 g , 2.6 mmol) and 3-nitrophenylboronic acid (0.86 g, 5.2 mmol). Purification by flash silica gel chromatography (eluent: 10: 0.5 hexane: ethyl acetate) gave the desired compound (0.60 g, 1.4 mmol, 55%) as a viscous oil: ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 ( 1 H, d), 9.69 (1 H, s); MS (ESI (−ve)) m / z 426 (M ⁻ H) ⁻ .

Course C

The last described compound (0.54 g, 1.26 mmol) was dissolved in dry methylene chloride (25 mL) 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 was quenched with saturated sodium bicarbonate (5 mL). The reaction mixture was allowed to warm to room temperature, the layers separated and the aqueous layer extracted with methylene chloride. Layers were dried (Na ₂ SO ₄ ), filtered and the solvent was removed in vacuo. The product was purified by flash silica gel chromatography (eluent: 8: 1 hexane: ethyl acetate) to give the title compound (0.33 g, 0.9 mmol, 78%): mp 221-224 ° C .; ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 '-(3-cyanophenyl) spiro [cyclohexane-1,3'-[3H] indole-2 '(1'H) -one oxime

3- [spiro [cyclohexane-1,3 '-[3H] indole]-(1'H) -one-2'-(O-benzyloxime) benzonitrile [3H] indol-5-yl] benzonitrile

According to process A of example 46, 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one 2 '(O-benzyloxime) (1.0 g , 2.6 mmol) and 3-cyanophenylboronic acid (0.76 g, 5.2 mmol). The product was purified by flash silica gel chromatography (eluent: 10: 0.5 hexanes: ethyl acetate) to give the desired product as a viscous oil (0.75 g, 1.8 mmol, 71%): ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (1 H, s), 9.65 (1 H, s); MS (ESI (−ve)) m / z 406 (M ⁻ H) ⁻ .

According to procedure C of Example 50, the last described compound (0.17 g, 0.43 mmol) and boron tribromide (1.2 mL, 1.2 mmol) were reacted to obtain the title compound (0.06 g, 0.2 mmol, 47%) as a white solid. mp 198-200 ° C .; ¹ H NMR (500 MHz, DMSO-d ₆ ) 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, s); (ESI (+ ve)) m / z 318 (M + H) ⁺ .

Example 52

3- [1 ', 2'-dihydro-2'-(hydroxyimino) spiro [cyclohexane-1,3 '-[3H] indol] -5'-yl] -5-fluorobenzonitrile

In a solution of 3-fluoro-5-cyano-bromobenzene (0.4 g, 2.0 mmol) dry DMF (10 mL), diboron pinacholate ester (0.63 g, 2.5 mmol), potassium acetate (0.65 g, 6.7 mmol) and PdCl ₂ (dppf) (0.2.g) was added and the reaction was heated to 80 ° C. under nitrogen atmosphere. After 8 hours, 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one 2 '(0-benzyloxime) (0.2 g, 0.5 mmol), PdCl ₂ (dppf) (0.05 g) and sodium carbonate (1.30 g, 12.5 mmol) were added and heating continued at 80 ° C. After 8 hours, the reaction was cooled and partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (Si0 ₂ , EtOAc: hexanes 1:20) to afford the desired product (0.14 g, 0.33 mmol, 66%).

According to procedure C of Example 50, the last described compound (0.14 g, 0.33 mmol) and boron tribromide (1.0 mL, 1.0 mmol) were reacted to obtain the title compound (0.019 g, 0.05 mmol, 17%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 9.49 (s, 1H), 8.04 (m, 1H), 7.89 (dt, 1H, J = 10.5 and 2 Hz), 7.72-7.68 (m, 2H), 7.54 (d, 1H, J = 8.1 Hz), 6.80 (d, 1H, J = 8.1 Hz), 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- (spiro [cyclohexane-1,3 '-[3H] indole] -2'-(hydroxyimino) -5'-yl) -4-methyl-2-thiophencarbonitrile

4-Methyl-5-trimethylstannyl-thiophene-2-carbonitrile

5-bromo-4-methyl-thiophene-2-carbonitrile (3.08 g, 15.2 mmol), tetrakis (triphenylphosphine) Pd (0) (0.82 g, 0.71 mmol), hexamethylditin under nitrogen 5.0 g, 15.2 mmol) and ethylene glycol dimethyl ether (20 mL). The mixture was heated to reflux for 14 hours. The reaction mixture was concentrated in vacuo and purified using flash silica gel chromatography (eluent: 2% MeOH: methylene chloride) to recover the desired product (2.8 g, 0.01 mmol, 67%) as an oil that tends to flow: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.41 (9H, s), 2.28 (3H, s), 7.83 (1H, s).

The last described compound (0.20 g, 0.50 mmol), dichlorobis (triphenylphosphine) palladium (II) (0.02 g, 0.03 mmol) and triphenyl arsine (0.03 g, 0.13 mmol) in DME (8.0 mL) Stir under nitrogen for minutes. 5'-Bromospiro {cyclohexane-1,3 '-[3H] indole} -2' (1'H) -one 2 '(0-benzyloxime) (0.18 g, 0.64 mmol) in DME (2.0 ml) ) Was added to the solution. The solution was heated to reflux overnight. The reaction solution was concentrated in vacuo and purified by flash silica gel chromatography (eluent: 12: 1 hexanes: ethyl acetate) to afford crude product (0.10 g, 0.25 mmol, 50%), which was used without further purification.

Boron tribromide (2.6 mL, 1.0 M solution in methylene chloride) was added to a dry methylene chloride (1.7 mL) solution of the last described product (0.37 g, 0.86 mmol) at -78 ° C. The solution was stirred for 30 minutes and quenched with saturated sodium bicarbonate (10 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the crude product, which was purified by flash silica gel chromatography (eluent: 6: 1 hexane: ethyl acetate) to give the title compound (0.02 g, 24%). Obtained: mp 173-176 ° C .; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.441.73 (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 = 1.7 Hz, 7.38 (1H, m), 7.82 (1H, m), 9.51 (1H, m), 9.66 (1H, m); MS (ESI (+ ve)) m / z 338 (M + H) ⁺ .

Example 54

5- (spiro [cyclohexane-1,3 '-[3H] indole] -2' (hydroxyimino) -5'-yl) -2-thiophencarbonitrile

To a dry THF (30 mL) solution of 2-cyanothiophene (1.0 g, 9.16 mmol) and triisopropylborate (2.3 mL, 10 mmol) under nitrogen at −78 ° C., lithium hexamethyldisilazide (1M in THF, 10 mL, 10 mmol) was added. After 30 minutes, the reaction was quenched with 1N HCl, extracted with ethyl acetate, the organic layer was washed with water, dried (Na ₂ SO ₄ ) and evaporated to afford the product (1.25 g, 8.17 mmol, 89%), which was further Used without purification: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.75 (br s, 2H), 7.97 (d, 1H, J = 8 Hz) and 7.73 (d, 1H, J = 8 Hz): MS (ESI (-ve)) m / z 152 (M ⁻ H) ⁻ .

According to process A of example 46, the last described product (0.91 g, 5.95 mmol) and 5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one Prepared from 2 '(O-benzyl oxime) (1.53 g, 3.97 mmol). Purification by flash silica gel chromatography (eluent: 5: 1 hexanes: THF) gave the desired product (0.66 g, 1.59 mmol), which was used without further purification: MS (ESI (-ve)) m / z 412 ( MH) ^- .

According to procedure C of Example 50, the title compound (0.036 g, 0.11 mmol, 8%) was reacted by reacting the last described compound (0.60 g, 1.45 mmol) with boron tribromide (1M in dichloromethane, 5 mL, 5 mmol). Obtained: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, J = 3.9 Hz), 7.63 (d, 1H, J = 1.5 Hz ), 7.54 (d, 1H, J = 3.9 Hz), 7.47 (dd, 1H, J = 8.1 and 1.6 Hz), 6.78 (d, 1H, J = 8.1 Hz), 2.13-1.90 (m, 2H) and 1.78 -1.60 (m, 6H): MS (ESI (+ ve)) m / z 324 (M + H) ⁺ .

Example 55

4- (spiro [cyclohexane-1,3 '-[3H] indole] -2' (hydroxyimino) -5'-yl) -2-thiophencarbonitrile

4- (trimethylstannyl) -2-thiophencarbonitrile

Of 3-bromo-2-thiophencarbonitrile (0.8 g, 4.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) The dimethoxyethane (5 cm ³ ) solution was heated to reflux for 14 hours and then cooled to room temperature. The reaction mixture was adsorbed on Florisil and purified by column chromatography (SiO ₂ , methylene chloride: hexane 1: 9) to give the title 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 = 0.9 Hz, 1H), 7.66 (d, J = 0.9 Hz, 1H).

5'-bromospiro {cyclohexane-1,3 '-[3H] indole} -2'(1'H) -one-2 '(0-benzyloxime) (1.65 g, 4.28 mmol), 4- ( Bis (triphenylphosphine) palladium (II) chloride was added to a solution of dry dimethoxyethane (20 mL) of trimethylstannyl) -2-thiophencarbonitrile (1.48 g, 5.44 mmol) and triphenyl arsine (330 mg). The mixture was heated to reflux for 16 hours. After cooling to room temperature, the mixture was evaporated and the residue was purified by column chromatography (Si0 ₂ , EtOAc: hexanes, gradient elution) to afford the desired product (0.61 g, 1.47 mmol, 56%). According to procedure C of Example 50, the last described compound (0.61 g, 1.47 mmol) and boron tribromide (1M in dichloromethane, 4.5 mL, 4.5 mmol) were reacted to give the title compound (0.084 g, 0.26 mmol, 18%). ) Was obtained: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H) , 7.48 (dd, IH, J = 8.1 and 0.9 Hz), 6.76 (d, IH, J = 8.1 Hz), 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 [cyclohexane-1,3 '-[3H] indole] -2' (hydroxyimino) -5'-yl) -1H-pyrrole-1-methyl-2-carbonitrile

2- {5 '[Spiro [cyclohexane-1,3'-[3H] indole]-(1'H) -one-2 '(O-benzyloxime)]}-1H-pyrrole-1-carboxylic acid tert-butyl ester

5'-Bromospiro {cyclohexane-1,3 '-[3H] indole] -2'(1'H) -one-2 '(0-benzyloxime) (7.4 g, 19.17 mmol) and tetragen under nitrogen A DME (100 mL) solution of kiss (triphenylphosphine) palladium (0) (2.5 g, 2.00 mmol) was stirred for 15 minutes. To this solution was added 1-tert-butoxycarbonylpyrroleboronic acid (5.5 g, 26 mmol) and 1 M sodium carbonate (50 ml). The mixture was heated at 80 ° C. for 6 hours and cooled. The reaction mixture was poured into water and extracted with ethyl acetate (3x100 mL). The combined organic layer was dried over magnesium sulfate. The solution was filtered and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (4.5: 1 hexanes / ethyl acetate) to give the product as a white solid (7.7 g, 88%): ¹ H NMR (DMSO-d ₆ , 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 = 3.26 Hz, 6.76 (d, 1H, J = 7.9 Hz), 7.02 (dd, 1H, J = 7.98, 1.4 Hz), 7.19 (s, 1H) 7.27-7.31 (m, 2H), 7.35 (t, 1H, J = 6.8 Hz), 7.43 (d, 1H, J = 8 Hz), 9.55 (s, 1H).

5 '-(1-tert-butoxycarbonyl-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2 '-(1'H) -one-2' (O-benzyl oxime) -1'-carboxylic acid tert-butyl ester

2- {5 '[spiro [cyclohexane-1,3'-[3H] indole]-(1'H) -one-2 '(0-benzyloxime))]}-1H-pyrrole-1-carboxyl Sodium hydride (0.665 g, 17 mmol) was added to a THF (anhydrous, 100 mL) solution of acid tert-butyl ester (7.7 g, 16.38 mmol) and di-tert-butyl dicarbonate (10.9 g, 50 mmol) ) And DMAP (0.20 g) were added and the reaction was stirred at 65 ° C. for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give the product (9.0 g, 15.76 mmol) which was used directly for the next step.

5 '-(1-tert-butoxycarbonyl-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2 '-(1'H) one-2' ( To a THF (anhydrous, 75 mL) solution of O-benzyl oxime) -1′-carboxylic acid tert-butyl ester (9.0 g, 15.76 mmol) was added chlorosulfonyl isocyanate (1.55 mL, 17.54 mmol) at −78 ° C. After 90 minutes, DMF (21 mL, 275 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was poured into water (200 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (10% ethyl acetate / hexanes) gave 5 '-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrole-2-yl) spiro [cyclohexane as a white powder. -1,3 '-[3H] indole] -2'(1'H) -one-2 '(0-benzyloxime) -1'-carboxylic acid tert-butyl ester (7.6 g, 82%) was obtained : ¹ H NMR (DMSO-d ₆ , 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).

5 '-(5-cyano-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) one-2' (O-benzyloxime) -1'-carboxylic acid tert-butyl ester

5 '-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H)- A sodium ethoxide ethanol (120 mL) solution was added to a THF (anhydrous, 30 mL) solution of on-2 '(0-benzyl oxime) -1'-carboxylic acid tert-butyl ester (7.6 g, 3.25 g, 48 mmol). The reaction mixture was heated to 80 ° C. and stirred overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo 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 = .8 Hz), 6.98-6.99 (d, 1H, J = .7 Hz), 7.29-7.37 (m, 1H), 7.35 (m, 2H ), 7.42 (m, 3H), 7.63 (dd, 1H, J = 1.8, .3 Hz), 7.76 (d, 1H, J = .4 Hz).

5 '-(5-cyano-1-methyl-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(O-benzyloxime) -1'-carr Acid tert-butyl ester

5 '-(5-cyano-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -one-2' in DMF (75 mL) Potassium carbonate (6.5 g, 47 mmol) and Met (1 mL, 15.4 mmol) were added to-(O-benzyl oxime) -1'-carboxylic acid tert-butyl ester (6.1 g, 12.29 mmol), and the reaction mixture was 2.5 hours. Stir at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and the solvent was concentrated in vacuo. The following step was carried out without further purification to give the desired product (6.1 g, 12.29 mmol): ¹ H NMR (DMSO, 300 MHz) δ 1.38 (s, 9H), 1.62-1.98 (m, 1OH), 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).

5- {5'-Spiro [cyclohexane-1,3 '-[3H] indole]-(1'H) -one-2'-(O-benzyloxime)]}-1H-pyrrole-1-methyl- 2-carbonitrile

5 '-(5-cyano-1-methyl-1H-pyrrole-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 dioxane (5 mL), 4M HCl in dioxane (10 mL) was added, and the reaction was heated at 45 ° C. for 3.5 hours. The mixture was carefully neutralized with sodium bicarbonate (saturated). 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 in vacuo. Purification by column chromatography on silica gel (5% ethyl acetate / hexanes) gave the product (4.36 g, 94%): ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 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)

5- {5'-spiro [cyclohexane-1,3 '-[3H] indole]-(1'H) -one-2'-(O-benzyloxime) in methylene chloride (50 mL) at -78 ° C. To 1 H-pyrrole-1-methyl-2-carbonitrile (4.36 g, 10.6 mmol) was added 1 M boric tribromide (35 mL, in methylene chloride). The reaction mixture was warmed to room temperature. After 4 hours, the reaction mixture was quenched with saturated sodium bicarbonate (100 mL). The organic layer was collected, the aqueous layer was extracted with ethyl acetate (2x100 mL), the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (7: 3 hexanes / ethyl acetate) to give the title compound (1.35 g, 40%) as a white solid: ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.58-1.71 (m, 8H), 1.99-2.00 (m, 2H), 3.69 (s, 3H) 6.24 (d, 1H, J = 4.07 Hz), 6.8 (d, 1H, J = 8.05 Hz), 6.99 (d, 1H , J = 4.01 Hz, 7.20 (dd, 1H, J = 8.04, 1.57 Hz), 7.36 (d, 1H, J = 1.12 Hz), 9.48 (s, 1H), 9.62 (s, 1H).

Example 57

5- (spiro [cyclohexane-1,3 '-[3H] indole] -2'-(hydroxyimino) -5'-yl) -1H-pyrrole-2-carbonitrile

5- (spiro [cyclohexane-1,3 '-[3] indole] -2' (1H)-(O-benzyloxime))-1H-pyrrole-2-carbonitrile

5- {5'-Spiro [cyclohexane-1,3 '-[3H] indole]-(1'H) -one-2'-0-benzyloxime)]}-1H-pyrrole-1-methyl-2 5 '-(5-cyano-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole]-dissolved in 2 mL of THF, depending on the procedure used to prepare the carbonitrile. Prepared from 2 '(1'H) -one-2'-(O-benzyloxime) -1'-carboxylic acid tert-butyl ester (0.395 g, 0.796 mmol) and 4M HCl dioxane / water (10 mL) The desired product (0.220 g, 0.745 mmol, 95%) was obtained: ¹ H NMR (DMSO-d ₆ , 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, 1.4 Hz), 7.65 (d, 1H, J = 1.5 Hz), 9.65 ( s, 1 H), 12.4 (s, 1 H).

5- (spiro [cyclohexane-1,3 '-[3H] indole] -2'-(hydroxyimino) -5'-yl) -1H-pyrrole-1-methyl-2-carbonitrile in the process Thus, 5- (spiro [cyclohexane-1,3 '-[3] indole] -2' (1H)-(O-benzyloxime))-1H-pyrrole-2-carbonitrile (0.325 g, 0.82 mmol) And the title compound was prepared from 1M boric tribromide (6 mL in methylene chloride) to give the product as a 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 = 4.0 Hz), 6.75 (d, 1H, J = 8.0 Hz), 6.94 (d, 1H, J = 3.47 Hz), 7.45 (dd, 1H, J = 8.1, 1.73 Hz), 7.63 (d, 1H, J = 1.73), 9.42 (s, 1H), 9.59 (s, 1H), 12.39 (s, 1 H).

Example 58

4- (spiro [cyclohexane-1,3 '-[3H] indole] -2' (acetoxyimino) -5'-yl) -2-thiophencarbonitrile

4- (spiro [cyclohexane-1,3 '-[3H] indole] -2' (hydroxyimino) -5'-yl) -2-thiophencarbonitrile (2.21 g, 6.83 mmol) and acetic anhydride ( 1 mL of dichloromethanepyridine (30 mL, 9: 1) was added 4-dimethylaminopyridine (250 mg) at room temperature. After 3 hours, the mixture was diluted with dichloromethane, washed with water, dilute hydrochloric acid, water, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (EtOAc: hexane, gradient elution) 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- [2 '-(hydroxyamino) spiro [cyclohexane-1,3'-[3H] indol] -5'-yl] benzene carboxyimidamide

5 '-(3-cyano-5-fluorophenyl) -2- (methylthio) spiro [cyclohexane-1,3'-[3H] indole]

According to the procedure described in Example 43, 3- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3 '-[3H] indol] -5'-yl) -5-fluoro Prepared from benzonitrile (0.451 g, 1.34 mmol) to afford the desired product (0.316 g, 0.90 mmol, 67%): ¹ H NMR (DMSO, 300 MHz) δ 7.74 (d, 1H, J = 1.7 Hz), 7.68 ( t, 1H, J = 1.4 Hz), 7.58 (d, 1H, J = 8.0 Hz), 7.54 (t, 1H, J = 2.3 Hz), 7.50 (dd, 1H, J = 8.0 and 1.9 Hz), 7.33- 7.29 (m, 1 H), 2.67 (s, 3 H), 2.04-1.78 (m, 7 H) and 1.58-1.50 (m, 3H); MS (ESI (+ ve)) m / z 351 (M + H) ⁺ .

Hydroxylamine (50% aqueous solution, 1 mL) was added to a DMSO (10 mL) solution of the last described product (0.30 g, 0.88 mmol) and the reaction heated to 120 ° C. After 1 hour, the mixture was cooled and partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (Si0 ₂ , 5% MeOH in dichloromethane) to give the title compound (0.079 g, 0.23 mmol, 26%) as a white foam: ¹ H NMR (DMSO, 300 MHz) δ 9.79 (s , 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.73 (s, 1H), 7.61 (d, 1H, J = 1.3 Hz), 7.46 (dd, 1H, J = 8.3 and 1.5 Hz) , 7.34 (d, 1H, J = 10 Hz), 6.81 (d, 1H, J = 8.0 Hz), 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 '-[3H] indole] -2' (hydroxyimino) -5'-yl) -4-methyl-2-thiophene carboxyimida mid

4-methyl-5- (spiro [cyclohexane-1,3 '[3H] indole] -2'-(methylthio) -5'-yl] -2-thiophencarbonitrile

To potassium tert-butoxide (0.32 g, 2.6 mmol) in THF 5- (1 ', 2'-dihydro-2'-thioxospyro [cyclohexane-1,3'-indol] -5'-yl) 4-Methyl-2-thiophencarbonitrile (0.84 g, 2.5 mmol) was added. After 15 minutes, methyl iodide (0.50 g, 3.48 mmol) was added. After 3 hours, the reaction was poured into ammonium chloride (saturated) and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate. The solution was filtered and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (4: 1 hexanes / ethyl acetate) to afford the desired product (0.530 g, 85%): (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 = 7.87 Hz, 1.46 Hz), 7.5 (d, 1H, J = 8.05 Hz), 7.77 (d, 1H, J = 1.46 Hz), 7.88 (s, 1H).

4-methyl-5- (spiro [cyclohexane-1,3 '[3H] indole] 2'-(methylthio) -5'-yl] -2-thiophencarbonitrile (0.450 g, in DMSO (1 mL) 1.3 mmol) was added hydroxylamine hydrochloride (2 mL, 50% sol. In water) and heated to 2.5 ° C. at 100 ° C. Water was added until the solution became slightly turbid and the mixture was allowed to warm to room temperature. And dissolved in ethyl acetate and dried over magnesium sulfate The solution was filtered and concentrated in vacuo to give the product (0.320 g, 69%): (DMSO-d ₆ , 500 MHz) δ 1.4-1.74 (m, 8H), 1.94 -2.4 (9m, 2H), 2.54 (s, 3H), 5.8 (s, 1H), 6.79 (d, 1H, J = 8.0), 7.16 (dd, 1H, J = 8.12, 1.83), 7.39 (m, 2H), 9.42 (s, 1H), 9.56 (s, 1H), 9.58 (s, 1H).

Example 61

N'-hydroxy-4- (spiro [cyclohexane-1,3 '-[3H] indole] -2' (hydroxyimino) -5'-yl-2-thiophenecarboxyimidamide

According to the procedure of Example 60, 4- (spiro [cyclohexane-1,3 '-[3H] indole] -2'-(methylthio) -5'-yl] -2-thiophencarbonitrile (0.077 g , 0.237 mmol) was reacted with a 50% hydroxylamine (1 mL) solution to afford the title compound (0.016 g, 0.044 mmol, 20%): MS (ESI, (+ VE)) m / z 357 [M + H] ⁺ .

Example 62

N'-hydroxy-5- (spiro [cyclohexane-1,3 '-[3H] indole] -2'-(hydroxyimino) -5'-yl) -2-thiophenecarboxyimidamide

According to the procedure of Example 60, 5- (spiro [cyclohexane-1,3 '-[3H] indole] 2'-(methylthio) -5'-yl] -2-thiophencarbonitrile (0.500 g, 1.5 mmol) and 50% hydroxylamine (2 mL, excess) to give the title compound to give the product (0.200 g, 0.56 mmol, 56%): ¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.45-1.75 ( m, 8H), 1.97-2.06 (m, 2H), 5.89 (s, 1H), 6.74 (d, 1H, J = 8 Hz), 7.3 (d, 1H, J = 3.9 Hz), 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-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2'-cyanamide

5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indol] -2'-amine

Hydrated hydrazine (0.600) in a turbid solution of 5 '-(3-chlorophenyl) -N-hydroxyspiro [cyclohexane-1,3- [3H] indol] -2-amine (0.500 g, 1.53 mmol) in 25 mL of ethanol. mL, 12.24 mmol) was added. The solution was warmed to 55 ° C. and ranney-nickel (50% in water) was added to the reaction to maintain a constant gas evolution. After 45 minutes, the hot reaction mixture was filtered through a plug of celite and rinsed with plenty of hot methanol. The filtrate was concentrated in vacuo to give 0.890 g of opaque solid. The product was purified by flash silica gel chromatography (eluent, 2% to 8% methanol-methylene chloride, 0.1% ammonium hydroxide) to give 0.310 g (65%) of the desired product as a white solid: mp 118-120 ° C. ¹ H NMR δ (300 MHz, DMSO-d ₆ ) 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 = 8 Hz, 7.41-7.46 (t, 2H), 7.55-7.58 (d, 1H), 7.62 (s, 1H), 7.72 (s, 1H); MS (ECI (+ ve)) m / z 311 (M + H) ⁺ .

1-tert-butoxycarbonyl-5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indole] 2'-amine

Di-tert-butyl dicarbonate (0.252) in 5 '-(3-chlorophenyl) spiro [cyclohexane-1,3- [3H] indol] -2'-amine (0.310 g, 0.96 mmol) dry methylene chloride solution g, 1.15 mmol) and 4-dimethylaminopyridine (0.117 g, 0.96 mmol) were added at 0 ° C. The solution was allowed to warm to room temperature and stirred for 24 hours. The reaction solution was diluted with water (50 mL) and the layers separated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield 0.355 g of a yellow oil. The product was purified by flash silica gel chromatography (eluent, 1% to 3% methanol-methylene chloride) to give the desired product as a white solid (0.081 g, 20%): ¹ H NMR δ (300 MHz, DMSO-d ₆ ) 1.58 (m, 2H), 1.63 (s, 9H, Boc), 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, 1 H, NH). MS (ECI (+ ve)) m / z 411 (M + H) ⁺ .

1'-tert-butoxycarbonyl-5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indol] -2'-amine (0.120 g, 0.29 mmol in 2.0 mL dry DMF) ) Was added a solution of 4-dimethylaminopyridine (0.089 g, 0.73 mmol) and cyanobromide (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. The reaction solution was poured into 0.1N NaHC0 ₃ (50 mL) and worked up, and extracted with ethyl acetate (3 × 50 mL). Layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford 0.091 g of a yellow residue. The product was purified by flash silica gel chromatography (gradient gradient from 5: 1 to 3: 1 hexanes: ethyl acetate) to give 0.031 g (32%) of product as a light yellow solid: mp 225 ° C. (decomposed). ¹ H NMR δ (500 MHz, DMSO-d ₆ ) 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 = 8 Hz ), 7.45-7.50 (m, 1H), 7.60-7.63 (dd, 2H, J = 6.4 Hz), 7.71 (s, 1H), 7.85 (s, 1H), 12.1 (s, 1H, NH); MS (ECI (−ve)) m / z 336 (M ⁻ H) ⁻ .

Other preferred compounds that can be prepared according to the methods described herein include 5 '-(3-cyano-5-fluorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2'-cyan Amide, 5 '-(5-cyano-1H-pyrrole-2-yl) spiro [cyclohexane-1,3'-[3H] indole] -2-cyanamide, 5 '-(5-cyano-1 -Methyl-1H-pyrrole-2-yl) spiro [cyclohexane-1,3 '-[3H] indole] -2'-cyanamide, 5'-(5-cyano-thiophen-2-yl) spiro [Cyclohexane-1,3 '-[3H] indole] -2'-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'-cyanamide , 3- (2'-cyanomethylenespiro [cyclohexane-1,3 '-[3H] indol-5'-yl])-5-fluoro-benzonitrile, 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-P 2-carbonitrile, 5- (2'-cyanomethylene-spiro [cyclohexane-1,3 '-[3H] indol-5'-yl])-thiophene-2-carbonitrile, 5- (2 '-Cyanomethylene-spiro [cyclohexane-1,3'-[3H] indol-5'-yl])-4-methyl-thiophen-2-carbonitrile, 4- (2'-cyanomethylene- Spiro [cyclohexane-1,3 '-[3H] indol-5'-yl])-thiophene-2-carbonitrile.

All publications cited herein are incorporated herein by reference. Although the present invention has been described with reference to certain preferred embodiments, it will be appreciated that modifications may be made without departing from the spirit of the invention. Such modifications are intended to be within the scope of the appended claims.

Claims (32)

A compound of Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof. (Formula 1) (Formula 2) Where R ₁ and R ₂ are H, alkyl, substituted alkyl; OH; O (alkyl); O (substituted alkyl); OAc; Aryl; Optionally substituted aryl; Heteroaryl; Optionally substituted heteroaryl; Alkylaryl; Alkylheteroaryl; 1-propynyl; Or independently selected from the group of 3-propynyl: or R ₁ and R ₂ are combined to -CH ₂ (CH ₂ ) nCH _2- ; -CH ₂ CH ₂ CMe ₂ CH ₂ CH _2- ; -O (CH ₂ ) mCH _2- ; O (CH ₂ ) pO-; -CH ₂ CH ₂ OCH ₂ CH _2- ; Or -CH ₂ CH ₂ N (H or alkyl) CH ₂ CH _2- To form a ring comprising one of; m is an integer from 1 to 4; n is an integer from 1 to 5; p is an integer from 1 to 4; or R ₁ and R ₂ together comprise a double bond with one of CMe ₂ , C (cycloalkyl), O, C (cycloether); R ₃ is selected from H, OH, NH ₂ , C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₆ alkenyl, alkynyl or substituted alkynyl, or COR ^A ; R ^A is H, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ aminoalkyl, or substituted C ₁ To C ₃ aminoalkyl; R ₄ is H, halogen, CN, NH ₂ , C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, substituted C ₁ to C ₆ alkoxy, C ₁ to C ₆ amino Alkyl, or substituted C ₁ to C ₆ aminoalkyl; R ⁵ is selected from the group a), b) or c); a) R ⁵ is a trisubstituted benzene ring containing substituents X, Y and Z as shown below; X is halogen, OH, CN, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ thioalkyl, substituted C ₁ to C ₃ thioalkyl, S (O) alkyl, S (O) ₂ alkyl, C ₁ to C ₃ aminoalkyl, substituted C ₁ to C ₃ aminoalkyl, NO ₂ , C ₁ to C ₃ perfluoro Alkyl, 5 or 6 membered heterocycle containing 1 to 3 heteroatoms, CONH ₂ , CSNH ₂ , CONHalkyl, CSNHalkyl, CON (alkyl) ₂ , CSN (alkyl) ₂ , COR ^B , OCOR ^B , NR ^C COR ^B is selected from; R ^B is H, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, aryl, substituted aryl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ aminoalkyl Or substituted C ₁ to C ₃ aminoalkyl; R ^C is H, C ₁ to C ₃ alkyl, or substituted C ₁ to C ₃ alkyl; Y and Z are independently selected from H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, or C ₁ to C ₃ thioalkyl; or b) R ⁵ has 1, 2 or 3 heteroatoms selected from O, S, SO, SO ₂ or NR ⁶ and has H, halogen, CN, NO ₂ and C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy A 5 or 6 membered heterocycle containing 1 or 2 independent substituents from the group of C ₁ to C ₃ aminoalkyl, COR ^D or NR ^E COR ^D ; R ^D is H, C ₁ to C ₃ alkyl, substituted C ₁ to C ₃ alkyl, aryl, substituted aryl, C ₁ to C ₃ alkoxy, substituted C ₁ to C ₃ alkoxy, C ₁ to C ₃ aminoalkyl Or substituted C ₁ to C3 aminoalkyl; R ^E is H, C ₁ to C ₃ alkyl, or substituted C ₁ to C ₃ alkyl; R ⁶ is H, or C ₁ to C ₃ alkyl; or c) R ⁵ is indol-4-yl, indol-7-yl or benzo-2, optionally substituted by 1 to 3 substituents selected from halogen, lower alkyl, CN, NO ₂ , lower alkoxy or CF ₃ A thiophene moiety; Q ¹ is S, NR ₇ , CR ₈ R ₉ ; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, acyl, substituted acyl, aroyl, substituted aroyl, SO ₂ CF ₃ , OR ¹¹ or NR ¹¹ R ¹² ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , A substituted heterocycle, NO ₂ , CN, or an independent substituent selected from the group of CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl; or CR ₈ R ₉ comprises a 6 membered ring as represented by the structure below; Q ² is part Is selected from; R ¹¹ , R ¹² and R ¹³ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl or Independently from substituted aroyl or sulfonyl. A compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure Where R ₅ is a disubstituted benzene ring of the formula X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ perfluor Roalkyl, a 5-membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy; Y is a substituent on the 4 'or 5'-position from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl; Q ¹ is S, NR ₇ , CR ₈ R ₉ . A compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure Where R ₅ is a 5-membered ring having the structure shown below; From here, U is O, S, or NR ₆ ; R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ C0 ₂ alkyl; X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy; Y 'is selected from the group of H, F or C ₁ to C ₄ alkyl; Q ¹ is S, NR ₇ , CR ₈ R ₉ . A compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure Where R ₅ is a 6 membered ring having the structure shown below, From here, X ¹ is N or CX ² ; X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and; Q ¹ is S, NR ₇ , CR ₈ R ₉ ; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , Substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl; CR ₈ R ₉ has the following structure It is within the range of the six-membered ring as indicated by. Claim 5 The compound according to claim 1, which is 5 '-(3-chlorophenyl) spiro [cyclohexane-1,3'-[3H] indole] -2 '(1'H) -thione or a pharmaceutically acceptable salt thereof. Characterized by a compound. The compound of claim 1, wherein the compound is 3- (1 ′, 2′-dihydro-2′-thioxospiro [cyclohexane-1,3 ′-[3H] indol-5′-yl) benzonitrile or pharmaceutically acceptable Compound, characterized in that its salt. The compound of claim 1, wherein the 4- (1 ′, 2′-dihydro-2′-thioxopyro [cyclohexane-1,3 ′-[3H] indol] -5′-yl) -2-thiophencarboni Compound, characterized in that it is tril or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound is 3- (1,2-dihydro-2-thioxopyro [cyclohexane-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile or pharmaceutically And a salt thereof, which is acceptable. A compound according to claim 1, wherein 4-methyl-5- (1,2-dihydro-2-thioxospyro [cyclohexane-1,3- [3H] -indol] -5-yl) -2-thiophenothio Amide or a pharmaceutically acceptable salt thereof. A compound of the formula: or a pharmaceutically acceptable salt thereof. In each formula above, R ₅ is a disubstituted benzene ring containing substituents X and Y, X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ perfluor Roalkyl, a 5-membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy; Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl. 12. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, having the formula: Where R ₅ is a 6 membered ring having the structure From here, X ¹ is N or CX ² ; X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and; Q ² is part Is selected from; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl; CR ₈ R ₉ has the following structure It is within the range of the six-membered ring as indicated by. A compound of the formula: or a pharmaceutically acceptable salt thereof. Where R ₁₄ is selected from the group of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, substituted sulfonyl, R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below, X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON (alkyl) ₂ , CSN (alkyl) ₂ , CNHNHOH, CNH ₂ NOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ perfluoroalkyl, 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy; Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl. 14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R ₅ is a five membered ring having the structure shown below. From here, U is O, S, or NR ₆ ; R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ C0 ₂ alkyl; X 'is halogen, CN, NO _2, CONH _2, CNHNHOH, CNH ₂ NOH, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl _2, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy Is selected from; Y 'is selected from the group of H, F or C ₁ to C ₄ alkyl. 14. A compound according to claim 13, wherein R ₅ is a thiophene or furan ring substituted by X 'and Y'. 14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R ₅ is a six membered ring having the structure: From here, X ¹ is N or CX ² ; X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl. A compound of the formula: or a pharmaceutically acceptable salt thereof. Where R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below; X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , CNHNOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ Perfluoroalkyl, a 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy; Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl. 18. The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein R ₅ is a 5-membered ring having the structure shown below. From here, U is O, S, or NR ₆ ; R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl; X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy; Y 'is selected from the group of H, F or C ₁ to C ₄ alkyl. 18. The compound of claim 17, wherein R ₅ is a thiophene or furan ring substituted by X 'and Y' as described above. 18. The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein R ₅ is a 6 membered ring having the structure: From here, X ¹ is N or CX ² ; X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocyclic or SO ₂ CF ₃ ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl. A compound having the formula: or a pharmaceutically acceptable salt thereof. Where R ₁₅ is selected from the group of H, Me, CO ₂ R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, CN; R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below; X is halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON alkyl ₂ , CSN alkyl ₂ , CNHNOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, NO ₂ , C ₁ to C ₃ Perfluoroalkyl, a 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy; Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl. 22. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R ₅ is a five membered ring having the structure shown below. From here, U is 0, S, or NR ₆ ; R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ C0 ₂ alkyl; X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy; Y 'is selected from the group of H, F or C ₁ to C ₄ alkyl. 22. The compound of claim 21, wherein R ₅ is thiophene or furan substituted by X 'and Y'. The compound or pharmaceutically acceptable salt thereof according to claim 21, wherein R ₅ is a 6 membered ring having the structure: From here, X ¹ is N or CX ² ; X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocycle, or SO ₂ CF ₃ ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl. A compound of the formula: or a pharmaceutically acceptable salt thereof. Where R ₅ is a disubstituted benzene ring containing substituents X and Y as shown below; X is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl _2, CNHNOH, C ₁ to C ₃ alkoxy, C ₁ to C ₃ alkyl, N0 _2, C ₁ to C ₃ Perfluoroalkyl, a 5 membered heterocycle containing 1 to 3 heteroatoms, or C ₁ to C ₃ thioalkoxy; Y is a 4 'or 5'-positioned substituent from the group comprising H, halogen, CN, NO ₂ , C ₁ to C ₃ alkoxy, C ₁ to C ₄ alkyl, or C ₁ to C ₃ thioalkyl. The compound or pharmaceutically acceptable salt thereof according to claim 25, wherein R ₅ is a 5-membered ring having the structure shown below. From here, U is O, S, or NR ₆ ; R ₆ is H, or C ₁ to C ₃ alkyl, or C ₁ to C ₄ C0 ₂ alkyl; X 'is selected from halogen, CN, NO _2, CONH _2, CSNH _2, CONH-alkyl, CSNH-alkyl, CON-alkyl _2, CSN ₂ alkyl, C ₁ to C ₃ alkyl, or C ₁ to C ₃ alkoxy; Y 'is selected from the group of H, F or C ₁ to C ₄ alkyl. 27. The compound of claim 26, wherein R ₅ is a thiophene or furan ring substituted by X 'and Y'. 27. The compound or pharmaceutically acceptable salt thereof according to claim 26, wherein R ₅ is a six membered ring having the structure: From here, X ¹ is N or CX ² ; X ² is _{halogen, CN, CONH 2, CSNH 2} , CONH -alkyl, CSNH-alkyl, CON-alkyl _2, CSN alkyl ₂ or NO _2, and; R ₇ is CN, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted Heterocyclic or SO ₂ CF ₃ ; R ₈ and R ₉ are H, C ₁ to C ₆ alkyl, substituted C ₁ to C ₆ alkyl, C ₃ to C ₈ cycloalkyl, substituted C ₃ to C ₈ cycloalkyl, aryl, substituted aryl, heterocycle , An independent substituent from the group comprising a substituted heterocycle, NO ₂ , CN or CO ₂ R ₁₀ ; R ₁₀ is C ₁ to C ₃ alkyl. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 29. A method of inducing contraception in a mammal comprising administering the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof to a mammal in need thereof. 29. A method of treating dysfunctional bleeding in a mammal comprising administering to the mammal in need thereof a pharmaceutically effective amount of the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof. 29. The method of endometrium, ovary, breast, colon or prostate in a mammal comprising administering to a mammal in need of such treatment a compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof. How to treat carcinoma and adenocarcinoma.