CN1143847C - Thio-oxindole derivatives - Google Patents

Abstract

The present invention relates to compounds which are agonists of the progesterone receptor having the general formula (1) or (2) shown below, wherein the substituents are as defined herein; and the use of these compounds for inducing contraception or treating progesterone-related and adenocarcinoma.

Description

Thio-oxindole derivatives

field of invention

The present invention relates to compounds as progesterone receptor agonists, their preparation and use.

Background of the invention

Intracellular receptors (IRs) 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 subclass of the IR family, including the progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptors. body (MR).

The natural hormone or ligand for PR is the steroid progesterone, but compounds such as medroxyprogesterone acetate or levonorgestrel have also been synthesized as ligands. Once the ligand is present in the fluid surrounding the cell, the ligand passes through the membrane by passive diffusion and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to DNA, the complex regulates the production of mRNA and the protein encoded by that gene.

Compounds that bind the IR and mimic the action of the natural hormone are called agonists, while compounds that inhibit the action of the hormone are called antagonists.

Natural and synthetic PR agonists are known to play an important role in women's health. PR agonists can be used in birth control formulations, usually in the presence of ER agonists, or they can be combined with PR antagonists. ER agonists are used to treat menopausal symptoms but have been associated with uteroproliferative effects that lead to an increased risk of uterine cancer. Administration with a PR agonist reduces/eliminates this risk.

Compounds of the invention have been shown to act as competitive inhibitors of progesterone binding to PR, and may act as agonists. These compounds are useful in contraception and postmenopausal hormone replacement therapy.

The PR antagonist dihydroquinoline A is described by Jones et al. in US Patent No. 5,688,810.

A

Jones et al. in US Patent No. 5,693,646 describe enol ether B as a PR ligand.

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

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

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

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

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

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

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

PR ligand L was described by Kurihari et al. (J. Antibiotics, 50, 360, 1997).

Kuhla et al. disclose oxindole M with cardiotonic activity (WO 86/03749).

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

Fischer et al. describe the preparation of compounds comprising the general structure O (U.S. Patent No. 5,453,516)

R = various

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

The cytotoxic agent Q is described by Andreani et al. (Acta. Pharn. Nord., 2, 407, 1990).

Binder et al. describe structure R as an intermediate for the preparation of COXII inhibitors (WO 97/13767).

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

R1=F, Cl, Br, alkyl, _NH2

R2 = alkyl, alkoxy, F, Cl, NH2, _CF3

Oxindole T as a cardiovascular drug is claimed by Bohm et al. (WO 91/06545).

The general structure U was proposed by Bohm et al. (WO 91/04974).

JP 63112584 A has a general structure V:

Boar et al. describe dioxolane W as an intermediate for the preparation of acetylcholinesterase inhibitors (WO93/12085 A1).

Kende et al. describe a method for the preparation of 3,3 substituted oxindoles (eg X) which is used in the present invention (Synth. Commun., 12, 1, 1982).

Detailed description of the invention

The present invention provides compounds having formula 1 or 2:

or

in:

R _and R _{are independently} selected from H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; Optionally substituted heteroaryl; alkaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl:

or _R1 and _R2 join to form a ring comprising one of the following:

-CH ₂ (CH ₂ ) _n CH ₂ -; -CH ₂ CH ₂ CMe ₂ CH ₂ CH ₂ -; -O(CH ₂ ) _m CH ₂ -; O(CH ₂ ) _p O-;

_{-CH2CH2OCH2CH2-} ; _{or -CH2CH2N (} H _or alkyl _{) CH2CH2- ;}

m is an integer 1-4;

n is an integer 1-5;

p is an integer 1-4;

or _R1 and _R2 together form a double bond connected to one of the following:

_CMe2 ; C(cycloalkyl), O, C(cyclic ether).

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

^RA is selected from H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ ammonia Alkyl, or substituted C ₁ -C ₃ aminoalkyl;

R ₄ is selected from H, halogen, CN, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy , C ₁ -C ₆ aminoalkyl group, or substituted C ₁ -C ₆ aminoalkyl group;

R ^is selected from a), b) or c):

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

X is selected from halogen, OH, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ - C ₃ alkylthio, substituted C ₁ -C ₃ alkylthio, S(O) alkyl, S(O) ₂ alkyl, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkane radical, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5- or 6-membered heterocycle containing 1-3 heteroatoms, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , COR ^B , OCOR ^B , NR ^C COR ^B ;

R ^B is selected from H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy group, C ₁ -C ₃ aminoalkyl group, or substituted C ₁ -C ₃ aminoalkyl group;

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

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

or

b) R ⁵ is a 5 or 6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S, SO, SO ₂ or NR ⁶ and containing 1 or 2 independent substituents selected from the following groups: H , halogen, CN, NO ₂ and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, ^CORD , or NR ^{E CORD} ;

R ^D is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy , C ₁ -C ₃ aminoalkyl group, or substituted C ₁ -C ₃ aminoalkyl group;

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

R ⁶ is H, or C ₁ -C ₃ alkyl; or

c) R ⁵ is an indol-4-yl, indol-7-yl or benzo-2-thiophene group, which can be replaced by 1-3 members selected from halogen, lower alkyl, CN, NO ₂ , Lower alkoxy, or a substituent of CF ₃ is optionally substituted;

Q ¹ is S, NR ₇ , CR ₈ R ₉ ;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, 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 substituents independently selected from the following: H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CN, or CO ₂ R ₁₀ ,

R ₁₀ is C ₁ -C ₃ alkyl; or

CR ₈ R ₉ is a 6-membered ring shown in the structure below

^Q2 is selected from the following groups:

或

or

R ¹¹ , R ¹² and R ¹³ are independently selected from H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl , substituted acyl, aroyl or substituted aroyl or sulfonyl;

or a pharmaceutically acceptable salt thereof.

A group of preferred substituents represented by R ¹¹ , R ¹² and R ¹³ in the compounds of the present invention are H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, -C(O)- (C ₁ -C ₆ alkyl), —S(O) ₂ -(C ₁ -C ₆ alkyl), phenyl or benzyl.

It is to be understood that the present invention includes all tautomers of the compounds, formulas and substituents described herein.

Two groups of preferred compounds of the present invention are represented by structures 2 and 3 respectively:

where _R5 is a disubstituted benzene ring which contains substituents X and Y as shown below

X is selected from halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkane group, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocycle containing 1-3 heteroatoms, or C ₁ -C ₃ thioalkoxy;

Y is a substituent at the 4' or 5' position selected from the group consisting of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ alkylthio;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 2 are those compounds wherein R is _{a 5} membered ring having the structure shown below

in:

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ -C ₃ alkyl, or C ₁ -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(alkyl) ₂ , C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy;

Y' is selected from H, F or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subclass of the above compounds are those wherein _R5 is a thiophene or furan ring substituted by X' and Y' as above.

Another subgroup of preferred compounds of formulas 2 and 3 are those wherein R is _a 6-membered ring having the structure:

where 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 ;

Q ¹ is S, NR ₇ , CR ₈ R ₉ ;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, heterocycle, substituted heterocycle, or SO ₂ CF ₃ ;

R _and R _are independently substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ Cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CN CO ₂ R ₁₀ , R ₁₀ is C ₁ -C ₃ alkyl;

CR ₈ R ₉ is within a 6-membered ring with the structure shown below

or a pharmaceutically acceptable salt thereof.

Yet another group of preferred compounds includes those compounds having the general formula:

wherein each _R is a disubstituted phenyl ring as shown below containing substituents X and Y

X is selected from halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkane group, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocycle containing 1-3 heteroatoms, or C ₁ -C ₃ thioalkoxy;

Y is a substituent at the 4' or 5' position selected from the group consisting of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ Alkylthio;

or a pharmaceutically acceptable salt thereof.

Another subgroup of preferred compounds has the formula

are those compounds wherein R is a ₆ -membered ring having the structure:

where 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 ;

Q ² as above;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, heterocycle, substituted heterocycle, or SO ₂ CF ₃ ;

R _and R _are independently substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CNCO ₂ R ₁₀ ,

R ₁₀ is C ₁ -C ₃ alkyl;

CR ₈ R ₉ is within a 6-membered ring with the structure shown below

or a pharmaceutically acceptable salt thereof.

Another group of preferred compounds of the present invention is shown in structure 4,

wherein R _is selected from H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, substituted sulfonyl.

where _R5 is a disubstituted benzene ring containing substituents X and Y as shown below

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

Y is a substituent at the 4' or 5' position selected from the group consisting of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ Alkylthio;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 4 is wherein R is a ₅ -membered ring having the structure shown below

in:

U is O, S, or NR ₆ ;

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

X' is selected from halogen, CN, NO ₂ , CONH ₂ , CNHNHOH, CNH ₂ NOH, CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , C ₁ -C ₃ Alkyl, or C ₁ -C ₃ alkoxy;

Y' is selected from H, F or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of the above compounds are those wherein _R5 is a thiophene or furan ring substituted by X' and Y' as described above.

Another subgroup of preferred compounds of formula 4 are those wherein _R is a 6-membered ring having the structure:

where 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 ;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, heterocycle, substituted heterocycle, or SO ₂ CF ₃ ;

R _and R _are independently substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CNCO ₂ R ₁₀ ,

R ₁₀ is C ₁ -C ₃ alkyl;

or a pharmaceutically acceptable salt thereof.

Another group of preferred compounds of the present invention is shown in structure 5,

where _R5 is a disubstituted benzene ring containing substituents X and Y as shown below

X is selected from halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , CNHNOH, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocycle containing 1-3 heteroatoms, or C ₁ -C ₃ thioalkoxy;

Y is a substituent at the 4' or 5' position selected from the group consisting of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ Alkylthio;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 5 are those wherein R is a ₅ -membered ring having the structure

in:

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ -C ₃ alkyl, or C ₁ -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(alkyl) ₂ , C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy;

Y' is selected from H, F or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of the above compounds are those wherein _R5 is a thiophene or furan ring substituted by X' and Y' as above.

Another preferred group of compounds of formula 5 are those compounds wherein _R is a 6-membered ring having the following structure:

where 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 ;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, heterocycle, substituted heterocycle, or SO ₂ CF ₃ ;

R _and R _are independently substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CNCO ₂ R ₁₀ ,

R ₁₀ is C ₁ -C ₃ alkyl;

or a pharmaceutically acceptable salt thereof.

Another group of preferred compounds of the present invention is shown in structure 6,

wherein R ₁₅ is selected from H, methyl, CO ₂ R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, CN.

where _R5 is a disubstituted benzene ring containing substituents X and Y as shown below

X is selected from halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , CNHNOH, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocycle containing 1-3 heteroatoms, or C ₁ -C ₃ thioalkoxy;

Y is a substituent at the 4' or 5' position selected from the group consisting of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ Alkylthio;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formula 6 are those compounds wherein R is _{a 5} membered ring having the structure shown below

in:

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ -C ₃ alkyl, or C ₁ -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(alkyl) ₂ , C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy;

Y' is selected from H, F or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of the above compounds are those wherein _R5 is a thiophene or furan ring substituted by X' and Y' as described above.

Another preferred subgroup of compounds of formula 6 are those compounds wherein _R is a 6-membered ring having the following structure:

where 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 ;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, heterocycle, substituted heterocycle, or SO ₂ CF ₃ ;

R ₈ and R ₅ are independently substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CNCO ₂ R ₁₀ ,

R ₁₀ is C ₁ -C ₃ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of the present invention is shown in structure 7,

where _R5 is a disubstituted benzene ring containing substituents X and Y as shown below

X is selected from halogen, CN, CONH ₂ , CSNH ₂ , CONH alkyl, CSNH alkyl, CON(alkyl) ₂ , CSN(alkyl) ₂ , CNHNOH, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocycle containing 1-3 heteroatoms, or C ₁ -C ₃ thioalkoxy;

Y is a substituent at the 4' or 5' position selected from the group consisting of H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ Alkylthio;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 7 are those wherein R is a ₅ -membered ring having the structure shown below

in:

U is O, S, or NR ₆ ;

R ₆ is H, or C ₁ -C ₃ alkyl, or C ₁ -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(alkyl) ₂ , C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy;

Y' is selected from H, F or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of the above compounds are those wherein _R5 is a thiophene or furan ring substituted by X' and Y' as described above.

Another preferred subgroup of compounds of formula 7 are those compounds wherein _R is a 6-membered ring having the following structure:

where 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 ;

_R is selected from CN, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl radical, heterocycle, substituted heterocycle, or SO ₂ CF ₃ ;

R _and R _are independently substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NO ₂ , CNCO ₂ R ₁₀ ,

R ₁₀ is C ₁ -C ₃ alkyl;

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain asymmetric carbons, and some of the compounds of the present invention may contain one or more asymmetric centers, and thus may exist as optical isomers and diastereomers. Although Formulas 1 and 2 are not shown in stereochemistry, the present invention includes these optical isomers and diastereomers; as well as the racemic and resolved enantiomerically pure R and S stereoisomers; and R and Other mixtures of S stereoisomers and their pharmaceutically acceptable salts.

The term "alkyl" as used herein refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing 1-8 carbon atoms (preferably 1-6 carbon atoms); "alkenyl" includes 1 or Straight and branched chain alkyl groups with 2 carbon-carbon double bonds and 2-8 carbon atoms (preferably 2-6 carbon atoms); "alkynyl" includes at least 1 or 2 carbon-carbon triple bonds and straight-chain and branched-chain alkyl groups of 2-8 carbon atoms (preferably 2-6 carbon atoms).

The term "acyl" refers to a carbonyl substituent, including straight and branched chain saturated aliphatic hydrocarbon groups having 1-8 carbon atoms, preferably 1-6 carbon atoms. The term "substituted acyl" refers to an acyl group as described above optionally substituted with 1-6 substituents selected from halogen, CN, OH and _NO2 .

The term "aroyl" also refers to a carbonyl substituent bearing a phenyl or heteroaryl group. Such heteroaryl groups include 2-, 3- or 4-pyridyl, 2- and 3-furyl, 2- or 3-thienyl, or 2- or 4-pyrimidinyl. The term "substituted aroyl" also refers to an aroyl group as described above optionally substituted with 1-6 substituents selected from halogen, CN, OH and _NO2 .

The terms "substituted alkyl", "substituted alkenyl" and "substituted alkynyl" refer to the aforementioned alkyl, alkenyl and alkynyl groups having one or more of the following substituents: halogen, CN, OH, NO ₂ , amino, aryl, heterocycle, substituted aryl, substituted heterocycle, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio . These substituents may be attached to any carbon atom of the alkyl, alkenyl or alkynyl group, provided that such attachment constitutes a stable chemical group.

The term "aryl" herein refers to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together, at least a portion of the fused or linked rings forming a conjugated aromatic system. Aryl groups may include, but are not limited to: phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, phenanthrenyl.

The term "substituted aryl" refers to the aforementioned aryl group having 1-4 substituents selected from the group consisting of halogen, CN, OH, _NO2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy radical, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio.

The term "heterocycle" as used herein refers to a stable 4- to 7-membered monocyclic or stable polycyclic heterocyclic ring, which may be saturated, partially saturated or unsaturated, and consists of carbon atoms and 1-4 It consists of heteroatoms selected from N, O and S atoms. N and S atoms can be oxidized. The heterocyclic ring may also include any polycyclic ring in which the aforementioned heterocyclic ring may be fused to an aromatic ring. A heterocycle may also be attached to any heteroatom or carbon atom, provided that the resulting structure is chemically stable. These heterocyclic groups include, but are not limited to, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazine Base, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuryl, benzothienyl, thiomorpholine group, thiomorpholinyl sulfoxide and isoquinolinyl group.

The term "substituted heterocycle" as used herein refers to the above heterocycle having 1-4 substituents selected from the group consisting of halogen, CN, OH, NO ₂ , amino, alkyl, substituted alkyl, cycloalkyl, Alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

The term "alkylthio" as used herein refers to the group SR wherein R is an alkyl or substituted alkyl group containing 1-8 carbon atoms, preferably 1-6 carbon atoms. The term "alkoxy" refers to an OR group wherein R is an alkyl or substituted alkyl group containing 1-8 carbon atoms, preferably 1-6 carbon atoms. The term "aryloxy" refers to an OR group where R is an aryl or substituted aryl as described above. The term "alkylcarbonyl" herein refers to an RCO group wherein R is an alkyl or substituted alkyl group containing 1-8 carbon atoms, preferably 1-6 carbon atoms. The term "alkylcarboxy" herein refers to a COOR group in which R is an alkyl or substituted alkyl group containing 1-8 carbon atoms, preferably 1-6 carbon atoms. The term "aminoalkyl" refers to secondary and tertiary amines, wherein the alkyl or substituted alkyl group contains 1-8 carbon atoms, preferably 1-6 carbon atoms, which may be the same or different, and the point of attachment is at on a nitrogen atom. The term "halogen" refers to Cl, Br, F or I.

The compounds of the present invention can be prepared by the following methods.

plan 1

According to Scheme 1, in the presence of lithium chloride or N, N, N', N'-methylethylenediamine, in an inert solvent (such as THF, diethyl ether) under nitrogen at low temperature (about -20 ° C), use Strong organometallic bases (e.g., butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide) treated commercially available oxindole 3 (Kende, et al., Synth. Commun., 12, 1, 1982). The resulting dianion is then treated with an excess of an electrophile such as an alkyl halide, preferably an alkyl iodide. If R ₁ and R ₂ are to be connected, such as a spiro ring at the 3-position of product 4, then the electrophile should be bifunctional, that is, diiodide. Subsequent bromination of 4 is smooth with bromine in the presence of sodium acetate in acetic acid (with the addition of an organic co-solvent such as dichloromethane as needed) to afford the aryl bromide 5. In an inert atmosphere (argon, nitrogen) at room temperature, the bromide 5 is mixed with a palladium salt (such as tetrakis(triphenylphosphine) Palladium (O) or palladium acetate) reaction. The mixture is then treated with aryl or heteroaryl boronic acid or boronate and base (sodium carbonate, triethylamine, potassium phosphate) in water or with fluoride (cesium fluoride) under anhydrous conditions. The desired product 6 is then isolated and purified by standard methods.

The indolin-2-one derivative 6 is dissolved in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, Toluene, xylene) react with Lawessen' reagent or phosphorus pentasulfide to obtain thiocarbonyl derivative 7. Additives such as sodium bicarbonate may help.

If _R1 and _R2 are different, intermediate 4 can be prepared by reacting the dianion of 3 with 1 equivalent of electrophile R1- _X (X is a leaving group such as I). The resulting monoalkylated compound can then be isolated and re-reacted with _R2 -X under the same conditions or subjected to a second alkylation with _R2 -X in situ. Alternatively, if the desired product 7 is to contain _R2 =H, the monoalkylated intermediate isolated by subsequent steps.

Scenario 2

Other methods can also be used to connect the pendant aryl or heteroaryl (Ar) to the oxindole platform (i.e. the skeleton), such as compound 5 and aryl or heteroaryl stannane, aryl radical or heteroaryl zinc or aryl or heteroaryl magnesium halide (Scheme 2). The desired aryl or heteroaryl metal species described above are prepared by standard techniques.

According to Scheme 3, other functional groups can also be added to the 3-position of the indoline platform. Oxidation of the unsaturated indoline 8 (preferably under neutral or acidic conditions (eg, refluxing selenium dioxide in dry dioxane)) affords isatin 9. Compound 9 can be further functionalized to give ketal 11 by treatment with alcohol and acid catalyst under dehydrating conditions. Alternatively, reaction of 9 with a second ketone under appropriate conditions (piperidine in toluene at reflux; or _TiCl4 /Zn in THF) affords the alkylene derivative 11. Reaction of isatin 9 with a Grignard reagent or organolithium affords tertiary alcohol 12 (R=H). These alcohols can then be further functionalized by an alkylation or acylation step.

Option 3

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, the indoline Indol-2-one derivative 6 reacts with Lawessen reagent or phosphorus pentasulfide to give thiocarbonyl derivative 7. Additives such as sodium bicarbonate may also be used.

Option 4

Another mode of preparation is in an inert atmosphere (nitrogen or argon) in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) Reaction of compound 5 with Lawessen's reagent or phosphorus pentasulfide at temperatures between room temperature and the reflux temperature of the solvent affords thiocarbonyl derivatives 13 . Bromide 13 is then reacted with a strong base (sodium hydride, sodium hexamethyldisilazane, potassium hydride) in an anhydrous solvent (such as THF, diethyl ether), and then reacted at low temperature (-50 ° C to -20 °C) with n-butyllithium and N,N,N',N'-tetramethylethylenediamine, after a suitable time, with trialkyl borate (trimethyl borate or triisopropyl borate), Acid work up affords boronic acid 14 (Scheme 4). Then, compound 14 can be catalyzed by palladium (tetrakis (triphenylphosphine) palladium (O) or palladium acetate, base (sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, CsF) solvent (toluene/ethanol/ water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl triflate Or heteroaryl ester, or fluorosulfonic acid aryl ester or heteroaryl ester reaction to obtain the desired compound 7.

Alternatively, compound 13 is subjected to palladium-catalyzed conditions (tetrakis(triphenylphosphine) palladium (O) or palladium acetate, base (sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, CsF) solvent (acetone/water, Toluene/ethanol/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with aryl or heteroaryl bromide, aryl or heteroaryl iodide, trifluoroform Reaction of an aryl or heteroaryl sulfonate, or an aryl or heteroaryl fluorosulfonate, affords the desired compound 7.

Option 5

The bromide 5 is reacted with a strong base (preferably sodium hydride, sodium hexamethyldisilazane, potassium hydride) in an anhydrous solvent (such as THF, (di) ether), and then at low temperature (-50 ° C to - 20°C) to react with n-butyllithium and N,N,N',N'-tetramethylethylenediamine, and after an appropriate time, react with trialkyl borate (trimethyl borate or triisopropyl borate), Acid work up affords boronic acid 15 (Scheme 5). Then, compound 15 can be prepared under palladium-catalyzed conditions (tetrakis(triphenylphosphine) palladium (O) or palladium acetate, base (sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, CsF) solvent (toluene/ethanol/ water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl triflate Or heteroaryl ester, or fluorosulfonic acid aryl ester or heteroaryl ester reaction, to obtain the desired compound 6.

Another strategy is to prepare organozinc or magnesium reagents from compound 5, and then react in situ with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl triflate or heteroaryl Esters, or aryl or heteroaryl fluorosulfonates were reacted to give compound 6. These organozinc or magnesium species can be prepared by treating bromide 57 with a strong base (preferably sodium hydride, sodium hexamethyldisilazane, potassium hydride) in anhydrous solvents (e.g. THF, diethyl ether) followed by Reaction with n-butyllithium and N,N,N',N'-tetramethylethylenediamine at low temperature (-50 to -20°C) and after an appropriate time with anhydrous zinc chloride or magnesium bromide .

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, the indoline Indol-2-one derivative 6 reacts with Lawesson's reagent or phosphorus pentasulfide to give thiocarbonyl derivative 15. Additives such as sodium bicarbonate may also be used.

Option 6

Thioamide derivative 7 can be transformed into enamine derivative 16 according to Scheme 6 (Wrobel et al., J. Med. Chem., 1989, 2493).

Thus, thioamide 7 (Pg = H, 2-(trimethylsilyl)-ethoxymethyl, benzyl, etc.) reacts with triethyloxonium tetrafluoroborate followed by nucleophile (nitrogen methyl methane, cyanamide, trifluoromethanesulfonamide, Meldrum acid, etc.), and then react under suitable conditions (such as tetrabutylammonium fluoride in THF for PG=2-(trimethylsilyl)-B Oxymethyl) to remove the protecting group to give enamine derivative 16. Suitable solvents for the two steps are selected from dichloromethane, THF, dioxane, 1,2-dichloroethane, and the reaction is carried out under an inert atmosphere (nitrogen or argon) at a temperature ranging from -78°C to the boiling point of the solvent.

Option 7

According to Scheme 7, in the presence of a suitable base (such as an amine base such as pyridine, triethylamine or di-iso-propylethylamine or lithium carbonate, sodium, potassium or cesium), in a suitable organic solvent (such as DMF, THF , DMSO, dioxane or acetonitrile), at a temperature between -78°C and the boiling point of the solvent, with an alkylating agent (such as methyl iodide, ethyl iodide, 2,4-dinitrofluorobenzene or 4-nitrofluorobenzene) treatment of intermediate 7 affords thioimino ether 17. Intermediate 17 and hydroxylamine or an acid addition salt of hydroxylamine (such as hydrochloric acid) are then dissolved in a suitable solvent (such as but not limited to pyridine, methanol, ethanol, isopropanol, DMF, THF or DMSO, optionally in the presence of additives such as tertiary amine bases or sodium or potassium acetate), affords N-hydroxyamidines 18.

In a suitable base (such as an amine base such as pyridine, triethylamine or diisopropylethylamine or lithium carbonate, sodium, potassium or cesium) or a Lewis acid (such as boron trifluoride etherate, lead II salt, tetrachloride Titanium chloride, II-valent magnesium salt or silver salt), in a solvent compatible with the selected base or Lewis acid (such as DMF, THF, DMSO, dioxane or acetonitrile, chloroform, benzene, toluene or dichloromethane) , similar treatment of intermediate 17 with a carbon nucleophile such as a malonate derivative such as malononitrile, cyanoacetate, nitroacetate or malonate affords the adduct 19. If the group R3 in adduct 19 is a carboxylate, it can be directly decarboxylated to give the enamine derivative 20, eg by treatment with eg sodium iodide in DMSO at temperatures between room temperature and the boiling point of the solvent. Alternatively, the ester is first hydrolyzed to the carboxylic acid in a suitable solvent (e.g. THF, dioxane, acetonitrile, methanol or ethanol) (treatment with aqueous base, e.g. with lithium, sodium or potassium hydroxide) , followed by decarboxylation in a suitable solvent (eg, acetonitrile, THF, dioxane) in the presence of an acid (eg, hydrochloric acid or sulfuric acid) to give derivative 20. Alternatively, xanthates of carboxylic acids can be prepared by reaction with a base such as sodium or potassium hydride in THF followed by treatment with carbon disulfide. Subsequently, at elevated temperature, under an atmosphere of inert nitrogen or argon, in a solvent such as benzene or toluene, in the presence of a free radical initiator (such as benzoyl peroxide or azobisisobutyronitrile) Butyltin was reacted to give product 20.

Option 8

Scheme 8 describes another strategy for the synthesis of product 18. at a temperature between -78°C and the boiling point of the solvent in the presence of a suitable base such as an amine base such as pyridine, triethylamine or diisopropylethylamine or lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate , in a suitable organic solvent (such as DMF, THF, DMSO, dioxane or acetonitrile), with an alkylating agent (such as methyl iodide, ethyl iodide, 2,4-dinitrofluorobenzene, 4- Nitrofluorobenzene) bromide 13 (or the corresponding chloride, iodide or triflate) affords thioimidate 21. Subsequently, at a temperature between -78°C and the boiling point of the solvent, in a suitable solvent such as but not limited to pyridinemethanol, ethanol, isopropanol, DMF, THF or DMSO, optionally in a solution such as a tertiary amine base or sodium acetate or in the presence of additives such as potassium acetate), the intermediate 21 is reacted with hydroxylamine or a salt of hydroxylamine and an acid (such as hydrochloric acid, hydrobromic acid) to obtain N-hydroxyamidine 22. Intermediate 22 is then protected with a compatible group (eg, benzyl ether, acyl derivative, tetrahydropyranyl ether, methoxymethyl ether, silyl ether) to afford derivative 23. Alternatively, compound 21 can be directly reacted with a protected hydroxylamine derivative (selected from but not limited to the above-mentioned protecting groups) to obtain derivative 23 directly. Then, compound 23 and palladium salt (such as tetrakis(triphenylphosphine) Palladium (O) or palladium acetate) reaction. The mixture is then treated with aryl or heteroaryl boronic acids or boronate esters and a base (sodium carbonate, triethylamine, potassium phosphate) in water or with fluoride (cesium fluoride) under anhydrous conditions and the reactants Heat to solvent boiling point. The desired product 24 is then isolated and purified by standard methods.

Compound 24 can then be deprotected under conditions dictated by the nature of the protecting group. For example, if the protecting group is benzyl ether, then treatment with boron tribromide or trimethylsilyl iodide in a suitable solvent such as dichloromethane will give compound 18. Other methods of benzyl ether removal include hydrogenation (hydrogen gas or other source of hydrogen such as cyclohexadiene or ammonium formate) in the presence of a palladium catalyst. Solvents suitable for this method include methanol, ethanol, THF, ethyl acetate, and dioxane,

It is performed at a temperature between room temperature and the boiling point of the solvent. If the protecting group is an acetal derivative (tetrahydropyranyl ether or methoxymethyl ether), then it can be used in a solvent (methanol, ethanol, THF dioxane or acetonitrile) under acidic conditions (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or acidic ion exchange resin) for hydrolysis. If the protecting group is an acyl derivative (e.g. acetate, benzoate), it can be hydrolyzed under acidic conditions as described above, or in a solvent (e.g. alcohol, THF, dioxane or acetonitrile) at room temperature to The hydrolysis is carried out under basic conditions (lithium hydroxide, sodium hydroxide or potassium hydroxide) at temperatures between the boiling points of the solvents. If the protecting group is a silyl ether, compound 18 can be prepared, for example, by hydrolysis of intermediate 24 under acidic conditions as described above, or in a solvent such as alcohol, THF, dioxane or acetonitrile at room temperature to Compound 24 is contacted with a fluorine source such as potassium fluoride, cesium fluoride, or t-butylammonium fluoride at a temperature between the boiling point of the solvent. An inert atmosphere of nitrogen or argon may be required.

An alternative approach to the synthesis of compound 18 is the conversion of the protected N-hydroxyamidine 23 to a boronic acid or boronic acid ester (by lithium halide exchange followed by quenching with triisopropyl borate, or by palladium-catalyzed interaction with pinacol diboronpinacolate coupling) followed by coupling of the boronic acid or boronic acid ester derivative with aryl chloride, aryl bromide, aryl iodide or aryl triflate in a suitable palladium catalyzed system as described above couplet. Subsequent deprotection as described in Scheme 8 affords the desired compound 18.

Option 9

Treatment of N-hydroxyamidines 18 under reducing conditions (eg, catalytic hydrogenation, iron in acetic acid, or hydrazine-Raney nickel) affords intermediates 25 according to Scheme 9. Solvents suitable for this method include methanol, ethanol, THF, ethyl acetate, and dioxane, at temperatures between room temperature and the boiling point of the solvent. Protection of the secondary nitrogen under standard conditions (tert-butyl carbamate is shown as a non-limiting example) affords compound 26. Compound 26 is in a suitable solvent (THF, acetonitrile or DMF, optionally there are bases such as pyridine, sodium hydride or potassium tert-butoxide), and compound 26 is reacted with an electrophilic cyanation reagent (such as cyanogen bromide, N- cyanobenzotriazole or cyanogen bromide/4-dimethylaminopyridine complex) to give the desired compound 27. In some cases, the cyanation step occurs with the removal of the secondary nitrogen protecting group, and if this deprotection does not occur in situ, further hydrolysis is required.

Following the synthesis of Compound 18 in Scheme 8, Compound 27 can also be synthesized, where N-cyanoamidine bromide 28 prepared from Compound 22 using a similar strategy to the reaction shown in Scheme 9 can be combined with an appropriate functionalized aryl Coupling with boronic acid or aryl boronic acid gives compound 27. In another strategy, intermediate 28 can be converted to the corresponding boronic acid or boronic acid ester and then coupled with an appropriately functionalized aryl bromide in a Suzuki or Suzuki-type palladium coupling reaction.

The compounds of the present invention may be used in the form of pharmaceutically or physiologically acceptable salts derived from acids or bases. These salts include, but are not limited to, those formed with inorganic acids such as hydrochloric, sulfuric, nitric, phosphoric, organic acids such as acetic, oxalic, succinic and maleic. Other salts include those formed with alkali or alkaline earth metals, such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates or other conventional "prodrugs" (when administered in this form, it can converted into the active moiety in vivo).

The present invention includes pharmaceutical compositions and methods of treatment comprising administering to a mammal a pharmaceutically effective amount of one or more of the above compounds or a pharmaceutically acceptable salt thereof as a progesterone receptor agonist.

Used alone or in combination with the progesterone receptor agonist of the present invention, it can be used for contraception and treatment and/or prevention of dysfunctional bleeding, uterine leiomyoma, endometriosis; polycystic ovary syndrome, endometrium, Ovarian, breast, colon, prostate carcinoma and adenocarcinoma. Other uses of the invention include stimulating feeding.

When the compounds are used for the above purposes, they can be mixed with one or more pharmaceutically acceptable carriers or excipients, such as solvents, diluents, etc., and can be orally administered in the following forms: tablets, capsules, dispersions powders, granules or suspensions (e.g. containing about 0.05-5% suspending agent), syrups (e.g. containing 10-50% sugar), and elixirs (e.g. containing about 20-50% ethanol), etc., or aseptically Parenteral administration is in the form of injection solutions or suspensions (containing about 0.05-5% of suspending agent in an isotonic medium). These pharmaceutical formulations may contain about 25-90% active ingredient in admixture with a carrier, usually between about 5%-60% by weight.

The effective dosage of the active ingredient employed will vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. Usually, however, satisfactory results are obtained when the compounds of the present invention are administered at a dose of about 0.5-500 mg/kg of animal body weight per day, preferably in 2-4 divided doses per day, or in sustained release form. For most large mammals, the total daily dosage will be about 1-100 mg, preferably about 2-80 mg. Dosage forms suitable for internal administration comprise about 0.5-500 mg of active compound intimately admixed with a solid or liquid pharmaceutically acceptable carrier. This dosing regimen may be adjusted to obtain the optimum therapeutic response. For example, several divided doses per day may be administered or the dose may be proportionally reduced as indicated by the therapeutic situation.

The active compounds can be administered orally as well as intravenous, intramuscular or subcutaneous routes. Solid carriers include: starch, lactose, calcium hydrogen phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include: sterile water, polyethylene glycol, nonionic surfactants, and edible oils (such as corn oil, peanut oil, and sesame oil), as appropriate to the properties of the active ingredient and the desired form of administration. Adjuvants commonly used in the preparation of pharmaceutical compositions such as flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA are preferably included.

Preferred pharmaceutical compositions, from the standpoint of ease of preparation and administration, are solid compositions, especially tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

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

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders (for the extemporaneous preparation of sterile injectable solutions or dispersion). In all cases, the forms must be sterile and must be fluid for easy syringe use. It must be stable under the conditions of manufacture and storage and must be resistant to the contaminating influence of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, alcohols (such as glycerol, propylene glycol, and liquid polyethylene 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′-[3′H]indole]-2′(1′H)-thione

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

Oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800 cm ³ ) was cooled to -20°C, then n-butyllithium (2.5M in hexane, 152 cm ³ , 0.38 mol) was added slowly, followed by N,N,N',N'-Tetramethylethylenediamine (51 cm ³ , 0.38 mol,). After 15 minutes, 1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture was allowed to warm to room temperature. After stirring for 16 hours, saturated aqueous ammonium chloride (1 L) and ethyl acetate (1 L) were added. After 15 minutes, the layers were separated and the aqueous phase was extracted with ethyl acetate (x2). The combined organic layers were extracted with hydrochloric acid (1 N), then washed with brine (500 cm ³ ), dried (MgSO ₄ ), and concentrated to an oil. The oil was triturated with hexane (200cm ³ ) and benzene (20cm ³ ). The precipitate was collected and dried in vacuo to obtain the subtitle compound (26.3 g, 69.6%) as colorless crystals: melting point 110-114°C; ¹ H NMR (DMSO-d6) δ 1.67 (m, 10H), 6.84 (d, 1H , J=8Hz) 6.94(t, 1H, J=8Hz), 7.17(t, 1H, J=8Hz), 7.44(d, 1H, J=8Hz), 10.3(S, 1H).

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

Sodium ^acetate ( 8.0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol) and stirred. After 30 minutes at room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with water, dried ( _MgSO4 ) and evaporated, and the residue was triturated with hexanes. The precipitate was collected and dried in vacuo to obtain the subtitled compound (16.5 g, 67%) as off-white crystals: mp 196-199°C; ¹ H NMR (DMSO-d6) δ 1.62 (m, 10H), 6.8 (d, 1H , J=6.8Hz), 7.36(d, 1H, J=8.2, 1.8Hz), 7.58(dd, 1H, J=8.2, 1.8Hz), 10.44(S, 1H).

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

Under nitrogen, a mixture of 5'-bromospiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one (0.32 g, 1.14 mmol) and tetrakis( Triphenylphosphine) palladium(O) (0.14 g, 0.12 mmol) in dimethoxyethane (6 cm ³ ) for 20 minutes. To this mixture was then added 3-chlorophenylboronic acid (0.21 g, 1.37 mmol) and sodium carbonate (0.36 g, 3.4 mmol) in water (3 cm ³ ). The solution was refluxed for 6 hours, then cooled to room temperature, poured into water and extracted with ethyl acetate (x3). The combined organic extracts were washed with water and brine, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate:hexane 1:3) to give the subtitle compound (0.28 g, 0.89 mmol, 80%) as a yellow solid: mp 164-165°C, 1H NMR (CDCl ₃ ) δ1.60-1.78(m, 6H), 1.81-1.99(m, 4H), 7.04(d, J=8.1Hz, 1H), 7.22-7.47(m, 4H), 7.53(s, 1H), 7.61(s, 1H), 9.28(brs, 1H); 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) ⁺ ; Anal. (C ₁₉ H ₁₈ ClNO) C, H, N.

Under nitrogen, in the presence of 5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one (0.63 g, 2.0 Millimoles) of dry xylene (20cm ³ ) was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane (diphosphetane)- 2,4-Disulfide (0.89 g, 2.2 mmol), and the mixture was heated to reflux. After 72 hours, the mixture was evaporated and the residue was subjected to column chromatography ( _SiO2 , ethyl acetate:hexanes, gradient elution) to give a solid which was recrystallized from diisopropyl ether/hexanes to give the title as yellow crystals Compound (0.17 g, 0.51 mmol, 26%): melting point 223-227 C; ¹ H NMR (CDCl ₃ ) δ 1.53-1.66 (m, 8H), 1.83-2.05 (m, 4H), 2.07-2.17 ( m, 2H), 7.11(d, 1H, J=8.0Hz), 7.31-7.53(m, 3H), 7.54(s, 1H), 7.86(S, 1H), 9.93(s, 1H, br): MS( (+APCI) m/z 328(M+H)+.

Example 2

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

In dimethoxyethane (20cm ³ ) Tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) was added to the solution. After 15 minutes, 3-formylphenylboronic acid (1.00 g, 6.93 g) was added followed by potassium carbonate (2.90 g, 21 mmol) in water (10 ^cm3 ). After 20 hours at reflux, the mixture was cooled, poured into water and extracted with ethyl acetate (x3). The organic extracts were combined, washed with saturated brine, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate:hexanes, gradient elution) to give the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, ¹ HNMR (CDCl ₃ ) δ 1.65- 1.85(m, 6H), 1.86-2.08(m, 4H), 7.22(d, 1H, J=8Hz), 7.48(dd, 1H, J=8, 2Hz), 7.61(t, 1H, J=8Hz) , 7.66(d, 1H, J=2Hz), 7.81-7.88(m, 2H), 8.06(t, 1H, J=2Hz), 8.30(s, 1H, br); MS((+)ESI)m/ z306(M+H) ⁺ .

3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol-5′-yl)benzaldehyde oxime

In 3-(1',2'-dihydro-2'-oxospirocyclohexane-1,3'-[3'H]indol-5'-yl)benzaldehyde (0.59 g, 1.95 mg mol) of ethanol:water (10cm ³ , 8:2) were added hydroxylamine hydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5 mmol). After 20 minutes, the mixture was concentrated, water was added and the product was extracted with ethyl acetate (x2). The organic layers were combined, washed with saturated sodium bicarbonate solution, water and saturated brine, dried (MgSO ₄ ) and evaporated to give the subtitled oxime (0.63 g, 1.95 mmol, 100%) which was recovered without further purification Direct use, ¹ HNMR(CDCl ₃ )δ1.60-1.84(m, 6H, 1.85-2.00(m, 4H), 6.86(d, 1H, J=8Hz), 7.36(dd, 1H, J=8, 2Hz ), 7.43-7.50(m, 1H), 7.57-7.67(m, 2H), 7.85(s, 1H, br), 8.25(s, 1H), 8.68(s, 1H, br), 8.94(s, 1H , br); MS ((-)ESI) m/z 319 (MH) ^- .

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

Treatment of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole] with selenium dioxide (0.38 g, 3.50 mmol) -5′-yl) benzaldoxime (0.48 g, 1.49 mmol) in chloroform (10 cm ³ ) was heated to reflux. After 16 hours, the mixture was concentrated, the residue was purified by column chromatography ( _SiO2 , ethyl acetate:hexane 1:4), and the product was recrystallized from ethyl acetate-hexane to give the subtitled compound (0.161 g , 0.53 mmol, 35%): melting point 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= 8Hz), 7.42(dd, 1H, J=8, 2Hz), 7.54(t, 1H, J=8Hz), 7.58-7.65(m, 2H), 7.78(dt, 1H, J=7, 2Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+)ESI) m/z 303 (M+H) ⁺ .

According to the steps of Example 1, 3-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)benzyl Nitrile reacted with Lawesson's reagent to give the title compound: melting point>231°C (decomposition); ¹ H NMR (DMSO-d ₆ ) δ1.38-1.55 (m, 3H), 1.82-1.99 (m, 7H), 7.16 (d, 1H, J=8.1Hz), 7.63-7.69(m, 2H), 7.80(d, 1H, J=7.7Hz), 8.01(d, 1H, J=8Hz) and 12.76(s, 1H); MS ((-)-APCI) m/z 317[MH] ^- .

Example 3

4-(1′,2′-dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol-5′-yl)-2-thiophenecarbonitrile 3-( Trimethylstannyl)-2-thiophenecarbonitrile . A solution containing 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis(triphenylphosphine) palladium (O) (0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) of dimethoxyethane (5cm ³ ) was heated to reflux for 14 hours, and then cooled to room temperature. The reaction mixture was adsorbed on a magnesium silicate support and purified by column chromatography ( _SiO2 , dichloromethane:hexane 1:9) to give the subtitle compound (1.04 g, 3.8 mmol, 90%) as a clear viscous oil: ¹ H NMR (CDCl ₃ ) δ 0.35 (s, 9H), 7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).

4-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol-5′-yl)-2-thiophenecarbonitrile

5′-Bromospiro[cyclohexane-1,3′-[3′H]indole]-2′(1′H)-one (0.53 g, 1.9 mmol), dichlorobis (Triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) and triphenylarsenic (0.14 g, 0.47 mmol) in dimethoxyethane (8 cm ³ ) for 20 minutes. Then, 3-(trimethylstannyl)-2-thiophenecarbonitrile (0.64 g, 2.35 mmol) was added to the mixture. The solution was refluxed for 32 hours. After cooling to room temperature, the reaction mixture was adsorbed on a magnesium silicate support and purified by column chromatography ( _SiO2 , ethyl acetate:hexane 2:3) to give the subtitle compound (0.43 g, 1.39 mmol, 74 %): ¹ H NMR (CDCl ₃ ) δ 1.56-2.1 (m, 10H), 6.97 (d, J=8.0Hz, 1H), 7.39 (dd, J=8.03, 1.45Hz, 1H), 7.57 (d , J=1.45Hz, 1H), 7.59(d, J=1.4Hz, 1H), 7.84(d, J=1.4Hz, 1H), 8.32(brs, 1H); ¹³ C-NMR(CDCl ₃ )δ22. 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)+; Anal. (C18H16N2OS ) C} , H, N.

Make 4-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)-2-thiophenecarbonitrile (1.0 g, 3.2 mmol) and Lawesson's reagent (1.3 g, 3.2 mmol) in o-xylene (20 mL) were heated for 2.5 hours. The reaction mixture was washed with distilled water (5 x 100 mL), dried over magnesium sulfate, and evaporated. The product was purified by column chromatography (SiO2, ethyl acetate:hexane 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 ) δ12.72(s, 1H), 8.52(d, 1H, J=1.5Hz), 8.36(d, 1H, J=1.5Hz), 8.00(d, 1H, J=1.5Hz), 7.69(dd, 1H , J=6.4, 1.8Hz), 7.10(d, 1H, J=8.3Hz), 1.98-1.77(m, 7H), 1.43-1.33(m, 3H); MS(EI)M ⁺ @m/z324.

Example 4

3-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-5-fluorobenzonitrile

in dry tetrahydrofuran ( ^200cm Sodium hydride (60% dispersion in mineral oil, 1.6 g, 0.04 mol) was added to the solution. After stirring at room temperature for 30 minutes, the mixture was cooled to -78°C and butyllithium (1.7M in hexane, 23.2 cm ³ , 0.04 mol) was added slowly. After 30 minutes, diisopropyl borate (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. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried ( _MgSO4 ) and evaporated. The residue was triturated with hexane and the precipitate was dried in vacuo to obtain (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indole]-5'- base) boronic acid (8.3 g, 86%) as an off-white solid which was used without further purification. The sample obtained by further triturating with ethyl acetate has the following properties: melting point 255-260° C. dec.; ¹ H NMR (DMSO-d6) δ 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J = 7.72Hz) 7.66 (d, 1H, J = 7.72Hz) 7.91 (s, 3H, br), 10.36 (s, 1H); MS ((-)ESI) m/z 244 [MH].

3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-5-fluorobenzonitrile

At -78°C, n-butyllithium (2.5M, 8cm ³ , 20 mmol) was added dropwise to diethyl ether (100cm ³ ) containing 3,5-dibromofluorobenzene. After 30 minutes, the mixture was treated with DMF (20 cm ³ ) in diethyl ether (10 cm ³ ) and stirring was continued at -78°C. After 30 minutes, the mixture was quenched with dilute aqueous hydrochloric acid, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (MgSO ₄ ) and evaporated to give 3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: ¹ H NMR (CDCl ₃ ) δ where 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 the last described compound (4.0 g, 19.7 mmol) in ethanol:water (8:2, 50 cm ³ ), sodium acetate (1.72 g, 21 mmol) and hydroxylamine hydrochloride (1.45 g, 21 mmol mol), the mixture was heated to reflux. After 30 minutes, the mixture was cooled, evaporated and the residue partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, the combined organic layers were washed with water, saturated sodium bicarbonate solution and brine, dried (MgSO ₄ ) and evaporated to give 3-fluoro-5-bromobenzaldehyde 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 ⁺ ].

Under nitrogen, the above oxime (3.76 g, 17.24 mmol) and copper(II) acetate (370 mg) were dissolved in acetonitrile (100 cm ³ ), and heated to reflux. After 5 hours, the mixture was evaporated and the residue was taken up in ethyl acetate, washed with sulfuric acid (1N), water and brine, dried (MgSO ₄ ) and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mg mol, 89%), which was used without further purification.

The above bromide (3.0 g, 15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.75 mmol) were dissolved in dimethoxyethane (130 cm ³ ) under nitrogen. After 15 minutes, (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indole]-5 dissolved in water (40cm ³ ) was added '-yl) boronic acid (2.82 g, 11.5 mmol) and sodium carbonate (3.1 g, 29.3 mmol), and the mixture was heated to reflux. After 8 hours, the mixture was cooled, poured into water and extracted with ethyl acetate (x3). The combined organic layers were then washed with water, dried ( _MgSO4 ) and evaporated. The residue was then purified by column chromatography (ethyl acetate:hexanes, gradient elution) and the product was recrystallized from methanol to give 3-(1',2'-dihydro-2'-oxospiro[cyclohexane -1,3'-[3'H]indol]-5'-yl)-5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%): melting point 199-205°C; ¹ H NMR (CDCl ₃ )δ1.64-2.03 (m, 10H), 7.03 (d, 1H, J=8Hz), 7.31 (dt, 1H, J=7.7 and 1.6Hz), 7.41 (dd, 1H, J=8, 1.7Hz) , 7.49(dt, 1H, J=9.6, 2Hz), 7.58(d, 1H, J=2Hz), 7.64(s, 1H) and 8.37(s, 1H): MS(EI) m/z 320[M ⁺ ] .

Under nitrogen, in the presence of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-5 To a solution of -fluorobenzonitrile (0.32 g, 1.0 mmol) in xylene (10 cm ³ ) was added Lawesson's reagent (0.89 g, 2.22 mmol), and the reaction was heated to reflux. After 4 hours, the mixture was cooled, evaporated, and the residue was subjected to column chromatography ( _SiO2 , ethyl acetate:hexane, gradient elution) to give (0.143 g, 0.42 mmol, 42%) a white solid: mp 236-250 ℃; ¹ H NMR (CDCl ₃ ) δ1.54-1.66 (m, 3H), 1.86-2, 18 (m, 7H), 7.16 (d, 1H, J=8.1Hz), 7.33-7.36 (m, 1H ), 7.46-7.52(m, 2H), 7.65(s, 1H), 7.85(d, 1H, J=1Hz), 10.05(s, 1H); MS((+)-APCI) m/z337[M+ H] ⁺ .

Example 5

4-Methyl-5-(1′,2′-dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]-indol]-5′-yl)-2 - Thiophene Thioamide

2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)boronic acid (2.45 g, 10 mmol), 2-Bromo-5-cyano-3-methylthiophene (2.4 g, 12 mmol), potassium (4 g, 29 mmol), and tetrakis(triphenylphosphine)palladium(O) (0.6 g, 0.5 mmol) of dimethoxyethane:water:ethanol (130cm ³ , 10:2:1) was heated to 80°C for 16 hours, then poured into 1 liter of water and extracted with ethyl acetate. The organic layer was washed with brine, dried ( _MgSO4 ) and concentrated. The crude product was subjected to column chromatography (SiO ₂ , ethyl acetate:hexane, 1:1) to obtain the title compound (0.9 g, 28%): melting point 200-203° C.; ¹ H NMR (DMSO-d ₆ ) δ1. 63(m, 8H), 1.87(m, 2H), 2.27(s, 3H), 6.95(d, 1H, J=8.13Hz), 7.34(dd, 1H, J=8.13, 1.98Hz), 7.54(d, 1H, J = 1.98 Hz), 7.82 (S, 1H) 10.50 (S, 1H); MS ((+)APCl) m/z 323 [M+H] ⁺ .

Containing 4-methyl-5-[2'-oxo-2'3'-dihydrospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)-2 - A solution of thiophenecarbonitrile (0.61 g, 1.9 mmol) and phosphorus pentasulfide (0.92 g, 2.1 mmol) in dioxane (17 mL) was heated to 85°C for 30 minutes. The reaction mixture was poured into distilled water, washed with aqueous sodium bicarbonate and distilled water, dried over magnesium sulfate, and evaporated to dryness. 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 ) δ12. 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, 1.8Hz), 7.14(d, 1H, J=7.9Hz), 2.26(s, 3H), 1.98-1.89(m, 7H), 1.83-1.81(m, 3H); MS((+)APCI)[M +H] ⁺ @m/z373.

Example 6 - Pharmacology

The progestational activity of the compounds of the invention was evaluated in the following in vitro and in vivo tests. In vitro potency ranges from 0.01 nM to 10,000 nM, and in vivo potency ranges from 1 microgram/kg to 30 mg/kg.

A. In Vitro Biology

In vitro biology was determined by the following assays: (1) competitive radioligand binding: human progesterone receptor type A with progesterone as radioligand; (2) co-transfection assay, provided with agonist EC ₅₀ (3) _T47D cell proliferation, which is another functional assay that provides agonist and antagonist data; and (4) T47D cell alkaline phosphatase assay, which also provides Functional testing of agonist and antagonist data.

1. hPR binding assay: refer to Pathirana, C.; Stein, R.B.; Berger, T.S.; Fenical, W; Ianiro, T.; Somatic regulation of seaweed cymopliabarbata", J.Steroid Biochem.Mol.Biol., 1992, 41, 733-738.

2. PRE-Luciferase Assay in CV-1 Cells

The purpose of this test is to determine the pro- or anti-pregnancy effect of compounds based on their activity against PRE-luciferase reporter molecules in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. The materials and methods used in this test are as follows:

a. Growth medium: DMEM (BioWhittaker), which contains 10% (v/v) fetal bovine serum (heat inactivated), 0.1mMMEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin and 2mMGlutaMax (GIBCO , BRL). Test medium: DMEM (BioWhittaker), without phenol red, containing 10% (v/v) activated carbon-desorbed fetal bovine serum (heat-inactivated), 0.1 mM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin and 2mM GlutaMax (GIBCO, BRL).

b. Cell culture, transfection, treatment and luciferase assay

CV-1 cell stocks were maintained in growth medium. Use 1.2 x ¹⁰⁷ cells, 5 mg pLEM plasmid (hPR-B inserted at Sph1 and BamH1 sites), 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA (as Carrier DNA) (250ml) co-transfection. Electroporation was performed with a BioradGene Pulser II at 260V and 1,000mF. After electroporation, cells were resuspended in growth medium and cultured in 96-well plates at 40,000 cells/well (200 μl). After culturing overnight, the medium was changed to the test medium. These cells are then treated with control or test compounds in assay medium. The contraceptive activity of the compounds was determined in the presence of 3 nM progesterone. After 24 hours of treatment, the medium was discarded, and the cells were washed 3 times with D-PBS (GIBCO, BRL). 50 μl of cell lysis buffer (Promega, Madison, WI) 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 with Promega's luciferase reagent.

c. Result analysis

Each treatment was repeated at least 4 times. Log-scaled data were analyzed for variance and nonlinear dose-response curve fitting for agonist and antagonist patterns. Use the Huber weighting method to reduce the influence of outliers. EC ₅₀ or IC ₅₀ was calculated using the rescaled values. JMP software (SAS Institute, Inc.) was used in one-way analysis of variance and nonlinear response analysis.

d. Control compound

The control progestins were progesterone and trimegestone, and the control antiprogestin was RU486. All compounds were subjected to full dose-response curve determination, and _EC50 or _IC50 values were calculated.

Table 1 Estimates of _EC50 , Standard Deviation (SE) and 95% Confidence Interval (CI) of Control Progestins in Three Independent Studies

EC50 95%CI

Compound Example. (nM) SE Lower Limit Upper Limit

Progesterone 1 0.616 0.026 0.509 0.746

2 0.402 0.019 0.323 0.501

3 0.486 0.028 0.371 0.637

Trimegestone 1 0.0075 0.0002 0.0066 0.0085

                                                       

3 0.0067 0.0003 0.0055 0.0082

Table 2. Estimates of the _EC50 , standard deviation (SE) and 95% confidence interval (CI) of the antiprogestin RU486 from three independent studies

IC50 95% CI

Compound Example (nM) SE Lower Limit Upper Limit

RU486 1 0.028 0.002 0.019 0.042

2 0.037 0.002 0.029 0.048

3 0.019 0.001 0.013 0.027

Progestational activity: Compounds were considered active when they resulted in a significant increase (p<0.05) of PRE-luciferase activity compared to the control vehicle.

Anti-progestational activity: Compounds significantly decreased 3 nM progesterone-induced PRE-luciferase activity (p<0.05).

_EC50 : Compound concentration and standard deviation that produced half-maximal increase in PRE-luciferase activity (default -nM).

_IC50 : Compound concentration and standard deviation that produced a half-maximal reduction in 3 nM progesterone-induced PRE-luciferase activity (default -nM).

3. T47D cell proliferation assay

The purpose of this experiment is to use the cell proliferation assay of T47D cells to determine the efficacy of progestation and antipregnancy. The effect of compounds on DNA synthesis in T47D cells was determined. The following are the materials and methods used in this experiment:

a. Growth medium: DEME:F12 (1 : 1) (GIBCO, BRL).

b. Treatment medium: Phenol red-free minimal essential medium (MEM) supplemented with 0.5% charcoal-desorbed fetal bovine serum, 100 U/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) (#51200 -038 GIBCO, BRL).

c. Cell culture

T47D cell stocks were maintained in growth medium. For BrdU incorporation experiments, cells were plated at 10,000 cells/well in growth medium in 96-well plates (Falcon, Becton Dickinson Labware). After overnight culture, the medium was changed to treatment medium and the cells were cultured for an additional 24 hours before treatment. The compound stock solution was dissolved in an appropriate vehicle (100% ethanol or 50% ethanol/50% DMSO), then diluted with treatment medium, and added to the cells. Both progestogen and antiprogestogen control compounds are indicated in the full dose-response curve. The final concentration of vehicle was 0.1%. In control wells, cells received vehicle only. Antiprogestogens were assayed in the presence of 0.03 nM trimegestone (as a control progesterone agonist). After 24 hours of treatment, the medium was discarded and the cells were labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) in the treatment medium for 4 hours.

d. Cell proliferation experiment

When BrdU labeling was complete, the medium was discarded, and BrdU incorporation was measured using a cell proliferation ELISA kit ((#RPN 250, Amersham Life Science) according to the supplier's instructions. Briefly, cells were incubated with fixative Fix in ethanol for 30 minutes, and then incubate in blocking buffer for 30 minutes to reduce the background. Add the anti-BrdU antibody labeled with peroxidase to the well and incubate for 60 minutes. Rinse the cells 3 times with PBS, and use 3,3',5,5'-Tetramethylbenzidine (TMB) substrate was incubated for 10-20 minutes (depending on the potency of the compound being tested). Then 25 μl of 1M sulfuric acid was added to each well to terminate the color reaction , read the optical density at 450 nm with a plate reader within 5 minutes.

e. Result analysis

Analysis of variance and non-linear dose-response curves matched agonist and antagonist patterns using square root scaled data. Use the Huber weighting method to reduce the weight influence (downweight) of the abnormal value effect. _EC50 or _IC50 was calculated from the rescaled values. JMP software (SAS Institute, Inc.) was used in single-dose and dose-response analyzes of one-way analysis of variance and nonlinear dose-response analysis.

f. Control compound

Trimegestone and medroxyprogesterone acetate (MPA) were used as control progestins, and RU486 was used as control antiprogestin. All control compounds were assayed as full dose response curves and _EC50 or _IC50 values were calculated.

Table 3. Estimates of _EC50 , standard deviation (SE) and 95% confidence interval (CI) from independent studies

_EC50 95%CI

Compound Example (nM) SE Lower Limit Upper Limit

Trimegestone 1 0.017 0.003 0.007 0.040

2 0.014 0.001 0.011 0.017

3 0.019 0.001 0.016 0.024

MPA 1 0.019 0.001 0.013 0.027

2 0.017 0.001 0.011 0.024

Table 4. _EC50 , Standard Deviation (SE) and 95% Confidence Interval (CI) Estimates for Antiprogestin RU486

_IC50 95% CI

Compound Example (nM) SE Lower Limit Upper Limit

RU486 1 0.011 0.001 0.008 0.014

2 0.016 0.001 0.014 0.020

3 0.018 0.001 0.014 0.022

EC ₅₀ : compound concentration and standard deviation at which BrdU incorporation reaches half maximum increase; IC ₅₀ : compound concentration and standard deviation at which BrdU incorporation induced by 0.1 trimegestone reaches half maximum decrease.

4. T47D cell alkaline phosphatase experiment

The purpose of this experiment is to identify progestogens or antiprogestogens by measuring the effect of compounds on alkaline phosphatase activity in T47D cells. The following are the treatments and methods used in this experiment.

a. Medium: DMEM:F12 supplemented with 5% (v/v) charcoal-desorbed fetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100 μg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) (1:1) (GIBCO, BRL).

b. Alkaline phosphatase assay buffer:

I. 0.1M Tris-HCl, pH 9.8, containing 0.2% Triton X-100; II. 0.1M Tris-HCl, pH 9.8, containing 4mM p-nitrophenyl phosphate (Sigma)

c. Cell culture and treatment:

Thaw frozen T47D cells in a 37°C water bath and dilute to 280,000 cells/ml with culture medium. 180 microliters of the diluted cell suspension was added to each well of a 96-well plate (Falcon, Becton Dickinson Labware). Then 20 microliters of control or test compound diluted in culture medium was added to each well. When testing progesterone antagonist activity, control antiprogestins or test compounds are added in the presence of 1 nM progesterone. These cells were incubated for 24 hours at 37°C in a 5% CO ₂ /humidified atmosphere.

d. Alkaline phosphatase test

At the end of the treatment, the medium in the plate was discarded and 50 μl of Assay Buffer I was added to each well. The plates were shaken for 15 minutes on a plate shaker. 150 microliters of Assay Buffer II was then added to each well. Optical density was measured at 5 minute intervals for 30 minutes at a test wavelength of 405 nM.

e. Analysis of Results: Analysis of Dose Response Data

Dose response curves are plotted as dose (X-axis) versus enzyme reaction rate (slope) (Y-axis) for control and test compounds. Square-root transformed data were used for analysis of variance and nonlinear dose-response curve fitting for agonist and antagonist models. Use Huber weighting to reduce the influence of outliers. _EC50 or _IC50 was calculated from the rescaled values. JMP software (SAS Institute, Inc.) was used in the single-dose and dose-response studies of one-way analysis of variance and nonlinear response analysis.

f. Control compound

Progesterone and trimegestone were used as control progestogens, and RU486 was used as control antiprogestin. All control compounds were assayed in full dose response curves and _EC50 or _IC50 values were calculated.

Table 5. _EC50 , Standard Deviation (SE) and 95% Confidence Interval (CI) Estimates for Control Progestins from Three Independent Experiments

EC50 95%CI

Compound Example (nM) SE Lower Limit Upper Limit

Progesterone 1 0.839 0.030 0.706 0.996

2 0.639 0.006 0.611 0.669

3 1.286 0.029 1.158 1.429

Trimegestone 1 0.084 0.002 0.076 0.091

2 0.076 0.001 0.072 0.080

3 0.160 0.004 0.141 0.181

Table 6. _EC50 , Standard Deviation (SE) and 95% Confidence Interval (CI) Estimates for Control Progestins from Three Independent Experiments

IC50 95% CI

Compound Example (nM) SE Lower Limit Upper Limit

RU486 1 0.103 0.002 0.092 0.115

2 0.120 0.001 0.115 0.126

3 0.094 0.007 0.066 0.134

B. In Vivo Biology

The initial in vivo assay was a rat decidualization model, which was used to determine the progestational effects of agonists and antagonists. The second in vivo experiment was a rat model of ovulation suppression, which is still under development and therefore no protocol is provided.

1. Rat decidualization assay: The purpose of this procedure is to evaluate the effects of progestogens and antiprogestins on rat uterine decidualization and compare with the relative efficacy of various test compounds. The following are the materials and methods used:

a. Method: Test compounds were dissolved in 100% ethanol and mixed with corn oil (vehicle). Stock solutions of test compounds in oil (Mazola™) were then prepared by heating (-80°C) the mixture to evaporate the ethanol. The test compounds were then diluted with 100% corn oil or 10% ethanol in corn oil prior to treatment of the animals. When the two vectors were compared, no difference was found in the decidual response.

b. Animals (RACUC procedure #5002)

Ovariectomized female Sprague-Dawley rats (-60 days old and 230 g) were obtained from Taconic (Taconic Farms, NY). Ovariectomy was performed at least 10 days prior to treatment to reduce circulating sex steroids. The animals were housed in a room with a 12 hour light/dark cycle and fed standard rat chow with water ad libitum.

c. processing

Before treatment, rats were weighed and randomly divided into groups of 4 or 5. 0.2 ml of vehicle containing the test compound was administered to the nape of the neck by subcutaneous injection, or 0.5 ml by gavage. Animals were handled once daily for 7 days. For the tested antiprogestins, animals were given the test compound and an _EC50 dose of progesterone (5.6 mg/kg) during the first three days of treatment. Following decidua stimulation, animals continued to receive progesterone until necropsy four days later.

d. Dose

Doses were prepared based on mg/kg group mean body weight. In all studies, there was a control group that received vehicle. The half value of the logarithmic increase is used to determine the dose response curve (eg 0.1, 0.3, 1.0, 3.0 mg/kg...).

e. Decidual induction

Approximately 24 hours after the third injection, one uterine horn was decidualized by scraping the antimesometrial luminal epithelium with a 21G needle. Diagonal corners were not scratched as an unstimulated control. Approximately 24 hours after the final treatment, rats were sacrificed by _CO2 asphyxiation and body weights were measured. The uterus is removed and the fat cleaned. Weigh the decidual uterine horn (D-horn) and control uterine horn (C-horn) separately.

f. Results Analysis

The increase in decidual uterine horn weight was calculated from the D-horn/C-horn, using a logarithmic transformation to maximize normality and homogeneity of variance. The Huber M-estimation algorithm was used to downweight the effect of abnormally transformed values observed in dose-response curve fitting and one-way analysis of variance. JMP software (SAS Institute, Inc.) was used in one-way ANOVA and nonlinear response analysis.

g. Control compound

All progestogen control compounds were tested in a full dose-response curve and the _EC50 was calculated for wet uterine weight.

Table 7. _EC50 , Standard Deviation (SE) and 95% Confidence Interval (CI) Estimates from Independent Experiments

_EC50 95%CI

Compound Example (mg/kg, s.c.) SE lower limit upper limit

Progesterone 1 5.50 0.77 4.21 7.20

                                                                                                                                      

3-Ketodesogestrel 1 0.11 0.02 0.07 0.16

(3-Ketodesogestrel) 2 0.10 0.05 0.11 0.25

                                                                                                                   

Levonorgestrel 1 0.08 0.03 0.04 0.16

                                                                         

                                                                 

                                                                                         

MPA 1 0.42 0.03 0.29 0.60

                                                                         

                                                                 

Table 8. Mean _EC50 , Standard Deviation and 95% Confidence Interval Estimates in Dose Response Curves for Three Control Compounds

EC50 95%CI

Compound (mg/kg, s.c.) SE lower limit upper limit

Progesterone 5.62 0.62 4.55 7.00

3-Ketodesogestrel 0.10 0.02 0.07 0.14

Levonorgestrel 0.10 0.01 0.08 0.12

Table 9. _EC50 , Standard Deviation and 95% Confidence Interval Estimates for Antiprogestin RU486

_IC50 95% CI

Compound Example (mg/kg, p.o.) SE Lower Limit Upper Limit

RU486 1 0.21 0.07 0.05 0.96

2 0.14 0.02 0.08 0.27

Concentration: The concentration of the compound in the experiment (default is mg/kg body weight)

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

Body weight: Average overall weight of the animal (kg by default).

D-horn: Wet weight of the decidualized uterine horn (mg by default).

C-horns: Wet weight of control uterine horns (mg by default).

Decidual response: [(D-C)/C]×100%

Progestational activity: Compounds that induced decidualization significantly (p<0.05) compared to control vehicle were considered active.

Antiprogestational activity: Compounds that significantly reduce (p<0.05) _EC50 progesterone-induced decidualization.

_EC50 for uterine weight: the concentration of compound that results in a half-maximal increase in decidual response (mg/kg by default).

_IC50 for Uterine Weight: The concentration of compound that achieves a half-maximal reduction in the _EC50 progesterone-induced decidual response (mg/kg by default).

Table 10 Data for Representative Compounds

Example# Ki/nM CV-1IC50/nM Ovulation inhibition IC100mg/kg

5 0.3

3 0.1 0.2

1 0.2 0.8

4 0.06 0.1 0.1

Example 7

5-(1′,2′-Dihydro-2′-thiospiro[cyclopentane-1,3′-[3′H]indol]-5′-yl)-1H-pyrrole-2-metha Nitrile

5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3′H]indol]-5′-yl)-2-cyanopyrrole: in A mixture of 5'-bromospiro[cyclopentane-1,3'-[3'H]indole]-2'(1'H)-one (2.0 g, 7.5 mmol) and tetrakis(triphenylene) was stirred under nitrogen flow. Phosphine) palladium(0) (430 mg, 0.3 mmol) in ethylene glycol dimethyl ether (50 mL) for 15 minutes. To this solution were added successively 1-tert-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in water (10 ml). The mixture was heated to 80°C for 3 hours and then allowed to cool. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (30 mL), and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexanes gave 2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3′H]indole]-5 '-yl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (2.2 g, 83%) white powder, melting point 179-180.5°C. ¹ H NMR (DMSO-d ₆ , 400MHz) 1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H, J=1.8, 3.3Hz), 6.22 ('t', 1H, J =3.3, 3.3Hz), 6.79(d, 1H, J=7.9Hz), 7.08(dd, 1H, J=1.8, 7.9Hz), 7.14('d', 1H, J=1.5Hz), 7.28(dd , J=1.9, 3.3Hz), 10.30(s, 1H). MS (EI) m/z 352 [M ⁺ ]. Anal _. Calcd. _{for C2iH24N2O3 :} C, 71.57; H, 6.86; N, 7.95 _. Found: C, 71.08; H, 6.83; N, 7.74.

At -78°C, in the presence of 2-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl) - To tert-butyl 1H-pyrrole-1-carboxylate (2.2 g, 6.0 mmol) in THF (anhydrous, 25 mL) was added chlorosulfonyl isocyanate (0.63 mL, 7.0 mmol). 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), extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, 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/hexane) gave 5-(2'-oxo-2',3'-dihydrospiro[cyclopentane-1,3'- [3H]indole]-5'-yl)-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (1.7 g, 75%), melting point 167-9°C. ¹ HNMR (DMSO-d ₆ , 400MHz) 1.34(s, 9H), 1.75-1.98(m, 8H), 6.39(d, 1H, J=3.7Hz), 6.84(d, 1H, J=7.9Hz), 7.17 (dd, 1H, J=1.8, 7.9Hz), 7.28 ('t', 2H), 10.41 (s, 1H). MS (ESI) m/z 376 [MH] ^- . _{Anal .} Calcd. _{for C22H23N3O3 :} 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'-[3'H]indol-5'-yl)-2-cyanopyrrole-1 - tert-Butyl carboxylate (1 g, 2.7 mmol) was added to a 25 ml round bottom flask stoppered with a rubber septum and equipped with a nitrogen inlet and a needle eye to allow the gas to escape. A vigorous nitrogen flow was maintained while the flask was placed in an oil bath and heated to 165°C. After 20 minutes at this temperature, the flask was removed from the oil bath and allowed to cool. Crystallization from diethyl ether gave the title compound (600 mg, 79%) as a yellow powder, m.p. 285-286°C. ¹ H NMR (DMSO-d ₆ , 400MHz) 1.75-2.03 (m, 8H), 6.60 (dd, 1H, J=2.4, 3.7Hz), 6.84 (d, 1H, J=8.1Hz), 6.94 (dd, 1H, J=2.4, 3.7Hz), 7.52(dd, 1H, J=1.8, 8.1Hz), 7.60(d, 1H, J=1.8Hz), 10.38(s, 1H), 12.45(s, 1H). MS (ESI) m/z 276 [MH] ^- . Anal. Calcd. for _C17H15N3O : C, 73.63; H, _5.45 ; _N , 15.15. Found: C, 73.24; H, 5.34; N, 14.96.

In 5-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3′H]indol]-5′-yl)-1H-pyrrole-2- Totonitrile (0.18 g, 0.7 mmol, 1 eq) in p-xylene (20 mL) was added Lawesson's reagent (0.14 g, 0.36 mmol, 0.5 eq) and the reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and absorbed onto silica gel. Purification by flash column chromatography on silica gel (20% ethyl acetate/hexanes) gave the product as an orange powder. Further purification by HPLC gave the title compound (0.144 g, 70%) as a green solid, mp 275-276°C (dec.). ¹ H NMR (d ₆ -DMSO, 300MHz) 1.8 1-2.16 (m, 8H), 6.69 (dd, 1H, J=2.3, 3.7Hz), 6.98 (dd, 1H, J=1.8, 3.7Hz), 7.04 (d, 1H, J=8.2Hz), 7.63(dd, 1H, J=1.6, 8.2Hz), 7.72(d, 1H, J=1.3Hz), 12.57(s, 1H), 12.65(s, 1H) . MS(ESI)[MH] ^- =292. Anal _. Calcd _{for C17H15N3S} : 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'-thiospiro[cyclohexane-1,3'-[3'H]indol-5'-yl)-1-(tert-butoxycarbonyl) -Pyrrole-2-carbonitrile

5'-Bromo-spiro[cyclohexane-1,3'-indoline]-2'-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under nitrogen Tetrakis(triphenylphosphine)palladium(0) (70 mg, 5 mol%) was added to the solution. After 15 minutes, 1-tert-butyl 2-borono-1H-pyrrole-1-carboxylate (1.3eq, 3.31g, 15.6mmol) and _K2CO3 ( _2.3eq , 3.83g, 27.6 mmol) in water (5 mL). The solution was heated to 80°C for 3 hours and then allowed to cool. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with brine (150 mL), and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% ethyl acetate/hexanes) to give 2-(1',2'-dihydro-2'-oxospiro[ Cyclohexane-1,3'-[3'H]indol]-5'-yl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (3.4 g, 76%) white powder, melting point 177°C. ¹ H NMR (CDCl ₃ ; 300MHz) 1.38(s, 9H), 1.59-1.93(m, 10H), 6.18(m, 1H), 6.23('t', 1H, 3Hz), 6.91(d, 1H, J = 8 Hz), 7.21 (d, 1H, J = 8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (brs, 1H, D ₂ Oex). MS ((+)-APCI) m/z 367 [(M+H) ⁺ ]. _Anal . Calcd. _{for C22H26N2O3} : C, 72.11; H, _7.15 ; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.

At -78°C, in the presence of 2-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl) -1H-pyrrole-1-carboxylate tert-butyl ester (0.75 g, 2 mmol) in THF (anhydrous, 20 ml) was added by adding chlorosulfonyl isocyanate (1.15 equivalents, 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), extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, 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) afforded 5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3 'H]indole]-5'-yl-2-cyanopyrrole-1-carboxylic acid tert-butyl ester (0.5 g, 63%), the oil was crystallized from acetone to give white crystals, melting point 156°C. ¹ H NMR (d ₆ -DMSO, 400 MHz) 1.32(s, 9H), 1.50(m, 3H), 1.60-1.70(m, 5H), 1.75-1.85(m, 2H), 6.38(d, 1H, J= 3.7Hz), 6.87(d, 1H, J=7.9Hz), 7.18(dd, 1H, J=1.5, 7.9Hz), 7.27(d, 1H, J=3.7Hz), 7.48(d, 1H, J= 1.8 Hz), 10.42 (bs, 1H). MS (EI) m/z 391 (M ⁺ ). Anal. Calcd. for C ₂₃ H ₂₅ N ₃ O ₃ : C, 70.57; H, 6.44; N, 10.73. Found : C, 69.82; H, 6.46; N, 10.43.

Containing 2-cyano-5-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)- 1H-Pyrrole-1-carboxylic acid tert-butyl ester (0.7 g, 1.8 mmol, 1 eq) in toluene (70 mL) was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq) and the reaction was heated Reflux for 1 hour. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, 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, 500MHz) 1.30-1.98 (m, 19H), 6.45 (d, 1H, J=3.7Hz), 7.09 (d, 1H, J=7.9Hz), 7.31-7.34 (m, 2H), 7.81 (d, 1H, J = 1.4 Hz), 12.74 (s, 1H). MS (ESI) [MH]-=406. _{Anal .} Calcd. _{for C23H25N3O2S} : 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′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5-yl)-1-H-pyrrole-2- Formaldehyde

Containing 5-(1′,2′-dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5-yl)-1-(tert-butoxy Carbonyl)-pyrrole-2-carbonitrile (0.5 g, 1.2 mmol, 1 eq) in THF (5 mL) was added sodium ethoxide (0.25 g, 3.6 mmol, 3 eq) in ethanol (5 mL), 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 (50 mL) with ethyl acetate. The organic layers were combined, 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) afforded the title compound (0.27 g, 68%) as a yellow powder. ¹ H NMR (d ₆ -DMSO, 500MHz) 1.32-1.99 (m, 10H), 6.71 (d, 1H, J=3.7Hz), 7.00 (d, 1H, J=3.7Hz), 7.09 (d, 1H, J=8.4Hz), 7.70(dd, 1H, J=1.6, 8.4Hz), 8.05(d, 1H, J=1.1Hz), 12.67(s, 1H), 12.73(s, 1H). MS(ESI)[MH] ^- =306. _Anal . Calcd. _{for C18H17N3S} : C, 70.33; H, 5.57; N, 13.67. Found: C, 69.64; H, 5.79; N, 13.04.

Example 10

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

In 5-(2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)-1-methyl-pyrrole-2-carbonitrile (0.55 g , 1.8 mmol, 1 eq) in toluene (50 mL) was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq), and the reaction was heated at 80°C for 1 hour. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded the product as a yellow solid (0.32 g, 55%). ¹ H NMR (d ₆ -DMSO, 500MHz) 1.36-1.99 (m, 10H), 3.7 (s, 3H), 6.35 (d, 1H, J=4.2Hz), 7.05 (d, 1H, J=4.2Hz) , 7.16 (d, 1H, J=7.9Hz), 7.44 (dd, 1H, J=1.6, 8.1Hz), 7.83 (d, 1H, J=1.6Hz), 12.75 (s, 1H). MS(ESI)[MH] ^- =320. Anal. Calcd. _{for C19H19N3S} : 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′-thiospiro[cyclopentane-1,3′-[3′H]indol]-5′-yl)-3-thiophenecarbonitrile

5-Bromo-2-thiophenecarbonitrile: Under nitrogen, make 5-bromo-2-thiophenecarbaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) of the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oil. The crude product was triturated with ice water and the resulting solid collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper(II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated at 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 (2 x 30 mL), water (2 x 30 mL), brine (20 mL) and dried ( _MgSO4 ). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1 L) and allowed to crystallize. The resulting crystals were collected on a filter membrane and the filtrate was concentrated and chromatographed (silica gel, chloroform) to afford the subtitle compound as an off-white solid (31.5 g, combined, 58%). IR (film) cm ⁻¹ 2200. ¹ H-NMR (CDCl ₃ ) δ7.39-7.38 (d, 1H, J=4.1Hz), 7.10 (d, 1H, J=4.0Hz); MS (EI) m/z 187 (M ⁺ , 98% ) 189 (M ⁺ , 100%).

According to the steps of Example 5, using 5-bromo-2-thiophenecarbonitrile and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]ind Indol]-5'-yl)boronic acid to produce 5-(1',2'-dihydro-2'-oxospiro[cyclopentane-1,3'-[3'H]indole]-5' -yl)-3-thiophenecarbonitrile: melting point 225-228°C; ¹ H NMR (DMSO-d ₆ ) δ 1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J=8.13Hz ), 7.55 (dd, 1H, J = 8.13, 1.76Hz), 7.60 (d, 1H, J = 4.17Hz), 7.75 (d, 1H, J = 1.76Hz), 7.93 (d, 1H, J = 4.17Hz ), 10.51 (s, 1H); MS ((+)APCl) m/z 309 [M+H] ⁺ .

Stir at 80°C containing 5-(1',2'-dihydro-2'-oxospiro[cyclopentane-1,3'-[3'H]indol]-5'-yl)-3 - Thiophenecarbonitrile (0.66 g, 2.4 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphetane-2,4- Disulfide (0.97 g, 2.4 mmol) in toluene (250 mL) for 2 hours. The solution was concentrated in vacuo. The residue was extracted with ethyl acetate, and 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=8.1Hz, 1H), 7.55 (dd, J=8.1, 1.7Hz, 1H), 7.7 (d, J =1.7Hz, 1H), 7.95(d, J=1.3Hz, 1H), 8.49(d, J=1.3Hz, 1H), 8.49(d, J=1.3Hz, 1H), 12.68(s, 1H); MS (EI NEG) m/z 309 (MH) ^- .

Example 12

5-(1′,2′-Dihydro-thiospiro(cyclopentane-1,3′-[3′H]indol)-5′-yl)-2-thiophenecarbonitrile

From 5-(1′,2′-dihydro-oxospiro(cyclopentane-1,3′-[3′H]indole)-5′- y1)-2-thiophenecarbonitrile (2 g, 6.8 mmol) and Lawesson's reagent (3.32 g, 8.2 mmol) gave the title compound. The yield was 1.5 g (48.3%). Melting point 250-253°C. ¹ H NMR (DMSO-d ₆ ) δ12.75 (S, 1H), 7.98-7.97 (d, 1H, J=3.9Hz), 7.71- 7.70(d, 1H, J=5.2Hz), 7.65-7.62(d, 1 hour, J=8.1Hz), 7.09-7.07(d, 1 hour, J=8.1Hz), 2.13 2.08(m, 6H,), 1.99 -1.85 (m, 2H,); MS.[MH] ^- 309. IR (SP ATR) 1430, 1620, 2220 cm ^-1 . Calcd. Analytical value of C ₁₇ H ₁₄ N ₂ S ₂ C, 65.77; H, 4.55; N, 9.02. obs'd C65.27; H, 4.41; N, 8.84.

Example 13

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

5'-(3-fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one: according to Example 5 The steps from 4-bromo-2-fluoroanisole and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indole]- 5′-yl)boronic acid to give the subtitled compound as a white solid, melting point 178-180°C; ¹ H-NMR (DMSO-d ₆ ) 10.4 (s, 1H), 7.65 (d, 1H, J=1.1Hz), 7.5-7.4(m, 3H), 7.2(t, 1H, J=dJ=8.8Hz), 3.9(s, 3H), 1.9(m, 2H) 1.7-1.6(m, 8H); MS(APCI(- )) m/z 324 [MH] ⁻ ; Anal. Calcd. for 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.

Make 5'-(3-fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-ketone and A mixture of phosphorus pentasulfide in pyridine was refluxed overnight to give the title compound. Pyridine was removed in vacuo, and the residue was treated with 5N hydrochloric acid solution, followed by recrystallization in ethanol to give a gray solid, melting point 228-229 °C; ¹ H-NMR (DMSO-d6) 12.7 (s, 1H), 7.9 (s, 1H), 7.6-7.5(m, 2H), 7.5-7.4(m, 1H), 7.2(t, 1H, J=8.8Hz), 7.1(d, 1H, J=8.1Hz), 3.9(s, 3H ), 1.9-1.8(m, 7H), 1.4-1.3(m, 3H); MS(APCI(-))[MH] ^- m/z 324. Analytical calculated value _{for C20H20FNOS} . 0.25 water 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'-[3'H]indole]-2'(1'H)-thione

Through 5'-(2-amino-5-pyrimidinyl)spiro[cyclohexane-1,3'-[3'H]-indol]-2'(1'H)-ketone and phosphorus pentasulfide containing the same weight A mixture of pyridines was prepared at reflux overnight. Pyridine was removed in vacuo, and the residue was treated with 5N hydrochloric acid solution, followed by recrystallization in ethanol to give a gray solid; mp 274-277°C (decomposition); ¹ H-NMR (DMSO-d ₆ ) 12.7 (s, 1H), 8.6(s, 2H), 7.9(s, 1H), 7.5(d, 1H, J=8.1Hz), 7.1(d, 1H, J=8.1Hz), 6.8(s, 2H), 1.9-1.8(m , 7H), 1.4-1.3 (m, 3H). MS(APCI(-))[MH] ^- m/z 309.

Example 15

3-(1′,2′-Dihydro-2′-thiospiro[cyclopentane-1,3′-[3′H]indol]-5′-yl)-5-fluorobenzonitrile spiro[ Cyclopentane-1,3'-[3'H]indole]-2'(1'H)-one

To a solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm ³ ) of dry THF at -25°C was added dropwise n-butyl lithium (1.6M in hexane, 19.7 cm ³ , 31.5 mmol). To the resulting milky solution was added N,N,N',N'-tetramethylethylenediamine (4.75 cm ³ , 31.5 mmol). After 30 minutes, a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm ³ ) 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, extracted with ethyl acetate (x2), the combined organic layers were washed with dilute hydrochloric acid (pH 1 ) and water (x2), dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate:hexane 1:4) to give the subtitle 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, 1.0Hz, 1H), 7.01(dd, J7.5, 1.0Hz, 1H), 7.14-7.25(m, 2H), 9.30(brs, 1H) .

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

Spiro[cyclopentane- ^1,3 '-[3'H]indole]-2'(1'H)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm ³ ). After 30 min, the mixture was poured into saturated sodium bicarbonate solution, extracted with ethyl acetate (x2), the combined organic layers were washed with water, saturated sodium bicarbonate solution and water, dried ( _MgSO4 ) and evaporated to give an off-white solid The subtitled compound (0.37 g, 1.47 mmol, 96%) 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 (brs, 1H). 5'-(3-cyano-5-fluorophenyl)-spiro[cyclopentane-1,3'-[3'H]indole]-2'(1'H)-one:

Under nitrogen, 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol) tetrakis(triphenylphosphine)palladium(O) (0.2 g) in ethylene glycol dimethyl ether (20 cm ³ ) solution for 20 minutes. Then, (spiro[cyclopentane-1,3'-[3'H]indole]-2'(1'H)-on-5-yl)boronic acid (0.9 g, 3.9 mmol ) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm ³ ). The solution was refluxed for 18 hours, then cooled to room temperature, poured into 2N NaOH and extracted with ethyl acetate (x3). The combined extracts were washed with water and brine, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography ( _SiO2 , ethyl acetate, hexane) to give the subtitle compound (0.35 g, 44%) as white needles. Melting point: 235-237°C; ¹ HNMR (DMSO-d ₆ ) δ10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0Hz), 7.8-7.7 (m, 2H), 7.6(dd, 1H, J=1.8, 6.4Hz), 6.9(d, 1H, J=8.1Hz), 2.0-1.9(m, 8H); MS(EI)M ⁺ @m/ z306.

General Step A

Reflux in a sealed test tube containing 5'-(3-cyano-5-fluorophenyl)-spiro[cyclopentane-1,3'-[3'H]indole]-2'(1'H)- Ketone (40 mg) and Lawesson's reagent (50 mg) in toluene (10 mL) for 16 hours gave the title compound. The mixture was concentrated, the residue was dissolved in a minimum of THF, and purified by HPLC ( _SiO2 , 30 cm x 2.5 cm, ethyl acetate-hexane 2:8, 20 mL/min) to afford the title compound as an off-white solid (0.022 g): melting point 236-238°C; ¹ H NMR (DMSO-d ₆ ) δ 12.66 (brs, 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 1.7Hz), 7.07(d, 1H, J=8.1Hz), 2.10-2.05(m, 6H) and 1.97-1.88(m, 2H); MS (EI) m/z 322[M] ⁺ .

Example 16

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

5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one. Under nitrogen, a mixture containing 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) and tetrakis(triphenylphosphine)palladium ( O) (0.239 g) in dimethoxyethane (35 cm ³ ). After 15 minutes, 3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added, followed by potassium carbonate (3.40 g, 45 mmol) in water (15 cm ³ ). The reaction was heated to reflux for 2 hours, then stirred at room temperature overnight. The mixture was diluted with saturated ammonium chloride and extracted with ethyl acetate (x3). The organic layers were combined, dried ( _MgSO4 ), filtered and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate:hexane, 1:3) to give the subtitle compound (0.284 g, 25%): melting point 188-189°C; ¹ H NMR (DMSO-d ₆ )δ3 .34(s, 6H), 6.93(d, 1H, J=8.04Hz), 7.38-7.35(m, 1H), 7.53-7.43(m, 2H), 7.61(d, 1H, J=7.68Hz), 7.70(s, 2H), 10.40(s, 1H); IR(KBr) 3420, 3150, 3050, 1700cm ^-1 ; MS(EI) m/z 270(MH) ^- ; CHN calculated for C ₁₆ H ₁₄ ClNO+ _0.1C4H8O2 : 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-chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (100 mg) and The title compound was prepared by Lawesson's reagent (120 mg) to give the title compound (0.031 g) as an off-white solid: mp 158-160 °C; ¹ H NMR (CDCl ₃ ) δ 9.67 (brs, 1H), 7.55 (s, 1H ), 7.47-7.43(m, 3H), 7.40-7.30(m, 2H), 7.08(d, 1H, J=8.7Hz) and 1.50(s, 6H); MS(EI) m/z287/289[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-chloro-phenyl)-3-methyl-1,3-dihydro-indol-2-one (100 mg ) and Lawesson's reagent (120 mg) to give the title compound (0.022 g) as an off-white solid: melting point 168-170 °C; ¹ H NMR (CDCl ₃ ) δ9.23 (brs, 1H), 7.49 (s , 1H), 7.49-7.30(m, 4H), 7.21(s, 1H), 7.15-7.09(m, 3H), 6.96-6.94(m, 2H), 6.89(d, 1H, J=8.0Hz), 3.19 (dd, 2H, J = 40.5 and 13 Hz) and 1.57 (s, 3H); MS (EI) m/z 363/365 [M] ⁺ .

Example 18

4-(3,3-Dimethyl-2,3-2,3-dihydro-1H-indol-5-yl)-2-furylcarbonitrile

4-(3,3-Dimethyl-2oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile.

According to the steps of Example 5, with (2'-oxo-[2,3-dihydro-3,3-dimethyl-1,3'-[3H]indol]-5'-yl)boronic acid ( 354 mg, 1.7 mmol) and 4-bromo-furan-2-carbonitrile (200 mg, 1.2 mmol) gave the subtitle compound (76 mg, 0.3 mmol, 26%) as a white solid: mp. 199.6- 201.4°C, ¹ H NMR (DMSO-d ₆ ) δ1.28(s, 6H), 6.89(d, J=8.0Hz, 1H), 7.48(dd, J=8.0, 1.8Hz, 1H), 7.65(d , J=1.5Hz, 1H), 8.1(s, 1H), 8.5(s, 1H), 10.46(s, 1H); MS (ESI) m/z 251(MH) ^- ; Anal. C ₁₅ H ₁₂ N ₂ O ₂ .0.6H ₂ O

According to general procedure A, 4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2- The title compound was prepared from forminonitrile (73 mg) and Lawesson's reagent (120 mg) to give the title compound (0.003 g) as an off-white solid: mp 188-191°C; ¹ H NMR (CDCl3) δ 9.63 (brs, 1H ), 7.83(s, 1H), 7.36-7.33(m, 3H), 7.06(d, 1H, J=7.9Hz) 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: stirred mol) and sodium acetate (0.33 g, 4.07 mmol) in acetic acid (5 cm ³ ), then bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm ³ ) was added dropwise to the reaction mixture. The reaction was stirred for 50 minutes, then poured into water. The mixture was basified with sodium carbonate, extracted with ethyl acetate (x3), dried (MgSO ₄ ), filtered and evaporated to give the subtitle compound (0.89 g, 92%) ¹ H NMR (DMSO-d ₆ ) δ 1.21 (s, 6H), 6.76 (d, 1H, J = 8.22Hz), 7.29 (dd, 1H, J = 2.12Hz, 8.23Hz), 7.49 (d, 1H, J = 2.03Hz), 10.4 (s, 1H ).

Under nitrogen, stir a mixture containing 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) in dimethoxyethane (12 cm ³ ). After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by potassium carbonate (1.15 g, 8.34 mmol) in water (5 cm ³ ). The reaction was heated to reflux for 5 hours, then cooled to room temperature. Saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was filtered. The aqueous layer was extracted (x2) with ethyl acetate and the combined organic layers were dried ( _MgSO4 ), filtered and evaporated. The residue was purified by column chromatography ( _SiO2 , ethyl acetate:hexane 1:3) to give 5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro- Indol-2-one (0.11 g, 31%), melting point = 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=1.14Hz), 10.4(s, 1H) ; MS (EI) m/z 266 (MH) ⁻ ; CHN Anal. for 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-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (100 mg ) and Lawesson's reagent (120 mg), the title compound was obtained as an off-white solid (0.022 g): melting point 149-150 °C; ¹ H NMR (CDCl ₃ ) δ9.69 (brs, 1H), 7.49- 7.46(m, 2H), 7.37(t, 1H, J=8.0Hz), 7.16(d, 1H, J=7.7Hz), 7.09-7.06(m, 2H), 6.90(dd, 1H, J=8.2 and 2.3 Hz) 3.88 (s, 3H) and 1.50 (s, 6H); MS (EI) m/z 283 [M] ⁺ .

Example 20

3-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-4-fluorobenzonitrile

3-(1′,2′-Dihydro-2-oxospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-4-fluorobenzonitrile

Prepared according to the steps of Example 5: melting point 205-206°C. ¹ H NMR (DMSO-d ₆ ) δ10.47(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, 1HJ=7.9Hz), 1.97-1.83(m, 2H), 1.69-1.55(m, 8H); MS(EI) m/z320(M ⁺ ).

According to general procedure A, 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole]- 5'-yl)-4-fluorobenzonitrile (100 mg) and Lawesson's reagent (120 mg) prepared the title compound to give the title compound (0.037 g) as an off-white solid: mp 230-233°C; ¹ H NMR ( CDCl ₃ ) δ 9.82 (brs, 1H), 7.86 (s, 1H), 7.77 (dd, 1H, J = 7.0 and 1.8 Hz), 7.68-7.63 (m, 1H), 7.45 (d, 1H, J = 8.0Hz), 7.31(d, 1H, J=9.0Hz), 7.15(d, 1H, J=8.1Hz), 2.17-1.84(m, 7H) and 1.60-1.54(m, 3H); MS(EI) m/z336[M] ⁺ .

Example 21

5-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-3-pyridinecarbonitrile

A solution containing 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol), hexamethylditin (5.00 g, 15.26 mmol) and tetrakis(triphenylphosphine) palladium (O) (0.20 g, 0.17 mmol) in anhydrous dimethoxyethane (30cm ³ ) was heated to reflux under nitrogen. After 16 hours, the mixture was concentrated and purified by column chromatography ( _SiO2 , ethyl acetate:hexane 5:95) to give 3-cyanopyridine-5-trimethylstannane (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'-[3'H]indole]-2'(1'H)-one (1.97 g, 7.05 mmol), 3-cyanopyridine- 5-trimethylstannane (2.26 g, 8.46 mmol), bis(triphenylphosphine)palladium(II) chloride (0.33 g, 0.47 mmol) and lithium chloride (1.48 g, 35 mmol) Anhydrous toluene (30cm ³ ) solution was heated to reflux. After 16 hours, the mixture was cooled and partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate (x2) and the combined organic extracts were washed with water, dried ( _MgSO4 ) and evaporated. The residue was subjected to column chromatography (SiO ₂ , ethyl acetate:hexane, 1:2), and then further purified by preparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN:water 1:1, 100 cm ³ / minutes, room temperature 7.92 minutes), to obtain 3-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl) White crystals of pyridinecarbonitrile (0.56 g, 1.84 mmol, 26%): melting point 232-234°C, ¹ H NMR (CDCl ₃ ) δ 1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12(d, 1H, J=8Hz), 7.49(dd, 1H, J=8, 2Hz), 7.66(d, 1H, 2Hz), 8.15(t, 1H, J=2Hz), 8.39(s, 1H, br), 8.89 (d, 1H, J = 2Hz), 9.06 (d, 1H, J = 2Hz); MS ((+)-ESI) m/z 304 (M+H) ⁺ ; Anal. for C ₁₉ H ₁₇ N ₃ OCHN.

According to general procedure A, reflux 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole-5 in toluene (10 mL) '-yl) pyridinecarbonitrile (100 mg) and Lawesson's reagent (120 mg) to prepare the title compound to give the title compound (0.004 g) as a yellow solid: mp 237-238°C; ¹ H NMR (CDCl ₃ ) δ9 .56(brs, 1H), 9.03(d, 1H, J=1.9Hz), 8.87(d, 1H, J=1.4Hz), 8.12(s, 1H), 7.87(s, 1H), 7.50(d, 1H, J=8.1Hz), 7.17(d, 1H, J=8.1Hz), 2.19-1.85(m, 7H) and 1.59-1.54(m, 3H); MS((-)-APCI) m/z318[ MH] ^- .

Example 22

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

5'-(3,5-difluorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one: prepared according to the steps of Example 5 Obtained: melting point 180-183°C; ¹ H-NMR (CDCl ₃ ) δ8.35 (s, 1H), 7.59 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=6.2, 2.0Hz) , 7.10-7.03(m, 2H), 6.99(d, 1H, J=8.1Hz), 7.76(tt, 1H, J=4.3, 2.3Hz), 2.05-1.62(m, 10H); MS((+) APCI) m/z 314 [M+H] ⁺ .

According to general procedure A, 5′-(3,5-difluorophenyl)spiro[cyclohexane-1,3′-[3H]indole]-2′(1′H )-ketone (100 mg) and Lawesson's reagent (120 mg) to prepare the title compound to give the product (0.020 g) as a yellow solid: melting point 232-233°C; ¹ H NMR (CDCl ₃ ) δ 10.05 (brs, 1H), 7.83(s, 1H), 7.44(dd, 1H, J=8.1 and 1.4Hz), 7.38-7.30(m, 1H), 7.26-7.19(m, 3H), 7.11(d, 1H, J= 8.1 Hz), 2.17-1.82 (m, 7H) and 1.66-1.53 (m, 3H); MS ((-)-APCD m/z 328[MH] ^- .

Example 23

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

5'-(5-chloro-2-thienyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one: prepared according to the steps of Example 5 Obtained: melting point 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=4.0Hz, 1H), 7.36 (dd , J=7.5, 1.6Hz, 1H), 7.53(d, J=0.9Hz, 1H), 7.80(brs, 1H); ¹³ C-NMR(THF-d ₈ )δ21.35, 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) ⁺ ; Analytical value (C ₁₇ H ₁₆ ClNOS)C, H, N.

According to general procedure A, 5′-(5-chloro-2-thienyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′(1 'H)-ketone (100 mg) and Lawesson's reagent (120 mg) prepared the title compound to give the product (0.041 g) as a yellow solid: mp 231-232°C; ¹ H NMR (CDCl ₃ ) δ 9.75 ( brs, 1H), 7.82 (d, 1H, J=1.2Hz), 7.43 (dd, 1H, J=8.1 and 1.6Hz), 7.04-7.02 (m, 2H), 6.89 (d, 1H, J=3.8) , 2.15-1.84 (m, 7H) and 1.59-1.52 (m, 3H); MS ((-)-APCI) m/z 332/334 [MH] ^- .

Example 24

5-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-3-furancarbonitrile 5- (1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)-3-furancarbonitrile:

Prepared according to the steps of Example 5: melting point 243-245°C. ¹ H-NMR (DMSO-d ₆ ) δ10.48(s, 1H), 8.62(d, 1HJ=0.7Hz), 7.76(d, 1HJ=1.5Hz), 7.58-7.55(dd, 1H), 7.33( d, 1HJ=0.7Hz), 6.92-6.90(d, 1HJ=8.1Hz), 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′-oxospiro[cyclohexane-1,3′-[3′H]indole]- 5'-yl)-3-furancarbonitrile (100 mg) and Lawesson's reagent (120 mg) prepared the title compound to give the product as a yellow solid (0.020 g): melting point 264-268°C; ¹ H NMR (CDCl ₃ ) δ9.66 (brs, 1H), 7.98 (s, 2H), 7.59 (dd, 1H, J = 8.2 and 1.5Hz), 7.08 (d, 1H, J = 8.2Hz), 6.78 (s, 1H) , 2.16-1.85 (m, 7H) and 1.56-1.52 (m, 2H): MS ((-)-APCI) m/z 307 [MH] ^- .

Example 25

5′-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′(1′H)-thione

5'-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one . Prepared according to the steps of Example 5: melting point 188-189°C; ¹ H-NMR (CDCl ₃ ) δ7.97 (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′-[3′H]indole]-2′( 1'H)-ketone (100 mg) and Lawesson's reagent (100 mg) prepared the title compound to give the product (0.036 g) as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.74 (brs, 1H ), 7.92 (d, 1H, J = 1.4Hz), 7.87 (dd, 1H, J = 7.1 and 2.3Hz), 7.70-7.65 (m, 1H), 7.61 (dd, 1H, J = 7.1 and 1.5Hz) , 7.49(t, 1H, J=8.9Hz), 7.14(d, 1H, J=8.1Hz), 1.99-1.82(m, 7H) and 1.40-1.37(m, 3H): MS((-)-APCI )m/z344/346[MH] ^- .

Example 26

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

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

Prepared according to the procedure of Example 5: melting point 178-180°C; ¹ H-NMR (CDCl ₃ ) δ8.50 (s, 1H), 7.57 (d, 1H, J=1.8Hz), 7.39 (dd, 1H, J=6.2, 1.9Hz), 7.33-7.32(m, 1H), 7.15(dq, 1H, J=5.7, 1.7, 0.7Hz), 7.06(dq, 1H, J=4.2, 1.9, 0.4Hz), 7.00 (d, 1H, J = 8.1 Hz), 2.05-1.64 (m, 10H); MS ((-)ESI) [MH] ^- @m/z328.

According to general procedure A, 5′-(3-chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′( 1'H)-ketone (100 mg) and Lawesson's reagent (100 mg) prepared the title compound to give the product (0.039 g) as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.76 (brs, 1H ), 7.97 (d, 1H, J = 1.1Hz), 7.67 (dd, 1H, J = 8.1 and 1.4Hz), 7.60-7.54 (m, 2H), 7.40 (dt, 1H, J = 8.65 and 2.0Hz) , 7.14 (d, 1H, J = 8.1 Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m, 3H): MS ((-)-APCI) m/z 344/346 [MH] ^- .

Example 27

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

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

Prepared according to the procedure of Example 5: melting point 180-183°C; ¹ H-NMR (CDCl ₃ ) δ8.35 (s, 1H), 7.59 (d, 1H, J=2.0Hz), 7.40 (dd, 1H, J=6.2, 2.0Hz), 7.10-7.03(m, 2H), 6.99(d, 1H, J=8.1Hz), 7.76(tt, 1H, J=4.3, 2.3Hz), 2.05-1.62(m, 10H ); MS ((+)APCI) m/z 314[M+H] ⁺ .

According to general procedure A, 5′-(3,5-difluorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′(1 Preparation of the title compound from 'H)-ketone (100 mg) and Lawesson's reagent (100 mg) gave the title compound (0.029 g) as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.76 (brs, 1H ), 7.84(s, 1H), 7.64-7.56(m, 1H), 7.46(d, 1H, J=8.1Hz), 7.40-7.32(m, 1H), 7.22-7.15(m, 2H), 1.99- 1.80 (m, 7H) and 1.38-1.35 (m, 3H); MS ((-)-APCI) m/z 328 [MH] ^- .

Example 28

5-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol-5′-yl)-4-propyl-2-thiophene Formaldehyde

5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-4-propyl-2- Thiophenecarbonitrile. The title compound was obtained in a manner similar to Example 5 by making 5-bromo-4-n-propylthiophene-2-carbonitrile (1.17 g, 5 mmol), (1,2-dihydro-2-oxo Spiro[cyclohexane-1,3-[3H]indole)-5-boronic acid (1.24 g, 5 mmol), tetrakis(triphenylphosphine)palladium, potassium carbonate (2.75 g, 21 mmol), Water (10ml) and dimethoxyethane (50ml) were heated to reflux overnight to give the product (0.7g, 40%): melting point 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=1.5Hz), 7.33-7.29(dd, 1H, J=1.6Hz), 7.00-6.96(d, 1H, J=8.0Hz ), 2.62-2.57(t, 2H), 1.86(m, 2H), 1.70-1.56(m, 11H), 0.88-0.84(t, H); MSm/z(APCI(+))351[M+H ] ⁺ . IR(KBr) _{1620 ,} 1700, 2200 cm ^-1 Calcd for _C21H22N2OS1 / _2H2O C, 70.2; H, 6.39; N, 7.79. Found: C, 70.67; H, 6.34; N, 7.62.

According to general procedure A, 5-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole]- 5'-yl)-4-propyl-2-thiophenecarbonitrile (90 mg) and Lawesson's reagent (90 mg) prepared the title compound to give the title compound (0.037 g) as an orange solid: ¹ H NMR (DMSO -d ₆ ) δ12.83(brs, 1H), 7.96(s, 1H), 7.77(s, 1H), 7.44(d, 1H, J=7.7Hz), 7.19(d, 1H, J=8.0Hz) , 2.60(t, 2H, J=8.0Hz), 1.98-1.79(m, 7H), 1.64-1.56(m, 2H), 1.39-1.35(m, 2H) and 0.87(t, 3H, J=7.3Hz ): MS ((-)-APCI) m/z 365[MH] ^- .

Example 29

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

5'-(3-fluoro-4-nitrophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one : as described in Example 5 As described, from (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)boronic acid (3.2 g, 12.5 mg mol) and 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) to give the title compound (0.7 g, 16%) as a yellow solid: mp 213-215°C; ¹ H NMR (DMSO-d ₆ )δ1.5-1.8(m, 8H), 1.8-2.0(m, 2H), 6.96(d, 1H, J=8.13Hz), 7.68(dd, 1H, J=8.13, 1.76Hz), 7.74(dd , 1H, J=8.68, 1.76Hz), 7.86 (d, 1H, J=1.98Hz), 7.92 (dd, 1H, J=13.4, 1.76Hz), 8.18 (t, 1H, J=8.46Hz) and 10.52 (s, 1H); MS (EI) m/z = 340 (M ⁺ ).

According to general procedure A, reflux 5'-(3-fluoro-4-nitrophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2' in toluene (10 mL) The title compound was prepared from (1'H)-ketone (90 mg) and Lawesson's reagent (90 mg) to give the product (0.021 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ 12.82 (brs, 1H ), 8.21 (t, 1H, J = 8.4Hz), 8.07 (d, 1H, J = 1Hz), 7.98 (dd, 1H, J = 13.1Hz), 7.79 (dt, 1H, J = 8.1 and 2.6Hz) , 7.19 (1H, J = 8.2Hz), 1.99-1.83 (m, 7H) and 1.42-1.39 (m, 3H): MS ((-)-APCI) m/z 355 [MH] ^- .

Example 30

4-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-2-furancarbonitrile

4-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-2-furancarbonitrile: in A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.4 g) in ethylene glycol dimethyl ether (20 cm ³ ) was stirred under nitrogen. 20 minutes. Then, (spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-on-5-yl)boronic acid (1.6 g, 6.5 mmol ) and sodium acetate (1.4 g, 13.1 mmol) in water (5 cm ³ ). The solution was refluxed for 18 hours, then cooled to room temperature, poured into 2N NaOH and extracted with ethyl acetate (x3). The combined extracts were washed with water and brine, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography ( _SiO2 , ethyl acetate, hexanes) to give the product as an off-white solid (0.45 g, 36%). Melting point: 240-242°C; ¹ H NMR (DMSO-d ₆ ) δ10.4(s, 1H), 8.5(s, 1H), 8.2(s, 1H), 7.7(s, 1H), 7.5(dd, 1H, J = 1.5 6.5 Hz), 6.9 (d, 1H, J = 8.0 Hz), 2.0-1.6 (m, 10H); MS (EI) M ⁺ @m/z 292.

According to general procedure A, 4-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole]- 5'-yl)-2-furancarbonitrile (67 mg) and Lawesson's reagent (67 mg) prepared the title compound to give the title compound (0.018 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ12 .74(s, 1H), 8.68(s, 1H), 8.26(s, 1H), 7.96(s, 1H), 7.62(dd, 1H, J = 8.0 and 1.0Hz), 7.10(s, 1H, J = 8.1 Hz), 1.94-1.78 (m, 7H) and 1.35-1.32 (m, 3H): MS ((-)-APCI) m/z 307 [MH] ^- .

Example 31

5'-(3-Chlorophenyl)spiro[cyclobutane-1,3'-[3'H]indole]-2'(1'H)-thione

5'-Bromospiro[cyclobutane-1,3'-[3'H]indole]-2'(1'H)-one: In containing spiro[cyclobutane-1,3'-[3'H]indole]-2'(1'H)-one (J.Med.Chem.1987,824-9) (1.0 g, 6 mmol) in a stirred solution of glacial acetic acid (10 ml) at room temperature A solution of bromine (0.30 mL, 6 mmol) in glacial acetic acid (6 mL) was added dropwise. 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 ether (50 mL), washed successively with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), water (50 mL) and brine (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization from diethyl ether gave the product as a white fluffy solid (1.1 g, 73%), m.p. 235-7°C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ2.15-2.41 (m, 6H), 6.74 (d, 1H, J=8.2Hz), 7.33 (dd, 1H, J=2, 8.2Hz), 7.75 ( d, 1H, J=2Hz), 10.36 (bs, 1H). MS (EI) m/z 251 [M ⁺ ]. Anal. Calcd. for _C11H10BrNO : C, 52.41; _H , 4.00; N, 5.56. Found: C, 51.98; H, 4.24; N, 5.42.

Under nitrogen, 5'-bromospiro[cyclobutane-1,3'-[3'H]indole]-2'(1'H)-one (0.6 g, 2 mmol) in ethylene di Tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.1 mmol) was added to the solution in alcohol dimethyl ether (50 mL). To this solution were added successively 3-chlorophenylboronic acid (0.48 g, 3 mmol) and potassium carbonate (0.76 g, 5 mmol) in water (5 mL). The mixture was heated at 80°C for 3 hours and then allowed to cool. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (50 mL), and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by HPLC (Zorbax PRO, C18, 10u, 15A, 50 x 250 mm; 35% H ₂ O/65% AcCN; 254 NM; room temperature) to give 5-(3-chloro Phenyl)spiro[cyclobutane-1,3-[3H]indole]-2(1H)-one (200 mg, 35%), melting point 199.5-201°C. ¹ H NMR (DMSO-d ₆ , 300MHz) δ2.21-2.28 (m, 2H), 2.40-2.45 (m, 4H), 6.87 (d, 1H, J=8.1Hz), 7.37 ('d', 1H ), 7.44-7.52 (m, 2H), 7.65 (bd, 1H, J=7.8Hz), 7.76 (bs, 1H), 7.92 (bs, 1H), 10.35 (s, 1H). MS (EI) m/z 283 [M ⁺ ]. Anal. Calcd. for _C17H14ClNO : C, 71.96; _H , 4.97; N, 4.94. Found: C, 70.75; H, 5.07; N, 4.68.

According to general procedure A, reflux 5'-(3-chlorophenyl)spiro[cyclobutane-1,3'-[3'H]indole]-2'(1'H) in toluene (10 mL) - Ketone (55 mg) and Lawesson's reagent (55 mg) to prepare the title compound gave the title compound (0.016 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.58 (brs, 1H), 8.07 (d, 1H, J = 1.5Hz), 7.82 (t, 1H, J = 1.7Hz), 7.70 (d, 1H, J = 7.74Hz), 7.60 (dd, 1H, J = 8.12 and 1.71Hz), 7.49 (t, 1H, 7.9Hz), 7.41(d, 1H, J=8.32Hz), 7.05(d, 1H, J=8.14Hz) and 2.57-2.27(m, 6H); MS((-)-APCI) m/z298/300[MH] ^- .

Example 32

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

According to general procedure A, 5′-(2-chlorophenyl)spiro[cyclohexane-1,3′-[3′Hindole]-2′(1′H)- Thione (90 mg) and Lawesson's reagent (90 mg) yielded 0.042 g of product as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.75 (brs, 1H), 7.80 (d, 1H, J= 1.1Hz) 7.58-7.55(m, 1H), 7.48-7.36(m, 4H), 7.16(d, 1H, J=8.0Hz); MS((-)-APCI) m/z326/328[MH] ^- .

Example 33

5'-(4-Chlorophenyl)spiro[cyclohexane-1,3'-[3'H]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 Lawesson's reagent (90 mg) gave 0.035 g of product as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.74 (brs, 1H), 7.91 (d, 1H, J = 1.3 Hz), 7.69 (d, 2H, J = 5.5Hz), 7.60 (dd, 1H, J = 8.1 and 1.4Hz), 7.50 (d, 2H, J = 8.5Hz), 7.15 (d, 1H, J = 8.1Hz), 1.99-1.83 ( m, 7H) and 1.50-1.36 (m, 3H); MS ((-)-APCI) m/z 326/328 [MH] ^- .

Example 34

5-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl)-4-methyl-2- Thiophenecarbonitrile

5-Bromo-4-methyl-2-thiophenecarbaldehyde : Add n-butyllithium to a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 ml) at -40°C under nitrogen (2.5M, 153 mL, 0.383 mol) in hexane. After the addition was complete, the solution was stirred at -40°C under nitrogen for 30 minutes, cooled to -78°C, and 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450 mL) was added dropwise solution is processed. The reaction solution was stirred at -78°C for 30 minutes and treated with anhydrous DMF (100 mL). The mixture was allowed to warm to room temperature and quenched with 1N aqueous hydrochloric acid (1 L). The solution was extracted with ethyl acetate (3 x 450 mL), washed with water and brine, dried ( _MgSO4 ). After removing the solvent in vacuo, the title compound was obtained as a white solid (46 g, 88.3%). A sample of the product was crystallized from hexane: 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 ⁺ ). Anal. Calcd. _{for C6H5BrOS :} C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.

5-Bromo-4-methyl-2-thiophenecarbonitrile: prepared from 5-bromo-4-methyl-2-thiophenecarbaldehyde by the procedure of Example 5. White solid: melting point 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 ⁺ , 98%/100%); Anal _. Calcd. for _C6H4BrNS : C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00; H, 2.14; N, 6.76.

According to the steps of Example 5, with (2'-oxo-[2',3'-dihydro-3',3'-dimethyl-1,3'-[3'H]indole]-5 '-yl)boronic acid (357 mg, 1.7 mmol) and 5-bromo-4-methylthiophene-2-carbonitrile (295 mg, 1.5 mmol) to give 5-(3,3-dimethyl-2- Oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile (227 mg, 0.8 mmol, 55%) white solid: melting point 192.3-193°C, ¹ H NMR (DMSO-d ₆ ) δ1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d, J=8.0Hz, 1H), 7.34 (dd, J=8.0, 1.8Hz, 1H) , 7.49 (d, J=1.7 Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); MS (EI) m/z 282 (m) ⁺ ; Anal. for C ₁₆ H ₁₄ N ₂ OS.

Reflux 5-(3',3'-dimethyl-2'-oxo-2',3'-dihydro-1'H-indol-5'-yl)-4 in toluene (20 mL) -Methylthiophene-2-carbonitrile (0.77 g, 2.39 mmol) and phosphorus pentasulfide (0.42 g, 0.96 mmol) yielded the title compound. After 3 hours, the reaction was cooled, partitioned between water and ethyl acetate, the organic layer was separated, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate-hexane gradient elution) to give the product (0.25 g, 0.73 mmol, 30%) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.82 (brs, 1H), 7.88 (s, 1H), 7.82 (d, 1H, 2Hz), 7.49 (dd, 1H, J=8.1, 1.6Hz), 7.18 (d, 1H, J=8.1Hz), 1.99- 1.80 (m, 7H) and 1.40-1.36 (m, 3H); MS ((-)-APCI) m/z 321 [MH] ^- .

Example 35

5-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol-5′-yl)-2-thiophenecarbonitrile

5-Bromo-2-thiophenecarbonitrile: Under nitrogen, make 5-bromo-2-thiophenecarbaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and A mixture of ethanol (500 mL) was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oil. The crude product was triturated twice with ice water and the resulting solid was collected by filtration. A portion of the above solid (44.31 g, 215 mmol), a mixture of copper acetate (ID monohydrate) (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated at reflux for 3 h. The solvent was removed in vacuo and the residue was Dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (2 x 30 mL), water (2 x 30 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) and allowed to crystallize. The resulting crystals were collected on a filter membrane and the filtrate was concentrated and purified by chromatography (silica gel, chloroform) to give the subtitle compound as an off-white solid (31.5 g of combined, 58% ). IR (film) cm ^-1 2200. ¹ H-NMR (CDCl ₃ ) δ7.39-7.38 (d, 1H, J = 4.1 Hz), 7.10 (d, 1H, J = 4.0 Hz); MS ( EI) m/z 187 (M ⁺ , 98%) 189 (M ⁺ , 100%).

According to the steps of Example 5, using 5-bromo-2-thiophenecarbonitrile and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indole] -5'-yl)boronic acid yields 5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indol]-5'yl) -2-thiophenecarbonitrile: melting point 225-228°C; ¹ H NMR (DMSO-d ₆ ) δ1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J=8.13Hz), 7.55 (dd, 1H, J=8.13, 1.76Hz), 7.60 (d, 1H, J=4.17Hz), 7.75 (d, 1H, J=1.76Hz), 7.93 (d, 1H, J=4.17Hz), 10.51 (s, 1H); MS ((+)APC1) m/z 309 [M+H] ⁺ .

Reflux 5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3'H]indol]-5'yl)- 2-thiophenecarbonitrile (0.69 g) and phosphorus pentasulfide (0.4 g) gave the title compound. After 3 hours, the reaction was cooled, poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was separated, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate-hexane gradient elution) to give the title compound (0.215 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.82 (brs, 1H), 8.00-7.98(m, 2H), 7.74(d, 1H, J=4.1Hz), 7.69(dd, 1H, J=8.2 and 1.6Hz), 7.14(d, 1H, J=8.1Hz), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H); MS ((-)-APCI) m/z 323 [MH] ^- .

Example 36

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

5'-(3-fluorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one: prepared according to the procedure of Example 5: melting point 171-172°C; ¹ H-NMR (CDCl ₃ ) δ8.43 (s, 1H), 7.62 (d, 1H, J=1.8Hz), 7.42 (dt, 1H, J=6.2, 2.0Hz), 7.39- 7.37(m, 1H), 7.33(dt, 1H, J=5.1, 1.3Hz), 7.26(dq, 1H, J=5.9, 2.1Hz), 7.05-6.99(m, 2H), 2.03-1.64(m, 10H); MS((+)APCI)m/z296[M+H] ⁺ .

5'-(3-fluorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one (0.70 g ) and phosphorus pentasulfide (0.4 g) to give the title compound. After 3 hours, the reaction was cooled, poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, the organic layer was separated, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate-hexane gradient elution) to give the product (0.42 g) as an off-white solid: ¹ H NMR (DMSO-d ₆ ) δ 12.75 (brs, 1H), 7.95 ( d, 1H, J=1.5Hz), 7.64(dd, 1H, J=8.13 and 1.5Hz), 7.53-7.48(m, 3H), 7.21-7.14(m, 2H), 1.99-1.83(m, 7H) and 1.40-1.37 (m, 3H); MS ((-)-APCI) m/z 310 [MH] ^- .

Example 37

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

5'-(3-hydroxyphenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H]-one: prepared according to the procedure of Example 5: melting point 213-216°C; ¹ H NMR (CDCl ₃ ) δ1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J=8Hz), 7.01-7.04 (m, 2H ), 7.23(t, 1H, J=7.7Hz), 7.38(d, 1H, J=8Hz), 7.61(s, 1H), 8.91(s, 1H) and 9.73(s, 1H, br); MS( (+)-APCI) m/z 294[M+H] ⁺ .

According to general procedure A, 5′-(3-hydroxyphenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′(1 'H)-ketone (100 mg) and Lawesson's reagent (110 mg) gave the title compound (0.0045 g) as an off-white solid: ¹ H NMR (CDCl ₃ ) δ 9.59 (brs, 1H), 7.89 (s, 1H), 7.49(dd, 1H, J=8.1 and 1.5 Hz), 7.33(t, 1H, J=7.9Hz), 7.15-7.10(m, 3H), 6.84(dd, 1H, J=8.0 and 2.2Hz ), 2.17-2.05 (m, 2H), 1.98-1.88 (m, 5H) and 1.57-1.53 (m, 3H): MS ((-)-APCI) m/z 308 [MH] ^- .

Example 38

5-(3-Chlorophenyl)-3,3-diethyl-1,3-dihydro-2H-indole-2-thione

Under nitrogen, a solution of oxindole (40 g, 0.3 mol) in dry THF (400 mL) was cooled to -25°C and n-BuLi (2.5M in hexane, 240 mL, 0.6 mol) was added dropwise to process. To the resulting solution was added N,N,N',N'-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 minutes, ethyl iodide (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 aqueous _NH4Cl , extracted with ethyl acetate (2x), the combined organic layers were washed with dilute hydrochloric acid, water and brine, dried ( _MgSO4 ) and concentrated. The oily residue was triturated with hexanes to give the crude product (24.5 g, 51%). 3 g of the sample were recrystallized from ethyl acetate/hexane to obtain 3-ethyl-indol-2-one (1.4 g), melting point 100-101°C; ¹ H-NMR (DMSO-d ₆ ) δ 0.76 (t, 3H, J=7.5Hz), 1.8-2.0(m, 2H), 3.38(t, 3H, J=5.7Hz), 6.8(dt, 1H, J=7.69, 0.45Hz), 6.93(dt, 1H, J = 7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270 [M+H].

Under nitrogen, 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF (200 mL) was cooled to -25 °C and n-butyllithium (2.5 M in hexane, 80 ml, 0.2 mol) for treatment. To the resulting solution was added N,N,N',N'-tetramethylethylenediamine (30 mL, 0.2 mol). After 30 minutes, ethyl iodide (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 _NH4Cl , extracted with ethyl acetate (2x), the combined organic layers were washed with dilute hydrochloric acid, water and brine, dried ( _MgSO4 ) and concentrated. The oily residue was triturated with hexane to give 3,3-diethylindol-2-one (9 g, 45%), melting point 156-159° C.; ¹ HNMR (DMSO-d ₆ ) δ 10.44 (s, 1H), 7.70-7.69(t, 1H), 7.62-7.59(m, 1H), 7.58(d, 1HJ=1.7Hz), 7.53-7.50(m, 1H), 7.45-7.41(t, 1H), 7.36 -7.35(m, 1H), 7.34-7.33(m, 1H), 6.91-6.89(d, 1HJ=8.2Hz), 1.87-1.80(m, 2H), 1.77-1.70(m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z 190 (M+H).

3,3-Diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 mL) were treated with bromine (6.4 g, 40 mmol) solution. After 30 minutes, the mixture was diluted with water and extracted with ethyl acetate (2x); the combined organic layers were washed with water, saturated sodium bicarbonate solution and brine, dried ( _MgSO4 ) and evaporated to give the crude product (7.6 g, 75%). The sample was recrystallized from ethyl acetate/hexane to obtain 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one with a melting point of 164-165°C; ¹ H-NMR (DMSO-d ₆ ) δ10.45(s, 1H), 7.41-7.40(d, 1H, J=2.2Hz), 7.34-7.31(m, 1H), 6.78-6.76(d, 1HJ=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), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine) palladium (O) (0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 mL), and a solution of water (25 mL) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (2x). The combined organic extracts were washed with water and brine, dried ( _MgSO4 ) and evaporated. The residue was purified by column chromatography ( _SiO2 , ethyl acetate:hexane 1:3) to give 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indole -2-Kone compound (0.8 g, 27%), melting point 195-197°C; ¹ H-NMR (DMSO-d ₆ ) δ7.70 (t, 1H, J=2Hz), 7.62-7.60 (m, 1H) , 7.58(d, 1H, J=1.7Hz), 7.52, (dd, 1H, J=8.1, 2Hz), 7.43(t, 1H, 7.9Hz), 7.36-7.33(m, 1H), 6.90(d, 1H, J=8.1 Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, J=7.4 Hz); MS (+APCI) m/z 300/302 (MH).

5-(3-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100 mg) was refluxed in toluene (10 mL) according to general procedure A and Lawesson's reagent (100 mg) gave the product (0.023 g) as a yellow solid: ¹ H NMR (DMSO-d ₆ ) δ 12.73 (brs, 1H), 7.77 (t, 1H, J=1.8Hz), 7.75(d, 1H, J=1.6Hz), 7.68-7.62(m, 2H), 7.48(t, 1H, J=7.9Hz), 7.40(d, 1H, J=8.3Hz), 7.09(d, 1H , J=8.1Hz), 2.07-2.00(m, 2H), 1.86-1.79(m, 2H) and 0.37(t, 6H, J=7.3Hz): MS((-)-APCI) m/z314/316 [MH] ^- .

Example 39

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

As described in Example 5, from (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl)boronic acid (2.5 g, 10 mmol) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 g, 8 mmol) to obtain 5′-[4-fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane Alkane-1,3'-[3'H]indol]-2'(1'H)-one gave the title compound (0.87 g, 30%) as a solid: melting point 222°C; ¹ H NMR (DMSO-d ₆ ) δ1.5-1.8(m, 8H), 1.8-2.0(m, 2H), 6.92(d, 1H, J=8.13Hz), 7.51(dd, 1H, J=8.13, 1.76Hz), 7.55( dd, 1H, J=10.54, 9.01Hz) 7.72(d, 1H, J=1.76Hz), 7.90(dd, 1H, J=7.03, 2.20Hz), 7.98(m, 1H) and 10.39(s, 1H) ; MS (EI) m/z 363 (M ⁺ ).

Reflux 5'-[4-fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3'-[3'H]indole in toluene (10 mL) according to general procedure A ]-2'(1'H)-one (90 mg) and Lawesson's reagent (90 mg) gave the product (0.016 g) as a yellow solid: ¹ H NMR (DMSO-d ⁶ ) δ 12.75 (brs, 1H), 8.06-8.00(m, 1H), 7.96-7.92(m, 2H), 7.66-7.56(m, 2H), 7.16(d, 1H, J=8.1Hz), 1.99-1.83(m, 7H) and 1.41-1.38 (m, 3H): MS ((-)-APCI) m/z 378[MH] ^- .

Example 40

4-(1′,2′-Dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol-5′-yl)-2-fluorobenzonitrile

According to general procedure A, 4-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole]- 5-yl)-2-fluorobenzonitrile (90 mg) and Lawesson's reagent (90 mg) gave the title compound (0.050 g) as an orange solid: ¹ H NMR (DMSO-d ₆ ) δ 12.80 (brs, 1H ), 8.04 (d, 1H, J = 1.3Hz), 7.98 (t, 1H, J = 7.5Hz), 7.92 (dd, 1H, J = 11.3 and 1.3Hz), 7.76 (d, 2H, J = 8.0Hz ), 7.18 (d, 1H, J=8.2Hz), 1.99-1.82 (m, 7H) and 1.40-1.38 (m, 3H); MS ((-)-APCI) m/z 335 [MH] ^- .

Example 41

5-(1',2'-dihydro-2'-thiospiro[cyclohexane-1,3'-[3'H]indol]-5'-yl)4-n-butyl-2- Thiophenecarbonitrile

The title compound was obtained in a manner similar to that of sub-example 5, making 5-bromo-4-n-butylthiophenonitrile (1.24 g, 5.1 mmol), (1′,2′-dihydro-2′-oxospiro [Cyclohexane-1,3'-[3'H]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) were heated to reflux for 5 hours to obtain 5-(1,2-dihydro-2-oxospiro[cyclohexane-1, 3-[3H]indol]-5-yl)4-n-butyl-2-thiophenecarbonitrile (1 g, 54%), melting point 130-132°C. ¹ H NMR (DMSO-d ₆ ) δ10.56(s, 1H), 7.92(s, 1H), 7.52-7.51(d, 1H, J=1.2Hz), 7.32-7.29(dd, 1H, J=1.5 Hz), 6.98-6.96(d, 1H, J=8.0Hz), 2.64-2.59(t, 2H), 1.99-1.86(m, 2H), 1.70-1.50(m, 11H), 1.32-1.22(m, 2H), 0.86-0.82(t, 3H); MS (APCI(+)) m/z 365[M+H] ⁺ ; IR(KBr) 1620, 1700; 2200cm ^-1 ; Anal. C ₂₂ H ₂₄ N ₂ OS1 /4H ₂ O. Calcd. C, 71.61; H, 6.69; N 7.59. Found C, 71.13; H, 6.61; N, 6.91.

According to general procedure A, 5-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3′H]indole]- 5'-yl) 4-n-butyl-2-thiophenecarbonitrile (90 mg) and Lawesson's reagent (90 mg) gave the title compound as an orange solid (0.050 g): ¹ H NMR (DMSO- d ₆ ) δ12.83(brs, 1H), 7.95(s, 1H), 7.77(s, 1H), 7.44(d, 1H, J=8.1Hz), 7.18(d, 1H, J=8.1Hz), 2.63(t, 1H, J.79=8.0Hz), 1.99-1.77(m, 7H), 1.60-1.50(m, 2H), 1.39-1.35(m, 3H), 1.29-1.22(m, 2H) and 0.81 (t, 3H, 7.3Hz): MS ((-)-APCI) m/z 379 [MH] ^- .

Example 42

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

According to general procedure A, 5'-(3-fluoro-5-methoxyphenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2 was refluxed in toluene (10 mL) Preparation of the title compound from '(1'H)-ketone (90 mg) and Lawesson's reagent (90 mg) afforded the product (0.043 g) as an off-white solid: ¹ H NMR (DMSO-d6) δ 12.74 (brs, 1H), 7.90(s, 1H), 7.63(dd, 1H, J=8.1 and 1.2Hz), 7.13(d, 1H, J=8.1Hz), 7.08(d, 1H, J=10Hz), 7.01(s , 1H), 6.83 (dt, 1H, J=11 and 2.0Hz), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H): MS ((-)-APCI) m/z 340 [MH] ^- .

Example 43

5′-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3′-[3′H]indole]-2′-amine

At room temperature, in 5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′(1′H)-thione (0.74 g, To 2.25 mmol) in dry THF (15 mL) was added sodium hydride (60% in oil, 0.1 g, 2.5 mmol). After 15 minutes, methyl iodide (0.18 mL, 2.88 mmol) was added. After 1 hour, the reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed with brine, dried (MgSO4) and evaporated to give 5'-(3-chlorophenyl)-2'-(methylthio) Spiro[cyclohexane-1,3'-[3'H]indole] (0.80 g, 100%) which was used without further purification:

To a solution of the last described compound (1.96 g, 5.73 mmol) in DMSO (20 mL) was added hydroxylamine (60% _H2O , 5 mL) and the mixture was heated to 120°C. After 1 hour, the reaction was cooled and partitioned between diethyl ether and saturated aqueous ammonium chloride. The organic layer was washed with water and brine, then dried (MgSO4) and evaporated. The crude was then crystallized from methanol to afford the title compound (1.67 g, 5.08 mmol, 89%) as a white solid: ¹ H NMR (CDCl3) δ 7.52 (t, 1 H, J = 1.7 Hz), 7.43-7.28 ( m, 7H), 6.83 (d, 1H, J=8Hz) and 1.98-1.51 (m, 10H); MS (ESI(+)) m/z 327/329 [M+H] ⁺ .

Example 44

N-(Acetoxy)-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′-amine

Under nitrogen, in the presence of 5-(3-chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3'-[3'H]indole]-2-amine (0.23 g, 0.71 mmol) Acetic anhydride (0.08 mL, 0.8 mmol) and 4-dimethylaminopyridine (catalytic amount) were added to a solution of dichloromethane-methanol (9:1, 10 mL). After 20 minutes, the reaction was evaporated and the product was purified by column chromatography (SiO2, methanol:dichloromethane 5:95). The product was then triturated with diisopropyl ether to give the title compound (0.12 g, 0.32 mmol, 45%): ¹ H NMR (CDCl3) δ 7.52-7.51 (m, 2H), 7.43-7.27 (m, 5H) , 6.88(d, 1H, J=8Hz), 2.27(s, 3H), 2.04-1.92(m, 4H), 1.84-1.74(m, 4H) and 1.72-1.57(m, 2H); MS(ESI( +)) m/z 369/371 [M+H] ⁺ ; C ₂₁ H ₂₁ ClN ₂ O ₂ ·0.5H ₂ O requires 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'-[3'H]indole]-2'(1'H)-ketoxime

According to the method of Example 43, from 5'-(3-fluorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-thione (0.59 g, 1.90 mmol) to obtain the title compound (0.053 g, 0.17 mmol, 10%): ¹ H NMR (DMSO-d6) δ9.59 (s, 1H), 9.40 (s, 1H), 7.57 (d, 1H, J=1.5Hz), 7.46-7.39(m, 4H), 7.11-7.05(m, 1H), 6.80(d, 1H, J=8.1Hz), 2.04-1.97(m, 2H), 1.82-1.74 (m, 2H) and 1.66-1.42 (m, 6H): MS (ESI(-)) m/z 309 [MH] ^- , C ₁₉ H ₁₉ FN ₂ O required C: 73.53, H: 6.17, N: 9.03. Found values C: 73.33, H: 6.07, N: 8.83.

Example 46

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

5'-Bromospiro{cyclohexane-1,3'-[3'H]indole}-2'(1'H)-one 2'(O-benzyl oxime). 5'-bromo-2'-(methylthio)spiro[cyclohexane-1,3'-[3'H]indole] (9.0 g, 28.98 mmol) and O-benzyl hydroxylamine hydrochloride (13.8 g, 86.9 mmol) were combined into methanol (150 mL) 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. The ethyl acetate was dried over magnesium sulfate, collected, evaporated in vacuo and the residue flash chromatographed on alumina 90 (9:1 hexane/ethyl acetate) to give the desired product (6.5 g, 60%) .

¹ H NMR (DMSO-d ₆ , 300MHz) δ1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H), 6.71 (d, 1H, J=8.26Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1H).

Step A

5'-(2-Fluorophenyl)-spiro[cyclohexane-1,3'-[3'H]indole]-2'(1H)-one 2'(O-benzyl oxime). 5′-Bromospiro{cyclohexane-1,3′-[3′H]indole}-2′(1′H)-one 2 was stirred in ethylene glycol dimethyl ether (23 mL) under nitrogen. '(O-benzyl oxime) (1.0 g, 2.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol). After 15 minutes, 2-fluorophenylboronic acid (0.72 mg, 5.2 mmol) was added, followed by sodium carbonate (1.6 g, 15.6 mmol) in water (6.0 mL). The reaction was heated to reflux overnight, cooled to room temperature, and filtered through a pad of celite. Saturated ammonium chloride was added and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried ( _MgSO4 ), filtered and the solvent was removed in vacuo. The product was purified by flash silica gel chromatography (eluent: 10:0.5 hexane:ethyl acetate) to give the desired title compound (0.75 g, 1.8 mmol, 72%) as a viscous oil. ¹ H NMR (500MHz, DMSO-d ₆ ) δ1.44-1.73 (8H, m) 1.93-2.06 (2H, q) 5.00 (2H, s) 6.88 (1H, d, J = 8.1Hz) 7.24-7.38 ( 6H, m) 7.44-7.56 (5H, m) 9.64 (1H, s); MS (ESI (+ve)) m/z 399 (MH) ^- .

Step B

Containing 5'-(2-fluorophenyl)-spiro[cyclohexane-1,3'-[3'H]indole]-2'(1H)-ketone 2'(O-benzyl oxime)( A solution of 0.55 g, 1.37 mmol) in ethanol (15 mL) was added to palladium on carbon (10%, 0.11 g) in ethanol (10 mL). The mixture was stirred at room temperature under an atmosphere of hydrogen (balloon bottle) for 24 hours. The reaction mixture was filtered through a pad 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%), melting point 200-203°C; ¹ H NMR (500 MHz, DMSO-d ₆ )δ1.45-1.73 (8H, m) 1.96-2.00 (2H, q) 6.83 (1H, d, J=7.9) 7.23-7.50 (6H, m) 9.42 (1H, s) 9.58 (1H, s); MS (ESI (+ve)) m/z 311 (M+H) ⁺ .

Example 47

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

5'-(4-Fluorophenyl)-spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one 2'(O-benzyl oxime). According to step A of Example 46, from 5'-bromospiro{cyclohexane-1,3'-[3'H]indole)-2'(1'H)-one 2'(O-benzyl oxime ) (1.0 g, 2.6 mmol) and 4-fluorophenylboronic acid (0.72 g, 5.2 mmol). The product was purified by flash chromatography on silica gel (eluent: 10:0.5 hexane:ethyl acetate) to give the desired product as a viscous oil (0.70 g, 1.7 mmol, 67%). ¹ HNMR (500MHz, DMSO-d ₆ ) δ1.42-1.77 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.84 (1H, d, J = 8.1Hz) 7.21-7.63 (1H , m) 9.58 (1H, s); MS (ESI (-ve)) m/z 399 (MH) ⁻ .

According to step B of Example 45, 5'-(4-fluorophenyl)-spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one 2 '(O-benzyl oxime) (0.70 g, 1.74 mmol) synthesized product. The product was purified by flash silica gel chromatography (hexane:ethyl acetate, gradient elution) to give the title compound (0.44 g, 1.4 mmol, 81%), melting point 205-208°C; ¹ HNMR (500 MHz, DMSO-d ₆ )δ1.43-1.77 (8H, m) 2.00-2.05 (2H, q) 6.80 (1H, d, J = 8.2Hz) 7.21-7.24 (2H, m) 7.33-7.35 (1H, dd, J = 1.9Hz ) 7.49 (1H, s) 7.60-7.63 (2H, m) 9.35 (1H, s) 9.56 (1H, s); MS (ESI (+ve)) m/z 311 (M+H) ⁺ .

Example 48

5′-(3,4-Difluorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′(1′H)-ketoxime

5'-(3,4-difluorophenyl)-spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one 2'(O-benzyl oxime). According to step A of Example 46, from 5'-bromospiro{cyclohexane-1,3'-[3H]indole}-2'(1'H)-one 2'(O-benzyl oxime)( 1.0 g, 2.6 mmol) and 3,4-difluorophenylboronic acid (1.6 g, 5.2 mmol, 50% acid in THF/ _H2O ). The product was purified by flash chromatography on silica gel (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 ) δ1.41-1.78 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.82 (1H, d) 7.28-7.46 (8H, m) 7.58 (1H, q) 7.67-7.71 (1H, m) 9.61 (1H, s); MS (ESI (-ve)) m/z 417 (MH) ^- .

The last described compound (0.70 g, 1.6 mmol) was reacted according to step B of Example 46 to afford the title compound (0.44 g, 1.3 mmol, 80%), ¹ H NMR (500 MHz, DMSO-d ₆ )δ1.42-1.79 (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'-[3'H]indole]-2'(1'H)-ketoxime

5′-(3-methoxyphenyl)-spiro[cyclohexane-1,3′-[3′H]indole]-2′(1′H)-one 2′(O-benzyl oxime ). According to step A of Example 45, from 5'-bromospiro{cyclohexane-1,3'-[3'H]indole)-2'(1'H)-one 2'(O-benzyl oxime ) (1.0 g, 2.6 mmol) and 3-methoxyphenylboronic acid (0.79 g, 5.2 mmol). The product was purified by flash chromatography on silica gel (eluent: 10:0.5 hexane:ethyl acetate) to give the desired product as a viscous oil (0.80 g, 1.9 mmol, 75%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ1.43-1.78 (8H, m) 1.95-2.00 (2H, q) 3.80 (3H, s) 5.00 (2H, s) 6.82-6.86 (2H, m) 7.10 -7.16(2H,m)7.28-7.53(10H,m)9.57(1H,s); MS(ESI(-ve))m/z411(MH) ^-

Following the procedure of Example 46, Step B, the last described compound (0.80 g, 1.9 mmol) was reacted to afford the title compound (0.48 g, 1.4 mmol, 77%) as a white solid. Melting point 101-104°C; ¹ HNMR (500MHz, DMSO-d ₆ ) δ1.44-1.78 (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'-[3'H]indole]-2'(1'H)-ketoxime 5'-(3-nitrobenzene base)-spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)-one 2'(O-benzyl oxime). According to step A of Example 45, from 5'-bromospiro{cyclohexane-1,3'-[3'H]indole}-2'(1'H)-one 2'(O-benzyl oxime ) (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 as a viscous oil (0.60 g, 1.4 mmol, 55%). ¹ HNMR (500MHz, DMSO-d ₆ ) δ1.42-1.82 (8H, m) 2.02-2.04 (2H, q) 5.01 (2H, s) 6.88 (1H, d) 7.28-7.71 (8H, m) 8.08- 8.13 (2H, m) 8.38 (1H, d) 9.69 (1H, s); MS (ESI (-ve)) m/z 426 (MH)-.

                            Step C

The last described compound (0.54 g, 1.26 mmol) was dissolved in dry dichloromethane (25 mL) and cooled to -78°C under nitrogen. Boron tribromide (3.8 mL, 3.8 mmol, 1.0 M in dichloromethane) 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 were separated, and the aqueous layer was extracted with dichloromethane. The organic _layers were combined, dried ( _Na2SO4 ), filtered and the solvent was removed in vacuo. The product was purified by flash chromatography on silica gel (eluent: 8:1 hexane:ethyl acetate) to afford the title compound (0.33 g, 0.9 mmol, 78%). Melting point 221-224°C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ1.42-1.83 (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′-[3′H]indole]-2′(1′H)-ketoxime 3-[ spiro[cyclohexane- 1,3'-[3'H]indole]-(1'H)-keto-2'-(O-benzyl oxime)]benzonitrile[3'H]indol-5'-yl]benzonitrile . According to step A of Example 46, from 5'-bromospiro{cyclohexane-1,3'-[3'H]indole}-2'(1'H)-one 2'(O-benzyl oxime ) (1.0 g, 2.6 mmol) and 3-cyanophenylboronic acid (0.76 g, 5.2 mmol). The product was purified by flash chromatography on silica gel (eluent: 10:0.5 hexane: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 ) δ1.41-1.81 (8H, m) 1.96-2.03 (2H, q) 5.01 (2H, s) 6.86 (1H, d) 7.28-7.33 (9H, m) 7.95-7.97 (1H, d) 8.12 (1H, s) 9.65 (1H, s); MS (ESI (-ve)) m/z 406 (MH) ^- .

Following step C of Example 50, the last described compound (0.17 g, 0.43 mmol) was reacted with boron tribromide (1.2 mL, 1.2 mmol) to give the title compound (0.06 g, 0.2 mmol) as a white solid (0.06 g, 0.2 mmol, 47%), melting point 198-200°C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ1.41-1.80 (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′-[3′H]indol]-5′yl]-5-fluorobenzonitrile

To a solution of 3-fluoro-5-cyano-bromobenzene (0.4 g, 2.0 mmol) in dry DMF (10 mL) was added diboron pinacolate ester (0.63 g, 2.5 mmol) , potassium acetate (0.65 g, 6.7 mmol) and PdCl ₂ (dppf) (0.2 g), the reaction was heated to 80° C. under nitrogen. After 8 hours, 5′-bromospiro{cyclohexane-1,3′-[3H]indole}-2′(1′H)-one 2′(O-benzyl oxime) (0.2 g, 0.5 mmol), PdCl ₂ (dppf) (0.05 g) and sodium carbonate (1.30 g, 12.5 mmol), continue heating at 80°C. After 8 hours, the reaction was cooled, partitioned between water and ethyl acetate, the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:20) to give the desired product (0.14 g, 0.33 mmol, 66%).

According to Step C of Example 59, the last described compound (0.14 g, 0.33 mmol) was reacted with boron tribromide (1.0 mL, 1.0 mmol) to afford the title compound (0.019 g, 0.05 mmol, 17% ): ¹ HNMR (300MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 9.49 (s, 1H), 8.04 (m, 1H), 7.89 (dt, 1H, J=10.5 and 2Hz), 7.72- 7.68(m, 2H), 7.54(d, 1H, J=8.1Hz), 6.80(d, 1H, J=8.1Hz), 2.05-1.99(m, 2H), 1.84-1.76(m, 2H) and 1.65 -1.44 (m, 6H): MS (ESI (+ve)) m/z 336 (M+H) ⁺ .

Example 53

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

4-Methyl-5-trimethylstannyl-thiophene-2-carbonitrile. Under nitrogen, from 5-bromo-4-methyl-thiophene-2-carbonitrile (3.08 g, 15.2 mmol), tetrakis(triphenylphosphine)palladium(O) (0.82 g, 0.71 mmol), hexa Methyl ditin (5.0 g, 15.2 mmol) and ethylene glycol dimethyl ether (20 ml) were prepared. The mixture was heated to reflux for 14 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (eluent: 2% MeOH:dichloromethane) to recover the desired product as a free flowing oil (2.8 g, 0.01 mmol, 67%). 1H 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 triphenylene were stirred in DME (8.0 mL) under nitrogen. Arsenic (0.03 g, 0.13 mmol) for 20 minutes. Add 5′-bromospiro{cyclohexane-1,3′-[3′H]indole}-2′(1′H)-one 2′(O-benzyl oxime) (0.18 g, 0.64 mg mol) in DME (2.0 mL). The solution was heated to reflux overnight. The reaction solution was concentrated in vacuo and purified by flash silica gel chromatography (eluent 12:1 hexane:ethyl acetate) to give the crude product (0.10 g, 0.25 mmol, 50%) which was used without further purification

Boron tribromide (2.6 mL, 2.6 mmol, 1.0 M solution in dichloromethane) was added to a solution of the last described product (0.37 g, 0.86 mmol) in dry dichloromethane (1.7 ml) in the solution. The solution was stirred for 30 minutes and quenched with saturated sodium bicarbonate (10 mL). The mixture was warmed to room temperature and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a 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% ): melting point 173-176°C; ¹ H NMR (500MHz, DMSO-d ₆ ) δ1.44-1.73 (8H, m), 1.96-2.00 (2H, m), 2.28 (3H, s), 6.82-6.84 ( 1H, m), 7.24-7.26 (1H, dd, J=1.7Hz), 7.38 (1H, m) 7.82 (1H, m) 9.51 (1H, m) 9.66 (1H, m); MS (ESI (+ve )) m/z 338(M+H) ⁺ .

Example 54

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

To a solution of 2-cyanothiophene (1.0 g, 9.16 mmol) and triisopropyl borate (2.3 mL, 10 mmol) in dry THF (30 mL) was added hexamethanone dropwise at -78 °C under nitrogen. Lithium disilazane (1M in THF, 10 mL, 10 mmol). After 30 min, the reaction was quenched with 1N HCl, then extracted with ethyl acetate, the organic layer was washed with water, dried (Na2SO4) and evaporated to give the product (1.25 g, 8.17 mmol, 89%) which was carried on without further purification Use: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.75 (brs, 2H), 7.97 (d, 1H, J = 8Hz) and 7.73 (d, 1H, J = 8Hz): MS (ESI (- ve))m/z152(MH) ^- .

Following step A of Example 46, from the last described product (0.91 g, 5.95 mmol) and 5'-bromospiro{cyclohexane-1,3'-[3'H]indole}-2'(1 Prepared from 'H)-one 2' (O-benzyl oxime) (1.53 g, 3.97 mmol). Purification by flash chromatography on silica gel (eluent: 5:1 hexane:THF) gave the desired product (0.66 g, 1.59 mmol) which was used without further purification: MS (ESI(-ve))m /z412(MH) ^- .

According to Example 50, Step C, the last described compound (0.60 g, 1.45 mmol) was reacted with boron tribromide (1M in dichloromethane, 5 mL, 5 mmol) to afford the title compound (0.036 g, 0.11 mmol, 8%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, J=3.9Hz), 7.63 ( d, 1H, J = 1.5Hz), 7.54 (d, 1H, J = 3.9Hz), 7.47 (dd, 1H, J = 8.1 and 1.6Hz), 6.78 (d, 1H, J = 8.1Hz), 2.13- 1.90 (m, 2H) and 1.78-1.60 (m, 6H): MS (ESI (+ve)) m/z 324 (M+H) ⁺ .

Example 55

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

4-(Trimethylstannyl)-2-thiophenecarbonitrile made 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis(triphenylphosphine)palladium (O) (0.25 g, 0.2 mmol) and hexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm ³ ) was heated at reflux for 14 hours and then cooled to room temperature. The reaction mixture was adsorbed on a magnesium silicate support and purified by column chromatography (SiO ₂ , dichloromethane:hexane 1:9) to give the subtitle compound (1.04 g, 3.8 mmol, 90%) as a clear viscous oil: 1H NMR (CDCl ₃ ) δ 0.35 (s, 9H), 7.56 (d, J=0.9Hz, 1H), 7.66 (d, J=0.9Hz, 1H).

Under nitrogen, in the presence of 5'-bromospiro{cyclohexane-1,3'-[3'H]indole}-2'(1'H)-one 2'(O-benzyl oxime) (1.65 g, 4.28 mmol), 4-(trimethylstannyl)-2-thiophenecarbonitrile (1.48 g, 5.44 mmol), triphenylarsenic (330 mg) in dry dimethoxyethane (20 mL) solution, bis(triphenylphosphine)palladium(II) chloride was added, and 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 (SiO2, ethyl acetate:hexanes, gradient elution) to give the desired product (0.61 g, 1.47 mmol, 56%).

Following step C of Example 50, the last described compound (0.61 g, 1.47 mmol) was reacted with boron tribromide (1M in dichloromethane, 4.5 mL, 4.5 mmol) to afford the title compound (0.084 g, 0.26 mmol, 18%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.65 ( s, 1H), 7.48 (dd, 1H, J = 8.1 and 0.9Hz), 6.76 (d, 1H, J = 8.1Hz), 2.03-1.96 (m, 2H) and 1.78-1.42 (m, 6H): MS (ESI(+ve))m/z324(M+H) ⁺ .

Example 56

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

2-{5'[spiro[cyclohexane-1,3'-[3'H]indole]-(1'H)-one-2'(O-benzyl oxime)]}-1H-pyrrole- tert-Butyl 1-carboxylate. 5'-bromospiro{cyclohexane-1,3'-[3H]indole)-2'(1'H)-one 2'(O-benzyl oxime) (7.4 g, 19.17 mmol) and A solution of tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.00 mmol) in DME (100 mL) was stirred under nitrogen for 15 min. To this solution were added 1-tert-butoxycarbonylpyrrole boronic acid (5.5 g, 26 mmol) and 1M sodium carbonate (50 mL). The mixture was heated at 80°C for 6 hours and then allowed to cool. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo and the residue was flash chromatographed on silica gel (4.5:1 hexane/ethyl acetate) to give the product as a white solid (7.7 g, 88%). ¹ H NMR (DMSO-d6, 300MHz) δ1.28(s, 9H), 1.55-1.66(m, 8H), 1.83-1.98(m, 2H), 4.99(s, 2H), 6.12-6.14(m, 1H), 6.22(t, 1H, J=3.26Hz), 6.76(d, 1H, J=7.9Hz), 7.02(dd, 1H, J=7.98, 1.4Hz), 7.19(s, 1H) 7.27-7.31 (m, 2H), 7.35 (t, 1H, J=6.8Hz), 7.43(d, 1H, J=8Hz), 9.55(s, 1H).

5'-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3'H]indole]-2'-(1'H)one-2 tert-butyl '-(O-benzyl oxime)-1'-carboxylate. Containing 2-{5'[spiro[cyclohexane-1,3'-[3H]indole]-(1'H)-one-2'(O-benzyl oxime)]}-1H-pyrrole- To a solution of tert-butyl 1-carboxylate (7.7 g, 16.38 mmol) in THF (anhydrous, 100 mL) was added sodium hydride (0.665 g, 17 mmol), and after hydrogen evolution had ceased, di-tert-butyl dicarbonate was added Ester (10.9 g, 50 mmol) and DMAP (0.20 g), the reaction was stirred at 65°C for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to afford the product (9.0 g, 15.76 mmol), which was used directly in the next step.

At -78°C, in the 5'-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3'H]indole]-2'- (1′H)ketone-2′-(O-benzyl oxime)-1′-carboxylate tert-butyl ester (9.0 g, 15.76 mmol) in THF (anhydrous, 75 mL) was added chlorosulfoisocyanate Acyl ester (1.55 mL, 17.54 mmol). 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 (2 x 100 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (10% ethyl acetate/hexanes) afforded 5'-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane- 1,3'-[3'H]indole]-2'(1'H)one-2'(O-benzyl oxime)-1'-carboxylate tert-butyl ester (7.6 g, 82%) white powder . ¹ H NMR (DMSO-dy, 300MHz) δ1.30(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-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)ketone-2'-( O-benzyl oxime)-1'-carboxylate tert-butyl ester. Containing 5'-(5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1 'H) To a solution of tert-butyl keto-2'(O-benzyl oxime)-1'-carboxylate (7.6 g, 3.25 g, 48 mmol) in THF (anhydrous, 30 mL) was added sodium ethoxide containing ethanol (120 ml) solution. The reaction mixture was heated to 80-°C and stirred overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product (6.1 g, 95%). ¹ H NMR (DMSO, 500MHz) δ1.38(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 =.8Hz), 6.98-6.99(d, 1H, J=.7Hz), 7.29-7.37(m, 1H), 7.35(m, 2H), 7.42(m, 3H), 7.63(dd, 1H, J= 1.8, .3Hz), 7.76 (d, 1H, J=.4Hz).

5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3′H]indole]-2′-(O-benzyl oxime)-1′-tert-butyl carboxylate. Containing 5'-(5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3'H]indole]-2'(1'H)ketone-2' Potassium carbonate (6.5 g, 47 mmol) and methyl iodide (1 mL, 15.4 mmol), and the reaction mixture was stirred at room temperature for 2.5 hours. 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 desired product was obtained (6.1 g, 12.29 mmol) which was used directly in the next step without further purification. ¹ HNMR (DMSO, 300MHz) δ1.38(s, 9H), 1.62-1.98(m, 10H), 3.71(s, 3H), 5.08(s, 2H), 6.34(d, 1H, J=4.1), 7.03 (d, 1H, J=3.99), 7.30-7.53 (m, 8H).

5-{5′-spiro[cyclohexane-1,3′-[3′H]indole]-(1′H)-one-2′-(O-benzyl oxime)}-1H-pyrrole- 1-Methyl-2-carbonitrile. 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3′H]indole]-2′-(O-benzyl Oxime)-1′-carboxylate tert-butyl ester (6.1 g, 12.29 mmol) was dissolved in dioxane (5 ml), and 4 M HCl-containing dioxane (10 ml) was added, and the reactant was dissolved at 45 °C for 3.5 hours. The mixture was carefully neutralized with saturated sodium bicarbonate. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo. Purification by column chromatography on silica gel (5% ethyl acetate/hexanes) afforded the product (4.36 g, 94%). ¹ H NMR (DMSO-d6, 300MHz) δ1.57-1.7 (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)

At -78°C, in the presence of 5-{5'-spiro[cyclohexane-1,3'-[3'H]indole]-(1'H)-keto-2'-(O-benzyl Oxime)}-1H-pyrrole-1-methyl-2-carbonitrile (4.36 g, 10.6 mmol) in dichloromethane (50 mL) was added 1M boron tribromide (35 mL in dichloromethane) . The reaction mixture was allowed to warm 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 (2 x 100 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 hexane/ethyl acetate) to afford the title compound (1.35 g, 40%) as a white solid. ¹ H NMR (DMSO-d6, 300MHz) δ1.58-1.71 (m, 8H), 1.99-2.00 (m, 2H), 3.69 (s, 3H) 6.24 (d, 1H, J=4.07Hz), 6.8 ( d, 1H, J=8.05Hz), 6.99(d, 1H, J=4.01Hz), 7.20(dd, 1H, J=8.04, 1.57Hz), 7.36(d, 1H, J=1.12Hz), 9.48( s, 1H), 9.62 (s, 1H).

Example 57

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

5-(spiro[cyclohexane-1,3'-[3'H]indole]-2'(1H)-(O-benyloxime))-1H-pyrrole-2-carbonitrile. 5-{5'-spiro[cyclohexane-1,3'-[3H]indole]-(1'H)-one-2'-(O-benzyl oxime)}-1H-pyrrole- Procedure for 1-methyl-2-carbonitrile from 5'-(5-cyano-1H-pyrrol-2-yl)spiro [Cyclohexane-1,3'-[3H]indole]-2'(1'H)-2'-(O-benzyl oxime)-1'-carboxylic acid tert-butyl ester (0.395 g, 0.796 mmol), the desired product (0.220 g, 0.745 mmol, 95%) was obtained. ¹ H, NMR (DMSO-d6, 500 MHz) δ1.44-1.50 (m, 1H), 1.61-1.70 (m, 7H), 1.94-1.99 (m, 2H), 5.0 (s, 2H), 6.55 ( d, 1H, J=4Hz), 6.79(d, 1H, J=8.0Hz), 6.95(d, 1H, J=4Hz), 7.27-7.31(m, 1H), 7.34-7.37(m, 2H), 7.42-7.43 (m, 2H), 7.47 (dd, 1H, J = 8.0, 1.4Hz), 7.65 (d, 1H, J = 1.5Hz), 9.65 (s, 1H), 12.4 (s, 1H).

According to 5-(spiro[cyclohexane-1,3'-[3'H]indole]-2'-(hydroxyimino)-5'-yl)-1H-pyrrole-1-methyl-2- The step of carbonitrile, from 5-(spiro[cyclohexane-1,3′-[3′H]indole]-2′(1′H)-(O-benzyl oxime))-1H-pyrrole- 2-Carbonitrile (0.325 g, 0.82 mmol) and 1M boron tribromide (6 mL in dichloromethane) gave the title compound as an off-white solid (0.110 g, 0.326 mmol, 44%). ¹ H, NMR (DMSO-d6, 500 MHz) δ1.46-1.5(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=8.0Hz), 6.94(d, 1H, J=3.47Hz), 7.45(dd, 1H, J=8.1, 1.73Hz), 7.63(d, 1H, J=1.73 ), 9.42(s, 1H), 9.59(s, 1H), 12.39(s, 1H).

Example 58

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

At room temperature, in 4-(spiro[cyclohexane-1,3'-[3'H]indole]-2'(hydroxyimino)-5'-yl)-2-thiophenecarbonitrile (2.21 g, 6.83 mmol) and acetic anhydride (1 mL) in dichloromethane-pyridine (30 mL, 9:1) was added 4-dimethylaminopyridine (250 mg). After 3 hours, the mixture was diluted with dichloromethane, washed with water, dilute hydrochloric acid and water, dried (MgSO4) and evaporated. The residue was purified by column chromatography (ethyl acetate:hexanes, 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'-(hydroxylamino)spiro[cyclohexane-1,3'-[3'H]indole]-5'-yl]benzimidic acid amide

(carboximidamide)

5'-(3-cyano-5-fluorophenyl)-2-(methylthio)spiro[cyclohexane-1,3'-[3'H]indole]. According to the procedure described in Example 43, from 3-(1′,2′-dihydro-2′-thiospiro[cyclohexane-1,3′-[3′H]indol]-5′-yl )-5-fluorobenzonitrile (0.451 g, 1.34 mmol) yielded the desired product (0.316 g, 0.90 mmol, 67%): ¹ H NMR (DMSO, 300 MHz) δ7.74 (d, 1H, J =1.7Hz), 7.68(t, 1H, J=1.4Hz), 7.58(d, 1H, J=8.0Hz), 7.54(t, 1H, J=2.3Hz), 7.50(dd, 1H, J=8.0 and 1.9Hz), 7.33-7.29(m, 1H), 2.67(s, 3H), 2.04-1.78(m, 7H) and 1.58-1.50(m, 3H); MS(ESI(+ve))m/z351 (M+H) ⁺ .

To a solution of the last described product (0.30 g, 0.88 mmol) in DMSO (10 mL) was added hydroxylamine (50% in water, 1 mL) and the reaction was heated to 120°C. After 1 hour, the mixture was cooled and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, 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=1.3Hz), 7.46(dd, 1H, J=8.3 and 1.5Hz) , 7.34(d, 1H, J=10Hz), 6.81(d, 1H, J=8.0Hz), 6.01(s, 2H), 2.11-2.02(m, 2H) and 1.81-1.56(m, 8H): MS (ESI(+ve))m/z369(M+H) ⁺ .

Example 60

N'-Hydroxy-5-(spiro[cyclohexane-1,3'-[3'H]indole]-2'(hydroxyimino-5'-yl)-4-methyl-2-thienyl imine acid amide

4-methyl-5-(spiro[cyclohexane-1,3'[3'H]indole]2'-(methylthio)-5'-yl)-2-thiophenecarbonitrile. In THF containing potassium tert-butoxide (0.32 g, 2.6 mmol) was added 5-(1′,2′-dihydro-2′-thiospiro[cyclohexane-1,3′-[3H]indole ]-5'-yl)-4-methyl-2-thiophenecarbonitrile (0.84 g, 2.5 mmol). After 15 minutes, methyl iodide (0.50 g, 3.48 mmol) was added. After 3 hours, the reaction was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo and the residue was flash chromatographed on silica gel (4:1 hexane/ethyl acetate) to give the desired product (0.530 g, 85%). (DMSO, 300MHz) δ1.48(m, 3H), 1.70(m, 2H), 1.81(m, 5H), 2.32(s, 3H), 2.62(s, 3H), 7.48(dd, 1H, J= 7.87Hz, 1.46Hz), 7.5(d, 1H, J=8.05Hz), 7.77(d, 1H, J=1.46Hz), 7.88(s, 1H).

In 4-methyl-5-(spiro[cyclohexane-1,3'[3'H]indole]2'-(methylthio)-5'-yl)-2-thiophenecarbonitrile (0.450 g, 1.3 mmol) in DMSO (1 mL) was added hydroxylamine hydrochloride (2 mL, 50% solution in water) and heated at 100°C for 2.5 hours. Water was added until the solution became slightly cloudy, and the mixture was cooled to room temperature. The white solid was filtered, collected and dissolved in ethyl acetate and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to afford (0.320 g, 69%). (DMSO-d6, 500MHz) δ1.4-1.74(m, 8H), 1.94-2.49m, 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'-[3'H]indole]-2'-(hydroxyimino)-5'-yl 2-thiophene carboximide acid amide

According to the steps of Example 60, 4-(spiro[cyclohexane-1,3'-[3'H]indole]-2'-(methylthio)-5'-yl]-2-thienyl Nitrile (0.077 g, .237 mmol) was reacted with 50% solution of hydroxylamine (1 mL) to give the title compound (0.016 g, 0.044 mmol, 20%). MS (ESI, (+VE)) m/z 357[ M+H] ⁺ .

Example 62

N'-Hydroxy-5-(spiro[cyclohexane-1,3'-[3'H]indole]-2'-(hydroxyimino)-5'-yl)-2-thiophenecarboximidic acid Amide

According to the steps of Example 60, from 5-(spiro[cyclohexane-1,3'-[3'H]indole]2'-(methylthio)-5'-yl]-2-thiophenecarbonitrile (0.500 g, 1.5 mmol) and 50% hydroxylamine solution (2 ml, excess) to prepare the title compound to give the product (0.200 g, 0.56 mmol, 56%). ¹ H NMR (DMSO-d6, 500 MHz) δ1. 45-1.75m, 8H), 1.97-2.06(m, 2H), 5.89(s, 1H), 6.74(d, 1H, J=8Hz), 7.3(d, 1H, J=3.9Hz), 7.34(dd , 1H, J=8.06, 1.46Hz), 7.4(d, 1H, J=8.0Hz), 7.5(d, 1H, 1.95Hz), 9.44(s, 1H), 9.58(s, 1H), 9.6(s , 1H).

Example 63

5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3'H]indoline]-2'-ylcyanamide

5'-(3-Chlorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'-amine . In 25 containing 5'-(3-chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3'-[3'H]indole]-2'-amine (0.500 g; 1.53 mmol) To the cloudy solution in mL of ethanol was added hydrazine hydrate (0.600 mL; 12.24 mmol). The solution was allowed to warm to 55°C at which time Raney nickel (50% in water) was added to the reaction, maintaining constant gas evolution. After 45 minutes, the hot reaction mixture was filtered through a pad of celite, washing with copious amounts of hot methanol. The filtrate was concentrated in vacuo to yield 0.890 g of an opaque solid. The product was purified by flash chromatography on silica gel (eluent, 2%-8% methanol-methylene chloride with 0.1% ammonium hydroxide) to afford 0.310 g (65%) of the desired product as a white solid. The melting point is 118-120°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H), 7.1 (br, 2H, 2NH), 7.31-7.34 (dt, 1H, J=8Hz), 7.41-7.46(t, 2H), 7.55-7.58(d, 1H), 7.62(s, 1H), 7.72(s, 1H); MS(ECI(+ve)) m/z 311(M+H) ⁺ .

1-tert-butoxycarbonyl-5'-(3-chlorophenyl)spiro[cyclohexane-1,3'-[3'H]indole]-2'-amine. At 0°C, in dry solution containing 5'-(3-chlorophenyl)spiro[cyclohexane-1,3-[3'H]indole]-2'-amine (0.310 g; 0.96 mmol) Di-tert-butyl dicarbonate (0.252 g; 1.15 mmol) and 4-dimethylaminopyridine (0.117 g; 0.96 mmol) were added to dichloromethane. The solution was warmed to room temperature and stirred for 24 hours. The reactant solution was diluted with water (50 mL) and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 0.355 g of a yellow oil. The product was purified by flash chromatography on silica gel (eluent, 1%-3% methanol-dichloromethane) to give the desired product as a white solid (0.081 g, 20%). ¹ H NMR (300MHz, DMSO-d ₆ ) δ1.58(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, 1H, NH). MS (ECI (+ve)) m/z 411 (M+H) ⁺ .

At 0°C, 1′-tert-butoxycarbonyl-5′-(3-chlorophenyl)spiro[cyclohexane-1,3′-[3′H]indole]-2′-amine ( 0.120 g; 0.29 mmol) in 2.0 mL of dry DMF was added to a solution of 4-dimethylaminopyridine (0.089 g; 0.73 mmol) and cyanogen bromide (0.077 g; 0.73 mmol) in 4.0 mL of dry DMF. The yellow solution was heated to 40°C for 16 hours. Work-up included pouring the reaction solution into 0.1 N _NaHCO3 (50 mL), and extraction with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.091 g of a yellow residue. The product was purified by flash silica gel chromatography (step gradient of 5:1 to 3:1 hexane:ethyl acetate) to afford 0.031 g (32%) of the product as a bright yellow solid. The melting point is 225°C (decomposition). ¹ H NMR (500MHz, DMSO-d ₆ ) δ1.46-1.73 (m, 8H), 1.89-1.90 (m, 2H), 7.13-7.16 (d, 1H), 7.38-7.41 (dt, 1H, J= 8Hz), 7.45-7.50(m,1H), 7.60-7.63(dd,2H, J=6.4Hz), 7.71(s,1H), 7.85(s,1H), 12.1(s,1H,NH); MS (ECI(-ve))m/z336(MH) ^- .

Other desired compounds that can be prepared according to the methods described herein include: 5'-(3-cyano-5-fluorophenyl)spiro[cyclohexane-1,3'-[3H]indoline] -2'-ylcyanamide, 5'-(5-cyano-1H-pyrrol-2-yl)spiro[cyclohexane-1,3'-[3H]dihydroindoline]-2'-yl Cyanamide, 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]dihydroindoline]-2′-yl Cyanamide, 5'-(5-cyano-thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indoline]-2'-ylcyanamide, 5'-( 5-cyano-3-methyl-thiophen-2-yl)spiro[cyclohexane-1,3'-[3H]indoline]-2'-ylcyanamide, 5'-(5- Cyano-thiophen-3-yl)spiro[cyclohexane-1,3′-[3H]dihydroindoline]-2′-ylcyanamide, 3-(2′-cyanomethylene-spiro [Cyclohexane-1,3'-[3H]indol]-5'-yl)-5-fluoro-benzonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1, 3'-[3H]indole]-5'-yl)-1H-pyrrole-2-carbonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H ]indole]-5'-yl)-1-methyl-1H-pyrrole-2-carbonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H ]indole]-5'-yl)-thiophene-2-carbonitrile, 5-(2'-cyanomethylene-spiro[cyclohexane-1,3'-[3H]indole]-5' -yl)-4-methyl-thiophene-2-carbonitrile, 4-(2′-cyanomethylene-spiro[cyclohexane-1,3′-[3H]indole]-5′-yl )-thiophene-2-carbonitrile.

All publications cited in this specification are incorporated herein by reference. Although the invention has been described in terms of preferred embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are within the scope of the appended claims of the invention.

Claims (13)

1. compound with following formula, or its pharmacy acceptable salt:

Wherein:

R ₁And R ₂Independently be selected from C ₁-C ₆The C that alkyl, phenyl replace ₁-C ₆Alkyl;

Or R ₁And R ₂Be connected to form and comprise-CH ₂(CH ₂) _nCH ₂-ring;

N is integer 1-5;

R ₃Be selected from H, OH and COR ^A

R ^ABe C ₁-C ₃Alkoxyl group;

R ₄Be H;

R ₅Be selected from a) and b):

A) contain substituent X, the phenyl ring of the replacement as follows of Y and Z:

X is selected from H, halogen, OH, CN, C ₁-C ₄Alkyl, C ₁-C ₃Alkoxyl group, NO ₂, C ₁-C ₃Perfluoroalkyl and C (=N-OH)-NH ₂

Y and Z independently are selected from H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl group and C ₁-C ₄Alkyl;

Wherein X, Y and Z not all are H also;

B) contain 1 in the skeleton and be selected from O, S or NR ⁶Heteroatomic pyridine ring, furan nucleus, thiphene ring, pyrrole ring, or pyrimidine ring, these heterocycles contain 1 or 2 and are selected from following independent substituting group: H, halogen, CN, C ₁-C ₄Alkyl, CSNH ₂And C (=N-OH)-NH ₂

R ⁶Be H, do not exist, COR ^DOr C ₁-C ₄Alkyl; R ^DBe C ₁-C ₄Alkoxyl group; With

Q ¹Be S or NR ₇

R ₇Be H or OR ₁₁

R ¹¹Be H or C (O) (C ₁-C ₃Alkyl).

2. compound according to claim 1, it is characterized in that, it is selected from 5 '-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime, 5 '-(2-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime, 5 '-(4-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime, 5 '-(3, the 4-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime, 5 '-(3-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime, 5 '-(3-nitrophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime, with 5 '-(3-cyano-phenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-ketoxime or its pharmacy acceptable salt.

3. compound according to claim 1, it has following formula:

Wherein:

R ₅Be phenyl ring with replacement of following formula:

Wherein:

X is selected from H, halogen, CN, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl, NO ₂And C ₁-C ₃Perfluoroalkyl;

Y 4 ' or 5 ' position on, it is selected from: H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl group and C ₁-C ₃Alkyl;

Wherein X and Y not all are H.

4. compound according to claim 1, it has following formula:

Wherein:

R ₅Be to have 5 yuan of rings that show structure down:

Wherein:

U is O, S or NR ₆

R ₆Be H or C ₁-C ₃Alkyl;

X ' is selected from halogen, CN and C ₁-C ₃Alkyl;

Y ' is selected from H, halogen and C ₁-C ₃Alkyl;

Wherein said halogen is F.

5. compound according to claim 1, it has following formula:

Wherein:

R ₅Be 6 yuan of rings with following structure

X ¹Be CX ²,

X ²Be halogen or CN.

6. compound according to claim 1, it is selected from 5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 3-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl) benzonitrile, 4-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-2-thiophene formonitrile HCN, 3-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-5-fluorine benzonitrile, 4-methyl-5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H]-indoles]-5 '-yl)-2-thiophene thioamides, 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [pentamethylene-1,3 '-[3 ' H] indoles]-5 '-yl)-1 ' H-pyrroles-2-formonitrile HCN, 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-1 ' H-pyrroles-2-formonitrile HCN, 5-(2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-1-methyl-pyrroles-2-formonitrile HCN, 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [pentamethylene-1,3 '-[3 ' H] indoles]-5 '-yl)-3-thiophene formonitrile HCN, 5-(1 ', 2 '-dihydro-sulfo-spiral shell (pentamethylene-1,3 '-[3 ' H] indoles)-5 '-yl)-2-thiophene formonitrile HCN, 5-(3-fluoro-4-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5-(2-amino-5-pyrimidyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 3-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [pentamethylene-1,3 '-[3 ' H] indoles]-5 '-yl)-5-fluorine benzonitrile, 3-(1 ', 2 '-dihydro-2-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-the 2-yl)-4-fluorine benzonitrile, 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-yl)-the 3-pyridine carbonitrile, 5 '-(3, the 4-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-(5-chloro-2-thienyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-3-furans formonitrile HCN, 5-(3-chloro-4-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-(3-chloro-5-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-(3, the 5-difluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-4-propyl group-2-thiophene formonitrile HCN, 5 '-(3-fluoro-4-nitrophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 4-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-2-furans formonitrile HCN, 5 '-(3-chloro-phenyl-) spiral shell [tetramethylene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-(2-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-(4-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-4-methyl-2-thiophene formonitrile HCN, 5 '-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-2-thiophene formonitrile HCN, 5 '-(3-fluorophenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5-(3-hydroxy phenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 5 '-[4-fluoro-3-(trifluoromethyl) phenyl] spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 4-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-2-fluorine benzonitrile, 5 '-(3-fluoro-5-p-methoxy-phenyl) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 ' (1 ' H)-thioketones, 3-[1 ', 2 '-dihydro-2 '-(oxyimino) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl]-5-fluorine benzonitrile, 5-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-4-methyl-2-thiophene formonitrile HCN, 5-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-2-thiophene formonitrile HCN, 4-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-2-thiophene formonitrile HCN, 5-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-1H-pyrroles-1-methyl-2-formonitrile HCN, 5-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-1H-pyrroles-2-formonitrile HCN, 4-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(acetoxyl group imino-)-5 '-yl)-2-thiophene formonitrile HCN, 3-fluoro-N '-hydroxyl-5-[2 '-(hydroxyl amino) spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl] the benzenecarboximidic acid acid amides, N '-hydroxyl-5-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-4-methyl-2-thiophene azomethine acid acid amides, N '-hydroxyl-4-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-2-thiophene azomethine acid acid amides, N '-hydroxyl-5-(spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-2 '-(oxyimino)-5 '-yl)-2-thiophene azomethine acid acid amides, 5 '-(3-chloro-phenyl-) spiral shell [hexanaphthene-1,3 '-[3 ' H] indylidene]-2 '-the Ji cyanamide, 5-(3-chloro-phenyl-)-3,3-dimethyl-1,3-dihydro-2H-indoles-2-thioketones, 3-benzyl-5-(3-chloro-phenyl-)-3-methyl isophthalic acid, 3-dihydro-2H-indoles-2-thioketones, 4-(3,3-dimethyl-2-sulfo--2,3-dihydro-1H-indoles-5-yl)-2-furyl formonitrile HCN, 5-(3-p-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-2H-indoles-2-thioketones, 5-(3-chloro-phenyl-)-3,3-diethyl-1,3-dihydro-2H-indoles-2-thioketones or their pharmacy acceptable salt.

7. compound according to claim 1, it be 5-(1 ', 2 '-dihydro-2 '-sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-1-(tertbutyloxycarbonyl)-pyrroles-2-formonitrile HCN or 5-(1 ', 2 '-dihydro-2 '-the sulfo-spiral shell [hexanaphthene-1,3 '-[3 ' H] indoles]-5 '-yl)-4-normal-butyl-2-thiophene formonitrile HCN or its pharmacy acceptable salt.

8. compound according to claim 1, wherein R ₅Be thiophene or furans.

9. pharmaceutical composition that is used in conjunction with progesterone receptor, it comprises the described compound of claim 1 or its pharmacy acceptable salt, and pharmaceutically acceptable carrier or vehicle.

10. the described compound of claim 1 or its described acceptable salt are used for giving the application that mammalian object is treated the hemorrhage medicine of described object functionality dysfunctional in preparation.

11. described compound of claim 1 or described acceptable salt are used for giving the application that mammalian object is treated the medicine of described object uterine endometrium, ovary, breast, colon or prostatic cancer and gland cancer in preparation.

12. described compound of claim 1 or described acceptable salt are used for giving the application of mammalian object as the medicine of contraceptive bian in preparation.

13. the application of described compound of claim 1 or the described acceptable salt medicine of hormone replacement therapy after preparation is used for giving mammalian object to carry out menopause.