EA005034B1 - Thio-oxindole derivatives - Google Patents

Abstract

1. A compound of the formula: wherein: R1 and R2 are chosen independently from the group of H, C1-C8 alkyl, substituted C1-C8 alkyl; OH, O (C1-C8 alkyl), O(substituted C1-C8 alkyl), OAc, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C1-C8 alkylaryl, C1-C8 alkylheteroaryl, 1-propynyl and 3-propynyl: or R1 and R2 are joined to form a ring comprising one of the following: -CH2(CH2)nCH2-, -CH2CH2C(CH3)CH2CH2-, -CH2CH2OCH2CH2-, -O(CH2)mCH2-, O(CH2)pO-, -CH2CH2N(H)COCH2CH2-, or -CH2CH2N(alkyl)CH2CH2-; m is an integer from 1 to 4; n is an integer from 1 to 5; p is an integer from 1 to 4; or R1 and R2 together comprise a double bond to one of the following: C(CH3)2; C(cycloalkyl), O or C (cycloether); R3 is selected from H, OH, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 alkenyl, alkynyl or substituted alkynyl, or COR<A>; R<A> is selected from H, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C1-C3 aminoalkyl; R4 is selected from H, halogen, CN, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 aminoalkyl, or substituted C1-C6 aminoalkyl; R5 is selected from the groups a), b) or c): a ) is a benzene ring containing the substituents X, Y and Z as shown below: X is selected from H, halogen, OH, CN, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 thioalkyl, substituted C1-C3 thioalkyl, S(O) alkyl, S(O)2alkyl, C1-C3 aminoalkyl, substituted C1-C3 aminoalkyl, NO2, C1-C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CONH2, CSNH2, CONH(C1-C8) alkyl, CSNH(C1-C8) alkyl, CON(C1-C8 alkyl)2, CSN (C1-C8 alkyl)2, COR<B>, OCOR<B>, or NR<C>COR<B>; R<B> is selected from H, C1-C3 alkyl, substituted C1-C3 alkyl, aryl, substituted aryl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C1-C3 aminoalkyl; R<C> is H, C1-C3 alkyl, or substituted C1-C3 alkyl; where all X, Y and Z can not be H; b) a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group of H, halogen, CN, NO2 and C1-C3 alkyl, C1-C3 alkoxy, C1-C3 aminoalkyl, COR<D>, or NR<E>COR<D>; R<D> is H, C1-C3 alkyl, substituted C1-C3 alkyl, aryl, substituted aryl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C1-C3 aminoalkyl; R<E> is H, C1-C3 alkyl, or substituted C1-C3 alkyl; R<6> is absent or is H, COR<D> or C1-C3 alkyl; or c) indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, CN, NO2, C1-C6 alkoxy, or CF3; Q<1> is S, NR7 or CR8R9; R7 is selected from the group including CN, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, acyl, substituted acyl, aroyl, substituted aroyl, SO2CF3, OR<11> or NR<11>R<12>; R8 and R9 are independent substituents selected from the group of H, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, or CO2R<10>, R10 is C1-C3 alkyl; or CR8R9 comprises a six membered ring as shown by the structure below R<11> and R<12> are independently selected from H, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl or substituted aroyl or sulfonyl; said aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl and phenanthryl; said heterocyclic or heteroaryl is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl, sulfoxide, and isoquinolinyl; said substituted alkyl and substituted alkynyl comprise 1 or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio; said substituted aryl comprises 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio; said substituted heterocyclic or heteroaryl comprises 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted acyl and aroyl comprise 1 to 6 groups selected from the group consisting of halogen, CN, OH and NO2; said substituted alkoxy, substituted aminoalkyl and substituted thioalkyl comprise 1 to 3 substituents selected from the group consisting of alkyl and substituted alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of the formula wherein: R1 and R2 are joined to form a five or six-membered carbocyclic ring; R3 is selected from the group consisting of H, OH, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 alkenyl, alkynyl, substituted alkynyl, and COR<A>; R<A> is selected from the group consisting of H, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, and substituted C1-C3 aminoalkyl; R4 is selected from the group consisting of H, halogen, CN, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 aminoalkyl, and substituted C1-C6 aminoalkyl; R5 is a) or b): a) a substituted benzene ring of the formula: X is selected from the group consisting of H, halogen, CN, CONH2, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alkyl), CON(C1-C8-alkyl)2, CSN(C1-C8-alkyl)2, C1-C3 alkoxy, C1-C3 alkyl, NO2, C1-C3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C1-C3 thioalkoxy; Y is on the 4' or 5' position selected from the group consisting of H, halogen, CN, NO2, C1-C3 alkoxy, C1-C4 alkyl, and C1-C3 thioalkyl; wherein X and Y are not both H; or b) a six membered ring of the structure: wherein: X' is N or CX<2>, X<2> is halogen, CN, CONH2, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alky), CON(C1-C8-alkyl)2, CSN(C1-C8-alkyl)2, or NO2; Q<1> is S, NR7, or CR8R9; R7 is selected from the group consisting of CN, C1-C6-alkyl, substituted C1-C6- alkyl, C3-C8-cycloalkyl, substituted C3-C8-cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, and SO2CF3; R8 and R9 are independent substituents selected from the group consisting of H, C1-C6-alkyl, substituted C1-C6-alkyl, C3-C8-cycloalkyl, substituted C3-C8-cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, and CO2R10; R10 is C1-C3alkyl; or CR8R9 is a six membered ring of the structure below: wherein; said aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl; said heterocyclic is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl; said substituted alkyl and substituted alkynyl comprise 1 or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted aryl comprises 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted heterocyclic comprise 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted acyl and aroyl comprise 1 to 6 groups selected from the group consisting of halogen, CN, OH and NO2; said substituted alkoxy, substituted aminoalkyl, and substituted thioalkyl comprise 1 to 3 substituents selected from the group consisting of alkyl and substituted alkyl; or pharmaceutically acceptable salt thereof. 3. A compound of the formula: or a tautomer thereof wherein: R14 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; R5 is a), b), or c): a) a substituted benzene ring containing the substituents X and Y as shown below: wherein: X is selected from the group consisting of H, halogen, CN, CONH2, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alkyl), CON(C1-C8-alkyl)2, CSN(C1-C8-alkyl)2, CNHNHOH, CNH2NOH, C1-C3-alkoxy, C1-C3-alkyl, NO2, C1-C3-perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C1-C3-thioalkoxy; Y is on the 4' or 5' position and is selected from the group consisting of H, halogen, CN, NO2, C1-C3-alkoxy, C1-C3-alkyl, and C1-C3-thioalkyl; wherein X and Y are not both H; b) a five membered ring of the structure shown below: wherein: U is O, S, or NR6; R6 is H, C1-C3-alkyl, or alkoxycarbonyl(C1-C4)alkyl; X' is selected from the group consisting of halogen, CN, NO2, CONH2, CNHNHOH, CNH2NOH, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alkyl), CON(C1-C8-alkyl)2, CSN(C1-C8-a

Description

FIELD OF THE INVENTION

This invention relates to compounds that are agonists of the progesterone receptor, the method for their preparation and their use.

State of the art

Intracellular receptors (1K.) Form a class of structurally related gene regulators known as ligand-dependent transcription factors (K.M. Euaik, 8c1eise, 240, 889, 1988). The steroid receptor family is a subgroup of the 1K family, including progesterone receptor (PK), estrogen receptor (EC), androgen receptor (AK), glucocorticoid receptor (SC), and mineralocorticoid receptor (MK).

The natural hormone or ligand for the PK receptor is a progesterone steroid, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, can be used as the same ligand. As soon as the ligand appears in the fluid surrounding the cell, it passes through the membrane through passive diffusion and binds to the 1K receptor, forming a receptor / ligand complex. This complex binds to specific gene promoters present in cellular DNA. After binding to DNA, the complex produces tRNA and the protein encoded by this gene.

A compound that binds to the 1K receptor and mimics the action of a natural hormone is called an agonist here, while a compound that inhibits the action of a hormone is called an antagonist.

RK agonists (natural and synthetic) are known to play an important role in women's health. PK receptor agonists are used in birth control formulations, usually in the presence of an EC receptor agonist, alternatively they can be used together with a PK receptor antagonist. EC receptor agonists are commonly used to treat menopausal symptoms, but their effects have been associated with a proliferating effect on the uterus, which can lead to an increased risk of cancer. Joint treatment with PK receptor agonists reduces / eliminates this risk.

The compounds of the present invention act as competitive inhibitors of the binding of progesterone to the PK receptor, and they act as agonists. These compounds can be used for contraception, as well as postmenopausal hormone replacement therapy.

1st 5. e! a1. US Pat. No. 5,688,810, a PK receptor antagonist, dihydroquinoline A.

1st 8, e! a1. describe enol B ester (US Pat. No. 5,693,646) as a ligand for the PK receptor.

1st 8, e! a1. describe compound C (US Pat. No. 5,696,127) as a PK receptor ligand.

from

ΖΙιγ e! a1. describe lactones -O, E, P as antagonists of the receptor of the Republic of Kazakhstan (1. Meb. Sb., 41, 291, 1998).

g

ΖΙιγ e! a1. describe ester C as an antagonist of the PK receptor (1. Meb. Sb., 41, 291, 1998).

FROM

Sotk, e! a1. describe amide H as a ligand for the PK receptor (1. Meb. Sb., 38, 4880, 1995).

Reg1tap, e! a1. describe an analogue of vitamin Ό I as a ligand for the RK receptor (Te !. Eeyegs, 35, 2295, 1994).

Natapp, e! a1. describe a PK * 1 receptor antagonist (App. N. Υ. Asai. 8e1., 761, 383, 1995).

Cep, e! a1. describe an antagonist of the receptor RK K (Cep, e! a1., PO1-37, 16! b 1n !. Comp. Not !. Cet., Mop! apa, 1997).

Kipyap, e! a1. describe the ligand of the PK b receptor (I. Apylois, 50, 360, 1997).

Kitty, e! a1. disclosed that oxindole M has cardiotonic activity (AO 86/03749)

Aeb offers oxindole N for cardiovascular determinations (AO 91/06545)

T18seyeg, e! a1. patented a method for producing compounds having the general structure O (US patent 5.453.516)

K - various

81'pd11, e! a1. describe an inhibitor of RBE III P (I. May. Sb., 37, 248, 1994)

Upgeapts e! a1. describe the cytotoxic agent O (Ac! and Pbpn ΝογΤ., 2, 407, 1990).

What a f! a1. describe the structure of K, which is intermediate to obtain COX II inhibitors (AO 97/13767)

to

AaL1 describes oxindole 8 as an intermediate (US Pat. No. 4,440,785, US Pat. No. 4,670,566)

K ₁ = T, C1, Br, alkyl, ΝΗ ₂ K ₂ = alkyl, alkoxy, T, C1, ΝΗ 2 ST

Wow, e! a1. patent Oxindole T as a cardiovascular agent (AO 91/06545)

t

Wow, e! a1. include the general structure and (AO 91/04974)

DR 63112584 A contains the general structure V

Nz

V

Boag, e1 a1. described dioxolane V as an intermediate for the preparation of acetylcholinesterase inhibitors (XVO

93/12085 A1).

Keib1e, e1 a1. described the procedure for producing 3,3-substituted oxindoles, for example, X, which are used in accordance with the present invention. (8up. 1st. Sottip. 12,1,1982)

x

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula 1 or 2

where K.1 and K _{2 are} independently selected from the group consisting of H, alkyl, substituted alkyl, OH, O (alkyl), O (substituted alkyl), OAc, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl or 3propinyl or K.1 and K _{2 are} condensed to form a ring containing one of the following residues:

-CH2 (CH2) pCH2-; -CH2CH2CMe2CH2CH2-;

-O (CH2) tCH2-; -O (CH2) pO-;

-CH ₂ CH ₂ OCH ₂ CH ₂ -; or —CH ₂ CH ₂ H (H or alkyl) CH ₂ CH ₂ -;

t is an integer from 1 to 4;

n is an integer from 1 to 5;

p is an integer from 1 to 4;

or Κι and K ₂ together form a double bond to one of the following residues:

CMe2; C (cycloalkyl), O, C (cycloether).

K ³ is selected from the group consisting of H, OH, ΝΗ _2, C1-C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted _C1-C6 Alkeya neela, alkynyl or substituted alkynyl, or OBE ^A ;

K ^A is selected from the group consisting of H, C1 to _C3 alkyl, substituted _C1-C3 alkyl, _C1-C3 alkoxy, substituted C1 to _C3 alkoxy, C1 to _C3 aminoalkyl, or substituted C1-S3aminoalkila;

K4 is selected from the group consisting of H, halogen, CH ΝΗ ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ^ C ₆ alkoxy, C ₁ -C ₆ aminoalkyl or substituted C1-C6 aminoalkyl;

K ^{5 is} selected from the group consisting of a), b) or c):

a) To ⁵ represents a trisubstituted benzene ring containing the substituents X, Υ and Ζ, as shown below

Where

X is selected from the group consisting of halogen, OH, CH, 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 thioalkyl, substituted C ₁ -C ₃ thioalkyl 8 (O) alkyl, 8 (O) ₂ alkyl, C ₁ -C ₃ aminoalkyl, substituted C | -C ₃ aminoalkyl. NO _2, C ₁ -C ₃ perfluoroalkyl, 5 or 6-membered heterocyclic ring containing 1 to 3 heteroatoms SONTN, S8NN2, SONNalkil, S8NNalkil, SON (alkyl) _2, S8N (alkyl) _2, SOC ^B sedges ^B , 1NA ^C OK ^B ;

K ^{B is} selected from the group consisting of H, C ₁ -C ₃ alkyl, substituted C ₃ C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl;

K ^C is H, C1-C3 alkyl, or substituted C1 to C3 alkyl;

Υ and Ζ are substituents independently selected from the group consisting of H, halogen, CH, HO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkyl;

or

b) K ⁵ is a five or six membered heterocyclic ring with 1, 2 or 3 heteroatoms selected from the group O, 8, 8O, 8O2 or NK ⁶ and containing one or two independent substituents selected from the group H, halogen, CH, HO 2 and C-C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, SOK ^B or 1 HK ^E SOK ^B ;

^K represents H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ^ C ₃ alkoxy, C ₁ to C ₃ aminoalkyl, or substituted C1 C3 aminoalkyl;

K ^E represents H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl;

K ⁶ represents H or C ₃ C alkyl; or

c) K ⁵ is indol-4-yl, indol-7-yl or benzo-2-thiophene residue, a residue which may optionally be substituted by 1-3 substituents selected from the group consisting of halogen, lower alkyl, ΟΝ , ΝΟ ₂ , lower alkoxy or SG ₃ ;

() 'represents 8, ΝΚ ⁷ , SK ⁸ K ⁹ ;

K _{7 is} selected from the group consisting of ΟΝ, 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, heterocyclyl, substituted heterocyclyl, acyl, substituted acyl, aroyl, substituted aroyl, 8O ₂ SG ₃ , OK ¹¹ or \ KK ¹² ;

K ₈ and K ₉ are independent 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 , heterocyclyl, substituted heterocyclyl, ΝΟ ₂ , CN or CO ₂ K ₁₀ ;

K.10 represents C ₁ -C ₃ alkyl; or

SK ₈ K ₉ form a six-membered ring, the formula of which is shown below

() ² choose from residues

I am in I “—Ν-Ο-“ ^Κ . _UD_ _K ,, _or -O — AK

K ¹¹ , K ¹² and K ^{13 are} independently selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl, substituted aroyl or sulfonyl;

or their pharmaceutically acceptable salts.

A preferred list of substituents represented by the radicals K ¹¹ , K ¹² and K ¹³ in the groups of compounds described herein is defined as H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, -C (O) -, (C ₁ -C ₆ alkyl), -8 (O) ₂ - (C ₁ -C ₆ alkyl), phenyl or benzyl.

It should be understood that the present invention includes all tautomeric forms of the compounds, chemical formulas and substituents listed in the description.

Two preferred compounds in accordance with the present invention are represented by formulas 2 and 3, respectively

where each K ⁵ represents a disubstituted benzene ring containing the substituents X and Υ, as shown below

where X is selected from the group consisting of halogen, ΌΝ, СОyn ₂ , С8NΗ ₂ , СONNalkyl, С8NΗ-alkyl, СН alkyl ₂ , С8N-alkyl ₂ , С ₁ -С ₃ alkoxy, С ₁ -С ₃ alkyl, NΟ ₂ , С ₁ -С ₃ perfluoroalkyl 5 membered heterocyclyl ring containing from 1 to 3 heteroatoms or C ₁ -C ₃ thioalkoxy;

Υ is a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, ΟΝ, NΟ ₂ , C ₁ -C ₃ alkoxy, C1-C4 alkyl or C1-C3 thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 2 are compounds in which K ⁵ represents a five-membered ring of the formula below

where and represents O, 8 or ΝΕ ^;

K6 is selected from the group consisting of H, C ₁ -C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is selected from the group consisting of halogen, ΌΝ, Νφ, COCH ₂ , C8NΗ2, CΟNalkyl, C8Nalkyl, COnalkyl ₂ , C8Nalkyl ₂ , C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

Υ 'is selected from the group consisting of H, G or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

In addition, a preferred subgroup of compounds described above are those in which K ₅ is a thiophene or furan ring substituted with substituents such as x ′ and y ′ as described above.

Another preferred subgroup of compounds of formulas 2 and 3 includes compounds in which K ⁵ is a six-membered ring with the structure below

where X ¹ represents Ν or CX ² ,

X ² represents halogen, ΟΝ, СОЫН ₂ , С8NΗ2, СО \ [[alkyl. C8 Nalkyl, CΟNalkyl ₂ , C8Nalkyl ₂ or NO ₂ ;

p ¹ represents 8, ΧΙΕ, SK ⁸ K ⁹ ;

K _{7 is} selected from the group consisting of ΟΝ, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl or 8O ₂ SG ₃ ;

K ₈ and K ₉ are independent 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 , heterocyclyl, substituted heterocyclyl, ΝΟ ₂ , ΟΝ or CO ₂ K ₁₀ ;

K ₁₀ represents C ₁ -C ₃ alkyl;

SK ₈ K ₉ form a six-membered ring, the formula of which is given below

or a pharmaceutically acceptable salt thereof.

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

where each K ⁵ represents a disubstituted benzene ring containing the substituents X and Υ, as shown below

where X is selected from the group consisting of halogen, CE, SOEN SZMN2, SOENalkyl, SZENalkyl, SOEalkyl ₂ , C3Ealkyl ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, EO ₂ , C ₁ -C ₃ perfluoroalkyl, 5 membered a heterocyclyl ring containing from 1 to 3 heteroatoms, C ₁ -C ₃ thioalkoxy;

Υ is a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, CE, ΝΘ ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl or C ₁ -C ₃ thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of compounds are compounds of the formula

BUT; L * ~ -Ν "4 1 or "3 "but

in which K ⁵ represents a six-membered ring of the formula

where X ¹ represents N or CX ² ,

X ² represents halogen, CE, SOEN C3 \ 1b. SOY Kiki.I. SZHNaikii. СО№лки.ъ. C3Ealkyl ₂ or EO ₂ ;

p ² has the meanings given above;

K _{7 is} selected from the group consisting of CE, 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, heterocyclyl, or substituted heterocyclyl or 3O ₂ CP ₃ ;

K ₈ and K ₉ are independent 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 , heterocyclyl, substituted heterocyclyl, EO ₂ , CE or CO ₂ K ₁₀ ;

K ₁₀ represents C ₁ -C ₃ alkyl;

SK ₈ K ₉ form a six-membered ring of the formula below

or a pharmaceutically acceptable salt thereof.

Another group of preferred compounds of the present invention is represented by formula 4,

in which K _{14 is} selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, substituted sulfonyl, in which K ₅ is a disubstituted benzene ring containing substituents X and как, as shown below

where X is selected from the group consisting of halogen, CE, COEN2, C3E1P, COENalkyl, C3ENalkyl, COE (alkyl) ₂ , C3H (alkyl) ₂ , CENENON, CEN ₂ EOH, C ₁ -C ₃ alkoxy, C ₁ -C ₃ al -kyl, EO ₂ , C ₁ C ₃ perfluoroalkyl, a 5-membered heterocyclyl ring containing from 1 to 3 heteroatoms or C ₁ -C ₃ thioalkoxy;

Υ represents a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, CE, EO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl or C ₁ -C ₃ thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 4 are compounds in which K ⁵ is a five-membered ring of the formula below

where and represents Θ, 3 or EC ₆ ;

K _{6 is} selected from H, C ₁ -C ₃ alkyl, or C ₁ to C ₄ CO ₂ alkyl;

X 'is selected from the group consisting of halogen, ΟΝ, ΝΟ ₂ ; ΟΘΝΗ ₂ , ΟΝΗΝΗΘΗ, ΟΝΗ ₂ ΝΟΗ, C8 \ 1 K SOINalkyl, ΟδΝΗαΛκ ^, CO№alkyl ₂ , C8№alkyl ₂ , C ₁ -C ₃ alkyl or C _g C ₃ alkoxy;

Υ 'is selected from the group consisting of H, G or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of compounds of the invention includes the compounds listed above, wherein K ⁵ is a thiophene or furan ring substituted with X ′, Υ ′, as described above.

In addition, a preferred subgroup of compounds of formula 4 are those in which K ₅ is a six-membered ring of the formula

where X ¹ represents Ν or CX ² ,

X ² represents halogen, CK, ^ ΝΗ2, C8NΗ2, COXNalkyl, C8Nalkyl, СО СОalkyl ₂ , C8Nalkyl ₂ or ΝΟ ₂ ;

K _{7 is} selected from the group consisting of CH, 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, heterocyclyl, or substituted heterocyclyl or 8O ₂ SG ₃ ;

K ₈ and K ₉ are independent 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 , heterocyclyl, substituted heterocyclyl, ΝΟ ₂ , ΟΝ, CO ₂ K ₁₀ ;

K ₁₀ represents C ₁ -C ₃ alkyl; or a pharmaceutically acceptable salt thereof. In addition, a preferred group of compounds in accordance with the present invention are compounds of formula 5

in which K5 is a disubstituted benzene ring containing the substituents X and Υ, as shown below

where X is selected from the group consisting of halogen, CK, ^ ΝΗ2, C8NΗ2, CONNalkyl, C8Nalkyl, CΟNalkyl ₂ , C88alkyl ₂ , CNΗNΟΗ, C ₁ C ₃ alkoxy, C ₁ -C ₃ alkyl, ΝΟ ₂ , C ₁ -C ₃ perfluoroalkyl, a 5-membered heterocyclyl ring containing from 1 to 3 heteroatoms or C ₁ -C ₃ thioalkoxy;

Υ is a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, CM, ΝΟ ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 5 are compounds in which K ⁵ is a five-membered ring of the formula

where and represents O, 8 or ΝΚ ₆ ;

K ₆ represents H or C ₁ -C ₃ alkyl or alkoxycarbonyl (C ₁ -C ₄ ) alkyl;

X 'is selected from the group consisting of halogen, CH ΝΟ ₂ ; ^ ΝΗ ^ C8NΗ ₂ , CΟN Nalkyl, C8N Nalkyl, CNNalkyl ₂ , C8лalkyl ₂ , C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

Υ 'is selected from the group consisting of H, G or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred subgroup of compounds of the invention includes the compounds listed above, wherein K ⁵ is a thiophene or furan ring substituted with X ′, Υ ′, as described above.

In addition, a preferred subgroup of compounds of formula 5 are those in which K5 is a six-membered ring of the formula

where X ¹ represents Ν or CX ² ,

X ² represents halogen, C ^ ^ ΝΗ2, C8NH2, CONNalkyl, C8Nalkyl, CO№alkyl ₂ , C8Nalkyl ₂ or ΝΟ ₂ ;

K _{7 is} selected from the group consisting of C ^ 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, heterocyclyl, or substituted heterocyclyl or 8O2SR3;

K ₈ and K ₉ are independent 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 , heterocyclyl, substituted heterocyclyl, ΝΟ ₂ , C ^ or CΟ ₂ K ₁₀ ;

K ₁₀ represents C ₁ -C ₃ alkyl; or a pharmaceutically acceptable salt thereof.

The following preferred group of compounds in accordance with the present invention is defined by formula 6

in which K _{15 is} selected from the group consisting of H, Me, CO ₂ K, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, CU;

in which K ₅ represents a disubstituted benzene ring containing the substituents X and Υ, as shown below

where X is selected from the group consisting of halogen, CH, COCH ₂ , C8CH2, COalkyl, C8 CHalkyl, COalkyl ₂ , C8alkyl ₂ , CH, C ₁ C ₃ alkoxy, C ₁ -C ₃ alkyl, C ₂ , C ₁ -C ₃ perfluoroalkyl , A 5 membered heterocyclic ring containing from 1 to 3 heteroatoms or C1-C3 thioalkoxy;

Υ represents a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, CH, CH ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl or C ₁ -C ₃ thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 6 are those compounds in which K ⁵ represents a five-membered ring of the formula below

where it represents O, 8 or LK ₆ ;

K _{6 is} selected from the group consisting of H, C ₁ -C ₃ alkyl or C ₁ -C ₄ CO ₂ alkyl;

X 'is selected from the group consisting of halogen, CH, CH ₂ ; СОНЫ ₂ , С8ЫН ₂ , СОНАЛКyl, С8ЫН alkyl, СОН alkyl ₂ , С8Ы alkyl ₂ , С ₁ -С ₃ alkyl or С ₁ -С ₃ alkoxy;

Υ 'is selected from the group consisting of H, G or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another subgroup of preferred compounds of the invention includes the listed compounds, wherein K ⁵ is a thiophene or furan ring substituted with X ′, Υ ′, as described above.

A further preferred subgroup of compounds of formula 6 are those in which K ₅ is a six-membered ring with the structure shown below

where X ¹ represents N or CX ² ,

X ² represents halogen, CN, SOYN2, S8YN2, SOYNalkil, S8YNalkil, SOYalkil ₂ S8Yalkil ₂ uQ or _2;

K _{7 is} selected from the group consisting of CH, 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, heterocyclyl, or substituted heterocyclyl or 8O ₂ SG ₃ ;

K ₈ and K ₉ are independent 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 , heterocyclyl, substituted heterocyclyl, HO ₂ , CH or CO ₂ K ₁₀ ;

K ₁₀ represents C ₁ -C ₃ alkyl; or a pharmaceutically acceptable salt thereof.

The following preferred group of compounds has the formula 7

where K ₅ represents a disubstituted benzene ring containing the substituents X and Υ, as shown below x

where X is selected from the group consisting of halogen, CH, COYN2, C8YN2, COYNalkyl, C8YNalkyl, SOYalkyl ₂ , C8Yalkyl ₂ , SYNYON, C ₁ C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocyclic ring containing 1-3 heteroatoms or C ₁ -C ₃ thioalkoxy;

Υ represents a substituent at the 4 'or 5' position selected from the group H, halogen, CH, CHO2, C1-C3 alkoxy, C1-C4 alkyl or C1-C3 thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of formula 7 are compounds in which K ⁵ is a five-membered ring of the formula

where it represents O, 8 or LK ₆ ;

K _{6 is} selected from H, C ₁ -C ₃ alkyl or C ₁ -C ₄ CO ₂ alkyl;

X 'is selected from the group consisting of halogen, CH, CH2; СОН2, С8ЫН2, СОН alkyl, С8ЫН alkyl, СОЫ alkyl2, С8Ы alkyl2, С1С ₃ alkyl or С ₁ -С ₃ alkoxy;

Υ 'is selected from the group consisting of H, G or C ₁ -C ₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another subgroup of preferred compounds of the invention includes the listed compounds, wherein K ⁵ is a thiophene or furan ring substituted with X ′, Υ ′, as described above.

The next subgroup of preferred compounds of formula 7 are those in which I ₅ represents a six-membered ring of the formula below

where X ¹ represents N or CX ² ,

X ² is halogen, ΟΝ, ΝΗ ₂ , C8NΗ ₂ , CΟNalkyl, C81Malkyl, COnalkyl ₂ , C8Nalkyl ₂ or ΝΟ ₂ ;

I _{7 is} selected from the group consisting of ΟΝ, 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, heterocyclyl, or substituted heterocyclyl, or 8O ₂ CE ₃ ;

Z ⁸ and Z ⁹ are independent 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 , heterocyclyl, substituted heterocyclyl, ΝΟ ₂ , ΟΝ, CO ₂ Z ¹⁰ ;

I ₁₀ represents C ₁ -C ₃ alkyl;

salts or a pharmaceutically acceptable salt.

The compounds of the invention may contain an asymmetric carbon atom, and some of the compounds of the invention may contain one or more asymmetric centers, which may lead to the formation of optical isomers and diastereoisomers. Although the stereochemical structure is not shown in formulas 1 and 2, the present invention includes similar optical isomers and diastereoisomers, as well as racemates and separated enantiomerically pure I and 8 stereoisomers; as well as other mixtures of I and 8 stereoisomers and their pharmaceutically acceptable salt.

The term alkyl is used here to mean saturated linear and branched chain aliphatic hydrocarbon groups containing from one to eight carbon atoms, preferably from 1 to 6 carbon atoms; it is understood that the term alkenyl includes both straight and branched chain alkyl groups with 1 or 2 carbon-carbon double bonds and containing from two to eight carbon atoms, preferably from 2 to 6 carbon atoms; it is understood that the alkynyl group embraces both linear and branched chain alkyl groups with at least one or two carbon-carbon triple bonds containing from two to eight carbon atoms, preferably from 2 to 6 carbon atoms.

The term acyl embraces a carbonyl substituent, including both a linear and branched saturated hydrocarbon group containing from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms. The term substituted acyl refers to the acyl group that is just described, optionally substituted from 1 to 6 groups selected from halogen, MF OH and ΝΟ ₂ .

The term aroyl also refers to a carbonyl substituent bearing a phenyl or heteroaromatic group. The heteroaromatic group includes 2-, 3-, 4-pyridinyl, 2- and 3-furanyl, 2- or 3-thiophenyl, or 2- or 4-pyrimidinal. The term substituted aroyl also refers to the aroyl group that is just described, optionally substituted from 1 to 6 groups selected from halogen, MF, OH and ΝΟ ₂ .

The terms substituted alkyl, substituted alkenyl and substituted alkynyl mean the just described alkyl, alkenyl and alkynyl containing one or more substituents from the group consisting of halogen, ϋΝ, OH, ΝΟ ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy , aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents can be attached to any carbon atom in the composition of an alkyl, alkenyl or alkynyl group, provided that upon such addition a chemically stable residue is formed.

The term aryl is used here to mean an aromatic system, which may include one ring or several aromatic rings, condensed or linked to each other so that at least part of the condensed or connected rings forms a conjugated aromatic system.

Aryl groups include, but are not limited to groups such as phenyl, naphthyl, biphenyl, antryl, tetrahydronaphthyl, phenanthryl.

The term substituted aryl means the above-defined aryl containing from one to four substituents selected from the group consisting of halogen, C ^ OH, ΝΟ ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio.

The term heterocyclyl is used here to mean a stable 4-7 membered monocyclic or stable polycyclic heterocyclic ring, which may be saturated, partially or completely unsaturated and consists of carbon atoms and from one to four heteroatoms selected from the group consisting of Ν, O, and 8. Atoms Ν and 8 can be oxidized. Heterocyclic rings also include any polycyclic rings in which any of the above heterocyclic rings is fused to an aryl ring. A heterocyclic ring may be attached via any heteroatom or carbon atom, provided that the resulting structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl thiomorpholinyl sulphoxide and isoquinolinyl.

The term substituted heterocyclyl is used here to describe heterocyclyls defined above containing 1-4 substituents selected from the group consisting of halogen, CU, OH, ΝΟ ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio.

The term thioalkyl is used herein to mean an 8K group, where K is an alkyl containing from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms.

The term alkoxy is used herein to mean an OK group, where K is alkyl or substituted alkyl containing from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms.

The term aryloxy is used herein to mean an OK group, where K is aryl or substituted aryl, as defined above.

The term alkylcarbonyl is used herein to mean a CSR group, where K is alkyl or substituted alkyl containing from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms.

The term alkyl carboxy is used herein to mean a COOC group, where K is alkyl or substituted alkyl containing from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms. The term aminoalkyl means both secondary and tertiary amines, which include alkyl or substituted alkyl groups containing from one to eight carbon atoms, which may be the same or different, and the point of their attachment is a nitrogen atom. The term halogen means elements C1, Br, T or I.

Compounds of the invention may be prepared using the schemes depicted below.

Scheme 1

7

In accordance with Scheme 1, commercially available oxindole 3 is treated with a strong organometallic base (e.g., lithium butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (e.g. THF, diethyl ether) in a nitrogen atmosphere at low temperature (approximately -20 ° C) (Kepbe , e! a1., 8up1y. Sottip., 12, 1, 1982) in the presence of lithium chloride or Ν, Ν, Ν ', Ν'-tetramethylethylenediamine. The resulting dianion is then treated with excess electrophile, such as haloalkyl, preferably iodine. If K ₁ and K ₂ must be combined, as in the case of product 4, which contains a spirocycle at position 3, then the electrophile must be bifunctional, that is, diiodide. Subsequent bromination of 4 proceeds smoothly when treated with bromine in acetic acid (an organic cosolvent such as dichloromethane can be added if necessary) in the presence of sodium acetate to give aryl bromide 5. Bromide 5 reacts with a palladium salt (for example, tetrakis (triphenylphosphine) palladium ( 0) or palladium acetate), in a suitable solvent (for example, such as THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature in an inert atmosphere (argon, nitrogen). The mixture is then treated with aryl or heteroarylboronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or a fluorine source (cesium fluoride) under anhydrous conditions. The desired product 6 is then isolated and purified by standard means.

The reaction of the indolin-2-one 6 derivative with either the Loesson reagent (Bauzezep) or phosphorus pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) provides a temperature between room temperature and the boiling point of the solvent preparation of a thiocarbonyl derivative 7. The addition of a reagent such as sodium bicarbonate may also be useful.

If K ₁ and K ₂ are different, then intermediate 4 is obtained by the reaction of dianion 3 with one equivalent of electrophile K ₁ -X (X = leaving group, for example, iodine). The resulting monoalkylated compound can then be isolated and reacted using K ₂ -X, or alternatively, ΐη zy is used for secondary alkylation with K ₂ -X. Alternatively, if the desired product 7 is to contain K ₂ = H, then the isolated monoalkylated intermediate is fed to the next steps.

the addition of a pendant aryl or heteroaryl group, Ar, to an oxindole base, for example, by reacting compound 5 with aryl or heteroaryl tin, aryl or heteroaryl zinc or an aryl or heteroaryl magnesium halide in the presence of a palladium or nickel catalyst (Scheme 2). The desired aryl or heteroaryl metal residue described above is obtained by standard methods.

Other functional groups can also be introduced at the 3-position of the indoline base in accordance with Scheme 3. Oxidation of unsubstituted indoline 8, preferably under neutral or acidic conditions (for example, selenium dioxide in dry dioxane under reflux) leads to the production of isatin 9. Functional groups can further be introduced into compound 9 to obtain ketal 11 by treatment with an alcoholic and acidic catalyst under anhydrous conditions. Alternatively, reaction 9 with a second ketone under suitable conditions (piperidine in toluene under reflux; or Τίί'.Ί · | / Ζη in THF under reflux) results in alkylidene derivatives 11. The reaction of isatin 9 with Grignard reagent or organolithium leads to the production of tertiary alcohols 12 (K = H). The following functional groups can then be introduced into these alcohols by alkylation or acylation.

Scheme 3

at 9th

eleven

12

The reaction of the indolin-2-one 6 derivative with either the Loesson reagent (Latekkep'k) or phosphorus pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and temperature boiling the solvent provides a thiocarbonyl derivative 7. The addition of a reagent, such as sodium bicarbonate, can also be carried out.

Scheme 4

An alternative method of preparation is the reaction of compound 5 with either a Loesson reagent or phosphorus pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the boiling point of the solvent, in an inert atmosphere ( nitrogen or argon) that provides a thiocarbonyl derivative 13. Then the reaction of bromide 13 in an anhydrous solvent (e.g., THF, E1 ₂ O) with a strong base (preferably such as g sodium dride, as well as sodium hexamethyldisilazide, potassium hydride), followed by reaction at low temperature (-50 to -20 ° С) with n-butyllithium and Ν, Ν, Ν, Ν'-tetramethylethylenediamine, and then, after a suitable period of time, with trialkyl borate (trimethyl or triisopropyl borate) leads to, after treatment with acid, boronic acid 14 (Scheme 4). Compound 14 can then be reacted under conditions of catalysis with palladium, such as (tetrakis (triphenylphosphine) palladium (0) or palladium acetate, in the presence of a base (No. ₁ HCO ₃ , No. ₂ CO _3. K ₂ CO ₃ , triethylamine, CKE) solvent (toluene (EUN / water, THF / water, dimethoxyethane / water, anhydrous dimethoxyethane)) with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate, to give the desired compounds 7.

Alternatively, the reaction of compound 13 under the conditions of catalysis by palladium, such as (tetrakis (triphenylphosphine) palladium (0) or palladium acetate, in the presence of a base (No. 1 HCO ₃ , No. 1 ₂ CO ₃ , K ₂ CO ₃ , triethylamine, CKE) solvent ( acetone / water, toluene / EUN / water, THF / water, dimethoxyethane / water, anhydrous dimethoxyethane)) with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate 7 provide the desired compounds.

Scheme 5

7

Treatment of bromide 5 in an anhydrous solvent (e.g. THF, E1 ₂ O) with a strong base (preferably sodium hydride, sodium hexamethyldisilazide, potassium hydride), followed by reaction at reduced temperature (-50 to -20 ° С) with n-butyl lithium and Ν, Ν, Ν, Ν'-tetramethylethylenediamine, and then, after a suitable period of time, with trialkyl borate (trimethyl or triisopropyl borate), boronic acid 15 is obtained after treatment with acid (Scheme 5). Compound 15 can then react under the conditions of catalysis with palladium (tetrakis (triphenylphosphine) palladium (O), in the presence of a base (No. HCO ₃ , No. ₂ CO ₃ , K ₂ CO ₃ , triethylamine, CzE) solvent (toluene / UNN / water, THF (water, dimethoxyethane / water, anhydrous dimethoxyethane)) with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate or aryl or heteroaryl fluorosulfonate, to give the desired compounds 6.

An alternative strategy may be to obtain an organozinc or magnesium reagent from compound 5 and reacting it with aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethanesulfonate, aryl or heteroaryl fluorosulfonate, under conditions of catalysis, palladium organo or magnesium can give compound 6. Such obtained by treating bromide in an anhydrous solvent (e.g. THF, E1 ₂ O) with a strong base (preferably sodium hydride, sodium hexamethyldisilazide Oia, potassium hydride) followed by reaction at low temperature (-50 to -20 ° С) with n-butyl lithium and Ν, Ν, Ν ', Ν'-tetramethylethylenediamine, followed by a reaction with anhydrous zinc chloride or magnesium bromide after a suitable period of time .

The reaction of the indolin-2-one 6 derivative with either a Loesson reagent or phosphorus pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the boiling point of the solvent, in an inert atmosphere (nitrogen or argon) provides a thiocarbonyl derivative 15. An additional reagent, such as sodium bicarbonate, can also be introduced.

In accordance with Scheme 6, derivatives of thioamide 7 can be converted into derivatives of enamine 16 (ShgoBe !, e! Ay, b. Meb. Set., 1989, 2493).

So the reaction of thioamide 7 (Rd = H, 2 (trimethylsilyl) ethoxymethyl, benzyl, etc.) with triethyloxonium tetrafluoroborate followed by reaction with a nucleophile (such as nitromethane, cyanamide, trifluoromethanesulfonamide, Meldrum acid, etc.) with subsequent removal of the protective groups under suitable conditions (for example, tetrabutylammonium fluoride in THF for Rd = 2- (trimethylsilyl) ethoxymethyl), yields enamine derivatives 16. Suitable solvents for the two steps are selected from dichloromethane, THF, dioxane, 1,2-dichloroethane , and the reaction is carried out at a pace a temperature of -78 ° C to the boiling point of the solvent in an inert atmosphere (nitrogen or argon).

In accordance with Scheme 7, treatment of intermediate 7 with an alkylating agent, for example methyl iodide, ethyl iodide, 2,4-dinitrofluorobenzene or 4 nitrofluorobenzene, in the presence of a suitable base (for example, an amino base such as pyridine, triethylamine or diisopropylethylamine or lithium, sodium carbonate, potassium or cesium) in a suitable organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a temperature between -78 ° C and the boiling point of the solvent will then produce thioiminutesters 17. By the following reaction with intermediate 17 and hydroxylamine or an acid salt of hydroxoxylamine (e.g., hydrochloride) in a suitable solvent (e.g., but not limited to, pyridine, methanol, ethanol, isopropanol, DMF, THF or DMSO and optionally in the presence of an additional reagent such as tertiary amine base or sodium or potassium acetate) at a temperature between -78 ° C and the boiling point of the solvent, will then lead to the production of β-hydroxyamidines 18.

A similar treatment of intermediate 17 with a carbon nucleophile, such as a malonate derivative (e.g. malononitrile, cyanoacetate ether, nitroacetate ether or malonate) in the presence of a suitable base (e.g. amine base such as pyridine, triethylamine or diisopropylethylamine or lithium, sodium, potassium carbonate or cesium) or Lewis acid (e.g. boron trifluoride etherate, lead II salt, titanium tetrachloride, magnesium salt II, or silver salt) in a solvent compatible with the selected base or acid Lewis (e.g., DMF, THF, DMSO, dioxane or acetonitrile, chloroform, benzene, toluene or dichloromethane) will then lead to the preparation of the adduct 19. If the group K ³ in the adduct 19 is an ester of a carboxylic acid, then it can be decarboxylated directly to obtain the enamine derivative 20 by treatment with, for example, sodium iodide in DMSO at a temperature between room temperature and the boiling point of the solvent. Alternatively, the ester can be first hydrolyzed to a carboxylic acid (by treating with an aqueous base (e.g. lithium, sodium or potassium hydroxide) in a suitable solvent (e.g. THF, dioxane, acetonitrile, methanol or ethanol), followed by decarboxylation in the presence of acid (e.g. , hydrochloric or sulfuric acid) in a suitable solvent (e.g. acetonitrile, THF, dioxane), resulting in derivatives 20. Alternatively, a xanthate carboxylic acid ester can be obtained by reaction with bases Niemi, such as sodium or potassium hydride in THF, followed by treatment with carbon disulfide. Subsequent reaction with tin tributyl hydride at elevated temperatures in a solvent such as benzene or toluene in an inert atmosphere of nitrogen or argon in the presence of a radical initiator such as benzoyl peroxide or azo-bisisobutyronitrile will then produce product 20.

Scheme 8 X $ —— X $ х xA.r ^ X $ \ —- χ $ \ _ - x $ A — xA

An alternative strategy for synthesizing product 18 is shown in Scheme 8. Thus, bromide 13 (the corresponding chloride, iodide or triflate ether can also be used) is treated with an alkylating agent, such as methyl iodide, ethyl iodide, 2,4dinitrofluorobenzene or 4-nitrofluorobenzene, in the presence of a suitable bases (e.g., an amine base such as pyridine, triethylamine or diisopropylethylamine or lithium, sodium, potassium or cesium carbonate) in a suitable organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) p and a temperature between −78 ° C. of the boiling point of the solvent, which will then result in thioiminoesters 21. Subsequent reaction of intermediate 21 with hydroxylamine or an acidic salt of hydroxylamine (for example, hydrochloride, hydrobromide) in a suitable solvent (for example, but not limited to, such as pyridine, methanol, ethanol, isopropanol, DMF, THF or DMSO and optionally in the presence of an additional reagent, such as a tertiary amine base or sodium or potassium acetate) at a temperature between -78 ° C and the boiling point solvent, will then produce Ν-hydroxyamidine 22. Intermediate 22 can then be protected with a suitable group (e.g., benzyl ether, acyl derivative, tetrahydropyranyl ether, methoxymethyl ether, silyl ether) to give derivative 23. Alternatively, compound 21 may react directly with a protected hydroxylamine derivative (with selected but not limited to the protecting groups described above) to give derivative 23. Compound 23 may then react with olyu palladium (e.g. tetrakis (triphenylphosphine) palladium (0) or palladium acetate), in a suitable solvent (e.g., THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature under an inert atmosphere (argon, nitrogen). The mixture is then treated with aryl or heteroarylboronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or a fluorine source (cesium fluoride) under anhydrous conditions, and the reaction can then be heated to the boiling point of the solvent. The desired product 24 is then isolated and purified by standard methods.

Protecting groups can then be removed from compound 24 under the conditions described previously, depending on the nature of the protecting groups. For example, if the protecting group is benzyl ether, treatment with boronic tribromide or trimethylsilyl iodide in a suitable solvent (dichloromethane for example) will give compound 18. Other methods for removing benzyl ether include hydrogenation (hydrogen gas or another hydrogen source such as cyclohexadiene or ammonia format) in the presence of a palladium catalyst. Solvents suitable for such a process include methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature between room temperature and the boiling point of the solvent. If the protective group was an acetal derivative (tetrahydropyranyl or methoxymethyl esters), then hydrolysis can be carried out under acidic conditions (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or acidic ion-exchange resin) in a solvent such as methanol, ethanol, THF dioxane or acetonitrile. If the protecting group was an acyl derivative (acetate, or benzoate for example), then hydrolysis can be carried out under acidic conditions, as described above, or under basic conditions (lithium, sodium or potassium hydroxide) in a solvent such as alcohol, THF, dioxane or acetonitrile, at a temperature between room temperature and the boiling point of the solvent. If the protecting group was silyl ether, compound 18 can be prepared by hydrolysis of intermediate 24 under the acidic conditions described above or alternatively by treating compound 24 with a fluorine source (such as potassium fluoride, cesium fluoride or tetrabutylammonium fluoride) in a solvent such as alcohol , THF, dioxane or acetonitrile, at a temperature between room temperature and the boiling point of the solvent. An inert atmosphere of nitrogen or argon may be necessary.

Another way to synthesize compound 18 is to convert protected Ν hydroxyamidine 23 to boronic acid or boronic acid ester (by substituting lithium halide followed by quenching with triisopropyl borate, or a palladium-catalyzed compound with diborum pinacolate) and then condensing said boronic acid or ether derivative with aryl chloride iodide or triflate in a suitable palladium-catalyzed system as previously described. Subsequent deprotection as described for Scheme 8 will produce the desired compounds 18.

In accordance with Scheme 9, treatment of the hydroxyamidine 18 under reduction conditions (for example, catalytic hydrogenation, iron in acetic acid or Raney hydrazine nickel) will then give intermediate 25. Suitable solvents for this process include methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature between room temperature and the boiling point of the solvent. The protection of secondary nitrogen (tertiary butyl carbamate is shown by way of non-limiting example) under standard conditions will then give compound 26. The reaction of compound 26 with an electrophilic cyanate agent (for example, cyanobromide, Ν cyanobenzotriazole or cyanobromide / 4-dimethylaminopyridine complex) in an appropriate tritelumone, acetone, or tri-acetone solvent DMF, optionally in the presence of a base such as pyridine or sodium or potassium hydride tert-butoxide) can then produce the desired compound 2 7. In some cases, the cyanidation step may proceed with the concomitant removal of the protective group of the secondary nitrogen, if this deprotection does not occur pmPi, then a further hydrolysis step is necessary.

An alternative synthesis of compounds 27 may be that compound 18, scheme 8, where Ν-cyanoamidine bromide 28 obtained from compound 22, like a similar strategy for the reactions shown in scheme 9, can be condensed with a suitable functional group of arylboronic acid or boronic acid ester to give compound 27. According to another strategy, intermediate 28 can be converted to the corresponding boronic acid or boronic acid ester and introduced into the coupling reaction according to Suzuki or type of acid anija Suzuki palladium, with a suitable aryl bromide functional group.

The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and, if appropriate, organic acids such as acetic acid, oxalic acid, succinic acid, and maleic acid . Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other standard prodrug forms, which, when introduced in such forms, turn into the active part of ίη νίνο.

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

The progesterone receptor agonists of the present invention, used alone or in combination, can be used in contraceptive methods and methods for treating and / or preventing dysfunctional bleeding, uterine leiomyoma, endometriosis, polycystic ovary syndrome, endometrial carcinomas and adenocarcinomas, ovaries, breasts, colon, prostatitis. Additional uses of the invention include stimulation of food intake.

When using the compounds for the above purposes, they can be combined with one or more pharmaceutically acceptable carriers or excipients, for example, a solvent, diluent and the like, and can be administered orally in such forms as tablets, capsules, dispersion powders, granules or suspensions containing, for example, from about 0.05 to 5% of a suspended agent, syrups containing, for example, from about 10 to 50% sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form sterile injectable solutions or suspensions containing from about 0.05 to 5% of a suspended agent in an isotonic medium. Such pharmaceutical forms may contain, for example, from about 25 to about 90% of the active ingredient in combination with a carrier, more preferably between about 5% and 60% by weight.

The effective dose of the active ingredient used may vary depending on the characteristics of the compound used, the route of administration and the severity of the treatment conditions. However, in general, satisfactory results are obtained when the compounds of the invention are administered in a daily dose of from about 0.5 to about 500 mg / kg body weight of an animal, preferably administered in divided doses from two to four times a day, or in the form of a sustained release. For the largest mammals, the total daily dose is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use contain from about 0.5 to 500 mg of the active compound in an intended mixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide an optimal therapeutic response. For example, certain separate doses may be administered daily or the dose may be proportionally reduced, which is determined by the urgent need for a therapeutic situation.

These active compounds can be administered orally as well as intravenously, intramuscularly, or subcutaneously. Solid carriers include starch, lactose, calcium diphosphate, microcrystalline cellulose, sucrose and clay, while liquid carriers include sterile water, polyethylene glycol, non-ionic surfactants and edible oils such as corn, peanut and sesame oils that are suitable for nature active ingredient and desired particular administration form. Suitable adjuvants typically used to prepare pharmaceutical compositions may advantageously include components such as perfumes, colorants, preservatives and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

Preferred pharmaceutical compositions from the point of view of freedom 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 may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or a pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be obtained in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the unprepared preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it provides easy injection capability. It must be stable under conditions of production and storage and must be protected from the damaging effects of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol (e.g. glycerin, propylene glycol and liquid polyethylene glycol), an acceptable mixture thereof, and vegetable oil.

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

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

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

A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800 cm ³ ) is cooled to -20 ° C, then nbutyl lithium (2.5 M in hexane, 152 cm ³ , 0.38 mol) is slowly added followed by Ν, Ν, Ν, Ν'-tetramethylethylenediamine (51 cm ³ , 0.38 mol). After 15 minutes, 1,5-diiodopentane (174 g, 0.54 mol) was slowly added and the mixture was allowed to warm to room temperature. After stirring for 16 hours, a saturated aqueous solution of ammonium chloride (1 L) and EuAc (1 L) were added. After 15 minutes, the layers were separated and the aqueous phase was extracted with HEC Ac (x2). The combined organic layers were extracted with hydrochloric acid (1Ν), then washed with brine (500 cm ³ ), dried (MD8O ₄ ) and concentrated to give an oil. The oil is treated with hexane (200 cm ³ ) and benzene (20 cm ³ ). The precipitate was collected and dried in vacuo to give the title compound (26.3 g, 69.6%) as colorless crystals: mp. 110-114 ° C; 'H NMR (DMSOάβ) δ 1.67 (m, 10H), 6.84 (d, 1H, 1 = 8 Hz), 6.94 (t, 1H, 1 = 8 Hz), 7.17 (t, 1H, 1 = 8 Hz), 7.44 (d, 1H, 1 = 8 Hz), 10.3 (s, 1H).

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

To a solution of spiro [cyclohexane-1,3 '- [3H] indole] -2'(1'H) -one (17.6 g, 0.09 mol) in acetic acid (300 cm ³ ) sodium acetate was added with stirring (8.0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol). After 30 minutes at room temperature, the reaction mixture was separated into water and EyAc. The aqueous phase is extracted twice with EyAc. The combined organic layers were washed with water, dried (Md8O ₄₎ and evaporated, and the residue was treated with hexane. The precipitate was collected and dried in vacuo to give the subtitle compound (16.5 g, 67%) as dirty white crystals: mp. 196-199 ° C; 'H NMR (DMSO-d ₆ ) δ 1.62 (m, 10H), 6.8 (d, 1H, 1 = 6.8 Hz),

7.36 (d, 1H, 1 = 8.2, 1.8 Hz), 7.58 (dd, 1H, 1 = 8.2, 1.8 Hz), 10.44 (s, 1H).

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

A solution of 5'-bromospiro [cyclohexane-1,3 '[3H] indole] -2'(1'H) -one (0.32 g, 1.14 mmol) and tetrakis (triphenylphosphine) palladium (0) (0, 14 g, 0.12 mmol) in dimethoxyethane (6 cm ³ ) was stirred under a current of Ν2 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 allowed to reflux for 6 hours, then cooled to room temperature, poured into water and extracted with ЕУАс (х3). The combined organic extracts were washed with water, brine, dried (MD8O4), and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, 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, Ή NMR (ΟϋΟ1 ₃ ) δ 1.60-1.78 (m, 6H),

1.81-1.99 (m, 4H), 7.04 (d, 1 = 8.1 Hz, 1H), 7.22-

7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (broad s, 1H); ¹³ C-NMR (COS1 ₃ ) 20.17, 24.12,

31.92 (s), 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); M8 (E1) m / e 310, 312 (M-H) ⁺ Analysis (CH- ₈ C1 \ O) C, H, Ν.

To a solution of 5 '- (3-chlorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one (0.63 g, 2.0 mmol) in dry xylene (20 cm ³ ) 2,4-bis (4-methoxyphenyl) -1,3dithia-2,4-diphosphetane-2,4-disulfide (0.89 g, 2.2 mmol) is added under nitrogen atmosphere and the mixture is heated under reflux reflux condenser. After 72 hours the mixture was evaporated and the residue was purified by column chromatography ₍₂ occupies 8, EYuAs; hexanes gradient elution) to give a solid which was recrystallized from diisopropyl ether / hexane to give the title compound as yellow crystals (0.17 g, 0.51 mmol, 26%): M.p. 223227 C; '11 NMR (СОС1 ₃ ) δ 1.53-1.66 (m, 8Н), 1.832.05 (m, 4Н), 2.07-2.17 (m, 2Н), 7.11 (d, 1Н) , 1 = 8.0 Hz), 7.31-7.53 (m, 3H), 7.54 (s, 1H), 7.86 (s, 1H), 9.93 (s, 1H, broad) : M8 (+ APC1) m / e 328 (M + H) +.

Example 2. 3- (1 ', 2'-Dihydro-2-thioxospiro [cyclohexan-1,3' - [3H] indole] -5'-yl) benzonitrile.

To a solution of 5'-bromospiro [cyclohexane-1,3 '[3H] indole] -2'(1'H) -one (1.00 g, 3.57 mmol) in dimethoxyethane (20 cm ³ ) was added tetrakis (triphenylphosphine ) palladium (0.20 g, 0.17 mmol). After 15 minutes 3formyl phenylboronic acid (1.00 g, 6.93 g) was added followed by potassium carbonate (2.90 g, 21 mmol) in water (10 cm ³ ). After 20 hours at reflux, the mixture was cooled by pouring into water and extracted with ЕУАс (х3). The combined organic extract was washed with saturated brine, dried (MD8O ₄ ) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, ITS Ac: hexanes, gradient elution) to give the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, ¹ H NMR (CE JV) δ

1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, 1 = 8 Hz), 7.48 (dd, 1H, 1 = 8.2 Hz), 7.61 (t, 1H, 1 = 8 Hz), 7.66 (d, 1H, 1 = 2 Hz), 7.81-7.88 (m, 2H), 8.06 (t, 1H, 1 = 2 Hz), 8.30 (s, 1H, broad); M8 ((+) E81) m / e 306 (M + H) ⁺ .

3- (1 ', 2'-dihydro-2'-oxospiro [cyclohexane 1,3' - [3H] indole] -5 '-yl) benzaldehyde oxime.

To a solution of 3- (1 ', 2'-dihydro-2'-oxospirocyclohexan-1,3' - [3Н] indol-5'-yl) benzaldehyde (0.59 g, 1.95 mmol) in UNN: Н ₂ About (10 cm ³ , 8: 2) hydroxylamine hydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5 mmol) are added. After 20 minutes, the mixture was concentrated, water was added and the product was extracted with EAAc (x2). The combined organic layers were washed with saturated sodium bicarbonate solution, water, saturated brine, dried (MD8O4) and evaporated to give the indicated oxime (0.63 g, 1.95 mmol, 100%) which was used without further purification, ¹ N NMR (ΟΌΟ13) δ 1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H),

6.86 (d, 1H, 1 = 8 Hz), 7.36 (dd, 1H, 1 = 8.2 Hz), 7.437.50 (m, 1H), 7.57-7.67 (m, 2H ), 7.85 (s, 1H, broad), 8.25 (8, 1H), 8.68 (s, 1H, broad), 8.94 (s, 1H, broad);

M8 ((-) E8E) m / e 319 (M-H) ^- .

3- (1 ', 2'-dihydro-2'-oxospiro [cyclohexane1,3' - [3H] indole] -5 '-yl) benzonitrile.

Solution of 3 - (1 ', 2'-dihydro-2'-oxospiro [cyclohexan-1,3' - [3H] indole] -5'-yl) benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform (10 cm ³ ) is treated with selenium dioxide (0.38 g, 3.50 mmol) and heated at the boil under reflux. After 16 hours, the mixture was concentrated and the residue was purified by column chromatography (8X2, EYAc: 1: 4 hexane) and the product was recrystallized from EYAc-hexane to give the title compound (0.161 g, 0.53 mmol, 35%) as a white solid : Mp 190-191 ° C; ¹ H NMR (ΟΌΟ13) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, 1 = 8 Hz), 7.42 (dd, 1H, 1 = 8.2 Hz), 7.54 (t, 1H, 1 = 8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, 1 = 7.2 Hz), 7.83 (m, 1H), 8.26 (s, 1H, broad); M8 ((+) E8E) m / e 303 (M + H) ⁺ .

The reaction of 3 - (1 ', 2'-dihydro-2'-oxospiro [cyclohexan-1,3' - [3H] indole] -5'-yl) benzonitrile and Loesson's reagent in accordance with the procedure in example 1 leads to the specified in the name of the compound: So pl. > 231 ° C (decomposition); Ί1 NMR (DMSO-b ₆ ) δ 1.38-1.55 (m, 3H),

1.82-1.99 (m, 7H), 7.16 (d, 1H, 1 = 8.1 Hz), 7.63-

7.69 (m, 2H), 7.80 (d, 1H, 1 = 7.7 Hz), 8.01 (d, 1H, 1 = 8 Hz) and 12.76 (s, 1H); M8 ((-) - APC1) t / e 317 [M-H] ^- .

Example 3. 4- (1,2'-Dihydro-2'-thioxospiro [cyclohexan-1,3] - [3H] indole 1-5-yl) -2-thiophenecarbonitrile.

3- (Trimethylstannyl) -2-thiophenecarbonitrile.

A solution of 2-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.25 g, 0.2 mmol) and hexamethyldiol (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm ³ ) is heated under reflux for 14 hours, then cooled to room temperature. The reaction mixture was absorbed onto florisil and purified by column chromatography ₍₂ occupies 8, methylene chloride: hexanes 1: 9) to give the title compound (1.04 g, 3.8 mmol, 90%) as a clear viscous oil: 'H NMR ( CO CE) δ 0.35 (s, 9H), 7.56 (d, 1 = 0.9 Hz, 1H), 7.66 (d, 1 = 0.9 Hz, 1H).

4- (1,2-dihydro-2-oxospiro [cyclohexane1,3- [3H] indol] -5-yl) -2-thiophenecarbonitrile.

A solution of 5'-bromospiro [cyclohexane-1,3 '[3H] indole] -2'(1'H) -one (0.53 g, 1.9 mmol), dichlorobis (triphenylphosphine) palladium (11) (0, 1 g, 0.14 mmol) and triphenyl arsenic (0.14 g, 0.47 mmol) in dimethoxyethane (8 cm ³ ) are stirred under an atmosphere of Ν2 for 20 minutes. To this mixture was then added 3- (trimethylstannyl) -2thiophenecarbonitrile (0.64 g, 2.35 mmol). The solution was allowed to reflux for 32 hours. After cooling to room temperature, the reaction mixture was absorbed on florosil and purified by column chromatography (8X2, ethyl acetate: hexane 2: 3) to obtain the title compound (0.43 g, 1.39 mmol, 74%) as an off-white solid: ¹ N NMR (СОС13) δ 1.56-2.1 (m, 10Н), 6.97 (d, 1 = 8.0 Hz, 1Н), 7 39 (dd, 1 = 8.03, 1.45 Hz, 1H), 7.57 (d, 1 = 1.45 Hz, 1H), 7.59 (d, 1 = 1.4 Hz, 1H) 7.84 (d, 1 = 1.4 Hz, 1H); 8.32 (broad s, 1H); ¹³ C-NMR (COC1 ₃ ) δ 22.07, 26.56, 34.4 (t), 48.13 (s), 110.18 (d), 111.3,

114.75 (s), 122.92, 126.76 (d), 128.44 (s), 137.55 (s), 138.11, 142.71, 144.49, 182.13 (s) ; M8 (E1) m / e 307 (M-H) ⁺ ; Analysis: (C ₁₈ H _{1 (} ^ ₂ O8) C, H, Ν.

A solution of 4- (1,2-dihydro-2-oxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -2-thiophenecarbonitrile (1.0 g, 3.2 mmol) and Loesson's reagent (1 , 3 g, 3.2 mmol) in o-xylene (20 ml) was heated for 2.5 hours. The reaction mixture was washed with distilled water (5x100 ml), dried over MgSO ₄ and evaporated. The product was purified by column chromatography ₍₂ occupies 8,

ESAc: hexane 1: 5) to give the title compound (0.2 g, 20%) as a pale yellow solid: mp. 230-232 ° C; ^! H-NMR (DMSO-b ₆ ) δ 12.72 (s, 1H), 8.52 (d, 1H, 1 = 1.5 Hz), 8.36 (d, 1H, 1 = 1.5 Hz) 8.00 (d, 1H, 1 = 1.5 Hz), 7.69 (dd, 1H, 1 = 6.4, 1.8 Hz), 7.10 (b, 1H, 1 = 8.3 Hz), 1.98-1.77 (m, 7H), 1.43-1.33 (m, 3H); M8 (E1) M ⁺ @ m / e 324.

Example 4. 3- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile.

To a solution of 5'-bromospiro [cyclohexane-1,3 '[3H] indole] -2' - (1'H) -one (1 mg, 0.04 mol) in dry tetrahydrofuran (200 cm ³ ) was added sodium hydride ( 60% dispersion in mineral oil, 1.6 g, 0.04 mol). After 30 min stirring at room temperature, the mixture was cooled to -78 ° C and butyllithium (1.7 M in hexane, 23.2 cm ³ , 0.04 mol) was slowly added. 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 (1H, 500 cm ³ ) and ethyl acetate (500 cm ³ ) were added. The aqueous phase was extracted with ethyl acetate, then the combined organic layers were washed with water, brine, dried (MD8O4) and evaporated. The residue was taken up in hexane and the residue was dried in vacuo to give (2'oxo-2,3-dihydrospiro [cyclohexan-1,3 '- [3H] indol] -5'-yl) boronic acid (8.3 g, 86%) as an off-white solid which is used without further purification. The sample, which is further treated with ethyl acetate, has the following properties: mp. 255-260 ° C decomposition; 'H NMR (DMSO-th ₆ ) δ 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (s, 1H, 1 = 7.72 Hz) 7.66 (d, 1H 1 = 7.72 Hz) 7.91 (s, 3H, broad); 10.36 (s, 1H); M8 ((-) E8r m / e 244 [M-H].

3- (1,2-dihydro-2-oxospiro [cyclohexane1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile.

To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm ³ ) at -78 ° C, p-butyllithium (2.5 M, 8 cm ³ , 20 mmol) was added dropwise. 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 HC1, separated, and the aqueous layer was extracted with E! OAc. The combined organic layers were combined, washed with water, brine, dried (MD8O4) and evaporated to give 3 fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: ¹ H NMR (ΕΌΟ1 ₃ ) δ W ! ay ay 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); M8 (E1) m / e 202, 204 [M ⁴ ].

To a solution of the latter compound (4.0 g, 19.7 mmol) in ethanol: water (8: 2, 50 cm ³ ) are added sodium acetate (1.72 g, 21 mmol) and hydroxylamine hydrochloride (1.45 g, 21 mmol), after which the mixture is heated at the boil under reflux. After 30 minutes the mixture was cooled, evaporated and the residue was partitioned between water and E! OAc. The aqueous layer was re-extracted with E! OAc and the combined organic layers were washed with water, saturated sodium bicarbonate solution, brine, dried (MD8O ₄ ) and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76 g, 17.24 mmol, 87%), which is used as the eyes ^stki: H NMR (SPS1 ₃ ) δ 7.24-7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (§, 1H); M8 (E1) m / e 217 [M ⁴ ].

The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg) were dissolved in acetonitrile (100 cm ³ ) in a nitrogen atmosphere and heated under reflux. After 5 hours, the mixture was evaporated, the residue was poured into E! OAc, washed with sulfuric acid (1H), water, brine, dried (MD8O4) and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89%), which is used without further purification.

The above bromide (3.0 g, 15 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.86 g, 0.75 mmol) are dissolved in dimethoxyethane (130 cm ³ ) in a nitrogen atmosphere. After 15 minutes, (2'-oxo-2,3-dihydrospiro [cyclohexan-1,3 '- [3H] indole] -5'-yl) boronic acid (2.82 g, 11.5 mmol) and sodium carbonate were added (3.1 g, 29.3 mmol) dissolved in water (40 cm ³ ), after which the mixture is heated at the boil under reflux. After 8 hours, the mixture was cooled, poured into water and extracted with E! OAc (x3). The combined organic layers were then washed with water, dried (MgS04O4) and evaporated. The residue was purified by column chromatography (E! OAc: hexane, elution gradient) and the product was recrystallized from methanol to give 3- (1,2-dihydro-2-oxospiro [cyclohexane-1,3- [3H] indole] -5-yl) -5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%): M.p. 199205 ° C; ^! H NMR (SPS13) δ 1.64-2.03 (m, 10H), 7.03 (d, 1H, 1 = 8 Hz), 7.31 (dt, 1H, 1 = 7.7 and 1.6 Hz)

7.41 (dd, 1H, 1 = 8, 1.7 Hz), 7.49 (dt, 1H, 1 = 9.6, 2 Hz), 7.58 (d, 1H, 1 = 2 Hz), 7.64 (s, 1H) and 8.37 (s, 1H): M8 (E1) m / e 320 [M ⁴ ].

To a solution of 3- (1,2-dihydro-2-oxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -5-fluorobenzonitrile (0.32 g, 1.0 mmol) in xylene (10 cm ³ ) in a nitrogen atmosphere add Loesson's reagent (0.89 g, 2.22 mmol) and the reaction is heated at the boil under reflux. After 4 hours, the mixture was cooled, evaporated and the residue was subjected to column chromatography (81O ₂ , E! OAc: hexane, elution gradient) to give the product (0.143 g, 0.42 mmol, 42%) as a white solid: mp. 236-250 ° C;

^! H NMR (SPS1 ₃ ) δ 1.54-1.66 (m, 3H), 1.86-

2.18 (m, 7H), 7.16 (d, 1H, 1 = 8.1 Hz), 7.33-7.36 (m, 1H), 7.46-7.52 (m, 2H) 7.65 (s, 1H); 7.85 (d, 1H; 1 = 1 Hz); 10.05 (s, 1H); M8 ((+) - APST) m / e 337 [M + H] ⁺ .

Example 5. 4-Methyl-5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -2thiopentioamide.

2'-Oxo-2 ', 3, -dihydrospiro [cyclohexane1,3' - [3H] indol] -5'-yl) boronic acid (2.45 g, 10 mmol), 2-bromo-5-cyano-3 methylthiophene (2.4 g, 12 mmol), potassium carbonate (4 g, 29 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.6 g,

0.5 mmol) in dimethoxyethane: water: ethanol (130 cm ³ , 10: 2: 1) is heated to 80 ° C for 16 hours and then poured into 1 l of water and extracted with E (OAc (x3). The organic extract is washed with water , brine, dried (MD8O ₄ ) and evaporated.The crude residue was purified by column chromatography (81O ₂ , ethyl acetate: hexane 1: 1) to obtain the title compound (0.9 g, 28%): mp 200- 203 ° С, Ή NMR (SIS1 ₃ ) δ

1.63 (m, 8H), 1.87 (m, 2H), 2.27 (s, 3H), 6.95 (d, 1H, 1 = 8.13 Hz), 7.34 (dd, 1H , 1 = 8.13 Hz, 1.98 Hz), 7.54 (d, 1H, 1 = 1.98 Hz), 7.82 (s, 1H), 10.50 (s, 1H); M8 (+ APC1) m / e 323 (M + H) ⁺ .

Solution of 4-methyl-5- (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3' - [3H] indole] -5 '-yl) -2-thiophenecarbonitrile (0.61 g, 1 , 9 mmol) and phosphorus pentasulfide in dioxane (17 ml) are heated to 85 ° C for 30 minutes. The reaction mass was poured into distilled water (100 ml), washed with aqueous NaHCO ₃ , distilled water and dried over MgSO ₄ , evaporated to dryness. Purification of the residue by column chromatography (2.5% MeOH / CH2C12) on silica gel affords the product as an orange-brown solid (0.05 g, 8%), mp. 244-249 ° C; '11 NMR (b _6- DMSO) δ 12.75-1.99 (s, 1H), 9.54 (s, 1H), 9.34 (s, 1H), 7.76 (d, 1H, 1 = 1.5 Hz), 7.58 (s, 1H), 7.45 (dd, 1H, 1 = 6.4,

1.8 Hz), 7.14 (d, 1H, 1 = 7.9 Hz), 2.26 (s, 3H), 1.981.89 (m, 7H), 1.83-1.81 (m, 3H). M8 (+) (APC1) [M + H] ⁺ .

Example 6. Pharmacology.

The gestogenic activity of the compounds of the present invention is evaluated using the ίη νίίτο and ίη νΐνο studies described below. The activity values ίη νίίτο are in the range of 0.01-10,000 nM, and the activity values ίη νΐνο are in the range from 1 to 30 μg / kg.

A. Biological activity ίη νίίτο.

The biological activity of ίη νίίτο is determined using (1) a study of competitive binding to a radioactive ligand: use the A-form of the human progesterone receptor with progesterone as a radioactive ligand; (2) studies using co-transfection, the result of which is data on functional activity expressed using EC ₅₀ values for agonists and 1C ₅₀ for antagonists; (3) studies of Τ47Ό cell proliferation, which is also a source of data on the functional activity of agonists and antagonists; and (4) studies involving alkaline phosphatase Τ47Ό cells, which also provides functional data on agonists and antagonists.

1. NRK binding assay

This study is carried out in accordance with Raini-ta, S .; 8 (em, KV; Vegdeg, Τ. 8; Yeshesa 1, V .; Bingo, T .; May, I.E .; Τογιόκ, A .; Οΐοάιηηη,

M.Е.

2. A study using PKE luciferase in SU-1 cells.

The aim of this study is to determine the presence of gestagenic or antigestagenic activity of compounds based on their effect on the reporter activity of PKE luciferase in SU-1 cells co-transfected with human PP and PKE luciferase plasmids. The study uses the following materials and methods.

a. Medium: The following growth medium was used.

EMEM (ΈίοΧνΗΠΕιΙ ^ Γ), containing 10% (v / v) bovine germ serum (heat-inactivated), 0.1 mM MEM of non-essential amino acids, 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM C1u (aMax (C1BCO, ON). The following experimental medium was used: EMEM (Vu ^ Iyakeg) free of phenol red, containing 10% (v / v), purified with coal (heat-inactivated) bovine germ serum, 0.1 mM MEM of non-essential amino acids, 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM C1i (aMax (C1BCO.VKB).

b. Cell cultivation, transfection, processing and research involving luciferase.

The original SU-1 cells were stored in growth medium. Joint transfection was performed using 1.2x10 ⁷ cells, 5 mg of plasmid pEM with the NRK-B gene cloned at sites 8pH1 and BATH1, 10 mg of plasmid rsB3 with two PKE inserts above the luciferase sequence, and 50 mg of calf thymic DNA treated with ultrasound as Carrier DNA in 250 ml. Electroporation was performed at 260 V and 1000 mF in Vyugab Sen Ri1keg II. After electroporation, the cells were resuspended in growth medium and plated on 96-well plates at 40,000 cells / well in 200 μl. After incubation overnight, the medium was replaced with experimental. Then the cells were treated with comparative or test compounds in an experimental medium. Compounds were tested for antigestagenic activity in the presence of 3 nM progesterone. Twenty-four hours after treatment, the medium was removed, the cells were washed three times with E-PB8 (C1BCO, ON). 50 μl of cell lysis buffer (Primate, Mab ^ xi) was added to each well and the plates were shaken for 15 min on a plate shaker (Lab Kkbitey, 1 ps.). Luciferase activity was measured using special reagents from the company Rgoteda.

from. Analysis of the results.

Each treatment consisted of at least 4 repetitions of the experiment. Log-transformed data was used to analyze variance and non-linear dose response curves corresponding to the activity of both agonists and antagonists. Huber's weighting (Nigr \\ 'esl1Spd) was used to smooth out the effect of sharply distinguished values. EC ₅ о or 1С ₅ о values were calculated on the basis of repeatedly transformed values. DMR software (8A8 1p8Shi1e. 1ps.) Was used for one-way analysis of variance and analysis of nonlinear effects.

b. Comparative Compounds.

Progesterone and trimegestone served as comparative progestins, and VI486 served as comparative antiprogestin. For all comparative compounds, complete dose-response curves were constructed and EC50 or 1C50 values were calculated.

Table 1 Approximate values of EC50, standard errors (8E) and 95% confidence intervals (C1) of comparative progestins for three separate experiments

Compound Exp. EC50, nM 8E 95% C1 Lower value Upper value Progesterone one 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 Trimegeston one 0.0075 0,0002 0.0066 0.0085 2 0.0081 0,0003 0.0070 0.0094 3 0.0067 0,0003 0.0055 0.0082

Table 2 Approximate values of 1C ₅₀ , standard errors (8E) and 95% confidence intervals (C1) of antiprogestin VI486 for three separate experiments

Compound Exp. 1C50, nM 8E 95% C1 Lower value Upper value Vi486 one 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

Gestagenic activity: compounds that significantly (p <0.05) increase the activity of PBE luciferase compared to the control substance are considered active.

Antigestagenic activity: compounds that significantly (p <0.05) reduce the activity of PBE luciferase induced by 3 nM progesterone

EC ₅₀ : the concentration of the compound at which the activity of PBE luciferase increases by half from the maximum value (default - nM), with 8E.

1C ₅₀ : the concentration of the compound at which the activity of PBE luciferase induced by 3 nM progesterone decreases by half the maximum value (default nM), from 8E.

3. The study of the proliferation of Τ47Ό cells.

The aim of this study is to determine the presence of gestagenic or antigestagenic activity in compounds by studying the effect of Τ47Ό cells on proliferation. The magnitude of the effect of compounds on DNA synthesis in Τ47Ό cells was measured. The following materials and methods were used in the study.

a. Growth medium: EMEM: P12 (1: 1) (61BC0, BBB) supplemented with 10% (v / v) germinal bovine serum (not heat-inactivated), 100 U / ml penicillin, 100 mg / ml streptomycin, and 2 mM C1i1aMah (61BC0, BBB).

b. Processing medium: Minimum

Essential Medium (MEM) (# 51200-038 61ВС0, ВВ) free of phenol red, supplemented with 0.5% germ-derived bovine serum purified with coal, 100

Unit / ml of penicillin, 200 mg / ml of streptomycin, and 2 mM 61i! AMax (61BC0, BBB).

c. The cultivation of cells.

The original T47E cells were stored in growth medium. To investigate the incorporation of HBi, cells were plated on 96-well plates (Pa1cop, WesUp Eyukshkop Ba \\ 'age) at 10,000 cells / well in the growth medium. After overnight incubation, the medium was replaced with treatment medium and the cells were cultured for another 24 hours before treatment. The starting compounds were dissolved in a suitable solvent (100% ethanol or 50% ethanol / 50% EM80), and subsequently diluted with treatment medium and added to the cells. For progestin and antiprogestin comparative compounds, complete dose response curves were constructed. The final solvent concentration was 0.1%. In control wells, only solvent was added to the cells. Antiprogestins were tested in the presence of 0.03 nM Trimegestone, a comparative progestin agonist. 24 hours after the treatment, the medium was removed and the cells were labeled with 10 mM Brbi (Ategkat LiGe 8c1epse, Ag1ίη§1οη NeschlI8. 1b) in the treatment medium for 4 hours.

b. The study of cell proliferation.

At the end of the HBi labeling, the medium was removed and the inclusion of HBi was measured using an E8AA cell proliferation kit (# BPN 250, Ategyat LrGe 8c1epse) in accordance with the manufacturer's instructions. Briefly, cells were fixed using an ethanol-containing fixative for 30 minutes, followed by incubation in blocking buffer for 30 minutes to reduce background. A peroxidase-labeled anti-HBi antibody was added to the wells and incubated for 60 minutes. Cells were washed three times with PB8 and incubated with a 3.3'5.5'-tetramethylbenzidine (TMB) substrate for 10-20 min, depending on the activity of the tested compounds. Then, 25 μl of 1 M sulfuric acid was added to each well to stop the color reaction, and the optical density was measured using a plate reader at 450 nm for 5 minutes.

e. Analysis of the results.

The data converted by square root extraction was used to analyze the variance and non-linear dose-response curves corresponding to the activity of both agonists and antagonists. Huber weighting was used to smooth out the effect of sharply distinguished values. EC ₅₀ or 1C ₅₀ values were calculated based on the reconverted values. The 1MR software (ZAZ 1pkyi1e, 1ps.) Was used for one-way analysis of variance and analysis of non-linear dose-response curves for both a single dose and dose-response relationship

ί. Comparative Compounds.

Trimegestone and medroxyprogesterone acetate (MPA) served as comparative progestins, and KI486 served as comparative antiprogestin. For all comparative compounds, complete dose response curves were constructed and EC ₅₀ or 1C ₅₀ values were calculated.

Table 3 Approximate values of EC50, standard errors (WE) and 95% confidence intervals (C1) for individual experiments

Compound Exp. EC50, nM ZE 95% CT Lower value Upper value Trimegeston one 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 one 0.019 0.001 0.013 0,027 2 0.017 0.001 0.011 0.024

Table 4

Approximate values of 1С ₅₀ , standard errors (ЗЕ) and 95% confidence intervals (С1) of KI486 antiprogestin

Compound Exp. GS50, nM ZE 95% a Lower value Upper value KE486 one 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 : the concentration of the compound at which the inclusion of Vgya increases by half from the maximum value, with 3E; 1C ₅₀ : Concentration of the compound at which the inclusion of Vg, induced by 0.1 trimegestone, decreases by half the maximum value, with 3E.

4. A study involving alkaline phosphatase Τ47Ό cells.

The aim of this study is to identify progestins and antiprogestins by determining the effect of compounds on alkaline phosphatase activity in Τ47Ό cells. The following materials and methods were used in the study.

a. Cultivation medium: IMEM: E12 (1: 1) (SHVSO, VKV), supplemented with 5% (vol./about.) Purified germinal bovine serum (not heat-inactivated), 100 Units / ml penicillin, 100 mg / ml of streptomycin and 2 mM S1i1aMah (SHVSO, VKV).

b. The buffer for the study of alkaline phosphatase activity.

I. 0.1 M TP8-HC1, pH 9.8, containing 0.2% Τηΐοη X-100

II. 0.1 M TP8-HC1, pH 9.8, containing 4 mM p-nitrophenyl phosphate (Z1dta).

c. Cultivation and processing of cells.

Frozen Τ47Ό cells were thawed at 37 ° C in a water bath and diluted to 280,000 cells / ml with culture medium. A 180 μl diluted cell suspension was added to each well of a 96-well plate (Ta1Cop, WesTop Oucpopalbate). Then, 20 μl of comparative or test compounds were added to each well. When examining the activity of progestin antagonists, comparative antiprogestins or test compounds were added in the presence of 1 nM progesterone. Cells were incubated at 37 ° C in a humid atmosphere with 5% CO ₂ for 24 hours.

th. The study of the enzymatic activity of alkaline phosphatase.

At the end of the treatment, the medium from the plate was removed and 50 μl of assay buffer I was added to each well. The plates were shaken for 15 min on a plate shaker. Then, 150 μl of assay buffer II was added to each well. The optical density was measured with an interval of 5 min for 30 min at a control wavelength of 405 nm.

e. Analysis of the results: Dose-effect data analysis.

For comparative and tested compounds, dose-response curves were constructed based on the dose-dependent (X axis) rate of the enzymatic reaction (tilt angle) (ос axis). The data converted by square root extraction was used to analyze the variance and non-linear dose-response curves corresponding to the activity of both agonists and antagonists. Huber weighting was used to smooth out the effect of sharply distinguished values. EC ₅₀ or Κ '' ₅₀ values were calculated based on reconverted values. The 1MR software (ZAZ [n8111i1e. Shs.) Was used for one-way analysis of variance and analysis of non-linear dose-response curves for both a single dose and dose-response relationship

ί. Comparative Compounds.

Progesterone and trimegestone served as comparative progestins, and KI486 served as comparative antiprogestin. For all comparative compounds, complete dose-response curves were constructed and EC50 or 1C50 values were calculated.

Table 5 Approximate values of EC ₅₀ , standard errors (8E) and 95% confidence intervals (C1) of comparative progestins for three separate experiments

Compound Exp. EC50, nM 8E 95% C1 Lower value Upper value Progesterone one 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 Trimegeston one 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 Approximate values of 1C ₅₀ , standard errors (8E) and 95% confidence intervals (C1) of the comparative antiprogestin KI486 for three independent experiments

Compound Exp. 1C50, nM 8E 95% C1 Lower value Upper value No. 486 one 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. Biological activity ίη νίνο.

The primary study of ίη νίνο is a model for stimulating the release of a falling membrane in rats, and can be used to determine gestagenic effects of both agonists and antagonists. The secondary study of ίη νίνο is a rat ovulation suppression model; it is under development and therefore its protocol is not available.

1. The study of the allocation of dropping shell in rats.

The aim of this study is to evaluate the effects of progestins and antiprogestins on the release of the falling uterine membrane in rats, as well as the relative activity of various test compounds. The following materials and methods were used in the study.

but. Methods

Test compounds were dissolved in 100% ethanol and mixed with corn oil (solvent). Then, stock solutions of the test compounds in oil (MaζοΗ ™) were prepared by heating this mixture (-80 ° C) to evaporate ethanol. Subsequently, before treatment, the test compounds were diluted with 100% corn oil or 10% ethanol in corn oil. When comparing these two solvents, there was no difference in the effect of precipitating shell release.

b. Animals (KLSI Protocol # 5002).

Mature female 8gadie-OaMeu rats with removed ovaries (~ 60 days old and weighing 230 g) were obtained from (Ταοοηίο Bagtk, ΝΥ) after surgery. Ovarian removal was performed at least 10 days prior to treatment to reduce the circulation of sex steroid hormones. The animals were kept in a 12 hour light / dark cycle and were given standard rat food and water as needed.

c. Treatment.

Rats were weighed before treatment and randomly divided into groups of 4 or 5 animals. Test compounds were administered in 0.2 ml of solvent by subcutaneous injection into the back of the neck or in 0.5 ml using a probe. The animals were treated once daily for seven days. In the case of a study of progestins, animals received test compounds and a dose of EC50 of progesterone (5.6 mg / kg) during the first 3 days of treatment. After stimulating the release of the decaying shell, the animals continued to receive progesterone until the autopsy, which was carried out 4 days later.

b. Dosage.

Doses were selected based on mg / kg of the average body weight in the group. All experiments included a control group that received the solvent. To plot the dose-response curves, a semi-logarithmic increase in doses was used (for example, 0.1, 0.3, 1.0, 3.0 mg / kg ...)

e. Induction of precipitating shell release.

Approximately 24 hours after the third injection, precipitation of the falling membrane in one of the fallopian tubes was induced by scratching the antimesometric cavity epithelium with a blunt 21C needle. The opposite tube was not touched and was used as an unstimulated control. Approximately 24 hours after the final treatment, the rats were sacrificed by asphyxiation with CO ₂ and their bodies were weighed. The uterus was removed and purified from fat. The fallopian tubes with the separated falling-out shell (Ό-tube) and control tubes (C-tube) were weighed separately.

E Analysis of the results.

The increase in the weight of the fallopian tube with the released falling-off shell was calculated by the Ό-tube / C-tube ratio and the logarithmic transformation was used to optimize the normality and homogeneity of the dispersion. We used NiMeM-exBtaFg to smooth the effect of the observed sharply distinguished transformed values for constructing dose-response curves and a one-way analysis of variance. 1MP software (8L8 Ιη8ΐίΙι№. 1ps.) Was used for one-sided ΑΝΟνΑ and analysis of non-linear dose-response curves.

e. Comparative Compounds.

For all comparative progestin compounds, complete dose response curves were constructed and EC ₅₀ values were calculated for the wet weight of the uterus.

Table 7 Approximate values of EC ₅₀ , standard errors (8E) and 95% confidence intervals (C1) for individual experiments

Compound Exp. EC50, mg / kg, sc 8E 95% C1 Lower value Upper value Progesterone one 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.76 3-Ketodesogestrel one 0.11 0.02 0,07 0.16 2 0.10 0.05 0.11 0.25 3 0.06 0,03 0,03 0.14 Levonorgestrel one 0.08 0,03 0.04 0.16 2 0.12 0.02 0.09 0.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA one 0.42 0,03 0.29 0.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61

Table 8 Approximate average values of EC50, standard errors and 95% confidence intervals (C1) dose-response curves for the three comparative compounds

Compound EC50, mg / kg, sc 8E 95% C1 Lower value Upper value 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

Approximate values of 1C ₅₀ , standard errors and 95% confidence intervals (C1) for antiprogestin KI486

Compound Exp. 1C50, mg / kg orally 8E 95% C1 Lower value Upper value No. 486 one 0.21 0,07 0.05 0.96 2 0.14 0.02 0.08 0.27

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

Method of administration: the method by which the compound is administered to animals

Body Weight: Average total animal body weight (kg by default)

Ό-tube: wet weight of the fallopian tube with a falling out shell (default - mg)

C-tube: wet weight of the control fallopian tube (default is mg)

The effect of the allocation of the falling away shell: [(P-S) / C] x100%

Gestagenic activity: compounds that significantly (p <0.05) induce the release of a falling coat compared to a control solvent are considered active.

Antigestagenic activity: compounds that significantly (p <0.05) reduce the EC50 of progesterone-induced excretion of the falling coat.

EC50 for uterine weight: the concentration of the compound at which the release effect of the falling membrane increases by half the maximum value (default is mg / kg)

1С ₅₀ for uterine weight: the concentration of the compound at which the effect of the release of a falling membrane induced by progesterone is reduced by half the maximum value of the EU ₅₀ (default - mg / kg)

Data for some representative compounds

Example K1 / nM εν-1 EC50 / nM Ovulation Inhibition 1C ₅₀ mg / kg 5 0.3 3 0.1 0.2 one 0.2 0.8 4 0.06 0.1 0.1

Example 7. 5- (1 ', 2'-Dihydro-2-thioxospiro [cyclohexan-1,3' - [3H] indole] -5'-yl) -1H-pyrrole2-carbonitrile.

5- (2'-Oxo-2 ', 3'-dihydrospirocyclopentan-1,3'- [H] indole) -5'-yl-2-cyanopyrrole.

A solution of 5'-bromospiro [cyclohexane-1,3 '[3H] indole] -2'(1'H) -one (2.00 g, 7.5 mmol) and tetrakis (triphenylphosphine) palladium (430 g, 0, 3 mmol) in ethylene glycol dimethyl ether is stirred under nitrogen for 15 minutes. To the solution, 1-tert-butoxycarbonylpyrrolboronic acid (2.1 g, 9.7 mmol) was successively added followed by potassium carbonate (2.4 g, 17 mmol) in water (10 cm ³ ). The mixture is heated at 80 ° C. for 3 hours and cooled. The mixture was poured into water (50 ml) and extracted with EuAc (50x3). The combined organic extract was washed with brine (30 ml), dried (MD8O ₄ ). The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate / hexane affords 2- (1 ', 2'-dihydro-2-oxospiro [cyclopentane-1,3'- [3H] indole] -5' -yl) -1Npyrrole-2- tert-butyl ester carboxylic acid (2.2 g, 83%) as a white powder, mp. 179-180.5 ° C. ¹ H NMR (DMSO-be) 400 MHz δ 1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H, 1 = 1.8 Hz, 3, 3 Hz), 6.22 (t, 1H, 1 = 3.3, 3.3 Hz), 6.79 (d, 1H, 1 = 7.9 Hz), 7.08 (dd,

1H, 1 = 7.9 Hz), 7.14 (d, 1H, 1 = 1.5 Hz), 7.28 (dd,

1H, 1 = 1.9, 3.3 Hz), 10.30 (s, 1H); M8 ((+) E81) m / e 352 Anal. Calculated for ^ Η ₂₄ Ν ₂ Ο ₃ : C, 71.57; H, 6.86; Ν, 7.95. Found: C, 71.08; H, 6.83; Ν, 7.74.

To a solution of 2- (1 ', 2'-dihydro-2'-oxospiro [cyclohexan-1,3' - [3Н] indole] -5'-yl) -1H-pyrrole-1-carboxylic acid tert-butyl ester (2 2 g, 6.0 mmol) in THF (anhydrous, 25 ml), chlorosulfonyl isocyanate (0.63 ml, 7.0 mmol) is added at -78 ° C. After 90 minutes, dimethylformamide (11 ml, 140 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2x50 ml). The organic layers are combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (30% ethyl acetate / hexane) affords 5- (2'-oxo-2 ', 3'-dihydrospiro [cyclopentane-1,3' - [3H] indole] -5 'tert-butyl ester -yl) -2-cyanopyrrole-1-carboxylic acid (1.7 g, 75%) as white crystals, mp. 167-9 ° C. ¹ H NMR (DMSO-b6, 400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H, 1 = 3.7 Hz), 6.84 (d, 1H, 1 = 7.9 Hz), 7.17 (dd, 1H, 1 = 1.8, 7.9 Hz), 7.28 ('t', 2H), 10.41 (s, 1H). M8 (Ε8Ι) m / e 376 [M-H] ^- . Anal Calculated for C22H ₂₃ N ₃ O ₃ : C, 70.01; H, 6.14; S, 11.13. Found: C, 69.67; H, 6.38; S, 11.04.

5- (2'-Oxo-2 ', 3'-dihydrospiro [cyclopentane-1,3' - [3H] indole] -5'yl) -2-cyanopyrrole-1-carboxylic acid tert-butyl ester (1 g,

2.7 mmol) is placed in a 25 ml round-bottom flask, closed with a rubber stopper and equipped with a nitrogen inlet and a capillary allowing gas to be removed. Strong nitrogen purging is maintained while the flask is placed in an oil bath and heated to 165 ° C. After 20 minutes at this temperature, the flask was removed from the oil bath and allowed to cool. Crystallization from ethyl ether afforded the title compound (600 mg, 79%) as a yellow powder, mp. 285-286 ° C. ¹ H NMR (DMSO-δ ... 400 MHz) δ 1.75-2.03 (m, 8H), 6.60 (dd, 1H, 1 = 2.4, 3.7 Hz), 6.84 (d, 1H, 1 = 8.1 Hz), 6.94 (dd, 1H, 1 = 2.4,

3.7 Hz), 7.52 (dd, 1H, 1 = 1.8, 8.1 Hz), 7.60 (d, 1H,

1 = 1.8 Hz), 10.38 (s, 1H), 12.45 (s, 1H). M8 (Ε8Ι) m / e 276 [M-H] ^- . Anal Calculated for:

C ₁₇ H ₁₅ S ₃ O: C, 73.63; H, 5.45; S, 15.15. Found: C, 73.24; H, 5.34; S, 14.96.

K 5- (1,2-Dihydro-2-oxospiro [cyclopentan-1,3- [3H] indole] -5'-yl) -1H-pyrrole-2-carbonitrile (0.18 g, 0.7 mmol, 1 equiv.) In p-xylene (20 ml), Loesson's reagent (0.14 g, 0.36 mmol, 0.5 equiv.) Is added and the reaction is heated under reflux for 1 h. The reaction is cooled to room temperature and adsorb on silica gel. Purification by column chromatography (20% ethyl acetate / hexane) on silica gel affords the product as an orange powder. Further purification by HPLC afforded the title compound as a green solid (0.144 g, 70%), mp. 275-276 ° C (destruction). ¹ H NMR (DMSO-b ₆ , 300 MHz) δ 1.81-2.16 (m, 8H), 6.69 (dd, 1H, 1 = 2.3, 3.7 Hz), 6.98 ( dd, 1H, 1 = 1.8, 3.7

Hz), 7.04 (d, 1H, 1 = 8.2 Hz), 7.63 (dd, 1H, 1 = 1.6, 8.2 Hz), 7.72 (d, 1 H, 1 = 1.3 Hz), 12.57 (s, 1H), 12.65 (s, 1H). M8 (Ε8Ι) [M-H] ^- = 292. Anal Calculated for: C ₁₇ H ₁₅ S ₃ 8: C, 69.6; H, 5.15; S, 14.32. Found: C, 69; H, 5.31; S, 13.81.

Example 8. 5- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -1- (tert-butoxycarbonyl) pyrrole-2-carbonitrile.

Tetrakis (triphenylphosphine) is added to a solution of 5'-bromospiro [cyclohexane-1,3'indolin] -2'-one (3.4 g, 12 mmol) in 1,2-DME (dimethoxyethane) (100 ml) under nitrogen atmosphere. palladium (0) (70 mg, 5 mol%). After 15 minutes, 2-borono-1H-pyrrole-1-carboxylic acid 1-tert-butyl ester (1.3 eq., 3.31 g, 15.6 mmol) and a solution of K ₂ CO ₃ (2.3 eq.) Were successively added. 3.83 g, 27.6 mmol) in water (5 ml). The solution was heated to 80 ° C for 3 hours and allowed to cool. The reaction mixture was poured into water (200 ml) and extracted with HU Ac (2x100 ml). The organic layers were combined, washed with brine (150 ml) and dried over MgO ₄ . The solution was filtered, concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluting with 30% EJAc / hexane) to give 2- (1 ', 2'-dihydro-2'-oxospiro [cyclohexane-1,3') tert-butyl ether - [3H] indole] -5 '-yl) -1H-pyrrole-1-carboxylic acid, (3.4 g, 76%) as a white powder, mp. 177 ° C. ¹ H NMR (SPS13; 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m, 10H), 6.18 (m, 1H), 6.23 ('t', 1H , 3 Hz), 6.91 (d, 1H, 1 = 8 Hz), 7.21 (d, 1H, 1 = 5 Hz), 7.34 (m, 1H), 7.44 (s, 1H) 8.33 (broad s, 1H, E2Oex). M8 ((+) - APC1) m / e 367 [(M + H) ⁺ ]. Anal Calculated for: С22Н ₂₆ Н ₂ О ₃ : С, 72.11; H, 7.15; S, 7.64. Found: C, 71.7; H, 7.16; S, 7.5.

To a solution of 2- (1 ', 2'dihydro-2'-oxospiro [cyclohexan-1,3' - [3Н] indole] -5'-yl) -1H-pyrrole-1-carboxylic acid tert-butyl ester (0 , 75 g, 2 mmol) in THF (anhydrous, 20 ml) at -78 ° C, chlorosulfonyl isocyanate (1.15 equiv., 0.23 ml, 2.3 mmol) is added. After 90 minutes, DMF (20 eq., 3.6 ml, 46 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2x50 ml). The organic layers are combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (30% ethyl acetate / hexane) gives 5- (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3' - [3H] indole] -5 'tert-butyl ester -yl) -2-cyanopyrrole-1-carboxylic acid (0.5 g, 63%) as an oil, which crystallizes from acetone to give white crystals, mp. 156 ° C. ¹ H NMR (s-DMSO. 400 MHz) δ 1.32 (s, 9H), 1.50 (m, 3 H), 1.60-1.70 (m, 5H), 1.75-1, 85 (m, 2H), 6.38 (d, 1H, 1 = 3.7 Hz), 6.87 (d, 1H, 1 = 7.9 Hz), 7.18 (dd,

1H, 1 = 1.5, 7.9 Hz), 7.27 (d, 1H, 1 = 3.7 Hz), 7.48 (d, 1H, 1 = 1.8 Hz), 10.42 ( wide s, 1H). M8 (E1) m / e 391 (M '). Anal Calculated for: ^ ₃ Η ₂₅ Ν ₃ Ο ₃ : C, 70.57; H, 6.44; Ν, 10.73. Found: C, 69.82; H, 5.46; Ν, 10.43.

To a solution of 2-cyano-5- (1,2-dihydro-2-oxospiro [cyclohexane1,3- [3H] indole] -5-yl) -1H-pyrrole-1-carboxylic acid tert-butyl ester (0.7 g, 1.8 mmol, 1 equiv.) In toluene (70 ml), Loesson's reagent (0.47 g, 1.1 mmol, 0.65 equiv.) Was added and the reaction was heated under reflux for 1 h. The reaction was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml). The organic layers are combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (20-30% ethyl acetate / hexane) on silica gel afforded the title compound as a yellow solid (0.7 g, 96%). ¹ H NMR ( _6th DMSO, 500 MHz) δ 1.30-1.98 (m, 19H),

6.45 (d, 1H, 1 = 3.7 Hz), 7.09 (d, 1H, 1 = 7.9 Hz), 7.31-7.34 (m, 2 N), 7.81 ( d, 1H, 1 = 1.4 Hz), 12.74 (s, 1H). M8 (Ε8Ι) [M-H] ^- = 406. Anal Calculated for: CuH ^^^: C, 7.79; H, 6.18; Ν, 10.31. Found: C, 67.86; H, 5.99; Ν, 10.25.

Example 9. 5- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -1-H-pyrrole-

2-carbonitrile.

To a solution of 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -1- (tert-butoxycarbonyl) pyrrole-2-carbonitrile (0.5 g, 1.2 mmol, 1 equiv.) In THF (5 ml) was added ΝαΟΕί (0.25 g, 3.6 mmol, 3 equiv.) In UNN (5 ml) and the reaction was heated to 80 ° C for 24 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers are combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (30% ethyl acetate / hexane) on silica gel afforded the title compound (0.27 g, 68%) as a yellow powder. ¹ H NMR (ye-DMSO, 500 MHz) δ 1.32-1.99 (m, 10 N), 6.71 (d, 1H, 1 = 3.7 Hz), 7.00 (d, 1H, 1 = 3.7 Hz), 7.09 (d, 1H, 1 = 8.4 Hz), 7.70 (dd, 1H, 1 = 1.6, 8.4 Hz), 8.05 (d, 1H, 1 = 1.1 Hz), 12.67 (s, 1H), 12.73 (s, 1H). M8 (Ε8Ι) [M-H] ^- = 306. Anal Calculated for

C ^ NiX ^: C, 70.33; H, 5.57; Ν, 13.67. Found: C, 69.64; H, 5.79; Ν, 13.04.

Example 10. 5- (2'-Thioxospiro [cyclohexan-1,3 '- [3H] indol] -5'-yl) -1-methylpyrrole-2-carbonitrile.

To a solution of 5- (2'-oxospiro [cyclohexane1,3 '- [3H] indole] -5'-yl) -1-methylpyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 equiv.) In toluene (50 ml) add Loesson's reagent (0.47 g, 1.1 mmol, 0.65 equiv.) and the reaction is heated to 80 ° C for 1 h. The reaction is cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml). The organic layers are combined, washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography afforded the product as a white solid (0.32 g, 55%). Ίΐ NMR ( _6th DMSO, 500 MHz) δ 1.36-1.99 (m, 10H), 3.7 (s, 3H), 6.35 (d, 1H, 1 = 4.2 Hz), 7.05 (d, 1H, 1 = 4.2 Hz), 7.16 (d, 1 H, 1 = 7.9 Hz), 7.44 (dd, 1H, 1 = 1.6, 8.1 Hz), 7.83 (d, 1H, 1 = 1.6 Hz), 12.75 (s, 1H). M8 (Ε8Ι) [M-H] ^- = 320. Anal. Calculated for: 0 ^ 9 ^ 8: C, 70.99; H, 5.96; Ν, 13.07. Found: C, 68.69; H, 5.36; Ν, 12.27.

Example 11. 5- (1,2-Dihydro-2-thioxospiro [cyclopentan-1,3- [3H] indol] -5-yl) -3-thiophenecarbonitrile.

5-bromo-2-thiophenecarbonitrile.

A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol) of hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 ml) and ethanol (500 ml) is heated under reflux under reflux for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product is treated twice with ice water and the resulting solid is collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper acetate monohydrate (ΙΙ) (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated under reflux for hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (2X30 ml), water (2X30 ml), brine (20 ml) and dried (Μ§8Ο 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 and the filtrate was concentrated and purified by chromatography (silica gel, chloroform) to obtain the title compound as an off-white solid (31.5 g combined, 58%). 1H (film) cm ^-1 2200. 'H-NMR (SDC1 ₃ ) δ 7.39-7.38 (d, 1H, 1 = 4.1 Hz), 7.10 (d, 1H, 1 = 4, 0 Hz); M8 (E1) m / e 187 (M 98%) 189 (M '100%).

5- (1,2-Dihydro-2-oxospiro [cyclopentan1,3- [3H] indol] -5-yl) -3-thiophenecarbonitrile was prepared according to the procedure for Example 5 using 5-bromo-2-thiophenecarbonitrile and (2 'oxo-2', 3'-dihydrospiro [cyclohexan-1,3 '- [3H] indole] -5'-yl) boronic acid: mp. 225228 ° C; '11 NMR (DMSO-th ₆ ) δ 1.63 (m, 8H), 1.90 (m, 2H), 6.91 (d, 1H, 1 = 8.13 Hz), 7.55 (dd, 1H,

1 = 8.13, 1.76 Hz), 7.60 (d, 1H, 1 = 4.17 Hz), 7.75 (d, 1H, 1 = 1.76 Hz), 7.93 (d, 1H, 1 = 4.17 Hz), 10.51 (s, 1H); M8 ((+) APC1) m / e 309 [M + H] ⁺ .

A solution of 5- (1,2-dihydro-2-oxospiro [cyclopentan-1,3- [3H] indol] -5-yl) -3-thiophenecarbonitrile (0.66 g, 2.4 mmol), and 2.4 bis (4 methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4 disulfide (0.97 g, 2.4 mmol) in toluene (250 ml) was stirred at 80 ° C. for 2 hours. The solution was concentrated. in a vacuum. The residue was extracted with ethyl acetate, the ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate, hexane 20/80) to obtain the title compound, mp. 269272 ° C (0.24 g, 32%). ¹ H-NMR (DMSO-a ₆ ) δ 2.09 (m, 8H), 7.05 (d, 1 = 8.1 Hz, 1H), 7.55 (dd, 1 = 8.1, 1, 7 Hz, 1H), 7.7 (d, 1 = 1.7 Hz, 1H), 7.95 (d, 1 = 1.3 Hz, 1H), 8.49 (d, 1 = 1.3 Hz , 1H), 8.49 (d, 1 = 1.3 Hz, 1H), 12.68 (s, 1H); M8 (E1 HEC) m / e 309 (M-H) ^- .

Example 12. 5- (1,2-Dihydro-thioxospiro (cyclopentan-1,3- [3H] indol) -5-yl) -2-thiophenecarbonitrile.

The title compound is obtained from 5- (1,2-dihydrooxy-spiro (cyclopentan-1,3- [3H] indole) 5-yl) -2-thiophenecarbonitrile (2 g, 6.8 mmol) and Loesson's reagent (3.32 g, 8, 2 mmol) by heating under reflux in toluene (150 ml) for 3 hours. Yield 1.5 g (48.3%). Mp 250-253 ° C. ^! H NMR (DMSO-a6) δ 12.75 (C, 1H), 7.98-7.97 (d, 1H, 1 = 3.9 Hz), 7.717.70 (d, 1H, 1 = 5.2 Hz), 7.65-7.62 (d, 1H, 1 = 8.1 Hz), 7.09-7.07 (d, 1H, 1 = 8.1 Hz), 2.13-2.08 (m, 6H), 1.99-1.85 (m, 2H); M8. [M-H] ^- = 309. IR (8P ATC) 1430, 1620, 2220 cm ^-1 . Anal SPN ₁₄ H ₂ 8 ₂ . Calculated for C, 65.77; H, 4.55; H, 9.02. Found: C, 65.27; H, 4.41; H, 8.84.

Example 13. 5- (3-Fluoro-4-methoxyphenyl) spirocyclohexane-1,3- [3H] indole] -2 (1H) -thione.

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

Prepared from 4-bromo-2-fluoroanisole and (2'oxo-2 ', 3'-dihydrospiro [cyclohexan-1,3' - [3H] indole] -5'-yl) boronic acid according to the procedure for Example 5 c obtaining the title compound as a white solid, mp. 178-180 ° C; ¹ H-NMR (DMSO-6) δ 10.4 (s, 1H), 7.65 (d, 1H, 1 = 1.1 Hz), 7.5-7.4 (m, 3H), 7.2 ( t, 1H, 1 = ά1 = 8.8 Hz), 3.9 (s, 3H), 1.9 (m, 2H), 1.7-1.6 (m, 8H); M8 (APC1 (-)) m / e 324 [M-H] ^- ; Anal Calculated for: for С20Н ₂₀ ГНО ₂ : С, 73.83, Н, 6.20, Н, 4.30. Found: C, 73.55; H, 6.23; H, 4.40.

The title compound was obtained by refluxing overnight a mixture of 5- (3-fluoro-4-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) it and an equal weight of phosphorus pentasulfide in pyridine. Removal of pyridine in vacuo followed by treatment of the residue with a 5N hydrochloric acid solution and subsequent recrystallization from ethanol gives a gray solid, mp. 228-229 ° C; ^! NMR (DMSO-ae) δ 12.7 (s, 1H), 7.9 (s, 1H), 7.6-

7.5 (m, 2H), 7.5-7.4 (m, 1H), 7.2 (t, 1H, 1 = 8.8 Hz),

7.1 (d, 1H, 1 = 8.1 Hz), 3.9 (s, 3H), 1.9-1.8 (m, 7H), 1.4-1.3 (m, 3H) ; M8 (APC1 (-)) [M-H] ^- m / e 324. Anal. Calculated for: С ₂₀ Н ₂₀ ГНО8-0.25 Н ₂ О: С, 69.44; H, 5.97; H, 4.05. Found: C, 69.43; H, 5.75; H, 4.32.

Example 14. 5- (2-Amino-5-pyrimidinyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

A mixture of 5- (2-amino5-pyrimidinyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one and an equal weight of phosphorus pentasulfide in pyridine is obtained under reflux overnight. Removal of pyridine in vacuo followed by treatment of the residue with 5N hydrochloric acid and subsequent recrystallization in ethanol gives a gray solid; Mp 274277 ° C (dec.);

Я-NMR (DMSO-a ₆ ) δ 12.7 (s, 1H), 8.6 (s, 2H), 7.9 (s, 1H), 7.5 (d, 1H, 1 = 8.1 Hz), 7.1 (d, 1H, 1 = 8.1 Hz), 6.8 (s, 2H), 1.9-1.8 (m, 7H), 1.4-1.3 (m , 3H). M8 (APC1 (-)) [M-H] ^- m / e 309.

Example 15. 3- (1,2-Dihydro-2-thioxospiro [cyclopentan-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile.

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

To a solution of oxindole (2.0 g, 15.0 mmol) cooled to -25 ° C in 40 (cm ³ ) anhydrous THF in an H2 atmosphere, p-butyllithium (1.6 M in hexane, 19.7 cm ³ , 31 is added 5 mmol) dropwise. H, H, H ′, H′-tetramethylethylenediamine (4.75 cm ³ , 31.5 mmol) are added to the resulting turbid solution. 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 then stirred for 14 hours. The reaction mixture was poured into water , extracted with HEC Ac (x2), the combined organic layers were washed with diluted HCl (pH 1) and water (x2), dried (Md8O4) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, EYuAs: hexane 1: 4) to give the title compound (1.4 g, 7.5 mmol, 50%) as a tan ^solid: H NMR (СОС1 ₃ ) δ 1.8-2.2 (m, 8Н), 6.94 (dd, 1 = 7.5, 1.0 Hz, 1Н), 7.01 (dd, 1 = 7, 5, 1.0 Hz, 1H),

7.14-7.25 (m, 2H); 9.30 (broad s, 1H).

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

A solution of spiro [cyclopentane-1,3 '- [3H] indole] -2'(1'H) -one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm ³ ) is treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm ³ ). After 30 minutes, the mixture was poured into a saturated sodium hydrogencarbonate solution and extracted (EJAc x 2), the combined organic layers were washed with water, a saturated sodium hydrogencarbonate solution, water, dried (MD80 ₄ ) and evaporated to give the title compound (0.37 g , 1.47 mmol, 96%) as an off-white solid that is used without further purification: 'H NMR (СОС1 ₃ ) δ 1.8-2.27 (m, 8Н), 6.79 (d, 1 = 8 Hz, 1H), 7.30-7.39 (m, 2H), 8.63 (broad s, 1H).

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

A solution of 3-cyano-5-fluorobromobenzene (0.5 g, 2.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 g) in ethylene glycol dimethyl ether (20 cm ³ ) was stirred in an atmosphere of Ν2 for 20 min To this mixture are then added (spiro [cyclopentan-1,3 '- [3H] indole] -2' (1 'H) -on5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate ( 0.8 g, 7.8 mmol) in water (5 cm ⁵ ). The solution was allowed to boil under reflux for 18 hours and then cooled to room temperature, poured into 2Ν10H and extracted with ЕУАс (х3). The combined extracts were washed with water, brine, dried (MD80 ₄ ) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, EYuAs, hexane) to afford the title compound (0.35 g, 44%) as white needles, m.p. 235-237 ° C; Ή NMR (DMSO-b ₆ ) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, 1 = 1.7, 2.0, 7.0 Hz) 7.8-7.7 (m, 2H), 7.6 (dd, 1H, 1 = 1.8, 6.4 Hz), 6.9 (d, 1H, 1 = 8.1 Hz), 2.0-1.9 (m, 8H); M8 (E1) M ⁺ @ m / e 306.

General Procedure A.

The title compounds were prepared from 5 '- (3-cyano-5-fluorophenyl) spiro [cyclopentane-1,3' - [3H] indole] -2 '(1'H) -one (40 mg) and Loesson's reagent ( 50 mg) in toluene (10 mL) at reflux in a sealed tube for 16 h. The mixture was concentrated and the residue was dissolved in THF minutimalnom amount, then purified by HPLC ₍₂ occupies 8, 30 cm x 2.5 cm, ЕУАсГексан 2: 8 at 20 ml / min) to obtain the title compound (0.022 g) as an off-white solid: mp. 236238 ° C; Ή NMR (DMSO-b ₆ ) δ 12.66 (broad s, 1H), 8.11 (s, 1H), 7.97 (dt, 1H, 1 = 10.1 and 2.2 Hz), 7, 79-7.76 (m, 2H), 7.68 (dd, 1H, 1 = 8.1 and 1.7 Hz), 7.07 (d, 1H, 1 = 8.1 Hz), 2.10 -2.05 (m, 6H); and 1.971.88 (m, 2H); M8 (E1) m / e 322 [M] ⁺ .

Example 16. 5- (3-Chlorophenyl) -3,3-dimethyl1,3-dihydro-2H-indol-2-thion.

5- (3-chlorophenyl) -3,3-dimethyl-1,3-dihydroindol-2-one.

5-Bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) and tetrakis (triphenylphosphine) palladium (0) (0.239 g) are stirred in the atmosphere nitrogen 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 is heated at the boil under reflux for 2 hours and then stirred at room temperature overnight. The mixture was diluted with saturated ammonium chloride and extracted with EAAc (x3). The combined organic layers were dried (MD804), filtered and evaporated. The residue was purified by column chromatography (8X2, EJAc: hexane, 1: 3) to obtain the title compound (0.284 g, 25%): mp. 188-189 ° C; ^! H NMR (DMSO-b6) δ 3.34 (s, 6H), 6.93 (d, 1H, 1 = 8.04 Hz), 7.38-7.35 (m, 1H), 7.53- 7.43 (m, 2H), 7.61 (d, 1H, 1 = 7.68 Hz), 7.70 (s, 2H), 10.40 (s, 1H); IR (KBr) 3420, 3150, 3050, 1700 cm ^-1 ; M8 (E1) m / e 270 (MH) ^- ; 0ΉΝ Calculated for: Sk5N14SSh0 + 0.1S ₄ N ₈ 0 ₂ : C, 70.21; H, 5.32; Ν, 4.99; Found: C, 70.3; H, 5.44; Ν, 4.93.

The title compound was prepared from 5- (3-chlorophenyl) -3,3-dimethyl-1,3-dihydroindol-2-one (100 mg) and Loesson's reagent (120 mg) in toluene (10 ml) under reflux a refrigerator in accordance with General Procedure A, to give the title compound (0.031 g) as an off-white solid: mp. 158-160 ° C; ¹ H NMR (Scc1 ₃ ) δ 9.67 (broad s, 1H), 7.55 (s, 1H),

7.47-7.43 (m, 3H), 7.40-7.30 (m, 2H), 7.08 (d, 1H, 1 = 8.7 Hz) and 1.50 (s, 6H) ; M8 (E1) m / e 287/289 [M] ⁺ .

Example 17. 3-Benzyl-5- (3-chlorophenyl) -3methyl-1,3-dihydro-2H-indol-2-thion.

The title compound was prepared from 3-benzyl-5- (3-chlorophenyl) -3-methyl-1,3-dihydroindol-2-one (100 mg) and Loesson's reagent (120 mg) in toluene (10 ml) under reflux refrigerator according to General Procedure A, to give the title compound (0.022 g) as an off-white solid: mp. 168-170 ° C; ¹ H NMR (Scc1 ₃ ) δ 9.23 (broad s, 1H), 7.49 (s, 1H), 7.49-7.30 (m, 4H), 7.21 (s, 1H), 7.15 -7.09 (m, 3H), 6.96-6.94 (m, 2H), 6.89 (d, 1H, 1 = 8.0 Hz), 3.19 (dd, 2H, 1 = 40 5 and 13 Hz) and 1.57 (s, 3H); M8 (EL) m / e 363/365 [M] ⁺ .

Example 18. 4- (3,3-Dimethyl-2-thioxo-2,3-dihydro-1H-indol-5-yl) -2-furonitrile.

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

Receive in accordance with the method of example 5, using (2'-oxo- [2,3-dihydro-3,3dimethyl-1,3 '- [3H] indole] -5'-yl) boronic acid (354 mg, 1, 7 mmol) and 4-bromo-furan-2carbonitrile (200 mg, 1.2 mmol) to give the title compound (76 mg, 0.3 mmol, 26%) as a white solid: mp 199,6-201,4 ° ^C! H NMR (DMSO-b ₆ ) δ 1.28 (s, 6H), 6.89 (d, 1 = 8.0 Hz, 1H), 7.48 (dd, 1 = 8.0, 1.8 Hz , 1H), 7.65 (d, 1 = 1.5 Hz, 1H), 8.1 (s, 1H), 8.5 (s,

1H), 10.46 (s, 1H); M8 (E81); m / e 251 (M-H) ^- ; Anal C1 ₅ H ₁₂ S ₂ O ₂ .0.6 H ₂ O

The title compound was prepared from 4- (3,3-dimethyl-2-oxo-2,3-dihydro-1Nindol-5-yl) furan-2-carbonitrile (73 mg) and Loesson's reagent (120 mg) in toluene ( 10 ml) under reflux in accordance with General Procedure A, to give the title compound (0.003 g) as an off-white solid: mp 188-191 ° C; ¹ H NMR (СОС1 ₃ ) δ 9.63 (broad s, 1H), 7.83 (s, 1H), 7.36-7.33 (m, 3H), 7.06 (d, 1H, 1 = 7.9 Hz) and 1.48 (s, 6H); M8 (E1) m / e 268 [M] ⁺ .

Example 19. 5- (3-Methoxyphenyl-3,3-dimethyl-1,3-dihydro-2-H-indole) -2-thion.

5-Bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one.

3,3-Dimethylindol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g, 4.07 mmol) are stirred in acetic acid (5 cm ³ ), then dropwise to the reaction mixture add bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm ³ ). The reaction is stirred for 50 minutes, then poured into water. The mixture was alkalinized with sodium carbonate, extracted with ethyl acetate (x3), dried (MD8O4), filtered and evaporated to give the title compound (0.89 g, 92%) ¹ H NMR (DMSO-b6) δ 1.21 (s, 6H) ), 6.76 (d, 1H, 1 = 8.22 Hz), 7.29 (dd, 1H, 1 = 2.12 Hz, 8.23 Hz), 7.49 (d, 1H, 1 = 2 , 03 Hz), 10.4 (s, 1H).

5-Bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.094 g) are stirred in the atmosphere nitrogen in dimethoxyethane (12 cm ³ ). After 15 minutes 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added and then calcium carbonate (1.15 g, 8.34 mmol) in water (5 cm ³ ). The reaction is heated under reflux for 5 hours and then cooled to room temperature. Saturated aqueous ammonium chloride and E1OAc were added and the mixture was filtered. The aqueous layer was extracted with E1OAc (x2) and the combined organic layers were dried (Mg8O4), filtered and evaporated. The residue was purified by column chromatography (81O2, E1OAc: 1: 3 hexane) to give 5 (3-methoxyphenyl) -3,3-dimethyl-1,3-dihydroindol-2-one (0.11 g, 31%), Mp = 157-158 ° C; ¹ H NMR (DMSO-b6) 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, 1 = 1.14 Hz),

10.4 (s, 1H); M8 (E1) m / e 266 (M-H) ^- ; ΌΗΝ Analysis. Calculated for: C ₁₇ H ^ O ₂ : C, 76.38; H, 6.41; Ν, 5.24; Found: C, 76.02; H, 6.49; Ν, 5.02.

The title compound was prepared from 5- (3-methoxyphenyl) -3,3-dimethyl-1,3-dihydroindol-2-one (100 mg) and Loesson's reagent (120 mg) in toluene (10 ml) under reflux in in accordance with General Procedure A, to give the title compound (0.022 g) as an off-white solid: mp. 149-150 ° C; ¹ H NMR (SBSl) δ 9.69 (broad s, 1H), 7.49-7.46 (m, 2H), 7.37 (t, 1H, 1 = 8.0 Hz), 7.16 ( d, 1H, 1 = 7.7 Hz), 7.09-7.06 (m, 2H), 6.90 (dd, 1H, 1 = 8.2 and 2.3 Hz) 3.88 (s, 3H) and 1.50 (s, 6H); M8 (E1) m / e 283 [M] ⁺ .

Example 20. 3- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -4-fluorobenzonitrile.

3- (1,2-dihydro-2-oxospiro [cyclohexane1,3- [3H] indol] -5-yl) -4-fluorobenzonitrile.

Receive in accordance with the methodology of example 5: So pl. 205-206 ° C. ¹ H NMR (DMSO-b ₆ ) δ 10.47 (s, 1H), 8.08-8.06 (dd, 1H), 7.89-7.85 (m, 1H), 7.65 (s , 1H), 7.54-7.49 (m, 1H), 7.43-7.40 (tt, 1H), 6.95-6.93 (d, 1H, 1 = 7.9 Hz), 1.97-1.83 (m, 2H); 1.69-1.55 (m, 8H); M8 (E1) m / e 320 (M ⁸ ).

The title compound was prepared from 3- (1,2-dihydro-2-oxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -4-fluorobenzonitrile (100 mg) and Loesson's reagent (120 mg) in toluene (10 ml) under reflux in accordance with General Procedure A, to give the title compound (0.037 g) as an off-white solid: mp. 230-233 ° C; ¹ H NMR (SPS1 ₃ ) δ 9.82 (broad s, 1H), 7.86 (s, 1H), 7.77 (dd, 1H, 1 = 7.0 and 1.8 Hz), 7.68 -7.63 (m, 1H), 7.45 (d, 1H, 1 = 8.0 Hz), 7.31 (d, 1H, 1 = 9.0 Hz), 7.15 (d, 1H, 1 = 8.1 Hz), 2.17-1.84 (m, 7H) and 1.60-1.54 (m, 3H); M8 (E1) m / e 336 [M] ⁺ .

Example 21. 5- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -3-pyridinecarbonitrile.

A solution of 3-bromopyridin-5-carbonitrile (2.79 g, 15.26 mmol), hexamethyldiol (5.00 g, 15.26 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.20 g, 0.17 mmol) in anhydrous dimethoxyethane (30 cm ³ ) in an atmosphere of Ν _{2 is} heated at the boil under reflux. After 16 hours, the mixture was concentrated and purified by column chromatography (81O ₂ , EluAc: hexane 5:95) to give 3 cyanopyridin-5-trimethylstannan (2.82 g,

10.55 mmol, 69%): 11 NMR (SPS1 ₃ ) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); M8 ((+) APC1) m / e 269 (M + H) ⁺ .

A solution of 5'-bromospiro [cyclohexane-1,3 '[3H] indole] -2'(1'H) -one (1.97 g, 7.05 mmol), 3 cyanopyridin-5-trimethylstannan (2.26 g, 8.46 mmol), bis (triphenylphosphine) palladium (11) chloride (0.33 g, 0.47 mmol) and lithium chloride (1.48 g, 35 mmol) in anhydrous toluene (30 cm ³ ) are heated under reflux reflux condenser. After 16 hours, the mixture was cooled, partitioned between E1OAc and water, the aqueous layer was re-extracted with E1OAc (x2), the combined organic extracts were washed with water, dried (MD8O ₄ ) and evaporated. The residue was subjected to lonochnoy chromatography (8ίΟ _2, ΕιΟΑο: hexane, 1: 2) and then further purified by preparative liquid chromatography (Rpshskrysgs C18, 10 shyugop, 50h250 mm MCC \: Η ₂ Ο 1: 1, 100 ^cm3 / min, room temperature 7.92 min) to give 3 - (1 ', 2'-dihydro-2'-oxospiro [cyclohexan-1,3' - [3H] indole] -5'-yl) pyridinecarbonitrile as white crystals (0 56 g, 1.84 mmol, 26%): M.p. 232-234 ° C, ¹ H NMR (SPS1 ₃ ) δ 1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, 1 = 8 Hz), 7.49 (dd, 1H, 1 = 8.2 Hz), 7.66 (d, 1H, 2 Hz), 8.15 (t, 1H, 1 = 2 Hz), 8.39 ( s, 1H, broad),

8.89 (d, 1H, 1 = 2 Hz), 9.06 (d, 1H, 1 = 2 Hz); M8 ((+) - E81) m / e 304 (Μ + Η) ⁺ ; Anal C ^ H ^ O SIK

The title compound was prepared from 3- (1 ', 2'-dihydro-2'-oxospiro [cyclohexan-1,3' - [3H] indol-5'-yl) pyridinecarbonitrile (100 mg) and Loesson's reagent (120 mg ) in toluene (10 ml) under reflux in accordance with General Procedure A, to give the title compound (0.004 g) as a yellow solid: mp. 237-238 ° C; ¹ H NMR (SPS _{1 3} ) δ 9.56 (broad s, 1H), 9.03 (d, 1H, 1 = 1.9 Hz), 8.87 (d, 1H, 1 = 1.4 Hz), 8.12 (s, 1H), 7.87 (s, 1H), 7.50 (d, 1H, 1 = 8.1 Hz), 7.17 (d, 1H, 1 = 8.1 Hz), 2.19-1.85 (m, 7H); and 1.59-1.54 (m, 3H); M8 ((-) - APC1) m / e 318 [M-H] ^- .

Example 22. 5- (3,4-Difluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

5 '- (3,5-difluorophenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1'H) -one.

Receive in accordance with the methodology of example 5: So pl. 180-183 ° C; ^! H-NMR (ATP1 ₃ ) δ

8.35 (s, 1H), 7.59 (d, 1H, 1 = 2.0 Hz), 7.40 (dd, 1H, 1 = 6.2, 2.0 Hz), 7.10-7 03 (m, 2H), 6.99 (d, 1Η, 1 = 8.1 Hz), 7.76 (tt, 1H, 1 = 4.3, 2.3 Hz), 2.05-1, 62 (m, 10H); M8 ((+) APC1) m / e 314 [M + S] ⁺ .

The title compound was prepared from 5 '- (3,5-difluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one (100 mg) and Loesson's reagent (120 mg ) in toluene (10 ml) under reflux in accordance with General Procedure A, to give the product (0.020 g) as a yellow solid: mp. 232-233 ° C; ^! H NMR (SPS1 ₃ ) δ 10.05 (broad s, 1H), 7.83 (s, 1H), 7.44 (dd, 1H, 1 = 8.1 and 1.4 Hz), 7.38- 7.30 (m, 1H), 7.26-7.19 (m, 3H), 7.11 (d, 1H, 1 = 8.1 Hz), 2.17-1.82 (m, 7H) and

1.66-1.53 (m, 3H); M8 ((-) - APC1) m / e 328 [M-H] ^- .

Example 23. 5- (5-Chloro-2-thienyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

5- (5-Chloro-2-thienyl) spiro [cyclohexane1,3- [3H] indole] -2 (1H) -one.

Receive in accordance with the methodology of example 5: So pl. 191-192 ° C, Ή NMR (SPS1 ₃ ) δ 1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, 1 = 4.0 Hz, 1H), 7.36 (dd, 1 = 7.5, 1.6 Hz, 1H), 7.53 (d, 1 = 0.9 Hz, 1H), 7.80 (wide s, 1H) ; ¹³ C-NMR (THF-dq) δ 21.35, 25.33, 33.12 (t), 48.32 (s), 110.40, 121.66, 121.96, 125.44, 127, 25 (d), 128.17,

128.43, 136.92, 140.20, 143.43, 183.72 (s); M8 (E1) m / e 318 (M + H) ⁺ ; Anal (C ₁₇ Η ₁₆ C1NΟ8) C, H, Ν.

The title compound was prepared from 5- (5-Chloro-2-thienyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (100 mg) and Loesson's reagent (120 mg) in toluene (10 ml) under reflux in accordance with General Procedure A, to give the product (0.041 g) as a yellow solid: mp. 231-232 ° C; Ή NMR (SPS1 ₃ ) δ 9.75 (broad s, 1H), 7.82 (d, 1Η, 1 = 1.2 Hz), 7.43 (dd, 1H, 1 = 8.1 and 1.6 Hz), 7.04-7.02 (m, 2H), 6.89 (d, 1Η, 1 = 3.8), 2.15-1.84 (m, 7H) and 1.59-1, 52 (m, 3H); M8 ((-) - APC1) m / e 332/334 [M-H] ^- .

Example 24. 5- (1,2-Dihydro-2-thioxospiro [cyclohexane-1,3- [3H] indole] -5-yl) -3-furancarbonitrile.

5- (1 ', 2'-dihydro-2'-oxospiro [cyclohexane1,3' - [3H] indole] -5'-yl) -3-furancarbonitrile.

Receive in accordance with the methodology of example 5: So pl. 243-245 ° C. ^! H-NMR (DMSO-sE) δ 10.48 (s, 1Η), 8.62 (d, 1H, 1 = 0.7 Hz), 7.76 (d, 1H, 1 = 1.5 Hz), 7.58-7.55 (dd, 1H), 7.33 (d, 1Η, 1 = 0.7 Hz), 6.92-6.90 (d, 1H, 1 = 8.1 Hz), 1 87-1.83 (m, 2H); 1.73-1.53 (m, 8H). M8 ((+) E1) m / e 292 (M +).

The title compound was prepared from 5- (1 ', 2'-dihydro-2'-oxospiro [cyclohexan-1,3' - [3H] indol] -5'-yl) -3-furancarbonitrile (100 mg) and a reagent Loesson (120 mg) in toluene (10 ml) under reflux in accordance with General Procedure A to give the product (0.020 g) as a yellow solid: mp. 264-268 ° C; ¹ H NMR (SPS _{1 3} ) δ 9.66 (broad s, 1H), 7.98 (s, 2H), 7.59 (dd, 1H, 1 = 8.2 and 1.5 Hz), 7.08 (d, 1H, 1 = 8.2 Hz), 6.78 (s, 1H), 2.16-1.85 (m, 7H) and 1.561.52 (m, 2H): M8 ((-) - APC1) m / e 307 [M-H] ^- .

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' - [3H] indole] -2 '(1'H) -one.

Receive in accordance with the methodology of example 5: So pl. 188-189 ° C; ^! H-NMR (SPS1 ₃ ) δ 7.97 (s, 1H), 7.57-7.54 (m, 2H), 7.41-7.34 (m, 2H),

7.20 (t, 1H, 1 = 8.7 Hz), 9.96 (d, 1H, 1 = 8.1 Hz), 2.04-1.65 (m, 10H); M8 ((+) APC1) m / e 330 [M + S] ⁺ .

The title compound was prepared from 5 '- (3-chloro-4-fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one (100 mg) and Loesson's reagent ( 100 mg) in toluene (10 ml) under reflux in accordance with General Procedure A, to give the product (0.036 g) as an off-white solid: ¹ H NMR (DMSO- ₆ ) δ 12.74 ( broad s, 1H), 7.92 (s, 1H, 1 = 1.4 Hz), 7.87 (dd, 1H, 1 = 7.1 and 2.3 Hz), 7.70-7.65 ( m, 1H), 7.61 (dd, 1H, 1 = 7.1 and 1.5 Hz), 7.49 (t, 1H, 1 = 8.9 Hz), 7.14 (d, 1H, 1 = 8.1 Hz), 1.99-1.82 (m, 7H) and 1.40-1.37 (m, 3H): M8 ((-) - APC1) m / e 344/346 [M- H] ^- .

Example 26. 5- (3-Chloro-5-fluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

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

Receive in accordance with the procedure of example 5: So pl. 178-180 ° C; ¹ H-NMR (COC1 ₃ ) δ 8.50 (s, 1H), 7.57 (d, 1H, 1 = 1.8 Hz), 7.39 (dd, 1H, 1 = 6.2, 1, 9 Hz), 7.33-7.32 (m, 1 H), 7.15 (dq, 1H, 1 = 5.7, 1.7, 0.7 Hz), 7.06 (dq, 1H, 1 = 4.2, 1.9, 0.4 Hz), 7.00 (d, 1H, 1 = 8.1 Hz), 2.05-1.64 (m, 10H); M3 ((-) E31) [M-H] ^- @ m / e 328.

The title compound was prepared from 5 '- (3-chloro-5-fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one (100 mg) and Loesson's reagent ( 100 mg) in toluene (10 ml) under reflux in accordance with General Procedure A to give the product (0.039 g) as an off-white solid: ¹ H NMR (DMSO-b ₆ ) δ 12.76 ( broad s, 1H), 7.97 (d, 1H, 1 = 1.1 Hz), 7.67 (dd, 1H, 1 = 8.1 and 1.4 Hz), 7.60-7.54 ( m, 2H), 7.40 (dt, 1H, 1 = 8.65 and 2.0 Hz), 7.14 (d, 1H, 1 = 8.1 Hz), 1.99-1.83 (m , 7H) and 1.41-1.38 (m, 3H): M3 ((-) - APC1) m / e 344/346 [M-H] ^- .

Example 27. 5- (3,5-Difluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

5 '- (3,5-difluorophenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1'H) -one.

Receive in accordance with the methodology of example 5: So pl. 180-183 ° C; Ή-NMR (СОС1 ₃ ) δ

8.35 (s, 1H), 7.59 (d, 1H, 1 = 2.0 Hz), 7.40 (dd, 1H, 1 = 6.2, 2.0 Hz), 7.10-7 03 (m, 2H), 6.99 (d, 1H, 1 = 8.1 Hz), 7.76 (tt, 1H, 1 = 4.3, 2.3 Hz), 2.05-1, 62 (m, 10H); M3 ((+) APC1) m / e 314 [M + H] ⁺ .

The title compound was prepared from 5 '- (3,5-difluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one (100 mg) and Loesson's reagent (100 mg ) in toluene (10 ml) under reflux in accordance with General Procedure A, to obtain the title compound 0.029 g as an off-white solid: ¹ H NMR (DMSO-db) δ 12.76 (wide s , 1H), 7.84 (s, 1H), 7.64-7.56 (m, 1H), 7.46 (d, 1H, 1 = 8.1 Hz), 7.40-7.32 ( m, 1H), 7.22-7.15 (m, 2H), 1.99-1.80 (m, 7H) and 1.38-

1.35 (m, 3H); M3 ((-) - APC1) m / e 328 [M-H] ^- .

Example 28. 5- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -4-propyl-2thiophenecarbonitrile.

5- (1,2-dihydro-2-oxospiro [cyclohexane1,3- [3H] indol] -5-yl) -4-propyl-2-thiophenecarbonitrile.

The title compound was prepared analogously to Example 5 from 5-bromo-4-p-propyl thiophene-2-carbonitrile (1.17 g, 5 mmol), (1,2-dihydro-2-oxospiro [cyclohexane-1,3- [ 3H] indole]) - 5-boronic acid (1.24 g, 5 mmol), tetrakis (triphenylphosphine) palladium, potassium carbonate (2.75 g, 21 mmol), water (10 ml) and dimethoxyethane (50 ml), heated at reflux overnight to give the product (0.7 g, 40%): mp 168171 ° C; Ή NMR (DMSO-db) δ 10.56 (s, 1H), 7.93 (s, 1H), 7.52-7.51 (d, 1H, 1 = 1.5 Hz), 7.33- 7.29 (dd, 1H, 1 = 1.6 Hz), 7.00-6.96 (d, 1H, 1 = 8.0 Hz), 2.62-

2.57 (t, 2H), 1.86 (m, 2H), 1.70-1.56 (m, 11H), 0.88-0.84 (t, H); M3 m / e (APC1 (+)) 351 [M + H] ⁺ . 1K (KShirokiy) 1620, 1700, 2200 cm ^-1 . Anal С ₂₁ Н ₂₂ Е ₂ О3 1/2 Н ₂ О Calculated for: С, 70.2; H, 6.39; E, 7.79. Found: C, 70.67; H, 6.34; E, 7.62.

The title compound was prepared from 5- (1,2-dihydro-2-oxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -4-propyl-2-thiophenecarbonitrile (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) under reflux in accordance with General Procedure A to give the title compound (0.037 g) as an orange solid: ¹ H NMR (DMSO-b ₆ ) δ 12, 83 (broad s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.44 (d, 1H, 1 = 7.7 Hz), 7.19 (d, 1H, 1 = 8.0 Hz), 2.60 (t, 2H, 1 = 8.0 Hz), 1.98-1.79 (m, 7H), 1.64-1.56 (m, 2H), 1.39-1.35 (m, 2H) and 0.87 (t, 3H, 1 = 7.3 Hz): M3 ((-) APC1) m / e 365 [M-H] ^- .

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- [3H] indole] -2 (1H) -one.

Prepared from (2'-oxo-2,3-dihydrospiro [cyclohexan-1,3 '- [3H] indol] -5'-yl) boronic acid (3.2 g, 12.5 mmol) and 4-bromo- 2-fluoronitrobenzene (3 g, 13.6 mmol) as described in Example 5 to give the title compound (0.7 g, 16%) as a yellow solid: mp. 213-215 ° C; Ή NMR (DMSO-f) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H, 1 = 8.13 Hz), 7.68 (dd, 1H, 1 = 8.13, 1.76 Hz), 7.74 (dd, 1H, 1 = 8.68, 1.76 Hz), 7.86 (d, 1H, 1 = 1.98 Hz)

7.92 (dd, 1H, 1 = 13.4, 1.76 Hz), 8.18 (t, 1H, 1 = 8.46 Hz) and 10.52 (s, 1H); M3 (E1) m / e = 340 (M ⁺ ).

The title compound was prepared from 5- (3-fluoro-4-nitrophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) under reflux in accordance with General Procedure A to give the product (0.021 g) as a yellow solid: 'H NMR (DMSO-b ₆ ) δ 12.82 (broad s, 1H), 8 21 (t, 1H, 1 = 8.4 Hz), 8.07 (d, 1H, 1 = 1 Hz),

78.9 (dd, 1H, 1 = 13.1 Hz), 7.79 (dt, 1H, 1 = 8.1 and 2.6 Hz), 7.19 (1H, 1 = 8.2 Hz), 1.99-1.83 (m, 7H) and 1.42-

1.39 (m, 3H): M3 ((-) - APC1) m / e 355 [M-H] ^- .

Example 30. 4- (1,2-Dihydro-2-thioxospiro [cyclohexane-1,3- [3H] indole] -5-yl) -2-furancarbonitrile.

4- (1,2-dihydro-2-oxospiro [cyclohexane1,3- [3H] indol] -5-yl) -2-furancarbonitrile.

A solution of 3-bromo-5-cyanofuran (0.75 g, 4.4 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.4 g) in ethylene glycol dimethyl ether (20 cm ³ ) was stirred in an E2 atmosphere for 20 min To this mixture are then added (spiro [cyclohexan-1,3 '- [3H] indole] -2'(1'H) -on5-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 and then cooled to room temperature, poured into 2Ν No. 1OH and extracted with E! OAc (x3). The combined extracts were washed with water, brine, dried (MD8O4) and evaporated. The residue was purified by column chromatography (81O2, E! OAc, hexane) to give the product (0.45 g, 36%) as an off-white solid, mp. 240-242 ° C; ^! H NMR (DMSO-y6) δ 10.4 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd, one

H, 1 = 1.5, 6.5 Hz), 6.9 (d, 1H, 1 = 8.0 Hz), 2.0-1.6 (m, 10H); M8 (E1) M ⁴ @ m / e 292.

The title compound was prepared from 4- (1,2-dihydro-2-oxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -2-furancarbonitrile (67 mg) and Loesson's reagent (67 mg) in toluene (10 mL) at reflux, according to the general procedure a to give the title compound (0.018 g) as a yellow ^solid: H NMR (DMSO-de) δ 12.74 (s, 1H), 8.68 (s, 1H),

8.26 (s, 1H), 7.96 (s, 1H), 7.62 (dd, 1H, 1 = 8.0 and 1.0 Hz), 7.10 (s, 1H, 1 = 8, 1 Hz), 1.94-1.78 (m, 7H) and

I, 35-1.32 (m, 3H): M8 ((-) - ARSC m / e 307 [M-H] ^- .

Example 31. 5 '- (3-Chlorophenyl) spiro [cyclobutane-1,3' - [3H] indo l] -2 '(1'H) -thione.

5-Bromspiro [cyclobutane-1,3 - [3H] indole] 2 (1H) -one.

To a stirred solution of spiro [cyclobutane-1,3 '- [3H] indole] -2' (1 'H) -one (1. Mei. Set. 1987, 824-9) (1.0 g, 6 mmol) in glacial acetic acid (10 ml) was added dropwise at room temperature a solution of bromine (0.30 ml, 6 mmol) in glacial acetic acid (6 ml). After stirring for 10 minutes, anhydrous sodium acetate (0.47 g, 6 mmol) was added and the solution was evaporated in vacuo. The residue was dissolved in ethyl ether (50 ml) and washed successively with water (50 ml), aqueous saturated sodium bicarbonate (50 ml), water (50 ml) and brine (30 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Crystallization from ethyl ether gives the product as a white fluffy solid (1.1 g, 73%), mp. 235-7 ° C. ^! H NMR (DMSO-e, 300 MHz) δ 2.15-2.41 (m, 6H), 6.74 (d, 1 H, 1 = 8.2 Hz), 7.33 (dd, 1H, 1 = 2, 8.2 Hz), 7.75 (d, 1H, 1 = 2 Hz), 10.36 (broad s, 1H). M8 (EC m / e 251 | M '|. Anal. Calculated for: ScN ₁₀ B ^ O: C, 52.41; H, 4.00; Ν, 5.56. Found: C, 51.98; H , 4.24; Ν, 5.42.

To a solution of 5-bromospiro [cyclobutane-1,3 [3H] indole] -2 (1H) -one (0.6 g, 2 mmol) in ethylene glycol dimethyl ether (50 ml) under nitrogen atmosphere was added tetrakis (triphenylphosphine) palladium ( 0) (140 mg, 0.1 mmol). 3chlorophenylboronic acid (0.48 g, 3 mmol) and potassium carbonate (0.76 g, 5 mmol) in water (5 ml) are successively added to the solution. The mixture was heated to 80 ° C. for 3 hours and allowed to cool. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3x100 ml). The organic layers are combined, washed with brine (50 ml) and dried over magnesium sulfate. The solution was filtered off, evaporated in vacuo and the residue was purified by HPLC (2xLax PKO, C18, 10i, 15A, 50X250 mm; 35% Water / 65% AcC ^ 254MM; AMB temp.) To give 5- (3-chlorophenyl ) spiro [cyclobutane-1,3- [3H] indole] -2 (1H) -one (200 mg, 35%) as a white powder, mp. 199.5-201 ° C. ^! H NMR (DMSO-6, 300 MHz) δ 2.21-2.2 (8m, 2H), 2.40-2.45 (m, 4H), 6.87 (d, 1H, 1 = 8.1 Hz), 7.37 ('d', 1H), 7.44-7.52 (m, 2H), 7.65 (wide d, 1H, 1 = 7.8 Hz), 7.76 (wide s , 1H); 7.92 (broad s, 1H); 10.35 (s, 1H). M8 (ET) m / e 283 [M ⁴ ]. Anal Calculated for: С17Н ₁₄ СШО: С, 71.96; H, 4.97; Ν, 4.94. Found: C, 70.75; H, 5.07; Ν, 4.68.

The title compound was prepared from 5- (3-chlorophenyl) spiro [cyclobutane-1,3 [3H] indole] -2 (1H) -one (55 mg) and Loesson's reagent (55 mg) in toluene (10 ml) at refluxing, in accordance with General Procedure A, to give 0.016 g of the title compound as an orange solid: ¹ H NMR (DMSO-th ₆ ) δ 12.58 (broad s, 1H), 8.07 ( d, 1H, 1 = 1.5 Hz), 7.82 (t, 1H, 1 = 1.7 Hz), 7.70 (d, 1H, 1 = 7.74 Hz), 7.60 (dd, 1H, 1 = 8.12 and 1.71 Hz), 7.49 (t, 1H, 7.9 Hz), 7.41 (d, 1H, 1 = 8.32 Hz), 7.05 (d, 1H, 1 = 8.14 Hz) and 2.57-

2.27 (m, 6H); M8 ((-) - ARSC m / e 298/300 [M-H] ^- .

Example 32. 5 '- (2-Chlorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1' H) -thione.

The title compound was prepared from 5- (2-chlorophenyl) spiro [cyclohexane-1,3 [3H] indole] -2 (1H) -thione (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) at reflux, in accordance with the general method a to give 0.042 g of product as an off-white ^solid:! H NMR (DMSO _6th ) δ 12.75 (broad s, 1H),

7.80 (d, 1H, 1 = 1.1 Hz) 7.58-7.55 (m, 1H), 7.48-7.36 (m, 4H), 7.16 (d, 1H, 1 = 8.0 Hz); M8 ((-) - ARSC m / e 326/328 [M-H] ^- .

Example 33. 5 '- (4-Chlorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1' H) -thione.

The title compound was prepared from 5- (4-chlorophenyl) spiro [cyclohexane-1,3 [3H] indole] -2 (1H) -one (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) at refluxing, in accordance with General Procedure A, to give 0.035 g of the product as an off-white solid: ¹ H NMR (DMSO-th ₆ ) δ 12.74 (broad s, 1H), 7.91 (d , 1H, 1 = 1.3 Hz), 7.69 (d, 2H, 1 = 5.5 Hz), 7.60 (dd, 1H, 1 = 8.1 and 1.4 Hz), 7.50 (d, 2H, 1 = 8.5 Hz), 7.15 (d, 1H, 1 = 8.1 Hz), 1.99-1.83 (m, 7H) and 1.50-1.36 ( m, 3H); M8 ((-) - APC1) m / e 326/328 [M-H] ^- .

Example 34. 5- (1 ', 2'-Dihydro-2'-thioxospiro [cyclohexane-1,3' - [3H] indole] -5 '-yl) -4-methyl2-thiophenecarbonitrile.

5-bromo-4-methyl-2-thiophenecarboxaldehyde.

To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 ml), a solution of p-BCC (2.5 M, 153 ml, 0.383 mol) in hexane is added at -40 ° C in a nitrogen atmosphere. After addition, the solution was stirred at -40 ° C under nitrogen for 30 minutes, cooled to -78 ° C and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450 ml). 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 ambient temperature and quenched with an aqueous solution of hydrochloric acid (1 L). The solution was extracted with ethyl acetate (3x450 ml) and the extracts washed with water, brine and dried (MgO ₄ ). Removal of the solvent in vacuo gave the title compound as a white solid (46 g, 88.3%). A sample of the product is crystallized from hexane: So pl. 63-65 ° C; ΙΒ (kWh) 1654 cm ^-1 . Ή-NMR (СОС1з) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); M8 (E1) m / e 204/206 (M ⁺ ). Anal Calculated for: C ₆ H ₅ BrO8: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.

5-bromo-4-methyl-2-thiophenecarbonitrile.

Prepared from 5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure of Example 5. White solid: mp. 40-42 ° C; IR (KBr) 2200 cm ^-1 ; Ή-NMR (SPS1 ₃ ) δ 7.29 (s, 1H),

2.21 (s, 3H). M8 (E1) m / e 201/203 (M ⁺ ,

98% / 100%); Anal Calculated for: С ₆ Н ₄ ВгЫ8: С, 35.66; H, 1.99; Ν, 6.93. Found: C, 36.00; H, 2.14; Ν, 6.76.

Receive in accordance with the procedure of example 5, using (2'-oxo- [2,3-dihydro-3,3dimethyl-1,3 '- [3H] indole] -5'-yl) boronic acid (357 mg, 1, 7 mmol) and 5-bromo-4-methylthiophen-2-carbonitrile (295 mg, 1.5 mmol) to give 5- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) - 4-methyl thiophen-2carbonitrile (227 mg, 0.8 mmol, 55%) as a white solid: mp. 192.3-193 ° C, ¹ H NMR (DMSO-d ₆ ) δ 1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d, 1 = 8.0 Hz, 1H ), 7.34 (dd, 1 = 8.0, 1.8 Hz, 1H), 7.49 (d, 1 = 1.7 Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); M8 (E1) m / e 282 (m) ⁺ ; Anal C11 \ O8.

The title compound was prepared from 5- (3,3-dimethyl-2-oxo-2,3-dihydro-1-Nindol-5-yl) -4-methylthiophen-2-carbonitrile (0.77 g, 2.39 mmol) and pentasulfide phosphorus (0.42 g, 0.96 mmol) in toluene (20 ml) under reflux. After 3 hours, the reaction was cooled and partitioned between water and E1OAc, the organic layer was isolated, dried (MD8O ₄ ) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, EYuAs - hexane gradient elution) to give the product (0.25 g, 0.73 mmol, 30%) as an orange solid: ¹ H NMR (DMSO-db) δ 12, 82 (broad s, 1H), 7.88 (s, 1H),

7.82 (d, 1H, 2 Hz), 7.49 (dd, 1H, 1 = 8.1, 1.6 Hz),

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

1.36 (m, 3H); M8 ((-) - APC1) m / e 321 [M-H] ^- .

Example 35. 5- (1 ', 2'-Dihydro-2'-thioxospiro [cyclohexane-1,3] - [3H] indo l-5'-yl) -2-thiophenecarbonitrile.

5-Bromo-2-thiophenecarbonitrile: A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 ml), and ethanol (500 ml) are heated in nitrogen atmosphere at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and evaporated in vacuo to give an oil. The crude product is treated twice with ice water and the resulting solid is collected on a filter. A mixture of a part of the above solid (44.31 g, 215 mmol), acetate of copper monohydrate (11) (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated under reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (2X30 ml), water (2X30 ml), brine (20 ml) and dried (MgO 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 and the filtrate was evaporated and purified by chromatography (silica gel, chloroform) to obtain the title compound as an off-white solid (31.5 g combined, 58%). IR (film) cm ^-1 2200. ^! H-NMR (COC1 ₃ ) δ 7.39-7.38 (d, 1H, 1 = 4.1 Hz), 7.10 (ά, 1H, 1 = 4.0 Hz); M8 (E1) m / e 187 (M ⁺ , 98%) 189 (M ⁺ , 100%).

5- (2'-Oxo-2 ', 3'-dihydrospiro [cyclohexane1,3' - [3H] indole] -5'yl) -2-thiophenecarbonitrile was prepared according to the procedure for Example 5 using 5-bromo-2- thiophenecarbonitrile and (2'oxo-2 ', 3'-dihydrospiro [cyclohexan-1,3' [3H] indole] -5'-yl) boronic acid: mp. 225-228 ° C; Ή NMR (DMSO-d ₆ ) δ 1.63 (m, 8H),

1.90 (m, 2H), 6.91 (d, 1H, 1 = 8.13 Hz), 7.55 (dd, 1H, 1 = 8.13, 1.76 Hz), 7.60 (d , 1H, 1 = 4.17 Hz), 7.75 (d, 1H, 1 = 1.76 Hz), 7.93 (ά, 1H, 1 = 4.17 Hz), 10.51 ( ₈ , 1H ); M8 ((+) APC1) m / e 309 [M + H] ⁺ .

The title compound was prepared from 5- (2'-oxo-2 ', 3'-dihydrospiro [cyclohexane-1,3' - [3H] indole] -5 'yl) -2-thiophenecarbonitrile (0.69 g) and pentasulfide phosphorus (0.4 g) in toluene (20 ml) under reflux. After 3 hours, the reaction was cooled, placed in a saturated aqueous sodium hydrogen carbonate solution, and extracted with EuAc. The organic layer was isolated, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, E1OAs - hexane gradient elution) to give the title compound (0.215 g) as an orange solid: ¹ H NMR (DMSO-baa) δ 12,82 (br s, 1H) 8.00-7.98 (m, 2H), 7.74 (d, 1H, 1 = 4.1 Hz), 7.69 (dd, 1H, 1 = 8.2 and 1.6 Hz), 7.14 (d, 1H, 1 = 8.1 Hz), 1.99-

1.83 (m, 7H) and 1.40-1.37 (m, 3H); M8 ((-) - APC1) m / e 323 [M-H] ^- .

Example 36. 5 '- (3-Fluorophenyl) alcohol [cyclohexane-1,3' - [3H] indol] -2 '(1' H) -tdone.

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

Receive in accordance with the methodology of example 5: So pl. 171-172 ° C; Ή-NMR (SPS1 ₃ ) δ 8.43 (q, 1H), 7.62 (d, 1H, 1 = 1.8 Hz), 7.42 (dt, 1H, 1 = 6.2, 2.0 Hz), 7.39-7.37 (m, 1H), 7.33 (dt, 1H, 1 = 5.1, 1.3 Hz), 7.26 (dq, 1H, 1 = 5.9, 2.1 Hz), 7.05-

6.99 (m, 2H); 2.03-1.64 (m, 10H); M8 ((+) APC1) m / e 296 [M + H] ⁺ .

The title compound was prepared from 5 '- (3-fluorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1'H) -one (0.70 g) and phosphorus pentasulfide (0.4 g) in toluene (20 ml) at the boil under reflux. After 3 hours, the reaction is cooled, placed in a saturated aqueous sodium hydrogen carbonate solution and extracted with E1OAc, the organic layer is isolated, dried (MD8O ₄ ) and evaporated. The residue was purified by column chromatography (81O ₂ , E1OAc-hexane elution gradient) to give the product (0.42 g) as an off-white solid: 1 H NMR (DMSO-b ₆ ) δ 12.75 (broad s, 1H), 7.95 (d, 1H, 1 = 1.5 Hz), 7.64 (dd, 1H, 1 = 8.13 and 1.5 Hz), 7.53-7.48 (m, 3H ), 7.21-7.14 (m, 2H), 1.99-1.83 (m, 7H) and 1.40-1.37 (m, 3H); M8 ((-) - APC1) m / e 310 [M-H] ^- .

Example 37. 5- (3-Hydroxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

5 '- (3-Hydroxyphenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1'H) -one.

Receive in accordance with the methodology of example 5: So pl. 213-216 ° C; Ή NMR (COC1 ₃ ) δ

1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, 1 = 8 Hz), 7.01-7.04 (m, 2H), 7.23 (t, 1H, 1 = 7.7 Hz),

7.38 (d, 1H, 1 = 8 Hz), 7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (1H, broad s); M8 ((+) - APC1) m / e 294 [M + H] ⁺ .

The title compound was prepared from 5 '- (3-hydroxyphenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1'H) -one (100 mg) and Loesson's reagent (110 mg) in toluene ( 10 ml) under reflux in accordance with General Procedure A, to give the title compound (0.0045 g) as an off-white solid: ¹ H NMR (COCO ₃ ) δ 9.59 (broad s, 1H), 7.89 (s, 1H), 7.49 (dd, 1H, 1 = 8.1 and 1.5 Hz), 7.33 (t, 1H, 1 = 7.9 Hz),

7.15-7.10 (m, 3H), 6.84 (dd, 1H, 1 = 8.0 and 2.2 Hz),

2.17-2.05 (m, 2H), 1.98-1.88 (m, 5H) and 1.57-1.53 (m, 3H): M8 ((-) - APC1) m / e 308 [MH] ^- .

Example 38. 5- (3-Chlorophenyl) -3,3-diethyl1,3-dihydro-2H-indol-2-thion.

A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) in an atmosphere of Ν _{2 was} cooled to -25 ° C and treated dropwise with n-butyllithium (2.5 M in hexane, 240 ml, 0.6 mol) . Ν, добавляют, Ν ', Ν' tetramethylethylenediamine (90.4 ml, 0.6 mol) was added to the resulting solution. After 30 minutes, iodoethane (48 ml, 0.6 mol) was added and the reaction mixture was allowed to warm to room temperature, and then stirred overnight. After this, the reaction mixture was poured into an aqueous solution of ΝΉ ₄ Ο, extracted with EuAc (2x), and the combined organic layers were washed with diluted HCl, water, brine, dried (MD8O ₄ ) and concentrated. The resulting oil was treated with hexane to give a crude product (24.5 g, 51%). A sample (3 g) was recrystallized from E1OAc / hexane to give 3-ethylindol-2-one (1.4 g), mp. 100-101 ° C; ^! NMR (DMSO-be) δ 0.76 (t, 3H, 1 = 7.5 Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, 1 = 5.7 Hz ), 6.8 (dt, 1H, 1 = 7.69, 0.45 Hz), 6.93 (dt, 1H, 1 = 7.45, 1.10 Hz), 7.15 (m, 1H) 7.22 (m, 1H); 10.3 (s, 1H); M8 (E81) m / e 270 [M + H].

A solution of 3-ethylindol-2-one (16 g, 0.1 mol) in dry THF (200 ml) in an atmosphere of Ν _{2 is} cooled to -25 ° C and treated dropwise with η butyllithium (2.5 M in hexane, 80 ml, 0 , 2 mol). Ν, Ν, Ν ', Ν''- tetramethylethylenediamine (30 ml, 0.2 mol) are added to the resulting solution. After 30 minutes, iodoethane (8 ml, 0.1 mol) was added and the reaction mixture was allowed to warm to room temperature, and then stirred overnight. The reaction mixture was poured into an aqueous IN ₄ Cl solution, extracted with E1OAc (2x), and the combined organic layers were washed with diluted HCl, water, brine, dried (MD8O ₄ ) and concentrated. The resulting oil is treated with hexane to give 3,3-diethylindol-2-one (9 g, 45%), mp 156-159 ° C; Ή NMR (DMSO-b ₆ ) δ 10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H),

7.58 (d, 1H, 1 = 1.7 Hz), 7.53-7.50 (m, 1H), 7.45-

7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 6.91-6.89 (d, 1H, 1 = 8 , 2 Hz), 1.87-1.80 (m, 2H), 1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); M8 (+ E81) m / e 190 (M + H).

A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) is treated with bromine (6.4 g, 40 mmol). After 30 minutes, the mixture was diluted with water and extracted with E1OAc (2x), the combined organic layers were washed with water, saturated sodium bicarbonate solution, then brine, dried (MD8O ₄ ) and evaporated to give a crude product (7.6 g, 75%). The sample is recrystallized from

EJAc / hexane to give 5-bromo-1,3-dihydro-3,3-diethyl- [2H] -indol-2-one, mp. 164165 ° C; ^! H-NMR (DMSO-b ₆ ) δ 10.45 (s, 1H), 7.41-

7.40 (d, 1H, 1 = 2.2 Hz), 7.34-7.31 (m, 1H), 6.78-

6.76 (d, 1H, 1 = 8.2 Hz), 1.78-1.65 (m, 4H), 0.50-

0.46 (m, 6H); M8 (-E81) m / e 266/268 (M-H).

Solution of 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), carbonate potassium (4 g, 30 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml) and water (25 ml) are heated to boiling with reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EuAc (2x). The combined organic extracts were washed with water, then with brine, dried (MgO ₄ ) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, EYuAs: hexane 1: 3) to give compound 5 (3-chloro-phenyl) -3,3-diethyl-1,3-dihydro-indol-2ona (0.8 g, 27%), mp 195-197 ° C; ^! H-NMR (DMSO-b ₆ ) δ 7.70 (t, 1H, 1 = 2 Hz), 7.62-7.60 (m, 1H), 7.58 (d, 1H, 1 = 1.7 Hz), 7.52, (dd, 1H, 1 = 8.1, 2 Hz), 7.43 (t, 1H, 7.9 Hz), 7.36-7.33 (m, 1H), 6 90 (d, 1H, 1 = 8.1 Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, 1 = 7.4 Hz); M8 (+ APC1) m / e 300/302 (M-H).

The title compound was prepared from 5- (3-chloro-phenyl) -3,3-diethyl1,3-dihydro-indol-2-one (100 mg) and Loesson's reagent (100 mg) in toluene (10 ml) at reflux according to general procedure a to give the product (0.023 g) as a yellow ^solid: H NMR (DMSO-b ₆ ) δ 12.73 (broad s, 1H),

7.77 (t, 1H, 1 = 1.8 Hz), 7.75 (d, 1H, 1 = 1.6 Hz), 7.68-7.62 (m, 2H), 7.48 (t , 1H, 1 = 7.9 Hz), 7.40 (d, 1H, 1 = 8.3 Hz), 7.09 (d, 1H, 1 = 8.1 Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H, 1 = 7.3 Hz): M8 ((-) - APC1) m / e 314/316 [ MH] ^- .

Example 39. 5- [4-Fluoro-3- (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3 H] indole] -2 (1H) thion.

5- [4-Fluoro-3 - (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one is obtained 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), as described in example 5, to obtain the title compound (0.87 g, 30%) as a solid: mp. 222 ° C; ^! H NMR (DMSO-b ₆ ) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.92 (d, 1H, 1 = 8.13 Hz) 7.51 (dd, 1H, 1 = 8.13, 1.76 Hz), 7.55 (dd, 1H, 1 = 10.54, 9.01 Hz), 7.72 (d, 1H, 1 = 1.76 Hz), 7.90 (dd, 1H, 1 = 7.03, 2.20 Hz), 7.98 (m, 1H) and 10.39 (s, 1H); M8 (E1) m / e 363 (M ⁺ ).

The title compound was prepared from 5- [4-fluoro-3- (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Loesson's reagent (90 mg ) in toluene (10 ml) under reflux, in accordance with General Procedure A, to give the product (0.016 g) as a yellow solid: ¹ H NMR (DMSO-b ₆ ) δ 12.75 (wide s, 1H), 8.06-8.00 (m, 1H), 7.96-7.92 (m, 2H), 7.66-

7.56 (m, 2H), 7.16 (d, 1H, 1 = 8.1 Hz), 1.99-1.83 (m, 7H) and 1.41-1.38 (m, 3H) ; M8 ((-) - APC1) m / e 378 [M-H] ^- .

Example 40. 4- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -2-fluorobenzonitrile.

The title compound was prepared from 4- (1,2-dihydro-2-oxospiro [cyclohexane-

1.3- [3H] indol] -5-yl) -2-fluorobenzonitrile (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) under reflux, in accordance with General Procedure A, to obtain the name of the compound (0.050 g) as an orange solid: ¹ H NMR (DMSO-b ₆ ) δ 12.80 (broad s, 1H), 8.04 (d, 1H, 1 = 1.3 Hz), 7, 98 (t, 1H, 1 = 7.5 Hz), 7.92 (dd, 1H, 1 = 11.3 and 1.3 Hz), 7.76 (d, 2H, 1 = 8.0 Hz), 7.18 (d, 1H, 1 = 8.2 Hz), 1.99-1.82 (m, 7H) and 1.40-1.38 (m, 3H); M8 ((-) - APC1) m / e 335 [M-H] ^- .

Example 41. 5- (1,2-Dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -4-n-butyl-2thiophenecarbonitrile.

The title compound was prepared by a method analogous to Example 5 from 5-bromo-4-n-butylthiophenecarbonitrile (1.24 g, 5.1 mmol), (1,2-dihydro-2-oxospiro [cyclohexane-

1.3- [3H] indole]) - 5-boronic acid (1.24 g, 5.05 mmol), tetrakis (triphenylphosphine) palladium (0.25 g), potassium carbonate (2.75 g, 21 mmol), water (10 ml) and dimethoxyethane (50 ml), heated at the boil under reflux for 5 hours to obtain 5- (1,2-dihydro2-oxospiro [cyclohexane-1,3- [3H] indole] -5-yl) 4-n-butyl-2-thiophenecarbonitrile (1 g, 54%), M.p. 130-132 ° C. Ί1 NMR (DMSO-b ₆ ) δ 10.56 (s, 1H), 7.92 (s, 1H), 7.52-7.51 (d, 1H, 1 = 1.2 Hz),

7.32-7.29 (dd, 1H, 1 = 1.5 Hz), 6.98-6.96 (d, 1H, 1 = 8.0 Hz), 2.64-2.59 (t, 2H), 1.99-1.86 (m, 2H), 1.70-1.50 (m, 11H), 1.32-1.22 (m, 2H), 0.86-0.82 ( t, 3H); M8 (APC1 (+)) m / e 365 [M + H] 0 ⁺ ; ΙΚ (KBg) 1620, 1700; 2200 cm ^-1 ; Anal C ₂₂ H ₂₄ No. O8 1/4 H ₂ O. Calculated for: C, 71.61; H, 6.69; N, 7.59. Found: C, 71.13; H, 6.61; Ν, 6.91.

The title compound was prepared from 5- (1,2-dihydro-2-oxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -4-n-butyl-2-thiophenecarbonitrile (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) under reflux in accordance with General Procedure A to give the product (0.050 g) as an orange solid: ¹ H NMR (DMSO-be) δ 12.83 ( broad s, 1H), 7.95 (s, 1H),

7.77 (s, 1H), 7.44 (d, 1H, 1 = 8.1 Hz), 7.18 (d, 1H, 1 = 8.1 Hz), 2.63 (t, 1H, 1 = 7.9-8.0 Hz), 1.99-1.77 (m, 7H), 1.60-1.50 (m, 2H), 1.39-1.35 (m, 3H), 1.2967

1.22 (m, 2H) and 0.81 (t, 3H, 7.3 Hz): MOH ((-) - ARO) m / e 379 [M-H] ^- .

Example 42. 5- (3-Fluoro-5-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -thione.

The title compound was prepared from 5- (3-fluoro-5-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) -one (90 mg) and Loesson's reagent (90 mg) in toluene (10 ml) under reflux in accordance with General Procedure A, to give the product (0.043 g) as an off-white solid: ¹ H NMR (DMSO-th ₆ ) δ 12.74 (broad s, 1H) 7.90 (s, 1H), 7.63 (dd, 1H, 1 = 8.1 and 1.2 Hz), 7.13 (d, 1H, 1 = 8.1 Hz), 7.08 ( d, 1H, 1 = 10 Hz), 7.01 (s, 1H), 6.83 (dt, 1H, 1 = 11 and 2.0 Hz), 1.99-

1.83 (m, 7H) and 1.40-1.37 (m, 3H): MOH ((-) - ARO) m / e 340 [M-H] ^- .

Example 43. 5- (3-Chlorophenyl) -M-hydroxyspiro [cyclohexane-1,3 '- [3H] indole] -2-amine.

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

To a solution of the latter title compound (1.96 g, 5.73 mmol) in DMSO (20 ml), hydroxylamine (60% in water, 5 ml) was added and the mixture was heated to 120 ° C. After 1 h, the reaction was cooled, partitioned between diethyl ether and saturated aqueous ammonium chloride. The organic layer was washed with water and brine and then dried (MgSO ₄ ) and evaporated. The crude product is then crystallized from MeOH to give the title compound (1.67 g, 5.08 mmol, 89%) as a white solid: ¹ H NMR (CEEC) δ 7.52 (t, 1H, 1 = 1 , 7 Hz), 7.43-7.28 (m, 7H), 6.83 (d, 1H, 1 = 5 Hz) and 1.98-1.51 (m, 10H); MZ (EZ! (+)) M / e 327/329 [M + H] ⁺ .

Example 44. N- (Acetyloxy) -5 '- (3-chlorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2''amine.

To a solution of 5- (3-chlorophenyl) -M-hydroxy-spiro [cyclohexane-1,3 '- [3H] indole] -2-amine (0.23 g, 0.71 mmol) in methylene chloride-methanol (9: 1, 10 ml) acetic anhydride (0.08 ml, 0.8 mmol) and 4-dimethylaminopyridine (catalytic amount) are added in a nitrogen atmosphere. After 20 min the reaction was evaporated and the product was purified by column chromatography (Z1O _2, methanol: methylene chloride 5:95). The product is then treated with diisopropyl ether to obtain the title compound (0.12 g, 0.32 mmol, 45%): '11 NMR (COC1 ₃ ) δ 7.52-7.51 (m, 2H), 7.43 -7.27 (m, 5H), 6.88 (d, 1H, 1 = 8 Hz), 2.27 (s, 3H), 2.04-1.92 (m, 4H), 1.84- 1.74 (m, 4H); and 1.72-1.57 (m, 2H); MZ (E8! (+)) M / e 369/371 [M + H] ⁺ ; Analysis. Calculated for:

C ₂₁ H ₂₁ C1M ₂ O ₂ . 0.5 H ₂ O C 66.98: H 5.64: Ν 7.34. Found: C, 66.74; H, 5.86: Ν 7.41.

Example 45. 5 '- (3-Fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one oxime.

Obtained in accordance with the method for example 43 of 5 '- (3-fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -thione (0.59 g, 1.90 mmol) to obtain the title compound (0.053 g, 0.17 mmol, 10%): 'H NMR (DMSO-J6) δ 9.59 (s, 1H), 9.40 (s, 1H), 7, 57 (d, 1H, 1 = 1.5 Hz), 7.46-7.39 (m, 4H), 7.11-7.05 (m, 1H), 6.80 (d, 1H, 1 = 8.1 Hz), 2.04-1.97 (m, 2H),

1.82-1.74 (m, 2H) and 1.66-1.42 (m, 6H): MOH (E8! (-)) m / e 309 [M-H] ^- . Analysis. Calculated for: СЩ ^^ О: С 73.53, Н 6.17, Ν 9.03. Found: C, 73.33; H, 6.07; Ν 8.83.

Example 46. 5 '- (2-Fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -onoxime.

5'-Bromspiro [cyclohexane-1,3 '- [3H] indole] -2' (1'H) -one 2 '(O-benzyloxy).

5'-Bromo-2 '- (methylthio) spiro [cyclohexane 1,3' - [3H] indole] (9.0 g, 28.98 mmol) and O ^- benzylhydroxylamine hydrochloride (13.8 g, 86.9 mmol ) are mixed in methanol (150 ml) and heated to 45 ° C for 6 hours. Methanol is evaporated in vacuo. Ethyl acetate was added to the residue, and the resulting mixture was washed with a solution of ammonium chloride. Ethyl acetate was dried over magnesium sulfate, the collected ethyl acetate was evaporated in vacuo and the residue was chromatographed on 90 alumina (9: 1 hexane / E! OAc) to the desired product (6.5 g, 60%). ¹ H NMR (DMSO-6, 300 MHz) δ 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H), 6.71 (d, 1H, 1 = 8.26 Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1H).

Method A. 5 '- (2-Fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1H) -one 2 (O-benzyloxy).

5'-Bromspiro [cyclohexane-1,3 '- [3H] indole] -2'(1'H) -one 2 '(O-benzyloxy) (1.0 g, 2.6 mmol) and tetrakistriphenylphosphine Pb (0 ) (0.14 g, 0.12 mmol) was stirred under nitrogen in ethylene glycol dimethyl ether (23 ml). 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 is heated to reflux overnight, cooled to room temperature and filtered through a celite filter. Saturated ammonium chloride was added. The aqueous layer was extracted with ethyl acetate (3 X 100 ml). The combined organic layers were dried (MgSO ₄ ), filtered and the solvent was removed in vacuo. The product is purified by silica gel chromatography; (eluent: 10: 0.5 hexane: ethyl acetate) to obtain the desired target compound (0.75 g, 1.8 mmol, 72%) as a viscous oil. ¹ H NMR (500 MHz, DMSO-b ₆ ) δ 1.44-1.73 (8H, m), 1.93-2.06 (2H, q), 5.00 (2H, s), 6, 88 (1H, d, 1 = 8.1 Hz), 7.24-7.38 (6H, m), 7.44-7.56 (5H, m), 9.64 (1H, s); M8 (E81 (+ ye)) m / e 399 (M-Η) ^- .

Method B.

A solution of 5 '- (2-fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1H) -one 2 (O-benzyloxime) (0.55 g, 1.37 mmol) in ethanol (15 ml) was added to palladium on charcoal (10%, 0.11 g) in ethanol (10 ml). The mixture was stirred under a hydrogen atmosphere (from a balloon) for 24 hours at room temperature. The reaction mixture was filtered through a celite filter and the filtrate was evaporated in vacuo. The product was purified by silica gel chromatography (hexane: ethyl acetate, elution gradient) to obtain the title compound (0.45 g, 1.12 mmol, 82%), mp. 200-203 ° C; Ί1 NMR (500 MHz, DMSO-be) δ 1.45-1.73 (8Н, m), 1.962.00 (2Н, q), 6.83 (1Н, d, 1 = 7.9), 7, 23-7.50 (6H, m), 9.42 (1H, s), 9.58 (1H, s); M8 (E81 (+ ye)) m / e 311 (M + H) ⁺ .

Example 47. 5 '- (4-Fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -one oxime.

5 '- (4-Fluorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1'H) -one 2' (O-benzyloxy).

Prepared from 5'-bromo-spiro [cyclohexane1,3 '- [3H] indole] -2' (1'H) -one 2 '(O-benzyloxy) (1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid (0.72 g, 5.2 mmol) according to Example 46, method A. The product is purified by silica gel chromatography; (eluent: 10: 0.5 hexane: ethyl acetate) to obtain the desired product (0.70 g, 1.7 mmol, 67%) as a viscous oil. 'H NMR (500 MHz, DMSObe) δ 1.42-1.77 (8H, m), 1.95-1.99 (2H, q), 5.00 (2H, s), 6.84 (1H d, 1 = 8.1 Hz), 7.21-7.63 (1H, m),

9.58 (1Η, s); M8 (E81 (-y)) m / e 399 (M-Η) ^- .

The product is synthesized using 5 '- (4 fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] 2 '(1'H) -one 2' (O-benzyloxy) (0.70 g, 1.74 mmol ) according to Example 45, Method B. The product was purified by silica gel chromatography (hexane: ethyl acetate, elution gradient) to obtain the title compound (0.44 g, 1.4 mmol, 81%), mp. 205208 ° C; ^! H NMR (500 MHz, DMSO-b ₆ ) δ 1.43-1.77 (8H, m), 2.00-2.05 (2H, q), 6.80 (1H, d, 1 = 8, 2 Hz), 7.21-7.24 (2H, m), 7.33-7.35 (1H, dd, 1 = 1.9 Hz), 7.49 (1H, s), 7.60- 7.63 (2H, m), 9.35 (1H, s), 9.56 (1H, s); M8 (E81 (+ ye)) m / e 311 (M + H) ⁺ .

Example 48. 5 '- (3,4-Difluorophenyl) spiro [cyclohexane-10'-p-indole ^ X 1' I) -one oxime.

5 '- (3,4-difluorophenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1' H) -one 2 '(O-benzyloxy).

Prepared from 5'-bromo-spiro {cyclohexane1,3 '- [3H] indole} -2'(1'H) -one 2 '(O-benzyloxy) (1.0 g, 2.6 mmol) and 3.4- difluorophenylboronic acid (1.6 g, 5.2 mmol of a 50% acid solution in THF / water) in accordance with Example 46, Method A. The product was purified by silica gel chromatography (eluent: 10: 0.5 hexane: ethyl acetate) s obtaining the desired product (0.75 g, 1.7 mmol, 69%) as a viscous oil. ¹ 1 NMR (500 MHz, DMSO-b ₆ ) δ 1.41-1.78 (8H, m), 1.95-1.99 (2H, q), 5.00 (2H, s), 6, 82 (1H, d), 7.28-7.46 (8H, m), 7.58 (1H, q), 7.67-7.71 (1H, m), 9.61 (1Η, s) ; M8 (E81 (-ye)) m / e 417 (M-H) ^- .

The reaction of the last title compound (0.70 g, 1.6 mmol) in accordance with Example 45, method B, yields the title compound (0.44 g, 1.3 mmol, 80%) ^,! H NMR (500 MHz, DMSO-b ₆ ) δ 1.42-1.79 (8H, m), 2.01-2.05 (2H, q), 6.78-6.80 (1Η, d) 7.39-7.46 (3H, m), 7.55 (1Η, s), 7.70 (1Η, m), 9.10 (1Η, s), 9.59 (1Η, s); M8 (E81 (+ yy)) m / e 329 (M + H) ⁺ .

Example 49. 5 '- (3-Methoxyphenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1' H) -onoxime.

5 '- (3-Methoxyphenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1' H) -one 2 '(O-benzyloxy).

Prepared from 5'-bromo-spiro {cyclohexane1,3 '- [3H] indole} -2'(1'H) -one 2 '(O-benzyloxy) (1.0 g, 2.6 mmol) and 3-methoxyphenylboronic acid (0.79 g, 5.2 mmol) according to Example 46, method A. The product was purified by silica gel chromatography; (eluent: 10: 0.5 hexane: ethyl acetate) to obtain the desired product (0.80 g, 1.9 mmol, 75%) as a viscous oil. ¹ H NMR (500 MHz, DMSO ₆ ) δ 1.43-1.78 (8H, m), 1.95-2.00 (2H, q), 3.80 (3H, s), 5.00 ( 2H, s), 6.82-6.86 (2H, m), 7.10-7.16 (2H, m), 7.28-7.53 (10H, m), 9.57 (1Η, from); M8 (E81 (-ye)) m / e 411 (M-H) ^- .

The reaction of the last title compound (0.80 g, 1.9 mmol) according to Example 46, method B results in the title compound (0.48 g, 1.4 mmol, 77%) as white solid matter. Mp 101-104 ° C; ^! H NMR (500 MHz, DMSO-b ₆ ) δ

1.44-1.78 (8H, m), 1.99-2.03 (2H, q), 3.81 (3H, s),

6.78 (1Η, d), 6.85 (1Η, d), 7.10-7.16 (2H, m), 7.30-

7.38 (2H, m), 7.50 (1Η, d), 9.35 (1Η, s), 9.56 (1Η, s); M8 (E81 (+ ye)) m / e 323 (M + H) ⁺ .

Example 50. 5 '- (3-Nitrophenyl) spiro [cyclohexane-U'-p-indole ^ X 1' I) -one oxime.

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

Prepared from 5'-bromo-spiro {cyclohexane1,3 '- [3H] indole} -2'(1'H) -one 2 '(O-benzyloxy) (1.0 g, 2.6 mmol) and 3-nitrophenylboronic acid (0.86 g, 5.2 mmol) according to Example 46, method A. Purification by chromatography on silica gel (eluent: 10: 0.5 hexane: ethyl acetate) affords the desired compound (0.60 g, 1 , 4 mmol, 55%) as a viscous oil. ¹ H NMR (500 MHz, DMSO ₆ ) δ 1.42-1.82 (8H, m) 2.02-2.04 (2H, q), 5.01 (2H, s), 6.88 (1Η d) 7.28-7.71 (8H, m), 8.08-8.13 (2H, m), 8.38 (1H, d), 9.69 (1H, s); M8 (E81 (-ye)) m / e 426 (M-H) ^- .

Method C.

The last compound in the title (0.54 g, 1.26 mmol) was dissolved in dry methylene chloride (25 ml) and cooled to -78 ° C under nitrogen. Boron tribromide (3.8 ml, 3.8 mmol, 1.0 M in methylene chloride) was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched with saturated sodium bicarbonate solution (5 ml). The reaction mixture was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried (Na-28O4), filtered and the solvent was removed in vacuo. The product was purified by silica gel chromatography (eluent: 8: 1 hexane: ethyl acetate) to obtain the title compound (0.33 g, 0.9 mmol, 78%). Mp 221-224 ° C; ¹ H NMR (500 MHz, DMSO-bb) δ 1.42-1.83 (8H, m), 1.99-2.07 (2H, q), 6.84-6.85 (1H, dd) 7.50-7.52 (1H, m),

7.67-7.71 (2H, m), 8.08-8.12 (2H, m), 8.37-8.38 (1H, d), 9.48 (1H, s), 9, 64 (1H, s); M8 (E81 (+ ye)) m / e 338 (M + H) ⁺ .

Example 51. 5 '- (3-Cyanophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) -onoxime.

3- [Spiro [cyclohexan-1,3 '- [3H] indole (1'H) -one-2' - (O-benzyloxy) benzonitrile [3H] indole] -5-yl] benzonitrile.

Prepared from 5'-bromo-spiro {cyclohexane1,3 '- [3H] indole} -2'(1'H) -one 2 '(O-benzyloxy) (1.0 g, 2.6 mmol) and 3-cyanophenylboronic acid (0.76 g, 5.2 mmol) according to Example 46, method A. The product was purified by silica gel chromatography (eluent: 10: 0.5 hexane: ethyl acetate) to obtain the desired product (0.75 g, 1 , 8 mmol, 71%) as a viscous oil. ¹ H NMR (500 MHz, DMSOάβ) δ 1.41-1.81 (8H, m), 1.96-2.03 (2H, q), 5.01 (2H, s), 6.86 (1H d) 7.28-7.33 (9H, m), 7.95-7.97 (1H, d), 8.12 (1H, s), 9.65 (1H, s); M8 (E81 (-ye)) m / e 406 (M-H) ^- . The reaction of the last title compound (0.17 g, 0.43 mmol) and tribromidobor (1.2 ml, 1.2 mmol) in accordance with Example 50, method C, affords the title compound (0.06 g, 0.2 mmol, 47%) as a white solid, mp. 198-200 ° C; ¹ H NMR (500 MHz, DMSO-b ₆ ) δ 1.41-1.80 (8H, m), 1.97-2.04 (2H, q),

6.80 (1H, q), 7.45-7.69 (4H, m), 7.93-7.95 (1H, dd), 8.10 (1H, s), 9.42 (1H, s) 9.59 (1H, s); (E81 (+ ye)) m / e 318 (M + H) ⁺ .

Example 52. 3- [1 ', 2'-Dihydro-2' - (hydroxyimino) spiro [cyclohexane-1,3 '- [3H] indole] -5'yl] 5-fluorobenzonitrile.

To a solution of 3-fluoro-5-cyanobromobenzene (0.4 g, 2.0 mmol) in dry DMF (10 ml) was added diborous pinacolinium ether (0.63 g, 2.5 mmol), potassium acetate (0.65 g 6.7 mmol) and RbCl _{1 2} (άρρί) (0.2 g) and the reaction is heated to

80 ° C in an atmosphere of nitrogen. After 8 h, add 5'bromospiro {cyclohexane-1,3 '- [3H] indole} 2'(1'H) -one 2 '(O-benzyloxy) (0.2 g, 0.5 mmol), PbCl ₂ (άρρί) (0.05 g) and sodium carbonate (1.30 g, 12.5 mmol) and continue heating at 80 ° C. After 8 hours, the reaction was cooled and partitioned into water and ethyl acetate, the organic layer was washed with brine, dried (MgO ₄ ) and evaporated. The residue was purified by column chromatography ₍₂ occupies 8, ITS Ac: hexanes 1:20) to give the desired product (0.14 g, 0.33 mmol, 66%).

The reaction of the last title compound (0.14 g, 0.33 mmol) and boron tribromide (1.0 ml, 1.0 mmol) in accordance with Example 50, Method C, affords the title compound (0.019 g , 0.05 mmol, 17%): ¹ H NMR (300 MHz, DMSO-db) δ

9.65 (s, 1H), 9.49 (s, 1H), 8.04 (m, 1H), 7.89 (dt, 1H, 1 = 10.5 and 2 Hz), 7.72-7 68 (m. 2H), 7.54 (d, 1H, 1 = 8.1 Hz), 6.80 (d, 1H, 1 = 8.1 Hz), 2.05-1.99 (m, 2H), 1.84-1.76 (m, 2H) and 1.65-1.44 (m, 6H): M8 (E81 (+ ye)) m / e 336 (M + H) ⁺ .

Example 53. 5- (Spiro [cyclohexan-1,3- [3H] indole] -2 '- (hydroxyimino) -5'-yl) -4-methyl-2thiophenecarbonitrile.

4-Methyl-5-trimethylstannanylthiophen-2carbonitrile.

Prepared from 5-bromo-4-methylthiophen-2carbonitrile (3.08 g, 15.2 mmol), tetrakistriphenylphosphine Ρά (0) (0.82 g, 0.71 mmol), hexamethyldiol (5.0 g, 15.2 mmol) and ethylene glycol dimethyl ether (20 ml) in a nitrogen atmosphere. The mixture was heated under reflux for 14 hours. The reaction mixture was evaporated in vacuo and purified using silica gel chromatography (eluent: 2% MeOH: methylene chloride) to yield the desired product (2.8 g, 0.01 mmol, 67%) ) as a liquid oil. ¹ H NMR (300 MHz, DMSOL ₆ ) δ 0.41 (9H, s), 2.28 (3H, s), 7.83 (1H, s).

The last compound in the name (0.20 g, 0.50 mmol), dichlorobis (triphenylphosphine) palladium (ΙΙ) (0.02 g, 0.03 mmol) and triphenyl arsenic (0.03 g, 0.13 mmol) in dimethoxyethane (8.0 ml) was stirred under nitrogen for 20 minutes. 5'-Bromspiro {cyclohexane-1,3 '- [3H] indole} -2' (1'H) -one 2 (O-benzyloxy) (0.18 g, 0.64 mmol) was added to DME (2, 0 ml); the solution is heated under reflux overnight. The reaction solution was evaporated in vacuo and purified by silica gel chromatography (eluent 12: 1 hexane: ethyl acetate) to obtain a crude product (0.10 g, 0.25 mmol, 50%), which was used further without further purification.

Tribromideboron (2.6 ml, 2.6 mmol 1.0 M solution in methylene chloride) is added to a solution of the latter product (0.37 g, 0.86 mmol) in dry methylene chloride (1.7 ml) at -78 ° C .

The solution was stirred for 30 minutes and washed with saturated sodium hydrogen carbonate solution (10 ml). The mixture was allowed to warm to room temperature and the layers were separated. The organic layer was dried (No. ₂ 80 ₄ ), filtered and evaporated in vacuo to give a crude product, which was purified by silica gel chromatography (eluent: 6: 1 hexane: ethyl acetate) to obtain the title compound (0.02 g, 24 %): Mp 173-176 ° C; '11 NMR (500 MHz, DMSO-b ₆ ) δ

1.44-1.73 (8H, m), 1.96-2.00 (2H, m), 2.28 (3H, s),

6.82-6.84 (1H, m), 7.24-7.26 (1H, dd, 1 = 1.7 Hz),

7.38 (1H, m), 7.82 (1H, m), 9.51 (1H, m), 9.66 (1H, m); M8 (E81 (+ ye)) m / e 338 (M + H) ⁺ .

Example 54. 5- (Spiro [cyclohexan-1,3 '[3H] 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) under nitrogen atmosphere at -78 ° C, lithium hexamethyldisilazide (1M in THF, 10 ml, 10 mmol). After 30 minutes, the reaction was quenched in HC1, then extracted with ethyl acetate, the organic layer was washed with water, dried (No. 80 ₄ ) and evaporated to a product (1.25 g, 8.17 mmol, 89%), which was used without further purification: ¹ N NMR (500 MHz, DMSO-b6) δ 8.75 (broad s, 2H), 7.97 (d, 1H, 1 = 8 Hz) and 7.73 (d, 1H, 1 = 8 Hz): M8 ( E81 (-ye)) m / e 152 (M-H) ^- .

The title compound was prepared from the latter product (0.91 g, 5.95 mmol) and 5'-bromo-spiro {cyclohexane-1,3 '[3H] indole} -2'(1'H) -one 2 '(0-benzyloxy) (1.53 g, 3.97 mmol) according to Example 46, method A. Purification by silica gel chromatography (eluent: 5: 1 hexane: THF) affords the desired product (0, 66 g, 1.59 mmol), which is used further without further purification: M8 (E81 (-ye)) m / e 412 (MN) ^- .

The reaction of the last title compound (0.60 g, 1.45 mmol) and tribromidobor (1 M in dichloromethane, 5 ml, 5 mmol) in accordance with Example 50, Method C, affords the title compound (0.036 g, 0.11 mmol, 8%): '11 NMR (300 MHz, DMSO-b6) δ 9.71 (s, 1H), 9.62 (s, 1H), 7.92 (d, 1H, 1 = 3 , 9 Hz), 7.63 (d, 1H, 1 = 1.5 Hz), 7.54 (d, 1H, 1 = 3.9 Hz), 7.47 (dd, 1H, 1 = 8.1 and 1.6 Hz), 6.78 (d, 1H, 1 = 8.1 Hz), 2.13-1.90 (m, 2H) and 1.78-1.60 (m, 6H): M8 (E81 (+ ye)) m / e 324 (M + H) ⁺ .

Example 55. 4- (Spiro [cyclohexan-1,3 '[3H] indole] -2' - (hydroxyimino) -5'-yl) -2-thiophenecarbonitrile.

4- (Trimethylstannyl) -2-thiophenecarbonitrile.

A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.25 g, 0.2 mmol) and tildiol tin hexame (1.4 g, 4, 3 mmol) in dimethoxyethane (5 cm ³ ) is heated at the boil under reflux for 14 hours, then cooled to room temperature. The reaction mixture was absorbed on florisil and purified by column chromatography (8-02, methylene chloride: hexane 1: 9) to obtain the title compound (1.04 g, 3.8 mmol, 90%) as a pure viscous oil: ¹ H NMR (SES13) δ 0.35 (s, 9H), 7.56 (d, 1 = 0.9 Hz, 1H), 7.66 (d, 1 = 0.9 Hz, 1H).

To a solution of 5'-bromo-spiro {cyclohexane-1,3 '[3H] indole} -2'(1'H) -one 2 '(0-benzyloxy) (1.65 g, 4.28 mmol), 4- ( trimethylstannyl) -2thiophenecarbonitrile (1.48 g, 5.44 mmol), arsenic triphenyl (330 mg) in dry dimethoxyethane (20 ml) under nitrogen atmosphere, bis (triphenylphosphine) palladium (11) chloride is added, and the mixture is heated under reflux . fridge for 16 h After cooling to room temperature the mixture was evaporated and the residue was purified by column chromatography (8ί0 ₂ E10As: hexanes, gradient elution) to give the desired product (0.61 g, 1.47 mmol, 56%).

The reaction of the last title compound (0.61 g, 1.47 mmol) and boron tribromide (1 M in dichloromethane, 4.5 ml, 4.5 mmol) according to Example 50, method C, yields the title compounds (0.084 g, 0.26 mmol, 18%): 'H NMR (300 MHz, DMSO-b ₆ ) δ 9.61 (s, 1H), 9.42 (s, 1H), 8.41 (s) , 1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.48 (dd, 1H, 1 = 8.1 and 0.9 Hz), 6.76 (d, 1H, 1 = 8.1 Hz), 2.03-1.96 (m, 2H) and 1.78-1.42 (m, 6H): M8 (E81 (+ ye)) m / e 324 (M + H ) ⁺ .

Example 56. 5- (Spiro [cyclohexan-1,3 '[3H] indole] -2' - (hydroxyimino) -5'-yl) -1Hpyrrole-1-methyl-2-carbonitrile.

2- {5 '[Spiro [cyclohexane-1,3' - [3H] indole] (1'H) -one-2 '(0-benzyloxy)]} -1H-pyrrole-1-carboxylic acid, tert-butyl ether.

A solution of 5'-bromo-spiro {cyclohexane-1,3 '[3H] indole} -2'(1'H) -one 2 '(0-benzyloxy) (7.4 g, 19.17 mmol) and tetrakis (triphenylphosphine) palladium (0) (2.5 g, 2.00 mmol) in dimethyl ether (100 ml) was stirred under nitrogen for 15 minutes. To the solution was added 1 tert-butoxycarbonylpyrrolboronic acid (5.5 g, 26 mmol) and 1M sodium carbonate (50 ml). The mixture was heated to 80 ° C for 6 hours and allowed to cool. The reaction mixture was poured into water and extracted with ethyl acetate (3x100 ml). The organic layers are combined and dried over magnesium sulfate. The solution was filtered, evaporated in vacuo and the residue was purified by silica gel chromatography (4.5: 1 hexane / ethyl acetate) to obtain the product (7.7 g, 88%) as a white solid. 'H NMR (DMSO-b ₆ , 300 MHz) δ 1.28 (s, 9H), 1.55-1.66 (m, 8H), 1.83-1.98 (m, 2H), 4, 99 (s, 2H), 6.12-6.14 (m, 1H), 6.22 (t, 1H, 1 = 3.26 Hz),

6.76 (d, 1H, 1 = 7.9 Hz), 7.02 (dd, 1H, 1 = 7.98, 1.4 Hz), 7.19 (s, 1H), 7.27-7.31 (m, 2H), 7.35 (t, 1H, 1 = 6.8 Hz), 7.43 (d, 1H, 1 = 8 Hz), 9.55 (s, 1H).

5 '- (1-tert-Butoxycarbonyl-1H-pyrrol-2yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '- (1'H) he-2' - (0-benzyloxy) - 1'-carboxylic acid, tert-butyl ether.

To a solution of tert-butyl ether 2 {5 '[spiro [cyclohexane-1,3' - [3H] indole] - (1'H) -one2 '(0-benzyloxy)]} -1H-pyrrole-1-carboxylic acid (7.7 g, 16.38 mmol) in THF (anhydrous, 100 ml) add sodium hydride (0.665 g, 17 mmol) after stopping the evolution of hydrogen add di-tert-butyl dicarbonate (10.9 g, 50 mmol) and DMAP (0.20 g) and 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 are combined and dried over magnesium sulfate. The solution was filtered, evaporated in vacuo to give a product (9.0 g, 15.76 mmol), which was directly used in the next step.

To a solution of 5 '- (1-tert-butoxycarbonyl-1Npyrrol-2-yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '- (1'H) he-2' - (0-benzyloxy ) -1'-carboxylic acid, tert-butyl ether (9.0 g,

15.76 mmol) in THF (anhydrous, 75 ml) at -78 ° C, chlorosulfonyl isocyanate (1.55 ml, 17.54 mmol) is added. 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 are combined and dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by silica gel column chromatography (10% ethyl acetate / hexane) affords 5 '- (5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2-yl) spiro [cyclohexane1,3' - [3H] indole ] -2 '(1' N) he-2 '(0-benzyloxy) -1'-carboxylic acid, tert-butyl ether (7.6 g, 82%) as a white powder. ¹ H NMR (DMSO-b ₆ , 300 MHz) δ 1.30 (s, 9H), 1.38 (s, 9H), 1.58-1.83 (m, 8H), 1.72-1, 73 (m, 2H), 5.0 (s, 2H),

6.44-6.45 (d, 1H, 1 = 3.76), 7.25-7.46 (m, 10H).

5 '- (5-Cyano-1H-pyrrol-2-yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) he-2' - (0-benzyloxy) -1 '-carboxylic acid, tert-butyl ether.

To a solution of 5 '- (5-cyano-1-tert-butoxycarbonyl-1H-pyrrol-2yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'N) he-2' (0-Benzyloxy) -1′-carboxylic acid (7.6 g, 3.25 g, 48 mmol) in THF (anhydrous, 30 ml) add a solution of sodium ethoxide in ethanol (120 ml). The reaction mixture was heated to 80 ° C and stirred overnight. The mixture was cooled to room temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product (6.1 g, 95%). Ή NMR (DMSO, 500 MHz) δ 1.38 (s, 9H), 1.63-1.74 (m, 8H), 1.88-1.97 (m, 2H), 5.08 (s, 2H), 6.69-6.7 (d, 1H, 1 = 8 Hz), 6.98-6.99 (d, 1H, 1 = 8.1 Hz), 7.29-7.37 (m , 1H), 7.35 (m, 2H), 7.42 (m, 3H),

7.63 (dd, 1H, 1 = 1.8, 3 Hz); 7.76 (d, 1H, 1 = 4 Hz).

5 '- (5-Cyano-1-methyl-1H-pyrrol-2-yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '- (0-benzyloxy) -1'-carboxylic acid, tert-butyl ether.

To tert-butyl ether 5 '- (5-cyano-1Hpyrrol-2-yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) he-2' - (0-benzyloxy ) -1'-carboxylic acid (6.1 g, 12.29 mmol) in DMF (75 ml) add potassium carbonate (6.5 g, 47 mmol) and Me1 (1 ml, 15.4 mmol) and the reaction mixture 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 evaporated in vacuo to give the desired product (6.1 g, 12.29 mmol), which was used in the next step without further purification. ^! H NMR (DMSO, 300 MHz) δ 1.38 (s, 9H), 1.62-1.98 (m, 10H), 3.71 (s, 3H), 5.08 (s, 2H), 6 34 (d, 1H, 1 = 4.1), 7.03 (d, 1H, 1 = 3.99), 7.30-7.53 (m, 8H).

5- {5'-Spiro [cyclohexane-1,3 '- [3H] indole] (1'H) -one-2' - (0-benzyloxy)} - 1H-pyrrole-1-methyl-2-carbonitrile.

5 '- (5-Cyano-1-methyl1H-pyrrol-2-yl) spiro [cyclohexan-1,3' - [3H] indole] -2 '- (0-benzyloxy) -1'- tert-butyl ether carboxylic acid, (6.1 g, 12.29 mmol) was dissolved in dioxane (5 ml) and 4 M HC1 in dioxane (10 ml) was added and the reaction was heated at 45 ° C for 3.5 hours. The mixture was carefully neutralized with hydrogen carbonate sodium (saturated). The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo. Purification by silica gel column chromatography (5% ethyl acetate / hexane) affords the product (4.36 g, 94%). ^! H NMR (DMSO-b ₆ , 300 MHz) δ 1.57-1.7 (m, 8H), 1.9-2.05 (m, 2H), 3.68 (s, 3H), 5.00 (s, 2H), 6.25 (d, 1H, 1 = 3.92), 6.85 (d, 1H, 1 = 8.03), 7.00 (d, 1H, 1 = 4.08) 7.2-7.44 (m, 7H); 9.7 (s, 1H).

To 5- {5 '-spiro [cyclohexane-1,3' - [3H] indole] - (1 'H) -one-2' - (0-benzyloxy)} - 1H-pyrrole-1methyl-2-carbonitrile ( 4.36 g, 10.6 mmol) in methylene chloride (50 ml) was added 1M tribromide boron (35 ml in methylene chloride) at -78 ° C. The reaction mixture was allowed to warm to room temperature. After 4 hours, the reaction was quenched with saturated sodium bicarbonate solution (100 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2 X 100 ml), the organic layers were combined, washed with brine, dried over magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (7: 3 hexane / ethyl acetate) to obtain the title compound (1.35 g, 40%) as a white solid. Ή NMR (DMSO-b ₆ , 300 MHz) δ 1.58-1.71 (m, 8H), 1.99-2.00 (m, 2H), 3.69 (s, 3H), 6.24 (d, 1H, 1 = 4.07 Hz), 6.8 (d, 1H, 1 = 8.05 Hz), 6.99 (d, 1H, 1 = 4.01 Hz), 7.20 (dd , 1H, 1 = 8.04, 1.57 Hz),

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

Example 57. 5- (Spiro [cyclohexan-1,3 '[3H] indole] -2' - (hydroxyimino) -5'-yl) -1H-pyrrole-2-carbonitrile.

5- (Spiro [cyclohexane-1,3 '- [3H] indole] 2' (1H) - (O-benzyloxy)) - 1H-pyrrole-2-carbonitrile.

Prepared from 5 '- (5-cyano-1H-pyrrol-2-yl) spiro [cyclohexane-1,3' - [3H] indole] -2 '(1'H) he-2' (O-benzyloxy) - 1'-carboxylic acid, tert-butyl ether (0.395 g, 0.796 mmol) dissolved in 2 ml of THF and 4M HC1 dioxane / water (10 ml) following the method used to obtain 5- {5'-spiro [cyclohexane-1, 3 '[3H] indole] - (1'H) -one-2' - (O-benzyloxy)} - 1Npyrrole-1-methyl-2-carbonitrile, the desired product is obtained (0.220 g, 0.745 mmol, 95%). ¹ H NMR (DMSO-b ₆ , 500 MHz) δ 1.44-1.50 (m, 1H),

1.61-1.70 (m, 7H), 1.94-1.99 (m, 2H), 5.0 (s, 2H),

6.55 (d, 1H, 1 = 4 Hz), 6.79 (d, 1H, 1 = 8.0 Hz), 6.95 (d, 1H, 1 = 4 Hz), 7.27-7, 31 (m, 1H), 7.34-7.37 (m, 2H), 7.42-7.43 (m, 2H), 747 (dd, 1H, 1 = 8.0, 1.4 Hz) 7.65 (d, 1H, 1 = 1.5 Hz), 9.65 (s, 1H), 12.4 (s, 1H).

The title compound was prepared from 5- (spiro [cyclohexane-1,3 '- [3H] indole] 2' (1H) - (O-benzyloxy)) - 1H-pyrrole-2-carbonitrile (0.325 g, 0.82 mmol) and 1M boron tribromide (6 ml in methylene chloride), following the procedure for 5- (spiro [cyclohexane-1,3 '- [3H] indole] 2' - (hydroxyiminuto) -5'-yl) -1H-pyrrole -1-methyl-2-carbonitrile to give the product as an off-white solid (0.110 g, 0.326 mmol, 44%). '11 NMR (DMSO-b ₆ , 500 MHz) δ 1.46 - 1.5 (m, 1H), 1.62-1.71 (m, 7H), 1.952.05 (m, 2H), 6, 55 (d, 1H, 1 = 4.0 Hz), 6.75 (d, 1H, 1 = 8.0 Hz), 6.94 (d, 1H, 1 = 3.47 Hz), 7.45 ( dd, 1H, 1 = 8.1, 1.73 Hz), 7.63 (d, 1H, 1 = 1.73), 9.42 (s, 1H),

9.59 (s, 1H); 12.39 (s, 1H).

Example 58. 4- (Spir [cyclohexane-1,3 '- [3H] indol] -2' (acetoxyimino) -5 '-yl) -2-thiophenecarbonitrile.

To a solution of 4- (spiro [cyclohexane-1,3 '- [3H] indole] -2' (hydroxyiminuto) -5'-yl) -2-thiophenecarbonitrile (2.21 g, 6.83 mmol) and acetic anhydride ( 1 ml) in dichloromethane pyridine (30 ml, 9: 1) 4-dimethylaminopyridine (250 mg) was added at room temperature. After 3 hours, the mixture was diluted with dichloromethane, washed with water, dilute hydrochloric acid, water, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (E (OAc: hexane, elution gradient) to obtain the title compound (0.84 g, 2.29 mmol, 33%) as a white solid: M8 (E81 (+ ye)) m / e 366 [M + H] ⁺ .

Example 59. 3-Fluoro-N'-hydroxy-5- [2 '(hydroxyamine) alcohol [cyclohexane-1,3' - [3H] indole] -5'-yl] benzenecarboximidamide.

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

Prepared from 3- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3 '- [3H] indole] -5'-yl) -5-fluorobenzonitrile (0.451 g, 1.34 mmol) according to the method described in example 43 to give the desired product (0.316 g, 0.90 mmol, 67%): ¹ H NMR (DMSO, 300 MHz) δ 7.74 (d, 1H, 1 = 1.7 Hz), 7 68 (t, 1H, 1 = 1.4 Hz), 7.58 (d, 1H, 1 = 8.0 Hz), 7.54 (t, 1H, 1 = 2.3 Hz), 7.50 (dd, 1H, 1 = 8.0 and 1.9 Hz), 7.33-7.29 (m, 1H), 2.67 (s, 3H), 2.04-1.78 (m, 7H ) and 1.58-1.50 (m, 3H); M8 (E81 (+ ye)) m / e 351 (M + H) ⁺ .

To a solution of the latter product (0.30 g, 0.88 mmol) in DMSO (10 ml) was added hydroxylamine (50% aqueous solution, 1 ml), and the reaction was heated to 120 ° C. After 1 h, the mixture was cooled, partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (81O ₂ , 5% MeOH in dichloromethane) to give the title compound (0.079 g, 0.23 mmol, 26%) as a white paste: '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, 1 = 1.3 Hz) 7.46 (dd, 1H, 1 = 8.3 and 1.5 Hz), 7.34 (d, 1H, 1 = 10 Hz), 6.81 (d, 1H, 1 = 8.0 Hz) 6.01 (s, 2H), 2.11-2.02 (m, 2H) and 1.81-1.56 (m, 8H): M8 (E81 (+ ye)) m / e 369 (M + H) ⁺ .

Example 60. No.-Hydroxy-5- (spiro [cyclohexane-1,3 '- [3H] indole] -2' (hydroxyimino) -5'yl) -4-methyl-2-thiophenecarboximidamide.

4-Methyl-5 - (spiro [cyclohexan-1,3 '[3H] indole] 2' - (methylthio) -5'-yl) -2-thiophenecarbonitrile.

To potassium tert-butylate (0.32 g, 2.6 mmol) in THF, 5- (1 ', 2'-dihydro-2'-thioxospiro [cyclohexane-1,3' - [3H] indole] -5 ' -yl) -4-methyl-2thiophenecarbonitrile (0.84 g, 2.5 mmol). After 15 minutes, methyl iodide (0.50 g, 3.48 mmol) was added. After 3 hours, the reaction mass was poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate. The solution was filtered, evaporated in vacuo and the residue was purified by silica gel chromatography (4: 1 hexane / ethyl acetate) to obtain the desired product (0.530 g, 85%). (DMSO, 300 MHz) δ 1.48 (m, 3H), 1.70 (m, 2H), 1.81 (m, 5H), 2.32 (s, 3H), 2.62 (s, 3H) ), 7.48 (dd, 1H, 1 = 7.87 Hz, 1.46 Hz), 7.5 (d, 1H, 1 = 8.05 Hz), 7.77 (d, 1H, 1 = 1 , 46 Hz), 7.88 (s, 1H).

K 4-methyl-5 - (spiro [cyclohexan-1,3 '[3H] indole] 2' - (methylthio) -5'-yl) -2-thiophenecarbonitrile (450 g, 1.3 mmol) in DMSO (1 ml) hydroxylamine hydrochloride (2 ml, 50% solution in water) is added and heated at 100 ° C for 2.5 hours. Water is added until the solution becomes slightly cloudy, and the mixture is allowed to cool to room temperature. The white solid was filtered off, collected and dissolved in ethyl acetate, and then dried over magnesium sulfate. The solution was filtered, evaporated in vacuo to give (0.320 g, 69%). NMR (DMSO- ₆ , 500 MHz) δ 1.4-1.74 (m, 8H), 1.94-2.49 (m, 2H), 2.54 (s, 3H), 5.8 ( s, 1H),

6.79 (d, 1H, 1 = 8.0), 7.16 (dd, 1H, 1 = 8.12, 1.83),

7.39 (m, 2H), 9.42 (s, 1H), 9.56 (s, 1H), 9.58 (s, 1H).

Example 61. X-Hydroxy-4- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (hydroxyimino) -5'-yl) -2thiophenecarboximidamide.

4- (Spiro [cyclohexan-1,3 '- [3H] indole] -2' (methylthio) -5'-yl) -2-thiophenecarbonitrile (0.077 g, 237 mmol) is reacted with a 50% hydroxylamine solution (1 ml ), following the procedure of Example 60 to give the title compound (0.016 g, 0.044 mmol, 20%). M8 (Ε8Ι, (+ UE)) m / e 357 [M + H] ⁺ .

Example 62. X-Hydroxy-5- (spiro [cyclohexane-1,3 '- [3H] indole] -2' - (hydroxyimino) -5'yl) -2-thiophenecarboximidamide.

The title compound was prepared from 5- (spiro [cyclohexan-1,3 '- [3H] indole] 2' (methylthio) -5'-yl) -2-thiophenecarbonitrile (0.500 g, 1.5 mmol) and 50% hydroxylamine solution (2 ml, excess), following the procedure of example 60, to obtain the product (0.200 g, 0.56 mmol, 56%). ^! H NMR (DMSO-e, 500 MHz) δ 1.45-1.75 (m, 8H), 1.97-2.06 (m, 2H), 5.89 (s, 1H), 6.74 ( d, 1H, 1 = 8 Hz), 7.3 (d, 1H, 1 = 3.9 Hz), 7.34 (dd, 1H, 1 = 8.06, 1.46 Hz), 7.4 ( d, 1H, 1 = 8.0 Hz), 7.5 (d, 1H,

1.95 Hz), 9.44 (s, 1H), 9.58 (s, 1H), 9.6 (s, 1H).

Example 63. 5 '- (3-Chlorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2'-ylidene cyanamide.

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

Hydrazine hydrate (0.600 ml, 12.24 mmol) is added to a stirred solution of 5 '- (3chlorophenyl) -Hydroxyspiro [cyclohexane-1,3 [3H] indole] -2-amine (0.500 g, 1.53 mmol) in 25 ml of ethanol . The solution is heated at 55 ° C, then Nickel-Raney (50% in water) is added to the reaction, maintaining a constant evolution of gas. After 45 minutes, the hot reaction mixture was filtered through a celite filter and washed with a large amount of hot methanol. The filtrate was evaporated in vacuo to give 0.890 g of a colorless solid. The product is purified by chromatography on silica gel (eluent, 2% to 8% methanol methylene chloride with 0.1% ammonium hydrochloride) to give 0.310 g (65%) of the desired product as a white solid. Mp 118120 ° C. ^! H NMR δ (300 MHz, DMSO _6th ) 1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H), 7.1 (broad d, 2H, 2 ^), 7.31-7.34 (dt, 1H, 1 = 8 Hz), 7.41-

7.46 (t, 2H), 7.55-7.58 (d, 1H), 7.62 (s, 1H), 7.72 (s, 1H); M8 (EC1 (+ yy)) m / e 311 (M + H) ⁺ .

1-tert-Butoxycarbonyl-5 '- (3-chlorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2'-amine. To a solution of 5 '- (3-chlorophenyl) spiro [cyclohexane1,3- [3H] indole] -2'-amine (0.310 g, 0.96 mmol) in dry methylene chloride at 0 ° C was added ditretbutyl dicarbonate (0.252 g, 1 5 mmol) and 4dimethylaminopyridine (0.117 g, 0.96 mmol). The solution was allowed to warm to room temperature and was stirred for 24 hours. The reaction solution was diluted with water (50 ml) and the layers were separated. The organic layer was dried over Na ₂ 8 ₄ , filtered and evaporated in vacuo to obtain 0.355 g of a yellow oil. The product was purified by silica gel chromatography (eluent, 1% to 3% methanol methylene chloride) to give the desired product (0.081 g, 20%) as a white solid. ¹ H NMR (300 MHz, DMSO _6th ) δ 1.58 (m, 2H), 1.63 (s, 9H, Boc), 1.77-1.79 (m, 8H), 7.42-

7.48 (m, 2H), 7.64-7.68 (m, 3H), 7.70-7.80 (m, 2H), 9.72 (s, 1H, Ν4). M8 (EC1 (+ yy)) m / e 411 (M + H) ⁺ .

1'-tert-Butoxycarbonyl-5 '- (3-chlorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2'-amine (0.120 g; 0.29 mmol) in 2.0 ml of dry DMF add to a solution of 4-dimethylaminopyridine (0.089 g; 0.73 mmol) and bromine cyan (0.077 g; 0.73 mmol) in 4.0 ml of dry DMF at 0 ° C. The yellow solution was heated to 40 ° C for 16 hours. Treatment involves pouring the reaction solution into 0.1 Ν NaΗCΟz (50 ml) and extraction with ethyl acetate (3x50 ml). The combined organic layers are dried over anhydrous Ν; · ι ₂ 8Ο. · |. filtered and evaporated in vacuo to give 0.091 g of a yellow precipitate. The product was purified by silica gel chromatography (stepwise gradient 5: 1 to 3: 1 hexane: ethyl acetate) to give 0.031 g (32%) of the product as a bright yellow solid. Mp 225 ° C (decomposition). ¹ H NMR (500 MHz, DMSO _6th ) δ 1.46-1.73 (m, 8H), 1.89-

1.90 (m, 2H), 7.13-7.16 (d, 1 H), 7.38-7.41 (dt, 1 H, 1 = 8 Hz), 7.45-7.50 ( m, 1H), 7.60-7.63 (dd, 2H, 1 = 6.4 Hz), 7.71 (s, 1H), 7.85 (s, 1H), 12.1 (s, 1H , Ν4); M8 (EC1 (-y)) m / e 336 (M-H) ^- .

Other desired compounds that can be prepared according to the methods described herein include 5 '- (3-cyano-5 fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] 2'-ylidene cyanamide, 5 '- ( 5-cyano-1H-pyrrol-2yl) spiro [cyclohexane-1,3 '- [3H] indole] -2-ylidene cyanamide, 5' - (5-cyano-1-methyl-1H-pyrrol-2yl) spiro [cyclohexane -1,3 '- [3H] indole] -2'-ylidene cyanamide, 5' - (5-cyano-thiophen-2-yl) spiro [cyclohexane-1,3 '- [3H] indole] -2'-ylidene cyanamide 5 '- (5-cyano-3-methyl-thiophen-2-yl) spiro [cyclohexane-1,3 [3Н] indole] -2'-ylidene cyanamide, 5' - (5-cyanothiophen-3-yl) spiro [cyclohexane-1,3 '- [3H] indole] -2'-ylidenecyan mid, 3 - (2-cyano-methylene-spiro [cyclohexane-1,3 [3Н] indole] -5'-yl) -5-fluoro-benzonitrile, 5- (2'-cyanomethylene-spiro [cyclohexane-1,3 [3Н] indole] -5 '-yl) 1H-pyrrole-2-carbonitrile, 5- (2'-cyanomethylene spiro [cyclohexane-1,3 [3Н] indole] -5' -yl) -1 -methyl-1H-pyrrole-2-carbonitrile, 5 - (2'-cyano methylene-spiro [cyclohexan-1,3 '- [3H] indole] -5'-yl) thiophene-2-carbonitrile, 5- (2'-cyanomethylene-spiro [cyclohexane-1,3'- [ ZN] indole] -5'-yl) -4-methylthiophene-2-carbonitrile, 4- (2'-cyanomethylene spiro [cyclohexane-1,3'- [ZN] indole] -5 '-yl) thiophene-2-carbonitrile.

All publications referenced herein are incorporated herein by reference. Although the invention has been described with reference to particularly preferred embodiments, it is clear that modifications can be made without departing from the scope of the invention. Such modifications are intended to fall within the scope of the dependent claims.

Claims (18)

CLAIM 1. The compound of the formula where I am! and B ₂ are independently selected from the group consisting of H, _C1-C8 alkyl, substituted C] C ₈ alkyl, OH, O _(C1-C8 alkyl), O (substituted _C1-C8 alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, _C1-C8 alkylaryl; _C1-C8 alkylheteroaryl, 1-propynyl and 3-propynyl; or me! and I _{2 are} condensed to form a ring containing —CH ₂ (CH ₂ ) _P CH ₂ -, —CH ₂ CH ₂ C (CH ₃ ) ₂ CH ₂ CH ₂ -, —O (CH ₂ ) _t CH ₂ -; -O (CH ₂ ) _p O-, -CH ₂ CH ₂ OCH ₂ CH ₂ -; —CH ₂ CH ₂ M (H) CH ₂ CH ₂ - or —CH ₂ CH ₂ M (alkyl) CH ₂ CH ₂ -; t is an integer from 1 to 4; and an integer from 1 to 5; p is an integer from 1 to 4; or Κι and I ₂ together constitute a double bond to one of the following groups: C (CH ₃ ) ₂ , C (cycloalkyl), O or C (cycloether); I ₃ is selected from the group consisting of H, OH, ΝΗ _2, C1-C ₆ alkyl, substituted C 1 -C ₆ alkyl, C ₃ -C ₆ alkenyl, alkynyl; substituted alkynyl or SOYA ^A ; I ^A is selected from the group consisting of H, C1 to _C3 alkyl, substituted _C1-C3 alkyl, _C1-C3 alkoxy, substituted C1 to _C3 alkoxy, C1 to _C3 aminoalkyl, and substituted C1 to _C3 aminoalkyl; I ₄ is selected from the group consisting of H, halogen, ΟΝ, ΝΗ _{2, C1-C6} alkyl, substituted _C1-C6 alkyl, _C1-C6 alkoxy substituted _C1-C6 alkoxy, C1 to _C6 aminoalkyl, or substituted _C1-C6 aminoalkyl; I ₅ choose from groups a), b) or c) a) a substituted benzene comprising the substituents X, Υ and Ζ, as shown below: wherein X is selected from the group consisting of H, halogen, OH, ΟΝ, _C1-C3 alkyl, substituted _C1-C3 alkyl, _C1-C3 alkoxy substituted C1 to _C3 alkoxy, _C1-C3 thioalkyl, substituted C1 to _C3 thioalkyl, 8 (O) alkyl, 8 (O) ₂ alkyl, C1 to _C3 aminoalkyl, substituted C1 to _C3 aminoalkyl, ΝΟ _{2 C1-C3} perfluoroalkyl, 5 or 6-membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, ΟΟΝΗ _2, Ο8ΝΗ ₂ somnoj _(C1-C8) alkyl, Ο8ΝΗ (Οι-Ο ₈₎ alkyl, SOBG _(C1-C8 alkyl) _2, S8H (C | -C ₈ alkyl) _2. SOYA ^IN , OCEANA ^IN or OIA ^with SOYA ⁱⁿ ; ^I is selected from the group consisting of H, C1 to _C3 alkyl, substituted C1 to _C3 alkyl, aryl, substituted aryl, C1 to _C3 alkoxy, substituted C1 to _C3 alkoxy, C1 to _C3 aminoalkyl, and substituted C1 - C ₃ aminoalkyl; ^I is H, _C1-C3 alkyl, or substituted C1 to _C3 alkyl; Υ Ζ and are independently selected from the group consisting of H, halogen, ΟΝ, ΝΟ _{2, C1-C3} alkoxy, _C1-C4 alkyl and _C1-C3 thioalkyl; where all X, Υ and Ζ cannot be simultaneously H; b) a 5- or 6-membered heterocyclic ring with 1, 2 or 3 heteroatoms in the ring selected from the group consisting of O, 8, 8 (0), 8 (O ₂ ) and ΝΚ. ⁶ and containing one or two independent substituents selected from the group consisting of H, halogen, ΟΝ, ΝΟ ₂ and _C1-C3 alkyl, C] _C3 alkoxy, C1 to _C3 aminoalkyl, and SOYBEAN ^In SH'SSZH ¹ ' : ^I is H, C1C ₃ alkyl substituted C1C ₃ alkyl, aryl, substituted aryl, C1C ₃ alkoxy, substituted alkoxy C1C _3, C1C ₃ aminoalkyl, or substituted C] C ₃ aminoalkyl; I ^E represents H, a _C1-C3 alkyl, or substituted C1 to _C3 alkyl; I ⁶ is absent or represents H, ^B, or C1 SOYBEAN -C ₃ alkyl; or c) indol-4-yl, indol-7-yl or benzoltiofenovy residue which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, _C1-C6 alkyl, ΟΝ, ΝΟ _{2, C1-C6} alkoxy or CE ₃ ; Ω ¹ represents 8, ΝΕ- or CJ ₈ I ₉ ; I ₇ is selected from the group consisting of ΟΝ, _C1-C6 alkyl, substituted C1-C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, acyl, substituted acyl, aroyl, substituted aroyl, 8О2СГ3, ОК ¹¹ or ЛК ¹¹ К ¹² ; K ₈ and K ₉ are independent substituents selected from the group consisting of H, _C1-C6 alkyl, substituted C1-C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted _C3 C8 cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, NΟ ₂ , CN and СО2К10; Cul represents a _C1-C3 alkyl; or SK8K9 form a six-membered ring, the structure of which is shown below K ¹¹ and K ¹² are independently selected from the group consisting of H, _C1-C6 alkyl substituted S1S6alkila, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl, substituted aroyl, or sulfonyl; where aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, antryl, tetrahydronaphthyl or phenanthryl; heterocyclyl or heteroaryl is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxo-piperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzolinyl, thiolinyl azinolinyl, thiolinyl azinolinyl, thiolinyl azinolinyl thiamorpholinyl, thiamorpholinyl sulfoxide and isoquinolinyl; substituted alkyl or substituted alkynyl contain one or more substituents selected from the group consisting of halogen, ΟΝ, OH, NΟ ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted aryl contains 1-4 substituents selected from the group consisting of halogen, ΟΝ, OH, NΟ ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl or heteroaryl contain 1-4 substituents selected from the group consisting of halogen, ΟΝ, OH, NΟ ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted acyl and aroyl contain 1-6 groups selected from halogen SI, OH and NΟ ₂ ; substituted alkoxy, substituted aminoalkyl and substituted thioalkyl contain 1-3 substituents selected from the group consisting of alkyl and substituted alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound of the formula Pb where K | and K _{2 are} condensed to form a five or six membered carbocyclic ring; K ₃ is selected from the group consisting of H, OH, ΝΗ _{2, C1-C6} alkyl substituted S1S6alkila, C3-C6 alkenyl, alkynyl, substituted alkynyl, and CSB ^A; K ^A is selected from the group consisting of H, C1 to _C3 alkyl, substituted _C1-C3 alkyl, _C1-C3 alkoxy, substituted C1 to _C3 alkoxy, C1 to _C3 aminoalkyl, and substituted C ₁ to C ₃ aminoalkyl; R4 is selected from the group consisting of H, halogen, SR, ΝΗ _{2, C1-C6} alkyl, substituted _C1-C6 alkyl, C1-C ₆ alkoxy, substituted C ^ _C6 alkoxy, _C1-C6 aminoalkyl, and substituted S1S6aminoalkila ; K ₅ represents a) or b) a) a substituted benzene ring of the formula wherein X is selected from the group consisting of H, halogen, CI, CONH _; . S8H1G. СОХ11 (0- (2 alkyl), С8ЫН (С1-С ₈ alkyl), СО ^ С1-С ₈ alkyl) ₂ , С8 ^ С1-С ₈ alkyl) ₂ , С ₁ -С ₃ alkoxy, С ₁ -С ₃ alkyl, NΟ ₂ , C ₁ -C ₃ perfluoroalkyl, a 5-membered heterocyclic ring containing from 1 to 3 heteroatoms in its skeleton, and C1-C3 thioalkoxy; Υ is a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, SI, NΟ ₂ , C ₁ -C ₃ alkoxy, C ₁ C4 alkyl and C1-C3 thioalkyl; while X and Υ both are not simultaneously H; or b) a six-membered ring with the structure where X ¹ represents Ν or CX ² , X ² represents halogen, CK, СОНЫ2, С8ЫН2, СОН (С1-С8 alkyl), С8ЫН (С1С ₈ alkyl), СОМ ^ -Svalkyl ^, С8N (С ₁ -С ₈ alkyl) ₂ or NΟ ₂ ; O ¹ represents 8, YK ₇ or SK ₈ To ₉ ; K _{7 is} selected from the group consisting of SI, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and 8O ₂ SG ₃ ; K ₈ and K ₉ are independent substituents selected from the group consisting of H, C) -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ C ₈ cycloalkyl, aryl, substituted aryl, heterocyclyl substituted heterocyclyl, NO ₂ , CL and CO ₂ K ₁₀ ; K ₁₀ represents C) -C ₃ alkyl; or SK8K9 is a six-membered ring, the structure of which is shown below where aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, antryl, tetrahydronaphthyl or phenanthryl; heterocyclyl selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl thiomorpholinyl sulphoxide and isoquinolinyl; substituted alkyl or substituted alkynyl contain one or more substituents selected from the group consisting of halogen, CL, OH, NO ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted aryl contains 1-4 substituents selected from the group consisting of halogen, CL, OH, NO ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl contains 1-4 substituents selected from the group consisting of halogen, CL, OH, NO ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted acyl and aroyl contain 1-6 groups selected from halogen CL, OH and NO ₂ ; substituted alkoxy, substituted aminoalkyl and substituted thioalkyl contain 1-3 substituents selected from the group consisting of alkyl and substituted alkyl; or a pharmaceutically acceptable salt thereof. 3. The compound of the formula or its tautomer, where K _{14 is} selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl and substituted sulfonyl; K5 is a), b) or c) a) a substituted benzene ring containing the substituents X and Υ, as shown below: wherein X is selected from the group consisting of H, halo, CO, SOLSCH, S8H1O CO \ 11 (0- (7 alkyl) S8NN _(C1-C8 alkyl ), СОЛ (С) -С ₈ alkyl) ₂ , С8 ^ С1-С8 alkyl) 2, СЛНЛНОН, СЛЩЛОН, С1С ₃ alkoxy, С) -С ₃ alkyl, NO ₂ , С) -С ₃ perfluoroalkyl, 5-membered heterocyclic a ring containing from 1 to 3 heteroatoms in its skeleton, C ₁ -C ₃ thioalkoxy; Υ represents a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, CL, NO ₂ , 0) -0, alkoxy, C1-C3 alkyl or C1-C3 thioalkyl; while X and Υ both are not simultaneously H; b) a five-membered ring with the structure shown below, where it represents O, 8 or LC ₆ ; Kb is H, C) -C ₃ alkyl or alkoxycarbonyl (C) -C ₄ ) alkyl; X 'is selected from the group consisting of halogen, CL, LO ₂ ; SUN ₂ , SLLNONN, SLSHLON, С8Х1О СО ^ (С1-С8 alkyl), S8NN _(C1-C8 alkyl), LDF (C) -C ₈ alkyl) _2, S8L (C ₁ C ₈ alkyl) _2, C) -C ₃ alkyl and C) -C ₃ alkoxy; Υ 'is selected from the group consisting of H, halogen and C) -C ₄ alkyl; where halogen is T; or c) a six-membered ring of the formula below where X ¹ represents N or CX ² , X ² represents halogen, СЛ, СОЛН ₂ , С8Х1О СОЛН (С) -С ₈ alkyl), С8ЛН (С) С ₈ alkyl), СОЛ (С) -С ₈ alkyl) ₂ , С8Л (С) -С ₈ alkyl ) ₂ or LO ₂ ; where heterocyclyl is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxo-piperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, benzoxylinyl-phenyl-iniolinyl-thiolinyl-phenyl-inyl-phenyl-iniro-phenyl-inirolinyl thiamorpholinyl, thiamorpholinyl sulfoxide and isoquinolinyl; substituted acyl and aroyl contain 1-6 groups selected from the group consisting of halogen CH OH and NO ₂ ; or a pharmaceutically acceptable salt thereof. 4. The compound of the formula where K ⁵ represents a), b) or c) a) a substituted benzene ring containing the substituents X and Υ, as shown below: where X is selected from the group consisting of H, halogen, ΟΝ, СОМН ^ СЗМН ^ СОЯНССг С ₈ alkyl), С8НН (С1-С ₈ alkyl), СО ^ СрС ^ лкил) 2, СЗ ^ С ^ alkylД, СНННОН, С ^ alkoxy, C1-C ₃ alkyl, NO _2, C _r C ₃ perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms and C1-S3tioalkoksi; Υ represents a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, C ^ NO ₂ , C _g C ₃ alkoxy, C1-C ₃ alkyl or C _g C ₃ thioalkyl; while X and Υ both are not simultaneously H; b) a five-membered ring of the formula below where is O, 8 or ΝΚ ₆ ; By ₆ is selected from H, _C1-C3 alkyl or alkoxycarbonyl _(C1-C4) alkyl; X 'is selected from the group consisting of halogen, ΟΝ, Νθ2, SOL C8KH2, ^ ΝΠ (^ C ₈ alkyl), C8NH (C1-C ₈ alkyl), CO ^ CpC ^ lkyl) ₂ , C3 ^ CpC ^ lkyl) ^ C _g C ₃ alkyl and C _g C ₃ alkoxy; Υ 'is selected from the group consisting of H, halogen and _C1-C4 alkyl; where halogen is G; or c) a six-membered ring of the formula below where X ¹ represents Ν or CX ² , X ² represents halogen, C ^ SALCH C8KH2, COCAD ^ alkyl), C8NH (C ₁ C ₈ alkyl), CO ^ Cp ^ alkyl ^, C3 ^ Cp ^ alkyl ^ or NO ₂ ; where heterocyclyl is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxo-piperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, benzoxylinyl-phenyl-iniolinyl-thiolinyl-phenyl-inyl-phenyl-iniro-phenyl-inirolinyl thiamorpholinyl, thiamorpholinyl sulfoxide and isoquinolinyl; or a pharmaceutically acceptable salt thereof. 5. The compound of the formula where K1 _{5 is} selected from the group consisting of H, CO ₂ K1 ₀ , acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl and C ^ K ₁₀ represents C _g C ₃ alkyl; K ₅ represents a), b) or c) a) a substituted benzene ring containing substituents X and Υ, as shown below where X is selected from the group consisting of H, halogen, ΟΝ, SOYANZ, CONNECTING SOLISSO, alkyl), C8NH (C1-C8 alkyl), CO ^ Ca ^ alkyl, СЗ ^ СрС ^ дкил) ^ СННNОн, С _g С ₃ alkoxy, С ₁ С ₃ alkyl, НО ₂ , С _g С ₃ perfluoroalkyl, a 5-membered heterocyclic ring containing from 1 to 3 heteroatoms and С _Г С ₃ in its skeleton thioalkoxy; Υ represents a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, C ^, NO ₂ , C _g C ₃ alkoxy, C ₁ -C ₃ alkyl or C 1 -C ₃ thioalkyl; where X and Υ both are not simultaneously H; B) a five-membered ring of the formula below where is O, 8 or ΝΚ ₆ ; By ₆ represents H, _C1-C3 alkyl or alkoxycarbonyl _(C1-C4) alkyl; X 'is selected from the group consisting of halogen, ΟΝ, Νθ2, SALF SZSCH SOLNSg C8 alkyl), C8NH (C1-C8 alkyl), CO ^ Cp C ₈ alkyl) ₂ , C3 ^ Cp ^ alkyl ^, CpC ₃ alkyl, and C ₁ C3 alkoxy; Υ 'is selected from the group consisting of H, halogen and C1-C4 alkyl; or c) a six-membered ring of the formula below where X ¹ represents Ν or CX ² , X ² represents halogen, C ^ ^ Ν ^, C8NΗ2, СΟNΗ (С ₁ -С8 alkyl), С8NН (С ₁ С ₈ alkyl), СΟN (С1-С ₈ alkyl) ₂ , С8N (С1-С ₈ alkyl) ₂ or ΝΟ ₂ ; where substituted alkyl contains one or more substituents selected from the group consisting of halogen, C ^ OH, ΝΟ ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio ; heterocyclyl selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl thiomorpholinyl sulphoxide and isoquinolinyl; substituted acyl and aroyl contain 1-6 groups selected from the group consisting of halogen C ^ OH and ΝΟ ₂ ; or a pharmaceutically acceptable salt thereof. 6. The compound of the formula where K ₅ represents a), b) or c) a) a substituted benzene ring containing the substituents X and Υ, as shown below: wherein X is selected from the group consisting of H, halogen, C ^ ^ ΝΗ ^ S8NΗ2 alkyl) S8NΗ _(C1-C8 alκil) С8N (С1-С ₈ alkyl) ₂ , СNΗNΟн, С _g С ₃ alkoxy, С ₁ С ₃ alkyl, ΝΟ ₂ , С1-С ₂ perfluoroalkyl, a 5-membered heterocyclic ring containing from 1 to 3 heteroatoms and С in its skeleton _{G 3} thioalkoxy; Υ is a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, C ^ ΝΟ ₂ , C _g C ₃ alkoxy, C1-C ₃ alkyl and C _g C ₃ thioalkyl; where X and Υ both are not simultaneously H; B) a five-membered ring of the formula below where is O, 8 or ΝΚ ₆ ; K ₆ represents H, C _g C ₃ alkyl or alkoxycarbonyl (C 1 -C ₄ ) alkyl; X 'is selected from the group consisting of halogen, MF ΝΟ2, GOad, S8NΗ2, SΟNΗ (C1C ₈ alkyl), S8NΗ (C1C alκil _8), CO ^ SrSdayakil) _2, S8N (C1C alκil _{8) 2,} C _g C ₃ alkyl and C _G C ₃ alkoxy; Υ 'is selected from the group consisting of H, halogen and C _g C ₄ alkyl; wherein the halogen is G; or c) a six-membered ring of the formula below where X ¹ represents Ν or CX ² , and X ² represents halogen, C ^ C8NΗ2, CONΗ (C ₁ -C8 alkyl), C8NH (C ₁ C ₈ alkyl), CΟN (C1-C ₈ alkyl) ₂ , C8N (C1-C ₈ alkyl) ₂ or ΝΟ2; where heterocyclyl is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxo-piperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, benzoxylinyl-phenyl-iniolinyl-thiolinyl-phenyl-inyl-phenyl-iniro-phenyl-inirolinyl thiamorpholinyl, thiamorpholinyl sulfoxide and isoquinolinyl; or a pharmaceutically acceptable salt thereof. 7. A compound selected from the group consisting of 5- (3-fluorophenyl) spiro [cyclohexane-1,3 '[3H] indole] -2' (1'H) -one oxime, 5 '- (2-fluorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1'H) -one oxime, 5 '- (4-fluorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1'H) -one oxime, 5 '- (3,4-difluorophenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1'H) -one oxime, 5 '- (3-methoxyphenyl) spiro [cyclohexane1,3' - [3H] indole] -2 '(1'H) -one oxime, 5 '- (3-nitrophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1'H) -one oxime and 5 '- (3-cyanophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1'H) -one oxime, or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 1 or 2 of the formula where R ₅ represents a substituted ring of formula wherein X is selected from the group consisting of H, halogen, CE, SOEN2, S3EN2, Soen (C1-C8 alkyl), S3EN _(C1-C8 alkyl), SEC _(C1-C8 alkyl) _2, S3E (C1-C8alkyl) 2, C1 -C3 -alkoxy, C1 -C3 alkyl, EO2, C1-S3perftoralkila, 5-membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms and C1-C3 thioalkyl; Υ represents a substituent at the 4 'or 5' position selected from the group consisting of H, halogen, CE, EO2, C1-C3 alkoxy, C1-C3 alkyl and C1-C3 thioalkyl; where X and Υ are both not N. 9. The compound according to claim 1 or 2 of the formula where K ⁵ is a five-membered ring with the structure shown below where it represents Θ, 3 or ECB; By ₆ represents H or _C1-C3 alkyl; X 'is selected from the group consisting of halogen, SE, SW _{2, C1-C3} alkyl, _C1-C3 alkoxy; Υ 'is selected from the group consisting of H, halo and _C1-C3 alkyl; where halogen is E 10. The compound according to claim 1 or 2 of the formula where K ₅ represents a six-membered ring of the formula where X ¹ represents CX ² , X ² represents halogen, CE, COX1E SOEN (C! -C ₈ alkyl), COE (C! -C ₈ alkyl) ₂ , or EO ₂ ; K ₇ is selected from the group consisting of CE, _C1-C6 alkyl, substituted _C1-C6 alkyl, _C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl and 3O ₂ Cl _3. 11. A compound selected from the group consisting of 5 '- (3-chlorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2 '(1' H) thione, 3- (1 ', 2'-dihydro-2'-thioxospiro [cyclohexane-1,3' - [3H] indole] -5 '-yl) benzonitrile, 4- (1 ', 2'-dihydro-2'-thioxospiro [cyclohexane-1,3' - [3H] indole] -5 '-yl) -2-thiophenecarbonitrile, 3- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile, 4-methyl-5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3 H] -indole] -5-yl) -2-thiophentioamide, 5 '- (5-cyano-1-methyl-1H-pyrrol-2-yl) spiro [cyclohexane-1,3' - [3H] indole] -2'-ylidene cyanamide, 5- (1,2-dihydro-2-thioxospiro [cyclopentan-1,3- [3H] indole] -5'-yl) -1H-pyrrole-2-carbonitrile, 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -1H-pyrrole-2-carbonitrile, 5- (2'-thioxospiro [cyclohexane-1,3 '- [3H] indole] -5'-yl) -1-methylpyrrole-2-carbonitrile, 5- (1,2-dihydro-2-thioxospiro [cyclopentan-1,3- [3H] indol] -5-yl) -3-thiophenecarbonitrile, 5- (1,2-dihydro-2-thioxospiro (cyclopentan-1,3- [3H] indole) -5-yl) -2-thiophenecarbonitrile, 5- (3-fluoro-4-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione, 5- (2-amino-5-pyrimidinyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione, 3- (1,2-dihydro-2-thioxospiro [cyclopentan-1,3- [3H] indol] -5-yl) -5-fluorobenzonitrile, 3- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -2-yl) -4-fluorobenzonitrile, 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -2-yl) -3-pyridinecarbonitrile, 5- (3,4-difluorophenyl) spiro [cyclohexane 1,3- [3H] indole] -2 (1H) thione, 5- (5-chloro-2-thienyl) spiro [cyclohexane-1,3 [3H] indole] -2 (1H) thione, 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -3-furancarbonitrile, 5- (3-chloro-4-fluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione, 5- (3-chloro-5-fluorophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione, 5- (3,5-difluorophenyl) spiro [cyclohexane 1,3- [3H] indole] -2 (1H) thione, 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -4-propyl-2-thiophenecarbonitrile, 5- (3-fluoro-4-nitrophenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione, 4- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -2-furancarbonitrile, 5- (3-chlorophenyl) spiro [cyclobutane-1,3 [3H] indole] -2 (1 N) thione, 5- (2-chlorophenyl) spiro [cyclohexane-1,3 [3H] indole] -2 (1 N) thione, 5- (4-chlorophenyl) spiro [cyclohexane-1,3 [3H] indole] -2 (1 N) thione, 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3 H] indol] -5-yl) -4-methyl-2-thio phencarbonitrile, 5 '- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -2-thiophenecarbonitrile, 5- (3-fluorophenyl) spiro [cyclohexane-1,3 [3H] indole] -2 (1 N) thione, 5- (3-hydroxyphenyl) spiro [cyclohexane- 1,3- [3H] indole] -2 (1H) thione, 5- [4-fluoro-3- (trifluoromethyl) phenyl] spiro [cyclohexane-1,3- [3 N] indole] -2 (1 N) thione, 4- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indol] -5-yl) -2-fluorobenzonitrile, 5- (3-fluoro-5-methoxyphenyl) spiro [cyclohexane-1,3- [3H] indole] -2 (1H) thione, 3- [1 ', 2'-dihydro-2' - (hydroxyimino) spiro [cyclohexane-1,3 '- [3H] indole] -5' -yl] -5-fluorobenzonitrile 5- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (hydroxyimino) -5'-yl) -4-methyl-2-thiophenecarbonitrile, 5- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (hydroxyimino) -5'-yl) -2-thiophenecarbonitrile, 4- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (hydroxyimino) -5'-yl) -2-thiophenecarbonitrile, 5- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (hydroxyimino) -5'-yl) -1H-pyrrole-1-methyl-2carbonitrile, 5- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (hydroxyimino) -5'-yl) -1H-pyrrole-2-carbonitrile, 4- (spiro [cyclohexan-1,3 '- [3H] indole] -2' (acetoxyimino) -5'-yl) -2-thiophenecarbonitrile, 3-fluoro-M'-hydroxy-5 - [2 '- (hydroxyamino) spiro [cyclohexane-1,3' - [3H] indole] -5 '-yl] benzenecarboximidamide, No.-hydroxy-5 - (spiro [cyclohexane -1,3 '[3H] indole] -2' - (hydroxyimino) -5'-yl) -4-methyl2-thiophenecarboximidamide, no-hydroxy-4- (spiro [cyclohexane-1,3 '[3H] indole] -2 '(hydroxyimino) -5'-yl) -2-thiophenecarboximidamide, No.-hydroxy-5 - (spiro [cyclohexane-1,3' [3H] indole] -2 '- (hydroxyimino) -5'-yl) -2-thiophenecarboximidamide, 5 '- (3-chlorophenyl) spiro [cyclohexane-1,3' [3H] indole] -2'-ylidene cyanamide, 5 '- (3-cyano-5-fluorophenyl) spiro [cyclohexane-1,3' - [3H] indole] -2'-ylidene cyanamide, 5 '- (5-cyano-1H-pyrrol-2-yl) spiro [cyclohexan-1,3' - [3H] indole] -2'-ylidene cyanamide, 5 '- (5-cyanothiophen-2-yl) spiro [cyclohexan-1,3' - [3H] indole] -2'-ylidene cyanamide, 5 '- (5-cyano-3-methylthiophen-2-yl) spiro [cyclohexan-1,3' - [3H] indole] -2'-ylidene cyanamide, 5 '- (5-cyanothiophen-3-yl) spiro [cyclohexane-1,3' - [3H] indole] -2'-ylidene cyanamide, 3- (spiro [cyclohexane-1,3 '- [3H] indole] -5'yl) -5-fluorobenzonitrile, 5- (spiro [cyclohexan-1,3 '- [3H] indole] -2'cyanomethylene-5'-yl) -1H-pyrrole-2-carbonitrile, 5- (spiro [cyclohexan-1,3 '- [3H] indole] -2'cyanomethylene-5'-yl) - 1-methyl-1H-pyrrole-2-carbonitrile, 5- (2'-cyanomethylene spiro [cyclohexan-1,3 '[3H] indol] -5'-yl) thiophene-2-carbonitrile, 5- (spiro [cyclohexane-1,3 '- [3H] indole] -2'cyanomethylene-5'-yl) -4-methylthiophene-2-carbo nitrile, 4- (spiro [cyclohexan-1,3 '- [3H] indole] -2'cyanomethylene-5'-yl) thiophene-2-carbonitrile, 5- (3-chlorophenyl) -3,3-dimethyl-1,3-dihydro2H-indol-2-thione, 3- benzyl-5- (3-chlorophenyl) -3-methyl-1,3-dihydro-2H-indol-2-thione, 4- (3,3-dimethyl-2-thioxo-2,3-dihydro-1-indind-5-yl) -2-furonitrile, 5- (3-methoxyphenyl) -3,3-dimethyl-1,3-dihydro-2H-indol-2-thione; and 5- (3-chlorophenyl) -3,3-diethyl-1,3-dihydro2H-indole-2-thione, or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 2, which is 5- (1,2-dihydro-2-thioxospiro [cyclohexan-1,3- [3H] indole] -5-yl) -1- (tert-butoxycarbonyl) pyrrole- 2-carbonitrile or 5- (1,2-dihydro-2-thioxospiro [cyclohexane-1,3- [3H] indole] -5-yl) -4-n-butyl-2-thiophenecarbonitrile, or a pharmaceutically acceptable salt thereof . 13. The compound according to any one of claims 3 to 6, where K5 is thiophene or furan. 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 15. A method of contraception in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 16. A method of treating dysfunctional bleeding in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 17. A method of treating carcinoma and adenocarcinoma of the endometrium of the breast, uterus, ovaries, colon or prostate in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 18. A method of hormone replacement therapy in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2/6