UA112770C2 - Partially saturated tricyclic compounds and methods for their preparation and application - Google Patents

Abstract

The present invention provides tricyclic compounds and their use in the treatment of medical disorders such as obesity. Pharmaceutical compositions and methods for preparing various tricyclic compounds are presented. These compounds are intended to have activity against methionine aminopeptidase 2.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

ИО00О1) This application claims priority to prior US patent application 61/559856, filed Nov. 15, 2011, and prior US patent application 61/483257, filed May 6, 2011, which are incorporated herein by reference in their entirety.

TECHNICAL LEVEL

0002) It has been described that more than 1.1 billion people worldwide are overweight.

According to estimates, more than 90 million people are prone to obesity in the United States of America alone. Twenty-five percent of the population of the United States of America over the age of twenty is considered clinically obese. While being overweight or obese presents problems (e.g., limited mobility, discomfort in confined spaces such as theater or airplane seats, social difficulties, and so on), these conditions, particularly clinical obesity, impair other aspects of health, that is, diseases and other adverse health problems associated with, aggravated by, or caused by being overweight or obese. The annual estimate of mortality due to obesity-related diseases in the United States is over 300,000 cases (O'Vgiep et al. Ateg U Bigdegu (2002) 184:45-85; and NII et al. (1998) zZsieepse, 280 :1371). 0003) There is no medical treatment for overweight or obesity. Conventional pharmaceuticals for the treatment of overweight or obese patients, such as serotonin noradrenergic reuptake inhibitors, noradrenergic reuptake inhibitors, selective serotonin reuptake inhibitors, intestinal lipase inhibitors, or surgical procedures such as gastric suturing or gastric banding, have been shown to , provide minimal non-durable benefit or significant relapse rates, and have additionally been shown to have adverse patient side effects.

II0004| MegaAR? encodes a protein that acts, at least in part, by enzymatically removing the amino-terminal methionine residue in some newly translated proteins, such as glyceraldehyde-3-phosphate dehydrogenase (Umagdeg ei aY. (2008) U Rgoivote Kez 7:4807).

Increased expression of the MesARA gene has historically been associated with various forms of cancer. Molecules that inhibit the enzymatic activity of Mes(AP2) have been identified and have been investigated for their suitability for the treatment of various types of tumors (U/apod ei aiI. (2003) Sapseg Ke5. 63:7861) and infectious diseases such as microsporidiosis, leishmaniasis and malaria (2 papod ei ai. (2002) y.

Viotei. All together. 9:34). In addition, inhibition of MeiAR2 activity in animals with obesity and diabetes leads to a decrease in body weight, partly due to increased fat oxidation and partly due to a decrease in food consumption (KyrpiskK ei ai. (2002) Rgos. Mai. Asai. zsi. OBA 99 :10730).

ИО00О5И Such MegAR?2 inhibitors may also be used in patients with obesity and obesity-related conditions, including type 2 diabetes, fatty liver, and cardiovascular disease (eg, by improving insulin resistance, reducing liver lipids and reducing the load on the heart). Accordingly, compounds capable of modulating MegaAR2 should be directed to the treatment of obesity and related diseases, as well as other ailments that respond positively to treatment with a MegaARa2 modulator.

BRIEF DESCRIPTION OF THE INVENTION

0006) This invention presents, for example, compounds that can be modulators

MegaAR2, and their use as medicinal products, methods of their preparation, and pharmaceutical compositions containing them as the only active ingredient or in combination with other agents, as well as their use as medicinal products or in the production of medicinal products for inhibiting Me activity is presented (AP2 in warm-blooded animals such as humans. In particular, the present invention relates to compounds that are used to treat obesity, type 2 diabetes and other obesity-related conditions. Also provided are pharmaceutical compositions containing at least one described compound and pharmaceutically acceptable medium.

I0007| In one embodiment, this document provides compounds of general formula I and II:

Hey v" i do ek ikh v' do v y ke 9, | U Y A XX 9, r" Shche

AZY of the city of ATM pos

So; Formula I or Son Formula III or their pharmaceutically acceptable salts, stereoisomers, esters and prodrugs, while A,

B', ve, 0, 02, BA, Be, BB, BB, Y, X, X?2 and n are as described in this document.

DETAILED DESCRIPTION

0008) Next, specific features and other details of this description will be specifically explained. Before further description of this invention, some terms used in the description, examples and appended claims are provided here. These definitions should be read in the context of the rest of the specification and as understood by those skilled in the art. Unless otherwise indicated, all technical and scientific terms used in this document have the same meanings as are commonly understood by those skilled in the art.

Definition

І0009| "Treatment" includes any effect, such as attenuation, reduction, modulation, or elimination, that results in amelioration of a condition, disease, disorder, or the like.

I0010) The term "alkenyl" as used herein refers to an unsaturated unbranched or branched hydrocarbon having at least one carbon-carbon double bond. Examples of illustrative alkenyl groups include a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as

C2-valkenyl and C3-4alkenyl, but are not limited thereto. Examples of illustrative alkenyl groups include, but are not limited to, allyl, butenyl, pentenyl, and the like. 0011) The term "Alkoxy" as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Illustrative alkoxy groups include, but are not limited to, 1-6 or 2-6 carbon atoms, referred to herein as C1-balkoxy and C2-balkoxy, respectively. Illustrative alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

I0012| The term "alkoxyalkyl" as used herein refers to a straight or branched alkyl group attached to an oxygen attached to another straight or branched alkyl group (alkyl-O-alkyl-). Illustrative alkoxyalkyl groups include alkoxyalkyl groups in which each of the alkyl groups independently contains 1-6 carbon atoms, referred to herein as, but not limited to, C1-balkoxy-C1-alkyl. Illustrative alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

I0013| The term "alkoxycarbonyl" as used herein refers to a straight or branched alkyl group attached to an oxygen attached to a carbonyl group (alkyl-O-2(O-)-). Illustrative alkoxycarbonyl groups include, but are not limited to, 1-6 carbon atoms, referred to herein as C1- carboxycarbonyl. Illustrative alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.

I0014| The term "alkenyloxy" as used herein refers to a straight or branched alkenyl group attached to oxygen (alkenyl-O-).

Illustrative alkenyloxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms, referred to herein as C3-alkenyloxy. Illustrative "alkenyloxy" groups include, but are not limited to, allyloxy, butenyloxy, and the like.

ИЙО015| The term "alkynyloxy" as used herein refers to a straight or branched alkenyl group attached to oxygen (alkynyl-O).

Illustrative alkynyloxy groups include, but are not limited to, groups with an alkynyl group of 3-6 carbon atoms, referred to herein as C3-alkynyloxy. Illustrative alkynyloxy groups include, but are not limited to, propynyloxy, butynyloxy, and the like. 0016) The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon. Illustrative alkyl groups include straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-alkyl and C1-4alkyl and C1-Alkyl, respectively, but are not limited thereto.

Illustrative alkyl groups include methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl- 1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and so on, but are not limited to.

I0017| The term "alkylcarbonyl" as used herein refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-). Illustrative alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 carbon atoms, referred to herein as C1-alkylcarbonyl groups. Illustrative alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl 60, and the like.

I0O018) The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Illustrative alkynyl groups include straight or branched groups of 2-6 or 3-6 carbon atoms, referred to herein as C2-balkynyl and C3-balkynyl, respectively, but are not limited thereto. Illustrative alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

I0019| The term "carbonyl", which is used in this document, belongs to the radical -

C(O)-. 00201 The term "cyano", which is used in this document, belongs to the radical -CM.

I0021| The term "cycloalkyl" as used herein refers to a cycloalkyl group attached to oxygen (cycloalkyl-O-). Illustrative cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms, referred to herein as C3-bcycloalkoxy groups. Illustrative cycloalkyl groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, and the like.

I0022| The terms "cycloalkyl" or "carbocyclic group" used herein refer to a saturated or partially saturated hydrocarbon group, for example, of 3-6 or 4-6 carbon atoms, referred to herein as C3-bcycloalkyl or C4-bcycloalkyl, in accordance. Illustrative cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl. 00231 The terms "halo" or "halogen" as used herein refer to PE, SI, Bg or I. (0024) The terms "heteroaryl" or "heteroaromatic group" as used herein refer to monocyclic aromatic 5-6 -membered ring system containing one or more heteroatoms, for example, from one to three heteroatoms, such as nitrogen, oxygen and sulfur.

Where possible, the indicated heteroaryl ring may be linked to a neighboring radical through a carbon or nitrogen atom. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine, and so on. (0025) The terms "heterocyclyl" or "heterocyclic group" are known in the art and refer to saturated or partially saturated 4- to 10-membered ring structures, including bridged or fused rings, the structures of which contain from one to three heteroatoms, such as nitrogen, oxygen and sulfur. Where possible, heterocyclyl rings may be linked to a neighboring radical through a carbon or nitrogen atom. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran, and so on.

I0026| The term "heterocyclyloxy" as used herein refers to a heterocyclyl group attached to oxygen (heterocyclyl-O-).

I0027| The term "heteroaryloxy" as used herein refers to a heteroaryl group attached to oxygen (heteroaryl-O-).

I0028| The terms "hydroxy" and "hydroxyl" used in this document refer to the radical -OH. (00291 The term "oxo", which is used in this document, belongs to the radical 50. (0030) "Pharmaceutically or pharmacologically acceptable" includes molecular substances and compositions that do not cause adverse, allergic or other undesirable reactions when administered to an animal or a person, depending For human administration, drugs must meet the standards of sterility, pyrogenicity, and general safety, as well as the purity standards required by the Biological Substances Division of the US Food and Drug Administration (FDA).

ИЙОО31| The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersants, coatings, isotonic agents, and absorption delaying agents and the like that are compatible with pharmaceutical administration. . The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide auxiliary, additional or enhancing therapeutic functions.

I0032| The term "pharmaceutical composition" as used herein refers to a composition containing at least one compound described herein in a composition with one or more pharmaceutically acceptable carriers. 00331 "Individual", "patient" or "subject" are used interchangeably and include any 60 animal, including mammals, particularly mice, rats, other rodents, rabbits, dogs, cats, pigs,

cattle, sheep, horses or primates and more preferably man. The compounds of the present invention may be administered to a mammal, such as a human, but may also be administered to other mammals in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs , horses, and the like) and laboratory animals (eg, rats, mice, guinea pigs, and the like). A suitable mammal for treatment in the methods of the present invention is a mammal in which the treatment of obesity or weight loss is desired. "Modulation" includes antagonism (eg, inhibition), agonism, partial antagonism, and/or partial agonism. 0034) As used herein, the term "therapeutically effective amount" means the amount of a subject compound that elicits a biological or medical response in a tissue, system, or animal (eg, mammal or human) as observed by a researcher, veterinarian, physician, or other person skilled in the art . The compounds of the present invention are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is an amount necessary to achieve a given therapeutic and/or prophylactic effect, such as an amount that results in weight loss. 0035) The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. The compounds included in the compositions according to the present invention, which are basic in nature, are capable of forming a wide range of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions, including malate, oxalate, chloride, bromide, iodide, nitrate , sulfate, bisulfate, phosphate, hydrophosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate . which are acidic in nature, are capable of forming basic salts with various pharmacologically acceptable cations Examples of such salts include alkali metal salts iv or alkaline earth metals, in particular, salts of calcium, magnesium, sodium, lithium, zinc, potassium and iron. Compounds included in the composition according to the present invention containing a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. Compounds according to this description can contain both acidic and basic groups; for example, one amino group and one carboxylic acid group. In this case, this compound can exist as an acid addition salt, a zwitterion, or a base salt. 0036) Compounds according to this description may contain one or more chiral centers and therefore may exist as stereoisomers. The term "stereoisomer" as used herein includes all enantiomers or diastereomers. These compounds may be denoted by the symbols "(G)", "(-)", "K" or "5", depending on the configuration of the substituents around the stereogenic carbon atom, but it is understood by those skilled in the art that the structure may imply a chiral center. The present invention covers various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the nomenclature "(g)", but it is understood by those skilled in the art that the structure may imply a chiral center.

I0037| Compounds according to this description may contain one or more double bonds, and therefore may exist in the form of geometric isomers formed by rearrangement of substituents around the carbon-carbon double bond. The symbol represents a bond, which may be a single, double, or triple bond as described herein. Substituents around the carbon-carbon double bond are designated as existing in the "2" or "E" configuration, while the terms "2" and "E" are used according to the rules of MUPAC.

Unless otherwise indicated, structures depicting the double bond include both "2" and "E" isomers. Alternatively, substituents around the carbon-carbon double bond may be referred to as "cis" or "trans", with "cis" referring to substituents on one side of the double bond and "trans" referring to substituents on opposite sides of the double bond connection

I0038| The compounds described herein may contain a carbocyclic or heterocyclic ring, and therefore may exist as geometric isomers resulting from rearrangement of substituents around the ring. Rearrangements of substituents around the carbocyclic or 60 heterocyclic ring are denoted as existing in the "7" or "E" configuration, while the terms "2" and

"E" is used according to the rules of MUPAK. Unless otherwise indicated, structures depicting carbocyclic or heterocyclic rings include both "2" and "E" isomers.

Substituents around carbocyclic or heterocyclic rings may also be referred to as "cis" or "trans", where the term "cis" refers to substituents on one side of the plane of the ring and the term "trans" refers to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which the substituents are placed on one side of the plane of the ring or on opposite sides are designated as "cis/trans". 0039 Individual enantiomers and diastereomers of compounds according to this invention can be obtained synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by obtaining racemic mixtures followed by their separation by methods well known to specialists in this field. These separation methods are presented on the example of (1) addition of a mixture of enantiomers to a chiral excipient, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and separation of the optically pure product from the excipient, (2) preparation of a salt using an optically active separating agent, (3) direct separation of a mixture of optical enantiomers on chiral liquid chromatography columns or (4) kinetic separation using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be separated into their components using well-known methods, such as chiral-phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective syntheses, chemical or enzymatic reactions in which one reagent forms an unequal mixture of stereoisomers when creating a new stereocenter or when transforming an already existing stereocenter, are well known in the art. Stereoselective syntheses encompass enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. Examples are provided in the publication of Sagteiga apa Kmayegpo, Siav5is5 ip ZegeozeiYesiime Zupipebiv,

M/eu-USN: Meipneit, 2009. 0040) The compounds described herein may exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and it is intended that this the invention includes both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound exists in crystalline form. 0041) The present invention also encompasses isotopically labeled compounds according to the present invention that are identical to the compounds specified herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number numbers usually existing in nature. Examples of isotopes that can be included in the composition of the compound according to the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2Н, ЗН, 13С, 11С, 14С, 15М, 180, 170, Z1R, Z2R, 355, 18E and Z36SI, respectively. For example, a compound of the present invention may have one or more H atoms replaced by deuterium.

I0042| Some described compounds with an isotopic label (for example, compounds labeled with ЗН and 14С) are used in analyzes of the distribution of the compound and/or substrate in the tissue. The isotopes of tritium (i.e. ZN) and carbon-14 (i.e. 14C) are the most preferred due to ease of preparation and detection.

In addition, substitution with heavier isotopes such as deuterium (i.e. 2H) may provide some therapeutic advantage due to higher metabolic stability (eg, increased half-life of ip mimo or reduced dosages required) and therefore may be preferable in some cases. The isotopically labeled compounds of the present invention can be prepared, in general, by the same methods as described in the examples provided herein, by replacing the isotopically labeled reagent with the isotopically labeled reagent.

I0043| The term "prodrugs" refers to compounds that are converted directly to the described compound or a pharmaceutically acceptable salt, hydrate or solvate of this compound. Such conversion can occur by different mechanisms (such as esterase, amidase, phosphatase, oxidative or reductive) at different sites (such as the intestinal cavity or during passage through the intestine, blood or liver). Prodrugs are well known in the art (e.g., see Kasio, Kypriyaipep, et al., Maishge Kemiem5 YuOgyd ribsomegu 2008, 7, 255). For example, if a compound according to the present invention or a pharmaceutically acceptable salt, hydrate, or solvate of this compound contains a carboxylic acid functional group, then prodrugs may contain an ester obtained by replacing the hydrogen atom of an acid group with a group such as (C1-8)alkyl, (C2- 12) alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanyloxy)ethyl having 60 from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 atoms carbon, 1-

(Alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(Alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, M-(Alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(M-(Alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-M, M-(C1-2)alkylamino( C2-

C)alkyl (such as B-dimethylaminoethyl), carbamoyl-(C1-2)alkyl, M, M-di(C1-2)alkylcarbamoyl-(C1-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3 )alkyl. (0044) Likewise, if the compound according to the present invention contains an alcohol functional group, then prodrugs can be obtained by replacing the hydrogen atom of the alcohol group with a group such as (C1-6)alkylcarbonyloxymethyl, 1-(C1-6)alkylcarbonyloxy)ethyl, 1-methyl-1-(C1-b)alkylcarbonyloxy)ethyl, (C1-6)alkoxycarbonyloxymethyl, M-(C1-b)alkoxycarbonylaminomethyl, succinoyl, (C1-b)alkylcarbonyl, a-amino(C1-4)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl or α-aminoalkylcarbonyl-c-aminoalkylcarbonyl, while each α-aminoalkylcarbonyl group is independently selected from natural I-amino acids,

RIOHON)2, -P(IFOHO(C1-6)alkyl)2 or glycosyl (a radical obtained by cleavage of the hydroxyl group of the hemiacetal form of a carbohydrate).

I0045| If the compound according to the present invention contains an amine functional group, then prodrugs can be obtained, for example, by the formation of an amide or carbamate of an M-alkylcarbonyloxyalkyl derivative, (oxodioxolenylmethyl derivative, base /-M-

Mannich, amine or enamine. Alternatively, the secondary amine can be metabolically cleaved to form a bioactive primary amine, or the tertiary amine can be metabolically cleaved to form a bioactive primary or secondary amine. Examples are provided in the publication by Bitrisio, et al., Moiescie5 2008, 13, 519 and the references contained therein.

Y. Tricyclic compounds

I0046| In some embodiments, the present invention provides compounds of Formula | or

Formula II:

E: V i do Xv' do v v x 9, o V ich 9, M re: y x! Aza and x? in (VYN and (YAN I

Sleep Formula I or sleep Formula I, where

B' can be a 3-bene saturated or partially saturated heterocyclic or carbocyclic ring;

IN? can be a 3-6-membered saturated heterocyclic or carbocyclic ring; while ring B' or B? may be optionally substituted by one or more fluorine atoms near any of the available carbon atoms 0' may be a 5-7-membered heterocyclic, carbocyclic, heteroaromatic or aromatic ring; p can be a 5-7-ene heterocyclic or carbocyclic ring; while B' is condensed with O' in such a way that the two atoms common to B' and O are carbon atoms, and B2 is condensed with Ue- in such a way that the two atoms common to B2 and R are carbon atoms; and at the same time, for Formula 1, the bond common to the rings of Vy p can be a single or double bond;

X' can be selected from the group consisting of: 7-C(VO'VOg)-5, x-Mu1-x, -C(VOVOZg)-

С(ВО5ДОв) -х, х-6(82)-С(822)-", "-М2-С(ВО5ДОв) -х, "-ММ2-6(0)-7, "-б(ВО1ВО2)- Much-x, x-M-S(B22)-», vo

С(Бе)-М-У, х-с(ВО1892)-С(ВОЗВО)-С(ВО5ВОв) -x, "-М2-С(ВО3ВО1)-С(ВО5ВОв) -х, "-М2-С( 0)-C(VO5VOv) -x, --b(VO! Vog)-Mu/3-С(VO5DOv) -x, --b(VO! VOg)-Mu3-(0)-, x-c( VO1892)-С(ВОЗДО) uuch-x and --b(VO! Vog)-С(0)-

MuA-x; while "7 and " indicate the attachment points of X', as shown in Formula I;

X? can be selected from the group consisting of: 7-C(VO'VOg)-5, x-Mu1-x, -C(VOVOZg)-

С(ВО5ВОв)-х, х-Уу2-С(ВО5ВОв)-х, з-Му2г-0(0)-7, 1-С(ВО1ВОг)-Мул-х, х-С(ВО1ВОг)-С(ВОзВО )-С(ВО5ВОв)-, with-

Mu2-C(VOZVOg)-C(VO5DOv)-x 0 3-Mu2-C(0)-C(VO5VOv)-i, i-C(VOVVOg)LuZ-C(VO5VOv)-x, z-C(VOVVOg )-MuZ-

С(0)-7, -Ф(ВО1Вог)-С(ВОЗАО) х-С(ВО1ВОг2)-6(0)-МУ-7; while " and x indicate the attachment points of X2, as shown in Formula II;

U can be selected from the group consisting of: bond, 7-СНе-?, 7-0-5, 5-5Но-СНе-я, 7-0-СНе-я -бН»-О-Я - СН»АСН»-СНе-Я, 7-0-СНоАСНе-я ии -СНг-ОО-СНе-и; while " and 7? indicate the attachment points of Y, as shown in Formula I or Formula II;

M/ may be selected from the group consisting of O, 5 or M(B");

Uug can be selected from the group consisting of O or MSH(B2);

M/Z may be selected from the group consisting of O or M(B"3);

Mu" can be selected from the group consisting of O or M(K");

A may be a ring selected from the group consisting of phenyl, 5-6-ene heteroaryl having 1, 2, or 3 heteroatoms, each of which is selected from 5, M, or 0, of a 4-7 membered heterocycle, having 1, 2 or C heteroatoms, each of which is selected from M or 0;

ВВ and Бе are independently selected from the group consisting of H, E, OH, CM, Sigalkoxy or C. zalkyl; while C-alkyl and C-halkoxy are optionally substituted by a group selected from OH, C-halkoxy, CM, or one or more fluorine atoms;

BA" may be selected, independently in each case, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1 -alkyl or C 1 -alkoxy; wherein C 1 -alkyl or C 1 -alkoxy may be optionally substituted by one or more fluorine atoms, n can be 1 or 2;

VA? may be selected from the group consisting of hydrogen, P'VIM-, heterocyclyl, heterocyclyloxy, and heterocyclyl-"MH)-; wherein said heterocyclyl may be optionally substituted with one or more substituents selected from Co, and if the indicated heterocyclyl contains a -MH fragment, then this nitrogen may optionally be substituted by one or more B groups"; or

Be can be selected from the group consisting of: C.:-alkyl, Sevalkenyl, C.sub.3-valkynyl, C.sub.3-vcycloalkyl, C.sub.1-alkyl, C.sub.3-alkyloxy, C.sub.3-valkynyloxy, C.sub.3-cycloalkyl, C.sub.3-alkyl-5(O)m- ( while m is 0, 1 or 2), C-alkyl-M(H2g)-, C-alkyl-M(B2)-carbonyl-, C-alkylcarbonyl-

M(Hg)-, Stvalkyl-M(He)-carbonyl-M(He)-, Sti-valkyl-M(H2e)-5O2-, Stvalkyl-ZO2-M(H2)-, 000. valkoxycarbonyl-M(Nag )-, Ci-alkylcarbonyl-M(Nag)-C:i-alkyl-, Sci-alkyl-M(Hg)-carbonyl-C:-alkyl-,

C:-valkoxyC.-valkyl-; while C:-alkyl, C6-valkenyl, C6-valkynyl, C3-isocycloalkyl, C:-valkoxy,

C3-valkenyloxy, C3-valkynyloxy, C3-cycloalkyl, Ci-alkyl-5(O)»k-, Ci-alkyl-M(Va)-, Ci-alkyl-

M(Va)-carbonyl-, C-alkylcarbonyl-M(H2g)-, C-alkyl-M(HNe)-carbonyl-M(P2)-,. Si-valkil-M(Nag)-505-,

Sialkyl-502-M(H2g)-, Si-alkyloxycarbonyl-M(Neg)-, Si-alkylcarbonyl-M(H2g)C.-alkyl-, Si-alkyl-

M(B2)-carbonyl-C:-alkyl-, C1-alkoxy-Sialkyl may be optionally substituted with P", phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(MНА2г)-, heterocyclyl, heterocyclyloxy or heterocyclyl-M( H2d)-; and wherein said heteroaryl or phenyl may be optionally substituted with one or more substituents selected from B; and wherein said heterocyclyl may be optionally substituted with one or more substituents selected from Co; and wherein if the specified heterocyclyl contains a -MH fragment, then this nitrogen atom may optionally be replaced by one or more B groups";

BO and Cog2, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, C-halkyl or C-halkoxy; while Ci-halkyl and Sihalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano or hydroxyl;

WOH and COy, each independently, may be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1 -alkyl or C 1 -alkoxy; while C-alkyl and Sisalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or M(B2RAU);

BO5 and Cob, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C-halkyl or C-halkoxy; while C:-halkyl and Sihalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or (BP);

WOW! can be selected from the group consisting of hydrogen, halogen, C:halkyl or C-halkoxy; at the same time, C-halkyl and C-g2-alkoxy can be optionally substituted by one or more fluorine atoms;

B8eg can be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-alkyl or Sihalkoxy; while C-halkyl and Sihalukoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or

M(BeRKh);

B" can be selected from the group consisting of hydrogen or C. -halkyl;

B" can be selected from the group consisting of hydrogen or C. -halkyl;

BZ can be selected from the group consisting of hydrogen, C:-alkyl or C-alkylcarbonyl; while C-alkyl and C-alkylcarbonyl may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or MSH(B2RAU);

B can be selected from the group consisting of hydrogen, C:-alkyl or C:-alkylcarbonyl; while C-alkyl and C-alkylcarbonyl may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or MSH(B2RAU); 60 Weights of KU can be independently selected, for each case, from the group consisting of hydrogen and C:i-alkyl; while C:-alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo and hydroxyl; or with and PE", together with the nitrogen atom to which they are attached, can form a 4-6-membered heterocyclic ring, which can have an additional heteroatom selected from 0, 5 or M; in this case, the specified 4-6-membered heterocyclic the ring may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo or hydroxyl;

B may be independently selected, in each case, from the group consisting of B", hydrogen, C1-alkyl, C3-6cycloalkyl, subalkenyl, C1-6alkyl, C1-6alkyl, C1-6alkyl-Z(O)m -, (while m is 0, 1 or 2), C-alkylcarbonyl-M(B2g)- and C-valoxycarbonyl-M(Hg)-;

C1-alkyl, C3-ecycloalkyl, C1-valkenyl, C1-valkynyl, C1-valkoxy, C1-alkyl-Z(O)m-, C1-alkylcarbonyl-

M(vVag)-, Sivalkoxycarbonyl-M(He)- can be optionally substituted by one or more substituents selected from Be;

Vo may be independently selected, in each case, from the group consisting of PP, hydrogen, oxo, C:-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl-5(O) k-, (while y is equal to 0, 1 or 2), C-alkylcarbonyl-M(H2g)- and C-valoxycarbonyl-M(Neg)-; while C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-cycloalkyl, C-alkyl, C-alkyl-5(O)mz-, C-alkylcarbonyl-M(Hg)-, C-alkyloxycarbonyl-M(H2g)- can be optionally replaced by one or more substitutes selected from the VBR;

B" may be independently selected, for each case, from the group consisting of hydrogen,

Sialkyl, C3-valkenyl, C3-alkynyl, C3-cycloalkyl, C1-alkyl-5(0)2-, C1-alkoxycarbonyl-,

V'VIM-carbonyl- and V/VIM-502-; while C-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl and C3-alkyl-Z(O)2-, C3-alkoxycarbonyl- can be optionally substituted by one or more substituents selected from ER;

Vii VI can be independently selected, for each case, from the group consisting of hydrogen, C1-4 alkyl, C3-cycloalkyl, heterocyclyl and heterocyclylcarbonyl; while C.-alkyl and

C-cycloalkyl may be optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, CaBeM-, BaBeM-carbonyl- and C:1-alkoxy, and the heterocyclyl and heterocyclylcarbonyl may be optionally substituted with one or more substituents , selected from C1:-alkyl, C1-alkenyl, C1-valkynyl, C1-cycloalkyl, C1-valkoxy, halo-C:-c-alkyl, hydroxyl-C:-c-alkyl, VABeM-C1-alkyl- and C-c -Alkoxy-C: -C-Alkyl group; and at the same time, if the indicated heterocyclyl or heterocyclylcarbonyl contains a -MH fragment, then this nitrogen atom may optionally be substituted by one or more C-alkyl, C3 groups. valkenyl, C3-alkynyl, C3-cycloalkyl, C1-6 alkyl-5(O) 2- and C1-6-alkylcarbonyl; or B. and VI, taken together with the nitrogen atom to which they are attached, may form a 4-7-membered heterocyclic ring, which may have an additional heteroatom selected from 0, 5, or M; at the same time, the specified 4-7-membered heterocyclic ring may be optionally substituted near the carbon atom by one or more substituents selected from the group consisting of fluorine, hydroxyl, oxo, cyano, C:-alkyl, C-alkyl, B2BeM- , BaBeM-50"- and BaBeM-carbonyl-; at the same time, the specified C:i-alkyl or Sialkyl may be optionally substituted by fluorine, hydroxyl or cyano; and at the same time, the specified 4-7-membered heterocyclic ring may be optionally substituted near the nitrogen atom by one or more substituents selected from the group consisting of 3-Stialkyl and BaBeM-carbonyl-; and at the same time the indicated C:i-alkyl may be optionally substituted by fluorine, hydroxyl, cyano;

AR can be independently selected, for each case, from the group consisting of halogen, hydroxyl, cyano, Siwaloxy, B'VIM-, B/VIM-carbonyl-, B'VIM-50O2- and B!B/M-carbonyl -

M(No)-; and their pharmaceutically acceptable salts, stereoisomers, esters and prodrugs.

I0047| In some embodiments, X1 may be selected from the group consisting of: -0-7, -M(AM1)-7, -C(801802)-C(805806)- -C(8C1)-C(8C2) -7, -0-С(805806)- --MSH(ВМ2)-

Сб(8О5806)-, -0-0(0)-7, -М(АМ2)-С(0)- -М-С(8С2)-7 and -0-4(803804)-С(8058Об)- 7; at the same time and " indicate the attachment points of X1, as shown in Formula I. Illustrative fragments

X1 can be selected from the group consisting of: i-MH-", 4-0-CH2-7, 4-MH-CH2g-" 4--M-CH- and -CH-CH-", while x and " indicate the points of attachment of X1 as shown in Formula I. 0048) In some embodiments, X2 may be selected from the group consisting of -0-7, 55. A-M(8M1)-77 -C(B801802) -С(805806)-7 -0-С(805806)-7, --М(АМ2)-С(805806)-7,. -0-0(0)-7, -М(АМ2)-С(0)-7 and -0О-С(В03804)-С(ВО58Об6)-"; at the same time, and " indicate the attachment points

X2 as shown in Formula II. Illustrative fragments of X2 can be selected from the group consisting of: i-0-CH2-7 and 4-MH-CH2-" while and " indicate the points of attachment of X2, as shown in Formula II. 60 0049) In one embodiment, KO1, KO2, KS1, KMI1 and KM2 can be independently selected, for each case, from the group consisting of hydrogen and methyl. For example, KO,

CO2, SI, EM and KM2 can be hydrogen.

ИЙ0О050| In some embodiments, KOZ, KO4, KO5, and KOb may be independently selected, in each case, from the group consisting of hydrogen, fluorine, cyano, and C1-2alkyl.

For example, KOZ, 204, KO5 and KOE can be hydrogen.

I0OO51) In one embodiment, KS2 may be selected from the group consisting of hydrogen, halogen, cyano, and C1-2alkyl. For example, KS2 can be hydrogen.

I0052| In some embodiments, the CVI of the tricyclic compound of Formula II may be selected from the group consisting of H, E, or C1-2alkyl. For example, KIV can be H or methyl. 0053) In another embodiment, КВ2 of the tricyclic compound of Formula Я may be hydrogen. 0054) In some embodiments, ring 01 may be selected from the group consisting of 3:

H wherein ", G and i indicate the points of attachment to the phenyl ring and ring B' as shown in Formula I. Illustrative rings O" which may form part of the intended core may include rings selected from the group consisting of: d; г: -- ч о я M 0055) In some embodiments, the ring 02 may be selected from the group consisting of 203:

H at the same time ", Z and i- indicate the points of attachment to the phenyl ring and ring B, as shown in Formula II.

I0O56) In some embodiments, Y can be selected from the group consisting of the bond, x-O-CHne-I and -CH2R-O-CH2-Z; while " and Ж indicate the points of attachment to В, as shown in

Formula I or Formula II. For example, M can be a bond or "-0O-CH2-Z; while 7 and and indicate points of attachment to Y, as shown in Formula I or Formula II.

I0057| For example, ring B1 or B2, in some embodiments, can be selected from the group consisting of: o ho x 1 Ж ж ж Ж х х х! x! x v i i v" ve! i o v2g o v2g zo x m: : while " and 2 indicate the points of attachment to U, as shown in Formulas I and II. Illustrative B' and B' rings that may form part of the intended core may include rings selected from the group consisting of:

vi and i in g and d'. li -A Z o ve o 2 - 282

X x x! x x c

І0058| This document provides, for example, tricyclic compounds represented by the formulas Ia, IB, Is, a, Te, IK and Id: t, (V SON ts, p o o oo i: -x A choti vyag Ou scher r o, i t sht M an o - A M ve re M o re MM (VA N sFfni

TSI SON 14, TSI S2OeN Ie, IE or yes and HM and

ATOM about tn

Sso, n

Id. 0059) In some embodiments, A can be phenyl.

И00О60) This document also provides for the compound represented by the IP Formula: I de Khvyayu

UR (U (che y: "M shchi x! 4 sFN Formula PI; where:

B' can be a 3-bene saturated or partially saturated heterocyclic or carbocyclic ring; while ring B' can be optionally substituted by one or more fluorine atoms near any of the available carbon atoms;

P' can be a 5-7-ene heterocyclic, carbocyclic, heteroaromatic or aromatic ring; while B' is condensed with Or" in such a way that two atoms common to

V'i p', represent carbon atoms; and at the same time, the bond common to the rings can be a single or double bond;

X can be selected from the group consisting of: 5-С(ВО1НОг)-х, с-М/1-7, х-С(ВОТВОЗ)-

С(ВО5ДОв) -х, х-6(82)-С(822)-", "-М2-С(ВО5ДОв) -х, "-ММ2-6(0)-7, "-б(ВО1ВО2)- Much-x, x-M-S(B22)-», vo

С(Бе)-М-У, х-с(ВО1892)-С(ВОЗВО)-С(ВО5ВОв) -x, "-М2-С(ВО3ВО1)-С(ВО5ВОв) -х, "-М2-С( 0)-C(VO5VOv) -x, --b(VO! Vog)-Mu/3-С(VO5DOv) -x, --b(VO! VOg)-Mu3-(0)-, x-c( VO1892)-С(ВОЗДО) uuch-x and --b(VO! Vog)-С(0)-

MUA-h; while "7 and 7" indicate the attachment points of X', as shown in the PP Formula;

U can be selected from the group consisting of: bond, 7-СНе-?, 7-0-Я, х-СНоАСНе-Я, 7-0-СНе- я -бН»-О-Я, -СН "АСН"-СНе-и, -0-СНео-СНе-и and -СН2г-О-СНе-и; at the same time " and 7? indicate the attachment points of U, as shown in the PP Formula;

M/! can be selected from the group consisting of O, 5 or MSH(VM);

Mu can be selected from the group consisting of O or MSH(K");

M/Z may be selected from the group consisting of O or M(B"Z);

Mu" can be selected from the group consisting of O or M(K");

A" may be selected, independently for each case, from the group consisting of hydrogen,

hydroxyl, cyano, halogen, C1-alkyl or C1-alkoxy; while C-alkyl or C-alkoxy may be optionally substituted by one or more fluorine atoms; n can be 0, 1 or 2;

IN? may be selected from the group consisting of hydrogen, РВ'B/M-, heterocyclyl, heterocyclyloxy, and heterocyclyl-"MHe)-; wherein said heterocyclyl may be optionally substituted with one or more substituents selected from Co, and when that if the indicated heterocyclyl contains a -MH fragment, then this nitrogen may optionally be replaced by one or more B groups"; or

Be can be selected from the group consisting of: C1-alkyl, Sovalkenyl, C1-valkynyl, C3-vcycloalkyl, C1-alkoxy, C3-valkenyloxy, C3-valkynyloxy, C3-cycloalkyl, C1-alkyl-5(O)m- (while m is 0, 1 or 2), C-alkyl-M(H2)-, C-alkyl-M(B2g)-carbonyl-, C-alkylcarbonyl-

M(Hg)-, C-alkyl-M(Hg)-carbonyl-M(He)-, C-alkyl-M(Hge)-5O2-, S-alkyl-5O2-M(Nae)-, /C- alkyloxycarbonyl- M(Nag)-, Ci-alkylcarbonyl-M(Nag)-C:i-alkyl-, Sci-alkyl-M(Ng)-carbonyl-C:-alkyl-,

C:-valkoxyC.-valkyl-; while C:-alkyl, C6-valkenyl, C6-valkynyl, C3-isocycloalkyl, C:-valkoxy,

C3-valkenyloxy, C3-valkynyloxy, C3-cycloalkyl, C3-alkyl-Z(O)z-, C3-alkyl-M(B2)-, C3-alkyl-

M(B2g)-carbonyl-, C-alkylcarbonyl-M(H2g)-, C-alkyl-M(Be)-carbonyl-M(B2g)-,. Si-valkyl-M(Hg)-505-,

C-alkyl-502-M(Hg)-, C-valkoxycarbonyl-M(H2g)-, C-alkylcarbonyl-M(Hg)C:-alkyl-, Cc-alkyl-

M(B2)-carbonyl-C:-alkyl-, C1-alkoxy-Sialkyl may be optionally substituted by PE", phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(MНА2г)-, heterocyclyl, heterocyclyloxy or heterocyclyl-M( H2d)-; and wherein said heteroaryl or phenyl may be optionally substituted with one or more substituents selected from EC; and wherein said heterocyclyl may be optionally substituted with one or more substituents selected from Ke; and wherein if the specified heterocyclyl contains a -MH fragment, then this nitrogen atom may optionally be replaced by one or more B groups";

BO and Cog2, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, C-halkyl or C-halkoxy; while Ci-halkyl and Sihalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano or hydroxyl;

WHO and VO, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C1-alkyl or C1-alkoxy; while C-alkyl and C-alkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or (BP);

BO5 and Cob each independently can be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C-halkyl or C-halkoxy; while C:-halkyl and Sihalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or (BP);

WOW! may be selected from the group consisting of hydrogen, halogen, C:alkyl or C-halkoxy; while C-halkyl and C-haloxy can be optionally substituted by one or more fluorine atoms; 82 may be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1 -alkyl, or Si-halkoxy; while C-halkyl and Sihalukoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or magnesium);

B"! can be selected from the group consisting of hydrogen or C: alkyl;

B": may be selected from the group consisting of hydrogen or C: alkyl;

BZ can be selected from the group consisting of hydrogen, C:-alkyl or C-alkylcarbonyl; while C-alkyl and C-alkylcarbonyl may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or M(B2RU);

DM can be selected from the group consisting of hydrogen, C:-alkyl or C-alkylcarbonyl; while C-alkyl and C-alkylcarbonyl may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or M(B2RAU);

Ve and E? may be independently selected, for each case, from the group consisting of hydrogen and C:1-alkyl; while C:-alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo and hydroxyl; or RA and KE, together with the nitrogen atom to which they are attached, may form a 4- to 6-membered heterocyclic ring, which may have an additional heteroatom selected from 0, 5, or M; while the specified 4-6-membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of fluorine, cyano, oxo or hydroxyl;

IN! may be independently selected, in each case, from the group consisting of PP, 60 hydrogen, C1-alkyl, C3-6cycloalkyl, subalkenyl, C1-6alkyl, C1-6alkyl, C1-6alkyl-3(O)m- , (while m is equal to 0, 1 or 2), C-alkylcarbonyl-M(B2g)- and C-valoxycarbonyl-M(Hg)-; with

C1-alkyl, C3-ecycloalkyl, C1-valkenyl, C1-valkynyl, C1-valkoxy, C1-alkyl-Z(O)m-, C1-alkylcarbonyl-

M(Bg)-, Sivalkoxycarbonyl-M(He)- can be optionally substituted by one or more substituents selected from B;

Bé may be independently selected, in each case, from the group consisting of B", hydrogen, oxo, C:-alkyl, C₂-alkenyl, C₁-valkynyl, C₁-₄-cycloalkyl, C₁-₄-alkyl, C₂-₄-alkyl-5(O )k-, (while y is equal to 0, 1 or 2), C-alkylcarbonyl-M(H2g)- and C-alkyloxycarbonyl-M(Neg)-; while C-alkyl, C-valkenyl, C-valkynyl, C-cycloalkyl, C-alkoxy, C-alkyl-5(O)m-, C-alkylcarbonyl-M(Nag)-, C-alkoxycarbonyl-M(Nag)- can be optionally substituted by one or more substituents selected from ER;

A" may be independently selected, for each case, from the group consisting of hydrogen,

Sialkyl, C3-valkenyl, C3-alkynyl, C3-cycloalkyl, C1-alkyl-5(0)2-, C1-alkoxycarbonyl-,

V'VIM-carbonyl- and V/VIM-502-; while C-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl and C3-alkyl-Z(O)2-, C3-alkoxycarbonyl- can be optionally substituted by one or more substituents selected from B;

The VI can be independently selected, for each case, from the group consisting of hydrogen, C1-4 alkyl, C3-cycloalkyl, heterocyclyl and heterocyclylcarbonyl; while C.-alkyl and

C-cycloalkyl may be optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, CaBeM-, BaBeM-carbonyl- and C:1-alkoxy, and the heterocyclyl and heterocyclylcarbonyl may be optionally substituted with one or more substituents , selected from C':-alkyl, Scovalkenyl, C1-valkynyl, C3-cycloalkyl, C1-alkoxy, halo-Ci-c-alkyl, hydroxyl-Ci-c-alkyl, KaB»M-Ci-alkyl- and Ci-e- an alkoxy-Ci-C-alkyl group; and at the same time, if the indicated heterocyclyl or heterocyclylcarbonyl contains a -MH fragment, then this nitrogen atom may optionally be substituted by one or more C-alkyl, C3 groups. valkenyl, C3-alkynyl, C3-cycloalkyl, C1-6-alkyl-5(O)2- and C1-6-alkylcarbonyl; or BV and B), taken together with the nitrogen atom to which they are attached, may form a 4- to 7-membered heterocyclic ring, which may have an additional heteroatom selected from 0, 5, or M; at the same time, the specified 4-7-membered heterocyclic ring may be optionally substituted near the carbon atom by one or more substituents selected from the group consisting of fluorine, hydroxyl, oxo, cyano, C:-alkyl, C-alkyl, B2BeM- , BaBeM-50"- and BaBeM-carbonyl-; at the same time, the specified C:i-alkyl or Sialkyl may be optionally substituted by fluorine, hydroxyl or cyano; and at the same time the specified 4-7-membered heterocyclic ring may be optionally substituted near the nitrogen atom by one or more substituents selected from the group consisting of Stivalkyl and KaBeRM-carbonyl-; and at the same time the specified Sivalkyl can be optionally substituted by fluorine, hydroxyl, cyano;

AR can be independently selected, for each case, from the group consisting of halogen, hydroxyl, cyano, Siwaloxy, B'VIM-, B/VIM-carbonyl-, B'VIM-50O2- and B!B/M-carbonyl -

M(No)-; and its pharmaceutically acceptable salts, stereoisomers, esters and prodrugs.

I0061| In some embodiments, the CAT of the tricyclic compound of Formula IS can be selected from the group consisting of hydrogen, halogen, C1-2alkyl, and C1-2alkyl; while C1-2alkyl may be optionally substituted by one or more fluorine atoms. For example, KA1 can be hydrogen or fluorine.

I0062| In another embodiment, KA? the tricyclic compound of the Formula IS can be selected from the group consisting of hydrogen, KCl/)M, heterocyclyl, C1-alkyl, C3-alkenyl, C3-bcycloalkyl, C1-balkoxy; at the same time, the specified heterocyclyl may be optionally substituted by one or more Co groups; and at the same time, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen atom may be optionally substituted by one or more Ki groups; and at the same time the indicated C1-alkyl, C3-alkenyl, C3-bcycloalkyl and C1-balkoxy may optionally be substituted by one or more KR groups. For example, KA? may be selected from the group consisting of 3-(M,M-diethylamino)propyl, 3-(pyrrolidin-1-yl)propyl, (2)-3-(M,M-diethylamino)prop-1-enyl, (2)-3-(azetidin-1-yl)uprop-1-enyl and (2)-3-(pyrrolidin-1-yl)uprop-1-enyl. 0063) This document also provides for the compound represented by Formula IM:

two! d2

Her with re, - 2 (VAZ su and Xx 4 SON Formula IM,

OO? may be a 5-7-membered partially unsaturated heterocyclic or carbocyclic ring;

X? can be selected from the group consisting of: -C(VO'VOg)-5, x-Mu1-x, -C(VOVOZg)-

С(ВО5ВОв)-х, х-Уу2-С(ВО5ВОв)-х, з-Му2г-0(0)-7, 1-С(ВО1ВОг)-Мул-х, х-С(ВО1ВОг)-С(ВОзВО )-С(ВО5ВОв)-, with-

Mu2-C(VOZVOg)-C(VO5DOv)-x 0 3-Mu2-C(0)-C(VO5VOv)-i, i-C(VOVVOg)LuZ-C(VO5VOv)-x, z-C(VOVVOg )-MuZ-

С(0)-7, -Ф(ВО1Вог)-С(ВОЗАО) х-С(ВО1ВОг2)-6(0)-МУ-7; while " and x indicate the attachment points of X2, as shown in Formula IM;

M/! can be selected from the group consisting of O, 5 or MSH(VM);

Mu can be selected from the group consisting of O or MSH(K");

M/Z may be selected from the group consisting of O or M(B"3);

MU" can be selected from the group consisting of O or MSH(VMU);

VV! can be selected from the group consisting of H, E, OH, CM, C:-halkoxy or C-alkyl; while C-alkyl and C-halkoxy are optionally substituted by a group selected from OH, C-halkoxy,

CM, or one or more fluorine atoms;

BA" may be selected, independently in each case, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1 -alkyl or C 1 -alkoxy; wherein C 1 -alkyl or C 1 -alkoxy may be optionally substituted by one or more fluorine atoms, n can be 0, 1 or 2;

IN? may be selected from the group consisting of hydrogen, K'B/M-, heterocyclyl, heterocyclyloxy and heterocyclyl-""MHg)-, wherein said heterocyclyl may be optionally substituted with one or more substituents selected from Co, and at the same time, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen may optionally be replaced by one or more B groups"; or

Be can be selected from the group consisting of: C:-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl-5(O)m- (when where m is 0, 1 or 2), C-alkyl-M(H2g)-, C-alkyl-M(B2)-carbonyl-, C-alkylcarbonyl-

M(Hg)-, C-alkyl-M(Hg)-carbonyl-M(He)-, C-alkyl-M(Hge)-5O2-, S-alkyl-5O2-M(Nae)-, /C- alkyloxycarbonyl- M(Nag)-, Ci-alkylcarbonyl-M(Nag)-C:i-alkyl-, Sci-alkyl-M(Ng)-carbonyl-C:-alkyl-,

C:-valkoxyC.-valkyl-; while C:-alkyl, C6-valkenyl, C6-valkynyl, C3-isocycloalkyl, C:-valkoxy,

C3-valkenyloxy, C3-valkynyloxy, C3-cycloalkyl, Ci-alkyl-5(O)»k-, Ci-alkyl-M(Va)-, Ci-alkyl-

M(Va)-carbonyl-, C-alkylcarbonyl-M(H2g)-, C-alkyl-M(HNe)-carbonyl-M(P2)-,. Si-valkil-M(Nag)-505-,

C-alkyl-502-M(Hg)-, C-valkoxycarbonyl-M(Hg)-, C-alkylcarbonyl-M(Hg)C:-alkyl-, Cc-alkyl-

M(B2)-carbonyl-C:-alkyl-, C1-alkoxy-Sialkyl may be optionally substituted by PE", phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(MНА2г)-, heterocyclyl, heterocyclyloxy or heterocyclyl-M( H2d)-; and wherein said heteroaryl or phenyl may be optionally substituted with one or more substituents selected from EB; and wherein said heterocyclyl may be optionally substituted with one or more substituents selected from KU; and wherein if the specified heterocyclyl contains a -MH fragment, then this nitrogen atom may optionally be replaced by one or more Kg groups";

BO and Cog2, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, C-halkyl or C-halkoxy; while Ci-halkyl and Sihalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano or hydroxyl;

WHO and VO, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1 -alkyl or C 1 -alkoxy; while C-alkyl and Sisalkoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or M(B2RAU);

BO5 and Cob, each independently, can be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C1-halkyl or C1-halkoxy; while C:-halkyl and Sihalkoxy may be optionally substituted by a substituent or substituents selected from the group consisting of: one or more fluorine, cyano, hydroxyl or MSH(B2NAB) atoms;

WOW! can be selected from the group consisting of hydrogen, halogen, C:halkyl or C-halkoxy; while C-halkyl and C-haloxy can be optionally substituted by one or more fluorine atoms;

B8eg can be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C-alkyl or sigalkoxy; while C-halkyl and Sihalukoxy may be optionally substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl or

M(BeRKh);

B" can be selected from the group consisting of hydrogen or C. -halkyl;

B" can be selected from the group consisting of hydrogen or C. -halkyl;

BZ can be selected from the group consisting of hydrogen, C:-alkyl or C-alkylcarbonyl; while C-alkyl and C-alkylcarbonyl may be optionally substituted by a substituent or substituents selected from the group consisting of: one or more fluorine, cyano, hydroxyl or M(CURAU) atoms;

B can be selected from the group consisting of hydrogen, C:-alkyl or C-alkylcarbonyl; while C-alkyl and C-alkylcarbonyl may be optionally substituted by a substituent or substituents selected from the group consisting of: one or more fluorine, cyano, hydroxyl or M(B2RAU);

Ve and E? may be independently selected, for each case, from the group consisting of hydrogen and C:1-alkyl; while C:-alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo and hydroxyl; or with and PE", together with the nitrogen atom to which they are attached, can form a 4-6-membered heterocyclic ring, which can have an additional heteroatom selected from 0, 5 or M; in this case, the specified 4-6-membered heterocyclic the ring may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo or hydroxyl;

IN! may be independently selected, in each case, from the group consisting of PP, hydrogen, C1-alkyl, C3-6cycloalkyl, subalkenyl, C1-6alkyl, C1-6alkyl, C1-6alkyl-Z(O)m-, (while m is equal to 0, 1 or 2), C-alkylcarbonyl-M(B2g)- and C-valoxycarbonyl-M(Hg)-; with

C1-alkyl, C3-ecycloalkyl, C1-valkenyl, C1-valkynyl, C1-valkoxy, C1-alkyl-Z(O)m-, C1-alkylcarbonyl-

M(Bg)-, Sivalkoxycarbonyl-M(He)- can be optionally substituted by one or more substituents selected from B";

Bhe may be independently selected, in each case, from the group consisting of B", hydrogen, oxo, C1-alkyl, C6-alkenyl, C1-alkynyl, C3-6cycloalkyl, C1-valkoxy, C1-alkyl-5(O)m -, (while y is equal to 0, 1 or 2), C1-alkylcarbonyl-M(H2g)- and C1-alkylcarbonyl-M(H2g)-, while C1-alkyl, C1-alkyl, C1-alkynyl, C3-ecycloalkyl, C-alkyl-5(O)mz-, C-alkylcarbonyl-M(Nag)-, C-alkylcarbonyl-M(Nag)- can be optionally substituted with one or more substituents selected from ER;

A" may be independently selected, for each case, from the group consisting of hydrogen,

Sialkyl, C3-valkenyl, C3-alkynyl, C3-cycloalkyl, C1-alkyl-5(0)2-, C1-alkoxycarbonyl-,

V'VIM-carbonyl- and V/VIM-502-; while C-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl and C3-alkyl-Z(O)2-, C3-alkoxycarbonyl- can be optionally substituted by one or more substituents selected from B;

The VI can be independently selected, for each case, from the group consisting of hydrogen, C1-4 alkyl, C3-cycloalkyl, heterocyclyl and heterocyclylcarbonyl; while C.-alkyl and

SiCecycloalkyl may be optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, CaBeM-, BaBeM-carbonyl- and Sisalkoxy, and heterocyclyl and heterocyclylcarbonyl may be optionally substituted with one or more substituents selected from C C-alkyl, C-alkyl, C-alkyl, C-cycloalkyl, C-alkyl, halo-C-alkyl, hydroxyl-C-alkyl, CaV»M-C-alkyl- and C-alkoxy-C- β-alkyl group; and at the same time, if the indicated heterocyclyl or heterocyclylcarbonyl contains a -MH fragment, then this nitrogen atom may optionally be substituted by one or more C-alkyl, C3 groups. valkenyl, C3-alkynyl, C3-cycloalkyl, C1-6 alkyl-5(O) 2- and C1-6-alkylcarbonyl; or B and B), taken together with the nitrogen atom to which they are attached, may form a 4- to 7-membered heterocyclic ring, which may have an additional heteroatom selected from 0, 5, or M; at the same time, the specified 4-7-membered heterocyclic ring may be optionally substituted near the carbon atom by one or more substituents selected from the group consisting of fluorine, hydroxyl, oxo, cyano, C:-alkyl, C-alkyl, B2BeM- , BaBeM-50"- and BaBeM-carbonyl-; at the same time, the specified C:i-alkyl or Sialkyl may be optionally substituted by fluorine, hydroxyl or cyano; and at the same time the specified 4-7-membered heterocyclic ring may be optionally substituted near the nitrogen atom by one or more substituents selected from the group consisting of Stivalkyl and KaBeRM-carbonyl-; and at the same time, the indicated Sivalkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, 60 hydroxyl, cyano;

AR can be independently selected, for each case, from the group consisting of halogen, hydroxyl, cyano, Siwaloxy, B'VIM-, B/VIM-carbonyl-, B'VIM-50O2- and B!B/M-carbonyl -

M(No)-; and its pharmaceutically acceptable salts, stereoisomers, esters and prodrugs.

I0064| In some embodiments, the CAT of the tricyclic compound of Formula IM can be hydrogen or fluorine.

I0065| In other embodiments, KA2 of the tricyclic compound of Formula IM can be selected from the group consisting of hydrogen, KikKu)M, heterocyclyl, C1-alkyl, C3-alkenyl, C3-bcycloalkyl, C1-balkoxy, heterocyclyl-MPa-carbonyl-C1 -alkyl and heterocyclyl-carbonyl-MVa-

C1-balkylu; at the same time, the specified heterocyclyl may be optionally substituted by one or more Co groups; and at the same time, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen atom may be optionally substituted by one or more Ki groups; and at the same time indicated

C1-balkyl, C3-balkenyl, C3-bcycloalkyl and C1-balkoxy may be optionally substituted by one or more ER groups.

I0066) This document also provides compounds that can be selected from the group consisting of 3: cis-(Zane, 9585)-7-(benzenesulfonylamino)-1,3a, 4,9p-tetrahydro-2H-furo(2, 3-sichromene-b-carboxylic acid; cis-(Zane5, 95A5)-7-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H-furo|2, 3-sichromene-b-carboxylic acid; cis-(zanv, 9rAB)-7-(2-(3-«(pyrrolidine-1-ylpropyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p- tetrahydro- 2H-furo|2,3-c|Ichromene-6-carboxylic acid; cis-(zanz, 90A5)-7-(2-((2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-1 ,Za, 4,9p-tetrahydro-2H-furo!|2,3-sichromene-6b-carboxylic acid; cis-(Zzan, 906A)-7-(2-(2)-3-diethylaminoprop-1-enyl) -4- fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H-furo|2,3-sichromene-b-carboxylic acid; cis-(Zaie, /-955)-7-(2-(2) -3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-1,3a, - 4,9p- tetrahydro-2H-furo|2,3-c|Ichromene-b-carboxylic acid; 7-(2-( 2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenes lfonylamino!|-1,2-dihydrofuroi|2,3-s)|quinoline-b-carboxylic acid formate salt; 7-""benzenesulfonylamino))-1,2-dihydrofuro|2,3-c|quinoline-b-carboxylic acid formate salt; cis-(Zanvi, 9085)-7-(2-(2)-3Z-diethylaminoprop- 1-enyl)-4-fluorobenzenesulfonylamino!|-1,2,Za,4,5,9p-hexahydrofuro|2,3-c|quinoline-b-carboxylic acid; Pakzv, 76b5K)-5-(2-(( 2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1, Ta, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Yes, 7p5)-5-(2-(2)- 3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tab, 76LK)-5-(2-((2)-3-diethylaminoprop -1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Takz, 755E)-5-(2-(27)-3-diethylaminoprop-1-enyl )-4-fluorobenzenesulfonylamino|-7B-methyl-1Ta, 2,7pO-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; OPax, 76B5K)-5-(2-(E)-3-diethylaminoprop-1-enyl)- 4-fluorobenzenesulfonylamino|-7b-methyl-1,Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; cis-(Zane, 9085)-7-(2-(4-d) Imethylimine-butylamino)-benzenesulfonylamino|-1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-b-carboxylic acid; (tan, 705)-5-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (tan, 7658)-5-(2 -((2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1-difluoro-

T1la, /2,7β-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; (yes, 765)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-1,1-difluoro-1a, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylic acid ; (Taz, 7BK)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1-difluoro-1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carbon acids; Oiaks, 7B5K)-5-(2(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,70-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid;

Pan, 765)-5-(2(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Taz, 7BK)-5-(2(7)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Yes, 705K)-5-2I((2)-3-(pyrrolidin-1-yl)prop-1-enyl|-A-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid ; (yes, 765)-5-2((2)-3-(pyrrolidin-1-ylylprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|c)ichromene-4-carboxylic acid ; (Taz, 7BH)-5-2Y(2)-3-(pyrrolidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|cIIIchromene-4-carboxylic acid ; (tan, 7658)-5-(2-(3-dimethylaminopropylamino)-benzenesulfonylamino!|-1 Ta, 2,76- tetrahydrocyclopropa|sichromene-4-carboxylic acid; Pak, 765)-5-(2-(3- dimethylaminopropylamino)benzenesulfonylamino|-1,1a,-2,7b-tetrahydrocyclopropa|Cs|chromene-4-carboxylic acid; (Taz, 7BK)-5-(2-(3-dimethylaminopropylamino)benzenesulfonylamino|-1 Ta, 60 2, 7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; pPax, 7lb5K)-5-(2-(4-

dimethylaminobutylamino)benzenesulfonylamino|-1,1a, 2,7b-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; (Yes, 7B65)-5-(2-(4-dimethyliminebutylamino)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (ав, 7бК)-5-(2-(4 - dimethylaminobutylamino)benzenesulfonylamino|-1i,1a,2,7b-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; (also, 7B65K)-5-(2-(5-dimethylaminopentylamino)benzenesulfonylamino |- 1la,2,7p-tetrahydrocyclopropa| CIIIchromene-4-carboxylic acid; (Takv5, 7B5K)-5-21(2)-3-(propan-2-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7- tetrahydrocyclopropa| Sichromene-4-carboxylic acid; OPax, 7tb5K)-5-21(2)-3-((5)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2 ,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; Oiaks, 7tb5K)-5-4(2((2)-3-((8)-3- hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p- tetrahydrocyclopropa |cichromene-4-carboxylic acid; (Takz, 705K)-5-(2(27)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1 Ta, 2,7B-tetrahydrocyclopropa|cichromene-4- carboxylic acid; (Yes, 765)-5-(2((2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino|-1,1a, 2,7B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; ( Tab, 7BK)-5-(2(7)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Also, 7B5K)- 5-12-(2-(4-ethylpiperazin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Takz, 7p5K)-5-21 (2)-3-(azetidin-1-ylprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|c)ichromene-4-carboxylic acid; Pakz, 7tb5K)-5-(2 ((2)-3-(3-Hydroxyazetidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1,1a,.2,7b-tetrahydrocyclopropa-|sichrome n-4-carboxylic acid; (tan, 7658)-5-2I((2)-3-(azetidin-1-yl)/upropyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; Oiax, 7L5K)-5-(2((2)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino|-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; Pakz, 7L5K)-5-2- IIM-(4-dimethylaminobutyl)-M-methylamino|-benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa-|sichromene-4-carboxylic acid; (tav, /7658)-5-2-((5)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl|-4-fluorobenzenesulfonylamino)-

Ta, 2,7p-tetrahydrocyclopropa-Is|ichromene-4-carboxylic acid; (thiacz5, 7B6B5NK)-5-(2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino|-1,1a, 2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; pPax, 7B5K)- 5-2-((B8)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; (tan, 7658)-5-12-(2-(pyrrolidin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (So, 705K)-5-(2-(B)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Taz, 7BK)-5-(2-(B)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa(|c|ichromene-4-carboxylic acid; ( Yes, 765)-5-(2-(BA)-1-ethylpyrrolidine-

3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,70-tetrahydrocyclopropa|c|chromene-4-carboxylic acid; (also 5, /7B6B5E4)-5-2-((5)-1-ethylpyrrolidine-2-ylcarbonylaminomethyl|-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; (ав, /7658)-5-(2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino|-і,іа, --2,7р- tetrahydrocyclopropa-IsIchromene-4-carboxylic acid; (Also, 76Б5К)-5- (2-(5)-1-ethylpyrrolidine-

3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,70-tetrahydrocyclopropa|c|chromene-4-carboxylic acid; Pakz, 7B5K)-5-(2-(3- dimethylaminopropylcarbamoyl)benzenesulfonylamino!|-1Ta, 2,7- tetrahydrocyclopropa(|siIchromene-4-carboxylic acid; OIakz, 7B5K)-5-(2-M-( 5)-1-ethylpyrrolidin-3-yl)-N-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylic acid; OPakz, 76B5K)-5-(2-CM-((A)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa-|sichromene- 4-carboxylic acid; Pakzv, 7LK)-5-2-(2-((5)-1-ethylpyrrolidin-2-yl/ethylamino|-benzenesulfonylamino)-1Ta, 2,7p0-tetrahydrocyclopropa-

Isochromene-4-carboxylic acid; (Takb5, 7p5K)-5-2-(2-(B)-1-ethylpyrrolidin-2-yl)ethylamino|-benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa-|sichromene-4-carboxylic acid; (tan, 765)-5-(2-(3-M, M,-diethylaminopropylamino)benzenesulfonylamino!-1, Ta, 2,76- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tak, 765E)-5-( 2-|1(B)-1-ethylpyrrolidine-2-ylcarbonylamino|methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (х1акз5, 7Б6Б5К)-5-2-(1-ethylazetidin-3-ylmethyl)amino|benzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (tab, /7BN)-5-(2-(2)-3-diethylaminoprop-1-enyl/ubenzenesulfonylamino|-y,ia,-2,7B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Yes, 7p5) -5-(2-(2)-3-diethylaminoprop-1-60enyl)benzenesulfonylamino|-1,1a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid;

(Tanz, 7658)-5-(2-4M-((A)-1-ethylpyrrolidin-2-yl)ucarbonyl|-M-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene -4-carboxylic acid; (Tanz, 7658)-5-(2-1IM-((5)-1-ethylpyrrolidine-2-ylcarbonyl|-M-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4 - carboxylic acid; (tan, 7658)-5-(2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino!|-1Ta, 2,76p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Takz, 7p5K)-5-2-( (B)-1-ethylpyrrolidine-

(3-ylmethyl)amino|-benzenesulfonylamino)-1Ta, 2,7pO-tetrahydrocyclopropa-|cichromene-4-carboxylic acid; pPax, 7tB5K)-5-2-(5)-1-ethylpyrrolidin-3-ylmethyl)amino|-benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa-[sichromene-4-carboxylic acid; (Tavnv5, 7658)-5-(2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino|-1,Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (also, 7p5K)-5-(2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7b-tetrahydrocyclopropa-|sichromene-4-carboxylic acid; (iaz, 7p5K)-5-12 -(2-(1-ethylazetidin-3-yl)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; OPax, 7B5K)-5-2-((5) -1-azabicyclo|2.2.2|oct-3-yl)amino|benzenesulfonylamino)-1Ta, 2,7-tetrahydrocyclopropa|siIchromene-4-carboxylic acid; (jakz5, 7p5E)-5-2-((B)-1-azabicyclo- (2.2.2)oct-3-yl)amino|benzenesulfonylamino)-1Ta, 2,7p0-tetrahydrocyclopropa|c|Hychromene-4- carboxylic acid; (hTak5, 7B6B5K)-5-(2-1(5)-1-ethylpyrrolidine-3-carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid ; (tav, /7658)-5-2-(2-(B8)-1-ethylpyrrolidin-3-ylamino)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylic acid ; pPakz, 76B54K)-5-2-|(A)-1-ethylpyrrolidine-3-ylamino|-benzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa-Isochromene-4-carboxylic acid; (Yes, 76551E)-5-(2-|(5)-1-ethylpyrrolidin-3-yl)amino|-benzenesulfonylamino)-

Ta, 2,7p-tetrahydrocyclopropa-(c|ichromene-4-carboxylic acid; (chTakz5, 7B6B5E)-5-(2-|1(B8)-1-ethylpyrrolidine-3-carbonyl)amino|-methyl)-4 -fluorobenzenesulfonylamino)-1Ta, 2,7-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (also, 7B6B5K)-5-(2-(7)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino|-1, and, 2,7Br-tetrahydrocyclopropa|siIichromene-4-carboxylic acid; Pakz, 76B5K)-5-12-(2-(H)-1-ethylpyrrolidin-3-yl)ethylamino|-benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa-|sichromene-4-carboxylic acid; (chIan5, 7055H)-5-42-(2-((5)-1-ethylpyrrolidin-3-yl)ethylamino|-benzenesulfonylamino)-1,ia,-2,7p-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid; (yes, 7p)-5-(2-((5)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino|-1Ta, 2,70-tetrahydrocyclopropa-|c|ichromene-4-carboxylic acid; Pak .

Pan, 765) -5-(2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1 Ta, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (tav, 76065)-5- 2-(2-(B)-1-ethylpyrrolidin-2-yl)ethyl|-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylic acid; and its pharmaceutically acceptable salts, stereoisomers, esters and prodrugs.

I0067| Methods of obtaining the compounds described in this document are presented below with reference to Schemes 1-3. In the reactions described below, it may be necessary to protect chemically active functional groups (such as hydroxyl, amino, thio, or carboxyl groups) to exclude their unwanted participation in the indicated reactions. The use of such groups in methods where their introduction and removal are necessary are known to those skilled in the art (for example, see sgeepe,

MUtsiv, Rgoiesiime Stotsrv ip Ogdapis 5upipeziz. 2nd edition (1999)). The deprotection step may be the final step of the synthesis, so that deprotection gives compounds of Formula I described herein or represented, for example, by the general formula below. The starting materials used in the following schemes can be purchased commercially or prepared using methods described in the chemical literature or adapted using methods known to those skilled in the art. The order of performing the stages may vary depending on the groups being introduced and the reagents used, but will be understood by those skilled in the art. 0068) The general synthetic strategy used to prepare tricyclic compounds of general formula I is depicted in Scheme 1. The tricyclic system can be assembled in a number of ways starting from an appropriately substituted and protected phenyl ring TA. Group c" is a suitably protected carboxylic acid, such as methyl- or tert-butylcarboxylate, or is a functional group that can be easily converted into a carboxylic acid, such as a nitrile or aldehyde. Group C is a sulfonamide group or a functional group, which can then be converted to a sulfonamide group such as an appropriately protected aniline. The B" ring can be directly attached to the 60-substituted phenyl ring to form intermediate 1B, and then the M" ring can be formed

by an intramolecular reaction with the formation of intermediate compound 1E. Alternatively, ring B" can be attached to a substituted phenyl ring, TA, via a linker, X", to form intermediate 1C, and then ring 0" can be formed by an intramolecular reaction to form intermediate 1E. Alternatively, ring Y" can be formed on a substituted phenyl ring to form intermediate 10 and then connected to ring B" to form intermediate TE. Modifications to rings B" and O" may be necessary to provide the specified saturated or partially unsaturated ring systems, and they may be performed before or after the formation of the tricyclic nucleus.

For example, if ring B" is a dihydro- or tetrahydrofuran, it can be prepared from the corresponding furan compound by hydrogenation in the presence of a metal catalyst (eg, palladium or palladium hydroxide on a solid support such as carbon) in a solvent (such as ethyl acetate, ethanol or dioxane), optionally in the presence of an acid (such as acetic acid). The hydrogenation can be carried out at any stage during the synthesis of the compounds, either before or after the formation of the tricyclic ring. Compounds of Formula I can be prepared from the intermediate TE deprotection Alternatively, additional modifications, such as modifications at C, may be performed on 1E to remove all protection groups to form compounds of general formula I. The specific steps of the synthetic process are described in more detail below.

SCHEME 1 is in 18 c (and there is a t. v. and 18 o

WITH

"tv that / --68ЙОТ---sh in tr r" 7 ay

Is in (y o x in Kt ' ' is x (E; (with Ge IE 1A 1s son y de r General Formula ---- I vo (her) Ge x s 10

I0069| In Scheme 1, step (ii), compounds of structure 1A can be coupled under a range of conditions to compounds of structure 1B", where B" is the corresponding ring to produce compounds of type 18. A series of steps may be required to introduce ring B" and producing a number of intermediates. Protecting groups may also be required. If K1 is a leaving group (such as a halide or triflate), then 18" can be converted to 1B by the formation of a carbon-carbon bond.

A carbon-carbon bond can be formed by the interaction of compounds of structure 18", where CZ is a borane, boronate, or boronic acid group (such as 2-formylfuran-3-boronate), in the presence of a palladium catalyst (such as palladium arry chloride or tris -(dibenzylideneacetone)dipalladium), in the presence of a base (such as cesium carbonate) and a suitable reagent (such as a phosphine, for example tri-tertbutylphosphonium tetrafluoroborate or triphenylphosphine) in a suitable solvent (such as dioxane, water or tetrahydrofuran, or mixtures thereof) and under suitable conditions (such as heating, for example, heating at 80-1207C for 1-2 hours or microwave irradiation at 120-160 "C for 10 minutes to 1 hour), to produce 1B. Those skilled in the art are familiar with numerous reagents and conditions for binding organoboronates, boronates, and boronic acids to compounds such as TA.

For example, see Zy2iki, Spet. Chem. 1995, 95, 2457; 5y2yKi, Modegp Agepe Spetivigu 2002, 53-1061).

I0070| Alternatively, the carbon-carbon bond in Scheme 1, step () can be formed by coupling compounds of structure 1B", in which B" is the corresponding ring, and where KZ is a trialkylstannane (such as tri-n-butylstannane ) with compounds of the structure TA, where K1 is a leaving group (such as a halide or triflate) in the presence of a palladium catalyst (such as palladium chloride), in a suitable solvent (such as dimeth or tetrahydrofuran) and under suitable conditions (such as heating at 80-120 "C for 1-2 hours or microwaves at 120-160 "C for 10 minutes to 1 hour), to obtain 18.

A large number of suitable reagents and conditions for coupling stannanes with aryl halides such as 1A are known to those skilled in the art. (For example, see Ztiy, Magsy, Magsp'5 Admapsei

Ogdapis Spitivig, 1st edition, UMieeu: New York, 2001, pp. 931-932; Oe botsyga, Sitepi Ogdapis zZupipeziv 2006, Z(3), 31 3-326.|. 0071) Alternatively, compounds of structure 1A where K1 is a leaving group (such as a halide or triflate) can be treated, for example, with a diboronate (such as bispinacolate diboron) in the presence of a palladium catalyst (such as palladium chloride and a base ( such as potassium acetate or diisopropylamine) in a suitable solvent (such as a mixture of dioxane and water) and under suitable conditions (such as heating, for example, at 80-120 "C for 1-2 hours or microwaves at 120-160 "C for 10 minutes to 1 hour), to give a compound of structure TA, where K! is a boronate. A large number of suitable reagents and conditions are known to those skilled in the art to convert an aryl halide (or aryl triphthalate) to an aryl boronate (or arylborane) (for example, see Magepai! Spetigasie 2000, 13(4), 219-222).

An arylboronate (or arylborane) formed in such a way that it can then be treated with compounds of structure 18" (where KZ is a halogen or a triflate) in the presence of appropriate reagents such as a phosphine (e.g., tri-tert-butylphosphonium tetrafluoroborate), a base (such such as cesium carbonate) and a catalyst (such as tris-(dibenzylideneacetone)dipalladium) in an appropriate solvent (such as a mixture of water and dioxane) under appropriate conditions (such as heating at 80-120 "C for 1-2 hours or microwaves at 120- 160 "C for 10 minutes to 1 hour), to obtain compounds of structure 18.

I00721| In Scheme 1, step (im), the K2 and K4 groups of compound 18 can be bonded together to give the X" group, which forms an O'-ring. The K2 or KA in step (i) can be masked by protecting groups, and before the formation of group X" may require removal of the protecting group. Alternatively, chemical modification of K2 or K4 may be required prior to formation of the X group."

For example, if K2 or K4 is a nitro group, then this group can be reduced, for example, using hydrogen in the presence of a suitable catalyst (such as palladium on a solid support such as carbon); or treatment with an inorganic reducing agent (such as stannous chloride in DMF) to form an amino group. For example, if K2 or K4 is a hydroxyalkyl group, then this group can be treated with an oxidant (such as Jones reagent or manganese dioxide) to form an aldehyde; or another oxidizer (such as potassium permanganate) to form a carboxylic acid. For example, if K2 or K4 is an aldehyde, then this group can be treated with an oxidizing agent (such as potassium permanganate) to form a carboxylic acid, or a reducing agent (such as sodium borohydride) to form an alcohol.

For example, if K2 or KA is a ketone, then this group can be treated with a reducing agent (such as sodium borohydride) to form a secondary alcohol. For example, if K2 or K4 is a carboxylic acid or ester, then this group can be treated with a reducing agent (such as lithium aluminum hydride) to form an alcohol. For example, if K2 or K4 is an alkene group, then this group can be treated with a borane (such as 9-borobicyclononane) and converted to a primary or secondary alcohol. 0073) The formation of the linker X" can be performed in a number of ways known to those skilled in the art. For example, if one of the two groups K2 and K4 is a hydroxyl, and the other is a substituted alkyl alcohol, then 18 can be treated with a dehydrating agent (such as diisopropylazodicarboxylate) in the presence of a phosphine (such as triphenylphosphine) to give 1E, where X" is a simple ether. Alternatively, if one of the two groups K2 or

C4 is hydroxyl and the other group is an alkyl group substituted with a leaving group (such as halogen, tosylate, or triflate), then 18 can be treated with a base (such as diisopropylethylamine, potassium carbonate, or sodium hydride) to form 1E, where X" is a simple ether.0074) Alternatively, if one of the K2 or KA groups is a carboxylic acid and the other group is an alkyl halide or sulfonate, then 18 can be treated with a base such as diisopropylethylamine, potassium carbonate, or sodium hydride to give 1E, where X" is an ester.

I0075| Alternatively, if one of the two K2 or MK4 groups is a hydroxyl or substituted alkyl alcohol and the other group is a carboxylic acid or carboxylic acid ester, then 18 can be treated with an acid (such as hydrochloric acid) or 60 with a dehydrating agent (such as such as dicyclohexylcarbodiamide or acetic anhydride) to give 1E, where X" is an ester. 0076) Alternatively, if one of the two K2 or KA groups in 1B is a hydroxyl or a substituted alkyl alcohol and the other group is a carboxylic acid, then said carboxylic acid may first be converted to a mixed anhydride (e.g., by treatment with 2,4,6-trichlorobenzoyl chloride) or to an activated ester (e.g., by NATI treatment in the presence of a base such as diisopropylethylamine or pyridine), and the resulting mixed anhydride or activated complex the ether can then be treated with a base (such as diisopropylethylamine, pyridine, or potassium carbonate) to form 1E, where X" is a complex eph ir

I0077| Alternatively, if one of the K2 or KA groups in 18 is an amine or substituted alkylamine and the other group is a carboxylic acid, then the carboxylic acid can be converted to an activated ester (eg, by NATO treatment and a base such as diisopropylethylamine or pyridine , or TVTI in the presence of M-methylmorpholine), and the resulting activated ester can then be treated with a base to obtain 1E, where X" is an amide.

I0078)| Alternatively, if one of the two K2 or K4 groups in 18 is an amine or substituted alkylamine and the other group is a carboxylic acid, then 18 can then be treated with a dehydrating agent (such as diisopropylcarbodiamide) to form 1E, where X" is amide.

I0079| Alternatively, if one of the two K2 or CA groups is an amine or substituted alkylamine and the other group is an alkyl group substituted with a leaving group (such as halogen, tosylate, or triflate), then 1B can be treated with a base (such as diisopropylethylamine, pyridine or potassium carbonate) to form TE where X" is a substituted amine. (0080) Alternatively, if one of the two K2 or K4 groups is an aldehyde and the other group is a phosphorine (such as alkyltriphenylphosphorine) or an alkylphosphonate (such as an alkylphosphonic acid diethyl ether), then 18 can be treated with a base (such as diisopropylethylamine, potassium carbonate, or sodium hexmethyldisilazide) to form 1E, where X" is an alkene that may or may not be optionally substituted.

I0081| Alternatively, if one of the two K2 or KA groups is an amine and the other group is an aldehyde, then 18 can be treated with an acid (such as p-toluenesulfonic acid) or a Lewis acid (such as stannous tetrachloride) to give 1E, where X" represents -"SV-M- or -"M-SV-.

I0082| In scheme 1, stage (iii), compounds of structure TA can interact with 1C" to form linker X" and give compounds of structure 1C. The formation of linker X" in compounds of structure 1C may require a number of stages and the preparation of a number of intermediate compounds, as well as may require a number of stages of the use of protective groups. 0083) For example, if one of the two groups K2 or Kb is a hydroxyl group, and the other group is is a substituted alkyl alcohol, then TA and 1C" can be treated with a dehydrating agent (such as diisopropyl azodicarboxylate) in the presence of a phosphine (such as triphenylphosphine) to give 1C, where X" is a simple ether. Alternatively, if one of the two K2 groups or K4 is hydroxyl and the other group is an alkyl group substituted with a leaving group (such as halogen or mesylate), then 1A and 1C" can be treated with a base (such as diisopropylethylamine, potassium carbonate, or sodium hydride) to form 1C, where X" represents a simple ether. (0084) Alternatively, in Scheme 1, step (ii), if one of the two groups K2 or Kb is a hydroxyl or an alkyl alcohol and the other group is a carboxylic acid, then the specified carboxylic acid can be converted to an acyl halide (for example, by treatment with thionyl chloride or oxalyl chloride) or to a mixed anhydride (for example, by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as diisopropylethylamine), or to an activated ester (for example, by treatment NATO in the presence of a base such as diisopropylethylamine or pyridine, or by treatment with diisopropylcarbodiamide in the presence of

NOVT), then TA and 1C" can be linked to form 1C, where X is an ester. 0085) Alternatively, if one of the two groups K2 or Kb is an amine or alkylamine and the other group is a carboxylic acid , then the specified carboxylic acid can be converted to an acyl halide (e.g., by treatment with thionyl chloride or oxalyl chloride) or to a mixed anhydride (e.g., by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as diisopropylethylamine), or to an activated ester (e.g., treatment with NATI in the presence of diisopropylethylamine or pyridine, or treatment with diisopropylcarbodiamide in the presence of NOVT), then TA and 1C" can be linked to form 1C, where X' is an amide. (0086) Alternatively, if one of the two groups K2 or Kb is an amine or substituted alkylamine and the other group is an alkyl group substituted with a leaving group (such as halogen or triflate), then LA and 1C" can be treated with a base ( such as diisopropylethylamine, pyridine, or potassium carbonate) to form 1C, where X" is a substituted amine.

I0087| Alternatively, if one of the two groups K2 or Kb is an aldehyde and the other group is a phosphorine (such as alkyltriphenylphosphorine) or an alkylphosphonate (such as alkylphosphonic acid diethyl ether), then TA and 1C" can be treated with a base (such as diisopropylethylamine or potassium carbonate or sodium hexmethyldisilazide) to form 1cC, where X" represents an alkene which may or may not be additionally substituted. 0088) In scheme 1, stage (m), compounds of structure 1E can be obtained from compounds of structure 1C by the interaction of groups КИ and К5 in the range of conditions for the formation of a carbon-carbon bond. If one of the groups K! or K5 is a leaving group (such as a halide or triflate) and the other group is borane, boronate or boronic acid, then, in the presence of a palladium catalyst (such as palladium arry chloride) and in the presence of a base (such as cesium carbonate), in a suitable solvent (such as dioxane, water or tetrahydrofuran, or mixtures thereof) and under suitable conditions (such as heating, for example, heating at 80-120C for 1-2 hours or microwave irradiation at 120-160 "C for 10 minutes up to 1 hour), 1C can be converted to 1E. A large number of suitable reagents and conditions are known to those skilled in the art to bind organoboronates, boronates, and boronic acids to form compounds of type 1E. (0089) Alternatively, if one of the groups K or K5 is a leaving group (such as a halide or triflate) and the other group is a trialkylstannane, then the carbon-carbon bond can be formed in the presence of a palladium catalyst (such as palladium arry chloride), in an appropriate solvent (such as dimethoxyethane or tetrahydrofuran) and under appropriate conditions (such as heating at 80-120 "C for 1-2 hours or microwave irradiation at 120-160 "C for 10 minutes to 1 hour) to obtain 1E. A large number of suitable reagents and conditions for coupling aryl- or heteroarylstannanes into aryl- or heteroaryl halides are known to those skilled in the art.

I0090)| In Scheme 1, step (ii) compounds of structure 1A can interact under a range of conditions with intermediate compounds of type 10" to obtain compounds of structure 10, where Y" is a six- or seven-membered fused heterocyclic ring, and KU and K10 are the corresponding functional groups , which can be used to obtain the B'-ring. Groups КИ and К7 can interact with each other with the formation of a carbon-carbon bond, and groups К2 and К8 can interact with each other with the formation of group Х". Methods of formation of bicyclic compounds of structure 10 from substituted phenyl rings of structure 1А are well known to specialists in this field (see Soptrgepepztime Neiegosusiis Spetivigu Ei: KaiiyKku, Vatzaep, 5spmep, apa Tauog,

Eibemivy, 2008). 0091) For example, a compound of structure TA, where K2 is a hydroxyl group and K1 is hydrogen, can be treated with an appropriately protected and substituted 3-halopropanoic acid or ester in a suitable solvent (such as tetrahydrofuran or dimethylformamide) and in the presence of a base (such as sodium carbonate or diisopropylethylamine) at room temperature to the reflux temperature of the solvent to give a compound of type TA, where K2 is a substituted oxypropanoic acid or ester. This intermediate can be treated with an appropriate reagent (such as a strong acid, e.g., triflatic acid) to form 10, where KU is oxo, P10 is hydrogen, and X" is -OSNa-.

I0092| Alternatively, a compound of structure TA, where K2 is hydroxyl and K1 is hydrogen, can be treated with a propargyl halide or tosylate in the presence of a base (such as potassium carbonate or cesium carbonate) in a solvent (such as acetone) at room temperature to temperature of dephlegmation of the solvent, with the formation of a compound of type 1A, in which K2 is a propargyloxyl group. This intermediate can be heated to 200°C or treated with a suitable catalyst (such as a gold catalyst, e.g. gold triphenylphosphine triflamide) in a suitable solvent (such as toluene) at a temperature from 80°C to the reflux temperature of the solvent to give a compound of structure 10 , where X" is -ОСНа2-, КУ and К10 are H, and the bond between them is a double bond (i.e., chromene). 60 I0093| Additional modification of intermediate compounds of structure 10 having a double bond near carbon atoms to which CO and K10 are attached (such as chromene) can be achieved, for example, by treatment with a hydroborating agent (such as a borane-THF complex) followed by oxidation, for example, with hydrogen peroxide to form a mixture of compounds of structure 10, where X " represents OSH2, KU represents H, and K10 represents a hydroxyl group, and where X" represents -OSH2-, KU represents hydroxyl, and K10 represents H, which can be separated by chromatography.

I0094| An additional modification of the intermediate compound of structure 10 can be made, in which one of KZ and K10 is H and the other is hydroxyl. For example, this intermediate can be oxylated by treatment with an oxidizing agent (such as Desso-Martin periodinane) to form a compound of structure 10 in which one of KU and K10 is H and the other is oxo. (0095) Alternatively, a compound of structure 1A in which K1 is a suitable group (such as a halogen such as bromine or iodine or triflate) and K2 is a protected amine (such as acetamide or trifluoroacetamide) may be bonded to a terminal alkyne in the presence of a palladium catalyst (such as tetrakis(triphenylphosphine)palladium(0)), optionally in the presence of an additional copper catalyst (such as copper(I) iodide) in the presence of a base or salt (such as triethylamine or potassium acetate ), in a solvent (such as tetrahydrofuran or dimethylformamide) at a temperature from room temperature to the reflux temperature of the solvent, or by irradiation in a microwave reactor at a temperature from 100 "C to 160 "C, to obtain a compound of the structure TA, in which K! is a substituted alkyne, and K2 is a protected amine (such as acetamide or trifluoroacetamide). Alternatively, a compound of structure 1A in which K1 is a suitable group (such as a halogen such as bromine or iodine or triflate) and K2 is a protected amine (such as acetamide or trifluoroacetamide) can be linked to an acetylene stannane in the presence of a palladium catalyst (such as palladium chloride) in a suitable solvent (such as dioxane, dimethoxyethane, or tetrahydrofuran) at room temperature to the reflux temperature of the solvent, or, alternatively, by irradiation in a microwave reactor at a temperature of 100 "C to 160 "C, with the formation of a compound of structure TA, in which K1 is an alkyne, and K2 is a protected amine (such as acetamide or trifluoroacetamide).

I0096| In Scheme 1, step (iii), a compound of structure 1A, in which K1 is an appropriately substituted alkyne and K2 is a protected amine (such as acetamide or trifluoroacetamide), can be treated with a base (such as potassium carbonate or sodium methoxide) in a suitable solvent (such as acetone, DMF, or methanol) at room temperature to the reflux temperature of the solvent to give a compound of structure 10 in which X" is MH. Alternatively, a compound of structure 1A in which CI is appropriately substituted alkyne, and K2 is a protected amine (such as acetamide or trifluoroacetamide), can be treated with a palladium catalyst (such as bis-(triphenylphosphine)palladium chloride) in the presence of a base (such as triethylamine) and a suitable catalyst (such as copper iodide ( I)), in a solvent (such as dimethylformamide) at a temperature from room temperature to the reflux temperature of the solvent, with the formation of a compound of structure 10, in which X' is MH.

I0097| The general synthetic strategy for 10 is shown in Scheme 2.

SCHEME 2

N

N (m) in"

N

H 9 x H v a x sb 2V' o sy

N de vm mi Z x

E

With " (I) 9 r. That uy

AND

OO gA She A (ii) I | ! c) their about (them)

Wu (i) x a - shu u

God bless you! X (E ' '

Min" Y 10 (mii) o 20 a (khii) o / Sat hA po (hi) o

Хо у Х (хійі) а х х Ге х се ж В о се ' в' 1 2E s Х 20 sb 2E 0098) In scheme 2, compounds of structure 10 can be transformed into various compounds of structure 1E, using reactions known to specialists in this field In some cases it may be necessary to modify groups KU and K10 in 10 to ensure the possibility of creating given ring systems. It is understood by those skilled in the art that several stages of protection of various functional groups may be required prior to reaction. The specific steps of these synthesis methods are described in detail below. 0099) In scheme 2, step (ii), 10, in which both KU and K10 are H and the bond between the carbon atoms is a double bond, can be treated with diethylzinc and diiodomethane, optionally in the presence of additional reagents (such as trifluoroacetic acid or zinc iodide) in a solvent (such as 1,2-dichloroethane) at a temperature from -78 "C to room temperature, to obtain compounds of structure 2A, in which ring B" is a cyclopropyl ring. Alternatively, compounds of structure 10 in which both KU and K10 are H and the bond between the carbon atoms is a double bond can be treated with trimethylsulfoxonium iodide or trimethylsulfonium iodide in the presence of a base (such as sodium hydride) in a solvent (such as dimethylsulfoxide) at room temperature to 100 °C. Alternatively, compounds of structure 10 in which both KZ and

K10 is H, and the bond between the carbon atoms is a double bond, can be treated with diazomethane in the presence of a catalyst (such as palladium acetate) in a solvent such as diethyl ether at a temperature from 0 "C to room temperature.

ИЙ00100| Alternatively, compounds of structure 2A can be prepared in a two-step process. For example, in Scheme 2, step (ii), 10, in which both KU and K10 are H and the bond between the carbon atoms is a double bond, can be treated with trimethylsilyldiazomethane in the presence of a catalyst (such as palladium acetate) in a solvent (such as diethyl ether) at a temperature from 0 "C to room temperature to form intermediate 2A", in which y) is H and Y" is a trimethylsilyl group. In Scheme 2, step (iii), intermediate compounds 2A", in which )U represents H, and y" represents a trimethylsilyl group, can be converted into compounds of structure 2A by treatment with a source of fluoride (for example, tetrabutylammonium fluoride) in a solvent (such as tetrahydrofuran) at a temperature from 0 "С to room temperature. 00101) Alternatively, in scheme 2, stage(s), 10, in which both KZ and K10 are

H, and the bond between the carbon atoms is a double bond, can be treated with haloform (such as chloroform or bromoform) in the presence of a base such as sodium hydroxide or potassium tert-butoxide in the presence of a catalyst (such as triethylbenzylammonium chloride or tetrabutylammonium bromide) in a mixture of water and a halogenated solvent (such as dichloromethane or dichloroethane), or alternatively in an excess of haloform at temperatures from room temperature to 80 "C, to give intermediate 2A", in which both .) and U" are chlorine or bromine. In Scheme 2, step (iii), intermediates 2A", in which both ./ and y" are chlorine or bromine, can be converted to compounds of structure 2A by treatment with a base (such as sodium methoxide or tert-butoxide sodium) in a solvent (such as tetrahydrofuran) at room temperature to the reflux temperature of the solvent. Alternatively, intermediates 2A", in which both . i)" represent chlorine or bromine, can be converted to compounds of structure 2A by reduction; for example, by treatment with lithium aluminum hydride in a solvent (such as tetrahydrofuran) at a temperature from 0 "C to the reflux temperature of the solvent, or alternatively, for example, by hydrogenation using catalyst (such as palladium on carbon) in a solvent (such as methanol or ethanol), optionally in the presence of a base (such as triethylamine). Alternatively, intermediate compounds 2A", in which both .) and Y" represent chlorine or bromine, can be converted to compounds of structure 2A under radical conditions; for example, by treatment with stannous hydride (such as tributyltin hydride), optionally in the presence of a radical initiator (such as azo-bis-isobutyronitrile) in a solvent (such as toluene) at a temperature from room temperature to the reflux temperature of the solvent.

I00102| In scheme 2, stage (im), 10, in which X" contains a carbonyl (for example, where X" represents -0-0(0)-), and both KU and K10 represent H, and the bond between the atoms carbon represents a double bond, can be converted into the corresponding compounds 28 by treatment with ethylene in a solvent (such as dichloromethane) under photochemical conditions. 00103) Alternatively, compounds of structure 28 can be prepared in a multistep manner. For example, in Scheme 2, step (m), 10, in which both KU and K10 are H and the bond between the carbon atoms is a double bond, can be treated with an acrylate (such as ethyl acrylate) in a solvent (such as as acetonitrile) under photochemical conditions to give intermediate 2B", in which y" represents an ester group (such as an ethyl ester). This ester can be hydrolyzed, for example, by treatment with sodium hydroxide or lithium hydroxide in a solvent such as aqueous ethanol or aqueous dioxane, at a temperature from room temperature to the reflux temperature of the solvent, to form an intermediate compound of structure 28B", in which U" is carboxylic acid. In scheme 2, step (mi), the acid can be removed, for example, by heating, for example in quinoline, optionally in the presence of a catalyst (such as copper) to about 200 "C. 00104) In scheme 2, stage (mii) , 10, in which K10 is hydroxyl and CO is CH2OH, can be treated with a sulfonyl chloride (such as 4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine), optionally in the presence of 4-dimethylaminopyridine, in a solvent (such as dichloromethane or toluene) at room temperature to the reflux temperature of the solvent.The product can be treated with a base (such as triethylamine, diisopropylethylamine, or sodium hydride) in a suitable solvent (such as dichloromethane, tetrahydrofuran, or DMF) to afford the compound of structure 20. 00105) In scheme 2, stage (my), 10, in which KU is CH2CH2OH, and K10 is

CH2OH, can be converted to compounds 20. A series of steps may be required to protect one of the hydroxyl groups and treat the other with a sulfonyl chloride (such as o/4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine), optionally in the presence of 4- of dimethylaminopyridine, in a solvent (such as dichloromethane or toluene) at a temperature from room temperature to the reflux temperature of the solvent. After deprotection of the remaining hydroxyl group, this intermediate can be treated with a base (such as triethylamine, diisopropylethylamine, or sodium hydride) in a solvent (such as dichloromethane, tetrahydrofuran, or dimethylformamide) at room temperature to the reflux temperature of the solvent to give compounds of structure 20.

IІ00106| Alternatively, compounds of structure 20 can be prepared in a 2-step process. For example, in Scheme 2, step(s) 10, in which KU is CH2CO2H and K10 is CH2OH, can be converted to compounds of structure 20". This carboxylic acid can be converted to an acid chloride (by treatment with, for example, thionyl chloride or oxalyl chloride, optionally in the presence of a catalytic amount of DMF in a solvent such as dichloromethane or toluene) or to a mixed anhydride (e.g., by treatment with 2,4,6- 60 trichlorobenzoyl chloride in the presence of a base such as diisopropylethylamine) or to an activated ester ( for example, by treatment with NATI in the presence of a base such as diisopropylethylamine or pyridine, or by treatment with diisopropylcarbodiamide in the presence of NOHT. The acid chloride, mixed anhydride, or activated ester may then be treated with a base (such as triethylamine or pyridine) in a solvent (such as dichloromethane or toluene) to obtain the compound of structure 20". In Scheme 2, step (x), compounds of structure 20" can be converted to compounds of structure 20 by reduction, for example, treatment with lithium aluminum hydride, sodium-diisobutylaluminum hydride, or borane-dimethyl sulfide complex, in an appropriate solvent (such as tetrahydrofuran) at a temperature of - 780 C to room temperature.

I00107| In Scheme 2, step (xi), 20, in which KU is CH2CH2OH and K10 is hydroxyl, may be treated with a sulfonyl chloride (such as 4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presence of a base (such as triethylamine), optionally in in the presence of 4-dimethylaminopyridine, in a solvent (such as dichloromethane or toluene) at room temperature to the reflux temperature of the solvent, followed by treatment with a base (such as triethylamine, diisopropylethylamine, or sodium hydride) in an appropriate solvent (such as dichloromethane, tetrahydrofuran, or DMF) at a temperature from room temperature to the reflux temperature of the solvent, to obtain the compound of structure 2E. (00108) Alternatively, compounds of structure 2E can be prepared in a 2-step process.

In Scheme 2, step (xi), 10, in which CO is H and K10 is oxo, can be converted to compounds of structure 2E" by treatment with chloroacetaldehyde or bromoacetaldehyde in the presence of an aqueous base (such as sodium bicarbonate or sodium hydroxide in water ) at 0 C to room temperature, followed by treatment with an acid (such as concentrated sulfuric acid) in a mixture of water and an organic solvent (such as ethyl acetate). 00109) In Scheme 2, step (chii), compounds of structure 2E can be prepared from compounds of structure 2E" by hydrogenation in the presence of a metal catalyst (such as palladium or palladium hydroxide on a solid support such as carbon), in a solvent (such as an ether such as tetrahydrofuran or dioxane, or an alcohol such as methanol or ethanol), neob necessarily in the presence of an acid (such as acetic acid). Depending on the nature of the X" linker, the bond between the two rings can be reduced or unreduced, with the formation of tetrahydrofuran or dihydrofuran. For example, if X" is -M-O-, then ring B" in 2E is dihydrofuran, in while if X" represents -OSNE2-, then ring B" represents tetrahydrofuran. 00110) In Scheme 1, stage (my), compounds of the general structure TE can be transformed into compounds of the general formula | by the transformation of the C" group into a carboxylic acid. If group c" is a carboxylic acid ester (such as methyl, tert-butyl, or benzyl ester), then different reagents and conditions can be used to convert 1E into a compound of general formula I. For example, if c" is methyl, ethyl or benzyl ester, it can be converted to the carboxylic acid by treatment with an inorganic base (such as lithium hydroxide or sodium hydroxide) in a solvent (such as methanol, dioxane, or water, or mixtures thereof) at room temperature to reflux temperature solvent, or, alternatively, by microwaves at 120-180 C for 10 minutes to 1 hour. Alternatively, if c" is a benzyl ester, it can be converted to the carboxylic acid by hydrogenation in the presence of a catalyst (such as palladium on a solid support such as carbon) in a solvent (such as dioxane or ethyl acetate). Alternatively, if c" is tert-butyl ether, it can be converted to a carboxylic acid by treatment with an acid (such as trifluoromethanesulfonic acid or hydrogen chloride) in a solvent (such as dichloromethane or dioxane). 00111) Alternatively, if the C" group is a nitrile, it may be converted to the carboxylic acid by treatment with an aqueous acid (such as an inorganic acid, e.g., hydrochloric acid) under appropriate conditions (such as heating, e.g., to reflux); or by treatment with an aqueous base (such as aqueous hydroxide, e.g., aqueous sodium hydroxide) under appropriate conditions (such as heating, e.g., to reflux). 00112) Alternatively, if group c" is an aldehyde (CHO) or a hydroxymethyl moiety (CH2OH), then it can be converted to the carboxylic acid by treatment with a suitable oxidizing agent (such as potassium permanganate or chromic acid). 00113) A general synthetic strategy for the modification of the C group is presented in Scheme 3. The b group can be introduced and/or modified before, during, or after assembly of the tricyclic 60 ring system. The specific steps used to collect the sulfonamide are described in more detail below.

SCHEME Z z z z z - z z z - z

ЗА Св З 00114) In scheme 3, the asterisks mean the presence of groups К1 and К2 (as shown in scheme 1) or the presence of rings Y" and B", or intermediate compounds for obtaining these rings (as shown in

Schemes 1 and 2). 00115) In Scheme 3, step (iii), compounds of structure ZA, in which C is a nitro group, can be converted to compounds 3B by reduction, for example, catalytic hydrogenation in the presence of a metal catalyst (such as palladium on a solid support such as carbon) in a solvent (such as an ether, such as tetrahydrofuran, or an alcohol, such as methanol or ethanol). Alternatively, compounds of structure ZA, in which C is a nitro group, can be converted to compounds of structure ЗB by chemical reduction. For example, reduction can be achieved using a metal or a metal salt (such as ferric, zinc, or stannous (II) chloride) in the presence of an acid (such as hydrochloric acid or acetic acid). 00116) In scheme 3, stage (I), compounds of structure ZA, in which C is a protected amino group, can be converted into compounds of structure ЗB by removing protective groups. Protecting groups for amino groups are well known to those skilled in the art, and methods of removing them are also well known

For example, see Sgeepe, UUtsi5, Rgoiesiime (zgocr5 ip Ogdapis Zupipevzi5, 2nd edition (1999)|.

For example, compounds of the structure ЗА, in which E is an amino group protected by one or two

Bos groups, can be converted to compounds of structure ZB by treatment with an acid (such as trifluoroacetic acid, formic acid, or hydrogen chloride) in a solvent (such as dichloromethane or dioxane). 00117) Alternatively, in Scheme 3, step (i), compounds of structure 3A in which b is a pivaloyl-protected aniline can be converted to compounds of structure 3B by treatment with an acid (such as concentrated sulfuric acid) in a solvent (such as methanol ) at a temperature from room temperature to the dephlegmation temperature of the solvent. 00118) In Scheme 3, step (i), compounds of structure 3B can be converted to compounds of structure 3C by treatment with an appropriate sulfonyl chloride (such as substituted or unsubstituted benzenesulfonyl chloride) or an activated sulfonate ether (such as pentafluorophenylsulfonate ether) in the presence of an appropriate base (such as pyridine , diisopropylethylamine or cesium carbonate) in a suitable solvent (such as dichloromethane or dimethylformamide) at a temperature from room temperature to the reflux temperature of the solvent. 00119) For intermediates to obtain compounds of Formula 1 or, for example, general formula 1, a series of reduction steps of the aromatic ring system may be required to form the saturated ring system required in the compounds of Formula 1. This hydrogenation may be accomplished by hydrogenation of the intermediates in the presence of a metal catalyst (eg palladium or palladium hydroxide on a solid support such as carbon) in a solvent (such as ethanol, ethyl acetate or dioxane), optionally in the presence of an acid (such as acetic acid). The reduction of the aromatic rings can be performed before or after the formation of the tricyclic ring system, or at any stage during the synthesis, as understood by those skilled in the art.

I00120| Compounds of any of Formula I, Formula Y, or, for example, general formula Y, depicted above, or any of their intermediates described in the schemes presented above, may be further derivatized using one or more standard synthetic methods known to those skilled in the art. in this field. Such methods may involve substitution, oxidation, or reduction reactions. These methods can also be used to obtain or modify compounds of general formula I or any previous intermediate compounds by modifying the introduction or removal of appropriate functional groups.

Specific approaches to substitution include alkylation, arylation, heteroarylation, acylation, tidsacylation, halogenation, sulfonation, nitration, formylation, hydrolysis. These techniques can be used to introduce a functional group into the parent molecule (such as nitration or sulfonation of aromatic rings) or to bond two molecules (for example, to bond an amine to a carboxylic acid to form an amide; or to form a carbon-carbon bond bond between two heterocycles).

For example, alcohol or phenol groups can be converted to ether groups by coupling the phenol with an alcohol in a solvent (such as tetrahydrofuran) in the presence of a phosphine (such as triphenylphosphine) and a dehydrating agent (such as diethyl, diisopropyl, or dimethyl azodicarboxylate). Alternatively, ether groups can be obtained by deprotonating an alcohol using a suitable base (such as sodium hydride) followed by the addition of an alkylating agent (such as an alkyl halide or alkyl sulfonate).

I00121| In another example, a primary or secondary amine can be alkylated using a reductive alkylation technique. For example, the amine can be treated with an aldehyde and a borohydride (such as sodium triacetoxyborohydride or sodium cyanoborohydride) in a solvent (such as a halogenated hydrocarbon such as dichloromethane or an alcohol such as ethanol) and, if necessary, in the presence of an acid (such as acetic acid).00122) In another example, hydroxy groups (including phenolic OH groups) can be converted to leaving groups such as halogen atoms or sulfonyloxy groups (such as alkylsulfonyloxy, e.g., trifluoromethanesulfonyloxy, or arylsulfonyloxy, e.g., n- toluenesulfonyloxy), using conditions known to specialists in this field.

For example, an aliphatic alcohol can react with thionyl chloride in a halogenated hydrocarbon (such as dichloromethane) to form the corresponding alkyl chloride. A base (such as triethylamine) may also be used in this reaction.

I00123| In another example, ester groups can be converted to the corresponding carboxylic acids by acid- or base-catalyzed hydrolysis, depending on the nature of the ester group. Acid-catalyzed hydrolysis can be achieved by treatment with an organic or inorganic acid (such as trifluoroacetic acid in an aqueous solvent, or an inorganic acid such as hydrochloric acid in a solvent such as dioxane). Base-catalyzed hydrolysis can be achieved by treatment with an alkali metal hydroxide (such as lithium hydroxide in an aqueous alcohol such as methanol). 00124) In another example, the aromatic halogen substituents in the compounds can undergo halogen-metal exchange by treatment with a base (such as a lithium base, e.g., n-butyl or tert-butyllithium, optionally at a low temperature (such as -78 C), in solvent (such as tetrahydrofuran), and then this mixture can be quenched with an electrophile to introduce a given substituent. For example, a formal group can be introduced using dimethylformamide as the electrophile. Aromatic halogen substituents can also be reacted over a palladium catalyst to introduce groups such as as carboxylic acids, esters, cyano or amino substituents.

I00125| In another example, an aryl or heteroaryl ring substituted with an appropriate leaving group (such as a halogen or a sulfonyl ether, such as a triflate) can undergo a palladium-catalyzed coupling reaction with various substrates to form a carbon-carbon bond. For example, the Heck reaction can be used to link such a ring system to an alkene (which may or may not be optionally substituted) by treatment with an organopalladium complex (such as tetrakis(triphenylphosphine)palladium(0), palladium(I) acetate, or palladium chloride (II)) in the presence of a ligand (such as a phosphine, e.g., triphenylphosphine), in the presence of a base (such as potassium carbonate or a tertiary amine, e.g., triethylamine), in an appropriate solvent (such as tetrahydrofuran or DMF), under appropriate conditions (such as as heating, for example, to 50-120 "C). In another example, the Sonogashir reaction can be used to link such a ring system to an alkyne (which may or may not be optionally substituted) by treatment with a palladium complex (such as tetrakis( triphenylphosphine)palladium(0)) and a copper(I) halide salt (such as copper(I) iodide) in the presence of a base (such as potassium carbonate or a tertiary amine such as triethylamine) in a suitable solvent (such as tetra ahydrofuran or dimethylformamide), under appropriate conditions (such as heating, for example, to 50-120 "С). In another example, the Stille reaction can be used to couple such a ring system to an alkene by treatment with an organotin compound (such as an alkyltin reagent or an oalkenyltin, e.g., alkenyltributylstannane) in the presence of a palladium complex (such as tetrakis(triphenylphosphine)palladium (0 )), in the presence or absence of a salt (such as copper (I) halide), in a suitable solvent (such as dioxane or dimethylformamide), under suitable conditions (such as heating, for example, to 50-120 7С).

I00126| Specific approaches to oxidation include dehydrogenation and aromatization, decarboxylation, and addition of oxygen to certain functional groups. For example, aldehyde groups can be obtained by oxidation of the corresponding alcohol using conditions well known to those skilled in the art. For example, an alcohol can be treated with an oxidizing agent (such as Dess-Martin periodinane 60) in a solvent (such as a halogenated hydrocarbon, e.g.

dichloromethane). Alternative oxidation conditions can be used, such as treatment with oxalyl chloride and an activating amount of dimethylsulfoxide, followed by quenching by addition of an amine (such as triethylamine). Such a reaction can be carried out in an appropriate solvent (such as a halogenated hydrocarbon, e.g., dichloromethane) and under appropriate conditions (such as cooling below room temperature, e.g., to -78 "C followed by heating to room temperature). In another example, atoms sulfurs can be oxidized to the corresponding sulfoxide or sulfone with an oxidizing agent (such as a peroxyacid, such as 3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenated hydrocarbon, such as dichloromethane) at about room temperature.

I00127| Specific approaches to reduction include removal of oxygen atoms from certain functional groups or saturation (or partial saturation) of unsaturated compounds containing aromatic or heteroaromatic rings. For example, primary alcohols can be prepared from the corresponding ester or aldehyde by reduction using a metal hydride (such as lithium aluminum hydride or sodium borohydride, in a solvent such as methanol). Alternatively, CH2OH groups can be obtained from the corresponding carboxylic acid by reduction using a metal hydride (such as lithium aluminum hydride in a solvent such as tetrahydrofuran). In another example, the nitro group can be reduced to an amine by catalytic hydrogenation in the presence of a metal catalyst (such as palladium on a solid support such as carbon) in a solvent (such as an ether, such as tetrahydrofuran, or an alcohol such as methanol), or by chemical reduction using a metal (such as zinc, tin, or iron) in the presence of an acid (such as acetic acid or hydrochloric acid). In the following example, an amine can be prepared by reduction of a nitrile, for example, by catalytic hydrogenation in the presence of a metal catalyst (such as palladium on a solid support such as carbon) or Raney nickel in a solvent (such as tetrahydrofuran) and under suitable conditions (such as cooling below room temperature, for example, to -78 C, or heating, for example, to dephlegmation).

II00128| Salts of compounds of the general formula | may be prepared by reacting a compound of general formula I with an appropriate acid or base in an appropriate solvent or mixture of solvents (such as an ether, e.g., diethyl ether, or an alcohol, e.g., ethanol, or an aqueous solvent), using standard techniques. Salts of compounds of general formula I can be replaced by other salts by treatment using standard methods of ion exchange chromatography.

I00129| If it is necessary to obtain a specific enantiomer of a compound of the general formula Y, then it can be obtained from the appropriate mixture of enantiomers using any suitable standard technique for the separation of enantiomers. For example, diastereomeric derivatives (such as salts) can be obtained by the interaction of a mixture of enantiomers of a compound of general formula I (such as a racemate) and a corresponding chiral compound (such as a chiral base). The diastereomers can then be separated by any standard method, such as crystallization, and the given enantiomer can be isolated (such as by acid treatment, if the diastereomer is a salt). Alternatively, the racemic mixture of esters can be resolved by kinetic hydrolysis using various biocatalysts (e.g. see

Paradise! biegozviiesiime Viosaia|uviv, Mags! OesKeg; New York, 2000).

ІІ00130| In another method of separation, the racemate of compounds of general formula I can be separated using high performance liquid chromatography. Alternatively, a particular enantiomer can be prepared using an appropriate chiral intermediate in one of the techniques described above. Chromatography, recrystallization and other standard separation methods can also be used for intermediate compounds or final products, if it is necessary to obtain a specific geometric isomer according to the present invention.

II. Methods 00131) In another aspect, according to the present invention, methods of modulating the activity of Me(AP2) are presented. Such methods include the effect on the specified receptor of a compound described in this document. In some embodiments, a compound used according to one or more of the above methods, represents one of the general, group or specific compounds described in this document, such as a compound of Formula I, Ia, IB, Is, Id, Ie, Ii, Ii, Sh or IM.

The ability of the compounds described herein to modulate or inhibit Meg(AP2) can be assessed by methods known in the art or described herein. In another aspect, the present invention provides methods of treating a disease associated with the expression or activity MeiAR2 in a patient For example, the subject method comprises 60 administration of the described compound in an amount sufficient to inhibit intracellular MeiAR2,

effective for increasing the production of thioredoxin in the patient and for initiating multiorgan stimulation of anti-obesity processes in the subject, for example, by introducing the described compound in an amount insufficient to reduce angiogenesis in the patient. 00132) In some embodiments, the present invention provides a method of treating or ameliorating obesity in a patient by administering an effective amount of the described compound. This document also provides methods for initiating weight loss in a patient who needs it.

Possible patients include not only humans, but also other animals such as domestic animals (eg, dogs, cats).

IІ00133| Other methods of treatment contemplated include a method of treating or ameliorating an obesity-related condition or co-morbidity by administering to a subject a compound described herein. For example, this document discusses methods of treating type 2 diabetes in a patient who needs it. (00134) Illustrative comorbidities include cardiac disorders, endocrine disorders, respiratory disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders. 00135) Examples of cardiac disorders include hypertension, dyslipidemia, coronary heart disease, cardiomyopathy, myocardial infarction, stroke, venous thromboembolic disease, and pulmonary hypertension. Examples of endocrine disorders include type 2 diabetes and latent autoimmune diabetes in adults. Examples of respiratory disorders include obesity-related hypoventilation syndrome, asthma, and obstructive sleep apnea syndrome. An example of a liver disorder is non-alcoholic fatty liver disease. Examples of skeletal disorders include back pain and osteoarthritis of weight-bearing joints. Examples of metabolic disorders include Prader-Willi syndrome and polycystic ovary syndrome. Examples of reproductive disorders include sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities. Examples of psychiatric disorders include obesity-related depression and anxiety. 00136) In particular, in some embodiments, the present invention provides a method of treating the above medical indications, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound

Formulas I, Ia, IB, Is, Id, Te, IE PP or IM.

I00137| Obesity or the aforementioned "overweight" refers to an excess of fat relative to lean body mass. Excessive accumulation of fat is associated with an increase in the size (hypertrophy) and the number (hyperplasia) of adipose tissue cells. Obesity is measured in various ways in terms of absolute weight, weight:height ratio, distribution of subcutaneous fat, and according to social and aesthetic norms. A commonly accepted measure of body fat is the body mass index (BMI). BMI refers to the ratio of body weight (expressed in kilograms) to the square of height (expressed in meters). Body mass index can be accurately calculated using one of the formulas: weight (kg) / height? (m) (SI) or 703 X weight (lbs) / height? (inches?) (US).

I00138| According to the US Centers for Disease Control and Prevention (CDC), an overweight adult has a BMI of 25 kg/m2 to 29.9 kg/m2, and an obese adult has a BMI of 30 kg/m2 or higher. A BMI of 40 kg/m2 or higher is an indicator of morbid obesity or extreme obesity. Obesity may also apply to patients with a waist circumference of around 102 cm for men and around 88 cm for women. When determining overweight and obesity in children, the influence of age and sex on body fat content is taken into account. Patients from a different genetic background may be considered "obese" with values different from the general norms presented above. 00139) The compounds of the present invention are also useful for reducing the risk of secondary effects of obesity, such as reducing left ventricular hypertrophy. Treatment options for patients at risk of obesity, such as those who are overweight but not obese, for example with a BMI of around 25 to 30 kg/m2, are also considered. In some embodiments, the patient is a human.

I00140| VMI does not take into account the fact that excess fat can occur selectively in different parts of the body, and the development of adipose tissue in some parts of the body can be more dangerous to health than in other parts of the body. For example, "central obesity," commonly associated with an "apple" figure, results from excessive adiposity, particularly in the abdominal region, including abdominal and visceral fat, and carries a higher risk of comorbidity than "peripheral obesity," which is typically associated with a "pear-shaped" figure, which is the result of excessive obesity, especially on the hips. As an indicator of central obesity, measurement of the circumference ratio of 60 waist/hips (M/NC) can be used. The minimum value of M/NEC indicative of central obesity varies, and in an adult with central obesity, M/NEC is usually around 0.85 or more for women and around 0.9 or more for men. 00141) Methods of determining whether a subject is overweight or obese, which take into account the ratio of excess adipose tissue to lean body mass, include obtaining a body composition of the subject. Body composition can be obtained by measuring the thickness of subcutaneous fat in several places on the body, such as the abdominal area, subscapular area, arms, buttocks and thighs. These measurements are then used to estimate total body fat with a margin of error of approximately four percentage points. Another method is the analysis of bioelectrical resistance (BIO), in which the resistance of an electric current through the body is used to estimate the fat content. Another method uses a large container of water to measure body buoyancy. Increased body fat leads to higher buoyancy, while higher muscle mass leads to a tendency to sink. 00142) In another aspect, the present invention provides methods of treating overweight or obesity in a subject, comprising determining the level of at least one biomarker associated with overweight or obesity in the subject, and administering an effective amount of a described compound to achieve a predetermined level in the body of the subject. Examples of biomarkers include body weight, body mass index (BMI), waist/hip ratio (WHR), plasma adipokines, or a combination of the two. 00143) In some embodiments, the compound used according to one or more of the above methods is one of the general, group or specific compounds described herein, such as a compound of Formula I, Ia, IB, Is, a, Te, I, PI, Sh or IM.

I00144| The compounds of the present invention can be administered to patients (animals and humans) in need of such treatment in doses that provide optimal pharmaceutical efficacy. It should be understood that the dosage required for use in any particular application will vary from patient to patient not only with the particular compound or composition selected, but also with regard to the route of administration, the nature of the condition to be treated, the age and condition of the patient, accompanying treatment or special diets, which the patient must adhere to, as well as other factors known to specialists in this field, while the appropriate dose is established by the attending physician. For the treatment of the clinical conditions and diseases indicated above, the compound according to the present invention can be administered orally, subcutaneously, topically, parenterally, by inhalation by spray or rectally in single-dose compositions containing standard pharmaceutically acceptable carriers, adjuvants and liquid carriers. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusions. 00145) Treatment may be continued for as long or as short a period of time as is necessary. The compositions can be administered on a schedule, for example, from one to four or more times per day. A suitable treatment period may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. The treatment period can be ended when a given result is achieved, for example, a given weight loss. The treatment regimen may include a correction phase during which a dose sufficient to achieve weight loss is administered, followed by a maintenance phase during which, for example, a lower dose sufficient to prevent weight gain is administered. An appropriate maintenance dose is likely to be in the lower portions of the dose ranges presented herein, and correction and maintenance doses for specific patients can be readily determined by one skilled in the art without extensive experimentation based on the description provided herein. Maintenance doses may be used to maintain body weight in subjects whose body weight has previously been controlled by other means, including diet and exercise, by bariatric procedures such as surgical bypass or suturing, or by treatment with other pharmacologic agents.

IP Pharmaceutical Compositions and Kits 00146) In another aspect, the present invention provides pharmaceutical compositions comprising the compounds described herein in admixture with a pharmaceutically acceptable carrier.

In particular, this description presents pharmaceutical compositions containing the compounds described herein, mixed with one or more pharmaceutically acceptable carriers. These compositions include those suitable for oral, rectal, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although most

The appropriate form of administration in any particular case depends on the degree and severity of the disease to be treated, as well as the nature of the compound used.

For example, the described compositions may be formulated as standard doses and/or may be formulated for oral or subcutaneous administration.

I00147| Examples of pharmaceutical compositions according to the present invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semi-solid or liquid form, which contains one or more compounds according to the present invention as an active ingredient, in admixture with an organic or inorganic carrier or excipient, suitable for external, enteral or parenteral use. The active ingredient can be mixed, for example, with conventional non-toxic, pharmaceutically acceptable carriers for tablets, granules, capsules, suppositories, solutions, emulsions, suspensions and any other forms suitable for use. The active compound under consideration is included in the pharmaceutical composition in an amount sufficient to obtain a given effect in the process or disease state.

II00148| To obtain solid compositions such as tablets, the specific active ingredient may be mixed with a pharmaceutical carrier, for example, standard tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum. and with other pharmaceutical diluents, for example, water, to obtain a solid preformulated composition containing a homogeneous mixture of a compound according to the present invention or a non-toxic pharmaceutically acceptable salt thereof. These pre-compounded homogeneous compositions mean compositions in which the active ingredient is evenly dispersed throughout the composition, so that this composition can be easily divided into equally effective single dosage forms, such as tablets, pills and capsules.

I00149| In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any which of the following: (1) bulking agents or dry diluents such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agents such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate; (5) dissolution inhibitors such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and their mixtures; and (10) dyes. In the case of capsules, tablets and pills, the compositions may also contain buffering agents. Solid compositions of this type can also be used as fillers for soft and hard gelatin capsules, where such molding agents as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like are used. 00150) The tablet can be obtained by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (eg, gelatin or hydroxypromylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersing agent. Formed tablets can be obtained by forming in a suitable machine a mixture of the composition under consideration, moistened with an inert liquid diluent. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or provided with coatings and shells, such as enteric coatings, and other coatings well known in the art of pharmaceutical formulation. 00151) Compositions for inhalation or insufflation contain solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or their mixtures and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the composition under consideration, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol , benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cotton, peanut, corn, 60 germ oil, olive, castor and sesame oil), glycerin, tetrahydrofurfuryl alcohol,

polyethylene glycols and esters of sorbitol fatty acids, cyclodextrins and their mixtures. 00152) Suspensions, in addition to the composition under consideration, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and their mixtures. 00153) Compositions for rectal or vaginal administration may be presented in the form of a suppository, which may be prepared by mixing the subject composition with one or more non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which remains solid at room temperature but liquid at body temperature and therefore melts in the body cavity, releasing the active agent. (00154) Medicinal forms for transdermal administration of the composition under consideration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters, means for inhalation. The active ingredient may be admixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

I00155| Ointments, pastes, creams and gels may contain, in addition to the composition in question, molding agents such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or their mixtures.

II00156| Powders and sprays may contain, in addition to the composition in question, molding agents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

I00157| Alternatively, the compositions and compounds of the present invention may be administered as an aerosol. This is done by preparing an aqueous aerosol, a liposomal preparation or solid particles containing the specified compound. A non-aqueous (for example, fluorocarbon propellant) suspension may be used. Ultrasonic nebulizers can be used because they minimize the effect of shear on the agent, which can lead to the destruction of the compounds contained in the compositions in question. As a rule, an aqueous aerosol can be obtained by mixing an aqueous solution or suspension of the composition under consideration with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition under consideration, but typically include non-aqueous surfactants (tweens, pluronics or polyethylene glycol), harmless proteins such as serum albumin, sorbitol esters, oleic acid, lecithin, amino acids such as such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are usually obtained from isotonic solutions. 00158) Pharmaceutical compositions according to the present invention, suitable for parenteral administration, contain the subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted in sterile solutions or dispersions for injections immediately before use, which may contain antioxidants, buffers, bacteriostatic substances, dissolved substances that ensure isotonicity of the composition with the blood of the recipient, or suspending or thickening agents.

IІ00159| Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyhydric alcohols (such as glycerin, propylene glycol, polyethylene glycol and the like) and their respective mixtures, vegetable oils such as olive oil , and organic esters suitable for injection, such as ethyl oleate and cyclodextrins. The necessary fluidity can be provided, for example, by using coating materials such as lecithin, which maintain a given particle size in the case of dispersions, and also by using surface-active substances.

І00160| In another aspect, the present invention provides enteral pharmaceutical compositions containing the described compound and enteral material, and a pharmaceutically acceptable carrier or excipient. Enteral materials belong to polymers that are practically insoluble in the acidic environment of the stomach, and which are mainly dissolved in intestinal fluids at certain pH. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine and includes the duodenum, small intestine, and ileum. The pH 60 of the duodenum is approximately 5.5, the pH of the small intestine is approximately 6.5, and the pH of the ileum is approximately 7.5. Accordingly, enteral materials are insoluble, for example, to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Examples of enteral materials include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PMAP), hydroxypropylmethylcellulose acetate succinate (HPMCAF), cellulose acetate trimellitate, hydroxypropylmethylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, maleate cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methyl methacrylate and methyl methacrylate, copolymer of methyl acrylate, methyl methacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Sapige7 E5 series), copolymer of ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate, natural resins such as zein, shellac and coal rosin, as well as some commercially available enteric dispersion systems (for example, Ets4gadia

G30055, Eidgadiya 5300, Epadgadiya 1100, Eiadgadiya 5100, Koiisoai EMMZO0, Eviasgu! 300, Soagegis and

Adpaigiegis). The solubility of each of the materials presented above is known or can be easily determined by ip migo. A list of possible materials is provided above, but those skilled in the art will understand from this description that it is not exhaustive and that there are other enteral materials that satisfy the purposes of the present invention.

IІ00161| Preferably, the present invention also provides kits for use, for example, by a consumer who needs to reduce body weight. Such kits include a suitable dosage form, such as described above, and instructions describing how to use such a dosage form to treat, reduce or prevent inflammation. Instructions intended for the consumer or medical personnel to administer the dosage form according to the administration regimens known to those skilled in the art. Such kits may preferably be packaged and sold as single-use or multiple-use kits. An example of such a set is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging single-dose pharmaceutical forms (tablets, capsules, etc.). Blister packs usually consist of a sheet of relatively rigid material covered with a film, mostly transparent plastic. In the process of packaging, indentations are formed in the plastic film. The recesses are the size and shape of the tablets or capsules that are packed. Then the tablets or capsules are placed in these recesses and a sheet of relatively rigid material is welded to the plastic film from the front side of the film, which is on the opposite side relative to the direction of formation of the recesses. As a result, tablets or capsules are sealed in recesses between the plastic film and the sheet.

Preferably, the stiffness of the sheet is such that the tablets or capsules can be pulled out of the blister pack by hand by pressing on the indentation, resulting in an opening in the sheet at the indentation. Then the tablet or capsule can be pulled out through the specified hole 00162) It may be desirable to provide a reminder in the set, for example, in the form of tablet or capsule numbers, where the numbers correspond to the days of the prescribed regimen of tablets or capsules.

Another example of such a reminder is a calendar printed on a card, for example, with the designation "first week, Monday, Tuesday, ... and so on ... second week, Monday, Tuesday, ... " and so on. Obviously there are other types of reminders.The "daily dose" can be one pill or capsule or several pills or capsules to be taken in one day.

Also, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. This should be reflected in the memo. 00163) This document also discusses methods and compositions that include a second active agent, or the introduction of a second active agent. For example, in addition to being overweight or obese, a subject or patient may additionally suffer from comorbidities associated with being overweight or obese, i.e., diseases or other adverse health conditions associated with, exacerbated by, or manifested by being overweight or adiposity. This document contemplates the described compounds in combination with at least one other agent that has been previously shown to treat these conditions associated with overweight or obesity.

I00164| For example, type II diabetes can be associated with obesity. Some complications of type II diabetes, such as disability and premature death, can be prevented, 60 improved, or eliminated by sustained weight loss (Azigir, A. Rir Neayp Miig

(2001) 4:499-5 15). Agents administered to treat type I diabetes include sulfonylureas (eg, chlorpropamide, glipizide, glyburide, glimepiride); meglitinides (eg, repaglinide and nateglinide); biguanidines (for example, metformin); thiazolidinediones (rosiglitazone, troglitazone and pioglitazone); dipeptidyl peptidase-4 inhibitors (eg, sitagliptin, vildagliptin, and saxagliptin); glucagon-like peptide-1 mimetics (for example, exenatide and liraglutide); and alpha-glucosidase inhibitors (eg, acarbose and miglitol).

I00165| Being overweight or obese is associated with heart disorders and conditions, such as hypertension, dyslipidemia, coronary heart disease, cardiomyopathy, myocardial infarction, stroke, venous thromboembolism, and pulmonary hypertension. For example, hypertension is associated with obesity because excess adipose tissue secretes substances that affect the kidneys, leading to hypertension. In addition, obesity is usually associated with higher amounts of insulin produced (due to excess adipose tissue), and this excess insulin also increases blood pressure. The main way to treat hypertension is weight loss. Agents administered to treat hypertension include chlorthalidone; hydrochlorothiazide; indapamide, metolazone; loop diuretics (for example, bumetanide, ethacrynic acid, furosemide, Lasix, torsemide); potassium-sparing diuretics (for example, amiloride hydrochloride, benzamil, spironolactone, and triamterene); peripheral agents (for example, reserpine); central alpha-agonists (for example, clonidine hydrochloride, guanabenzacetate, guanfacine hydrochloride and methyldopa); alpha-blockers (eg, doxazosin mesylate, prazosin hydrochloride, and terazosin hydrochloride); beta-blockers (eg, acebutolol, atenolol, betaxolol, biisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, nadolol, penbutolol sulfate, pindolol, propanolol hydrochloride, and timolol maleate); combined alpha- and beta-blockers (for example, carvedilol and labetalol hydrochloride); direct vasodilators (for example, hydralazine hydrochloride and minoxidil); calcium antagonists (for example, diltiazem hydrochloride and verapamil hydrochloride); dihydropyridines (eg, amlodipine besylate, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine); ACE inhibitors (benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, quinapril hydrochloride, ramipril, trandolapril); angiotensin II receptor blockers (for example, losartan potassium, valsartan, and irbesartan); renin inhibitors (eg, aliskiren); and their combinations. These compounds are administered in regimens and doses known in the art. 00166) In the publication of the website of a. "(Te doshigpai oi Siiipisa! Epdoshypoiodu 4 Meiaroiiiet (2004) volume 89, Mo 6 2601-2607) discussed the relationship between overweight or obesity and dyslipidemia.

Dyslipidemia is usually treated with statins. Statins, inhibitors of NMoO-CoA reductase, slow down the production of cholesterol in the patient and/or remove excess cholesterol from the arteries. Statins include mevastatin, lovastatin, pravastatin, simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin, crilvastatin, bevastatin, cerivastatin , rosuvastatin, pitavastatin, and glenvastatin. These compounds are administered in regimens and doses known in the art. The association between overweight or obesity and coronary heart disease is reviewed in EskKey! (Sigsociation (1997) 96:3248-3250). Agents , administered to treat coronary heart disease include statins, nitrates (eg, isosorbide dinitrate and isosorbide mononitrate), beta-blockers, and calcium channel antagonists.These compounds are administered in regimens and doses known in the art.

I00167| In the publications of UMopud she is ai. (Maitsge Siipisa! Rgasiise Sagaiiomazsiag Meadisipe (2007) 4:436-443) discussed the relationship between overweight or obesity and cardiomyopathy. Agents administered to treat cardiomyopathy include inotropic agents (eg, digoxin), diuretics (eg, furosemide), ACE inhibitors, calcium antagonists, antiarrhythmic agents (eg, sotolol, amiodarone, and disopyramide), and beta-blockers. These compounds are administered in regimens and doses known in the art. In the publication of the Museum of Art. (Sapseyi (2005) 366(9497):1640-1649) discussed the relationship between overweight or obesity and myocardial infarction. Agents administered to treat myocardial infarction include ACE inhibitors, angiotensin II receptor blockers, direct vasodilators, beta-blockers, antiarrhythmic agents, and thrombolytic agents (eg, alteplase, retaplase, tenecteplase, anistreplase, and urokinase). These compounds are administered in regimens and doses known in the art. 00168) In the publication Byk ei ai. (ZygoKe (2003) 34:1586-1592) discussed the relationship between overweight or obesity and strokes. Agents administered to treat strokes include antiplatelet agents (eg, aspirin, clopidogrel, dipyridamole, and ticlopidine), anticoagulant agents (eg, heparin), and thrombolytic agents. In the publication 5ieip ei a. (That

Ategisap doshgtpai oi Medisipe (2005) 18(9):978-980) considered the connection between overweight or obesity and thromboembolic disease of veins. Agents administered to treat venous thromboembolism include antiplatelet agents, anticoagulant agents, and thrombolytic agents. In the publication Z2iguti ei ai. (Kem Rpeshitoi Siip (2002) 58(2):104-10) discussed the relationship between overweight or obesity and pulmonary hypertension. Agents administered to treat pulmonary hypertension include inotropic agents, anticoagulant agents, diuretics, potassium (eg, K-dig), vasodilators (eg, nifedipine and diltiazem), bosentan, epoprostenol, and sildenafil. Being overweight or obese is associated with respiratory disorders and conditions such as obesity-related hypoventilation syndrome, asthma, and obstructive sleep apnea syndrome. A publication in EIAtip (Spevi (2004) 125:1972-1974) discusses the relationship between overweight or obesity and asthma. Agents administered to treat asthma include bronchodilators, anti-inflammatory agents, leukotriene blockers, and anti-Id agents. Specific asthma agents include zafirlukast, flunisolide, triamcinolone, beclomethasone, terbutaline, fluticasone, formoterol, beclomethasone, salmeterol, theophylline, and xopenex. 00169) In the publication of Kev5ieg eyi aYi. (Eng Kezrig U (1996) 9:787-794) considered the relationship between overweight or obesity and obstructive sleep apnea syndrome. Agents administered to treat sleep apnea include modafinil and amphetamines.

ИЙ00170| Being overweight or obese is associated with liver disorders and conditions such as non-alcoholic fatty liver disease. In the publication Toitap ei aiYi. (Teg Siip Kik Mapad (2007) 6:1153-1163) discussed the relationship between overweight or obesity and non-alcoholic fatty liver disease. Agents administered to treat nonalcoholic fatty liver disease include antioxidants (eg, vitamins E and C), insulin sensitizers (metformin, pioglitazone, rosiglitazone, and betaine), hepatoprotectors, and lipid-lowering agents. 00171) Being overweight or obese is associated with skeletal disorders and conditions such as back pain and osteoarthritis of weight-bearing joints. In the publication of Saase's maps (v

Apeytaiyo! (1988) 15(7):1152-1158) discussed the relationship between overweight or obesity and osteoarthritis of weight-bearing joints. Agents administered to treat osteoarthritis of weight-bearing joints include acetaminophen, nonsteroidal anti-inflammatory agents (eg, ibuprofen, etodolac, oxaprozin, naproxen, diclofenac, and nabumetone), COX-2 inhibitors (eg, celecoxib), steroids, supplements (for example, glucosamine and chondroitin sulfate) and synthetic synovial fluid. 00172) Metabolic disorders and conditions associated with being overweight or obese, such as Prader-Willi syndrome and polycystic ovary syndrome. In the publication of Sazvzidu (doshigpai oi Meadisai

Sepoys (1997) 34:917-923) discussed the relationship between overweight or obesity and Prader-Willi syndrome. Agents given to treat Prader-Willi syndrome include human growth hormone (GH), somatropin, and weight-reducing agents (eg, orlistat, sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetamine, and topamax).

I00173| In Noedeg's publication (ObBzieyeigiskh apa Supesoiodu Siipisb5 oi Mohiy Ategisa (2001) 28(1):85-97) the relationship between overweight or obesity and polycystic ovary syndrome is considered. Agents administered to treat polycystic ovary syndrome include insulin sensitizers, combinations of synthetic estrogen and progesterone, spironolactone, eflornithine, and clomiphene. Being overweight or obese is associated with reproductive disorders and conditions such as sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal pathology. In the publication I agzep ei ai. (Ipi U Obez (I opa) (2007) 8:1189-1198) considered the relationship between overweight or obesity and sexual dysfunction. In the publication of Spipud ei a). (Eenig OgoY (1999) 36(1):68-70) considered the connection between overweight or obesity and erectile dysfunction. Agents administered to treat erectile dysfunction include phosphodiesterase inhibitors (eg, tadalafil, sildenafil citrate, and vardenafil), prostaglandin E analogs (eg, alprostadil), alkaloids (eg, yohimbine), and testosterone. In the publication Razdaaiyi ei ai. (Nit

Vergoa (1997) 1:82-87) discussed the relationship between overweight or obesity and infertility.

Agents administered to treat infertility include clomiphene, clomiphene citrate, bromocriptine, gonadotropin-releasing hormone (HRH), sPECN agonist, sPENn antagonist, tamoxifen/nolvadex, gonadotropins, human chorionic gonadotropin (hCs), menopausal human gonadotropin (Hts), progesterone, recombinant follicle-stimulating hormone (E5H), urofolitropin, heparin, follitropin alfa and follitropin beta.

I00174| In the publication of Mu/eiye5 ei aI. (Ategisap ChdChoigpa! oi Oreieigis5 apa Supesoiodu (2004) 190(4):1091-1097) described the relationship between overweight or obesity and obstetric 60 complications. Agents administered to treat obstetric complications include bupivacaine hydrochloride, dinoprostone ROE2, meperidine NSI, ferro-folic-500/bereth-folic-500, meperidine, methylergonovine maleate, ropivacaine NS, nalbuphine NSI, oxymorphone NS, oxytocin, dinoprostone, ritodrine , scopolamine hydrobromide, sufentanil citrate and uterotonics. 00175) Overweight or obesity is associated with psychiatric disorders and conditions, such as obesity-related depression and anxiety. In the publication Richhop ei ai. (Agsp Ipiegp May (2003) 163:2058-2065) considered the relationship between overweight or obesity and depression. Agents administered to treat depression include serotonin reuptake inhibitors (eg, fluoxetine, escitalopram, parotexine, sertraline, and venlafaxine); tricyclic antidepressants (eg, amitriptyline, amoxapine, clomipramine, desipramine, dozulepine hydrochloride, doxepin, imipramine, iprindole, lofepramine, nortriptyline, opipramol, protriptyline, and trimipramine); monoamine oxidase inhibitors (eg, isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iprocloside, toloxatone, linezolid, dienolide, cavapyrone, desmethoxyyangonin, and dextroamphetamine); psychostimulants (eg, amphetamine, methamphetamine, methylphenidate, and arecoline); antipsychotics (eg, butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, symbiax, tetrabenazine, and cannabidiol); and mood stabilizers (eg, lithium carbonate, valproic acid, divalproex sodium, sodium valproate, lamotrigine, carbamazepine, gabapentin, oxcarbazepine, and topiramate).

I00176| In the publication of bitop ei ai. (Agospime5oi (zepegaI! Reuspiaiu (2006) 63(7):824-830) reviewed the relationship between overweight or obesity and anxiety. Agents administered to treat anxiety include serotonin reuptake inhibitors, mood stabilizers, benzodiazepines ( such as alprazolam, clonazepam, diazepam, and lorazepam), tricyclic antidepressants, monoamine oxidase inhibitors, and beta blockers.

I00177| In another aspect, the present invention provides methods of facilitating and maintaining weight loss in a patient, comprising administering to a specified subject an amount of the described compound effective to achieve weight loss in the subject; and administering a therapeutically effective amount of the second weight loss agent to maintain the weight loss in the subject. Weight-loss agents include serotonin-noradrenergic reuptake inhibitors; noradrenergic reuptake inhibitors; selective serotonin reuptake inhibitors; and intestinal lipase inhibitors. Specific agents for weight loss include orlistat, sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetamine, bromocriptine, lorcaserin, topiramate, or agents that act as food intake modulators by blocking the action of ghrelin, inhibiting the activity of diacylglycerol acyltransferase 1 (OSATI), inhibition of the activity of stearoyl-sodium desaturase 1 (ZSOT), inhibition of the action of receptor 1 of neuropeptide B, activation of the function of receptor 2 or 4 of neuropeptide B, or inhibition of the activity of sodium-glucose cotransporters 1 or 2. These compounds are administered in regimens and doses , known in this field.

EXAMPLES

00178) The compounds described in this document can be prepared in many ways, based on the instructions contained in this document and synthetic methods known in the art. With respect to the synthetic methods described below, it should be understood that all suggested reaction conditions, including choice of solvent, reaction atmosphere, reaction time, duration of experiment, and isolation method, may be chosen to represent conditions standard for a given reaction, unless otherwise specified. Specialists in the field of organic synthesis understand that the functionalities present in various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions are understood by those skilled in the art, and therefore alternative methods are indicated. The starting materials for the examples are commercially available or can be easily prepared by standard methods from known materials.

I00179| At least some of the compounds defined herein as "Intermediate Compounds" are contemplated as compounds of the present invention. 00180) H NMR spectra were recorded at room temperature on a Magiap spectrometer

Opyu Ipoma (400 MHz) with a 5 mm triple resonance sensor for Example compounds, or on a VgyKeg Amapse OPX spectrometer (400 MHz) or on a VgyKeg Amapse OPX spectrometer (300 MHz) for Intermediate compounds. Chemical shifts are expressed in ppm. relative to tetramethylsilane. The following abbreviations are used: Bbg - broad signal, 5 - singlet, a - doublet, da - double doublet, ada - double double doublet, 4th - double triplet, Her - triplet, her - triple doublet, d - quartet, t - multiplet. 00181) Experimental mass spectrometry (LCMS) to determine the retention time and 60 correlated ion masses was performed using the following methods:

00182) Method A: the experiments were performed on a quadrupole mass spectrometer UMaiege "MO I S" connected to the Umayeg5 1525 I S system with a diode-matrix detector. The spectrometer is equipped with an electrospray source operating in the mode of negative and positive ions. Additional detection was performed with the help of an evaporative scattering detector zedeh 85. Liquid chromatography was performed on a 30 x 4.6 mm C18 column of 1 and 3 microns at a speed of 2 ml/min. The initial solvent system was 95 95 water containing 0.1 95 formic acid (solvent A) and 5 90 acetonitrile containing 0.1 96 formic acid (solvent B) for the first 0.5 minutes, followed by a gradient to 5 90 of solvent A and 95 95 of solvent B over the next 4 minutes. The final solvent system was kept constant for another 1 minute.

IІ00183| Method B: experiments were performed on a quadrupole mass spectrometer on a Z UmMaieg5M platform connected to a Neuley RasKaga 1050 IC system with a diode-matrix detector. The spectrometer is equipped with an electrospray source operating in the mode of negative and positive ions. Additional detection was performed with the help of an evaporative light scattering detector 5edeh 85. Liquid chromatography was performed on a 30 x 4.6 mm C18 column of 1 and 3 microns at a speed of 2 ml/min. The starting solvent system was 95595 water containing 0.195 formic acid (solvent A) and 595 acetonitrile containing 0.1 95 formic acid (solvent B) for the first 0.3 min, followed by a gradient to 5 95 solvent A and 95 95 of solvent B over the next 4 minutes. The final solvent system was kept constant for another 1 minute.

I00184| Method C: the experiments were performed on a UMaiege quadrupole mass spectrometer

Misgotavz5 2002000, connected to the UmMaieg5 Asdiyu ORIS system with a Uf-detector RBOA.

The spectrometer is equipped with an electrospray source operating in the mode of negative and positive ions. Liquid chromatography was performed on an Asdiyu VEN 1.7 micron C18 column, an Asdiyu VEN ZpPieia 1.7 micron KR18 column or an Asdiyu NZ5T 1.8 micron column. Each column had dimensions of 100 x 2.1 mm and was operated at 40 "С at a flow rate of 0.4 ml/min. The initial solvent system was 95 95 water containing 0.1 95 formic acid (solvent

A), and 5965 acetonitrile containing 0.1 95 formic acid (solvent B) for the first 0.4 minutes, followed by a gradient to 5 95 solvent A and 95 95 solvent B over the next 6 minutes.

The final solvent system was kept constant for another 0.8 minutes.

І00185| Method O: the experiments were performed on a Zpitadly ZhhMS-2020 spectrometer with an electrospray source operating in the mode of positive ions. Liquid chromatography was performed on a Zpitaidla Zpit-rask XA-00O5 2.2 micron 50 x 3.0 mm column.

The initial solvent system was 9595 water containing 0.05 956 trifluoroacetic acid (solvent A) and 5 90 acetonitrile (solvent B) for the first 0.01 minutes, followed by a gradient to 100 95 solvent B over the next 1.3 minutes . The final solvent system was kept constant for another 1 minute.

I00186| Method E: the experiments were performed on a quadrupole mass spectrometer UMaiege "MO S" connected to the NemulLei RasKaga NO 1100 system with a diode-matrix detector.

The spectrometer is equipped with an electrospray source operating in the mode of positive and negative ions. Liquid chromatography was performed on a 30 x 4.6 mm C18 30 x 4.6 mm C18 column at a flow rate of 2 ml/min. The initial solvent system was 95 95 water containing 0.1 95 formic acid (solvent A) and 5 95 acetonitrile containing 0.1 96 formic acid (solvent B) for the first 0.5 min, followed by a gradient to 5 90 of solvent A and 95 95 of solvent B over the next 4 minutes. The final solvent system was kept constant for another 1 minute.

I00187| Method P: experiments were performed on a quadrupole mass spectrometer on a Z UmMaieg5M platform connected to a Neuley RasKaga 1050 IS system with a diode-matrix detector. The spectrometer is equipped with an electrospray source operating in the mode of positive and negative ions. Additional detection was performed with the help of an evaporative light scattering detector 5edeh 85. Liquid chromatography was performed on a 30 x 4.6 mm C18 column of 1 and 3 microns at a speed of 2 ml/min. The starting solvent system was 95595 water containing 0.195 formic acid (solvent A) and 595 acetonitrile containing 0.1 95 formic acid (solvent B) for the first 0.3 min, followed by a gradient to 5 95 solvent A and 95 95 of solvent B over the next 4 minutes. The final solvent system was kept constant for another 1 minute. Microwave experiments were carried out using a Wioiade Ipiakg"M, which uses a single-mode resonator and dynamic tuning. Temperatures from 40 to 250 "C can be reached, and pressures up to 20 bar can be reached. There is a device for applying 60 air cooling during irradiation.

I00188| Preparative HPLC purification was performed using a Sepebviv C18 reverse-phase column (C18) or a Rpepotepeh Sb-phenyl column (Sb-phenyl) (100 x internal diameter 22.5 mm, with a particle size of 7 microns, UV detection at 230 or 254 nm, flow 5-15 ml/min.), eluting with gradients from 100-0 to 0-100 95 water/acetonitrile or water/methanol containing 0.196 formic acid. Fractions containing the target product (determined by

HPLC) were combined, the organic fraction was removed by evaporation, the remaining aqueous fraction was lyophilized to obtain the product. 00189) Compounds that required column chromatography were purified manually or fully automatically using a Vioiade 5RITM flash purification system from Toisi I odis

Sopigoi TM or prepackaged silica gel cartridge IsoYsheffFf 5RE of the SotrShavy system

SotrapiopF), cartridge Vioiade 5MAR or cartridge Kedizerob KI, respectively. 00190) Compounds were named using Astopot2000 in the IZIBOGgam program. 00191) Abbreviations:

DCM Dichloromethane

ЮМ5 industrial methylated alcohol

DMF M, M-Dimethylformamide

LOBSTER 4-Dimethylaminopyridine

THF Tetrahydrofuran

DMSO Dimethylsulfoxide

MMP M-methylpyrrolidinone

ДЭ 1,2-Dichloroethane

NATY 7-Azabenzotriazol-1-yl-M, M,M",M'-tetramethyluronium hexafluorophosphate

ERAS M-(3-Dimethylaminopropyl)-M'-ethylcarbodiamide hydrochloride

ЮМ5 industrial methylated alcohol

MMM M-methylmorpholine

ОВы 1,8-Diazabicyclo|5.4.O)undec-7-ene

Example 1: Cis-(Zano, 90A5)-7-(benzenesulfonylamino)-1,Za, 4,9p-tetrahydro-2H-furo|2,3-sichromene-6-carboxylic acid

N

9) x I, on

M Ge) od, ototan

A mixture of cis-enantiomers

II00192| Lithium hydroxide (0.048 g) was added to a solution of methyl cis-(Zane, 9BA5)-7-(benzenesulfonylamino)-1,Za,4,9Bb-tetrahydro-2H-furo|2,3-sichromene-b6-carboxylate (Intermediate compound 1, 0.08 g) in a mixture of dioxane (10 ml) and water (5 ml), and the resulting mixture was irradiated in a microwave reactor at 110 "C with air cooling for 20 minutes. An additional amount of lithium hydroxide (0.2 d), and the mixture was irradiated in a microwave reactor at 110 "C with air cooling for a total of 80 minutes. After cooling, the solution was acidified by adding an aqueous solution of formic acid (1095), and the resulting mixture was extracted with ethyl acetate, dried (Md5084) and filtered. The filtrate was evaporated to a dry residue. The residue was dissolved in a mixture of methanol (10 ml) and water (5 ml) and treated with lithium hydroxide (0.2 g), then irradiated in a microwave reactor at 110 C with air cooling for 40 minutes. After cooling, the solution was acidified by adding formic acid (10 95), and the resulting mixture was extracted with ethyl acetate, dried (M959054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by preparative

HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 30-50 95, to obtain cis-(Zane, 9ЬА5)-7-(benzenesulfonylamino)-1,За, 4.9р - tetrahydro-2H-furo|2,3-c|Ichromene-b6-carboxylic acid (0.019 g) in the form of a white solid.

I00193| "H NMR (SOzOB) 6: 7.71 (2H, 4), 7.54 (1H, 9, 7.44 (2H, U, 7.24 (IN, y), 7.12 (1H, 9) , 4.24 (IN, t), 4.09 (1H, aa), 3.92 (1H, ad), 3.8-3.65 (2H, t), 3.47 (1H, t), 2.45 (1H, t), 1.83 (1H, t).

I(00194| LCMS (Method C), retention time 3.79 (M-H) 374.

Example 2: Cis-(Zanoz5,9b5A5)-7-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1,Za,49p-tetrahydro-2H-furo|2,3-c|Ychromene-b6 -carbonic acid

With !

In o su" i

M 9

N

E (9 ON

Mixture of cis-enantiomers (00195) Solution of 17-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-4H-furo(2,3-sichromene-6-carboxylic acid) (Intermediate compound 8, 0.1 g) in a mixture of ХМ5 (2 ml) and glacial acetic acid (3 ml) was treated in a nitrogen atmosphere with palladium hydroxide on carbon (10 Fo, 0.02 g). The nitrogen was replaced with hydrogen and the mixture was stirred in a hydrogen atmosphere for 100 minutes . The mixture was filtered through, and the filtrate was evaporated to a dry residue. The residue was dissolved in toluene and the solution was re-evaporated. The residue was triturated with ether, and the solid was collected by filtration and purified by preparative HPLC (Cb-phenyl eluting with a mixture of acetonitrile and water containing 0.1 96 of formic acid, with a gradient of 20-40 95, to obtain cis-(Zano, 9ЬА5)-7-(2-(3-diethylaminopropyl-4-fluorobenzenesulfonylamino!|-1,За, 4,9р-tetrahydro-2H-furo |2,3-c|Ichromene-b-carboxylic acid (0.1 g) in the form of a white solid.

I00196| "H NMR (SOzOB) 6: 7.94 (1H, aa), 7.18 (1H, a), 7.17 (1H, t), 7.06 (1H, 4), 6.99 (1H, ayu, 4.21 (1H, t), 3.98 (1H, aa), 3.88 (1H, aa), 3.72 (2H, t), 3.42 (IN, t), 3.23 (6H, t), 3.10 (2H, t), 2.42 (1H, t), 1.98 (2H, t), 1.81 (1H, t), 1.91 (6H, i) .

I00197| LCMS (Method C), retention time 3.10 (M.N) 507.

Example 3: Cis-(Zane, 96A5)-7-(2-(3-«-pyrrolidin-1-ylylpropyl)-4-fluorobenzenesulfonylamino|- 1,Za, 4,9p-tetrahydro-2H-furo|2,3 -sichromene-6-carboxylic acid t H .

And oh

B

M Ge)

N

E at tone

A mixture of cis-enantiomers

I00198| Lithium hydroxide (0.028 g) was added to a solution of methyl cis-(Zanv, 9085)-7-(2-(3- ipyrrolidin-1-yl propyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H -furoic|2,3-sichromene-6-carboxylate (Intermediate compound 14, 0.06 g) in dioxane (2 ml) and water (1 ml) and stirred, and the mixture was heated at 80 "C for 8 hours. After cooling the mixture was acidified by adding an aqueous solution of formic acid (1095) and extracted with DCM.

The organic layer was dried (Mo95054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ammonia in methanol (2 M) and

DCM with a gradient of 1-10 95. The separated solid was triturated with a mixture of ether and cyclohexane (5095), and the solid was collected by filtration. The solid was purified preparatively

HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 10-95 95. The isolated product was triturated with ether, and the solid was collected by filtration to give cis-(zanz, 9rAB)-7- (2-(3-«(pyrrolidine-1-ylpropyl)-4-fluorobenzenesulfonylamino!|-1,3a,4,9p-tetrahydro-2H-furoic|2,3-sichromene-b6-carboxylic acid) (0.006 g) in in the form of a white solid.

I00199| "H NMR (SOzOB) b: 7.93 (1H, av), 7.21 (1H, a), 7.14 (1H, as), 7.08 (1H, a), 6.99 (1H, ayu, 4.21 (1H, t), 3.98 (1H, aa), 3.88 (1H, aa), 3.72 (2H, t), 3.43 (2H, t), 3.30 (4H, t), 3.13 (ЗН, t), 2.42 (1Н, t), 2.07 (4Н, t), 2.0 (2Н, t), 1.81 (1Н, t) .

I00200| LCMS (Method C), retention time 3.11 (M.--H) 505.

Example 4: Cis-(Zanz, 9rAB)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H-furo|2 ,3-sichromene-6-carboxylic acid

So what?

M (9

N

E (9) on

A mixture of cis-enantiomers

I00201| Obtained in the same way as Example 3, starting from methyl cis-(Zanz, 9ЬА5)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-1,3a, 4,9p -tetrahydro- 2H-furo|2,3-sichromene-b-carboxylate (Intermediate 17), and heating at 80 "C overnight. (00202| "H NMR (DMSO-α) 6: 7.65 (1H, aa), 7.30 (1H, 4), 7.19 (2H, t), 7.02 (1H, a), 6.92 (1H, 9), 6.10 (1H, t), 4, 09 (1H, t), 3.82-3.64 (4H, t), 3.63-3.30 (ZH, t), 3.03 (4H, a), 2.35 (1H, t) , 1.68 (IN, t), 1.07 (6H, . 00203) LCMS (Method C), retention time 3.05 (M'-H) 505.

Examples 5 and 6: Separation of enantiomers from Example 4.

I00204| The sample from Example 4 was subjected to chiral separation using a column

SpigaIiRak IC, 4.6 mm x 250 mm, 5 micron particle size. DHE sample solvent: absolute ethanol, 1:1, sample concentration 1 mg/100 μl, sample volume 120 μl. Elution solvent: absolute ethanol, flow rate 0.55 ml/min, temperature 21 °C.

Example 5: First eluted enantiomer: retention time on the above column: 34.96 minutes, d.i. 93 95.

I00205| "H NMR (DMSO-α) 6: 7.64 (1H, aa), 7.29 (1H, 4), 7.18 (2H, t), 7.01 (1H, a), 6.92 ( 1H, a), 6.08 (1H, t), 4.09 (1H, t), 3.75 (2H, t), 3.59 (2H, t), 3.933 (ЗН, t), 3, 03 (4H, Bi), 2.34 (1H, t), 1.68 (1H, t), 1.06 (6H, 9. (00206| LCMS (Method C), retention time 3.07 (M. --H) 505.

Example 6: Second eluted enantiomer: retention time on the above column 40.97 minutes, d.i. 65 90.

I00207| "H NMR (DMSO-α) 6: 7.64 (1H, av), 7.29 (1H, a), 7.18 (2H, t), 7.01 (IN, a), 6.92 ( IN, a), 6.08 (1H, t), 4.09 (1H, t), 3.75 (2H, t), 3.59 (2H, t), 3.33 (ЗН, t), 3.03 (4H, Bi), 2.34 (1H, t), 1.68 (1H, t), 1.06 (6H, 9. (00208) LCMS (Method C), retention time 3.06 ( M.N.) 505.

Example 7. 7-(2-(2)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,2- dihydrofuroic|2,3-c|quinoline-b-carboxylic acid formate salt in o

Am in; friends

M/ 5 -

M M

N

E (6) on

I00209| Obtained in the same way as Example 1, starting from methyl 7-|(M-(2-((2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino!|-1 ,2-dihydrofuro|2,3-c|quinoline-6-carboxylate (Intermediate compound 20), in the form of a yellow solid. (00210| "H NMR (COzOB) 6: 8.50 (1H, 5), 8, 47 (2H, 5), 7.96 (1H, t), 7.91 (IN, a), 7.79 (1H, da), 7.А45(1H, a), 7.11 (2H, t ), 6.13 (1H, t), 3.79 (2H, a), 3.59 (2H, U, 3.10 (6H, t), 1.16 (6H, t).

I00211| LCMS (Method C), retention time 2.84 (M.N) 500.

Example 8: 7-(Benzenesulfonylamino)-1,2-dihydrofuro|2,3-c|quinoline-b-carboxylic acid formate salt c 0)

VU

5 -

M M

That's the tone

I00212| Obtained in the same way as Example 1, starting from methyl 7-(benzenesulfonylamino)-1,2-dihydrofuro|2,3-c)quinoline-6-carboxylate (Intermediate compound 26).

(00213) "H NMR (DMSO-α) 6: 8.54 (1H, 5), 8.25 (1H, 5), 7.78 (ZH, t), 7.66 (1H, a), 7 .44 (ZH, t), 4.69 (2H, U), 3.46 (2H, 1). (00214) LCMS (Method C), retention time 3.66 (M'«H) 371.

Example 9: Cis-(Zanz, 9rAB)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,2,Za, 4,5,9p-hexahydrofuro|2 ,3-c|quinoline-6-carboxylic acid and NAU that Ge; that

B

M M

N N

E at on

Mixture of cis-enantiomers 00215) Lithium hydroxide (0.09 g) was added to a solution of methyl cis-(Zanv, 9085)-5-acetyl-7-(2- ((2)-3-diethylaminoprop-1-enyl)-4 -fluorobenzenesulfonylamino!|-1,2,3a,4,5,9B5-hexahydrofuro2,3-siquinoline-6-carboxylate (Intermediate compound 27, 0.06 g) in a mixture of dioxane (5 ml) and water (1 ml) and was stirred, and the mixture was heated at 80 "C overnight. Then the mixture was irradiated in a microwave reactor at 150 "C for 30 minutes, and then at 180 C for 30 minutes. After cooling, the mixture was filtered, and the filtrate was acidified by adding formic acid (1 ml) , and then evaporated to a dry residue. The residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 10-98 9o. The isolated product was dissolved in DCM and evaporated to a dry residue, then dissolved in ether and evaporated to a dry residue to obtain cis-(Zanz, 9АБ5)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1 2, Za, 4.5 ,9p- hexahydrofur of 2,3-quinoline-b-carboxylic acid (0.005 g) as a white solid. (00216) "H NMR (SOSI") 6: 8.54 (1H, Bg 5), 7.99 (1H, Bg 5), 7.48 (1H, 4), 7.04 (1H, t), 6.90 (1H, a), 6.76 (IN, a), 6.62 (IN, t), 6.11 (IN, t), 4.17 (1H, t), 3.82 (IN , t), 3.78-3.59 (2Н, t), 3.32-3.10 (4Н, t), 3.04-2.86 (ЗН, t), 2.35 (IN, t ), 1.79 (1H, t), 1.15 (6H, U. (00217| LCMS (Method C), retention time 3.31 (M.H) 504

Example 10: pPax, 76B5K)-5-(2-(2)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

M

And r. Eat what

ZU

M (c)

N

E c) on (00218) Methyl Pakz, 76B5K)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,71p-tetrahydrocyclopropa|sichromene-4 -carboxylate (Intermediate 40, 0.185 g) and lithium hydroxide monohydrate (0.159 g) were suspended in dioxane (4 mL) and water (1 mL). The reaction mixture was irradiated in a microwave reactor at 13570 for 30 minutes. After cooling, the mixture was acidified to pH 4 with formic acid, then ethanol and toluene were added, and the mixture was concentrated to np masso. The residue was triturated with a mixture of methanol and DCM (10 95), and the solid was filtered and washed with a mixture of methanol and DCM. The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-8 9o. The obtained product was triturated with ethyl acetate and dried in air at 50°C to obtain (tak5, 7rB51)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-1,1a, 2, 7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid (0.066 g) in the form of a white solid. (00219| "H NMR (DMSO-α) 0: 7.64 (1H, ad), 7.35 (1H, a), 7.27-7.19 (2H, t), 7.10 (1H, a), 6.93 (IN, a), 6.20-6.10 (IN, t), 4.17 (1H, a), 3.76 (2H, Bi, 5), 3.57 (IN, a), 3.10 (4H, B, a), 1.92 (1H, id), 1.75- 1.69 (1H, t), 1.13 (6H, ), 0.94 (1H, 19), 0.74 (1H, t). (00220) LCMS (Method C), retention time 3.32 ( M.N.) 475

Examples 11 and 12: Separation of enantiomers from Example 10.

I00221| The sample from Example 10 was subjected to chiral separation using a column

SpigaIiRak IC, 10 mm x 250 mm, particle size 5 microns. Solvent for elution: methyl tert-butyl ether: isopropanol: DCM (16:20:64).

Example 11: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 21.8 minutes, e.i. 29995: (Tab, 70H)-5-(2-(2)-3-Diethylaminoprop-1-enyl)-4-

fluorobenzenesulfonylamino!|-1 Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid and H

M n

ZM

M (in)

N

E c) on (002221 H NMR (SOSI") 6: 7.63 (1H, 4), 7.43 (1H, t), 7.15-7.08 (2H, t), 6.85 (1H , au, 6.72 (1H, da), 5.93 (1H, t), 4.27 (1H, a), 3.98 (1H, Bri t), 3.68 (1H, t), 3 .58 (1H, bi), 3.27-3.06 (4H, t), 1.87 (IN, t), 1.63 (1H, t), 1.23 (6H, U, 1.04 (TN, t), 0.91 (1Н, t).

LCMS (Method C), retention time 3.30 (MAN) 475

Example 12: Second eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 27.5 minutes, e.i. »99 95: (tan, 7p)-5-(2-(2)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid and h

M: - re E that n

ZM

M (c)

N

E c) on (00223| "H NMR (SOSI") 6: 7.63 (1H, a), 7.43 (1H, t), 7.15-7.08 (2H, t), 6.85 (1H, a, 6.72 (1H, da), 5.93 (1H, t), 4.27 (1H, a), 3.98 (1H, Bri t), 3.68 (1H, t) , 3.58 (1H, Bi), 3.27-3.06 (4H, t), 1.87 (IN, t), 1.63 (1H, t), 1.23 (6H, U, 1 .04 (TN, t), 0.91 (1Н, t).

LCMS (Method C), retention time 3.32 (M.--N) 475.

The absolute configuration of Examples 11 and 12 was determined by X-ray diffraction analysis

Example 12 from MegaARa2.

Example 13: pPax, 76B5K)-5-(2-(2)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-7b-methyl-1,Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carbon acid

M

And r; m

ZU

M 6)

N

E o7 on

I00224| Obtained in the same way as Example 3, starting from methyl (Takz, 7p5K)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-7p-methyl-1,1a, 2 ,76-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 48).

ИН NMR (SOSI») 6: 9.8-9.2 (1Н, Bug 5), 7.65 (1Н, а), 7.39 (1Н, т), 7.24 (IN, 9) , 7.18 (IN, a), 6.83 (IN, au, 6.72 (1H, aa), 5.91 (1H, t), 4.21 (1H, 4), 3.98 (IN , g U, 3.71 (1H, a), 3.61 (1H, Bu 5), 3.28-3.06 (4H, t), 1.41 (ZH, 5), 1.37 (1H , t), 1.24 (6H, U), 1.14 (IN, U, 0.74 (1H, da).

LCMS (Method C), retention time 3.55 (M.--N) 489.

Example 14: pPax, 76B5K)-5-(2-(E)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-7b-methyl-1,Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carbon acid with

AND

M 6)

N

E (6) on

I00225| It was isolated as a minor by-product by preparative HPLC during preparation

Example 13.

1H NMR (SOSI) 6: 11.9 (1H, Bg 5), 7.93 (1H, av), 7.70 (IN, a), 7.25 (1H, a), 7.10 (1H, a), 7.06

(IN, aa), 6.90 (1H, a), 6.19 (IN, t), 4.23 (1H, y), 3.76 (1H, a), 3.68 (2H, t) , 3.29 (AN, а), 1.36 (6Н,

Y), 1.35 (ZH, 5), 1.91 (IN, t), 1.10 (1 H, Y, 1.67 (1H, da).

LCMS (Method C), retention time 3.66 (M--H) 489.

Example 15: Cis-(Zane, 9BA85)-7-(2-(4-dimethylaminobutylamino)benzenesulfonylamino |- 1,Za, 4,9p-tetrahydro-2H-furo|2,3-sichromene-6-carboxylic acid

In ,

But what about her?

N alotan

A mixture of enantiomers (00226) 4-Dimethylaminobutylamine (0.348 g) and triethylamine (0.2 ml) was added to a suspension of cis- (Zzan5, 95A85)-7-(2-fluorobenzenesulfonylamino)-1,3a, 4,9Bb-tetrahydro-2H -furoic|2,3-c|ichromene-b-carboxylic acid (Intermediate compound 57, 0.15 g) in acetonitrile (1.5 ml) and heated the mixture at 130 "C in a closed test tube for 36 hours. Then the mixture was diluted water (2 ml) and purified the solution by preparative HPLC (Cb-phenyl), eluting with a mixture of methanol and water containing 0.1 Fo of formic acid, with a gradient of 5-98 95. The isolated product was further purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-15 95 to obtain cis-(Zanv, 9585)-7-(2-(4-dimethylaminobutylamino)-benzenesulfonylamino!|-1,Za, 4 9p-tetrahydro-2H-furo|2,3-s |Yichromene-b-carboxylic acid (0.062 g) in the form of a vitreous foam.

IN NMR (SOSI") 6: 11.21 (1H, Bg 5), 7.72 (IN, av), 7.37 (1H, a), 7.26 (IN, t), 7.02 (1H , a), 6.59 (IN, 9), 6.56 (1H, U, 5.85 (IN, U), 4.29 (IN, a), 4.05 (IN, aa), 3, 85 (1H, t), 3.77 (2H, t), 3.34 (1H, 9), 3.21 (2H, t), 2.98 (2H, U, 2.80 (6H, 5) , 2.41 (1H, t), 2.05 (1H, t), 1.83 (1H, t), 1.71 (2H, t).

LCMS (Method C), retention time 3.18 (M--H) 490

Example 16: (Yes, 765)-5-(2-(3-Diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid

With me

M, r. Y i zu

M (c)

N

And c) he

I00227| Obtained in the same way as Example 2, starting from (So, 7B65)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-1 and, 2,7-ter-tetrahydrocyclopropa|sichromene -4-carboxylic acid (Example 12).

NMR (SOCI3) 6: 7.81 (1H, ad), 7.31 (1H, a), 7.07 (1H, a), 6.82 (2H, t), 4.32 (1H, a ), 3.74 (1H, 9), 3.42-3.32 (1H, t), 3.18 (4H, t), 3.14-2.94 (ЗН, t), 2.00 ( 2H, t), 1.84 (IN, t), 1.62 (1H, t), 1.91 (6H, U, 1.04 (1H, t), 0.88 (1H, t).

LCMS (Method C), retention time 3.36 (M--H) 477.

Example 17: pPax, 76B5K)-5-(2-(2)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1-difluoro-1, Ta, 2,7p-tetrahydrocyclopropa|c| chromene-4-carboxylic acid

IS

With E

M

ZU

M o

N

E (c) on (00228) Obtained in the same way as Example 10, starting from methyl (Yes, 765H)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|- 1,1-difluoro-1a, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 59), in the form of a white solid.

IN NMR (SOSI") 6: 10.0-9.6 (1H, Bug 5), 7.64 (1H, a), 7.47 (1H, aa), 7.21 (IN, a), 7 .13 (1H, a), 6.687 (IN, au, 6.73 (1H, aa), 5.95 (1H, t), 4.28 (IN, a), 3.96 (1H, t), 3.92-3.79 (1H, Bug 5), 3.78-3.67 (1H, Bri 5), 3.17 (4H, a), 2.64 (1H, U, 2.23 (1H , t), 1.24 (6H, U.

LCMS (Method C), retention time 3.38 (M.N) 511.

Examples 18 and 19: Separation of enantiomers from Example 17.

I00229| The sample from Example 17 was subjected to chiral separation using a column

SpigaIRak A, 20 mm x 250 mm, particle size 5 microns. Elution solvent: methanol: ethanol: heptane (12.5:12.5:75).

Example 18: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 14.7 minutes, e.i. 295 95.

I00230| "H NMR (DMSO-α) 0: 7.83 (1Н, 9, 7.27-7.17 (ЗН, т), 7.09 (ТН, а), 6.85 (1Н, а), 5 .98 (IN, t), 4.27 (IN, a), 3.76 (IN, t), 3.56 (IN, U, 2.90 (1H, U, 2.85 (1H, U) , 2.77 (AN, Bree 5), 2.55 (1H, 5), 0.97 (6H, running U.

LCMS (Method C), retention time 3.39 (MAN) 511

Example 19: Second eluted enantiomer: retention time on the analytical column 19.0 minutes, e.i. 295 95. (002311 "H NMR (DMSO-av) 56: 7.72 (1H, av), 7.36 (IN, 4), 7.26 (1H, ayu, 7.21 (1H, ad), 7.18 (IN, 9), 6.99 (1H, 4), 6.13 (1H, t), 4.29 (1H, 49), 3.687-3.70 (ЗН, t), 3.10 (4H, t), 2.96 (1H, U, 2.56 (1H, t), 1.11 (6H, U).

LCMS (Method C), retention time 3.39 (MAN) 511.

Example 20: (1akz, 7B5K)-5-(2-(2)-3-Ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|- 11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid

N

M and r m

ZM

M o

N

E (c) on

A mixture of methyl OPax, 7B5K)-5-(2-(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 63, 0.09 g) and lithium hydroxide monohydrate (0.047 g) in a mixture of dioxane (10 ml) and water (5 ml) were stirred and heated at 120 "C for 32 hours. After cooling, the mixture was concentrated under vacuum, and the residue was acidified to pH 4 The resulting solid was collected by filtration and washed with water to give (Takz, 70B5K)-5-(2-(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7- tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.029 g) as a gray solid.

1H NMR (DMSO-α) 6: 10.4-9.95 (1H, Be 5), 7.51 (1H, aa), 7.21 (IN, a), 7.17 (1H, a ), 711 (H, aa), 7.07 (1H, a), 6.99 (IN, a), 5.93 (IN, t), 4.11 (1H, 49), 3.60 (2H , t), 3.51 (1H, a), 2.92 (2H, ad), 1.687 (1H, t), 1.67 (1H, t), 1.12 (ZH, ), 0.89 ( 1H, t), 0.69 (1H, t).

LCMS (Method C), retention time 3.32 (MAN) 447.

Examples 21 and 22: Separation of enantiomers from Example 20.

I00232| The sample from Example 20 was subjected to chiral separation using a column

SpigaIRak IC, 10 mm x 250 mm, particle size 5 microns. Solvent for elution: methyl tert-butyl ether: isopropanol: DCM (15:20:65).

I00233| Example 21: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 14.3 minutes, e.i. 299 Vol. (00234| "H NMR (DMSO-av) 6: 10.16 (2H, Bg 5), 7.56 (1H, av), 7.26 (1H, 49), 7.22 (1H, au, 7.17 (IN, aa), 7.12 ( 1H, a), 7.05 (1H, a), 5.99 (IN, t), 4.16 (1H, a), 3.65 (2H, t), 3.57 (1H, a), 2.98 (2H, a), 1.93 (1H , t), 1.73 (IN, t), 1.17 (ЗН, У, 0.94 (1Н, т), 0.78 (1Н, ad).

LCMS (Method C), retention time 3.27(M'-H) 447.

Example 22: Second eluted enantiomer: retention time on the analytical column 20.6 minutes, e.i. 299 95. (00235| "H NMR (DMSO-av) 6: 10.16 (2H, Bg 5), 7.56 (1H, av), 7.26 (1H, 4), 7.22 (1H, ayu, 7.17 (IN, aa), 7.12 (IN, a), 7.05 (1H, 49), 5.99 (IN, t), 4.16 (1H, a), 3.65 (2H, t), 3.57 (1H, a), 2.98 (2H, 50. yuyu a), 1.93 (1H, au, 1.73 (1H, t), 1.17 (ZH, )), 0.94 (IN, ayu, 0.75 (1H, ad).

LCMS (Method C), retention time 3.26(M'H) 447.

Example 23: pPax, 7tb5K)-5-21(2)-3-(Pyrrolidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carbon acid

With 8

M o

N

E (c) on

Obtained in the same way as Example 20, starting from methyl (Takz, 76551E)-5-2|(2)-

C-(pyrrolidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 66) as a white solid.

1H NMR (DMSO-α) 6: 12.2-11.6 (1H, Bug 5), 7.49 (1H, aa), 7.30 (1H, a), 7.21-7.12 (2H, t), 7.09 (IN, t), 6.97 (IN, 4), 6.10 (IN, t), 4.12 (IN, 9), 3.80 (2H, a) , 3.51 (IN, a), 3.28 (4Н, т), 1.89 (IN, т), 1.85 (4Н, т), 1.68 (1Н, т), 0.90 ( 1H, t), 0.69 (1H, t).

LCMS (Method C), retention time 3.39 (M--H) 473

Examples 24 and 25: Separation of enantiomers from Example 23.

I00236| The sample from Example 23 was subjected to chiral separation using a column

SpigaIRak IC, 10 mm x 250 mm, particle size 5 microns. Elution solvent: methyl tert-butyl ether: ethanol (75:25).

I00237| Example 24: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 17.5 minutes, e.i. 299 Fo: (002381 "H NMR (DMSO-av) 6: 7.55 (1H, av), 7.35 (1H, a), 7.22 (2H, t), 7.14 (1H, a) , 7.02 (IN, 9), 6.14 (IN, t), 4.17 (1H, 4), 3.84 (2H, rg a), 3.57 (1H, a), 3.30 (4H, Bg), 1.97-1.85 (5H, Big t), 1.73 (IN, t), 0.95 (1H, a), 0.74 (1H, a).

LCMS (Method C), retention time 3.33 (MAN) 473

Example 25: Second eluted enantiomer: retention time on the analytical column 21.4 minutes, e.i. 298 95.

I00239| "H NMR (DMSO-α) 6: 7.55 (1H, aa), 7.34 (1H, a), 7.24 (1H, aa), 7.19 (1H, aa), 7.14 ( IN, 94), 7.02 (1H, 4), 6.14 (IN, a), 4.17 (1H, a), 3.84 (2H, Bg a), 3.57 (1H, ad) , 3.29 (4H, Bi), 1.97-1.85 (5H,

Be t), 1.73 (1H, t), 0.95 (IN, a), 0.74 (1H, a).

LCMS (Method C), retention time 3.34 (M--H) 473.

Example 26: (1ак5, 7Б5К)-5-(2-(3-Dimethylaminopropylamino)benzenesulfonylamino!|-1Ta, 2,70B-tetrahydrocyclopropa(|sichromene-4-carboxylic acid -

ZU

M o

WITH

(c) he (00240) Mixture pPax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid (Intermediate compound 67, 0.15 g), 3-dimethylaminopropylamine (1.26 g) and triethylamine (0.62 g) in MMP (6 ml) were stirred and heated at 140 C for 48 hours. After cooling, the mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 5-10 95. The obtained product was repurified by preparative TLC, eluting with a mixture of methanol and DCM (10 9o), to obtain pPax, 7b5K)- 5-(2-(3- dimethylaminopropylamino)-benzenesulfonylamino!|-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.08 g) in the form of a grayish-white solid.

1H NMR (DMSO-dv) 6: 7.36 (1H, aa), 7.22 (IN, aO, 7.02 (2H, 5), 6.68 (1H, 49), 6.44 ( 1H, 9, 6.24 (IN, g 5), 4.11 (IN, a), 3.51 (IN, a), 3.30-3.10 (4H, t), 2.68 (6H, 5 ), 1.83 (1H, t), 1.72-1.52 (ZH, t), 0.85 (1H, t), 0.65 (1H, t).

LCMS (Method C), retention time 3.31 (M.N) 446.

Examples 27 and 28: Separation of enantiomers from Example 26.

I00241| The sample from Example 26 was subjected to chiral separation using a column

SpigaIiRak IV, 20 mm x 250 mm, particle size 5 microns. Elution solvent: hexane: ethanol: diethylamine (49.8:50:0.2).

Example 27: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm) 14.61 minutes (e.i. »98 b). (00242) "H NMR (DMSO-α) 5: 7.37 (1H, aa), 7.23 (IN, ayu, 7.02 (2H, 5), 6.68 (1H, a), 6, 45 (IN, 0, 6.24 (1H, ry 5), 411 (IN, a), 3.52 (1H, a), 3.35-3.02 (4H, t), 2.67 (6H , 5), 1.84 (IN, t), 1.74-1.52

(ZH, t), 0.85 (1Н, t), 0.66 (1Н, t).

LCMS (Method C), retention time 3.21 (M.--H) 446.

Example 28: Second eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm) 18.16 minutes (e.i. 298 b).

I00243| "H NMR (DMSO-ав) 6: 7.37 (1Н, ав), 7.23 (1Н, а9.7.02 (2Н, 5), 6.68 (IN, а), 6.44 (IN , U, 6.25 (IN, reg 5), 411 (IN, a), 3.51 (1H, a), 3.41-3.05 (4H, t), 2.69 (6H, 5) , 1.84 (IN, t), 1.74-1.52 (ЗН, t), 0.85 (1Н, t), 0.66 (1Н, t).

LCMS (Method C), retention time 3.20 (M.N) 446.

Example 29: (1ak5,7B5NK)-5-(2-(4-Dimethylaminobutylamino)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

Shores at ,0 8

M o

N

(c) he

It was obtained in the same way as Example 26, starting from (Takv5, 7B6B54)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (Intermediate compound 67), and 4- dimethylaminobutylamine. "H NMR (DMSO-α) 6: 13.0-12.0 (1H, Bg 5), 7.58 (IN, aa), 7.28 (IN, ayu, 7.02 (2H, 5), 6.69 (1H, a), 6.55 (1H, U, 5.70 (1H, t), 4.14 (1H, a), 3.53 (IN, 9), 3.15 (2H, t), 2.91 (2H, t), 2.67 (6H, 5), 1.83 (1H, t), 1.76 (2H, t), 1.66 (1H, t), 1, 53 (2H, t), 0.84 (1H, t), 0.67 (1H, t).

LCMS (Method C), retention time 3.43 (M.--N) 460.

Examples 30 and 31: Separation of enantiomers from Example 29.

A sample from Example 29 was subjected to chiral separation using a SpigaIRak IV column, 20 mm x 250 mm, 5 micron particle size. Elution solvent: hexane: ethanol: diethylamine (49.8:50:0.2).

Example 30: First eluted enantiomer: retention time on analytical column (4.6 mm x 250 mm) 12.69 minutes (e.i. 298 b).

1H NMR (DMSO-dv) 5: 13.0-12.2 (1H, Bg 5), 7.58 (1H, aa), 7.28 (1H, ayu, 7.02 (2H, t) , 6.69 (1H, a), 6.55 (IN, U, 5.71 (IN, t), 4.14 (1H, y), 3.53 (1H, 49), 3.15 (2H , t), 2.89 (2H, t), 2.67 (6H, 5), 1.83 (IN, t), 1.76 (2H, t), 1.66 (1H, t), 1 .54 (2H, t), 0.85 (1H, t), 0.68 (1H, t).

LCMS (Method C), retention time 3.33 (M.--N) 460.

Example 31: Second eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm) 16.82 minutes (e.i. 298 b).

NMR NMR (DMSO-α) 6: 12.9-12.1 (1H, Bri 5), 7.58 (IN, aa), 7.28 (IN, au, 7.02 (2H, 5) , 6.70 (1H, a), 6.55 (IN, U, 5.71 (IN, t), 4.14 (IN, 9), 3.53 (1H, a), 3.15 (2H , t), 2.91 (2H, t), 2.68 (6H, 5), 1.83 (IN, t), 1.77 (2H, t), 1.66 (1H, t), 1 .54 (2H, t), 0.85 (1H, t), 0.68 (1H, t).

LCMS (Method C), retention time 3.33 (M--H) 460.

Example 32: (chIak5, 7B52)-5-(2-(5-Dimethylaminopentylamino)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

TITAN 0.0 po

ZM

M (c) s o on

I00244| Obtained in the same way as Example 26, starting from (yes, 7rzK)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (Intermediate compound 67) and 5-dimethylaminopentylamine .

1H NMR (DMSO-α) 5: 12.8-12.2 (1H, Bg 5), 7.67 (1H, aa), 7.30 (1H, ayu, 6.98 (1H, a) , 6.85 (1H, a), 6.68 (1H, a), 6.60 (1H, U, 5.54 (IN, t), 4.14 (IN, a), 3.54 (1H , 49), 3.05 (4H, t), 2.66 (6H, 5), 1.81 (1H, t), 1.63 (BN, t), 1.51 (2H, t), 0 .83 (1H, t), 0.67 (1H, t).

LCMS (Method C), retention time 3.55 (M.--N) 474.

Example 33: pPax, 7tB5K)-5-42((2)-3-"Propan-2-yl)aminoprop-1-enyl/|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene- 4-carboxylic acid

M

Y r 8 81

M o

N

E o on (00245) Mixture of methyl OPax, 7tb5K)-5--2((2)-3-(propan-2-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1 a, 2,71B- tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 69, 0.12 g) and lithium hydroxide monohydrate (0.1 g) in a mixture of dioxane (10 ml) and water (5 ml) were stirred and heated at 100 "C overnight. After cooling, the mixture was concentrated under vacuum, and the residue was acidified to pH 4 with formic acid, then extracted with a mixture of ethyl acetate and THF (1:1). The organic phase was dried (Ma25954) and filtered. The filtrate was evaporated to a dry residue, and the residue was dissolved in ethyl acetate (2 mL) and hexane (10 mL) was added. The solid was collected by filtration and washed with ether to give tanz, 76B58)-5-(2((2)-3-(propan-2-yl)aminoprop-1-enyl|-4 - fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.04 g) in the form of a grayish-white solid.

NMR NMR (DMSO-α) 6: 10.5-9.8 (1H, Bug 5), 7.54 (1H, aa), 7.23-7.08 (ZH, t), 7.04 (1H, a), 6.96 (IN, a), 5.91 (IN, t), 4.09 (1H, a), 3.63 (2H, t), 3.53 (1H, t) , 3.49 (IN, a), 1.85 (1H, t), 1.67 (1H, t), 1.16 (6H, 4), 0.86 (IN, t), 0.67 ( 1H, t).

LCMS (Method C), retention time 3.37 (M.N) 461.

Example 34: (Tak5, 7658)-5-2((2)-3-((5)-3-Hydroxypyrrolidine-1-ylluaminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa SiIichromene-4-carboxylic acid no-« Z b o 8

M o

N

E (c) on (00246) It was obtained in the same way as Example 33, starting from methyl (so, 70zkK)-5-21(2)-3-((5)-3-hydroxypyrrolidine-1-ylaminoprop-1- enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 70).

1H NMR (DMSO-α) 6: 12.5-11.3 (1H, Bg 5), 7.62 (1H, t), 7.32 (1H, a), 7.22 (2H, t ), 7.13 (IN, a), 6.98 (IN, 9), 6.12 (1H, t), 5.26 (1H, t), 4.37 (1H, t), 4.19 (IN, a), 3.79 (2H, t), 3.59 (1H, aa), 3.20- 25...3.00 (ZH, Big 5), 2.05 (1H, t) , 1.94 (1H, t), 1.77 (2H, t), 0.96 (TN, t), 0.76 (1H, t).

LCMS (Method C), retention time 3.15 (M--H) 489.

Example 35: (chTak5, 7B6B5K)-5-(2((2)-3-(H)-3-Hydroxypyrrolidine-1-ylluaminoprop-1-enyl/|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p- tetrahydrocyclopropa|siIchromene-4-carboxylic acid b o 8

M o

N

E (c) on

I00247| It was obtained in the same way as Example 33, starting from methyl (so, 70zK)-5-21(2)-3-(A)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino) -1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 71).

1H NMR (DMSO-α) 6: 12.5-11.4 (1H, Bg 5), 7.62 (1H, t), 7.33 (1H, a), 7.22 (2H, t ), 7.13 (IN, a), 6.98 (IN, 94), 6.14 (1H, t), 5.26 (1H, t), 4.37 (1H, t), 4.19 (IN, a), 3.79 (2H, t), 3.59 (1H, aa), 3.20- 35. 3.00 (ZH, Big 5), 2.05 (1H, t), 1 .94 (IN, t), 1.77 (2H, t), 0.96 (1H, t), 0.76 (1H, t).

LCMS (Method C), retention time 3.14 (M.--H) 489.

Example 36: (1akz, 7B5K)-5-(2((2)-4-Diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino|- 11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid

RI, Me; what

A sia

M o

N

E (c) on (00248) Obtained in the same way as Example 33, starting from methyl (1akz, 705K)-5-(M-(methoxycarbonyl)-M-(2((2)-4-diethylaminobut-1- (enyl)-4-fluorobenzenesulfonyl|amino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 72).

NMR NMR (DMSO-α) 6: 12.8-11.4 (1H, Bug 5), 7.54 (1H, aa), 7.14-7.02 (4H, t), 6.83 (1H, a), 5.66 (IN, t), 4.09 (IN, a), 3.51 (1H, 49), 3.13 (2H, t), 2.92 (4H, t) , 2.34 (2H, t), 1.84 (1H, t), 1.66 (1H, t), 1.06 (6H, U, 0.86 (1H, t), 0.67 (1H , t).

LCMS (Method C), retention time 3.35 (M.--N) 489.

Examples 37 and 38: Separation of enantiomers from Example 36.

I00249| The sample from Example 37 was subjected to chiral separation using a column

SpigaIRak IC, 10 mm x 250 mm, particle size 5 microns. Solvent for elution: methyl tert-butyl ether: isopropanol: DCM (16:20:64).

Example 37: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 25.8 minutes, e.i. 298 9: (00250| "H NMR (DMSO-α) 6: 7.61 (1H, aa), 7.20-7.09 (4H, t), 6.90 (1H, a), 5.74 (IN, t), 4.16 (IN, a), 3.58 (1H, a), 3.22-3.11 (2H, t), 2.99 (4H, t), 2.50 ( 2H, t), 1.92 (1H, au, 1.72 (1H, t), 1.15 (6H, U, 0.93 (1H, t), 0.75 (1H, t).

LCMS (Method C), retention time 3.36(М--Н) 489

Example 38: Second eluted enantiomer: retention time on the analytical column 44.0 minutes, e.i. 298 95. (00251| "H NMR (DMSO-av) 6: 7.61 (1H, av), 7.20-7.10 (4H, t), 6.90 (1H, 49), 5.74 (1H, t), 4.16 (IN, a), 3.58 (IN, a), 3.23-3.10 (2H, t), 2.99 (4H, a), 2.51 ( 2H, t), 1.92 (1H, au, 1.72 (IN, t), 1.15 (6H, U, 0.93 (1H, t), 0.75 (1H, t).

LCMS (Method C), retention time 3.36 (M--H) 489

Example 39: pPax, 7B5K)-5-(2-(2-(4-Ethylpiperazin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid

Shk; oo xx 7; and cutting

E (6) on (002521 Pakz solution, 7tb5K)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a, :2,70B- tetrahydrocyclopropa|sichromene-4-carboxylic acid (Intermediate compound 74, 0.035 g) and From a drop of M-ethylpiperazine in isopropanol (0.5 ml) was irradiated in a microwave reactor at 160 "C for 15 minutes, then again at 170 "C for 15 minutes. After cooling, the mixture was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.195 formic acid, with a gradient of 20-60 95. The isolated product was further purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-10 95 to obtain (Tab, 7BK)-5-2-(2-(4-ethylpiperazin-1-yl)y-ethyl|-4--fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid ( 0.018 g) in the form of a grayish-white solid.

1H NMR (SOSIZ) 6: 7.95 (1H, aa), 7.07 (2H, 5), 6.95 (1H, ad), 6.91 (1H, au, 4.38 (1H , 49), 3.79 (IN, 9), 3.42 (2H, a), 3.35 (2H, 4), 3.21-3.05 (4H, t), 3.04-2, 88 (4H, t), 2.79 (2H, t), 1.86 (1H, a), 1.66 (IN, t), 1.22 (ЗН, У, 1.06 (IN, 29) , 0.93 (1H, t).

LCMS (Method C), retention time 2.95 (M.N) 504

Example 40: pPax, 76B5K)-5-21((2)-3-(Azetidin-1-yl)prop-1-enyl/|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4 -carbonic acid t. m. v

M o

N

E (c) on 00253) Obtained in the same way as Example 33, starting from methyl (yes, 70zkK)-

5-2-(2)-3-(azetidin-1-yl)prop-1-enyl|-A-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 76).

1H NMR (DMSO-α) 6: 12.8-11.1 (1H, B5), 7.51 (1H, aa), 7.26 (IN, a), 7.17 (1H, au , 7.10 (2H, t), 7.00 (IN, 49), 5.90 (1H, t), 4.12 (1H, 49), 3.96 (4H, t), 3.74 ( 2H, t), 3.52 (1H, 9), 2.27 (2H, t), 1.89 (1H, t), 1.69 (1H, t), 0.90 (1H, t), 0.69 (1H, t).

LCMS (Method C), retention time 3.26 (M.N) 459.

Example 41: pPax, 7tB5K)-5-4I(2((2)-3-(3-Hydroxyazetidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa| Siichromene-4-carboxylic acid

More) yes: b 8 by 8

M (c)

N

E (c) on

I00254| Obtained in the same way as Example 33, starting from methyl (yes, 70 zK)-5-2-(2)-3-(3-Hydroxyazetidin-1-yl)/prop-1-enyl|-4-fluorobenzenesulfonylamino)- 1 a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 77).

1H NMR (DMSO-α) 6: 12.8-11.2 (1H, ri 5), 7.53 (1H, t), 7.22 (1H, a), 7.17 (1H, ayu , 7.09 (2H, t), 6.97 (1H, 49), 5.90 (IN, t), 4.40 (1H, t), 4.18 (2H, t), 4.12 ( 1H, 4), 3.69 (4H, t), 3.52 (1H, a), 1.87 (IN, t), 1.69 (1H, t), 0.89 (1H, t), 0.70 (1H, t).

LCMS (Method C), retention time 3.18 (M--H) 475.

Example 42: (Also, 7B52)-5-(2((2)-3--"Azetidin-1-yl)/propyl|-4-fluorobenzenesulfonylamino)-11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carbonate acid and by r. /0 m:

M o

N

E (c) on (002551 Solution pPax, tb5K)-5-4I2((2)-3-(azetidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1,1a, 2,7p- tetrahydrocyclopropa|siIchromene-4-carboxylic acid (Example 40, 0.03 g) in methanol was treated in a nitrogen atmosphere with palladium on carbon (10 95, 0.01 g).

The nitrogen was replaced with hydrogen and the mixture was stirred under a hydrogen atmosphere overnight. The mixture was filtered and the filtrate was evaporated to a dry residue. The residue was purified by HPLC (C18) to obtain (iaz, 7p5E)-5-2|(2)-3-(azetidin-1-yl/upropyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene- 4-carboxylic acid (0.019 g) as a white solid.

1H NMR (DMSO-α) 5: 7.76 (1H, ad), 7.20 (1H, aa), 7.09 (1H, au, 7.05 (1H, a), 6.99 ( 1H, a) 4.15 (IN, a), 3.97 (2H, t) 3.56 (1H, a), 3.14 (2H, t), 2.99 (4H, t), 2, 29 (2H, t), 1.86 (1H, t), 1.81-1.64 (ZH, t), 0.88 (1H, t), 0.69 (1H, t).

I"INZHHMS (Method C), retention time 3.20 (M.N) 461.

Example 43: (Takz, 765K)-5-(2(2)-4-Diethylaminobutyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

RI, where; to

A sia

M o

N

E (c) on 00256) Obtained in the same way as Example 42, starting from (Takz, 7p5K)-5-(2((2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!-1a, 2,7B-tetrahydrocyclopropa-

Isyichromene-4-carboxylic acid (Example 36), in the form of a white solid.

1H NMR (DMSO-av) 6: 13.0-11.6 (1H, Bg 5), 7.82 (1H, av), 7.21 (1H, ad), 7.08 (1H, a ), 7.02 (IN, 9), 6.96 (IN, a), 4.14 (1H, 9), 3.55 (1H, 49), 2.99 (8H, t), 1.83 (IN, t), 1.65 (5Н, t), 1.14 (6Н, У), 0.85 (IN, t), 0.69 (1Н, t).

LCMS (Method C), retention time 3.45 (M.N) 491.

Example 44: pPax, 7B5K)-5-2-NIM-(4-Dimethylaminobutyl)-M-methylamino|-benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid about .0

M o

N

(c) he (00257 | Mixture pPax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid (Intermediate compound 67, 0.1 g), M-( 4-dimethylaminobutyl)-M-methylamine (Intermediate compound 78, 1.07 g) and triethylamine (0.42 g) in MMP (b ml) were mixed and heated in a closed test tube at 150 C for 3 days. After cooling, the mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (10 95), followed by repeated HPLC purification (C18) to give Pakz, 7B5K)-5-2-IM-(4-dimethylaminobutyl) -M-methylamino|- benzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropaseIchromene-4-carboxylic acid (0.03 g) in the form of a white solid.

1H NMR (DMSO-av) 5: 7.81 (1H, aa), 7.54 (1H, au, 7.41 (1H, av), 7.21 (1H, au, 6.94 (1H , a), 6.85 (1H, a), 412 (IN, a), 3.55 (1H, a), 2.96 (2H, U, 2.85 (2H, U), 2.64 ( 6H, 5), 2.49 (ZH, 5), 1.83 (1H, t), 1.74 (2H, t), 1.63 (ZH, t), 0.87 (IN, t), 0.68 (1H, t).

LCMS (Method C), retention time 3.37 (MAN) 474.

Example 45: pPax, 7B5K)-5-2-(5)-1-Ethylpyrrolidin-3-ylcarbamoyl)methyl-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid

H 05 20 r:

M c)

N

E o7 Ton

І00258| Mixture of methyl (chIak5, 7p5K)-5-2-((5)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl|-4-fluorobenzenesulfonylamino)-1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 80, 0.148 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 ml) and water (1 ml) were irradiated in a microwave reactor at 130 "C for 40 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated under massio .

The residue was triturated with 10 95 methanol in DCM and filtered. The filtrate was evaporated and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-20 95. The resulting solid was triturated with ether and filtered to obtain Pakzv, 7B5K)-5-2-((5)-1- ethylpyrrolidin-3-ylcarbamoyl)methyl|-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.091 g) as a white solid.

1H NMR (DMSO-dv) 6: 9.56 (0.5N, Bbg, a), 9.48 (0.5N, Bg, 4), 7.59 (1N, t), 7.34 ( IN, t), 7.16 (2H, t), 7.06 (1H, U, 4.46 (1H, Big, 4), 4.13 (IN, a), 3.92 (IN, da) , 3.70 (1H, t), 3.65 (1H, a), 3.58 (1H, Bi, t), 2.95-3.25 (6H, t), 2.40 (IN, t ), 1.95 (2Н, т), 1.76 (1Н, т), 1.20 (ЗН, У, 0.97 (1Н, т), 0.78 (1Н, т).

LCMS (Method C), retention time 3.04 (M.N) 518.

Example 46: (1ак5,7Б5Э)-5-(2-(1-Ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid sh teky tm (in ) N

E o7 tone

I00259| Obtained in the same way as Example 45, starting from methyl (1akz, 705K)-5-(2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino!-1Ta, 2,7B-tetrahydrocyclopropa-

isochromene-4-carboxylate (Intermediate 86), as a white solid.

I00260| "H NMR (DMSO-dv) 6: 7.91 (1H, aa), 7.64 (1H, ad), 7.24 (1H, ayu, 6.96 (1H, a), 6.66 (1H , 9), 4.79 (1H, t), 4.21 (IN, 9), 4.15 (2H, Bug, U, 3.89 (2H, brg, t), 3.62 (1H, a ), 3.06 (2H, a), 1.83 (1H, t), 1.70 (1H, t), 1.05 (ЗН, У, 0.88 (IN, t), 0.72 ( 1H, t). 5О0

LCMS (Method C), retention time 2.99 (M.N) 447.

Example 47: OIax, 7B5K)-5-2-((B8)-1-Ethylpyrrolidin-3-ylcarbamoyl)methyl|d-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid m

H 05 7.0 753

M|c)

N

E o7 Ton

I00261| Obtained in the same way as Example 45, starting from methyl (So, 70 zK)-5-2-I(B)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl|-4-fluorobenzenesulfonylamino)-1 and, 2,76- tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 92), in the form of a white solid.

NMR NMR (SOSI) 6: 10.30 (0.5Н, kg, 5), 10.25 (0.5Н, Bg, 5), 9.88 (1Н, Bkg, 5), 7.52 (IN, t), 7.18-7.41 (ZN, t), 6.75 (IN, t), 4.683 (0.5Н, t), 4.70 (0.5Н, t), 4, 17 (1.5N, t), 3.84-4.10 (1.5N, t), 3.60-3.86 (ЗН, t), 3.45 (0.5Н, а), 3, 91 (0.5N, t), 3.13 (0.5N, t), 2.98 (0.5N, t), 2.83 (2N, t), 2.46 (1N, t), 2 .29 (1H, t), 1.93 (1H, t), 1.67 (1H, a), 1.40 (ЗН, У), 1.13 (0.5Н, t), 1.07 ( 0.5N, t), 0.97 (1N, t).

LCMS (Method C), retention time 3.03 (M.N) 518.

Example 48: (Tak5, 7652K)-5-2-(2-(Pyrrolidin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

ZM

M o

N

E o7 sleep

I00262| Obtained in the same way as Example 39, starting from (yes, 76B5E)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1Ta, 2,7Bb-tetrahydrocyclopropa|c|Ichromene-4-carboxylic acid (Intermediate compound 74 ) and pyrrolidine, in the form of a white solid.

IN NMR (DMSO-dv) 6: 7.84 (1H, ad), 7.26 (1H, aa), 7.17 (1H, ayu, 7.02 (IN, a), 6.74 (1H, a), 416 (IN, a), 3.59 (1H, a), 3.36-3.20 (8H, t), 1.91 (4H, t), 1.85 (IN, t), 1.69 (1H, t), 0.89 (1H, t), 0.70 (IN, t).

LCMS (Method C), retention time 3.12 (M.N) 461.

Example 49: Pakz, 7B5K)-5-(2-(B8)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

There! Eat on u

M|c)

N

E (6) on

I00263| Lithium hydroxide (0.111 g) was added to a solution of methyl (Thus, 7rB5K)-5-(2-((H)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa-

isochromene-4-carboxylate (Intermediate compound 95, 0.13 g) in a mixture of dioxane (4 ml) and water (1 ml) and stirred, the mixture was heated at 85"C overnight. After cooling, the mixture was filtered, and the filtrate was acidified by adding 10 95 with aqueous citric acid (1 mL) and then extracted with DCM. The organic extract was dried (Mo95054) and filtered. The filtrate was evaporated to a dry residue, and the residue was triturated with diethyl ether, and the solid was collected by filtration to give (yes, 7p5K)-5 -(2-(B)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,7B-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid (0.085 g) in the form of a white solid .

1H NMR (DMSO-av) 6: 7.81 (1H, ad), 7.28 (1H, av), 7.16 (1H, ayu, 7.11 (1H, as), 6.99 ( 1H, aa), 4.20 (IN, aa), 3.60 (1H, 7), 3.48-2.98 (9H, horn t), 2.25 (1H, t), 1.91 ( 1H, a), 1.73 (2H, t), 1.23 (ZH, U, 0.93 (1H, au, 0.75 (1H, t).

LCMS (Method C), retention time 3.21 (M--H) 475.

Examples 50 and 51: Separation of enantiomers from Example 49.

I00264| The sample from Example 49 was subjected to chiral separation using a column

SpigaIRak IC, 10 mm x 250 mm, particle size 5 microns. Solvent for elution: methyl tert-butyl ether: isopropanol: DCM (10:15:75).

Example 50: First eluted enantiomer: retention time on an analytical column (4.6 mm x 250 mm): 30.0 minutes, e.i. 299 95.

I00265| "H NMR (DMSO-dv) 6: 7.81 (1H, av), 7.27 |1H, ad), 7.15 (1H, ayu, 7.10 (IN, a), 7.01 (IN , 9), 4.20 (1H, a), 3.58 (1H, a), 3.23-3.11 (6H, t), 3.11-3.06 (ZH, t), 2, 25 (IN, t), 1.91 (1Н, а), 1.73 (2Н, т), 1.22 (ЗН, У, 0.92 (IN, а), 0.73 (1Н, т) .

LCMS (Method C), retention time 3.25 (MAN) 475.

Example 51: Second eluted enantiomer: retention time on the analytical column 40.0 minutes, e.i. 299 95. (00266) "H NMR (DMSO-av) 6: 7.80 (1H, ad), 7.27 (1H, av), 7.15 (IN, ayu, 7.10 (IN, 49) , 7.03 (1H, 9), 4.18 (1H, a), 3.61 (1H, a), 3.48-2.97 (9H, horn t), 2.27 (IN, t) , 1.91 (1H, a, 1.71 (2H, t), 1.23 (ZH,

U, 0.93 (1H, au, 0.74 (1H, t).

LCMS (Method C), retention time 3.23 (MAN) 475.

Example 52: OPax, 7B5K)-5-2-((5)-1-Ethylpyrrolidine-2-ylcarbonylaminomethyl-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid

SA at 5

M o

N

E (c) on

I00267| A mixture of methyl (yes, 7B5K)-5-12-((5)-1-ethylpyrrolidin-2-yl/ucarbonylaminomethyl|)-4-fluorobenzenesulfonylamino)-1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 101, 0.212 g) and lithium hydroxide (0.05 g) in dioxane (5.5 ml) and water (2.5 ml) were irradiated in a microwave reactor at 150 "C for 30 minutes. After cooling, the mixture was diluted with water, acidified with formic acid to pH 5 and extracted with ethyl acetate.

The organic layer was washed with water, dried (M959054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1 96 formic acid, with a gradient of 35-75 95, to obtain (Takz, 7B05K)-5-2-( (5)-1-ethylpyrrolidine-2-ylcarbonylaminomethyl|-4-fluorobenzenesulfonylamino)-1,1a, 2,76-tetrahydrocyclopropa-|sichromene-4-carboxylic acid (0.064 g) as a white solid.

1H NMR (SOSI) 6: 10.8-9.6 (1H, Bg 5), 8.90 (1H, Bg U, 7.71 (1H, t), 7.20 (ZH, t), 6.86 (1H, t), 4.88 ( 2H, t), 4.37 (IN, aa), 3.85 (1H, a), 3.61 (IN, t), 3.43 (1H, t), 2.97 (1H, t), 2.77 (2H, t), 2.23 (2H , t), 2.03 (1Н, t), 1.91 (2Н, t), 1.69 (1Н, t), 1.18 (ЗН, а), 1.01 (2Н, t).

LCMS (Method C), retention time 3.09 (M.N) 518.

Example 53: Pakz, 7B5K)-5-(2-(4-Dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid c)

Sharov at ,0 to

M (in)

N

E (c) he (002681 Mixture of methyl OPax, 7LBZK)-5-(2-(4-dimethylaminobutyryl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 108 , 0.2 g), potassium carbonate (0.22 g), 1H-pyrazole-Z-amine (0.34 g) and lithium iodide (1.07 g) in DMF (10 ml) were irradiated in a microwave reactor at 150 "C for 1 hour.

After cooling, the mixture was diluted with methanol and acidified to pH with formic acid, then concentrated under vacuum. The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (595). The resulting product was purified by HPLC (C18) to obtain (tan, 7658)-5-(2-(3-dimethylaminobutyryl)-4-fluorobenzenesulfonylamino|-1 and, 2,76-tetrahydrocyclopropa-(c|ichromene-4-carboxylic acid) ( 0.03 g) in the form of a white solid.

1H NMR (DMSO-dv) 6: 7.95 (1H, av), 7.80 (1H, aa), 6.96 (1H, a), 6.95 (1H, a0, 6.79 ( 1H, a), 4.13 (IN, a), 3.56 (1H, a), 3.04 (2H, U, 2.68 (6H, 5), 2.56 (2H, U, 1, 94 (2H, t), 1.81 (1H, t), 1.64 (1H, t), 0.84 (1H, t), 0.66 (1H, t).

LCMS (Method C), retention time 3.12 (M.--N) 492.

Example 54: pPax, 76B5K)-5-(2-(5)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid ha

ZU

M (6)

N

E (6) on

I00269| Obtained in the same way as Example 49, starting from methyl (Takz, 7p5MK)-5-(2-((5)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7tr- tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 113).

1H NMR (DMSO-α) 6: 7.81 (1H, av), 7.27 (1H, aa), 7.15 (1H, au, 7.10 (1H, a), 7.02 ( 1H, aa), 4.19 (IN, aa), 3.56 (1H, U, 3.23-3.11 (6H, t), 3.11-3.06 (ZH, t), 2, 25 (1H, t), 1.91 (IN, a, 173 (2H, t), 1.22 (ЗН, ), 0.92 (1H, ayu, 0.73 (1H, t).

LCMS (Method C), retention time 3.21 (MAN) 475.

Example 55: (1akz5, 7p5K)-5-(2-(3-Dimethylaminopropylcarbamoyl)benzenesulfonylamino|- 11a, 2,7b-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid

N ran o po o, ,0 78

M o

N

(c) he (00270 Solution of tert-butyl OPax, 7L5K)-5-12-(M-(2,4-dimethoxybenzyl)-M-(3-dimethylaminopropyl)/carbamoyl|benzenesulfonylamino)-1,1a, 2,7p -tetrahydrocyclopropa-

Isochromene-4-carboxylate (Intermediate compound 119, 0.03 g) in trifluoroacetic acid (5 ml) was stirred and heated at 30 C overnight. The mixture was evaporated to a dry residue, and the residue was purified by HPLC (C18) to give pPax, Tb5K)-5-(2-(3-Dimethylaminopropylcarbamoyl)benzenesulfonylamino!|-1 and, 2,7ter-tetrahydrocyclopropa|sichromene-4-carboxylic acid ( 0.013 g) in the form of a white solid.

1H NMR (DMSO-α) 6: 8.61 (1H, Bg O, 7.73 (1H, a), 7.52 (1H, 9, 7.43 (2H, t), 6.97 ( 1H, a), 6.82 (1H, a), 414 (1H, 4), 3.58 (1H, 9), 3.26 (2H, t), 3.04 (2H, U), 2, 60 (6H, 5), 1.85 (ZH, t), 1.67 (1H, t), 0.87 (1H, t), 0.68 (1H, t).

LCMS (Method C), retention time 2.79 (M.--N) 473.

Example 56: (1akz, 7p5K)-5-(2-M-((5)-1-Ethylpyrrolidin-3-yl)y-M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1,Ta, 2.7p -tetrahydrocyclopropa|siIchromene-4-carboxylic acid - ; m that "M (in)

N

E 0) on

I00271| A mixture of methyl (Takz, 76B5K)-5-(2-1(M-((5)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|- methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2, 7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate compound 126, 0.047 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 ml) and water (1 ml) were irradiated in a microwave reactor at 130 "C for 40 minutes.

After cooling, the mixture was diluted with methanol, acidified with formic acid, and evaporated to dryness. The residue was triturated with 10 95 methanol in DCM, filtered, and the filtrate was evaporated on a massio.

The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-40 9o. The resulting solid was triturated with ethyl acetate and filtered to give OIax, 7B5K)-5-(2-1M4-((5)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|-methyl)-4-fluorobenzenesulfonylamino)-1 ,1a, 2,7B-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.022 g) in the form of a white solid.

1H NMR (DMSO-th at 80 "C, 6: 7.83 (1H, 9, 7.12 (1H, ayu, 7.08 (1H, 4), 7.01 (1H, a), 6 .84 (1H, t), 4.61 (IN, ri, 5), 419 (1H, a), 4.12 (2H, 5), 3.73 (1H, a), 2.71-3, 18 (7Н, Бг, т), 2.94 (ЗН, 5), 1.85-2.15 (ЗН, т), 1.72 (1Н, т), 1.17 (ЗН, ), 0, 95 (1H, t), 0.78 (1H, t).

LCMS (Method C), retention time 3.08 (M--H) 532.

Example 57: (chIak5, 7p5K)-5-(2-|M-(B)-1-Ethylpyrrolidin-3-yl)y-M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1,Ta, 2.7p -tetrahydrocyclopropa|siIchromene-4-carboxylic acid

Such as

M

"M (in;

N

E o7 sleep

I00272| A mixture of methyl (Tak5, 7B5K)-5-(2-CM-(B)-1-ethylpyrrolidin-3-yl)umethylcarbamoyl|-M-methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa| Sichromene-4-carboxylate (Intermediate compound 131, 0.076 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 ml) and water (1 ml) were irradiated in a microwave reactor at 130 "C for 40 minutes.

After cooling, the mixture was diluted with methanol, acidified with formic acid, and evaporated to dryness. The residue was triturated with 10 95 methanol in DCM, filtered, and the filtrate was evaporated on a massio.

The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-40 9o. The resulting solid was triturated with ethyl acetate and filtered to give OPax, 7B5K)-5-(2-CM-(B)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|-methyl)-4-fluorobenzenesulfonylamino)-1, 1a, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.028 g) in the form of a white solid.

1H NMR (DMSO-aiv at 80 C) b: 7.83 (1H, 9, 7.12 (1H, ayu, 7.08 (1H, a), 7.01 (1H, a), 6, 84 (IN, t), 4.61 (IN, rt, 5), 4.19 (IN, a), 4.12 (2H, 5), 3.73 (1H, a), 2.71-3 ,18 (7H, Bg, t), 2.94 (ZN, 5), 1.85- 15. 2.15(ZN, t), 1.72 (IN, t), 1.17 (ZN, U , 0.95 (1H, t), 0.78 (1H, t).

LCMS (Method C), retention time 3.08 (M.--N) 532.

Example 58: (Iakzv, 7tb5K)-5-(2-(2-((5)-1-Ethylpyrrolidin-2-yl)/'ethylamino|benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|c|Ichromene- 4-carboxylic acid

KA and with K4 on

ZM

M o

N

(c) he (00273 Mixture pPax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid (Intermediate compound 67, 0.1 g), 2-(( 5)-1-ethylpyrrolidin-2-ylylethylamine (Intermediate compound 136, 0.5 g) and triethylamine (0.5 ml) were mixed and heated in a closed test tube at 140 "C overnight. After cooling, the mixture was concentrated under vacuum, and the residue purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (10 95). The residue was re-purified by HPLC (C18) to obtain (tav, /7658)-5-2-(2-(5)-1-ethylpyrrolidin-2-yl/ uethylamino|benzenesulfonylamino)-1,1a, -- 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.022 g) in the form of a white solid.

NMR(DMSO-α) 6: 7.47 (1H, t), 7.25 (1H, U, 6.92 (1H, 4), 6.89 (1H, t), 6.72 (1H, a ), 6.53 (1H, au, 6b, 0-5.3 (1H, Bi 5), 4.11 (IN, aa), 3.53 (1H, U), 3.33-2.80 ( 7H, t), 2.19 (2H, t), 1.92 (2H, t), 1.82 (2H, t), 1.64 (2H, t), 1.17 (ЗН, У), 0.84 (1H, t), 0.67 (1H, t).

LCMS (Method C), retention time 3.34 (M.--N) 486.

Example 59: (Iakz, 70b5K)-5-2-(2-(H)-1-Ethylpyrrolidin-2-yl)/'ethylamino|benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|c|ichromene-4- carboxylic acid och bo po ro X/Y

From the west

M o

N

(c) he

I00274| Obtained in the same way as Example 58, starting from (1akz, 765E)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7Bb-tetrahydrocyclopropa-|sichromene-4-carboxylic acid (Intermediate compound 67) and 2- ((H)-1-ethylpyrrolidin-2-yl)ethylamine (Intermediate 141).

1H NMR (DMSO-α) 6: 7.47 (1H, t), 7.25 (IN, U, 6.97 (IN, 49), 6.90 (1H, t), 6.72 ( 1H, a), 6.53 (IN, a), 6.0-5.4 (1H, Bug 5), 4.12 (1H, da), 3.53 (1H, U, 3.35-2 .85 (7H, t), 2.20 (2H, t), 1.93 (2H, t), 1.81 (2H, t), 1.65 (2H, t), 1.18 (ЗН, ), 0.84 (1H, t), 0.67 (1H, t).

LCMS (Method C), retention time 3.32 (M.N) 486.

Example 60: (Takz, 7651E)-5-(2-(3-M, M,-Diethylaminopropylamino)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

UT TMNO about what

Mr. Sus

M o

N c) on

I00275| 3-Diethylaminopropylamine (0.975 g) was added to a solution of (Tax5, 7B5MK)-5-(2-fluorobenzenesulfonylamino)-1,1a, 2,7B-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (Intermediate compound 67, 0.091 g) in MMP (3 ml) and heated the mixture at 140 "C in a closed test tube for 36 hours. After cooling, the mixture was diluted with water (2 ml) and the solution was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1 95 formic acid , with a gradient of 10-98 9b5, to obtain Pakz, 7B5K)-5-(2-(3-diethylaminopropylamino)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.039 g) in the form white solid.

1H NMR (DMSO-αv) 6: 7.45 (1H, av), 7.28 (IN, ayu, 7.04 (2H, t), 6.74 (IN, 4), 6.51 ( 1H, 9, 6.17 (IN, Big 5), 4.16 (IN, 49), 3.57 (1H, a), 3.54-2.97 (8H, Bbg t), 1.87 ( 1H, a), 1.81-1.63 (ZH, t), 1.15 (6H,

I), 0.89 (1H, t), 0.72 (1H, t).

LCMS (Method C), retention time 3.31 (M--H) 474.

Example 61: pPax, 76B5K)-5-(2-C(B)-1-Ethylpyrrolidine-2-ylcarbonylamino|methyl)-4-fluorobenzenesulfonylamino)-1,Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid

WITH

In ; at; mo (c) 5

M o

N

E (c) on

I00276)| A mixture of methyl (Takz, 765K)-5-(2-C(B)-1-ethylpyrrolidine-2-ylcarbonylamino|methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate ( Intermediate compound 146, 0.120 g) and lithium hydroxide monohydrate (0.095 g) were suspended in dioxane (5 mL) and water (1 mL) and stirred, and the mixture was heated at 110 °C for 22.5 h. After cooling, the volatiles were removed by fat, and the residue was acidified by adding an aqueous solution of citric acid (10 95) and extracted with DCM. The organic layer was dried (Ma2595054) and filtered, and the filtrate was evaporated to a dry residue. The residue was purified by preparative

HPLC (C18), eluting with a mixture of methanol and water containing 0.195 of formic acid, with a gradient of 10-98 9b5, to obtain akz, 7B5K)-5-(2-C((B)-1-ethylpyrrolidin-2-yl) ucarbonylamino|methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-

Isochromene-4-carboxylic acid (0.043 g) as a white solid.

1H NMR (DMSO-α) δ: 8.77 (1H, 4), 7.83 (1H, ad), 7.22 (1H, ia), 7.12 (1H, av), 7.08 (1H, a), 6.16 (IN, aa), 4.73 (2H, 0), 4.24 (1H, y), 3.67 (1H, 49), 3.54 (1H, Bi 5 ), 3.37-3.28 (1H, t), 2.93-2.80 (1H, t), 2.80-2.61 (2H, t), 2.30-2.20 (1H , t), 1.95-1.70 (5H, t), 1.08 (ZH, ), 0.95 (1H, ayu, 0.76 (1H, 4).

LCMS (Method C), retention time 3.09 (M.N) 518.

Example 62: (1akz, 7p5K)-5-2-(1-Ethylazetidin-3-ylmethyl)amino|Ibenzenesulfonylamino)-11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid

Sa

From here, about

N

(c) he (00277 Mixture pPax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa-1|sichromene-4-carboxylic acid (Intermediate compound 67, 0.07 g) and (1 - ethylazetidin-3-yl)umethylamine (Intermediate compound 149, 0.7 g) in DMSO (1.4 ml) was evenly divided into 7 tubes for microwave reactions, and each was irradiated in a microwave reactor at 130 "C for 4 hours. After cooling, the combined mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (1095). The product was purified again by HPLC (C18) to obtain (also, 7p5(K)-5-42-MK1-ethylazetidin- 3-ylmethyl)amino|benzenesulfonylamino)-1 a, 2,76-

tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.012 g) in the form of a grayish-white solid.

NMR NMR (DMSO-α) 6: 7.34 (1H, 49), 7.22 (IN, 9, 7.04 (IN, 9), 6.97 (1H, 4), 6.74 ( 1H, 4), 6.49 (1H,

U), 6.34 (1H, Big 5), 4.10 (1H, 4), 3.75-3.55 (4H, t), 3.18 (IN, Big t), 3.03 (1H , re t), 2.88 (2H, t), 2.32 (IN, t), 1.85 (1H, t), 1.67 (1H, t), 1.19 (IN, t), 0.98 (ZN, U, 0.86 (1H, t), 0.69 (1H, t)

LCMS (Method C), retention time 3.21 (M.N) 457.

Examples 63 and 64: (yes, 7605)-5-(2-((2)-3-Diethylaminoprop-1-enyl)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid and ( av, 7tb)-5-(2-(2)-3-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1Ta, 2,7p0-tetrahydrocyclopropa-|sichromene-4-carboxylic acid

M

ZM

M (in)

N o on (00278) Mixture of methyl pPax, 76B5K)-5-(2-(2)-3-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1,1a,2,7B-tetrahydrocyclopropa|sichromene-4-carboxylate ( Intermediate compound 153, 0.495 g) and lithium hydroxide monohydrate (0.442 g) were suspended in dioxane (20 ml) and water (5 ml), stirred, and the mixture was heated at 80 "C for 12.5 hours. After cooling, the volatiles were removed by oil, and the residue was acidified by adding an aqueous solution of citric acid (10 95) and extracted with DCM. The organic layer was dried (Ma2595) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by preparative

HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 of formic acid, with a gradient of 35-70 90, to obtain akz, 7B5K)-5-(2-(2)-3-diethylaminoprop-1-enyl )benzenesulfonylamino!|-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.147 g) in the form of a white solid.

This material was subjected to chiral separation using a SpigaIRak IS column, 4.6 mm x 250 mm, 5 micron particle size. Solvent for elution: absolute ethanol.

Example 63: First eluted enantiomer: retention time on the above column: 25.71 minutes, e.i. 299 965. (00279| "H NMR (DMSO-av) 6: 7.65 (1H, av), 7.60 (1H, ia), 7.44-7.37 (2H, t), 7.28 (1H, a), 7.08 (IN, a), 6.95 (1H, a), 6.15-6.05 (IN, t), 4.16 (1H, a), 3.77- 3.67 (2H, t), 3.56 (1H, a), 3.13-3.03 (4H, t), 1.90 (IN, 49, 1.71 (1H, 4), 1, 12 (6H, , 0.92 (1H, a, 0.72 (1H, ad).

LCMS (Method C), retention time 3.20 (MAN) 457.

Example 64: Second eluted enantiomer: retention time on the above column 35.51 minutes, e.i. 299 95.

I00280| "H NMR (DMSO-α) 6: 7.65 (1H, aa), 7.60 (1H, 14), 7.43-7.38 (2H, t), 7.28 (1H, a), 7.08 (IN, 9), 6.95 (1H, a), 6.16-6.07 (1H, t), 4.16 (1H, a), 3.77-3.67 (2H, t), 3.56 (IN, a), 3.09 (4Н, о), 1.91 (IN, 49, 1.71 (1Н, 9), 1.12 (6Н, У, 0.93 ( 1H, a, 0.72 (1H, a).

LCMS (Method C), retention time 3.20 (M.N) 457.

Example 65: (Yes, 765E)-5-(2-(IM-((B)-1-Ethylpyrrolidine-2-ylcarbonyl|-M-methylamino-methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7b- Tetrahydrocyclopropa|c|Ichromene-4-carboxylic acid

WITH

(c) 5

M o

N

E (c) on

I00281| A mixture of methyl (chTakz5, 7B6B52E)-5-(2-(M-((B)-1-ethylpyrrolidin-2-yl)/ucarbonyl|-M-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a, 2 ,7B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 155, 0.177 g) and lithium hydroxide monohydrate (0.136 g) in dioxane (5 ml) and water (2 ml) were stirred and heated at 100 C for 19.5 hours. After cooling, the mixture was evaporated to a dry residue, and the residue was acidified by adding an aqueous solution of citric acid (10 95). The resulting solid was collected by filtration, washed with water and dried under vacuum at 40 "C. The solid was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1 95 formic acid, with a gradient of 10-98 9b, to obtain Oiaks, 7B5K)-5-(2-1M-((B)-1-ethylpyrrolidin-2-ylcarbonyl|-M-

methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a2,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.053 g) in the form of a white solid.

IN NMR (DMSO-α) 6: 7.93-7.78 (1N, t), 7.17 (1N, t), 6.99 (0.5N, t), 6.95 (0.5N, a), 6.90-6.76 (1.5N, t), 6.69 (0.5N, aa), 5.02 (1.5N, t), 4.86 (0.5N, ad) , 4.61-4.44 (1H, Bi 5), 4.15 (1H, aa), 3.55 (ZH, t), 3.11 (2H, t), 2.90 (ZH, 25) , 2.06-1.54 (6H, t), 1.18-1.05 (AN, t), 0.84 (1H, t), 0.68 (1H, t).

LCMS (Method C), retention time 3.14 (MAN) 532.

Example 66: (1akz5, 765E)-5-(2-(M-((5)-1-Ethylpyrrolidin-2-yl/ucarbonyl|-M-methylamino-methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2, 7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid

SA

(c) 5

M o

N

E (c) on 00282) Obtained in the same way as Example 65, starting from methyl (T1akz, 7655EK)-5-(2-14-((5)-1-ethylpyrrolidin-2-ylcarbonyl|-M-methylaminomethyl) -4-fluorobenzenesulfonylamino)-11a, 2,7p-tetrahydrocyclopropa(|sichromene-4-carboxylate (Intermediate compound 160), in the form of a white solid.

1H NMR (DMSO-av) 7.94-7.76 (1H, t), 7.18 (IN, t), 7.02-6.92 (1H, t), 6.92-6, 76 (1.5N, t), 6.68 (0.5N, t), 5.02 (1.5N, t), 4.86 (0.5N, aa), 4.65-4.49 ( 1H, Bug 5), 4.15 (1H, aa), 3.55 (ZH, t), 3.14 (2H, t), 2.91 (ZH, 25), 2.07-1.59 ( 6H, t), 1.13 (4H, t), 0.85 (1H, t), 0.68 (1H, t).

LCMS (Method C), retention time 3.15 (M.--N) 532.

Example 67: (1akz, 7065E)-5-(2-(4-Dimethylaminobutylamino)-4-fluorobenzenesulfonylamino|- 11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid tt g o, 50 rya

M (c) lo (00283) Mixture of methyl pPax, 7B5K)-5-(2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino!|-1,1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound) 161, 0.485 g) and lithium hydroxide monohydrate (0.505 g) in dioxane (9 ml) and water (3 ml) were irradiated in a microwave reactor at 130 "C for 45 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated under massio .

The residue was triturated with 20,956 methanol in DCM, filtered, and the filtrate was evaporated on a massio.

The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-20 9o. The resulting solid was triturated with ethyl acetate and filtered to obtain (1 aq, 765K)-5-(2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino!|-1 a, 2,7p-tetrahydrocyclopropa-|c|ichromene-4-carbonate acid (0.215 g) as a white solid.

1H NMR (DMSO-α) 5: 12.52 (2H, Bg, 5), 7.65 (1H, aa), 7.08 (2H, a), 6.56 (1H, aa), 6 .39 (1H, ayu, 5.98 (1H, t), 4.20 (IN, 49), 3.59 (1H, a), 5.22 (2H, 49), 2.98 (2H, t ), 2.75 (6H, 5), 1.91 (1H, t), 1.81 (2H, t), 1.72 (1H, t), 1.58 (2H, t), 0.92 (1H, t), 0.76 (1H, t).

LCMS (Method C), retention time 3.43 (M--H) 478.

Example 68: (Iacz, 7tb5K)-5-42-((A)-1-Ethylpyrrolidin-3-ylmethyl)amino|benzenesulfonylamino)-1,a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid seam: that

ZU

M o

WITH

(c) on (00284) pPax solution, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,7t-tetrahydrocyclopropa-1|sichromene-4-carboxylic acid (Intermediate compound 67, 0.105 g), ((K )-1-ethylpyrrolidin-3-yl)umethylamine (Intermediate compound 163, 0.5 g) and triethylamine (0.5 g) in DMSO (1 ml) were stirred and heated at 140 °C overnight. After cooling, the mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (5 95). The product was purified by HPLC (C18) to give (Takz, 765K)-5-12-I(B)-1-ethylpyrrolidin-3-ylmethyl) amino|benzenesulfonylamino)-1,1a, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.03 g) in the form of a white solid.

1H NMR (DMSO-α) 6: 7.38 (1H, aa), 7.24 (1H, 9, 7.06 (2H, 5), 6.81 (1H, 9), 6.49 ( IN, U, 6.14 (IN,

Be 5), 4.13 (1H, yes), 3.54 (2H, t), 3.25 (2H, t) 3.07 (4H, t), 2.82 (1H, t), 2, 63 (1H, t), 1.96 (1H, t), 1.86 (1H, t), 1.71-1.46 (2H, t), 1.19 (ЗН, t), 0.87 (1H, t), 0.70 (1H, t).

LCMS (Method C), retention time 3.31 (MAN) 472.

Example 69. of

OO what zu

M o

Cl (c) on (002851 Solution of pPax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76- tetrahydrocyclopropa-IsIchromene-4-carboxylic acid (Intermediate compound 67, 0.08 g) and ((5 )-1-ethylpyrrolidin-3-yl)umethylamine (Intermediate compound 169, 0.8 g) in DMSO (0.2 ml) was stirred and heated at 120 "C for 24 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to obtain (Takz, 765K)-5-12-

1(5)-1-ethylpyrrolidin-3-ylmethyl)iamino|1benzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.03 g) as a white solid.

1H NMR (DMSO-dv) 5: 7.37 (1H, aa), 7.24 (1H, 9, 7.05 (2H, 5), 6.80 (IN, 4), 6.48 ( IN, 9, 6.13 (1H, 20. Run 5), 4.13 (1H, aa), 3.54 (2H, t), 3.24 (2H, t), 3.05 (4H, t ), 2.82 (1H, t), 2.62 (IN, t), 1.95 (IN, t), 1.85 (1H, t), 1.71-1.46 (2H, t) , 1.18 (ZH, t), 0.86 (1Н, t), 0.69 (1Н, t).

LCMS (Method C), retention time 3.25 (M.--N) 472.

Example 70: pPax, 7B5K)-5-(2-(4-Ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid sh- k or o Ov o "M (v

N

E (c) on (00286) Mixture of methyl Pakzv, 7tb5K)-5-(2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,71B-tetrahydrocyclopropa| Cychromene-4-carboxylate (Intermediate compound 173, 0.28 g) and lithium hydroxide monohydrate (0.126 g) in dioxane (9 ml) and water (3 ml) were irradiated in a microwave reactor at 130 "C for 30 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid, and evaporated in vacuo.

The residue was triturated with 20,956 methanol in DCM, filtered, and the filtrate was evaporated on a massio.

The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-20 95. The resulting solid was triturated with ether and filtered to obtain Pakzv, 7B5K)-5-(2-(4-ethyl-2-oxo-piperazine-1- ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,7B-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid (0.176 g) as a white solid.

1H NMR (SOSI) 6: 11.28 (1H, Bg, 5), 8.02 (1H, aa), 7.31 (1H, 49), 7.23 (1H, 4), 6, 98 (2H, t), 4.98 (2H, 4), 4.57 (IN, 9), 4.04 (1H, a), 3.36 (2H, U, 3.30 (2H, 5) , 2.72 (2H, U, 2.51 (2H, 9), 1.96 (IN, t), 1.80 (1H, t), 1.11 (4H, t), 1.03 (1H , t).

LCMS (Method C), retention time 2.96 (MAN) 504.

Example 71: (chTak5, 705K)-5-(2-(1-Ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino|- 11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid ah

ZM

M o

N

E (c) one (00287) Methyl OPax, 76B5K)-5-(2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a, 2,71p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 177, 0.279 g) and lithium hydroxide monohydrate (0.233 g) were suspended in dioxane (7 mL) and water (3 mL) and stirred, and the mixture was heated at 80 °C for 25 h. Additional lithium hydroxide monohydrate ( . to a dry residue, and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1 96 formic acid, with a gradient of 10-98 956, to obtain (tan, 7658)-5-(2-(1 -ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino!|-1 Ta, 2,716- tetrahydrocyclopropa|sichromene-4-carbon acid (0.117 g) as a white solid.

NMR NMR (DMSO-dv) 6: 7.99 (1H, aa), 7.22-7.14 (2H, t), 6.99 (IN, a), 6.76 (IN, 4) , 4.20 (IN, da), 3.60 (1H, a), 3.34 (2H, a), 3.02-2.88 (4H, t), 2.71 (2H, re 5) . , ), 0.89 (IN, а, 0.73 (1Н, а).

LCMS (Method C), retention time 3.22 (M.--H) 489.

Example 72: (Tak5, 7652K)-5-12-(2-(1-Ethylazetidin-3-yl)ethyl|-4-fluorobenzenesulfonylamino)-11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid

WITH

ZK

M (in)

N

E oon (002881 Mixture of methyl pPax, 76B58)-5-12-(2-(1-ethylazetidin-3-yl)ethyl/-4-fluorobenzenesulfonylamino)-1a, 2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate ( Intermediate compound 183, 0.306 g) and lithium hydroxide monohydrate (0.421 g) in dioxane (7.5 ml) and water (2.5 ml) were irradiated in a microwave reactor at 130 "C for 45 minutes. After cooling, the mixture was diluted with methanol, acidified formic acid and evaporated ip massio.

The residue was triturated with 20,956 methanol in DCM, filtered, and the filtrate was evaporated on a massio.

The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-30 95. The resulting solid was triturated with ether and filtered to obtain (Yes, 7651E)-5-22-(2-(1-ethylazetidin-3-yl) /ethyl|-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.241 g) as a white solid.

1N NMR (DMSO-α) 6: 7.92 (1H, Og, 5), 7.35 (1H, av), 7.22 (1H, ayu, 7.17 (1H, a), 6.78 ( 1H, Bkg, 5), 4.27 (1H, 49), 4.05 (2H, t), 3.78 (2H, rg, 5), 3.70 (1H, a), 3.17 (2H , a), 2.86 (2H, B, 5), 2.70 (1H, Bk, 5), 1.95 (1H, t), 1.84 (2H, t), 1.75 (1H, t), 1.11 (ZH, U), 0.98 (1H, t), 0.76 (1H, t).

LCMS (Method C), retention time 3.36 (M--H) 475.

Example 13: pPax, 7B5K)-5-2-(5)-1-Azabicyclo|2.2.2|oct-3-yl)amino|benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|siIchromene-4-carboxylic acid more

ZU

M o s (c) on

(002891 pPax solution, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa-1|sichromene-4-carboxylic acid (Intermediate compound 67, 0.6 g) and (5)-1- azabicyclo|2.2.2|oct-Z-ylamine (6.0 g) in DMSO (b ml) was stirred and heated in a closed vessel at 140 "C for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to obtain (Takz, 765K)-5-12-

I(5)-1-azabicyclo(|2.2.2|oct-3-yl)amino|1benzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.107 g) as a white solid.

1H NMR (DMSO-av) 5: 7.58 (1H, dav), 7.25 (1H, 9, 6.94 (1H, aa), 6.76 (2H, 9, 6.62 (2H , t), 6.06 (1H, a), 4.14 (IN, U, 3.86 (1H, run 5), 3.57 (ZH, t), 3.16-2.87 (4H, t), 2.12 (IN, t), 2.01 (1Н, t), 1.682 (ЗН, t), 1.65 (2Н, t), 0.83 (1Н, t), 0.67 ( 1H, t).

LCMS (Method C), retention time 3.16 (M-А-Н) 470).

Example 74: (Iakzv, 7b5K)-5-2-((B)-1-Azabicyclo|2.2.2|oct-3-yl)amino|benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|siIchromene-4- carboxylic acid

BY

M o s (c) on

I00290| Obtained in the same way as Example 73, starting from (yes, 7rzkK)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7Bb-tetrahydrocyclopropa-|sichromene-4-carboxylic acid (Intermediate compound 67) and (K )-1-azabicyclo|2.2.2|oct-3-ylamine.

1H NMR (DMSO-av) 5: 7.58 (1H, dav), 7.25 (1H, 9, 6.94 (1H, aa), 6.76 (2H, 9, 6.62 (2H . 2.12 (1Н, t), 2.01 (IN, t), 1.83 (ЗН, t), 1.64 (2Н, t), 0.83 (IN, t), 0.67 (1Н , t).

LCMS (Method C), retention time 3.15 (M.N) 470

Example 15: OPax, 76B5K)-5-(2-C1(5)-1-Ethylpyrrolidine-3-carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1,Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4- carboxylic acid le M

Her oyu (in) 5

M o

N

E (c) on (002911 Methyl Pakzv, 76b5K)-5-(2-14(5)-1-ethylpyrrolidine-3-carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1a, 2,71p-tetrahydrocyclopropa| Cychromene-4-carboxylate (Intermediate 188, 0.190 g) and lithium hydroxide monohydrate (0.150 g) were suspended in dioxane (5 mL) and water (5 mL) and stirred, and the mixture was heated at 100 °C for 18.5 hours. After cooling, the volatiles were removed by mass, and the residue was acidified by adding aqueous citric acid (10 95) and extracted with DCM. The organic layer was dried (Ma2595054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by preparative

HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 25-60 9b, to obtain akz, 76b5K)-5-(2-14(5)-1-ethylpyrrolidine-3- carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1,1a,2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.092 g) as a white solid.

1H NMR (DMSO-dv) 6: 8.78 (1H, a), 7.89-7.82 (1H, t), 7.19 (IN, 19), 7.12 (1H, a) , 7.02 (1H, aa), 6.75 (1H, aa), 4.74 (2H, ad), 4.19 (IN, 49), 3.62 (1H, ayu, 3.50-3 .15 (5H, t), 3.10 (2H, a), 2.35-2.23 (1H, t), 2.10-1.99 (1H, t), 1.86 (1H, au , 1.75-1.67 (1H, t), 1.20 (ZH, ), 0.90 (1H, a), 0.73 (IN, d)

LCMS (Method C), retention time 3.01 (MAN) 518

Example 16: pPax, 76B5K)-5-12-(2-(H)-1-Ethylpyrrolidin-3-ylamino)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid -Och n x i "M (in)

N

Well, it's a dream

(00292 Pakz solution, 7t5K)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a, :2,70B- tetrahydrocyclopropa|sichromene-4-carboxylic acid (Intermediate compound 74, 0.150 g) and (K)- 1-ethylpyrrolidin-3-ylamine (Intermediate compound 193, 0.25 g) in ethylene glycol (1 ml) was irradiated in a microwave reactor at 200 "С for 30 minutes. After cooling, the mixture was diluted with water and loaded onto a 5СХ-2 5РЕ cartridge, then washed with water, methanol, and 2 M ammonia in methanol. The alkaline fractions were combined and evaporated to a dry residue. The residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.19% ammonia with a gradient of 10-98 95. Then it was further purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 10-60 95, to obtain (tav, /7658)-5-2-(2-( B8)-1-ethylpyrrolidine-3-ylamino)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.005 g) as a white solid.

IN NMR (SOSI") 6: 7.86 (1H, ad), 7.43 (1H, ad), 7.31 (1H, ayu, 7.27 (1H, a), 6.59 (T1H, a ), 4.31 (IN, 9), 4.18-3.97 (1.5Н, Bi), 3.82-3.64 (1.5Н, Bi), 3.79 (1Н, а), 3.33-3.20 (8H, bi), 2.931 (1H, Bug 5), 2.04 (IN, t), 1.84 (IN, a), 1.26 (4H, U), 1, 07 (IN, t), 0.86 (1Н, ad).

LCMS (Method C), retention time 2.60 (М--Н) 503.9

Example 77: (Also, 7655E)-5-2-((B)-1-Ethylpyrrolidin-3-yl)amino|1benzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

AND

Kaya to

ZU

M o

Compound (00293) Solution pPax, 7B5K)-5-(2-Fluorobenzenesulfonylamino)-1Ta, 2,7t-tetrahydrocyclopropa-1|sichromene-4-carboxylic acid (Intermediate compound 67, 0.13 g) and (K )-1-ethylpyrrolidin-3-ylamine (Intermediate compound 193, 1.22 g) in DMSO (0.7 ml) was stirred and heated in a closed vessel at 120 "C for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum The residue was purified by HPLC (C18) to obtain (1anz, 25.7b5i8)-5-(2-I(((5)-1-ethylpyrrolidin-3-yl)uamino|1benzenesulfonylamino)-1, a, 2.76- tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.107 g) as a white solid.

IN NMR (DMSO-α) 5: 7.32 (2H, t), 7.04 (IN, 4), 6.98 (IN, t), 6.72 (IN, a), 6.60 (1Н . , t), 3.18-2.94 (AN, t), 2.54 (IN, t), 1.86 (2Н, t), 1.66 (1Н, t), 1.22 (ЗН, Y), 0.86 (IN, t), 0.68 (1Н, t).

LCMS (Method C), retention time 3.40 (M--H) 458.

Example 78: (Tan, 7065H8)-5-2-((5)-1-Ethylpyrrolidin-3-yl)uamino|1benzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid m

Kaya to

ZU

M o

Sl og on

I00294| Obtained in the same way as Example 77, starting from (yes, 7rzK)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa-|c|ichromene-4-carboxylic acid (Intermediate compound 67) and (5)-1-ethylpyrrolidin-3-ylamine (Intermediate compound 194).

IN NMR (DMSO-α) 5: 7.32 (2H, t), 7.05 (1H, 4), 6.98 (IN, t), 6.72 (IN, a), 6.60 (1H , 9, 5.54 (IN, Big 5), 4.20 (IN, re 5), 4.11 (IN, 9, 3.680 (1H, Bug 5), 3.69-3.48 (2H, t ), 3.19-2.96 (AN, t), 2.56 (IN, t), 1.86 (2Н, t), 1.66 (1Н, t), 1.22 (ЗН, У) , 0.687 (IN, t), 0.68 (1Н, t).

LCMS (Method C), retention time 3.40 (M--H) 458.

Example 19: pPax, 76B5K)-5-(2-C(B)-1-Ethylpyrrolidin-3-ylcarbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1,Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4- carboxylic acid

/ WHAT; 0,, (c) 5

M o

N

E (c) on 00295) Mixture of methyl (Takz, 765K)-5-(2-C(B)-1-ethylpyrrolidin-3-ylcarbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1 a, 2,71B- Tetrahydrocyclopropa|c|Ichromene-4-carboxylate (Intermediate compound 195, 0.215 g) and lithium hydroxide monohydrate (0.170 g) were suspended in dioxane (5 mL) and water (5 mL) and stirred, and the mixture was heated at 80 "C for 21 hours. The temperature was raised to 100 "C and stirred, and the mixture was heated at this temperature for 2.5 hours.

An additional amount of lithium hydroxide monohydrate (0.05 g) was added and stirred, and the mixture was heated at 100 °C for 2 hours. After cooling, the volatiles were removed by massio, and the residue was acidified by adding aqueous citric acid (10 95) and extracted with DCM.

The organic layer was dried (Ma259054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 25-60 9o, to obtain (Takz, 765K)-5-(2- C(H)-1-ethylpyrrolidin-3-ylcarbonyl)-amino|methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.103 g) as a white solid.

1H NMR (DMSO-dv) 6: 8.78 (1H, a), 7.89-7.83 (IN, t), 7.18 (IN, 19), 7.11 (1H, a) , 7.01 (1H, ad), 6.76 (1H, aa), 4.74 (2H, 0), 4.19 (IN, 49), 3.61 (1H, ayu, 3.46-3 .12 (5H, t), 3.07 (2H, a), 2.34-2.22 1H, t), 2.10-1.98 (T1H, t), 1.86 (IN, 4) , 1.70 (1H, 4), 1.19 (ZH, )), 0.90 (IN, a, 0.73 (1H, a).

LCMS (Method C), retention time 3.04 (M.N) 518.

Example 80: (Tan, 7B5HA)B-(2-(2)-3-Diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carbon acid that 05 70 r:

M (in)

N

Oh, he

I00296| A mixture of methyl (Takv5, 7p54m4)-5-1M-(2-(2)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonyl|-M-methoxycarbonylamino|-1,1a, 2,7p- Tetrahydrocyclopropa-isochromene-4-carboxylate (Intermediate compound 200, 0.264 g) and lithium hydroxide monohydrate (0.505 g) in dioxane (9 ml) and water (3 ml) were irradiated in a microwave reactor at 130 "C for 40 minutes.

After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated with oil, then distilled by azeotropic distillation with a mixture of ethanol and toluene. The residue was triturated with 1595 methanol in DCM, filtered, and the filtrate was evaporated to mass. The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-40 95.

The resulting solid was triturated with ether and filtered to give (Takz, 7p5K)-5-(2-(2)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino|-1 and, 2,76- tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.202 g) as a white solid.

1H NMR (DMSO-α) 6: 7.95 (1H, ad), 7.28 (1H, au, 7.14 (1H, aa), 7.06 (1H, 49), 6.92 ( 1H, 5), 6.64 (IN, 94), 4.25 (IN, a), 3.64 (1H, 9), 3.36 (2H, b, 5), 2.63 (4H, a ), 1.96 (ZH, 5), 1.90 (1H, t), 1.74 (IN, t), 0.93 (1H, t), 0.86 (6H, 5), 0.75 (1H, t).

LCMS (Method C), retention time 3.27 (M.N) 489

Example 81: (Iakz, 70b5K)-5-2-(2-(H)-1-Ethylpyrrolidin-3-yl)/'ethylamino|benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid

CA

MN 9.0

ZM

M 6) c (00297 | Mixture pPax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa-IsIchromene-4-carboxylic acid (Intermediate compound 67, 0.2 g) and 2-( (8)-1-Ethylpyrrolidin-3-yl)ethylamine (Intermediate 203, 2.0 g) in DMSO (2 mL) was divided between two sealed tubes, and each was stirred and heated at 130 °C for 24 h. After cooling the combined mixture was diluted with methanol and then concentrated under vacuum.

The residue was purified by HPLC (C18) to obtain (Takz, 7p05H8)-5-(22-(2-(HA)-1-ethylpyrrolidin-3-yl)ethylamino|-benzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa| c|Yichromene-4-carboxylic acid (0.125 g) in the form of a white solid.

1H NMR (DMSO-α) 6: 7.62 (1H, ayu, 7.29 (1H, ayu, 7.02 (2H, 25), 6.70 (1H, 9), 6.58 (1H , 9, 5.84 (IN, g t), 4.14 (1Н, 9), 3.54 (1Н, ad), 3.936 (1Н t), 3.18 (ЗН, t), 3.06 ( 4H, t), 2.59 (1H, t), 2.01 (1H, t), 1.83 (1H, t), 1.80-1.49 (4H, t), 1.19 (ЗН , 94), 0.85 (1H, t), 0.69 (1H, t).

LCMS (Method C), retention time 3.35 (M--H) 486.

Example 82: (Iakzv, 7tb5K)-5-(2-(2-((5)-1-Ethylpyrrolidin-3-yl)/'ethylamino|benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|c|Ichromene- 4-carboxylic acid

M.

Kk Although oo to

M//

BY

M (c) s o on

I00298| Obtained in the same way as Example 58, starting from (yes, 7rzK)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa-|c|ichromene-4-carboxylic acid (Intermediate compound 67) and 2-((5)-1-ethylpyrrolidin-3-yl)ethylamine (Intermediate compound 208).

1H NMR (DMSO-α) 6: 7.62 (1H, ayu, 7.29 (1H, ayu, 7.02 (2H, 25), 6.70 (1H, 9), 6.57 (IN , 9, 5.84 (IN, g t), 4.14 (1H, 9), 3.54 (1H, ad), 3.96 (1H t), 3.17 (ZH, t), 3, 06 (4H, t), 2.57 (1H, t), 2.01 (1H, t), 1.83 (1H, t), 1.80-1.49 (4H, t), 1.19 (ZH, 4), 0.85 (IN, t), 0.68 (1H, t).

LCMS (Method C), retention time 3.34 (M--H) 486.

Example 83: Pak, 765)-5-(2-((5)-1-Ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid o: N o ho en

O5e2o "M (c)

N

E o7 ton (00299) Mixture of methyl Pak, 765)-5-(2-(5)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1 a, 2,71B-tetrahydrocyclopropa|c|Ichromene- 4-carboxylate (Intermediate compound 213, 0.217 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 ml) and water (1 ml) were irradiated in a microwave reactor at 130 "C for 40 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated to mass, and distilled by azeotropic distillation with a mixture of toluene and ethanol. The residue was triturated with 15 95 methanol in DCM, filtered, and the filtrate was evaporated to mass. The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-20 95. The resulting solid was triturated with ether and ethyl acetate and filtered to give (1ac, 765)-5-(2-((5)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1 and, 2 ,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.136 g) in the form of a white solid.

IN NMR (SOSI") 6: 7.35 (1H, ad), 7.23 (1H, a), 7.19 (1H, aa), 7.01 (1H, a), 6.83 (1H, a, 4.87 (1H,

Be, a), 4.73 (1H, Bg, a), 4.36 (2H, horn, t), 4.19 (1H, ad), 3.88 (1H, t), 3.84 (IN , a), 3.38 (IN, t), 2.94 (IN, t), 2.86 (1Н, t), 2.75 (1Н, t), 2.26-2.45 (2Н, t), 1.81 (IN, t), 1.60 (1TN, t), 1.39 (ЗН, и), 0.90 (СН, t).

LCMS (Method C), retention time 3.25 (M--H) 491

Example 84: Pak, 765)-5-(2-(A)-1-Ethylpyrrolidine-3Z-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid ho en

Oze2o "M (c)

N

E 7 ton 00300) Obtained in the same way as Example 83, starting from methyl (yes, 765)-5-(2-(8)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1 And, 2,7-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 217).

1H NMR (DMSO-α) 5: 7.83 (1H, aa), 7.44 (1H, aa), 7.20 (1H, ayu, 7.07 (1H, a), 7.03 ( 1H, a), 4.99 (IN, a), 4.49 (2H, ad), 4.19 (2H, a), 3.57 (2H, a), 2.93-3.30 (4H , t), 2.34 (1Н, t), 2.13 (IN, t), 1.88 (IN, t), 1.72 (1Н, t), 1.29 (ЗН, У), 0 .92 (IN, t), 0.75 (1Н, t).

LCMS (Method C), retention time 3.25 (M.N) 491.

Example 85: (yes, 765) -5-(2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino|- 11a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylic acid

M o, ro,

ZU

M o

N

E (c) on

Mixture of Methyl Pak, 7B5)-5-(2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,71B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 221, 0.071 g) and lithium hydroxide monohydrate (0.059 g) were suspended in dioxane (5 mL) and water (2 mL) and stirred, and the mixture was heated at 100 °C for 25 hours. Additional lithium hydroxide monohydrate (0.116 g) was added and heated the mixture at 100 "C for another 18 hours. After cooling, the volatiles were removed by massio, and the residue was acidified by adding an aqueous solution of citric acid (1095) and saturated with sodium chloride. The mixture was extracted with DCM, and the organic layer was dried (Ma25054) and filtered. The filtrate was evaporated to dryness of the residue, and the residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 25-60 95, to obtain

Pan, 765)-5-(2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1 a, 2,76-tetrahydrocyclopropa-|sichromene-4-carboxylic acid (0.032 g) in the form of a white solid substances

1N NMR (DMSO-α) 6: 8.01-7.91 (1H, t), 7.26-7.18 (2H, t), 7.10-7.00 (2H, t), 4.22-4.17 (1H, t), 3.61 (1H, a), 3.45-2.92 (5H, t), 3.02-2.88 (4H, t), 1, 94-1.85 (1H, t), 1.80-1.65 (ZH, t), 1.65-1.50 (IN, t), 1.30-1.14 (4H, t), 0.97-0.87 (1H, t), 0.77-0.68 (1H, t).

LCMS (Method C), retention time 3.21 (M--H) 489.

Example 86: Pak, 765)-5-4(2-(2-(8)-1-Ethylpyrrolidin-2-yl)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIichromene-4- carboxylic acid! N,,

MU school

ZM

M 6)

N

E (6) on

I00302| Lithium hydroxide (0.22 g) was added to a solution of methyl (Yes, 7B65)-5-12-(2-((8)-1-ethylpyrrolidin-2-yl)ethyl|-A-fluorobenzenesulfonylamino)-1 a, 2 ,7p-tetrahydrocyclopropa-

Isochromene-4-carboxylate (Intermediate compound 229, 0.26 g) in a mixture of dioxane (12 ml) and water (4 ml) and irradiated the mixture in a microwave reactor at 150 C for 20 minutes. After cooling, the mixture was evaporated to a dry residue, and the residue was acidified by adding 10 95 aqueous citric acid (3 ml), and then extracted with DCM. The organic layer was dried (Mo95054) and filtered, and the filtrate was evaporated to a dry residue. The residue was purified by preparative

HPLC (C18), eluting with a mixture of acetonitrile and water containing 0.1 96 formic acid, with a gradient of 25-3590, to obtain (yes, 7p5)-5-(2-(2-(H8)-1-ethylpyrrolidine- 2-yl)ethyl|/|-4-fluorobenzenesulfonylamino)-1,Ta, 2,7p-tetrahydrocyclopropa-|c|Ichromene-4-carboxylic acid

(0.11 g) as a white solid.

1H NMR (DMSO-dv) 6: 7.88 (1H, ad), 7.33 (1H, av), 7.15 (1H, ayu, 7.08 (1H, 4), 6.98 ( 1H, a), 4.18 (IN, 9), 3.68 (IN, rg t), 3.58 (1H, a), 3.56 (1H, t), 3.22-2.96 ( BN, t), 2.23 (1H, t), 2.03 (4H, t), 1.687 (2H, t), 1.72 (1H, 9), 1.91 (ЗН, У, 0.91 (1H, t), 0.72 (1H, ad).

LCMS (Method C), retention time 3.24 (M--H) 489.

Intermediate compound 1: methyl cis-(Zane, 9685)-7-(benzenesulfonylamino)-1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-6b-carboxylate

N c) x te, entry

M. a

S atcho

A mixture of cis-enantiomers

ИОО30О3| Formic acid (5 mL) was added to methyl cis-(Zane, 9BA5)-7-|bis-(tert-butoxycarbonyl)amino|-1,3a,4,9Bb-tetrahydro-2H-furo|2,3-sichromene- 6-carboxylate (Intermediate compound 2, 0.15 g) and stirred the mixture at room temperature for 1 hour. The resulting mixture was evaporated to a dry residue, and the residue was redissolved in toluene and evaporated to a dry residue three times. The residue was dissolved in DCM (2 mL) and pyridine (1 mL) was added, followed by benzenesulfonyl chloride (0.07 g). The resulting mixture was stirred at room temperature for 90 minutes, then diluted with DCM and washed with sodium hydroxide (1 M) and saturated saline. The sodium hydroxide washing solution was saturated with salt, and then extracted with ethyl acetate, dried (M95O4) and filtered. The filtrate was evaporated to a dry residue to give methyl cis-(Zanv, 9B5A85)-7-(benzenesulfonylamino)-1,3a,4,9p-tetrahydro-2H-furo(2,3-sichromene-6b-carboxylate) (0.082 g) in in the form of a resinous substance. 00304 "H NMR (SOSI") 0: 7.73 (2H, av), 7.53 (1H, 9, 7.42 (2H, 9, 7.25 (1H, 49), 7, 21 (IN, a), 4.29 (IN, t), 4.03 (IN, aa), 3.93 (1H, aa), 3.682 (2H, U, 3.70 (ZH, 5), 3 .45 (1H, t), 2.48 (IN, t), 1.87 (1H, t).

Intermediate compound 2: methyl cis-(Zanv, 9085)-7-Ibis-(tert-butoxycarbonyl)amino!|-1,Za, 4,9p-tetrahydro-2H-furo|2,3-s|Ychromene-6b- carboxylate nH c)

This is moss

Vos ota

A mixture of cis-enantiomers (0OZO5i Methyl solution / 7-Ibis-(tert-butoxycarbonyl)amino|-4H-furo|2,3-si|ichromene-b-carboxylate (Intermediate compound 3, 0.15 g) in a mixture of dioxane ( 15 mL) and acetic acid (1.5 mL) were treated under nitrogen with palladium on carbon (10 95 , 0.02 g). The mixture was stirred, and the nitrogen was replaced with hydrogen, then the mixture was stirred under hydrogen for 3 hours. The mixture was filtered through Celite, the precipitate on the filter were thoroughly washed with dioxane, and the filtrate was evaporated to a dry residue to obtain methyl cis-(Zanz, 9085)-7-|bis-(tert-butoxycarbonyl)amino|- 1,3a, 4,9B-tetrahydro-2H -furo|2,3-sichromene-b6-carboxylate (0.15 g) in the form of a resinous substance.

I00306| "H NMR (SOSI") b: 7.22 (1H, aa), 6.80 (1H, a), 4.96 (1H, t), 4.07 (2H, 4), 3.86 (2H , U, 3.84 (ZH, 5), 3.53 (1H, t), 2.50 (1H, t), 1.94 (IN, t), 1.40 (18H, 5).

Intermediate compound 3: methyl 7-bis-(tert-butoxycarbonyl)amino|-4H-furo|2,3-c|ichromene-6-carboxylate;

Vos,

M in);

Vos" o o

I00307| Carbon tetrabromide (2.66 g) was added to a solution of methyl 6-1|bis-(tert-butoxycarbonyl)amino|-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)-benzoate (Intermediate 4, 2, 65 g) and triphenylphosphine (2.1 g) in DCM (40 ml), and the resulting solution was stirred at room temperature for 1 hour. The mixture was evaporated to a dry residue, and DMF (60 mL) and cesium carbonate (5.59 g) were added to the residue. The resulting mixture was stirred for 1 hour, then partitioned between ethyl acetate and water. The organic layer was separated, dried (Ma25954) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25 965, to give methyl 7-Ibis-(tert-butoxycarbonyl)amino|-4H-furo|2,3-siIchromene- b6-carboxylate (0.735 g) in the form of a resinous substance, which crystallized upon standing. 00308) "H NMR (SOSI") 0: 7.45 (1H, t), 7.26 (1H, 5), 6.79 (IN, a), 6.65 (IN, a), 5.44 (2H, 5), 3.67 (ZH, 5), 1.42 (18H, 5).

Intermediate 4: methyl 6-bis-(tert-butoxycarbonyl)amino|-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)benzoate with GF)bosome on Ton

Vos" c) IF)

I00309| 1 M aqueous sodium hydroxide solution (50 mL) was added to a solution of methyl 6-bis-(tert-butoxycarbonyl)amino|-3-(2-hydroxymethylfuran-3-yl)-2-(4-methylbenzenesulfonyloxy)benzoate (Intermediate 5 , 3.82 g) in methanol (100 ml) and stirred, and the mixture was heated at 45 "C for 1.5 hours. The mixture was evaporated to a dry residue, and the residue was dissolved in ethyl acetate and acidified with acetic acid. The organic layer was separated, dried ( Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-50 95, to give methyl 6-Bis-(tert-butoxycarbonyl)amino|-2-hydroxy-3 -(2-hydroxymethylfuran)-3-yl)benzoate (2.65 g) in the form of a white foamy substance.

I00Z310| "H NMR (SOSI") b: 11.91 (1Н, 5), 7.50 (2Н, т), 6.80 (1ТН, 49), 6.57 (1Н, 4), 4.58 (2Н , 5), 3.97 (ZH, 5), 1.43 (18H, 5).

Intermediate 5: methyl 6-|bis-(tert-butoxycarbonyl)amino|-3-(2-hydroxymethyl-furan-3-yl)-2-(4-methylbenzenesulfonyloxy)benzoate 0);

Her

Vos and m o-8520

Vos 0) o / )

ИЙОО311| Sodium borohydride (0.304 g) was added to a solution of methyl 6-|bis-(tert-butoxycarbonyl)amino|-3-(2-formylfuran-3-yl)-2-(4-methylbenzenesulfonyloxy)-benzoate (Intermediate 6, 3 .9 g) in ethanol (50 ml) and the mixture was stirred for 15 minutes. The mixture was evaporated to a dry residue and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue to give methyl 6-bis-(tert-butoxycarbonyl)amino|-3-(2-hydroxymethylfuran-3-yl)-2-(4-methylbenzenesulfonyloxy)benzoate (3.82 g) as a white solid substances

I00312| "H NMR (SOS Z") 0: 7.40 (1H, a), 7.38 (2H, a), 7.30 (1H, a), 7.18 (1H, 49), 7.11 ( 2H, a), 6.28 (IN, a), 4.33 (2H, 5), 3.82 (ЗН, 5), 2.40 (ЗН, 5), 1.42 (18Н, 5).

Intermediate 6: methyl 6-|bis-(tert-butoxycarbonyl)amino|-3--2-formylfuran-3-yl)-2-(4- methylbenzenesulfonyloxy)benzoate

AND)

N ! o and o in TSI schu 0-20

Vos 0) Fr

IІ00313| Triethylamine (0.848 g) was added to a stirred solution of methyl b-amino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (Intermediate 7, 1.72 g), 4-methylbenzenesulfonyl chloride (1.25 g) and LOBSTER (0.804 g) in DCM (30 mL), and the resulting mixture was stirred for 1 hour. The mixture was diluted with water, and the organic layer was separated, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was dissolved in acetonitrile (30 mL) and UMAP (0.804 g) and di-tert-butyl dicarbonate (3.16 g) were added. The mixture was stirred for 2 hours, then diluted with ethyl acetate and water. The organic layer was separated, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-5095, to give methyl 6-Ibis-(tert-butoxycarbonyl)amino|-3-(2-formylfuran-3-yl) -2-(4-methylbenzenesulfonyloxy)-benzoate (3.91 g) in the form of a white foamy substance. 00314 "H NMR (SOCI") 6: 9.13 (1H, 4), 7.54 (1H, aa), 7.38 (1H, a), 7.31 (2H, a), 7.23 ( IN, a), 7.05 (2Н, а), 6.75 (1Н, а), 3.94 (ЗН, 5), 2.37 (ЗН, 5), 1.45 (18Н, 5).

Intermediate compound 7: methyl b-amino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate c)

N ; oh and

NM on

AI

00315) Mixture of methyl b-amino-3-bromo-2-hydroxybenzoate (obtained according to the publication

Umapa ei ai, Viosogda Med Spet I ei, 1 2007, 17, 2817; 1.84 g), pinacol ether 2-formylfuran-3-boronic acid (1.99 g), trit-tert-butylphosphonium tetrafluoroborate (0.218 g), cesium carbonate (7.33 g) and tris-(dibenzylideneacetone)dipalladium ( . .

The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-50 96, to obtain methyl 6-amino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (1, 72 g) in the form of a yellow solid. This material was used without further characterization.

Intermediate 8: 7-(2-(2)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-4H-furo(2,3-sichromene-6b-carboxylic acid

M lo r; in zu

M 6)

N

E (6) on (00316) Methyl 7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-4H-furo|(2,3-sichromene-6-carboxylate (Intermediate compound 9 , 0.129 g) was added to a solution of lithium hydroxide monohydrate (0.42 g) in water (2 ml) and dioxane (8 ml), and the mixture was irradiated in a microwave reactor at 130 "C for 1 hour. After cooling, the mixture was acidified with formic acid and evaporated to a dry residue. The residue was triturated with 1095 methanol in DCM, filtered, and the filtrate was evaporated to a dry residue. The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-10 95. The isolated product was triturated with ethyl acetate, and the solid was collected by filtration and dried in oil to obtain 7-(2- ((2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-4H-furo|2,3-c|chromene-6-carboxylic acid (0.056 g ) in the form of a white solid.

Y00317| "H NMR (DMSO-α) 6: 7.71 (1H, a), 7.68 (1H, 4), 7.38 (1H, 4), 7.28 (1H, ad), 7.26- 7.19 (2H, t), 7.02 (1H, 9), 6.686 (1H, a), 6.20-6.11 (1H, t), 5.28 (2H, 5), 3.79 (2H, a), 3.12 (4H, 9), 1.14 (6H, U. (00318) LCMS (Method C), retention time 3.48 (M.H) 501.

Intermediate compound 9: methyl 1-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-4H-furo|2,3-c|Ichromene-b-carboxylate d. more;

And r. vi

Ex

M 6)

N

E (6) 6)

Y00319| Mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo|2,3-c|Ichromene-6-carboxylate (Intermediate compound 10, 2.04 g), M, M-diethyl-M-(2 )-1-tributylstananylprop-1-en-3-yl)amine (Intermediate compound 11, 3.4 g), tri-tert-butylphosphonium tetrafluoroborate (0.246 g), tris-(dibenzylideneacetone)dipalladium (0.0.388 g) in dioxane (35 ml) was degassed and purged with argon, then heated at 100 "C for 3.5 hours. After cooling, the mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ammonia in methanol (2 M) and DCM with a gradient of 0-10 96. The product was triturated with ether, and the solid was collected by filtration to give methyl 7-(2-((2)-3-diethylaminoprop-1- en-1-yl)/-4-fluorobenzenesulfonylamino|-4H-furo(2,3-sichromene-b-carboxylate (1.47 g) in the form of a pale orange solid.

I00Z320| "H NMR (SOSI") 6: 8.06 (1H, aa), 7.40 (1H, t), 7.17 (1H, 4), 7.14-6.98 (2H, t), 7 ,0-6.9 (2H, t), 6.56 (IN, a), 6.06 (1H, t), 5.37 (2H, 5), 3.687 (ЗН, 5), 3.17 ( 2H, t), 2.55 (4H, t), 0.97 (6H, 1).

Intermediate compound 10: methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo|2,3-sichromene-6-carboxylate «o)

Vg o, vi zu

M in); Oh

E (c) o

IІ00321| Methyl 717-Ibis-(tert-butoxycarbonyl)amino|-4H-furo|2,3-sichromene-6-carboxylate (Intermediate 3, 2.66 g) was dissolved in formic acid (50 mL) and the mixture was stirred at room temperature within 90 minutes. The mixture was evaporated to a dry residue, and the crude residue was partitioned between ethyl acetate and aqueous potassium carbonate (10 95). The organic layer was separated, dried (М95О054) and filtered. The filtrate was evaporated to a dry residue, and the residue was dissolved in DCM (20 mL) and pyridine (10 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (1.95 g) was added. The resulting mixture was stirred for 3.5 hours, then evaporated to a dry residue. The residue was dissolved in DCM, washed with water and filtered through a phase separator. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60 95, to obtain methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo|2,3-s| Ichromene-6-carboxylate (0.47 g) as a pale yellow solid. (003221 "H NMR (SOSI") 6: 9.25 (1H, Bg 5), 8.14 (1H, aa), 7.40 (2H, t), 7.16 (2H, t), 7, 12 (1H, t), 6.55 (1H, a), 5.36 (2H, 5), 3.92 (ZH, 5).

Intermediate 11: M,M-Diethyl-M-((2)-1-tributylstananylprop-1-en-3-yl)-amine

M hu entrance

I00323| Diethylamine (19 mL) was added to a solution of ((2)-3-bromoprop-1-enyl)-tributylstannane (Intermediate 121, 7.52 g) in THF (60 mL) and the mixture was stirred for 3 hours. The reaction mixture was evaporated to a dry residue, and the residue was purified by chromatography on a silica gel column, which was pre-washed with 2095 triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10 9° to obtain M, M-diethyl-M-((2)-1-tributylstananylprop-1-en-3-yl)amine (4.75 g) in the form of an orange oily substances (003241 "H NMR (SOSIS") b: 6.59 (1H, ayu, 5.97 (1H, ayu, 3.08 (2H, aa), 2.53 (AN, 4), 1.49 (6H , t), 1.37-1.24 (6H, t), 1.04 (6H, i), 0.92-0.89 (15H, t).

Intermediate 12: (2)-3-Bromoprop-1-enyl)-tributylstannane

Vg village

That

IІ00325| A solution of triphenylphosphine (5.32 g) in DCM (60 mL) was added to a solution of (2)-3-tributylstananylprop-2-en-1-ol (Intermediate compound 13, 6.4 g) and carbon tetrabromide (9.18 g ) in

DCM (60 ml) and the mixture was stirred for 2.5 hours. The mixture was evaporated to a small volume and pentane was added. The solids were removed by filtration and the filtrate was evaporated to a dry residue. Pentane was added and the solids were removed again by filtration, and the filtrate was evaporated to a dry residue to give ((2)-3-bromoprop-1-enyl)-tributylstannane (12.14 g) as an oil. (00326) "H NMR (SOSIS") 6: 6.71 (1H, ayu, 6.11 (1H, 4), 3.88 (2H, a), 1.52-1.50 (6H, t) , 1.37-1.27 (6H, t), 0.99-0.97 (6H, t), 0.90 (9H, ).

Intermediate 13: (7)-3-Tributylstananylprop-2-en-1-ol and we

I00327| Propargyl alcohol (5 mL) was added to a solution of lithium aluminum hydride (1 M in T/F, 43 mL) in THF (70 mL) at -78°C. The resulting mixture was warmed to room temperature and stirred for 18 hours. The mixture was cooled again to -78 "С and a solution of tri-n-butyltin chloride (8.32 ml) in diethyl ether (50 ml) was added, and the mixture was stirred for 3 hours, gradually warming to room temperature. The reaction mixture was cooled to -5 "C and quenched by addition of water and 15 95 aqueous solution of lithium hydroxide, then warmed to room temperature. Ethyl acetate was added and the mixture was stirred for 1 hour. The mixture was filtered through Celite, and the filtrate was evaporated to a dry residue. The residue was purified by chromatography on a silica gel column prewashed with 20 95 triethylamine in acetonitrile.The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10 95 to give (72)-33-tributylstananyl-prop-2-en-1-ol (5.06 g) in the form of a transparent oily substance. (003281 "H NMR (SOSI") 6: 6.70 (1H, ayu, 6.08 (1H, ayu, 4.12 (2H, av), 1.49 (6H, t) , 1.31 (6Н, t), 0.98-0.84 (15Н, t).

Intermediate compound 14: methyl cis-(Zanv, 96A5)-7-(2-(3-«-pyrrolidin-1-yl)ipropyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H- furoi|2,3-siIchromene-6-carboxylate etc

M Ge) oo 0 uh

M o

N

E Ge) Z

Mixture of cis-enantiomers (00329) Solution of methyl 7-(2-(2)-3-"pyrrolidin-1-ylprop-1-enyl)-4-fluorobenzenesulfonylamino|- 4H-furo|2,3-sichromene-b- carboxylate (Intermediate compound 15, 0.06 g) in IM5 (4 ml) and formic acid (2 drops) was treated under a nitrogen atmosphere with palladium hydroxide on carbon (10 95, 0.02 g).

Nitrogen was replaced with hydrogen and the mixture was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered through Celite, and the filtrate was evaporated to a dry residue to give methyl cis-(Zano, 9ЬА5)-7-(2-(3-(pyrrolidin-1-ylpropyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4 ,9p-tetrahydro-2H-furo|2,3-c|Ichromene-b-carboxylate (0.06 g), which was used without additional determination of characteristics.

Intermediate compound 15: methyl 1-(2-(2)-3-"pyrrolidin-1-ylprop-1-enyl)-4-fluorobenzenesulfonylamino|-4H-furo|2,3-c|Ichromene-b-carboxylate

FI ho y

ZM

M |)

N

E |) 7

I00330| Obtained in the same way as Intermediate 9, starting from methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo|2,3-c|Ichromene-6-carboxylate (Intermediate 109) and 1-(2 )-Z-tributylstananylallyl)pyrrolidine (Intermediate 16).

Y00Z331| "H NMR (CO3O0) b: 8.02 (1H, aa), 7.51 (1H, t), 7.16 (2H, a), 7.11-7.01 (2H, t), 6, 76 (IN, 9), 6.69 (IN, a), 5.93-5.83 (IN, t), 5.91 (2Н, 5), 3.80 (ЗН, 5), 3.37 -3.33 (2H, t), 2.69 (4H, t), 1.78 (4H, t).

Intermediate 16: 1-((2)-3-Tributylstananylallyl)pyrrolidine

With zpPViz

IІ00332| Obtained in the same way as Intermediate 11, starting from ((2)-3-bromoprop-1-enyl)-tributylstannane (Intermediate 12) and pyrrolidine.

Y003331| "H NMR (SOSIZ") 6: 6.64 (1H, ayu, 5.96 (1H, ab, 3.10 (2H, ad), 2.51 (4H, t), 1.79-1.78 (АН, т), 1.54-1.45 (6Н, т), 1.36-1.26 (6Н, т), 0.91-0.88 (15Н, Х.

Intermediate compound 17: methyl cis-(Zane, 9BAB)-7-(2-(27)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,Za, 4,9b-tetrahydro-2H-furoyl| 2,3-sichromene-6-carboxylate t n

M Ge) "M o

N

E at 9

A mixture of cis-enantiomers

I00334| Obtained in the same way as Intermediate 9, starting from methyl cis-(zano, 9А5)-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,Za,4,9p-tetrahydro-2H-furo|2,3 - sychromene-6-carboxylate (Intermediate compound 18) and M,M-diethyl-M-((2)-1-tributylstananylprop-1-en-3-yl)-amine (Intermediate compound 11), and heating at 80 " C for 2 hours. 00335) LCMS (Method A), retention time 2.25 (M.N) 519.

Intermediate compound 18: methyl cis-(Zanb5, 9085)-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-6-carboxylate

N

Gee)

Vk oo

Kai

Her Ya M Ge)

N

E and Z

A mixture of cis-enantiomers 00336) 2-Bromo-4-fluorobenzenesulfonyl chloride (0.335 g) was added to a solution of methyl cis- (Zzan5, 9BA5)-7-amino-1,3a, 4,9p-tetrahydro-2H-furo|2, of 3-sichromene-β6-carboxylate (Intermediate 19, 0.255 g) in DCM (4 mL) and pyridine (2 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100 95, to obtain methyl cis-(Zanv5, 9585)-7-(2-bromo-4-fluorobenzenesulfonylamino)-1, For, 4 9p-tetrahydro-2H-furo|2,3-s|Ychromene-b-carboxylate (0.486 g) in the form of a yellow resinous substance.

I00337| "H NMR (SOCI3) b: 9.47 (1H, 5), 8.17 (1H, t), 7.42 (1H, av), 7.12 (1H, ayu, 7.11 (2H, 5 ), 4.28 (IN, t), 4.06 (1H, aa), 3.96 (1H, aa), 3.91 (ZH, 5), 3.82 (2H, t), 3.41 (IN, t), 2.45 (1Н, t), 1.84

(IN, t).

Intermediate compound 19: methyl cis-(Zanb5,9bA5)-7-amino-1,Za,4,9p-tetrahydro-2H-furo|2,3-sichromene-6-carboxylate

N

Ge) ev;

Sho

Mixture of cis-enantiomers 00338) Trifluoroacetic acid (7 ml) was added to a solution of methyl cis-(Zanvi, 905A5)-7-|bis-(tert-butoxycarbonyl)amino|-1,Za, 4,9p-tetrahydro-2H- of furo|2,3-siIchromene-b-carboxylate (Intermediate 2, 0.66 g) in DCM (15 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to a dry residue, and the residue was treated with an aqueous solution of sodium bicarbonate and extracted with DCM, dried (Mo50O84) and filtered. The filtrate was evaporated to a dry residue to obtain methyl cis-(Zanv, 9085)-7-amino-1,Za,4,9B-tetrahydro-2H-furo(2,3-sichromene-6b-carboxylate) (0.255 g) as a resinous substances

I00339| "H NMR (SOSI") 6: 7.0 (1H, aa), 6.31 (1H, s), 4.932 (1H, t), 4.01 (2H, t), 3.88 (ZH, 5 ), 3.84 (2H, t), 3.39 (1H, t), 2.41 (IN, t), 1.86 (1H, t).

Intermediate compound 20: methyl 1 -(M-(2-((2)-Z-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino|-1,2-dihydrofuro|2, 3-c|quinoline-b-carboxylate

I am

M

ZM -

M M

E oo 2

I00340| Obtained in the same way as Intermediate 9, starting from methyl 7-|(M-(2-bromo-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino|-1,2-dihydro-furo|2,3-si |quinoline-b-carboxylate (Intermediate compound 21) and M,M-diethyl-((2)-1-tributylstananylprop-1-en-3-yl)amine (Intermediate compound 11), and heating at 60 "C for 1 hours

I00341| "H NMR (SOSI") 6: 8.72 (1H, 5), 8.32 (1H, aa), 7.76 (1H, a), 7.62 (1H, 49), 7.22-7 .08 (ЗН, т), 6.03 (1Н, т), 4.687 (2Н, 1), 3.93 (ЗН, 5), 3.62 (ЗН, 5), 3.56 (2Н, U 3.20 (2H, t), 2.52 (4H, t), 0.97 (6H, U.

Intermediate compound 21: methyl 7-N-(2-bromo-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino!|-1,2-dihydrofuroyl|2,3-c|quinoline-b-carboxylate c c);

Co

Zh - lora

E oo t

IІ00342| A solution of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2-dihydro-furo|2,3-cquinoline-6-carboxylate (Intermediate 22, 0.29 g) in THF (5 mL) was slowly added to suspension of sodium hydride (40 95 dispersion in oil, 0.048 g) in THF (15 ml). After completion of hydrogen evolution, methyl chloroformate (0.147 g) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried (М950О84) and filtered. The filtrate was evaporated to a dry residue, and the residue was triturated with a mixture of ether and cyclohexane (111), and the solid was collected by filtration to give methyl 7-IM-(2-bromo-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino!|-1 ,2-dihydrofuro|2,3-c|quinoline-b-carboxylate (0.3 g) in the form of a pale orange solid. 003431) "H NMR (SOSI") 6: 8.73 (1H, 5), 8.48 (1H, as), 7.76 (2H, 5), 7.51 (1H, av), 7.25 (1Н, т), 4.86 (2Н, У), 4.01 (ЗН, 5), 3.66 (ЗН, 5), 3.56 (2Н, и).

Intermediate compound 22: methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2-dihydro-furo|2,3-si|quinoline-6-carboxylate c c); in o.o

Хх -

M M uod

E at 7

I00344| Prepared in the same manner as Intermediate 18, starting from methyl 7-amino-1,2-dihydrofuro|2,3-c|quinoline-b-carboxylate (Intermediate 23) and 2-bromo-4-fluorobenzenesulfonyl chloride, and mixing at room temperature for 3 days.

I00345| "H NMR (SOCI3) b: 8.60 (1H, 5), 8.07 (1H, aa), 7.84 (1H, a), 7.62 (1H, a), 7.43 (1H, ad), 7.06 (1H, t), 4.79 (2H, U, 4.02 (ZH, 5), 3.48 (2H, U.

Intermediate compound 23: methyl 7-amino-1,2-dihydrofuro|2,3-cIquinoline-b-carboxylate ) and its precursor (00346) Solution of methyl 7-aminofuro|2,3-c|quinoline-b-carboxylate ( Intermediate compound 24, 1.13 g) in a mixture of dioxane (5 ml) and acetic acid (5 ml) was treated under a nitrogen atmosphere with palladium hydroxide on carbon (10 95, 0.1 g). Nitrogen was replaced with hydrogen and the mixture was stirred under a hydrogen atmosphere for 24 hours. The mixture was diluted with ethyl acetate and filtered through Celite, and the filtrate was washed with 1 M aqueous sodium hydroxide solution, dried (Mo95O4) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and ethyl acetate with a gradient of 0-10 95. The isolated product was triturated with a mixture of ether and cyclohexane, and the solid was collected by filtration to obtain methyl 7-amino-1,2- dihydrofuro|2,3-c|quinoline-b-carboxylate (0.666 g) as a yellow solid.

I00347| "H NMR (SOSIZ"z) 6: 8.56 (1H, 5), 7.51 (1H, 4), 6.95 (1H, 4), 5.16 (2H, Bg 5), 4.74 (2H, U, 4.05 (ZH, 5), 3.46 (2H, 1).

Intermediate compound 24: methyl 7-aminofuro|2,3-si|quinoline-6-carboxylate) and its

І00348| A mixture of methyl 3-bromo-2,6-diaminobenzoate (Intermediate compound 25, 1.34 g), 2-formylfuran-Z-boronic acid pinacol ether (1.46 g), tri-tert-butylphosphonium tetrafluoroborate (0.305 g), cesium carbonate (5.15 g) and tris-(dibenzylideneacetone)dipalladium (0.49 g) in a mixture of dioxane (80 ml) and water (30 ml) were degassed and purged with argon, then heated at 60 C for 1 hour. After cooling, the mixture was filtered through Celite, and the precipitate on the filter was thoroughly washed with ethyl acetate. The filtrate was washed with water, dried (Mo509084) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100 9o, to obtain methyl 7-aminofuro|2,3-c|quinoline-b-carboxylate (1.13 g) in in the form of a brown resinous substance.

I00349| "H NMR (SOCI") 6: 9.11 (1H, 5), 7.95 (IN, a), 7.82 (1H, 49), 7.14 (1H, aa), 7.05 (1H , 9), 5.05 (ОН, Bi 5), 4.08 (ЗН, 5).

Intermediate 25: Methyl 3-bromo-2,6-diaminobenzoate

Ve "C c) |)

II00350| Iron powder (4.07 g) was slowly added with stirring and cooling to a solution of methyl 6b-amino-3-bromo-2-nitrobenzoate (obtained according to the publication of Vgosk ei ai,

Teigapeaigop, 1963, 19, 1911; 2.0 g) in a mixture of absolute ethanol (49 ml), acetic acid (5 ml), formic acid (0.7 ml) and water (15 ml). After the addition was complete, the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and water (1:1), then filtered through Celite. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with 1 M aqueous sodium hydroxide solution, dried (Md9d5O4) and filtered. The filtrate was evaporated to a dry residue and the residue was triturated with ether and cyclohexane (1:1), and the solid was collected by filtration to give methyl 3-bromo-2,6-diaminobenzoate (1.34 g) as a pale yellow solid.

І003511| "H NMR (SOCI") 6: 7.21 (1H, 49), 6.11 (2H, Bg 5), 5.88 (1H, a), 5.46 (2H, bg 5), 3.93 (ZN, 5).

Intermediate compound 26: methyl 7-(benzenesulfonylamino)-1,2-dihydroIfuro|2,3-c|quinoline-6-carboxylate c c); n 5 -

M M

With her

I00352| Prepared in the same manner as Intermediate 18 starting from methyl 7-amino-1,2-dihydrofuro|2,3-c|quinoline-b-carboxylate (Intermediate 23) and benzenesulfonyl chloride and stirring at room temperature overnight.

І003531| "H NMR (SOSI") 6: 8.59 (1H, 5), 7.94 (1H, a), 7.70 (1H, a), 7.50 (1H, t), 7.40 (2H , U), 7.21 (2H, t), 4.81 (2H, U, 3.75 (ZH, 5), 3.51 (2H, 1).

Intermediate 27: methyl cis-(Zano5, 90685)-5-acetyl-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,2,Za, 4,5 ,9p-hexahydrofuroi|2,3-s|quinoline-b-carboxylate

From thread

M. Shy rka and M

E a7lso Her"

A mixture of cis-enantiomers

I00354| Obtained in the same way as Intermediate 9, starting from methyl cis-(zano, 9А5)-5-acetyl-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3a,4,5,9p-hexahydrofuro |2,3-c|quinoline-b-carboxylate (Intermediate 28), and heating at 80" for 2 hours.

And(00355)| LCMS (Method B), retention time 2.29 (M--H) 560.

Intermediate 28: methyl cis-(Za3, 9bA5)-5-acetyl-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,Za,4,5,9p-hexahydrofuro|2,3-c|quinoline -b6-carboxylate and o

Wow, two

That's 7

Gee)

A mixture of cis-enantiomers 00356) was prepared in the same way as Intermediate 18, starting from methyl cis-(zano, 9rAB5)-5-acetyl-7-amino-1,2,3a,4,5,90-hexahydrofuro|2 ,3-c|quinoline-b-carboxylate (Intermediate compound 29) and 2-bromo-4-fluorobenzenesulfonyl chloride.

І00357| "H NMR (SOSI") 6: 9.51 (1H, Bg 5), 8.16 (1H, t), 7.42 (1H, aa), 7.34 (1H, a), 7.18 ( IN, a), 7.12 (1H, ayu, 4.46 (1H, a), 3.84 (2H, t), 3.81 (ЗН, 5), 3.67 (1H, t), 3 .49 (1H, t), 3.38-3.19 (1H, t), 2.41-2.30 (1H, t), 2.25 (ZH, 5), 1.57 (1H, t ).

Intermediate compound 29: methyl cis-(Zanv5, 9BA5)-5-acetyl-7/-amino-1,2,Za, 4,5,9p-hexahydrofuroi|2,3-s|quinoline-b-carboxylate

N '

Gee)

On M olsa Y"

Mixture of cis-enantiomers 00358) Concentrated sulfuric acid (5 drops) was added to a solution of methyl cis-(Zanz, 9ЬА5Б)-5-acetyl-7-(2,2-dimethylpropionylamino)-1,2,3а, 4,5,9р -hexhydrofuroic|2,3-c|quinoline-6-carboxylate (Intermediate compound 30, 0.15 g) in methanol (5 ml) and stirred, and the solution was heated with a reflux for 48 hours. After cooling, the mixture was evaporated to a small volume, and the residue was dissolved in ethyl acetate and carefully washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was filtered through a phase separator, and the filtrate was evaporated to a dry residue to obtain methyl cis-(Zanv, 9585)-5-acetyl-7-amino-1,2,3a,4,5,965-hexahydrofuro|2,3-c| quinoline-b-carboxylate (0.09 g) in the form of a brown resinous substance. 003591 "H NMR (SOSI") 6: 7.04 (1H, a), 6.53 (1H, 4), 4.97 (2H, bg 5), 4.47 (IN, t), 3.90 (2H, t), 3.79 (ZH, 5), 3.67 (IN, t), 3.45 (1H, t), 3.30 (IN, t), 2.4-2.32 ( 1H, t), 2.27 (ZH, 5), 1.68-1.54 (IN, t).

Intermediate 30: methyl cis-(Zano, 9BA5)-5-acetyl-7-(2,2-dimethylpropionylamino)-1,2,Za,4,5,9p-hexahydrofuro|2,3-cIquinoline-b-carboxylate

N

8) (9) ato 7 a

A mixture of cis-enantiomers

ИООЗ3б60О| Sodium hydride (6095 dispersion in oil, 0.02 g) was added to a solution of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-cis-(285, ЗА5)-2-(methanesulfonyloxymethyl)tetrahydrofuran-3- il|rsenzoate (Intermediate compound 31, 0.166 g) in THF (3 ml) and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted with DCM, dried (Mo95054) and filtered.

The filtrate was evaporated to a dry residue to obtain methyl cis-(Zanov, 90685)-5-acetyl-7-(2,2-dimethylpropionylamino)-1,2,3a, 4,5,96-hexahydrofuro|2,3-s| quinoline-bE-carboxylate (0.15 g) in the form of a yellow-brown solid. 003611 "H NMR (SOSI") b: 9.92 (1H, 5), 8.29 (1H, 4), 7.30 (1H, 9), 4.51 (1H, a), 3.82 ( ZH, 5), 3.75 (2H, t), 3.69 (1H, t), 3.56 (1H, t), 3.37-3.27 (1H, ri t), 2.44- 2.34 (1H, Bg t), 2.29 (ZH, 5), 1.68-1.58 (1H, Bg t), 1.29 (9H, 5).

Intermediate compound 31: methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(cis-(285,

C3B85)-2-(methanesulfonyloxymethyl)tetrahydrofuran-3-yl|renzoate

N

Ge) 9) t si ato Yi" vo

A mixture of cis-enantiomers (00362 | Methanesulfonyl chloride (0.042 mL) was added to a mixture of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-Cys-(285, ЗА5)-2-(hydroxymethyl)-tetrahydrofuran-3- yl|rsenzoate (Intermediate 32, 0.14 g) and triethylamine (0.15 mL) in DCM (5 mL) and the resulting mixture was stirred at room temperature for 30 min. The mixture was washed with 1 M hydrochloric acid, dried (M9504) and The filtrate was evaporated to a dry residue to give methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-CyCl-(285, ZA5)-2-(methanesulfonyloxymethyl)tetrahydrofuran-3-yl|benzoate (0.166 g). in the form of a resinous substance.

(00363) LCMS (Method B), retention time 2.57 (M--Ma) 493.

Intermediate compound 32: methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(cis-(285,

ZA5)-2-(hydroxymethyl)tetrahydrofuran-3-yl|benzoate

N

Gee)

Ge; I'm a lion, and M (9 Z Y"

Mixture of cis-enantiomers (003641) Solution of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(2-hydroxymethylfuran-3-yl)benzoate (Intermediate 38, 0.2) in dioxane (4 mL) and acetic acid (1 ml) was treated in a nitrogen atmosphere with palladium hydroxide on carbon (10 95, 0.03 g). The nitrogen was replaced with hydrogen and the mixture was stirred under a hydrogen atmosphere overnight. The mixture was filtered through

Celite, and the precipitate on the filter was thoroughly washed with ethyl acetate. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and ethyl acetate with a gradient of 0-1095°, to obtain methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-Icis-(285, ЗА5) -2-(hydroxymethyl)tetrahydrofuran-3-yl|benzoate (0.14 g) as a white solid.

І003651| "H NMR (SOCI3) 6: 9.70 (1H, Bg 5), 8.29 (1H, 4), 8.25 (1H, Bg 5), 7.36 (1H, 4), 4.22 ( 1H, t), 4.10 (IN, t), 3.91 (IN, t), 3.90 (ZH, 5), 3.64 (2H, t), 3.24 (1H, t), 2.41 (IN, t), 2.16 (ZN, 5), 211 (IN, t), 1.30 (OH, 5).

Intermediate compound 33: methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(2-hydroxymethylfuran-3-yl)benzoate (6)

M M

(6) (6) Her"

I00366| Tetrabutylammonium fluoride (1 M solution in THF, 1.1 mL) was added to a stirred, cooled solution of methyl 2-acetylamino-3-(2-(tert-butyldimethylsilanyloxymethyl)-furan-3-yl|-6-(2,2- of dimethylpropionylamino)benzoate (Intermediate compound 34, 0.43 g) in THF (10 ml) at 0 "C and the mixture was stirred at 0 "C for 40 minutes, then evaporated to a dry residue.

The residue was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried (M9504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and ethyl acetate with a gradient of 0-296, to give methyl 2-acetylamino-6-(-2,2-dimethylpropionylamino)-3-(2-hydroxymethylfuran-3 -yl)benzoate (0.2 g) in the form of a resinous substance.

I00367| "H NMR (SOSI") 6: 9.95 (1H, Bg 5), 8.36 (IN, a), 8.00 (1H, Brg 5), 7.46 (1H, 5), 7.36 (1Н, а), 6.32 (1Н, 5), 4.54 (2Н, а), 3.90 (ЗН, 5), 2.45 (1Н, У), 1.99 (ЗН, 5) , 1.32 (9H, 5).

Intermediate compound 34: methyl 2-acetylamino-3-(2-(tert-butyldimethylsilanyloxymethyl)-furan-3-yl|-6-(2,2-dimethylpropionylamino)benzoate c (F) uk

(c) (6) Her" (00368) Acetyl chloride (0.09 ml) was added to a stirred solution of methyl 2-amino-3-(2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl|-6-(2 ,2-dimethylpropionylamino)-benzoate (Intermediate 35, 0.47 g) in DCM (5 mL) and pyridine (0.16 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with water and brine solution, dried (M9504) and filtered.The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane

With a gradient of 20-50 905, to obtain methyl 2-acetylamino-3-(2-(tert-

butyldimethylsilanyloxymethyl)-furan-3-yl|-6-(2,2-dimethylpropionylamino)benzoate (0.442 g) in the form of a colorless foamy substance. 003691 "H NMR (SOSIZ"z) 6: 10.08 (1H, Bg 5), 8.34 (1H, 9), 8.15 (1H, Bg 5), 7.46 (1H, 5), 7 .36 (1Н, 9), 6.932 (1Н, 5), 4.51 (2Н, 5), 3.93 (ЗН, 5), 1.98 (ЗН, 5), 1.32 (9Н, 5) , 0.93 (9H, 5), 0.13 (6H, 5).

Intermediate compound 35: methyl 2-amino-3-(2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl|-"6-(2,2-dimethylpropionylamino)-benzoate" more;

M MN,

AI

00370) Pivaloyl chloride (0.353 g) was added to a stirred, cooled mixture of methyl 2,6-diamino-3-(2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl|renzoate (Intermediate compound 36, 1.0 g) and sodium bicarbonate (0.268 g) in ethyl acetate (20 mL) and water (7 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 1.5 h. An additional amount of pivaloyl chloride (0.048 g) was added and the mixture was stirred for 1 h. Ethyl acetate was added and the layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution, dried (M9504) and filtered. The filtrate was evaporated to a dry residue and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-2095 to give methyl 2- amino-3-(2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl|-6-(2,2-dimethylpropionylamino)benzoate (0.744 g) in the form of an oily substance. 003711 "H NMR (SOCI3) 6: 10.81 (1H, Bk 5), 7.97 (1H, 49), 7.48 (1H, 5), 7.18 (1H, 9), 6.41 (1H, 5), 5.67 (2H, 5 ), 4.51 (2Н, 5), 3.98 (ЗН, 5), 1.33 (9Н, 5), 0.87 (9Н, 5), 0.05 (6Н, 5).

Intermediate compound 36: methyl 2,6-diamino-3-(2-(tert-butyldimethylsilanyloxymethyl)-furan-3-yl|benzoate lev ukrai oh nm MH,

AI

I00372| A mixture of methyl 3-bromo-2,6-diaminobenzoate (Intermediate compound 25, 2.6 g), 2-(tert-butyldimethylsilanyloxymethyl)furan-3-boronic acid (Intermediate compound 37, 3.5 g), cesium carbonate (11 .35 g), tri-tert-butylphosphonium tetrafluoroborate (0.334 g) and tris-(dibenzylideneacetone)dipalladium (0.529 g) in dioxane (72 ml) and water (18 ml) were degassed and purged with argon, then heated at 70 "C for 75 minutes. After cooling, ethyl acetate and water were added, and the mixture was filtered through Celite. The filtrate was separated, and the organic layer was washed with brine, dried (M9504), and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-20 95, to obtain methyl 2,6-diamino-3-(2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl|densoate (2.39 g) in the form of a viscous oily substance, which was used without further specification.

Intermediate 37: 2-(tert-butyldimethylsilanyloxymethyl)furan-3-boronic acid

And there he is

I00373| n-Butyllithium (2.5 M in hexane, 11.25 mL) was slowly added to a stirred, cooled solution of 3-bromo-2-(tert-butyldimethylsilanyloxymethyl)/furan (Intermediate 38, 7.5 g) in dry ether ( 150 ml), maintaining the temperature below -70 "C. The mixture was stirred at -78 "C for 2.5 hours. Tri-isopropylborate (6.75 g) was added and the mixture was allowed to warm to room temperature and stirred for 1.75 h. Ethyl acetate and an aqueous solution of ammonium chloride were added and the layers were separated. The organic layer was washed with an aqueous solution of ammonium chloride, dried (M9504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-35 95, to obtain 2-(tert-butyldimethylsilanyloxymethyl)furan-3-boronic acid (3.6 g), which was used without further definition of characteristics.

Intermediate 38: 3-Bromo-2-(tert-butyldimethylsilanyloxymethylfuran pane: and oh

I00374| tert-Butyldimethylsilanyl triflate (17.13 g) was slowly added to a stirred, cooled solution of 3-bromo-2-hydroxymethylfuran (Intermediate 39, 10.1 g) in DCM (160 mL) and pyridine (9.57 g) while maintaining the temperature at 0 "C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was washed with aqueous citric acid solution, saturated saline solution, dried (Ma2504) and filtered.

The filtrate was evaporated to a dry residue to give 3-bromo-2-(tert-butyldimethylsilanyloxymethyl)furan (17.1 g).

I003751| "H NMR (SOCI3) 6: 7.35 (1H, 4), 6.38 (1H, a), 4.65 (2H, 5), 0.90 (9H, 5), 0.09 (6H, 5).

Intermediate 39: 3-Bromo-2-hydroxymethylfuran c) and it 00376) Sodium borohydride (1.14 g) was slowly added to the stirred, cooled solution

3-bromo-2-formylfuran (5 g) in a mixture of THF (50 ml) and methanol (25 ml), maintaining the temperature at about 0 C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was evaporated to a dry residue and the residue was partitioned between ethyl acetate and water.

The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated saline, dried (Ma2O4) and filtered. The filtrate was evaporated to a dry residue to give 3-bromo-2-hydroxymethylfuran (5.31 g) as a colorless oily substance.

І00377| "H NMR (SOCI") 6: 7.37 (1H, 4), 6.42 (IN, 4), 4.65 (2H, 9), 1.71 (IN, 0.

Intermediate compound 40: methyl (hTakv5, 7B55k)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

M and r. o

ZU

M (in)

N

E (c) (c)

IІ00378| A solution of methyl (chTakz5, 7B5K)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a, 2,7p- tetrahydrocyclopropylisochromene-4-carboxylate (Intermediate compound 41, 0.208 g) and M, M-diethyl-M- ((2)-1-Tributylstananylprop-1-en-3-yl-amine (Intermediate 11, 0.367 g) in dioxane (5 mL) and

DMSO (0.5 mL) was degassed and purged with nitrogen. Tris-(dibenzylideneacetone)-dipalladium (0.021 g) and tri-tert-butylphosphonium tetrafluoroborate (0.013 g) were added and the mixture was again degassed and purged with argon. The resulting mixture was heated at 95 "C for 45 minutes. After cooling, the mixture was partitioned between ethyl acetate and water, and the organic layer was dried (M9504) and filtered.

The filtrate was concentrated in massio, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-12 95, to obtain methyl (Takz, 765K)-5-(2-(2)-3-diethylaminoprop-1-enyl )-4-fluorobenzenesulfonylamino|-1 and, 2,7-tetrahydrocyclopropa|c|Ichromene-4-carboxylate (0.188 g) in the form of a yellow-brown oily substance. 003791 "H NMR (SOSI") 6: 8.06 (1H, aa), 7.16 (1H, a), 7.09-7.03 (2H, t), 6.94 (1H, 49), 6.86 (1H, a), 6.10-6.02 (1H, t), 4.933 (1H, a), 3.84 (ZH, 5), 3.78 (1H, a), 3.13 (2H, Bug, a), 2.54 (AN, b, a), 1.88 40. (1H, t), 1.71 (IN, t), 1.03-0.92 (ВН, t ).

Intermediate compound 41: methyl (Ta5, 765K)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

M o

N

E (in; ?

ИО0О380| Methyl (tac5,7p5K)-5-amino-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate 42, 0.120 g) was suspended in DCM (5 mL). Pyridine (0.885 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.180 g) were added. The mixture was stirred at room temperature for 5 hours, then concentrated by stirring. The residue was dissolved in ethyl acetate and washed with 0.5 M aqueous solution of hydrochloric acid, dried (М959054) and filtered.

The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-10 96, to obtain methyl (1akz, 7658)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1 Ta, 2 ,7B-tetrahydrocyclopropa(sichromene-4-carboxylate) (0.208 g) in the form of a colorless oily substance.

I00Z3811| "H NMR (SOCIz") b: 9.31 (1H, Bg, 5), 8.14 (1H, aa), 7.41 (1H, aa), 7.17 (1H, a), 7.11 «an, aa), 7.06 (1H, a), 4.34 (1H, aa), 3.90 (ZH, 5), 3.80 (1H, ad), 1.94-1.85 ( 1H, t), 1.75-1.67 (1H, t), 1.01 (2H, t).

Intermediate compound 42: methyl pPax, tBK)-5-amino-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

AI

(003821) Methyl (acz, Ttb5K)-5-(2,2-dimethylpropionylamino)-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 43, 0.310 g) was suspended in methanol (7.5 ml) and concentrated sulfuric acid (4 drops) was added. The reaction mixture was heated under reflux under nitrogen for 36 hours. 2 more drops of concentrated sulfuric acid were added and heating was continued for another 24 hours. After cooling, the mixture was concentrated by mass, and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Ma25054) and filtered. The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20 96, to obtain methyl (Takz, 7p5K)-5-amino-1 1a, 2, 7p-tetrahydrocyclopropa|c|ichromene-4-carboxylate (0.120 g) in the form of a grayish-white solid.

I003831| "H NMR (SOSI") 6: 7.06 (1H, 4), 6.26 (IN, a), 4.33 (1H, 4), 3.87 (ZH, 5), 3.85 (1H , a), 1.83 (IN, yuyu), 1.64 (1H, t), 0.99-0.89 (2H, t).

Intermediate compound 42A: methyl Pak, 765)-5-amino-1a, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylate

IІ00384| A sample of intermediate 42 was subjected to chiral resolution by supercritical fluid chromatography (HPLC) using a Gyx C-3 column, 50 mm x 250 mm, 5 micron particle size. Eluted with 5 90 methanol (10.1 90 diethylamine) in CO2.

The absolute configuration of Intermediate 42A was confirmed by sample transformation

Example 12 and comparable analytical chiral HPLC.

Intermediate compound 43: methyl (chIak5, 7B5K)-5-(2,2-dimethylpropionylamino)-1,ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate o iho

No

IІ00385| Methyl (Tak5, 7B5K)-1,1-dibromo-5-amino-(2,2-dimethylpropionylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 44, 1.13 g) suspended in ethanol (30 ml). Zinc dust (1.17 g) was added, followed by ammonium chloride (1.31 g), and the reaction mixture was heated with a reflux condenser under nitrogen for 6 hours. After cooling, the solid was filtered off and washed with ethyl acetate. The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ether and cyclohexane, with a gradient of 5-12.5 95, to obtain methyl (Takz, 705K)-5-(2,2-dimethylpropionylamino)-1 Ta, 2 ,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (0.310 g) in the form of a colorless oily substance. 00386) "H NMR (SOCIz") 0: 9.72 (1H, Bg, 5), 7.98 (1H, 4), 7.30 (1H, a), 4.36 (1H, ad), 3 .91 (ZH, 5), 3.84 (1H, aa), 1.95 (1H, 14), 1.73 (1H, t), 1.28 (9H, 5), 1.03 (2H, t).

Intermediate compound 44: methyl (Takz, 7p5K)-1,1-dibromo-5-(2,2-dimethylpropionylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate c ) Vg vk o

N

(c) (c)

I00387| Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 45, 2.372 g) and benzyl triethylammonium chloride (0.373 g) were suspended in bromoform (6.45 mL) and an aqueous solution was added dropwise sodium hydroxide (50 95, 3.64 ml). The resulting black suspension was heated to 60 "C for 2 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The resulting emulsion was filtered through a pad of Celite and the organic layer was decanted. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried (M9504) and filtered The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 2.5-1595, to obtain methyl 1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a, 2,7B-tetrahydrocyclopropa|siIchromene-4-carboxylate (1.557 g) in the form of a grayish-white solid. 003881 "H NMR (SOCI") 6: 9.89 (1H, Bg, 5), 8.13 (IN, a), 7.43 (1H, 4), 4.47 (1H, aa), 4.32 (1H, da), 3.91 (ZH, 5), 2.89 (IN, ad), 2, 45 (1H, aaa), 1.30 (9H, 5).

Intermediate compound 45: methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate

M (c) ik ) (c) (c) (0oz89) A solution of methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (Intermediate compound 46, 4.74 g) and adduct ( bis(trifluoromethanesulfonyl)imidate|-(triphenylphosphine)gold and toluene (2:1) (0.060 g) in toluene (70 ml) was heated to 85 °C under a nitrogen atmosphere for 3 hours. After cooling, the mixture was concentrated by mass, and the residue purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20 956, to obtain methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (3.59 g) as a colorless oily substance.

I00390| "H NMR (SOSI") 6: 10.02 (1H, Bg, 5), 8.05 (1H, a), 7.05 (1H, a), 6.39 (1H, aaa), 5.76 (1H, a, 4.83 (2H, aa), 3.93 (ZH, 5), 1.30 (9H, 5).

Intermediate compound 46: methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate

N t

I00391| A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 47, 4.57 g), propargyl bromide (80 95 solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 ml) was heated with a retort for 8 hours. After cooling, the mixture was filtered, and the filtrate was concentrated by weight. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20 9o, to obtain methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) in the form an oily substance, which crystallized upon standing to form a white solid. 003921 "H NMR (SOSIZ") 56: 9.89 (1H, rbg, 5), 8.16 (1H, aa), 7.41 (1H, 9, 6.83 (1H, aa), 4.74 (2H, 9), 103.95 (ZH, 5), 2.53 (1H, U, 1.91 (9H, 5).

Intermediate compound 47: methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (6) in B "on

N

AI

00393) Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (obtained according to Sotheby's publication, 052004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 ml) and water (18 ml). The reaction mixture was stirred at room temperature for 1 hour. An additional amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. An additional amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated, and the organic layer was separated, dried (Ma2O4) and filtered. The filtrate was concentrated in fat, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25 96, to obtain methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid matter. 003941 "H NMR (SOSIZ"z) 6: 10.32 (1H, bg, 5), 8.22 (1H, av), 7.41 (1H, 9, 6.71 (1H, aa), 4, 08 (ZN, 5), 1.33 (9H, 5).

Intermediate compound 48: methyl (hTakv5, 7B55k)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-7B-methyl-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4 -carboxylate

M r. at 5

M 6)

N

E|c) 7

IІ00395| It was obtained in the same way as Intermediate 40, starting from methyl (tan, 7658)-5-(2-bromo-4-fluorobenzenesulfonylamino)-7p-methyl-1Ta, 2,7-tetrahydrocyclopropa|siIchromene-4-carboxylate ( Intermediate 49) and M,M-diethyl-M-((2)-1-tributylstananylprop-1-en-3-yl)-amine (Intermediate 11).

IN NMR (SOCI3) 6: 8.07 (1H, aa), 7.28 (1H, a), 7.05 (2H, t), 6.95 (1H, a), 6.88 (IN, a ), 6.06 (1H, t), 4.28 (1H, a), 3.85 (ZH, 5), 3.83 (1H, a), 3.14 (2H, rg a), 2.53 (4H, a), 1.41 (ZH, 5), 1.12 (IN, t), 1.07 (IN, U), 0.93 (6H, U), 0.84 (1H, aa).

Intermediate compound 49: methyl (1ak5,7B6B5E)-5-(2-bromo-4-fluorobenzenesulfonylamino)-7p-methyl-1Ta, 2,7b-tetrahydrocyclopropa|siIchromene-4-carboxylate

M in);

N

E at 7

IІ00396| It was obtained in the same way as Intermediate 41, starting from methyl (tan, 76b58)-5-amino-7p-methyl-1a, 2,1p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 50) and 2-bromo -4-fluorobenzenesulfonyl chloride.

IN NMR (SOSI") 6: 9.18 (1H, bg 5), 8.14 (1H, ach), 7.41 (1H, aa), 7.29 (1H, a), 7.11 (1H , t), 7.08 (IN, 9), 4.28 (IN, 4), 3.89 (ZH, 5), 3.84 (1H, y), 1.44 (1H, t), 1 .42 (ZH, 5), 1.10 (1H, U, 0.83 (1H, ad).

Intermediate compound 50: methyl (alumino, 7b58)-5-amino-7p-methyl-1a, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylate

I00397| Trifluoroacetic acid (4 ml) was added to a solution of methyl (Takz, 7B5K)-5-(tert-butoxycarbonylamino)-7p-methyl-1,1a,2,71p-tetrahydrocyclopropa-|sichromene-4-carboxylate (Intermediate compound 51, 0 .6 g) in dichloromethane (4 mL), and the resulting dark solution was stirred at room temperature for 1 hour. The solution was evaporated to a dry residue, and the residue was partitioned between water and ethyl acetate, and treated with a small amount of solid sodium bicarbonate to the pH of the aqueous layer"7. The layers were separated and the aqueous layer was extracted with ethyl acetate.

The combined organic layers were washed with water, dried (M9504) and filtered. the filtrate was evaporated to a dry residue to give methyl (Takz, 7rek)-5-amino-7p-methyl-1Ta, 2,7B-tetrahydrocyclopropa-1|siIichromene-4-carboxylate (0.402 g) as a red-orange solid.

1H NMR (SOSI") 6: 7.20 (1H, 9), 6.30 (1H, 49), 4.27 (1H, a), 3.90 (1H, 4), 3.88 ( ЗН, 5), 1.42 (ЗН, 5), 1.37 (IN, t), 1.06 (1Н, У, 0.78 (1Н, aa).

Intermediate compound 51: methyl (Takz, 7p5zK)-5-(tert-butoxycarbonylamino)-7p-methyl-1a, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylate ring (6)

N

AI

I00398| Obtained in the same way as Intermediate 43, starting from methyl (tan, 7b58)-5-(tert-butoxycarbonylamino)-1,1-dibromo-7p-methyl-1a, 2,716-tetrahydrocyclopropa-|sichromene-4-carboxylate (Intermediate compound 52).

1H NMR (SOSI) 6: 8.27 (1H, rg 5), 7.72 (1H, a), 7.38 (1H, a), 4.29 (IN, a), 3.91 (ZH, 5), 3.88 (IN, 9), 1.50 (OH, 5), 1.46 (ZH, 5), 1.44 (1H, t), 1.13 (IN, U) , 0.84 (1H, yes).

Intermediate compound 52: methyl (1ax, 7B6B52)-1,1-dibromo-5-(tert-butoxycarbonylamino)-7p-methyl-1Ta, 2,7pO-tetrahydrocyclopropa-|sichromene-4-carboxylate in

Vg from To om (6)

N

her

I00399| Obtained in the same way as Intermediate 44, starting from methyl 4-methyl-7-(tert-butoxycarbonylamino)-2H-chromene-8-carboxylate (Intermediate 53).

1H NMR (SOSI) 6: 8.55 (1H, Bg 5), 7.87 (1H, a), 7.42 (1H, 9), 4.75 (1H, aa), 4.13 (1H, ad), 3.92 (ZH, 5), 2.05 (1TH, ad), 1.79 (ZH, 5), 1.50 (9H, 5).

Intermediate compound 53: methyl 4-methyl-7-(tert-butoxycarbonylamino)-2H-chromene-8-carboxylate ova 0)

H t 00400) Obtained in the same way as Intermediate 45, starting from methyl 2-1|bis-(tert-butoxycarbonyl)amino|-6-(but-2-ynyloxy)benzoate (Intermediate 54).

1H NMR (SOCI3) 6: 8.66 (1H, Bg 5), 7.77 (1H, a), 7.18 (1H, aa), 5.53 (1H, t), 4.73 (2H, t), 3.93 (ZH, 5), 1.99 (ZH, 49), 1.51 (9H, 5).

Intermediate compound 54: methyl 2-bis-(tert-butoxycarbonyl)amino|-6-(but-2-ynyloxy)benzoate o o

I) and oo

I00401| Prepared in the same manner as Intermediate 46, starting from methyl 2-|bis-(tert-butoxycarbonyl)amino|-6-hydroxybenzoate (Intermediate 55) and 1-bromobut-2-yne.

1H NMR (SOSI) 6: 7.36 (1H, 9, 7.08 (1H, aa), 6.82 (1H, av), 4.70 (2H, a), 3.84 (ЗН , 5), 1.84 (ZN,

Y), 1.39 (18H, 5).

Intermediate compound 55: methyl 2-bis-(tert-butoxycarbonyl)amino|-b-hydroxybenzoate » c) M on c) - oche

Prepared in the same manner as Intermediate 4 starting from methyl 2-|bis-(tert-butoxycarbonyl)amino|-6-(4-methylbenzenesulfonyloxy)benzoate (Intermediate 56).

1H NMR (SOSI) 6: 11.17 (1H, 5), 7.40 (IN, 9, 6.99 (1H, ad), 6.69 (1H, av), 3.92 (ZH , 5), 1.37 (18H, 5).

Intermediate compound 56: methyl 2-bis-(tert-butoxycarbonyl)amino|-6-(4- methylbenzenesulfonyloxy)-benzoate 0) zd 2 z

From the bell

AND)

ХК о

I00402| Obtained in the same way as Intermediate 6, starting from methyl 2-amino-6-hydroxybenzoate (obtained according to the publication of Sothebz5 ei ai, 052004 0167128).

IN NMR (SOCI3) 6: 7.72 (2H, 4), 7.40 (IN, 9, 7.31 (2H, a), 7.22 IN, ad), 7.11 (1H, aa), 3.71 (ZH, 5), 2.44 (ZH, 5), 1.33 (18H, 5).

Intermediate compound 57: Cis-(Zanb5, 9BA5)-7--2-fluorobenzenesulfonylamino)-1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-6-carboxylic acid

Io

EE oo and su a

N ottan

A mixture of cis-enantiomers

ЙО0403| A mixture of lithium hydroxide (0.5 g) and methyl cis-(Zan5,9BA5)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9p-tetrahydro-2H-furo|2,3-siIchromene-b-carboxylate

(Intermediate compound 58, 0.217 g) in a mixture of dioxane (13 mL) and water (4 mL) was divided into two microwave reaction tubes, and the mixture was irradiated in a microwave reactor at 15070 for 10 minutes. After cooling, the combined mixture was acidified by adding 10 95 aqueous solution of citric acid (2 ml), extracted with DCM, dried (M9504) and filtered.

The filtrate was evaporated to a dry residue to give cis-(Zan5,9BA5)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9p-tetrahydro-2H-furo|2,3-sichromene-b6-carboxylic acid (0.518 g ) in the form of a vitreous substance.

IN NMR (SOSI") 6: 12.00 (1H, bBg 5), 11.57 (1H, Bg 5), 7.97 (1H, ayu, 7.55 (IN, t), 7.43 (1H , a), 7.26 (2H, t), 7.15 (1H, 9, 4.43 (IN, aa), 4.37 (1H, t), 4.14 (1H, da), 3, 83 (2H, t), 3.50 (1H, t), 2.50 (IN, t), 1.87 (1H, t).

Intermediate compound 58: methyl cis-(Zano, 90685)-7-(2-fluorobenzenesulfonylamino)-1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-6b-carboxylate

N

Ge) goyu spirit zva

Nato

Mixture of cis-enantiomers 00404) 2-Fluorobenzenesulfonyl chloride (0.5 g) was added to a solution of methyl cis-(Zanvi, 9685)-7-amino-1,Za,4,9p-tetrahydro-2H-furo|2,3-sichromene -β-carboxylate (Intermediate 19, 0.53 g) in DCM (10 mL) and pyridine (20 mL), and the resulting mixture was stirred at room temperature for 48 hours. The mixture was evaporated to a dry residue, and the residue was treated with water and extracted with DCM, dried (Mo5054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-6095, to obtain methyl cis-(Zan5, 96085)-7-(2-fluorobenzenesulfonylamino)-1,3a, 4,9B6- tetrahydro-2H-furo|2,3-c|Ichromene-6-carboxylate (0.574 g) in the form of a pale yellow solid.

1H NMR (SOSI) 6: 9.11 (1H, 5), 7.85 (1H, ayu, 7.53 (1H, t), 7.23 (1H, a), 7.21 H, a, 7151Н, 25.а), 7.13 (IN, da), 4.28 (1Н, t), 4.04 (1Н, da), 3.95 (1Н, ad), 3.67 (ЗН , 5), 3.82 (2H, t), 3.41 (1H, t), 2.45 (IN, t), 1.84 (1H, t).

Intermediate compound 59: methyl (hTakv5, 7B55k)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1-difluoro-1Ta, 2,7b-tetrahydrocyclopropa| c) Ychromene-4-carboxylate

IS

7 E

M

And r. Zv

ZM

M o

N

E (c) (c) 00405) Obtained in the same way as Intermediate 9, starting from methyl (1akz, 7658)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1-difluoro-1Ta, 2 ,7-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate compound 60) and M,M-diethyl-M-((2)-1- tributylstananylprop-1-ene-Z-ylamine (Intermediate compound 11), in the form of pale yellow resinous substance.

1H NMR (SOSIv) 6: 8.11 (1H, av), 7.18 (1H, a), 7.13-7.04 (2H, t), 6.98 (1H, a), 6 .93 (1H, a), 6.08 (IN, t), 4.38 (IN, 9), 4.02 (1H, t), 3.67 (ZH, 5), 3.23-3, 04 (2H, Bi 5), 2.67 (1H, U), 2.60-2.43 (AN, ri 5), 3.32 (1H, t), 0.94 (6H, i).

Intermediate compound 60: methyl (1ak5, 7B6B5E)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1-difluoro-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

IS

Well, attention

M o

N

E (c)?

I00406| It was obtained in the same way as Intermediate 18, starting from methyl (Ta5, /7658)-5-amino-1,1-difluoro-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 61) and 2-bromo-4-fluorobenzenesulfonyl chloride, in the form of a colorless foamy substance.

IN NMR (SOSI") 6: 9.58 (1H, 5), 8.18 (1H, aa), 7.42 (1H, as), 7.20 (IN, a), 7.13 (1H, a), 7.16-7.08 (IN, t), 4.98 (IN, y), 4.03 (1Н, т), 3.91 (ЗН, 5), 2.67 (1Н, У , 2.32 (1H, t).

Intermediate compound 61: methyl (1αkzv, tb5K)-5-amino-1,1-difluoro-1Ta, 2,7p-tetrahydrocyclopropa-IsIchromene-4-carboxylate

IS

Well, (in) (in)

I00407| Obtained in the same way as Intermediate 42, starting from methyl (tan, 7658)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,76-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 62), as an off-white solid.

IN NMR (SOSIZz) 6: 7.07 (1H, a), 6.30 (1H, a), 5.19-4.95 (2H, Bi5), 4.92 (1H, a), 4, 11 (1H, t), 3.87 (ZH, 5), 2.60 (1H, U, 2.27 (1H, t).

Intermediate 62: methyl (also, 765K)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

IS

And on o

H p (00408) Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate compound 45, 1.0 g) was dissolved in diglyme (30 ml) and the solution was heated to 160 °C. sodium chlorodifluoroacetate (4.27 g) in 15 minutes, and the last portion was washed with diglyme (15 ml). After the addition was complete, the mixture was heated at 180 "C for 15 minutes. After cooling, the mixture was poured into water and extracted with ethyl acetate, washed with water, dried (Mo50854) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane, with a gradient of 2.5-15 95, to give methyl akz, tb5K)-5-(2,2-dimethylpropionylamino)-1,1- difluoro-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylate (0.66 g) in the form of a colorless oily substance. "MMA (SOSI") 6: 9.86 (1H, Bg 5), 8.12 (1H, 4), 7.33 (1H, a), 4.41 (1H, a), 4.07 (1H , t), 3.92 (ZH, 5), 2.74 (IN, U, 2.34 (1H, t), 1.29 (9H, 5).

Intermediate compound 63: methyl (Tak5, 7B51K)-5-(2-(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

M

Shi

ZM

M (in)

N

E (c)?

I00409| Methanesulfonic anhydride (0.09 g) was added to a stirred, cooled mixture of methyl pPax, 7B5K)-5-1M-Imethoxycarbonyl|-M-(2-(2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonylamino)- 1 a, 2,7B-tetrahydrocyclopropa|c|ichromene-4-carboxylate (Intermediate compound 64, 0.17 g) and M,M-di-isopropyl-M-ethylamine (0.134 g) in DCM (10 ml) at 0 "with.

The temperature was allowed to rise to room temperature and the mixture was stirred for 2 hours. A solution of ethylamine (2 M in toluene, 2 ml) was added, and the resulting mixture was stirred at room temperature for 3 hours, then diluted with water. The organic layer was separated, dried (Ma25054) and filtered. The filtrate was evaporated to a dry residue to give methyl (aq, 7tb5K)-5-(2(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropasichromene-4-carboxylate ( 0.09 g) in the form of a white solid.

1H NMR (DMSO-α) 6: 7.89 (1H, ad), 7.35 (1H, 4), 7.16 (1H, t), 7.08 (1H, a), 6.83 (1H, a), 6.58 (IN, 49), 5.69 (1H, t), 4.17 (1H, ad), 3.84-3.04 (2H, Bi 5), 3.67 (ZH, 5), 3.58 (1H, a), 2.78 (2H, t), 1.83 (IN, t), 1.66 (1H, t), 1.04 (ZH, U) , 0.88 (1H, t), 0.64 (1H, t).

Intermediate compound 64: methyl (taq5, 7B514K)-5-1M4-(2-(2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl|-M-|methoxycarbonyl|amino|-1Ta, 2.7b -tetrahydrocyclopropa-isochromene-4-carboxylate no 0 o zu

M o i

E (c) (c) и0Б3-7О (00410) Mixture of methyl ОПакз, 7Б5К)-5-IM-(2-bromo-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino|-1,1a,. 2,7p-Tetrahydrocyclopropa-1-cyclochromene-4-carboxylate (Intermediate compound 65, 0.6 g), (27)-3-tributylstananylprop-2-en-1-ol (Intermediate compound 12, 0.81 g), tris -(dibenzylideneacetone)dipalladium (0.1 g) and tri-tert-butylphosphonium tetrafluoroborate (0.07 g) in dioxane (18 ml) and DMSO (2 ml) were stirred at room temperature for 30 minutes.

The resulting mixture was diluted with ethyl acetate and washed with water, dried (Ma2509084) and filtered.

The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether, with a gradient of 30-50 9o, to obtain methyl pPax, 76B5K)-5-1M-(2-(2)-3-hydroxyprop- 1-enyl)-4-fluorobenzenesulfonyl|-M-

Imethoxycarbonyl|amino)-1Ta, 2,7B-tetrahydrocyclopropa-(sichromene-4-carboxylate) (0.55 g) in the form of a grayish-white solid.

NMR NMR (SOSI) 6: 8.19 (1H, t), 7.39 (1H, a), 7.16 (IN, t), 7.02 (IN, t), 6.96 ( 2H, t), 6.03 (1H, t), 4.41 (IN, t), 4.23 (2H, t), 3.88 (1H, aa), 3.71 (ЗН, 25), 3.65 (ZH, 25), 2.06 (IN, t), 1.82 (1H, t), 1.25 (IN, t), 1.14 (1H, t).

Intermediate compound 65: methyl (Tax5,7B6B5K)-5-IM-(2-bromo-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino!|-1, Ta, 2,7p-tetrahydrocyclopropa-IsIchromene-4-carboxylate: and OO

Where

M (c) i

E (c) (c) -9

IІ00411| A solution of methyl (chTax5,7B5K)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 41, 1.7 g) in THF (20 ml ) was added to a suspension of sodium hydride (70 95 dispersion in oil, 0.2 g) in THF (10 mL). The resulting solution was stirred for 30 minutes, then methyl chloroformate (0.53 g) was added. The resulting mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Ma25054) and filtered.

The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (30 95), to give methyl (1akz, 765)-5-(IM-(2-bromo-4-fluorobenzenesulfonyl)-M- (Methoxycarbonyl)amino!|-1 and, 2,716-tetrahydrocyclopropa-|sichromene-4-carboxylate (1.6 g) as a white solid.

1H NMR (SOSI) 6: 8.42 (1H, t), 7.48 (1H, aa), 7.37 (1H, a), 7.19 (2H, t), 4.42 ( 1H, t), 3.95 (1H, aa), 3.86 (ZH, 5, ), 3.69 (ZH, 5), 2.06 (1H, t), 1.84 (1H, t) , 1.16 (2H, t).

Intermediate compound 66: methyl (tTak5,7p5K)-5-2(2)-3-(pyrrolidin-1-yl)uprop-1-enyl|-4-fluorobenzenesulfonylamino)-1, Ta, 2,7p-tetrahydrocyclopropa|sichromene -4-carboxylate

WITH

ZM

M o

N

E (c)?

I00412| It was obtained in the same way as Intermediate 63, starting from methyl (Tanz, 76b58)-5-(M-|methoxycarbonyl|-M-(2-((2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl |amino)-1Ta, 2,7b-tetrahydrocyclopropa(c|ichromene-4-carboxylate (Intermediate compound 64) and pyrrolidine, in the form of a brown oily substance.

LCMS (Method 0), retention time 1.28 (MAN) 487

Intermediate compound 67: (t1ak5,7p5K)-5-(2-Fluorobenzenesulfonylamino)-1,Ta,-2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid

ZU

M o

WITH

(c) he

Y00413| A mixture of methyl (Tax5, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1,1a, -2,7B- tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 68, 0.6 g) and lithium hydroxide monohydrate (1.5 d) in dioxane (45 ml) and water (13.8 ml) were stirred and heated at 1007 overnight. After cooling, the mixture was concentrated under vacuum, and the residue was diluted with water and acidified to pH 3 using 1 M hydrochloric acid. The precipitated solid was collected by filtration to give Pakz, T5K)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (0.58 g) as a white solid matter. "H NMR (DMSO-α) 6: 13.05 (1H, rg 5), 9.96 (1H, 5), 7.73 (2H, t), 7.45-7.31 (2H, t) , 7.23 (1H, a), 6.64 (IN, 9), 4.29 (IN, a), 3.74 (IN, 9), 2.01 (1H, t), 1.80 ( TN, t), 1.02 (1Н, t), 0.81 (1Н, t).

Intermediate compound 68: methyl (1ax, 7B5K)-5-(2-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate su

M (c)

N

(c) (c)

I00414| It was obtained in the same way as Intermediate 41, starting from methyl (Ta5, 7654p)-5-amino-1,1a, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 42) and 2-fluorobenzenesulfonyl chloride.

1H NMR (SOSI) 6: 8.90 (1H, 5), 7.84 (1H, ayu, 7.53 (1H, t), 7.24-7.11 (4H, t), 4 .34 (1H, ad), 3.88 (ZH, 5), 3.80 (1H, aa), 1.91 (1H, t), 1.74 (1H, t), 1.02 (2H, t).

Intermediate compound 69: methyl (Iak5,7p5K)-5-2|(2)-3-(propan-2-yl)aminoprop-1-enyl/|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa| Siichromene-4-carboxylate

M

M (in)

N

E (c)?

I00415)| It was obtained in the same way as Intermediate 63, starting from methyl (Tanz, 76b58)-5-(M-|methoxycarbonyl|-IM-(2-((2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl |amino)-1Ta, 2,7b-tetrahydrocyclopropa(c|ichromene-4-carboxylate 5 (Intermediate compound 64) and 2-aminopropane.

LCMS (Method 0), retention time 1.17 (MAN) 475.

Intermediate compound 70: methyl (chia5,7p5K)-5-2((2)-3-((5)-3-hydroxypyrrolidin-1-ylluaminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2.7p -tetrahydrocyclopropa|siIchromene-4-carboxylate no-4 1

ZM

M o

N

E o (c)

I00416Y was obtained in the same way as Intermediate 63, starting from methyl (Tanz, 76b58)-5-(M-|methoxycarbonyl|-IM-(2-((2)-3-hydroxyprop-1-enyl)-4- fluorobenzenesulfonyl|amino)-1Ta, 2,7b-tetrahydrocyclopropa(c|Ichromene-4-carboxylate (Intermediate compound 64) and (5)-3-hydroxypyrrolidine.

LCMS (Method 0), retention time 1.14 (MAN) 503.

Intermediate compound 71: methyl (Ta5,7B5H8)-5-2((2)-3-(B)-3-hydroxypyrrolidin-1-ylluaminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p- tetrahydrocyclopropa|siIchromene-4-carboxylate p; 8 8

M o

N

E (c)?

I00417| It was obtained in the same way as Intermediate 63, starting from methyl (Tanz, 76b58)-5-(M-|methoxycarbonyl|-IM-(2-((2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl |amino)-1Ta, 2,7b-tetrahydrocyclopropa(c|ichromene-4-carboxylate (Intermediate compound 64) and (K)-3-hydroxypyrrolidine, and were used without additional characterization.

Intermediate compound (72: methyl (Iakv5, 7b5K)-5-(M-(methoxycarbonyl)-M-(2(2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl|amino)-1Ta, 2, 7-tetrahydrocyclopropa|sichromene-4-carboxylate p and Zoo

And ate:

M o o-y

IS

0-9 (00418) Methylsulfonic anhydride (0.062 g) was added to a stirred, cooled mixture of methyl pPax, 7B5K)-5-M-|methoxycarbonyl|-M-(2-((2)-4-hydroxybut-1-enyl) -4-fluorobenzenesulfonylamino)-1a,2,7B-tetrahydrocyclopropa|c|ichromene-4-carboxylate (Intermediate compound 73, 0.12 g) and M,M-di-isopropyl-M-ethylamine (0.046 g) in DCM (15 ml) at 0 "s.

The resulting mixture was stirred at 0 "C for 20 minutes. Diethylamine (0.026 g) was added, and then the mixture was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with DCM, dried (Ma25054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 2-10 95, to obtain methyl (thiax5, 7p5K)-5-(M-(methoxycarbonyl)-M-(2((2)-4- diethylaminobut-1 -enyl)-4-fluorobenzenesulfonyl|amino)-1Ta, 2,7p-tetrahydrocyclopropa-

Isochromene-4-carboxylate (0.08 g) in the form of a light yellow solid.

LCMS (Method 0), retention time 1.22 (M.N) 561.

Intermediate compound 73: methyl (Takz, 765K)-5-1M-Imethoxycarbonyl|-M-(2-(2)-4-hydroxybut-1-enyl)-4-fluorobenzenesulfonyl|amino!-1Ta, 2,7p- tetrahydrocyclopropa|siIchromene-4-carboxylate

What oh 8

M (in)

Oh, that's b-

I00419| Obtained in the same way as Intermediate 64, starting from methyl (tan, 7658)-5-(M-(2-bromo-4-fluorobenzenesulfonyl)-M-(methoxycarbonyl)amino|-1,1Ta, -:2, 7B-tetrahydrocyclopropa-|sichromene-4-carboxylate (Intermediate compound 65) and (2)-4-tributylstananylprop-3-en-1-ol (obtained according to the publication of Misiga et al., Ogdapis I eNegv, 2005, 7(3) 503).

IN NMR (SOCI3) 6: 8.18 (1H, t), 7.38 (1H, a), 7.13 (3H, t), 6.96 (1H, 4), 5.91 (1H, t ), 4.44 (1H, t), 3.98 (1H, aa), 3.79 (ЗН, 5), 3.75 (2Н, t), 3.65 (ЗН, 5), 2.49 (2H, t), 2.07 (1H, t), 1.81 (IN, t), 1.27 (IN, t), 1.15 (1H, t).

Intermediate compound 74: (1akz5, 7p5K)-5-(Fluoro-2-vinylbenzenesulfonylamino)-1,1a, -2,7B- tetrahydrocyclopropa|sichromene-4-carboxylic acid

BY

M c)

N

And c) he

I00420| Lithium hydroxide (0.101 g) was added to a solution of methyl (Takz, 7rB5kK)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7B-tetrahydrocyclopropa|c|ichromene-4-carboxylate (Intermediate compound 75, . (2 mL), extracted with DCM, dried (М959054), and filtered. -(4-fluoro-2-vinylbenzenesulfonylamino)-1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (0.0.35 g) in the form of a vitreous substance.

1H NMR (SOSI") 6: 11.69 (1H, Bg 5), 8.10 (1H, av), 7.50 (1H, aa), 7.31-7.17 (ZH, t) , 7.03 (1H, a)", 5.60 (1H, a), 5.50 (1H, a), 4.60 (1H, a), 4.04 (IN, 9), 1.97 (IN, t), 1.81 (IN, t), 1.20 (IN, t), 0.99 (IN, t).

Intermediate compound 75: methyl (Ta5,7p5K)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate to o

ZM

M IF)

N

E c) 7

I00421| A mixture of methyl (T1akz5, 7B5K)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 41, 0.1 g), vinylboronic acid, pinicol ether (0.073 g), bis(triphenylphosphine) palladium (I) chloride (0.034 g) and cesium carbonate (0.215 g) in dioxane (5 ml) and water (1 ml) were degassed and purged with argon, then irradiated in a microwave reactor at 130 " C for 20 min. After cooling, the mixture was partitioned between 1 M hydrochloric acid and ethyl acetate. The organic layer was dried (Mo95904) and filtered, and the filtrate was evaporated to a dry residue to give methyl (tan, 76518)-5-(4-fluoro-2- vinylbenzenesulfonylamino)-1 Ta, 2.76-

tetrahydrocyclopropa|sichromene-4-carboxylate (0.15 g) in the form of a yellow vitreous substance.

1H NMR (SOSI) 6: 8.99 (1H, Bg 5), 7.97 (1H, aa), 7.38 (1H, ad), 7.21 (1H, aa), 7.18 (IN, a), 7.05 (IN, a), 7.00 (IN, t), 5.59 (1H, a), 5.38 (IN, a), 4.32 (1H, 49) , 3.77 (4H, t), 1.90 (IN, au, 1.71 (IN, t), 1.00 (2H, t).

Intermediate compound 76: methyl (Takv5, 7B51IK)-5-42-((2)-3-(azetidin-1-yl)uprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa| c|Yichromene-4-carboxylate kt

ZU

M o

N

E (c)?

I00422| It was obtained in the same way as Intermediate 63, starting from methyl (Tanz, 76b58)-5-(M-|methoxycarbonyl|-M-(2-((2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl |amino)-1Ta, 2,7b-tetrahydrocyclopropa(c|ichromene-4-carboxylate (Intermediate compound 64) and azetidine, in the form of a yellow oily substance.

LCMS (Method 0), retention time 1.17 (M.--H) 473.

Intermediate 77: methyl (also, 765K)-5-42-K2)-3-(3-Hydroxyazetidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa( Siichromene-4-carboxylate

Ishv) yes! r Y what 8

M (in)

N

E (c) o

I00423| It was obtained in the same way as Intermediate 63, starting from methyl (Tanz, 76b58)-5-(M-|methoxycarbonyl|-M-(2-((2)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl |amino)-1Ta, 2,7b-tetrahydrocyclopropa(|siIchromene-4-carboxylate (Intermediate compound 64) 3-Hydroxyazetidine, in the form of a yellow oily substance.

LCMS (Method 0), retention time 1.15 (M--H) 489.

Intermediate 78: M-(4-Dimethylaminobutyl)-M-methylamine

JSC N

(00424) A solution of lithium aluminum hydride in THF (1 M, 28 mL) was added dropwise to a stirred, cooled solution of M-(4-dimethylaminobutyl)/formamide (Intermediate 79, 2.7 g) in THF (60 mL), maintaining temperature of 0 "C in a nitrogen atmosphere. After completion of the addition, the mixture was stirred and heated at 75 "C for 2 hours. The reaction mixture was cooled to 0 °C and ethanol was added, then the mixture was evaporated to a dry residue. The residue was diluted with a mixture of diethyl ether and DCM (30 95), and the solid was filtered off. The filtrate was evaporated to a dry residue to obtain M-(4-dimethylaminobutyl)- M-methylamine (1.5 g) in the form of a yellow oily substance.

IN NMR (SOCI3) 6: 2.56 (2H, t), 2.41 (ZH, 5), 2.25 (2H, t), 2.20 (6H, 5), 1.47 (AN, t ).

Intermediate 79: M-(4-Dimethylaminobutyl)/formamide tt H sno (00425) A solution of 4-dimethylaminobutylamine (3.0 g) in ethyl formate (30 mL) was stirred and heated with a reflux under a nitrogen atmosphere for 3 hours. After cooling, the mixture was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (20 95), to give M-(4-dimethylaminobutyl)/formamide (2.7 g) as a pale yellow oily substance.

IN NMR (SOSI") 6: 8.14 (1H, 5), 6.80 (1H, 5), 3.50 (2H, t), 2.28 (2H, t), 2.20 (6H, 5), 1.61 (4H, t).

Intermediate 80: methyl (Tak5, 765K)-5-2-((5)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl|- 4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa(siIchromene-4-carboxylate

M Ov

H 0. 70 75

M|c)

N

E o7To7

I00426| A solution of methyl (1ак5,7р5К)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1/1a, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 83, 0.180 g), (5)-1- ethylpyrrolidin-3-ylamine ditrifluoroacetic acid salt (Intermediate 81, 0.171 g), EOAS (0.144 g) and triethylamine (0.202 g) in DCM (5 mL) was allowed to stand at room temperature for 6 days, then washed with water and filtered through a phase separator . The filtrate was purified directly by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-2095 to obtain methyl (Takz5, 7B65НЕ)-5-2-(5)-1-ethylpyrrolidin-3-ylcarbamoyl)methylI|-4-fluorobenzenesulfonylamino)- 1 Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (0.178 g) in the form of a grayish-white foamy substance.

LCMS (Method E), retention time 2.57 (M.N) 532

Intermediate compound 81: (5)-1-Ethylpyrrolidin-3-ylamine difluoroacetic acid salt

Academy of Sciences,

M

And RTEA

I00427| A solution of tert-Butyl ((5)-1-ethylpyrrolidin-3-yl)ucarbamate (Intermediate 82, 0.107 g) in a solution of trifluoroacetic acid (2 mL) and DCM (2 mL) was allowed to stand at room temperature for 30 minutes, then concentrated ip mass. The residue was azeotropically distilled with toluene to obtain /(5)-1-ethylpyrrolidin-3-ylamine difluoroacetic acid salt (0.231 g) as a light brown resinous substance, which was used without further characterization.

Intermediate 82: tert-Butyl ((5)-1-ethylpyrrolidin-3-yl)ucarbamate

H 0-4-

M in 4

I00428| A mixture of tert-butyl (5)-pyrrolidine-3-ylcarbamate (1.048 g), iodate (0.90 g), and potassium carbonate (1.55 g) in acetonitrile (15 mL) was stirred at room temperature for 17 h, then filtered . The filtrate was concentrated by mass, and the residue was triturated with DCM and filtered. The filtrate was concentrated over mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-35 95, to obtain tert-butyl ((5)-1-ethylpyrrolidin-3-yl)ucarbamate (0.891 g) as a resinous light-colored substances.

1H NMR (SOCI) 6: 5.11 (1H, Bg, 5), 4.29 (1H, Bg, 5), 3.88 (1H, Bkg, 5), 3.18 (1H, bg , 5), 2.90 (2H, Bg, t), 2.76 (2H, ri, t), 2.62 (1H, re, a), 2.38 (IN, t), 1.44 ( 9H, 5), 1.28 (ZN, U.

Intermediate compound 83: methyl pPax, 7tb5K)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate i) 0.0 750

M i) nN

E (c) and)

I00429| 1 M sodium hydroxide solution (3 ml) was added to a solution of methyl (Takz, 7605K)-5-(4-fluoro-2-methoxycarbonylmethylbenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa-

isochromene-4-carboxylate (Intermediate 84, 0.438 g) in methanol (6 mL) and heated the mixture at 50 °C for 2 h. After cooling, the mixture was evaporated to a dry residue, and the residue was dissolved in ethyl acetate and water and acidified with concentrated hydrogen chloride acid

The organic layer was dried (Ma2504) and filtered, and the filtrate was concentrated by mass, the residue was dissolved in toluene and re-evaporated to obtain methyl (also, 7B5K)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1Ta, 2.7p- tetrahydrocyclopropa|c|ichromene-4-carboxylate (0.422 g) in the form of a white solid.

1H NMR (SOCI3) 6: 8.83 (1H, g, 5), 7.86 (1H, ad), 7.22 (1H, 4), 7.01 (ZH, t), 4.32 (IN, a), 4.00 (2H, t), 3.76 (1H, a), 3.73 (ЗН, 5), 1.94 (IN, t), 1.73 (IN, t) , 1.02 (2H, t).

Intermediate compound 84: methyl opax, 7B5K)-5-14-fluoro-2-(methoxycarbonylmethyl)benzenesulfonylamino!|-1Ta, 2,7pO-tetrahydrocyclopropa|c|Ichromene-4-carboxylate 6) that oxide

M 6)

N

E|c) t

I00430| A solution of methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (Intermediate compound 85, 0.293 g) Its methyl (chIak5,7B5K)-5-amino-1,1a,2,7p-tetrahydrocyclopropa(c|ichromene-4-carboxylate ( Intermediate 42, 0.219 g) in pyridine (1 mL) and DCM (3 mL) was allowed to stand at room temperature for 4 days. The mixture was diluted with DCM, washed with 2 M hydrochloric acid, and filtered through a phase separator. The filtrate was concentrated by mass, and the residue purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-40 95, to obtain methyl (Tak5, 7p5K)-5-(4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino!|-1,1a, 2,7p -tetrahydrocyclopropa|sichromene-4-carboxylate (0.438 g) in the form of a colorless resinous substance.

IN NMR (SOCIz") 6: 8.77 (1H, Bg, 5), 7.84 (1H, ad), 7.22 (IN, 4), 7.01 (ZN, t), 4.33 ( 1Н, 49), 4.01 (2Н, 5), 3.79 (1Н, а), 3.76 (ЗН, 5), 3.69 (ЗН, 5), 1.93 (1Н, t), 1.73 (IN, t), 1.03 (2Н, t).

Intermediate compound 85: methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (6) then

Ov (6)

IS

I00431| Methyl (3-fluorophenyl)acetate (1.51 g) was added dropwise to chlorosulfonic acid (7 mL) with stirring and cooling on ice. The cooling bath was removed, and the mixture was left to stand at room temperature for 16 hours, then ice and ethyl acetate were carefully added to the mixture. The organic layer was separated, washed with water, dried (Md5o4) and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20 9°, to obtain methyl (2-chlorosulfonyl-5-fluorophenyl)acetate (1.42 g) as a white solid.

1H NMR (SOCI3) 6: 8.16 (1H, aa), 7.21 (2H, t), 4.19 (2H, 5), 3.76 (ZH, 5).

Intermediate 86: Methyl pPax, 7tB5K)-5-(2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

S nku (c)

N

E 07To7 00432) Mixture of methyl (Yes, 705H)-5-(2-(azetidin-3-yl)-4-fluorobenzenesulfonylamino!|-1 a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 87, 0.216 g), iodate (0.078 g), and potassium carbonate (0.138 g) in acetonitrile (5 mL) were stirred at room temperature for 18 h. The mixture was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with gradient 0-15 95, to obtain methyl (Yes, 765K)-5-(2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino!|-1 a, 2,7p-tetrahydrocyclopropa-|sichromene-4- carboxylate (0.051 g).

1H NMR (SOCIz") 6: 7.97 (1H, av), 7.62 (1H, av), 7.24 (IN, 9), 6.99 (IN, ayu, 6.96 (1H , 49), 4.35 (1H, 9), 4.91 (1H, t), 3.79 (ZH, 5), 3.77 (1H, y), 3.58 (2H, t), 3 .22 (2H, horn, t), 2.53 (2H, 4), 1.93 (1H, t), 1.74 (1H, 49), 0.99 (BN, t).

Intermediate compound 87: methyl pPax, 7tB5K)-5-(2-(azetidin-3-yl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

M de "M (o)

N

Io E oto

Y00433| A mixture of methyl (Takb5, 7B5K)-5-(4-fluoro-2-(11-(2,2,2-trifluoroacetyl)azetidin-3-yl|Icenezolsulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|cIchromene- 4-carboxylate (Intermediate 88, 0.294 g) and potassium carbonate (0.155 g) in methanol (5 mL) and water (0.5 mL) were stirred at room temperature for 45 min. 90 methanol in DCM and filtered. The filtrate was concentrated ip massio, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-40 95, to give methyl (yes, 7rz5kK)-5-(2-(azetidine-3 -yl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (0.216 g) in the form of a pale yellow foamy substance.

IN NMR (SOSI") 6: 6: 7.94 (1H, aa), 7.54 (1H, av), 7.27 (1H, a), 7.09 (1H, au, 6.99 (1H , 49), 4.87 (IN, t), 4.32 (ЗН, t), 4.12 (2Н, У, 3.78 (1Н, т), 3.73 (ЗН, 5), 1, 94 (IN, t), 1.73 (1Н, t), 0.99 (2Н, t).

Intermediate compound 88: methyl (Takz, 765K)-5-14-fluoro-2-11-(2,2,2-trifluoroacetyl)azetidin-3-yl|Hsensolsulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|c| chromene-4-carboxylate pi

M de "M (o)

N

E oto (00434) A solution of methyl 4-fluoro-2-(1-(2,2,2-trifluoroacetyl)azetidin-3-yl|H-benzenesulfonyl chloride (Intermediate compound 89, 0.192 g) and methyl (Takz, 765K)-5- amino-1Ta, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylate (Intermediate 42, 0.122 g) in pyridine (1 mL) and DCM (3 mL) was allowed to stand at room temperature for 18 h. The mixture was diluted with DCM, washed with 1 M hydrochloric acid and filtered through a phase separator.The filtrate was concentrated and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-30 to give methyl pPax, tb5K)-5-14-fluoro- 2-(1-(2,2,2-trifluoroacetyl)azetidin-3-yl|Icenezolsulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylate (0.294 g) in the form of a colorless resinous substance.

1H NMR (SOSI") 6: 8.99 (1H, bg, 5), 7.99 (1H, t), 7.81 (2H, t), 7.06 (2H, t), 4, 68 (2H, t), 4.41 (IN, t), 4.34 (IN, 0), 4.19 (1H, t), 4.08 (IN, t), 3.79 (1H, t ), 3.72 (ZH, 5), 1.94 (1H, t), 1.75 (IN, t), 1.02 (2H, t).

Intermediate 89: 4-Fluoro-2-(1-(2,2,2-trifluoroacetyl)-azetidin-3-yl|H-benzenesulfonyl chloride

EC. 2O

T

05 7.0 75 (o)

IS

І00435| Chlorosulfonic acid (5 ml) was added to /2,2,2-trifluoro-1-|3-(3-fluorophenyl)azetidin-1-yl|ethanone (Intermediate compound 90, 1.15 g) with stirring and cooling on ice . The mixture was stirred for 1 hour, then carefully poured into a mixture of ice and ethyl acetate. The organic layer was washed with water and concentrated with oil. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20 9, to obtain 4-fluoro-2-(1-(2,2,2-trifluoroacetyl)azetidin-3-yl|I-benzenesulfonyl chloride (0.910 g) in in the form of a white solid.

NMR NMR (SOSI) 6: 8.22 (1H, t), 7.51 (1H, ad), 7.26 (1H, t), 4.95 (2H, t), 4.70 ( 1H, 9, 4.42 (IN, t), 4.91 (1H, t).

Intermediate compound 90: 2,2,2-Trifluoro-1-I3-(3-fluorophenyl)azetidin-1-yl|vetanone

M r (00436) A solution of tert-Butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (Intermediate 92, 2.51 g) in trifluoroacetic acid (15 mL) and DCM (15 mL) was left to stand at room temperature for 30 minutes. The mixture was concentrated by mass, and the residue was distilled by azeotropic distillation with toluene. The residue was dissolved in DCM (15 mL) and pyridinine (5 mL) and trifluoroacetic anhydride (3.15 g) was added. The mixture was left to stand at room temperature for 30 minutes, then washed with 1 M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20 9°, to obtain 2,2,2-trifluoro-1-13-(3-fluorophenyl)azetidin-1-yl| vetanone (2.31 g) in the form of a light brown oily substance.

IN NMR (SOSI") 6: 7.36 (1H, t), 7.10 (IN, a), 7.02 (2H, t), 4.81 (IN, 9, 4.57 (1H, 9 , 4.44 (IN, aa), 4.20 (1H, aa), 3.96 (1H, t).

Intermediate compound 91: tert-Butyl 3-(3-fluorophenyl)azetidine-1-carboxylate

IS

I00437| A solution of 1,2-dibromoethane (0.30 g) in anhydrous DMF (25 ml) was stirred with zinc dust (1.39 g) at 70 °C for 10 minutes, then cooled to room temperature and chlorotrimethylsilane (0.155 g) was added. The resulting mixture was stirred at room temperature for 45 minutes. tert-Butyl C-iodazetidine-1-carboxylate (5 g) was added. Stirring was continued at 40 C for 45 minutes, then a solution of 3-fluoroiodobenzene (4.08 g), tris( idibenzylideneacetone)idipalladium (0) (0.325 g) and tris(2-furyl)phosphine (0.165 g) in DMF (15 ml) and the mixture was stirred at 70 "C for 3 hours. After cooling, the mixture was diluted with water and ethyl acetate and filtered through celite. The organic layer was washed twice with water, dried (Ma2504) and filtered. The filtrate was concentrated in fat, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-10 95. The crude product was further purified by chromatography on silica gel, eluting with a mixture of DCM and cyclohexane with a gradient of 0-100 906, to obtain tert-

Butyl 3-(3-fluorophenyl)azetidine-1-carboxylate (2.52 g) as a colorless oily substance.

IN NMR (SOSI") 6: 7.32 (1H, t), 6.90-7.11 (ZH, t), 4.34 (2H, U, 3.95 (2H, aa), 3.72 (1H, t), 1.48 (9H, 5).

Intermediate 92: methyl Takz, 7652EK)-5-(2-I(A)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl|- 4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa(siIchromene-4-carboxylate on 05 20 57

M i)

N

E |) t

IІ00438| It was obtained in the same way as Intermediate 80, starting from methyl (tan, 76b58)-5-(2-carboxymethyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7ter-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate 83 ) and (K)-1-ethylpyrrolidin-3-ylamine difluoroacetic acid salt (Intermediate compound 93), in the form of a light brown foamy substance.

LCMS (Method E), retention time 2.57 (MAN) 532.

Intermediate compound 93: (K)-1-Ethylpyrrolidin-3-ylamine difluoroacetic acid salt

MH,

M

And RTEA

I00439| Obtained in the same manner as Intermediate 81, starting from tert-Butyl (8)-1-ethylpyrrolidin-3-ylcarbamate, as a light brown resinous substance, which was used without further characterization.

Intermediate compound 94: tert-Butyl (K)-1-ethylpyrrolidin-3-yl)ucarbamate

AND

(00440) Obtained in the same manner as Intermediate 82, starting from tert-butyl (B)-pyrrolidin-3-yl-carbamate and iodate, in the form of a light-colored resinous substance.

1H NMR (SOCI3) 6: 5.09 (2H, Bg, 5), 4.25 (1H, Bg, 5), 3.08 (1H, Bg, 5), 2.82 (2H, Bg, t), 2.69 (2H, Bg, a), 2.52 (1H, Be, 49), 2.35 (1H, t), 1.44 (9H, 5), 1.21 (ZH, U .

Intermediate compound 95: methyl (Ta5,|7BK)-5-(2-(B8)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate hmm

ZM

M o

N

E at 7

I00441| A solution of methyl (Ttakz, 7p5K)-5-amino-1,1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 42, 0.257 g) in DCM (10 ml) and pyridine (5 ml) was treated with a solution of 2 -(8)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 96, 0.36 g) in DCM (10 mL) and the mixture was stirred at room temperature overnight. The resulting mixture was evaporated to a dry residue, and the residue was re-dissolved in DCM, washed with water, dried (Ma9504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-10 95, then washed with 10095 methanol to obtain methyl (Tab, 7BK)-5-(2-(A)-1- ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1a, 2,7B-tetrahydrocyclopropa-|c|ichromene-4-carboxylate (0.13 g) in the form of a resinous substance.

IN NMR (SOSIS") 6: 7.88 (1H, Og U, 7.23 (1H, 4), 7.13 (1H, Bg a), 6.98 (2H, t), 4.33 (1H , 9), 3.79 (IN, a), 3.77 (ZH, 5), 3.20-2.90 (6H, t) 2.24 (1H, Bi 5), 2.04-1, 18 (ZN, Big 5), 1.93 (2H, a), 1.74 (1H, a), 1.45 (ZN, U, 1.02 (2H, t).

Intermediate compound 96: 2-(B)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride

M. 9, ro)

ZM

SI

IS

(00442) A solution of (K)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (Intermediate 97, 0.24 g) in DHE (1.2 mL) was carefully added to chlorosulfonic acid and the mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into ice water and extracted with DCM, dried (M9504) and filtered. The filtrate was evaporated to a dry residue to give 2-((8)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.36 g) as an oily substance, which was used without further characterization.

Intermediate 97: (K)-1-Ethyl-3-(3-fluorobenzyl)pyrrolidine and

IS

(00443) Ethyl bromide (0.22 g) was added to a suspension of 3-(H8)-(3-fluorobenzyl)pyrrolidine (Intermediate 98, 0.36 g) and potassium carbonate (0.55 g) in acetonitrile and the mixture was stirred at at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate, filtered, and the filtrate was evaporated to a dry residue. The residue was triturated with DCM, the solvent was decanted and evaporated to a dry residue to obtain (K)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (0.24 g) as an oily substance.

IN NMR (SOSI") 6: 7.22 (IN, t), 6.95 (1H, a), 6.88 (2H, t), 2.73-2.60 (4H, t), 2, 52-2.38 (4H, t), 2.17 (IN, da), 1.97 (1H, t), 1.49 (1H, t), 1.09 (ZN, U.

Intermediate 98: 3-(H2)-(3-Fluorobenzyl)pyrrolidine

NM

IS

(00444| Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl (K)-3-(3-fluorobenzyl)-pyrrolidine-1-carboxylate (Intermediate compound 99, 0.515 g) in DCM (10 ml) and the mixture was stirred for 1 h at room temperature. The mixture was evaporated to a dry residue and the residue was partitioned between DCM and sat. fluorobenzyl)pyrrolidine (0.402 g) in the form of an oily substance.

IN NMR (SOCIz) b: 7.30-7.23 (2H, t), 6.94 (1H, 49), 6.88 (1H, ayu, 3.45-3.16 (ZN, Bg t) , 2.90 (1H, t), 2.76 (2H, a), 2.63 (IN, t), 2.12 (IN, t), 1.74 (1H, t).

Intermediate compound 99: tert-Butyl (K)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate i) y--y --

IS

I00445| Nickel iodide (0.147 g), trans-2-aminocyclohexanol HCl salt (0.74 g), C3-

fluorobenzeneboronic acid (0.78 g) and sodium hexamethyldisilazide (0.208 g) were placed in a closed test tube, degassed, and purged with argon. Isopropanol (8 ml) was added and the mixture was stirred at 40 °C for 5 minutes. A solution of tert-butyl (K)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 100, 1.44 g) in isopropanol (8 ml) was added and stirred, the mixture was heated at 70"C overnight. After cooling, the mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was evaporated to a dry residue. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60-95, to obtain tert-Butyl (K)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate (0.515 g) in the form of an oily substance.

1H NMR (SOSIv) 6: 7.27-7.21 (2H, t), 6.95-6.84 (2H, t), 3.46 (2H, t), 3.26 (IN, t), 2.98 (IN, aa), 2.67 (2H, t), 2.40 (IN, t), 1.92 (1H, t), 1.58 (IN, t), 1, 46 (9H, 5).

Intermediate 100: tert-Butyl (K)-3-iodomethylpyrrolidine-1-carboxylate

IN-

In iv) 00446) Iodine (1.91 g) was added in portions to a vigorously stirred ice-cooled suspension of imidazole (0.681 g) and triphenylphosphine (1.97 g) in diethyl ether (12 mL). Then the mixture was stirred for 10 minutes, then a solution of tert-butyl (K)-3-hydroxymethylpyrrolidine-1-carboxylate (1 g) in dioxane (b ml) was added dropwise. The resulting mixture was stirred at room temperature overnight, then diluted with diethyl ether and filtered.

The solid was washed with diethyl ether, and the combined filtrate was evaporated to a dry residue. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-2095, to obtain tert-butyl (K)-3-iodomethylpyrrolidine-1-carboxylate (1.44 g) as an oily substance.

1H NMR (SOCI3) 6: 3.64-3.46 (2H, t), 3.33 (1H, t), 3.19 (2H, a), 3.02 (1H, ad), 2.49 (1H, t), 2.07 (IN, t), 1.65 (1H, t), 1.46 (OH, 5).

Intermediate compound 101: methyl (akz, 7b5K)-5-2-((5)-1-ethylpyrrolidin-2-ylcarbonylaminomethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7pO-tetrahydrocyclopropa-

Isochromene-4-carboxylate

SA at 5

M o

N

Eh oh?

I00447| A mixture of methyl (1ак5, 7Б5К)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 102, 0.515 g), NATI (0.483 g), (5)-M-Ethylpyrrolidine-2-carboxylic acid (Intermediate 106, 0.182 g) and M,M-diisopropyl-M-ethylamine (0.328 g) in dry DMF (25 mL) were stirred at room temperature for 2 h . The mixture was concentrated under vacuum, and the residue was diluted with water and extracted with ethyl acetate, washed with water, dried (M9504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 1-2 95, to give methyl (yes, 7rB5H)-5-2-(5)-1-ethylpyrrolidin-2-yl )ucarbonylaminomethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa-

Isochromene-4-carboxylate (0.505 g) as a vitreous solid.

1H NMR (SOCIz") 6: 9.2-8.9 (1H, Bi5), 7.82 (2H, t), 7.24 (2H, t), 7.00 (1H, a) , 6.95 (1H, aa), 4.75 (2H, t), 4.93 (IN, a), 3.99 (1H, Big 5), 3.79 (1H, t), 3.77 (ZH, 5), 3.67 (1H, t), 3.15-2.87 (ZH, t), 2.48 (IN, t), 2.02 (2H, t), 1.93 ( 2H, t), 1.74 (1H, t), 1.20 (ZH, t), 1.02 (2H, t).

Intermediate compound 102: methyl (Iakzv, 76b58)-5-(2-(aminomethyl)-4-fluorobenzenesulfonylamino)-1,Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate

NM at ,0 8

M o

N

E (c; ? (00448) A solution of potassium carbonate (2.1 g) in water was added to a solution of methyl (Takz, 7rzkK)-5-(4-fluoro-2-trifluoroacetylaminomethyl)benzenesulfonylamino)-1 a, 2.76- tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 103, 1.53 g) in methanol (50 mL), and the resulting mixture was stirred and heated at 45 "C for 4 hours. After cooling, the mixture was concentrated under vacuum, and the residue was diluted with water and saturated with salt. The resulting solid was collected by filtration, washed with water and ethyl acetate, then dried under vacuum at 50"C to obtain methyl (Takw5, 7p5K)-5-(2-aminomethyl)-4-fluorobenzenesulfonylamino)-1Ta, 2.7p -tetrahydrocyclopropa|sichromene-4-carboxylate (1.06 g) as a white solid.

1H NMR (DMSO-α) 6: 8.52 (1H, Bg 5), 7.99 (1H, da), 7.32 (2H, t), 6.89 (1H, a), 6, 74 (1H, 49), 4.32 (2H, 5), 4.17 (1H, ad), 3.70 (ZH, 5), 3.64 (IN, a), 1.82 (IN, t ), 1.65 (1H, t), 0.89 (IN, t), 0.61 (1H, t).

Intermediate compound 103: methyl (also 5, 7p5K)-5-(4-fluoro-2-trifluoroacetylaminomethyl)benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa|sichromene-4-carboxylate vs. M p o o o 5

M o

N

E o c)

IІ00449| Methyl (1ak5, 7B55K)-5-amino-1,1a,2,7B-tetrahydrocyclopropa|c|ichromene-4-carboxylate (Intermediate compound 42, 0.972 g) was added to a solution of 4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride ( Intermediate 104, 1.53 g) in DCM (25 mL) and pyridine (b mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with water, NSI (1 M), water, dried (M95905) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane, with a gradient of 5-30 95, to give methyl (tan, 7658)-5-(2-trifluoroacetylaminomethyl)-4-fluorobenzenesulfonylamino)-1, 1a, 2,716-tetrahydrocyclopropa-I|sichromene-4-carboxylate (1.76 g) in the form of a glassy foamy substance.

1H NMR (SOSI) 6: 9.04 (1H, Bg 5), 7.83 (1H, aa), 7.49 (IN, rg Yu, 7.30 (1H, aa), 7.29 (1H, a), 7.09 (IN, a), 7.06 (IN, ayu, 4.61 (2H, 9), 4.34 (IN, a), 3.78 (1H, aa), 3.73 (ZN, 5), 1.95 (IN, t), 1.75 (IN, t), 1.04 (2Н, t).

Intermediate 104: 4-Fluoro-2-(trifluoroacetylaminomethyl)/benzenesulfonyl chloride

N

EC. M

Shen

R

00450) 3-Fluoro-M-trifluoroacetylbenzylamine (Intermediate 105, 1.11 g) was added portionwise to chlorosulfonic acid (5 mL) with stirring and cooling in an ice bath.

After the addition was complete, the ice bath was removed, and the mixture was allowed to warm to room temperature, then heated to 70 °C for 3 hours. After cooling, the mixture was slowly added to ice, and the resulting suspension was extracted with ethyl acetate, washed with water, dried (M9504), and filtered. The filtrate evaporated to a dry residue to give 4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride (1.53 g) as a brown solid.

1H NMR (SOCI3) 6: 8.18 (1H, aa), 7.47 (1H, t), 7.29 (1H, t), 7.18 (1H, Bg 5), 4.92 ( 2H, a).

Intermediate 105: 3-Fluoro-M-trifluoroacetylbenzylamine

N

May

IS

I00451| Trifluoroacetic anhydride (5.05 g) was added dropwise to an ice-cooled solution of 3-fluorobenzylamine (2.5 g) and triethylamine (2.22 g) in ethyl acetate (75 mL), maintaining the temperature below 10 °C. The mixture was stirred at -0-5 "C for 1 hour, then allowed to warm to room temperature and stirred for 2 hours. Water was added and the layers were separated. The organic layer was washed with water, dried (Mo950O4) and filtered. The filtrate was evaporated to a dry residue to give 3-fluoro-M-trifluoroacetylbenzylamine (4.58 g) as an oily substance which crystallized on standing to a white solid.

IN NMR (SOS z) 6: 7.34 (1H, t), 7.03 (ZH, t), 6.72 (1H, Bg 5), 4.53 (2H, a).

Intermediate compound 106: (5)-M-Ethylpyrrolidine-2-carboxylic acid 5:

M

A o 00452) Palladium on carbon (10 95, 0.2 g) was added to a solution of benzyl (5)-M-ethylpyrrolidine-2-carboxylate (Intermediate compound 107, 0.603 g) under a nitrogen atmosphere. Then the mixture was hydrogenated under a pressure of 4 bar for 3 hours. The mixture was filtered through Celite and the filtrate was evaporated to a dry residue to give (5)-N-ethylpyrrolidine-2-carboxylic acid (0.378 g) as a straw-colored resinous solid.

IN NMR (SOSI") 6: 4.01 (1H, t), 3.78 (1H, t), 3.31 (1H, t), 3.18 (1H, t), 2.87 (IN, t), 2.38 (IN, t), 2.27 (1Н, t), 2.02 (2Н t), 1.39 (ЗН, и).

Intermediate 107: Benzyl (5)-N-ethylpyrrolidine-2-carboxylate hydrochloride

M x - 9 00453) Iodetane (1.34 g) was added to a mixture of benzyl (5)-pyrrolidine-2-carboxylate (1.0 g) and potassium carbonate (1.77 g) in dry DMF (7 mL), and the resulting mixture was stirred at room temperature for three days. The mixture was diluted with water, extracted with ethyl acetate, washed with water, dried (Mo5034) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane with a gradient of 10-20 95, to give benzyl (5)-M-ethylpyrrolidine-2-carboxylate (0.643 g) as an oily substance, pale salt of the same color.

1H NMR (SOSI) 6: 7.35 (5H, t), 5.17 (2H, 5), 3.19 (2H, t), 2.74 (1H, t), 2.45 ( 1H, t), 2.34 (IN, t), 2.12 (1H, t), 1.93 (2H, t), 1.81 (IN, t), 1.10 (ЗН, М).

Intermediate compound 108: methyl (Takz, 7p5K)-5-(2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa-(siIchromene-4-carboxylate)

IF) ol no o

T8

M (c) uo

E (c)?

I(00454| Mixture of methyl (Tak5, 7B5K)-5-M-|methoxycarbonyl|-M-(2-(4-chlorobutyrylamino)-4-fluorobenzenesulfonylamino)-1 a, 2,7B-tetrahydrocyclopropa-I|cYchromene-4 -carboxylate (Intermediate compound 109, 0.15 g) and dimethylamine (30 905 aqueous solution, 5 ml) in acetonitrile (10 ml) were stirred and heated at 40"C for 10 hours. After cooling, the mixture was concentrated under vacuum, and the residue was extracted with a mixture of ethyl acetate and THF (50 95), dried (MA2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by thin-layer chromatography on silica gel, eluting with a mixture of methanol and DCM (1095), to give methyl (chTak5, 7B5K)-5- (2-(4-dimethylaminobutyrylamino)-4-

fluorobenzenesulfonylamino!|-1, Ta, 2,7p-tetrahydrocyclopropa-isochromene-4-carboxylate (0.14 g) in the form of a yellow oily substance.

LCMS (Method 0), retention time 1.24 (M--H) 506.

Intermediate 109: methyl pPax, 76B5K)-5-1M-Imethoxycarbonyl|-M-(2-(4-chlorobutyrylamino)-4-fluorobenzenesulfonyl|amino)-1,1a,-2,7p-tetrahydrocyclopropa-IsIchromene-4- carboxylate o sati no o

yours

M o in Hv and 7 (is; o

I00455| 4-Chlorobutyryl chloride (3.0 g) was added to a stirred, cooled solution of methyl (Takz5, 7B6B5E)-5-IM-(methoxycarbonyl)-M-(2-amino-4-fluorobenzenesulfonyl|amino)-1Ta, 2.7g -tetrahydrocyclopropa-|c|ichromene-4-carboxylate (Intermediate compound 110, 0.135 g) and triethylamine (1.0 g) in THF (10 mL) at 0 "C. After the addition was complete, the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate, dried (Ma2504) and filtered. . 15 g)) in the form of a yellow oily substance.

LCMS (Method 0), retention time 1.72 (MAN) 555.

Intermediate compound 110: methyl (Ta5,7B6B54)-5-I(IM-(methoxycarbonyl)-M-(2-amino-4-fluorobenzenesulfonyl)amino|-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate , Me

ZU

M c)

Su A o, and 76 o (00456) Mixture of methyl Pakzv, 7B5K)-5-(M-(methoxycarbonyl)-M-(4-fluoro-2-nitrobenzenesulfonyl)amino!1-1, 1a, 2,7B-tetrahydrocyclopropa |c|Ichromene-4-carboxylate (Intermediate compound 111, 0.2 g), zinc (0.54 g) and acetic acid (0.5 g) in ethanol (20 ml) were stirred and heated with a reflux for 1 hour. After cooling, the solid was filtered and the filtrate was evaporated to a dry residue. The residue was treated with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether. with a gradient of 30-5095, to obtain methyl (Ttak5, 7B6B51E)-5-(M-(methoxycarbonyl)-M-(2-amino-4-fluorobenzenesulfonyl)amino!|-1,1a, 2,7Bb-tetrahydrocyclopropa|sichromene -4-carboxylate (0.15 g) as a white solid.

1H NMR (SOSI") 6: 7.74 (1H, t), 7.36 (1H, a), 6.95 (1H, 4), 6.47 (1H, t), 6.39 ( 1H, a), 5.37 (2H, t), 4.42 (1H, t), 3.91 (IN, a), 3.74 (ЗН, 25), 3.70 (ЗН, 25), 2.06 (1H, t), 1.84 (1H, t), 1.28 (1H, t), 1.15 (1H, t).

Intermediate compound 111: methyl (Ta5,7p5K)-5-I(M-(methoxycarbonyl)-M-(4-fluoro-2-nitrobenzenesulfonyl)amino!|-1Ta, 2,7b-tetrahydrocyclopropa(c|Ichromene-4 -carboxylate

MO; ro)

ZU

M c) su He and To o

I00457| A solution of methyl (х1акз5, 7р5Н)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1,1а,2,7р-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 112.0.25g) in THF (10 ml) was added dropwise with stirring to a cooled suspension of sodium hydride (0.1 g) in THF (5 ml) at 0 "C. After completion of the addition, the mixture was stirred at room temperature for 30 minutes. Methyl chloroformate (0.3 g) was added dropwise and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Ma 2 O 4 ) and filtered. The filtrate was evaporated to a dry residue and the residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and petroleum ether, to give production of methyl (Takz, 76551E)-5-(M-(methoxycarbonyl)-

M-(4-fluoro-2-nitrobenzenesulfonyl)amino!|-1Ta, 2,7p-tetrahydrocyclopropa-|c|ichromene-4-carboxylate (0.2 g) in the form of a white solid.

LCMS (Method 0), retention time 1.58 (M--H) 481.

Intermediate compound 112: methyl (Tak5, 765K)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

MO, O o to 5

M (c) (U ;

E (c) t

I(00458| Mixture of methyl (also 5, 7B5K)-5-amino-1,1a, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylate (Intermediate compound 42, 0.1 g), 4-fluoro-2-nitrobenzenesulfonyl chloride (0.115 g) and pyridine (2 mL) in DCM (5 mL) were stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Ma2504) and filtered, and the filtrate was evaporated to dryness The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (2095), to obtain methyl (1akz, 7B65E)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|c| Ichromene-4-carboxylate (0.11 g) in the form of a yellow oily substance.

1H NMR (SOSI) 6: 8.56 (1H, Bg 5), 7.92 (1H, t), 7.55 (1H, ad), 7.31 (2H, t), 7.24 (1H, t), 4.34 (IN, a), 3.85 (ZH, 5), 3.82 (1H, a), 1.98 (1H, t), 1.74 (1H, t) , 1.08 (2H, t).

Intermediate compound 113: methyl (Ta5,7BK)-5-(2-(5)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate o and Y on 5 Zh

M o

N

E (c)?

IІ00459| A solution of methyl 5-amino-11a, 2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylate (Intermediate 42, 0.19 g) in DCM (10 mL) in pyridine (3.5 mL) was treated with a solution of 2-( (5)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate compound 114, 0.26 g) in DCM (5 ml) and stirred, and the mixture was heated at 40 "C for 1 hour. The resulting mixture was evaporated to dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of DCM and methanol, with a gradient of 0-25 95, then washed with 100 95 methanol to obtain methyl (Tab, 70K)-5-(2-((5)-1-ethylpyrrolidine) -3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylate (0.107 g) in the form of a resinous substance.

LCMS (Method A), retention time 2.29 (M.--H) 489.

Intermediate compound 114: 2-((5)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride xi 9 ro) 5 Zx

SI

IS

I00460| Obtained in the same way as Intermediate 96, starting from (5)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (Intermediate 115).

LCMS (Method A), retention time 1.95 (M.--H) 308.

Intermediate 115: (5)-1-Ethyl-3-(3-fluorobenzyl)pyrrolidine

Mk

EE

I00461| Obtained in the same way as Intermediate 97, starting from 3-(5)-(3-fluorobenzyl)pyrrolidine (Intermediate 116).

IN NMR (SOSI»z) 6: 7.22 (1H, t), 6.95 (1H, 4), 6.88 (2H, t), 2.81-2.62 (4H, Big t), 2.61-2.39 (AN,

Be t), 2.21 (1H, Big 5), 1.99 (1H, t), 1.52 (1H, t), 1.11 (ZH, ).

Intermediate 116: 3-(5)-(3-Fluorobenzyl)-pyrrolidine no 00462) Prepared in the same manner as Intermediate 98 starting from tert-Butyl (5)-3-(3-fluorobenzyl)-pyrrolidine-1 -carboxylate (Intermediate compound 117).

1H NMR (SOSI") 6: 7.27 (1H, t), 6.96-6.84 (ZH, t), 3.32 (IN, t), 3.25 (1H, aa), 3.16 (1H, t), 2.83 (IN, t), 2.73 (2H, 9), 2.58 (IN, t), 2.08 (1H, t), 1.68 (1H , t).

Intermediate compound 117: tert-Butyl (5)-3-(3-fluorobenzyl)-pyrrolidine-1-carboxylate i)

wow oh

EE and 00463) was obtained in the same way as Intermediate 99, starting from tert-Butyl (5)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 118).

IN NMR (SOCI3) 6: 7.27 (1H, t), 6.97-6.83 (ZH, t), 3.46 (2H, t), 3.25 (1H, t), 2.98 (1H, t), 2.67 (2H, t), 2.40 (1H, t), 1.91 (1H, t), 1.58 (IN, t), 1.45 (9H, 5) .

Intermediate compound 118: tert-Butyl (5)-3-iodomethylpyrrolidine-1-carboxylate 6);

In about 1

I00464| Obtained in the same way as Intermediate 100, starting from tert-butyl (5)-3-hydroxymethylpyrrolidine-1-carboxylate.

Н"Н NMR (СОСИ") b: 3.59 (1Н, аЯ), 3.51 (1Н, т), 3.33 (НН, т), 3.19 (2Н, 4), 3.02 ( 1H, ad), 2.49 (IN, t), 2.07 (1H, t), 1.65 (1H, t), 1.46 (9H, 5).

Intermediate compound 119: tert-Butyl (1akz, 7p5K)-5-12-(M-(2,4-dimethoxybenzyl)-M-(3-dimethylaminopropyl)ucarbamoyl|Ibrensolsulfonylamino)-1Ta, 2,7- tetrahydrocyclopropa|sichromene -4-carboxylate rora a o o,,0

X Zh

M o

N

J

00465) A solution of M-(2,4-dimethoxybenzyl)-M-(3-dimethylaminopropylamine (Intermediate compound 120, 0.179 g) in DCM (2 ml) was added dropwise with stirring to a cooled solution of 2-chlorosulfonylbenzoyl chloride (Intermediate compound 121, 0 ,17 g) in DCM (20 ml) at 0 "C. The mixture was stirred at 0 "C for 1 hour, then a solution of tert-butyl (Yes, 7p5K)-5-amino-1a, 2,7b-tetrahydrocyclopropa- |cychromene-4-carboxylate (Intermediate 122, 0.185 g) in DCM (2 mL). The resulting mixture was stirred and heated at 30-35 "C overnight. After cooling, the mixture was concentrated under vacuum, and the residue was purified by HPLC (C18) for preparation of tert-butyl (akz, 7L5K)-5-12-(M-(2,4-dimethoxybenzyl)-M-(3-dimethylaminopropyl)/carbamoyl|-benzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-

Isochromene-4-carboxylate (0.03 g) in the form of a yellow oily substance.

LCMS (Method 0), retention time 3.16 (M--H) 680.

Intermediate compound 120: M-(2,4-Dimethoxybenzyl)-M-(3-dimethylaminopropyl)amine ra o.

SAAZHT

M

I00466| A mixture of 3-dimethylaminopropylamine (3.06 g), 2,4-dimethoxybenzaldehyde (6.0 g) and sodium triacetoxyborohydride (9.54 g) in methanol (20 ml) was stirred at room temperature for 10 hours. The mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate and washed with water and saturated saline, dried (Ma25904) and filtered. The filtrate was evaporated to a dry residue to give M-(2,4-dimethoxybenzyl)-

M-(3-dimethylaminopropyl)amine (7.2 g) as a brown oily substance, which was used directly without further characterization.

Intermediate 121: 2-Chlorosulfonylbenzoyl chloride

SI (in) 0, i Zh

SI

I00467| A mixture of 1,1-dioxo-1H-Ilambda"b"benzoyl|c|I(/1,2|oxathiol-3-one (4.5 g) and phosphorus pentachloride (15 g) was stirred and heated at 60°C overnight After cooling, a mixture of ice and water was added, and the solution was extracted with DCM, dried (Ma25054), and filtered.

Intermediate compound 122: tert-Butyl (Takz, 7BrB5K)-5-amino-1Ta, 2,7p-tetrahydrocyclopropa-

Isochromene-4-carboxylate (c) o zo Zh (00468) Sodium borohydride (0.32 g) was added in portions to a stirred solution of tert-Butyl (tan, 7658)-5-(trifluoroacetylamino)-1,1a, 2,7p- of tetrahydrocyclopropa-|sichromene-4-carboxylate (Intermediate compound 123, 0.5 g) in ethanol (20 ml). The resulting mixture was stirred at room temperature for 1 hour, then concentrated under vacuum. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether with a gradient of 2-495, to obtain tert-Butyl (tak5,7p5K)-5-amino-1,1a,2,7B-tetrahydrocyclopropa-|sichromene-4-carboxylate ( 0.2 g) in the form of a white solid.

1H NMR (SOCI) 6: 7.04 (1H, 9), 6.25 (1H, a), 4.57 (2H, Lg 5), 4.32 (1H, a), 3.87 (IN, 9), 1.86 (IN, t), 1.65 (1H, t), 1.60 (9H, 5), 0.95 (2H, t).

Intermediate compound 123: tert-Butyl (Iax5,7B5K)-5-(trifluoroacetylamino)-1,1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate o shka o

N

J

I00469| Mixture (Takz5, 7B65K)-5-("trifluoroacetylamino)-1,1a, 2,7p-tetrahydrocyclopropa-

isochromene-4-carboxylic acid (Intermediate 124, 0.97 g), OMAR (02 p), dicyclohexylcarbodiamide (1.33 g) and di-tert-butyl dicarbonate (3.51 g) in tert-butanol (20 ml) stirred and heated with a dephlegmator for 7 hours. After cooling, the mixture was concentrated under vacuum, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (2 95), to obtain tert-Butyl (Yes, 765K)-5-(trifluoroacetylamino)-1,1a, 2,7p- tetrahydrocyclopropa|siIchromene-4-carboxylate (0.5 g) in the form of a yellow oily substance.

IN NMR (SOSI") 6: 10.47 (1H, Bg 5), 7.89 (1H, 4), 7.34 (IN, a), 4.39 (1H, 4), 3.88 (1H , a), 2.02 (IN, t), 1.77 (1H, t), 1.60 (9H, 5), 1.09 (2H, t).

Intermediate compound 124: pPax, 7tb5K)-5-trifluoroacetylamino)-1Ta, 2,7p-tetrahydrocyclopropa-[sichromene-4-carboxylic acid o a (c)

N

(c) he

I00470| Trifluoroacetic anhydride (2.98 g) was added dropwise to a stirred, cooled solution of (also 5, 7B54K)-5-amino-1,1a, 2,7p-tetrahydrocyclopropa-(sichromene-4-carboxylic acid) (Intermediate compound 125, 0, 97 g) and triethylamine (2.39 g) in THF (20 ml).

The resulting mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate, dried (Ma2509054) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (2 95), to obtain (also, 70B5K)-5-(trifluoroacetylamino)-1/1a, 2,7p-tetrahydrocyclopropa-IsIIchromene- 4-carboxylic acid (0.97 g) as a white solid.

1H NMR (DMSO-dv) 6: 7.92 (1H, 4), 7.28 (1H, 4), 4.54 (1H, a), 3.94 (1H, 49), 2.27 (1H, t), 2.02 (IN, t), 1.21 (IN, t), 0.95 (1H, t).

Intermediate compound 125: (yes, 7B5K)-5-Amino-1,1a, 2,7p-tetrahydrocyclopropa|c|Ichromene-4-carboxylic acid (c) one

I00471| A mixture of methyl (Takz, 7B5K)-5-amino-1,1Ta,2,7rb-tetrahydrocyclopropa|c|Ichromene-4-carboxylate (Intermediate compound 42, 1.0 g) and lithium hydroxide monohydrate (0.96 g) in dioxane (16 ml) and water (14 ml) were mixed and heated at 90 "C for 1 hour. After cooling, the mixture was concentrated under vacuum, and the residue was diluted with water and neutralized to pH 7 with formic acid. Then the mixture was extracted with ethyl acetate, dried (Ma250904) and filtered, and the filtrate was evaporated to a dry residue to obtain (T1akz, 7B5K)-5-amino-11a, 2,7b-tetrahydrocyclopropa-|c|ichromene-4-carboxylic acid (0.97 g) as a yellow oily substance.

LCMS (Method 0), retention time 2.13 (M.--H) 206.

Intermediate compound 126: methyl (Ta5, 7p55)-5-(2-M-(5)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|-methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2.7 - tetrahydrocyclopropa(|siIchromene-4-carboxylate o

Ka m

Oh 22o

ZU

M i)

N

E c) 7 (00472| EOAS (0.058 g) was added to the mixed solution of methyl (chTakz, 7B51kK)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|c|Yichromene-4- carboxylate (Intermediate 83, 0.109 g) in DCM (3 mL) and the mixture was stirred at room temperature for 10 min. A solution of M-((5)-1-ethylpyrrolidin-3-yl)y-M-methylamine dihydrochloride (Intermediate compound 127, 0.102 g) and triethylamine (0.151 g) in DCM (3 mL) and the mixture was stirred for 17 h. The mixture was concentrated by mass evaporation, and the residue was dissolved in dioxane (4 mL) and the mixture was heated at 75 °C for 20 h. After cooling, the mixture was diluted

DCM and water and filtered through a phase separator. The filtrate was evaporated in a vacuum, and the residue was combined with the product of the same reaction performed earlier. The material was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-50 95, to obtain methyl (Tanz, 7658)-5-(2-1(5)-1-ethylpyrrolidin-3-ylmethylcarbamoyl|methyl)-4- fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (0.48 g) in the form of a light brown foamy substance.

LCMS (Method E), retention time 2.65 (MN) 546.

Intermediate compound 127: M-((5)-1-Ethylpyrrolidin-3-yl)-M-methylamine dihydrochloride "MH

AND

A - 2 NOI

I00473| A mixture of benzyl M-((5)-1-ethylpyrrolidin-3-yl-M-methylcarbamate (Intermediate 128, 0.682 g) and 10 95 palladium on carbon (0.10 g) in ethanol (20 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixture was filtered and concentrated hydrochloric acid (2 mL) was added. The solution was concentrated by mass, then re-dissolved in a mixture of toluene and ethanol, then re-evaporated to give M-((5)-1-ethylpyrrolidine-3 -yl)-M-methylamine dihydrochloride (0.531 g) in the form of a light-colored viscous oily substance, which was used without additional characterization.

Intermediate 128: Benzyl M-((5)-1-ethylpyrrolidin-3-yl)y-M-methylcarbamate that and

M

5

AND

I00474| A mixture of benzyl M-methyl-(5)-pyrrolidin-3-ylcarbamate (Intermediate 129, 1.28 g), iodate (0.853 g) and potassium carbonate (1.51 g) in acetonitrile (12 mL) was stirred at room temperature within 4 hours. The mixture was concentrated by massio, and the residue was basified with 5 M sodium hydroxide solution and filtered through a phase separator. The filtrate was concentrated in fat, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-30 95, to obtain benzyl M-((5)-1-ethylpyrrolidin-3-yl)y-M-methylcarbamate (0.686 g ) in the form of a colorless oily substance.

IN NMR (SOSI") b: 7.35 (5H, t), 5.13 (2H, 5), 4.84 (1H, Bg, 5), 2.91 (ZN, 5), 2.30-2, 82 (6H, t), 35. 212 (1H, horn, t), 1.79 (IN, t), 1.10 (ZN, U.

Intermediate 129: Benzyl M-methyl-(5)-pyrrolidin-3-ylcarbamate

X what:

M

M

N

(00475) A solution of tert-Butyl (5)-3-(M-benzyloxycarbonyl-M-methylamino)pyrrolidine-1-carboxylate (Intermediate compound 130, 1.81 g) in trifluoroacetic acid (8 ml) and DCM (8 ml) left to stand at room temperature for 30 minutes. The resulting mixture was concentrated by massio, and the residue was dissolved in DCM and saturated saline solution, basified with 2 M sodium hydroxide and filtered through a phase separator. The filtrate was concentrated by mass to give benzyl M-methyl-(5)-pyrrolidin-3-ylcarbamate (1.46 g) as a light colored oily substance.

NMR NMR (SOSI) 6: 7.35 (5Н, т), 5.14 (2Н, 5), 4.68 (1ТН, Bg, т), 3.08 (2Н, т), 2, 88 (ZN, 5), 2.76- 102.95 (ZN, t), 2.01 (IN, t), 1.75 (1Н, t).

Intermediate 130: tert-Butyl (5)-3-(M-benzyloxycarbonyl-M-methylamino)pyrrolidine-1-carboxylate

M in

M

00476) Sodium hydride (60 95 dispersion in oil, 0.32 g) was added to the mixed solution of tert-

Butyl (5)-3-benzyloxycarbonylaminopyrrolidine-i-carboxylate (obtained according to the publication of Spepo ei ai, M/O2007 142585, 1.73 g) in THF (20 ml) and the mixture was stirred for 15 minutes. Iodomethane (1.85 g) was added and the mixture was stirred at room temperature for 1 hour. Methanol was cautiously added to destroy excess sodium hydride, then ethyl acetate and water were added, and the organic layer was washed with brine, dried (Ma250544) and filtered. The filtrate was concentrated by mass to obtain tert-Butyl (5)-3-(M-benzyloxycarbonyl-M-methylamino)pyrrolidine-1-carboxylate (1.66 g) as a pale oily substance.

IN NMR (SOSI") 6: 7.36 (5H, t), 5.15 (2H, 5), 4.79 (1H, Bg, 5), 3.54 (2H, bBg, t), 3, 11-3.38 (2H, Big, t), 2.86 (ZH, 5), 1.98 (2H, t), 1.46 (9H, 5).

Intermediate compound 131: methyl (tTax5,7B5(kK)-5-(2-1M-(HA)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2, 7B-tetrahydrocyclopropa-

IsYichromene-4-carboxylate in Ii

M what tm (in)

N

E (c) t

I00477| It was obtained in the same way as Intermediate 126, starting from methyl (tan, 76b58)-5-(2-carboxymethyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7ter-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 83 ) and M-(B)-1-ethylpyrrolidine-

C-yl)-M-methylamine dihydrochloride (Intermediate compound 132), in the form of a light brown foamy substance.

LCMS (Method E), retention time 2.63 (M.N) 546

Intermediate 132: M-(A)-1-Ethylpyrrolidin-3-yl)-M-methylamine dihydrochloride

MN

VI -2 NOI (00478) Obtained in the same way as Intermediate 127, starting from benzyl M-((8)-1-ethylpyrrolidin-3-yl)-M-methylcarbamate (Intermediate 133), in the form of a viscous a light-colored oily substance that was used without further characterization.

Intermediate 133: Benzyl M-(A)-1-ethylpyrrolidin-3-yl)y-M-methylcarbamate that .

Same about

AND

I00479| Obtained in the same way as Intermediate 128, starting from benzyl M-methyl-(B)-pyrrolidine-Z-ylcarbamate (containing the bridged or fused rings of Intermediate 134) and iodate, in the form of a light-colored oily substance.

IN NMR (SOSI") b: 7.35 (5H, t), 5.13 (2H, 5), 4.84 (1H, Bg, 5), 2.91 (ZH, 5), 2.30- 2.87 (6H, t), 212 (IN, horn, t), 1.80 (IN, t), 1.10 (ZN, U.

Intermediate compound 134: Benzyl M-methyl-(H)-pyrrolidin-3-ylcarbamate - 7 o

M

N

(00480) Obtained in the same manner as Intermediate 129, starting from tert-Butyl (8)-3-(M-benzyloxycarbonyl-M-methylamino)-pyrrolidine-1-carboxylate (Intermediate 135), as a pale oily substance color

NMR NMR (SOSI) 6: 7.35 (5H, t), 5.14 (2H, 5), 4.79 (1H, Bg, 5), 3.08 (2H, t), 2, 88 (ZH, 5), 2.76-2.95 (ZH, t), 2.01 (1H, t), 1.75 (1H, t).

Intermediate 135: tert-Butyl (K)-3-(M-benzyloxycarbonyl-M-methylamino)pyrrolidine-1-carboxylate

X what. M-K

M

00481) Obtained in the same way as Intermediate 130, starting from tert-Butyl (8)-3-benzyloxycarbonylaminopyrrolidine-1-carboxylate (obtained according to publication 2poi egai, 05 2008 0293771) and iodomethane, in the form of an oily substance of pale color.

IN NMR (SOSI") 6: 7.35 (5H, t), 5.15 (2H, 5), 4.69 (1H, Bkg, 5), 3.54 (2H, bBg, t), 3, 11-3.38 (2H, Big, t), 2.86 (ZH, 5), 1.98 (2H, t), 1.46 (9H, 5).

Intermediate 136: 2((5)-1-Ethylpyrrolidin-2-yl)ethylamine ol (004821 ((5)-1-Acetylpyrrolidin-2-yl)acetonitrile (Intermediate 137, 1.0 g) was added in portions to the stirred , a cooled solution of lithium aluminum hydride (0.36 g) in THF (30 ml) under a nitrogen atmosphere, maintaining the temperature at 0 "C. The mixture was allowed to warm to room temperature, then heated with a reflux for 2 hours. After cooling, ethanol was added dropwise ( 4 mL), and the resulting solid was filtered.

NMR NMR (0209) 6: 3.59 (1H, t), 3.37 (2H, t), 3.01 (4H, t), 2.24 (2H, t), 1.98 (ЗН , t), 1.65 (IN, t), 1.21 (ZN, U.

Intermediate 137: ((5)-1-Acetylpyrrolidin-2-yl)acetonitrile ra o (00483) Acetyl chloride (8.6 g) was added dropwise to a stirred, cooled solution of ((5)-pyrrolidin-2-ylacetonitrile hydrochloride ( Intermediate 138, 8.0 g) and triethylamine (16.5 g) in DCM (80 mL), maintaining the temperature at 0 °C. The resulting solution was stirred at 07 for 30 min. Water was added and the layers were separated. The aqueous layer was further extracted DCM, and the combined organic layers were washed with brine, dried (Ma25954), and filtered. 5.0 g) in the form of a light yellow oily substance, which was used directly, without additional determination of characteristics.

Intermediate 138: ((5)-Pyrrolidin-2-ylacetonitrile hydrochloride

N

NOAH

I00484| A solution of tert-Butyl (5)-2-cyanomethylpyrrolidine-1-carboxylate (Intermediate 139, 13.0 g) in methanol (130 mL) and concentrated hydrochloric acid (13 mL) was stirred and heated at 40 °C overnight. After after cooling, the mixture was concentrated under vacuum, and the residue was diluted with toluene and re-concentrated. Ethanol (20 mL) was added, and the resulting solid was collected by filtration and washed with hexane to give ((5)-pyrrolidin-2-yl)acetonitrile hydrochloride (8.0 g ) in the form of a white solid.

LCMS (Method 0), retention time 0.50 (M.N) 111.

Intermediate compound 139: tert-Butyl (5)-2-cyanomethylpyrrolidine-1-carboxylate with o X

IІ00485| Sodium cyanide (8.2 g) was added to a solution of tert-butyl (5)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate compound 140, 29.6 g) in

DMSO (300 ml), and the resulting mixture was stirred and heated at 90 "C for 5.5 hours. After cooling, the mixture was treated with a saturated aqueous solution of iron (II) sulfate and the mixture was stirred for another 5 hours, then extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (5905) to give tert-Butyl (5)-2-cyanomethylpyrrolidine-1-carboxylate (13, 0 g) in the form of a light yellow oily substance, which was used without additional determination of characteristics.

Intermediate compound 140: tert-Butyl (5)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate

AND

I00486| 4-Methylbenzenesulfonyl chloride (22.7 g) was added in portions to a stirred, cooled solution of tert-butyl (5)-2-hydroxymethylpyrrolidine-1-carboxylate (20.0 g) in pyridine (70 ml), maintaining the temperature at 0 "C. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in DCM and washed with water and saturated aqueous sodium bicarbonate and brine, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue to give tert-Butyl (5)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (34 g) in the form of a yellow oily substance, which was used without further characterization.

Intermediate 141: 2-((A)-1-Ethylpyrrolidin-2-yl)ethylamine

I00487| Prepared in the same manner as Intermediate 136 starting from ((5)-1-acetylpyrrolidin-2-yl)luacetonitrile (Intermediate 142) and used without further characterization.

Intermediate compound 142: (K)-1-Acetylpyrrolidine-2-yl acetonitrile -

I00488| It was prepared in the same way as Intermediate 137, starting from ((K)-pyrrolidin-2-yl acetonitrile hydrochloride (Intermediate 143), and used without further characterization.

Intermediate 143: (K)-Pyrrolidin-2-yl)lacetonitrile hydrochloride

N

NOAH

(00489) Prepared in the same manner as Intermediate 138 from tert-Butyl (8)-2-cyanomethylpyrrolidine-1-carboxylate (Intermediate 144) and used without further characterization.

Intermediate compound 144: tert-Butyl (K)-2-cyanomethylpyrrolidine-1-carboxylate and G

I00490| Prepared in the same manner as Intermediate 139, starting from tert-Butyl (8)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 145), and used without further characterization.

Intermediate compound 145: tert-Butyl (K)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate vv) these

H

I00491| Obtained in the same way as Intermediate 140, starting from tert-Butyl (8)-2-hydroxymethylpyrrolidine-1-carboxylate, and used without further characterization.

Intermediate compound 146: methyl (Takz, 7065K)-5-(2-1(B)-1-ethylpyrrolidin-2-yl)ucarbonylamino|- methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa(| c|Ichromene-4-carboxylate

With

And what about, m (s; ; 8

M o

N

E (c)?

I00492| Obtained in the same way as Intermediate 101, starting from methyl (tan, 7658)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1a, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 102) and (K)-1-ethylpyrrolidine-2-carboxylic acid (Intermediate 147), as a solid.

LCMS (Method B), retention time 2.37 (MAN) 532

Intermediate compound 147: (K)-1-Ethylpyrrolidine-2-carboxylic acid also

M NO

4 IF) 00493) Obtained in the same way as Intermediate 106, starting from tert-Butyl (8)-1-ethylpyrrolidine-2-carboxylate (Intermediate 148), as a solid.

I"H NMR (SOSI") 6: 3.99 (1H, t), 3.76 (1TH, da), 3.37-3.23 (1H, t), 3.21-3.08 (IN , t), 2.84 (1H, au, 2.45-2.21 (2H, t), 2.07-1.94 (2H, t), 1.39 (ZH, .

Intermediate 148: Benzyl (K)-1-ethylpyrrolidine-2-carboxylate with

M Ka -o

I00494| Obtained in the same way as Intermediate 107, starting from benzyl (K)-pyrrolidine-2-carboxylate, in the form of a colorless oily substance.

IN NMR (SOS ») b: 7.34 (5H, t), 5.17 (2H, 5), 3.19 (2H, t), 2.75 (1H, t), 2.45 (1H, t), 2.33 (IN, t), 2.12 (1Н, t), 1.93 (2Н, t), 1.81 (1Н, t), 1.09 (ЗН, У.

Intermediate compound 149: (1-Ethylazetidin-3-yl)methylamine gu -

І00495| A solution of 3-I|bis-(tert-butoxycarbonylamino)methyl|-1-ethylazetidine (Intermediate compound 150, 0.83 g) in a mixture of methanol (6 ml) and concentrated hydrochloric acid (1 ml) was stirred and heated at 50 "С for 3 hours. After cooling, the mixture was concentrated in vacuo, and the residue was dissolved in isopropanol and treated with potassium carbonate (3 g). The mixture was stirred at room temperature for 48 hours, then the solid was filtered off and the filtrate was evaporated to a dry residue to give (1- ethylazetidin-3-yl)umethylamine (0.18 g) in the form of a light viscous resinous substance, which was used without additional determination of characteristics.

Intermediate compound 150: 3-I(bis-(tert-Butoxycarbonylamino)methyl)|-1-ethylazetidine in put -

I00496| A mixture of acetaldehyde (1.5 g) and 3-bis-(tert-butoxycarbonylamino)methyliazetidine (Intermediate 151, 1.0 g) in ethanol (20 mL) was stirred at room temperature for 30 minutes, then 10 95 palladium on carbon was added (0.3 g). The mixture was stirred under hydrogen overnight. The solid was filtered off and the filtrate was evaporated to a dry residue. The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and

DXM (10 95), to obtain 3-|bis-(tert-butoxycarbonylamino)methyl/|-1-ethylazetidine (0.83 g) as a colorless liquid, which was used without further characterization.

Intermediate 151: 3-[bis-(tert-Butoxycarbonylamino)methyl]iazetidine

I am

Ime (00497 A mixture of 3-Ibis-(tert-butoxycarbonylamino)methyl|-1-(diphenylmethyl)azetidine (Intermediate 152, 6.4 g) and 10 95 palladium on carbon (3 g) in ethanol (100 mL) and acetic acid (2 mL) was stirred under hydrogen overnight. The solid was filtered off and the filtrate was evaporated to a dry residue. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate solution, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM (10 95), to obtain 3-I|bis-(tert-butoxycarbonylamino)methyl|azetidine (4.0 g) in the form of a colorless liquid, which was used without additional characterization.

Intermediate 152: 3-|bis-(tert-Butoxycarbonylamino)methyl|-1-(diphenylmethyl)-azetidine

Eh

Oostrkh

M

F vi (00498) Di-tert-butyl dicarbonate (22 g) was added to a solution of 1-(diphenylmethyl)azetidin-3-ylmethylamine (5 g), OMAR (0.5 g) and triethylamine (12 g) in THF (150 ml ), and the resulting solution was stirred and heated at bbo C for 5 hours. After cooling, the mixture was added to saturated saline solution and extracted with ethyl acetate, washed with saturated saline solution, dried (Ma2O4) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (10 95), to give 3-Ibis-(tert-butoxycarbonylamino)methyl-1-(diphenylmethyl)azetidine (6.4 g) in in the form of a white solid, which was used without additional characterization.

Intermediate 153: methyl pPax, 7B5K)-5-(2-(2)-3-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylate

M

She

ZU

M (in)

N t

І00499| A mixture of methyl (Tax5, 7p5K)-5-(2-bromobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 154, 0.612 g), M, M-diethyl-M- (( 2)-1-tributylstananylprop-1-ene-3-ylamine (Intermediate 11, 1.13 g), tri-tert-butylphosphonium tetrafluoroborate (0.041 g), tris-(dibenzylideneacetone) dipalladium (0.064 g) in dioxane (12 ml) and DMSO (0.4 ml) were degassed, purged with nitrogen, then heated at 100 s for 1.5 hours. After cooling, the mixture was diluted with saturated saline and extracted with ethyl acetate. The organic layer was washed with water, dried (Ma2504) and filtered. The filtrate evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-1595, to give methyl (Tanz, 7B5NA)-5-(2-(2)-3-diethylaminoprop-1-enyl) /benzenesulfonylamino|-1 a, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylate (0.495 g) in the form of a solid substance.

1H NMR (SOSI") 6: 8.06 (1H, ad), 7.52 (1H, t), 7.40 (1H, t), 7.30 (1H, t), 7.14 ( IN, a), 7.01 (IN, t), 6.86 (IN, a), 6.02 (1H, t), 4.93 (1H, a), 3.84 (ЗН, 5), 3.77 (1H, 9), 3.12 (2H, horn 5), 2.51 (AN, Bi 5), 1.687 (1H, t), 1.70 (1H, t), 1.05-0 .85 (VN, t).

Intermediate compound 154: methyl (Tak5, 7p5K)-5-(2-bromobenzenesulfonylamino)-1,1a, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylate 81

M (in)

00500) 2-Bromobenzenesulfonyl chloride (0.559 g) was added to a solution of methyl (Takw, 70B5NA)-5-amino-1Ta, 2,7p-tetrahydrocyclopropa(|2,3-siIchromene-4-carboxylate (Intermediate compound 42, 0 .40 g) in DCM (12 mL) and pyridine (4 mL), and the resulting mixture was stirred at room temperature for 1 h. The mixture was evaporated to a dry residue, and the residue was dissolved in DCM and washed with 2

N NOI, dried (Ma250544) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-35 95, to obtain methyl (Takz, 755K)-5-(2-bromo-benzenesulfonylamino)-1Ta, 2.7p -tetrahydrocyclopropa|sichromene-4-carboxylate (0.612 g) in the form of a solid substance.

IN NMR (SOCI3) 6: 9.85 (1H, 5), 7.89 (1H, aa), 7.85 (1H, av), 7.57-7.49 (2H, t), 7.26 (1H, a), 6.64 (Na), 427 (1H, a), 3.72 (1H, a), 3.66 (ZH, 5), 2.05-1.95 (1H, t) , 1.86-1.76 (1H, t), 1.08-0.98 (1H, t), 0.84-0.76 (1H, t).

Intermediate 155: methyl (yes, 765K)-5-(2-1M-((B)-1-ethylpyrrolidin-2-yl)ucarbonyl|-M-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a, 2, 7p-tetrahydrocyclopropa-|(siIchromene-4-carboxylate

SH

Mt. oo to o u

M o

N

Eh oh?

I0O5011 NATO (0.136 g) was added to a mixture of Pakz, TtBK)-5-(4-fluoro-2-methylaminomethylbenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|c|chromene-4-carboxylate (Intermediate compound 156, 0.150 g ), (K)-1-ethylpyrrolidine-2-carboxylic acid (Intermediate 147, 0.061 g) and M,M-diisopropyl-M-ethylamine (0.124 mL) in DMF (5 mL) and the mixture was stirred for 3 days at room temperature temperature The volatiles were removed with oil and the residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 ml), saturated saline solution, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-10 95, to obtain methyl (Takz, 7605K)-5-(2-1М-|((А)-1- ethylpyrrolidin-2-yl)ucarbonyl|methylamino|-methyl)-4-fluorobenzenesulfonylamino)-1a, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylate (0.177 g) as a solid.

LCMS (RE method), retention time 2.33 (M.a-N) 546.

Intermediate compound 156: methyl pPax, t(5K)-5-(4-fluoro-2- methylaminomethylbenzenesulfonylamino)-1Ta, 2,7pO-tetrahydrocyclopropa|c|ichromene-4-carboxylate ne o, ro,

X Zh

M (in)

N

E (c) t 00502) A solution of potassium carbonate (0.345 g) in water (2 ml) was added to a solution of methyl (1akz, 7658)-5-(4-fluoro-2-(M-methyl-M-(2,2 ,2-trifluoroacetyl)-aminomethyl|-benzenesulfonylamino)-1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 157, 0.257 g) in methanol (12 ml) and heated the mixture at 45 "C for 3 hours . After cooling, the volatiles were removed by mass, and the residue was treated with water (30 mL) and saturated with sodium chloride, and extracted with ethyl acetate (50 mL). The organic layer was dried (Ma25054) and filtered, and the filtrate was evaporated to a dry residue to give methyl (Yes .

LCMS (Method B), retention time 2.14 (M.N) 421.

Intermediate 157: methyl Pakzv, 7tb5K)-5-(4-fluoro-2-(N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl|benzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa| SiIichromene-4-carboxylate in.

So (in) 5

M o

N

E (c)?

I0O50O3I A mixture of 4-fluoro-2-I(M-methyl-M-(2,2,2-trifluoroacetyl)aminomethyl|benzenesulfonyl chloride (Intermediate compound 158, 0.182 g) was added to a solution of methyl (Takb5, 7B5NIK)-5-amino- 1,1a,2,7B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 42, 0.100 g) in DCM (3 mL) and pyridine (1 mL), and the resulting mixture was stirred at room temperature for 1 h. The mixture was evaporated to dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-40 9o, to obtain methyl (Takz, 7B5K)-5-(4-fluoro-2-IM-methyl-

M-(2,2,2-trifluoroacetyl)aminomethyl|benzenesulfonylamino)-1Ta, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylate (0.257 g) as a solid.

LCMS (Method P), retention time 3.77 (MAN) 517.

Intermediate compound 158: 4-Fluoro-2-(M-methyl-M-(2,2,2-trifluoroacetyl)aminomethyl|benzenesulfonyl chloride, total oo 6) C

SI

IS

IІ00504| A solution of 3-fluoro-M-methyl-M-(trifluoroacetyl)/benzylamine (Intermediate 159, 0.497 g) in DHE (0.5 mL) was added to stirred, cooled chlorosulfonic acid (3 mL).

The mixture was allowed to warm to room temperature and then heated at 70°C for 3 hours. After cooling, the mixture was carefully added to a mixture of ice and water, then extracted with ethyl acetate, washed with water, dried (M9504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-1095, to obtain 4-fluoro-2-(M-methyl-M-(2,2,2-trifluoroacetyl)aminomethyl|-benzenesulfonyl chloride (0. 21 g) in the form of a transparent oily substance.

IN NMR (SOSI") 6: 8.20 (1H, t), 7.24 (1H, t), 7.01 (1H, 4), 5.21 (2H, 5), 3.24 (2H, 5), 3.13 (1H, 5).

Intermediate compound 159: 3-Fluoro-M-methyl-M-(trifluoroacetyl)benzylamine sor

IS

00505) A solution of 3-fluoro-M-(trifluoroacetyl)benzylamine (Intermediate compound 105, 0.508 g) in

THF (5 mL) was added to a stirred suspension of sodium hydride (60 95 dispersion in oil, 0.096 g) in

THF (5 ml). The resulting mixture was stirred at room temperature for 30 minutes.

Iodomethane (0.653 g) was added and the mixture was stirred at room temperature overnight.

The mixture was poured into water and extracted with ethyl acetate, washed with water, dried (Mo9509054) and filtered. The filtrate was evaporated to a dry residue to give 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (0.497 g) as a white solid.

1H NMR (SOCI3") b: 7.34 (1H, t), 7.10-6.90 (ZH, t), 4.63 (2H, 5), 3.07 (2H, 4), 2.94 (1H, 5).

Intermediate compound 160: methyl (Yes, 76B5K)-5-(2-(M-(5)-1-ethylpyrrolidine-2-ylcarbonyl-M-methylaminomethyl|-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa -|(ciichromene-4-carboxylate and about 5

M o

N

Oh, oh

IІ00506| Obtained in the same way as Intermediate 155, starting from methyl (tan, 7658)-5-(4-fluoro-2-methylaminomethylbenzenesulfonylamino-1Ta, 2,7-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 156) and (5)-1-ethylpyrrolidine-2-carboxylic acid (Intermediate compound 106), as a solid.

LCMS (Method B), retention time 2.47 (M.N) 546.

Intermediate compound 161: methyl (Tab, 705H)-5-(2-4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate tt about 0.20 r:

M 0) lo

E (c)?

І00507| A solution of methyl (Ta5,7B5K)-5-(2,4-difluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate compound 162, 0.675 g) and M,M-dimethylbutanediamine (0.496 g) ) in dioxane (20 ml) was stirred and heated at 80 "C for 17 hours, then left at room temperature for three days. The solution was diluted with ethyl acetate, washed with potassium carbonate solution and water, then dried (Ma2504) and filtered.

The filtrate was concentrated by massio, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-40 95, to obtain methyl (also, 7p5K)-5-(2-(4-dimethyl-aminobutylamino)-4-fluorobenzenesulfonylamino) !|-1,1a, 2,7B-tetrahydrocyclopropa-

Isochromene-4-carboxylate (0.499 g) in the form of a colorless resinous substance.

IN NMR (SOCI3) 6: 7.51 (1H, aa), 7.26 (1H, 49), 7.12 (IN, 49), 6.29 (2H, t), 6.00 (1H, g , 5), 4.31 (IN, 9), 3.75 (1Н, а), 3.50 (ЗН, 5), 3.01 (2Н, t), 2.25 (6Н, 5), 2 .11 (2H, U, 1.94 (IN, t), 1.73 (1H, t), 1.58 (4H, t), 1.03 (2H, t).

Intermediate compound 162: methyl (1ак5, 7р5К)-5-(-2,4-difluorobenzenesulfonylamino)-1Ta,

2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

E eye) 750

M (in)

E (c)? . 2 ml) and DCM (4 ml), and left the solution at room temperature for 2 hours.

The mixture was diluted with DCM water, washed with 2 M hydrochloric acid, dried (Ma2595) and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-30 to, to obtain methyl OPax, 7B5K)-5-(2,4-difluorobenzenesulfonylamino)-1,1a, 2,7tr - tetrahydrocyclopropa|sichromene-4-carboxylate (0.761 g) in the form of a light-colored resinous substance.

IN NMR (SOSIZ") 6: 8.90 (1H, Bg, 5), 7.82 (1H, t), 7.22 (1H, 4), 7.13 (1H, 4), 6.88 ( 2H, t), 4.32 (IN, a), 3.89 (ZH, 5), 3.79 (1H, a), 1.90 (1H, t), 1.71 (1H, t), 1.01 (2H, t).

Intermediate compound 163: (K)-1-Ethylpyrrolidin-3-ylmethyl)amine ure

IІ00509| Lithium aluminum hydride was added to a stirred solution of ((K)-1-acetylpyrrolidin-3-ylmethyl)amine (Intermediate 164, 1.5 g) in THF (50 mL), and the resulting mixture was stirred and refluxed for 2 hours. After cooling, ethanol was added slowly and the mixture was concentrated under vacuum. The residue was diluted with DCM and the solid was filtered off.

The filtrate was evaporated to a dry residue to give ((K)-1-ethylpyrrolidin-3-ylmethyl)amine (0.9 g) as a yellow solid.

LCMS (Method 0), retention time 0.396 (M.N) 129.

Intermediate 164: (K)-1-Acetylpyrrolidin-3-ylmethyl)amine kutya o 00510) Benzyl M-((5)-1-acetylpyrrolidin-3-ylmethyl)-M-benzylcarbamate mixture (Intermediate 165, 4.2 g) and palladium hydroxide on carbon (0.4 g) in methanol (42 ml) were stirred in a hydrogen atmosphere at 60 "C for 48 hours. The mixture was filtered, and the filtrate was evaporated to a dry residue to obtain ((K)-1-acetylpyrrolidine -3-ylmethyl)amine (1.5 g) in the form of a light yellow oily substance.

LCMS (Method 0), retention time 0.49 (M--H) 143.

Intermediate 165: Benzyl M-((5)-1-acetylpyrrolidin-3-ylmethyl)-M-benzylcarbamate that a c) g 00511) Acetyl chloride (2.86 g) was added to a stirred solution of benzyl M-((5)- pyrrolidin-3-ylmethyl)-M-benzylcarbamate (Intermediate 166, 5.9 g) and triethylamine (3.68 g) in DCM (80 ml) under cooling on ice. The resulting mixture was stirred at room temperature for 2 hours, then concentrated under vacuum. The residue was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate, dried (Ma2O4) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by silica gel chromatography, eluting with ethyl acetate, to give benzyl M-((5)-1-acetylpyrrolidin-3Z-ylmethyl)-

M-benzylcarbamate (4.2 g) in the form of a yellow oily substance.

LCMS (Method 0), retention time 1.65 (M.N) 367.

Intermediate 166: Benzyl M-(5)-pyrrolidin-3-ylmethyl)-M-benzylcarbamate which

FI o tert-Butyl (5)-3-N-benzyl-M-(benzyloxycarbonyl)aminomethyl|pyrrolidine-1-carboxylate (Intermediate compound 167, 11 g) was added dropwise to a solution of acetyl chloride (15 g) in methanol (50 ml ), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum, and the residue was purified by HPLC (C18) to give benzyl M-((5)-pyrrolidin-3-ylmethyl)-M-benzylcarbamate (8.0 g) as an off-white solid, which was used without additional definition of characteristics.

Intermediate 167: tert-Butyl (5)-3-(M-benzyl-M-(benzyloxycarbonyl)aminomethyl|pyrrolidine-1-carboxylate

Y Z o

Bite c) g (005121 A solution of tert-Butyl (K)-3-(M-benzyloxycarbonyl)aminomethylpyrrolidine-1-carboxylate (Intermediate compound 168, 19 g) in DMF (90 ml) was added dropwise to a suspension of sodium hydride (60 95 , 4.55 g) in DMF (100 mL). After stirring for 30 minutes, benzyl bromide (11.7 g) was added dropwise. The resulting mixture was stirred and heated at 70 C overnight. After cooling, a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (MA2504) and filtered. The filtrate was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (10 95) to give tert-Butyl (5)-3-N-benzyl-M-(benzyloxycarbonyl)iaminomethyl|- pyrrolidine-1-carboxylate (11.0 g) in the form of a light yellow oily substance, which was used without further characterization.

Intermediate compound 168: tert-Butyl (K)-3-(M-benzyloxycarbonyl)aminomethylpyrrolidine-1-carboxylate

AND

(o; 7th

X- y H o 00513) Benzyl chloroformate (14.1 g) was added dropwise to a cooled solution of tert-

Butyl (K)-3-aminomethylpyrrolidine-i-carboxylate (15 g) in THF (150 ml), keeping the temperature below 0 "C. After the addition was complete, triethylamine (15.2 g) was added dropwise.

The resulting mixture was stirred at -5 "C for 30 minutes, then at room temperature overnight. Saturated brine was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue to give tert-butyl (K)-3-(M-benzyloxycarbonyl)aminomethylpyrrolidine-1-carboxylate (23 g) in the form of a colorless viscous resinous substance, which was used without further characterization.

Intermediate compound 169: ((5)-1-Ethylpyrrolidin-3-yl)umethylamine su" mn,

I00514| Palladium on carbon (10 95, 0.3 g) was added to a solution of benzyl M-((5)-1-ethylpyrrolidin-3-ylmethyl)carbamate (Intermediate 170, 1.8 g) in methanol (20 mL), and the resulting mixture was stirred in a hydrogen atmosphere for 24 hours. The mixture was filtered and the filtrate was evaporated to a dry residue to give ((5)-1-ethylpyrrolidin-3-yl)umethylamine (0.8 g) as a colorless oily substance, which was used without further characterization.

Intermediate compound 170: Benzyl M-((5)-1-ethylpyrrolidin-3-ylmethyl)ucarbamate c) layer

N

Y00515| Iodethane (4.1 g) was added to a cooled mixture of benzyl M-(A)-pyrrolidin-3-ylmethyl)carbamate trifluoroacetate salt (Intermediate 171, 7.6 g) and potassium carbonate (12.2 g) in DMF (10 ml), maintaining the temperature at 0 "C. The mixture was then stirred at room temperature for 4 hours. Water was added and the mixture was extracted with ethyl acetate, washed with saturated brine, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue to give benzyl M-( (5)-1-ethylpyrrolidin-3-ylmethyl)carbamate (1.8 g) in the form of a colorless oily substance, which was used without additional characterization.

Intermediate compound 171: Benzyl M-(K)-pyrrolidin-3-ylmethyl)carbamate trifluoroacetate salt

Se.SO,Hn c) -

(00516) A mixture of tert-Butyl (5)-3-(M-benzyloxycarbonyl)aminomethylpyrrolidine-1-carboxylate (Intermediate 172, 8.0 g) in trifluoroacetic acid (10 mL) was stirred at room temperature for 5 hours. The mixture was concentrated under vacuum to give crude benzyl M-((B)-pyrrolidin-3-ylmethylucarbamate trifluoroacetate salt (7.6 g) as a light brown oily substance, which was used without further purification or characterization.

Intermediate compound 172: tert-Butyl (5)-3-(M-benzyloxycarbonyl)aminomethylpyrrolidine-1-carboxylate c) 9 -o

M c)

H- KU N o

I00517| It was prepared in the same way as Intermediate 168, starting from tert-Butyl (5)-3-aminomethylpyrrolidine-1-carboxylate, and used without further characterization.

Intermediate compound 173: methyl (х1ак5, 7Б514К)-5-(2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate in o va "M (o)

N

E (c)? (005181 Solution of 2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate compound 174, 0.368 g) and methyl (Tak5, 7B5K)-5-amino-1,1a, (2.7B - tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 42, 0.219 g) in pyridine (3 mL) and DCM (3 mL) was left to stand at room temperature for 17 h. The mixture was evaporated to mass, and the residue was dissolved in water and DCM, and the organic layer was dried (Ma2594) and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 50-100 96, to give a resinous substance, which was triturated with ether and filtered to give methyl ( 1akz, 76b58)-5-(2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino|-1Ta, 2,716-tetrahydrocyclopropa|sichromene-4-carboxylate (0.312 g) in the form of a white solid .

1H NMR (DMSO-av) 6: 9.95 (1H, Bg, 5), 7.81 (IN, da), 7.26 (2H, t), 6.89 (1H, aa), 6 .59 (1H, a), 4.75 (2H, 5), 4.29 (1H, a), 3.71 (1H, a), 3.62 (ZH, 5), 3.15 (4H, t), 2.70 (2H, U, 2.45 (2H, a), 2.02 (IN, t), 1.72 (1H, t), 1.06 (1H, t), 1.02 (ЗН, У), 0.80 (1Н, а).

Intermediate compound 174: 2-(4-Ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonyl chloride and o, 20 (c) ZK (Fi

IS

00519) Chlorosulfonic acid (2 mL) was added to 4-ethyl-1-(3-fluorobenzyl)-piperazin-2-one (Intermediate 175, 0.59 g) with stirring and cooling on ice. Cooling was removed, and the solution was stirred at room temperature for 4 hours, then carefully added to a mixture of ethyl acetate, ice, and sodium bicarbonate. The organic layer was dried (Ma2504) and filtered, and the filtrate was concentrated by mass to obtain 2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.37 g) as a colorless resinous substance.

LCMS (Method E), retention time 1.99 (M-H) 335, 337

Intermediate compound 175: 4-Ethyl-1-(3-fluorobenzyl)-piperazin-2-one a

IS

00520 Sodium hydride (60 95 dispersion in oil, 0.176 g) was added to a stirred solution of 4-ethylpiperazin-2-one (Intermediate 176, 0.512 g) in anhydrous THF (10 mL) and the mixture was stirred at room temperature for 10 minutes. 3-Fluorobenzyl bromide (0.827 g) was added and stirring was continued for 2 hours. The solution was diluted with water and ethyl acetate, and the organic layer was dried (Ma2504) and filtered. The filtrate was concentrated in fat, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-5 95, to obtain 4-ethyl-1-(3-fluorobenzyl)piperazin-2-one (0.595 g) as a colorless oily substances

IN NMR (SOSI") 6: 7.26 (1H, t), 6.91-7.10 (ZH, t), 4.61 (2H, 5), 3.27 (2H, U, 3.23 (2H, 5), 2.65 20. (2H, U, 2.48 (2H, 4), 1.09 (ZN, U.

Intermediate 176: 4-Ethylpiperazin-2-one

In ие (in)

I00521| A mixture of 2-oxopiperazine (1.07 g), iodate (1.72 g) and potassium carbonate (2.76 g) in acetonitrile (50 ml) was stirred at 55 °C for 3 hours. After cooling, the mixture was filtered and the filtrate was concentrated ip masso. The residue was triturated with DCM and filtered, and the filtrate was concentrated ip masso. The residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM with a gradient of 0-40 95, to give 4-ethylpiperazin-2-one (0.991 g) as a colorless oily substance.

IN NMR (SOSI") 6: 6.81 (1H, Bg, 5), 3.37 (2H, t), 3.14 (2H, 5), 2.66 (2H, 9, 2.50 (2H , 49), 1.11 (ZN,

IN.

Intermediate compound 177: methyl (TchTakv5, 7B5BK)-5-(2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa-(siIchromene-4-carboxylate)

AND

M o

N

Eh oh? (00522) 2-(1-Ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate compound 178, 0.165 g) was added to a solution of methyl (Tak5, 7p5K)-5-amino-1,1a, (2,7p-

tetrahydrocyclopropa|2,3-sichromene-4-carboxylate (Intermediate 42, 0.290 g) in DCM (5 mL) and pyridine (1 mL), and the resulting mixture was stirred at room temperature for 21 h.

The mixture was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of 2 M MNH in methanol and DCM, with a gradient of 0-20 95, to obtain methyl (Takz, 705K)-5-(2-(1-ethylpiperidine-4 -ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7tr-tetrahydrocyclopropa-|sichromene-4-carboxylate (0.200 g) as a solid.

LCMS (Method P), retention time 2.34 (MAN) 503

Intermediate compound 178: 2-(1-Ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonyl chloride author;

BY

SI

IS

005231) A solution of 1-ethyl-4-(3-fluorobenzyl)piperidine (Intermediate 179, 0.210 g) in DHE (1 mL) was added to chlorosulfonic acid (2 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was carefully added to a mixture of ice and water and extracted with DCM. The organic layer was dried (Ma2509054) and filtered, and the filtrate was evaporated to a dry residue to give 2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonyl chloride ( 0.290 g) as a solid.

IN NMR (SOCIz") 6: 8.17 (1H, aa), 7.17 (1H, t), 7.08 (1H, da), 3.59 (2H, a), 3.13-2, 99 (АН, т), 2.57 (2Н, т), 2.24 (2Н, т), 1.95-1.77 (ЗН, т), 1.47 (ЗН, У.

Intermediate compound 179: 1-Ethyl-4-(3-fluorobenzyl)piperidine and

IS

I00524| Bromoethane (0.1 mL) was added to a mixture of 4-(33-fluorobenzyl)piperidine (Intermediate 180, 0.259 g) and potassium carbonate (0.204 g) in acetonitrile (10 mL). The mixture was stirred for 20 hours, then filtered. The filtrate was acidified by adding a few drops of 2 M HCl. the solution was passed through a 5СХ-2 column (10 g). The product was eluted with 2 M ammonia in methanol, and the residue after evaporation was triturated with diethyl ether. The solid was filtered and the filtrate was concentrated by mass to give 1-ethyl-4-(3-fluorobenzyl)piperidine (0.210 g).

1H NMR (SOSI") 6: 7.24-7.16 (1Н, т), 6.94-6.79 (ЗН, т), 2.91 (2Н, а), 2.52 (2Н , ad), 2.36 (2H, 9), 1.682 (2H, 19), 1.68-1.57 (2H, t), 1.56-1.44 (1H, t), 1.30 ( 2H, t), 1.06 (ZH, 0).

Intermediate 180: 4-(3-Fluorobenzyl)piperidine

IS

00525) A mixture of benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (Intermediate compound 181, 1.05 g), 20 95 palladium hydroxide on carbon (0.227 g), IM5 (30 ml) and acetic acid (10 ml) , degassed with nitrogen, blown with vacuum. The mixture was placed in a hydrogen atmosphere with rapid stirring. After 2 hours, the mixture was filtered, and the filtrate was diluted with water (40 ml) and neutralized with Ma2СО3. The solution was saturated with sodium chloride, extracted with ethyl acetate, dried (M95054) and filtered. The filtrate was concentrated in oil, and the residue was dissolved in a mixture of methanol and water (20 ml, 1:1) and passed through a 5СХ-2 column. The product was eluted with 2 M ammonia to give 4-(3-fluorobenzyl)piperidine (0.532 g).

IN NMR (SOSIZ»z) 6: 7.24-7.16 (1Н, т), 6.95-6.77 (ЗН, т), 3.04 (2Н, а), 2.56 (2Н, aa), 2.51 (2H, 9), 1.71-1.54 (ZH, t), 1.42 (1H, 5), 1.14 (2H, t)

Intermediate compound 181: Benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate i) su ch

IS

I00526| Sodium hydride (0.245 g) was added in portions to a solution of diethyl (3-fluorobenzyl)uphosphonate (Intermediate compound 182, 1 g) in THF (40 ml) at 0°C. The mixture was stirred for 30 minutes, then 4-oxopiperidine-1-benzyl was added -carboxylate (0.947 g) at 0 "С. The mixture was allowed to warm to room temperature and stirred for 21.5 hours. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated saline, dried (Ma2O4) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25 95, to give benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (1.05 g). "H NMR (SOS33) 6: 7.39-7.22 (6H, t), 6.98-6.83 (3H, t), 6.33 (1H, 5), 5.15 (2H, 5 ), 3.54 (4H, a), 2.41 (4H, au.

Intermediate 182: Diethyl (3-fluorobenzyl)/phosphonate o do

Sho

IS

(00527| A mixture of 3-fluorobenzyl bromide (2 g) and triethylphosphine (2.2 ml) was heated at 160 "С under a nitrogen atmosphere for 4 hours. After cooling, volatile substances were removed by massio, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and of cyclohexane with a gradient of 0-100 95 to obtain diethyl (3-fluorobenzyl)phosphonate (2.46 g).

IN NMR (SOSI") b: 7.31-7.22 (1H, t), 7.11-6.89 (ZH, t), 4.09-3.97 (4H, t), 3.13 (2H, a), 1.25 (6H, 5.

Intermediate compound 183: methyl (Tax5, 7B51HK)-5-i(2-(2-(1-ethylazetidin-3-yl)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4- carboxylate

C on (o) nn

E (c)?

IІ00528| A solution of tert-Butyl (tac5,7p5K)-3-12-(5-fluoro-2-(4-methoxycarbonyl-1,Ta,2,7B- tetrahydrocyclopropa|sichromen-5-ylsulfamoyl)phenyl|ethyl)azetidin-1- carboxylate (Intermediate 184, 0.397 g) in DCM (5 mL) and trifluoroacetic acid (5 mL) was left at room temperature for 30 min, then evaporated with ip massio, and the residue was dissolved in toluene and re-evaporated. The residue was dissolved in DCM (15 mL) and acetaldehyde (0.063 g) was added, followed by sodium triacetoxyborohydride (0.301 g). The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and water, and the organic layer was dried (Ma259054) and filtered. The filtrate was concentrated over mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-25 95, to obtain methyl (tan, 765)-5-12-(2-(1-ethylazetidin-3-yl) ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,76-tetrahydrocyclopropa|sichromene-4-carboxylate (0.312 g) in the form of a white foamy substance.

LCMS (Method E), retention time 2.75 (M--H) 489.

Intermediate 184: tert-Butyl (Ta5,7B6B5E)-3-(2-(5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7p-tetrahydrocyclopropa|sichromen-5-ylsulfamoyl)phenyl|ethylazetidin- 1-carboxylate o M Oso p shikne o N

E c) 7 00529) Mixture of tert-Butyl (also, 7652K)-3-(E/2)-2-(5-fluoro-2-(4-methoxycarbonyl-1Ta, 2,75- tetrahydrocyclopropa|sichromene-5 -ylsulfamoyl)phenyl|vinyl azetidine-1-carboxylate (Intermediate 185, 0.502 g) and 10 95 palladium on carbon (0.05 g) in ethanol (25 mL) were stirred under hydrogen for 30 min. The suspension was filtered and the filtrate was concentrated The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40 95, to obtain tert-Butyl (Tanv5, 765H)-3-12-(5-fluoro-2-(4-methoxycarbonyl-1a) .

IN NMR (SOCI3) 6: 9.01 (1H, Bg, 5), 7.90 (1H, ad), 7.21 (IN, 4), 7.02 (1H, a), 6.94 (2H , t), 4.32 (IN, 9), 4.00 (2H, U, 3.79 (1H, a), 3.77 (ZH, 5), 3.56 (2H, aa), 2, 79 (2H, aa), 2.56 (1H, t), 1.89 (ZH, t), 1.72 (1H, t), 1.45 (9H, 5), 0.99 (2H, t ).

Intermediate compound 185: tert-Butyl (Tak, 765K)-3-(E/2)-2-(5-fluoro-2-(4-methoxycarbonyl-1/1a, 2,7b-tetrahydrocyclopropa|sichromen-5-ylsulfamoyl) )phenyl|vinylazetidine-1-carboxylate and Ox 20 iv) M Za? and MY t (c) o N

E o7so

IІ00530| A mixture of methyl (T1akz5, 7B5K)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 41, 0.456 g), tert-Butyl 3- ( E/2)-2-trimethylstananylvinyl azetidine-1-carboxylate (Intermediate 186, 0.433 g), tris(idibenzylideneacetone)dipalladium(0) (0.046 g) and tri-tert-butylphosphonium tetrafluoroborate (0.029 g) in dioxane (15 mL) and DMSO (1.5 ml) were stirred and heated at 90 "C under nitrogen for 1 hour. After cooling, the solution was diluted with ethyl acetate, washed with water, dried (Ma25054) and filtered. The filtrate was concentrated by mass, and the residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-4095, to obtain tert-Butyl (Ta, 7p5K)-3-(E/2)-2-(5-fluoro-2-(4-methoxycarbonyl-1Ta, 2.7p) -tetrahydrocyclopropa|sichromen-5-ylsulfamoyl)phenylvinyl-azetidine-1-carboxylate (0.508 g) in the form of a colorless resinous substance.

LCMS (Method E), retention time 4.47 (M-H) 557

Intermediate compound 186: tert-Butyl 3-(E/27)-2-trimethylstananylvinyl)azetidine-1-carboxylate 00531) solution of tert-Butyl 3-(E/7)-2-iodovinyl)azetidine-1 -carboxylate (Intermediate compound 187, 1.39 g), hexamethyldiol (2.95 g) and tetrakis(triphenylphosphine)palladium (0) (0.52 g) in anhydrous THF (40 ml) were stirred and heated at 50 "C in under nitrogen atmosphere for 2 hours. After cooling, the mixture was concentrated and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-10 95, to obtain tert-Butyl 3-(E/7)-2-trimethylstananylvinyl) uazetidine-1-carboxylate (0.601 g) in the form of a pale yellow oily substance.

NMR NMR (SOSI) 6: 5.79-6.5 (2H, t), 3.95 (2H, t), 3.62 (2H, t), 2.88-3.12 (1H , t), 1.32 (ЗН, 5), 0.0 (9Н, 5).

Intermediate 187: tert-Butyl 3-(E/27)-2-iodovinyl)azetidine-1-carboxylate (c) 00532) A solution of tert-Butyl 3-formylazetidine-1-carboxylate (1.97 g) and iodoform (8.37 g) in anhydrous THF (25 mL) was added to a stirred suspension of anhydrous chromium(II) chloride in anhydrous THF (100 mL) under nitrogen, and the mixture was stirred at room temperature for 4 hours. The resulting mixture was diluted with water and ethyl acetate, and the organic layer was dried (Ma2504) and filtered. The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-15 95, to obtain tert-Butyl 3-(E/7)-2-iodovinyl)azetidine-1-carboxylate (2, 01 g) in the form of a pale yellow oily substance.

IN NMR (SOSI") 6: 6.71 (0.8Н, as), 6.55 (0.2Н, 9, 6.33 (0.2Н, а), 6.18 (0.8Н, 49) , 4.20 (0.4Н, 9, 4.08 (1.6Н, 7), 3.76 (2Н, t), 3.45 (0.2Н, t), 3.19 (0.8Н, t), 1.44 (9H, 5).

Intermediate compound 188: methyl (Yes, 7p5K)-5-(2-1(5)-1-ethylpyrrolidine-3-carbonyl)amino|- methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa(| c|Yichromene-4-carboxylate M

Her o, o 5

M o

N

E (c)?

IІ00533| NATO (0.234 g) was added to a mixture of (5)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 189, 0.089 g) and MMM (0.068 mL) in DMF (4 mL) and the mixture was stirred for minutes. Methyl (Tak5, 765K)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1 and 2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylate (Intermediate compound 102, 0.250 g) were added and the mixture was stirred for 20 hours The mixture was diluted with water and extracted with ethyl acetate.

The organic layer was washed with saturated Mansoz solution, dried (Ma25054) and filtered.

The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of 2 M ammonia in methanol and DCM, with a gradient of 0-15 9565, to obtain methyl (ав, 76б58)-5-(2-1(5)-1 -ethylpyrrolidine-3-carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-1 1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (0.190 g) as a solid.

IN NMR (SOSIZ") 6: 7.81 (1H, aa), 7.46-7.38 (1H, t), 7.30-7.20 (ZH, t), 7.06-6.93 (2H, t), 4.58 (2H, 49), 4.32 (1H, ad), 3.79 (1H, aa), 3.76 (ZH, 5), 2.93-2.78 ( ZN, t), 2.70-2.49 (4Н, t), 2.24-2.08 (IN, t), 2.00-1.687 (2Н, t), 1.78-1.68 ( 1H, t), 1.15 (ZH, 0), 1.06-0.98 (2H, t)

Intermediate compound 189: (5)-1-Ethylpyrrolidine-3-carboxylic acid / I gene o

I00534| A mixture of benzyl (5)-1-ethylpyrrolidine-3-carboxylate (Intermediate compound 190, 0.563 g), 20 95 g of palladium hydroxide on carbon (0.056 g), ethyl acetate (9 ml) and IM5 (1 ml) was degassed and hydrogenated for 4 hours . The catalyst was removed by filtration, washed with ethyl acetate, and the filtrate was concentrated by mass to obtain (5)-1-ethylpyrrolidine-3-carboxylic acid (0.318 g) as a solid.

IN NMR (SOSI") 6: 12.46-10.55 (1H, Bg 5), 3.84-3.57 (1H, BE 5), 3.49-3.26 (1H, Bg 5), 3.26-2.93 (BN, t), 2.50-2.33 (1Н, t), 2.28-2.11 (1Н, t), 1.35 (ЗН, ).

Intermediate 190: Benzyl (5)-1-ethylpyrrolidine-3-carboxylate

RO a 6)

IІ00535| Ethyl bromide (0.21 mL) was added to a mixture of benzyl (5)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (Intermediate 191, 0.897 g), potassium carbonate (0.971 g), and DMF (10 mL) at room temperature and the mixture was stirred for 25 hours. An additional amount of ethyl bromide (0.11 mL) was added and stirring was continued for 24 hours. An additional amount of ethyl bromide (0.05 mL) was added and stirring was continued for 22 hours.

The resulting mixture was diluted with water and extracted with diethyl ether, washed with a saturated saline solution, dried (Ma2509054) and filtered. The filtrate was concentrated in fat to give benzyl (5)-1-ethylpyrrolidine-3-carboxylate (0.563 g).

1H NMR (SOSI) 6: 7.38-7.30 (5H, t), 5.13 (2H, 5), 3.09 (1H, t), 2.93 (1H, 9, 2 .76-2.66 (1H, t), 2.63 (IN, aa), 2.56-2.А41 (ЗН, t), 2.16-2.05 (2H, t), 1.10 (ZN, U.

Intermediate compound 191: Benzyl (5)-pyrrolidine-3-carboxylate trifluoroacetic acid salt "Z pe (c)

І00536| Trifluoroacetic acid (2.5 mL) was added to a solution of benzyl (5)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (Intermediate 192, 0.859 g) and DCM (10 mL) at room temperature. The mixture was stirred for 4 hours, then concentrated to massio.

The residue was azeotropically distilled with toluene, then with ethyl acetate to obtain benzyl (5)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (1 g).

IN NMR (SOSI") 6: 7.41-7.29 (5H, t), 5.16 (2H, aa), 3.64-3.45 (2H, t), 3.44-3.23 (ZH, t), 2.42-2.20 (2Н, t).

Intermediate 192: Benzyl (5)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate

In this life

M o) -- IV 6)

I(00537| OVO (0.764 ml) was added to a mixture of benzyl bromide (0.61 ml), (5)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (1 g) in anhydrous toluene (10 ml) and the mixture was stirred at room temperature temperature for 24 hours. The mixture was filtered, and the filtrate was concentrated by mass. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35 95, to give benzyl (5)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (0.859 d).

IN NMR (SOSIZ") 6: 7.39-7.29 (5Н, т), 5.14 (2Н, 5), 3.70-3.41 (ЗН, т), 3.41-3.27 (1H, t), 3.08 (IN, t), 2.13 (2H, 4), 1.45 (9H, 5).

Intermediate 193: (K)-1-Ethylpyrrolidine-3-ylamine

MH,

I

I00538| Acetyl chloride (15 mL) was added to methanol (120 mL) and the resulting solution was stirred for 20 minutes. Then a solution of tert-butyl M-((B)-1-ethylpyrrolidin-3-yl)ucarbamate (Intermediate compound 94, 8.4 g) in methanol (30 ml) was added and stirred, and the mixture was heated at 80 7C overnight. After cooling, the mixture was concentrated under vacuum, and the residue was redissolved in methanol (150 mL) and potassium carbonate (25.8 g) was added. The mixture was stirred and heated at 30 °C for 30 hours. After cooling, the solid was filtered off, and the filtrate was distilled, collecting the product at 100 °C, to obtain (K)-1-ethylpyrrolidin-3-ylamine (2.10 g) as yellow oily substance, which was used without further characterization.

Intermediate 194: (5)-1-Ethylpyrrolidine-3-ylamine

MH,

IN

It was prepared in the same way as Intermediate 193, starting from tert-Butyl M-((5)-1-ethylpyrrolidin-3-yl)ucarbamate (Intermediate 82), and used without further characterization.

Intermediate compound 195: methyl (Takz, 7B65E)-5-(2-C(B)-1-ethylpyrrolidine-3-carbonyl)amino|- methyl)-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa(| c|Ichromene-4-carboxylate

N

/ what; o,,0 o b 8

M o

N

E|c) t

I00539| Obtained in the same way as Intermediate 188, starting from methyl (tan, 7658)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1a, 2,7tr-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 102) and (K)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 196).

IN NMR (SOSI") 6: 7.81 (1H, aa), 7.43-7.34 (1H, t), 7.30-7.20 (ZH, t), 7.05-6.93 (2H, t), 4.59 (2H, 49), 4.32 (1H, ad), 3.79 (1H, aa), 3.76 (ZH, 5), 2.99-2.84 ( ЗН, t), 2.81-2.73 (1Н, t), 2.73-2.60 (ЗН, t), 2.27-2.12 (1Н, t), 2.01-1, 88 (2H, t), 1.78-1.67 (1H, t), 1.17 (ZH, 5), 1.08-0.98 (2H, t).

Intermediate 196: (K)-1-Ethylpyrrolidine-3-carboxylic acid / Cohen 0 o 00540) was prepared in the same way as Intermediate 189, starting from benzyl (K)-1-ethylpyrrolidine-3-carboxylate (Intermediate 197 ).

1H NMR (SOSI) 6: 11.05-9.55 (1H, Bi 5), 3.71 (1H, Be 5), 3.37 (1H, bBg 5), 3.27-2, 94 (BN, t), 2.49-2.32 (1H, t), 2.29-2.13 (1H, t), 1.95 (ZN, U.

Intermediate compound 197: Benzyl (K)-1-ethylpyrrolidine-Z-carboxylate / A e C Y c)

It was obtained in the same way as Intermediate 190, starting from benzyl (K)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (Intermediate 198).

IN NMR (SOSIZ") 6: 7.38-7.30 (5Н, т), 5.13 (2Н, 5), 3.09 (1Н, т), 2.93 (1Н, 0), 2, 76-2.66 (1H, t), 202.63 (1H, aa), 2.52-2.42 (ZH, t), 2.16-2.06 (2H, t), 1.11 ( ZN, ).

Intermediate compound 198: Benzyl (K)-pyrrolidine-3-carboxylate trifluoroacetic acid salt "According to MI c)

I00541| Obtained in the same way as Intermediate 191, starting from benzyl (K)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (Intermediate 199).

1H NMR (SOSI) b: 7.41-7.29 (5H, t), 5.16 (2H, aa), 3.64-3.45 (2H, t), 3.42-3 .23 (ZN, t), 2.41-2.20 (2Н, t).

Intermediate compound 199: Benzyl (K)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate 9; u- o

In c) (00542) Obtained in the same way as Intermediate 192, starting from (K)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid.

IN NMR (SOSIZ") 6: 7.42-7.29 (5Н, т), 5.15 (2Н, 5), 3.72-3.42 (ЗН, т), 3.42-3.26 (1H, t), 3.08 (IN, t), 2.13 (2H, 4), 1.45 (OH, 5).

Intermediate compound 200: methyl (Takz, 765K)-5-1M4-(2-(2)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonyl|-M-(methoxycarbonyl)amino)-1Ta , 2,7p-tetrahydrocyclopropa-|siIchromene-4-carboxylate

OO HU

"M (in)

Ao 9

Eh oh ah

I00543| Methanesulfonic anhydride (0.159 g) was added to a solution of methyl (also, 7p5K)-5-1M-

14-Fluoro-2-(27)-3-hydroxy-2-methylprop-1-enyl)ubenzenesulfonyl|-N-(methoxycarbonyl)amino)-1 and, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate compound 201, 0.310 g) and M, M-diisopropyl-M-ethylamine (0.118 g) in DCM (10 ml) and left the mixture at room temperature for 1 hour. Diethylamine (1 ml) was added and the solution was left for another 16 hours. The mixture was washed with water and filtered through a phase separator. The filtrate was concentrated over mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-8 95, to obtain methyl (melt, /7058)-5-(M-(2-(72)-Z-diethylamino -2-methylprop-1-enyl)-4-fluorobenzenesulfonyl|-M-methoxycarbonylamino)-1,1a, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylate (0.268 g) in the form of a white foamy substance.

LCMS (Method E), retention time 2.79 (M.--H) 561.

Intermediate compound 201: methyl (Takz, 7B5K)-5-1M-(4-fluoro-2-(2)-3-hydroxy-2-methylprop-1-enyl)benzenesulfonyl|-M-(methoxycarbonyl)amino)-1 Ta, 2,7p-tetrahydrocyclopropa-isochromene-4-carboxylate

More) p

OO

"M (c)

YES

E 9 od zh

I00544| Concentrated hydrochloric acid (1 ml) was added to a solution of methyl (1akz, 7658)-5-(M-2-(2)-3-(tert-butyldimethylsilanyloxy)-2-methylprop-1-enyl|/|-4-fluorobenzenesulfonyl |-N-methoxycarbonylamino)-1,1a,2,7p-tetrahydrocyclopropa|ciichromene-4-carboxylate (Intermediate compound 202, 0.385 g) in methanol (20 mL) and left the mixture at room temperature for 45 minutes. The solution was concentrated over mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-60 95, to obtain methyl Pakz, 76B5K)-5-1M-(4-fluoro-2-((2)-3 -hydroxy-2-methylprop-1-enyl)benzenesulfonyl|-M-methoxycarbonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-Isochromene-4-carboxylate (0.314 g) in the form of a white foamy substance.

NR NMR (SOCI3) 6: 8.18 (1H, aa), 7.35 (1H, a), 7.11 (1H, ayu, 6.94 (1H, a), 6.89 (1H, 4) , 6.74 (1Н, 5), 4.39 (IN, а), 3.82-4.17 (ЗН, t), 3.76 (1.5Н, 5), 3.72 (1.5Н , 5), 3.64 (ZH, 5), 1.98 (4H, t), 1.82 (1H, a), 1.14 (2H, t).

Intermediate compound 202: methyl (Yes, 76551EK)-5-(M-2-(2)-3-(tert-butyldimethylsilanyloxy)-2-methylprop-1-enyl|-4-fluorobenzenesulfonyl|-M-(methoxycarbonyl)amino )-1Ta, 2,7p-tetrahydrocyclopropa-|siIchromene-4-carboxylate he y: oo x 587

M (in)

And 9

E o od (00545) Mixture of methyl pPax, 7B5)-5-N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino|-1,1a,. 2,7p-tetrahydrocyclopropa-|siIchromene-4-carboxylate (Intermediate compound 65, 0.257 g), tert-butyldimethyl-((7)-2-methyl-3-tributylstananylallyloxy)silane (0.475 g), tris(dibenzylideneacetone)dipalladium ( 0) (0.023 g) and tri-tert-butylphosphonium tetrafluoroborate (0.015 g) in dioxane (8 ml) and DMSO (0.8 ml) were stirred and heated at 90 "C under a nitrogen atmosphere for 1 hour. An additional amount of tris( dibenzylideneacetone)dipalladium (0) (0.023 g) and tri-tert-butylphosphonium tetrafluoroborate (0.015 g) and heating was continued for another 40 minutes.

After cooling, the mixture was diluted with ethyl acetate, washed with water, dried (Ma250904) and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 0-20 9o, to obtain methyl (chiak5, 76B5K)-5-(M-2-(2)-3-"(tert -butyldimethylsilanyloxy)-2-methylprop-1-enyl|-4-fluorobenzenesulfonyl|-M-methoxycarbonylamino)-1,1a, 2,7p-tetrahydrocyclopropa|ciichromene-4-carboxylate (0.231 g) in the form of a colorless resinous substance.

LCMS (Method E), retention time 5.22 (M--Ma) 642.

Intermediate 203: 2-((A)-1-Ethylpyrrolidin-3-yl)ethylamine

MH,

I

(00546) Lithium aluminum hydride (1.0 g) was added portionwise to a stirred, cooled solution of 2-((5)-1-ethylpyrrolidine-3-ylluacetonitrile (Intermediate 204, 3.8 g) in THF (20 mL) at 0 "with.

After the addition was complete, the mixture was stirred at room temperature for 4 hours.

Water was carefully added, then 1595 aqueous sodium hydroxide solution and an additional amount of water were added. The solid was filtered off and the filtrate was evaporated to a dry residue.

The residue was dissolved in DCM, dried (Ma2509054) and filtered. The filtrate was evaporated to a dry residue to give 2-((B)-1-ethylpyrrolidine-3-yl)oethylamine (2.0 g) as a colorless oily substance, which was used without further characterization.

Intermediate compound 204: 2-((5)-1-Ethylpyrrolidin-3-ylacetonitrile n

AND

00547) Iodetane (10.1 g) was added to a mixture of 2-((5)-pyrrolidin-3-yl)acetonitrile hydrochloride (Intermediate 205, 7.9 g) and potassium carbonate (29.7 g) in DMF (30 ml), and the resulting mixture was stirred at room temperature for 5 hours. Water was added and the mixture was extracted with ethyl acetate, washed with saturated saline, dried (Ma25054) and filtered.

The filtrate was evaporated to a dry residue to give 2-((5)-1-ethylpyrrolidin-3-yl)acetonitrile (3.8 g) as a yellow oily substance, which was used without further characterization.

Intermediate compound 205: 2-((5)-Pyrrolidin-3-yl)acetonitrile hydrochloride p

M

But on 00548) A solution of tert-butyl (5)-3-cyanomethylpyrrolidine-1-carboxylate (Intermediate compound 206, 12.3 g) in methanol (150 ml) and concentrated hydrochloric acid (12 ml) was stirred and heated at 50 "С After cooling, the mixture was concentrated in vacuo to afford crude 2-((5)-pyrrolidin-3-yl acetonitrile hydrochloride (9.0 g) as a white solid, which was used without further characterization.

Intermediate compound 206: tert-Butyl (5)-3-cyanomethylpyrrolidine-1-carboxylate p

M vi (00549) A mixture of tert-Butyl ((K)-3-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate compound 207, 22.3 g) and sodium cyanide (6.13 g) in DMSO (100 ml ) were stirred and heated at 100 "C for 4 hours. After cooling, a saturated aqueous solution of iron (II) sulfate was added and the mixture was stirred at room temperature for 8 hours. The resulting mixture was extracted with ethyl acetate, washed with saturated saline, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether

(20 95) to obtain tert-Butyl (5)-3-cyanomethylpyrrolidine-1-carboxylate (12.3 g) in the form of a white solid, which was used without additional characterization.

Intermediate compound 207: tert-Butyl ((K)-3-(4-methylbenzenesulfonyloxymethyl)-pyrrolidine-1-carboxylate c) o 7 droo-

M oo

AND

It was obtained in the same way as Intermediate 140 starting from tert-Butyl (K)-3-hydroxymethylpyrrolidine-1-carboxylate and 4-methylbenzenesulfonyl chloride, and used without further characterization.

Intermediate compound 208: 2-((5)-1-Ethylpyrrolidin-3-yl)/ethylamine in ; yu - 00550) was obtained in the same way as Intermediate 203, starting from 2-((H)-1-ethylpyrrolidin-3-yl acetonitrile (Intermediate 209), and used without further characterization.

Intermediate 209: 2-((A)-1-Ethylpyrrolidin-3-yl)luacetonitrile

M

15. AND

IІ00551| Iodethane (6.46 g) was added in portions to a cooled mixture of 2-((H)-pyrrolidin-3-yl)acetonitrile (Intermediate 210, 4.6 g) and potassium carbonate (8.6 g) in acetonitrile (30 mL ) at 0 "C. The mixture was stirred for 3 hours at 0 "C, then concentrated under vacuum.

The residue was partitioned between water and DCM. The organic layer was washed with a saturated saline solution, dried (Ma259054) and filtered. The filtrate was evaporated to a dry residue to give 2-(8)-1-ethylpyrrolidin-3-yl)lacetonitrile (2.1 g) as a colorless liquid, which was used without further characterization.

Intermediate 210: 2-(A)-Pyrrolidin-3-yl)acetonitrile hydrochloride

M

Sy

N her 00552) was prepared in the same manner as Intermediate 205 starting from tert-Butyl (8)-3-cyanomethylpyrrolidine-1-carboxylate (Intermediate 211) and used without further characterization.

Intermediate 211: tert-Butyl (K)-3-cyanomethylpyrrolidine-1-carboxylate

YAM

M vi 00553) was prepared in the same manner as Intermediate 206, starting from tert-Butyl ((5)-3-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 212), and used without further characterization.

Intermediate 212: tert-Butyl ((5)-3-(4-methylbenzenesulfonyloxymethyl)-pyrrolidine-1-

carboxylate c) about a background

SA vi

I00554| It was prepared in the same way as Intermediate 140, starting from tert-Butyl (5)-3-hydroxymethylpyrrolidine-1-carboxylate and 4-methylbenzenesulfonyl chloride, and used without further characterization.

Intermediate compound 213: methyl (Yes, 765)-5-(2-(5)-1-ethylpyrrolidine-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate o

N N

(about) ; en

Ote2o 7M (c)

N

Oh, that's it

І00555| Solution of tert-butyl (5)-3-(Chav, 7p05)-5-fluoro-2-(4-methoxycarbonyl-1,Ta, 2,7p-tetrahydrocyclopropa|sichromen-5-ylsulfamoyl)benzyloxy|pyrrolidin-1-carboxylate (Intermediate 214, 0.284 g) in trifluoroacetic acid (4 mL) and DCM (4 mL) was left at room temperature for 30 minutes. The mixture was evaporated with oil, and the residue was azeotropically distilled with toluene. The residue was dissolved in DCM (4 mL) and acetaldehyde (0.044 g) was added, followed by sodium triacetoxyborohydride (0.212 g). The mixture was stirred at room temperature for 1 hour. The resulting solution was diluted with DCM and 1 M sodium hydroxide solution, and the organic layer was dried (Ma2504) and filtered. The filtrate was evaporated and the residue was purified by chromatography on silica gel, eluting with a mixture of methanol and DCM, with a gradient of 0-20 95, to obtain methyl ak, 765)-5-(2-((5)-1-ethylpyrrolidine-3-yloxymethyl) )-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate (0.221 g) in the form of a white foamy substance.

1H NMR (SOSI) 6: 7.76 (1H, av), 7.32 (1H, av), 7.16 (1H, 4), 6.94 (1H, ab, 6.87 (1H , 4), 4.86 (1H, 9), 4.68 (IN, a), 4.32 (1H, 9), 4.19 (IN, t), 3.79 (1H, a), 3 .73 (ZH, 5), 3.13 (1H, 9), 2.92 (1H, a), 2.35-2.75 (4H, t), 2.10 (2H, t), 1, 92 (1H, t), 1.72 (IN, t), 1.14 (ZH, U, 1.03 (2H, t).

Intermediate 214: tert-Butyl (5)-3-Ktanyl, 7065)-5-fluoro-2-(4-methoxycarbonyl-1Ta, 2,7p-tetrahydrocyclopropa|sichromen-5-ylsulfamoyl)benzyloxy|pyrrolidine-1- carboxylate 0-4 o-4 o: N o ho en 05.20; ry (c)

N

E c) 7 (00556) A solution of tert-Butyl (5)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate compound 215, 0.295 g) in DCM (2 ml) was added to a solution of methyl ( 1ac, 765)-5-amino-1Ta,2,7B-tetrahydrocyclopropa|sichromene-4-carboxylate (Intermediate 42A, 0.11 g) in DCM (2 mL) and left the mixture at room temperature for 5 days. The mixture was diluted with DCM, washed with 1 M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated by mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30 9°, to obtain tert-Butyl (5)-3-15-fluoro-2-(α, 765)-4-methoxycarbonyl -1 Ta, 2,70-tetrahydrocyclopropa-|c|ichromene-5-ylsulfamoyl)benzyloxy|pyrrolidine-1-carboxylate (0.288 g) in the form of a white foamy substance.

IN NMR (SOSI") 6: 8.86 (1H, bg, 5), 7.76 (1H, av), 7.41 (1H, aa), 7.25 (1H, 9), 7.07 ( 1H, a), 6.95 (IN, au, 4.69-4.91 (2H, Br, a), 4.92 (IN, 9), 4.19 (IN, t), 3.77 ( 1H, a), 3.71 (ZH, 5), 3.49 (AN, ri, t), 1.89-2.18 (ZH, t), 1.73 (1H, t), 1.47 (9H, 5), 1.00 (2H, t).

Intermediate compound 215: tert-Butyl (5)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate 0-4 o-i o (o) o5,270 zu

SI and

I00557| n-Butyllithium (1.6 M in hexane, 3.3 ml) was added to a solution of tert-Butyl (5)-3-(2-bromo-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate compound 216, 1.87 g ) in anhydrous TG F (20 ml) at -78 "C in a nitrogen atmosphere and the mixture was stirred for 30 minutes. Sulfur dioxide was passed through the resulting solution for 30 minutes, then the cooling bath was removed, and the mixture was left to warm to room temperature and stirred for 15 minutes The solution was concentrated and the residue was dissolved in DCM (20 mL) and M-chlorosuccinimide (0.668 g) was added.

The mixture was stirred for 30 minutes, then diluted with ether and water. The organic layer was dried (M9504) and filtered, and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25595, to obtain tert-Butyl (5)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (1.01 g) in the form colorless, viscous oily substance.

IN NMR (SOSI") 6: 8.09 (1H, ad), 7.58 (1H, aa), 7.18 (1H, ayu, 4.98 (2H, 49), 4.28 (1H, t ), 3.40-3.61 (4H, t), 1.92-2.20 (2H, t), 1.47 (9H, 5).

Intermediate compound 216: tert-Butyl (5)-3-(2-bromo-5-fluorobenzyloxy)pyrrolidine-1-carboxylate 0-4 o-i o (9) c

IS

00558) Sodium hydride (60 95 dispersion in oil, 0.24 g) was added to the mixed solution of tert-

Butyl (5)-3-hydroxypyrrolidine-1-carboxylate (0.935 g) in THF (15 mL) and the mixture was stirred for 5 minutes. 2-Bromo-5-fluorobenzyl bromide (1.608 g) was added and stirring was continued for 20 hours. The resulting suspension was filtered, and the filtrate was evaporated to a dry residue. The residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15 95, to obtain tert-Butyl (5)-3-(2-bromo-5-fluorobenzyloxy)-pyrrolidine-1-carboxylate (1.88 g) in in the form of a colorless oily substance.

IN NMR (SOCI3) 6: 7.46 (1H, av), 7.22 (1H, av), 6.88 (1H, ayu, 4.52 (2H, 5), 4.19 (IN, t) , 3.40-3.65 (4H, Bi, t), 1.91-2.18 (2H, t), 1.49 (9H, 5).

Intermediate compound 217: methyl (Yes, 7p65)-5-(2-(B8)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate c chn (c) and en

Ote2o 7M (c)

N

E o t 00559) Obtained in the same way as Intermediate 213, starting from tert-Butyl (8)-3-IChavB, /765)-5-fluoro-2-(4-methoxycarbonyl-1,1a, 2,7p -tetrahydrocyclopropa|siIchromen-5-ylsulfamoyl)benzyloxy|-pyrrolidine-1-carboxylate (Intermediate compound 218).

1H NMR (SOCI3) 6: 7.76 (1H, av), 7.32 (1H, av), 7.17 (IN, 4), 6.95 (IN, ab, 6.88 (1H , 49), 4.85 (1H, 9), 4.68 (IN, a), 4.32 (IN, 9), 4.18 (IN, t), 3.81 (1H, 4), 3 .72 (ZH, 5), 3.11 (1H, 9), 2.92 (1H, a), 2.25-2.75 (4H, t), 2.09 (2H, t), 1, 91 (1H, t), 1.72 (IN, t), 1.14 (ZH, U, 1.03 (2H, t).

Intermediate 218: tert-Butyl (K)-3-Tau, 765)-5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7p-tetrahydrocyclopropa|sichromen-5-ylsulfamoyl)benzyloxy|pyrrolidine-1 -carboxylate 0-4 o-4

M

I would

ONE person (c)

N

That's it

Y00560)| Prepared in the same manner as Intermediate 214, starting from tert-Butyl (8)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate 219) and methyl (Yes, 765)-5- amino-1,1a,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate compound 42A).

IN NMR (SOSI") 6: 8.86 (1H, bg, 5), 7.76 (1H, av), 7.41 (1H, aa), 7.25 (1H, 9), 7.07 ( 1H, a), 6.95 (IN, a), 4.78 (2H, p, 5), 4.92 (IN, 9), 4.19 (IN, t), 3.77 (1H, a ), 3.71 (ZH, 5), 3.49 (4H, horn, t), 1.89- 2.18 (ZH, t), 1.73 (1H, t), 1.47 (OH, 5), 1.00 (2H, t).

Intermediate compound 219: tert-Butyl (K)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate 0-0

F) o5,270

ZU

SI

IS

Obtained in the same way as Intermediate 215, starting from tert-Butyl (K)-3-(2-bromo-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate 220).

IN NMR (SOSI") 6: 8.10 (1H, ad), 7.58 (1H, aa), 7.17 (1H, ayu, 4.99 (2H, 4), 4.28 (IN, t ), 3.40-3.61 (4H, t), 1.92-2.20 (2H, t), 1.48 (9H, 5).

Intermediate compound 220: tert-Butyl (K)-3-(2-bromo-5-fluorobenzyloxy)pyrrolidine-1-carboxylate

0-4 o-y her (in) bu

IS

I00561| Obtained in the same way as Intermediate 216, starting from tert-Butyl (8)-3-hydroxypyrrolidine-1-carboxylate.

IN NMR (SOSI") 6: 7.46 (1H, av), 7.22 (1H, av), 6.88 (1H, ayu, 4.52 (2H, 5), 4.19 (IN, t ), 3.40-3.65 (4H, Bi, t), 1.91-2.18 (2H, t), 1.49 (9H, 5).

Intermediate compound (221: methyl (aq, 765)-5-(2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylate

N,

With Fo 0, in

M 6)

N

E|c) 7 (00562). 2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate compound 222, 0.21 g) was added to a solution of methyl Pak, 765)-5-amino-1Ta, 2,76-tetrahydrocyclopropa|siIchromene-4 -carboxylate (Intermediate compound 42A, 0.290 g) in DCM (10 ml) and pyridine (2 ml), and the resulting mixture was stirred at room temperature for 4 hours.

The mixture was evaporated to a dry residue and the residue was partitioned between DCM and water. The organic layer was dried (Ma2504), filtered, and the filtrate was concentrated by massio. The residue was purified by chromatography on silica gel, eluting with a mixture of 2 M ammonia in methanol and DCM, with a gradient of 0-15 965, to obtain methyl Pak, 765)-5-(2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino! |-1 Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (0.071 g).

1H NMR (SOSI) 6: 7.95-7.88 (1H, t), 7.21-7.15 (1H, t), 7.03-6.86 (ZH, t), 4 .31 (1H, a), 3.81-3.73 (AN, t), 2.89-2.63 (4H, t), 2.39-2.28 (2H, t), 2.09 -2.08-1.95 (1Н, t), 1.94-1.44 (ВН, t), 1.06-0.94 (6Н, t).

Intermediate compound 222: 2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride and 0.0

ZU

SI

IS

00563) A solution of 1-ethyl-3-(3-fluorobenzyl)piperidine (Intermediate 223, 0.214 g) in DHE (1 mL) was added to chlorosulfonic acid (2 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was added dropwise to a mixture of ice and brine and extracted with DCM. The organic layer was dried (Ma2504) and filtered, and the filtrate was evaporated to a dry residue to give 2-(1-ethylpiperidin-4-ylmethyl)-4- of fluorobenzenesulfonyl chloride (0.44 g) as a solid.

IN NMR (SOS) 6: 8.17-8.11 (1H, t), 7.43-7.37 (1H, t), 7.19-7.12 (1H, t), 3.62- 3.52 (1H, t), 3.42-3.32 (1H, t), 3.16 (2H, a), 3.11-2.92 (ZH, t), 2.64-2, 29 (ЗН, т), 1.91 (2Н, а), 1.43 (ЗН, У), 1.39-1.23 (1Н, т).

Intermediate 223: 1-Ethyl-3-(3-fluorobenzyl)-piperidine

:

IN

I00564| A solution of lithium aluminum hydride (2 M in THF, 2.8 mL) was added dropwise to a solution of 1-(|3-(3-fluorobenzyl)piperidin-1-yl|IIIethanone (Intermediate 224, 0.66 g) in anhydrous THF ( 20 ml) at 0 "C in an argon atmosphere. The mixture was stirred for 30 minutes, then allowed to warm to room temperature and stirred for 2 hours. The mixture was re-cooled to 0 "C and water was added. The mixture was extracted with ether, washed with saturated saline, dried (Ma2504) and filtered. The filtrate was evaporated to a dry residue to give 1-ethyl-3-(3-fluorobenzyl)piperidine (0.535 g). "H NMR (SOCI"c) 6: 7.25-7.17 (1H, t), 6.95-6.80 (ZH, t), 2.92-2.73 (2H, t), 2.58-2.42 (2H, t), 2.42-2.26 ( 2H, t), 1.96-1.76 (2H, t), 1.74-1.48 (4H, t), 1.04 (ZH, U, 1.00-0.84 (1H, t ).

Intermediate 224: 1-(3-(3-Fluorobenzyl)piperidin-1-yl|Iethanone (c) is p

I00565| A mixture of 1-(3-(/1-(3-fluorophenyl)methylidene|piperidin-1-yl)iethanone (Intermediate 225, 0.7 g), palladium hydroxide (20 95 on carbon, 0.07 g) in ethyl acetate (20 mL) and IM5 (1 mL) were degassed with nitrogen/vacuum purging. The mixture was stirred under hydrogen for 21.5 h. The mixture was filtered and the filtrate was evaporated to a dry residue to afford 1-I|3-(3-Fluorobenzyl)piperidine -1-yl|ethanone (0.66 g).

IN NMR (SOSI") 6: 7.31-7.17 (1Н, t), 6.97-6.80 (ЗН, t), 4.52-4.43 (0.5Н, t), 441 -431 (0.5N, t), 3.76-3.65 (0.5N, t), 3.65-3.55 (0.5N, t), 3.07-2.95 (0, 5H, t), 2.82-2.62 (1.5H, t), 2.60-2.49 (1H, t), 2.45-2.33 (1H, t), 2.08 ( 1.5Н, 5), 1.95 (1.5Н, 5), 1.83-1.63 (ЗН, t), 1.50-1.32 (1Н, t), 1.29-1, 09 (IN, t).

Intermediate compound 225: 1-13-11-(3-Fluorophenyl)methylidene|piperidine-1-iluethanone (c) rest

IS

I00566)| Acetyl chloride (0.515 mL) was added to a mixture of 3-(1-(3-fluorophenyl)methylidene|-piperidine hydrochloride (Intermediate 226, 1.5 g) and M,M-diisopropyl-M-ethylamine (2.52 mL) in anhydrous THF (50 mL) at 0 "C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with water (100 mL) and extracted with ether, washed with brine, dried (Ma2O4) and filtered.

The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 75-100,956, to give 1-1(3-|1-(3-fluorophenyl)-methylidene|piperidin-1-yl) of ethanone (1.38 g).

IN NMR (SOSI") 6: 7.37-7.21 (1H, t), 7.04-6.82 (ZH, t), 6.48-6.26 (1H, 45), 4.39 -4.00 (2H, t), 3.72-3.48 (2H, t), 2.61-2.41 (2H, t), 2.18-2.02 (ZH, 45), 1 .83-1.61 (2H, t).

Intermediate 226: 3-(/1-(3-Fluorophenyl)methylidene|piperidine hydrochloride

N

M "NS

AND

IS

IІ00567| A solution of NCI in dioxane (4 M, 30 ml) was added to a solution of tert-Butyl 3-|(1-(3-fluorophenyl)methylidene|Ipiperidine-1-carboxylate (Intermediate compound 227, 2.38 g) in ether (30 ml ) and the mixture was stirred at room temperature for 5 h. The mixture was concentrated i.p. mass and the residue was treated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 3-(1-(3-fluorophenyl)methylidene|piperidine hydrochloride (1 .64 g).

IN NMR (SOCI), the ratio of E and 2 isomers is 3:2, b: 9.34 (2H, Bg 5), 7.48-7.37 (1H, t), 7.22-7.00 (ZH , t), 6.59 (1H, 5), 3.78-3.68 (2H, t), 3.13 (2H, t), 2.52 (1.2H, t), 2.43 ( 0.8N, t), 1.84 (1.2N, t), 1.76 (0.8N, t).

Intermediate 227: tert-Butyl 3-(1-(3-fluorophenyl)methylidene|piperidine-1-carboxylate no

M re

IS

00568) (3-Fluorobenzyl)utriphenylphosphonium bromide (Intermediate compound 228, 5.3 g) was added in portions to a solution of sodium tert-butoxide (1.06 g) in anhydrous THF (20 mL) at room temperature and the mixture was stirred for 30 minutes. A solution of tert-Butyl was added dropwise

C-oxopiperidine-1-carboxylate (2 g) in anhydrous THF (10 ml) at room temperature and the mixture was stirred for 24 hours. The mixture was diluted with water (100 ml) and extracted with ether (100 ml), washed with saturated saline, dried (Ma2504) and filtered.

The filtrate was concentrated over mass, and the residue was purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20 95, to obtain tert-Butyl 3-|/1-(3-fluorophenyl)-methylidene|piperidine-1-carboxylate (1 ,42 g).

1H NMR (SOScI3), ratio of E and 7 isomers 3:2, 6: 7.33-7.21 (1H, t), 7.05-6.85 (ZH, t), 6.37 (0 ,6H, 5), 6.28 (0.4H, 5), 4.16 (0.8H, 5), 4.00 (1.2H, 5), 3.50 (2H, U, 2.50 (1.2N, t), 2.39 (0.8N, t), 1.72 (0.8N, t), 1.62 (1.2N, t), 1.48 (5.4N, 5 ), 1.34 (3.6H, Bi 5).

Intermediate 228: (3-Fluorobenzyl)utriphenylphosphonium bromide

With

IS

IІ00569| A mixture of 3-fluorobenzyl bromide (5 g) and triphenylphosphine (6.94 g) in toluene (50 ml) was heated with a reflux condenser for 3 hours. After cooling, the solid was collected by filtration, washed with toluene and dried under vacuum at 50 °C to obtain (3-fluorobenzyl)utriphenylphosphonium bromide (10.1 g). H NMR (DMSO-α) 6: 7.96-7.87 (ZH, t), 7.81-7.64 (12Н, t), 7.35-7.26 (1Н, t), 7.20-711 (1Н, t), 6.88-6.82 (1H, t), 6.78-6.70 (1H, t), 5.21 (2H, a).

Intermediate 229: methyl (So, 7p)-5-(2-(2-(H)-1-ethylpyrrolidin-2-yl)ethyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene- 4-carboxylate

With E

Mo in - ro Y to u

M 6)

N

E|c) 7 00570) Obtained in the same way as Intermediate 95, starting from 2-(2-(B)-1-ethylpyrrolidin-2-yl)-ethyl|-4A-fluorobenzenesulfonyl chloride (Intermediate 230) and methyl (tav, 765)-5-amino-1Ta,2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylate (Intermediate compound 42A).

LCMS (Method A), retention time 2.30 (M.--N) 503.

Intermediate 230: 2-(2-((8)-1-Ethylpyrrolidin-2-yl/ethyl|-4-fluorobenzenesulfonyl chloride)

Moss with 0 70 5

SI

IS

I00571| Obtained in the same way as Intermediate 96, starting from (K)-1-ethyl-2-(2-(3-fluorophenyl)ethyl|pyrrolidine (Intermediate 231).

IN' NMR (SOSIz") 6: 8.11 (1H, aa), 7.42 (IN, av), 7.14 (1H, 9, 3.93 (IN, t), 3.46-3, 21 (2H, t), 3.13 (IN, t), 2.91 (2H, t), 2.43 (2H, t), 2.32 (2H, t), 2.11 (ЗН, t ), 1.50 (ZN, i).

Intermediate 231: (K)-1-Ethyl-2-(2-(3-fluorophenyl)ethyl|pyrrolidine schi:

IS

I00572| A solution of 1-((A)-2-(2-(3-fluorophenyl)ethyl|pyrrolidine-1-ilioethanone) (Intermediate compound 232, 0.48 g) in THF (20 ml) was cooled to 0 °C and treated with aluminum hydride solution lithium (2 M in THF, 3.6 mL) under nitrogen. The resulting mixture was allowed to warm to room temperature, then heated to 60 °C overnight. The mixture was cooled to 0 °C and treated with water (0.35 mL), 4N sodium hydroxide solution (0.35 mL) and additional water (0.9 mL). Sodium bisulfate powder was added to the suspension and the suspension was filtered through Celite, and the filtrate was evaporated to a dry residue to give (K)-1-ethyl-2- (2-(3-fluorophenyl)ethyl|pyrrolidine (0.41 g) in the form of an oily substance.

NMR (SOCI3) 6: 7.22 (1H, t), 6.96 (1H, 4), 6.87 (2H, t), 3.18 (1H, aa), 2.87 (1H, t ), 2.69 (1H, t), 2.55 (1H, t), 2.20 (IN, da), 2.12-1.91 (4H, t), 1.75 (2H, t) , 1.54 (2H, t), 1.10 (ZH, 9. H NMR 205205

Intermediate compound 232: 1-(H8)-2-(2-(3-Fluorophenyl)ethyl|pyrrolidin-1-iluethanone (is;

IS

Acetyl chloride (0.29 mL) was added to a solution of M,M-diisopropyl-M-ethylamine (0.71 mL) and (K)-2-(2-(3-fluorophenyl)ethyl|-pyrrolidine (Intermediate 233, 0 .39 g) in DCM (30 mL) and the mixture was stirred for 1.5 h. The mixture was washed with 1M HCl, dried (Moz) and filtered. The filtrate was evaporated to a dry residue to give 1-(H)-2-(2-( of 3-fluorophenyl)ethyl|-pyrrolidin-1-yl)ethanone (0.48 g) in the form of an oily substance.

IN NMR (d6-DMSO, 80 C) 6: 7.28 (IN, 4), 7.02 (2H, U, 6.92 (1H, 0, 3.93 (1H, Big 5), 3.41 (2H, t), 2.60 (2H, t), 2.05-1.54 (6H, t), 1.90 (ZH, 9.

Intermediate 233: (K)-2-(2-(3-Fluorophenyl)ethyl|pyrrolidine

N

IS

IІ00573| Trifluoroacetic acid (5 mL) was added to a solution of tert-Butyl (K)-2-(2-(3-fluorophenyl)ethyl|-pyrrolidine-1-carboxylate (Intermediate 234, 0.55 g) in DCM (5 mL) and stirred the mixture at room temperature for 1.5 hours. The mixture was evaporated to a dry residue, and the residue was dissolved in a small amount of methanol and loaded onto a 20 g 5СХ-2 5РЕ cartridge, washed with methanol, then eluted with 2 M ammonia in methanol to obtain (K )-2-(2-(3-fluorophenyl)-ethyl|pyrrolidine (0.39 g).

1H NMR (SOSI") 6: 7.23 (1H, a), 6.97 (1H, 4), 6.88 (2H, t), 2.99 (2H, t), 2.85 ( 1H, t), 2.69 (2H, t), 1.91 (1H, t), 1.75 (ЗН, t), 1.61 (1H, Big 5), 1.28 (1H, t) .

Intermediate compound 234: tert-Butyl (K)-2-(2-(3-fluorophenyl)ethyl|pyrrolidine-1-carboxylate 5-4

IS

I00574| A solution of tert-Butyl (5)-2-(3-fluorophenylethynyl)pyrrolidine-1-carboxylate (Intermediate 235, 1.26 g) in IM5 (70 mL) was carefully added to 20 95 palladium on carbon (0.6 g) in a carbon dioxide atmosphere. The mixture was degassed under vacuum and placed in a hydrogen atmosphere.

This technique was repeated three times, then the mixture was stirred in a hydrogen atmosphere for 18 hours. The mixture was filtered through Celite and the filtrate was evaporated to a dry residue. The residue was purified by chromatography on silica gel, eluting with a mixture of DCM and pentane with a gradient of 0-100 95, to obtain tert-Butyl (K)-2-(2-(3-fluorophenyl)ethyl|pyrrolidine-1-carboxylate (0.55 g) in the form of an oily substance.

IN NMR (SOSIv) 6: 7.21 (1H, Bg t), 6.99-6.81 (ZH, Bg t), 3.80 (1H, Bg a), 3.37 (2H, Bg a) , 2.61 (2H, Bg t), 1.97 (2H, rg t), 1.83 (2H, t), 1.65 (2H, Bri t), 1.45 (9H, 5).

Intermediate compound 235: tert-Butyl (5)-2-(3-fluorophenylethynyl)pyrrolidine-1-carboxylate (c) (c)

I00575| A suspension of 3-fluorobromobenzene (0.62 ml), tris(dibenzylideneacetone)dipalladium (0) (0.276 g), tri-tert-butylphosphonium tetrafluoroborate (0.165 g) and tert-Butyl (5)-2-tributylstananylethynylpyrrolidine-1-carboxylate ( Intermediate compound 236, 2.94 g) in anhydrous toluene (40 mL) was degassed under nitrogen and stirred at room temperature for 1.5 hours. The mixture was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of DCM and pentane with a gradient of 0-100 956, to give tert-Butyl (5)-2-(3-fluorophenylethynyl)pyrrolidine-1-carboxylate (1.26 d) in the form of an oily substance.

IN NMR (SOSI") 6: 7.25 (1H, t), 7.16 (1H, Bg a), 7.08 (1H, Bg 4), 6.99 (1H, Bg U, 4.69 ( IN, Bg 9), 3.51 (1H, Bi 5), 3.37 (1H, Big 5), 2.11 (ZN, Bg t), 1.94 (1H, ru 5), 1.49 ( 9H, 5).

Intermediate compound 236: tert-Butyl (5)-2-tributylstananylethynylpyrrolidine-1-carboxylate 5-0 g, 00576) n-Butyllithium (2.5 M solution in hexane, 11 ml) was added dropwise to a cooled solution of tert-Butyl ( 5)-2-ethynylpyrrolidine-1-carboxylate (obtained according to publication A

Crayfish! ей айЙ, Teigapedgop, 2006, 62, 8919, 4.49 g) in dry THF (230 ml) in a nitrogen atmosphere,

maintaining the temperature below -65 °C. After the addition was complete, the mixture was stirred at -787 °C for 15 minutes, then allowed to warm to 0 °C and stirred for 2.5 hours. Tributyltin chloride (7.7 mL) was added dropwise over five minutes, and the mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0 °C and saturated sodium bicarbonate solution was added, maintaining the temperature below 15 °C. The layers were separated, and the aqueous layer was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, dried (Mo5O4) and filtered. The filtrate was evaporated to a dry residue, and the residue was purified by chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate with a gradient of 0-7.5 9°, to obtain tert-Butyl (5)-2-tributylstananylethynylpyrrolidine-1-carboxylate (0.39 g) in in the form of an oily substance.

1H NMR (SOSI) 6: 4.41 (1H, Bg 5), 3.45 (1H, Bg t), 3.28 (1H, B 5), 2.03 (ZN, Bi t), 1.86 (1H, Bi 5), 1.54 (6H, t), 1.48 (9H, 5), 1.33 (6H, ad), 0.95 (6H, U), 0.90 ( 9N, V.

Biological example:

I00577| The compounds were tested for their ability to inhibit the activity of recombinant human MegaAR2 using the following assay. 00578) Recombinant human Me(AP2) expressed in 519 cells followed by affinity purification and EDTC treatment to remove the endogenous active site cation was dialyzed against MpyCl2 to obtain the manganese enzyme used in the assay. The assay was performed for 30 minutes at 25"C in 50 mM NEREZ5 buffer containing 100 mM Mass, pH 7.5, in the presence of 0.75 mM methionine-alanine-serine (MAB) substrate and 50 μg/ml amino acid oxidase using a dilution of purified MegaAR2 that gives a greater than 3-fold ratio signal:noise Substrate cleavage by MeiARAZ and oxidation of free methionine by amino acid oxidase were detected and quantitatively measured using fluorescence caused by the reagent "Red Atrieh" (10-acetyl-3,7-dihydroxyphenoxazin) in combination with horseradish peroxidase, which detects H2O2 , which is released at the oxidation stage.

The fluorescent signal was detected using a multibeam fluorimeter. Before adding to the analytical buffer, the compounds were diluted in DMSO, the final concentration of DMSO in the analysis was 1 Fo.

I00579| IC50 was determined as the concentration at which the compound achieves 5095 relative to the control inhibition. IC5O values were calculated with the help of the software package Khyya (version 2.0.5). 00580) Compounds according to the present invention showed activity in the assay of this Example, which is shown in the table below, where A represents "0.05 µM, B represents IC50 from 0.05 µM to 0.5

MKM, and C is IC5O » 0.5 µM.

Cis-(Zav5, 9685)-7-(Benzenesulfonylamino)-1,Za, 4,90-tetrahydro-2H-furo|2,3-vo sichromene-6b-carboxylic acid

Cis-(Zav5, 9685)-7-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1,Za, in 4,9p-tetrahydro-2H-furo|2,3-s|Yichromene-b- carboxylic acid

Cis-(Zav5, 9685)-7-(2-(3-"Pyrrolidin-1-ylylpropyl)-4-fluorobenzenesulfonylamino|- 1,Za, 4,9p-tetrahydro-2H-furo|2,3-sichromene-6 -carbonic acid

Cis-(zano, 90A5)-7-(2-((2)-Z-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H-furoi|2,3 -c|chromene-6-A carboxylic acid

The first eluted enantiomer of cis-(Zana, 9685)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H-furo|2 ,3-sichromene-6-A carboxylic acid

The second eluted enantiomer cis-(Zanz, 9585)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Za, 4,9p-tetrahydro-2H-furo|2 ,3-sichromene-6-carboxylic acid 7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,2- dihydrofuroic|2,3-s|quinoline-b-carboxylic acid acid formate salt of 7-(Benzenesulfonylamino))-1,2-dihydrofuro|2,3-cIquinoline-b6-carboxylic acid formate salt

Cis-(zano, 90A5)-7-(2-((2)-Z-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,2,Za, 4,5,9p-hexahydrofuroi|2,3 -c|quinoline-6-carboxylic acid 5-(2-((7)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1 a, 2,70-tetrahydrocyclopropa|cIchromene-4-carboxylic acid acid

(tab, 708) 5-(2-(7)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1a, in 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (tab, 7655) 5-(2-(7)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1a, 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-(2- (7)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|- 70-methyl-1,1a, 2, 70-tetrahydrocyclopropa(|siIchromene-4-carboxylic acid (tavb, 7058)-5-(2- (E)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino |- 70-vo methyl-1,1a, 2, 70-tetrahydrocyclopropa(|siIchromene-4-carboxylic acid

Cis-(Zav5, 9085)-7-(2-(4-dimethylamine-butylamino)-benzenesulfonylamino|-1,3a, in 4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-b-carbonova acid (tav, 7055)-5-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!-1,1a, 2,7p- tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-(2- (7)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1, 1 A difluoro-1,1a, 2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid

The first eluted enantiomer (tTakz, 70B5K)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1-difluoro-1α, 2,7β-tetrahydrocyclopropa|sichromene- 4-carboxylic acid

The second eluted enantiomer (also, 705K)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1-difluoro-1Ta, 2,7b-tetrahydrocyclopropa|siIchromene- A of 4-carboxylic acid (tavb5, 7058)-5-(2(2)-3-Ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1a, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylic acid

The first eluted enantiomer (also, 705K)-5-(2((2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene-4-A carboxylic acid acid

The second eluted enantiomer (Yes, 7065H)-5-(2(27)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene-4-carboxylic acid ( tavb5, 7058)-5-2((2)-3-(Pyrrolidin-1-yl)/prop-1-enyl|-A-fluorobenzenesulfonylamino)-1,ta, 2,70-tetrahydrocyclopropa|sichromene-4-carbon acid

The first eluted enantiomer (Takz, 705K)-5-12|(2)-3-(pyrrolidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene -4- carboxylic acid

The second eluted enantiomer (Yes, 705K)-5-42((2)-3-(pyrrolidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa(cIIIchromene-4 - carboxylic acid (tavb, 7058)-5-(2-(3-dimethylaminopropylamino)dbenzenesulfonylamino!-1,1a, 2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid

The first eluted enantiomer (Takz, 70p5K)-5-(2-(3- dimethylaminopropylamino)benzenesulfonylamino|-1Ta, 2, 7B- (0; tetrahydrocyclopropa|sichromene-4-carboxylic acid

The second eluted enantiomer (Tak, 765K)-5-(2-(3- dimethylaminopropylamino)benzenesulfonylamino|-1Ta, 2, 7B-A of tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-(2-( 4-dimethylaminobutylamino)benzenesulfonylamino!

The first eluted enantiomer (Takz, 7p5K)-5-(2-(4- dimethylaminobutylamino)benzenesulfonylamino!|-1Ta, 2,7B- tetrahydrocyclopropa|sichromene-4-carboxylic acid

The second eluted enantiomer (Tak, 765K)-5-(2-(4- dimethylaminobutylamino)benzenesulfonylamino!|-1Ta, 2,7p-A tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-(2- (5-dimethylaminopentylamino)benzenesulfonylamino!-1Ta, 2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid (Tanz, 7058)-5-2((2)-3-(propan-2-yl)aminoprop-1- enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid

(Tanz, 7058)-5-(2((2)-3-((5)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa |SiCichromene-4-carboxylic acid (Tanz, 7058)-5-2((2)-3-(B8)-3-Hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (tavb, 7058)-5-(2(2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1 Ta, 2,7p-tetrahydrocyclopropa| Cychromene-4-carboxylic acid

The first eluted enantiomer (1anz, 705Н8)-5-(2(2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene-4-carboxylic acid

The second eluted enantiomer (Yes, 705K)-5-(2((27)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene-4-carboxylic acid (tavb, 7058)-5-(2-(2-(4-Ethylpiperazin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-vo 1,ta, 2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid ( tavb, 7058)-5-2((2)-3-(Azetidin-1-yl)prop-1-enyl|-4A-fluorobenzenesulfonylamino)-vo 1,ta, 2,70-tetrahydrocyclopropa|sichromene-4-carbonova acid (Tanz, 7058)-5-2((2)-3-(3-Hydroxyazetidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4 - A carboxylic acid (tavb5, 7058)-5-2((2)-3-(Azetidin-1-yl)propyl|-4-fluorobenzenesulfonylamino)-1Ta, in 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid acid (Taub, 7058)-5-(2(7)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino!-1,1a, in tetrahydrocyclopropa|sichromene-4-carboxylic acid (Tanz, 7058)-5-(2-IM -(4-dimethylaminobutyl)-M-methylamino|-benzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa-|c|Ichrome n-4-carbonate (0; acid (Tanz, 7058)-5-(2-((5)-1-Ethylpyrrolidin-3-ylcarbamoyl)-methyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7b-tetrahydrocyclopropa-|sichromene-4- carboxylic acid (tav, 7658)-5-(2-(1-Ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino!-1Ta, 2,7-tetrahydrocyclopropa|sichromene-4-carboxylic acid (Tanz, 7058)- 5-(22-I(A)-1-Ethylpyrrolidin-3-ylcarbamoyl)-methylyl|-4-fluorobenzenesulfonylamino)-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (tavb, 7058)-5- 2-(2-(Pyrrolidin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-1,1a, in 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-(2-( B8)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino-1,ta,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid

The first eluted enantiomer (Takz, 70p5K)-5-(2-(B)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid

The second eluted enantiomer (also, 765K)-5-(2-(A)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-A carboxylic acid ( Tanz. 7058)-5-(2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino|- in 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4-carboxylic acid (tavb, 7058)-5-(2- ((5)-1-Ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino-1,ta,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-(2-(Z- dimethylaminopropylcarbamoyl)benzenesulfonylamino! M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-|c|Ichromene-4- carboxylic acid

(Tanz, 7058)-5-(2-N-(A)-1-Ethylpyrrolidin-3-yl)-M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1,1a, 2,7p-tetrahydrocyclopropa-|c Ychromene-4-carboxylic acid (tav, 7058)-5-12-(2-(5)-1-Ethylpyrrolidin-2-yl)/ethylamino|-benzenesulfonylamino)-1,ta, 2,70-tetrahydrocyclopropa-( c|Ichromene-4-carboxylic acid (tav, 7058)-5-12-(2-(B)-1-Ethylpyrrolidin-2-yl)ethylamino|-benzenesulfonylamino)- 1,ta, 2,70-tetrahydrocyclopropa-( c|Chromene-4-carboxylic acid (tavb, 7058)-5-(2-(3-M, M,-diethylaminopropylamino)benzenesulfonylamino!-1,1a, 2,7p-tetrahydrocyclopropa|cChromene-4-carboxylic acid (Tanz . )-5-2-(1-Ethylazetidin-3-ylmethyl)amino|benzenesulfonylamino)-1, Ta, in 2,7bB-tetrahydrocyclopropaHsichromene-4-carboxylic acid

The first eluted enantiomer (Takz, 705K)-5-(2-(2)-Z-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene-4-carboxylic acid

The second eluted enantiomer (Yes, 705K)-5-(2-(2)-Z-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa|c|chromene-4-A carboxylic acid (Tanz . - carboxylic acid (Tanz, 7058)-5-(2-1M-((5)-1-Ethylpyrrolidin-2-yl)carbonyl|-M-methylamino-methyl)-4-fluorobenzenesulfonylamino)-1, Ta, 2, 7p-tetrahydrocyclopropa|ciichromene-4-carboxylic acid (tavb, 7058)-5-(2-(4-dimethylaminobutylamino)-4-fluoro-benzenesulfonylamino |- in 1,ta, 2,70-tetrahydrocyclopropa-(ciichromene- 4-carboxylic acid (tav, 7058)-5-2-((B8)-1-Ethylpyrrolidin-3-ylmethyl)amino|-benzenesulfonylamino)-vo 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4 -carboxylic acid (tav, 7058)-5-12-((5)-1-Ethylpyrrolidin-3-ylmethyl)amino|-benzenesulfonylamino)- in 11a, 2,7b-tetrahydrocyclopropa-Isichromene-4-carboxylic acid (Tanz, 705H8)-5-(2-(4-Ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenes sulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa-|siIchromene-4-carboxylic acid (taub5, 7058)-5-(2-(1-Ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino!-1,1a, 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylic acid (tavb, 7058)-5-(2-(2-(1-Ethylazetidin-3-yl)ethyl|-4-fluoro-benzenesulfonylamino)-vo 1,ta . in 1, and, 2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid (tavb, 7058)-5-H2-((B)-1-Azabicyclo/2.2.2)oct-3-yl)amino|benzenesulfonylamino) - 1, and, 2,70-tetrahydrocyclopropa|c|chromene-4-carboxylic acid (Tanz, 7058)-5-(2-C1(5)-1-ethylpyrrolidine-3-carbonyl)amino|methyl)-4- fluorobenzenesulfonylamino)-1, Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4-carboxylic acid (Tanz, 7058)-5-(2-(2-(A)-1-Ethylpyrrolidine-3-ylamino)ethyl|-4- fluorobenzenesulfonylamino)-1, Ta, 2,7p-tetrahydrocyclopropa-|c|Ichromene-4-carboxylic acid (tav, 7058)-5-12-((B8)-1-Ethylpyrrolidin-3-yllam ino|-benzenesulfonylamino)-1 and, in 2,7b-tetrahydrocyclopropa-Isichromene-4-carboxylic acid (tlav5, 7058)-5-(2-((5)-1-Ethylpyrrolidin-3-yl)amino|-benzenesulfonylamino )-1,1a, in 2,7p-tetrahydrocyclopropa-|sichromene-4-carboxylic acid (Tanz, 7058)-5-(2-C(A)-1-Ethylpyrrolidine-3-carbonyl)amino|-methyl)- 4-fluorobenzenesulfonylamino)-1, Ta, 2,7p-tetrahydrocyclopropa|siIchromene-4- carboxylic acid

(Tanz, 705H8)-5-(2-(2)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta, 2,7p-tetrahydrocyclopropa-|siIchromene-4-A carbon acid (tav, 7058)-5-12-(2-(B)-1-Ethylpyrrolidin-3-yl)ethylamino|-benzenesulfonylamino)-vo 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4- carboxylic acid (tav, 7058)-5-12-(2-(5)-1-Ethylpyrrolidin-3-yl)ethylamino|-benzenesulfonylamino)-vo 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4 -carboxylic acid (tav, 705)-5-(2-(5)-1-Ethylpyrrolidine-3-yloxymethyl)-4-fluorobenzenesulfonylamino|- in 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4- carboxylic acid (tav, 705)-5-(2-(8)-1-Ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino|- 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4-carboxylic acid acid (tav, 765) -5-(2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!-1,1a, in 2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid (tav, 705)- 5-(2-(2-(B8)-1-Ethylpyrrolidin-2-yl)ethyl|-4-fluorobenzenesulfonylamino)-vo 1,ta, 2,70-tetrahydrocyclopropa-(c|ichromene-4- carboxylic acid

Incorporation by reference

I0O581| All publications and patents referred to herein, including those listed below, are incorporated herein by reference in their entirety and for all purposes as if each individual publication or patent were specifically and individually incorporated by reference. In case of conflict, this description shall govern, including any definitions herein.

Equivalents

I00582| Although specific embodiments of the invention have been considered, the above description is only illustrative and not restrictive. In view of this description, numerical variations according to 3 of this invention will become clear to those skilled in the art.

The full extent of the present invention should be determined by reference to the claims together with the scope of equivalents and this description together with such variations. 00583) Unless otherwise indicated, all numerical values expressing amounts of ingredients, reaction conditions, etc., used in the description and claims of the invention should be understood to be modified in all cases by the term "approximately". Accordingly, unless otherwise indicated, the numerical parameters given in the description of the invention and the attached formula are approximations that may vary depending on the given properties to be obtained according to the present invention.

Claims (1)

FORMULA OF THE INVENTION 1. Tricyclic compound represented by formula II: Beer ATM (VAZY N son SHI 25. where: In? is a 3-6-membered saturated heterocyclic or carbocyclic ring; while ring B2 is optionally substituted by one or more fluorine atoms near any of the available carbon atoms; r is a 5-7-membered heterocyclic or carbocyclic ring; while B: is condensed with 0-, so that the two atoms common to B: and F0- are carbon atoms; X2 is "-M/2-C(IVO5HOv)-": where : and "7 indicate the points of attachment of X? as shown in formula II; U is selected from the group consisting of: bond, 7-0O -СНе-" and -0-СНо-СНе-и; while 7 and? indicate the attachment points of Y, as shown in formula II; MU? selected from the group consisting of O or M(B"2); A is phenyl; BA and A 82 are independently selected from the group consisting of H, E, OH, CM, C:-halkoxy or C: alkyl; while C-alkyl and C-halkoxy are optionally substituted by a group selected from OH, C-halkoxy, CM, or one or more fluorine atoms; BA" is selected, independently for each case, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C:-alkyl or C.i-alkoxy; while C:-alkyl or C.:-alkoxy is optionally substituted by one or more fluorine atoms; n equals 0, 1 or 2; Be selected from the group consisting of hydrogen, B'B/M-, heterocyclyl, heterocyclyloxy and heterocyclyl-(MNa)-; while the specified heterocyclyl may be optionally substituted by one or more substituents selected from He, and in this case, if the specified heterocyclyl contains a -MH fragment, then this nitrogen may be optionally substituted with one or more groups B"; or Be selected from the group consisting of: C1-alkyl, C3-alkyl, C3-valkynyl, C3-cycloalkyl, C3-valkoxy, C3-valkynyloxy, C3-valkynyloxy, C3-cycloalkyl, C:-alkyl-3(O)»z- (while m / is equal to 0, 1 or 2), C-alkyl-M(B2)-, C-alkyl-M(Veg)-carbonyl-, C-alkylcarbonyl-M(H2)-, C-alkyl-M(Hg)-carbonyl -M(H2)-, C-alkyl-M(Hg)-505-, C-alkyl-502-M(Hg)-, C-alkyloxycarbonyl- M(Hg)-, C-alkylcarbonyl-M(Naeg)- C: -alkyl-, Ci-alkyl-M(Hg)-carbonyl-C: -alkyl-, Ci-valkoxy:- alkyl-; while C3-alkyl, C3-alkenyl, C3-valkynyl, C3-cycloalkyl, C3-valkoxy, C3-alkenyloxy, C3-valkynyloxy, C3-cycloalkyl, C3-alkyl-3(O)k-, C3-alkyl- M(B2)-, C-alkyl-(MH2g)-carbonyl-, C- alkylcarbonyl-M(Na)-, Si-alkyl-M(Hg)-carbonyl-M(H2)-, Si-alkyl-M(H2g)-50", Si-alkyl-5BO2-M(B2)-, Si -valkoxycarbonyl-M(Vag)-, C-alkylcarbonyl-M(B2)Ci-alkyl-, C-alkyl-M(Vag)-carbonyl-C. alkyl-, C-valoxy-C:-alkyl may optionally be substituted by PP, phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(MA2)-, heterocyclyl, heterocyclyloxy or heterocyclyl-M(H2)-; and at the same time the indicated heteroaryl or phenyl may be optionally substituted by one or more substituents selected from B; and at the same time the indicated heterocyclyl may be optionally substituted by one or more substituents selected from Not; and at the same time, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen atom may optionally be replaced by one or more B groups"; Vo" and DeOE are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, Sigalkilu or Sigalkoxy; while C-halkyl and C-halkoxy may be optionally substituted by a substituent or substituents selected from the group consisting of: one or more fluorine, cyano, hydroxyl or M(VaX) atoms; B" is selected from the group consisting of hydrogen or C1-alkyl; Wag and EE are independently selected, in each case, from the group consisting of hydrogen and C1-alkyl; while C-alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo and hydroxyl; or Wag and PE, together with the nitrogen atom to which they are attached, may form a 4-6b-membered heterocyclic ring, which may have an additional heteroatom selected from 0, 5, or M; while the indicated 4-6-membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of fluorine, cyano, oxo or hydroxyl; IN! independently selected, in each case, from the group consisting of B", hydrogen, C3-alkyl, C3-vcycloalkyl, C1-6alkenyl, C1-valkynyl, C1-valkoxy, C1-alkyl-Z(O)"k- ( while m is equal to 0, 1 or 2), Sialkylcarbonyl-M(Nag)- and Si-alkylcarbonyl-M(H2g)-, while C-alkyl, C3-bicycloalkyl, C1-valkenyl, C1-valkynyl, Si-valkoxy , C-alkyl-B(O)x-, C-alkylcarbonyl-M(B2g)-, Ch- valkoxycarbonyl-M(Nag)- may be optionally substituted by one or more substituents selected from Be; Be is independently selected, for each case, from the group consisting of Be, hydrogen, oxo, C-alkyl, Sovalkenyl, C-alkyl, C-cycloalkyl, C-alkyl, C-alkyl-B(O)k- (while m is equal to 0, 1 or 2), Sialkylcarbonyl-M(B2)- and Si-vealkoxycarbonyl-M(B2)-; while C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-cycloalkyl, C-alkyl, C-alkyl-C(O)k-, C-alkylcarbonyl-M(C)-, C-alkylcarbonyl-M( H2d)- may optionally be substituted by one or more substituents selected from Rhe; B" is independently selected, in each case, from the group consisting of hydrogen, C:-alkyl, C3-valkenyl, C3-valkynyl, C3-isocycloalkyl, C1-alkyl-5(0)2-, C1-alkoxycarbonyl-, V'VIM-carbonyl- and VI'VIM-505; while C-alkyl, C3-valkenyl, C3-valkynyl, C3-cycloalkyl and C1-alkyl-5(O)"-, C3-alkyloxycarbonyl- can be optionally substituted by one or more substituents selected from Be; B1 and B1 are independently selected, for each case, from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, and heterocyclylcarbonyl; and C-alkyl and C-cycloalkyl can 60 be optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, NaReM-, VaM-carbonyl- and C-alkoxy, and heterocyclyl and heterocyclylcarbonyl may be optionally substituted with one or more substituents selected from C:-alkyl, Co-valkenyl, C-alkyl, C3-cycloalkyl, C -vealkoxy, halo-C:-c-alkyl, hydroxyl-C:-c-alkyl, BaBeM-C. alkyl- and C-C-Alkoxy-C-C-Alkyl group; and at the same time, if the specified heterocyclyl or heterocyclylcarbonyl contains a -MH fragment, then the specified nitrogen atom may be optionally substituted by one or more C:-alkyl, C3-alkenyl, C3-alkynyl, C3-ecycloalkyl, C3-alkyl-5(O )2- and C-6-alkylcarbonyl; or B. and B), taken together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring which may have an additional heteroatom selected from 0, 5 or M; and the specified 4-7-membered heterocyclic ring may be optionally substituted near the carbon atom by one or more substituents selected from the group consisting of fluorine, hydroxyl, oxo, cyano, C:-alkyl, Si-valoxy, NaBeM -, VNaVeM-50-- and gave M-carbonyl-; at the same time, the specified C-:-alkyl or C:-valkoxy may be optionally substituted by fluorine, hydroxyl or cyano; and at the same time, the indicated 4-7-membered heterocyclic ring may be optionally substituted near the nitrogen atom by one or more substituents selected from the group consisting of C:-alkyl and BaBRM-carbonyl-; and at the same time, the specified C-.-alkyl may be optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, cyano; BP is independently selected, for each case, from the group consisting of halogen, hydroxyl, cyano, C:i-valkoxy, B'B/IM-, B'VIM-carbonyl-, B'VIM-505- and B'VIM -carbonyl-M(H2)-; and its pharmaceutically acceptable salts and stereoisomers. 2. A tricyclic compound according to claim 1, characterized in that Be: and B2 are independently selected, in each case, from the group consisting of hydrogen, fluorine, cyano and C:-alkyl. 3. A tricyclic compound according to any one of claims 1-2, which differs in that ВС" and ДВОЕ represent hydrogen. 4. Tricyclic compound according to any of claims 1-3, which differs in that VV! is selected from the group consisting of H, E and C:-halkyl. 5. Tricyclic compound according to any one of claims 1-4, which differs in that U is a bond. 6. Tricyclic compound according to claim 1, which differs in that this compound is represented by: (c) vag B vag M AK o TAM o (BA) 4 and (BA) 4 N z o p son a p son L (c) wa M where M TAM M A o A 4 y y (VU) y y (7, sleep Is or p sleep 9. 7. Tricyclic compound according to claim 6, which is characterized in that B"! is selected from the group consisting of hydrogen, halogen, C-alkyl and C-haloxy; and C:-alkyl may be optionally substituted by one or more atoms fluoride 8. A tricyclic compound according to any one of claims 6-7, which is characterized in that B": selected from the group consisting of hydrogen, B/VIM, heterocyclyl, C:-alkyl, C-alkyl, C-cycloalkyl, C-alkyl; and the specified heterocyclyl may be optionally substituted by one or more РХ groups; and at the same time, if the specified heterocyclyl contains a -MH fragment, then this nitrogen atom may optionally be substituted by one or more B groups"; and at the same time the specified C 1 -alkyl, C 3 -alkenyl, C 3 -cycloalkyl and C 1 -alkoxy may optionally be substituted by one or more Be groups. 9. Tricyclic compound according to any of claims 6-8, which is characterized in that HB" is selected from the group consisting of 3-(M,M-diethylamino)propyl, 3-(pyrrolidin-1-yl)propyl, (2)-3-(M,M-diethylamino)prop-1-enyl, (2)-3-(azetidin-1-yl)prop-1-enyl and (2)-3-(pyrrolidin-1- yl)prop-1-enyl. 10. A tricyclic compound represented by the formula IM: VV! ra o o X r? /, (ВА, и ше son M where р? is a 5-7-membered partially unsaturated heterocyclic or carbocyclic ring; X2 is 7-Mu/2-C(IVR»ov); while and " indicate the attachment points of X ?, as shown in the IM formula; MU? selected from the group consisting of O or M(B"2); BP! selected from the group consisting of H, E, OH, CM, C-halkoxy or C-alkyl; while C-:- alkyl and Sihalkoxy is optionally substituted by a group selected from OH, C.i-halkoxy, CM, or one or more fluorine atoms; A" is selected, independently for each case, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C:-alkyl or C-1-alkoxy, wherein C:-alkyl or C-1-alkoxy is optionally substituted by one or more fluorine atoms; n is 0, 1 or 2; Bhe is selected from the group consisting of hydrogen, B'B/M-, heterocyclyl, heterocyclyloxy and heterocyclyl-(МНА2)-; while the indicated heterocyclyl may be optionally substituted by one or more substituents selected from He, and in this case, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen may be optionally substituted by one or more groups B"; or Be selected from the group consisting of: C1-alkyl, C3-alkyl, C3-valkynyl, C3-cycloalkyl, C3-valkoxy, C3-valkynyloxy, C3-valkynyloxy, C3-cycloalkyl, C:-alkyl-3(O)»z- (while m / is equal to 0, 1 or 2), C-alkyl-M(B2g)-, C-alkyl-M(Vag)-carbonyl-, C-alkylcarbonyl-(MNAa)-, C-alkyl-(MAg)-carbonyl-( MNag)-, C-alkyl-M(Hg)-505-, C-alkyl-502-M(Hg)-, C-alkyloxycarbonyl- M(Vag)-, C-alkylcarbonyl-(MNag)-C: -alkyl -, Ci-alkyl-M(Nag)-carbonyl-C: -alkyl-, Ci-valkoxy:- alkyl-; while C3-alkyl, C3-alkenyl, C3-valkynyl, C3-cycloalkyl, C3-valkoxy, C3-alkenyloxy, C3-valkynyloxy, C3-cycloalkyl, C3-alkyl-Z(O)k-, C3-alkyl -M(B2)-, C-alkyl-M(H2g)-carbonyl-, C- alkylcarbonyl-M(HB2)-, C-alkyl-M(Hg)-carbonyl-M(H2)-, C-alkyl-M(Hg)-505-, C-alkyl-BO2-M(H2)-, Si -valkoxycarbonyl-M(H2g)-, C-alkylcarbonyl-(MA2g)-Ci-alkyl-, C-alkyl-M(H2g)-carbonyl-C:-alkyl-; Ci.valoxyC:-alkyl may be optionally substituted by BP, phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(MA2g)-, heterocyclyl, heterocyclyloxy or heteroaryl-M(Hg)-; and at the same time the indicated heteroaryl or phenyl may be optionally substituted by one or more substituents selected from B; and at the same time the indicated heterocyclyl may be optionally substituted by one or more substituents selected from Not; and at the same time, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen atom may optionally be replaced by one or more B groups"; A: and deOe are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C-halkyl or C-haloxy; while C:-halkyl and C-halkoxy may be optionally substituted by a substituent or substituents selected from the group consisting of: one or more fluorine, cyano, hydroxyl or M(B2PX); B" is selected from the group consisting of hydrogen or C -alkyl; Be and B? are independently selected, in each case, from the group consisting of hydrogen and C:-alkyl; while C-alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo and hydroxyl; or Wag and PE, together with the nitrogen atom to which they are attached, may form a 4-6b-membered heterocyclic ring, which may have an additional heteroatom selected from 0, 5, or M; while the indicated 4-6-membered heterocyclic ring may be optionally substituted by one or more substituents selected from the group consisting of fluorine, cyano, oxo or hydroxyl; IN! independently selected, in each case, from the group consisting of R e , hydrogen, C 1 -alkyl, C 3 -cycloalkyl, C 1 -alkenyl, C 1 -alkynyl, C 1 -valkoxy, C 1 -alkyl-Z(O)»k- ( while m is equal to 0, 1 or 2), Sialkylcarbonyl-M(H2g)- and Si-vealkoxycarbonyl-(МНА2g)-; while C-alkyl, C3-vcycloalkyl, C1-valkenyl, C1-valkynyl, C-valkoxy, C-alkyl-B(O)x-, C-alkylcarbonyl-(MA2g)-, C- valkoxycarbonyl-(MHAg)- may be optionally substituted by one or more substituents selected from Be; Be is independently selected, in each case, from the group consisting of Be, hydrogen, oxo, C1-alkyl, subalkenyl, C1-alkyl, C3-cycloalkyl, C1-alkyl, C1-alkyl-B(O)"- ( while xm is equal to 0, 1 or 2), Ci-alkylcarbonyl-(MA2)- and Ci-vealkoxycarbonyl-(MA2)-; while C-alkyl, C1-valkenyl, C1-valkynyl, C3-"cycloalkyl, C1-valkoxy, C1-alkyl-Z(O)x-, C1-alkylcarbonyl-(МНА2)-, C1-alkoxycarbonyl- (МНА2г)- may be optionally substituted by one or more substituents selected from Бе; B" is independently selected, in each case, from the group consisting of hydrogen, C1-alkyl, C3-valkenyl, C3-valkynyl, C3-6cycloalkyl, C1-alkyl-5(0)2-, C1-6alkylcarbonyl-, B'VIM-carbonyl- and B'VIM-505-, while C-alkyl, C3-alkenyl, C3-valkynyl, C3-cycloalkyl and C1-alkyl-5(O)2-, C3-alkoxycarbonyl- may be optional substituted with one or more substituents selected from Be; B1 and B1 are independently selected, in each case, from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl, and heterocyclylcarbonyl, wherein C1-6 alkyl and C3-6 cycloalkyl may be optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, BaBeM-, BaBeM-carbonyl- and C-alkoxy, and heterocyclyl and heterocyclylcarbonyl may be optionally substituted with one or more substituents selected from C:-alkyl, Co-valkenyl, C-valkynyl, C3--cycloalkyl, C-C-alkyl, halo-C:-C-alkyl, hydroxyl-C:-C-alkyl, BaBeM-C-C-alkyl- and C-C- AlkoxyS:-in-alkylov of the group; and at the same time, if the specified heterocyclyl or heterocyclylcarbonyl contains a -MH fragment, then the specified nitrogen atom can be optionally substituted by one or more groups of C:-alkyl, C:-alkyl, C3-valkynyl, C3-vcycloalkyl, C:-alkyl-5( O)2- and C-6-alkylcarbonyl; or B! and B), taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring, which may have an additional heteroatom selected from O, 5, or M; and the indicated 4-7-membered heterocyclic ring may be optionally substituted near the carbon atom by one or more substituents selected from the group consisting of fluorine, hydroxyl, oxo, cyano, C:-alkyl, Si-valkoxy, NaBeM-, BaBeM- 5O»- and BeBeM-carbonyl-; at the same time, the indicated C -alkyl or C:i-alkyl may optionally be substituted by fluorine, hydroxyl or cyano; and at the same time the indicated 4-7-membered heterocyclic ring may be optionally substituted near the nitrogen atom by one or more substituents selected from the group consisting of C:-alkyl and BaBRM-carbonyl-; and at the same time, the specified C-.- alkyl may be optionally substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, cyano; BP is independently selected, for each case, from the group consisting of halogen, hydroxyl, cyano, C:i-valkoxy, B'VIM-, B'VIM-carbonyl-, B/VIM-505- and B'B)M -carbonyl-M(H2)-; and its pharmaceutically acceptable salts and stereoisomers. 11. Tricyclic compound according to claim 10, which differs in that B"! is selected from hydrogen and fluorine. 12. A tricyclic compound according to any one of claims 10-11, which is characterized in that B"- is selected from the group consisting of hydrogen, B'B/M, heterocyclyl, C:-alkyl, C3-alkyl, C3-cycloalkyl, Si-valkoxy; and the indicated heterocyclyl may be optionally substituted by one or more РХ groups"; and at the same time, if the indicated heterocyclyl contains a -MH fragment, then this nitrogen atom may be optionally substituted by one or more B groups"; and at the same time, the specified C-alkyl, C-alkyl, C-cycloalkyl and C-alkyl may optionally be substituted by one or more Be groups. 13. A compound selected from the group consisting of: cis-(Zano, 9ЬА5)-7-(benzenesulfonylamino)-1,За,4,9р-tetrahydro-2H-furo|2,3-c|chromene-6- carboxylic acid; cis-(zZanz,zn5)-7-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-b-carbon acids; cis-(Zano, 9ЬА5)-7-(2-(3-«(pyrrolidin-1-ylpropyl)-4-fluorobenzenesulfonylamino|-1,Za,4,9p-tetrahydro-2H-furo|2,3- c|Ichromene-b-carboxylic acid; cis-(Zano, 9А5)-7-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Za,4,9p-tetrahydro -2H-furo|2,3-c|chromene-b-carboxylic acid; cis-(zan,zbya)-7-(2-(7)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|- 1,Za,4,9p-tetrahydro-2H-furo|2,3-c|Ichromene-b-carboxylic acid; cis-(Zanv,9n5)-7-(2-(2)-3-diethylaminoprop-1- enyl)-4-fluorobenzenesulfonylamino!|-1,Za,4,9p-tetrahydro-2H-furo|2,3-s|Ichromene-b-carboxylic acid; 7-(2-(2)-3-diethylaminoprop-1 -enyl)-4-fluorobenzenesulfonylamino|-1,2-dihydrofuro|2,3-s|quinoline- b-carboxylic acid formate salt; 7-(benzenesulfonylamino)-1,2-dihydrofuro|2,3-s|quinoline- 6-carboxylic acid formate salt; cis-(Zano, 9АА5)-7-(2-(2)-3-diethylaminoprop-1-enyl )-4-fluorobenzenesulfonylamino |- 60 1,2,3a,4,5,9p-hexahydrofuro2,3-c|quinoline-b6-carboxylic acid; (Tan5,765H)-5-(2-(2)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ta,705)-5-(2-(27)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tab, 7068)-5-(2-(27)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H8)-5-(2-(72)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-7p-methyl-1/1a,2,7p-tetrahydrocyclopropa|c|Ichromene-4-carbon acids; (Tanz,705H8)-5-(2-(E)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino|-7p-methyl- 1/1a,2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; ( tTav,765)-5-(2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,76B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2-(72)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1-difluoro-11a,2,7b-tetrahydrocyclopropa|c|Ichromene-4- carboxylic acid; (Tav,7605)-5-(2-(27)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1-difluoro-11a,2,7b-tetrahydrocyclopropa|c|ichromene-4-carbon acids; (Tab, 7068)-5-(2-(27)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!-1,1-difluoro- 11a,2,7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; (Tanz,705H)-5-(2(2)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ta,7605)-5-(2((27)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-1Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ta5,7068)-5-(2(27)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino!|-11a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H8)-5-21(2)-3-(pyrrolidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tav,765)-5-21(2)-3-(pyrrolidin-1-yl)uprop-1-enyl|-4-fluorobenzenesulfonylamino)-1 Ta,2,7p- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tab5,768)-5-21(2)-3-(pyrrolidin-1-yl)uprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ianz5,765H)-5-(2-(3-dimethylaminopropylamino)benzenesulfonylamino!|-1,1a,2,76B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ta,765)-5-(2-(3-dimethylaminopropylamino)benzenesulfonylamino!-1Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ta5,768)-5-(2-(3-dimethylaminopropylamino) )benzenesulfonylamino!-1Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H8)-5-(2-(4-dimethylaminobutylamino)benzenesulfonylamino!|-1,Ta,2,7p- tetrahydrocyclopropa(|cichromene-4-carboxylic acid; (tTa8,765)-5-(2-(4-dimethylaminobutylamino)benzenesulfonylamino|-1,T1a,2,7p- tetrahydrocyclopropa|cichromene-4-carboxylic acid; (Ta5,7068 )-5-(2-(4-dimethylaminobutylamino)benzenesulfonylamino|-1,T1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ianz5,765H)-5-(2-(5-dimethylaminopentylamino)benzenesulfonylamino!|-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H8)-5-2((2)- 3-(Propan-2-ylaminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tan5,765H8)-5-(21(2)-3 -((5)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4- fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tan5,765H8)-5-(2((2)-3-((B8)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl|-4-fluorobenzenesulfonylamino)-1,1a,2,7p- Tetrahydrocyclopropa|c|Ichromene-4-carboxylic acid; (Tanz,705H)-5-(2(2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,7p- tetrahydrocyclopropa| Sichromene-4-carboxylic acid; (Tab,7605)-5-(2((2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Table 5, 708)-5-(2((2)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)- 5-(2-(2-(4-ethylpiperazin-1-yl)-ethyl|-4-fluorobenzenesulfonylamino)-1Ta,2,7p- 60 tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H8)-5-2((2)-3-«(azetidin-1-yl)prop-1-enyl|-4-fluorobenzenesulfonylamino)-1Ta,2,7p- tetrahydrocyclopropa|sichromene-4-carbon acids; (Tanz,705H)-5-2((2)-3-(3-hydroxyazetidin-1-yl)uprop-1-enyl|-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c|ychromene-4 - carboxylic acid; (Tanz,705H8)-5-2((2)-3-"azetidin-1-yl)propyl|-A-fluorobenzenesulfonylamino)-1Ta, 2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2(2)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino!|-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H8)-5-(2-(M-(4-dimethylaminobutyl)-M-methylamino|benzenesulfonylamino)-1,1a,2,76B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2-|(5)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl|-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; (Tanz,765H8)-5-(2-(1-ethylazetidin-3-yl)-A-fluorobenzenesulfonylamino!|-1,Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2-I|(A)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl|-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; (Tanz,75Н)-5-(2-(2-(pyrrolidin-1-yl)ethyl|-4-fluorobenzenesulfonylamino)-1,Ta,2,76- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705НА )-5-(2-(B)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,76B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (tTav,7605)-5-(2-(B8)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Table 5,768)-5-(2-(B)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H8)-5-(2-I((5)-1-ethylpyrrolidine-2-ylcarbonylaminomethyl|-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c)ychromene-4-carboxylic acid; (Tanz, 705H)-5-(2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino!|-1,Ta,2,70B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2 -((5)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H)-5-(2-(3-dimethylaminopropylcarbamoyl)benzenesulfonylamino!|-1Ta,2,7B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz5,765H)-5-(2-11М-( (5)-1-ethylpyrrolidin-3-yl)-N-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; (Tan5,765H8)-5-(2-TM-(A)-1-ethylpyrrolidin-3-yl)-M-methylcarbamoyl|methyl)-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|c| Ichromene-4-carboxylic acid; (Tan5,7065H)-5-(2-(2-((5)-1-ethylpyrrolidin-2-yl)ethylamino|benzenesulfonylamino)-1,1a,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid; ( Tan5,765H)-5-(2-(2-((8)-1-ethylpyrrolidin-2-yl)ethylamino|benzenesulfonylamino)-1,1a,2,70- tetrahydrocyclopropa(|cichromene-4-carboxylic acid; (Tanz,705НА)-5-(2-(3-М,М,-diethylaminopropylamino)benzenesulfonylamino|-1,Ta,2,7p- tetrahydrocyclopropa|cichromene-4-carboxylic acid ; 4-carboxylic acid; (Ianz5,765H8)-5-2-((1-ethylazetidin-3-ylmethyl)amino|benzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tan,705)-5-(2-(2)-3-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1,Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ia5,706H8)-5-(2-(27)-3-diethylaminoprop-1-enyl)benzenesulfonylamino!|-1 Ta,2,7p- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Ian5,765H)-5-(2-1M-((A)-1-ethylpyrrolidin-2-yl)ucarbonyl|-M-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|c |Yichromene-4-carboxylic acid; (Ian5,765H)-5-(2-1M4-((5)-1-ethylpyrrolidin-2-yl)ucarbonyl|-M-methylaminomethyl)-4-fluorobenzenesulfonylamino)-1,1a,2,7p-tetrahydrocyclopropa|c |Yichromene-4-carboxylic acid; (Iano5,765H)-5-(2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tan5,765H8)-5-2- I(A)-1-ethylpyrrolidin-3-ylmethyl)amino|benzenesulfonylamino)-1,1a,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tano5,765H8)-5-(2-((5)-1-ethylpyrrolidin-3-ylmethyl)amino|benzenesulfonylamino)-1Ta,2,7p- 60 tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,Ta,2,76B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz ,705H)-5-(2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino|-1Ta,2,76B-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H8)-5-(2 -(2-(1-ethylazetidin-3-yl/ethyl|-4-fluorobenzenesulfonylamino)-1Ta,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2-|( 5)-1-azabicyclo(2.2.2)oct-3-yl)amino|benzenesulfonylamino)-1Ta,2,76-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2-I |(A)-1-azabicyclo|2.2.2|oct-3-yl)lamino|benzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,705H)-5-(2 -C1(5)-1-ethylpyrrolidine-3-carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid; (Tanz,75H)-5-(2-(2-(B)-1-ethylpyrrolidin-3-ylamino)dethyl|-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c|Ichromene-4-carboxylic acid ; (Tan5,765H8)-5-(2-|(A)-1-ethylpyrrolidin-3-ilyamino|1benzenesulfonylamino)-1Ta,2,76p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tan5,765H)-5-(2-((5)-1-ethylpyrrolidin-3-yl)amino|1benzenesulfonylamino)-1,1a,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tanz,7065H8)-5-(2-C(B)-1-ethylpyrrolidine-3-carbonyl)amino|methyl)-4-fluorobenzenesulfonylamino)-11a,2,7b-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid ; (Tanz,705H8)-5-(2-(2)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino |- 11a,2,7b-tetrahydrocyclopropa|c|Ichromene-4-carboxylic acid; (Tan5,765H)-5-(2-(2-((8)-1-ethylpyrrolidin-3-yl)ethylamino|benzenesulfonylamino)-1,1a,2,70-tetrahydrocyclopropa|sichromene-4-carboxylic acid; ( Ianz5,765H8)-5-(2-(2-((5)-1-ethylpyrrolidin-3-yl)/'ethylamino|benzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; ( Tav,7605)-5-(2-(5)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1 Ta,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tav,7605) -5-(2-(B8)-1-ethylpyrrolidine-3-yloxymethyl)-4-fluorobenzenesulfonylamino!|-1,T1a,2,7p-tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tav,765)-5- (2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino!|-1,1a,2,76B- tetrahydrocyclopropa|sichromene-4-carboxylic acid; (Tav,7605)-5-2-(2-( B8)-1-ethylpyrrolidin-2-yl/ethyl|-4-fluorobenzenesulfonylamino)-1Ta,2,7p-tetrahydrocyclopropa|c|ichromene-4-carboxylic acid and their pharmaceutically acceptable salts, stereoisomers. 14. A pharmaceutically acceptable composition containing a compound according to any one of claims 1-13 and a pharmaceutically acceptable excipient. 15. A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of the compound according to any one of claims 1-13. 16. A method of inducing weight loss in a patient in need thereof, comprising administering to said patient an effective amount of the compound of any one of claims 1-13. 17. The method according to claim 15 or 16, which differs in that the patient is a person. 18. The method according to claim 15 or 16, which differs in that the patient is a cat or a dog. 19. The method according to any one of claims 15-17, which is characterized in that the patient has a body mass index which, before said administration, is greater than or equal to about 30 kg/m. 20. The method according to any one of claims 15-19, characterized in that the compound is administered orally. 21. The composition according to claim 14, which differs in that the specified composition is made in the form of a single dose. 22. The composition according to claim 14, which is characterized by the fact that the specified composition is formulated for oral administration. 23. The composition according to claim 14, which differs in that the specified composition is formulated for intravenous or subcutaneous administration. 24. The method according to claim 15 or 16, which includes the introduction of the specified compound in an amount sufficient to create inhibition of intracellular MeiAR2g, effective to increase the production of thioredoxin in the patient and to initiate multi-organ stimulation of anti-obesity processes in the subject. 25. The method according to claim 24, which includes the introduction of the indicated compound in an amount insufficient to reduce angiogenesis in the patient.