UA79632C2 - Indols having antidiabetic activity - Google Patents

Abstract

Indoles having aryloxyalkanoic acid substituents or arylalkanoic acid substituents are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type II diabetes.

Description

Description of the invention

The present invention relates to aryloxyalkanoic acid-substituted indoles and 2 pharmaceutically acceptable salts and prodrugs of said compounds useful as therapeutic compounds, particularly for the treatment of type 2 diabetes and conditions often associated with said disease, including obesity and lipid disorders.

Diabetes is a disease resulting from numerous etiological factors and is characterized by elevated levels of glucose in the plasma (hyperglycemia), detected by an oral glucose tolerance test of up to 70 fasting or after glucose administration. There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDM), the patient's body produces little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes, or non-insulin-dependent diabetes mellitus (MIOM), insulin is still produced in the body. Patients with type 2 diabetes often suffer from hyperinsulinemia (have elevated levels of insulin in the plasma); however, such patients are 12 insulin-resistant, which means that these patients are resistant to the action of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which include muscle, liver and adipose tissue. Patients who are insulin resistant but not diabetic compensate for insulin resistance by secreting more insulin such that serum glucose levels are not elevated enough to meet criteria for type 2 diabetes. Patients with type 2 diabetes even have elevated levels. of insulin in the plasma are insufficient to overcome clearly expressed resistance to insulin.

Persistent or uncontrolled hyperglycemia, observed in diabetes, leads to increased morbidity and premature mortality. Abnormal glucose homeostasis is often closely related, both directly and indirectly, to obesity, hypertension, and changes in lipid, lipoprotein, and apolipoprotein metabolism, as well as other metabolic and hemodynamic diseases. Patients with type 2 diabetes are at a significantly higher risk of macrovascular and microvascular complications, such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension is extremely important for clinical practice and treatment of diabetes.

Many patients with insulin resistance or type 2 diabetes are often characterized by a number of symptoms that are collectively known as syndrome X, or metabolic syndrome. A patient with such a syndrome is characterized by the presence of three or more symptoms selected from the group consisting of the following five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low level of high-density lipoprotein (HDL) cholesterol; (4) high blood pressure and (5) elevated fasting glucose, which may be within the characteristics of type 2 diabetes if the patient is also diabetic. Each of the indicated 39 symptoms is defined in the recently released

Rapei op Oeiesiop, Emaiitsayop apa Tgeaitepi oi Nidy Viood SPoieviegoY ip Adiyv (AdiyS Tteaitepi Rapei! I, oh ATR I), Mayopa! Ipvziyshevz oi Neak, 2001, MIN Rybiysayop Mo. 01-3670)Y. Patients with metabolic syndrome, regardless of whether these patients already have or are developing overt diabetes mellitus, are at increased risk of developing the macrovascular and microvascular complications listed above that occur in type 2 diabetes, such as atherosclerosis and coronary heart disease. hearts c Insulin resistance is not primarily caused by a reduced number of insulin receptors, but

With" post-insulin violation of receptor binding, which has not yet been fully studied. Such a loss of response to insulin leads to insufficient insulin-mediated activation of glucose uptake, oxidation, and accumulation in muscle tissue and inadequate insulin-mediated suppression of lipolysis in adipose tissue and glucose production and secretion in the liver. and There are several accepted treatments for type 2 diabetes, each with limitations and (se) potential risks. Physical activity and reducing the calories consumed with food often dramatically improve the condition of a diabetic patient and are, at the first stage, the best treatment for type 2 diabetes.

Me is very burdensome as a result of the well-rooted habit of a sedentary lifestyle and excessive consumption of food, so 20 especially, food containing a large amount of fat. Common medical treatments include meglitinide or a sulfonylurea (such as tolbutamide or glipizide), which are agents that increase insulin secretion. Such drugs increase the level of insulin in the plasma by stimulating pancreatic B-cells to secrete more insulin. When the administration of sulfonylurea or meglitinide becomes ineffective, the amount of insulin in the body can be replenished by injection of 29 insulin, so that insulin concentrations become high enough to provide stimulation even strongly

GF) of insulin-resistant tissues. However, administration of insulin and/or secretagogues can lead to dangerously low plasma glucose levels, and increased levels of insulin resistance can result from even higher plasma insulin levels.

Biguanides are another class of drugs widely used in the treatment of type 2 diabetes 60. The two best known biguanides, phenformin and metformin, produce some correction of hyperglycemia without the risk of hypoglycemia. Biguanides can be used with either insulin or a secretagogue without increasing the risk of hypoglycemia. However, phenformin and metformin can cause lactic acidosis and nausea/diarrhea. Metformin is associated with a lower risk of side effects than phenformin and is widely indicated for the treatment of type 2 diabetes because Glitazones (ie, 5-benzylthiazolidine-2,4-diones) are a new class of compounds that may provide improvement in hyperglycemia and other symptoms of type 2 diabetes. Such agents significantly increase insulin sensitivity in muscle, liver, and adipose tissue in some animal models of type 2 diabetes, leading to partial or complete correction of elevated plasma glucose levels without hypoglycemia. Glitazones that are currently available for sale (rosiglitazone and opioglitazone) are agonists of the gamma subtype of the activated peroxisome-proliferating agent receptor (regochizote rgoiiGegaiog asiimagei heseriog (PRAK)). It is generally accepted that agonism in relation to gamma-PPRA is the cause of increased sensitivity to insulin, which is observed in the case of glitazones. New PRAC agonists are being developed for the treatment of type 2 diabetes and/or dyslipidemia. Many of the newly discovered PRAC compounds are agonists for one or more of the 70 PRAC subtypes: alpha, gamma, and delta. Compounds that are agonists of both subtypes, alpha-PPRAC and gamma-PPRAC, (dual alpha/gamma-PPRAC agonists) are very promising because they reduce hyperglycemia and also improve lipid metabolism.

PRAC agonists and, in particular, glitazones, have drawbacks that reduce their attractiveness at this time. Some of the compounds, and especially troglitazone, show hepatotoxicity. Eventually, troglitazone was withdrawn from the market due to hepatotoxicity. Another disadvantage of PPRA agonists that are currently on sale is that monotherapy of type 2 diabetes provides little effectiveness - a decrease in average plasma glucose by "2095" and a deviation in the range from "9.095 to "8.095 in hemoglobin AIS. The compounds in question also slightly improve lipid metabolism and may, in fact, have a negative effect on the lipid profile.

These shortcomings are the reason for the development of improved insulin sensitizers for type 2 diabetes, acting on a similar mechanism(s).

Recently, there have been reports of compounds that are antagonists or partial agonists of gamma-PRAC. IV UMO 01/30343) describes a specific compound, which is a partial agonist/antagonist of PRAK, which is useful for the treatment of obesity and type 2 diabetes. |In MUO 02/08188| described a class of agonists and partial agonists of PRAC that are derivatives of indole and useful in the treatment of type 2 diabetes with reduced side effects with respect to weight gain and heart.

The class of compounds described in this description is a new class of PPAK agonists that do not contain 1,3-thiazolidinedione i) fragment. The class of compounds includes a plurality of compounds that are partial agonists of y-PPAK, but may also include full agonists of y-PPAK and/or antagonists of y-PPAK. Some compounds may also have activity against A-PPRA in addition to activity against y-PPRA. A number of compounds can be mixed full or partial agonists of A//-PPRAK. Such compounds are useful in the treatment and prevention of diabetes, hyperglycemia, and insulin resistance.

The compounds may also be useful in the treatment of one or more lipid disorders, including disorders such as mixed or diabetic dyslipidemia, isolated hypercholesterolemia, which may be manifested by elevated HO-C and/or absence of NOI-C, hyperapocholesterolemia, hypertriglyceridemia , elevated triglyceride-rich lipoproteins, and low concentrations of NOI cholesterol. These compounds may also be useful in the treatment or amelioration of conditions that include atherosclerosis, obesity, vascular restenosis, inflammatory conditions, psoriasis, polycystic ovary syndrome, and other PRAC-mediated diseases, disorders and conditions."

This invention relates to compounds of formula I: - ! z y f t i - 45 in! so I (2) and their pharmaceutically acceptable salts and prodrugs. about 20 V compounds of the formula |,

B" is selected from r" (a) -X-aryl-y-7 and (c) -X-heteroaryl-y-2, where aryl and heteroaryl are unsubstituted or substituted 1-3 groups independently selected from A; 59 aryl means phenyl or naphthyl;

F! heteroaryl means a monocyclic or condensed bicyclic aromatic ring structure containing 1-4 heteroatoms independently selected from M, O and (OO); (it should be noted that 5(O) and 5(0)" are included in the ring o structure. Through atom 5 and heteroaryl can mean a benzene ring condensed with an aromatic heterocycle, as it exists in indole); 6o X means a bond or a divalent group selected from CH», CH(ISNU»), C(CH»3)» and C3-Socycloalkylidene;

U means a divalent group selected from -"CH-CH-, -"CH(IONYUISN(OH)-, -ОСВ "в8-, -ЗСВ "В. ии -СНоСеЗе.; 7 is selected from the group including -СО2Н and tetrazole;

A is selected from the group that includes C.alkyl, C.-alkenyl, -OC.,alkyl and halogen, where alkyl, alkenyl and -Oalkyl are each optionally substituted with 1-5 halogens; bo 27, 9, in i 8, each independently selected from the group including H, halogen, Si-Svalkyl, -OS.-Svalkyl,

C.-Salkenyl, -OCo-Svalkenyl, C3.6vcycloalkyl, phenyl and -COOH, where C--Svalkyl, -OS.-Svalkyl, Co-Svalkenyl, -O.S.-Svalkenyl, C.S.cycloalkyl and phenyl are optionally substituted by 1- 5 halogens, and C 2 -bcycloalkyl and phenyl are additionally optionally substituted by 1-3 groups, independently selected from C 1 -C alkyl and -C 4 -C alkyl, while C 4 -C alkyl and -C 6 alkyl are not specified necessarily substituted by 1-3 halogens; or alternatively, K'/ and BEZ together can form a C3-Seccycloalkyl group, while the indicated

C.-Socycloalkyl group is optionally substituted with 1-3 halogens; or alternatively, when B! means -X-phenyl-y-7, Y means -OCE B and B" are selected from the group consisting of H, halogen, C-Salkyl, -OC.i-Salkyl, Sovalkenyl, -OSorvalkenyl, Ss-cycloalkyl and phenyl, then KZ may, optionally, mean a 1-2-carbon bridge connected to a phenyl ring in an ortho position relative to U, thereby forming a 5- or b-membered heterocyclic ring condensed with a phenyl ring;

IN? means S.-Slalkyl, which is optionally substituted with 1-5 halogens;

BZ is selected from the following substituent groups: (a) benzisoxazolyl, (b) benzisothiazolyl, (c) benzpyrazolyl, (94) aryl, (e) -(-O)aryl. (9-C(O)heteroaryl, (9)-Oaryl, (n)-Heteroaryl, ()-5(O)raryl and ()-5(O)pheteroaryl, where KZ is optionally substituted with 1-3 substituents by groups independently selected from halogen, C4alkyl, -OC, dalalkyl and -5Calkyl, where C..alkyl, -OC.alkyl and -BS..alkyl are optionally substituted by 1-5 halogens; i) each B" , optionally, is selected from the group consisting of H, halogen, C and -Salkyl and -OOC.-Salkyl, where

S.-Salkyl and -OS.-Svalkyl are optionally substituted with 1-5 halogens; n is equal to the whole number 0-2 and c p is equal to the whole number 1-3. co

In the above definitions and further definitions, alkyl groups can be both linear and branched, unless otherwise specified. (Se)

These compounds are effective in reducing the levels of glucose, lipids and insulin in diabetic patients and non-diabetic Fo patients with impaired glucose tolerance and/or who are in a prediabetic state. The compounds are expected to be effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) in humans and mammals, particularly in the treatment of hyperglycemia and conditions associated with NIDDM, including hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, inflammatory conditions and other PRAK-mediated diseases, disorders and conditions. "

The present invention has multiple embodiments. The invention relates to compounds of formula I, including pharmaceutically acceptable salts and prodrugs of the specified compounds, and pharmaceutical compositions containing the specified compounds and a pharmaceutically acceptable carrier. "» In preferred embodiments, B C is selected from the group consisting of 3-benzisoxazolyl, -O-phenyl and "-C(xO)phenyl, where KZ is optionally substituted with 1-3 substituents independently selected from halogen, -OC 1-Szalkyl and S.-Szalkyl, where indicated -OS.-Szalkyl and Si-Szalkyl are optionally mixed with 1-5 halogens. 15 In preferred embodiments of the invention, KO! means -X-phenyl-U-7, where phenyl is unsubstituted or - ; r r d du, dD sh substituted by 1-3 groups independently selected from A. (Ce) The subgroup of compounds of formula I includes compounds in which X represents a bond. b A subgroup of compounds of the formula | includes compounds in which X stands for CH".

In the preferred subgroup of compounds, ХУ means -OSB"B8-; K" is selected from the group including H and C.-Salkyl, and KZ and means C.-Salkyl, where B 28 is optionally substituted with 1-3 halogens.

Kz In another preferred subgroup of compounds, X is -OSB"B8-; B" is selected from the group consisting of H and C-4-C alkyl, and KZ means C-C-C alkyl.

In yet another useful group of compounds, U stands for -"CH-SNE U, where KZ is selected from the group consisting of C. alkyl. and -OS. alkyl, which are optionally substituted with 1-3 halogens.

Gee! In yet another group of compounds, U means -tolerable., where K5 means -OS. alkyl, which is optionally substituted with 1-3 halogens. In preferred embodiments, A is selected from the group consisting of C, C, C, C, C, C, C, C, and halogen. 6o The preferred subgroup of compounds includes compounds in which K? means Si zalkil or SEz.

In many preferred compounds, BZ is -C(-O)phenyl, where KZ is optionally substituted with 1-3 substituents independently selected from the group consisting of -OSN", -OSE", and halogen.

In other useful compounds, CZ means 3-benzisoxazolyl or aryl, which is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, OCH3, OSE", CH3 and CE3. b5 In another subset of compounds, BZ is 3-benzisoxazolyl, aryl, -Ophenyl, or -5-phenyl, wherein BZ is optionally substituted with 1 substituent selected from halogen, OCN", OCE", and CEz.

In another subgroup of compounds, B" means -X-pyridinyl-x7.

A subgroup of compounds includes compounds in which P is 1.

Preferred compounds usually have group 7, which is -СО5Н.

In the preferred groups of compounds, B" usually means - Y-th no ech in 2 where X is selected from the group that includes the bond, CH", CH(CHu"), C(CHaz)" and C3-Socycloalkylidene;

X is selected from the group that includes -ОСЕ 28 - and SNSERV Е; 7 is chosen from -СО-Н and tetrazole;

And choose from S.-Szalkil, SEz, -OSN»z, -"OSE" and halogen; 2, 9 and B", each independently selected from the group consisting of H, halogen, C.4-Salkyl and -OC.-Salkyl, and Gese is selected from the group consisting of halogen, C.-Salkyl and -OC.- Szalkyl, where C-Szalkyl and -OS.-Szalkyl in ER, 9, B and 28, each optionally substituted with 1-3 halogens, 4 equal to the whole number 0-3, p equals 1;

IN? choose from SE»z and С41-Szalkilu;

BZ is selected from the group consisting of (a) 3-benzisoxazolyl, (b) 3-benzisothiazolyl, (c) 3-benzpyrazolyl, and) (94) aryl, (e) -F(O)phenyl, (9 -C (O)heteroaryl, c(9)-Ophenyl, (n)-Heteroaryl, o()-8(O)pphenyl and "o(O)-5(O)heteroaryl. where the heteroaryl is selected from the group consisting of pyridyl and quinolyl, me) n is equal to the whole number 0-2 and i-

BZ is optionally substituted by 1-3 groups independently selected from halogen, -OS 1-Szalkyl and C.salkyl, where the indicated -OS.-Ssalkyl and C.salkyl are optionally substituted with 1-5 halogens.

A preferred subset of the compounds described immediately above have the following substituents:

X means connection or CH";

M means -ОСЕ /В8- or -"СНСЕВ-; - c 2 means -SOZN; хз" песню with СН", СЕз, -ОСН», -"ОСЕ" and halogen; means H; 25 is selected from the group consisting of H, C.-Szalkyl and -OS.-Szalkyl, where C-Szalkyl and -OS.-Szalkyl are optionally substituted with 1-3 halogens; and B" are selected from the group consisting of H and S.-Salkyl; (Ce) EZ means S.-Salkyl; b" B? means SNU;

VZ is chosen from the group that includes

OO. . (a) Z-benzisoxazolyl,

From (B) aryl, (c) -(O)phenyl, (a) -K(O)pyridyl and (e) -(-O)quinolyl, where KZ is optionally substituted with 1-3 groups independently selected from halogen , -OS 4-Szalkyl and C. zalkyl, where the specified -OS.-Szalkyl and Si zalkyl are optionally substituted with 1-5 halogens; and code d is equal to the whole number 0-3.

In the preferred groups of the above-mentioned compounds, U means -OSB/B8-, B" means H and EZ means C. alkyl, which is optionally substituted with 1-3 halogens.

In other preferred groups of the above-mentioned compounds, U stands for -"СНСВЕРВ9-, ВК? means H and K9 means

S. dalalkyl or -OS.-Szalkyl, where S.-zalkyl and -OS.-Szalkyl are optionally substituted with 1-3 halogens.

In preferred compounds, the substituents X and -Y7 on the aforementioned phenyl groups are in the meta or para positions relative to each other, and in more preferred compounds, X apa -yX7 are relative to each other in the meta position, as shown below in formula IA.

The compounds of formula IA below and their pharmaceutically acceptable salts have particularly useful properties in the treatment of insulin resistance, type 2 diabetes and dyslipidemia associated with type 2 diabetes and insulin resistance:

IA to 70 M

Xh -E

IA

In compounds of formula IA, X means a bond or CH";

U means -ОС"В"В8- or -СНоС"ВоК-; 2 means -СОЗН;

And choose from CH», SEz, -OSN», -OSE» and halogen; a is equal to 0 or 1;

В" means Су залкіл, СЕз, -ОСНа or -ОСЕ"; с р equals 0 or 1; o

IN? choose from H and S.-Szalkyl, where C--Szalkyl is optionally substituted with 1-3 halogens; 25 means S.-Szalkyl or -OS.-Szalkyl, where S.i-Szalkyl or -Si-Szalkyl are optionally substituted by 1-3 halogens;

B" is selected from the group including H and C.-Szalkyl, which is optionally substituted with 1-3 halogens; c

EZ means S.-Szalkyl, which is optionally substituted with 1-3 halogens; Geo)

IN? means SNzhi so

BZ is selected from the group consisting of (a) 3-benzisoxazolyl, me) (c) -O-phenyl and y-(c) -(O)phenyl, where BZ is optionally substituted with 1-3 groups independently selected from halogen .

In the subgroup of compounds just given, p is equal to 1.

The carbon atom marked in the above structures with an asterisk (C) is for cases where M means - с - "ОСН(К8). or -"СНоС"Н(ВУ)-, is an asymmetric atom. Of course, both B and C stoichiometric and configurations relative to carbon C" are active, although the specified configurations have different activities, partly because "" refers to the quantitative activity relative to A -PRAK and u-PRAK.

Preferred groups of compounds of formula IA, in which X represents a bond, have the following substituents:

У means -ОС"В'ВВ.-; and В means СНа, СЕз, -ОСНа or -ОСЕ"; (se) p is equal to 0 or 1;

F B" means No

VZ means S.-Szalkyl, which is optionally substituted with 1-3 halogens. o Such compounds have an asymmetric center on the carbon of group M. Compounds having K and 5 stoichiometric

With the configuration at C", they are active PRAC agonists, although such compounds have slightly different activity in terms of the quantitative ratio of activity relative to A-PPRAC and y-PPRAC.

In another preferred subgroup of compounds of formula IA, X means CH";

У means -ОС"В'/КВ.-; о в" means СН, СЕз, -ОСНз or -ОСЕ»; p is equal to 0 or 1; name) B" means No

VZ means S.-Szalkyl, which is optionally substituted with 1-3 halogens. because such compounds also have an asymmetric center on the carbon of the U group. Compounds having K and Z stoichiometric configuration at C" are active PPAK agonists, although such compounds have slightly different activity in terms of the quantitative ratio of activity in relation to A-PPAK and y- RRAK.

In other preferred subgroups of compounds of the formula IA, where X is either CH", or the bond B C is -C(5O)phenyl, which is optionally substituted by 1-2 groups independently selected from the group consisting of CI, CH with , b cSEz,-OSNa and-OSE".

In the above subgroup of compounds, p is equal to 1.

The structures of characteristic compounds are described in Tables 1-4. The names of the compounds are given in separate tables 1A-4A.

Each of the compounds has the same number in both types of tables. Methods of synthesis of some of the specified compounds are also given in the examples.

The compounds of the present invention can be used in pharmaceutical compositions containing the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compounds according to the present invention can also be used in pharmaceutical compositions in which a compound of formula I or a pharmaceutically acceptable salt thereof is the only active ingredient. 70 Compounds according to the present invention and pharmaceutically acceptable salts of these compounds can be used in the manufacture of a medicinal product for the treatment of type 2 diabetes in humans or other mammals.

The compounds find particular utility in a method of treating or alleviating hyperglycemia in a human or other mammal suffering from type 2 diabetes and in need of such treatment by administering to the patient a therapeutically effective amount of the compound.

Specific variants of characteristic compounds according to the present invention are presented in the examples and attached tables.

Some of the compounds according to the present invention are described in a prior application filed after the filing dates of the two prior US applications from which priority is claimed in the present application, in order to illustrate the use of such compounds according to the present invention disclosed in the latter application. The seven compounds are listed below with an indication of where these compounds are described: 1. Tables 1 and 1A, compound 1 2. Tables 1 and 1A, compound 10 3. Tables 2 and 2A, compound 8; and also example 31 4. Tables 2 and 2A, compound 25 s 5. Tables C and ZA, compound 29 6. Tables C and ZA, compound 60; and also example 29 (8) 7. Tables C and ZA, compound 78

It is understood that this invention includes the general claims of the invention in the given form and, moreover, includes each of the general claims of the invention with the exception of one or more of the seven c of the compounds listed above. Such exclusion may be made during the examination. The above compounds are also claimed herein. and,

The compounds defined in this description can be used in the treatment of the following diseases, as well as other diseases not listed below, by administration in a therapeutically effective amount to a patient in need of such treatment: Me (1) type 2 diabetes, and, in particular, hyperglycemia, (2) metabolic syndrome, (3) obesity and hypercholesterolemia;

Definition "Ac" means acetyl, which is CH3C(O)-. "Alkyl" means saturated hydrocarbon chains, which can be linear or branched, or contain a combination of the specified chains, if the concept of a carbon chain is not specifically defined. Other groups with the prefix "alk" in their name, such as alkoxy and alkanoyl, can also be linear or ;" branched, or represent a combination of the specified chains, if the concept of a carbon chain is not specifically defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. -And "Alkenyl" means carbon chains containing at least one carbon-carbon double bond, which may be linear or branched, or a combination of these chains. Examples of se) alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, b 2-methyl-2-butenyl, and the like. "Alkynyl" means carbon chains containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination of these chains. Examples

He alkynyl includes ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. "Cycloalkyl" means mono- or bicyclic saturated carbocyclic rings each having from 3 to 10 carbon atoms, unless otherwise specified. The term also includes a monocyclic ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. (F, Cycloalkylidene group means a divalent cycloalkane radical in which both valences ka refer to the same carbon atom. For example, the cyclopropyl group of 1,1-dimethylcyclopropane is a cyclopropylidene group. in "Aryl" (and "arylene") when used to denote a substituent or group in the structure, means a monocyclic, bicyclic, or tricyclic compound in which all the rings are aromatic and which contains only ring carbon atoms. The term ``aryl'' may also mean an aryl group fused to a cycloalkyl or heterocycle." Heterocyclyl", "heterocycle" and "heterocyclic" mean a fully or partially saturated monocyclic, bicyclic or tricyclic ring system containing at least one heteroatom selected from M, C and O, each of said rings containing from C to 10 atoms . Examples of aryl substituents include phenyl and naphthyl. Aryl rings fused with cycloalkyls form the basis of indanyl, indenyl, and tetrahydronaphthyl. Examples of a ryl fused with heterocyclic groups include 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like. Examples of heterocycles include tetrahydrofuran, piperazine, and morpholine. Preferred aryl groups are phenyl or naphthyl. Phenyl is usually the most preferred.

"Teteroaryl" (and heteroarylene) means a mono-, bi-, or tricyclic aromatic ring containing at least one ring heteroatom selected from M, O, and 5 (including 5O and 5O5), where each ring contains 5-6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, 70 pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazole, benzothiophenyl (including 5-oxide and dioxide), furo(2,3-c)pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like. "Halogen" includes fluorine, chlorine, bromine and iodine. "Me" means methyl.

It is understood that the term "composition" in the concept of a pharmaceutical composition includes a product containing the active ingredient(s) and inert ingredient(s) that make up the carrier, as well as any product formed, directly or indirectly, by by combination, complexation or aggregation of two or more ingredients, or by dissociation of one or more ingredients, or by other types of interactions or effects on one or more ingredients. Therefore, pharmaceutical compositions according to this invention include any composition obtained by displacing a compound according to this invention and a pharmaceutically acceptable carrier.

The substituent "tetrazole" means the substituent group 2H-tetrazol-5-yl or the corresponding tautomer.

Optical isomers - diastereomers - geometric isomers - tautomers

Compounds of formula I may contain one or more asymmetric centers and may thus exist in the form of racemates, racemic mixtures, individual enantiomers, diastereomeric mixtures, and individual diastereomers. It is understood that the present invention covers all such isomeric forms of the compounds of formula I. i)

Some of the compounds described herein may contain olefinic double bonds, and unless otherwise specified, both E- and 7-geometric isomers are intended to be included.

Some of the compounds described herein can exist with different hydrogen bonding sites, which are called tautomers. An example is a ketone and its enol form, known as keto-enol tautomers.

Individual tautomers, as well as their mixtures, are included in the number of compounds of formula I. o

Compounds of formula I having one or more asymmetric centers can be resolved into diastereomers, enantiomers, and the like by methods well known in the art.

Alternatively, enantiomers and other compounds with chiral centers can be synthesized by stereospecific syntheses using optically pure starting substances and/or reagents of known configuration.

Salt

The term "pharmaceutically acceptable salts" means salts obtained with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts obtained with inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric iron, divalent iron, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form;" can exist in more than one crystal structure and can also be in the form of hydrates. Salts prepared with pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ionogenic -I ion exchange resins such as arginine, betaine, caffeine, choline, M,M '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, M-ethylmorpholine, M-ethylpiperidine, se) glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine,

He» piperidine, polyamine resins, procaine, nurine, theobromine, triethylamine, trimethylamine, tripropylamine, 5p tromethamine and the like. o When the compound according to the present invention is basic, the salts can be obtained from pharmaceutically

Ge acceptable non-toxic acids, including organic and inorganic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrogen bromide, hydrogen chloride, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucilage, nitric, pumice, pantothenic, phosphoric, succinic , sulfuric, tartaric, p-toluenesulfonic acid and the like. Lemon, hydrogen bromide, hydrogen chloride,

F) maleic, phosphoric, sulfuric and tartaric acids. It is obvious that, as used herein, references to compounds of formula | also mean the inclusion of pharmaceutically acceptable salts. in Metabolites - prodrugs

Therapeutically active metabolites of other compounds, in the case when the metabolites themselves are included in the scope of the claimed invention, are also compounds according to the present invention. Prodrugs, which are compounds that are converted to the claimed compounds upon or after administration to a patient, are also compounds of the present invention. A non-limiting example of carboxylic acid prodrugs according to the present invention can be an ester formed by a carboxylic acid group, for example, a C.--Cv-ester, which can be linear or branched and is converted during metabolism into a carboxylic acid according to the present invention . An ester containing a functional group that facilitates hydrolysis of said ester after administration to a patient may also be a prodrug.

Utility

The compounds according to the present invention are effective ligands possessing agonistic, partial agonistic or antagonistic activity against one or more different subtypes of receptors activated by the peroxisome-proliferating agent, in particular, γ-PPRA. The compounds may also be agonists, partial agonists or antagonists for the A-PPRAC subtype as well as the y-PPRAC subtype, resulting in mixed A//-PPRAC agonism or, preferably, A-PPRAC subtype. Some compounds (of course, less preferred) 70 may also be 5-PPAK ligands and possess activity towards 59-PPAK in addition to the other

RRABK-activities. The compounds of the present invention are useful in the treatment or prevention of diseases, disorders or conditions mediated by one or more ligands of particular subtypes of PRAC (eg, G or

A), or combinations of subtypes of PRAC (for example, A/G). One aspect of the present invention relates to a method of treating or controlling diseases, such as type 2 diabetes, by administering a 75 agonist or partial agonist of PRAC.

Administration and dose intervals

Any suitable method may be used to administer to a mammal, particularly a human, an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compounds of formula I are administered orally.

The effective dose of the active ingredient used may vary depending on the particular compound used, the route of administration, the condition being treated, and the severity of the condition being treated. Such a dose can easily be determined by a person skilled in the art. Ge

In the treatment or control of diabetes and/or hyperglycemia or hypertriglyceridemia, or other (5) diseases for which the compounds of formula I are indicated, satisfactory results are usually obtained when the compounds of the present invention are administered at a daily dose of from about 0.1 milligrams to 100 milligrams per kilogram of the animal's body weight, which is preferably administered in the form of a single daily dose, or in the form of divided doses two to six times a day, or in the form of delayed release. For the largest mammals, the total daily dose is from about 1.0 milligrams to 1000 milligrams, preferably from 1 milligram to 50 milligrams. In the case of an adult weighing 7Okg, the total daily dose usually ranges from approximately 1 milligram to 350 milligrams. In the case of a particularly effective compound, the dose for an adult can be as low as possible, (se) equal to 00 mg. The medication regimen can be selected taking into account the specified interval or Ф even beyond the specified interval to achieve an optimal therapeutic response.

Oral administration is usually carried out using tablets. Examples of dosages in tablets are 0.5mg, mg, 2mg, bmg, 1Omg, 25mg, 5Omg, 1O0Omg and 250mg. A similar dosage may also be used in other oral formulations (eg, capsules).

Pharmaceutical compositions "

Another aspect of this invention consists of pharmaceutical compositions containing compounds of the formula | and a pharmaceutically acceptable carrier. Pharmaceutical compositions according to the present invention contain compounds of the formula - c Y or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients. The term "pharmaceutically acceptable salts" means salts obtained with "pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids."

Compositions include formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), nullmonal (nasal or buccal inhalation) or nasal administration, but the most appropriate route in in this case depends on the nature and severity of the conditions being treated and the nature of the active ingredient. The specified (22) compositions can usually be presented in a single dosage form and obtained by any of the well-known 50 methods in the field of pharmacy.

For practical application of the compound of the formula | can be combined, as an active ingredient, with what) a pharmaceutical carrier according to generally accepted methods of manufacturing pharmaceutical products. The carrier can take many different forms depending on the form of the drug required for administration, for example, oral or parenteral (including intravenous). When preparing the compositions for the dosage form intended for oral administration, any generally accepted pharmaceutical medium can be used, such as, for example, water, glycols, oils, alcohols, corrigents, preservatives, dyes, and the like, in the case of liquid preparations for oral administration, such as, for example, suspensions, elixirs (elixirs) and solutions; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like in the case of solid preparations for oral use, for example such as powders, hard and soft capsules and tablets, while solid preparations for oral administration are more preferable than liquid preparations.

Due to the convenience of their use, tablets and capsules represent the most advantageous single dosage form for oral administration, in this case, of course, solid pharmaceutical carriers are used. If necessary, tablets can be coated using standard aqueous and non-aqueous techniques. 65 Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of active compound in such compositions may, of course, vary and may typically range from about 2 percent to 60 percent by weight of the unit form. The amount of the active compound in such therapeutically suitable compositions is such as to provide an effective dosage. The active compounds can also be administered intranasally, for example, in the form of liquid drops or spray.

Tablets, pills, capsules and the like may also contain a binding agent such as gum tragacanth, acacia sap, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, said form may contain, in addition to substances of the above-mentioned type, a liquid carrier such as 7/0 fatty oil.

Various other substances may be present as a coating or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. The syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetener, methyl- and propylarabene as preservatives, a colorant, and a flavoring agent such as cherry or orange flavoring.

Compounds of formula I may also be administered parenterally.

Solutions or suspensions of such active compounds can be obtained in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be obtained in glycerol, liquid polyethylene glycols and their mixtures in oils. Under normal conditions of storage and use, such preparations contain a preservative to prevent the reproduction of microorganisms.

Pharmaceutical forms suitable for use by injection include sterile aqueous solutions or dispersions and sterile powders to obtain sterile solutions for injection or dispersions prepared for immediate administration. In all cases, the form must be sterile and must be sufficiently liquid to ensure ease of injection. The specified form must be stable under the conditions of production and storage and must be protected from the infectious action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures of these substances and)

Eat vegetable oils.

Combined treatment

Compounds of formula I can be used in combination with other drugs that are also useful

For the treatment or amelioration of conditions in the case of diseases or conditions in which the compounds of formula I are useful. Such other drugs may be administered by a method conventionally used for these purposes and in amounts conventional for them, simultaneously with the compound of formula I or sequentially. When compounds of the formula | using He simultaneously with one or more drugs, a preferred pharmaceutical composition in a unit dosage form containing other drugs and compounds of formula I. However, combined treatment includes me) zv Also treatment in which the compounds of formula I! and one or more other drugs are administered by different, overlapping administration schedules. It is also believed that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when each is used separately. Therefore, pharmaceutical compositions according to the present invention include compositions that contain one or more active ingredients in addition to the compound of formula I. with c. Other active ingredients that can be administered with the compounds according to the present invention include other antidiabetic agents, such as sulfonylurea, metformin, insulin or inhibitor of OR-IM, or reducing;" lipid levels a medicine such as a statin (eg simvastatin). Statins that may be co-administered with compounds of the present invention include simvastatin, lovastatin, rosuvastatin, atorvastatin, fluvastatin, itavastatin, rivastatin and 20-4522. -I Biological tests

A) PRAC binding assay se) To obtain recombinant human H-PPRAC, 5-PPRAC, and A-PPRAC: human γ-PPRAC, human 5-PPRAC, and human β-PPRAC were expressed as zi-fusion proteins in E soybeans. The full-length human cDNA for Go-PPRAK is subcloned 5p in the expressing vector pOEX-2T (RNagtasia). Full-length human cDNAs for 5-PPRAC and A-PPRAC are subcloned in

Mami expressing vector ROEH-KT (RIagtasia). E. soybeans containing the appropriate plasmids are propagated, induced and collected by centrifugation. The resuspended sediment after centrifugation is destroyed using

Egepspy press and debris are removed by centrifugation at 12000x9. Recombinant human PRAK receptors are purified by affinity chromatography on glutathione sepharose. After applying to the column and washing once, the receptor is eluted with glutathione. Glycerin (1095) is added to stabilize the receptor and aliquots are stored at -802C. To bind to G-PPRAK, an aliquot of the receptor is incubated in TESM (10 mM Ttiv, pH7 2, 1 mM

IF) EOTA, 1095 glycerol, 7 µl/L0Oml B-mercaptoethanol, 1O0MM molybdate Ma, 7mM dithiothreitol, µg/ml im) aprotinin, 2µg/ml leupeptin, 2µg/ml benzamidine and 0.5MM PM5BRE) containing 0.195 skim milk powder and ionM INAAOBO075, (21Ci/mmol) - the tested compound, (as described in Vegdeg ei a! (Momei! regohizote 60 rgoiGegayug-asiimage(y geseriog (RRAKG) apa RRAK5 Iidapaz rgodise divipsi bBiiodisa! epesiv. 9. VioIi. Spet. (1999), 274: 6718-6725). Samples are incubated for -16 hours at 42C in a final volume of 150 μl. Unbound ligand is removed by incubation with 100 μl of a mixture of dextran/gelatin-coated charcoal, on ice, for 1 hour.

After centrifugation at 300 rpm. within 1 Okhv. at 42 5 Ωcl of the supernatant fraction is used to count pulses in Torsoshpa. For binding to 5-PPRAK, an aliquot sample of the receptor is incubated in TEOM (10 mM Tgtgiv, pH7.2, 1 mM EOTA, 1095 glycerol, 7 µl/LbOml B-mercaptoethanol, 10 mM Molybdate Ma, 1 mM dithiothreitol, 5 µg/ml aprotinin, 2 µg/L ml of leupeptin, 2 μg/ml of benzamidine and 0.5 MM of PMR), containing 0.195 of skimmed milk powder and 2.5 nM (|ZNaOY

Y-783483, (17Ci/mmol) - the tested compound, |As described in Wegdeg ey a). (Mome! regohizote rooiiegayog-asiimaey geseriog (RRAKu) apa RRAK5 Iishdapaz rgodise aiviipsi rioiodisa! ePesiv. 1999 9 Vioi Spet 274; 6718-6725). (I-783483 means 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6b-benzi|4,5|isoxazoloxy)propylthio)phenylacetic acid, example 20|in UMO 97/281371). Samples are incubated for -16 hours at 42C with a final volume of 15 Ωcl. Unbound ligand is removed by incubation with 100 μl of a mixture of dextran/gelatin-coated charcoal, on ice, for 1 hour. After centrifugation at 3000 rpm. within 1 Okhv. at 4 es, 70 BOmcl of the supernatant fraction is used to count pulses in Torsoitspa.

For binding to A-PPRAK, an aliquot sample of the receptor is incubated in TEOM (10 mM Tgtgiv, pH7.2, 1 mM EOTA, 10960 glycerol, 7 μl/LOOml B-mercaptoethanol, 10 mM molybdate Ma, 1 mM dithiothreitol, 5 μg/ml aprotinin, 2 μg/ml leupeptin, 2 μg/ml benzamidine and 0.5 MM PMP), containing 0.195 skimmed milk powder and 5.0 nM (|ZnaoY

I-797773, (Z4Ki/mmol) of the tested compound. (I1-797733 means 19 (3-(4-(3-phenyl-7-propyl-b-benz|4 5|isoxazoloxy)butyloxy)) phenylacetic acid, example 62 | in UMO 97/281371). Samples are incubated for 16 hours at 42C with a final volume of 150 μl. The unbound ligand is removed by incubating with 1000 μl of a mixture of dextran/gelatin-coated charcoal, on ice, for 1 hour. After centrifugation at 3000 rpm. within 1 Okhv. at 4 "C bOmcl of the supernatant fraction is used to count pulses in Torsoshpa.

C) Test for transactivation of PRRAK Sai!-4

The chimeric constructs of receptor expression, rsrmMAZZ-PRRAKU/SAGA, rsrmMAZ-pPRRAKB/OAI 4, reOMAZ-pPRRACALZA, 4 are obtained by introducing the OVO of the yeast SAI4 transcription factor next to the ligand binding domains (80) of РРРАК y, РРРАКb, PRРАКА, respectively. The construction of the reporter, according to the WHO (BH) ChK is, is created by introducing 5 peaks of the SAG4 response element in the "upstream" position relative to the minimal thymidine kinase promoter of the herpes virus and the luciferase reporter gene. pOMM-Ias/ contains (8) galactosidase 2 gene under the regulation of the cytomegalovirus promoter. CO5-1 cells are seeded on 96-well plates for growing cell cultures at a density of 12 x 1OZ cells/well in Dulbecco's modified Eagle's medium with a high glucose content (OMEM), which contains carbon-desorbed 1095. fetal calf serum (Setipi Vio-Rgodisiv , Saiarazaz, SA), substitute amino acids, 10 units/ml of penicillin C and 100 Ωg/ml of streptomycin sulfate, at 372 in a humidified atmosphere of 1095 CO". After 24 hours and. carry out transfection with Lipofectamine (SIVSO VK, Saynegzrigd, MO) according to the manufacturer's instructions. Briefly, the transfection mixture for each well contains 0.48 μl of lipofectamine, 0.00075 μg of the expression vector rOMAZ-PPAK/ZAT4, 0.045 μg of the reporter vector rOAB(5X)-IC-Is, and 0.0002 μg of pSMM-Ias2 as an internal o

Control of transactivation efficiency. Cells are incubated in the transfection mixture for 5 hours. at 379С in an atmosphere of 1095 СО". Then the cells are incubated for 48 hours. in fresh OMEM with a high glucose content containing charcoal-desorbed 595 fetal calf serum, replacement amino acids, 10 units/ml of penicillin C and 100 ug/ml of streptomycin sulfate - increasing concentrations of the tested compound. Since compounds are solubilized in DMSO, control cells are incubated with equivalent concentrations of DMSO; final concentrations of DMSO are 0.195, a concentration that has been shown to have no effect on transactivation activity. Cell lysates are obtained using reporter lysis buffer (Rgoteda, Madizop, UMI) and according to the manufacturer's instructions. The activity of luciferase in cell extracts is determined using "buffer for determination of luciferase (Rgoteda, Madizop, MU!) in a luminometer MI 3000 (Bupayesp I Arogayogiev,

Spapiyu, MA). B-galactosidase activity is determined using B-YOO-galactopyranoside (SaiIriospet, Zap Obiedo, SA). -i Agonism is evaluated in comparison with the maximum activity of transactivation for a full agonist of PPAK, such as rosiglitazone. Of course, if the maximal stimulation of transactivation is less than 5095 of the effect observed with a full agonist, then the compound is considered a partial agonist. If the maximal stimulation (22) of transactivation is greater than the effect observed with a full agonist, the compound is considered a full agonist. Compounds according to the present invention usually have EC50 values in the range from 1NM to 3000NM.

C) Study of ip mimo che) Male 4B/45 mice (age 10-11 weeks, С57В1/КРЕУ, daskgop I arz, Vag Nagbrog, ME) are placed 5/cage and provided with free access to crushed food for rodents of Rygipa company and water . Animals and fodder are weighed every 2 days and dosed daily by gavage, solvent (0.590 carboxymethylcellulose) - tested compound in the indicated doses. Drug suspensions are prepared daily. o Plasma glucose levels and triglyceride concentrations are determined in blood taken from the tail at intervals of 3-5 days during the study period. Glucose and triglyceride analyzes are carried out on the Voepgipdeg Mappipet Niaspi 911 automatic analyzer (Voeipdeg Mappeit, Ipaiaparoiiv, IM), using heparinized plasma diluted 1:6b (0о6./06.) with physiological solution. Lean animals were 60 age-matched heterozygous mice maintained in a similar manner.

Examples

The following examples are presented for the purpose of illustrating the invention and are not to be construed as limiting the invention in any way. The scope of the invention is determined by the applied formula of the invention.

Specific compounds obtained are presented in Tables 1-4. The names of the compounds are given in Tables 1A-4A. The specified 65 tables are given directly after the examples. The compounds in the tables are grouped by similar structural features, as indicated below. Below are presented typical methods of synthesis of some compounds. Other compounds can be obtained using similar synthetic approaches and techniques and readily available reagents and starting materials. Such methods of synthesis are absolutely obvious to specialists practicing in the field of organic synthesis.

Table 1: EZ means phenoxy or thiophenoxy;

Table 2: EZ means benzisoxazole;

Table 3: EZ stands for benzene and

Table 4: EZ stands for phenyl.

All compounds in Tables 1-4 are analyzed by tandem high-performance liquid chromatography-mass spectrometry (LC-MS) and/or proton NMR. Samples for LC-MS are analyzed using a 70 high-performance liquid chromatograph Adiepi 1100 Zegiez, coupled with a mass spectrometer UUaiegv

Misgogaazz. 223. A UMaiegz Khtegit column is used and the compounds are eluted according to the gradient elution program (1095 8V-10095 V in 4.5 min.) at a volumetric flow rate of 2.5 ml/min. Solvent A: water containing 0.0695 trifluoroacetic acid. Solvent B: acetonitrile containing 0.0595 trifluoroacetic acid. Holding time is given in minutes.

Synthesis of compounds in which KZ means benzoyl (Table 3)

Example 1 vd zbo Kk vo,

IN,

(2kK)-2-13-13-(4-methoxy)benzoyl-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|phenoxy)propanoic acid

Stage 1: 1-(3-methoxy)phenyl-2-methyl-b-trifluoromethoxyindole (1): 2-methyl-b6-trifluoromethoxyindole (645mg,

Z,ommol), Z-bromoanisole (0.45bml, Z,bmmol), sodium tert-butylate (404mg, 4.2mmol), He trisdibenzylidenedipalladium (20bmg, 0.225mmol) and 2-di-tert-butylphosphinobiphenyl (201mg, 0.675 mmol) are stirred in toluene at 802C and monitored by TLC (3/1 hexane/methylene chloride) or reversed-phase HPLC until the reaction is complete. The reaction mixture is then cooled, filtered through celite and the (Ce) filtrate is evaporated to give a crude isolated material which is then purified by silica gel chromatography to give the title compound. F 7TN-NMR (500 MHz, SOSIv): δ 7.53 (d, RI, 1H), 7.48 (t, RI, 1H), 7.05 (dd, RI, 1H), 7.02 (m, RI, 2H), 6.95 them (dd, RI, 1H), 6.89 (t, RI, 1H), 6.42 (s, RI, 1H), 3.88 (s, OSN», ZN) , 2.33 (c, 2-CH», ZN).

Stage 2: 1-(3-hydroxy)phenyl-2-methyl-b-trifluoromethoxyindole (2): 46mg (1.4 mmol) (1) is dissolved in 7/ml of dichloromethane at 02C. Boron tribromide (1.0 N, 2.8 bml) in dichloromethane was added, the cooling bath was removed, and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture is quenched with ice for 30 minutes and distributed between immiscible solvents. The organic layer is washed with water and (c) dried over sodium sulfate. After filtering off the desiccant, the filtrate is evaporated and the residue is purified by chromatography on silica gel, obtaining the title compound. , 1H), 7.00 (d, RY, 1H), 6.98 (s, RY, 1H), 6.95 (dd, ry, 1H), 6.92 (dd, RY, 1H), 6, 82 (t, RY, 1H), 6.39 (s, RY, 1H), 5.03 (s, OH, 1H), 2.31 (s, 2-CH, ЗН). -I 75 Stage 3: 1-(3-hydroxy)phenyl-2-methyl-3-(4-methoxy)benzoyl-b-trifluoromethoxyindole (3): 242 mg (0.788 mmol) of compound (2) are dissolved in methylene chloride (4 ml) and cooled to -2090. Slowly (in 1-2 minutes) add (Ce) a solution of diethylaluminum chloride in toluene (1.8 M, 1.2 ml) and stir for 5-15 minutes. A solution of 4-methoxybenzoyl chloride (377 mg, 2.21 mmol) in methylene chloride (1 mL) was then added and allowed to stir overnight, allowing the temperature to rise slowly to room temperature. A buffer with a pH of 7.0 is added dropwise until (95) gas evolution ceases, then the mixture is distributed between immiscible solvents. The aqueous layer is additionally extracted twice with methylene chloride and then the combined organic layers are washed twice with saturated Massey solution, dried over sodium sulfate, filtered and evaporated. Then the crude isolated substance is dissolved in methanol (5 ml) and sodium hydroxide solution (1.0 M, 1, bml).Monitoring is carried out by the method

TLC until the disappearance of diacylindole, then neutralize with NSI (1.0M, 1.bml). Then the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate, filtered, evaporated and

HF) the residue is purified by chromatography on silica gel, obtaining the title compound. g 7"H-NMR (5O00MHz, SOSIv): δ 7.84 (d, RI, 2H), 7.46 (d, RI, 1H), 7.42 (t, RI, 1H), 7.06 ( dd, RY, 1H), 6.98 (m, RY, ЗН), 6.95 (s, RY, 1H), 6.92 (dd, RY, 1H), 6.86 (t, RY, 1H) , 6.38 (c, OH, 1H), 3.91 (c, OSN», ZN), 2.35 (c, 2-CH», in ZN).

Stage 4: (2kK)-2-13-13-(4-methoxy)benzoyl-2-methyl-6-"trifluoromethoxy)-1H-indol-1-yl|phenoxy)propanoic acid ethyl ester (4): 45 .9 mg (0.100 mmol) of compound (3) is dissolved in tetrahydrofuran (0.5 ml) and cooled to 020. Then triphenylphosphine (34 mg, 0.13 mmol) and (8)-ethyl lactate (14.7 μl, 0.130 mmol) are added, followed by by addition of diethyl azodicarboxylate 65 (20.5 µl, 0.1 mmol).The reaction mixture was stirred overnight and then immediately purified by silica gel chromatography to afford the title compound.

7TH-NMR (500 MHz, SOSIv): δ 7.88 (d, RI, 2H), 7.53 (t, RI, 1H), 7.47 (d, RI, 1H), 7.090 (d, RI, 1H ), 7.01 (m, RY, 4H), 6.95 (m, RY, 1H), 6.89 (s, RY, 1H), 4.83 (ush.m, OSN (СН»н) СО , 1H), 3.93 (s, OSN», ZN), 4.25 (sq.,

ОоСНн(СНУЗ)СОоСНоСН», 2Н), 2.40 (c, 2-СНЗз, ЗН), 1.70 (d, OSН(СНУЗ)СО EI, ЗН), 1.28 (q. OSN(СНУЗИСОСНоСН»,

ZN).

Step 5: (2K)-2-(3-I3-(4-methoxy)benzoyl-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-ylphenoxy)propanoic acid (5): 5 mg of compound (4) ) is dissolved in ethanol (tml) and aqueous sodium hydroxide (1.0M, 0.200Oml) and stirred until the hydrolysis is complete. The solution is diluted with water, acidified with diluted aqueous NOSI and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound 70. "H-NMR (5000 MHz, SOSIv): δ 7.87 (d, RY, 2H), 7.54 (tt, RY, 1H), 7.45 (ush.s, RY, 1H), 7.11 ( ush.s, RY, 1H), 7.02 (m, RY, 4H), 6.95 (m, RY, 2H), 4.88 (ush.m, OSN(СНаЗ)СО»5Н, 1Н), 3.93 (c, OSN», ZN), 2.41 (c, 2-CH»z, ZN), 1.74 (d, OSN(SNU)CO-H, ZN).

OFRH/MS: ir-3.88 min., t/e 514 (M.-1)

Example 2 so; (25)-2-13-13-(4-methoxy)benzoyl-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl)|renoxy)propanoic acid

This compound is obtained using a synthesis method similar to example 1, and readily available reagents and (o) starting substances. Such a synthesis can easily be carried out by a specialist in the field of organic synthesis. "H-NMR (5000 MHz, SOSIv): δ 7.87 (d, RI, 2H), 7.54 (t, RI, 1H), 7.45 (us.s, RI, 1H), 7.11 ( ush.s, RY, 1H), 7.02 (m, RY, 4H), 6.95 (m, RY, 2H), 4.88 (ush.m, OSN(SNUZ) SON, 1H), 3, 93 (s, OSN", ZN), 2.41 (s, 2-SNU5, ZN), 1.74 s zo (d, OSN (SNZU)SON, ZN).

OFRH/MS: ir-3.88 min., t/e 514 (M.-1) o

Example With Ge)

Scheme for example 3: (22) and - "shi s;" -I se) (22) at 50

Co.)

F) name) 60 b5

ШЯ 2 звив шчи и и зарси 70 что к И З

V I Sh Zhanna a

Wiener B. I

What is that? y: do o de BA e-yashkh NI ia 0 shshchy RU ey r : nave so zv sha shi v. and I knit she Z:z» Example Z 18 In - in this. I live with you

F Su st what. o) what - ! ! (2kK)-2-13-I3-(4-Methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|phenoxy)butanoic acid

Stage 1: 1-(3-methoxy)phenyl-2-methyl-b6-trifluoromethoxyindole (I): 2-methyl-b-trifluoromethoxyindole (645mg,

C,Ommol), C-bromoanisole (0.45bml, C,bmmol), sodium tert-butylate (404mg, 4.2mmol), trisdibenzylidenedipalladium (20bmg, 0.225mmol) and 2-di-tert-butylphosphinobiphenyl (201mg, 0.675mmol )

HF) are mixed in toluene at 802C and monitored by TLC (3/1 hexane/methylene chloride) or HPLC with

Ge reversed phase until the end of the interaction. The reaction mixture is then cooled, filtered through celite and the filtrate is evaporated to give a crude isolated substance which is purified by silica gel chromatography to give the title compound. 7"H-NMR (5O00MHz, SOSIv): δ 7.53 (d, RI, 1H), 7.48 (t, RI, 1H), 7.05 (dd, RI, 1H), 7.02 (m ) , 2.33 (c, 2-CH», ZN).

Stage 2: 1-(3-hydroxy)phenyl-2-methyl-b6-trifluoromethoxyindole (2): 46 mg (1.4 mmol) of compound (1) is dissolved in 7 ml of dichloromethane at 02C. Boron tribromide (1.On, 2.8 bml) in dichloromethane is added, the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. Then the reaction mixture is quenched with ice for 30 minutes and distributed between immiscible solvents. The organic layer is washed with water and dried over sodium sulfate. After filtering off the desiccant, the filtrate is evaporated and the residue is purified by silica gel chromatography to give the title compound. 7"H-NMR (BO0MHZ, SOSIA): 5 7.51 (d, RY, 1H), 7.42 (t, RY, 1H), 7.00 (d, RY, 1H), 6.98 (s , RY, 1H), 6.95 (dd, ry, 1H), 6.92 (dd, RY, 1H), 6.82 (t, RY, 1H), 6.39 (s, RY, 1H), 5.03 (c, OH, 1H), 2.91 (c, 2-CH», ЗН).

Stage 3: 1-(3-hydroxy)phenyl-2-methyl-3-(4-methoxy)benzoyl-b-trifluoromethoxyindole (3): 242 mg (0.788 mmol) of compound (2) are dissolved in methylene chloride (4 ml) and cooled to -2020. Slowly (in 1-2 minutes) add a solution of diethylaluminum chloride in toluene (1.8M, 1.2ml) and stir for 5-15 minutes. A solution of 4-methoxybenzoyl chloride (377 mg, 2.21 mmol) in methylene chloride (1 mL) was then added and allowed to stir at 70 overnight, allowing the temperature to rise slowly to room temperature. A buffer with a pH of 7.0 is added dropwise until gas evolution stops, then the mixture is distributed between immiscible solvents. The aqueous layer is additionally extracted twice with methylene chloride and then the combined organic layers are washed twice with saturated Massey solution, dried over sodium sulfate, filtered and evaporated. Then the crude isolated substance is dissolved in methanol (5 ml) and sodium hydroxide solution (1.0 M, 1.0 ml) is added. Monitoring is carried out by the 75 TLC method until the disappearance of diacylindole, then neutralized with NSI (1.0M, 1.bml). Then the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate, filtered, evaporated, and the residue is purified by chromatography on silica gel to give the title compound. 7"H-NMR (5O00MHz, SOSIv): δ 7.84 (d, RI, 2H), 7.46 (d, RI, 1H), 7.42 (t, RI, 1H), 7.06 (dd , RI, 1H), 6.98 (m, RI, ЗН), 6.95 (s, RI, 1H), 6.92 (dd, RI, 1H), 6.86 (t, RI, 1H), 6.38 (s, OH, 1H), 3.91 (s, OSN», ZN), 235 (s, 2-CH»

ZN).

Stage 4: tert-butyl ether (2kK)-2-13-13-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|phenoxy)butanoic acid (4): 110 mg (0.25 mmol) of compound (3) is dissolved in tetrahydrofuran (1.225 ml) and cooled to 0 2C. Triphenylphosphine (78.5 mg, 0.00 mmol) and tert-butyl-(5)-2-hydroxybutyrate (Zydta-Alagisn, 48 mg, 0.000 mmol) were then added, followed by the addition of diisopropyl azodicarboxylate (5 µM, 0.000 mmol). The reaction mixture was stirred overnight and then immediately purified by chromatography on silica gel to give 10 mg of the title compound.

Chiral purity is assessed by chromatographic comparison on a SpPigaise column! AU (heptane/isopropanol as eluents) with the opposite enantiomer (prepared as above, using tert-butyl-(K)-2-hydroxybutyrate instead of tert-butyl-(5)-2-hydroxybutyrate). with

Chiral PH: 1095 isopropanol/heptane, 0.5 ml/min., X-:22 Ohm, column SpigaiseI AO (4.6x25 Ohm, 1 Ohmuk): so ate for compound (4): 12.68 min. (99.790), 14.16 (0.395). Er for the (5)-enantiomer (complex tert-butyl ether of example 2): 12.68 min. (2,290), 14.18 min. (97895). 2nd "H-NMR (BO0MGCz, SOSIa): 5 7.87 (d, RY, 2H), 7.51 (t, RY, 1H), 7.47 (d, RY, 1H), 7.08 (d, RY, IN), 7.00..0 (m, RY, 4H), 6.93 (m, RY, 1H), 6.89 (ush.t, RY, 1H), 4.52 ( 5 OSN(СНСНУ) СО2И-Вы, 1Н), 3.93 (s, OSN», ZN), 2.39 (s, M 2-СН3, ЗН), 2.03 (m, OSN(СНСНН)О- Vy, 2H), 1.45 (s, OSN(СНСНХО-Vy, 9H), 113 (

OoSnN (СНСНУЗСО- Vy, ZN).

Stage 5: (2K)-2-(3I3-(4-Methoxy)benzoyl-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl|phenyxy)butanoic acid (5): 17mg (0, 0 zmol) of compound (4) is dissolved in dichloromethane (1 ml) and trifluoroacetic acid « 20 (0.5 ml, large excess) is added. The reaction mixture is stirred until the reaction is complete (monitoring by TLC method). -in

The solvent and trifluoroacetic acid are evaporated, redistributed in dichloromethane, washed successively with phosphate buffer with pH 7.0 (Rizpeg Zsiepiys) and sodium chloride solution. Dichloromethane is dried over sodium sulfate, filtered and evaporated. The compound can then be purified either by 005 or on a silica gel column (a mixture of 0.595-195 acetic acid/ethyl acetate/hexane is required for silica gel purification). "H-NMR (B5O00MGCs, SOSIZ): 5 7.84 (d, RY, 2H), 7.62 (t, RY, 1H), 7.61 (ush.m, RY, 1H), 7.22 ( dd, RY, 1H), -I 7.17 (ush.m, RY, 2H), 7.11 (m, RY, 1H), 7.08 (m, RY, 2H), 7.04-6, of -СН», ZN), 2.06 (m, OSN(СНСНУя)СОН, 2Н), 1.11 (5 OSN(СНСНУя)СОН, ЗН). ее, OFHR/MS: IR-3.74 min., /e 528 (M.-1)

Ф Examples 4-27

The following compounds are obtained by methods similar to those described in the above examples, using similar synthesis methods and approaches, as well as readily available starting materials and reagents. Such methods and starting materials are absolutely obvious to a specialist in the field of organic synthesis.

Example 4

That's it

F) se KK. ka z 60 o (25)-2-13-I3-(4-methoxy)benzoyl-2-methyl-6-"-trifluoromethoxy)-1H-indol-1-ylphrenoxy)butanoic acid 65 "H-NMR (B5О00МГЦц SOSIZ): 5 7.84 (d, RY, 2H), 7.62 (t, RY, 1H), 7.61 (ush.m, RY, 1H), 7.22 (dd, RY, 1H), 7.17 (m, RI, 2H), 7.11 (m, RI, 1H), 7.08 (m, RI, 2H), 7.04-6.96 (m, pH, 1H ), 4.90 (m, OSN(СНСНУя)СО»5Н, 1Н),

3.93 (s, OSN»z, ZN), 2.33 (ush.s, 2-СН», ZN), 2.06 (m, OSN(СНСНУя)СОН, 2Н), 1.11 (5 OSN (SНІСНУя) SON, ZN).

OFRH/MS: ir-3.74 min., t/e 528 (M'-1).

Example 5 vdo khzSO M

Fo,

AT

Me 2-(3-13-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylphenoxy)-2-methylpropanoic acid 7"H-NMR (5O00MHCc, SOCIv): 5 7.88 (ear, RY, 2H), 7.53 (t, RY, 1H), 7.44 (d, RY, 1H), 7.14 (d, RY, 1H), 7.08 (d , RI, 1H), 7.01 (m, RI, ZN), 6.95 (d, RI, 2H), 3.93 (s, OSN», ZN), 2.43 (ush.s, 2- CH»z, ЗН), 1.70 (c, ОСН(СНЗ»СОН, bН).

OFRH/MS: ir-3.96 min., t/e 528 (M.-1)

Example 6 (2kK)-2-13-I3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indole-1- yl|phenoxy)propanoic acid co "H-NMR (5O00MHz, SOCI): δ 7.79 (d, RI, 2H), 7.55 (t, RI, 1H), 7.49 (d, RI, 2H) , 7.37 (ush.m, RI, 1H), so 7.12 (ush.m, RA, 1H), 7.03 (ush.m, RY, 2H), 6.93 (ush.m . ,74 (d, OSN(SNUZ)SOZN, ZN). b»

OFRH/MS: ir-4.18 min., t/e 518 (M.-1) ich-

Example 7

With "tod?" c o i C a - (25)-2-13-I3-(4-chloro)benzoyl-2-methyl-6-trifluoromethoxy)-1H-indol-1-ylrenoxy)propanoic acid

He) "H-NMR (5000 MHz, SOSI): 5 7.79 (d, RY, 2H), 7.55 (t, RY, 1H), 7.49 (d, RY, 2H), 7.37 ( ush.m, RI, 1H), 7.12 (ush.m, RA, 1H), 7.03 (ush.m, RY, 2H), 6.93 (ush.m, RY, 2H), 4, 88 (us.m, OSN(СНаз)СО»5Н, 1Н), 3.93 (s, OSN», ЗН), b 2.41 (с, 2-СН», ЗН), 1.74 (d, OSN (SNUZ) SOZN, ZN). o 70 OFRHK/MS: id-4.18xV., t/e 518 (M--1)

Example 8 th and o

That's it

GF! Mr. M ime) 60 a (2kK)-2-13-I3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|renoxy)butanoic acid

TNA-NMR (500 MHz, SOSI): 5 7.79 (d, RY, 2H), 7.55 (t, RY, 1H), 7.50 (d, RY, 2H), 7.37 (us.m , RY, 1H), because 7.13 (ush.m, RY, 1H), 7.03 (ush.m, RY, 2H), 6.95 (ush.m, RY, 2H), 4.72 ( ush.m, OSN(СНоСНУИ)СО-Н, 1Н), 2.42 (s, 2-СНа,

ЗН), 2.11 (m, ОСН(ИНСНАУИ)СОН, 2Н), 1.17 (t, ОСН (СНСНаЗ)СО5Н, Н).

OFRH/MS: ir-4.01 min., t/e 532 (M.-1)

Example 9 g with o i

TO chu ve 70 ha

WITH

He (25)-2-13-I3-(4-chloro)benzoyl-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|phenoxy)butanoic acid

TNA-NMR (500MHz, SOSIz): 5 7.79 (d, RY, 2H), 7.55 (t, RY, 1H), 7.50 (d, RY, 2H), 7.37 (us.m , RY, 1H), 7.13 (ush.m, RY, 1H), 7.03 (ush.m, RA, 2H), 6.95 (ush.m, RY, 2H), 4.72 (ush .m, OSN(ISНСНУя)СО»5Н, 1Н), 2.42 (s, 2-СН»,

ЗН), 2.11 (m, OSN(СНСНУ)СОЗН, 2Н), 1.17 (t, OSN (СНСН3) СОН, ЗН).

OFRH/MS: ir-4.01 min., t/e 532 (M.-1)

Example 10 o and o yes:

EzschbO and o, sch o o azo 2-(3-I3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl||phenoxy)-2-methylpropanoic acid 7 "H-NMR (5000 MHz, SOSIv): 5 7.79 (us., RI, 2H), 7.53 (t, RI, 1H), 7.44 (d, RI, 2H), 7.37 (d , RY, 1H), 7.15 o (dd, RY, 1H), 7.07 (dd, RY, 1H), 7.03 (d, RY, 1H), 6.95 (t, RY, 1H) , 6.93 (s, RI, 1H), 2.42 (ush.s, 2-CH", ZN), 1.71 (s,

ОоСсн(СНУ)СОН, 6Н).

OFRH/MS: ir-4.30 min., t/e 532 (M-1) o

Example 11 h-s "

E shi s ;" ik

Sh-. ! ! (2kK)-2-13-13-(4-chlorobenzoyl-2-methyl-6-"-(trifluoromethoxy)-1H-indol-1-yl|-5-fluorophenoxy)propanoic acid ee, "H-NMR ( Б00МГЦц, СОСИз): 5 7.79 (d, РИ, 2Н), 7.49 (d, РИ, 2Н), 7.36 (ush.m, РИ, 1Н), 7.04 (d, РИ, m ), 6.97 b (ush.m, RI, 1H), 6.86 (d, RP, 1H), 6.78 (d, RH, 1H), 6.72 (m, RI, 1H), 4 ...

OFRH/MS: ir-4.21 min., t/e 536 (M'-1)

From Example 12

K o

(25)-2-13-13-(4-chlorobenzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|-b-fluorophenoxy) propanoic acid "H-NMR (BOOMHCz, SOCIz): 5 7.79 (d, RI, 2H), 7.49 (d, RI, 2H), 7.36 (us.m, RI, 1H), 7, 04 (d, RY, 1H), because 6.97 (ush.m, RY, 1H), 6.86 (d, RY, 1H), 6.78 (d, RY, 1H), 6.72 (m , RI, 1H), 4.85 (sq., OSN(SNaI)SO»H, 1H), 2.43 (s,

2-CH3, ZN), 1.75 (d, OSN(SNUZ)SOZN, ZN).

OFRH/MS: ir-4.21 min., t/e 536 (M'-1)

Example 13

Kk o

(2kK)-2-13-I3-(4-chlorobenzoyl-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl|-5-fluorophenoxy)butanoic acid"H -NMR (BOOMHCts, SOSIv): 5 7.79 (d, RY, 2H), 7.49 (d, RY, 2H), 1H), 7.36 (ush.m, RY, 1H), 7.04 (d, RY, 1H), 6.97 (ush.m, RY, 1H), 6.86 (d, RY, 1H), 6.78 (d, RY, 1H), 6.73 (m, RY . 1.16 (t, OSN(ISNSNyaZ)СО5Н, ЗН).

OFRH/MS: ir-4.05 min., t/e 550 (M'-1)

Example 14

In him

CO M and c o) (I a c (25)-2-13-I3-(4-chlorobenzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|-5-fluorophenoxy)butanoic acid co "H-NMR (B5O00MGCs, SOSIZ): 5 7.79 (d, RY, 2H), 7.49 (d, RY, 2H), 7.36 (ush.m, RY, 1H), 7.04 (d, RY, 1H), so 6.97 (ush.m, RY, 1H), 6.86 (d, RY, 1H), 6.78 (d, RY, 1H), 6.73 (m, РЙ, 1Н), 4.68 (sq. OSN(СНСНУЗ)СО5Н, 1Н), 2.43 (s, 2-СН3, ЗН), 2.11 (m, OSN(SNСНУ)СОБН, 2Н), 1, 16 (t, OSN(ISNSNUZ)СО5Н, ЗН). (22)

OFRH/MS: ir-4.05 min., t/e 550 (M'-1) ich-

Example 15

E o 5th, ch ev) M - c fo 2" - zosi -43-I3-(4-chlorobenzoyl)-2-methyl-6-"-trifluoromethoxy)-1H-indol-1-yl|I- 5-Fluorophenoxy)-2-methylpropanoic and 2-13-3-(4 byl)-2 b-(triph)-1H-y 1-ylI-5-fluoro 12 o acid "H-NMR (B0MHCc, SOCIv) : 5 7.79 (d, RY, 2H), 7.49 (d, RY, 2H), 7.35 (d, RY, 1H), 7.03 (d, RY, 1H), 6.94 b (c, RY, 1H), 6.87 (dt, RY, 1H), 6.80 (dt, RY, 1H), 6.71 (m, RY, 1H), 2.42 (s, 2-CH », ZN), 1.71 (s, OSN(SNUI)СО5Н, 6Н). o 70 OFRH/MS: id-4.41xV., t/e 550 (M--1)

Example 16 o) and her he eESO GO o vo, o o yu y;

VO

(2K)-2-13-I3-(4-Methoxybenzoyl)-2-methyl-6-"trifluoromethoxy)-1H-indol-1-yl|-b-fluorophenoxy)propanoic acid

TNA-NMR (500 MHz, SOSIz): 5 7.86 (d, RI, 2H), 7.44 (us.m, RI, 1H), 7.03 (d, RI, 1H), 7.00 (d , RY, 2H), 65 6.97 (ush.m, RY, 1H), 6.85 (d, RY, 1H), 6.79 (d, RY, 1H), 6.73 (m, RY, 1H), 4.86 (sq., OSH(CH»Z)CO»H, 1H), 3.93 (s,

OSNU», ZN), 2.42 (c, 2-CH»z, ZN), 1.75 (d, OSN(CH»)СО5Н, ZN).

OFRH/MS: ir-3.64 min., t/e 532 (M-1)

Example 17

IS

; So,

Chabot "7 sho, o (2kK)-2-13-I3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|-b-fluorophenoxy)butanoic acid "H- NMR (B5O00MHZc, SOSIZ): 5 7.86 (d, RY, 2H), 7.44 (us.m, RY, 71H), 7.03 (d, RY, 1H), 7.00 (d, RY , 2H), t 6.97 (ush.m, RY, 1H), 6.86 (d, RY, 1H), 6.78 (d, RY, 1H), 6.73 (m, RY, 1H) . (t, OSN(ISNSNUZ)СО5Н, ЗН).

OFRH/MS: ir-4.13 min., t/e 546 (M.-1)

Example 18 c o a (2kK)-2-13-I3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|-4-fluorophenoxy)propanoic acid c 7"H -NMR (5O00MHz, SOSIv): δ 7.78 (d, RY, 2H), 7.49 (d, RY, 2H), 7.36 (dd, RY, 1H), 7.31 (m, RY, 1H), 7.02 so (ush.m, RY, 2H), 6.96 (ush.d, RY, 1H), 6.89 (d, RY, 1H), 4.88 (m, OSN(СН »U)СО5Н, 1Н), 2.40 (s, 2-СН», ЗН), 1.76 (d,

OoSsNn(SNU)SON, ZN). ish

OFRH/MS: ir-4.15 min., t/e 536 (M'-1) He»!

Example 19 m. on gzsO. Hn ch y shi s;" a -I (25)-2-13-I3-(4-chlorobenzoyl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|-4-fluorophenoxy)propanoic acid 7"H-NMR ( 5О00МГЦц, СОСИв): 5 7.78 (d, RI, 2H), 7.49 (d, RI, 2H), 7.36 (dd, RI, 1H), 7.31 (m, RI, 1H), 7.02 ish (ush.m, RY, 2H), 6.96 (ush.d, RY, 1H), 6.89 (d, RY, 1H), 4.88 (m, OSN(SNUZ)СО5Н, 1H), 2.40 (c, 2-CH3, ZN), 1.76 (d, b OoCsNn(SNU)SON, ZN).

OFRH/MS: ir-4.15 min., t/e 536 (M'-1) o Example 20

Co.)

E at 25 J on

GF! ace name) 60 s (28)-2-13-I3-(4-chlorobenzoyl)-2-methyl-6-"-"trifluoromethoxy)-1H-indol-1-yl|-4-fluorophenoxy)-2-methylpropanoic acid 65 7"H-NMR (5000 MHz, SOSIv): 5 7.79 (d, RI, 2H), 7.49 (d, RI, 2H), 7.36 (dd, RI, 1H), 7.34 ( m, RY, 1H), 7.12 (m, RY, 2H), 7.03 (us.d, RY, 1H), 6.89 (d, RY, 1H), 2.42 (s, 2- СН», ЗН), 1.70 (с, ОСН(СНУЗ)СО5Н, 6Н).

OFRH/MS: ir-4.33Xhv., t/e 550 (M'-1)

Example 21 Fr

And with -M on go M in, and 5

Meb 2-(16-13-(4-methoxybenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl|pyridin-2-yloxy)-2-methylpropanoic acid" H-NMR (B5О0МГЦц , SOSIya): 5 7.67 (d, RY, 2H), 7.51 (m, RY, 1H), 7.11 (d, RY, 1H), 7.00 (s, RY, 1H), 6 ... , 6H).)

OFRH/MS: ir-3.91 min., t/e 529 (M.-1)

Example 22

That's it

2-(16-13-(4-chlorobenzoyl)-2-methyl-6-"-trifluoromethoxy)-1H-indol-1-yl|pyridin-2-yloxy)-2-methylpropane sc acid CO 7"H-NMR (BO0MGCz, SOCI): 5 7.90 (t, RI, 1H), 7.79 (d, RI, 2H), 7.49 (d, RI, 2H), 7, 41 (d, RI, 1H), 7.05 so (m, RI, ZN), 6.98 (d, RI, 1H), 2.44 (c, 2-CH»z, ZN), 1.65 (c, OSN(SNU)»СОН, 6Н).

OFRH/MS: ir-4.17 min., t/e 533 (M'-1) b»

Example 23 ch o

In h gzso M o, s OSY;" (25)-2-13-13-(4-methoxybenzoyl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|-4-chlorophenoxy)propanoic acid

TNA-NMR (B5O0MGCz, SOSi3): 5 7.85 (d, RI, 2H), 7.65 (d, RI, 1H), 7.31 (m, RI, 1H), 7.03-6.90 (ush.m, RI, b 6H), 4.85 (m, OSN(SNUZ)SOZN, 1H), 3.93 (s, OSN», ZN), 2.41 (s, 2-CH»z, ZN), 1.78 (d, OSN(SNUZ)СО5Н, ZN). so 20 Example 24

Ko) , and 59th century. M

F) t o 60 a (25)-2-13-I3-(4-chlorobenzoyl)-2-methyl-6-"-trifluoromethoxy)-1H-indol-1-yl|-4-chlorophenoxy)propanoic acid

TNA-NMR (5O00MHz, SOSIv): 85 7.78 (d, RI, 2H), 7.65 (d, RI, 1H), 7.49 (d, RI, 2H), 7.34 (m, RI . », ЗН), 1.79 (d, ОСН(СНЗ)СОН, ЗН).

OFRH/MS: ir-4.37 min., t/e 551 (M.-1)

Example 25 0 oh, to her

(2kK)-2-13-I3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|-4-chlorophenoxy)propanoic acid

TN-NMR (BOO0MHz, SOSIv): 5 7.78 (d, RA, 2H), 7.65 (d, RY, 1H), 7.49 (d, RY, 2H), 7.34 (m, RY . ), 1.79 (d, ОСН(СНаЗ)СО5Н, ЗН).

Example 26 (8) 2-(3-I3-(4-chlorobenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl|phenoxy) butanoic acid so

TNA-NMR (5O00MHz, SOSIv): 5 7.80 (d, RI, 2H), 7.55 (t, RI, 1H), 7.50 (d, RI, 2H), 7.37 (m, RI . . Fo

Example 27 and - about N aso M " fig g shi s in 2" s " 2-(3-I3-(4-chlorobenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl| renoxy)pentanoic acid -I "H-NMR (BO00MHCz, SOSIZ): δ 7.79 (d, RI, 2H), 7.54 (t, EI, 1H), 7.49 (d, RI, 2H), 7.38-7.34 (m, RY, 1H), 7.12-6.89 (us.m, RY, 5H), 4.74 (us.s, OSN(СНОСН»З)СОоН, 1) , 2.41 (c, 2-CH5u, ЗН), 2.04 (m, se)

ОоСнН(СНСНСНСНУ)СОН, 2Н), 1.63 (m, OSН (СННСНСНУИ)СОН, 2Н), 1.03 (t, ОСНСНОСНСНУЗ)СОЗН, ЗН).

Gee! Synthesis scheme according to example 28 o 50

Co.)

F) name) 60 b5

SC would not play it; with and Shk x. what is the glory of the United States? Shchi a Bay

What is the name of the Saint, what is the dream that she has about Her. :- Her. vna Kv. yury |, von u shock ss duch y un ge

Se ey yik tsu She ee v t- kh Y pila la bere y shche she zi oz zo ! Z r (Se) (22) and as a m.

What dream are you VEAOKerVu; for Pp 20 in 8 nab: 4th - in village

Example 28 "with r d o ek

What is he?

Fuck her

F 5 o Ketone 2: suspension of chloroacetone (6.00 g, ppm, before use, chloroacetone was filtered through

Ge basic aluminum oxide), phenol 1 (10.00 g, bbmmol) and potassium carbonate (8.96 g, bbmmol) are stirred in DMF at room temperature under a nitrogen atmosphere for 1 h. After the specified time, the reaction mixture is diluted with a mixture of ethyl acetate/Nos and the layers are separated. The aqueous layer is acidified with MnHCII and extracted with ethyl acetate (3x).

Then the organic layer is washed with water (2x) and a saturated solution of salt(s), dried with sodium sulfate, filtered and evaporated, obtaining a pink solid: 7"H-NMR (SOCI, 500 MHz): 5 8.14 (t, 1Н ), 7.53 (t, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 3.78 (s, 2H), 2.35 (s, ЗН). ime) ex Oh

SEZ n b5 z

Indole C: ketone 2 (1.84g, 8.75mmol) and 4-trifluoromethoxyphenylhydrazine hydrochloride (2.00g, 4.7bmmol) were stirred at 1002C in acetic acid (40ml, 0.22M) for 1 hour under nitrogen to give a mixture 1:2 4- and b-riftomethoxyindoles (the necessary b-substituted indole is slightly less polar according to TLC data). The reaction mixture is cooled to room temperature, acetic acid is removed under reduced pressure and the residue is diluted with ethyl acetate and washed with water (1x) and saturated salt solution (1x). The organic layer is dried with sodium sulfate, filtered and evaporated to give compound C as a yellow oil after column chromatography (hexane/ethyl acetate/19o5 acetic acid, 6:1); 7"H-NMR (SOCIz, 500 MHz): δ 8.43 (us.s, 1H), 8.16 (dd, 1H), 7.46 (d, 1H), 7.23 (t, 1H), 7.14 (t, 1H), 7.03 70 (d, 1H), 6.74 (d, 1H), 2.54 (s, ZN).

CoO-

Se M y n 4

3-H-indole 4: a solution of indole 3 (0.29g, 0.78mmol) and thiosalicylic acid (0.12g, 0.18mmol) in trifluoroacetic acid (3ml, 0.26M) is heated to 5023 under a nitrogen atmosphere for 2 hours. After the specified time, the reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with In Mmaon (2x) and a saturated solution of its salt(s). The organic layer is dried with sodium sulfate, filtered and evaporated, obtaining a brown solid: 7H-NMR (SOCI, 500MHz): δ 8.01 (ush.s, 1H), 7.49 (d, 1H), 7.17 ( s, 1H), 6.99 (d, 1H), 6.26 (s, 1H), 2.46 (s, ЗН).

Ge) SI s so o

IS.

SEZ N

5 3-Acylindole 5: zinc chloride (0.23 g, 1.6 mmol) and ethylmagnesium bromide (0.29 ml of a 3M solution in diethyl ether,

0.87 mmol) is added to a solution of indole 4 (0.16 g, 0.4 mmol) in СНоОС. The resulting mixture is stirred at 95 room temperature in a nitrogen atmosphere for an hour. Then 4-chlorobenzoyl chloride (0.21 g, 1.18 mmol) was added and stirring was continued for 1 hour. Finally, aluminum chloride (0.053 g, 0.39 mmol) was added and the reaction mixture was stirred for 3 hours. After the specified time, the reaction is quenched with MH Si (aq.), F) diluted with CH Si", washed with yin MaonH (its) and a saturated salt solution (Х). The organic layer is dried over sodium sulfate, filtered and evaporated, obtaining after purification by column chromatography (hexane/ethyl acetate mixture, 4:1) a clear yellow oil; c, 1H), 7.73 (d, 2H), 7.48 (d, 2H), 7.40 (d, 1H), 7.24 (c, 1H), 7.02 (d, 1H), 2.60 (c, ZN). " and US 7 with o

I" va p syo M o i -

In 6 se) M-benzylindole 6: sodium hydride (14mg, 0.35mmol, 6095 dispersion in mineral oil) was added to a solution of b-indole 5 (111mg, 0.32mmol) in DMF (3.0ml, 0.1M). The resulting mixture is stirred at room temperature in a nitrogen atmosphere for 10 minutes, then bromide 10 (110 mg, O, ZB5 mmol) is added. Stirring is continued at room temperature for 2 hours. Then the reaction mixture is diluted with ethyl acetate, washed with water

With (2x) and a saturated solution of salt(s), dried with sodium sulfate, filtered and evaporated, obtaining after purification by column chromatography (hexane/ethyl acetate mixture, 4:1) a yellow oil; "H-NMR (SOSIS, BOOMHz): 5 7.76 (d, 2H), 7.48 (d, 2H), 7.37 (d, 1H), 7.26 (dd, 1H), 7.14 (c, 1H), 7.02 (d, 1H), 6.79 (dd, 1H), 6.65 (d, 1H), 6.60 (c, 1H), 5.34 (c, 2H) . 85 (d, 6H). yin m r (8) o n svo 7 bo Acid 7: M-benzylindole 6 (121mg, 0.20bmmol) and aqueous sodium hydroxide (0.5O0ml, 5.0M) are mixed in a mixture of tetrahydrofuran, methanol and water (2.5 mL, 3:1:1) at room temperature for 7 h. After the specified time, the reaction mixture was concentrated by evaporation on a rotary evaporator and purified by reversed-phase HPLC to give acid 7 as a white solid. "H- NMR (SOSIS, 50 MHz): δ 7.76 (d, 2H), 7.48 (d, 2H), 7.34 (d, 1H), 7.26 (d, 1H), 7.16 (s, 1H), 7.02 (d, 1H), 6.82 (dd, 1H), 6.72 (d, 1H), 6.44 (c, 1H), 5.36 (dd, 2H), 4, 64 (sq., 1H), 2.51 (s, ZN), 1.62 (d, ZN). eh

IN

Phenol 9: 3-Methoxybenzyl bromide (3.0 g, 15 mmol) is dissolved in СНеСи» and cooled to 020. Then a 1 M solution of boron tribromide in СНСи» (17.9 ml, 17.9 mmol) is added dropwise. Through ЗОхв. the ice bath is removed and the stirring is continued during ЗОхв. Then the reaction mixture is quenched with ice and diluted with CH 2Si", 75 HO. The layers are separated and the organic layer is washed with HO (2x) and saturated salt solution(s), dried over sodium sulfate, filtered and evaporated to give phenol 9 as a white solid. "H-NMR (SOCI3, 500 MHz): δ 7.25 (t, 1H), 6.99 (d, 1H), 6.90 (s, 1H), 6.80 (d, 1H), 4.81 (ush.s, 1H), 4.45 (s, 2H), grade 10

Bromide 10: K-isobutyl lactate (1.02g, 6.905mmol) is dissolved in СНоСи» and cooled to 02С. Then add triphenylphosphine (1.83g, b6.95mmol) followed by dropwise addition of diethylazodicarboxylate (1.21g, Ge) 6.95mmol). Finally, add phenol 9. At the end of the addition, remove the ice bath and continue stirring for 30 minutes. The reaction mixture is diluted with СНоСи», washed with HO (2x) and a saturated solution of salt(s), dried with sodium sulfate, filtered and evaporated, obtaining after purification by chromatography (a mixture of hexane/ethyl acetate, 8:1) a colorless oil (1.02 g, 60905). "H-NMR (SOCI3, 500 MHz): δ 7.26 (dd, 1H), 7.01 (d, 1H), 6.94 (dd, 1H), 6.83 (dd, 1H), 4.81 (q, 1), « 4.46 (s, 2H), 3.23-4.01 (m, 2H), 1.95 (m, 1H), 1.65 (d, ЗН), 0.90 (dd, 6H). co

Synthesis scheme according to example 29 (22) m. « shi s z -I se) (22) o 50

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ShK ok and yes b Be shva o svy eh a NE in: Ne Z zo - ze V V ponntvslnesnvy ri rya s. m: a v y nyny s ky ZY HER dov y uk p z :Z de Y lah: taka sk sr IY schoi seluluezhi syidevia ps sa Ks ken nn i khn sh

Her father (ua y | o » ny va nyshYsh ЖЙ fev ШЙ s

Z ya, Java ish sy ek za " in che Za soins s Z (Se) mm S F

Zo E - shch schi un bo ih

What es SYADE ag Lo vs sha I - Be M Ts. » a How -I Sha TE She i tt o i-o Example 29 (22) uk (95) 50 in "Hu

And about Ethyl-2-(3-formyl)phenoxybutyrate:

To a solution of 3-hydroxybenzaldehyde (26.8g, 219, mmol) in DMF (250ml) at 0-109C, add C825SO3 (142g, 4309mmol) and ethyl 2-bromobutyrate (32.4ml, 219.0mmol). The reaction mixture is first stirred at 0-109C for 2 hours, then at room temperature overnight. The mixture is diluted with water (40 Oml) and extracted with diethyl ether (2x15 Oml). The ether extract is washed with water (2x10O0ml) and saturated salt solution (100ml), dried over anhydrous Mo950O, and concentrated to dryness under vacuum, obtaining the product in the form of a clear oil. "H-NMR (SOSIS, 500 MHz): δ 9.97 (s, 1H), 7.51 (m, 2H), 7.36 (s, 1H), 7.21 (dd, 1H), 4.66 (t, 1H), 4.21 ve (sq., 2H), 2.06 (m, 2H), 1.28 (t, ЗН), 1.12 (t, ЗН).

Y Y mavn" lk n 07 --- TO o

Ethyl 2-(3-hydroxymethyl)phenoxybutyrate

Sodium borohydride (Mavn, 7.4 g, 194 mmol) was added in portions to a solution of ethyl 2-(3-formyl)phenoxybutyrate (46 g, 194 mmol) in ethanol (50 Oml) at 02. The reaction mixture was stirred in an ice bath for 1 hour.

Water is slowly added to destroy excess Mavn ud. Then the mixture is diluted with 300 ml of water and extracted with 70% diethyl ether (2 x 200 ml). The ether extract is washed with water (2 x 100 ml) and saturated salt solution (100 ml), dried over anhydrous Mo5O, and concentrated to dryness under vacuum, obtaining the product in the form of a clear oil.

TN-NMR (SOSIS, BOOMHz): 5 7.27 (dd, 1H), 6.97 (d, 1H), 6.93 (s, 1H), 6.81 (d, 1H), 4.65 ( s, 2H), 4.58 (t, 1H), 4.22 (sq., 2H), 2.01 (m, 2H), 1.28 (t, ЗН), 1.11 (t, ЗН) . o no ol 00 oVo/RR V du i p

Ethyl 2-(3-bromomethyl)phenoxybutyrate

To a solution of ethyl 2-(3-hydroxymethyl)phenoxybutyrate (41g, 172.2mmol) in dichloromethane (400ml) at 09С, carbon tetrabromide (СВg;, 8bg, 260mmol) and triphenylphosphine (РАзР, b8g, 260mmol) are added. The reaction mixture is stirred at 02C for 2 hours, then washed with saturated sodium bicarbonate (Manso, 2b0ml) and saturated salt solution (200ml) and concentrated in a vacuum to a small volume. The residue is purified by chromatography on silica gel using a mixture of hexane/ethyl acetate (9:1) as the solvent system, which gives i) the product as a colorless oil.

TN-NMR (SOSIZ, B00MHz): δ 7.26 (t, 1H), 7.01 (d, 1H), 6.95 (s, 1H), 6.82 (d, 1H), 4.58 ( m, 1H), 4.46 (s, 2H), 4.25 (sq., 2H), 2.01 (m, 2H), 1.28 (t, ЗН), 1.11 (t, ЗН) . with o | so "ru ttiya 7. poh F chiral HPLC - F

Preparation of optically active ethyl-2-(3-bromomethyl)phenoxybutyrate: To analyze the product for enantiomeric purity: 1 μl of a sample solution with a concentration of approximately 1.00 mg/ml is injected onto a Spigasea analytical column

OO (4.6x250mm, 10 microns). Then the column is eluted with an isocratic solvent system containing 590 isopropanol in heptane at a volumetric flow rate of O.bml/min. Peaks are recorded at a wavelength of 254 μm using a UV detector. Under these conditions, the retention time of the 5Z-enantiomer is about 10 minutes, while the retention time of the K-enantiomer is about 20 minutes. The enantiomeric excess (eeto) is calculated by subtracting the area bounded by the curve of the 5-enantiomer, the area bounded by the curve of the K-enantiomer, and . by dividing by the sum of two areas. For preparative purposes, a semi-preparative SPpigasei 00 and Zeti-Rger column (20x2500mm, 10 microns) is used. Inject 1.8 ml of a sample solution with a concentration of approximately 4 Ω/ml. Then the column is eluted with an isocratic solvent system containing 595 isopropanol in heptane, with a volumetric

Flow rate 9.Oml/min. Peak fractions registered above the threshold of О0.5mMV at a wavelength of 254μm are collected using the Siizop fraction collector. Fractions containing the C-enantiomer are collected within 20-25 minutes after injection, while fractions containing the K-enantiomer are collected at approximately 40-45 minutes. o Repeated injections lead to continuous separation of the two enantiomers. The fractions containing the selected b enantiomers are then combined and concentrated, obtaining an optically active product in the form of a clear oil. o 50 The enantiomeric purity of the product is within 96-9990 o ee. with in" ind

Fa aa ve o Vol niva nin SO M ime)

SggSOzi DISK "in "m 60

Ethyl-(2kK)-2-13-I(3-(4-chlorobetoyl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-ylmethyl|phenoxy)butyrate

To a solution of 3-(4-chlorobenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indole (15g, Hommol) in DMF (300ml) at 0-10; add Св»СО» (45g, 124mmol) and ethyl-(2K)-2-(3-bromomethyl)phenoxybutyrate (18g, 5ZOmmol). The reaction mixture is first stirred at 0-10927 for 2 hours, then at room temperature overnight. bo The mixture is diluted with water (400 ml) and extracted with ethyl acetate (2 x 15 Oml). The organic extract is washed with water (2 x 100 ml) and saturated salt solution (100 ml), dried over anhydrous Mo5O, and concentrated in vacuo.

The residue is purified by silica gel chromatography using a hexane/ethyl acetate (4:1) solvent system to give the product as a white solid.

TN-NMR (SOSIS, BOOMHz): 5 7.76 (d, 2H), 7.48 (d, 2H), 7.36 (d, 1H), 7.25 (t, 1H), 7.15 ( c, 1H), 7.02 (d, 1H), 6.79 (d, 1H), 6.67 (d, 1H), 6.56 (c, 1H), 5.35 (c, 2H), 4.49 (t, 1H), 4.21 (sq., 2H), 2.55 (s, ЗН), 1.97 (m, 2Н), 1.28 (t, ЗН), 1.07 ( t, ZN).

The enantiomeric purity of the product is in the range of 98-9995 ee, as determined by analysis using analytical chiral HPLC (Spigase! OO, 1095 ethanol in heptane). and si mongone preinuch pintniirn tschu (2k)-2-13-((3-(4-chlorobenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-ylylmethyl1|phenoxy)butyric acid:

To a solution of ethyl-(2K)-2-(3-I(3-(4-chlorobenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl|methylIfenoxy)butyrate (233g, 4Omol) in tetrahydrofuran (THF, 200 ml) add 200 ml of methanol and 1 bbml of Mahon's solution (16 mmol).

The clear solution is stirred at room temperature overnight and neutralized (to pH-4) with a 2N solution of HCl. The mixture is concentrated under reduced pressure to remove most of the organic He solvent and then stirred at room temperature for crystallization. The suspension is then filtered and (5) the solid is washed with water and dried in vacuo to give the product as a white solid. 7"H-NMR (SOCI3, 50 MHz): δ 7.77 (d, 2H), 7.48 (d, 2H), 7.35 (d, 1H), 7.27 (t, 1H), 7, 17 (s, 1H), 7.02 (d, 1H), 6.84 (d, 71H), 6.73 (d, 71H), 6.38 (s, 1H), 5.36 (sq., 2H), 4.44 (t, 1H), 2.49 (s, ZN), 1.98 (m, 2H), 1.07 (t, ZN). MO: (M-1)-546. s

The enantiomeric purity of the product is in the range of 98-9995 ee (SPpigaseb О0О-КН, gradient mixture with acetonitrile/water).

Synthesis of compounds in which EZ stands for phenoxy (Table 1) ee,

Compounds in which KZ means phenoxy or thiophenoxy are presented in Table 1. The synthesis of the characteristic compound (F) (Example 30) from Table 1 is represented by the scheme below, accompanied by a detailed description of the synthesis. Other compounds of Table 1 can be synthesized by a skilled person in the art using similar synthetic techniques and readily available substances. shi s z -I se) (22) at 50

Co.)

F) ime) 60 b5 gays B ey . oh and

Kg which Y z -Sh zo IY Bilavy PI ay p Z 70 Y also a : chk i: o she i s 30 i ME so (Se) (22) and 7 zhi - Oh i; SHE. and Sho and KE ze yad: I BE I 40 va with B Z s o . ,» Example 30 vn HIGHER F 00 Oct,

He» To a solution of 4-chlorophenol (15.3b6g) in DMF (150ml) at room temperature, add С8в2СО»z (64.4Hg). 5 o In 15 min. inject chloroacetone (14.8 ml) with a syringe. The reaction mixture was stirred for 3 hours, then partitioned between diethyl ether and water. The organic layer is washed successively with water, then aqueous

He with Mahon's solution (2x) and a saturated salt solution, dried over anhydrous M950O,4, filtered and concentrated in a vacuum. Distillation in a deep vacuum gives 14 g of the product in the form of a light yellow oil. "H-NMR (SOCI3, 500 MHz): δ 7.28 (d, 2H), 6.83 (d, 2H), 4.54 (s, 2H), 2.29 (s, Н). n o Ou but AY bno these relatives 60 and Benzol you

The ketone obtained above (12.89g) and 3-trifluoromethoxyphenylhydrazine (12.22g) are dissolved in benzene (50ml).

The reaction mixture is heated to 602C for 45 minutes, cooled to room temperature, dried over 65% anhydrous Ma»5O), filtered and concentrated in vacuo to give phenylhydrazone (23g), which is used directly without additional purification.

N n eru, - s A A -like 4 s sleep o a

To the solution of the hydrazone obtained above (23g) in СНоСи» (200ml) at room temperature, ReSiz (11ml) is added. The reaction mixture is stirred at room temperature for 24 hours, then water (Zml) is added and the reaction mixture is vigorously stirred for another 15 minutes. After cooling to 02C in an ice-water bath, the reaction mixture is neutralized to pH 7 by adding a 5N aqueous solution of MaonN. Most of the solvent is removed under vacuum.

The residue is partitioned between diethyl ether and water. The organic layer was washed with water and saturated salt solution, dried over anhydrous MazoO, filtered and concentrated in vacuo. Purification by flash chromatography (5O", BE As/hexane 25/1) gives the required product (7.3g) along with the corresponding isomer of 4-trifluoromethoxyindole (2.4g). "H-NMR (SOSIS, 500MHz): 5 7.80 (s, broadened, 1H), 7.24 (d, U-8.7Hz, 2H), 7.22 (d, 9-84Hz, 1H), 7.19 (s, 1H), 6.95 (d, U-8.4Hz, 1H), 6.91 (d, U-8.7Hz, 2H), 2.35 (s, ЗН). To a solution of indole (3.16 g) and benzyl bromide (3.55 g) obtained above in DMF (40 ml) at room temperature, add SO"CO" (6.03 g). The reaction mixture is stirred for 15 hours. poured into water, extracted with EtOAc and (2x). The combined organic layers were washed with water and saturated salt solution, dried over anhydrous NaCl, filtered and concentrated in vacuo.

Purification by flash chromatography gives the required product. o 7"H-NMR (SOCIz, 50O0MHz): δ 7.34 (d, 9U-8.2Hz, 1), 7.28 (d, 9U-7.6Hz, 1H), 7.25 (d, U -9.0Hz, 2H), 7.08 (s, 1H), 6.96 (d, U-8.0Hz, 1), 6.92 (d, 9U-9.0Hz, 2H), 6, 60 (dd, 9U-8.0, 1.7Hz, 1H), 6.46 (d, 9-1.7Hz, 1H), 5.23 (s, 2H), 4.62 (sq., 9U- 6.8Hz, 1), 3.85 (dd, U-6.8, 10.5Hz, 1H), 3.70 (dd, 9U-6.8, 10.5Hz, 1H), 2.24 (s , ЗН), 1.81 (w, 1Н), 1.64 (d, U-6.9Hz, ЗН), 0.84 (d, У-6.6Hz, 6Н). Well, that's okay

СооО-ny t Ka

F "a (22) . - . .

Aqueous Maoson (1.On, 20 ml) is added to a solution of the complex ether (5.0 g) in MeonN (200 ml). The mixture is stirred (95) 50 at room temperature for 2 hours, cooled to 02С, acidified with 1.00 N HCl, diluted with water

Kz (200ml), extracted with EtOAc (2x). The combined organic layers are washed with water and saturated salt solution, dried over anhydrous Mo5O), filtered and concentrated in vacuo. The residue is purified by crystallization from a mixture of diethyl ether/hexane, obtaining the product.

TN-NMR (SOSIZ, 500MHz): 5 7.36 (d, U-8.2Hz, 1), 7.28 (d, U-7.6Hz, 1H), 7.25 (d, 9U-92Hz, 2H), 7.09 (s, 1H), 6.96 (d, 9U-8.7Hz, 1H), 6.90 (d, 9U-9.0Hz, 2H), 6.65 (d, 9U- 8.0 Hz, 1H), 6.45 (s, 1H), 5.26 (s, 2H), 4.63 i) (sq., U-6.9Hz, 1H), 2.24 (s, ZN ),1.64(d, U-6.9Hz, ZN). Name 7 Additives 65 Alcohol (14.1 ml) is added to a solution of phenol (10.23 g) in methylene chloride (200 ml) at room temperature,

RRPz (244g) and OEAO (14, bml). The reaction mixture is stirred overnight. The solvent is removed in vacuo.

Purification by flash chromatography gives the required product.

TNA-NMR (SOSIZ, 500MHz) 5 7.25 (d, 9-8.0GHz, 1), 6.75 (d, 9U-8.0Hz, MN), 6.70 (s, 1H), 4, 79 (sq., -6.7Hz, 1H), 3.99 (m, 1H), 2.30 (s, ЗН), 1.97 (m, 1H), 1.70 (d, U-6, 9Hz, ZN), 0.90 (d, U-6.8Hz, 6H). and so on

ХК мв8, ЛИВ и нный ня и се, 70 To a solution of the original complex ether (15.3 g) in SSI. add MV5 (9.58g) and a catalytic amount of AEVM (200mg). The mixture was stirred at 80927 overnight, cooled to room temperature, filtered and concentrated in vacuo. Purification by chromatography gives the required benzyl boromid. "H-NMR (SOSIi, 500MHz): 85 7.35 (d, 9U-8.0Hz, 1H), 6.98 (dd, U-8.0, 2.0Hz, 1H), 6.89 (d , 9-2.0Hz, 1H), 4.84 (sq., 9U-6.7Hz, 1H), 4.43 (d, 9U-10.5Hz, 1H), 4.41 (d, 9-10 ,5Hz, 1H), 3.98 (m, 1H), 1.97 (m, 1H), 1.72 (d, 75 4-6.9Hz, ZN), 0.90 (d, 3-6, 7Hz, ZN), 0.90 (d, U-6.7Hz, ZN).

Compounds in which VZ stands for benzisoxazole (Table 2)

The synthesis of the compound in which BK C is benzisoxazole is represented by the scheme below, which is accompanied by a description of the method in Example 31. Other compounds in which K C is benzisoxazole are shown in Table 2. All of the specified compounds can be obtained by a skilled specialist in the field of organic synthesis , using the methods and techniques described in this description. s o s so (Se) (22) and - "shi s;" -I se) (22) at 50

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What guys are: me; "a Zheya Ye TZ V y I Kont yan sii z Ts za shcha y I En v ; MO: yekya a - 4. Shchi r. y EK ev yk YN "de i 7 sho eajsn (a

And sch pr (5) zo y. - peshervo VyH. what about in and KO; vintschon-noi « 7 - khr y I sh loh Mo A, ts ia H es o ny m Yak tsk "y

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E BYA and Be. I went and Ta sii x What in water Me IV SCHE. more, de Te E i im Z shk y Vikh Kavu u che ŽI te u i inn vodne ev Y we A s as tro more: o s

From Ks. AD shoshsche eko so "che m. sia "

Хов, не) - 2 - 75 Example 31 (2kK)-2-(4-chloro-3-13-(6-methoxy-1,2-benzisoxazol-3-yl)- 2-Methyl-6-trifluoromethoxy)-1H-indol-1-yl|Imethylufenoxy)propanoic acid 60 Stage 1. Methyl 2-(allyloxy)-4-methoxybenzoate (2):

IHAAI

65 To a solution of methyl-4-methoxysalicylate (2.0g, 11mmol) in DMF (20ml) at room temperature is added

С82СО" (1, Eq., 4.7g) and allyl bromide (1, Eq., 1.23ml). After 2 hours, the reaction mixture is diluted with EOAc and washed with water (Х), saturated salt solution (Х). The organic layer was dried over NaCl5O and concentrated to give the product as a light yellow oil. The product is used without additional cleaning.

TN-NMR (5000 MHz, SOSi3): δ 7.89 (d, 1H), 6.53 (dd, 1H), 6.49 (d, 1H), 6.08 (m, 1H), 5.55 ( d, 1H), 5.33 (D, 1H), 4.63 (d, 2H), Z, 89 (s, ЗН), 3.86 (s, ЗН).

Stage 2. 2-(Allyloxy)-4-methoxybenzoic acid (3): to a solution of 2 (2.5g, 11mmol) in aqueous methanol (30ml) add KOH (Tequ., 63Omg). The reaction mixture is heated to 502 for 12 hours, then an additional amount of KOH (633Omg) is added. After 12 hours, the mixture is cooled, diluted with EOAc and washed with 1M HCl. The aqueous layer is extracted with EtOAc (3x). The combined organic layers were dried over Na»5O and concentrated. The product is isolated in the form of a not quite white solid /5 component and used without additional purification. "H-NMR (BO0MHz, CO500): δ 7.85 (d, 1H), 6.60 (m, 2H), 6.08 (m, 1), 5.49 (d, 1H), 5.30 (d, 1H), 4.68 (d, 2H), 3.84 (s, ЗН).

Stage 3. (2-(Allyloxy)-4-methoxyphenyl((2-methyl-6--trifluoromethoxy)-1H-indol-3-yl|methanone (6):

N

EzSO 7 Go o s (in o nso M

To a suspension of compound 4 (6.34 g, 29 mmol) and 7pSi" (2.1 equiv., 8.3 g) in СНоСі" (220 ml) at ambient temperature EM, add EIMmMaVg (3.0 M in diethyl ether). In a separate vessel, oxalyl chloride CO (1, Zequ., 3, 3ml) is added to a solution of compounds C (1, Zeq., 6b, 8g) in SNHS" (200ml). After 1 hour, a freshly prepared acid chloride solution (5) is added to the indole through a cannula. The reaction mixture is stirred for 1 (C) hour, then quenched by pouring into a saturated solution of МН.АСИ. The layers are allowed to separate, and then the organic layer is washed with MNaCl (2x) and ManClSO (2x). The organic layer is dried over NaCl, then filtered through a loose layer

From silica gel, eluting with a mixture of 2:11 SNSI./EUAs. The filtrate is concentrated to give a red solid, c. which is rubbed with MeonN (50-100 ml). The mother liquor is concentrated and the operation is repeated. The product is isolated as a colorless solid. 7"H-NMR (B5O0MGCz, SOSi3): 5 8.48 (us.s, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.16 (s, 1H), 6.97 (d, 1H), 6.60 " (d, 1H), 6.52 (d, 1H), 5.67 (m, 1H), 5.03 (d, 1H), 5.00 ( c, 1H), 4.40 (d, 2H), 3.89 (c, 3H), 2.54 (c, 3H). - 50 Stage 4. c (2-(Allyloxy)-4-methoxyphenyl|( 2-methyl-1-(4-methylphenyl)sulfonyl|-6--trifluoromethoxy)-1H-indol-3-yl|methanone xz" (7):

Ta haSOo "M - i | Y se) v- shcha (22)

FO in that so in

Man (1.5 eq.) was added to a solution of compound 6 (8.0 g, 20 mmol) in DMF (200 mL). The mixture is stirred for 25 15 min., then T8CI (1, beq., 5.6 g) is added. After 1 hour, the reaction mixture is poured into ice water and

HF) extract SNoSi". The organic layer is washed with MNACI (2x), MnSOO" and a saturated salt solution, then dried (7 MnSO) and concentrated. Purification by flash chromatography eluting with a mixture of 2095 EAs/hexane gives the product as a viscous yellow oil. in "H-NMR (B5O0MHCz, SOSI): δ 8.17 (s, 1H), 7.75 (d, 2H), 7.58 (d, 1H), 7.29 (d, 2H), 7, 24 (d, 1H), 7.05 (d, 1H), 6.60 (dd, 1H), 6.42 (d, 1H), 5.41 (m, 1H), 4.91 (m, 2H ), 4.20 (d, 2H), 3.89 (s, ЗН), 2.70 (s, ЗН), 2.41 (s, ЗН)

Stage 5. (2-Hydroxy-4-methoxyphenyl)(2-methyl-1-(4-methylphenyl)sulfonyl|-6--trifluoromethoxy)-1H-indole-3-yl|Imethanone (8): b5 chi u. that's what

Diisopropylethylamine (1.eq. , 4.2 ml). Through ЗОхв. the reaction mixture is diluted with OSM and washed with 0.05M

NOSI (Zh), Manso" and saturated salt solution. The organic layer is dried (MA»5O»), then filtered through a loose 7/5 layer of silica gel to remove residual palladium. The product is purified by flash chromatography, eluting with a mixture of 1490 E(OdAc/hexane, which gives the product in the form of an amorphous yellow solid, with an impurity of "1090 allylated dimedone. The product is used without additional purification. "H-NMR (5O00MHz, SOCI): 5 12 .66 (c, 1H), 8.20 (c, 1H), 7.77 (d, 2H), 7.32 (d, 1H), 7.30 (m, ЗН), 7.14 (d, 1H), 6.52 (d, 1H), 6.37 (dd, 1H), 3.89 (s, ЗН), 2.63 (s, ЗН), 2.42 (s, ЗН).

Stage b. (2-Hydroxy-4-methoxyphenyl)(2-methyl-1-(4-methylphenyl)sulfonyl|-6--trifluoromethoxy)-1H-indol-3-yl|Imethanonex im (9):

TK

EzSO From GA school to mon

M u u si niso o

A solution of compound 8 (1 mmol), hydroxylamine hydrochloride (110 eq., 11.2 g) and pyridine (27 0 ml) was heated to x, 802 for 24 hours. An additional amount of hydroxylamine (Zg) is added and the temperature is raised to 90260. He»)

After LC-analysis, confirming the consumption of the starting material, the reaction mixture is cooled and pyridine

Zo is removed on a rotary evaporator. The residue is dissolved in OSM and washed with water and 1M NA. The organic layer is dried over NaCl and concentrated. The reaction mixture is purified by flash chromatography, eluting with a mixture of 2095 EoAs/hexane, Kl-O,4. The product is released in the form of a white foam.

TN-NMR (BOOMHCc, SOSIv): 5 8.15 (s, 1), 7.71 (d, 2H), 7.45 (ush.s, 1H), 7.27 (d, 2H), 7, 09 (m, 2H), 6.56 « 20 (m, 2H), 6.23 (dd, 1H), 3.79 (s, ЗН), 2.47 (s, ЗН), 2.40 (s , ZN). Stage 7. 6-Methoxy-3-(2-methyl-1-((4-methylphenyl)sulfonyl|-6-"-trifluoromethoxy)-1H-indole-3-yl|-1,2-benzisoxazole ( 10): . » t " 8

So M fi y -I and A x (o) (22)

Basic at 50

To a solution of compound 9 (3.8g, 7.immol) and MaOdAs (Eq., 1.8g) in DMF (120ml) add ACOO (Eq., 2ml).

IR) The reaction mixture is heated to 1102C for 4 hours, until the indicated time the starting substance is not detected by LC analysis. The reaction mixture is cooled and diluted with OSM. The solution is washed with MNACI, a saturated solution of salt and ManSO»z, then dried over Ma»5O,; and concentrate. The residue is purified by flash chromatography at 22 elution with a mixture of 2095 E(OAc/hexane. The product is isolated in the form of a white foam.

F! "H-NMR (B5O0MGCz, SOSI): δ 8.23 (s, 1H), 7.77 (d, 2H), 7.48 (d, 1H), 7.36 (d, 1H), 7.28 (d, 2H), 7.15 (d, kyu 1H), 7.09 (d, 1H), 6.94 (dd, 1H), 3.92 (s, ЗН), 2.74 (s, ЗН ), 2.39 (c, ZN).

Stage 8. 6-Methoxy-3-(2-methyl-6-trifluoromethoxy)-1H-indol-3-yl|-1,2-benzisoxazole (11): 60 b5 n

EZSO M food

C c) basic 70 KSO" (Zeq.) and compound 10 (2.5 g, 4.8 mmol) are heated to boiling point under reflux in aqueous methanol for 2 hours, by the indicated time the starting substances are found to be spent. The reaction mixture is concentrated, diluted with E(Ac) and washed with a saturated salt solution. The organic layer is dried over

Ma»zO), and concentrate. The residue is purified by flash chromatography eluting with a mixture of 2095 E(OAc/hexane), which gives the product in the form of a light green solid. "H-NMR (B5O00MHz, SOCI3): 5 8.45 (us.s, 1H), 7, 62 (d, 1H), 7.56 (d, 1H), 7.25 (s, 1H), 7.09 (d, 1H), 7.05 (d, 1H), 6.94 (dd, 1H ), 3.93 (c, ZN), 2.63 (c, ZN).

Stage 9.

Methyl-(2K)-2-(4-chloro-3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-ylmethyl )phenoxy)propanoate (15):

IR)

ЭЗСО гч 5) т шч

More and more

Dream" o t o sch

Osn, v

A mixture of compound 11 (208mg, 0.57mmol), Su2CO3z (Eq., 500mg), compound 14 (1.1eq, 202mg) and DMF (4ml) were combined at rt and stirred for 15 hours. The reaction mixture is diluted with EtOAc and washed with 1M HCl (2x). The organic layer is dried over NaCl5O and concentrated. The residue is purified by flash chromatography eluting with a mixture of 5-1595 EIUAs/hexane. The isolated product is a white foam.

From TN-NMR (BOOMHCc, SOSI): 5 7.71 (d, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 7.11 (m, ЗН), 6.96 (dd, 1H), 6.72 - (dd, 1H), 5.94 (d, 1H), 5.40 (s, 2H), 4.41 (sq., 1H), 3.93 (s, ZN), 3.49 (s, ZN), 2.54 (s, ZN), 1.44 (d, ZN).

Stage 10. (2kK)-2-(4-chloro-3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-trifluoromethoxy)-1H-indole-1- ylImethyl)phenoxy "propanoic acid (16): du P (16) Z c a;"

EzZSO To a solution of compound 15 (312 mg, 0.4 mmol) in aqueous methanol, add 1.0 M Masson's solution (1.5 equiv.) . After 2 hours, TLC data indicate the completion of the reaction. The solution is concentrated and purified by preparative LC (SIV, 100x2Omm v.d., 5μm). The product is isolated as a white amorphous solid. "H-NMR (BOOMHCc, SOS): δ 7.60 (d, 1H), 7.56 (d, 71H), 7.34 (d, 1H), 7.17 (s, 1H), 7.09 (m, 2H), 6.99 (dd, 1H), 6.80 (dd, 1H), 5.61 (d, 1H), 5.41 (dd, 2H, 4.22 (q, 1H), 3.94 (s, ZN), 2.41 (s, ZN), 1.46 (d, ZN). id-4.34 min., (F) 575.1 (MN). ka Stage 11. Methyl- (2K)-2-(4-chloro-3-methylphenoxy)propanoate (13):

OEAO ( 1.2 eq., 1 Zml) according to their The reaction mixture is heated to 5°C room temperature overnight. Then the mixture is filtered through a loose layer of silica gel and concentrated.

The residue is purified by flash chromatography, eluting with a mixture of 10950 E(Ac/hexane), which gives the product in the form of a colorless oil. 1H), 6.63 (dd, 1H), 4.71 (sq., 1H), 3.75 (s, ЗН), 2.31 (s, ЗН), 1.60 (d, ЗН).

Stage 12. Methyl-(2K)-2-3-(bromomethyl)-4-chlorophenoxy|propanoate (14): si -

Pace

To a solution of lactate (15.8 g, bomole) in SSI/ (150 ml) add MV5 (1.Eq., 13.5 g) and AOVM (10 Ωg). The reaction mixture is heated at reflux temperature for 24 hours. The solution is filtered through a loose layer of silica gel and concentrated. The residue is purified by flash chromatography, eluting with mixture 590

EtOAc/hexane to give the product as a white solid. "H-NMR (BO00MHz, SOSIia): 5 7.27 (d, 1H), 6.96 (d, 1H), 6.76 (dd, 1H), 4.74 (q., 1H), 4, 52 (c, 2H), 3.77 (c, ЗН), 1.62 (d, ЗН).

Synthesis of compounds in which EZ stands for phenyl

Below, example 32 presents a method of synthesis of a compound in which KE? means phenyl. This and other compounds, in which VZ means phenyl, are given in Table 4. Other compounds of Table 4 are synthesized using the described methods and techniques and easily available substances. Such synthesis methods and techniques are absolutely obvious to a specialist in the field of organic synthesis.

Example 32 s e r ; ;

HU - Miss M

4-Methoxyphenylacetone (1.12 g) and 3-trifluoromethoxyphenylhydrazine (0.96 g) are dissolved in benzene (20 ml). b

The reaction mixture is heated to 602C for 45 min., cooled to room temperature, dried over anhydrous Ma»5ZO), filtered and concentrated in a vacuum, obtaining phenylhydrazone, which is used - directly without additional purification.

To a solution of hydrazone (2.0 g) obtained as described above in CHCl (100 ml) at room temperature, PCI13z (0.7 bml) is added. The reaction mixture is stirred at room temperature for 24 hours. After cooling to 02C in an ice-water bath, the reaction mixture is neutralized to pH by adding an aqueous solution of Maon. Most of the solvent is removed under vacuum. The residue is partitioned between diethyl ether and water. The organic layer is washed with water and a saturated salt solution, dried over anhydrous Mo5O, filtered and concentrated in vacuo. and, and and b-trifluoromethoxy product A (1.0 g) along with the corresponding isomer of 4-trifluoromethoxyindole B (0.5 g).

Isomer A: TN-nMR (SOCIz, 5B0OMHZ): δ 8.01 (s, broadened, 1H), 7.56 (d, 9U-8.7Hz, 1H), 7.40 (d, U-8.6Hz , 2H), 7.20 (s, 1H), 7.02 (d, 9-8.7Hz, 2H), 6.99 (d, U-8.7Hz, 1H), 3.88 (s, ЗН ), 2.49 (c, ZN). Isomer B: TN-NMR (SOCIz, 5BOOMMHz): δ 8.09 (s, broadened, 1H), 7.31 (d, 9U-8.7Hzc, 2H), 7.26 (d, uU-8, 6Hz, (se) 1H), 7.1 (t, U-8.0Hz, 1H), 6.96 (overlapping signals, ZN), 3.87 (s, ZN), 2.39 (s, ZN). (o) po i sho -k oz 7 her Zh

Ko) still eat kosha I and What With ; To a solution of indole B (1.0 g) and benzyl bromide (1.0 g) in DMF (40 ml) at room temperature, add C8»CO3 (2.0 g). The reaction mixture was stirred for 15 hours, poured into water, extracted with EtOAc (2x). The combined organic layers are washed with water and saturated salt solution, dried over anhydrous Mo950, filtered and concentrated in vacuo. Purification by flash chromatography gives the product of the combination.

Aqueous Maon (1.On, 1Oml) is added to a solution of the complex ester obtained above (1.5g) in MeonH (100ml). The mixture is stirred at room temperature for 5 hours, cooled to 0e2C, acidified with 1.0 N HCl, diluted with water (200 ml), and extracted with EtOAc (2x). The combined organic layers are washed with water and saturated salt solution, dried over anhydrous Mo95O5, filtered and concentrated in vacuo.

The residue is purified by crystallization from a mixture of diethyl ether/hexane, obtaining the product. 7"H-NMR (SOSIZ, 50MHz): 5 7.32 (d, U-8.5Hz, 2), 7.23 (t, 9U-8.0Hz, 1), 7.17 (d, 9- 8.2Hz, 1H), 7.08 (t, u8.0Hz, 1H), 6.96 (dkd, overlapping signals, ZN), 6.78 (d, 9U-8.2GuC, 1H), 6 .66 (d, U-7.6Hz, 1H), 6.58 (s, 1H), 5.34 (s, 2H), 4.53 (t, U-8.2Hz, 1H), 3.87 (s, ЗН), 2.29 (s, ЗН), 1.99 (m, 2Н), 1.06 (t, 9-7 4Hz, ЗН).

Claims (36)

70 Formula of the invention 1. A compound of formula I: Z I She : Shah , or its pharmaceutically acceptable salt, where VK is selected from (a) - X-aryl-y-7 and (5) - X-heteroaryl-y-2, where aryl and heteroaryl are unsubstituted or substituted by 1-3 groups independently selected from A; aryl means phenyl or naphthyl; c heteroaryl means a monocyclic or fused bicyclic aromatic ring structure containing (U 1-4 heteroatoms independently selected from M, O and 5(O); where the monocyclic ring or each ring of the bicyclic ring structure means a 5-6-membered ring ; X is selected from the group that includes the bond, CH", CH(CH"), C(CHNa)" and C3-Cvcycloalkylidene; Y is selected from the group that includes -CH-CH-, -CH(ОНИСН(OH )-, -OSV "B8-, -ZSV B. and -СНоСЕв.; cm and 7 are chosen from -СО-Н and tetrazole; (ze) A is chosen from C..alkyl, C.alkenyl, -OC.alkyl and halogen, where alkyl, alkenyl and -Oalkyl are each optionally substituted with 1-5 halogens; 27, in, in and 8 are each independently selected from the group consisting of H, halogen, C.-Svalalkyl, -OC.- Svalkil, (is) S.-Sralkenyl, -OSo-Svalkenyl, C3-Swecycloalkyl, phenyl and -COOH, where S.-Svalkyl, -OS.-Svalkyl, Co-Svalkenyl, i.e. -0C-Salkylenyl, C3-Seccycloalkyl and phenyl are optionally substituted with 1-5 halogens, and C 3-Seccycloalkyl and phenyl are additionally optionally substituted with 1-3 groups, which are independently selected from C 4-Csalkyl and -OC.- Szalkyl, while the indicated S.i-Szalkyl and -OS.-Szalkyl are optionally substituted with 1-3 halogens; or alternatively, B/ and KZ together can form a C3-Seccycloalkyl group, while " C.Ccycloalkyl group is optionally substituted with 1-3 halogens; - with or alternatively, when В! means -X-phenyl-y-7, Y means -OCE'B8 and B" is selected from the group consisting of H, "» halogen, C.-Salkyl, -OC.i-Salkyl, Sovalkenyl, -OSorvalkenyl, Csescycloalkyl and phenyl, then KZ may, "optionally, mean a 1-2-carbon bridge connected to a phenyl ring in an ortho position relative to U, thus forming a 5- or b-membered heterocyclic ring condensed with a phenyl ring; -I 45 B2 means C-Sulfyl, which is optionally substituted with 1-5 halogens; BZ is selected from the group consisting of) (a) benzisoxazolyl, FU (B) benzisothiazolyl, (c) benzpyrazolyl, o) 70 (a) aryl, Kz (e) -F(xO)aryl, (9) -C(O)heteroaryl, (9) -Oaryl, (n) -Heteroaryl, () -5(O)raryl and (F) () -(O) pheteroaryl, where KZ is optionally substituted with 1-3 substituents independently selected from halogen, C 4 alkyl, -C 4 alkyl, and -5C 4 alkyl, where C 4 alkyl, -C 4 alkyl, and -5C 4 alkyl .alkyl are optionally substituted by 1-5 halogens; each B" is optionally selected from H, halogen, C4-Svalkyl and -OS.-Svalkyl, where C-Svalkyl and -OS.-Sv alkyl is optionally substituted with 1-5 halogens; n is equal to the whole number 0-2 and p is equal to the whole number 1-3. 2. The compound according to claim 1, where EZ is selected from the group consisting of C3-benzisoxazolyl, -O-phenyl and -C(-O)phenyl, where C 65 is optionally substituted with 1-3 substituents independently selected from halogen, - OS 4-Szalkyl and Si-Szalkyl, where indicated -OS.-Szalkyl and S.-Szalkyl are optionally substituted with 1-5 halogens. 3. The compound according to claim 1, where B' means -X-phenyl-/-7, where phenyl is unsubstituted or substituted by 1-3 groups independently selected from A. 4. The compound according to claim 1, where X means connection. 5. The compound according to claim 1, where X means CH". 6. The compound according to claim 1, where U means -OSV'/VU-, B" is selected from the group including H and S.-Szalkyl, and Z means S.-Szalkil, where V 28 are optionally substituted with 1-3 halogens. 7. The compound according to claim 1, where U means -osv'vU8., v is selected from the group including H and S.-Szalkil, and 28 means S.-Szalkil. then 8. Compound according to claim 1, where U means -tolerable., where V? is selected from the group consisting of C..alkyl and -OS. alkyl, which are optionally substituted with 1-3 halogens. 9. The compound according to claim 1, where A is selected from the group consisting of C.-Szalkyl, CEz, -OSN»z, -OSE» and halogen. 10. Compound according to claim 1, where is VE? choose from S. zalkilu and SE. 11. The compound according to claim 1, where VZ means -Щ(50) phenyl, where VZ is optionally substituted by 1-3 substituents independently selected from the group including -ОСН», -ОСЕ». and halogen. 12. Compound according to claim 1, where p is equal to 1. 13. The compound according to claim 1, where 7 means -СО2Н. 14. Compound according to claim 1, where B! means 0-th that ds сх where X is selected from the group that includes the bond, CH», CH(CHNa), C(CH»)» and C3-Svecycloalkylidene; o M is selected from the group that includes -OSV'/B8- and СНСЕ re; 7 is chosen from -СО-Н and tetrazole; A is chosen from the group that includes S.-Szalkyl, SEz, -OSN»z, -OSE» and halogen; 2, 89th VE" are each independently selected from the group consisting of H, halogen, C.4-C alkyl and -OC.4-C alkyl, and BZ c is selected from the group including halogen, C.-C alkyl and -OC. -Szalkyl, where Si-Szalkyl and -OS.-Szalkylv BU, Kb vyivZ so each optionally substituted by 1-3 halogens; d is equal to the whole number 0-3; i-o p is equal to 1; He») B? is selected from CE»z and C41-Salkyl; ych- BZ is selected from the group consisting of (a) 3-benzisoxazolyl, (b) 3-benzisothiazolyl, (c) 3-benzpyrazolyl, « (a) aryl, with c (e ) -F(O)phenyl, .(9-C(O)heteroaryl, "» (9)-"Ophenyl, (n)-Oheteroaryl, ()-8(O)pphenyl and -I ()-5(O )pheteroaryl, where heteroaryl is selected from the group consisting of pyridyl and quinolyl, and n is equal to the whole number 0-2 and He») BZ is optionally substituted with 1-3 groups independently selected from halogen, -OC 4-Salkyl and C .alkyl, where -OS.4-Alkyl and C..alkyl are indicated optionally substituted by 1-5 halogens. 15. The compound according to claim 14, where Kz X is selected from the group that includes the connection and CH"; M is chosen from the group that includes -ОСВ 8. ии -СНоСВ З -; 2 means -СО2Н; A is chosen from the group that includes СН»з, СЕз, -ОСН»з, -ОСЕ. and halogen; o VZ means H; 25 is selected from the group consisting of H, C.i-Szalkyl and -OC.1-Szalkyl, where C-Szalkyl and -OS.-Szalkyl are optionally substituted with 1-3 halogens; B" is selected from the group consisting of H and C-Salkyl; because 28 means C-Salkyl; B? means SNU; BZ is selected from the group including (a) 3-benzisoxazolyl, 65 (B) aryl, (c ) -(O)phenyl, (4) -(-O)pyridyl and (e) -(O)quinolyl, where KZ is optionally substituted by 1-3 groups, which are independently selected from halogen, -OC/-Szalkyl and C. dalalkyl, where the indicated -OS.-Szalkyl and C.4.salkyl are optionally substituted with 1-5 halogens; and d is equal to the whole number 0-3. 16. The compound according to claim 15, where d is 0 or 1 and X and 7 are relative to each other in meta- or parapositions. 17. The compound according to claim 1, where the specified compound has the formula IA, or its pharmaceutically acceptable salt: "; In is selected from the group including -OSB B8- or -СНоСВЕ-; 2 means -SOZN; A is chosen from the group that includes СН»з, СЕз, -ОСН»з, -ОСЕ. and halogen; c 4 equals 0 or 1; Ho) B" is selected from the group that includes C. alkyl, CEz, -"OSN" and -OCE"; p is 0 or 1; БЕ? is selected from the group that includes H and C.-C. S-alkyl is optionally substituted with 1-3 halogens; c 25 is selected from the group consisting of C-S-alkyl and -O-S-alkyl, where C-4-S-alkyl and -O-S-alkyl are optionally substituted with 1-3 halogens ; i. B is selected from the group consisting of H and C4-Salkyl, which is optionally substituted with 1-3 halogens; (se) EZ means C-Salkyl, which is optionally substituted with 1-3 halogens; Fo B? means CH" and EZ are selected from the group consisting of Zo (a) Z-benzisoxazolyl, y-(5)-O-phenyl and (c) -(O)phenyl, where KO is optionally substituted by 1-3 groups, which independently choose from halogen, -OS 4-Szalkyl and " y S. zalkyl, where the indicated -OS.-Szalkyl and S. zalkyl are optionally substituted by 1-5 halogens. - 18. The compound according to claim 17, where X means connection; c U means -ОС"В'ВВ.-; c Ge is selected from the group including СН", СЕз, -ОСН» and -ОСЕ»; B means H and КЕ? means S.-Szalkyl, which is optionally substituted 1-3 halogens. 19. The compound according to claim 18, where the carbon atom C" of the indicated group U has the K stereochemical configuration. - 20. The compound according to claim 18, where the carbon atom C" of the indicated group U has a stereochemical configuration of 5. 21. A compound according to claim 18, where EZ means -C(-O)phenyl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of CI, CH3, CE35, -OSN" and -OSE". Gee) 22. The compound according to claim 17, where X means CH"; оз о У means -ОС"В/В8.; 7 is chosen from the group including СН", СЕз, -ОСН» and -ОСЕ»; и» В means Н and КЕ? means S.-Szalkil, which is optional substituted by 1-3 halogens. 23. The compound according to claim 22, where the carbon atom C" of the indicated group U has the K stereochemical configuration. 24. The compound according to claim 22, where the carbon atom C" of the indicated group U has a stereochemical configuration of 5. 25. The compound according to claim 22, where EZ means -C(-O)phenyl, which is optionally substituted with 1-2 substituents, independently of HF) selected from the group consisting of SI, CH3, CE35, -OSN" and -OSE" . 7 26. The compound according to claim 1, named below, or a pharmaceutically acceptable salt of the specified compound: and 1H-indol-1-ylmethylufenoxy)butanoic acid phenoxy)propanoic acid 6BE 4 (2kK)-2-(4-chloro-3-X12-methyl -3-(phenylthio)-1H-indol-1-yl)methyl)phenoxy)propanoic acid -d41- 12-(3-13-(4-chlorophenoxy)-2-methyl-6-trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)-3-methylbutanoic acid 2-(3-113-(4-chlorophenoxy)-2 -methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 9 7. (25)-2-(3-13-(4-chlorophenyl)thio|-2-methyl-6-"-trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 2-(3-13- (4-Methoxyphenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 2-(3-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethoxy)- 70 1H-indol-1-ylmethyluphenoxy)butanoic acid (25)-2-(3-13-(4-chlorophenoxy)-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|)methyluphenoxy)propanoic acid 11 12-(3-T3-(4-chlorophenoxy)-6b-methoxy-2-methyl-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 12 12-(3-4I3-(4-chlorophenoxy)-6b- Methoxy-2-methyl-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 13 12-(3-13-(4-chlorophenoxy)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy )-Z-methylbutanoic acid 14. |2-(3-413-(4-chlorophenoxy)-6-isopropyl-2-methyl-1H-indol-1-yl)methyluphenoxy)butanoic acid 15 12-(3-13-(4-chlorophenoxy) -6-isopropyl-2-methyl-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 16 (2k)-2-(3-13-(4-methoxyphenoxy)-2-methyl-4--trifluoromethyl)- 1H-indol-1-ylmethyluphenoxy)propanoic acid 17 (25)-2-(3-13-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-ylmethyluphenoxy)propanoic acid c 18 (2k)-2-(3-13-(4-methoxyphenoxy)-2-methyl-6-('trifluoromethyl)-o1H-indol-1-ylmethyluphenoxy)propanoic acid 19 |(25)-2-(3- 13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-ylmethyluphenoxy)propanoic acid 20 (2k)-2-(3-13-(4-chlorophenoxy)-2-methyl- 6-(trifluoromethoxy)-Ha 1H-indol-1-ylmethylufenoxy)propanoic acid 21. 12-(3-13-(4-chlorophenoxy)-2-methyl-4-trifluoromethoxy)-Geo)1H-indol-1-ylmethyluphenoxy)butanoic acid 22 12-(3-13-(4A-chlorophenoxy) -2-methyl-4-trifluoromethoxy)iso)1H-indol-1-ylmethylufenoxy)butanoic acid F 23 12-(3-413-(4-chlorophenoxy)-6-fluoro-2-methyl-1H-indole- 1-yl|methyluphenoxy)butanoic acid in 24 2-(3-13-(4-chlorophenoxy)-6-fluoro-2-methyl-1H-indol-1-yl|methyluphenoxy)butanoic acid 25 2-(3-413 -(4-chlorophenoxy)-4-fluoro-2-methyl-1H-indol-1-yl|methyluphenoxy)butanoic acid « 26 2-(3-13-(4-chlorophenoxy)-4-fluoro-2-methyl- 1H-indol-1-yl|methyluphenoxy)butanoic acid c 27 12-(3-4I3--4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)- p z» 1H-indol-1-ylmethyluphenoxy) butanoic acid k 28 12-(3-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H -Indol-1-yl| methyl)phenoxy)butanoic acid 29 12-(3-413-( 4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H -I -Indol-1-yl|Imethyluphenoxy)butanoic acid 30 2-(3-13-(4-methoxyphenoxy)-2-methyl-4-( trifluoromethyl)-1H (se)-Indol-1-yl|Imethyluphenoxy)butanoic acid ota b 31 12-(3-73-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-Indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid o 50 32 12-(3-13 -(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H -Indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid Ko) 33 12-(3-13-(4-methoxyphenoxy)-2- methyl-6-(trifluoromethyl)-1H-Indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid ZA 2-(3-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-Indole -1-yl|Imethyluphenoxy)-3-methylbutanoic acid 35 I2-(4-chloro-3-113-(4-chlorophenoxy)-2-methyl-6b-(trifluoromethoxy)- HF) 1H-indol-1-ylmethyluphenoxy) -2-methylpropanoic acid 36 |2-(2-chloro-5-113-(4-chlorophenoxy)-2-methyl-6b-(trifluoromethoxy)-ko i ); 1H-indol-1-ylmethylufenoxy)-2-methylbutanoic acid 37 2-(4-chloro-3-1(3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)- bo 1H-indole-1- ylmethyluphenoxy)-2-methylpropanoic acid 38 (25)-2-(2-chloro-5-1І3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid acid 39 (25)-2-(4-chloro-3-1Y3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid 40 |2-( 2-Chloro-5-1Y3-(4-methoxyphenoxy)-2-methyl-6-b5y (trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid 41. 2-(2-chloro-5-113-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl)meth-42-znoxy)-2-methylbutanoic acid 42 |2-(2-fluoro-5-1І3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid 43 І2-(2- fluoro-5-1I3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid 44 2-(2-chloro-5-1(3-(4 -chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 45 2-(2-chloro-5-1(3-(4-chlorophenoxy)-2-methyl-6- (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 70 46 -indol-1-yl|Imethyluphenoxy)propanoic acid At(2k)-2-(2-chloro-5-1H3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-IN-indol-1-yl |Imethyluphenoxy)propanoic acid 48 (2kK)-2-(4-fluoro-3-113-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-IN-indol-1-yl|Imethyluphenoxy)propanoic acid 49 |((25)-2-(4-fluoro-3-113-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid 5O (2kK)- 2-(2-fluoro-5-1H3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl |Imethyluphenoxy)propanoic acid 51 (25)-2-(4-chloro-3-113-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 52 |2 -(4-chloro-3-113-(4-chlorophenoxy)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 53 2-(5-13-(4-chlorophenoxy) )-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|methyl)-2-fluorophenoxy)butanoic acid 54 (25)-2-(3-13-(4-methoxyphenoxy)-2-methyl -6-(se trifluoromethoxy)-1H-indol-1-yl|methyluphenoxy)propanoic acid o 55 2-(3-13-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indole-1 -ylmethyluphenoxy)-2-methylpropanoic acid 56 (2K)-2-(2-chloro-5-13-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid ch 57 |2-(4-chloro-3-13-(4-chlorophenyl)thio|-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyl)phenoxy)-2-co methylpropanoic acid 58 | 2-(4-chloro-3-113-(4-chlorophenyl)thio|-2-methyl-b-(se) (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)pentanoic acid 59 |2-(4-chloro -3-113-(4-chlorophenyl)thio|-2-methyl-6-Me. (trifluoromethoxy)-1H-indol-1-ylmethyl)phenoxy)-3- and -methylbutanoic acid 2-13-I(3-(4-chlorophenoxy)-2-methyl-6b-(trifluoromethoxy)-1H-indole-1 -yl|renoxy)butanoic acid 61 2-13-I(3-(4-chlorophenoxy)-2-methyl-6b-(trifluoromethoxy)- « 1H-indol-1-yl|)phenoxy)butanoic acid 62. (283-2-(3-(3-C4-chlorophenyl)thio|-2-methyl-6- - c (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 63 2-(3-13- (4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)- and . и - 1H-indol-1-ylmethyluphenoxy)butanoic acid 64 2-(3-13-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-ylmethyluphenoxy)butanoic acid 65 |3- (3-13-(4-chlorophenoxy)-2-methyl-6-""trifluoromethoxy)- - 1H-indol-1-ylmethyluphenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid (Te) 2 -(2-chloro-5-1І3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid Ge) 67 |2-(3-13-( 4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-ylmethyluphenoxy)-2-methylpropanoic acid (95) 2-(2-chloro-5-1H3-(4-methoxyphenoxy)-2- methyl-6- He (trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid 2-(2-fluoro-5-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H- Indole-1-yl|Imethyluphenoxy)-3-methylbutanoic acid 70 12-(2-fluoro-5-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|Imethyluphenoxy )-3-(F) methylbutanoic acid ke 71 12-(2-fluoro-5-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid in 72 12-(2-fluoro-5-13-(4-methoxyphenoxy)-2 -methyl-6-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid 73 (25)-2-(3-13-(4-chlorophenyl)thio|-2-methyl-6-"trifluoromethoxy) - 1H-indol-1-ylmethyl)-4-fluorophenoxy)propanoic acid 74. (2k)-2-(3-13-(4-chlorophenyl)thio|-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyl)-4-fluorophenoxy)propanoic acid 6BE 75 (25 )-2-(5-13-(4-chlorophenyl)thio|-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|methyl)-2-fluorophenoxy)propanoic acid 76 (28)-245 -13-CYA chlorophenyl)gioi 2-74 57 l-6-(trifluoromethoxy). 1H-indol-1-yl)methyl)i-2-fluorophenocoylropanoic acid 77 (25)-2-(2-chloro-5-13-(4-chlorophenyl)thio|-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 78 (2k)-2 -(2-chloro-5-13-(4-chlorophenyl)thio|-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 79 2-(3-13-(4-chlorophenoxy) )-2-methyl-6-(trifluoromethyl)-1H-indol-1-ylmethylufenoxy)-3-methylbutanoic acid 2-(3-13-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H- Indole-1-ylmethylufenoxy)-3-methylbutanoic acid 70 81 2-(3-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-ylmethylufenoxy)-2-methylpropanoic acid 82 (2kK)-2-(3-13-(4-chlorophenoxy)-5-iodo-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 83 2-(3-13-( 4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-ylmethyluphenoxy)-2-methylbutanoic acid 84 2-(3-13-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl) )- 1H-indol-1-ylmethyluphenoxy)-2-methylbutanoic acid 85 (2k)-2-(3-13-(4-chlorophenyl)sulfinyl|-2-methyl-5-(trifluoromethoxy)-1H-indole-1 -yl|methyluphenoxy)butanoic acid 2-13-I(3-(4- chlorophenoxy)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl)renoxy)-2-methylpropanoic acid 87 (25)-2-(3-13-(4-chlorophenoxy)-2-methyl- 6-"trifluoromethyl)-1H-indol-1-ylmethyl)-4-fluorophenoxy)propanoic acid 88 (25)-2-(2-chloro-5-1H3-(4-chlorophenoxy)-2-methyl-6- ( trifluoromethyl)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid NT PO sc 1. (25)-2-(3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6- o (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 2. 1(25)-2-(3-13-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid c 3 (2kK)-2-(3-13-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6b-so (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 4 (2k)-2-(3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(Ce) (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propano 5 (25)-2-(3-13-(7-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-ia(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid M (2k)-2-(3-13-(7-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 7. (2k)-2-(2-chloro-5-113-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl |Imethyluphenoxy)propanoic acid « (2k)-2-(4-chloro-3-113-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indole -1-yl|Imethyluphenoxy)propanoic acid - c (283-2-(2-chloro-5-113-(6-methoxy-1,2-benzisoxazol-3-yl)- c 2-methyl-6-(trifluoromethoxy )-1H-indol-1-yl|Imethyluphenoxy)propanoic acid and » 10 |(25)-2-13-I(3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl- 6b-(trifluoromethoxy)-1H-indol-1-yl|renoxy)propanoic acid 11 (2k)-2-13-(3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl- 6- and -1 (trifluoromethoxy)-1H-indol-1-yl|renoxy)butanoic acid 12 (2k)-2-13-(3-(6-methoxy-1,2-benzisoxazol-3-yl)- 2-methyl-6-(se) (trifluoromethoxy)-1H-indol-1-yl|renoxy)propanoic acid 13 ((25)-2-13-I(3-(6-methoxy-1,2-benzisoxazol- 3-yl)-2-methyl-6b-He) (trifluoromethoxy)-1H-indol-1-yl|renoxy)butanoic acid c 50 14 (25)-2-(3-13-(6-methoxy-1, 2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-i lmethyluphenoxy)butanoic acid From 15 (2k)-2-(3-173-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy )butanoic acid 16 (2k)-2-(3-173-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyl)phenoxy )-3-o methylbutanoic acid 17 (25)-2-(4-chloro-3-13-(6b-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6b-ke (trifluoromethoxy)- 1H-indol-1-ylmethyluphenoxy)propanoic acid 18 (25)-2-(2-chloro-5-1I3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6b- 60 ( trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 19 (2kK)-2-(4-chloro-3-1Y3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6 - (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 20 (25)-2-(3-13-(6b-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6- ( trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 6BE 21. (2k)-2-(3-113-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6b- ( trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 22 (25)-2-(4-chloro-3-13-(b-methoxy-1 "DA visoxazol-3-yl)-2-me tyl-6b-(trifluoromethoxy)-1H-indse", ; «l|methylphenoxy)propanoic acid 23 (25)-2-(3-13-(5-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 24 ( 2kK)-2-(3-13-(5-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 25 (2kK) -2-(4-chloro-3-Y3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 26 (25)-2-(4-chloro-3-1H3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl| Imethyluphenoxy)butanoic acid 27 12-(3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)pentanoic acid 28 12 -(3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)pentanoic acid 29 (25)-2-( 3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyl)phenoxy)-3-methylbutanoic acid 30 (2kK)- 2-(2-chloro-5-113-(b-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy )propanoic acid 31 (25)-2-(4-chloro-3-113-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6b-(trifluoromethoxy)-1H-indole-1 -ylmethylufenoxy)butanoic acid 32 (2kK)-2-(4-chloro-3-113-(b-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indole -1-ylmethyluphenoxy)butanoic acid 33 (25)-2-(5-13-(6b-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indole-1 -yl|methyl)-2-fluorophenoxy)propanoic acid with 34 |(28)-2-(5-43-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-He) (trifluoromethoxy)-1H-indol-1-yl|methyl)-2-fluorophenoxy)propanoic acid (25)-2-(3-13-(6b-chloro-1,2-benzisoxazol-3-yl)-2- methyl-6-trifluoromethoxy)-1H-indol-1-yl|methyl)-4-isofluorophenoxy)propanoic acid 36 (2kK)-2-(3-113-(6-chloro-1,2-benzisoxazol-3 -yl)-2-methyl-6b-He)trifluoromethoxy)-1H-indol-1-yl|methyl)-4-fluorophenoxy)propanoic acid (se) 37 (25)-2-(2-fluoro-5-113 -(6-methoxy-1,2-benzisoxazol-3-yl)-F 2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid 35 38 (2kK)-2-(2 -fluoro-5-1(3-(6-methoxy-1,2-ben zisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid 39 |2-(4-chloro-3-113-(b-methoxy-1, 2-benzisoxazol-3-yl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyl)phenoxy)-2-methylpropanoic acid « (25)-2-(4-fluoro-3-1( 3-(6-Methoxy-1,2-benzisoxazol-3-yl)-40 2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl)imithylphenoxy)propanoic acid - p 41. (28)-2 -(4-fluoro-3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-a 2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid p » 42 2-(2-chloro-5-1I3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)pentanoic acid AZ 2-(2-chloro-5-1(3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-yl-1 (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy) )pentanoic acid 44 2-(4-chloro-3-Y(3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(Ce) (trifluoromethoxy)-1H-indol- 1-ylmethylufenoxy)pentanoic acid 45 2-(4-chloro-3-Y(3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-He) (trifluoromethoxy)-1H- indole-1 -ylmethylufenoxy)pentanoic acid c 50 46 2-(4-chloro-3-Y(3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indole -1-ylmethyl)phenoxy)-3-He methylbutanoic acid AT 2-(4-chloro-3-Y(3-(b-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6- ( trifluoromethoxy)-1H-indol-1-ylmethyl)phenoxy)-3-methylbutanoic acid tro HF) 1.(25)-2-(3-13-(4-methoxybenzoyl)-2-methyl-1H-indol-1- 2. 1(25)-2-(3-13-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy) Propanoic acid C 1(25)-2-(3-4II3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 4 (25)-2-(3 -13-(4-methoxybenzoyl)-2-methyl-5-"(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)propanoic acid 5 (2K)-2-(3-13-(4-methoxybenzoyl)-2- methyl-6-trifluoromethoxy)-6E 1H-indol-1-ylmethylufenoxy)propanoic acid (25)-2-413-I3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indole -1-ylphrenoxy)propane di-lota 7 12-(3-13-(4-methoxybenzoyl)-2-methyl- 6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)-2-methylpropanoic acid 2-13-(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|renoxy)-2-methylpropanoic acid 3-(3-13-(4-methoxybenzoyl) -2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|methyliuphenyl)upropanoic acid |2-ethoxy-3-(3-1(3-(4-methoxybenzoyl)-2-methyl-6- ( trifluoromethoxy)-1H-indol-1-yl|methyl)iphenyl)propanoic acid 11. 13-(3-(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid 12 12 -43-(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-70 1H-indol-1-yl|renoxy)-2-methylpropanoic acid 13 12-3-I3-(b-chloropyridine- 3-yl)carbonyl|-2-methyl-b-(trifluoromethoxy)-1H-indol-1-yl|phenoxy)-2-methylpropanoic acid 14 12-43-3-(b-ethoxypyridin-3-yl)carbonyl| -2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylphenoxy)-2-methylpropanoic acid 15 /3-3-(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)- 1H-indol-1-yl|renylpropanoic acid 16 /3-3-(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|phenyl)-2-(2 ,2,2-trifluoroethoxy)propanoic acid 17 12-13-I3-K2-chloropyridin-3-yl)carbonyl|-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|renoxy)-2- methylpropanoic acid 18 |(2-methyl-2-3-(2-methyl-3-((b-methylpyridin-2-yl)carbonyl/|-6-(trifluoromethoxy)-1H-indol-1-yl|renoxy) propanoic acid 19 |(2-methyl-2-3-(2-methyl-3-(quinolin-2-ylcarbonyl)-6-(trifluoromet sy)-1H-indol-1-yl|renoxy)propanoic acid 20 13-3-I3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-c 1H-indol-1-yl|phenyl)- 2-(2,2,2-trifluoroethoxy)propanoic acid o 21. 12-43-I3-(2-chloro-6b-methylisonicotinoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylphenoxy)-2-methylpropanoic acid 22 12-413-IZ-( isoquinolin-1-ylcarbonyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|renoxy)-2-methylpropanoic acid with 23 |((25)-2-(2-chloro-5-41III3 -(4-methoxybenzoyl)-2-methyl-b-so (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 24 (25)-2-(3-13-(4-chlorobenzoyl)-2-methyl- 6-(trifluoromethoxy)-(se) 1H-indol-1-ylmethyl)-4-propylphenoxy)propanoic acid (2k)-2-(3-13-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy) - ia 1H-indol-1-yl)methyl)-4-propylphenoxy)propanoic acid d 1y-4-propyl)pr h- 26 (25)-2-(2-chloro-5-1Y3-(4-chlorobenzoyl) )-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)propanoic acid 21 |(25)-2-42-chloro-5-(3-(4-methoxybenzoyl)-2-methyl-6 - (trifluoromethoxy)-1H-indol-1-yl|renoxy)propanoic acid « 28 (2kK)-2-(2-chloro-5-113-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)- 1H-indol-1-ylmethyl)phenoxy)propanoic acid - c 29 (28)-2-(2-chloro-5-Y3-(4-chlorobe) nzoyl)-2-methyl-b-c (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid p » o ((25)-2-(4-chloro-3-113-(4-methoxybenzoyl)-2 -methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 31 ((25)-2-(4-chloro-3-113-(4-chlorobenzoyl)-2-methyl-6b- -1 (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 32 (2K)-2-42-chloro-5-(3-(4-chlorobenzoyl)-2-methyl-6-(se) (trifluoromethoxy) -1H-indol-1-yl|renoxy)propanoic acid 33 ((25)-2-42-chloro-5-(3-(4-chlorobenzoyl)-2-methyl-6-He) (trifluoromethoxy)-1H- indol-1-yl|renoxy)propanoic acid o 50 34 |(2K)-2-(4-chloro-3-13-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indole-1 -ylmethyluphenoxy)propanoic acid From 35 (2K)-2-(4-chloro-3-113-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 36 ( 25)-2-(3-71-I(3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylylethylphenoxy)propanoic acid 25 37 |((25)-2- (3-1(3-(2,4-dichlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-HF) 1H-indol-1-ylmethyluphenoxy)p propanoic acid 38 ((2K)-2-(3-113-(2,4-dichlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)- ime) 1H-indol-1-ylmethyluphenoxy)propanoic acid 39 |2-ethyl -5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)- 60 1H-indol-1-ylmethyl)-2,3-dihydro-1-benzofuran-2-carboxylic acid 40 5- 13-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|methyl)-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid A1 6- (3-(4-Methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|methyl)-2-methylchroman-2-carboxylic acid 42 (25)-2-13-(3- (4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-65 indol-1-yl|renoxy)propanoic acid AZ (2K)-2-13-(3-(4-chlorobenzoyl)-2-methyl -6b-(trifluoromethoxy)-1H-indol-1-yl)phenoxypropanoic AD 44 6-13-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|methyl)-2-methylchroman-2-carboxylic acid 45 (25)-2-(3- 13-(4-chloro-2-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 9 46 (2kK)-2-(3-13-(4-chloro- 2-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid AT (25)-2-(3-13-(4-chloro-2-methylbenzoyl)-2-methyl -b- (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid AB (2K)-2-(3-13-(4-chloro-2-methylbenzoyl)-2-methyl-b- 70 (trifluoromethoxy)- 1H-indol-1-ylmethyluphenoxy)propanoic acid 49 (3-113-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)(cyclohexyl)acetic acid 50 |2 -(3-4I3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 51 12-(3-4I3-(4-chlorobenzoyl)-2- methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)-4-methylpentanoic acid 52 |2-(3-4I3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H- indol-1-yl|Imethyluphenoxy)pentanoic acid lot 53 |(3-73-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|imimethyluphenoxy)(phenyl)acetic acid 54 |1-(3-1Т3-(4 -chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)cyclobutanecarboxylic acid 55 (2kK)-2-(3-13-(4-chlorobenzoyl)-2-methyl-6- (trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)propanoic acid 56 |2-(3-4I3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl| Imethyluphenoxy)-3-methylbutanoic acid c 57 (25)-2-(3-1Й3-(4-methoxy-2-methylbenzoyl)-2-methyl-b- o (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid acid 58 (2kK)-2-(3-13-(4-methoxy-2-methylbenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 59 /(25)-2 -(3-4І3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-Ha 1H-indol-1-ylmethyluphenoxy)butanoic acid (2k)-2-(3-13-(4-chlorobenzoyl)- 2-methyl-6-(trifluoromethoxy)-Geo)1H-indol-1-ylmethylufenoxy)butanoic acid 61 2-(3-13-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H- ise) indol-1-yl|Imethyluphenoxy) pentanova acid F 62 2-(3-Y13-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)pentanoic acid in 63 (2kK)-2-ethyl-7- 4II3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|methyl)uchroman-2-carboxylic acid 64 |((2K)-7-13-(4-chlorobenzoyl) -2-methyl-6-(trifluoromethoxy)-1H-"indol-1-yl|methyl)-2-ethylchroman-2-carboxylic acid C 65 (2K)-7-(3-(2,4-dichlorobenzoyl) -2-methyl-6b-(trifluoromethoxy)-c 1H-indol-1-ylmethyl)-2-ethylchroman-2-carboxylic acid p (25)-2-ethyl-7-4(3-(4-methoxybenzoyl)- 2-methyl-6-p» (trifluoromethoxy)-1H-indol-1-yl|methyl)uchroman-2-carboxylic acid 67 (25)-7-4(3-(4-chlorobenzoyl)-2-methyl-6b -(trifluoromethoxy)-1H- -1 indol-1-yl|methyl)-2-ethylchroman-2-carboxylic acid (25)-2-(3-C2-methyl-3-(2,4,6-trichlorobenzoyl) -6-(se) (trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)propanoic acid (2k)-2-(3-(2-methyl-3-(2,4,6-trichlorobenzoyl)-6-He) (trifluoromethoxy)-1H-indol-1-yl|methyluphenoxy)propanoic acid o 50 70 (25)-2-43-(2-methyl-3-(quinolin-2-ylcarbonyl)-6- (trifluoro ethoxy)-1H-indol-1-yl|renoxy)propanoic acid From 71 (2k)-2-13-(2-methyl-3-(quinolin-2-ylcarbonyl)-6-"-trifluoromethoxy)-1H-indole -1-yl|renoxy)propanoic acid 72 2-13-I(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|renoxy)butanoic acid 25 78 2- (3-13-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H HF)-Indol-1-yl|Imethyluphenoxy)butanoic acid 74 2-(3-13-(2,4- dichlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-ime)indol-1-yl|methyl)phenoxy)butanoic acid 75 2-(3-13-(2,4-dichlorobenzoyl)-2-methyl- 6b-"(trifluoromethoxy)-1H- 60 indol-1-yl|Imethyluphenoxy)pentanoic acid 76 2-(3-13-(2,4-dichlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H- indole -1-yl|Imethyluphenoxy)pentanoic acid 77 2-13-I(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|renoxy)pentanoic acid 78 2-( 3-13-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H- 65 indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid 79 2-(3-13-(4-chlorobenzoyl)- 2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl)methyluphenoxy)-3-methyl/ . do new acid 2-(4-chloro-3-1(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 81 |2-(2-chloro-5- 113-(4-methoxybenzoyl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)butanoic acid 82 |2-(2-chloro-5-4113-(4-chlorobenzoyl)-2-methyl -6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 83 |2-(4-chloro-3-113-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indole- 1-ylmethylufenoxy)pentanoic acid 84 |2-(2-chloro-5-113-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)- 70 1H-indol-1-ylmethylufenoxy)pentanoic acid 85 |2- (4-chloro-3-113-(4-methoxybenzoyl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 2-(4-chloro-3-1(3-(4 -methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)pentanoic acid 87 |2-(4-chloro-3-113-(2,4-dichlorobenzoyl)-2-methyl-b - trifluoromethoxy)-1H-indol-1-yl|methyluphenoxy)butanoic acid 88 |2-(4-chloro-3-113-(2,4-dichlorobenzoyl)-2-methyl-b-(trifluoromethoxy)-1H-indole -1-ylmethylufenoxy)pentanoic acid (2k)-2 -(3-13-(2-chloro-4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid (25)-2-(3-4III3-(2- chloro-4-methoxybenzoyl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 91 12-43-I3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)- 1H-indol-1-yl|Imethyluphenoxy)-2-methylbutanoic acid 92 12-43-(3-(4-chlorobenzoyl)-2-ethyl-6-trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)- 2-methylbutanoic acid c 93 12-43-I3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-g) indol-1-yl|Imethyluphenoxy)-2-methylpentanoic acid 94 |2-( 2-chloro-5-113-(4-methoxybenzoyl)-2-methyl-b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)-2-methylbutanoic acid 95 |2-(2-chloro-5-113- (4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-Ha indol-1-yl|Imethyluphenoxy)-2-methylbutanoic acid 2-(2-chloro-5-1(3-(4-methoxybenzoyl )-2-methyl-6b-(trifluoromethoxy)-c 1H-indol-1-ylmethylufenoxy)-2-methylpentanoic acid 97 |2-(2-chloro-5-4113-(4-chlorobenzoyl)-2-methyl-6b -(trifluoromethoxy)- ise) 1H-indole-1 -ylmethylufenoxy)-2-methylpentanoic acid F 2-(2-chloro-5-1(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)-2-ethylpentanoic acid acid in 2-(2-chloro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)-2-ethylpentanoic acid 100 2-(2- chloro-5-1(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)-2-ethylbutanoic acid « 101 2-(2-chloro-5-1( 3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)- 1H-indol-1-ylmethylufenoxy)-2-ethylpentanoic acid c 102 2-(3-13-(2,4-dichlorobenzoyl) -2-methyl-6b-"(trifluoromethoxy)-1H-""indol-1-yl|imithyphenoxy)-3,3,33-trifluoropropanoic acid" 103 2-(3-13-(2-chloro-4-methoxybenzoyl) )-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)butanoic acid 104 2-(3-13-(4-chlorobenzoyl)-2-methyl-6b-«(trifluoromethoxy)-1H- - I indol-1-yl|Imethyluphenoxy)-2-methylbutanoic acid 105 2-(3-13-(4-chlorobenzoyl)-2-methyl-6b-«(trifluoromethoxy)-1H-(se)indol-1-yl| Imethyluphenoxy)-2-methylbutanoic acid FO 106 2-(2 -chloro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid OO 20 107 2-(2-chloro-5-1(3 -(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid I» 108 2-(2-fluoro-5-1(3-(4-methoxybenzoyl)-2 -methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)pentanoic acid 109 2-(2-fluoro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H -indol-1-ylmethyluphenoxy)pentanoic acid 110 2-(2-fluoro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)- HF) 1H-indol-1-ylmethyluphenoxy)pentanoic acid acid 111 (4-chlorophenyl)(2-methyl-1-13-(15)-1-(2H-tetrazol-5-yl)ethoxy) ime) : : benzyl)-6-(trifluoromethoxy)-1H-indol- 3-yl|methanone 112 2-(3-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-bo indol-1-yl|methylubenzyl)butanoic acid 113 2-(3-13- (4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-indol-1-yl|methylubenzyl)butanoic acid 114 (3-13-(4-methoxybenzoyl)-2-methyl-6b-"(trifluoromethoxy )-1H-indol-1-yl|methylubenzyl)(methyl)malonov acid 115 3-(3-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-b5 y y y indol-1-yl|ymethyluphenyl)-2-phenylpropanoic acid 116 |3-( 3-13-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyliphenyl)-2-phenylpr-48-oic acid 117 2-(2-fluoro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)-3-methylbutanoic acid 118 2-(5-13 -(4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-indol-1-yl|methyl)-2-fluorophenoxy)-3-methylbutanoic acid 119 2-(2-chloro-5-1( 3-(4-Methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)-3-methylbutanoic acid 120 2-(2-chloro-5-1(3-(4-chlorobenzoyl) -2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)-3-methylbutanoic acid 121 3-(3-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H- 70 indol-1-yl|methyluphenyl)-2-methylpropanoic acid 122. 3-(3-13-(4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-indol-1-yl|imimethyluphenyl)-2-methylpropanoic acid 123 2-(5-13-( 4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-indol-1-yl|methyl)-2-fluorophenoxy)pentanoic acid 124 (25)-2-15-(3-(4-(ethylthio )benzoyl|-2-methyl-b-(trifluoromethoxy)-1H-indol-1-yl|-2-fluorophenoxy)propanoic acid 125 )(2K)-2-(3-13-(4-fluorobenzoyl)-2- methyl-6-"trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 126 (2K)-2-I(3-(2-methyl-6-(trifluoromethoxy)-3-I4-(trifluoromethoxy)benzoyl/| -1H-indol-1-ylmethyluphenoxy|propanoic acid 127 (2K)-3-(3-13-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|methyl)iphenyl )dacrylic acid 128 (25,3K)-3-(3-113-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenyl)-2,3-dihydroxypropanoic acid 129 ( 4-chlorophenyl)(2-methyl-1-13-(1-(2H-tetrazol-5-yl)upropoxy benzyl)-6-(trifluoromethoxy)-1H-indol-3-yl|methanone c 130 (2kK)- 2-(3-13-(4-methoxybenzoyl)-2-methyl-6-trifluoromethoxy)-o1H-indol-1-ylmethylufeno xy)butanoic acid 1381 2-(2-fluoro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 132 2-(2- fluoro-5-1(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-Ha 1H-indol-1-ylmethyluphenoxy)butanoic acid 133 2-(5-13-(4-chlorobenzoyl)-2 -methyl-6b-«(trifluoromethoxy)-1H-c indol-1-yl|methyl)-2-fluorophenoxy)butanoic acid 134 2-(5-13-(4-chlorobenzoyl)-2-methyl-6b-«( trifluoromethoxy)-1H-iso)indol-1-yl|methyl)-2-fluorophenoxy)butanoic acid F 135 2-(3-13-(4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H- Indole-1-yl-methyl-phenoxy)-4,4,4-trifluorobutanoic acid in 136 (2K)-2-(3-13-(4-chlorobenzoyl)-2-ethyl-6-trifluoromethoxy)-1H-indole -1-yl|Imethyluphenoxy)butanoic acid 137 (25)-2-(3-13-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid « 138 2-15-(3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indole-in-1-yl|---fluorophenoxy)-2-methylpropanoic acid c 139 (25 )-2-15-(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-"" and ndol-1-yl|-2-fluorophenoxy)propanoic acid " 140 (2K)-2-15-(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl| -2-fluorophenoxy)propanoic acid 141 2-(3-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H- -I indol-1-yl|Imethyluphenoxy)-2-methylbutanoic acid 142 2 -(3-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-(se)indol-1-yl|Imethyluphenoxy)-2-methylpentanoic acid FO 143 2-(3-13-( 4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl|methyluphenoxy)-3-methylbutanoic acid o 50 144 |2-(3-13-(4-chlorobenzoyl)-2-isopropyl -6--trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid Ko) 145/|2-(3-13-(4-chlorobenzoyl)-2-propyl-6--trifluoromethoxy)-1H - indol-1-yl|Imethyluphenoxy)butanoic acid 146 |2-(3-13-(4-chlorobenzoyl)-2-propyl-6--trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 147 |2-(3-13-(4-chlorobenzoyl)-2-propyl-6--trifluoromethoxy)-1 H- HF) indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid GI 148 |2-(3- 13-(4-chlorobenzoyl)-2-propyl-6-trifluorometh oxy)-1H-indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid 149 2-(3-13-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-bo yl|methyluphenoxy)-3-methylbutanoic acid 150 2-(3-13-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl|methyluphenoxy)-3-methylbutanoic acid 151. 2-(3-13-(4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-indol-1-yl|Imethyl)-4-fluorophenoxy)-4,4,4-trifluorobutanoic acid bo 152. 2-13-(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|-5-fluorophenoxy)-2-methylpropanoic acid 153 (25)-2 -13-I3-(4-chlorobenzoyl)-2-methyl-4U-trifluoromethoxy)-1H-indol-1-yl|-5-fluorophenoxy)propanoic acid 154 (2K)-2-13-(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|-5-fluorophenoxy)propanoic acid 155 2-(16-( 3-(4-chlorobenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-indol-1-yl|Ipyridin-2-yloxy)-2-methylpropanoic acid 156. 2-(3-13-(4-chlorobenzoyl)-2-(methoxymethyl)-6-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 157 2-(3-13-(4-chlorobenzoyl) -2-(chloromethyl)-6-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)butanoic acid 158 2-(3-13-(4-chlorobenzoyl)-2-(hydroxymethyl)-6-("trifluoromethoxy)- 70 1H-indol-1-ylmethylufenoxy)butanoic acid 159 2-(3-12-(bromomethyl)-3-(4-chlorobenzoyl)-6-trifluoromethoxy)- 1H-indol-1-ylmethylufenoxy)butanoic acid 160 2- (3-2-methyl-6-(trifluoromethoxy)-3-(4-trifluoromethoxy)benzoyl|-1H-indol-1-ylylmethyl)phenoxy|butanoic acid 161 2-(3-32-methyl-6-( trifluoromethoxy)-3-(4-trifluoromethoxy)benzoyl|-1H-indol-1-ylylmethyl)phenoxy|butanoic acid 162 |33-methyl-2-(3-((2-methyl-6-(trifluoromethoxy)- 3-I4- (trifluoromethoxy)benzoyl/|-1H-indol-1-ylylmethyl)uphenoxy|butanoic acid 163 |3-methyl-2-(3-((2-methyl-6-(trifluoromethoxy)-3-I4- (trifluoromethoxy)benzoyl/|-1H-indol-1-ylmethyl)uphenoxy|butanoic acid 164 (2K)-2-(3-13-(4-chlorobenzoyl)-2-methyl-1H-indol-1-yl|methyluphenoxy ) propanoic acids and 165 (25)-2-(3-13-(4-chlorobenzoyl)-2-methyl-1H-indol-1-yl|methyluphenoxy)propanoic acid 166 | (2K)-2-(3-13-(4-methoxybenzoyl)-2-methyl-1H-indol-1-yl|methyluphenoxy)propanoic acid c 167 2-(3-13-(4-methoxybenzoyl)-2 -methyl-6b-(trifluoromethoxy)-1H- d) indol-1-yl|methylubenzyl)butanoic acid 168 2-(16-(3-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H- Indole-1-yl|Ipyridin-2-yloxy)-2-methylpropanoic acid 169 (2K)-2-(3-13-(4-chlorobenzoyl)-2-(chloromethyl)-6-Ha (trifluoromethoxy)-1H- Indole-1-ylmethyluphenoxy)butanoic acid 170 (2kK)-2-(3-13-(4-chlorobenzoyl)-2-(fluoromethyl)-6- Geo) (trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 171 2-(3-13-(4-methoxybenzoyl)-2-methyl-6b-«(trifluoromethoxy)-1H- ise)indol-1-yl| methyl)phenyl)sulfinyl|-2-methylpropanoic acid Ф 172 2-((3-І13-(4-methoxybenzoyl)-2-methyl-6b-«(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenyl)sulfonyl| -2-methylpropanoic acid in 178 2-((3-13-(4-methoxybenzoyl)-2-methyl-6b-«(trifluoromethoxy)-1H-indol-1-yl|methyluphenyl)thio|-2-methylpropanoic acid 174 2-((3-13-(4-methoxybenzoyl)-2-methyl-6b-«(trifluoromethoxy)-1H-indol-1-yl|methyluphenyl)thio|propanoic acid « 175 2-((3-І13-( 4-Methoxybenzoyl)-2-methyl-6b-"(trifluoromethoxy)-1H-s-indol-1-yl|methyluphenyl)thio|propanoic acid c 176 (2К)-2-13-(3-(4-methoxybenzoyl) )-2-methyl-6b-(trifluoromethoxy)-"» 1H-indol-1-yl|renoxy)butanoic acid" 177 (2K)-2-13-(3-(4-chlorobenzoyl)-2-methyl-6b -(trifluoromethoxy)-1H-indol-1-yl|renoxy)butanoic acid 178 (2K)-2-43-fluoro-5-(3--4-methoxybenzoyl)-2-methyl-6b--I (trifluoromethoxy) -1H-indol-1-yl|renoxy)propanoic acid 179 (2K)-2-13-(3-(4-chlorobenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-(se) indole-1- yl|-5-fluorophenoxy)butanoic acid FO 180 (25)-2-(2-13-(4-methoxybenzoic acid) 1)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid o 50 181 (2kK)-2-(2-13-(4-methoxybenzoyl)-2-methyl-6-" "'trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid I" 182 2-(2-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy )-2-methylpropanoic acid 183 (2K)-2-(2-13-(4-methoxybenzoyl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 184 (25) -2-(2-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)- ГФ) 1Н-indol-1-ylmethyluphenoxy)butanoic acid GI 185 (25)-2-(4-13-( 4-Methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 186 (2K)-2-(4-73-(4-methoxybenzoyl)-2-methyl-6-« "'trifluoromethoxy)-bo1H-indol-1-ylmethyluphenoxy)propanoic acid 187 2-(4-13-(4-methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy) -2-methylpropanoic acid 188 (2K)-2-(4-73-(4-methoxybenzoyl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)butanoic acid 65 189 2-( 4-1 3-(4-Methoxybenzoyl)-2-methyl-6b-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)-2-methylpropanoic acid 1 (25)-2-(3-3-(4-methoxyphenyl) -2-k:2O71-6-(trifluoromethoxy)-1H-indol-1-ylmethylufenoxy)propanoic acid 2. (2kK)-2-(3-4I3-(4-methoxyphenyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy)propanoic acid 3 12-(3-13-(4 -methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 9 4 12-(3-13-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy) )-1H-indol-1-yl|Imethyluphenoxy)butanoic acid (25)-2-(3-13-(4-methoxyphenyl)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-ylmethyluphenoxy) propanoic acid (2k)-2-(3-13-(4-methoxyphenyl)-2-methyl-4-"-"trifluoromethoxy)-70 1H-indol-1-ylmethyluphenoxy)propanoic acid 7. 12-(3-13-(4-methoxyphenyl)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 2-(3-I13-(4-methoxyphenyl) -2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)butanoic acid 2-(3-I13-(4-methoxyphenyl)-2-methyl-6-"trifluoromethoxy)-1H- 15 indol-1-yl|Imethyluphenoxy)-3-methylbutanoic acid 12-(3-413-(4-methoxyphenyl)-2-methyl-6-("trifluoromethoxy)-1H-indol-1-yl|Imethyluphenoxy)- 3-methylbutanoic acid 11 12-(3-13-(4-methoxyphenyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-indol-1-ylmethyluphenoxy)butanoic acid 12 12-(3-413-(4 -methoxyphenyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid 13 2-(2-chloro-5-1(3-(4-methoxyphenyl)-6- "(trifluoromethoxy)-2-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)butanoic acid 14 (25)-2-(3-13-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl) -1H-indol-1-yl|Imethyluphenoxy)butanoic acid with 15 (25)-2-(3-13-(4-chlorophenyl)-2-methyl-4-(trifluoromethyl)-1H- o indol-1-yl |Imethyluphenoxy)butanoic acid 16 |((25)-2-13-I(3-(4- chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|renoxy)propanoic acid 17 (2k)-2-13-I(3-(4-chlorophenyl)-2-methyl-6 -(trifluoromethoxy)-1H-Ga indol-1-yl|renoxy)propanoic acid 18 12-(3-4I3-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl)-1H-indol-1-s yl|methyluphenoxy)butanoic acid 19 12-(3-4І3-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl)-1H-indol-1- ise) yl|methyluphenoxy)butanoic acid Ф 20 12-(3 -413-(4-chlorophenyl)-2-methyl-6-trifluoromethoxy)-1H-indol-1-yl|methyluphenoxy)butanoic acid in 21 12-(3-4I3-(4-chlorophenyl)-2-methyl -6-(trifluoromethyl)-1H-indol-1-yl|methyluphenoxy)-2-methylpropanoic acid 22 12-(3-13-(4-chlorophenyl)-2-methyl-6-«"«trifluoromethoxy)-1 H -indol-1-yl|methyluphenoxy)-2-methylpropanoic acid « 23 12-43-I3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|renoxy )butanoic acid c 24 |2-43-I3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indole-1-pyl|renoxy)butanoic acid and 27. The compound according to claim 1, which is (2K)-2-(3-I3--4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl|phenoxy)butanoic acid with / Eh GO . (22) apartment block 50. In EzSO sya eV iz schi y o -zhk o X Its mass 60 or its pharmaceutically acceptable salt. 28. The compound according to claim 1, which is 2-(16-I(3-(4-methoxybenzoyl)-2-methyl-6-"-"trifluoromethoxy)-1H-indol-1-yl|pyridin-2-yl )ioxy)-2-methylpropanoic acid b5 o Gu on zu gzSO ! ssh M OA about 75 months or its pharmaceutically acceptable salt. 29. The compound according to claim 1, which is (2kK)-2-13-I(3-(4-chlorobenzoyl)-2-methyl-6-"(trifluoromethoxy)-1H-indol-1-yl| methyl|phenoxy ) butyric acid WITH. at. with TM o gzso shk o y Y vl ie 3o or its pharmaceutically acceptable salt. co 30. The compound according to claim 1, which is c (2kK)-2-(4-chloro-3-13-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-trifluoromethoxy )-1H-indol-1-ylmethyl)phenoxy)propanoic acid (He)SI; - ES kK and not « and SHISHE about with s hron. t pan p M y x pp- sh -I -OosNn, Ge) or its pharmaceutically acceptable salt. 31. A pharmaceutical composition containing a compound according to claim 1 or its pharmaceutically acceptable salt and Me, a pharmaceutically acceptable carrier. 2) 20 32. A method of treating type 2 diabetes in a mammal in need of it, comprising administering to the mammal a therapeutically effective amount of the compound according to claim 1. g" 33. The method according to claim 32, which includes co-administering to the mammal one or more additional anti-diabetic compounds selected from the group consisting of metformin, sulfonylurea, insulin, and an OR-IM inhibitor. 34. The method of claim 32, comprising co-administering to the mammal a therapeutically effective amount of a statin selected from the group consisting of simvastatin, lovastatin, rosuvastatin, atorvastatin, fluvastatin, itavastatin, rivastatin and 20-4522. F) 35. Use of the compound according to claim 1 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment of type 2 diabetes. 36. A pharmaceutical composition containing a compound according to claim 27 or its pharmaceutically acceptable salt and 60 a pharmaceutically acceptable carrier. b5