UA82876C2 - Hydroxamates, pharmaceutical composition and method for cancer treatment - Google Patents

Abstract

The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

Description

Description of the invention

This invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These 2 compounds are also histone deacetylase inhibitors and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and methods of their preparation are also disclosed.

Hepatitis C.

Chronic hepatitis C is a slowly progressive disease that has a significant impact on morbidity and mortality. Although many patients infected with hepatitis C virus may develop subclinical or mild disease, at least 8,095 people infected with hepatitis C virus develop chronic infection and hepatitis. The number of people who eventually develop cirrhosis ranges from 20 to 5,095, and liver cancer develops in 1-295 cases (Nooipadie, 9. N.; 1997; NeraiioiIodu 26: 155-205). There are 170 million NSM carriers worldwide, and end-stage liver disease, 72 caused by NSM, is now the leading cause of liver transplantation. In the United States alone, hepatitis C kills 8,000 to 10,000 people each year.

Currently, interferon-a2B/ribavirin combination therapy is the only available treatment. Long-term viral response to interferon-a2b-ribavirin combination therapy is noted in 40-4595 of those to whom this therapy was applied. For those patients who have had an unfavorable response to interferon-α2p/ribavirin combination therapy, there is currently nothing else to prevent progression of liver disease

Thus, there is a need to develop an alternative therapy for the treatment of chronic NSU infection. The present invention satisfies this need.

Histone deacetylases:

The interest in histone deacetylase enzymes (NAS) as drugs that can be used in the pharmaceutical industry lies in their ability to regulate genes that control the sequence of the cell cycle and the occurrence and development of cancer (a review was made by Kgateg. AI. 2001. Ttepaz Epadosgipoi!

Magyar. 12:294-300). A number of studies have shown that the use of various cell lines with NOAS inhibitors leads to hyperacetylation of histone proteins and termination of the cell cycle at the end (from the phase or during

C2/M transitions. Genes involved in the cell cycle that have been shown to be significantly regulated by NSAIDs include p21, p27, p53, and cyclin E. Cyclin A and cyclin 20 have been found to be up-regulated by NSAIDs to a lesser extent. Several studies have shown that in tumor cell lines of application

NOAS inhibitors can lead to growth inhibition, growth arrest, terminal differentiation of cells and/or apoptosis. IP mimo studies have shown inhibition of tumor growth and reduction of tumor metastases, which occur as a result of the use of NOAS inhibitors. 3o There is an extremely clear connection between abnormal NOAS activity and cases of cancer in acute promyelocytic leukemia. In this case, chromosomal translocations lead to the fusion of the retinoic acid receptor KAKo with proteins of promyelocytic leukemia (PMI) or zinc-binding proteins of promyelocytic leukemia (PI 7E). Both RMI-KAKo, , and RI 7E-KAKo contribute to the progression of leukemia by "repressing genes that regulate the synthesis of retinoic acid due to abnormal recruitment of the 70 ZMKT-t5ip3-NOAS complex |Sip ei. AI., 1998, Maishge 391:811-814; Ogidpapi ei aiI., 1998, Maishge 391:815-818). While the RMI-KAKo form of the disease is treated with retinoic acid, the RI 7E-KAKo form is resistant to this method of treatment. For patients with a form of the disease resistant to retinoic acid, the addition of sodium butyrate of the NOAS inhibitor to the dosing regimen leads to complete clinical and cytogenetic remission (MMaggei et al.,, 1998, ..Main.Sapseg.Ipei. 90:1621-1625). Histone deacetylase enzymes are also associated with Huntington's disease.

КкЗз Based on this, it can be concluded that an increase in the activity of ASAP contributes to the emergence of pathology and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of NOAS are useful as therapeutic agents in the treatment of such diseases. -| In the first embodiment, this invention provides a compound according to formula (1):

Аг СОоМНо--жх AS TM zle NN schi in which: ' ko

Whew! is hydrogen or alkyl; because X is -O-, -МВ2-, or -5(О) g, where n represents 0-2 and ВК? - hydrogen or alkyl;

M represents alkylene, optionally substituted by cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;

Ah! is phenylene or heteroarylene, where the indicated Ag! optionally substituted by one or two groups independently selected from alkyl, halo, hydroxy, aluoxy, haloalkyl, or haloalkyl;

3 is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and Ag 2 is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocyclopoalkyl, or heterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof.

In a second embodiment, this invention is directed to obtaining a pharmaceutical composition that includes a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In the third embodiment, this invention is aimed at developing a method of treating a disease caused by

NSAIDs, in an animal, which includes administering to the animal a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Preferably, the disease is a proliferative disorder such as cancer and bipolar disorder, and the animal is a human. Preferably, the cancer is prostate cancer, breast cancer, lung melanoma, gastric cancer, neuroblastoma, rectal cancer, pancreatic cancer, ovarian cancer, T-cell lymphoma, or leukemia, such as myelogenous leukemia (ML) and acute myelogenous leukemia ( GML).

In a fourth embodiment, this invention is directed to the development of a method of treating cancer in animals, which includes administering to the animal a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and, optionally optionally, in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an inhibitor

NMO-CoA reductase, HIV protease inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, or DNA methyltransferase inhibitor.

Applicants have also discovered that the compounds of the present invention are useful in the treatment of hepatitis

C. Accordingly, in the fifth embodiment, this invention is directed to the development of a method of treating hepatitis C in the urine of an animal, which includes administering to the animal a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable o an excipient, optionally in combination with one or more hepatitis C treatment agents.

Predominantly, substances for the treatment of hepatitis C are interferon-a2b, ribavirin and psu-polymerase inhibitors.

In the sixth embodiment, the invention is directed to intermediate compounds according to Formula (11): "se o yt- o "0 so du--somna-zh-x (А ok сч со (1 where BO is hydrogen or alkyl and Ag", Ag . In the seventh embodiment, this invention is aimed at developing a method of preparing a compound according to the Formula "z" (I), which includes: (iii) the interaction of a compound according to the Formula (PP): what at (42) where KE?! is a hydroxy, alkoxy, halo or succinimido ester with hydroxylamine according to the formula МНоОВ", where EC" is a hydrogen, alkyl or oxygen protecting group; or (its) purification of the compound according to the Formula (IM): at;

Ф) у Аг сОМАЗ-у-х-(му том - where M" is an alkali metal with an acid; after which there is treatment with the help of MNOOV", where B" is hydrogen, alkyl, or an oxygen protecting group; as a result, a compound is obtained according to Formula (M): b5

(at:

Ah - SOMA? U-X (mu U mNOv"

SHI

70 (ii) optional displacement of the K" group in compound (M) in order to obtain a compound of Formula (I) where B! is hydrogen; (im) optional formation of an acid addition salt of the product formed above at stage ( i), (ii), or (iii); (y) optional formation of the free base of the product formed above in stage (1), (ii), (iii), or (im), or (mi) optional mandatory modification of any of X, M, B 7, 82, 23, Ag and Ag? groups in the product formed above at stage (1), (ii), (ii), (m), or (khm).

In an eighth embodiment, this invention is directed to the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of drugs for the treatment of cancer.

In the ninth embodiment, this invention is directed to the use of compounds of formula (I) or (II) of their pharmaceutically acceptable salts in the production of medicinal preparations for the treatment of hepatitis C.

Definition:

Unless otherwise stated, the following terms are used in the detailed description and in the claims as defined for the purposes of this application and have the following meanings: "Alkyl" means a linear saturated monovalent hydrocarbon radical comprising from one to six carbon atoms, or a branched saturated monovalent hydrocarbon radical comprising from about three to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), etc. "Alkylene" means a linear saturated divalent hydrocarbon radical containing from one to six carbon atoms, or a branched saturated divalent hydrocarbon radical containing from "about three to six carbon atoms, unless otherwise specified, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc. ate "Alkenylene" means a linear divalent hydrocarbon radical comprising from two to six atoms. o carbon, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, which include one or two double bonds, for example, ethenylene, propenylene, 2-propenylene, c butenylene (including all isomeric forms), etc. co "Alkylthio" means a -5Z radical in which K is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), etc. "Alkylsulfinyl" means -5B(O )Z radical in which K is alkyl as defined above, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl (including all isomeric forms), etc. ""Alkylsulfonyl" means -5021k radical in which K is alkyl as defined above , e.g., methylsulfonyl, ethylsulfonyl, etc. "Amino" means -MH»o; or an M-oxide derivative or protected derivatives thereof, e.g., -MH-»O, -MNBos, -MNOBz, is», etc. Preferably , -MH." "Alkylamino" means an -MNK radical in which K is alkyl as defined above; or an M-oxide derivative or protected derivatives thereof, for example, methylamino, ethylamino, n-, iso-propylamino, H-, iso-, tert-, butylamino, (ee) methylamino-M-oxide, -M(BoC)CH3, etc. t "Alkoxy" means an -OK radical in which K is alkyl as defined above, e.g., methoxy, ethoxy , propoxy , or 2-propoxy, n-, iso-, or tert-butoxy, etc. (se) "Alkoxycarbonyl" means a -C(O)OC radical in which K is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, etc. - "Alkoxyalkyl" means a linear monovalent hydrocarbon radical containing from one to six carbon atoms or a branched monovalent hydrocarbon radical containing from three to six carbon atoms substituted by at least one alkoxy group, preferably by one or two alkoxy groups , as defined above, for example, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl, etc. "Alkoxyalkyloxy" means an -OK radical in which K is alkoxyalkyl as defined above, for example, methoxyethoxy, 2-ethoxyethoxy, etc.

F, "Alkoxyalkyloxyalkyl" means a -(alkylene)-K radical in which K is alkoxyalkyloxy as defined above,

For example, methoxyethoxy methyl, 2-ethoxyethoxymethyl, etc. "Aminoalkyl" means a linear monovalent hydrocarbon radical, which includes from one to six carbon atoms, or a branched monovalent hydrocarbon radical, which includes from three to six carbon atoms, substituted by at least one, or preferably two, -MKK, where K - hydrogen, alkyl, or -SOKU, where Ka- alkyl, and B! selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or haloalkyl; or an M-oxide derivative or its protected derivatives. Predominantly, Vi and V are b5 independently selected from hydrogen, alkyl, or -"SOK-", where is KK? is alkyl, or a derivative of M-oxide, or its protected derivative, for example, aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, aminomethyl-M-oxide, etc. "Aminoalkyl" means an -OK radical in which K is aminoalkyl as defined above, for example, 2-aminoethoxy, 2-dimethylaminopropoxy, etc. "Aminocarbonyl" means -"SOMKK radical in which each K is independently hydrogen or alkyl as defined above, for example -СОМН", methylaminocarbonyl, 2-dimethylaminocarbonyl, etc. "Acylamino" means a -MNHCO radical in which K is alkyl as defined above, e.g., acetylamino, propionylamino, etc. 70 "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical comprising from 6 to 12 ring atoms, e.g. , phenyl, naphthyl or anthracenyl. Unless otherwise specified, the aryl ring is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkyl, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkylalkyl, alkoxyalkyloxyalkyl, neoob' optionally substituted /phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkyloxy , optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyl, optionally substituted 2o Heterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyl sy, -alkylene-v(O) 4-K2 (where n is an integer from 0 to 2, and KU is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-MNZO"-B (where B? is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene-MNSO-K U (where KO is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or -(alkylene)p1-SOME 9B2e (where n1 is 0 or 1, KU and Be are independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, sho 3o optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, che optionally substituted heteroaralkyl , or optionally substituted heterocycloalkylalkyl; or B 9 and Be together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl) in which the alkyl chain in the haloalkyl, optionally substituted phenyloxyalkyl li, optionally substituted by He 35 heteroaryloxyalkyl, or aminoalkyl optionally substituted by one or two fluoroderivative compounds. co

Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-yl-methoxy, 2-hydroxyethoxy, 2-(|M, M-dimethylamino)-ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-yl-ethyl, morpholino-4-yl-methyl, M,M-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl. ""Aralkyl" means a -(alkylene-K radical in which K is aryl as defined above. 373 "Aralkenyl" means a -(alkenylene)-K radical in which K is aryl as defined above. c "Cycloalkyl " means a cyclic saturated monovalent hydrocarbon radical containing from three to three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl. Cycloalkyl is optionally substituted with optionally substituted phenyl. "Cycloalkenyl" means cyclic unsaturated a monovalent hydrocarbon radical containing from about three to six carbon atoms, e.g., cyclopropenyl, cyclobutenyl, cyclohexenyl, and the like.

Cycloalkylalkyl" means a -(alkylene)-K radical where K is cycloalkyl as defined above; e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl or cyclohexylmethyl, etc. "Cycloalkyloxy" means a -OC radical where K is cycloalkyl as as defined above, e.g., cyclopropyloxy, cyclohexyloxy, etc. -And "Cycloalkenyloxy" means an -OC radical in which K is cycloalkenyl as defined above, e.g., cyclopropenyloxy, cyclohexenyloxy, etc. and "Dialkylamino" means a -MKK radical , wherein K and K' are independently alkyl as defined above, e.g., dimethylamino, diethylamino, methylpropylamino, methylethylamino, n-, iso-, or tert-butylamino, etc. "Halo" means fluoro-, chloro-, bromo- and iodo-substituted compounds, preferably fluoro- or chloro-substituted compounds. "Haloalkyl" means an alkyl substituted with one or more halogen atoms, preferably from one to five

HF) by halogen atoms, preferably fluorine or chlorine, including also alkyls substituted by various halogens, e.g. - about СНСИ, -СЕз, -СНЕ», -СРоСЕ»з, -СК(СН»)з, etc.

"Haloalkyl" means an -OC radical in which K is haloalkyl as defined above, e.g., -OCE z, in -OSNE", etc. "Haloalkyloxyalkyl" means a -(alkylene)-OC radical in which K is haloalkyl, as defined above, e.g., trifluoromethyloxymethyl, 2,2,2-trifluoroethyloxymethyl, 2-trifluoromethoxyethyl, etc. "Hydroxyalkyl" means a linear monovalent hydrocarbon radical that includes from one to six carbon atoms, or a branched monovalent hydrocarbon radical that includes from three up to six 65 carbon atoms substituted with one or two hydroxy groups, provided, when two hydroxy groups are present, they are not bonded to the same carbon atom Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2 -hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl , 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hyd oxypropyl, preferably, 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl. "Hydroxyalkyloxy" or "hydroxyalkyloxy" means -"OK radical in which K is hydroxyalkyl as defined above. "Hydroxyalkyloxyalkyl" or "hydroxyalkyloxyalkyl" means a -(alkylene)-OC radical in which K is hydroxyalkyl as defined above, for example, hydroxymethyloxymethyl, hydroxyethyloxymethyl, etc. 70 "Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group comprising from 3 to 8 ring atoms, in which one or two ring atoms are heteroatoms selected from M, O, or 5(O), where n is an integer from 0 to 2, and the rest of the ring atoms are C. One or two ring carbon atoms may optionally be replaced by a -CO- group. More specifically, the term "heterocycloalkyl" includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tertahydroquinolinyl. and 7/5 lyomorpholino, and their derivatives (formed when the heterocycloalkyl ring is replaced by the substituent listed below); as well as M-oxide or its protected derivatives. Heterocycloalkyl is optionally connected to aryl. Unless otherwise stated, the heterocycloalkyl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxy, 2o alkyloxyalkyl, neoob optionally substituted phenyl, optionally substituted phenylalkyl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkylalkyl, optionally substituted phenyloxy , optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-z(O)12-K? (in which n is an integer from 0 to 2 and K 2 is alkyl, o haloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl ), -alkylene-MNYAZOa-B g (in which BK 9? is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, (se) optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-MNSO-K 2 (in which part

KW: is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), or -(alkylene)p1-SOME 982 (in which p1 co is 0 or 1, BU and Be are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, FM optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, co optionally substituted heteroaralkyl, or optionally optionally substituted heterocycloalkylalkyl, or B 9 and Be together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl) in which the alkyl chain in haloalkoxyalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl or aminoalkyl is optionally substituted by one or two fluoroderivatives. Preferably, "70 substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, -c 2-(morpholin-4-yl)ethoxy, pyridin-3-yl-methoxy, 2-hydroxyethoxy, 2- (M,M-dimethylamino)ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-yl-methyl, M,M-dimethylaminomethyl, i-propoxymethyl or with phenoxymethyl. "Heterocycloalkylalkyl" means a -(alkylene)-K radical in which K is a heterocycloalkyl ring as defined above, for example, furanylmethyl, piperazinylmethyl, morpholinylethyl, etc. oo "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical comprising from 5 up to 10 ring atoms, wherein one or more, preferably one, two, or three ring atoms, are heteroatoms selected from M, O, or 5, the remaining ring atoms being carbon More specifically, the term heteroaryl includes, but is not limited to , pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, -I benzofuranyl, benzopyranyl and thiazolyl, and their derivatives (which are formed in in that case, if

Fo heterocycloalkyl ring is substituted by the substituents listed above); or M-oxide or its protected derivative. Unless otherwise stated, the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkyl, amino, alkylamino, alkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkylalkyl, hydroxyalkyloxyalkyl, neoob' optionally substituted phenyl, cycloalkyloxy, cycloalkenyloxy, optionally substituted

HF) phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy,

F optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkyloxy, optionally substituted phenylalkyl, optionally substituted phenyloxy, optionally substituted phenylalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-5(O)0-K? (where n is a number from 0 to 2, and KU is alkyl, hydroxyalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or 65 optionally substituted heteroaralkyl), -alkylene- MINVO 5-K? (where BC? - alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -alkylene-МНСО-В У (where KO - alkyl, haloalkyl, hydroxyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), -(alkylene)pi-SOME ZB (where pi is 0 or 1, I is hydrogen or alkyl, and B/ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally necessarily substituted heterocycloalkylalkyl, or VUZ and B!, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl), -alkylene-ME-alkylene-MIXTURE (where KO has the value defined above, and 70 Va ve is independently hydrogen or alkyl), or carbo xyalkylaminoalkyl, in which the alkyl chain in haloalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoro compounds. Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(M,M-dimethylamino )ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N,M-dimethylamino-methyl, i-'propoxymethyl or phenoxymethyl.

If the heteroaryl ring is divalent, it is called a heteroarylene in this invention. "Heteroarylamino" means an MNK radical in which K is heteroaryl as defined above. "Heteroaralkyl" means a -(alkylene)-K radical in which K is heteroaryl as defined above. "Heteroaralkenyl" means a -(alkenylene)-K radical in which K is heteroaryl as defined above. "Methylenedioxy" means -O-СНо-О-.

The present invention also includes prodrugs of compounds of formula (I). The term "prodrugs" is intended to represent covalently bonded carriers that are capable of releasing the active ingredient of Formula (1) upon administration of the prodrug to a mammal. The release of the active ingredient occurs over time. Prodrugs can be prepared using techniques known to anyone skilled in the art. These techniques, as a rule, modify the acceptable sch 29 functional group in this compound. However, these modified functional groups are restored to the original (U functional groups) by known manipulations or ip mimo. Prodrugs of the compounds of Formula (1) include compounds in which the hydroxy, amino, carboxyl or the like groups are modified. Examples of such prodrugs include, but not limited to, esters (e.g., derivatives of acetates, formates, and benzoates), carbamates (e.g., N-dimethylaminocarbonyl) of hydroxy- or amino-functional groups in compounds of Formula (I)), and amides (e.g., trifluoroacetylamino, acetylamino, etc.) etc. Prodrugs of the compounds of Formula (I) are also within the scope of this invention.

The present invention also includes derivatives of M-oxides and protected derivatives of compounds of Formula (I). For example, if the compounds of Formula (I) contain a nitrogen atom capable of oxidation, the nitrogen atom can be converted to an M-oxide using methods well known in the art. If the compounds of Formula (I) contain groups such as hydroxyl, carboxyl, thio, or any other group containing nitrogen atom(s), these groups may be protected by suitable protecting groups. A comprehensive list of acceptable protective groups can be found in T.M. Sgeepe, Rgoiesiime Sgoimrz ip Ogdapis Zupipevziv, dopp UmMieu 4 Bopv, Ips. 1981, which is incorporated herein by reference in its entirety. Protected derivatives of compounds according to Formula (I) can be obtained using methods generally accepted in the field. 70 "Phenylene" means a divalent phenyl radical. o, c "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the main compounds. Such salts include: acidic addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed by organic acids such as 75 acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, so 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, -. 50 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4"-methylene-bis-(3-hydroxy-2-ene-1-carboxylic acid), 0 C-phenylpropionic acid acid, trimethylacetic acid, tert-butylacetic acid, laurylsulphuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; 99 or salts formed when an acidic proton that is present in the original compound, is replaced by an ion

GF! of a metal, e.g., alkali metals, alkaline earth metals, or aluminum ion; or an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, M-methylglucamine, etc. It is understood that the pharmaceutically acceptable salts must be non-toxic. Additional information regarding pharmaceutically acceptable salts can be found in the Code of Pharmaceutical Sciences, 171st Ed., Mask Rybiizpippd Sotrapu, 60 Easiop, RA, 1985, which is incorporated herein by reference.

The compounds of this invention may have asymmetric centers. The compounds of this invention, which include an asymmetrically substituted atom, can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, in particular, by reverse dissolution of materials.

All chiral, diastereomeric, racemic forms are within the scope of this invention, unless special stereochemical 62 properties or isomeric forms are not separately indicated.

Certain compounds of formula (I) may exist as tautomers and/or geometric isomers. All possible tautomers, cis and trans isomers, individually or their mixtures are within the scope of the present invention. Additionally, as used herein, the term alkyl includes all possible isomeric forms of the specified alkyl group, although only a few examples are disclosed herein. In addition, when substituted cyclic groups such as aryl, heteroaryl, heterocycloalkyl, they include all possible positional isomers, although only a few examples are disclosed here. In addition, all polymorphic forms and hydrates of compounds of Formula (I) are within the scope of the present invention. "Optionally substituted phenyl" means a phenyl ring optionally substituted with one, two or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkyl, 7/0 heteroaryl (which is optionally substituted with one or with two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino or dialkylamino), heterocycloalkyl (which is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino , alkylamino or dialkylamino), amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, acylamino, hydroxyalkyl, alkoxycarbonyl, aminoalkyl or carboxy or optionally substituted with five fluorine atoms. "Optionally substituted phenyloxy or phenoxy" means an -OC radical in which K is optionally substituted phenyl as defined above, for example, phenoxy, chlorophenoxy, etc. "Optionally substituted phenylcarbonylamino" means a -MNSOC radical in which K is optionally substituted phenyl as defined above, eg, benzoylamino, etc. "Optionally substituted phenylalkyl" means a -(alkylene)-K radical in which K is optionally substituted phenyl as defined above, for example, benzyl, phenylethyl, etc. "Optionally substituted phenylalkyloxy" means an -OC radical in which K is optionally substituted phenylalkyl as defined above, for example, benzyloxy, phenylethyloxy, etc. "Optionally substituted phenylalkylthio" means a -5-(alkylene)-A radical in which K is optionally substituted phenyl as defined above, e.g. benzylthio, phenylethylthio, etc. "Optionally substituted phenylalkylsulfonyl" means a -50 o-(alkylene)-K radical in which K is (8) optionally substituted phenyl as defined above, for example, benzylsulfonyl, phenylethylsulfonyl, etc. "Optionally substituted phenylalkenyl" means a -(alkenylene)-K radical in which K is optionally substituted as defined above, eg, phenylethenyl, phenylpropenyl, etc. "optionally substituted phenoxyalkyl" means a -(alkylene)-OR radical in which K is optionally substituted phenyl as defined above, eg, phenoxymethyl, phenoxyethyl, etc. - "Optionally substituted heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical with from 5 to 10 ring atoms, of which one or more, preferably one, two, or three atoms in the ring are heteroatoms selected from M, O , or 5, the remaining atoms in the ring are carbon, optionally substituted with

3z5 with ONE, two, or three substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, co-amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optional optionally substituted phenoxy, carboxy, or heteroaryl, which is optionally substituted with alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino, heterocycloalkyl, optionally substituted with one or two substituents independently selected from alkyl, halo, "hydroxy . , independently: with" selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino or dialkylamino. More specifically, the term "optionally substituted heteroaryl" includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, coquinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl and their derivatives (formed if the heteroaryl ring is replaced by the substituent listed above); or M-oxide or its protected derivatives. co "Optionally substituted heteroaryloxy" means an -OC radical in which K is optionally substituted o heteroaryl as defined above, eg, furanyloxy, pyridinyloxy, etc. "Optionally substituted heteroaralkyloxy" means an -OK radical in which K is an optionally substituted -i heteroaralkyl ring, as defined below.

Fo "Optionally substituted heteroaryloxyalkyl" means a -(alkylene)-OK radical in which K is an optionally substituted heteroaryl ring as defined above. "Optionally substituted heteroaralkyl" means a -(alkylene)-K radical in which K is optionally substituted in the Heteroaryl ring as defined above. "Optionally substituted heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group,

HF) which includes from 3 to 8 ring atoms, among which one or two ring atoms are heteroatoms selected from M,

ФО, or 5(0), where n is an integer from 0 to 2, and the rest of the ring atoms are C. One or two carbon atoms in the ring may optionally be replaced by a -CO- group. More specifically, the term "heterocycloalkyl" includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and their derivatives (formed when the heterocycloalkyl ring is substituted with a substituent listed below); or

M-oxide or its protected derivative. Heterocycloalkyl is optionally fused to aryl and optionally substituted with one, two, or three substituents independently selected from alkyl, cycloalkyl, halo, alkoxy, haloalkyl, haloalkyl, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted 65 phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl or carboxy.

"Optionally substituted heterocycloalkyloxy" means an -OK radical in which K is an optionally substituted heterocycloalkyl ring as defined above. "Optionally substituted heterocycloalkylalkyl" means a -(alkylene)-K radical in which K is an optionally substituted heterocycloalkyl ring as defined above. "Optionally substituted heterocycloalkylalkyloxy" means an -OK radical in which K is an optionally substituted heterocycloalkylalkyl ring as defined above. "Optionally substituted heterocycloalkyloxyalkyl" means a -(alkylene)-OR radical in which K is optionally substituted heterocycloalkyl as defined above, eg, piperidinyloxymethyl, pyrrolidinyloxyethyl, etc. "Optionally" or "optionally" means that the event or circumstance described later may or may not have occurred, and that the description includes instances where the event or circumstance does occur as well as instances where it does not.

For example, "heterocycloalkyl optionally mono- or disubstituted alkyl" means that alkyl may be present, but need not be, and the description includes situations in which the heterocycloalkyl /5 group is mono- or disubstituted alkyl, and as well as situations in which the heterocycloalkyl group is not substituted by an alkyl group. "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient which is useful in the manufacture of a pharmaceutical composition and which is generally safe, non-toxic, against which there are no biological or other precautions, and includes a carrier or excipient which is acceptable for

Veterinary use," as well as for human pharmaceutical use. "Pharmaceutically acceptable carrier/excipient" as used in this detailed description and claims includes both one and more than one such excipient. "Treatment" or "course of treatment "disease includes: (1) Prevention of disease, i.e. preventing the development of clinical symptoms of the disease in a mammal for which there is a possibility of contracting or being susceptible to the disease, but it does not yet suffer from the disease and does not show its symptoms; (o) ( 2) Slowing down the progression of the disease, i.e. stopping or reducing the progression of the disease or its clinical symptoms; or (3) Attenuating the disease, i.e. causing the reversal of the disease or its clinical symptoms. The term "cancer therapy" or "cancer treatment" refers to administration of a medicament to a mammal affected by cancer and having the effect of ameliorating the condition caused by the cancer by killing cancer cells, but the term also includes the effect of leads to delayed growth and/or metastases of a cancer tumor. "Therapeutically effective amount" means an amount of a compound of Formula (I) which, when administered to a mammal for the treatment of a disease, is sufficient to effect such treatment of the disease. A "therapeutically effective amount" will vary depending on the compound, disease, severity, age, weight, etc. from the mammal to which the treatment was applied.

Representative compounds of Formula (I) are disclosed below in Tables I-IM.

Compounds according to Formula (I), where B! and EZ are hydrogen, Ag 7 is phenyl, and Ag and M are as defined below in

Tables I: « o - s --E DYU khz» An SOoMmNnA-I S O-- 4 m so shchi so - 2 t on 00000001 ono z von o vav lnyunyu z » 6BE 16 4-tert-butylphenyl -Sno-SNo -

I

I

» cm 7 o

Ф зо щ с ч 7 со их з з с

I»: pirch so with so in fFernafeya 00000000 bNasnya t and z o introduced 00000000 bnasnya yu 5 ommdtetemnontyatenyurnyak 1 snnk bo velychi 11111111 bnasny de 5-1 "cyclopropylpiperidin-4-yloxy)benzof. 4 v-gyl 76 5-(1- cyclopropylpiperidin-4-yloxy)benzofuran-2-yl --К-СнНо-СН(СН 3)-

; 00001 вн

I have spent a long time dreaming of 00000000 2 zvynsnosnyunya 1000111 vyunvmusnh sch 2 eootayefentonoyuo 00000000 vonortyuyuny o 5opeeeteevoyuo 00000000 bonbeidsnh

F

» in so sch » so « i. z s ch v yo so so 7 v o yu v v ools50 Ai methylpiperazin-1-iluphenyl -16- 136 4-(4-hydroxypiperidin-1-yl)phenyl -Сно-СНо-

; yu

I am a high school student

F

» in so sh » so « i, z - « z mm m so i 7

F z o km vo and named as:

M-hydroxy-4-(2-1benzenecarbonylamino-ethoxy)benzamide; b5 M-hydroxy-4-(2-trans-cinnamoylaminoethoxy)benzamide;

M-hydroxy-4-(2-trans-2-phenylcyclopropylcarbonylaminoethoxy)benzamide;

M-hydroxy-4-(2-trans-4-methoxycinnamoylaminoethoxy)benzamide;

H-hydroxy-4-(2-(2-phenylethylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(1H-indol-3-ylmethylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-thiophen-2-ylcarbonylaminoethoxy)benzamide,

M-hydroxy-4-(2-pyridin-3-ylcarbonylaminoethoxy)benzamide;

M-hydroxy-4-(2-biphen-4-lcarbonylaminoethoxy)benzamide;

M-hydroxy-4-(2-biphen-3-ylcarbonylaminoethoxy)benzamide; 70 M-hydroxy-4-(2-(5-phenylthiophen-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(thiophen-2-ylmethylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(naphth-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(quinolin-6-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(4-tert-butylphenylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(trans-5-3-pyridin-3-ylacryloylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(4-pyrrol-1-ylphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-cyclohexene-3-oxyphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(benzthiazol-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(benzoxazol-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(octahydroisoquinolin-2-ylmethylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-pyridin-4-ylpiperazin-1-ylmethylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(furan-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(4-pyridin-3-ylphenylcarbonylamino)ethoxy|Senzamide; c

M-hydroxy-4-(2-(4-pyridin-2-ylphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(benzimidazol-2-ylcarbonylamino)ethoxy|benzamide; (8)

M-hydroxy-4-(2-(1H-pyrrol-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(4-benzoylaminophenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-pyridin-4-ylthiazol-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(2,4-difluorophenylcarbonylamino)ethoxy|benzamide; -

M-hydroxy-4-(2-(3-trans-3,4-methylenedioxyphenylacryloylamino)ethoxy|-benzamide; co

M-hydroxy-4-(2-(3,4-methylenedioxyphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(3,4-dimethoxyphenylcarbonylamino)ethoxy|benzamide, c

M-hydroxy-4-(2-(3,5-dimethoxyphenylcarbonylamino)ethoxy|benzamide; so

M-hydroxy-4-(2-(3,4-difluorophenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(2,5-dimethyl phenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(2,3-dichlorophentcarbontamino)ethoxy|benzamide;

M-hydroxy-4-(2-(2,3-dimethylphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-chloro-2-methoxyphenylcarbonylamino)ethoxy|benzamide; with M-hydroxy-4-(2-(3-ethoxyphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-methoxy-2-methylphenylcarbonylamino)ethoxy|benzamide; ; t M-hydroxy-4-(2-(3-fluoro-4-methoxyphenylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(2-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(3-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy|benzamide; oo M-hydroxy-4-(2-(biphen-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(1H-indol-5-ylcarbonylamino)ethoxy|benzamide; co M-hydroxy-4-(2-(1H-indol-3-ylcarbonylamino)ethoxy|benzamide; o M-hydroxy- 4-(2-(quinolin-3-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(quinolin-8-ylcarbonylamino)ethoxy|benzamide; -I M-hydroxy-4-(2-(1H-indazol-3-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(1H-benzotriazol-5-ylcarbonylamino)ethoxy|benzamide; (42)

M-hydroxy-4-(2-(isoquinolin-1-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(isoquinolin-3-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(quinoxalin-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(naphth-1-ylcarbonylamino)ethoxy|Senzamide;

HF) M-hydroxy-4-(2-(quinolin-2-ylcarbonylamino)ethoxy|benzamide;

F M-hydroxy-4-(2-(2-pyrrol-1-ylphenylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-fluoronaphth-1-ylcarbonylamino)ethoxy|Senzamide; in M-hydroxy-4-(2-(1H-benzimidazol-5-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(1-methylindol-3-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(4-methoxyquinolin-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(3-methoxynaphth-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(2-methoxynaphth-1-ylcarbonylamino)ethoxy|benzamide; 65 M-hydroxy-4-(2-(quinolin-4-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(trans-2-methylcinnamoylamino)ethoxy|benzamide;

M-hydroxy-4-(2--2-M,M-dimethylaminomethylbenzofuran-5-ylcarbonylamino)ethoxy)|-benzamide;

M-hydroxy-4-(2-indolin-1-ylcarbonylaminoethoxy)benzamide;

M-hydroxy-4-(2-(1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-25-|grans-3-(5-hydroxybenzofuran-2-yl)but-2-enoylamino|butoxy)benzamide;

M-Hydroxy-4-25-[butoxy]benzamide;

M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)-4-phenylbutoxy)benzamide;

M-hydroxy-4-42-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino|-ethoxy) benzamide; 70 M-hydroxy-4-4-25-15-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino|-butoxy) benzamide;

M-hydroxy-4-42-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino|-1k-methylethoxy)benzamide

M-hydroxy-4-42-(5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)benzofuran-2-ylcarbonyl-amino|-ethoxy)benzamide;

M-hydroxy-4-12K-(benzofuran-2-ylcarbonylamino)-3-benzylsulfonylpropoxy|Senzamide;

M-hydroxy-4-I(2K-(benzofuran-2-ylcarbonylamino)-3-benzylthiopropoxy|benzamide;

M-hydroxy-4-(2-(trans-3-(5-methoxybenzofuran-2-yl)but-2-enoylcarbonylamino)-ethoxy|Senzamide;

M-hydroxy-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(isoindolin-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(morpholin-4-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-benzylpiperazin-1-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(3(K)-hydroxypyrrolidin-1-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(piperidin-1-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(b-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(2-methylindolin-1-ylcarbonylamino)ethoxy|benzamide; c

M-hydroxy-4-(2-(b-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)-ethoxy)|-benzamide;

M-hydroxy-4-(25-(isoindolin-1-ylcarbonylamino)butoxy|benzamide; (8)

M-hydroxy-4-IZ-"trans-cinnamoylamino)propoxy|benzamide,

M-hydroxy-4-IZ-"trans-4-methoxycinnamoylamino)propoxy|benzamide;

M-hydroxy-4-I3-(4-phenylthiazol-2-ylcarbonylamino)propoxy|benzamide, "with zo M-hydroxy-4-I(25-(trans-cinnamoylamino)propoxy)benzamide;

M-hydroxy-4-I2K-(transo-cinnamoylamino)propoxy)benzamide; -

M-hydroxy-4-I(25-(trans-cinnamoylamino)-4-methylpentoxy|Senzamide; so

M-hydroxy-4-I25-(trans-cinnamoylamino)-3-cyclohexylpropoxy|benzamide;

M-hydroxy-4-I(25-(trans-cinnamoylamino)-3-methylbutoxy|Senzamide; c

M-hydroxy-4-I2K-(transo-cinnamoylamino)-3-phenylpropoxy|Senzamide; co

M-hydroxy-4-I2K-(transo-cinnamoylamino)-3-phenylpropoxy|Senzamide;

M-hydroxy-4-I2K-(trans-cinnamoylamino)-4-methylpentoxy|benzamide;

M-hydroxy-4-I2K5-(trans-cinnamoylamino)-3-methylbutoxy|benzamide;

M-hydroxy-4-(2K5-(transo-cinnamoylamino)hexyloxy|benzamide;

M-hydroxy-4-I2K5-(trans-cinnamoylamino)-3-(4-chlorophenyl)propoxy)benzamide; with c M-hydroxy-4-I(25-(trans-cinnamoylamino)butoxy|benzamide;

M-hydroxy-4-I2K-(/77rans-cinnamoylamino)butoxy|Senzamide; ; t M-hydroxy-4-I(25-(trans-cinnamoylamino)-4-methylthiobutoxy)benzamide;

M-hydroxy-4-I(2K-(transo-cinnamoylamino)-4-methylthiobutoxy|Senzamide;

M-hydroxy-4-I(25-(trans-cinnamoylamino)-2-phenylethoxy|Senzamide; co M-hydroxy-4-I2K-(trans-cinnamoylamino)-2-phenylethoxy|benzamide;

M-hydroxy-4-I(25-(trans-cinnamoylamino)-4-methylsulfonylbutoxy|benzamide; co M-hydroxy-4-I2K-(trans-cinnamoylamino)-4-methylsulfonylbutoxy|benzamide; o M-hydroxy-4- I2K-(transo-cinnamoylamino)-3-benzylsulfonylpropoxy|benzamide;

M-hydroxy-4-(25-(thiophen-2-ylcarbonylamino)butoxy|benzamide; -I M-hydroxy-4-(25-(biphen-4-ylcarbonylamino)butoxy|benzamide;

M-hydroxy-4-I(25-(naphth-2-ylcarbonylamino)butoxy|benzamide; (42)

M-hydroxy-4-I2K-(transo-cinnamoylamino)-3-benzylthiopropoxy|benzamide;

M-hydroxy-4-I(25-(benzenecarbonylamino)butoxy|benzamide; 5B M-hydroxy-4-I(25-(benzylcarbonylamino)butoxy|benzamide;

M-hydroxy-4-I(25-(2-phenylethylcarbonylamino)butoxy|benzamide;

HF) M-hydroxy-4-I(25-(trans-cinnamoylamino)-3-hydroxypropoxy|benzamide;

F M-hydroxy-4-(25-(4-phenylthiazol-2-ylcarbonylamino)butoxy|benzamide,

M-hydroxy-4-(25-(trans-4-methoxycinnamoylamino)butoxy|Senzamide; in M-hydroxy-4-(25-(2-M,M-dimethylaminomethylbenzofuran-5-ylcarbonylamino)butoxy|-benzamide;

M-hydroxy-4-(2-(trans-cinnamoylamino)-1K-methylethoxy|benzamide;

M-hydroxy-4-(2-(trans-cinnamoylamino)-15-methylethoxy)benzamide;

M-hydroxy-4-(2-(4-phenylthiazol-2-ylcarbonylamino)-1k-methylethoxy|benzamide;

M-hydroxy-4-(2-(4-phenylthiazol-2-ylcarbonylamino)-15-methylethoxy|benzamide; 65 M-hydroxy-4-(2-(biphen-4-ylcarbonylamino)-1k-methylethoxy|Senzamide;

M-hydroxy-4-(2-(trans-4-methoxycinnamoylamino)-1k-methylethoxy|bSenzamide;

M-hydroxy-4-42-I4-(2-pyridin-2-ylthiazol-5-yl)uphenylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-(2-(7-chloro-4-methylbenzofuran-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-42-I4-(2-(4-methylpiperazin-1-yl)thiazol-5-yl)phenylcarbonylamino)|-ethoxy)-benzamide;

M-hydroxy-4-42-I4-(2-pyridin-4-ylaminothiazol-5-yl)phenylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-I(4--4-methylpiperazin-1-yl)uphenylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-I4-(4-hydroxypiperidin-1-yl)uphenylcarbonylamino|)ethoxy)benzamide;

M-hydroxy-4-42-I(4--4-morpholin-4-ylmethylthiazol-5-yl)phenylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-(2-(7-fluoro-4-methylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; 70 M-hydroxy-4-42-(7-fluoro-4-(2-methoxyethoxymethyl)benzofuran-2 -ylcarbonylamino)-ethoxy). benzamide;

M-hydroxy-4-(2-(4-hydroxyquinolin-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(7-fluoro-4-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy)|-benzamide;

M-hydroxy-4-42-I(4-(2-(4-methylpiperazin-1-ylmethyl)thiazol-5-yl)uphenylcarbonyl-amino|-ethoxy) benzamide;

M-hydroxy-4-(2-(pyridin-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(3-hydroxypyridin-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(b-hydroxypyridin-2-ylcarbonylamino)ethoxy|Senzamide;

M-hydroxy-4-42-(6-(4-nitrophenoxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-I(4-2-methoxyethoxy)quinoline-2-tricarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-I(4--2-M,M-dimethylaminoethoxy)quinolin-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-(2-(6-bromopyridin-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(5-bromopyridin-3-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(25-(4-methoxyquinolin-2-ylcarbonylamino)butoxy|benzamide;

M-hydroxy-4-(2-(1-methoxynaphth-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(4-methoxyquinolin-2-ylcarbonylamino)-1k-methylethoxy|benzamide; c

M-hydroxy-4-(2-(5-phenylpyridin-3-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-(2-(b-benzyloxypyridin-2-ylcarbonylamino)ethoxy|Senzamide; (8)

M-hydroxy-4-42-I(6-(2-methylpropyloxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-16-(2-phenylethyloxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-I4-(3,3,3-trifluoropropoxy)quinolin-2-ylcarbonylamino|ethoxy)-benzamide; "c zo M-hydroxy-4-425-14-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino|butoxy)-benzamide;

M-hydroxy-4-42-I4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino|-1K-methyl-ethoxy) benzamide; -

M-hydroxy-4-(2-(trans-3-hydroxycinnamoylamino)ethoxy|benzamide; so

M-hydroxy-4-(2-(trans-4-hydroxycinnamoylamino)ethoxy|benzamide;

M-hydroxy-4-42-(3'-(2-hydroxyethyl)biphen-4-ylcarbonylamino|ethoxy)benzamide; with

M-hydroxy-4-42-(3'-(2-hydroxyethyl)biphen-3-ylcarbonylamino|ethoxy)benzamide; co

M-hydroxy-4-12-(2'-(2-hydroxyethyl)biphen-4-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-(2-(trans-2-benzofuran-2-ylacryloylamino)ethoxy|benzamide;

M-hydroxy-4-42-(2'-(2-hydroxyethyl)biphen-3-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-2-|5-(thiophen-3-yl)pyridin-3-ylcarbonylamino|ethoxy)benzamide; "

M-hydroxy-4-42-(6-(4-acetylaminophenoxy)pyridin-2-ylcarbonylamino|ethoxy)-benzamide; with c M-hydroxy-4-42-I(I6-(4-aminophenoxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-(2-(trans-2-methoxycinnamoylamino)ethoxy|benzamide; t M-hydroxy-4-(2-(trans-3-methoxycinnamoylamino)ethoxy|benzamide;

M-hydroxy-4-42-15-(4-dimethylaminophenyl)pyridin-3-ylcarbonylamino|ethoxy)-benzamide;

M-Hydroxy-4-42-(Itrans-3-(5-bromothiophen-2-yl)iacrylotamino|ethoxy)benzamide; co M-hydroxy-4-(2-(trans-3-furan-3-yl acryloylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(trans-3-thiophene-3-ylacryloylamino)ethoxy|benzamide; co M-hydroxy-4-(2-(trans-thiophene-2-ylacryloylamino)ethoxy|benzamide; o M- hydroxy-4-42-(trans-3-methylcinnamoylamino|ethoxy)benzamide;

M-hydroxy-4-22-(trans-4-methylcinnamoylamino|ethoxy)benzamide; - I M-hydroxy-4-42-(trans-3-(benzofuran-2-yl)but-2-enoylamino|ethoxy)benzamide;

Pho M-hydroxy-4-42-(cis-3-(benzofuran-2-yl)but-2-enoylamino|ethoxy)benzamide;

M-hydroxy-4-(2-(trans-4-dimethylaminocinnamoylamino)ethoxy|Senzamide;

M-hydroxy-4-(2-(trans-3-indol-3-ylacryloylamino)ethoxy|Senzamide;

M-hydroxy-4-42-(trans-2-methylcinnamoylamino|ethoxy)benzamide;

M-hydroxy-4-(2-(trans-2-hydroxycinnamoylamino)ethoxy|benzamide;

HF) M-hydroxy-4-42-(Itrans-3-(7-methoxybenzofuran-2-yl)acryloylamino|ethoxy)benzamide;

F M-hydroxy-4-2K-trans-3-(7-methoxybenzofuran-2-yl)acryloylamino|butoxy)benzamide;

M-hydroxy-4--25-|Igrans-3-(5-methoxybenzofuran-2-yl)but-2-enoylamino|butoxy)benzamide; in M-hydroxy-4-(2-(trans-3-furan-2-yl acryloylamino)ethoxy|benzamide; and

M-hydroxy-4-42-I4-(4-(2-morpholin-4-ylethyl)thiazol-2-yl)uphenylcarbonylamino|ethoxy)-benzamide.

Compounds according to Formula (1), where B! there is hydrogen, Ah! is phenyl, and 23, Ag? and M represent the compounds listed below in Table I: b5 v o

And till

AI s-tbom-uno- m

N yu and 5001 snz Prandeniastsni snysnosnya

They are named as: 20 M-hydroxy-4-(2-M-trans-cinnamoyl-M-hydroxyethylaminoethoxy)benzamide;

M-hydroxy-4-(2-M-trans-cinnamoyl-M-phenylaminoethoxy)benzamide;

M-hydroxy-4-(2-M-trans-cinnamoyl-M-methylaminoethoxy)benzamide;

M-hydroxy-4-(2-M-benzothiophen-2-yl-M-isopropylaminoethoxy)benzamide;

M-hydroxy-4-(2-M-trans-cinnamoyl-M-isopropylaminoethoxy)benzamide; and M-hydroxy-4-(3-M-trans-cinnamoyl-M-methylaminopropoxy)benzamide. sia

Compounds according to the Formula (I), where there is hydrogen in its VZ, Ah! is phenyl, Ah? and M represent the compounds listed below in (o)

PI tables: mk o (Se) yayu Vit /- Don F i i tsOomnn-u-o DM in 7 M y N so 7 1 sch 35 so seuyuyet i 1 ih zo 6 100vneasnya z s khz ' 51910000 sbnasnasnya shchi 30000000 yunemusnu yu 80000000 social bonuses » 19000001 compulsory t

F

50000000 yuyunsovnu with about km vovilynuyunuyu zvnn bo voi 00000000 sleep in oo sleep

O|B-methoxy -СНо-СНо-

o» for directing 00000001 bnsnu about 00000000 benyu in Btrdnzteyuyu 00000000 benyu; wolf o volya 100 snysnuy z vomldetmtannyyuyu 000 snsnk yu zo o benyuenyyuyu 00000001 aries oo emorrolnatetyyu 00000000 beonyu trdnzteyuyu 00000000 benyyu in 00000001 wn

I am enjoying 00000000 snysnk byu | zyuyutm 00000000 sleep » in zhevoluchtjem 00000000 onov in bhchdvetmnmtyu 00000000 banyu volume 00000000 bnyu in ote 00000000 snisnu in ootonyueva 00000000 snisnu sch 2 i (o tyuyuyuyat 0000000 temnik o ootonyueva 00000000

F

» I agree with 00000000 snesnostyu 01100000 Snospesn v. o vsnyusnyutyu 00 yaMonosnsnou so 90011 vsnsnmetusnu sch v 19111111 vyunonovolyumtuonu shchi vv o Zafenlemiu 00111111 sNasnya so

ПЕЛНСЯ СН ши со НН сх НН 0 zalroyuironatmetih 0000 snosnh «

I. oo zchopdroyuiropleulsnymetyh 000000 sno z - in ziopdvyustropreulnyuntnetyh 0 onesnh cho z |o ziszhtumanattttttemnoyutyah 000 sno 800 rolo 00010000 oeonk oo rolet 00100000 onov i 80010 ripdrosyumnotrvonimetnlnieth | 00 оон 00 ровых 00001000 боонк ю 9000001 бвуснюниреюютетяу со яв о запопо 0 sнаснх » 5 | zoaozheyusteth snyh t o btoyuyuyuyeteu 00000010 beonyu

Ф по бноюююютеу 00000010 бненю о режюеютююттю 00000000 беоню з 010 іридію 00000000 снесни о явори 0 снсн о то зооюопридинттюетму 0 снснх км то зооифюрекномеиу 1 снснк ро вамдаюрлієеююттях 00000 нов во тво ротик 010000 беонк во бполдятимх 00000000 бнеоню о бпевджтимех 00000000 беоню в зіпркторметнятеридинтнетих 000000 сно в 0,000,000 sneshnh 0,000,000 sneshnh 85 o 3-(4-fluorophenylthiomethyl)- -Сно-СНо-

86 o (and fftorfenyluslusluslusluslhmethylmethyl methylthylthylthylthylthylthylthylthylthylthyl only methythylthylthyl only meth (00000000 00000000 onesn

ПИ СтИ з НН ПОН в (0 омеюкюжтиююттх 0001онеттснх (ве 00 Вометоколетилоюиметил 00000000 (СНаснметлу яв о емдетеннмию 1 снисню аю о Ббмеюсютюю 00000010 онетсни ло 0 (блетапдропіраняіююи 00000000 сНасНх о 5 о Бтетепярранттюи 00000000 снення (103 | (Блетапдропіранятююи 00000000 (СНаснметилу 09 вблатиеютюю 0000 Snone (lo 00 B (opirolidinelletylelet 00000000000000 (o biaprolidintineletum 00000000 it is 7 07 О 00000000000000000000000000000000000000000000000000

M-hydroxy-4-(2-(benzothiophen-2-ylcarbonylamino)ethoxy|-benzamide; so

M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)ethoxy)|-benzamide;

M-hydroxy-4-(2-(1H-indol-2-ylcarbonylamino)ethoxy|-benzamide; se

M-hydroxy-4-(2-(1-methylindol-2-ylcarbonylamino)ethoxy|-benzamide, , , , , , , (se)

M-Hydroxy-4-13-"benzothiophen-2-ylcarbonylamino)propoxy|-benzamide;

M-Hydroxy-4-IZ-"benzofuran-2-ylcarbonylamino)propoxy|-benzamide;

M-hydroxy-4-(25-(benzothiophen-2-ylcarbonylamino)-3-methylbutoxy)|-benzamide;

M-hydroxy-4-(25-(benzothiophen-2-ylcarbonylamino)butoxy|-benzamide; "

M-hydroxy-4-(25-(benzothiophen-2-ylcarbonylamino)-propoxy|-benzamide;

M-hydroxy-4-(2K-(benzothiophen-2-ylcarbonylamino)-propoxy)|-benzamide; c M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)butoxy)|-benzamide; ; c» N-hydroxy-4-(2-(benzothiophen-2-ylcarbonylamino)-1k-methylethoxy)-benzamide;

M-hydroxy-4-(2-(benzothiophen-2-ylcarbonylamino)-15-methylethoxy|-benzamide;

M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)-1k-methylethoxy)-benzamide;

M-hydroxy-4-(2-(b-methoxybenzothiophen-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(5-methylbenzothiophen-2-ylcarbonylamino)ethoxy|-benzamide; io) M-hydroxy-4-(2-(3-chlorobenzothiophen-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(5-methylbenzofuran-2-ylcarbonylamino)ethoxy)|-benzamide; so : : "pam po

M-hydroxy-4-(2-(b-methylbenzofuran-2-ylcarbonylamino)ethoxy)|-benzamide; -j| M-hydroxy-4-(2--«4--fluoromethylbenzothiophen-2-ylcarbonylamino)ethoxy)|-benzamide;

M-hydroxy-4-(2-(5-fluorobenzothiophen-2-ylcarbonylamino)ethoxy)|-benzamide; (42) M-th Com. : 8: : : And we hydroxy-4-(2-(5-methoxybenzothiophen-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(5-chlorobenzofuran-2-ylcarbontamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(7-methoxybenzofuran-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(5-methoxybenzofuran-2-ylcarbonylamino)ethoxy|-benzamide;

HF) M-hydroxy-4-42-(15-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-(15-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; ko M- Я -А.. 4 sh Y - i - i Y Y Sh t hydroxy-4-(2-I5-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; in M-hydroxy-4-(2-(3-methylbenzofuran-2-ylcarbonylamino)ethoxy)|-benzamide;

M-hydroxy-4-(2-(3-methylbenzothiophen-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-42-15-(2-hydroxyethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-(5-(2-M,M-dimethylaminoethoxy)benzofuran-2-ylcarbonylamino)|-ethoxy)-benzamide;

M-hydroxy-4-42-I6-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; 65 M-hydroxy-4-42-I(6-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-(b-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-(2-(3-ethylbenzofuran-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(5-fluoroindol-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-(2-(5-methoxyindol-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-42-3-(methoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-3-phenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-(2-(5,6-dimethoxyindol-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-42-13-"morpholin-4-ylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-I(I3--"M,M-dimethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; 70 M-hydroxy-4-42-IZ-(i-propoxymethyl)benzofuran-2 -ylcarbonylamino|ethoxy) benzamide;

M-hydroxy-4-42-(7-"phenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy) benzamide;

M-hydroxy-4-42-(7-«(«methoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy). benzamide;

M-hydroxy-4-42-(7-«(morpholin-4-ylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-(7-(M,M-dimethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-13-(5-(methyl)benzothiophen-2-ylcarbonylamino|Ipropoxy)-benzamide;

M-hydroxy-4-3-(b-(methoxy)benzothiophen-2-ylcarbonylamino|propoxy)-benzamide;

M-hydroxy-4-13-(7-(methoxymethyl)benzofuran-2-ylcarbonylamino|propoxy)-benzamide;

M-hydroxy-4-13-(7-"phenoxymethyl)benzofuran-2-ylcarbonylamino|propoxy)-benzamide;

M-hydroxy-4-42-(15-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino|-1K-methyl ethoxy) benzamide;

M-hydroxy-4-(2K-benzofuran-2-ylcarbonylamino-3-methylthiopropoxy)benzamide;

M-hydroxy-4-(2k-benzofuran-2-ylcarbonylamino-3-methylsulfonylpropoxy)benzamide;

M-hydroxy-4-42-I(I3--2-phenylethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide;

M-hydroxy-4-42-I3-(M-methyl-M-benzylaminomethyl)benzofuran-2-ylcarbonylamino)-ethoxy) benzamide;

M-hydroxy-4-42-I3-(M-methyl-M-2-phenylethylaminomethyl)benzofuran-2-ylcarbonylamino|-ethoxy) benzamide; with

M-hydroxy-4-42-I3-(3-hydroxypropylthiomethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide;

M-hydroxy-4-42-I3-(3-hydroxypropylsulfinylmethyl)benzofuran-2-ylcarbonylamino|-ethoxy) benzamide; (8)

M-hydroxy-4-42-I3-(3-hydroxypropylsulfonylmethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide;

M-hydroxy-4-42-I3-(M-methyl-M-2-indol-3-ylethylaminomethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide;

M-hydroxy-4-42-I3-(2-(3-trifluoromethylphenyl)ethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide; "with zo M-hydroxy-4-42-I3-(2-(3-trifluoromethoxyphenyl)ethyl)benzofuran-2-ylcarbonylamino|-ethoxy). benzamide;

M-hydroxy-4-42-I3-(M-hydroxyaminocarbonylmethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy) benzamide; -

M-hydroxy-4-42-I3--2-carboxyethylaminomethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide; and co

M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)-LYAK5-phenoxymethylethoxy)-benzamide.

M-hydroxy-4-42-I3-(3-hydroxypropoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; with

M-hydroxy-4-42-I(3--2-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; co

M-hydroxy-4-42-I3-3-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-I(3--4-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-I(3--2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-2-3-(pyridin-4-yloxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; "

M-hydroxy-4-42-(3-(2,4,6-trifluorophenoxymethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide; with c N-hydroxy-4-42-13-(2-oxopyridin-1-ylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-(3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide; with M-hydroxy-4-42-I3-(4-imidazol-1-ylphenoxymethyl)benzofuran-2-ylcarbonylamino|-ethoxy) benzamide;

M-hydroxy-4-42-(3-(4-(1.2.41-triazin-1-ylphenoxymethyl)benzofuran-2-ylcarbonyl-amino|)ethoxy) benzamide;

M-hydroxy-4-42-3-(pyrrolidin-1-methyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; co M-hydroxy-4-42-3-(piperidin-1-methyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-42-I(3--4-trifluoromethylpiperidin-1-methyl)benzofuran-2-ylcarbonylamino|-ethoxy) benzamide; co M-hydroxy-4-42-(3--4-methylpiperazine-1-methyl)benzofuran-2-ylcarbonylamino|-ethoxy)benzamide; o M-hydroxy-4-42-I3-(3,3,3-trifluoropropyloxymethyl)benzofuran-2-ylcarbonylamino|-ethoxy). benzamide;

M-hydroxy-4-(2--4-methylbenzofuran-2-ylcarbonylamino)-ethoxy|benzamide; -I M-hydroxy-4-42-I3--4-fluorophenylthiomethyl)benzofuran-2-ylcarbonylamino)|-ethoxy)-benzamide;

Pho M-hydroxy-4-42-I(I3--4-fluorophenylsulfinylmethyl)benzofuran-2-ylcarbonylamino|-ethoxy)-benzamide;

M-hydroxy-4-42-I(I3--4-fluorophenylsulfonylmethyl)benzofuran-2-ylcarbonylamino)|-ethoxy)-benzamide;

M-hydroxy-4-425-I3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino|-butoxy)benzamide;

M-hydroxy-4-(2-(4-hydroxybenzofuran-2-ylcarbonylamino)ethoxy|-benzamide;

M-hydroxy-4-I(25-(5-chlorobenzofuran-2-ylcarbonylamino)butoxy|Senzamide;

HF) M-hydroxy-4-(2-(5-chlorobenzofuran-2-ylcarbonylamino|-1k-methylethoxy|Senzamide;

F M-hydroxy-4-(2-(4-pyridin-3-ylmethyloxymethylbenzofuran-2-ylcarbonylamino)-ethoxy|benzamide;

M-hydroxy-4-(2-(4-methoxybenzofuran-2-ylcarbonylamino)ethoxy|benzamide; in M-hydroxy-4-42-14--2-methoxyethyloxy)benzofuran-2-ylcarbonylamino)ethoxy)-benzamide;

M-hydroxy-4-(2-(4-pyridin-3-ylmethyloxybenzofuran-2-ylcarbonylamino)-ethoxy|Senzamide,

M-hydroxy-4-(2-(4-methoxyindol-2-ylcarbonylamino)ethoxy|benzamide;

M-hydroxy-4-4-25-|3-(-2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino|-butoxy)benzamide;

M-hydroxy-4-42-(3--2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino|-1k-methyl-ethoxy) benzamide; 65 M-hydroxy-4-42-I3-(M,M-diethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-4-25-|5-(2-methoxyethyloxy)benzofuran-2-ylcarbonylamino)|-butoxy)-benzamide;

M-hydroxy-4-(2-|(5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-425-|5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino|butoxy)-benzamide;

M-hydroxy-4-(2-|(5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino|-1k-methyl-ethoxy) benzamide;

M-hydroxy-4-42-(15-(2,2,2-trifluoroethyloxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-(2-|15-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide;

M-hydroxy-4-425-|5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|butoxy)-benzamide;

M-hydroxy-4-(2-|15-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|-1K-methyl-ethoxy) benzamide;

M-hydroxy-4-42-(5-(piperidin-4-yloxy)benzofuran-2-ylcarbonylamino|ethoxy)-benzamide; 70 M-hydroxy-4-(25-(benzofuran-2-ylcarbonylamino)-4-methylthiobutoxy|benzamide; and

M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)-4-methylsulfonylbutoxy|Senzamide.

Compounds of Formula (I) where B is hydrogen, Ag is isoxazol-5-yl, and Ag- and Y are the compounds shown below in Table 4:

WITH

I m-O in the forest

AND

Tabis IM ii o

F

» - 81 zve 000 sonosnysnu so sch zv rea 000000 sbnesnh so 50000 zbe 0000 neon " y z - :" 5 so sch so - 5 yy 5 o m y 65 and named as:

M-hydroxy-3-(2-(biphen-4-ylcarbonylamino)-1k-methylethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(25-(biphen-4-ylcarbonylamino)butoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(benzofuran-2-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(trans-cinnamoylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-I3-(4-(2-ethoxyphenyl)phenylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-3-(biphen-3-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-3-(biphen-4-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(naphth-2-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(3-methylbiphen-4-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; 70 M-hydroxy-3-(2-(2'-ethoxybiphen-4-ylcarbonylamino)ethoxy|isoxazole- 5-ylcarboxamide;

M-hydroxy-3-3-(3-methylbiphen-4-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-I3-(4-phenylthiazol-2-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-3-(naphth-2-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-3-(naphth-1-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-13-(2-(2-phenylethyl)phenylcarbonylamino|propoxy)isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(naphth-1-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(25-(benzofuran-2-ylcarbonylamino)butoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(25-(biphen-3z-ylcarbonylamino)butoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(benzofuran-2-ylcarbonylamino)-1k-methylethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(biphen-3-ylcarbonylamino)-1k-methylethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(biphen-3-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(biphen-4-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-2-(2-(2-phenylethyl)phenylcarbonylamino|ethoxy)isoxazol-5-ylcarboxamide; with

M-hydroxy-3-(2-(biphen-2-ylcarbonylamino)ethoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-3-(biphen-2-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide; (8)

M-hydroxy-3-(25-(naphth-2-ylcarbonylamino)butoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(25-(naphth-1-ylcarbonylamino)butoxy|isoxazol-5-ylcarboxamide;

M-hydroxy-3-(2-(naphth-2-ylcarbonylamino)-1k-methylethoxy|isoxazol-5-ylcarboxamide; isoxazole-5-ylcarboxamide;

M-hydroxy-3-3-(benzofuran-2-ylcarbonylamino)propoxy|isoxazol-5-ylcarboxamide; -

M-hydroxy-3-3-"trans-cinnamoylamino)propoxy|isoxazole-5-ylcarboxamide; and so

M-hydroxy-3-(2-(3-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy|isoxazol-5-yl-carboxamide.

Despite the fact that the most complete definition of this invention is given in the Formula of the Invention, certain p

Compounds of Formula (I) should be preferred. For example: co

Y. The best group of compounds according to Formula (I) is the one where:

B is hydrogen or alkyl;

X represents -O4 -MA2-, or -(O)u, where n is 0-2, and K2 is hydrogen or alkyl; "

Y is alkylene, optionally substituted by cycloalkyl, optionally substituted by phenyl, alkylthio, alkylsulfonyl, optionally substituted by phenylalkylthio, optionally substituted by phenylalkylsulfonyl, C, or hydroxy; h Ah! - this is phenylene or heteroarylene, where Ag! is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkyl, or haloalkyl; c3 is hydrogen, alkyl, hydroxyalkyl or optionally substituted phenyl; and Ag2 is aryl, aralkyl, aralkenyl,

Heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, or co-heterocycloalkylalkyl; where the terms aryl, heteroaryl, heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and aminoalkyl, alone or as part of another term o (e.g., aralkyl optionally substituted with phenylalkylthio, aminoalkoxy, optionally substituted -1 20 phenylcarbonylamino, optionally substituted heteroaryl, etc.), included above within the limits of the preferred Groups I, have the following meanings: (42) "aryl" means a monovalent monocyclic or bicyclic aromatic a hydrocarbon radical comprising from 6 to 12 ring atoms, e.g., phenyl, naphthyl, or anthracenyl, optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, 22 alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxyalkyl, o alkyloxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, neo optionally substituted phenylcarbonylamino, optionally substituted co-heteroaryloxy, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkyl, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkyl, optionally substituted phenyloxyalkyl, optionally 60 substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-5(0),-K2 (where n is in the range from O to 2, and K2 is alkyl, haloalkyl, neoob optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), -alkylene-MNVO 5-K? (where BK? is alkyl, haloalkyl, because optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl,

optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or -alkylene-MNSO-K U (where KO is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally "optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl) where the alkyl chain in haloalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluoroderivatives. Preferably, the aryl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, optionally substituted phenyl, optionally substituted 70 Pphenylalkyl, optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, optionally substituted 75 heterocycloalkyloxyalkyl, or optionally substituted heterocycloalkyloxy. Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(M,M-dimethylamino )ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, N,M-dimethylaminomethyl, i-propoxymethyl or phenoxymethyl; "heterocycloalkyl" means a saturated monovalent cyclic group comprising from 3 to 8 ring atoms, in which one or two ring atoms are heteroatoms selected from M, O, or 5(O), where n is an integer from 0 to 2, the remaining ring atoms are C. More specifically, the term "heterocycloalkyl" includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and their derivatives (formed when a heterocycloalkyl ring is substituted with a substituent listed below); or M-oxide or its protected derivatives. Heterocycloalkyl is optionally fused to aryl and is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkyl, hydroxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkyloxy, optionally substituted phenyl, optionally i) substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, optionally substituted phenyloxyalkyl, optionally optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkyloxy, or optionally substituted heterocycloalkyloxy. Preferably, the substituents are independently methoxy, methyl, ethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, su 2-(M, M-dimethylamino)ethoxy, methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl,

M,M-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl; "heteroaryl" means a monovalent c mMonocyclic or bicyclic aromatic radical comprising from 5 to 10 ring atoms, and containing one or more, preferably one, two or three ring heteroatoms selected from M, O, or 5, the remaining ring atoms - it is carbon. More specifically, the term "heteroaryl" includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, and their derivatives « 70 (formed when the heteroaryl ring is replaced by the substituent shown below), or M-oxide or its c-protected derivatives. The heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkyl, amino, alkylamino, dialkylamino, and? hydroxy, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxyalkyl, alkoxyalkyloxyalkyl, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted

Go! heteroaralkyloxy, aminoalkyl, aminoalkyloxy, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, haloalkyloxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, where optionally substituted heterocycloalkyloxyalkyl, optionally substituted heterocycloalkylalkyl,

Go! optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkyloxy, -alkylene-5(0),-K2 (where n is from 0 to 2, and KZ? is alkyl, haloalkyl, optionally substituted phenyl, optionally - substituted phenylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl), o -alkylene-MNZO-K? (where ve is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl), or -alkylene-MNSO-KO (where KO is alkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heteroaryl, optionally substituted o heteroaralkyl, or optionally substituted heterocycloalkyl), where the alkyl chain is haloalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or aminoalkyl is optionally substituted with one or two fluorine. Preferably, the substituents are independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, optionally substituted phenyl, optionally substituted heteroaryl, cycloalkyloxy, cycloalkenyloxy, optionally substituted phenylcarbonylamino, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, aminoalkyl, aminoalkyl, alkoxyalkyl, alkoxyalkyloxy, methylenedioxy, optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkyloxyalkyl, optionally substituted heterocycloalkyl, necessarily substituted heterocycloalkylalkyloxy, or optionally substituted heterocycloalkyloxy. Better,

substituents are independently methoxy, methyl, oethyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-(morpholin-4-yl)ethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-(M,M-dimethylamino)ethoxy , methoxymethyl, phenoxymethyl, 2-morpholino-4-ylethyl, morpholino-4-ylmethyl, M,M-dimethylaminomethyl, i-propoxymethyl, or phenoxymethyl; "optionally substituted phenyl" means a phenyl ring optionally substituted with one, two or three substituents independently selected from alkyl, halo, alkoxy, alkylthio, haloalkyl, haloalkoxy, heteroaryl (which is optionally substituted with one or two substituents, independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), heterocycloalkyl (which is optionally substituted with one or 7/0 two substituents independently selected from alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino), amino, alkylamino, dialkylamino, shydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl or carboxy or optionally substituted with five fluorine atoms. Even more preferably, the substituents are independently selected from alkyl, halo, alkoxy, alkylthio, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, methylenedioxy, aminocarbonyl, 7/5-hydroxyalkyl, alkoxycarbonyl, aminoalkyl, or carboxy or neobo necessarily substituted by five fluorine atoms; "optionally substituted heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical comprising from 5 to 10 ring atoms and containing one or more, preferably one, two or three ring heteroatoms selected from M, O, or 5, the remaining ring atoms - carbon, which is optionally substituted by one, two or three substituents independently selected from alkyl, halo, alkoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, aminocarbonyl, hydroxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted phenyl, optionally substituted phenoxy, carboxy, or heteroaryl, which is optionally substituted alkyl, halo, hydroxy, alkoxy, carboxy, amino, alkylamino, or dialkylamino. More specifically, the term "optionally substituted heteroaryl" includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, and thiazolyl, as well as their derivatives (o) (which are formed when the heteroaryl ring is substituted with a substituent listed below), or M-oxide or its protected derivatives; "optionally substituted heterocycloalkyl" is a saturated monovalent cyclic group containing from C to C of 8 ring atoms, of which one or two ring atoms are heteroatoms selected from M, O, or 5(O), where n is an integer from 0 to 2, and the rest of the ring atoms are C. Heterocycloalkyl is optionally fused with aryl and is optionally substituted with one, two or three substituents independently selected from alkyl, halo, alkoxy, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, nitro, optionally substituted phenylalkyl, optionally substituted heteroaralkyl, aminocarbonyl, hydroxyalkyl, C 35 alkoxycarbonyl, aminoalkyl, or carboxy. More specifically, the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino, and derivatives thereof (formed when the heterocycloalkyl ring is substituted with a substituent specified below); or M-oxide or its protected derivatives; and "aminoalkyl" means a linear monovalent hydrocarbon radical containing from two to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms substituted with at least one, preferably one or two, -MEV" , in which В and ВЕ" are independently selected from hydrogen, alkyl, or -СОМК?, where МКУ? is alkyl, and a derivative of M-oxide, or its protected derivatives, e.g., "» aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, etc.; and 45 other terms , which are within the best Group I, are as defined in the "Definitions" paragraph

Go | of this invention

Within this Group I: dk (A) The group of the best compounds, which should be given preference, is formed by those compounds in which K " and BZ are hydrogen, X is (se) -O- and M is ethylene or n-propylene, better is ethylene. -1 20 (B) Another group of the best compounds is formed by compounds in which B and EZ are hydrogen, X represents -O-, and U represents -CH(СНН)СН»-, - СН(И-СзНАСНН "-, or -CH(SNUZ)CH"- and the stereochemistry at the chiral carbon is (5). Even better, 42) if U represents -CH(CoHv)CH". (C) Another group of better compounds are those, in which B and KZ are hydrogen, X is -O-, and M is -CH.CH(СНУ) - and the stereochemistry at the chiral carbon is (K). (Y) Within the group (A)-(C ), the best group of compounds includes compounds in which Ag" is phenylene, in which the hydroxamate and (F) X group are in the para position to each other, and Ag? is aryl. Mostly Ag? is

F is phenyl and is optionally substituted with one or two substituents independently selected from methoxy, ethoxy, phenyl, methyl, tert-butyl, pyrrole-1-yl, cyclohexen-3-oxy, pyridin-3-yl, pyridin-2- yl, benzoylamino, fluoro, chloro, or thiofen-2-ylmethoxy. It is even better if Ag 2 is phenyl, 4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(cyclohexene-3-oxy)phenyl, 4-(pyridine-2- yl)phenyl, 4-(pyridin-3-yl)-phenyl, 2,4-difluorophenyl, 33,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-difluorophenyl, 2,5-dimethylphenyl, 2,3- dichlorophenyl, 2,3-dimethylphenyl, 4-chloro-2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-thiophen-2-ylmethoxyphenyl, / 3-thiophen-2 -ylmethoxyphenyl, 65 2-biphenyl, or 2-pyrrole-1-ylphenyl. (i) Within group (A)-(C), another, even better group of compounds includes compounds in which Ag" is phenylene, in which the hydroxamate and the X group are in the para position to each other, and Ag" is trans aryl-CH-CH-.

Mostly Ag? is trans phenyl-CH-CH- and is optionally substituted alkoxy, preferably methoxy.

Mostly, Ah? is trans phenyl-CH-CH-. (her) Within group (A)-(C) another, even better group of compounds includes compounds in which Ag! is a phenylene in which the hydroxamate and the X group are in the para position to each other, and Ag? is heteroaryl-CH-CH-.

Mostly Ag? is pyridinyl-CH-CH-. Mostly, Ah? is trans 5-bromothiophen-2-yl-CH-CH- or trans indol-3-yl-CHe:CH-, 70 (im) Within group (A)-(C), another, even better group of compounds includes compounds , in which Ag is a phenylene, in which the hydroxamate and the X group are in the para position to each other, and Ag? is heteroaryl. Mostly Ag? is pyridin-3-yl, thiophen-2-yl, quinolin-b-yl, thiazol-2-yl, benzthiazol-2-yl, benzoxazol-2-yl, furanyl, pyrrole-2-yl, indol-5- yl, indol-3-yl, indazol-3-yl, quinolin-3-yl, quinolin-1-yl, quinolin-8-yl, benzotriazol-4-yl, benzofuran-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, or 7/5 benzimidazol-5-yl, wherein said rings are optionally substituted with phenyl, pyridin-4-yl, methyl, methoxy, or dimethylaminomethyl. (y) Within group (A)-(C), another, even better group of compounds includes compounds in which Ag is phenylene, in which the hydroxamate and the X group are in the para position to each other, and Ag? is indol-2-yl, benzofuran-2-yl or benzothiophen-2-yl, which is optionally substituted by alkyl, alkoxy, halo, haloalkyl, alkoxyalkyloxy, optionally substituted heterocycloalkylalkyloxy, optionally substituted heteroaralkyloxy, hydroxyalkyloxy, aminoalkyl, aminoalkyloxy, alkoxyalkyloxy, alkoxyalkyl, optionally substituted phenyloxyalkyl, or optionally substituted heterocycloalkylalkyl. Preferably, Ag 2 is benzofuran-2-yl or benzothiophen-2-yl, wherein the benzofuran-2-yl or benzothiophen-2-yl is optionally substituted with methoxy, methyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2- morpholin-4-ylethoxy, pyridin-3-ylmethoxy, EM 2-phydroxyethoxy, 2-M,M-dimethylaminoethoxy, ethyl, methoxymethyl, 2-propyloxymethyl, phenoxymethyl, o morpholin-4-ylmethyl, or M,M-dimethylaminomethyl, which located in the 3-position or 5-position, preferably in the 3-position, benzothiophen-2-yl or benzofuran-2-yl ring. Even better if Ah? is benzofuran-2-yl, 3-M,M-dimethylaminomethylbenzofuran-2-yl, or 3-phenoxymethylbenzofuran-2-yl. (mi) Within group (A)-(C), another, even better group of compounds includes compounds in which Ag is a phenylene, in which the hydroxamate and the X group are para-substituted to each other, and Ag? is indol-2-yl, benzofuran-2-yl, or benzothiophen-2-yl and is substituted by phenyloxyalkyl, substituted heteroaryloxyalkyl, substituted heterocycloalkyloxyalkyl, or haloalkyloxyalkyl, which are located in the C-position of the rings of benzothiophen-2-yl and with benzofuran- 2-il. Even better if Ah? is 3-(2,2,2-trifluoroethyloxymethyl)benzofuran-2-yl. He (mi) Within group (A)-(C) another, even better group of compounds includes compounds in which Ag! is co heteroarylene and Ag? is aryl. Preferably Ag is a five-membered heteroarylene ring consisting of one, two or three heteroatoms independently selected from M, O or 5, even better Ag! is isoxazolyl, in which the hydroxamate and X groups are in the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the "ring" is in position 1, and Ag? - aryl Mostly Ag? is phenyl which is optionally substituted with one or two substituents independently selected from methoxy, ethoxy, phenyl, optionally substituted ethoxy or /- with methyl, methyl, tert-butyl, pyrrol-1-yl, cyclohexen-3- oxy, pyridin-3-yl, pyridin-2-yl, benzoylamino, "» fluoro, chloro, or thiophen-2-ylmethoxy. Even better, if Ar? is phenyl, 4-biphenyl, 3-biphenyl, " 2- (2-ethoxyphenyl)phenyl, 3-methylbiphen-4-yl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(cyclohexen-3-oxy)phenyl, 4-(pyridin-2-yl)phenyl , 4-(pyridin-3-yl)-phenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 34-difluorophenyl, 2,5-dimethylphenyl, 2,3-dichlorophenyl, 2,3 -dimethylphenyl, 4-chloro-2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-thiophen-2-ylmethoxyphenyl, 3-thiophen-2-ylmethoxyphenyl, 2 -biphenyl, or 2-pyrrole-1-ylphenyl. (my) Within group (A)-(C) another, even better group of compounds includes compounds in which Ag! represents co heteroarylene, and Ag? is aryl-CHNA-CH-. Preferably, Ag is a five-membered ring of heteroarylene, which -I 50 contains one, two or three heteroatoms, which are independently selected from M, O or 5, even better Ag! is isoxazolyl in which the hydroxamate and X groups are located in the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring occupies position 1, and Ag? is phenyl-CH-CH- and is optionally substituted alkoxy. (ih) Within group (A)-(C), another, even better group of compounds includes compounds in which Ag is a heteroarylene, and Ag? is heteroaryl-CH-CH-. Preferably Ag" is a five-membered heteroarylene ring containing one, two or three heteroatoms independently selected from M, O or 5, even better Ag! is isoxazolyl in which the hydroxamate and X groups are located in the 5- and З -positions of the isoxazolyl ring, the oxygen atom in the ring occupies position 1, and Ag is pyridinyl-CH:CH-., (5) Within group (A)-(C) another, even better group of compounds includes compounds in which Ag! is heteroarylene and Ag? is heteroaryl. Preferably Ag! is a five-membered heteroarylene ring containing one, two or three heteroatoms independently selected from M, O or 5, even better Ag! is isoxazolyl, in which the hydroxamate and X groups are located in the 5- and 3-positions of the isoxazolyl ring, the oxygen atom in the ring occupies position 71, and Ag 2 is pyridine-Z-yl, thiophen-2-yl, quinoline-b-yl, thiazol-2-yl, benzthiazol-2-yl, 65 benzoxazol-2-yl, furanyl, pyrrole-2-yl, indol-b-yl, indol-3-yl, indazol-3-yl, quinoline-3-yl , quinolin-8-yl, benzotriazol-4-yl, isoquinolin-1-yl, iso quinolin-Z-yl, quinoxalin-2-yl, quinolin-2-yl, or benzimidazol-b-yl, in which the indicated rings are optionally substituted with phenyl, pyridin-4-yl, methyl, methoxy, or dimethylaminomethyl. (xi) Within group (A)-(C), another, even better group of compounds includes compounds in which Ag! is a heteroarylene, and Ag? is indol-2-yl, benzofuran-2-yl or benzothiophen-2-yl, which are optionally substituted by alkyl, alkoxy, halo, haloalkyl, alkoxyalkyloxy, optionally substituted heterocycloalkylalkyloxy, optionally substituted heteroaralkyloxy, hydroxyalkyloxy, aminoalkyloxy, alkoxyalkyloxy, alkoxyalkyl, optionally substituted phenyloxyalkyl, or optionally substituted heterocycloalkylalkyl. Preferably, Ag" is a five-membered heteroarylene ring containing one, two 70 or three heteroatoms independently selected from M, O or 5, more preferably Ag is isoxazolyl in which the hydroxamate and X groups are located in the 5- and C-positions of the isoxazolyl ring, the oxygen atom in the ring is in the 1 position, and Ar is benzofuran-2-yl and benzothiophen-2-yl, which are optionally substituted with methoxy, methyl, chloro, trifluoromethyl, fluoro, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-33-ylmethoxy, 2-hydroxyethoxy, 2-M,M-dimethylaminoethoxy, ethyl, methoxymethyl, phenoxymethyl, 19 morpholin-4-ylmethyl, or dimethylaminomethyl and located in the C-position of the rings of benzothiophene- 2nd and benzofuran-2-yl. Even better, if Ag is benzofuran-2-yl or 3-phenoxymethylbenzofuran-2-yl. (chii) Within groups (A) and (B) another, better group of compounds , includes compounds in which Ar" is substituted by alkoxyalkyloxy, optionally substituted by heterocycloalkylalkyloxy, hydroxyalkyloxy, aminoalkyloxy, alkoxyalkyloxy, alkoxyalkyl, not optionally substituted phenyloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted heterocycloalkylalkyl. Within this group, the group of best compounds includes those compounds in which Ag! and Ag" have the values indicated above in the preferred embodiments.

I. The other best group of compounds according to Formula (I) include compounds in which X is -O-, av and BZ are hydrogen. with

I. Another better group of compounds according to Formula (I) includes compounds in which X represents -5(0) d-, and o

Sq. it is hydrogen.

Within the limits of the above-mentioned best groups II and I, it is possible to single out an even better group of compounds in which M is an alkylene.

Within the limits of the above-mentioned best groups II and II, it is possible to single out an even better group of compounds in which U represents (Ce) alkylene substituted by cycloalkyl, optionally substituted by phenyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, optionally substituted by phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl, or optionally substituted phenoxy. co

Within the limits of the above-mentioned best groups ІІ and ІІ and even better groups considered here, and even better groups of Ч compounds are those in which Аг! is phenylene.

Within the limits of the above-mentioned best groups of ІІ and ІІ and even better groups considered here, and even better groups of compounds are those in which Аг! is a heteroarylene.

Within the limits of the above-mentioned best groups of ІІ and ІІ and even better groups considered here, and even better groups of compounds are those in which Ag" is phenylene, especially preference should be given to those groups of compounds in which -"SOMNON" 20 and X groups are in positions 1 and 4 of the phenylene ring. Z c IM. Still another group of preferred compounds according to Formula (I) includes compounds in which Ag" is phenylene, X is -O-,

Vy 83 is hydrogen, and -SOMNON and X groups are in positions 1 and 4 of the phenylene ring. ;" Within the above preferred group of IM, an even better group of compounds consists of compounds in which M is alkylene.

Within the above preferred group IM, another, even better group of compounds consists of compounds in which U is alkylene, substituted with cycloalkyl, optionally substituted with phenyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, co hydroxyl or optionally substituted phenoxy. () Within the above preferred groups II, I, and M, an even better group, and an even better and especially preferred 5p group, are discussed herein, and a particularly best group includes compounds in which U is aralkenyl. Mostly, - Huh? is aryl(Co-C)alkenyl. Even better Ah? represented by Formulas: и рпепуго з рем у дит ! I And; HNN I o where phenyl is optionally substituted by one or two substituents independently selected from alkyl, alkoxy, le methylenedioxy, dialkylamino or hydroxy, even more preferably alkyl, alkoxy, methylenedioxy or hydroxy. In Even better, if Ah? is trans phenyl-CH-CH-, trans 4-MeO-phenyl-CH-CH-, trans

3,4-methylenedioxyphenylCH-CH-, trans 3-hydroxyphenyl-CHCH-, trans 4-hydroxyphenyl-CHCH-, trans 2-methoxyphenyl-CHCH-, trans 3-methoxyphenyl-CHCH-, trans 3-tolyl-"CHCH-, trans 4-tolyl-CH-CH-, trans 4-dimethylaminophenyl-CH-CH-, trans 2-tolyl-CH-CH-, or trans 2-hydroxyphenyl-CH-CH-. (her) Within the above-mentioned best groups II, Ш, and IM, and even better ones, and even better ones, and especially the 65 best groups considered here, the other best group of compounds is represented by compounds in which Ag 7? is heteroaryl(Co z)alkenyl. Preferably, Ag is trans heteroaryl-CH-CH- or trans heteroaryl-C(CHNUZ)-CH-, preferably the heteroaryl ring is pyridinyl, benzofuranyl, thienyl (thiophene), furanyl, or indolyl, optionally substituted by one or two substituents selected from hydroxyl, alkoxy, halo, or optionally substituted heterocycloalkyl.

Even better if Ah? is trans pyridin-3-yl-CH-CH-, trans 5-hydroxybenzofuran-2-yl -«С(CH83)-СНУ-, trans 5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl. -С(СНа)-СН-, trans 5-methoxybenzofuran-2-yl -СНАз)-СН-, trans benzofuran-2-yl-СНАСН-, trans 5-bromothiophen-2-yl-СНА-СН-, trans furan -z3-yl-CH-CH.-, trans // thiophene-3-yl-CHe:CH-, trans thiophene-2-yl-CH-CH-, trans benzofuran-2-yl-C(SNU)-cSnH -, cis benzofuran-2-yl-С(СНа)-СН-, trans indol-3-yl-СНАСН-, trans 7-methoxybenzofuran-2-yl-СНА-СН-, trans 70 5-methoxybenzofuran-2-yl -C(CH 3): CH-, or trans furan-2-yl-CH:CH. (ii) Within the limits of the above-mentioned best groups I, PS, and M, a still better group, and even a better and especially better group, is considered here, and a still more especially best group includes compounds in which Ag? is aryl. Preferably, the substituents on the aryl ring are independently selected from optionally substituted phenyl, alkyl, alkoxy, halo, optionally substituted heteroaryl, optionally substituted cycloalkenyloxy, optionally substituted heteroaralkyloxy, optionally substituted heterocycloalkyl, optionally substituted phenylcarbonylamino, or methylenedioxy. Even better if Ah? is phenyl, 4-biphenyl, 3-biphenyl, 4-tert-butylphenyl, 4-pyrrol-1-ylphenyl, 4-(pyridin-3-yl)uphenyl, 4-(pyridin-2-yl)phenyl, 4- (benzoylamino)phenyl, 2,4-difluorophenyl,

C,4-methylenedioxyphenyl, C,4-dimethoxyphenyl, C,5-dimethoxyphenyl, C3,4-difluorophenyl, 2,5-dimethylphenyl, 2,3-dichlorophenyl, 2,3-dimethylphenyl, 4-chloro-2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxy-2-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(thiophen-2-ylmethoxy)phenyl, 3-(thiophen-2-ylmethoxy)-phenyl, 2-biphenyl, naphth-1 -yl, 2-pyrrol-1-yl-phenyl, 4-fluoronaphth-1-yl, 3-MeO-naphth-2-yl, 2-MeO-naphth-1-yl, naphth-2-yl, 4-( 2-pyridin-4-ylthiazol-5-yl)phenyl, 4-(2-(4-methylpiperazin-1-yl)thiazol-5-yl|-phenyl, 4-(2-pyridin-4-ylaminothiazol-5- yl)phenyl, 4-(4-methylpiperazin-1 -yl)phenyl, 4-(4-hydroxypiperidin-1-yl)phenyl, 4-(4-morpholin-4-ylmethylthiazol-2-yl)uphenyl, 4-( 2-(4-methylpiperazin-1-ylmethyl)thiazol-5-yl|Ifenyl, c 1-methoxynaphth-2-yl, 3-(2-hydroxyethyl)biphen-4-yl, 3-(2-hydroxyethyl)biphen- c-yl, o 2-(2-hydroxyethyl)biphen-4-yl, 2'-(2-hydroxyethyl)biphen-3-yl or 4-I4-(-2-morpholin-4-yl-ethyl)thiazol- 2-yl|phenyl (m) Within the limits of the above-mentioned best groups Ii, Ii, and M, an even better group, and an even better and especially better group, considered here, and more especially the best group includes compounds in which Ag ? is a heteroaryl.

Mostly, Ah? is a heteroaryl, optionally substituted by one or two substituents, regardless of those selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkylalkyl, r 6 hydroxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkyl, haloalkyl, haloalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted with heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, with optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, ' : pap ; ah! and Fo is optionally substituted heterocycloalkylalkyloxy, -alkylene-(O)pK 2 (where n has a value from 0 to 2, and K is hydroxyalkyl or optionally substituted phenyl), -alkylene-ME. 2-alkylene-MIXTURE (where KS is hydroxyl, and KU is independently hydrogen or alkyl), or carboxyalkylaminoalkyl.

Is it better if Ah? is thiophen-2-yl, pyridin-3Z-yl, quinolin-b-yl, benzothiazol-2-yl, benzoxazol-2-yl, « 70 benzofuran-2-yl, benzofuran-5-yl, benzothien-2- yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 73 s thiazol-2-yl, 1H-indol-2-yl, 1H-indol-5-yl, 1H- indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, and 1H-benzotriazol-b-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2 -yl, quinolin-2-yl, 1H-benzimidazol-5-yl, and? quinolin-1-yl, pyridin-2-yl, pyridin-2-yl, quinolin-2-yl, furan-3-yl, thiophen-2-yl, or thiophen-33-yl, even better, benzofuran-2- yl, or benzothien-2-yl, which is optionally substituted with one or two of the substituents just described in the paragraph above. (se) Even better if Ah? is benzofuran-2-yl and is monosubstituted in the 3-, 4-, or 5-positions or disubstituted in the 4- and 7-positions, preferably benzofuran-2-yl, monosubstituted in the 3- or 5-positions with the substituent that has just been was described in the paragraph above. It is best if the substituents are independently selected from chloro, fluoro, or trifluoromethyl, methyl, ethyl, methoxy, 1-cyclopropylpiperidin-4-yloxy, 50.1-2,2,2-trifluoroethyl)piperidin-4-yloxy, M,M-dimethylaminomethyl , M,M-diethylaminomethyl, and 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-yl methoxy,

Pr 2-hydroxyethoxy, /2-M,M-dimethylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl,

3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl,

3-Methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-(1.2.4-triazine -1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-yl methyl, (F, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl , 4-fluorophenylthiomethyl,

Ho) 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3Z-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, 60 /M-methyl- M-benzylaminomethyl, M-methyl-M-2-phenylethylaminomethyl, Z-hydroxypropylthiomethyl,

3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonylmethyl, M-methyl-M-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, M-hydroxyaminocarbonyl-methylaminomethyl, or 3 -(2-carboxyethylamino-methyl).

It is even better if Ag 2 is benzofuran-2-yl, which is substituted in the C-position by 65 M,M-dimethylaminomethyl, M,M-diethylaminomethyl, 2-fluorophenoxymethyl, Z-fluorophenoxymethyl, 4-fluorophenoxymethyl, pyridine-4- yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl,

2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxy-methyl, 4-(1.2.41-triazin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, pyrrolidine-1 -ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethyl-piperidin-1-ylmethyl, 4-methyl piperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenyl-sulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2-(3-trifluoromethoxyphenylethyl)-, M-methyl-M-benzyl-aminomethyl,

M-methyl-M-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl,

C-hydroxypropylsulfonylmethyl, M-methyl-M-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl,

M-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylamino-methyl. 70 Even better, if Ag 2 is benzofuran-2-yl, which is substituted in the 5-position of 1-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1-ylethyloxy, or 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy.

Even better, if Ag 2 is /7-chloro-4-methylbenzofuran-2-yl, 4-methyl-benzofuran-2-yl, 7-fluoro-4-methylbenzofuran-2-yl, or 7-fluoro-4- phenoxymethylbenzofuran-2-yl.

Even better if Ah? is thiophen-2-yl, pyridin-Z-yl, 5-phenylthiophen-2-yl, quinoline-b-yl, 4-phenylthiazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, furan- 2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 4-(pyridin-4-yl)-thiazol-2-yl, 1H-indol-5-yl, 1H-indol-3- yl, quinolin-3-yl, quinolin-8-yl, 1H-indazol-3-yl, 1H-benzotriazol-b-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin- 2-yl, 1H-benzimidazol-5-yl, 1-methyl-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl, 4-hydroxyquinolin-2-yl, pyridin-2- yl, 3-hydroxypyridin-2-yl, b-hydroxypyridin-2-yl, 6-(4-nitrophenoxy)pyridin-2-yl, 4-(2-methoxyethoxy)quinolin-2-yl, 4-(2-dimethylaminoethoxy) )quinolin-2-yl, b-bromopyridin-2-yl, 5-bromopyridin-Z-yl, 4-methoxyquinolin-2-yl, 5-phenylpyridin-Z-yl, b-benzyloxypyridin-2-yl, 6-( 2-methylpropyloxy)-pyridin-2-yl, 6-(2-phenylethyloxy)pyridin-2-yl, 4-(3,3,3-trifluoropropyloxy)quinolin-2-yl, 5-thiophen-3-ylpyridin-3 -yl, 6-(4-acetylaminophenoxy)-pyridin-2-yl, 6-(4-aminophenoxy)-pyridin-2-yl, or E 5-4-dimethylaminophenyl)pyridin-3-yl. at

M. Another group of compounds according to Formula (I), which should be preferred, are formed by compounds in which Ag? is a heteroaryl. Mostly, Ah? is a heteroaryl, optionally substituted by one or two substituents, independently chosen by Kk! alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkyl, haloalkyl, co-haloalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted with heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-3(O) o K2 (where n has a value from 0 to 2, and K 92 is hydroxyalkyl or optionally substituted phenyl), co-alkylene-ME 2-alkylene-"SOME BZ (where EKO is hydroxyl, and B 4 is independently hydrogen or alkyl), or carboxyalkylaminoalkyl.

It is even better if Ag 2 is thiophen-2-yl, pyridin-3-yl, quinolin-b-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothien-2-yl, furan-2-yl, 1H-benzimidazol-2-yl, "

H-pyrrole-2-yl, thiazol-2-yl, 1H-indol-2-yl, 1H-indol-5-yl, 1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, - with 1H-indazol-3-yl, 1H-benzotriazol-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxalin-2-yl, quinolin-2-yl, and 1H-benzimidazol-b-yl , quinolin-1-yl, pyridin-2-yl, pyridin-2-yl, quinolin-2-yl, furan-3-yl, thiophen-2-yl, or "" thiophen-3-yl, even better benzofuran- 2-yl, or benzothien-2-yl, which is optionally substituted with one or two of the substituents just described in the paragraph above.

Even better if Ah? is benzofuran-2-yl and is monosubstituted in the 3-, 4-, or 5-position or is disubstituted in the 4- and 7-position, preferably benzofuran-2-yl is monosubstituted in the 3- or 5-position with the substituent just described in para. above. Substituents independently selected from chloro, fluoro, o trifluoromethyl, methyl, ethyl, methoxy, i-cyclopropylpiperidin-4-yloxy, o 1--2,2,2-trifluoroethyl)piperidin-4-yloxy, M,M-dimethylaminomethyl, M,M-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-yl methoxy, and 2-hydroxyethoxy, /2-M,M-dimethylaminoethoxy , methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl,

Pr of 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl,

3-Methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-(1.2 4-triazine- 1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, (F, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy,

Ho) 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, M-methyl-M-benzylaminomethyl,

M-methyl-M-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 60o 3-hydroxypropylsulfonyl-methyl, / M-methyl-M-2-indol-3-ylethylaminomethyl, 2-(4--rifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, M-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl).

It is even better if Ag 2 is benzofuran-2-yl, which is substituted in the C-position

М,М-dimethylaminomethyl, М,М-diethylaminomethyl, 2-fluorophenoxymethyl, З-fluorophenoxymethyl, b5 4-fluorophenoxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2 ,2-trifluoroethoxy-methyl, 4-imidazol-1-ylphenoxymethyl, 4-(1.2.4-triazin-1-yl-phenoxymethyl,

2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, pyrrolidin-1-ylmethyl, piperidin-1-yl methyl, 4-trifluoromethyl-piperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl , 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2-(3-trifluoromethoxyphenylethyl)-, M-methyl-M-benzyl-aminomethyl,

M-methyl-M-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinyl-methyl,

C-hydroxypropylsulfonylmethyl, M-methyl-M-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl,

M-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylamino-methyl.

Even better, if Ag 2 is benzofuran-2-yl, which is substituted in the 5-position of 70 i-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1-ylethyloxy, or 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy.

Even better, if Ag 2 is 7-chloro-4-methylbenzofuran-2-yl, 4-methyl-benzofuran-2-yl, 7-fluoro-4-methylbenzofuran-2-yl, or 7-fluoro-4- phenoxymethylbenzofuran-2-yl.

Even better, if Ag 2 is thiophen-2-yl, pyridin-3-yl, 5-phenylthiophen-2-yl, quinoline-b-yl, 4-phenylthiazol-2-yl, benzothiazol-2-yl, benzoxazole -2-yl, furan-2-yl, 1H-benzimidazol-2-yl, 1H-pyrrol-2-yl, 4-(pyridin-4-yl)-thiazol-2-yl, 1H-indol-5-yl , 1H-indol-3-yl, quinolin-3-yl, quinolin-8-yl, 1H-inazol-3-yl, 1H-benzotriazol-b-yl, isoquinolin-1-yl, isoquinolin-3-yl, quinoxaline -2-yl, quinolin-2-yl, 1H-benzimidazol-5-yl, 1-methyl-indol-3-yl, 4-MeO-quinolin-2-yl, quinolin-4-yl, 4-hydroxyquinolin-2 -yl, pyridin-2-yl,

C-hydroxypyridin-2-yl, b-hydroxypyridin-2-yl, 6-(4-nitrophenoxy)pyridin-2-yl, 4-(2-methoxyethoxy)quinolin-2-yl, 4-(2-dimethylaminoethoxy)quinoline -2-yl, b-bromopyridin-2-yl, 5-bromopyridin-3-yl, 4-methoxyquinolin-2-yl, 5-phenylpyridin-3-yl, b-benzyloxypyridin-2-yl, 6-(2- methylpropyloxy)-pyridin-2-yl, 6-(2-phenylethyloxy)pyridin-2-yl, 4-(3,3,3-trifluoropropyloxy)quinolin-2-yl, 5-thiophen-3-ylpyridin-3-yl , 6-(4-acetylaminophenoxy)-pyridin-2-yl, 6-(4-aminophenoxy)-pyridin-2-yl, or 5-(4-dimethylaminophenyl)pyridin-3-yl. with

Within the above preferred groups of Y, PP, IM, and M, and even better groups, and even better and especially preferred o groups discussed herein, the best preferred group includes compounds in which U is a direct alkylene , preferably ethylene or p-propylene, preferably ethylene.

Within the above-mentioned best groups II, X, IM and M, and even better groups, and even better and especially best groups, considered here, another group of compounds that should be most preferred includes compounds "O in which M represents a branched alkylene, preferably -CH(СоН)CH»-, -CH(I-СЗНАСН»-, or -СН(СНУЗ)СН»- and M stereochemistry in chiral carbon (5). It is better to give preference to U, which is -СН(СН)СН»о-.

Within the above preferred groups II, PI, IM, and M, and even better groups, and even better and especially preferred 9 groups, discussed herein, another group of compounds that is most preferred includes compounds in which U represents itself -СНХСН(СН з) - and the stereochemistry in the chiral carbon is (К). sia

Within the above-mentioned best groups II, PS, IM and M, and even better groups, and even better and especially the best groups, considered here, another group of compounds that is most to be preferred includes compounds in which M represents is -CH(ІСН 2К)СН»- or -"СН(ІСНоОСНОК)СН»-, where CC represents alkylthio, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or "optionally substituted phenoxy , preferably, phenyl, phenoxy, 4-chlorophenyl, cyclohexyl, benzylthio, benzylsulfonyl, methylthio, methylsulfonyl or hydroxy. - with MI. Another preferred group of compounds of Formula (I) wherein X is -O-.avi

From" there is hydrogen, Ah! - phenylene, Ag - aralkenyl, XU is a branched alkylene, and -SOMNON and X are in the 1st and 4th positions of the phenylene ring. Mostly, Ah? is trans phenyl-CH-CH-, where phenyl is optionally substituted with one or two substituents independently selected from alkyl, alkoxy, methylenedioxy, 15 or hydroxyl. co Limits of the terms of the compounds included above in the II-M groups are defined in the "Definitions" section of this Application.

Cz References to preferred embodiments above have been made to include all combinations of the individual and preferred groups, unless otherwise specified. co General synthesis -I 50 The compounds of the present invention can be obtained using the methods described in the reaction schemes below. The starting materials and reagents used to prepare these compounds are either available from commercial suppliers such as Algiers Spetis! So., (Mim/aiKee, UUiz.), Waspet (Toitapse, Saiyi.), or

Zidt (51. I otsiv, Mo.), or may be prepared by methods well known to one of ordinary skill in the art, if the techniques given in references such as Riezeg apa Rieezegz Keadepiv og

F! Ogdapis Zupipeviv, Moishtev 1-17 (doip UMpeu apa Bopv, 1991); Kodaz Spetivigu oi Sagrop Sotroshpaz, MoYptev 1-5 apa Birrietepia! (EiIvemieg Zsiepse Rybiizpege, 1989); Ogdapis Keasipvs, Moishteves 1-40 (add. UMieu apa ki ope, 1991), Magsiys Aidmapsei Ogdapis SPpetivigu, (dopyp MUpeu apa Bopz, 4 Eayyop) apa Iiagosk5

Sotrgepepzime Ogdapis Tgapviogtaiope (MSN Rybiizpegv Ips., 1989). These schemes are merely illustrative of certain methods by which the compounds of the present invention may be synthesized, and various modifications of these schemes may be made and will be encouraged by anyone having reference to this disclosure. Starting materials and reaction intermediates can be isolated and purified, if desired, using conventional techniques, including filtration, distillation, crystallization, chromatography, etc., without limiting the use of other techniques. Such materials can be described using traditional means, including physical constants and spectral data.

Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure in the temperature range of from about -78°C to about 1502°C, preferably from about 09°C to about 1252°C, and most preferably at room temperature ( or ambient temperature), for example around 2096.

Compounds according to Formula (I), in which X represents -O- or -5(0) ,-, where n has a value from 0 to 2, and other groups, as described in the section "Gist of the Invention", can be obtained by using the technique given and described below in Scheme A.

SchemaA o o « I sh Ka nh--Sld) ozh ROMN-H-ON OO -- servnmsu-h SA TOD osn sh- 1 2 Z o E o

Ak-SOH 4 5 s o o 1 de--somna- uh (in own n

And (Se)

The reaction of a compound of Formula 1, where K is alkyl, X is -O- or -5-, and Ag! has the meaning as defined in the Essence vol

The invention, with an amino alcohol according to Formula 2, where RO is an acceptable amino protecting group, provides a compound according to (co)

Formula 3. The reaction takes place in the presence of triphenylphosphine and diisopropylazodicarboxylate in an acceptable organic solvent, such as tetrahydrofuran, etc. sia

Compounds of Formula 1, such as methyl 4-hydroxybenzoate, methyl 4-mercaptobenzoate, and methyl c o)

C-Hydroxyisoxazole-5-carboxylate, are commercially available. Compounds of Formula 2 can be prepared from commercially available amino alcohols by reacting an amine with a suitable amino protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, and the like. under reaction conditions well known in the art. A detailed description of acceptable amino protecting groups and reaction conditions for their preparation can be found in T.MuU. Sgeepe, Rgogesiipa

Sgoyrz ip Ogdapis Zupipeziv, dopp Umieu b Bopv, Ips. 1981, which is incorporated herein by reference in its entirety - c Amino alcohols such as 2-ethanolamine, 2-amino-1-propanol, 2-methylaminoethanol, 2-amino-2-methyl-1-propanol, h 2-amino-1 -propanol, 4-amino-2-butanol, and 1-amino-2-butanol are commercially available. In addition, compounds of Formula 2 can be prepared from commercially available amino acids by protecting the amino groups with suitable protecting groups followed by reduction of the acid group to the hydroxyl group with a suitable reducing agent under conditions well known in the art. If it is desired to obtain compounds of Formula o (I) in which X is -50 5 , the corresponding compound of Formula C in which X is -5- can be treated with an oxidizing agent such as OHOMEF, t-chloroperbenzoic acid, and the like. o Removal of the amino protecting group from a compound of Formula C affords a compound of Formula 4. The reaction conditions (se) used to remove the amino protecting group depend on the nature of the protecting group. For example, if the protecting group is tert-butoxycarbonyl, it is removed under acidic conditions. They are acceptable. acids are trifluoroacetic acid, hydrochloric acid, etc. in an acceptable organic solvent such as

I methanol, dioxane, tetrahydrofuran, etc. If the protecting group is benzyl or benzyloxycarbonyl, it is removed under the conditions of the catalytic hydrogenation reaction. Acceptable catalysts are palladium-based catalysts and other catalysts well known in the art. Other reaction conditions acceptable for its removal can be found in TMU. OSgeepe, Rgoiesiipd Sgoiyyrz ip Ogdapis Zupipevziv, dopyp UMPeu 8 Zopv, Ips. 1981. Reactions are carried out in an inert organic solvent, methylene chloride, tetrahydrofuran, dioxane, etc. o The reaction of 4 with an acid or acid derivatives (eg, halides) of the Formula Ag2-CO7, where 7 is io)hydroxy or halo, provides a compound of the Formula 5. In addition, the reaction conditions used depend on the nature of the 7 group. If 7 is hydroxy, the reaction, as a rule, takes place in the presence of an acceptable binding agent, for example, benzotriazol-1-yloxytrispyrrolidine-phosphonium hexafluorophosphate (RUVORF),

O-benzotriazol-1-yl-M,M,M',M'-tetramethyl-uronium hexafluorophosphate (NVTu),

O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HAT)U), 1-"3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EUS. NOI) or 1, 3-dicyclohexylcarbodiimide (OCS), optionally in the presence of 1-hydroxybenzotriazole hydrate (NOVT. H 20), and a base such as /M,M-diisopropylethylamine, triethylamine, M-methylmorpholine, etc. The reaction is usually carried out at a temperature of from 20 to 302, preferably at about 252 C, the reaction requires from 2 to 24 hours to complete.Acceptable reaction solvents are inert organic solvents such as hapogenized organic solvents (e.g., methylene chloride, chloroform, etc.), acetonitrile, M ,M-dimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, etc.

Preferably, the reaction is carried out with NEW. BUT, EOS. NOSI in dichloromethane or M,M-dimethylformamide.

If AgCO7 is a halogen anhydride, the reaction is carried out in the presence of an acceptable base (eg, triethylamine, diisopropylethylamine, pyridine, etc.). Acceptable reaction solvents are polar organic solvents such as tetrahydrofuran, acetonitrile, M,M-dimethylformamide (OME), dichloromethane, or any acceptable mixture thereof. 70 Anhydride, such as chloride, can be prepared by reacting the appropriate acids with a halogenating agent, such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc. Acids for

AgCO7 of the formula are either commercially available or can be prepared from commercially available starting materials using methods known in the art. For example, benzoic acid, cinnamic acid, phenylacetic acid, nicotinic acid, isonicotinic acid, 3-methylbenzofuran-2-carboxylic acid, and 75 benzofuran-2-carboxylic acid are commercially available. Other acids such as

C-phenoxymethylbenzofuran-2-carboxylic acid can be easily prepared from commercially available

of 3-methylbenzofuran-2-carboxylic acid by first converting it to 2-bromomethylbenzofuran-2-carboxylic acid (by brominating it with M-bromosuccinimide under conditions well known in the art) and then reacting with phenol Compound 5 in which KZ is hydrogen, can optionally be converted to the corresponding compound of Formula 5, in which B C is not hydrogen, by reacting it with an alkylating agent under conditions known in the art.

Compound 5 is then converted into a compound of Formula (1) by reaction with aqueous hydroxylamine in the presence of a base such as sodium hydroxide and a mixture of organic solvents such as tetrahydrofuran and methanol. In addition, the acid group in 5 is first activated by an acceptable coupling agent, with 29 such as i-(3-dimethylaminopropyl)-33-ethylcarbodiimide hydrochloride (EOS.HC), or Ge) 1,3-dicyclohexylcarbodiimide (OCS), neoob necessarily in the presence of 1-hydroxybenzotriazole hydrate (NOVT.H2O) in an acceptable organic solvent such as dimethylformamide, etc., and then by reacting with hydroxylamine hydrochloride in the presence of a base such as M,M-diisopropylethylamine, triethylamine, M-methylmorpholine, etc.

Compounds of Formula (I) can also be prepared from compound 5 using the methods described in O.5. Rayepi so 5998412, the disclosure of which is incorporated herein in its entirety by reference. Cha

A compound of Formula (I) can be converted into other compounds of Formula (I). For example, the compound for

Formula (I), where Ag' is phenylene, X is -O-, Y is ethylene, Ag? is a co

3-Dimethylaminomethylbenzofuran-2-yl, EK and BZ are hydrogen, can be prepared by reaction of compounds. CM zv According to Formula 4, where Ap is phenylene, X is -0-, M is ethylene, and K is alkyl with

3-methylbenzofuran-2-carboxylic acid as described above to give a compound of Formula 5, wherein

Huh? is 3Z-methylbenzofuran-2-yl. Bromination of the methyl group with a suitable brominating agent such as M-bromosuccinimide followed by reaction with dimethylamine provides the corresponding

of the 3-dimethylaminobenzofuran-2-yl compound, which is then converted into the desired compound under the conditions described above. c Uses and Compounds of the present invention are inhibitors of histone deacetylase enzymes and, thus, are useful in the treatment of proliferative diseases such as cancer, namely lung cancer, rectal cancer, acute myelogenous leukemia (AML), myelomonocytic leukemia (MML) , skin, breast, ovaries, prostate gland, liver,

Brain and skin, psoriasis, fibroproliferative disorders such as liver fibrosis, proliferative disorders

Go! smooth muscle such as atherosclerosis and restenosis, inflammatory diseases such as arthritis, diseases involving angiogenesis such as cancer, diabetic retinopathy, hematopoietic disorders such as anemia, fungal, co-parasitic and bacterial infections, viral infections, autoimmune diseases such as arthritis, multiple sclerosis, lupus, allergies, asthma, allergic rhinitis, organ transplants, and bipolar disorders. In addition, the compounds of the present invention are useful in the treatment of infectious hepatitis C. Testing The ability of the compounds of the present invention to inhibit histone deacetylase enzymes can be determined in the IPM and IPM assays, as described below in the biological tests of Examples 1 and 2. - the activity of the compounds of the present invention was determined using the Psu-replicon test at Georgetown University.

Compounds can also be tested for activity using the replicon assay described in Kogpeg, M.

IM. Yeeai., Zsiepse 1999 )tsi 2:285 (5424)! 10-3. (F) Application and Pharmaceutical Compositions In general, the compounds of the present invention can be administered in a therapeutically effective amount using any of the accepted methods of administration of agents having a similar application. The actual amount of the compound of the present invention, that is, the active ingredient, will depend on a number of factors, such as the severity of the disease requiring treatment, the age and relative health of the subject, the effectiveness of the compounds used, the method of administration and the form medicinal product and other factors.

The therapeutically effective amount of compounds according to Formula (I) can vary in the range of approximately 0.1-50 mg per kilogram of the recipient's body weight during one day; preferably, approximately, 0.5-20mg/kg/day. Thus, for B5 administration to a person whose body weight is 7Okg, it is best if the dose is approximately ЗB5mg to 1.4g for one day.

In general, the compounds of the present invention can be administered as pharmaceutical compositions by any of the following methods: oral, systemic (eg, transdermal, intranasal, or suppository), or parenteral (eg, intramuscular, intravenous, or subcutaneous) administration.

The preferred route of administration is oral or parenteral, using an acceptable daily dosage regimen that can be adjusted to the extent of the disease. Oral compositions may be in the form of tablets, dragees, capsules, semisolids, powders, pulsatile release preparations, solutions, suspensions, elixirs, aerosols, or any other acceptable compositions.

The choice of the preparation technology (form) of the medicinal product depends on various factors, such as the method of administration of the medicinal product (for example, for oral administration, preference should be given to medicinal products in the form of tablets, dragees or capsules) and the bioavailability of the medicinal product. Until recently, pharmaceutical formulations were developed especially for drugs with low bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, that is, by reducing the particle size. For example, O.5. Paradise Mo. 4,107,288 discloses a pharmaceutical form having a particle size ranging from 10 to 1,000 nm in which the active substance is held in a cross-linked matrix of macromolecules. O.5. Paradise Mo. 5,145,684 discloses the manufacture of a pharmaceutical formulation in which a drug substance is atomized into nanoparticles (average particle size of 40 Ohm) in the presence of a surface modifier and then dispersed in a liquid medium, yielding a pharmaceutical formulation that exhibits extremely high bioavailability.

Basically, the compositions consist of a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients should be non-toxic, facilitate the administration of the drug and not cause an adverse effect against the therapeutic effect of the compounds of Formula (1).

Such fillers can be any solid, liquid, semi-solid or, in the case of aerosol compositions, gaseous fillers, which are generally available to any person skilled in the art. with

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, maltose, rice flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skimmed milk powder, etc. Liquid and semisolid fillers can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum products, oils of animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.

The best liquid carriers, especially for injection solutions, are water, saline, aqueous solution, and - dextrose and glycols. co

Compressed gases can be used to spray the compounds of the present invention in the form of aerosols.

Inert gases such as nitrogen, carbon dioxide, etc. are acceptable for this purpose. with

Other acceptable pharmaceutical excipients and their formulas are described in Ketipdiop'z Rnagtaseciysa! Zsiepsev, co-edited Bu E. MU. Mapip (Mask Rybiizpipd Sotrapu, 18!" ed., 1990).

The amount of the compound in the composition can vary significantly within the broad limits accepted in the art. As a rule, the composition may contain, in weight percent (by weight, 90), from about 0.01-99.99 weight 95 of the compound by

Formulas (I) from the total weight of the composition, taking into account the fact that one or more acceptable pharmaceutical fillers are present. Preferably, the content of the compound is approximately 1-8095 (from 3.v.). Representative pharmaceutical formulations containing a compound of Formula (I) are described below. y As established earlier, the compounds of the present invention can be used in combination with known "" anticancer agents. Such known anticancer agents are: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, 5 antiproliferative agents, prenylprotein transferase inhibitors, NMO-CoA reductase inhibitors, inhibitors

Go! HIV proteases, reverse transcriptase inhibitors, DNA methyltransferase inhibitors, and other angiogenesis inhibitors. The compounds of this invention are particularly effective when used in combination with radiation therapy. Preferred angiogenesis inhibitors are selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor

Go! epidermal growth factor, fibroblast growth factor inhibitor, platelet growth factor inhibitor, MMP (matrix metalloprotease) inhibitor, integrin blocker, interferon-A, interleukin-12, pentosan

Sh- polysulfate, cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine,

Fo 6-O-chloroacetyl-carbonyl)-fumagilol, thalidomide, angiostatin, troponin-1, and antibodies to MESE.

The best estrogen receptor modulators are tamoxifen and raloxifene. "Estrogen receptor modulators" refer to compounds that stop or inhibit the binding of estrogen to the receptor, regardless of

From the mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, I 353381, I M117081, toremifene, fulvestrant, (F) 4-(7-(2,2-dimethyl-1-oxopropoxy-4-methyl- 2-|4-(2-(1-piperidinyl)ethoxy|phenyl|-2H-1-benzopyran-3-yl|-phenyl-2,2-z dimethylpropanoate, 4,4"-dihydroxybenzophenone-2,4-dinitrophenyl -hydrazone, and 5Hb46. "Androgen receptor modulators" refer to compounds that stop or inhibit the binding of androgens to the receptor, regardless of the mechanism. Examples of androgen receptor modulators include finasteride and other 5o, -reductase inhibitors, nilutamide, flutamide, bicalutamide , liarozole, and abiraterone acetate. "Retinoid receptor modulators" refer to compounds that stop or inhibit the binding of retinoids to the receptor, regardless of the mechanism. Examples of such retinoid receptor modulators include bexatoren, tretinoin, 13-cis-retinoic acid, 9-cis -retinoic acid, c -difluoromethylornithine, 65 1 X23-7553, transo-M -(4-hydroxyphenyl) retinamide, and M-4-carboxyphenyl retinamide. "Cytotoxic agents" refers to compounds that cause cell death primarily by directly affecting cell function or by inhibiting or terminating meiosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.

Examples of cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectine, ifosfamide, tazonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trophosphamide, nimustine , dibrospidu chloride, pumitepa, lobaplatin, satraplatin, profiromucin, cisplatin, irofulven, deoxyphosphamide, cis-aminodichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, ZRH100, (trans, trans, 70 trans)-bis-mu-( hexane-1,6-diamine)-mu-|Idiamine-platinacyII)|bis|idiamine(chloro)platinacyI))-tetrachloride, diarizidinylspermine, arsenic trioxide, 1--11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pyrarubicin, pinafid, valrubicin, amrubicin, antineoplaston, 3'-deamino-3--morpholino-13-deoxo-10-hydroxycarminomycin, anamycin, galarubicin, elinafid,

MEM 10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see UMO 00/50032).

Examples of microtubule inhibitors include paclitaxel, vindesine sulfate, 34-didehydro-4"-deoxy-8'i-norvincaleukoblastin, docetaxel, rizoxin, dolastatin, mivobulin isothionate, auristatin, cematodin, KRE109881, vM5184476, vinflunine, cryptophycin, 2,3,4 ,5,6-pentafluoro-M-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine,

M,M-dimethyl3- and -valyl-| -valyl-M-methylch-and -valyl-! -prolyl-I -proline-I-butylamide, TOKH258, and VM5188797.

Some examples of topoisomerase inhibitors are topotecan, sigcaptamine, irinotecan, rubitecan, b-ethoxypropionyl-3',4"-O-exo-benzylidene-chartresine, 9-methoxy-M,M-dimethyl-5-nitropyrazol!|Z,4, 5-Clacridin-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo|de|pyranoyl3,4"5 ,71-indolizino|1,26quinoline-10,13(9H, 15H)dione, lurtothecan, 7-(2-(M-isopropylamino)-ethyl|-(205)camptothecin, ВМР1З50, ВМРНИТОО, ВМ80915, с вмМмм80942, etoposide phosphate, teniposide, sobuzoxan, 2"--dimethylamino-2'--deoxy-etoposide, SI 331, -(2--(dimethylamino)ethyl-9-hydroxy-5,6-dimethyl-bH-pyrodo|4,3 -b|carbazole-1-carboxamide, azulacrine, (ba, 5av, (8) 8aa,95)-9-I(2-(M-(2--dimethylamino)ethyl|-M-methylamino|ethyl/d| -5-I(4-hydroxy-3,5-dimethoxyphenyl|-5,5a,6,8,va,Z-hex ahydrofuro(3,4":6,7)colchik(2,3-9)-1 ... |benzos|d|isoguinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-( 2-hydroxyethylaminomethyl)-6H-pyrazolo|4,5,1-de|iacridin-6-one, -

IM-(1-(r(diethylamino)ethylamino|-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl|formamide, so

M-(2--dimethylamino)ethyl)acridine-4-carboxamide, 6-(2-(dimethylamino)ethyl)amino|-3-hydroxy-7H-indenao|2,

I-c)quinolin-7-one, and dimesna. se "Antiproliferative agents" include antisense RNA and DNA oligonucleotides, such as (33139, О0Юмб98, со

KEMABKKA5, ZEM231, and ИМХЗ30О01, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxyfluridine, trimetrexate, fludarabine, capecitabine, halocitabine, cytarabine oxphosphate, fosteabine sodium hydrate, raltitrexide, paltitrexide, emitefur, thiazofurin, decitabine, nolatrexide, pemetrexed , nelzabarin, 2'-deoxy-2'--methylidencytidine, 2-fluoromethylene-2'--deoxycytidine, "

IR-I5-(2,3-dihydro-benzofuryl)sulfonyl|-M'-(3,4-dichlorophenyl)urea, M6-I(4-doxy4-|(M2-(2(E), with c 4( E)-tetradecadienoyl|glycylamino)-I -glycero-B-I -manno-heptopyranosyl|-adenine, aplidine, ecteinascidin, troxacitabine, 4-(2-amino-4-oxo-4,6,7 8-tetrahydro-ZM -pyrimidine|5.,4-51(I,thiazin-6b-yl-; t (5)-ethyl)|-2,5-thienoyl-Y-glutamic acid, aminopterin, 5-fluorosuracil, alanosine, 11-acetyl Acetic acid -8-"(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,b-trien-o-yl ester , swansonine, lometrexol, dextrazoxan, co-methioninase, 2-cyano-2'-deoxy-M4-palmitoyl-1-8-O-arabino furanosyl cytosine, and

Z-aminopyridine-2-carboxaldehyde thiosemicarbazone. "Antiproliferative agents" also include monoclonal antibodies to growth factors other than those defined under "angiogenesis inhibitors" such as trastuzumab, and tumor suppressor genes such as p53 that can be transferred by recombinant viral genes (for example, see O.5. Rai. Mo. 6,069,134). - And "NMO-CoA reductase inhibitors" belong to 3-hydroxy-3-methylglutaryl -CoA reductase inhibitors.

Compounds exhibiting inhibitory activity against HMO-CoA reductase can be readily identified using tests known in the art. For example, one should refer to the analysis methods described or cited in O.5. Paradise Mo. 4,231,938 ai of soybeans. b, apa MUO 84/02131 ai years 30-33. The terms "NMO-CoA reductase inhibitor" and "NMO-CoA reductase inhibitor" have the same meaning when used in this invention. It was established (pi. y). Sapseg, 20:97(6):746-50, 2002), that combination therapy with lovastatin,

GF) inhibitor of NMO-CoA butyrate reductase, inducer of apoptosis was shown in a mouse model of lung carcinoma

F. Levis potentiates the antitumor effect.

Examples of NMO-CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (MEMASOCO); see ).5. Paradise As. 4,231,938; 4,294,926; 4,319,039), simvastatin (27OSOKF; see O.5.

Paradise As. 4,444,784; 4,820,850; 4,916,239), pravastatin (rhamasny is; see 0 5. Languages. 5,118,853; 5,290,946; 5,356,896), atorvastatin (IIROKOY; see I.5. ). The structural formulas of these and other NMO-CoA reductase inhibitors that can be used in these methods are described on p. 87 in M. Mairap, "Spoieviegoi! I omegipd YuOgidv", Spetivigu 5 Ipdivigu, years 85-89 (Reb.

5, 1996) and ShSh.5. Paradise As. 4,782,084 apa 4,885,314. The term HMO-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactones and forms with "opened acids" (ie, those in which the lactone ring is opened to form the free acid), as well as salts and esters of compounds having the ability to inhibit NMO-CoA reductase, and colchicine, the use of such salts, esters, forms with "open acids" and lactones are included within the scope of the present invention.

In HMO-CoA reductase inhibitors, where "open" acid forms may exist, salts and esters may be predominantly formed from open acids, and all such forms are included within the meaning of the term "HMO-CoA reductase inhibitor" as used herein . Preferably, the NMO-CoA reductase inhibitor is selected from lovastatin and 7/0 simvastatin, and simvastatin is preferred.

In the present invention, the term "pharmaceutically acceptable salts" in relation to HMO-CoA reductase inhibitors may mean non-toxic salts of the compounds used in the present invention, which are generally obtained by reaction of the free acid with acceptable organic or inorganic bases, in particular those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed with amines such as ammonia, ethylenediamine, M-methylglucamine, lysine, arginine, ornithine, choline, M, M'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, M-benzylphenethylamine,

N-p-chlorobenzyl-2-pyrrolidin-1'-yl-methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl)aminomethane.

The following examples of salts that are inhibitors of NMO-CoA reductase include, but are not limited to, acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, calcium hydroxyls, calcium carbonates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides ) , napsylates, nitrates, oleates, oxalates, pamoates, palmitates, pantothenates, phosphate/diphosphates, polygalacturonates, salicylates, stearates, subacetates, succinates, sov tannates, tartrates, theoclates, tosylates, teriodides, and valerates.

Ester derivatives of the described NMO-CoA reductase inhibitor compounds can act as prodrugs, which (8) when absorbed into the bloodstream of warm-blooded animals can split and, thus, release the drug, which makes it possible to increase the therapeutic effectiveness of drugs. "Prenyl-protein transferase inhibitor" refers to compounds that inhibit each or any combination of prenyl-protein transferase enzymes, including farnesyl-protein transferase (ERT), geranylgeranyl-protein transferase type ! (sORTase-I), and geranylgeranyl-protein transferase type-II - (sORTase-II, also called Kar zORTase). Examples of compounds that inhibit prenyl-protein transferases include (-3-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl|-4-(33-chlorophenyl)-1 -methyl-2(1H)-quinolinone, c (-)-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-chlorophenyl)-1 -methyl-2(1H)-quinolinone, so (-3-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl|-4-(33-chlorophenyl)-1- methyl-2(1H)-quinolinone, 5(5)-p-butyl-1-(2,3-dimethylphenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethyld|-2-piperazinone, (5 )-1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethylide|-5-(2-«-ethanesulfonyl)-methyl)-2-piperazinone, 5(5)-p- butyl-1-(2-methylphenyl)-4-(1-(4-cyanobenzyl)-5-imidazolylmethyl)|-2-piperazinone, « (5)-1-(3-chlorophenyl)-4-(1-( 4-cyanobenzyl)-2-methyl-5-imidazolylmethyl|)|-2-piperazinone, with c 1(2,2-diphenylethyl)-3-(M-(1-(4-cyanobenzyl)-1H-imidazole-5 -ylethyl)carbamoyl|piperidine, 4-(5-14-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidin-1-ylmethyl)|-2-methylimidazol-1-ylmethyl)benzonitrile, t 4- (5-I4-hydroxymethyl-4-(3-chlorobenzyl)-pi peridin-1-ylmethyl|-2-methylimidazol-1-ylmethyl)benzonitrile, 4-(3-I4-(2-oxo-2H-pyridin-1-yl)benzyl|-3H-imidazol-4-ylmethyl)benzonitrile, 4-(3-I4-(5-chloro-2-oxo-2H-|1,2bipyridin-5'-ylmethylI-3H-imidazol-4-ylmethyl)benzonitrile, so 4-(3-I4-(2-oxo -2H-I11,2Ibipyridin-5'-ylmethyl|-ZH-imidazol-4-yl methyl)benzonitrile, 4-I3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-ZH- imidazol-4-ylmethyl)benzonitrile, 18,19-dihydro-19-oxo-5H, 17nH-6,10: co 12,16-dimetheno-1H-imidazo|4,3-cI(1,11,4)dioxa -azacyclononadecine-9-carbonitrile, (-- bo )-19,20-dihydro-19-oxo-5H-18,21-ethano-2,14-etheno-6,10-metheno-22M-benzo|d|imidazoi - 12,16-dimetheno-22H-imidazoi3,4-H1(1,8,11,1oxatriazacyclo-eicosine-9-carbonitrile, and b (--19,20-dihydro-3-methyl-19-oxa-5H-18 .

Other examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: UMO 96/30343, MO 97/18813, MO 97/21701, MO 97/23478, MO 97/38665, MO 98/28980, MO 98/29119, MO 95/32987,

O.85. Rai Mov. 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, Eigoreap Raiepi Riri. O 618 (F) 221, Eigoreap Raiepi Riri. 0 675 112, Eigoreap Raiepi Riri. 0 604 181, Eigoreap Raiepi RybI. 0 696 593, MO km 94/19357, MO 95/08542, UMO 95/11917, MO 95/12612, MO 95/12572, MO 95/10514, 0.5. Paradise Mo. 5,661,152, MO 95/10515, MO 95/10516, MO 95/24612, MO 95/34535, MO 95/25086, MO 96/05529, MO 96/06138, MO 96/06193, bo MO 96/16443, UMO 96 /21701, MO 96/21456, MO 96/22278, MO 96/24611, MO 96/24612, MO 96/05168, MO 96/05169, MO 96/00736, 0.5. Paradise Mo. 5,571,792, MO 96/17861, MO 96/33159, MO 96/34850, UMO 96/34851, MO 96/30017, MO 96/30018, MO 96/30362, MO 96/30363, MO 96/31111, MO 96/ 31477, MO 96/31478, MO 96/31501,

MO 97/00252, MO 97/03047, MO 97/03050, MO 97/04785, MO 97/02920, MO 97/17070, MO 97/23478, MO 97/26246, MO 97/30053, UMO 97/44350, MO 98/02436, apa 0.5. Paradise Mo. 5,532,359 For example, the effect of 65-prenyl-protein transferase inhibitor on angiogenesis, see in -). Oi Sapseg, Moi. 35, Mo. 9, pp. 1394-1401 (1999).

Examples of HIV protease inhibitors include amprenavir, abacavir, COP-73547, COP-61755, YMP-450,

indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, AVT-378, AC 1776, and VM5-232, 632. Examples of reverse transcriptase inhibitors include delaviridine, efavirenz, 535-840, HB M097, lamivudine, nevirapine,

AT, ZTS, aasS, and adi. HIV protease inhibitors such as indinavir or saquinavir have been shown (Mai Messi.; 8 (3):225-32, 2002) to have strong antiangiogenic activity and cause regression of Kaposi's sarcoma. "Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of the mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors such as receptor tyrosine kinase E-1 inhibitors (MESEKTI) and RICAL/COC (MESEK2O), epidermal, fibroblast, or platelet-derived growth factor inhibitors, matrix metalloprotease (MMP) inhibitors, blockers of 7 /0 Integrin, interferon-os, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, as well as selective cyclooxygenase-2 inhibitors such as celecoxib, valecoxib, and rofecoxib (РМА5, My. 89 , p. 7384 (1992); UMSI, Moi. 69, p. 475 (1982); Agsp. ); REV5 Iecegv,

My. 372, p. 83 (1995); Siip., Oppor. My. 313, p. 76 (1995); 9. Mine. EpdoshypoIi, My. 16, p. 107 (1996);

Urp. U. Rnaptasoi., Moi. 75, p. 105 (1997); Sapseg Kev., Moi. 57, p. 1625 (1997); Seyi, Moi. 93, p. 705 (1998); pF. 9. Mine. honey, my 2, p. 715 (1998); 3. Vioi Spet., Moi. 274, p. 9116 (1999), carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagilol, thalidomide, angiostatin, troponin-1, angiotensin I antagonists (see Regpapde et al., 9. Ga. Si. May. 105:141-145 (1985)) and antibodies to MESE (see, Maishge Vioiespoiodu, Moi. 17, pp. 963-968 (Osioreg 1999); Kit ei ai.,

Maishge, 362, 841-844 (1993); UMO 00/44777; apa UMO 00/61186).

As described above, combinations with M5AIIUO are directed towards the use of M5ZAI!U, which are potent COX-2 inhibitory agents. For the purpose of this specification, an M5AIIIO is potent if it has an IC for COX-2 inhibition greater than or less than 1mM, as determined by cellular or microsomal assays known in the art. high school

The present invention also encompasses combinations with MAOIs that are selective COX-2 inhibitors. For the purposes of this specification, M5A!OYs that are selective inhibitors of COX-2 are defined as having specificity for (8) inhibition of COX-2 over COX-1 at least 100-fold greater, as determined by the ratio of IS in for COX-2 over the IC for COX-1 as determined by the cellular or microsomal assay disclosed herein. Such compounds include, but are not limited to, those compounds disclosed in 0.5 Rai. Mo. 5,474,995, "with izziei JuOes. 12, 1995, 5. Rai. Mo. 5,861,419, izvtsey Chuap. 19, 1999, O.5. Paradise Mo. 6,001,843, izvtsey YuOes. 14, 1999, Sh. 8. Paradise Mo. 6,020,343, ivvcey Ber. 1, 2000, Sh.85. Paradise Mo. 5,409,944, ivvtsey Arg. 25, 1995, 0.5. uh-

Ram Mo. 5,436,265, AI. 25, 1995, 0.5. Paradise Mo. 5,536,752, AI AI. 16, 1996, 0.5. Paradise Mo. p 5,550,142, ivvtsei Atsa. 27, 1996, 0.5. Paradise Mo. 5,604,260, izzzei Rer. 18, 1997, OO 5. Rai. Mo. 5,698,584, no

Oes. 16, 1997, 0.5. Paradise Mo. 5,710,140, izvtsey Chap. 20, 1998, UUO 94/15932, fish eat. 21, 1994, 0.8. Rai E

Rev. Mo. 5,344,991, ivvtsey dip. b, 1994, 0.5. Paradise Mo. 5,134,142, ivvtsei Ushi. 28, 1992, 0.5. Paradise Mo. 5,380,738, with addendum no. 10, 1995, 5. Rai. Mo. 5,393,790, izvtsey Reb. 20, 1995, 0.5. Paradise Mo. 5,466,823, izvtsey Mom. 14, 1995, 5. Rai. Mo. 5,633,272, issued May 27, 1997, apa 0.5. Paradise Mo. 5,932,598, izvciea Atsa. 3, 1999, each of which is incorporated herein by reference. Other examples of specific COX-2 inhibitors include those disclosed in Section 5. Raiepi 6,313,138, the disclosure of which is incorporated herein by reference in its entirety. General and specific methods of synthesis for the preparation of COX-2 inhibitor compounds are described above and can be found in ).5. Paradise with Mo. 5,474,995, ivvcei Jues. 12, 1995, I),5. Paradise Mo 5,861,419, ivzzei Tzap. 19, 1999, apa Sh.5. Paradise Mo. 6,001,843, izvtsey Oes. 14, 1999, all of which are incorporated herein by reference. Compounds that have been described as specific inhibitors of COX-2, and are thus useful in the present invention, include, but are not limited to, the following compounds:

ZON; I don't eat, but I drink

M i nya - Mo i; There are other reasons why 5053MNSOSsNosnU schi SEZ or their pharmaceutically acceptable salts. 59 The compounds described herein as specific inhibitors of COX-2, and thus useful in the present invention, and methods of their synthesis, can be found in the following patents, patent applications, and publications, which are incorporated herein by reference: MO 94/15932, Rybriyivpei Shi. 21, 1994, 0.5. Paradise Mo. 5,344,991, izvtsey dip. b, 1994, 0.5. co Cancer Mo. 5,134,142, etc. 28, 1992, CI.5. Paradise Mo. 5,380,738, izvtsey app. 10, 1995, 0.5. Paradise Mo. 5,393,790, izvtsey Rer. 20, 1995, 0.5. Paradise Mo. 5,466.23, ivzzey Mom. 14, 1995, 0.5. Rai Mo. 5,633,272, 60 ivvcei Mau 27,1997, apa 0.5. Paradise Mo. 5,932,598, izzzei Atsa. Z, 1999.

Compounds that are specific inhibitors of COX-2, and thus are useful in this invention, as well as methods of their synthesis, can be found in the following patents, applications, and publications, which are incorporated herein by reference: O.5. Paradise Mo. 5,474,995, izvtsey YuOes. 12, 1995, O).5. Paradise Mo. 5,861,419, izvtse add. 19, 1999, 5.

Paradise Mo. 6,001,843, izzzei JuOes. 14, 1999, I,5. Rai Mo. 6,020,343, dated Ber. 1, 2000, 0.5. Paradise Mo. bo 5,409,944, ivvcei Arg. 25, 1995, 0.5. Paradise Mo. 5,436,265, ivvcei SH. 25, 1995, O.85. Paradise Mo. 5,536,752,

ivzzei shi 16, 1996, 0.5. Paradise Mo. 5,550,142, izvtsei Atsa. 27, 1996, 0.5. Paradise Mo. 5,604,260, ivvtsey Ber. 18, 1997, 0.5. Paradise Mo. 5,698,584, izzzei Oes. 16, 1997, apa 0.5. Paradise Mo. 5,710,140, izvceid add. 20, 1998.

Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukraine, ranpirnase,

IM862, 5-methoxy-4-(2-methyl-3-(3-methyl-2-butenyl)oxiranyl|-1-oxaspiro|2,5|oct-6-yl(chloroacetyl)carbamate, acetyldinanalin, 5-amino -1-I((3,5-dichloro-4-(4-chlorobenzoyl)phenyl|-methyl)|-1H-1,2,3-triazo 1e-4-carboxamide,

CM101, squalamine, combretastatin, КРИ4610, МХ31838, sulfated mannopentose phosphate, 7,7-(carbonyl-bis(amino-M-methyl-4,2-pyrrolocarbonyl-imino|M-methyl-4,2-pyrrolI|-carbonylimino| -Bis-(1,3-naphthalene disulfonate), and 3-((2,4-dimethylpyrrol-5-yl)umethylene|-2-indolinone (505416). 70 As used above, "integrin blockers" refers to compounds that selectively compete with, inhibit or oppose the binding of a physiological ligand to an integrin, to compounds that selectively compete, inhibit, or oppose the binding of a physiological ligand to an integrin, to compounds that selectively compete, inhibit, or oppose the binding of a physiological ligand both with the oVz integrin and with the ouDv integrin, and to compounds that compete with, inhibit, or antagonize the activity of a particular integrin(s) expressed on capillary endothelial cells. This term also refers to ouUVv antagonists; ouVa" 944: 0284; sia" obi" and sv integrins. This term also belongs to antagonists of any combinations oB3» ou/Vv» suVe» ouVv» sa V» sov» BV» or 1 horde of integrins.

Some specific examples of tyrosine kinase inhibitors include

M-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-«(allalamino)-17-demethoxygeldanamycin, 4-(3 -chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxyl)/dhinazoline,

M-(3-ethynylphenyl)-6,7-Biv(2-methoxyethoxy)-4-quinazolinamine, VIVH1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9 -methyl-9,12-epoxy-1H-diindolo|1,2,3-4:32,1/-kI pyrrolo|Z,4-C11,6b|benzodiazocin-1-one, H2bV, genistein, 5Т1571, СЕР2563 . (4-hydroxyphenyl)amino-b,7-dimethoxyquinazoline,

Ibb668, 5011248, 5T1I571A, M-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMO121974.

These compounds are also useful alone or in combination with platelet fibrinogen receptor antagonists (FRP), such as tirofiban, which inhibit cancer cell metastasis. Tumor cells can activate platelets largely through the generation of thrombin. This activation is associated with the release of MES. uh-

The release of MESE enhances metastases due to the increase in transudation at the points of adhesion to the vascular endothelium (Atigkpozgami, Riayeiiv 10, 285-292, 1999). Thus, these compounds can be used for (he) inhibition of metastases, alone or in combination with OR Pr/Pa antagonists. Examples of other fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban,

From cromofiban, and ST5O352. Co. "Inhibitor of DNA methyltransferase" belongs to compounds that inhibit methylation of the cytosine base of DNA in

C-5 position of this base with the help of DNA methyltransferase enzyme. Examples of such inhibitors

DNA methyltransferases include compounds disclosed in US patents 6,329,412 and 6,268,137. Specific "inhibitors of DNA methyltransferases include 5-azacytosine and zebularinf).

When formulating a formulation of a medicinal product with fixed doses, such compositions include the compounds of the present invention within the dosage limits described above, and other pharmaceutically active agent(s) within the approved "» limits of its dosage. The compounds of the present invention can alternatively be used sequentially with a known "pharmaceutically acceptable agent(s)" if the formulation is unacceptable.

The term "administration" or its variants (eg, "administration" of compounds) with respect to compounds of the present invention means the introduction of compounds or prodrugs of compounds into the system of an animal in need of treatment. If a compound of the invention or its prodrugs is provided in combination with one or two active agents (eg, a cytotoxic agent, etc.), one should understand that "use" and its variations include simultaneous or sequential administration of the compound or its prodrugs and other agents. o As used herein, the term "composition" is intended to encompass a product that includes - 20 specified ingredients in specified amounts, as well as any product that is obtained, directly or indirectly, from a combination of specified ingredients in specified amounts. (42. The compounds of the present invention may also be administered in conjunction with other well-known therapeutic agents selected on the basis of their particular efficacy for the treatment of a condition in need thereof. For example, the compounds of the present invention may also be administered in conjunction with other well-known anti-cancer therapeutic agents , which are selected on the basis of their particular efficacy for the treatment of cancer. Included in such combinations of therapeutic agents are combinations of farnesyl protein transferase inhibitors, disclosed in 05 RAIP 6,313,138, and an antitumor agent. It is also known that such combinations of an antitumor agent and an io) farnesyl inhibitor -protein transferases can be used in combination with other methods of treating cancer and/or tumors, including radiation therapy and surgery. 60 Examples of anticancer agents include, in general, agents that polymerize microtubules (such as paclitaxel (also known as Tacho!F), docetaxel (also known as TahoegeF, epothilone A, epothilone B, deoxyepothilone A, deoxyepothilone B, or derivatives thereof); agents , which stabilize microtubules; alkylating agents, antimetabolites; epidophyllotoxin; antitumor enzyme; topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/antihormonal therapeutic agents and hematopoietic growth factors.

Examples of classes of anticancer agents include, for example, drugs of the anthracycline family, vincaine drugs, mitomycins, bleomycins, cytotoxic nucleosides, taxanes, epothilones, discodermolides, drugs of the pteridine family, diuneneses (diupepev), and podophyllotoxins. Particularly useful representatives of this class include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, metopterin, dichlor-methotrexate, mitomycin C, porphyromycin, Negseript, KyhapF, 5-fluorouracil, b-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or derivatives podophyllotoxin such as colchicines, etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel, etc. Other useful anticancer agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosfamide, melphalan, hexamethyl melamine, thiotepa, cytarabine, 70 idatrexate, trimetrexate, dacarbazine, I-asparaginase, camptothecin, CPT-11, topotecan, aga-C , bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins. The best class of antineoplastic agents are the taxanes and the best antineoplastic agent is paclitaxel.

Radiation therapy, including X-rays or gamma radiation from an external beam or from implanted miniature radioactive sources, may also be used in combination with the 7/5 compounds of the present invention solely to treat cancer.

EXAMPLES

The following formulations and examples are provided to enable those skilled in the art to clearly understand and practice the present invention. They are not to be construed as limiting the invention, but merely to illustrate and represent it.

Examples of synthesis

Example 1

Synthesis of M-hydroxy-4-(2-benzenecarbonylamino-ethoxy)benzamide

She is happy and what about; zo Te o M (ge)

Stage 1

To a solution of 2-aminoethanol / (3.1 g, 5 mmol) in tetrahydrofuran (TNE) (10 ml) was added tert-butyloxycarbonyl hydride (10.9 g, 50 mmol) in TNE (15 ml). The reaction mixture was stirred for 3 h, after which it was filtered using ethyl acetate and washed with a 0.5 M aqueous solution of HCl and saline solution.

The organic layer was dried (Mo 5 O 4 ), filtered, and concentrated in vacuo to give 2-M-Boc-aminoethanol, which could be used directly in the next step. "

Stage 2 shsh s To a solution of triphenylphosphine (17.7g, 67.5mmol) in anhydrous TNE (135ml) was added OIAO (13.bg, c 67.B5mmol). The solution was stirred until a white precipitate formed (from 2 to 1 Ohv.). A solution of 2-M-Voc amino-ethanol (7.2g, 45mmol) and methyl 4-hydroxybenzoate (6.8g, 45mmol) in TNE (25ml) was added after a few minutes and stirred for 5 hours. The reaction mixture was concentrated by massio and purified by flash chromatography to give methyl 4-(2-M-Bos-aminoethoxy)benzoate. Alternatively, in the next stage, the crude material can be used.

Stage 3 o To a solution of crude methyl 4-(2-M-Boc-aminoethoxy)benzoate in methanol (200 ml) was added 4 M NeSi/dioxane o (180 ml). After stirring for 3 h, diethyl ether (30 mL) was added, which resulted in the formation of a white precipitate. The solid precipitate was collected, suspended in ethyl acetate and stirred for 15-20 minutes. The solid was collected again and dried under high vacuum to give methyl 4-(2-aminoethoxy)benzoate as hydrochloride 6.3g (6095 over 2 steps).

Stage 4

To a suspension of methyl 4-(2-amino-ethoxy)benzoate hydrochloride (0.232g, immole) in TNE (bml) was added benzoyl chloride (0.140g, immole), and then triethylamine (0.121g, 1.2mmol). The reaction mixture was stirred for 1 hour. and then diluted with ethyl acetate. The organic layer was washed with 0.5M aqueous CARRIER saturated with the solution

F) sodium bicarbonate and saline solution. The organic layer was concentrated in fat, which resulted in the formation of methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate, which was directly used in the next step.

Stage 5 60 To a solution of crude methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate (0.Bmmol) in a 1:1 mixture

TNE/methanol (20ml) was added with 50 units of 956 aqueous hydroxylamine (Zml), and then TM aqueous Mahon solution (ml), bringing the pH to 10-11. The reaction mixture was stirred for 14 hours, neutralized to pH-7-8 with the help of 1M aqueous solution of HCl and concentrated by weight. The precipitate was collected and purified by high performance chromatography (HPLC) to give the title compound as a white solid. 65 NMR (DMSO - av): 5 8.69 (t, 9U-5.8Hz, 1H), 7.83 (d, 9U-7.5Hz, 2H), 7.69 (d, U-9.1Hz, 2H), 7.46 (m , ZN), 6.99 (d, 9-9.1Hz, 2H), 4.16 (t, U-5.8Hz, 2H), 3.63 (q, 9U-5.8Hz, 2H). EM (calc.): 300.1; MS (EI) m/e: 301.1 (M-1)7,

299.0 (MAT).

The procedure is the same as in Example 1, Steps 1-4 above, but replacing 2-aminoethanol with (5)-(-)-2-amino-1-butanol, which gives methyl 4-(25-aminobutoxy)benzoate hydrochloride.

Example 2

Synthesis of M-hydroxy-4-I(I2-(benzofuran-2-yl-carbonylamino)-ethoxy|-benzamide)

Stage 1

A mixture of benzofuran-2-carboxylic acid (0.162 g, Tmmol), (EUOS). NSI (0.268g, 1.44mmol) and NOVT. NHO (0.203 g, 1.5 mmol) in OME (bml) was stirred for 2 h. Methyl 4-(2-aminoethoxy)benzoate hydrochloride (0.232 g, tmmol) was added, followed by triethylamine (0.121 g, 1.2 mmol). The reaction mixture was stirred for 2 hours, then diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution. with

The organic layer was concentrated and the crude 4-(2-(benzofuran-2-ylcarbonylamino)ethoxy|benzoate was converted to the desired compound as described above in Example 1, Step 5. o

H NMR (0MSO-α) 5 11.05 (s, 1H), 8.92 (t, 9U-5.6Hz, 71H), 8.88 (s, 1H), 7.76 (d, 9U-8.0Hz, 1H), 7.70 (d , 3-9.2Hz, 2H), 7.64 (d, 9U-8.0Hz, 1H), 7.55 (s, 1H), 7.46 (t, 9-6.8Hz, 1H), 7.32 (t, U-8.0Hz, 1H ), 7.01 (d,

U-8.2Hz, 2H), 4.18 (t, 9-5.6Hz, 2H), 3.67 (m, 2H). EM (calc.): 340.1; MS (EBI) M/e: (MAN): 341.0, (M-1H) 7: 339.1. "That's it

Example C

Synthesis of M-hydroxy-4-(2-(benzothiophen-2-yl-carbonylamino)-ethoxy|-benzamide)

Benzothiophene-2-carbonyl chloride (0.150g, Tmmol) was added to a suspension of methyl 4-(2-aminoethoxy)benzoate hydrochloride (0.232g, Tmmol) in TNE (bml) for 73 seconds, after which triethylamine (0.121g, 1.2mmol) was added. . The reaction mixture was stirred for 1 hour. and diluted with ethyl acetate (5 Oml). The organic layer was washed with a 0.5 M aqueous solution of NOI, saturated sodium bicarbonate solution, and brine. The organic layer was concentrated i.p. and crude methyl 4-(2-(benzothiophen-2-yl-carbonylamino)ethoxy|benzoate) was converted into the desired compound as described above in Example 1, Step 5. The procedure is the same as in Example C above, but substituting methyl 4-(2-aminoethoxy)benzoate hydrochloride for methyl 4-(25-aminobutoxy)benzoate hydrochloride and benzothiophene-2- carbonyl chloride - to cinnamoyl de chloride, which gives M-hydroxy-4-(25-(trans-cinnamoylamino)butoxy|benzamide. o Example 4

Synthesis of M-hydroxy-4-(2-(3-dimethylaminobenzofuran-2-ylcarbonylamino)-ethoxy|-benzamide -

F (NzS)oM o ra o. yu shto pn cha, in dOchNONn

Stage 1

Oxalyl chloride (0.53 ml, 6.1 mmol) was added to a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98 g, 5 mmol) and 5 drops of OME in TNE (25 ml). After stirring the solution for 1 hour. at room temperature 65, methanol (20 ml) and tertylamine TEA (7 ml) were added. The suspension was stirred overnight at room temperature, then concentrated, dissolved in ethyl acetate (1000 mL) and washed with weak Manceau with

(100ml). The organic layer was dried (Mo5O)), filtered and concentrated, which made it possible to collect

Z-methyl-benzofuran-2-carboxylic acid methyl ester (1g) in the form of a yellow-brown solid. The crude methyl ester was used without further purification.

Stage 2

A solution of 3-methylbenzofuran-2-carboxylic acid methyl ester (1.0g, 5.mmol), MV (0.95g, 5.mmol) and

AIIVM (87 mg, 0.53 mmol) was heated in a reflux condenser in SSI) (40 ml) for 3 h, then cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried (Ma5O)), filtered and concentrated to collect 70 3-bromomethylbenzofuran-2-carboxylic acid methyl ester (1.55g) as a yellow-brown/yellow solid, which was used in the next step without further purification .

Stage Z

3-Bromomethylbenzofuran-2-carboxylic acid methyl ester (269mg, mmol) was dissolved in anhydrous OME, after which 2M dimethylamine/tNE solution (1.5ml, 3mmol) was added. After 1-2 hours, the reaction mixture was diluted with EtOAc and washed twice with saturated MnHsCO»z (aq.) and saline solution.

The organic extract was dried over NaCl, and then concentrated with NaCl. The crude product was purified on a silica gel column (590 Meon in dichloromethane) to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid methyl ester (131mg).

Stage 4

To a solution of 3-dimethylaminomethylbenzofuran-2-carboxylic acid methyl ester (131 mg, 0.5 mmol) in

Meon was added 1M Maon (aqueous) until the pH value reached 13. The reaction mixture was stirred for 60-9O0min. Upon completion of the reaction, the reaction mixture was acidified to pH 3 with the help of HC! (aq.) and concentrated to dryness, which gave dimethylaminomethylbenzofuran-2-carboxylic acid in the form of the HCI salt, which was used in the next stage without further purification. with

Stage 5

ESO was added to 3-dimethylaminomethylbenzofuran-2-carboxylic acid (140 mg, 0.5 mmol). NS (8) (15Omg, 0.7v4mmol) and NEW. NO (114 mg, 0.4 mmol) in anhydrous OME. The reaction mixture was stirred for 30 h, after which methyl-(4-(2-ethoxyamine))benzoate hydrochloride salt (13 Ωg, 0.5 mmol) and triethylamine (94 μl, 0.672 mmol) were added, the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed twice with saturated NaOH (aq) and brine. The organic extract was concentrated to mass, which gave methyl 4-(2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)ethoxy|benzoate, which was then used without further purification.

Stage 6

To a solution of crude methyl 4-(2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)-ethoxy|-benzoate in

An excess of an aqueous solution of hydroxylamine and Mahon (aqueous) was added to Meon and TNE until pH 10-11 was reached. with

The reaction mixture was stirred overnight, after which it was neutralized to pH 7-8 with an aqueous solution of hydrochloric acid and concentrated by weight. The residue was dissolved in acetonitrile and water and purified using preparative NRI C to give the desired compound (107 mgH). "H NMR (400MHz, DMSO-α5) 5 9.88 (m, 1H), 9.31 (t, 9U-6.0Hz, 1), 8.04 (d, 9U-7.6Hz, 1H), 7.70 (m, ЗН), " 407.57 (t, u7.6bHz, 1H), 7.45 (t, 9U-7.6Hz, 1H), 6.99 (d, 9U-9.2Hz, 2H), 4.76 (d, 9U-4.8Hz, 2H), 4.23 ( t, 9-6.0 Hz, pt) s 2H), 3.71 (m, 2H), 2.84 (s, ЗН), 2.83 (s, ЗН). in EM (calc.): 397.2; MS (E5I) m/e (MA1H) 7": 398.1, (M-1H) 7: 396.2. ,” Example 5

Synthesis of M-hydroxy-4-12-I3-(2,2,2-trifluoroethyloxymethyl)benzofuran-2-yl-carbonylamino|ethoxy)benzamide so 45 Se. yu s so o (4 more What about her! And nak

Y, 0 n and o 7 soch ko

Step 60 Sodium hydride (15mg, 0.5bmmol) was suspended in anhydrous UOME and stirred over Ma(g). 2,2,2-Trifluoroethanol (27 µl, 3.7 mmol) was added and after stirring the reaction mixture for 15-20 min., added

C-bromomethylbenzofuran-2-carboxylic acid methyl ester. After 8 hours, 1 M Mahon (aq.) was added and the reaction mixture was stirred for 10-15 minutes. The reaction mixture was acidified to pH 3 with an aqueous solution of hydrochloric acid, after which the product was extracted with EAs. The organic layer was then dried over MA»ZO, and concentrated ip mUuasso, which gave

3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylic acid (38 mg), which was then used without further purification.

Stage 2

To a solution of 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylic acid (38 mg, 0.139 mmol) in anhydrous

OME added EOS. NSI (Zumg, 0.195mmol) and NEW NEW (2bmg, 0.195mmol). After 60-90 minutes, methyl-(4-(2-ethoxyamine))benzoate hydrochloride salt (32 mg, 0.139 mmol) and triethylamine (2 µl, 0.167 mmol) were added, after which the reaction mixture was stirred for 1-2 hours. The reaction mixture was diluted with EOAc and washed twice with sat. -carbonylamino|ethoxy)benzoate, which was then used without further purification.

Step C 4-(2-I3-(-2,2,2-Trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino)|-ethoxy)-benzoate was dissolved in Meson and excess aqueous hydroxylamine solution, then Mahon (aq. ) in order to bring the pH to 10-11. 7/5 After stirring overnight, the reaction mixture was neutralized to pH 7-8 with an aqueous solution of hydrochloric acid. The reaction mixture was concentrated to mass to give a solid, which was collected and washed with water, then dissolved in acetonitrile and water and purified using preparative HRI C to give the desired compound (35mgH). "NMR (400MHz, UMSO-av) 5 11.04 (s, 1n), 8.95 (t, 9-5.6Hz, 1H), 8.89 (s, 1H), 7.81 (d, 9-7.6HzC, 1H), 7.70 (d, uU-8.8Hz, 2H), 7.63 (d, uU-8.8Hz, 1H), 7.50 (t, 9U-8.8Hzc, 1), 7.36 (t, U-8.0Hz, 1H), 7.00 ( d, 9U-9.2Hz, 2H), 5.25 (s, 2H), 4.18 (m, 4H), 3.67 (m, 2H).

EM (calc.): 452.1; MS (EI) m/e (M-АА1Н) 7": 453.0, (М-1Н) 7: 451.0.

Example 6

Synthesis of M-hydroxy-4-(2-(5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide

SOMNON i- (ge)

Step 1c 5-Methoxybenzofuran-2-carboxylic acid (5.04g, 2bmmol) was weighed into a 200-mL round-bottomed flask equipped with a stir bar, membrane, and nitrogen inlet valve. Anhydrous Meon (5 Oml) was added under a nitrogen atmosphere. The solution was cooled in an ice bath, thionyl chloride was added dropwise (2.Zml,

C2mmol) with vigorous stirring. After stirring for 72 hours. at room temperature, the reaction mixture was poured into water (15 Oml) and a white solid was collected. The solid substance was dissolved in toluene "40. (100 ml), the solution was washed with 1M Manso" and saline solution and dried over Ma5O4. Removal of the organic layer Ш-) with gave 5-methoxy-benzofuran-2-carboxylic acid methyl ester in the form of a solid white substance (5.15G). a Stage 2 "» A solution of 5-methoxybenzofuran-2-carboxylic acid methyl ester (5.15g, 25mmol) in anhydrous methylene chloride (15ml) was cooled to -402 under a nitrogen atmosphere. Boron tribromide in СНоСі" (27ml 1.0M) was added

After 1 hour using a syringe-pump. The reaction mixture was left to cool to room temperature. After 16 h, the reaction mixture was cooled in an ice bath and then quenched with

Meon (15 ml). The reaction mixture was poured into a saline solution (100 ml) and extracted with Es. The organic extracts were dried over anhydrous NaCl and the solvent was removed on a rotary evaporator. The residue (ee) was triturated with hexane, and the yellow solid was filtered and dissolved in anhydrous - 50 Meon (ZOml). The solution was cooled in an ice bath and thionyl chloride (1.9 mL, 2 mmol) was added dropwise. After 72 h, water (100 mL) was added and the solid was collected. Cleansing of the raw product by ZO0cm? silica gel in 5x15 cm (42. cylinders) with the help of E(Ac) led to the formation of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (4.53G).

Stage Z

Anhydrous tetrahydrofuran (15 mL) was added to a mixture of 5-hydroxybenzofuran-2-carboxylic acid methyl o ester (1.10 g, 5.7 mmol), triphenylphosphine (1.50 g, 5.7 mmol), and 1-(2-hydroxyethyl)-pyrrolidine (0.6 bg, 5.7 mmol) in a nitrogen atmosphere. Diisopropyl azodicarboxylate (1.15 mL, 5.8 mmol) was slowly added to the solution (io) at room temperature. After 2 days, the solvent was removed and the residue was dissolved in a 2:1 mixture

ESCO: EUAc (150 ml). The solution was washed with 1.0M aqueous Mahon solution. The product was extracted in 1.0M hydrochloric acid and the combined acid extracts were washed with EBO. The extracts were cooled, the pH of the extracts was adjusted to pH 12 with the help of 5095 aqueous solution of MasoN. The main solution was extracted with SNCl and the organic layer was dried over anhydrous Mo 5 O 2 , which resulted in the formation of 5-(2-pyrrolidin-1-yl-ethoxy)benzofuran-2-carboxylic acid methyl ester (0.96 g) as solid amber color. because Stage 4

To a solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid methyl ester (96Omg, 3.Zmmol),

cooled in an ice bath, a degassed aqueous solution of lithium hydroxide (2.O0ml, 2.0M) was added dropwise to anhydrous ethylene glycol of dimethyl ether (100ml). After stirring at room temperature for 4 h, the solution was cooled, the pH was adjusted to 2 with 4.0 M CARRIER in dioxane. A clayey yellow-brown precipitate was formed. The solvent was removed and the resinous residue was frozen and lyophilized. The yellow-brown solid was dissolved in boiling 2-propanol (90 mL), the hot solution was filtered and then cooled to give 5-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-2-carboxylic acid as acicular crystals, colored in beige color (528mg). Additionally, 153 mg of the substance was obtained from the mother liquor. 70 Stage 5

To a solution of /5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid (15 mg, 0.5 mmol) and 4-(2-aminoethoxy)benzoic acid methyl ester hydrochloride (129 mg, 0.5 mmol) in OME (4.5 ml) in a 20-ml test tube, diisopropylethylamine (0.8 ml, 5.mmol) was added. The solution was added

O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (74µl, 0.82M, 0.6b1mmol) in OME, which /5 led to the formation of a bright yellow solution. The contents of the tube were released with nitrogen and then stirred at room temperature for 18 h. The solution was removed, the residue was dissolved in EtOAc (25 mL) and washed with HO, 1.0 M aqueous CoCoO 2 , and brine. The organic layer was dried over anhydrous Mo950 and the solvent was removed on a rotary evaporator. Purification of the residue by column chromatography on silica gel columns using 93:5:2 CH 5Si»"MeonH:TEA as eluent 2o resulted in the formation of 4-(2-15-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino |-ethoxy)-benzoic acid methyl ester as a beige solid (174mg).

Stage 6

To a solution of /4-02-D|5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino|-ethoxy)-benzoic //- acid methyl ester (169mg, 0.37mmol) in methanol (8ml) and tetrahydrofuran (4 ml) was added hydroxylamine in water with ov (2.3 ml of 50 ml of solution) and 4.0 M aqueous solution of sodium hydroxide (0.65 ml). After stirring for 18 h, the organic layers were removed and the aqueous solution was cooled in an ice/water bath and the pH was adjusted to (o) about 8 with 4.4 mL of 1.0 M hydrochloric acid, causing a precipitate to form. The heterogeneous solution was heated to room temperature, acetonitrile was added to dissolve the precipitate. The solution was chromatographed on C-18 NRI C with the reverse phase. Fractions with a spectral absorbance at 214 nm were selected, frozen and lyophilized, which gave the desired compound (31 mg) H NMR (400 MHz, OMSO-y4v) 5 : 11.05 (s, 1H), 10.4 (s, 1H) . 1H), 7.13 (d, 1H, 9U-9.0Hz), 7.00 (d, 2H, 9-7.4Г3)), 437 (3 (m, 2H), 4.18 (m, 2H), 3.62 (m, 6H) , 3.12 (m, 2H), 2.02 (m, 2H), 1.89 (m, 2H). EM (calc.): 453.2; MO (E5I) m/e (MAN): 454.1, (M-ATN):: 452.2. p

Example 7 p

Synthesis of M-hydroxy-4-(2--3-dimethylaminobenzofuran-2-ylcarbonylamino)-ethoxy|-benzamide hydrochloride (НзСьМ « z - s and g» и U. M dity. dn MC 1 -ish more. НН щ со Step 1 (2-Hydroxyethyl)carbamic acid tert-butyl ester (152.0 g, 0.942 mol) and 4-hydroxy-benzoic acid methyl ester (174.0 g, 1.12 mol) were dissolved in tetrahydrofuran (2000 ml) and cooled. to 0-50. Triphenylphosphine (292.8g, 1.116 mol) was added to the cooled mixture. A solution of diisopropyl azodicarboxylate (246.0g, 1.218 mol) in tetrahydrofuran (400ml) was added dropwise over a period of one to two hours, maintaining the reaction temperature below 102 C. After the addition, the reaction mixture was allowed to cool slowly at ambient temperature with stirring overnight.

After the completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting oily liquid was dissolved in ethanol (50 mL) and ethyl acetate (200 mL). Acetyl chloride (222.0 g, 2.826 mol) was added dropwise over 15 minutes, while the temperature rose to 402C. The resulting suspension was stirred at 402C until the reaction was complete. After completion of the reaction, the obtained crystals were filtered on a coarse frit and washed with ethyl acetate (300 ml). The material was dried under vacuum to give 4-(2-aminoethoxy)benzoic acid methyl ester hydrochloride (204.1g) as a white crystalline substance.

Step 2 4-(2-Aminoethoxy)benzoic acid methyl ester hydrochloride (78.90 g, 0.34 mol) and 3-methylbenzofuran-2-carboxylic acid (60.0 g, 0.340 mol) were suspended in acetonitrile (ZbOml) and cooled to 0- 59. Pyridine (137.bml, 1.702mol) was quickly added. A solution of phosphorus oxychloride (52.2Hg, 0.34Omol) in acetonitrile (bOml) was added dropwise over 30 to 45 minutes at a temperature maintained below 202C. The reaction mixture was stirred for one hour, heating slowly to ambient temperature. After completion of the reaction, the solution was added to a mixture of chlorobenzene (100Oml) and 1M hydrochloric acid (100O0ml), which was vigorously stirred at 0-5 "С. The reaction mixture was quickly stirred and allowed to warm to room temperature. The organic layer was washed with water, 3905 potassium hydroxide and again with water. Chlorobenzene (100 ml) was added to the washed organic layer. After that, the solvent (100 ml) was distilled at atmospheric pressure until the cube temperature reached 1322 C. After cooling to 70 ambient temperature, 4-2-((3-methylbenzofuran-2- carbonyl)amino|ethoxy)benzoic acid methyl ester was stored in solution for use in the next Stage.

Stage Z

A solution of 4-(2-(3-methylbenzofuran-2-carbonyl)amino|)ethoxy)benzoic acid methyl ester (0.340 mol) in chlorobenzene (1000 mL) was treated with 2,2'-azobisbutyronitrile (5.60 g, 0.017 mol) and M -bromosuccinimide 75. (75.76 g, 0.42 bmol). The resulting mixture was heated to 802C and stirred for one hour.

After completion of the reaction, the reaction mixture was cooled to ambient temperature and washed with water, 390 sodium hydrogen sulfite, and again with water. The solvent was distilled off under reduced pressure and after cooling to ambient temperature, dichloromethane was added, resulting in the formation of 4-2-((3-bromo-methylbenzofuran-2-carbonyl)amino|)ethoxy)benzoic acid methyl ester, which was 20 used in the next Stage.

Stage 4

A solution of 4-2-(3-bromomethylbenzofuran-2-carbonyl)amino|ethoxy)benzoic acid methyl ester (0.340 mol) in chlorobenzene (200 ml) and dichloromethane (800 ml) was added dropwise to a 0-59 C solution of 2M dimethylamine in tetrahydrofuran ( 51Oml, 1.022 mol) for 30 minutes at a temperature below 2020. "EM 25 The resulting mixture was stirred for one hour in order to heat it to ambient temperature. After completion of the reaction, the reaction mixture was washed with 595% potassium carbonate and water.

The solvent was distilled at atmospheric pressure until the cube temperature reached 100°C. After cooling to -50°C, acetonitrile (400ml) and ethyl acetate (400ml) were added to the cube. The reaction mixture was heated in a reflux condenser until complete dissolution of the solid substance. The reaction mixture was allowed to cool for 30 hours, which gave 4-2-((3-dimethylaminomethyl-benzofuran-2-carbonyl)amino)ethoxy)benzoic acid methyl ester (76.6 g) as a white powder.

Step 5: 4-2-(3-Dimethylaminomethylbenzofuran-2-carbonyl)amino|ethoxy)benzoic acid methyl ester (70.0, 0.177 mol) was suspended in methanol (35 mL). 50905 potassium hydroxide (139.8g, 1.062mol) was added, and the reaction

The mixture was heated to 602 C until the reaction was complete. After cooling to room temperature, the crystals that formed were filtered on a coarse frit and washed with methanol. The crystals were dried and dried to give 4-2-(3-dimethylaminomethylbenzofuran-2-carbonyl)amino|)ethoxy)benzoic acid potassium salt (72.0g) as a white solid. "

Step 6 70 4-2-(3-Dimethylaminomethylbenzofuran-2-carbonyl)amino|ethoxy)benzoic acid potassium salt (20.Og, in s 0.0476 mol) was suspended in M,M-dimethylformamide (10Oml). 4 molar hydrochloric acid in dioxane (11.9 Uml, 0.047 bmol) was added to the suspension. After stirring for 30 minutes at ambient temperature, the reaction mixture was filtered through a medium frit. 1-(3-dimethylamino)propyl|-3-ethylcarbodiimide hydrochloride (10.94g, 0.0571mol) and 1-hydroxybenzotriazole (7.71g, 0.0571mol) were added to the solution, after which the reaction mixture was stirred for one hour at room temperature the surrounding environment. In a separate cube, hydroxylamine hydrochloride (13.2g, 1.904 mol)

Kz was suspended in M,M-dimethylformamide (10O0ml) and treated with triethylamine (33.ml, 2.38O0mol). After stirring the reaction mixture for 1 hour, the salt was filtered off, and the resulting sodium chloride solution was added to the above-activated acid solution and stirred at ambient temperature until the completion of the reaction. After the product began to crystallize, methanol (150 ml) was added slowly over 30 minutes. The reaction mixture was stirred for 1 hour. at ambient temperature, then cooled to 0-52C, then stirred for another 1 hour. The crystals were filtered off and washed with methanol (40ml) before drying on a hot plate to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid (2-(4-hydroxy-carbamoylphenoxy)ethylamide) (11.88g) as a white solid. (13.25 g, 0.033 mol) was suspended in M,M-dimethylformamide (8 Oml) and heated to 1009C until the formation

HF) solution. After cooling, ethanol (80ml) was added dropwise within 30 minutes, and the resulting suspension was left to cool for 1 hour. The crystals were filtered and washed with ethanol (40 mL), then dried to give the pure product (9.82 g) as a white solid. in Stage 7

3-Dimethylaminomethylbenzofuran-2-carboxylic acid (2-(4-hydroxy-carbamoylphenoxy)ethylamide (22.7 g, 0.057 mol) was suspended in 2-propanol (220 mL). 12M HCl (5.2 mL, 0.063 mol) was added to in one portion, the resulting mixture was heated in a reflux condenser. Water (44 mL) was added dropwise until a homogeneous solution was formed. The reaction mixture was left to cool and crystallize overnight. After cooling below 59 for 1 h, the crystals were filtered off and washed with 2-propanol before dried and weighed to give the desired compound (22.0 g) as a white solid.

Example 8 Synthesis of M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)-ethylsulfanyl|benzamide o. sh-- - Ts

K 7 M ma and 5 vl non S ! their SOoMchNON

Stage 1

75 g of triphenylphosphine (5.25 g, 20 mmol) was added to a solution of diisopropyl azodicarboxylate (OIAO, 4.04 g, 200 mmol) in TNE (100 ml) at 092 C. After 1 hour, a solution of Bos-ethanolamine (3.22 g, 20 mmol) in TNE (1 Oml) was added. After 20 min, a solution of methyl 4-mercaptobenzoate (3.8 mg, 200 mmol) in TNE (1 Oml) was added, after which the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated, after which ethyl acetate (1500 ml) was added. The solution was washed with 1M HCl, saturated aqueous ManHsSO»z, saline solution, dried over Mo5O, filtered, and evaporated to dryness. The oily yellow residue was eluted through a silica gel column (0-20 ethyl acetate in hexane as mobile phase), after which the product was recrystallized from ether and hexane to give methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate (4.00 g).

Stage 2

A solution of methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)benzoate (1.00 g, 3.21 mmol) in dichloromethane (vml) was treated with a solution of NH in dioxane (4M, ml, 10 equiv.) at room temperature for 3 h. Ether (100 ml) was added, the mixture was filtered, washed with ether and dried with a pump to dryness, which gave methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride. and)

Stage Z

Methyl 4-(2-aminoethylsulfanyl)benzoate hydrochloride (0.248g, 1.00mmol) was combined with benzofuran-2-carboxylic acid (0.162g, 1.00mmol) and NVTO (0.379g, 1.00mmol) in OME (5ml) at room temperature. Triethylamine (0.307 mL, 2.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. Saturated aqueous Manso with (15 ml) was added to the formation of a precipitate, which was destroyed by the addition of water (20 ml). The solid was filtered and the "pancake" was dissolved in ethyl acetate. The remaining water was removed with a pipette, after which hexane was added, which gave methyl 4-2-((benzofuran-2-ylcarbonyl)-amino|ethylsulfanyl)ubenzoate (0.138g) as a resinous substance, which was used in the next step stage without further purification. co

Stage 4

A solution of 5090 hydroxylamine in water (4 ml) was added to a solution of methyl 4-12-(benzofuran-2-yl-carbonyl)aminodetylsulfanyl)-benzoate in TNE (2 ml). Methanol (2ml) and 0.1M Mahon (0.1ml) were added. The reaction mixture was stirred for three days at room temperature. The solvents were evaporated and the residue was crystallized from dichloromethane/ethyl acetate to give the desired compound (46 mg). -o c H NMR (DMSO-α): 3.12 (2Н, m); 3.5 (2H, m); 7.33 (IN, t); 7.42 (2H, d); 7.45 (IN, m"); 7.53 (1Н, s); 7.62 (1Н, d); 7.7 (2Н, d); 7.78 (1Н, d); 8.96 (1Н, t); s). MS (M.n1): 357. "" Example 9 Synthesis of M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)detylsulfonyl|benzamide zkh o 0, so re x. so b nn h

SshOomnOian - (42) ,

Stage 1

To a solution of methyl 4-(2-tert-butoxycarbonylaminoethylsulfanyl)-benzoate (3.00g, 9.63mmol) in methanol/water (17, 10bml) was added OkhopefF (13.03g, 21.19mmol). After 48 h, the methanol was removed under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and saturated aqueous MnHsCO 3 (150 O0 mL). The organic phase (F) was washed with saline solution (1000 ml), dried over Mo950O;, filtered, concentrated to mass, after which the residue was recrystallized by Kk! ethyl acetate/hexane to give methyl 4-(2-tert-butoxycarbonylamino-ethylsulfonyl)benzoate (2.86 g). in Stage 2

A solution of methyl 4-(2-tert-butoxycarbonylaminoethylsulfonyl)benzoate (2.86g, 8.33mmol) in dichloromethane (20ml) was treated with 4M NH in dioxane (200ml) for 2 h. Ether (200ml) was added, the suspension was filtered, washed with ether (2x500ml), hexane (50ml) and dried to dryness using a pump to give methyl 4-(2-aminoethylsulfonyl)benzoate hydrochloride (2.23g), which was condensed from benzofuran 2- carboxylic acid 65 as described above to give the desired compound. MS (M'n1): 388.

The procedure is the same as described above in Examples 1-3, but the following compounds from Tables I-IM were prepared using acceptable commercially available starting materials.

Table 1:

Spl.1 "NMR (400MHz, DMSO - av) 5 8.69 (t, 9U-5.8Hz, 1), 7.83 (d, 9U-7.5Hz, 2H), 7.69 (d, uU- 9.1Hz, 2H) . 300.1; MS (E5I) m/e: 301.1 (M-1)7, 299.0 (М'А1) U.

Spl.2 "H NMR (400MHz, DMSO-av) 5 11.08 (s, 1H), 8.92 (s, 1H), 8.41 (t, 9U-6Hz, 1), 7.74 (d, 9U-8.8Hz, 2H) . 9U-15.6Hz, 1H), 4.13 (t, U-5.2Hz, 2H), 3.60 (kv, U-5.6Hz, 2H).

EM (calc.): 326.1; MS (E5I) m/e (MA1H)": 327.1, (MA1H)7: 325.2.

Spl.Z "N' NMR (400MHz, DMOSO-yv5) 5 11.07 (s, 1H), 8.91 (s, 1H), 8.42 (t, 9-4.8Hz, 1), 7.72 (d, 9U-8.4АГцС, 2H), 79 T.Rt (t, dET.?Hgu, 2.0Hz), 7.18 (t, 9-7.2Hz, 1), 7.13 (d, 9U-7.2Hz, 2H), 7.01 (d, 9U-8.8 HC, 2H), 4.07 (t,

U5.6Hz, 2H), 3.49 (dkv, 9U4-5.6Hz, 9U2-1.6Hz, 2H), 2.28 (ddd, 94-4.0Hz, 9U2-5.6Hz, 9U3-59.6Hz, 1H), 1.95 (ddd, - 6. AGC,

U4210. AGC, 1H). EM (calc.): 340.1; MS (E5I) m/e (MA1TN)": 341.2, (М-Т1Н): 339.2.

Spl.4 "NMR (400 MHz, DMSO-a6) 5 11.08 (s, 1H), 8 92 (s, 1), 8 31 (t, 9U-5.6 Hz, 1H), 7.73 (d, 9U-9.2 Hz, 2H), 7.52 (d, 9-9.2Hz, 2H), 7.41 (d, 9-15.6Hz, 1), 7.03 (d, 9U-8.8Hz, 2H), 6.99 (d, 9U-8.8Hz, 2H), 6.55 (d, 9-15.6Hz, 1H), 4.12 (t, 9-5.6HzC, 2H), 3.81 (s, ZH), 3.58 (q, U-5.6Hz, 2H). EM (calc. ): 356.1; MS (E5I) m/e (MAN): 357.2, (МА1Н) 7": 355.2.

Spl.5 sya "H NMR (400MHz, DMSO-de) 5 10.96 (s, 1H), 8 80 (s, 1H), 8 01 (t, 9-4 8Hz, 1H), 7 61 (d, U- 8.8Hz, 23), OO 7.14-7.02 (m, 5H), 6.86 (d, 9U-8.8Hz, 2H), 3.32 (q, 9U-5.6Hz, 2H), 2.71 (t, 9U-7.2, 2H) , 2.30 (t, 9U-7.6Hz, 2H).

EM (calc.): 328.1; MS (EI) m/e (MA1H) 7: 329.2, (M-1H) 7: 327.0.

Spl.b "s zo "H NMR (400MHz, DMSO-dv) 6 11.11 (s, 1H), 10.89 (s, 1H), 8.95 (br s, 1H), 8.22 (t, 9-5.6Hz, 1H) . (t, U-7.6Hz, - 1H), 7.02 (d, 9U-8.АХц, 2H), 6.93 (t, 9U-8.4Hz, 1H), 4.09 (pseudo Her, 9U-6.0Hz, 2H), 3.58 (s, 2H), 3.50 (pseudo so sq, U-5.6Hz, 2H). EM (calc.): 353.1; MS (EI) m/e (MA1H)": 353.9, (M-1H) 7: 252.0.

Spl. 7 p

H nMR (400MHz, DMSOo-av) 5 11.11 (s, 1H), 8.80 (t, 9-5.6Hz, 71H), 7.82 (d, 9U-7.6Hz, 1H), 7.81 (d, s

U-8.OGCts, 1H), 7.76 (d, U-8.4Hz, 2H), 7.19 (t, 9U4-5.2Hz, 1H), 7.06 (d, 9U-8.8Hz, 2H), 4.21 (pseudo t, 9U-6.0Hz, 2H), 3.67 (pseudo square, 4-5.6Hz, 2H). EM (calc.): 306.1; MS (E5I) m/e (MATN)": 307.0, (M-1H) 7: 304.9.

Spl. 8 « "NMR (400 MHz, DMOSO-av) 5 8.98 (s, 1H), 8.9 (t, 9U-5.4Hz, 1), 8.67 (d, 9U-4.6Hz, 1H), 8.16 (d, U -8.Hz, 1H), 7.69 (d, 9U-8.9Hz, 2H), 7.48 (m, 1H), 6.99 (d, 9U-8.9Hz, 2H), 4.17 (t, 9-5.4Hz, 2H) , 3.65 (m, 2H). EM - s (calc.): 301.11; MS (E5I) m/e (M-1H). 300.0. "» Spl. 9 " "H NMR (400 MHz, OMSO-ydv) 5 11.03 (1IN, s), 8.87 (1Н, bs), 8.74 (1Н, t, 9У-5.6Hz), 7.93 (2Н, d, 9У-8.0Гу) . , 4.18 (2H, t, but U5.6Hz), 3.66 (2H, m). EM (calc.): 376.41; MS (E5I) m/e (MA1H) 7: 377.1, (M-A1H)": 375.0. so Spl. 10 io) EM (calc.): 376.1; MS (E5I) m/e (M--1) 7: 376.9. HC, 1H), 7.83 (d, 9U-4.0Hz, 1), -I 7.77 (d, 9-9.2HzC, 2H), 7.75 (d, 9U-7.2Hz, 2H), 7.59 (d, 9U-4.0 HC, 71H), 7.49 (pseudo t, 9-7.2Hz, 2H), 7.41

Fo (pseudo t, 9-7.6Hz, 1H), 7.07 (d, U-8.8Hz, 2H), 4.22 (pseudo t, 9-5.6Hz, 2H), 3.69 (pseudo kv, U-5.2Hz, 2H) .

EM (calc.): 382.1; MS (EB5I) m/e (МА1Н)": 383.1, (М-1Н): 381.0.

Spl. 12 "NMR (400 MHz, UOMSO-av) 5 11.05 (s, 1H), 10.15 (s, 1H), 8.36 (t, 9U-5.6Hz, 1H), 7.70 (d, U-8.8Hz, 2H) , 7.32 (m, 1H), 6.97 (d, 9U-8.8Hz, 2H), 6.92 (m, 1H), 6.88 (m, 71H), 4.04 (t, 9U-5.6Hz, 2H), 3.66 (s 2H), 3.45

F, (m, 2H). EM (calc.): 320.1; MS (E5I) m/e (MA1H)": 320.9, (M-1H): 319.0. ko Spl. 13 "H NMR (400 MHz, OMSO-av) 5 11.04 (s, 1H), 8.87 (m, 2H ), 8.45 (s, 1H), 7.97 (m, 4H), 7.71 (d, uU-8.8Hz, 60 2H), 7.59 (m, 2H), 7.02 (d, U-8.8Hz, 2H), 4.21 ( t, 9-5.6 Hz, 2H), 3.71 (m, 2H). EM (calc.): 350.1; MS (E5I) m/e (Mans); 350.9, (M-1H)": 349.1.

Spl. 14 "H NMR (400MHz, DMSO-a6) 5 11.04 (s, 1H), 8.98 (m, 2H), 8.52 (m, 2H), 8.19 (d, 9U-8.8Hz, 1H), 8.08 (d, 3-8.8Hz, 1), 7.71 (d, U-8.8Hz, 2H), 7.62 (m, 1H), 7.02 (d, 9U-8.8Hz, 2H), 4.22 (t, 9-5.6Hz, 2H) , 3.72 (m, 65 2H). EM (calc.): 351.1; MS (E5I) m/e (MA1H)": 351.8, (M-1H) 7: 349.9.

Spl. 15

EM (calc.): 383.1; MS (E5I) m/e (M--1)": 383.9, (M-1)7: 382.2.

Spl. 16 "H NMR (400MHz, DMSO-dv) 6 11.04 (s, 1H), 8.88 (s, 1H), 8.61 (t, 9U-4.8Hz, 1H), 7.78 (d, U-8.4Hz, 2H), 7.70 (d, 9U-8.8Hz, 2H), 7.46 (d, uU-8.8Hz, 2H), 6.99 (d, 9-8.6HzC, 2H), 4.15 (t, 9-5.6HzC, 2H), 3.62 ( m, 2H), 1.29 (s, 9H). EM (calc.): 356.2; MO (E5I) m/e (MA1H)": 357.0, (M-1H): 355.1.

Spl.17 "H NMR (400MHz, OMSO-yv) 5 11.06 (s, 1H), 8.95 (s, 1H), 8.72 (d, 9-5.2HzC, 1H), 8.56 (t, 9U-4.8Hz, 1H ), 70 8.40 (d, 9-7.6Hz, 71H), 7.80 (m, 1), 7.71 (d, 9U-8.8Hz, 2H), 7.55 (d, 9U-16.0Hz, 1), 7.00 (d, U-8.8Hz, 2H), 6.90 (d, 9-16.0HzC, 1H), 4.12 (t, 9U-5.6Hz, 2H), 3.59 (m, 2H). EM (calc.): 327.1; MS (EB5I ) m/e (MAN): 328.1, (M-1N): 326.1.

Spl.18 "H NMR (400MHz, DMSO-dv) 6 11.04 (s, 1H), 8.88 (s, 1H), 8.73 (t, 9U-5.6Hz, 1H), 7.93 (d, 9U-9.2Hz, 2H ), 9,769 (m, 4H), 7.47 (t, 9-2.4Hz, 2H), 7.01 (d, 9U-9.2Hz, 2H), 6.29 (t, 9U-2.4Hz, 2H), 4.18 (t, U-5.6Hz, 2H), 3.66 (m, 2H). EM (calc.): 365.1; MS (E5I) m/e (M-1H)": 366.0, (M-1H) 7: 364.2.

Spl. 19

H NMR (400MHz, DMSO-α) 6 11.04 (s, 1H), 8.53 (t, 9U-5.6Hz, 71H), 7.80 (d, 9U-9.2Hz, 2H), 7.70 (d, 5-9.2Hz, 2H), 6.99 (m, 4H), 5.95 (m, 1H), 5.80 (m, 1H), 4.96 (s, 1H), 4.14 (t, 9-5.6Hz, 2H), 3.60 (m, 2H), 2.00 (m, ZN), 1.72 (m, ZN). EM (calc.): 396.2; MS (E5I) m/e (MA1TN)": 397.1, (MATN): 395.2.

Spl. 20

H NMR (400MHz, DMSO-α) 6 11.08 (s, 1H), 9.35 (t, 9U-5.6Hz, 71H), 8.25 (d, 9U-7.6Hz, 1H), 8.15 (d,

U-8.0Hz, 71H), 7.73 (d, uU-8.8Hz, 2H), 7.68-7.58 (m, 2H), 7.03 (d, 9U-9.2 Hz, 2H), 4.23 (pseudo, U-6.4Hz, 2H), with 3.74 (pseudo square, U-6.OHc, 2H). EM (calc.): 357.1; MS (E5I) m/e (MA1H)": 358.1, (M-1H) 7: 356.0.

Spl.21 o "H NMR (400MHz, DMSO-dv) 5 11.07 (s, 1H), 9.47 (t, 9-56 Na, 1H), 7.90 (pseudo t, 9-9.2Hz, 2H), 7.73 (d , U-8.8Hz, 2H), 4.59 (td, 9U4-7.6Hz, 9U2-0.8Hz, 1H), 7.52 (td, 9U2-8.0 Hz, d2-1.2Hz, 1H), 7.03 (d, U-8.8 Hz, 2H), 4.24 (t, 96.0Hz, 2H), 3.72 (pseudo sq, U-6.0Hz, 2H). EM (calc.): 341.1; MS (E5I) m/e (MA1H)": 342.1, (М-А1Н) 7: 340.2. (se)

Spl.22 M "H NMR (400MHz, DMSO-av) 5 11.08 (s, 1H), 9.70 (s, 1H), 8.91, (t, 9U-5.6Hz, 1), 7.72 (d, 9U-8.4Hz , 2H), 6.97 (d, U-8.4Hz, 2H), 4.10 (m, 2H), 3.93 (m, 2H), 3.54 (m, 2H), 3.27 (m, 2H), 3.08 (m, 2H) . . with

Spl. 23

H NMR (400MHz, DMSO-4v) 5 11.09 (s, 1H), 8.35 (d, 9-6.8Hz, 2H), 7.72 (d, 9-9.2Hz, 2H), 7.25 (d, 0

U-6.8Hz, 2H), 6.98 (d, 9U-9.2Hz, 2H), 4.10 (t, 9-5.6Hz, 2H), 3.97 (m, 2H), 3.54 (M, 10H). EM (calc.): 399.2;

MS (E5I) m/e (MA1N) 7: 400.1, (M-1N)": 398.1.

Spl. 24 "

EM (calc.): 290.1; MS (E5I) m/e (M--1)7: 291.1, (M-1H) 7: 289.2. -o s Spl.25 and EM (calc.): 377.1; MS (EBI) m/e (M-n1)7: 377.9, (M-ATN): 376.0. "» Spl. 26

EM (calculated): 377.1; MS (E5I) m/e (M--1)7. 378.0, (M-1H) 375 9

Spl. 27

Go | "H NMR (400MHz, DMSO-ydv) 6 11.04 (s, 1H), 9.11 (t, 9U-5.6Hz, 1H), 7.70 (d, 9U-9.2Hz, 2H), 7.62 (m, 2H), with 7.29 (m, 2H), 7.01 (d, 9-9.2Hz, 2H), 4.21 (t, 9-5.6Hz, 2H), 3.71 (m, 2H). EM (calc.): 340.1; MS (E5I) m/e (MATN)": 341.0, (М-Т1Н)7: 339.1. so Spl. 28 -I 50 EM (calc.): 289.1; MS (E5I) m/e (MA1N) 7": 290.0, (M-1N) 7: 287.8.

Spl.29 0 "H NMR (400MHz, DMSO-dv) 5 11.04 (s 1H), 10.43 (s, 1H), 8.62 (t, 9U-6.0Hz, 1), 7.94 (d, 9U-6.4Hz, 2H ), 7.853 (m, 4H), 7.70 (d, 9-9.2Hz, 2H), 7.60 (m, 1H), 7.52 (m, 2H), 7.00 (d, 9U-9.2Hz, 2H), 4.16 (t . M-1H): 418.3.

Spl. 3O0

HF) "H NMR (400MHz, OMSO-yv) 5 11.04 (s, 1H), 9.23 (t, 9U-6.0Hz, 1H), 9.01 (s, 1H), 8.89 (d, 9U-6.8Hz, 2H) , from 8.38 (d, 9U-6.4Hz, 2H), 7.70 (d, 9U-9.2Hz, 2H), 7.00 (d, 9-9.2Hz, 2H), 4.22 (t, 9-5.6Hz, 2H), 3.71 (m, 2H). EM (calc.): 384.1; MS (EI) m/e (MATN)": 384.9, (M- 1H)7: 382.9. 6 o Spl. 31

H NMR (400 MHz, DMSO-α) 6 11.04 (s, 1), 7.69 (d, uU-8.4Hz, 2H), 7.56 (t, 9U-5.6Hz, 1H), 7.01 (d,

U-8.8Hz, 2H), 4.01 (t, 9U-5.6Hz, 2H), 3.40 (m, 2H), 1.95 (m, ЗН), 1.69 (m, 12H). EM (calc.): 358.2; MS (EZ5I) m/e (M--1H) 7": 358.9, (M-1H)7: 357.2.

Spl.32 65 EM (calc.): 336.09; MS (EI) m/e (M-1H) 7: 335.3.

Spl. 33

EM (calc.): 370.12; MS (E5I) m/e (M-1H) 7: 369.0.

Spl. 34

EM (calc.): 344.10, MS (E5I) m/e (MA1H)": 345.0, (M-1H)": 343.1.

Spl. 35

EM (calc.): 360.13, MS (EI) m/e (M-1H) 7: 359.1.

Spl. 3b

EM (comp.). 344.10, MS (EI) m/e (M-1H)": 358.8

Floor 37

EM (calc.): 336.09; MS (E5I) m/e (MA1H)": 337.2, (M-1H)": 335.0.

Spl. 38

EM (calc.): 328.14; MS (E5I) m/e (MA1H)": 329.2, (M-1H)7: 327.2.

Spl.39 75 EM (calc.): 368.03; MS (EI) m/e (M-1H) 7: 367 0.

Spl. 40

EM (calc.): 328.14; MS (E5I) m/e (MA1H)". 328.8, (M-1H)7: 327.2.

Spl. 41

EM (calc.): 364.08; MS (E5I) m/e (MAN): 365.1 (M-1H): 363.2.

Spl. 42

EM (calc.): 344.14; MS (E5I) m/e (MA1N)": 345.1, (M-1N)": 343.1.

Spl. 43

EM (calc.): 344.14; MS (E5I) m/e (MA1H)": 345.0, (M-1H)": 343.2.

Spl. 44 p

EM (calc.): 348.11; MS (E5I) m/e (MA1H)": 348.8, (M-1H): 346.9. Ge)

Spl. 45

EM (calc.): 412.11, MS (E5I) m/e (MA1H)". 413.3, (M-1H). 411.0.

Spl. 46

EM (calc.): 412.11; MO (E5I) m/e (MIN): 413.2, (M-1H): 411.1. i-th 3o SplA7 M

EM (calc.): 376.14; MS (E5I) m/e (МА1Н)": 377.0, (М-А1Н): 375.2. (ge)

Spl. 48

EM (calc.): 339.12, MS (E5I) m/e (MA1H)": 340.1, (M-1H)": 338.3. with

Spl.49 so "H NMR (400MHz, DMSO-dv) 5 11.53 (s, 1H), 11.04 (s, 1H), 8.12 (d, 2-7.6Hz, 2H), 8.01 (s, 1H), 7.70 ( d, 3-9.2Hz, 2H), 7.40 (d, 9U-8.0, Hz, 1), 7.10 (m, 2H), 7.017 (d, 9-8 8Hz, 2H), 4.16 (t, 9-5 b6Hz , 2H), 3.64 (m, 2H). EM (calc.): 339.1; MS (EBI) m/e (MA1H) 7: 340 0, (M-1H) 7: 338.1.

Spl. 50 "

H NMR (400MHz, DMSO-α) 6 9.37 (s, 1H), 9.21 (t, 9-5.2Hz, 1H), 9.02 (s, 1H), 8.15 (t, 9U-9.2Hz, 2H), Z s 7.94 (m, 71), 7.74 (m, ZN), 7.02 (d, U-8.8Hz, 2H), 4.24 (t, 9-5.6Hz, 2H), 3.75 (m, 2H). EM (calc.): 351.1; h MO (E5I) m/e (MATN)": 352.0, (M-1H) 7: 349.9. i Spl. 51 pl.

NN NMR (400MHz, DMOSO-av) 5 11.11 (s, 1H) 9.09 (d, 9-44Gu, 1), 8.70 (d, 9-7.6Hz, 71), 8.65 (d, dET.bHz, 1), 8.29 (d, 9U-8.0Hz, 1H), 7.79 (m, 4H), 7.10 (d, 9U-8.8Hz, 2H), 4.30 (t, 9U-5.6Hz, 2H), 3.89 (m, so 2H) . EM (calc.): 351.1; MS (E5I) m/e (МА1Н)": 352.0, (М-1Н) 7: 349.9. ko Spl.52 "Н NMR (400MHz, DMSO-dv) 5 13.57 (s, 1Н), 11.04 (s, 1Н ), 8.88 (s, 1H), 8.53 (t, 9U-5.6Hz, 1H), 8.16 (d, so 3-8.0Hz, 71), 7.70 (d, 9-8.8Hz, 2H), 7.60 (d, 9U-8.4Hz, 1H), 7.40 (t, 9-8.0Hz, 1), 7.23 (t, U-8.0HzC, 1), -I 50 7.01 (d, 9U-8.8Hz, 2H), 4.19 (t , 9-6.0Hz, 2H), 3.68 (m, 2H). EM (calc.): 340.1; MS (E5I) m/e (MA1N)": 341.1, (M-1N)": 339.2. in Spl. 53 "NMR (400MHz6, UMSO-ag) 5 11.04 (s, 1H), 8.89 (m, 2H), 8.45 (s, 1H), 7.93 (s, 2H), 7.70 (d, 9U-8.AHz , 5 2H), 7.01 (d, U-8.8Hz, 2H), 4.20 (t, U-5.6Hz, 2H), 3.69 (m, 2H). EM (calc.): 341.1; MS (EI) m/ e (MAN): 341.8, (M-1H): 340.0. iF) Spl.54 ko "H NMR (400MHz, DMSO-dv) 5 9.07 (s, 1H), 9.24 (d, 9U-8.0Hz, 1H ), 8.53 (m, 1H), 8.03 (m, 2H), 7.82 (t, 3-6.8Hz, 1), 7.71 (m, ЗН), 7.03 (d, 9U-8.4Hz, 2H), 4.24 (t , 9-4.8 Hz, 2H), 3.76 (m, 2H). EM (calc.): 351.1; 60 MS (E5I) m/e (MA1H)": 351.9, (M-1H): 350.1.

Spl.55 "N-NMR (400 MHz, DMSO-y65) 5 9.39 (s, 1H), 9.11 (s, 1H), 8.59 (s, 1H), 8.25 (m, 1H), 7.87 (m, 2H), 7.70 (m, 2H), 7.02 (m, 2H), 4.23 (s, 2H), 3.76 (s, 2H). EM (calc.): 351 1; MS (E5I) m/e (MA1H)": 351.8 , (M-1H): 349.9

Spl. 56b bo "H' NMR (400 MHz, DMSO-Idv) 5 11 04 (s, 1H), 9 47 (m, 1H), 9 23 (m, 1H), 8 19 (m, 2H), 7.98 ( m, 2H), 7.70 -BO0-

(d, 9U-8.8Hz, 2H), 7.02 (d, 9U-8.4Hz, 2H), 4.25 (t, 9-5 2Hz, 2H), 3.78 (m, 2H). EM (calc.): 352.1; MS (E5I) m/e (MAN); 352.8, (М-1Н). 350.9.

Spl. 57

EM (calc.): 350.11; MS (EBI) m/e (MA1TN)": 351.1, (MATN) 7: 349.1.

Spl. 58

EM (calc.): 351.12; MS (E5I) m/e (MA1H)": 352.2, (M-1H): 350.0.

Spl. 59

EM (calc.): 365.14; MS (E5I) m/e (MA1H)": 366.0, (M-1H) 7: 364.2.

Spl.bo

EM (calc.): 368.12; MS (EBI) m/e (MA1TN)": 369.0, (MATN) 7: 367.1.

Spl.61 "H NMR (400MHz, DMSO-dv) 6 11.04 (s, 1H), 8.88 (s, 1H), 8.68 (t, U-5.6Hz, 1H), 8.34 (s, 1H), 8.14 (s , 1), 7.75 (d, U-8.0Hz, 1), 7.70 (d, U-8.4Hz, 2H), 7.61 (d, 9-8 OHC, 1H), 7.01 (d, 9U-8.8Hz, 2H ), 4.18 (t, schi U-6.OGz, 2H), 3.66 (m, 2H). EM (calc.): 340 1; MS (E5I) m/e (MA-1H)": 341.0, (M- 1H): 339.2

Spl. 62 "H NMR (400 MHz, OMSO-ydv) 5 11.04 (s, 1H), 8.11 (m, 2H), 7.98 (s, 1H), 7.70 (d, 9-9.2 Hz.2H), 7.47 (d ,

U-7.6Hz, 1), 7.20 (t, 9-8.4Hz, 1H), 7.13 (t, 9U-6.8Hz, 1H), 7.01 (d, 9U-9.2Hz, 2H), 4.15 (t, 9U- 6.0Hz, 2H), 3.82 (s, ЗН), 3.62 (m, 2H). EM (calculated): 353.1; MS (EI) m/e (MA1N)": 354.0, (M-ATN): 351.9.

Spl. 63

NN NMR (400MHz, OMSO-av) 5 11.05 (s, 1H), 9.14 (t, 9-5.6Hz, 71H), 8.19 (d, U-8.4Hz, 1H), 8.08 (d,

U-8.4Hz, 1H), 7.85 (t, 9U-8.4Hz, 1), 7.69 (m, 4H), 7.03 (d, 9U-8.8Hz, 2H), 4.24 (t, U-6.0Hz, 2H) , 4.15 (c,

ЗН), 3.78 (m, 2Н). EM (calc.): 381.1; MS (EI) m/e (MATN)": 381.9, (M-1H): 380.1. se

Spl. 6b4 o

EM (calc.): 380.14; MS (E5I) m/e (MATN)": 381.0, (MAN): 379.0.

Spl.b5

EM (calc.): 380.14; MS (EBI) m/e (MA1TN)": 381.2, (MATN) 7: 378.9.

Spl. b6 so

EM (calc.): 351.12; MS (E5I) m/e (MA1N)": 352.0, (M-TNU: 350.0. cha

Spl.67 "N NMR (400MHz, OMSO-yv) b 11.05 (s, 1H), 8.26 (t, 9-5.6Hz, 1H), 7.70 (d, 9U-8.8Hz, 2H), 7.41-7.35 (m . Hz, 28), ch 2.01 (s, ZN). EM (calc.): 340.1; MS (EBI) m/"e M.аAT1Н)": 340.9, (М-1Н) 7: 339.2. with

Spl.b68 "H NMR (400 MHz, DMSO-dv) 5 11.08 (s, 1H), 10.72 (br s, 1H), 8.81 (t, U-5.2Hz, 1H), 7.94 (dd, 9U4-8.4Hz, 92-2.0Hz, 1), 7.73 (d, U-8.8Hz, 2H), 7.32 (s, 1H), 7.03 (d, 9U-9.2Hz, 2H), 4.60 (s, 2H), 4.13 (pseudo t . 398.1, (M-1H): 396.0. "

Spl.71 - in s H NMR (DMSO-α): 0.92 (ZH, t, 7Hz); 1.53 (IN, m); 1.72 (1H, m); 2.48 (ZN, p); 3.94 (1H, m); 4.03 (2H,

And m); 6.62 (1Н, с); 6.78 (1Н, dd); 6.92 (1IN, d); 7.01 (2H, d); 7.08 (IN, p); 7.31 (1IN, d); 7.7 (2H, d); 8.27 "" (2H, d, 7Hz); 9.25 (1H, p). MS (M-1): 425.

Spl. 72

H NMR (DMSO-γ): 0.90 (2H, dd); 0.91 (ZN, t, 7Hz); 1.1 (2H, br. C); 1.52 (1IN, m); 1.68 (IN, m); 1.92 bo (IN, m); 2.0-2.1 (ЗН, mu; 2.25 (1Н, m); 2.48 (ЗН, с); 3.24 (1Н, m); 3.37 (4Н, m); 3.54 (1Н, m); 3.95 (1Н, m); 4.03 (2H, m); 6.66 (1H, s); 6.97 (1H, m); 6.99 (2H, d, 9Hz); 7.07 (IN, dd, 9.2Hz); 7.12 (IN, d, 6Hz): ko 7.28 (1H, dd, 20.2Hz); 7.45 (1H, t, 9Hz), 7.7 (2H, d, 9Hz); 8.29 (1H, d, 8Hz). MS (M--1): 548. so Spl. 7Z3

H NMR (0MSO-SW): 2.00 (2H, m); 2.64 (1IN, m); 2.75 (1H, m); 4.1 (IN, m); 4.18 (IN, m); 4.39 (1H, m); - and 6.98 (2H, d, 9Hz); 7.14 (1IN, m); 7.19-7.28 (5H, m); 7.32 (1H, t, 8Hz); 7.45 (1IN, m); 7.58 (1H, s); 7.65 (1H,

F d, 7Hz); 7.68 (2H, d, 9Hz); 7.76 (1H, d, 9U-7Hz), 8.74 (1H, d, 7Hz). MO (M-1): 443.

Spl. 78

H NMR (DMSO-α): 3.56 (2Н, m); 4.15 (1IN, m); 4.23 (1H, m); 4.57 (2Н, с); 4.94 (1H, m); 6.99 (2H, d, vv ZHC); 7.33 (1H, t, 7Gsh); 7.38 (5H, c); 7.47 (1H, t, 7Hz) 7.58 (IN, s); 7.65 (IN, d, 8Gsh); 7.70 (2H, d, 9Gu); 7. (1H, d, 8Hz); 8.90 (1H, s); 9.0 (1H, d, 8Hz). MO (Mt): 509.

F) Spl. 79 with H NMR (0MSO-yv): 2.7-2.81 (2H, m); 3.78 (2Н, с); 4.12 (1H, dd, 10.5Hz); 4.22 (1H, dd, 10.7Hz); 4.51 (IN, m); 6.97 (2H, d, 9HC); 7.22 (IN, m); 7.28 (2H, m); 7.29 (2Н, с); 7.33 (1H, t, 7HC); 7.46 (1H, td, in 07414); 7.58 (1H, s); 7.65 (1H, d, 8Hz); 7.70 (2H, d, 9Hz); 7.77 (2H, d, 8Hz); 8.79 (1H, d, 8Hz). MO (Ma1): 475.

Spl.80 "H NMR (O0MSO-dv): 2.47 (ZH, d, 1Hz); 3.57-3.62 (ZH, m); 3.77 (ZH. s); 4.08 (1H, t, 6Hz); 6 64 (1H , c); 6.92 (IN, dd, 9.3Hz); 6.99 (2H, d, 9Hz); 7.12-7.15 (2H, c and d); 7.42 (1H, d, 9 Hz); 7.7 (2H, d . ), 8.91 (s, 1H), 8.24 (t, 9U-5.6Hz, 1H), 7.73 (d, 9-9.2Hz, 2H),

7.57 (d, 9U-6.8Hz, 2H), 7.44 (d, 9U-16.0HzC, 1H, is under m at 7.41), 7.41 (m, ЗН), 7.00 (d, 9-8.8Hz, 2H), 6.63 (d, 9U-16.0Hz, 1H), 4.10 (pseudo t, 9U-6.0Hz, 2H), 3.37 (pseudo kv, U-6.4HzC, 2H), 1.96 (pseudo n, 9UEb.АГhz, 2H). EM (calc.): 340.1; MS (E5I) m/e (MA1TN)": 341.2, (M-1H)": 339.3.

Spl.92 "H NMR (400MHz, DMOSO-yv5) 5 11.07 (s, 1H), 8.15 (s, 1H), 7.73 (d, 9U-8.4Hz, 2H), 7.51 (d, U-8.4HzC, 2H), 7.38 (d, 9U-15.6Hz, 1H), 6.99 (m, 4H), 6.48 (d, 92-15.6Hz, 71H), 4.09 (pseudo t, U-6.0Hz, 2H), 3.80 (s ) 371.0, (M-1H)": 368.9.

Spl.93 "H NMR (400 MHz, DMSO-div) 5 10.96 (s, 1H), 8.90 (t, U-5.6Hz, 1H), 8.31 (s, 1H), 7.98 (dd, U4-7.2Hz, 92 -1.6Hz, 2H), 7.62 (d, U-8.A4Hz, 2H), 7.40 (pseudo t, U-7.2Hz, 2H), 7.31 (pseudo tt, U4-7.2Hz, 92-2.0Hz, 1H) . ).EM (calc.): 397.1;

Me 3.AZ (E5I) m/e (MA1N)": 397.9, (M-1N)": 396.0.

Spl. 94

NN NMR (400MHz, OMSO-yv) 6 11.09 (s, 1H), 8.26 (d, 9-7.2HzC, 1), 7.74 (d, 9U-8.4Hz, 2H), 7.58 (d,

U-7.2Hz, 2H), 7.44 (m, 4H), 7.05 (d, uU-8.8Hz, 2H), 6.68 (d, 9-16.4Hz, 1H), 4.27 (m, 1H), 4.07 (m, tn), 3.96 (m, 1H), 1.25 (d, U-6.8Hz, ZN). EM (calc.): 340.1; MS (E5I) m/e (MATN)": 341.1, (М-1Н): 339.1.

Spl. 95

NN NMR (400MHz, OMSO-yv) 5 11.09 (s, 1H), 8.27 (d, 9U-8.0Hz, 1), 7.74 (d, 9U-8.8Hz, 2H), 7.58 (d,

U-7.2Hz, 2H), 7.46 (d, 9U-16.0Hz, 1), 7.42 (m, ЗН), 7.04 (d, 9U-9.2Hz, 2H), 6.68 (d, 9U-16.4Hz, 1H) . , 9U-7.2Hz,

ZN). EM (calc.): 340.1; MS (EI) m/e (MATN)": 341.1, (M-1H): 339.1. si

Spl. 96b "H NMR (400 MGu, DMSO-dyv) 6 11.05 (s, 1H), 8.87 (s, 1H), 8.12 (d, U-8.0Hz, 1H), 7.67 (dt, U4-8.8Hz, 9U2-2.0Hz, and) 1H), 7.54 (dd, 9U--8.4Gu, 92-1.6Hz, 2H), 7.43-7.33 (m, 4H), 6.99 (dt, 9U4-9.2Hz, 9U2-:2Hz . -5.6Hz, 1H), 1.66 (m, 1H), 1.49 (m, 2H), 0.91 (d, U-6.8Hz, ZN), 0.87 (d, U-6.4Hz, ZN). EM (calc.) : 382.2; MS (E5I) m/e (MA1H)": 383.0, (M-1H) 7: 381.1. (That)

Spl.97 "H NMR (400 MHz, DMSO-y5) 5 10.95 (s, 1H), 8.81 (s, 1H), 8.05 (d, 9U-8.4Hz, 1H), 7.62 (d, U-8.8Hz, 2H), - 7.47 (d, 9U-6.8Hz, 2H), 7.37-7.28 (m, 4H), 6.92 (dt, uU4-8.4Hz, 9U2-1.6Hz, 2H), 6.61 (d, U-16Hz, 1H), 4.21 (m, 1n), so 3.94 (m, 1), 3.86 (m, 7), 1.69 (d. 9U-12.4HZ, 1H), 1.59-1.52 (M, 4H), 1.42 (t, 9-7.2 Hz, 2H), 1.28 (m, 1H), 1.15-1.05 (m, ЗН), 0.90 (m, 1H), 0.77 (m, 1H). EM (calc.): 422.2; MS (E5I) m/e (МА1Н)": 423.2, (М-1Н):: 421.2. si

From Spl.98 so "N' NMR (400MHz, OMSO-av) 5 11.03 (s, 1H), 8.88 (s, 1H), 8.09 (d, U-8.4Hz, 1H), 7.69 (dt, U4-8.8 Hz, 9Ua-2.8Hz, 2H), 7.432-7.32 (bands m, 4H), 6.99 (dt, 9U4-9.2Hz, 9U2-2.4Hz, 2H), 6.73 (d, 9U-15.6Hz, 1H), 4.05 (s, ЗН), 1.98 (m, 1Н), 0.95 (d, U-2.4Hz, ЗН), 0.93 (d, 9У-2.4Hz, ЗН). EM (calc.): 368.2; MS (Е5И) m /e (МА1Н)": 368.7, (М-1Н): 367 1. «

Spl.99 t0 "NN 'NMR (400MHz, UOMSO-a65) 5 11.04 (s, 1H), 8.32 (d, 9U-8Hz, 1H), 7.69 (d, 9U-9.2HzC, 2H), 7.53 (m, 2H), Z c 7.43-7.34 (m, 4H), 7.28-7.22 (m, ЗН), 7.18 (m, 2H), 6.99 (d, 9-9.2Hz, 2H), 6.63 (d, 9U-16Hz, 1). : 416.2; MS (E5I) m/e (MAN): 417.3, (MA1H) 7 415.2. 415 Spl.100 so "H NMR (400MHz, OMSO-iv) 5 11.04 (s, 1H), 8.78 (s, 1H ), 8.32 (d, U-8Hz, 1H), 7.69 (d, U-8.8Hz, 2H), 7.52 (dd, 34-8.4Hz, 9U2-1.6Hz, 2H), 7.41-7.34 (m, 4H) . ), 4.01 (d, 9U-4.АHz, 2Н), 2.99 (dd, 9У4-13.6Hz, 9У2-6Hz, 1Н), 2.88 (dd, У4-14Hz, 95-8Hz, оо 1Н). EM (calc.): 416.2; MS (E5I) m/e (МА1Н) 7: 417.2, (М-А1Н): 415.2.

Spl.101 sho "H NMR (400MHz, DMSO-av) 5 11.05 (s, 1H), 8.87 (s, 1H), 8.12 (d, 9U-8.0Hz, 1), 7.69 (d, 9U-8.4Hz, 2H), t 7.53 (d, 9U-7.2Hz, 2H), 7.43-7.33 (m, 4H), 6 99 (d, 9U-9.2Hz, 2H), 6.65 (d, 9-15.6Hz, 1H), 4.25 (m, 1H), 4.01 (dd, 9U-9.6Hz, 4 8Hz, 1H), 3.94 (dd, 9U4-9.6Hz, 9Ua-5.6Hz, 1H), 1.66 (m, 1H), 11.48 (m, 2H), 0.91 (d, 9U-6.8Hz, ZN), 0.87 (d, U-6.4Hz, ZN). EM (calc.): 382.2; MS (EBI) m/e (MA1H)": 383.2, ( M-1H) 7: 381.2.

Spl.102 "NMR (400 MHz, DMOSO-av) 5 11.03 (s, 1H), 8.87 (s, 1H), 8.08 (d, 9U-8Hz, 1H), 7.69 (d, uU-8.8Hz, 2H ),

F, 7.55 (d, 9-1.2Hz, 2H), 7.43-7.32 (m, 4H), 6.99 (d, 9-9.2Hz, 2H), 6.73 (d, 9U-16Hz, 71), 4.05 (s, ЗН), 1.98 (m, ko 1Н), 0.946 (d, U-2Hz, ЗН), 0.93 (d, У-2.АГц, ЗН). EM (calc.): 368.2; MS (E5I) m/e (MA1H)": 369.1, (M-1H) 7: 367.1.

Spl.103 bo "H NMR (400MHz, OMSO-dv) 5 11.04 (s, 1H), 8.14 (d, U-8.4Hz, 1H), 7.69 (dt, 9U4-8.8Hz, 92-2.8 Hz, 2H) . 1H), 4.16 (m, 1H), 4.03 (dd, U4-10Gu, 9U2-5.6Hz, 1H), 3.96 (dd, U4-10Гц, 9У2-5.2Гц, 1Н), 1.67 (m, 1Н), 1.53 (m, 1H), 1.36-1.27 (m, 4H), 0.87 (t, U-6.4Hz, ЗН). 1H, MH or OH are missing. EM (calc.): 382.2; MS (E5I) m/e ( MATN)": 383.1, (М-1Н): 381.1.

Spl.104 bo "NMR (400MHz, OMSO-av) 5 10.97 (s, 1H), 8.25 (d, U-8.4Hz, 1H), 7.64 (dt, U4-8.8Hz, 95-2Hz, 2H) , 7.46 (dd,

U1-7.6bHz, 9U2-2Hz, 2H), 7.34-7.18 (bands m, 6H), 6.93 (dt, 9U4-9.2Hz, 9U2-2.8Hz, 2H), 6.54 (d, U-15.6Hz, 1H) . Hz, 1H). EM (calc.): 450.1; MS (E5I) m/e (MA1N) 7. 451.2, (M-1N):: 449.2.

Spl.105 "H NMR (400MHz, OMSO-av) 5 10.97 (s, 1H), 8.07 (d, U-8HzC, 1H), 7.62 (dt, 9U4-8.8Hz, 92-2.8Hz, 2H), 7.47 (dd,

U428.8Hz, 9U2-1.6Hz, 2H), 7.34-7.26 (bands m, 4H), 6.93 (dt, U4-8.8Hz, 92-2.8Hz, 2H), 6.61 (d, 9U-15.6Hz, 1H) . m, 1H), 0 85 (t,

U-6.8Hz, ZN). EM (calc.): 354.2; MS (EBI) m/e (МА1Н)": 354.6, (М-1Н) 7: 353.2.

Spl.106 "H NMR (400MHz, DMSO-arg) 5 10.97 (s, 1H), 8.07 (d, 9U-8Hz, 1H), 7.62 (d U-8.8Hz, 2H), 7.47 (dd, 9U4-6.8 Hz,

U2-1.6Hz, 2H), 7.35-7.62 (bands m, 4H), 6.93 (dt, 9U4-9.2, 92-2Hz, 2H), 6.61 (d, 9U-15.6Hz, 1H), 3.98 (dd, uU4 -9.6Hz, 3U25.6Hz, 1H), 3.90 (dd, 9U4-9.6, 92-4.8Hz, 1H), 1.65 (m, 1H), 1.49 (m, 1H), 0.85 (t, 9-7.2Hz, ZN). EM (calc.): 354.2; MS (EBI) m/'e(M-1H) "7: 354.8, (M-1H): 353.1.

Spl. 107

EM (calc.): 400.49; MS (E5I) m/e (M.-1): 401.0, (M-1): 399.0.

Spl. 108

EM (calc.): 400.49; MS (E5I) m/e (M.-1): 401.1, (M-1): 399.2.

Spl.109 "H NMR (400MHz, UMSO-ag5) 65 10.97 (s, 1H), 8.80 (br s, 1H), 8.73 (d, U-8.4HzC, 1H), 7.62 (d, 9U-9.2Hz, 2H), 7.48 (d, 9U-6.8Hz, 2H), 7.38-7.27 (bands m, 8H), 7.21 (t, 9U-7.2Hz, 1H), 6.93 (d, U-8.8, 2H), 6.69 ( d,

U-15.6Hz, 71H), 5.30 (dd, 9U4-13.6Hz, 9U2-7.6Hz, 1H), 4.19 (d, 9U-6.4Hz, 2H). EM (calc.): 402.2; MS (E5I) m/e (Man): 403.2, (M-1H): 400.9. high school

Spl.110 "H NMR (400 MHz, DMSO-dv) 5 10.97 (s, 1H), 8.80 (br s, 1H), 8.74 (d, U-8Hz, 1H), 7.62 (dt, uU4-8.8Hz, 9U5 -2Hz, 2H), (o) 7.48 (dd, U-6.4Hz, 92-1.6Hz, 2H), 7.39-7.27 (bands m, 8H), 7.21 (tt. 9U4-7.6Hz, 92-1.2Hz, 1H), 6.93 (dt, 9U4-9.2Hz, 32-2.4Hz, 2H), 6.69 (d, 9U-15.6,1H), 5.29 (dd, U4-9Hz, 9U2-6.4Hz, 1H), 4.18 (d , U-6.4Hz, 2H). EM (calc.): 402.2;

MO (E5I) m/e (MATN)": 402.9, (М-1Н) 7: 401.2. "se

Spl. 111

H NMR (400MHz, DMSO-α) 5 8.25 (d, 9U-8Hz, 1), 7.83 (d, 9U-8.8HzC, 2H), 7.48 (d, 9-64 Hz, 2H), - 7.39-7.27 ( bands m, 4H), 7.01 (d, U-8.8Hz, 2H), 6.58 (d, U-16.4Hz, 1H), 4.25 (m, 1H), 4.03 (m, 2H), 3.73 (m, so

ZN), 3.12 (m, 2H), 2.06 (m, 1H), 1.93 (m, 1H). EM (calc.): 432.1; MS (EBI) m/e (МА1Н)": 433.2, (М-1Н): 430.0.

Spl. 112 p

NN nMR (400 MHz, OMSO-46) 5 8.24 (d, 9U-8Hz, 1H), 7.82 (d, 9U-8.8Hz, 2H), 7.48 (d, U-8.8 Hz, 2H), so 7.84-7.29 ( bands m, 4H), 7.01 (d, 9U-8.8Hz, 2H), 6.58 (d, 9U-16.4Hz, 1H), 4.35 (m, 1H), 4.03 (m, 2H), 3.70 (s,

ZN), 3.13 (m, 2H), 2.06 (m, 1H), 1.93 (m, 1H). EM (calc.): 432.1; MS (E5I) m/e (МА1Н)": 432.2, (М-А1Н) 7: 430.2.

Spl.113 « "H NMR (400MHz, DMSO-av) 5 8.50 (d, U-8.0Hz, 1H), 7.83 (dt, U4-9.2Hz, 9U2-2.8Hz, 2H), 7.48 (dd, 9U- -6Hz, d2-1.6Hz, 2H), 7.39 (d, 9-16Hz, 1H), 7.31 (m, 9H), 6.97 (dt, U4-9.2Hz, 92-2.4Hz, 2H), 6.57 (d, 9U-16Hz, 1H), 4.72 - s (m, 1H), 4.50 (s, 1H), 4.16 (dd, 9U4-9.6 Hz, 9U2-5.2GuTs), 1H, 4.08 (dd, U4-10Hz, 95- 4.8Hz, 1H), 3.45 (dd, 9U--14.4Hz,

From" batoya Ya 3.36 (dd, uU4-14.АХ, 9d2-6.8Х, 1Н). EM (calc.): 492.2; MS (EI) m/e (MA1N) 7: 494.3, (M-1N) 7: 492.2. sq. "H NMR (400MHz, DMSO) 5 11.07 (br s, 1H), 8.38 (d, U-7.6Hz, 2H), 7.84 (dc, 9U4-3.6Hz, 92-1.2Hz, 1H), 7.77 (dd, 395 U4-4.8Hz, 9U2-1.2Hz, 1H), 7.72 (d, U-8.4Hz, 2H), 7.16 (dd, U4-3.6Hz, 9U2-5.2Hz, 1H), 7.02 (d, U4-8.4 Hz, 2H), 4.20 (m, so 1H), 4.13 (dd, U4-6.4Hz, 9U2-9.6Hz, 1H), 4.04 (dd, U4-5.2Hz, 9Ua-9.2Hz, 2H) 1.77 (m, 1H), 1.63 (m, 1H), 1.21 (d, ko 9UEb.AGC, 1H), 0.96 (d, U-7.2Hz, ZN). EM (calc.): 334.1; MS (E5I) m/e ( MA1H)": 335.0, (M-1H) 7: 333.0.

Spl.115 so 50 "H NMR (400MHz, OMSO-ydv) 5 11.03 (s, 1H), 8.37 (d, U-8.0HzC, 1H), 7.94 (d, U-8.4Hz, 2H), 7.72 (m , 6H), and 7.A8 (m, 2H), 7.39 (m, 1H), 7.00 (d, 9-8.4 Hz, 2H), 4.24 (m, 7H), 4.06 (m, 2H), 1.74 ( m, 2H), 0.95 (t,

Ф U-7.2Hz, ЗН). EM (calc.): 404.2; MS (EBI) m/e (MA1N) 7: 405.2, (M-1N) 7: 403.2.

Spl.116 "NMR (400 MHz, DMOSO-yv5) 5 11.03 (s, 1H), 8.87 (s, 1H), 8.50 (d, U-8.4Hzc, 1H), 8.44 (s, 1H), 7.97 ( m, 4H), 7.70 (d, U-8.8HzC, 2H), 7.59 (m, 2H), 7.02 (d, 9U-8.8Hz, 2H), 4.29 (m, 1H), 4.14 (m, 2H), 1.68 (m, 2H), 0.98 (t, U-7.2Hz, ZN). EM (calc.): 378.2; MS (E5I) m/e (MA1H)": 378.9, (M-1H)7: 377.0. iF) Spl. 117 ko "H NMR (400MHz, OMSO-dv) 5 10.98 (s, 1H), 8.82 (s, 1H), 8.27 (d, U-8.4HzC, 1H), 7.64 (d, U-9.2Hz, 2H) . m, tn), 6.92 60 (d, y-8.8Hz, 2H), 6.61 (d, 9U-15.6Hz, 1H), 4.29 (m, 1H), 4.08 (dd, 9U4-9.6Hz, 9Ua-5.6Hz ) .

Spl. 118

NN NMR (400MHz, OMSO-yv) 5 11.02 (s, 1H), 8.31 (d, 9U-8.4Hz, 1H), 7.83 (d, 9U-7.2Hz, 2H), 7.68 (d, bo ude8.8Hzc, 2H), 7.52-7.42 (m, ЗН), 6.99 (d, U-9.2Hz, 2H), 4.22 (m, 1H), 4.11 (dd, U4-6.4Hz, uU2-10.0Hz, 1H), 4.01 ( dd,

U4-6.0Hz, 92-9.6Hz, 1H), 1.73 (m, 1H), 1.62 (m, 1H), 0.93 (t, U-7.6Hz, ЗН). EM (calc.); 328.1; MS (E5I) m/e (Man): 329.1. (МА1Н)7: 327.0.

Spl.119 "NMR (400 MHz, DMSO-a6) 5 11.03 (s, 1H), 8.08 (d, 9U-7.2Hz, 1H), 7.69 (d, U-8.8Hz, 2H), 7.24 (m, 5H), 6.96 (d, 9U-9.2Hz, 2H), 3.94 (m, ЗН), 3.43 (s, 2H), 1.64 (m, 7H), 1.47 (m, 1H), 0.86 (t, 7.2Hz, EM (calc.): 342.2; MS (E5I) m/e (MA1H)": 343.0, (M-1H)7: 341.1.

Spl.120 "N NMR (400MHz, OMSO-yv) 5 11.03 (s, 1H), 7.81 (d, 9-7.6Hz, 1H), 7.69 (d, U-8.4Hz, 2H), 7.23-7.10 (m , 70 BN), 6.94 (d, U-9.2Hz, 2H), 3.94 (m, 2H), 3.84 (m, 1H), 2.81 (t, 9-7.2Hz, 2H), 2.40 (t, 9-7.6 HC, 2H), 1.61 (ddd,

U1-4.4Hz, d2-7.6Hz, yes-18.4Hz, 1), 1.41 (m, 1H), 0.81 (t, U-6.8Hz, ЗН). EM (calc.): 356.2; MS (E5I) m/e (MAN): 357.1, (M-ATN)": 355.1.

Spl. 121

EM (calc.): 356.38; MS (E5I) m/e (Mn): 357.0, (M-1): 355.1.

Spl.122 "N NMR (400MHz, OMSO-yv) 5 10.96 (s, 1H), 8.65 (d, 9U-8.8Hz, 71H), 8.33 (s, 1H), 8.00 (d, 9-7.2Hz, 2H ), 7.62 (d, 9U-8.4Hz, 2H), 7.39 (pseudo t, 9-7.2Hz, 2H), 7.30 (pseudo t, 9U-7.6bHz, 1H), 6.93 (d, 9U-9.2Hz, 2H ), 4.20 (m, 1H), 4.23 (dd is partially under the peak at 4.20,, 9 4-9.2Hz, 9d2-16.8Hz, 1H), 4.05 (dd, U4-10.0Hz, 52-4.8Hz, 1H) .

Spl. 123 nNMR (400 MHz, DMOSO-avb) 5 11.03 (s, 71H), 8.03 (d, 9U-7.6bHz, 1), 7.69 (d, 9U-8.8Hz, 2H), 7.48 (d, 3-9.2 Hz, 2H), 7.36 (d, 9U-15.6Hz, 1H), 6.99 (d, 9-9 2Hz, 2H), 6.95 (d, U-8.8Hz, 2H), 6.52 (d, 9U-15.6Hz, 1H), 4 09 (m, 1H), 4 04 (dd, 9U4-5.2Hz, 92-9.6Hz, 1H), 3.95 (dd, 9U1-25.2Hz, 92- 9.6Hz, 1H), 3.77 (s, ЗН), 1.71 (с, 1), сч 1.52 (m, 1Н), 0.91 (t, 9U-6.8Hz, ЗН) EM (calculated): 384.2, MS (Е5И) m/e (МА1Н)" 385.0, ( M-1H) 7: 383.2.

Spl. 124 i) "H NMR (400MHz, OMSO-yv) 5 11.07 (s, 1H), 10.62 (br s, 1H), 8.43 (d, U-8.0Hz, 1H), 8.28 (d, 9U-1.6Hz, 1H), 7.94 (dd, 9U4-8.4Hz, 9Ua-2.0Hz, 1), 7.23 (d, 9U-8.4Hz, 2H), 7.32 (s, 1H), 7.03 (d, 9U-8.8Hz, 2H) . (c, 6H), 1.80 (m, «0 1H), 1.65 (m, 1H), 0.98 (t, 9-7.6Hz, ZN). EM (calc.): 425.2; MS (E5I) m/e ( MA1H) 7: 426.2, (M-1H):: 424.1. g

Spl. 125 "H NMR (400MHz, DMSO-av) 5 10.96 (s, 1H), 8.80 (s, 1H), 8.27 (t, 9-5.2Hz, 1H), 7.62 (y-8.8Hz, 2H), 746 DS 1сО (d, U-6.8HzC, 2H), 7.36 (d, 9-12.8Hz, 1), 7.33-7.28 (m, ZN), 6.95 (d, U-8.4HzC, 2H), 6.60 (d, 9 -12.8Hz, 1H), sch 4.53 (ddd, 9U-5.6Hz, 1H), 3.40 (m, 1H), 3.29 (m, 1H, hidden by an underwater peak), 1.19 (d, 9U-6.4Hz, ЗН). EM

Zo (calc.): 340.1. co

Spl.126 "NMR (400MHz6, UOMSO-av) 5 11.02 (s, 1H), 8.87 (s, 1H), 8.34 (n, 9U-5.6Hz, 1H), 7.68 (d, U-8.4Hz, 2H), 7.53 (d, 9U-8.8Hz, 2H), 7.43 (d, 9-13.2Hz, 1), 7.40-7.35 (m, ZN), 7.02 (d, 9U-8.8Hz, 2H), 6.67 ( d, 9U-16Hz, « 1H), 4.60 (ddd, 9U4-6.0Hz, 9Ua-11.6Hz, 9uU3-17.6Hz, 1H), 3.47 (m, 1H), 3.36 (m 1H, hidden by an underwater peak), 1.26 t0 (d, 9-6.O0Hz, ZN). EM (calc.): 340.1; MS (E5I) m/e (МА1Н)": 341.0, (М-1Н)": 339.2. With s Spl.127: with" EM (calc.): 397.1; MS (E5I) m/e (M-1H): 396.1.

Spl. 128

EM (calc.): 3971; MS (E5I) m/e (MA1TN)": 398.2, (M-1H): 396.2. so Spl. 129

NN NMR (400 MHz, OMSO-y6) 5 10.96 (s, 1H), 8.69 (t, 9U-5.6Hz, 1H), 7.84 (d, 9U-8.4Hz, 2H), 7.67 (d, ko U-8.4Hz . . (d, U-6.0 Hz, ZN). EM (calc.): 390.2; MS (E5I) m/e (MATN)": 391.3, (M-1H): 389.0. - Spl.130 p NN NMR (400MHz, DMOSO-avb) 5 11.03 (s, 1H), 8.24 (t, 9U- 5.2Hz, 71), 7.68 (d, 9U-8.8HzC, 2H), 7.48 (d, 3-8.8Hz, 2H), 7.37 (d, 9-15.6Hz, 71H), 7.02 (d, 9U-8.8Hz . (ddd, uU4-4.8Hz, 9Ua-13.2Hz, uU3-19.2Gu, 1H), 3.32 (ddd, 9U4-5.2Hz, d2-10.8Hz, 9Ua-13.2Hz, 1H), 1.25 (d, U-6.0 Hz, ZN). EM (calc.): 370.2; MS (EI) m/e (MATN)": 371.0, (M-1H): 369.1.

Spl. 131 iF) NN NMR (0MSO-yv): 3.67(q, 2H), 4.18(t, 2H), 7.01 (d, 2H), 7.7 (d, 2H), 7.98 (d, 2H), 8.12 (d, 2H), io) 8.17 (d, 2H), 8.55 (s, 1H), 8.79 (m, ЗН), 11.05 (s, 1H). LCMS: (Ma-1)77 461.2, (М-А1Н)У" 459.0.

Spl.132 bo "H NMR (400 MHz, DMSO-av) b: 11.08 (s, 1H), 8.94 (m, 2H), 7.75 (m, ЗН), 7.47 (d, 1H, 9U-8.1Hz), 7.16 (d, 1H, 9-8.1Hz), 7.04 (d, 2H, -9.6Hz), 4.22 (t, 2H, 9-5.5Hz), 3.71 (t, 2H, 9U-5.5Hz), 3.36 (s, EM (calc.): 388.08; MS (E5I) m/e (MA1TN)": 388.9, (M-IN):: 387 1.

Spl. 133

NN NMR (0MSO-yv): 2.85 (s, ЗН), 3.4 (s, 8Н), 3.65 (q, 2Н), 4.17 (t, 2Н), 7.00 (d, 2Н), 7.54 (s, 1Н), 62 71 (d, 2H), 7.9 (dd, 4H), 8.74 (t, 1H), 8.9 (s, 1H), 10.2 (s, 1H), 11.05 (s, 18). RHMS: (M.-1)77 482.0, (M-1)7 480.2. -B4-

Spl. 134

H NMR (DMSO-α): 3.66 (q, 2H), 4.18 (t, 2H), 7.01 (d, 2H), 7.69 (m, 4H), 7.91 (d, 2H), 8.02 (d, ЗН), 8.33 (dd, 2H), 8.75 (t, 1H), 9.16 (s, 1H), 10.99 (s, 1H), 11.05 (s, 1H). RZhMS: (Ma-1)77 476.1, (M-1)7 474.9.

Spl. 135

H NMR (DMSO-α): 2.85 (s, 3H), 3.01 (m, 4H), 3.51 (d, 2H), 3.60 (q, 2H), 4.00 (d, 2H), 4.13 (t, 2H), 6.98 (dd, 4H), 7.74 (dd, 4H), 8.48 (t, 1H), 9.97 (s, 1H), 11.05 (s, 1H). RM: (M-1)77 399.3, (M-1)7 397.2.

Spl. 136 "H NMR (0MSO-av): 1.4 (m, 2H), 1.8 (m, 2H), 2.95 (m, 2H), 3.6 (m, 5H), 4.12 (t, 2H), 4.69 (s, 1H ), 6.91 70. (d, 2H), 6.99 (d, 2H), 7.7 (dd, 4H), 8.36 (t, 1H), 8.87 (s, 1H), 11.03 (s, 1H). LCMS: (Ma -1)77 400.2, (M-1)77 398.3.

Spl. 138 "H NMR (400MHz, UMSO-ag) b: 9.02 (t, 2H, 2-5.3Hz), 7.77-7.72 (m, ЗН), 7.27 (m, 1H), 7.11 (m, 1H), 7.03 (d, 2H, U-8.8Hz), 4.22 (t, 2H, 9-5.3Hz), 3.70 (t, 2H, 9U-5.3Hz), 2.51 (s, ЗN). EM (calc.): 372; MS (E5I) m/e (MATN)": 373.0, (M-ATN): 371.0. t Spl. 139

NN NMR (400mMHz, OMOSO-a6) 6: 11.04 (s, 1H), 10.04 (s, 1H), 9.02 (t, 1H, U-5.7Hz), 7.74 (d, 1H, 9-2.7Hz), 7.70 (d, 2H, 9U-8.5Hz), 7.32 (m, 1), 7.25 (m, 7), 7.00 (d, 2H, 9U-8.5Hz), 4.72 (s, 2H), 4.19 (t, 2H, 9-5.7Hz), 3.67 (m, 2H), 3.59 (m, 2H), 3.48 (m, 2H), 3.24 (s, ЗН). EM (calc.): 446.15; MS (E5I) m/e (MATN)": 447.4, (МА1Н): 445.3.

Spl. 140 "NMR (400MHz, DMSO-dv) 6: 11.04 (res. s, 1H), 9.25 (t, 1H, U-5.9Hz), 8.07 (d, 1H, 92-8.6Hz), 7.96 ( d, 1H, 2-8.6Hz), 7.70 (m, ЗН), 7.39 (t, 1H 9-7.6Hz), 7.01 (d, 2H, 9U-9.1Hz), 6.88 (disc, 1H), 4.21 ( t, 2H, 9-5.9Hz), 3.70 (sq. 2H, U-5.9Hz). EM (calc.): 367; MS (E5I) m/e (MA1H)": 368.0, (M-1H) 7 : 366.2. with

Spl.141 "NMR (400 MHz, OMOSO-av) 5 ; 11.04 (res. s, 1H), 9.04 (t, 1H, 9U-5.9Hz), 7.80 (d, 1H, 9U-2.6Hz), 7.70 ( d, o 1H, 9uU-8.7Hz), 7.40 (m, 2H), 7.28 (t, 1H, 9-8.1Hz), 7.05-6.92 (m, 5H), 5.35 (s, 2H), 4.18 (t, 2H, 9U-5.9Gu), 3.66 (sq, 2H, 9U-5.9Hz). EM (calc.): 464; MO (E5I) m/e (MA1H)": 465.3, (M-1H): 463.1.

Spl.143 (se)

H'NMR (0MSO-sw): 2.55 (t, ЗН), 2.80 (s, ЗН), 3.07 (d, ЗН), 3.4 (d, 2Н), 3.65 (q, 2Н), 4.02 (s, 2Н) , cha 4.17 (t, 2H), 6.99 (d, 2H), 7.69 (d, 2H), 7.91 (d, 2H), 8.01 (d, 2H), 8.23 (c, 1H), 8.75 (t, 1H) , 9.6 (c, 1H)U, 11.05 (c, 1H). RHMS: (M-n1)77 496.3, (M-1H)7 494.4 so

Spl. 144 Sc

MS (E5I) m/e: (M-1H)": 302.0, (M-1H) 7: 300.2.

Spl. 145 so

MS (E5I) m/e: (МА1Н)": 318.1, (М-1Н) 7: 316.1.

Spl. 146

MS (E5I) m/e: (МА1ТН)": 318.1, (М-1Н) 7: 316.2. « 20 Spl. 147 -o s "N'NMR (400 MHz, DMOSO-av) 5 11.04 (s, 1Н) , 8.28 (m, 2H), 8.15 (m, 1H), 7.94 (m, 2H), 7.66 (m, 2H), 7.41 (m, ЗН), 6.89 (m, 2H), 4.10 (m, 2H) , 3.63 (m, 2H). MS (E5I) m/e: (МА1ТН)": 439.2, (М-1Н) 7: 437.2. "» Spl.148

NN NMR (400MHz, DMOSO-a6) 5 11.04 (s, 1H), 9.10 (t, 9U-8.0HuЦs, 71), 8.18 (d, 9U-8.0Hz, 1), 8.06 (Her, y-8.0ХЦs, 1), 7.85 (t, U-8.0Hz, 1), 7.67 (m, 4H), 7.04 (d, U-8.0Hz, 2H), 4.45 (m, 2H), 4.23 (t, U-8.0Hz, (se) 2H), 3.84 (m, 2H), 3.76 (m, 2H). MS (E5I) m/e: (МА1ТН)": 426.3, (М-1Н): 424.2.

Spl.149 o "H NMR (400MHz, DMSO-av) 5 11.06 (s, 1H), 10.31 (s, 1H), 9.10 (t, U-8.0Hz, 1H), 8.40 (d, 9U-8.0Hz, 1). m, 2H), 4.23 (t, -1 20 )-8.OGC, 2H), 3.77 (m, 2H), 3.70 (m, 2H). MS (E5I) m/e. (MATN) 7: 439.3, (М-А1Н) 7: 437.3.

Spl.150 0 MS (E5I) m/e: (МА1Н)": 379.9, (М-1Н) 7: 379.9.

Spl. 151

MS (E5I) m/e: (МА1Н)": 379.9, (М-1Н) 7: 379.9.

Spl. 152

F! "H NMR (400 MHz, UMSO-av) 6: 11.04 (res. s, 1H), 8.85 (d, 1H, uU-9.0 Hz), 8.20 (d, 1H, 9U-1.2Hz), 8.18 (d, ko 1H , 9-1.2Hz), 7.85 (m, 71H), 7.70-7.65 (m, 4H), 7.01 (t, 2H, U-8.7Hz), 4.32 (m, 1H), 4.25 (m, 1H), 4.15 (with,

ЗН), 4.13 (m, 1Н), 1.77 (m, 2Н), 0.95 (t, ЗН, У-7.0). EM (calc.): 409, MS (E5T) m/e (MA1H)": 410.2, (M-1H) 408.2. 60 Spl.153 "N'NMR (400 MHz, DMOSO-yv5) 5 : 011.05 (s, 1H), 10.17 (s, 1H), 8.65 (m, 1H), 8.14 (m, 1H), 7.95 (m, tn), 7.88 (d, 71, uU-8.2HC), 7.73-7.66 (m, ZN ), 7.62-7.59 (m, 2H), 7.05 (m, 2H), 4.24 (m, 2H), 3.89 (s, ЗН), 3.73 (m, 2H). EM (calc.): 380; MS (E5I) m/e (MA1TN)": 381.0, (M- 1H)7: 379.1.

Spl.154 65 "H NMR (400MHz, DMSO-dv) 5 : 11.04 (s, 1H), 9.14 (t, 1H, U-6.0Hz), 8.18 (d, 1H, 9U-7.7Hz), 8.07 (d , 1H, 3-8.2Hz), 7.85 (t, 1H, 9U-7.7Hz), 7.72-7.64 (m, 4H), 7.08 (d, 2H, 9-9.1Hz), 4.78 (m, 7), 4.14 (c, ZN), 3.66

(m, 1H), 3.55 (m, 1H), 1.31 (d, ZN, U-6.1Hz). EM (calc.): 395; MS (EV8I) m/e (MAN): 396.1, (MAN): 394.2

Spl. 155

MS (EZ8I) m/e: (MATN)": 377.9, (MATN)": 376.1.

Spl. 156

MS (EZ8I) m/e: (MA1TN)": 408.3, (M-TN): 406.2.

Spl. 157

MS (EZ8I) m/e: (MATN)": 373.9, (MATN) 7: 372.1.

Spl.158 70 MS (EZ8I) m/e: (MA1TN)": 422.3, (M-TN): 420.3.

Spl. 159 "H NMR (400MHz, DMSO-4v) 5 : 11.04 (s, 1), 9.10 (t, 1H, 9U-5.9Hz), 8.16 (d, 1H, 9U-8.4Hz), 8.07 (d, МН, d-8.4Hz), 7.85 (t, YAN, 9-7.9Hz), 7.71-7.65 (m, 4H), 7.03 (d, ?2H, 9-8.9Hz), 4.60 (t, ?2H, 9-5.9 Hz), 4.23 (t, ut5 ?Н, 3e5Hz), 3.75 (kv, 2Н, 4-5.9HZ), 3.00 (m, 2Н). EM (calc.): 463; MS (EVI) m/e (MAN ): 464.3, (M-1NU: 462.2.

Spl.160 "H NMR (400 MHz, OMSO-yv) 5 : 11.04 (s, 1H), 8.78 (d, 1H, 9-9.0Hz), 8.15 (d, 1H, U-8.3Hz), 8.09 (d, MH, d-8.5Hz), 7.85 (t, 1H, 9-6.7Hz), 7.68 (m, 4H), 7.00 (d, 2H, 9-9.0Hz), 4.61 (t, ?2H, 9U-5.9Hz ), 4.32 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H), 3.00 (m, ?H), 1.76 (m, 2H), 0.95 (t, ЗН, 9-7.0Hz). EM (calc.): 491; MS (E8I) m/e 20. (Manu: 492.1, (M-1H)7: 49041.

Spl.161 "H NMR (400MHz, DMSO-c4v) 5 : 9.13 (t, 1H, 9-6.1GHz), 8.15 (I, 1H, 9-8.1Hz), 8.07 (d, 1H, 9U-8.3Hz) . 5.5 Hz), 3.65 (m, 1H), 3.55 (m, 1H), 3.00 (m, 2H), 1.31 (d, ZN, U-6.0Hz). EM (calc.): 477; MS (EVI) m /e (МА1Н)": 477.9, (М-1Н): с 25 476.1.

Spl. 162 o'H NMR (OMSO-yv): 3.56 (s, 2H), 4.09 (t, 2H), 6.57 (d, 1H), 6.77 (d, 1H), 6.95 (m, ЗН), 7.18 ( t, 1H), 7.32 (d, 2H), 7.69 (d, 2H), 8.38 (t, 1H), 9.6 (s, 1H), 11.05 (s, 1H). RIMS: (M-1)7" 343.2, (M-1)7 341.3.

Spl. 163 (se) z H NMR (DMSO-4c): 3.55 (s, 2H), 4.08 (t, 2H), 6.4 (d, 1H), 6.8 (d, 2H), 7.0 (d, 2H), 7.35 ( d, 1H), 74 Kk, (d, 2H), 7.69 (d, 2H), 8.25 (t, 1H), 9.85 (s, 1H), 11.05 (s, 1H). RYUMS. (Ma1)7! 343 1, (М-1Н)" 341.1.

Spl. 164 (ge)

EM (calc.): 420.17; MS (E8I) m/e (MAN) ": 421.2, (MATN)": 419.5. high school

Spl.165 35 EM (calc.): 420.17; MS (EBI) m/e (MAN): 421.3, (M-1NU: 419.3. so

Spl. 166

EM (calc.): 420.17; MS (E8I) m/e (MAN) ": 421.3, (MATN)": 419.3.

Spl. 167 " y H NMR (DMSO-4v); 5 8.89 (1H, s), 8.58 (IN, m), 7.71 (2H, m), 7.65 (IN, d), 7.56 (1H, d), 7.41 (IN, d), -- s 7.36 ( 1H, t), 7.25 (1H, t), 7.21 (1H, s), 7.00 (2H, d), 6.74 (1H, dd), 4.11 (2H, t), 3.58 (2H, sq).

Spl. 168;" EM (calc.): 420.17; MS (E8I) m/e (MAN) ": 421.2, (MATN): 419.3.

Spl.169 "H NMR (400 MHz, DMSO-ide) 5 11.07 (s, 1H), 9.14 (s, 1H), 9.11 (t, 9-8.0 Hz, 1H), 8.93 (s, 1H), 8.63 (t . (m, 2n). MS (EBI) m/e: (MAN): 384.1, (M-1H): 382.0. o Spl.170

He MS (EZ8I) m/e: (MA1TN)": 451.0, (M-TN): 449.2. -1 50 Spl.171

MS (EZ8I) m/e: (MA1TN)": 409.3, (M-TN) 7: 407.2. 4) Spl. 172 'N NMR (OMSO-yv): 3.54 (sq, 2H), 3.84 (s, ЗН ), 4.08 (t, 2H), 6.6 (d, 1H), 6.98 (m, 4H), 7.35 (t, 1H), 7.5 (d, 1H), 7.65 (d, 1H), 7.69 (d, 2H) , 8.36 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1H). LCMS: (Me-1)7" 356.9, (M-1)77 355.2.

Spl. 173 o'H NMR (OMSO-yv): 3.56 (q, 2H), 3.77 (s, ЗН), 4.09 (t, 2H), 6.66 (d, 1H), 6.93 (m, 2H), 6.99 ( d, 2H), 7.1 (d, 2H), 7.29 (t, 1H), 7.39 (d, 1H), 7.70 (d, 2H), 7.87 (d, 1H), 8.36 (t, 1H), 8.9 (s , 1H), 11.05 (c, 1). RYUMS: (MA)! ki 357.1, (M-1NU" 355.1.

Spl.174 60 "H NMR (400 MHz, DMSO-ydv) 5 11.05 (s, 1H), 9.21 (t, 9-8.0 Hz, 1H), 9.07 (s, 1H), 8.92 (s, 1H), 8.67 ( s, 1H), 7.70 (m, 4H), 7.01 (d, 9-8.0Hz, 2H), 6.92 (m, 1H), 4.21 (t, U-8.0Hz, ?2H), 3.71 (m, 2H) MS (E5I) m/e: (MATN)": 421.2, (M-1H)": 419.4.

Spl. 175 v5 '"H NMR (DMSO-4v): δ 8.91 (1H, s), 8.44 (1H, t), 7.73 (2H, d), 7.72 (1H, s), 7.57 (1H, d), 7.44 (1H, d), 7.02 (2H, d), 6.50 (1H, d), 4.11 (2H, t), 3.58 (2H, sq.) PH/MS, Ma: 413.1.

Spl. 176

H NMR (DMSO-α): 3.54 (sq, 2H), 4.07 (t, 2H), 6.36 (d, 1H), 6.68 (s, 1H), 6.98 (d, 2H), 7.32 (d, 1H), 7.69 (m, ZN), 7.98 (s, 1H), 8.27 (t, 1H), 8.9 (s, 1H), 11.04 (s, 18). RHMS: (Ma-1)77 316.9, (M-1U71 315.3.

Spl. 177

H NMR (0MSO-sw): 3.55 (sq, 2H), 4.08 (t, 2H), 6.47 (d, 1H), 6.98 (d, 2H), 7.31 (d, 1H), 7.42 (d, 1H) , 7.58 (m, 1H), 7.69 (d, 2H), 7.78 (s, 1H), 8.30 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1). RHMS: (M-n1)7! 333.0, (M-1)77 331.0.

Spl.178 "H NMR (DMSO-yv): 5 8.91 (1H, s), 8.40 (1H, t), 7.73 (2H, d), 7.61 (2H, m), 7.38 (IN, d), 7.11 ( 1H, dd), 70.77.01 (2H, d), 6.43 (1H, d), 4.11 (2H, t), 3.57 (2H, sq). LC/MS, M.n1: 333.0.

Spl. 179

NN NMR (0MSO-yv): 2.31 (s, ЗН), 3.55 (q, 2Н), 4.09 (t, 2Н), 6.6 (d, 1Н), 6.99 (d, 2Н), 7.2-7.4 (m,

EN), 7.70 (d, 2H), 8.33 (t, 1H), 8.9 (s, 1H), 11.04 (p. 13). RYUMS: (M-n1)77 341.1, (M-1H)U" 3394.

Spl. 180

NN NMR (OMSO-yv): 2.31 (s, ЗН), 3.55 (q, 2Н), 4.09 (t, 2Н), 6.6 (d, 1Н), 6.99 (d, 2Н), 7.2 (d, 2Н), 7.38 (d, 1H), 7.42 (d, 2H), 7.69 (d, 2H), 8.33 (t, 1H), 8.9 (c, 1H), 11.04 (c, 1H). RHMS: (Ma-1)77 341.2, (M-1)7 339.2.

Spl. 181

H NMR (0MSO-av): δ 8.87 (IN, s), 8.52 (1H, t), 7.70 (2H, d), 7.64 (1H, d), 7.52 (1H, d), 7.34 (1H, m ), 7.24 (1H, t), 7.22 (1H, s), 6.99 (2H, d), 6.67 (1H, m), 4.09 (2H, t), 3.52 (2H, sq), 2.48 (ЗН, m) . RH/MS, M.n1: 381.0.

Spl. 182

H NMR (0MSO-av): δ 8.88 (IN, s), 8.33 (IN, t), 7.68 (2Н, d), 7.54 (1Н, m), 7.41 (1Н, d), 7.28 (1Н, s ), 7.24 (1H, M), 7.19 (1H, m), 6.95 (2H, d), 6.07 (1H, m), 4.11 (2H, t), 3.52 (2H, sq), 2.15 (ЗН, m) . RH/MS, M.1: 381.1.

Spl. 183

H NMR (DMSO-α): 2.94 (s, 6H), 3.54 (sq, 2H), 4.07 (t, 2H), 6.38 (d, 71H), 6.69 (d, 2H), 6.98 (d, 2H), c 7.29 (d, 1H), 7.35 (d, 2H), 7.69 (d, 2H), 8.15 (t, 1H), 8.87 (c, 1H), 11.04 (c, 1H). RZhMS: (Ma-1)77 370.1, (M-1U77 368.3. (o)

Spl. 184

H NMR (DMSO-α): 3.57 (q, 2H), 4.10 (t, 2H), 6.65 (d, 1H), 7.0 (d, 2H), 7.14 (m, 2H), 7.42 (m, 1H), 7.6 (d, 1H), 7.72 (m, ЗН), 7.87 (d, 1H), 8.149 (t, 1H), 8.87 (s, 1H), 11.04 (s, 1H), 11.52 (s, 1H). RHMS: (Ma1)77 366.2, "with zo (M-1u7 364.4.

Spl. 185 -

H NMR (DMSO-α): 2.36 (s, ЗН), 3.56 (q, 2Н), 4.10 (t, 2Н), 6.56 (d, 71Н), 7.00 (d, 2Н), 7.23 (m, ЗН), so 7.5 (d, 1H), 7.65 (d, 1H), 7.7 (d, 2H), 8.4 (t, 1H), 8.87 (s, 1H), 11.04 (s, 1H). RYUMS: (Ma-1)7! 341.2, (M-1)77 339.3.

Spl. 186 Sc

H NMR (OMSO-yv): 3.55 (sq, 2H), 3.93 (s, ЗН), 4.08 (t, 2H), 6.66 (d, 1H), 6.79 (t, 1H), 6.86 (d, IN), so 6.98 (d, 2H), 7.15 (m, 1H), 7.4 (d, 1H), 7.65 (d, 1H), 7.7 (d, 2H), 8.31 (t, 1H), 10.0 (s, 1H), 11.04 (c, 1H). RAHMS: (Ma-1)7! 343.1, (M-1U7! 340.9.

Spl. 187 "

H NMR (0MSO-sw): 3.57 (q, 2H), 3.93 (s, ЗН), 4.09 (t, 2Н), 6.75 (d, 1Н), 6.98 (m, ЗН), 7.18 (m, ЗН), 40. 7.38 (d, 1H), 7.7 (d, 2H), 8.5 (t, 1H), 8.87 (s, 1H), 11.04 (s, 1). RHMS: (Ma-1)7! 396.7, (M-1)77 395.0. - s Spl.188 "» NN NMR (DMSO-av): 0.922 (t, ЗН), 1.5-1.8 (m, 2Н), 3.93 (s, ЗН), 3.95-4.07 (m, ЗН), 6.8 (d . RYUMS: (Ma-1)77 425.2, (M-1)7 423.2.

Spl.189 "H NMR (0MSO-av): 0.95 (ZN, t, 7HC); 1.53 (IN, m); 1.72 (IN, m); 2.52 (ZN, s); 3.79 (ZN, s); 3.94 (1H, so s); 4.06 (2H, s); 6.66 (1H, s); 6.93 (IN, dd); 7.02 (2H, d); 7.15 (2H, m); 7.42 (1H, d); 7.7 (2H, d); 8.27 with (2H, d, 7Hz); 8.87 (1H, d, 2Hz). MO (Mt): 439

Spl.190 so NN NMR (0MSO-sw): 3.54 (q, 2H), 4.08 (t, 2H), 6.44 (d, 1H), 6.56 (s, 1H), 6.75 (s, 1H), 6.98 (d , 2H), -I 50 7.23 (d, 1H), 7.70 (d, 2H), 7.75 (s, 1H), 8.41 (t, 1H), 8.9 (s, 1H), 11.04 (s, 1H). RHMS: (Ma-1)377 317.0, (M-1U71 315.2.

Spl. 191 m NN NMR (0MSO-irv): 3.5-4.05 (m, 14Н), 4.18 (t, 2Н), 6.99 (d, 2Н), 7.69 (d, 2Н), 7.93 (d, 2Н), 8.02 (d, 2H), 8.2 (s, 1H), 8.76 (t, 1H), 8.97 (s, 1H), 11.05 (s, 1H). RHMS: (M--1)77 497.4, (M-1)7 495.4.

Table 2:

Spl. 1

HF) EM (calc.): 370.2; MS (E5I) m/e (M--1)7: 371.1, (M-1H)": 369.2. t Spl.2 "H NMR (400 MHz, OMSO-ydv) 5 11.03 (s, 1H), 8.88 ( s, 1H), 7.67 (d, 9U-9.2Hz, 2H), 7.51 (m, ЗН), 7.36 (m, 6o 8H), 6.92 (d, U-9.2Hz, 2H), 6.27 (d, 9- 15.2Hz, 1H), 4.16 (m, 4H). EM (calc.): 402.2; MS (E5I) m/e (MA1TN)": 403.1, (M-1H) 7 401.1.

Spl Z

EM (calc.): 340 1; MS (E5I) m/e (MA1H)": 341.0, (M-1H) 7: 339.4.

Spl.4 b5 EM (calc.): 398.13; MS (E5I) m/e (MA1H)": 399.0, (M-1H)": 397.1.

Spl. 5

EM (calc.): 36817; MO (EI) m/e (МА1Н)": 368.8, (М-1Н) 7: 367.2.

Spl. b

EM (calc.): 354.1; MS (EI) m/e (МА1Н)": 354.8, (М-1Н) 7: 353.2.

Table 3:

Spl.1 "H NMR (400MHz, DMSO-av) 5 11.11 (s, 1H), 9.07 (t, U-5.2Hz, 1H), 8.94 (s, 1H), 8.16 (s, 1H), 8.07 (dd . . EBI) m/e (МА1Н)": 357.0, (М-1Н)7: 355.1.

Spl.2 "H NMR (400MHz, DMOSO-y65) 5 11.05 (s, 1H), 8.92 (t, 9U-5.6Hz, 1H), 8.88 (s, 1H), 7.76 (d, U-8.0HzC, 1H), 7.70 (d, 9U-9.2HzC, 2H), 7.64 (d, 9U-8.0Hz, 1), 7.55 (s, 1H), 7.46 (t, U-6.8Hzc, 1H), 7.32 (t, 9U-8.0Hz, MN), iz 7.01 (d, 9-8.2Hz, 2H), 4.18 (t, 9-5.6Hz, 2H), 3.67 (m, 2H). EM (calc.): 340.1; MS ( E5I) m/e: (MaА1Н)": 341.0, (М-1Н): 339.1.

Spl. Z

NN NMR (400 MHz, UOMSO-y5) 5: 011.57 (s, 1H), 11.04 (s, 1H), 8.71 (t, 9U-5.6Hz, 1H), 7.70 (d, 9-8.8Hz, 2H), 7.59 (d, uU-8.4ГЦs, 7Н), 7.40 (d, 9-8 4Gu, 1Н), 7.16 (t, У-8.4Gu, 1Н), 7.12 (M, 1), 7.00 (m, zn), 4.18 (t, 9-5.6Hz, 2H), 3.68 (m, 2H). EM (calc.): 339.1; MS (E5I) m/e (MATN)": 340.1, (M-TN) 7: 338.3.

Spl. 4

EM (calc.): 353.1; MS (E5I) m/e (M--1)7: 354.1, (M-1H) 7: 352.2.

Spl.5 Ha "H NMR (400MHz, OMSO-av) 5 8.84 (t, U-5.6Hz, 1H), 8.05 (s, 1H), 7.99 (dd, uU4-6.0Hz, 9a2-2.0Hz, 1H) . 4.06 (t, 9U-6.0HzC, 2H), 3.43 (pseudo kv, U-5.6Hz, 2H), 2.00 (pseudo n, U-6.0Hz, 2H). EM (calc.): 370.1; MS (EBI) m/e (MATN)": 371.1, (M-1H): 369.0.

Spl. b co

NN NMR (400MHz, DMOSO-avb) 5 10.96 (s, 1H), 8.74 (t, 9U-6.0Hz, 1), 7.67 (d, 9U-7.6Hz, 1H), 7.62 (d, chn 3-8. A4Hzc, 2H), 7.44 (s, 1H), 7.55 (dd, U4-8.4Hz, 9U2-0.8Hz, 1H), 7.43 (d, 9U-0.8Hz, 1H), 7.37 (td, U4-7.2Hz, 9do-1.2Hz, 1H)U, 7.241 (td, 9U4-8.0Hz, 92-0.8Hz, 71H), 6.89 (d, 9U-8.8Hz, 2H), 4.01 (t, 9U-64Hz, 2H), 3.37 (pseudo kv, co

U-6.OHHz, 2H), 1.94 (pseudo n, U-6.0Hz, 2H). EM (calc.): 354.1; MS (EBI) m/e (МА1Н)": 355.2, (М-1Н): 353.1. си

Spl.7 "N'YAMRe (400MHz, DMOSO-av) 6 11.07 (s, 1H), 8.91 (s, 1H), 8.65 (div, 9U-7.2Hz, 1H), 8.20 (s, 1H), 8.03 so (m, 1), 7.95 (m, 1), 7.72 (d, U-8.4Hz, 2H), 7.46 (m, 2H), 7.03 (d, 9-8.8 Hz, 2H), 4.20 (m, ЗН ), 2.08 (m, 1H)U, 1.02 (d, U-6.8Hz, 6H). EM (calc.): 398.1; MS (EI) m/e (MATH)": 399.0, (MA1H) 7: 397.1 .

Spl.v « 20 "H NMR (400MHz, OMSO-av) 5 11.07 (s, 1H), 8.91 (s, 1H), 8.68 (d, 9U-8.0Hz, 1H), 8.17 (s, 1H), 8.03 (dd, -o s 34-252.0Hz, 9Ua-6.4Gu, 1), 7.96 (dd, 9U4-4.0Gu, 92-6.8Hz, 1), 7.73 (d, 9U-8.8Hz, 2H), 7.46 (m, 4H), 7.04 (d, 5-9.2Hz, 2H), 4.24 (m, 1H), 4.18 (dd, 9U--6.8Hz, 9U2-10.0Hz, 1H), 4.09 (dd, U4-5.2 Hz, 9U2-9.6HzC,), 1.81 (m, 1H), 1.67 ;» (m, 1H), 0.99 (t, 9-7.6Hz, ZN). EM (calc.): 384.1; MS (E5I) m/e (MAN): 385.0, (M-1H) 7: 383.1.

Spl. 9 "H' NMR (400 MHz, OMSO-dv) 6 11.11 (s, 1H), 8.95 (res. s, 1H), 8.80 (d, 9U-8.0GuC, 1H), 8.19 (s, 1H), 8.06 (dd,

Go | U425.6Hz, 9Ua-1.6Hz, 1), 7.98 (dc, 9U4-6.8Hz, 9U2-1.6Hz, 1H), 7.76 (d, 9U-8.4HzC, 2H), 7.49 (m, 2H), 7.08 ( d, 3-8.8Hz, 2H), 4.42 (p, U-6.4Hz, 1H), 4.20 (dd, 9U4-9.6Hz, 9U2-6.4Hz, 1H), 4.07 (dd, 9U4-9.6Hz, 9U2- 5.6Hz, 1H), 1.36 (d, dk U-6.8Hz, ZN). EM (calc.): 370.1; MO (EI) m/e (MA1TN)": 371.0, (M-1H)": 368.9 (ee) Spl.10 "H NMR (400 MHz, DMOSO-a65) 5 10.95 (s, 1H), 8.65 (d , U-7.6Hz, 1H), 8.04 (s, 1H), 7.91 (d, 9U-7.2Hz, 1), 7 7.83 (d, 9U-6.4Hz, 1H), 7.61 (d, U-8.8Hz, 2H), 7.34 (m, 2H), 6.93 (d, U-8.8Hz, 2H), 4.27 (p, 9-6.4Hz, 1H), 4.05 (dd, (42) 3U4-6.8Hz, 9U2-10.0HzC . ) 7: 370.9, (M-1H) 7: 369.0.

Spl.11 29 nNMR (400 MHz, DMOSO-avb) 5 10.96 (s, 71Н), 8.54 (d, 9-8.4Hz, 1), 7.68 (d, 9U-7.6Hz, 1Н), 7.61 (d, o U-8.АЦС, 2Н), 7.58 (d, U-8.4HzС, 1Н), 7.48 (d, 9У-0.8HzС, 1Н), 7.38 (td, U4-8.0 Hz, 95-0.8Hz, 1Н) . 1H), 3.99 (dd, 9U4-10.0Hz, 9U2-5.6Hz, about 1H), 1.68 (m, 1H), 1.55 (m, 1H), 0.86 (t, U-7.2Hz, ЗН). EM (calc.): 368.1; MO (E5I) m/e (M-1H)7: 367.1.

Spl 12 bo "N' NMR (400MHz, DMOSO-y65) 5 11.06 (s, 1H), 9.03 (t, 9U-6.0Hz, 1H), 8.11 (s, 1H), 8.03 (d, 9-7.2HzC, 1H), 7.94 (d, 9U-6.4Hz, 1H), 7.72 (d, U-8.8Hz, 2H), 7.46 (m, 2H), 7.07 (d, 9U-9.2Hz, 2H), 4.72 (pseudo square ) (MATN)": 371.0, (MATN) 7 369.1. 65 Spl.13 "H NMR (400MHz, OMSO-av) 5 11.06 (s, 1H), 9.03, (t, 9U-5.6Hz, 1H), 8.11 (s, 1H), 8.03 (d, 9U-6.8 HzC, 1H),

7.94 (d, 9U-7.2Hz, 1), 7.72 (d, 9-8.4Hz, 2H), 7.46 (pseudo n, U-5.6Hz, 2H), 7.07 (d, U-8.4Hz, 2H), 4.74 (pseudo square, U-5.6Hz, 1Н), 3.63 (m, 1Н), 3.42 (m, 1Н), 1.34 (d, 76.0Hz, ЗН). EM (calc.): 370.1; MS (E5I) m/e (MAN): 371.0, (MAN): 369.1.

Spl. 14

H NMR (400MHz, DMSO-α) 6 11.02 (s, 1), 8.92 (t, 9U-6.0Hz, 1H), 7.75 (d, 9U-7.6Hz, 1H), 7.68 (d,

U-8.8Hz, 2H), 7.54 (d, U-0.8Hz, 1H), 7.44 (td, 9U4-7.2Hz, 9U2-0.8Hz, 1H), 7.31 (td, U4-7.6Hz, 9U5-0.8Hz . , 3.39 (ddd, 44-6.0 Hz,

Уо12.АХц, У3-19.6 ХЦ, 1), 1.29 (d, У-6.АХц, ЗН). EM (calc.): 354.1; MS (EBI) m/e (MA1N) 7: 354.7, (M-1N) 7: 353.1.

Floor 15

EM (calc.): 386.09; MS (E5I) m/e (M-1H) 7: 384.7.

Spl. 16

EM (calc.): 370.10; MS (EI) m/e (M-1H) 7: 369.0.

Spl. 17 t EM (calc.): 390.0; MS (EI) m/e (MAN) ": 391.2.

Spl. 18

EM (calc.): 354.12; MS (E5I) m/e (M-1H) 7: 353.2.

Spl. 19

EM (calc.): 354.12; MS (E5I) m/e (M-1H) 7: 353.1.

Spl. 20

EM (calc.): 424.07; MS (E5I) m/e (M-1H) 7: 423.9.

Spl. 21

EM (calc.): 374.0; MS (E5I) m/e (M--1)7: 375.0, (M-1H)7: 373.0. with

Spl. 22 o

EM (calc.): 386.1; MS (E5I) m/e (M--1)7: 387.1, (M-1H) 7: 384.7.

Spl. 23

EM (calc.): 374.1; MS (E5I) m/e (M--1)7: 374.9, (M-1H)7: 372.9.

Spl. 24 re)

EM (calc.): 370.1; MS (E5I) m/e (M-n1)7: 370.8, (M-1H) 7: 369.0. M.Sc

Spl. 25

EM (calc.): 370.1; MS (E5I) m/e (M--1)7: 371.0, (M-1H) 7: 369.1. co

Spl. 26 Sep

EM (calc.): 414.14; MS (E5I) m/e (MA1N)": 415.2, (M-1N):: 413.2. so

Spl. 27

EM (calc.): 469.18; MS (E5I) m/e (MA1N) 7": 470.1, (M-ATN): 468.4.

Spl. 28

EM (calc.): 447.14; MO (E5I) m/e (M-1H)": 448.1, (M-1H)": 446.2. "

Spl 29 -o s EM (calc.): 354.1; MS (E5I) m/e (M--1)7: 355.1, (M-1H)7: 353.1. ts Spl.3O0 is" EM (calc.): 370.1; MS (E5I) m/e (M--1)7: 371.0, (M-1H) 7: 368.9.

Spl.. 31

EM (calc.): 400.1; MS (E5I) m/e (M-1H)": 401.0, (M-1H): 399.2. o Spl.32 t EM (calc.): 427.1; MS (E5I) m/e (MA1H)": 428.2 , (М-А1Н) 7: 426.2.

Spl. 33 so EM (calc.): 414.1; MS (E5I) m/e (M--1)7: 415.4, (M-1H) 7: 413.2. -170 Spl.a

EM (calc.): 469.2; MS (E5I) m/e (M-n1)7: 470.1, (M-1H) 7: 468.3. še Spl 35

EM (calc.): 447.1; MS (E5I) m/e (M-n1)7: 448.2, (M-1H) 7: 446.5.

Spl. 3b

EM (calc.): 368.1; MS (E5I) m/e (M-n1)7: 369.0, (M-1H) 7: 367.2. (F) Spl.37 t "H NMR (400MHz, DMSO-av) 5 11.69 (s, 1H), 11.04 (s, 1H), 8.77 (t, 9U-5.6Hz, 1H), 7.70 (d, 9U- 8.4Hz, 2H), 7.39 (m, 2H), 7.11 (s, 1H), 7.05 (m, 7), 7.01 (d, 9-8.4Hz, 2H), 4.18 (t, 9U-6.0Hz, 2H) , 3.67 (m, 2H). EM 60 (calc.): 357.1; MS (E5I) m/e (MA1H)": 357.8, (M-1H) 7: 356.2.

Spl. 38

H NMR (400MHz, DMSO-dv) b 11.42 (s, 1H), 11.05 (s, 1H), 8.66, (t, 9U-5.6Hz, 71H), 7.70 (d, 9U-9.2Hz, 2H), 7.29 (d, U-8.4Hz, 1H), 7.03 (m, 4H), 6.81 (m, 1H), 4.17 (t, 9U-5.6Hz, 2H), 3.75 (s, ЗН), 3.66 (m, 2H) . EM (calc.): 369.1; MS (E5I) m/e (MA1N)": 369.9, (M-1N) 7: 368.2. 65 Spl.39

EM (calc.): 384.13; MS (E5I) m/e (MA1H)": 384.9, (M-1H): 383.2.

Spl. 40

EM (calc.): 446.15; MS (E5I) m/e (МА1Н)": 447.2, (М-1Н):: 445.А.

Spl.41 "H NMR (400MHz, DMSO-ydv) 5 11.28 (s, 1H), 11.04 (s, 1H), 8.53 (t, 9U-5.6Hz, 1H), 7.70 (d, 9U-9.2Hz, 2H ), 7.02 (m, 4H), 6.86 (s, 1H), 4.16 (t, 9U-5.6HzC, 2H), 3.76 (s, ЗН), 3.75 (s, ЗН), 3.63 (m, 2Н). EM (calc.): 399.1; MS (E5I) m/e (MA1H) 7: 400.0, (M-1H)": 398.1.

Spl.42 "H NMR (400MHz, DMSO-av) 5 11.09 (rs, 1H), 10.60 (rs, 1H), 9.29 (t, U-6.0Hz, 1H), 8.08 (d, 9U-8.0Hz, 1 ), 7.70 (m, ZN), 7.57 (t, 9-7.2Hz, 1), 7.45 (t, 9U-7.2Hz, 1), 7.00 (d, 2-9.2Hz, 2H), 4.83 (m, 2H ), 4.23 (t, U-6.0Hz, 2H), 3.94 (m, 2H), 3.73 (m, 4H), 3.44 (m, 2H), 3.27 (m, 2H). EM (calc.): 439.2; MS (E5BI) m/e (MAN): 439.8, (M-1H): 438.2. 75 Spl.44

EM (calc.): 412.16; MS (E5I) m/e (MA1H) 7: 413.1, (M-1H):: 411.3.

Spl. 45

H NMR (400MHz, DMSO-α) 6 11.05 (s, 1), 8.92 (t, 9U-5.2Hz, 1H), 7.74 (d, 9U-7.6Hz, 1H), 7.70 (d, 3-8.8Hz, 2H), 7.59 (s, 1), 7.55 (d, 9U-6.8Hz, 71H), 7.32 (m, ЗН), 7.06 (d, 9U-7.6Hz, 2H), 7.00 (d, 9U-9.2Hz, 2H), 6.95 (t, U9-7.2Hz, 1H), 5.44 (s, 2H), 4.19 (t, U-6.0Hz, 2H), 3.69 (m, 2H). EM (calc.): 446.2; MS (E5I) m/e (MAN); 447.2, (M-1H) 7: 445.3.

Spl.46 "H NMR (400MHz, OMSO-yv) 5 11.08 (s, 1H), 8.91 (t, 9U-5.6Hz, 1H), 7.71 (m, ЗН), 7.58 (s, 1H), 7.44 (d ,

U-7.6Hz, 71), 7.32 (t, 9U-7.6Hz, 71H), 7.03 (d, U-8.8Hz, 2H), 4.78 (s, 2H), 4.20 (t, 9-6.0Hz, 2H) , 3.69 (m, EM ?H), 3.36 (s, ZN). EM (calc.): 384.1; MS (EBI) m/e (MA1N) 7: 385.9, (M-1N) 7: 383.2. (5)

Spl. 47 "NMR (400MHz, DMOSO-yv5) 5 11.33 (s, 1H), 11.09 (s, 1H), 9.32 (t, 9-5.6Hz, 1H), 7.88 (d, 9U-8.4Hz, 1H), 7.71 (m, ЗН), 7.61 (s, 1H), 7.43 (t, 9О-7.6ГЦц, 71Н), 7.03 (d, уУ-8.8ГЦц, 7), 4.68 (с, 2Х), 4.23 ( t, 9-5.6 Hz, 2H), 3.83 (m, 6H), 3.37 (m, 2H), 3.20 (m, 2H). EM (calc.): 439.2; MS (E5I) m/e (MA1H)" : 440.2, (M-1H) 7: 438.4. co

Spl.48 M "H NMR (400MHz, DMSO-dv) 5 11.09 (s, 1H) 10.74 (s 1H), 9.31 (t, 9U-5.6Hz, 1H), 7.88 (d, 9U- 8.0Hz, 1H) . 8.8Hz, 2H), so 4.63 (d, 9U-5.2Hz, 2H), 4.23 (t, U-6.0Hz, 2H), 3.70 (m, 2H), 2.78 (s, ЗН), 2.770 (s, ЗН ). EM (calc.): 397.2; si

MS (E5I) m/e (MA1H)": 398.0, (M-1H). 396.1.

Spla9 so

EM (calc.): 384.1; MS (EI) m/e (M-1N): 382.9.

Spl. 50

EM (calc.): 400.1; MS (EI) m/e (M-1H)": 398.7. "

Spl. 51 with s "H NMR (400MHz, OMSO-yv) 5 11.07 (s, 1H), 8.78 (t, 9U-6.0Hz, 1H), 7.71 (m, ЗН), 7.54 (s, 1H), 7.43 (d , . U-72Hz, 1H), 7.32 (d, 9U-7.6Hz, 1H), 6.99 (d, U-8.4Hz, 2H), 4.77 (s, 2H), 4.10 (t, 9-6.0Hz, 2H ), 3.47 (m, 2H), "» 3.36 (s, ЗН), 2.02 (m, 2H). EM (calc.): 398.2; MS (EBI) m/e (MA1N) 7: 399.1, (M-1N): 397.1.

Spl. 52 "NMR (400 MHz, DMSO-α5) 5 8.82 (t, 9-5.6 Hz, 1), 7.71 (m, ЗН), 7.54 (m, 2Н), 7.31 (m, ЗН), 7.06 (d, (axis) 3-8.0Hz, 2H), 6.95 (m, ЗН), 5.43 (s, 2H), 4.09 (t, U-6.0Hz, 2H), 3.47 (m, 2H), 2.02 (m, 2H) EM (calc.): 460.2; MS (E5I) m/e (MA1H) 7: 461.0, (M-1H)": 459.1. io)

Spl.53 (og) EM (calc.): 428.16; MO (E5I) m/e (MA1N)": 428.9, (M-1N)": 427 1. -1 20 Spl.54

HnH NMR (DMSO-iv): 2.11 (ZN, s); 2.78 (IN, dd, 14.8Hz); 2.86 (1H, dd, 14.5Hz); 4.17 (IN, dd, 10.4Gu); (42) 4.23 (1H, dd, 10.6Hz); 4.49 (1IN, m); 7.00 (2H, d, 9Hz); 7.32 (IN, t, 7Hz); 7.46 (IN, td, 8.1Hz); 7.56 (1H, s); 7.64 (1H, d, 8Hz); 7.70 (2H, d, 9Hz); 7.77 (1H, d, 8Hz); 8.77 (1H, d, 8Hz); 8.88 (1H, p). MS (M.n1): 401.

Spl. 55

H NMR (DMSO-α): 3.31 (ZN, s); 3.53 (1Н, dd, 13.3.5Hz); 3.66 (1H, dd, 13.8Hz); 4.16 (1H, dd, 9.6Gu); at 4.24 (1H, dd, 98Hz); 4.87 (IN, m); 7.00 (2H, d, 9Hz); 7.33 (IN, t, 7Hz); 7.47 (IN, t, 8Hz); 7.57 (1H, s); 7.65 (1H, d, 8Hz); 7.70 (2H, d, 9Hz); 7.77 (1H, d, 8Hz); 8.89 (1H, s); 9.0 (1H, d, 8Hz). MO (M-1): 431. ko Spl. 56

NN NMR (400MHz, DMSO-dv) 5 : 7.92 (resoln s, 1H), 8.76 (t, 1H, 9U-5.9Hz), 7.75 (m, ЗN), 7.60 (d, 1H, 60U-7.6Hz) . 2H, 9-5.9Hz), 3.69 (m, 2H), 3.39 (m. 2H), 2.96 (t, 2H, 9U-8.3Hz). EM (calc.): 444; MS (EBI) m/e (МА1Н)": 445.3, (М-1Н): 443.3.

Spl.57 v5 "NMR (400 MHz, DMOSO-v5) 5 11.07 (s, 1H), 9.38 (s, 1H), 8.90 (s, 1H), 7.94 (d, 9U-8.0Hz, 1H), 7.57 (m, 10OH), 6.97 (d, U-8.0Hz, 2H), 4.80 (m, 2H), 4.20 (s, 2H), 3.70 (m, 2H), 3.31 (m, ЗН), 2.66 (m, 2H). MS (E5I) m/e:

(Man): 474.4, (MA1N)7: 472.1.

Spl.58 "H NMR (400MHz, DMOSO-y65) 5 11.05 (s, 1H), 9.73 (m, 1H), 8.89 (s, 1H), 7.75 (d, 9U-8.0Hz, 2H), 7.70 ( t, chu8.ОГц, 2Н), 7.61 (d, 9U-8.0Цц, 1), 7.43 (t, 9У-8.0Цц, 1), 7.18 (m, 6Н), 6.98 (d, 9-8.0Ццc, 2Н ), 4.13 (t,

UE8.OHz, 2H), 3.95 (m, 2H), 3.58 (m, 2H), 2.78 (m, 2H), 2.65 (m, 2H), 1.24 (s, ЗН). MS (E5I) m/e: (МА1Н)": 487.9, (М-ТН)-; 486.1.

Spl.59 "H NMR (400MHz, DMOSO-y65) 5 11.04 (s, 1H), 8.88 (s, 1H), 8.84 (t, 9U-8.0Hzc, 1), 7.82 (d, U-8.0HzC, 1H), 70 7.70 (d, 9-8.0Hz, 2H), 7.59 (d, 9U-8.0Hz, 1), 7.48 (t, 9-8.0Hz, 1), 7.34 (t, 9-8.0Hz, 1 ), 7.00 (d, 9U-8.0Hz, 2H), 4.31 (s, 2H), 4.18 (t, U-8.0Hz, 2H), 3.66 (m, 2H), 3.38 (m, 2H), 2.45 (t , U-8.0Hz, 2H), 1.65 (m, 28). MS (EBI) m/e: (МА1Н)": 445.2, (М-1Н):: 443.1.

Spl. bOo

H NMR (400 MHz, OMSO-a5) 5 11.05 (s, 1H), 9.04 (t, 9U-8.0Hz, 1), 7.86 (d, U-8.0Hz, 1H), 7.70 (d, t5 3-8.0Hz , 2H), 7.63 (d, 9U-8.0Hz, 1), 7.50 (t, 9U-8.0Hz, 1), 7.36 (t, U-8.0Hz, 1), 7.00 (d, U-8.0Hz, 2H ), 4.57 (m, 2H), 4.18 (t, 9-8.0Hz, 2H), 3.65 (m, 2H), 3.46 (t, 9U-8.0 Hz, 2H), 2.77 (m, 2H), 1.80 (m , 2H). MO (EBI) m/e: (МА1Н) 7: 461.0, (М-1Н): 459.1.

Spl.. 61 20 NN NMR (400MHz, OMSO-yv) 5 11.04 (s, 1H), 9.05 (t, U-8.0Hz, 1H), 7.87 (d, 9U-8.0HzC, 1H), 7.70 (d, 3-8.0Hz, 2H), 7.64 (d, 9-8.0Hz, 1), 7.51 (t, 9U-8.0Hz, 1), 7.38 (t, U-8.0Hz, 1), 7.00 (d, U- 8.0Hz, 2H), 5.11 (s, 2H), 4.19 (t, U-8.0HzC, 2H), 3.68 (m, 2H), 3.44 (t, 2-8.0Hz, 2H), 3.13 (m, 2H) , 1.83 (m, 2H). MS (EI) m/e: (MATN) 477.0, (MA1N): 475.0.

Spl.62 s 25 MS (E5I) m/e: (МА1Н)": 527.6, (М-1) 525.5.

Spl. b63 o "NMR (400MHz, DMOSO-y65) 5 : 11.04 (s, 1H), 8.88 (res. s, 1H), 8.73 (t, 1H, 9U-5.9Hz), 7.75-7.69 (m,

ZN), 7.57-7.42 (m, 6H), 7.28 (t, 1H, 9U-7.7Hz), 7.00 (d, 2H, 9U-8.7Hz), 4.17 (t, 2H, 9U-5.9Hz), 3.65 ( sq. 2H, 4-5.9Hz) 3.40 (t, 2H, U-6.9Hz), 3.04 (t, 2H, 9-6.9Hz). EM (calc.): 512; MS (EBI) m/e (MATN)": 513.3, (MAN): 511.2... TSO 30 Spl.b64 M

H'NMR (400 MHz, UOMSO-ydv) 5 : 11.04 (s, 1H), 8.87 (res. c, 1H), 8.83 (t, 1H, 92-5.9Hz), 7.70 (m, ЗН), 7.55 (d, 1H, 9-8.3Hz), 7.43 (t, 1H, 9U-7.4Hz), 7.34 (t, 1H, 9-8.0Hz), 7.28-7.20 (m, ЗН), 7.11 (d, IN, 8.0Hz) , 99 7.00 (d, 2H, 3U-8.6Hz), 4.17 (t, 2H, 9-5.9Hz), 3.65 (square, 2H, 9U-5.9Hz) 3.38 (t, 2H, 9U-8.3Hz), 3.00 (t, 2H, p

U8.ZHz). EM (calc.): 528; MS (EI) m/e (МА1Н) 7: 529.4, (М-1Н) 7: 527.5.

From Spl.65 so "NMR (400 MHz, UOMSO-av) 5 11.06 (s, 1H), 10 93 (s, 1H), 9.32 (m, 2H), 9 23 (s, 1H), 8.89 (s , 1H), 7.96 (d, U-8.0Hz, 1), 7.70 (m, ZN), 7.56 (t, 9U-8.0Hz, 1), 7.44 (t, 9U-8.0Hz, 1H), 7.00 (d , U-8.0Hz, 2H), 4.64 (s, 2H), 4.23 (t, 9-8.0Hz, 2H), 3.71 (m, 4H). (M-1H): 441.4. "

Spl.bb Z "N' NMR (400MHz, UMSO-av) 5 11.06 (s, 1H), 9.33 (t, 9U-8.0Hzc, 1H), 8.89 (s, 1H), 8.00 (d, U-8.0HzC . s, 2H), 4.23 (t, :z» UEv8.OGcC, 2H), 3.71 (m, 2H), 3.20 (t, U-8.O0Hz, 2H), 2.72 (t, U9-8.0Hz, 2H) MS (E5I) m/e: (МА1Н)": 442.3, (М-1Н)7: 440.1.

Spl.67 "H NMR (400MHz, OMSO-ydv) 5: 9.11 (t, 1H, U-6.0Hz), 7.82 (d, 1H, 9U-7.7Hz), 7.76 (d, 2H, 9-8.5Hz) , 7.69

Go! (d, 1H, 9U-8.5Hz), 7.62 (s, 1), 7.51 (t, 71H, U-8.5Hz), 7.40-7.30 (m, ЗН), 7.21 (d, 2H, U-8.5Hz) , 7.00-6.97 (m, ZN), 4.99 (m, 1H), 4.35 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.70 (m, 1H). EM (calc.): 446.15; MS (E5I) m/e (MA1TN) at 15 447.4, (M-1H). 445.3. about Spl.b8

NN NMR (400MHz, OMSO-4v) 6 11.04 (s, 1H), 8.86 (t, 9U-4.0Hz, 1), 7.83 (d, 9U-8.0Hz, 1H), 7.70 (d, - 3-8.0Hz , 2H), 7.61 (d, 9U-8.0Hz, 1), 7.47 (t, 9U-8.0Hz, 1), 7.33 (t, 9U-4.0Hz, 1), 7.00 (d, U-8.0Hz, 2H ),

GE) 5.02 (s, 2H), 4.18 (t, 9-8.0Hz, 2H), 3.65 (m, 2H), 3.52 (t, 9U-8.0 Hz, 2H), 3.44 (t, U-8.0Hz, 2H ), 1.68 (m, 2H). MS (E5I) m/e: (MA1H) 7: 429.1, (M-1H) 7: 426.9.

Spl. 69 "NMR (400MHz, DMSO-a6) 65: 11.04 (s, 1H), 9.03 (t, 1H, 9-5.9Hz), 7.86 (d, 1H, 9U-9.2Hz), 7.70 (d, 2H , at 3-8.3Hz),7.63 (d, 1H, 9U-8.3Hz), 7.49 (t, 1H, U-8.8Hz), 7.36 (t, 1H, 9U-7.0Hz), 7.29 (t, 1H, U-8.8Hz), 7.18 (m, 1), 7.07 (t, 1H, U-7.0Hz), 7.00 (d, 1H, y-8.3Hz), 6.91 (m, 71), 5.78 (s, 2H) . -1H) 7: 463.1.

Spl.70 60 NN NMR (400MHz, DMSO-dv) 5 : 11.04 (s, 1H), 9.04 (t, 1H, 9-5.9Hz), 9.00 (res. s, 1H), 7.84 (d, 1H,

U-7.3Hz), 7.70 (d, 2H, 9U-9.2Hz), 7.63 (d, 71H, 9-8.1Hz), 7.49 (t, 1H, U-8.6Hz), 7.35 (t, 1H, 9U- 7.7Hz), 7.27 (m, 1), 7.18 (m, 1H), 7.00 (d, 1H, U-9.2Hz), 6.95 (m, 7H), 6.87 (m, 7), 6.74 (m, 1) , 5.71 (s, 2H), 4.21 (t, 2H, 9-5.9Hz), 3.69 (q, 2H, 9U-5.9Hz). EM (calc.): 464; MS (E5I) m/e (MA1H)": 465.0, (M-1H) 7: 463.1.

Spl.71 b5 "NMR (400MHz, DMSO-a6) 65: 11.04 (s, 1H), 9.00 (t, 1H, 9-5.9Hz), 7.84 (d, 1H, 9U-8.4Hz), 7.70 ( d, 2H,

3-9.2Hz), 7.62 (d, 71Н, у-8.8Hz), 7.48 (t, 1Н, У-8.4HZ), 7.34 (t, 71Н, 9У-7.3Х), 7.10-7.00 (m, 6Н) , 5.67 (s, 2H), 4.20 (t, 2H, 7-5.9Hz), 3.68 (sq, 2H, 9U-5.9Hz). EM (calc.): 464; MS (E5I) m/e (MA1TN)": 464.9, (M-1H): 463.0.

Spl.72 "H NMR (400MHz, OMSO-av) 5 11.04 (s, 1H), 8.88 (m, 2H), 7.86 (d, U-8.0Hz, 1), 7.70 (d, U-8.0Hz, 2H), 7.61 (d, U-8.0Hz, 1), 7.47 (t, 9-8.0Hz, 1H), 7.33 (t, 9U-4.0Hz, 1), 7.00 (d, 9-8.0Hz, 2H) . ) m/e: (МА1Н)": 428.9, (М-1Н): 426.9.

Spl. 7Z3

NN NMR (400MHz, DMOSO-av) 5 11.05 (s, 1H), 9.20 (t, 9U-4.0Hz, 71H), 8.83 (d, 9U-8.0Hz, 2H), 7.86 (d, 3-8.0Hz, 71), 7.71 (d, 9U-8.0Hz, 2H), 7.66 (d, 9U-8.0Hz, 1H), 7.51 (t, 9-8.0Hz, 1), 7.38 (t, U-8.0HzC, 1) . ). MS (E5I) m/e: (MATN)": 448.0, (МА1Н): 446.4.

Spl. 74

NMR (400MHz, DMSO-yd5) 5 : 8.86 (m, 1H), 8.81 (res. c, 1H), 7.80 (d, 1H, 9U-8.2Hz), 7.63 (d, 2H, 3-9.4Hz) ,7.57 (d, 71H, 9U-8.2Hz), 7.44 (t, 1H, U-7.8Hz), 7.32 (t, 1H, 9U-7.0Hz), 7.12 (t, 1H, 9U-9.0Hz), 6.91 (t, 1H, 2-8.6Hz), 5.64 (s, 2H), 4.06 (t, 2H, U-6.0Hz), 3.54 (t, 2H, U-6.0Hz). EM (calc.): 500.13; MS (E5I) m/e (MAN): 501.5, (MATN):: 499.3

Spl.75 "NMR (400MHz, UMSO-av) 5 11.04 (s, 1H), 9.14 (t, 9-4.0GuC, 1H), 7.89 (m, 1H), 7.70 (m, ЗН), 7.61 ( d, 3-8.0Hz, 71), 7.46 (m, 71), 7.40 (m, 1H), 7.29 (t, 9-4.0Hz, 71), 7.02 (d, 9U-8.0Hz, 2H), 6.43 ( d, U-80Hz, 1), 6.23 (t, 9-4.OGts, 1H), 5.62 (s, 2H), 4.23 (t, U-4.0Hz, 2H), 3.72 (m, 2H). MS ( E5I) m/e: (MA1TN)": 448.2, (M-1H) 7: 446.4.

Spl.76 s "H NMR (400 MHz, DMOSO-y65) 5 11.04 (s, 1H), 8.96 (t, 9U-4.0Hz, 1H), 8.88 (s, 1H), 7.82 (d, U-8.0Hz . ), 7.00 (d, U-8.0Hz, o 2H), 5.24 (s, 2H), 4.18 (m, 4H), 3.66 (m, 2H). MS (E5I) m/e: (MA1H) 7: 453.3 , (M-1H) 7: 451.1.

Spl.77 "H NMR (400 MHz, OMSO-iv) 5 11.05 (s, 1H), 9.04 (t, U-4.0 Hz, 1H), 8.89 (s, 1H), 8.09 (s, 1H), 7.87 (d ,)i (FO dE8.О0ХЦ, 1), 7.70 (d, У-8.0ХЦ, 2Н), 7.63 (d, 9 -8.0ХЦ, 1), 7.89 (m, 1Х), 7.50 (m, ЗН), 7.35 (t, U-8.0Hz, cha 1H), 7.17 (d, U-8.0Hz, 2H), 7.03 (m, ЗН), 5.77 (s, 2H), 4.22 (t, 9-8.0Hz, 2H) , 3.70 (m, 2H). MS (E5I) m/e: (MATN)": 513.1, (MATN): 511.1. co

Spl.78 urine "NMR (400MHz6, UMSO-ag) 5 : 9.05 (s, 1H), 8.97 (t, 1H, U-5.9HC), 8.81 (s, 1H), 8.08 (s, 1H), 7.80 (d, 1H, 2-7.6Hz), 7.66-7 62 (m, 4H), 7.56 (d, 71H, 9U-8.6Hz), 7.42 (t, 1H, 9U-8.1Hz), 7.28 (t, 1H, 9U-7.6Hz), 7.15 so (m, 2H), 6.94 (d, 2H, 2-8.6Hz), 5.70 (s, 2H), 4.15 (t, 2H, 9U-5.9Hz), 3.64 (t .

Spl.79 « 20 "H NMR (400MHz, DMSO-av) 5 11.08 (s, 1H), 10.33 (s, 1H), 9.25 (t, 9-4.0Hz, 1H), 8.11 (d, U-8.0Hz , 1). . , 2H), 1.90 (m, 2H). MS (E5I) m/e: (МА1ТН)": "» 424.1, (МА1Н)7: 422.3.

Spl.80 "H NMR (400 MHz, DMOSO-y65) 5 11.06 (s, 1H), 9.87 (s, 1H), 9.29 (t, 9U-4.0 Hz, 1H), 8.03 (d, U-8.0 Hz, 1H), (se) 7.71 (m, ЗН), 7.57 (t, 9-8.0HZ, 1), 7.45 (t, U-8.0HZ, 1H), 6.99 (d, 9У-8.0HZc, 2H), 4.77 (c, 2H), 4.23 (t, with UE8.OHc, 2H), 3.70 (m, 2H), 3.48 (m, 2H), 3.04 (m, 2H), 1.73 (m, 5H), 1.38 (m, 1H). MS (E5I) m/e: (MA1H)": 438.0, (M-TN)-; 436.3. so Spl.81 -I 20 "NMR (400 MHz, UMSO-ag) 5 11.05 (s, 1H), 9.55 (t, 9U-4.0Gu, 1H), 8.89 (s, 1H), 7.89 (d, U -8.0Hz, 1H), 7.70 (d, 9U-8.0Hz, 2H), 7.61 (d, 9U-8.0Hz, 1), 7.45 (t, 9-8.0Hz, 1), 7.33 (t, 9U- 8.0Hz, 1H), 6.99 (d, U-8.0Hz, m 2H), 4.19 (t, U-8.0Hz, 2H), 3.96 (s, 2H), 3.68 (m, 2H), 2.95 (m, 2H ), 2.28 (m, 1H), 2.09 (m, 2H), 1.78 (m, 2H), 1.44 (m, 2H). MS (E5I) m/e: (MA1H) 7: 506.1, (M-1H) 7: 504.2.

Spl.82 "H NMR (400MHz, DMSO-dv) 65 11.07 (s, 1H), 9.18 (s, 1H), 8.04 (s, 1H), 7.70 (m, ЗН), 7.53 (t, 9U-8.0Hz ,

HF) 1), 7.39 (t, U-8.0Hz, 1), 7.00 (d, U-8.0Hz, 2H), 4.21 (t, 9-8.0Hz, 2H), 3.70 (m, 12H), 2.76 ( with, ZN). MO t (EBI) m/e: (МА1Н) 7: 453.0, (М-1Н) 7: 451.1.

Spl.83 60 "H NMR (400 MHz, OMSO-av) 5 11.05 (s, 1H), 8.90 (m, 2H), 7.83 (d, 9U-8.0Hz, 1), 7.70 (d, U-8.0Hz , 2H), 7.61 (d, U-8.0Hz, 1), 7.48 (t, 9-8.0Hz, 1H), 7.34 (t, 9U-8.0Hz, 1H), 7.00 (d, 9-8.0Hz, 2H ), 5.08 (s, 2H), 4.19 (t, 928.OHz, 2H), 3.68 (m, 4H), 2.58 (m, 2H). MO (E5I) m/e: (MA1H)": 467.0, ( M-1H) 7: 465.1.

Spl.84 "H NMR (400MHz, DMSO-av) 5 : 11.07 (s, 1H), 8.91 (m, 2H), 7.73 (d, 2H, 92-9.0Hz), 7.66 (s, 1H), 7.47 ( d, 65 NN, 9U-8.7ГЦСХ), 7.37 (t, 1Н, У-8.4ГЦС). 7.15 (d, YAN, 9-7.4ГЦЦЦ), 7.04 (d, 2Н, 2U-9.0ГЦЦ), 4.21 (t , YAN, U-5.7Gu), 3.69 (t, 2H, U-5.7 Hz), 3.36 (s, ZN). EM (calc.): 354.12; MS (E5I) m/e (MA1TN)": 354.7, (M-1H): 353.1.

Spl.85 "NMR (400MHz, UMSO-ag) 5 11.05 (s, 1H), 8.88 (s, 1H), 8.80 (t, U-8.0Hz, 1H), 7.76 (d, U-8.0Hz, 1H), 7.11 (d, U-8.0Hz, 2H), 7.57 (d, 9U-8.0Hz, 1), 7.46 (t, 9U-8.0Hz, 1), 7.32 (m, ЗН), 7.03 (m, 4H), 4.76 (s, 2H), 4.15 (t, 9-8.0Hz, 2H), 3.62 (m, 2H). MS (E5I) m/e: (MA1H) 7: 481.1, (M-1H): 479.0.

Spl.86 "H NMR (400MHz, DMSO-yv5) 5 11.05 (s, 1H), 8.88 (m, 2H), 7.71 (d, 9U-8.0Hz, 2H), 7.55 (m, 4H), 7.46 ( t, 3-8.0Hz, 1), 7.28 (m, ЗН), 7.00 (d, U-8.0Hz, 2H), 4.77 (s, 2H), 4.15 (t, U-8.0Hz, 2H), 3.60 ( m, 2H). MO (EBI) m/e: (MA1H)": 497.3, (M-1H) 7: 495.1.

Spl.87 "H NMR (400 MHz, DMSO-dv) 65 11.05 (s, 1H), 8.89 (s, 1H), 8.82 (t, 9U-8.0Hz, 1H), 7.74 (d, U-8.0Hz, 1H ), 7.71 (d, U-8.0Hz, 2H), 7.63 (m, ЗН), 7.50 (t, 9U-8.0Hz, 1), 7.34 (m, ЗН), 7.00 (d, 9-8.0Hz, 2Н ), 5.32 (s, 2H), 4.06 (t, U-8.0Hz, 2H), 3.49 (m, 2H). MS (E5I) m/e: (MA1H)": 513.2, (M-1H) 7: 511.2.

Spl.88 12 "NMR (400MHz, UOMSO-ag) 5 11.03 (s, 1H), 8.88 (s, 1H), 8.68 (d, U-8.0Hz, 1H), 7.81 (d, U-8.0Hz , 1H), 7.69 (d, 9U-8.0Hz, 2H), 7.64 (d, 9U-8.0Hz, 1), 7.50 (t, 9U-8.0Hz, 1), 7.36 (t, U-8.0Hz, 1H ), 6.98 (d, U-8.0Hz, 2H), 5.25 (s, 2H), 4.18 (m, 5H), 1.72 (m, 2H), 0.94 (t, U-8.0Hz, ЗН). MO (E5I ) m/e: (МА1Н)": 481.2, (М-1Н)7: 479.2.

Spl. 89 "H' NMR (400 MHz, UOMSO-av) 5 : 11.94 (s, 1H), 11.04 (m, 1H), 9.36 (m, 71H), 8.88 (res. s, 1H), 8.63 (s, 1H ), 7.71 (d, 2H, 9-8.5Hz), 7.22 (t, 1H, 9U-8.1Hz), 7.07 (dd, 1H, 9-81, 1.7Hz), 7.02 (d, 2H, 9U-8.5Hz ), 6.65 (dd, 1H, 9-7.6, 1.6Hz), 4.21 (t, 2H, 9-5.6Hz), 3.73 (2H, sq, U-5.2Hz). EM (calc.): 356; MS ( E5I) m/e (МА1Н)": 357 2, (М-1Н)": 354.9.

Spl.90 urine "N'YAMRe (400MHz, DMOSO-av) 6: 11.03 (s, 1H), 8.69 (d, 1H, 9U-8.3Hz), 7.86 (d, 1H, 9-2.1Hz), 7.69 ( m. 1H), 4.06 (m, 1H), and) 1.75 (m, 1H), 1.62 (m, 1H), 0.93 (t, ЗН, 9-7.3Hz). EM (calc.): 402; MO (E5I) m/e (МА1Н)": 403.0, (М-1Н) 7: 400.9.

Spl.91 "H NMR (400 MHz, UOMSO-ag) 6: 11.02 (s, 1H), 9.00 (t, 1H, 9U-5.8Hz), 7.85 (d, 1H, 9-1.9Hz), 7.68 (m, ЗН), 7.52 (с, 1Н), 7.46 (dd, 1Н, У-8.5Hz, 1.9HzС), 7.03 (d, 2Н, 2-8.5Hz), 4.69 (m, 71Н), 3.57 (m, 1Н) . 387.0.

Spl. 92 so

H NMR (400 MHz, UMSO-av) 65: 11.05 (resol s, 1H), 8.96 (t, 1H, U-5.6Hz), 8.80 (d, YAN, 9U-2.0Hz), 8.75 s (dd, 1H . -8.0Hz), 7.45 (t, 1H, U-6.8Hz), 7.34 (d, 1H, 9U-7.2Hz), 7.00 (m, 2H), 4.91 (s, 2H), 4.75 (s, 2H), 4.18 (t, so 2H, 9-5.6Hz), 3.66 (q, 2H, 9U-6.0Hz). EM (calc.): 461; MS (E5I) m/e (MA1TN)": 462.2, (M-1H) 7: 460.3.

Spl.93 "H NMR (400MHz, DMSO-av) 5 : 11.00 (s, 1H), 8.82 (m, 1H), 8.37 (s, 1H), 7.67 (dd, 2H, U-6.8, 1.6Hz), « du 7.32-7.24 (m, 2H), 7.01 (d, 2H, 2-9.6Hz), 6.90 (d, IN, 9-8.0Hz), 4.17 (t, 2H, y- 5.2Hz), 3.89 (s , ZN), 3.69 Z (m, 2H). EM (calc.): 370; MS (EI) m/e (MA1TN)": 371.2, (M-1H) : 369.1. s Spl.94 :z» "H NMR (400MHz, UOMSO-av) 6 : 11.04 (s, 1H), 8.96 (t, 1H, 9U-5.6Hz), 8.45 (s, 1H), 7.70 (d. 2H . (t, 2H, 9U-5.6Gu), 3.82 (m, 2H), 3.69 (q, 2H, U-6.0Hz), 3.34 (s, ЗN). EM (calc.): 414; MS (EI) m /e (MAN) 7": 415.2, (M-1H):: 413.3.

Go! Spl. 95

NN NMR (400 MHz, DMSO-dv) 5 : 11.04 (resoln s, 1H), 8.86 (m, 7H), 8.65 (t, 1H, 5.6Hz), 8.61 (dd, 1H, ki 3-4.8, 1.6Hz) , 8.37 (c, 1H), 8.13 (m, 1), 7.67 (m, 2H), 7.54 (m, 1H), 7.38-7.31 (m, 2H), 7.07 (dd, /1H, (os) 3- 7.6, 0.8Hz), 6.88 (m, 2H), 5.40 (s, 2H), 3.91 (t, 2H, U-6.0Hz), 3.40 (m, 2H). EM (calc.): 447; MS (E5I) m/e 50. (MAN): 448.2, (М-А1Н) 7: 446.1. and Spl. 96b

HI "H NMR (400MHz, DMSO-av) 5 : 11.57 (s, 1H), 8.65 (t, 1H, 9-4.5Hz), 7.69 (d, 2H, 9U-8.5Hz), 7.20 (s, 1H) . ; MS (EBI) m/e (MATN)": 370.1, (M-TN): 368.2. 29 Spl. 97 o "H' NMR (400 MHz, DMOSO-a6) 65: 11.06 (s, 1H), 8.62 (d, 1H, 9U-8.7Hz), 7.88 (d, 1H, 9U-7.6Hz), 7.72 (d, 2H, 3-8.5Hz), 7.65 (d, 1H, 9U-8.5Hz), 7.50 (t, 1H, 9U-8.5Hz), 7.36 (t, IN, 9U-8.5Hz), 7.02 (d , 2H, U-8.5Hz), 5.08 ko (s, 2H), 4.29 (m, 1H), 4.18 (m, 7H), 4.10 (m, 71H), 3.62 (m, 2H), 3.51 (m, 2H ), 3.26 (s, ЗН), 1.77 (m, tn), 1.67 (m. 1Н), 0.97 (t, ЗН, 9-7.3Hz). EM (calc.): 456; MS (E5I) m/e (МА1Н)": 457.1, (М-1Н):: 455.2. 60 Spl.98 "H NMR (400MHz, DMSO-dv) 5 : 11.05 (s, 1H), 8.91 (t, 1H, U-6.1Hz), 7.88 (d, 1H, 9U-7.5Hz), 7.72 (d , 2H, 3-8.4Hz), 7.63 (d, 71H, 9U-8.4Hz), 7.50 (t, 1H, U-8.5Hz), 7.36 (t, 1H, 9U-8.5Hz), 7.07 (d, 2H , 9U-8.4Hz), 5.07 (s, 2H), 4.74 (sq. .

Spl. 99

"H NMR (400MHz, DMSO-av) 5 : 11.09 (s, 1H), 9.54 (s, 1H), 9.40 (t, IN, 9-5 6Hz), 8.04 (d, 1H, 9U-7.8Gu), 7.14 (d, 2H, 2U-8.3Hz), 7.61 (t, 1H, 9-7 HZC), 7.49 (t, YAN, 2U-7.3Hz), 7.03 (d, 2H, U-8.5Hz), 4.82 ( s, 2H), 4.26 (t, 2H, 2-5.6Hz), 3.75 (kv, 2H, 9-5.6Hz), 3.50 (m, 2H), 3.25 (m, 4H), 1.32 (t, bH, 9U -7.AGC). EM (calc.): 425; MS (E5I) m/e (МА1Н)": 426.1, (М-А1Н) 7: 424.2.

Spl. 109

H NMR (DMSO-α): 1.95 (2Н, m); 2.05 (ZN, p); 2.48-2.62 (2H, m); 4.08 (IN, dd, 11.6Hz); 4.16 (1H, dd, 11.7Hz); 4.45 (IN, m); 6.99 (2H, d, 9Hz); 7.32 (1IN, t, 7Hz); 7.45 (IN, td, 8.1 Hz); 7.55 (1H, d, 1Hz); 7.64 (TN, d, 8Gu); 7.69 (2H, d, 9Hz); 7.76 (1H, d, 8Hz); 8.7 (1H, d. 8Hz); 8.87 (1H, p). MS (Mt): 415.

Spl. 110

H NMR (DMSO-α): 2.03-2.21 (2Н, m); 2.99 (1Н, с, ЗН); 3.22 (2H, t, 7Hz); 4.12 (1H, dd, 11.6Hz); 4.19 (IN, dd, 11.7Hz); 4.46 (IN, m); 7.00 (2H, d. 9HC); 7.33 (IN, t, 7Hz); 7.46 (IN, td, 8.1 Hz); 7.57 (1H, d, 1Hz); 7.64 (1H, d, 8Hz); 7.70 (2H, d, 9Hz); 7.77 (1H, d. 8Hz); 8.79 (1H, D, 8Hz); 8.88 (1H, p). MS (M.-1): 447.

Table 4:

Spl. 1

EM (calc.): 381.13; MS (E5I) m/e (MA1N)": 382.3, (M-1N)- 380.2.

Spl. 2

EM (calc.): 395.15; MS (E5I) m/e (MA1N)": 396.1, (M-1N)- 394.2.

Spl. 3Z

EM (calc.): 331.08; MS (E5I) m/e (MA1N)": 331.7, (M-1N) - 330.1.

Spl. 4

EM (calc.): 317.10; MS (E5I) m/e (MA1H)": 318.10, (M-1H) 7: 315.9.

Spl. b

EM (calc.): 425.2; MS (E5I) m/e (M--1)7: 426.1, (M-1H) 7": 424.1.

Spl. b o

EM (calc.): 381.1; MS (E5I) m/e (M-n1)7: 382.0, (M-1H)7: 380.1.

Spl. 7

EM (calc.): 381.1; MS (E5I) m/e (M-n1)": 382.0, (M-1)- 380.2. "se

SPL 8

EM (calc.): 341.1; MS (E5I) m/e (M-n1)7: 341.9, (M-1H)7: 340.1. She

Spl. 9 so

EM (calc.): 381.1; MS (E5I) m/e (M-n1)7": 381.8, (M-1H) 7: 380.0.

Spl. 10 p

From EM (calc.): 411.1; MS (E5I) m/e (M--1)7: 412.0, (M-1H) 7: 410.3. (heh)

Spl. 11

EM (calc.): 395.2; MS (E5I) m/e (M--1)7: 396.0, (M-1H)": 394.2

Spl. 12 "

EM (calc.): 388.1; MS (E5I) m/e (M--n1)7": 389.1, (M-1H)7: 387.0. 70 Spl.13 With EM (calc.): 355.12; MS (E5I) m/e (M --1)": 355.9, (M-1H) 7: 354.1. :z» Spl. 14

EM (calc.): 355.1; MS (E5I) m/e (M--1)7: 355.9, (M-1H) 7: 353.8.

Spl. 15

Go! EM (calc.): 409.2; MS (E5I) m/e (M--1)7: 410.2, (M-1H) 7: 408.3.

Spl. 16 and EM (calc.): 341.1; MS (E5I) m/e (M-n1)7: 341.8, (M-1H) 7: 340.2. with SPL 17

NN NMR (400 MHz, OMSO-yv) 5 11.64 (s, 1H), 8.66 (d, 9U-8.0Hz, 1H), 7.76 (d, 9U-8.0Hz, 1), 7.64 (a, - 3-8.0Hz . 4 (m, 2H), 0.92 (t, U-7.2Hz, ЗН). EM (calc.): 359.1; MS (E5I) m/e: (МА1Н)": 359.8, (М-1Н): 358.1.

Spl.18 "H NMR (400MHz, DMSO-av) 5 11.64 (s, 1H), 9.48 (s, 1H), 8.47 (d, 7-8.0Hz, 1H), 8.09 (m, 1H), 7.82 (m . ), 0.94 (t,

Gee! U1..2Hz, ZN). EM (calc.): 395.2; MS (E5I) m/e: (MA1H)": 395.8, (M-1H) 7: 394.0.

Spl.19 ko NN NMR (400 MHz, DMOSO-avb) 5 11.63 (s, 1H), 8.93 (t, 9U-5.6Hz, 71), 7.75 (d, 9U-7.6Hz, 1H), 7.63 (d,

U-7.6Hz, 1), 7.54 (s, 1), 7.45 (t, 9-7.6Hz, 1), 7.32 (t, 9U-7.6Hz, 71H), 6.72 (s, 1H), 4.90 (m, 1), 3.56 bo (m, 2H), 0.35 (d, 9-1.2Hz, ZN). EM (calc.): 345.1; MS (E5I) m/e: (МА1Н)": 345.8, (М-1Н): 344.0.

Spl.20 "H NMR (400 MHz, DMSO-a6) 5 11.64 (s, 1H), 9.480 (s, 1H), 8.83 (t, 9-5.6 Hz, 1H), 7.07 (m, 1H), 7.80 ( d,

U-7.6Hz, 71), 7.70 (d, 9-7.6Hz, 1), 7.53 (t, 9U-7.6Hz, 1), 7.48 (m, 2H), 7.39 (m, 1H), 6.72 (s, 1H), 4.91 65 (m, 1H), 3.58 (m, 2H), 1.36 (d, U-7.OGc, ZN). EM (calc.): 381.1; MS (E5I) m/e: (MA1H)": 382.0, (M-1H) 7: 380.0.

Spl. 21

EM (calc.): 367.1; MS (EBI) m/e (M-n1)7: 367.8, (M-1H) 7: 366.2.

Spl. 22

EM (calc.): 367.12; MS (E5I) m/e (MA1H)": 368.0, (M-1H) 7: 366.1.

Spl. 23

EM (calc.): 374.0; MS (E5I) m/e (M--1)7: 374.7, (M-1H)7: 372.9.

Spl. 24

EM (calc.): 395.2; MS (E5I) m/e (Ma-1)7: 396.1. (M-1H)7: 394.1

Spl. 25

EM (calc.): 367.1; MS (E5I) m/e (M--1)": 368.1, (M-1H): 366.2.

Spl.. 26

EM (calc.): 381.1; MS (EBI) m/e (M-n1)": 382.0, (M-1H)7: 380.1.

Spl.27 "NMR (400 MHz, DMOSO-yv5) 5 11.62 (s, 1H), 9.45 (s, 1H), 8.54 (d, 2-7.6 Hz, 1H), 8.43 (s, 1H), 7.97 ( m, then AN), 7.60 (m, 2H), 6.73 (s, 1H), 4.33 (m, ЗН), 1.70 (m, 2Н), 0.96 (t, 9U-7.6Hz, ЗН). EM (calc. ); 369.1; MS (E5I) m/e: (MA-1H)": 369.9, (M-1H) 7: 368.0.

Spl.28 "NMR (400MHz, DMSO-a6) 5 11.66 (s, 1H), 9.50 (s, 1H), 8.53 (d, 9U-7.6Hz, 1H), 8.11 (m, 1H), 7.96 ( m, 2H), 7.55 (m, 4H), 6.78 (s, 1H), 4.33 (m, ЗН), 1.68 (m, 2Н), 1.01 (t, 9-7.2 Hu, ЗН). EM (calc.) : 369.1; MS (E5I) m/e: (MA1H)": 370.0, (M-1H) 7: 368.2.

Spl.29 "NMR (400MHz, UMSO-ag) 5 11.64 (s, 1H), 8.86 (t, 9-5.6Hz, 1H), 8.40 (s, 1H), 7.90 (m, 4H), 7.59 ( m, 2H), 6.73 (s, 1H), 4.94 (m, 1H), 3.60 (m, 2H), 1.38 (d, U-6.0Hz, ZN). EM (calc.): 355.1; MO (E5I) m/e: (MATN)": p. 355.9, (М-А1Н): 353.9. at

Spl.30 "H NMR (400MHz, OMSO-av) 5 11.66 (s, 1H), 8.78 (t, 9U-5.6Hz, 1H), 8.09 (d, U-7.6Hz, 1), 7.96 (m, 2H), 7.50 (m, 4H), 6.74 (s, 1H), 4.97 (m, 1H), 3.61 (m, 2H), 1.41 (d, 2-6.4Hz, ЗН). EM (calc.): 355.1 ; MS (E5I) m/e: (MAN); 356.1, (M-1H): 353.9. i-th 3o Spl. 31 M

EM (calc.): 345.1; MS (EBI) m/e (M--1)7: 345.8, (M-1)7: 344.0.

Spl. 32 so

EM (calc.): 331.1; MS (E5I) m/e (M--1)": 331.9, (M-1H) 7: 330.2. s

Spl. 33 so

EM (calc.): 437.12; MS (E5I) m/e (MATN)": 438.0, (M-1H) 7: 436.2.

Example 4

Synthesis of acetyl-siu-AIa-(M-acetyl-!ug)-AMS

Tret-Voc (M-Acetyl-1 ug)-AMC (445 mg, 1 mmol, purchased from Vaspet) was dissolved in 4 M NOS in dioxane, which gave 420 N-(M-acetyl-1 ug)-AMC as a white solid substances To a solution of H-(M-acetyl-Ig)-AMC in DMF (5 ml) was added Ас-с1у-АІа-OH (188 mg, Тmmol) using RUVOR (520 Омг, Тmmol), NOVI (135mg, Тmmol) , and MMM and (0.296 bml, 2 mmol). The reaction mixture was stirred for 1 hour. and monitored by MS/LC for "" the presence of H-(M-acetyl-I uz)-AMOS. An additional amount of RUVOR (260Omg, 0.5mmol), NOVI (7Omg, 00.Bmmol), and MMM (0.14bmL, tmmol) was added, stirring was continued for another 4 h, after which the product was isolated

Quantitatively. o Biological Examples

Example 1: Inhibition of SPSS by spp. The ability of the compounds of the present invention to inhibit SPSS was determined by the following method.

The measurement was performed in a reaction volume of 100 μl using 96-cell analytical tablets. -. NAAS-1 (final concentration 200 parts per million) in the reaction buffer (X00MM NERE5. 100mm KSI, 0.001956 Tmeep-20,

Fo 56 DMSO, pH 7.4) was mixed with the inhibitor in various concentrations, incubated for 30 minutes, after which trypsin and acetyl-Si-Al-A-(M-acetyl-I uz)-AMS were added to the final concentrations of 5OHM and 25μM, respectively, for to initiate a reaction. Negative control reactions were performed in the absence of inhibitor in eight PppOVTORNOoSSTTY.

The reaction was monitored using a fluorescent tablet reader. Through the 330-minute (F) Iad phase, fluorescence was measured in the 330-minute mode using an excitation wavelength of 355 nm and a detection wavelength of 4 bOhm. The increase in fluorescence over time was used as a measure of the reaction rate. Inhibition constants were obtained using VaisnKi software (Kigtis ei a). because /Apai. Viospet. 2000, 286, 45-50). Most of the compounds of the present invention had a Ki of 40nm.

Example 2

Proliferation reaction of IP Migo cells

The ability of the compound of Formula (I) to inhibit the growth of tumor cells was determined as follows.

Stock cultures of the HST11E6 rectal carcinoma cell line were cultured in KRMI medium 65 1640 containing 1095 (v/v) fetal bovine serum, 2 mM I-glutamine, TMM sodium pyruvate, 50 units/ml penicillin, and 5 µg/ml streptomycin at 372C in 595 CO" in a humidified atmosphere. Cells were cultured in

75 cm? cultivation flasks, subcultivation was carried out every 3-4 days so that the confluence of the culture did not exceed 9095.

NSTI116 cells were collected to determine the proliferation reaction by trypsinization (0.059565 trypsin/0.53 mM EOTA), washed twice in culture medium, resuspended in an acceptable volume of medium, and then counted using a hemacytometer. Cells were seeded in flat-bottomed 96-well plates at a density of 5,000 cells/well in 10 µl. Cells were cultured for 1.5 to 2 hours at 379 C.

Compounds were diluted from 10 mM stock solutions in DMSO. Serial 3-fold dilutions were carried out in 70 medium containing 0.696 DMSO in the cells (in triplicate) of 96-well plates, the cells of which have an O-shaped bottom, with a bOmK solution. After the dilution was complete, 100 μl of each compound dilution (in triplicate) was transferred into triplicate wells of 96b cell plates containing cells in 100 μl medium. The final dose-dependent concentrations for the compounds in the analytical tablets varied from 0.12 to ZOμM. 100 μl of 0.690 DMSO in the culture medium was added to control cells (cells were not treated with any substance). Cells containing cell-free medium were used as background cells. Cells were cultured with compounds for 48 and 72 hours at 372C in a humidified CO" incubator.

Cell proliferation was measured by measuring fluorescence after the addition of a fluorescent redox indicator, AlitagVidetm (Viobocgse Ipiegpaiopa!). To each cell of a 96-well plate(s), 1 µl AliatagVidetm was added 3 or 4 hours before the end of the incubation time. The analytical plates were was investigated using a fluorescent tablet reader (excitation, 533OHM; emission, 62OHM).

The C.50 value (concentration at which the growth of tumor cells is inhibited to 5095) for the compound was determined by plotting the control percentage of fluorescence against the logarithm of the concentration of the compound.

The compounds of the present invention inhibited the growth of tumor cells. si

Examples of Pharmaceutical Compositions

The following prescriptions represent pharmaceutical compositions containing a compound of Formula (I)

Tablet composition

The following ingredients are thoroughly mixed and pressed into separate tablets. (Se)

Ingredient Quantity per Tablet, mg

The compound of this invention 400 t

Corn starch 50 (se)

Croscarmellose sodium 25

Lactose 120 cm 3 Magnesium stearate 5 g)

Capsule composition

The following ingredients are thoroughly mixed and filled with hard gelatin capsules "

Ingredient Amount per capsule, mg shsh s Compound of this invention 200 i Lactose, spray dried 148 "» Magnesium stearate 2

Composition of suspension oo The following ingredients are mixed to give a suspension for oral use Ingredient Amount oo Compound of this invention 1.0g

Fumaric acid OBG-I Sodium chloride 2.0 g

Pho Methyl paraben 0l15g

Propyl paraben 0.o5g

Granulated sugar 25.5 g

Corn starch 50

Sorbitol (7095 solution) 12.85g (F; Meedit K (Mapaegriii So.) 1.0g

Go) Flavorings О.оЗ5ml

Dyes O.Bmg 6bo Distilled water a.5. up to 10 Oml a.5. (dova zpame) - in recipes

The composition of the injection composition

The following ingredients are mixed, which gives a composition intended for injections and b5

Ingredient Quantity

The compound of this invention 1.2g

Lactate buffer solution, 0.1 M 10.Oml

BUT (IM) or mason (1Mm) a. 5. to the desired pH

Physiological solution (optional) 4.5. to the required osmolality

Water (distilled, sterile) 4.5. up to 20 ml

The compound (1.27) is combined with 0.1M lactate buffer (1Oml) and gently mixed. Sonication for a few minutes may be applied if dissolution is required. An acceptable amount of acid /0 UM base is added 4.5. until an acceptable pH (mainly pH 4) is obtained. Then add a sufficient amount of water a.8. up to 20 ml.

The composition of her suppositories

A suppository with a total weight of 2.5 g, which is prepared by mixing the compound of the invention with UMierzo! tm |H-15 (triglycerides of saturated vegetable fatty acids; Kispez-Meyvop, Ips., Mem Mogk), have the following composition: the compound of the invention - 500 mg of UMerzoitm H-15 can be changed

The above invention has been described in some detail by way of illustrations and examples for purposes of clarity and understanding. It will be apparent to one of ordinary skill in the art that changes and modifications may be made within the scope of the claims set forth below. Thus, it should be understood that the above description is intended to illustrate the invention and not to limit it. Accordingly, the limits of the present invention should be determined based not on the above description, but on the appended claims, together with the full set of equivalents that are named in the claims.

All patents, patent applications cited in this invention are hereby incorporated in their entirety for use for any purpose by reference to the same extent as if each individual patent, patent application, or publication were separately designated. . at

Claims (24)

The formula of the invention (Ce) from 1. The compound according to the formula (1): a ! - (o Her gu» ov so m, M sh Ar MOH N o o o where: B! is hydrogen or alkyl, which includes from 1 to 6 carbon atoms; X is -O-, -MV 2- or -5( O)y-, where n has a value from 0 to 2, and y2- is hydrogen or alkyl, which includes "from 1 to b carbon atoms; shsh c U is alkylene, which includes 2 or 3 carbon atoms, optionally substituted alkyl, which includes from 1 to 6 carbon atoms, cycloalkyl, which includes from 3 to 10 carbon atoms, optionally substituted by phenyl, is» alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxyl or optionally substituted phenoxy; 3 is hydrogen, alkyl containing from 1 to 6 carbon atoms, hydroxyalkyl containing from 1 to 6 carbon atoms or from 3 to 6 branched saturated monovalent carbon atoms substituted with one or two hydroxy groups, provided that, if two hydroxy groups are present, they are not bonded to the same carbon atom, or optionally substituted eny phenyl; and with Ag? - is an optionally substituted aryl, which includes from b to 12 carbon atoms in the ring; aralkyl, where -I 20 adalkyl is alkylene, which includes from 17 to b carbon atoms connected to aryl; aralkenyl, where alkenyl is alkenylene, which includes from 2 to 6 linear divalent or from 3 to 6 branched monovalent 0 carbon atoms that contain 1 or 2 double bonds connected to the aryl; heteroaryl, which includes from 5 to 10 carbon atoms in the ring, which includes 1, 2 or C ring atoms selected from M, O or 5, where the remaining ring atoms are C, optionally substituted with one or two substituents independently selected from alkyl, which includes from 1 to b carbon atoms, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, o hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkyl, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenyl, coloxyal optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted 60 heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-5(O) 1-K? (where p o is a number from 0 to 2, and Ba is hydroxyalkyl or optionally substituted phenyl), -alkylene-ME "-alkyleneSOoMv sv (where B is hydroxyl, and VU Her ve is independently hydrogen or alkyl, which includes from 1 to 6 carbon atoms) or carboxyalkylaminoalkyl; heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, which includes saturated and unsaturated 65 monovalent cyclic groups having from 3 to 8 ring atoms, where one or two ring atoms are heteroatoms selected from M, O or 5(O), the remaining atoms are C, where one or two ring atoms of C may optionally be substituted by a -CO group, or heterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which differs in that X is -0-, and E'ivB3- is hydrogen. 3. The compound according to claim 1, which differs in that X is -5(0)-, and B and BZ are hydrogen. 4. The compound according to claim 1, which differs in that U is an unsubstituted alkylene with 2 or C carbon atoms. 5. A compound according to any of claims 2-4, which differs in that Ag? is aryl or aralkenyl. 6. A compound according to any of claims 2-4, which differs in that Ag? is heteroaryl, optionally substituted with one or two substituents independently selected from alkyl, which includes from 1 to 6 carbon atoms, halo, 70 haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkylalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkyl, haloalkyl, haloalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-5(O),K2 (where n has a value from 0 to 2, and KU is hydroxyalkyl or optionally substituted phenyl), -alkylene-ME. "-alkylene-"MIXTURE (where BO is hydroxyl, and CH is independently hydrogen or alkyl, which includes from 1 to b linear saturated monovalent or from C to 6 branched saturated monovalent carbon atoms) or carboxyalkylaminoalkyl. 7. The compound according to claim 6, which differs in that Ag? is benzofuran-2-yl, and is a benzofuran-2-yl ring monosubstituted in the C-position, where the substituent is M,M-dimethylaminomethyl, M,M-diethylaminomethyl, 2-fluorophenoxymethyl, Z-fluorophenoxymethyl, 4-fluorophenoxymethyl, Hydroxyl-4-yloxymethyl, 2,4,6--trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-(1.2.41-triazin-1- ylphenoxymethyl, 2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, c pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl . 3-hydroxypropylsulfonylmethyl, M-methyl-M-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, "with M-hydroxyaminocarbonylmethylaminomethyl or 2-carboxyethylaminomethyl. 8. The compound according to claim 6, which differs in that Ag? - is benzofuran-2-yl, and is a monosubstituted benzofuran-2-yl ring in the B-position. co 9. The compound according to claim 8, which differs in that the substituent is cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy, 2-pyrrolidin-1-ylethyloxy or There is 1--2,2,2-trifluoroethyl)piperidin-4-yloxy. co 10. The compound according to claim 5, which differs in that Ag? is aralkenyl. 11. The compound according to claim 10, which differs in that Ag? is trans-phenylCH-CH-, in which the phenyl is optionally substituted with one or two substituents independently selected from alkyl, which includes from 1 to 6 linear saturated monovalent or from 3 to b branched saturated monovalent carbon atoms, « 470 Alkoxy , methylenedioxy or hydroxyl. shsh c 12. The compound according to claim 1, which has the structure: ;" about Iya; s ialn Sr ra: M y to y Sh Go! samnan with or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 1, which has the structure: o (Nzsi M , -i (8) Ф Соря а Н that СОоМнайНн or its pharmaceutically acceptable salt. (F, 14. The compound according to claim 1, which differs in that it has the structure: ko ve , in 60 Y Z. blo rosa in! that 65 OoMnaINn or its pharmaceutically acceptable salt. 15. The compound according to claim 1, which has the structure: Я, И ШХВ) и З Шче о ж я--о Н щ сОоМчнаНн or its pharmaceutically acceptable salt. 16. A compound selected from the group consisting of compounds: M-hydroxy-4-(2-benzenecarbonylaminoethoxy)benzamide; M-hydroxy-4-(2-trans-cinnamoylaminoethoxy)benzamide; M-hydroxy-4-(2-trans-2-phenylcyclopropylcarbonylaminoethoxy)benzamide; M-hydroxy-4-(2-trans-4-methoxycinnamoylaminoethoxy)benzamide; M-hydroxy-4-(2-(2-phenylethylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(1H-indol-3-ylmethylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-thiophene) -2-ylcarbonylaminoethoxy)benzamide; M-hydroxy-4-(2-pyridin-3-ylcarbonylaminoethoxy)benzamide; M-hydroxy-4-(2-biphen-4-ylcarbonylaminoethoxy)benzamide; M-hydroxy-4-(2- biphen-3-ylcarbonylaminoethoxy)benzamide; c M-hydroxy-4-(2-(5-phenylthiophen-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(thiophen-2-ylmethylcarbonylamino)ethoxy|benzamide ; o M-hydroxy-4-(2-(naphth-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(quinolin-6-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2 -(4-phenylthiazol-2-ylcarbonylamino)ethoxy|Senzamide; "se M-hydroxy-4-(2-(4-tert-butylphenylcarbonylamino)ethoxy|Senzamide; pyridin-3-ylacryloylamino)ethoxy|benzamide; - M-hydroxy-4-(2-(4-pyrrole-1-ylphenylcarbonylamino)ethoxy|benzamide; c M-hydroxy-4-(2-(4-cyclohexene-3- oxyphenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(benzthiazol-2-ylcarbonylamino)ethoxy |benzamide; se M-hydroxy-4-(2-(benzoxazol-2-ylcarbonylamino)ethoxy|benzamide; se M-hydroxy-4-(2-(octahydroisoquinolin-2-ylmethylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2 -(4-pyridin-4-ylpiperazin-1-ylmethylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(furan-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(4- pyridin-3-ylphenylcarbonylamino)ethoxy|benzamide; « M-hydroxy-4-(2-(4-pyridin-2-ylphenylcarbonylamino)ethoxy|benzamide; - with M-hydroxy-4-(2-(benzimidazol-2-ylcarbonylamino) )ethoxy|benzamide; and M-hydroxy-4-(2-(1H-pyrrol-2-ylcarbonylamino)ethoxy|Senzamide; "" M-hydroxy-4-(2-(4-benzoylaminophenylcarbonylamino)ethoxy|benzamide; M- hydroxy-4-(2-(4-pyridin-4-ylthiazol-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2--admantane-1-ylcarbonylamino)ethoxy|Senzamide; Go! M-hydroxy- 4-(2-(2,4-difluorophenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(3-trans-3,4-methylenedioxyphenylacryloylamino)ethoxy|Senzamide; where M-hydroxy-4-(2- (3,4-methylenedioxyphenylcarbonylamino)ethoxy|benzamide; H!M-hydroxy-4-(2-(3,4 -dimethoxyphenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(3,5-dimethoxyphenylcarbonylamino)ethoxy|benzamide; Ш- M-hydroxy-4-(2-(3,4-difluorophenylcarbonylamino)ethoxy|benzamide; Fo M-hydroxy-4-( 2-(2,5-dimethylphenylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(2,3-dichlorophenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(2,3-dimethylphenylcarbonylamino)ethoxy |Senzamide; M-hydroxy-4-(2-(4-chloro-2-methoxyphenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(3-ethoxyphenylcarbonylamino)ethoxy|benzamide; (F) M-hydroxy- 4-(2-(4-methoxy-2-methylphenylcarbonylamino)ethoxy|bSenzamide; with M-hydroxy-4-(2-(3-fluoro-4-methoxyphenylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2- (2-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy|benzamide; in M-hydroxy-4-(2-(3-thiophen-2-ylmethoxyphenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(biphen-2- ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(1H-indol-5-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(1H-indol-3-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(quinolin-3-ylcarbonylamino)ethoxy|benzamide; 65 M-hyd roxy-4-(2-(quinolin-8-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(1H-indazol-3-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-«"1H-benzotriazol-5-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(isoquinolin-1-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-( 2-(isoquinolin-3-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(quinoxalin-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(naphth-1-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(quinolin-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(2-pyrrole-1-ylphenylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2 -(4-fluoronaphth-1-ylcarbonylamino)ethoxy|benzamide; 70 M-hydroxy-4-(2-(1H-benzimidazol-5-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(1-methylindol-3-ylcarbonylamino)ethoxy|Sensamide; M-hydroxy-4 -(2-(4-methoxyquinolin-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(3-methoxynaphth-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(2 -methoxynaphth-1-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(quinolin-4-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(trans-2-methylcinnamoylamino)ethoxy|benzamide; M-hydroxy-4-(2-- 2-M,M-dimethylaminomethylbenzofuran-5-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-indolin-1-ylcarbonylaminoethoxy)benzamide; M-hydroxy-4-(2-(1,2,3,4 -tetrahydroquinolin-1-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-25-|grans-3-(5-hydroxybenzofuran-2-yl)but-2-enoylamino|butoxy)benzamide; M-Hydroxy-4-25-|grans-3-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-yl)but-2-enoylamino|butoxy)benzamide; M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)-4-phenylbutoxy|benzamide; M-hydroxy-4-42-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino| ethoxy)benzamide; p M-hydroxy-4-4-25-15-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino|butoxy)benzamide; M-hydroxy-4-42-(5-(1-cyclopropylpiperidin-4-yloxy)benzofuran-2-ylcarbonylamino|-1kK-methylethoxy)benzamide (8) M-hydroxy-4-42-(5-(1-( 2,2,2-trifluoroethyl)piperidin-4-yloxy)benzofuran-2-ylcarbonyl-amino|)ethoxy)benzamide; M-hydroxy-4-12K-(benzofuran-2-ylcarbonylamino)-3-benzylsulfonylpropoxy|Senzamide; "with zo M-hydroxy-4-I(2K-(benzofuran-2-ylcarbonylamino)-3-benzylthiopropoxy|benzamide; M-hydroxy-4-(2-(trans-3-(5-methoxybenzofuran-2-yl) but-2-enoylcarbonylamino)ethoxy|benzamide; - M-hydroxy-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)ethoxy|benzamide; co M-hydroxy-4-(2-( isoindoline-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(morpholin-4-ylcarbonylamino)ethoxy|benzamide; c M-hydroxy-4-(2-(4-benzylpiperazin-1-ylcarbonylamino)ethoxy|Senzamide; co M-hydroxy-4-(2-(3(K)-hydroxypyrrolidin-1-ylcarbonylamino)ethoxy|Senzamide; hydroxy-4-(2-(piperidin-1-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(b-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(2-methylindolin-1-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(b-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylamino)ethoxy|benzamide; with c M-hydroxy-4-(25-(isoindoline- 1-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-13-"trans-cinnamoylamino)propoxy|benzamide; ; t M-hydroxy-4-IZ-"trans-4-methoxycinnamoylamino)propoxy|benzamide; M-hydroxy-4-I3-(4-phenylthiazol-2-ylcarbonylamino)propoxy|benzamide; M-hydroxy-4-I25-(trans-cinnamoylamino)propoxy|benzamide; co M-hydroxy-4-I2K-(transo-cinnamoylamino)propoxy|benzamide; M-hydroxy-4-I(25-(trans-cinnamoylamino)-4-methylpentoxy|Senzamide; co M-hydroxy-4-I25-(trans-cinnamoylamino)-3-cyclohexylpropoxy|benzamide; o M-hydroxy-4-I(25-(trans-cinnamoylamino)-3-methylbutoxy|Senzamide; M-hydroxy-4-I(25-(trans-cinnamoylamino)-3-phenylpropoxy|benzamide; -I M-hydroxy-4-I2K-(transo-cinnamoylamino)-3-phenylpropoxy|Senzamide; M-hydroxy-4-I2K-(trans-cinnamoylamino)-4-methylpentoxy|benzamide; (42) . oh M-hydroxy-4-I2K-(trans-cinnamoylamino)-3-methylbutoxy|benzamide; M-hydroxy-4-I2K5-(trans-cinnamoylamino)hexyloxy|Senzamide; M-hydroxy-4-I2K5-(trans-cinnamoylamino)-3-(4-chlorophenyl)propoxy|benzamide; M-hydroxy-4-I(25-(trans-cinnamoylamino)butoxy|benzamide; HF) M-hydroxy-4-I(2K-(trans-cinnamoylamino)butoxy|benzamide; F M-hydroxy-4-I(25-(trans-cinnamoylamino)-4-methylthiobutoxy|benzamide; M-hydroxy-4-I(2K-(trans-cinnamoylamino)-4-methylthiobutoxy|Senzamide; in M-hydroxy-4-I(25-(trans-cinnamoylamino)-2-phenylethoxy|Senzamide; M-hydroxy-4-I2K-(trans-cinnamoylamino)-2-phenylethoxy|benzamide; M-hydroxy-4-I (25-(trans-cinnamoylamino)-4-methylsulfonylbutoxy|benzamide; M-hydroxy-4-I2K-(trans-cinnamoylamino)-4-methylsulfonylbutoxy|benzamide; M-hydroxy-4-I2K-(trans-cinnamoylamino)-3 -benzylsulfonylpropoxy|benzamide; 65 M-hydroxy-4-(25-(thiophen-2-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-(25-(biphen-4-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-I(25-(naphth-2-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-I2K-(transo-cinnamoylamino)-3-benzylthiopropoxy|benzamide; M-hydroxy-4-I(25 -(benzenecarbonylamino)butoxy|Senzamide; M-hydroxy-4-I(25-(benzylcarbonylamino)butoxy|benzamide; M-hydroxy-4-I(25-(2-phenylethylcarbonylamino)butoxy|benzamide; M-hydroxy-4-I(25-(trans-cinnamoylamino )-3-hydroxypropoxy|benzamide; M-hydroxy-4-(25-(4-phenylthiazol-2-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-(25-(trans-4-methoxycinnamoylamino)butoxy|Senzamide; 70 M-hydroxy-4-(25-(2-M,M-dimethylaminomethylbenzofuran-5-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-(2-(trans-cinnamoylamino)-1K-methylethoxy|benzamide; M- hydroxy-4-(2-«(trans-cinnamoylamino)-15-methylethoxy|benzamide; M-hydroxy-4-(2-(4-phenylthiazol-2-ylcarbonylamino)-1k-methylethoxy|benzamide; M-hydroxy-4 -(2-(4-phenylthiazol-2-ylcarbonylamino)-15-methylethoxy|benzamide; M-hydroxy-4-(2-(biphen-4-ylcarbonylamino)-1k-methylethoxy|Senzamide; M-hydroxy-4-(2-(trans-4-methoxycinnamoylamino)-1k-methylethoxy|bSenzamide; M-hydroxy- 4-42-I4-(2-pyridin-2-ylthiazol-5-yl)uphenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-(2-(7-chloro-4-methylbenzofuran-2-ylcarbonylamino)ethoxy|benzamide M-hydroxy-4-42-I4-(2-(4-methylpiperazin-1-yl)thiazol-5-yl)uphenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I4-(2-pyridin-4-ylaminothiazol-5-yl)phenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I(4--4-methylpiperazin-1-yl)uphenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I4-(4-hydroxypiperidin-1-yl)uphenylcarbonylamino|)ethoxy)benzamide; M-hydroxy-4-42-I(4--4-morpholin-4-ylmethylthiazol-5-yl)uphenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-(2-(7-fluoro-4-methylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; c M-hydroxy-4-42-(7-fluoro-4-(2-methoxyethoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-(2-(4-hydroxyquinolin-2-ylcarbonylamino)ethoxy|Senzamide; (8) M-hydroxy-4-(2-(7-fluoro-4-phenoxymethylbenzofuran-2-ylcarbonylamino)ethoxy|benzamide ; M-hydroxy-4-42-I(4-(2-(4-methylpiperazin-1-ylmethyl)thiazol-2-yl)uphenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-(2-(pyridin-2 -ylcarbonylamino)ethoxy|benzamide; "with zo M-hydroxy-4-(2-(3-hydroxypyridin-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(b-hydroxypyridin-2-ylcarbonylamino) ethoxy|Senzamide; - M-hydroxy-4-42-(6-(4-nitrophenoxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide; co M-hydroxy-4-42-I(4-(2-methoxyethoxy)quinoline -2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I(4--2-M,M-dimethylaminoethoxy)quinolin-2-ylcarbonylamino|ethoxy)benzamide; c M-hydroxy-4-(2-(6-bromopyridin-2-ylcarbonylamino)ethoxy|benzamide; co M-hydroxy-4-(2-(5-bromopyridin-3-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4 -(25-(4-methoxyquinolin-2-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-(2-(1-methoxynaphth-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(4 -methoxyquinolin-2-ylcarbonylamino)-1K-methylethoxy|benzamide; M-hydroxy-4-(2-(5-phenylpyridin-3-ylcarbonylamino)ethoxy|benzamide; with M-hydroxy-4-(2-(b-benzyloxypyridin-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy- 4-42-I(6-(2-methylpropyloxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide; ; t M-hydroxy-4-42-16-(2-phenylethyloxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino|)ethoxy)benzamide; M-hydroxy-4-425-I4-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino|butoxy)benzamide; co M-hydroxy-4-42-14-(3,3,3-trifluoropropyloxy)quinolin-2-ylcarbonylamino|-1k-methylethoxy)benzamide; M-hydroxy-4-(2-(trans-3-hydroxycinnamoylamino)ethoxy|benzamide; co M-hydroxy-4-(2-(trans-4-hydroxycinnamoylamino)ethoxy|benzamide; o M-hydroxy-4-42-(3'-(2-hydroxyethyl)biphen-4-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(3'-(2-hydroxyethyl)biphen-3-ylcarbonylamino|ethoxy)benzamide; - I M-hydroxy-4-42-(2-(2-hydroxyethyl)biphen-4-ylcarbonylamino|ethoxy)benzamide; Pho M-hydroxy-4-(2-(trans-2-benzofuran-2-ylacryloylamino)ethoxy|benzamide; M-hydroxy-4-42-(2-(2-hydroxyethyl)biphen-3-ylcarbonylamino|ethoxy)benzamide M-hydroxy-4-42-(5-(thiophen-3-yl)pyridin-3-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(6-(4-acetylaminophenoxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I(I6-(4-aminophenoxy)pyridin-2-ylcarbonylamino|ethoxy)benzamide; HF) M-hydroxy-4-(2-(trans-2-methoxycinnamoylamino)ethoxy|benzamide; F M-hydroxy-4-(2-(trans-3-methoxycinnamoylamino)ethoxy|benzamide; M-hydroxy-4-42-(15-(4-dimethylaminophenyl)pyridin-3-ylcarbonylamino|ethoxy)benzamide; in M-hydroxy-4-42-(Itrans-3-(5-bromothiophen-2-yl)acryloylamino|ethoxy)benzamide; M-hydroxy-4-(2-(trans-3-furan-3-ylacryloylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(trans-3-thiophen-3-ylacryloylamino)ethoxy|benzamide; M- hydroxy-4-(2-(trans-thiophene-2-ylacryloylamino)ethoxy|benzamide; M-hydroxy-4-42-(trans-3-methylcinnamoylamino|ethoxy)benzamide; 65 M-hydroxy-4-42-(trans-4-methylcinnamoylamino|ethoxy)benzamide; M-hydroxy-4-42-(trans-3-(benzofuran-2-yl)but-2-enoylamino|ethoxy)benzamide; M-hydroxy-4-42-(cis-3-(benzofuran-2-yl)but-2-enoylamino|ethoxy)benzamide; M-hydroxy-4-(2-(trans-4-dimethylaminocinnamoylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(trans-3-indol-3-ylacryloylamino)ethoxy|Senzamide; M-hydroxy-4-42-(trans-2-methylcinnamoylamino|ethoxy)benzamide; M-hydroxy-4-(2-(trans-2-hydroxycinnamoylamino)ethoxy|benzamide; M-hydroxy-4-42-(Itrans-3-(7-methoxybenzofuran-2-yl)acryloylamino|ethoxy)benzamide; M- hydroxy-4-2K-Itrans-3-(7-methoxybenzofuran-2-yl)acryloylamino|butoxy)benzamide; M-hydroxy-4--25-|Igrans-3-(5-methoxybenzofuran-2-yl)but-2-enoylamino|butoxy)benzamide; 70 M-hydroxy-4-(2-(trans-3-furan-2-ylacryloylamino)ethoxy|Senzamide; M-hydroxy-4-42-I4-(4-(2-morpholin-4-ylethyl)thiazol-2 -yl)uphenylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-(2-M-trans-cinnamoyl-M-hydroxyethylaminoethoxy)benzamide; M-hydroxy-4-(2-M-trans-cinnamoyl-M-phenylaminoethoxy)benzamide; M-hydroxy-4-(2-M-trans-cinnamoyl-M-methylaminoethoxy)benzamide; M-hydroxy-4-(2-M-benzothiophen-2-yl-M-isopropylaminoethoxy)benzamide; M-hydroxy-4-(2-M-trans-cinnamoyl-M-isopropylaminoethoxy)benzamide; M-hydroxy-4-(3-M-trans-cinnamoyl-M-methylaminopropoxy)benzamide; M-hydroxy-4-(2-(benzothiophen-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(1H-indol-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(1-methylindol-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4- 13-"benzothiophen-2-ylcarbonylamino)propoxy|benzamide; M-hydroxy-4-13-"(benzofuran-2-ylcarbonylamino)propoxy|benzamide; M-hydroxy-4-(25-(benzothiophen-2-ylcarbonylamino)- 3-methylbutoxy|bSenzamid; M-hydroxy-4-(25-(benzothiophen-2-ylcarbonylamino)butoxy|benzamide; M-hydroxy-4-(25-(benzothiophen-2-ylcarbonylamino)propoxy|benzamide; (8) M-hydroxy-4-( 2K-(benzothiophen-2-ylcarbonylamino)propoxy|benzamide; M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)butoxy|Senzamide; M-hydroxy-4-(2-(benzothiophen-2-ylcarbonylamino) -1k-methylethoxy|benzamide; 1kK-methylethoxy|Senzamide; - M-hydroxy-4-(2-(b-methoxybenzothiophen-2-ylcarbonylamino)ethoxy|benzamide; co M-hydroxy-4-(2-(5-methylbenzothiophen-2-ylcarbonylamino)ethoxy| benzamide; M-hydroxy-4-(2-(3-chlorobenzothiophen-2-ylcarbonylamino)ethoxy|benzamide; c M-hydroxy-4-(2-(5-methylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; co M-hydroxy-4-(2-(b-methylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4 -(2--4-rifluoromethylbenzothiophen-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(5-fluorobenzothiophen-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-( 5-methoxybenzothiophen-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(5-chlorobenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; with M-hydroxy-4-(2-(7-methoxybenzofuran-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy- 4-(2-(5-methoxybenzofuran-2-ylcarbonylamino)ethoxy|benzamide; ; t M-hydroxy-4-42-(5-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(5-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(5-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; co M-hydroxy-4-(2-(3-methylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-(2-(3-methylbenzothiophen-2-ylcarbonylamino)ethoxy|benzamide; co M-hydroxy-4-42-(5-(2-hydroxyethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; o M-hydroxy-4-42-(5-(2-M,M-dimethylaminoethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(6-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; - I M-hydroxy-4-42-(6-(2-morpholin-4-ylethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(b-(pyridin-3-ylmethoxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; (42) . . and and M-hydroxy-4-(2-(3-ethylbenzofuran-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(5-fluoroindol-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-(2-(5-methoxyindol-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-42-3-(methoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; HF) M-hydroxy-4-42-IZ--phenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; F M-hydroxy-4-(2-(5,6-dimethoxyindol-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-42-13-""morpholin-4-ylmethyl)benzofuran-2-ylcarbonylamino|ethoxy ) benzamide; in M-hydroxy-4-42-IZ3--M,M-dimethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-3-(i-propoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(7-"-phenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(7-"("methoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(7-«(morpholin-4-ylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; 65 M-hydroxy-4-42-(7-(M,M-dimethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-13-(5-(methyl)benzothiophen-2-ylcarbonylamino|propoxy)benzamide; M-hydroxy-4-3-(b-(methoxy)benzothiophen-2-ylcarbonylamino|propoxy)benzamide; M-hydroxy-4-13-(7-(methoxymethyl)benzofuran-2-ylcarbonylamino|propoxy)benzamide; M-hydroxy-4-13-(7-«(phenoxymethyl)benzofuran-2-ylcarbonylamino|propoxy)benzamide; M-hydroxy-4-42-(5-(2-methoxyethoxy)benzofuran-2-ylcarbonylamino|-1k-methylethoxy)benzamide; M-hydroxy-4-(2K-benzofuran-2-ylcarbonylamino-3-methylthiopropoxy)benzamide; M-hydroxy-4-(2k-benzofuran-2-ylcarbonylamino-3-methylsulfonylpropoxy)benzamide; M-hydroxy-4-42-I(I3--2-phenylethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(M-methyl-M-benzylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; 70 M-hydroxy-4-42-I3-(M-methyl-M-2-phenylethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(3-hydroxypropylthiomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(3-hydroxypropylsulfinylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(3-hydroxypropylsulfonylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(M-methyl-M-2-indol-3-ylethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(2-(3-trifluoromethylphenyl)ethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(2-(3-trifluoromethoxyphenyl)ethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(M-hydroxyaminocarbonylmethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(-2-carboxyethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-(2-(benzofuran-2-ylcarbonylamino)-LIK5-phenoxymethylethoxy|benzamide; M-hydroxy-4-42-I3-(3-hydroxypropoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3--2-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-"Z-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3--4-fluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I(I3--2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; c M-hydroxy-4-42-3-(pyridin-4-yloxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(3-(2,4,6-trifluorophenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; (8) M-hydroxy-4-42-I3-(2-oxopyridin-1-ylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I(3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3-(4-imidazol-1-ylphenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; "with zo M-hydroxy-4-42-(3-(4-(1.2.41-triazin-1-ylphenoxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-IZ-(pyrrolidine -1-methyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; - M-hydroxy-4-42-3-(piperidin-1-methyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; co M-hydroxy-4-42-I(I3--4-trifluoromethylpiperidin-1-methyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-(3--4-methylpiperazine-1-methyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; with M-hydroxy-4-42-I3-(3,3,3-trifluoropropyloxymethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; co M-hydroxy-4-(2--4-methylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; M-hydroxy-4-42-I3--4-fluorophenylthiomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-42-I3--4-fluorophenylsulfinylmethyl)benzofuran-2-ylcarbonylamino)|-ethoxy)benzamide; " M-hydroxy-4-42-I3--4-fluorophenylsulfonylmethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; with c M-hydroxy-4-425-|3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-ylcarbonylamino|butoxy)benzamide; M-hydroxy-4-(2-(4-hydroxybenzofuran-2-ylcarbonylamino)ethoxy|benzamide; ; t M-hydroxy-4-I(25-(5-chlorobenzofuran-2-ylcarbonylamino)butoxy|Senzamide; M-hydroxy-4-(2-(5-chlorobenzofuran-2-ylcarbonylamino)-1k-methylethoxy|benzamide; M-hydroxy-4-(2-(4-pyridin-3-ylmethyloxymethylbenzofuran-2-ylcarbonylamino)ethoxy|Senzamide; co M-hydroxy-4-(2-(4-methoxybenzofuran-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-42-I(4-(-2-methoxyethyloxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide ; co M-hydroxy-4-(2-(4-pyridin-3-ylmethyloxybenzofuran-2-ylcarbonylamino)ethoxy|benzamide; o M-hydroxy-4-(2-(4-methoxyindol-2-ylcarbonylamino)ethoxy|benzamide; M-hydroxy-4-4-25-|3-(2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino|butoxy)benzamide; -I M-hydroxy-4-42-I(I3--2-methoxyethyloxymethyl)benzofuran-2-ylcarbonylamino|)-1k-methylethoxy)benzamide; Pho M-hydroxy-4-42-I3-(M,M-diethylaminomethyl)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-425-|5-(2-methoxyethyloxy)benzofuran-2-ylcarbonylamino|butoxy)benzamide; M-hydroxy-4-42-(5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-4-25-|5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino|butoxy)benzamide; M-hydroxy-4-2-(5-(tetrahydropyran-4-yloxy)benzofuran-2-ylcarbonylamino|-1k-methylethoxy)benzamide; HF) M-hydroxy-4-42-(I5-(2,2,2-trifluoroethyloxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; F M-hydroxy-4-42-(5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-425-|5-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|butoxy)benzamide; in M-hydroxy-4-42-(15-(2-pyrrolidin-1-ylethyloxy)benzofuran-2-ylcarbonylamino|-1k-methylethoxy)benzamide; M-hydroxy-4-42-(5-(piperidin-4-yloxy)benzofuran-2-ylcarbonylamino|ethoxy)benzamide; M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)-4-methylthiobutoxy|benzamide; M-hydroxy-4-I(25-(benzofuran-2-ylcarbonylamino)-4-methylsulfonylbutoxy|bSenzamide; M- hydroxy-3-(2-(biphen-4-ylcarbonylamino)-1K-methylethoxy|isoxazol-5-ylcarboxamide; 65 M-hydroxy-3-(25-(biphen-4-ylcarbonylamino)butoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(2-(benzofuran-2-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(2-(trans-cinnamoylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-I3-(4-(2-ethoxyphenyl)phenylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; M- hydroxy-3-I3-(biphen-3-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-I3-(biphen-4-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3- (2-(naphth-2-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(2-(3-methylbiphen-4-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3- (2-(2'-ethoxylbiphen-4-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-3-(3-methylbiphen-4-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; 70 M-hydroxy -3-I3-(4-Phenylthiazol-2-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-13-"(naphth-2-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; M-hydroxy- 3-3-(naphth-1-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-13-(2-(2-phenylethyl)phenylcarbonylamino|propoxy)isoxazole-5-ylcarboxamide; M-hydroxy-3 -(2-(naphth-1-ylcarbon ilamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(25-(benzofuran-2-ylcarbonylamino)butoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(25-(biphen-3-ylcarbonylamino)butoxy|isoxazole-5-ylcarboxamide; M- hydroxy-3-(2-(benzofuran-2-ylcarbonylamino)-1kC-methylethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(2-(biphen-3-ylcarbonylamino)-1kC-methylethoxy|isoxazole-5- ylcarboxamide; M-hydroxy-3-(2-(biphen-3-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(2-(biphen-4-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide); M-hydroxy-3-(2-(4-phenylthiazol-2-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-2-(2-(2-phenylethyl)phenylcarbonylamino|ethoxy)isoxazole-5- ylcarboxamide; M-hydroxy-3-(2-(biphen-2-ylcarbonylamino)ethoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-I3-(biphen-2-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide; c M-hydroxy-3-(25-(naphth-2-ylcarbonylamino)butoxy|isoxazole-5-ylcarboxamide; M-hydroxy-3-(25-(naphth-1-ylcarbonylamino)butoxy|isoxazole-5-ylcarboxamide; ) M-hydroxy-3-(2-(naphth-2-ylcarbonylamine). o)-1k-methylethoxy|isoxazol-5-ylcarboxamide; M-Hydroxy-3-(2-(naphth-1-ylcarbonylamino)-1k-methylethoxy|isoxazole-5-ylcarboxamide; M-Hydroxy-3-3-(benzofuran-2-ylcarbonylamino)propoxy|isoxazole-5-ylcarboxamide ; "with zo M-hydroxy-3-3-"trans-cinnamoylamino)propoxy|isoxazol-5-ylcarboxamide and M-hydroxy-3-(2-(3-phenoxymethylbenzofuran-2-yl-carbonylamino)ethoxy|isoxazole-5 -ylcarboxamide or their pharmaceutically acceptable salts 17. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. with 18. A pharmaceutical composition containing a therapeutically effective amount of a compound according to claim 16 or its pharmaceutically acceptable salts and a pharmaceutically acceptable excipient. 19. A method of treating an animal disease caused by an ASAO, in which compounds according to any of claims 1-15 are administered. 20. A method of treating a disease in animals caused by NAAS, in which compounds according to claim 16 are administered. 21. The method according to any one of claims 19 or 20, characterized in that the disease is cancer. " 22. The method according to claim 21, which differs in that the cancer is acute myelogenous leukemia (AML) or myelomonocytic leukemia (MML). 23. A method of treating cancer in an animal, wherein the compound according to any one of claims 1-15 is administered in combination with one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent , other antiproliferative agents, prenylprotein transferase inhibitor, NMO-CoA reductase inhibitor, ViIL protease inhibitor, reverse transcriptase inhibitor, DNA methyltransferase inhibitor, or angiogenesis inhibitor. 24. A method of treating cancer in animals, in which compounds according to claim 16 are administered in combination with one or more co-compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic agent, other antiproliferative agents, 5p prenylprotein transferase inhibitor, NMO-CoA reductase inhibitor, ViL protease inhibitor, reverse-I transcriptase inhibitor, DNA methyltransferase inhibitor, or angiogenesis inhibitor. Fo 25. A method of treating cancer in an animal, wherein the compounds of any one of claims 1-15 are administered in combination with radiation therapy and, optionally, in the presence of one or more compound(s) independently selected from an estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, two CYTOTOXIC agents, other antiproliferative agents, prenylprotein transferase inhibitor, NMO-CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, GF) DNA methyltransferase inhibitor, or angiogenesis inhibitor. F 26. A method of treating cancer in animals, in which the compounds according to claim 16 are administered in combination with radiation therapy and, optionally, in the presence of one or more compounds independently selected from an estrogen receptor modulator, an androgen receptor modulator, a modulator retinoid receptor, cytotoxic agent, other antiproliferative agents, prenylprotein transferase inhibitor, NMO-CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, DNA methyltransferase inhibitor, or angiogenesis inhibitor. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated 65 microcircuits", 2008, M 10, 26.05.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine.