EA003283B1 - N-hydroxy-2-(alkyl, aryl, or heteroaryl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl, or heteroarylamides as matrix metalloproteinase inhibitors - Google Patents

Abstract

1. A compound according to formula I wherein: R<1> is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; saturated or unsaturated 5 to 10-membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>, optionally substituted with one or two groups selected independently from R<5>; or heteroaryl- (CH2) 0-6- wherein the heteroaryl group is 5 to 6-membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R<5>; A is -S-,-SO-or -SO2-; R<2> and R<3>, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R<7> optionally having one or two double bonds; R<4> is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; phenyl or naphthyl optionally substituted with one or two groups selected independently from R<5>; C3-C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R<5>; saturated or unsaturated 5 to 10-membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>, optionally substituted with one or two groups selected independently from R<5>; R<5> is H, C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6 alkylamine, C1-C12 perfluoro alkyl, S (O) n-C1-C6 alkyl, S (O) n-aryl where n is 0,1 or 2; OCOO C1-C6 alkyl, OCOOaryl, OCONR<6>, COOH, COO C1-C6 alkyl, COOaryI, CONR<6>R<6>, CONHOH, NR<6>R<6>, SO2NR<6>R<6>, NR<6>SO2aryl, -NR<6>CONR<6>R<6>, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2- C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3-C8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>, wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; R<6> is H, C1-C18 alkyl optionally substituted with OH; C3-C6 alkenyl, C3-C6alkynyl, C1-C6 perfluoro alkyl, S (O) n-C1-C6 alkyl S (O) n aryl where n is 0,1 or 2; or CO-heteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and R<7> is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S (O) n-C1-C6-alkyl, S (O) n-aryl where n is 0,1 or 2; COO-C1-C6-alkyl, COOaryl, CONHR<6>, CONR<6>R<6>, CONHOH, SO2NR<6>R<6>, SO2CF3, SO2NH-heteroaryl, SO2NHCO-aryl, CONHSO2-C1-C6-alkyl, CONHSO2aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-C1-C6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R<5>; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R<5>; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R<5>; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R<5>; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R<5>; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatoms selected from O, S or N-C1-C6 alkyl, optionally substituted with one or two groups selected independently from R<5>; or R<8>R<9>N-C1-C6-alkoxyaryl-C1-C6-alkyl where R<8> and R<9> are independently selected from C1-C6 alkyl or R<8> and R<9> together with the interposed nitrogen forms a 5-7-membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein: R<1> is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R<5>; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R<5>; saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR<7>, optionally substituted with one to two groups selected independently from R<5>; or heteroaryl- (CH2) 0-6- wherein the heteroaryl group is 5 to 6-membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R<5>; A is-S-,-SO-or -SO2- ; R<2> and R<3>, taken with the carbon atom to which they are attached, form a 5 to 7-membered heterocyclic ring containing O, S or N-R<7> optionally having one or two double bonds; R<4> is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R<5>; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R<5>; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R<5>; phenyl or naphthyl optionally substituted with one or two groups selected independently from R<5>; C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R<5>; R<5> is H, F, Cl, Br, I, CN, CHO, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2to C12 alkenyl, C2-C12 alkynyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6alkenyloxy, C3-C6 alkynyloxy, C1-C6alkoxyheteroaryl, C1-C6alkoxyaryl, C1-C6-alkylamino-C1-C6 alkoxy, C1-C2-alkylene dioxy, aryloxy-C1-C6 alkylamine, C1-C12 perfluoro alkyl, S (O)n-C1-C6 alkyl, S (O) n-aryl where n is 0,1 or 2; OCOO- C1-C6 alkyl, OCOOaryl, OCONR<6>, COOH, COO-C<1>-C<6> alkyl, COOaryl, CONR<6>R<6>, CONHOH, NR<6>R<6>, SO2NR<6>R<6>, NR<6>SO2-aryl, NR<6>CONR<6>R<6>, NHSO2CF3, SO2NH-heteroaryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl,CONHSO2-aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl; or saturated or unsaturated 5 to 10-membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR<7>; wherein heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; R<6> is H, C1 to C18 alkyl optionally substituted with OH; C3-C6 alkenyl, C3-C6alkynyl, C1-C6 perfluoro alkyl, S (O) n alkyl or aryl where n is 0,1, or 2; or CO-heteroaryl; wherein heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR<7> and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and R<7> is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S (O) n-alkyl, S (O) n-aryl where n is 0,1 or 2; COOalkyl, COOaryl, CONHR<6>, CONR<6>R<6>,CONHOH, SO2NR<6>R<6>, SO2CF3, SO2NH-heteroaryl, SO2NHCOaryl, CONHSO2alkyl, CONHSO2aryl, aryl, heteroaryl; wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10-membered mono or bicyclic heteroaryl group

Description

Matrix metalloproteinases (MMPs) are a group of enzymes that take part in the pathological destruction of connective tissue and basement membranes. These zinc-containing endopeptidases consist of several subpopulations of enzymes, including collagenases, stromelysins, and gelatinases. Among these classes of gelatinase, it was found that they represent MMPs that are very closely related to the growth and spread of tumors. It is known that the level of expression of gelatinase increases in malignant tumors and that gelatinase can destroy the basement membrane, which leads to the formation of tumor metastases. Recently, it was also found that in the pathology of angiogenesis (development of blood vessels), required for the growth of solid tumors, there is a gelatinase component. In addition, there is evidence that suggests that gelatinase is involved in rupture of plaques associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenia, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulcer, abnormal wound healing, bone disease, proteinuria, and aneurysm disease degenerative loss of cartilage after traumatic damage to the joints, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular kidney disease, premature rupture of pl membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, premature development retinopathy, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular development of blood vessels and new blood vessels corneal transplant. See the latest reviews: (1) Vesey Abuapsek ίη Ma1px Ms1a11orgo1s1pa5s 1p1nByog Kekeagsy, K.R. Veskey

A.N. Iau1b8op, A.N. Igitshopb, R. Nih1eu apb M. ^ yakeg, Kekeagsy Eosik, Uo1.1, 16-26 (1996), (2) Sigg. Ορίη. Tneg. Ra1epTs (1994) 4 (1): 716, (3) Sigg. Mebusha 1 C1et., (1995) 2: 743-762, (4) Exp. Orsh. Tneg. Ra1ep18 (1995) 5 (2): 1087-110, (5) Exp. Orsh. Tneg. Ra1epC (1995) 5 (12): 12871196.

The ΤΝΡ-α-converting enzyme (TACE) catalyzes the formation of ΤΝΡ-α from the membrane-bound ΤΝΡ-α precursor protein. ΤΝΡ-α is an anti-inflammatory cytokine that is now thought to play a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory central nervous system disease, inflammatory bowel disease, insulin resistance and HIV infections besides its well-documented antitumor properties. For example, a study using antibodies against ΤΝΡ-α and transgenic animals showed that blocking the formation of ΤΝΡ-α inhibits the development of arthritis. Such a study has recently continued with the same success for people.

It is believed that, as small molecules, MMPK and TACE inhibitors have the potential to treat various disease states. Although various MMP and TACE inhibitors have been identified and described in the literature, the vast majority of these molecules are peptide and peptide-like compounds that can be assumed to have bioavailability and have pharmacokinetic problems common to such compounds that may limit their clinical efficacy. Low molecular weight, efficacy, and prolonged action of orally biologically available MMP and / or TACE inhibitors are therefore desirable for potential long-term treatment of the aforementioned disease states.

Recently, two references have appeared (US Pat. No. 5,455,258 and European Patent Application 606046) which describe arylsulfonamide substituted hydroxamic acids. These references include compounds, as an example of which CC8 27023A is indicated. These compounds are the only non-peptide matrix metalloproteinase inhibitors described to date.

S63 27023A

8a1ay e! A1., Lebsc App. C1, 195 (1973) described some derivatives of aryl-substituted thio- and aryl-substituted sulfonylacetohydroxamic acids of the general formula I. These compounds were prepared to study the Mannich reaction. Then they were tested for their fungicidal activity.

Some sulfonyl carboxylic acids are described in US Pat. No. 4,933,367. It has been found that these compounds exhibit hypoglycemic activity.

Summary of the invention

This invention relates to new, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and the enzyme converting TXP-α (TACE), for the treatment of arthritis, tumor metastases, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.

In accordance with this invention, there is provided a group of compounds of formula I

I where

Z ¹ is alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ;

aryl containing from 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R ⁵ ;

cycloalkyl containing from 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R ⁵ ;

saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or NY ⁷ , optionally substituted with one or two groups selected independently from ⁵ ;

or heteroaryl- (CH ₂ ) _0-6 -, where the heteroaryl group is a 5- or 6-membered group with one or two heteroatoms selected independently from O, 8 or Ν, and may optionally be substituted with one or two groups selected independently from I ⁵ ;

And provides -8-, -80- or -8O ₂ -;

I ² and I ³ are taken together with the carbon atom to which they are attached form 5-7chlennoe heterocyclic ring containing O, 8 or Ν-I ⁷ and optionally having one or two double bonds;

Z ⁴ is hydrogen, alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ;

phenyl or naphthyl optionally substituted with one or two groups selected independently from Z ⁵ ;

C3-C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ⁵ ;

saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-Z ⁷ , optionally substituted with one or two groups selected independently from Z ⁵ ;

I ⁵ represents H, C7-Ci-aroyl, C2-C6 alkanoyl, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, P, C1, Br, I, CX, CHO, C1-C6-alkoxy, aryloxy , heteroaryloxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C6-alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6-alkylamino-C1-C6-alkoxy, C1-C2-alkylenedioxy, aryloxy-C1-C6-alkylamine, -perfluoroalkyl, 8 (O) p-C1-C6 alkyl, 8 (O) p-aryl, where η is 0, 1 or 2; OSOOC1-C6-alkyl, OSOO-aryl, ОСОНЯ ⁶ , СОО, СОО-С1-С6-alkyl, СОО-aryl, СОХНЯ '. (ΌΧΙ UN. XYA ⁶ I ⁶ , 8O2XYA ⁶ I ⁶ , XYA ⁶ 8О2-aryl, -XYA ⁶ SOKHYA ⁶ I ⁶ , ХН8О2СР3, 8О2ХН-heteroaryl, 8О2ХНСО-aryl, СОХН8О ₂ -С ₁ -С _6- alkyl,

СОХН8О ₂ -ryl, ХН ₂ , ОН, aryl, heteroaryl, С ₃ С8-cycloalkyl or saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or XY ⁷ , where C | -C6-alkyl straight or branched, heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or XY ⁷ , and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups selected from halo, cyano, amino, nitro, C1-C ₆ alkyl, C ₁ -C ₆ al hydroxy or hydroxy;

I ⁶ represents H, C1-C18 alkyl optionally substituted by OH; C3-C6 alkenyl, C3-C6 alkynyl, C1-C6 perfluoroalkyl, 8 (O) p-C1C6-alkyl, 8 (O) p-aryl, where η is 0, 1 or 2, or CO-heteroaryl, where heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or XY ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups, selected from halogen, cyano, amino, nitro, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy;

and R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, 8 (O) _p -C ₁ -C ₆ alkyl, 8 (O) p-aryl, where n is 0, 1 or 2; COOC1-C6-alkyl, COO-aryl, SOX ⁶ , SOX ⁶ I ⁶ ,

SOHNON, 8O2HYA ⁶ I ⁶ 8O2SR3, 8O2HN5 heteroaryl 8o ₂ JISC aryl SONN8O ₂ -C ₁ -C ₆ alkyl, SONN8O ₂ -aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy; and heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or L-C ₁ -C ₆ -alkyl;

alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ;

arylalkyl containing from 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R ⁵ ;

heteroarylalkyl, where the alkyl contains from 1 to 6 carbon atoms and the heteroaryl contains 1 or 2 heteroatoms selected from O, 8 or Ν, and is optionally substituted with one or two groups selected independently from R ⁵ ;

biphenylalkyl containing from 13 to 18 carbon atoms, where biphenyl is optionally substituted with one or two groups selected independently from R ⁵ ;

arylalkenyl containing from 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R ⁵ ;

cycloalkylalkyl or bicycloalkylalkyl containing from 4 to 12 carbon atoms, where the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R ⁵ ;

saturated or unsaturated mono-bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-C, C6-alkyl, optionally substituted with one or two groups selected independently from Z ⁵ ; or

I ⁸ I ⁹ No. C1-C6-alkoxyaryl-C1-C6-alkyl, where I ⁸ and I ⁹ are independently selected from C1-C6-alkyl, or I ⁸ and I ³ together with the nitrogen between them form 5-7 a membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and their pharmaceutically acceptable salts.

A more preferred aspect of the invention is a group of compounds of general formula (1a)

^Where _one

Z ¹ is alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ;

aryl containing from 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R ⁵ ;

cycloalkyl containing from 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R ⁵ ;

saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or NY ⁷ , optionally substituted with one or two groups selected independently from ⁵ ;

or heteroaryl- (CH2) 0-6, wherein the heteroaryl group is a 5- or 6-membered group with one or two heteroatoms independently selected from O, 8 and Ν, and may optionally be substituted with one or two groups, selected independently from I ⁵ ;

A represents -8, -8O- or -8O ₂ -;

I ² and I ³ are taken together with the carbon atom to which they are attached form 5-7chlennoe heterocyclic ring containing O, 8 or Ν-I ⁷ and optionally having one or two double bonds;

Z ⁴ is hydrogen, alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ;

phenyl or naphthyl optionally substituted with one or two groups selected independently from Z ⁵ ;

C3-C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ⁵ ;

I ⁵ represents H, B, C1, Vg, I, CH CHO,

C ₇ -Sc-aroyl, C ₂ -C ₆ alkanoyl, C1-C1 ₂ -alkyl, C ₂ 7

C 1 -C ₂ -alkenyl, C ₂ -C 1 ₂ alkynyl, _C1-C6 alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ -alkeniloksi, C ₃ -C ₆ -alkiniloksi, C ₁ -C ₆ -alkoksiaril, C ₁ -C ₆ alkoxyheteroaryl, C ₁ -C ₆ -alkylamino-C ₁ -C ₆ alkoxy, C ₁ -C ₂ -alkylenedioxy, aryloxy-C ₁ -C ₆ alkylamine, C ₁ -C ₁₂ -perfluoroalkyl, 8 (O) _p -C ₁ -C ₆ alkyl, 8 (O) _p- aryl, where η is 0, 1 or 2; OSOO ₁ -C ₆ -alkyl, OSOO-aryl, OSOKhK ⁶ , COOH, СОО-С1-С6-alkyl, СОО-aryl, SOIK ⁶ К ⁶ , (ΌΧΙ UN. ΝΚ ⁶ Κ ⁶ , 8О2ХК. ⁶ К ⁶ , ХК ⁶ 8О2-aryl, ХК ⁶ СОХК ⁶ К ⁶ , ХН8О2Сез, 8О2Х1Н-heteroaryl, 8О ₂ Х1НСО-aryl, СОХН8О ₂ -С ₁ -С _6- alkyl, СОХН8О ₂ -aryl, ΝΗ ₂ , ОН, aryl, heteroaryl, С ₃ -C ₈ cycloalkyl or a saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or ΝΚ ⁷ ;

where heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy;

K ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted with OH; C3-C6 alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, 8 (O) _p alkyl or aryl, where η is 0, 1 or 2, or CO heteroaryl, where heteroaryl is 5-10 membered a mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy;

and K ⁷ is C7-C11-aroyl, C2C6-alkanoyl, C1-C12-perfluoroalkyl, 8 (O) p-alkyl, 8 (O) p-aryl, where n is 0, 1 or 2; COO-alkyl, COO-aryl, REMAINING SOKH ⁶ K ⁶ , SOKHNON, 8O2KHK ⁶ K ⁶ , 8O ₂ CE ₃ , 8O ₂ IN-heteroaryl,

8O2INSO-aryl, SOIN8O2-alkyl, COXH8O, aryl, aryl or heteroaryl, where C | -C ₆ -alkyl is straight or branched, heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms, independently selected from O, 8 or Ν-K ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C _6- alkoxy or hydroxy;

alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from K ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ;

arylalkyl containing from 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from K ⁵ ;

heteroarylalkyl wherein alkyl contains from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, 8 or Ν, and is optionally substituted with one or two groups selected independently from K ⁵ ;

biphenylalkyl containing from 13 to 18 carbon atoms, where biphenyl is optionally substituted with one or two groups selected independently from K ⁵ ;

arylalkenyl containing from 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from K ⁵ ;

cycloalkylalkyl or bicycloalkylalkyl containing from 4 to 12 carbon atoms, where cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected independently from K ⁵ ;

a saturated or unsaturated mono-bicyclic heterocycle containing one heteroatom selected from O, 8 or X-C ₁ C 6 -alkyl and optionally substituted with one or two groups selected independently from K ⁵ ;

K ⁸ K ⁹ -C1 -C6-alkoxyaryl-C1-C6 -alkyl, where K ⁸ and K ⁹ are independently selected from C1-C ₆ -alkyl, or K ⁸ and K ³ together with the nitrogen between them form 5- A 7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and their pharmaceutically acceptable salts.

The most preferred group of compounds are compounds of the following formula (! B)

1Ъ ^where ₁

K ¹ represents phenyl, naphthyl, alkyl containing 1-18 carbon atoms, or heteroaryl, such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, halogen; or 8 (O) _p -C ₁ -C ₆ -alkyl-C ₁ C6-alkoxyaryl or C1-C6-alkoxyheteroaryl;

A represents -8, -8O- or -8O ₂ -;

K ² and K ³ taken together with the carbon atom to which they are attached form a 5-7 membered heterocyclic ring containing

O, 8 or Ν-K ⁷ and optionally having one or two double bonds;

K ⁴ represents hydrogen;

alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ;

phenyl or naphthyl optionally substituted with one or two groups selected independently from K ⁵ ;

C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from K ⁵ ;

K ⁵ represents H, C7-C11-aroyl, C2-C6 alkanoyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, P, C1, Br, I, ΟΝ, CHO, C1-C6 alkoxy, aryloxy , heteroaryloxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C6-alkylamino-C1-C6 alkoxy, C1-C2-alkylene-dioxi, aryloxy-C1-C6-alkylamine, C1-C12-perfluoroalkyl, 8 (O) P C1-C6 alkyl, 8 (O) p-aryl, where η is 0, 1 or 2; OSOOS1-C6-alkyl, OSOO-aryl, OSOIK ⁶ , COOH, СОО-С1-С6-alkyl, СОО-aryl, СОНК ⁶ К ⁶ , СОННОН, ΝΚΉ ⁶ , 8О; НК ⁶ К ⁶ . NK ⁶ 8O2-aryl, -NK ⁶ СОНК ⁶ К ⁶ , НН8О2СР3, 8О2НН-heteroaryl, 8О2Н1НСО-aryl, СОНН8О2-С1-С6-alkyl, ί, ΌΝН8О2-aryl, ΝΗ2, OH, aryl, heteroaryl, C3 saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or ΝΚ ⁷ , where C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl a group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and the aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halo, cyano, amino, nitro, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy;

K ⁶ represents H, C1-C18 alkyl optionally substituted by OH; C3-C6 alkenyl, C3-C6 alkynyl, C1-C6 perfluoroalkyl, 8 (O) palkyl or aryl, where η is 0, 1 or 2, or CO heteroaryl, where heteroaryl is a 5-10 membered mono- or a bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and the aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6- alkyl, C ₆ -C ₆ alkoxy or hydroxy;

and K ⁷ represents C ₇ -C-aroyl, C ₂ C ₆ -alkanoyl, C1-C1 ₂ -perfluoroalkyl, 8 (O) _p -alkyl,

8 (O) p-aryl, where n is 0, 1 or 2; COO-alkyl, COO-aryl, SOINK ⁶ , SOIC. ⁶ To ⁶ SOHNON. 8O2IK ⁶ K ⁶ 8O2SR ₃ 8o ₂ IN-heteroaryl,

8О ₂ INSO-aryl, СНН8О ₂ -С1-С ₆ -alkyl,

SOIN8O ₂ -aryl, aryl or heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy or hydroxy; and heteroaryl represents a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or Ν-CiC6-alkyl;

alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ;

alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ;

arylalkyl containing from 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

heteroarylalkyl wherein alkyl contains from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, 8 or Ν, and is optionally substituted with one or two groups selected independently from K ⁵ ;

biphenylalkyl containing from 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

arylalkenyl containing from 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

cycloalkylalkyl or bicycloalkylalkyl containing from 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ;

saturated or unsaturated mono-bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-Ο ₁ C6-alkyl, optionally substituted with one or two groups selected independently from K ⁵ ;

K ⁸ K ⁹ N-C1-C6-alkoxyaryl-C1-C6-alkyl, where K ⁸ and K ^{9 are} independently selected from C1-C6-alkyl or K ⁸ and K ⁹ together with the nitrogen between them form a 5-7 membered a saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and their pharmaceutically acceptable salts.

The most preferred compounds of the invention inhibiting matrix metalloproteinase and TACE are:

1-benzyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid hydroxyamide, 1- (3, 4-dichlorobenzyl) -4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid, 4- (4-methoxybenzenesulfonyl) hydroxyamide -1- (4-methylbenzyl) piperidine-4-carboxylic acid, 4- (4-methoxybenzenesulfonyl) hydroxyamide naphthalene-2-yl-methylpiperidin-4-carboxylic acid, 1-biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) -piperidin-4-carboxylic acid hydroxyamide, hydroxyamides d 4- (4-methoxybenzenesulfonyl) -1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid, 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidine-4-carboxylic acid hydroxyamide, 1-tert-butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 1-butyl-4 hydroxyamide - (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid, hydroxyamide 1-cyclooctyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid, hydroxyamide 1-ethyl-4- (4-methoxybenzenesul phonyl) piperidine-4-carboxylic acid, 1-isopropyl-4- (4-methoxybenzenesulfonyl) hydroxyamide, 4-carboxylic acid piperidine, 1-methyl-4- (4-methoxybenzenesulfonyl) 4-carboxylic acid hydroxyamide, 1-benzyl hydroxyamide -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid, 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 1- (4-fluorobenzyl) -4- ( 4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid, 4- (4-methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidin-4-carboxylic acid hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (2-phenylethyl) -piperidin-4-carboxylic hydroxyamide acids, hydroxyamide 4- (4-n-butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid, hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid, 4- (4-n-butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid hydroxyamide 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxybenzenesulfonyl) hydroxyamide -1- [4- (2-piperidin-1-ylethoxy) benzyl ] piperidine-4-carboxylic acid, hydroxyamide 1-benzyl-4- (4-benzyloxybenzenesulfonyl) piperidine-4-carboxylic acid, hydroxyamide 4- (4-butoxybenzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid, 4- (4-butoxybenzenesulfonyl) -1- [3- (2-morpholinyl-1-ylethoxy) hydroxyamide, benzyl] piperidine-4-carboxylic acid, 1-methyl-4- (4 hydroxyamide -butoxybenzenesulfonyl) pip 4-carboxylic acid eridine, 1-ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 1-n-butyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 4- [hydroxyamide 4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid, 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-ethylpiperidin-4-carboxylic acid hydroxyamide 1-butyl-4- [ 4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid, 1-benzyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid hydroxyamide, hydroxyamide 1-benzyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid, 1-butyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid hydroxyamide, 1- hydroxyamide benzyl 4- [4- (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid, 4- (4-butoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid hydroxyamide, 4- (4- hydroxyamide methoxybenzenesulfonyl) -1- (4-thiophen-2-ylbenzyl) piperidine-4-carboxylic acid, 4- (4-methoxybenzenesulfonyl) hydroxyamide) -1- (4-pyridin-2-ylbenzyl) piperidine-4 carboxylic acid, 1- (hydroxyamide 3.4 -dichlorobenzyl) -4- (4butoxybenzenesulfonyl) piperidine-4-carboxylic acid, [4- (4-chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid hydroxyamide, 4- (4-butoxybenzenesulfonyl) hydroxyamide -phenoxybenzyl) piperidine-4-carboxylic acid, hydroxyamide [4- (4-chlorobenzyloxy) benzenesulfonyl] -1- (4-methylbenzyl) piperidin-4 carboxylic acid, hydroxyamide 4- (4-butoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid, 4- (4-butoxybenzenesulfonyl) -1- (4-cyanobenzyl) piperidine-4-carboxylic acid hydroxyamide and 4- (4-butyroxyamide oksibenzolsulfonil) -1-pyridin-4-ylmethylpiperidin-4-carboxylic acid and pharmaceutically acceptable salts thereof.

It is clear that the definition of compounds of formulas I, 1a and 1b, where K ¹ , K ² , K ³ and K ⁴ contain asymmetric carbons, includes all possible stereoisomers and their mixtures, which have the activity discussed below. In particular, this definition includes racemic modifications and any optical isomers that possess the indicated activity. Optical isomers can be obtained in pure form by standard resolution techniques. Unless otherwise specified, the term “alkyl” refers to a straight or branched Οι-Cb-alkyl group, and the aryl is phenyl or naphthyl. Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.

The present invention provides a pharmaceutical composition which comprises a compound of the present invention in combination or in association with a pharmaceutically acceptable carrier. In particular, the invention provides a pharmaceutical composition that includes an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration. However, they can be adapted for other routes of administration, for example, for parenteral administration to patients.

In order to achieve consistent administration, it is preferred that the composition of the invention is in unit dosage form. Suitable unit dosage forms include tablets, capsules, and powders in sachets or ampoules. Such unit dosage forms may contain from 0.1 to 100 mg of a compound of the invention. The compounds of this invention can be administered orally at a dosage range of from about 0.01 to 100 mg per kg. Such a composition can be administered 1 to 6 times a day, more typically 1 to 4 times a day.

The compositions of this invention can be prepared with conventional excipients, such as fillers, disintegrating agent, binder, lubricant, flavoring agent and the like. They are made in the usual way.

In accordance with the present invention, methods for preparing the compounds of this invention are also provided.

Method of invention

The compounds of this invention can be obtained by one of the General methods listed below.

A suitably substituted mercaptan derivative was alkylated using either a substituted (Scheme 1) or unsubstituted (Scheme 2) α-bromoacetic acid ester derivative in refluxing acetone using K2CO3 as the base. The sulfide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH ₂ Cl ₂ or by using an oxone in a methanol / water mixture. The sulfone obtained by the above method can either be further alkylated using various alkyl halides to produce a disubstituted derivative, or it can be hydrolyzed using IAOH / MeOH at room temperature. However, instead of using ethyl ether, if a tertiary butyl ester is present, hydrolysis can be carried out with the TFA / CH ₂ Cl _{2 system} at room temperature. The resulting carboxylic acid was then converted to the hydroxamic acid derivative by reaction with a mixture of oxalyl chloride / ΌΜΧ (catalytic amount) and a mixture of hydroxylamine / triethylamine.

Scheme 1. Synthesis

but. K ₂ CO 3 / acetone / reflux;

b. m-chlorobenzoic acid;

c. K ₂ CO ₃ /18-crown-6 / I ₃ Vg / acetone / reflux;

b. NaOH / MeOH / THF / CT;

e. (СОС1) 2 / СН ₂ С12 / Е1зК / НН ₂ ОН-НС1.

Scheme 2. Synthesis

^K '- ^{5H +} Β ^ γ ^0Ε ' ----- ”O About 1 ^b A ² „ ^And on the exhaust ^I'm 'HG ^OE ' 1 ^a n ³ in ^{3 eL} , about ^A about T

a. K ₂ CO ₃ / acetone / reflux;

b. m-chlorobenzoic acid;

c. K ₂ CO ₃ /18-crown-6 / I ₃ Vg / acetone / reflux;

b. I am ₃ Vg / 10n. HaO11 / Βζ \ (Εΐ) _; / (Ί GSE / CT;

e. NaOH / MeOH / THF / CT;

ί. (СОС1) 2 / СН2С12 / ЕШ№ОН-НС1.

As indicated in Scheme 3, the sulfide derivative can be further alkylated using lithium bis (trimethylsilyl) amide in THF at 0 ° C. The alkylated or monosubstituted compound was hydrolyzed and converted to the hydroxamic acid derivative. Sulfinyl derivatives were prepared by the oxidation of sulfide derivatives of hydroxamic acid H ₂ O ₂ in a solution of MeOH.

Scheme 3. Synthesis

but. K ₂ CO ₃ / acetone / reflux;

b. I am ₃ W / NMP8 / THF;

c. NaOH / MeOH / THF / CT;

b. (SOAH / UTB / ESH / MON-Na;

e. Meon / H ₂ O ₂ / CT.

The corresponding hydroxyamides of 1-substituted 4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acids were prepared starting from diethanolamine and correspondingly substituted alkyl or aryl halides (Scheme 4). Derivatives of Ν-substituted diethanolamines were converted to dichloro compounds using thionyl chloride. The corresponding dichlorides were reacted with derivatives of substituted ethyl esters of sulfonylacetic acids in the presence of K ₂ CO ₃ /18-crown-6 in boiling acetone. The ethyl esters of 1-substituted 4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acids thus obtained were converted to hydroxyamide as indicated in Scheme 4. Alternatively, these classes of compounds and other heterocycles can be prepared as indicated in Schemes 5 and 6.

Scheme 4

IN

i ί

but. K ₂ CO ₃ / JBr / acetone / reflux;

b. 8OC12 / CH2C12;

c. I ¹ 8О ₂ СН ₂ СООЕ1 / К ₂ СО ₃ /18-crown-6 / acetone / reflux;

b. No. YUN / THF / Meon / CT

e. (SS) C1) AN _; OHNS1 / ESh

Scheme 5

Υ = Ν or CH

a. KBg / K ¹ 8H / CHC1 ₃ / reflux;

b. Oxon / Meon;

e. (soatsnon-na / Yesh

Scheme 6

a. NM (TM§) ₂ / THF / 0 ^C / CO _2;

b. (СОС1) ₂ / МН ₂ ОН-НС1 / Е1 ₃ Н.

Alternatively, schemes 7 to 11 provide methods for preparing compounds of a number of hydroxamic acids using a solid phase carrier (P).

Scheme 7

Reagents and conditions: a) 2-Halogen acid (3.0 equiv.); 1-hydroxybenzotriazole hydrate (HOB1, 6.0 eq.); 1,3-diisopropylcarbodiimide Shch, C, 4.0 equiv.); DMF, 25 ° C; 2-16 hours;

b) Thiol (5.0 equiv.); sodium iodide (5.0 equiv.); 1,8-diazabicyclo- [5.4.0] undec-7-ene (EVI, 3.0 eq.); THF; 25 ° C; 12-16 h;

c) 70% tert-butyl hydroperoxide (40 equiv.); benzenesulfonic acid (2.0 equiv.); Όί, ’Μ; 25 ° C; 12-24 h;

b) tSRVA (5.0 equiv.); 1) CM; 25 ° C; 12-24 h;

e) TFKUSM (1: 1); 25 ° C; 1 hour

The 4-O-methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin (hydroxylamino resin) can be combined with the 2-halogen acid to obtain the hydroxamate ester-resin combination product. The coupling reaction can be carried out in the presence of a carbodiimide, such as E1C. in an inert solvent, such as DMF, at room temperature. The halogen group can be replaced with thiol in the presence of a base such as ΌΒυ in an inert solvent such as THF at room temperature. The sulfide can be oxidized to sulfoxide by reaction with an oxidizing agent, such as tert-butyl hydroperoxide, in the presence of an acid catalyst, such as benzenesulfonic acid, in an inert solvent, such as Όί.'Μ, at room temperature. Alternatively, the sulfide can be oxidized to sulfone by reaction with an oxidizing agent, such as meta-chloroperoxybenzoic acid, in an inert solvent, such as Όί, 'при, at room temperature. The sulfide, sulfoxide or sulfone can be treated with an acid, such as trifluoroacetic acid (TFA), in an inert solvent, such as 1) CM, to liberate free hydroxamic acid.

Scheme 8 shows a method for producing hydroxamic acids having alkoxy groups attached to an aromatic ring.

Scheme 8

about

Reagents and conditions:

a) 2-Halogen acid (3.0 equiv.); 1-hydroxybenzotriazole hydrate (HOB1, 6.0 eq.); 1,3 diisopropylcarbodiimide (O1C, 4.0 eq.); DMF, 25 ° C; 2-16 hours;

b) 4-Fluorobenzenethiol (5.0 eq.); sodium iodide (5.0 equiv.); 1,8-diazabicyclo [5.4.0] undec-7en SchVC 3.0 equiv.); THF; 25 ° C; 12-16 h;

c) Alcohol (15 equiv.); sodium hydride (15.0 equiv.); DMF; 80 ° C; 15 h;

b) 70% tert-butyl hydroperoxide (40 equiv.); benzenesulfonic acid (2.0 equiv.); Όί, ’Μ; 25 ° C; 12-24 h;

e) tSBRA (5.0 equiv.); 1) CM; 25 ° C; 12-24 h; ί) TFKYUSM (1: 1); + 25 ° C; 1 hour

Hydroxylamino resin can be combined with 2-halogen acid and the halogen group can be replaced with fluorobenzenethiol as described above. The fluorine group can then be replaced with alcohol in the presence of a base, such as sodium hydride, in an inert solvent, such as DMF, at about 80 ° C. The alkoxybenzenesulfanyl hydroxamate ester can then be oxidized to either the corresponding sulfinyl or sulfonyl hydroxamate ester as described above. Free hydroxamic acids can be isolated as described above.

Scheme 9 shows a process for the preparation of 2 bisarylsulfanyl, sulfinyl and sulfonyl hydroxamic acids.

Scheme 9

Pattern 10

ABOUT

about

Reagents and conditions:

a) 2-Halogen acid (3.0 equiv.); 1-hydroxybenzotriazole hydrate (ΗΘΒ1, 6.0 eq.); 1,3 diisopropylcarbodiimide (O1C. 4.0 eq.); DMF, 25 ° C; 2-16 hours;

b) 4-Bromobenzenethiol (5.0 equiv.); sodium iodide (5.0 equiv.); 1,8-diazabicyclo [5.4.0] undec-7en (ΌΒυ, 3.0 equiv.); THF; 25 ° C; 12-16 h;

c) 70% tert-butyl hydroperoxide (40 equiv.); benzenesulfonic acid (2.0 equiv.); OSM; 25 ° C; 12-24 h;

g) tCBBA (5.0 eq.); OSM; 25 ° C; 12-24 h;

e) arylboronic acid (2.0 equiv.); tetrakis (triphenylphosphine) palladium (0) (0.1 equiv.);

10% aqueous sodium carbonate (10.0 equiv.); OME 80 ° C; 8 h;

1) TFKYUSM (1: 1); 25 ° C; 1 hour

Hydroxylamino resin can be combined with 2-halogen acid and the halogen group can be replaced with fluorobenzenethiol as described above. The bromobenzenesulfanylhydroxamate ester can then be oxidized to either the corresponding sulfinyl or sulfonylhydroxamate ester as described above. The bromine group can then be replaced by an aryl group by reaction with arylboronic acid in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0) and a base such as sodium carbonate in an inert solvent such as OME at about 80 ° C. Free hydroxamic acids can be isolated as described above.

Scheme 10 shows a method for producing hydroxamic acids having amino groups attached to an aromatic ring.

A ⁶

Reagents and conditions:

a) 2-halogen acid (3.0 equiv.); 1-hydroxybenzotriazole hydrate (ΗΘΒ1, 6.0 eq.); 1,3 diisopropylcarbodiimide (O1C, 4.0 eq.); DMF, 25 ° C; 2-16 hours;

b) 4-bombenzenethiol (5.0 eq.); sodium iodide (5.0 equiv.); 1,8-diazabicyclo [5.4.0] undec-7en (ΌΒυ, 3.0 equiv.); THF; 25 ° C; 12-16 h;

c) amine (20.0 equiv.); tris (dibenzylidene acetone) dipalladium (0) (0.2 eq.); (8) - (-) - 2,2'bis (diphenylphosphino) -1,1'-binaphthyl ((8) 0,8, 0.8 equiv.); sodium tert-butoxide (18.0 equiv.); dioxane; 80 ° C; 8 h;

j) TFA: OSM (1: 1); 25 ° C; 1 hour

Hydroxylamino resin can be combined with 2-halogen acid and the halogen group can be replaced with bromobenzenethiol as described above. The bromine group can then be replaced by an amine in the presence of a catalyst, such as Tris (dibenzylideneacetone) dipalladium (0), and a ligand, such as (8) -ΒΙΝΑΡ, and a base, such as sodium tert-butoxide, in an inert solvent such as dioxane at approximately 80 ° C. Free hydroxamic acids can be isolated as described above.

Scheme 11 shows a method for producing hydroxamic acids having sulfonate groups attached to an aromatic ring.

Scheme 11

Reagents and conditions:

a) 2-halogen acid (3.0 equiv.); 1-hydroxybenzotriazole hydrate (ΗΘΒ1, 6.0 eq.); 1,3 diisopropylcarbodiimide (O1C, 4.0 eq.); DMF

25 ° C; 2-16 hours;

b) 4-hydroxybenzenethiol (5.0 equiv.); sodium iodide (5.0 equiv.); 1,8-diazabicyclo [5.4.0] undec7-ene (ΌΒυ, 3.0 equiv.); THF; 25 ° C: 12-16 h;

c) sulfonyl chloride (5.0 eq.); triethylamine (2.0 equiv.); OSM; 25 ° C; 8 h;

b) 70% tert-butyl hydroperoxide (40 equiv.); benzenesulfonic acid (2.0 equiv.); ESM; 25 ° C; 12-24 h;

e) tSBRA (5.0 equiv.); Compulsory medical insurance; 25 ° C; 12-24 h;

£) TFA: OSM (1: 1); 25 ° C; 1 hour

Hydroxylamino resin can be combined with 2-halogen acid and the halogen group can be replaced with hydroxybenzenethiol as described above. The hydroxybenzenesulfanylhydroxamate ester can then be oxidized to either the corresponding sulfinyl or sulfonylhydroxamate ester as described above. The hydroxy group can then be sulfonylated by reaction with a sulfonyl chloride in the presence of a base such as triethylamine in an inert solvent such as an ESM at about room temperature. Free hydroxamic acids can be isolated as described above.

The following examples are presented to illustrate and not to limit the scope of the present invention. The purity of the compounds by HPLC obtained by combinatorial methods is presented as a percentage of the area at a given wavelength (% (@) nm).

Example 1. No. Hydroxy-2- (4-methoxyphenylsulfanyl) -2-methyl-3-phenylpropionamide.

Ethyl 2bromopropionate (3.6 g, 20 mmol) was added to a solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous K ₂ CO ₃ (10 g, excess) in dry acetone (100 ml), which was stirred in a round-bottom flask, and the reaction mixture is heated at the boil under reflux for 8 hours with good stirring. At the end of this time, the reaction mixture was allowed to cool and the potassium salts were separated by filtration and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O and 0.5N. solution No. 1OH. The organic layer was then washed well with water, dried over MgSO ₄ , filtered and concentrated to give 2- (4 methoxyphenylsulfanyl) propionic acid ethyl ester as a light yellow oil. Yield 4.5 g (94%); MS: 241 (M + H) ⁺ .

To a stirred solution of 2- (4-methoxyphenylsulfanyl) propionic acid ethyl ester (2.44 g, 10 mmol) in THF (100 ml) at -4 ° С lithium bis (trimethylsilyl) amide (1 M solution, 15 ml, 15 mmol). The orange reaction mixture was stirred at room temperature for 15 minutes and then cooled to 0 ° C, after which it was stirred for an additional hour. The temperature of the mixture was again brought to -40 ° C and benzyl bromide (1.72 g, 10 mmol) in THF was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight before it was quenched with ice water, extracted with chloroform and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated and chromatographed on a silica gel column using a 10% ethyl acetate: hexane mixture to give 2- (4-methoxyphenylsulfanyl) -2methyl-3-phenylpropionic acid ethyl ester as a colorless oil. Yield: 860 mg (26%); MS: 331 (M + H) ⁺ .

2- (4-Methoxyphenylsulfanyl) -2-methyl-3-phenylpropionic acid ethyl ester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10N are added. No. 1OH (20 ml). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated, diluted with 1: 1 hexane: diethyl ether and extracted with H ₂ O. The aqueous layer was cooled with ice and acidified to pH 3. The acid was then extracted with chloroform and the organic layer was dried over MgSO ₄ , filtered and concentrated to give 2- (4-methoxyphenylsulfanyl) -2-methyl-3phenylpropionic acid as a low-melting solid. Yield 580 mg, 16%;

MS: 303.2 (M + H) ⁺ .

To a stirred solution of 2- (4-methoxyphenylsulfanyl) -2-methyl-3-phenylpropionic acid (0.5 g, 1.65 mmol) and DMF (2 drops) in CH2C12 (100 ml) at 0 ° C, oxalyl chloride is added dropwise (1.0 g, 8 mmol). After addition, the reaction mixture was stirred at room temperature for 1 h. Simultaneously, in a separate flask, a mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) and triethylamine (5 ml, excess) was stirred in a mixture of THF: water (5: 1, 30 ml) at 0 ° C for 1 h. At the end of this hour, the reaction mixture of oxalyl chloride is concentrated and the pale yellow residue is dissolved in 10 ml of CH2C12 and slowly added to hydroxylamine at 0 ° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The resulting residue was extracted with chloroform and washed well with water. The resulting product was purified by silica gel column chromatography and eluted with ethyl acetate. No. Hydroxy-2- (4-methoxyphenylsulfanyl) -2-methyl-3-phenylpropionamide is isolated as a colorless solid. Mp 88 ° C; yield 300 mg, 57%; MS: 318 (M + H) ⁺ ;

Ή NMR (300 MHz, COC1 ₃ ): δ 1.32 (s, 3H), 3.07 (d, 1 = 11 Hz, 1H), 3.23 (d, 1 = 11 Hz, 1H),

3.79 (s, 3H); 6.83-7.36 (m, 9H).

Example 2. No. Hydroxy-2- (4-methoxyphenylsulfanyl) -2-phenylacetamide.

2- (4-Methoxyphenylsulfanyl) -2-phenylacetic acid ethyl ester was prepared according to the general method as described in Example 1. Starting from ethyl α-bromophenyl acetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol (4 , 4 g, 31.4 mmol) secrete 8.5 g of this product as a pale yellow oil. Yield 90%; MS:

303.1 (M + H) ⁺ .

2- (4-Methoxyphenylsulfanyl) -2-phenylacetic acid is prepared from 2- (4-methoxyphenylsulfanyl) -2-phenylacetic acid ethyl ester (3.0 g, 10 mmol) dissolved in methanol (50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was treated as in Example 1. Yield 1.9 g, 70%. Low melting solid. MS: 273 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) phenylacetic acid (1.05 g, 3.83 mmol) and following the procedure described in Example 1, 154 mg of N-hydroxy-2- (4-methoxyphenylsulfanyl) -2 phenylacetamide was isolated as a colorless solid, mp 155 ° C; yield 14%; MS: 290 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO _6th ): δ

3.72 (s, 3H); 4.68 (s, 1H); 6.86-7.44 (m, 9H).

Example 3. Hydroxyamide 2- (4-methoxyphenylsulfanyl) -2,5-dimethylhex-4-enoic acid.

2- (4-Methoxyphenylsulfanyl) -2,5-dimethylhex-4-enoic acid ethyl ester was prepared according to the procedure for EXAMPLE 1, second paragraph. Starting from ethyl ester of (4-methoxyphenylsulfanyl) propionic acid (3.5 g, 14.3 mmol) and isoprenyl bromide (2.25 g, 15 mmol), 2.2 g of product are isolated in the form of an oil. Yield 50%; MS: 310 (M + H) ⁺ .

2- (4-Methoxyphenylsulfanyl) -2,5-dimethylhex-4-enoic acid was prepared from 2- (4-methoxyphenylsulfanyl) 2,5-dimethylhex-4-enoic acid ethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml), and 10N. No. 1OH (20 ml). The reaction mixture is treated as described in Example 1. Yield 1.9 g, 99% low melting point solid. MS: 280 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) 2,5-dimethylhex-4-enoic acid (1.67 g, 5.8 mmol) and following the procedure described in Example 1, 2- (4-methoxyphenylsulfanyl) hydroxyamide, 5-dimethylhex-4-enoic acid is isolated in the form of a colorless solid, so pl. 89 ° C; yield 94%; MS: 296 (M + H) ⁺ .

^! H NMR (300 MHz, SIS1 ₃ ): δ 1.34 (s, 3H),

1.61 (s, 3H), 1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 (t, 1 = 7, 5 Hz, 1H), 6.86 (d, 1 = 12.4 Hz, 2H), 7.35 (d, 1 = 12.4 Hz, 2H).

Example 4. N-Hydroxy-2- (4-methoxyphenylsulfanyl) -3-methylbutyramide.

2- (4-Methoxyphenylsulfanyl) -3-methylbutyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methylbutanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of product are isolated. Yield 99%; light yellow oil; MS: 271 (M + H) ⁺ .

2- (4-Methoxyphenylsulfanyl) -3-methylbutyric acid is prepared from 2- (4-methoxyphenylsulfanyl) -3methylbutyric acid ethyl ester (5.8 g, 21.6 mmol) dissolved in methanol (50 ml) and 10N. No. 1OH (30 ml). The resulting reaction mixture was treated as described in example 1. Yield 5.0 g, 99%. Low melting solid. MS: 242 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) 3-methylbutyric acid (4.39 g, 18.3 mmol) and following the procedure described in Example 1, идhydroxy-2- (4-methoxyphenylsulfanyl) -3methylbutyramide in an amount of 1.5 g isolated in the form of a colorless solid, so pl. 119 ° C; yield 33%; MS: 256 (M + H) ⁺ .

^! H NMR (300 MHz, DMSO- ₆ ): δ 0.90-1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d, 1 = 8.8 Hz, 1H),

3.75 (s, 3H), 6.88 (d, 1 = 15 Hz, 2H), 7.35 (d, 1 = 15 Hz, 2H).

Example 5. N-Hydroxy-2- (4-methoxybenzenesulfinyl) -2-methyl-3-phenylpropionamide.

N-Hydroxy-2- (4-methoxybenzenesulfanyl) -2-methyl-3-phenylpropionamide (400 mg, 1.26 mmol) (obtained in Example 1) was dissolved in methanol (100 ml) and 30% H ₂ O ₂ ( 10 ml). The reaction mixture was stirred for 48 hours at room temperature, at the end of this time it was cooled to 0 ° C and quenched with saturated solution No. ₂ 8O ₃ (20 ml). The reaction mixture becomes cloudy. It was stirred for 4 hours, after which it was concentrated in a room temperature water bath, diluted with water, extracted with CHC13 and washed with H2O. The organic layer was dried over Md8O _4, filtered and concentrated. The title compound was isolated by silica gel column chromatography, eluting with 75% ethyl acetate: hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M + H) ⁺ ; ^! H NMR (300 MHz, SIS1 ₃ ): δ 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H) .

Example 6. Hydroxyamide 2- (4-methoxybenzenesulfinyl) -2,5-dimethylhex-4-enoic acid.

Starting from 2- (4-methoxybenzenesulfanyl) -2,5-dimethylhex-4-enoic acid hydroxyamide (900 mg, 3.0 mmol) (obtained in Example 3) and following the procedure described in Example 5, hydroxyamide 2- (4 -methoxybenzenesulfinyl) 2,5-dimethylhex-4-enoic acid is isolated as a colorless solid. Yield: 104 mg (10%); t. pl. 108 ° C; MS: 312 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO-e): δ 0.88 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 2.27-2.80 (m, 2H ), 5.02 (t, 1 =

7.5 Hz, 1H), 7.09 (d, 1 = 9 Hz, 2H), 7.39 (d, 1 = 9 Hz, 2H).

Example 7. N-Hydroxy-2- (4-methoxybenzenesulfinyl) -3-methylbutyramide.

Starting from H-hydroxy-2- (4-methoxybenzenesulfanyl) -3-methylbutyramide (1 g, 3.9 mmol) obtained in Example 4, and following the procedure of Example 5, Y-hydroxy-2- (4-methoxybenzenesulfinyl) - 3-methylbutyramide is isolated as a colorless solid. Yield: 420 mg (40%); so pl. 163 ° C; MS: 272 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.89-1.12 (m, 6H), 1.63-1.74 (m, 1H), 3.13 (d, ί = 7 Hz, 1H), 3.83 (s, 3H), 6.94-7.65 (m, 4H).

Example 8. Y-Hydroxy-2- (4-methoxybenzenesulfinyl) -2-phenylacetamide.

Starting from Y-hydroxy-2- (4-methoxyphenylsulfanyl) -2-phenylacetamide (240 mg, 0.83 mmol) obtained in Example 2, and following the procedure described in Example 5, Y-hydroxy-2 (4-methoxybenzenesulfinyl ) -2-phenylacetamide is isolated as a colorless solid. Yield: 100 mg (40%); so pl. 135 ° C; MS: 304 (M + H) ⁺ . Ή NMR (300 MHz, DMSO-b ₆ ): δ 3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H).

Example 9. Y-Hydroxy-2- (4-methoxybenzenesulfonyl) -3-phenylpropionamide.

To a stirred solution of 4 methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous K2CO3 (10 g, excess) in dry acetone (100 ml) in a round-bottom flask was added α bromoacetate (3.3 g, 20 mmol) and the reaction mixture was heated under reflux reflux for 8 hours with good stirring. At the end of this time, the reaction mixture was allowed to cool and the potassium salt was separated by filtration and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O and 0.5N. ΝαΟΗ solution. The organic layer is then washed well with water, dried over MgSO ₄ , filtered and concentrated. (4-Methoxyphenylsulfanyl) acetic acid ethyl ester was isolated as a pale yellow oil. Yield 4.4 g (100%); MS: 227 (M + H) ⁺ .

To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 g, 40 mmol) in methylene chloride (100 ml) at 0 ° C, ethyl 2- (4-methoxyphenylsulfanyl) acetic acid (4.4 g, 20 mmol) in CH is slowly added ₂ C1 ₂ (15 ml). The turbid reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexanes (300 ml) and stirred for 15 minutes. The solid is filtered off and the Να ₂ 8Ο ₃ solution is added to the organic layer, which is stirred for at least 3 hours before the mixture is extracted with CHC13 and washed with H ₂ O. The organic layer is dried over MgSO ₄ , filtered and concentrate and give off the colorless ethyl ester of (4-methoxyphenylsulfonyl) acetic acid as an oil. Yield: 100%; MS: 259.1 (M + H) ⁺ .

To a stirred solution of ethyl ester (4-methoxybenzenesulfonyl) acetic acid (2.5 g, 10 mmol), benzyl bromide (1.8 g, mmol) and 18-crown-6 (500 mg) in acetone (250 ml) add K2CO3 ( 10 g, excess) and the mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed well with water, dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2- (4methoxybenzenesulfonyl) -3-phenylpropionic acid ethyl ester, is isolated as a low-melting solid.

Yield: 3.0 g, 86%; low melting solid; MS: 349 (M + H) ⁺ .

To a stirred solution of 2- (4-methoxybenzenesulfonyl) -3-phenylpropionic acid ethyl ester (348 mg, 1 mmol) in methanol (25 ml) was added 10N. ΝαΟΗ (10 ml). The reaction mixture was stirred at room temperature for 48 hours. At the end, the reaction mixture was concentrated and carefully neutralized with dilute HCl. The resulting residue was extracted with chloroform, washed well with water, dried and concentrated. The resulting product was purified by silica gel column chromatography, eluting with ethyl acetate: methanol (95: 5), to give 2- (4-methoxybenzenesulfonyl) -3-phenylpropionic acid as a colorless oil. Yield: 250 mg, 89%; MS: 321 (M + H) ⁺ .

Starting from (4-methoxybenzenesulfonyl) -3-phenylpropionic acid (200 mg, 0.625 mmol) and following the procedure described in Example 1, Y-hydroxy-2- (4-methoxybenzenesulfonyl) -3-phenylpropionamide was isolated as a brown solid. Yield: 71%; t. pl. 180 ° C; MS: 336 (M + H) ⁺ . Ή NMR (300 MHz, SES1 ₃ ): δ 3.2 (m, 1H), 3.8 (s, 3H), 4.0-4.2 (m, 2H), 7.0-8.0 ( m, 9H).

Example 10. Hydroxyamide 2- (4-methoxybenzenesulfonyl) hexanoic acid.

2- (4-Methoxyphenylsulfanyl) hexanoic acid ethyl ester was prepared according to the general method described in Example 1. Starting from ethyl 2-bromohexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of product are isolated. Yield 98%; light yellow oil; MS: 283 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) hexanoic acid ethyl ester (2.8 g, 10 mmol) and following the procedure described in Example 9, 9.3 g of 2- (4-methoxybenzenesulfonyl) hexanoic acid ethyl ester are isolated as a colorless solid . Yield: 95%; so pl. 62 ° C: MS: 314 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) hexanoic acid ethyl ester (2 g, 6.3 mmol), 1.5 g (83%) of 2- (4-methoxybenzenesulfonyl) hexanoic acid was isolated as a colorless solid, according to procedure 27, described in example 9. So pl. 116 ° C; MS 287 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) hexanoic acid (1.0 g, 3.1 mmol) and following the procedure described in Example 1, 700 mg of 2- (4-methoxybenzenesulfonyl) hexanoic acid hydroxyamide was isolated as a colorless solid. Yield: 60%; so pl. 130 ° C; MS: 302 (M + H) ⁺ , Ή NMR (300 MHz, SIS1 ₃ ): δ 0.786 (t, I = 7.2 Hz, 3H), 1.1-1.3 (m, 4H), 1, 6-1.8 (m, 2H), 3.7 (m, 1H), 3.9 (s, 3H), 7.2 (d, I = 11 Hz, 2H), 7.8 (d, I = 11 Hz, 2H), 9.3 (s, 1H), 10.9 (s, 1H).

Example 11. Hydroxyamide 2- (4-methoxybenzenesulfonyl) tetradecanoic acid.

2- (4-Methoxyphenylsulfanyl) tetradecanoic acid ethyl ester was prepared according to the general method described in Example 1. Starting from the corresponding ethyl 2-bromo myristate (5.0 g, 14.9 mmol) and 4 methoxythiophenol (1.9 g, 13, 4 mmol), 5.0 g of product are isolated. Yield 98%; light yellow oil; MS: 393 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) tetradecanoic acid ethyl ester (3.9 g, 10 mmol) and following the procedure described in Example 9, 3.2 g of 2- (4-methoxybenzenesulfonyl) tetradecanoic acid ethyl ester are isolated in the form of a colorless solid matter. Yield: 76%; oil; MS: 425 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) tetradecanoic acid ethyl ester (2.5 g, 5.9 mmol) 2.0 g (85%) of 2- (4-methoxybenzenesulfonyl) tetradecanoic acid was isolated as a colorless solid, following the procedure described in example 9. So pl. 82 ° C, MS 397 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) tetradecanoic acid (1.14 g, 2.9 mmol) and following the procedure described in Example 1, 670 mg of 2- (4-methoxybenzenesulfonyl) tetradecanoic acid hydroxyamide was isolated as an off-white solid. Yield: 57%; so pl. 114 ° C; MS: 414 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.85 (t, I = 7 Hz, 3H), 1.16-1.27 (m, 20 N), 1.66 (m, 2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, I = 15 Hz, 2H), 7.73 (d, I = 15 Hz, 2H).

Example 12. I-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3-phenylpropionamide.

To a stirred solution of 2- (4-methoxybenzenesulfonyl) -3-phenylpropionic acid ethyl ester (1.0 g, 3 mmol) (Example 9), methyl iodide (1 ml, excess) and 18-crown-6 (500 mg) in acetone (250 ml) K2CO3 (10 g, excess) was added and the reaction mixture was refluxed for 24 hours. At the end of this time, the reaction mixture was filtered and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed well with water, dried over anhydrous

MdZO ₄ , filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexanes, to give 2 (4-methoxybenzenesulfonyl) -2-methyl-3-phenylpropionic acid ethyl ester as a colorless oil. Yield: 1.0 g, 98%; MS: 349 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3-phenylpropionic acid ethyl ester (900 mg, 2.7 mmol), 850 mg (quantitative yield) of 2- (4-methoxybenzenesulfonyl) -2-methyl-3- phenylpropionic acid is isolated according to the procedure described in example 9. Colorless oil. MS: 335 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3-phenylpropionic acid and following the procedure described in Example 1, 450 mg of hydroxy-2- (4-methoxybenzenesulfonyl) -2methyl-3-phenylpropionamide was isolated as a brown solid. Yield: 48%; t. pl. 58 ° C; MS: 350 (M + H) ⁺ ; ¹ H NMR (300 MHz, SIS1 ₃ ): δ 1.4 (s, 3H), 3.1 (d, I = 9 Hz, 1H), 3.6 (d, I = 9 Hz, 1H), 3 9 (s, 3H); 6.8-7.8 (m, 9H).

Example 13. 2- (4-Methoxybenzenesulfonyl) -2,5-dimethylhex-4-enoic acid hydroxyamide.

Starting from 2- (4-methoxyphenylsulfanyl) propionic acid ethyl ester (Example 1) (12 g, 50 mmol) and following the procedure described in Example 9, 12 g of 2- (4-methoxybenzenesulfonyl) propionic acid was isolated as a semi-solid. Yield: 100%; oil; MS: 256.1 (M + H) ⁺ .

According to the procedure described in Example 12, 2- (4-methoxyphenylsulfonyl) 2,5-dimethylhex-4-enoic acid ethyl ester was prepared from (1 g, 3.6 mmol) of 2- (4methoxybenzenesulfonyl) propionic acid ethyl ester and isoprenyl bromide (1.0 g, 6 mmol). Yield 1.0 g, 81%; colorless oil; MS: 341 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2,5-dimethylhex-4-enoic acid ethyl ester (900 mg, 2.6 mmol), 800 mg (96%) of 2- (4-methoxybenzenesulfonyl) -2,5-dimethylhex- 4enoic acid is isolated as a semi-solid according to the procedure described in example 9. MS: 313 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2,5-dimethylhex-4-enoic acid (1.0 g, 3.2 mmol) and following the procedure described in Example 1, 700 mg of 2- (4-methoxybenzenesulfonyl) - 2,5-dimethylhex-4-enoic acid is isolated as a low-melting solid. Yield: 67%; MS: 328 (M + H) ⁺ ; Ή NMR (300 MHz, COC1 ₃ ): δ 1.3 (s, 3H),

1.5 (d, I = 6.2 Hz, 6H), 2.5-3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, I = 11 Hz, 2H ), 7.8 (d, I = 11 Hz, 2H).

Example 14. 3- (Biphenyl-4-yl) -№hydroxy2- (4-methoxybenzenesulfonyl) -2-methylpropionamide.

According to the procedure described in example 12, 3- (biphenyl-4-yl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester was prepared from (2.7 g, 10 mmol) ethyl 2- ( 4-methoxybenzenesulfonyl) propionic acid and 4- (chloromethyl) diphenyl (2.5 g, 12 mmol). Yield 4.0 g, 91%; colorless oil; MS: 438 (M + H) ⁺ .

Starting from 3- (biphenyl-4yl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester (3 g, 6.8 mmol), 2.5 g (89%) 3- (biphenyl-4-yl ) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid is isolated as a colorless solid according to the procedure described in example 9. So pl. 161 ° C; MS: 411 (M + H) ⁺ .

Starting from 3- (biphenyl-4-yl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid (2.0 g, 4.8 mmol) and following the procedure described in Example 1, 1.2 g of 3- (biphenyl-4-yl) N-hydroxy-2- (4-methoxybenzenesulfonyl) -2 methylpropionamide is isolated as a colorless solid. Yield: 58%; so pl. 177 ° C; MS: 426 (M + H) ⁺ ; '11 NMR (300 MHz, GOST): δ 1.4 (s, 3H), 3.2 (d, 1 = 9 Hz, 1H), 3.7 (d, 1 = 9 Hz, 1H), 3, 9 (s, 3H), 7.0-7.8 (m, 13H), 9.7 (br s, 1H).

Example 15. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2,5,9-trimethyldec-4,8-dienoic acid.

According to the method described in example 12, ethyl 2- (4-methoxybenzenesulfonyl) -

2.5.9-trimethidec-4,8-dienoic acid is prepared based on (2.7 g, 10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and geranyl bromide (3.0 g, 13 mmol). Yield 4.0 g, 98%; colorless oil; MS: 409 (M + H) ⁺ .

Starting from ethyl 2- (4-methoxybenzenesulfonyl) -2,5,9-trimethyldec-4,8dienoic acid (3 g, 7.4 mmol) 2.8 g (96%) 2 (4-methoxybenzenesulfonyl) -2, 5,9-trimethyldec-4,8-dienoic acid is isolated as a colorless oil according to the procedure described in example 9. MS: 379 (M-H) ^- .

Based on 2- (4-methoxybenzenesulfonyl) -

2.5.9-trimethyldec-4,8-dienoic acid (2.0 g, 5.2 mmol) and following the procedure described in Example 1, 1.8 g of 2- (4-methoxybenzenesulfonyl) hydroxyamide -2.5.9 β-trimethyldec-4,8-dienoic acid is isolated as a colorless oil. Yield: 88%; MS: 396 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.4 (s, 3H), 1.6 (s, 3H), 1.65 (s, 3H), 1.7 (s, 3H), 2, 0-3.1 (m, 6H), 3.9 (s, 3H), 5.5 (m, 2H), 6.98 (d, 1 = 9.0 Hz, 1H), 7.7 (d , 1 = 9.0 Hz, 2H).

Example 16. 3-Cyclohexyl-Y-hydroxy-2 (4-methoxybenzenesulfonyl) -2-methylpropionamide.

According to the procedure described in example 12, 3-cyclohexyl-2- (4-methoxybenesulfonyl) -2-methylpropionic acid ethyl ester was prepared from (2.7 g, 10 mmol) of 2- (4-methoxybenzenesulfonyl) propionic ethyl ester acid and bromomethylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; yellow oil; MS: 369 (M + H) ⁺ .

Starting from 3-cyclohexyl 2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester (3 g, 8.1 mmol), 2.5 g (90%) of 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2 methylpropionic acid is isolated as colorless solid according to the method described in example 9. So pl. 116 ° C; MS: 341 (M + H) ⁺ .

Starting from 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid (2.0 g, 5.8 mmol) and following the procedure described in Example 1, 1.1 g of 3-cyclohexyl-Hydroxy-2- (4-Methoxybenzenesulfonyl) -2methylpropionamide is isolated as a colorless solid. Yield: 55%; so pl. 58 ° C; MS: 356 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.4 (s, 3H), 2.3-1.0 (m, 13H), 3.9 (s, 3H), 7.0 (d, 1 = 8.8 Hz, 2H), 7.69 (d, 1 = 9.0 Hz, 2H).

Example 17. Y-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionamide.

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid ethyl ester was prepared from (2.7 g, 10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 4- (2piperidin-1-yl-ethoxy) benzyl chloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; Brown oil; MS: 490 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionic acid ethyl ester (4.0 g, 7.9 mmol) 3.5 g (yield: 94%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionic acid was isolated as colorless crystals according to the procedure described in Example 9. mp. 106 ° C; MS:

462.5 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid (2.0 g, 4.2 mmol) and following the procedure described in Example 1 , 1 g of hydroxy-2- (4-methoxybenzenesulfonyl) -2methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionamide is isolated as a colorless solid. Yield: 1 g, 48%; t. pl. 98 ° C; MS: 477 (M + H) ⁺ ; '11 NMR (300 MHz, ATP1 ₃ ): δ

1.2 (s, 3H), 3.5-1.5 (m, 16H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (br s, 1H).

Example 18. Hydroxyamide of 2- [4- (2-azepan1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) propionic acid.

According to the procedure described in example 12, ethyl 2- [4- (2-azepan-1-yl-ethoxy) benzene] -2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester was prepared starting from (2.7 g, 10 mmol) 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester and 1- [2- (4-chloromethylphenoxy) ethyl] azepane (3.03 g, 10 mmol). Yield 4.5 g, 90%; brown oil; MS: 504 (M + H) ⁺ .

Starting from ethyl 2- [4- (2-azepan-

1- yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) propionic acid (4.0 g, 7.9 mmol) 3.5 g (94% yield) 2- [4- (2-azepan-1-yl- ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) propionic acid was isolated as a semi-solid according to the procedure described in Example 9. MS: 476 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) propionic acid (2.0 g, 4.2 mmol) and following the procedure described in Example 1, 1 g hydroxyamide

2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) propionic acid is isolated as a colorless solid. Yield: 1.8 g, 87%; t. pl. 68 ° C; MS: 491 (M + H) ⁺ ; Ή NMR (300 MHz, C1) C1 _; ): δ 1.23 (s, 3H), 3.5-1.7 (m, 18H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4-7.89 (m, 8H),

10.9 (br s, 1H).

Example 19. Hydroxyamide 2- [4- (2-azepan-

1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) pentanoic acid.

2- [4- (2-Azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) pentanoic acid ethyl ester was prepared according to the general method described in Example 12, starting from 2- (4-methoxybenzenesulfonyl) pentanoic ethyl ester acids (3.5 g, 11.7 mmol) and 1- [2- (4chloromethylphenoxy) ethyl] azepane (3.9 g, 12.8 mmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M + H) ⁺ .

2- [4- (2-Azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) pentanoic acid is prepared from 2- [4- (2azepan-1-yl-ethoxy) benzyl] -2- (4- methoxybenzenesulfonyl) pentanoic acid (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10 N ΝαΟΗ (15 ml). The resulting mixture was treated as described in example 1. Yield 830 mg (44%); brown solid; t. pl. 55 ° C; MS: 504.4 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) pentanoic acid (690 mg, 1.37 mmol) and following the procedure described in Example 1, 240 mg of hydroxyamide 2 - [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) pentanoic acid is isolated as a yellow solid. Yield: 34%; t. pl. 85 ° C; MS: 519.2 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.71 (t, 1 = 7.3 Hz, 3H), 0.78-1.77 (m, 16 N), 3.04-3.46 (m, 4H), 3.87 (s, 3H), 4.26 (m, 2H), 6.87 (d, 1 = 8.7 Hz, 2H), 7.14 (m, 4H), 7 71 (d, 1 = 9 Hz, 2H), 9.07 (s, 1H), 10 (s, 1H).

Example 20. No. Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-X # diisopropylaminoethoxy) phenyl] propionamide.

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-X # diisopropylaminoethoxy) phenyl] propionic acid ethyl ester was prepared from (5.4 g, 20 mmol) ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 4- (2-X # diisopropylaminoethoxy) benzyl chloride (6.1 g, 20 mmol). Yield 8.9 g, 88%; yellow oil; MS: 506.5 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-X # diisopropylaminoethoxy) phenyl] propionic acid ethyl ester (4.0 g, 7.9 mmol) 3.5 g (yield: 92%) 2- (4methoxybenzenesulfonyl) -2-methyl-3- [4- (2-X # diisopropylaminoethoxy) phenyl] propionic acid was isolated as colorless crystals according to the procedure described in Example 9. mp. 68 ° C; MS: 478.6 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-Х№diisopropylaminoethoxy) phenyl] propionic acid (2.0 g, 4.1 mmol) and following the procedure described in Example 1, 1 g No. hydroxy-2- (4-methoxybenzenesulfonyl) -2methyl-3- [4- (2-X # diisopropylaminoethoxy) phenyl] propionamide is isolated as a colorless solid. Yield: 1 g, 49%; so pl. 98 ° C (salt with HC1); MS: 493 (M + H) ⁺ ; Ή NMR (300 MHz, C1) C1 _; ): δ 1.2 (s, 3H), 1.3 (d, 6H), 1.4 (d, 6H), 3.5-1.5 (m, 6H), 3.9 (s, 3H) ), 4.4 (s, 2H),

6.5-7.8 (m, 8H), 10.8 (br s, 1H).

Example 21. No. Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-X # diethylaminoethoxy) phenyl] propionamide.

According to the procedure described in example 12, ethyl 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-X # diethylaminoethoxy) phenyl] propionic acid is obtained from (5.4 g, 20 mmol) ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 4- (2U # diethylaminoethoxy) benzyl chloride (5.5 g, 20 mmol). Yield 8.5 g, 89%; brown oil; MS: 478.6 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-X-diethylaminoethoxy) phenyl] propionic acid ethyl ester (3.5 g, 7.7 mmol) 3.0 g (yield: 85%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-Х№ diethylaminoethoxy) phenyl] propionic acid was isolated as colorless crystals according to the procedure described in Example 9. mp. 96-98 ° C; MS: 450.5 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-Х№ diethylaminoethoxy) phenyl] propionic acid (2.0 g, 4.4 mmol) and following the procedure described in Example 1, 1 g of hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-X-diethylaminoethoxy) phenyl] propionamide is isolated as a colorless solid. Yield: 1 g, 48%; t. pl. 56-59 ° C (salt with HC1); MS: 465.5 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.1 (t, 6H), 1.3 (s, 3H), 3.2-3.9 (m, 8H), 3.9 (s, 3H) ), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (br s, 1H).

Example 22. X-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-ethoxy) phenyl] propionamide.

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid ethyl ester was prepared from (5.2 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 3- (2piperidin-1-yl-ethoxy) benzyl chloride (6.0 g, 20 mmol). Yield 8.2 g, 83%; brown oil; MS: 490 (M + H) ⁺ .

Starting from ethyl 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-ethoxy) phenyl] propionic acid (6.0 g, 12.2 mmol) 4.9 g (yield: 79%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) phenylpropionic acid was isolated as colorless crystals according to the procedure described in Example 9. mp. 112 ° C; MS: 462.5 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [3- (2-piperidin-1-ethoxy) phenyl] propionic acid (3.0 g, 6.5 mmol) and following the procedure described in Example 1 , 1.8 g of X-hydroxy-2- (4-methoxybenzenesulfonyl) -2methyl-3- [3- (2-piperidin-1-yl-ethoxy) phenyl] propionamide is isolated as a colorless solid. Yield: 1.8 g, 58%; t. pl. 74 ° C; MS: 477 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.25 (s, 3H), 1.6-1.8 (m, 6H), 2.5-3.7 (m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7-7.8 (m, 8H), 10.8 (br s, 1H).

Example 23. 3- (4- {3- [4- (3-Chlorophenyl) piperazin-1-yl] propoxy} phenyl) -X-hydroxy-2 (4-m-ethoxybenzenesulfonyl) -2-methylpropionamide.

According to the procedure described in example 12, 3- (4- {3- [4- (3-chlorophenyl) piperazin-1-yl] propoxy} phenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester was obtained starting from (2.72 g, 10 mmol) of 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester and 1- [2- (4-chloromethylphenoxy) ethyl] -4- (3-chlorophenyl) piperazine (4.2 g 11 mmol). Yield 5.5 g, 89%; brown oil; MS: 616 (M + H) ⁺ .

Starting from 3- (4- {3- [4- (3chlorophenyl) piperazin-1-yl] propoxy} phenyl) -2 (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester (4.0 g, 6.5 mmol ) 3.0 g (yield: 78%) 3 - (4- {3 - [4- (3-chlorophenyl) piperazin-1-yl] propoxy} phenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid isolated in the form of colorless crystals according to the method described in example 9. So pl. 196 ° C; MS: 588.1 (M + H) ⁺ .

Starting from 3- (4- {3- [4- (3-chlorophenyl) piperazin-1-yl] propoxy} phenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid (3.0 g, 5.1 mmol) and following the procedure described in Example 1, 1.8 g of 3- (4- {3- [4- (3-chlorophenyl) piperazin-1-yl] propoxy} phenyl) -X-hydroxy2- (4-methoxybenzenesulfonyl ) -2-methylpropionamide is isolated as a pale yellow solid. Yield: 1.8 g, 55%; t. pl. 122 ° C (salt with HC1); MS: 640 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.2 (s, 3H), 3.4-1.5 (m, 14 N), 3.9 (s, 3H), 4.5 (m, 2H), 6.5-8.2 (m, 12H), 10.3 (br s, 1H).

Example 24. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4ylethoxy) benzyl] hex-4-enoic acid.

To a stirred solution of ethyl ether (4-methoxybenzenesulfonyl) acetic acid (5.16 g, 20 mmol), isoprenyl bromide (3.0 g, 20 mmol) and 18-crown-6 (500 mg) in acetone (250 ml), add ₂ CO ₃ (10 g, excess) and the mixture was refluxed for 24 hours. At the end of this time, the reaction mixture was filtered and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed well with water, dried over anhydrous MgO ₄ , filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2- (4-methoxybenzenesulfonyl) -5-methylhex-4-enoic acid ethyl ester, is isolated as a colorless oil. Yield: 3.0 g, 93%.

According to the method described in example 12, 2- (4-methoxybenzenesulfonyl) 5-methyl-2- [4- (2-morpholin-4-ylethoxy) benzyl] hex-4-enoic acid ethyl ester is prepared from (3, 26 g, 10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) -5-methylhex-4-enoic acid and 4- (2-morpholin-1-yl-ethoxy) benzyl chloride (3.0 g, 11 mmol). Yield 4.5 g, 82%; brown oil; MS: 546 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-ethoxy) benzyl] hex-4-enoic acid ethyl ester (3.0 g, 5.5 mmol) 2.1 g (yield: 75%) 2- (4-methoxybenzenesulfonyl) -5-methyl-2- [4- (2-morpholine-4-ethoxy) benzyl] hex-4-enoic acid is isolated as a semi-solid according to the procedure described in the example 9. MS: 518.6 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 5-methyl-2- [4- (2-morpholin-4-ylethoxy) benzyl] hex-4-enoic acid (1.0 g 1.9 mmol) and following the procedure described in Example 1, 450 mg of 2- (4-methoxybenzenesulfonyl) 5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] hex-4-enoic acid hydroxyamide was isolated as a pale yellow solid. Yield: 450 mg, 45%; so pl. 92 ° C (salt with HC1); MS: 570 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.3 (d, 3H), 1.65 (d,

2H), 3.5-1.8 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m, 1H), 6.5-7.9 (m, 8H), 11.5 (br s, 1H).

Example 25. Y-Hydroxy-2- (4-ethoxybenzenesulfonyl) -2-methyl-3- [4- (2-Y, Y-diethylaminoethoxy) phenyl] propionamide.

To a stirred solution of 4-hydroxythiophenol (12.6 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in chloroform (400 ml) was added 2-bromoethyl propionate (18.2 g, 100 mmol) dropwise. The reaction mixture was refluxed for 1 h and cooled to room temperature. The reaction mixture was washed with water, dried and concentrated. 2- (4-Hydroxyphenylsulfanyl) propionic acid ethyl ester is isolated as a colorless oil. Yield: 22.0 g, 99%; MS: 227 (M + H) ⁺ .

Ethyl iodide (20 ml, excess) was added to a stirred solution of ethyl 2- (4-hydroxyphenylsulfanyl) propionic acid (11.3 g, 50 mmol) and K2CO3 (50 g, excess) in acetone (300 ml) and refluxed for 8 hours. At the end of this time, the reaction mixture was filtered and concentrated. The resulting residue was extracted with chloroform and washed well with water. It is dried and concentrated. The product, 2- (4-ethoxyphenylsulfanyl) propionic acid ethyl ester, is isolated as a colorless oil. Yield: 12.0 g, 98%; MS: 255 (M + H) ⁺ .

2- (4-Ethoxyphenylsulfanyl) propionic acid ethyl ester is converted to 2- (4-ethoxyphenylsulfonyl) propionic acid ethyl ester according to the procedure described in Example 9, paragraph 2.

According to the procedure described in example 12, 2- (4-ethoxybenzenesulfonyl) -2methyl-3- [4- (2-OH, Y-diethylaminoethoxy) phenyl] propionic acid ethyl ester was prepared from (3.5 g, 12, 2 mmol) of 2- (4-ethoxybenzenesulfonyl) propionic acid ethyl ester and 4- (2M, M-diethylaminoethoxy) benzyl chloride (3.5 g, 12.2 mmol). Yield 4.8 g, 80%; brown oil; MS: 492.6 (M + H) ⁺ .

Starting from 2- (4-ethoxybenzenesulfonyl) -2-methyl-3- [4- (2-U, Y-diethylaminoethoxy) phenyl] propionic acid ethyl ester (4.0 g, 8.1 mmol) 3.2 g ( yield: 80%) 2- (4-ethoxybenzenesulfonyl) -2-methyl-3- [4- (2-N, Y-diethylaminoethoxy) phenyl] propionic acid was isolated as a colorless semi-solid according to the procedure described in Example 9. MS : 464.5 (M + H) ⁺ .

Starting from 2- (4-ethoxybenzenesulfonyl) -2methyl-3- [4- (2-N, Y-diethylaminoethoxy) phenyl] propionic acid (2.0 g, 4.3 mmol) and following the procedure described in Example 1, 1.2 g of 2 (4-ethoxybenzenesulfonyl) -2-methyl-3- [4- (2HH-diethylaminoethoxy) phenyl | propionamide is isolated as a colorless low-melting solid. Yield: 1.2 g, 57%; (salt with HC1); MS: 478.5 (M + H) ⁺ ; '11 NMR (300 MHz,

SES1 ₃ ): δ 0.9 (t, 3H), 1.1 (t, 6H), 1.3 (s, 3H), 3.23.9 (m, 8H), 3.9 (s, 3H) ), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (br s, 1H).

Example 26. Hydroxyamide (4E) -2- (4methoxybenzenesulfonyl) -5,9-dimethyl-2- [4- (2morpholin-4-ylethoxy) benzyl] deca-4,8-dienoic acid.

To a stirred solution of ethyl ether (4-methoxybenzenesulfonyl) acetic acid (5.16 g, 20 mmol), geranyl bromide (4.2 g, 20 mmol) and 18-crown-6 (500 mg) in acetone (250 ml) add K2CO3 (10 g, excess), and the mixture was refluxed for 24 hours. At the end of this time, the reaction mixture was filtered and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed well with water, dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. Product, ethyl 2 (4-methoxybenzenesulfonyl) -5,9-dimethyldec-

4.8-dienoic acid, isolated as a colorless oil. Yield: 7.0 g, 89%.

According to the method described in example 12, ethyl 2- (4-methoxybenzenesulfonyl) -

5.9-dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] deca-4,8-dienoic acid is prepared from 2- (4-methoxybenzenesulfonyl) ethyl ester -5,9-dimethyldec-4,8-dienoic acid; and 4- (2-morpholin-1-yl-ethoxy) benzyl chloride (800 mg, 2.5 mmol). Yield 1.2 g, 76%; brown oil; MS: 614 (M + H) ⁺ .

Starting from 2- (4-ethoxybenzenesulfonyl) -5,5-dimethyl-2- [4- (2-morpholin-4-ylethoxy) benzyl] deca-4,8-dienoic acid ethyl ester (2.0 g, 3, 2 mmol) 1.5 g (yield: 80%) 2- (4methoxybenzenesulfonyl) -5,9-dimethyl-2- [4- (2morpholin-4-ylethoxy) benzyl] deca-4,8-dienoic acid was isolated as semi-solid substance according to the method described in example 9. MS:

586.6 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 5,9-dimethyl-2- [4- (2-morpholin-4-ylethoxy) benzyl] deca-4,8-dienoic acid (1.0 g, 1.7 mmol) and following the procedure described in Example 1, 550 mg of hydroxyamide (4E) -2- (4-methoxybenzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-ylethoxy) benzyl] deca-4, 8-dienoic acid is isolated as a pale yellow solid. Yield: 550 mg, 53%; t. pl. 61 ° C (salt with HC1); MS: 638 (M + H) ⁺ .

Example 27. Hydroxyamide 2- [4- (2-diethylaminoethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) hexanoic acid.

2- [4- (2-Diethylaminoethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) hexanoic acid ethyl ester was prepared according to the general method described in Example 12, starting from 2- (4-methoxybenzenesulfonyl) hexanoic acid ethyl ester (4 g 12.7 mmol) and [2- (4chloromethylphenoxy) ethyl] diethylamine (3.38 g, 14 mmol). Yield 8.21 g of crude product (100%); brown oil; MS: 520.4 (M + H) ⁺ .

2- [4- (2-Diethylaminoethoxy) benzyl] -2- (4methoxybenzenesulfonyl) hexanoic acid is prepared from 2- [4- (2 diethylaminoethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) hexanoic acid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10N. No. 1OH (30 ml). The resulting mixture was treated as described in example 1. Yield 3.88 g of crude product (51%); brown oil; MS: 492 (M + H) ⁺ .

Starting from 2- [4- (2-diethylaminoethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) hexanoic acid (3.88 g, 7.89 mmol) and following the procedure described in Example 1, 800 mg of hydroxyamide 2- [ 4- (2-diethylaminoethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) hexanoic acid was isolated as a yellow powder. Yield 20%; t. pl. 67 ° C; MS: 507.4 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.75 (t, 1 = 7.1 Hz, 3H), 1.05 (m, 2 N), 1.23 (t, 1 = 7.2 Hz, 6H), 1.37-1.91 (m, 2H), 3.13 (m, 4H), 3.38-3.51 (m, 4H), 3.87 (s, 3H), 4 , 3 (t, 1 =

4.8 Hz, 2H), 6.88 (d, 1 = 8.7 Hz, 2H), 7.15 (m, 4H),

7.7 (d, 1 = 9 Hz, 2H), 9.07 (s, 1H), 10.1 (s, 1H).

Example 28. N-Hydroxy-2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionamide.

According to the procedure described in example 12, 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ylethoxy) phenyl] propionic acid ethyl ester was prepared starting from (3.1 g, 10 mmol) of 2- (4-n-butoxybenzenesulfonyl) propionic acid ethyl ester (obtained from 2- (4-hydroxyphenylsulfanyl) propionic acid ethyl ester and nbutyl bromide according to the procedure described in Example 27) and 4- (2-piperidin-1- ilethoxy) benzyl chloride (3.0 g, 10.1 mmol). Yield 4.5 g, 84%; brown oil; MS: 532.7 (M + H) ⁺ .

Starting from 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionic acid ethyl ester (5.0 g, 9.4 mmol) 4.2 g ( yield: 88%) 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionic acid was isolated as a colorless solid according to the procedure described in Example 9. MS : 504.6 (M + H) ⁺ .

Starting from 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid (3.0 g, 5.9 mmol) and following the procedure described in Example 1, 1.3 g of 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3 [4- (2-piperidin-1-yl-ethoxy) phenyl] propionamide was isolated as a colorless solid. Mp 65 ° C. Yield: 1.3 g, 42% (salt with HC1); MS: 478.5 (M + H) ⁺ ; ¹ H NMR (300 MHz, SIS1 ₃ ): δ 0.9 (t, 3H), 1.2 (s, 3H), 1.3-1.9 (m, 10H),

2.8-4.5 (m, 12 N), 6.8-7.8 (m, 8H), 10.8 (br s, 1H).

Example 29. N-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylaminoethoxy) phenyl] propionamide.

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [3- (2-N, N-diethylaminoethoxy) phenyl] propionic acid ethyl ester was prepared from (5.0 g, 18 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 3- (2N, N-diethylaminoethoxy) benzyl chloride (4.9 g, 18 mmol). Yield 8.1 g, 93%; brown oil; MS: 478.1 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylaminoethoxy) phenyl] propionic acid ethyl ester (8.1 g, 16.9 mmol) 6.7 g ( yield: 88%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylaminoethoxy) phenyl] propionic acid was isolated as a colorless semi-solid according to the procedure described in Example 9. T .pl. 78-81 ° C; MS: 450.1 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [3- (2-N, N-diethylaminoethoxy) phenyl] propionic acid (6.7 g, 15 mmol) and following the procedure described in Example 1, 1 5 g of hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethylaminoethoxy) phenyl] propionamide are isolated as a colorless low-melting solid. Yield: 1.5 g, 21% (salt with HC1); MS: 450.5 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): 1.21 (t, 6H), 1.26 (s, 3H), 3.18-3.24 (m, 2H), 3.38 (m, 4H) ), 3.43-3.46 (m, 2H),

3.80 (s, 3H), 4.30 (s, 2H), 6.76-6.78 (d, 2H), 6.847.2 (m, 6H), 10.3 (br s, 1H) .

Example 30. N-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-ethoxy) phenyl] propionamide.

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) phenyl] propionic acid ethyl ester was prepared from (5.2 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 3 (2-morpholin-1-yl-ethoxy) benzyl chloride (6.0 g, 20 mmol). Yield 9.1 g, 93%; brown oil; MS: 492 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-morpholine-1-ethoxy) phenyl] propionic acid ethyl ester (10.0 g, 20.3 mmol), 8.0 g (yield : 86%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) phenyl] propionic acid was isolated as colorless crystals according to the procedure described in Example 9. MS: 464 5 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) phenyl] propionic acid (4.55 g, 9.8 mmol) and following the procedure described in Example 1 440 mg

N-hydroxy-2- (4-methoxybenzenesulfonyl) -2methyl-3- [3- (2-morpholin-1-yl-ethoxy) phenyl] propionamide is isolated as a colorless solid. Yield: 440 mg, 9%; t. pl. 63 ° C; MS: 479.5 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-yb): 1.26 (s, 3H), 3.18-3.8 (m, 12H), 3.9 (s, 3H), 4.4 (m, 2H) ), 6.7-8.8 (m, 8H), 10.8 (br s, 1H).

Example 31. Hydroxyamide 6- (1,3-dioxo -

1.3-dihydroisoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methylhexanoic acid.

According to the procedure described in example 9, 6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methylhexanoic acid ethyl ester was prepared starting from (5.0 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) acetic acid and 4phthalimidobromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; colorless oil; MS: 474 (M + H) ⁺ .

Starting from 6- (1,3-dioxo-

1.3- dihydro-isoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methylhexanoic acid (8.4 g, 17.7 mmol), 6.95 g (88%) 6- (1,3- dioxo-1,3-dihydroisoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methylhexanoic acid was isolated as a colorless oil according to the procedure described in Example 9. MS: 446 (M-H) ^- .

Starting from 6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2 methylhexanoic acid (4.9 g, 11 mmol) and following the procedure described in example 1, 3.1 g of 6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methylhexanoic acid hydroxyamide was isolated as a light brown solid. Yield: 46%; so pl. 146-148 ° C; MS: 461.2 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO- ₆ ): 1.55 (s, 3H), 1.61-

3.77 (m, 8H), 3.82 (s, 3H), 6.92-8.21 (m, 8H), 10.70 (br s, 1H), 11.20 (br s, 1H).

Example 32. 3- [4- (2-Diethylaminoethoxy) phenyl] -2- (4-furan-2-ylbenzenesulfonyl) -hydroxy-2-methylpropionamide.

To a stirred solution of 4-bromothiophenol (19.0 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in chloroform (400 ml), 2-bromoethyl propionate (18.2 g, 100 mmol) was added dropwise. The reaction mixture was refluxed for 1 h and cooled to room temperature. The reaction mixture was washed with water, dried and concentrated. 2- (4-Bromophenylsulfanyl) propionic acid ethyl ester is isolated as a colorless oil. Yield: 28.0 g, 99%, MS: 290 (M + H) ⁺ .

2- (4-Bromophenylsulfanyl) propionic acid ethyl ester is converted to 2- (4-bromophenylsulfonyl) propionic acid ethyl ester according to the procedure described in Example 9, paragraph 2.

A mixture of ethyl 2- (4-bromophenylsulfonyl) propionic acid (6.4 g, 20 mmol), 2- (tributylstannyl) furan (7.5 g, 21 mmol) and (P ₃ R) ₄ P ₁ (500 mg) is boiled under reflux in degassed toluene (250 ml) for 8 hours. At the end of this time, the reaction mixture was filtered through celite and concentrated. The product was purified by silica gel column chromatography, eluting with 50% ethyl acetate: hexane. Colorless oil. Exit:

5.9 g, 95%, MS: 309 (M + H) ⁺ .

According to the procedure described in example 12, 2- [4- (2-furanylbenzenesulfonyl)] 2-methyl-3- [4- (2-S, M-diethylaminoethoxy) phenyl] propionic acid ethyl ester was prepared starting from (3 08 g, 10.0 mmol) of ethyl ether

2- [4- (2-furanylbenzenesulfonyl)] propionic acid and 4- (2-OH, M-diethylaminoethoxy) benzyl chloride (3.5 g, 12.2 mmol). Yield 5.0 g, 97%; brown oil; MS: 514.6 (M + H) ⁺ .

Starting from 2- [4- (2-furanylbenzenesulfonyl)] 2-methyl-3- [4- (2-O, Mdiethylaminoethoxy) phenyl] propionic acid ethyl ester (5.1 g, 10.0 mmol) 3.8 g (yield: 78%) 2- (4- (2furanylbenzenesulfonyl) -2-methyl-3- [4- (2-S, Mdiethylaminoethoxy) phenyl] propionic acid was isolated as a colorless solid according to the procedure described in Example 9. M.p. 58 ° C; MS: 486.5 (M + H) ⁺ .

Starting from 2- [4- (2-furanylbenzenesulfonyl)] - 2-methyl-3- [4- (2-S, M-diethylaminoethoxy) phenyl] propionic acid (5.0 g, 10.3 mmol) and following the procedure described in Example 1, 1.2 g of 2- (4-ethoxybenzenesulfonyl) -2-methyl-3- [4 (2-S, M-diethylaminoethoxy) phenyl] propionamide was isolated as a colorless low-melting solid. Yield: 3.2 g, 62%; (salt with HC1); MS: 502 (M + H) ⁺ ; Ή NMR (300 MHz, SES1 ₃ ): δ 1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q, 4H), 3.0 (t, 2H), 4.1 (t, 2H); 6.5-8.0 (m, 7H).

Example 33. Y-Hydroxy-2- (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-ylethoxy) benzyl] butyramide.

Ethyl 2- (4-methoxyphenylsulfanyl) butyric acid was prepared according to the general method as described in Example 9, starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4 methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); light oil; MS: 255.2 (M + H) ⁺ .

2- (4-Methoxyphenylsulfonyl) butyric acid ethyl ester was prepared according to the general method as described in Example 9, starting from 2- (4-methoxyphenylsulfanyl) butyric acid ethyl ester (5 g, 20 mmol). Yield 5.74 g (100%); light oil; MS: 287.1 (M + H) ⁺ .

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2- [4- (2-morpholin-4-yl-ethoxy) benzyl] butyric acid ethyl ester was obtained from (3.5 g, 12.2 mmol) ethyl 2- (4-methoxybenzenesulfonyl) butyric acid; and 4- [2- (chloromethylphenoxy) ethyl] morpholine (2.34 g, 6.7 mmol). Yield 5.7 g, 100%; brown oil; MS: 506.4 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-ethoxy) benzyl] butyric acid ethyl ester (5.54 g, 11 mmol) 2.9 g (yield: 55%) 2- (4- methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) benzyl] butyric acid was isolated as a colorless semi-solid according to the procedure described in Example 9. MS: 478.3 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2- [4- (2-morpholin-4-yl-ethoxy) benzyl] butyric acid (2.6 g, 4.4 mmol) and following the procedure described in Example 1, 510 mg S -hydroxy-2 (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin4-ylethoxy) benzyl] butyramide is isolated as a brown solid. Yield 2%; so pl. 51 ° C; MS: 493.3 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.90 (t, 1 = 7.2 Hz, 3H), 1.69-

1.96 (m, 4H), 2.67 (t, 2H), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H), 6.8 (d , 1 = 8.7 Hz, 2H), 7.14 (m, 4H), 7.73 (d, 1 = 4.7 Hz, 2H), 9.08 (s, 1H), 10.8 (s , 1H).

Example 34. Y-Hydroxy-2- (4-methoxybenzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) benzyl] butyramide.

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2- [4- (2-piperidin-1-yl-ethoxy) benzyl] butyric acid ethyl ester was obtained from (1.0 g, 3.33 mmol) 2- (4-methoxybenzenesulfonyl) butyric acid ethyl ester and 1- [2- (4-chloromethylphenoxy) ethyl] piperidine (0.85 g, 3.36 mmol). Yield 1.07 g, 62%; brown oil; MS: 504.4 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2- [4- (2-piperidin-1-ethoxy) benzyl] butyric acid ethyl ester (3.7 g, 7.3 mmol) 2.2 g (yield: 63%) 2- ( 4-methoxybenzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) benzyl] butyric acid was isolated as a colorless semi-solid according to the procedure described in Example 9. MS: 476 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2- [4- (2-piperidin-1-yl-ethoxy) benzyl] butyric acid (2.2 g, 4.63 mmol) and following the procedure described in Example 1, 360 mg S -hydroxy-2 (4-methoxybenzenesulfonyl) -2- [4- (2-piperidin-1-ylethoxy) benzyl] butyramide is isolated as a brown solid. Yield 16%; t. pl. 75 ° C; MS: 491.3 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-b ₆ ): δ 0.90 (t, 1 = 7.1 Hz, 3H), 1.36-1.96 (m, 4H), 2.4-2.63 (m, 14H), 3.87 (s, 3H), 4.01 (t, 1 = 5.9 Hz, 2H), 6.8 (d, 1 = 8.5 Hz, 2H),

7.11 (m, 4H), 7.71 (d, 1 = 8.8 Hz, 2H), 9.09 (s, 1H),

10.8 (s, 1H).

Example 35. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-ylethoxy) benzyl] pentanoic acid.

2- (4-Methoxyphenylsulfanyl) pentanoic acid ethyl ester was prepared according to the general method as described in Example 9, starting from ethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4 methoxythiophenol (5 g, 35.7 mmol) 10.46 (100%); light oil; MS: 269 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) pentanoic acid ethyl ester was prepared according to the general method as described in Example 9, starting from 2- (4-methoxyphenylsulfanyl) pentanoic acid ethyl ester (6.9 g, 27.4 mmol). Yield 7.07 g (86%); light oil; MS:

300.9 (M + H) ⁺ .

According to the procedure described in example 12, 2- (4-methoxybenzenesulfonyl) 2- [4- (2-morpholin-4-yl-ethoxy) benzyl] pentanoic acid ethyl ester was prepared starting from (3.0 g, 10.8 mmol) 2- (4-methoxybenzenesulfonyl) pentanoic acid ethyl ester and 4- [2 (chloromethylphenoxy) ethyl] morpholine (3.45 g,

11.9 mmol). Yield 3.08 g, 62%; brown oil; MS: 520.4 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-ylethoxy) benzyl] pentanoic acid ethyl ester (2.73 g, 5.27 mmol), 1.45 g (yield: 56 %) 2- (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) benzyl] pentanoic acid was isolated as a colorless semi-solid according to the procedure described in Example 9. MS: 492.3 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2- [4- (2-morpholin-4-yl-ethoxy) benzyl] pentanoic acid (1.01 g, 2.05 mmol) and following the procedure described in Example 1, 190 mg of hydroxyamide 2- (4-methoxybenzenesulfonyl) -2- [4 (2-morpholin-4-yl-ethoxy) benzyl] pentanoic acid was isolated as a brown solid. Yield 18%; so pl. 101 ° C; MS: 507.4 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-be): δ 0.71 (t, 1 = 7 Hz, 3H), 1.58-1.82 (m, 4H), 3.12-3.98 (m, 12H), 3.87 (s, 3H), 4.35 (t, 2H), 6.89 (d, 1 = 8.7 Hz, 2H), 7.15 (m, 4H), 7.74 ( d, 1 = 8.9 Hz, 2H), 9.08 (s, 1H).

Example 36. Hydroxyamide 2- [4- (2-azepan-

1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) octanoic acid.

2- (4-Methoxyphenylsulfanyl) octanoic acid ethyl ester was prepared according to the general method as described in Example 9, starting from ethyl 2-bromoctanoate (11.8 g, 47.3 mmol) and 4 methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); light oil; MS: 311.2 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) octanoic acid ethyl ester was prepared according to the general method as described in Example 9, starting from 2- (4-methoxyphenylsulfanyl) octanoic acid ethyl ester (4.0 g, 13.6 mmol). Yield 3.7 g (83%); light oil; MS: 343.3 (M + H) ⁺ .

According to the procedure described in example 12, 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) octanoic acid ethyl ester was obtained from (1.69 g, 5.18 mmol) ) 2- (4-methoxybenzenesulfonyl) octanoic acid ethyl ester and 1- [2- (4-chloromethylphenoxy) ethyl] azepane (1.73 g, 6.0 mmol). Yield 4.86 g, 99%; brown oil;

MS: 574.5 (M + H) ⁺ .

Starting from 2- [4- (2-azepan1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) octanoic acid ethyl ester (4.8 g, 8.37 mmol), 1.55 g (yield: 34%) 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) octanoic acid was isolated as a colorless semi-solid according to the procedure described in Example 9. MS: 551 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) octanoic acid (1.09 g, 2.0 mmol) and following the procedure described in Example 1, 300 mg 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxybenzenesulfonyl) octanoic acid hydroxyamide is isolated as a yellow solid. Yield 27%; so pl. 65 ° C; MS: 561.6 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.81 (t, 1 = 6.6 Hz, 3H), 1.08-1.82 (m, 14H), 3.13-3.51 (m, 12H), 3.87 (s, 3H), 4.33 (t, 2H), 6.88 (d, 1 = 8.7 Hz, 2H), 7.14 (m, 4H), 7 7 (d, 1 = 9 Hz, 2H), 9.06 (s, 1H), 10.28 (C, 1H).

Example 37. Hydroxyamide 2- (4-methoxybenzenesulfanyl) octanoic acid.

2- (4-Methoxyphenylsulfanyl) octanoic acid ethyl ester was prepared according to the general method as described in Example 9, starting from ethyl 2-bromoctanoate (11.8 g, 47.3 mmol) and 4 methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); light oil; MS: 311.2 (M + H) ⁺ .

Starting from ethyl 2- (4-methoxybenzenesulfanyl) octanoic acid (3.1 g, 10 mmol) 2.55 g (yield: 90%) 2- (4-methoxybenzenesulfanyl) octanoic acid was isolated as a colorless semi-solid according to the procedure, described in example 9. MS: 283 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfanyl) octanoic acid (4.25 g, 16 mmol) and following the procedure described in Example 1, 3.64 g of 2- (4-methoxybenzenesulfanyl) octanoic acid hydroxyamide was isolated as a colorless solid. Yield 76%; so pl. 90 ° C; MS:

298.2 (M + H) ⁺ .

Example 38. Hydroxyamide 2- (4-fluorophenylsulfanyl) octanoic acid.

2- (4-Fluorophenylsulfanyl) octanoic acid ethyl ester was prepared according to the general procedure as described in Example 9, starting from ethyl 2 bromoctanoate (6.47 g, 24.7 mmol) and 4 fluorothiophenol (3 g, 23.4 mmol). Yield 6.31 g (90%); light oil; MS: 299 (M + H) ⁺ .

Starting from 2- (4-fluorobenzenesulfanyl) octanoic acid ethyl ester (3.1 g, 10 mmol), 2.89 g (yield: 100%) of 2- (4-fluorobenzenesulfanyl) octanoic acid was isolated as a colorless semi-solid according to the procedure described in example 9. MS: 268.9 (M + H) ⁺ .

Starting from 2- (4-fluorobenzenesulfanyl) octanoic acid (2.49 g, 9.2 mmol) and following the procedure described in Example 1, 272 g of 2- (4-fluorobenzenesulfanyl) octanoic acid hydroxyamide was isolated as a colorless solid. Yield 99%; so pl. 58 ° C; MS: 284 (M + H) ⁺ .

Example 39. Hydroxyamide 2- (1-methyl-1Nimidazol-2-ylsulfanyl) octanoic acid.

Ethyl 2- (1-methyl-1H-imidazole-2ylsulfanyl) octanoic acid was prepared according to the general method as described in Example 9, starting from ethyl 2-bromoctanoate (12.1 g, 48 mmol) and 1-methyl-2- mercaptoimidazole (5 g, 43.8 mmol). Yield 12 g (96%); light oil; MS: 285 (M + H) ⁺ .

Starting from 2- (1-methyl-1Nimidazol-2-ylsulfanyl) octanoic acid ethyl ester (12 g, 42.2 mmol), 10.2 g (yield: 95%) 2- (1methyl-1H-imidazole-2- ylsulfanyl) octanoic acid is isolated as a colorless solid according to the procedure described in example 9. mp 95 ° C; MS: 257.1 (M + H) ⁺ .

Starting from 2- (1-methyl-1H-imidazol-2-ylsulfanyl) octanoic acid (7.84 g, 30.6 mmol) and following the procedure described in Example 1, 2.77 g of 2- (1-methyl hydroxyamide -3 Nimidazol-2-ylsulfanyl) octanoic acid is isolated as a colorless solid. Yield 33%; t. pl. 125 ° C; MS: 272.2 (M + H) ⁺ .

Example 40. X-Hydroxy-2- (4-methoxybenzenesulfonyl) -3-naphthalene-2-ylpropionamide.

According to the method described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

3-naphthalene-2-yl-propionic acid is prepared based on (5.0 g, 20 mmol) of ethyl ester

2- (4-methoxybenzenesulfonyl) acetic acid and 2-bromomethyl-naphthalene (4.4 g, 20 mmol). Yield 7.2 g, 91%; colorless oil; MS: 399 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -3-naphthalen-2-yl-propionic acid ethyl ester (3.7 g, 9 mmol), 3.3 g (96%)

2- (4-methoxybenzenesulfonyl) -3-naphthalene-2ylpropionic acid was isolated as a colorless oil according to the procedure described in Example 9. MS: 369.1 (M-H) ^- .

Based on 2- (4-methoxybenzenesulfonyl) -

3-naphthalene-2-yl-propionic acid (2.2 g, 5.9 mmol) and following the procedure described in example 1, 820 mg of X-hydroxy-2- (4-methoxybenzenesulfonyl) -3-naphthalene-2-ylpropionamide in the form of a light brown solid. Yield: 36%; so pl. 161-163 ° C; MS: 385.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, ATP1 ₃ ): 3.32 (d, 1 = 7.0 Hz, 1H), 3.69 (d, 1 = 7.0 Hz, 1H), 3.82 (s, 3H ), 5.02 (s, 1H), 6.92-7.89 (m, 11H).

Example 41. Hydroxyamide X-hydroxy-2 (4-methoxyphenylmethanesulfonyl) -2-methyl-3phenylpropionic acid.

A mixture of 4-methoxybenzyl mercaptan (7.0 g, 45 mmol), ethyl 2-bromopropionate (8.2 g, 46 mmol) and powdered, oven-dried potassium carbonate (10 g, 72 mmol) in 150 ml of acetone is heated by boiling with reflux for 18 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue was dissolved in 150 ml of methylene chloride, washed with water (150 ml), dried over anhydrous sodium sulfate and evaporated, yielding 12 g (99%); colorless liquid; MS 255.1 (M + H). This product is used without further purification.

To an ice-cooled (5 ° C) solution of 2- (4-methoxyphenylmethanesulfanyl) propionic acid ethyl ester (5.7 g, 21 mmol) in 100 ml of CH2C12 was added portionwise (7.2 g, 40 mmol) of m-chloroperbenzoic acid and the mixture stirred for 1 h. The reaction mixture was diluted with hexanes (500 ml) and stirred at 25 ° C for 30 min at room temperature. The mixture was filtered and the organic layer was treated with saturated aqueous sodium bisulfite (200 ml). The solution containing the product in hexanes was washed with water, dried (No. ₂ 8 O ₄ ) and concentrated. Yield 5.5 g (91%); colorless oil; MS 287.1 (M + H) ⁺ .

According to the procedure described in example 9, 2- (4-methoxyphenylmethanesulfonyl) -2-methyl-3-phenylpropionic acid ethyl ester was prepared from 2- (4 methoxyphenylmethanesulfonyl) propionic acid ethyl ester (2 g, 7 mmol) and benzyl bromide (1 3 g, 7.7 mmol). Yield 3.0 g, 100%; low melting solid; MS: 377 (M + H) ⁺ .

2- (4-Methoxyphenylmethanesulfonyl) -2-methyl-3-phenylpropionic acid is prepared from 2- (4-methoxyphenylmethanesulfonyl) -2-methyl-3-phenylpropionic acid ethyl ester (3.5 g, 9.0 mmol), dissolved in methanol (50 ml) and 10n. No. 1OH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 930 mg, 31%. Colorless solid, mp 106-108 ° C; MS: 347 (M-H) ⁺ .

Starting from 2- (4-methoxyphenylmethanesulfonyl) -2-methyl-3-phenylpropionic acid (2.7 g, 7.0 mmol) and following the procedure described in Example 1, 266 mg Hydroxy-2- (4-methoxyphenylmethanesulfonyl) hydroxyamide 2-methyl-3-phenylpropionic acid is isolated as a light, colorless solid. Yield: 10%; so pl. 58-59 ° C; MS: 364.2 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.28 (s, 3H), 2.84-2.88 (d, 1H), 3.75 (s, 3H), 3.81-3, 86 (d, 1H), 4.59-4.63 (d, 1H), 4.69-4.74 (d, 1H), 6.94-6.98 (d, 2H), 7.19 ( m, 2H), 7.29-7.33 (d, 4H), 9.24 (s, 1H), 10.88 (s, 1H).

Example 42. Hydroxyamide 5-methyl-2- (3methylbut-2-enyl) -2- (toluene-4-sulfonyl) hex-

4-enoic acid.

5-Methyl-2- (3-methylbut-2enyl) -2- (toluene-4-sulfonyl) hex-4-enoic acid ethyl ester was prepared according to the general method described in Example 9 based on ethyl α- (p-tolylsulfonyl ) acetate (2.9 g, 10.9 mmol) and 4-bromo-2-methylbutene (3.42 g, 23 mmol). Yield: 4.6 g; tan oil; MS: 379.2 (M + H) ⁺ .

5-Methyl-2- (3-methylbut-2-enyl) -2- (toluene-

4-sulfonyl) hex-4-enoic acid is prepared according to the general method described in example 9, starting from 5-methyl-2- (3-methylbut-2-enyl) -2- (toluene-4-sulfonyl) hex ethyl ester -4-enoic acid (4.5 g, 11 mmol), ethanol (15 ml) and 10N. sodium hydroxide.

Starting from 5-methyl-2- (3-methylbut-2-enyl) 2- (toluene-4-sulfonyl) hex-4-enoic acid (4.1 g, 11 mmol) and following the procedure described in example 1, 1.07 g of 5-methyl hydroxyamide

2- (3-methylbut-2-enyl) -2- (toluene-4-sulfonyl) hex-4-enoic acid is isolated as a colorless solid. Yield: 30%; so pl. 108-110 ° C; MS: 366.2 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.49 (s, 6H), 1.62 (s, 6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-

7.43 (d, 2H), 7.59-7.62 (d, 2H), 9.04 (s, 1H), 10.80 (s, 1H).

Example 43. Hydroxyamide 2-methyl-2- (2 methylfuran-3-sulfonyl) -3-phenylpropionic acid.

2-methyl-2- (2-methylfuran- ethyl ester

3-sulfonyl) -3-phenylpropionic acid (obtained from 3-mercapto-2-methylfuran) is obtained according to the general method described in example 9, starting from 2- (2 methylfuran-3-ylsulfanyl) propionic acid ethyl ester (2.9 g , 11.9 mmol), benzyl bromide (2.22 g, 13 mmol) and potassium carbonate (10 g) in acetone (75 ml). Yield (99%); amber oil; MS: 337.1 (M + H) ⁺ .

2-Methyl-2- (2-methylfuran-3-sulfonyl) -3phenylpropionic acid was prepared according to the general method described in example 9, starting from 2-methyl-2- (2-methylfuran-3-ylsulfanyl) -3- ethyl ester phenylpropionic acid (4.8 g, 14.3 mmol) dissolved in ethanol (25 ml) and 10N. sodium hydroxide (10 ml). Yield 3.7 g (84%); white solid, MS 307.4 (M-H).

Starting from 2-methyl-2- (2-methylfuran-3sulfonyl) -3-phenylpropionic acid (3.58 g, 12 mmol) and following the procedure described in Example 1, 1.078 g of 2-methyl-2- (2methylfuran- 3-sulfonyl) -3-phenylpropionic acid is isolated as an orange solid; yield: 29%; so pl. 68-70 ° C; MS: 324 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b6): δ 1.27 (s, 3H), 2.81-2.86 (d, 1H), 3.33 (s, 3H), 3.61-3, 66 (d, 1H), 6.66 (s, 1H), 7.19-7.25 (m, 5H),

7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H).

Example 44. 2-Methyl-2- (2-methylfuran-3-sulfonyl) -3- [4- (2-piperidin-1-ethoxy) phenyl] propionic acid hydroxyamide.

2-methyl-2- (2-methylfuran3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid ethyl ester was prepared according to the general method described in Example 9, starting from 2- ethyl ester (2-methylfuran-3-sulfonyl) propionic acid (2.4 g, 9.8 mmol) and 1- [2 (4-chloromethylphenoxy) ethyl] piperidine (2.96 g,

10.7 mmol); yield 2.4 g (92%); amber oil; MS: 464.2 (M + H) ⁺ .

2-Methyl-2- (2-methylfuran-3-sulfonyl) -3 [4- (2-piperidin-1-ylethoxy) phenyl] propionic acid was prepared according to the general method described in example 9, starting from 2-methyl ethyl ester -2- (2-methylfuran-3-sulfonyl) 3- [4- (2-piperidin-1-ylethoxy) phenyl] propionic acid (2.01 g, 4.5 mmol) dissolved in ethanol (20 ml) and 10n sodium hydroxide (10 ml). The resulting mixture was treated as described in Example 9. Yield 2.03 g; amber crystals with mp 66-68 ° C; MS 434 (M-H).

Starting from 2-methyl-2- (2-methylfuran-3sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid (2.03 g, 6.0 mmol) and following the procedure described in Example 1, 1.36 mg of 2-methyl-2- (2-methylfuran-3sulfonyl) -3- [4- (2-piperidin-1-ylethoxy) phenyl] propionic acid hydroxyamide was isolated as an amber-colored solid; yield: 32%; so pl. 115-117 ° C; MS: 451.1 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO-e): δ 1.15-1.22 (m, 2H),

1.75 (s, 3H), 1.78 (C, 3H), 2.98-3.03 (m, 2H), 3.42-

3.47 (m, 2H), 3.5 (s, 3H), 6.65 (s, 1H), 6.87-6.90 (d, 2H), 7.12-7.17 (d, 2H), 10.35 (s, 1H), 10.60 (s, 1H), 11.70 (C, 1H).

Example 45. Hydroxyamide 2-methyl-3- [4- (2piperidin-1-ylethoxy) phenyl-2- (thiophen-2sulfonyl)] propionic acid.

2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl-2- (thiophen-2-sulfonyl)] propionic acid ethyl ester was prepared according to the general method described in Example 9, starting from 2- ethyl ester (thiophen-2-sulfonyl) propionic acid (obtained from 2-mercaptothiophene and 2-bromopropionic acid ethyl ester) (4.4 g, 17.7 mmol) and 1- [2- (4-chloromethylphenoxy) ethyl] piperidine (5 3 g, 19.5 mmol); yield (96%); semi-solid substance; MS: 466.

2-Methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl-2- (thiophen-2-sulfonyl)] propionic acid was prepared according to the general method described in Example 9, starting from 2-methyl- ethyl ester 3- [4- (2-piperidin-1-yl-ethoxy) phenyl-2- (thiophen-2-sulfonyl)] propionic acid (9.8 g, 20 mmol) dissolved in ethanol (20 ml) and 10N. sodium hydroxide (20 ml). The resulting mixture was treated as described in example 1. Yield 4.5 g (49%); white solid with so pl. 170-172 ° C; MS 436.3 (M-H).

Starting from 2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl-2- (thiophen-2-sulfonyl)] propionic acid (3.6 g, 8.0 mmol) and following the procedure described in the example 1, 1,345 mg of 2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl-2- (thiophen-2-sulfonyl)] propionic acid hydroxyamide is isolated as a light, colorless solid; yield: 10%; t. pl. 115-118 ° C; MS: 451.2 (M + H) ⁺ ; ^! H NMR (300

MHz, DMSO-th ₆ ): δ 1.29 (s, 3H), 1.66-1.78 (m, 6H), 2.81-2.86 (d, 1H), 2.96-3, 99 (m, 4H), 3.39-

3.47 (m, 2H), 3.51-3.59 (d, 1H), 4.32 (m, 2H), 6.726.74 (d, 1H), 6.87-6.96 (d, 2H), 7.01-7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-7.84 ( m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H), 10.0 (s, 1H), 10.78 (s , 1H).

Example 46. Hydroxyamide 2- (octane-1sulfonyl) -3- [4- (2-piperidinylethoxy) phenyl] propionic acid.

2- (Octane-1-sulfonyl) -3 [4- (2-piperidinylethoxy) phenyl] propionic acid ethyl ester was prepared according to the general method described in Example 9, starting from 2- (octane-1-sulfonyl) propionic acid ethyl ester (5.0 g, 18 mmol) and 1- [2- (4-chloromethylphenoxy) ethyl] piperidine (5.6 g, 19.7 mmol); yield 8.9 g (96%); amber oil; MS: 495.

2- (Octane-1-sulfonyl) -3- [4- (2-piperidinylethoxy) phenyl] propionic acid was prepared according to the general method described in example 9, starting from ethyl 2- (octane-1sulfonyl) -3- [4 - (2-piperidinylethoxy) phenyl] propionic acid (8.9 g, 18 mmol), ethanol (25 ml) and 10N. sodium hydroxide (25 ml). Yield 6.0 g (72%).

Starting from 2- (octane-1-sulfonyl) -3- [4- (2piperidinyl ethoxy) phenyl] propionic acid (3.6 g, 7.7 mmol) and following the procedure described in Example 1, 3.3 g of hydroxyamide 2 (octane-1-sulfonyl) -3- [4- (2-piperidinylethoxy) phenyl] propionic acid is isolated as a tan solid; yield: 89%; so pl. 69-70 ° C; MS: 483.2 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO- ₆ ): δ 0.687 (t, 3H), 1.27-1.69 (m, 15H), 2.71-2.75 (d, 1H), 3.51 ( s, 3H),

3.65-3.69 (d, 1H), 6.86-6.89 (d, 2H), 7.08-7.11 (d, 2H), 9.16 (s, 1H), 10, 70 (s, 1H).

Example 47. Hydroxyamide 3-biphenyl-4-yl2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) propionic acid.

3-Biphenyl-4-yl-2-methyl-2 (1-methyl-1H-imidazole-2-sulfonyl) propionic acid ethyl ester was prepared according to the general method described in Example 9, starting from 2-methyl- (1 -methyl-1H-imidazolsulfonyl) propionic acid (obtained from 1-methyl-2-mercaptoimidazole and 2-bromoethyl propionate) (3.0 g, 12.2 mmol) and 4-chloromethyl biphenyl (2.97 g, 15 mmol); yield 5.0 g (99%); low melting solid; MS: 413 (M + H) ⁺ .

3- Biphenyl-4-yl-2-methyl-2- (1-methyl-1Nimidazole-2-sulfonyl) propionic acid was prepared according to the general method described in example 9, starting from 3biphenyl-4-yl-2-methyl ethyl ester -2- (1-methyl-1H-imidazole-2-sulfonyl) propionic acid (5.0 g, 11.9 mmol), ethanol (15 ml) and 10N. sodium hydroxide (10 ml). Yield 2.8 g (61%); brown solid with so pl. 119-122 ° C; MS: 385.2 (M + H).

Starting from 3-biphenyl-4-yl-2-methyl-2- (1 methyl-1H-imidazole-2-sulfonyl) propionic acid (2.8 g, 7.0 mmol) and following the procedure described in example 1, 112 mg of 3-biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) propionic acid hydroxyamide is isolated as a tan solid; yield: 4%; so pl. 112 ° C; MS: 399.0 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.911 (s, 3H), 3.3 (s, 3H), 3.5 (d, 1H), 4.2 (d, 1H), 6.8 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m, 5H), 7.30-7.33 (d, 2H), 7.55-7.58 (d, 2H).

Example 48. Hydroxyamide 2-methyl-3-phenyl-2- (thiophen-2-sulfonyl) propionic acid.

2-methyl-3-phenyl-2- (thiophen-2-sulfonyl) propionic acid ethyl ester was prepared according to the general method described in example 9, starting from 2- (thiophen-2sulfonyl) propionic acid ethyl ester (3.0 g, 12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g (%); tan oil; MS:

339.1 (M + H).

2-Methyl-3-phenyl-2- (thiophen-2-sulfonyl) propionic acid was prepared according to the general method described in Example 9, starting from 2-methyl-3-phenyl-2- (thiophen-2sulfonyl) propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 ml) and 10N. sodium hydroxide (10 ml). Yield 5.6 g, MS 310.0 (M + H).

Starting from 2-methyl-3-phenyl-2- (thiophen-2sulfonyl) propionic acid (5.0 g, 16 mmol) and following the procedure described in Example 1, 1.8 g of 2-methyl-3-phenyl- hydroxyamide 2 (thiophen-2-sulfonyl) propionic acid is isolated as a colorless solid; yield: 40%; so pl. 116-117 ° C; MS: 325.9 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.29 (s, 3H), 3.33 (d, 1H), 3.69 (d, 1H), 7.18-7.30 (m, 5H), 7.74 (m, 1H), 8.22 (m, 1H), 9.13 (s, 1H), 10.80 (s, 1H).

Example 49. Hydroxyamide 2- [8- (1-carboxyethanesulfonyl) octane-1-sulfonyl] propionic acid.

Ethyl 2- [8- (1-carboxyethanesulfonyl) octane-1-sulfonyl] propionic acid was prepared according to the general method described in Example 9, starting from 2- [8 (1-ethoxycarbonylethylsulfanyl) octylsulfanyl] propionic acid ethyl ester (10, 2 g, 26 mmol) and sodium peroxymonopersulfate (64 g, 104 mmol). Yield 9.87 g (86%); colorless liquid; MS: 442.9 (M + H).

2- [8- (1-Carboxyethanesulfonyl) octane-1sulfonyl] propionic acid was prepared according to the general method described in example 1, starting from 2- [8- (1-carboxyethanesulfonyl) octane-1-sulfonyl] propionic acid ethyl ester (3 0 g, 6.8 mmol), ethanol (15 ml) and

10n sodium hydroxide (15 ml). Yield 2.7 g (98%); white solid with so pl. 99-102 ° C; MS 387 (M + No. H ₃ ) ⁺ .

Starting from 2- [8- (1-carboxyethanesulfonyl) octane-1-sulfonyl] propionic acid (2.5 g,

6.5 mmol) and following the procedure described in Example 1, 641 mg of 2- [8- (1 carboxyethanesulfonyl) octane-1-sulfonyl] propionic acid hydroxyamide was isolated as an amber colored oil; yield: 23%; MS: 434.0 (M + XH ₄ ) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.27-3.23 (m, 22H), 3.33 (m, 2H), 8.9 (s, 1H), 9.28 (s, 1H).

Example 50. Hydroxyamide 2- (4-bromobenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ethoxy) phenyl] propionic acid.

2- (4-Bromobenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid ethyl ester was prepared according to the general method described in Example 9 based on ethyl a- (4- bromophenylsulfonyl) acetate (5.0 g, 16 mmol) and 1- [2- (4-chloromethylphenoxy) ethyl] piperidine (4.97 g, 16 mmol). Yield 6.1 g (71%); tan oil; MS: 541.1 (M + H) ⁺ .

2- (4-Bromobenzenesulfonyl) -2-methyl-3- [4 (2-piperidin-1-yl-ethoxy) phenyl] propionic acid was prepared according to the general method described in Example 9, starting from 2- (4-bromobenzenesulfonyl ethyl ester) -2-methyl-3- [4- (2piperidin-1-yl-ethoxy) phenyl] propionic acid (6.5 g, 20 mmol), ethanol (30 ml) and 10N. sodium hydroxide (15 ml). Yield 6.3 g (100%); yellow solid with so pl. 125-127 ° C; MS

512.5 (M + H) ⁺ .

Starting from 2- (4-bromobenzenesulfonyl) -2methyl-3- [4- (2-piperidin-1-ylethoxy) phenyl] propionic acid (6.1 g, 612 mmol) and following the procedure described in example 1, 1, 07 g of 2- (4-bromobenzenesulfonyl) -2methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionic acid hydroxyamide is isolated as a light yellow solid; yield: 17%; MS: 525.4 (M + H) ⁺ .

Example 51. 3- (4-Bromophenyl) -Y-hydroxy-

2- (4-methoxybenzenesulfonyl) -2-methylpropionamide.

According to the procedure described in Example 9, 3- (4-bromophenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester was obtained from (3.0 g, 11 mmol) ethyl 2- (4 -methoxybenzenesulfonyl) propionic acid and 4-bromobenzyl bromide (3.0 g, 12 mmol). Yield 4.67 g, 96%; colorless oil; MS: 441 (M + H) ⁺ .

3- (4-Bromophenyl) -2- (4-methoxybenzenesulfonyl) -2-methyl-propionic acid is prepared from 3- (4-bromophenyl) 2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester (4, 0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10n. NaOH (30 ml). The resulting reaction mixture was treated as described in Example 9. Yield 3.0 g, 78%; low melting solid. MS 413 (M + H) ⁺ .

Starting from 3- (4-bromophenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid (2.7 g, 6.5 mmol) and following the procedure described in Example 1, 2.26 g of 3- (4 β-bromophenyl) No. hydroxy-2- (4-methoxybenzenesulfonyl) -2 methyl propionamide is isolated as a light, colorless solid; yield: 81%; so pl. 86-88 ° C; MS: 429.8 (M + H) ⁺ ; ¹ H NMR (300 MHz, COCB): δ 1.42 (s, 3H), 1.77 (br s, 1H), 3.26 (d, 1 = 7.0 Hz, 1H), 3.68 (d, 1 = 7.0 Hz, 1H),

3.85 (s, 3H), 7.01-7.76 (m, 8H), 9.71-9.88 (br s, 1H).

Example 52. No. Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3-naphthalen-2-ylpropionamide.

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

2-methyl-3-naphthalen-2-yl-propionic acid is prepared based on (5.4 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 2-bromomethylnaphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; colorless crystals, mp 182-184 ° C; MS: 413 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester (4.6 g, 11 mmol), 4.2 g (98%) of 2- (4-methoxybenzenesulfonyl) - 2-methyl

3-naphthalene-2-yl-propionic acid is isolated as colorless crystals according to the procedure as described in example 9. So pl. 144-146 ° C; MS:

384.9 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3-naphthalen-2-yl-propionic acid (2.4 g, 6.2 mmol) and following the procedure described in Example 1, 1.6 g No. hydroxy-2- (4methoxybenzenesulfonyl) -2-methyl-3-naphthalene2-ylpropionamide is isolated as a light, colorless solid; yield: 64%; so pl. 185-187 ° C; MS: 400.2 (M + H) ⁺ ; Ή NMR (300 MHz, COCB): δ 1.56 (s, 3H), 3.28 (d, 1 = 8.0Hz, 1H), 3.81 (d, 1 = 8Hz, 1H), 3.93 (s, 3H), 4.88 (br s, 1H), 7.02-7.92 (m, 11H).

Example 53. No. Hydroxy-2- (4-methoxybenzenesulfonyl) -3-methylbutyramide.

Ethyl 2- (4-methoxyphenylsulfanyl) -3-methylbutyric acid was prepared according to the general method as described in Example 1, starting from ethyl 2-bromo-3-methylbutanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14 , 0 g, 100 mmol). 30 g of 2- (4-methoxyphenylsulfanyl) -3-methylbutyric acid ethyl ester are isolated. Yield 99%; light yellow oil; MS: 269 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) -3-methylbutyric acid ethyl ester (2.68 g, 10 mmol) and following the procedure as described in Example 9 for oxidation, 3 g of 2- (4-methoxybenzenesulfonyl) ethyl ester α-methylbutyric acid is isolated as a colorless solid, yield: 99%; so pl. 53 ° C; MS: 273 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -3-methylbutyric acid ethyl ester (3 g, 10 mmol), 2.7 g (96%) of 2- (4-methoxyphenylsulfanyl) -3-methylbutyric acid was isolated as a colorless solid according to the method described in example 9. So pl. 96 ° C; MS: 273 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 3-methylbutyric acid (2.0 g, 7.34 mmol) and following the procedure described in Example 9, 590 mg No. hydroxy-2- (4-methoxybenzenesulfonyl) -

3-methylbutyramide is isolated as a colorless solid. Mp 220 ° C; yield: 28%; MS: 288 (M + H) ⁺ . Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.88 (d, 1 = 6.7 Hz, 3H), 1.07 (d, 1 = 6.7 Hz, 3H), 2.09-2 20 (br s, 1H), 3.53 (d, 1 = 9 Hz, 1H), 7.127.17 (m, 2H), 7.74-7.79 (m, 2H).

Example 54. Hydroxyamide 1- (4-methoxybenzenesulfonyl) cyclopentanecarboxylic acid.

According to the procedure described in Example 9, 1- (4-methoxybenzenesulfonyl) cyclopentanecarboxylic acid ethyl ester was prepared from (3,0 g, 11.6 mmol) of 2 (4-methoxybenzenesulfonyl) acetic acid ethyl ester and 1,4- dibromobutane (2.4 g, 7.6 mmol). Yield 2.4 g, 78%; colorless solid with so pl. 8688 ° C; MS: 313 (M + H) ⁺ .

1- (4-Methoxybenzenesulfonyl) cyclopentanecarboxylic acid was prepared from ethyl 1- (4-methoxybenzenesulfonyl) cyclopentanecarboxylic acid (2.2 g, 7.0 mmol) dissolved in methanol (50 ml) and 10N. No. 1OH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.66 g, 83%; colorless solid: mp 112-115 ° C; MS 285 (M + H) ⁺ .

Starting from 1- (4-methoxybenzenesulfonyl) cyclopentanecarboxylic acid (442 mg, 1.5 mmol) and following the procedure described in Example 1, 410 mg of 1- (4-methoxybenzenesulfonyl) cyclopentanecarboxylic acid hydroxyamide was isolated as a colorless solid; so pl. 89-91 ° C; yield: 88%; MS: 300 (M + H) ⁺ ; Ή NMR (300 MHz, COC1 ₃ ): δ 1.65-1.82 (m, 4H), 2.17-2.42 (m, 4H), 3.87 (s, 3H), 7.0 ( d, 1 = 8 Hz, 2H), 7.7 (br s, 1H), 7.72 (d, 1 = 0 Hz, 2H),

9.73 (br s, 1H).

Example 55. 3- (2-Bromophenyl) -Nohydroxy 2- (4-methoxybenzenesulfonyl) -2-methylpropionamide.

According to the procedure described in Example 9, 3- (2-bromophenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester was prepared from (2.0 g, 7.3 mmol) 2- ethyl ester (4-methoxybenzenesulfonyl) propionic acid and 2- (bromo) benzyl bromide (2.0 g, 8 mmol). Yield 3.1 g, 87%; colorless oil; MS: 441 (M + H) ⁺ .

3- (2-Bromophenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid is prepared from 3- (2-bromophenyl) 2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid ethyl ester (3.0 g , 68 mmol) dissolved in methanol (50 ml), and 10N. No. JUN (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.7 g, 63%; a waxy solid; MS 414 (M + H) ⁺ .

Starting from 3- (2-bromophenyl) -2- (4-methoxybenzenesulfonyl) -2-methylpropionic acid (470 mg, 1.1 mmol) and following the procedure described in Example 9, 380 mg of 3- (2 bromophenyl) -hydroxy -2- (4-methoxybenzenesulfonyl) -2-methylpropionamide is isolated as a colorless solid; so pl. 9396 ° C; yield: 77%; MS: 429 (M + H) ⁺ . ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.3 (s, 3H), 3.32 (d, 1 = 7.0 Hz, 1H), 3.69 (d, 1 = 7.0 Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (m, 8H).

Example 56. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-methyl-5-phenylpent-4enoic acid.

According to the procedure described in Example 9, 2- (4-methoxybenzenesulfonyl) 2-methyl-5-phenylpent-4-enoic acid ethyl ester was prepared from (3.0 g, 11 mmol) 2- (4- ethyl ester) methoxybenzenesulfonyl) propionic acid and cinnamyl bromide (2.1 g, 11 mmol). Yield 3.51 g, 82%; colorless oil; MS: 389 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -2-methyl-5-phenylpent-4-enoic acid is prepared from 2- (4-methoxybenzenesulfonyl) -2-methyl-5-phenylpent-4-enoic acid ethyl ester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10N. No. JUN (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.9 g, 68%; yellowish oil; MS 361 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-5-phenylpent-4-enoic acid (440 mg, 1.2 mmol) and following the procedure described in Example 1, 420 mg of 2- (4-methoxybenzenesulfonyl) - 2-methyl-5-phenylpent-4enoic acid is isolated as a colorless solid; so pl. 162-164 ° C; yield: 92%; MS: 376 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.41 (s, 3H), 3.0-3.16 (m, 1H), 3.30 (d, 1 = 11 Hz, 2H), 3, 92 (s, 3H), 5.9-6.1 (m, 1H), 6.53 (d, 1 = 11 Hz, 1H), 7.1-7.72 (m, 9H), 9.12 (br s, 1H).

Example 57. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -5-phenyl-2- (3-phenylpropyl) pentanoic acid.

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

5-phenyl-2- (3-phenylpropyl) pentanoic acid is prepared based on (4.0 g, 15.8 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) acetic acid and 3-bromopropylbenzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; colorless oil; MS: 495 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -5-phenyl-2 (3-phenylpropyl) pentanoic acid is prepared from 2- (4-methoxybenzenesulfonyl) -5-phenyl-2- (3-phenylpropyl) pentanoic acid ethyl ester (2, 0 g, 4 mmol) dissolved in methanol (50 ml) and 10n. No. JUN (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.18 g, 63%; a waxy solid; MS 449.2 (M + HH2O) ⁺ .

Based on 2- (4-methoxybenzenesulfonyl) -

5-phenyl-2- (3-phenylpropyl) pentanoic acid (600 mg, 1.2 mmol) and following the procedure described in Example 1, 420 mg of 2- (4methoxybenzenesulfonyl) -5-phenyl-2- (3-phenylpropyl hydroxyamide ) pentanoic acid is isolated as a colorless solid; so pl. 118-120 ° C; yield 68%; MS: 482 (M + H) ⁺ . '11 NMR (300 MHz, COC1 ₃ ): δ 1.52-1.68 (m, 2H), 1.74-1.92 (m, 2H), 1.98-2.20 (m, 4H) 2.58-2.72 (m, 4H), 3.86 (s, 3H),

6.93 (d, 1 = 11 Hz, 2H), 7.02-7.63 (m, 10H), 7.81 (d, 1 = 11 Hz, 2H).

Example 58. Hydroxyamide 2-allyl-2- (4methoxybenzenesulfonyl) pent-4-enoic acid.

By the procedure as described in Example 9, 2-allyl-2- (4-methoxybenzenesulfonyl) pent-4-enoic acid ethyl ester was prepared from 2 (4-methoxybenzenesulfonyl ethyl ester) (3.0 g, 11.6 mmol) ) acetic acid and allyl bromide (4 ml, excess). Yield 3.6 g, 92%; yellow oil; MS: 338 (M + H) ⁺ .

2-Allyl-2- (4-methoxybenzenesulfonyl) pent-4-enoic acid is prepared from 2-allyl-2- (4-methoxybenzenesulfonyl) pent-4-enoic acid ethyl ester (2.2 g, 6.5 mmol ) dissolved in methanol (50 ml) and 10n. No. GON (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.76 g, 87%; yellowish oil; MS 311 (M + H) ⁺ .

Starting from 2-allyl-2- (4-methoxybenzenesulfonyl) pent-4-enoic acid (1.5 g, 4.8 mmol) and following the procedure described in Example 1, 1.5 g of 2-allyl-2- hydroxyamide (4-methoxybenzenesulfonyl) pent-4-enoic acid is isolated as a colorless solid; t. pl. 114-116 ° C; yield 99%; MS: 326 (M + H) ⁺ ; '11 NMR (300 MHz, ATP1 ₃ ): δ 1.62 (s, 1H), 2.70-2.80 (m, 4H), 3.9 (s, 3H), 5.16-5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d, 1 = 8 Hz, 2H).

Example 59. 2- (4-Methoxybenzenesulfonyl) -2-propylpentanoic acid hydroxyamide.

2-Allyl-2- (4-methoxybenzenesulfonyl) pent-4-enoic acid hydroxyamide (326 mg,

1.0 mmol) (Example 58) was dissolved in methanol (50 ml) and hydrogenated over 10% Pb / C (100 mg) at room temperature and a pressure of 3.445 atm (49 psi) for 4 hours. At the end of this time, the reaction mixture filtered and methanol removed. The resulting solid is crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M + H) ⁺ ; ^! H NMR (300 MHz, SES1 ₃ ): δ 0.92 (t, 1 = 4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H),

3.86 (s, 3H), 6.04 (br s, 1H), 6.97 (d, 1 = 9 Hz, 2H), 7.76 (d, 1 = 9 Hz, 2H).

Example 60. 2-Benzyl-X-hydroxy-2- (4-methoxybenzenesulfonyl) -3-phenylpropionamide.

By the procedure as described in Example 9, 2-benzyl-2- (4-methoxybenzenesulfonyl) -3-phenylpropionic acid ethyl ester was prepared from 2- (4-methoxybenzenesulfonyl ethyl ester) (1.0 g, 3.8 mmol) ) acetic acid and benzyl bromide (4 ml, excess). Yield 1.2 g, 72%; yellow oil; MS: 439 (M + H) ⁺ .

2-Benzyl-2- (4-methoxybenzenesulfonyl) -3 phenylpropionic acid is prepared from 2-benzyl-2- (4-methoxybenzenesulfonyl) -3-phenylpropionic acid ethyl ester (1.0 g, 2.2 mmol) dissolved in methanol (50 ml) and 10n. HaON (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield: 580 mg, 62%; a waxy solid; MS: 409 (M-H) ⁺ .

Starting from 2-benzyl-2- (4-methoxybenzenesulfonyl) -3-phenylpropionic acid (410 mg, 1 mmol) and following the procedure described in Example 1, 225 mg of 2-benzyl-X-hydroxy-2- (4 methoxybenzenesulfonyl) - 3-phenylpropionamide is isolated as a waxy solid. Yield: 52%; MS: 426 (M + H) ⁺ . ¹ H NMR (300 MHz, SES1 ₃ ): 3.25 (d, 1 = 14 Hz, 2H),

3.52 (d, 1 = 14 Hz, 2H), 3.9 (s, 3H), 6.93 (d, 1 = 8 Hz, 2H), 7.02-7.26 (m, 9H), 7.61 (d, 1 = 8 Hz, 2H),

7.87 (d, 1 = 4 Hz, 1H), 9.58 (br s, 1H).

Example 61. X-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3-pyridin-3-ylpropionamide.

To a stirred solution of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid (2.7 g, 10 mmol), hydrochloride

3-Picolyl chloride (3.2 g, 20 mmol) and triethylbenzylammonium chloride (1 g) in methylene chloride (400 ml) were added 10N. HaON (30 ml). The reaction was continued at room temperature for 48 hours. At the end of this time, the organic layer was separated and washed well with water. The organic layer was dried, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography. The column was eluted with 50% ethyl acetate: hexane. 2- (4-Methoxybenzenesulfonyl) 2-methyl-3-pyridin-3-yl-propionic acid ethyl ester was isolated as a brown oil. Yield 3.0 g, 82%; brown oil; MS: 364 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3-pyridin-3-ylpropionic acid ethyl ester (2.5 g, 6.8 mmol) 1.8 g (79%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3-pyridin-3-ylpropionic acid is isolated as a colorless solid according to the procedure as described in example 9. So pl. 58 ° C; MS: 336 (M + H) ⁺ .

Based on 2- (4-methoxybenzenesulfonyl) -

2-methyl-3-pyridin-3-yl-propionic acid (410 mg, 1 mmol) and following the procedure described in example 1, 225 mg X-hydroxy-2- (4methoxybenzenesulfonyl) -2-methyl-3-pyridine-

3-ylpropionamide is isolated as a colorless solid. Yield 52%; so pl. 98 ° C; MS: 351 (M + H) ⁺ ; ^! H NMR (300 MHz, SES1 ₃ ): δ

1.4 (s, 3H), 3.1 (d, 1 = 9.0 Hz, 1H), 3.65 (d, 1 = 9.1, 1H), 3.9 (s, 3H), 7 -8.5 (m, 8H).

Example 62. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyldecanoic acid.

Starting from 2- (4-methoxybenzenesulfonyl) acetic acid ethyl ester (7.5 g, 29 mmol) and 1-bromoctane (6.7 g, 35 mmol), 8 g of monoctylated compound, 2- (4-methoxybenzenesulfonyl ethyl ester) decanoic acid, isolated by the method described in example 9. Yield: 8.0 g, 74%; MS: 370 (M + H) ⁺ .

According to the procedure described in Example 29, 2- (4-methoxybenzenesulfonyl) 2-pyridin-3-ylmethyldecanoic acid ethyl ester was prepared from (8.0 g, 21.6 mmol) of 2- (4-methoxybenzenesulfonyl ethyl ester) decanoic acid and 3-picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 6.5 g, 68%; brown oil; MS: 462 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyldecanoic acid ethyl ester (5.0 g, 11 mmol), 4.5 g (91%) 2- (4 methoxybenzenesulfonyl) -2-pyridin-3- Ilmethyldecanoic acid is isolated as a colorless solid according to the procedure as described in example 9. So pl. 159 ° C; MS: 434 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-pyridin-3-ylmethyldecanoic acid (2.5 g, 5.7 mmol) and following the procedure described in Example 1, 1.4 g of 2- (4-methoxybenzenesulfonyl) - 2-pyridin-3-ylmethyldecanoic acid is isolated as a colorless solid. Yield: 50%; so pl. 62 ° C; MS: 448 (M + H) ⁺ ; ^! H NMR (300 MHz, SES1 ₃ ): δ 0.86 (t, 1 =

6.9 Hz, 3H) 1.25-2.17 (m, 14 N), 3.3 (d, 1 = 14 Hz, 1H), 3.5 (d, 1 = 14 Hz, 1H), 3 9 (s, 3H); 6.8-8.6 (m, 8H).

Example 63. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -5-methyl-2-pyridin-3-ylmethylhex-4-enoic acid.

According to the procedure described in Example 9, 2- (4-methoxybenzenesulfonyl) 5-methylhex-4-enoic acid ethyl ester was prepared from (6.0 g, 23 mmol) of 2- (4 methoxybenzenesulfonyl) ethyl ester ethyl acetate and isoprenyl bromide (3.0 g, 20 mmol). Yield 6.52 g, 86%; colorless oil; MS: 327 (M + H) ⁺ .

According to the procedure as described in example 29, ethyl 2- (4-methoxybenzenesulfonyl) 57

5-methyl-2-pyridin-3-ylmethylhex-4-enoic acid is prepared based on (4.0 g, 12.2 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) -5-methylhex-4-enoic acid and 3-picolyl chloride hydrochloride (2.1 g, 13 mmol). Yield 4.14 g, 81%; brown oil; MS: 418 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -5-methyl-2pyridin-3-ylmethylhex-4-enoic acid is prepared from 2- (4methoxybenzenesulfonyl) -5-methyl-2-pyridin3-ylmethylhex-4-enoic acid ethyl ester (4 0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10N. No. 1OH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 3.2 g, 87%; ivory solid; so pl. 117-119 ° C; MS: 390 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 5-methyl-2-pyridin-3-ylmethylhex-4-enoic acid (2.1 g, 5.4 mmol) and following the procedure as described in Example 1, 1.82 g 2- (4-methoxybenzenesulfonyl) -5-methyl-2pyridin-3-ylmethylhex-4-enoic acid hydroxyamide is isolated as a colorless solid. Yield: 82%; so pl. 89-92 ° C; MS: 405 (M + H) ⁺ . '11 NMR (300 MHz, SIS1 ₃ ): δ 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, b) = 4.0 Hz, 1H), 3.63 (d, b = 4.0 Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.127.88 (m, 6H ), 8.27-8.33 (m, 2H).

Example 64. 2-Benzyl-4-diisopropylaminohydroxy-2- (4-methoxybenzenesulfonyl) butyramide.

According to the procedure described in Example 29, 2-benzyl-4-diisopropylamino 2- (4-methoxybenzenesulfonyl) butyric acid ethyl ester was obtained from (3.0 g, 8.5 mmol) 2- (4-methoxybenzenesulfonyl) ethyl ester) -3-phenylpropionic acid (Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g, 20 mmol). Yield 3.2 g, 79%; ivory oil, so pl. 89-91 ° C; MS: 476.4 (M + H) ⁺ .

Starting from 2-benzyl-4-diisopropylamino-2- (4-methoxybenzenesulfonyl) butyric acid ethyl ester (3.53 g, 7.5 mmol), 2.8 g (86%) 2-benzyl-4-diisopropylamino-2- ( 4-methoxybenzenesulfonyl) butyric acid is isolated in the form of colorless crystals according to the procedure described in example 9. So pl. 136-138 ° C; MS: 448.5 (M + H) ⁺ .

Starting from 2-benzyl-4-diisopropylamino 2- (4-methoxybenzenesulfonyl) butyric acid (1.85 g, 4.1 mmol) and following the procedure described in Example 1, 1.3 g of 2-benzyl-4-diisopropylamino-No. hydroxy-2- (4-methoxybenzenesulfonyl) butyramide is isolated as a low-melting waxy solid. Yield: 68%; MS: 463.3 (M + H) ⁺ ; '11 NMR (300 MHz, SIS1 ₃ ): δ 0.98 (d, b = 11 Hz, 6H), 1.16 (d, b = 11 Hz, 6H), 1.92 (m, 2H), 2 46 (m, 2H); 2.71 (m,

2H), 3.18 (m, 1H), 3.48 (m, 1H), 3.86 (s, 3H), 6.98 (d, b = 8 Hz, 2H), 7.18-7, 22 (m, 5H), 7.92 (d, b = 8 Hz, 2H), 8.12 (s, 1H).

Example 65. 3-Cyclohexyl-Nohydroxy-2 (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpropionamide.

According to the procedure described in Example 9, 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester was prepared from (4.0 g, 15 mmol) of 2 (4-methoxybenzenesulfonyl) acetic acid ethyl ester and 1- bromomethylcyclohexane (2.7 g, 15 mmol). Yield 5.0 g, 94%; colorless oil; MS: 355 (M + H) ⁺ .

According to the procedure described in Example 29, 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpropionic acid ethyl ester was prepared from 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester (1.5 g, 4.2 mmol) and

3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0 g, 38%; colorless oil; MS: 446 (M + H) ⁺ .

Starting from 3-cyclohexyl 2- (4-methoxybenzenesulfonyl) -2-pyridin-3ylmethylpropionic acid ethyl ester (1.3 g, 2.9 mmol), 1.0 g (83%) 3-cyclohexyl-2- (4-methoxybenzenesulfonyl ) -2-pyridin-3-ylmethylpropionic acid is isolated in the form of colorless crystals according to the procedure as described in example 9. So pl. 92 ° C; MS: 417.5 (M + H) ⁺ .

Starting from 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpropionic acid (1.0 g, 2.4 mmol) and following the procedure described in Example 1, (80 mg) 3cyclohexyl-Nohydroxy -2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpropionamide is isolated as a colorless hydrochloride salt; yield: 71%; so pl. 57-60 ° C; MS: 433 (M + H) ⁺ ; '11 NMR (300 MHz, ATP1 ₃ ): δ 0.8-2.08 (m, 13 N), 3.3 (d, b = 14 Hz, 1H), 3.7 (d, b = 14 Hz , 1H); 3.9 (s, 3H); 7.0-8.5 (m, 8H).

Example 66. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanoic acid.

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

4-methylpentanoic acid is prepared based on (5.0 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) acetic acid and 1-bromo-2-methylpropane (2.6 g, 20 mmol). Yield 6.0 g, 95%; colorless oil; MS: 315 (M + H) ⁺ .

According to the method as described in example 29, ethyl 2- (4-methoxybenzenesulfonyl) -

4-methyl-2-pyridin-3-ylmethylpentanoic acid is prepared based on (3.1 g, 10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) -4-methylpentanoic acid and 3-picolyl chloride hydrochloride (1.8 g, 11 mmol). Yield 3.0 g, 75%; colorless oil; MS: 406 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanoic acid ethyl ester (1.2 g, 2.9 mmol), 1.0 g (91%) 2- (4-methoxybenzenesulfonyl ) -4-methyl2-pyridin-3-ylmethylpentanoic acid is isolated in the form of colorless crystals according to the procedure as described in example 9. So pl. 188-186 ° C; MS: 378 (M + H) ⁺ .

Based on 2- (4-methoxybenzenesulfonyl) -

4-methyl-2-pyridin-3-ylmethylpentanoic acid (800 mg, 2.1 mmol), and according to the procedure as described in Example 1, 180 mg of hydroxyamide 2 (4-methoxybenzenesulfonyl) -4-methyl-2pyridin- 3-ylmethylpentanoic acid is isolated as a colorless solid; yield: 21%; t. pl. 78 ° C; MS: 393.4 (M + H) ⁺ ; '11 NMR (300 MHz, СОС1 ₃ ): δ 0.65 (d, 1 = 6.3 Hz, 3Н), 0.89 (d, 1 = 6.2 Hz, 3Н), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5 (m, 10H).

Example 67. Y-Hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3-quinolin-6-ylpropionamide.

According to the method as described in example 29, ethyl 2- (4-methoxybenzenesulfonyl) -

2-methyl-3-quinolin-6-yl-propionic acid is prepared based on (5.2 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) propionic acid and 7-bromomethylquinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%; a pale yellow solid; so pl. 86 ° C; MS: 414 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3-quinolin-6ylpropionic acid ethyl ester (3.0 g, 7.2 mmol), 2.5 g (90%) of 2- (4-methoxybenzenesulfonyl) - 2-methyl

3-quinolin-6-ylpropionic acid is isolated as colorless crystals according to the procedure as described in example 9. So pl. 106-108 ° C; MS:

386.4 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3-quinolin-6-yl-propionic acid (2.0 g, 5.2 mmol) and following the procedure described in Example 1, 1.2 g of Y-hydroxy-2 - (methoxybenzenesulfonyl) -2-methyl-3-quinolin-6-ylpropionamide is isolated as a colorless solid; yield: 57%; so pl. 206 ° C;

MS: 401.4 (M + H) ⁺ ; '11 NMR (300 MHz, SESb): δ 1.4 (s, 3H), 3.19 (m, 1H), 3.8-4.0 (m, 4H), 7.1-8.95 ( m, 12H).

Example 68. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethylhexanoic acid.

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

6-Phenoxyhexanoic acid is prepared starting from (2.5 g, 10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) acetic acid and 1-bromo-4-phenoxybutane (2.2 g, 10 mmol). Yield 3.8 g, 93%; colorless oil; MS: 407 (M + H) ⁺ .

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

6-Phenoxy-2-pyridin-3-ylmethylhexanoic acid is prepared based on (3.1 g, 10 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) -6-phenoxyhexanoic acid and 3picolyl chloride (1.8 g, 11 mmol) ) Yield 3.5 g, 71%; colorless oil; MS: 498 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethylhexanoic acid ethyl ester (3.0 g, 6.0 mmol), 2.8 g (quantitative yield) 2- (4-methoxybenzenesulfonyl ) -6-phenoxy-2-pyridin-3-ylmethylhexanoic acid is isolated as colorless crystals according to the procedure as described in example 9. So pl. 148-151 ° C; MS: 470.5 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 6-phenoxy-2-pyridin-3-ylmethylhexanoic acid (2.0 g, 4.3 mmol) and following the procedure as described in Example 1, 1.5 g of 2- ( 4-methoxybenzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid is isolated as a colorless solid; yield: 72%; so pl. 68 ° C; MS: 485.5 (M + H) ⁺ ; ¹ H NMR (300 MHz, COC1 ₃ ): δ 1.5-2.5 (m, 8H), 3.4 (br s, 2H), 3.8 (s, 3H), 6.8-8 7 (m, 13H).

Example 69. 2- (4-Methoxybenzenesulfonyl) -5-methyl-2-pyridin-3-ylmethylhexanoic acid hydroxyamide.

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

5-methylhexanoic acid is prepared based on (10.0 g, 39 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) acetic acid and

1-bromo-3-methylbutane (6.0 g, 40 mmol). Yield 8.5 g, 62%; colorless oil; MS: 329 (M + H) ⁺ .

According to the method as described in example 9, ethyl 2- (4-methoxybenzenesulfonyl) -

5-methyl-2-pyridin-3-ylmethylhexanoic acid is prepared based on (6.0 g, 18 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) -5-methylhexanoic acid and picolyl chloride hydrochloride (4.1 g, 25 mmol) ) Yield 4.5 g, 60%; brown oil; MS: 420 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -5-methyl-2-pyridin-3-ylmethylhexanoic acid ethyl ester (3.0 g, 7.1 mmol), 2.6 g (92%) of 2- (4-methoxybenzenesulfonyl ) -5-methyl-

2-Pyridin-3-ylmethylhexanoic acid was isolated as a colorless solid according to the procedure as described in Example 9. mp. 173 ° C; MS: 392 (M + H) ⁺ .

Based on 2- (4-methoxybenzenesulfonyl) -

5-methyl-2-pyridin-3-ylmethylhexanoic acid (1.0 g, 2.5 mmol) and following the procedure as described in Example 1, 800 mg of hydroxyamide 2 (4-methoxybenzenesulfonyl) -5-methyl-2 -pyridin-3-ylmethylhexanoic acid is isolated as a colorless solid. The hydrochloride is obtained by passing gaseous hydrogen chloride through a solution of hydroxyamide in methanol. Yield: 72%; so pl. 62 ° C (salt with HC1); MS: 408 (M + H) ⁺ ; '11 NMR (300 MHz, SPS1 ₃ ): δ 0.76 (m, 6H), 1.2-2.0 (m, 5H), 3.5 (br.s, 2H), 7.18.8 (m, 8H), 11.1 (br s, 1H).

Example 70. 2- (4-Methoxybenzenesulfonyl) -2-pyridin-3-ylmethylhexanoic acid hydroxyamide.

(4-Methoxyphenylsulfanyl) acetic acid tert-butyl ester was prepared according to the general method as described in Example 1. Starting from the corresponding 1-bromo-tert-butyl acetate (5.3 g, 27 mmol) and 4-methoxybenzenethiol (3.7 g , 27 mmol), 6.4 g of product are isolated. Yield 98%; light yellow oil; MS: 255 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) acetic acid tert-butyl ester was prepared according to the general method described in Example 9. Starting from 2- (4-methoxybenzenesulfanyl) acetic acid tert-butyl ester (5.0 g, 20 mmol) and 57% 3-chloroperoxybenzoic acid (12.0 g, 40 mmol), 5.3 g of product are isolated. Yield 92%; a waxy solid; MS: 287.1 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) pyridin-3-yl-propionic acid tert-butyl ester was prepared according to the procedure described in Example 9. Starting from 2 (4-methoxybenzenesulfonyl) acetic acid tert-butyl ester (20.0 g, 70.0 mmol) and 3-picolyl chloride (7.28 g, 44.4 mmol), 10.5 g of the product are isolated by silica gel chromatography (50% ethyl acetate: hexane). Yield 63%; white solid; so pl. 9394 ° C; MS: 378.0 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -2-pyridin-3-ylmethylhexanoic acid tert-butyl ester was prepared according to the procedure described in Example 9. Starting from 2 (4-methoxybenzenesulfonyl) pyridin-3-yl-propionic acid tert-butyl ester (2 0 g, 5.3 mmol) and nbutyl bromide (0.73 g, 5.3 mmol), 1.20 g of product is isolated. Yield 52%; yellowish resin; MS: 434.3 (M + H) ⁺ .

A mixture of 2- (4methoxybenzenesulfonyl) -2-pyridin-3-ylmethylhexanoic acid tert-butyl ester (1.1 g, 2.5 mmol) in methylene chloride / TFA (1: 1) was stirred at room temperature for 2 hours. Solvents then evaporated and 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylhexanoic acid was purified by silica gel chromatography (30% methanol / methylene chloride). Yield 0.90 g, 94%; white solid; so pl. 70 ° C; MS:

376.1 (M-H) ^- .

2- (4-Methoxybenzenesulfonyl) -2-pyridin-3-ylmethylhexanoic acid hydroxyamide was prepared according to the method as described in Example 1. Starting from 2- (4-methoxybenzenesulfonyl) -2pyridin-3-ylmethylhexanoic acid (0.31 g, 0 , 81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of product is isolated. Yield 37%; a pale yellow solid; so pl. 65 ° C; MS: 392.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-bb): δ 0.80 (t, 1 = 7.2 Hz, 3H), 1.10-

1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H),

3.53 (d, 1 = 14.4 Hz, 1H); 3.62 (d, 1 = 14.4 Hz, 1H),

3.88 (s, 3H), 7.15 (d, 1 = 8.9 Hz, 2H), 7.71 (d, 1 =

8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (br s, 1H); IR (KBr, cm ^-1 ): 3064m, 2958s, 2871m, 1671m.

Example 71. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-oct-2-ynyldec-4-inic acid.

The title compound was prepared according to the procedure described in Example 9. Starting from 2- (4-methoxybenzenesulfonyl) acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-octine (3.80 g, 20 mmol), 4.4 g of product are isolated. Yield 100%; yellowish resin; MS: 446.9 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -2-oct-2inyl-dec-4-inic acid is prepared according to the method described in Example 70. Starting from 2- (4-methoxybenzenesulfonyl) -2-oct-2-ynyl-dec-4-new tert-butyl ester acid (4.40 g, 10.0 mmol), 2.0 g of product is isolated. Yield 49%; white solid; so pl. 61 ° C; MS:

345.1 (M-H) ⁺ .

Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-oct-2-in-yldec-4-inic acid is prepared according to the method described in Example 1. Starting from 2- (4-methoxybenzenesulfonyl) -2-oct2-ynyldec-4- another acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) secrete 0.25 g of the product. Yield 62%; white solid; t. pl. 83-84 ° C; MS: 462.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO ₆ ): δ 0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.902.05 (m, 4H), 2.86 (broad d, 1 = 17.0 Hz, 2H), 3.00 (wide d, 1 = 17.0 Hz, 2H), 3.87 (s, 3H), 7.15 (d, 1 = 10.0 Hz, 1H), 7.71 (d, 1 = 10.0 Hz, 1H), 9.20 (br s, 1H), 10.90 (br s, 1H); IR (KBr, cm ^-1 ): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s.

Analysis. Calculated for C ₂₅ H ₃₅ XO ₅ 8: C 65.05; H 7.64; N, 3.03.

Found: C, 65.26; H7.68; N, 2.90.

Example 72. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-but-2-ynyl-hex-4-inic acid.

2- (4-Methoxybenzenesulfonyl) -2-but-2-ynylhex-4-inic acid tert-butyl ester was prepared according to the procedure described in Example 9. Starting from 2- (4-methoxybenzenesulfonyl) acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of product are isolated. Yield 90%; white solid; t. pl. 85-87 ° C; MS: 391.0 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -2-but-2-vinylhex-4-inic acid was prepared according to the procedure described in Example 70. Starting from tert-butyl ether 2- (4-methoxybenzenesulfonyl) -2-but-2-ynylhex-4 -inic acid (3.0 g, 7.7 mmol), 2.5 g of product are isolated. Yield 97%; white solid; so pl. 141-143 ° C; MS: 333.1 (M-H) ^- .

2- (4-Methoxybenzenesulfonyl) -2-but-2-ynylhex-4-inic acid hydroxyamide was prepared by the method described in Example 1.

Starting from 2- (4-methoxybenzenesulfonyl) -2-but2-ynylhex-4-inic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g of product is isolated. Yield 89%; white solid; t. pl. 135-137 ° C; MS: 349.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO ₆ ): δ 1.67 (s, 6H), 2.70-3.10 (m, 4H), 3.88 (s, 3H),

7.15 (d, 1 = 10.0 Hz, 2H), 7.71 (d, 1 = 10.0 Hz, 2H),

9.20 (br s, 1H); 10.90 (br s, 1H); (KVg, cm ^-1 ): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.

Example 73. Hydroxyamide of 2- (4-methoxybenzenesulfonyl) -2-prop-2-ynylpent-4inic acid.

2- (4-Methoxybenzenesulfonyl) -2-prop-2-ynylpent-4-inic acid tert-butyl ester was prepared according to the procedure described in Example 9. Starting from 2- (4-methoxybenzenesulfonyl) acetic acid tert-butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 mmol), 1.90 g of product is isolated. Yield 75%; white solid; so pl. 113-115 ° C: MS: 362.1 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -2-prop-2inyl-pent-4-inic acid was prepared according to the procedure described in Example 70. Starting from tert-butyl ether 2- (4-methoxybenzenesulfonyl) -2-prop-2-ynylpent-4 -inic acid (1.70 g, 4.7 mmol), 1.30 g of product is isolated. Yield 90%; white solid; t. pl. 156 ° C; MS: 305.1 (M-H) ^- .

2- (4-Methoxybenzenesulfonyl) -2-prop-2-ynylpent-4-inic acid hydroxyamide is prepared according to the method described in Example 1. Starting from 2- (4-methoxybenzenesulfonyl) -2prop-2-ynylpent-4-inic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of product is isolated. Yield 85%; white solid; t. pl. 156 ° C; MS: 321.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-be): δ 2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90 (s, 3H), 7, 01 (d, 1 = 9.0 Hz, 2H), 7.82 (d, 1 = 9.0 Hz, 2H), 8.76 (br s, 1H), 10.65 (br s, 1H ); IR (KBr, cm ^-1 ): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s.

Analysis. Calculated for C1 ₅ H ^ O ₅ 8: C 56.07; H 4.70; Ν 4.36. Found: C 55.65; H 4.67; Ν 4.10.

Example 74. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyldec-4inovoy acid.

The title compound was prepared according to the procedure described in Example 38. Starting from 2- (4-methoxybenzenesulfonyl) pyridin-3-yl-propionic acid tert-butyl ester (2.20 g, 5.8 mmol) and 1-bromo-2 α-octin (1.14 g, 6 mmol), 2.60 g of product is isolated. Yield 92%; yellowish resin; MS: 486.0 (M + H) ⁺ .

A mixture of 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyl-de-4-inic acid tert-butyl ester (2.60 g, 5.35 mmol) in a methylene chloride / TFA mixture (1: 1) was stirred at room temperature for about 2 hours (reference example 70). The solvents were then evaporated, and 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyl-de-4-inic acid was purified by silica gel chromatography (~ 30% methanol / methylene chloride). Yield 2.0 g, 87%; white solid; t. pl. 146 ° C; MS: 428.1 (MH) ^- .

Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyldec-4-inic acid was prepared according to the procedure described in Example 1. Starting from 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyldec-4- of other acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of product is isolated. Yield 67%; whitish solid; so pl. 65 ° C; MS: 445.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.84 (t, 1 = 6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, 1 =

17.9 Hz, 1H), 2.90 (d, 1 = 17.9 Hz, 1H), 3.50 (d, 1 =

13.7 Hz, 1H), 3.74 (d, 1 = 13.7 Hz, 1H), 3.89 (s, 3H), 7.19 (d, 1 = 9.0 Hz, 2H), 7 76 (d, 1 = 9.0 Hz, 2H), 7.85-7.89 (m, 1H), 8.37-8.40 (m, 1H), 8.708.80 (m, 2H), 11.0 (br s, 1H); IR (KBr, cm ^-1 ): 3157m, 3095m, 2954s, 2932s, 2858s, 1671m, 1593s.

Analysis. Calculated for С ₂ ЗН ₂₈ Н ₂ О ₅ 8-НС1 · 0.9 Н2О: С 55.56; H6.24; Ν 5.63.

Found: C 55.84; H, 6.19; Ν 5.59.

Example 75. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpent-4inic acid.

2- (4-Methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpent-4inic acid tert-butyl ester was prepared according to the procedure described in Example 38. Starting from 2- (4-methoxybenzenesulfonyl) pyridin-3-yl-propionic acid tert-butyl ester (3 , 77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 g of product are isolated. Yield 60%; yellowish solid; so pl. 132-133 ° C; MS: 416.0 (M + H) ⁺ .

2- (4-Methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpent-4-inic acid is prepared according to the procedure described in Example 70. Starting from tert-butyl ether 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpent 4-acid acid (2.0 g, 4.8 mmol), 1.2 g of product are isolated. Yield 69%; white solid; so pl. 119-121 ° C; MS: 358.1 (M-H) ^- .

Hydroxyamide 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethylpent-4-inic acid is prepared according to the method described in Example 1. Starting from 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylpent-4- another acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) secrete 0.065 g of the product. Yield 25%; whitish solid; so pl. 70 ° C; MS: 375.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 1.19 (br s, 1H), 2.90-3.00 (m, 2H), 3.55 (d, 1 = 13.8 Hz , 1H), 3.67 (d, 1 = 13.8

Hz, 1H), 3.89 (s, 3H), 7.18 (d, 1 = 9.0 Hz, 2H), 7.75 (d, 1 = 9.0 Hz, 2H), 7.80- 7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (br s, 1H); IR (KBr, cm ^-1 ): 3168m, 3095s, 1670m, 1593s.

Example 76. Hydroxyamide 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylmethylhex-4ic acid.

2- (4-Fluorobenzenesulfanyl) acetic acid tert-butyl ester was prepared according to the procedure described in Example 1. Starting from 4 fluorothiophenol (30.0 g, 230 mmol) and tert-butyl bromoacetate (45.67 g, 230 mmol), 53 4 g of product. Yield 100%; pale yellow oil; MS: 243.1 (M + H) ⁺ .

2- (4-Fluorobenzenesulfonyl) acetic acid tert-butyl ester was prepared according to the general method described in Example 9. Starting from 2- (4-fluorobenzenesulfanyl) acetic acid tert-butyl ester (48.4 g, 200 mmol) and 3- chloroperoxybenzoic acid (121.3 g, (57%), 400 mmol), 48.0 g of product are isolated. Yield 88%; pale yellow oil; MS: 275.1 (M + H) ⁺ .

The title compound was prepared according to the procedure described in Example 70. Starting from 2- (4-fluorobenzenesulfonyl) -3-pyridin-3-yl-propionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo- 2 butyne (0.67 g, 5.0 mmol), 2.18 g of product is isolated. Yield 100%; yellowish resin; MS:

419.2 (M + H) ⁺ .

2- (4-Fluorobenzenesulfonyl) -2-pyridin-3ylmethylhex-4-inic acid is prepared according to the method described in Example 38. Starting from 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylhex-4 tert-butyl ester -inic acid (2.1 g, 5.0 mmol), 1.20 g of product is isolated. Yield 67%; whitish solid; t. pl. 150 ° C; MS: 360.2 (M-H) ^- .

Hydroxyamide 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylhex-4-inic acid is prepared according to the method described in Example 1. Starting from 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylmethylhex-4- of other acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.15 g of product is isolated. Yield 45%; white solid; so pl. 190 ° C; MS: 377.2 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-bb): δ 1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, 1 = 13.8 Hz, 1H) 3.74 (d, 1 = 13.8 Hz, 1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40 (m, 1H), 8.74-8.79 (m, 2H), 11.1 (br s, 1H); IR (KBr, cm ^-1 ): 3154m, 3105s, 3068s, 2875m, 1696s, 1630m, 1590s.

Analysis. Calculated for C1 ₈ H1 ₇ W ₂ O ₄ §-HC1 · 0.5 H ₂ O: C 51.24; H 4.54; N, 6.64. Found: C, 51.21; H 4.35; N, 6.46.

Example 77. Hydroxyamide 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylmethyldec-4-inic acid.

The title compound was prepared according to the procedure described in Example 9. Starting from 2- (4-fluorobenzenesulfonyl) -3-pyridin-3-yl-propionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1- bromo-2-octine (0.95 g, 5.0 mmol), 1.80 g of product is isolated. Yield 56%; yellowish resin; MS: 474.3 (M + H) ⁺ .

2- (4-Fluorobenzenesulfonyl) -2-pyridin-3ylmethyldec-4-inic acid was prepared according to the method described in Example 70. Starting from tert-butyl ether 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylmethyldec-4 -inic acid (1.80 g, 3.8 mmol), 1.40 g of product is isolated. Yield 88%; whitish solid; so pl. 123-124 ° C; MS: 416.3 (M-H) ^- .

Hydroxyamide 2- (4-fluorobenzenesulfonyl) -2-pyridin-3-ylmethyldec-4-inic acid is prepared according to the method described in Example 1. Starting from 2- (4-fluorobenzenesulfonyl) 2-pyridin-3-ylmethydec-4-new acids (0.67 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 g of product is isolated. Yield 29%; white solid; so pl. 180-182 ° C; MS: 433.2 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.84 (t, 1 = 6.8 Hz, 3H), 1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, 1 =

19.9 Hz, 1H), 2.94 (d, 1 = 19.9 Hz, 1H), 3.54 (d, 1 =

13.7 Hz, 1H), 3.75 (d, 1 = 13.7 Hz, 1H), 7.40-7.60 (m, 2H), 7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.708.80 (m, 2H), 11.1 (br s, 1H); IR (KBr, cm ^-1 ): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m.

Analysis. Calculated for C ₂₂ H ₂₅ B ^ O ₄ 8CH1: C 56.34; H 5.59; N, 5.97. Found: C 56.18; H 5.54; N, 5.76.

Example 78. Hydroxyamide 2- (4-fluorobenzenesulfonyl) -2-but-2-ynylhex-4-inic acid.

2- (4-Fluorobenzenesulfonyl) -2-but-2-ynylhex-4-inic acid tert-butyl ester is prepared as described in Example 9. Starting from 2- (4-fluorobenzenesulfonyl) acetic acid tert-butyl ester (4, 87 t, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of product are isolated. Yield 77%; white solid; so pl. 85 ° C; MS: 379.1 (M + H) ⁺ .

2- (4-Fluorobenzenesulfonyl) -2-but-2-ynylhex-4-inic acid is prepared according to the procedure described in Example 70. Starting from tert-butyl ether 2- (4-fluorobenzenesulfonyl) 2-but-2-ynylhex-4- acid acid (3.50 g, 8.47 mmol), 2.35 g of product is isolated. Yield 79%; white solid; so pl. 129-131 ° C; MS:

642.8 (2M-H) ^- .

The hydroxyamide of 2- (4-fluorobenzenesulfonyl) -2-but-2-ynylhex-4-inic acid was prepared according to the method described in Example 1.

Starting from 2- (4-fluorobenzenesulfonyl) -2-but-2-vinylhex-4-inic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.21 g of product is isolated. Yield 77%; white solid; so pl. 161-163 ° C; MS:

338.1 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-L): δ

1.67 (s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, 1 = 9.0, 9.0 Hz, 2H), 7.87 (m, 2H) 9.26 (br s, 1H); 10.95 (br s, 1H); IR (KBr, cm ^-1 ): 3336s, 3245m, 1681s, 1589m, 1493m.

Analysis. Calculated for C1 ₆ H1 ₆ PNO ₄ 8: C 56.96; H 4.78; Ν 4.15. Found: C 56.59; H 4.75; Ν 4.04.

Example 79. Hydroxyamide 2- (4-methoxybenzenesulfonyl) -5-methyl-2- (3-methylbut-2enyl) hex-4-enoic acid.

By the procedure as described in Example 9, 2- (4-methoxybenzenesulfonyl) 5-methyl-2- (3-methylbut-2-enyl) hex-4-enoic acid ethyl ester was prepared starting from (5.0 g, 20 mmol) of ethyl 2- (4-methoxybenzenesulfonyl) acetic acid and isoprenyl bromide (6.0 g, 40 mmol). Yield 7.0 g, 88%; colorless oil; MS: 395 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -5-methyl-2- (3-methylbut-2enyl) hex-4-enoic acid ethyl ester (3.5 g, 9 mmol), 3.3 g (97%) 2 - (4-Methoxybenzenesulfonyl) -5-methyl2- (3-methylbut-2-enyl) hex-4-enoic acid was isolated as a colorless oil according to the procedure as described in Example 9. MS: 365 (M-H) ^- .

Starting from 2- (4-methoxybenzenesulfonyl) 5-methyl-2- (3-methylbut-2-enyl) hex-4-enoic acid (2.6 g, 7.0 mmol) and following the procedure described in example 1, 1.36 g of 2- (4-methoxybenzenesulfonyl) -5-methyl-2- (3methylbut-2-enyl) hex-4-enoic acid hydroxyamide are isolated as a colorless solid. Yield: 67%; t. pl. 93-96 ° C; MS: 383 (M + H) ⁺ ; ¹ H NMR (300 MHz, SES1 ₃ ): δ 1.68 (s, 6H), 1.73 (s, 6H), 2.72 (m, 4H), 3.82 (s, 3H), 5, 12 (m, 2H), 6.92 (d, 1 = 8 Hz, 2H), 7.33 (br s, 1H), 7.72 (d, 1 = 8 Hz, 2H), 9.71 ( broad s, 1H).

Example 80. Hydroxyamide 2- (4-methoxyphenylsulfanyl) heptanoic acid.

2- (4-Methoxyphenylsulfanyl) heptanoic acid ethyl ester (13.8 g, 98%) was prepared according to the general method as described in Example 1, starting from ethyl 2-bromoheptanoate (11 g, 47 mmol) and 4-methoxythiophenol (6 g, 42.8 mmol) as a yellow oil; MS: 297.2 (M + H) ⁺ .

2- (4-Methoxyphenylsulfanyl) heptanoic acid is prepared from 2 (4-methoxyphenylsulfanyl) heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10N. No. 1OH (25 ml). The resulting reaction mixture was worked up as described in Example 1. Yield 3 g (83%), yellow oil. MS:

267.1 (M-H) ^- .

Starting from 2- (4-methoxyphenylsulfanyl) heptanoic acid (2.49 g, 9.32 mmol) and following the procedure described in Example 1, 1.83 g of 2- (4-methoxyphenylsulfanyl) heptanoic acid hydroxyamide was isolated as an off-white solid substances. Mp 90-95 ° C; yield 70%; MS: 284.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.826 (t, 1 = 6.9 Hz, 3H), 1.135-1.76 (m, 8H), 3.35 (m, 1H), 3, 82 (s, 3H); 6.91-7.49 (m, 4H).

Example 81. (49A) 2K * - (4methoxyphenyl-8 * -sulfinyl) heptanoic acid hydroxyamide and (49B) 28 * - (4-methoxyphenylK * -sulfinyl) heptanoic acid hydroxyamide.

Starting from 2- (4-methoxyphenylsulfanyl) heptanoic acid hydroxyamide (1.69 g, 6 mmol) and following the procedure described in Example 5, two 2- (4 methoxyphenylsulfinyl) heptanoic acid diastereomers are separated on a silica gel column using a 75% mixture ethyl acetate: hexanes. The less polar isomer, 2K * - (4methoxyphenyl-8 * -sulfinyl) heptanoic acid hydroxyamide, is isolated as a white powder. Yield: 390 mg (22%); so pl. 115 ° C; MS: 300.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.828 (t, 1 = 6.2 Hz, 3H), 1.18-1.23 (m, 6H), 1.73-1.99 (m , 2H), 3.11-

3.15 (m, 1H), 3.82 (s, 3H), 7.09-7.61 (m, 4H).

The more polar isomer, 28 * - (4-methoxyphenyl-K * -sulfinyl) heptanoic acid hydroxyamide, is isolated as a gray solid. Yield: 200 mg (11%); so pl. 112 ° C; MS: 300.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.754 (t, 1 = 6.9 Hz, 3H), 1.014-1.121 (m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m, 1H), 3.834 (s, 3H),

7.13-7.65 (m, 4H).

Example 82. Hydroxyamide hydrochloride 2 (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2morpholin-4-ylethoxy) phenyl] propionic acid

According to the procedure described in Example 12, 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) phenyl] propionic acid ethyl ester was obtained from (4.0 g, 15 mmol) of 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester of 4- (morpholin-1-yl-ethoxy) benzyl chloride hydrochloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; brown oil; MS: 492 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-ethoxy) phenyl] propionic acid ethyl ester (4.0 g, 8.1 mmol), 3.2 g (yield 84%) 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-morpholin-1-ethoxy) phenyl] propionic acid was isolated as colorless crystals according to the procedure as described in Example 9. mp. 171 ° C; MS: 464 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) phenyl] propionic acid (4.0 g, 8.6 mmol) and following the procedure described in Example 1 2.5 g of 2- (4-methoxybenzenesulfonyl) 2-methyl-3- [4- (2-morpholin-1-yl-ethoxy) phenyl] propionic acid hydroxyamide are isolated as a colorless solid. The hydrochloride salt is obtained by reacting the free base with hydrogen chloride in methanol at 0 ° C. Yield: 2.5 g, 60%; so pl. 98 ° C; MS: 479 (M + H) ⁺ ; Ή NMR (300 MHz, ATP1 ₃ ): δ 1.36 (s, 3H), 3.8-12.6 (m, 16H), 3.9 (s, 3H), 4.1-4.3 ( m, 1H),

6.6 (d, ί = 8 Hz, 2H), 6.96 (d, ί = 9 Hz, 2H), 7.1 (d, ί = 8 Hz, 2H), 7.84 (d, ί = 9 Hz, 2H), 10.8 (br s, 1H).

Example 83. Hydroxyamide 1-benzyl-4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

To a stirred solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous K2CO3 (10 g, excess) in dry acetone (100 ml) in a round bottom flask was added α-bromoethyl acetate (3.3 g, 20 mmol) and the reaction mixture heated at the boil under reflux for 8 hours with good stirring. At the end of this time, the reaction mixture was allowed to cool and the potassium salts were separated by filtration and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O and 0.5N. solution No. 1OH. The organic layer was then washed well with water, dried over MgSO ₄ , filtered and concentrated. (4-Methoxyphenylsulfanyl) acetic acid ethyl ester was isolated as a pale yellow oil. Exit:

4.4 g (100%); MS: 227 (M + H) ⁺ .

Ethyl (4-methoxyphenylsulfanyl) acetic acid ethyl ester (4.4 g, 20 mmol) in CH2C12 (15) is slowly added to a stirred solution of 60% 3chloroperoxybenzoic acid (14.0 g, 40 mmol) in methylene chloride (100 ml) at 0 ° C. ml). The reaction mixture, which becomes cloudy, is stirred at room temperature for 6 hours. The reaction mixture is then diluted with hexanes (300 ml) and stirred for 15 minutes. The solids were filtered off and a Na ₂ 8O ₃ solution was added to the organic layer, which was stirred for at least 3 hours before the mixture was extracted with CHC13 and washed with H2O. The organic layer was dried over MgSO ₄ , filtered and concentrated, and the colorless ethyl ester of (4-methoxyphenylsulfonyl) acetic acid was isolated as an oil. Yield: 100%; MS: 259.1 (M + H) ⁺ .

To a stirred solution of diethanolamine (10.5 g, 100 mmol) and anhydrous K ₂ CO ₃ (30 g, excess) in dry acetone (250 ml) in a round bottom flask was added benzyl bromide (17.2 g, 100 mmol) and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end of this time, the reaction mixture was allowed to cool and the potassium salts were separated by filtration and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H ₂ O. The organic layer was then washed well with water, dried over MgSO ₄ , filtered and concentrated. Colorless oil. Yield: 19.0 g, 97%; MS: 196 (M + H).

Ν-Benzyldiethanolamine (9.75 g, 50 mmol) is dissolved in a saturated solution of hydrochloric acid in methanol and concentrated to dryness. The hydrochloride thus formed was dissolved in methylene chloride (300 ml) and thionyl chloride (20 g, excess) was added dropwise and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated to dryness and the product, bis- (2-chloroethyl) benzylamine hydrochloride, was used for further conversion without any purification. Yield: 13.0 g, 97%, mp: MS: 232 (M + H).

To a stirred solution of bis- (2-chloroethyl) benzylamine hydrochloride (6.6 g, 24.7 mmol), 18-crown-6 (500 mg) and anhydrous K2CO3 (30 g, excess) in dry acetone (250 ml) in ethyl ester (4 methoxyphenylsulfonyl) acetic acid (6.12 g, 24 mmol) was added to the round bottom flask and the reaction mixture was heated at reflux for 16 hours with good stirring. At the end of this time, the reaction mixture is allowed to cool and the potassium salts are removed by filtration and the reaction mixture is concentrated. The residue was extracted with chloroform and washed with H ₂ O. The organic layer was then washed well with water, dried over MgSO ₄ , filtered and concentrated. The dark brown reaction mixture was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane, and the product 4- (4-methoxybenzenesulfonyl) -1benzylpiperidin-4-carboxylic acid ethyl ester was isolated as a brown oil. Yield: 6.0 g, 60%; MS: 418 (M + H).

4- (4-Methoxybenzenesulfonyl) -1-benzylpiperidin-4-carboxylic acid ethyl ester (5.0 g, 11.9 mmol) was dissolved in MeOH / THF (1: 1, 200 ml) and the solution was stirred at room temperature in for 72 hours. At the end of this time, the reaction mixture was concentrated and the product was neutralized with concentrated HCl, dissolving in water (200 ml).

After neutralization, the reaction mixture was concentrated to dryness. Ice-cooled water (100 ml) was added to the solid and filtered. The product, 4- (4-methoxybenzenesulfonyl) -1-benzylpiperidin-4-carboxylic acid, was dried at 50 ° C and used in the next step without any purification. Colorless solid. Yield: 3.2 g, 69%; MS: 390 (M + H).

To a stirred solution of 4- (4-methoxybenzenesulfonyl) -1-benzylpiperidine 4-carboxylic acid (2.0 g, 5.1 mmol) and DMF (2 drops) in CH2C12 (100 ml) at 0 ° C., oxalyl chloride (1.0) was added dropwise. g, 8 mmol). After addition, the reaction mixture was stirred at room temperature for 1 h. At the same time, in a separate flask, a mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) and triethylamine (5 ml, excess) was stirred in a mixture of THF: water (5: 1, 30 ml) at 0 ° C for 1 h. At the end of 1 h, the reaction mixture of oxalyl chloride was concentrated and the pale yellow residue was dissolved in 10 ml of CH2C12 and slowly added to hydroxylamine at 0 ° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The resulting residue was extracted with chloroform and washed well with water. The resulting product was purified by silica gel column chromatography and eluted with chloroform. The product, 4- (4-methoxybenzenesulfonyl) -1benzylpiperidin-4-carboxylic acid hydroxyamide, is isolated as a colorless solid, mp. 90-95 ° C; yield 1.2 g, 48%; MS: 405 (M + H) ⁺ . '11 NMR (300 MHz, DMSO-b ₆ ): δ 2.29 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H), 4.30 (s , 2H),

7.14-7.17 (d, 2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H),

10.53 (s, 1H); 11.18 (s, 1H).

Example 84. 4- (4-Methoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid hydroxyamide.

2- [(2-Hydroxyethyl) - (3-methoxybenzyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g, 31.9 mmol). Yield 9.28 g (99%); yellow oil; MS: 226 (M + H).

3- Methoxybenzyl bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from 3-methoxybenzyl diethanolamine (4.4 g, 20 mmol). Yield 4.5 g (93%); yellow solid with so pl. 86-88 ° C; MS: 263 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) ethyl acetate (5.0 g) , 22 mmol) and bis- (2-chloroethyl) - (3methoxybenzyl) amine (8.0 g, 23.5 mmol). Yield 2.4 g (24%); low melting solid; MS: 447.9 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid is prepared from 4- (4methoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid ethyl ester (2 4 g, 5.36 mmol) dissolved in methanol (30 ml), 10N. sodium hydroxide (10 ml), tetrahydrofuran (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 710 mg (32%), white solid, mp. 199 ° C, MS: 419.9 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (3-methoxybenzyl) piperidine-4-carboxylic acid (830 mg, 1.98 mmol) and following the procedure described in Example 83, 190 mg of 4- (4-methoxybenzenesulfonyl hydroxyamide ) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid is isolated in the form of a white solid, so pl. 130 ° C; yield 20.4%; MS: 435.0 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-b ₆ ): δ 2.24-2.32 (m, 2H),

2.51 (d, 2H), 2.73-2.83 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 4 32 (s, 2H), 7.01-7.77 (m, 8H), 9.38 (s, 1H), 10.1 (s, 1H).

Example 85. Hydroxyamide 1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

2 - [(2-Hydroxyethyl) - (3,4-dichlorobenzyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9 , 0 g, 46 mmol). Yield 13.8 g (99%); colorless oil; MS: 264.3 (M + H) ⁺ .

3,4-Dichlorobenzyl-bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from 3,4-dichlorobenzyl-diethanolamine (10.7 g, 41 mmol). Yield 99%; yellow solid with so pl. 218-220 ° C; MS: 301.8 (M + H).

1- (3,4-Dichlorobenzyl) -4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (2.9 g , 11 mmol) and 3,4-dichlorobenzylbis- (2-chloroethyl) amine (3.4 g, 11 mmol). Yield 5.9 g (60%); brown oil; MS: 494.5 (M + H) ⁺ .

1- (3,4-Dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidin-4-carboxylic acid ethyl ester (5.0 g, 10 mmol) dissolved in methanol (50 ml), 10 n. sodium hydroxide (15 ml) and tetrahydrofuran (75 ml). The resulting reaction mixture was worked up as described in Example 83. Yield

2.94 g (62%), MS: 458.3 (M + H) ⁺ .

Starting from 1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (2.67 g, 5.8 mmol) and following the procedure described in Example 83, 2 g of hydroxyamide 1- (3,4-Dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a white solid, mp. 192-195 ° C; yield 10%; MS: 472.9 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-b ₆ ): δ 2.20-2.28 (m, 2H), 2.76-2.79 (m, 2H), 3.43-3.44 (m, 4H), 4.30 (s, 2H),

7.14-7.17 (d, 1 = 0.030, 2H), 7.50-7.73 (d, 1 = 0.027, 1H), 7.65-7.68 (d, 1 = 0.029, 2H) 7.72-7.75 (d, 1 = 0.027, 2H), 7.87 (s, 1H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s , 1H).

Example 86. 4- (4-Methoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid hydroxyamide.

2 - [(2-Hydroxyethyl) - (4-methylbenzyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol). Yield 9.8 g (99%); MS: 209.9 (Μ + Η) ⁺ .

4-Methylbenzyl-bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from 4-methylbenzyldiethanolamine (6g, 20 mmol). Yield 5.2 (84%); yellow solid with so pl. 145-147 ° C; MS: 245.9 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (7.0 g , 27 mmol) and 4-methylbis- (2chloroethyl) amine (5.0 g, 17 mmol). Yield 4.64 g (63%); low melting solid; MS:

431.9 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid is prepared from 4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (4.3 g, 9.9 mmol ) dissolved in methanol (30 ml), 10N. sodium hydroxide (10 ml), tetrahydrofuran (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.6 g (40%), white solid, mp. 207-208 ° C; MS: 404.3 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (4-methylbenzyl) piperidine-4-carboxylic acid (1.59 g, 3.9 mmol) and following the procedure described in Example 83, 0.505 g of 4- (4- hydroxyamide methoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid is isolated in the form of a white solid, so pl. 176-177 ° C; yield 32%; MS: 419.0 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-e): δ 2.24-2.32 (m, 2H),

2.51 (t, 3Η), 2.73-2.80 (m, 2H), 3.35-3.50 (m, 4H),

3.87 (s, 3Η), 4.24 (s, 2H), 7.13-7.17 (d, I = 0.039, 2H), 7.23-7.60 (d, I = 0.036, 2H ), 7.38-7.41 (d, I = 0.025, 2H), 7.65-7.68 (d, I = 0.039, 2H).

Example 87. 4- (4-Methoxybenzenesulfonyl) -1-naphthalen-2-ylmethylpiperidin-4-carboxylic acid hydroxyamide.

2 - [(2-Hydroxyethyl) - (2-naphthyl-2-ylmethyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (6.18 g, 59 mmol) and 2- (bromomethyl) naphthalene (10 g, 45 mmol). Yield 12.7 g (96%); yellow solid with so pl. 162-164 ° C; MS: 246.0 (M + H) ⁺ .

1-Naphthalen-2-ylmethyl-bis- (2-chloroethyl) amine is prepared according to the general method as described in Example 83, starting from 2-naphthylmethyldiethanolamine (2 - [(2-hydroxyethyl) - (2-naphthyl-2ylmethyl) amino ] ethanol) (10 g, 36 mmol). Yield 9.1 (79%); brown solid with so pl. 124-126 ° C; MS: 281.9 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1-naphthalen-2-ylmethylpiperidin-4 carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) ethyl acetate (8.4 g, 32 mmol) ) and 1-naphthalene 2-ylmethyl-bis- (2-chloroethyl) amine (8.6 g, 27 mmol). Yield 6.5 g (52%); low melting solid; MS: 440.0 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1-naphthalen-2-ylmethylpiperidin-4-carboxylic acid is prepared from 4- (4methoxybenzenesulfonyl) -1-naphthalen-2-ylmethylpiperidin-4-carboxylic acid ethyl ester (6.3 g, 13 mmol) dissolved in methanol (30 ml), 10N. sodium hydroxide (30 ml) and tetrahydrofuran (30 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.3 g (36%), yellow solid with mp. 226228 ° C; MS: 440.0 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1-naphthalen-2-ylmethylpiperidin-4-carboxylic acid (2.18 g, 5.0 mmol) and following the procedure described in Example 83, 0.753 g of 4- (4-methoxybenzenesulfonyl hydroxyamide ) -1-naphthalene-2-ylmethylpiperidin-4-carboxylic acid is isolated in the form of a whitish solid, so pl. 168-170 ° C; yield 31%; MS: 455.0 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-th ₆ ): δ 2.29-

2.33 (m, 2H), 2.86-2.89 (m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3Η), 4.46 (s, 2H), 7.13-7.16 (d, I = 0.030, 2H), 7.56-7.64 (m, 3Η), 7.65-7.68 (d, I = 0.030, 2H), 7.98-8.00 (m, 3Η), 8.21 (s, 1H), 10.70 (s, 1H),

11.20 (s, 1H).

Example 88. 1-Biphenyl-4ylmethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide.

2 - [(2-Hydroxyethyl) - (1-biphenyl-4-ylmethyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (5.2 g, 49 mmol) and 4- (chloromethyl) biphenyl (10 g, 49 mmol). Yield 9.98 g (66%); white solid with so pl. 160-162 ° C; MS: 271.9 (M + H) ⁺ . It is converted to dichloride as described in Example 83.

1-Biphenyl-4-ylmethyl-4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (2.85 g, 11 mmol) and 1-biphenyl-4ylmethylbis- (2-chloroethyl) amine (3.4 g, 11 mmol). Yield 2.1 g (39%); solid, mp 176-178 ° C, MS: 494.1 (Μ + Η) ⁺ .

1-Biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) piperidin-4-carboxylic acid ethyl ester (5.7 g, mmol) dissolved in ethanol (20 ml), tetrahydrofuran (20 ml) and 10N. sodium hydroxide (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.1 g (39%), MS: 465.8 (M + H) ⁺ .

Starting from 1-biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (1.0 g, 2.2 mmol) and following the procedure described in Example 83, 0.132 g of 1-biphenyl- hydroxyamide 4-ylmethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated in the form of a tan solid, mp. 168 ° C; yield 20%; MS: 440.9 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO _6th ): δ 2.30-

2.35 (m, 2H), 2.83-2.87 (m, 2H), 3.35-3.5 (m, 4H),

3.87 (s, 3H), 7.15-7.721 (d, 1 = 0.059, 2H), 7.49-

7.65 (m, 5H), 7.68-7.74 (d, 1 = 0.06 Hz, 2H), 9.3 (s, 1H), 10.3 (C, 1H), 11.15 (s, 1H).

Example 89. 4- (4-Methoxybenzenesulfonyl) -1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid hydroxyamide.

2 - [(2-Hydroxyethyl) -1- (3-methylbut-2-enyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (4.1 g, 39 mmol) and 4-bromo. -2-methylbutene (6.0 g, 40 mmol). Yield (98%); brown oil; MS: 173.8 (M + H) ⁺ .

1- (3-Methylbut-2-enyl) bis- (2-chloroethyl) amine is prepared according to the general method as described in Example 83, starting from 2 - [(2-hydroxyethyl) -1 (3-methylbut-2- enyl) amino] ethanol (10.4 g, 50 mmol). Yield 10.5 g (99%); brown solid; MS: 210.3 (M + H).

4- (4-Methoxybenzenesulfonyl) -1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid ethyl ester is prepared according to the general method as described in Example 1, starting from (4-methoxybenzenesulfonyl) acetic acid ethyl ester (11, 32 g, 44 mmol) and 1- (3 methylbut-2-enyl) bis- (2-chloroethyl) amine (10.4 g, 50 mmol). Yield 6.2 g (36%); brown oil; MS: 395.6 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid is prepared from 4- (4methoxybenzenesulfonyl) -1- (3-methylbut-2enyl) piperidin-4- ethyl ester carboxylic acid (6.2 g, 16 mmol) dissolved in ethanol (15 ml), 10N. sodium hydroxide (10 ml) and tetrahydrofuran (75 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.2 g (21%), brown solid, mp. 196-197 ° C, MS: 367.9 (M + H) '.

Starting from 4- (4-methoxybenzenesulfonyl) 1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid (1.0 g, 3.0 mmol) and following the procedure described in Example 83, 110 mg of hydroxyamide 4 - (4-methoxybenzenesulfonyl) -1- (3-methylbut-2-en-yl) piperidine-4-carboxylic acid is isolated as a yellow solid, mp. 142-145 ° C; yield 12%; MS: 382.9 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO _6th ): δ 1.67 (s, 3H),

1.79 (s, 3H), 2.18-2.23 (m, 2H), 2.66-2.73 (m, 2H),

3.37-3.46 (m, 2H), 3.67-3.69 (m, 2H), 5.19-5.24 (m, 1H), 7.15-7.18 (d, 1 = 0.03, 2H), 7.67-7.70 (d, 1 = 0.030, 2H), 9.34 (s, 1H), 9.88 (s, 1H), 11.15 (s, 1H )

Example 90. Hydroxyamide 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine 4-carboxylic acid.

2 - [(4-Bromobenzyl) - (2-hydroxyethyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (22.5 g, 150 mmol) and 4-bromobenzyl bromide (25 g, 100 mmol ) Yield 33.66 g (99%); yellow oil; MS: 273.8 (M + H) ⁺ .

(4-Bromobenzyl) -bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from 2 - [(4-bromobenzyl) - (2-hydroxyethyl) amino] ethanol (33.28 g, 122 mmol). Yield 47 g (99%); brown solid; so pl. 125 ° C; MS: 309.8 (M + H) ⁺ .

1- (4-Bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) ethyl acetate (8.6 g, 33 5 mmol) and (4-bromobenzyl) bis- (2-chloroethyl) amine (13.3 g, 38.6 mmol). Yield 17 g (44%); brown oil; MS: 497.8 (M + H) ⁺ .

1- (4-Bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 6.18 g (40%), tan solid, mp. 215 ° C, MS:

469.7 (M + H) ⁺ .

Starting from 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (1.95 g, 4.2 mmol) and following the procedure described in Example 83, 1.29 g of hydroxyamide 1- (4-Bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a whitish solid. Yield 60%; so pl. 180 ° C; MS: 484.7 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO _6th ): δ 2.18-2.29 (m, 2H),

2.46 (d, 2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s, 2H), 7 , 18 (d, 1 = 17 Hz, 2H), 7.49 (d, 1 = 8.1 Hz, 2H), 7.65-7.68 (m, 4H), 9.37 (s, 1H) 10.5 (s, 1H).

Example 91. 4- (4-Methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidine-4-carboxylic acid hydroxyamide.

2- [(2-Hydroxyethyl) - (3-phenylpropyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (15.8 g, 151 mmol) and 1-bromo-3-phenylpropane (20 g, 101 mmol). Yield 21.31 g (95%); yellow oil; MS: 223.9 (M + H) ⁺ .

Bis- (2-chloroethyl) - (3-phenylpropyl) amine is prepared according to the general method as described in Example 83, starting from 2 - [(2-hydroxyethyl) - (3phenylpropyl) amino] ethanol (20.32 g, 90, 7 mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) ethyl acetate (12 g) 46.5 mmol) and bis- (2-chloroethyl) (3-phenylpropyl) amine (24.8 g, 93.8 mmol). Yield 11.24 g (54%); brown oil; MS: 446 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidine-4-carboxylic acid is prepared from 4- (4methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidine-4-carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. NaOH (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.67 g (47%), whitish powder; t. pl. 203 ° C, MS: 418.2 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (3-phenylpropyl) piperidine-4-carboxylic acid (4.37 g, 10.4 mmol) and following the procedure described in Example 83, 1.64 g of 4- hydroxyamide (4-Methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidine-4-carboxylic acid is isolated as a whitish solid. Yield 37%; so pl. 143 ° C; MS: 432.9 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-e): δ 1.92-1.97 (m, 2H), 2.18-2.29 (m, 2H), 2.47 (d, 2H), 2.58 (t, ί = 7.7 Hz, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (d, ί = 12.3 Hz, 2H), 3.87 (s, 2H), 7.15-7.30 (m, 7H), 7.68 (d, ί = 9 Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

Example 92. Hydroxyamide 1-tert-butyl-4 (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

The tert-butyl bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from 1-tert-butyl diethanolamine (6 g, 37.2 mmol). Yield 11.15 g (99%); white solid; MS: 197.8 (M + H) ⁺ .

1-tert-Butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4methoxybenzenesulfonyl) acetic acid (10 g, 38.76 mmol) and tert-butyl bis- (2-chloroethyl) amine (5.25 g, 22.53 mmol). Yield 5.37 g (62%); brown oil; MS: 384 (M + H) ⁺ .

1-tert-Butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-tert-butyl-4 (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (5.37 g, 14 mmol) dissolved in methanol (300 ml) and 10n. sodium hydroxide (23 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.52 g (30.6%); White powder; t. pl. 204 ° C; MS: 356 (M + H) ⁺ .

Starting from 1-tert-butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (320 mg, 0.9 mmol) and following the procedure described in Example 83, 190 mg of 1-tert-butyl-4- hydroxyamide (4-Methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a green solid. Yield 52%; t. pl. 40 ° C; MS: 371.1 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO- ₆ ): δ 1.29 (s, 9H), 1.54 (m, 2H), 1.66 (m, 2H), 2.39 (m, 2H), 2 98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.67 (d, 2H).

Example 93. Hydroxyamide 1-butyl-4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

Butyl bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from Ν-butyldiethanolamine (6 g, 37.2 mmol). Yield 11.3 g (99%); White powder; t. pl. 165 ° C; MS: 197.9 (M + H) ⁺ .

1-Butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4methoxybenzenesulfonyl) acetic acid (5 g, 19.38 mmol) and butyl bis- (2-chloroethyl) amine (4.52 g, 19.38 mmol). Yield 6.86 g (93%); brown oil; MS: 384 (M + H) ⁺ .

1-Butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (6.42 g, 16.8 mmol ) dissolved in methanol (200 ml) and 10n. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.6 g (27%), white powder; t. pl. 206 ° C, MS: 356.4 (M + H) ⁺ .

Starting from 1-butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (1.51 g, 4.3 mmol) and following the procedure described in Example 83, 200 mg of 1-butyl-4- (4-methoxybenzenesulfonyl hydroxyamide ) piperidine-4-carboxylic acid is isolated as a whitish solid. Yield 9.3%; so pl. 75 ° C; MS: 371.1 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-de): δ 0.87 (t, ί = 7.2 Hz, 3H), 1.27 (m, 2H), 1.59 (m, 2H), 2.27 ( m, 2H), 2.45 (m, 2H),

2.50 (m, 2H), 2.65 (m, 2H), 2.97 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.69 (d , 2H).

Example 94. Hydroxyamide 1-cyclooctyl-4 (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

Cyclooctyl bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from Ν-cyclooctyl diethanolamine (6 g, 28 mmol). Yield 10 g (99%); whitish solid; so pl. 158 ° C; MS: 251.9 (M + H) ⁺ .

1-Cyclooctyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (5 g, 19.4 mmol) ) and cyclooctyl bis- (2-chloroethyl) amine (5.57 g, 19.4 mmol). Yield 8.2 g (96%); brown oil; MS: 438 (M + H) ⁺ .

1-Cyclooctyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-cyclooctyl-4 (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (8 g, 18.3 mmol), dissolved in methanol (200 ml) and 10n. No. JUN (25 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.36 g (32%), white powder; so pl. 180 ° C, MS: 410 (M + H) ⁺ .

Starting from 1-cyclooctyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (2.26 g, 5.53 mmol) and following the procedure described in Example 83, 570 mg of 1-cyclooctyl-4- (4 -methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a white powder. Yield 22%; t. pl. > 200 ° C; MS: 425 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.42-1.66 (m, 14H), 1.83 (m, 2H),

2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H), 3.88 (s, 3H), 7.17 (d, 2H), 7 66 (d, 2H).

Example 95. Hydroxyamide 1-ethyl-4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1-Ethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4 methoxybenzenesulfonyl) acetic acid (3 g, 11.6 mmol) and ethyl bis- (2-chloroethyl) amine (2.39 g, 11.6 mmol). Yield 3.09 g (75%); low melting brown solid; MS: 356 (M + H) ⁺ .

1-ethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-ethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol ) dissolved in methanol (100 ml) and 10n. No. JUN (15 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.29 g (58%), white solid; t. pl. 209 ° C, MS: 328 (M + H) ⁺ .

Starting from 1-ethyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (1.23 g, 3.76 mmol) and following the procedure described in Example 83, 1.02 g of 1-ethyl-4- hydroxyamide (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield 80%; so pl. 85 ° C; MS: 343 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.926 (t, 1 = 7.1 Hz, 3H), 1.68-1.89 (m, 4H), 2.052.24 (m, 4H), 2 73 (q, 2H), 3.85 (s, 3H), 7.07 (d, 2H), 7.64 (d, 2H).

Example 96. 1-Isopropyl-4 (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide.

1-Isopropyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4 methoxybenzenesulfonyl) acetic acid (5.7 g, 22.2 mmol) and isopropyl bis- (2chlorethyl) amine (4.9 g, 22.2 mmol). Yield 5.64 g (68%); low melting brown solid; MS: 370 (M + H) ⁺ .

1-Isopropyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-isopropyl-4 (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10n. No. JUN (25 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.18 g (42%) white powder; so pl. 204 ° C, MS: 341.9 (M + H) ⁺ .

Starting from 1-isopropyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (2.13 g, 6.25 mmol) and following the procedure described in Example 83, 590 mg of isopropyl-4- (4- hydroxyamide 1 methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a white powder. Yield 2.4%; so pl. 75 ° C; MS: 357 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.21 (d, 1 = 6.6 Hz, 6H), 2.33-3.53 (m, 9H), 3.88 (s, 3H) 7.16 (d, 2H); 7.66 (d, 2H).

Example 97. Hydroxyamide 1-methyl-4- (4methoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1-Methyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4methoxybenzenesulfonyl) acetic acid (3 g, 11.6 mmol) and methyl bis- (2-chloroethyl) amine (2.2 g, 11.6 mmol). Yield 3.09 g (75%); low melting brown solid; MS: 342 (M + H) ⁺ .

1-Methyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-methyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (8.7 g, 25.6 mmol ) dissolved in methanol (300 ml) and 10n. No. JUN (35 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.23 g (41%), white solid; so pl. 204 ° C, MS: 313.9 (M + H) ⁺ .

Starting from 1-methyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (2.0 g, 6.38 mmol) and following the procedure described in Example 83, 1.10 g of 1methyl-4- hydroxyamide (4 -methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a yellow powder. Yield 53%; so pl. 89 ° C; MS: 329 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.67-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05 (s, 3H), 2, 17 (d, 1 = 11.4 Hz, 2H), 2.57 (d, 1 = 10.4 Hz, 2H),

3.83 (s, 3H), 7.02 (d, 2H), 7.62 (d, 2H).

Example 98. Hydroxyamide 1-benzyl-4- (4butoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1-Benzyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4butoxybenzenesulfonyl) acetic acid (6 g, 20 mmol) and bis- ( 2-chloroethyl) benzylamine (10 g, 30 mmol). Yield 5.15 g (56%); yellow oil; MS: 460 (M + H) ⁺ .

1-Benzyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-benzyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol ) dissolved in a 3: 1 mixture of THF: methanol and 10n. No. JUN (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.66 g (56%), whitish solid; t. pl. 210 ° C, MS: 432 (M + H) ⁺ .

Starting from 1-benzyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid (2.61 g, 6.06 mmol) and following the procedure described in Example 83, 860 mg of 1-benzyl-4- (4-butoxybenzenesulfonyl hydroxyamide ) piperidine-4-carboxylic acid is isolated as a whitish powder. Yield 32%; so pl. 144 ° C; MS: 446.9 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO ₆ ): δ 0.94 (t, 1 = 7.3 Hz, 3H), 1.44 (q, 1 = 7.5 Hz, 2H), 1.70 (q, 2H), 2.28-2.32 (m, 2H), 2.50 (d, 2H), 2.74-2.83 (m, 2H), 3.35 (d, 2H), 4.08 (t, 1 = 6.3 Hz, 2H), 4.34 (s, 2H), 7.13 (d, 1 = 8.7, 2H), 7.45 (s,

3H), 7.54 (s, 2H), 7.74 (d, 1 = 8.7, 2H), 9.35 (s,

1H), 10.7 (s, 1H).

Example 99. Hydroxyamide 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine 4-carboxylic acid.

1- (4-Fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) ethyl acetate (18.8 g, 72 , 8 mmol) and (4-fluorobenzyl) bis- (2-chloroethyl) amine (20.8 g, 73 mmol). Yield 25 g (79%); brown oil; MS: 436.9 (M + H) ⁺ .

1- (4-Fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (17.4 g, 40 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10n. No. YOUNG (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 10.8 g (66%), white solid; so pl. 154 ° C, MS: 408 (M + H) ⁺ .

Starting from 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (8.14 g, 20 mmol) and following the procedure described in Example 83, 4.3 g of hydroxyamide 1- ( 4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield 51%; so pl. 176-178 ° C; MS: 484.7 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 2.12-2.20 (m, 2H), 2.64-2.79 (m, 2H), 3.32-3.45 (m, 4H ), 3.87 (s, 3H),

4.31 (s, 2H), 7.14-7.19 (d, 1 = 17 Hz, 2H), 7.27-

7.33 (d, 1 = 8.1 Hz, 2H), 7.50-7.54 (d, 2H), 7.65-

7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).

Example 100. Hydroxyamide 1- (4-fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1- (4-Fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-butoxybenzenesulfonyl) ethyl acetate (6 g, 20 mmol) and (4-fluorobenzyl) bis- (2chloroethyl) amine (5.73 g, 20 mmol). Yield 8.2 g (86%); yellow oil; MS: 478 (M + H) ⁺ .

1- (4-Fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1- (4-fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidin-4-carboxylic acid ethyl ester (4 , 77 g, 10 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. No. 1OH (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.5 g (79%), whitish solid; so pl. 114 ° C, MS: 450 (M + H) ⁺ .

Starting from 1- (4-fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid (2.24 g, 5.0 mmol) and following the procedure described in Example 83, 200 mg of hydroxyamide 1- (4 -fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is isolated as a whitish powder. Yield 9%; so pl. 112 ° C; MS: 465.9 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.94 (t, 1 = 7.3 Hz, 3H), 1.35-

1.50 (m, 2H), 1.68-1.77 (m, 2H), 2.20-2.28 (m, 2H),

2.66-2.77 (m, 2H), 3.77-3.78 (m, 4H), 4.06-4.10 (m, 2H), 4.19 (s, 2H), 7, 14-7.19 (d, 1 = 8.7, 2H), 7.27-

7.33 (d, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H),

9.34 (s, 1H); 10.55 (s, 1H).

Example 101. 4- (4-Methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid hydroxyamide.

2- [(2-Hydroxyethyl) - (4-methoxybenzyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride (14.2 g, 100 mmol). Yield 17.5 g (77%); yellow oil; MS: 226 (M + H).

The 4-methoxybenzyl bis- (2-chloroethyl) amine was prepared according to the general method as described in Example 83, starting from 4-methoxybenzyl diethanolamine (10 g, 44 mmol). Yield 10 g (75%); yellow solid, mp 55 ° C; MS: 263.1 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidin-4-car83bonic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (5.0 g, 20 mmol) and bis- (2-chloroethyl) - (4methoxybenzyl) amine (7.0 g, 22 mmol). Yield 5.0 g (56%); low melting solid; MS: 448.5 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid is prepared from 4- (4methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid ethyl ester (4.2 g, 10 mmol) dissolved in methanol (30 ml), 10n. sodium hydroxide (10 ml), tetrahydrofuran (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (71%), white solid, mp. 190 ° C. MS: 420.4 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (4-methoxybenzyl) piperidine-4-carboxylic acid (2.0 g, 4.7 mmol) and following the procedure described in Example 83, 1.2 g of hydroxyamide 4- ( 4-methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid is isolated as a white solid, mp. 175 ° C (HC1); yield: 1.2 g, 59%; MS: 433.0 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO _6th ): δ 1.8 (m, 4H), 2.3 (m, 2H), 2.73 (m, 2H), 3.37 (d, 2H), 3 76 (s, 3H), 3.88 (s, 3H), 6.87 (d, 2H), 7.11 (d, 2H),

7.21 (d, 2H), 7.65 (d, 2H), 9.2 (br s, 1H), 10.9 (br s, 1H).

Example 102. 4- (4-Methoxybenzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid hydroxyamide.

2 - {(2-Hydroxyethyl) - [2- (4-methoxyphenyl) ethyl] amino} ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (10.0 g, excess) and 1- (2- chloroethyl) -4 methoxybenzene (8.5 g, 50 mmol). Yield 11 g (92%); yellow oil; MS: 240 (M + H).

The corresponding dichloride, bis- (2-chloroethyl) - (4-methoxyphenyl-2-ethyl) amine, is prepared according to the general method as described in Example 83, starting from 2 - {(2-hydroxyethyl) - [2- (4- methoxyphenyl) ethyl] amino} ethanol (10 g, 41.8 mmol). Yield 11 g (95%); brown oil; MS: 277.2 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine 4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) acetic acid ethyl ester (5 , 0 g, 20 mmol) and bis (2-chloroethyl) - (4-methoxyphenyl-2-ethyl) amine (6.4 g, 20 mmol). Yield 6.0 g (65%); brown oil; MS: 462.5 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid is prepared from 4 (4-methoxybenzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl ester ] piperidine-4-carboxylic acid (5.0 g, 10.8 mmol) dissolved in a 3: 1 THF mixture:

methanol and 10n. HaON (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.0 g (85%), whitish powder, mp. 205 ° C. MS: 434.5 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid (1.5 g, 3.46 mmol) and following the procedure described in Example 83, 900 mg of hydroxyamide 4- (4-methoxybenzenesulfonyl) -1 [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid is isolated as a whitish solid. Yield 58%; so pl. 206 ° C (HC1);

MS: 449.5 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSO _6th ): δ 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H),

2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m, 4H), 3.60 (d, 1 = 12.3 Hz, 2H), 3.77 (s, 3H ), 3.99 (s, 3H), 6.9 (d, 2H), 7.1-7.25 (q, 4H), 7.7 (d, 2H), 9.3 (C, 1H) 10.6 (s, 1H).

Example 103. Hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- (2-phenylethyl) piperidine-4 carboxylic acid.

2 - [(2-Hydroxyethyl) - (2-phenylethyl) amino] ethanol was prepared according to the general method as described in Example 1, starting from diethanolamine (6.0 g, 57) and 2-bromoethylbenzene (9.0 g, 48 , 3 mmol). Yield 9 g (90%); yellow oil; MS: 210 (M + H).

Bis- (2-chloroethyl) - (2-phenylethyl) amine was prepared according to the general method as described in Example 83, starting from 2 - [(2-hydroxyethyl) - (2-phenylethyl) amino] ethanol (8.5 g, 40.6 mmol). Yield 11 g (95%); brown oil; MS: 247.1 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (2-phenylethyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (5.0 g , 20 mmol) and bis- (2-chloroethyl) - (2phenylethyl) amine (5.6 g, 20 mmol). Yield 5.5 g (63%); brown oil; MS: 432.5 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (2-phenylethyl) piperidine-4-carboxylic acid is prepared from 4- (4methoxybenzenesulfonyl) -1- (2-phenylethyl) piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. HaON (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.0 g (72%), whitish powder, mp. 208 ° C; MS: 404.5 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (2-phenylethyl) piperidine-4-carboxylic acid (1.5 g, 3.7 mmol) and following the procedure described in Example 83, 900 mg of 4- (4- hydroxyamide methoxybenzenesulfonyl) -1- (2-phenylethyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield 58%; t. pl. 205 ° C (HC1); MS: 419.4 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-a ₆ ): δ 2.3 (m, 2H), 2.5 (m, 3H),

2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m, 4H),

3.9 (s, 3H), 7.22-7.8 (m, 9H), 10.6 (s, 1H), 11.2 (br s, 1H).

Example 104. 4- (4-n-Butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid hydroxyamide.

4- (4-n-Butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-n-butoxybenzenesulfonyl) acetic acid ethyl ester (2, 5 g, 10 mmol) and bis (2-chloroethyl) - (4-methoxybenzyl) amine (3.0 g, 10 mmol). Yield 3.5 g (71%); low melting solid; MS: 490.5 (M + H) ⁺ .

4- (4-n-Butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid is prepared from 4- (4-n-butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidin-4-carboxylic acid ethyl ester (3.0 g, 6.1 mmol) dissolved in methanol (30 ml), 10N. sodium hydroxide (10 ml), tetrahydrofuran (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.5 g (53%), white solid, mp. 207 ° C; MS: 462.5 (M + H) ⁺ .

Starting from 4- (4-n-butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid (1.0 g, 2.1 mmol) and following the procedure described in Example 83, 1.2 g of hydroxyamide 4- (4-n-butoxybenzenesulfonyl) -1- (4methoxybenzyl) piperidine-4-carboxylic acid is isolated as a white solid, mp. 173 ° C (HC1); yield: 800 mg, 77%; MS:

477.5 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-be): δ

0.9 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H),

2.5 (m, 2H), 2.7 (m, 2H), 3.3 (m, 2H), 3.5 (m, 2H),

4.1 (t, 2H), 4.3 (m, 2H), 6.97 (d, 2H), 7.14 (d, 2H),

7.48 (d, 2H), 7.7 (d, 2H), 9.4 (br s, 1H), 10.9 (br s, 1H).

Example 105. 4- (4-Methoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid hydroxyamide.

2 - [(2-Hydroxyethyl) - (3-phenoxypropyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (15.8 g, 151 mmol) and 3-phenoxypropyl bromide (21.5 g, 100 mmol). Yield 21.31 g (95%); yellow oil; MS: 238.1 (M + H).

Bis- (2-Chloroethyl) - (3-phenoxypropyl) amine was prepared according to the general method as described in Example 83, starting from 2 - [(2-hydroxyethyl) - (3phenoxypropyl) amino] ethanol (20.0 g, 84 mmol) ) Yield 24.0 g (91%); brown oil; MS: 277.8 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl (4-methoxybenzenesulfonyl) acetic acid (5.2 g , 20 mmol) and bis- (2-chloroethyl) - (3phenoxypropyl) amine (7.0 g, 22 mmol). Exit

6.5 g (70%); brown oil; MS: 462.5 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid is prepared from 4- (4-methoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid ethyl ester g, 9.1 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. HaON (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (75%), whitish powder, mp. 195 ° C; MS: 434.5 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (3-phenoxypropyl) piperidine-4-carboxylic acid (2.5 g, 5.77 mmol) and following the procedure described in Example 83, 1.2 g of hydroxyamide 4- ( 4-methoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield 46%; t. pl. 101 ° C; MS: 448.5 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (m, 2H), 3.87 (s, 3H), 4.01 (t, 2H),

6.9-7.7 (m, 9H), 9.33 (br s, 1H), 10.28 (br s, 1H).

Example 106. 4- (4-n-Butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid hydroxyamide.

4- (4-n-Butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-n-butoxybenzenesulfonyl) ethyl acetate ( 3.0 g, 10 mmol) and bis- (2-chloroethyl) - (3phenoxypropyl) amine (3.0 g, 11 mmol). Exit

4.5 g (89%); brown oil; MS: 504.6 (M + H) ⁺ .

4- (4-n-Butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid is prepared from 4- (4-n-butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid ethyl ester (4.0 g, 7.9 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. HaON (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (79%), whitish powder, mp. 191 ° C; MS: 476.5 (M + H) ⁺ .

Starting from 4- (4-n-butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid (700 mg, 1.4 mmol) and following the procedure described in Example 83, 300 mg of hydroxyamide 4- (4 -n-butoxybenzenesulfonyl) -1 (3-phenoxypropyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield: 43%; t. pl. 84 ° C; MS: 491.5 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.9 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 2.18 (m, 2H), 2 3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.2 (m, 2H), 3.40 (m, 6H), 3, 97 (t, 2H), 4.1 (t, 2H), 6.9-7.7 (m, 9H), 10.7 (br s, 1H), 11.28 (br s, 1H) .

Example 107. Hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid.

2 - [(2-Hydroxyethyl) - (2-phenoxyethyl) amino] ethanol was prepared according to the general method as described in Example 83, starting from diethanolamine (15.0 g, 150) and 2-chlorophenetole (15.6 g, 100 mmol). Yield 18 g (80%); colorless oil; MS: 226 (M + H) ⁺ .

Bis- (2-Chloroethyl) - (2-phenoxyethyl) amine was prepared according to the general method as described in Example 83, starting from 2 - [(2-hydroxyethyl) - (2phenoxyethyl) amino] ethanol (20.0 g, 88, 8 mmol). Yield 25 g (94%); brown oil; MS: 263.1 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) ethyl acetate (5.0 g) , 20 mmol) and bis- (2-chloroethyl) - (2phenoxyethyl) amine (6.0 g, 20 mmol). Yield 5.8 g (64%); brown oil; MS: 448.5 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid is prepared from 4- (4-methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid ethyl ester (5 , 0 g, 11.1 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. NaOH (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (63%), whitish powder, mp. 235 ° C; MS: 420.5 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (2-phenoxyethyl) piperidine-4-carboxylic acid (2.5 g, 5.9 mmol) and following the procedure described in Example 83, 1.3 g of hydroxyamide 4 (4 -methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield: 50%; so pl. 168-172 ° C (HC1); MS: 435.4 (M + H) ⁺ ; 'H NMR (300 MHz, DMSO-b ₆ ): δ 2.3 (m, 2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m, 2H), 3.9 (s, 3H), 4.4 (m, 2H), 6.9-7.8 (m, 9H),

9.3 (s, 1H), 10.2 (br s, 1H), 11.3 (s, 1H).

Example 108. 4- (4-n-Butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid hydroxyamide.

4- (4-n-Butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from (4-methoxybenzenesulfonyl) acetic acid ethyl ester (2, 5 g, 10 mmol) and bis- (2-chloroethyl) - (2phenoxyethyl) amine (2.98 g, 10 mmol). Yield 3.0 g (69%); brown oil; MS: 490.6 (M + H) ⁺ .

4- (4-n-Butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid is prepared from 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. NaOH (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.5 g (56%), whitish powder, mp. 204 ° C; MS: 462.5 (M + H) ⁺ .

Starting from 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid (1.0 g, 2.16 mmol) and following the procedure described in Example 83, 600 mg of 4- hydroxyamide (4-n-butoxybenzenesulfonyl) -1- (2phenoxyethyl) piperidine-4-carboxylic acid is isolated as an off-white solid. Yield: 58%; t. pl. 112 ° C; MS: 477.4 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-b6): δ 0.942 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 4H), 2.8 (m, 2H), 2.9-3.4 (m, 4H), 3.3 (m, 4H), 4.2 (t, 2H),

4.4 (m, 2H), 6.9-7.7 (m, 9H), 9.4 (s, 1H), 10.5 (br s, 1H), 11.3 (s, 1H).

Example 109. 4- (4-Methoxybenzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide.

Bis- (2-chloroethyl) - [4- (2-piperidin-1-yl-ethoxy) benzyl] amine was prepared according to the general method as described in Example 83, starting from diethanolamine (15.0 g, 150) and 4- (2 -piperidin-1-yl-ethoxy) benzyl chloride (5.9 g, 20 mmol). Exit

5.5 g (85%); brown semi-solid; MS: 323 (M + H) ⁺ .

Bis- (2-chloroethyl) - [4- (2-piperidin-1-yl-ethoxy) benzyl] amine is prepared according to the general method as described in Example 83, starting from 2 - [(2-hydroxyethyl)] - [4- (2- piperidin-1-yl-ethoxy) benzyl] amine (3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS:

361.1 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid ethyl ester was prepared according to the general method as described in Example 83, starting from ethyl ester (4- methoxybenzenesulfonyl) acetic acid (5.0 g, 20 mmol) and bis- (2-chloroethyl) - [4- (2-piperidin-1-yl-ethoxy) benzyl] amine (8.6 g, 20 mmol). Yield 6.0 g (55%); brown oil; MS: 545.7 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid is prepared from 4- (4-methoxybenzenesulfonyl) -1- [4- ( 2piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid (5.4 g, 10 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. NaOH (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.0 g (77%), whitish powder, mp. 174 ° C; MS:

517.6 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid (3.5 g, 6.78 mmol) and following the procedure described in Example 83 , 1.8 g of 4- (4-methoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid hydroxyamide are isolated in a vi89 pale yellow solid. Yield: 49%; so pl. 114 ° C (HC1); MS: 532 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 1.4-1.6 (m, 4H), 1.9 (m, 2H), 2.3 (m, 2H), 2.8 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H), 4.2 (m, 1H), 6.9-7.8 (m, 8H), 9.1 (s, 1H ),

10.8 (br s, 1H).

Example 110. No. Hydroxy-2- (4-methoxybenzenesulfonyl) propionamide.

Stage A. The combination of 2-bromopropionic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ^! (2 g,

1.1 meq / g) was placed in a vessel for the synthesis of peptides (Syetd1a88 1ps. Paradise Shtieg CO-1866) and suspended in DMF (20 ml). 2 Bromopropionic acid (0.6 ml, 3.0 equiv.), 1-hydroxybenzotriazole hydrate (HOB !, 1.8 g, 6/0 equiv.) And 1,3-diisopropylcarbodiimide (E1C, 1.4 ml, 4) are added. , 0 equiv.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with ESM (3 x 20 ml), MeOH (2 x 20 ml) and ESM (2 x 20 ml). (Washing consists of adding solvent and stirring, either by bubbling nitrogen, or by shaking on a vibrator with a circular motion for 1-5 minutes, then filtering in vacuum). The resin is dried in vacuo at room temperature.

A resin sample (5-20 mg) was digested with ESM (0.5 ml) and TFA (0.5 ml) for 1 h at room temperature. The reaction mixture was filtered and the resin washed with an ESM (1 x 1 ml). The filtrate and washings are combined and concentrated in vacuo to 8 auap! 8 reebuas R1ik. Methanol (1 ml) was added and the mixture was concentrated. The product is then characterized by ¹ H NMR (DMSO-b6) δ 4.54 (q, 1H), 1.83 (d, 3H).

Stage B. Replacement of bromide 4-methoxybenzenethiol.

The product of the combination, No. hydroxy-2-bromopropionamide resin obtained in stage A (0.35 g, 1.1 meq. / G), was placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 4-methoxybenzenethiol (0.23 ml, 5.0 equiv.), Sodium iodide (288 mg, 5.0 equiv.) And 1,8 diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0.17 ml) are added. , 3.0 equiv.). The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2 x 2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF ( 2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product No. Hydroxy-2- (4-methoxybenzenesulfanyl) propionamide resin obtained in stage B (175 mg, 1.1 meq / g) was suspended in an ESM (3.0 ml) and 70% tert-butyl hydroperoxide was added (1, 0 ml) and benzenesulfonic acid (50 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product No. Hydroxy-2- (4-methoxybenzenesulfanyl) propionamide resin obtained in Step B (175 mg, 1.1 meq / g) was suspended in an ESM (3.0 ml) and tCPBA (180 mg) was added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2 x 2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Step E. Cleavage of No. Hydroxy-2- (4-methoxybenzenesulfonyl) propionamide from the resin.

Product No. Hydroxy-2- (4-methoxybenzenesulfonyl) propionamide resin obtained in step стадии (73 mg, 1.2 meq. / G) was suspended in an ESM (1.0 ml) and TFA (1.0 ml) was added. ) The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8auap! 8reebUas P1i8. Methanol (1 ml) was added and the mixture was concentrated.

84% @ 215 nm; Ή NMR (DMSO-b ₆ ) δ 10.75 (br.s. 1H), 7.95 (br.s, 1H), 7.71 (dd, 2H), 7.16 (dd, 2H), 3 87 (s, 3H); 3.83 (q, 1H); 1.26 (d, 3H).

The hydroxamic acids of Examples 111-113 are synthesized using suitable starting materials and following the steps in Example 110.

Example 111. No. Hydroxy-2- (4-methoxybenzenesulfanyl) propionamide.

72% @ 215 nm.

No. Hydroxy-2- (4-methoxybenzenesulfinyl) propionamide.

76% @ 215 nm; Ή NMR (DMSO-b ₆ ) δ 10.90 and 10.60 (br s, 1H), 7.95 (br s, 1H), 7.61 and 7.52 (dd, 2H), 7, 15 and 7.10 (dd, 2H), 3.83 and 3.82 (s, 3H), 3.42 and 3.28 (q, 1H), 1.23 and 0.97 (d, 3H).

Example 112. No. Hydroxy-2- (3-methylbutan1-sulfanyl) propionamide.

74% @ 215 nm.

No. Hydroxy-2- (3-methylbutane-1-sulfinyl) propionamide.

Ή NMR (DMSO-b ₆ ) δ 10.8 (br s, 1H), 7.95 (br s, 1H), 3.45 and 3.31 (q, 1H), 2.71-2, 50 (m, 2H), 1.71-1.46 (m, 3H), 1.33 and 1.25 (d, 3H), 0.940.82 (m, 6H).

Example 113. No. Hydroxy-2- (3-methylbutane-

1-sulfonyl) propionamide.

84% @ 215 nm.

Example 114. No. Hydroxy-3-methyl-2- (naphthalen-2-ylsulfanyl) butyramide.

Stage A. Combination of 2-bromo-3-methylbutyric acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (5 g,

1.1 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). 2-Bromo-3-methylbutyric acid (9.96 g, 10.0 eq) and E1C (9.04 ml, 10.5 eq) are added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of a free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with ISM (3 x 20 ml), MeOH (2 x 20 ml) and ISM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. 3amen bromide 2-naphthalene thiol.

The coupling product, 2-bromohydroxamates, obtained in Step A (0.15 g, 1.1 meq / g), was placed in a 20 ml scintillation vessel and suspended in THF (2 ml). Add

2- naphthalentiol (183 mg / 5.0 equiv), sodium iodide (129 mg, 5.0 equiv) and 1,8-diazabicyclo [5.4.0] undec-7-ene (IVI, 0.078 ml, 3, 0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and ISM (2 x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (2-naphthalenesulfanyl) -Nohydroxypropionamide resin obtained in stage B (175 mg, 1.1 meq / g), was suspended in an ISM (3.0 ml) and 70% tert-butyl hydroperoxide was added (1, 0 ml) and benzenesulfonic acid (50 mg). The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ISM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ISM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 2- (2-naphthalenesulfanyl) -Nohydroxypropionamide resin obtained in stage

In (175 mg, 1.1 meq./g), suspended in ISM (3.0 ml) and tSPBA (180 mg) was added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ISM (2x2 ml), DMF (2 x 2 ml), MeOH (2x2 ml) and ISM (2x2 ml). The resin is dried in vacuo at room temperature.

Step E. Cleavage of No. Hydroxy-3methyl-2- (naphthalen-2-ylsulfanyl) butyramide from the resin.

The product, 2- (2-naphthalenesulfanyl) -Nohydroxypropionamide resin obtained in step B (73 mg, 1.2 meq / g), was suspended in ISM (1.0 ml) and TFA (1.0 ml) was added. . The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ISM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8aui8i8 &lt; RTI &gt; Methanol (1 ml) was added and the mixture was concentrated.

83% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 276 (M + H) ⁺ . '11 NMR (DMSO-b ₆ ) δ

10.7 (broad s, 1H), 7.91 (broad s, 1H), 7.91-7.81 (m, 4H), 7.55-7.45 (m, 3H), 3 41 (d, 1H), 2.09-1.97 (m, 1H), 1.05 (d, 3H), 0.97 (d, 3H).

The hydroxamic acids of Examples 115-118 are synthesized using suitable starting materials and following the steps in Example 114.

Example 115. No. Hydroxy-3-methyl-2- (naphthalen-2-ylsulfinyl) butyramide.

67% @ 215 nm.

Example 116. No. Hydroxy-3-methyl-2- (naphthalen-2-ylsulfonyl) butyramide.

97% @ 215 nm; BCM8 (AP1 electrospray) t / ζ: 308 (M + H) ⁺ .

Example 117. No. Hydroxy-3-methyl-2-phenethylsulfinyl butyramide.

93% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 254 (M + H) ⁺ .

Example 118. No. Hydroxy-3-methyl-2-phenethylsulfonylbutyramide.

97% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 286 (M + H) ⁺ .

Example 119. Methyl ester of (1-hydroxycarbamoylpropane-1-sulfanyl) acetic acid.

Stage A. The combination of 2-bromobutyric acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (5 g,

1.1 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). Add 2-bromobutyric acid (3.0 g, 3.0 eq), NEW! (4.86 g, 6.0 eq.) And E1C (3.75 ml, 4/0 eq.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with ESM (3 x 20 ml), MeOH (2 x 20 ml) and ESM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide methylthioglycolate.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.45 g, 1.1 meq. / G), was placed in a 20 ml scintillation vessel and suspended in THF (2 ml). Methyl thioglycolate (286 mg, 5.0 eq), sodium iodide (404 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0.24 ml, 3 , 0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and OSM (2 x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, methyl (1-hydroxycarbamoylpropane-1-sulfanyl) acetic acid-resin obtained in step B (150 mg, 1.1 meq / g), was suspended in OCM (3.0 ml) and 70% tert- butyl hydroperoxide (1.0 ml) and benzenesulfonic acid (50 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with OS.M (2x2 ml), DMF (2 x 2 ml), MeOH (2x2 ml) and OSM (2x 2 ml ) The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, (1-hydroxycarbamoylpropane-1-sulfanyl) acetic acid methyl ester-resin obtained in Step B (150 mg, 1.1 meq / g), was suspended in OCM (3.0 ml) and tSPBA (180 mg) was added. ) The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with OSM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and OSM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of methyl ester (1-hydroxycarbamoylpropane-1-sulfanyl) acetic acid from the resin.

The product, methyl (1-hydroxycarbamoylpropane-1-sulfanyl) acetic acid-resin obtained in step B (150 mg, 1.2 meq / g), was suspended in OCM (1.0 ml) and TFA was added (1, 0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with OSM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8aua! 8 reebuas P1i§. Methanol (1 ml) was added and the mixture was concentrated. BCM8 (AP1 electrospray) t / ζ 228 (M + Νη) '.

The hydroxamic acids of Examples 120-124 are synthesized using suitable starting materials and following the steps in Example 119.

Example 120. Hydroxyamide (1-hydroxycarbamoylpropane-1-sulfonyl) acetic acid.

BCM8 (AP1 electrospray) t / ζ 224 (M + H) ⁺ .

Example 121. Hydroxyamide (1-hydroxycarbamoylpropane-1-sulfinyl) acetic acid.

100% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 240 (M + H) ⁺ .

Example 122. Hydroxyamide (1-hydroxycarbamoylpropane-1-sulfanyl) propionic acid.

'H NMR (DMSO-be) δ 10.7 (br s, 1H), 4.03 (t, 2H), 2.95 (q, 1H), 2.75-2.70 (m, 1H) 2.60-2.54 (m, 1H), 1.74-1.66 (m, 2H), 1.58-1.50 (m, 4H), 1.32 (sextet, 2H), 0 88 (t, 3H); 0.85 (t, 3H); BCM8 (AP1 electrospray) t / ζ 264 (M + H) ⁺ .

Example 123. Hydroxyamide (1-hydroxycarbamoylpropane-1-sulfinyl) propionic acid 83% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 280 (M + H) ⁺ .

Example 124. Hydroxyamide (1-hydroxycarbamoylpropan-1-sulfonyl) propionic acid.

100% @ 220 nm.

Example 125. 2- (4-Hydroxybenzenesulfanyl) -Nohydroxy-3-phenylpropionamide.

Stage A. Combination of 2-bromo-3-phenylpropionic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (5 g,

1.2 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). Add 2-bromo-3-phenylpropionic acid (3.5 g, 3.0 equiv), NEW! (4.4 g, 6.0 eq.) And E1C (3.4 ml, 4.0 eq.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of a free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with OCM (3 x 20 ml), MeOH (2 x 20 ml) and OSM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide 4-hydroxythiophenol.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.33 g, 1/2 meq./g), is placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 4-hydroxythiophenol (250 mg, 5.0 equiv.), Sodium iodide (297 mg, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0.18 ml) are added. , 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (4-hydroxybenzenesulfanyl) No. Hydroxy-3-phenylpropionamide resin obtained in Step B (110 mg, 1.1 meq / g), was suspended in an ESM (3.0 ml) and 70% tert-butyl hydroperoxide ( 0.73 ml) and benzenesulfonic acid (36 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage O. Oxidation of sulfide to sulfone.

The product, 2- (4-hydroxybenzenesulfanyl) No.Hydroxy-3-phenylpropionamide resin obtained in step B (110 mg, 1.1 meq / g), was suspended in an ESM (3.0 ml) and tCPBA (132 mg) was added. ) The reaction mixture was shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture was filtered and washed with ESM (2x2 ml), DMF (2 x 2 ml), MeOH (2 x 2 ml) and OSM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of 2- (4-hydroxybenzenesulfanyl) -I-hydroxy-3-phenylpropionamide from the resin.

The product, 2- (4-hydroxybenzenesulfanyl) No. Hydroxy-3-phenylpropionamide resin obtained in stage B (110 mg, 1.2 meq. / G), is suspended in an ESM (1.0 ml) and TFA is added (1, 0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8aui8i8 &lt; RTI &gt; Methanol (1 ml) was added and the mixture was concentrated. 84% @ 215 nm;

'H NMR (DMSO-b ₆ ) δ 10.41 (br s, 1H),

7.95 (br s, 1H), 7.30-7.15 (m, 5H), 7.10 (dd, 2H),

6.75 (dd, 2H), 3.53 (q, 1H), 3.05 (dd, 1H), 2.79 (dd, 1H).

The hydroxamic acids of Examples 126-130 are synthesized using suitable starting materials and following the steps in Example 125.

Example 126. 2- (4-Hydroxybenzenesulfinyl) -I-hydroxy-3-phenylpropionamide.

73% @ 215 nm.

Example 127. 2- (4-Hydroxybenzenesulfonyl) -I-hydroxy-3-phenylpropionamide.

77% @ 215 nm; '11 NMR (DMSO-b ₆ ) δ 10.50 (br s, 1H), 7.95 (br s, 1H), 7.68-7.57 (m, 2H), 7.28-7 17 (m, 3H), 7.08-7.98 (m, 2H), 6.95-6.87 (m, 2H), 3.96 (t, 1H), 3.02 (d, 2H) )

Example 128. 2- (4-Acetylaminobenzenesulfanyl) -I-hydroxy-3-phenylpropionamide.

86% @ 215 nm; Ή NMR (DMSO-b ₆ ) δ 10.50 (br s, 1H), 10.03 (br s, 1H), 8.13 (br s, 1H), 7.56-7.12 ( m, 9H), 3.67 (q, 1H), 3.08 (dd, 1H), 2.84 (dd, 1H), 2.04 (s, 3H).

Example 129. 2- (4-Acetylaminobenzenesulfinyl) -I-hydroxy-3-phenylpropionamide.

73% @ 215 nm.

Example 130. 2- (4-Acetylaminobenzenesulfonyl) -I-hydroxy-3-phenylpropionamide.

95% @ 215 nm.

Example 131. 4hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) butyric acid methyl ester.

Stage A. Combination of 2-bromo-5-methylglutaric acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (4.5 g,

1.2 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). Add 8-2-bromo-5-methylglutarate (3.87 g, 3.0 equiv), NEW! (4.4 g, 6.0 equiv.) And ΌΙΟ (3.4 ml, 4.0 equiv.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of a free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with OCM (3 x 20 ml), MeOH (2 x 20 ml) and OSM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide 4-hydroxythiophenol.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.22 g, 1.2 meq./g) is placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 4- (methylthio) thiophenol (206 mg, 5.0 equiv.), Sodium iodide (197 mg, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (EVI, 0) are added. 12 ml, 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2 x 2 ml) and OSM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 4-hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) butyric acid methyl resin methyl ester obtained in Step B (73 mg, 1.1 meq / g), was suspended in OCM (1.5 ml) and 70% was added. tert-butyl hydroperoxide (0.49 ml) and benzenesulfonic acid (24 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2 x 2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 4-hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) butyric acid methyl resin methyl ester obtained in Step B (73 mg, 1.1 meq / g), was suspended in an ESM (1.5 ml) and tSPBA ( 87 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2 x 2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Step E. Cleavage of 4-hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) butyric acid methyl ester from the resin.

The product, 4-hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) butyric acid methyl resin methyl ester obtained in Step B (73 mg, 1.2 meq / g), was suspended in an ESM (1.0 ml) and TFA ( 1.0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8auap1 8reauas P1i8. Methanol (1 ml) was added and the mixture was concentrated. 77% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 316 (M + H) ⁺ .

The hydroxamic acids of Examples 132-139 are synthesized using suitable starting materials and following the steps in Example 131.

Example 132. Hydroxyamide 4-hydroxycarbamoyl-4- (4-methanesulfinylphenylsulfinyl) butyric acid.

79% @ 215 nm. BCM8 (AP1 electrospray) t / ζ 348 (M + H) ⁺ .

Example 133. Hydroxyamide 4-hydroxycarbamoyl-4- (4-methanesulfonylphenylsulfonyl) butyric acid.

78% @ 215 nm. BCM8 (AP1 electrospray) t / ζ 380 (M + H) ⁺ .

Example 134. Hydroxyamide 4-hydroxycarbamoyl-4- (4-bromobenzenesulfanyl) butyric acid.

93% @ 215 nm.

Example 135. Hydroxyamide 4-hydroxycarbamoyl-4- (4-bromobenzenesulfinyl) butyric acid.

80% @ 215 nm.

Example 136. Hydroxyamide 4-hydroxycarbamoyl-4- (4-bromobenzenesulfonyl) butyric acid.

77% @ 215 nm.

Example 137. Hydroxyamide 4-hydroxycarbamoyl-4- (2-trifluoromethylbenzenesulfanyl) butyric acid.

93% @ 215 nm.

Example 138. Hydroxyamide 4-hydroxycarbamoyl-4- (2-trifluoromethylbenzenesulfinyl) butyric acid. 72% @ 215 nm.

Example 139. Hydroxyamide 4-hydroxycarbamoyl-4- (2-trifluoromethylbenzenesulfonyl) butyric acid. 90% @ 215 nm.

Example 140. 2- (3-Methoxybenzenesulfanyl) decanoic acid hydroxyamide.

Stage A. The combination of 2-bromodecanoic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (4.5 g,

1.2 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). 2-Bromodecanoic acid (4.07 g, 3.0 eq), HOB1 (4.4 g, 6.0 eq) and E1C (3.4 ml, 4.0 eq) are added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with ESM (3 x 20 ml), MeOH (2 x 20 ml) and ESM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide with 3-methoxybenzenethiol.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.22 g, 1.2 meq. / G), was placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 3-methoxybenzenethiol (185 mg, 5.0 eq.), Sodium iodide (197 mg, 5.0 eq.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (EVI, 0.12 ml) are added. , 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (3-methoxybenzenesulfanyl) decanoic acid hydroxyamide resin obtained in Step B (73 mg, 1.1 meq / g), was suspended in an ESM (1.5 ml) and 70% tert-butyl hydroperoxide (0.49) was added. ml) and benzenesulfonic acid (24 mg). The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2 x 2 ml), MeOH (2 x 2 ml) and ESM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

Product, 2- (3-methoxybenzenesulfanyl) decanoic acid hydroxyamide-resin obtained in Step B (73 mg, 1.1 meq / g), suspension99

100 was dihydrated in OSM (1.5 ml) and tSPBA (87 mg) was added. The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with OSM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and OSM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of hydroxyamide 2 (3-methoxybenzenesulfanyl) decanoic acid from the resin.

The product, 2- (3-methoxybenzenesulfanyl) decanoic acid hydroxyamide-resin obtained in Step B (73 mg, 1.2 meq / g), was suspended in OSM (1.0 ml) and TFA (1.0 ml) was added. . The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with OSM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8auap1 8reauas P1ik. Methanol (1 ml) was added and the mixture was concentrated. 89% @ 215 nm.

The hydroxamic acids of Examples 141-145 are synthesized using suitable starting materials and following the steps in Example 140.

Example 141. Hydroxyamide 2- (3-methoxybenzenesulfinyl) decanoic acid.

% @ 215 nm.

Example 142. Hydroxyamide 2- (3-methoxybenzenesulfonyl) decanoic acid.

96% @ 215 nm.

Example 143. Hydroxyamide 2- (4-methanesulfanylbenzenesulfanyl) decanoic acid. 85% @ 215 nm; BCM8 (ΑΡΙ-electrospray) t / ζ 342 (M + H) ⁺ .

Example 144. Hydroxyamide 2- (4-methanesulfinylbenzenesulfinyl) decanoic acid.

86% @ 215 nm; BCM8 (ΑΡΙ-electrospray) t / ζ 374 (M + H) ⁺ .

Example 145. Hydroxyamide 2- (4-methanesulfonylbenzenesulfonyl) decanoic acid.

92% @ 215 nm.

Example 146. 3-Benzyloxy-Nohydroxy-2 (4-methanesulfanylbenzenesulfanyl) propionamide.

Stage A. Combination of 2-bromo-3-benzyloxypropionic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (4.5 g,

1.2 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). Add 8-2-bromo-3-benzyloxypropionic acid (4.2 g, 3.0 eq), ΗΘΒΐ (4.4 g, 6.0 eq) and E1C (3.4 ml, 4.0 eq) . The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of a free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with OCM (3 x 20 ml), MeOH (2 x 20 ml) and OSM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide 4- (methylthio) thiophenol.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.22 g, 1.2 meq. / G), was placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 4- (methylthio) thiophenol (206 mg, 5.0 equiv.), Sodium iodide (197 mg, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0 12 ml, 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and OSM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 3-benzyloxy-no. Hydroxy-2- (4 methanesulfanylbenzenesulfanyl) propionamide resin obtained in step B (73 mg, 1.1 meq / g), was suspended in OCM (1.5 ml) and 70% tert-butyl hydroperoxide ( 0.49 ml) and benzenesulfonic acid (24 mg). The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with OSM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and OSM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 3-benzyloxy-no. Hydroxy-2- (4 methanesulfanylbenzenesulfanyl) propionamide resin obtained in step B (73 mg, 1.1 meq./g), was suspended in OCM (1.5 ml) and tSPBA (87 mg) was added. ) The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with OSM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and OSM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of 3-benzyloxy-No. hydroxy-2- (4-methane-sulfanylbenzenesulfanyl) propionamide from the resin.

The product, 3-benzyloxy-no. Hydroxy-2- (4 methanesulfanylbenzenesulfanyl) propionamide resin obtained in stage B (73 mg, 1.2 meq./g), was suspended in OSM (1.0 ml) and TFA was added (1, 0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with OSM (2x1 ml). The filtrate and washings are combined and concentrated to dryness at 8; · ιν; · ιηΙ 8 fluff Ρ1ι.ικ. Add methanol

101

102 (1 ml) and the mixture was concentrated. 76% @ 215 nm. BCM8 (AP1 electrospray) t / ζ 350 (M + H) ⁺ .

The hydroxamic acids of Examples 147-151 are synthesized using suitable starting materials and following the steps in Example 146.

Example 147. 3-Benzyloxy-Nohydroxy-2 (4-methanesulfinylbenzenesulfinyl) propionamide. 70% @ 215 nm. BCM8 (AP1 electrospray) t / ζ 382 (M + H) ⁺ .

Example 148. 3-Benzyloxy-Nohydroxy-2 (4-methanesulfonylbenzenesulfonyl) propionamide.

63% @ 215 nm. BCM8 (AP1 electrospray) t / ζ 414 (M + H) ⁺ .

Example 149. 3-Benzyloxy-Nohydroxy-2 (2-chlorobenzylsulfanyl) propionamide.

90% @ 215 nm.

Example 150

3- Benzyloxy-N-hydroxy-2- (2-chlorobenzylsulfinyl) propionamide.

70% @ 215 nm.

Example 151. 3-Benzyloxy-Nohydroxy-2 (2-chlorobenzylsulfonyl) propionamide.

72% @ 215 nm.

Example 152. 2- (2-Bromobenzenesulfanyl) N-hydroxy-2- (3H-imidazol-4-yl) propionamide.

Stage A. Combination of 2-bromo-3- (3H-imidazol-4-yl) propionic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (4.5 g, 1/2 meq./g) was placed in a vessel for the synthesis of peptides and suspended in DMF (40 ml). Add 8-2-bromo-3- (3H-imidazol-4-yl) propionic acid (3.55 g, 3.0 eq), NEW! (4.4 g, 6.0 eq.) And E1C (3.4 ml, 4.0 eq.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with OSU (3 x 20 ml), MeOH (2 x 20 ml) and ESM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide with 2-bromothiophenol.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.22 g, 1.2 meq. / G), was placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 2-bromothiophenol (249 mg, 5.0 equiv.), Sodium iodide (197 mg, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0.12 ml) are added. , 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene cylinder of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), with a mixture

9: 1 DMF: water (2x2 ml), DMF (2 ml), MeOH (2 x 2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (2-bromobenzenesulfanyl) -No hydroxy-3- (3H-imidazol-4-yl) propionamide resin obtained in step B (73 mg, 1.1 meq / g), was suspended in an ESM (1.5 ml) and 70% tert-butyl hydroperoxide (0.49 ml) and benzenesulfonic acid (24 mg) are added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 2- (2-bromobenzenesulfanyl) -No hydroxy-3- (3H-imidazol-4-yl) propionamide resin obtained in step B (73 mg, 1.1 meq / g), was suspended in an ESM (1.5 ml) and tSPBA (87 mg) was added. The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2 x 2 ml), DMF (2 x 2 ml), MeOH (2 x 2 ml) and ESM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage E: Cleavage of 2- (2-bromobenzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) propionamide from the resin.

The product, 2- (2-bromobenzenesulfanyl) -No hydroxy-3- (3H-imidazol-4-yl) propionamide resin obtained in step B (73 mg, 1.2 meq / g), was suspended in an ESM (1.0 ml) and TFA (1.0 ml) was added. The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8auap! 8reebUas P1iz. Methanol (1 ml) was added and the mixture was concentrated. 86% @ 215 nm.

The hydroxamic acids of Examples 153-154 are synthesized using suitable starting materials and following the steps in Example 152.

Example 153. 2- (4-Bromobenzenesulfinyl) N-hydroxy-3- (3H-imidazol-4-yl) -propionamide.

69% @ 215 nm.

Example 154. 2- (4-Chlorobenzenesulfonyl) N-hydroxy-3- (3H-imidazol-4-yl) propionamide.

Example 155. 2- (3-Fluorophenylsulfanyl) -5-guanidinopentanoic acid hydroxyamide

Stage A. Combination of 2-bromo-5-guanidinopentanoic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (4.5 g,

103

104

1.2 meq / g) is placed in a vessel for the synthesis of peptides, suspended in DMF (40 ml). Add 8-2-bromo-5-guanidinopentanoic acid (3.85 g, 3.0 eq.), NEW! (4.4 g, 6.0 eq.) And E1C (3.4 ml, 4.0 eq.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with ESM (3 x 20 ml), MeOH (2 x 20 ml) and ESM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide with 3-fluorothiophenol.

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.22 g, 1/2 meq./g), is placed in a 20 ml scintillation vessel and suspended in THF (2 ml). 3-fluorothiophenol (169 mg, 5.0 equiv.), Sodium iodide (197 mg, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0.12 ml) are added. , 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (3-fluorophenylsulfanyl) -5-guanidinopentanoic acid hydroxyamide obtained in Step B (73 mg, 1.1 meq / g), was suspended in an ESM (1.5 ml) and 70% tert-butyl hydroperoxide (0) was added. , 49 ml) and benzenesulfonic acid (24 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours

The reaction mixture was filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 2- (3-fluorophenylsulfanyl) -5-guanidino-pentanoic acid hydroxyamide obtained in step B (73 mg, 1.1 meq / g), was suspended in an ESM (1.5 ml) and tSPBA (87 mg) was added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of 2 (3-fluorophenylsulfanyl) -5-guanidinopentanoic acid hydroxyamide from the resin.

The product, 2- (3-fluorophenylsulfanyl) -5-guanidinopentanoic acid hydroxyamide obtained in Step B (73 mg, 1.2 meq / g), was suspended in an ESM (1.0 ml) and TFA (1.0 ml) was added. ) The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8 aiap1 8peaUas P1i§. Methanol (1 ml) was added and the mixture was concentrated. 93% @ 215 nm.

The hydroxamic acids of Examples 156-159 are synthesized using suitable starting materials and following the steps in Example 155.

Example 156. Hydroxyamide 2- (3-fluorophenylsulfinyl) -5-guanidinopentanoic acid.

80% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 317 (M + H) ⁺ .

Example 157. Hydroxyamide 2- (2-bromosulfanyl) -5-guanidinopentanoic acid. 92% @ 220 nm; ^! H NMR (DMSO _6th ) δ 10.90 (br s, 2H), 10.41 (br s, 1H), 7.95 (br s, 1H), 7.667.14 (m, 5H) 3.72 (q, 1H), 3.13 (q, 2H), 1.90-1.66 (m, 2H), 1.58-1.43 (2H).

Example 158. Hydroxyamide 2- (2-bromosulfinyl) -5-guanidinopentanoic acid.

79% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 379 (M + H) ⁺ .

Example 159. Hydroxyamide of 2- (2-bromosulfonyl) -5-guanidinopentanoic acid. ¹ N

NMR (DMSO- _6th ) δ 8.03-7.45 (m, 5H), 4.52 (q, 1H),

3.16 (q, 2H), 2.07-1.90 (m, 2H), 1.66-1.59 (2H).

Example 160. 2- (2,5-Dichlorobenzenesulfanyl) octanoic acid hydroxyamide.

Stage A. The combination of 2-bromoctanoic acid with hydroxylamino resin.

4-0-Methylhydroxylamine phenoxymethyl copoly (styrene-1% divinylbenzene) resin ¹ (10.0 g, 1.2 meq / g) was placed in a vessel for the synthesis of peptides and suspended in DMF (80 ml). 2-Bromoctanoic acid (8.4 g, 3.0 eq) was added, NEW !; (8.8 g, 6.0 equiv.) And E1C (7.2 ml, 4.0 equiv.). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 2-16 hours. The reaction mixture is filtered and washed with DMF (3 x 20 ml). A resin sample was taken and subjected to a Kaiser test. If the test shows the presence of free amine (the resin turns blue), the combination described above is repeated, otherwise the resin is washed with ESM (3 x 20 ml), MeOH (2 x 20 ml) and ESM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Replacement of bromide with 2,5-dichlorothiophenol.

105

106

The product of the combination, 2-bromohydroxamates, obtained in stage A (0.45 g, 1.2 meq. / G), was placed in a 20 ml scintillation vessel and suspended in THF (6 ml). 2,5-Dichlorothiophenol (483 mg, 5.0 equiv.), Sodium iodide (404 mg, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 0, 24 ml, 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours. The reaction mixture is poured into a polypropylene barrel of a syringe equipped with a polypropylene frit, filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x2 ml), DMF (2 ml ), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (2,5-dichlorobenzenesulfanyl) octanoic acid hydroxyamide-resin obtained in step B (150 mg, 1.1 meq / g), was suspended in an ESM (3.0 ml) and 70% tert-butyl hydroperoxide was added (1.0 ml) and benzenesulfonic acid (50 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 2- (2,5-dichlorobenzenesulfanyl) octanoic acid hydroxyamide-resin obtained in step B (150 mg, 1.1 meq / g), was suspended in an ESM (3.0 ml) and tCPBA (180 mg) was added. . The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of hydroxyamide 2 (2,5-dichlorobenzenesulfanyl) octanoic acid from the resin.

The product, 2- (2,5-dichlorobenzenesulfanyl) octanoic acid hydroxyamide-resin obtained in Step B (73 mg, 1.2 meq / g), was suspended in an ESM (1.0 ml) and TFA (1.0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on Zauap! ZreebUas P1ik. Methanol (1 ml) was added and the mixture was concentrated. 92% @ 215 nm;

Ή NMR (DMSO-b ₆ ) δ 10.96 (br s, 1H),

9.26 (br s, 1H), 7.93-7.76 (m, 3H), 4.07 (q, 1H), 2.04-1.85 (m, 1H), 1.78- 1.64 (m, 1H), 1.32-1.09 (m, 8H), 0.81 (t, 3H).

The hydroxamic acids of Examples 161-167 are synthesized using suitable starting materials and following the steps in Example 160.

Example 161. Hydroxyamide 2- (2,5-dichlorobenzenesulfonyl) octanoic acid.

96% @ 215 nm.

Example 162. Hydroxyamide 2- (3-methoxybenzenesulfanyl) octanoic acid.

86% @ 220 nm. LMP3 (AP1 electrospray) t / ζ 298 (M + H) ⁺ .

Example 163. Hydroxyamide 2- (3-methoxybenzenesulfinyl) octanoic acid.

96% @ 220 nm.

Example 164. Hydroxyamide 2- (3-methoxybenzenesulfonyl) octanoic acid.

83% @ 220 nm.

Example 165. 2- (3,4-Dimethoxybenzenesulfanyl) octanoic acid hydroxyamide; 87% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 328 (M + H) ⁺ .

Example 166. Hydroxyamide 2- (3,4-dimethoxybenzenesulfinyl) octanoic acid; 90% @ 215 nm.

Example 167. Hydroxyamide 2- (3,4-dimethoxybenzenesulfonyl) octanoic acid; 87% @ 215 nm.

The compounds of a number of hydroxamic acids of Examples 168-198 are synthesized using suitable starting materials and following the steps of Example 160. The crude products are dissolved in DMSO: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described below.

Column: ΟΌ3-Α, 20 mm x 50 mm, particle size 5 μm (UMS, 1ps. ΝοΠίι SagoNpa).

Solvent gradient Time Water Acetonitrile 0.0 95 5 min 5 95

Flow rate: 15 ml / min.

Example 168. Hydroxyamide 2- (2-benzimidazol-2-ylsulfanyl) octanoic acid; 81% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 308 (M + H) ⁺ .

Example 169. Hydroxyamide 2- (2-benzooxazol-2-ylsulfanyl) octanoic acid.

72% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 309 (M + H) ⁺ .

Example 170. Hydroxyamide 2- (2-benzothiazol-2-ylsulfanyl) octanoic acid; 72% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 325 (M + H) ⁺ .

Example 171. Hydroxyamide 2- (2-pyridin2-sulfanyl) octanoic acid.

76% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 269 (M + H) ⁺ .

Example 172. Hydroxyamide 2- (4-phenylthiazole-2-sulfanyl) octanoic acid.

97% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 336 (M + H) ⁺ .

Example 173. Hydroxyamide of 2- (2-pyridin2-yl-ethylsulfanyl) octanoic acid.

84% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 297 (M + H) ⁺ .

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108

Example 174. Hydroxyamide 2- (2-phenyl-5Netetrazol-5-ylsulfanyl) octanoic acid.

67% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 338 (M + H) ⁺ .

Example 175. Hydroxyamide 2- (2-pyrazine-

2-yl-ethylsulfanyl) octanoic acid.

98% @ 215 nm, bCM8 (AP1 electrospray) t / ζ 298 (M + H) ⁺ .

Example 176. Hydroxyamide 2- (1-methyl-1Netetrazol-5-ylsulfanyl) octanoic acid.

66% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 274 (M + H) ⁺ .

Example 177. Hydroxyamide 2- (2-benzimidazole-2-sulfinyl) octanoic acid.

81% @ 215 nm.

Example 178. Hydroxyamide 2- (2-pyridine-

2-sulfinyl) octanoic acid.

76% @ 215 nm.

Example 179. Hydroxyamide 2- (4-phenylthiazole-2-sulfinyl) octanoic acid.

78% @ 215 nm.

Example 180. Hydroxyamide 2- (2-pyrazin2-yl-ethylsulfinyl) octanoic acid.

96% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 314 (M + H) ⁺ .

Example 181. Hydroxyamide 2- (3-hydroxy-1H-benzimidazole-2-sulfonyl) octanoic acid.

63% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 356 (M + H) ⁺ .

Example 182. Hydroxyamide 2- (4-phenylthiazole-2-sulfonyl) octanoic acid.

70% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 383 (M + H) ⁺ .

Example 183. Hydroxyamide 2- [2- (1-hydroxypyridin-2-yl) ethanesulfonyl] octanoic acid.

77% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 345 (M + H) ⁺ .

Example 184. Hydroxyamide 3- (1-hydroxycarbamoylheptylsulfanyl) benzoic acid.

100% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 312 (M + H) ⁺ .

Example 185. 3- [4- (1-Hydroxycarbamoylheptylsulfanyl) phenyl] propionic acid hydroxyamide.

90% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 340 (M + H) ⁺ .

Example 186. Hydroxyamide 2- (thiazole-2ylsulfanyl) octanoic acid.

75% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 275 (M + H) ⁺ .

Example 187. Hydroxyamide 2- (2,5-dioxoimidazolidin-4-ylmethylsulfanyl) octanoic acid.

98% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 304 (M + H) ⁺ .

Example 188. Hydroxyamide 3- (1-hydroxycarbamoylheptylsulfinyl) benzoic acid.

84% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 328 (M + H) ⁺ .

Example 189. Hydroxyamide 3- [4- (1-hydroxycarbamoylheptylsulfinyl) phenyl] propionic acid.

78% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 356 (M + H) ⁺ .

Example 190. Hydroxyamide 2- (quinoline-8sulfinyl) octanoic acid.

87% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 335 (M + H) ⁺ .

Example 191. Hydroxyamide 2- (naphthalene-2ylmethanesulfinyl) octanoic acid.

83% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 391 (M + H) ⁺ .

Example 192. Hydroxyamide 3- (1-hydroxycarbamoylheptylsulfinyl) benzoic acid.

72% @ 215 nm.

Example 193. Hydroxyamide 3- [4- (1-hydroxycarbamoylheptylsulfonyl) phenyl] propionic acid.

67% @ 215 nm.

Example 194. Hydroxyamide 2- (1H-imidazole-2-sulfonyl) octanoic acid.

95% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 290 (M + H) ⁺ .

Example 195. Hydroxyamide 2- (thiazole-2ylsulfonyl) octanoic acid;

91% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 307 (M + H) ⁺ .

Example 196. Hydroxyamide 2- (quinoline-8sulfonyl) octanoic acid.

94% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 351 (M + H) ⁺ .

Example 197. Hydroxyamide 2- (naphthalene-2ylcarbamoylmethanesulfonyl) octanoic acid.

79% @ 220 nm; BCM8 (AP1 electrospray) t / ζ 407 (M + H) ⁺ .

Example 198. Hydroxyamide 2- (2,5-dioxoimidazolidin-4-ylmethylsulfonyl) octanoic acid.

97% @ 215 nm.

Example 199. Step A. Replacement of bromide with 4 fluorothiophenol.

The product, 2-bromohydroxamate resin, obtained in Example 160, Step A (9.4 g, 1.2 meq / g), was placed in a peptide synthesis vessel and suspended in THF (50 ml). 4-fluorothiophenol (6.6 g, 5.0 equiv.), Sodium iodide (7.7 g, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec7-ene (EVI, 4, 6 ml, 3.0 equiv.). The reaction mixture was shaken at room temperature for 12-16 hours, then filtered and washed with DMF (2 x 30 ml), 9: 1 mixture of DMF: water (2 x 30 ml), DMF (30 ml), MeOH (2 x 20 ml) and OSM (2 x 20 ml). The resin is dried in vacuo at room temperature.

Stage B. Combination of the product 2- (4-fluorobenzenesulfanyl) octanoic acid-hydroxyamide resin with benzyl alcohol.

Product, 2- (4-fluorobenzenesulfanyl) octanoic acid hydroxyamide-resin, obtained 109

110 in stage A (330 mg, 1.1 meq / g), suspended in DMF (2.0 ml) and benzyl alcohol (731 mg, 15 equiv.) And sodium hydride (237 mg, 15 equiv.) Were added. The reaction mixture is heated to 80 ° C. for 15 hours while shaking on a circular vibrator. After cooling to room temperature, the mixture was filtered and washed with DMF (2 × 2 ml), 9: 1 mixture of DMF: water (2 × 3 ml), MeOH (2 × 2 ml) and ESM (2 × 2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product, 2- (4-benzyloxyphenylsulfanyl) octanoic acid hydroxyamide resin obtained in Step B (110 mg, 1.1 meq / g), was suspended in an ESM (2.2 ml) and 70% tert-butyl hydroperoxide (0) was added. , 73 ml) and benzenesulfonic acid (36 mg). The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2x2 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product, 2- (4-benzyloxyphenylsulfanyl) octanoic acid hydroxyamide-resin obtained in Step B (110 mg, 1.1 meq / g), was suspended in an ESM (2.2 ml) and tCPBA (132 mg) was added. The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2x2 ml), DMF (2 x 2 ml), MeOH (2 x 2 ml) and ESM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of hydroxyamide 2 (4-benzyloxybenzenesulfanyl) octanoic acid from the resin.

The product, 2- (4-benzyloxyphenylsulfanyl) octanoic acid hydroxyamide resin obtained in Step B (110 mg, 1.2 meq / g), was suspended in an ESM (1.0 ml) and TFA (1.0 ml) was added. . The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on Zauap! ZreeiWas P1i§. Methanol (1 ml) was added and the mixture was concentrated. The crude product is dissolved in a mixture (1: 1, 2 ml) of DMSO: methanol and purified by reverse phase HPLC under the conditions described below.

Column: ΟΌ8-Α, 20 mm x 50 mm, particle size 5 μm (UMS, 1ps. ED11tshd1oi, ΝοΠίι Sagoyia).

Solvent Gradient Time Water Acetonitrile

0.0 95 5 min 5 95

Flow rate: 5 ml / min

2- (4-Benzyloxyphenylsulfanyl) octanoic acid hydroxyamide; 100% @ 215 nm; LMP (AP1 electrospray) t / ζ 374 (M + H) ⁺ .

The compounds of a number of hydroxamic acids of Examples 200-220 are synthesized using suitable starting materials and following the steps in Example 199.

Example 200. Hydroxyamide 2- (4-butoxybenzenesulfanyl) octanoic acid.

100% @ 215 nm; LMP (AP1 electrospray) t / ζ 374 (M + H) ⁺ .

Example 201. Hydroxyamide 2- [4- (2-piperazin-1-ylethoxy) benzenesulfanyl] octanoic acid.

98% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 340 (M + H) ⁺ .

Example 202. Hydroxyamide 2- [4- (5-hydroxypentyloxy) phenylsulfanyl] octanoic acid.

65% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 370 (M + H) ⁺ .

Example 203. Hydroxyamide 2- [4- (3-pyridin-2-ylpropoxy) benzenesulfanyl] octanoic acid.

95% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 403 (M + H) ⁺ .

Example 204. Hydroxyamide 2- (4-benzyloxyphenylsulfinyl) octanoic acid.

100% @ 215 nm.

Example 205. Hydroxyamide 2- (4-butoxybenzenesulfinyl) octanoic acid.

98% @ 215 nm.

Example 206. Hydroxyamide 2- [4- (2-piperazin-1-ylethoxy) benzenesulfinyl] octanoic acid.

98% @ 215 nm.

Example 207. Hydroxyamide 2- [4- (3-pyridin-2-ylpropoxy) benzenesulfinyl] octanoic acid.

99% @ 215 nm.

Example 208. Hydroxyamide 2- (4-benzyloxyphenylsulfonyl) octanoic acid.

100% @ 215 nm.

Example 209. Hydroxyamide 2- (4-butoxybenzenesulfonyl) octanoic acid.

100% @ 215 nm.

Example 210. Hydroxyamide 2- [4- (2-piperazin-1-ylethoxy) benzenesulfonyl] octanoic acid.

97% @ 215 nm.

Example 211. Hydroxyamide 2- [4- (3-pyridin-2-ylpropoxy) benzenesulfonyl] octanoic acid.

100% @ 215 nm.

Example 212. Hydroxyamide 2- [4- (1-methylpyrrolidin-3-yloxy) benzenesulfanyl] octanoic acid.

91% @ 215 nm; LMP3 (AP1 electrospray) t / ζ 367 (M + H) *.

Example 213. Hydroxyamide 2- [4- (1-ethylpropoxy) benzenesulfanyl] octanoic acid.

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112

100% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 354 (M + H) *.

Example 214. Hydroxyamide 2- [4- (tetrahydropyran-4-yloxy) benzenesulfanyl] octanoic acid.

97% @ 215 nm; 6CM8 (AP1 electrospray) t / ζ 368 (M + H) *.

Example 215. Hydroxyamide 2- [4- (1-methylpyrrolidin-3-yloxy) benzenesulfinyl] octanoic acid.

96% @ 215 nm.

Example 216. Hydroxyamide 2- [4- (1-ethylpropoxy) benzenesulfinyl] octanoic acid.

97% @ 215 nm.

Example 217. Hydroxyamide 2- [4- (tetrahydropyran-4-yloxy) benzenesulfinyl] octanoic acid.

97% @ 215 nm.

Example 218. Hydroxyamide 2- [4- (1-methylpyrrolidin-3-yloxy) benzenesulfonyl] octanoic acid.

96% @ 215 nm.

Example 219. Hydroxyamide 2- [4- (1-ethylpropoxy) benzenesulfonyl] octanoic acid.

100% @ 215 nm.

Example 220. Hydroxyamide 2- [4 (tetrahydropyran-4-yloxy) benzenesulfonyl] octanoic acid.

100% @ 215 nm.

Example 221

Stage A. Replacement of bromide 4-bromothiophenol.

The product, 2-bromohydroxamate resin, obtained in Example 160, step A (5.0 g, 1.1 meq / g), was placed in a peptide synthesis vessel and suspended in THF (60 ml). 4-Bromothiophenol (5.2 g, 5.0 eq.), Sodium iodide (4.1 g, 5.0 eq.) And 1,8-diazabicyclo [5.4.0] undec7-ene (EVi, 2, 5 ml, 3.0 equiv.). The reaction mixture is shaken at room temperature for 12-16 hours, then filtered and washed with DMF (2 x 30 ml), 9: 1 mixture of DMF: water (2 x 30 ml), DMF (30 ml), MeOH (2 x 30 ml) and ESM (2 x 30 ml). The resin is dried in vacuo at room temperature.

Stage B. Oxidation of sulfide to sulfoxide.

The product, 2- (4-bromobenzenesulfanyl) octanoic acid hydroxyamide resin obtained in Step A (4.4 g, 1.1 meq / g), was suspended in an ESM (60 ml) and 70% tert-butyl hydroperoxide (30 ml) was added. and benzenesulfonic acid (1.5 g). The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2 x 30 ml), DMF (2 x 30 ml), MeOH (2 x 30 ml) and ESM (2 x 30 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfone.

The product, 2- (4-bromobenzenesulfanyl) octanoic acid hydroxyamide-resin obtained in Step B (4.4 g, 1.1 meq / g), was suspended in an ESM (60 ml) and tCPBA (5.2 g) was added. . The reaction mixture is shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture is filtered and washed with ESM (2 x 30 ml), DMF (2 x 30 ml), MeOH (2 x 30 ml) and ESM (2 x 30 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Product combination, 2- (4-fluorobenzenesulfinyl) octanoic acid hydroxyamide-resin, with 4-chlorobenzeneboronic acid.

The product, 2- (4-bromobenzenesulfinyl) octanoic acid hydroxyamide-resin obtained in step B (150 mg, 1.1 meq / g), is suspended in OME (2.0 ml) and nitrogen gas is bubbled through the suspension for 1- 2 minutes. 4-Chlorobenzeneboronic acid (51.6 mg, 2 equiv.), Tetrakis- (triphenylphosphine) palladium (0) (19.07 mg, 0.1 equiv.) And sodium carbonate (2 M solution, 0.825 ml, 10 equiv.) Are added. .). The reaction mixture is heated to 80 ° C for 8 hours while shaking on a circular vibrator. After cooling to room temperature, the mixture was filtered and washed with DMF (2x2 ml), 9: 1 mixture of DMF: water (2x3 ml), MeOH (2x2 ml) and ESM (2x2 ml). The resin is dried in vacuo at room temperature.

Stage E. Cleavage of hydroxyamide 2 (4'-chlorobiphenyl-4-sulfinyl) octanoic acid from the resin.

The product of the combination, 2- (4'chlorobiphenyl-4-sulfinyl) octanoic acid hydroxyamide obtained in step Ό (150 mg, 1.1 meq / g), is suspended in an ESM (1.0 ml) and TFA is added (1, 0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with ESM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8auap1 8reebuas P1ik. Methanol (1 ml) was added and the mixture was concentrated. The crude product is dissolved in a mixture (1: 1, 2 ml) of DMSO: methanol and purified by reverse phase HPLC under the conditions described below:

Column: OE8-A, 20 mm x 50 mm, particle size 5 μm (UMS, 1ps. Νί1αίη§1οη, СοΠίι Sagoypa).

Solvent gradient Time Water Acetonitrile 0.0 95 5 min 5 95

Flow rate: 15 ml / min

2- (4'-chlorobiphenyl-4-sulfinyl) octanoic acid hydroxyamide; 96% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 394 (M + H) ⁺ .

The compounds of a number of hydroxamic acids of Examples 222-224 are synthesized using suitable starting materials and following the steps in Example 221.

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Example 222. Hydroxyamide 2- [4- (5-chlorothiophen-2-yl) benzenesulfinyl] octanoic acid.

100% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 400 (M + H) ⁺ .

Example 223. Hydroxyamide 2- (4'-chlorobiphenyl-4-sulfonyl) octanoic acid.

94% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 410 (M + H) ⁺ .

Example 224. Hydroxyamide 2- [4- (5-chlorothiophen-2-yl) benzenesulfonyl] octanoic acid.

85% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 416 (M + H) ⁺ .

Example 225. Step A. Product Combination Hydroxyamine 2- (4-bromo-benzenesulfanyl) octanoic acid-resin with X- (3-aminopropyl) morpholine.

The product, 2- (4-bromobenzenesulfanyl) octanoic acid hydroxyamide-resin obtained in Example 199, Step A (100 mg, 1.1 meq / g), was suspended in dioxane (2.0 ml) and nitrogen gas was bubbled through the suspension within 1-2 minutes N- (3aminopropyl) morpholine (346 mg, 20 equiv.), Tris (dibenzylideneacetone) dipalladium (0) (22 mg, 0.2 equiv.), (8) - (-) - 2,2'-bis ( diphenylphosphino) -1,1'binaphthyl ((8) -ΒΙΝΑΡ, 60 mg, 0.8 eq.) and sodium tert-butoxide (207 mg, 18 eq.). The reaction mixture is heated to 80 ° C. for 15 hours while shaking on a circular vibrator. After cooling to room temperature, the mixture was filtered and washed with DMF (2 × 2 ml), 9: 1 mixture of DMF: water (2 × 3 ml), MeOH (2 × 2 ml) and OSM (2 × 2 ml). The resin is dried in vacuo at room temperature.

Stage B. Cleavage of hydroxyamide 2 [4- (3-morpholin-4-yl-propylamino) phenylsulfanyl] octanoic acid from the resin.

The product, 2- [4- (3-morpholin4-ylpropylamino) phenylsulfanyl] octanoic acid-hydroxyamide resin obtained in Step A (100 mg, 1.1 meq / g), was suspended in OCM (1.0 ml) and added TFA (1.0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with OSM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8-acap1 8reebuas P1i§. Methanol (1 ml) was added and the mixture was concentrated. The crude product is dissolved in a mixture (1: 1, 2 ml) of DMSO: methanol and purified by reverse phase HPLC under the conditions described below.

Column: OE8-A, 20 mm x 50 mm, particle size 5 μm (UMS, 1ps. KhUPttTop, Khog111 SagoNpa).

Solvent Gradient Time Water Acetonitrile

0.0 95 5 min 5 95

Flow rate: 15 ml / min

2- [4- (3-Morpholin-4-ylpropylamino) phenylsulfanyl] octanoic acid hydroxyamide.

88% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 410 (M + H) ⁺ .

The compounds of a number of hydroxamic acids of Examples 226-231 are synthesized using suitable starting materials and following the steps in this example.

Example 226. Hydroxyamide 2- [4- (biphenyl4-ylamino) phenylsulfanyl] octanoic acid 95% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 435 (M + H) ⁺ .

Example 227. Hydroxyamide 2- [4- (pyridin4-ylamino) phenylsulfanyl] octanoic acid.

97% @ 215 km; BCM8 (AP1 electrospray) t / ζ 360 (M + H) ⁺ .

Example 228. Hydroxyamide 2- (4-cyclopentylaminophenylsulfanyl) octanoic acid.

77% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 351 (M + H) ⁺ .

Example 229. Hydroxyamide 2- (4-methylaminophenylsulfanyl) octanoic acid.

99% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 297 (M + H) ⁺ .

Example 230. 2- (4-Piperidin-1-ylphenylsulfanyl) octanoic acid hydroxyamide.

72% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 351 (M + H) ⁺ .

Example 231. Hydroxyamide of 2- (4-piperazin-1-ylphenylsulfanyl) octanoic acid.

74% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 352 (M + H) ⁺ .

Example 232. Step A. Replacement of bromide with 4-hydroxythiophenol.

The coupling product, 2-bromoctanoic acid-hydroxamate resin obtained in Example 160, step A (15.0 g, 1.1 meq./g) was placed in a peptide synthesis vessel and suspended in THF (120 ml). 4hydroxythiophenol (11.3 g, 5.0 equiv.), Sodium iodide (13.5 g, 5.0 equiv.) And 1,8-diazabicyclo [5.4.0] undec-7-ene (ΌΒυ, 8, 1 ml, 3.0 equiv.). The reaction mixture was shaken at room temperature for 12-16 hours, then filtered and washed with DMF (2 x 60 ml), 9: 1 mixture of DMF: water (2 x 60 ml), DMF (60 ml), MeOH (2 x 60 ml) and OSM (2 x 60 ml). The resin is dried in vacuo at room temperature.

Step B. Product Combination, 2- (4-hydroxybenzenesulfanyl) octanoic acid-hydroxyamide resin, with benzenesulfonyl chloride.

The product, 2- (4-hydroxybenzenesulfanyl) octanoic acid hydroxyamide resin obtained in Step A (240 mg, 1.2 meq / g), was suspended in OCM (3.0 ml). Benzene sulfonyl chloride (225 mg, 5 equiv.) And triethylamine (0.06 ml, 2 equiv.) Are added. The reaction mixture is shaken on a circular vibrator at room temperature for 8 hours, then filtered and washed with OME (2x2 ml), 9: 1 mixture of DMF: water (2 x 3 ml), MeOH (2 x 2

115

116 ml) and ESM (2 x 2 ml). The resin is dried in vacuo at room temperature.

Stage C. Oxidation of sulfide to sulfoxide.

The product of the combination, 4- (1-hydroxycarbamoylheptylsulfanyl) phenyl ester of benzenesulfonic acid-resin obtained in step B (80 mg, 1.2 meq / g), is suspended in an ESM (3 ml) and 70% tert-butyl hydroperoxide (1 ml) and benzenesulfonic acid (23 mg). The reaction mixture was shaken on a circular vibrator at room temperature for 12-24 hours. The reaction mixture was filtered and washed with ESM (2 x 3 ml), DMF (2 x 3 ml), MeOH (2 x 3 ml) and OSM (2 x 3 ml). The resin is dried in vacuo at room temperature.

Stage Ό. Oxidation of sulfide to sulfone.

The product of the combination, 4- (1-hydroxycarbamoylheptylsulfanyl) phenyl ester of benzenesulfonic acid-resin obtained in step B (80 mg, 1.2 meq / g), is suspended in an ESM (3 ml) and tSPBA (84 mg) is added. The reaction mixture is shaken on a vibrator with a circular motion at room temperature for 12-24 hours. The reaction mixture is filtered and washed with OSM (2x3 ml), DMF (2x3 ml), MeOH (2x3 ml) and OSM (2x3 ml). The resin is dried in vacuo at room temperature.

Step E. Cleavage of 4- (1-hydroxycarbamoylheptylsulfanyl) phenyl benzenesulfonic acid ester from the resin.

The product of the combination, 4- (1-hydroxycarbamoylheptylsulfanyl) phenyl ester of benzenesulfonic acid-resin obtained in step B (80 mg, 1.2 meq / g), is suspended in OSM (1.0 ml) and TFA (1.0 ml). The reaction mixture was shaken for 1 h at room temperature. The reaction mixture was filtered and the resin washed with OSM (2x1 ml). The filtrate and washings are combined and concentrated to dryness on 8aui1 8reebuas P1i8. Methanol (1 ml) was added and the mixture was concentrated. The crude product is dissolved in a mixture of DMSO: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described below:

Column: OE8-L. 20 mm x 50 mm, particle size 5 μm (UMS, 1ps. APTTsop, ΝογΙΙι SagoNia).

Solvent gradient Time Water Acetonitrile 0.0 95 5 min 5 95

Flow rate: 15 ml / min

4- (1-Hydroxycarbamoylheptylsulfanyl) phenyl ester of benzenesulfonic acid.

91% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 424 (M + H) ⁺ .

The compounds of a number of hydroxamic acids of Examples 233-240 are synthesized using suitable starting materials and following the steps in Example 232.

Example 233. 4- (1-Hydroxycarbamoylheptylsulfanyl) hydroxyamide 2,5-dichlorothiophene

3-sulfonic acid.

98% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 498 (M + H) ⁺ .

Example 234. Ethane sulfonic acid 4- (1-hydroxycarbamoylheptylsulfanyl) hydroxyamide.

72% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 376 (M + H) ⁺ .

Example 235. 4- (1-Hydroxycarbamoylheptylsulfinyl) hydroxyamide 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid.

99% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 492 (M + H) ⁺ .

Example 236. 4- (1-Hydroxycarbamoylheptylsulfinyl) hydroxyamide 2,5-dichlorothiophene

3-sulfonic acid.

96% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 514 (M + H) ⁺ .

Example 237. 4- (1-Hydroxycarbamoylheptylsulfinyl) 5-pyridin-2-ylthiophen-2-sulfonic acid hydroxyamide.

96% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 523 (M + H) ⁺ .

Example 238. 4- (1-Hydroxycarbamoylheptylsulfonyl) hydroxyamide 2-nitrobenzenesulfonic acid.

97% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 501 (M + H) ⁺ .

Example 239. 4- (1-Hydroxycarbamoylheptylsulfonyl) hydroxyamide 3-bromo-2-chlorothiophen-3-sulfonic acid.

97% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 576 (M + H) ⁺ .

Example 240. 4- (1-Hydroxycarbamoylheptylsulfonyl) benzo [1,2,5] thiadiazole-4-sulfonic acid hydroxyamide.

83% @ 215 nm; BCM8 (AP1 electrospray) t / ζ 514 (M + H) ⁺ .

Example 241. Hydroxyamide 1-benzyl-4- (4benzyloxybenzenesulfonyl) piperidine-4-carboxylic acid.

To a stirred solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous K ₂ CO ₃ (10 g, excess) in dry acetone (100 ml) in a round bottom flask was added α-bromoethyl acetate (3.3 g, 20 mmol) and the reaction mixture is heated at the boil under reflux for 8 hours with good stirring. At the end of this time, the reaction mixture was allowed to cool and the potassium salts were separated by filtration and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H ₂ O and 0.5 N. solution No. YUN. The organic layer was then washed well with water, dried over MgSO ₄ , filtered and concentrated.

(4-Methoxyphenylsulfanyl) acetic acid ethyl ester was isolated as a yellow oil. Yield: 4.4 g (100%); MS: 227 (M + H) ⁺ .

117

118

To a stirred solution of ethyl ether (4-methoxyphenylsulfanyl) acetic acid (4.4 g, 20 mmol), anhydrous K2CO3 (10 g, excess) in dry acetone (100 ml) was added benzyl bromide (3.5 g, 20 mmol) and the mixture refluxed for 4 hours. At the end of this time, the reaction mixture was filtered, concentrated and the residue was extracted with chloroform. The extract is washed well with water, dried and concentrated. The resulting crude product is converted into ethyl acetate (4benzyloxyphenylsulfonyl) acetic acid by oxidation with m-chloroperbenzoic acid as described in Example 83. Low melting solid. Yield: 6.6 g, 97%; MS: 335 (M + 1).

To a stirred solution of bis- (2-chloro-ethyl) benzylamine hydrochloride (6.6 g, 24.7 mmol), 18-crown-6 (500 mg) and anhydrous K2CO3 (30 g, excess) in dry acetone (250 ml ) ethyl ester (4benzyloxyphenylsulfonyl) acetic acid (8.01 g, 24 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 16 hours with good stirring. At the end of this time, the reaction mixture was allowed to cool and the potassium salts were separated by filtration and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O. The organic layer was then washed well with water, dried over MgSO ₄ , filtered and concentrated. The dark brown reaction mixture was purified by silica gel column chromatography, eluting with a mixture of 30% ethyl acetate: hexanes, and the product 4- (4-benzyloxybenzenesulfonyl) -1benzylpiperidin-4-carboxylic acid ethyl ester was isolated as a brown oil. Yield: 6.5 g, 55%; MS: 494 (M + H).

4- (4-Benzyloxybenzenesulfonyl) -1-benzylpiperidin-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH / THF (1: 1, 200 ml) and stirred at room temperature for 72 h. At the end of this time, the reaction mixture was concentrated and the product was neutralized with concentrated HCl, dissolving in water (200 ml). After neutralization, the reaction mixture was concentrated to dryness. Ice-cooled water (100 ml) was added to the solid and the mixture was filtered. The product, 4- (4-benzyloxybenzenesulfonyl) -1benzylpiperidin-4-carboxylic acid, was dried at 50 ° C and used in the next step without any purification. Colorless solid. Mp 66-68 ° C; yield: 4.3 g, 91%; MS: 466 (M + H).

Starting from 4- (4-benzyloxybenzenesulfonyl) -1-benzylpiperidin-4-carboxylic acid (4.65 g, 10.0 mmol) and following the procedure described in Example 83, 1.1 g of 4- (4-benzyloxybenzenesulfonyl hydroxyamide are isolated ) -1-benzylpiperidin-4-carboxylic acid as a colorless solid. Yield 21%; t. pl. 89 ° C; MS: 481.1; ^! H NMR (300 MHz, DMSO _6th ): δ 2.27 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),

4.30 (s, 2H), 7.14-7.17 (d, 2H), 7.50-7.73 (m, 5H),

9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).

Example 242. 4- (4-Butoxybenzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide.

2 - [(2-Hydroxyethyl) - [4- (2-piperidin-1-ethoxy) benzyl] amine was prepared according to the general method described in Example 83, starting from diethanolamine (15.0 g, 150 mmol) and 4- (2 piperidine- 1-yl-ethoxy) benzyl chloride (5.9 g, 20 mmol). Yield 5.5 g (85%); brown semi-solid; MS: 323 (M + H) ⁺ .

Bis- (2-chloroethyl) - [4- (2-piperidin-1-yl-ethoxy) benzyl] amine is prepared according to the general method described in Example 83, starting from 2 - [(2-hydroxyethyl) - [4- (2-piperidin- 1-yl-ethoxy) benzyl] amine (3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS:

361.1 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from (4-butoxybenzenesulfonyl ethyl ester ) acetic acid (6.0 g, 20 mmol) and bis- (2-chloroethyl) - [4- (2-piperidin-1-yl-ethoxy) benzyl] amine (8.6 g, 20 mmol). Yield 8.0 g (68%); brown oil; MS: 587.7 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- [4- (2piperidin-1-yl-ethoxy) benzyl] piperidin-4 carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1 [4- (2-piperidin-1 ethyl ester) -ylethoxy) benzyl] piperidine 4-carboxylic acid (5.8 g, 10 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. HaON (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.8 g (86%). Spongy brown solid; t. pl. 98 ° C; MS: 559.6 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid (5.5 g, 10 mmol) and following the procedure described in Example 83, the 2.4 g of 4- (4-butoxybenzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide as a pale yellow solid. Yield 41%; t. pl. 155 ° C (HC1); MS: 574 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO-a ₆ ): δ 0.9 (t, 3H), 1.1-1.8 (m, 6H), 1.9 (m, 4H), 2.3 (m, 4H), 2.8 (m, 6H), 3.2-3.6 (m, 8H), 4.2 (m, 2H), 6.9-7.8 (m, 8H), 9.1 (s, 1H),

10.8 (br s, 1H).

Example 243. 4- (4-Butoxybenzenesulfonyl) -1- [3- (2-morpholinyl-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide.

Bis- (2-hydroxyethyl) - [3- (2-morpholin-1-ethoxy) benzyl] amine is prepared according to the general method described in example 83, starting from

119

120 diethanolamine (15.0 g, 150 mmol) and 3- (2 morpholin-1-yl-ethoxy) benzyl chloride (5.9 g, 20 mmol). Yield 6.2 g (95%); brown semi-solid; MS: 325 (M + H) ⁺ .

Bis- (2-chloroethyl) - [3- (2-morpholin-1-yl-ethoxy) benzyl] amine is prepared according to the general method described in Example 83, starting from bis (2-hydroxyethyl) - [3- (2-morpholin- 1-yl-ethoxy) benzyl] amine (3.24 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 363 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- [3- (2-morpholin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from (4-butoxybenzenesulfonyl ethyl ester ) acetic acid (6.0 g, 20 mmol) and bis- (2-chloroethyl) - [3- (2-morpholin-1-yl-ethoxy) benzyl] amine (8.6 g, 20 mmol). Yield 8.5 g (72%); brown oil; MS: 589.7 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- [3- (2morpholin-1-yl-ethoxy) benzyl] piperidin-4carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1 [3- (2-morpholin-1 ethyl ester) -ylethoxy) benzyl] piperidine 4-carboxylic acid (5.8 g, 10 mmol) dissolved in a 3: 1 mixture of THF: methanol and 10N. No. YOUNG (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.8 g (85%). Spongy brown solid; MS: 561.6 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1- [3- (2-morpholin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid (5.6 g, 10 mmol) and following the procedure described in Example 83, the 4.02 g of 4- (4-butoxybenzenesulfonyl) -1- [3- (2-morpholin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide as a pale yellow solid. Yield 62%; t. pl. 123 ° C (HC1); MS: 576 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-be): δ 0.9 (t, 3H), 1.4 (m, 2H),

1.8 (t, 2H), 2.3-4.7 (m, 24H), 7.0-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (br. s, 1H).

Example 244. Hydroxyamide 1-methyl-4- (4butoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1-Methyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from ethyl ester (4 butoxybenzenesulfonyl) acetic acid (3 g, 10 mmol) and methyl bis ( 2-chloroethyl) amine (2.2 g, 11.6 mmol). Yield 4.0 g (98%); low melting brown solid; MS: 384 (M + H) ⁺ .

1-Methyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-methyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (7.6 g, 20 mmol), dissolved in methanol (300 ml) and 10n. No. JUN (35 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 6.0 g (84%); white solid; t. pl. 195 ° C; MS: 356.4 (M + H) ⁺ .

Starting from 1-methyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid (4.0 g, 11.2 mmol) and following the procedure described in Example 83, 3.9 g of 1-methyl-4 hydroxyamide are isolated - (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid as a yellow powder. Yield 85%; t. pl. 118 ° C; MS: 371 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-b ₆ ): δ 0.9 (t, 3H), 1.45 (q, 2H), 1.8 (q, 2H), 2.1 (s, 3H), 2.3 (d, 1 = 11.4 Hz, 2H), 2.5-3.7 (m, 8H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H).

Example 245. 1-Ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide.

Ethyl 1-ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid was prepared according to the general method described in Example 83, starting from ethyl ester (4 butoxybenzenesulfonyl) acetic acid (3 g, 10 mmol) and ethyl bis ( 2-chloroethyl) amine (2.2 g, 10.6 mmol). Yield 3.5 g (88%); low melting brown solid; MS: 398 (M + H) ⁺ .

1-Ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10n. No. 1OH (35 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 6.5 g (88%); white solid; t. pl. 162 ° C; MS: 370 (M + H) ⁺ .

Starting from 1-ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid (3.7 g, 10 mmol) and following the procedure described in Example 83, 3.2 g of 1-ethyl- hydroxyamide

4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid as a yellow powder. Yield 76%; t. pl. 98 ° C; MS: 385 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-b ₆ ): δ 0.9 (t, 3H), 1.2 (t, 3H),

1.46 (q, 2H), 1.9 (q, 2H), 2.3 (d, 1 = 11.4 Hz, 2H),

2.5-3.6 (m, 10H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H).

Example 246. Hydroxyamide 1-n-butyl-4- (4butoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1-n-Butyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from ethyl ester (4 butoxybenzenesulfonyl) acetic acid (3 g, 10 mmol) and n- butyl bis- (2-chloroethyl) amine (2.0 g, 10.1 mmol). Yield 3.8 g (89%); low melting brown solid; MS: 426 (M + H) ⁺ .

1-n-Butyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1-n-butyl-4- (4-buto121 ethyl

122 xibenzenesulfonyl) piperidine-4-carboxylic acid (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10N. ΝαΟΗ (35 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 7.5 g (88%); white solid; so pl. 182 ° C; MS: 398 (M + Η) '.

Starting from 1-n-butyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid (3.9 g, 10 mmol) and following the procedure described in Example 83, 1.8 g of 1-n-butyl hydroxyamide are isolated -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid as a yellow powder. Yield 40%; t. pl. 121 ° C; MS: 413 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO- ₆ ): δ 0.9-1.0 (m, 6H), 1.2-1.8 (m, 8H), 2.2-2.8 (m, 8H), 3.0-3.6 (m, 4H), 4.2 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H), 9.3 (br s , 1H), 10.3 (br s, 1H), 11.1 (br s, 1H).

Example 247. Ethyl ester of [4- (4-chlorophenoxy) phenylsulfanyl] acetic acid.

A mixture of 4-bromochlorobenzene (1.92 g, 10 mmol), ethyl ester (4-hydroxyphenylsulfanyl) acetic acid (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper chloride (11) (500) mg) is refluxed in anhydrous pyridine (50 ml) for 12 hours. The reaction mixture is carefully quenched with ice-cold water and acidified with concentrated HCl. The product is extracted with chloroform, washed well with water, dried and concentrated. The product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. Yield 2.5 g (77%); colorless, low melting solid; MS: 323 (M + H) ⁺ .

Alternatively, the title compound may be prepared from 4- (4-chlorophenoxy) benzenethiol and bromoethyl acetate as described in Example 83.

Example 248. Ethyl ester of [4- (4-chlorophenoxy) phenylsulfonyl] acetic acid.

[4- (4-Chlorophenoxy) phenylsulfonyl] acetic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (4-chlorophenoxy) phenylsulfanyl] acetic acid ethyl ester (3.23 g, 10 mmol) and oxone (10 g). Yield 3.5 g (99%); oil; MS: 356ΕΙ (M + Η) ⁴ .

Example 249. Hydroxyamide 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidine-

4-carboxylic acid.

4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid ethyl ester was prepared according to the general procedure described in Example 83, starting from [4- (4-chlorophenoxy) benzenesulfonyl] acetic acid ethyl ester ( 2.0 g, 5.6 mmol) and mechlorethanamine hydrochloride (L1g1sy) (1.9 g, 10 mmol). Yield 2 g (81%); brown oil;

MS: 438 (M + H) ⁺ .

4- [4- (4-Chlorophenoxy) benzenesulfonyl] -1 methylpiperidin-4-carboxylic acid is prepared from 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidine 4-carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10 N. ΝαΟΗ (100 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.5 g (86%); white solid; t. pl. 185 ° C; MS: 410 (M + H) ⁺ .

Starting from 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid (1.0 g, 2.4 mmol) and following the procedure described in Example 83, 460 mg of 4- [hydroxyamide 4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid as a salt with HC1; White powder. Yield 41%; t. pl. 52 ° C; MS: 426 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO- ₆ ): δ 1.3 (s, 3Η), 2.2-2.9 (m, 6H),

3.5 (br d, 2H), 7.2-7.9 (m, 8H), 8.1 (s, 1H), 11.0 (br s, 1H).

Example 250. Hydroxyamide 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-ethylpiperidin-4carboxylic acid.

4- [4- (4-Chlorophenoxy) benzenesulfonyl] -1-ethylpiperidin-4-carboxylic acid ethyl ester was prepared according to the general procedure described in Example 83, starting from [4- (4-chlorophenoxy) benzenesulfonyl] acetic acid ethyl ester ( 4 g, 11.3 mmol) and ethyl bis- (2 chloroethyl) amine (2.32 g, 16.9 mmol). Yield 3.36 g (66%); brown oil; MS: 452.0 (M + H) ⁺ .

4- [4- (4-Chlorophenoxy) benzenesulfonyl] -1 ethylpiperidin-4-carboxylic acid was prepared from 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-ethylpiperidin-4-carboxylic acid ethyl ester (3.02 g, 6.7 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. ΝαΟΗ (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.8 g (65%); white solid; t. pl. 184 ° C; MS: 423.9 (M + H) ⁺ .

Starting from 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-ethylpiperidin-4-carboxylic acid (1.75 g, 4.14 mmol) and following the procedure described in Example 83, 650 mg of 4- [hydroxyamide 4- (4-chlorophenoxy) benzenesulfonyl] -1-ethylpiperidin-4-carboxylic acid as a salt with HC1; White powder. Yield 33%; t. pl. 158 ° C; MS: 438.9 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO- ₆ ): δ 1.78 (t, I = 7.23 Hz, 3Η), 2.23-

2.27 (m, 2H), 2.51-2.73 (m, 4H), 3.04 (m, 2H), 3.81 (d, I = 24 Hz, 2H), 7.16-7 27 (m, 4H), 7.50-7.57 (m, 2H), 7.76 (d, I = 7 Hz, 2H), 9.34 (s, 1H), 9.85 (s, 1H).

Example 251. Hydroxyamide 1-butyl-4- [4 (4-chlorophenoxy) benzenesulfonyl] piperidine-4 carboxylic acid.

1-Butyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (4-chlorophenoxy) benzenesulfonyl] acetic acid ethyl ester (6 g, 18.3 mmol) and butyl bis123

124 (2-chloroethyl) amine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M + H) ⁺ .

1-Butyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid is prepared from 1-butyl-4- [4 (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester (3, 3 g, 6.9 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10 N. No. JUN (25 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.08 g (67%); white solid; t. pl. 201 ° C; MS: 451.9 (M + H) ⁺ .

Starting from 1-butyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid (2 g, 4.43 mmol) and following the procedure described in Example 83, 630 mg of 1-butyl- hydroxyamide are isolated 4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid as a salt with HC1; white solid. Yield 31%; t. pl. 212 ° C; MS: 466.9 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.87 (t, 1 = 7.3 Hz, 3H),

1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, 2H), 2.50 (m, 2H), 2.70 (q, 2H), 3.00 (m , 2H), 3.57 (d, 2H), 7.167.26 (m, 4H), 7.49-7.56 (m, 2H), 7.77 (d, 1 = 9 Hz, 2H), 9 34 (s, 1H); 10.13 (s, 1H).

Example 252. Hydroxyamide 1-benzyl-4- [4 (4-chlorophenoxy) benzenesulfonyl] piperidine-4 carboxylic acid.

1-Benzyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (4-chlorophenoxy) benzenesulfonyl] acetic acid ethyl ester (6 g, 16.9 mmol) and bis- (2 chloroethyl) benzylamine (6.44 g, 24 mmol). Yield 2.21 g (25%); yellow oil; MS: 513.9 (M + H) ⁺ .

1-Benzyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid is prepared from 1-benzyl-4- [4 (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester (2, 11 g, 4.1 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.11 g (56%); white solid; t. pl. 201 ° C; MS: 485.9 (M + H) ⁺ .

Starting from 1-benzyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid (1 g, 2.06 mmol) and following the procedure described in Example 83, 430 mg of 1-benzyl- hydroxyamide are isolated 4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid as a salt with HC1; whitish solid. Yield 39%; t. pl. 90.4 ° C; MS: 500.9, (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-be): δ 2.18-2.30 (m, 2H), 2.73-2.81 (m, 4H), 3.36 (d, 2H), 4.28 (d, 1 = 4.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), 7.517.56 (m, 4H), 7, 74 (d, 1 = 9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

Example 253. Ethyl ester of [4- (3-methylbutoxy) phenylsulfanyl] acetic acid.

To a stirred solution of ethyl ester (4-hydroxyphenylsulfanyl) acetic acid (2.12 g, 10 mmol) in boiling acetone was added K ₂ CO ₃ (anhydrous, 10 g) and 1-bromo-3-methylbutane (3 g, excess). The reaction mixture was refluxed for 24 hours and cooled to room temperature. The reaction mixture was filtered and concentrated. The resulting residue was extracted with chloroform, washed well with water and concentrated. The resulting crude product is used in the next step without purification. Exit

2.7 g (94%); 283 (M + H) ⁺ .

Example 254. Ethyl ester of [4- (3-methylbutoxy) phenylsulfonyl] acetic acid.

[4- (3-Methylbutoxy) phenylsulfonyl] acetic acid ethyl ester was prepared according to the general method described in Example 83 from [4- (3-methylbutoxy) phenylsulfanyl] acetic acid ethyl ester (2.8 g, 10 mmol) and oxone ( 10 g). Yield 3.0 g (99%); oil; MS: 314ΕΙ (M + H) ⁺ .

Example 255. 1-Benzyl-4- [4 (3-methylbutoxy) benzenesulfonyl] piperidine 4-carboxylic acid hydroxyamide.

1-Benzyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (3-methylbutoxy) phenylsulfonyl] acetic acid ethyl ester (6 2 g, 20 mmol) and bis (2-chloroethyl) benzylamine (6.44 g, 24 mmol). Yield 8 g (84%); yellow oil; MS: 474 (M + H) ⁺ .

1-Benzyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid is prepared from 1-benzyl4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester (4 7 g, 10 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3 g (67%); white solid; t. pl. 182 ° C; MS: 446 (M + H) ⁺ .

Starting from 1-benzyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid (2.2 g, 5 mmol) and following the procedure described in Example 83, 1.82 g of 1- hydroxyamide are isolated benzyl 4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid as a salt with HC1; whitish solid. Yield 73%; t. pl. 106 ° C; MS: 498 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.8 (d, 6H), 1.5 (m, 1H), 1.6-2.0 (m, 6H), 2.73-2, 81 (m, 4H), 3.5 (d, 2H), 4.28 (d, 1 = 4.5 Hz, 2H), 7.15-7.25 (m, 4H),

7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H), 7.74 (d, 1 = 9 Hz, 2H), 9.53 (s, 1H), 10 47 (s, 1H).

Example 256. Hydroxyamide 1-butyl-4- [4 (3-methylbutoxy) benzenesulfonyl] piperidine 4-carboxylic acid.

1-Butyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester

125

126 acids are prepared according to the general method described in Example 83, starting from [4- (3-methylbutoxy) phenylsulfonyl] acetic acid ethyl ester (6.2 g, 20 mmol) and butyl bis- (2 chloroethyl) amine (5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M + H) ⁺ .

1-Butyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid is prepared from 1-butyl-4- [4 (3-methylbutoxy) benzenesulfonyl] piperidine 4-carboxylic acid ethyl ester (4, 4 g, 10 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.2 g (77%); white solid; t. pl. 188 ° C; MS: 412 (M + H) ⁺ .

Starting from 1-butyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid (2.0 g, 5 mmol) and following the procedure described in Example 83, 1.6 g of 1- hydroxyamide are isolated butyl 4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid as a salt with HC1; whitish solid. Yield 69%; t. pl. 201 ° C; MS: 464 (M + H) ⁺ .

Example 257. Ethyl ester of [4- (2 ethylbutoxy) phenylsulfanyl] acetic acid.

To a stirred solution of ethyl ester (4-hydroxyphenylsulfanyl) acetic acid (2.12 g, 10 mmol) in boiling acetone are added K2CO3 (anhydrous, 10 g) and 1-bromo-2-ethylbutane (3 g, excess). The reaction mixture was refluxed for 24 hours and cooled to room temperature. The reaction mixture was filtered and concentrated. The resulting residue was extracted with chloroform, washed well with water and concentrated. The crude product is used in the next step without purification. Yield 2.8 g (94%); (M + H) ⁺ 297.

Example 258. Ethyl ester of [4- (2-ethylbutoxy) phenylsulfonyl] acetic acid.

[4- (2-Ethylbutoxy) phenylsulfonyl] acetic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (2-ethylbutoxy) phenylsulfanyl] acetic acid ethyl ester (2.96 g, 10 mmol) and oxone (10 g). Yield 3.1 g (99%); oil; MS: 329E1 (M + H) ⁺ .

Example 259. Hydroxyamide 1-benzyl-4- [4 (2-ethylbutoxy) benzenesulfonyl] piperidine-4 carboxylic acid.

1-Benzyl-4- [4- (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (2-ethylbutoxy) phenylsulfonyl] acetic ethyl ester acids (6.4 g, 20 mmol) and bis- (2 chloroethyl) benzylamine (6.44 g, 24 mmol). Yield g (82%); yellow oil; MS: 488 (M + H) ⁺ .

1-Benzyl-4- [4- (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid is prepared from 1-benzyl-4- [4 (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester (4, 8 g, 10 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4 g (87%); semi-solid substance; MS: 460 (M + H) ⁺ .

Starting from 1-benzyl-4- [4- (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid (2.2 g, 5 mmol) and following the procedure described in Example 83, 1.02 g of 1- hydroxyamide are isolated benzyl 4- [4- (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid as a salt with HC1; whitish solid. Yield 40%; t. pl. 114 ° C; MS: 512 (M + H) ⁺ .

Example 260. 4- (4-Butoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid hydroxyamide.

4- (4-Butoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from (4-butoxybenzenesulfonyl) ethyl acetate (20 g, 77, 5 mmol) and bis- (2-chloroethyl) (3-methoxybenzyl) amine (34 g, 116 mmol). Yield 9.53 g (25%); brown oil; MS: 490.2 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine-4-carboxylic acid ethyl ester (2.61 g, 5.34 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. No. OH (15 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1 g (41%); brown solid; t. pl. 175 ° C; MS: 462.0 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1- (3-methoxybenzyl) piperidine-4-carboxylic acid (900 mg, 1.95 mmol) and following the procedure described in Example 83, 200 mg of 4- (4-butoxybenzenesulfonyl hydroxyamide was isolated ) -1- (3methoxybenzyl) piperidine-4-carboxylic acid as a salt with HC1; brown powder. Yield 20%; t. pl. 137 ° C; MS: 477.0 (M + H) ⁺ ; '11 NMR (300 MHz, DMSO-b ₆ ): δ 0.96 (t, 1 = 7.11 Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H), 2, 27 (m, 2H), 2.47 (m, 2H), 2.78 (m, 2H), 3.35 (m, 2H), 3.77 (s, 2H), 4.08 (t, 1 = 6.3 Hz, 3H), 4.32 (s, 2H), 7.03 (t, 2H),

7.15 (m, 3H), 7.36 (t, 1 = 7.8 Hz, 1H), 7.64 (d, 1 = 9 Hz, 2H), 9.36 (s, 1H), 10, 22 (s, 1H).

Example 261. Hydroxyamide of 4- (4-methoxybenzenesulfonyl) -1- (4-thiophen-2-ylbenzyl) piperidine-4-carboxylic acid.

4- (4-Methoxybenzenesulfonyl) -1- (4-thiophen-2-ylbenzyl) piperidine-4-carboxylic acid ethyl ester is prepared from 1- (4-bromobenzyl) -4- (4-methoxybenzenesulfonyl) piperidin-4- ethyl ester Carbon Ki127

128 slots (3 g, 6.05 mmol) and 2- (tributylstannyl) thiophene (6.8 g, 18.14 mmol) in the presence of tetrakispalladium (0) in boiling toluene. Yield 1.58 g (52%); brown solid; t. pl. 130 ° C; MS: 500 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (4-thiophen-2-ylbenzyl) piperidine-4-carboxylic acid is prepared from 4 (4-methoxybenzenesulfonyl) -1- (4-thiophen-2ylbenzyl) piperidin-4 ethyl ester -carboxylic acid (1.3 g, 2.61 mmol) dissolved in the mixture

THF: methanol (3: 1, 150 ml) and 10N. No. 1ON. (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 950 mg (77%); brown solid; t. pl. 235 ° C; MS:

471.8 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (4-thiophen-2-ylbenzyl) piperidine-4-carboxylic acid (920 mg, 1.95 mmol) and following the procedure described in Example 83, 510 mg of 4- hydroxyamide are isolated (4-methoxybenzenesulfonyl) -1- (4-thiophen-2-ylbenzyl) piperidine-4 carboxylic acid as a salt with HC1; brown solid. Yield 50%; t. pl. 166 ° C; MS: 486.9 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO-e): δ 2.12-2.21 (m, 2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39 (m, 2H ), 3.87 (s, 3H), 4.29 (d, 2H),

7.17 (m, 3H), 7.54-7.75 (m, 8H), 9.36 (s, 1H), 10.07 (s, 1H).

Example 262. Hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- (4-pyridin-2-ylbenzyl) piperidine-4-carboxylic acid.

4- (4-Methoxybenzenesulfonyl) -1- (4-pyridin-2-ylbenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 261 starting from 1- (4-bromobenzyl) -4- ( 4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid (4.65 g, 9.38 mmol) and 2- (tributylstannyl) pyridine (12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M + H) ⁺ .

4- (4-Methoxybenzenesulfonyl) -1- (4-pyridin-2-ylbenzyl) piperidin-4-carboxylic acid is prepared from 4 (4-methoxybenzenesulfonyl) -1- (4-pyridin-2ylbenzyl) piperidin-4 ethyl ester -carboxylic acid (1.83 g, 3.7 mmol) dissolved in a mixture of THF: methanol (3: 1, 150 ml) and 10N. No. 1OH (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.38 g (80%); whitish solid; t. pl. 217 ° C; MS:

466.9 (M + H) ⁺ .

Starting from 4- (4-methoxybenzenesulfonyl) 1- (4-pyridin-2-ylbenzyl) piperidine-4-carboxylic acid (1.32 g, 2.83 mmol) and following the procedure described in Example 83, 480 mg of hydroxyamide is isolated 4- (4-methoxybenzenesulfonyl) 1- (4-pyridin-2-ylbenzyl) piperidine-4-carboxylic acid as a salt with HC1; White powder. Yield 33%; t. pl. 214 ° C; MS: 482.0 (M + H) ⁺ ; ^! H NMR (300 MHz, DMSO-e): δ 2.30 (m, 2H), 2.80 (m, 2H), 3.42 (d, 1 = 12.5 Hz, 2H),

3.75 (m, 2H), 3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, 1 =

8.9 Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, 1 = 8.1 Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H),

10.68 (s, 1H); 11.17 (s, 1H).

Example 263. Hydroxyamide 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid.

1- (3,4-Dichlorobenzyl) -4- (4butoxybenzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from (4-butoxybenzenesulfonyl) acetic acid ethyl ester (13.2 g, 44 mmol) and (3,4-dichlorobenzyl) bis- (2-chloroethyl) amine (14.3 g, mmol). Yield 14.1 g (60%); white solid; t. pl. 86 ° C; MS: 527.9 (M + H) ⁺ .

1- (3,4-Dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid is prepared from 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidin-4-carboxylic acid ethyl ester (14.0 g, 26.5 mmol) dissolved in a mixture of THF: methanol (100: 50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 7.87 g (60%); whitish solid; t. pl. 239 ° C; MS: 501.9 (M + H) ⁺ .

Starting from 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid (7.7 g, 15.5 mmol) and following the procedure described in Example 83, 4.05 g are isolated 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide as a salt with HC1; white solid. Yield 48%; t. pl. 256.8 ° C; MS: 514.9 (M + H) ⁺ . ^! H NMR (300 MHz, DMSO _6th ): δ 0.94 (t, 3H), 1.38-1.48 (q, 2H), 1.68-1.75 (q, 2H), 2, 27 (m, 4H), 2.72 (m, 2H), 4.10 (t, 2H), 4.24 (s, 2H), 7.12-

7.15 (d, 1 = 8.9, 2H), 7.51-7.53 (d, 1 = 8.1, 1H), 7.63-7.65 (d, 1 = 8.8, 2H), 7.72-7.75 (d, 1 = 9.9, 2H), 7.87 (s, 1H), 9.36 (s, 1H), 10.5 (C, 1H), 11 , 2 (s, 1H).

Example 264. Hydroxyamide [4- (4-chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid.

[4- (4-Chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid ethyl ester is prepared according to the general method described in Example 83, starting from [4- (4-chlorobenzyloxy) benzenesulfonyl] acetic acid ethyl ester (13, 79 g, 37 mmol) and 4- (4 chlorobenzyloxy) bis- (2-chloroethyl) amine (8.7 g, 45 mmol). Yield 10.9 g (65%); brown oil; MS: 451.9 (M + H) ⁺ .

[4- (4-Chlorobenzyloxy) benzenesulfonyl] 1-methylpiperidin-4-carboxylic acid is prepared from [4- (4-chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in a mixture of THF: methanol (75:75 ml) and

10n No. 1OH (20 ml). The resulting reaction

129

130 the mixture is treated as described in example 83. Yield 4.9 g (50%); whitish solid; MS: 426.2 (M + H) ⁺ .

Starting from [4- (4-chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid (4.9 g, 12 mmol) and following the procedure described in Example 83, 1.2 g of hydroxyamide [4- (4 -chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid as a salt with HC1; whitish solid. 24% yield; t. pl. 117.8 ° C; MS: 438.9 (M + H) ⁺ . Ή NMR (300 MHz, DMSO-b ₆ ): δ 2.2 (m, 2H), 2.49 (m, 4H), 2.5 (s, 3 N), 2.6 (m, 2H), 5.2 (s, 2H), 7.257.23 (d, ί = 8.7, 2H), 7.5 (d, ί = 2.7, 4H), 7.68-7.71 (d, ί = 9.6, 2H), 9.33 (s, 1H), 10.11 (s, 1H).

Example 265. 4- (4-Butoxybenzenesulfonyl) -1- (3-phenoxybenzyl) piperidine-4-carboxylic acid hydroxyamide.

4- (4-Butoxybenzenesulfonyl) -1- (3-phenoxybenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from (4-butoxybenzenesulfonyl) ethyl acetate (10.1 g, 34 mmol) and 1- (3-phenoxybenzyl) bis- (2-chloroethyl) amine (18 g, 50 mmol). Yield 8.9 g (49%); brown oil; MS: 552.1 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- (3-phenoxybenzyl) piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (3-phenoxybenzyl) piperidine-4-carboxylic acid ethyl ester (10 7 g, 24 mmol) dissolved in a mixture of THF: methanol (75:50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 5.0 g (76%); whitish solid; MS: 524.3 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1- (3-phenoxybenzyl) piperidine-4-carboxylic acid (5.9 g, 11 mmol) and following the procedure described in Example 83, 0.39 g of hydroxyamide 4- (4 -butoxybenzenesulfonyl) -1- (3phenoxybenzyl) piperidine-4-carboxylic acid as a salt with HC1; tan solid. Yield 11%; t. pl. 92.5 ° C; MS: 539.1 (M + H) ⁺ ; ¹ H NMR (300 MHz, DMSOά ₆ ): δ 0.93-0.97 (t, ί = 3.6, 3H), 1.49 (m, 2H), 1.73 (m, 2H), 2 51 (m, 4H), 4.09 (t, 2H), 4.29 (br s, 2H), 7.06-7.10 (d, ί = 12, 2H), 7.13-7 15 (m, 3H), 7.39-7.42 (d, 2H), 7.63-7.66 (d, 2H), 9.50 (s, 1H), 9.98 (s, 1H )

Example 266. Hydroxyamide [4- (4-chlorobenzyloxy) benzenesulfonyl] -1- (4-methylbenzyl) piperidine-4-carboxylic acid.

[4- (4-Chlorobenzyloxy) benzenesulfonyl] -1- (4-methylbenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from [4- (4-chlorobenzyloxy) benzenesulfonyl] acetic acid ethyl ester (5.47 g, 15 mmol) and 1- (4-methylbenzyl) bis- (2-chloroethyl) amine (5.23 g, 18 mmol). Yield 8.0 (96%); brown oil; MS: 542.0 (M + H).

[4- (4-Chlorobenzyloxy) benzenesulfonyl] 1- (4-methylbenzyl) piperidine-4-carboxylic acid is prepared from ethyl [4 (4-chlorobenzyloxy) benzenesulfonyl] -1- (4methylbenzyl) piperidin-4-carboxylic acid (7.9 g, 124 mmol) dissolved in a mixture of THF: methanol (50:50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.6 g (61%); whitish solid; t. pl. 204 ° C; MS:

514.2 (M + H) ⁺ .

Starting from [4- (4-chlorobenzyloxy) benzenesulfonyl] -1- (4-methylbenzyl) piperidine-4-carboxylic acid (4.2 g, 8 mmol) and following the procedure described in Example 83, 1.3 g of hydroxyamide are isolated [4- (4-chlorobenzyloxy) benzenesulfonyl] -1- (4-methylbenzyl) piperidine-4 carboxylic acid as a salt with HC1; yellow solid. Yield 29%; t. pl. 172.8 ° C; MS: 528.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSOάβ).

Example 267. Hydroxyamide 4- (4-butoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid.

4- (4-Butoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general procedure described in Example 83, starting from ethyl (4-butoxybenzenesulfonyl) acetic acid (5.47 g, 15 mmol) and 1- (4-methylbenzyl) bis- (2-chloroethyl) amine (15.3 g, 51 mmol). Yield 10.1 g (57%); white solid; t. pl. 93 ° C; MS: 474.1 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid ethyl ester (10 , 0 g, 22 mmol) dissolved in a mixture of THF: methanol (50:50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.2 g (72%); whitish solid; so pl. 244 ° C; MS: 446.3 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1- (4-methylbenzyl) piperidine-4-carboxylic acid (6.6 g, 1.5 mmol) and following the procedure described in Example 83, 2.06 g of 4- hydroxyamide are isolated (4-butoxybenzenesulfonyl) -1- (4methylbenzyl) piperidine-4-carboxylic acid as a salt with HC1; yellow solid. Yield 28%; t. pl. 137 ° C; MS: 461.3 (M + H) ⁺ ; Ή NMR (300 MHz, DMSO-b ₆ ): δ 0.91-0.964 (t, ί = 7.3, 3H), 1.41 (m, 2H), 1.70 (m, 4H), 1, 79 (t, s, 3H),

2.52 (m, 2H), 2.76 (m, 2H), 3.33 (br d, 2H), 4.10 (t, 2H), 4.22 (d, 2H), 7.12 -7.14 (d, ί = 8.7, 2H), 7.25-7.28 (d, ί = 8.1, 2H), 7.42-7.45 (d, ί = 7.8 , 2H), 7.63-7.65 (d, ί = 8.7, 2H), 10.31 (s, 1H), 10.75 (br s, 1H).

131

132

Example 268. Hydroxyamide 4- (4-butoxybenzenesulfonyl) -1- (4-cyanobenzyl) piperidine-4-carboxylic acid.

4- (4-Butoxybenzenesulfonyl) -1- (4-cyanobenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from ethyl (4-butoxybenzenesulfonyl) acetic acid (5.29 g, 17.6 mmol) and 1- (4-cyanobenzyl) bis- (2-chloroethyl) amine (6.19 g, 21 mmol). Yield 6.8 g (80%); reddish brown oil; MS: 485.0 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1- (4-cyanobenzyl) piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (4-cyanobenzyl) piperidine-4-carboxylic acid ethyl ester (10.0 g, 124 mmol) dissolved in a mixture of THF: methanol (75:50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 7 g (11%); whitish solid; MS: 456.0 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1- (4-cyanobenzyl) piperidine-4-carboxylic acid (0.600 g, 1.2 mmol) and following the procedure described in Example 83, 0.21 g of hydroxyamide 4- (4 -butoxybenzenesulfonyl) -1- (4 cyanobenzyl) piperidine-4-carboxylic acid in the form of a salt with HC1; whitish solid. Yield 34%; t. pl. 241.6 ° C; MS: 472.0 (M + H) ⁺ . 'H NMR (300 MHz, DMSO- ₆ ): δ 0.915-0.964 (t, I = 7.2, 3H), 1.51 (q, 2H), 1.75 (q, 2H), 2.27 (m, 2H),

2.49 (m, 4H), 4.11-4.19 (t, 2H), 4.37 (s, 1H), 7.12-

7.15 (d, I = 8.7, 2H), 7.63-7.66 (d, I = 9, 2H), 7.72-

7.74 (d, I = 7.8, 2H), 9.36 (s, 1H), 10.23 (s, 1H), 11.16 (s, 1H).

Example 269. 4- (4-Butoxybenzenesulfonyl) -1-pyridin-4-ylmethylpiperidin-4-carboxylic acid hydroxyamide.

4- (4-Butoxybenzenesulfonyl) -1-pyridin-4-ylmethylpiperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 83, starting from (4-butoxybenzenesulfonyl) ethyl acetate (6.0 g, 20 , 0 mmol) and pyridin-4ylmethyl-bis- (2-chloroethyl) amine (4.89 g, 21 mmol). Yield 4.5 g (48%); brown oil; MS: 461.0 (M + H) ⁺ .

4- (4-Butoxybenzenesulfonyl) -1-pyridine 4-ylmethylpiperidin-4-carboxylic acid is prepared from 4- (4butoxybenzenesulfonyl) -1-pyridin-4-ylmethylpiperidin-4-carboxylic acid ethyl ester (3.0 g, 6, 5 mmol) dissolved in a mixture of THF: methanol (75:50 ml) and 10N. No. 1OH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.2 g (42%); whitish solid; MS: 433.0 (M + H) ⁺ .

Starting from 4- (4-butoxybenzenesulfonyl) 1-pyridin-4-ylmethylpiperidin-4-carboxylic acid (0.864 mg, 2.0 mmol) and following the procedure described in Example 83, 600 mg of 4- (4-butoxybenzenesulfonyl) hydroxyamide was isolated) 1-pyridin-4-ylmethylpiperidin-4-carboxylic acid as a salt with HC1; whitish solid. Yield 67%; t. pl. 118 ° C; MS: 447.9 (M + H) ⁺ . '11 NMR (300 MHz, DMSO- ₆ ): δ 0.94 (t, 3H), 1.11 (t, 1H), 1.23 (t, 1H), 1.44 (m, 1H), 1.73 (m, 1H), 2.34 (m, 2H), 2.78 (m, 2H), 3.10 (m, 2H),

3.38 (m, 2H), 4.08 (t, 2H), 4.42 (br s, 2H), 7.13 (d, 2H), 7.64 (d, 2H), 7.94 (d, 2H), 8.82 (d, 2H),

11.2 (br s, 1H); 11.4 (br s, 1H).

References: 1. Klsk1eg, LZ, Oekats M.S. Teyayeyugoi Leyegk, 1997, 38, 321-322.

The compounds of this invention were tested for biological activity by the following methods.

Gelatinase Assay ΐη νίίτο

The analysis is based on the cleavage of the thiopeptide substrate ((Ac-Prgo-Lei-C1u (2-mercapto

4-methylpentanoyl) -Bey-C1u-OE1), Basket Βίο8с1еисе) enzyme, gelatinase, which releases a substrate product that reacts colorimetrically with ΌΤΝΒ (5,5'-dithio-bis- (2 nitrobenzoic acid)). Enzymatic activity is measured by the staining enhancement rate.

The thiopeptide substrate is applied freshly obtained as a 20 mM stock solution in 100% DMSO, and ΌΤΝΒ is dissolved in 100% DMSO and used as a 100 mM stock solution and stored in the dark at room temperature. Both the substrate and ΌΤΝΒ are diluted together with up to 1 mM substrate buffer (50 mM NEREZ, pH 7.5, 5 mM CaCl ₂ ) before use. The stock gelatinase B solution of human neutrophils was diluted with assay buffer (50 mM NEREZ, pH 7.5, 5 mM CaCl ₂ , 0.02 Vp) to a final concentration of 0.15 nM.

An assay buffer, an enzyme, ΌΝΤΒ / substrate (final concentration of 500 μM) and an excipient or inhibitor are added to a 96 well plate (total reaction volume of 200 μl) and staining is monitored spectrophotometrically for 5 minutes at 405 nm on a reader plate. The increase in O1U is plotted and the slope of the curve is calculated, which is the reaction rate.

The linearity of the reaction rate is confirmed (g ² > 0.85). The mean value (x ± ket) of the control speed is calculated and compared for statistical significance (p <0.05) with the speed when treated with the drug using the EippeC multiple comparison test. The dose-response relationship can be obtained using many doses of the drug and 1C ₅₀ values with 95% C1 are estimated using linear regression (1PKEO, NTV).

References: EDDdayei N. apy Eeyeg, ί .. Zresyoryokteits Akkau £ og waeyeygak so11adeyake,

Aia1. Vusyet., 147, 437-440 (1985).

133

134

Collagenase Analysis ΐη υϊΙιό

The analysis is based on the cleavage of the peptide substrate ((Ppr-Rto-CEa-C1u-Suz (Me) -H1zA1-uz (NMa) -NH ₂ ), Reybe 1p! Etpayopa1, 1ps.) Collagenase, which releases the fluorescent IMa group, which is quantitatively determined on a fluorometer. Opportunity extinguishes XMa fluorescence in an intact substrate. The analysis is carried out in the NSVS analysis buffer (50 mM HEPE8, pH 7.0, 5 mM Ca ⁺² , 0.02 V <0.5% cysteine) with recombinant fibroblast collagenase (processed, molar mass 18828, HUAK, Kabpog) . The substrate is dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase is kept frozen in a buffer in 25 μM aliquots. For analysis, the substrate is dissolved in NSAID buffer to a final concentration of 10 μM and collagenase to a final concentration of 5 nM. The compounds are dissolved in methanol, DMSO or NSBC. Methanol and DMSO are diluted in NSVS to <1.0%. The compounds are added to a 96-well plate containing the enzyme, and the reaction is started by adding a substrate.

The reaction indicators are taken (excitation at 340 nm, emission at 444 nm) for 10 min and the increase in fluorescence over the entire time is plotted on a graph in the form of a linear curve. The slope of the curve, which is the reaction rate, is calculated.

The linearity of the reaction rate is confirmed (g ² > 0.85).

The average value (x ± zeta) of the control speed is calculated and compared for statistical significance (p <0.05) with the speed during drug treatment using the Eippe Multiple Comparison Test. The dose-response relationship can be obtained using many doses of the drug and 1C ₅₀ values with 95% C1 are estimated using linear regression (ΙΡΒΕΌ, NTV).

Links: V1ske! EM. e! A1., But N1dy ΙΙιΐΌΐίβΙιri! Piogodeshs zbz! Ga! E £ ogt! Krz! 1ya1 s11adepase (MMP-1) apb de1a! 1pase (MMP-9), ApaEVyusket., 212, 58-64 (1993).

TACE inhibition measurement procedure

When using 96-well black microtiter plates, a solution of 10 μl of TACE (1 microtiter, final concentration of 1 μg / ml), 70 μl of Tris buffer, pH 7.4, containing 10% glycerol (final concentration of 10 mM) was added to each well. ) and 10 μl of a solution of the test compound in DMSO (final concentration 1 μM, DMSO concentration <1%), and incubated for 10 min at room temperature. The reaction is initiated by adding a fluorescent peptidylsubstrate (final concentration of 100 μM) to each well and then shaking on a vibrator for 5 s.

The reaction indicators are taken (excitation at 340 nm, emission at 444 nm) for 10 min and the increase in fluorescence over the entire time is plotted on a graph in the form of a linear curve. The slope of this curve, which represents the reaction rate, is calculated.

The linearity of the reaction rate is confirmed (g ² > 0.85).

The mean value (x ± zeta) of the control speed is calculated and compared for statistical significance (p <0.05) with the speed when treated with the drug using the Eippey multiple comparison test. The dose-response relationship can be obtained using many doses of the drug and 1C ₅₀ values with 95% C1 are estimated using linear regression.

The results obtained from these standard experimental test procedures are shown in the following table.

1C50 (nM or% inhibition at 1 micromole or 10 micromoles (*))

Example MMP1 MMP9 MMP13 Tase one ΝΤ 559.6 193.3 31.62% 2 ΝΤ 10.50% 0% 403 3 ΝΤ 308.9 169.4 27.43% 4 371 22.20% 17.10% 21% 5 ΝΤ 7.7 4.7 25% 6 267 21,4 15.6 40.43% 7 844 72.9 42.1 33% 8 ΝΤ 346 307.9 47% nine 313 107 ΝΤ 20.30% 10 8% 128 64 54.75% eleven 18.80% 2925 319 942 12 one hundred 10.8 eleven 15.50% thirteen 239 eleven 14 626 14 158 23 8 17.18% fifteen 285 17 4 137 sixteen 325 nine 24 180 17 238.6 8.9 1.4 41.00% eighteen 540 18.9 11.5 29.2% nineteen 446 95.8 4.8 33.1% twenty 423 14.6 18.7 31% 21 318 13,2 15.3 39% 22 219 3.2 2,5 thirty% 23 593 7.9 4.0 40.6% 24 413 20.9 31.3 47.5 25 262 26.7 8.0 ΝΤ 26 304.6 6.3 3.2 34.6 27 629 106 30.1 ΝΤ 28 761 3,1 2.0 30.6% 29th 297 4.3 3.6 41% thirty 397 8.1 5.7 25.2% 31 162 15,2 5.7 688 32 13.7 3,7 1,0 ΝΤ 33 318 53.9 18,4 23.9% 34 519.8 34.7 26.1 28.1% 35 455.8 233.6 48,2 44.9 36 622 83.8 20.7 826 37 nine% 31.6% 14.3% 87 38 48.3% 1.7% 5.8% 55.1% 39 29.4% 35.2% 26.6% 69,4 40 583 197 14 160 41 one hundred 10.8 eleven 15.50% 42 262 50.9 6.2 36.5 43 66.1% 34.7% 55.5% 46.6% 44 47.1% 36.9% 39.5% 14.9%

135

136

45 49% 48.6% 36.7% 20.4% 46 78.9% 79.12% 84.7% 1.4% 47 17.1% 12.9% 7.12% 3.3% 48 99.1% 79.1% 85.4% 51.1% 49 10.1% 23.7% 54.6% N1 fifty 51.1 58.4 10.6 N1 51 178.1 10,4 13.1 48.14% 52 139.3 7.9 9.1 N1 53 647.9 27.80% 188 52.57% 54 110 66 21 55.10% 55 303 10 7 21.70% 56 299 sixteen 12 65% 57 258 332 191 16.57% 58 211 35 39 7.70% 59 30.20% 447 141 24.86% 60 N1 184 N1 23.60% 61 258 38 22 17.21% 62 522 174 43 669 63 156 nine 3 203 64 40.90% 25.60% 36.70% 29.70% 65 1000 63 thirteen 42.21% 66 1600 131 226 42.33% 67 364 2,3 43.7 690 68 297 29th 27 522 69 574.5 120,2 90 41.32% 70 1139 88.80% 127 764 71 1000 63 thirteen 42.21% 72 117 eleven one 51.64% 73 300 141 12 20.17% 74 138.1 9.2 4.3 47.86% 75 672.3 83,4 32,7 23.77% 76 805 N1 500 N1 77 205.5 N1 170 N1 78 262 560 34 24.58% 79 25 0.54 0.4 805 80 22.1% 26% 63.6% 191 81a 2036 230.9 43.9 27.1 81b 3765 154 15.7 228 82 237.6 19,4 5.1 34.5% 83 492 10,2 2.0 229 84 519 8.8 2.0 213 85 450 5.8 1,5 115 86 494 16.8 1,5 222 87 368 5,0 1,6 170.7 88 1329 12.8 3,1 610 89 1389 38.6 7.0 49% 90 598 10.3 2.2 71.9 91 1929 13.3 10.8 503 92 59.6% 649 148 9.7 93 56.3% 452 38 15.8% 94 2640 138 28.6 22.9 95 3681 364 33.1 25.4% 96 4437 374 33.8 18.1 97 5109 484 43.7 20.20% 98 2383 3.8 1,2 154 99 656 16,2 2,4 250 one hundred 4729 19.1 5.3 39.5% 101 642 12.3 2.1 197 102 662 33.7 1.9 53% 103 1306 45.1 8.8 470 104 2610 3,1 1.4 208 105 1214 44,2 4.1 50.2% 106 3788 5.1 0.9 631 107 629 26.8 2,5 293 108 2896 5,4 1.7 270 109 393 2.7 2,5 386 241 48.2% * 2.7 15.8 277 242 1950 2 1.3 581 243 2181 1.9 1,5 506 244 3417 9.8 1,5 594 245 7062 43,4 2.2 51.95% * 246 50.30% * 28.3 2,4 880 249 1412 2 1,6 270

250 1717 1,6 0.8 413 251 1067 0.8 0.9 301 252 801 1,1 0.9 278 255 2558 3.6 1,5 565 256 10,000 7.2 2.9 43.01% * 259 3160 14.3 5.3 39% * 260 1495 2.9 1.3 272 261 513 10.9 2.7 273 262 422 6.1 2,3 298 263 3669 20.3 5.2 57.70% * 264 4293 2.9 3,1 182 265 1944 9.3 7.8 1037 266 4746 6 5.7 421 267 3620 5,4 2,3 508 268 2292 2,8 1,1 278 269 2071 2.2 1.4 296

N7- ^ tested

Compounds obtained by solid phase synthesis. Data for examples from 110 to 240

Example No. MMP1 MMP9 MMP 13% inhibition with 0.2 μM (NT8) MMP 13% inhibition at 0.2 μM (manual) TACE% inhibition with 1 μM 110 75 17.6 111 10 40,4 112 fifty 33.7 113 0 13.1 114 0 0 115 0 0 116 0 9.1 117 7 8.1 118 24 16.7 119 0 7.8 120 31 19.9 121 0 6.1 122 0 3,1 123 0 2,5 124 0 0 125 5 2,3 126 25 10,4 127 47 29.2 128 1.9 tM 213 pM 91 255 pM 19.31 129 90 32.77 130 28 27.9 131 71 20.73 132 71 20.76 133 53 22.04 134 25 -9.31 135 79 42.67 136 89 42.69 137 83 13.35 138 twenty 5,284 139 8 28.05 140 29th -4.22 141 32 11.76 142 69 54.27 143 53 43.9 144 38 19.7 145 45 2,5 146 68 7,317 147 73 11.95 148 fifteen 43,46 149 thirteen 4,408 150 54 1,818 151 6 5,927 152 nine 10.03 153 12 11.8 154 89 13.14 155 31 18.62 156 23 -2.09 157 nineteen 13.7

137

138

158 33 -7.48 159 49 5,852 160 14 -3.57 161 0 12.7 162 thirteen 0 163 84 9,515 164 74 62.69 165 71 73.7 166 nine 4.16 167 27 8,961 168 21 3,688

Example No. MMP 13% inhibition at 36 nM (NT8) MMP 13% inhibition at 0.36 nM (HT8) MMP 13% inhibition at 3.6 μM (HT8) TACE% 1C50 nM TACE% inhibition at 1 μM 169 28 40 72 41.7 170 32 49 90 25.5 171 31 38 48 16.6 172 34 32 42 29.4 173 eighteen 46 56 25.5 174 10 nineteen 40 27.7 175 sixteen twenty 37 32.9 176 6 5 sixteen 26.6 177 5 one nine 38.5 178 -10 74 39 26 179 12 32 60 42.7 180 14 nineteen 45 34,4 181 6 35 62 15.7 182 -nine -8 7 28.6 183 -6 12 70 34.6 184 sixteen 24 44 24.8 185 nine 0 23 7.21 186 -14 -4 35 19.5 187 -14 -12 twenty 85.5 188 -27 -24 4 16,2 189 -thirty -eighteen -nine 14 190 -35 -28 -thirteen 38.3 191 -45 -3 22 2.9 192 -32 5 61 33,2 193 -32 -fifteen 56 14.9 194 -17 -8 5 5,4 195 -nine -2 10 27.0 196 -eighteen one eleven 35.7 197 -33 -26 -3 17.8 198 -39 -7 fifteen 17.1 199 -10 -7 thirty -1.0 200 37.9 201 50.9 202 10.6 203 32.8 204 7.75 205 84.0 206 89.8 207 -6.3 208 67.7 209 31,2 210 52,2 211 20.7 212 56.0 213 -17.5 214 11.03 215 895 60.12 216 2.49 217 55.1 218 380 68.7 219 7.3 220 256 53.1 221 146 98.9 222 212 89.3 223 226 107.3

224 -404 75.0 225 96.6 114.3 226 28 22 28 2.2 227 fifteen -sixteen -22 7.3 228 37 28 65 6.8 229 29th 17 33 34,4 230 29th 31 26 700 72.1 231 23 thirteen 5 41.6 232 thirty 17 42 20.8 233 33 29th 46 19.8 234 26 28 40 18,4 235 59 70 70 48.3 236 44 44 64 35 237 55 65 72 38,2 238 22 eleven 24 930 54,4 239 54 74 83 45.9 240 48 51 46 40.3

The compounds of this invention can be administered undiluted to a patient in need thereof or with a pharmaceutical carrier. The pharmaceutical carrier may be solid or liquid.

Suitable solid carriers may include one or more substances, which may also act as flavoring agents, lubricants, solvents, suspending agents, fillers, glidants, compression aids, tablet binders or disintegrating agents or encapsulating materials. In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the properties necessary for compression, in suitable proportions and compressed into the desired shape with the required size. Powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat. The liquid carrier may contain other suitable pharmaceutical additives, such as solvents, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral or parenteral administration139

140 administration include water (especially containing the additives mentioned above, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and oils (e.g. fractionated coconut oil and peanut butter). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions of sterile liquid forms for parenteral administration.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. For oral administration, either a liquid or a solid composition can be used.

The compounds of this invention can be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention can be formulated as an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally by using a transdermal patch containing the active compound and a carrier that is inert to the active compound, non-toxic to the skin, and enables delivery of this systemic absorption agent into the bloodstream through the skin. The carrier may take any number of forms, such as creams and ointments, pastes, gels and closed devices. Creams and ointments can be viscous, liquid or semi-solid emulsions either of the oil in water type or of the water in oil type. Pastes, including absorbent powders dispersed in oil or hydrophilic oil containing the active ingredient, may also be acceptable. Various closed devices can also be used to release the active ingredient into the bloodstream, such as a semi-permeable membrane covering the reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other closed devices are known in the literature.

The dose used in the treatment of a particular patient suffering from a disease or condition in which MMP§ and TACE are involved should be subjectively determined by the staff doctor of the hospital. Included variable factors include the severity of the dysfunction and the size, age, and nature of the patient's susceptibility. Treatment usually begins with small doses less than the optimal dose of the compound. After which the dose is increased until, under these conditions, the optimum effect is achieved. The exact doses for oral, parenteral, nasal or intrabronchial administration will be determined by the doctor who administers them based on the knowledge of the individual subject being treated and standard medical principles.

The pharmaceutical preparation is preferably in unit dosage form, for example, in the form of tablets or capsules. In this form, the composition is subdivided into unit doses containing suitable amounts of the active ingredient; the unit dosage form can be packaged compositions, for example, packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form may be, for example, a capsule or tablet, or it may be a suitable number of any such compositions in package form.

Claims (10)

1. The compounds of formula I where I ¹ represents alkyl containing from 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from I ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ; aryl containing from 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R ⁵ ; cycloalkyl containing from 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or XY ⁷ , optionally substituted with one or two groups selected independently from Z ⁵ ; or heteroaryl- (CH2) 0-6-, where the heteroaryl group is a 5- or 6-membered group with one or two heteroatoms selected independently from O, 8 or X, and may optionally be substituted with one or two groups selected independently from I am ⁵ ; 141 142 A represents -8-, -8O- or -8O2-; K ² and K ³ taken together with the carbon atom to which they are attached form a 5-7 membered heterocyclic ring containing O, 8 or Ν-K ⁷ and optionally having one or two double bonds; K ⁴ represents hydrogen, alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ; phenyl or naphthyl optionally substituted with one or two groups selected independently from K ⁵ ; C3-C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from K ⁵ ; saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-K ⁷ , optionally substituted with one or two groups selected independently from K ⁵ ; K ⁵ represents H, C7-Ci-aroyl, C2-C6 alkanoyl, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, P, C1, Br, I, ΟΝ, CHO, C1-C6-alkoxy, aryloxy , heteroaryloxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C6-alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6-alkylamino-C1-C6-alkoxy, C1-C2-alkylenedioxy, aryloxy-C1-C6-alkylamine, -perfluoroalkyl, 8 (O) p-C1-C6 alkyl, 8 (O) p-aryl, where n is 0, 1 or 2; OSOOC1-C6-alkyl, OSOO-aryl, OSOK ⁶ . COOH, СОО-С1-С6-alkyl, СОО-aryl, СОНК ⁶ К ⁶ , ίΌΝНОН, ΝΚ ⁶ ^ ⁶ , 8О; ΧК ⁶ К ⁶ . ΧΚ ⁶ 8О2-aryl, -ΧΚ ⁶ СΌΧΚ ⁶ Κ ⁶ . ΧΗ8О2СРЗ, 8О2ΧΗ-heteroaryl, 8О2NНСО-aryl, СНН8О2-С1-С6-alkyl, ίΌΝН8О2-aryl, Ν ^, ОН, aryl, heteroaryl, С3-С8 cycloalkyl or a saturated or unsaturated 5-10 membered monocycle, one heteroatom selected from O, 8 or ΝΚ ⁷ , where C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono-bicyclic heteroaryl group having from 1 to 3 heteroatoms selected independently from O, 8 or ΝΚ ⁷ and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups shaven GOVERNMENTAL from halo, cyano, amino, nitro, C1-C ₆ alkyl, C ₁ to C ₆ alkoxy or hydroxy; K ⁶ represents H, C1-C1 ₈ -alkyl optionally substituted by OH; C3-C6 alkenyl, C ₃ -C ₆ -alkynyl, _C1-C6 perfluoroalkyl, 8 (O) _n -S1S6-alkyl, 8 (O) n -aryl where n is 0, 1 or 2, or CO-heteroaryl, wherein heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halo, cyano, amino, nitro, _C1-C6 alkyl, _C1-C6 alkoxy or hydroxy; and K ⁷ is C7-Cc-aroyl, C2-C6 alkanoyl, C1-C12 perfluoroalkyl, 8 (O) p-C1-C6 alkyl, 8 (O) p-aryl, where n is 0, 1 or 2; СООС1-С6-alkyl, СОО-aryl, СОΧΗΚ ⁶ , СОNΚ ⁶ Κ ⁶ , СО ^ ОН, 8О2 ^ ⁶ К ⁶ , 8О2СР3, 8 () ^ 11 heteroaryl, 8О2ΧΗСО-aryl, СОNΗ8О ₂ -С1-С ₆ alkyl, СОΧΗ8О ₂ -aryl, aryl or heteroaryl, wherein aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, 8 or _N-C1-C6 alkyl; alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ; arylalkyl containing from 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from K ⁵ ; heteroarylalkyl wherein alkyl contains from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, 8 or Ν, and is optionally substituted with one or two groups selected independently from K ⁵ ; biphenylalkyl containing from 13 to 18 carbon atoms, where biphenyl is optionally kneaded with one or two groups selected independently from K ⁵ ; arylalkenyl containing from 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from K ⁵ ; cycloalkylalkyl or bicycloalkylalkyl containing from 4 to 12 carbon atoms, where the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from K ⁵ ; saturated or unsaturated mono-bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-SnC6-alkyl, optionally substituted with one 143 144 or two groups selected independently from K ⁵ ; or ΠΉ'Ν-Ο'ι-C ₆ -alkoxyaryl-C) -C ₆ -alkyl, where K ⁸ and K ^{9 are} independently selected from C1-C ₆ -alkyl, or K ⁸ and K ³ together with the nitrogen between them form A 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or their pharmaceutically acceptable salts. 2. The compound according to claim 1, where K ¹ represents alkyl containing from 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from K ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ; aryl containing from 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; cycloalkyl containing from 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or ΝΚ ⁷ , optionally substituted with one or two groups selected independently from K ⁵ ; or heteroaryl- (CH2) 0-6, wherein the heteroaryl group is a 5- or 6-membered group with one or two heteroatoms selected independently from O, 8 and Ν, and may optionally be substituted with one or two groups selected independently from K ⁵ ; A represents -8, -8Ο- or -8Ο ₂ -; K ² and K ³ taken together with the carbon atom to which they are attached form a 5-7 membered heterocyclic ring containing O, 8 or Ν-K ⁷ and optionally having one or two double bonds; K ⁴ represents hydrogen, alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ; phenyl or naphthyl optionally substituted with one or two groups selected independently from K ⁵ ; C3-C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from K ⁵ ; K ⁵ represents H, E, C1, Br, I, ΟΝ, CHO, C7-Cc-aroyl, C2-C6 alkanoyl, C1-C12-alkyl, C2C12-alkenyl, C2-C12-alkynyl, C1-C6-alkoxy , aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6-alkylamino-C1-C6 alkoxy, C1-C2-alkylenedioxy, aryloxy-C1-C6-Alkyl -C12-perfluoroalkyl, 8 (O) p-C1-C6 alkyl, 8 (O) p-aryl, where η is 0, 1 or 2; OSOO) -C6 -alkyl, OSOO-aryl, ΟΟ'ΟΝΡ ⁶ . COOH, COO-C1-C6-alkyl, COO-aryl, SOMK' ^6, CO \ NΟN, ΝΚ ⁶ Κ ^6, 8Ο2ΝΚ Κ ^{6 6 6} MC 8O2-aryl, ΝΚΉΟΝΚΉ ⁶ MN8O2SEe, 8O2MN-heteroaryl 8O2HNSO- aryl, СОМН8О2-С1-С6-alkyl, СО \ Н8О2-aryl, ΝΉ ₂ , OH, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl or a saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom, selected from O, 8 or ΝΚ ⁷ ; where heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, _C1-C6 alkyl, _C1-C6 alkoxy or hydroxy; K ⁶ represents H, C1-C1 ₈ -alkyl optionally substituted by OH; C ₃ -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, _C1-C6 perfluoroalkyl, 8 (O) _n alkyl or aryl where η is 0, 1 or 2 or SOgeteroaril, wherein heteroaryl is a 5- 10-membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚ ⁷ , and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, _C1-C6 alkyl, _C1-C6 alkoxy or hydroxy; and K ⁷ represents C7-Cc-aroyl, C2C6-alkanoyl, C1-C12-perfluoroalkyl, 8 (O) p-alkyl, 8 (O) p-aryl, where n is 0, 1 or 2; COO-alkyl, COO-aryl, SOHNA ⁶ , SOMK ⁶ K ⁶ , SOINON, 8Ο2ΝΚ ⁶ Κ ⁶ , 8О ₂ CE ₃ , 8О ₂ ХН-heteroaryl, 8O2MHCO-aryl, СОМН8О2-alkyl, СОΝ180 aryl, aryl or heteroaryl, where С1-С6-alkyl, straight or branched, heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O 8 or K ^Ν-7 and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups selected independently from halogen, cyano, amino, nitro, _C1-C6 alkyl, _C1-C6 alkoxy or hydroxy ; 145 146 alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ; arylalkyl containing from 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R ⁵ ; heteroarylalkyl, where alkyl contains from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, 8 or Ν, and is optionally substituted with one or two groups selected independently from R ⁵ ; biphenylalkyl containing from 13 to 18 carbon atoms, where biphenyl is optionally substituted with one or two groups selected independently from R ⁵ ; arylalkenyl containing from 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R ⁵ ; cycloalkylalkyl or bicycloalkylalkyl containing from 4 to 12 carbon atoms, where cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected independently from R ⁵ ; saturated or unsaturated mono-bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-C ^ C6 -alkyl and optionally substituted with one or two groups selected independently from R ⁵ ; I ⁸ I ⁹ -C1-C6-alkoxyaryl-C1-C6-alkyl, where R ⁸ and I ⁹ are independently selected from C1-C ₆ alkyl or H ⁸ and H ³ together with the interjacent nitrogen to form a 5-7 membered a saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2 where R ¹ is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl optionally substituted with C1-C ₆ -alkyl, C 1 -C C ₆ alkoxy, C ₆ -C ₀ aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, halogen; or 8 (O) _{n -C1-C6--alkilS1} -alkoksiaril C ₆ or C ₁ -C ₆ alkoksigeteroaril; A represents -8, -8Ο- or-8O ₂ -; I ² and I ³ , taken together with the carbon atom to which they are attached, form a 5-7 membered heterocyclic ring containing O, 8 or S ⁷ and optionally having one or two double bonds; Z ⁴ is hydrogen, alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from Z ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R ⁵ ; phenyl or naphthyl optionally substituted with one or two groups selected independently from Z ⁵ ; C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from Z ⁵ ; I ⁵ represents H, C7-Cc-aroyl, C2-C6 alkanoyl, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, E, C1, Βγ, Ι, CH CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C6-alkylamino-C1-C6 alkoxy, C1-C2-alkylenedioxy, aryloxy-C1-C6 alkylamine, C1-C12 perfluoroalkyl, 8 (Ο) η-C1- C6 alkyl, 8 (Ο) p-aryl, where n is 0, 1 or 2; 1С1-С6-alkyl, ОСОО-aryl, ΟСΟNЯ ⁶ , СОО, СΟΟ-С1-С6-alkyl, СОО-aryl, СΟNЯ ⁵ Я ⁶ , СС) \ ΗΟΗ, ХЯЯ ': 8Ο2№ ^< ^ ⁶ , МЯ ^^ il , -ΝΚΥΟΝ ^ ⁶ NN8Ο2SEz, 8Ο2NN-heteroaryl, 8Ο ₂ NHCO-aryl, -C1 SONΗ8Ο _{2-C 6} -alkyl, СОМН8О ₂ -aryl, ΝΗ ₂ , ОН, aryl, heteroaryl, С ₃ С ₈ -cycloalkyl or saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing one heteroatom selected from O, 8 or ΝΚΛ where С1-С _6- alkyl straight or branched, heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or ΝΚΛ and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halo, cyano, amino, nitro, C1-C ₆ alkyl, C ₁ -C ₆ al hydroxy or hydroxy; I ⁶ represents H, C1-C18 alkyl optionally substituted by OH; C3-C6 alkenyl, C ₃ -C ₆ alkynyl, C1-C ₆ perfluoroalkyl, 8 (Ο) _η alkyl or aryl, where n is 0, 1 or 2, or CO heteroaryl, where heteroaryl is 5-10- a mono- or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from O, 8 or ΝΚΛ and aryl is phenyl or naphthyl, optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, C1- _C6 alkyl, _C1-C6 alkoxy or hydroxy; and R ⁷ is C ₇ -Ci-aroyl, C ₂ C ₆ -alkanoyl, C1-C1 ₂ -perfluoroalkyl, 8 (Ον-alkyl, 147 148 8 (O) _p -aryl, where η is 0, 1 or 2; COO-alkyl, COO-aryl, SOMN ⁶ , SOMKK ⁶ , SOMTNON, 8O2MK ⁶ K ⁶ , 8O2CE ₃ , 8O ₂ NH-heteroaryl, 8O21MHCO-aryl, COM ^ O-alkyl. CON1180aryl, aryl or heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy or hydroxy; and heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl group having from 1 to 3 heteroatoms independently selected from O, 8 or M-C 1 -C ₆ -alkyl; alkyl containing from 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; alkenyl containing from 3 to 18 carbon atoms, having from 1 to 3 double bonds, optionally substituted with one or two groups independently selected from K ⁵ ; alkynyl containing from 3 to 18 carbon atoms, having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from K ⁵ ; arylalkyl containing from 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; heteroarylalkyl, where alkyl contains from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, 8 or или, and is optionally substituted with one or two groups independently selected from K ⁵ ; biphenylalkyl containing from 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; arylalkenyl containing from 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; cycloalkylalkyl or bicycloalkylalkyl containing from 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from K ⁵ ; a saturated or unsaturated mono-bicyclic heterocycle containing one heteroatom selected from O, 8 or Ν-CC6-alkyl, optionally substituted with one or two groups selected independently from K ⁵ ; Ρ ⁸ Ρ ⁹ Ν-ί.'ι -C6-alkoxyaryl-C1-C6-alkyl, where K ⁸ and K ^{9 are} independently selected from C1-C6-alkyl or K ⁸ and K ⁹ together with the nitrogen between them form 5- A 7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, which is a compound selected from the group consisting of 1-benzyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) hydroxyamide - 1- (3-methoxybenzyl) piperidine-4 carboxylic acid or a pharmaceutically acceptable salt thereof, 1- (3,4-dichlorobenzyl) -4- (4 methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof 4- (4 -methoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidin-4-carboxy acid or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) -1-naphthalen-2-ylmethylpiperidin-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-biphenyl-4-ylmethyl-4- (4methoxybenzenesulfonyl) piperidine hydroxyamide -4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) -1- (3-methylbut-2-enyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1- (4-bromobenzyl hydroxyamide ) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid or its fa a pharmaceutically acceptable salt, 4- (4-methoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-benzyl-4- (4 hydroxyamide -benzyloxybenzenesulfonyl) piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-butoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable thereof salt, hydroxyamide 4- (4-butoxybenzenesulfonyl) -1- [3- (2-morpholin-1-ylethoxy) benzyl] piperidine-4-carbon an acid or a pharmaceutically acceptable salt thereof, 1-methyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-ethyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or its pharmaceutically acceptable salt, 1-n-butyl-4- (4-butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or its pharmaceutically acceptable salt, 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-methylpiperidin-4 hydroxyamide -carboxylic acid or its pharmaceutically acceptable salt, hydro siamid 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-ethylpiperidine-4-carboxylic ki149 150 slots or a pharmaceutically acceptable salt thereof, 1-butyl-4- [4- (4-chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-benzyl-4- [4- (4- chlorophenoxy) benzenesulfonyl] piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 1-benzyl-4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-butyl- hydroxyamide 4- [4- (3-methylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid or its pharmaceutical and an acceptable salt, 1-butyl-4- [4- (2-ethylbutoxy) benzenesulfonyl] piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 4- (4-butoxybenzenesulfonyl) -1- (3-methoxybenzyl) piperidine hydroxyamide 4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) -1- (4-thiophen-2-ylbenzyl) piperidine-4 carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) hydroxyamide - 1- (4-pyridin-2-ylbenzyl) piperidin-4 carboxylic acid or a pharmaceutically acceptable salt thereof , 1 - (3,4-dichlorobenzyl) -4- (4butoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, [4- (4-chlorobenzyloxy) benzenesulfonyl] -1-methylpiperidin-4-carboxylic acid hydroxyamide or its pharmaceutically acceptable salt, 4- (4-butoxybenzenesulfonyl) -1- (3-phenoxybenzyl) piperidine-4-carboxylic acid hydroxyamide or its pharmaceutically acceptable salt, [4- (4-chlorobenzyloxy) benzenesulfonyl] hydroxyamide] -1- (4- methylbenzyl) piperidine-4 carboxylic acid or a pharmaceutically acceptable salt thereof, hydroxyamide 4- (4-Butoxybenzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-butoxybenzenesulfonyl) -1- (4-cyanobenzyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof acceptable salt, 4- (4-butoxybenzenesulfonyl) -1-pyridin-4-ylmethylpiperidin-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) -1- (3-phenylpropyl) piperidin-4- hydroxyamide carboxylic acid or a pharmaceutically acceptable salt thereof, 1-tert-butyl-4- (4-methoxybenz hydroxyamide olsulfonyl) piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 1-butyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-cyclooctyl-4- (4-methoxybenzenesulfonyl) hydroxyamide) piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 1-ethyl-4- (4-methoxybenzenesulfonyl) hydroxyamide or piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-isopropyl-4- (4-methoxybenzenesulfonyl) piperidine- hydroxyamide 4-carboxylic acid or its headlights a macetically acceptable salt, 1-methyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1-benzyl-4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable thereof salt, 1- (4-fluorobenzyl) -4- (4-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 1- (4-fluorobenzyl) -4- (4-butoxybenzenesulfonyl) piperidin-4- hydroxyamide carboxylic acid or a pharmaceutically acceptable salt thereof, hydroxyamide 4- (4- methoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine-4-carboxylic acid hydroxyamide or its pharmaceutically acceptable salt, 4- (4-methoxybenzenesulfonyl) -1- (2-phenylethyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 4- (4-n-butoxybenzenesulfonyl) -1- (4-methoxybenzyl) piperidine hydroxyamide -4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesul hydroxyamide phonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 4- (4-n-butoxybenzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable thereof salt, hydroxyamide 4- (4-methoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carbo151 152 new acid or a pharmaceutically acceptable salt thereof, 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxyethyl) piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof, 4- (4-methoxybenzenesulfonyl) -1- hydroxyamide [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidin-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 5. A method of inhibiting pathological changes mediated by matrix metalloproteinases in mammals, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of formula Ι according to any one of claims 1 to 4. 6. The method according to claim 5, where the pathological changes mediated by matrix metalloproteinases are atherosclerosis, the formation of atherosclerotic plaques, decreased coronary thrombosis due to rupture of atherosclerotic plaques, restenosis, MMR-mediated osteopenia, inflammatory diseases of the central nervous system, skin aging, skin aging blood vessels, tumor metastases, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulcer, abnormal wound healing, bone disease, prote inuria, aortic aneurysm disease, degenerative loss of cartilage after traumatic joint damage, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular kidney disease, premature rupture of membranes, inflammatory bowel disease or periodontal disease. 7. The method according to claim 5, where the pathological changes mediated by matrix metalloproteinases are age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, premature development retinopathy, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, eye tumors, eye tumors, eye tumors blood vessels / vascular formation and corneal transplant rejection. 8. A method of inhibiting pathological changes mediated by an α-α-converting enzyme (TACE) in mammals, which comprises administering to a mammal in need thereof a therapeutically effective amount of a TACE inhibitory compound of formula Ι according to any one of claims 1 to 4. 9. The method of claim 8, where the pathological changes mediated by the ΤΝΕ-α-converting enzyme (TACE) are rheumatoid arthritis, transplant rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease central nervous system, inflammatory bowel disease or HIV infection. 10. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound of formula Ι according to any one of claims 1 to 4.