JP2003520852A - Method for producing α-sulfonylhydroxamic acid derivative - Google Patents

Abstract

Abstract: Formulas that can be important as matrix metalloproteinase (MMP) and TNF-α converting enzyme (TACE) inhibitors, phosphodiesterase inhibitors, renin inhibitors, antithrombotic agents, and 5-lipoxygenase inhibitors The compound (I) is produced by the novel method of the present invention. Embedded image

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention is important as a matrix metalloproteinase (MMP) and TNF-α converting enzyme (TACE) inhibitor, a phosphodiesterase inhibitor, a renin inhibitor, an antithrombotic drug and a 5-lipoxygenase inhibitor. It relates to a novel method for preparing possible α-sulfonylhydroxamic acid derivatives. The present invention also relates to novel α-sulfonylhydroxamic acid derivatives, their production by a novel method and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION Matrix metalloproteinases are a family of structurally related zinc-containing enzymes that mediate the degradation of extracellular matrix proteins. Members of this family include collagenase, stromelysin and gelatinase,
It is involved in the process of rebuilding normal tissues such as wound healing, angiogenesis and pregnancy. During these pathological processes, MMP activity is tightly regulated by the endogenous tissue inhibitor of matrix proteinases (TIMP). In pathological conditions, MMP
This delicate balance between -TIMPs can be disrupted leading to several disease states including rheumatism and osteoarthritis, atherosclerosis, tumor growth, metastasis, and fibrosis. Therapeutic inhibition of MMPs represents a promising approach for treating these diseases, and therefore MMPs are an attractive goal for rational drug design.

DISCLOSURE OF THE INVENTION TACE is also a new member of the metalloproteinase family and catalyzes the formation of tumor necrosis factor-α precursor protein. TNF-α was selected as one of the initial goals, leading to the successful cloning and sequencing of human TNF-α in 1984 by Goeddel and coworkers. THF-α is a very potent proinflammatory mediator produced by activated macrophages, blood monocytes and mast cells. In addition to its antitumor properties, TNF-α is a proinflammatory cytokine with a central role in rheumatoid arthritis and Crohn's disease. Related studies in animal models and humans have shown a possible role of TNF in insulin resistance, multiple sclerosis, organ failure, pulmonary fibrosis and HIV infection. Therefore, inhibition of TNF-α is the focus of drug discovery.

Lipoxygenases are a family of enzymes that catalyze the oxidation of arachidonic acid and lead to the production of leukotrienes. Leukotrienes have been implicated as important mediators in asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxic shock and inflammatory bowel disease. Inhibition of these enzymes is believed to provide effective systematic treatment of these diseases.
Renin inhibitors can be used to suppress or prevent hypertension and heart failure.

Α-Sulfonylhydroxamic acids of general formula I are effective MMP and TACE inhibitors (Venkatesan, AM; Grosu, GT; Davis, JM; Baker, JL; Levin, JI.
PCT International Application No. WO 9942436; Barta, TE; Becker, DP; Boehm, TL; De
Crescenzo, GA; Villamil, CI; McDonald, JJ; Freskos, JN; Getman,
DP PCT International Application No. 9925687; Almstead, NG; Bookland, RG; Taiwo, YO
Bradley, RS; Bush, RD; De B .; Natchus, MG; Pikul, S. PCT International Application No. 9906340; Venkatesan, AM; Grosu, GT; Davis, JM; Baker, JL; Hu
, B .; O'Dell, MJ; Cole, DC; Jacobson, MP PCT International Application No. WO 9838163; Venkatesan, AM; Grosu, GT; Davis, JM; Baker, JL PCT International Application No. W
O 9837877; Levin, JI; Venkatesan, AM; Zask, A .; Sandanayaka, VP
PCT International Application No. WO 0001864; Zook, SE; Dagnino, R .; Reason, ME; Bender
, SL; Melnick, M. PCT International Application No. WO 9720824), renin inhibitors (Branca, Q.
Heitz, MP; Neidhart, W .; Stadler, H .; Vieira, E .; Wostl, W. EP 50935
4) 5-lipoxygenase inhibitors (Brooks, DW; Summers, JB; Rodriques, K.
E .; Maki, RG; Dellaria, JF; Holms, JH; Moore, JL US 5250565) and antithrombotic agents (Nakane, M .; Reid, J. US 4734425).

In the general preparation of α-sulphonylhydroxamates in the above mentioned literature, an appropriately substituted mercaptan derivative is first alkylated with a substituted or unsubstituted α-bromoacetic acid ester to give the α-thioester. Oxidation of sulfur to sulfone gives α-sulfonyl ester. This α-sulfonyl ester is converted to the corresponding hydroxamic acid derivative via a carboxylic acid. Alternatively, the enolate of the carbonyl compound is treated with an appropriately substituted disulfide to give the α-thioester, which is then oxidized to the corresponding sulfone. The α-sulfonyl ester is converted to the hydroxamic acid derivative as described above. In either case, the production of thiols or disulfides requires a number of steps involving sulfonyl chlorides, protected thiols, or disulfides as intermediates and oxidation steps to convert α-thioesters to α-sulfonyl esters.

An object of the present invention is to provide a novel method for producing an α-sulfonylhydroxamic acid derivative, which gives a target molecule in a highly concentrated and efficient manner.

[0008] (Summary of invention)   According to the invention, formula I:

[0009]

[Chemical 32]

[0010] [In the formula, X is hydrogen, alkyl having 1 to 6 carbon atoms, benzyl, hydroxyethyl, t
-Butyldimethylsilyl, trimethylsilyl or tetrahydropyranyl;   Y is hydrogen, alkyl having 1 to 6 carbons, aryl having 6 to 10 carbons, N, NR_Four 5-10 membered hetero having 1-3 heteroatoms selected from,
Aryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cycloheteroalkyl
Where Y is the alkyl, aryl, heteroaryl, cycloalkyl and
The cycloheteroalkyl group has a halogen atom or a carbon number of 1 to 1 on a substitutable atom.
6 alkyl, C 2-6 alkenyl having 1-3 double bonds, 1-3
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms
Le, -OR₅, = O, -CN, -COR₅, C1-4 perfluoroalkyl
, C1-C4 -O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅ , -OPO (OR₅) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR ₅ R₆, -OC (O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH
, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR ₆ , SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R
₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆ , -NR₅C (= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_Two
NHCN, -SO_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-
Positioned with 1 to 3 substituents selected from the group consisting of 10-membered cycloheteroalkyl.
May be replaced;   R₁And R_TwoAre each independently hydrogen, aryl having 6 to 10 carbon atoms, N, N
R_Four, 10 and 5 to 10 membered heteroatoms having 1 to 3 heteroatoms selected from O and S.
Teloaryl, C3-C6 cycloalkyl, 5- to 10-membered cycloheteroar
Kill, alkyl having 1 to 18 carbons, 2 to 18 carbons having 1 to 3 double bonds
An alkenyl, a C2-18 alkynyl having 1-3 triple bonds;
I, R₁And R_TwoTogether with the carbon atom to which they are attached has 3 carbon atoms
Form a cycloalkyl of ~ 8 or a cycloheteroalkyl ring of 5-10 members;
Where aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,
Alkyl, alkenyl and alkynyl are halogen on the substitutable atom.
, Alkyl having 1 to 6 carbons, and alkyl having 2 to 6 carbons having 1 to 3 double bonds.
Kenyl, C2-6 alkynyl having 1-3 triple bonds, C3-6
Cycloalkyl, -OR₅, = O, -CN, -COR₅, Perfumes with 1 to 4 carbon atoms
Luoroalkyl, -O-perfluoroalkyl having 1 to 4 carbon atoms, -CONR₅R₆
, -S (O)_nR₅, -OPO (OR₅) OR₆, -PO (OR₅) R₆, -OC (O) OR ₅ , -OR₅NR₅R₆, -OC (O) NR₅R₆, -C (O) NR₅OR₆, -COO
R₅, -SO_ThreeH, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆,
-NR₅COOR₆, SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR ₅ CONR₅R₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (= NR₆) N (
SO_TwoR₅) R₆, -NR₅C (= NR₆) N (C = OR₅) R₆, -Tetrazole-5
-Ill, -SO_TwoNHCN, -SO_TwoNHCONR₅R₆, Phenyl, hetero ant
1-3 substituents selected from aryl and 5- to 10-membered cycloheteroalkyl
May be substituted with;   R_ThreeIs alkyl having 1 to 18 carbons, 2 to 3 carbons having 1 to 3 double bonds
18 alkenyl, 2 to 18 alkynyl having 1 to 3 triple bonds,
Cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, and 6 carbon atoms
-10 aryl, N, NR_Four, 1 and 3 heteroatoms selected from O and S
5- to 6-membered heteroaryl having children; where R_ThreeOf said alkyl, alkenyl
, Alkynyl, cycloalkyl, cycloheteroalkyl, aryl and hetero
Aryl is halogen, alkyl having 1 to 6 carbons,
C2-C6 alkenyl having 1-3 double bonds, 1-3 triple bonds
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -OR₅,
= O, -CN, -COR₅, C1-4 perfluoroalkyl, C1-4
-O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅, -OPO (OR ₅ ) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR₅R₆, -OC (
O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH, -NR₅R₆
, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR₆, SO_TwoN
R₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R₆, -NR₅C
(= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆, -NR₅C (
= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_TwoNHCN, -S
O_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-10 membered cyclo
Optionally substituted with 1 to 3 substituents selected from heteroalkyl;   R_FourIs hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, charcoal
Alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -C (O)_nR₅, -CO
NR₅R₆Or SO_TwoR₅;   R₅And R₆Are each independently hydrogen, optionally substituted aryl, N
, NR_Four, 4 and 8 members having 1 to 3 heteroatoms selected from O and S
Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cyclohetero
Alkyl, alkyl having 1 to 18 carbons, alkenyl having 2 to 18 carbons or carbon number
2-18 alkynyl; or R₅And R₅Is the nitrogen source they bind to
May form a 5- to 10-membered cycloheteroalkyl ring together with the child
;and   n is 1 or 2] To produce an α-sulfonylhydroxamic acid derivative or a pharmaceutical salt thereof
Provide a way. Such a manufacturing method is represented by the formula III:

[0011]

[Chemical 33]

A sulfonyl fluoride of the formula: wherein R ₃ ′ is as defined above for R ₃ ; provided that R ₃ ′ does not contain a group capable of forming an anion under basic conditions. , An ether organic solvent, in the presence of a metal hydride or an amide base, at a temperature of about -78 ° C to about room temperature (eg, about 15 ° C to about 30 ° C, preferably about 20-25 ° C), a compound of formula IV :

[0013]

[Chemical 34]

[Wherein Z is H, OH, YNOX or OR ₅ ; X, Y, R ₁ , R ₂ , R and R ₆ have the same meanings as defined above], and a compound of formula V :

[0015]

[Chemical 35]

[Wherein Z, R ₁ , R ₂ and R ₃ ′ are as defined above] to form an α-sulfonylcarbonyl compound and convert the compound of formula V into a hydroxamic acid derivative. .

[0017]   The compound of formula I has formula III:

[0018]

[Chemical 36]

A sulfonyl fluoride of the formula where R ₃ ′ is as defined above for R ₃ ; provided that R ₃ ′ does not contain a group capable of forming an anion under basic conditions. , An ether organic solvent in the presence of a Lewis acid or a fluoride reagent at a temperature in the range of about -78 ° C to about room temperature (eg, up to about 15-30 ° C), Formula VIII:

[0020]

[Chemical 37]

[Wherein, Z is H, OH, YNOX or OR ₅ ; R ₁ and R ₂ are as defined above; R ₇ is cycloalkyl having 3 to 6 carbon atoms, 5 to 10 membered cycloheteroalkyl,
C1-C18 alkyl, C2-C18 alkenyl having 1-3 double bonds, C2-C18 alkynyl having 1-3 triple bonds, or -S.
iR ₈ R ₉ R ₁₀ ; R ₈ , R ₉ and R ₁₀ are each independently a 4-8 membered 1 to 3 heteroatom selected from aryl, N, NR ₄ , O and S. Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, 1 to carbon atoms
18 alkyl, C 2-18 alkenyl having 1 to 3 double bonds, 1
A C2-C18 alkynyl having 3 to 3 triple bonds; or two of R ₈ , R ₉ and R ₁₀ together with the silicon atom to which they are bonded are a 5- or 6-membered heterocycle. To form a compound of formula V:

[0022]

[Chemical 38]

[Wherein Z, R ₁ , R ₂ and R ₃ ′ have the same meanings as defined above] to produce an α-sulfonylcarbonyl compound, which is produced by converting the compound of formula V into a hydroxamic acid derivative. You may.

[0024]   In another embodiment of the present invention, general formula I:

[0025]

[Chemical Formula 39]

[0026] [In the formula, X is hydrogen or alkyl having 1 to 6 carbon atoms;   Y is hydrogen, alkyl having 1 to 6 carbons, aryl having 6 to 10 carbons, N, NR_Four 5-10 membered hetero having 1-3 heteroatoms selected from,
Aryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cycloheteroalkyl
Where Y is the alkyl, aryl, heteroaryl, cycloalkyl and
The cycloheteroalkyl group has a halogen atom or a carbon number of 1 to 1 on a substitutable atom.
6 alkyl, C 2-6 alkenyl having 1-3 double bonds, 1-3
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms
Le, -OR₅, = O, -CN, -COR₅, C1-4 perfluoroalkyl
, C1-C4 -O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅ , -OPO (OR₅) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR ₅ R₆, -OC (O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH
, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR ₆ , SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R
₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆ , -NR₅C (= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_Two
NHCN, -SO_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-
Positioned with 1 to 3 substituents selected from the group consisting of 10-membered cycloheteroalkyl.
May be replaced;   R_ThreeIs alkyl having 1 to 18 carbons, 2 to 3 carbons having 1 to 3 double bonds
18 alkenyl, 2 to 18 alkynyl having 1 to 3 triple bonds,
Cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, and 6 carbon atoms
-10 aryl, N, NR_Four, 1 and 3 heteroatoms selected from O and S
5- to 6-membered heteroaryl having children; where R_ThreeOf said alkyl, alkenyl
, Alkynyl, cycloalkyl, cycloheteroalkyl, aryl and hetero
Aryl is halogen, alkyl having 1 to 6 carbons,
C2-C6 alkenyl having 1-3 double bonds, 1-3 triple bonds
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -OR₅,
= O, -CN, -COR₅, C1-4 perfluoroalkyl, C1-4
-O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅, -OPO (OR ₅ ) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR₅R₆, -OC (
O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH, -NR₅R₆
, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR₆, SO_TwoN
R₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R₆, -NR₅C
(= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆, -NR₅C (
= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_TwoNHCN, -S
O_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-10 membered cyclo
Optionally substituted with 1 to 3 substituents selected from heteroalkyl;   R_FourIs hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, charcoal
Alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -C (O)_nR₅, -CO
NR₅R₆Or SO_TwoR₅;   R₅And R₆Are each independently hydrogen, optionally substituted aryl, N
, NR_Four, 4 and 8 members having 1 to 3 heteroatoms selected from O and S
Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cyclohetero
Alkyl, alkyl having 1 to 18 carbons, alkenyl having 2 to 18 carbons or carbon number
2-18 alkynyl; or R₅And R₅Is the nitrogen source they bind to
May form a 5- to 10-membered cycloheteroalkyl ring together with the child
;and   n is 1 or 2] To produce an α-sulfonylhydroxamic acid derivative or a pharmaceutical salt thereof
A method is provided. Such a manufacturing method is represented by the formula a):

[0027]

[Chemical 40]

Reacting a compound of formula with diisopropylamide or lithium hexamethyldisilazide to form an enolate; b) converting the enolate to the formula III:

[0029]

[Chemical 41]

[0030] The compound is reacted with a sulfonyl fluoride represented by:

[0031]

[Chemical 42]

[0032] To form;   c) hydrolyzing the compound of step b),

[0033]

[Chemical 43]

And d) adding the compound of step c) to about 0 in the presence of a coupling reagent and a polar organic solvent.
At a temperature in the range of ℃ to about room temperature (eg, up to about 15 to 30 ℃), Formula VII:

[0035]

[Chemical 44]

[0036] It comprises a step of reacting with a hydroxylamine or a hydroxylamine derivative represented by

[0037]   In another aspect of the invention, Formula 8:

[0038]

[Chemical formula 45]

[In the formula, R ₄ is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl having 1 to 6 carbons, cycloalkyl having 3 to 6 carbons, and —C (O) _n R ₅
, -CONR ₅ R ₆ or SO ₂ R ₅ ; R ₅ and R ₆ are each independently hydrogen, optionally substituted aryl, N
, NR ₄ , ₄ and 8-membered heteroaryl having 1 to 3 heteroatoms selected from O and S, cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, and 1 to 1 carbon atoms. 18 alkyl, alkenyl having 2 to 18 carbons or alkynyl having 2 to 18 carbons; or R ₅ and R ₅ together with the nitrogen atom to which they are attached are a 5 to 10 membered cycloheteroalkyl ring. R ₁₂ is methyl, n-butyl, 2-butynyl or p-chlorophenyl; and n is 1 or 2], or a pharmaceutical salt thereof. The manufacturing method is as follows:

[0040]

[Chemical formula 46]

Reacting a compound of formula with diisopropylamide or lithium hexamethyldisilazide to form an enolate; b) converting the enolate to the formula 2:

[0042]

[Chemical 47]

[0043] By reacting with a sulfonyl fluoride of formula 13:

[0044]

[Chemical 48]

[0045] To form a compound represented by:   c) hydrolyzing the compound of formula 13 with lithium hydroxide to give formula 14:

[0046]

[Chemical 49]

D) adding a compound of formula 14 at a temperature in the range of about 0 ° C. to about room temperature (eg, up to about 15-30 ° C.) oxalyl chloride, triethylamine and hydroxylamine hydrochloric acid. It consists of treating with salt.

[0048]   In some aspects of the invention, Formula V:

[0049]

[Chemical 50]

[Wherein R ₁ , R ₂ and R ₃ ′ have the same meanings as described above; Z is H, OH, YNOX, O
The compound represented by R ₅ or NR ₅ R ₆ ] has the formula III:

[0051]

[Chemical 51]

[Wherein R ₃ ′ has the same meaning as above], and a sulfonyl fluoride represented by the following formula is used in the presence of a metal hydride or an amide base in an ether organic solvent at about −78 ° C. At a temperature of 15 ° C. up to about 30 ° C.) and having the formula IV:

[0053]

[Chemical 52]

[In the formula, Z, R ₁ and R ₂ have the same meanings as above], and are produced by reacting with a carbonyl compound.

[0055]   Alternatively, the formula V:

[0056]

[Chemical 53]

[Wherein, R ₁ , R ₂ and R ₃ ′ are as defined above; Z is H, OH, YNOX, O
The compound represented by R ₅ or NR ₅ R ₆ ] has the formula III:

[0058]

[Chemical 54]

[Wherein R ₃ ′ has the same meaning as above], and a sulfonyl fluoride represented by the formula: At temperatures in the range of 15 ° C. up to about 30 ° C.), Formula VIII:

[0060]

[Chemical 55]

[Wherein Z is H, OH, YNOX, OR ₅ or —NR ₅ R ₆ ; R ₁ and R ₂
Is as defined in claim 1; R ₇ is cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members,
C1-C18 alkyl, C2-C18 alkenyl having 1-3 double bonds, C2-C18 alkynyl having 1-3 triple bonds, or -S.
iR ₈ R ₉ R ₁₀ ; R ₈ , R ₉ and R ₁₀ are each independently a 4-8 membered 1 to 3 heteroatom selected from aryl, N, NR ₄ , O and S. Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, 1 to carbon atoms
18 alkyl, C 2-18 alkenyl having 1 to 3 double bonds, 1
A C2-C18 alkynyl having 3 to 3 triple bonds; or two of R ₈ , R ₉ and R ₁₀ together with the silicon atom to which they are bonded are a 5- or 6-membered heterocycle. To form an α-sulfonylcarbonyl compound of the formula V to produce an α-sulfonylcarbonyl compound of formula V. When Z is OR ₅ , the compound of formula V is obtained by converting the α-sulfonylcarbonyl compound of formula V in the presence of water and / or an ether organic solvent or alcohol at a temperature in the range of about 0 ° C. to about 100 ° C. Reacting with an alkali metal hydroxide, formula VI:

[0062]

[Chemical 56]

[Wherein R ₁ , R ₂ and R ₃ have the same meanings as defined above] are produced; the carboxylic acid of formula VI is prepared in the presence of a suitable coupling reagent and a polar organic solvent.
Formula VII:

[0064]

[Chemical 57]

[Wherein X and Y have the same meanings as above], and are reacted with a hydroxylamine or a hydroxylamine derivative,
Formula I:

[0066]

[Chemical 58]

[Wherein X, Y, R ₁ , R ₂ and R ₃ have the same meanings as defined above] may be converted into the hydroxamic acid derivative of the formula I according to the step of producing the hydroxamic acid derivative.

In another embodiment of the present invention, when Z is OH, the compound of formula V is obtained by combining the α-sulfonylcarbonyl compound of formula V in the presence of a coupling reagent and a polar organic solvent at about 0 ° C. to about. At a temperature in the range of room temperature (eg, about 15 ° C. to about 30 ° C.), Formula VII:

[0069]

[Chemical 59]

[Wherein X and Y have the same meanings as above], and may be converted into a hydroxamic acid derivative by reacting with a hydroxylamine or a hydroxylamine derivative.

[0071]   Further in accordance with the present invention, the sulfonyl fluoride compound of formula III has the formula II:

[0072]

[Chemical 60]

Wherein R ₃ ′ is as defined above for R ₃ ; provided that R ₃ ′ does not contain a group capable of forming an anion under basic conditions. In the presence of a polar organic solvent, room temperature (eg, about 15 ℃
˜about 30 ° C.) to react with a fluorinating agent to form a sulfonyl fluoride of formula III.

[0074]   Further chemical transformations can be achieved by₁, R_TwoOr R_ThreeIs the starting material R₁, R _Two Or R_Three'Is different for compounds of formula I, V and VI before each step
You can do it later.

Groups excluded from the definition of R ₃ ′ because they can form an anion under the basic conditions of the invention include —OH, —NH, —SH, —COCH, —SO ₂ CH, —CHNO. ₂ , CHCN, but not limited thereto. Thus, during sulfonylation of carbonyl compounds, such substituents on R ₃ are avoided or protected,
Later deprotection opens as indicated by R ₃ '.

The sulfonyl chloride compound of the present invention may be a commercially available product, or a method described in the literature by those skilled in the art (eg, Kende, AS; Medoza, JS, J. Org. Chem., 199).
0, 55, 1125-1126).

Suitable fluorinating agents are, for example, Clark, JH; Hyde, AJ; Smith, DKJ Ch
em. Soc. Chem. Comm. 1986, 791-792; Ichihara, J .; Matsuo, T .; Hanafusa,
T .; Ando, TJ Chem. Soc. Chem. Comm. 1986, 793-794, and includes but is not limited to potassium fluoride, potassium fluoride-calcium fluoride mixtures or cesium fluoride. .

Preferred ether organic solvents of the present invention are known to those skilled in the art and include, but are not limited to, tetrahydrofuran, diethyl ether or dioxane.

The bases used in the method of the present invention are known to those skilled in the art and preferably include metal hydride or amide bases such as lithium diisopropylamide, lithium hexamethyldisilazide and sodium hydride. However, it is not limited to these.

Lewis acids and fluoride reagents used in the methods of the invention are known to those of skill in the art and include, but are not limited to, boron tribromide, tetrabutylammonium and sodium hydride.

Polar organic solvents useful in the methods of the present invention are known to those of skill in the art and include, but are not limited to, acetonitrile, tetrahydrofuran and dimethylformamide.

Alkali metal hydroxides used in the preferred methods of the present invention are known to those skilled in the art and include, but are not limited to, lithium hydroxide and sodium hydroxide.

Alcohols used in some of the methods of the present invention are known to those of skill in the art and include, but are not limited to, methanol and ethanol.

Coupling reagents of the present invention are known to those skilled in the art and include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxybenzotriazole, N-methylmorpholine and oxalyl chloride. And one or more of triethylamine, but is not limited thereto.

Furthermore, the present invention provides a matrix metalloproteinase (MMP) for treating rheumatoid arthritis, tumor metastasis, tissue ulcer, abnormal wound healing, periodontal disease, bone disease, diabetes and HIV infection. It relates to low molecular weight non-peptide inhibitors of TNF-α convertase (TACE).

[0086]   Thus, according to the invention, formula IX:

[0087]

[Chemical formula 61]

[Wherein, X is hydrogen or alkyl having 1 to 6 carbon atoms; Y, R ₃ and R ₄ are as defined above], and a pharmaceutical salt thereof.

Particularly preferred is 1-benzyl-3- (4-methoxybenzenesulfonyl) piperidine-3-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

Some compounds prepared by the novel methods of this invention contain one or more asymmetric carbon atoms and give rise to enantiomeric and diastereomeric forms of such compounds. In addition, some compounds of the present invention contain carbon-carbon double bonds, giving rise to cis- and trans-geometric isomers. The present invention relates to enantiomers, diastereomers and geometric isomers and mixtures thereof (including racemic mixtures)
Should be understood to include.

Alkyl, as used herein, refers to branched and straight chain alkyl groups preferably having from 1 to 18 carbon atoms, more preferably 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl, n-heptyl, octyl and the like.

Alkenyl, as used herein, preferably has 2 to 18 carbon atoms, more preferably 2 to 6 carbon atoms, and has 1 to 3 alkenyl unsaturated sites (double bonds). Means

Alkynyl, as used herein, preferably has 2 to 18 carbon atoms, more preferably 2 to 6 carbon atoms, and has 1 to 3 alkynyl unsaturated moieties (triple bonds). means.

Cycloalkyl means a cyclic alkyl group having 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.

Heteroaryl, as used herein, includes N, NR ₄ , S and O within the ring.
It is a 5- to 10-membered monocyclic or bicyclic aromatic carbocycle having 1 to 3 heteroatoms selected from Such heteroaryl rings can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., benzothienyl) (fused rings may or may not contain heteroatoms). . Heteroaryl is preferably

[0096]

[Chemical formula 62]

Wherein K is defined as O, S or —NR ₄ , and R ₄ is as defined above. More preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, Mention may be made of isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole and benzoxazole. The heteroaryl group of the present invention may have 1 to 3 substituents, and more preferably 1 or 2 substituents.

The 5- to 10-membered cycloheteroalkyl has a monocyclic ring or a polycondensed ring and has 2 carbon atoms.
10 is a saturated or unsaturated group having 1 to 3 heteroatoms selected from S, N, O or NR ₄ in the ring (wherein in the fused ring system, one of the rings is Or more can be aryl or heteroaryl).

[0099]   Preferred cycloheteroalkyl is

[0100]

[Chemical formula 63]

[Wherein, K is O, N, S or NR ₄ ; R ₄ is as defined above]. In addition, the ring shown above as a monovalent group may be exemplified as a divalent group, for example, when R ₁ and R ₂ together form a cycloheteroalkyl ring.

Preferred cycloheteroalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. The cycloheteroalkyl groups of this invention may be mono-, di- or tri-substituted.

Aryl, as used herein, has a single ring (phenyl) or multiple condensed rings (naphthyl), where the condensed rings may be aromatic or non-aromatic. It means a saturated aromatic carbocyclic group having 6 to 10 carbon atoms. Preferred aryl includes
Examples include phenyl and naphthyl. The aryl group may be mono-substituted, di-substituted or tri-substituted.

Alkyl, alkenyl, alkynyl and perfluoroalkyl include both straight chain and branched moieties. The alkyl, alkenyl, alkynyl and cycloalkyl groups may be unsubstituted (carbon bonded to hydrogen or other carbon in the chain or ring), mono- or polysubstituted.

[0105]   Halogen means bromine, chlorine, fluorine and iodine.

[0106]   Aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, ar
Suitable substituents on alkenyl, alkynyl and cycloalkyl include halogen,
Alkyl having 1 to 6 carbons, alkenyl having 2 to 6 carbons, alkynyl having 2 to 6 carbons
L, cycloalkyl having 3 to 6 carbon atoms, -OR₅, -CN, -COR₅, Carbon number 1
4 perfluoroalkyl, 1 to 4 carbon-O-perfluoroalkyl, -CO
NR₅R₆, -S (O)_nR₅, -OPO (OR₅) OR₆, -PO (OR₅) R₆, -O
C (O) OR₅, -OR₅NR₅R₆, -OC (O) NR₅R₆, -C (O) NR₅OR
₆, -COOR₅, -SO_ThreeH, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR
₅COR₆, -NR₅COOR₆, SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO
_TwoR₆, -NR₅CONR₅R₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (
= NR₆) N (SO_TwoR₅) R₆, -NR₅C (= NR₆) N (C = OR₅) R₆, -Te
Trazol-5-yl, -SO_TwoNHCN, -SO_TwoNHCONR₅R₆, Phenyl
, Heteroaryl and 5-10 membered cycloheteroalkyl, including
Not limited to these; R₅And R₆Is as defined above; -NR₅R₆Is
Loridin, piperidine, morpholine, thiomorpholine, oxazolidine, thiazo
Cycloheteroaryl such as lysine, pyrazolidine, piperazine or azetidine ring
It may form a kill ring.

Pharmaceutically acceptable salts are lactic acid, succinic acid, acetic acid, tartaric acid, succinic acid, maleic acid, malonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulphonic acid and likewise known. Are derived from pharmaceutically acceptable organic acids and inorganic acids such as permissible acids of

In the compounds mentioned above, examples of Z are preferably OH or OR ₅ , for example where R ₅ is alkyl (preferably 1 to 6 carbon atoms, eg methyl, ethyl, propyl, isopropyl). , Butyl and pentyl).

R ₃ is preferably an optionally substituted aryl group, for example a phenyl group,
Most preferably, it is a 4-substituted phenyl group. Aryl groups are preferably substituted with one or more —OR ₅ groups, eg where R ₅ is alkyl (preferably 1 to 6 carbon atoms, eg methyl, ethyl, propyl, isopropyl). ,
Butyl or pentyl), alkynyl (preferably having from 2 to 7 carbon atoms) or optionally substituted aryl, for example where the substituents are C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and halogen. (Eg chlorine).

R ₁ and R ₂ , together with the carbon atom to which they are attached, are preferably 5
A 10-membered heteroalkyl ring, for example a ring having 1 to 3 heteroatoms selected from N, NR ₄ , O and S, most preferably containing a single NR ₄ group, for example 6 Form a membered piperidine ring. They are preferably 3,3-disubstituted, 4
It forms 1,4-disubstituted, 1,3,3-trisubstituted or 1,4,4-trisubstituted piperidine.

Examples of R ₄ are hydrogen, alkyl having 1 to 6 carbons, —COR ₅ , —COOR ₅ , and —S.
O ₂ R ₅ and optionally substituted benzyl (eg, 4-chlorobenzyl, 4
-Methoxybenzyl or 4- (2-piperidin-1-yl-ethoxy) benzyl).

Examples of R ₅ include optionally substituted alkyl having 1 to 18 carbons (eg, methyl, trifluoromethyl), optionally substituted alkenyl having 2 to 18 carbons, substituted Optionally aryl (eg, phenyl), optionally substituted 4
8-membered heteroaryl (e.g., pyridyl, thienyl) or optionally substituted by 5-10 membered also cycloheteroalkyl (e.g., pyrrolyl) a; preferably, R ₅ is methyl, ethyl, n- butyl, t-Butyl, but-2-ynyl, 4-chlorophenyl, 4-methoxyphenyl, 1-pyrrolidinyl, 3-pyridinyl, 2-thienyl, 2,2,5-trimethyl-1,3-dioxan-5-yl or 2 -Hydroxy-1- (
Hydroxymethyl) -1-methylethyl.

Typical optional substituents, as used herein, include C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and halogen.

The present invention therefore provides pharmaceutical compositions wherein a compound of the invention is combined or associated with a pharmaceutically acceptable carrier. In particular, the invention provides a pharmaceutical composition which comprises an effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

These compositions are preferably adapted for oral administration. But they are
It may be adapted for other modes of administration, for example parenteral administration to a patient.

For consistency of administration, the compositions of the invention are preferably in unit dose form. Suitable unit dosage forms include tablets, capsules, and powders in sachets or vials. Such unit dose forms are compounds of the invention of 0.1-
It suffices if it contains 100 mg. The compound of the present invention is about 0.01 to 1 kg.
It can be administered orally in a dosage range of 100 mg. 1 such composition
It may be administered 1 to 6 times daily, more usually 1 to 4 times daily.

The compositions of the present invention may be formulated with conventional excipients such as fillers, disintegrants, binders, lubricants, flavoring agents and the like. They are formulated in conventional manner.

DISCLOSURE OF THE INVENTION To prepare compounds of Formula I, α-sulfonylation of an enolizable carbonyl compound can be used as a key step in this process to employ several synthetic routes. it can. Several preferred routes for making these compounds are described in Squam I-III. Each route is represented by Formula I [wherein X and Y are hydrogen, R ₃
Is aryl, R ₁ and R ₂ together with the carbon atom to which they are attached are N
Form a 6-Membered Cycloheteroalkyl Ring Containing R ₄ ], but additional compounds of the invention will be recognized by those skilled in the art,
Similar preparations can be made using the appropriate starting materials and routes illustrated in the specific examples. The reagents and solvents for the individual steps are provided for illustrative purposes only and may be replaced with other reagents and solvents known to those skilled in the art.

[0119]

[Chemical 64]

In Step 1, Scheme I, sulfonyl chloride 1 (wherein R ₁₂ is methyl, n-butyl, 2-butynyl or p-chlorophenyl) in acetonitrile at room temperature
Potassium fluoride-calcium fluoride mixture (commercially available or in Ichihar
(prepared according to the method according to a)) to give the sulfonyl fluoride 2.

In step 2, ester 3 (produced by treating commercially available Boc-isonicopetic acid with methyl iodide / potassium carbonate) and lithium diisopropylamide (LDA) (n-butyllithium and diisopropylamine) were added. make use of,
Prepared in-situ) is treated with compound 2 at -78 ° C to 25 ° C to give compound 4.

In step 3, the protecting group t-butoxycarbonyl is cleaved with trifluoroacetic acid in trifluoroethanol to give compound 5 as a salt.

In step 4, R ₄ (which has the same meaning as above) is prepared by treating compound 5 with R ₄ L (where L is a leaving group) in the presence of other reagents such as triethylamine and solvents known to those skilled in the art. , For example, but not limited to halogen) to give compound 6.

In step 5, ester 6 is hydrolyzed with lithium hydroxide or sodium hydroxide at 50 ° C. for 15 hours to give acid 7.

In step 6, compound 7 is treated with N-hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-methylmorpholine and aqueous hydroxylamine to give the desired hydroxamic acid. Get 8.

[0126]

[Chemical 65]

The target compound can also be obtained by altering the order of the transformations performed on compound 4, as shown in Scheme II.

In step 1 of scheme II, compound 4 is treated with lithium hydroxide as in step 5 of scheme I to give the N-protected carboxylic acid 9.

In step 2, acid 9 is treated with oxalyl chloride, triethylamine and hydroxylamine hydrochloride in dimethylformamide to give N-protected hydroxamic acid 10. It was then deprotected with 4M hydrochloric acid in dioxane,
Obtain salt 11 of step 3.

In Step 4, R ₄ (as defined above) is selectively introduced using the conditions in Step 4 of Scheme I to give the hydroxamic acid 8.

[0131]

[Chemical formula 66]

Alternatively, the target compound can be obtained according to the synthetic route of Scheme III.

In Step 1 of Scheme III, the sulfonyl fluoride 2 is obtained by treating the sulfonyl chloride 1 with potassium fluoride or cesium fluoride in acetonitrile. Alternatively, the reaction is carried out in tetrahydrofuran and the resulting solution is used in the next step without isolation of the sulfonyl fluoride.

In step 2, R ₄ (as defined above) is a starting material such as ethyl isonipecotate R ₄ L (where L is a leaving group such as, but not limited to, halogen). Is introduced early in the pathway by treating with commercially available ethyl isonipecotate in the presence of a suitable reagent such as triethylamine.

In step 3, the enolate prepared by reacting compound 12 with lithium diisopropylamide or lithium hexamethyldisilazide is treated with fluoride 2
Is treated with to give compound 13.

In step 4, ester 13 is hydrolyzed with lithium hydroxide to give acid 14.
Alternatively, step 3 and step 4 can be performed in one pot without isolating ester 13.
The (one-pot) method is sequentially performed.

In Step 5, acid 14 is treated with oxalyl chloride, tritylamine and hydroxylamine hydrochloride as in Step 2 of Scheme II to give compound 8.

The following examples describe some preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to particular embodiments.

General Method for Producing Sulfonyl Fluoride from Sulfonyl Chloride Method A : To a solution of sulfonyl chloride (1 equivalent) in acetonitrile is added potassium fluoride.
-Calcium fluoride mixture (2 equivalents with respect to potassium fluoride) was added and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the product. Method B : To a solution of sulfonyl chloride (1 equivalent) in acetonitrile is added potassium fluoride.
(2 eq) was added. The resulting suspension was stirred at 20-25 ° C for 18 hours. The suspension was filtered and the solid washed with diethyl ether. Concentrate the mother liquor in vacuo,
The resulting oil was seeded with crystals to give the product as a white crystalline solid. Method C : To a solution of sulfonyl chloride (1 equivalent) in acetonitrile, add cesium fluoride.
(2 eq) was added. The resulting suspension was stirred at 20-25 ° C for 18 hours. The suspension was filtered and the solid washed with diethyl ether. Concentrate the mother liquor in vacuo,
The resulting oil was seeded with crystals to give the product as a white crystalline solid. Method D : A solution of sulfonyl chloride (1 eq) in tetrahydrofuran was mixed with potassium fluoride (2 eq) and stirred at 20 ° C. for 30 hours. The suspension was filtered and the solid was washed with tetrahydrofuran. This solution was used in the next step without isolation.

General Method for α-Sulfonylation of Carbonyl Compounds (Step 1) Lithium diisopropylamide (1 eq) in tetrahydrofuran cooled to −78 ° C. (commercially available or n-butyllithium and diisopropylamine) Solution of carbonyl compound (1 eq) in tetrahydrofuran and the resulting mixture was stirred at that temperature for 0.5-1 h. Then a solution of sulfonyl fluoride (1.1 eq) in tetrahydrofuran was added to this mixture and the resulting mixture was stirred at room temperature for 4-15 hours, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The crude product was recrystallized or purified by silica gel chromatography to give the desired product.

General Method for Producing Carboxylic Acids from Esters (Step 3) Ester (in a 3: 3: 2 tetrahydrofuran / methanol / water mixture)
A solution of 1 eq) and lithium hydroxide or sodium hydroxide (1.5-2 eq) is stirred at room temperature or heated at 55 ° C for 15 hours. The mixture was concentrated, acidified to pH 3-5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give the product.

General Method for Producing Hydroxamic Acid from Carboxylic Acids (Step 4) Method A : To a solution of acid (1 eq) in dimethylformamide was added hydroxybenzotriazole (1.2 eq) followed by 1 -(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.4 eq) and N-methylmorpholine (1.5 eq) were added. When 50% aqueous hydroxylamine solution (5 eq) was added, the resulting mixture was stirred at room temperature for 1 hour and the mixture was stirred at that temperature for 15 hours. The solvent was removed in vacuo and ethyl acetate / water was added to the crude product. The organic layer was separated and washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give the product. Method B : To a solution of oxalyl chloride in methylene chloride was added dimethylformamide followed by acid (1 eq) in methylene chloride at 0 ° C and the mixture was stirred at room temperature for 1 hour. This mixture was added to a solution containing hydroxylamine hydrochloride (10 equivalents) and triethylamine (15 equivalents) in tetrahydrofuran / water (5: 1) stirred at 0 ° C for 0.25 to 1 hour. The reaction was warmed to room temperature and stirred at that temperature for 15-24 hours. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the crude product was triturated or purified by silica gel chromatography to give the product.

Example 1 4-But-2-ynyloxybenzenesulfonyl fluoride

[0144]

[Chemical formula 67]

General reaction of sulfonyl fluoride with 4-but-2-ynyloxybenzenesulfonyl chloride (2.0 g, 8.18 mmol) and potassium fluoride-calcium fluoride mixture in acetonitrile (10 ml). 1.5 according to various manufacturing methods
g (80%) of product was obtained as a solid. IR: 2925, 2242, 1596, 1579, 1406, 1261, 99
7 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.87 (t, 3H, J = 1.8 Hz)
, 4.76 (q, 2H, J = 1.8 Hz), 7.14 (d, 2H, J = 6.6 Hz), 7.9
5 (d, 2H, J = 6.6 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ): δ3.6, 56.9, 72.4, 85.
4,115.8,130.8,163.3.

Example 2 1- (tert-Butyl) 4-methyl 1,4-piperidinecarboxylic acid

[0147]

[Chemical 68]

N-t-butoxycarbonylisonipecotic acid (20 g, 0.087 mmol),
Methyl iodide (62g, 0.435mmol) and potassium carbonate (120g, 0.4g).
The mixture of 87 mmol) was stirred for 2 days. The mixture was filtered and the solvent removed in vacuo. The crude product was dissolved in methylene chloride, washed with water and dried over anhydrous sodium sulfate. The solvent was removed to give 20 g (95%) of product as a white solid.

[0149] Example 3 4- (4-but-2-y oxy benzenesulfonyl) - piperidine-1,4-Time carboxylic acid tert- butyl ester methyl ester

[0150]

[Chemical 69]

Lithium diisopropylamide (70 mmol), the product of Example 2 (15.5 g)
, 64 mmol) and the product of Example 1 (70 mmol) according to the general procedure of Step 1 to give 24.5 g (85%) of product as a white solid. IR: 2978, 2242, 1740, 1697, 1594, 1418, 13
01, 1002, 908 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.44 (s, 9H), 1.87 (m,
3H), 1.98 (m, 2H), 2.32 (m, 2H), 2.62 (m, 2H), 3.74 (s,
3H), 4.17 (m, 2H), 4.74 (m, 2H), 7.09 (d, 2H, J = 7.2Hz
), 7.71 (d, 2H, J = 7.2 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 4.0, 28.2, 28.7, 53.
5, 57.2, 72.9, 73.1, 80.5, 85.4, 115.3, 127.0,
132.6,154.7,162.9,167.8; HR-MS: Calculated _{(C 22 H 29 NO 7 S} (M + Na) 474.1557; Found 474.1547.

Example 4 1- (tert-Butoxycarbonyl) -4-{[4- (2-butynyloxy) phenyl] sul
Honyl} -4-piperidinecarboxylic acid

[0153]

[Chemical 70]

The product of Example 3 (15 g, 33.2 mmol), methanol (50 ml), tetrahydrofuran (50 ml) and lithium hydroxide hydrate (2.73 g, 66.4 mmol) in water (100 ml). 14.5 g (100%) of the acid was obtained as a white powder according to the general procedure of Step 3 at reflux temperature for 8 hours. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.38 (s, 9H), 1.7-1.
8 (m, 2H), 1.85 (t, 3H, J = 2.2Hz), 2.2-2.3 (m, 2H), 2.5
-2.7 (m, 2H), 3.95-4.05 (m, 2H), 4.89 (q, 2H, J = 2.2Hz
), 7.1-7.8 (m, 4H); MS-ES: m / z 482 (MH); Results of elemental analysis (as C ₂₁ H ₂₇ NO ₇ S): Calculated value: C, 57. 65; H, 6.22; N, 3.20 Found: C, 57.59; H, 6.49; N, 3.20.

Example 5 tert-Butyl 4-{[4- (2-butynyloxy) phenyl] sulfonyl} -4-[(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid

[0156]

[Chemical 71]

Dimethylformamide (3.53 ml, 46 mmol), oxalyl chloride (22.9 ml of a 2.0M solution in dichloromethane), product of Example 4 (10 g, 22.9 mmol), hydroxylamine hydrochloride (16 g). , 229 mmol) and triethylamine (48 m, 344 mmol) according to the general procedure of Step 4,
The product was obtained as a white powder, 6.3 g (61%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.38 (s, 9H), 1.6-1.
7 (m, 2H), 1.85 (t, 3H, J = 2.2Hz), 2.2-2.3 (m, 2H), 2.5
-2.7 (m, 2H), 3.9-4.0 (m, 2H), 4.87 (q, 2H, J = 2.2Hz),
7.1-7.7 (m, 4H); MS-ES: m / z 453 (M + H) ^<+> .

Example 6 4-{[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-pipet
Lysine Carboxamide Hydrochloride

[0159]

[Chemical 72]

To a solution of the product of Example 5 (6.3 g, 13.9 mmol) in methylene chloride was added 4N hydrochloric acid in dioxane. After 6 hours, the reaction mixture was concentrated in vacuo. Methanol was added and the resulting mixture was concentrated in vacuo. Methylene chloride was added and removed in vacuo (twice). Trituration with diethyl ether gave the product as a white powder, 5.14 g. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.86 (t, 3H, J = 2.2H)
z), 2.0-2.7 (m, 8H), 4.89 (q, 2H, J = 2.2Hz), 7.1-7.8 (
m, 4H), 8.8-11.0 (m, 4H); MS-ES: m / z 353 (M + H) ^<+> .

Example 7 4- (4-chlorophenoxy) phenylsulfonyl fluoride

[0162]

[Chemical formula 73]

4- (4-chlorophenoxy) phenylsulfonyl fluoride (770 mg, 2.5
4 mmol) and potassium fluoride-calcium fluoride mixture (1.47 g, 2 equivalents)
) Was used according to the general procedure for the preparation of sulfonyl fluorides to give 660 mg (91%
) Product was obtained. IR: 1599, 1579, 1484, 1395, 1258, 1210, 11
83,768 cm ⁻¹ ; ¹ H NMR (300 MHz, (CDCl ₃ ): δ 7.03 to 7.13 (m, 4H), 7.
38-7.43 (m, 2H), 7.93-8.00 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 117.6, 117.7, 122.
0, 129.7, 130.5, 131.1, 152.9, 163.7; MS-ES: m / z 285.9.

[0164] Example 8 4 - {[4- (4-chlorophenoxy) phenyl] sulfonyl} -1,4-piperidine dicaprate carboxylic acid 1-(tert-butyl) 4-methyl

[0165]

[Chemical 74]

Lithium diisopropylamide (2.31 mmol), the product of Example 1 (510
mg (2.1 mmol) and the product of Example 7 (600 mg, 2.2 mmol) were followed according to the general procedure for Step 1 to give 520 mg (49%) of the product as a solid. ^{IR: 1727,1682,1485,1427,1252,1153cm - 1; 1 H} NMR (300MHz, CDCl 3): δ1.44 (s, 9H), 1.97-2.
07 (m, 2H), 2.29-2.33 (m, 2H), 2.62 (br s, 2H), 3.76 (
s, 3H), 4.08-4.15 (m, 2H), 7.01-7.07 (m, 4H), 7.36-7
.42 (m, 2H), 7.68-7.73 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 28.3, 53.3, 72.6, 8
0.2, 117.1, 121.9, 128.5, 130.4, 130.7, 132.6
, 153.2,154.4,162.8,167.4; HR-MS: m / z calcd _{(as C 24 H 28 ClNO 7 S)} (M + Na) 532
.1167; found 532.1152.

Example 9 1- (tert-Butoxycarbonyl) -4-{[4- (4-chlorophenoxy) phenyl] su
Rufonyl} -4-piperidinecarboxylic acid

[0168]

[Chemical 75]

The product of Example 8 (450 mg, 0.88 mmol) and lithium hydroxide (32 m) in tetrahydrofuran (3 ml) / methanol (3 ml) / water (2 ml).
g, 1.32 mmol) at 55 ° C. for 15 hours, following the general procedure for Step 3, to give 375 mg (86%) of product. IR: 3438, 2976, 1693, 1627, 1484, 1248, 1139c
m ^-1 ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.38 (s, 9H), 1.55-
1.64 (m, 2H), 2.09 (s, 1H), 2.13 (s, 1H), 2.68 (br s, 2)
H), 3.39 (br s, 1H), 3.90 (m, 2H), 7.06 (d, 2H, J = 9.0)
Hz), 7.16 (d, 2H, J = 12.0 Hz), 7.52 (d, 2H, J = 12.0 Hz
), 7.70 (d, 2H, J = 9.0 Hz); ¹³ C NMR (75 MHz, DMSO-d ₆ ): δ 116.6, 121.9, 128.
8,130.2,131.2,132,7,153.7,153.8,160.7,165.2
; HR-MS: m / z calcd _{(as C 23 H 26 ClNO 7 S)} (2M + H) 991
.2311; measured value 991.2273.

Example 10 4-{[4- (4-chlorophenoxy) phenyl] sulfonyl} -4-[(hydroxyamido
No) carbonyl] -1-piperidinecarboxylic acid 1- (tert-butyl)

[0171]

[Chemical 76]

The product of Example 9 (350 mg, 0.1 ml) in dimethylformamide (7 ml).
71 mmol), hydroxybenzotriazole (114 mg, 0.85 mmol)
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (190m
g, 0.99 mmol), N-methylmorpholine (117 μL, 1.06 mmol) and 50% aqueous hydroxylamine solution (217 μL, 3.55 mmol) according to the general procedure of Step 4, 150 mg (41 %) Product was obtained. IR: 3739, 3382, 2931, 1664, 1484, 1249, 11
50 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.38 (s, 9H), 1.68 (
m, 2H), 2.14 (m, 2H), 2.51 (m, 2H), 3.95 (m, 2H), 7.14 (
d, 2H, J = 9Hz), 7.20 (d, 2H, J = 9Hz), 7.55 (d, 2H, J = 9)
Hz), 8.01 (d, 2H, J = 9Hz), 9.20 (s, 1H), 11.02 (s, 1H)
¹³ C NMR (75 MHz, DMSO-d ₆ ): δ27.9,70.0,79.2,1
17.3, 122.2, 128.4, 129.2, 130.4, 132.8, 153.3, 15
3.7,160.2,161.8; HR-MS: m / z calcd _{(as C 23 H 27 ClN 2 O 7} S) (2M + H) 10
21.2527; found 1021.2523.

Example 11 4-{[4- (4-chlorophenoxy) phenyl] sulfonyl} -N-hydroxy-4-pi
Peridinecarboxamide

[0174]

[Chemical 77]

The product of Example 10 (105 mg, 0.21 in methylene chloride (20 ml).
4M hydrochloric acid solution (258 μL, 1.03 mmol) and the resulting mixture was stirred at room temperature for 4 hours. The solvent was removed and diethyl ether was added. The solid that precipitated was filtered and dried to give 80 mg (85%) of product. IR: 3392, 3214, 2875, 1664, 1484, 1250, 11
42,1087 cm ⁻¹ ; ¹ H NMR (300 MHz, DMSO): δ2.13 (m, 2H), 2.46 (m, 2)
H), 2.59 (m, 2H), 3.33 (m, 2H), 7.19 (m, 4H), 7.52 (d, 2)
H, J = 9.0Hz), 7.72 (d, 2H, J = 9.0Hz), 9.19 (br s, 1H)
, 9.56 (br s, 1H); HR-MS: calculated m / z (as C ₁₈ H ₁₉ ClN ₂ O ₅ S) (M + H)) 41.
1.07776; found 411.0777.

Example 12 Piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester

[0177]

[Chemical 78]

To a stirred solution of ethyl nipecotate (5.1 g, 33 mmol) and triethylamine (3.7 g, 36 mmol) in methylene chloride (75 ml) was added di-t-butyl dicarbonate (7.1 g, 33 mmol). ) Was added little by little. The reaction mixture was stirred at room temperature for 18 hours, quenched with ice water and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated and chromatographed on a silica gel column with 20:80 ethyl acetate: hexane. Piperidine 1,
3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as waxy solid 6
Isolated as .86 g (82%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.26 (t, 3 H), 1.46 (s,
9H), 1.63 (m, 2H), 2.03 (m, 1H), 2.41 (m, 1H), 2.76 (m,
2H), 3.89 (m, 1H), 4.14 (m, 2H); MS-ES: m / z 258.2 (M + H) ⁺ ; Elemental analysis results (as C ₁₃ H ₂₃ NO ₄ ): Calculation Value: C, 60.68; H, 9.08; N, 5.44 Found: C, 60.60; H, 9.10; N, 5.38.

Example 13 4-Methoxyphenylsulfonyl fluoride

[0180]

[Chemical 79]

4-Methoxyphenylsulfonyl chloride (11.0 g, 53 mmol) and potassium fluoride-calcium fluoride mixture in acetonitrile (100 ml)
(17.0 g) according to the general procedure for the production of sulfonyl fluorides, 10.0
g (100%) of product was obtained. MS-ES: m / z 187.0 (MH) ^- .

Example 14 1- ( tert-Butyl) 3-ethyl 3-[(4-methoxyphenyl) sulfonyl] -1,3-piperidinedicarboxylic acid

[0183]

[Chemical 80]

Lithium diisopropylamide (28 mmol), product of Example 12 (5.3 g
, 28 mmol) and the product of Example 13 (5.3 g, 28 mmol),
Following the general procedure of Step 1, 7.2 g (60%) of product is obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.15 (t, 3H), 1.44 (
s, 9H), 1.69 (m, 2H), 2.14 (m, 2H), 3.17 (m, 2H), 3.35 (
d, 2H), 3.8 (s, 3H), 4.06 (m, 2H), 7.19 (d, 2H), 7.69 (d
, 2H); MS-ES: m / z 428.5 (M + H) ⁺ ; Elemental analysis result (as C ₂₀ H ₂₉ NO ₇ S): Calculated value: C, 56.19; H, 6.84; N, 3.28 Found: C, 56.84; H, 7.20; N, 3.48.

Example 15 Ethyl 3-[(4-methoxyphenyl) sulfonyl] -3-piperidinecarboxylate

[0186]

[Chemical 81]

The product of Example 14 (1.72 g, 4 in methylene chloride (25 ml) at 0 ° C.
To a stirred solution of 0.0 mmol) was added a saturated solution of hydrogen chloride in methylene chloride (25 ml). After 5 hours, the solution was concentrated to give 1.23 g (84.5%) of product. MS-ES: m / z 328.3 (M + H) ⁺ ; Elemental analysis result (as C ₁₅ H ₂₁ NO ₅ S): Calculated value: C, 49.51; H, 6.09; N, 3.85 actual measurement Value: C, 47.91; H, 7.08; N, 4.16; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.09 (t, 3H), 2.29 (
d, 2H), 2.99 (m, 2H), 3.07 (m, 2H), 3.72 (d, 2H), 3.89 (
s, 3H), 4.11 (m, 4H), 7.22 (d, 2H), 7.72 (d, 2H).

Example 16 Ethyl 1-benzyl-3-[(4-methoxy) sulfonyl] -3-piperidinecarboxylate

[0189]

[Chemical formula 82]

The product of Example 15 (1.23 g, 3.4 mmol), benzyl bromide (0.64 g, 3.7 mmol) and dry powdery potassium carbonate (3.3 mg) in dry acetone (60 ml). A solution of 8 g) was heated at reflux temperature for 18 hours. Cool the mixture,
The potassium salt was removed by filtration and the filtrate was concentrated. The residue was dissolved in chloroform, washed with water, dried over sodium sulfate and concentrated to give 1.8g (94%) of product as a yellow oil. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.04 (t, 3H), 2.71 (
m, 2H), 3.39 (m, 3H), 3.54 (m, 2H), 3.38 (m, 4H), 3.92 (
s, 3H), 4.02 (m, 4H), 4.54 (s, 2H), 7.13 (d, 2H), 7.21 (
d, 2H), 7.29 (d, 2H), 7.62 (d, 2H); MS-ES: m / z 418.5 (M + H) ⁺ .

Example 17 1-Benzyl-3- (4-methoxybenzenesulfonyl) -piperidine-3-carvone
acid

[0192]

[Chemical 83]

The product of Example 16 (1.7 g, 4.0 mmol), sodium hydroxide (10 N,
3 ml), methanol (10 ml) and tetrahydrofuran (10 ml) at 50 ° C. for 2 hours, following the general procedure for Step 3, to give 1.13 g (67%) of product. Melting point 103 [deg.] C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.04 (t, 3H), 2.71 (
m, 2H), 3.36 (m, 6H), 3.55 (m, 2H), 3.85 (3, 3H), 7.12 (
d, 2H), 7.27 (d , 2H), 7.64 (d, 2H), 7.77 (d, 2H); MS-ES: m / z344.4 (M-H) - CO 2.

Example 18 1-Benzyl-3- (4-methoxybenzenesulfonyl) piperidine-3-carboxylic acid hydroxyamide

[0195]

[Chemical 84]

The product of Example 17 (1.g, 2.9) in methylene chloride (30ml) at 0 ° C.
Mmol) and dimethylformamide (5 ml) in a stirred solution of oxalyl chloride (
1.8 g, 14.5 mmol) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 1 hour. At the same time, in a separate flask, a mixture of hydroxylamine hydrochloride (1.6 g, 23 mmol) and triethylamine (3 ml, excess) was stirred in tetrahydrofuran: water (5: 1, 30 ml) at 0 ° C. for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml methylene chloride,
It was added slowly to the hydroxylamine solution at 0 ° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The obtained residue was extracted with chloroform and washed thoroughly with water.
The obtained product was purified by silica gel column chromatography and eluted with 2% methanol: chloroform. The product was dissolved in methanol (10 ml) at 5 ° C,
Converted to the hydrochloride salt by adding saturated hydrogen chloride in methanol (5 ml). 1-Benzyl-3- (4-methoxybenzenesulfonyl) -piperazine-3-carboxylic acid hydroxyamide propionamide was isolated as a white solid, 1.17 g (91%). Melting point 132.9 [deg.] C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.08 (m, 23H), 2.49
(m, 2H), 3.87 (s, 3H), 4.25 (d, 2H), 7.10 (d, 2H), 7.44
(s, 5H), 7.58 (d, 2H), 8.85 (s, 1H), 9.45 (s, 1H); MS-ES: m / z 405.3 (M + H) ⁺ .

[0197] Example 19 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1,4-piperidine dicarboxylic acid 1-(tert-butyl) 4-ethyl

[0198]

[Chemical 85]

Lithium diisopropylamide (20 mmol), the product of Example 1 (4.4 g,
Using 19.5 mmol) and the product of Example 12 (5.0 g, 19.5 mmol), 10.97 g (76%) of product was obtained according to the general procedure for the preparation of sulfonyl fluorides. . Melting point 103.4 [deg.] C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.07 (t, 3H), 1.34 (
s, 9H), 3.31 (s, 3H), 3.84 (m, 2H), 4.00 (m, 4H), 4.53 (
d, 2H), 4.91 (m, 4H), 7.22 (d, 2H), 7.71 (d, 2H); MS-ES: m / z 466.4 (M + H) ⁺ ; Results of elemental analysis (as _{C 23 H 31 ClNO 7 S)} : calculated: C, 59.34; H, 6.71 ; N, 3.01 Found: C, 59.49; H, 6.84 ; N, 3. 16.

Example 20 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -3-piperidinecarvone
Ethyl acid

[0201]

[Chemical 86]

Following the procedure of Example 15, using the product of Example 19 (5.45 g, 11.7 mmol) dissolved in methylene chloride, 3.47 g (7%) of the desired product was obtained as a white solid.
4%). The solid is very hygroscopic and is stored under nitrogen. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.08 (t, 3H), 2.30 (
bd, 1H), 2.96 (t, 2H), 3.07 (m, 2H), 3.33 (s, 3H), 3.3
8 (m, 4H), 4.09 (m, 2H), 4.93 (s, 2H), 7.26 (d, 2H), 7.7
4 (d, 2H); MS-ES: m / z 366.2 (M + H) ⁺ ; Elemental analysis results (as C ₁₈ H ₂₃ O ₅ S): Calculated value: C, 53.79; H, 6.02 N, 3.49 Found: C, 52.34; H, 6.17; N, 3.52.

Example 21 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-3-piperidi
Ethyl carboxylate

[0204]

[Chemical 87]

Following the procedure of Example 16 with the product of Example 20 (2.97 g, 8.0 mmol) in dry acetone (50 ml), the desired product was an amber gum 3. Isolated as 47 g (99%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.89 (t, 3H), 1.05 (
t, 3H), 2.72 (d2H), 3.28 (m, 2H), 3.31 (s, 3H), 4.01 (
m, 4H), 4.91 (m, 2H), 7.19 (d, 2H), 7.70 (d, 2H); MS-ES: m / z 394.3 (M + H) ⁺ .

Example 22 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-3-piperidi
Carboxylic acid

[0207]

[Chemical 88]

Using the product of Example 21 (3.2 g, 8.0 mmol) in tetrahydrofuran: methanol (15:25 ml) and sodium hydroxide (15 ml),
2.11 g (71%) of the product was obtained as a white solid according to the general procedure in Step 3 at 50 ° C. for 2 hours. Melting point 159.2 [deg.] C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.02 (t, 3H), 2.70 (
m, 4H), 2.92 (d, 2H), 3.47 (d, 2H), 4.865 (m, 2H), 7.0
9 (d, 1H), 7.17 (d, 1H), 7.60 (d, 1H), 7.68 (d, 1H); MS-ES: m / z 366.3 (M + H) ⁺ ; Elemental analysis results _(as C _{18 H} 23 _{O 5):} calculated: C, 59.16; H, 6.34 ; N, 3.83 Found: C, 59.2; H, 6.45 ; N, 3 .67.

Example 23 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-N-hydroxy
Ci-3-piperidinecarboxamide

[0210]

[Chemical 89]

Following the procedure of Example 18, using the product of Example 22 (2.0 g, 5.5 mmol), 0.193 g (10%) of the desired product was isolated as a white solid. did.
Melting point 190 [deg.] C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.18 (m, 3H), 1.97 (
m, 2H), 2.55 (m, 2H), 3.21 (m, 5H), 3.52 (s, 3H), 3.82 (
d, 1H), 4.91 (m, 2H), 7.19 (d, 2H), 7.51 (s, 5H), 8.67 (
s, 1H), 9.48 (s, 1H); MS-ES: m / z 405.3 (M + H) ^<+> . Elemental analysis _{(as C 18 H 24 N 2 O 5} S): Calculated: C, 51.86; H, 6.04 ; N, 6.72 Found: C, 50.03; H, 6 . 33; N, 6.42.

Example 24 Ethyl 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -3-piperidinecarboxylate

[0213]

[Chemical 90]

Following the procedure of Example 16, using the product of Example 20 (2.97 g, 8.0 mmol) in dry acetone (50 ml), 1.66 g (99%) of product was brown. Isolated as an oil. MS-ES: m / z 491.3 (M + H) ^<+> .

Example 25 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -3-piperidinecarboxylic acid

[0216]

[Chemical Formula 91]

Using the product of Example 24 (1.64 g, 8.0 mmol) and sodium hydroxide (15 ml) in tetrahydrofuran: methanol (15:50 ml).
Following the general procedure in Step 3 at 50 ° C. for 2 hours, 1.11 g (75%) of product was obtained as a white solid. Melting point 115.2 [deg.] C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.33 (d, 2H), 2.7 (d,
2H), 3.29 (s, 32H), 3.33 (m, 2H), 3.52 (q, 2H), 4.47 (
s, 2H), 4.81 (s, 2H), 7.16 (d, 2H), 7.27 (d, 2H), 7.34 (
d, 2H), 7.67 (d , 2H); MS-ES: m / z462.1 (M + H) +; as Elemental analysis _{(C 23 H 24 ClNO 5 S} ): Calculated: C, 59. 16; H, 6.34; N, 3.83 Found: C, 59.64; H, 5.65; N, 2.66.

Example 26 3-{[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenze
) -N-Hydroxy-3-piperidinecarboxamide

[0219]

[Chemical Formula 92]

Following the procedure of Example 18, using the product of Example 25 (2.0 g, 5.5 mmol), 0.48 g (43%) of the product was isolated as a white solid. Melting point 12
4.4 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.0 (m, 2H), 339 (m,
5H), 4.27 (d, 2H), 4.89 (m, 2H), 7.14 (d, 42H), 7.15 (
m, 45H), 7.61 (d, 2H), 8.95 (s, 1H), 9.46 (s, 1H); MS-ES: m / z 477.1 (M + H) ⁺ ; Results of elemental analysis (as _{C 18 H 24 N 2 O 5} S): calculated: C, 53.8; H, 5.10 ; N, 5.46 Found: C, 51.4; H, 5.42 ; N, 6.32.

Example 27 Sodium 4-butoxybenzenesulfonate

[0222]

[Chemical formula 93]

To a suspension of sodium 4-hydroxybenzenesulfonate (40.0 g, 0.172 mol) in 2-propanol (300 ml) was added 1N sodium hydroxide (19
0 ml, 0.189 mol) was added. After 10 minutes, n-butyl bromide (38.9 g,
0.28 mol) was added and the cloudy solution was heated at reflux temperature. The reaction mixture is partially evaporated, filtered, washed with diethyl ether, dried and 38.6.
g (88.4%) of product was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ7.5 (d, 2H, J = 8.7 Hz)
), 6.83 (d, 2H, J = 8.7 Hz), 3.96 (t, 2H, J = 6.5 Hz), 1.6
8 (m, 2H), 1.42 (m, 2H), 0.92 (t, 3H, J = 7.4Hz); HPLC: area 99.94%; LC-MS: consistent.

Example 28 4-n-Butoxybenzenesulfonyl chloride

[0225]

[Chemical 94]

To the product of Example 27 (34.0 g, 0.134 mol) was added phosphorus oxychloride (60 m
1, 0.643 mol) was added and the heterogeneous mixture was heated at reflux temperature (105 ° C.) for 4 hours. After 4 hours, the reaction mixture was cooled to ambient temperature and ice water (600 ml) was added with stirring. The mixture was extracted with diethyl ether. Water the organic layer (2
00 ml), saturated sodium bicarbonate solution (200 ml) and water (200 ml). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and 33.3 g (
99.3%) of the product was obtained as a colorless liquid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.96 (d, 2H, J = 6.0 Hz)
, 7.02 (d, 2H, J = 6.0 Hz), 4.07 (t, 2H, J = 4.3 Hz), 1.8
2 (m, 2H), 1.51 (m, 2H), 0.99 (t, 3H, J = 4.9Hz); GC-MS: 100% pure.

Example 29 4-n-butoxybenzenesulfonyl fluoride

[0228]

[Chemical 95]

The product of Example 28 (33.3 g, 0.1 ml) in acetonitrile (200 ml).
134 mol) in a solution of potassium fluoride on calcium fluoride (85.8 g, 0.2
98 mol) was added and the resulting heterogeneous mixture was stirred at ambient temperature for 20 hours. The reaction mixture was filtered, washed with acetonitrile (20 ml x 2) and evaporated.
The oily residue was dissolved in ethyl acetate (200 ml) and saturated sodium chloride solution (20 ml) was added.
Washed with 0 ml), dried over anhydrous sodium sulfate and concentrated to 30.4 g (98
%) Of the product as a clear colorless liquid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.92 (d, 2H, J = 6.0 Hz)
, 7.04 (d, 2H, J = 6.0 Hz), 4.06 (t, 2H, J = 4.3 Hz), 1.8
2 (m, 2H), 1.5 (m, 2H), 0.99 (t, 3H, J = 4.9Hz); GC-MS: 97.6% pure, 2.4% starting material .

Example 30 1- [4- (2-Piperidin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid methyl ester

[0231]

[Chemical 96]

Methyl isonipecotate (5.0 g, 34.9 mmol) in acetone, 4
-Piperidine ethoxybenzyl chloride hydrochloride (10.13 g, 34.9 mmol)
And a mixture of potassium carbonate (10.6 g, 76.6 mmol, -325 mesh) was heated at reflux temperature for 24 hours. After cooling to room temperature, the reaction was filtered and washed with acetone (2
Wash with 5 ml x 3) and evaporate to give a light brown oil. This oil was dissolved in ethyl acetate (100 ml), washed with water (100 ml x 2), saturated sodium chloride solution (100 ml), dried over sodium sulfate, concentrated and 9.0.
g (72%) of product was obtained as a light brown oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ7.19 (d, 2H, J = 5.7 Hz)
, 6.84 (d, 2H, J = 5.7 Hz), 4.09 (t, 2H, J = 4.06 Hz), 3.
66 (s, 3H), 3.41 (s, 2H), 2.8 (m, 4H), 2.51 (m, 4H), 2.3
(m, 1H), 2.02 (m, 2H), 1.87 (m, 2H), 1.76 (m, 2H), 1.51
(m, 4H), 1.45 (m, 2H); GC-MS: 94.1% pure.

Example 31 4- (4-Butoxybenzenesulfonyl) -1- [4- (2-piperidin-1-yl-eth
Xy) benzyl] piperidine-4-carboxylic acid methyl ester

[0234]

[Chemical 97]

Diisopropylamine (0.67 ml, in tetrahydrofuran (6 ml)
To a 0 ° C. solution of 4.8 mmol) n-butyllithium (2.0 ml, 2.
5M) was added. The resulting mixture was stirred for 20 minutes, cooled at -78 ° C and a solution of the product of Example 30 (1.5g, 4.16mmol) in tetrahydrofuran (6ml) was added dropwise. After 1 hour at −78 ° C., the product of Example 3 (1.01 g, 4.36 mmol) in tetrahydrofuran (4 ml) was added in one portion and the mixture was warmed to ambient temperature. After 3 hours, the reaction mixture was treated with saturated ammonium chloride solution (
It was quenched with 8 ml) and extracted with ethyl acetate (20 ml × 2). Water the organic layer (30
ml) and saturated sodium chloride solution (30 ml), dried over sodium sulphate and concentrated to give 2.24 g of crude product as a brown syrup. MS-ES: m / z 573 (M + H) ^<+> .

Example 32A 1-Benzylpiperazine-4-carboxylic acid ethyl ester

[0237]

[Chemical 98]

Ethyl isonipecotate (72.8 g, 0.1 ml) in ethanol (150 ml).
To a solution of 45 mol) was added benzyl bromide (101 g, 0.59 mol) at 0-10 ° C., followed by the addition of triethylamine (68.8 g, 0.68 mol). The resulting suspension was warmed to ambient temperature and stirred for 6 hours. Dilute the reaction mixture with water (200 ml),
Extracted with ethyl acetate (3 x 150 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered through a pad of silica and concentrated to give 98.6 g (89%) of product as a yellow viscous liquid. ¹ H-NMR (CDCl ₃ ): δ7.9-7.0 (m, 5H), 4.4-4.1 (q, 2H)
, 3.5 (s, 2H), 2.9-2.8 (m, 4H), 2.62.3 (m, 1H), 2.1-1.6
(m, 4H), 1.3-1.2 (t, 3H); GC-MS: 99.4% pure.

Example 32B 1-Benzylpiperidine-4-carboxylic acid methyl ester

[0240]

[Chemical 99]

The compound with the above name was prepared from methyl isonipecotate in methanol using the method of Example 32A (97% yield). ¹ H-NMR (CDCl ₃ ): δ 7.7-6.9 (m, 5H), 3.7 (s, 3H), 3.5
(s, 2H), 3.0-2.8 (m, 4H), 2.4-2.2 (m, 1H), 2.1-1.6 (m, 4)
H); GC-MS: 92% pure.

Example 33 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-benzylpiperidine- 4-carboxylic acid methyl ester

[0243]

[Chemical 100]

Prepared using LDA as base : Freshly distilled diisopropylamine (1.58 g, 15.6 mmol) was dissolved in tetrahydrofuran (18 ml) and cooled to 0 ° C. Hexane (5 ml, 12.5
A solution of 2.5 M n-butyllithium in (mmol) was added at a temperature below 5 ° C and the resulting yellow solution was stirred for 0.5 hours while cooling to -20 ° C. The product of Example 32B (1.46 g, 6.25) in tetrahydrofuran (5 ml).
(Mmol) solution was added dropwise at -20 ° C, and the resulting mixture was stirred for 2 hours. A solution of the product of Example 6 in tetrahydrofuran (5 ml) is -20 to -25 ° C.
And the dark yellow reaction mixture was stirred at −20 ° C. for 1 hour. The mixture was quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 15 ml). The organic solution was dried over magnesium sulfate, filtered through a pad of silica and concentrated to a slight residue. The residue was triturated with isopropyl ether (10 ml) to give 1.73 g (69%) of product as yellow gummy crystals. ¹ H-NMR (CDCl ₃ ): δ 7.8-7.0 (m, 13H), 3.7 (s, 3H), 3.
4 (s, 2H), 3.0-1.8 (m, 8H); HPLC: 87% pure.

Prepared using LiHMDS as base : A solution of the product of Example 32B (2 g, 6 mmol) in tetrahydrofuran (15 ml) was cooled to -20 to -22 ° C under nitrogen atmosphere. A solution of lithium hexamethyldisilazide (LiHMDS) (1.0 M in THF, 7.2 ml, 7.2 mmol) was added dropwise, maintaining the temperature at -20 to -22 ° C. After the addition, the solution was stirred at -20 to -22 ° C for 2 hours. A solution of the product of Example 7 (2.26 g, 8 mmol) in tetrahydrofuran (10 ml) was -20 to -22 ° C.
It was dripped at. The reaction was stirred for an additional 2.5 hours, keeping the temperature low. The mixture was quenched with saturated ammonium chloride solution (15 ml) and washed with ethyl acetate (3 x
10 ml). The organic extract was dried over anhydrous magnesium sulfate, filtered through a pad of silica and concentrated to a slight residue. n-Heptane (10 ml) was added and the solution was left at room temperature overnight to give 2.4 g (69%) of product as white crystals. HPLC: 90% pure.

Example 34 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-benzylpiperidine- 4-carboxylic acid

[0247]

[Chemical 101]

A solution of the product of Example 33 (30.7 g, HPLC area 99.4%, 123 mmol) in t-butyl methyl ether (100 ml) at −25 ° C. was heated to −
While maintaining at 20 to -25 ° C, 2M lithium diisopropylamide solution (13
6 ml, 272 mmol) was added over 15-20 minutes. The yellow solution was stirred at this temperature for 2 hours. The product of Example 7 (1
Solution (08 ml, 136 mmol) was added at −20 ° C. over 15 minutes and the reaction was stirred for an additional hour while keeping the temperature low. The progress of the reaction was monitored by thin layer chromatography showing the formation of the intermediate ester of Example 8. The reaction mixture was quenched with water and warmed to 20-25 ° C with stirring for 0.5h. The organic solvent that forms an oil layer at the bottom of the flask was removed by distillation (50 mmHg, 35 ° C). Lithium hydroxide (15.5 g, 370 mmol) and methanol (150 m
1) was added and the reaction mixture was heated at reflux temperature (70 ° C.) overnight. The reaction mixture was clarified by filtering with filter paper to remove a small amount of gel-like insoluble material. The clear solution was acidified to pH = 5 with acetic acid (30 ml) at 20-25 ° C. The resulting slurry was stirred at ambient temperature for 1 hour and filtered. The solid residue was washed with water, slurried with ethanol (500 ml) for 0.5 h, filtered and dried in vacuo at 40 ° C. to give 36.4 g (61% HPLC) of the desired product as a yellow color. Obtained as a solid. MS-ES: m / z 486 (M + H) ^<+> .

Example 35 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-benzylpiperidine- 4-carboxylic acid hydroxyamide

[0250]

[Chemical 102]

A suspension of the product of Example 34 (122.0 g, 0.251 mol) in acetonitrile (1.0 L) containing catalytic amount of dimethylformamide (1.0 ml) at 0 ° C. (ice bath) was stirred. Oxalyl chloride (55.1 g, 0.402 mol) was added to the suspension over 30 minutes (caution: gas evolution). The cooling bath was removed and the mixture was stirred at room temperature for 5 hours. (Aliquot of reaction mixture was added to excess methanol and then monitored for completion by TLC, MS or HPLC). To a cooled solution of powdered hydroxylamine hydrochloride (175.0 g, 2.51 mol) and triethylamine (330.9 g, 3.27 mol) in acetonitrile (2.5 L) (stirred at room temperature for 3-5 hours). The above acid chloride suspension was added over 20 minutes. The reaction temperature should not exceed about 8 ° C. After stirring for 18 hours at room temperature, the reaction mixture was concentrated to give an off-white residue. Ethyl acetate (2.0 L) and water (2.0 L) were added to the residue and the mixture was stirred for 15-20 minutes. The ethyl acetate layer was separated, filtered through anhydrous sodium sulfate and concentrated to give 130.4 g (103% crude yield) as a semi-solid product. _{^{1 H NMR (DMSO-d 6}} , 300MHz): δ10.9 (br s, 1H); 9.
1 (br s, 1H); 7.71 (d, 2H, J = 8.8Hz); 7.52 (d, 2H, J = 8)
7.8 Hz); 7.33-7.19 (m, 7H); 7.14 (d, 2H, J = 8.8 Hz); 3.
4 (s, 2H); 2.7 (m, 2H); 2.28 (m, 2H); 1.95-1.8 (m, 4H);
HPLC: product 94.06% (carboxylic acid 0.3% and mixed anhydride 2.88%
).

Example 36 4- [4- (4-chlorophenoxy) benzenesulfonyl] -1-benzylpiperidine- 4-carboxylic acid hydroxyamide hydrochloride

[0253]

[Chemical 103]

The crude product of Example 35 (130.4 g, 0.260 mol) was treated with ethyl acetate (350 m
l) and concentrated hydrochloric acid (31.3 ml, 0.313 mol) was added over 20 minutes.
Salts precipitated from the solution and the mixture was cooled in an ice bath at 2 ° C for 30 minutes. The mixture was filtered, washed with cold (0 ° C) ethyl acetate (50 ml x 2) and placed in an oven for 1
After drying for 8 hours, 118.6 g (85%) of the product was obtained. This compound was recrystallized as follows. Ethanol (2.3 L, 200 proof) in a 5 L flask equipped with a reflux condenser, thermometer / controller, and mechanical stirrer and the crude product from above (118.
6 g) was added. After heating the contents of the flask at reflux temperature, water (850 ml) was added over 60 minutes. The solution was clarified by filtration and reheated to boiling. The heating mantle was removed and the reaction mixture was cooled. Crystallization started at 60 ° C. The reaction was cooled slowly in an ice bath and kept at 2-4 ° C for 30 minutes. The white crystals were collected, washed with cold ethanol (100 ml x 2), and extracted with nitrogen (nitrogen).
bleed) and dried in vacuum at 60 ° C. for 18 hours to give 89.23 g (75%)
To give the desired product as crystals. Melting point 233-235 [deg.] C. HPLC: 98.5% _{^{pure; 1 H NMR (DMSO-d}} 6, 300MHz): δ1
1.2 (s, 1H); 10.9 (br s, 1H); 9.35 (s, 1H); 7.73 (d, 2H)
, J = 8.8 Hz); 7.52 (m, 4H); 7.44 (br s, 3H); 7.23 (d, 2)
H, J = 8.8Hz); 7.17 (d, 2H, J = 8.8Hz); 4.26 (s, 2H); 2.
78 (m, 2H); 2.30 (m, 2H); IR (KBr pellet): 3700-3300, 3156, 2931, 2543
, 1677, 1483, 1244, 1144, 1087, 598 cm ^-1 .

Example 37 4- (4-But-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester

[0256]

[Chemical 104]

To a solution of the product of Example 3 (500 mg, 1.11 mmol) in methylene chloride (10 ml) was added 4M HCl (2 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solid was filtered and washed with ether to give 410 mg (95%) of product as a solid. IR: 3096,2741,2422,1726,1668,1590,11
44,836 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.86 (m, 3H), 2.52 (m,
4H), 2.89 (m, 2H), 3.52 (m, 2H), 3.74 (s, 3H), 4.74 (m,
2H), 7.10 (d, 2H, J = 8.7 Hz), 7.69 (d, 2H, J = 8.7 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ): δ3.6, 25.2 , 41.2, 53.
8, 56.9, 69.7, 72.6, 85.2, 115.4, 125.7, 132.3
, 163.1,166.6; HR-MS: m / z calcd _{(as C 17 H 21 NO 5 S)} 352.121; Found 352.1207.

Example 38 1-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-
4-carboxylic acid methyl ester

[0259]

[Chemical 105]

To a solution of the product of Example 37 (105 mg, 0.23 mmol) in methylene chloride (1 ml) was added triethylamine (93 mg, 0.92 mmol), acetyl chloride (18 mg, 0.23 mmol). After that, a catalytic amount of dimethylaminopyridine was added. The resulting mixture was stirred at room temperature for 8 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to 75 mg (
80% of product was obtained as a solid. IR: 2928, 2242, 1726, 1636, 1595, 1451, 13
02,1150,996 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.87 (t, 3H, J = 2.4 Hz)
, 1.97-2.13 (m, 2H), 2.09 (s, 3H), 2.22-2.51 (m, 3H),
3.02 (m, 1H), 3.76 (s, 3H), 3.89 (m, 1H), 4.63 (m, 1H),
4.74 (q, 2H, J = 2.4Hz), 7.08 (d, 2H, J = 7.5Hz), 7.14 (
d, 2H, J = 7.5 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 4.1, 21.7, 28.4, 28.
5,38.9, 43.9, 53.7, 57.2, 72.7, 73.1, 85.5, 11
5.5, 126.9, 132.6, 163.1, 167.8, 169.2; MS-ES: m / z 393.9 (M + H) ^<+> .

Example 39 1-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-
4-carboxylic acid

[0262]

[Chemical formula 106]

The product of Example 38 (2) in 4 ml of tetrahydrofuran: water (3: 1).
According to the general procedure of Step 3, using 40 mg, 0.61 mmol) and lithium hydroxide (18 mg, 0.75 mmol), 200 mg (87%) of the acid was obtained. IR: 2923, 2246, 1713, 1591, 1575, 1494, 12
32,994 cm ^-1 ; ¹ H NMR (300 MHz, acetone-d ₆ ): δ1.84 (t, 3H, J = 2.8H)
z), 1.90-2.05 (m, 2H), 2.06 (s, 3H), 225-2.51 (m, 3H)
), 3.06 (m, 1H), 4.04 (m, 1H), 4.63 (m, 1H), 4.86 (q, 1H)
, J = 2.4 Hz), 7.18 (d, 2H, J = 8.4 Hz), 7.80 (d, 2H, J = 8.
4 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 3.3, 21.3, 28.7, 39.
0, 44.0, 57.4, 72.8, 74.2, 85.0, 115.8, 128.3
133.4,163.5,168.4,169.0; HR-MS: m / z calcd _{(as C 18 H 21 NO 6 S)} 380.1162; Found 380.1160.

Example 40 1-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-
4-carboxylic acid hydroxyamide

[0265]

[Chemical formula 107]

The product of Example 39 (180 mg, in dimethylformamide (4 ml)
0.48 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1
27 mg, 0.66 mmol), N-methylmorpholine (0.078 ml, 0.71 mmol) and hydroxylamine (0.145 ml, 2.37 mmol) according to the general procedure of Step 4, 100 mg ( 53%) of the product was obtained as a solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ1.64 (m, 1 H), 1.85 (m,
3H), 1.99 (s, 3H), 2.31 (m, 4H), 2.83 (m, 1H), 3.88 (m,
1H), 4.41 (m, 1H), 4.88 (m, 2H), 7.16 (d, 2H, J = 9.0Hz
), 7.66 (d, 2H, J = 9.0Hz), 9.20 (m, 1H), 11.00 (m, 1H)
¹³ C NMR (75 MHz, CDCl ₃ ): δ3.5, 21.5, 36.1, 56.
8, 70.2, 74.3, 84.7, 115.3, 126.7, 132.6, 162.
3, 168.6; MS-ES: m / z 395.2 (M + H) ^<+> .

Example 41 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine -4-carboxylic acid methyl ester

[0268]

[Chemical 108]

The product of Example 37 (400 mg, 1.03) in chloroform (10 ml).
Triethylamine (416 mg, 4.12 mmol) and benzoyl chloride (144 μl, 1.24 mmol) were added to a solution of (mmol) and then a catalytic amount of dimethylaminopyridine was added. The resulting mixture was stirred at room temperature for 15 hours, quenched with water,
It was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated,
Obtained 375 mg (80%) of the product as a solid. MS-ES: m / z 456.1 (M + H) ^<+> .

Example 42 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine -4-carboxylic acid

[0271]

[Chemical 109]

The product of Example 41 (3) in 4 ml of tetrahydrofuran: water (3: 1).
Following the general procedure in Step 3, using 00 mg, 0.66 mmol) and lithium hydroxide (18 mg, 0.75 mmol), 250 mg (86%) of acid was obtained. HR-MS: m / z calcd _{(as C 23 H 23 NO 6 S)} 442.1319; Found 442.1317.

Example 43 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine -4-carboxylic acid hydroxyamide

[0274]

[Chemical 110]

The product of Example 42 (100 mg, in dimethylformamide (2 ml)
0.23 mmol), 1-hydroxybenzotriazole (36 mg, 0.27 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (6
2 mg, 0.32 mmol), N-methylmorpholine (0.038 ml, 0.35 mmol) and hydroxylamine (0.083 ml, 1.15 mmol),
According to the general procedure in Step 4, 40 mg (38%) of product was obtained as a solid. MS-ES: m / z 457.2 (M + H) ^<+> .

[0276] Example 44 1- (4-methoxybenzoyl) -4- (4-but-2-y oxy benzene sulfonyl Le) piperidine-4-carboxylic acid methyl ester

[0277]

[Chemical 111]

Example 37 (260 mg, 0.77 mmol) in chloroform (7 ml)
To the solution of the product in (3) was added triethylamine (311 mg, 3.08 mmol), 4-methoxybenzoyl chloride (158 mg, 0.92 mmol), followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 280 mg (75%) product as a solid. HR-MS: m / z calcd _{(as C 25 H 27 NO 7 S)} 486.1581; Found 486.1576.

[0279] Example 45 1- (4-methoxybenzoyl) -4- (4-but-2-y oxy benzene sulfonyl Le) piperidine-4-carboxylic acid

[0280]

[Chemical 112]

The product of Example 44 (250 mg, 0.51 mmol) and 1N sodium hydroxide (1.03 ml) in 4 ml of tetrahydrofuran: methanol (1: 1).
1.03 mmol) according to the general method of Step 3, 150 mg (6
2%) acid is obtained. HR-MS: m / z calcd _{(as C 24 H 25 NO 7 S)} 472.1425; Found 472.1426.

[0282] Example 46 1- (4-methoxybenzoyl) -4- (4-but-2-y oxy benzene sulfonyl Le) piperidine-4-carboxylic acid hydroxyamide

[0283]

[Chemical 113]

The product of Example 45 (90 mg, 0.1 mg) in dimethylformamide (2 ml).
19 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol)
) 1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (51 m
g, 0.27 mmol), N-methylmorpholine (0.031 ml, 0.28 mmol)
) And hydroxylamine (0.068 ml, 0.95 mmol) according to the general procedure of step 4 to give 70 mg (76%) of the product as a solid. HR-MS: m / z calcd _{(as C 24 H 26 N 2 O 7} S) 487.1534;
Found 487.1531.

Example 47 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (pyrrolidine-1-carl
Bonyl) piperidine-4-carboxylic acid methyl ester

[0286]

[Chemical 114]

Example 37 (400 mg, 1.03 mmol) in chloroform (10 ml).
To the product solution of) was added triethylamine (208 mg, 2.06 mmol), pyrrolidine carbonyl chloride (206 mg, 1.54 mmol), followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 400 mg (87%) of product as a solid. MS-ES: m / z 449.3 (M + H) ^<+> .

Example 48 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (pyrrolidin-1-carl
Bonyl) -piperidine-4-carboxylic acid

[0289]

[Chemical 115]

The product of Example 47 (400 mg, 0.89 mmol) and lithium hydroxide (48 m) in 4 ml of tetrahydrofuran: methanol: water (1: 1: 0.5).
g, 2.0 mmol) according to the general procedure of Step 3, 300 mg (7
8%) acid was obtained. MS-ES: m / z 435.2 (M + H) ^<+> .

Example 49 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyro
Lysine-1-carbonyl) -4-piperidinecarboxamide

[0292]

[Chemical formula 116]

The product of Example 48 (255 mg, in dimethylformamide (6 ml))
0.23 mmol), 1-hydroxybenzotriazole (96 mg, 0.71 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1
57 mg, 0.82 mmol), N-methylmorpholine (0.099 ml, 0.84 mmol) and hydroxylamine (0.181 ml, 2.8 mmol),
According to the general method of step 4, 150 mg (60%) of product was obtained as a solid. HR-MS: m / z calcd _{(as C 21 H 27 N 3 O 6} S) 450.1693;
Found 450.1692.

Example 50 4- (4-But-2-ynyloxybenzenesulfonyl) -1,4-piperidinedicar
1-ethyl 4-methyl borate

[0295]

[Chemical 117]

The product of Example 37 (400 mg, 1.03) in chloroform (10 ml).
Sodium bicarbonate (865 mg, 10.3 mmol) and ethyl chloroformate (0.147 ml, 1.54 mmol) were added to a solution of (mmol). The resulting mixture was stirred at room temperature for 15 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 425 mg (98%) of product as a solid. MS-ES: m / z 424.4 (M + H) ^<+> .

Example 51 1- (Ethylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl)-
1-piperidinecarboxylic acid

[0298]

[Chemical 118]

The product of Example 50 (400 mg, 0.95 mmol) and lithium hydroxide (50 m) in 8 ml of tetrahydrofuran: methanol: water (1: 1: 0.5).
g, 2.04 mmol) according to the general method of Step 3, 340 mg (
88%) of acid was obtained. HR-MS: m / z calcd _{(as C 19 H 23 NO 7 S)} 408.1122; Found 408.1126.

Example 52 4- (4-but-2-ynyloxybenzenesulfonyl) -4-[(hydroxyamino)
Carbonyl] -ethyl-1-piperidinecarboxylate

[0301]

[Chemical formula 119]

The product of Example 51 (225 mg, in dimethylformamide (5 ml)
0.55 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1
150 mg (48 mg, 0.77 mmol), N-methylmorpholine (0.091 ml, 0.86 mmol) and hydroxylamine (0.168 ml, 2.75 mmol) according to the general procedure of Step 4 ( 64%) of the product was obtained as a solid. HR-MS: m / z calcd _{(as C 19 H 24 N 2 O 7} S) 425.1377;
Found 425.1375.

Example 53 Methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1-[(trifluoromethyl ) sulfonyl] -4-piperidinecarboxylate

[0304]

[Chemical 120]

The product of Example 37 (350 mg, 0.90) in chloroform (10 ml).
To a solution of (3 mmol) triethylamine (182 mg, 1.81 mmol) and trifluoromethanesulfonyl chloride (0.125 ml, 1.17 mmol) were added, followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15
Stir for hours, quench with water, and extract with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 245 mg (56%) of product as a solid. HR-MS: m / z calcd _{(as C 18 H 20 F 3 NO 7} S 2) 484.070
6; Found 484.0700.

Example 54 4- (4-But-2-ynyloxybenzenesulfonyl) -1-[(trifluoromethyl ) sulfonyl] -4-piperidinecarboxylic acid

[0307]

[Chemical 121]

The product of Example 53 (225 mg, 0.47 mmol) and lithium hydroxide (24 m) in 5 ml of tetrahydrofuran: methanol: water (1: 1: 0.5).
g, 0.98 mmol) according to the general procedure for Step 3, 175 mg (
80%) acid was obtained. MS-ES: m / z 468.1 (MH) ^- .

Example 55 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1-[( trifluoromethyl) sulfonyl] -4-piperidinecarboxamide

[0310]

[Chemical formula 122]

The product of Example 54 (145 mg, in dimethylformamide (3 ml))
0.31 mmol), 1-hydroxybenzotriazole (50 mg, 0.37 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8
3 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol) and hydroxylamine (0.095 ml, 1.55 mmol),
According to the general method of step 4, 90 mg (60%) of product was obtained as a solid. HR-MS: m / z calcd _{(as C 17 H 19 F 3 N 2} O 7 S 2) 485.06
59; Found 485.0666.

[0312] Example 56 4- (4-but-2-y oxy benzenesulfonyl) -1- (3-Pirijinirukarubo) -4- piperidine carboxylate

[0313]

[Chemical 123]

The product of Example 37 (500 mg, 1.29) in methylene chloride (10 ml).
To a solution of triethylamine (443 mg, 4.39 mmol) and nicotinyl chloride (276 ml, 1.55 mmol) were added a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 460 mg (78%) of product as a solid. HR-MS: m / z calcd _{(as C 23 H 24 N 2 O 6} S) 457.1428;
Found 4571.428.

[0315] Example 57 4- (4-but-2-y oxy benzenesulfonyl) -1- (3-Pirijinirukarubo) -4- piperidinecarboxylic acid

[0316]

[Chemical formula 124]

The product of Example 56 (430 mg, 0.94 mmol) and 1N sodium hydroxide (1.89 ml) in 8 ml of tetrahydrofuran: methanol (1: 1).
189 mg (5.89 mmol) according to the general procedure of Step 3.
7%) acid was obtained. HR-MS: m / z calcd _{(as C 22 H 22 N 2 O 6} S) 443.1271;
Found 443.1270.

[0318] Example 58 4- (4-but-2-y oxy benzenesulfonyl) -N- hydroxy-1- (3-pin lysine) -4- piperidine-carboxamide

[0319]

[Chemical 125]

The product of Example 57 (195 mg, in dimethylformamide (4 ml))
0.44 mmol), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1
19 mg, 0.62 mmol), N-methylmorpholine (0.072 ml, 0.66 mmol) and hydroxylamine (0.135 ml, 2.2 mmol),
According to the general procedure of Step 4, 65 mg (32%) of product was obtained as a solid. HR-MS: m / z calcd _{(as C 22 H 23 N 3 O 6} S) 458.1380;
Found 458.1373.

[0321] Example 59 4- (4-but-2-y oxy benzenesulfonyl) -1- (2-Chienirukaruboni) -4- piperidine carboxylate

[0322]

[Chemical formula 126]

The product of Example 37 (500 mg, 1.29) in methylene chloride (10 ml).
To a solution of (3 mmol) triethylamine (261 mg, 2.58 mmol) and thiophenylcarbonyl chloride (227 mg, 1.55 mmol) were added, followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 480 mg (81%) product as a solid. HR-MS: m / z calcd _{(as C 22 H 23 NO 6 S 2} ) 462.1040;
Found 462.1039.

[0324] Example 60 4- (4-but-2-y oxy benzenesulfonyl) -1- (2-Chienirukaruboni) -4- piperidinecarboxylic acid

[0325]

[Chemical 127]

The product of Example 59 (435 mg, 0.94 mmol) and 1N sodium hydroxide (1.89 ml) in 8 ml of tetrahydrofuran: methanol (1: 1).
1.89 mmol) according to the general procedure of Step 3, 360 mg (8
6%) acid was obtained. HR-MS: m / z calcd _{(as C 21 H 21 NO 6 S 2} ) 448.0883;
Found 448.0882.

[0327] Example 61 4- (4-but-2-y oxy benzenesulfonyl) -N- hydroxy-1- (2-thienylcarbonyl) -4-piperidine carboxamide

[0328]

[Chemical 128]

The product of Example 60 (335 mg, in dimethylformamide (7 ml))
0.75 mmol), 1-hydroxybenzotriazole (121 mg, 0.90 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (
201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13)
Mmol) and hydroxylamine (0.229 ml, 3.75 mmol) were used to afford 216 mg (62%) of the product as a solid according to the general procedure of Step 4. HR-MS: m / z calcd _{(as C 21 H 22 N 2 O 6} S 2) 463.0992
Found 463988.

Example 62 4- (4-but-2-ynyloxybenzenesulfonyl) -1-[(4-methoxyphenyl)
L) Sulfonyl] -4-piperidinecarboxylic acid methyl ester

[0331]

[Chemical formula 129]

The product of Example 37 (500 mg, 1.29) in methylene chloride (10 ml).
To a solution of triethylamine (261 mg, 2.58 mmol) and 4
-Methoxyphenylsulfonyl chloride (320 mg, 1.55 mmol) was added, followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of product as a solid. HR-MS: m / z calcd _{(as C 24 H 72 NO 8 S 2} ) 522.1251;
Found 522.1252.

Example 63 4- (4-but-2-ynyloxybenzenesulfonyl) -1-[(4-methoxyphenyl)
) Sulfonyl] -4-piperidinecarboxylic acid

[0334]

[Chemical 130]

The product of Example 62 (545 mg, 1.04 mmol) and 1N sodium hydroxide (2.09 ml) in 8 ml of tetrahydrofuran: methanol (1: 1).
2.09 mmol) according to the general procedure of Step 3, 446 mg (8
5%) acid was obtained. HR-MS: m / z calcd _{(as C 23 H 25 NO 8 S 2} ) 508.1094;
Found 508.1073.

Example 64 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1-[(4-
Methoxyphenyl) sulfonyl] -4-piperidinecarboxamide

[0337]

[Chemical 131]

The product of Example 63 (402 mg, in dimethylformamide (8 ml)
0.79 mmol), 1-hydroxybenzotriazole (128 mg, 0.95 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (
212 mg, 1.11 mmol), N-methylmorpholine (0.130 ml, 1.19)
Mmol) and hydroxylamine (0.242 ml, 3.95 mmol) were used to afford 396 mg (96%) of the product as a solid according to the general procedure of Step 4. HR-MS: m / z calcd _{(as C 23 H 26 N 2 O 8} S 2) 523.1203
Found 523.2198.

Example 65 4- (4-But-2-ynyloxybenzenesulfonyl) -1-[(2,2,5-trimethyl)
Methyl ru-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylate

[0340]

[Chemical 132]

The product of Example 37 (500 mg) in dimethylformamide (10 ml)
1.29 mmol), (2,2,5-trimethyl-1,3-dioxan-5-yl) carboxylic acid (224 mg, 1.29 mmol), 1-hydroxybenzotriazole (20
9 mg, 1.56 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (346 mg, 1.81 mmol) and N-methylmorpholine (
0.212 ml, 1.94 mmol) according to the general procedure of Step 4,
Obtained 385 mg (59%) of the product as a solid. HR-MS: m / z calcd _{(as C 25 H 33 NO 8 S)} 508.2000; Found 508.1998.

Example 66 4- (4-But-2-ynyloxybenzenesulfonyl) -1-[(2,2,5-trimethyl)
L-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylic acid

[0343]

[Chemical 133]

The product of Example 65 (335 mg, 0.66 mmol) and 1N sodium hydroxide (1.3 ml, 4 ml of tetrahydrofuran: methanol (1: 1)).
(1.3 mmol) according to the general procedure of Step 3, 315 mg (97%)
Was obtained. HR-MS: m / z calcd _{(as C 24 H 31 NO 8 S)} 494.1843; Found 494.1835.

Example 67 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1-[(2,
2,5-Trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecar
Voxyamide

[0346]

[Chemical 134]

The product of Example 66 (280 mg, in dimethylformamide (6 ml)
0.57 mmol), 1-hydroxybenzotriazole (92 mg, 0.68 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1
53 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol) and hydroxylamine (0.174 ml, 2.85 mmol) according to the general procedure of Step 4, 180 mg ( 62%) of the product was obtained as a solid. HR-MS: m / z calcd _{(as C 24 H 32 N 2 O 8} S) 531.1771;
Found 531.1768.

[0348] Example 68 4- (4-but-2-y oxy benzenesulfonyl) -N- hydroxy-1- [3- arsenide Dorokishi 2- (hydroxymethyl) -2-methylpropanoyl] -4 Piperidine cal
Voxyamide

[0349]

[Chemical 135]

The product of Example 67 (150 mg, 0.1 ml) in tetrahydrofuran (2 ml).
To a solution of the product (29 mmol) was added 1N aqueous hydrochloric acid solution (2 ml) and the resulting mixture was stirred for 4 hours. The organic layer was washed with sodium bicarbonate, saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic solvent was concentrated to 40 mg (2
9%) of product was obtained. HR-MS: m / z calcd _{(as C 21 H 28 N 2 O 8} S) 469.1639;
Found 469.1637.

Example 69 ({4-{[4- (2-butynyloxy) phenyl] sulfonyl} -4-[(hydroxyamido
No) Carbonyl] -1-piperidinyl} methyl) methyl benzoate hydrochloride

[0352]

[Chemical 136]

The product of Example 6 (2.5g, 6. 5g in methanol (100ml) at 50 ° C.
To a solution of (43 mmol) and methyl 4- (bromomethyl) benzoate (1.62 g, 7.07 mmol) was added triethylamine (2.25 ml, 16.1 mmol). After 30 minutes, additional methanol (50 ml) was added. The reaction mixture was stirred for 18 hours, concentrated in vacuo and 1N aqueous hydrochloric acid solution (10 ml) and water were added. The solid obtained was isolated and methanol (20 ml) and 1N hydrochloric acid in diethyl ether (15 ml) were added. After adding more diethyl ether, the precipitate was triturated to give the desired product as a white powder (2.4g). _{^{1 H NMR (DMSO-d 6}} , 300MHz): δ1.85 (t, 3H, CH 3, J =
2.2Hz), 2.1-3.5 (m, 8H), 3.87 (s, 3H), 4.40 (bd s, 2H)
), 4.89 (q, 2H, J = 2.2Hz), 7.1-8.1 (m, 8H), 9.3-11.2. (
MS-ES: m / z 501.5 (M + H) ^<+> .

The subject compounds of the invention may be tested for biological activity according to the following methods.

In the In Vitro Gelatinase Assay This assay uses the enzyme gelatinase to bind the thiopeptide substrate ((Ac-Pro-L
eu-Gly (2-mercapto-4-methyl-pentanoyl) -Leu-Gly-OEt)
, Baychem Bioscience was cut and DTNB (5,
5'-dithio-bis (2-nitro-benzoic acid)) is based on releasing a substrate product which shows a color reaction. Enzyme activity is measured by the rate of color increase.

The thiopeptide substrate is freshly prepared as a 20 mM stock solution in 100% DMSO and DTNB is dissolved in 100% DMSO to give a 100 mM stock solution and stored at room temperature in the dark. Before use, both substrate and DTNB had a substrate buffer (50 mM).
Dilute with HEPES, pH 7.5, 5 mM CaCl ₂ ) to 1 mM. Stock solution of human neutrophil gelatinase B was added to assay buffer (50 mM HEPES, pH 7.5).
Dilute with 5 mM CaCl ₂ , 0.02% Brij) to a final concentration of 0.15 nM.

Assay buffer, enzyme, DTNB / substrate (final concentration 500 μM) and excipients or inhibitors are added to 96 well plates (total reaction volume 200 μl) and the absorbance is measured at 405 nm using a plate reader. Monitor the increase in color for 5 minutes.

The rise in OD ₄₀₅ is plotted and the slope of the line representing the reaction rate is calculated.

The linearity of the reaction rate is confirmed (r ² > 0.85). Average velocity of control group (x ± se
m) is calculated and the statistical significance is calculated using the Dunnett's multiple comparison judgment method.
(p <0.05) is compared with the velocity of the drug-treated group. Dose-response relationships can be determined using various doses of drug, and linear regression analysis (IPRED, HT
B) is used to assess IC ₅₀ values at 95% CI. Reference: Weingarten, H and Feder, J., Spectrophotometric assay for ve
rtebrate collagenase, Anal. Biochem. 147, 437-440 (1985).

In the In Vitro Collagenase Assay This assay uses a peptide substrate ((Dnp-Pro-Cha-
Gly-Cys (Me) -His-Ala-Lys (NMa) -NH ₂ ) and Peptide International, Inc.) are cleaved to release a fluorescent NMa group quantified by a fluorimeter. Is based on. Dnp quenches the NMa fluorescence of the untreated substrate. This assay uses human recombinant fibroblast collagenase
(Truncated, mw = 18,828, WAR, Radnor) using HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM Ca ⁺² , 0.02%).
Brij, 0.5% cysteine). Substrate dissolved in methanol, 1m
Store frozen in an aliquot of M. Collagenase is stored frozen in 25 μM aliquots in buffer. In this assay, the substrate is dissolved in HCBC buffer to a final concentration of 10 μM and collagenase to a final concentration of 5 nM. The compound is methanol,
Dissolves in DMSO or HCBC. Methanol and DMSO are diluted with HCBC to <1.0%. The reaction is initiated by adding the compound to a 96-well plate containing the enzyme and adding the substrate.

The reaction is read for 10 minutes (excitation wavelength 340 nm, emission wavelength 444 nm) and the fluorescence increase with time is plotted linearly. If the slope of the straight line is calculated, this represents the reaction rate.

The linearity of the reaction rate is confirmed (r ² > 0.85). Average velocity of control group (x ± se
m) is calculated and the statistical significance is calculated using the Dunnett's multiple comparison judgment method.
(p <0.05) is compared with the velocity of the drug-treated group. Dose-response relationships can be determined using various doses of drug, and linear regression analysis (IPRED, HT
B) is used to assess IC ₅₀ values at 95% CI. References: Bickett, DM et al., A high throughput fluorogenic substrate for
interstitial collagenase (MMP-1) and gelatinase (MMP-9), Anal. Biochem.
212, 58-64 (1993).

Method for measuring TACE inhibition Using a black 96-well microtiter plate, Tris buffer containing 10 μL of TACE (Immunex, final concentration 1 μg / mL) and 10% glycerol (final concentration 10 mM). A solution consisting of 70 μL (pH 7.4) and 10 μL of a test compound solution in DMSO (final concentration 1 μM, DMSO concentration <1%) is added to each well and incubated at room temperature for 10 minutes. After adding fluorescent peptidyl substrate (final concentration 100 μM) to each well, the reaction is started by shaking for 5 seconds on a shaker.

The reaction is read for 10 minutes (excitation wavelength 340 nm, emission wavelength 420 nm) and the increase in fluorescence with time is plotted linearly. If the slope of the straight line is calculated, this represents the reaction rate.

The linearity of the reaction rate is confirmed (r ² > 0.85). Average velocity of control group (x ± se
m) is calculated and the statistical significance is calculated using the Dunnett's multiple comparison judgment method.
(p <0.05) is compared with the velocity of the drug-treated group. Dose-response relationships can be determined using various doses of drug, and linear regression analysis (IPRED, HT
B) is used to assess IC ₅₀ values at 95% CI.

The compound of Example 18 was found to inhibit MMP and TACE as follows: TACE inhibition (at 10 μM): 54%; MMP1 (IC ₅₀ ): 1.3 μM; MMP9 ( _{IC 50): 0.732μM; MMP13 (} IC 50): 0.14μM. Thus, the compounds of the present invention are useful inhibitors of MMPs and TACE.

Pharmaceutical Compositions The compounds of the present invention may be administered to patients in need thereof either neat or with a pharmaceutical carrier. The pharmaceutical carrier may be either solid or liquid.

Applicable solid carriers may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow agents, compression aids, binders or tablet disintegrating agents 1. Mention may be made of one or more substances or encapsulating materials. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing 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 a pharmaceutically acceptable oil or fat. Liquid carriers include solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents,
Other suitable pharmaceutical additives such as suspending agents, thickening agents, coloring agents, viscosity adjusting agents, stabilizers or osmotic pressure adjusting agents may be included. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing the above-mentioned additives (e.g., cellulose derivative, preferably sodium carboxymethylcellulose solution)), alcohol (
Mention may be made of monohydric and polyhydric alcohols (eg glycols) and their derivatives, as well as oils (eg fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. The sterile solution can also be administered intravenously. Oral administration may be either liquid or solid composition form.

The compounds of the present invention may be administered rectally in the form of conventional suppositories. When administered by intranasal or intrabronchial inhalation or insufflation, the compounds of the present invention
It may be formulated in an aqueous solution or a semi-aqueous solution. These are then available in the form of aerosols. The compounds of the present invention may be administered transdermally by use of a transdermal patch containing the active compound and a carrier. However, the carrier should be inert to the active compounds, non-toxic to the skin, and should allow delivery of the drug for systemic absorption through the skin and into the bloodstream. Such carriers can take any number of forms, including creams and ointments, pastes, gels, and closures. Creams and ointments can be viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. A paste consisting of absorbent powder dispersed in petrolatum containing the active ingredient or hydrophilic petrolatum is also suitable. The active ingredient may be released into the bloodstream using various closure devices, such as a semipermeable membrane covering a reservoir containing the active ingredient, optionally with a carrier, a matrix containing the active ingredient, and the like. . Other closures are known in the literature.

The dosage to be used in the treatment of a particular patient suffering from a disease or disorder involving MMPs and TACE must be subjectively determined by the attending physician. Variables involved include the severity of dysfunction, and the size, age and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter, the dosage is increased until the optimum effect under these circumstances is reached. Precise dosages for oral, parenteral, nasal or intrabronchial administration will be decided by the administering physician based on experience with the individual patient being treated and standard medical principles.

The pharmaceutical composition is preferably in unit dosage form, for example a tablet or capsule. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; The unit dosage form can be a packaged composition, for example, a packaged powder, a vial, an ampoule, a prefilled syringe or a liquid-containing sachet. The unit dosage form is
For example, it may be a capsule or tablet itself, or the composition may be in a suitable number of package forms.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/454 A61K 31/454 31/4545 31/4545 A61P 1/02 A61P 1/02 1/04 1 / 04 1/16 1/16 3/10 3/10 9/04 9/04 9/10 9/10 9/14 9/14 13/12 13/12 15/06 15/06 17/00 17/00 17 / 02 17/02 19/02 19/02 19/08 19/08 19/10 19/10 25/00 25/00 27/02 27/02 29/00 29/00 101 101 101 31/04 31/04 31 / 18 31/18 35/00 35/00 35/04 35/04 37/06 37/06 43/00 107 43/00 107 111 111 C07D 211/60 C07D 211/60 211/96 211/96 401/06 401/06 405/06 405/06 409/06 409/06 // C07M 7:00 C07M 7:00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (B F, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL , IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Ally Zasque United States 10128 21st (72) East 90th Street, New York York NY 90 Inventor Alana Pakham Mudam by Venkatesan United States 11374 LEGO Park, NY 63 Road No. 97 Kay 97-07 (72) Inventor Jenny Lee Baker United States 29927 Oakwood Drive, Hardyville, SC 22 (72) Inventor Larisa Krishnan USA 10901 Suffern, NY Sonia Court No. 2 (72) Inventor Sleni Basle Megaty USA 10956 New York NY City, Hearth Court No. 1 (72) Inventor Joseph Zeldis USA 10956 New York NY・ City, long Clove Road 195F Term (Reference) 4C054 AA02 BB01 CC02 CC04 CC08 CC09 DD01 EE01 EE27 EE32 EE33 EE38 FF01 FF27 FF32 FF33 FF38 4C063 AA01 BB04 CC10 CC12 CC82 CC02 GA02 A02 A02 A02 A02 A02 A04 A02 A02 A02 A02 MA02 MA05 NA14 ZA33 ZA36 ZA44 ZA45 ZA67 ZA75 ZA81 ZA89 ZA96 ZB08 ZB11 ZB15 ZB26 ZB33 ZB35 ZC35 ZC55

Claims (53)

[Claims] 1. Formula V: [Chemical 1] [In the formula, Z is H, OH, -NYOX, -OR₅Or-NR₅R₆;   X is hydrogen, alkyl having 1 to 6 carbons, benzyl, hydroxyethyl, t-butyl
Rudimethylsilyl, trimethylsilyl or tetrahydropyranyl;   Y is hydrogen, alkyl having 1 to 6 carbons, aryl having 6 to 10 carbons, N, NR_Four 5-10 membered hetero having 1-3 heteroatoms selected from,
Aryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cycloheteroalkyl
Where Y is the alkyl, aryl, heteroaryl, cycloalkyl and
The cycloheteroalkyl group has a halogen atom or a carbon number of 1 to 1 on a substitutable atom.
6 alkyl, C 2-6 alkenyl having 1-3 double bonds, 1-3
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms
Le, -OR₅, = O, -CN, -COR₅, C1-4 perfluoroalkyl
, C1-C4 -O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅ , -OPO (OR₅) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR ₅ R₆, -OC (O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH
, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR ₆ , SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R
₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆ , -NR₅C (= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_Two
NHCN, -SO_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-
Positioned with 1 to 3 substituents selected from the group consisting of 10-membered cycloheteroalkyl.
May be replaced;   R₁And R_TwoAre each independently hydrogen, aryl having 6 to 10 carbon atoms, N, N
R_Four, 10 and 5 to 10 membered heteroatoms having 1 to 3 heteroatoms selected from O and S.
Teloaryl, C3-C6 cycloalkyl, 5- to 10-membered cycloheteroar
Kill, alkyl having 1 to 18 carbons, 2 to 18 carbons having 1 to 3 double bonds
An alkenyl, a C2-18 alkynyl having 1-3 triple bonds;
I, R₁And R_TwoTogether with the carbon atom to which they are attached has 3 carbon atoms
Form a cycloalkyl of ~ 8 or a cycloheteroalkyl ring of 5-10 members;
Where aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,
Alkyl, alkenyl and alkynyl are halogen on the substitutable atom.
, Alkyl having 1 to 6 carbons, and alkyl having 2 to 6 carbons having 1 to 3 double bonds.
Kenyl, C2-6 alkynyl having 1-3 triple bonds, C3-6
Cycloalkyl, -OR₅, = O, -CN, -COR₅, Perfumes with 1 to 4 carbon atoms
Luoroalkyl, -O-perfluoroalkyl having 1 to 4 carbon atoms, -CONR₅R₆
, -S (O)_nR₅, -OPO (OR₅) OR₆, -PO (OR₅) R₆, -OC (O) OR ₅ , -OR₅NR₅R₆, -OC (O) NR₅R₆, -C (O) NR₅OR₆, -COO
R₅, -SO_ThreeH, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆,
-NR₅COOR₆, SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR ₅ CONR₅R₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (= NR₆) N (
SO_TwoR₅) R₆, -NR₅C (= NR₆) N (C = OR₅) R₆, -Tetrazole-5
-Ill, -SO_TwoNHCN, -SO_TwoNHCONR₅R₆, Phenyl, hetero ant
1-3 substituents selected from aryl and 5- to 10-membered cycloheteroalkyl
May be substituted with;   R_ThreeIs alkyl having 1 to 18 carbons, 2 to 3 carbons having 1 to 3 double bonds
18 alkenyl, 2 to 18 alkynyl having 1 to 3 triple bonds,
Cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, and 6 carbon atoms
-10 aryl, N, NR_Four, 1 and 3 heteroatoms selected from O and S
5- to 6-membered heteroaryl having children; where R_ThreeOf said alkyl, alkenyl
, Alkynyl, cycloalkyl, cycloheteroalkyl, aryl and hetero
Aryl is halogen, alkyl having 1 to 6 carbons,
C2-C6 alkenyl having 1-3 double bonds, 1-3 triple bonds
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -OR₅,
= O, -CN, -COR₅, C1-4 perfluoroalkyl, C1-4
-O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅, -OPO (OR ₅ ) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR₅R₆, -OC (
O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH, -NR₅R₆
, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR₆, SO_TwoN
R₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R₆, -NR₅C
(= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆, -NR₅C (
= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_TwoNHCN, -S
O_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-10 membered cyclo
Optionally substituted with 1 to 3 substituents selected from heteroalkyl;   R_FourIs hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, charcoal
Alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -C (O)_nR₅, -CO
NR₅R₆Or SO_TwoR₅;   R₅And R₆Are each independently hydrogen, optionally substituted aryl, N
, NR_Four, 4 and 8 members having 1 to 3 heteroatoms selected from O and S
Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cyclohetero
Alkyl, alkyl having 1 to 18 carbons, alkenyl having 2 to 18 carbons or carbon number
2-18 alkynyl; or R₅And R₅Is the nitrogen source they bind to
May form a 5- to 10-membered cycloheteroalkyl ring together with the child
;and   n is 1 or 2] A method for producing an α-sulfonyl derivative or a pharmaceutical salt thereof represented by:   Formula III: [Chemical 2] [In the formula, R_Three'Is R above_ThreeAs defined above; where R_Three'Is basic condition
Does not contain a group capable of forming anions below] Is a metal hydride or amine in an ether organic solvent.
Formula IV in the presence of a base and at a temperature of about -78 ° C to about 30 ° C. [Chemical 3] [In the formula, Z is H, OH, YNOX, -NR₅R₆Or OR₅; X, Y, R₁,
R_Two, R₅And R₆Has the same meaning as above] By reacting with a carbonyl compound represented by
Forming a bonyl compound (wherein the reactive substituents are
Protected, then removed; and, if necessary, chiral or stereoisomeric
Isolation of the body product as individual isomers). 2. A compound of formula (V) produced, wherein Z is H, OH, -NR ₅
R ₆ or OR ₅ ] is further reacted to form a compound of formula I: [Wherein, X, Y, R ₁ , R ₂ and R ₃ have the same meanings as those defined in claim 1] and are converted to an α-sulfonylhydroxamic acid derivative or a pharmaceutically acceptable salt thereof (wherein The substituents are protected during the reaction and then removed; and further comprising isolating the chiral or stereoisomeric products as individual isomers). Method. 3. Z in the compound of formula V prepared is (i) OR ₅ (wherein R ₅ is other than hydrogen and conversion to the α-sulfonylhydroxamic acid derivative of formula I is represented by a) A compound of formula V is reacted with an alkali metal hydroxide in the presence of water and / or an ether organic solvent or alcohol at a temperature in the range of about 0 ° C to about 100 ° C to give a compound of formula VI: [Wherein R ₁ , R ₂ and R ₃ have the same meanings as defined above], and (b) the carboxylic acid of formula VI is prepared in the presence of a suitable coupling reagent and a polar organic solvent. Formula VII: [Wherein X and Y have the same meanings as above], and are reacted with a hydroxylamine or a hydroxylamine derivative,
Or (ii) OH (wherein the conversion to the α-sulfonylhydroxamic acid derivative of formula I is carried out according to step b) above). The method described. 4. The ether organic solvent in step a) is tetrahydrofuran,
The method of claim 3 selected from diethyl ether and dioxane. 5. A process according to claim 3 or 4, wherein the alcohol in step a) is selected from methanol and ethanol. 6. The method according to claim 3, wherein the alkali metal hydroxide in step a) is selected from lithium hydroxide and sodium hydroxide. 7. The method according to claim 3, wherein the polar organic solvent in step b) is dimethylformamide. 8. The coupling reagent is selected from the group consisting of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxybenzotriazole, N-methylmorpholine and oxalyl chloride and triethylamine. The method according to any one of 3 to 7. 9. The method according to claim 3, wherein the coupling reaction is carried out at a temperature of about 0 ° C. to 30 ° C. 10. The process according to claim 1, wherein the ether organic solvent used in the reaction between the compounds of formulas III and IV is selected from tetrahydrofuran, diethyl ether and dioxane. 11. A metal hydride base or amide base used in the reaction between compounds of formula III and IV is selected from lithium diisopropylamine, lithium hexamethyldisilazide and sodium hydride. The method according to item 1. 12. A sulfonyl fluoride of formula III has the formula II: [Wherein R ₃ ′ is as defined for R _{3 in} claim 1; provided that R ₃ ′ does not contain a group capable of forming an anion under basic conditions]. In the presence of an organic solvent at about 15 ° C to about 30 ° C,
The method according to any one of claims 1 to 11, which is produced by reacting with a fluorinating agent. 13. The method according to claim 12, wherein the fluorinating agent is selected from potassium fluoride, potassium fluoride-calcium fluoride mixtures and cesium fluoride. 14. The method according to claim 12 or 13, wherein the polar organic solvent is selected from acetonitrile and tetrahydrofuran. 15. The general formula V: [Wherein Z, R ₁ , R ₂ and R ₃ ′ have the same meanings as in claim 1] and a method for producing an α-sulfonyl derivative or a pharmaceutically acceptable salt thereof, comprising: a) a formula III : [Chemical 9] [Wherein R ₃ ′ has the same meaning as in claim 1], and a sulfonyl fluoride represented by At temperature, Formula VIII: [Wherein, Z is H, OH, YNOX, OR ₅ or —NR ₅ R ₆ ; R ₁ and R ₂
Is as defined in claim 1; R ₇ is cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members,
C1-C18 alkyl, C2-C18 alkenyl having 1-3 double bonds, C2-C18 alkynyl having 1-3 triple bonds, or -S.
iR ₈ R ₉ R ₁₀ ; R ₈ , R ₉ and R ₁₀ are each independently a 4-8 membered 1 to 3 heteroatom selected from aryl, N, NR ₄ , O and S. Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, 1 to carbon atoms
18 alkyl, C 2-18 alkenyl having 1 to 3 double bonds, 1
A C2-C18 alkynyl having 3 to 3 triple bonds; or two of R ₈ , R ₉ and R ₁₀ together with the silicon atom to which they are bonded are a 5- or 6-membered heterocycle. To form an α-sulfonylcarbonyl compound of formula V (wherein the reactive substituents are protected during the reaction and then removed). And further optionally comprising isolating the chiral or stereoisomeric product as individual isomers). 16. A compound of formula (V) prepared, wherein Z is H, OH, --NR. ₅ R₆Or-OR₅) Is further reacted to give it formula I: [Chemical 11] [Wherein X, Y, R₁, R_TwoAnd R_ThreeHas the same meaning as in claim 1.] Α-Sulfonylhydroxamic acid derivative represented by or a pharmaceutically acceptable salt thereof
(Wherein reactive substituents are protected during the reaction and then removed
And, if necessary, the chiral or stereoisomeric products as individual isomers.
16. The method according to claim 15, which comprises isolating the protein by isolation. 17. Z in the compound of formula V prepared is (i) OR ₅ (wherein R ₅ is other than hydrogen and conversion to the α-sulfonylhydroxamic acid derivative of formula I is represented by a) A compound of formula V is reacted with an alkali metal hydroxide in the presence of water and / or an ether organic solvent or alcohol at a temperature in the range of about 0 ° C to about 100 ° C to give a compound of formula VI: [Wherein R ₁ , R ₂ and R ₃ have the same meanings as defined above], and (b) the carboxylic acid of formula VI is prepared in the presence of a suitable coupling reagent and a polar organic solvent. Formula VII: [Wherein X and Y have the same meanings as above], and are reacted with a hydroxylamine or a hydroxylamine derivative,
Or (ii) OH (wherein the conversion to the α-sulfonylhydroxamic acid derivative of formula I is carried out according to step b) above). The method described. 18. The method according to claim 17, wherein the ether organic solvent in step a) is selected from tetrahydrofuran, diethyl ether and dioxane. 19. The method according to claim 17 or 18, wherein the alcohol in step a) is selected from methanol and ethanol. 20. The method according to claim 17, wherein the alkali metal hydroxide in step a) is selected from lithium hydroxide and sodium hydroxide. 21. The method according to claim 17, wherein the polar organic solvent in step b) is dimethylformamide. 22. The coupling reagent is 1- (3-dimethylaminopropyl) -3-
22. The method according to any one of claims 17 to 21, selected from the group consisting of ethylcarbodiimide hydrochloride, N-hydroxybenzotriazole, N-methylmorpholine and oxalyl chloride and triethylamine. 23. The method according to any one of claims 17 to 22, wherein the coupling reaction is carried out at a temperature of about 0 ° C to 30 ° C. 24. The Lewis acid or fluoride reagent is selected from boron tribromide, tetrabutylammonium fluoride and sodium fluoride.
23. The method according to any one of 23. 25. The method of claim 24, wherein the ether organic solvent is selected from tetrahydrofuran, diethyl ether and dioxane. 26. A sulfonyl fluoride of formula III has the formula II: Wherein R ₃ ′ is as defined above for R ₃ ; provided that R ₃ ′ does not contain a group capable of forming an anion under basic conditions. In the presence of about 15 ° C to about 30 ° C,
26. A method according to any one of claims 15 to 25 prepared by reacting with a fluorinating agent to produce a sulfonyl fluoride of formula III. 27. The method of claim 26, wherein the fluorinating agent is selected from potassium fluoride, potassium fluoride-calcium fluoride mixtures and cesium fluoride. 28. The method according to claim 26 or 27, wherein the polar organic solvent is selected from acetonitrile and tetrahydrofuran. 29. X is H or lower alkyl having 1 to 6 carbons.
29. The method according to any one of to 28. 30. The method of any one of claims 1-29, wherein Y is H. 31. Z is OH or OR ₅ (wherein R ₅ is C ₁ -C ₆ alkyl)
) Is the method according to any one of claims 1 to 30. 32. R ₁ and R _{2 taken} together are N, NR ₄ , O and S.
(Wherein R ₄ has the same meaning as in claim 1) to form a 5- to 10-membered cycloheteroalkyl ring containing 1 to 3 heteroatoms. The method described. 33. The method of claim 32, wherein the cycloheteroalkyl ring is saturated. 34. The cycloheteroalkyl ring having 6 atoms.
Or the method described in 33. 35. The hetero atom is NR_FourAnd R_FourIs hydrogen, trifluorome
Cylsulfonyl, optionally substituted aralkyl having 7 to 10 carbon atoms, (C₆-C ₁₀ -Aryl) carbonyl-, cycloheteroalkyl-carbonyl or heteroaryl
35. The method of any one of claims 32-34 which is reel-carbonyl. 36. The method according to any one of claims 1 to 35, wherein R ₃ is an optionally substituted C ₆ -C ₁₀ aryl group. 37. The method of any one of claims 1-36, wherein R ₃ is a phenyl group substituted with one or more OR ₅ groups. 38. R ₅ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C _2-
The method of any one of claims 1-37 C ₆ alkynyl or halophenyl. 39. The compound as prepared has the general formula IA: embedded image [Wherein, X is hydrogen or alkyl having 1 to 6 carbon atoms; Y, R ₃ and R ₄ have the same meaning as in claim 1], or an α-sulfonylhydroxamic acid derivative or a pharmaceutically acceptable salt thereof. 38. A method according to any one of claims 1-37. 40. The general formula IA: embedded image [Wherein X is hydrogen or alkyl having 1 to 6 carbon atoms; Y, R ₃ and R ₄ have the same meanings as in claim 1], or an α-sulfonylhydroxamic acid derivative or a pharmaceutically acceptable salt thereof is produced. A) in formula a): Reacting the compound of formula with diisopropylamide or lithium hexamethyldisilazide to form an enolate; b) converting the enolate to a sulfonyl fluoride: By reacting with the compound: C) hydrolyzing the compound of step b) to give And d) adding the compound of step c) to about 0 in the presence of a coupling reagent and a polar organic solvent.
At temperatures in the range of ℃ to about 30 ℃, the formula: And a hydroxylamine derivative represented by the following formula; and, if necessary, isolation as a pharmaceutically acceptable salt. 41. The coupling reagent is 1- (3-dimethylaminopropyl) -3-
41. The method of claim 40 selected from the group consisting of ethylcarbodiimide hydrochloride, N-hydroxybenzotriazole, N-methylmorpholine and oxalyl chloride and triethylamine. 42. The method according to claim 41 or 41, wherein the polar organic solvent is dimethylformamide. 43. The formula: [Wherein R ₃ and R ₄ are as defined in claim 1] or a pharmaceutically acceptable salt thereof, comprising: a) a compound represented by the formula: Reacting a compound of formula with diisopropylamide or lithium hexamethyldisilazide to form an enolate; b) converting this enolate to the formula: The manufacturing method which consists of a process of making it react with sulfonyl fluoride shown by. 44. Formula 8: [Wherein R ₄ has the same meaning as in claim 1; R ₁₂ is methyl, n-butyl, 2-butynyl or p-chlorophenyl; and n is 1 or 2] or a pharmaceutically acceptable salt thereof. A) Formula 12: embedded image A compound of formula (I) is reacted with diisopropylamide or lithium hexamethyldisilazide to form an enolate; b) this enolate is represented by the formula 2: By reacting with a sulfonyl fluoride of formula 13: C) hydrolyzing the compound of formula 13 with lithium hydroxide to give a compound of formula 14: D) a compound of formula 14 is treated with oxalyl chloride, triethylamine and hydroxylamine hydrochloride at a temperature in the range of about 0 ° C to about 30 ° C. 45. Formula IX: [Chemical 30] [In the formula, X is hydrogen or alkyl having 1 to 6 carbon atoms;   Y is hydrogen, alkyl having 1 to 6 carbons, aryl having 6 to 10 carbons, N, NR_Four 5-10 membered hetero having 1-3 heteroatoms selected from,
Aryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cycloheteroalkyl
Where Y is the alkyl, aryl, heteroaryl, cycloalkyl and
The cycloheteroalkyl group has a halogen atom or a carbon number of 1 to 1 on a substitutable atom.
6 alkyl, C 2-6 alkenyl having 1-3 double bonds, 1-3
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms
Le, -OR₅, = O, -CN, -COR₅, C1-4 perfluoroalkyl
, C1-C4 -O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅ , -OPO (OR₅) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR ₅ R₆, -OC (O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH
, -NR₅R₆, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR ₆ , SO_TwoNR₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R
₆, -NR₅C (= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆ , -NR₅C (= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_Two
NHCN, -SO_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-
Positioned with 1 to 3 substituents selected from the group consisting of 10-membered cycloheteroalkyl.
May be replaced;   R_ThreeIs alkyl having 1 to 18 carbons, 2 to 3 carbons having 1 to 3 double bonds
18 alkenyl, 2 to 18 alkynyl having 1 to 3 triple bonds,
Cycloalkyl having 3 to 6 carbon atoms, cycloheteroalkyl having 5 to 10 members, and 6 carbon atoms
-10 aryl, N, NR_Four, 1 and 3 heteroatoms selected from O and S
5- to 6-membered heteroaryl having children; where R_ThreeOf said alkyl, alkenyl
, Alkynyl, cycloalkyl, cycloheteroalkyl, aryl and hetero
Aryl is halogen, alkyl having 1 to 6 carbons,
C2-C6 alkenyl having 1-3 double bonds, 1-3 triple bonds
Alkynyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -OR₅,
= O, -CN, -COR₅, C1-4 perfluoroalkyl, C1-4
-O-perfluoroalkyl, -CONR₅R₆, -S (O)_nR₅, -OPO (OR ₅ ) OR₆, -PO (OR₅) R₆, -OC (O) OR₅, -OR₅NR₅R₆, -OC (
O) NR₅R₆, -C (O) NR₅OR₆, -COOR₅, -SO_ThreeH, -NR₅R₆
, -N [(CH_Two)_Two]_TwoNR₅, -NR₅COR₆, -NR₅COOR₆, SO_TwoN
R₅R₆, -NO_Two, -N (R₅) SO_TwoR₆, -NR₅CONR₅R₆, -NR₅C
(= NR₆) NR₅R₆, -NR₅C (= NR₆) N (SO_TwoR₅) R₆, -NR₅C (
= NR₆) N (C = OR₅) R₆, -Tetrazol-5-yl, -SO_TwoNHCN, -S
O_TwoNHCONR₅R₆, Phenyl, heteroaryl and 5-10 membered cyclo
Optionally substituted with 1 to 3 substituents selected from heteroalkyl;   R_FourIs hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, charcoal
Alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, -C (O)_nR₅, -CO
NR₅R₆Or SO_TwoR₅;   R₅And R₆Are each independently hydrogen, optionally substituted aryl, N
, NR_Four, 4 and 8 members having 1 to 3 heteroatoms selected from O and S
Heteroaryl, cycloalkyl having 3 to 6 carbon atoms, 5 to 10-membered cyclohetero
Alkyl, alkyl having 1 to 18 carbons, alkenyl having 2 to 18 carbons or carbon number
2-18 alkynyl; or R₅And R₅Is the nitrogen source they bind to
May form a 5- to 10-membered cycloheteroalkyl ring together with the child
;and   n is 1 or 2] The compound represented by or its optical isomer, or a pharmaceutically acceptable salt thereof. 46. The compound according to claim 45, which is 1-benzyl-3- (4-methoxybenzenesulfonyl) piperidine-3-carboxylic acid hydroxyamide. 47. Formula IX as defined in claim 45 or 46: A pharmaceutical composition comprising a compound represented by: or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 48. In a mammal in need thereof, a TNF-α converting enzyme (T
A method of inhibiting pathological changes mediated by ACE), the method comprising administering to said mammal a therapeutically effective amount of a compound of formula I according to any one of claims 44 to 46 or a pharmaceutically acceptable compound thereof. A method comprising administering an acceptable salt. 49. The condition to be treated is rheumatoid arthritis, graft rejection,
Cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure,
49. The method of claim 48, wherein the method is an inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection. 50. A method of inhibiting a matrix metalloproteinase-mediated pathological change in a mammal in need thereof, wherein the mammal has a therapeutically effective amount of any of claims 44-46. A method comprising administering a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof. 51. The condition to be treated is age-related macular degeneration, diabetic retinopathy, proliferative hyaline retinopathy, retinopathy of prematurity, eye inflammation, keratoconus, Sjogren's syndrome, myopia, ocular 51. The method of claim 50, which is a tumor, ocular angiogenesis / neovascularization or corneal graft rejection. 52. The symptom to be treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenia, central. Nervous system inflammatory disease, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulcer, abnormal wound healing, bone disease, proteinuria, aneurysm 51. Aortic disease, loss of degenerated cartilage after traumatic joint injury, demyelinating disease of nervous system, liver cirrhosis, glomerular disease of kidney, premature rupture of fetal membrane, inflammatory bowel disease or periodontal disease. Method. 53. The method according to any one of claims 1 to 28, wherein the product is a compound of formula IX according to claim 45.