SK63498A3 - Novel macrocyclic compounds as metalloprotease inhibitors - Google Patents

Abstract

This invention relates to macrocyclic molecules which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF). In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor. The present invention also relates to pharmaceutical compositions comprising such compounds and to methods of using these compounds for the treatment of inflammatory diseases.

Description

Technical field

The present invention relates to macrocyclic molecules which inhibit methacrylate, methacrylate, thrombocyte necrosis factor (TIMF), pharmaceutical compositions containing these molecules and their use as pharmaceutical agents. These compounds are, in particular, inhibitors of metalloproteinases which; are involved in tissue degradation, and inhibitors of tumor necrosis factor release.

D o t c r e s w a t e clm i k

It has now been found that metalloproteases (IMPs) are enzymes that inhibit the control of uncontrolled fibrous tissue, including proteoglycan and collagen, leading to resorption of 1 µl extraction. rnejmatric e. These include, but are not limited to, joint conditions, such as joint rheumatism and osteoarthritis (inflammation of the bone and joints), corneal ulceration, epidermal ulceration, or gastrointestinal ulceration; a n d o c t e c t a t a t e a 1. e b o 1 n th e; perlodontal and tooth and bone diseases. These catabolic enzymes are usually mildly regulated by the action of cephalic enzymes. b, p a n a n a d a 1 f a - 2 - m a c r o g u b u n i n TI IM P <t a n i. v o h o i n h i b t o r e m e t a 1 o p o t e n e z); Inactive complexes, at the level of their synthesis as well as at the level of x x r a c e u u r i n e n i e n i e n t e r i n e.

Osteoarthritis and joint rheumatism (OA, respectively RA) are destructive joint cartilage diseases characterized by localized cartilage surface erosion. It has been found that the articular cartilage of the femoral head of patients suffering from (JA has, for example, a reduced concentration compared to a control sample with an uncontrolled disability, suggesting an increased degree of cartilage degradation in the case of JA). (IMankin et al., J. Bone Joirit Surg. 52A, 1970, 424-434.) In mammalian cells, four classes of protein degradation enzymes exist: · serine, cysteine, aspartic, and metalloproteinases. it is the metalloproteinase that is responsible for the degradation of the extracellular matrix of the articular cartilage in the case of JA and RA. In the case of osteoarthritis of the cornea, increased activity of collagenases and skies has been found to be correlated. with the severity of lesion C Hankin et al., Arthribis Rheum. 21, 1978, 761-766; Woessner et al., Arthritls Rheum. 26, 1983, 63-68 and ibld. 27, 1984, 305-7. In addition, aggrecariase C (a newly identified metalloprotease enzymatic activity), which is a specific cleavage product of proteoglycan, has been identified in patients suffering from joint rheumatism and osteoarthritis by C. Lohmander L.S. et al., Arthritis Rheum. 36, 1993, 1214-22).

Therefore, as key enzymes, β-taloproteinases (HR) are involved in the destruction of mammalian cartilage and bone. It is expected that the pathogenesis of these diseases can be successfully modified by the administration of HP Inhibitors, and a number of compounds C have been suggested for these purposes. See Wahl et al., Ann. Rep. Lledo. Chem. 25, 175-184 (AP, San Diego, 1990).

mac r o y y 'i. c: c o c .. o u s, y c o c t e o t o 1 o p o o t e s. T i e t o o o

P r e c J1 o o e; invention. they inhibit aggrecanase and other molecules are provided as therapeutic agents that protect cartilage. Inhibition of aggrecanase and other metalloproteinases by these new molecules prevents cartilage degradation by the enzymes described, thereby alleviating the pathological conditions of osteoarthritis and joint rheumatism.

Tumor necrosis factor (CTNF) is a cell-associated cytokine that is processed from a 26kd precursor form to a 17kd active form. TNF has been shown to be a major mediator of inflammation, fever and acute phase responses in humans and animals, similar to those seen during acute infection and shock. Excess TNF ⁷ has been shown to be fatal. It is now clear that blockade of the effects of TNF by specific antibodies may be present under various conditions including autoimmune diseases, such as arthritic rheumatism of CFeldmari et al., Oeinza 3. or new dependent diabetes.

(1994, 344, 3.95),

C Lohmander L. S. et al. 22) and Crobna's disease

Immunol. 81, 3,990, 301),

Arthrltis Rheum. 36 1993, 3,214 CMacDonald T. a al. , Clin. Exp successful.

C o rd e c tio n s that inhibit this conversion and thereby

Thus, compounds that inhibit the production of INF are therapeutically important for the treatment of inflammatory disorders. Recently, it has been shown that matrix metalloproteinase or metalloproteinase family, later known as TNF-corivertase (CTNF-C), as well as other 1 * 1 P are able to cleave TNI- from its inactivated form to the active form CGearirtg et al., Nature, 1994, 370, 555).

They also secrete active TNF-α from cells.

These new molecules provide a means of a mechanism based on therapeutic mixing for diseases including, but not limited to, septic shock, hemodynamic shock, septic syndrome, postischemic reperfusion injury, malaria, Crob's disease, inflammatory bowel disease, mycobacterial infection, meningi 11 du, p s r i . acute, congestive disease, fibrotic disorders, cachexia, graft ejection, cancer, diseases including angiogenesis, autolmuncular diseases, skin inflammatory diseases, joint arthritis and 11 zmus, en 3. er y zum 3. tip 1 ex, radiation-related damage, hyperoxic thi 3. veo 3. A d i n i n e n e e n e n n n n n e 3. Innovation dependent diabetes mellitus.

Because in severe disease states, which are also characterized by tissue degradation by the intermediary of the eye 1 * 11 * 1 P, excess production of INF has been reported, for diseases in which both mechanisms are present, v. they inhibit both l * IMP production and production. INF.

There are several patents that disclose inhibitors based on hydroxamates and carboxylates.

PC3 International Publication 92/213260 describes N-carboxyalkylpeptidyl compounds having the general formula:

where AA is an amino acid, as disease inhibitors, the disease may be one or more patients.

PCT International Publication WO 90/05716 discloses hydroxamic acid collagenase inhibitors having the general formula:

PCT International Publication WO 92/13831 discloses related hydroxamic acids having collagenase inhibitory activity of the general formula:

PCT's international publication may include three amino acids of the general formula:

WO

94/02446 p o s i e d e r d a l d r o r o r o r o r o r o r o r o o r o o o r o r o r o r o r o r o r o o r o r o r o r o r o r o r o r o r o r o r o r o r o r o r o r o r o r o o o

Μ e d z i 11 r o p o b b i. 1 and P C T WO 95/09841, characterized in that they are hydroxamic acid derivatives as cytokine production inhibitors.

European patent application no. No. 574,758 A1 discloses hydroxamic acid derivatives as collagenase inhibitors of the general formula.

GB 2 268 934 and WO 94/24140 claim hydroxamate inhibitors of IL-1β as inhibitors of INF-production.

The compounds of the invention act as inhibitors of IL-ββ, in particular aggrecanase and TIMF-C, preventing cartilage loss and destruction and preventing prevention of inflammatory disorders involving TNF. Hydroxamic acid, carboxylic acid and derivatives thereof are cyclic compounds which are therefore non-peptide in nature, which represents a considerable advantage over e x i s, h e b i b i b, because the pharmacokinetic parameters are excellent. The advantage of these molecules is that they are a bioreactor and a bioreactor.

P o t s t a t i n e n e n e

The invention provides novel hydroxanoic acids and carboxylic acids and derivatives thereof having the general formula (I) (see below).

C o n t e c t e c h e n g a n g a n g a n g y T N F - C.

as well as methods of using these compounds in the treatment of arthritis and other inflammatory diseases of the patient as described above. .

The invention also provides pharmaceutical kits comprising one or more containers with pharmaceutical dosage units comprising a compound of formula (I) for the treatment of arthritis and other inflammatory diseases described above.

The method includes methods for inhibiting metalloproteinases such as aggrecanase and TNF-C, and methods for treating arthritis by administering a compound of formula (I ') in combination with another or several secondary therapeutic agents selected from other metalloproteinase inhibitors, such as aggrecanase and TMI-. C, and / or therapeutic agents for the treatment of arthritis and inflammation.

The invention provides novel hydroxamic acids and carboxylic acids and derivatives thereof having the general formula (I) (see below), which are useful as metalloproteinase inhibitors, for example aggrecanase and TNF-C. The invention also encompasses pharmaceutical compositions comprising compounds of formula (I) and methods of using such compounds in the treatment of arthritis and other inflammatory diseases described above and a patient.

The invention also provides pharmaceutical kits comprising one or more containers with pharmaceutical dosage units comprising a compound of formula (I) for treatment; arthritis and other inflammatory diseases described above.

The invention includes methods for inhibiting metalloproteinases such as aggrecariase and TNI-C, and methods for treating arthritis by administering a compound of formula CD in combination with other or several secondary therapeutic agents selected from other metalloproteinases such as aggrecariase and TNF-C, and / or therapeutic agents for the treatment of arthritis and inflammation.

In the following description: - symbolizes the binding site.

Cl] The present invention provides compounds of the general formula (Cl)

General formula:

or a pharmaceutically acceptable salt thereof, or a prodrug form thereof, in which:

U is selected from -CO _and H, -CONHOH, -CONHOR ¹¹ , -SH, -NHCOR ¹¹ , -MC OH) COR ¹¹ , -SN 4 H 4 R 4, -SONI-IR 4, CH _and CO _and H, POCOH) _S ,

POCOH) NHR ^<&, Chash, -CC O) NHOR ^122, -COAr ^{1 S} - current and prodrug derivatives;

R ¹ is selected from hydrogen,

-0-CC _{of 6)} alkyl-S CC _and CD pC) alkyl,

C _Co-A 0) _x -CO 1-0 alkyl -0 _ώ) alkyl group J,

..... CC _of -C't,) alkyl-S CD pC _of C-C ₆₎ alkylénar yl,

C Co-CLID alkyl-O-C C _O C _R) alkylénar yl, alkyl of 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl love: j group, which is selected from substituerit ...... CCo ~ CC _o subst -CC _O -ccx ·· -C Co • cc _o is ar -C Citi eat ome hydrogen, ha 1, ethoxy, hydroxy, and 1 alkoxy, ary 1 oxy group i. (C (e.g. 1 adphenoxy), amino, mono-1-aminosulfonyl, dia 1-am (1-acyl), ac: y-am (1-acetylamino) , aryl 1-amine, guanidyl, M-methyl imidazylyl. jskupiny, i. midazo 1 y 1 ogroups, 1 n to 1 y 1 ogroups, mercapto groups, and 1 y 1 µs, y, yry 11 j. C group on μ:> r k k and t and d 11: j. o-groups), carboxy group 1, carbox am idogroup d. ny, carboa 1 alkoxy and 1 e phoso 1 phonamido,

C. _θ ) and 1-cyano-1-group,

A (C 1-6) alkylenearyl group in which the aryl radical is tertiary,

C o) aryl 1 - _{CC: L} - C ₄₎ alkyl and 1 1 1 s nary ove: jskupiny, _(θ j) and 1 s 1 s 1 ribiary ester group,

C) a) 1 - SC 0) p - CC _o - C. ®) and 1.

C ©) alkyl SCOT) p C _o -C®) alkylénar en upirty yl, or vkt ej yl radical substituted,

From C ,.) and 1 s 1 s 1 nary - _the CC - C ®) and 1 s 1 s nary 1 - s. '. SC CJ) p - CC _o - C. _{f: 1} ) and 1 cy 1 groups],

As CED-C-alkyl-S CJ) p C _o -C®) alkyléribiarylovej group,

- _the CC-C ₀₎ alkyl, -CO-0-C _{of (a)} alkylénar yl, j groups,

Co-C-C ®) alkyl-S pC C CD _{N N)} alkylériarylove j group, vk tor ej is an aryl radical substituted,

- CC x - C) alkyl, and one aryl 1 1 - of CC - C ®) and 1 s 1 s nary 1 - LC J = CC - C _θ), and 1 1 alkyl group ove ... j].

-CC _of -C®> alkyl-O-C C _o -C®) j alkylénbiar yl group, a

in which ... he is

- <C o -1 ?. , =,) and 1 - O - C ( _{o o} - C _θ ) and 1 - o oary 1 group: i. rt y ,, aryl radical substituted in which the substituent is selected from:

a hydrogen atom, an alkyl group having from 1 to 5 atoms, u. k a, h y d r o x y s u p x n yh and 1 o g ó n s u u p :: i. n y, and 1 k o x y s k u p i n y, am i. n o s k u p i n, m o n o a 1 k y 1 a mri., n o s k u p i. n y, d i and 1 k y 1. and m i. n o s k u p x n y, and c y i. a m i. n o s k u p i n y, t x o groups, t i. o a 1ky 1 - s k u p j. n y, k ar boxes with k u p i n y, karb o m i. d o s k u p i. n y a 1 e b o a r y 1 o e s s p i. n y;

R ² 'is selected · from the alkyl aryl group, hydrogen, -Ca _p, R ^a, -CONR' R ^55, CONR ^& <0R ^'s), 1 gr ny, and one alkyl aryl 1 1 ovejskupiny and 1-heterocyclyl, and 1-heterocyclyl. c: ke J s piiny, ary 1 ove ... jheteroary 1 ohogroupa 1 eboheterooyk 1 i. which is substituted by one or more.

substituents selected from the group consisting of hydrogen, halo, hydroxy, alkoxy; n y, a r y 1 o x y s k p 1. n y C n a p r. k 1 a d f e n o x y s k p i n y), am in o s k u p i. n y, m o n o a 1 k y 1 a m in o s p p n n, d i a 1 k y p a. n y, and c :: y 1 and m x n s k u i. n y C n a n i c d e c: e t a m x s s p p a n y and benzamido),. arylamino, guani.di.nos k u p i. n y, M - m e t y 1 m x d a z 1 y 1 o o s p i n i, i m x d a z 1 y 1 o e s e s. n y, 1. n d o 1 y 1 o ... e s s u i. n y, m e r k a p t o s u u i. n y, n i n e ... j a 1 k y 11 i. o s k u p i n y, and r y 11 i o s k u p i. n y (n i i n i e d i d i e i i s x u), k a r b i x y s k u p x n y, s u 1 f n n i i. d o s p p n n y, k a r b o x m x d o p p n n y a 1 e b o k p r n o a 1 k o x y s p p n n;

R ⁵ is selected from:

hydrogen, hydroxy, OR ', amino, -NHR', ^ώ -MCR, - CC i - C i _ώ 1 s 1 ... jsku ove r> ny J., _{-CC: L} - C), and 1 an aryl group, -SR ', halide or nitrile;

alternatively, R ^a and R ³ may form a three to eight membered saturated, unsaturated, aryl, heteroaryl or heterooyl ring;

R "'is selected from:

H, hydroxyskupxny, -0R ^R, amino, -NHR ^<I>.

1.0

..... N CR ^R) - (. The D- _and C) an alkyl of l <UPIN, - _{CC: l.} - C _Ä ·) and 11 <s 1 s 1 s nary e. j group, SCO) _ρ-C0: ι. ~ 0 _ώ) alkyl, halide or nibrilu;

R ^s is selected from:

CHR'-C) CC R R ^{x, a),} -N-R CC R ^{X ij)} ..... RO CC ^Cl R R ^X) "R" ⁵ ".

CCR ^x R ' ^:: ' n-aryl, -CCR ^x R ^e ) n-CONR ^x R ^e ',

- CCR ^x R ^G3 ) ', ..... substituent variations of the heteroaryl group,

- CCR ⁷ R ® - Substitutedbeterocyclic group in which the subsbibuenb is selected from:

a hydrogen atom, an alkyl group having 1 to 5 carbon atoms. k a, h y d r o x y s p i n y, h a 1 o <3 é n s k i:> i n y, a 1 k o x y s k p i n y, a m 1 no s k u p Iny, m o n o a l. k y 1 and.no s k u p i n y, d i a 1 k y 1 a m i n o s k p 1 n y, c y 1 am: i. s, s s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. o v e. j s k u p i n y;

R * ⁵ 'is selected from:

hydrogen, alkyl,

-CO x - (?. _ώ) alkyľLénarylove j groups,

-CC x -C _A ) alkyleneheberoaryl group, · w

- CCX - C _R) and a 1 s 1 s 1 nheberooyk ickejskupiny,

- CC x - C _ώ ) and 1-cyano group. ny, alternatively, R @ ⁵⁵ is fallen APRIL saturated Abome O, -NR,

R ** may be bvorib broj up to an eight-membered ring containing 1 to 3 heberoabomas, selected from -S (CO) p a l e b o u b o v o n e s and c y 1 o e s; > i. n y, optionally condensing to an aryl ring;

R ^x and R ® can be independently selected from hydrogen, R ¹ , or bvorib can form a 7-membered sub-bonded ring with 0 to 3 unsaturated bonds in which the subsbibuenb is selected from hydrogen, an alkyl group of 1 to 5, and 1 to 5 ka, hydroxys; ku r> iny, ha ll. og groups, and 1 alkoxy groups, aminosupines, monoalkylamino groups, dialkylamino groups, acyl groups, bio groups, bio groups 1 11 s l <upines, carbox groups, carbo groups 1 groups but be

ar'ylove groups; possibly ob extending -0- -SCO) p NR ⁶ , p eventual condensation n a s u b s t t t o o t aryl circle, h who is s u b s 111 u e n t z o 3. í z: atom h a, a 3_ k y 3_ o e j groups s 3. až b atoms alkyl, (ί d o o y s,, halogen-based k upiny. alkoxy-

s k u p 1 n y, am 1 n o s k u p i n y, m e n o a 3. k y 3. am j. noskup 1 ny, dia 3. cy 3 .. am 3 .. nos μ: · yy, acy 1 am 3. nosgroups, bigroups, t :: i_ oa 3. ky upskins, carbaxys μ:> 1 ny, carboxamido groups and 3. eboary 1 ove.

represents a hydrogen atom, an alkyl group, a cycloalkyl moiety or a six-membered ring, optionally containing one to two nitrogen, oxygen or SCO 11 atoms, optionally substituted by hydroxy, -O-C 1 -C ₆ ) alkyl, -O-aeylalkyl. nou, NHR10 and 3. eboaryl;

R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl group;

R 'is H, alkyl having 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from the. · Hydrogen, halo, hydroxy groups, the alkoxy chicken ins ¹ · · , ary 3. oxysku μ -:> i. For example, the amino acids C, e.g., 3-adphenoxy, amino, diabenzylamino, acy-3-amino C (e.g. acetamido or benzamido), amino-amino, guanine. dino groups, imidazolyl group 3, indolyl group, mercapto group, and 3 thio groups, aryl 111 of group C e.g. to the 3 th ad group of the 3 thio group, k arboxy group, k arboxamido group, carboa 3. coxy groupsa 3. ebosu 3. f ó namidosku μ:> 1 ny,

- CC _{: l} . - (C) - arylic groups 1,

- CC _x - C) - 1 and CC-1 s _x - _θ C) and 1 s 1 s 3 .. nary ovejskup ins,

- CC j. -C ( _B ) -alk ylenebiaryl j ups.

subs 111 uovan e. s - _<C-Ce) -alkyl s 1 s 1 nary ove ... l is <UPIN vktorejsa substituent is selected from;

hydrogen, halo, hydroxy, alkoxy, aryl 1-oxy (e.g., 1 to 1 adphenoxy), am 1-r, 1-d and 1-amine, aoy 1-am, 1-amine (E.g., acetamido and benzamido), aryl and ingroups, guanidyl, nosyl, 1 ml of dazolyl, indolyl, mercapto, and 1 ' , ary 1.1 i. C, e.g. k 1 adphenes (carboxy), carboxy: carboxy: oxamido, carboalkoxy, and ebos li 1 phonam 1 plate, p ¹¹ · '' represents a hydrogen atom

-Silo-C 1 -C 7 -alkyl group,

-St) _x.-C I-C ^ -alkylénar yl group in which the aryl ej incr uovan characterized oksubs 111, - 0 S ₂ - 1 · s account aryl gr 1 nu - S 0 »- substituted halosubstituted heteroaryl, -COR ³ ', -CO tBu, -C 0 _of L3N or -alkylenearyl radical, wherein the aryl radical is substituted, the substituent is chosen from;

a hydrogen atom, an alkyl group of 1 to 5 atoms at h 11 k a, h y d r x y y k p j. n y, h a 1 o g e n s u p i r t y, and I. k o x y-s k p piny, am i n o s p u n y, m o n a 1 kylamj.no s k u p j. n-y, d-a-1-amino, acylamino, thio, thioalkyl, up-box, up-box, or arboxamidoscopy, or arylic groups. n y;

is selected from: a hydrogen atom, and r y 1 o e .j s k u p i n y,

C C-C j. o) - a 1 ky 1 ove .jskup j. (ary l l .. CC - C _ώ ) - and 1 of 1

C _{C-C: l)} -cycloalkyl, <35 C - Co) - and one club. J. oxycarbonyl carbons; ny,

C C 35 - C x o 5 - o 1 k o x y k a r b o n y 1 o x y a 1 k y 1 o s s p o n y, ζ Axis - C o) -a l.l <oxy k ar bony love j sk upiny,

C C 3> - C i o> - o y k ll. o and ll. k y 1 k a r b o n y 1 o x y and 1 k y J. o v e j s k u p i n y,

CC _Sä - ( _L.: 10o) - Cycl. oa J. Coxycarbonyloxy O I. group j. ny, CC s - C 10) - cycl. o and 1 coxycarbones of the same group,

1.3 ary 1 oxycarbonyl 1 ove: J s l <upiny, ary 1 oxycarbonyl 1 oxy (C 1 -C _ώ a 11 <y 1 ove J s l <upiny) -, ary 1 carbony 1 oxy CC _t - C _ώ a ľ .L keel group) -,

CC _s - (C 1 _s ) - and 1 alkoxycarbonyloxycarbonyl: groups,

L 5 - C C. t - C s a 1 k y 1) -1, 3 - d i o x a c y k 1 o p e: n t e n - 2 - o n - y

C 5 - aryl-1 -1, 3 - dinxac: yk cyclopentene 1 - 2 - on - 1 yl) methyl-1 ovejskupiny, CR ¹⁵ ') (R ¹⁷⁾ NC-C and C _<:, alkyl) -,

-CHCR ^{1 3)} OCC = O) R ^lz \

-CMC R ¹⁷³⁾ OCX = 0) OR, or ^{1 S}

wherein r 1.3 represents a hydrogen atom or a th am1 carbon a;

linear up to 4

R ¹ '* is selected from Z:

a hydrogen atom, an alkyl group having 1 cycloalkyl group having said alkyl or substituted with up to 2 groups of up to 8 carbon atoms or up to 8 carbon atoms, the cycloalkyl group being independently of one another from:

(C1-C4) alkyl group,

CC - C o) OYK o 1 1 1 ove .jskupiny alkyl, _<C-C) alkoxy, aryl substituted with 0 to 2 groups independently selected from:

halogen, phenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro, -SC (C 1 -C ₅ alkyl), -SC = O (C 1 -C 6 alkyl (14 aryl)), SO _{CC L} -Csalkylovej hydroxy group, - R ^{1 x} NC) CR ^'Χ · ^ΪΛ).

-CC i'ONCR ^{'x) 1xA} CR) or C _W F _W, v is 1 to 3 and w = 1 to 2v + 1), substituted with 0-2 groups of).

- CO.- .I ·? wherein, independently selected from halogen, phenyl. , alkyl of 1 to e carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, -SCC _x C _s alkyl), -S-C = 0) CC j. - a _C 1 alkyl ovejskupiny 1), -S0 ^. (C 1 -C ₅ alkyl group), hydroxy, -NC R ⁷ (CR ¹⁷ * ¹ ),

-CC- (J) NCR ¹⁷ ') CR ^17' **) or C _W F _W where v = 1 to 3 and w is "1 to (2v + l);

is selected from:

(C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl group, wherein said alkyl or cycloalkyl group is substituted with 1 to 2 groups independently selected from:

(C až-C) alkyl, (C až-C o) cycloalkyl, (C až-C alko) alkoxy, (C až-Cry) aryl group independently selected from:

halogen, phenyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, -SO-C j Csalkylove group), -SC = O) CC _x j -Csalkylove group), -SO- -C (C (C 8 alkyl)), hydroxy, -NCR ¹⁷ ') (R ^17a ), -CC- _and R ¹

-CO-C) ^of the NC R ^J) (R ^{l of H} or C _W F _W where v = 1 to 3 and ui = 1 to 2v + 1);

aryl substituted with 0-2 groups independently selected from.

halogen, phenyl, alkyl) group of 1 to 6 carbon atoms, alkoxy of 1 to 6 v O s mamiuh 1 ms, nitro, - _{SCC: t} - 1, and _C 1 alkyl ester group), -S (= 0) _{((7: l} ~ _C alkylove..j group), _and -SO _(C-C, and 11 <y 1 ouej group), hy le Roxys l <UPIN, - ^{NCR: lx) (1} R ^x ''')

-CO., R ^7a , y is

- (7 (= 0) NCR ^{1 x} ) (R ^{1 17 Λ} ) or -17J- _W of which up to 3 and ω means 1 to (2v + 1);

R ^1a represents a C 1 -C 4 alkyl, benzyl or phenyl group, _R 1a _{and R} 1a _are independently selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, cycloalkylalkyl C 4 -C 11 carbon and C 1 -C 6 arylalkyl;

combinations of A, B and IJ and / or variables are permissible only if these combinations provide stable compounds (as defined herein);

And may be omitted or may represent C ^R CHR) m -0CCHR ^'&) m -NR CHR *) ™ -, -S (O) p, (CHR) ~, or _In may be selected t; from an alkyl group. with 1 to 10 C atoms which include branched, cyclic and unsaturated alkyl and 1 eb cj - · _{(C l} - C _ώ) alkyl and one aryl 1 1 OJ OJ J gr. nu;

may be a bond or may be selected from:

-NI-I-, -NR ' ¹ ....., -NR ^11' -, -O-, -55CO) p-CC 1 -C 6 -alkyl-HN- (C 1 -C 6) - and 1 1-J group, - ((7 J-C 1-6) - and 1-NR ¹¹ - (C: L- (7 _ώ )) - and 1-C 1-4 alkyl, -C _x -C 6 NH-aryl, -0- _{(17; L} -C ₆₎ --alkylovej the group - (C j. _A-C) -alkyl-aryl y1-0 sl <UPIN, -S- _{(C l} - 0 _ώ) -alkyl, - _{((7: L} -C,) alkyl-S -aryl, - (C _R) yl alk en UPIN, - (C _x -0 _ώ) alk enyl en UPIN, -CO, -C _those) - alkynyl, -CON-I, -COMR ^11, -MHCO-, -MR ¹¹ (70-, -0C0-, -C00-, -0C0,: .- -R ¹ OMCOMR ^{1: L-} , HNCONH-, -OCOMR ¹¹ -, -MR ^{: 11} COO-, -HNSO ⁵ -, -SO 5 NH-, aryl.

c y k 1 o and 1 k y 1 o e J s k p i n y h e t e r o c 1 o ει 1 k y J. o e ..

groups,

-R ¹¹ NCSMR ¹¹ -, -HNCSNH

OO.SNR ¹¹ -, ^-NR ~ ^I1 CSO, -HNCNNH-, and

P e; p t id e i j bond;

μ: m

l) w

it may be absent or may be an alkyl group having 1 to 10 carbon atoms, optionally containing an oxygen atom, a sulfur atom or an MR 1 'group which includes a branched cyclic or unsaturated alkyl group and an arylalkyl group having 1 to 6 carbon atoms in the alkyl radical;

can be 0, 1 or 2;

represents an integer from 0 to 5;

represents an integer from 1 to 5;

is -O ·· -, -SCO-p - or -NR ¹⁰ -;

is selected. FROM :

--C0NR ¹⁰ -, -NH ^lo C0-, ^{-SOÄNR: I} ° -, -NR ° S0Ä- ^1, a peptide bond a five membered heterocyclic ring which is saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, provided that the macrocycle, in formula 1 with R -ABDCC ^£>) CR ³⁵⁾ -Y-CC R ¹⁾ -CO IJ) CR ^{+ z)} -, be connected by no less than 11 and not more than 22 carbon.

C 23 The present invention provides compounds of formula (II)

General formula II

or a pharmaceutically acceptable salt thereof, or a prodrug form thereof, in which:

is selected from CH _a , NH, NR ^S

SCO) β or an oxygen atom;

U, Y, R ¹

R ⁵¹ ', R ^3' , R ', R ^5' , R **

R ^x , R ^a , R * ⁵ *, R ^x o, R '·', R ^{1 :,} - \ R ¹ *,

R ^13, R ¹ 'R ^1: and

R ³

R ³

R ³

P>

m, n,

A, as defined for formula I above, with the proviso that a compound with a generally stable compound; and

13, D and W are all common formulas I, provided that the macrocycle, represented in formula I by --AB - D - CC R ³ '- (CR ³ ) -Y-CC R ¹ ) -X-CC (R ( ¹ ) -) is connected by a minimum of 11 and a maximum of 22 atoms.

C 33 The present invention provides compounds of formula (III)

General formula III

-B

U '

R '

R ¹

D / Sat,

For Sci, choose Z:

-COaH, "-CONHOH, --CONHOR ^{1 1,} -SH, -NHCOR ¹ \ -NCOIDCOR SNaHaR ¹ ^, ^ -SONHR, CH _{and CO, and} H OH POC) and, -during OH) NI-IR * '. CH .SH _with a common derivative niedziproduktov -CC O) NHOR ^1A and -CO · R ^{1 3;}

Z is selected from:

a nitrogen atom or CH;

R ¹ , R *, R *, R ¹¹ , R ¹¹ '', R ^1A , R ¹³ 'R ¹ ' ¹ , R ¹ ' ³ , R ^{1 <s>} , R ¹⁷ ', R ¹⁷ '**,

D are defined as in the general formula provided that they provide stable compounds.

A, B. I at

E 43 Preferred compounds of the invention are those of formula (I)

General formula

or a pharmaceutically acceptable salt or prodrug thereof, thereof

U is selected from:

-CONHOH, -CONHOR ¹¹ , -NCOH) COR ¹¹ , -SNaH 4 R * ⁵ ', -SONHR *. -COaH, CH and SH, - CCO) NH ^{OR1 52} Abe n t ohderiv the tovprekurzora;

R ¹ is selected from hydrogen,

-0-CC _{of A)} alkyl-S 0) _x ρ-CC-C ,,,) alkyl,

-Co-Ο, ζ, alkyl-OC ( _a -O _ώ ) alkyl,

- CC o 0 _ώ ) a 1 ky 1 -SCO) p - C C-C _Λ ) a 1 ky 3. éary 3. ove .jskup 3. ny,

- C C _<:> -0 _A) alk y 1-0 - CC _of -0 _ώ) ylénaryloveJ alk groups of the alkyl group of J to 20 carbon, atoms which include branched, and SOBs. bold ... cyclic time; The thioalkyl group, the alkyl group in which the substituent of the carbon atom, the halo group, the hydroxy group, and the 1 alkoxy group, the aryloxy group C, e.g. 1 and cl phenoxy), amino groups, mono-1 amino groups, cl ia 1-ky 1 and τη in o .....

s k p p n n, a c: y J, a m n n p p n n c n a p n k a n a n a n a n e n a p n n a n e n n a p n p n. ny), a r y 1 am i n o s u p i o y, g u a n i. d 1 n-O, N-methylimidazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, aryl, arido, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio, arboxio

--C

-CC,:, subs

-C 0 -CC _{: I.}

-CWhat arboalkoxy groups or sulfonamido groups,

- C,: ( ₃ ) and the first group of the first group,

-C _e ) an alkylene aryl group in which the aryl residue is substituted,

..... C a) a r y 1 - C (C-C) a 1 y y n y r o y s p d. n y,

- C (a) a l c 1 é nb d. ary 1 ogroup. ny, -Ca) alkyl SC0) _of p-CC-C ₀₎ alkyl-aryl,

Co-Ca-C) alk-Y1 SC O) p C _o -Ca) yl alk ylénar sk j to clamp, in which the aryl radical is substituted.

-CC i - C ₄ ) and 1 cyanene 1 - -CC, vej groups], -CC o-Ca) alkyl-SC0) p -CC -CC o-Ca) alkyl-O-CC _of - -c -C C o C 1-6 alkyl-SO 2 p -CC,

the aryl radical is substituted,

T-CC - CC ,.) alkylénar yl-C ₀ -C _o C) LL 'alkylénar yl 0--CC _{of 0-C)} alkyl],

--C-Ca) alkyl-O-C _{0 o} CC) alkylénbiarylovej group,

- Co C - C a) alk y 1 ~ 0 - CC-C _{of a)} yl alk ylénar en UPIN, j is vkt hours ary1ový radical -substituted, wherein the substituent is selected from:

hydrogen, C 1 -C 5 alkyl. h, h y d r o x y s p d n y, h a h o g g e s h e s s, s, s, s, amino, monoalkylamino s, s, dialkylamino, acylamino, thio, thioalkyl2C, s, s, s, s; ku p 1. n y a 1 e b o a ry 1 o e: j s k u p i n y;

R * is selected from hydrogen. -CO R ^'5, CONR ^a R ^{:, t,} - COMIX'C0R ^s), and the bandage 1 of gravity of the full E ..., and 1 1 alkyl aryl ove 1: ny jskup s, 1 alkyl, and one of the heter .....

a ~ 1 1 vej i i,,,, t t t t k ľ l l arylic group:> 1 rt y, h e t h a r y h e t h e t h e r e t h e r e c h e l e e a group which is substituted by one or more substituents selected from:

hydrogen, halogen, hydroxy, alkoxy; aryls (aryloxy groups (e.g. (a (aphenoxy) groups), amino groups, monoalkylamino groups, dialkylamino groups, aoylamino groups (for example 1 adacetamido groups up to 1 group), amino group 1) ny, gu, or dinoskupirty, M - methyl 1 im idazo 1 y 1 ove .jskup 1 ny, imidazo ľl. y 1 ovejskupioy, in to 1 y 1 ov ó jskupirty, mercapto groups, r 11. ó eja lky 11 iogroups, ary 11 ioskupioy (for example. 1 ad beny 11 io groups), carboxy groups, with uphonamidoscopes clamps, carboxamido sk u piiny or k ar boaxy oxy clamps;

R ³ _{is called} ] SW:

a hydrogen atom, a hydroxy group and an amino group;

alternatively R ¹² or R ³ may form a ^three to six membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring;

R.

select Z:

a hydrogen atom, h y d r o x y s and p amine;

R ^{! =>} Is selected from:

-CCHR ¹ R, - • R ' ⁵ ', -CC R ^X R '), W-CC R (R) m-R' ⁵ ', -CC R ⁷ R') -R R .

R ⁷ -CO R®) _m -N j yl group, -CO R® R ^X) ", -CONR R®,

- CCR ⁷ F? ®) - substituted ... ii ethereroaryl groups,

- CCR ® R ⁷⁾ _t - substituovaoejheteroc: yk 1 ic: kejskupiny, vktor S C R I is selected from H, _{-CO: l} -C _SA) alkyl, hydroxy to clamp, clamps the halogértsk, alk oxy en to clamp, amino , πι ο ι ί aky 1 ami rt oskupiriy, c: 1 a 1 amino groups, ac: y 1 amino groups, ie. oskupiny, ti oa 1 club. groups, carboxy groups, carboxamido or aryl groups;

R ^A is selected from:

a hydrogen atom, an alkyl group,

- · C i -),, a)) i i a,,,,,,

- CC _{: 1} . - C _ώ ) a 1 ky 1 é nheter · oary 1 ovejskupirty,

- CC _{: 1} -C _A ) alkylene (etherocyclic); jskupi rt y,

-CC ₃ -C ₆ ) alkylene acyl groups, alternatively R ⁵³ and R ⁵ * may form a three to eight membered ring, optionally unsaturated, containing 1 to 3 heteroatoms selected from oxygen, -NR ' ⁵ ', --SCO) p or an optionally acyl group, optionally fused to an aryl ring;

R ^x and R ® may be independently selected from hydrogen, R ¹ , or may form a three to seven membered substituted ring with 0 to 3 unsaturated bonds in which the substituent is selected from:

hydrogen, C 1 -C 5 -alkyl, hydroxy, halo, alkoxy; n y, and m i n o s k u p. n y, m a n i a m e n i s p p i n, d i a 1 k y n a p i n s, p a n a p n a p n, p a n p, p a p n p, p a p n p a p n e p e n p e n p e n p e n p e n p e n p e n p;

if applicable -0--. • SCO), NR ' with any k o n d e n c o o n a s u b s t t o t o aryl circle, in which s u b s t i t u e n t o o o. hydrogen atom. alkyl groups s 1 up to 5 atoms

carbon, hydroxy, halo, alkoxy, amino, monoalkylamino, dialkylamino, and alkyl, 11 and 11, 11 and 1 .....

s, p a r b o x y s, p a r b o x a m 1 d o s p p a n y a 1 e b o a r y o s p i n y;

R ⁵ * represents a hydrogen atom, an alkyl group, a cycloalkyl five or optionally a 6-membered ring, nitrogen, oxygen or SCO) | optionally containing 1 gr sub Nou, - 0- C C _L - C _ώ) alkyl and 1 1 1 ovouskup Nou, one or two atoms of the monosubstituted characterized Hydroxy - ..... (J 3 ... _C y p, p _and j (1) VOU, NHR ¹ ° and 1 earyaryl;

R ¹⁰ represents an atom group;

1 1 a b e a n e a n e a n e a n e a n e a n e 1

R ¹¹ represents a group of up to 10 carbon atoms which includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected from:

and aryloxy groups (e.g. phenoxy groups) such as phenoxy groups;

(E.g., atamido and benzamido), aryl amine, guanidino, imidazolyl, indolyl, mercapto, alkylthio, aralkylthio (e.g. phenyltosoyl), carboxy, carboxy - boxamidoskurin, carboa 1 coxy groups and 1 ebosu 1 f ó namidosku ρ iny,

- CC _x - C z).

-C (C 1 -C 4) -alkyl-C (C 0 -C 10) alkylenearyl groups,

-CCχ-C _e! ) -alkylenibiaryl groups, substituted with ... j - CC χ - C _{ε 3} ) - alkynyl groups, in which the substituent is selected from.

hydrogen, halo, hydroxy, alkoxy, aryl (C (e.g., adenoxy)), aminosupines, alkylamino groups, acylamino groups (e.g. acetylamino and benzamido), aryl and amine groups, aryl and amine groups d 1 noso, imidazo 1 y 1 o, 1 n to 1 y 1 o, mercapto group i. n y, a 1 k y 11 i s s p i n i, a y s i n i n i n i n d i n i n e n i n e n i n e s, box boxes complete, box boxainidos upins, carabino a 1 k o x y s e s

^R1a represents a hydrogen atom, -SO _and -Cx-C11, - an alkyl group,

-SO-C _and -Cx -alkylénar -yl; _and wherein the aryl radical is substituted, _{-aryl, and} -S0 de vampire -S0 _ffi --substituovanú heteroaryl, -CCR * ⁵ *, -CO t Either, -CCb..Bn or an -alkylenaryl group in which the aryl radical is substituted, the substituent selected from ·.

a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxy group, a hydrophenyl group, and 1 alkoxy groups, amino groups, monoalkylamino groups, dialkylamino groups, acylamino groups, thio groups, thioalkyl groups; , carboxy group, carboxamido group 1 nya 1 eboaryl group;

R ^ia is selected from Z:

a hydrogen atom, an aryl group,

C C C n) -a1k y1ovej en UPIN, _{aryl-C, L} j --alkylové group,

CC _{; 3} - C ₍ x) - Cyclic and cycloalkyl groups,

C _{Cg-C l} o) alkylcarbonyloxyalkyl,

(C ₃ -C 10) -alkoxycarbonyloxyalkyl,

CC _S -C _{: I} , _O ) -alkoxycarbonyl ,.

_<C -Cxo) cycloalkylcarbonyloxyalkyl,

_{CC-C: l} <;>) --cykloalkoxykar bonyloxyalkylove j groups,

C Cg-Cj. a) cycloalkoxycarbonyl, aryl 1 oxykarborty ovejskup ynyl 1, aryl 1 oxy alkyloxycarbonyl C 1 (I '. x - C, ί, and one alkyl ovejskupiny 1) - ·, aryl of 1 or oxy rbon 1 _x CC - C and _ώ 1 keel e .jskupin) -,

(C8-C8a) -alkoxyalkyloxy-1-aronyloxyalkylalkyl,

5 5 - C 1 - C g a 1 k y 1) -1, 3 - d 1 o x a e y k 1 o p e n t - n - 2 - o n - y 13 mylyl group size,

C 5-aryl-l, 3-dioxa-cyclopenten-2-one-yl) methyl, (R ^{17) R: a, X)} N-CCX C j. oa '1 ky 1 up sk)) -) -,

--CH R ^'3) 0 DEG C. = 0) ^R3

-CH CR ^{1: s} } CC C = O) OR 1 ^{S 3} or

(3) a hydrogen atom or a linear alkyl group having 1 to 4 carbon atoms;

and choose Z: a hydrogen atom, alkyl group having 1 to 8 carbon atoms or c: y k 1 o and 1 k y 1 o e s s u u s s 3 to 8 carbon atoms, while

said alkyl or cycloalkyl group is substituted with 1 to 2 groups independently selected from:

(C1-C6) alkyl group,

C C s - C e>) c y k 1 o and 1 k y 1 o e ... s s u u. n y,

CC j. C _{: 3} ) and 1 alkoxy, an aryl group substituted with 0 to 2 groups independently selected from.

a halogen atom, a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, -S (C ₁ -C 6). ₅ alkyl groups), -S (= O) CC ₃ . -G _{with an} alkyl group), a hydroxy group, - (CC = O) NCR ¹ '' CR ^{: a} )

-SC1-.CC j. -Craalkylove NC j • ^{R: L} ^) ^{(R: lx} '), and aryl is selected from 1 to 3 and w = 1 to 2v + -1) substituted with 0-2 groups of) -CO ^ R ^1, where, independently, halogen, phenyl, alkyl of 1 to G alkyl, C 1 -C G alkyl, nitro, s _{(C: L-C} j _{with an} alkyl group), -S-C = 0) _{CC: l} . ~ J C _{with an} alkyl group), -S0 _{R (C: L p} C ~ alkyl), hydroxy, -N (R ^1x) CR ^1),

** ..... CCKaR ^17, -CC = O) NCR ^IX) (R ¹⁷⁾ or C ~ _W F _W where v = 1 to 3 and w = 1 to 2v + 1);

R ¹ ' ⁵ is selected from:

C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, wherein said alkyl or cycloalkyl group ... is substituted with 1 to 2 groups independently selected from:

C1-C4alkyl; cycloalkyl; (C až-C skupiny), (C až-C alko alko) alkoxy, (C až-Cry a) aryl group, but (c) C:-C::;

a halogen atom, a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 atoms. carbon, nitro.

- SCC j. (C ₅ and 1 keel groups), hydroxy groups, -CX = (O) (IC ^(1x ) CR ^(L groups), -SC- (j) C 1 -C 4 alkylo-SO 2 _and CC 1; . -C _s alk y love (slins),

-NCR 1 (CR 2 ^{X 4} ), 4H ₂ R ¹⁷ or -C _V F _W , wherein v is 1 to 3 and w is 1 to 2 (1 + 1); aryl substituted with 0-2 groups independently selected from Z:

halogen, phenyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro oskupiny, _{-S-C t.-C s} alkyl), -S-C = 0) CC _x -C alkyl C 6 -C 6 groups. -C. _5- alkyl groups), hydroxyoxy.

NCR ¹¹⁰ CR

'),

-COaR ³ v means

CC-O) NC R ¹ -CR ¹ 'O or -C _V F _W , up to 3 aw means 1 to C 2 + 1;

in which

R ^{@ 1} is C1 -C4 alkyl, carbon, benzyl or phenyl.

r: iz- _and pi / a _are independently selected from:

a hydrogen atom, a C 1 -C 10 alkyl group, a C 2 -C 8 alkenyl group, a C 4 -C 11 cycloalkylalkyl group and a C 1 -C 6 arylalkyl radical;

combinations of A, B and D and / or variables are permissible only if these combinations provide stable compounds (as defined herein);

And may be omitted or may be a C IR * ")", -, ^& -OCCHR) m -NR * · CHR) ,,, -, - S (0) p ^(CHR) m or It may be selected from an alkyl group having 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl or -0-CC _{x ώ)} alkylaryl;

B may be a bond or may be selected from s

-NH-, -NR ¹¹ -, -NR ^11a -, -O-, -S (O) p- (C 1 -C 6) -alkyl-H N-CC 1 -C 6 -alkyl, - (C 1 -C 6) alkyl-NR ¹¹ - (C,. _R-C) -alkyl,,

alkyl

- O - (C 3 - _R 0) -alkyl ovejskup ny 1, - S - (C _x - C _ώ) group, the group -NHCO-, HNCONH-, groups, groups.

C _R C -NH-aryl,

-0-CC and _ώ) -alkyl-C-j ar yl group, - (C _x -0 _ώ) -alkyl-S-aryl

0-3.-C 0.5) alkyl, -CO-C _{X R)} -alkenyl-C _{x R} 0) j -alkynyl group, -CONH-, -CONR ¹¹ NR ¹¹ 00- - 000-, -000-, -000 ^ -, -R ¹⁰ NCONR ^1χ -,

-OCONR ¹¹ -, -NR ¹¹ 000-, -HNSO 2 _and -, -SO _and NH-, aryl cycloalkyl and 1'1. halo groups, heterocycle and alkyl groups;

-F? ¹¹ NCSNR ¹¹ -, -HNCSNI-1, peptide bond;

--OCSNR ¹¹ -NR ¹¹ CSO-HNCNNH-

D may be absent or may be an alkyl group with .1. up to 10 carbon atoms, optionally containing oxygen, sulfur or NR * ', which includes a branched cyclic and unsaturated alkyl group and an arylalkyl group; and

C C C _R) -alkylaryl group ·

P can be 0, 1 or 2;

m is an integer from 0 to 5;

n is an integer from 1 to 5;

W represents -O-, -SCO-p- or -NR ¹⁰ -;

is selected. FROM :

-CONR ^XO -, -NH ^xo CO-, -SOaNR ^xo -, -NR ^xo SOs-, a peptide bond of a five-membered heterocyclic ring which is saturated, unsaturated or partially saturated and contains 1 to 4 heteroatoms rolled from a nitrogen atom , oxygen or sulfur, provided that the macrocycle, represented by the formula (1) by -ABDC-CR ^s ) CR ³ ) -Y-CCR ¹ -C ¹ -C ⁴ CR ⁴ ), is linked by a minimum of 11 and a maximum of 22 atoms.

Cb3 Preferred compounds of the invention are those of formula (II)

General formula II

or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in which:

X is selected from CHs »,

NH, sulfur, and oxygen;

U, Y, R ¹ , R 1 R ²⁵ , R ⁴ , R ^s , R ⁶ , R ^x , R ' ^a , R' *, R ^1C ', R', R ¹³³ , R ¹ - *, R ^{: IS} , * ¹ R ^5, R ^17, R ^ ¹ 'and p, m, n. A, as defined in formula (1) above, provided that the compound of formula (I) is stable. a compound; and

R ' ¹ ', R ^11a , 13, D and W are all; generally it Formula 1 is provided, the macrocycle, in formula I, by -AB - DCC ^RA) CR ³⁾ -Y-CCR ¹⁾ -XC (U) * CR) is linked to at least 11 and most : 22 atoms.

E 61 More preferred compounds of the invention are those of formula (I)

General formula

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

U is selected from:

--CONHOH, -COsäH, C <0) NHOR ^{1 52} and the current derivative precursor;

R ¹ is selected from hydrogen,

- (C o - (1 _ώ) and one alkyl-SCO) p - _{(C l} - C _R) al ky ny 1 ovejskup 1,

-CC C, - 0 _ώ) alk y 1 -O- (C _t - C _ώ) and one alkyl ove 1: 1 .jskup ny,

- <Co-Cl,) alkyl-SCO) p C _O C _R> alkyl-aryl,

-0 _{o C)} alkyl-O-CCO-Cz) alkyl-aryl, alkyl of 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from

at ó muvod i. ka, Γ a and 1 ogene groups, hydroxy groups, alkoxy groups, aryloxy groups (e.g., C1 and C1 phenoxy groups), ammonium ions: amino, monoalkylamino groups, dialkyl amino groups, aoyls 1 am 1 noskupi rt y (oaprik 1 a cl aoetami cl oskupinya lo e rt z z cl group), ary 1 am 1 noskupky, guan 1 dinosku μ> 1 ny, M - met 1 im i cl azo 1 y I o o group, J. midazo 1 y 1. ny, in cl o 1 y 1, mercapto, and 1 in 11 µs:> y, ary]. 11 groups (eg 1 adphenes 111 axes full), carboxyl group μ:> 1 ny, car boxamic J group, carbo group 11 <oxy group 1 nya 1 ebosu I phon am ido group, (C o ~ C e,) and 1 Caryenary groups, shock ((o-CE)) and caryenary groups, in which the aryl group is higher, (C _O -C _B ) aryl- (C ₁ -C 6) alkylenearyl, (C 1 -C 6) and 11-ynylaryl,

CC _O C _~) alkyl-SC9) p (C _o -C _e) alkyl-aryl, (C o - C es) and I s 1 - SC 0) μ:> - _(θ CC) and 1 cyanenyl groups in which the aryl radical is substituted,

- <C i -C b |.) Alkylénar yl <Co-C _B) alkylenearyl, C SC-0) p C _a -C _a) alkyl],

C Co-Ce) aľ.Lkyl SC-0) p C _a -C _a) alkylénbiarylovej group,

--C-Ca) alkyl-O-C _{e o} CC) alkylaryl] group,

- (C o - C 3) and 1 - S (O) p - · C _o - C _e ) 1. is a group in which the aryl radical is substituted,

-CC and -CL ') alkylénar l- yl (C _o C _EI) alkylenearyl-C 0 -C _.Co-C) alkyl],

C _o -C,) alkyl-O-C C-C _{of a)} alkylénbiarylove j groups,

- (C ₀ -C 18) alkyl-OC (C ₀ -C _B ) alkylene aryl, in which the aryl radical is substituted, in which the substituent is selected from:

a hydrogen atom, a C 1 -C 5 alkyl group, a hydroxy group, a halogen atom, an alkoxy ...

s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. a m no s k p p n y, a y y a m p n p p y, t i o p p p. n y, 11 o a 1 k y 1 sk ups, k ar boxes sk ups, k ar boamlclosk ups or a y y ll. o v e j s k u p i n y?

is selected from H, -CO ^_and R, -CONR ^{R S} R, -CONR C OR ^55), a first one alkyl ove ... iskup different, and 1ky II. ary 1 ovejs l <up 1 ny, and 1. heteroaryl groups, and heterocyclic groups. an halo group which is substituted with one or more substituents selected from hydrogen, halo, hydroxy, alkoxy, aryl 1-oxy. amino (e.g., 1 adphenoxy), amino: i. mono, 1-amino-amino, d-1-amino-amino .....

and cylamine oscines (C (a) (such as three plates and benzamido), arylamino, guanidino, N - methylmethylamine. o e s s p i n y, im i d o z 1 y 1 o s s p 1 n y, i. n d o 1 y 1 o e s p e n e, p e n e p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p e n p

R ³ and R ¹¹ are hydrogen?

R ' ^{: S} is selected from:

- C CHR ¹ Y) ,, - R ⁵ ', -CO R R ³⁾ n-W-CC R ⁷ R ^e') n R ⁵ ', -CO R ⁷ R ⁶³⁾ _IT R ^<3> ,

- CCR ⁷ R ^s ) Tn - ary ll. - CCR ⁷ R ^s ) m - (l: CM R ⁷ R,

- CCR ⁷ R ^θ ) _Tn - · Substituents of the fatty heteroaryl group,

- CCR R ^7), _N - 1 y k substituovanejheteroc ickejskupioy, characterized vktor the chloro substituent is selected from = H, _{-CO, L} C _p) alkyl group, a hydroxy l <UPIN ha II. og é nskup .1. ny, and 1 alkoxy, amino groups, mono-1-amine groups, d 1 and 3-cyano groups, acyl-1 and min-group, thio-group, t: i. oa 1 ky ll. skup i. carboxy, carboxamido or aryl groups?

R * ’is selected from:

a hydrogen atom, an alkyl group,

- C-C 0 _ώ) alk y j en 3.énary love to clamp,

- CC _{: L} - C _ώ ja 1 ky 3. é nheteroary 3. ovejskup 1 riy,

- C (l i - C d ;,) and 11 <y l e h e t e r o c y k i i c k e j s k u p. n y,

- CC j. - C 1-6 alkyl groups, alternatively R ⁵ and R ⁵ may form a three to eight membered ring, optionally unsaturated, containing up to 3 heteroatoms selected from oxygen, -MR '', SCO) p or any aryl group, e.g. padondcondensation: aryan aryl ring;

R ^x and R ^B can be independently selected from:

a hydrogen atom, R ¹ , or may form a three to seven membered substituted ring with 0 to 3 unsaturated bonds in which the substituent is selected from:

a hydrogen atom, a (C 1 -C 5) alkyl group, a hydrogen atom, a hydrogen atom, a hydrogen atom, an alkane, an alkenyl, anthiazolyl, anthiazolyl, anthiazolyl, anthiazolyl, anthiazolyl, anthiazolyl, thiazolyl, thiazolyl, thiazolyl, and thiazolyl. n y, a c y 1 and i n o s k u i. n y, i. o s k u p i n y, i. o a 1. k y 1 - s u p i n y, kar b o x y s k p p i r y, k a r b o a m i d o s p p i n y a 1. e b o ary 1 o s p p i n y;

optionally containing -O- »-SCO 1, -NR ⁶ , with optional condensation to a substituted aryl ring, wherein the substituent is selected from:

hydrogen, C 1 -C 5 alkyl. ka, hydroxy groups, halo groups, and 1 alkoxy groups, aminosupines, monoalkylamino groups, dialkylamino groups, acylamino groups, thio groups, thioalkyl groups, carboxy groups, ka rt) oxamido or aryl groups;

R * represents a hydrogen atom, an alkyl group, a five-membered or six-membered cycloalkyl group, optionally containing one to two nitrogen, oxygen or SCO 1 p atoms, optionally substituted with hydroxy, -OC 1 -C 1 -C 6 alkyl, -O-acylenealkyl NHR 10 and 1 eboaryl;

^R, 'represents a hydrogen atom or an optionally substituted alkyl group;

R ¹¹ is H, alkyl having 1 to 6 carbon, atoms, "which include branched, cyclic and unsaturated alkyl buy up: · in yl, substituted alkyl wherein the substituent is selected zsat delta muvod s lv, h 1 og s n, hydroxy, and 1 alkoxy; ny, ary 1. oxy group:> i. ny C for ± k 1 adphenoxy. ny), am in oskup i. currency, distance 1 and min group, aoy 1 and mi. noskup i. (e.g., acetamido and benzamido), arylamino, guanide. noskup i. ny, im i. dazo 1 y 1 group, i. ndo 1 y 3. ovejgroups, mercaptogroups, lower than 'J. thioskupiny, ary ľl. t i. groupings (eg 1 of 11th group), carbox groups, carboxam i. doskup i. ny, carboa 11 <oxy group i. nya 1 ebosu 1 fo n am idoskup i. ny,

-C ( ₁ -C 6) -alkylenaryl, subst. tuovaný ú - CC _{: 1} - C _θ ) - a 1 ky 1 éary r. wherein the substituent is selected from hydrogen, halo, hydroxy, alkoxy or the like. ary 1 oxyxy i. (C (e.g. 1 ac (phenoxy)), am i. noskup i. ny, d i. and 1 cy 1 and i. noskup i. ny, aoy 1 am i. no skup i. C (e.g. acetamido and benzamido), aryl III. and inoskup i. ny,. guanidinokup i. ny, im idazo 1 y 1 of the group, i. ndo 1 y I ovejgroup i. ny, mercapto groups ri y, n i. ž eja 1 ky 11 ioskup i. ny, ary 11 i. oskup i. ny C eg k adrenes 3. ti. carboxy, carbox, and the like. doskupi ri y, k ar boalkoxy sk upiny or sulfonamidid upiny,

rxxa. _{znan) black,} and-H, -S0 _a -C-C, alkyl group,

- S Ct _s - C x - C _d:> - and 3. I <y 3. o ú - substi. 3. The credit group,

- S 0-> - aryl-s U is 3, - S 0 _R - heteroaryl substituted with D s 1 U is - COR ^'5', -C 0-naphth-l3u, C0-.Bn ~, where R choose Z:

a hydrogen atom, a (C 1 -C 5) alkyl group, a hydroxy group and a hydrogen atom; and (1) a hydroxy group. n y, and m i. n o s k u p i. n y, m o n o a 1 k y 3. a m i n o s k u p. n y, d i a 1 k y 1 a m in o s k u p. n y, and c :: y 3. a m i. n o s k u p i. n y, t i. 3. k y 1 s k p i n y, caraboxy s k p p i y, k a r b o x a m i. d o s k u p i. n y a 1 e b o a r y 3. n y;

- Z is selected:

a hydrogen atom,

CC x-C x _t; ,) - a 1 ky 1: 'j groups, ary 1C (- C _ώ ) - a 1 ky 1 ov e. j groups,

C C: s - C χ χ) - c y k 1 o and 1 k y 1 o ... i s k u p »i n y,

C C s - C χ o) - a 1 k y 1 k a r b o n y 1 o x y and 1 k y 1 o e ... i s p u n y,

C C 35 - C χ a 1 1 x y a r r r o <<<<<<<<<<

C (C 8 -C 18) -cycloalkylcarbonyloxyalkyl,

_CC -Cχ a) cycloalkoxycarbonyloxyalkyl, _CC --C χ <;,) - j cykloalkoxykar alkylcarbonyl group, an aryloxycarbonyl group, aryloxycarbonyl bonyloxyC Cx alkyl group j) -, arylkarbonyloxyC C _x -C? Alkyl) -,

(C8-C8-3) -alkoxyalkylcarbonyloxyalkyl,

15-CC (C1-C6alkyl) -1,3-dioxaoyl-penten-2-one-yl] -methyl group,

C 5-aryl-l, 3-dioxa-cyclopenten-2-one-yl) methyl, ¹ CR ^) C R'Cx -C _x,:> The alkyl group j) -,

-CHC R ¹²⁵ ) OCC = O) R ¹

-Cl-I (R ¹³ ) OCC = O) OR ^{x 5} or

In which

R ¹³ represents a hydrogen atom or a linear alkyl group having 1 to 4 carbon atoms;

R ^{1 '1'} is selected jr hydrogen.

alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms, said alkyl or cycloalkyl group being substituted with 1 to 2 groups independently selected from.

(C i - C _4.) Alkyl and 1 1 ovejskupiny,

C C s - C e)) c y k 1 o and 1 k y 1 o ...

(C1- _C5 ) and 1 alkoxy, aryl substituted with 0-2 groups.

independently selected from t halo, phenyl, C ... 1 -C 6 alkyl, C p: 1 to 6 carbon atoms, nitro, -S-C Csalkylovej group), -SO-O) _x CC -CsalkyΙον e jskupiny ...), - s _R 0 C C C 1 alkyl and _with one ove .jskupiny), hydroxyl ny 1, - MCR ¹⁾ CR ^{1 'a), l)} and C _W F _W,

CC _S .R '

--C (O) NCR (O) R is 1 to 3 and w is 1 to 2 (+ 1), an aryl group substituted with 0 to 2 groups independently selected from.

halogen, phenyl, alkyl of 1 to 8 carbon atoms, C 1 -C G alkyl, nitro, _{-S-C l -C?} ... jskupiny _with alkyl), - SC = 0) and CC - C alkyl of 1 1 jskupiny ove ...), - with _a CC 0 _x - C 1 alkyl and _with one ovejskup ynyl), hydroxy, - NCR ^ ^Ί) CR '^ ^7).

-CO-R ¹⁷ '**, -CC = O) NCR ³ · ⁷ ') CR ^{3 Χ, ΪΛ} ) or -C _V F _W , wherein v is 1 to 3 and w is 1 to C 2 -h);

R 18 _is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, wherein said alkyl or cycloalkyl group is substituted with 1 to 2 groups independently selected from:

alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 5 carbon atoms, aryl groups substituted with 0 to 2 groups.

regardless of t Zvalený halo, feriylovej, alkyl of 1 to (j carbon atoms, alkoxy of 1 to 6 carbon atoms, nitroskuplny, -SCC and _the C lo alk y j of sl <UPIN), -SC = 0) CC x _p-C alk yl Ιον ejskupiny), -S 0.-. CC _t - 1, and _C 1 alkyl ovejskupiny), hydroxy, -NHC R ^x) CR ^), CI.UR '1 ^Z

-C (O) MCR ( ^1X , CR ^{: 1: Z} ) or C (1) wherein v is 1 to 3 and w is 1 to (2v + 1);

aryl substituted by C 1 to 2 groups independently selected from:

a halogen atom, a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, nitro groups, -SC CC _{with an} alkyl group;

-SC = O) ([C 1 -C 6 alkyl), - Stf. _; . (CC ( ₅ groups), hydroxy, - NCR ^{1 x} ) CR ^{: 1} ,

-CO-O) ^{NCR: I x) and CR, a)} aleiio C _W F _W wherein ej group), alkyl

-C ¹ R ^{1 x} ®, v is 1 to 3 and w is 1 to 2 (+ 1);

R ^: represents an alkyl group of up to 4 carbon atoms, a benzyl group or a phenyl group,

R ¹⁷ and R ¹⁴ are independently selected from:

a hydrogen atom, a C 1 -C 10 alkyl group, a C 2 -C 6 alkenyl group, a C 4 -C 6 cycloalkylalkyl group and a C 1 -C 6 arylalkyl radical;

combinations of A, B and D and / or variables are permissible only if these combinations provide stable compounds (as defined herein);

And may be omitted or denotes --C CHR ') ™ -, -O ^(CHR) t ~,; - NR * C * C IR') -SC 0) p, ^(CHR) m-, or may be selected from alkyl of 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl and EBO 1 - CC i - C _ώ) and 1 s 1 s 1 account aryl group; .

B may be a bond or may be selected from $

-NH-, -NR ¹¹ -, -NR ¹¹ · * -, -0-, SCOT) CCx p-CA) ~ alkyl-HN-C-CCx <&) -alkyl, -C CX-ca) alkyl-NR ¹¹ - C-C _and CX) to clamp --alkylovej en, C _x -C-NH-aryl, -0 - (C _x -C &) - alkyl, C 6 _x -6 _ώ ) -alkyl-O-aryl, -S-C ~ CC & _x) - alkyl, -CO well. _Ώ -6) -alkyl-S-aryl, - CC i - C _R) - and 1 s 1 ove .jskupiny, - CC _x -C ₆₎ alkenyl-al ovejskupiny 1, -CO-C _{& x)} - alkynyl, -C0NH-, -CONR ^11, -NHC0-, -NR 60- ^11, -C1C0-, -600-, -0C0 ₂ -, R ¹¹ n CONR ¹ HNC0NH-,

-OCONR ~ ^11, -NR ¹¹ 600-, -HNSO _p .-, -SO _and -NH-, aryl, cycloalkyl o 1 1 1 ovejskupiny alkyl, heterocycloalkyl o 1 1 1 ovejskupiny alkyl,

-R ¹¹ N 6SNR ¹ -HNCSNH, -OCSNR ¹¹ -, -NR ^1X CSO-, -HNCNNH-, and peptide bonds;

D can be absent or denotes alkyl having 1 to 6 C atoms which include branched cyclic Aneny characterized the U and one alkyl group, and D 1 s 1 eho CC _x C 's) - s alkylene aryl group accounts;

P can be 0, 1 or 2;

m is an integer from 0 to 3;

n is an integer from 1 to 4;

W represents -O-, -SCO-p- or -NR ¹⁰ -;

Y is selected from:

-C0NR ¹⁰ -, -NH ^lo C0-, _and -S0 NR ¹⁰ -, -NR ¹⁰ SO --.-, the peptide bond on a five-membered heterocyclic ring which is saturated, unsaturated or partially: unsaturated containing 1 to 4 heteroatoms , selected from nitrogen, oxygen or sulfur, provided that the macrocycle, represented by the formula (1) by -ABDCC R ³² ) CR ³ ) -Y-CC R ¹ -C -U 1 CR ¹ ) -, is interconnected by at least 11 and up to 22 atoms.

Only compounds that form stable compounds are claimed for: compounds of formula I.

More preferred compounds of the invention are those of the general formula. C11)

General formula:

or a pharmaceutically acceptable salt or prodrug thereof, in which:

X is selected from CH 2, IMH, sulfur, and oxygen;

U is selected from: -CO II, cos-R ^132, and common prodrug derivatives accounts active substance;

Y, R ^{@ 1} , R ^{@ 32} , R @ ³ , R @. R ³ , R ⁶ , R ⁷ , R ®, R * ⁷ , R ¹⁰ , R ¹¹ , R ³¹³² , R ¹³ , R ¹ ', R ³¹ · ³ , R ^{1 ώ} , R ³¹³⁷ , R ³¹³⁷ "* _a | _Π>ι> A, B, D and W are as defined above for formula I, provided that: the compound of formula I is stable, provided that the macrocycle, expressed in formula I, by - ABDC-CRDC R ³ ) -Y-CCR ¹ ) -X-CCU 1 CR ⁴ ) -, is interconnected by a minimum of 11 and a maximum of 22 atoms.

C 83 More preferred compounds of the invention are those of formula CD

General formula

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

U is selected from:

-CONHOH, -CO-.H, -CC O) NHOR a current ^LSA prodrug derivatives;

is selected from a hydrogen atom,

-C 0 -C 0 -alkyl-SO 3 -PC 1 _L -CDalkyl,

- CC o - 0 _ώ ) and 1 cy 1 - O - CC χ - CD and 1 cy 1,

-0-CC _{of ώ)} alk yl-SC 0) p C _o -C ₆₎ alk en ylénarylovej to clamp,

-C 0 -C 0 alkyl-O-C 0 -C 0 alkylene aryl, a C 1 -C 20 alkyl group which includes branched, cyclic and unsaturated alkyl groups, of a substituted alkyl group in which the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy (C, for example, phenoxy), amino, mono-1-amino groups, dia. 1-amino groups, acylamino laminos (e.g., acetylaminocups, benzamide) and benzamide arylamino groups, guanidino groups, N-methyl 11-piperazin-1-yl groups. n y, im i d o z 1 y 1 o e s s p i n y, i n d o 1 y l l. o v e j s k u p i. n y, m e r k a p t o s p u n y, a 1 k y 11 i s p u p i. n y, a n i n i n i n i n n e n i n n e n d i n n e n n e n n n e n n n n n n n n n n n n n n n n n n n n n n n s u 1 f ó n a m i d o s u u p i n y,

- C C © - C e) a 1 k y 1 n ary 1. o e e s s p. n y,

C-CC _{of a)} alkyl-aryl, wherein the aryl moiety is substituted by Y,

-C (C 0 -C 8) aryl-C (1 ' _x -CS 3) alkylenearyl groups,

- C (C-C) a 1-ynyl bryl group,

- <C o - C s) alkyl and 1-SCOT 1) p - CC _o - _θ C) alkyl, and one aryl 1 Step 1 ovejskupiny,

- <C _o -CB) alkyl-SCO) p-CC _of -CB) alkyl-aryl, wherein the aryl moiety is substituted,

-CC _χ-C4) alkylenearyl, C-C _of C ₍₃₎ -C alkylenearyl SC O) p C _a -C _s) alkyl "],

Co-C-C b) SCO-a1k Y1) p C _a -C _s) a1k en y1énbiary1ovej to clamp,

-CO-C _o) alkyl-O-C-CC _{of a)} alkyl-aryl,

-CO-C _o) alkyl-SC H) p C _o -CB) alkyl-aryl, wherein the aryl moiety is substituted,

(C1-O5) alkylenearyl-CC. _o -CB) alkylenearyl, C-0-C-CC _{of a)} alkyl],

Cq-C a -C b) alkyl, C-O-C _<:, -CB) alkyléribiarylove j groups,

-CCo-Cb) alkyl-O-CC _o -Cb) alkylenearyl in which the aryl moiety is substituted, in which the substituent is selected from:

a hydrogen atom, a (C1-b) alkyl group, a hydroxy group, a halogen group, an alkoxy group, an amino group, a mono-1-amino group, a long-1-amino group, an acylamino group, a thio group, a thioalkyl group β1, carboxy, carboam 1, or 1 or aryl;

the network selected from an atom and an alkyl group and an alkyl group, hydrogen, -CO ³ R ⁵³ , aryl aryl, and 1 heterocyclic

-CONR (R ⁵⁾ , -CONR (R OR ⁵ ), a group, an alkyl group, an aryl group, a heteroaryl, an aromatic group, or a heteroaryl. an alkyl group which is substituted with one or more substituents selected from the group consisting of: from;

hydrogen atom, hydroxy groups, hydroxy groups, aryloxy groups:> 1 ny (eg to 1 adphenoxy groups), amine groups, mono groups 1 and 1 groups , diastyl 1 amino groups, aey 1 am 1 groups, e.g. C and adetamido groups. n y a b e n z a m 1 d o s p u r t y), a r y 1 a m :: i .. n o s p u n y, g u and n: i. d i n o s k pines, N - meters 1 i. m i d o z 1 y 1 o e e s s p i n i, i. m i d a z o y y o o e s p i. mercaptogroup, mercaptogroup 1, lower 11 groups, ary 111 of group C (eg 1 adphenes 11, group), box boxes, suamphonamidos upiny, karboxam 1 doskupinya 1. e I :: jokarboa 1 coxy group;

^R: and R ¹ 'are H;

R ⁵ is selected from:

C CHR Y) _n-R ^<5 ', -CO R ⁷ R ^{s: l)} ,, - N-CC R ^X R ⁽³⁾ ril - R ^<5>, -CO R ^x R ^e') m ^,? .

- CCR 'R ^θ ) _rT , - aryl groups,

- R ^x ® CCR) _m - 1 ovejskup heteroaryl ins,

CCRR ⁶³ ) _TT , - heteroeyl J groups;

R ⁵ 'is selected zs a hydrogen atom, an alkyl group -CO x C _ώ) a1k y1énarylove, j en clamps the -CO x C _R) and a 1 s 1 s nheteroary ovejs 1 - x C and CC) and 1 s 1 s n liet eroeyk ical - · CC x - C _ώ ) and 1 cy cle y y o o y groups. an eight-membered ring, up to 3 beteroatoms, selected from 1 or 1 of the ring group;

alternatively, R ^S and R ⁶ may form an optionally unsaturated containing from 1 O, NR ^R, SCOT) p, and Bishop padnoukondenz s s s 1 characterized oiounaary

R ^x and R® can independently of zvoliť- * H, ^R1, or form a three to seven membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from the ·.

hydrogen, C 1 -C 5 -alkyl, hydroxy, halo, and 1-oxy, amino, mono-1-amine, di-1-amino, acy 1 am, tin, t i. o a 1 k y 1 - s u p i n y, carb o x y s u p i n y, k a r b o m i n o s p i r i y a 1 e b n aryl group;

optionally containing -O-, -SCO 1, -NR with optional condensation to a substituted aryl ring, in which the substituent is selected from hydrogen, C 1 -C 5 alkyl, hydroxy, hydroxy 1. og ó oskupioy, and 1 alkoxy groups, aminosupines, monoalkylamines, acyl groups, ac groups, groups, 11 groups and 1 groups, curry: :) n, 1-carboxy or aryl;

R ' ⁷ represents a hydrogen atom, an alkyl group, a cycloalkyl group of five or a six-membered ring, optionally containing one to two nitrogen, oxygen or SCO 11 atoms, optionally substituted by hydroxy, -O-C 1 -C ₆ alkyl, -O an acyl-alkyl group, an MHR of ¹ ° and an aryl or aryl group;

R X O _A is H or optionally substituted alkyl;

represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, which includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected from hydrogen, halogen, hydroxy, alkoxy of the aryloxy group C e.g. k 1 adfen oxy grp. n y), aminosupplines, longyllamines, aoylamino (C, for example, acetamido and benzamido), and y and min. n y, g a n i d i n i n i n i n i d i z o y y o n o n y, n o n y y o n s, m e r i o n i n o n 1, o n o l 1.11 o s cos p 1 n y, aryl

phenylethicos), aroxycouss, k arboxamidoscups, k a r b o a 11 <oxy s k p i n y a 1 e b o s 1 phon c m i d o groups,

- CC j. - C) - C 1 - C 1 -aryl group, subs 111 - CC _{: L} - C ₈ ) - C 1 -tyl-ryl group, as defined in Section 11 of the.

and b < l, a, h and lg g with l < p i r, y y y y x y with l < p i n y, and 11 < x y-s l < i. n y, a y y o x y s p 1 n y C n a p y. k 1 a d f e n o x y s k p i riy), a τη i n o groups, d 1 and 1 k y 1 a m i n o s k u piny, a e y 1 a nt i n o s k u p 1 n y

(E.g., acetamido and benzamido), aryl 1 amine, guanidino, indidazolyl, indole 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 3, 2, 3, 2, 3 (a) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) (1) groups, ary (1) (1 groups), carboxy groups, carboxamido groups;

^{R:, la} is H, -SO _{p -Cl-C6} alkyl group,

-SO _and-C-C and _A, -all <substl yl-halosubstituted aryl,

- S 0 _a - aryl group, - S 0 ₂ - sub-substituted heberoaryl group, -COR ^<5> , -Cl 3 -t-Bu, -CO _with Bn, in which the substituent is selected, from:

a hydrogen atom, an alkyl group having 1 to 5 carbon atoms; cyano, hydroxy, monoalkylamino, monoalkylamino, alkylalkylamino, thioxy, carboxy, thio, carboxy, thio, carboxy, thio, carboxamido, carboxy, thio, carboxamido, carboxy, thio, carboxamido, carboxy, thio, carboxamido, carboxy, thio, carboxamido, carboxy, thio, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxylic acid;

rxa _is selected _from ( _Z: hydrogen, aryl, (C x - C xo) - and C 1 -C 3, ary 1 C _3. - C _A ) - C 1 -,

CC _{: 3} - C xx) - Cycloalkyloxy, (C - C xo) - and 1 - C - oxyalkyloxy,

(C ₃ -C 10) -alkoxycarbonyloxyalkyl, (C 2 -C 10) -alkoxycarbonyl,

CCs - C xocycloalkyloxycarbonyloxy, (Cs - C _{χ ο} ) - Cycloalkyloxycarbony II. Ó xya 11 <y 1 ove .js l <up: iny,

_CC - C io> - cyclohexane 1 o 1 alkoxycarbonyl 1 ovejskupiny, ar yloxycarbonyl en UPIN, and the aryl oxycarbonyl 1 oxy _{CC: L} - C _ώ a 1 s 1 of Vej gr 1 ny) -, aryl 1 carbenes 1 oxy CC ₃ . - C _£ , and 1 ky li. ove .jsku full) -, (C: 5 - C i _a ) - and ll. alkoxy 11 <y 1 carbonyloxy 11 y y e groups,

II '5 - _(C-C, 1 _{g of} a 1 s) -1, 3 - cyclopentene dioxacyk 1 - 2 - on - 1 lj yl methyl ester of 1 (5-aryl-and 1, 3 - 1 dioxaeyk openten - 2 - on - y 1) methy ll. (R ¹ (R ') N- (G x -C 0 alkyl groups) -, -CH (R ¹³ ) OC (= O) R ¹ ',

-CH (R ^{1: 3} >> 0C (= O) OR ^{1 s} or

In which

R ' ³ represents a hydrogen atom or a linear alkyl group having 1 to 4 carbon atoms;

and select from Z: hydrogen, alkyl of 1 to 8 atoms. C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl, wherein said alkyl or cycloalkyl group is substituted with 1 to 2 groups independently selected from:

(C-C x ,.) alk yl, j group, (C ₃ -C _s) cycloalkyl, _(Ci-s) alkoxy, aryl substituted with 0-2 groups independently selected from:

a halogen atom, a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having

1 to 6 carbon atoms, nitro, SCC χ - -C ₍ alkynyl), - SC = 0) (CC x ~ C _with all (y left), hydroxy,

-CC = O) NCR ¹⁷ ) CR ¹⁷ ) means 1 to 3 awaryl groups substituted by:

SllaC C χ C j _{with an} alkyl group), -NCR ¹⁷⁾ CR ^17), -CtdR ^17, or ~ C _W F _W where v = 1 to 2v + -1).

J 0-2 groups independently halogen, phenyl, alkyl of 1 to G carbon atoms, alkoxy of 1 to 6, II t om am IUH 1 IKA, nitro, - SCC χ - C _s and 1 s 1 ester group), -S-C = 0) C C x - _C alkyl), -SO _R C C x -C _s alkyl

-CC ₂ R ¹⁷ , represents groups 1, hydroxy, -NCR ¹⁷ (CR ^17a ), -CC-O (NCR ¹⁷ ) CR ¹⁷ ) or -C _V F _W , wherein up to 3 aw is 1 to C 2v - <- l);

R ¹³ shall be selected from:

alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, said alkyl or cycloalkyl group being substituted with 1 to 2 groups independently selected from:.

(C až-C) alkyl, (C až-Clo) cycloalkyl, (C až-C alko) alkoxy, (C až-Cry) aryl group independently selected from halogen, phenyl, (C až-C alky) alkyl alkyl, C1-G alkyl, nitro, - SCC χ - C 1 alkyl and _with one jskupiny ove ...), - SC = O) CC x - _C 1 alkyl and s. a group Vej), -S0 _R (C x C j _S5 The alkyl groups), hydroxy, -NCR ¹⁷⁾ CR ¹⁷⁾ -CO- _with R ^17, -CC = O) NCR ¹⁷⁾ CR ¹⁷⁾ C _V F and _V wherein v is 1 to 3 and w is 1 to C 2 + 1);

aryl groups substituted with G to 2 groups independently selected from about 14 ha of phenyl, phenyl, and alkyl of 1 to 6 carbon atoms, alkoxy. of 1 to 6 carbon atoms, nitro, _-S-Ci-C alkyl IN UPIN), -SC = 0) _{CC: L-C s} alkyl), -S-C _{and CC: l} -C _s alkyl), hydroxy groups, -NC (R ¹⁷ ) CR ^{: 1 Xia} ), -CO 2 R ( ^17a) , -CC-C (NCR ( ^1X ) CR ¹⁷ ') or - CVF'. wherein jv is 1 to 3 and w is 1 to (2u + 1);

R ^1A represents a C 1 -C 4 alkyl, benzyl or phenyl group, combinations of A, B and D and / or variables are permissible only if these combinations provide stable compounds C as defined herein);

And, in the case of -S-CCH 3), it is present, -NR ^A -CCH 3) _m - ';

means -CCH _a ),

-O-CCH _2),

may be a bond or may be selected from t

-NH-, -NR ¹¹ -, -NR ¹¹ ** -, -C-, -SCO-p-CCl-C (alkyl) -HN- (C 1 -C 6) - alkyl the mounting .jsk, -CO x - C ώ) - a 1 s 1 - NR ¹¹ - CC: L - C _ώ) - and one alkyl ester šk to clamp 1, and C-C-NH-yl, j ar en clamps the , -O- CC j. C _R) yl alk j, -C _C-C6) -alkyl-O-aryl, S-CCi-C _R) -alkyl, -C C-C _R) -alkyl-S-aryl groups,

- CC a. - C _ώ ) - a. jskup ins, -CC _third - C, «,) - and 1 kennel,

-CC 1 -C 4 -alkynyl, -CONFI-, -CONR ¹¹ , -NHCC-, -NR 2 ^{: 1} CO-, -CCC-, -C00-, -CCC 5a-, -R ¹¹ NCCNR ^{1 χ} -, HNCONH -, -CCCNR ¹¹ -, -NR ^1:, CCC-, -HNSC ₂ -, -SO ₂ -, NH-, aryl, cyclic and 3-th, 3-heteroaryl, heteroaryl and 3-th, 3-heteroaryl groups .

D is CCH _{2) m);}

P can be 0, 1 or 2;

m is an integer from 0 to 3;

n is an integer from 1 to 4;

W is -0-, SCOT) p- or ^{-NR I <:} '-;

select Z:

-CONR ¹⁰ -, -NH ^{: 10} ° CO-, -SOJMR * ⁰ -, -NR ^xO SO _ff1 -, a peptide bond of a five membered heterocyclic ring that is saturated, unsaturated or partially: saturated and containing 1 to 4 heteroatoms selected from from nitrogen, oxygen, or sulfur, provided that: makroeyklus, in formula I, by -ABD - CC R · ²⁾ CR ^{L 3)} -Y-CC R ¹⁾ -CO U) C R ¹⁾ -, is connected by a minimum of 11 and a maximum of 22 atoms.

For: compounds of formula I are claimed only with respect to t. t u e: n t y, k t o r t v o r 1. a s t a b b i n y fused compounds.

Γ. [9] Most preferred compounds of the invention are those of the general formulas CIVa, IVb, IVc and IVd)

HOHNOC

R

IVc iva or a pharmaceutically acceptable salt or prodrug thereof, in which:

R ¹ is selected from hydrogen,

- <C _of -0A> alkyl-S <0) p-C _and CC) alkyl,

-C0-C 1-6 alkyl-O-CC 1 -C ₄ alkyl groups,

_{-C0 ο} -0 _ώ ) alkyl-SC (O) pC (Co-C (X)) alkylenearyl groups,

-CC _t; - (¾) alkyl-OC (C 1 -C 4) alkylene aryl, a C 1 -C 20 alkyl group that includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group wherein the substituent is selected from:

hydrogen, halo, hydroxy, alkoxy, aryloxy (C, for example, phenoxy), amino, amino, di-amino, diabutylamino, acylamino (for example, acetamido and benzamido), arylamino, guanidino, guanidino, guanidino, guanidino, guanidino, guanidino, guanidino, guanidino, guanidino, guanidino, N, N, N, N, N, N; , imidazolyl sl <up d. ny, ind 1 y 1 group d. ny, mercapto: L ny, alkylthio, arylthio (C, for example, phenylthio), carboxylic acid d. ny, karbox am d. doskup d. ny, karboa 1. Coxy groupsa 1 ebosu 1 f ó nam d. groups using, _a -CO-C _s) alkyl-aryl,

-C (Cq-Cq) an alkylene aryl group in which the aryl moiety is an aromatic moiety,

- C (o o - C b) ar y 1 - <C: - · - C) and 1 k y I. é n y r o o e j s l <u p 1 n y,

- · CC: t - C _θ D a 1 cy I é nb 1 ary 1 of the group,

- <Co-Cg) a'lkyl SC-0) p (C _o -C _r) alkylénar yl,

- the CC - C g) and a 1 s 1 ..... SCO) p - _o CC - _{E C)} 5 and 1 s 1 s 1 nary oue ... jskupiny, vktorej is an aryl radical substituted,

- • CC j. -CB, alkylenearyl D - CC _<:> - C ®) alkylénar yl-l S (0) p C _o C ©> alkylated · mil skupinyJ,

- CC o - (l _θ ) and 1 - 1 (SCU) p - CC ₍ - - _θ ) and 1 - onbio 1,

~ _O -CO-0-CePalkyl CC _o -C) alkyl-aryl,

--CCq-Cej) alkyl SCCDp _{the CC-B-C)} alkyl-aryl, wherein the aryl moiety is substituted,

C-1 C -CmiD alkylénar yl-C C-II _of alkylenearyl C) CC _{C e>)} alkyl !,

R - C Co-CTA) alkyl-0-C CC _{of R A)} of alkylénbiarylovej.

--C Co-Cg) alkyl-O-C-C _r C _o) J alkylénar yl group, wherein the aryl moiety is substituted, wherein the substituent is selected from:

a hydrogen atom, a (C 1 -C 5) alkyl group, a hydrocarbyl group, a h and a gene atom. n y, a 1 k o x y s, aminosupines, monocylaminocyanates, diaxamines, acyles, threes, 11 ar ups, arboxysplines, arboxysplines, arboxyscines, arboxysplines, arboxysclines, arboxysplines, arboxysplines, arboxysplines, arboxysplines, arboxysplines;

is selected from H, -CO, R ^55, -CONR ^R R ^S, -COMR ^ 'C 0R ^s), clamp the alky1ovej sk, sk a1k y1ary1ovej up1ny, a1k y1hetero éI hole Vej 1 of the group 1 and one alkyl heterocyclyl J groups, aryl J groups, a heterocyclic group or a heteroaryl group which is substituted with one or more substituents selected from the group consisting of a heterocyclic group and a heteroaryl group. (hydroxy), and hydroxy groups, aryloxy groups (e.g. phenoxy groups), amino groups, monoalkyl groups, diastyl groups, acyl amino groups (e.g. acetylamino and benzamido groups), arylamino , guanidno - skup j. ny, N - methy 11 midazo 1 y 1 group, im idazo 1 y 1 ov group,: i .. n mines 1 ove: are l, mercapto groups, lower ... i 1 The aryl group (s) (eg C (e.g., 1-adhenyl-thiogroups), carboxy, sulfonamido, carboxamido and I. ebocarbo-1-alkoxy;

R® is selected from · ~ C CHF? ¹ Y), -, - R 6, -CC R ⁷ R ⁶ ) W CC R ^X R ^B ) n -R ', -CC R 7 R 6 -R', CCR ^x R ^{e, i} ... aryl, CC (R) R ( ^B ) n CONRHR ^B ,

- CCR ^x R ( ^B ) ', - hete r oary 1 ogroup:

CCR ⁷ R ( ^B ) -heterocyclic;

R ⁶ shall be selected from:

atom

CC

-CC

-CO x C x C x C H, alkyl _ώ) alkyl-aryl _R) and 1 s 1 s 1 nhetero aryl ovejs _R) and 1 s 1 s 1 nheteroeyk icke .j

- CC x - (1) and cyanoyl e. groups, k upins, groups alternatively R ⁵⁵ and R ^A can form a three to eight membered ring, optionally unsaturated, containing 1 to 3 heteroatoms selected from an oxygen atom, -NR ⁶ , -SCOl or any aryl group, s optional condensation to an aryl ring;

R ^x and R ® are independent of the hydrogen atom. R ¹ , substituted by Z ring:

or may form a three to seven member with 0 to 3 unsaturated bonds in which

u b with 11 tu e; n t selects a hydrogen atom, and 1 k y 1. o v e j s; k u p: i. n y to b with u h 1 i. k a, 11 y d r o x y s k u p i. n y, h and 10 of the gene; a) alkoxy groups, such as a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group, a group and a group; j s k u p i n y;

if it contains - 0 -, - SC 0) p, -NR ⁶ , eq. by condensation to a substituted aryl ring in which the substituent is selected from:

hydrogen, C 1 -C 5 alkyl, hydroxy, hydroxy, halo, alkoxy ...

groups, aminosupines, monoalkylaminosupines, dialkylamino groups, acyl groups, thioyl groups, arboxyclines, arboxamidoscines, or acetylamines;

R ' ⁵ ' represents a hydrogen atom, an alkyl group, a cycloalkyl pat or a six-membered ring, optionally containing one to two nitrogen, oxygen or SCO 11 atoms, optionally substituted with hydroxy, -O-CO 2. -CD alkyl, -O-acylene alkyl, NHR ¹⁰ or aryl;

Rio _{zt. Anie} ,, s H or an optionally: substituted alkyl group;

R ¹¹ represents a hydrogen atom, an alkyl group having 1 to E> carbon atoms, which includes branched, cyclocycle and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected from:

hydrogen, halogen, hydroxy, alkoxy, aryloxy (C (e.g. phenoxy)), aminosupines, dialkylamino ups, acylamino groups

(For example, acetamido and benzamido), and arylamino, glycine and urine. d i n o s k u p i n y, d., m d. d a z 1 y 1 o e s s p 1 n y, i. n d o 1 y 1 o e s e p d., n y, m e r k a p t o s p u n y, n d. ž š e; 'J a 1 k y 11 d. o s k u p d. n y, a r y 11 d. o s k u p d. n y C n a n d e t d i t i t i 11 i. o s k u pina), k a r b o x y s k u pina, k a r b o x a m d. d o s k u p d. n y, k a r b o a 1 k c x y s k u d, n y a 1 e b o s u d. f)) n am d. d o s k u d d, ny,

CC _x -CD-alkylenearyl, ubst d. bolded - CC _x - C _θ ) - a lkylenic group, in which d. tuentzvo 1 iz:

hydrogen, halogen, alkoxy, alkoxy, aryl 1 d. C · ny e.g., Example 1 ^ADF enoxysku full), am d. noskupj d. ny, dialk y 1 am d. noskupiny, acy 1 am d. noskup d. C (e.g. acetamido and benzamido), aryl am d, noskup d. ny, guan d. (d d. acylamino group, d. d. dazoyl y group of dny, 1 n to 1 y1 group of dny, mercury group of dny, lower alkylthio, arylthio C for example phenylene 11 ioskup ins), carboxy, carboxymethyl Box-τη a sulfide, carbonyl a1k the xysk to clamp clamps the de a1ebn su1fónamido, px x ® is H, -S0 ₂ -Cx _R-C alkyl group,

- S 0-. ~ C χ - C <<, - and ll. k y 1 o v - s u b s t u o v a n u a r y ll. o v o s k u i r i u,

- SC 1 's; ary ľl. s U is - SO _p -, substituted heterocyclic account Roar s 1 U is, -COR ⁵ ', ~ (I' O .-. t-l3u, -CO _and B n, wherein the substituent is selected from;

hydrogen, C 1 -C 5 -alkyl, hydroxy, halo, and 1-alkoxy, amino, moralkylamino, diamino-amino, aoyl-amine, thio, thioa 1 groups, carboxy: i. n y, k a r b o x a m i d o s p i n y a 1 e b o and r-y 1 o v e groups;

m is an integer from D to b;

n is an integer from 1 to 5, it may be 0, 1 or 2;

W is -I 1 -, -SCO 3 - or -NR ¹⁰ -;

represents CH _a or an oxygen atom;

is selected from:

-C0NR ¹⁰ -, -NH "° (I: 0-, S0-.NR ¹⁰ -, -NR ° _R S0 -, peptide bond

P h a r e c h e t e r o c: y k ll. The unsaturated or partially saturated, containing 1 to 4 heteroatoms, is unsaturated or partially saturated. selected from nitrogen, oxygen or sulfur.

For compounds of the formula I, only the compounds of claim 1 are claimed. compounds.

52nd

Most preferred compounds of the invention include compounds of Formula I or a pharmaceutically acceptable salt or prodrug thereof selected from the following compounds.

S, 5 R, 6 S - 3 - aza - 4 - oxo - 10 - nxa - 5 - isobutyl _ - 2 - CN - methyl 1 carboxamido - C 1 C.) r l r> aracycl 1 of n n - 6 - N - hydroxycarboxylic acid;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2 '(carboxyniethyl) - ľ1' (l1'1 'paracyclohexan-6-N-hydroxycarboxamido) ;

S, 5 R, 6 $ - 3 - and z a - 4 - o x o - - ll. 0 - o x a - 5 - o z o u u 1 - 2 - C N - b e n z y l. k a r b o x a m i cl o) - to 1D 3 p a r a c y k 1 o f a n - 6 - N - h y cl r o x y k t r b o x am 3. cl;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (hydroxymethyl) -1,103 paracyclophan-6-N-hydroxycarbamide;

S, 5 R, 6 S-3-aza-4 ..... oxo -10-oxa-5-i zobytes 1 - 2 - (L ..... and 3. anin - M -meters 1 am i cl)

-I '1 (33 par acyclophan-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-CL- (O-methyl) tyrosine-N-methylamidyl-11 '(33) paracyclophane-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5 ... isobutyl-2-CL-C (O-tert-butyl) serine-N-methylamidyl-11,13 paracyclophan-6- N-hydroxycarboxamide;

S, 5 R, 6 S-3 - and z a - 4 - o x o - µl. 0 - o x a - · 5 - 3. z o u t 1 - 2 - (L - s-rin-N - methyl 3 and m 3. d) to 103 paracyclophan-6-N-hydroxycarboxylic acid boxamld;

2S, 5R (6S-3-aza-4-oxo-10-oxa-5-i-isobutyl-2-C-glycine-N-methylamide) · - 3.0 3.0 3 paracycl 3. ofan - 6 - - N - hy cl roxycarboxam 3. d;

2S (5R (6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-C (D-alanine-N-methylamide)) - E10 3 paracycl 3-o-n-6-M hydroxycarboxam 1 d;

S, 5 R, 6 S- 3 - aza - 4 - oxo - 3.0 - oxa - 5 - 3. zobuty 3. - 2 - C bet aa 3. anin - N -methylamide -I '103 paracyclophan 6-N-hydroxycarboxamide;

2S, 5R, OS-3-aza-4-oxo-10-oxa-5-isobutyl-2- (D-C (tert-butyl) serine)

M-methyl 1 and m: i. d J - 1010 l p a e l <<<f E E E E E E E M M M M M M M M M M M M M M M M M:::::::::;

2S '5R, 10S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (D-serine ... N - methylamd) - C 10 3 paracycl 1 o F a n-6-N-hydroxycarboxam 1 d;

2S, 5R, 10S-3-aza-4-oxo-10-axa-5-isobutyl-2-L-lysine-N-methylamide).

- E 1 E) l p a a 1 f f á - ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES ES;

S, 5 R, G S-3 - a z a - 4 - o x o - · 1 E) - o x a - 5 - i z. o b u t 1 - 2 - C L - v a n n - N - methyl 1 am: i. d) - E 10 ľ l p a k 1 f f E E>>>>>>>>>>>>>>>>>>>>>>;;;;;;;

2S, 5R, OS-3-aza-4-oxo ... 10-oxa-5-isobutyl-2'-C 2 -pyrrole trifluoroacetate. d y 1) - e t y 1 k a r k x o x y i d - 10 10 10 ľ ľ ľ ľ ľ F á á á á á á á á á á á á M M M M M M M M;;;;;;;

2S (5R) OS-3-aza-4-oxo-10-oxa-5-isobutyl-2-C (4-methyl) piperazinylcarbonylamino-E-10'-para-phenylamino-6-M-hydroxy-6-methyl-piperazinyl;

S, 5 R, E) S - 3 - aza - 4 - oxo - 10 - oxa - 5 - isobutyl 1 - 2 - C 2 - benzimidazol 1 y 1) - 10 10 3 p ara oyk 1 of á o 6-IM hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-1,0-oxa-5-isobutyl-2-E (2-imidazolyl) carboxamido-1-103 paracyclophan-O-1M-hydroxycarboxamide;

2S (5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-CC (2-benzimidazolazolyl) methyl) methylthiazole-11'-11 '. O l l p a r a c: y k 3. o f n n - 6 - M -1 ί y d r o x y k a r · b o x a m 1 d ·

2S, 5R, 6S-3-aza-4'-oxo-10-oxa-5- ± isobutyl-2-β (3-imidazolyl) Petroleum 1 carboxamido o 1 - 11 par 10 par paracycl l o F n - 6 - M - hydroxycarboxamide;

S, 5 R, G S-3 - a z a - 4 - o x o - 3.0 - o x a - 5 - i z o b u t y 3. - 2 - I 2 - C 4 ..... a m: i. n o s u ll. phenyl 3-ethylcarboxamido-3,103 paracyclophan-6-N-hydroxycarboxamide;

S, 5 R, OS-3-aza-4-oxo-J. (C) -oxa-5-isobutyl-2-Cg y-in-IM, N-dimethy 3. amide) -E 103 paracyclophan-6-N-hydroxycarboxamide;

S, 5 R, 6 S-3-aza-4-oxo-1 (E) -oxa-5-isobutyl-2-C '1-ad am anty 1 carbox 54 amido) - E103 Paracyclophan-6-N ~ hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-EC (4-aminoindazolyl) carboxamide 3 - E 3.0 3 paracycl 3 - of ^{: a} - 6 - N - hydroxycarboxamide;

S, 5 R, 6 S-3-aza ·· 4-oxo-3.0-oxa-5-isobutyl-2-CM, N-dimethylene-1 carboxam 3. do) - E 3. E) 3 paracyc 3 .. of n - 6 - M - hydroxycarboxam j. d;

S, 5 R, 6 S-3-aza-4-oxo 3. C) oxa-5-3 3. zobuty 3. -2-C (isopropyl) carboxy oxido) -E 103 paracyclophan-6 N-hydroxycarboxamide;

2.S, 5R, 6S-3-aza-4-oxo-10-oxa-5-3-isobutyl-2-C (N-cyclopropylcarboxamido) -E 103 par acyclophane-K-N-dihydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-b-isobutyl-2-CN-tert-butylcarboxamido) -1,103 paracyclophan-6-N-hydroxycarboxamide;

2. S, b R, 6 S - 3 - aza - 4 - oxo - 3 - oxa - 5 - 3. zobuty 3. - 2 - E g 3. yo n - C IM - isopropyl 1) - amide3 -E 103 paracyclophane-CN-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-C-glycine-N-ethyl) amide] - E 103 paracyclophan-5-N-hydroxycarboxamide;

S, 5 R, 6 S-3 - a z a - 4 - o x o - 3.0 - o x a - · 5 -1 z. 3. - 2 - E g 3. yolin-C M-oylpropyl 1) 3-Ľ 103 amide paracyclophane-K-N-hydroxycarboxamide;

S, b R, 6 S-3 - a z a - 4 - o x o - 3.0 o x a - 5 - 3. z o b u t 1 - 2 - E g 3. y o n - C N - b e r o. b u byl) amide] - E103 Paracyclophan-6-N-hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-β-glycine-N-cyclobutyl) amide] -E 103 paracyclophane-K-N-hydroxycarboxamide;

S, 5 R, 6 S - 3 - and z a 4 - o x o - 3.0 - o x a - 5 - 3. 1- [2- (E) 3-cyano-M-morpholin-4-yl] amide] -E 103 paracyclophan-6-yl hydroxycarboxamide;

S, b R, 6 S ™ 3 - aza - 4 - oxo - 3.0 - ox a - b - 3. Zobuty 3. - 2 - E g 3, ycin - - CN - 2 - hydroxydimethylethyl) amide] -E 103 paracyclophan-6-N-hydroxycarboxamide;

2S (bR, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-C-carbohydrate-N-ethyl-ethylpropyl) amide -C 103 paracyclophan-6-N-hydroxycarboxamide;

S, 5 R, 6 S-3-aza-4-oxo-3.0-oxa-5-isobutyl 1-2 ..... C g 3. yci rt - C N ..... d 1 methyl 3. propyl) amd 3 -C 103 paracyclophan-6-N-hydroxycarboxamide;

S, 5R-6S-3-aza-4-oxo-3-oxa-5-isobutyl-2-E glycine (C 1 -C 2 dihydroxymethyl) ethylamide 3-E 3 -O 3 paracyl 3. of tert-6-M-11-hydroxycarboxamide;

S, 5 R, 6 S-3-aza-4-oxo-10-oxa-5-± isobutyl-2-E g 3-yt-C 4 -hydroxy-piperidinyl) -ld 3 -E 103 paracyclophan-6 ..... N-hydroxycarboxamide;

S, b R, 6 S - EJ - aza - 4 - oxo - 3.0 - oxa - b - isobuty 3. - 2 - C 2 -1) enz int 3. dazo 3. carboxamido) -E 103 paracyclophan-6- N - hydroxycarboxamide;

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-ES- (methyl) -2 ..... phenyl methyl I. carbox am 3. do 3 - E 3.0 3 p ara-cyclo-3-a-6-N-hydroxycarboxam 3. d;

S, 7 R, 8 S-5 - a z a - 6 - o x o - J. 2 - o x a - 7 - 3 z o t o 3. - 2 - C o r b o x y m e t 3) -E 123paracyclophane-8-N-hydroxycarboxamide;

S, 7 R, 8 S - 5 - aza - 6 - oxo - 3 - 2 - oxi - 7 - isobutyl 1 - 2 - CN - nt ethyl 3 - carboxy nt 3. do) -E 123 Paracyclophan-8- N-hydroxycarboxamide,

S, 7 R, 8 S- 5 - aza - 6 - oxo -12 - oxa - 7 - 3. zobuty 3. - 2 - C g 1 ycin - N -methy 1 am 3. d) - E12 3 paracycle 3. of? N ..... 8-M-hydroxycard: ox am 1 d;

S, 3 R, 6 S -10 - 1 - Etutoxycarb, y 3 - 5, 3 .. O - d 3. Aza - 2 - CN - 11 ydroxycar Et oxam 3_ do) - 6 - CN - methyl 3 carboxamido) -1-oxa-4-oxo-3-C-3-fertylprop-1-yl) cyclotetradecane;

hydrochloride 2S (3R, 6S-5, 10-palza-2-CN-hydroxy oxycarboxamido) -6- (N-methyl-3-ethoxycarbamido) -3-oxa-4-oxo-3-C3-phenyl 1 - 3. - propy 1) cyclotreatment of decane;

2S (3R, 6S-10-acetyl-5,10-palza-2-N-hydroxycarboxamido) 56

6-C (N-methylcarbamido) -1-oxa-4-Oxo-3- (3-phenyl-1-propyl) cyclotetra-adecane;

2S (3R, 6S-10-Benzenesulfonyl-5,10-diaza-2-CN-hydroxycarbamoyl) -6- (N-methylcarboxamido) -1-oxa-4-oxo-3-C 3 -phenyls 1-1-propyl) cyclotetradecane;

2S (3R (6S, 12CR, S) -10-acetyl-5,10-diaza-2-C (N-hydroxycarboxamido)

- 6 - C N - m e t y 1 k a r boxes d o) -12 - m e t y 3. -1 - o x a - 4 - o x o - 3 - C 3 - pheny 1 - -1 - p o p i) c y k l. o t r i d e k i r;

S, 3 R, 6 S — 3 - aza - 4 - oxo - 10 - oxa - 6 - hexy 1 - 2 - C carboxmethylene 1) - C '10 3 paraoyk 1 of a - 6 - M -hyd roxycarboxamide;

S, 3 R, 6 S - 3 - a z a - 4 - o x o - '10 - o x a - 5 - h e x y 1 - 2 - C h y d r o x y k a r b o x y 1) - C 10

S, 3 R, 6 S - 3 - aza ..... 4 ..... o x o -10 - o x a - 5 - hexes 1 - 2 - C 2 - m e b o x y 1 e t y l. oxy) k a r b o x y 3.) - 10 10 µl p a r a c y k 3. o f - 6 - N - h y d r o x y k a r b o x am i d;

2S, 3R, 6S-3-aza-4-axo-10-oxa-5-hexyl-2-C (2-phenylethyloxy) carboxy) -1,13 paracyclophan-6-N-hydroxycarbamide;

2S (3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C1-C1-methylcarboximido) methylcarboxy) -1,13 paracyclophan-6-N-hydroxycarboxamide;

S, 3 R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - 5 - hexy 3. - 2 - C 2 - C 1 -methylated nose 3 phony 1> ethylcarboxamido) -1,13 paracyclophan -6-N-hydroxycarboxamide;

S, 3R, 6 S-3-aza-4 ..... oxo -10-oxa-5-hexy 3.-2-C 4-CN-methyls. do) - L10 3 par acyk 3. ofan - 6 - N - hydroxycarbamide;

S, 3R, 6 S-3-aza-4-oxo-10-oxa-5-hexy 1 - 2 - C 2 - CM -methy 1 am 1 nose 3. phony 1) hexes 3. carboxamido) - I 10 10 3 paracycl 1-a-6-N-hydroxycarboxam 3. d;

2S, 3R, 6S-3-aza-4-oxo-10-oxa-b-hexyl-2- (2-C (carbomethoxy) ethylcarboxamido) -1,13 paracyclophan-6-N-hydroxycarboxamide;

2S (3R, 6S-3-azaa-4-oxo-10-oxa-5-hexyl-2 ..... (2-Cyclohexylcarbonyl) ethyl carboxamide) - C10 β ara cyclic of rt-6-M-hydroxycarboxamide;

S, 3 R, 6 S - 3 - az a ..... 4 - oxo -10 - ox and ..... 5 - hexy 1 - 2 CL - ornithe 1 n C 4 -1 - butoxycit rbony 1) carboxymethyles 1) - - 11 1 C. 11 'paracycl 1-rt-6-N-hydroxycarboxaid in id;

hydrochloride 2.S, 3R, 6S-3-aza-4-oxo-10-oxa-5-bexyl-2 ..... CL - orriitin to the carboxymethyl-1'-10'-paracycophane-Ei- N-hydroxy to arboxamide;

S, 3 R, 6 S-3-aza-4-oxo-10-oxa-5-hexy 1-2-C-l-orni-n-C-4 ..... t - either carbanyl) -N (methylamide) -1,11,11 par acyclophane-6-N-hydroxycarboxamide;

S y r c c h h h S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S

-methylamides) - 11 µl of paracyclofor-6-M-hyroxycarboxamide;

S, 3 R, 6 S — 3 - a z a - 4 - o x o -10 - o x a - 5 - h e x y I - 2 - C L -1 y z i n k a r b o x a m i d) - ¾ l. 0 3 p a r a c y o x a - Ei - N - h y d r o x y k a r b o x am 1 d;

2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C-L-serine C [i-tert. butyl-N-methylamide) -C 10.1 par acyclophane-6-N-hydroxycarboxamide

S, 3R, 6S-3 'aza-4-oxo-10 "Oxa-5-hexyl-2-C (L-alanine-N-methylamide) -1 to 10 µl acyclophan-6-N-hydroxycarboxamide;

S, 3 R, EJ S — 3 — aza-4-oxo-10-oxa-5-bexy I - - 2 - CD - a 1 o 1 n - N - methyl 1 am 1 d) - up to 10 µl paracycl 1 of n - G - N - dihydroxycarboxamide;

2S '3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C-glycine-N-methyl-amide (d) - 11' hydroxycarboxamide;

S, 3R, E! S - 3 - a z a - 4 - o x o - 10 - o x a - Ei - h e x y 1 - 2 - C b e z y ll. k a r b o x am i d o) - 11 10 10 µl paracyclopropane-Ei-N-hydroxycarboxamide;

S, 3 R, Ei S-3 - and z a - 4 - o x o - µl. 0 - o x a - · 5 - h e x y ll. - 2 - C f e n y c t y 1 k a r b o x am i d o)

ľ ľ 10 l p a k k 1 1 f - - - - E E E E E E E E M M M M M M M M M M

S, 3 R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - 5 - h & xy 1 - 2 - C diphenyls 3 - ethyl 11 (aroxamido) · - L 3 0 J paracyl <I bfan-6-1H-hydroxylcarboxamide;

2S, 3R, 6S-3-aza-4-oxo-10'-Oxa-5-hexyl-2- (2-C2-pyridyl) ethylcarboxamido) - C10 J paracycl 1-a-E - M - hydroxycarboxylic acid oxam i. d;

2S '3R, 6S-3-aza-4-oxo-1H-oxa-5-hexyl-2- (2- (4-sulfonylaminophenyl) 1-ethylcarboxamido) E 10 3 paracycl 1 of a n-G-M-1-hydroxycarboxylic acid;

2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (2-C3 (4-dimethoxyphenyl) ethylcarboxamido) - E 10 3 paraoyl 3 of-n-6-M-hydroxycarbonylamide;

2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C2-C4-morpholino) carbonyl oxamido-E103 paraoyl 3. ofan-6 - IM - hydroxyk ar box am id;

2S, 3R, 6S-3-aza-4-oxo-10-oxa-b-hexyl-2-C 3- (4-morphol-3-oxo) pyrrolidine hydrochloride hydrochloride. d o) - E 3.0 3 p a r y c 1 o f a - 6 - N - h y d r o x y k a r b o x a m i d

2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (3- (1-imidazolyl) propyl) carb oxamido-E 3.03 para 3. o of α - 6 - 1 H -hydroxycarboxylic oxamide;

trifluoroacetate 2S, 3R, E1S-3-aza-4-oxo-10-oxa-5-bexyl-2-C3- (1-imidazol-3-yl) propy 3. carboxamide (E 10 3) paracycl 3. ofan-G-N-hydroxy carboxamide;

S, 3 R, GS - 3 - aza - 4 - oxo - J - O - oxa - 5 - hexy 3 - 2 - C 3 - cyclohexyl 3 - carboxamido) - E 103 paracyclophan-6-N- hydroxycaroxoxide;

2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (4-methylpiperazin-1-ylcarlaoxamldo) -1,103 paracyclophan-G-N-hydroxycarboxamide;

S, 3 R, 6 S — 3 - aza - 4 - oxo - 10 - oxa - 5 - h (2 xy 3 - 2 - · (d im ethyl 3 carboxamido) -L 3.03 paracyclophan-GN- hydroxycarboxamidei

S, 3.3 S, 14 R-1, 7 - d i a z 8 - 3,5 - d i o x o -9 - o x a - 3.4 - j. z ta la u t y 1 - 7 -met y 1 -2 - C IM - met y 1 k a r b o x a m i. d o) - c y k 3. o p e o t a d a - 3.3 - N - h y d r o x y k a r b o x a m i d;

2S, 13S, 14R-1,7-diaza-dia, 15-dioxo-9-oxa-14-isobutyl trifluoroacetate

- 7 - nitrile 1 - 2 - C M - C 2 - pyrrolidine 1) methylenedioxy-thiocylene-13-N-hydroxycarboxainide;

S. '13 S, 14 R-1, 7-d a z a-8, 15-d x a x o-9-o x a -14-i z o u u u u ll. - 7 -meters 1 - 2 - mile 2 - · C 5 - m e t y l. t i a z o 1 y ll) k a r b o x a m i d o ll - c y k ll. o p e n t a d k a n -13 - - M -11 y cl r o x y k a r b c> x ani; i. d;

S, ll. 3 S, Art. 4 R-1, 7 - d 3. and za-8, '15 - d 3. o x o - 9 - o x and -14 - 3. z o b u t y 1 ..... 7 - τη e t y ll. 2-I '(2-pyrimidyl) carboxamido-cyclopentadecan-13-In-yloxycarbonylamin 3. d;

S, 13 S, p. 4 R-1, 7-d 3. aza -8, 15-d 3. oxo-9-oxa-3,4-3 3. zobuty 1- 7-methyl 1- 2 -I '(3-pyridyl) carboxamidol-cyclopentadecane -13- Ν -hydroxy-carboxamide;

S, 13 S, 1.4 R- 1, 7 - d i a z - 8, 15 - d x o o - 9 - o x a - 3.4 - 3. z o u u u ll. - - 7 - Meters 1 - 2

- (C 4 -C 4 -pyridyl) carboxamidol-1-yl-lopentadecane-13-N-hydroxycarboxamide;

S, 3.3 S, 14 R- 3., 7 - d 3. and z a - 8, 3.5 - d i o x o - 9 ..... o x a - 3.4 - 3. z o u u u u - 7 - m e th e l. - 2

-I 'C 4- (N-ethoxycarbonyl) piperidinecarboxamidol-1-cyclopentadecane-1,3-N-hydroxydexylcarbamido;

S, ll. 3 S, 14 R-1, 7-d 3. Aza - 8, 15 - d 3. Oxo - 9 - oxa - 3,4 - 3. 1 ohexy 1 k ar box am 3. into β-cyclic opentadecan-13-N-hydroxy oxycarboxamide;

S, 13 S, 14 R-1, 'l - d 3. and z a - 8, 15 - cl 3. o x o - 9 - o x a - 3.4 - 3. z o u u t 1 - 7 -met y 1 - 2 - C g ll. y c i n - N - m e: tulle. and m 3. d) - c: y k ll. o c t e e n e - 3.3 - N - h y d r o x y k a r b o x am i d;

S, 13 S, 14 R-1, 7-d 3. Aza - 8, 15 - d 1 oxo - 9 - oxa - 3,4 - 3 - 1 - 7 - ethyl - 2 - (gly clri-N, N -dimethylamide-cyano-lopentadan-13 -N-hydroxy to arboxamide

S, ll. 3 S, 3.4 R-1, 7 - d 3. Aza - 8, 3.5 - d 3. Oxo - 9 - oxa - 3.4 - 3. 2-pyridyl amide) -cyclopentadecan-13-M-1-hydroxycarboxamide 3. d;

S, 13 S, 14 R -1, 7-diaza-8,15-dioxo-9-oxa-4 ..... isobutyl-7-methyl-2-glycine-2-C3 Cyclopentadecane-13-N-hydroxycarboxamide; 4,5,5-tetrahydropyridyl) amide;

S, 13 S, 14R-1, 7 - d i and z a - 8 '15 - d i o x o - 9 - o x a -14 -1. z o ti u t y- ·· 7 -m e t y 1 - 2 ......

- I g g y y: - 11 - M - C 4 - y y d r y) when d i d i d i - 3 - y y d e l t -13 - N - y y d x y y and b y x y m, ·

S, 3..3 S, 14 R -1, 7-diaza-815-dioxo-9-oxa -14-isobubes 1-7 -meths 1 - 2 - 1-gylamino - IM - pyrrole . d i n am .1 d 3 - c y k e o p e rt b a d e k e -13 - N - h y d e x y k a r b o x am j. D

S, 13 S, 14 R -1, 7 - diaza - 8, 15 - d 1. Oxo - 9 - oxa - 14 · - isobubes 1 - 7 - methyl 1 - 2 - C g 3. yc: n - 3-Cyclopentadecarboxylic acid 3-cyclopentan-3-yl-hydroxycarboxamide trifluoroacetate 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl

- 7 - meby 3. - 2 - I g g 3. ycine - (4 ..... methyl) M - piperazines 3. a τη 1 d 3 - cycl 3-opentadecarte -13 - M - hydroxycarboxam: i. d u;

trifluoroacetate 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7- _methyl -2-ylmethyl-2-C5-methyl) thiazol-3-yl-3-cyclopentanecarbonyl-13-IM-hydroxycarboxamide;

2S '3 3 S, 14R-1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-2-C-glycrt-N-morpho-3-inoamide 3-Cyclo-opentadecan - 13 - hydroxycarboxamide;

S, 11S, 12R-1,7-diaza-8,13-dioxo-2- (N-methylcarboxamido) -12-isobutylcyclohexyl-1,3-dioxane. - C M - h y d r x y k and r b x x i d);

S, 13. S, 3.2 R-1 ', 7-cdiaza-8,3,3-dioxo-1'-2'-3'-th' 3'-cyclotyr-2-C glycine-N-methylamide ) -LL-CN hydroxycarboxamide);

2S '11S, 12R-1,7-diaza-8,13-dioxo-12-isobutylcyclo-lotridecar-2 (Nepeiion-11-giycin-α-Mn-amide trifluoroacetate) -11-C-N-hydroxycarboxam 3. d) ;

S, 11S, 12 R- · 1,7 - d i and z a - 8, 13 - d x o x o - 3.2-3. 3. Cyclobutyl-2-CH2-a-1-en-N-H-methyl-amine d) -13. - C N - h y d r x y k and r b x x i d);

S, 11S, 12 R -1, 7 cl. and z a - 8, 13 - cl i o x o -12 - i. (b-alanine-N-methylamide) -11- (N-hydroxycarboxamide);

2S, 1'IS, 12R-1, 7-diaza-8, 13-dioxo-2-C Nmethylcarboxamido) --7-- N -methyl Zity 1e 1f CPR ^:: y 1 of 11 -12 - izobuty ľl. cyclotropin-11-C (hydroxycarbamoxamide); /

2S, 11S, 12R - 1,7 -za-8,13-dioxo-2- (N-methylcarboxamido) ... 7-M-1-butyl oxycarbones 1 ... 12-isobutyl 1 c: yk 1 otr j. d e k a - X 1 - CN- h y d r x y k a r b o x a m 1 cl);

2S, 11S, 12R-1,7-diaza-8,13 -clooxo-2- (N-methylcarbamoyl) -12-isobutylcyclohexylhydrochloride-11-CM- hy cl roxykar ti oxamide)

5S, 8R, 9S-6-aza-2,7-dioxo-b-CN-1-methylcarboxamido) -1-oxa-8- i. z o u u 1. c y k o o o o o n - 9 - C N - h y d o x y k a r b o x and m i cl);

2S, 11S, 12R-7-N-Benzenesulfonyl-1,7-diaza-8,13-dioxo-2- (N-methylcarbonyl and methyl) -12. - i z b u t y I. c: y k 1 o t d e k a n -11 - C N - h y d o x y k a r b o x and m d);

2S, 11S, 12R-1,7-diaza-8,13-cliooxo-2-C (N-methylcarboxamido) -7- (p-amino-N-benzenesulfonyl) -12- · isobutyl (C-1-otridecan-11-N-hydroxycarboxamide);

2S, 11S, 12R-1,7-diaza-8,13-dioxo-2- (N-methylcarboxamido) -7-N-1-fluoro-methanesulfonyl-12-isobutylic acid; y k 1 o t r d e k a n -11 - C N - h y d r o x y k a r b o x a m i cl)

2S, 11S, 12R-1,7-cliaza -8,13 -clooxo-2-C (N-methylcarboxamido) -7-NCN-methyl imidazo 1-4 -... isobutylcyclohexyl-11-N-hydroxycarboxamide);

S, 11 S, 12 R-1, 7-cliazole-8,13-clioxo-12 -1-cyclobutyrene-2 (1-norleucine-a: -N-methylamide) -11-C N-hydroxycarboxamide);

S, 11 S, 12 R -1, 7 - d 1 a z a - 8, 13 - d i o x o - X 2 - i z o u u t 1 c: y k 1 o t r 1 cl c-: k a - 2 G 2

(L-serine-α-N-methylamide) -1'-C-N-hydroxycarboxainide);

S, 11 S, 12 R-1, Ί - d 1 and z a - 8, 13 - d i o x o -12 - i. z o b u t y 1 c y k 1 o three. (dec-2C glycine-N-dimethylamide) -11-C (hydroxycarboxamide);

2S, 11S, 12R-1,7-diaza-S, 13-dioxo-12 (R) -isobutyloxy-cyclodecan-2CS) glycine-N-1,2-ethylenedianin-N ', 1'-dimethylamide-11CS) - CIM-hydroxycarbox am 1. d);

S, 11 S, 12 R-1, 7-d 1 aza - 8, 13 · - dioxo -12-isobutylcyclotridecan-2 (glycine-N-morpholinoamide) -11-C (N-hydroxy oxycarboxamide) ;

S, 11S, 12 R -1, 7-diaza-8,13-d 1 oxo -12 · isobutyl 1-cyclotridecan-2 (L-leucine-α-N-methylamide) -11-C N-hydroxycarboxamide);

S, 11. S, 12 R-1, 7-diaza-8,13-dioxo-12-isobutyl-1-cyclotridecan-2 (L-threonine-1'-N-methylamide) -11- (IM-hydroxy oxycarboxamide);

The invention shows that the above compounds are useful as metalloproteinase inhibitors, including aggrecanase and TNF-C, and that they are useful in the treatment of joint rheumatism, osteoarthritis and related diseases, as described above, from inflammatory diseases, which inhibit the production of TNF in animal models and are useful in the treatment of diseases mediated by IMF.

The invention also provides methods of treating osteoarthritis, joint rheumatism, and related inflammatory diseases as described above, by administering to a patient a pharmaceutically or therapeutically effective or acceptable amount of a compound of formula (I) to (IV) as described above. By therapeutically effective amount is meant an amount of a compound of the invention that is effective in inhibiting the targeted enzyme or treating the symptoms of osteoarthritis, or joint rheumatism or related diseases of the patient.

The compounds of the invention may also be administered in combination with one or more therapeutic agents. By administering the compounds of Formulas I-IV of the present invention in combination with this additional therapeutic agent, the efficacy of these components can be enhanced over the administration of the individual agents alone, thus reducing the doses of the individual agents administered. Reducing the dose reduces the possibility of side effects and thus increases the safety margin of the therapeutic composition.

The term "therapeutically effective amount" as represented by the general formula (1) herein, when administered alone or with another therapeutic agent to or from a cell, means an amount of compound IV which, in combination with a mammal, is effective in irihibition of the targeted enzyme, thereby preventing or ameliorating the inflammatory disease state or progression of the disease.

As used herein, the terms administered in combination or combination therapy, as used herein, means that a treated mammal is administered simultaneously with a compound of Formulas I-IV and one or more other therapeutically active agents. For combination administration. all components may be administered at the same time, that is, at the same time or sequentially in any order, although each component may be administered alone, but must be self-administered.

time intervals between sufficiently short to give a therapeutic effect.

d o s j., a h n u t o o o d

The term stable compound or stable structure as used herein refers to a compound that can be isolated at a sufficient degree of purity from the reaction mixture to prepare an active therapeutic agent formulation.

If any variable appears more than once in any building block or compound of formula (1) to (2). IV (or any other formula herein), its definition at each location will depend upon its definition at each other location. Thus, for example, when substituted with 0-2 ^R32, then said group may optionally be substituted with up to two R, and ^{those of} R in each occurrence is chosen independently from the defined list of possible R ^3rd Also, combinations of substituents and / or variables are permissible only if these combinations provide stable compounds. The compounds described herein may have a methetric center.

Unless otherwise specified, all chiral, diastereomeric and racemic forms are included within the scope of the invention. The compounds described herein may also contain many geometric isomers of olefins, C-N double bonds, and the like, and all such stable isomers are also within the scope of the invention. It is contemplated that the compounds of the invention may contain asymmetrically substituted carbon atoms and may be isolated in optically active or racemic form. Methods for the preparation of optically active forms are known in the art, for example, resolution of racemic forms, or a disc.

synthesis from. optically active All chiral, diastereomeric and racemic forms and all geometric isomeric forms of the structure should be considered unless the specific stereochemistry or isomeric form is specifically indicated.

If the bond to the substituent is indicated to cross a bond linking two atoms in the ring, then this substituent may be attached to any ring atom.

If the atom through which this substituent binds to the remainder of a compound of formula I to IV is not indicated for the substituent, then this substituent may be bonded via any atom in the substituent. For example, if the substituent is a plperazinyl, piperidinyl or tetrazolyl group, unless otherwise specified, said piperazinyl, piperidinyl or tetrazolyl group may be attached to the remainder of the compound of formula I via any of the following atoms. o n y 3. o o, in the case of the third and third groups.

Combinations of substituents and / or variables are permissible only if these combinations provide stable compounds. By stable compound or stable structure as used herein is meant a compound that is sufficiently resistant to survive isolation from the reaction mixture to the desired degree of purity and processing into an active therapeutic agent formulation.

The term "substituted", when referred to herein, any one or more hydrogen atoms will replace a proposed atom of a group selected from the proposed list of suitable substituent groups, provided that no; the normal valency of the proposed atom is redundant and that the substitution provides a stable compound. If the substituent is a keto group (i.e., = O), then one oxygen atom will replace the two hydrogen atoms.

The expression alk yl hunters group as intended to include saturated aliphatic hydrocarbon groups such as branched as well as straight-chain, having the specified number of carbon atoms (e.g., C-C _H denotes an alkyl group having 1 to 16 carbon atoms); in addition, a lower alkyl group defines a straight and / or branched alkyl chain of 1 to 8 carbon atoms; as used herein, includes a straight and / or branched chain saturated hydrocarbon group having a specific number of carbon atoms substituted by one or more halogen atoms (e.g. ~ C _V F _W , wherein v = ·· = 1 to 3 and w = 1 to (2v -'-1), - the term '' and 1 cox, as defined herein, represent a ... The term cycloalkyl, as used herein, includes saturated cyclic groups, including mono-, bi-, or poly-cyclic ring systems, to the term &quot; carbon atom &quot; Example 1 Cyclopolymer Clamp, Cyclic 1 Butyl group, Cyclopentents 1 Cyclic group, Cyclic 1 Ohexy group, Cyclic 1 ohepty group, Cyclococci And the term bioycloalkyl, as used herein, includes saturated b. á n, Iľ 4.3.0 ¾l bike 1 onon á n,

(Decalin), II 2.2.2 µl bicyclooctane as described herein, z a b r n u. is a branched-chain configuration, with a white plate of the above-mentioned branched carbon-carbon, and may be as follows:

and which chains, and the like; and the term z and h) r n u u h h o o h. e n e a n i e n e a n e a b e which may be located in the following examples. n y ľl. o in the case, eg k1a d I 4.4 4.4.0 µl bicyclodecane, etc. The term alkenyl, straight-chain or one or more unsaturated hydrocarbon chains) may be present in any of the examples. o v ú s; k u p i n u, '' and ll. k i n y ll. If the strings are straight or not. e b o l o t o c t e b v 1 u b o v o n o m s s a b i 1 n s s u p i. n u, p r o p i n y 1 o u s p u n u

The term alkylcarbonyl, as used herein, includes an alkyl group with an indicated number of carbon atoms attached through a carbonyl group at the indicated location to the remainder of the compound. The term alkylcarbonylamino, as used herein, includes an alkyl group having a designated number of carbon atoms attached through a carbonyl group to an amine bridge, which bridge is attached to the remainder of the compound at the indicated location. The term alkylcarbonyloxy, as used herein, includes an alkyl group having a designated number of carbon atoms attached to a carbonyl group, the carbonyl group being attached via the oxygen atom to the remainder of the compound at the indicated location.

Expressions a 1 k y 1 é n o s k p p a, a 1 k e r, y ľl. phenylene, and the like, as used herein, denotes an alkyl group, an alkenyl group, and the like. a phenyl group which is attached by two bonds to the rest of the structure of the general formulas III 'and III' 11. They have an alkyl group, and a phenyl group, 1 new group under. Here, it can be 11 e r n a t e n o z. by equivalent terms such as -C 1-6 alkyl, -C 1-6 alkyl, and the like.

The terms halogen or halogen, as used herein, include fluorosulfur, chlorosulfur, bromosupin, and iodo; and the term counterion ”is used to denote small, negatively charged species, for example chloride, bromide, hydroxide, acetate, sulfate and the like.

The terms "arbocycle" or "arbocylic residue" or "carbocyclic ring system" as used herein mean any stable three to three. a seven-membered monocyclic or bicyclic or a seven- to fourteen-day bicyclic or tricyclic or up to twenty-six-membered polycyclic carbon ring which may be saturated, partially saturated or aromatic. Examples of carbocycles include, but are not limited to, tert-butyl, tert-butyl, phenyl, biphenyl, naphthyl, indanyl, and am and nyl. or tetrahydronaphthyl (tetralin).

The terms aryl group I or aretic residue, when used herein, include a phenyl group or a naphthyl group as well as commonly denote a heterocyclic group or a heteroaryl group. a group or heterocyclic compound; the term arylalkyl group refers to an aryl group linked through an alkyl bridge.

the heteroaryl group and / or herein are stable

The terms heterocycles ¹ 'and / or heterocyclic compounds when they are 5- to 7-membered monocyclic or bicyclic, or 7 to 10-membered bicyclic rings, which may be partially unsaturated or aromatic, and which are carbon atoms and 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen may optionally be quaternized and include any bicyclic group in which any of the above-defined heterocyclic rings is fused to the benzene ring, the 1-leterocyclic ring may be attached to its a pendant group via any heteroatom or carbon atom, provided that the linkage provides a stable structure. The aromatic rings described herein may be substituted with a carbon or nitrogen atom if this substitution provides a stable compound. Aryl groups include, but are not limited to, for example, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzoturyl. : i., phenylene 1, indole 1 y1, i. n-1-enylene 1, quinolinyl 1, isocyanine 1, benzimidazolyl 1, piperidines 1, ^z ... per peridones 1 , pyro 1 idiny 1, 2 - pyro 1 idony I.,

Pyrrolidines 1, tetrahydro-furanyl 1, tetrabydroquinoline 1, tetrahydroisoquinoline 1, decahydroquinoline 1 and 1 ebooktabydroisocbinin 1, azooinyl, triazinyl, 6A7 ..... 1, 2, 5- thiadiazinyl, 2H, 6 / 7-1, 5, 2-dithiazines 1, thiophenyl 1, thietrene 1, pyrans 1, isobenzofuran 1, phenoxanthines 1, 2H-pyrrole 1 y, pyro 1 y 1 , iso 11. azo 1 y 1, 1 zoxazol 1 y 1, oxaz 1 y 1, pyrimidinyl, in doly 1, overwhelmed, imidazolyl, pyridirtyl, isolndolyl.

xanthene, pyrazolyl, pyrazlnyl,

3/7-iridolyl,

P y r i z y n y 1, i n d o 1 i z y n y 1,

1/7-ind i z 1 y 1, p r i n y 1, c h i n y 1, f t i n y 1, 7-t i n y 1, z e h i r t o i y 1, e t i d y 1, e h. n o x ery n y 1, c h i n y n y 1, c n n o 1 y n y 1, p r i d y n y 1, 4 era / 7 - k ery r b ery z o 1, k a r b a z o, e. - k a r b o l i n y 1, f e n a n t r i d i. n y 1, a n i 1, f n a n t r 11 n y 1, f n z 1 n y 1, f r t a r z a n y 1, f r r z a n y 1, f n a x y z 1 n y 1 imidazolidin 1, imidazolidin 1, irazazinyl 11, piperidinyl 1, piperazinyl 1, hexahydropyridazines 1, indolyl 11, isoindolin 11, equinucinyl 1, morpholiriyl or oxazolidinyl. Aryl groups also include fused rings and spiro compounds containing, for example, the above heterocycles.

perimidinyl, phenoxy, i. n y 1, pyrrolidirtyl,

P y r a z 1 i d 1 n y 1,

The term "aryl" as used herein refers to a stable 5- to 7-membered mortocyclic or bicyclic ring or a 7- to 10-membered bicyclic ring, which may be partially saturated or aromatic, and is formed from carbon atoms of 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen may optionally be an ethoxylated tertiary group. j ú 1 u b o v o n n b i c y k 1. j. c c u s k u p i. n, wherein any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group via any heteroatom or carbon atom, provided that such a linkage provides a ring structure. T u μ '-> o p 1. s a n é a r they a t :: i. The carbon or nitrogen atom substituted when this substitution gives: a stable compound. Aryl groups include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furyl (furyl), 11. and zyryl, thienyl, pyrimidyl,

P y r a z o ll. y 1, Im i. d and z o ll. y 1, t: a y o 1 y l., b e n o f u r y n y 1, b e n o o t y o f e: o y 1, i. n d o 1 y 1 i. n o 1 e n y 1, c o i o n y 1, i o o h o n o 1 n y 1, b e n o o o y y, p1 p e: d 1 n y 1, 4 - p o r 1 d y n 1, pyr o 1. d i. o y 1, 2 - p y r o i d o n y 1,

P YRO 11 ny 1 that: tetrahydro - f ^:: urany 1, te t r ti hy (Droe: h: i. 1 and no. Ny LL., Te: trahydroizochi no ll. Ll ins. Dekahydroohino 1 Other 1 and 1 e: booktahydroiso: i. no. 1, azoolnyl, triazinyl, 6 / 7-1, 2,5-thiadiazinyl, 2/7, 6 / 7-1, 5, 2. 1, thiophenes 1, thiaotrenes 1, pyran 1, isobenzofurans 1, e: noxane 11, 1 H-pyrrolyl, pyrrole 1, isothiazol 1 y 1, isoxazol 1 y 1, oxazo 1, 1. y 1,

P y r · 1 m i d i n y 1, p y r i d i z y 1, i o d o 1 i z 1 n y 1,

i. n mines 1, xantenyl, pyrazolyl pyraziriyl,

3/7-indolyl chromenyl, imidazolyl pyridinyl, isoindolyl

4/7-c-hlyl-11-naphthyridinyl, 4a / 7-arbazole, perimidinyl, phenylo-zinc,

P y rolidinyl, p y r a z o l. i d: i. n y 1,

1 / 7- i n d a z 1 y 1, p u r i n y l, o n 1 n o 1 i n y 1, f t a 1 and z 1 n y 1, c: h i n o x and 11 n y 1, c h i n a z o 1 i. ny 1, cinno 1 in 1, pteridiny l 1, kar baso 1, a - carb 1 in J., fe: nantrid: i_ ny 1, acridyl, phenanthrolines 1, phenylene 1, fe: for r-soot 1, furazanyl, phenoxazinyl, isochromanyl, chromanyl.

p y r o i i y y, im i d and z o i i i y y 1,

P y r a z o i. n y 1, if i d y n y 1, h e x a b y d o o y y n y 1, i. n d o ll. d. n y 1, d. z o d. n d o lJ. d. n y 1 m o r 1 d. n y 1 and ll. e b o o x a z o ll. i d d. phenyl. Ary 1 o e s p d. n y fused rings and spd.products comprising: a. e.

imidazolinyl, piperazinyl, o h i i d d. n y l. t t t a a a n ú ú k 1 a d d i w d. e

The term amino acid as used herein refers to an organic compound containing both a basic amino group and an acidic carboxyl group. The term includes natural amino acids, modified unusual amino acids, as well as amino acids that are known to biologically occur in free or combined form, but are not usually found in proteins. This term also includes m o d d. f: 1 k a n e a n e: o b v y k d e. n o k s s 1 d. n y, n a n l <1 a d d o p a s 1 R ober t s a Veli a e i. o in the publication T h e: P e: p t .i. d e: s, 5: 342-429, et al., 1983). Modified or unusual amino acids that can be used in the present invention include, but are not limited to, D-am inocyanates, hydroxy-1-hydroxy-4-hydroxypropyl, N-Cbz-protected amino acid, ornithine, acid: 11 nu 2, 4 - di amine n o as u, b oarginine, nor J., eucine, acid 1 j, N N-methylaminomethyl ú, naphthalenes 1 and 1 anine, ferry 1 g 1 yoline, β-phenyls 3. pro 1 in, ter. 1 eucine, 4'am 1 nocyk 1 oh exy I. and 1 chine, N -methy 1 - nor 1 eucine, 3, 4 - dehydropropin, N „N - d 1 methy 1 a τη 1-N-1-ynyl, N-methyl-1-yno-3-ynyl, acid 3.1 nu 4-amine 3-per-3-ynyl-4-carboxylic acid, 6-aminocaproic acid, traris acid -4- (aminomethyl) cyclohexanecarboxylic acid 2- (aminomethyl) benzoic acid

3-C (aminomethyl) benzoic acid and 4- (aminomethyl) benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid 3.-n-2-benzoic acid-5-amino-pentanoic acid.

The term "amino acid residue" as used herein refers to the portion of an amino acid (as defined herein) that is present in a peptide.

The term peptide, as used herein, means a compound that is made up of two or more weeks. amino acids (as defined herein) linked to each other by a peptide bond. The term peptide also includes compounds containing both peptide and non-peptide moieties, such as those resembling residues, or other non-amino acid residues. Such a compound containing both the peptide and non-peptide components may also be referred to as a peptide analog.

The term peptide bond as used herein refers to a covalent amide bond formed by the loss of a molecule between the carboxyl group of one amino acid and the amino group of the other amino acid.

The term prodrug, as used herein, is intended to be any covalently bonded carrier which, when administered to a mammalian subject, releases the parent active compound of Formulas I-III in vivo. Prodrugs of compounds of Formulas I-III the

The third group of compounds in the compounds is carried out in such a way that the modifications are cleaved either by conventional manipulation or in vivo to the parent compounds. Prodrugs include compounds of formulas (1) to (IV) wherein the hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfide hydryl groups, respectively. carboxyl group. Examples of precursors include, but are not limited to, acetic, methane, and benzo derivatives of amine functional groups in the compounds of formulas I-IV, phosphate esters, dimethylglycine esters, aminoalkylbenzole esters, aminoalkyl esters, and aralkylalkenyl esters. yl esters of alcohol and phenol functional groups in the compounds of formula (1) and the like.

The term pharmaceutically acceptable salts as used herein refers to derivatives of the compounds of the invention in which the parent compound of formulas I 'to IV is modified by preparation. in the form of an acid or base salt of a compound of formula I to IV. Examples of pharmaceutically acceptable salts. include, but are not limited to, salts of mineral or organic acids and basic residues such as amines; alkali or organic salts of acidic residues, for example, carbamides. n and after d.

Pharmaceutically acceptable salts of the compounds of the general formulas (1) to (1). IV include, but are not limited to, non-toxic salts or quaternary ammonium salts of compounds of formulas I-IV, formed, for example, from non-toxic inorganic or organic acids. Conventional non-toxic salts include, for example, salts derived from inorganic salts. n, n and n. k 1 a d k y s e l i n y c h1 o r o o o. s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. r o v e ... j, f o s f o r e l e s, s e l i n y d e s s e n e n e s 3. í. n, n and n. k 3. a d k y s e 1 i n y s u k c. n o ov, k s s 3.1 n y s u l f o m e ... i, k s s 3. i n y pod. ; and salts. prepared from acetic acid, glycolic acid, organic propionic acid.

stearic acid, lactic acid, malic acid, tartaric acid.

citric acid, ascorbic acid, pamoic acid, cyanoacrylic acid, cyanoacrylic acid, pamoic acid, cyanoacetic acid, cyanoacetic acid and pamoic acid. j, l <y s e 1 i n y g l l. u t o o e j, k y s e ll. i n y b e n o o e e, s s 11 n y s a ll. 1 c y ll. v, k k 1 1 1 1 f f f f f f f f 2 - acetylene fumaric acid, toluenesulphonic acid, methanesulfonic acid, methanesulfonate, ulphonic acid, cationic acid. o n y, s y 3.1 n y 2 - h y d r o x y e t s n s 3. f ó n o e j a p o cl.

The pharmaceutically acceptable salts of the invention synthesized from the compounds of formula I to III may be III, which, by chemical, base or or organic in various ways, contain the basic or acidic moiety by conventional means. Salts are usually prepared by reacting the free acid with a stoichiometric amount of the excess to form a 3% organic or acid or base in a suitable solvent, or with a suitable solvent. tadie 3 ..

The pharmaceutically acceptable acid salts of formulas (III ') to (IV) may be reacted with an appropriate amount of a base such as an alkali metal or alkaline earth metal hydroxide, especially sodium, lithium, calcium or magnesium, or an organic base such as an amine such as cl 3. benzylethylenediamine, triethylenediamine, pyrimidine, pyro 3.3. tin, benzylamine and the like, or quaternary ammonium hydroxide, for example tetramethylammonium hydroxide and the like.

^: arm. 3. d. 3. Acidic or steric acceptable salts. The compounds of the invention, as above, may be prepared by reacting the free base form of these compounds with an amount of the respective base, respectively. acids in water or an organic solvent or a mixture thereof; usually anhydrous media such as ether, ethyl acetate, ethanol, isopropanol are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., 1 * ack Publishing Company, Aston, PA, 1985), p. 1418th

, synthesis

The compounds of the invention can be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, used in conjunction with synthetic methods well known in the art of synthetic organic chemistry, or variations thereof, which can be derived by those skilled in the art. Preferred methods include, but are not limited to, those described below. All documents cited herein are incorporated by reference in the following.

The novel compounds of the invention may be prepared using the reactions and techniques described in this section of the application. The reactions are carried out in solvents suitable for the respective reagents and materials used and are suitable for ongoing transformations. It will also be apparent from the description of the synthetic methods below that all of the proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and production procedures, are standard conditions for the type of reaction known to those skilled in the art. of their knowledge can easily determine. It will be apparent to those skilled in the art of organic synthesis that functional groups present in different parts of the molecule must be compatible with the reagents and reactions proposed. In the case of such limitation of substituents, one of ordinary skill in the art must employ alternative methods.

A series of compounds of formula 21 are prepared by the methods outlined in Reaction Schemes 1 to 5. Deprotected 2,3-dlaminopropionic acid, 2,4-diaminobutyric acid and ornithine or lysine (Compound 1, Reaction Scheme 1) ) are converted using a coupling agent, such as BPO, to the corresponding amide compound 2. After the merger of 1 diaminobenzene followed by reaction in acetic acid at ⁶⁰ ° C, which produces a benzimidazole analog 3. 1 can also be converted to an aldehyde 4 which is put reacted with ammonia and a glyoxal trimmer to give the imldazole analogue 5.

of compounds 2, 3, and 5 k y s e 1 n y, n a p i k a and d

M ^{, ax} * ** - B nc: groups for dioxane, provides the protective compound 4N 1-IC1 in the

Removal of the side-chain group of compound 2, using hydrogenation affords compound 7.

deprivation

L use 5eoiou 6. and 5 pri.

A.

B.

R e a tio n s .1.

ABOUT

BocHN. JL

OH (\) n

NHCl 2 n = 0-4

BocHN

NHCbz

HNR ⁵ R ⁶ / BOP ^BocHN

( ⁵ ) n

NR ⁵ R ^p

NHCbz

1. NHCH 3 OCH 3 / BOP / DIEA / DMP

2. LiAlH 4 / THF

BocHN

Oh (\) n

NHCbz

NH: i / glyoxal trimmer MeOH

BocHN

(\) n

NHCbz

(\) n (\) n NHCbz

NH ₂

The synthesis of the 2,3-disubstituted Šukein acid moiety schematically expresses; Scheme 2 below. The acid halide (e.g., X = Cl) is converted to its oxazolinedione derivative 8 using n-butyl 11a. Evan's aldol reaction with glyoxalate (JACS, 1982, 104, 1737) converts compound 8 to an intermediate. 9. The oxazolidinone group is removed using H and 0 _a / L. OH and the resulting carboxylic acid is converted to the benzyl ester 11. Alkylation of 11 with t-butyl bromoacetate gives 12. The benzyl ester of 12 is removed by hydrogerization to give 13.

Removal of the t -butyl group of compound 12 gives the compound

14th

Reaction Scope 2

The macrocyclic ring formation of this series of compounds can be accomplished in two ways, which are schematically outlined in Reaction Schemes 3 and 4 below. The reaction of intermediates 6 and 13 produces intermediate 15. Hydrogenation is followed by deprotection to afford compound 16. Cyclization of compound 16 alternatively, compound 17 can be synthesized by reacting compounds 7 and 14 and then deprotecting and cyclizing as shown in Reaction Scheme 4. Saponification of compound 17 followed by HPLC separation with a coupling reagent such as BOP. two isomers 20a and 20b are obtained by the reverse phase. The final two products 21a and 21b are obtained by combining compounds 20a and 20b with O-benzylhydroxylaminohydro.

chloride and subsequent hydrogenation.

6 + 13

1 H ₂ / Pd / C

-> second 4 N HCl / dioxane

BuO ₂ C

R e a tio n s 4

R e a k a s c h e a b)

1. LiOH / THF

2. HPLC

ABOUT

21

R ¹

21b

Additional series of compounds of formula 30 are synthesized as outlined in Reaction Schemes 8 and 7 below. Cyclic 2,3-diaminopropionic acid is substituted with triphenyluronic acid. with a side chain group, 2,3-diaminobutyric acid and ornithine or n 22 ski were combined, with alkylamine or then alkylated to give compound 23a. The amino acid derivative 22 can also be converted to the methyl ester, which is then alkylated to give compound 24. Removal of the TFA group from compound 24 and subsequent protection of the resulting amine at. use of benzyl chloromethane provides compound 25. This compound 25 can be converted to the benzimidazole derivative 23b or the imidazole derivative 23c. Removal of the TFA group from compound 23a at. using an L..1.0H or Cbz group from 23b and 23c at. use of hydrogerization affords intermediate 26. Cannon compound 30 is obtained using the procedures outlined in Reaction Scheme 7, which are similar to those used to synthesize the first series of compounds 21 (Reaction Schemes 4 to 5 above).

Reaction scheme 8

BocHN

ABOUT

X OH

1. H NR ⁵ R ⁵ / BOP / D1EA / DMF

2. R ^e X / K ₂ CO 3 / DMF / 100 ° C (On

NHTfa 22

BocHN. > L

X ^ NR ^S R ⁶

Qn

NHR ⁵

23a

BocHN

R ²

23a, 23b, 23c

LOH / THF or H3 / Pd / C / MeOH (< Qn

NHR ⁶

Reaction scheme 7

HOHN

HOHN

30a

30b

Another series of compounds of Formula 43 is prepared by the methods outlined in Reaction Schemes 8 and 9 ^{below. Nα-} Cbz-serine or homoserine is converted to the corresponding amide which is alkylated with ethyl bromoacetate to give compound 31. Another starting material. material which .is N-Boc ^{al fa} ..... Serir or homoserine is converted to benzyl ester that is also alk y lu. is ethyl bromoacetate to give compound 32. The benzyl ester from compound 32 is removed by hydrogenation to give compound 33, which can be converted to the benzimidazole derivative 34 or the imidazole derivative 35. compound 31, which deprotects the Boe group to yield 3. Product 36.

Removal of the Cbz protecting group z.o is from the compounds 34 and 35 with acid

Reaction scheme 8

Cb _Z HN 2 OO ₂ H ₁ . _{HNRS (16), BOF} , _(D , _{EM) M} pb ₂ H _N = CONR = R =

B.

(Forces

2. E t y 1 b a t a c: e t a t

OH NaH / THF (S • CO ₂ Et

BocHN. CO ₂ H BocHN. .CO ₂ Bn

1. BnBr / NaHCO3 / DMF

2. Ethyl bromoacetate NaH / THF (Si

OH (Si

H ₂ / PdC / i-prOH

CO ₂ Et

BocHN. CO ₂ H (Sl

(S 'CO ₂ Et

O CO ₂ Et

1. NHGH3OCH3 / BOP / DIEA / DMF 2. UAIH4 / THF

3. NHVglyoxa! trimer / MeOH

BocHN

C.

_R H / Pd-C / i-PrOH and ^H ± 2 ^N <^ ^{r 2}

31, 34 or 35 -; - ► =

4NHCl / dioxane (Sn ^of the ^ '' 36

N HCl / dioxane CO ₂ Et

Reaction scheme 9

H ₂ O ₍ 1-iOH ₎

THF OC

-N

ButoaC

BrBuk ^ C

R ¹

2LDA (THF) -78 ° C

R ¹

2. LiOH / THF

NH ₂ ^H 2 ^C ° ·

1. H ₂ / PdC / EtOH / HCl ----> B 1 O 3 C

BOP / DIEA / CHCl

Hohn

Bu ^ C;

H

θΊΓ 'h) 1.4 N HCl / dioxane HPLC R ¹ 2. BnONH ₂ HCl / BOP / DLEA / DMF. 3. Ha / Pd / C / MeOH 42 ° C T B ίγχ ° u t : H R ¹ HOHN .J ABOUT R ¹ 43a 43b

Synthesis of the disubstituted succinic acid derivatives of formula 39 is shown in Reaction Scheme 9 above. Alkyne 1 of the Effect 8 tbuty 1. Bromo Acetate cm cm Provided from 1 to 37. alkylation of the resulting acid 38 with bromoacetonitrile gives a mixture of two isomers 39. Combination of isomers 39 and compound 36 with subsequent hydrogenation and saponization affords compound 41. The cyclization using BOP affords the cyclic compound 42. t-butyl is removed with acid and isomers removed separated by reverse phase HPLC. The carboxyl group of both isomers is converted to the corresponding O-benzylhydroxamide and subsequent hydrogenation affords the cannon products 43a and 43b.

Another group of compounds of formula 51 is prepared as outlined in Reaction Schemes 10 to below.

11. Reaction of cysteine or homocysteine with halo nitrobenzene and subsequent treatment of the resulting intermediate with t-butyl bicarbonate affords | ^and,: "* · ^R · N-Boc-S-2-nitrofenylcysteín or - •• homocysteine 44. The compound 44 is converted to amide 46 or a benzimidazole derivative 45. Deprotection of compounds 45 and 46 in use, provide the intermediate ester 47th

Combination of compound 47 with the formula 48. A mixture of acetic acid and water using 4N HCl in dloxane.

the acid component 8 provided is reduced in use. The macrocyclization of compound 49 yielded two isomers 50a and 50b, which separated in silica gel. The saponification of each isomer and the subsequent use of the BOP, hydroxylamine-merge column provides the target products 51a and 51b.

Reaction scheme .10

1. LiOH / THF

2. ΝΗ2ΟΗ hci / bop / diea / dmf

51b

51b

A further embodiment of formula (61) is synthesized according to the methods schematically shown in the following:

The carboxylic acid in the side ^L * ^R N-Boc-aspartic acid, or the reaction schemes 12 and 13 re L azcibenz y1estern yse1iny of benzyl N "* ^{3 t-Boc-glu} Lam j is reduced to the alcohol using a foxtail and the alcohol was converted to thromide using tetrabromomethane and triphenylphosphine. Reaction of compound 53 with acetoxyphene affords intermediate 54. The benzyl ester would be drug. The resulting carboxylic acid is converted to the amide, berizimidazole or imidazole. The saponification of compounds 56a to 56c for removal of the acetyl group and subsequent treatment with 4N HCl in dloxane for removal of the t-butyl group yields compound 57.

Reaction of intermediate 38 with trifluoromethanesulfonate affords 58. Combination of acid component 58 with compound 57 yields compound 59. The benzyl group of compound 59 is removed by hydrogenation and the resulting alcohol is converted to the bromide at α-triphenyl. f o s f ín. The process is carried out when used for the purpose of the process. 60. The t-butyl group is removed by TFA and the resulting carboxylic acid is converted by treatment with hydroxylamine or hydroxamic acid from the catalyst 61.

p o u t h e t r a b r e mm e t í t í u s s s,,,,,,,,,

BocHN

CO ₂ Bzl

H ₂ / Pd C / i-PrOH

Reaction scheme 12

ΛΤ ⁰ * * (Γ7 ^ ⁽

BocHN - ^{/ -} CO ₂ H 55

H ₂ N '

BOP / DIEA / 2. AcOH / 60 ° C

BocHN

1. NHCH ₃ OCH ₃ V ^NR5R6 ^ ^{0P / DLEAroM} F BOP / DiEA / DMF

2. LiAlH 4 / THF

3. NHs / Glyoxa! TriMet

56b (Ex

BocHN 2 O ^{5 -5} 56c

OAc

OAc

1.LOH / THF, 2.4 N HCl / dioxane

H? OH, 7

Reaction scheme 13 +

OTf

Bu ^ C

LDA / THF / -78 ° C

Another series of compounds of formula 67b is prepared according to Reaction Scheme 14 below. The side chain of the aspartic acid derivative or glutamic acid derivative is reduced to the alcohol which is converted to the bromide 62. Reaction of compound 62 with sodium acetylide affords compound 63 which is converted to the amide, benzimidazole, or imidazole derivative 64 as described above.

Alkylation of 11 with bromoacetal followed by acidic yield or intermediate 65. Use of the 66. Removal of the Bn group by treatment and reaction with hydroxylammonium The reaction of 65 with 64 in reaction with a compound of formula (64). The oxidation of the protective Boe group by acidification followed by cyclization in use. BOP affords cyclic compound 67a. Saponification followed by hydroxyl amine affords the target compound 67b.

merger

R e a tio n s: h e a 14

A.

CbzHN

1 == - The

2. TFA

II formation of the amide, imidazole

BocHN

a 1 e: b o b e n im 1 d and z o 3. u

B.

+ Br

OR

JDR

I.NaH / THF , ΐ 2. HCl 3. NH 2 OH ^ CO ₂ Bn BuO ₂ C R ¹ 65

1. HCl

2. _H2 / Pd-C

3. BOP / DIEADMF

67a

1. LiOH / THF

-> second ^ ^ ΝΗ ΟΗ ΒΟΡ / ΟΙΕΑ

HOHNOC

67b

Another series of compounds of formula (71) is synthesized according to the procedure outlined in the reaction scheme below.

AI. The reaction of the compound affords compound 69. The protecting Boe group and the Bn group are removed and the macrocyclization is carried out using 3. BOP. The saponification and subsequent coupling with hydroxylamine affords cannon compounds 71a and 71b.

d e r i v t o m t r · y p t o f u n

Reaction scheme 1.5

HOHN

and

71b

Compounds of formula 75 may be prepared as described in the reaction scheme below

16. The succinate 61 can be combined with the I30P reagent to form a tyrosine derivative to form the amide 72. Removal of the protecting benzyl group of the dihydrogen and alkanol provides an alcohol that can be converted to the bromide 73. Macrocyclization yields compound 74. Tert. the butyl ester is converted to an acid by deprotection to a benzyl protected hydroxamic acid. Removal of the protecting groups by hydrogenation affords the title compound 75.

Reaction scheme 16 +

HX

(Cham

H ₂ N 1 R 2 m = 1-2

1. H ₂ / Pd-C / MeOH / HCl

--2. CBr ₄ / PPh 3 / CH ₂ Cl ₂

HX

^B 1 (CH 2) n O (CH ₂ ) m -BuO ₂ C ' ^X ^ i ^/ ^ ^X R ²

R ¹

Cs ₂ CO 3 / DMF / DMSO -> -

1.TFA (CH ₂ ) n O (CH ₂ ) m ΛΛΛ 2. BnONHjj / BOP

t-BuO ₂ C '£ £

R ¹ _R 2 dieaomph 3. HyPd-C / MeOH

HOHNOC (CH ₂ ) n O (CH ₂ ) m

ΑΛΛ

R ²

R ¹

Compounds of formula 79 can be prepared by the method outlined in Reaction Scheme 17 below. Succinate 61 can be used. BOP of the reagent to combine with the histidine derivative to form amide 76. Removal of the protecting benzylcarbamate group and benzyl ether under hydrogenation conditions affords an alcohol that can be converted to bromide 77. Lacrocyclization affords compound 78. Tert. the butyl ester is deprotected to an acid which is converted to a benzyl protected hydroxamic acid. Removal of the protecting groups by hydrogenation affords the title compound 79.

Reaction scheme 17

Br.

1 H ₂ / Pd-C ->.

2. CBr ₄ / PPh ₃ t -BuO ₂ C v vnjyii v ^ π π ₂ ;

HR = HR ¹

R ¹

1. TFA

2. BnONHs / BOP / DlEA

---> 3rd H ₂ / Pd-C

(CH 2) n O (CH 2 m 2)

HOHNOC

· · · H

CIC

Compounds of formula 84 are as outlined in Reaction Scheme 18 below. Succinate 38 can be converted by LDA to enolate and alkylated with trifluoromethanesulfonate to give compound 80. This material can be prepared by compounding a derivative of

The use of liposomes will also provide amidhydrogenation esters of the theacto-reactive actin 1 a, Phases 3 and 1, and the novel 81. Removal of protective benzylic conditions affords amino acid 82 of 3. 83. T erc. 3. The protective group is converted to an acid which, by deprotection, is converted to a benzyl-protected hydroxamic acid. Removal of the protecting groups by hydrogerization affords the title compound

100

Reaction scheme 18

cbz

Bn N _N ^ _{T f} of f $ LDAfrHFA76 C \ _{Hj) n-Q}

(CH ₂ ) m

Λ.

ΛΛ t-BuO ₂ C '' OH ''

HpNľXR ²

BOP / DIEA / DMF

H ₂ / Pd-C

(CH ₂ ) n O (CH 2 m 2)

ΜΛ

Bn _X N

Cbz 2 (CH ₂ ) n O (CH ₂ ) m

- JL JL 1 t-BuO ₂ C 1 H 2 ^R 2 R ¹ 81

BOP / DIEA / DMF t-BuO ₂ C

1.TFA

BOP / DIEA

HN (CH ₂ ) n O (CH

NIGHT - H

101

Compounds of formula 98 can be prepared as outlined below in Reaction Scheme 21. Succinate 38 can be converted with LDA riolate and alkylated with trifluoromethanesulfonate to give compound 95. This material is combined using a lysine BOP reagent. derivative to give amide 96. Removal of benzylcarbamate protecting groups at. hydrogenation conditions and saponification of the ethyl ester yields: an amino acid. However, recyclization yields compound 96. Tert. butyl with ter is deprotected; to an acid which is converted to a benzyl protected hydroxamic acid. Removal of the protecting groups by hydrogenation affords the title compound 98.

Reaction scheme 21

R ¹ »6

102

Compounds with _; Succinate 58 can be combined with the tryptophan derivative according to the above Reaction Scheme 22. By reaction of OP, the amide 99 is formed to form the amide 99. Removal of the protective benzyl groups and conversion to the tosylate affords compound 100. Macrocyclization affords: The tert-butyl ester converts the compound to the acid by deprotection,

One hundred and first

to be converted to benzyl protected hydroxamic acid. Removal of the protecting groups by hydrogenation affords the title compound 102.

Reaction scheme 22 +

R ²

NaH / DMF

102

103

Compounds of formula 108 can be prepared as outlined in Reaction Scheme 23 below. Imiel 8 can be converted to the enolate and alkyl trifluoromethanesulfonate using L. D A to give compound 103. The chiral auxiliary is then saponified. to the acid 104. As in the previous case, this material can be converted by LDA to the enolate and alkylated with trifluoromethanesulfonate. The resulting compound 105 is combined, in use. The BOP of the reagent, with the tyrosine derivative, gives amide 106. Removal of the benzyl protecting group under hydrogenation conditions provides an alcohol that can be transferred to the pile. Macrocyclisation P o c t i n i n i n e n 107. T e r c. A compound of the formula: which yields the desired compound 108.

104 .7

R e a tio n s 2 3 + VI

LDÄ / THF.

OTf

t-BuOg

LiOH / H + / THF

xc

R ¹

103 t-BuO ₂

OH

^ηΟχ ^, ΟΤί t-BuO ₂

(CHaJn _R 1

? H

104

LDA / THF

BnO

105

(CH ₂ ) m

H ₂ N 2 R ²

BOP / DIEA / DMF ^νΒυ ° ²

HX

(CH 2 R ¹

O (CH ₂ ) m 1.H ₂ / Pd-C _n a _{f 2} 2. CBr ₄ / PPhyCH ₂ Cl ₂ ^H 3. K ₂ CO 3 / DMF

BnO

106

R e a tio n s 4 4

4-nitrophenyl · ^1- chloroformate t-BuO

-> NMMZTHF

OR ¹

Cozma

CbzHN

K2CO- / DMF

OR ¹

X x t -BuO4 'Y' ^ COaBzl

114

O-benzylhydroxylamfnhydrochlorid

BOP / NMM / DMF

106

107

A further series of compounds of formula 131 is prepared as outlined in the Schemes 25 to 27 below. Methyl 3S-4-benzyloxy-3-hydroxybutyrate (119) was prepared as described in Abood, IM. A. Synth. Commun. 1993, 23, 811. Stereoselectivization of allyleate of compound 119 with allyl bromide 120 gives compound 121. After ester hydrolysis, the resulting acid 122 is coupled with suitably functionalized lysine (123 n = 2), ortho (123, 1) == 1) or 1,4 -diamlnobutyr (123, rrd). Reaction of compound 124 with 1,1'-1,4-dibromo-2-butenone gives bromide 125.

When using a weak base, the cationic acid is 1 d. z a c i a. in . 1 - D e d i n d i d - 1 u s 1 After removal of the I30C group n a n d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d z o r o p y 3. e t y 1. amí n u,

The resulting cyclic amine is protected with bicarbonate. Treatment of Compound 127 Pd (OH) p. under nitrogen leads to the reaction of both olefinic bonds as well as to cleavage of the benzyl ether. Oxidation of alcohol 128 followed by treatment with O-benzylhydroxyamine yields compound 130. At this point, the R @ 3 group is introduced by acid hydrolysis of the I30C group and reaction with R @ 1 - (33).

3..08

Reaction scheme 25

OH OH II b-Xä '-SA,

OMe _R 3 =

OH O

119

R ² y, "

NaOH, MeOH ---

H ₂ 0

NHBOC

NHBOC

OH O (CH ₂ ) _n . f γ'ΧΠ, w ^H fl ( ^CH α ^{) n}

Rn (Rn) ^Bn ° ^{X /} ^^ U ^ CONR ^

122 ^B X ^C

CH ₂ Br

NaH, DMF

BOP, iPr ^ NEt. DMF _R 3

CH ₂ Br

BnO

R ²

124

NHBOC γ 5 p> m ^ confXr ⁵

R ²

R ²

125

109

Reaction scheme 26

CH ₂ 8r

NHBOC

OO 2 (CH 2 n HCl _N - / -) CONRS ⁶

T ¹²⁵

R ²

CH ₂ Br nh ₂ oo (CH ₂ ) n _n ^ _CONR 5 _R si H

R ² J,

HCl salt R * 126

N '

BOC iPr ₂ NEt CH ₃ CN

BnO

OO (CH ₂ ) n 5/6 ⁵ d ^{6 3} 3

Ύ ¹²⁷

R ^ť

BOC

H ₂ , Pd (OWC 0 O (CH ₂ ) n)

R ¹

128

110

128

BnONHi iPijNEt DCC.HOBt.THF ---> -

H ₂ . Pd / _BaSO4 or

-> 1) HCl

2) R ⁴ -C ¹

3) H2, Pd / _BaSO4

131

1.11

Another series of compounds of Formula 133 can be prepared as outlined in the Reaction Scheme below.

28. Reaction of alcohol 124 with sodium hydride and 3-bromo-2-bromomethyl-1-propene yields compound 132. Compound 132 is converted by the following procedure, which is an analogue of the procedure depicted in Schemes 28 and 27, to a compound of formula 133.

R e a tio n s 2 8

br

-_>

NaH, DMF _n g Q

CH ₂ Br

NHBOC f> ^ (CH ₂ ) ΛΛΛοο conr ⁵ r ⁶

The schemes outlined in Schemes 26i, Reaction and Reaction Schemes

132

133

13.2

The invention also includes cyclic hydroxamates. as described in Reaction Scheme 29. In the first step, succinate 134 is combined with the L-lyzínC N ⊕ ^{F "3i lor,} Cbz) -NHľle give the amide 135. The primary alcohol of the amide 135 using RuCl ^ .HaO oxidized to the acid 136 After removal of the carbamate group, macrocyclization afforded the lactam 138. The t-butyl ester of compound 138 is then converted to acid 139. This acid is combined with BnONI-1 · -. to form a hydroxamate 140 with a protecting group. Hydrogenation of the hydroxamate 140 gives the canned hydroxamate 141.

R e a tio n s 2 9

RuCl ₃ · H2O

H ₅ 1Os _r ch ₃ cn cci ₄ . h ₂ o

136R = Cbz) H? 137 R = H. / Pd / C

138U = CO ₂ tBu J TFA BOP / 139U = CO ₂ HH ₂ NOBn \ 140U = CONHOBn \ _H

141UeCONHOH> p§

1.13

The present invention also includes compounds which may be obtained by methods described in Reaction Scheme 30, to allow easy change of ^{R: p} in the formula 145a. In a first step, the succinate 134 is combined with L-lysine ( ^lor, -Cbz) -CO 2 Me to form an amide

142. The primary alcohol amide 142 is treated with RuOI. _{: 3} .1-1-.0 of the oxide is on the acid 143. After items 13 and 3, the conversion of the carbamate to the macrocyclic group I is as follows: 144. The 144-t-butyl ester of compound 144 was then protected using a standard protected hydroxamate 145. The methyl ester hydroxamate at 145 was hydrolyzed. using LiOH. The resulting acid 145a was treated to give the desired R ⁷³ substituent. Hydrogenation of compound 146 gave the target hydroxamate 147.

1.1.4

Reaction scheme 30

R ¹

BOP

134

L-Lys (Cbz) -CO ₂ Me iPr ₂ NEt © uOjC

, ch ₂ oh (CH2) ₃ NHCbz RuCb + lsO tx 1) » N COžMe HslOs, CH ₃ CN CCl ₄ , H ₂ O R ¹ • 142

HBTO iPint, DMF

j

HNR ^S R ⁶

143 R = Cbz J h ₂

143aR yp = H _H 144 _R 2 _{= C} a Me _2, u = _CO2 tBu \ TFA

BOP / 144a R ² = CO ₂ Me, U = CO ₂ H> H ₂ NOBn \ 145 _{R2 = C0} ^ _Sj u = CONHOBn \

145a R ² = CO ₂ H. U = CONHOBn> ^UOH

U = 146 CONHOBn, R ² = CONR ⁵ R ⁶ \

147 U = CONHOH, R ² = CONR ⁶ R ^S J

The present invention also includes cyclic amino carboxylates of formula II, where U is CO _with H, R '''is H, X is NH, ^R1 = alkylaryl, Y = CC 0) NH-, R ² represents hydrogen. R ³ is -C (O) NH 1, C is alkyl, B is -C (O) NH, A is alkyl. Reaction Scheme 31 indicates how this compound can be obtained from α-Fmoc-ND-glucamine or α-butyl ester to Fmoc-ND-aspartic acid by standard peptide chemistry. Standard I3C.1R coupling of this material with compound 7 affords amide 148. The fococ group can be converted to the primary amine 149 followed by alkylation with trifluoromethylsulfonate to the secondary amine 150 CKogan

t.r .; Somers T.C .; Venutti 1 * 1.C. Tetrah & Dron 1990, 46, 6623).

Double deprotection through hydrogenation affords amino acid 151, which can be cyclized to form macrolactam 152. Simple deprotection with TFA provides the desired cyclic aminocarboxylate 153.

110

Reaction scheme 31 tBuOsC ', CO ₂ H n BOP, iPr ^ NEt' NHFmoc 7

TfO4 ^ CO ^ nBuOaC

R ¹

150 ^x R = Bn, R = Cbz \

151 R * = H, R ^y = HJ

152

153

The invention also includes a cyclic amino carboxylates of formula II, wherein W is - (11th:. 1-1, R ⁺ is H, X is NH, ^R1 is alkylaryl, Y is -NHCCO) -, R ^p is hydrogen. R ³ is -C (O) N 11-11, C is alkyl, B is -CXONH, A is alkyl. Reaction Scheme 32 indicates how this compound can be obtained from Frnoc-ND ... lysinic acid t-butyl ester and 1-tert-butyl ester Fm α-N-D-ornion by standard peptide chemistry. . Standard BOP amalgamation of this material with L.-M ^{, α-} β-Cbz-glulamic acid methyl ester or LN ^alpha -aspartic acid affords amide 154. The Fmoc :: group can be converted to primary amine 155 followed by alkylation with Trifluoromethylsulphonate, described in 1 sec., is followed by a reaction scheme, to the secondary amine 156. Double depletion of ocular :::: Coupin through the hydro gene 1., iuposkytneaminokyse I i rt u

157, which can be macrocyclized with BOP to form lactam

158. Saponification of lactam 158 by standard BOP and methylamine compound affords amide 159. Simple deprotection with TFA affords cyclic amiriocarboxylate 160.

1.1.8

Chemistry 82 tBuOaC reaction, ₂ N NH

NHFmoc

156 R ³ = Cbz, R ⁴ = Bn i _w 157 R ³ = HR ⁴ = H Sa

159

160

119 is also a C 1-4 alkyl amine of the formula 11, wherein U is -09-1-1, 11 is arylalkyl group. , H, R ³ is

Invention with a general hydrogen atom, X is -NH, R ¹ is Y is -CCONH-, R ^a is atom

-CC0) NI-other, 0 is alkyl, B is -O- _d-b | .CO _R .....,

A represents an alkyl group. Reaction Scheme 33 indicates how this compound can be obtained from the N-B α-C α-aspartic acid t-butyl ester or the t-butyl ester of the N-B α-C (a) t-butyl ester. -glutamic by standard peptide chemistry. The β-acid is converted to aldehyde 161 by Weinreh reaction procedures (Wernic D .; DiNaio J .; Adams J, J. Org. Chem. 1939, 54, 4224).

This material can be converted by reaction with ^a Wlttlgovej

4-Cyclohexyl-phenylamine 11-phenylamino-phenylenediamine C t and nc and terlin and clephine with a compound of general formula I

162. The serine amide is compounded with Formula 163 to form the ester 164. The Boe protected amine of ester 164 is deprotected with HCl to give the primary amine 165. The primary amine can be alkylated as described above to form the fluorosulfonate fluoride to form the secondary amine. 166. Double deprotection through hydrogerization affords amino acid 167, which can be converted to lactam 168. A simple macrocycle with a B 0 P removal of the protecting group by TFA provides the cyclic aminocarboxylate 169.

120

R e: a c c h h a c 3 h, CHO n

tBuO 4 NHBoc 161

162R = Bn Λ 1) H ₂ . PdC 163 R = H> 2) LiOH

DCC, DMAP tBuOgC

164 _R2 = Boc, _R3 = Cbz \ HCl

165 _R2 = H, _R3 = Cbz yl toluene

121

The invention also encompasses cyclic amnocarboxylates of formula II wherein U is -CO-II, R * is hydrogen, X is -NH, R ^x is alkylaryl.

Y is -C (O) NH-, R ^a is - (R) (O) NH 1, C is alkyl.

hydrogen. R 'B means means

C 1 'represents an alkyl group. Reaction scheme 34 indicates by way

0, 0-, how this compound can be obtained from N-Fmoc-C (D) -D-homoserine t-butyl ester by standard peptide chemistry. The primary alcohol of the Sherin derivative can be coupled to the phenol thyroid derivative through the Illeunobu reaction to give compound 170 (Hughes D.I. Org. React. 1992, 42, 335). The Fmoc was deprotected with Et 2 -NH to give the primary amine

171. As mentioned above, this primary amine is alkylated with trifluoromethylsulfonate to form a secondary aniline.

172. Double deprotection through hydrogenation provides; amino acid 173, which can be converted to lactal 174 by macrocyclization with BOP. Simple removal of the protecting group by TFA affords: cyclic amnocarboxet 175.

^{Reaction; to} chemistry

22.1.

Ο ₂ 0

CONHMe t 170 R = F ^mOC Et ₂ NH ₁₇₁ R = H

BOP iPr ₂ NH

174

123

The invention also include, e s cykliek amino carboxylates of the general 'Formula II, wherein W is CO; .H, ^Ac is R, hydrogen, X is NH, ^R1 is alkylaryl,

Y is -C (O) NH-, R ^f is H, R ⁵ is -CC0) NHľ1e, II '. 13 represents - (COCO) NH-, A represents an alkyl group. Reaction scheme 35 indicates how ... it is

M-Cbz-C10 -L.

- aspartic from methyl glutamic acid or N- Cbz - (-L ..... methyl ester)

using standard peptide chemistry. This material can be bound. to 2-N-Boc-amlnomethanol by DCC and DMAP to form ester 176. Functional group manipulation in use, standard chemistry results in acid formation followed by amide 177. The 13oc group amide 177 is then removed by TFA to give a compound of formula 178. This material ... can be attached to N-Fmoc-CoO-D-glutamic acid t-butyl ester or 'N-Fmoc- (tf) -D-aspartic acid t-butyl ester to give amide 179. Fmoc It is removed with diethylamine to give the primary amine 180. As mentioned above, this primary amine can be alkylated with trifluoromethylsulfonate to give the secundary amine. I30P provides lactam

181. Double deprotection and macrocyclization of this amino acid by

182. T i n t h e t h e t h e n e t h e n e t e c e s TFA yields the cyclic aminocarboxylate 183.

124

Reaction scheme 3Γ5 ^Ηθ2θ -ή) π m BocHN '

CbzHN ' ^X ' ^with CO ₂ Me DO

RHN

TFA {

177 R = Boc 178 R = H

TfO _x ^ _/ CO ₂ Bn

R ¹ tBuOgC

I.HyPd -C

R ¹

181

182

R ¹

183

125

The present invention also includes cyclic amino carboxylates of general 'formula 11, wherein U is -80-.11, R ⁴ is H, X is NH, ^{R: L} = alkylaryl.

Y means

-CCO) NHR ^{72 represents a} hydrogen atom,

R @ - represents

-C (O) NH 1 - C represents an alkyl group, B represents an -NR 2 -, - A represents an alkyl group. Reaction Scheme 38 indicates how it is possible to obtain this compound from the acid ester

N-Fmoc-C10-L-aspartic or N-Fmoc t-butyl ester

-L-glutamic using standard peptide chemistry. As described above, the acid can be converted to ⁷² to aldehyde 184 in use. Weinreb's chemistry. This aldehyde may be involved in the reductive amination with a lysine derivative, resulting in the formation of amine 185. After deprotection by C18-18, it is removed with diethylamine. Fmoc to form the primary amine 185. As mentioned above, this primary amine can be alkylated.

Double deprotection via hydrogenation affords amino acid 187, which can be converted by macrocyclisation with BOP, to poppy thymus 188. Easily deprotection with TFA affords cyclic aminocarboxylate 189.

1.26

Reaction Scheme 36, CHO n

CbzHN

MeHNOC tBuOgC NHFmoc

AcOH. NaBH ₃ CN

CONHMe

183 R = Fmoc, R ₂ = H * \ (Boc) ₂ O

184 R = Fmoc, R ₂ = R Boe

185 R = H. R ₂ = Boc

TfO '^^ _{of a,} CO ₂ R ¹ B n ^ tBuO

CONHMe

BOP iPr ₂ NEt

186 R ₃ = CH n, _R4 = Bn, _R5 = Cba 187R ₃ 8n = _{CH2, R4} = H, _R5 = HJ

H ₂ Pd / C

ROjjC

tc _A f 188 R = tBu, R ₂ = Boe, R ₃ = CH 3 n = 189 TFA R = H. R ₂ = H, R ₃ = CH ₃ Bn

127

Another series of compounds can be synthesized as outlined in Scheme 37. The succinate 134 is coupled with L-N lyzínC ^L * ^a * -l LTS) -NHľle afford the amide 190. This material ial, cyclizing the ňitsunobuových conditions and give the macrocycle 191. The t-butyl ester of cycle 191 is converted to acid 192. The resulting acid is coupled with BOP to Ι-1-Ni (Br) to give the hydroxamate 193 with a protecting group. Hydrogenation of the benzyl group gives the target hydroxamate 194.

Reaction scheme 37

R ¹

134

Ŕ ¹

DIAD

PPh ₃

190 R = 2.4, e- (Me) 3-C _with H2 so ₂ r /

TFA f 191 R = 2.4,6- (Me> 3-C6H ^2. R ² = CO ² tBu.

192 R = 2.4, G (Me>3-C5H2> R ² = CO 2 H H _H HoNOBn Z 193 R = 2,4,6- (Μβ) _3-Ο ε Η _second R ² = CONHOBn '

Pd 194 R · -. 2.4 and - (Μθ) 3ΌβΗ2, ^R2 = CONHOH

128

Another series of compounds can be synthesized as outlined in Reaction Scheme '38. The mesitylene sulfonamide 191 of Reaction Scheme 37 is converted to amine 195 with HBr. The amine 195 obtained is reacted with Boc _and O to give carbamate 196. Carbamate 196 is coupled with H 3 NO to H 3 OH to give the hydroxamate 197 with a protecting group. I-lydrogenization of the benzyl group gives the hydroxamate 198, which is converted to the amine 199 with HCl.

R e a tio n s 3 8

191 R ² = CO ₂ tBu

195 R = H (HBr, R ² = CO ₂ H) _(Boc) . _o BOP Z196R = Boc. R ^ ² = 00>

H ₂ NOBn \ _{197r Boc =} R ² = CONHOBn, ₂ h, 193 Boe R = ^R2 = CONHOH> Pd ^HCl K199 R = H <HCl. ^R2 = CONHOH

Mts SO ₂

129

Another series of compounds 205 can be synthesized using procedures outlined in Scheme 39. The succinate 134 is coupled with N-methylamide L-glutamátCx-C 0 _R B n) to yield the amide 200. Removal of the benzyl group, the compound is cyclized under the conditions of a ľlitsunobuových give the macrocycle 202 The t-butyl ester of cycle 202 is converted to acid 203. The resulting acid is bound to BnIMOBn to give a hydroxamate 204 with a protecting group. Hydrogenation of the hydroxamate 204 yields the target hydroxamate 205.

Reaction scheme 39

R ¹

L-Glu (CO28n) -OH iPr ₂ NEt

BOP tBuO2

R ¹

134

200 R = Bn \ H ₂₂₀₁ R = H> pd

DIAD

PPh ₃

R ¹

TFA (202 R ² = CO ₂ tBu ^- 203 R ² = CO ₂ H ^B0P _H (204 R ² = CONHOBn ^{1 H} 2 ^NOBn Pd 205R ^Z = CONHOH: 1.30

Compounds of general formula 3004 in which Z is N-alkyl amide, imidazole or benzimidazole can be prepared as shown in scheme 40 below. Deproionization of compound 8 with a strong base (e.g., LDA) and with a single base. Combination of intermediate 3000 with intermediate 7 using standard peptide chemistry yields 3001. Removal of the chiral auxiliary followed by deprotection of the amino group yields an amino acid of formula 3002. Hydrolysis affords compound 3003. Hydrolysis affords compound 3003. Esterolysis by subsequent formation of hydroxylamine with

O-benzyl protecting group and final hydrogenation affords the title compound 3004.

131

Reaction chemistry 40

1. LiOHTTHF

2. BnONH ₂ / BOP / DIEA

3. Hj / Pd-C

HOHN

132

Compounds of general interest. and r 3010, wherein Z is

N-alkylamide, imidazole, or a compound of formula 41. Intermediate product 3005, reaction scheme 40, alcohol 3006. Mitsunobu benzimidazole, may be prepared from the following. ž š i. The preparation prepared in the same manner as in v is treated with a weak base and provides a reaction with an appropriately substituted tyrosine derivative to give compound 3007. Removal of the thrombolytic moiety. e d k u a d e r o t o n o n c. o u a m i n o s k u p i. n y to obtain the amino acid of formula 3008. Macrocyclization affords compound 3009. The conversion to the desired final product 3010 is carried out in a manner analogous to the procedure outlined in

The above reaction scheme 40.

133

Reaction scheme 41

NHBoc

3007

3009

3010

1.34. C D l. procedures.

Compounds of formula 3014 in which Z is N-alkylaninide, imidazole or bertzimidazole can be prepared as shown in Scheme 42 below. and deprotonating the amino group to give the amino acid of formula 3012 which is subjected to macrocyclization to give compound 3013. The conversion to the desired final product 3014 is carried out in a manner analogous to that outlined in Reaction Scheme 40 above.

R e a tio n s 42

CDI

3006115-►CH ₃ O

YC

NHBoc

1, LiOH / H ₂ O 4

2. TFA

Q. Q.

Jf ^OH

O Ŕ,

3012

1. LiOH / THF

2. BnONH ₂ / BOP / DIEA

3. _H2 / Pd-C

3014

135

Cyclic ureas of general formula 3019, wherein Z is N-alkyl amide, imidazole or benzimidazole, can be prepared according to Reaction Scheme 43 below.

3015 is obtained by reacting intermediate 8 with an a-ketone-amino-arylamino ester. t) d s t h e n e e h h. The compound of formula 3017 is obtained by hydrogenation of the protecting groups and treatment with GDI to give the cyclic urea 3018. Conversion to the desired final product 3019 is carried out in a manner analogous to that of as outlined in Reaction Scheme 40 above.

136

Reaction scheme 43

1. LiOH / THF

->.

2. BnONH / BOP / DlEA

3. _H2 / Pd-C

3019

137

The cyclic lactams of formula 3023 in which Z is N-alkyl amide, imidazole or benzimidazole can be prepared according to the scheme schematically outlined in Reaction Scheme 44. Intermediate 3015 is hydrogenated to form amine 3019. Amine 3019 is combined with aspartic acid derivative or acyl 1-aminogenetic acid derivative yields the compound of formula 3020. Removal of the chiral auxiliary and hydrogenolysis yields amino acid 3021. Macrocyclization of the amino acid yields cyclic lactam 3022, which yields cyclic lactam 3022, using the conditions described in Reaction Scheme 40, n the compound 3023 required herein.

138 .1

Reaction scheme 44

3020

1. LiOH / THF

----> 2nd BnONH ₂ / BOP / DIEA

3 _H2 <Pd-C

HOHN

ABOUT

R

3023

139

Reaction Scheme 29 can be used to prepare compounds of Formula 141 wherein Z is N-alkyl amide, imidazole, or benzimldazole. Reduction of 9ibal of an appropriately substituted amino acid ester to an aldehyde is followed by preparation of the cyanohydrin which undergoes hydrolysis to give the acid. 134. The acid obtained is converted to the benzyl ester 135 which is subjected to treatment. Mitsunobu reaction to give a compound of formula 136. Removal of the protecting group from tert-butyl ester followed by peptide lysis to a new or ornithine derivative affords compound 138. Basic hydrolysis yields an amino acid that undergoes macrocyclisation to form cycle 139. Hydrolysis of the obtained cycle 139 gave the carboxylic acid 140. Compound: 140 with O-benzy1-hydroxylamine followed by hydrogenation gave the final compound 141.

The compounds of the invention may be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, used in conjunction with synthetic methods well known in the art of synthetic organic chemistry, or variations thereof, which those skilled in the art can deduce. Preferred methods include, but are not limited to, those described below. All of the documents cited herein are as follows: &lt; tb &gt; &lt; tb &gt;

The novel reactions and reactions of the compound of the invention can be prepared using the techniques described in this section of the invention, and performed in solvents suitable for the respective reagents and materials used, and are suitable for the ongoing transformations. It is also evident from the description of the synthetic methods below that all of the proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, duration of experiment and manufacturing procedures, are standard conditions for a given type of reaction which are known to those skilled in the art. capable, easy to determine. It will be apparent to those skilled in the art of organic synthesis that functional groups present in different parts of the molecule must be compatible with the reagents and reactions proposed. In the case of such limitation of substituents, the skilled artisan must employ alternative methods.

EXAMPLE 1

Abbreviations used in the Examples: defined once, 2X designation as follows: IX is used to designate: used to designate: twice, 3X is used three times, bs denotes broad singlet, denotes degrees: Celsius, Cbz is: abbreviation for: benzyloxycarbonyl, d is an abbreviation for doublet, dd is an abbreviation for; doublet of doublets, eq is the abbreviation for equivalent or equivalents, g is: abbreviation for gram or grams, mg stands for milligram or milligrams, mL "is an abbreviation for milliliter or milliliters, H stands for a hydrogen or halogen ^{atom: I} H is an abbreviation for proton, throw is an abbreviation for hour or hours, m is: an abbreviation for mul t Iple t, ll is: an abbreviation for molar, min is: an abbreviation for minute or minutes, an abbreviation for melting temperatures.

MHz stands for: megahertz; MS stands for mass spectroscopy; nmr or MMR stands for nuclear magnetic resonance spectroscopy; is an abbreviation for volume / volume ratio. rt,

R and S are stereochemical designations well known to those skilled in the art.

1. (a) C y s e: 1 i n a 3 R - a 1 y I - 3 - 1 - b u t o x y k a r b o n y - 2 C R)

After stirring the cooled (78 ° C) solution of 20 grams (87 mmol) of acid 3 -1 -butyl-y and b-ynyl-2 (R) -1. (15 g, 5 mmol) (previously aziotroped with toluene) in 400 mL of anhydrous T H1- was added via cannula over 30 minutes 180 mmol of L.DA. After stirring for one day, 8.3 ml was added dropwise. (96 mmol) of allyl bromide. The reaction mixture was allowed to warm slowly to room temperature overnight with stirring. room temperature. Then the reaction mixture was quenched with a 10% aqueous citric acid solution and reduced

141

The remaining material was then the aqueous phase was then the organic fractions were removed under pressure, the volatiles were removed, taken up in ethyl acetate and washed with water. three times with ethyl acetate and the combined washed '10% citric acid, saturated NaHC0 _{::. 3} (twice), water (twice) and brine, and then dried over anhydrous IMgStti. After removal of the solvent under reduced pressure,

23.3 g (99% yield) of the product which was used in the next reaction without prior purification. Mass Spectroscopy (1 * 1 + Na) - 293.

(b) 3R -alyl acid; 3 t -butoxycarbonyl-2 (R) ... isobutylpropanoic

To a stirred and cooled solution (-78 ° C) of 2 grams of K a) acid (previously twice aziotroped with benzene) in 25 mL of anhydrous T PIF was added LDA 16.3 mmol over 15 minutes via cannula.

The reaction mixture was stirred for 15 minutes at ... 78 ° C and then for 15 minutes in a water bath at room temperature (24 ° C). The reaction mixture was then cooled to -78 ° C over 15 minutes, after which time 1.5 µl mL was added. 1.1 * 1 diethylaluminum chloride (hexane). The reaction mixture was stirred for an additional 16 minutes at -78 ° C, 15 minutes in a water bath at room temperature and then again for 1.5 minutes at -78 ° C. Then, the reaction mixture was quenched by rapid addition of methanol. The reaction mixture was concentrated at rt. under reduced pressure to approximately 1/4 of its original volume, and the resulting material was dissolved in 200 mL of ethyl acetate and washed with a mixture of 70 mL of 1N HCl and 1.00 grams of ice. The aqueous phase was extracted with ethyl acetate. The combined organic fractions were washed with a solution of 3.5 g of KF dissolved in 1.00 ml of water and 1.5 ml of 1N HCl (pH 3-4). The organic phase was washed with brine, dried over MgSO4, filtered and, after evaporation, the solvent at. under reduced pressure gave 92% of the product. ¹ H 1 * 1 R in acetone d-Ei indicated an 'S: 1, anti syn ratio.

Mass Spectrometry (µl-i-Na) = ^: 293.

(c) B e n z 1 3 S - a 1, y I, ..... 3 - 1 - b u t o x y k a r b o n y 1 - 2 (R) - i. z o b u t y 1 p o o t a n o

To a stirred and cooled solution (0 ° C) of 20 .mu.g (7E)

mmol) of untreated, fixed acid 1 (b) (8: 1 mixture) in 75 mL

142 benzene, 11.4 mL <76 mmol) of DBU and a field of 9.98 mL <84 mmol) of berrzyl bromide were added. After ten minutes, the reaction mixture was refluxed for the next 4 hours. The reaction mixture was diluted with ethyl acetate to three times its original volume and washed three times with a 10% aqueous citric acid solution. The combined aqueous phases were extracted. three times with ethyl acetate. The combined organic fractions were then washed, brine, dried over MgSO4 and concentrated. depressurized, volatile components. The resulting material was chromatographed over silica gel at. using an elution kit of 2.2% in hexanes gave 16.9 grams of the benzyl ester (62% yield).

Cod copy mass (IM-i-MI-b,) = 978.

<d) Benzyl 3S- (3-hydroxypropyl) -3-t-butoxycarbonyl-2 (R) -isobutylpropanate

To a stirred and cooled <8 ° C) solution of 5.2 grams of olefin K o) in 108 mL of anhydrous THF was added 72.2 ml of 0.511 9-BBN in THF over one hour. The reaction mixture was left for 12 hours at room temperature. Warm to room temperature with stirring. The reaction was cooled to 0 ^C 'C and to this cooled mixture. . 2.9 ml of H _with 0 (baking attention) was added dropwise over 5 minutes). After stirring for 20 minutes, 8 ml of 30% hydrogen peroxide, containing 3.21 grams of NaOAo, was added simultaneously with 8 ml of 30% hydrogen peroxide. The mixture was stirred for a further twenty minutes, after which time 1 ostst; r á nen i. exotherm i. e 1, carried out under reduced pressure. The remaining material was dissolved in ethyl acetate and brine. The residue is extracted with ethyl acetate and ethyl acetate. The combined organic fractions were washed, water and then brine, dried. over lgSCU and finally at. depressurized, volatile components. The resulting material was chromatographed on silica gel eluting with a gradient of 1:20, then 1:10, and then 1: 5 ethyl acetate in hexanes to give 3.5 g (64% yield) of the product.

Mass Spectroscopy (1 H-1 H) = 379.

143 :: 1 .. C e) B e n z in I. 3 S- (3 - b ó m p r o p v 1) - 3 - b a u b x yk ar b o n v 1 2 (R) -1. z o b u b in ll. propanoáb

To a stirred and cooled (0 ° C) solution of 8.32 grams of biphenylphosphine, 2.15 grams of imidazole, and 18.54 grams of tetra bromoethane in 60 ml of anhydrous 611.61 .61, a solution of 8.0 grams was added dropwise over fifteen minutes. The reaction mixture was stirred at 0 [deg.] C. for 30 minutes, after which an additional 1/2 equivalent of triphenylphosphine, Imidazole and the tertiary bromine was added in one portion. ml 611-61,61. The reaction mixture was stirred for an additional two and a half hours at 0 ° C, 20 minutes at room temperature (24 ° C) and then diluted with 320 mL hexanes and filtered through a short column of silica gel using 25% ethyl acetate in hexane. The volatiles were removed under reduced pressure and the resulting material was chromatographed. on silica gel, eluting with a 1 to 10% gradient of ethyl acetate in hexanes to give 6.1 g (65% yield) of the product.

Weight speck of cod and IM-i-l-l ~ 442.

1C (f) 3S-C3-Thromopropyl) -3-t-butoxycarbonyl-2 (R) -isohubylpropanoic acid

1 g of 10% Pd-6 was added to 10.5 g of the benzyl ester K e) in 250 ml of methanol. The mixture was stirred under a hydrogen balloon for three hours. After removing the catalyst by filtration and the solvent under reduced pressure, 8.3 g of product were obtained.

Mass spectroscopy ΓΊ - + - Η - 352.

Kg) 3S-C 3-Bromopropyl) ..... 3-b-hu carbonyl-2 (R) -isohutylpropanovil-1: byrosinomethyl berlyl

To 8.4 g of the acid in 200 mL of 1F was added 5.5 g of tyrosine methyl ester hydrochloride and 9.1 mL of 1x11 * 11 * 1. To this mixture, 9.55 g of T B10 dissolved in 120 ml of D 1 * 1 F were added over 30 minutes. The reaction mixture was stirred at room temperature for two hours and then freed from the volatiles under reduced pressure. The resulting mass is

144 was dissolved in ethyl acetate and washed with cold 1M HCl. The aqueous phase was extracted three times with ethyl acetate. The combined organic fractions were washed successively with water, saturated NaHCO 3, water and brine and dried over MgS (X 1). After removal of the solvent under reduced pressure, the resulting material was chromatographed on silica gel, eluting with 25% EtOAc. up to 33% ethyl acetate in hexanes gave 9.5 grams (75% yield) of the reaction product and 2.35 grams of the HOBt addition product. The HOBt adduct was dissolved in 25 ml of DMF and to this solution was added 0.57 ml of 1x11 * 11 * 1 and 1.2 g of tyrosine methyl ester hydrochloride. The reaction mixture was heated to 60 ° C and at room temperature. This temperature was maintained for 30 minutes, during which 1.4 ml NMM and 2.4 g ester were added. The mixture was kept at room temperature for the next thirty minutes. 60 ° C. Next, the material was worked up in a manner analogous to the initial reaction to give 2.6 grams of additional product.

W o rk s e c t e n e s 1 * 1 - + - H - 329.

(h) 2S, 5R, 6S ..... 3-aza-4-oxo-10-oxa ... 5-isobutyl-2-1 carboxymethyl) ..... IP aracyk í. o f a 6 -1 - b u t o x y k a r b o rt v 1

To a stirred and heated (60 ° C) suspension of 5.2 g of Css-CO 3 in 130 mL of anhydrous DMF and 32.5 mL of anhydrous DMSO was added over 15 minutes a solution of 3.25 bromide Kg) dissolved in 25 mL of DMF. The reaction was warmed to 00 ^{<:: C} at which temperature was maintained for an additional thirty minutes. After this time, it was cooled in an ice bath and quenched with a 10% aqueous citric acid solution. After removal of the volatile fractions at. under reduced pressure, the resulting material was added to a mixture of ethyl acetate and water. The aqueous phase was extracted four times with ethyl acetate, and the five combined extracts were washed four times with water and once with brine, dried over MgSO 4. and freed from volatile constituents under reduced pressure. The resulting material was chromatographed on silica gel at. using an eluent consisting of 1.5% MeOH in CH ₂ Cl ₂ gave. 2.0 grams (74% yield) of the macrocycle.

MS + H = 448.

145 <i) K e s 1.1. n a 2 S, 5 R, 6 S-3 - a z a - 4 - o x o -1.0 - o x a - 5 - i z o t u t 1 - 2 - C a r b x y y methyl) -1 103 paracyclophane-6-t-carboxyl

About 0.77 g of t-butyl ester K h) was added 25 m 3 .3 FA. The reaction mixture was stirred at room temperature for one hour. Removal of 3FA under reduced pressure yielded 0.67 g of acid.

Mass Spectroscopy MiH ^: = 392.

1, C. j) 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (carboxyiriethyl) -1,110 paracyclophar-6-III-M .... (O-benzyl) carboxamide

0.08 g of acid in 150 m @ 3. CH 2 Cl 2, 0.75 g HOBt, 2 ml NMM, 0.91 g O-benzylhydroxylamine hydride chloride and 1.0 g EDO were added.

The reaction mixture was stirred at room temperature for three hours. 31.13 in% l ⁱⁿ 0I I / CH C1 at 1 Ex. tomorrow, profit. g. so that 50 mg of TBTU was added and the reaction mixture was stirred for an additional 30 minutes.

The moment TI .... C showed that all the acid had already been consumed, it took. 50 ml of D PIF and 4.3 g of the free base were added to the remaining material under reduced pressure.

0-benzylhydroxylamíriu. The reaction mixture was heated to 80 ° C and at room temperature.

this temperature was maintained for one hour. After removal, the volatile fractions at. reduced pressure, the resulting material was dissolved in ethyl acetate and washed with IM HCl, ^ Η, Ο, saturated NaHCO ^, H _and 0 and brine, and dried over MgSO. Removal of volatile fractions. under reduced pressure gave material slightly contaminated with HOBT adduct, as shown by ¹ H NI * 1R. The pale yellow solid was three. Turova Ia in boiling Et H _R and the Filtration afforded

2, 1.8 g C 9 5%) C).

The above reactions may be carried out, alternatively in the. use. H A 31J.

A solution of 2.4 g of acid in 75 ml of anhydrous DMF was added

3.37 ml NMM, 5.24 g HATI and 3.77 g O-benzylhydroxylamine. After stirring overnight at. at room temperature, the reaction mixture was warmed to 60 ° C and held at that temperature for an additional 30 minutes. After cooling. the volatiles were removed under reduced pressure and

1.46 The resulting material was dissolved and washed with a 10% aqueous citric acid solution. The organic layer was extracted three times with ethyl acetate. The four combined organic extracts were washed three times with water, once with brine, dried over MgSO 4 and freed from the volatiles under reduced pressure. The resulting material was triturated four times with 1: 2: 2 ethyl acetate: hexane: ether to give 1.4 g of the product. The mother liquor was concentrated and the resulting material was subjected to silica gel chromatography eluting with a gradient of 2b to 90% ethyl acetate in hexane to give 1.0 g of product (total yield 91%).

C k) 2S, 5R, 6S 3-aza ..... 4-oxo-10-oxa ... 5 -thiohutyl-2- (carboxyl) -II1011 paracyclophan-6-IM - (O-benzyl) carboxamide

To 0.7 g of the methyl ester of K i) in 65 mL of THF and 15 mL of H 2 O was added 2.23 mL of saturated aqueous LiOH. The reaction mixture was stirred at room temperature for 2 hours and then quenched by the addition of 10 mL of 1M HCl. After removing most of the solvent under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with water and 20 mL of 1M HCl. The aqueous phase was extracted four times with ethyl acetate. The combined ethyl acetate fractions were washed with water, brine, dried, over MgSO 4. and after removal of the solvent under reduced pressure gave 0.67 g (99% yield) of a white solid.

Mass Spectroscopy β 1 + H = ¹ 493.

Example 15

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (hydroxymethyl) -II1011 vapor and cyclophan-6-N-hydroxycarboxboxamide

To a stirred and cooled (0 ^c, 0) solution of 0.031 g (0.064 mmol) of acid in 2 mL of anhydrous THF was added 0.19 mL of 11 * 1 B ₂ H ₂ O TP and then an additional 0.19 mL was added over 2 hours. The reaction mixture was allowed to slowly cool to room temperature while stirring overnight. The excess demolished was cooled by dropwise addition of water. The material was partitioned between EtOAc and 0.10. and after separation, the aqueous phase was extracted three more times with EtOAc. All four organic extracts were combined and washed, with water and brine, dried over 1 ⁱⁿ IgG1. and the volatiles were removed under reduced pressure. The resulting material was purified by preparative thin layer chromatography in a manner analogous to that described above to give 19 mg of material.

To 18 mg of alcohol in 10 mL of MeOH was added 25 mg of 5% Pd / BaStL. Shaking under a hydrogen atmosphere (0.34 L * 1Pa) for four hours, filtering and removing the volatiles under reduced pressure gave 15 mg of hydroxamic acid.

MS + H = 379.

Example 20

2S, 5R, 6S-3-aza-4-oxo-10-oxa-b-isobutyl-2-l '- (3-imidazolyl) propyl carboxy; - hydroxycarboxamide

A solution of 0.035 g of acid in 2 m 3. 1F, to which 0.044 ml of NIII1, 17 ml of aminopropyl imidazole and 0.030 g of TBTU was added, was stirred overnight. at room temperature and then heated to 80 ° C and held at that temperature for an additional 30 minutes. After removal of the volatiles under reduced pressure, the resulting material was purified by preparative thin layer chromatography: (1 mm with 0.25 mm concentration zone) by double elution with 5% t

11111 / CHCl3 to give 0.042 g of product.

LRMS: found (ΓΉ-Η) - 590

HPLC reverse phase 70-5% _H 0 / _{CH; 5} CN (0.1% TFA) 30 minute gradient: retention time = 4.96 minutes.

0.065 g of 5% Pd / BaSCl 3 was added to 0.040 g in 10 mL of 1 N OH. The reaction mixture was shaken (0.34 µPa) for 6 hours, filtered and the resulting material was purified. by reverse phase HPLC (90% to 30% H _S H / _CH3CN with 0.1 TFA over 45 min) to give 0.025 grams of the hydroxamic acid: j.

LR18S: found (L + H) * = ^: 500.

148

Example 23

S, 5 R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - 5 - isobutyl - 2 - C 2 - pyridyl - 2 - ethyl 11 (arboxamido) - Ľ1 C) 1 paracvk 1 O-6-N-hydroxycarboxam A, d

To a stirred mixture of 0.037 grams of acid in 2 mL of CIT. 0.05 ml of N1 * 11 * 1, 10 ml of aminoethylpyridine and 0.022 g of TBTU were added. The reaction was carried out in a manner analogous to that described above and gave 20 mg of product after purification.

To 20 mg in 1.0 mL of 1L was added 35 mg of 5% Pd / BaSCt. S formed from 1 new shaking under carbon atom C 0.034 NP a), filtration and removal of volatiles under reduced pressure gave material which, after purification by reverse phase HPLC (90% to 30% H 2 O / O / 1 · 1 CM with 0.1. TFA over 30 minutes) afforded. 15 mg of hydroxamic acid as TFA salts. MS + I - 497.

Example 27

S, 5 R, 6 S — 3-aza-4-oxo-10-oxa-5-isobutyl-2- (4-methylpiperazines 1 carbox am 1. do) - Il 1.0 µl paracycl 1 of a n - 6 - M - hydroxycarboxam 1 d

To 0.130 grams of acid in 2 mL of CH _and O- ₂ was added 0.1.6 mL of MIIl ⁱⁿ 1.4 mL of N-methylpiperazine. The reaction was carried out in an analogous manner to the previous example and gave, after purification, 25 mg of the product.

To 25 mg in 10 mL of MeOH was added 45 mg of 5%. Pd / BaSO4. Four hours for shaking under a hydrogen atmosphere (0.34 MPa), filtering and removing volatiles at a reduced pressure of 1.5 m / m. n y h y d r o x y o j.

MS + H = 475.

149

Example 41

2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (2-imidazolyl) -1,11,11-paracolin-1-yl-N-hydroxy-oxyl-m-d

A solution of 1111 061 grams of acid in 4 ml of 11F to which was added (1119 ml of 11µl, 1103 grams of 2-amirioimidazole and 1053 grams of TBTU) was stirred overnight at room temperature and then heated to 80 ° C. After removal of the volatiles under reduced pressure, the resulting material was purified by preparative thin layer chromatography (1 mm with a Cl 25 mm concentration zone) by double elution with 5% 1: 1 OH / CHC 1: 3, thereby 0.088 g of the desired product (total) was obtained.

0.10 (10.015 g amu in 5 mL 1LOH was added 0.0220 g amu 5% Pd / BaSCl +. The reaction mixture was shaken <0.34 µL) for 6 hours, filtered and the resulting material was purified by C 90 reverse phase HPLC % to 30% H-1 / CH 2 Cl 2 using 0.1. TFA over 30 minutes) to give 0.007 g of hydroxamic acid as the TFA salt. MS + H-457.

Example 50

S, 5 R, 15 S-3 - and z. a - 4 - o x o - 10 - o x a - b - i. z o b u t v 1 - 2 - <M -metry 1. k a r b o x or 1 d o) - - I '10 l l p a r a o y k i o f - 6 - IM - h d d o x yk ar box a m i d

IM-methylamide (ICk) was prepared as described above and described in 1 of 1. n u 5 0 <a).

0.19 g of 5Q (a) in 14 ml of 1L OH was added 0.19 g of 5% Pd / BaSCLv. The mixture was shaken for two hours under a hydrogen atmosphere at a pressure of 0.31 µL in a Parr bottle. The mixture was then filtered through a 0.45 ml PTFE membrane filter, and after removal of the volatiles under reduced pressure, 0.12 g of a white solid was obtained. The melting point ranged from 350 to 352 ° C to 1. and d).

150

S, 5 R, ti S — 3 - and z a - 4 - o x o -10 - o x ti - 5 - i z o u u 1 - 2 - C 2 - b e n z. im i d a z o 1. y 1) -L 1.0 3 p ara o y k o o f a - Ei - M - h d d o x y k a r b o x a m 1 d

Mass spectroscopy 406 ^ν Η-ίί - 406.

Example 55

A solution of 0, 050 grams of acid in 3 mL of CH C1 _{and R,} to which was added 0, 020 ml Nl * ll * L, 0, and 022 gf enylamíndíamínu 0, 043 g TBTU was stirred, RES day sucks. room temperature. After removal of the aliquots under reduced pressure, the resulting material was purified by preparative thin layer chromatography (1 mm with 0.25 mm concentration zone) by double elution with 5% 1: 1OH / CHCl 3 to give 0.025 g of product.

To a solution of 0.022 g of product in 3 mL of T'HP was added 3 mL of HOAc. The reaction mixture was allowed to boil for one hour under reflux and the volatiles were removed under reduced pressure to give 0.021 g of the benzamidisole product.

To 0.052 grams in 1.0 mL INellH was added (3.035 grams of 5% Pd / BaSO 4). The reaction mixture was shaken at 0.24 NPa for four hours, filtered and, after removal of the volatiles under reduced pressure, yielded 0.012 grams of product. .

Mass Spectroscopy 1b-H = 465.

Example 61.

S, 5 R, 6 S - 3 - aza - 4 - oxo -1.0 - oxa - 5 - isobutyl 1 - 2 - C g 3. yoin - M - methyl 1 am 1 d) - 1010 3 paraoyk 1 of á n - 6 - N - bydroxvka r- box am j. D

A solution of 0.030 g of acid in 2 ml of DI * IF to which was added 0.030 ml. 141 * 11 * 1.0, 0.025 grams of glycine-N-diethylamide hydrochloride and 0.026 grams of TBTU were stirred at room temperature for 3.0 hours and then heated to 80 ° C for a further 1.5 minutes. After removal of the volatiles, the resulting material was purified by preparative (TLC (1 min with 0.25 mm concentration zone)) eluting twice with 5% MeOH / CHCl 3 to give 0.130 g of product.

To 0.025 grams in 10 mL MeOH was added 0.035 grams of 5% Pd / BaSO 4. The reaction mixture was shaken for six hours at 50 psi, filtered and, after removal of the volatiles under reduced pressure, gave 0.20 grams of product.

M + H = 403.

Example 03

S, 5 R, 6 S-3 - and z a - 4 - o x o -10 - o x a - 5 - j. z o b u t v 1. -2-1L - a 1 a n n - N-methyl 1 am i d) - í 0 ľ p a r a c y k j. o f - n - G - M -by d r o x y k a r b o x a m i d

To a stirred solution of 0.030 g (0.062 mmol) of acid in 2 ml of CH 2 Cl 2 was added 0.034 ml of IM MM and 17 mg of L-alanine tylamide hydrochloride and 20 mg of MM ΊΊ..Ι. The reaction mixture was stirred overnight at room temperature and then poured into a 10% aqueous solution of 1-acyclohexanecarboxylic acid and CH 1 - ₃ eyes. All of the CI-101-5 fractions were combined and washed with 1L (1L) saturated IMaHCO 3, Ι-ΙΙΟ and brine and dried over MgSO 4. After removal of the volatiles under reduced pressure, the resulting material was purified by preparative purification. TL (Cl mm (0.25 mm concentration zone)) by double elution with SXMeOH / CHCl 3. The main band was isolated, triturated and rinsed with 150 ml. MeOH / CHCl _{: 3} gave 20 mg of the desired product.

To a solution of 20 mg of the product in 10 mL of MeOH was added 30 mg of 5% Pd / BaSCU. The reaction mixture was shaken for 4 hours at 50 psi and filtered. After being freed from the volatiles under reduced pressure, it yielded 1.5 mg of the desired hydr oxamic acid.

M + H-447.

Example 04

152

S, 5 R, 0 S-3 - a z a - 4 - o x o -10 - o x a - 5 - i z o t u 1 - 2 - C D - a 1 a n. n - IM - me 1 amid) -1 ’. 10 3 par acy to lofan-G-N-hydroxycarboxamide

A solution of 0.035 g of acid in 2 ml of DMF, to which 0.037 ml of NMM, 0.023 g of IM-methylamide D-alariine and 0.0333 g of TBTU was added, was stirred overnight at room temperature and then heated to 80 ° C, where it was held for an additional 15 minutes. The volatiles were removed under reduced pressure and the resulting material was purified by preparative thin layer C3 chromatography. mm with 0.25 mm concentration zone) eluting twice with 5% 1 H / CHCl 3 to give 0.050 g of the reaction product.

ml. IleOH was added at 0, 050 shaking for 4 hours at and after removal of the volatile 0.029 grams of water. ¾l · + · I - I

To 0.040 grams in 10 mL of 1 H in gram of 5% Pd / BaSO4. The reaction mixture was pressurized to 0.34 psi, prefiltered with portions under reduced pressure to give = 477.

Example 07

S, 5 R, 0 S - 3 - aza - 4 - oxo - 10 - oxa - 5 - isobutyl 1 - 2 - CL - va 3 - n - N - methyl 1 carboxamido) -1 103 paracyclophane-SN- hydroxycarboxamidei

A solution of 0.035 g of acid in 2 ml. DIF to which 0.39 ml NMM, 0.922 g of L-valine-N-methylamide, and 0.03 g were added

TBTU, was stirred overnight at room temperature and then heated to 80 ° C and the volatiles were removed by temperature. 30 minutes. under reduced pressure and the resulting material was purified by preparative thin layer chromatography (1 mm (0.25 mm concentration zone)) eluting twice with 5% MeOH / CHCl 3 to give 0.038 g of the reaction product.

Up to 0.035 grams in 10 ml. MeC'JH was added 0.150 grams of 5% Pd / BaSO 4. The reaction mixture was shaken for G hours at room temperature. pressure, and filtered to remove the volatiles under reduced pressure to give 0.030 g of product.

MS: M + H = 505.

153

Example 70

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-CL-O-methyl) tyrosine-1-methyl-1-imidazole-1 '; 1.0 Ϊ.Ι p a r a c v 1 o f a n - 6 - IM - - h in cl r o x y k a r bi o x a n d

To 0.333 g (3.332 mmol) of acid in 3 mL of DIMF was added 3.330 mL. IMIMIM and 0.023 grams of O-methyl-tyrosine-IM-methylamide and 3,328

C at this temperature removed at a reduced gram of TBTU. The reaction mixture was heated to 80 and maintained for an additional 23 minutes. D1 ^at II - pressure and the resulting material was taken up in EtOAc and washed with a 10% aqueous citric acid solution. The water was extracted three times with EtOAc, the extracts were combined and washed, with water, saturated aqueous IMaHCO ^ H, _R 3 and brine, dried, over ľlgSCL ,. and, after removal of the solvent under reduced pressure, yielded 3,333 grams of the product used in the following previous a. what? sten i. a.

step without

0.040 gr of amine 5% Pd / BaSO 4 was added to the product at 3:33 gr amu of the product in 13 ml of IMe 3 H. The reaction mixture was shaken for 8 hours at a pressure of 3.34 IMPa, prefiltered and the resulting material was shaken. člsti.1 by reverse-phase <93% to 33% _with H, 0 / CH ₅ 8IM by 3.1 TFA over 33 m i. n ú t) ar ¹ oskyto 1 1.9 mg of I-hydroxyhydroxamic acid.

MS: 1 H-H = 583.

Example 7i

S, 5 R, 8 S - 3 - az - 4 - oxo - 13 - oxa - 5 - isohuty 1 - 2 - CI .... - ser ± n - IM - methyls 3 amidol-13 J Paracyclophen-6-N-byoxyoxycarboxamide

To 3.355 g of the above t-butyl ether 75 was added 3 mL of TFA. The reaction mixture was stirred at room temperature for 2 hours. room temperature. After removal of the volatile fractions at. under reduced pressure, 3,323 grams of product were obtained.

MS: 1 H + = 493.

154

Example 72

2.S, 5R, 6S (.beta.-aza-4-oxo-.alpha.-oxa-5-): iobutyl: 2-beta-alanine-N-methylcarboxamido-10 &apos;] paracyclophane-f. -Nl-iydroxycarboxaline d

A solution of 0.035 grams of acid in 2 ml of D 1 * 1 F, to which 0.039 ml of MMM, 0.0520 grams of s-alanine-N-methylamide, and 0.03 grams of TBTU was added, was stirred overnight at room temperature. and then heated to 80 ° C for an additional 15 minutes. The volatiles were removed under reduced pressure and the resulting material was purified by preparative thin layer chromatography (mm (0.25 mm concentration zone)) twice eluting with 5% MeOH / HCl _{: 3} to give 0.043 g of the reaction product.

To 0.040 g of the product obtained in 10 ml of MeOH was added 0.050 g of SXPd / BaSCU. The reaction mixture was agitated for 6 hours at 0.34 ° C, and the filtrate was boiled to yield 0.030 g of product after removal of the volatiles under reduced pressure. Mass Spectrometry t l * l + H - 499.

Example 73

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-CD-serine-N-methylamide) - E 10 3 para-oxo-6-N-hydrate oxy k ar hoxamide

To 0.020 g of ether was added 3 mL of TFA. The reaction mixture was stirred at room temperature for two hours. After removal of the volatiles under reduced pressure, 0.015 g of product was obtained.

LRMSs found C M + H + = 493, CM + Na + - 515.

Reversed phase HPLC (90-20% H 2 O / CH 2 CN (0.1% TFA) minute gradient: retention time === 11.7 min.

Example 75

S, 5R, SS-3-aza-4-oxo-10-oxa-5-isobutyl-2-C L-O-tert. butyl-serine - N - methylamide) - 10 10 3 paracyclophan-6-N-hydroxycarboxamide

A solution of 0.062 g of acid in 3 ml of DMF to which 0.035 ml of ΝΙΊΜ, 0.045 g of tert-butylserine-N-methylamide and 0.054 g of TBTU was added was stirred overnight at room temperature and then warmed to room temperature. 80 ° C, which was maintained for an additional 15 minutes. The volatiles were removed under reduced pressure, and the resulting material was purified by preparative thin layer chromatography (1 mm (0.25 mm concentration zone)) eluting twice with 5% MeOH / CHCl ₃ to give 1.080 g of the reaction product.

To 0.075 grams of the obtained product in 1.0 mL · MeOH was added 0.01.0 grams of 5% Pd / BaSCU. The reaction mixture was shaken for 4 hours at 50 psi, filtered and, after removal of the volatiles under reduced pressure, yielded 0.050 g of product. Mass spectrometry. M + H = 540.

Example 77

2S, 5R, 6S-3-aza-4-oxo-10-oxa-b-isobutyl-2H-D-C-O-ter. butyl) serine-M-methyl-1-methyl-1-methyl-1-methyl-6-methyl-meth-1-yl-a-b-a-b

A solution of 0.035 g of acid in 2 ml of DMF to which was added 0.044 ml of IMMM, 0.033 g of O-butyl-D-serine-N-methylamide and 0.033 g of TBTU was stirred overnight at room temperature and then warmed. at 80 ° C, where it was held for a further 30 minutes. The volatiles were removed under reduced pressure and the resulting material was purified by preparative thin layer chromatography (1 mm (0.25 mm concentration zone)) eluting twice with 3% MeOH / CHCl 3 to give 0.040 g of the reaction product.

To 0.035 g of the obtained product in 10 ml of MeOH was added 0.050 g of 5% Pd / BaSO4. The reaction mixture was agitated for 6 hours at 0.3 MPa, filtered to give 0.030 g of product after removal of the volatiles under reduced pressure.

C LRMS M + H) + ^1-549.

: 1:56

Example 90

2. S, 5 R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - S - isobubes 1 - 2 - C 1 -1 yzin - M - methyl 3. amide) - Γ10 3 para c . v k 3 .. o á a n - - 6 - - N - b v d r o x v a r b o x ani j. D

A solution of 0.035 grams of acid in 2 ml of DMF to which was added 0.024 ml of NH4.0, 0.035 g of L-lyophilized skies of 0.030 g of TBTU was stirred overnight, overnight. at room temperature and then heated at ^80:> C where it was maintained for 30 min. The volatiles were removed under reduced pressure and the resulting material was purified by preparative thin layer chromatography (mm (0.25 mm concentration zone)) double elution with 5% NeOH / CHCl 3 and one elution with 10% HeOH / CHCl 3 to give 0.035 g of the reaction product.

0.040 g of 5% Pd / BaSCU was added to 0.030 g of the product obtained in 10 ml of 1L OH. The reaction mixture was agitated (5 hours at 0, 34 µl, eff.) And, after removal of the volatiles under 3 and 3, by decomposition of 11 and 0, 026 gr am uprodukt u.

Found: C 14 + 1-1) - - 520.

Example 95

S, b R, 6 S- 3 - aza - · - 4 oxo - 10 - ox a ..... 5 - isobutyl 1 - 2 - C - benzyls I. carboxamido) - í 0 3 paracycl 1 of α - 6 - N - hydroxycarboxamide id

To a suspension of 0.030 grams of CO (06 mmol) acid in 2 mL. OH _{with R} dľ.l was added 0.015 ml Nľlľl and 24 mg of TBTU. 10 ml of benzylamine was added to the reaction mixture over 30 minutes and the reaction mixture was stirred for another hour. The mixture was diluted with CHCl 3 and washed once with 1N HCl and once with H _; -, 0th The two aqueous phases were combined and extracted three times with CHCl 3. All four CHCl ₃ extracts were combined and washed with water, saturated aqueous NaHCO ₃ , water and brine, and dried over MgSO 4. Removal of the solvent under reduced pressure gave 30 mg (85% yield) of benzylamide.

MS (CI + H) = 572; CM-i-Na) · '

594.

7

To 25 mg of the above product in 10 mL of MeOH was added 35 mg of 52 Pd / BaSCU. The reaction mixture was shaken under hydrogen gas at 50 psi for 5 hours, filtered through a 0.45 mM PTFE membrane filter and, after removal of the volatiles under reduced pressure, gave 15 mg of hyclroxamic acid.

Hm o t n o s t; n a n d e n t 1 and C M · + · H) 482.

Example 106

S, 5 R, 6 S-3 - a z a - 4 - o x o ..... 10 - o x a - 5 - i, z o u u 1 - 2 - i. ' 2- (4-amino-1-phenyl-1-phenyl) -ethylthioarboxamido-1'-I '. 10 µl of acyclophan-6-N-hydroxyloxycarbamide

A solution of 0.035 added 0.024 µL-ethylamine and 0.038 temperature and was then heated for an additional 30 minutes. The volatile pressure and the resulting material of a gram of acid in 2 ml of DMF to which NMM, 0.029 grams of (4-aminosulfonylphenyl) gram of TBTU were stirred overnight at room temperature at 80 ° 6 while keeping the fractions removed at The reduced residue was purified by preparative thin layer chromatography (1 mm with 0.25 mm concentration zone) of double elution with 5% MeOH / CH ₃ O ₃ and one elution with 102 MeOH / CHCl 3 to give 0.04 g of the reaction product.

.RMS found (M + H) '

665

M + Na)

687th

Reverse phase HPLC 70-52 _H H / _CH3 CN (0.12 TFA) 30 minute ramp: re teričná time = 11, 39 minutes.

To 0.035 g of the product obtained in 10 ml of MeOH was added 0.050 g of 52 Pd / BaSlX. The reaction mixture was shaken for 6 hours at 0.3 MPa, filtered and, after removal of the volatiles under reduced pressure, yielded 0.030 g of product.

LRMS found (M + H) + = 575, CM + Na + = 597.

Example 107

S, 5 R, 6 S-3 - and z a - 4 - o x o - o. 0 - o x - b - i. z o b u t y 1. - 2 - I n (2 - z z m m a 1 y y y y y y y y y y y)))))) - - - - - - -

A solution of 0.035 g of acid in 2 ml of DMF to which is added

158 added 0.044 ml ΝΙ * 1.0, 0.021 grams of aminomethylbenzimidazole and 0.030 grams of TBTU, stirred overnight at room temperature, and then held at 80 ° C for 30 minutes. The volatiles were removed under reduced pressure and the resulting material was purified by preparative thin layer chromatography (1 mm with 0.25 mm concentration zone) double eluting with 3% 14eOH / CHCl ₃ to give 0.030 g of the reaction product.

L R14 S found (14 + 1-1) - - 6 2.

Reverse phase HPLC 90 to 20% H 2 O / CH 2 CN (0.1% TFA) minute gradient: retention time = 13.01. minutes.

To 0.025 grams of the obtained product in 1.0 ml of 14eOH was added 0.035 grams of 5% Pd / BaSEL. The reaction mixture was shaken for 6 hours at 0.3414 P, filtered and the resulting material was purified. Reverse phase HPLC (90% to 30% H 2 O / CH 2 CN using 0.1% TFA over 45 minutes) gave 0.520 grams of hydroxamic acid.

L.R14S found (14 + H) * = 522.

Example 108

S, 5 R, 6 S — 3 - aza = 4 - oxo -1.0 - oxa - b -1 zobuty 1 - · 2 - (2 - b) enz im 1 dazo 1 carboxamido 3 - C 1.03 paracvk 1 of a n - 6 N - bydroxycarboxam 1 c J

A solution of 0.035 g of acid in 2 ml. DI4F, to which was added 24 ml NI4I4, 0, and 01.9 g aminomethylbenzimidazole 0, 030 g ΤΒΊU, was stirred overnight at room temperature then heated to 80 ^{<:: C,} where

The volatiles were removed and held for an additional 30 minutes. under reduced pressure and the resulting material was purified by preparative thin layer chromatography (1. mm with 0.25 mm, concentration zone) by double elution with 3% 14eOH / CHCl ₃ to give. 0.036 grams of the reaction product.

0.045 g of 5% Pd / BaSO4 was added to 0.030 g of the product obtained in 10 ml of 1L OH. The reaction mixture was shaken for 6 hours at 0.3 psi, filtered and the resulting material was purified by reverse phase HPLC (90% to 30% H 2 O / CH 2 CN using 0.1% TFA for 45 minutes) to give 0.020 gram of hydroxamic acid.

159

MS + H = 508.

120 <(a) 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (carboxymethyl) -101p a r a k aloxane-6-N-beno z a x a k a r b a x a m i d

The title compound 120 (a) was prepared as described above as a white solid.

ESI-LLS (II-H) ^4b calcd 525.3, found 525.6.

Example 120

2S, 5R, 6S-3-aza-4-oxo-10-oxa-b-hexyl-2- (carboxymethyl) -1,11-parahydro-6-naphthalenone

As described above, the title compound 120 (a) (122.1 mg, 0.233 mmol) was hydrogenated to give the hydroxamate (102 mg, 100%).

ESI-11S < 1 &gt; + 11H + calculated 435.3, found 435.3.

Example 126

2S, 5R, 6S -3-aza-4-oxo-10-oxa-5-hexyl-2- (< 2-methoxylethyloxy) carboxvv 1) -1,11 1-paraeyk 1 of n - 6 - M - bydroxycarboxam 1 d

Compound 126 (a) (50.6 mg, 0.0890 mmol) was hydrogenated as described above to give hydroxamate 126 (42.6 mg, 100%).

ESI-SS (ľI + H) calcd 473.3, found 473.4.

Example 126 <a)

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (2-methoxy-ethyloxy) -carbonyl-11,11'-parahydanoan-6 - M - benzy 1 oxvcarbox or mid

UM Dichloromethane solution of 1M, 1'-dicyclohexylcarbodiimide (0.2 ml, 1 equiv) was added. at room temperature to a solution of 212 (a) (100.6 mg, 0.197 mmol), 2-methoxyethanol (0.020 mL, 1.3 equiv).

160 1-hydroxybenzotriazole hydrate (0.0266 g, 1 equiv.) In tetrahydrofuran; (6 mL). After 20 hours at room temperature and 4 hours at reflux temperature, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4) and concentrated. Silica gel chromatography (methanol-dichloromethane, 2:08, then 4:96 and then 6:94) gave compound 126 (a) (61.2 mg, 46%) as a white solid.

ESI-1S (1'+ H) +: calcd. 669.4, found 569.5.

Example 128

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2 - ((2-phenylethyloxy) carbonyl) -1,11-paracyclonan-6-M - hydroxycarboxam i. D

In analogy to the procedure described above, compound 212 (a) (32.3 mg, 9.063 mmol) was reacted with 2-phenylethanol (9.3 mg, 1.2 equiv) to give the desired reaction product (34.6 mg, 89%). %). Hydrogenolysis of the reaction product (34.6 mg, 0.6563 mmol) then gave the hydroxamate <26.0 mg, 88%).

ESI-1S (1'+ H) *: calcd 525.3, found 525.4.

Example 129

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (dimethylcarboxamido) -Γ. 103 - p a r a c v 1 o f a n - 6 - N - h v d r o x v a r b o x a m i d

Analogous to (40, 8 mg, 0, 080 amine iodides I or 1), the reaction product (31.7 mg, as described above, 212 (a) mmol) was reacted with dimethyl (1.6). mg, 2.45 equiv.) to give the desired (36.0 mg, 84%)

0.0590 mmol) then gave the hydroxamate (26.2 mg, 99%).

ESI-1 '(1' + H) +: calcd. 448.3, found 448.5.

1.61.

Example 1.32

2S, 5R, 6S-3-aza-4-oxo-1,0-oxa-5-bexyl-1- (1-C-methylcarboxamido) methyl 1-carboxy-1.01-para 1. ofan - G - N-hvdr oxycarboxam: i_ d

In analogy to the procedure described above, 2 'L2 (a) (32.9 mg, 0.664 mmol) was reacted with 2-hydroxy-N-methylacetamide (8.6 mg, 1.5 equiv) to give the desired compound. of the reaction product (26.3 mg, 68%). Hydrogenolysis of the reaction product (25.1 mg, 6.0431 mmol) then gave the hydroxamate (21.1 mg, 99%).

Li-IMS (IM + H) +: calcd 429.3, found 429.4.

Example 1.39

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (3- (1-imidazolyl) propyl arboxamido) -1,1.0 3-Paracylophan-6-M - hvdroxvkarboxamic J

In analogy to the procedure described above, compound 212 (a) (97.2 mg, 0.90 mmol) was reacted with 1- (3-amiriopropyl) imidazole (0.273 mg, 1.2 equiv.) To give the desired reaction product. product (96.0 mg, 82%). Hydrogenolysis of the reaction product (92.9 mg, 0.150 mmol) then gave the hydroxamate (76.0 mg, 96%).

PSI-IMS (M + H) ^- : calcd 528.3, found 528.5.

Example. 1.39 Tl-A

Trifluoroacetate 2.S, 5R, 6S-3-aza-4-oxo-10-oxa-5-bexyl-2- (3- (1-imidazolyl) propylcarboxamide) - β101-paracycl 1 of n - Ei - M - Inydroxycarbox am i, du

Trifluoroacetic acid (1 drop) was added to the suspension

1.39 (38.5 mg, 0.0730 mmol) in dichloromethane (E1 mL). After stirring at room temperature for several hours, the homogeneous solution was concentrated to give the compound of formula 34 (48 mg, 1.00%) as a white solid.

162

E S1 - l N S C 1 * 1 H) * = 528, 3.

Example 142

S, 5 R, 6 S-3-aza-4-oxo -1 Cl-oxa ··· 5-hexy 1 - 2 - (2- (2 - · pyridyl) ethylcarboxamido) - 10 µl - para-cyclophan-6-N-hydroxy-hydroxycarboxamide

By analogy with compound 212 (a) (3b, 2 mg,

0.689 mmol) was reacted with 2- (2-aminoethyl) pyridine (10.9 mg, 1.3 equiv) to give the desired reaction product (36.1 mg, 85%). Hydrogenolysis of the reaction product (35.8 mg, 0.0582 mmol) then gave the hydroxamate (31.3 mg, 100%).

E SI - ll S (1 * 1 + · H) *: hear. 525, 4, z 1 s 525, 5.

Example 146

S, 5 R, 6 S - 3 - az a ..... 4 - oxo - 10 - oxa - 5 - hexyl 1 - 2 - (4-methylpiperazin-1-y-1) - · 11 µl - Paracycl-1-ene - 6 - M - hydroxycarboxamide

A gion of the described method, the compound 212 (a) (43.5 mg, 0.0852 mmol) was reacted with 1-methylpiperazine (0.044 2 m &lt; -1 &gt; , 5 equiv.). a n d e c h e r e c t i n d e n e (43.5 mg, 86%). Hydrogenolysis of the reaction product (43.5 mg, 0.0734 mmol) then gave the hydroxamate (38.2 mg, 99%).

ESI-1S (1 '+ H) + _s calcd 503.3, found 503.6.

Example 156

2S, 5R, 6S3-aza-4-oxo-10-oxa-5-hexyl-2- (2- (1H-methylaminosulphonyl) ethylcarboxamido) - 11,11,1-paracykk 1 of aan - 6 - N-Hydroxycarboxam 1 c J

In analogy to the procedure described above, 212 (a) (34.9 mg, 0.0683 mmol) was reacted with ethylenediamine (0.050 mL, 1.1 equiv.) Followed by methanesulfonyl chloride (0.145 mL,

27.5 equiv) to give the desired reaction product (35.6 mg, 83%). Hydrogenolysis of the reaction product (46.9 mg, 0.0743 mmol) then gave the hydroxamate (40.3 mg, 100%).

163

ΙΞ S1 - ll S (ΙΊll) ⁺ ': vyggled 54' 1, 3, st 5 5 41, 5.

Example 1.5 7

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C 4- (N-methylaminosulfonyl) -butyl carboxamide k 1 of a — 6 — M — hydroxycarbox am 1. d

analogously,

P c p s s p p s c t) o m

(35 mg, 0.0689 mmol) was reacted with C 1 to 212 C a); 1,4-diaminobutane

C 84, 6 mg, 1.4 equiv) and then with methanesulfonyl chloride (<0.1.86 mi, 35 e k vi v) to give the desired reaction product (24.2 mg, 53%). Hydrogenolysis of the reaction product (C24, 0 mg, 0.0364 mmol) then gave the hydroxamate (20.0 mg, 97%).

ESI-14S (f1 + H) * s calc. 569.3, found 569.5.

Example 158

S, 5 R, 6 S - 3 - aza - 4 - oxo -1.0 - oxa - 5 - hexy 1 - 2 - Cyclic 1 ohexy I. carbox am 1. do) - L 1.01 - paracycl 1 of a n - 6 - N-hydroxycarboxamide

Analogous to the procedure described above, compound 21.2 (a) (40.8 mg, 0.0689 mmol) was reacted with cyclohexylamine < 0.01.2 mL, 1.3 eq vv. ) a n d e c t i n e n d e n e n e n e n e n e n e n e n d 41 41 mg, 88%). Hydrogenolysis of the reaction product (35.4 g, 0.0598 mmol) then gave the hydroxamate (30.5 mg, 100%).

ESI-MS (M-H-1): calcd. 502.4, found 502.5.

Example 1.59

2S, 5R, GS-3-aza-4-oxo-1,0-oxa-5-hexyl-2- (2- (N-methyl-oxosulfonyl) -hexyl-1-carboxamido) -1'-101-para-cyanophen-6-N-hydroxycarbox am 1 d

Analogous to <35.2 mg (0.0689 mmol) <89.6 mg, 1.1. equiv.) and reacted as described with compound 21.2 (a) with 1,6-diaminohexane then methanesulfonyl chloride <0.150 mL.

equiv.) to give the desired reaction product <28.1 mg,

164

59%). Hydrogeriolysis of the reaction product (28, 1 mg, 8.0489 mmol) then gave the hydroxamate (25.0 mg, 100%).

ESI-1 ⁱⁿ IS (M + H) +: calc. 597.3, found 597.6.

Example 165

S, 5 R, 6 S-3 - · a z - 4 o x o -10 - o x a - 5 - h e x y 1 - 2 - (L - · o r n i 11 n - N - m in 1 or 1 d) - Ir. 10 ll - p a r a c v i o f a n - 6 M - h y d r ox yk ar box a m h d d d o e d

Hydr oxamate 205 (25 mg, 0.386 mmol) was treated with 4 M dloxane hydrogen chloride solution for 40 min. mL) and then concentrated to give the desired product (18.2 mg, 81%) as a white solid.

ESI-MS (M + H) + calcd 548.4, found 548.5.

Example 169

2S, 5R, 6S-3-aza - 4-oxo-10-oxa-5-hexyl-2- (methylcarbamoyl) - [eta] &lt; 0 &gt; - parac :: vk 1 of a - 6 - - N - In ydroxycarbox am 1 dbydrooh 1 or 1 d

Using a method analogous to that used for the synthesis of compound 50, compound 169 was synthesized in the form

t) more rigidly.

ESI-MS (M + H) +: calcd 434.3, found 434.4.

Example 1.80

S, 5 R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - 5 - hexy 1 - 2 - (glycine - N - methyl amide) 10 µl - araecyciophane - 6-N-hydroxycarboxamide

In analogy to the procedure described above, compound 21.2 (a) (40.8 mg, 0.080 mmol) was reacted with glycine-N-methylamide hydride chloride (1.5.0 mg, 1.5 reactant <42.2 mg). product (33.1 mg, 0.057 mmol) mg, 97%).

ESI + - MS (MiH) ¹ : calcd. 491.3, equiv. To give the desired 91.%). Hydrogenated product then gave the hydroxamate (27.1.

found 491.5.

165

Example 182

S, 5 R, 6 S-3 - a z a - 4 - o x o -10 - oxa- 5 - H e x v 1 - · 2 - <L. - a 1 a n n - N - m v t 1 and m. d) - ¾ 3.0 3-p a r k a k 1. o f a n - 6 - IM - h y <: j r o x y k a r la o x a m i. D

In analogy to the method described above, compound 212 (a)

<40.8 mg, 0, 080 mmol) stated to react with L-alanine- -IM -methy 1 am i. House <1.2, 2 mg, 1, 5 equiv. ) to form the desired r e a c h a n d o o t u t u <40, 9 mg 86%). H y d r o g e r icj 3 <33.0 mg 0, 0555 mmol) then gave a hydroxamate <280 mg, 1.00%). ES1-IMS <IM. I I) calculated ítané! 505, 4 found 505, 6.

Example 184

S, b R, 6 S-3-aza-4-oxo-3.0-oxa-5-hexv3-2- <D-a 1-anin-IM-methyl-1-amide) - L10 3-parac: yk 1 of a - Ei - IM - hydroxycarbox am j. in both cases, compound 212 (a) reaction with D-alanine-N to give the desired compound to give a hydroxamate <27.9

505, 5.

Analogous to the procedure described above (40 (EJ mg, 0.1 OSM mmol), it was introduced into methylamide <12.2 mg (1.5 equiv.) And the reaction (39 mg, 82%).

product (32.0 mg, 0.054 mmol) then mg, 100%).

E S1 - IM S (IM + H): Ei 05,4 z i s

Example 194

2S, 5R, 6S-3-aza-N-oxo-3-oxo-5-hexyl-2- (L-serine-0-tero). butyl) -N- methyl 1 am i d) - β 10 3 - p a r a c c 1-phane - Ei - IM - h y d r x y k i r Ei o x am i d

Analogically. Compound 212 (a) reaction equiv) (77.6%) was obtained.

(81.6 mg, 0.160 mmol) was introduced with s-tert. Butyl 1-L-serine-IM-methylamide <41.8 mg, 1.5 formation of the desired reaction product <82.8 mg

Hydrolysis of the reaction product (76.0 mg, 0.114 mmol) then gave the hydroxamate (66.7 mg, 100%).

166 fc. SI - l ⁱⁿ l S CM + H) * -. calculated 577.4 z. ist et rt é 577, 6.

Example 199

S, 5 R, 6 S - 9 ..... aza - 4 ..... oxo -10 - oxa - 5 - hexv 1 - 2 - C 2 · carboxmethoxy) etv 1 carboxid () [10 II - Parac: yk one ^of: and R - 6 - N - hydroxycarboxamide

In analogy to the procedure described above, 212Ca (¢ 95.2 mg, 0.0699 mmol) was reacted with methyl 3-aminopropionate hydrochloride ¢ 12.4 mg, 1.3 equiv) to give the desired group 2. (product C 3 6, 9 mg, 90%). Hydrogenolysis of the reaction product (36.9 mg, 0.0620 mmol) then gave the hydroxamate (31.0 mg, 100%).

E SI - M S C M + H) ´ '´: C a tio n 506, 3, s t o n t 506, 4.

Example 20i.

S, 5 R, 6 S- 3 - aza - 4 - oxo - 10 - oxa - 5 - bexy 1 2 - C 2 - C carboxycarbones I.) ethyl 1 carboxamido - 1.0 1.0 µJ - paracycl 1 of á n - 6 - N - hydr ox y c aram i. D

Analogous to the procedure described above, compound 212C (a) ¢ 35.2 mg, 0.0689 mmol) was reacted with benzyl 3-aminopropionate ¢ 31.5 mg, 1.3 equiv.) To give the desired salt. % of the title product (40 mg (90%)). The reaction product ¢ 40 (5 mg, 0.061.7 mmol) then gave the hydroxamate ¢ 30.5 mg, 100%).

ESI - MS (M + H) +: calcd. 4-92.3, found 4-92.3.

Example 203

S, 5 R, 6 S — 3 - a z a - 4 - o x o -1.0 - o x a - 5 -11 e x y i. - 2 C L - o rtitin C 4 -1 - b u t o x y k a r b o r t y 1) k a r b o x y m t y 1) - I nl 1.0 a - p a r a c v k o o f á n - 6 -

Analogous to the procedure described above (50 mg, 0.0983 mmol), the - B (1 ') O - or mercury 1 ester hydrochloride (I) with C 3 EI 2 gave the desired reaction product carbon black. en ina 2 i. 2 C (a) N * ^{: 1} θ ¹ -mg, 1.3 equiv) to ¢ 58.2 mg, 80%).

167

Hydrogenolysis of the reaction product (28 mg, 0.0669 mmol) then gave the hydroxamate (24.6 mg, 100%).

ESI -MS (M + H) +: calcd 649.4, found 649.5.

Example 205

S, 5 R, 6 S-3-aza-4-oxo-10-oxa-5-hexyl-2- (.L.-ornithin < ^z 1 ..... t - butoxycarbones 1) - M - methyl 1 am td) - Il 10µl - paracycl 1 of a - 6 - M - hydroxycarboxamide

Analogous to the method described above, compound 212 (a) <60 mg (0.119 mmol) was reported as reaction duty

-BOC-ornithine-N-methylamine dihydrochloride C 42.9 mg, 1 formation of the desired reaction product <52.2 I-Cl y rogenoic reactive product <21, ()) mg, 0.0285 gave hydroxamate <18.6 mg, 1.00%).

IR (MS (M + H)): calcd 648.4, found 648.6.

equiv., Za mg, 60%). mmol) then

Example 207

S, 5 R, 6 S - 3 - · aza - 4 - oxo -10 - oxa - 5 - bexv 1 - 2 - <L - ornithine carboxymethyl 1) - Ily 1.0 J - paracycl 1 of a - 6 - N - h in cl roxvcarboxam 1 dhydroc :: h I. o ri cl

Amide reaction product ¢ 31., 1. mg, 0.0421. mol / l) used to prepare compound 203 was treated. ... one hour with 4M dioxane hydrogen chloride solution <1. ml) to remove the 806 group. Hydrogenolysis of the crude material then gave a hydroxamate <24.8 mg

100%).

MSI-MS (M + H) +: calc. 549.4, found 549.5.

Example 209

S, 5 R, 6 S - 3 · - · aza - 4 - oxo -1.0 - oxa - 5 - hexv 1 - 2 - <L. -1 (rbox or rboxamide) - Il 1.0 µl - p or racyk 1 of α-6-M-hydroxycarboxamide id

By analogy with the above-described method, the compound! 21.2Ca) .05 1.05.6 mg, 0.207 mmol) was reacted with ¹ + -.

-Cbz-L-lysine-dihydrochloride <85.0 mg, 1.3 equiv) to give

168 of the desired reaction product (C188 mg, 82%). Hydrogenolysis of the reaction product (113 mg, 2 mg, 8.147 mmol) then gave the hydroxamate (74.5 mg, 83%).

ESI-MS (P1 + H) + calculated 548.4, found 548.5.

Example 211

S, 5 R, (5 S ..... 3 - - aza - 4 - oxo - 10 - oxa - 5 - exy 1 - 2 - C phenylethylcarboxamido) - L 10 3 - parac: ykiophane 13-N-hydroxycarboxamide

Analogous to the procedure described above, 212Ca (¢ 44.6 mg, 8.8873 mmol) was reacted with phenethylamine ¢ 8.8219 mg, 2 equiv) to give the desired reaction product ¢ 46.5 mg, 87%). Hydrogenolysis of the reaction product ¢ 46.5 mg, 6.6758 mmol.) Then gave the hydroxamate ¢ 39.2 mg, 99%).

ESI-MS (M-H-H): calcd 524.4, found 524.5.

Example 212

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-bexyl-2-C-hydroxycarbonyl) -L 163 - - pyrrolidin-G-N-pyrimidin-a-b

Analogous to the procedure described above, hydrogenolysis of compound 212C (a) (265 mg, 6.461 mmol) gave the hydroxamate (168 mg, 99%). ESI-MS (F1 + H) ⁺ : calcd 421.3, found 421.4.

Example 212Ca)

2S, 5R, 6S-3-aza-4-oxo-16-oxa-b-hexyl-2-C by droxycarbony 1) -1 '103 6-M-benzyl I. oxycarboxamide

1N aqueous lithium hydroxide solution ¢ 7.5 mL, 4.23 equiv) was added to a solution of 12 C (¢ 930 mg, 1.77 mmol) in tetrahydrofuran (20 mL) prd. Low: 14 ° C. After 25 minutes at. at room temperature, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate (3 x 40 mL). The combined extracts were washed with brine.

169 was dried (18 g / ml) and concentrated to give 212 (a) (840 mg, 93%) as a white solid.

E S1 - 1 ⁱⁿ l S (1 - 1 - H): calculated 511, 3, z i. you are: 5 11, 4.

Example 213

2S, bR, 6S-3-aza-4 ..... oxo-10-oxa-5-hexyl-2- (2- (3,4-dimethoxyphenyl) ethylcarboxamido) -L10II -paracyclophane-6 -N-hydroxy oxycarboxamide

Analogous to the procedure described above, compound 212 (a) <29.2 mg, 0.0672 mmol) was reacted with 2- (3,4-dimethoxyphenyl) ethylamine <14.7 mg, 1.2 equiv. To give of the desired reaction product (31.8 mg, 83%). Hydrogenolysis of the reaction product (31.6 mg, 0.0469 mmol) then gave the hydroxamate (24 mg (90%).

ESI-lS (hH-H) ': calculated 584, 4, found 584.6.

Example 214

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (benzylcarboxamido)

- p a r y c 1 o fan - Ei - IM - h y d r oxyc a r b o x am i d

Analogously to the procedure described above, compound 212 (a) (40 mg (0.080 mmol)) was reacted with benzylamine (0.0114 mL, 1.3 equiv) to give the desired reaction product <43.0 mg, 90 %). Hydrogenolysis of the reaction product (33.0 mg, 0.055 mmol) then gave the hydroxamate (28.2 mg, 100%).

ESI-1 * IS (I * I + H) calcd 510.3, found 510.5.

Example 215

2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (14-morpholinoethylcarboxamido) -II10II-par acyclophan-6- M-hydroxycarboxamide

Analogous to the procedure described above, compound 212 (a) (41.2 mg, 0.0807 mmol) was reacted with 4-C (2-amirioethyl) morpholine (0.015 mL, 1.4 equiv.) To give the desired Ei. about

170 r e a l d u n d o c t u c t 4 0, 0 τη g8 0%). The product (39 mg, 0.0626 mmol) then gave the hydroxamate (30.4 mg, 91%).

ESI-11 (14 + 14) -: calc. 593.4, found 533.5.

Example 2: 1.7

2S, 5R, 6S8-aza-4-oxo-10-oxa-b-hexyl-2- [3- (4-morpholino) propylcarboxamido] -1,11-paraffin-6-N - hydroxycarboxamidhydrohydride

By analogy with already. as described, compound 2 '(a) (44.4 mg, 0.0870 mmol) was reacted with 4- (3-aminopropyl) ethyl. ) to form the desired reaction I-I y d r o g e n o n e n e n e n e n e n o n e t o ¢ 40 m g,

0.0628 mmol) in the presence of hydrogen chloride ¢ 1 equiv) then gave the hydroxamate ¢ 34.2 mg, 93%).

ESI &lt; + &gt; - &lt; 14 &gt; + 14) = = calculated 547.4, found 547.5.

pyrldine ¢ 0.0254 mg, 2 products ¢ 40.0 mg, 72%).

Example 224

2. S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexy1-2-di. f ^:: phenyl etyikarboxam 1 to 1) - Ll L10 - paracyk of 1 s n - 6 - N - 1 d hvdroxykarboxam previously described, compound 21 ^ a) mmol) was reacted ¢ 11.5 mg, 1.2 equiv .) to form an iroduct ¢ 32.2 mg, 80%). Hydrogenolysis (0.0464 mmol) was then afforded

Analogous to ¢ 29, 8 mg, 0, 9584 with 2,2-diphenylethylamine P h a r a tio n s and c h e r e c tio n ¢ 32, 0 m g,

Iny d r o x a t 27.6 mg, 1 (¾) 0%).

ESI-I4S (14 + 14) -: calculated 660.4, found 600.6.

Example 225

2S, 5R, 6S-3-aza-4-oxo-1- [1 '] -oxa-5-hexyl-2- (2- (4-sulfonyl-amino-phenyl) -ethyl) -ethyl. k a r b o x a m i d o) - 11.0 l l - p a r a c y k 1 f á £ £ £ o h d IM a IM IM m IM IM IM IM IM n 212 212 ¢ a)

By analogy with the method described above: 1.71

0.137 reaction (70.0 g, g) indicated cic with 4- (2-aminoethyl) benzenesulfonamide (33.0 mg, 1.2 equiv.) To give the desired reaction product (80.7 mg, 8b%) . 1-Lyclrogenolysis of the reaction product (76.6 mg, 0.11: 1 mmol) then gave the hydroxamate (65.4 mg, 98%).

ESI-1S (1'+ H) +: calcd 603.3, found 603.6.

Example 710

4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2- (carboxymethyl) -121-acylpropane-8-N hydroxycarboxamide

Synthesis of homogeneity

710 (a) To a stirred and cooled (0 ° C) solution of 5.0 grams of 3- (4-henzyloxyphenyl) propanol in 100 mL of anhydrous D 1 -1 Cl 2 · 4 was added 4.3 mL of triethylamine and then over 10 min. minutes 1.76 ml of methanesulfonyl chloride. The reaction mixture was stirred for 1 hour and then poured into saturated aqueous NaHCO ₃ . The aqueous phase was extracted twice with CH _and 61 _sec . extr instruments are combined, washed with water, 10% aqueous citric acid, _with H, 0 and Selanka, dried over ľlgSCU and the solvent removed in. under reduced pressure gave a quantitative yield of the mesylate as a white solid.

LR18S11 + H-338.

7: 1.0 (b) To the above mesylate in 100 mL of acetone was added 3.9 grams of Mal. After the reaction mixture was stirred at room temperature overnight, followed by an additional 3.9 grams of Mal, the mixture was refluxed for 1 hour. The reaction mixture was filtered. 11 at the reduced pressure to remove volatile constituents. The solid, which turned yellow immediately after formation, was dissolved in hexane and washed with water, twice with 5% aqueous sodium thiosulfate solution, H 2 O, brine, dried over MgSO 4. and after removal, the solvents under reduced pressure gave 6.79 g of the product as a white solid.

LR18S1 + H = 379.

172

710 (c) To a stirred and cooled suspension (-78 ° C) of the suspension

1.15 g of LiCl (flame dried in a flask under vacuum) and D, 99 g of Meyer reagent (Ileyers et al., JACS, 1995, 117, 8488) in 39 mL anhydrous THF were added for 10 min.

The mixture was stirred for 20 minutes ^Y I 1 I ml of LDA in THF at 78 ^<::> 0 and then 30 minutes at hexánocl · at 0 ° C. The mixture was then added dropwise over 10 minutes

1.57 g of iodide in 10 ml of anhydrous THF. The reaction mixture was allowed to warm slowly to room temperature overnight with stirring. It was then quenched with a 10% aqueous citric acid solution and freed from the volatiles under reduced pressure in EtOAc. The remaining material was the H + Ok, 5% aqueous sodium thiosulfate, H _and 0, saturated aqueous NaHCO _3, H _and 0, solaokou, dried over MgSO and the solvent is evaporated under reduced pressure. The resulting material was chromatographed on silica gel, eluting with 4: 100 MeOH / CHCl 3 to give 0.9 g of 710 (c).

LRMS M-H = 447.

H y d e r d e d e e d e d e d e d e d m d d

(D) To 3.5 grams of alkylation product 710 (c) in 40 mL of Η-Ό and 25 mL of 1 LOH was added 15.7 mL of 1 M aqueous MaOH. The reaction mixture was refluxed for 1 hour and added during boiling

2.5 ml MeOH. The reaction mixture was boiled for another three. The reaction mixture was refluxed for 20 hours and then freed from volatiles under reduced pressure. The solid was triturated with CH 2 Cl 2. and after filtration gave 5.5 g of sodium hydroxide and the product as the sodium salt. After removal. CH 2 Cl 2 from the filtrate under reduced pressure, the residual solid was triturated with Et _and O to give an additional 1.1 grams of 710 (d).

LRMS M + H-298.

At. p r a v a m e t v 1 e s t e r u

710 (e) To MaOH and the above sodium salt. in 150 mL of MeOH was added 3 mL of concentrated HCl. The reaction mixture was boiled overnight

173 under reflux, during which time the volatiles were removed under reduced pressure. The resulting material was taken up in EtOAc and washed with saturated aqueous NaHCO ₃ solution and brine and dried. over MgSO4. After removal. volatiles under reduced pressure gave 2.4 g of the methyl ester.

LRI 4 S 14 -t-H = 314.

Binding of homo-homo tyrosine to the succinate fragment

F) To a stirred and cooled (0 ° C) solution of 0.90 g of acid in 20 ml of anhydrous DI4F was added 0.79 g of amino acid 710 (e) methyl ester, 1.14 ml of N144 and 0.884 g of TBTU. The reaction mixture was stirred for 20 minutes at 0 ° 0 and for 2 hours at room temperature. The reaction mixture was diluted with 300 mL EtOAc and washed five times with a 10% aqueous citric acid solution. All water washes were combined and extracted five times with EtOAc. All six of the organic extracts were combined and washed five times with saturated aqueous solution of N, makeup Selanka once and dried over MgSf.t _r. After deletion it sounds. TLC on a gradient of 15 to 20% EtOAc in hexane gave 1.2 g of bound material.

I ... R14S 14 + 11 = 074.

The volatile fractions at P abrasion of the final material using an elution

710 (g) To a stirred solution of 1.2 g of benzyl ether in 50 ml of 14 e OH was added 5 ml of acetic acid and 0.15 g of palladium carbon black as 1PA slurry. The mixture was stirred for 3 hours at a pressure of H _with > 0.1 bar. After removal of the catalyst by filtration and removal of the volatiles under reduced pressure, the protective group is protected.

LRI4S14 + H = 494.

yielded 0.76 g of the stripped product

710C h) To anhydrous stirred CH _and CI. _with the solution of 0.40 g of alcohol 710C1) in 20 mL pr Idala 0.89 g of carbon tetrabromide and 0, 70 g trifluoromethyl-phenyl phosphine ha yne. The reaction mixture was stirred for one hour, after which it was poured into a 10% aqueous citric acid solution, separated and the aqueous phase was extracted three times with CH _and Cl _and

174

The C 11 extracts were combined and taken up in water, brine and dried over MgSO 4. The solvent was removed under reduced pressure and the resulting material was subjected to silica gel chromatography eluting with a gradient of 25 to 50% EtOAc in hexanes to give 0.02 g of bromide (710Ch).

LR18: found C11 ⁱⁿ H @ + = 55.

(I) To a stirred and cooled CO ° C) solution of 0.20 g of bromide in 00 mL. Anhydrous DMF was added at once to 0.21 g. 0s _: > 00 ₃ - After stirring for 2 hours, the mixture was poured into EtOAc and washed twice with 1.0% aqueous citric acid solution and three times with water. All aqueous washings were combined and extracted five times with EtOAc. The six EtOAc extracts were combined, washed with water, then twice with brine, and dried over MgSO4. After removal of the solvent under reduced pressure, the resulting material was subjected to silica gel chromatography using a 2.0% EtOAc in hexane eluent system. och, aposkyto 1. 0,08 g C 8 2% yield) macrocycle 1. u.

Found: C11 + H + - 476; CI + Na + = 498.

To 0.1.50 g of 710C.j) was added 5 mL of TFA. After stirring for 2 hours and subsequent removal of the volatiles under reduced pressure, 0.125 g of acid was obtained.

LR18S (M + H +) = 420.

7100.) To a stirred solution of 0.073 g 710Ck) in 8 ml. of anhydrous CH 3 Cl 2 was added 0.044 g HOD 0.077 ml. N ', 1.033 g of O-benzylhydroxylamine hydrochloride and 0.043 g of DEC. After stirring for 2 hours. the volatiles were removed under reduced pressure. To the remainder of the material was added 3 mL of anhydrous DIF and 0.1 g of O-benzylhydroxyl amine. The reaction mixture was warmed to 8 (1 ° C and held at this temperature for 45 min.) Then poured into EtOAc and washed five times with 10% aqueous citric acid solution. The combined aqueous washes were extracted five times with EtOAc and the six extracts were washed twice with H The resulting material was subjected to chromatography on silica gel, eluting with 3% 1: 1OH / CHCl 3, to give 0.079 g of O-benzyl hydroxamate.

175

Example 710

4S, 7R, BS-3-aza-6-oxo-12-oxa-7-isobutyl-2- (carboxymethyl) -121-pyrimidin-8-one-hydroxybenzyl-8-oxo-7-isobutyl

To 1.0 mg of 710C e) with 5 mL of MeOH was added 25 mg of 5% Pd / BaSO 4. The reaction mixture was shaken for two hours at H, pressure 0.33 IIP a, filtered and stripped of the volatiles under reduced pressure to give 7 mg hydroxamic acid.

LRMS found (M + H) + - 435.

of methyl ester 710 (1) in 3 mL of THF and 1 mL of H _and O saturated aqueous LiOH. The mixture was diluted with EtOAc, acidified with 1N HCl a. EtOAc. All three EtOAc extracts were combined and

759 (a) To 0.035 g, 0.13 mL of nas was allowed to stir 4 [deg.] C hl and d 11 εί 2 mL of HCl and water. and washed three times with water and then with brine, dried over MgSO 4. and after removal of solvents under reduced pressure gave 0.025 g of acid.

LRMS found (ΙΊ + Η) * = 511; (l * l + Na) * = 533.

Example 759

S, 7 R, B S-- 5 - aza - ES - oxo - 1 - 2 - oxa - 7 - isobutyl 1 - 2 - (N - methyl carboxamido) 12 12 l - par ŕ c :: vk 1 ofán - 8 - N-hydroxycarboxamide

To a solution of 0.023 g of acid 759 (a) in 1 mL of DMF was added 15 mL of NMM and 0.016 g of TBTU. After stirring for 5 minutes, 16 mL of a 40% aqueous MMA solution was added and the reaction mixture was stirred at room temperature for 15 minutes, diluted with EtOAc and washed four times with a 10% aqueous citric acid solution. All five EtOAc fractions were combined and washed with H 2 O and then brine and dried over MgSO 4. After removal of the volatiles under reduced pressure, the resulting material was purified by preparative thin layer chromatography (ľ mm with 0.2 mm concentrate), eluting once with 3% MeOH / CHCl 3 to afford 0.011 g of product. .

176

LRMS found CM + H + - 524; (M + Na) - 546.

To 11 mg in 10 mL of MeOH was added 30 mg of 5% Pd / BaSO4. The reaction mixture was shaken under H ₂ pressure for 3 hours. 0, 31 bar, _e pr filtered and freed of volatiles under vacuum to give 7 mg of hydroxamic acid Example 759th

LRMS found (Μ + Η) '= 434.

Example 869

2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-methyl- (N-methylcarboxamido) -ocyclopentadecan-1 3 - N - hydroxycarboxam i. D

869 (a) To a solution of the alcohol intermediate 1 (d) (11.4 g, 33, mmol) and 4-nitro-enyl chloroformate (10.0 g,

CH _and C 1.-2, cooled in an ice bath,

N-methylmorpholine (4.4 mL, 40 mmol) and the mixture was stirred at room temperature overnight. After removal of the solvent in vacuo, the residue was taken up in 200 mL EtOAc. The solution was washed three times with brine, dried (MgSO 4) and concentrated. Purification on a silica gel column, eluting with 102 EtOAc gave the desired product (15.0 g, 912) as a pale yellow solid.

DCI-MS: calcd (M + NI-L,) = 561; found 561.

mm o se porn

I ..) in 50 ml L y added

869 (b) To a solution of 869 (a) (15.20 g, 27.28 mmol) and N ^AXF '- N-Cbz; - ^ ¹ ^^ - methylmorphinan-L-lyzínmetylesterhydrochloridove j of (11.22 potassium carbonate (15 g, 109 mmol) was added and the mixture was heated to 50 ° C. At. this temperature was maintained for one hour. After insoluble material was filtered off, EtOAc was added. The solution was washed with 102 citric acid solution, brine, NaHCO3 _, and again brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 152 EtOAc in hexanes gave an oil product (17.0 g, 912).

ES1-MS: calcd. M + 1

713, 5; found 713, 7.

869 (c) Oil from one plant. n and 869 (b) (10.0 g

14.02 mmol) was added

177 was dissolved in 30 mL of MeOH and the solution was hydrogenated for 1 hour at atmospheric pressure and in use. 10% Pd-C (1.0 g) as a zinc salt. The catalysed oil and the thickening gave an oily product (6.8 g, 100%).

EST - MA: calcd. 1 * 1 + 1 = 489.1; found 489.0.

8 (39 (d) To a solution of BOP (9.2 g, 20.8 mmol) and diisopropylethylamine (12 mL, 70 mmol) in 600 mL ClIClg, cooled in an ice bath, drip drop and add two hours. 869 (c) ((5.8 g, 13.9 mmol) in 50 mL of CHCl ₃ and the mixture was stirred at room temperature overnight The CHCl 3 was removed in vacuo and EtOAc was added and the solution was washed with 5% citric acid solution. Purification on a silica gel column using an elution system of 4% MeOH / CHaCl 3 afforded the cyclic product (3.4 g, 46%) as a scrubber. .

ESI-11S: calcd. 1 * 1 + 1 = '471.4; found 471.5.

869 (e) ring compound 869 (d) (2.6 g, 5.5 mmol) was treated for 1 h 20 ml 50% TFA in CH _ffi duties, and the solution was concentrated to 1 L of oskyto I ejov product characterized (2.3 g, 10%).

ESI-iS: calcd 1 * 1 + 1 - 415.3; found 415.4.

(F) To a solution of 869 (e) (1 ') -benzylhydroxyaminohydrocyclide cooled in an ice bath, ml, 24, (E) mmol) or then BOE' (2.72 (2.2 g, h, 3 mmol) and (0.96 g, 6.15 mmol) in 16 mL of DMF, diisopropylethylamine (4.3 g, 6.15 mmol) was added and the solution was allowed to stir overnight, EtOAc was added and the solution was washed 5% citric acid, brine, NaHCO 3 and again brine, dried (MgSO 4) to give, after concentration, the crude product which was washed with ether to give the desired product as a pure solid (2.9 g,

90%)

ESI-iS: calculated ll + 1 = 520, b; found 520.5.

869 (g) Compound 869 (f) (0.5 g, 0.96 mmol) was treated with 5 mL TUF and 4 mL IM LiOH for 1 h and the solution was acidified with TFA and concentrated. EtOAc was added and the solution was washed with brine, dried (MgSO 4) or after

Concentration of 1.78 gave the acid as a solid (8.8 g, 83%). ESI-1 * 1 S t calculated M + 1 - 506.5; found 506.5.

869C5) To a solution of 869Cg (CO), 2 g, 0.39 (5 mmol) and methylamine hydrochloride (11 g, 1.58 mmol) in 2 mL of ice-cold DMF was added OOP CO, 18 g, 0.4 mmol) followed by dlisopropylethylamine CO (52 mL, 3 mmol). The mixture was allowed to stir for 2 hours at room temperature. EtOAc was then added and the product precipitated. The precipitate was filtered off and washed with FtOAe and water to give the title compound as a solid (CO, 1.5 g, 73%).

ESI-1 * ISt calculated 1 * 1 + 1 = 51.9.4; found 519.5.

Example 869

Compound 869 (1220 mg, 0.23 mmol) in 5 mL MeOH was hydrogenated at atmospheric pressure for 30 minutes using 10% Pd-C (40 mg) as a catalyst. The catalyst was filtered off and the solution was concentrated. Purification by reverse phase HPLC afforded the final ESI-MSx product as a powder calculated M + -1 = 429.3;

(81 mg, 82%). from 1 to 429, 4.

Example 871.

2. S, 1.3 S, 14 R-1, 7-day and a-8, 15-day. o x o - 9 - o x a - i 4 - i z o u u 1 - 7 - m e t v 1 - 2 - ·

- C g 1 y c i n - N, IM - d i m i d i d) - c y c e t e t e n d e -13 - M - h y d r x y k a r b o x a m d

This compound! was prepared at. using procedures analogous to those described in Example 869.

ESI-MS calculated for M + 1 - 500.5, found 500.5.

Example 880

S, i 3 S, 1.4 R - i, 7 · - d i and z a - 8, 15 - d i. o x o - 9 - o x and -14 - i z o u t 1 -7-in t e 1 -2-C g i e n n-N e m e t v 1 a m i. d) - e y k i p e n t a d e k--13 - N — h y d r o x y k a r b o x a m i. d fabrics from 1 print. n a b o 1 a prepared at

P o u i i. t í. p O S t U p o v

179 a n o o g g c c c h e s: p s s p m 1 p o s s t e m e s i c e 869.

ESI — 1 * 1 S: calculated M + 1. - 486.3; found 486.5.

Example 994

S, 13 S, 14 R -1, 7 ··· d i a z a - 8,1 Εϊ - d i. o x o - 9 - o x and -14 - i. z o bi u t v 1 7 -mets 1 - 2

3-Cyclopentadecar-13-Ν-hlycryloxy-4-methyl-N-glycine-C-4-methyl-N-piperazinylamide

This compound was prepared using procedures analogous to those described in Example 869.

EI-MS was calculated M + 1 = 555.6; found 555.5.

Example 908

S, 1.3 S, 14 R — 1, 7 — d a and z a — 8, 1.5 - cl o x o — 9 — o x a — 1,4 — i z o b n t 1-7 -met y-2. - g y - n - N N no no no no no no no no no no no d d d d d d d d 13 13 13 13 13 13 13 13 13 13 13 D

This compound was prepared using procedures analogous to those described in Example 869.

ESI-MS t calculated M + 1. - 542.4; found 542, 5. .

Example 91.0

S, 1.3 S, 1.4 R-1, 7-Cliazole - 8, 1,5-dioxo-9-oxa -1,4-Isobutyl-7-methyl 1 - 2 - L 2 - pyridyl 1) carboxamido 1 - cycl 1. opeotade: k n n — 1.3 — N - hy cl roxycarb ox ox id

This compound was identified by ESI-MS: found 555.7.

prepared as described in Example 869.

procedures

Example 91.6

S, 1.3 S, 1.4 R -1., 7 - d i and z a - 8, 1.5 - d i. oxo-9-oxa -14 -1 for 1 - 7 - meth 1 - 2 -1 .. (2 - P 1 cl) carboxes, up to 1 - 1. -N-hydroxycarboxamide

This compound was prepared using procedures analogous to those described in Example 869.

1.86

ESI-18: calcd M + 1 = 492.5; found 496.5.

Example 919

S, 13 S, 14 R-1,7-diaza-6,5,5-dioxo-9-oxa -14-isobutyl-7-methyl-2- (givin-2-pyridyl): (d) Cyclopentadecan-i 3 M - Hydroxycarboxam i. D

This compound was prepared at. using procedures analogous to those described in Example 869.

ESI-1 * IS = calculated M + 1. - 549.4; found 549.5.

Example 926

S, 13 S, 1.4 R -1., 7 - d 1. and z a - 8, i 5 - d i. o x o - 9 - o x and -14 -1. z o u u - 7 - m e t 1 - 2 - I 2 - C 5 - m e t 1.11. and z o 1 in I.) k a r b o x and m i. d o l l - e y k 1 o p e n t a d e k -1.3 - N - h y d r o x y k a r · b o x a m 1. d

This compound was prepared at. using procedures analogous to those described in Example 869.

ESI-MS: calcd. M + 1 - 512.3; found 512, 4.

Example 927

S, 13 S, 1.4 R-1, 7-diaza-8, 1,5-di, oxo-9-oxa -1,4-isobutyl-7-methyl-2-methyl-2- (3 4, 5, 6-tetropyridopyridyl) -cyclopentadecane-13-ΙΜ

- y y d r o x y k and r b o x and m i. D

This compound, analogous to the procedures of EI-MS: M + 1.

was prepared for: i. described in the example?

- 553.6; found 553.6 using 869.

procedures

Example 928

S, 1.3 S, 1.4 R-1. and from a - 8, 15 - d i. o x o - 9 - o x a -14 - i z o u u t 1 - 7 - m e t y 1 - 2 - I ‘41 y o n n - 2 - (5-met e v 1) t o y 1 y 1 a m i. d l - y k o o a a--13 13 13 13 13 13 13 13 13 11 13 13 13 13 13 11 13 13 13 13 13 13 13 13 13 13 -13-N -11 D

This compound was prepared at. use. procedures

181 analogous to the procedures described in Example 869. ESI — 1 * 1 S: calculated 1 * 1 + 1. = 569.3; found 569.3.

Example 929

S, 13 S, 14 R-1, 7 - diaza - 8, 15 - dioxo - 9 - oxa - 1,4 - isobutyl 1 - 7 ..... methy 1 - 2 - L N - C 2 - P incl i. d v 1) m e t v 1 k a r b o x a m i d o ll - c v k o o n t d e l <ά n -13 - N -

- y d x a a .. .. .. .. .. .. .. .. .. .. .. .. ..

This compound was prepared at. using procedures analogous to those described in Example 869.

E S ľ H + -1 * 1 S: calculated 1 * 1 + 1 = 506.3; found 506.5.

Example 1175

S, 1.3 S, 1.4 R -1.7-di.aza-8,

15-dioxo-9-oxa-14-C3-phenylpropyl) -7-methyl

- 2 ...... (M-m f r i n k a r b o x a m i) - c y k 1. o p e n t e d e -13 - N - b y d x o k a r b o x a m i. D

This compound was prepared at. using procedures analogous to those described above.

ESI-lS: calculated l1 + 1. = 547.4; found 547.4,

Example 1176

2S, 13S, 14R-1,7-diaza-8,5,5-dioxo-9-oxa-14- (3-phenylpropyl) -7-methyl-2 - ((4-methyl)) M - p 1. 1. D. - d. I - opentadanone - 1 - 3 - IM - hydroxy carboxamide

This compound was prepared at. using procedures analogous to those described above.

E S l lľ-1 * 1 S: calculated ľ l + 1. - = 560.4; found 560.6.

Example 1228

2S, 13S, 14R-1, 7-Diaza-8,15-dioxo-9-oxa-14- (3-phenylpropyl) -7-methyl-

-2- (M - m e t y 1 k a r b o x a m i d) - e y k 1 o p e n t e d e -13 - M - h y d r o x y k a r b o x a m d

This from the account. n a b o 1 a prepared at. use of procedures

182 analogous to those described above. ESI-MS calcd M + 1 = 491.3; found 491.5.

Example 1442

S, 1.1 S, ¾ .. 2 R- ¾ .., 7 ··· d i a z a - 8, 1.3 — d i, o x o — 12 — i. z o b u t v 1 c y k o o r e d e k - 2—

- C g 1 y tin - M - ni e t v 1 a m i d) -1 J .. - (N - h in d r - o x y k and r b o x am i d)

1.442Ca) To a solution of succinate To c) (2.7 g, 9.4 mmol) and ^lor, -benzyloxycarbonyl-L-lysyl methyl ester (C4, 6 g, 14.0 mmol) in DMF (18 ml) was added diisopropylethylamine C 4.1 mL, 23.4 mmol)

BOP ¢ 4.9 g, 11.2. mmol). After stirring, ethyl acetate and obtained with citric acid, saturated solution were added. The ethyl acetate solution was dried (¢ MgSO 2). The residue was purified by silica gel chromatography to give an amit ¢ 4.1 g (77%) as a white foam.

ES-MS ¢ M + H 56 565.5.

the solution was left overnight the solution was washed with 10% N and HCO 2 -, and with 10 and 10%. and z a h u s t i 1. ý ý s 1 e d d i i

^ 1442) Compound 1442 and ¢) ¢ 2.9 g, 3.5 mmol) was dissolved in CH _CN ¢ 8.3 ml), CCl ^. ¢ 8.3 ml) and H _S .O ¢ 12.3 ml). At room temperature, added _with H I'0 _Ä ¢ 3.7 g, 16.2 mmol) and RuClg. H 2 O (16.4 mg, 0.08 mmol). After 1.5 hours, 10% citric acid was added and the layers were separated. The organic layer was dried and concentrated. The resulting residue was purified by silica gel chromatography to give the acid ¢ 1.1 g (56%) as a white foam.

ES-MS O * H-H) '579.5.

1442 ¢ c) Example 1442 (¢ 500 mg, 0.8 mmol) was hydrogenated in MeOH 5 10 mL (5% Pd / O-Degussa ¢ 58 mg) under a hydrogen atmosphere ¢ 0.31 MPa). After stirring overnight, the catalyst was removed by filtration and then concentrated to give the amino acid (¢ 370 mg, 97%) as a white foam.

ES-MS (M + - H) - 445.5.

1442 ¢ d) To a solution of HBTU ¢ 375 ing, 1.0 mmol) and NMM ¢ 0.07 mL, 0.7 mmol) in DMF-¢ 5 mL) at 60 ^<::> C was added compound 1442 ^) ¢ 100.0

183 mg, 0.2 mmol) in DMF (5 mL). After the addition was complete, the mixture was stirred for an additional 30 minutes. The solution was concentrated and chromatographed on silica gel to afford the lactams (60 mg, 63%) as a white solid.

ES-IMS (MH +) 427.5.

1442 (e): Compound Example 1442 (d) (250 mg, 0.6 mmol) was dissolved in 0H ..-. 01 _p (2 mL) and TFA (2 mL). After stirring overnight, the solution was concentrated to give the crude acid (220 mg) which was dissolved in DIF. O-benzylhydroxylamir (157 mg,

1.3 mmol), diisopropylethylamine (0.2 mL, 1.1 mmol) and BCJP (334 mg, 0.7 mmol). After stirring overnight. The solid product was filtered from the solution to give O-benzyl hydroxyamate (165 mg, 60%).

ES-IMS (1 H-H) * 476.4.

1.442 (f) Example 1442 (e) (50 mg, 0.1 mmol) was dissolved in 1: 1 THF / 1LOH (EJ mL) and UM LiOH (0.5 mL, 0.5 mL) was added to the obtained solution. mmol). After two hours, additional 1 M t 1 OH (0.5 mL, 0.5 mmol) was added. The reaction mixture was stirred for an additional 1.5 hours, after which time the solvent was removed. The remaining water was acidified with 1N HCl and extracted with CHCl ₃ . CHC1 ₃ was dried (IMgSCL ,.) and concentrated to give (52 mg, 86%) as a white foam.

ES-IMS (MH +) 371.4.

1442 (g) To a solution of compound 1.142 (f) (70 mg, 0.15 mmol) and glycine-N-methylamide (29 mg, 0.25 mmol) in DIMF was added diisopropylethylamine (0.1E> mL, 0.37) mmol) and HBTU (85 mg, 0.25 mmol). After stirring overnight, the solid product was filtered from the solution to give bound glycine (60 mg, 75%) as a white solid.

ES-IMS (MH +) * 532.4.

Example 1442

Example 1442 (g) (60 mg, 0.1 mmol) was hydrogenated in IMeOH-CHCl ₃ (3: 1, 15 mL) with 5% Pd / BaSCU

184 ¢ 120 mg) under a hydrogen atmosphere ¢ 0.31 MPa). After stirring for 3.5 hours, the catalyst was filtered off and the solution was concentrated to give the title hydroxamate (20 mg, 41%) as a white solid. ES-MS (M + H) &lt; + &gt; - 442.4.

Example 1443

2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecan-2-CL- and 1-anine-N-methylamin-11-CN-hydroxycarboxylic acid box am id)

1443Ca) To a solution of the compound of Example 14 42 C f) ¢ 80 mg. 0.17 mmol.) And L-alanine-N-methylamide (23 mg, 0.22 mmol) in DMF were added NMM (0.06 mL, 0.52 mmol) and HUTU (256 mg, 0.69 mmol). . After stirring overnight, the solid product was filtered from the solution to give the reacted material (66 mg), which was dissolved in MeOH-CHCl 3 (: 3: 1, 30 mL). This mixture was hydrogenated with 5%

Pd / BaSCU (150 mg) under a hydrogen atmosphere ¢ 0.34 MPa). After stirring for 3 hours, the catalyst was filtered off and after concentration, the solution gave the title hydroxamate (¢ 27 mg, 45%) as a yellowish solid.

ES-MS (M + H) + 456.4.

Example 1447

2S, 11S, 12R-1,7-diaza-8,13-dioxo-12-: i -butylcyclotrididecan-2-carboxylic acid; · - N - met y 1 a m i d) -11 - (. N - h y d r o x y k a r b o x a m i d)

D M f- was added After overnight

1447 C a) D o r o z. 1442 (f) C (700 mg, 1.5 mmol) and L-serine N-methylenide (234 mg, 1.9 mmol) in NMM ¢ 0, 5 mL, 5.4 mmol) and HBTU (2.2 mg, 5.9 mmol), stirring to filter the solid product to give the bound product (640 mg). The obtained product was dissolved in MeOH-CHCl 3 (3: 1, 300 mL). This mixture was hydrogenated with 5% Pd / BaSCU (1.6 g) under a hydrogen atmosphere (0.34 MPa). After three hours, the catalyst was filtered off from the solution and concentrated to give the title hydroxamate (250 mg, 47%) as a yellowish solid. ES-MS (M + H) + 472.4.

185

Example 1452 '

2S, 11S, 12R-1,7-diaza-8,13-dioxo-2- (N-methylcarboxamido) -12-isobutyl-1-thiocyan-2-11-C-1-iodine

1452 (a) To a solution of succinate K o (170 mg, 0.6 mmol) and 1'-benzyloxycarbonyl-L-lysine-N-methylamide (224.6 mg, 0.8 mmol) in DMF (E> diisopropylethylamine (0.26 mL, 1.5 mmol) and BOP (286.9 mg, 0.6 mmol) were added. After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCO ₃ and brine. The ethyl acetate solution was dried (MgSO 4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide (255 mg, 77%) as a white foam.

ES-MS (M + H) + 564.4.

1462 (a) (813 mg, 1.4 mmol) was CC1.Z + (3 ml) and II _R (j (4.5 mL). The. G, 5.9 mmol) and Ruoli-j. 6, -, Ο (6

1462 (b) Dissolve the compound of the example in CH 2 CN (3 mL) at room temperature and add H 2 _{O 10} (1.3 mg, 0.03 mmol). After 1.5 hours, 10% citric acid was added and the layers were allowed to separate. The resulting residue was purified by silica gel chromatography to give the acid (504 mg, 60%) as a white foam.

ES-MS (M + H) + 578.5.

1462 (c) Example 1462 (b) (45 mg, 0.08 mmol) was hydrogenated in MeOH (5 mL) with 5% Pd / C-Degussa (15 mg) under a hydrogen atmosphere (0.34 MPa). After stirring overnight, stirring the catalyst was removed by filtration and then concentrated to give the amino acid (32 mg, 90%) as a white foam.

ES-MS (M + H) + 444.4.

1462 (d) To a solution of HBTO (769 mg, 2.0 mmol) and IMMM (0.15 mL, 6.0 mmol) in DMF (10 mL) at rt. Compound 1462 (c) (200.0 mg, 0.4 mmol) in DMF (10 mL) was added dropwise at 60 ° C. After adding. the mixture was stirred for an additional 30 minutes. The solution was concentrated and after

186 silica gel chromatography of this solution afforded the lactams (135 mg, 78%) as a light yellow solid.

ES-1S (M + H) + 426.3.

3..462 <e): Compound Example 1462 <D) <85 mg, 0.2 mmol) was dissolved in CH C1 _{S S} <2 mL) and TFA <2 mL). After stirring overnight, the solution was concentrated to give the acid <80 mg (quant.) As a white foam.

ES-1S (M + H +) 370.3.

1462 (f) To a solution of the compound of Example 1462 (e) mmol) and O-benzylhydroxylamine (78.8 mg, 0.6 mmol) was added dlisopropylethylamine (0.07 mL, 0.4 mmol) and 0.2 mmol). After stirring overnight, the solid product of the solution gave O-benzyl hydroxamate (58 mg, 61%).

<75.0 mg, 0.2 in DF (1.5 ml)

BOP <97.3 mg, filtered from

ES-11 (M + H +) 475.3.

1462 Example 1462 (f) (50 mg, 0.3 mmol) was hydrogenated in IMeOH-CHCl _{: S5} (3: 1, 40 mL) with 10% Pd / C (20 mg) under a hydrogen atmosphere < balloon). After stirring for 6 hours, the catalyst was filtered off and the solution after concentration gave the title hydroxamate (38 mg, 93%) as a white foam.

ES-1S (MH +) ^{1 H} + 385.4.

Example 1478

2S, US, 12R-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2-a-amino-N-methyl-amino. d) - i 1 - <M - Iny d r o x k a r b o x a m i d)

1473 (a) To a solution of the compound of Example 1442 (f) (100 mg, 0.22 mmol) and ε-glycine-N-methylamide (29 mg, 0.28 mmol) in DMF was added IM1β <0.07 mL, 0.66 mmol) and HBTU <320 mg, 0.84 mmol). After stirring overnight, the solid product was filtered from the solution to give bound material (80 mg) which was dissolved in 1: 1 CH 2 Cl ₂ (1: 1, 30 mL). This mixture was hydrogenated with 5% Pd / BaSO 4 (180 mg) under a hydrogen atmosphere (balloon). After stirring for 3 hours, the catalyst was filtered off and the solution was concentrated

187 of the title hydroxamate (78 mg, quant.) As a white solid.

ES-MS (M + H) + 458.4.

Example 1491

S, 11. S, 12 R-1,7-diaza-8,13-dioxo -12. - isobuty 1 evk 1 otrándan - 2 - <n «ps * ⁿ _ p -1 _ - χ _{ν c} jp - -1 \ | _ ... _am n j _c 1 jjrif the raoet o t s) - 1 d. <M - hydroxy - carboxamide)

1.491 <a) To a solution of the compound of Example 1.442 <f) <50 mg, 0.11.

mmol) and N ® ( ¹ · ^{1, 1 ' , 1'} -benzyloxycarbonyl-1-lycinamide <41 mg, 0.13 mmol) in DMF were added diisopropylethylamine (0.05 ml, 0.27 mmol) and 80P <57 mg, 0.13 mmol). After stirring overnight, the solid product was isolated from the solution and coupled with 1-tin (58 mg, 72%) as a white solid.

ES-MS (M + H) + 723.4.

1491 Compound of Example 1491. <a) <60 mg, 0.1. mmol) was hydrogenated in MeOH-CFCl 3 (3: 1, 1.5 mL) with TFA <1 mL) containing 5% Pd / BaSCU <1.50 mg), under a hydrogen atmosphere <0.31 MPa). After stirring for 5 hours, the catalyst and the solution after filtration were filtered to give the title hydroxamate <21. mg, 45%) in the form of a biodegradable substance.

ES-MS (M + H) + 499.5.

Example 1990

2S, 11S, 12R-1,7-Plasa-8,13-dioxo-2- (N-methylcarboxamido) -12-isobutylcyclohexyl-11. - CN-hydroxycarbonyl and m) d) h yr g e n c b 1 r i d

1.930 (a) The compound of Example 7 (c) (56 mg, 0.1.2 mmol) was dissolved in 4M HCl / dioxane (2 mL) at room temperature. After 3 hours the solvent was removed to give the amine salt (<45 mg, quant.) As a pale yellow solid.

ES-MS (M + H) - 471.4.

188

Example 2838

2S, 11S, (2R-7-1H-Benzenesulfonyl-1,7-dihydro-8,13-dioxox-2-ylmethyl-carboxamido) -12-i-butyl ¾l otr 1 decan -11 - C IM - hydroxycarboxam i. d)

2038 (a) To a solution of the succinate to e) (480.0, 1.8 mmol) and ΙΜ ^{'δίΓ>< "1} · ^Lc' -benzérisulf ooyľl ..-- E-lysine-IM-metyľl..ami ddu (698.5 mg, 2.1 mmol) and dlisopropylethylamine (0.84 mL, 4.8 mmol) in DIMF were added BOP (849, E> mg, 1.9 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated IMaHCO and brine. The ethyl acetate was dried (MgSO 4) and concentrated. The resulting residue was purified by silica gel chromatography to give the amide (833 mg, 90%) as a white foam.

ES-1S (1'+ H) - 570.3.

2038 (b) Example compound 2038 (a) (875 mg, 1.5 mmol) and PPh _; (1.21 g, 4.6 mmol) were dissolved in THI- (137 mL). To the mixture was added dropwise. da I. DIA D (0, 8 8 m 1,

1.5 mmol) in THI- (27 mL). After the residue was purified by overnight stirring, the solution was concentrated and by silica gel chromatography to give the cyclic material (470 mg, 55%) as a white solid.

ES-1S (1 '+ H) - 552.3.

2038 (c) Example compound 2038 (b) (473.0 mg, 0.86 mmol) was dissolved in C 1 - 61. (6 mL) and TFA (5 mL). After stirring overnight, the solution was concentrated to give the acid (500 mg, quant.) As the title compound. E. j p e v e ... n of the substance.

IMS (ll + H)

496, 3.

2038 (d) To the solution of Example 2938 (o) (266.6 mg, 0.52 mmol), O-benzyl-benzyloxy-oxylamine (192.0 mg, 1.6 mmol) and dlisopropylethylamine (0.18 mL) , 1.0 mmol) in DIMF was added BOP (278.0 mg, 0.63 mmol). After stirring overnight, the solid product was filtered from the solution to give O-benzyl hydroxamate (172 mg, 57%).

CIIMS-IMHs (1 H + H) - 601.2.

189

Example 2938 The compound of Example 2038 (d) (150.0 mg, 0.2.5 mmol) was hydrogenated in MeOH-CHCl ₃ (3: 1, 50 mL) with 5% Pd / BaSO ₄ . <300 mg) under a hydrogen atmosphere <0.34 MPa). After stirring for 3 hours, the catalyst was filtered off and the solution after concentration gave the title hydroxamate (52 mg, 41%) as a white solid. ES-MS (M + H) + 511.3.

Example 2135

2S, 11S, 12R-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -7-N-trifluoromethanesulfonyl-12-1 cycl 1 ot 1 decan -11 - - <N - hydroxycarboxam i. (d)

2135 <a) To a solution of the succinate C) <608.0 mg, 2.1 mmol), _{N EP} and ^lor '.- triflučrTnetánsulf sulfonyl-L-lyzíri-N-methylamide <900, 0 mg

2.7 mmol) and diisopropylethylamine (1.09 mL, 6.3 mmol) in DMF (8 mL) were added BOP (1.12 g, 2.5 mmol). After stirring overnight, DMF was removed and CH-, 61- 61 was added. The CH ^Cl Cl was washed with 10% citric acid, saturated NaHCO ^, and brine. The residue was dried (MgSO 4) and concentrated. The resulting residue was purified by silica gel chromatography to give the crude amide <1.30 g) which was dissolved in TUF (<100 mL). PPb _{:: 3} (1.84 g, 7.0 mmol) was added first, followed by DIAD (1.33 mL, 6.8 mmol in TUF <35 mL). After stirring overnight, the solution was concentrated and the residue purified by silica gel chromatography afforded the cyclic material (600 mg, 52%) as a white solid.

ES-MS (M + H) + 544.3.

2135 <b): Compound Example 2135 <a) <300 mg, 0.55 mmol) was dissolved in OHC1 _R <4 ml) and TFA <4 mL). After stirring overnight, the solution was concentrated to give an acid which was dissolved in DMF (<6 mL). The solution was added. O-benzylhydroxylamine (146.0 mg, 1.18 mmol) and dlisopropylethylamine (0.19 mL, 1.9 mmol) followed by BOP (270 mg, 0.61 mmol). After stirring overnight, DMF was removed to give O-henzyl hydroxyamate (190 mg, 58%).

ES-MS (M + H) - 593.4.

: 1.90

2: 1.35 Example 2i35 (b) (180.0 mg, 0.3 mmol) was hydrogenated in MethylJH (35 mL) with 5% Pd / E 3aSft ₊ (2: 1.0 mg) under a hydrogen atmosphere (0.34 l * LPA). After stirring for two and a half hours, ca. 11 rova 1 kata l y t a t or thosening thens. 1 t i. tu ľl. Hydroxamate (150 mg, 98%) as a solid.

ES-I * IS (14 + 0), 503.3.

Example 2227

2S, 11.S, 12R-1,7-diaza-8,13-dioxo-2- (N-methylcarboxamido) -7- (p-amino-M-benzenesulfon-1-one) -12- isobutyl 1-otradecan -11 - · (M-hydroxycarboxamid)

2227 (a) To the succinate K solution (c) (850.0 mg, 2.95 mmol), N ^eps11 o. trO-benzenesulfonylphenyl-l-lysine-N-methyl-l-du (1,45 mg,

3.80 mmol) and dilzopropylethylamine (1.54 mL, 8.80 mmol) in DI4F- were added 13 OP (1.56 g, 3.50 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid saturated with water. E t y ll. and the residue 1 (1 * 1 g S C t.) and the residue after purification. Silica gel chromatography gave the amide (1.37 g, 75%) as a white foam.

ES-14S (14 + H) * * ^M 570, 3.

NaHCO _{3 3} solution and thickened 1

2227 (b) Z1 Account. a n d a n d 2227 (a) (547, 0 m g, 0.8 9 mm o 1) and

PPF'i-5 (700.1 g, 2.67 mmol) was dissolved in THF (30 mL). To the mixture was added DIAD (0.50 mL, 2.5 mmol) in Tl-IF '(6 mL) dropwise. After stirring overnight. The solution was concentrated and the residue obtained after purification by silica gel chromatography gave the cyclic material (0.14 g, 26%) as a white foam.

ES-14S (14 + H) * 597.4.

2135 (c) Example 2227 (b) (24.0 mg, 0.04 mmol) was hydrogenated in 14e0H-CHCl _{; 3} (1: 1, 2 mL) with 10% Pd / C (12 mg) under a hydrogen atmosphere (0.2114Pa). After stirring overnight, the catalyst and the solution were filtered off after concentration. to give the amino compound (20 mg, 90%) as a white foam

ES-I * 1 S (14 + H) * 567.4.

191

2227 (d) Example 2227 (e) (226.0 mg, 0.46 mmol) was dissolved in CH-> 61. _ra (2 mL) and TEA (2 mL). After stirring overnight, the solution was concentrated to give the crude acid, which was dissolved in DMF (4 mL). To this DI * IF solution was added O-benzylhydroxylamine (166.6 mg, 6.88 mmol) and diisopropylethylamine (6.2 mL, 1.12 mmol) and OOP (2: 36.6 mg, 6.52) mmol). After stirring overnight. the solvent was removed to give O-benzyl hydroxamate (176 mg, 69%).

ES-MS (1 * 1-t-FI) * 616.4.

2227 Example 2227 (d) (156.6 mg, 6.24 mmol) was hydrogenated in the mixture. MeOH-CHCl 3 (1.7: 1, 19 mL) with 5% mg) under a hydrogen atmosphere (6.34

Pd / BaSCU (266 th e s in th e s w a tio n s e t i o t i t i n i e e e n e n e 11 <y.

ES-MS (m / z +) 526.3.

MPa). After stirring, the catalyst and the hydroxamate solution (167 ng.

84%) in the form

Example 2323

2S, 1S, 12R-1,7-diaza-8,13-dioxo-2- (1H-methicarboxamido) -7-M-m-azylthiophenil-12-: 1. z o b u t y 1 c. y k 1. o t r i. d e l <án - í. 1- (IM-F) y aroxyk arboxamide)

2323 (a) To the solution of succinate K c) (996 mg, 3.4 mmol) and _X | ei ·. ·, sxlc, n _ _{TT) z} -jy | _r , _{s L1} '| f _{Q ny} χ ._. | ._] y _c χ _n _ | \ | _n) ethyl amide Dichloride (1.7 g, 4.5 mmol) in DI * IE was added diisopropylethylamine (1.8 mL).

16.2 mmol) and BOP (1.8 mg, 4.1 mmol). After stirring overnight, DMF was removed and CFI was added. _and Cl. _a . The solution was washed with 16% citric acid, saturated NaHCO 3 solution and brine. CH _with Cla dried (MgSFLi.) And concentrated. The resulting residue gave, after purification by chromatography on silica gel, the crude amide (2 g), which was dissolved in THE (158 mL). To THF was added. PPh _{: 3} (2.8 mg, 1.6.6 mmol) and then DIAD (2 mL, 16.1 mmol) in TFIF. After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material. (686 mg, 36%) as:

to 1.1 k a s t e. j p e v e n 1. a t k y. ES-MS (M + FD + 594.5).

192

2323 <b> Compound Example 2323 <a) <280 mg, 0.47 mmol) was dissolved in CH _{S S} C 1 <3, '5 stirring the solution was concentrated dissolved in DI4F. To 0-benzyloxymethylamine (11 µM) and IF A (3.5 ml). After overnight and gave the crude acid, which was added to the obtained DMF solution was added mg (0.9 mmol), diisopropylethylamine (<0.15 mL, 0.8 mmol) and BOP (218 mg, 0.15 mmol). After stirring overnight and removing the solvent, O-benzyl hydroxyamate (<70 mg, 25%) was obtained.

ES-MS (M + 1) = 643.5.

2323 Example 2323 (b) <120 mg (0.19 mmol) was hydrogenated in MeOH-CHCl 3 (3: 1, 28 mL) with 5% Pd / 8aSO ₄ (180 mg) under a hydrogen atmosphere <0 34 MPa). After stirring for four hours, the catalyst was filtered off and the solution after concentration gave the title white foam hydroxamate.

ES-MS (M + H) - 553.5.

<100 mg, 96%) in the form

Example 2413

5S, 8R, 9S-6-aza-2,7-dioxo-5- (N-methylcarboxamido) -1-oxa-8-isobutylcyclohexane-9- <M -hydroxylcarboxamido. (d)

2431 (a) Succinate succinate 1C c) <200 mg (0, Ei 9 mmole) and ED-T-benzyl ester glutamate-d-N-methylanniide (200 g, 0.70 mmol) in DMF (E1 mL) diisopropylethylamine (0.25 ml, 1.5 mmol) and BOP (305 mg, 0.69 mmol) were added. After stirring overnight, DMF was removed. The resulting residue was purified by silica gel chromatography to give the amide (22 mg (70%) as an oil.

ES-MS (M + H) - 521.3.

(240 mg (0.4Ei mmol)) with 10% Pd / C (25 mg) below. After stirring overnight, the mixture was stirred for 4 hours.

413 (b)) Z1. čč en i. na z. EXAMPLE 2 413 (a) hydrogenated in MeOH (E1 ml) hydrogenated hydrogenphosphoric acid filtered the catalyst and the solution which was dissolved in THF (<40 ml). PPh ₃ <346.0 was added to THF

193 mg, 1.4 mmol) followed by D1 AD (0.27 mL, 1.4 mmol) in THF (9 mL). After stirring overnight. the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material. (45 mg, 24%) as a white solid.

ES-MS (M + H) + 413.3.

2413 (o) The compound of Example 2413 (b) (200 mg, 0.49 mmol) was dissolved in 08.01 µL (5 mL) and TFA (5 mL). After stirring overnight, the solution was concentrated, and gave the acids, which were dissolved in DMF (50 mL). To this solution was added O-benzylhydroxylanine (122.0 mg, 0.93 mmol) and diisopropylethylamine (0.1.6 mL, 0.92 mmol) followed by HUP (226.0 mg, 0.5 mmol). After stirring overnight. solid product was filtered from the solution to give C-benzyl hydroxyamate (110 mg, 46%).

CIMS-IMH-j (IM + H)

462nd

2413 The compound of Example 2413 (c) (105 mg, 0.23 mmol) was hydrogenated in a mixture of MeOH-CH 1 Cl ₃ (3: 1, 40 mL) with 5% Pd / BaCl 3. (150 mg) under a hydrogen atmosphere (0.34 MF ³ a). After stirring for 2 hours, the catalyst was filtered off and the solution after concentration gave the title hydroxamate (100 mg) as a white solid.

ES-MS (M + H) + 372.3.

Example 2890

2S, 11S, 1,2R-1,7-diaza-8,13-dioxo-2- (N-methylcarboxamido) -7 -N- (1-methyl-1,1-midazo-4-one) 1) -12 - isobutyl 1.1 ::: yk 1, otradecan-11 - (IM-bydr oxycarboxamide)

2890 (a) D; ocusuccinate 1 (c) (1,27 mg, 4,3 9 mm o 1) and θ ^{1 = 1 xx} ° ^r '- 4 - (IM - methyl 1) -1. midazo 1. su 1. fony 1 ..... I ... -1. Methylmethylamine, du (1.73 g, 5.70 mmol) and diisopropylethylamine (3.1.9 mL, 17.6 mmol) in DMF were added FiOP (2.34 g, 5 mmol). , 27 mmol). After stirring overnight, the DMF was removed and gave 1. 08.2.01¾ washed. saturated IMaHCO 3 solution and brine. CH .Cl- _p> dried (MgSFU) and concentrated. The resulting residue after purification by chromatography on s. 1. i. kag é 1. eposkyto 1. am i. d (1.7 g, E = 9%) in 1.

1.94

ES ..... 1 H (1 H + H) * 574.5.

2890 (5) Example compound 2890 (a) (200.0 mg, 0.35 mmol)

(274, 0 g. 1. 05 mmol) were dissolved in THE (1.5.5 mL). To mixtures the S ubjectofthepair. d and 1 D Γ A D (0, 2 0 ml, 1.05 mmol) in

and PPh _{:: 5} t ej it

THE (5 mL). After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to give the cyclic material. (1.00 mg, 52%) as a white foam.

ES &lt; 1 &gt; S ([delta] + H) * 556.5.

2890 (b) (400 mg, 0.72 mmol) and TFA (5.5 mL). After the night and provided the acids that took

To this solution was added 1.40 mmol) and diisopropylethylamine BOP (341.0 mg, 0.77 mmol). After D 1 * 1 E and the remainder of the scrubbing with O-benzylhydroxamate (1.40 mg, stirring dissolved in

2890 (c) Dissolve ₁ Cl F (6.4 mL) in CH ₂ Cl ₂ (5.5 mL).

O-beosylhydroxylamine.n (1.72, 0 mg, (0.24 mL, 1.38 mmol) followed by overnight stirring with silica gel

33%).

Cls-NH4 (N + H) + 605.5.

2890 Example 2890 (c) (1.35.0 mg, 0.22 mmol) was hydrogenated in 1L OH (25 mL) with 5% Pd / BaSbt + (202 mg) under a hydrogen atmosphere (0.34 µPa). After stirring for 3 hours, the catalyst was filtered off and the resulting solution after concentration, afforded the title hydroxamate (98 mg, 85%) as a solid.

ES-1 * 13 (1 * 1 + H) * 51.5.4.

Example 2900

2900 (a) 2 R, 3 S - methyl 1 - - 4 ..... beozy I. ox y ..... 3 - h ydrox y ..... 2 - (2 - 3 - fenv I. - 2 propen-1-y-1,) butvrate

A 1.61 * 1 hexane solution of n-butyl lithium (1.40.4 mL, 2.1 equiv.) Was added to a solution of diisopropyl amine (29.48 mL, 2.1 equiv.) In 1.5 min. tetrahydrofuran (650 mL) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes and then cooled to -78 ° C. Using kaoyl: 1.95, methyl ... 4-henzyloxy-3,7-hydroxy .....

butyrate (24, 90 (3, 1.07 mmol) in tetrahydrofuran (40 mL) and the residue was rinsed with tetrahydrofuran (2 x 20 mL). The resulting mixture was stirred at 45 ° C for 1 hour, at -20 ° C for 0.5 hours and cooled to -78 ° C. Tetrahydrofuran solution (90 ml) was gradually added.

(phenyl-2-propen-1-yl) bromide (C 31, 69 mL, 2.0 equiv.) and pure

M, M, IM ', M'-tetramethylethylenediamine (34.33 ml, 2.0 equiv.). After 1.5 minutes at 40 C and 4 h at-20 ^C> 0 was added saturated amóriiumchlorid (500 ml) and hexane (400 ml). After extraction of the aqueous phase with ether (3 x 80 mL), the combined organic extracts were washed with water (50 mL), with 1 mL of 50 mL, dried (1 mL, 1 mL, 1 mL) and concentrated. i. Chromatography on silica gel (ethyl acetate / hexane, 20:80, then 30:70 anakonia: c 50:50) gave the 11th product (28.78 g, 73%, d. ~ 8: 1) in a yellow oil. .

ESI-1S (1'-1-H) ··: calculated 341.2, found 341.2.

2900 (t)) Ky s e 1 i n a 2 R, 3 S - 4 - b e n z v 1 o x v - 3 - h d r o x y 2 - C 2. - - y 1) b u t y r o v

A 1.01 * 1 aqueous sodium hydroxide solution (450 mL) was added to a solution of 2900 (a) (28.08 g, 82, E> mmol) in methanol (450 mL) at 0 ° C and the resulting mixture was discarded. The mixture was stirred at room temperature for 2 hours. After vacuum, the aqueous residue was adjusted to pH 5 with 1 N sulfuric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4) and concentrated to give the product (27.0E> g, 1.00%) as a solid.

001-1 * 18 (µl + MEU) *: calcd. 344.2; found 340.

2900 (c) 2R, 3S-4-benzyl-3-hydroxy-2- (2L · 3-phenyl-2-propen-1-yl) butyryl-N ^{and 1} * * -1 - butoxycarbone 1 -1 ... - orn 11 í. n-N-methyl 1 and id

Diisopropylethylamine (12.1.8 mL, 4 equiv) was added. to a solution of 2900 (b) (b, 70 g, 17.48 mmol.), - IM ** ^{6 'J-1} butoxykart> onyl - L - ornit s. n-1-methyl-amide (7.49 g, 1.5 equiv., 1 H Cl) and benzotriazol-1-yloxy-tri. with (dimethylamino) phosphorium umhexafluorophosphate (7.97 g, 1.03 equiv) in N, N-dimethylformamide (20 mL) at 0 ° C. about

196 hours at. Ethyl acetate (200 mL) was added at 0 ° C. The mixture was washed with 10% citric acid (2 x 25 mL), brine (25 mL), saturated sodium bicarbonate (2 x 25 mL), and again with brine (25 mL), dried (µgSCU) and concentrated. Chromatography on I.l. i. Methyl (methylmethylamine, 5:95, 0:92) 11 and the product (7.16 g, 74%) as a solid.

ESI-1 * 1S (1 * 1 + 0) - calcd 554.4, found 554.4.

2900 (d) 2R, 3S-4-henzyloxy-3- (2R-4-chlorothi-2-butene-1-vi) -2- (2R-3-phenylethyl) -2-propene -1 - v 1) ti utvir 1 - IM ® ¹ -1 - butoxycarbones 1 -1 ... - or ri i. tin-N-methyl amide

Sodium llydride (0.28 g, 1.8 equiv., 60% dispersion in mineral oil) was added at rt. 0 ° C to a solution of 2900 (o) (2.13 g, 3.85 mmol) and 2Z -1.4-bromo-2-butene (8.00 g, 9.7 equiv.) In

N, N-dimethylformamide (100 mL). Every twenty minutes, an additional portion of 2E-1,4-dibromo-2-butene (4 g each) and sodium hydride (0.23 g each) was added and disappearance of the starting material was monitored by TLC analysis. After 1.5 hours, the reaction appeared complete. After addition of saturated ammonium chloride (40 mL) and ethyl acetate (120 mL), the aqueous phase was separated and extracted with ethyl acetate (6 x 60 mL). The combined extracts are dried. 1. i. (1 * 1 g S CU) and per hour; t i 1 i. C h r om a t; o g r and f i. and n and s 11 i. k e g 1. (methariol / chloroform, 3:97, then 4:96) gave the desired solid (1.86 g, 70%).

ESI-1 * 13 (1 * 1 + H) ¹ : calcd. 688.3, found 688.2.

2900 (e) 2R, 3R, 6S, 11E-2-benzyloxymethyl-10-t-butoxycarbonyl-5,10-di. aza-6- (N-methyl-carbamido) -1-ox a ..... 4-oxo-3- (2 / 1'-3-pheny1) - • - 2-propene -1 - y 1) cycl 1. otetradek á n

N d i. o x a n o o t o l o e h h o o o l o (20 m 1) s a p i i. d and 1. to compound 2900 (e) (1.86 g, 2.707 nunol). After 1.5 hours at. at room temperature at. the solvent was removed in vacuo. The solid residue was washed with a little ether, pumped to dryness to give the product (1, E &gt; 4 g).

197

To a solution of the crude material in acetonitrile (1.3 L) at D ° C was added dlisopropylethylamine (2.33 mL, 5 equiv.). The resulting mixture was stirred at RT. at room temperature for 3 hours. D i added. (butyl carbonate C 2, 33 g, 4 equiv.). After 20 minutes at.

at room temperature, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried. (MgSO 4) and concentrated. Two times chromatography on silica gel C isopropanol / chloroform, 3x97, then 4 x 96 and n. e: 6: 9 (4) (5: 9b) (11) and <0.73 g, 45% for two steps).

ESI-MS C M + 1-D * x calcd. 000.4, found 600.4.

2900 (f) 2 S, 3 R, 6 S - 0 0 - 1 - b u t o x y k a r b o n y - 5, i 0 - d i. if z a 2 - h y d r o x y m t 1 - 6 .....

- C IM - measuring 1 k ί! r b o x and m i. d o) -3 .. - o x and - Ί - o x o - 3 - <3 - f e n v i. 1 - p r o p i i - c: v k 1 o t e t r a d e k a

A suspension of 2900 (e) (0.73 g, 1.205 mmol) and Pearlman's catalyst (0.35 g) in methanol (200 mL) was stirred under a hydrogen atmosphere (balloon) for 1 hour and 20 minutes. The catalyst was removed by filtration. o u. F i. 1.1. 1 s i 1. i. chromatography (methanol / chloroform, 3:97, then 5:95) to give the product <0.35 g, 56%).

ESI-MS (M + H) + x calcd 520.4, found 520.3.

2900 (g) 2S, 3R, 6S-10-t-butoxycarbonyl-5,10-diaza-2-hydroxycarbonyl-6- (N-methyl-1-arboxamido) -1-oxa-4-oxo-3- 3-ženyi ~ :: l.-1: »ro P y I.) c: yk 1 otetradek á n

Ruthenium chloride <7.2 mg, 0.04 equiv) and sodium periodate <0.74 g, 4 equiv) were added sequentially to the mixture. 2900 (f) <0.45 g, 0.866 mmol), acetonitrile <8 mL), carbon tetrachloride <8 mL) and water <12 mL). After two hours at. chloroform (68 ml) was added at room temperature. The aqueous layer was separated and extracted with chloroform (5 x 30 mL). The combined organic phase was dried <MgSO ₊₎ and the EEA preflltrovaní celite gave the desired ar boxy1ovú yse1inu to 0 C, 43 g, 93%).

ESI-MS (M + H) +: calcd 534.4, found 534.3.

198

9 Ο Ο C 11) 2 S, 3 Ŕ, 6 S - 2 - C N - b e n z in I. o x in l <a r b o x a m i. d o) -1.0 -1 - b u t o x y k a r b o n y 1 - 5, 1 Cl - d i. a z a ..... 6 - C N - m e t in 1. k a r b o x m I. d o) - ·· 1 - o x a - 4 ..... o x o - 3 - C 3 - ph ei v 1 -1. - · propyCycle o b e t r a d e k a

111 dichloromethane solution of dicyclohexylcarbodiimide (CO, 038 mL, 1 equiv.) Was added, to a solution of 29 ° C (20 mg, 1 mg, 0.377 mmol), O-benzylhydroxyamine hydrochloride (7 mg, 2 mg, 1.2 equiv), hydrate 1. -thiroxy benzothiazole C 5, 1 mg.

1.0 eq. Diisopropylethylammonium (0.0079 mL, 1.2 eq.) In tetrahydrofuran (2 mL). The mixture was stirred until the starting material monitored by TLC disappeared and then quenched with ammonium chloride. After extraction with ethyl acetate, the combined extracts were washed with brine, chromatographed on silica gel, and concentrated under vacuum to give a layer of ethyl acetate / chloroform, 5 · 9. 5) gave the desired product (1.2, 8 mg, 53%) as a white solid.

ESI-CLL LLS + H) ¹ '.- calcd 039.4, found 639.3.

2900 2S, 3 R, 6 S -1.0 -1 - u t o x v a r b o n y 1 5, 1.0 - - d i. az ci - 2 - CM - hydroxycarboxamido - 6 - CM - methyl 1 carbox am 1 do) - 1 - oxa - 4 - oxo - 3 - C 3 - phenyl 1 - 1 - propy 1,) evk 1 otetradek á n

P r 1 1. z. b o e j i; e p ľl. o t e.

Bascle. ¢ 1.1.5.3 mg).

A mixture of 2900 (C34, 0 mg, 0.0532 mmol) and 5% Pd on BaSCL. (56.7 mg) in ethanol (4 ml) was stirred under a hydrogen atmosphere (balloon) After one hour, additional Pd was added. After a total of 2 hours, the catalyst was filtered off. The filtrate was concentrated to give the desired hydroxamate (26.7 mg, 91%) as a white solid.

E S X - l S S l + + + H) * vy 549, 549, 3, z i. s t e n 549, 3.

Example 2910

291.0C a) 2S, 3R, 6S-2-C (benzyloxycarboxamido) -5, 10-diaza-6-C max methyl. k a r b o x m i. d o) -1. - o x a - - 4 - o x o - - 3 - - C 3 - pheny I. -1 -prop y 1) c k k o o t e b a d e k a h h d d o c b 1 o r, 1, d

199

A mixture of 2909 ¢ 3 (5.1 mg, 0.05 (55 µl) and 4 N dioxane tartrate HCl ¢ 1.0 mL) was stirred at room temperature for 30 minutes. Removal of the solvent in vacuo gave the desired product as a white solid. The crude material was used in the next step without pretreatment. a.

LSI-IMS (0 + 14) -: calcd. 539.3, found 539.3.

291.0 (b) 2S, 3R, (5S-5,10-diaza-2- (1 H -hydroxycarboxamido) (5 ... C 1 -methylcarboxamido) -1-oxa-4 oxo-3- ( 3 - phenyl · 1 ..... propy 1) cvk 1 otetradek á n ti ydroch 1 orid

In a manner analogous to that of 2900C (290 ° C), the product was <2 (5.3 mg, 95% for both steps). ESI-14S (11 + 14) -: calcd. 449.3, found 449.4.

used when converted to

Example 2920

2920C a) 2S, 3R, 6S-10-Ethyl-2- (N-benzyloxycarboxamido) -5,10-diaza-6-methyl-1-carboxamido-1-oxa-4 - oxo - 3 - C 3 · - pheny 1 1. -propyDecycle otetradecan

Crude material 2910 (a) derived from 2900 (h) (45.4 mg, 0.071 mmol) was treated with acetic anhydride (1.5 mL) and diisopropylethylamine (0.040 mL, 3.2 equiv). After 10 minutes, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The mixture was saturated with sodium bicarbonate and brine, dried (MgSO 4) and concentrated. Silica gel chromatography (methanol 1: 5 (9: 5, then 7.5: 92.5) gave the desired product (3, 9 mg, 90%). . d v and steps).

ESI - 1S <11 + 14) U calculated 581.4, found 581.5.

292 (I ') 2 S, 3 R, 6SlQ-acetyl-5, 1.0 ~ diaza-2- <N-hydroxycarboxylic boxamldo) .... [--I _{add hc} J | _<ar i-q _{x n)} j (· | _f ·,) "j _oxa 4 _ox 3" ζ 3. ... f .: _env ] j -propyl 1) cyclotetradecan

200

In a manner analogous to that used for the conversion of 2900 (h) rta 2900 (1), 2920 (a) (31.8 mg, 0.0548 mmol) was converted to the desired product (24.0 mg, 89%). ). ESI-SS (+I + H) *: calcd 491.3, found 491.4.

2930 2S, 13S, 14R-1. „7 - d i a z a - 8, l.E 5 - d i. o x o - 9 - · o x a -14 - i z o u t u t 1 - 2 - E g 1 v: n - N - h d d o r i d e n d e n d e n d e n d e n e -13 - N - h d d o x v a r b o x a m i d

This compound was prepared at. use. procedures analogous to those described above.

ESI-18: found 527.6.

Example 2931

2S, 13S, 14R-1,7-diaza-8, 1,5-dioxo-9-oxa-14-isobutyl-2-glycine-N- (4-11-ydroxy-peridin)] cyentaline n-13-N-hydroxycarboxamide

This compound was prepared at. using procedures analogous to those described above.

ESI-18: found 541.7.

Example 2940

2940 (a) 2S, 3R, 6S-2- (N-benzyloxycarboxamido) -TO-benzenesulfonyl-5,10-diaza-6- (N-methylcarboxamido) -1-oxa-4-oxo-3- ( 3f env 1 -1 - propy I.) cycl 1 otetradecan

Benzenesulfonyl chloride (0.13 mL, 25 equiv.) Was added to compound 2910 (a) (23.2 mg, 0.0430 mmol) and 4- (N, N-dimethylamino) .....

pyridine (0.5 mg, 0.1 equiv) in pyridine (1 mL). After 30 minutes at room temperature, saturated ammonium chloride (2 mL) was added and the mixture was extracted with ethyl acetate. The combined extracts were washed, water and then brine, dried (MgSO 4) and concentrated. Preparative thin layer chromatography (methanol / methylene chloride, 10:90) gave the desired product (11.1 mg, 41%).

ESI-1S (1'+ H) +: calcd. 679.4, found 679.3.

201

Pr <3 ad 2940 '

S, 3 R, GS — i 0 ..... benzene 3. phony 1 - 5, 1.0 ..... d 1. ch z a ..... 2 - CN - hydroxyc or rbox am ido ) - 6 .... (| \ | _e f _; yxcarboxamido) - 1 ..... oxa - 4 - - oxo 3 ..... (3 - bitches 1 - 1 - propy 1) cycl 1 ote Ť ra - deká n

Using a procedure analogous to the procedure used to convert 29Q0 (h) to 2900 (i), whether compound 2940 (a) (3.4 mg, 0.023 mmol) was converted to the desired product (3.2.7 mg, 3.00). %) that he had. form of a white solid.

ESI-MS (M + H) +: calcd 599.3, found 589.4.

Example 2950

2950C a) 2 P, 3 S-4-benzyloxy-3- (2-bromoethyl-3-propen-1-yl) -2- (2E ..... 3 .. ...

- Pheny1 - 2 - propen - 1 - y 1) butyry 1 - M ^{r: 11} 1 - 1 - butoxycarbones 3 - L - orn 11 - n - ethyl, amid

Using a procedure that is analogous to the procedure used in. conversion. 2900 (o) to 2900 (d), compound 2900 (c) (1.1.2 g, 2.03 mmol) was reacted with 3-bromo-2'-bromomethylpropene to give the desired bromide (0.93 g, 67%). ), which was a white solid.

ESI-MS (M + H) +; calcd. 688.3, found 688.2.

2950 (b) 2 R, 3 S - 4 - e e. y 3. ox y ..... 3- (2-bromomethyls 1 - 2 - propene - 3 - in 1) - 2 - (2Zľ - 3 -phenyls 1 - 2 - ope .. ... 3 - y I.) but vryl - L - ornith. n - N - m e t y 1 am i d h v d r o cti l o r i. D

Using a procedure analogous to Synthesis 2900 (e), 2950 (a) (0.33 g, 0.48 mmol) was deprotected and deprotected. S u r o v i b i e a n e a t i n e s. 1 and in the next step without prior purification.

E SI - M S (M + H): 588, 3. z. 588, 1.

2.02.

9 5 C) C c :) 2 S, 3 R, 6 S -10 - a c e t v 1 - 2. - bi e: n z in I. o x in m t v 1 - 5, i 0 - d i. and za - 6 - (M-methyl y-1-b) o x and i-o) -12-methyl in 1 n -1. - o x a - 4 - o x o - 3 - (2E- 3 - f e n in l .... 2 - p r o pi e n -1 ..... v 1) c v k I. o t three decane

Using a procedure analogous to the conversion of 2900 (d) and 2900 (e), crude 2950C (b) was cyclized and reacted with acetic anhydride to give the desired product <0.202 g, 76% for: both steps) which it was a white solid.

E S1 -1Ί S (IΊ + H) *: hear. 548.3, and 548.3, 4.

2950 (d) the 2 S, 3 R, 6 S, .1.2CR, S) -lO-acetyl-5, 10-diaza-2-6-hvdroxymetvl ... ζ | \ | ..... _Me tyikarbox am ido) - i 2-Methyl-1-i-oxa-4-oxo-3- (3-phenynyl-1-propyl) c: yk 1 otr i. dek á o

Using a procedure analogous to the conversion of 2900 (e) to 2900 (f), 2950 (o) (0.20 g, 0.365 mmol) was reduced with hydrogen to the desired product (6.14 g, 83%), which represented a non-separable product. mixture (1: 1) of two diastereomers.

ESI-14S (M + H) +: calcd 462.3, found: 462.4.

2950 (e) 2S, 3R, 6S, 12 (R, S) -10-acetyl-b, 10-diaza-2-hydroxycarbonyl methyl 1 '- G - (M ..... methyl 1 carbohydrate) -12-Methylen-i. - o xa-4-oxo - 3 ..... (3 - phenylen - i - p r o p v 1) o y k 1 o t th e k a

2906 (

Using the procedure described in g), 2950 (d) is a conversion analogue: 2900 (f) (0.14 g, 0.303 mmol) is oxidized to na

C onnectio n s e. i. nu (0.113 g, 78%).

ESI + - MS (M + H) +: calcd 476.3, found 476.3.

2950 (f) 2 S, 3 R, 6 S, 12 (R, S) - 10 - acetylen-2 - ~ (IM - benzoyloxycarboxamido) -

- 5, 10 - diaza - 6 - (IM -me: tv 1 carbox and i do) --12 - methy 1 ..... 1 - ox and ..... 4 ..... oxo - 3 - (3-phenyl. -1-propy i.) Cycles 1. otri, de: kán

Using a procedure analogous to the conversion: 2900 (g) to 2900 (h), compound 2950 (e :) (0.113 g, 0.237 mmol) was converted to the desired product (46 mg, 33%) which had m.p. form of white solid

2 (J3 substances.

ESI-MS (M + H) +: calcd 581.3, found 581.2.

2950 (g) 2S, 3R, 6S, 12 (R, S) -10-acetyl-5, 10-diaza-2- (N-hydroxycarboxarolo) -6- (1-methylcarboxamido) -12-methyl 1- 1-oxa-4-oxo-3-C 3 .....

- f e n v 1 -1 - p o p v 1) c v k 1 o t ri. d es kà n

Using a procedure analogous to the conversion of 2900 (h) to 2966 (1), compound 2950 (1) (51 mg, 0.088 mmol) was converted to about 3 mg (76%).

ESI-MS (M + H) +: calcd 491.3, found 491.2.

Example 2969

S, b S, 12 R-12-carboxy-3, 10-dioxo-5-IM-methyl 1. carbamoxam 1 to - 2 - phenethyl 1. -1, 4, 9 - triazine ... ntrif 1 u ó raoet á t

2960 2S, 5 S, 1.2 R -12 - k a r boxes - 3, 1.0 - d: i. o x o - 5 - N - m e t y 1. kar b o x a m i d o - 2 ..... f e n e t y 1. -1., 4, 9 -1 r i a z a - c y k 1. o t r, d e k a t r i f1. u ó r a c e t a t

Compound 2960 (d) (100 mg, 0.2 mmol) was dissolved in methylene chloride prior to the addition of II-A (1.7 mL). The reaction mixture was stirred at room temperature for 4 hours. The solution was concentrated to give the title compound (80 mg, 75%).

MS (O) m / e 419 (M + D +).

2960 C a) 1-8-butyl ester ter. IM- (9-fluoro-enylmethoxycarbony 1)

- D - (a) - aspartic acid and IM - methyl amide N _xf (benzyloxycarbonyl) -1- (epsilori) -lysirium </ - 1 - B uty 1. esterkyse 1.1 ny

of aspartic (5 g, 12.1 mmol) was cooled to 0 ° C. Gradually

4-methylmorpholine (4.4 ml,

IM _and it _α - (benzyloxycarbonyl) -1 ... -1 yzg, 15.7 mmol.). The reaction mixture was stirred for 1b hours. The solution was washed

N-C 9 - (1-methyl-1-methyl-1-methoxy) -D - was dissolved in methylene chloride and HOBt (δ, 8 g, 13.3 mmol) was added,

39.9 mmol), N-methylamide (4.8 g, 1.4.5 mmol) and EDO (3.0 were warmed to room temperature and aqueous

204 of sodium bicarbonate, 102 of aqueous citric acid, and brine. The organic layer was dried and concentrated. The resulting material was purified by chromatography to give the desired ainide (3.1 g, 472).

MS (O) m / e 007 (M + 1).

2960 (b) D- (e>) ..... aspartic acid, i and M-methyl amide t-butyl ester

N. _a - _t - (benzyloxycarbonyl) - L, - · - (eps 11 on) - lysine

Compound 2960 (a) (3.1 g of diethylethylamine (7 mL)) at rpm and min.

A pplication 1 A pplication (1,9 g, 802).

4.6 mmol) was added before DMF was added. The reaction mixture was stirred for 20 chromium and tag purifications

MS (CI) m / e 405 (MH +).

2960 (c) t-Buyl ester of N-2 * - (benzyl-4'-phenylbutanoate) -D- (p) -asparagine and N-methylamide M. _xf .-., - (benzyloxy carboxy) bony 1) • - L ...... (eps i. 1 on) -1 pattern

Compound 2960 (b) (220 mg, 0.5 mmol) was added prior to the addition of Hunig's base (0.09 mL, 0.5 mmol) and (R) -benzyl-2- (trifluoromethyl) methyl 1 phony 1 oxy - 4 ..... bitches of I. butanoate (19 0 mg, 0.5 mm o I.) (B enn. On,

C .; Brown, R.C .; Cook, A. R. .;

R obi n so n, DHJ light. Chem. methylene chloride. F ³ at 15 o'clock with P om ooouctir om at og raf i. MS to MS (01) m / e 717 (M + D +).

Manners, C.N .; Payling, D.W .;

1991, 94, 439) dissolved in and the solution thickened and after purification the secondary amine (290 mg, 802).

2960 (d) 2 S, 5 S, 12 R -12 -1-butyl carboxy-3, 10-dioxo-b-N-methyl 1 carboxamido-2-phenethyl 1 -1, 4, 9 - 1 chain - cvk 1 otr i. d e c o o

Compound 2660 (c) (270 mg, 0.4 mmol) in methanol was taken up with methanol

102 Pd / C (60 mg) was placed under a hydrogen atmosphere. After five hours, the solution was filtered and concentrated. The resulting material was dissolved in DMF and added to a solution of BOP (150 mg, 0.4 mmol) and Hunig's base (0.1 mL, 0.8 mmol) in DMF. The mixture was stirred for 24 hours. The solution was concentrated and purified by chromatography

205 gave the desired trlamide (55 mg, 30%). IMS (01) m / e. 475 (IM + 1).

Example 2001

S, 5 S, 13 R-13-carboxy-3, 10-dioxo-5-N-ethoxy-1-carbox nor ido-2-phenethy 1-i, 4,9 -1 r 1 aza-cycl I. otetradek á ntrif 1 u o racetate

2961 2S, b S, 1.3 R-13 - k a r b o x y - 3, 10 - · d i o x o - b - N - e t y 1 k a r b o x a 1 d o - 2 -

- f e n e t y 1 -1, 4, 9 -1 r i. and z a - e y k 1 o t e t a d e k a n t r i f 1 u ó r a e e t a t

Compound 2961 (d) (09 mg, 0.1 mmol) was dissolved in methylene chloride before the addition of TFA (1 mL). The reaction mixture was stirred at room temperature for 4 hours. room temperature. The solution was concentrated to give the title compound (50 mg, 74%).

IMS (CI) m / e 433 (MH + D +).

2.9 01 (a) t - B utyl 1 esterkvse 1 inv N - (9 - f iorene vime toxicarbon 1) - D - (e) -glutamic. and N-methylamide N ... ₃ . _Ά - (benzyloxycarbonyl 1) - L - (e P si 1 on) ..... isyzinut - B utyl 1 esterky l iny ï. N - F - power - 0 - g 1 is secreted (bg (1.1 L is dissolved in DIMF - and cooled to 0 ° C. 8 g, 13.3 mmol), 4 ..... .metylmorfolín

Gradually (4.0 ml).

-Cbz-L-lysine-1-methylcarboxamide. HCl (5 g, 12, 9, 11, 8 mmol) was added HOBt

36.6 mmol), mmol) and BOP (6.8 g, 15 stirred 1 mmol). The reaction mixture was hours. The shielding solution was diluted to room temperature with ethyl acetate and washed with aqueous sodium bicarbonate, 10% aqueous citric acid, and brine. The organic layer was dried and concentrated. The resulting material after purification by chromatography gave the desired amide (8 g, quant.).

IMS (01) m / e 701 (M + +1).

2961 (b) D- (E,) -glutamic acid t-butyl ester and N-methylamide N _{: L} - (be 11-oxycarbonyl) - L - (eps 11 on) - lysine

Compound 2961 (a) (8 g.

11.8 mmol) before addition

206 cl i t i 1 n i <3 6 m 1) minutes. The solution was desirably dissolved in concentrated and arginine <2.9 g,

IMS CCI) m / e 479 (C) 1) -.

DľlF. The reaction mixture was stirred 45 after chromatography (49% purification).

2961 (c) t -Butyl ester ester of 1 - N '- 2' - <1 - 4 '..... phenyl 1-butanoate - D - (ia) -glutamic and N-methylamide N, -, _x . _f C be nzvloxycarb onv 1) - ··

- | 'Ζ _e p ;;; i] _{(1 R)} ..... j and _Mk. nu

Compound 2961 (b) (2.1 g) before addition of Hunlg base (0.4 ml, 2.1 mmol) and (R) -benzyl-2-trifluoromethyl) sulfonyloxy-4-phenylbutanoate C 0.6 mg, 2.1. mmol) (Bennion, C .; Broun, R. C .; Cook, A. R. .; Llanners, C. N. .; Payllng, D. W. .; Robinson, D. H. J. &amp; Chem. 1991, 34, 439) was dissolved in methylene chloride. After 15 hours, the solution was concentrated and purified by chromatography to give a secondary amine (2.3 g, 78%).

IMS (Cl) m / e 731 (M + D).

2961 <d) 2 S, b S, 13 R-13 - 1 - b u t i k or r b o x y 3, 10 - d i. o x o - b - N -methy 1 k a r b o x m i. d o - 2 - e e e v 1 -1, 4, 9 -1 r i. aza c y k i. o t e t r a d e k a n

A compound with 10% Pd / C < 430 and a half hour was treated. 1 1 µ <4 0 0 BOP solution <454 in DF. That blend r o z t o k h s t i. 1 desired trlamic <60 mg IMS (CI) m / e 489 (M + 1) +.

2661 (cc) <2.1. g, 2.9 mmol) in methariol together with g. e s t i. 1. P o t y r o c; h the solution was filtered and concentrated. Part of the resulting mg (0.8 mmol) was dissolved in DMF (added to mg, 1. mmol) and Hunlg base (0.3 ml, 1.0 mmol) was stirred for 24 hours. After this time, this was and after purification by chromatography provided

1.6%).

207 i

Table 1

For cycles o f

Pr. R ² (CI-MS) ΧΠ B Pr. R ² (CI-MS) m b 1. C0 ₂ Me 406 2 CONH-cyclopentyl 3 C0 ₂ Ec 4 CONH ₂ 5 CO ₂ iPr 6 CONHiPr 7 CO2 (CH 2) 2 ° M ^e 8 CONH-tert-butyl 9 CO ₂ (CH ₂ ) ₂ Ph 10 CONMe ₂ 11 CO ₂ -tBu 12 CONEt ₂ 13 CO ₂ CH ₂ CONHMe 14 CONH-3-indazolyl 15 CH ₂ OH 379 16 CON-adamancyl 17 CH2OCH2CH3 18 CONHCH 2 (p-SO ₂ NH ₂ -Ph) 19 CH2OCH2CH2CO2CH3 20 CONH _(CH2) 3-limidazolvl 500 21 CHOBn 22 CONHSO ₂ NH ₂ 23 CONH _(CH2) 2-2-pyridyl 497 24 CONHSO2CH3 25 CO (N-Znorfolinyl) 26 CONHS0 ₂ Ph 27 C0 (N-Me-NDioerazinvl) 475 28 CONHS0 ₂ Bn 29 CONH (CH ₂ ) ₂ - (N-Me-Npiperazinyl) 30 CONHSO ₂ -N-Meimidazolyl 31 CONH- cyclopropyl - 32 CONHSO2-p-NH ₂ -Ph 33 CON-cyclobutyl 34 CONHSO2-p-MeOPh 35 CONHSOj-p-F-Ph 36 CONH-S-CH [CH ₂ CH (CH 3) 21 CONHMe 37 CONH (CH ₂ ) ₂ NHSO ₂ Me 38 CONH (CH ₂ ) 4 NHHSO ₂ Me

208

39 CONH-cyclohexyl 40 CONH (CH2? 6NHSO2Me 41 C0NH-2-im-idazolyl 457 42 CONH-R-CH [CH ₂ CH (CH 3) 2) CONHMe 43 CH2SO2NHCH3 44 CONH-S-CH [(CH2) 4NH2] CONHMe 45 CH2SO2NHPh 46 CONH-SCH ((CH 2) 3 NH 2) CONHMe 47 CH2SO2NK- | 4-NH2Ph) 48 CONH-SCH [(CH 2) 2 NH 2] CONHMe 49 2-imidazolyl 50 CONHMe 406 51 2-oxazolyl 52 CONHCH2CONMe2 53 2-thiazolyl 54 CONHCH2CONHEC 55 2-benzinudazolyl 465 56 CONHCH2CONEC2 · - 57 CONH-R-CH (CH3) Ph 58 CONHCH2CONHcyklopropyl 59 C0NH-S-CH (CH3) Ph 60 CONHCH2CONHcyklobutyl 61 C0NHCH2C0NHMe 463 . 62 CONHCH2CONHcyklopentyl 63 CONH-S-CH (CH3) CONHMe 477 64 CONHCH2CONHcyklohexyl 65 CONH-R-CH (CH3) CONHMe 477 66 CONHCH2-t. bucyl 67 CONH-S-CH (2-propyl) CONHMe 505 68 CONH-SCH (CH 2 Ph) CONHMe 69 CONH-SCH (CH 2 OH) CONHMe 70 CONH-S-CH (CH 2 'P MeOPh) CONHMe 583 71 CONH-SCH (CH2OH) CONHMe 493 72 CONHCH2CH2CONHMe 499 73 CONH-RCH (CH 2 OH) CONHMe 493 74 CONHCH2CH2CH2CONHMe 75 CONH-S-CH (CH20-CMA) CONHMe 549 76 CONH-SCH (CH 2 CH 2 OH) CONHMe 77 CONH-R-CH (CH 2 O-t Bu) CONHMe 549 78 CONH-S (CH {CH2) 3CH3) CONHMe 79 C0NH-CH (Ph) 2 80 CONH (CH 2) 2 ^C 2 Me 81 CO-L-proline -NHMe 82 CONH (CH 2) 2 ^C 2 H 83 C0NHCH2C0 (NoiDerazinvl) 84 CONH-SCH [(CH ₂ ) 3 NHBOC) CO ₂ Me 85 CONHCH 2 CO (N-methyl-N-oioerazinyl) 86 CONH-SCH [(CH ₂ ) 3 NHBOC) CONHMe 87 CONHCH2CO (N-acetylN-piperazinyl) 88 CONH-S-CH ((CH ₂ ) 3 NH ₂ ) CO ₂ Me 89 CONHCH2CO-N-morpholino 90 CONH-SCH ((CH 2) 4 NH 2 CONH 2) 520 91 CONHCH2CO- [N- (4-hydroxyDididin) 92 CONH _(CH2) 2 Ph 93 CO 2 H 94 CONH (CH2) 2 (3,4-dimethoxyphenyl)

209

95 · CONHBn 482 96 CONH (CH2) 2- ( ^n- xorpholinyl) 97 CONH-2-pyridyl 98 CONH (CH 2) 3 - (Nmorpholino) 99 CON-Ph 100 CONHCH 2 CONH- (2-pyridyl). 101 CONH-3-pyridyl 102 O • CONHCH2-pyridyl) 103 CONH-4-pyridyl '104 CONHCH2CONH- (4-pyridyl) 105 CONH ₂ CH ₂ CH (Ph) j 600.6 106 CONH (CH3) j (P-SO3NH3Ph) 575 107 CONHCHj-2benzimidazol 522 108 CONH-2-benzimidazole 508

210

Table 2

F ^{3 -} e: cyclophane =

Px. R ² (CI-MS) xa 8 Pr. R ² (CI-MS) EB. 120 C02M 435.3 121 CONH- cyclopentyl 122 CO2EC 123 CONH2 124 CO2ÍPr 125 CONHiPr 126 CO2 <CH 2) 2OMe 479.4 127 CONH- tert-butyl 128 CO2 (CH2) 2 Ph 525.4 129 CONWe2 446.5 130 CO2-Bu 131 CONEC2 132 CO2CH2CONHMe 429.4 133 C0NH-3-indazolyl 134 CH 2 OH 135 CON-adamantyl 136 CH2OCH2CH3 137 CONHCH2 (p-SO2NH2 "Ph) 138 CH2OCH2CH2CO2CH3 139 CONH (CH2) 3-imidazolyl 528.5 140 CHOBn 141 CONHSO2NH2 142 CONH_ (CH 2) 2-2 -pyridyl 525.5 143 CONHSO2CH3 144 CO (N-morpholinyl) 145 CONHSO2PH 146 CO (N-Me-Npiperazinyl) 503.6 147 CONHSO2Bn 14 8 CONH (CH2) 2 "(N-Me-Hpiperazinyl) 149 CONHSO2-N-Meimidazolyl 150 CON-cyclopropyl 151 CONHSO2-p-NH2 Ph 152 CON-cyclobutyl 153 CONHSO2 ~ p-MeOPh 154 CONHSO2-p-F-Ph 155 CONH-S-CH [CH 2 CH (CH 3) 2) CONHMe 156 CONH (CH2) 2NHSO2Me 541.5 157 CONH (CH2) 4NHSO2Me 569.5 158 CONH-cyclohexyl 502.5 159 CONH (CH2) 6NHSO2Me 597.6

211

160 CONH-2-imidozolyl 161 CONH-R-CH (CH? CH (CH 3) 2) CONHMe 162 CH2SO2NHCH3 163 CONH-S-CH [(CH 2) 4 NH 2 ICONHMe 164 CH2SO2NHPh 165 CONH-SCH ((CH 2) 3 NH 2 CONHMe) 548.5 166 CH2SO2NH- [4-NH2PH] 167 CONH-SCH [(CH 2) 2 NH 2 CONHMe 168 2-imiäazolyl 169 CONHMe 434.4 170 2-oxazolyl 171 CONHCH ₂ CONMe ₂ 172 2-C thiazolyl 173 CONHCH2CONHEC 174 2-benzimidazolyl 175 CONHCH ₂ CONEt ₂ 176 CONH-R-CH (CH3) Ph 177 CONHCH2CONHcyklopropyl 178 CONH-S-CHCCH3) Ph 179 CONHCH2CONHcyklobutyl 180 CONHCH ₂ CONHMe 491.5 181 CONHCH2CONHcyklopentyl 182 CONH-S-CH (CH3) CONHMe 505.6 183 CONHCH2CONHcyklohexyl 184 CONH-R-CH (CH3) CONHMe 505.5 185 CONHCH ₂ CONH-tert. butyl 186 CONH-S-CH (2-propyl) CONHMe 187 CONH-SCH (CH ₂ Ph) CONHMe 188 CONH-SCH (CH 2 OH) CONHMe 189 CONH-S-CH _(CH2 -pMeOPh) CONHMe 19.0 CONH-SCH (CH 2 OH) CONHMe 191 CONHCH ₂ CH ₂ CONHMe 192 CONH-RCH (CH 2 OH) CONHMe 193 CONHCH ₂ CH ₂ CH ₂ CONHMe 194 CONH-S-CH (CH2O-CMA) CONHMe 577.6 195 CONH-SCH (CH 2 CH 2 OH) CONHMe 196 CONH-R-CH (CH2O-CMA) CONHMe 197 CONH-S (CH (CH ₂ ) 3 CH 3) CONHMe 198 CONH-CH (Ph> 2 199 CONH _(CH2) 2 ^Me 2 ^C ° 506.4 200 CO-L-proline -NHMe 201 CONH _(CH2) 2CO2H 492.3 202 CONHCH2CO (Npiperazinvl) 203 CONH-SCH [(CH ₂ ) 3 NHBOC] CO ₂ Me 649.5 204 CONHCH ₂ CO (N-methyl-NpiDerazinyl) 205 CONH-S-CH [(CH ₂ ) 3 NHBOC) CONHMe .648.6 206 CONHCH ₂ CO (N-acetyl-NoiDerazinyl) 207 CONH-S-CH [(CH ₂ ) 3 NH ₂ ] CO ₂ Me 549.5 208 CONHCH2CO-Niaoxfolinol 209 CONH-SCH ((CH ₂ ) 4 NH ₂ ) CONH ₂ 548.5 210 CONHCH2CO- [N- (4hvdroxvDiperidinvl) 1 211 CONH (CH ₂ ) ₂ P ^h 524.5 212 CO ₂ H 421.4 213 CONH (CH ₂ ) 2 "(3,4, oxyphenyl dimethyl) 584.6 214 CONHBn 510.5 215 CONH _(CH2) 2- (N-morpholino) 533.5

212

216 CONH-2-pyridyl 217 CONH (CH 2) 3 "(N. Morpholino) 547.5 218 CON-Ph 219 CONHCH2CONH- (2-pyridyl) 220 CONH-3-pyridyl 221 CONHCH2CONH- (3-pyridyl) 222 CONH-4-pyridyl 223 CONHCH2CONH- (4pvridyl) 224 CONH-CH3CH (Ph) j 600.6 225 C0NH (CH) j (P-SO ₂ NHjPh) 603.6

213

Table 3

Pr. R ² (CI-MS) ae Pr. R ² (CI-MS) ae 240 CO2M 241 CONH-cyclopentyl 242 CO2EC 243 CONH2 244 CO2ÍPr 245 CONHiPr 246 CO2 (CH2) 2 ° Me 247 CONH-tert-butyl 248 CO2 (CH2) 2 Ph 249 CONMe2 250 CO2 ~ CBu 251 CONEC2 252 CO2CH2CONHMe 253 CONH-3-indazolyl 254 CH 2 OH 255 CON-adamanty1 256 CH2OCH2CH3 257 CONHCH2 (p-SO2NH2-Ph) 258 CH2OCH2CH2CO2CH3 259 CONH (CH2) 3-limidazolvl 260 CHOBn 261 CONHSO2NH2 262 CONH (CH2) 2-2-pyridyl 263 CONHSO2CH3 264 CO (N-morpholinyl) 265 CONHSO2Ph 266 CO (N-Me-N-piperazinyl) 267 CONHSO2B11 268 CONH (CH2) 2- (N-Me-NpiDerazinyl) 269 CONHSO2-N-Meimidazolyl 270 CON-cyclopropy1 271 CONHSO2-p-NH2Ph 272 CON-cyclobutyl 273 CONHSO2-p-MeOPh

214

274 CONHSO2-p-F-Ph 275 CONH-S-CH [Plume (CH3) 2] CONHMe 276 CONH (CH2) 2NHSO2Me 277 CONH (CH2) 4NHSO2Me 278 CONH-cyclohexyl 279 CONH (CH2) 6NHSO2Me 280 CONH 2 inu.dozolyl 281 CONH-R-CH (CHjCH (CH 3) 2) CONHMe 282 CH2SO2NHCH3 283 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 284 CH2 SO ₂ NH-Ph 285 CONH-SCH ((CH 2) 3 NH 2) CONHMe 286 CH2 SO ₂ NK [4-NH2Ph] 287 CONH-SCH [(CH 2) 2 NH 2) CONHMe 288 2-imidazolyl 289 CONHMe 290 2-oxazolyl 291 CONHCH2CONMe2 292 2-C thiazolyl 293 CONHCH2CONHEC 294 2-benzimidazolyl 295 CONHCH2CONEC2 296 CONH-R-CH (CH3) Ph 297 CONHCH2CONHcyklopropyl 298 CONH-S-CH (CH3) Ph 299 ČONHCH2.CONHcyklobutyl 300 CONHCH2CONHMe 301 CONHCH2.CONHcyklopentyl 302 CONH-S-CH (CH3) CONHMe 303 CONHCH2CONHcyklohexyl 304 CONH-P.-CH (CH 3) CONHMe 305 CONHCH2CONH- tert. butyl 306 CONH-S-CH (2-propyl) CONHMe 307 CONH-SCH (CH 2 Ph) CONHMe 308 CONH-SCH (CH 2 OH) CONHMe 309 CONH-S-CH (CH2-PMeOPh) CONHMe 310 CONH-SCH (CH 3 OH) CONHMe 311 CONHCH2CH2CONHMe 312 CONH-RCH (CH 3 OH) CONHMe 313 CONHCH2CH2CH2CONHMe 314 CONH-S-CH (CH 2 O t Bu) CONHMe 315 CONH-SCH (CH 2 CH 2 OH) CONHMe 316 CONH-R-CH (CH2O-CMA) CONHMe 317 CONH-S (CH (CH2) 3CH3) CONHMe 318 CONH-CH (Ph) 2 319 CONH (CH 2) 2 ^co 2 ^Me 320 CO-L-proline -NHMe 321 CONH (CH2) 2CO2H 322 CONHCH2COÍNDÍDerazinyl) 323 CONH-SCH ((CH 2) 3 NHBoc) CO2M 324 CONHCH 2 CO (N-mefcyl-NpiDerazin) 325 CONH-SCH ((CH 2) 3 NHBoc] CONHMe 326 CONHCH2CO (N-acetyl-NpÍDerazinvl) 327 CONH-S-CH [(CH ₂ ) 3 NH ₂ ] CO ₂ Me 328 CONHCH2CO-N-morpholino 329 CONH-SCH [(CH 2) 4 NH 2 CONH 2

215

330 CONHCH2CO- [N- (4hvdroxyDÍDeridinvl) 1 331 CONH (CH2) 2 Ph 332 CO 2 H 333 CONH (CH2) 2- <3.4, dimethoxyphenyl) 334 CONHBn 335 CONH (CH2) 2 (N-morpholino) 336 CONH-2-pyridyl 337 CONH (CH2) 3 '(N-morpholino) 338 CON-Ph 339 CÓNHCH2CONH- (2pvridyl) 340 CONH-3-pyridyl 341 CONHCH2CONH- (3-pyridyl) 342 CONH-4-pyridyl 343 CONHCH2CONH- (4-pyridyl) 344 CONH-CH 3 CH (Phj 3 600.6 345 CONH (CH3) J (P - SO3NH JPh) 603.6

216

Table 4

For cyclists:

Pr. R ² (CI-MS) again Pr. R ² (CI-MS) no 350 C02M 351 CONH-cyclopentyl 352 C02EC 353 CONH2 354 C02ÍPr 355 CONHiPr 356 CO ₂ (CH ₂ ) 2 OMe 357 CONH-tert-butyl 358 CO ₂ (CH ₂ ) ₂ Ph 359 CONMe2 360 CC> 2-Bu 361 CONEC2 362 CO2CH2CONHMe 363 CONH-3-indazolyl 364 CH 2 OH 365 CON-adamantyl 366 CH2OCH2CH3 367 CONHCH2 (p-SO2NH2-Ph) 368 CH2OCH2CH2CO2CH3 369 CONH (CH2) 3-1imidazolvl 370 CHOBn 371 CONHSO2NH2 372 CONH (CH2) 2-2-pyridyl 373 CONHSO2CH3 374 CO (N-morpholinyl) 375 CONHSO2Ph 376 C0 (N-Me-NDiDerazinyl) 377 CONHSO2Bn 378 CONH (CH 2) 2 - (N-Me-Npiperazinyl) 379 CONHSO2-N-Meimidazolyl 380 CON-cyclopropyl 381 CONHSO2-P ~ NH2Ph 382 CON-cyclobutyl 383 CONHS02-p-MeOPb

23..7

384 CONHSO2-p-F-Ph 385 CONH-S-CH [CH 2 CH (CH 3) 2ICONHMe 386 CONH (CH2) 2NHSO2Me 387 CONH (CH2) 4NHSO2Me 388 CONH-cyclohexyl 389 CONH (CH2) 6NHSO2Me 390 CONH-2-inú.dozolyl 391 CONH-R-CH (CH 2 CH (CH 3) 21CONHMe 392 CH2SO2NHCH3 393 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 394 CH2SO2NHPh 395 CONH-SCH [(CH 2) 3 NH 2 ICONHMe 396 CH2SO2NH- [4-NH2Ph] 397 CONH-SCH [(CH2) 2 NH2ICONHMe 398 2-imidazolyl 399 CONHMe 400 2-oxazolyl 401 CONHCH2CONMe2 402 2-thiazolyl 403 CONHCH2CONHEC 404 2-benzimidazolyl 405 CONHCH2CONEC2 406 CONH-R-CH (CH3) Ph 407 CONHCH2CONHcyklopropyl 408 CONH-S-CH (CH3) Ph 409 CONHCH2CONHcyklobutyl 410 CONHCH2CONHMe 411 CONHCH2CONHzyklopentyl 412 CONH-S-CH (CH3) CONHMe 413 CONHCH2CONHcvklohexyl 414 CONH-R-CH {CH3) CONHMe 415 CONHCH2-t. butyl 416 CONH-S-CH (2-propyl) CONHMe 417 CONH-SCH (CH 2 Ph) CONHMe 418 CONH-SCH _(CH2 SH) CONHMe 419 CONH-S-CH (CH2-PMeOPh) CONHMe 420 CONH-SCH (CH ₂ OH) CONHMe 421 CONHCH2CH2CONHMe 422 RCH-CONH (CH 2 OH) CONHMe 423 CONHCH2CH2CH2CONHMe 424 CONH-S-CH (CH 2 O t Bu) CONHMe 425 CONH-SCH (CH 2 CH 2 OH) CONHMe 426 CONH-R-CH (CH 2 O t Bu) CONHMe 427 CONH-S (CH (CH2) 3CH3) CONHMe 428 CONH-CH (Ph) 2 429 CONH (CH2) 2 Me 2 C ° 430 CO-L-proline -NHMe 431 CONH (CH2) 2CO2H 432 CONHCH2CO (NpiDerazinvl) 433 CONH-SCH [(CH 2) 3 NHBOC) CO 2 Me 434 CONHCH2CO (N-mechyl-NpiDerazinyl) 435 CONH-SCH [(CH 2) 3 NHBOCJCONHMe 436 CONHCH2CO (N-acetyl-Npiperazinvl) 437 CONH-S-CH [(CH 2) 3 NH 2) ^c 2 Me 438 CONHCH2CO-Nftiorfolino 439 CONH-SCH ((CH 2) 4NH2lCONH2

2: 1.8

440 CONHCH ₂ CO- [N- (4-hydroxypiperidin)] '441 CONH (CH ₂ ) 2 ^ph 442 co ₂ h 443 CONH (CH 2) 2 ~ V ³ · ⁴ · dimethoxyphenyl) 444 CONHBn 445 CONH (CH ₂ ) 2 '(N-morpholino) 446 CONH-2-pyridyl 447 CONH (CH ₂ ) 3 (N-morpholino) 448 CON-Ph 449 CONHCH ₂ CONH- ( _2- pyridyl) 450 CONH-3-pyridyl 451 CONHCH ₂ CONH- (3-pyridyl) 452 CONH-4-pyridyl 453 CONHCH ₂ CONH- (4-pyridyl) 454 CONH-CH3CH (Ph) j 455 CONH (CH3) j (P-SO3NH3Ph)

2X9

Tabuika 5

For cyclists:

Pr. F ² (CI-HS) ββ Pr. R ² (CI-MS) 3AB 47C C02M 471 CONH-cyclopentyl 472 CO2e 473 CONH2 474 CO2ÍPr 475 CONHiPr 476 CO2 (CH2> 20me 477 CONH-tert-butyl 478 CO ₂ (CH ₂ ) 2 Ph 479 CONMe2 480 CO2-Bu 481 CONEC2 482 CO2CH2CONHMe 483 C0NH-3-indazolyl 484 ch ₂ oh 485 CON-adamantyl 486 CH2OCH2CH3 487 CONHCH2 (p-SO2NH2-Ph) 488 CH2OCH2CH2CO2CH3 489 CONH (CH2) 3-1imidazolyl 490 CHOBn 491 CONHSO2NH2 492 CONH _(CH2) 22-pyridyl 493 CONHSO2CH3 494 CO (N-morpholinyl) 495 CONHSO2Ph 496 CO (N-Me-Npiperazinyl) 497 CONHSO2Bn 498 CONH (CH2) 2 (N-Me-Npiperazinyl) 499 C0NHSO2-N-Meimidazolvl 500 CONH = yklopropy1 501 CONHSO2-p-NH2Ph 502 CON-cyclobutyl 503 CONHSO2-p-MeOPh

220

504 CONHSO ₂ -pF-Ph 505 CONH-S-CH (CH ₂ CH (CH 3) 2 -CONHMe 506 CONH (CH ₂ ) ₂ NHSO ₂ Me 507 CONH (CH 2) 4 NHSO 2 Me 508 CONH-cyclohexyl 509 CONH (CH 2) 6 NHSO 2 Me 510 C0NH-2-inddozolyl 511 CONH-R-CH (CH 2 CH (CH 3) 21CONHMe 512 CH2SO2NHCH3 513 CONH-S-CH [(CH ₂₎ 4 NH ₂ JCONHMe 514 CH ₂ SO ₂ NHPh 515 CONH-SCH ((CH ₂ ) 3 NH ₂ ) CONHMe 516 CH ₂ SO ₂ NH- (4-NH ₂ Ph) 517 CON-SCH! (CH ₂ ) ₂ NH ₂ ] CONHMe 518 2-imidazolyl 519 CONHMe • 520 2-oxazolyl 521 CONHCH ₂ CONMe ₂ 522 2-C thiazolyl 523 CONHCH ₂ CONHEC 524 2-benzimidazolyl 525 CONHCH ₂ Conel ₂ 526 CONH-R-CH (CH3) Ph 527 CONHCH ₂ CONHcyclopropyl 528 CONH-S-CH (CH3) Ph 529 CONHCH2CONHcyklobutyl 530 CONHCH ₂ CONHMe 531 CONHCH2CÓNHcyklopentyl 532 CONH-S-CH (CH3) CONHMe 533 CONHCH2CONHcyklohexyl 534 CONH-R-CH (CH3) CONHHe 535 CONHCH2-t. butyl 536 CONH-S-CHÍ2propyl) CONHMe 537 CONH-SCH (CH 2 Ph) CONHMe 538 CONH-SCH (CH 2 OH) CONHMe 539 CONH-S-CH (CH2-PMeOPh) CONHMe 540 CONH-SCH (CH ₂ OH) CONHMe 541 CONHCH2CH2CONHMe 542 CONH-RCH (CH 2 OH) CONHMe 543 CONHCH2CH2CH2CONHMe 544 CONH-S-CH (CH2O-CMA) CONHMe 545 CONH-SCH (CH 2 CH 2 OH) CONHMe 546 CONH-R-CH (CH 2 O t Bu) CONHMe 547 CONH-S (CH (CH2) 3CH3) CONHMe 548 CONH-CH (Ph) 2 549 CONH (C'12) 2 ^ε θ2 ^β 550 CO-L-proline -NHMe 551 CONH (CH2) 2 ^ 02 ^ 552 CONHCH2CO (NDiDerazinyl) 553 CON-SCH! (CH2) 3NHB0C] CO2M 554 CONHCH 2 CO (N-methyl-NpiDerazinyl) 555 CONH-SCH [(CH 2) 3 NHBOC] CONHMe 556 CONHCH2CO {N-acetyl-NpiDerazinyl) 557 CONH-S-CH [(CH 2) 3 NH ₂ ) CO ₂ Me 558 ; CONHCHoCO.-Nmorfolino1 559 CONH-SCH [(CH 2) 4 NH ₂ ) CONH ₂

221st

560 CONHCH 2 CO- (N- (4-hydroxypineridin) 1) 561 CONH (CH 2) 2 ^ph 562 co ₂ h 563 CONH (CH2) 2- (3,4, dimethoxyphenyl) 564 CONHBn 565 CONH (CH 2) 2 - (N-morpholino) 566 CONH-2-pryidyl 567 CONH (CH2) 3- (N- morpholino) 568 CON-Ph 569 CONHCH2CONH- (2-pyridyl) 570 CONH-3-pyridyl 571 CONHCH2CONH- (3-pyridyl) 572 CONH-4-pyridyl 573 CONHCH2CONH- (4-pyridyl) 574 CONH-CH ₂ CH (Ph) i 575 CONH (CH 2) 2 (P-SO 3 NH 3 Ph)

222

Table 6

For cyclo f and n =

Pr. R ² (CI-MS) again Pr. R ² (CI-MS) as ^: 600 CC> 2 Me 601 CONH-cyclopentyl 602 CO2EC 603 CONH2 604 CO2ÍPr 605 CONHiPr 606 CO 2 (CH 2) 2 OMe 607 CONH-tert-butyl 608 CO ₂ (CH ₂ ) 2 Ph 609 CONMe2 610 CO2-Bu 611 CONEC2. 612 CO2CH2CONHMe 613 CONH-3-indazolyl 614 CH 2 OH 615 CON-adamantyl 616 CH2OCH2CH3 617 CONHCH2 (p-SO2NH2-Pb) 618 CH2OCH2CH2CO2CH3 619 CONH (CH2) 3-1imidazolyl 620 CHOBn 621 CONHSO2NH2 622 CONH (CH2) 2 "2-pyridyl 623 CONHSO2CH3 624 CO (N-morpholinyl) 625 CONHSO ₂ Ph 626 CO (N-Me-NDiDerazinyl) 627 CONHSO2Bn 628 CONH (CH2) 2 (N-Me-NDerazinyl) 629 CONHSO ₂ -N-Meimidazolyl 630 CON-cyclopropyl 631 CONHSO2-P-NH2PH 632 CON-cyclobutyl 633 CONHSO2-p-MeOPh 634 CONHSO2-P-F-Ph 635 CONH-S-CH (CH2CHCCH3) 21CONHMe

223

636 CONH (CH2) 2NHSO2Me 637 CONH (CH2) 4NHSO2Me 638 CONH-cyclohexyl 639 CONH (CH2) 6NHSO2Me 640 CONH-2-imidozolyl 641 CONH-R-CH (CH 2 CH (CH 3) 21CONHMe 642 CH2SO2NHCH3 643 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 644 CH2SO2NHPh 645 CONH-SCH ((CH 2) 3 NH 2) CONHMe 646 CH2SO2NH- [4-NH2PH) 647 CONH-SCH [(CH 2) 2 NH 2) CONHMe 648 2-imidazolyl 649 CONHMe 650 2-oxazolyl 651 CONHCH2CONMe2 652 2-C thiazolyl 653 CONHCH2CONHEC 654 2-benzimidazolyl 655 CONHCH2CONEC2 656 CONH-R-CH (CH3) Ph 657 CONHCH2CONHcyklopropyl 658 CONH-S-CH (CH3) Ph 659 CONHCH2CONHcyklobutyl 660 CONHCH2CONHMe 661 CONHCH2CONHcyklopentyl 662 CONH-S-CH (CH3) CONHMe 663 CONHCH2CONHcyklohexyl 664 CONH-R-CH (CH3) CONHMe 665 CONHCH2-t. butyl 666 CONH-S-CH (2-propyl) CONHMe 667 CONH-SCH (CH 2 Ph) CONHMe 668 CONH-SCH (CH 2 OH) CONHMe 669 CONH-S-CH (CH2-pMeOPh) CONHMe 670 CONH-SCH (CH 2 OH) CONHMe 671 CONHCH2CH2CONHMe 672 CONH-RCH (CH ₂ OH) CONHMe 673 CONHCH2CH2CH2CONHMe 674 CONH-S-CH (CH2O-t'Bu) CONHMe 675 CONH-SCH (CH 2 CH 2 OH) CONHMe 676 CONH-R-CH (CH2O-CMA) CONHMe 677 CONH-S (CH (CH2) 3CH3) CONHMe 678 CONH-CH (Ph) 2 679 CONH (CH2) 2CO2Me 680 CO-L-proline -NHMe 681 CONH (CH2) 2CO2H 682 CONHCH2CO (NDiDerazinyl) 683 CONH SCH-I, (CH ₂₎ 3 NHBoc) CO2M 684 CONHCH2CO (N-methyl-Npiperazinvl) 685 CONH-SCH ((CH 2) 3 NHBOC] CONHMe 686 CONHCH2CO (N-acetyl-NpiDerazinyl) 687 CONH-S-CH ((CH2) 3NH2) CO2M 688 CONHCH2CO-N-morpholino 689 CONH-SCH ((CH ₂ ) 4 NH ₂ CONH ₂₎ 690 CONHCH2CO- (N- (4hvdroxvoioeridinvl)) 691 CONH (CH2> 2 Ph

224

692 CO ₂ H 693 CONH (CH 2) 2 <3 · ⁴ > -dimethoxyphenyl) 694 CONHBn 695 CONH (CH2) 2 ^<n morpholino) 696 CONH-2-pyridyl 697 CONH (CH2) 3 (N-morpholino) 698 CON-Ph 699 CONHCH2CONH- (2-pyridyl) 700 CONH-3-pyridyl 701 CONHCH2CONH- (3-pyridyl) 702 CONH-4-pyridyl 703 CONHCH2CONH- (4-pyridyl) 704 CONH-CH3CH (Ph) ₂ 705 CONHCCHJjCP SOjNH-Ph)

225

Table 7

For cyclophane:

Pr. R ² (CI-MS) bb Pr. R ² (CI-MS) bb 710 CO2M 435 711 CONH- cyclopentyl 712 CO ₂ Ec 713 CONH2 714 CO ₂ iPr 715 CONHiPr 716 CO ₂ (CH ₂ ) ₂ OMe 717 CONH-tert-butyl 718 CO ₂ (CH ₂ ) ₂ Ph 719 CONMe2 720 CO ₂ -tBu 721 CONEC2 722 CO ₂ CH ₂ CONHMe 723 CONH-3-indazolyl 724 CH ₂ OH 725 CON-adamancyl 726 CH ₂ OCH ₂ CH 3 727 CONHCH2 (p-SO 2 NH ₂ -Ph) 728 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 729 CONH (CH2) 3-1 inddazolyl 730 CHOBn 731 CONHSO2NH2 732 CONH (CH2) 2 "2-pyridyl 733 CONHSO2CH3 734 CO (N-morpholinyl) 735 CONHS02Ph 736 CO (N-Me-Npiperazinvl) 737 CONHSO2Bn 738 CONH (CH 2) 2- (N-Me-N-piperazinyl) 739 C0NHS02-N-Meimidazolyl 740 CONH- cyclopropyl 741 CONHSO2-P-NH2P ^ 742 CONH- cyclobutyl 743 CONHSO2-p-MeOPh 744 CONHSO2-P-F-PH 745 CONH-S-CH [CH 2 CH (CH 3) 2) CONHMe

226

746 CONH (CH2) 2NHSO2Me 747 CONH (CH2) 4NHSO2Me 748 CONH-cyclohexyl 749 CONH (CK2) 6NHSO2Me 750 CONH-2-imidozolyl 751 CONH-R-CH [CH? CH (CH 3) 2JCONHMe 752 CH2SO2NHCH3 753 CONH-S-CH [(CH 2) 4 NH 2] CONHMe 754 CH2SO2NHPh 755 CONH-SCH [(CH 2) 3 NH 2 CONONHMe 756 CH2SO2NH- [4-NH2Ph] 757 CONH-SCH [(CH 2) 2 NH 2) CONHMe 758 2-iraidazolyl 759 CONHMe 434 760 2-oxazolyl 761 CONHCH2CONMe2 762 2-thiazolyl 763 CONHCH2CONHEC 764 2-benzimidazolyl 765 CONHCH2CONEC2 766 CONH-R-CH (CH3) Ph 767 CONHCH2CONHcyklopropyl 768 CONH-S-TA (Ph CH 3} 769 CONHCH2CONHcyklobutyl 770 CONHCH2CONHMe 771 CONHCH2CONHcyklopentyl 772 CONH-S-CH (CH3) CONHMe 773 CONHCH2CONHcyklohexyl 774 CONH-R-CH (CH3) CONHMe 775 CONHCH2-t. butyl 776 Čonka-S-CH (2propy1) CONHMe 777 CONH-SCH (CH 2 Ph) CONHMe 778 CONH-SCH (CH 2 OH) CONHMe 779 CONH-S-CH (CH2-PMeOPh) CONHMe 780 CONH-SCH (CH2OH) CONHMe 781 CONHCH2CH2CONHMe 782 CONH-RCH (CH 2 OH) CONHMe 783 CONHCH2CH2CH2CONHMe 784 CONH-S-CH (CH2O-t'Bu) CONHMe 785 CONH-SCH (CH 2 CH 2 OH) CONHMe 786 CONH-R-CH (CH 2 O t Bu) CONHMe 787 CONH-S (CH (CH2) 3CH3) CONHMe 788 CONH-CH (Ph) 2 789 CONH (CH2) 2 Me 2 C ° 790 CO-L-proline -NHMe '791 CONH (CH2) 2CO2H 792 CONHCH2CO {Npioerazinyl) 793 CONH-SCH ((CH 2) 3 NHBOCJCO 2 Me) 794 CONHCH2CO (N-mechyl-NpiDerazinyl) 795 CONH-SCH ((CH 2) 3 NHBOC) CONHMe 796 CONHCH2CO (N-acetyl-NpiDerazinyl) 797 CONH-S-CH ((C "2) 3NH2] CO2M 798 CONHCH2CO-N-morpholino 799 CONH-SCH [(CH ₂ ) 4 NH ₂ ) CONH 2 800 CONHCH 2 CO- (N- (4-hydroxypiperidinyl)) 801 CONH (CH 2) 2 ^p h

27Ί

802 CO ₂ H 803 CONH (CH ₂ ) ₂ - (3,4, dimethoxyphenyl) 804 CONHBn 805 CONH (CH ₂ ) 2 - ( ^N 'morpholino) 806 CONH-2-pyridyl 807 CONH (CH2) 3- (N-morpholino) 808 CON-Ph 809 CONHCH2CONH- (2-pyridyl) 810 CONH-3-pyridyl 811 CONHCH2CONH- (3-pyridyl) 812 CONH-4-Pyridyl 813 CONHCH2CONH- (4-pyridyl) 814 CONK-CH ₂ CH (Ph) j 815 CONH (CH 3) j (P-SO ₂ NH ₂ Ph)

228

Table 8

For cyclic carbaniate.

Pr. R2 (CI-KS) TT6 Pr. R 2 (CI-HS) SXB 820 CO ₂ Me 821 CONH-cyclopentyl 822 CO ₂ Et 823 CONH2 824 CO ₂ iPr 825 CONHiPr 826 CO2 (CH2) 20He 827 CONH-tert-butyl 828 CO ₂ (CH ₂ ) 2 Ph 829 C0NMe ₂ 830 CO ₂ -tBu 831 CONEC2 832 CO ₂ CH ₂ CONHMe 833 CONH-3-indazolyl 834 ch ₂ oh 835 CON-adamantyl 836 CH2OCH2CH3 837 CONHCH 2 (p-SO ₂ NH ₂ -Ph) 838 CH2OCH2CH2CO2CH3 839 CONH (CH2) 3-limidazolvl 840 CHOBn 841 CONHSO2NH2 842 CONH (CH2) 2-2-pyridyl 843 CONHSO2CH3 844 CO (N-morpholinyl) 845 CONHSO ₂ Ph 846 CO (N-Me-Npiperazinyl) 847 CONHSO ₂ Bn 848 CONH (CH ₂ ) 2 (N-Me-NpiDerazinyl) 849 CONHSO ₂ -N-Meimidazolyl 850 CONH- cyclopropyl 851 CONHSO ₂ -p-NH ₂ Ph 852 CON-cyclobutyl 853 CONHSO ₂ -p-MeOPh 854 CONHSO2-p-F-Ph 855 CONH-S-CH (CH 2 CH (CH 3) 2) CONHMe

2.29

856 CONH (CH2) 2NHSO2Me 857 CONH (CH 2) ₄ NHSO ₂ Me 858 CONH- (4-hydroxy-cyclohexyl) 542.5 859 CONH (CH2) 6NHSO2Me 860 C017H-2-iniidozolyl 861 CONH-R-CH [CH 2 CH (CH 3) 2) CONHMe 862 CH2SO2NHCH3 863 CONH-S-CH [(CH 2) 4 NH 2 J CONHMe 864 CH2SO2NHPh 865 CONH-SCH [(CH ₂₎ 3NH2ICONHMe 866 CH2SO2NH- [4-NH2PhJ 867 CONH-SCH [(CH2) 2 NH2 CONHMe 868 2-itaidazolyl 869 CONHMe 429.3 870 2-oxazolyl 871 CONHCH ₂ CONMe ₂ 500.3 872 2-C thiazolyl 873 CONHCH2CONHEC 874 2-benzimidazolyl 875 CONHCH ₂ CONEt ₂ 876 CONH-R-CH (CH 3) Ph 877 CONHCH2CONHcyklopropyl 878 CONH-S-CH (CH3) Ph 879 CONHCH ^ CONHcyklobutyl 880 CONHCH ₂ CONHMe 486.5 881 CONHCH2CONHcyklopentyl 882 CONH-S-CH (CH3) CONHMe 883 CONHCH2CONHcyklohexyl 884 CONH-R-CH (CH3) CONHMe 885 CONHCH2-t. butyl 886 CONH-S-CH (2-propyl) CONHMe 887 CONH-SCH (CH 2 Ph) CONHMe 888 CONH-SCH (CH 2 OH) CONHMe 889 CONH-S-CH _(CH2 -pMeOPh) CONHMe 890 CONH-SCH (CH 2 OH) CONHMe 891 CONHCH ₂ CH ₂ CONHMe 892 CONH-RCH (CH ₂ OH) CONHMe 893 CONHCH ₂ CH ₂ CH ₂ CONHMe 894 CONH-S-CH (CH ₂ O-tBu) CONHMe 895 CONH-SCH (CH 2 CH 2 OH) CONHMe 896 CONH-R-CH (CH ₂ O-tBu) CONHMe 897 CONH-S (CH (CH ₂ ) 3 CH 3) CONHMe 898 CO-L-proline 556.5 899 CONH (CH ₂ ) ₂ CO ₂ Me 900 CO-L-proline -NHMe 901 CONH _(CH2) 2CO2H 902 CONHCH ₂ CO (NDiDerazinyl) 903 CONH-SCH [(CH ₂ ) 3 NHBOC] CO ₂ Me 904 CONHCH ₂ CO (N-mechyl-NpiDerazinyl) 555.5 905 CONH-SCH [(CH2) jNHBOCICONHMe 906 CONHCH 2 CO (N-ethyl -NDiDerazin) 569.6 907 CONH-S-CH [(CH ₂ ) 3 NH ₂ CO ₂ Me 908 CONHCH2CO-Nmorpholino. 542.5 909 CONH-SCH [(CH ₂₎ 4NH2ICONH2

230

910 CONHCH2CO- [N- (4-methoxyxidiridin)] 555.7 911 CONH (CH2) 2 Ph 912 CO 2 H 913 CONH (CH2) 2- ⁽ 3,4-dimethoxyphenyl) 914 CONHBn 915 CONH (CH2) 2 (N-morpholino.) 916 Čonka-2-pryidyl 496.5 917 CONH (CH2) 3 (N-morpholino.) 918 CON-Ph 919 CONHCH2CONH- (2-pyridyl) 549.5 920 CONH-3-pyridyl 921 CONHCH2CONH- (3-pyridyl) 922 CONH-4-pyridyl 923 CONHCH2CONH- (4-pyridyl) 924 CONH-CH3CH (Ph) ₂ 925 CONH-4- (N-ecoxycarbonylpiperidinyl) 570.5 926 CONH-2- (3-methyl) -thiazolyl 512.4 927 CONHCHjCNH-2 (3,4,5,6tetrahydropyridinyl) 553.6 928 CONHCH3CO-2- (3-meth) -thiazolyl 569.3 929 CONHCHj-2-pyridyl 506.5

231

Table 9

For cyclic c a r b a m =

Pr. R ² (C HS) again Pr. R ² (CI-MS) ms 930 CO ₂ Me 931 CONH-cyclopentyl 932 CO ₂ Ec 933 CONH ₂ 934 CO ₂ iPr 935 CONHiPr 936 CO ₂ (CH ₂ ) ₂ OMe 937 CONH-tert-butyl 938 CO ₂ (CH ₂ ) ₂ Ph 939 CONMe ₂ 940 CO ₂ -cBu 941 CONEC ₂ 942 CO ₂ CH ₂ CONHMe 943 CONH-3-indazolyl 944 CH ₂ OH 945 CON-adamantyl 946 CH ₂ OCH ₂ CH 3 947 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 948 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 949 CONH (CH ₂ ) 3 -imidazolyl 950 CHOBn 951 CONHSO2NH2 952 CONH (CH ₂ ) ₂ -2-pyridyl 953 CONHSO2CH3 954 CO (N-morpholinyl) 955 CONHSO2Ph 956 CO (N-Me-NpiDerazinyl) 957 CONHSO2Bn - 958 CONH (CH ₂ ) ₂ - (N-Me-Npiperazine) 959 CONHSO2-N-Meinddazolyl 960 CON-cyclopropyl 961 CONHS02-p-NH2Ph 962 CON-cyclobutyl 963 CONHS02-p-MeOPh 964 CONHSO ₂ -pF-Ph 965 CONH-S-CH [CH 2 CH (CH 3) 2lCONHMe 966 CONH (CK ₂ , ₂ NHSO ₂ Me 967 CONH {CH2) 4NHSO2Me

232

968 CONH-cyclohexyl 969 CONHCCH2) 6NHSÔ2Me 970 CONH 2 inu.dozolyl 971 CONH-R-CH (CH 2 CH (CH 3) 2lCONHMe 972 CH2SO2NHCH3 973 CONH-S-CH [(CH 2) 4 NH 2 CONHMe 974 CH2SO2NHPh 975 CONH-SCH [(CH 2) 3 NH 2 CONHMe 976 CH2SO2NH- [4-NH2Ph] 977 CONH-SCH [(CH 2) 2 NH 2] CONHMe . 978 2-imidazolyl 979 CONHMe 980 2-oxazolyl 981 CONHCH2CONMe2 982 2-thiazolyl 983 CONHCH2CONHEC 984 2-benzimidazolyl 985 CONHCH2CONEC2 986 CONH-R-CH (CH3) Ph 987 CONHCH2CONHcyklopropyl 988 CONH-S-CH (CH3) Ph 989 CONHCH2CONHcyklobutyl 990 CONHCH2CONHMe 991 CONHCH2CONHcyklopentyl 992 CONH-S-CH (CH3) CONHMe 993 CONHCH2CONHcyklohexyl 994 Conn-R-CH (CH3) CONHMe 995 CONHCH2-t. butyl 996 CONH-S-CH (2-propyl) CONHMe 997 CONH-SCH (CH 2 Ph) CONHMe 998 CONH-SCH (CH 2 OH) CONHMe 999 CONH-S-CH (CH2-PMeOPh) CONHMe 1000 CONH-SCH (CH 2 OH) CONHMe 1001 CONHCH2CH2CONHMe 1002 CONH-P.CH (CH2OH) CONHMe 1003 CONHCH2C H2CH2 CONHMe 1004 CONH-S-CH (CH 2 O-t Bu) CONHMe 1005 CONH-SCH (CH 2 CH 2 OH) CONHMe 1006 CONH-R-CH (CH2O-CMA) CONHMe 1007 CONH-S (CH (CH2) 3CH3) CONHMe 1008 CONH-CH (Ph) 2 1009 CONH (CH2) 2CO2Me 1010 CO-L-proline -NHMe 1011 CONH (CH2) 2CO2H 1012 CONHCH2COCNDÍDerazinvl) 1013 CONH-SCH [(CH 2) 3 NHBOC) CO 2 Me 1014 CONHCH2CO (N-mechylN-piperazinyl) 1015 CONH-S-CH ((CH 2) 3 NHBOC] CONHMe 1016 CONHCH2CO (N-acetylN-piperazinyl) 1017 CONH-S-CH ((CH2) 3NH2] CO2M 1018 CONHCH2CO-morpholino ^ NMOR 1019 CONH-SCH [(CH 2) 4 NH 2 J CONH 2 1020 CONHCH2CO- [N- (4hvdroxvniDeridinvl)) 1021 CONH (CH2) 2 Ph 1022 CO 2 H 1023 CONH (CH2) 2 <3.4, dimethoxyphenyl)

233

1024 CONHBn 1025 CONH (CH2) 2 (Ňmorfolinoi) 1026 CONH-2-pyridyl 1027 CONH (CH 2) 3 "(Nmorpholino) 1028 CON-Ph 1029 CONHCH2CONH- (2pvridyl) 1030 CONH-3-pyridyl 1031 CONHCH2CONH- (3-pyridyl) 1032 CONH-4-pyridyl 1033 CONHCH2CONH- (4pyridvl) 1034 CONH-CH3CH (Ph) 2 1035 CONH (CH 2) 2 (P-SO 3 NH 3 Ph)

234

Table 10

For cyclic carbaniate;

Pr. R ² (C KS) SXB Pr. R ² (CI-MS) SXB 1050 CO ₂ Me 1065 CONH-cyclopentyl 1051 CO ₂ Ec 1066 CONH ₂ 1052 CO ₂ iPr 1067 CONHiPr 1053 CO ₂ (CH ₂ ) ₂ OHe 1068 CONH-tert-butyl 1054 CO ₂ (CH ₂ ) ₂ Ph 1069 CONMe ₂ 1055 CO ₂ -tBu 1070 CONEC ₂ 1056 CO ₂ CH ₂ CONHMe 1071 CONH-3-indazolyl 1057 CH ₂ OH 1072 CON-adamantyl 1058 CH ₂ OCH ₂ CH 3 1073 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 1059 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 1074 CONH (CH ₂ ) 3 -imidazolyl 1060 CHOBn 1075 CONHSO ₂ NH ₂ 1061 CONH _{(CH2) 2} -2pyridvl 1076 CONHSO ₂ CH3 1062 CO (N-morpholinyl) 1077 CONHSO ₂ Ph 1063 CO (N-Me-Npiperazinyl) 1078 CONHSO ₂ Bn 1064 CONH (CH ₂ ) ₂ - (N-He-NpiDerazinyl) 1079 CONHSO ₂ -N-Meimidazolyl 1080 CONH- cyclopropyl 1107 CONHSO ₂ -p-NH ₂ Ph

235

1081 CON-cyclobutyl 1108 CONHSO ₂ -p-MeOPh 1082 CONHSO ₂ -pF-Ph 1109 CONH-S-CH [CH ₂ CH (CH 3) ₂ ] CONHMe 1083 CONH (CH ₂ , ₂ NHSO ₂ Me 1110 CONH (CH ₂ ) 4 NHHSO ₂ Me 1084 CONH-cyclohexyl 1111 CONH (CH ₂ > $ NHSO ₂ Me 1085 C0NH-2-imidozolyl 1112 CONH-R-CH [CH ₂ CH (CH 3) 2 CONHMe 1086 CK2SO2NHCH3 1113 CONH-S-CH [(CH ₂ ) 4 NH ₂ ) CONHMe 1087 CH ₂ SO ₂ NHPh 1114 CONH-SCH [(CH ₂ ) ₃ NH ₂ ] CONHMe 1088 CH ₂ SO ₂ NH- (4-NH ₂ Ph) 1115 CONH-SCH [(CH ₂ ) ₂ NH ₂ ] CONHMe 1089 2-imidazolyl 1116 CONHMe 1090 2-oxazolyl 1117 CONHCH ₂ CONMe ₂ 1091 2-thiazolyl 1118 CONHCH ₂ CONHEC 1092 2-benzimidazolyl 1119 CONHCH ₂ CONECT ₂ 1093 CONH-R-CH (CH3) Ph 1120 CONHCH ₂ CONHcyclopropyl 1094 CONH-S-CH (CH3) Ph 1121 CONHCH ₂ CONHcyclobutyl 1095 CONHCH ₂ CONHMe 1122 CONHCH ₂ CONHcyclopentyl 1096 CONH-SCH _(CH3) CONHMe 1123 CONHCH ₂ CONHcyclohexyl 1097 CONH-RCH (CH 3) CONHMe 1124 CONHCH ₂ CONH-tert-butyl 1098 CONH-S-CHC2propyl) CONHMe 1125 CONH-SCH (CH ₂ Ph) CONHMe 1099 CONH-SCH (CH 2 OH) CONHMe 1126 CONH-S-CH _(CH2 -pMeOPh) CONHMe 1100 CONH-CHC (CH ₂ OH, CONHMe 1127 CONHCH ₂ CH ₂ CONHMs 1101 CONH-RCH (CH ₂ OH) CONHMe 1128 CONHCH ₂ CH ₂ CH ₂ CONHMe 1102 CONH-S-CH (CH ₂ O-tBu) CONHMe 1129 CONH-SCH (CH ₂ CH ₂ OH) CONHMe 1103 CONH-R-CH (CH ₂ O-tBu) CONHMe 1130 CONH-S (CH (CH ₂ ) 3 CH 3) CONHMe 1104 CONH-CH (Ph) ₂ 1131 CONH (CH ₂ ) ₂ CO ₂ Me 1105 CO-L-proline -NHMe 1132 CONH (CH ₂ ) ₂ CO ₂ H 1106 CONHCH ₂ CO (Npiperazine) 1133 CONH-SCH [(CH ₂ ) 3 NHBOC) CO ₂ Me 1134 CONHCH ₂ CO (N-methyl-N-oiperazinyl) '1144 CONH-S-CH ((CH ₂ ) 3 NHBOC] CONHMe 1135 CONHCH ₂ CO (N-acetyl-N-Diperazinyl) 1145 CONH-S-CH [(CH ₂ ) 3 NH ₂ CO ₂ Me

236

1136 CONHCH2CO-N morpholino 1146 CONH-SCH ((CH2) 4NH2) CONH2 1137 CONHCH 3 CO-1 N- (4-hydroxy-thioeridin)} 1147 CONH (CH2) 2 Ph 1138 CO 2 H 1148 CONH (CH2> 2- (3,4-dimethoxyphenyl)) 1139 CONHBn 1149 CONH (CH 2) 2 (Nmorpholino) 1140 CONH-2-pyridyl 1150 CONH (CH 2) 3- (N 'morpholino) 1141 CON-Ph 1151 CONHCH2CONH- (2pvridvl) 1142 CONH-3-pyridyl 1152 CONHCH2CONH- (3pvridvl) 1143 CONH-4-pyridyl 1153 CONHCH2-Upyridvl) 1144 CONH-CHjCH (Ph) J 1154 CONH (CH) ₂ (L-SO ₂ NHjPh)

237

her

Table 11

For cyclic carbamates

Pr. R ² (CI-MS) EB Pr. R ² (CI-MS) tas 1163 CO ₂ Me 1177 CONH-cyclopentyl 1164 CO ₂ Et 1178 CONH ₂ 1165 CO ₂ iPr 1179 CONHiPr 1166 CO ₂ (CH ₂ ) ₂ OMe 1180 CON t-bucyl 1167 CO ₂ (CH ₂ ) ₂ Ph 1181 CONMe ₂ 1168 CO ₂ -tBu 1182 CONEe ₂ 1169 CO ₂ CH ₂ CONHMe 1183 CONH-3-indazolyl 1170 ch ₂ oh 1184 CON-adamantyl 1171 CH ₂ OCH ₂ CH 3 1185 CONHCH ₂ (p-SO ₂ NH ₂ Ph) 1172 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 1186 CONH _(CH2) 3-imidazolyl 1173 CHOBn 1187 CONHSO ₂ NH ₂ 1174 CONH (CH ₂ ) ₂ -2-pyridyl 1188 CONHSO2CH3 1175th CO (N-morpholinyl) 547.4 1189 CONHSO ₂ Ph 1176 CO (N-Me-NpiDerazinvl) 560.4 1190 CONHSO ₂ Bn

238

1191 CONH (CH 2) 2 - (N-Me-NpiDerazinyl) 1218 CONHSO2-N-Meimidazolyl 1192 CON-cyclopropyl 1219 CONHSO2-p-NH2Ph 1193 CON-cyclobutyl 1220 CONHSO2-p-MeOPh 1194 CONHSO2-p-F-Ph 1221 CONH-S-CH (CH? CH (CH 3) 2] CONHMe 1195 CONH (CH2) 2NHSO2Me 1222 CONH (CH2) 4NHSO2Me 1196 CONH-cyclohexyl 1223 CONHÍCH2) 6NHSO2Me 1197 CONH-2-imidozolyl 1224 CONH-R-CH (CH2CHCCH3) 2] CONHMe 1198 CH2SO2NHCH3 1225 CONH-S-CH [(CH 2) 4 NH 2] CONHMe 1199 CH2SO2NHPh 1226 CONH-SCH [(CH 2) 3 NH 2] CONHMe 1200 CH2SO2NH- (4-NH2Ph] 1227 CONH-SCH ((CHP) 2NH2) CONHMe 1201 2-imidazolyl 1228 CONHMe 491.5 1202 2-oxazolyl 1229 CONHCH2CONMe2 1203 2-thiazolyl 1230 CONHCH2CONHEC 1204 2-benzimidazolyl 1231 CONHCH2CONEC2 1205 CONH-R-CH (CH3) Ph 1232 CONHCH2CONKcyklopropyl 1206 CONH-S-CH (CH3) Ph 1233 CONHCH2CONHcyklobutyl 1207 CONHCH2CONHMe 1234 CONHCH2CONHcyklopentyl 1208 CONH-S-CH (CH3) CONHMe 1235 CONHCH2CONHcyklohexyl 1209 CONH-R-CH (CH3) CONHMe 1236 CONHCH2-t. bucyl 1210 CONH-S-CH (2 'propyl) CONHMe 1237 CONH-SCH (CH 2 Ph) CONHMe 1211 CONH-SCH (CH 2 OH) CONHMe 1238 CONH-S-CH (CH2-PMeOPh) CONHMe 1212 CONH-SCH (CH 2 OH) CONHMe 1239 CONHCH2CH2CONHMe 1213 CONH-RCH (CH 2 OH) CONHMe 1240 CONHCH2CH2CH2CONHMe 1214 Čonka-S-CH (CH2O-CMA) CONHMe 1241 CONH-SCH (CH 2 CH 2 OH) CONHMe 1215 CONH-R-CH (CH 2 O t Bu) CONHMe 1242 CONH-S (CH (CH2) 3CH3) CONHMe 1216 CONH-CH (Ph) 2 1243 CONH (CH2) 2CO2Me 1217 CO-L-proline -NHMe 1244 CONH (CH2) 2CO2H

239

1245 CONKCH2CO (Npiperazinyl) 1256 CONH-SCH [(CH ₂ ) 3 NHBOOCO ₂ M e 1246 CONHCH ₂ CO (N-methyl-N-piperazinyl) 1257 CONH-SCH ((CH ₂ ) 3 NHBOCJCONH Me 1247 CONHCH ₂ CO (N-acetyl-N-dierazinyl) 1258 CONH-S-CH [(CH ₂ ) 3 NH ₂ ] CO ₂ He 1248 CONHCH ₂ CO-N-morpholinolinol 1259 CONH-SCH [(CH ₂ ) 4 NH 2) CONH 2 1249 CONHCH2CO- [N- (4hvdroxvoiperidinyl) 1 1260 CONH (CH2) 2 Ph 1250 CO ₂ H 1261 CONH (CH 2) 2- (3,4, dixnethoxyphenyl) 1251 CONHBn 1262 CONH (CH2) 2 (N-morpholino) 1252 CONH-2-pyridyl 1263 CONH _(CH2) 3- (N-morpholino). - 1253 CON-Ph 1264 CONHCH2CONH- (2-pyridyl) 1254 CONH-3-pyridyl 1265 CONHCH2CONH- (3-pyridyl) 1255 CONH-4-pyridyl 1266 CONHCH2CONH- (4pvriävl) 1256 CONH-CH3CH (Ph), 1267 CONH (CH3), (P-SO3NH3Ph)

240

Table 12

For cyclic carbaniate:

Pr. R ² (CI-MS) no Pr. R ² (CI-MS) no 1277 CO2M 1292 CONH-cyclopentyl 1278 CO2EC 1293 CONH2 1279 CO2ÍPr 1294 CONHiPr 1280 CO 2 (CH 2) 2 OMe 1295 CONH-tert-butyl 1281 CO ₂ (CH 2) 2 ^p h 1296 CONMe2 1282 CO2-Bu 1297 CONEt2 1283 CO2CH2CONHMe 1298 CONH-3-indazolyl 1284 CH 2 OH 1299 CON-adamantyl 1285 CH2OCH2CH3 1300 CONHCH2 (P-SO2NH2Ph) 1286 CH2OCH2CH2CO2CH3 1301 CONH (CH2) 3-1imidazolyl 1287 CHOBn 1302 CONHSO2NH2 1288 CONH (CH2) 2-2-pyridyl 1303 CONHSO2CH3 1289 CO (N-morpholinyl) 1304 CONHSO2Ph 1290 CO (N-Me-Npiperazinyl) 1305 CONHSO2Bn 1291 CONH (CH2) 2 (N-Me-NpiDerazinvl, 1306 CONHSO2-N-Meimidazolyl 1307 CON-cyclopropyl 1333 C0NHSO2-p-NH2Ph

2.41.

1308 CONH-cyclobutyl 1 1334 CONHSO ₂ -p-MeOPh 1309 CONHSO ₂ -pF-Ph 1335 CONH-S-CH (CH ₂ CH (CH 3) 2 JCONHMe 1310 CONH (CH ₂ ) ₂ NHSO ₂ Me 1336 CONH (CH ₂ ) 4 NHHSO ₂ Me 1311 CONH-cyclohexyl 1337 CONH (CH ₂ ) 6 NHHSO ₂ Me 1312 CONH-2-imidozolyl 1338 CONH-P.-CH [CH ₂ CH (CH 3) 2] CONHMe 1313 CH2SO2NHCH3 1339 CONH-S-CH ((CH ₂ ) 4 NH ₂ ) CONHMe 1314 CH ₂ SO ₂ NHPh 1340 CONH-SCH [(CH 2) 3 NH 2 CONHMe 1315 CH2SO2NK- (4-NH ₂ Ph] 1341 CONH-SCH ((CH ₂ ) 2 NH 2) CONHMe 1316 2-imidazolyl 1342 CONHMe · - 1317 2-oxazolyl 1343 CONHCH ₂ CONMe ₂ 1318 2-thiazolyl 1344 CONHCH2CONHEC 1319 2-benzinu.dazolyl 1345 CONHCH2CONEt2 1320 CONH-R-CH (CH3) Ph 1346 CONHCH ₂ CONHcyclopropyl 1321 CONH-S-CH (CH 3) Ph 1347 CONHCH ₂ CONHcyclobutyl 1322 CONHCH ₂ CONHMe 1348 CONHCH ₂ CONHcyclopentyl 1323 CONH-S-CH (CH3) CONHMe 1349 CONHCH ₂ CONHcyclohexyl 1324 CONH-R-CH (CH3) CONHMe 1350 CONHCH ₂ CONH-tert-butyl 1325 CONH-S-CH (2-propyl) CONHMe 1351 CONH-SCH (CH ₂ Ph) CONHMe 1326 CONH-SCH (CH 2 OH) CONHMe 1352 CONH-S-CH _(CH2 -pMeOPh) CONHMe 1327 CONH-CHC (CH ₂ OH) CONHMe 1353 CONHCH ₂ CH ₂ CONHMe 1328 CONH-RCH (CH ₂ OH) CONHMe 1354 CONHCH ₂ CH ₂ CH ₂ CONHMe 1329 CONH-S-CH (CH ₂ O-tBu) CONHMe 1355 CONH-SCH (CH ₂ CH ₂ OH) CONHMe 1330 CONH-R-CH (CH ₂ O-tBu) CONHMe 1356 CONH-S (CH (CH ₂ ) 3 CH 3) CONHMe 1331 CONH-CH (Ph) 2 1357 CONH (CH ₂ ) ₂ CO ₂ Me 1332 CO-L-proline -NHMe 1358 CONH (CH ₂ ) 2 ^C 2 H 1359 CONHCH ₂ CO (Noiperazinyl) 1370 CONH-S-CH ((CH ₂ ) 3 NHBOC] CO ₂ Me 1360 CONHCH ₂ CO IN-met. yl-N-DÍDerazinyl) 1371 CONH-S-CH ((CH ₂ ) 3 NHBOC] CONHMe 1361 CONHCH ₂ CO (N-Acetyl N-DiDerazinyl) 1372 CONH-S-CH ((CH ₂ ) 3 NH ₂ ) CO ₂ Me

242

1362 CONHCH ₂ CO-Nmorpholino 1373 SCHF CONH _(CH2) 4NH2JCONH2 1363 CONHCH ₂ CO- (N- (4-hydroxypiDeridinvl)) 1374 CONH _{(CH2) 2} Ph 1364 co ₂ h 1375 CONH _(CH2) 2- (3,4, dimethoxy phenyl) 1365 CONHBn 1376 CONH (CH ₂ ) ₂ - (Nmorpholino ·) 1366 CONH-2-pryidyl 1377 CONH (CH ₂ ) 3 - (Nmorpholino) 1367 CON-Ph 1378 CONHCH ₂ CONH- 1368 CONH-3-pyridyl 1379 CONHCH ₂ CONH- (3-pyridyl) 1369 CONH-4-pyridyl 1380 CONHCH ₂ CONH- (4-pyridyl) 1381 CONH-CH3CH (Ph) j 1382 CONH (CH3) 2 (P-SO3NH3Ph)

243 Ď

Table 13

For lactam:

Pr. R ² (CI-MS) you are Pr. R ² (C Msy no 1395 CO2M 1412 CONH-cyclopentyl 1396 CO2ĽC 1413 CONH2 1397 CO2ÍPr 1414 CONHiPr 1398 CO ₂ (CH ₂ ) ₂ OMe 1415 CONH-tert-butyl 1399 CO2 (CH2,2Ph 1416 CONM & 2 1400 CO2 Bu ~ 1417 CONEC2 1401 CO2CH2CONHMe ' 1418 CONH-3-indazolyl 1402 CH 2 OH 1419 CON-adamantyl 1403 CH2OCH2CH3 1420 CONHCH2 (P-SO2NH2Ph) 1404 CH2OCH2CH2CO2CH3 1421 CONH (CH2) 3-imidazolyl 1405 CHOBn 1422 CONHSO2NH2 1406 CONH (CH2) 2-2-pyridy1 1423 CONHSO2CH3 1407 CO (N-morpholinyl) 1424 CONHSO2Ph 1408 CO (N-Me-Npipérazinyl) 1425 CONHSO.2Bn 1409 CONH (CH 2> 2 (N-Me-N-piperazinyl) 1426 CONHSO2-N-Meimidazolyl 1410 CON-cyclopropyl 1427 CONHSO2-p-NH2Ph 1411 CON-cyclobutyl 1428 CONHSO2-p-MeOPh

244

1429 CONHSO ₂ -pF-Ph 1455 CONH-S-CH (CH ₂ CH (CH ₃ ) ₂ ) CONHMe • 1430 CONH (CH ₂ ) ₂ NHSO ₂ Me 1456 CONH (CH ₂ ) 4 NHHSO ₂ Me 1431 CONH-cyclohexyl 1457 CONH (CH ₂ ) 6 NHSO ₂ Me 1432 CONH-2-imidozolyl 1458 CONH-R-CH [CH ₂ CH (CH 3) 2) CONHMe 1433 CH ₂ SO ₂ NHCH 3 1459 CONH-S-CH [(CH ₂ ) 4 NH ₂ ] CONHMe 1434 CH ₂ SO ₂ NHPh 1460 CONH-SCH [(CH ₂ ) 3 NH ₂ ] CONHMe 1435 CH ₂ SO ₂ NH- [4-NH ₂ Ph] 1461 CONH-SCH ((CH ₂ ) ₂ NH _{2 1} CONHMe 1436 2-imidazolyl 1462 CONHMe 385.4 1437 2-oxazolyl 1463 CONHCH ₂ CONMe ₂ 1438 2-thiazolyl 1464 CONHCH ₂ CONHEt 1439 2-benzimidazolyl 1465 CONHCH ₂ CONEt ₂ 1440 CONH-R-CH (CH3) Ph 1466 CONHCH ₂ CONHcyclopropyl 1441 CONH-S-CH (CH3) Ph 1467 CONHCH ₂ CONHcyclobutyl 1442 CONHCH2CONHMe 442.4 1468 CONHCH ₂ CONHcyclopentyl 1443 CONH-S-CH (CH3) CONHMe 456.4 1469 CONHCH ₂ CONHcyclohexyl 1444 CONH-R-CH (CH3) CONHMe 1470 CONHCH ₂ CONH-tert. butyl 1445 CONH-S-CH {2-propyl) CONHMe 1471 CONH-SCH (CH ₂ Ph) CONHMe 1446 CONH-SCH _(CH2 SH) CONHMe 1472 CONH-S-CH _(CH2 -pMeOPh) CONHMe 1447 CONH-SCH (CH ₂ OH) CONHMe 472.4 1473 CONHCH ₂ CH ₂ CONHMe 456.4 1448 CONH-CHC (CH ₂ OH) CONHMe 1474 CONHCH ₂ CH ₂ CH ₂ CONHMe 1449 CONH-S-CH (CH ₂ O-tBu) CONHMe 1475 CONH-SCH (CH ₂ CH ₂ OH) CONHMe 1450 CONH-R-CH (CH ₂ O-tBu) CONHMe 1476 CONH-S (CH (CH ₂ ) 3 CH 3) CONHMe 1451 CONH-CH (Ph) ₂ 147 '# CONH (CH ₂ ) ₂ CO ₂ Me 1452 CO-L-proline -NHMe 1478 CONH (CH ₂ ) ₂ CO ₂ H 1453 CONHCH ₂ CO (NDioerazin) 1479 CONH-S-CH 1 (CH ₂ ) ₃ NHBOC] CO ₂ Me 1454 CONHCH ₂ CO (N-methyl-N-piperazinyl) 1480 CONH-SCH ((CH ₂ ) 3 NHBOC) CONH Me 1481 CONHCH ₂ CO (N-acetyl-N-oiperazinyl) 1490 CONH-S-CH ((CH ₂₎ 3 ^NH 2 l ^{c <)} 2U

245

1482 . CONHCH ₂ CO-N-morpholino 1491 CONH-SCH [(CH 2) 4NH21CONH2 1483 CONHCH ₂ CO- [N- (4-hydroxyDiperidin) 1] 1492 CONH _(CH2) 2 Ph 1484 co ₂ h 1493 CONH (CH ₂ ) ₂ O · 4-dimethoxyphenyl) 1485 CONHBn 1494 CONH _(CH2) 2- (N-morpholino) 1486 CONH-2-pyridyl 1495 CONH (CH ₂ ) 3 - (Nmorpholino) 1487 CON-Ph 1496 CONHCH ₂ CONH- (2-pyridyl) 1488 CONH-3-pyridyl 1497 CONHCH ₂ CONH- (3-pyridyl) 1489th 'CONH-4-pyridyl 1498 CONHCH ₂ CONH- 1490 CONH-CH ₂ CH (Ph) ₂ 1499 CONH (CH j) j (P - SO ₂ NH j Ph) =

• y *.

246

Table 13

For lactam

Pr. R ² (CI-MS) xn b Pr. R ² (CI-MS). xn b 1511 CO2M 1529 CONH- cyclopentyl 1512 CO2EC 1530 CONH2 1513 CO2ÍPr 1531 CONHiPr 1514 CO 2 (CH 2) 2 OMe 1532 CONH- tert. butyl 1515 CO ₂ (CH ₂ ) ₂ Ph 1533 CONMe2 1516 CO2 Bu ~ 1,534 CONEC2 1517 CO2CH2CONHMe 1535 CONH-3-indazolyl 1518 CH 2 OH 1536 CONH-adamanc y1 1519 CH2OCH2CH3 1537 CONHCH2 (P-SO2NH2Ph) 1520 . CH2OCH2CH2CO2CH3 1538 CONH (CH2) 3-1imidazolvl 1521 CHOBn 1539 CONHSO2NH2 1522 CONH (CH 2) 22 -pyridyl 1540 CONHSO2CH3 1523 CO (N-morpholinyl) 1541 CONHS02Ph 1524 CO (N-Me-Npiperazinyl) 1542 CONHSO2Bn 1525 CONH (CH 2) 2 (N-Me -Npiperazinyl) 1543 CONHSO2-N-Meimidazolvl 1526 CONH- cyclopropyl 1544 C0NHSO2-p-NH2Ph 1527 CONH- cyclobutyl 1545 CONHSO2-p-MeOPh 1528 CONHSO2-PF-Ph 1546 CONH-S-CH [CH? CH (CH 3) 2lCONHMe 1547 CONH (CH2) 2NHSO2Me 1573 CONH (CH2) 4NHSO2Me

247

1548 CONH-cyclohexyl 1574 CONH (CH2) 6NHSO2Me 1549 CONH-2-imidozolyl 1575 CONH-R-CH [CH 2 CH (CH 3) 21CONHMe 1550 CH2SO2NHCH3 1576 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 1551 CH2SO2NHPh 1577 CONH-SCH ((CH 2) 3 NH 2) CONHMe 1552 CH2SO2NH- (4-NH2Phl 1578 CONH-SCH ((CH 2) 2 NH 2) CONHMe 1553 2-imidazolyl 1579 CONHMe 1554 2-oxazolyl 1580 CONHCH2CONMe2 1555 2-a. triazolyl 1581 CONHCH2CÓNHEC 1556 2-benzimidazolyl 1582 CONHCH2CONEC2 1557 CONH-R-CH (CH3) Ph 1583 CONHCH2CONHcyklopropyl 1558 CONH-S-CH (CH3) Ph 1584 CONHCH2CONHcyklobutyl 1559 CONHCH2CONHMe 1585 CONHCH2CONHcyklopentyl 1560 CONH-S-CH (CH3) CONHMe 1586 CONHCH2CONHcyklohexyl 1561 CONH-R-CH (CH3) CONHMe 1587 CONHCH2-t. butyl 1562 CONH-S-CH (2-propyl) CONHMe 1588 CONH-SCH (CH 2 Ph) CONHMe 1563 CONH-SCH (CH2 SH) CONHMe 1589 CONH-S-CH (CH2-PMeOPh) CONHMe 1564 CONH-SCH (CH 2 OH) CONHMe 1590 CONHCH2CH2CONHMe 1565 CONH-RCH (CH 2 OH) CONHMe 1591 CONHCH2CH2CH2CONHMe 1566 CONH-S-CH (CH 2 O t Bu) CONHMe 1592 CONH-SCH (CH 2 CH 2 OH) CONHMe 1567 C.ONH-R-CH (CH 2 O-tBu) CONHMe 1593 CONH-S (CH (CH2) 3CH3) CONHMe 1568 CONH-CH (Ph) 2 1594 CONH (CH2) 2CO2Me 1569 CO-b-proline -NHMe 1595 CONH <CH2) 2CO2H 1570 CONHCH2CO (Npiperazinyl) 1596 CONH-S-CH ((CH 2) 3 NHBOC] CO ₂ Me 1571 CONHCH2CO (N-methyl-N-piperazinyl) 1597 CONH-S-CH [(CH 2) 3 NHBOC) CONHMe 1572 CONHCH2CO (N-acetylN pÍDerazinyl) 1598 CONH-S-CH ((CH2> 3NH2) CO2M 1599 CONHCH2CO-N-morpholino 1607 CONH-SCH [(CH 2) 4 NH ₂ ) CONH ₂ 1600 CONHCH2CO- (N- (4hvdroxvpiperidinvl) 1608 CONH (CH2) 2 Ph 1601 CO 2 H 1609 CONH (CH 2) 2 (3,4, dimethoxyphenyl)

248

1602 CONHBn 1610 CONH (CH ₂ ) 2 (N-morpholino) 1603 CONH-2-pyridyl 1611 CONH (CH ₂ ) 3 '(Nmorpholino) 1604 CON-Ph 1612 CONHCH ₂ CONH- (2-pyridyl) 1605 CONH-3-pyridyl 1613 CONHCH ₂ CONK- (3-pyridyl) 1606 CONH-4-pyridyl 1614 CONHCH ₂ CONH- (4-pyridyl) CONH-CH3CH (Ph) j CONH (CH3), (P-SO3NH3Ph)

240

Table 14

Pir. R ² (CI-MS) , ae Pi. R ² (CI-MS) and 1625 CO ₂ Me 1642 CONH- cyclopentyl 1626 CO ₂ Et 1643 CONH ₂ 1627 CO ₂ Ír 1644 CONHiPr 1628 CO ₂ (CH ₂ ) ₂ OMe 1645 CONH- tert-butyl 1629 CO ₂ (CH ₂ ) ₂ Ph 1646 CONMe ₂ 1630 CO ₂ -tBu 1647 CONEt ₂ 1631 CO ₂ CH ₂ CONHMe 1648 CONH-3-indazolyl 1632 CH ₂ OH 1649 CON-adamantyl 1633 CH ₂ OCH ₂ CH 3 1650 CONHCH 2 (p-SO ₂ NH ₂ -Ph) 1634 CH2OCH2CH2CO2CH3 1651 CONH (CH ₂ ) 3 -imidazolyl 1635 CHOBn 1652 CONHSO ₂ NH ₂ 1637 CONH _(CH2) 2-2-pyridyl 1653 CONHSO2CH3 1638 CO (N-morpholinyl) 1654 CONHS0 ₂ Ph 1639 CO (N-Me-Noiperazinvl) 1655 CONHSO ₂ Bn 1640 CONH (CH ₂ ) 2 '(N-Me-Npioerazin) 1656 CONHSO ₂ -N-Methylidazolyl 1641 CON-cyclopropyl 1657 CONHSO ₂ -p-NH ₂ Ph 1658 CON-cyclobutyl 1686 CONHSO ₂ -p-MeOPh •

2

1659 CONHSO2-p-F-Ph 1687 CONH-S-CH [CH 2 CH (CH 3) 2ICONHMe 1660 CONH (CH2) 2NHSO2Ms 1688 CONH (CH2) 4NHSO2Me 1661 CONH-cyclohexyl 1689 CONH (CH2) 6NHSO2Me 1662 CONH-2-inú.äozoiyl 1690 CONH-R-CH [CH 2 CH (CH 3) 2) CONHMe 1663 CH2SO2NHCH3 1691 CONH-S-CH [(CH2> 4NH2ICONHMe) 1664 CH2SO2NHPh 1692 CONH-SCH [(CH 2) 3 NH 2 ICONHMe 1665 CH2SO2NH- [4-NH2Ph] 1693 CONH-SCH 1 (CH 2) 2 NH 2 ICONHMe 1666 2-imidazolyl 1694 CONHMe 1667 2-oxazolyl 1695 CONHCH2CONMe2 1668 2-i. triazolyl 1696 CONHCH2CONHEt 1669 2-benzimidazolyl 1697 CONHCH2CONEt2 1670 CONH-R-CH (CH3) Ph 1698 CONHCH2CONHcyklopropyl 1671 CONH-S-CH (CH3) Ph 1699 CONHCHpCÔNH- cyclobutyl 1672 CONHCH2CONHMe 1700 CONHCH2CONHcyklopentyl 1673 CONH-S-CH (CH3) CONHMe 1701 CONHCH2-cyclohexyl 1674 CONH-R-CH (CH3) CONHMe 1702 CONHCH2 -.- butyl, 1675 CONH-S-CH (2proDvlICONHMe 1703 CONH-S-CH (CH2 Ph) CONHMe 1676 CONH-SCH (CH 2 OH) CONHMe 1704 CONH-S-CH (CH2-PMeOPhICONHMe 1677 CONH-SCH (CH 2 OHICONHMe 1705 CONHCH2CH2CONHMe 1678 CONH-RCH (CH 2 OHICONHMe 1706 CONHCH2CH2CH2CONHMe 1679 CONH-S-CH (CH 2 O t Bu) CONHMe 1707 CONH-SCH (CH 2 CH 2 OH) CONHHe 1680 CONH-R-CH (CH 2 O t Bu) CONHMe 1708 CONH-S (CH (CH2) 3CH3) CONHMe 1681 CONH-CH (Ph) 2 1709 CONH (CH 2) 2 ^c &gt; 2Me 1682 CO-L-proline -NHMe 1710 CONH (CH2) 2CO2H 1683 CONHCH2CO (Npiperazinyl) 1711 CONH-SCH [(CH 2) 3 NHBOC] CO 2 Me 1684 CONHCH 2 CO (N-methyl-N-oioerazinyl) 1712 CONH-SCH [(CH 2) 3 NHBOC) CONHMe 1685 CONHCH2CO (N-acetylN oioerazinvl) 1713 CONH-S-CH (<CH2) 3NH2lCO2Me 1714 CONHCH2CO-Nmorfolinoi 1722 CONH-SCH [(CH 2) 4 NH 2 CONH 2 1715 CONHCH2CO- (N- (4hvdroxvoiperidinvl) 1 1723 CONH (CH2) 2 Ph

251

1716 co ₂ h 1724 CONH _(CH2) 2- (3,4, dimethoxy phenyl) 1717 CONHBn 1725 CONH (CH 2) 2 - (N-morpholino) 1718 CONH-2-pyridyl 1726 CONH (CH2) 3 (N-morpholino) 1719 CON-Ph 1727 CONHCH2CONH- (2-pyridyl) 1720 CONH-3-pyridyl 1728 CONHCH2CONH- (3-pyridyl) 1721 CONH-4-pyridyl 1729 CONHCH2CONH- (4-pyridyl) 1722 CONH-CH ₂ CH (Ph) ₂ 1730 CONH (CH ₃ ) 3 (P-SO 3 NH 3 -Ph)

252

Table 15

For lactam

Pr. R ² (CI-MS) BB Pr. R ² (CI-MS) BB 1740 CO ₂ Me 1758 CON-cyclopentyl 1741 CO ₂ Et 1759 CONH2 1742 CO ₂ iPr 1760 CONHiPr 1743 CO ₂ (CH ₂ ) 2 OMe 1761 CONH-tert-butyl 1744 CO2 _(CH2) 2 Ph 1762 CONMe ₂ 1745 CO ₂ -tBu 1763 CONEC2 1746 CO ₂ CH ₂ CONHMe 1764 CONH-3-indazolyl 1747 CH ₂ OH 1765 CON-adamantyl 1748 CH2OCH2CH3 1766 CONHCH 2 (p-SO ₂ NH ₂ -Ph). 1749 CH2OCH2CH2CO2CH3 1767 CONH (CH ₂ ) 3 -imidazolyl 1750 CHOBn 1768 CONHSO ₂ NH ₂ 1751 CONH (CH ₂ ) ₂ -2-pyridyl 1769 CONHSO2CH3 1752 CO (N-morpholinyl) 1770 CONHSO ₂ Ph 1753 CO (N-Me-Npiperazinyl) 1771 CONHSO ₂ Bn 1754 .CONH (CH 2) 2 "(N-Me-Npiperazinyl) 1772 CONHSO ₂ -N-Meimidazolyl 1755 CON-cyclopropyl 1773 CONHSO2-p-NH ₂ -Ph 1756 CONH - cyclobutyl 1774 CONHSO ₂ -p-MeOPh 1757 CONHSO2-p-F-Ph 1775 CONH-S-CH [CH ₂ CH (CH 3) 2) CONHMe

253

1776 CONH (CH2) 2NHSO2Me 1804 CONH (CH2) 4NHSO2Me 1777 CONH-cyclohexyl 1805 CONH (CH2) 6NHSO2Me 1778 CONH-2-imidozolyl 1806 CONH-R-CH [CH 2 CH (CH 3) 2) CONHMe 1779 CH2SO2NHCH3 1807 CONH-S-CH [(CH 2) 4 NH 2 CONONHMe 1780 CH2 SO ₂ NH-Ph 1808 CONH-SCH [(CH 2) 3 NH 2) CONHMe 1781 CH2SO2NH- [4-NH2Ph) 1809 CONH-SCH ((CH 2) 2 NH 2) CONHMe 1782 2-imidazolyl 1810 CONHMe 1783 2-oxazolyl 1811 CONHCH2CONMe2 1784 2-thiazolyl 1812 CONHCH2CONHEt 1,785 2-benzimidazolyl 1813 CONHCH2CONEC2 1786 CONH-R-CH (CH3) Ph 1814 CONHCH2CONHcyklopropyl 1787 CONH-S-CH (CH3) Ph 1815 CONHCH2-cyclobutyl 1788 CONHCH2CONHMe 1816 CONHCH2CONHcyklopentyl 1789 CONH-S-CH (CH3) CONHMe 1817 CONHCH2-cyclohexyl 1790 CONH-R-CH (CH3) CONHMe 1818 CONHCH2 "t-butyl] 1791 CONH-S-CH (2-propyl) CONHMe 1819 CONH-S-CH (CH 2 Ph) CONHMe 1792 CONH-SCH (CH 2 OH) CONHMe 1820 CONH-S-CH (CH2-PMeOPh) CONHMe 1793 CONH-SCH (CH 2 OH) CONHMe 1821 CONHCH2CH2CONHMe 1794 CONH-RCH (CH 2 OH) CONHMe 1822 CONHCH2CH2CH2CONHMe 1795 CONH-S-CH (CH2O-CMA) CONHMe 1623 CONH-SCH (CH 2 CH 2 OH) CONHMe 1796 CONH-R-CH {CH 2 O t Bu) CONHMe 1824 CONH-S (CH (CH2) 3CH3) CONHMe 1797 CONH-CH (Ph) 2 1825 CONH (CH2) 2 ^ 02Me 1798 CO-L-proline -NHMe 1826 CONH (CH2) 2CO2H 1799 CONHCH2CO (Npiperaj; ynyl) 1827 CONH-SCH [(CH 2) 3 NHBOC] CO 2 Me 1800 CONHCH 2 CO (N-methyl N-oiperazinyl) 1828 CONH-SCH ((CH 2) 3 NHBOCJCONHMe) 1,801th CONHCH2CO (N-acetylN oÍDerazinyl) 1829 CONH-S-CH [(CH2) 3NH2] CO2M 1802 CONHCH2CO-N-morpholino 1830 CONH-SCH ((CH 2) 4 NH 2 CONH 2) 1803 CONHCH 2 CO- (N- (4-hydroxypiperidinyl) 1) 1831 CONH (CH 2) 2 ^p h 1832 CO ₂ H 1838 CONH (CH2) 2d4, dimethoxyphenyl)

254

1833 CONHBn 1839 CONH (CH ₂ ) 2 (NmordFolino) 1834 CONH-2-pyridyl 1840 CONH _(CH2, 3- (N-morpholino) 1835 CON-Ph 1841 CONHCH ₂ CONH- ( _2- pyridyl) 1835 CONH-3-pyridyl 1842 CONHCH ₂ CONH- 1837 CONH-4-pyridyl 1843 CONHCH ₂ CONH- (4-pyridyl) 1838 CONH-CH, CH (Ph), 1844 CONH (CH 2), (P-SO, NH, -Ph)

255

Table 16 in i. I. c amine:

Pr. R ² (CI-MS) Breakfast Pr. R ² (CI-MS) races 1860 CO ₂ Me 1878 CONH-cyclopentyl 1861 CO ₂ Ec 1879 CONH ₂ 1862 CO ₂ iPr 1880 CONHiPr 1863 CO ₂ (CH ₂ ) ₂ OMe 1881 CONH-tert-butyl 1864 CO ₂ (CH ₂ ) ₂ Ph 1882 CONMe ₂ 1865 CO ₂ -tBu 1883 CONEt ₂ 1866 CO ₂ CH ₂ CONHMe 1884 CONH-3-indazolyl 1867 CH ₂ OH 1885 CON-adamantyl 1868 CH ₂ OCH ₂ CH 3 1886 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 1869 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 1887 CONH _(CH2) 3-1inddažolyl 1870 CHOBn 1888 CONHSO ₂ NH ₂ 1871 CONH (CH ₂ ) ₂ -2-pyridyl 1889 CONHSO ₂ CH3 1872 CO (N-morpholinyl) 1890 CONHS0 ₂ Ph 1873 CO (N-Me-Npiperazinvl) 1891 CONHSO ₂ Bn 1874 CONH (CH ₂ ) ₂ - (N-Me-Npiperazinyl) 1892 CONHSO ₂ -N-Meimidazolyl 1875 CON-cyclopropyl 1893 CONHSO2-p-NH ₂ -Ph 1876 CON-cyclobutyl 1894 CONHSO ₂ -p-MeOPh 1877 CONHSO ₂ -pF-Ph 1895 CONH-S-CH [CH ₂ CH (CH 3) 2 CONHMe 1896 CONH (CH ₂ ) ₂ NHSO ₂ Me 1924 CONH _(CH2) 4NHSO2Me

256

1897 CONH-cyclohexyl 1925 CONH (CH ₂ ) 6 NHSO ₂ Me 1898 CONH-2-imidozolyl 1926 CONH-R-CH (CH ₂ CH (CH 3) ₂ ) CONHMe 1899 CH2SO2NHCH3 1927 CONH-S-CH ((CH ₂ ) 4 NH ₂ ) CONHMe 1900 CH ₂ SO ₂ NHPh 19:28 CONH-S- * CH ((CH ₂ ) 3 NH ₂ ) CONHMe 1901 CH ₂ SO ₂ NH- (4-NH ₂ Ph) 1929 CONH-SCH ((CH ₂ ) ₂ NH ₂ JCONHMe 1902 2-imidazolyl 1930 CONHMe 471.4 1903 2-oxazolyl 1931 CONHCH ₂ CONMe ₂ 1904 2-thiazolyl 1932 CONHCH ₂ CONHEt 1905 2-benzimidazolyl 1933 CONHCH ₂ CONEt ₂ 1906 CONH-P.-CH (CH 3) Ph 1934 conhch ₂ concyclopropyl 1907 CONH-S-CH (CH3) Ph 1935 CONHCH ₂ CONH-cyclobutyl 1908 CONHCH2CONHME 1936 CONHCH ₂ CONHcyclopentyl 1909 CONH-S-CH (CH3) CONHMe 1937 CONHCH ₂ CONH-cyclohexyl 1910 CONH-R-CH (CH3) CONHMe 1938 CONHCH2CONH · tert. butyl 1911 CONH-S-CH (2DroDyl) CONHMe 1939 CONH-S-CH (CH ₂ Ph) CONHMe 1912 CONH-SCH _(CH2 SH) CONHMe 1940 CONH-S-CH _(CH2 -pMeOPh) CONHMe 1913 CONH-SCH (CH ₂ OH) CONHMe 1941 CONHCH ₂ CH ₂ CONHMe 1914 CONH-RCH (CH ₂ OH) CONHMe 1942 CONHCH ₂ CH ₂ CH ₂ CONHMe 1915 CONH-S-CH (CH ₂ O-tBu) CONHMe 1943 CONH-SCH (CH ₂ CH ₂ OH) CONHMe 1916 CONH-R-CH (CH ₂ O-tBu) CONHMe 1944 CONH-S (CH (CH ₂ ) 3 CH 3) CONHMe 1917 CONH-CH (Ph) ₂ 1945 CONH (CH ₂ ) ₂ CO ₂ Me 1918 CO-L-proline -NHMe 1946 CONH (CH ₂ ) ₂ CO ₂ H 1919 CONHCH ₂ CO (NoiDerazinyl) 1947 CONH-SCH [(CH ₂ ) 3 NHBOC) CO ₂ Me 1920 CONHCH ₂ CO (N-methyl-N-piperazinyl) 1948 CONH-SCH [(CH ₂ ) 3 NHBOC) CONHMe 1921 CONHCH ₂ CO (N-acetyl-N-piperazinyl) 1949 CONH-S-CH [(CH ₂ ) 3 NH ₂ CO ₂ Me 1922 CONHCH ₂ CO-N: morpholinol 1950 CONH-SCH ((CH ₂ ) 4 NH ₂ ) CONH ₂ 1923 CONHCH ₂ CO- (N- (4-hydroxymorpholinyl)) 1951 CONH _(CH2) 2 Ph 1952 co ₂ h 1958 CONH _(CH2) 2 (3,4, dimethoxy. Phenyl) 1953 CONHBr 1959 CONH (CH ₂ ) ₂ - (N-morpholinyl.)

257

1954 CONH-2-pryidyl 1960 CONH (CH2) 3 (N-morpholino) 1955 CON-Ph 1961 CONHCH2CONH- (2pyridyl) 1956 CONH-3-pyridyl 1962 CONHCH2CONH- (3pvridyl) 1957 CONH-4-pyridyl 1963 CONHCH2CONH- (4pvridyl) CONH-CH2CH (Ph) 2 CONH (CH2) 2 (P-SO2NH2-Ph)

258

Table 17

For cyclic sulphoninide:

Pr. R ² (CI-MS) XEX 8 Pr. R ² (CI-MS) xab 1975 CO2M 1992 CONH-cyclopentyl] 1976 CO ₂ Et 1993 CONH2 • 1977 CO2ÍPr 1994 CONHiPr 1970 CO 2 (CH 2) 2 OMe 1995 CONH-tert-butyl 1979 CO ₂ (CH ₂ ) 2 ^p h 1996 CONMe2 1980 CO2 Bu ~ 1997 CONEt2 1981 CO2CH2CONHMe 1998 CONH-3-indazolyl 1982 CH 2 OH 1999 CON-adamantyl 1983 CH2OCH2CH3 2000 CONHCH2 (p-SO2NH2-Ph) 1984 CH2OCH2CH2CO2CH3 2001 CONH (CH2} 3-1iitiidazolyl 1985 CHOBn 2002 CONHSO2NH2 1986 CONH (CH2) 22-pyridyl 2003 CONHSO2CH3 1987 CO (N-xuorfolinyl) 2004 CONHSO2Ph 1988 CO (N-Me-NpiDerazinyl) 2005 CONHSO2Bn 1989 CONH (CH2) 2- (N-Me-Npiperazinyl) 2006 CONHSO2-N-Meimidazolyl 1990 CONH-cyclopropyl] 2007 CONHSO2-p-NH2Ph 1991 CONH-cyclobutyl] 2008 CONHS02-p-MeOPh 2009 CONHSO2-p-F-Ph 2031 CONH-S-TA ICH2CH (CH 3) 2lCONHMe

259

2010 CONH (CH ₂ ) ₂ NHSO ₂ Me 2032 CONH (CH ₂ ) 4 NHHSO ₂ Me 2011 CONH - cyclohexyl 2033 CONH (CH ₂ ) 6 NHSO ₂ ME 2012 CONH-2-imidozolyl 2034 CONH-R-CH (CH 2 CH (CH 3) ₂ ) CONHMe 2013 CH ₂ SO ₂ NHCH 3 2035 CONH-S-CH [(CH ₂ ) 4 NH ₂ ] CONHMe 2014 CH ₂ SO ₂ NHPh 2036 CONH-SCH [(CH ₂ ) 3 NH ₂ ) CONHMe 2015 CH ₂ SO ₂ NH- [4-NH ₂ pH] 2037 CONH-SCH [(CH 2) 2 NH ₂ ) CONHMe 2016 2-imidazolyl 2038 CONHMe 511.3 2017 2-oxazolyl 2039 CONHCH ₂ CONMe ₂ 2018 2-C thiazolyl 2040 CONHCH ₂ CONHEC 2019 2-benzimidazolyl 2041 CONHCH ₂ CONHCH ₂ 2020 CONH-R-CH (CH3) Ph 2042 CONHCH ₂ CONHcyclopropyl 2021 CONH-S-CH (CH 3) Ph 2043 CONHCH ₂ CONH-cyclobutyl 2022 CONHCH ₂ CONHMe 2044 CONHCH ₂ CONHcyclopentyl 2023 CONH-S-CH (CH3) CONHMe 2045 CONHCH ₂ CONH-cyclohexyl 2024 CONH-R-CH (CH3) CONHMe 2046 CONHCH ₂ CONH-tert. butyl 2025 CONH-S-CH (2prooyl) CONHMe 2047 CONH-S-CH (CH ₂ Ph) CONHMe 2026 CONH-SCH _(CH2 SH) CONHMe 2048 CONH-S-CH _(CH2 -pMeOPh) CONHMe 2027 CONH-SCH (CH ₂ OH) CONHMe 2049 CONHCH ₂ CH ₂ CONHMe 2028 CONH-RCH (CH ₂ OH) CONHMe 2050 CONHCH ₂ CH ₂ CH ₂ CONHMe 2029 CONH-S-CH (CH ₂ O-CBu) CONHMe 2051 CONHH-SCH (CH ₂ CH ₂ OH) CONHMe 2030 CONH-R-CH (CH ₂ O-tBu) CONHMe 2052 CONH-SCH _(CH2) 3CH3) CONHMe

260

Tabuika 18

For cyclic sulfonide i

Pr. R ² (CI-MS) and b Pr. R ² (CI-MS) BB 2072 CO ₂ Me 2089 CONH-cyclopentyl 2073 C0 ₂ Et 2090 CONH2 2074 CO ₂ iPr 2091 CONHiPr 2075 CO2 (CH2) 20me 2092 CONH-tert-butyl 2076 CO ₂ (CH ₂ > 2Ph 2093 CONMe ₂ • 2077 CO ₂ -tBu 2094 CONEt ₂ 2078 CO ₂ CH ₂ CONHMe 2095 CONH-3-indazolyl 2079 CH ₂ OH 2096 CON-adamantyl 2080 CH2OCH2CH3 2097 CONHCH 2 (p-SO ₂ NH 2 -Ph) 2081 CH2OCH2CH2CO2CH3 2098 CONH _(CH2> 3-1imidazolyl 2082 CHOBn 2099 CONHSO ₂ NH ₂ 2083 CONH _(CH2) 2-2-pyridyl 2100 CONHSO2CH3 2084 CO (N-; morpholinyl.) 2101 CONHSO ₂ Ph 2085 CO (N-Me-Npiperazinyl) 2102 CONHSO ₂ Bn 2086 CONH (CH ₂ ) ₂ (N-Me-N-piperazinyl) 2103 CONHSO ₂ -N-Meimidazolyl 2087 CON-cyclopropyl 2104 CONHSO ₂ -p-NH ₂ Ph 2088 CON-cyclobutyl 2105 CONHSO2-p-MeOPh 2106 CONHSO ₂ -PF-Ph 2128 CONH-S-CH [CH ₂ CH (CH 3) 21 ^C ° NHMe

and

2107 CONH (CH ₂ ) ₂ NHSO ₂ Me 2129 CONH (CH ₂ ) 4 NHHSO ₂ Me 2108 CONH-cyclohexyl 2130 CONH (CH ₂ ) 6 NHSO ₂ MB 2109 CONH-2-imidozolyl 2131 CONH-R-CH [CH ₂ CH (CH 3) 2) CONHMe 2110 CH2SO2NHCH3 2132 CONH-S-CH [(CH ₂ ) 4 NH ₂ ) CONHMe 2111 CH ₂ SO ₂ NHPh 2133 CONH-SCH [(CH ₂ ) 3 NH ₂ ) CONHMe 2112 CH ₂ SO ₂ NH- (4-NH ₂ pH) 2134 CONH-SCH [(CH ₂ ) ₂ NH ₂ ] CONHMe 2113 2-imidazolyl 2135 CONHMe 503.3 2114 2-oxazolyl 2136 CONHCH ₂ CONMe ₂ 2115 2-thiazolyl 2137 CONHCH ₂ CONHEt; 2116 2-benzimidazolyl 2138 CONHCH ₂ CONH £ t ₂ 2117 CONH-R-CH (CH3) Ph 2139 CONHCH ₂ CONHcyclopropyl 2118 CONH-S-CH (CH3) Ph 2140 CONHCH ₂ CONH-cyclobutyl 2119 CONHCH2CONHMe 2141 CONHCH ₂ CONHcyclopentyl 2120 CONH-S-CH (CH3) CONHMe 2142 CONHCH ₂ CONH-cyclohexyl 2121 CONH-R-CH (CH3) CONHMe 2143 CONHCH ₂ CONHterc.butyl] 2122 CONH-S-CH (2Drooyl) CONHMe 2144 CONH-S-CH (CH ₂ Ph) CONHMe 2123 CONH-SCH _(CH2 SH) CONHMe 2145 CONH-S-CH (CH ₂ PMeOPh) CONHMe 2124 CONH-SCH (CH ₂ OH) CONHMe 2146 CONHCH ₂ CH ₂ CONHMe 2125 CONH-RCH (CH ₂ OH) CONHMe 2147 CONHCH ₂ CH ₂ CH ₂ CONHMe 2126 CONH-S-CH (CH ₂ O-tBu) CONHMe 2148 CONHH-SCH (CH ₂ CH ₂ OH) CONHMe 2127 CONH-R-CH (CH ₂ O-tBu) CONHMe 2149 CONH-SCH _(CH2) 3CH3) CONHMe

262

Table 19

Pr. R ² (CI-MS) n s Pr. R ² (C KS1 no 2164 CO2M 2180 CONH- cyclopentyl 2165 CO2EC 2181 CONH2 2166 CO2ÍPr 2182 CONHiPr 2167 CO2 <CH2) 20me 2183 CONH-tert-butyl 2168 CO2 (CH2) 2 Ph 2184 CONMe2 2169 CC> 2-Bu 2185 CONEC2 2170 CO2CH2CONHMe 2186 CONH-3-indazolyl 2171 CH 2 OH 2187 CON-adamantyl 2172 CH2OCH2CH3 2188 CONHCH2 (p-SO2NH2-Ph) 2173 CH2OCH2CH2CO2CH3 2189 CONH (CH2) 3-1imidazolyl 2174 CHOBn 2190 CONHSO2NH2 2175 CONH (CH 2) 22 -pyridyl 2191 CONHSO2CH3 2176 CO (N-morpholinyl) 2192 CONHSO2Ph 2177 CO (N-Me-NDinerazinvl) 2193 CONHSO2Bn 2178 CONH (CH2) 2 (N-Me-NpiDerazinvl) 2194 CONHSO2-N-Meimidazolyl 2179 CON-cyclopropyl 2195 CONHSO2-p-NH2Ph 2196 CON-cyclobutyl 2219 CONHSO2-p-MeOPh

263

2197 CONHSO ₂ -pF-Ph 2220 CONH-S-CH [Plume (CH 3) 21CONHMe 2198 CONH (CH ₂ ) ₂ NHSO ₂ Me 2221 CONH (CH ₂ ) 4 NHHSO ₂ Me 2199 CON-eyc1ohexýl 2222 CONH _(CH2) 6NHSO2MS 2200 CONH-2-imiäozolyl 2223 CONH-R-CH (CH ₂ CH (CH 3) 2) CONHMe 2201 CH ₂ SO ₂ NHCH 3 2224 CONH-S-CH [(CH ₂₎ 4NH21CONHMe 2202 CH2SO2NHPÍ1 2225 CONH-SCH ((CH ₂ ) 3 NH ₂ J CONHMe 2203 CH2SO2NH- (4-NH2PH) 2226 CONH-SCH ((CH ₂ ) ₂ NH ₂ ) CONHMe 2204 2-iniidazolyl 2227 CONHMe 526.3 2205 2-oxazolyl 2228 CONHCH ₂ CONMe2 ^: 2206 2-thiazolyl 2229 CONHCH2CONHEt 2207 2-benzimidazolyl 2230 CONHCH ₂ CONHCH ₂ 2208 CONH-R-CH (CH3) Ph 2231 CONHCH? CONHcyklopropyl 2209 CONH-S-CH (CH3) Ph 2232 CONHCH ₂ CONH-cyclobutyl 2210 CONHCH ₂ CONHMe 2233 CONHCH2CONHcyklopentyl. 2211 CONH-S-CH (CH3) CONHMe 2234 CONHCH ₂ CONH-cyclohexyl 2212 CONH-R-CH (CH3) CONHMe 2235 CONHCH ₂ CONH-tert. -butvl 2213 Comhat-S-CH (2proDvl) CONHMe 2236 CONH-S-CH (CH ₂ Ph) CONHMe 2214 CONH-SCH _(CH2 SH) CONHMe 2237 CONH-S-CH _(CH2 -pMeOPh) CONHMe 2215 CONH-SCH (CH ₂ OH) CONHMe. 2238 CONHCH2CH ₂ CONHMe 2216 CONH-RCH (CH ₂ OH) CONHMe 2239 CONHCH ₂ CH ₂ CH ₂ CONHMe 2217 CONH-S-CH (CH ₂ O-tBu) CONHMe 2240 CONHH-SCH (CH ₂ CH ₂ OH) CONHMe 2218 CONH-R-CH (CH ₂ O-tBu) CONHMe 2241 CONH-SCH _(CH2) 3CH3) CONHMe

264 ./

Table 20

For cyclic u 1 f ó n a d d

HOHNOC

Pr. R ² (CI-MS) no Pr. R ² (CI-MS) ns 2260 C0 ₂ Me 2276 CONH-cyclopentyl 2261 CO2EC 2277 CONH ₂ 2262 CO ₂ iPr 2278 CONHiPr 2263 CO ₂ (CH ₂ ) ₂ OMe 2279 CONH-tert-butyl 2264 CO ₂ (CH ₂ ) ₂ Ph 2280 CONMe ₂ 2265 CO ₂ -tBu 2281 conec ₂ 2266 CO ₂ CH ₂ CONHMe 2282 CONH-3-indazolyl 2267 CH ₂ OH 2283 CON-adamantyl 2268 CH ₂ CH ₂ CH 3 2284 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 2269 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 2285 CONH _(CH2) 3-1-. imidazolyl 2270 CHOBn 2286 CONHSO ₂ NH ₂ 2271 CONH (CH ₂ ) ₂ -2-pyridyl 2287 CONHSO ₂ CH3 2272 CO (N-: morpholinyl) 2288 CONHSO ₂ Ph 2273 CO (N-Me-Npiperazinyl) 2289 CONHSO ₂ Bn 2274 CONH (CH ₂ ) 2 "(N-Me-Npiperazinyl) 2290 CONHSO ₂ -N-Meimidazolyl 2275 CON-cyklopropy1 2291 CONHSO ₂ -p-NH ₂ Ph

265

2292 CON-cyclobutyl 2315 CONHS02-p-MeOPh 2293 CONHSO2-p-F-Ph 2316 CONH-S-CH (CH 2 CH (CH 3) 21CONHMe 2294 CONH (CH2) 2NHSO2Me 2317 CONH (CH2) 4NHSO2Me 2295 CONH-cyclohexyl 2318 CONH (CH2) 6NHSO2MS 2296 CONH-2-imidozolyl 2319 CONH-R-CH (CH 2 CH (CH 3) 2lCONHMe 2297 CH2SO2NHCH3 2320 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 2298 CH2SO2NHPh 2321 CONH-SCH ((CH 2) 3 NH 2 CONHMe) 2299 CH2SO2NH- (4-NH2PH] 2322 CONH-SCH [(CH 2> 2NH 21 CONHMe 2300 2-imidazolyl 2323 CONHMe 553.5 2301 2-oxazolyl 2324 CONHCH2CONMe2 2302 2-thiazolyl 2325 CONHCH2CONHEt 2303 2-benzimidazolyl 2326 CONHCH2CONHEC2 2304 CONK-P.-CH (CH 3) Ph 2327 CONHCH2CONHcyklopropyl 2305 CONH-S-CH (CH3) Ph 2328 CONHCH2-cyclobutyl 2306 CONHCH2CONHMe 2329 CONHCH2CONHcyklopentyl 2307 CONH-S-CH (CH3) CONHMe 2,330 CONHCH2-cyclohexyl 2308 CONH-R-CH (CH3) CONHMe 2331 CONHCH2-t. butyl 2309 CONH-S-CH (2DroDvl) CONHMe 2332 CONH-S-CH (CH2 Ph) CONHMe 2310 CONH-SCH (CH 2 OH) CONHMe 2333 CONH-S-CH (CH2-pMeOPh) CONHMe 2311 CONH-SCH (CH 2 OH) CONHMe 2334 CONHCH2CH2CONHMe 2312 CONH-RCH (CH 2 OH) CONHMe 2335 CONHCH2CH2CH2CONHMe 2313 CONH-S-CH (CH 2 O t Bu) CONHMe 2336 CONHH-SCH (CH2CH2OH) CONHMe 2314 CONH-R-CH (CH 2 O-t Bu) CONHMe 2337 CONH-SCH (CH 2) 3 CH 3) CONHMe

266

Table 21

For lactone

Pr. R ² (CI-MS) xae Pr. R ² (CI-MS) no 2350 CO2M 2368 CONH-cyclopentyl 2351 CO2Ec 2369 CONH2 2352 CO2ÍPr 2370 CONHiPr 2353 CO 2 (CH 2) 2 OMe 2371 CONH · -ter c. butyl 2354 CO ₂ (CH ₂ ) 2 Ph 2372 CONMe2 2355 CO ₂ -CBu 2373 CONEC2 2356 CO ₂ CH ₂ CONHMe 2374 CONH-3-indazolyl 2357 ch ₂ oh 2375 CON-adamantyl 2358 CH ₂ OCH ₂ CH 3 2376 CONHCH2 (p-SO2NH2-Ph) 2359 CH2OCH2CH2CO2CH3 2377 CONH (CH 2) 3-1 "imidazolyl 2360 CHOBn 2378 CONHSO2NH2 2361 CONH (CH ₂ ) ₂ -2-pyridyl 2379 CONHSO2CH3 2362 CO (N - r f 01 ir 1) 2380 CONHSO2Ph 2363 CO (N-Me-NDiôerazinvl) 2381 CONHSO2Bn 2364 .CONH _(CH2) 2- (N-Me-NDiDerazinyl) 2382 CONHSO2-N-Meimidazolyl 2365 CON-cyclopropyl 2383 CONHSO2-p-NH2Ph 2366 CON-cyclobutyl 2384 CONHSO2-p-MeOPh 2367 CONHSO2-p-F-Ph 2385 CONH-S-CH [CH 2 CH (CH 3) 2lCONHMe

267

2386 CONH (CH2) 2NHS02Me 2407 CONH (CH ₂ ) 4 NHHSO ₂ Me 2387 CONH-cyclohexyl 2408 CONH (CH ₂ ) 6 NHSO ₂ ME 2388 CONH-2-imidozolyl 2409 CONH-R-CH (CH ₂ CH (CH 3) 2) CONHMe 2389 CH ₂ SO ₂ NHCH 3 2410 CONH-S-CH [(CH ₂ ) 4 NH ₂ ] CONHMe 2390 CH ₂ SO ₂ NHPh 2411 CONH-SCH [(CH ₂₎ 3NH2JCONHMe 2391 CH ₂ SO ₂ NH- (4-NH ₂ pH) 2412 CONH-SCH [(CH ₂ ) ₂ NH ₂ ) CONHMe 2392 2-imidazolyl 2413 CONHMe 372.3 2393 2-oxazolyl 2414 CONHCH ₂ CONMe ₂ 2394 2-i. triazolyl 2415 CONHCH ₂ CONHEC 2395 2-benzimidazolyl 2416 CONHCH ₂ CONHCH ₂ 2396 CONH-R-CH (CH3) Ph 2417 CONHCH ₂ CONHcyclopropyl 2397 CONH-S-CH (CH3) Ph 2418 CONHCH ₂ CONH-cyclobutyl 2398 CONHCH ₂ CONHMe 2419 CONHCH ₂ CONHcycloDentvl 2399 CONH-S-CH (CH3) CONHMe 2420 CONHCH ₂ CONK-cyclobutyl 2400 CONH-R-CH (CH3) CONHMe 2421 CONHCH ₂ CONH-tert. butyl 2401 CONH-S-CH (2Dropyl) CONHMe 2422 CONH-S-CH (CH ₂ Ph) CONHMe 2402 CONH-SCH (CH 2 OH) CONHMe 2423 CONH-S-CH _(CH2 -pMeOPh) CONHMe 2403 CONH-SCH (CH ₂ OH) CONHMe 2424 CONHCH ₂ CH ₂ CONHMe 2404 CONH-RCH (CH ₂ OH) CONHMe 2425 CONHCH ₂ CH ₂ CH ₂ CONHMe 2405 CONH-S-CH (CH ₂ O-CBu) CONHMe 2426 CONHH-SCH (CH ₂ CH ₂ OH) CONHMe 2406 CONH-R-CH (CH ₂ O-tBu) CONHMe 2427 CONH-SCH _(CH2) 3CH3) CONHMe

268 ii

Table 22

Pr. R ² (CI-MS) no Pr. R ² (CI-MS) KB 2440 CO ₂ Me 2458 CONH-cyclopentyl 2441 CO ₂ EC 2459 conh ₂ 2442 CO ₂ iPr 2460 CONHiPr 2443 CO ₂ (CH ₂ ) ₂ OMe 2461 CONH-tert-butyl 2444 CO ₂ (CH ₂ ) ₂ Ph 2462 CONMe ₂ 2445 CO ₂ -tBu 2463 CONEt ₂ 2446 CO ₂ CH ₂ CONHMe 2464 CONH-3-indazolyl 2447 CH ₂ OH 2465 CON-adamantyl 2448 CH ₂ OCH ₂ CH 3 2466 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 2449 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 2467 CONH (CH ₂ ) ₃ -1 -indazolyl 2450 CHOBn 2468 CONHSO ₂ NH ₂ 2451 CONH (CH ₂ ) ₂ -2-pyridyl 2469 CONHSO ₂ CH3 2452 CO (N-morpholinyl) 2470 CONHSO ₂ Ph 2453 C0 (N-Me-Npiperazinvl) 2471 CONHSO ₂ Br 2454 CONH (CH ₂ ) ₂ - (N-Me-Npioerazinyl) 2472 CONHSO ₂ -N-Meimidazolyl 2455 CON-cyklopropy1 2473 CONHSO ₂ -p-NH ₂ Ph 2456 CON-cyclobutyl 2474 CONHSO ₂ -p-MeOPh 2457 CONHSO ₂ -pF-Ph 2475 CONH-S-CH [CH ₂ CH (CH 3) 2) CONHMe 2476 CONH (CH ₂ ) ₂ NHSO ₂ Me 2497 CONH _(CH2) 4NHSO2Me

269

2477 CONH-cyclohexyl 2498 CONH _(CH2) 6NHSO2KE 2478 CONH-2-imidozolyl 2499 CONH-R-CH [CH ₂ CH (CH 3) 2) CONHMe 2479 CH2SO2NHCH3 2500 CONH-S-CH ((CH ₂ ) 4 NH ₂ ) CONHMe 2480 CH ₂ SO ₂ NHPh 2501 CONH-SCH ((CH ₂ ) 3 NH ₂ ) CONHMe 2481 CH ₂ SO ₂ NH- [4-NH ₂ PH] · 2502 CONH-SCH ((CH _{2) 2} NH2JCONHMe 2482 2-imidazolyl 2503 CONHCH ₂ CONHMe 2483 2-oxazolyl 2504 CONHCH ₂ CONMe ₂ 2484 2-thiazolyl 2505 CONHCH ₂ CONHEt 2485 2-benzimidazolyl 2506 CONHCH ₂ CONHCH ₂ 2486 CONH-R-CH (CH3) Ph 2507 CONHCH2CONHcyklopropyl 2487 Čonka-S-CH (CH3) Ph. 2508 CONHCH ₂ CONH-cyclobutyl 2488 CONHCH ₂ CONHMé 2509 CONHCH ₂ CONHcyclopentyl 2489 CONH-S-CH (CH3) CONHMe 2510 CONHCH ₂ CONH-cyclohexyl 2490 CONH-R-CH (CH3) CONHMe 2511 CONHCH ₂ CONH-tert. butyl 2491 CONH-S-CH (2propvl) CONHMe 2512 CONH-S-CH (CH ₂ Ph) CONHMe 2492 CONH-SCH (CH 2 OH) CONHMe 2513 CONH-S-CH (CH2-PMeOPh) CONHMe 2493 CONH-SCH (CH 2 OH) CONHMe 2514 CONHCH2CH ₂ CONHMe 2494 CONH-RCH (CH 2 OH) CONHMe 2515 CONHCH ₂ CH ₂ CH ₂ CONHMe 2495 CONH-S-CH (CH ₂ O-tBu) CONHMe 2516 CONHH-SCH (CH ₂ CH ₂ OH) CONHMe 2496 CONH-R-CH (CH ₂ O-tBu) CONHMe 2517 CONH-SCH _(CH2) 3CH3) CONHMe 2518 CONHMe 387.3 2519 CONHPh 449.3

270

Table 23

Pre laktárn.-

Pr. R ² (CI-MS) well Pr. R ² (CI-MS) no 2530 CO ₂ Me 2547 CONH-cyclopentyl 2531 .CO ₂ Et 2548 CONH ₂ 2532 CO ₂ iPr 2549 CONHiPr 2533 CO ₂ (CH ₂ ) ₂ OMe 2550 CONH-tert-butyl 2534 CO ₂ (CH ₂ ) ₂ Ph 2551 CONMe ₂ 2535 CO ₂ -tBu 2552 CONEt ₂ 2536 CO ₂ CH ₂ CONHMe 2553 CONH-3-indazolyl 2537 CH ₂ OH 2554 CON-adamantyl 2538 CH ₂ OCH ₂ CH 3 2555 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 2539 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 2556 CONH (CH ₂ ) 3 -imidazolyl 2540 CHOBn 2557 CONHSO ₂ NH ₂ 2541 CONH (CH ₂ ) ₂ -2-pyridyl 2558 CONHSO ₂ CH3 2542 CO (N-morpholinyl) 2559 CONHSO ₂ Ph 2543 CO (N-Me-NpiDerazinvl) 2560 CONHSO ₂ Bn 2544 CONH (CH ₂ ) ₂ - (N-Me-Npiperazine) 2561 CONHSO ₂ -N-Meimidazolyl 2545 CON-cyclopropyl 2562 CONHSO ₂ -p-NH ₂ Ph 2546 CONH- cyclobutyl 2563 CONHSO ₂ -p-MeOPh 2564 CONHSO ₂ -pF-Ph 2586 CONH-S-CK {CH ₂ CH (CH 3) ₂ ] CONHMe

271

2565 CONH (CH ₂ ) ₂ NHSO ₂ Me 2587 CONH (CH ₂ ) 4 NHHSO ₂ Me 2566 CONH-cyclohexyl 2588 CONH (CH ₂ ) 6 NHSO ₂ ME 2567 CONH-2-imidozolyi 2589 CONH-R-CH (CH ₂ CH (CH 3) 2 CONHMe) 2568 CH ₂ SO ₂ NHCH 3 2590 CONH-S-CH (CH ₂ ) 4 NH ₂ ) CONHMe 2565 CH ₂ SO ₂ NHPh 2591 CONH-SCH ((CH ₂ ) 3 NH ₂ ) CONHMe 2570 CH ₂ SO ₂ NK- [4-NH ₂ pH] 2592 CONH-SCH [(CH ₂ ) ₂ NH ₂ ] CONHMe 2571 2-imidazolyl 2593 CONHCH2CONHMe 2572 2-oxazolyl 2594 CONHCH ₂ CONMe ₂ 2573 2-thiazolyl 2595 CONHCH ₂ CONHEt 2574 2-benzimidazolyl 2596 CONHCH ₂ CONHCH ₂ 2575 CONH-R-CH (CH) Ph 2597 conhch ₂ conhcyclopropyl 2576 CONH-S-CH (CH3) Ph 2598 CONHCH ₂ CONH-cyclobutyl 2577 CONHCH ₂ CONHMe 2599 conhch ₂ concyclopropyl 2578 CONH-S-CH (CH3) CONHMe 2600 CONHCH ₂ CONH-cyclohexyl 2579 CONH-R-CH (CH3) CONHMe 2601 CONHCH ₂ CONH * tert. butyl 2580 CONH-S-CH (2-propyl) CONHMe 2602 CONH-SC H (CH ₂ Ph) CONHMe 2581 CONH-SCH _(CH2 SH) CONHMe 2603 CONH-S-CH _(CH2 -pMeOPh) CONHMe 2582 CONH-SCH (CH ₂ OH) CONHMe 2604 CONHCH ₂ CH ₂ CONHMe 2583 CONH-RCH (CH ₂ OH) CONHMe 2605 CONHCH ₂ CH ₂ CH ₂ CONHMe 2584 CONH-S-CH (CH ₂ O-tBu) CONHMe 2606 CONHH-SCH (CH ₂ CH ₂ OH) CONHMe 2585 CONH-R-CH (CH ₂ O-tBu) CONHMe 2607 CONH-SCH _(CH2) 3CH3, CONHMe

272

Pr. R ² (CI-MS) BB Pr. R ² (CI-MS) BB 2630 CO ₂ Me 2647 CONH-cyclopentyl 2631 CO ₂ Et 2648 CONH ₂ 2632 CO2ÍPr 2649 CONHiPr 2633 CO2 <CH 2) 2 OMe 2,650 CONH-tert-butyl 2634 CO ₂ (CH ₂ ) ₂ Ph 2651 CONMe ₂ 2635 CO ₂ -tBu 2652 CONEt ₂ 2636 CO ₂ CH ₂ CONHMe 2653 CONH-3-indazolyl 2637 CH ₂ OH 2654 CON-adamantyl 2638 CH ₂ OCH ₂ CH 3 2655 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 2639 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 2656 CONH (CH ₂ ) 3 -imidazolyl 2640 CHOBn 2657 CONHSO ₂ NH ₂ 2641 CONH _(CH2) 2-2-pyriäyl 2658 CONHSO2CH3 2642 CO (N- * iorfolinyl) 2659 CONHSO ₂ Ph 2643 CO (N-Me-NDiDerazinvl) 2660 CONHSO ₂ Bn 2644 CONH (CH ₂ ) ₂ - (N-Me-Npiperazine) 2661 CONHSO ₂ -N-Meimidazolyl 2645 CONH - cyclopropyl 26.62 CONHSO ₂ -p-NH ₂ Ph 2646 CON-cyclobutyl 2663 CONHSO2-p-MeOPh 2664 CONHSO ₂ -pF-Ph 2686 CONH-S-CH (CH ₂ CH (CH 3) 2) CONHMe

273

2665 CONH (CH2) 2NHSO2Me 2687 CONH (CH2) 4NHSO2Me 2666 CONH-cyclohexyl 2688 CONH (CH2) 6NHSO2ME 2667 CONH-2-imidozolyl 2689 CONH-R-CH [CH 2 CH (CH 3) 21CONHMe 2668 CH2SO2NHCH3 2690 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 2669 CH2SO2NHPh 2691 CONH-SCH [(CH 2) 3 NH 2) CONHMe 2670 CH2SO2NH- (4-NH2PH] 2692 CONH-SCH [(CH 2> 2NH 2 J CONHMe 2671 2-imidazolyl 2693 CONHCH2CONHMe 2672 2-oxazolyl 2694 CONHCH2CONMe2 2673 2-a. triazolyl 2695 CONHCH2CONHEC 2674 2-benzimidazolyl 2696 CONHCH2CONHEC2 2675 CONH-R-CH {CH3) Ph 2697 CONHCH2CONHcyklopropyl 2676 CONH-S-CH (CH3) Ph 2698 CONHCH2-cyclobutyl 2677 CONHCH2CONHMe 2699 CONHCH2CONKcyklopentyl 2676 CONH-S-CH (CH3) CONHMe 2700 CONHCH2-cyclohexyl 2679 CONH-R-CH (CH3) CONHMe 2701 CONHCH2CONH-ter c. butyl 2680 CONH-S-CH (2DroDvl) CONHMe 2702 CONH-S-CH (CH 2 Ph) CONHMe 2681 CONH-SCH (CH 2 OH) CONHMe 2703 CONH-S-CH (CF'2-pMeOPh) CONHMe 2682 CONH-SCH (CH 2 OH) CONHMe 2704 CONHCH2CH2CONHMe 2683 CONH-RCH (CH 2 OH) CONHMe 2705 CONHCH2CH2CH2CONHMe 2684 CONH-S-CH (CH 2 O t Bu) CONHMe 2706 CONHH-SCH (CH2CH2OH) CONHMe 2685 CONH-R-CH (CH2O-CMA) CONHMe 2707 CONH-SCH (CH 2) 3 CH 3) CONHMe 2708 [CONHMe 401.6

'274

Table 25

For lactam:

Pr. R ² (CI-MS) no Pr. R ² (CI-MS) 2X8 2730 CO ₂ Me 2747 CONH-cyclopentyl 2731 CO ₂ Et 2748 CONH ₂ 2732 CO ₂ iPr 2749 CONHiPr 2733 CO ₂ (CH ₂ ) ₂ OMe 2750 CONH-tert-butyl 2734 CO ₂ (CH ₂ ) ₂ Ph 2751 CONMe ₂ 2735 CO ₂ -tBu 2752 CONEc ₂ 2736 CO ₂ CH ₂ CONHMe 2753 CONH-3-indazolyl 2737 ch ₂ ok 2754 CON-adaroantyl 2738 CH ₂ OCH ₂ CH 3 2755 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 2739 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 2756 CONH _(CH2) 3-1itnidazolyl 2740 CHOBn 2757 CONHSO ₂ NH ₂ 2741 CONH (CH ₂ ) ₂ -2-pyridyl 2758 CONHSO ₂ CH3 2742 CO (N- morpholinyl) 2759 CONHSO ₂ Ph 2743 CO (N-Me-NoiDerazinvl) 2760 CONHSO ₂ Bn 2744 CONH (CH ₂ ) 2 (N-Me-NDiperazinyl) 2761 CONHSO ₂ -N-Meimidazolyl 2745 CON-cyclopropyl 2762 CONHSO ₂ -p-NH ₂ Ph 2746 CONH- cyclobutyl 2763 CONHSO ₂ -p-MeOPh 2764 CONHSO ₂ -pF-Ph 2786 CONH-S-CH (CH ₂ CH (CH 3) ₂ ) CONHMe

276

2765 CONH (CH2) 2NHSO2Me 2787 CONH (CH2) 4NHSO2Me 2766 CONH-cyclohexyl 2789 CONH (CH2) 6NHSO2ME 2767 CONH-2-imidozolyl 2790 CONH-R-CH [CH 2 CH (CH 3) 2] CONHMe 2768 CH2SO2NHCH3 2791 CONH-S-CH ((CH 2) 4 NH 2) CONHMe 2769 CH2SO2NHPh 2792 CONH-SCH ((CH 2) 3 NH 2) CONHMe 2770 CH2SO2NH- [4-NH2PH] 2793 CONH-SCH ((CH 2) 2 NH 2) CONHMe 2771 2-imidazolyl 2794 CONHCH2CONHMe 2772 2-oxazolyl 2795 CONHCH2CONMe2 2773 2-thiazolyl 2796 CONHCH2CONHEt ^: 2774 2-benzimidazolyl 2797 CONHCH2CONHEt2 2775 CONH-R-CH (CH3) Ph 2798 CONHCH2CONHcyklopropyl 2776 CONH-S-CH (CH3) Ph 2799 CONHCH2-cyclobutyl 2777 CONHCH2CONHMe 2800 CONHCH2CONHcyklopentyj 2778 CONH -S-CH (CH 3) CONHMe 2801 CONHCH 2 CONH-cyclohexyl I 2779 CONH-R-CH (CH3) CONHMe 2802 CONHCH2-t. butyl 2780 CONH-S-CH 2 (Propyl) CONHMe ¹ 2803 CONH-S-CH (CH2 Ph) CONHMe 2781 CONH-SCH (CH 2 OH) CONHMe 2804 CONH-S-CH (CH2-PMeOPh) CONHMe 2782 CONH-SCH (CH 2 OH) CONHMe 2805 CONHCH2CH2CONHMe 2783 CONH-RCH (CH 2 OH) CONHMe 2806 CONHCH2CH2CH2CONHMe 2784 CONH-S-CH (CH 2 O t Bu) CONHMe 2807 CONHH-SCH (CH2CH2OH) CONHMe 2785 CONH-R-CH (CH 2 O t Bu) CONHMe 2808 CONH-SCH (CH 2) 3 CH 3) CONHMe 1 2809 CONHMe 475

276

For lactam:

Pr. R ² (CI-MS) Pr. R ² (CI-MS) TTB 2820 CO ₂ Me 2837 CONH- cyclopentyl 2821 CO ₂ Et 2838 CONH ₂ 2822 CO ₂ iPr 2839 CONHiPr 2823 CO ₂ (CH ₂ ) ₂ 0Me 2840 CONH-tert-butyl 2824 CO ₂ (CH ₂ ) ₂ Ph 2841 CONMe ₂ 2825 CO ₂ -tBu 2842 CONEt ₂ 2826 CO ₂ CH ₂ CONHMe 2843 CONH-3-indazolyl 2827 CH ₂ OH 2844 CON-adamantyl 2828 CH ₂ OCH ₂ CH 3 2845 CONHCH 2 (p-SO ₂ NH ₂ -Ph) 2829 CH2OCH2CH2CO2CH3 2846 CONH (CH ₂ ) 3 -imidazolyl 2830 CHOBn 2847 CONHSO ₂ NH ₂ 2831 CONH _(CH2) 2-2-pyridyl 2848 CONHSO2CH3 2832 CO (N-morpholinyl) 2849 CONHSO ₂ Ph 2833 CO (N-Me-Npioerazinyl) 2850 CONHSO ₂ Bn 2834 CONH _(CH2) 2- (N-Me-NDiDerazinyl) 2851 CONHSO ₂ -N-Meimidazolyl 2835 CON-cyclopropyl 2852 CONHSO ₂ -p-NH ₂ Ph 2836 CON-cyclobutyl 2853 CONHSO ₂ -p-MeOPh 2854 CONHSO ₂ -pF-Ph 2876 CONH-S-CH [CH ₂ CH (CH 3) 21 CONHMe

277

2855 CONH (CH2) 2NHSO2Me 2877 CONH (CH2) 4NHSO2Me 2856 CONH-cyclohexyl 2878 CONH (CH 2) 6 NHSO 2 MM 2857 CONH-2-imidozoles1 2879 CONH-R-CH (CH 2 CH (CH 3) 2] CONHMe 2858 CH2SO2NHCH3 2859 CH2SO2NHPh 2860 CH2SO2NH-I4-NH2PH) 2861 2-imidazolyl 2862 2-oxazolyl 2863 2-thiazolyl 2864 2-benzimidazolyl 2865 CONH-R-CH (CH3) Ph • 2866 CONH-S-CH (CH3) Ph 2867 CONHCH ₂ CONHMe 2868 CONH-S-CH (CH3) CONHMe 2869 CONH-R-CH (CH3) CONHMe 2870 CONH-S-CHC2oropvl) CONHMe 2,871 CONH-SCH _(CH2 SH) CONHMe 2872 CONH-SCH (CH 2 OH) CONHMe 2873 CONH-RCH (CH 2 OH) CONHMe 2874 CONH-S-CH (CH 2 O t Bu) CONHMe 2875 CONH-R-CH (CH2O-CMA) CONHMe

278

Table 27

BOC

HOHNOť

Pr. R ² (CI-MS) ns Pr. R ² (CI-MS) ns 2880 CONHMe 471.5

Table 28

Pf. R ² (CI-MS) ns Pr. R ² (CI-MS) ns 2890 CONHMe 515.4

279 /

Table 29

HOHN

R ²

Pr. R ² (CI-MS) ns Pr. R ² (CI-MS) b 2900 CONHMe 549.3

Table 30

HOHN

R ²

Pr. R ² (CI-MS) IBS Pr. R ² (CI-MS) ns 2910 CONHMe 449.4

HLI

Table 31

HOHN

R ²

Pr. R ² (CI-MS) SXB Rx R ² (C K8) ae 2920 CONHMe 491.4 •

Table 32

Pr. R ² (CI-MS) ae Pr. R ² (CI-MS) ae 2930 CONHCH, CON-morpholino 527.6 2931 CONHCH, CO (N-hydroxypiperidine) 541.7

281

Table 33

HOHN

R ²

px. R ² (CI-MS) xn b Px. R ² (CI-MS) xn b 2940 CONHMe 589.4

Table 34

Pr. R ² (CI-MS) OB Pr. R ² (CI-MS) XZXB 2950 CONHMe 491.2

282

Table 35

HOHN

Pr. R ² (C .HS) ZUB Pr. R ² (CI-MS) b 4000 CO ₂ Me 4054 CONH-cyclopentyl 4001 CO ₂ Et 4055 conh ₂ 4002 CO ₂ iPr 4056 CONHiPr 4003 CO ₂ (CH ₂ ) ₂ OMe 4057 CONH-tert-butyl 4004 CO ₂ (CH ₂ ) ₂ Ph 4058 CONMe ₂ 4005 CO ₂ -tBu 4059 CONEc ₂ 4006 CO ₂ CH ₂ CONHMe 4060 CONH-3-indazolyl 4007 CH ₂ OH 4061 CON-adamantyl 4008 CH ₂ OCH ₂ CH 3 4062 CONHCH ₂ (p-SO ₂ NH ₂ -Ph) 4009 CH ₂ OCH ₂ CH ₂ CO ₂ CH 3 4063 CONH (CH ₂ ) 3 -imidazolyl 4010 CHOBn 4064 CONHSO ₂ NH ₂ 4011 CONH (CH ₂ ) ₂ -2-pyridyl 4065 CONHSO ₂ CH3 4012 CO (N-morpholinyl) 4066 CONHSO ₂ Ph 4013 CO (N-Me-Npiperazinyl) 4067 CONHSO ₂ Bn 4014 CONH (CH ₂ ) ₂ - (N-Me-NpiDerazin) 4068 CONHSO ₂ -N-Meimidazolyl 4015 CON-cyclopropyl 4069 CONHSO ₂ -p-NH ₂ Ph

283

4016 CON-cyclobutyl 4070 CONHSO2-p-MeOPh 4017 CONHSO2-p-F-Ph 4071 CONH-S-CH (CH 2 CH (CH 3) 21CONHMe 4016 CONH (CK2) 2NHSO2He 4072 CONH (CH2) 4NHSO2Me 4015 CONH-cyclohexyl 4073 CONH (CH2) 6NHSO2Me 4020 CONH-2-imidozolyl 4074 CONH-R-CH (CH 2 CH (CH 3) 2 JCONHMe 4021 CH2SO2NHCH3 4075 CONH-S-CH [(CH 2) 4 NH 2] CONHMe 4022 CH2SO2NHPh 4076 CONH-SCH [(CH 2) 3 NH 2 ICONHMe 4023 CH2SO2NK- [4-NH2PhJ 4077 CONH-SCH [(CH 2) 2 NH 2) CONHMe 4024 2-imidazolyl 4078 CONHMe 4025 2-oxazolyl 4079 CONHCH2CONMe2 4026 2-thiazolyl 4080 CONHCH2CONHEt 4027 2-benzimidazolyl 4081 CONHCH2CONEC2 4028 CONH-R-CH (CH3) Ph 4082 CONHCH2CONHcyklopropyl 4025 CONH-S-CH (CH3) Ph 4083 CONHCH2-cyclobutyl 4031 CONHCH2CONHMe 4084 CONHCH2CONHcyklopentyl 4032 CONH-S-CH (CH3) CONHMe 4085 CONHCH2-cyclohexyl 4033 CONH-R-CH (CH 3) CONHMe 4086 CONHCH2CONH'terc.-butyl 4034 CONH-S-CH (2Dropvl) CONHMe 4087 CONH-S-CH (CH2 Ph) CONHMe 4035 CONH-SCH (CH 2 SH) CONHMe 4088 CONH-S-CH (CH2-PMeOPh) CONHMe 4036 CONH-SCH (CH 2 OH) CONHMe 4089 CONHCH2CH2CONHMe 4037 CONH-RCH (CH 2 OH) CONHMe 4090 CONHCH2CH2CH2CONHMe 4038 CONH-S-CH (CH 2 O t Bu) CONHMe 4091 CONH-SCH (CH 2 CH 2 OH) CONHMe 4039 CONH-R-CH (CH 2 O t Bu) CONHMe 4092 CONH-S (CH (CH2) 3CH3) CONHMe 4040 CONH-CH (Ph) 2 4093 CONH (CH 2) 2 ^C 2 Me 4041 CO-L-proline -NHMe 4094 CONH (CH 2) 2 H 2 ^C ° 4042 COŇHCH2CO (Npiperazinvl) 4095 CONH-SCH [(CH 2) 3 NHBOC] CO 2 Me 4043 CONHCH 2 CO (N-methylN-αDerazinyl) 4096 CONH-SCH [(CH 2) 3 NHBOC) CONHMe 4044 CONHCH2CO (N-acetylN DÍDerazinvl) 4097 CONH-S-CH [(CH2) 3NH2) CO2M 4045 CONHCH2CO-N-morpholino 4098 CONH-SCH [(CH ₂ ) 4 NH ₂ ) CONH ₂

284

4046 CONHCK ₂ CO- [N- (4-HydroxyDeridin) 1] 4099 CONH _{(CH2) 2} Ph 4047 CO ₂ H 4100 CONH _(CH2) 2 (3,4, dimethoxy phenyl) 4046 CONHBn 4111 CONH (CH ₂ ) 2 '(N-morpholino) 4049 CONH-2-pyridyl 4112 CONH (CH ₂ ) 3- (Nmoxfolino j 4050 CON-Ph 4113 CONHCH ₂ CONH- (2-yridyl) 4051 CONH-3-pyridyl 4114 CONHCH ₂ CONH- (3-pyridyl) 4052 CONH-4-pyridyl 4115 CONHCH ₂ CONH- (4-pyridyl) 4053 CONH-CH3CH (Ph) ₂ 4116 CONH (CHJ, (P-SO 3 NH-Ph))

At. em y s e 1 usin g. i e n o s

Compounds of formula III 'exhibit inhibitory activity in conjunction. é m e t a 1 o r o t e n o o o, a g g e c o o o a T M F-. · 1 * 11 * 1 P — 3 i. The inhibitory activity of the compounds according to the invention is demonstrated by assays for the activity of 11 * 11 * IP-3, for example the assay described below, which aims to test the IMMP-d activity of inhibitors. The compounds of the invention are bioavailable in vivo, e.g. using the ex vivo assay described below. The compounds of formula 1 have the ability to suppress / promote cartilage degradation in vivo, as exemplified by the animal model of acute clearances below. e cartilage.

Compounds according to. of the invention are also useful as standards and reagents for determining the inhibitory potency of potential pharmaceuticals in the case of metalloproteinases. Thus, these compounds could be included in commercially available kits.

M e t a 1 o r o t e i. n a z y s a t a k i. s t o z u s and t t u. It is based on the basement membranes, which allows: Cancer infiltration

285 cells of the days of the ob and subsequent penetration of the cancer cells of the other tissues, thereby participating in the tumor metastasis.

(Stetler-Stevenson, Cancer and Revastasis Revieus, 9, 289-303, 1990). The compounds of the invention should. be, thanks to its s: s o n t s i n h 1 b o v t t e n t o a t e t m e t a s t o z, u o u. t e 1 o é p r i. prevention and treatment of invasive tumors.

The compounds of the invention will also find utility in the art. the prevention and treatment of osteopenia associated with matrix-mediated metalloproteinase mediated cartilage and bone fracture that occurs in patients with osteoarthritis. c h o s t e o p o r o z o.

Z. 1 Account. n y, k th o r i. n h i. b u. T N F 'and / or aggrecanase and / or IM P are potentially useful in the treatment. or preventing various inflammations, infectious, immunological or malignant diseases. These diseases include notwithstanding that, with the following: o v a s u u r i n e n o. haemorrhage, coagulation and acute phase response, acute infection), septic shock, hemodynamic shock and septic syndrome, p> o s t - i. s c h em i. c k e r e p e r f u n e p o r a n e n i. e, ma 1 á r i. u, C r o h n o u c h o r o b u, m y k o b a k t e r i a l. n e i. n f e k e 1 e, m e n i. n g i. t d d, p o i z,, p p o d o n t i. class, gingivitis, congestive heart failure, fibrotic disease, k a c h e x i. u a o o r e x i. u, u p u d e o i. ulceration or tumor invasion of secondary metastases, autoimmune disease, skin inflammatory diseases, osteoarthritis multiplex and joint rheumatism, multiple sclerosis, radiation damage, HIV and hyperoxic alveolar.

For example, using the IMF induction assay in mice described below and the INF ⁷ indication assay in whole human blood, the compounds of the invention were found to irritate INF production in mice. st im u o oh ed oh ipipo 1 ysaeharido m.

The compound of the invention has been shown to inhibit aggrecanase, which is a key enzyme involved in the destruction, as shown in the aggrecanase assay described below.

286

The abbreviation ug stands for micrograin, mg stands for milligram, g stands for grani, ul stands for microliter, ml stands for milliliter, 1 stands for liter, nM stands for nanomolar, “µM stands for micromolar, mM” stands for millimolar, M stands for molar and nm stands for nanometer. Sigma refers to Sigma-Aldrich Corp. o f St. Louis, MO.

A compound is considered to be active for the inhibition of MMP-3 when the IC ₅₀ or K _± value is less than about imM.

A g g r e a n d a n d a n g

A new enzyme assay has been developed to detect potential aggrecanase inhibitors. This assay employs active aggrecanase, accumulated in media, obtained from stimulated bovine nasal cartilage (BMC) or derived cartilage sources, and a purified cartilage aggrecan monomer or fragment thereof as substrate.

The substrate concentration, aggrecanase incubation time, and the amount of product for Western analysis were optimized so that this assay could be used to screen for putative aggrecanase inhibitors. Aggrecanase production was achieved by inhibition of uterine cartilage with non-eucine-J, (IL-1), tumor necrosis factor alpha (INFaD, or other stimuli). the active enzymes present, the matrix metalloproteinases (hereinafter referred to as MMPs) with those from the cartilage, are eliminated in their inactive, zymogenic form, which is then stimulated. MMPs are released into the culture medium (Tortorella MD et al., Trans. Ortho. Res. Soc. 20, 341, 1995) In order to collect BNC aggrecanase in the culture medium, the cartilage is first depleted of endogenous aggrecan by stimulating 580 ng / ml human for six days. recombinant IL-β in which the medium changes every two days, and the cartilage is then stimulated for an additional eight days without changing the medium, allowing the accumulation of soluble active aggrecanase in cultures. R nom medium. The amount of other matrix metalloproteinases

287 released into the culture medium during aggrecanase accumulation is reduced by the introduction of agents that inhibit the biosyritesis of lIIβ-1, Ι * ΙΙ * ΙΡ-2, βII-β-3 and Ι * 1Ι * 1Ρ · ~ 9 during stimulation. This BIMC conditioned medium, containing the active following assay as enzymatic and aggecanase, is then used as an aggrecanase source. Aggrecanase activity is delegated by monitoring the production of segments resulting exclusively from cleavage into

01u373 - Ala374 binding within an aggrecan core protein, using

Uestern analysis using monoclonal antibody, BC ..... 3

C H u g h e s, C E a k o 1., B i o c h em (3Q6 t 799-804, 1.995). It recognizes aggrecan fragments with an IM-terminus, 374ARGSVIL. Resulting from cleavage of aggrecanase. The BG-3 antibody recognizes this neoepitope only when it is located at the IM-terminus. and but not if it is present inside the g g e g e g e g e g e g e g e g e g e g e g e n g e r e g e r i n g e r e g e r e g e r i n g e r e g e r i n g e r i n g. n o h o ... kernels. The other proteinases it produces: cartilage, do not cleave aggrecan at the Glu373-Ala374 aggrecanase site due to IL-1 stimulation, so that only products resulting from aggrecanase cleavage are delegated. Kinetic studies conducted using this assay reported an Km value of 1.5 +/- · G, 35 for 1 * 1 for aggrecanase.

Compounds that were evaluated for their ability to inhibit aggrecanase were prepared as 10 µl stock solutions in D 110, water or other solvents and then diluted with water to the appropriate concentrations. To 50 µl of aggrecanase-containing medium and 50 µl of 2 mg / ml aggrecanase substrate was added 50 µl of the active ingredient and 0.2 µl of Tris is used to make up to a volume of 200 µl. The assay was run for 4 hours at 37 ° L and after this time, the assay was stopped by adding 20 µl of EDTA and analysis of the aggrecanase-generated products was performed. The sample containing enzyme and substrate without drug was a positive control and the enzyme incubated in the absence of substrate was used as background value.

For the B0-3 antibody to recognize the ARGSVIL epitope on the core protein, it is necessary to remove the glycosaminoglycan side chain from aggrecan and from c. For t o s a p r 1 a n o ag g r e c a n t h f r g m a m

288 generated by cleavage at the G1373-Ala374 site, aproteogylalanase and gamma entyenzymes. This enzymatic cleavage was carried out with two glycosylate proteogylates. hours at 37 ° C using chondrol t: i. ABC COase, 1 unit / 10 µg GAG) and then using keratanase CO, 1 single-dose (1.0 µg GAG) and kerataoase 11 <0.002 single-dose / 10 µg GAG) for two hours at 87 ^{<; ,} G and R buffer, the content JUCOM 50 mM sodium acetate, 0, 1 M ľ'ris / l IC1, pH 6.5. After digestion, aggrecan in the samples is precipitated with five volumes of acetone and resuspended in 30 µl of Tris sample buffer.

(Novex), separated by glicin SOS

1: 500. 1 a t o u P r o t; I g G k t o r e a t i o s 2, 5% b e t t e r l <a p t o e t a n o 1.

E n G L I S S - P A G E r i s e d i n e g Ei gels with 4 to 1.2% gradlent, then n. t r o c e 1 u 1 o z and im u o 1 o g i c k y 1. o k a 1 i. z u j u n r e e d e o m

BG3. Then, the membranes are incubated with a goat and a capsule and a capsule.

(1: 5000 dilution) and aggrecan catabolytes are 10 to 10 suitable for achieving

0 m i n t o o o i. n k u th e i. o u s s u b s, with optimal color development. The blots are determined by comparing the amount of product produced in the presence of the test compound. with the amount of product produced in the absence of this compound.

k v a n t i. f j. The key is determined on the basis of

E '1 u e r s e c tio n s t b 1 s a n e n t e n t a n d P / M M P - 3

A high-capacity enzyme assay has been developed to detect potential MMP-3 inhibitors. The test uses a peptide derivative of Ei osubstrate, 1 PCA rg - P ro - · L ys - F ³ ro - G1 n - G1 n - E ³ Ei e - G1 y ..... Leu - Met) that cleaves MMP-3 exclusively at the glutamine-phenylalanine site of the binding. In order to adapt this assay to high throughput screening, a fluorometric method for product detection has been developed. The measure of production of the hydrolysis product, F ³ 7-11, is the reaction with fluororescamine, which is a fluorogenic compound that reacts with the primary amine of this fragment. On the substrate, the substance F ³ is bisacetylated to block the primary amines of the intact substrate. Thus, the resulting fluorescence represents the production of product <7-11

283 peptide), which is generated by cleavage of 11βP-3 and quantitated using a standard curve constructed based on known concentrations of 7-11 peptide. Kinetic studies using a bisacetylated substrate gave the following parameters for β1β-3: Km 769 +/- 52 µl; Vitamin? X 6.090 +/- 0.003 nmol 7 ... 11 peptide / min.

Compounds which were evaluated for their ability to inhibit 1 * 1 µl of F 1 ... 3 were prepared at a concentration of 10 µl in 1.00% methanol and then diluted 1 µl. extraordinary self-equilibrium different solutions. F ⁵ ä m m i. kro 1 itrovz á é-rig horozbokuka f .j account of active substance used, the f 1 and a total of 20 modified splicing NLL ľlľlP-3 at 67, 5 mM sodium trlcínu (pH 7, 5), 10 mM sodium _R CaCl, 40 mM sodium NaCl and 0.005% Br j 35 in a final volume of 100 microliters. Then the bisacetylated substance P (C1000mL * 1) was added and the test was allowed to run. 1 stab at 25 ° C. The reaction was terminated by the addition of EDTA (20 ml) and after the addition of fluorescence (0.075 mg / ml) the product was delegated fluorometrically. The fluorescence of each sample was converted to the amount of product generated using a standard curve for substance P 7-1.1. Under these conditions, the assay up to 1.0 pmol µL * IP-3 is linear. The µbi-1β-3 was determined by comparing the amount of product produced in the presence of the test compound with the amount of product produced in the absence of the compound.

The selected compounds of the invention were analyzed using the tests described above, and the results obtained showed that they exhibited t v a k k and a b b b.

Ex vivo bioavailability test of 1 * 11 * 1 P - 3 inhibitors

To determine inhibitor levels, they used rat blood samples that had cardiac puncture at different time points). The extract was extracted with 1.0% TCA in 95% methanol present, obtained moments after the compound. and placed in the blood, in use

1.0., I.P.

Plasma was applied for ten minutes on ice. After this time, the plasma was centrifuged for 1.5 minutes at 1,4000 rpm in an Eppendorf microcentrifuge.

290

The removed supernatant was centrifuged and pale in a 1:19 ratio in 59 mL of 1 * 1 triciria, pH 8.5. The sample, whose pH value was set to 7.5, was then subjected to the fluorescence enzyme assay 11 * 11 * IP-3 described above and P. Plasma from rats which had not previously been performed. and days experiment, was extracted by the same method and used as a negative control. This plasma was further used to prepare a plasma compound enriched for the test compound. Known concentrations of compound ει were added to the control plasma and the thus enriched plasma was extracted by an analogous method and subjected to a Γ1ΙΊΡ-3 erismymatic test. Based on the data obtained, οει constructed a standard curve expressing the dependence of the percent inhibition in the 1 * 11 * 11 · ⁵ —3 test from the concentration of active ingredient added in the enriched samples. The concentration of the test value, the plasma of the O compound, was subtracted, which corresponds to the percentage of ó f opotkan ει.

from the Standard curve as i. n h i b i. c i 1, z i. with it

Rat, model, acute cartilage degradation

New in vlvo. the model of acute cartilage degradation in the rat is one of the following: 1. e proteoglycaria content in synovial fluid after induction, cartilage degradation. Experimental groups of rats show increased levels of proteoglycan in the synovial fluid compared to control rats. The criterion for demonstrating compound activity in this model ... is the ability to inhibit the manifestation of cartilage degradation. or ability ... can be expressed as the rate of increase by b with ε! h u r o t e o g 1. y k a n v s y n o v a n i n i n a p a 1 i n e p o t o n o n o o n o. compound. Indometaine, a non-steroidal anti-inflammatory drug, has been shown to be ineffective in this model. Indomethacin administration did not exacerbate cartilage degradation in experimental animals. Conversely, administration of a compound of the invention substantially inhibited cartilage degradation in this model.

Human whole blood TNE test

In tubes containing 143 USP units of heparin / 10

291 ml, blood collected by an ordinary donor was introduced. 225 µl of blood was placed directly into sterile polypropylene tubes. Compounds were diluted with serum-free D16SO medium and added to blood samples to represent final concentrations of the compounds. 50, 10, 5, 1, 0, 5, 0, 1, and 0, 01, j..tl ^yl. The final concentration of D105 did not exceed 0.5%. Compounds were incubated for 15 minutes before addition of 100 nm / ml LPS. Plates were incubated for 5 hours in an atmosphere enriched in 5% µl. For a 5-hour period, 750 µl of serum-free medium was added to each tube, and the samples were centrifuged for 10 minutes. The supernatant, after separation, was subjected to a standard sandwich ELISA assay to determine the production of INF-alpha. The ability of compounds to inhibit TNF-alpha production by 50% compared to cultures treated. D50 is given as a value

..1 .. (., P.

INF-induction in mice

Test compounds were administered to mice at time zero with either I.P. or P. t), by the method. Immediately after administration of the compound, I.P. injected with 20 mg of D-galactosamine and 10 µg of lipopropylamine. d u. 0 e: d o u h o d i. n u n e c r e a n e n e r a t o p o r i b i 1 i.

anesthesia or cardiac puncture was taken from their blood. TNF level in blood plasma was evaluated by ELISA, designed to analyze mouse INF '. Administration of representative compounds of the invention caused dose-dependent suppression of plasma TNE levels after one hour in mice.

Dosage and formulation

The compounds of the invention may be administered orally in the form of any pharmaceutically acceptable dose known in the art for this purpose. The active ingredient may be administered in solid dosage forms, for example, in the form of dry powders, granules, tablets or capsules, or in liquid dosage forms, for example, syrups or aqueous suspensions. The active ingredient may be administered alone, but is usually administered together with

292 f a r m a c e u t i. c is an acceptable carrier.

A valuable professional

a publication in which it is possible to find information relating to Remington's Pharmaceutical ·

Sciences,

I j a c: k P u b ¾. i s h i n g

The compounds of the invention may be administered in oral dosage forms such as tablets, capsules (both containing sustained release or sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, sir ups and emulsions. Thus, it can be administered by intravenous form C (infusion or infusion), including administration, and administration, using dosage forms well known to those skilled in the pharmaceutical industry. An effective but nontoxic amount of a compound of the invention may be used as an anti-inflammatory and anti-arthritic agent.

The compounds of the invention may be administered by any means which allows the active ingredient to contact the site of action of the agent. This site is in the body of mammals IL-3 ~ 3. The compounds may also be administered by any conventional means available for the administration of pharmaceuticals, either in the form of a formulation. n d i. v i d u a n i c h t e: r a p e u t i c h o o k b b. n i c i. e: t e r a p e u t i o c c b i n i. d i. e; 1. While alone, but usually a pharmaceutical carrier which can be administered in combination with the usual route of administration and the standard reagents or in the form of a compound can be administered in combination with a compound of formula (I). of pharmaceutical practice.

The dosage regimen for the compounds of the invention will be understood: vary, depending on known factors such as the pharmacodynamic properties of the agent, its mode and mode of administration; the species, age, sex, health and weight of the recipient; the nature and extent of the symptoms; type of concurrent treatment; frequency of treatment; the route of administration, renal and hepatic function of the patient and the desired effect. The human or veterinarian is able, on the basis of his knowledge, to determine and prescribe the effective amount of the drug required for

293 e n e c. already. a s e a n e: a 1 e b o o o n e a n e n e n e n e n d e n d e s.

As a general guideline, the daily dose of each active ingredient intended for the above-mentioned effects will be approximately in the range of C), 991 to 1999 mg / kg of recipient's body weight per day, preferably approximately in the range of 9, 91 to 199 mg. per kg of body weight of the recipient per day, and most preferably about 1.9 to 29 mg / kg / day. For a normal male adult weighing approximately: 79 kg, it will therefore be an appropriate dose of 79 to 1499 mg / day. Preferably, the more ml doses for intravenous administration are doses; is approximately: ranging from 1 to 19 mg / kg / min, at a constant rate. Advantageously, the compounds of the invention may be administered in a single daily dose: or the total daily dose to be administered may be divided into two, three or four steps and one or more doses.

The compounds of the invention may be administered in an intranasal form, with the aid of the intranasal formulations. The use of transdermal patches known to those skilled in the art is known in the art. If the compounds are to be administered via the transdermal dosage system, it will be appreciated that the administration of the dose will be continuous rather than intermittent throughout the dosing regimen.

In the process of the invention, the compounds described herein may represent the active ingredients, which are usually; administered in admixture with suitable pharmaceutical diluents, butter bases or carriers (collectively referred to herein as carrier materials), which are suitably selected with cold for the intended form of administration, i.e., whether or not; oral; tablets, capsules, elixirs, syrups and the like, and in accordance with conventional pharmaceutical practice.

If the active ingredient is to be formulated in the form of a tablet or capsule for oral administration, then sorbitol, nontoxic, may be combined, farmed to be acceptable, even if the oral dosage form is 1. such as lactose, starch, sucrose, glucose, but not as a stearate, stearate, dithium citrate, with rart

294

calcium, mannitol, sor bitol, and the like. ; When formulated in a liquid form for oral administration, the active ingredient may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. In addition, if desired or unavoidable, it is possible to mix the composition. , disintegrants and dyes. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. The Luhricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methylcellulose, agar, heritoriite, xanthan gum, and the like.

The compounds of the invention may also be administered in the form of liposome delivery systems, e.g., small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from many phos; f o 1 i o o o n o l <1 a d c h o e s t e r o 1, s t e a r y 1 am a n e a b o f o s f a t. d y 1 c h o l nov.

The compounds of the invention may also be coupled to soluble polymers as targeted carriers; of the active substance. These polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl 1-methacrylamidophenol, polyhydroxyethyl-1-aspartic acid, and 1-ebopolyl-ethylenedioxide. 1 y 1 yz. n s u b s t i t u o t s palmitoyl residues. Next is; it is possible to bind the compounds according to the invention to polymers belonging to the class of biodegradable polymers, to use controlled release of the active substance, for example poly-2-hydroxypropanoic acid, polyglycolic acid, polyacrylic acid, polyglycolic acid, polyacrylic acid, <opolyméry

P o 1 y - 2 - h y d r o x y p o n o y a p n y y g o y o o y, o o y - e p s i o o n - · —k a p o o y a k t o, y y s; 1 i n u o y y y y y y y y y y, y o y y y o y; you are; r y,

P o 1 y a n t a n d, a n d e n d e n d e n d e n d, a n d a n d a n c a n d a n d

295 or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 milligram to 100 milligrams of active ingredient of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will usually be from 0.5 to 95 bm% based on the total weight of the composition.

The active ingredient may be administered orally in solid dosage forms, for example, capsules, tablets and powders, or in liquid dosage forms, for example, elixirs, syrups and suspensions. It can also be administered parenterally in sterile liquid dosage forms.

The gelatin capsules may contain the active ingredient and powdered powders, powders, borates, stearic acid and the like. Similar diluents can be used for the manufacture of tablets. Both tablets and capsules can be formulated as sustained release products for continuous drug release over a period of hours. Compressed tablets may be coated with a sugar or film that masks an unpleasant footwear and protects the tablet from environmental influences, or may be provided with an enteric coating that disintegrates in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring agents which make the dosage forms more acceptable. Water, a suitable oil, saline, aqueous dextrose (glucose), and derived sugar solutions and glycols, or polyethylene glycols, are usually a n t e r i n e r i n e r i e n e. R o t o y n a n a p r. Suitable carriers for arenteral administration preferably comprise a water-soluble salt. active ingredient, suitable stabilizing agents. A n 11 o x 1 d a y d e g e n s i r i. Ascorbic acid, either alone or in stabilizing agents. Also lemon and its EDTA sodium salts.

and, if necessary, 1 n I. a, n a p i n i n d a n e a n e n e n e n e n e n e n 11, s h o n d i n e.

It is possible to use acid P and sterile solutions

296

also contain preservatives, for example, benzoyl, methyl, methyl and benzyl and aryanil.

Suitable pharmaceutical carriers are described in Remington's Pharmaoeutioal Science, Black Publishing Company.

Useful pharmaceutical dosage forms for administration of the compounds of the invention may be:

capsules

Capsules are prepared by conventional procedures such that the dosage unit contains 666 milligrams of active ingredient, 106 milligrams of cellulose and 10 milligrams of magnesium stearate.

A plurality of unit capsules can be made by mixing the hard capsules. Each of which will contain 100 milligrams of active ingredient in powder form, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of magnesium stearate.

Syrup i. The liquid sugar Sorbitol 1-lm. %

1.0

glycerin

Thickeners, coloring agents and dyes

Water as needed P o d1a needs

The final volume is made up by adding distilled. water up to 1.00%.

297

A}

Aqueous suspension

Active ingredient

S a c h a r a n d o d

Keltrol (food xantal gum)

Liquid sugar

Uchu ť. o soap, dye and o z e r o o tio ns. n i. d 1 o

Water

Um. %

1.0

0, 010

0, 2

P o d 1 'a p o t r e s y o n 1 a p o t r e s y

Xantal gum is slowly added to distilled water before the active ingredient and the remaining ingredients of the formulation are added. The final slurry is passed through a homogenizer which, with the final product from a.

The solution is a powder

Active ingredient

lactose

sugar

acacia

Tools um k a r b o x y Im rs t y 1 o e 1 u 1 o z a

Um. % 50, 0 95, 0 10, by 4, 7 0, 3

The ingredients are finely ground and then mixed evenly. Alternatively, the powder may be prepared as a suspension and then spray dried.

Half-goal

Active ingredient

Are u! c h a r 1. d s

gelatin

Flavoring, coloring and flavoring agents. n i. d 1. o Water

Hm. %

1.0

2.0 as required

298

Get ready! in hot water. The finely divided active ingredient is suspended in a gelatin solution and then the remainder of the ingredients are mixed into the solution. The suspension is introduced into a suitable packaging container and cooled to form a gel.

Fixing paste

Effective 1

Gelcarin (Carrageenan S and o l and gelatine)

Flavoring, coloring and flavoring agents 1

Water

Hm. % rubber) 1

0, o :: i "

P o d e r o p e r y P o d 1 a p o tr e b y

The gelcarin is dissolved in hot water (about 80 ° C) and the finely divided powdered active ingredient is suspended in this solution. Sodium saccharin and the remaining formulation ingredients are added to the still warm suspension. The suspension is homogenized and then filled with a suitable container.

E m u 1 g o v e t e n a t s

Hm. %

Active ingredient

Tween 80 and Spao 80 6

Keltrol 0.5

Mineral oil 03.5

All ingredients are mixed thoroughly to provide a homogeneous paste.

Soft gelatin capsules

Gelatin capsules containing 100 milligrams of active ingredient are prepared by injecting a pre-formulated mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil.

299 peristaltic gelatin pump. The capsules thus prepared are then washed and dried.

tablets

Tablets may be prepared by conventional procedures to contain 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate.

A large number of tablets may also be prepared, by conventional methods, to contain 100 milligrams of active ingredient, 0.2 milligrams of colloidal magnesium oxide, 5 milligrams of magnesium stearate, 275 1.1 milligrams of starch and 98.8 mg / ml. i. absorption.

Ah o Lehi _; mi 1 i. gramovm i. 11th Greek milligrams of lactose. Tablets that enhance the susceptibility of cellulosic and / or cellulose may be delayed

I n j e t i n t e n n o n o n t a n c a c a

A parenteral composition suitable for injection is prepared by mixing 1.5% by weight of the active ingredient into 10% by volume. % propylene glycol and water. An isotonic solution is prepared by the addition of sodium chloride, which is then sterilized.

suspension

An aqueous suspension for oral administration is prepared such that each 5 ml contains 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium berizoate, 1.0 g of sorbitol solution, USP and 0.025 ml of vanillin.

The compounds of the invention may be administered in combination with a second therapeutic agent, in particular in combination with non-steroidal anti-inflammatory agents. (NSAIDs). The compound of Formula 1 and this secondary therapeutic agent can be administered alone: or as a physical combination in a single dosage form, by various routes already described.

The compound of formula I may be formulated together with the second therapeutic agent in a single dosage form (i.e., they may be combined together in a single capsule, tablet, powder or liquid and calf). If the compound of formula I and the second therapeutically active agent are not formulated together in a single dosage unit, they may be administered substantially simultaneously or in any order. For example, a compound of Formula I may be administered first and a secondary agent second. If they are not administered at the same time, it is preferred that the delay between the administration of the compound of Formula 1 and the second therapeutic agent is less than about one hour, preferably less than 5 to 30 minutes.

A preferred method of administering the compounds of Formula 1 is oral administration. Although: it is preferred that the compound of formula I and the second therapeutic agent are administered in the same manner (i.e., if both active substances are administered orally), "it is possible to administer" the individual substances in the Isny. ways. That is, "one component of the combination product may be administered orally and the other component may be administered intravenously).

The dose of a compound of Formula 1 when administered alone or in combination with a second therapeutic agent may vary in particular cases, depending on various factors, for example, the pharmacodynamic characteristics of the agent, and the mode and mode of administration. age, health and body weight, recipient, nature and extent

I nd e r i s e d i n d e c t i o n s n o n e n d e s, the efficacy of the desired effects.

In particular, where the active ingredients are as a &quot; single dosage form &quot; merger. effective. components. Gelatin treatments and provided i. n t e r k k a c p a 1

301

containing 100 milligrams of active ingredient, in the case where the compound of formula I and the second therapeutic agent are provided in a single dosage form, both components are formulated such that even when combined in a single dosage form, their physical contact with each other is minimized. For example, one of the active ingredients may be provided with an enteric coating. By providing one of the active ingredients with an enteric coating, it is possible to minimize both the active ingredients and the release of one of these ingredients in the gastrointestinal tract, so that one of these ingredients will be released in the intestine rather than in the stomach. One of the active ingredients may also be provided with a sustained-release material that causes sustained release throughout the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. The sustained-release component may further be provided with an enteric coating, i.e., it may be provided with an enteric coating. A n d e n d e n e n e n e n e n n e n n e n e. Another approach is to formulate a combination product in which one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a polyol, e.g. The use of HPP1C or other suitable materials known in the art to further separate the active ingredients from one another. The role of the polymer coating is to create an additional barrier to the interaction of the active ingredients.

summer, as well as other ways of minimizing contact between the bottom of the present invention, which are separate, and the ingredients of the combination products administered in a single dosage form or in a single instant, would be an expert in the art, after which as they become familiar with the present disclosure, obvious.

The invention also provides pharmaceutical series useful in the art. treating or preventing osteoarthritis or joint rheumatism, which comprise one or more containers with a pharmaceutical composition, comprising an therapeutically effective amount of a compound of formula I. These series may further include (J 2) if desirable, one or more conventional pharmaceutical components, for example, containers with one or more of the following pharmaceutical ingredients: minicabs, auxiliary cartridges, etc., known to those skilled in the art. The series also contain instructions which are in the form of an enclosed leaflet or label and which contain information regarding the dosage of the ingredient, instructions for administration: and / or instructions for mixing the ingredients.

It should be apparent from the present disclosure that only those materials and conditions that are important for the practice of the invention are specified. If the materials and conditions do not adversely affect the successful implementation of the invention, then they are not delimited.

In conclusion, it should be noted that the above examples are illustrative only and are not intended to limit the scope of the invention as set forth in the appended claims.

303

7 / t- 9S

P ATÉN T 0 V É

Claims (1)

TOOLS 1. Compound of formula 1 Formula I, or a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein: U is selected from: -00, -3-1, -CONHOH, -CONHOR ¹¹ , -SPI, -NHCOR ¹¹ , -N (OH) COR ^11, -SNsHsR ^<s', -SONHR *, CH ^ CO H, OH POC), and, POCO1-DNHR (*), CH _and SH, -C (O) NHOR1Sa ^,. -CO _R R ^{Í a} and common to ureasic derivatives; R ¹ is selected from hydrogen, --C-CU) alkyl-SCO) _x p-CC-C ₆₎ alkyl, - (C q - O a) and 1 - O - CC _{: K} - C _ώ ) and 1. ny, O a C-Cq) alkyl-S O) _of ρ-CC -Ca) alkyl-aryl, --C-0 and> alkyl-O-CC _of -Ca> alkyl-aryl, alkyl of 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from: hydrogen, halogen, hydroxy, alkoxy, aryloxy (e.g., ferioxo), and amino, amino and amino, acylamino (e.g., acetamido) 304 a b e n z m i c o s p i n y), r y 1 am i n o s; k u p i n y, guan i. cl i n o s u p i n y, IM - m e t y 1 im i cl a z o I. y 1 o o s s p i. 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1. n y, 1 k y 11 i. o s k u i. n is aryl. t i o s k u p i. n y (n a p r i k a i f f i n i th th o s p u n y), k a r b o x y s k p i n, car b o x a m i d o s p u p i, - C C o - C e) a .. 1 1 1 1 1. 1. 1. 1. o o o o i i i i i n y, - ·· C (C) - (e)) a 1-ylen-1-y-1-yne, wherein the aryl moiety is s, - CC o - C e) ary 1 - CC _t - C) and cyanogenic causes, - C C j - C e)) 1 k y 1 é b b a r y 1. o o s s p i n y, - CC o - C: g)) 1 - SCO) p - CC _o - C) and 1 y. ny, - C <C _; , C _e,) alk y II. SCO) p -OO _the CC> alkyl lériar y j en clamp the love, vk tor ej is an aryl radical substituted, C-C (o |.) Alkylenearyl, C-C-C _{o r)} alkylenearyl-II SC 0) p (C _o -CE »> alkyl !, - CC _a -C alk yl J-1 SCO) p-C _{of the} CC) yl alk lénbiar love .j y sk to clamp, - CC o - fľ: s) and 1. ky 1 - O - CC: _o - C <=,) and µl. I. I nary 1 ove .jsku ρ »1. ny, C ₀ -C 6 alkyl-SC CD (C ₀ -C ₀ -C _B ) alkylene aryl groups in which the aryl radical is substituted, - CC _a . C. ,,.) Állj <ylaryl- _(Co -CE)> 0 alkylénaryl- LL '- CC _of --CeD j The alkyl group], _Ο C 0 --0 _θ) alkyl-O-C C-C _{of E)} alkylénblarylove j groups, C Co-Ce) alkyl-CC C _o -C _s) alkyl-aryl, wherein the aryl moiety is substituted, wherein the substituent is selected from hydrogen, alkyl of 1 to 5 carbon 1 s uh ka, hy cl roxyskup i. ny, ha 1 og é nskup i. ny, and 1 alkoxy groups, aminos upines, monoalk y lamirioskines, dlalkylamines, acylamino groups, thio, thioalkyls, k arboxamidines, arboamidoscines or aryl groups; R ^a is selected from H, -CO R ^55, R ⁵⁵ -COIMR ^, C ^ 0R -COIMR ^s), alk yl love j en <clamp the alk y lo ylaria the j en clamps the alk ylhet ero aryl] .. ovejskup i. and heterocyclic groups, aryl groups, heteroaryl. j sk ups or heterocyclic 305 group which is substituted with one or more substituents selected from: a t h o d e, h a 1. o g e n g u p n n, h y d r x y s p u. n y, a 1. k o x y s k ρ 1. n y, a r y 1 o x y s k p i n C n a p k k a d f e n o x y e; ketone), aminosupines, monoalkylaminobutyls, dialkylamines, such as C 1, and C 1, and C 1 and C 1 and C 1 and C 1. n y a b e n z a m 1. d o s c u p u s), a r y 1. a m i. n o s k u p i. n y, g u and n i. d 1. n o s k p 1. n y, N - meters 1 Im 1. d a z o 1. y 1 o s s p. ιί y, i. m i d a z o 1. y 1. n u s u p i. n y, 1. n d o 1. y 1. o e e s s p i. n y, m e r k a p t o s u u i. n y, n i. I n e s 1 k y 11 i o s k p i. n y, and r y 11 i. o s k u i. n y C n a n d e n d e n y 1.1 i. o s k u p 1. n y), kar b o x y s k p i n y, s u 1 f n n m i d o s k u p i. n y, carboxy or carboalkoxy; choose from: is H, hydroxy, ^R ~ 0r, to clamp an amino, - MCR ^ώ , - CC i - C _ώ ) and 1 ky of the 1st group, - CC _{: L} - C _ώ ) and 1 cy 1 nary group. ny, -SR ⁰ , ¹ , and 1 ogen i. duo 1 ebon i. tr i. 1. u; alternatively, R ^{* 'and} R ³ may form a three to eight membered saturated, satur characterized characterized that, aryl 1 characterized ov, heteroaryl 1 or characterized heteroeyk s 1 i. a circle; R ^ is selected from: hydrogen, hydroxy, -OR ^ ', amino, -NHR ", - NCR ^ώ) π, - <C i - C) alkyl and the first 1 and ovejskup. ny, -CC _{: 1} . - - C) and 1 1 O Riart alkyl ester of 1, -S-O) p-Οχ _Ο ώ) alkyl, or halide and n. tr i. 1 u; R ^! - ⁵ shall be selected from: -CCHR ³ Y) -R ' ⁵ ', -CC R ⁷ R ^a ) -W-CC R ^Z R _m ) -R ^<5> , -CC R ^x R ^a ) n-R ^<5> , -CC R ' ^x R ^a ) Itl aryl groups, -CC R' R ^{S '} n, -CO 1' IR ⁷ 'R ^s , - CCR ^x R ^s ) _Tn - subst. tuovaoe ... iheteroary 1 group, - CCRR ^θ ) _m - subst. fatheterocycle 1 i. ekejskup i. currencies, in which subst. tu en t chooses from: a hydrogen atom, a C 1 -C 15 alkyl group, carbon a, hydroxy, halo, alkoxy, p, amine, p, mono and 1, and mi. n, s, 1-amino groups, acylamino groups, thio groups, thioalks, thioalks, carbonyl, and thioalks, thioalks, thioalks, thioalks, thioalks, thioalks, thioalks, thioalks, thioalks, thioalks, thioalks, thioalks; R ⁶ is selected from: a hydrogen atom, an alkyl group, - C C χ - C D a 1 k y 1 é n a r y 1 o e j s k u p: i .. n y, - CC x - C _Λ ) and 1-cyano-heteroaryl, - C C i - C) or 1 k y I. n h e t e r o o k 11 c k e j s k p i n y, The oxygen atom, alternatively R ⁵³ and R ^6, may form a three to eight membered back, optionally unsaturated, containing 1 to 3 heteroatoms selected from the group consisting of 1 to 3 heteroatoms. -NR ⁶ , -SCO 1 or any acyl group. p o p a d o u o o n d e n o c: i o u n a a y y 1. o o y h; R ^z a R® can be independently selected from: hydrogen, R ¹ , or may form a three to seven membered substituted ring with C 1 to 3 unsaturated bonds wherein the substituent is selected from hydrogen, C 1 -C 5 alkyl, hydroxy, halo, alkoxy, aminosupines , monoalk ylaminosk upiny, distiny1amino, acylamlnosk upiny, tiosk upiny, thioalk yΙέ kupiny, kar boxy, carboamido 1 nya ľl. eboary 1 ove .jskup i. ny; containing. -O-, -SCO 1, -NR ⁶ , with optional condensation to a substituted aryl ring, in which subs 11.1 is selected from: a hydrogen atom, a (C 1 -C 5) alkyl group, such as a hydrogen atom, an alkyl group having from 1 to 5 atoms; n y, b and ll. o g é n s u u i. n y, and 1 k o x y s k u i. n y, am i. n o s k u p i n y, m o n o 1 k y 1 am i. n o s k u p i. n y, d i. and 1 k y .. .. am i. n o s k u p i. n y or c y ll. am i. n o s k u p i. r i y, t i. o s k u i. n y, t i o and 1 k y ll. k, aralkyl, arboxamido or aryl; R * ⁵ represents a hydrogen atom, an alkyl group, a cycloalkyl five-membered ring, optionally containing one to two or atoms 307 cl us; (e) (SCO) p, in the case of esubst: i. fatty alkyl, - O - C ₃ - O -, alkyl, - O-acylenealkyl. nou, IM HR ¹ ° and 1. R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl group; R ¹¹ is H, alkyl having 1 to 10 C atoms which include branched, cyclic and unsaturated alkyl and 1 1 of b s, subs 111 and uovan D 1 s 1 s account not gr X, the vktorej the substituent is selected from: hydrogen, halo, hydroxy, alkoxy; Amino, aryloxy, acylamino (e.g., acetamido and benzamido), aryl and amino. n y, g u a n 1 d i n o s p p n n, i m 1 d a z o 1. y 1 o e s p p n n, :: i. n d o 1 y 1. o v e. j s k u p 1 n y, m axis r a p t o s k u p i. n y, a 1 k i n i i n i, ary i n i i n i n i n i n i n i n i n i n i n i n i n i n o l groups), carboxy s u p i n, k and rboxamidosyl, k arboalkoxy and sulfonamido groups, ..... (Ci-C) - a 1 k y 1 é n a r y 1. o e. j s k u p 1 n y, - (C) alk yl _{(C i. E} -C,) alk y y lo Lenárt the clamps the j en, - (Ci - Ci = j) - and 1. cy 1. é nb i. ary 1 ov e. jskupiny, substituted - (C _x - C _θ) - 1 and s 1 s 1 ovejskup nary ny 1, vktorej the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy groups (e.g., 1-adphenoxy), amino, d 1 and alkylamino 1, acy 1 and 1 acynyl (for example, acetamido and benzamido), aryl 1 and i. n o s k u p i. n y, g u a n d i n o s p p. 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 and 1 groups respectively. idogroup 1, carboa 1 coxys; k u p i n y a 1 e b o s u 1. f ó n a m i. groups R ^lla is hydrogen, C -.- -SO _x -C - alkyl, Ci--SOss -C -alkylénar yl, wherein the aryl 308 radical substituted, -SO _and -aryl, -SO5.-substituted 'heteroaryl, -COR' ⁵ ', -COat-Bu, -CO _with Bn or -alkylenaryl in which the aryl radical is substituted, with a substituent is selected from: a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydrogen atom, a hydrogen atom, or a hydrogen atom; and m. n o s k u p j., n y, m o n o a 1 k y 1 and m i n o groups, d i. a 1 k y 1 a m o s p u piny, a c; y 1. and m i. n o s k p i n y, t: i .. o s k p i n y, 11. o a 1 k y 1 s k p i n y, k and r ti o x y s k p y, carb o x am i. an aryl group; R ^{1 2} _{is 2VO]} _- F _from: hydrogen, aryl, <χ C χ -C) -alkyl, aryl, C 3. -0 _ώ ) -alkyl groups, CC ₃ - C 3.3. ) - Cycles 1 and 1st group, (C 3 -C 10) -alkylcarbonyloxyalkyl, (C 3 -C 10) -alkoxyl, and biphenyl-xyl, and cycloalkylalkyl, C C - C 10 -alkoxycarbony n o 1. o v e. J s k u p 1 n y, _The CC ~ Cj.o) -eykloalkylkar bonyloxyalkylovej of, _<C, -Cio) -eykloalkoxykarbonyloxyalkylovej group, _CC-C 3 ';.) -ey the loalk oxyk ar bony love to clamp j en, aryl 1 oxycarbonyl ester of 1, aryloxykarbooyloxyC _{C: l} -Csalkylovej group) -, C arylkarbonyloxyC -Csalkylove ... _x i of ) -, _CC-C 1 p ') - alkoxyalkylkarboriyloxyalkylovej group, C 5 ~ <C]. ~ C _alkyl) -1, 3-dioxa-cyclopenten-2-on-yl.3metylovej group, <5-aryl-1,3- d 10 x a c y k .. 0 p e n t e n -: 2-ori-yl) methyl groups; (R ^lz) (R ¹⁷⁾ N 1 - C C 3. - C1 © a 1. k y 10 v e groups) -, -CHC R ¹³ ) OCX = clay) R ¹⁴ , -CHCR ¹³ ) OCC = 0) 0R 'or ^DC 309 in which R ¹³ represents a hydrogen atom or a linear alkyl group of up to 4 carbon atoms; R ^{: 1} ^ · is selected from: hydrogen, C 1 -C 8 alkyl or C 3 -C 3 cycloalkyl. Wherein said alkyl or cycloalkyl group is substituted with 1 to 2 groups independently selected from: (C 1 -C ₄ ) alkyl, (C ₃ -C 8) cycloalkyloxy, CC _: i. - C ₅ ) and 1. coxys; a aryl group substituted with 0-2 groups independently selected from: halogen, phenyl, alkyl of 1 to 6 carbon atoms, C 1 -C G alkyl, nitro, C t -C --SC _the alkylove.j group), --SC = O) CC _x -Csalkylove. j groups) SO · -. (C - C · ₃ and 1 - group),. -NCR ^ XR ¹ ^) C (.tR ^'; L (= O) N (R ¹⁷ ) CR ¹⁷ '*') or - C _V F _W , wherein v is from 1 to 3 and w is from 1 to C 2 + 1), an aryl group substituted with 0 to 2 groups independently? selected from a halogen atom, a phenyl group, an alkyl group having 1 to 6 atoms. carbon, alkoxy groups of 1 to 6 and t? om am i. uh ľl. í ka, n i. trio, - SCC _{: 1} - C and 11 (y1) -), -S (-O) <C _; , .- _C, alkyl), -S0 _{a (C l} --C _of a 1 s 1 ovejs l <UPIN), and hydroxyl. ny, - NCR ¹ * CR ¹ *, CO _and R @ ^17, --C - 0) ¹ NC R ^) CR ^ - ^), or C _W F _W wherein ESU = 1 to 3 and w = 1 to (2v + l); R ¹³ is selected from Z: (C 1 -C 8) -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkyl; 310 or a cycloalkyl group is substituted with 1 to 2 groups independently selected from: an alkyl group having from 1 to 5 carbon atoms; (C-C) alkyl, (C až-Cykl e) alkyl, (C až-C alko) alkoxy, (C až-Cry) aryl group independently selected from: halogen, phenyl, alkyl of 1 to 6 carbon atoms, C 1 to C carbon atoms, nitro oskupiny, -S-C ~ C i -C j _{with an} alkyl group), SC == 0) CC _Ί. --C ₍ alkyl groups), hydroxy, -C (C = O) NCR ( ^1X ) CR ⁽ 1); - SO ;. CC i - C _s 1 and s 1 ... ove iskup ny 1), -NCR ¹⁾ CR ^1), - CO, R and C _V F _W where v = 1 to 3 w is ει 1 to C2v + 1); aryl substituted by 0-2 groups independently selected from: a halogen atom, a phenyl group, an alkyl group of up to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms. k, n 11 ny, - _{SCC: L} - 1, and _C 1 alkyl ove ... j -SO -0) C C. C _s alkyl), -S0 _and (C-C-sskuplny), hydraulic oxyskuplny, -MC ^R17) ^ CR ^1), (C-O) NCR ( ^IX ) CR ^{: I} - ^X ') or ..... In _{V W} , in which the atoms of the group (I), alkyl CO, R ^{1, x} , R 2, R 3, R 3, R 3, R 3 ^or R 3 ^; , v is 1 to. 3 ει w means up to C2v + 1) It denotes an alkyl group having 1 to 4 carbon atoms, benzyls having a nitrogen atom. e b o f e n y 1 o u s u p i. ny, R ^{: LX} and R ¹⁷ ® are independently selected from Z: a hydrogen atom, a C 1 -C 10 alkyl group, a carbon atom, a C 2 -C 10 alkenyl group, a C 4 -C 11 cycloalkylalkyl group and a C 1 -C 6 aryl alkyl group; combinations of A, B and D and / or variables are only permitted if three. n e e e n e n e n e n e n e n e n n e n e n e n e n e n e n n e n n e n n e n n e n n e n n e n n e n n e n n i n n i n n e n n e n n e n n e n n i n n e n n e n n e n n e); 311th A can be omitted or can be: -CCHR () -, -, -0 ^<CHR> '-, -NR ^ C ^ C IR) -S-O) p CHR ^R) or selected from an alkyl group of up to 10 carbon atoms which include branched, cyclic and unsaturated alkyl and 1 EBO - CC _x - · C _ώ) and 1 s 1 s n aryl, U is s; (3 can be a bond or can be selected from: · -NH-, -NR ¹¹ -, -NR ¹¹ -, -O-, -SCOlp-CC 1 -C 4 -alkyl-HN-CC 1 -C (*) - alkyl, -C 0 (O-O) -alkyl -NR ¹¹ -CC1-0 _ώ) -alkyl, -C _{x R} C -NH-j of the aryl, -0-CC and - □ <=,) -alkyl, - _{(C: 1st} ~ C _and ) -alkyl-O-j of the aryl, -S-C-C and _A) -alkyl, _{-CO: l} C _R) -alkyl-S-aryl, -CCl _A-C) -alkyl, -CO _{R X} -C) -alkenyl -CC x -C (1) - and 1 cinema are: i. ny, -CON11-, -CONR ¹¹ -NR ^{1 x} CO-, -CO-, -C00-; -OCO -.-, -R ¹¹ NCONR ¹¹ -, -OCONR ¹¹ -, -NR 4 COO-, -HNSO 4 _and -, -SO 3 -NH-, arylcyclic and 1-keelic: are groups, hete: cycloalkylalkyl. -R ¹¹ NCSNR ^11- . -HNCSNH, -OCSNR ¹¹ -, -NR CSO--, P e: p t i cl u d o b n e :. j bonds; groups, -NHCO- HNCONH-, groups, groups, HNCNNH- D may be absent or may be an alkyl group having 1 to 1.0 carbon atoms, optionally containing an oxygen atom, a sulfur atom or NR ⁰ , which comprises: a branched cyclic or unsaturated alkyl group and an arylalkyl group having 1 to E; carbon atoms in the alkyl radical. P can be 0, 1 or 2; m is an integer from 0 to 5; 312 n is an integer from 1 to 5; W represents -O-, -SCO-p- or -NR ¹⁰ -; Y is selected from: --C0NR ¹⁰ -, -NH C0-- ^lo, ~ S0ÄNR ¹⁰ -, -NR ^lo S0a-, mimicking the binding of the peptide bond heterocyklickébo five membered ring which .is saturated, unsaturated or partially unsaturated containing from 1 to 4 beteroatómy selected from a nitrogen, oxygen or sulfur atom, provided that the macrocycle, represented by formula (I) by -ABDCC R ² ) CR ³ ) -Y-CC R ¹ ) - CC U 1 C R ¹ ) -, is connected at least 11 and at most 22 atoms. . C o n e n e n n e n e n e n e n e n c e) Formula II, or a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein; X is selected from CH _and, NI4, NR ^S, SCO) p or O; IJ, Y, R ¹ , R ² , R ³ , R ' ⁺ , R ^s , R ⁶ , R ^x , R °, R *, R ^{1 <:>} , R ¹¹ , R ^11a , R ^isa , R ^13, R ^lx \ R ^{1 S,} R ^d; ', R ^17, R ^1xA ap, m, n. A, B, D and W are as defined in formula I above provided that: they provide stable compounds; 31.3. Provided that the macrocycle, expressed in formula I by -ABDC- CR ² ) CR ³ ) -Y-CC R ¹ ) -XC CU CR ⁴ ), is at least interconnected: 1.1. and up to 22 atoms. 3. Compound s; (C111) R ¹ Formula II.I or a pharmaceutically acceptable salt thereof, or a prodrug form thereof, in which: U is selected from: -CO _and H, -CONHOH, -CONHOR ¹¹ , -SH, -NHCOR ¹¹ , -MC OH) COR ¹¹ , SNaHaR *. -SO 2 NH * ⁵ , CHaCO 3 H, POC 3 OH, and -POC 3 OH 3 MH 3 +, CH 3 OH and the common derivatives of the intermediates -C (O) NHOR ¹² and -COa R ¹² ; Z is selected from: and nitrogen or CH; R ¹ , R ¹ , R ⁶ , R ¹¹ , R ^11a , R ^XS2 , R ¹³⁵ , R ¹ \ R ^1S , R ^{1 <5} ', R ^1X , R ^1Xe * A, B, D are as defined for formula I or i define stable compounds. 4. A compound according to claim 1, wherein: U is selected Z: -CONHOH, -CONHOR ¹¹ , NCOI-DCOR ¹¹ , -SN ₂ H ₂ R ⁶ , -SONHR ^Ä , -COaH, 314 CH-1SH, -C (O) IMHOR ^12, and common prodrug derivatives; R ¹ is selected from H, - CC o - 0 _Ä ) a 1 ky 1. - With CO p p - CC _{: l} . - C ,,,) and 1. - CC o - · 0 _ώ ) and Article 1. - O- CC ₃ . - C <?.,) And group 1, -CC _of ..... 0 _ώ) alkyl-S O) p C _o ..... C 's,) alkyl-aryl, - the CC - - 0 <d,) alkyl and 1 1 - CC O _o - ±) and 1 s 1 s 1 nary ovejskupiny, alkyl of 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted ... alkyl groups, wherein ... the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy (e.g., phenoxy), and amino, amino and amino; acylamino groups (e.g. acetamido and benzamido groups), arylamino groups, guanldino groups, IM-methylamino groups, imidazolyl groups, imidazolyl groups. groups, mercapto groups, aryl groups, aryl groups, aryl groups (e.g., 1 adphenyls, thio groups), carboxines ups, carboxamido, carboalkoxy trials or sulphonamide ups, COC-C _p) ... and alkylaryl groups, -C (C 1 -C 6), _(a ) an alkylenearyl group in which the aryl radical is substituted, - the CC - C _θ) aryl 1 - CC ,. - C) and Art. ky 1. énary 1. ovejs l <upiny, - C 1 - C, =,) a 1 y y y b y y y y o p y. n y, -CC _a C _~) alkyl-SC O) p-C ~ CC _{of a)} alkylénar.ylovej group, - the CC - _θ C) alkyl, and 1. 1 - S CO) p --- CC _o - _θ C) and 1 s 1 s 1 nary ove .jskup ny 1, vktorej is an aryl radical substituted, -CC _i, -C) alkylenearyl, C-C-C _{o r)} alkylenearyl-II SC O) p ..... CC _H -C _b) alkyl group !, Vej -C (C 0 -C 8) alkyl-SC (O) p -C (C 1 -C 8) alkylenebiaryl, 0ο C ~ _θ 0) alkyl.-0-CC _of C _e)) alkyl-aryl, -C (1, -O (=,) alkyl-SC (O) pC (C (-C ₎ ) alkylenearyl group in which the aryl radical is substituted, And _-CO-C4) alkylenearyl, C-C _of -CE ') _{alkylenearyl-t0-CC;} , -C _s) alkyl Group 1, 5 - CC o - C o) and 11 <y 1 - O- <C _o - C _e > a 1 k VJ - é nb i. ary í ovejgroup i. ny, - CC-C _{o r)} '0-alkyl, - CC-C _{of a)} alkylénar j-yl group, wherein the aryl moiety is substituted, wherein the substituent is selected from: hydrogen, C 3 -C 5 alkyl. h 1, i r, o o 1 1 1 1 1 1 1 1 1 1 1. 1. 1. salines, amylosines, monoalkylaminosines, diols and amino acids, acyl groups, arboxamino groups, or aramino groups; and choose. from H, -CO _S ^S R, -CONR R ^55, CONR ^R ~ 0r C ^s), and 1 1 ovejskupiny alkyl, and one aryl alkyl 1 1 ovejskupiny, and 1 heteroaryl alkyl 1 ... 1 ove the jskup . and heteroaryl, heteroaryl, heteroaryl, and heteroaryl substituted with one or more substituents selected from: a t h a d h, h a l o g g n s u p l n y, h y d r o x y s p u. n y, a 1 k o x y s k p 1 n y, and r y 1 o x y s k p i. n y C n a n. k-1 adphenoxy, amine and acylamino, mono-J., amino-amino, amino-1-amino, aoylamino (C, for example, aminoethoxy and henzamido), arylamino, guanidino, N - meth 1 im idazoiy 1 ove ... groups, im idazo 1 y 1 group, indolyl group, mercapto group, lower acyl group 1, aryll thio group (eg 1 adphenyls 3 thio group), carboxy group 1, su 3 f (5 namidoskup i. ny, carbox and 1 doskup i. nya 1 ehokarhoa 1 coxy groups · R ³ is selected from: an hydrogen atom of an amino group; alternatively, R ^and Aneny characterized ej t n t, s 1 characterized aryl, a three to six-membered saturated, heteroaryl 3 Lots 1 and characterized ebohet e: roc: yk keel I ic ring; R ⁴ is selected from: a hydrogen atom, a hydroxy group and an amino group; 31.6 R ³ is selected from: C IR C _'r Y ^5.-R, -CO R ⁷ R®) ,. V CC R® R ⁷⁾ _m IK, -CO R ⁷ R ^s) '.- R ^5', - CC R® R ⁷⁾ _In - aryl, R ⁷ -CO R®) -CONR ⁷ R®, - · CCR ⁷ R ®) - subsiitu c of the most heterogeneous group I, ..... CCF? ⁷ R ^θ ),, -subs tit uo vheterooyk 1 i. of the okeygroup, in which the subsituency is chosen from. hydrogen, -C (C 1 -C ₅ ) alkyl, hydroxy ... halo-galo-halo-gon-s-p-tyl, thio-p-syl, thio-p-syl, thio-p-s, thio-c-s, p-c, s-c-s, p-c, p-c, p-c, p-c, p-c, p-c, p-c R ^d: "is selected from the. · H, alkyl, - C C i - C) s a 1 k y 1 é n a r y 1 o e ... i s k p i n y, - CC i - C _ώ ) a 1. ky 1. é nhete: roary 1 ovejskup 1 oy, - CC j, - C _ώ) and 1 s 1 s t NH es es es roeyk 1 and HRG de UPIN, -CC al. _C6) alkyl-group j, the windfall al vNES R ^a and R ** may form a three to eight membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from oxygen, -NR ®, SCOT) and p any aeyl group, optionally fused to an aryl ring; R ⁷ and R ® can be selected from: hydrogen, R ¹ , or may form a three to seven membered substituted ring with 0 to 3 unsaturated bonds in which the substituent is selected from hydrogen, C 1 -C 5 alkyl, hydroxy, halo, alkoxy, amino, mono-1-amines, acylamino, thioalkyls, thioalkyls, carboxy, carboamido or aryl groups; optionally containing -O-, -SCOl, -MR ' ² ·, optionally condensing to a substituted aryl ring, wherein the substituent is selected from ·. 317 of a hydrogen atom, an alkyl group having 1 to 5 atoms, at H11. k a, h y d r o x y s p i n y, h a 1 o g e n s k p i n y, and 1 k o x y s k p i n y, am i. n o s k u p i. n y, m o n o and 1 k y 1 am i. n o s k u p i. n y, d i. and i. k y 1 - a m i. r i o s p i n y, a y y am i n o s p i n y, th e s p i n y, th e alkyl- ··· s p i n y, k a r b o x y s; n u, n y, kar b o x a m e d o p u n i a 1 e b o ary 1. o ej s k u p. n y; R ^'5 is hydrogen, alkyl, cycloalkyl of five or six membered ring optionally having one to two N, O, or SCO) p, optionally substituted with hydroxy, -HCC _{:). C-RF>)} alkyl, -O -acylénalkylovou group, NHR ^10, or an aryl group; R (10 ^{) is} hydrogen or optionally substituted alkyl; R ¹¹ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, which includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected from: hydrogen, halogen, hydroxy, alkoxy, and aryl. o x y s k u i, n y C n a r> k i a d f e n oxy s k u i. o y), and m i o o groups, d i. alkyl and i. n o s k u p i n y, c y 1 and m i. (e.g. acetamido and benzamido), aryl and amino. n y, g u and n i cl i n o s u p i. n y, im i. d a z o y y s u u i. o y, i. n d o 1 y 1 o e s s p i n y, m e r a a p t o s p u n y, a 1 k y 11 i o s p u p. n y, and r y 11 i. o s k u i. o y C n i n d a n d e n y 1.1 i. o s k u p i n), k a r b o x y s k u p i. n y, kar b o x and m i. d o s k upiny, l <a r b o a 1 k o x y s k u p i n y a 1 e b o s u 1 phon m i d o s k u p i. n y, -C Cx 0) ..... a1k ylenaryl group, - CC ,. - C) - and i. s 1 - CC _x - _θ C) and 1 s 1 s 1 ovejskup nary i. ny, - C x - C b) -alkylenebir y. j s k u p i. n y, u b s t i. t o (- (- (Οχ-- C ei - 1 y 1 1 é é 1 1,,,,,,,,,,,,,,::: hydrogen, halo, hydroxy, alkoxy, and aryloxy. n y (o and ex k i ad phe o x y s k p i n y), amino s k u p i. n y, d i. a 1 k y 1. a m i. n o s k u p i o, a c y 1 a m in o s k u p. n y 318 (For example, acetamido and benzamido), such as amine, amine, and amine. p i n y, im i d o z 1 y 1 o s e p i. n y, i. n d o 1 y 1 o v e s s p 1 p, m e r a a p t o s p p a n y, and 11 <y 11 i n s l <u p p a y, r y 1.1 i. o s l <u pi n y C n a p rI <1 a d f e n y 11 i. carboxy, carboxamido, carboxyamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, carboxamido, and carboxamido groups. n y a 1 e: b o s u 1. f n n m i d o s k u p i n y, R ^11a represents a hydrogen atom, -SO _and -C 1 -C 11 alkyl, -S0 ₂ .-- C ₁ -C _<& -alkylenearyl radical, wherein the aryl Rest of 111uovaný are bs, -S0 _R -ary1ovú halosubstituted heteroaryl, --COR '''de Detailed - StJjs-subs ti ~ -CO 2 _{R 1} -Bu, -Cfh..Bn or an alkylenearyl group in which the aryl is substituted, the substituent selected from Z: hydrogen, C 1-5 alkyl, hydroxy, halo, the rest alkoxy, amino, monoalkylamino, dialkyl and amino, acyl amino, thio, 11th and 10th groups, k ar boxyskupioy, carbox, and 1. doskupioya 1 or aryl 1 groups; and choose from: a hydrogen atom, an aryl group, CC a. C to) - a 1. ky 1 ovejsgroup, ary 1C C _{: 1} - C <<,) ..... a 1 ky 1 ovejs l <upiny, CC ₃ - (C) - oy l <1 o and 1 o 1 o groups CC ₃ - C xo) - and I. ky 1 carbonones I. oxya I. ky j. ove; jskup i. ny, CC ₃ -C 10 -alkoxycarbonyloxycarbonyl; ny, C ( _and C) -alkyloxycarbonynylupins, C C - C 10) - c y k 1. o and 1 k y 1 k and r-bony 1 o x y and 1 k y I. o v e; j s k u p i. n y, _L3 CC - · C io) - 1 o cycloalkyl alkoxycarbonyl 1 1 1 s 1 Oxya ovejs l <in full, _the ζC -Cio) cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (C --C alk ^ yl group j) and r - 1 y 1 oxy carbonyl (C _t - C <1 and a alkyl ester of 1) -, C g, - C j) - a 11 <o x y a] J <v 1 k a r b o n y 1 x y and J. k y 1 s s u u i. n y, C 5- (C ₁ -C 6 alkyl) -1,3-dioxacyclopenten-2-on-yl] methyl 319 groups, C 5 - aryl-1 -1, 3 - <3 ioxac: yk cyclopentene 1 - 2 - one - I yl) methyl-1 ovejskup ynyl, CR ^{17) 1xA} CR) NC C x C x _{of the} alk yl en UPIN) -, - CHCR ¹³ ) OCC = O) R ¹ ^, -CH CR ¹³ ) CC C = O) C ¹ R ^{1 s} or About which R ¹³ represents a hydrogen atom or a linear alkyl group having 1 to 4 atoms, carbon; ¹ R ¹ 'is selected from: hydrogen, C 1 -C 8 alkyl or cycloalkyl. having from 3 to 8 carbon atoms, said alkyl or cycloalkyl group being substituted with 1 to 2 groups independently selected. z = (C1-C4) alkyl group, C C-Co) cycloalkyl group j, x CC - C _E,), and alkoxy groups I ynyl, aryl en completely substituted independently: selected from: halogen, phenyl of up to 2 sec. en clamps the alk yl group of 1 to S carbon atoms, alkoxy groups a to 6 carbon atoms, nitro, -SCC x C j _{with an} alkyl group), -S-C = 0) CC χ _{C, 5} alkyl), hydroxy . -CC = O) NCR ¹⁷ ) CR ^{17 e} ) denotes 1 to 3 aw S0 χ _CC - _C ove alk y 1 j -NCR ¹⁷⁾ (R ^{17 a),} or - _(ΥΡ Ν, v is from 1 to 2v + 1) group), _{-CO 2} R ^{17 <a} wherein in the aryl group substituted with 0-2 groups independently 320 rolled, of: a halogen atom, a fertyl group, and an alkyl group. nys having 1 to 6 atoms. (C,-C s _s alkyl), -SO a _{and (} Ci-C _{5 5} alkyl), hydroxy, NCR ¹⁷ ) CR ' ^{7, a} ), • Ctf> R ^{: 17 , Λ} , r: C = O (1) (ICR) ^{, 7} ) CR ¹⁷ ··') or in which v is 1 to 3 and w is 1 to 2v + 1); is selected from: alkyl groups having from 1 to 8 atoms, groups having from 3 to 8 carbon atoms, and alkylthio and alkylthio. wherein said alkyl substituted with 1 to 2 groups independently selected from: (C až-C) alkyl, (C až-C cyk) cycloalkyl, (C až-C alko) alkoxy, (C až-Cry) aryl group independently selected from: atom uha 1 og é nu, beny 1 ovejskupi. ny, and 1 1 alkyl ester group having 1 to 6 carbon atoms, alkoxy having up to 6 carbon atoms, nitro, - SCC x - C 1 alkyl and _with one ovejskup i. ny), - SC - H) _{CC: l} - C 1 alkyl and _with one of the Vej), S0 ~ _CC O _{x with} alkyl), hydroxy, -NCR ¹⁷⁾ C R · ^x ")" - -00 ^ 13 ¹⁶ % -CC Unit) NCR ^{17) 17} · CR *) or C _W F _W where v = 1 to 3 and w = 1 to 2v + 1) ·, aryl substituted with 0 to 2 groups independently selected from: atom of the pack 1 -C alkyl group), an alkyl -C0- _and R ^17e>, ogen, phenyl, an alkyl group G carbon atoms, alkoxy of 1 to 6 and 1 Ιί il <a, nitrnskup ny 1, - _x SCC - C _p> 1 and the alkyl ester 1 -SC = O) (C 0 x -alkyl groups), -SO _with CC _x -1.1, groups), by hydroxy group, - NCR ^{1 7} ) CR ¹⁷ "'), -CC = O) NCR ¹⁷⁾ CR ¹⁷⁾ or ~ C _W F _W where v = 3 and a = 1 to ω 2v + 1); R ^1ώ represents an alkyl group 321 having 1 to 4 carbon atoms, benzyl having 1 to 4 carbon atoms and 1 to 6 carbon atoms. n y, R ¹⁷ and R ^17a are independently: selected from: a hydrogen atom, a C 1 -C 10 alkyl group, a C 2 -C 6 alkenyl group, a C 4 -C 11 cycloalkylalkyl group and a C 1 -C 6 arylalkyl group; combinations thereof; A, E3 and D and / or variables) are permissible only if these combinations provide stable compounds (as defined herein); can be: and can be omitted: CHR represent -C ^"5") ,,, -, -0C • CHR ⁵ ') -NR CHR *) ™ -, -SC 0) p CHR) _m - and may be: be selected from alkyl group e; From 1 to 10 carbon, atoms which include branched, cyclic and unsaturated alkyl or -CO _{x C6)} alkylaryl; can; may be a bond or may be selected from: -NH-, -NR ¹¹ -, -NR ¹¹ -. -O-, -SCO-p-CCl-C1-4-alkyl-HN-CCx-C1-4-alkyl, -C3. - (¾) -alkyl-NR ¹¹ -C 3. -0 '',) alkyl, -Cx _R-C-NH-aryl, O-C _and CC _x) -alkyl en UPIN, - _CCX - (¾) alk y 1-0-ar s love j en <UPIN, -S- CC _L) -alkyl, -CO _third-¾) --alkyl-j or S-aryl group, - x CC - C _ώ) - 1 and s 1 ove; jskup 1 ny, - (C χ - C _£ ,) - and 1 keny 1. -CC 1 -C 6 -alkynyl, -CONH-, -CONR ¹¹ , -NHCO-, -NR ^{1: 1} CO-, -CO-, -COO-, -OCO-, -R ¹ 'NCONR ¹³ - , HNCONH-, -OCONR ¹¹ -, --NR @ ^II ~ COO, _R -HNSO -, -SO- .NH-, aryl, cycloalk yl, j en <UPIN, heterocyclic loalk yl, j en <UPIN -R ¹¹ NCSNR ^1x -, -HNCSNH, -OCSNR ¹¹ -, -NR ¹ XSO-, -HNCNNH-, and a peptide bond resembling a bond; S or O 322 D may be absent or may be an alkyl group having 1 to 10 carbon atoms, optionally containing an oxygen atom, a sulfur atom, or NR, which includes a branched cyclic and unsaturated alkyl group and an arylalkyl group and C 1-6 alkyl. - (C 1 -C 4) -alkylene aryl; P can be 0, 1 or 2; m is an integer from 0 to 5; represents an integer from 1 to 5; W is -0-, SCOT) p- or -NR ¹⁰ -; Y is selected from: CONR ¹⁰ -, -NH ^lo C0-, -S0ÄNR ¹⁰ -, -NR ^lo S0a-, mimicking the binding of the peptide bond five membered heterocyclic ring which is saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N , O or s, with the proviso that the macrocycle, in formula I, by -ABDC; - CR ^p) CR ³⁾ -Y-CCR ¹⁾ -CO U) s C ^) -, it is linked to at least 11 and up to 22 carbon . A compound according to claim 2 wherein a is selected from CH NH, sulfur and oxygen; U, Y, R ^1, R. R ³ , R ¹ ', R ³ , R ^A , R ^x , R ^13, R ^{1 1,} R ^13, R ¹ *, R ^17, R ^{17: the} same as defined for R ⁶³ , R ' ⁵ ', R '°, R ¹¹ , ap, m, n, A, above R ¹¹ * ', R ¹ B, D and W are general 323 of formula I, provided they provide stable compounds; and provided that the macrocycle, expressed in the general formula. T by -ABDCC RD CR ³ ) -Y-CC RD -X-CC LO C RD is connected by a minimum of 1.1 and a maximum of 22 atoms. 6. A compound according to claim 1, wherein: l.J is chosen from: -C 1 NHCH, -CO 3> H, -C (O) IMOR ^1, and common derivatives of precursors; R ¹ is selected from hydrogen, -CC _of -0D alkyl-S O) p CO. -CO 1) alkyl, -0-CC _of &) alkyl-O-C C _x CO.) Alkyl, -0-CC _{of 6)} alkyl-S O) p C _a ~ j Ud alkylaryl group, ... C 0 -C 0 alkyl-OC C ₀ -C ₆ ) alkylene aryl, a C 1 -C 20 alkyl group that includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected from: hydrogen, halogen, hydroxy, alkoxy, aryloxy (for example phenoxy), and m and n. n y, mono and I. k y I. and m i n o k u piny, d i. a 1 k y 1 and m i. n o s k u p i. n y, acy 1 and m i. n o s k u p i. n y C n a r i c d a c e there i. d o s k u p i. n y and benzamido), arylamino, guanidino, N-methylimidazolyl, imidazolyl groups. n y i i n d o 1 y 1 o v e j s k p i. n y, m e r k a p t o s p u n y, and 1 k y 11 i o buy. n y, a r y 111. o s k u p i. n y C n a n d e n g e n i 1 ti. k arginites, k arboxides, k arboxamidoscines, k arboalkanes, or sulfonamido groups, -Co-C0) alkylenearyl, - the CC - _θ C) and 1 s 1 Step 1 aryl ester .1 gr. in which the aryl moiety is substituted. tuovan ý, - the CC - _Ce) aryl 1 - _x CC - C ,,) alkyl, and 1 1 1 s nary ove; jskup i. ny, - CC _: i. - C ₀ ) and 1-cyano. aryl group. ny, Co-C-alkyl-S CD O) p C _o -C ₀₎ alkylaryl latter group, 324 - (C _O C _~) alkyl-SCO) p (C _a -C _s) alkyl-aryl, wherein the aryl moiety are monosubstituted with BstEII. - (C- (x x,) and 1-kylenes 1 - (C _o -C _θ ) and 1 1 ery nary 1. - Iľ S (O) p - (C _o -C _θ ) a ľl .. group 1], - (C y - C o) alkyl, and I 1 - S (0) p - _o CC - C ®) and 1 s 1 s 1 nbiary ove ..jskupiny, (Co ~ _C) allcyl-O-CC _o -C _ra ) alkylenearyl, - ·· (Co-CEI) alkyl-S O) p ~ (C _r C _o) j alkylaryl groups, wherein the aryl moiety is substituted, TLT--CCχ ,.) alkylénaryl- _(Co --Cs) alkylenearyl-l O- (C ₀ -C _a) alkyl skuplnyľl,; - (C o - C s) alkyl and 1 1 - CC O _o - _θ C) and 1 s 1 s nt) i. ary 1 ove .groups, - (C ~ _o C _e)) alkyl-O-C C _a -C (=>) alkyl-aryl, wherein the aryl moiety is substituted, wherein the substituent is selected from: a hydrogen atom, a C 1 -C 5 alkyl group, a hydroxy group, a halogen group, an alkoxy group, an amino group, an amino group, a monoalkylamino group, a dialkyl amino group, and an amino group; 1. o s k u p i n y, t i. o a 1 k y 1 s k upiny, k a r b o x y s k p i n y, karb o a m i d s s k p u p a a 1. e t) o aryľl. o v e s s p i n y; R ^s is selected from hydrogen, -CO _Ä R ^{3 3} , —CONR ^Ä R,, --CONR C C (R ^{s s} ), and ileyl groups, and I. 1. Arylamino, and 1-heteroaryl, and 1-heterocyclyl, aryl 1, heteroaryl. a group which is substituted with substituents selected from: a hydrogen atom, a halogen atom, and a hydrogen atom. y k 1 i o k e j one or more h y d r o x y s k p .1. n y, a 1 k o x y s u p a n y, a y. 1 o x y s u p a n y (r t a p o k i a d f e n o x y s p u n y), ami. n o s k u p i n y, m o n o alk y l .. a m i. The acylaminoscupines (e.g. acetamidosups and benzamidosups), arylaminosups, guanidino. n y, M -met y 1 i. m i. d a z o 1 y 1 o e e s p i. n y, i. m i. d and z is a group, an indolyl group, a mercapto group, a lower group and a lower group. n y, a r y 11 i s p u n i (eg k 1 a d d e n y 11 i o o groups), k a r b o x y s k u p. n y, s 1 f ó n a m i d k p in in, k a r b o x a m i. d o s k u p i. n y a 1 e b o k a r b o a 11 <o x y s k p i n y; 825 R ³ and R ' ¹ ' are hydrogen; R ^{: ä} is selected zs -CHR'Y) -CC R ⁷ R 10 ', -, - W-CC R ^x R ^e '), - R ' ⁵ ', CC R ⁷ R ⁸ 'R * ⁵ ', -C (R ⁷ R ¹⁰ ) m-aryl, -C (R ⁷ R ⁸ ) m -COIMR 8 ^from R 8, CCR ^x R ¹³ ) _m - Substituted heteroaryl group. ny, - CCR ⁷ R ⁶³ ) -, which is substituted by a heterocyclic group, in which the substituent is selected from a hydrogen atom, - CC _x - C) and the alkyl group . hydroxy groups i. ny, ha ll. ogene groups, and 1 alkoxy group, amogroups, monoalkyl groups and i. no groups, long 1 amino groups, aoyl and m. noskup i. oy, t i. oskup i. ny, t i. an alkyl group, a carboxy group, a carboxamido group or an aryl group; a hydrogen atom, an alkyl group, -CCx-ί ?. _ώ ) alkylenearyl, - (C 1 -C ₆ ) and alkylene heteroaryl. ny, -CO and x C) alk ylénheterocykliek ej en UPIN, - CC _t x C,) alkyl, and I 1 s triggering: y 1 ovejskupiny, alternatively, R ^a and R 'may form a nitro * j membered ring optionally unsaturated containing: !. 1 to 3 beteroatoms, selected from oxygen, -NR * ⁵ *, -SCO 1 or any acyl group, optionally condensed to an aryl ring; R ¹ 'and R ® may be independently selected from hydrogen, R ¹ , or may form a three to seven membered substituted ring having 0 to 3 unsaturated bonds in which the substituent is selected from; a hydrogen atom, a (C 1 -C 5) alkyl group, a hydrocarbyl group. n y, ha 1 g g n; k u p i. n y, a 1 k x y groups, amino, monoalkylamino, dialkylamino 1. n o e; k u p i. n y, a c: y 1 and i n o s u u i. n y, t i. axis, three and three y 1 s k u p. n y, k and rb o x y with k u p i n y, k a r b o a m i. d o s k u p i. n y a 1 e: t) o a r y I. o v e. 326 p p d d e o b s a h u. j u c i. -0-, S (tl) p. NR * ¹ , p eventual k o n d e n i c. o u n u s ti ti > You. nitrosubstituted aryl circle, h who is s u b s t i. t u e n t o o t i: a hydrogen atom, alkyl groups with 1 to 5 atoms. carbon, hydroxy, halogen-based groups, alkoxy - s k u p i. n y, nor i. n o s l <u p 1. n y, ni o n o a 1l <y ¾ a m i. The amino groups, acylamino, thio groups, thioalkyl groups, carboxy groups. n y, l <a r b o x m 1. d o s u p .1 n y a .. l. represents a hydrogen atom, an alkyl group, a cycloalkyl five or a six-membered ring, optionally containing one to two carbon atoms, and a (b) s (O) p; t u o v h y d r o x y ..... - (C _{1 L)} -alkyl, 1'-acylenealkyl, 1R, RR ¹ °, and 1 e oaryl; ^JO R is a hydrogen radical; hydrogen or optionally substituted alkyl R ^l is hydrogen, alkyl having 1 to 6 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from: -CC of hydrogen, halo, hydroxy, alkoxy, aryloxy (e.g. phenoxy), amino, di, or alk. n o s l <u p i. n y, a o y 1. and m i. n o s k u p i. n (e.g., acetamido and benzamido), and r 1 and m i. n o s k u p i. n y, g u and n i. d i. n o s k u p i. n y, im i. d a z o 1 y i. o v e ... s l <u p i n y, i n d o 1 y ll. o e ... i s k u p i. n y, m r r <a p t o s l <u p i. n y, n i. s e ... j a 1 k y 11 i. o s k u piny, ary 11 i. o s k u i. n y (for example, a c f e y l i t i p i p), k a r b oxy s l <u p i. o y, kar b o x and i d o s l <u p i. n y, karb o a 1 k o x y s k p i n y a I. e: b o s 1 f ó m a 1. d o s p p. n y, - (l: _4. ) - and 1.1 <y ll. é n s 1 <s i <up i. n, substituted - (C ₅ -C ₆ ) -alkylene aryl in which the sub-group is selected from the group consisting of hydroxy, hydroxy, alkoxy upines, aryloxy groups (e.g., 1 adphenoxy groups), 327 am. η ο s k u p i n y „d i. and 1. k y 1 am i. n o s k u p i. n y, a y y and m y n i o n y (for example acetamido and benzamido), and y amam. n o s k u p i. n y, g u n i n o s p p n i, im i d o z 1 y 1. o v e s s p 1 n y, n d o 1 y 1. o v e s s p .1. n y, m e r k a p t o s p p n n, r i n i n i n i 11 i s p n n i, and y y 11 i s p i n. n y (on p r i k a d f & n y 1. th th s p u p uy), k a r b o x y s k p p nn y, kar b o x a m i. d o s k u p i. n y, k and r b o and 1 k o x y s k u p. n y a 1 e b o su 1 phon a m i d o s p u n y, · R ¹¹ 'is hydrogen, _R ~ SO-C _and -Cx -al.kyl.ovú - O., S ₂ - χ C - C _ώ - alkyl D 1 s -, substituted aryl ú ú Item 1 s when not , group, - With Wh:. - ary 1. ovová skupina, - With Cl ₂ - subs 111 uovan úet; an eroaryl group, ~ COR ' ^{, J} , -CO _with t-Bu, -COCOBn, in which the substituent is selected from: hydrogen atoms, alkyl carbons of hydroxy groups, groups having 1 to 1 groups, alkoxy group atoms, and inos upi. ny, monoa 1 ky i. am i. groups, diamines and amines. ny, acylamino group i. ny, 11. oskup i. groups, carboxy groups, carboxam i. doskup i. nya I. or ² is selected from: a hydrogen atom, an aryl group, C C x · - · C o) -alk y 1 o e s. n y, a r y 1C C χ - C) - a 1 keel e j s k p i n y, (C ₃ -C 6) -cycloalkyl, C 3 -C 6 -alkylene and 1-carbonyl oxyalkyloxy, C 3 -C 3 -alkoxyalkylalkyl group, C C - s - C: χ o) - a 1 k o x y k a r b o n y 1 o e s s p i. n y, C C - C 1 - C y k 1 o and 1 k y 1 k a r b o n y 1 o x y and 1 k y 1 o e :. j s k u p i. n y, CC _s - C (o) - cyclo 1 and 1 - Coxycarbonyloxy groups 1, CC _s - C (o) - cyclo and 1 coxycarbones 1. and aryloxycarbonyl, and aryl. oxyc r-bony 1. oxy CC χ - C _ώ a 1 ky 1. ny) -, ary 1. carbony 1. oxy CC χ - C and 1 keel of ejgroup) -, CC _with —C χ) - and 1 alkoxy 1. carbones 1. oxya 1. cyanobacteria, E 5 - C C χ - C and I. k y 1.) - i, 3 - d 1 o x a c y k 1. o p e n t e n - 2 - o n - y 1.3 m e t y o ... j Of 328, (5-aryl-l, 3-dioxa-cyclopenten-2-one-yl) metylove.j group (R ¹⁷⁾ (R ¹⁷⁾ N- (C ₁ -C _1P alk yl en UPIN) -CHCR ^ OCC ^ CDR ¹ ^, -CHC R ¹⁷³ ) OCX = O) OR ¹⁵⁵ or in which R ¹ represents a hydrogen atom or a linear alkyl group having 1 to 4 carbon atoms; R ^1Z1 is selected from: a hydrogen atom, a C 1 -C 8 alkyl group or a C 3 -C 8 cycloalkyl group, said alkyl or cycloalkyl group being substituted with 1 to 2 groups independently selected from: (C1-C6) alkyl group, CC ₃ -C _s) a cycloalkyl group, (C1-C6) alkoxy, aryl substituted with 0-2 groups independently selected from. halogen, phenyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, riitroskupiny, -SCC the -Cgalk yl, j en UPIN), -SC = 0) CC _{II-C with the} alk yl group j ), _and cc -SO _x -C ₅ alkyl), hydroxy, -NCR ¹⁷⁾ CR ¹⁷ "), -COAr ¹ -CC = O) NCR ¹⁷⁾ CR ¹⁷⁾ or C _W F _W where v = 1 to 3 and ui = 1 to 2v + l), aryl substituted with 0-2 groups independently 329 selected from: halogen, phenyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbons, nitroskuplny, _{-S-C l} -C _s alkyl - SC = 0) CC i. -C _s alkylalkyl groups, -S0 _with CC _x -C _s groups), hydroxy groups, - MCR ^{1 x} ) CR ^{17 (a} ), --C (F ^{1 x} ) CR ^{1 X 1 a} ) or - C ₁ F _w> in which 1 to 3 and w is 1 to C 2 + 1); alkyl) -CO- R ¹⁷ ' ^O , v is selected from: (C 1 -C 8) -alkyl, (C 3 -C 8) -cycloalkyl, wherein said alkyl to (or cycloalkyl) group is substituted by groups independently selected from: (C až-C) alkyl, (C až-C cyk) cycloalkyl, (C až-C alko) alkoxy, (C až-Cry) aryl group independently selected from: a halogen atom, a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to B carbon atoms, a nitro group, -SCC j. C j _{with an} alkyl group), -S-C = 0) C C -C _{alkyl-SOS> (C,} C _{L ss} j The alkyl -NCR ¹⁷⁾ (R ^J ^), or C _W F _W, a group), -CFF ³ R ¹ , wherein in the group (1), hydroxy groups, -C (C = O) NC R ¹⁷ ) CR ¹ '( ^O ) means 1 to 3 and w is 1 to C 2 + 1); aryl groups substituted with 0-2 groups independently selected from halogen, phenyl, C 1 -C 6 alkyl. alkyl) -c, _with R ¹⁷ ' ^e , carbon atoms, alkoxy groups of 1 to B carbon, nitro groups, -SC _CΊ . C _{to the} alkyl s - SC - H) _{CC: l} - 1 and _the C s i. - SCC _{: L} -C _with groups), hydroxy groups, -MCR ¹ (CR ¹ ), -CC = O) NCR ^{: 17} ) CR 11 ^a ) or -C _V F _W , wherein v is 1 to 3 or w is 1 to C 2 + 1); 330 R ^<1> represents an alkyl group having 1 to 4 carbon atoms, a benzyl group or a phenyl group, R ^1X and R ^1XÄ are independently selected from: a hydrogen atom, a C 1 -C 10 alkyl group, a C 2 -C 11 alkenyl group, a C 4 -C 11 cycloalkylalkyl group and a C 1 -C 10 arylalkyl group. Ei carbon atoms in the alkyl moiety; combinations of A, B and D and / or variables are permissible only if these combinations provide stable compounds (as defined herein); It may be omitted or may be a -CCHR ⁶⁾ ™ -, -CKCHR *) ™ -, -NR CHR ⁶⁾ ™ -, -SC 0) ρ ^(ΟΗΡ ώ) _π, - or selected from alkyl of 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl or - (C 0 _χ-ώ) ylénarylovú en alk is hydroxyalkyl; may be a bond or may be selected from: -NH-, -NR ¹¹ -, -NR ¹¹ ** -, -O-, -SCCDp-CCx-O (alkyl) -HN-CCx-C () - alkyl groups, - (C 1 -C 6) -alkyl-NR ¹¹ -C ¹¹ x -C _A 1 -alkyl groups, -C ¹ -C 4 -NH-aryl. jskup i. ny, - O (C _x - Ei _ώ) - 1, and one alkyl ester group, - (CIX -0 _ώ) -alkyl-O-j of the aryl, -S-C-C _{x R)} -alkyl, - ( C _x -C *) -alkyl-S-j of the aryl, - (C χ - Ei _ώ) - 1 and 1 ovejskupiny alkyl, - (E χ - Ei _ώ) - and I keoy ovejskupiny 1, - (C ₁ -C a _- alkynyl, -CONH-, -CONR ¹¹ , -NHCO-, -NR ¹¹ CO-, -OCO-, -C00-, -OCOa-, -R ¹¹ NCONR ¹ HNCONH-, -OCONR ¹¹ -, -NR ^II COO-, -HNSO _p -, -SO _and -NH-, aryl, cycloalkyl alkyl 1 1 o 1 ove .jskupiny, heterocyclic alkyl of 1 1 ovejskup ins, -R 1 NCSNR ¹¹ -, -HNCSNH, -OCSNR ¹¹ -, -NR 5 CSO-. -HNCNNH- and peptide bond mimicking bonds; S or 0 ' 331 D may be absent or may be an alkyl group with; (1) to (6) carbon atoms, which includes a branched cyclic anesthesia and / or a CC _{: 1} ; - C 1 -C 1 -alkenylcarboxylic acid; P can be 0, 1 or 2; m is an integer from 0 to 3; n is an integer from 1 to 4; W is -0-, SCOT) P--, or -NR ¹⁰ -; is selected from: -C0NR ¹⁰ -, -NH ^1O CC1, -SO ^ NR ° -, -NR ° SO _and ^L -, a peptide bond mimicking the binding of five membered heterocyclic ring which is saturated, unsaturated or partially unsaturated containing 1 to 4 heteroatoms , selected from N, O or S, with the proviso that the macrocycle, expressed by the general -ABDCC R ^a) CR ³⁾ -Y-CC R ¹⁾ -CO IJ) CR ⁴⁾ -, .is formula I, connected at least 1.1 and up to 22 atoms; wherein, for compounds of formula I, they are only claimed for which compounds of formula I are claimed. 7. Compound P o d l. 2, v y z n a n u ... j ú c a s a T that x is selected from _a CH, NH, sulfur and and thymocycloalkyl; ll is selected from: -CC ilči n n ... j 1. a t k y; 1..J4, -CC), R ¹²² and _S al .. o n c l d e r i v o t o prodrug Y, R ^{@ 1} , R @ ²² , R @ - R1S, Ia · _R ,. R RR ⁷ , RT R RT R ³ R ^: R 1 and p, m, n A, B, D and W are as defined 332 as in the case of formula I above stable compounds. and define on condition that the macrocycle, represented by the general formula I by - AB-11-CC R ² 'C R''-Y-CCR''-X-CC (CR ¹ ) -, is linked at least 11 and up to 22 atoms. 8. A compound according to claim 1, wherein: 1J is selected from: -CONHOH, -CO-H, -CCO) NHOR ¹ and common prodrug derivatives; R ¹ is selected from hydrogen, - C Co. -Cl,) yl alk-1 SCO) p-C CC _{T R)} en clamps the alkyl, - CC _o - (C 1-6) alkyl 1.-O- (CC _A ) alkyl group, Co-C-0 <&) C alkyl-S) p C _o -C ₆₎ alkylenearyl ester group, -0-CC _{of a)} alkyl-O-C C _O C _R) alkylenearyl ove j moiety, an alkyl group having 1 to 28 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected , from: hydrogen, halogen, hydroxy, alkoxy, aryloxy (C 1 -yloxy (e.g., 1-adphenoxy), aminosupines, monoalkylaminoscupines, acyl amino groups, acylamino (e.g., 1-acetamido and benzamido), guanidlnos kupiiny, N - methy 1. imidazo 1. y 1. o o o o, im 1 dazo 1. y 1 o o o o o. j s k u p 1. n y, m e r k a p t o s k u p i. n y, a 1 k y 1.1 i os ;; k i p i n y, ary 1.1 i o groups C n i p. k 1. a d f e n y 1.1 i o s k p i n y), k arb xysk upiny, k arboxamidosk upiny, k a r b o a 1. k o x y s k p 1 n y a 1. e b o s u 1. f n n m i d o s k p 1 n y, - C o - C g,) a 1. k y 1 é n a r y 1. o v. j s k u p 1 n y, -C (Co-C0) alkylenearyl group in which the aryl radical is s, b, s, c, c, c, c, C, C, C - CC o - C g, ary 1 - CC _{: 1} - C) a. j ss, - C.,. -C _B ) alkylenebiaryl groups, 333 C (o. _O --Cra) alkyl-S O) p ll. _o -C ( _E) ) alkylenearyl, - the CC - Ce, and 1 1 s 1 - SCC) p - _θ CC _C) and 1 s 1 s 1 ovejskup nary ny 1, vktorej is an aryl radical substituted, T ^ -CO-C) alkylénaryl- (Cg-Ce) alkylénar yl-C S (0) p (-L _'E C _O) alkyl ..... skuplnyľl, -C (C 1 -C 6) alkyl-SC (O) (C (C ₀ -C ( _E) ) alkylene-aryl groups, --C THE PIN alkyl-0- _(Co -Ce3> j alkylaryl group, - C C-1: a) one alkyl and one SCOT) p - CC _{of the} C _r) and a 1 s 1 s nary ove 1: 1 jskup ny, vktorej is an aryl radical substituted, -CCl-Ctl ·) alkylenearyl, _C-O-C C _B) alkylenearyl-C0- C _Co-C) -alkyl j Group3, -CO-C _{O E))} alkyl-0- CC _H C _B) alkylénblarylove j groups, - _the CC - C _θ) and y Ik _1-0-o CC - Ce) alkyl, and 1 1 1 s nary ove ... jskup ny 1, vktorejje an aryl radical substituted, wherein the substituent is selected from: a hydrogen atom, an alkyl group having 1 to 5 atoms, a hydrocarbon atom, a hydrogen atom, a hydrogen atom, and a hydrogen atom. n y, am i. n o s k p i, n y, m o n o a 1 k y 1 am 1. n o s k u p 1. n y, d i. a 1 ky 1 am 1. nose coupons, acy 1 am 1. noskup 1. ny, 11. oskup 1. ny, 11. oa 1 ky 1. sk upiny, k ar boxogroup, k arboamido or ary I. group 1. ny; and selected from H, -lľ.O _p, R ^'R, -CONR ⁶ R ^S, CONR ⁶ C 0R ^s), and one alkyl ester of 1, 1 and 1 alkyl aryl 1 ovejskup i. 1, 1-heteroaryl-1-yl, and 1-heterocyclyl 1.1. c: a 1-group, ary 1-group, a thi er oar y 1-group, nya 1 or a heterocyclic group which is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryl, aryl, amino, amino, monoalkino laminos, dialkylamino, dialkylamino. n y, a c y 1. a m i. n o s k p p n n C n p p r i n t c t t 1. d o s k p p. n y a b e n z i i. d o s k u p 1 n y), ary I. and m 1 n o s k u ρ »1. n y, g u a n 1. d i. n o s k u p i. n y, N - m e t y 11. m i d azol 1 o v e s s u>. n y, im i. d a z 1 y 1 o e e s s p 1. n y, i. n d o I. y 1 o e s e p i, r i y, m e r k a f> t o s u p 1. n y, pi i. e s i i k s 11 i o s k p i n y, ary 111. o buy. n y C n a p> r i. hair dryer 11 i. o s k u p> i n y), k a r b o x y s k u p> 1 n y, s u 1 f n n m 1. d o s k u p i. n y, 334 k a r b o x a m 1. d o s k u p. n y a i b o l <a r b o or I. k o x y s k u i. rt y; R @ ⁵ and R @ ¹ is hydrogen; R ⁵ is selected from: C CHR Y) _R, -R ^7, -CO R R ^63),., - IAI CC-R ^x R ^Fi) m R ^7, -CO R ^X R ^F ') tt, R ^7, -CCR ^X R ^B ) -aryl, - CCR ^x R ^θ ) ', ..... heteroaryl group i. ny, - CCRR ⁶³⁾ _m - Et eteroc: yk 1 1 iokejskup NY; R ** is selected from: a hydrogen atom, an alkyl group, -CC. ·, .- C _O) alkyl-aryl, - CC _; - C s) and 1-cyano-heteroaryl, - CC i - C: _A ) and 1. cy et é et etococ: yk 1 ic: groups, - CC χ - C s) alkyl and 1 1 ert and Cy 1 ovejskupiny, alternatively, R ^a and R ⁶ may form a three to eight membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from O, NR **, -SCO) p or any acyl group, optionally condensed to an aryl ring; R ⁷ 'and R ^you can be independently selected from: hydrogen, R ¹ , or may form a three to seven membered substituted ring. with 0 to 3 unsaturated bonds in which the substituent is selected from = hydrogen of an alkyl group of up to 5 atoms in Et 1, hydroxy; ny, ha 1 og é nskup i. or I. alkoxy groups, amino groups, moieties and amines. no skupirty, d i. or 1. ky 1 am i. noskup i. ny, acy 1 and 1 noskupin y, t i. groups, i. oa ľl. ky 1 ..... s k u p i n, k a r E> o x y s k u p i. n y, k a r Et o and i d o s u u. n y a 1 e ε »o of an aryl group; optionally containing -O-, -SCOl, -NR **, optionally with condensation to a substituted aryl ring in which the Et is a hydrogen atom, a C 1 -C 5 alkyl group, an alkoxy group i. n y, ha 1 o g e n s u i. n y, a 1 k o x y 3315 groups, aminos ups, monoalkylamino groups, dialkylamino, acyl, acylamino, 11 o, acylamino, 11 and acylamino. d o s p u n y a 1 e b o arylic s p u n y ·, R ' ⁷ represents a hydrogen atom, an alkyl group, a cycloalkyl five or six-membered ring, optionally containing one to two nitrogen atoms, acid. ca or SC thi p, optionally substituted by hydroxy, -O-C 1 -C 4 alkyl; -O-acyl-alkyl, ^NHR10, or aryl; R ¹ c is at om s H or P r 1 p a d e s u b s t a t u t a t u a l k y ll o o a group; R ^{1: 1} represents a hydrogen atom, a C 1 -C 8 alkyl group that includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected. z = hydrogen, halogen, hydroxy, alkoxy, aryloxy (for example phenoxy), amino, dialkylamino, acylamino; (C (for example, acetamidocycles and benzamido groups), arylamines. nosk ups, guanidlrios ups, imidazoles in groups, mercapto groups, mercapto groups, n. alkyl. t í. os; kup i. ary, ary 11 groups (for example, adenylen 1.1 ios), carboxy group 1, carboxamido group, carbo group 1 thio group 1 phoneme 1 into group, - CC ₃ . - (lb ,.) and 1. ny, ed substituent ej - _(C3. - C @) - 1, and alkyl aryl Step 1 and gr. those who reject :; ubst í. tu entzvo 1 í. from : hydrogen, halogen, hydroxy, alkoxy, aryloxy (C, for example, phenoxy), amino, dialkylamino, acylamino and acylamino (e.g. acetamido and benzamido), aryl 1-amino, guan 1 dinoskup i. n y, i. m 1 d a z o y y p o y, i n d o 1. y 1. o o g y p y y, it can be: -: r y a p y y p y, n 1 th e n y 1 y y p i y. n y, a r y 11 i o s p i n C n a p l i 1 a d 336 ph e y 11 i s l (u p i n y), l <a r- b o x y si <u p i. n y, k and r b o x and i d o s k u p. n y, k and r b o and 1 k o x y s k u p. n y a 1 e l :: i o s u 1 f r rt a m i d o s u u piny, R ¹¹ '' represents a hydrogen atom, -SO _and -C ₁ -C ₁ -alkyl, - S 0 _s . - C: j. - C - alkyls - substituted loans i. in the accounting group, - S 6 s> - aryl 1 group. nu, - - S 0 _Ä - subst. disubstituted heteroaryl D s 1 U is, CCjR * ⁵ * -60 .--. 1-13, -C n 0 _r J 3, wherein the substituent is selected from: hydrogen, C 1 -C 5 alkyl. k a, h y d r o x y s k u p i n y, h a ll. o g e n s u p i n y, a m i. n o s k u p 1. n y, sea a 1. k y 1. a m i. r t o s k u p i. n y, d i. and 1 k y .. .. - am i. n o s u> u. n y, and c: y 3. am i. rt o s k u p i. n y, th e s p i n y, th e a 1 k y 1-s k p i n y, k a r b o x y s k p J, rt y, k a r b o x am i. d o s k p p n y a 1. e b o ary 1 o s p p rt y; is selected from: a hydrogen atom, an aryl group, C C - C x O) -alkyl groups J, CC _and aryl) alkyl, C Css-Cj. (x) -cycloalkyl, C 6 _{:: ϊ} -6 xo) - alkylcarbonyloxyalkylLove j sk upirty, C (-, - C x) - a 1 k o x y k a r b o n y 1 o x y and 1 k y ll. Buyer. n y, C 6 _s - C xo) - and 1 alkoxycarbonyl groups, _CC - C * o) -CY 1 to about and II .. 1 alkyl carbonyl Oxya II .. 1 1 alkyl ester group, C 6 _s -C x) -cycloalkoxycarbonyloxyalkyl groups. ny, CC _s - C xo) - cyclo and 1 cox or rborty 1 group. lips, aryl oxycarb on y love jskup i. ny, aryl 1 oxycarbonyl rt yl oxy CC 1 x - C 1 alkyl and _R 1 ovejskup s. ny) -, ary 1 carbonyloxy oxy (1: - C and 1 keel group) -, C 5 -C 6 -alkoxyalkylcarbortyloxyalkyl, II '5 - CC x - (I: II _with a. S q) -1, 3 - dioxac: 1 yk the ope rt - 2 - o rt - 1 II yl methyl ester of 1, C 5 - ary l l .. -1, 3 - d 1 oxacycl 1. Openten - 2 - on - y 1) methyl e. (R ¹⁷ ) (R ¹⁷ '') IM - (C χ - C: χ o and 1 cy 1) -, - CHC R ^ ¹⁾ 06 (-0) R ¹ -CHC R ¹³ ) 06 (== 0) OR ^J '··' or 337 R ¹³ represents a hydrogen atom or a linear alkyl group having 1 to 4 atoms, carbon; up to 8 carbon atoms or up to 8 carbon atoms, the cycloalkyl group being R ¹ ' ¹ is selected from: and the alkyl group having 1 cycloalkyl group having 3 said alkyl groups or substituted by 1 to 2 groups independently selected from: (C1-C4) alkyl groups, CC ₃ -C _s) cycloalkyl, C 1 -C ₅ ) alkoxy, aryl substituted with 0-2 groups independently selected from = halogen, phenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy. alkyl, nitro, -S (C, -C _s alkyl), -S-C-C) _{x-C in} CC with alkyl with 0-. CC i C sä 1 -NCR ^1? (R ^1Xa ), or C group), -CO _R R ^{X 7 '£} \ in which Vej), -OH, -COO) NCR ^1x ) (R ^17a ) means 1 to 3 and w is 1 to 2 (+ 1) -1, an aryl group substituted with 0 to 2 groups independently selected from. halogen, phenyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, C ^ -SCCi-alkyl), -S-C = 0) C C ~ _C alkyl), -SO C C C _{x s} alkyl), hydroxy, -N <R ¹⁷⁾ CR ^{17 N),} 338 CO _and R ³ = -CO 4j) ^{3 3} NCR) CR = ¹ ^), or C _W F _W vk therefore v'znamená '1 to 3 and uj is 1 to 2v + 1st); choose Z: alkyl of 1 to EJ atoms, carbon, cycloalkyl of EJ to 8 atoms, carbon, said alkyl or cycloalkyl group being substituted with 1 to 2 groups independently selected. z = C1-C4alkyl, carbon, cycloalkyl of EJ to EJ carbon atoms, alkoxy of 1 to EJ atoms, carbon, aryl substituted by C1-C2 groups independently selected from z. halogen, phenyl, alkyl of 1 to Ei carbon, atoms, C1-Ei alkyl, ni.troskupi.ny, • - SCC x - C 1 alkyl and _with one ove: i jskup. ny), - S (= CO CC χ - C 1-6 alkyl groups), hydroxy group. ny, -CC-EJ NC R ³ - CR ¹ - - S O »C C C _a a 1 1 alkyl ester -NCR ^{3 3) 3} CR ^ - ^)) or C _W F _E in the group), ~ _S CO wherein R ¹ is 1 and the 3 aw means 1 to C2v + 1); aryl substituted by 0-2 groups independently selected from: a halogen atom, a phenyl group, an alkyl group having 1 to 6 atoms. carbon, alkoxy groups having 1 to E1 atoms. carbon, low-group, —SC C _{: 1} - C _{with an} alkyl group. ny), - SC = O) CC χ - C _s and alkyl group. ny), - EF> CC χ - Ei _alkyl group), -OH, -NO R ¹³⁾ CR ¹³ **), -CE1, ^R-1 '''X-CC = O) NCR ³³⁾ CR ^{L 3 a} ) or -C _V F _W , wherein v is 1 to EJ and o is 1 to C 2 + 1); represents a C1-C4 alkyl group, a carbon, a group or a phenyl group, benzyl combinations of A, B and D and / or variables are only permitted if they are:. e t o k om k:> i rtation. e p o s k y t rt u s t a b i. (1) (a) (c and k are defined herein); 339 And it can mean -NR ⁶ - (CH 2) _n -; -C (CH-), -O-C (CH-)), -S-C (CH-)), B may be a bond or may be selected from: -NH-, -NR ¹¹ -, -NR ¹¹ '-, -O-, -SCO-p-CCl-C (alkyl) -HN-CCl-C 1-6 alkyl, - CC : L - CA) - a 11 <y 1 - N f ¹¹ - CC a. - C _ώ) - 1 and s 1 j ... ove, -C _third -C-NH-aryl, -OC _{C L} C _R) -alkyl, - CC _T - C) - a 1 s 1 - 1 O-aryl ovejskup different, alkyl, -CO-C _{x A)} -alkyl-S-aryl and -CO-C _R) -alkyl, -CO _{third C6)} -alkenyl -CCl _A ~ C) -alkynyl, -CONH-, -CONR ¹¹ CO NR ^II, -0C0-, -C00-, -OCO -.-, n CONR ¹¹ R ¹¹ -OCONR ¹¹ -, NR ¹¹ COO ~ ~, _R ~ -HNSO, -SO ₂ NH-, aryl, cycloalk yl en UPIN yl heterocykIoalk -R ¹¹ NCSNR ^1x -, -HNCSNH, - -OCSNR ¹¹ -, -NR ¹¹ CSO-, a peptide bond mimic bond; S-CCx-C *) groups, groups, -NHCO- HNCONH-, groups, groups, HNCNNH- and may: mean. 0, 1 or 2; represents an integer from 0 to 3; represents an integer from 1 to 4; is -0-, SCOT) p- or -NR ¹⁰ -; select Z: CONR ¹⁰ -, -NH ^lo C0-, -S0aNR ¹⁰ -, -NR ^lo S0a-. a peptide bond imitating the bonds of a five membered heterocyclic ring which 340 .is a saturated, unsaturated or partially unsaturated containing up to 4 beteroatómy 1, selected from N, O or S, with the proviso that the macrocycle, in formula 1 with -ABDC- (R ²⁾ CR ³⁾ -Y CCR ¹ ) ~ C.CU1C R '*) -, is connected at least. 11 and up to 22 atoms. A compound according to claim 1, or ... an acceptable salt thereof, having the formula IVa or or IVd, characterized in that the pharmaceuticals IVb or IVc _R 11a / HOHNOC R ¹¹ R ¹ IVb HOHNOC R ² R ¹ 341 or a pharmaceutically acceptable salt thereof; or prodrugs of effective activity. R ¹ is selected from hydrogen, -CC _of -OD alkyl-S O) p Cj. CD-j alkyl group, -CC _o -OD alk y 1-0 ..... CC j. -CD alkyl groups, - CC: o ..... (CU) and 1-SCO) p - CC: _o - C (1) and 1-cyan-1-group, - CC o - C 1, 1 and 1. - O - CC: _o - C _A ) 1. C1-C20alkyl, which includes branched, cyclic and unsaturated alkyl, of a substituted alkyl group in which the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy (e.g. phenoxy), amino; mono-, mono- or mino-groups, dia- and amyno-groups, acylamino (C (e.g. acetamido and benzamido)), arylamino, guanidino groups. N - methyl imidazolyl group. ny, 1mi da z. o 1 y 1 ove ... groups, i. ndo ľl. y ľl. mercapto groups, mercapto groups, alkylthio groups, arylthio group C (e.g., phenylthio), carboxy, carboxamido groups, carboalpha. koxyskur> inya 1 ebosu 1 phon am i. - CC _o —CD and 1ylenic groups, - C 0 - C 1-6 alkenyl groups, wherein the aryl moiety is substituted, - CC: o - C e,) ary 1 - CC _x - C a 1 ky 1. é nary žl .. ove ... jskup .1. ny, - C 1 - C 1) and Art. k y 1 é n b i a r y ll. o e e s; k u p i n y, -CO-C _o) alkyl-SC H) p C _O-CD alkylénar ..j yl group, - CC o - C o o a 1 ky 1 - S CO) p - CC _o - CD a 1 ky l. an aryl group in which the aryl radical is substituted, - CC: χ - CD and cyanogen 1 - CC; o -C _θ ) and 1. - IO SCO (p - CC: _o - C: _θ ) or Article 1 o], - CC: _o - t = C>) and a 1 s 1 - SCO) p - CC _{of the} - _and C) and one alkyl ll. é nb 1 ary 1 of the group, - CC: o - C ₀ ) and I. ky I. - O- CC _o - C _θ ) als I of the 1st group, - CC o - C _Θ ) and 1 - S (CO) p - CC _o - C _θ ) and 1. ny, vktor e. j is an aryl radical substituted, - CC χ - CD and 1 ky ll. s Reg-yl C C _o - C: _θ) and s 1 II. Step 1 and the hole - II _{'of the} CC O - _θ C) al ky I ove' j 342 groups !, CC - E C,) alkyl, and I 1 - O (C _o - C _θ) and II .. s .. s II nbiary I ove ... jskupiny, - (C _a -C _ej) alkyl-0- (C-C _{of C,)} j aľlkylénar yl group in which the aryl radical is substituted, wherein the substituent is selected. FROM: a hydrogen atom, an alkyl group of 1 to 5 carbon atoms; 5 carbon atoms, h ydroxyxy, b and thioxy, and 11 &apos; s-upines, aminosupines, monoalkylaminosupines, alkaloids, and alkanoids. o a 1 k y ll ..... carbonyloxy, carbonyloxy, cyclohexyl and aryl and aryl; R · is selected from hydrogen, CO, _and R ^3, -COMR * 'R ^3, -COIMR * "(OR ^3), and I s II. ary 1, ary 1 ary 1, ary 1, y 1 hete: roary 1 oy, a 1 y 1 hete: rooyk y. halo groups, aryl groups, heteroaryl groups, or heteroaryl groups. which is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy groups, aryloxy groups (e.g., to 1 adphenoxy groups), complete amino, monoalkylamino groups, dialkylamino groups, acylamino groups (e.g. for example: tamidosl (up 1 nyabenz am 1 doskup 1 ny), or ry 1 am inogroup, gu or dino group, IM - methyl 1 i. m i d a z o ll. y 1 o e: .j s k u p 1 n y, im i d a z o 1. y ll. ool, indolyl, mercapto, lower and 11 &apos; carboxy, sulforiamino groups, k ar boxamidosupines or arboalkoxy groups R ³ is selected from: - (C ^{IR: l} Y) _n · R'C - C (R ^X R®), ·, - ·· U) C (R R®) "· R *, -C (R ^ R®) ^ -1 ^. -C (R ^X R R) ', - aryl, C (R R R)', CCIIMR R R ', - (¾: (R ®), _T1 - · hete: roary ll .. C (RR ®) _In - heterooyk 1. R * ’is selected from: a hydrogen atom, an alkyl group, 343 - the CC - _R C), and 11 <s 1 s 1 nary ovejs l <UPIN - C C C _φ) and s 1 s 1 s n Het lo er oar in jskup: i. ny. - CC _{; 1,1} -C, *) alkylene heterocyclic group, - CC: i. - - C _Ä ) and 1 ky. Alternatively, R ⁵ and R ⁵ * may form a three to eight membered ring, optionally unsaturated, containing from 1 to 3 heteroatoms selected from an oxygen atom, -NR ***, -SCO) or any aryl group , condensation condensation of the ring; R ⁷ and R ® can be independently selected. FROM: a hydrogen atom, R ', or may form a three to seven membered substituted ring with 0 to 3 unsaturated bonds in which the substituent is selected from ·. a hydrogen atom, an alkyl group of up to 5 carbon atoms, thyridine, h and phenylene, and aryloxy, and amine. n y, m o n o ľ y ľ am .. .. .. am am am am am am 1 am am am am 1 am am 1 1 1 am 1 am am 1 1 am am 1 i i i i a l .. ľ .. amin amin amin amin amin amin amin amin amin amin amin amin amin amin osk osk amin amin amin amin osk osk osk osk amin osk osk osk osk amin osk amin osk osk osk osk osk osk osk osk osk osk osk osk; optionally containing -O-, -SCOl, -NR ^ώ , with optional condensation to a substituted aryl ring in which the substituent is selected from: a hydrogen atom, a (C 1 -C 5) alkyl group having 1 to 5 carbon atoms, h y d r-o x y s; k, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p, p; k u p 1 n y, k a r b o x y s k u p i n y, carb o x m i d o s p u n y a 1, e b o ary 1 o of a group; R ' ⁷ represents a hydrogen atom, an alkyl group, a five-membered or six-membered cycloalkyl group, optionally containing one to two nitrogen, oxygen or SCO 1 atoms, optionally substituted with hydroxy, -O-CC 1 -C ( _A ) alkyl, -O-acylenealkyl, NHR ¹ '' or aryl; R ¹⁰ represents a hydrogen atom or an optionally substituted alkyl 344 group; R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, which includes branched, cyclic and unsaturated alkyl groups, a substituted alkyl group in which the substituent is selected from: a hydrogen atom, halogen, hydroxy, alkoxy groups, aryloxy groups, and n. k 1 and ó f e n x y s k u p i r i y), am 1 n o s k u p i. n y, d 1 and 1 k y 1 and m i. (e.g., acetamido and henzamido), arylaminocupines, guarvidino, imldazolyl groups, such as those described in claim 1, wherein the compound is a compound of formula (I). n y, a r y o p p n y (n a p h e p i p d p i n p p n y), k a r la x y s l p u p i n, l <a r h o x a m o s p p n n, k a r h o a 1 k o x s e. f ó n a m 1 d o s k u p 1 n y, - CC i - C) - a l i 3. é nary i. 1 gr s account not substituted by - (C-C _B) -alkylenearyl radical, where the substituent is selected from hydrogen, halo, hydroxy, alkoxy, aryloxy (e.g., phenoxy), and m and n; a 1 k y 1 and m i. n o s k u p i. n y, and c; y 1 a m i n o s l <u p i. n y (e.g. acetamido and henzamido), aryl 1 and m i. n o s k u p i. n y, g u and n i d i. o o s p i n y, i. m i. d a z o 1 y 1 o e e s p i. n y, i. n d o 1 y 1 o v e s e. r> y, m e r k a p t o s u p i n y, where e .j a 1 k y 11 i. s p p n n y, p n p p n n y (on p r 3. I <1 a d f e n y p n n p n y), kar b o x y s p p n n, k a r b o x a m i. d o s k u p i. n y, l <a r b o a 1. k o x y s l <u p 1. n y a 1. e b o s u 1 f n n a m i d o s l <u p i. n y, represents a hydrogen atom, -SO 2 -C 1 -C 6 -alkyl, -SO 2 -C 1 -C 6 -alkyl-substituted aryl, - S Os - - aryl 1-upin, - S 0 _- > substituted heteroaryl, -CfJR ^<3> , -CO _and t-Bu, -C (J -, Bn, wherein the substituent is selected from: a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, and a hydrogen atom, and a hydrogen atom, and a hydrogen atom, and an alkenyl group. n y, d 1 and 3, k y 1 and m 1 n o s k u i. n y, a y y am i n o s p i n y, 11 o s l <u p i n y, t i. 3. 345 TIl with l <u p i. n y, card o x y s p 1 n y, ary I. o v e s s p i n y; k a r b o x and i d o s k u p i. n y a 1 e b o is an integer from 0 to z o and not an integer from 1 to 5; P can be, 0, 1 or 2; W is - (.); -, SCOT) p- or -NR ¹⁰ -; Z is CH-. or an oxygen atom; is selected from: -C0NR ¹⁰ -, -NH ^{3 O} C0-, -NR ³ -SO-.NR ° ³ S0 ₂ - _(peptide bond mimicking the binding of five membered heterocyclic ring which is saturated, unsaturated or partially unsaturated, and which contains from 1 to 4 beteroatómy, selected from nitrogen, oxygen or sulfur. 10. The compound of claim 1 wherein: is selected from the group consisting of: S, 5 R, 6 S-3 - and z a - 4 - o x o -10 - o x a - 5 - · i. 1 - 2 - - C N - m e: t y 1 k a r b o x a m i d o) - C101 p a r a e; y k 1 o fan - 6 - N - h y d r o x y k a r b o x am i. d; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-b-isobutyl-2-C-carboxymethyl) -1- (3-arylamino) -6-N-hydroxybenzyl-amine. d; S, 5 R, 6 S-3-a z a ~ 4-o x o -10-o x a-b-i. z o b u t 1 - 2 - C N - b e n z y 1 k a r · b o x a m i. d) -1113 paracyclopropane-6-N-hydroxycarbamamide; 2S, 5R, 5S-3-aza-4-oxo-10-oxa-5-isobutyl-2-C hydroxymethyl) -C10 3 paracyclophan-6-N-hydroxycarboxamide; S, 5 R, 8 S - 3 - and z a - 4 - o x o -10-o x a-5 i. 3. 2. 2-C1-a-1-en-N-methyl 1. am i. d) -1113 paracyclophan-6-N-hydroxycarboxamide; 34 (5 2S, 5R, 6S-3-aa-4-oxo-10-oxa-5-isobutyl-2-C1- (O-methyl) tyrosine-N-methyl lamellae; -I '1.0µl paracyclophan-6 · -N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-yl; butyl) serine · - M - cysteine 1. a m i. d l - - 1. 1. ()) l p a a::: 1. 1. o o o o o o o o o o ((((((((((( 2S, 5R, 6S-3-aza-4-oxo-1,0-oxa-5- ± isobutyl-2- (L-serine-N-methylamide) - 11,11a paraeyk 1. ofan - (5-N - hydroxycarboxamide; 2S (5R, 6S-3-aza-4-oxo-1Q-oxa-5-isobutyl-2-C glycine-N-methylamide) - I 1.0 1.0 '1 p a r a c: y k 1. o f n n - 6 - M - h y d r o x y k a r b o x m i. d; 2S, 5R '6S-3 - and z a - 4 - o x o - 1. (l) - o x and - 5 -1. z o b u t 1. -2 - C D- a 1. a n n - M -methy 1 am 1 d) - Γ1.0 µl p a r a c k k o o ph - - 6 - M - h y d r x x k a r b o x a m i cl; S, b R, 6 S-3-aza-4-oxo-β-O-oxa-b-isobutyl-2-C beta-a-n-N-methyl-1-amide -I '1.0 11 'paracyclophan-6-N-hydroxycarboxamide; 2S (bR, 6S-3-aza-4-oxo (1,10-oxa-5-isobutyl-2- (1D-C0-tert-butyl) serine) -N-methylamide! -I '1.01 paracyclophan-G-N-hydroxycarboxamide; S, 5 R, 6 S- 3 - aza - 4 - oxo -1.0 - oxa - b - isobuty 1 - - 2 - CD - serine - N -methy I. am i cl) Ily 10 µl paracycl 1 of á n-6-N-hydroxycarboxamines c1; S, 5 R, (5 S- 3 - a z a 4 - o x o -1.0 - o x a - 5 - i z. O u u t 1 - 2 - C L -1 y z 1 n - N - m y t 1 am 1. d) 1.0 1.0 l l p a k 1 f á 6 6 6 6 6 6 6 M M 6 M M M M 2.S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-C (L-valine-N-methylamide) - C 1.01 par. M-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-CC2-pyridyl) ethylcarboxamido trifluoroacetate -Ill 1.0! paracyclophan-6-N-hydroxycarboxamide; 2S, 5R, 6S ™ 3-aza-4-oxo-10-oxa-b-isobutyl-2-1H (4-methyl) piperazinyl carboxamido; -Ill 10! paracyclophan-G-N-hydroxycarboxamide; 347 S, 5 R, 6 S-3-aza-4-oxo-10-o x a-5 -1 z o b u t 1 - 2 - C 2 - b e n z. m i. d a z o 1. y 1) · - - L10 ll p a r a c y k l. o f a - 6 - M - h y d r o x y k a r b o x a m i d; 2S, 5R (6S-3-aza-4-oxo-10-oxa-5-isobubyl-2-1 '(2-imidazolyl) carboxamido] -1'-10] paracyclophan-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-1 '(2-benzimidazolyl) methylcarboxanidol-11' 3 3-acyl to lophane-6-N-hydroxycarbamide ; 2S (OR, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-1 '(3-imidazolyl) P petroleum 1 carboxes up to 3 - 1 10 3 paracycl 1 of a n - 6 - N-hydroxycarboxamide · S, 5 R, (5 S - 3 - aza - 4 - oxo - 10 - oxa - 5 - isobutyl 1 - 2 - 11 - 2 - C 4 - no 1 u phony 3 phenyl) ethylcarboxamido 3 - 11 103 paracyclophane 6-N-hydroxycarboxamide; S, 5 R, 6 S - 3 a z a - · 4 - o x o -10 - o x a - 5 - 3 .. z o b u b y ll. (2-Cyclin-N, N-dimethylamide) - 11 103 paracyclophan-6-N-hydroxycarboxamide; S, 5R, 6S-3-a z a-4-o x o -10-o x a-5-i z o t-tyl-2-C1-aminamido) -flo 103 paracyclophan-6-N-hydroxycarboxamide; 2S (5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-CC (4-aminoindazolyl)) arboxam i. d o 3 - I 10 3 p a r a c k k o o f - 6 - N - h y d r o x y k a r boxes d; S, 5 R, GS - 3 - aza - 4 - oxo - 3 - O - oxa - 5 - isobutyl 3 - 2 - CN, M - d 1 methyl 1 carboxamido) -1,13 paracyclophan-6 N-hydroxycarboxamide; S, 5 R, 6 S - 3 - a z a - 4 - o x o - 3.0 - o x a - 5 - i o b u t 1 - 2 - C N - i o p o r o p o l y r b o x amido) -1,13 paracyclophan-G-N-hydroxycarboxamide; S, 5 R '6 S - 3 - a z a - 4 - o x o -10 - o x a - 5 - i z o u u u 1 - 2 - C M - o y k 3. o o o o 3 .. k o r o x amido) -Γ. 103 paracyclophan-6-N-hydroxycarboxamide; 2S, bR, 6S-3-aza-4-oxo-1H-oxa-5-isobutyl-2- (N-tert-butylcarboxamido) -1,13 paracyclophan-6-N-hydroxycarboxamide; S, 5 R, 6 S - 3 - a z a - 4 - o x o -10 - o x a - 5 - i z o u u t 1 - 2 - C g 1 y c 1 n - C N -1 z o r o p y 1) 348 A m i d J-C10 'J P ara c y c o rio-6-N-hydro x y a r b o x am 1. d; S, 5R, EI-3-aza-4-oxo-10-oxa-5-isobutyl-2-C-glycine-1-methyl-amide-1 '. 103 par acyclophane-E-N-hydroxycarboxamide; S, 5 R, 6 S-3-aza-4-oxo -10-oxa-5 ..... 1 zobuty 1. — 2 · I g 3. n-CN-cyclopropyl 1) amid 3-I-10 3 p-racemic 3. of ^{: a} n - ··· E - N -hydrycarboxamide; 2S, 5R, E, S-3-aza-4-oxo-10-oxa-5-isobutyl-2-yl-glyoine-C N-tert. butyl) amidyl-11 '103 paracyclophane-E-N-hydroxycarboxamide; S, 5 R 16 S - 3 - aza - 4 - oxo - 10 - oxa - b - isobutyl 1 - 2-1 g 1 - ycin - CN - cyclobutyl 1) amide -1103 Paracyclophane-Ei-IM hydroxycarboxamide; S, 5 R, 6 S - 3 aza - 4 - oxo - 10 - oxa - 5 - isobutyl 1 - 2 - 1 g 1 yo 1 n - CN - morpholinoamido-11,13 paracyclophan-6-IM- hydroxycarboxamide; S, 5 R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - 5 -1 zobuty 3. - 2 - I g 1 ycine - CM - 2 - domyroxy dimethyl tyl. paracyclophan-E &apos;-N-hydroxycarboxamide; S, b R, 6 S - 3 - aza - 4 - oxo - 10 - oxa - b - isobutyl 1 - 2 - 1 g I. yo 1 n - C 1 - ethyl 1-methylpropyl) amide 3 -1103 paracyclophof α-6-N-hydr oxycarboxamide; S 5 5 R, Ei S - 3 - a z a - 4 - o x o - l. 0 - o x a - 5 - i o o h 1 - 2 - g g 3 .. y c: n n - C IM - d i. methyl-propyl) amide-11 '103 par acyclophane-6-N-hydroxycarboxamide; 2S '5R' 6S-3-aza-4-axo-10-oxa-5-isobutyl-1'-1'-glycine-1'-C'-di-2-hydroxymethyl) ethylamide-1 '' 6-IM-hydroxy oxycarboxamide; S, 5 R, Ei S - 3 - aza - 4 - oxo - 10 - oxa - b - isobutyl 1 - 2 - 1 g gylamino - (4 - hydroxy piperidine) amidyl - 1,103 par acyclophane - E1-IM-hydroxycarboxamide; S, b R, Ei S - 3 - aza - 4 - oxo - 10 - oxa - b - isobutyl 1 - 2 - C 2 - benz 1 m 1 dazo I. carboxamido) - 1,13 par acyclophane -6-IM- bydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-isobutyl-2-methyl-2-phenyl-methyl 3. carboxamido 3 - 1 10 3 paraoyl 1-one - E - N - hydroxycarboxamide; 349 4S, 7R, 8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-carboxyinetyl) -L12 (pyrimidin-8-N-hydroxy) -benzoyl-a-b-oxyl-m-i. cl; S „7 R, 8 S- 5 ·· - aza - 6 - oxo -12 - oxa - 7 -1 zobuty 1 - 2 - C IM -methy I. carbox ain 1. do) - L 12 µl paracyl < 1-a-8-M-hyoxyl <arboxamide; S, 7 R, 8 S-5 - a z a - 6 - o x o -12 - o o x a - 7 -1. - 2 - C - g - c - i - m - m e t y 1 a m i cl) - 11 - 12 µl par acyl l-lo-phane - -8-IM - by dr oxy l <ar boxamide; S. 3 R, 6 S -10 -t-butoxycarbones 1. - 5, 1.0 - diaza - 2 - C IM - hyc roxycarbox am ido) .... g .... (| \ j _ _me {- yj ( _ar 5 _oxamido ) -1-oxa-4-oxo-3- (3-phenylprop-1-yl) cyclo tetradecane; 2S, 3R, 6S-5,10-Cliaza-2- (1 H -hydroxycarboxamido) -6-CIM-methyl-hydrochloride hydrochloride. -ox a - - 4 - o x o - 3 - C 3 - phenyl 1 - · 1 - p r o p 1) c: y l <1 o t e t r a decane; 2S, 3R, 6S-10-Acetyl-5,10-diaza-2-C1-hydroxycarboxamido) -b-C1-methylethyl. k and r b o x and m i. cl o) - 1 - - o x and - · - 4 o x o - 3 - C 3 - pheny 1 - ¾. 1) e y l <o tetradecane; S, 3R, E! S-10 - ·· b e n z e s 1 f o n y 1. - · - 5, 10 ..... d i a z a - 2 - (IM - h y d r o x y l <a r b o x a m i d o) - b - (IM — m e t y 11 <a r b o x am j) -1 - o x a — 4 - o x o - 3 — C 3 - pheny 1 - l — —p r o p y 1) c y l <ľ l. o tetradecane; 2S (3R, bS, 12C (R, S) -1O-acetyl-b, 10'-di.aza-2-C-hydroxycarboxainido) ... β ... (N-methyl 11 <ar box amido) -12-mety ll. - · 1 - o x a - 4 - o x o - 3 - (3 - pheny 1. -1 - p y o 1) c y k l. about three decades S 3 3 R, 6 S 3 3 - a z a - 4 - o x o -10 - o x a - - 5 - h e x y 1 - 2 - C k a r b o x y m e t; y 1) - 10 10 l p a a:: o::: E E E E E IM IM IM IM IM IM IM IM IM Et IM y k a r am am IM d d d d; S, 3 R '8 S-3 - a z a - 4 - o x o -10 - · o x a - 5 - h e x y ll. - 2 - Cyclo-oxyl-1-carboxamide 1) - 11 µl of acyclophan-6-N-hydroxycarboxamide; 2S, 3R, bS-3-aza-4-oxo-10-oxa-5-hexyl-2-C (2-methoxy-1-ethyloxy) 350 carboxyl] -1: 1.0 paracyclophan-6-N-hydroxycarboxamides; 2S, 3R, EI-3-aza-4-oxo-10-oxa-5-hexyl-2-C (2-phenylethyloxy) carboxy] -1,11,11 paracyclophan-E> -N-hydroxycarboxaniide; 2S, 3R, EiS-3 ..... aza ..... 4-oxo-10-oxa-5-bexyl-2-C (C-n-methylcarboximido) methylcarboxyl) -1,11 paracyclophan-6 N-hydroxykarboxain: id; S, 3 R, Ei S-3 - aza - 4 ..... o x o -1.0 - o x a - 5 -1 ß e xyl - 2 - · C 2 - C N -methy 1 am i. rt o s u ll. f o rt y 1) et y 1 car b o x a m i d -) 10 l l p a r a c k k o o f n n - Ei - N - h y d o x y k a r b o x a m 1 (d; S, 3 R, Ei S-3 - a z a - 4 - o x o -1.0 - oxa - Ei - lt e x y 1 - 2 - C 4 - C IM - - m e t y 1. a m i. (1) butylcarboxamido-E10 µl par aoyl-lofan-Ei-1M-hydroxyoxycarboxamide; S, 3 R, Ei S- 3 - aza - 4 - oxo - 10 - oxa - 5 - hexy 1 - 2 - ¢ 2 - (IM -methy 1 or m 1 oosu 1. fo rt y l l .) hexy 11 <arboxam 1 do) - E 10 µl paraoyl <1 of ar - E 1 - IM - Et ydroxy k ar Et oxam 1 d; 2S (3R, EiS-3-aza-4-oxo-10-oxa-5-hexyl-2-C2-C-carbonethoxy) -ethylcarboxamido) - E 1.0 µl paracyl <1 of a rt - Ei - IM - hydroxycarbox or m i. d ·, S, 3 R, Ei S-- 3 aza - 4 - oxo - 10 - oxa - 5 hexy 1 - 2 - C 2 - C hydroxyl (arethio) 1) ethylcarbonyloxy) - E ľl. 0 l p r y <<1 E E E E E E E E E E E E E E E E E IM E IM,,, S, 3 R, Ei S-3-aza-4-oxo-10-oxa-5-Ethyl-2-CL-ortho-tin (4-t-butoxycarbonyl) carboxymethyl) 1.01 Paracyclophan-6-N-hydroxycarboxamide; Et ydroohoride 2 S, 3 R, Ei S-3-aza-4-oxo-10-oxa-Et-Et exy 1-2-Cl-1-carboxymethyl-L 1.01 paracyclophan- 6-N-Etydroxykarboxamldu; S, 3 R, Ei S — 3 - a z a ..... 4 - o x o -1.0 - o x a - 5 - Et e x y ll. - 2 - C L - o rt i 11 rt C 4 -1 - Ethoxycarbonyl (1-N-methylamide) -E 10 µl paracyclophan-6-N-hydroxycarbamides; Et y d r o c: Et 1 o r 1 d 2 S, 3 R, 6 S-3 - and for-- · 4 - o x o - ll. O-o-a-Et-hlyl-2-C-1-olimine-1-N-methylamid-1'-10 µl of paracyclophan-6-1-hydroxycarboxamide; S, 3 R, Ei S - 3 - a z a - 4 - o x o -10 - o x a - Εϊ - h e x y 1 - 2 - CI ... -1 y z i n k a r b o x a m d) -1,11 µl paracyclophan-6-N-Eydroxycarboxamide; 351 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (L-serine (O-tert-butyl) -N-methyl) -1,103 paracyclophane-GN-hydroxycarboxamide ; S, 3 R, 6 S-3-aza-4-oxo-10-oxa-5-hexyl-2-CL-a-l-n-N-methylamide) -113 paracyclophane-O-IM-hydroxycarboxamide ; S, 3 R, 6 S-3 - a z a - 4 - o x o -1.0 - o x a - 5 - hexy 1-2 - (D - a 1 a n - N - methylamide) - 11 103 paracyclophane-G-N-hydroxycarboxamide; S, 3 R, G S-3-a z a-4-o x o-10-o x a-5-h e x y 1 - 2 - C g y y 1 n - 1 -methylamide) - 11 103 paracyclophane-G-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C benzylcarboxamido) -1,13 paracyclophan-G-N-hydroxycarboxamide; S, 3 R, G S-3-a z a-4-o x o-10-o x a-5-h e x y 1 - 2 - C phenylen e y r b o x y m d) -1,13 paracyclophan-G-N-hydroxycarboxamide; S, 3 R, 6 S - 3 - a z a - 4 - o x o -10 - o x a - 5 - h e x y 1 - 2 - (diphenylethylmethoxy) -1,13 paracyclophan-G-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C2-C2-pyridyl) ethylcarboxamido) -1,13 paracyclophan-G-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C2-C4-sulfonylaminophenyl) ethylcarboxamido) -1,13 paracyclophan-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-b-hexyl-2- (2- (3,4-dimethoxyphenyl) ethylcarboxamido) -1,13 paracyclophan-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C2-C4-morpholinoethylcarboxamido) -1,13 paracyclophan-G-N-hydroxycarboxamide; hydrochloride 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-C3-C4-morpho 3. i n o) p o l l ar ar am i d o) - I 10 3 p a r a c y k 1. o f n n — G — N — h y d r x y k a r b o x a m i d 352 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (3- (1-imidazolyl) P crude 1 carboxamido) - C10 3 paracycl 1 of a n - 6 - N-hydroxycarboxamide; d; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (3-C 1 -imidazolyl) propyl arboxamido trifluoroacetate-E 103 paracyclophane-6-N-hydroxycarboxamide trifluoroacetate; S, 3 R, 6 S- 3 - a z a - 4 - o x o -10 - c x a - 5 - h e x y 1 - 2 - C y y 1 h e x y 1 b a r b o x ami d o) S, 3R, 6 S-3-aza-4-oxo-10-cxa-5-hexyl-2-C-4-methylpiperazin-1-ylcarboxamido-E 103 paracyclophan-6-ol N-hydroxycarboxamide; 3-carboxamido) -1,13 paracyclophan-6-N-hydroxycarboxamide; S, 13 S, 14 R-1, 7 - d i a z 8 - 1 b - d i o x o - 9 - o x a - 14 i. 1-7 - Methyl 1 -2 ~ - (M - Methyl 1 k a r b o x a m d d) - C y n d e d e n e - 13 - IM - hydroxycarboxam 3. d; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl trifluoroacetate · - · 7-Methyl-2-EM-C-2-Pyrid 1L) methyl 1 carbox 3-cyano-1-opentadecan-13-IM hydroxycarboxamide; 5,3,3S, 14R-1,7-diaza-8,15-dloxo-9-oxa-14-isobutyl-7-methyl-2- 11,2-C5-methyl 11 i. and z o 1 y 1) k a r b o x m i. D-3-Cycloquinone-13-N-hydroxycarboxamide; S, 13 S, 14 R-1, 7-d aza-8, 1 b-d x o-9-o x and -14-i. 7-Methyl-2-methyl-2-pyridyl) carboxamido] -cyclopentadecan-13-1H-pyrrolidine; S, 13 S, 14 R-1,7-diaza-8,15-di-oxo-9-oxa -14-isobutyl-7-methyl-2- (3-pyridyl) carboxamido-cyclopentadecane-13 N-hydroxycarboxamide; S, 13 S, 14 R -1, 7-d i aza-8, i b - d 1 o x o -9-o x and -14-i z o b u t y 3. -7-met e; y 1 -2-E C 4 -pyridyl) cyclohexanedio 3-cyclohexanedioxy-3 3-M 353 -bydroxyc ar boxamide; S1.3 S, 14R-1, 7 ..... d i and z a - E), 1.5 - d i. o x o - 9 - oxa - i 4 - i z o t u s 1 - 7 - methyl 1 - 2 - C (4 - C m - e t o x y l <a r hons I.) in the process. n car b o x a m 1 dol y y 1. o p e r 11 a d e k n -1.3 IM - h y d r o x y k a r b o x am i d; S, 13 S, 14 R-1. a - 8, 1.5 - d i o x o - 9 - o x a -14 - i z o b u t y 1. - 7 - m e t y 1 - 2 ··· - l. 4 ..... h y d r o x y o k 1. o h e: x y 1. k a r b o x a m i. d o 1 ..... o y k 1. o p e n t a n d -13 - IM - h y d r o x y car box am i d; S, 1.3 S, 14 R-i, 7-diaza-Ei, 15-dioxo-9-oxa-1,4-iso: debris 1. - 7 - - met, y 1. - 2 - C g1 yc 1 1'-IM-methyl 1. amide) -cyclohexane-1,3-IM-hydroxycarboxamide; S, 1.3 S, 14 R-1. and z a ..... E), 1.5 - d i o x o - 9 - o x a -1.4— i z o t) u t y 1. - 7 - methyl. - 2 ··· - · C 91. y tin - N, IM - d i m e t y 1. a m i d) - c y t i n e n e -13 - IM - h y d r x y k a r b o x a i m d; S, 1.3 S, 1.4 R-1., 7 - d i aza - EF, 1.5 - d i. o x o - 9 - o x a - 14 - isobutyl 1-7 -methylen-2-C glyl-2-pyridyl) cyclopentadiene-13-IM-hydroxycarboxamide; S, 1.3 S, 1.4 R ..... 1 .7 - d laz a - 8, 1.5 - d j. oxo - 9 - oxa - 1 - 4 - isohutyl 1 - 7 - methyl 1 - 2 - 1 - 1 - yoin -2- (3, 4, 5, 5 - 1; etrahydropyrides 1) am 1 d 1 - cycl. opentadecan-13-IM-hydroxycaroxamide; S, 13 S, 14 R-1, 7-diaza-8,15-dioxo-9-oxa -14-isohuty 1. -7-methyl 1.-2-I g 1. yo 1 n - N - C 4-hydroxy) p 1. per 1 d 1 namid β 1 - - cyclic opentadecan -13 - IM - hydroxycarboxa τη 1 d; S, 13 S, 14 R -1., 7 ..... diaza - Ei, 1b - dioxo - 9 ..... oxa -1,4 - isobutyl 1 - 7 - methyl 1. - 2 - I g 1 yc: in-IM-pyrrolidinamide 11-olyk 1 opentadecan-13-IM-hydroxycarboxamide; S, 13 S, 14 R-1, 7-diaza-Et 15-dioxo-9-oxa -14-isobutyl-7-methyl-1-methyl-1-morphine i. n o am i d 1-c y k e o p e n t e d -13-IM - h y d rxy k a r b o x am 1 d; t r i f 1. u ó r a c: e t; a t 2 S, 1.3 S, 14 R-1, 7 - diaza - 8, 1.5 - d 1 oxo - 53 - oxa -1.4 -1 zoboty 1. - 7 - mety 1. - 2 - Ľ g 1. ycin - C 4 - mt; y 1.) IM - p i z e n y 1. a m 1 d l k 1. 1. 1. '' '' '' '' .3 '.3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 354 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl trifluoroacetate] - 7-m e t y 1 - 2 - I g o y o i - 2 - C 5 - m e y y 1) t y o y y 1 or 1 d e - y y o l o n e a n e ..... -13-N-hydroxycarboxamide; S, 13 S, 14 R -1, 7 - d i a z a - 8, 1 b - d i o x o - 9 ..... o x a -14 - i z o u u 1 - 2 - E g l l .. y c; í o - N -morpholinoamide-1-cyclopentadecane-13-IM-hydroxycarboxamide; 2S, 11S, 12R-1,7-diaza-8,13-dioxo-2- (1H-methylcarboxamido) -12 ..... -11 - C IM - Ei y d r x y k a r b o x and m d); S, 11S, 12 R -1, 7 - d i a z a - 8, 13 ..... d i o x o -12 - i z o u t u t 1 c y k 1 o t r i d e ..... 2 ..... (C-glyciri-N-methylamide) -11-C-hydroxycarboxamide); 2S, 11S, 12R-1,7-diaza ..... 8 -C · = ”** · ι« --· ^Γ '- |) ..- | "Jr ,, ... , 13 - d 1 o x o -12 - o o o t o c o c o o o t o o o - 2 o-N-H-amidetrifluoroacetate) -11- CIMl'i y d r o x y i d); S, 11 S, 12 R-1, 7-d a z a - 8, 13 - d a x o -12 - i t a l c y k l o t; r: i .. d o o o - 2 - C L - a 1 a n in - ac - IM - m e t yl. and m 1. d) -11-C N-h y d r x y k and r b x x m i d); S, 11 S, 12R-1, 7-d aza a - 8, 13 - d x o x o -12 - i t o l c y k l o t r i. decan-2-C 1 -alanine-N-methylamide ... 11-CIM-hydroxycarboxamide; 2S, 1S, 12R-1,7-di-aza-8,13-dioxo-2 - (1-methylcarboxamido) -7-IM-m-azyl-1-phenylethyl-12-i. z o b u t y 1. c y k 1 o r e d e k - · 11 - C IM - h y d r o x y k a r b o x a m. d); 2S, 11S, 12R-1,7-diaza-8,3,3-dioxo-2-methyl-1-methylcarboxamido) -7-IM-1-butyloxycarbonyl-12-isobutyl 1-cycle o o -11-C IM - hydroxycarbox and. d); hydrochloride 2S, US, 12R-1,7-diaza-8,13-dioxo-2- (1-methylcarbamoyl) -12-azobutyl-1-thiocarbonyl-11-C 1 H -dioxo-2- (1-methylcarbamoyl) 5S, 8R, 9S - 6-aza-2,7-dloxo-5-C 1 -methylcarboxamido) -1-oxa-8-isobutyl 1-cyclododecane 9-C 1 -hydroxycarboxamide ); 355 S, 11S, 12 R- 7-N-benzenesulfony 1 -1, 7-clza-8, 1.3-cl i. oxo - ^L 2 - C IM - methyl 1 - ·· l <arboxam i. cl o) -1. zobuty I. cycl 1 otradekan - 11 - C IM ..... hy cl roxyka r-boxam .1. (d) 2S '11S, 12R-1,7-d: i.aza-8,13-dioxo-2-C1-methylcarboxamyclo-7-C-a τη i. no - IM - - b e n z e n u 1 f o n y 1) · -12 - i z b u t u 1 c y k 1. o t r i. decan-1 (-C (N-hydroxy oxycarboxamide)); 2S, 11S, 12R-1, 7-diaza-8,13-dioxo (2 N, N-methylcarboxamido) -7-IM 1; r i. f 1 u ó r m e: t a n s 1 f o n y 1 -12 -1. 1 c: y k 1 o t r i cl e -11 - C IM - h y d x x y a r b x x 1 d); 2S, 11S, 12R-1,7-diaza-8,13-dioxo-2-C (N-methylcarboxamido) -7 ... IM-C 1 -methylated. m 1 cl a z o 1 - 4 - s 1 f o n y 1) - i 2 · - i. (11-C (hydroxycarboxamide)); S, 1.1 S, 12 R-1., 7 - d 1. and z a - 8, 13 - cl 1. o x o - 12 -1. 1. c: y k 1 o t r 1. cl e c - n - 2 C L - n o r o e n - or - N - met y 1 a m i. d) -11 - C IM - h y d r o x y k a r b o x a m i. d); 2S, 11S, 1.2R ..... 1, 7 - dlaza-8, 1,3-dloxo - 12-l.zobutyloyk lo t-shirts án- ~ 2 C (L-serine-oc-N-methylamide) -11-C IM -hydroxycarboxamyl); S, 11S, 12 R -1, 7 - cl 1. Aza - 8, 13 - d 1 ox o ..... 12 - isobutyl 1 cyclic acid - 2 C glycine-N-dimethylamide) -11-C (hydroxycar boxamide); 2S, 1.1.S, 12R-1, 7-diaza-8,13-dioxo ... 12C (R) -isobutylcyclotridecane-2. ethylenediamine-N &apos;, 1 &apos; -dimethylamidyl-1,1 (CS) -CM hydroxycarboxamide; S, 11 S, 12 R-1, 7-cl i. and z a - 8, 13 - clio x o -1.2 i o o o o o o o o o o o o o o - 2 C glycine (1-morpholinoinoid) -11- (N-hydroxycarboxamide); S, 1.1. S, 1.2 R-1,7-diaza-8,13-d-1-oxo-12-isobutyl-1-cyclotridine: 2-C-L-leucine-α-N-methylamide) -11-C N-hydroxycarboxamide); S, 11 S, 12 R-1, 7-diaza-8,13-d 1 oxo -12-isobutyl-1-cyclohexyl-2-C (L-threonine-N-N-methylamide) -11 (N-hydroxycarboxamide). 356 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1. j ti c a s a t: e r a p e: u t i c k y 12. A pharmaceutical composition comprising a pharmaceutically acceptable effective amount of a compound according to claim 2. and carrier and therapeutically 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of a compound of claim 3. u .j u e: a s a a te r · or p e u t. c k y 14, A pharmaceutical composition comprising effectively a pharmaceutically acceptable ingredient. 4. n a č u ..j u c a s a n o s i. c a t e: r a p e u t i. c k y 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier an effective amount of a compound of claim 5. j u c a s a t e r a p e u t i. c k y 16. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a pharmaceutical composition. 17. Pharmaceutical composition, characterized in that: that; it contains: a pharmaceutically acceptable ingredient: a. carrier ... j o o s t e: r or p e u 11. c k y 18. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier an effective amount of a compound of claim 8. j u c a s a t e r ape u t i. ck y 19. A pharmaceutical composition comprising; comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 9. 0. F- and r m e e; e: u t i c. composition. A ss a n s: a s 357 comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 10. 21. A method of treating an inflammatory disease in a mammal, said method; comprising administering a therapeutically effective ..... % of a compound of formula (1) to a mammal, which comprises: e č e n i. e p o t r e b u j e. 22. A method for treating an inflammatory disease in a mammal, said method. which comprises administering to a mammal a therapeutically effective amount of a compound of formula 2, said composition being administered to a mammal. 23rd S o b b o i o o i. and. wherein the amount of the compound is about 1 j. e č e n i. e needs. an inflammatory disease in a mammal, which may be severe. e t e r a p e u t i. c. the general formula of EJ to a mammal which: 24. A method of treating an inflammatory disease in a mammal comprising administering a therapeutically effective amount of a compound of formula (I). of formula (4) to a mammal who is a mammal. e p o t r e b u. is a . 25. A method of treating an inflammatory disease in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 5. 2 (5) A method of treating an inflammatory disease in a mammal, comprising i. comprising administering to a mammal a therapeutically effective amount of a compound of formula EJ 1.1. e č e; n i e p o t r e b u j e. 27. A method of treating an inflammatory disease in a mammal, said method. comprising administering to a mammal a therapeutically effective amount of a compound of Formula 7. e Č e n i. e p o t r e b u j e. 358 - A method of treating an inflammatory disease in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of formula 8. 29. A method of treating an inflammatory disease in a mammal, comprising: which comprises administering a therapeutically effective amount of a compound of formula 9 to a mammal, which is about 1: i. e c e n 1 e pot r e b u _ j e. 30. A method for treating an inflammatory disease in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 10. 31. The method of any one of claims 21 to 30, wherein the administration is oral: administration. 32. An assay for the detection of aggrecanase inhibitors, comprising: (a) Generating soluble aggrecanase by stimulating the cartilage plates: d e t e: g e s: soluble m o n 1.1 o r o n n e s containing a g g e n e n e n e n e n e m e t; wherein the aggrecanase activators generated in step (a) and 11: -: a g g a n i n g a n d a n d a n d a n d s: A R G S VIL; (c) evaluating the aggrecanase inhibition by comparing the amount of product produced in the presence of the compound with the amount of the product. t om o o t i z 1 o o o i n y.