LV12167B - Novel macrocyclic compounds as metalloprotease inhibitors - Google Patents

Novel macrocyclic compounds as metalloprotease inhibitors Download PDF

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LV12167B
LV12167B LVP-98-104A LV980104A LV12167B LV 12167 B LV12167 B LV 12167B LV 980104 A LV980104 A LV 980104A LV 12167 B LV12167 B LV 12167B
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alkyl
aryl
oxa
oxo
oxycarboxamide
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LVP-98-104A
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LV12167A (en
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Chu-Biao Xue
Robert Joseph Cherney
Carl Peter Decicco
William Frank Degrado
Xiaohua He
Carl Nicholas Hodge
Irina Cipora Jacobson
Ronald Louis Magolda
Elizabeth Catherine Arner
Jingwu Duan
David J. Nelson
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Dupont Pharmaceuticals Company
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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Description

LV 12167
TTTLE NOVEL MACROCYCLIC COMPOUNDS AS METALLOPROTEASE INHIBITORS Cross-reference ,to-Earlier-Filed. Application
This application is a continuation-in-part of U.S.Provisional Patent Application Serial Number 60/006,684 filed November 14, 1995. The disclosure of this earlier filed application is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to macrocyclic molecules which inhibit mētailoproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF), pharmaceutical preparations containing them and to their use as pharmaceutical aģents. In particular the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor.
BACKGROŪND OF THE INVENTION
There is now a body cf evidence that metalloproteinases (M?) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological ccnditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bcne disease. Normally these caoabclic enzymes are tightly reguiated at the Ievel of their synthesis as well as at their Ievel of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form' inactive complexes wich the MP' s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of arcicular cartilage characterized by localized erosion of che cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over Controls, suggesting that there must be an enhanced rāte of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian celis: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromeiysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly iaentified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglvcan, found in RA and OA patients (Lohmander L.S. et ai. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction' of mammalian cartilage and bone. It can be expected that the pathogenesis cf such diseases can be modified in a beneficiai manner by the ādministration of MP inhibitors,. and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San -Diego, 1990).
This invention describes macrocyclic molecules that inhibit aggrecanase and otner metalloproteinases. These novel molecules are provided as cartilage protecting -2- LV 12167 therapeutics. The inhibiton of aggrecanase and other metalloproteinases by these novel molecules prevenc the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Tumor necrosis factor (TNF) is a celi associated cytokine that is processed from a 26kd precursor form to a 17kd active form. TNF has been shown to be a primary mediator in humāns and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shovm to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial.in a variety of circumsatnces including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L.S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301) .
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shovm that a matrix mētailoproteinase or family of metalloproteinases, hereafter knovm as TNF-convērtasēs (TNF-C), as well as other MP’s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes macrocyclic molecules that inhibit this conversion and hence the secretion of active TNF-o from celis. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restrictea to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria,
Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases invoiving angiogenesis, autoimmune diseases, skin infiammatcrv diseases, rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediaced tissue degradation, compounds which inhibic both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors. PCT International Publication No. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of general formula:
wherein AA is an amino acid, as inhibitors of matrix metallproteinase mediated diseases. PCT International Publication No. WO 90/05716 discloses hydroxamic acid based collagenase inhibitors having the general formula:
PCT International Publication No. WO 92/13831 describes related hydroxamic acids having collagenase inhibiting activity with the general formula: -4- LV 12167
PCT International Publication No. WO 94/02446 discloses metalloproteinase inhibitors which are natūrai amino acid derivatives of general formula:
WOS5/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine productior..
O R3 R4 I
European Patent Application Publication No. 574,758 AI, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula: -5- ΗΟΝΗ
GB 2 263 934 Α and W0 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
The compounds of the current invention act as inhibitors of MMPs, in particular aggrecanase and TNF-C, thereby preventing cartilage 1oss and destruction and inflammatory disorders involving TNF. The hydroxamic and carboxylic acids and derivatives are cyclic, and thus non-peptide in nature, which offers a distinct advantage over existing inhibitors because they have superior pharmacokinetic parameters. A selection of these molecules are water soluble and are orally bioavailable.
STTMMARV OF THF TNVPNTTON
Tnis invention provides novel hydroxamic acids and carboxvlic acids and derivatives thereof of formula (II (described below) which are useful as inhibitors of metalloproteinases, such as aggrecanase and TNF-C. The present invention also includes pharmaceutical compcsitions comprising such compounds of formula (I) and methods of using such compounds for the treatment of arthritis and other inflammatory disorders as described previouslv, in a patient.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of formula (I), for the treatment of arthritis and other inflammatorv disorders as described previouslv, . -o - LV 12167
The present invention also includes methods of inhibiting metalloproteinases, such as aggrecanase and TNF-C, and for the treatment of arthritis by administering a compound of formula (I) in combination with one or more second therapeutic aģents selected from other inhibitors of metalloproteinases, such as aggrecanase and TNF-C and/or therapeutic aģents for the treatment of arthritis and inflammation.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides novel hydroxamic acids and carboxylic acids and derivatives thereof of formula (I) (described below) which are useful as inhibitors of metalloproteinases, such as aggrecanase and TNF-C. The present invention also includes pharmaceutical compositions comprising such compounds of formula (I) and methods of using such compounds for the treatment of arthritis and other inflammatory disorders as described previously, in a pacient.
Also included in the present invention are pharmaceutical kits comprising one or more containers cor.taining pharmaceutical dosage units comprising a compound of formula (I), for the treatment of arthritis and other infiammacory disorders as described previously.
The present invention also includes methods of inhibiting metalloproteinases, such as aggrecanase and tumor necrosis factcr alpha, and for the treatment of arthritis by administering a compound cf formula (I) in combination wich one or more second therapeutic aģents selected from other inhibitors of metalloproteinases, such as aggrecanase and tumor necrosis factcr alpha and/or therapeutic aģents for the treatment of arthritis and inflammation.
Ir. the fcllowing description a (-: svmbolizes the poir.t of atcachment. -7-
Formula I
or pharmaceutically acceptable salts or prodrug forms thereof, wherein: U is selected from: -CO2H, -CONHOH, -CONHOR11, -SH, -NH- COR11, -N(OH)COR11, -SN2H2R6, -S0NHR6,CH2C02H, PO(OH)2, PO(OH)NHR°, CH2SH, -C(0)NH0R12, -C02R12, and common prodrug derivatives; R1 is selected from: H, - (C0-C6)alkyl-S(O)p- (Ci-C6)alkyl, - (C0-C5) alkyl-0- (Ci-C6)alkyl, - (Co-Cs)allcyl-S (O)p- (Co-C6)alkyl-aryl, - (Co-Cg)alkyl-0- (Co-C6)alkyl-aryl, alkyl of from 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkvl groups, substituted alkyl wherein the substituent is selected from; hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono- alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as p'nenylthio) , carboxy, carboxamido, carbo alkoxy, or sulfonamidc. -8- LV 12167 -(Co-C8)alkyl-aryl, - (Co-Ce)alkyl-substituted aryl, - (Co-Ce)aryl-(Ci-C4)alkyl-aryl, -(Ci-Ce)alkyl-biaryl, -(C0-C8)alkyl-S(O)p-(C0-C8)alkyl-aryl, - (Co-Cg)alkyl-S(0)p-(Co-C8)alkyl-substituted aryl, -(Ci-C4)alkyl-aryl-(Co-C8)alkyl-aryl-[S(0)p- (Co~ C8)alkyl], - (Co-C8) alkyl-S (0) p- (Co-C8)alkyl-biaryl, - (Co-Ce) alkyl-0- (Co-C8)alkyl-aryl, - (Co-Ce)alkyl-S(0)p- (Co-C8)alkyl-substituted aryl, - (C1-C4) alkyl-aryl- (C0-C8)alkyl-aryl-[0- (C0-Ca) alkyl], - (Co-Ce)alkyl-0- (Co-C8)alkyl-biaryl, - (Co-C8)alkyl-0- (Co-C8)alkyl-substituted aryl, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, balo, alkoxy, amino, mono-alkylanu.no, di-alkylamino, acylairu.no, chio, thioalkyl, carboxy, carboamido or aryl; r2 is selected from h, -CO2R5/ -CONR6R5, -CONR6(OR5), -alkyl, -aikylaryl, -alkylheteroaryl, -alkylhecerocyclic, -aryl, -heteroaryl or ~hecerocyclic which is substituted with one or mcre substituents selected from: hydrcgen, halo, hydroxy, alkoxy, aryloxy, (such as p'nenoxy) , amino, mono-alkylamino, di-alkylamino, acylainino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; r3 is selected from: -K, -OH, -CR6 -NH2, -NHR6, -N(R6)2, - (Ci-C6)alkyl, - (C:-Co)alkyl-aryl, -SR6, halide, or nitrile; -3-
Aiternatively R2 and R3 can form a 3 to 8 membered saturated, unsaturated, aryl, heteroaryl or heterocvclic ring; R4 is selected from: H, -OH, -OR6 -NH2, -NHR6, -N(R6)2, -<Ci-C6)alkyl, -(Cj-Ce)alkyl-aryl, -S(O)p-(Ci-Ce)alkyl, halide, or nitrile; R5 is selected from: - (CHR^Jn-R9- -C(R7R8)n-W-C(R7R8)in-R9< -C(R7R8)m-R9, -C (R7R8) m-aryl, -C(R7R8)mCONR7R8, -C (R7R8)m-substituted heteroaryl, -C (R7R8) m-substituted heterocyclic, wherein the substituent is selected from; hvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxv, amino, mono-alkylamino, di-alkylaminc, acvlaminc, thio, thioalkvl, carboxy, carboxamido or aryl; R6 is selected from: H, alkvl, - (C:-Ce)alkyl-aryl, -(C1-C5) alkvl-heteroaryl, - (Ci-Cc)alkyl-heterocyclic, -(C1-C0) alkyl-acyl;
Alternativelv, R5 and R6 may form a 3 to 8 membered ring optior.ally unsaturated containing from 1 to 3 hetercacoms selected from -0, -NR6, -S(0)p, or an acvl group, cptionally fused to an aryl ring; -10- LV 12167 R7 and R8 may be selected independently from: H, R1, or form a 3 to 7 membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acyiamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing -0-, -S(0)p, -NR6, optionally fused to a substituted aryl ring, wherein the substituent is selected from; hvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acvlamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl 5 or 6 membered ring optionaily containing from 1 to 2 N, 0 or S(0)p, optionally substituted with -OH, -0- (C1-C6)alkyl, -0-acyl-alkyl, NHR10, or aryl; R10 is H or ar. cptionally substituted alkvl group; R11 is hydroger., alkyl of from 1 to 10 C atoms which include branched, cyclic and unsaturated alkyl groups, s'ubstituted alkyl wherein the substituent is selected from: hydrogen, halo, hydroxy, alkos<y, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arvlamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carbcxamido, carbo-alkoxy, or sulfonamide, - (Ci-C4)alkyl-aryl, - (C1-C4)alkvl-(Ci-Ce)alkyl-aryl - (Ci-Cg)alkyl-biaryl, substituted -(Ci-Cg)alkyl-aryl, -11- wherein the substituent is selēcced from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;
Rlla is H, -S02-Ci-C6-alkyl, -S02-Ci-C6-alkyl-substicuted aryl, -S02-aryl, -S02-substituted heceroaryl, -COR9, -C02t-Bu, -C02Bn, or -alkyl-substicuted aryl wherein the substituenc is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di~alkylainino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: K, aryl, (Ci to Cio)alkyl-, aryl (Ci to C6)alkyl-, C3 to C11 cycloalkyl, C3 to C10 alk\'lcarbonyloxyalkyl, C3 to C10 alkoxycarbonyloxyal]cyl, C2 to C10 alkcxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 to Cio cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy(Ci to C6 alkyl)-, arylcarbonyloxy(Ci to C6 alkyl)-, C5 to C12 alkoxyalkylcarbonyloxyalkyl, [5- (C1-C5 alJc/1)-1,3-dioxa-cyclopenten-2-one-yl]methi'l, (5-aryl-l,3-dioxa-cyclopenten-2-one-yl) methyl, (R17) (R17a)N- (C1-C10 alkyl) - , -CH(R13 ) OC (=0) R14, -CH(Rl3;0C(=0)0Rl5, or -12- LV 12167
R13 is K or C1-C4 linear alkyl; R14 is seiected from: K,
Ci-Ce aikyl or C3-C8 cycloalkyl, said alkyl or cycloalkyi being substituted with 1-2 groups independently seiected from: C1-C4 alkyl, C^-Ce cycloalkyl C3-C5 alkoxy, aryl substituted with 0-2 groups independently seiected from: halogen, phenyl, C1-C6 alkyl, Ci-Cg aikoxy, N02, -S(Ci-Cs alkyl}, -S(=0)(C:-C5 alkvl), -S02(Ci-C5 alkyl) , -0K, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R17a) , or -CVFW where v = 1 3 and w = 1 to (2v+l), arvl substituted wich G-2 groups indepenaently seiected from: halogen, phenyl, C1-C5 alkvi, Ci-Ce alkoxy, NQ2, -S(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -S02(Cļ-Cs alkyl), -OK, -N(Rl7) (R-7a) , -C02R17a, -C (=0) N(R17) (Rl7a} ; cr -CVFW where v = 1 to 3 and w = 1 to (2v+l); -13- R15 is selected from:
Ci-Ce alkyl, C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups indepenaently selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C6 alkyl, Ci-C6 alkoxy, N02, -S(Ci-Cs alkyl), -S(=0){C1-C5 alkyl), -S02(Ci-C5 alkyl) , -OK, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R17a), or -CvFw where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, Ci-Cg alkoxy, N02, -S(Ci-Cs aikyl), -S(=0)(Ci-Cs alkyl), -S02 (C1-C5 alkvl), -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R17a) , or -CVFW where v = 1 tc 3 and w = 1 tc (2v+l); R16 is C1-C4 alkyl, benzyl, or phenyl, R17 and R17a is independently selected from: H, Ci-Cio alkyl,C2-C6 alkenyl, C4-C11 cycloalkylalkyl, and aryl(Ci-C6 alkyl);
Combinations of A, B and D, and/or variables are permissable only if such combinations result in stable compounds (as defined herein) -14- LV 12167 A can be absent, -(CHR6)m-, -0{CHR6)m-, -NR6 (CHR6)m-, - S(0)p(CHR5)m-, or selected from an alkvl from 1 to 10 carbon atoms which include brancned, cyclic and unsaturated alkyl groups or - (C-.-C6)alkyl-aryl; B can be a bond or selected from -NK-, -NR11-, - NRlla- -0-, -S (0)p- (Ci-C6)alkyl-NH- (Ci-C6)alkyl-, (Ci-Cg)alkvl-NR11- (Ci-C6)alky-, -Ci-C6-NH-aryl-, -0-(Ci-Ce)alkyl-, -(Ci-Ce)alkyl-0-aryl-, -S- (Ci-Cg)alkyl-, -(C1-C6)alkyl-S-aryl-, - (Ci-Ce)alkyl-, -(Ci-Cg)alkenyl-,- (Ci-Cs)alkynyl-, -CONH-, -CONR11, -NHCO-, -NRi:lCO-, -OCO-, -COO-, -0C02~ -R11NCONR11- , KNCONH-, -OCONR11-, -NR11CCX0-, -HNS02-, -SO2NH-, aryl, cycloalkyl, heterocycloalkyl, -R11NCSNR11-, -HNCSNH, -OCSNR11-, -NR^CSO-, -HNCNNK-, and a peptide bond mimic;
D can be absent or an alkvl from 1 to 10 carbon atoms optionallv containing 0, S or NR6, which include brancned and cyclic and unsaturated alkyl groups and aryl Ci-Ce alkyi-; p can be 0, 1 or 2; m is an integer from 0 to 5; n is an integer from 1 to 5; W is -C-, -S(O)p- or -NR10-; Y is selected from: -CONR10-, -NR10CC-, -SO2NR10-, -15- -NR10SO2~/ a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsacuraced or partially unsaturated containing from 1 to 4 heteroatoms selected from N,0 or S, with the proviso that the size of the macrocycle encompased in formula I by -A-B-D-C (R2) (R3)-Y-C (R1)-C (U) (R4) -, be connected by no less than 11 atoms and no more than 22 atoms to form the cycle.
[2] Tnere is provided by this invention compounds of the formula(II):
Formula II
R3 or p'narmaceutically acceptabie salts or prodrug forms tnereof, wherein,- X is selected from CH2, NK, NR5, S(0)p, or 0;
R33» R14· R15’ R16 R17 R17a and p, m, η, A, B, D and W are as specifiea previouslv in Formula I and defined as stable compounds; with the proviso that the size of the macrocycle encompased in formula I by -A-5-D-C (R2) (R3)-Y-C (R1)-X-C(U) (R4)be connected by no less than 11 atoms and no more than 22 atoms to fcm the cvcle. -16- LV 12167 [3] There is provided by this invention compounds of the formula(III) :
Formula III
R1 U is selected from; -C02H, -CONHOH, -CONHOR11, -SK, -NH- COR11, -N{OH)CORrs -SN2H2R6, -SONHR6,CH2C02H, PO(OK)2, ?0(0K)NHR6, CH2SH, and common prodrug derivatives -C (0) NHOR12 and -C02R12; Z is selecned from: N cr CH; R1, R4, R«, R~, Rlla, p.12, R13 ( Rl4, R15, R16, R17 R17a, A, E, C, are as specrfied previouslv in Formula I and defined as snable compounds; (4] Preferred compounds of the present invention are compounds of formula I where;
Formula I
B
or pharmaceutically acceptable salts or prodrug forms thereof, wherein; U is selected from; -CONHOH, -CONHOR11, NiOHICOR11, -SN2K2R', -SONHR6, -C02K, -CK2SK, -C(0)NH0R12'· and common prodrug derivatives; R1 is selected from: H, - (Co-Cg)aikyl-S (0)p- (Ci-Cg)alkyl, - (C0-C6) alkyl-0- (Ci-C6) alkyl, - (Co-C0>alkyl-S(0)p- (Co-Cg)alkyl-aryl, - (Cp-Cg) alkyl-0- (Co-Cg)alkyl-aryl, alkyl cf from 1 to 20 carbon atoms which incluce branchea, cyclic and ur.saturated alkyl groups, substituted alkyl wherein the substituent is selected from; hydrogen, halc, hydroxy, alkoxy, aryloxy, (such as phencxy) , amino, mono- alkyianu.no, di-alkylanu.no, acylanu.no (such as acetamido and benzamido;, arylamino, guanidinc, N-methyl imidazolyl, imidazolyl, indolvl, mercapto, alki/lthio, arylthio (such as phenylthio), carboxy, carboxamiao, carbo alkoxy, or sulfonamidc, - (Co-Cs'!alkyl-aryl< - (Co-Ca)alkyl-substituted aryl, -18- LV 12167 - (Co-Ce)aryl- (C1-C4) alkyl-aryl, -(Ci-Ce)alkyl-biaryl, -(C0-C8)alkyl-S(0)p-(Co-Ce!alkyl-aryl, -(Co-Ce)aikyl-S(O)p-(Co-Ce)alkyl-substituted aryi, - (C1-C4) alkyl-aryl- (Cq-Cs ) alkyl-aryl- (S (0) p- (Co~
Ca)alkyl], - (Co-Ce)alkyl-S(0)p- (Co-C8)alkyl-biaryl, - (C0-C8) alkyl-0- (Co-Cs) alkyl-aryl, - (Co-Ce) alkyl-S (0)p- (Co-C8)alkyl-substituced aryl, - (C1-C4) alkyl-aryl- (Co-Ce) alkyl-aryl- (0- (Co-Ce) alkyl], - (Co-Ce) alkyl-0- (Co-C8)alkyl-biaryl, - (Co-Ce )alkyl-0- (Co-C8)alkyl-substituted aryl, wherein the substituent is selected from; hydrogen, C3.-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl; r2 is selected from H, -CO2R5, -CONR6R5, -CONR6(OR5), -alkvl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryi, -heteroaryl or -heterocyclic which is substituted with one or more substituents selected from: hydrogen, halc, hydroxy, alkoxv, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkvlthio, arylthio (such as ohenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R3 is selected from H, -OH, and -NH2;
Alternatively R2 and R3 can form a 3 to 6 membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; R4 is selected from: K, -0K, and -NH2; R5 is selected from: - (CHRlY)n-R3- -C (R7R8) n-W-C (R7R8) m-R9, -C (R7R8)m-R9 , -C (R7R8) m-aryl, -C (R7R8) mCONR7R8, -C (R7R8) m-substituted heteroaryl, -C (R7R8) m-substituted heterocyclic wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R6 is selected from: H, alkvl-, - (Ci-Ce)alkyl-aryl, - (C1-C5)alkyl-heteroaryl, - ;Ci-Cč>alkyl-heterocyclic, - (Ci-Cs)alkyl-acyl;
Alternatively, R5 and R6 may form a 3 to 8 membered ring opticrally unsaturated containing from 1 to 3 heteroatoms selected from -0, -NR6, -S(0)p, cr an acyl group, optionallv fused to an aryl ring; R7 and R8 ray be selected independer.tly from: H, R1, or form a 3 to 7 membered substituted ring with 0-3 unsaturations, wnerein the substituent is selected from; bvdrogen, Ci-Cs alkyl, hydroxy, halo, alkoxy, ami'r.c, mcr.o-alkvlamino, di-alkylamino, -20- LV 12167 acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionallv containing -O-, -S(0)p, -NR6, optionally fusea to a substituted aryl ring, wnerein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acyland.no, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkvl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, 0 or S(0)p, optionally substituted with -OK, -0- (Ci-C6)alkyl, -0-acyl-alkyl, NHR10, or aryl; F.10 is K or ar. optionally substituted alkyl group; R11 is hydrogen, al3cyl of from 1 to 10 C atoms which include branched, cyclic and unsaturated ailcyl groups, substituted alkyl whereir. the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, ai-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidito, imidazolyl, indolyl, mercapto, alkylthio, arylthio {such as phenylthio) carboxy, carboxamidc, carbo-alkoxy, or sulfonainide, - (Ci-C4)alkyl-aryl, - (C1-C4)alkyl-(C:-Ce)alkyl-aryl -(Ci-Ca)alkyl-biaryl, substituted -(C:-Cg) alkyl-aryl, whereir. the substituent is selected from: hvdrogen, halo, hydro^y, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylairu.no such as acetamido and benzamido, aryiamino, guanidino, imidazolvl, indolyl, mercapto, alkylthio, arylthio (such as phenyithio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;
Rlla is H, -S02-Ci-Cg-alkyl, -S02-Ci-Ce-alkyl-substituted aryl, -SC>2-aryl, -SC>2-substituted heteroaryl, -COR9, -C02t Bu, -C02Bn, or -alkyl-substituted aryl wherein the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkyl amino, acylairu.no, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: H, aryl, (Cļ to Cio)alkyl-, aryl (Ci to Cg)alkyl-, C3 to Cii cycloalkyl, C3 to C10 alkylcarbonyioxyalkyl, C3 to C10 alkoxycarbonyloxyalkyl, C2 to Cio alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to Cio cycioalkoxycarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy(Ci to Cg aikyl) arylcarbonyloxy(Ci to Cg alkyl)-, C5 to C12 alkoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl) methyl, (R17) (R17a)N- (C1-C10 alkvl) - , -CHtR13)0C(=0)R14, -CH(R12)OC (=0)0R15, 0Γ 0
whereir.
-22- LV 12167 R14 is selected from: n ** /
Ci-Cs alkyl or C3-C8 cycloalkyl, said alkyl or cvcloalkyl being substituted with 1-2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl C1-C5 alkoxy, aryl substituted wlth 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, Ci-Ce alkoxy, NO2/ -S(Ci-Cs alkyl), -S(=0)(Ci-C5 alkyl), -S02(C1-C5 alkyl) , -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R17a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l) , aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C6 alkyl, C1-C6 alkoxy, N02, -S(Ci-Cs alxyl), -S(=0)(Ci-Cs alkyl!, -S02 (C1-C5 alk^ū;, -OH, -N(R17} (R17a) , -C02R17a, -C (=0) N(R17) (R-7a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l); R15 is selected from:
Ci-Ce alkyl, C3-C8 cycloalkyl, said alkyl or cycloaikyl being substituted with 1-2 groups independer.tlv selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independentlv selected from: -23- halogen, phenyl, Ci-c6 alkyl, Ca-C6 alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(Ci-C5 alky1), -SO2 (C1-C5 alkyl) , -0H, -N(Rl7) (Rl7aj / -co2R17a, -C (=0) N(R17) (R17a) , or -CVFW wnere v = 1 to 3 and w = 1 to (2v+l), aryi substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C6 alkyl, Ci~C6 alkoxy, N02, -S(Ci-c5 alkyl), -S(=0)(Ci-C5 alkyl), -S02(Ci-C5 alkyl) , -0H, -N(Rl7) (Rl7aj , -C02R17a, -C(=0)N(Rl7) (Rl7aj , or -CvFw where v = 1 to 3 and w = 1 to (2v+l); R16 is C1-C4 alkyl, benzyl, or phenyl; R17 ar.d R17a is independently selected from: H, C1-C10 alkyl,C2-C6 alkenyl, C4-C11 cycloalkylalkyl, and aryi(C:-C6 alkyl);
Combmations of A, 3 and D, and/or variables are permissable cnlv if such combinatior.s result in stable compounds (as detinec hsrein) A can be absent, -(CHR6)m-, -0(CHRS)m-, -NR6(CKR6)m-, - S (O) p (CHR6)m-, or selected from an alkyi from 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl groups cr - {Ci-C6)alkyl-aryl; B can be a bond or selected from -NH-, -NR^7-, - NR7·13— -C-, -S (0)p- (C--Cs) alkv’l-NH- (C:-C6) alkyl-, (Ci-Cg)aikyl-N?:i- (Ci-C5)alky-, -Ci-C6-NH-aryi-, -0-{Ci-C6)alkiv-:-f - (C;-C6)alkyl-0-aryl-, -24- LV 12167 -S-(Ci-Cg)alkyl-, -(Ci-C6)alkyl-S-aryl-, -(C:-C6)alkyi-, -(Ci-C6)alkenyl-,-(Ci-Cg)alkynyl-, -CONK-. -CONR11, -NHCO-, -NR^CO-, -OCO-, -COO-, -0C02-, -R--NCONR*--, KNCONH-, -OCONR11-, -NRUCOO-, -HNS02-, -S02NH-, arvl, cycloalkyl, heterocycloalkyl, -R11NCSNR1l-, -HNCSNH, -OCSNR11-, -NR^CSO-, -HNCNNH-, and a peptide bond mimic;
D can be absent or an alkyl from 1 to 10 carbon atoms cptionally interupted by 0, S or NR6, which include branched and cyclic and unsaturated alkyl groups and -(Ci-Cg)-alkyl-aryl; p can be C, 1 or 2; ir. is an inceger from 0 to 5; n is an inceger from 1 to 5; W is -0-, -S(0)p- or -NR10-; Y is selecceč from: -CONR10-, -NR-°CO-, -SO2NR10-, -NR10SO2-< a peptide bond mimic, a 5 membered heterocvclic rir.g saturated, unsaturated or partiallv unsaturated containing from 1 to 4 heteroatoms selected from N,0 or S, with the proviso that the size cf the macrocycle encompased in formula I by -A-B-D-C(R2) (R3)-Υ-CiR1)-C(U) (R4)-, be connected by no less than 11 atcrs and no more than 22 atoms to forr. the cycle. -25- [5] Preferred compounds of the present invention are compounds of formula II where;
Formula II
or pharmaceutically acceptabie salts or prodrug forms thereof, wherein,· X is selected from CK2, NH, S and 0;
r13, r14, r15, pīs, r17, ^17a apš In< n# j>i) B, d and w are as specified previouslv in Formula I and defined as stable compounds; with tne proviso that the size of the macrocycle encompased in formula I by -A-3-D-C (R2) (R3)-Y-C (R1) -X-C (U) (R4) -, be connected by no less than 11 atoms and no more than 22 atoms to form the cycle. LV 12167 [6] More preferred compounds of the present inventior. are compounds of formula I where,
Formula I
R or p'narmaceutically accepcable salts or prodrug forms thereof, wherein; U is selected from: -CONHOH, -C(0)NH0R12· -CO2H and common prodrug derivatives; R1 is selected from: H, - (Co-Ce) alkyl-S (0)p- (Ci-C6)alkyl, - (C0-C5)alkyl-O-{Ci-C6)alkyl, - (Co-Cg) alkyi-S (0) p- (Co-Ce)alkyl-aryl, - (Co-Cg) alkyi-0- (Co-Cg) alkyl-aryl, alkyl of from 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from; hydrogen, nalo, hydroxy, alkcxy, aryloxy, (such as phenoxy), amino, mono- alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imiaazolyl, imidazolvi, indolyl, mercapto, alkylthio, arylthic (such as pher.ylthic :, carboxy, carboxamido, carbo alkoxy, or sulfonamido, -(Co-Ce)alkyl-aryl, -27- - (Co-Cg)alkyl-substituted aryl, - (Co-C8)aryl- (Ci-C4)alkyl-aryl, - (Ci-Ce) alkyl-biaryl, - (C0-C8 5 alkyl-S (0) p- (Co-Cs) alkyl-aryl, - (Co-Cs)alkyl-S(0)p- (Co-Cs)alkyl-substituted aryl, -(C1-C4)alkyl-aryl- (Co-Cs)alkyi-aryl-[S(0)p-(Co-
Cs) alkyl], - (Co-Cs)alkyl-S (0)p- (Co-Cs>alkyl-biaryl, - (Co-Cs )alkyl-0- (Co-Cs)alkyl-aryl, - (Co-Cs) alkyl-S (0)p- (Co-Cs)alkyl-substituted aryl, - (C1-C4) alkyl-aryl- (Co-Cs) alkyl-aryl- [0- (Co-Cs) alkyl] - (Co-Cs)alkyl-0- (Co-Cs)alkyl-biaryl, - (Co-Cg) alkyl-0- (Co-Ce )alkyl-substituted aryl, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkyiamino, di-alkylamino, acyianu.no, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from K, -CO2R5, -CONR6R5, -CONR6(OR5), -alkyl, -alkylaryl, -alkylheteroaryi, -alkyiheterocyciic, -aryl, -heteroaryl or -heterocvclic which is substituted with one cr more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methvl imidazolyl, imidazolyl, indolyl/ mercaptc, lowe alkvltnic, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkcxy ; R3 and R4 are H; ?.5 is selecced from: -28- LV 12167 - (CHRlY)n-R5' -C(R7R8 )^-0^^8)^9, -C(R7R8)m-R3, -C(R7Re)n,-aryl, -C(R7R8)mCONR7R8, -C (R7R8)m-substituted heteroaryl, -0 (R7R8) m-substicuced heterocyclic, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylanu.no, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamiao or aryl; R6 is selected from: H, alkyl-, - (Ο^-Οβ)alkyl-aryl, - (Ci-Cg)alkyl-heteroaryl, - (Ci-Ce)alkyl-heterocyclic, - (Ci-Cg)alkyi-acyl;
Aiternatively, R5 and R6 may form a 3 to 8 membered ring cptionally unsaturated containing from 1 to 3 heteroatoms selected from -0, -NR6, -S(0)p, or an acyl group, cptionallv fused to an aryl ring; R7 and r8 may be selected independently from: H, R1, or form a 3 tc 7 membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylainino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing -0-, -S(0)p, -NR6, optionally fused to a substituted aryl ring, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkvlamino, di-alkylamino, acylaminc, thic, thioalkyl, carboxy, carboxamido or ar/1; -25- R5 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, 0 or S(0)p, optionally substituted with -0H, -0-(Ci-Cg)alkyl, -0-acyl-alkyl, NHR10, or aryl;
Rlc is H or an optionally substituted alkyl group; R11 is hydrogen, alkyl of from 1 to 6 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl; wherein the substituent is selected from: - hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylanu.no such as acetamido and benzamido, arylamino, guanidino, imiaazolyl, indolyl, mercapto, loweralkylthio, arylthio (such as phenylthio) carboxy, carboxairu.dc, carbo-alkoxy, and sulfonamide; - (Ci-C4)alkyl-aryl, - (Ci-Ce) alkyl-substituted aryl, wherein the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arvlamino, guanidino, imidazolyl, indolvl, mercapto, loweralkylthio, arvlthio (such as phenylthio) carboxy, carboxamido, carbc-alkoxy, and sulfonamide;
Rlla is H, -S02-Ci-C6-alkyl, -S02-Ci-C6-alkyl-substituted aryl. -S02-aryl, -S02-substituted heteroaryl, -COR9, -C02t-Bu, -C02Bn, wherein the substituent is selected from: hydrogen, C:~C5 alkyl, hydroxy, halo, alkoxy, amino, monc-alkylamino, di-alkylamino, acylamino, thio, tnioalkyl, carboxy, carboxamidc or ar-yl ; -30- LV 12167 R1·2 is selecced from: K, aryl, (Ci to Cio)alkyl-, arvl (Ci to C6)alkyl-, C3 to Cn cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 alkoxycarbonyloxyalkyl, C2 to C10 alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy(Ci to Ce alkyl)-, arylcarbonyloxy(Ci to Cg alkyl)-, C5 to C12 alkoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkyl)-i,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, (R17) (RitajN-(Ci-C1Q alkyl)-, -CH(R13)0C(=0)R14, -CH(R13)0C(=0)0R15, or
R13 is K or C1-C4 linear alkyl; R14 is selected from: K,
Ci-Ce alkyl or C3-C8 cycloalkyl, said alkyi or cycloalkyl bemg substituted with 1-2 groups independently selected from: C1-C4 alkvl, C3-C3 cycloalkyl C1-C5 alkoxy, arvl subsrituted with 0-2 groups rndepender.clv selected from: -31- halogen, phenyl, Οχ-Οβ alkyl, Ci-C6 alkoxy, NO2/ -S(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -302(01-05 alkyl) , -OH, -N(Rl7) (Rl7a), -co2Rl7a, -C(=0)N(R17) (Rl7a), or -CVFW where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, 0χ-06 alkyl, Ci-C6 alkoxy, N02, -S(C1-C5 alkyl), -S(=0) (Ci-Cs alkyl), -S02 (Ci-C5 alkyl), -OH, -N(R17) (Rl7a) , -C02R17a, C(=0)N(R17) (Rl7a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l); R15 is selected from: Οχ-Cs alkyl, C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independentlv selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independentiy selected from: halogen, phenvl, Οχ-Οβ alkyl, Οχ-Οβ alkoxy, N02, -S(Cx-Cs alkyl), -S(=0!(Ci-Cs alkyl), -S02(0χ-05 alkyl) , -OH, -N(R17) (R17a) , -C02Rl7a, -C(=C)N(R17) (R17a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups independently selected from: halogen, phenvl, Οχ-Οβ alkyl, Οχ-Οβ alkoxy, N02, -S(Cx-C5 alkyl) , -S(=0'(Ci-C5 alkyl;, -S02(Ci-C5 alkyl), -OH, -N(R") (Rl7a) , -C02R17a, -C(=0)N(Rl7) JR’*7·) , -32- LV 12167 or -CVFW where v = 1 to 3 and w = 1 to (2v+l); R16 is C1-C4 alkyl, benzyl, or phenyl; R17 and R17a is independently selected from: H, C1-C10 alkyl,C2-C6 alkenyl, C4-C11 cycloalkylalkyl, and aryl(Ci-Cg alkyl);
Combinations of A, B and D, and/or variables are permissable only if such combinations result in stable compounds (as defined herei.n). A can be absent, -(CHR6)m-, -0(CHR6)m-, -NR6 (CHR6) jji- , - S (O) p (CHR6) m~« or selected from an alkyl from 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkvl groups or - (Ci-C6)alkyl-aryl; B can be a bond or selected from -NK-, -NR11-, -NRlla-, -C-, -S(0)p-Ci-C6alkyl-NH-Ci-C6alkyl-, Ci-C6alkyl-NRH-Ci-C6alky-, Ci-Ce-NK-aryi-, -0-Ci-C6alkyl-, Ci-C6alkyl-C-aryl-, -S-Cl-C6alkyl-, Cl-C6alkyl-S-ar'yl-, Ci-Cealkvi-, Ci-C6alkenyl-, Ci-C5alkynyl-, -CONH-, -CONR11, -NHCO-, -NR^CO-, -OCO-, -COO-, -0C02-, -R^NCONR11-, HNCONH-, -OCONR11-, -NRUCOC-, -HNSC2-, -SO2NK-, aryl, cycloalkyl, heterocycloalkyl, -RUNCSNR11-, -HNCSNH, -OCSNR11-, -NRnCSO-, -HNCNNK-, and a peptide bond mimic;
-33- D can be absent or an alkyl of from 1 to 6 carbon atoms which include branched and cyclic and unsaturated aikyl groups or -(Ci-C6>alkyl-aryl; p car. be 0, 1 or 2; m is an integer from 0 to 3; n is an integer from 1 to 4; W is -0-, S(0)p or NR10; Y is selected from: -CONR10-, -NR10CO-, -SO2NR10-, -NR10SO2-/ a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,0 or S, with the proviso that the size of the macrocycle encompased in formula I by -A-B-D-C(R2) (R3)-Y-C (R1)-C (U) (R4)-, be connected by nc less than 11 atoms and no more than 22 atoms to form the cycie.
Onlv substituents that form stable compounds are claimed for formula I. LV 12167 [7] More preferred compounds of the present invencion are compounds of formula II where,
Formula II
B
or pharmaceutically acceptable salts or prodrug forms thereof, wherein; X is selected from CK2. NH, S and 0; U is seiected from; -CO2H, -CO2R12 and common prodrug derivatives;
r15, r16, pi7. pi7a p, τρ^ n, A, B, D and W are as specified previouslv in Formula I and defined as stable compounds; with the proviso Chat the size of the macrocycle encompased in formula I by -A-B-D-CiR2) (R3)-Y-C(Rl)-X-C(U) {R4) -, be connected by no less thar 11 atoms and no more than 22 atoms tc form the cycle. -35- [8] More preferred compounds of the present invention are compounds of formula I where,
Formula I
B
cr pharmaceutically acceptable salts or prodrug forms thereof, wherein; U is selected from: -CONHOH, -C(0)NH0R12, -CO2H, and coiranon prodrug derivatives; R- is selected from: H, - (Cc-Cg) aikyl-S (0) p- (Ci-Cg) alkyl, - {Cc-C6)alkyl-0- (Ci-C6)alkyl, - (Co-Ceialkyl-S(0)p- (Co-C6)alkyl-aryl, - (Cc-Cg ,'alkyl-C- (Co-Cg)alkyl-aryl, alkvi cf from 1 to 20 carbon atoms which include branchec, cyclic and unsaturated alkyl groups, substituted alkyl whereir. the substituent is selected from; hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy) , aminc, mono- alkyiamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylairu.no, guanidino, N-methvl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arvlthio (such as phenvlthio) , carboxy, carboxamido, carbo alkcxy, or sulfonamido, - (Co-Ce i alkyl-aryl, - (Cc-Cg: alkvi-substituted aryl, - (Cc-Cg! aryl- (C:-C4)alkyl-aryl, -36- LV 12167 - (Ci-Ca) alkyl-biaryl, -(Co-C8)alkyl-S(0)p- (Co-Cg)alkyl-aryl, - (Co-Ce!alkyl-S(0)p- (Co-Ce)alkyl-substitutea aryl, -(Ci-C4)alkyl-aryl-(Co-Ce)alkyl-aryl-(S(O)p-(Co~
Cg)alkyl], -(Co-Cg)alkyl-S(O)p-(Co-Ce)alkyl-biaryl, -(Co-Ce)alkyl-0- (Co-C8)alkyl-aryl, - (Co-Ce)alkyl-S(0)p- (Co-C8)alkyl-substituted aryl, - (Ci-C4)alkyl-aryl- (Co-C8)alkyl-aryl- [0- (Co~Ca)alkyl], - (Co-Ce )aikyl-0- (Co-C8)al)<yl-biaryl, - (Co-Ce)alkyl-0- (Co-C8)alkyl-substituted aryl, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylaminc, di-alkylairu.no, acylairu.no, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, -CO2R5- -CONR6R5, -CONR6(OR5), -alkyl, -alkviarvl, -alkvlheteroaryl, -alkylheterocycliC/ -aryl, -heteroaryl or -heterocvclic which is substituted with one or more substituer.es selected from: hvdrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylairu.no, di-alkylami.no, acylamino (such as acetamido and benzamido), arylairu.no, guanidino, N-methyl imidazolyl, imidazciyl, indoiyl, mercapto, lower alkvithic, arylthic (such as phenylthio), carboxy, sulfonamido, carboxarru.dc, or carboalkcxy; R3 and R4 are H; R5 is selected from: - (CKR1Y)ri-Rs* -C(R'R3'in-W-:(R7R8)m-R9, -C (R7Ra) m-Rs, C (R~R8) m-ary:, -C (R7R8)m-heteroary1, -C(R7R8)m-heterocyclic; R6 is selected from: H, alkyl-, - (Ci-Cg)alkyl-aryl, - (Ci-Cg)alkyl-heteroaryl, - (C1-C6) alkyl-heterocyclic, -{Ci-C6)alkyl-acyl;
Alternativeiy, R5 and R6 may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -O, -NR6, -S(0)p, or an acyl group, optionally fused to an aryl ring; R7 and R8 may be selected independentlv from: K, R1, or form a 3 to 7 membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mcno-alkylamino, di-alkvlamino, acvlamino, thio, thioalkyl, carboxy, carboamido or aryl, cpticnally containing -0-, -S(0)p, -NR®, optionally fused to a substituted aryl ring, wherein the siistituent is selected from; hvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mcno-alkylamino, di-alkylamino, acylaminc, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is K, alkvl, cycloalkyl, 5 or 6 membered ring optionally con-aining from 1 to 2 N, 0 or S(0)p, optionally substituted with -OH, -O- (C1-C6) alkyl, -0-acyl-alkyl, NHR10, or aryl; R10 is H or an cpricnally substituted alkvl group; -38- LV 12167 R11 is hydrogen, alkyl of from 1 to 6 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; wherein the substituent is sslected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-al}cylamino, acylaiiiino such as acetamido and benzamido, arylartu.no, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, and sulfonamide; - (Ci-C4)alkyl-aryl, - (Ci-Ce)alkyl-substituted aryl, wherein the substituent is selected from: hydrogen, halo, hydroxv, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylairu.no, guanidino, imidazolyl, indolvl, mercapto, loweralkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, and sulfonamide,·
Rlla is K, -SO2-(Ci-Cg) alkyl, -SO2-(Ci-C§)alkyl substituted arvi, -S02-aryl, -S02-substituted heteroaryl, -COR9, -C02t-Bu, -C02Bn, wherein the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylanu.no, thio, thioalkyl, carbox\·, carboxamido or aryi; r!2 is selected from: K, aryl, (Ci to Cio)alkyl-, arvl -(Ci to C6>alkyl, C3 to C11 cycloalkyl, C3 to Cio alkylcarbonyloxyalkyl, C3 to C10 alkoxycarbonyioxyalkyl, C2 to C10 alkoxycarbonyl, C5 to C10 cycicalkylcarbonyloxyalkyl, C5 to C:o cycioalkoxycarbor.yloxyalkyl, -:a_ C5 to Cio cycloalkoxycarb0nyl, aryloxycarbonyl, aryloxycarbonyloxy(Ci to C6 alkyl), arylcarbonyloxy(Ci to Cg alkyl), C5 to C12 alkoxyalkylcarbonyloxyalkyl, [5- (C1-C5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-l,3-dioxa-cyclopenten-2-one-yl)methyi, (R17) (R17a)N-(C1-C10 alkyl) - , -CH(Rl3)OC (=0)R14, -CH(R13)OC (=0)0R15, or 0
wherein R13 is K or C1-C4 linear alkyl; R14 is selected froir.: H,
Ci-Cg alkyl or C3-C8 cycloalkyl, saic alkyl or cycioalkyi beina substituted with 1-2 groups independencly selected fron: C1-C4 alkyl, C3-C3 cycloalkyl C1-C5 alkoxy, aryl substituted wich 0-2 groups ir.aependettly selected from: halcgen, p'nenyl, Ci-Ce alkyl, Ci-Ce alkcxy, N02, -S(Ci-Cs alkyl) , -S(=0)(C1-C5 alkyl), -S02(Ci-C5 alkvl), -OK, -N(R17) (R17a) , -C02R17a, -C(=3)N(R17) (R17a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups inaependently selected ircnu -40- LV 12167 halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, N02, -S(Ci-C5 alkyl), -S<=0)(C1-C5 alkyl), -S02(Ci-Cs alkyl), -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R^7a) , or -CVFW where v * 1 to 3 and w = 1 to (2v+l); R15 is selected from:
Ci-C8 allcyl, C3-C3 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independentiy selected from: C1-C4 alkyl, C3-C8 cvcloalkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independer.tlv selected from: halogen, phenyl, Ci-Cg alkyl, Ci-Cg alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -S02(Ci-C5 alkvl) , -OK, -N(R17) (R17a) , -C02R17a, -C(=0)N'R17) (R17a; , or -CvFw where v = 1 tc 3 and w = 1 to (2v+l), arvl substituted with 0-2 groups independently selected from: halogen, pnenvl, C1-C6 alkyl, Ci-Cg alkoxy, N02, -S(Ci-Cs alkyl), -S(=0) (Ci-C5 alkyl), -S02(C:-C5 alkyl), -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N;R17) (Ri7a) , or -CvFw where v = 1 to 3 and w = 1 to (2vi-l); R15 is C1-C4 alkyl, ber.zvl, or phenyl;
Combinations ci A, 3 and D, anc/or variables are ņermissabie cnly if such combinations resuit in stable compcunds (as defined harein). -41- A can be; -NR6-(CH2)m-; -(CH2)> -0-(CH2)m-, -S-(CH2)m-, B can be a bond or selected from -NH-, -NR11-, -NRlla-, -0-, -S(0)p-Ci-C6al)cyl-NH-Ci-C6al)cyl-, Ci-C6alkyl-NRH-Ci-Cealky-, Ci-Ce-NK-aryl-, -0-Ci-C6alkyl-, Ci-C6alkyl-0-aryl-, -S-Cl-C6alkyl-, Cl-C6alkyl-S-aryl-, Ci-C6alkyl-, Ci-C6alkenyl-, Ci-C6alkynyl-, -CONH-, -CONR11, -NHCO-, -NRnCO-, -OCO-, -COO-, -0C02-, -R11NCONR11-, HNCONH-, -OCONR11-, -NR1:lCOO-, -HNS02-, -S02NH-, aryl, cycloalkyl, heterocycloalkyl, -R^NCSNR11-, -HNCSNH, -OCSNR11-, -NRUCSO-, -HNCNNH-, and a peptide bond mimic,-
D is -(CH2)m~ ; p can be C, 1 or 2; m is an integer from j to 3; n is an integer from 1 to 4; W is -0-, S(0)p or N?.10; Y is selected from: -CONR10-, -NR10CO-, -S02NR10-, -NR10SO2-, a peptide bond mimic, a 5 membered heterocyclic rir.g saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected frcm N,C or S, LV 12167 with the proviso Chat the size of the macrocycle encompased in formula I by -A-B-D-C(R2)(R3)-Y-C(R1)-C(U)(R4)-, be connected by no less t'nan 11 atoms and no more than 22 atoms to form the cycle.
Onlv substituents that form stable compounds are claimed for formula I. -43- [9] The most preferred compounds of the present invention are compounds of formula la, Ib, Ic and Id where,
Formula IV
īve ivd or pharmaceutically accepcable salts cr prodrug forms therecf, wherein; R1 is selected from: H, - (Co-Cg) allcyl-S(0)p- (Ci-C6)alkyl, -(Cc-Cg)alkyI-0-(Ci-Cg)aikyl, - (Co-Cg) alkyI-S (Ci p- (C0-C5) alkyl-aryl, - (Co-Cg) = IkyI-C:- (Co-Cg) alkyl-aryl, -44- LV 12167 alkyl of from 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from; hvdrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono- alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imida20lyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, -(Co-Ce)alkyl-aryl, -(Co-Ce)alkyl-substituted aryl, - (Co-Ce)aryI- (Ci-C4)alkyl-aryl, - (Ci~Cg) al)cyl-biaryl, - (Co-Ce) alkyl-S (O)p- (Co-Cs)alkyl-aryl, -(Co-Cg)aikyl-S(O)p-(Co-Cs)alkyi-substituted aryl, - (C1-C4) alkyi-aryl- (Co-Cs) alkyl-aryl- (S (0) p- (Co-
Cs) alkvlj, -(Co-Cs)alkyi-5(O)p- (Co-Cs)alkyi-biaryl, - (Co-Cg)alkvI-O- (Co-Cs)alkyl-arvl, - (Co~Ca) alkyi-S (0) p- (Co-Cs)alkyl-substituted aryl, - (C1-C4) alkyl-aryl- (Co-Cg) alkyl-aryl- [C- (Cq-Cs)alkvl] , - (Co-Ca) alkyi-0- (Co-Cg)alkyl-biaryl, - (Co-Cg)alkyi-0- (Co-Cg)alkyl-substituted arvl, wherein the substituent is selected from; hvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mc:io-alkylamino, di-alkylamino, acylaminc, thio, thioalkyl, carboxy, carboamido cr aryl; R2 is selected from H, -CO2R5, -CONR°R5, -CONR5 (OR5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkyiheterocyciic, -aryl, -heteroaryl cr -45- -heterocyclic which is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (suc’n as phenoxy), amino, mono-alkylamino, di-alkylaitu.no, acylaitu.no (such as acetamido and benzamido) , arylanu.no, guanidino, N-methyl imidazolyI, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R5 is selected from: - (CHR^n-R9' -C(R7R8)n-W-C(R7R8)m-R9, -C(R7R8)m-R9, -C(R7R8)m-aryl, -C(R7R8)mCONR7R8' -C (R7R8 i m-heteroaryl, -C (R7R8;m-heterocyclic; R6 is selected from: H, alkvl-, -[(Ci-C6)alkyl-aryl, - (C1-C5;alkyl-heteroaryl, - (Ci-Ca-alkyl-heterocyclic, -(Ci-C6;alkyl-acyl;
Alternativeiv, R5 and R° may form a 3 to 8 memberea ring optionallv unsaturated containinc from 1 to 3 heteroatoms selected from -0, -NR6, -S(0)p, or an acvl group, optionallv fused toan aryl ring; R7 and R8 may be selected independently from: H, R1, or form a 3 to ~ membered substituted ring with 0-3 unsaturations, whereir. the substituer.t is selected from; hvdrogen, C1-C5 alkyl; hydroxy, halo, alkcxy, arc.no, mcno-alkylaitu.no, di - alkylartu.no, ar/lamir.c, thio, thioalkyl, carboxy, carboamido or arvl, -46- LV 12167 optionally containing -0-, -S(0)p, -NR6, optionally fused to a substituted aryl ring, wnerein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is H, alkyl, cycloalkyl, 5 or 6 membered ring opūionallv concaining from 1 to 2 N, 0 or S{0)p, optionailv substituted with -OH, -0- (Ci-Ce)alkyl, -0-acyl-alkyl, NHR10, or aryl; R10 is K or ar. optionally substituted alkyl group; R11 is hvdroger, alkv*l of from 1 to 6 C atoms which irclude branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; wherein tre substituent is selected from: hvdrogen, halo, hydroxy, alkoxv, aryloxy, such as pheroxy, amino, di-alkylamino, acylanu.no such as acetamido and benzamido, arylamino, guanidirc, imidazolyl, indolyl, mercapto, loweralkylthic, arylthio (such as phenylthio) carboxy, carboxaitu.dc, carbo-alkoxy, and sulfonamide; - (C:-C4)alkyl-aryl, - (Ci-Ce) alkyl-substituted aryl, wherein the substituent is selected from: hydrcgen, halo, hydroxy, alkcxy, aryloxy, such as pher.oxy, amino, di-a.lkylaminc, acylamino such as acetamido and benzamido, arylamino, guanidirc, imidazolyl, indolyl, mercapto, loweralkylthic, arylthio (such as phenylthio) carboxy, carbcxanu.dc, carbo-alkoxy, and sulfonamide; -47-
Rlla is H, -SO2-<Ci-C6) alkyl, -SO2- (Ci-Ce) alkyl substituted aryi, -S02~aryl, -SC>2-substituted heteroaryl, -COR9, -CO2C-Bu, -CC^Bn, wherein the substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylanu.no, acylaitu.no, thio, thioalkyl, carboxy, carboxamido or aryl; m is an integer from 0 to 5; n is an integer from 1 to 5; p can be 0, 1 or 2; W is -O-, S(0)p or NR10; Z is CK2 or 0 Y is selected from.- -CONR10-, -NR10CO-, -SO2NR10-, -NR10SO2~, a peptide bond mimic, a 5 membered heterocvclic ring saturated, unsaturated or partially unsaturatēd containing from 1 to 4 heteroatoms selected from N.O or S,
Only substituents that form stable compounds are claimed for formula la to Id.
[103 Most preferred compounds of the present invention include compounds of formula I, or a pharmaceutically acceptable salt or prodrug form thereof, selected from the following: 2S, 5R, 6S-3-aza-4-cxo-10-oxa-5-isobutyl-2-(N-methylcarbcxamido) - [10] paracyclophane-6-N-hydroxy carbcxami de ; -48- LV 12167 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobucyl-2-(carboxymethyi)-[10]paracyclophane-6-N-hydroxycarboxanu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxanu.de; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(hydroxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-alanine-N-methylamide) -[ 10 ]paracyclophane-6-N-hydroxycarboxanu.de 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L-(0-methyl) tyrosine-N-methylairu.de]-[10]paracyclophane-6-N-hydroxycarboxaiiu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L-(O-tert-butyl)serine-N-methylanu.de]-[10]paracyclophane-6-N-hydroxycarbcxami de; 2S,5R,SS-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-serine-N-merhylanu.de;-[10]paracyclophane-6-N-hydroxycarboxamide ; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N-methviamide) -(10]paracyclophane-6-N-hydroxycarboxanu.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-alanine-N-mechylairu.de) - [10] paracyclophane- 6-N-hydroxycarboxamide ; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(beta-alanine-N-methylaird.de) - [10] paracyclophane- 6-N-hydroxycarboxanu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyi-2-[D-(0-tert-butvl) serine-N-methyiamide] - [10] paracvclophane-6-N-hydroxycarbcxanu.de ; -49- 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-serine-N-methyianu.de)-[10]paracyclophane-6-N-hydroxycarboxanu.de; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-lysine-N-mechylamide)-[10]paracyclophane-6-N-hydroxycarboxamide ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-valine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-pyridyl)ethylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxamide tri fluoroacetate; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4-mechyl)piperazinylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxaiiu.de ; 2S,5R,6S-3-aza-4-oxc-10-oxa-5-isobutyl-2-(2-ber.zimidazolvl) - [10] paracyclophane-6-N-hydroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-imidazolyI) carboxar,iido] - [10]paracyclophane-6-N-hydroxycarboxanu.de ; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-benzimidazolvi) mechylcarboxamido] - [10]paracyclop'nane-6-N-hydroxycarbcxanu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyi-2-[(3-imidazolyl)propylcarboxairido] - [10]paracyciophane-6-N-hydroxycarbcxanu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[2-(4-aminosulfonyiphenyl) echylcarboxamido] - [10]paracyclophane-6-N-hydroxycartoxanu.de ; 50- LV 12167 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N,N-dimethylamide) - [10] paracyclophane-6-N-hydroxycarboxamide; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(1-adamantylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4-aminoindazolyl) carboxamido] - [10] paracyclophane-6-N-hydroxycarboxamide ; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N,N-diethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (N-isopropylcarboxamido)-[10]paracyclophane-6-N-hvdroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (N-cyclopropy!carboxamido) - [10]paracyclophane-6-N-hydroxycarboxanu.de ; 2S, 5R, 6S-3-aza-4-cxo-10-oxa-5-isobutyl-2-(N-tert-butylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- [giycine- (N-isopropyl) amide] - [10] paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-cxo-10-oxa-5-isobutyl-2- [glycine- (N-echyl)amide] - [10]paracyclophane-6-N-hydroxycarboxairu.de; 2S, 5R, 6S-3-aza-4-cxo-10-oxa-5-isobutyl-2- [glycine- (N-cyclopropyl) amide] - [10] paracyclophane-6-N-hydroxycarboxamiae ; -51- 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-i'sobutyl-2- [glycine- (N-tert-butyl) amide] - [10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cyciobutyl)amide] - [10]paracyclophane-6-N-hydroxycarboxairu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-morpholino)amide]-[10Jparacyclophane-6-N-hydroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-2-hydroxydimechylethyl)amide]-[10]paracyclophane-6-N-hydroxycarboxami de; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethylmezhylpropyl)amide]-[10]paracyclophane-6-N-hydroxycarboxami de; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(K-dimezhyipropyl) amide]-[10]paracyclophane-6-N-hydrcxycarboxairu.de; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- [glycine-(N-(di-2 hydroxymethyl)ethylamide]-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(4-hydroxypiperidine)amide]-[10]paracyclophane-6-N-hydroxycarbcxairu.de ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-benzimidazolecarboxamido)-[10]paracyciophane-6-N-hydroxycarboxairu.de; -52- LV 12167 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[S-(methyl)-2-phenylmechvicarboxamido]-[10]paracyclophane-6-N-hydroxycarboxanu.de; 4S,7r,8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(carboxymethyl)-[ 12 ] paracyclophane-8-N-hydroxycarboxanu.de ; 4S, 7R,8S-5-aza-6-oxo-12-oxa-7-isobucyl-2-(N-methylcarboxamido) - 112 ] paracyclophane-8-N-hydroxycarboxanu.de ; 4S,7r,8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(glycine-N-methlamide) - [12] paracyclophane-8-N-hydroxycarboxanu.de; 2S, 3R,6S-10-t-Bucoxycarbonyl-5,10-diaza-2-(N-hydroxycarboxamido>-6-(N-methy1carboxamido)-l-oxa-4-oxo-3-(3 -phenylprop- l-yl) cyclotet radecane ,* 2S, 3R, 6S-5,10-Diaza-2- (N-hydroxycarboxainido} -6- (N-methylcarboxamido) -l-oxa-4- oxo-3-(3-phenylprop-1-yl)cyclotetradecane hydrochloride; 2S, 3R, 6S-10-Acecyl-5,10-diaza-2- (N-hydroxycarboxaiTiido) -6-(N-methylcarboxamido)-l-oxa-4-oxo-3-(3-phenylprop-l-yi)cyclotecradecane; 2S( 3R,6S-10-Benzenesulfonyl-5,10-diaza-2-(N-hydroxycarboxamido) -6- (N-methylcarboxamido) -l-oxa-4-oxo-3-(3-phenylprop-l-yl)cyclotecradecane; 2S, 3R, 6S,12(R,S)-10-Acetyl-5,10-diaza-2-(N-hydroxycarboxamido; -6- {N-methylcarboxamido) -12-mechyl-l-oxa-4-oxo-3-(3-phenylprop-l-yl)cyclotridecane? 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(carboxymethyl)-[10 jpar acyc1cphane-8-N-hydroxycarbcxamide; -53- 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(hydroxycarboxyl) -[ 10 ] paracyclophane-6-N-hydroxycarboxanu.de ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-((2-mechoxylechyloxy)carboxyl)-[10]paracyclophane-6-N-hy droxycarboxanu.de ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-((2-phenylethyloxy)carboxy)-[10]paracyclophane-6-N-hydroxycarboxami de; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(1-(n-mechylcarboximido)methylcarboxyl) - [10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(N-methylaminosulfonyl) ethylcarboxamido) - [10] paracyclophane-6 N-hydroxycarboxamiae; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4-(N-mechylaminosulfonyl) butylcarboxamido) - [ 103 paracyclophane-6 N-hydroxycarboxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(N-mechylaminosulfonyl)hexyllcarboxamido) -[10]paracyclophane-6-N-hydroxycarboxamiae; 2S,3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(carbomethoxy) ethylcarboxamido) - [ 10 ] paracyclophane- 6 -N-hydr oxy c arboxami de ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(hydroxycarbonyl) echyicarboxamido) - [10]paracyclophane-6-N-hydroxyc arboxami de; LV 12167 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-he*yl-2-(L-ornithine(4-t-butoxycarbonyl)carboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide ; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithinecarboxymethyl) - [10]paracyclophane-6-N-hydroxycarboxairu.de hydrochloride; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithine(4-t-butoxycarbonyl) -N-methylairu.de) - [10]paracyclophane-6-N-hydroxycarboxamide ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (L-ornithine-N-methylairu.de) - [ 10 ] paracyclophane- 6 -N-hydroxycarboxairu.de hvdrochloride; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-lysinecarboxamiae5 - [10]paracyclophane-6-N-hydroxycarboxaxnide ; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-serine(O-tert-butyl) -N-methylairu.de) - [10] paracyclophane-6-N-hydroxycarboxamide; 2S, 3R,6S-3-aza-4-cxo-10-oxa-5-hexvl-2-(L-alanine-N-methylamide) - [10] paracyciophane-6-N-hydroxycarboxairu.de; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(D-aianine-N-methylamide) - [10] paracyclophane-6-N-hydroxycarboxaitu.de; 2S, 3R,6S-3-aza-4-cxo-10-cxa-5-hexyl-2-(glycine-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R, 6S-3-aza-4-cxo-10-oxa-5-hexvl-2- (benzylcarboxamido)-[10]paracyclopnane-5-N-hvdroxycarboxamide; -55- 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(phenylet:hylcarboxamido) - [10]paracyclophane-6-N-hydroxycarboxarrd.de ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(aiphenylechylcarboxamido) - [10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(2-pyridyl)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxam± de; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(4-sulfonylaminophenyl)ethylcarboxamido) - [10]paracyclophane-6-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-οχο-10-oxa-5-hexyl-2-(2-(3,4-dimethoxyphenyl) ethylcarboxamdo) - [10]paracyclophane-6-N-hyaroxycarboxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(4-morpholinc)eznylcarboxamido)-[10]paracyc!ophane-6-N-hydroxycarboxami de; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(3-(4-morpholino) propyīcarboxairiido) - [10] paracyclophane-6-N-hydroxycarboxazu.de hvdrochloride; 2S, 3R, 6S-3-aza-4-oxc-10-oxa-5-hexyl-2-(3-(1-imidazclyl)propylcarboxamido)-[10]paracvclophane-6-N-hydroxycarboxarrii de ; 2S,3R,6S-3-aza-4-oxc-10-oxa-5-hexyl-2-(3-(1-imidazolvl) propylcarboxaziido) - [10] paracyclophane-6-N-hydroxycarboxazu.de zrifluoroacetate; LV 12167 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(cyclohexylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxarru.de; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4-methylpiperazin-l-ylcarboxajnldo)-[103 paracyclophane-6-N-hydroxycarboxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(dimethylcarboxamido) - [10] paracyclophane-6-N-hydroxyc arboxami de ; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (N-methylcarboxamido) -cyclopencadecane-13-N-hydroxycarboxami de; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [N-(2-pyridyl)metbylcarboxamidoj-cyclopentadecane-13-N-hydroxycarboxaira.de trifluoroacetate; 2S, 13S, 14R-1,7-diaza-S,15-dioxc-9-oxa-14-iSobutyl-7-mechyl-2-[2-(5-mechylchiazolyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxairo.de ; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [ (2-pyridyl) carboxarrd.do] -cyclopentadecane-13-N-hydroxycarboxamide ; 2S,13S,14R-1,7-diaza-8,15-dioxc-9-oxa-14-isobutyl-7-methyl-2-[(3-pyridyl)carboxamido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S,14R-1,7-diaza-8,l5-dioxo-9-oxa-14-isobucyl-7-merhyl-2-[(4-pyridyl)carboxamido]-cyciopentadecane-13-N-hydroxycarboxamide ; -57- 2S,13S,14R-l,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(4-(N-ethoxycarbonyl)piperidinecarboxamido]-cvclopent adecane-13 -N-hydroxycarboxairu.de; 2S, 13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[4-hydroxycyclohexylcarboxamido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N-methylamide)-cyclopentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(glycine-N,N-dimethylamide)-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-inethyl-2-(glycine-2-pyridylamide)-cyclopentadecane-13-N-hydroxycarbcxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-iriethyi-2- [glycine-2- (3,4,5,6-tetrahydropyridyi) amide] -cyclopencadecane-13-N-hydroxycarboxairu.de; 2S, 13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobucyl-7-methyl-2-[glycine-N-(4-hydroxy)piperidineamide]-cyclcpentadecane-13-N-hydroxycarboxamide; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (giycine-N-pyrolidineairu.de] -cyclopencadecane-13-N-hydr oxycarboxaitu.de; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-morpholinoamide]-cycloper.r adecane-13-N-hydroxycarboxamide; -58- LV 12167 2S, 13S, 14R-1,7-diaza-8,15-dioxb-9-oxa-14-isobutyl-7-methyl-2- (glycine- (4-methyl) N-piperazinylanu.de] -cyclopentadecane-13~N-hydroxycarboxanu.de tri fluoroacetate; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-2-(5-methyl)thiazolylanu.de]-cyclopentadecane-13-N-hydroxycarboxamide trifluoroacetate; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[glycine-N-morpholinoamide]-cyclopentadecane-13-N-hydroxycarboxanu.de ; 2S, 11S, 12R-l,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -12-isobutvlcyclotridecane-ll- (N-hydroxycarboxanu.de) ; 2S,11S, 12R-l,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine N-methyl anude)-11-(N-hydroxycarboxarru.de) ; 2S, 11S, 12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (N^-H-L-lycine-a-N-H-anu.de triflucroacetate) -11- (N- hydroxycarboxanu.de; ; 25.115, 12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-aianine-a-N-methyl aird.de) -11- (N-hydroxycarboxamide) ; 2S,11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(ļ5-alanine N-methvl amide)-11-(N-hydroxycarboxairu.de) ; 25.115, 12R-1,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-mesitylenesuldonyl-12-isobutylcyciotridecar.e-l] - (N-hydroxycarboxamide) ; 2S, 11S/ 12R-l,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-t-butyloxycarbonyl-12-isobutylcyclotridecane-ll-(N-hydroxycarboxairu.de) ; -59- 2S, 11S, 12R-1,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclozridecane-ll-(N-hydroxycarboxamide) hydrogen chloride; 5S, 8R, 9S-6-Aza-2,7-dioxo-5- (N-methylcarboxaitiido) -l-oxa-8-isobucylcyclododecane-9- (N-hydroxycarboxairu.de) ; 2S,11S,12R-7-N-Benzenesulfonyl-l,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobutylcyclotridecane-ll-(N-hydroxycarboxamide); 2S, 11S,12R-1,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-(p-amino-N-benzenesulfonyl)-12-isobutylcyclotridecane-ll-(N-hydroxycarboxamide); 2S, 11S, 12R-1,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-trifluoromezhanesulfonyl-12-isobutylcyclotridecane-ll- (N-hydroxycarboxamide); 2S, 11S, 12R-l,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N- (N-methyl-iriidazolesulfon-4-yl) -12-isobutylcyclocridecane-ll-(N-hydroxycarboxami de); 2S,līs,12R-i,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-norleucine-a-N-methyl amide)-11-(N- hydroxycarboxaiuide) ; 2S,11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-serine-a-N-methyl amide) -11- (N-hydroxycarboxaiiu.de) 2S, 11S, 12R-l,7-Diaza-8,13-dioxo-12-iscbutylcyciotridecane-2-(glycine N-dimethyl amide)-11-(N-hydroxycarboxamidei ; 2S, 11S, 12R-1,7-Diaza-8,13-dioxo-12 (R)- isobutylcyclotridecane-2 (S) - (glycine N-l, 2-ethylenediamine-N', N' -dimechyl amide) -11 (S) — (N-hydroxyc arboxamide) ; -60- LV 12167 2 S, 11S, 12R-1,7-Dia2a-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine N-morpholino amide)-11-(N-hydroxycarboxairu.de); 2S, 11S, 12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-leucine-a-N-methyl amide) -11- (N-hydroxycarboxamide) ; 2S,11S,12R-l,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-threonine-a-N-methyl amide)-11-(N-hydroxycarboxamide) ;
In che present invention it has been discovered that the compounds above are useful as inhibitors of metalloproteinases, including aggrecanase and TNF-C, and are useful for the treatment of rheumatoid arthritis, osteoarthritis and related inflammatory disorders, as described previously. These compounds inhibit the production of TNF in animal models and are useful for the treatment of diseases mediated by TNF.
The present invention also provides methods for the treatment of osteo- and rheumatoid arthritis and related disorders as described previouslv, by administering to a host a pharmaceutically or therapeutically effective or acceptable amount of a compound of formulas (I to IV) as described above. By therapeutically effective amount, it is meant an amount of a compound of the present invention effective to inhibit the target enzyme or to treat the symptoms of ostec- or rheumatoid arthritis or related disorder, in a host.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic aģents. Ādministration of the compounds of Formulas I-IV of the invention in combination with such additional therapeutic aģent, may afford an efficacy advantage over the compounds and aģents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizēs the potential of side effects, thereby providing an increased margin of safety. -61-
By "therapeutically effective amount" it is meant an amount of a compound of Formulas I-IV that when administered alone or in combination with an additional therapeutic aģent to a celi or mammai is effective to inhibit the target enzyme so as to prevent or ameliorate che inflamatory disease condition or the progression of the disease.
By "administered in combination" or "combination therapv" it is meant that the compound of Formulas I-IV and one or more additional therapeutic aģents are administered concurrently to the mammai being treated. When administered in combination each component may be administered at the same time or seguentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
By "stable compound" or "stable structure" is meant herein a compound that is sufficientlv robust to survive isolation to a useful degree of puritv from a reaction mixture, and formulation into an efficacious therapeutic aģent.
Wher. ar.v variable occurs more than one time in any constituent or in Formulas Ī-IV (or any other formula herein) , its defir.ition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R5, then said group may optionally be substituted with up to two R5 and R5 at each occurrence is selected independently from the defined list of possible R5. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, ali chiral, diastereomeric and racemic forms are included in the present inver.tion. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and ali such stable isomers are -62- LV 12167 contemplated in the presenc invention. It will be appreciated that compounds of the present invention may contain asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materiāls. Ali chiral, diastereomeric, racemic forms and ali geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formulas I-IV then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyi, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic aģent.
The term “substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normai valency is nct exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. -63-
As used herein, Halkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "Ci-Cio" denotes alkyl having 1 to 10 carbon atoms); in addition lower alkyl defines branched and/or unbranched alkyl Chain of from 1 to 8 C atoms; 'haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CVFW where v = 1 to 3 and w = 1 to (2v+l)); “alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the Chain, such as ethenyl, propenyl and the like; and *alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the Chain, such as ethynyl, propynyl and the like. "Alkylcarbonyl" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location. 'Alkylcarbonylamino" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location. "Aikylcarbcnyloxy" is intended to include an alkyl group of an indicated number of carbon -64- LV 12167 atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
The terms "alkylene", "alkenylene", "phenylene,‘, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I-III. Such "alkylene", “alkenylene", "phenylene", and the like, may altematively and equivalently be denoted herein as *-(alkyl), * -(alkyeny1}-" and "-(pheny1)-", and the like, "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, "carbocycle" or "carbocyclic residue" or "carbocyclic ring svstem" is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or up to 26-membered polycyclic carbor. ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, "aryl" or "aromatic residue" is intended to include phenyl or naphthyl as well as commonly referred to "heterocycle" or "heteroaryl" or ’heterocyclic" compounds; the term "arylalkyl" represents an aryl group attached through an alkyl bridge.
As used herein, the terms "heterocycle" or "heteroaryl" or "heterocyclic" is intended to mean a stable 5- to 7- membered mcnocyclic or bicyclic or 7- to 10-membered bicyclic ring which may be partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consistinc of 'N, 0 and S and wherein the nitrogen and suifur heteroatoms may optionallv be oxidized, and the -65- nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. A hecerocyclic ring may be attached to its pendant group at anv heteroatom or carbon atom which results in a stable structure. The aromatic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of aryl groups include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, βΗ-1,2,5-tniadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyi, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3tf-indolyl, indolyl, lH-indazolyl, purinyl, 4if-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinvl, pteridinyl, 4aH-carbazole, carbazole, £-carbolinyi, phenanthridinyl, acridinvl, perimidinyl, phenanthrolinvl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro· compounds containing, for example, the above heterocycles.
As used herein, the term -aryl" is intendea to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to LV 12167 10-membered bicyclic ring which may be partially unsaturated, or aromatic, and which consistš of carbon atoms and from 1 to 4 heteroatoms independentļy selected from the group consisting of N, 0 and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom whi.ch results in a stable structure. The aromatic rings described herein may be substituted or. carbon or on a nitrogen atom if the resulting compound is stable. Examples of aryl groups include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenvl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonvl, pyrrolidinvi, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydrcisoquinolinyl, azocinyl, triazinyl, 6tf-l,2,5-thiadiazinyi, 2H, 6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pvranyl, isobenzofuranyl, chromenyl, xar.thenyi, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazclyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, ltf-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, guinoxalinyl, guinazolir.vl, cinnolinyl, pteridinyl, 4aJi-carbazole, carbazole, S-carbolinyl, phenanthridinyl, acridinvl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinvl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyi, pvrazolidir.vl, pyrazclinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, indolinyl, isoindclinyl, -67- quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above hecerocycles.
The term "amino acidM as used herein means an organic compound containing both a basie amino group and an acidic carboxyl group. Included within this term are natūrai amino acids, modified and unusual amino acids, as well as amino acids which are knovrn to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids,such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides. 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention inelude, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, £-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-aehydroproline, N,N-dimethylaminogIycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, β-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl) -benzoic acid, l-aminocyclopentanecarboxylic acid, l-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The term 'amino acid residue" as used herein means . that portion of an amino acid (as defined herein) that is present in a peptide.
The term "peptide" as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term "peptide" also ineludes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other nen-amino acid components. Such a compound containing both peptide and -68- LV 12167 non-pepcide components may also be referred to as a "peptide analog".
The term "peptide bond" means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid. "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to Formula I-III in vivo when such prodrug is administered to a mammalian subject, Prodrugs of the compounds of Formula I-III are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formulas I-IV wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to forrn a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Exaitples of prodrugs include, but are not limited tc, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formulas I-IV, phosphate esters, dimethvlglycine esters, aminoalkylbenzyl esters, aminoalkvl esters and carboj^alkyl esters of alcohcl and phenol functional groups in the compounds of formula (I) and the like.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wnerein the parent compound of Formulas I-IV is modified by making acid or base salts of the compound of Formulas I-IV. Examples of pharmacautically acceptable salts include, but are not limited to, mineral or organic acid salts of basie residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids and the like.
The pharmaceutically acceptable salts of the compounds of Formulas I-IV include the conventional non-toxic salts or the guaternarv ammcnium salts of the compounds of Formulas I-IV fermed, for example, from non-toxic inorganic -69- or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maieic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I-III which contain a basie or acidic moiety by conventional Chemical methods. Generaliy, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formulās I-IV with an appropriate amount of a base, such as an alkaii or alkaline earth mētai hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, cr a quatemary ammonium hydroxide such as tecramethylammonium hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can 'be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base cr acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, .isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remincton's Pharmaceutical Sciences. 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure cf which is herebv incorporated by reference. -70- LV 12167
SmTHESIS
The compounds of the present invention can be prepared in a number of ways well known co one skilled in the art of organic synthesis. The compounds of the present invention can be synthesizea using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
Ali references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reaģents and materiāls employed and are suitable for the transformations being effected. Alsc, in the description of the synthetic methods described below, it is to be understood that ali proposed reactior. conditions, inciuding choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions Standard for that reaction, wnich should be readiiv recognized by one skilled in the art. It is understood by one skilled in the art of organic syntnesis that the functionality present cn various portions of the molecule must be compatible with the reaģents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readiiv apparent to one skilled in the art and aitemate methods must then be used. A series of compounds of formula 21 are prepared bv the methods outlined in Schemes 1-5. A diprotected 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, omithine or lysine (compcund 1, Scheme 1' is ccr.verted to its corresponding amide 2 using a ccupling aģent such as BCP. -71-
Coupling of 1 with a diaminobenzene followed by reaction in acetic acid at 60' C producēs a benzimidazole analog 3. 1 can also be converted to an aldehyde 4 which is reacted with ammonia and glyoxal trimer to give an imidazole analog 5. Deprotection of the N°-Boc group of 2, 3 and 5 using an acid such as 4 N HC1 in dioxane gavē compound 6. Removal of the side Chain protecting group of 2, 3 and 5 using hydrogenation afforded compound 7. -72- A.
Scheme 1
HNR5R1/BOP BocHN nr5r1
BocHN. JL V 0H ( \)n NHCbz ( \)n NHCbz BocHN
2, 3,5
( \)n NHCbz nh2
(U vn LV 12167 -73- 1
The synthesis of the 2,3-disubstituted succinic acid portion is described in Scheme 2 below. An acid halide (e.g. X=C1) is ccnverted to its oxazoliainone derivative 8 using n-butvi iithium. An Evan's aldol reaction with a glyoxylate (JACS, 1982, 1Q4, 1737) converts 8 to an intermediate 9.The oxazolidinone group is removed using H202/Li0H and the resulting carboxylic acid is converted to a benzyl ester 11. Alkylation of 11 with t-butyl bromoacetate gives compound 12. The benzyl ester of 12 is remcved by hvdrogenation to give 13. Removal of the t-butyl group cf 12 affords 14. -74- LV 12167
Scheme 2
The fonraūicn of the macrocvclic ring of chis serdes of compounds car. be accomplished via two routes as described - / 3- in schemes 3 and 4 below. Coupling of the intermediates 6 and 13 producēs the intermediate 15. Hydrogenation followed by acid deprotection gives compound 16. Cyclization of 16 using a coupling aģent such as BOP affords the inacrocyclic intermediate 17. Alternatively, compound 17 can be synchesized by coupling 7 and 14 followed by deprotection and cyclization as described in Scheme 4. Saponification of 17 followed by reversed phase HPLC separation gives two isomers 20a and 20b. The final two products 21a and 21b were obtained by coupling 20a or 20b with 0-benzylhydroxylamine hydrochloride followed by hydrogenat ion.
Scheme 3 6+13
- o- 7 + 17
Scheme 4 14
BOP/DIEA/DMF —-
LV 12167 -77-
Scheme 5 17 ο
R1 20a
1. UOH/THF 2. HPLC O
R1 20b
1. BnONH gHCI/BOP DIEA/DMF 2. Hj/Pd/C
Another series of compounds of formula 30 are synthesized as shown in schemes 6 and 7 below. A side Chain trifluoroacetvl protectied 2,3-diaminopropionic acid, 2,3-diaminobutyric acid, ornithine or lysine 22 is coupled with an alkylamine followed by alkylation to give 23a. The amino acid derivative 22 can also be converted to a methyl ester which is alkylated to give 24. Removal of the TFA grouņ of 24 followed bv protection of the resulting amine usinc benzvl chloroformate affords compound 25. 25 can be converted to a benzimidazole derivative 23b or an imidazole derivative 23c. Removal of the TFA grotp of 23a using LiOH or of the Cbz group of 23b and 23c using hydrogenation producēs the intermediate 26. The target compound 30 is obtained using the procedures described in Scheme 7 which -78- LV 12167 are sinilar to those used for the synthesis of the first series of compounds 21 (Schemes 4-5 above).
Scheme 6
A
BocHN nAh
1.H NRsR6/BOP/DIEA/DMF BocHN
nA 5q6 (v)n
2. R6X/K2C03/DMF/100°C
NR5R V NHTfa 22 (\Jn NHR6 23a
1. MeOH/DCC/DMAP/THF 2. R6I/K2C03/DMF/100C O
BocHN
BocHN OMe
1. LiOH/THF >Ah (\ļn NR6Cbz ( \)n 2. BnOCOCI/NaOH/H20 NR®Tfa
25 1. NHCH3OCHy BOP/DIEA/DMF 2. UAIH4/THF r3. NH3/glyoxal trimer
B
BocHN, ,R2 23a, 23b, 23c
LiOH/THF_ or H^d/C/MeOH (:\Jn NHR6 -79- 26
Scheme 7 Ο
1. 4 N HClAļioxane 2. H2/Pd/C
Bu02C>
BOP/DIEA CHCI3 28 R1'
1. LiOH/THF, HPLC
2. BnNH2HCI/BOP/DIEA/DMF
3. Hg/Pd/C/MeOH 29
Another series of compounds of formula 43 are prepared by the methods outlined in Schemes 8-9 below. A N°-Cbz-serine or homoserine is converted to ies rorresponding amide which is aikylated with ethyl bromoacetate to give 31. A different starting material N^-Boc-serine or homoserine is converted to a benzyl ester which is also alkylated with ethyl bromoacetate to give 32. The ber.zyl ester of 32 is removed by hydrogenation to give 33 which car. be converted to a benzimidazole derivative 34 or an imidazole derivative 35. Deprctection of the Cbz grcup of -8> LV 12167 31 bv hydrogenation or the Boc group of 34 and 35 using acid producēs the intermediate 36.
Scheme 8
CbzHN 1 .HNR5R6/BOP/DIEA/DMFbZHN ^χ·ΟΟΝΒ R ,: , 2. Ethyl Bromoacetate ^ ^ ^OH NaH/THF ^o'^'CC^Et 31 B.
BocHN. .C02H BocHN- .C02Bn
1. BnBr/NaHCQ3/DMF (Mij oh
2. Ethyl Bromoacetate NaH/THF
C02Et
BocHN. .C02H
H2N
(SLn 33 H2N'
BOP/DIEA/DMF/2. AcOH/60°C 'CC^Et
1. NHCH3OCH3/BOP/DIEA/DMF
2. ŪAIH4/THF
3. NH3/glyoxal trimer/MeOH C.
BocHN
BocHN
35 31, 34 or 35 H2/Pd-C/t-PrOH or 4 N HCI/dioxane H2N. R2 (VJn 0 'COjčt -81- 36
Scheme 9
Br^^COsBu1 LDA/THF -78°C
•BuO2C
H2Og^-iOH THFo'c
Bu’O^^'V^00^ R1
2LDA/THF/-78 C 38
-82
Lv 12167
The synthesis of disubscituted succinic acid derivative 39 is described in Scheme 9 above. Alkylation of 8 with t-butyl bromoacetate producēs the intermediate 37. The auxiliary group of 37 is removed and alkylation of che resulcanc acid 38 with bromoacetonitrile gives a mixcure of cwo isomers 39. Coupling of 39 with 36 followed by hydrogenation and saponification yields 41. Cyclization is carried out using BOP to give the cyclic compound 42. The t-butyl group is reinoved using acid and the two isomers are separated using reversea phase HPLC. The carboxylic acid of each isomer is converted to its corresponding 0-benzylhydroxairu.de and subsequent hydrogenation affords the target products 43a and 43b.
Another series of compounds of formula 51 are prepared as depictea in Schemes 10-11 below. Reaction of a cysteine cr homocysteine with a halo-nitrobenzene followed by treatment of the resulting intermediate with di-t-butvl dīcarbonate vielas Na-Boc-S-2-nirrophenyl-cysteine or -hcmocysteine 44. 44 is converted to an amide 46 or a benzinidazole derivative 45. Deprotection of 45 and 46 using an acid producēs the intermediate 47.
Coupling of 47 with the acid componer.t 8 gives the intermediate 48. The nitro group is reduced using zinc in acetic acid/water and the t-butyl group is removed using 4 N KCi in dioxane. Macrocyclizacion of 49 using BOP yields two isomers 50a and 50b which are separated on a silica gel column. Saponification of each isomer followed by coupling with hydroxylamine producēs the target products 51a and 51b. -83-
Scheme 10
-84- 8+47
1. Zn/AcOH
Scheme 11
2. 4 N HCl/dioxane
BOP/DtEA
1. LiOH/THF 2. NH2OH HCI/BOP/DIEA/DMF LV 12167
O R1 HOHN
HOHN
Anocher saries cf compounds of forzuīia 61 are svnrhesized rv the merhoas described ir. Schemes 12-13 -85- below. The side Chain carboxylic acid of Ne-Boc-aspartic acid benzyl ester or I^-Boc-glutamic acid benzyl ester is reduced to an alcohol using borane and the the alcohol is converted co a bromide using carbon tetrabromide and triphenylphosphine. Reaction of 53 with an acetoxyphenol yields intermediate 54. The benzyl ester is deprotected by hydrogenation and the resulting carboxylic acid is converted to an amide, a benzimidazole or an imidazole. Saponification of 56a-56c to remove the acetyl group followed by treatment with 4 N HC1 in dioxane to remove the t-butyl group affords compound 57.
Reaction of the intermediate 38 with a triflate producēs 58. Coupling of the acid component 58 with 57 yields 59. The benzyl group of 59 is taken off by hydrogenation and the resulting alcohol is converted to a bromide using carbon tetrabromide and triphenylphosphine. Macroyclizacion of the resultant intermediate is carried out using potassium carbonate to give the cyclic product 60. The t-butyl group is deprotected using TFA and the resulting carboxylic acid is converted to a hydroxamic acid by coupling with hydroxylamine to affcrded the target product 61. -86- LV 12167
Scheme 12 OH \ 17" BocHN ^^C02Bzl
CBr4/Ph3P/CH2CI2
Br
K2CO3/DMF OAc
- JC X>°··
BocHN COsBn 54
H2/Pd/C/i-PrOH
(ns BocHN ,X)oac
-8~-
Scheme 13
Another series of compounds of formula 67b are prepared as shown in scheme 14 below. The side Chain of an aspartic acid or a glutamic acid derivative is reduced to an alcohol which is converted to a bromide 62. Reaction of 62 with sodium acetylide yields 63 which is converted to an amide, a benzimidazole or an imidazole derivative 64 as described above.
Alkylation of 11 with a bromoacetal followed ty acid treatment and reaction with nydroxviamine producēs cne mtermediate 65. Reaction of 65 witn 64 using bleacn affords an isoxazole derivative 66. Deprotection ci the Boc -38- LV 12167 group using acid and the Bn gro'up by hydrogenation followed by cyclizaoion using BOP yields che cyclic compound 67a. Saponification followed by coupling with hydroxylamine producēs the target compound 67b. -85-
Scheme 14 A.
1. BH3/THF 2. CBr4/PPh3 C02Bu t
1==-Na 2. TFA
CbzHN
B.
II 11 +
Br
.OR
OR
1. NaH/THF 2. HCI 3. NH20H
64 NaOCI/CH2CI2
1. HCI 2. Hg/Pd-C 3. BOP/DIEA/DMF R1 66
Amide. imidazole or benzimidazole formation
Arccher saries cf compounas of formula 71 are syntnesized as depicred in scheme 15 beiow. Alkylation of che incermediace 11 vith a dihaloalkane producēs 68. LV 12167
Reaction of 68 with a tryptophan derivative gives 69. The Bcc group and the Bn group are deprotected and macrocyclization is carried out using BOP to afford the cyclic compound 70. Saponification followed by coupling with hydroxylainine yields the target compounds 71a and 71b. -9i-
Scheme 15
kT\
CONRsR6
CONR5R6
NaH/DMF NHBoc 1.4 N HCl/dioxane 2. H2/Pd/C/i-PrOH 3. BOP/DIEA/CHCI3
-92- LV 12167
Compounds of formula 75, could be prepared by the route shown in scheme 16 below. The succinate 61 could be coupled with a tyrosine derivative using the BOP reaģent to afford the amide 72. Deprotection of the benzyl ether under hydrogenation conditions gavē an alcohol, which could be converted to the bromide 73. Macrocylization provides compound 74. The tert-butyl ester is deprotected to the acid, wnich is converted to the benzyl protected hydroxamic acid. The desired compound 75 is obtained after deprotection by hydrogenation.
Scheme 16 61 +
m=1-2
HX
72 HX 1, H^/Pd-C/MeOH/HCI 2. CBr4/PPh3/CH2Cl2
Cs2COyDMF/DMSO R1 73
-93-
Compounds of formula 79, could be prepared by the route shown in scheme 17 below. The succinate 61 could be coupled with a histidine derivative using the BOP reaģent to afford the amide 76. Deprotection of the benzyl carbamate and the benzyl ether under hydrogenation conditions would give an alcohol, which could be converted to the bromide 77. Macrocylization would provide compound 78. The tert-butyl ester is deprotected to the acid, which is converted to the benzyl protected hydroxamic acid. The desired compound 79 is obtained after deprotection by hydrogenat ion.
Scheme 17 58
Ņ=\ Ι,Ν-Chz (^2)11 BOP/DIEA/DMF^ h2n R2 t-Bu02C
Cbz
BnO^ (CH2)n 0 (CH2)mΛΛΛ
N' H 76
LV 12167
Compounds of formula 84, could be prepared by the route shown in scheme 18 below. The succinace 38 could be converted to the enolate with LDA and alkylated with a triflace to provide 80. This material is coupled with a phenylalanine derivative using the BOP reaģent to afford the amide 81. Deprotection of the benzyl groups under hydrogenation conditions gives the amino acid 82. Macrocylization would provide compound 83. The tert-butyl ester is deprotected to the acid, which is converted to the benzyl protected hydroxamic acid. The desired compound 84 is obtained after deprotection by hydrogenation. -95-
Scheme 18
OH
t*Bu02C Βπ /N.
Cbz X Λ
Cbz^ LDA/THF/-78°C (CH2)n 0 38 * 1
Bn * o. ^
HņN Λ,
BOP/DIEA/DMF 80
81
83 84
Compounds of formula 98, could be prepared by the rcute shown converced c: crifiare to scheme 21 below. The succinate 38 coul; he enoiace wich LDA and alkylated with a ovide 95. This materiai is coupled with be a _ci_ LV 12167 lysine derivative using the BOP reagenc co afford the amide 96. Deprotection of the benzyl carbamate under hydrogenation conditions and saponification of the ethyl ester gives the amino acid. Macrocylization provides compound 96. The tert-butyl ester is deprotected to the acid, which is converted to the benzyl protected hydroxamic acid. The desired compound 98 is obtained after deprotection by hydrogenation. 38 +
Scheme 21
R1 95
1. UOH/THF 2. Hj/Pd-C 3. bop/diea/dmf 96
Compound route snov»T. ·> of fcrzvala 102, could be prepared by the scheme 22 beiow. The succinate 58 could be -57- couplea with a tryptophan derivative using the BOP reaģent to afford the amid 99. Deprotection of the benzyl group and ccnversion to the tosylate gives 100. Macrocylization would provide compound 101. The tert-butyl ester is deprotected to the acid, which is converted to the benzyl protected hydroxamic acid. The desired compound 102 is obtained after deprotection by hydrogenation.
Scheme 22
-98- LV 12167
Compounds of formula 108, could be prepared by che route shown in scheme 23 below. The imide 8 can be converted to the enolate with LDA and alkylated with a triflate to. provide 103. The chiral auxiliary is then saponified to the acid 104. As above, thls material can be converted to the enolate with LDA and alkylated with a triflate. The resulting 105 can be coupled with a tyrosine derivative using the BOP reaģent to afford the amide 106. Deprotection of the benzyl ether under hydrogenation conditions gives an alcohol, which could be converted to the bromide. Macrocylization provides compound 107. The tert-butyl ester is then deprotected to give the desired acid 108.
Scheme 23 8 + t-l
Bu02C>^^\ OTf
LDA/THF
ŪOH/H2O2/THF Xc
OH
3. K2C03/DMF BnO 106
-ICC-
Scheme 24 O R1 JL 4-Nitrophenyl t-Bu(j ΛΓ C02Bzl Chlorofomate O R1.-ΒυΟ^'^Α
CO2BZI
NMM/THF 109 110
OH CO^e
O R
CbzHN Tin NHR K^Ojj/DMF 6 C02Bzl ŅHCbz O (rt^COsMe 111 O N R6 O R1 112 LV 12167
no2
Hg/Pd-C/MeOH O R1 *co2h o Λ
113 NL· .C02Me O R1
0-Banzylhydroxy<amine Hydrochloride BOP/NMM/DMF 114
Another series of compounds of formula 131 are prepared.by the methoa outlined in Schemes 25-27 beiow. Methyl 35-4-benzy1oxy-3-hydroxy but yr ate (119) is prepared according to a published procedure (Abood, N. A. Synth. Commun. 1993, 23, 811). Stereoselective allylation of 119 with allyl bromide 120 gives compound 121. Following ester hydrolysis, the resultant acid 122 is coupled with appropriateiv functionalized Iysine (123, n=2), ornithine (123, n=l) or 1,4-diaminobutyric acid (123, n=0) .
Reaction of 124 with 5-1,4-dibromo-2-butene yields bromide 125.
Following removal of BOC group, the macrocyclization is achieved with a mild base, such as •102- LV 12167 diisopropylethylamine. The resultant cyclic amine is protected with di-t-butyl dicarbonate in one pot.
Treacment of 127 with Pd(0H)2 under hydrogen leads to reduction of both olefinic bonds as well as cleavage of benzyl ether. Oxidation of alcohol 128 followed by coupling with 0-benzyl hydroxyamine yields 130. At this point, the R4 group is introduced by acid hydrolysis of BOC group and reaction with R4-CI. Finally, hydrogenolysis gives 131. -103-
Scheme 25
NHBOC
BnO k
NHBOC (CH2)n h2n^s‘conr5r6 wH Jļ *Ch Rij 123 2^ R2
OH O (CH2),
BOP, iPrgNEt. DMF
N CONR5R6 H 122
124 CH2Br
NHBOC k CH2Br
BnO
NaH, DMF
JUU (CH2)n R3
N CONRsR6 H R2 r 125 -104-
Scheme 26 CH2Br
NHBOC k (CH2)n CHoBr
Bn°. X,. X. HC1 CONR5R6 LV 12167 R2
125 n conr5r6 i H ļļ HCI salt R* 126
iPrjNEt, CHjCN (BOCbO
H2, PdiOHh/C
128
Scheme 27 Ν'
Ο O ^(CH2)n
BOC ruC13. NaI04 Η conr5r6
HO \ 128
BnONH* iPr2NEt DCC, HOBuTHF
BnO
130 H* Pd/BaS04 or 1) HCI 2) R4-CI 3) Hi,Pd/BaS04 H0‘ Q ° lCH2)n *CONRsR6 131
Another series of compounds of formula 133 are prepared by the method outlined in Scheaies 28 below. Reaction of alcohol 124 with sodium hydride and 3-bromo-2-bromomethyl-i-propene provides 132. 132 is converted to 133 following seguence analogous to that outlined in Schemes 26 and 27. LV 12167
k. CONR5R6
Scheme 28 CHjBr
NHBOC Ο O '(CH2)n
NaH, DMF BnO. JL JL JL ^ r n co = H 132 r R2
Follovving the sequence in
Sehemes 26 and 27 -
This invention also includes cyclic hydroxamates as aescribed in scheme 29. In the first step, succinate 134 is coupled with L-^sined^-Cbz) -NHMe to yield the amide 135. The primarv alcohci of 135 is oxidized to the acid 136 with RuC13«H20. After removal of the carbamate group, a macrocyclization affords the lactam 138. The t-butyl ester of 138 is then converted to the acid 139. This acid is coupled with BnONH2 to give the protected hydroxamate 140. Hydrogenation of 140 provides the targeo hydroxamate 141. -107-
Scheme 29
RuCl3*H20 HglOe t CH3CN CCI4> h2o
IBuO^C
136 R=Cbz ) H2 138 U = C02tBu I TFA 137 R=H J Pd/C BOP / 139 U = C02H * H2NOBn \ 140 U * CONHOBn \ H 141 U = CONHOH A p§
This inventior. also includes compounds availabie by t'ne methods described in Scheme 30 which aliows for che simple variation of R3 frcm the commcn intermediate 145a. In che first step, succinace 134 is coupled with L-lysine (N?-Cbz) -C02Me to yieid the amide 142. The primary alcohol of 142 is oxidized to the acid 143 with RuCl3»H20. After removal of the carbamate group, a macrocyclizacion affords the lactam 144. The t-butyl ester of 144 is converted to the protected hydroxamace 145 under our Standard protocol. The mechyl ester of 145 is hyčrolyred with LiOH. The resulting acid 145a is manipulated to give a desired R3 . Hvdrogenation of 146 gives the target hydroxamate 147. -108-
Scheme 30 LV 12167
R1 134
BOP CH2OH L-Lys(Cbz)-C02Me iPr2NEt tBuO^
CO^e R1 (CH^NHCbz \ H5I06 _ / m -** CH3CN CCI4> H20 tBuO^
143 R=Cbz ) h2 143a R=H J Rd 142
144 R2 = C02Me, U = C02tBu J TFA BOP / 144a R2 s C02Me, U = CO2H > H2NOBn V 145 R2 = CO^e. U = CONHOBn * 145a R2 = C02H, U= CONHOBn J UOH
146 U = CONHOBn. R2 = CONRsR6 \ 147 U » CONHOH. R2 * CONRsR6 J
This invencion also includes cyclic amlno carboxylates of formula II. where U = -CO2H, R4 * Η, X = -NH, R1 = alkylaryl, Y = -C(0)NK-, R2 = H,"R3 = -C(0)NHMe, C = alkyl, B = -C (0) NH, A = alkvi. Scheme 31 depicts how a ccmpound of this type is available frcm D-glutamic-N-Fmoc t-butyl ester or D-aspartic -N-Fmoc't-butyl ester through Standard peptide chemissrv. Standard BOP coupling of this material with 7 gives the amide 14 8. The Fmoc group can be deprotected to the primary amine 149 followed by alkylation with a trifate to yield the secondary amine 150 (Kogan, T.P.; Somers, T.C.; Venuti, M.C. Tetrahedron 1990, 46, 6623) .
Dual deprotection via hydrogenation affords the amino acid 151, which can be cyclized to give the macrolactam 152. Simple deprotection with TFA provides the desired, cyclic amino carboxylate 153.
Scheme 31
CO2H BOP. iPr2NEt JBUO2C NHFmoc
©UO2C
148 R-ļ * Fmoc 149 R, = H J EtjļNH
Pd/C
BOP iPr2NEt 150 Rx a Bn, Ry = Cbz \ H 151 Rx a H, Ry = H J 2
LV 12167
This invencion also includes cyclic amino carboxylates of formula II, where U = -C02H, R4 = Η, X = -NH, R1 = alkylaryl, Y = -NHC(0)R2 = H, R3 = -C(0)NHMe, C = alkyl, B = -C(0)NH, A = alkyl. Scheme 32 depicts how a compound of this type is available from D-lysine-N-Fmoc t-butyl ester or D-ornithine-N-Fmoc t-butyl ester through Standard peptide chemistry. Standard BOP coupling of this material with L-glutamic-N^Cbz methyl ester or L-aspartic-N0 gives the amide 154. Deprotection of the Fmoc group leads to the prīmary amine 155. The primary amine can be alkylated as above with a triflate to give the secondary amine 156.
Dual deprotect via hydrogenation gives the amino acid 157. Macrocycization can be performed using BOP to give lactam 158. Saponification of 158 followed by Standard coupling with BOP and methylamine gives the amide 159. Simple deprotection with TFA affords the cyclic amino carboxylate 160 .
Scheme 32 COjMe / VNH2 ψ n
HO2C m BOP, iPr2NEt tBuOjC NHFmoc
CbzHN CO^e
tBu02C
(|J« ^NHR m NHCbz 154 R = Fmoc j
155 R = H *r Et2NH
156 R3 = Cbz, R4 = Bn . H 157 R3 = H,R4 = H * p§/c
1® 160
This invention aiso includes cyclic amino carboxylates of formula II, where U = -CO2H, R4 = Η, X = -NH, R1 = alkylaryl, Y = -C(0)NH-, R2 = H, R3 = -C(0)NHMe, C = alkyl, B = -C6H4CO2-, A = alkyl. Scheme 33 depicts how a compound of this type is availabie from D-Aspartic-N-Boc- (a)-t-butyl ester or D-glutamic-N-Boc-(a)-t-butyl ester through Standard peptide chemistry. The β-acid is converted into an aldehyde 161 using Weinreb chemistrv (Weimic, D.;
DiMaio, J.; Ādams, I. J. Org. Chem. 1939, 54, 4224). -112- LV 12167
This material can be converted into the olefin 162 via a Wittig2 reaction with 4-carbomethoxybenzyl triphenylphosphonium bromide (Lancaster). A serine amide is coupled with 163 to make the ester 164. The Boc protected amine of 164 is deprotected with HC1 to provide the prīmary amine 165. The primary amine can be alkylated as above with a triflate to give the secondary amine 166. Dual deprotect via hydrogenation gives the amino acid 167. Macrocycizatior. can be performed to give lactam 16Θ.
Simple deprotection with TFA affords the cyclic amino carboxylate 169. -113-
Scheme 33
SUO2C ϊ·
CHO NHBoc
f P(Ph)3\=/ C02Me
LDA
162 R = Bn }1)H2, Pd/C 163 R = H * 2) LiOH 161
164 R2 =Boc, R3 =Cbz \ nci. 165 R2 = H, R3 — Cbz toiuene
RO^
168 R = tBu \TFA 169 R = H *TFA r
This invention also includes cyclic amino carboxyiates of formula II, where U = -CO2K, R4 = η, X = -NH, R1 = alkylaryl, Y = -C(0)NH-, R2 = H, R3 = -C(0)NHMe, C = alkyl, B = -CgHiO-, A = alkvl. Scheme 34 depicts how a compound of this type is available from D-homoserine-N-Fmoc-(a)-t-butyl ester through Standard peptide chemistrv. The primary alcohol of the serir.e derivative can be coupled to the phenol of a tvrosine derivative via a Kitsunobu reaction to give 170 (Hughes, D.i. Org. React. 1952, 42, 335). The -114- LV 12167
Fmoc is deprotected with EC2NH to give the primary amine 171. As above, this primary amine is alkylated with the a triflate co give the secondary amine 172. Dual deprotection gives the amino acid 173. Macrocyclization of 173 wich BOP affords the lactam 174. Simple deprotection with TFA gives the desired amino carboxylate 175.
Scheme 34
170 R =Fmoc 171 R » H
TfO Ύ C02Bn
CO2R3 Y_
BOP iPr2NH
172 R3=Bn, R4 = Cbz 173 R3 =H, R4=H
174 175
This inver.tion alsc includes cyciic amino carboxyiates cf formula II, vhere U = -C02H, R4 = Η, X = -NK, R1 = -115- alkylaryl, Υ = -C(0)NH-, R2 = H, R3 = -C(0)NHMe, C = -alkylC02~/ B - -C(0)NH-, A = alkyl. Scheme 35 depicts how a compound of this type is available from L-glutamic-N-Cbz-(a)-methyl ester or L-aspartic-N-Cbz-(a)-methyl ester through Standard peptide chemistry. This material can be coupled to 2-N-Boc-aminoethanol with DCC and DMAP to yield the ester 176. Functional group manipulation leads to the acid followed by the amide 177 by Standard chemistry. The Boc group of 177 is then removed with TFA to give 178.
This material can be coupled to D-glutamic-N-Fmoc-(a)-t-butyl ester or D-aspartic-N-Fmoc-(a)-t-butyl ester to give the amide 179. The Fmoc is removed with diethylamine to reveal the primary amine 180. As above, this primary amine can be alkylated with a triflate to give 181. Hydrogenation and macrocyclization of this amino acid with BOP affords the lactam 182. Simple deprotection with TFA gives the desired amino carboxylate 183.
Scheme 35 H°^~(ļ)m BocHN-O^OH B°CHN/^)kī> H)- LV 12167
1. UOH/THF » 2. NH^e/BOP/DIEA
CbzHN'^vC02Me DCC/DMAP JL CbzHN^''COļMe 176
R1
1Θ1 tBuC>2C
). ^CONHMe
This invencior. aiso includes cyclic amino carboxylates of formula II, wnera U = -COjH, R4 = Η, X = -NH, R1 = alkylaryl, Y = -C(C:NK-, R2 = R, R3 = -C(0)NHMe, C = -alkyl, B = -NR-, A = alkyl. Scheme 3 5 depicts how a compouna of this cype is available frer. L-aspartic-N-Fmoc-(a)-t-butyl escer cr L-glutamic-N-Fmcc-(a)-t-butyl escer chrough scandard peppide chemistry. As above, the acid car. -117- be converted2 into the aldehyde 184 using weinreb chemistry. This aldehyde can participate in a reductive amination with a lysine derivative to producē the amine 185. After protection with (Boc^O, the Fmoc is removed with diethylamine to give primary amime 185. As above, the priinary amine 185 can be alkylated with a trifate to provide the secondary amine 188. Dual deprotection of the material via hydrogenation yields the amino acid 189. Macrocyclization of this amino acid with BOP affords the lactam 188. Simple deprotection with TFA gives the desired amino carboxylate 189. -118-
I LV 12167
Scheme 36 t yCHO ' γ n
CbzHN tBu02C NHFmoc
MeHNOC _ m NH2
AcOH, NaBH3CN
©UO2C
CONHMe 183 R s Fmoc, R2 *H N (BocJpO
186 R3*CH^n, R4aBn, R5 = Cba .. 187 R3 = CH2Bn, R4 = H. R5 * H J M2 Pd/C RO^
-re* ( 188 R = tBu. R2 = Boc, R3 3 Ch^Bn \ 189-TFA R * H, R2 = H, R3 = CH2Bn
Anocher series of compounds are synthesized as showr. in Scheme 37. The succinate 134 is coupled with L-^sined^-Mts) -NHMe to afford the amide 190. This matertal is cyclized under Mitsunobu conditions to give the macrocycle 191. The t-butyl ester of 191 is converted to the acid 192. This acid is coupled to H2NOBn with BOP tc give the protected hydroxamate 21193. Hydrogenation of the ber.zvl group gives the target hydroxamate 194. -119-
Scheme 37
134 190 R s 2.4.6-(Me)rC6H2
TFA f 191 R = 2.4.6-(^16)3-0^2. R2 - C02tBu
* 192 R 2.4.6-^6)3-0^2, R2 * 0O2H -v HoNOBn H ( 193 R = 2.4.6-^6)3-0^2. R2*CONHOBn p§ > 194 R = 2.4.6-(Μθ)3-ΟβΗ2. R2 = CONHOH
Another series of compounds are synthesized as showr. in Scheme 38. The mesicylenesulfonamide 191, from Scheme 37, is converted to the amine 195 with HBr. The amine 195 is reacted with Boc20 to afford the carbamate 196. The acid of -196 is coupled to H2NOBn with BOP to give the protected hydroxamate 197. This material is hydrogenated to provide the hydroxamate 198. The carbamate is then converted to the amine 199 with HCi. -120- LV 12167
Scheme 38
195 R » H«HBr, R2 = C02H j 196 R =Boc, R2 = CO2H > 197 R * Boc, R2 = CONHOBn 198 R = Boc, R2 = CONHOH 199 R = H«HCI, R2=CONHOH
BOP / h2nobīA
(Boc)20
Another series of compounds of formula 205 are synthesized as s'nown in Scheme 39. The succinate 134 is coupled with L-glucamace (y-C02Bn) N-methyl amide to afford the amide 200. After benzyl removal, the compound is cyclized under the Mitsunobu conditions to yield 202. The t-butyl ester of 202 is converted to the acid 203. This acid is coupled with BnONH2 to give the protected hydroxamate 204. Hydrogenation of 204 provides the target hydroxamate 205.
Scheme 39 tBuO^
C02H BOP L-Glu(CC>2Bn)-OH iPr2NEt
200 R =Bn \ h2 201 R = H > Pd 134
DIAD PPh3
R2 = C02tBu R2 = COoH
Compounčs cf formula 3004, where Z is a N-alkyl amide, an imidazole or benzimidazole cculd be prepared bv the route shown in scheme 40 below. Deprotonation of 8 with a strong base (e.g. LDA) followed by treatment wich an a-ketoescer producēs intermediate 3000. Coupling of 3000 with the intermediate 7 using Standard peptide chemistry affords 3001. Removal of the chiral auxiliary, followed by the deprotection of the amino group af fords amino acicl of the formula 3002. Macrocvclization provides compound 3003. Hydrolysis of the ester, followed by the formation of 0-benzyl prctected hydroxylamine and final hydrogenation gives the desired compound 3004. -122- LV 12167
Scheme 40
3001
BOP/DIEA/DMF
HOHN
3004 1. LiOH/THF_
2. BnONH2/BOP/DIEA
3. H2/Pd-C
Compounds cf formula 3010, where Z is a N-alkyl amide, an imidazole or a benzimidazole could be prepared by the route s'nown in scheme 41 below. An intermediate 3005 prepared in the same manner as depicted in scheme 40 is treated with a miid base to give the alcohol 3006. A Mitsunobu reaction with an appropriately substituted tyrosine derivative affords coirpound 3007. Removal of the chiral auxiliary and deprotection cf the amino group af fords amir.o acid 3008. Macrocyclization provides -123- compound of formula 3009. Conversion to the desired final product 3010 is done in a manner analogous to that depicted in scheme 40 above.
-124- LV 12167
Compounds of formula 3014, where Z is a N-alkyl amide, an imidazole or a benzimidazole could be prepared as shown in scheme 42 below. Coupling of 7 with 3006 using CDI producēs the carbamate 120. Hydrolysis of che chiral auxiliary and deprotectior. of the amino group affords the amino acid 3012 that undergoes macrocyclization to producē.compound 3013. The desired compound of formula 3014 is then obtained in a manner analogous to that aepicted in scheme 40.
Scheme 42 3006115-
CDI
3012 U. H £ hq^ 5 NHBoc
1. LiOH/H20^ 2. TFA *
Ri 3011
1. LiOH/THF -
2. BnONH2/BOP/DIEA
3. H2/Pd-C
Cyclic ureas of formula 3019, where Z is a N-alkyl amide, an imidazole or a benzimidazole could be prepared as shown in scheme 43 below. An ir.termediate 3015 is obtained bv reaction of 8 with a a-keto-aminocarboxylic ester. Removal of the chiral' auxiliary is followed by the Standard peptide coupling with a lysine or ornithine derivative 6 to afford 3017. Hydrogenolysis of the protecting groups and treatment with CDI yields cyclic urea 3018. Conversion to the final compound 3019 is done in a manner analogous to that described in scheme 40.
Scheme 43
o
3019 1. LiOH/THF -
2. BnONH2/BOP/DIEA
3. H^d-C
Cyclic lactams of formula 3023 ,where Z is a K-alkyl amide, ar. imidazole or a ber.rimidazole cculd be prepared as -126- LV 12167 depicted in scheme 44. The intermediate 3015 is hydrogenated to give the amine 3019. Coupling of 3019 with an aspartic acid or a glutamic acid derivative under Standard peptide coupling conditions affords 3020. Removal of chiral auxiliary and hydrogenolysis afford amino acid 3021. Macrocyclization producēs cyclic lactam 3022, which is converted to the desirea compound 3023 using conditions described in scheme 40.
Scheme 44 3015
H;>/Pd-C
ho2c CbzHN £. DEC/HOBt/DMF
Preparation of the compounds of formula 141 ,where Z is a N-alkyl amide, an imidazole or a benzimidazole could be achieved as desribed in scheme 29 below. Dibal reduction of an appropriately substituted ester of an amino acid to an aldehyde is followed by the formation of a cyanohydrin which is hydrc' -zed to afford an acid 134. The acid is converted to a benzyi ester 135 that undergoes Mitsunobu reaction to afford 136. Deprotection of the t-butyl ester followed by peptide coupling with a lysine or an ornithine derivative affords 138. Base hyarolysis affords an amino acid that undergoes macrocyclization to give 139. Hydrogenolysis of 139 producēs the carboxylic acid 140. Coupling of 140 with 0-benzylhydroxylamine followed by hydrogenation affords the final compound 141.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of orgar.ic svnthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations t'nereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
Ali references cited herein are herebv incorporated in tneir ehtirety herein by reference.
The novel compounds of Formula I may be prepared using the reactions and technigues described in this section.
The reactions are performed in solvents appropriate to the reaģents and materiāls emploved and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be unaerstood that ali proposed reaction conditions, inciuding choice of solvent, reaction atmosphere, reaction temperature, duratior. of the experimer.t and workup procedures, are choser. to be the conditions Standard for
g_ LV 12167 that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various pcrtions of the molecule must be compatible wit’n the reaģents and reactions proposed. Not ali compounds of Formula I falling into a given class may be compatible with some of the reaction conditions reguired in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Examples
Abbreviations used in the Examples are defined as follows: "IX" for once, "2X" for twice, "3X“ for thrice, "bs" for broad singlet, "°C" for degrees Celsius, “Cbz" for benzyloxycarbonyl, "d" for doublet, "dd" for doublet of doublets, "eg" for eguivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, " 1H" for proton, *'nr" fcr hour or hours, "m" for multiplet, "M" for molar, "min" for minūte or minūtes, "mp" for melting point range, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "tic" for thin layer chromatography, "v/v" for volume to volume ratio. "a", "β", "R* and "S" are stereochemical designations familiar to those skilled in the art. l(a) 3R-Allvl-3-t-Butoxvcarbonvl-2(R)-isobutvl -prooanoic acidj-
To a stirred cooledi-78 °C) solution of 20 grams (87 mmol) of 3-t-Butoxycarbonyl-2(R)-isobutylpropanoic acid (1.15 g, 5 mmol) (previously aziotroped with toluene) in 400 mL of anhydrous THF, vas added 180 mmcl of LDA via cannula over 30 minūtes. After stirring fcr 1 hour, 8.3 mi -129- (96 mmol) of allyl bromide was added dropwise. The reaction was allowed to slowly warm to room temperature wnile stirring overnight. The reaction was quenched with 10% agueous citric acid followed by removal of the volatiles under reduced pressure. The remaining material was taken into ethyl acetate and washed with H2O. The aqueous phase was then extracted 3 times with ethyl acetate and the combined orgānic fractions were washed with 10% citric acid, saturated NaHC03 (2x), H2O (2x), and brine then dried over MgSŪ4. The solvent was removed under reduced pressure obtaining 23.3 grams (99% yield) which was carried on without purification. MS (M+Na)+ = 293 1(b) 3S-Allvl-3-t-butoxvcarbonvl-2(R)-isobutvl .propanoic acid.;.
To a stirred, cooled (-78 °C) solution of 2 grams of acid Ka) (previously aziotroped 2 times with benzene) in 25 ml of anhydrous THF, was added 16.3 mmol of LDA via cannule over 15 minūtes. The reaction was stirred 15 minūtes at -78 °C and then for 15 minūtes in a room temperature (24 *C) water bath. The reaction was then cooled to -78 °C for 15 minūtes, followed by the addition of 15.6 ml of 1 M diethylalluminum chloride (hexane) . The reaction was stirred 10 minūtes at -78 °C, 15 minūtes in a room temperature water bath, then for 15 minūtes at -7 8°C again, followed by ouench with the rapid addition of methanol. The reaction mixture was concentrated to -1/4 its origional voiume under reduced pressure and the resuiting material was dissolved in 200 ml of ethyl acetate and washed with a mixture of 70 mL of IN HC1 and 100 grams of ice. The aqueous was extracted 2 times with ethyl acetate. The combined organic fractions were washed with a solution of 3.5 grams of KF dissolved in 100 mL of water and 15 mL of 1 N HC1 (pH 3-4). The organic phase was washed with brine, dried with MgS04, filtered and the solvent was removed under reduced pressure affording a 92% -130- LV 12167 mass recovery. 2Κ NMR in acetone d-6 indicated an ~8:1 anti svn ratio. MS (M+Na)+ = 293 1(0 Benzvl 3S-Allvl-3-t-butoxvcarbonvlr2(R)-isobutvloropanoate:
To a stirred cooled (0 eC) solution of 20.6 grams(76 mmol) of crude equilibrated acid l(b) (8:1 mixture) in 75 mL of benzene, was added 11.4 mL (76 mmol) of DBU followed by 9.98 mL (84 mmol) of benzyl bromide. After 10 minūtes the reaction was refluxed for 4 hours. The reaction was then diluted to 3 times origional volume with ethyl acetate and washed 3 times with 10% aqueous citric acid. The combined aqueous was extracted 3 times with ethyl acetate. The combined organic fractions were then washed with brine, dried over MgS04 and the volatiles were removed under reduced pressure. The resulting material was chromatographed over silica gel eluting with 2.2 % et'nyl acetate/'nexanes affording 16.9 grams of benzyl ester (62% yield) . MS (M+NK4)* = 378 l!d) Benzvl 3 S- (3 -hvdroxvproDVl) -.3 - t-but OKvearbonvL- 2 LRLz isoburvlororanoate:
To a stirred, cooled (0 °C) solution of 5.2 grams of olefin 1(0 in 100 mL of anhvdrous THF, was added 72.2 mL of C.5M 9-BBN in TKF over 1 hour. The reaction was allowed to warm to room temperature while stirring 12 h. The reaction was cooled to 0 °C followed by the addition of 2.9 mL of H2O added (caution foaming) dropwise over 5 minūtes. After stirring for an additional 20 minūtes, 8 mL of H2O cor.taining 3.21 grams of NaOAc was added simultaneously with 8 mL cf 30% H2O2 over 5 minūtes. The mixture was stirred 20 additional minūtes followed by removal of the volatiles under reduced pressure. The remaining material was dissolved in ethyl acetate and washed with brine. The agueous phase was extracted 2 times with ethyl acetate.
The combined organtc fractions were washed with water, brine, dried MgSC4 followed by removal of the volatiles -131- under reduced pressure. The resulting material was chromatographed on silica gel wich an eluting gradient from 1:20 to 1:10 to 1:5 ethyl acetate/hexanes affording 3.5 grams (64% yield). MS (M+H)+ = 379 1(e) Benzvl 3S-(3-bromoproDvl)-3-t-butoxvcarbonvl-2(R)- isobutvlpropanoatg;
To a stirred, cooled (0 °C) solution of 8.32 grams of triphenylphosphine, 2.15 grams of imidazole and 10.54 grams of carbon tetrabromide in 60 mL of anhydrous CH2CI2/ was added a solution of 8.0 grams of alcohol l(d) dissolved in 60 mL of anhydrous CH2CI2 dropwise over 15 minūtes. The reaction was stirred at 0 °C for 30 minūtes and then an additional 1/2 equivalent of triphenylphosphine, imidazole and carbon tetrabromide in 30 mL of CH2CI2 was added at one time. The reaction was stirred an additional 2.5 hours at 0 °C, 20 minūtes at room temperature (24 *C) then diluted with 320 mL of hexanes and filtered through a short silica gel plug rinsing with 25% ethyl acetate/hexanes. The volatiles were removed under reduced pressre and the resulting material was chromatographed on silica gel eiutinc with a 1-10% ethyl acetate/hexanes gradient affording 6.1 grams (65% yield) of the bromide. M+H = 442. 1 (f) 3S- (3-bromopropvl) -3-t-butoxvcarbonvl-2 (R) -isobutvlorocanoic acid:
To 10.5 grams of benzyl ester l(e) in 250 mL of methanol, was added lg of 10% Pd-C. The mixture was stirred under H2 (balloon) for 3 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure affording 8.3 grams of material. M+H =352. l(g) 33-(3-bromopronvl)-3-t-butoxvcarbonvl-2R-isobutvlprotanovl-ftvrosine-methvlesterl :
To 8.4 g of acid in 20C mL of DMF was added 5.5 g of tvrosine methylester hydrochloride and 9.1 mL of NMM. To -132- LV 12167 this mixture was added 9.52 g of TBTU dissolved in 120 mL of DMF over 30 minūtes. The reaction was stirred 2 hours ac room temperature followed by removal of the volatiles under reduced pressure. The resulting mass was dissolved in ethyl acetate and washed with cold 1N HC1. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic fraction was washed sequentially with H2O, saturated NaHCC>3, H20, brine, and dried over MgS04. The solvent was removed under reduced pressure and the resulting material was chromatographed on silica gel eluting with 25 to 33% ethyl acetate /hexanes affording 9.5 grams (75% yield) of coupled material and 2.35 grams of HOBt addition product. The HOBT adduct was dissolved in 25mL of DMF, and to this was added 0.57 mL of NMM and 1.2 grams of tyrosine methylester hydrochloride. The reaction was heated at 60° C for 30 minūtes at which time 1.4 ml of NMM and 2.4 grams of ester were added followed by an additional 30 minūtes at 60 0 C. This was worked up in a mannor analogous to the initial reaction affording 2.6 grams of additional product. M+H = 329. l(n) 2S,5R.6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(carboxvmethvl)-flO1paracvclophane-6-t-bu£oxvcarbonvl:
To a stirred, heated (60 °C) suspension of 5.2 g of CS2CO3 in 130 mL of anhydrous DMF and 32.5 mL of anhydrous DMSO, was added a solution of 3.25 g of bromide l(g) dissolved in 25 mL, of DMF over 15 minūtes. The reaction was then heated at 80 °C for an additional 30 minūtes. It was then cooled in an ice bath and guenched with 10% aqueous citric acid. The volatiles were removed under reduced pressure and the resulting material was partitioned ir. ethyi acetate/H20. The aqueous was extracted 4 times with ethyl acetate and the combined 5 extracts were washed 4 times with H2C, once with brine, dried over MgS04 followed by removal of the volatiles under reduced pressure. The resulting material was chromatographed or. -133- silica gel eluting with 1.5% MeOH/CH2Cl2 affording 2.0 grams(74% yield) of the macrocycle. M+H = 448. l(i) 2S.5R.6S-3-aza-4-oxo-lQ-oxa-5-isobutvl-2-(carboxvmethvl)-ri0lparacvclophane-6-carboxvlic acid: To 0.77 g of t-butyl ester 1 (h), was added 25 ml of TFA. The reaction was scirred for 1 h at room temperature. The TFA was removed under reduced pressure affording 0.67 grams of acid. M+H =392. 1(j) 2S.5R.6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(carboxvmethvl)- flOl oaracvclophane-6- ΓΝ- (0-benzvl) carboxamide1 :
To 1.8 g of acid in 150 mL of CH2CI2 was added 0.75 g of HOBt, 2 mL of NMM, 0.81 g of 0-benzylhydroxylamine hydrochloride, and 1.06 g of EDC. The reaction was stirred for 3 h at room temperature. TLC in 10% MeOH/CHCl3 indicated presence of starting acid so 50 mg of TBTU was added and the reaction was stirred 30 additional minūtes. Wher. TLC indicated consumption of acid, the solvent was removed under reduced pressure and to the remaining material was added 50 mL of DMF and 4.3 g of the free base of 0-benzylhydroxylamine. The reaction was heated to 80 °C for one hour. The volatiles were removed under reduced pressure and the resulting material was dissolved in ethyi acetate and washed with IN HC1, H2O, saturated aqueous NaHC03, H2O, brine and driea over MgS04. The volatiles were then removed under reduced pressure affording material slightly comtaminated with HOBT adduct as determined by ΧΗ NMR. The slightly yellow solid was triterated in boiling Et20 followed by filtration to afford 2.18 g (95%) of white solid. or alternatively the above coupling can be carried out using HATU;
To a soiution cf 2.4 g cf acid in 75 mL of anhydrous DMF was added 3.37 mL of NMM, 5.24 g cf HATU and 3.77 grams of 0-benzyihvdrcxylamine. After stirring ovemight at room -134- LV 12167 temperature, the reaction mixture was heated to 60 °C for 30 minūtes. After cooling, the volatiles were removed under reduced pressure and the resulting material was dissolved in ethyl acetate and washed with 10% aqueous citric acid. The organic layer was extracted three times with ethyl acetate. The 4 combined organic extracts were washed three times with H2O, once with brine, dried over MgS04 and the volatiles were removed under reduced pressure. The resulting material was triterated 4 times with a mixture of 1:1:2 ethyl acetate:hexane:ether to afford 1.4 g of product. The mothor liquor was concentrated and the resulting material was chromatographed on silica gel eluting with a gradient of 25-90% ethyl acetate/hexane affording another 1.05 grams of product for a combined yield of 81%. l(k) 2S.5R.6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(carboxv)-riOlbaracvclophane-6-ΓΝ-(O-benzvl)carboxamide1:
To 0.7 g of methylester 1(j) in 65 mL of THF and 15 mL of H2O was added 2.23 mL of saturated aqueous LiOH. The reaction was stirred 2 hours at room temperature and quenched with 10 mL of IN HC1. The majority of solvent was removed under reduced pressure, diluted with ethyl acetate and washed wtih H2O and 20 mL of IN HC1. The aqueous was extracted 4 times with ethyl acetate. The combined ethyl acetate fractions were washed with H2O, brine, dried over MgS04 and the solvent was removed under reduced pressure affording 0.67 g (99 % yield) cf white solid. M+H = 483.
Example 15: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2- (hvdroxv methvl)-f101paracvclophane-6-N-hvdroxvcarboxamide: To a stirred, cooled (0° C) solution of 0.031 grams (0.064 iranols) of acid in 2 mL cf anhydrous TKF was added 0.19 mL of 1M B2Hg in THF followed in 2 hours by the addition of an additicnal 0.19 mL of 1M B2Hg. The reaction was allowed to slowlv warm to room temperature while stirring overnighz. īxcess borane was cuenched with the • 1 dropwise addition of H2O. The material was partitioned in EtOAc and H20, separated then the aqueous was extracted an additional 3 times with EtoAc. Ali 4 extracts were combined and washed with H2O, brine, dried over MgS04 and the volatiles were removed under reduced pressure. The resulting material was purified by prep-plate chromatography in a mannor analogous to previously described, affording 19 mg of material.
To 18 mg of alcohol in 10 mL of MeOH was added 25 mg of 5% Pd/BaS04. Shaken under 50 psi H2 for 4 hours, filtered and volatiles removed under reduced pressure affording 15 mg of hydroxamic acid. M+H = 379.
Example 20: 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-Γ(3-imidazolvl)oroDvlcarboxamido1-f101 paracvclophane-6-Ν-hvdroxvcarboxamide: A solution of 0.035 grams of acid in 2 mL of DMF was added 0.024 mL of NMM, 17 mL of aminopropylimidazole and 0.030 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatographv (1 mm with 0.25 mm concentration zone} eluting two times with 5% MeOH/CHCl3 affording 0.042 grams of the product. LRJMS found (M+H)+ = 590 HPLC reverse phase 70-5% H20/CH3CN (0.1% TFA) 30 minūte ramp: RT = 4.96minutes
To 0.040 grams in 10 mL of MeOH was added. 0.065 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30 % H2O/CH3CN with 0.1 TFA ove 45 minūtes) affording 0.025 grams of the hydroxamic acid. LRMS found (M+H)+ = 500 -135- LV 12167
Example 23: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(2- nvridvl-2-ethvlcarboxamido)-(101paracvclophane-6-Ν-hvdroxvcarboxamide:
To a stirred mixture of 0.037 grams of acid in 2mL of CH2CI2 was added 0.020 mL of NMM, 10 mL of aminoethyl pyridine and 0.032 grams of TBTU. The reaction was run in a mannor analogous to the above affording 20 mg after purification.
To 20 mg in 10 mL of MeOH was added 35 mg of 5% Pd/BaS04. Shaken under 50 psi H2 for 4 hours, filtered and volatiles removed under reduced pressure affording material purified by reverse phase HPLC (90% to 30 % H2O/CH3CN with C.l TFA over 30 minūtes) affording 15 mg of the hydroxamic acid as the TFA salt. M+H = 497.
Example 27: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(4- methvlpiperazinvlcarboxamido)-Γ101 paracvcloohane-6-Ν-hvdroxvcarboxamlde.:
To 0.030 grams of acid in 2 mL of CH2CI2 was added 0.016 mL of NMM and 14 mL of N-methylpiperazine. The reaction was run in a mannor analogous to the above affording 25 mg after purification.
To 25 mg iniO mL of MeOH was added 45 mg of 5% Pd/BaS04. Shaken under 50 psi H2 for 4 hours, filtered and volatiles removed under reduced pressure affording 15 mg of the hydroxamic acid. M+H = 475.
Exampie 41: 2S, 5R, 6S-3-aza-4-.oxo-10-oxa-5-isobutvl-2-(2-imidazolvU-Γ101paracvclophane-6-N-hvdroxvcarboxamide: A solution of 0.061 grams of acid in 4 mL of DMF was added 0.096 mL of NMM, 0.033 grams of 2-aminoimidazole and 0.053 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatographv [1 mm with 0.25 mm concentration zone) -137- eluting two times with 5% MeOH/CHCl3 affording 0.018 grams of the coupled product.
To 0.015 grams in 5 mL of MeOH was added 0.020 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30 % H2O/CH3CN with 0.1 TFA over 30minutes) affording 0.007 grams of the hydroxamic acid as the TFA salt. M+H = 457.
Example 50: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-isobutvl-2- (N-methvl carboxamido)-f101paracvclophane-6-Ν-hvdroxvcarboxamide:
The N-methyl amide of 1(k) was prepared as described previouslv to give 50(a).
To 0.139 grams of 50(a) in 14 mL of MeOH was added 0.19 grams of 5% Pd/BaS04. The mixture was shaken under 45 psi H2 in a Parr bottle for 2 hours. The mixture was then filtered through a 0.45 mM PTFE membrane filter and the volatiles were removed under reduced pressure affording 0.12 grams of a white solid. MP 350-352° C decoirp. M+H = 406.
Example 55: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(2-benzimidazolvl)-Γ10;paraevclophane-6-N-hvdroxvcarhQxamide: A solution of 0.050 grams of acid in 3 mL of CH2CI2 was added 0.C28 mL of NMM, 0.022 grams of phenylamine diamine and 0.043 grams of TBTU was stirred at room temperature ovemight The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeOH/CHCl3 affording 0.025 grams of the product.
To a solution of 0.022 grams of the above in 3 mL of TKF was added 3 mL of HOAc. The reaction was refluxed 1 hour then the volatiles were removed under reduced pressure affording 0.021 grams of benzamidizole product. -138- LV 12167
To 0.020 grams in 10 mL of MeOH was added 0.035 grams of 5% Pd/BaS04. The reaccion was shaken at 50 psi for 4 hours, filtered and the volatiles were removed under reduced pressure affording 0.012 grams product. M+H = 465.
Example 61: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2- (alvcine-N-methvlamide)-riOlparacvclophane-6-Ν-hvdroxvcarboxamide: A solution of 0.030 grams of acid in 2 mL of DMF was added 0.030 mL of NMM, 0.015 grams of glycine-N-methylamide hydrochloride, and 0.026 grams of TBTU was stirred at room temperature for 18 h then heated at 80° C for 15 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-TLC (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeOH/CHCl3 affording 0.030 grams of the product.
To 0.025 grams in 10 mL of MeOH was added 0.035 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the volatiles were removed under reduced pressure affording 0.020 grams product. M+H = 463.
Example 63: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-!L- alanine-N-methvlamide)-riQ]paracvclophane-6-N- bYtoxycagbQ?amide;
To a stirred solutior. of 0.030 grams (0.062mmol) of acid in 2 mL of CH2CI2 was added 0.034 mL of NMM and 17 mg of L-alanine methylamide hydrochloride and 26 mg of TBTU. The reaction was stirred ovemight at room temperature. It was poured into 10 % aqueous citric acid and extracted 3 times with CHCI3. Ali CHCI3 were combined and washed with H2O, saturated aqueous NaHC03, H20, brine and dried over MgS04. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (lmm with 0.25mm concentration zone) eluting two times with 5% MeOH/CKCl3. The main band was removed, pulverized and rinsed with 150 ml of 10 % MeOH/CHCl3 affording 20 mg of the desired product. -139-
To a solution of 20mg of che above in 10 mL of MeOH was added 30 mg of 5% Pd/BaS04- This was shaken at 50 psi for 4 hours, filtered and the volatiles were removed under reduced pressure affording 15 mg of the desired hydroxamic acid. M+H = 477.
Example 65: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-fD-alanine-N-inethvlamido) - f 10lDaracvclophane-6-N-hvdroxvcarboxami de: A solution of 0.036 grams of acid in 2 mL of DMF was added 0.037 mL of NMM, 0.021 grams of D-alanine N-methylaitu.de and 0.031 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 15 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times witn 5% MeOH/CHCl3 affording 0.050 grams of coupled product.
To 0.040 grams in 10 mL of MeOH was added 0.050 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 4 hours, filtered and the volatiles were removed under reduced pressure affording 0.029 grams product. M+H = 477.
Example 67: 2S, 5R. £S-3-aza-4-oxo-lQ-oxa-5-isobutvl-2-(L-valine-N-methvlcarboxamico)- ΓΙΟΙnararvclophane-6-Ν-hvdroxvcarboxamide: A solution of 0.035 grams of acid in 2 mL of DMF was added 0.039 mL of NMM, 0.022 grams of L-valine-N-methylamide and 0.030 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatograp’ny (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeOH/CHCl3 affording 0.038 grams of the coupled product.
To 0.03 5 grams ir. 10 mL of MeOH was added 0.050 grams of 5% Pd/BaSC>4. The reaction was shaken at 50 psi for 6 -140- LV 12167 hours, filtered and the volatiles were removed under reduced pressure affording 0.030 grams product. M+H = 505.
Example 70: 2S, 5R. 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(L- (0-methvl)tvrosine-N-methvlamido)-ri0lparacvclophane-6-N-hvdroxvcarboxamide:
To 0.030 grams (0.062 mmols) acid in 3 mL of DMF was added 0.030 mL of NMM and 0.029 grams of 0-methyltyrosine N-methylamide and 0.026 grams of TBTU. The reaction was heated to 80°C for 20 minūtes. The DMF was removed under reduced pressure and the resulting material was taken into EtOAc and washed with 10% agueous citric acid. The_ water was extracted 3 times with EtOAc, combined and washea with H2O, saturatea aqueous NaHC03, H2O, brine, dried over MgS04 and the solvent was removed under reduced pressure affording 0.033 grams of product which was carried on with out purification.
To 0.030 grams of the above in 10 mL of MeOH was added 0.040 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30 % H2O/CH3CN with 0.1 TFA over 30minutes; affording 19 mg of. the hydroxamic acid. M+H = 583.
Example 71: 2S. 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(L-serine-N-methvlamido) - r101 paracvclophane-6-Ν- hvdroxvcarboxamide:
To 0.025 grams of the above t-butyiether 75 was added 3 mL of TFA. The reaction was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure affording 0.C20 grams of product. M+H = 493.
Example 72: 2S. 5R, 6S-3-a2a-4-oxo-10-oxa-5-isobutvl-2-(beta-alanine-N-methvlcarboxamido)-f101paracvclophane-6-Ν-hvdroxvcarboxamide: A sclution of 0.0ΞΞ grams of acid ir 2 mL of DMF was added 0.039 mL cf NMM, C.020 grams of β-aianine-N- -141- methylamide and 0.030 grams of TBTU was stirred at room temperature overnighc then heaced at 80° C for 15 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeOH/CHCl3 affording 0.043 grams of coupled product.
To 0.040 grams of the above in 10 mL of MeOH was added 0.050 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the volatiles were removed under reduced pressure affording 0.030 grams product. M+H = 49S.
Example 73: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-isobutvl-2- (D-serine-N-methvlamide) -Γ101paracvclophane-6-Ν-hvdroxvcarboxamide:
To 0.020 grams of ether was added 3 mL of TFA. The reaction was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure affording 0.015 grams of product. LRMS found (M+H)+ = 493, (M+Na)+ = 515. HPLC reverse phase 90-20% H20/CH3CN (0.1% TFA) 30 minūte ramp: RT = 11.67 minūtes
Example 75: 2S_, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(L-Q.-tertbutvl).serine-N-methvlamide) - ΓΙΟΙ paracvclophane-6-Ν-hvdroxvcarboxamide: A solution of 0.062 grams of acid in 3 mL of DMF was added 0.035 mL of NMM, 0.045 grams of 0-t-Butyl serene-N-methylamide, and 0.054 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 15 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatograpny (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeCH/CHCl3 affording 0.080 grams of the product. -142- LV 12167
To 0.075 grams of the above in 10 mL of MeOH was added 0.100 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 4 hours, filtered and the volatiles were removed under reduced pressure affording 0.050 grams product. M+H = 549.
Example 77: 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-ΓΡ-fO-tert-butvl)serine-N-methvlamidel -ri0lparacvclophane-6-N-hvdroxvcarboxamide.: A solution of 0.035 grams of acid in 2 mL of DMF was added 0.024 mL of NMM, 0.033 grams of 0-t-butyl-D-serine-N-metylamide and 0.030 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times with 3% MeOH/CHCl3 affording 0.040 grams of the product.
To 0.035 grams in 10 mL of MeOH was added 0.050 grams of 5% Pd/BaS04- The reaction was shaken at 50 psi for 6 hours, filtered and the volatiles were removed under reduced pressure affording 0.030 grams product. LRMS found (M+H!* = 54S.
Exampie 90: 2S.5R, 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(L-lvsine-N-methvlamide)-Γ101paracvclophane-6-Ν-hvdroxvcarboxamide: A solution of 0.035 grams cf acid in 2 mL of DMF was added 0.024 mL cf NMM, 0.035 grams of L-lysine-N-methylamide and 0.030 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeOH/CHCl3 and one elution with 10% MeOH/CKCl3 affording 0.035 grams of the coupled product. -143- LRMS found (M+H)+ = 744, (M+Na)+ = 766.
To 0.03 0 grams in 10 mL of MeOH was added 0.040 grams of 5% Pd/BaSC>4. The reaction was shaken at 50 psi for 6 hours, filtered and the volatiles were removed under reduced pressure affording 0.026 grams product. LRMS found {M+K)+ = 520
Example 95: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-(N-benzvl carboxamido)-Γ101oaracvclophane-6-N-hvdroxvcarboxamide:
To a slurry of 0.030 grams (0.06 iranol) of acid in 2 mL of CH2CI2 was added 0.015 mL of NMM and 24 mg of TBTU. The reaction was stirred 30 minūtes at which time lOmL of benzyl amine was added and the reaction was stirred for 1 hour. The mixture was diluted with CHCI3 and washed once with IN HC1 and once with H2O. Both aqueous were combined and extracted 3 times with CHCI3. Ali 4 CHCI3 were combined and and washed with H2O, saturated aqueous NaHC03, water, brine, and dried over MgS04- The solvent was removed under reduced pressure affording 30 mg (85% vield) of the benzyl amide. M+H = 572; M+Na = 594.
To 25 mg of the above in 10 mL of MeOH was added 35 mg of 5% Pd/BaS04. The mixture was shaken under 50 psi K2 for 5 hours. The reaction was filtered thrcugh a 0.45 mM PTFE membrane filter and the volatiles were removed under reduced pressure affording 15 mg. of the hydroxamic acid. M+H = 482.
Example 106: 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutvl-2- Γ2-(4-aminosulf onvlohenvl) ethvlcarboxamiao1 -Γ1Q1 paracyclQghane.--ž -.Nr.hydrQxycarboxa.Tiiide; A solution of 0.035 grams of acid in 2 mL of DM? was added 0.024 mL of NMM, 0.029 grams of (4-aminosulfonylphenyl)ethylamine and 0.030 grams of TBTU was stirred at rocm temperature ovemight then heated at S0° C fcr 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep- -144- LV 12167 plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times with 5% MeOH/CHCl3 and one elution with 10% MeOH/CHCl3 affording 0.040 grams of the coupled product. LRMS found (M+H)+ = 665, (M+Na)+ = 687 HPLC reverse phase 70-5% H2O/CH3CN (0.1% TFA) 30 minūte ramp: RT = 11.39 minūtes
To 0.035 grams in 10 mL of MeOH was added 0.050 grams of 5% Pd/BaS04- The reaction was shaken at 50 psi for 6 hours, filterea and the volatiles were removed under reduced pressure affording 0.030 grams product. LRMS found <M+H)+ = 575, (M+Na)+ = 597
Example 107: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-isobutvl-2-Γ(2-benzimidazolvl)methvlcarboxamido1-Γ101 Daracvclophane-6-Ν- hydrpxycarbgxamide; A solution of 0.035 grams of acid in 2 mL of DMF was added 0.024 mL of NMM, 0.021 grams of aminomethylbenzamidizole and 0.030 grams of TBTU was stirred at room temperature ovemight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatographv (1 mm with 0.25 mm concentration zone) eluting two times with 3% MeOH/CKCl3 affording 0.03C grams cf the product. LRMS found (M+H)+ = 612. HPLC reverse phase 90-20% H2O/CK3CN iC.1% TFA) 30 minūte ramp: RT = 13.01 minūtes
To 0.025 grams in 10 mL of MeOH was added 0.035 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30 % H2O/CH3CN with 0.1 TFA over 45 minūtes) affording 0.020 grams of the hydroxamic acid. LRMS found (M+K)+ * 522. - -145-
Example 108: 2S.5R.6S-3-aza-4-oxo-lQ-oxa-5-isobutvl-2-(2-benzimidazo.lecarboxamido) - flQlparacvcloDhane-6-N-hYdiQK/.c arfroxaiTU.de; A solution of 0.035 grams of acid in 2 mL of DMF was added 24 mL of NMM, 0.019 grams of aminobenzamidazole and 0.030 grams of TBTU was stirred at room temperature overnight then heated at 80° C for 30 minūtes. The volatiles were removed under reduced pressure and the resulting material was purified by prep-plate chromatography (1 mm with 0.25 mm concentration zone) eluting two times with 3% MeOH/CHCl3 affording 0.036 grams of the coupled product.
To 0.030 grams in 10 mL of MeOH was added 0.045 grams of 5% Pd/BaS04. The reaction was shaken at 50 psi for 6 hours, filtered and the resulting material was purified by reverse phase HPLC (90% to 30 % H2O/CH3CN with 0.1 TFA over 45 minūtes) affording 0.020 grams of the hydroxamic acid. M+H = 508. 120(a): 2S,5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(carboxvmethvl)-f101paracvclophane-6-N-benzvloxvcarboxamide Following the synthetic sequence used previouslv 120 (a) was prepared as a white solid. ESI-MS (M+K)·'·: calcd 525.3, found 525.6.
Example 120: 2S,5R. 6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(carboxvmethvl)-f101oaracvclophane-6-N-hvdroxvcarboxamide Following a procedure analogous to that used previously, hydrogenolysis of 120(a) (122.1 mg, 0.233 mmol) gavē the hydroxamate (102 mg, 100%). ESI-MS (M+H)+: calcd 435.3, found 435.3.
Example 12 6: 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexvl-2-((2- ... methoxvlethvloxv) carboxvl) - (101 paracvcloohane-6-Ν- . hvdroxvc arboxami de mmol)
Followinģ a procedure analogous to that used previouslv, hydroger.olysis cf 126 (a) (50.6 mg, 0.0893 -146- LV 12167 gavē nydroxamate 126 (42.6 mg, 100%). ESI-MS (M+H)+: calcd 479.3, found 479.4. 126(a). 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2-((2-methoxvlethvloxv)carboxvl)-Γ101paracvclophane-6-Ν-ben2vloxvcarbQxamide A 1.0 N dichloromethane solution of N, N'-dicyclohexylcarbodiimde (0.2 mL, 1 equiv.) was added to a solution of 212(a) (100.6 mg, 0.197 mmol), 2-methoxyethanol (0.020 mL, 1.3 equiv.), l-hydroxybenzotriazole hydrate (0.0266 g, 1 equiv.) in tetrahydrofuran (6 mL) at room temperature. After 20 h at room temperature and 4 h at refloc, the reaction mixture was guenched with saturated ammonium chloride and extracted with ethyl acetate. The ccmbined extracts were washed with brine, dried (MgS04) and concentrated. Silica gel chromatography (methanol-dichloromethane, 2:98 then 4:96 then 6:94) gavē 126(a) (51.2 mg, 46%) as a white solid. ESI-MS (M+H)+: calcd 565.4, found 569.5.
Example 128: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2-f(2- p'nenvIet.hvloxv) carboxv) - riOlparacvclophane-6-Ν-hvdroxvcarboxamide
Following a procedure analogous tc that used previously, 212(a) (32.3 mg, 0.063 mmol) was reacted with 2-pher.ylethanol (9.3 mg, 1.2 equiv.) to give the desired coupling product (34.6 mg, 89%). Hydrcgenolysis of the coupling product (34.6 mg, 0.0563 mmol) then gavē the hydroxamate (26.0 mg, 88%). ESI-MS (M+H)+: calcd 525.3, found 525.4.
Exampie 129: 2S.5R. 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- ldimethvlcarbcxainido)· - f 101 oaracvclophane-6-Ν-hvdrnwrarbQxamide
Following a procedure analogous to that used previouslv, 212(a; (40.8 mg, 0.0800 mmcl) was reacted with dimētnvlamine hvdrochioride (16 mg, 2.45 eguiv.) to give -147- the desirea coupling product (36.0 mg, 84%).
Hydrogenolysis of the coupling product (31.7 mg, 0.0590 mmol) then gavē the hydroxamate (26.2 mg, 99%). ESI-MS (M-rK! ^: calcd 448.3, found 448.5.
Example 132: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(1-(n- methvlcarboximido) methvlcarboxvl) - Γ101 paracvclophane-6-Μ-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (32.9 mg, 0.0644 mmol) was reacted with , 2-hydroxy-N-methylacetamide (8.6 mg, 1.5 eguiv.) tc give the aesired coupling product (25.3 mg, 68%).
Hydrogenolysis of the coupling product (25.1 mg, 0.0431 mmol) then gavē the hydroxamate (21.1 mg, 99%). ESI-MS (M+H)+: calcd 429.3, found 429.4.
Example 139: 2S,5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(3-(1- imidazolvl)proDvlcarboxamido)-Γ101paracvclophane-6-Ν-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (97.2 mg, 0.190 mmol) was reacted with I- (3-aminopropyl)imidazole (0.0273 mL, 1.2 equiv.) to give the desired coupling product (96.0 mg, 82%).
Hydrogenoiysis of the coupling product (92.9 mg, 0.150 mmcl) then gavē the hydroxamate (76.0 mg, 96%). ESI-MS (M-rH)+: calcd 528.2, found 528.5.
Example 13S.TFA: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(3- II- imidazolvl) ūropvlcarboxamido) - Γ10 ‘paracvclophane-6-Ν-hvdroxvcarboxamide trifluoroacetate
Trifiuoroacetic acid (1 drop) was added to a suspension of 139 (38.5 mg, 0.0730 mmol) in dichlcromethane (6 mL). After stirring for several minūtes at room temperature, the homogeneous soluticr. was concentrated to give 34 (48 mg, 100%) as a white solid. ESI-MS (M-^H) + : calcd 528.2, found 528.6. -148- LV 12167
Example 142: 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (2-.(2.- pvridvl)ethvlcarboxamido)-f101paracvclophane-6-Ν-hvdroxvcarboxamide
Foliowing a procedure analogous to that used previously, 212 (a) (35.2 mg, 0.0689 mmol) was reacted with 2-(2-aminoethyl)pyridine (10.9 mg, 1.3 equiv.) to give the desired couplir.g product (36.1 mg, 85%). Hydrogenolysis of the coupling product (35.8 mg, 0.0582 mmol) then gavē the hydroxamate (31.3 mg, 100%). ESI-MS (M+H)+: calcd 525.4, found 525.5.
Example 146: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4- methvlpjperazin-l-vl)-f101paracvclophane-S-N-hvdroxvcarboxami de
Following a procedure analogous to that used previously, 212(a) (43.5 mg, 0.0852 mmol) was reacted with l-methylpiperazir.e (0.0142 mL, 1.5 equiv.) to give the desired coupling product (43.5 mg, 86%). Hydrogenolysis of the coupling product (43.5 mg, 0.0734 mmcl) then gavē the hydroxamate (38.2 mg, 99%). ESI-MS (M+K)+: calcd 503.3, found 503.6.
Example 156: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (2- .'N- methvlaminosulfonvl) ethvlcarboxamido) - Γ10 i paracvclophar.e-6-N-hvdroxycarboxamide
Following a procedure analogous to that used previouslv, 212(a) (34.9 mg, 0.0683 mmol) was reacted with ethylenediamine (0.050 mL, 11 equiv.) and then methanesulfonyl chloride (0.145 mL, 27.5 equiv.) to give the desired coupling product (35.6 mg, 83%).
Hydrogenolvsis of the coupling product (45.9 mg, 0.0743 mmol) gavē the hydroxamate (40.3 mg, 100%). ESI-MS (M-H:+: calcd 541.3, found 541.5.
Exampie 157: 2S.5R.6S-3-aza-4-oxo-lQ-oxa-5-hexvl-2-f4- 'N-methvlaminosulfcr.vl) butvlcarboxamido) - Γ11' paracvclophar.e-5-M-nvdroxvcarnoxamide -149-
Fcllowing a procedure analogous to that used previousiy, 212 (a) (35.2 mg, 0.0689 nnnol) was reacted with 1,4-diaminobutane (84.6 mg, 14 equiv.) and then methanesulfonyl chloride (0.186 mL, 35 equiv.) to give the desired coupling product (24.2 mg, 53%). Hydrogenolysis of the coupling product (24.0 mg, 0.0364 mmol) gavē the nydroxamate (20.0 mg, 97%). ESI-MS (M+H)+: calcd 569.3, found 569.5.
Example 158: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (cvclohexvlcarboxamido)-f10lparacvclophane-6-N-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (40.8 mg, 0.0689 mmol) was reacted with cyclohexylamine (0.012 mL, 1.3 equiv.) to give the desired coupling product (41.7 mg, 88%). Hydrogenolysis of the coupling product (35.4 mg, 0.0598 mmol) then gavē the hydroxamate (30.5 mg, 100%). ESI-MS (M+H)+: calcd 5C2.4, found 502.5.
Example 159: 2S.5R,65-3-aza-4-oxo-10-oxa-5-hexvl-2-'2-(N-methvlamincsulfonvl)hexvllcarboxamido'> - Γ101 paracvclorhane-6-N-hvdroxv=arboxamide
FoiIowing a procedure analogous to that used previouslv, 212(a) (35.2 mg, 0.0689 mmol) was reacted with 1,6-diaminchexane (89.6 mg, 11 equiv.) and then methanesulfcnyl chloride (C.150 mL, 28 equiv.) to give the desired coupling product (28.1 mg, 59%). Hydrogenolysis of the coupling product (28.1 mg, 0.0409 mmol) gavē the hyaroxamate (25.0 mg, 100%). ESI-MS (M+K)+: calcd 59“.3, . found 597.6.
Example 165: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-'L- ornithine-N-methvlamide)-Γ101paracvcloohane-6-Ν-hvdroxvcarbcxamd.de hvdrochloride
Hydrcxanate 205 (25 mg, 0.0386 mmol) was treated. with 4 N dicxane scluticn of hydrcgen chlcride (1 mL) fcr 40 min -150- LV 12167 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 163: 2S.5R.6S-3-aza-4-oxo-lQ-oxa-5-hexvl-2- (methvlcarboxamido) - ri01paracvcloDhane-6-N-hvdroxvcarboxamidg
Following a sequence analogous to that used in the preparation of 50, 169 was synthesized as a white solid. ESI-MS (M+H)+: calcd 434.3, found 434.4.
Example 180: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (glvcine-N-methvlamideλ- Γ101 paracv.clophang-6-Ν-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (40.8 mg, 0.080 mmol) was reacted with giycine-N-methyIamide hydrochloride (15.0 mg, 1.5 equiv.) to give the desired coupling product (42.2 mg, 91%) . Hydrogenolysis of the coupling product (33.1 mg, 0.057 mmci) then gavē the hydroxamate (27.1 mg, 97%). ESI-MS (M+H!+: calcd 491.3, found 491.5.
Example 182: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (L- alanine-N-methvlamide-riOTparacvclophane-6-Ν-hvdroxvcarboxami.de
Following a procedure analogous to that used previouslv, 212ia) (4C.8 mg, 0.080 mmol; was reacted with L-alanine-N-methylamide (12.2 mg, 1.5 ecuiv.) to give the desired coupling product (40.9 mg, 86%). Hydrogenclysis of the coupling product (33.0 mg, 0.0555 mmel) then gavē the hydroxamate (28.0 mg, 100%). ESI-MS (M-*-H)+: calcd 505.4, found 505.6.
Exampie 184: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(D- alanine-N-ir.er.hvlaird.de: - [101oaracvclophane-6-N-hvdroxvcarbcxa.-i de
Following a procedure analogous to that used previouslv, 212(a) (40.8 mg, 0.080 mmol) was reacted witn D-alanine-N-methylamide (12.2 mg, 1.5 equiv.) to give the desired coupling product (39.0 mg, 82%). Hydrogenolysis of the coupling product (32.0 mg, 0.054 mmol) then gavē the hydroxamate (27.9 mg, 100%). ESI-MS (M+H)+: calcd 505.4, found 505.5.
Example 194: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(L- serine (0-t.ert-butvl) -N-methvlamide) - riOlparacvclophane-6-Ν-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (81.6 mg, 0.160 mmol) was reacted with 0-tert-butyl-L-serine-N-methylamide (41.8 mg, 1.5 eguiv.) to give the desired coupling product (82.8 mg, 77.6%). Hydrogenolysis of the coupling product (76.0 mg, 0.114 mmol) then gavē the nydroxamate (66.7 mg, 100%). ESI-MS (M+H)*: calcd 577.4, found 577.6.
Exampie 199: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(2- (carbomethoxvļathvlcarboxamido)-Γ101caracvclophane-6-Ν-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (35.2 mg, 0.0689 mmol) was reacted with methyl 3-aminopropionate hydrochloride (12.4 mg, 1.3 equiv.) to give the desired coupling product (36.9 mg, 90%). Hydrogenolysis of the coupling product (36.9 mg, 0.0620 mmol) then gavē the hvdroxamate (31.0 mg, 100%). ESI-MS (M+H)+: calcd 506.3, found 506.4.
Example 201: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(2- (hvdroxvcarbonvl) etr.vlcarboxa.Ttdo) -(lO'oaracvclophar.e-g-N·-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (35.2 mg, 0.0689 mmol) was reacted with ber.zyl 3-aminopropicr.ate (31.5 mg, 1.2 eguiv.) to give the desired coupling product (40.6 mg, 90% . HydrogencIysis of LV 12167 the coupling product (40.6 mg, 0.0617 mmol) then gavē the hydroxamate (30.5 mg, 100%) as a white solid. ESI-MS (M+H)*: calcd 492.3, found 492.3.
Example 203: 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(L- omithine (4-t-butoxvcarbonvl) carboxvmethvl) -Γ101paracvclophane-6-N-hvdroxvcarbQxamide
Following a procedure analogous to Chat used previously, 212(a) (50.2 mg, 0.0983 mmol) was reacted with Νδ-BOC-omithine methyl ester hydrochloride (36.2 mg, 1.3 equiv.) to give the desired coupling product (58.2 mg, 80%). Hydrogenolysis of the coupling product (28.0_mg, 0.0379 mmol) then gavē the hydroxamate (24.6 mg, 100%). ESI-MS (M+H)*: calcd 649.4, found 649.5.
Example 205: 23.5R. 6S-3-a2a-4-oxo-10-oxa-5-hexvl-2-(L- omithine (4-t-butoxvcarbonvl) -N-methvlamide) - IIQ1 pararolcptiang-e -Nr.hydrQxv^arbQxamice
Following a procedure analogous to tnat used previouslv, 212(a) (6C mg, 0.118 mmol) was reacted with Νδ- BOC-ornithine N-methylamide hvdrochloride (42.9 mg, 1.3 equiv.) to give the desired coupling product (52.2 mg, 60%). Hydrogenclysis cf the coupling product (21.C mg, 0.0285 mmol) then gavē the hydroxamate (18.6 mg, 100%). ESI-MS (M+H)*: calcd 648.4, found 648.6.
Example 207: 23.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(I- ornithinecarboxvmethvl~-Γ101paracvclophane-6-N-hvdroxvcarboxamide hvdrochloride
The airtide ccuplir.g product (31.1 mg, 0.0421 mmol) for the preparātion of 203 was treated with 4 N dioxane solution of hvdrogen chloride (1 mL) for 1 h to remove the BOC group. Hydrogenolysis of the crude material then gavē the hydroxamate (24.8 mg, 100%). ESI-MS (M+H)*: calcd 549.4, found 549.5. -153-
Example 209: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(L- lvsinecarboxamide)- ΓΙΟΙparacvclophane-6-N-hvάroxvcarboxanide
Following a procedure analogous to that used previously, 212(a) (105.6 mg, 0.207 mmol) was reacted with t^-Cbz-L-^sine amide hydrochloride (85.0 mg, 1.3 eguiv.) to give the desired coupling product (130 mg, 82%). Hydrogenolysis of the coupling product (113.2 mg, 0.147 mmol) then gavē the hydroxamate (74.5 mg, 93%). ESI-MS (M+H)+: calcd 548.4, found 548.5.
Example 211: 2S.5R,6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (Dhenvlethvlcarboxamido)-flQlparacvclophane-6-N-hvdroxvcarboxanu.de
Following a procedure analogous to that used previous'ly, 212 (a) (44.6 mg, 0.0873 mmol) was reacted with phenethylamine (0.0219 mL, 2 equiv.) to give the desired coupling product (46.5 mg, 87%). Hydrogenolysis of the coupling product (46.5 mg, 0.0758 mmol) then gavē the hydroxamate (39.2 mg, 99%). ESI-MS (M+H)+: calcd 524.4, found 524.5 .
Exair.ple 212: 2S. 5R. 6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(hvdroxvcarboxvl) - Γ101 paracvclophane-6-N-hvdroxvcarboxamide
Following a procedure analogous to that used previcusly, hvdrogenolvsis of 212(a) (205 mg, 0.401 mmol) gavē the hydroxamate (168 mg, 99%). ESI-MS (M+E)+: calcd 421.3, found 421.4. 212(a). 2S.5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(hvdroxycarbcxvl)-flOlparacvclophane-e-N-benzvlOKvcarr^^amide A 1 N agueous solution of lithium hydroxide (7.5 mL, 4.23 eguiv.) was added to a solution of 120(a) (930 mg, 1.77 mmol) ir. tetrahydrofuran (20 mL) at 0 °C. After 25 min at rocm temperature, the mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate (3 x -154- LV 12167 40 mL). The combined extracts were washed with brine, dried (MgS04) and concentraced to give 212(a) (840 mg, 93%) as a white solid. ESI-MS (M+H)+: calcd 511.3, found 511.4.
Example 213: 2S..5R, 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (2- (3.4-dimethoxvphenvl)ethvlcarboxamido)-riOlparacvclophane-6-N-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (29.2 mg, 0.0572 mmol) was reacted with 2-(3,4-dimethcxyphenyl)ethylamine (14.7 mg, 1.2 equiv.) to give the desired coupling product (31.8 mg, 83%). Hvdrogenolvsis of the coupling product (31.6 mg, 0.0469 mmol) then gavē the hydroxamate (24.6 mg, 90%). ESI-MS (M+H)+: calcd 584.4, found 584.6.
Example 214: 2S. 5R, 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (benzvlcarboxamido)-riOlparacvclonhane-6-Ν-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (40.8 mg, 0.080 mmol) was reacted with benzylamine (0.0114 mL, 1.3 equiv.) to give the desired coupling product (43.0 mg, 90%). Hydrogenolysis of the coupling product (33.0 mg, 0.055 mmol) then gavē the hyaroxamate (28.2 mg, 100%). ESI-MS (M+H) + : calcd 510.3, found 510.5 .
Example 215: 2S.5iL6S-3:-aza-4-cxo-10-oxa-5-hexvl-2-(2-'4- morpnolmn) prhvlcarboxamido) - TICI naracvglophane-6-Ν-hvdrnvvrarhoxamide
Following a procedure analorous to that used previously, 212(a) (41.2 mg, 0.0807 mmol) was reacted with 4-(2-aminoethylimorpholine (0.015 mL, 1.4 equiv.) to give the desired coupling product (40.0 mg, 80%).
Hydrogenoiysis ci the coupling product (39 mg, 0.0626 mmol) then gavē the hydrcxamate (30.4 mg, 91%). ESI-MS (M+H)": calcd 533.4, ftur.d 533.5. -i ς = _
Example 217: 2S,5R.6S-3-aza-4-oxo-10-oxa-5-hexvl-2-(3-(4- mcrpholino)propvlcarboxamido)-Γ101paracvclophane-6-Ν-hvdroxvcarboxamide hvdrochloride
Following a procedure analogous to that used previously, 212(a) (44.4 mg, 0.0870 mmol) was reacted with 4-(3-aminopropy1)pyridine (0.0254 mL, 2 equiv.) to give the desired coupling product (40.0 mg, 72%). Hydrogenolysis of the coupling product (40.0 mg, 0.0628 mmol-) in the presence of hydrogen chloride (1 equiv.) then gavē the hydroxamate (34.2 mg, 93%). ESI-MS (M+H)+: calcd 547.4, found 547.5.
Exam.ple 224: 2S,5R, 6S-3-aza-4-oxo-10-oxa-5-hexvl-2- (diphenvlethvlcarboxamido) - ΓΙΟΙ paracvclophane-6-Ν-hvdroxvcarboxamide
Following a procedure analogous to that used previously, 212(a) (29.8 mg, 0.0584 mmol) was reacted with 2,2-diphenylethylamine (11.5 mg, 1.2 eguiv.) to give the desired coupling product (32.2 mg, 80%). Hydrogenolysis of the coupling product (32.0 mg, 0.0464 mmol) then gavē the hydroxamate (27.6 mg, 100%). ESI-MS (M+H)+: calcd 600.4, found 600.6.
Example 225: 2S, 5H, 65-3-aza-4-oxo-lQ-oxa-5-hexvl-2-(2-(4- sulfonvlaminophenvl)ethvlcarboxamido)-f101paracvclophane-6-N-hvdroxvcarboxamide
Following a procedure analogous to that used previousiy, 212(a) (70.0 mg, 0.137 mmol) was reacted with 4-(2-aminoethyl)benzenesulfonamide (33.0 mg, 1.2 eguiv.) to give the desired coupling product (8C.7 mg, 85%). Hydrogenolysis of the coupling product (76.6 mg, 0.111 mmol) then gavē the hydroxamate (65.4 mg, 98%). ESI-MS (M+H)+: calcd 603.3, found 603.6.
Example 710: 4S. 7R, 8S-_5_-aza-6-oxo-12-cxa-7-isobutvi-2-(carboy/methvl) - ri2lparacvclophane-9-N-hvdroxvcarboxami.de
Svr.tnesis cf homo-hcmc tvrnsins: -156- LV 12167 710(a) To a stirred, cooled (0°C) solution of 5.0 grams of the 3-(4-benzyloxyphenyl)propanol in 100 mL of anhydrous CH2CĪ2 was added 4.3 mL of triethylamine followed in 10 minūtes by 1.76 mL of methanesulfonyl chloride. The reaction was stirred for one hour then poured into saturated aqueous NaHC03. The aqueous was extracted 2 times with CH2CI2. Ali three CH2CI2 were combined, washed with H2O, 10% aqueous citric acid, H2O, brine, dried over MgS04 and the solvent was removed under reduced pressure affording a quantitative yield of the mesylate as a white solid. LRMS M+K =338. 710(b) To the mesylate above in 100 mL of acetone was added 3.9 grams of NaI. After stirring overnight at room temperature then an additional 3.9 grams of NaI was added and the reaction was refluxed 1 hour. The reaction mixture was filtered and the volatiles were removed under reduced pressure. The solid, which immediatelv turned yellow, was aissclved in hexane and washed with H2C, two times with 5% aqueous sodium. t'niosulfate, H2O, brine, dried over MgS04 and the solvent was removed under reduce pressure affording 6.79 grams of the iodide as a white solid.
LRMS H+K = 37C 710(c) To a stirred, cooled (-78° C) slurry of 1.15 grams of LiCl (flame dried in flask under vacuum) and 0.99 grams Meyers reaģent(Meyers et al. JACS, 1995, 117, 8488), in 30 mL of anhydrous THF was added 8.7 mL of 1M LDA in TH?/nexanes c-ver 10 minūtes. The mixture was stirred for 20 minūtes at -78° C and 30 minūtes at 0° C then 1.57 grams cf the iodide ir. 10 mL of anhydrous THF was added dropvise over 10 minūtes. The reaction was allowed to slowly warm to room temperature whiie stirring ovemight. It was guenched with 10% aqueous citric acid and the volatiles were removec -under reduced pressure. The remaining material was dissolved in EtoAc, wasned with H2O, 5% aqueous sodium thiosulfate, H2O, saturated aqueous NaHCC>3, K2C, brine, dried over MgS04 and the solvent was removed under reduced pressure. The resulting material was chromatographed on silica gel eluting with 4:100 MeOH/CHCl3 affording 0.9 grams of the product 7l0(c) LRMS M+H = 447.
Kvdrolvsis of Pseudoephedrine amide: 710(d) To 3.5 grams of the alkylation product 710(c) in 40 mL of H2O and 25 mL of MeOH was added 15.7 mL of IN aqueous NaOK. The reaction was refluxed 1 hour at which time 25 mL more MeOH was added. The reaction was refluxed ar. additional 3 hours then the volatiles were removed under reduced pressure. The solid was tricherated with CK2CI2 and filtered affording 5.5 grams of sodium hydroxide and the sodium salt of the product. The CH2CI2 in the filtrate was removec under reduced pressure and the remaining solid was tricherated with Et20 affording an additional 1.1 grams of product "10(d). LRMS sM+H = 298
Eg rma tic r. c:. Me t ireiasLe r t 710(e) Tc the NaOH and sodium salt above in 150 mL of MeOH was added 3 mL of concentrated HC1. The reaction was refluxed overnight at which time the volatiles were removed under reduced pressure and the resulting material was taken up in EtOAc and washed with saturated aqueous NaHCCs, brine, and dried over MgS04. The volatiles were removed under reduced pressure affording 2.4 grams of the methviester. LRMS found .M+H)·'· = 314
Couolinc of Homo-homo tvrosine to the succinate. fragment: 710(f! To a stirred, cooled (0°C) sclution of C.9C grams of acid ir. 20 rL cf ar.hydrous DMF was added 0.79 grams of amir.o acid r.ethyl ester 710(e), 1.14 mL of NMM and 0.884 -158- LV 12167 grams of TBTU. The reaction was stirred 20 minūtes at 0° C and 2 hours at room temperature. The reaction was duluted with 300 mL of EtoAc and washed 5 times with 10 % aqueous citric acid. Ali aqueous washes were combined and extracted 5 times with EtoAc. Ali 6 organics were combined and washed 5 times with saturated aqueous NaHC03, once with brine and dried over MgS04. The volatiles were removed under reduced pressure and the resulting material was chromatographea on silica gel eluting with a gradient of 15-20% EtoAc in hexanes affording 1.2 grams of the coupled material. LRMS M+K = 574 710(g) To a stirred solution of 1.2 grams of benzylether in 50 mL of MeOH was added 5 mL of acetic acid and 0.15 grams of paliadium black as an IPA slurry. The mixture was stirred under 1 ATM of H2 for 3 hours. The catalyst was removed by filtration and the volatiles were removed under reduced pressure affording 0.76 grams of the deprotected product. LRMS M+R = 494 710(h) To a stirred solution of 0.40 grams of the alcohol 710 (i) in 20 mL of anhvdrous CH2CI2 was added 0.89 grams of carbon tetrabrcmide and 0.70 g of triphenyl phosphine. The reaction was stirred 1 hour then poured into 10% agueous citric acid, separated and the aoueous was extracted 3 times with CH2CI2- Ali 4 CK2CI2 were combined and washed with H2O, brine and dried over MgS04. The solvent was removed under reduced pressure and the resulting material was chromatcgraņhed on silica gel eluting with a gradient of 25-50% EtoAc in hexanes affording 0.32 grams of the bromide 710(h). LRMS found (M+K)+ = 558 710 (;) To a sttrred, cooled (0°C) solution of 0.29 grams of bromide in 50 mL cf anhydrcus DM? was added 0.21 grams of CS2CC3 in one portion. Afcer stirring for 2 hours the mixture was poured inco EtoAc and washed two times wich 10% aqueous citric acid and 3 times with K2O. Ali aqueous were combined and extracted 5 times with EtOAc. Ali six EtOAc were combined, washed with H2O, two times with brine and dried over MgS04. The solvent was removed under reduced pressure and the resulting material was chromatographed on silica gel eluting with 20% EtOAc/hexanes affording 0.08 g (32% yield) of the macrocycle. LRMS found (M+H)+ = 476; (M+Na)+ = 498 710 00 To 0.150 grams of 710(j) was added 5 mL of TFA.
After stirring for 2 hours the volatiles were removed under reduced pressure affording 0.125 grams of the acid. LRMS (M+H)+ = 420 710(1) To a stirred solution of 0.073 grams of 710(k) in 8 mL of a anhyarous CK2CI2 was added 0.024 grams of HOBT, 0.077 mL of NMM, 0.033 grams of 0-benzylhydroxylamine hydrochloride and 0.043 grams of DEC. The reaction was stirred 2 hours then the volatiles were removed under reduced pressure. To the remaining material was added 3 mL of anhydrous DMF and 0.16 grams of 0-benzylhydroxylamine. The reaction was heated at 80° C for 45 minūtes then poured into EtOAc ar.d washed 5 times with 10 % aqueous citric acid. The combined aqueous was extracted 5 times witn EtoAc, and the 6 combined extracts were washed 2 times with H2O, twc times with brine and dried over MgS04. The resulting material was chromatographed on silica gel eluting with 3% MeOK/CHCl3 affording 0.079 grams of the 0-benzylhydroxamate.
Example 710: 4S.7R,SS-5-aza-6-oxo-12-cxa-7-isobutvl-2-(carboxvmethvl) - Γ121 oaracvclophane-8-N-hvdroxvcarboxamiQe To 10 mg in 5 mL of MeOK was added 25 mg of 5% ?d/3aSC4. Shaken under 50 psi K2 for 2 hours, filtered and -160- LV 12167 volatiies removed under reduced pressure affording 7 mg of hydroxamic acid. LRMS founc (M+K)+ = 435 759(a)To 0.035 grams of methyiester 710(1) in 3 mL of THF and 1 mL of H2O was added 0.13 mL of saturated agueous LiOH. The reaction was stirred 4 hours at room temperature and guenched with 2 mL of 1N HC1. The mixture was diluted with EtOAc and acidified with 1N HC1 and extracted three times with EtOAc. Ali 3 EtOAc were combined and washed with H2O, brine, dried MgS04 and solvent was removed under reduced pressure affording 0.025 grams of the acid. LRMS found (M+H)+ = 511; (M+Na)+ = 533
Exam.ple 759: 4S, 7R^8S-5-aza-6-oxo-12-oxa-7-isobutvl-2- (N-methvlcarboxam.ido' - ri2~!DaracvcloDhane-8-N-hvdroxvcarboxamide: A solution cf 0.C23 grams of acid 759(a) in 1 mL of DMF was added 15 mL of NMM,ana 0.016 grams of TBTU. After stirring 5 minūtes 16 mL of 40% agueous MMA was added and the reaction was stirred at room temperature for!5 minūtes diluted with EtoAc and washed 4 times with 10% aqueous citric acid. Ali 5 EtoAc were combined and washed with H2O, brine, and dried cver MgSG**. The volatiies were removed under reduced pressure and the resulting materiai was purified by prep-plate chromatograp’nv (1 mm with 0.25 mm concentratior. zone) eluting cnce wirh 3% MeOH/CHCls affording 0.011 grams cf the product. LRMS found (M+H)T = 524; (M+Na)’ = 546
To 11 mg in 10 mL of MeOH vas added 30 mg of 5% Pd/BaSC4- Shaker. under 45 psi H2 for 3 hours, filtered and volatiies removed under reduced pressure affording 7 mg of hydrcxamic acid Example 759. LRMS found (M+K;T = 434 -1
Example 869: 2S,13S.14R-1.7-diaza-8,15-diOXO-9-OXa-14- isobutvl-7-mer.hvl-2- (N-methvlcarboxamido) -cvclopentadecane-13-N-hvdroxvcarboxamide 869(a). To a solution of che alcohol intermediate l(d) (11.4 g, 33.1 mmol) and 4-nicrophenyl chloroformate (10.0 g, 50 mmol) in 50 mL CH2CI2 cooled in an ice bath was slowly added N-methylmorphcline (4.4 mL, 40 jnmol} and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was taken up in 200 mL EtOAc.The solution was washed with brine 3 times, dried (MgSOi) and concentrated. Purification on a silica gel column using 10% EtOAc/hexane gavē the desired product (15.0 g, 91%) as a pale yellow solid. DCI-MS: calcd (M+NK4)+=561; found 561. 8o9(b). To a solution of 869(a) (15.20 g, 27.28 mmol! and
Ntt-Cbz-t^-methvl-L-lvsine methyl ester HC1 salt (11.22 g, 32.78 mmol) was added potassium carbonate (15 g, 109 mmol) and the mixture was heated at 50 *C for 1 hour. Insoluble material was filtered off and EtOAc was added. The solution was washea wtth 10% citric acid, brine, NaHCCb and brine, dried (MgSOi) and ccr.centrated. Purification on a silica gel columr. using 15% EtOAc/hexane gavē an oily product (17.0 g, 91%). ESI-M5: calcd M+l=713.5; found 713.7. 869(c). 869(b! (10.0 g, 14.02 mmol) was dissolved in 33 mL MeOH and the soluticr. was hydrogenated_ for 1 hour under atmospheric pressure using 10% Pd-C (1.0 g) as catalvst.
The catalyst was filtered off and the solution was concentrated to give an oily product (6.8 g, 100%). ESI-MS: calcd M+1=489.4; found 489.6. 869(d). To a soluticr. of BO? (9.2-g, 20.8 inmoi! and diisopropy 1 ethy 1 amiue (12 mL, 70 inmol) in 600 mL CHC1; cooled in ar. ice bath was arcpwise added a solution cf 869(c) (6.8 g, 13.9 mmol) in 50 mL CHCI3 over 2 hours and LV 12167 the mixture was stirred at room cemperature overnight. CHCI3 was removed in vacuo and EtOAc was added. The solution was washed with 5% citric acid, brine, NaHC03 and brine, dried (MgS04) and concentrated. Purification on a silica gel column using 4% MeOH/CH2Cl2 gavē the cyclic product (3.4 g, 46%) as a powder. ESI-MS: calcd M+l=471.4; found 471.5. 869 (e). 869(d) (2.6 g, 5.5 mmol) was treated with 20 mL 50% TFA in CH2CI2 for 1 hour and the solution was concentrated to give an cily product (2.3 g, 100%). ESI-MS: calcd. M+l=415.3; found 415.4. 869(f). To a solution of 869(e) (2.2 g, 5.3 mmol) and 0-benzylhydroxylamine hydrochloride (0.96 g, 6.15 mmol) in 10 mL DMF cooled in an ice bath was added
Diisopropylethylamine (4.3 mL, 24.6 mmol) followed by BOP (2.72 g, 6.15 mmol) and the solution was allowed to stir overnight. EtOAc was added and the solution was washed with 5% citric acid, brine, NaHC03 and brine, dried (MgSOi) and concentrated to give a crude product which was washed with ether to give the desired product as a pure solid (2.9 g, 90%). ESI-MS: calcd. M-l=520.5; found 520.5. 869(g). 869(f) (0.5 g, 0.96 mmol) was treated with 5 mL THF and 4 mL 1 N LiOK for 1 hour and the solution was acidified with TFA and concentrated. EtOAc was added and the solution was washed with brine, dried (MgS04) and concentrated to give the acid as a solid (0.3 g, 63%). ESI-MS: calcd M^l=506.5; found 506.Ξ. 869(h) To a solution cf 869(g) (0.2 g, 0.396 mmol) and methylamine hvdrochloride (0.11 g, 1.58 mmol) in 2 mL DMF cooled in an ice bath was added BOP (0.13 g, 0.4 mmol) fcllowed by diisopropyiethylamine (0.52 mL, 3 mmol). The mixture was ailowed tt stir at room temperatūra for 2 hours. EtOAc was added and the product precipitated cut. -1
The precipicate was filtered and washed with EtOAc and water to give the title compound as a solid (0.15 g, 73%) . ESI-MS: calcd M+l=519.4; found 519.5.
Exampie 869: 869 (h) (120 mg, 0.23 inmol) in 5 mL MeOH was hydrogenated for 30 min at atmospheric pressure using 10% Pd-C (40 mg) as cataiyst. The catalyst was filtered off and the solution was concentrated. Purification on reversed phase HPLC afforded the final product as a powder (81 mg, 82%). ESI-MS: calcd M+l=429.3; found 429.4.
Example 871: 2S,13S,14R-1.7-diaza-8.15-dioxo-9-oxa-14- isohutv.l-7-methvl.-2- (alvcine-N.N-dimethvlamide) -cv.clopentadecane^3-N-hv.droxvcarboxamide
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=500.5? found 500.5.
Example 880: 2S.13S.14R-1.7-diaza-8,15-dioxo-9-oxa-14- ischutvl-7-methvl-2-(alvcine-N-methvlamide)-cvclot>entadecane-13-N-hvdroxvcarboxamide
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=486.3; found 486.5.
Exampie 904: 2S.13S.14R-1.7-diaza-S.15-dioxo-9-oxa-14- isobutvl-7-methvl-2- >'alvcine- (4-methvl) N-pjperazinvlamidel -cvclopentadecane-13-N-hvdroxvcarboxamide trifluoroacetate
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=555.6; found 555.5. -164- LV 12167
Example 908: 2S,13S,14R-1,7-diaza-8.15-dioxo-9-oxa-14- is.obut:vl-7-methvl-2- falvcine-N-morpholinoamidel -cvclopentadecane-13-N-hvdroxvcarboxamide
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=542.4; found 542.5.
Exampie 910: 2S.13S.14R-1.7-diaza-8.15-dioxo-9-oxa-14- isobutvl-7-methvl-2- r f2-Pvridvl) carboxamido1 -cvclopentadecane-n-N-hvdroxvcarboxamide
This compound was prepared using the procedures analogous to Example 869. ESI-MS: found 555.7
Example 916: 2S,13S.14R-1.7-diaza-8.15-dioxo-9-oxa-14- is.ob-U t v 1 - 7 - me t hvl^ 2 - . Π 2 - pv r i dv 1) carboxarldo1 -cvclopentadecane-13-N-hvdroxvcarboxamide
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=492.5; found 496.5.
Example 919: 2S,13S.14R-1.7-diaza-8.l5-dioxo-9-oxa-14- isobutvl-7-methvl-2- folvcine-2-pvridvlamide)-cvclopentadecane-13-N-hvdroxvcarboxamids
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=549.4;.found 549.5.
Example 92 6: 2S, 13S. 14R-1.7-diaza-8.15-dioxo--3-Sxa-14- isobutvl-7-methv:-2-Γ2-'5-methvlthiazolvDcarbOKamido1-cvclopentadecane-13-N-bvdroxvcarboxamide
This compound was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=512.3; found 512.4.
Example 927: 2S.13S,14R-1.7-diaza-8.15-dioxo-9-oxa-14- ispbu£yl-7-meEhvl-2-_rqlvcine-2- (3.4.5.6- tetrahvdropvridvl)amidel-cvclopentadecane-13-Ν-hvdroxvcarboxamide
This compour.d was prepared using the procedures analogous to those for Exampie 869. ESI-MS: calcd. M+l=553.6; found 553.6.
Example 928: 2S,13S.14R-1.7-diaza-8.15-dioxo-9-oxa-14- l£.obutvl-7-methvl-2-_l.alycine-2- (5-methvl) thiazolvlamidel -CYClopentadecane-13“N-hvdroxvcarboxamide trifluoroacetate
This compour.d was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=569.3; found 569.3
Example 929: 2S.13S.14R-1. 7-diaza-8.15-dioxo-9-oxa-14- iSQbutvl-7-methvl-2- iN- (2-pvTidvl)methvlcarboxamidol -cvclo pentadecane-13-N-hvdroxvcarboxamide trifluoroacetate
This compour.d was prepared using the procedures analogous to those for Example 869. ESI-MS: calcd. M+l=506.3; found 506.5.
Example 1175: 25,13S.14R-1.7-diaza-8.15-dioxo-9-oxa-14- (3- sher.V-1 oropvlJ -~-methvl-2- (N-irorpholir-scarboxamido) -cvcl ooer.t a-decane-13 -N-hvdroxycarboxaTd de
This compound was prepared using the procedures analogous to those above. ESI-MS: calcd. M-rl=547.4; found 547.4. --00- LV 12167
Example 1176: 2S J.2&..14R-1.7-dia2a-8.15-dioxo-9-oxa-14- (3-phenvl propvl)-7-methvl-2-(f4-methvl)N-oiperazinvlamide)-Cvclasen.ta-de,cane-.12-N-hvdroxvcarboxamide trifluoroacetate
This compound was prepared using the procedures analogous to those above. ESI-MS: calcd. M+l=560.4; found 560.6.
Exampie 1228: 25,_135,.14R-1. 7-diaza-8.15-dioxo-9-Qxa-14- (3- phenvl -DgQPVlž.-7-methvl-2- (N-methvlcarboxamido) -evclopenta-decar.e-13-N-hvdroxvcarboxamide
This compound was prepared using the procedures analogous to those above. ESI-MS: calcd. M+l=491.3; found 491.5.
Exampie 1442: 2.S.J.15.I2R-1,7-Piaza-8. l3-dioxo-12- isobutvlcvclotridecane-2-(clvcine N-methvl amide)-11-(N-liYdroxycarfroxaniide). 1442(a): To a solution of the succinate l(c) (2.7 g, 9.4 mmol) and NE-benzyloxycarbonyl-L-lysine methyl ester (4.6 g, 14.0 mmcl) in DMF (10 mL) was added diisopropylethylamine (4.1 ml, 23.4 mmcl) and BO? (4.9 g, 11.2 mmol). After stirring overnight, etnyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCC>3 solution, and brine. The ethyl acetate was dried (MgS04) and concentrated. The resultinc residue was purifiea by silica gel chromatography to yieid the amide (4.1 g, 77%) as a white foam: ES-MS (M+H)+ 565.5. 1442 (b) : Ccmpour.d 1442(a) (2.0 g, 3.5 mmcl) was dissolved in a mixture ci CH3CN (8.3 mL), CC14 (8.3 mL), and H2O (12.3 mL). At room temperature, HsIOs (3.7 g, 16.2 mmol) and RuCl3*H20 (16.4 mg, 0.08 mmol) were added. After 1.5 h, 10% citric acid was added and the layers were separated. The orgar.ic laver was dried and concentrated. The resultir.g residue was purtfied by silica cel chromatography to yieid the acid (l.i g, 56%) as a white foam: ES-MS (M+H)+ 579.5. -16"- 1442(c): Compound Example 1442(b) (500 mg, 0.8 mmol) was hvarogenated in MeOK (10 mL) with 5% Pd/C-Degussa (58 mg) under a hydrogen atmosphere (40 psi). After stirring overnighc, the catalyst was filtered off and the solucion was concentrated to yield the amino acid (370 mg, 97%) as a white foam: ES-MS (M+H)+ 445.5. 1442(d): To a solution of HBTU (375 mg, 1.0 mmol) and NMM (0.07 mL, 0.7 mmol) in DMF (5 mL) at 60'C was added compound 1442 (c) (100.0 mg, 0.2 mmol) in DMF (5 mL) . After the addition was complete, the mixture was stirred an additional 30 min. The solution was concentrated and silica gel chromatography afforded the lactam (60 mg, 63%) as white solid: ES-MS (M+H)+ 427.5. 1442(e): Compound Example 1442(d) (250 mg, 0.6 mmol) was dissclved in CH2CI2 (2 mL) and TFA (2 mL). After stirring overnighc, the solution was concentrated to affcrd the crude acid (220 mg) , which was dissolved in DMF. To the DMF was added 0-benzylhydroxylamine (157 mg, 1.3 mmol), diisopropyīethylamine (0.2 mL, 1.1 mmol), and BOP (334 mg, 0.7 mmol). After stirring ovemight, the solid product was filtered from the solution to give the 0-benzyl hydroxamate (165 mg, 60%): ES-MS (M+H)+ 476.4. 1442 (f) : Compound Example 1442 (e) (50 mg, 0.1 mmol) was dissolved in 1:1 THF/MeOH (8 mL) and 1M LiOH (0.5 mL, 0.5 mmol) was added. After 2 h, more 1M LiOH (0.5 mL, 0.5 mmol) was added. The reaticn was stirred an addition 1.5 h before the sclvent was removed. The remaining H2O was acidified witn IN HC1 and was extracted with CHCI3. The CHCI3 was driea (MgSŪ4) and concentrated to give the acid (52 mg, 86%) as a white foam: ES-MS (M+H) + 371.4.
1442(g): To a solution of Compound 1442(f) (70 mg, 0.15 mmol) and glvcine N-methyl amide (29 mg, 0.25 mmol) ir. DMF -168- LV 12167 was added diisopropylethylamine (0.06 mL, 0.37 mmol) and HBTU (85 mg, 0.25 mmol). After stirring overnight, the sciid product was filtered from the solution to give the coupled glycine (60 mg, 75%) as a white solid: ES-MS (M-rH)* 532.4.
Example 1442: Compound Example 1442(g) (60 mg, 0.1 mmol) was hydrogenated in a MeOH-CHCl3 mixture (3:1, 15 mL) with 5% Pd/BaS04 (120 mg) under a hydrogen atmosphere (40 psi). After stirring 3.5 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (20 mg, 41%) as a white solid: ES-MS (M+H)+ 442.4.
Example 1443: 2S.11S,12R-1.7-Diaza-8 .13-dioxo-12- isobutvlcvclotridecane-2- (L-alanine-a-N-methvl amide' -11-(N-hvdroxvcarboxamide) . 1443(a): To a solution of Compound Example 1442(f) (80 mg, 0.17 mmol} and L-alar.ine N-methyl amide (23 mg, C.22 mmol) in DMF was added NMM ;0.06 mL, 0.52 mmcl) and HBTU (256 mg, 0.69 mmol}. After stirring overnight, the solid product was filtered from the solution to give the coupled material (66 mg) , which was aissolved in a MeOH-CHCl3 mixture (3:1, 30 mL) . This was hydrogenated with 5% Pd/BaS04 (150 mg) under a hvdroger. atmosphere (50 psi) . After stirring 3 h, the catalvst was filtered off and the solution was concentrated tc vield the title hydroxamate (27 mg, 45%) as a yellowish solid: ΕΞ-MS (M+H)+ 456.4.
Example 1447 : 2S,11S,12R-1,7-Diaza-8,13-dioxo-12- 1 soh.utvlcvclotriQecar.g-2- (I-serine-n-N-methv] ami de) -11- (N-hvdroxvcarboxa.Td.de) . 1447 (a; : To a soluticr. of Compound Examgle 1442 (f) (7C0 mg, 1.5 mmol) and L-serir.e N-methvl amide (234 mg, 1.9 mmcl' in DMF was added NMM (0.5 mL, 5.4 mmol) and HBTU (2.2 mg, 5.9 mmol). After stirring overnight, the sciid product wa= filtered from the solution to give the coupled material (640 mg) , which was dissolved in a MeOH-CHCl3 mixture (3:1, 300 mL) . T'nis was hvdrogenated with 5% Pd/BaS04 (1.6 g) under a hydrogen atmosphere (50 psi). After stirring 3 h, the catalvst was filtered off and the solution was concentrated to yield the title hydroxamate (250 mg, 47%) as a yeilowish solid: ES-MS (M+H) + 472.4.
Example 1462: 2S. 11S. 12R-1.7-Dia2a-8.13-dioxo-2- (N- methvlra.rboxamido) -12-isobutvlcvclotridecane-ll- (N-hvdroxvcarboxamide). 1462(a): To a solution of the succinate l(c) (170 mg, 0.6 mmol) and Nt-benzyloxycarbonyl-L-lysine N-methyl amide (224.6 mg, 0.8 mmol) in DMF (6 mL) was added diisopropylethylamine (0.26 mL, 1.5 mmol) and BOP (286.9 mg, 0.6 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCOj solution, and brine. The ethyl acetate was dried (MgSŪ4) and concentrated. The resulting residue was purified by silica gel chromatography to yield the amide (255 mg, 77%) as a white foam: ES-MS (M+H)* 564.4. 1462(b): Compound Example 1462(a) (813 mg, 1.4 mmol! was dissolved in a mixtura of CH3CN (3 mL), CCI4 (3 mL) , and H2O (4.5 mL! . At room temperature, K5IO6 (1.3 g, 5.9 mmol' and RuCl3»H20 (6 mg, 0.03 mmol) were added. After 1.5 h, 10% citric acid was added and the layers were separated. The organic layer was dried and concentrated. The resulting residue was purified bv silica gel chrcmatographv to vield the acid (504 mg, 60%' as a white foam: ES-MS (M+H)* 578.5. 1462 (c) : Compcund Example 1462 (b). (45 mg, 0.08 mmol) was hvdrogenated in MeOH (5 mL) with 5% Pd/C-Degussa (15 mc) under a hvdrcgen atmosphere (50 psi). After stirring overnight, the catalvst was filtered off and the solution LV 12167 was concentrated to yield the amino acid (32 mg, 90%) as a whice foam: ES-MS (M+H)+ 444.4. 1462(d): To a solucion of HBTU (769 mg, 2.0 mmol) and NMM (0.15 mL, 6.0 mmol) in DMF (10 mL) at 60’C was added compound 1462 (c) (200.0 mg, 0.4 mmol) in DMF (10 mL) dropwise. After the addition was complete, the mixture was stirrea an additional 30 min. The solution was cor.centrated and silica gel chromatograpny afforded the lactam (135 mg, 70%) as light yellow solid: ES-MS (M+H)+ 426.3. 1462(e): Compound Example 1462(d) (85 mg, 0.2 mmol) was dissolved in CH2CI2 (2 mL) and TFA (2 mL) . After stirring overnight, the solution was concentrated to afford the acid (60 mg, auant.) as a white foam: ES-MS (M+H)+ 370.3. 1452(f): To a solution of compound Example 1462(e) (75.0 mg, 0.2 mmol) and 0-benzylhydroxylamine (78.8 mg, 0.6 mmol) ir. DMF (1.5 iri) was added diisopropylethylamine (0.07 mL, 0.4 mmol) and 30P (97.3 mg, 0.2 mmol). After stirring overnight, the sclid proauct was filtered from the solution to give the C-benzyl hydroxamate (58 mg, 61%): ES-MS (M+K)* 475.3. 1462: Compound ExampLe 1462 (f) (50 mg, 0.1 mmol) was hydrogenated in a MeCH-CHCi3 mixture (3:1, 40 mL) with 10% Pd/C (20 mg) under a hydrogen atmosphere (balloon). After stirring 6 h, the catalyst was filtered cff and the solution was concentrated to vield the tītie hydroxamate (38 mg, 93%) as a white foam.: ES-MS (M-H)+ 385.4.
Example 1473 : 2S.11S,12R-1.7-pjaza-8.13-dioxo-12-isobutvlcvclctridecane-2- (B-alanine N-meohvl amide'. -11- (N-hvdroxvcarhoxamide). 1473(a): To a solution of Compound Example 1442 (f) (100 mg, 0.22 mmol) and β-glvcine N-methyl amide (29 mg, 0.28 iranol) ir. DMF was added NMM (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 the coupled material (80 mg), which was dissolved, in a MeOH-CHCl3 mixture (1:1, 30 mL). This was hydrogenated with 5% Pd/BaS04 (180 mg) under a hydrogen atmosphere (balloon). After stirring 3 h, the catalyst was filtered off and the solution was concentrated to yield the tītie hydroxamate (70 mg, quant.) as a white solid: ES-MS (M+H) + 456.4.
Example 1491: 2S.11S.12R-1.7-Diaza-8.13-dioxo-12- isobutvlcvclotridecane-2- (Kg-H-L-lvcine-a-N-H-amide trif luoroacetate.) -11- (N-hvdroxvcarboxamide) . 1491(a): To a solution of Compound Example 1442(f) (5C mg, 0.11 mmol) and NE-ber.zyloxycarbonyl-L-lycine amide (4i mg, 0.13 mmol) in DMF was added diisopropylethylamine (0.05 mL, 0.27 mmol) and 30P (57 mg, 0.13 mmol). After stirring overnight, the solid product was filtered from the solution to give the coupled Ivcine (53 mg, 72%) as a white solid: ES-MS (M+H)~ 723.4. 1491: Compound Exampie 1491(a) (60 mg, 0.1 mmol) was hvdrogenated in a MeCH-CKCl3 mixture (3:1, 15 mL) with TFA (1 mL) includir.g 5% ?d/BaS04 (150 mg) under a hydroger. atmosphere (40 psi) . After stirring 5 h, the catalvst was filtered off and the solution was concentrated to yieid the title hydroxamate (21 mg, 45%) as a white solid: ES-MS (M+K)+ 499.5.
Example 1930: 2S.11S,12R-1.7-Piaza-g.13-dioxo-2-(N-methvlcarboxamido) -12-isobutvlcvclQtrič5canerll- (N-hvdroxvcarboxamide' hvdroaen chloride. LV 12167 1530(a): Compound Example 7(c) {56 mg, 0.12 mmol) was dissolved in 4 M HCl/dioxane (2 mL) ac room temperature. After 3 h, the solvent was removed co yield the amine salt (45 mg, quant.) as a pale yellow solid: ES-MS (M+H)+ 471.4.
Example 2038: 2S.11S.12R-7-N-Benzenesulfonvl-1.7-Diaza- 8,13-dioxo-2-(N-methvlcarboxamido) -12-isobutvlcvclocridecane-ll- m-hvdroxvcarboxamide) . 2038(a): To a solution of the succinate l(c) (460.0 mg, 1.6 mmol), Ne-benzenesulfonyl-L-lysine N-methyl amide (696.5 mg, 2.1 mmol), and diisopropylethylamine (0.84 mL, 4.8 mmol) in DMF was added BO? (849.6 mg, 1.9 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCCh solution, and brine. The ethvl acetate was dried (MgS04) and concentrated. The resulting residue was purified by silica gel chromatography to yield the amide (833 mg, 90%) as a white foam: ES-MS (M*H)+ 570.3. 2038 (b) : Compcur.d Example 2038{a) (875.0 mg, 1.5 mmcl' and ?Ph3 (1.21 g, 4.6 mmol) were dissolved in THF (137 ml). DIAD (0.88 mL, 4.5 mmcl) in THE (27 mL) was added dropvise to the mixture. After stirring overnight, the solution was concentrated ar.d the residue was purified by silica gel chromatograpny to yield the cyclic material (470 mg, 55%) as a white solid: ES-MS (M+H;* 552.3- 2038 (c) : Compound Example 2038Γο) (473.0 mg, 0.86 mmcl'· v/as dissolved in CH2CI2 (5 mL) and TFA (5 mL). After stirring overnight, the solution was concentrated to afford the acid (500 mg, quant.; as a white solid: ES-MS (M+H)+ 496.3. 2 03 8 (d) : To a solution of compound Example 2038(c) (261.0 mg, 0.52 mmol), C-benrylhydrcxylamine :192.0 mg, 1.6 mmol), and diisopropyl-ethylamine (C.13 mL, 1.0 mmol) in DMF vas added ΒΟΡ (278.0 mg, 0.63 mmol). After stirring overnight, the solid product was filtered from the solution to give the 0-ber.zyl hydroxamate (172 mg, 57%) : CIMS-NH3 (M+H) + 601.2. 2038: Compound Example 2038(d) (150.0 mg, 0.25 mmol) was hyarogenated in a MeOH-CHCl3 mixture (3:1, 50 mL) with 5% Pd/BaS04 (300 mg) under a hydrogen atmosphere (50 psi).
After stirring 3 h, the catalyst was filtered off and the solution was concentrated to yield 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- methvlcarboxamido)-7-N-trifluoromethanesulfonvl-12-isobutvlcvclotridecane-11-(N-hvdroxvcarboxamide). 2135(a): To a solution of the succinate l(c) (608.0 mg, 2.1 mmol), NE-trifluoromethanesulfonyl-L-lysine N-methyl amide (900.0 mg, 2.7 mmol), and diisopropylethylamine (1.09 mL, 6.3 mmol) in DMF (8 mL) was added BOP (1.12 g, 2.5 mmol). After stirring overnight, the DMF was removed and CH2CI2 was added. The CH2CI2 was washed with 10% citric acid, saturated NaKC03 solution, and brine. The CH2CI2 was dried (MgS04) and concentrated. The resulting residue was purified by silica gel chromatography to yield the crude amide (1.30 g), which was dissolved in THF (100 mL). PPhs (1.84 g, 7.0 mmol) was added followed by DIAD (1.33 ml, 6.8 mmol) in THF (35 mL). After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to yield the cyclic material (600 mg, 52%) as a white solid: E5-MS (Μ+Κ'χ 544.3 2135(b): Compound Example 2135(a) (300.0 mg, 0.55 mmol' was dissolved in CH2CI2 ¢4 mL) and TFA. (4 mL). After stirring overnight, the solution was concentrated to the acid, vhich was dissolved ir. DMF (6 mL) . To this solution was added O-benzylhydrcxylamine (146.0 mg, 1.18 mmol) and diisoprcņvl- LV 12167 ethylamine (0.19 mL, 1.0 minci) followed by BOP (270.0 mg, 0.61 mmol). After stirring overnight, the DMF was removed to give the 0-benzyl hydroxamate (190 mg, 58%): ES-MS (M+H)+ 593.4. 2135: Compound Example 2135(b) (180.0 mg, 0.3 mmol) was hvdrogenated in MeOH (35 mL) with 5% Pd/BaSC>4 (210 mg) under a hydrogen atmosphere (50 psi). After stirring 2.5 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (150 mg, 98%) as a solid: ES-MS (M+H)+ 503.3.
Example 2227: 2S.11S.12R-1.7-Diaza-8.13-dioxo-2-(N- met±ylcarboxamido) -7- (Pramino-N-benzenesulfonvl)-12-isobutvlcvclotridecane-11-(N-hvdroxvcarboxamide). 2227(a): To a solution of the succinate 1(c) (850.0 mg, 2.95 mmol), Nt-p-nitro-benzenesulfonyl-L-lysine N-methyl amide (1.45 g, 3.80 mmol), and diisopropylethylamine (1.54 mL, 8.80 mmol) in DMF was added BOP (1.56 g, 3.50 mmol). After stirring overnight, ethyl acetate was added and the solution was washed with 10% citric acid, saturated NaHCOj solution, and brine. The ethyl acetate was dried (MgSOJ and concentrated. The resulting residue was purified by silica gel chromatograp'ny to yield the amide (1.37 g, 75%) as a white foam: ES-MS (M+H) + **570.3. 2227(b): Compound Example 2227(a) (547.0 mg, 0.89 mmol) and P?h3 (700.1 g, 2.67 mmol) were dissolved in THF (30 mL). DIAD (0.50 mL, 2.5 mmol! in THF (6 mL) was added dropwise to the mixture. After stirring overnight, the solution was concentrated and the residue was purified by silica gel chromatography to yield the cyclic material (0.14 g, 26%) as a white foam: ES-MS (M+H)+ 597.4. 2227 (c) : Compound Example 2227(b) (24.0 mg, C.04 mmol) was hydrogenated in a MeOK-CHCl3 mixture (1:1, 2 mL) with 10% -175-
Pd/C (12 mg) under a hydrogen atmosphere (30 psi). After stirring overnight, the catalyst was filtered off and the solucion was concentraced to yield the amino compound (20 mg, 90%) as a white foam: ES-MS (M+H)+ 567.4. 2227(d): Compound Example 2227(c) (226.0 mg, 0.40 mmoi) was dissolved in CH2CI2 (2 mL) and TFA (2 mL) . After stirring overnight, the solution was concentrated to the crude acid, which was dissolved in DMF (4 mL). To this DMF solution was added 0-benzylhydroxylamine (108.0 mg, 0.88 mmol), diisopropyl-ethylamine (0.2 mL, 1.2 mmol), and BOP (230.0 mg, 0.52 mmoi). After stirring overnight, the solvent was removed to give the 0-benzyl hydroxamate (170 mg, 69%) .-ES-MS (M+H)+ 616.4. 2227: Compound Example 2227(d) (150.0 mg, 0.24 mmol) was hydrogenated in a MeOH-CHCl3 mixture (1.7:1, 19 mL) with 5% Pd/BaSC>4 (2 00 mg) under a hydrogen atmosphere (50 psi) . After stirring 4 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (107 mg, 84%) as a white solid: ES-MS (Μ+Η)+ 526.3.
Example 2323: 2S.11S.12R-1.7-Diaza-8.13-dioxo-2-(N-methvlcarboxamido) -7-N-mesitvlenesulfonvl-12_-isobutvlcvolotridecane-11-(N-hvdroxvcarboxamide). 2323(a): To a solution cf succinate l(c) (990 mg, 3.4 mmol) and Nt-mesityienesulfonyl-L-lycine N-methyl amide hydrcgen chloride (1.7 g, 4.5 mmol) in DMF was added diisopropylethylamine (1.8 mL, 10.2 mmol) and BOP (1.8 mg, 4.1 mmol). After stirring overnight, the DMF was removed and CH2CI2 was added. The solution was washed with 10% citric acid, saturated NaHCOļ solution, and brine. The CH2CI2 was dried (MgS04) and concentrated. The resultrng residue was purified bv silica gel chromatography to vield the crude amide (2 g) , which was dissolved in THF (138 mL) .. To the THF was added ?Ph3 (2.8 mg, 10.6 mmol) followed by LV 12167 DIAD (2 mL, 1C.1 inmol) in THF. After stirring overnight, che solucion was concentrated and the residue was purified by silica gel chromatography to yield the cyclic material (680 mg, 30%) as a yellowish solid: ES-MS (M+H)+ 594.5. 2323 (b): Compound Example 2323(a) (280 mg, 0.47 jnmol) was dissolved in CH2CI2 (3.5 mL) and TFA (3.5 mL) . After stirring overnight, the solution was concentrated to afford the crude acid, which was dissolved in DMF. To this DMF solution was adaed 0-benzylhydroxylamine (118 mg, 0.9 mmol), diisopropyl-ethylamine (0.15 mL, 0.8 mmol), and BOP (218 mg, 0.5 mmol). After stirring overnight, the solvent was removed to give the 0-benzyl hydroxamate (70 mg, 25%): ES-HS (M+H)+ 643.5. 2323: Compound Example 2323(b) (120 mg, 0.19 mmol) was hydrogenated in a MeOH-CHCl3 mixture (3:1, 28 mL) witn 5% Pd/BaS04 (180 mg) under a hydrogen atmosp'nere (50 psi).' After stirring 4 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (100 mg, 96%) as a white foam: ES-MS (M+H) + 553.5.
Example 2413: 5S,8R.9S-6-Aza-2.7-dioxo-5-(N-methvlcarboxamido)-l-oxa-8-isobutvlcvclododecane-9-(N-hvdroxvcarboxamide ’ 2413(a): To a solution of the succinate 1(c) (200 mg, C.69 mmol) and (L)-y-benzyl ester Glutamate-a-N-methyl amide (200 mg, 0.70 mmol) in DMF (6 mL) was added diisopropylethylamine (0.25 mL, 1.5 mmol) and BOP (305 mg, 0.63 mmol). After stirring overnight, the DMF was removed. The resulting residue was purified by silica gel chromatograņhy to yield the amide (255 mg, 70%) as an oil: ES-MS (M+H)+ 521.3. 2413(b): Compound Example 2413(a) (240.C mg, 0.46 mmol; was hvdrogenated in MeOK (5 mL) wi~h 10% Pd/C (25 mg) under a -177- hydrogen atmosphere (balloon). After stirring overnight, the catalyst was filtered off and the solution was concentrated to yield the acid, which was dissolved in THF (40 mL) . To the THF was added PPI13 (364.0 mg, 1.4 inmol) followed by DIAD (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 yield the cyclic material (45 mg, 24%) as a white solid: ES-MS (M+H)+ 413.3. 2413(c): Compound Example 2413(b) (200 mg, 0.49 mmol) was dissolved in CH2CI2 (5 mL) and TFA (5 mL) . After stirring overnight, the solution was concentrated to afford the acid, which was dissolved in DMF (50 mL). To this solution was added 0-benzylhydroxylamine (122.0 mg, 0.93 mmol) and diisopropyl-ethylamine (0.16 mL, 0.92 mmol) followed by BOP (226.0 mg, 0.5 mmol). After stirring overnight, the solid product was filtered from the solution to give the 0-benzyl hydroxamate (110 mg, 48%): CIMS-NH3 (M+H)+ 462. 2413: Compound Example 2413(c) (105 mg, 0.23 mmol) was hydrogenated in a MeOK-CHCl3 mixture (3:1, 40 mL) with 5% Pd/BaSC>4 (150 mg) under a hydrogen atmosphere (50 psi).
After stirring 2.5 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (100 mg) as a white sclid: ES-MS (M+H)^ 372.3. 2518 (a) Ng-t-Butvloxvcarbonvl-Ng-benzvloxvcarbonvl-L-Lvsine N-methvl amide.
To a solution of Na-Butyloxycarbonyl-Ne-benzyloxycarbonyl-L-Lysine (12.39 g, 32 mmol) and methylamir.e hydrochloride (4.4 g, 65 mmol) in 30 mL DMF cooled in an ice bath was added BOP (14.16 g, 32 mmol) foilowed by diisopropyiethylamine (25 mL, 128 mmol). The solution was allowed to stir at rccn temperature overnight. Ethyl acetate (150 mL) was added and the solution was washed with 10% citric acid, brine, saturated NaHCOs and brine, dried -178- LV 12167 (MgSC<ļ), and concentrated. Purification on a silica gel column using 80% EtCAc/hexane gavē 12.92 g (95%) product. ES-MS (.M+H)*: calcd 3 94.3; found 394.4. 2518 (b). tf-benzylQXvrcarbonvl-L-Lvsine N-methvl amida
Mrgcruaridž,
Compound Example 2518 (a) (6 g, 15.26 mmol) was dlssolved in 25 mL of 4 N HCi in dioxane. After stirring at room temperature for l hour, the solution was concentrated. The residue was trituraced with ether to give 5.2 g (100%) product. ES-MS (M+H)+: Calcd 294.2; found 294.3. 2518 (c). 4-Methvloentanoic acid 4(S)-phanvlmethvl-2-oxazolldinonamlde.
To a sclution of 4(S)-phenylmethyl-2-oxazolidinone (48.3 g, 272 minci) in 500 mL TKF cooled to -78°C was added 131 mL of 2.5 M n-butyilithium (327 mmol) in hexane over 20 min and the sclution was stirred at -78°C for 45 min. To it was added 4-methylpentancy chloride (44 g, 327 mmcl) and the SOiuticr was stirred at room temperature for 2.5 hours and guenched with ethyl acetate. The solvents were removed by concentratior. to a small amount and 500 mL ethyl acetate was added. The sclution was washed with 10% citric acid, water. NaHCOj and brine, dried (MgSCU). and concentrated. Purification on a silica gel column using 10% ethyl acetate in hexane as eluer.c gavē 68.53 g (91.5%) oily product. ES-MS (M+H)+: calcd 276.2; found 276.3. 2518 (d) . 3-n-Butc.v/carhcnvl-3 (R. S) -hvdroxv-2 (R) -isobutvlpronionir acid 4 i S)-Dhenvlm&¢hvl-2-oxazolidinonamide-
Tc a solution of diisopropylethylamine (3.25 mL·, 23.25 mmol) in 20 mL THF cooled to -78°C was added 9.3 mL of 2.5 M n-butyllithium (23.25 rmol) in hexane and the solution was warmed tc 0°C for 30 min and then cooled to -78°C. The resulting soluticr. was added to a sclution cf Example 2518(c) (5.82 g, 21.13 mmol) in 50 mL dry THF cooled to -179- -78°C over 20 min and the mixture was stirred at -78°C for 1 hour. To it was added a solution of n-butyl glyoxalate (4.12 g, 31.69 iranol) in 10 mL dry THF cooled to -78°C over 20 min and the mixture was stirred at -78°C for 3 hours.
The rsaction was auenched with ice waoer. 2thyl acetate was added followed by 10% citric acid. The organic layer was separaoed, washed with water, NaHC03 and brine, dried (MgSOi), and concentrated. Purification on a silica gel column using 5% ethyl acetate, 10% ethyl acetate and 20% ethyl acetate in hexane gradually as eluent gavē 3.1 g (35%) ciiy product. ES-MS (M+H!+: calcd 406.3; found 406.2. 2518(e). 3Tn-Butoxvcarbonvl-3(R.S)-hvdroxv-2(R)- iegbusvloropignic acid.
To a solution of the compound Example 2518(d) (5.1 g, 12.57 mmol) in 250 mL TKF/H2O (4:1) cooled in an ice bath was added hydrogen peroxide (7.84 mL, 50.3 mmol) followed by a solution of LiOH (791 mg, 18.85 rranol) in 8 mL water. After 1 hour, the reaction was qenched with a solution of Na2S03 (6.33 g, 50.23 mmcl). THF was removed by concentration under reduced pressure and the solution was extracced v/ith with ethyl acetate twice. The water layer was acidified with cold concentrated HC1 to pH 3 and extracted 3x with CH2CI2. The organic solution was washed with water and brine, dried (MgS04) and concentrated. Purification on a silica gel column using CHC13, 5% MeCH/CHC13 and then 10% MeOH/CHCl3 as eluents gavē 2.29 g (74%) oily product. CI-MS {M+NK4) +1 calcd 264.1; found 264.0. 2518(f). Benzvl 3-n-butoxvcarbnnvl-3 fR. 9)-hvdroxy-2 (R) -isgbucYlprQPiQnat£d, A solution of Exair.ple 2518 (e) (8.33 g, 33.82 mirto!), benzyi bromide (7.0 g, 37.2 rranol) and OSU (6.07 mL, 40.58 mmol) in 100 mL benzene was heated at 50°C for 3 hours and concentrated. Ethyl acetate was added and the solution was washed wich brine 3x, dried (MgSC*), and concentrated. Purification on a silica gel column using 10% ethyl -18Q- LV 12167 acetate/hexane as eluenc gavē 9 g (79%) oiiv product. ES-MS (M-H)*: caicd 337.3; found 337.3. 2518(g). Benzvl 3-n-butoxvcarbonvi-3 (R,3)-t-butoxvcarbonvlmethcxv-2 (R) -isobutvloropionate. A solution of Example 2518 (f) (8.95 g, 26.64 mmol) and t-butyl bromoacetate (4.33 mL, 29.3 mmol) in 50 mL THF was cooled to 0°C and to it was added NaH (1.5 g,60% oil dispersion, 32 mmol). The mixture was stirred at 0°C for 30 min and at room tenperature for 2 hours. THF was removed by concentration. Ethyl acetate was added and the solution was washed with 10% citric acid and brine/ dried (MgSOi), and concentrated. Purification on a silica gel column gavē 8.6 g (71%) product. ES-MS (M+H)+: caicd 431.3; found 451.4. 2518 (h). 3-n-Butoxvcarbonvl-3 (R. 9) -t-buto»^rbonvlinethQxy-2(R)-isobutvloropionic acid.
Compound 3xampie 2518(g) (5 g, 11.11 mmol) was hydrogenated in 25 mL isopropanol in the presence of 1.4 mL 4 N HCl/dioxane' using 10% Pd/C as catalyst at atmospheric pressure for 3 hours. The catalyst was filtered off and the solution was concentrated to give 3.96 g (99%) product. 23-MS (M+K)+: caicd 361.3; found 361.4. 2518(1). 3-n-Butoxvcarbonvl-3(R.3)“t-butoracarbonvlinetžmv-2 (R) -isobutvlpropiQnovl>^-benzvloxvrcagbon^l-L-lvaine N-methvl ainide.
Compound Example 2518(h) (1.76 g, 4.88 mmol) and compound Ejcample l(b) (1.61 g, 4.38 mmol) were dissclved in 10 mL DMF and the solution was cooled in an ice bath. To it was added BOP (2.16 g, 4.88 mmol) followed by diisopropylethylamine (3.42 mL, 10.58 mmol',. After stirring at room temperature for 4 hours, ethyl acetate was added and the solution was v/ashed with 10% citric acid, brine, NaHC03 and brine. dried (MgS04), and concentrated. Purification on a silica gel column using 10% MeOH/CHCl3 as -181- eluent gavē 2.32 g (75%) product. ES-MS (M+H)*: calcd 636.4; found 636.6. 2518(3). 3-n-But-.oxvcarbonvl-3 fR.S) -carboxvTne-hoxv-2 (R) -iscbucvlBroaionovl-L-lvsina N-methvi amide.
Compound Example 2518 (i) (2.21 g, 3.47 mmol) was hydrogenated in 15 mL isopropanol in the presence of 4 N HCl/dioxane (1 mL) for 2 hours using 10% Pd/C (0.35 g) as catalyst. The catalysc was filtered off and the solution was concentrated. The residue was taken up in 4 N KCl/dioxane (30 mL). The solution was stirred for 2 hours and concentrated to give 1.78 g (99%) producc. ES-MS (M+H)*: calcd 446.3? found 446.4. 2518(k) BOP (1.64 g, 3.7 mmol) was dissolved in 30 mL CHCl} and the solution was cooled in an ice bath. To it were added compound Exampie 2518 (j) (1.78 g, 3.7 mmol) and diisopropylethylamir.e (2.6 mL, 14.6 mmol) in 50 mL CHCI3 over 2 hours. The solution was allowed to stir at rocm temperature' overnight and concentrated. The residue was taken up in ethyl acetats and the solution was washed with 10% citric acid, brine, NaHCOj and brine, dried (MgSC>4) , and concentrated. Purification on a silica gel column using 15% MeCH/CH2Cl2 as eluent gavē 0.8 g (50%) product. ES-MS (M+H)*: calcd 428.3; found 428.3. 2518(1) 'Čompound Example 2518 (k! (0.77 g, 1.8_mmol) was treated with 4 mL 1 N LiOH in 20 mL THF for 2 hours and the solution was acidified with 4 N HCl/dioxane to pH 3. t-Butanol was added and the solution was washed with brine 3x, dried (MgS04) and concentrated to give 0.49 g (73%) product. ES-MS (M+H)*: calcd 372.3; found 372.2. 2518(m) To a solution cf compound Example 2518(1) (0.47 οι. 27 mmol) and C-benzylhydroxylamine hydrochloride (0.2 5. 1.27 mmol) :n 5 mL DMF cooled in an ice bath was added BC? (0.56 g, 1.27 mmol) followed by diisoprcpylethylamine (1-0 -182 LV 12167 mL, S.2 irmol) . The solution was allowed to stir at rcom temperature ovemight. Ethyl acetate was added and the solution was washed with 10% citric acid, brine, NaHC03 and brine, dried (MgS04) and concencrated. Purification on a silica gel column using 5% MeOH/CH2Cl2 gavē 0.13 g (21%) of the first isomer and 80 mg (14%) of the second isomer. ES-MS (M-+H) *: calcd 477.3; found 477.3 (both isomers).
Example 2518: Ccnpound Example 2518(m), isomer 1 (100 mg, 0.21 mmol) was hydrogenated in 5 mL MeOH for 2 hours at atmospheric pressure using 10% Pd/C (15 mg) as catalyst.The catalyst was filtered and the solution was concencrated to give 5C mg (62%) prcduct. ES-MS (M+H)+: calcd 387.3; found 387.3.
Compound Example 2518(m), isomer 2 (50 mg, 0.105 mmol) was hydroger,ated in a similar manner to give 2 0 mg (50%) product. ES-MS (M*H)*: calcd 387.3; found 387.3.
Exampīe 2519
This compctind was synthesized in a manner analogous to that described in above. ES-MS (M*H)*: calcd 44S.3; found 449.3.
Example 2703: 2708 (a). Na-t-Butvloxvcarbonvl-Ng-_trifluorc-L-Lvsine K-methvl amide.
To a solution of Na-t-Butylcxycarbonyl-Ne-trifluoro-L-Lysine (10.27 g, 30 mmol) and methylamine hydrochloride (4.05 q, 60 mmol) in 30 mL DMF ccoled in an ice bath was added BC'P (13.27 g, 30 mmol) followed by diisopropylethylam.ine (23.5 mL, 135 mmol) and the mixture was stirred at room temperatūra ovemight. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCOj and brine, dried (MgS04) , and concentraced. Crystallization from ethyl acetate-ether gavē 10.1 g (94.8%) product. m.p. 95-93°C. ES-MS (M-H)*: calcd 356.2; found 356.3. -183- 2708 (b). m-t-Bu.tvloxvcar bon vl-Eg-met hyl- N8- c r 1 ff 1 uor o - l -Lvslne N-m°r.hvl amide. A mixture of compound 2708 (a), ioctomethane (14 mL,223 mmol) and potassium carbcnate (7.7 g, 56 mmol) in 50 mL DMF was stirred at 100°C cvemight and insoluble mterial was filtered off. Ethyl acetate was added and the solution was washed with cicric acid, brine, NaHC03 and brine, dried (MgSO<), and concentrated. Purification on a silica gel column gavē 4.45 g (43%) product. ES-MS (M+H)^: calcd 370.2; found 370.3. 2708 (c). NgT.t-Burvloxvcarbonvl>Ng-meĒhvl-L-Lvfiine N-methvl ^iide.
Compound 2708 (b) (4.'35 g, 11.78 mmol). was treated with 14.5 mL 1 N NaOH in 20 mL MeOH for 30 min and the solution was concentrated. The residue was taken up in chloroform and insoluble material was filtered off. The filtrate was concentrated to give 3.65 g (100%) product. ES-MS (M+H)·*·; calcd 274.3; found 274.5. 2708 (d.) . Kg-t-3unvloxvcarbonvl-tg-methvl-Ī*-f Γ (1 (R.S) -n- butoxvcarbcnvl~2(R)-ben2vloxvcarbonvl-3- methvl)pentvIoxv1acetvl)-L-Lvsine N-methvl amide.
Compound 2518(g) (3.5 g, 7.77 mmol) was treated with 25 mL 4 N HCl in dioxane for 2 hours and the solution was concentrated. The residue was taken up in 15 mL DMF and the solutiotl was cooled in an ice bath. To it was added compound 4(c) (2.4 g, 7.77 mmol) followed by BOP (3.44 g, 7.77 mmol) and diisopropylethylamine (4.74 mL, 27 mmol).
The mixture was stirred at room temperature overnight.
EtOAc was added and the solution was washed with citric acid, brine, NaHC03 and brine, dried (MgSC^), and concentrated. Purification on a silica gel column gavē 4.46 g (93%) product. ES-MS (M+H)*: calcd 650.7; found 650.7. 2708(6). Ņg-Me'thvi-ĶS- ( r f 1 (R. 9) -p.-butoxvcarbonvl-2 fR! -carboy/-3-methvl)cenr.vloxv1acetvl)~L-Lvfiina. N-methvl amide. -184- LV 12167
Compound 2708(d) (4.31 g, 6.98 mmol) was treated with 50 mL 4 N HC1 in dioxane fcr 1 hour and the solution was concentrated. The residue was taken u? in 60 mL isopropanol and the solution was hydrogenated at atmospheric pressure foc 2 hours using 10% Pd-C (0.5 g) as catalyst. The catalyst was filtered off and the solution was concentrated to give 3.15 g (91%) product. ES-MS-(M+H)*: calcd 460.4; found 460.5. 2708if; . To a solution of BO? (2.68 g, 6.05 mmol) in 20 mL chlorcform cooled in an ice bath were slowly added compound 2708 (e) (3 g, 6.05 mmol) in 20 mL chloroform and diisopropylethylamine (3.69 mL, 21.2 mmol) in 20 mL' chloroform simultaneously over 1 hour. The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in EtOAc and the solution was washed with citric acid, brine, NaHCOļ and brine, dried (MgSO*), and concentrated. Purification on a silica gel column gavē l. y \ 11·* t , ta-Ms ίΜ+ίΐ)’·ί caica 442.3; tound 442.5. 2708(g). Compound 2708(f) (1.8 g, 4 mmol) was created with 4.9 ml 1 N LiOH in.10 mL THF for 1 hour and the solution was concentrated. Purification on HPLC gavē 390 mg (25%) product. ES-MS (M+H)+: calcd 386.3; found 386.3.
Example 2708: To a solution of compound 4(g) (0.17 g, 0.48 mmol) and Obenzylhydroxyiamine hydrochloride (91 mg, 0.576 rrmol) in 2 mL DMSC cooled in an ice bath was added BOP (254 mg, 0.576 mmol) folioved by diisopropylethylamine (0.33 mL, 1.92 mmol) and the solution was stirred at room temperature fcr 1 hour. Purification on reversed phase HPLC gavē 30 mg isomer 1 and 14G mg isomer 2. ES-MS (M+H)*: calcd 491.5; found 491.6 (both isomers) .
Exampie 2708: Compounds 2708(h), isomer 1 and isomer 2 were hydrogenated in a manner analogous to Chat described in 1 (n). ES-MS (M+H)*: calcd 401.5; found 401.6. -185-
Example 2809 2809 (a) . Na-Boc-S^(2-nitrophenvl 1 -L-cvstelne. 2-Chlero-nitroben2ene (7.88 g, 50 mmol), L-cysteine (6.66 g, 55 mmol) and pocassium carbonate (7.6 g, 55 mmol) were suspended in 30 mL DMF and the solution was stirred at 8Q°C for 4 hours and cooled to room temperature. Water (20 mL) was added and the solution was cooled in an ice bath. To it was added di-t-butyl dicarbonate (10.9 g, 50 mmol). After stirring for 2 hours, water was added and the solution was extracted with ether 3x. The water layer was acidified with HC1 at 0°C and the solution was extracted with ethyl » 4 acetate 3x. The combined extracts were washed with brine, dried (MgS04) and concentrated to give 8.21 g (48%) product. ES-MS (M+K) +: calcd 343.3; found 343.2. 2809 (b) .Na-Boc-g-f2-nltrophenvl)-L-cvstelne N-methvI amlde.
To a solution of compound 2518(a) (8,1 g, 23.66 mmol) and methylamine hydrccnloride (2.03 q, 30 mmol) cooled in an ice bath was added diisopropylethylamine (16.5 mL, 95 mmol) followed by BOP (10.47 g, 23.66 mmol).After stirring for 2 hours at rccm temperature, ethyl acetate was added and the solution was washed with citric acid, brine, NaHCOa and brine, dried (MgS04) and concentrated. Purification on a silica gel column using 5% methanol in met’nylene chloride as eluent gavē 6.24 g (82%) product. ES-MS (M+H)·*·: calcd 356.2; found 356.3. 2809(c). g-2-Nitrochenvl-L-cvsceine N-methvi amide.
Compound 2518 (b) (6.0 g, 17 mmol) was treated with 4 N HC1 in dioxane for 1 hour and the solution was concentrated.
The residue was triturated with ether to 3.88 g (71%) product. ES-MS (M+fi) *: calcd 256.1; found 256.1. Ιή) 1 C*. *!) <a. hmaar.-garhar.·,·1.Γ.-^ίΙ-^Λ 2.(111.-isobutvloroclcnovl-S- (2-nit.rochenvl) -L-cvsteine N-methvl amide. -186- LV 12167
To a solution of compound 2518(h) (2.36 g, 6.5 mmol) and compound 3(c) (1.91 g, 6.5 mmol) in 15 mL chloroform cooled in an ice bath was added diisopropylethylamine (4.53 mL, 26 mmol) foilowed by BOP (2.88 g, 6.5 iraiol) and the solution was stirred at room temperature ovemight and concentrated. The residue was taken up in ethyl acetate and the solution. was washed with citric acid, brine, NaKCOļ and brine, dried (MgSO*), and concentrated. Purification on a silica gel column using 3% MeOH-25% EtOAc-72% CH2CI2 as eluent gavē 3.21 g (83%) product. ES-MS (M+H)+: calcd 598.3; found 598.6. 2809 (e) . 3-n-Butoxvcarbonvl-3 (R. S) -cagboxvinethoxy-2 (R) -isobutvlpropionovl-S- (2-aminonhenvl) -L-rvstelne.. N-methvI amide.
Compound 2809(d) (3.05 g, 5.1 mmol) was treated with 3 g 2inc in 15 mL acetic acid and 0.5 mL water for 30 min. 30 mL methanol was added and the solid was filtered off. The anU. ulitĪ W3S up in ethyl acetate. The solution was washed with NaHCO^ 3x, dried (MgSC^) , and concentrated. The residue was treated wich 30 mL 4 N HCi in dioxane and 0.5 mL water for 1 hour and the solution was concentrated to give 2.2 g (84%) product. ES-MS (M-*-H)*: calcd 512.5; found 512.5. 2809(f). BOP (1.36 g, 3.06 mmol) was dissolved in 10 mL DMF and the-solution was cocled in an ice bath. To it were added compound 2809(e) (1.4 g, 2.55 mmol) and diisopropylethylamine (1.78 mL, 10.2 mmol) slowly over 2 hours. The solution was allowed to stir at room temperatūra overnight. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHC03 and brine, dried (MgS04) and concentrated. The crude product was purified on a reversed phase HPLC tc give 250 mg isomer 1 and 620 mg isomer 2 (69%). ES-MS (M-H)+: calcd 494.3; found 494.3 (both isomers) . -187- 2809 ig). Compound 28C9(f), isomer 1 (0.2 g, 0.4 mmol) or isomer 2 (0.55 g, i.il mmol) was treaced with 1.1 equivalent L10H in ?KF for 1 hour and both products were purified on HPLC. Yield: isomer 1 0.15 g; isomer 2 0.41 g. ES-MS (M+Na)*: calcd 460.2; found 460.3 (bcth isomers). 2809. To a solution of compound 2809(g), isomer 1 (100 mg, 0.228 mmol) and hydroxylamine hydrochloride (20 mg, 0.274 mmol) in 3 mL DMF cooled in an ice bath was added diisopropylechylamine (0.15 mL, 1 mmol) and BOP (0.12 g, 0.274 mmol) and the solution was stirred at room temperature for 2 hours. Purification on HPLC gavē 85 mg (82%) product. ES-MS (M+H)+: calcd 453.2; found 453.3. Compound 2809(g), isomer 2 was converted to the same product in the same manner. ES-MS (M+Na)+: calcd 475.2; found 475.3.
Example 2880: 2S . 11S. 12R-1.7-Diaza-8.13-dioxo-2- (N-. mflthvlcarboxamido) -7-N-t-.butvloxvcarbonvl-12-isobutvlcvclotrldacane-ll-fN-hvdrrxvgarhoxamide). 2880 (a) : Compound E;<ample 2323 (a) (300 mg, 0.5 mmol) was dissolved in 33% K3r/AcOK (6.3 mL) containing phenol (63 mg, 0.67 mmol). After stirring for 5 h, the solution was concentrated and the solid was fiitered of: wich CH2Cl2/Et20. This provided the crude aminc acid salt (500 mg, guant.): ES-MS (M+H)~ 356.4. 288Q(b). Compound Example 2880(a) (140 mg, 0.32 mmol) was dissolved in THF (4 mL)/H:C (0.6 mL) and EtjN (0.38 mL, 2.6 mmol) was added. Next, (H0O2O (452 mg, 205 mmol) was added at room temperacure. After stirring cvernight, the solvent was removed and CK2CI2 was added. The CH2CI2 was washed with 10% HC1, dried (MgSC>4), and concentrated. The resulting residue was purified by silica gel chromatography to yield the crude carbamate, which was dissolved in DMF (5 mL) . To this solution was added 0-benzylhydroxylamine (103 -188- LV 12167 mg, 0.87 mmol), diisopropylethylamine (0.15 mL, 0.82 mmol) and BO? (214 mg, 0.48 mmol). After stirring overnight, the sclid producc was filtered from solution with CH2CI2 to give the 0-benzyl hydroxamate (12C mg, 67%).· ES-MS (M-t-H) + 561.5. 2880: Compound Example 2880(b) (160 mg, 0.29 mmol) was hvdrogenated in MeOH (40 mL) with 5% Pd/BaSC>4 (240 mg) under a hydrogen atmosphere (50 psi). After stirring 3 h, the catalyst was filtered off and the solution was concentrated to vield the title hydroxamate (140 mg, quant.) as a pale yellow solid: ES-MS (M+H)+ 471.5,
Example 2890: 25, nS.il2R-l, 7-piaza.-8-ul2--diQXP-2- (N- methvlcarboxamido)-7-N-(N-methvl-imidazolesulfon-4-vl'-12-isobutvlcvclotridecane-ll--(N-hvdroxvcarboxamide) . 2890 (a) : To a scluticr. of the succinate l(c) (1.27 g, 4.39 mmol), N*-4-(N-methyl)imidazolesulfonyl-L-lysine N-methyl arr.ide (1.73 g, 5.70 mmcl), and diisopropylethylamine (3.19 mL, 17.6 mmol) in DMF was added BOP (2.34 g, 5.27 mmcl). After stirring overnight, the DMF was removed and CH2CI2 was added. The CH2CI2 was washed with saturated NaHCC3 solution and brine. The CH2CI2 was dried (MgS04) and concentrated. The resulting residue was purified by silica gel chromatography to yielt the amide (1.73 g, 69%) as a white foam: ES-MS (M+H)+ 574.5. 2890 (b) . Compour.d Example 2890(a) (200.0 mg, 0.35 iranol; and PPh3 (274.0 g, 1.05 mmcl) were dissolvec in THF (15.5 mL). DIAD (0.2C mL, 1.05 mmol) in THF (5 mL) was added dropvise to the mixture. After stirring overnight, the soluticr. was concentrated and the residue was purified by silica gel chromatography to vield the cyclic matenal (100 mg, 52%) as a white foam: ES-ΚΞ (M-H)* 556.5. -185- 2890(0: Compound Example 2890(b) (400.0 mg, 0.72 mmol) was dissclved in CH2CI2 (5.5 mL) and TFA (5.5 mL) . After stirring overnight, the solution was concentrated to the acid, which was dissolved in DMF (6.4 mL). To this solution was added 0-benzylhydroxylamine (172.0 mg, 1.40 mmol) and aiisopropyl-ethylamine (0.24 mL, 1.38 mmol) followea by BOP (341.0 mg, 0.77 mmol). After stirring overnight, the DMF was removed and silica gel chromatograp’nv gavē the 0-benzyl hydroxamate (140 mg, 33%) : ES-MS (M+H)+ 605.5. 2890: Compound Example 2890(c) (135.0 mg, 0.22 mmol) was hydrogenated in MeOH (25 mL) with 5% Pd/BaS04 (202 mg) under a hydrogen atmosphere (50 psi). After stirring 3 h, the catalyst was filtered off and the solution was concentrated to yield the title hydroxamate (98 mg, 85%) as a solid: ES-MS (M+H)+ 515.4.
Example 2900: 2900(a>. 2R.3S-Methvl 4-benzvloxv-3- hvdroxv-2-(2F-3-phenvl-2-prooen-l-vl)butvrate A 1.6 M hexane solution of n-butyllithium (140.4 mL, 2.1 eguiv.) was added over 15 min to a solution of diiscpropylamine (29.48 mL, 2.1 eguiv.) in tetrahydrcfuran (650 mL) at 0 °C. The mixture was stirred at 0 °C fcr 15 min and cooled to -78 °C. Methyl 4-benzyloxy-3S-hydroxybutyrate (24.00 g, 107 mmol) in tetrahydrofurar. (40 mL) was added over 20 min via a canula and the residue was rir.sed with tetrahydrofuran (2 x 20 mL) . The resultar.t mixture was stirred at -45 °C for 1 h, -20 °C for 0.5 h and cooled to -78 °C. A tetrahydrofuran (90 mL) solution cf cinnamyl bromide (31.69 mL, 2.0 eguiv.) and neat Ν,Ν,Ν',Ν'-tetramethyiethylenediamine (32.33 mL, 2.0 eguiv.) were added seguentiallv. After 15 min at -40 °C and 4 h at -20 °C, saturated ammonium chloride (500 mL) and hexane (400 mL) were added- ?ollowing extractior. of the agueous ņhase with ether (3 :< 8*0 mL;, the ccmbined crgar.ic extract= were washed with water (5C mL), brir.e (50 ml), dried (MgS04 and LV 12167 concentrated. Silica gel chromatography (ethyl acetate-hexane, 20:80, then 30:70, then 50:50) gavē product (28.78 g, 73%, d.s.=8:l) as a vellow oil. ESI-MS (M+H)+: calcd 341.2, found 341.2. 2500(b). 2R.3S-4-Benzvloxv-3-hvdroxv-2-(2E-3-phenvl-2-prooen-1-vl)butvric acid A 1.0 M agueous solution of sodium hydroxide (450 mL) was added to a solution of 2900(a) (28.08 g, 82.6 iranol) in methanol (450 mL) at 0 °C and the resultant mixture was stirred at room temperature for 2 h. Following removal of methanol in vacuo, the aqueous residue was adjusted to pK 5 witn 1 N sulfuric acid, and extracted with ethyl acetate.
The combined extracts were washed with brine, dried (MgS04) and cor.centrated to give the product (27.06 g, 100%) as a solid. DCI-ΜΞ (Μ-ΓΝΗ4)+: calcd 344.2, found 340. 2900(c). 2R.3S-4-3enzvloxv-3-hvdroxv-2-(2E-3-pnenvl-2-propen-l-vl) butvryl-N&-t-butoxvcarbonvl-L-omithine N-metnvl amide
Diisoprcpylethylamine (12.18 mL, 4 equiv.) was added to a solution of 2900(b) (5.70 g, 17.48 mmol), N^-t-butoxycarbonyi-L-ornithine N-methyl amide (7.49 g, 1.5 equiv., HC1 salt! ar.d benzotriazol-l-yloxy-tris(dimethvlamino)phosphonium hexafluorophosphate (7.97 g, 1.03 equiv.) in N,N-dimethylfcrmamide (20 mL) at 0 °C.
After 2 h at 0 °C, echvl acetare (200 mL) was added. The mixture was washed with 10% citric acid (2 x 25 mL), brine (25 mL) , saturated scdium bicarbonate (2 x 25 mL), brine (25 mL), dried (MgSC4) and concentrated. Silica gel chromatcgraphv (methanol-dichloromethar.e, 5:95 then 8:92) gavē product (7.16 g, 74%) as a solid. ESI-MS (M+H)+: calcd 554.4, found 554.4. 2900 (d). 2R. 3S-4-3er.zvloxv-3- ?2E-4-bromo-2-buten-l-vl -2-(2 Γ- 3 - chsnvl - 2 -p roper.-1 - vl) butvrvl-N^~" -but cxvcarbonv3 -L-crr.ithme N-meth·.·! amide
Sodium hydride (0.28 g, 1.8 equiv., 60% dispersion in mineral oil) was added to a solution of 2900(c) (2.13 g, 3.85 rnmol) and 2E-1,4-dibromo-2-butene (8.00 g, 9.7 equiv.) in N,N-dimēthylformamide (100 mL) at 0 °C. Additional portions of 2E-1,4-dibromo-2-butene (4 g each) and sodium hvdride (0.23 g each) were added every 20 min and the disappearar.ee of starting material was monitored by TLC analysis. After a total of 1.5 h, reaction seems complete. Following 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 were dried (MgS04), and concentrated. Silica gel chromatography (methanol-chloroform, 3:97 then 4:96) provided the desired product (1.86 g, 70%). ESI-MS (M+H)+: calcd 688.3, found 688.2. 2900 (e) . 25.I.3R, SS< ΙΙΕ-Ζ^ηζνΙοχγιηβ^ηγΙ-ΙΟ-Ε- bAitoxvrarhonvl-5,10-dia2a-6- (N-methvlcarboxamido) -l-oxa-4-Qxo.r3- (2£-3-phenvl-2-ūrooen-l-vl) cvclotetradecene A 4 N dioxane solution of hydroger. chloride (20 mL) was added to 2900(e) (1.86 g, 2.707 mmol). After 1.5 h at room temperature, the solvent was removed in vacuo. The selid residue was washed with small amcunc ether, pumņed to drvness to give the product (1.64 g) .
ESI-MS
Diisopropyiethylamine (2.33 mL, 5 equiv.) was added to a solution of this crude material in acetonitrile (1.3 L) at 0 °C. The resultant nixture was stirred at room temperature for 3 h. Di-t-butyl dicarbonate (2.33 g, 4 equiv.) was added. After 20 min at room temperature, the mixture was then guer.ched with saturated ammonium chloride and extracted with ethyl acetate. The combined orgar.ic extracts were dried (MgS04), and concentrated. Silica gel chromatograpnv twi.ee ;isopropar.ol-chlorcform, 3:97 then 4:96 then 6:94 the first time, 5:95 the second time) provided the product (0.73 g, 45% for two steps). (M-r-H) ^: calcd 606.4, found 606.4. LV 12167 2900 (f) . 2S. 3R. 6S-10-t-Butoxvcarbonvl-5.10-diazan2.-hvdroxvmethvl-6- (N-methvlcarboxamido) -l-Qxa-4-QXQ_-2-i2-phenvlprop-l-vl)cvclotetradecane 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 ballocr. pressure hydrogen for 1 h 20 min.
The catalyst was removed by filcration. The filtrate was concentrated and purified by silica gel chromatography (methancl-chloroform, 3:97 chen 5:95) to give the product (0.35 g, 56%). ESI-MS (M+H)+: calcd 520.4, found 520.3. 2900(g). 2S.3R.65-10-t-Butoxvcarbonvl-5.10-diaza-2-hvdroxvcarbonvl-6-(N-methvlcarboxamidoi-l-oxaT4-oxo-3-(3-phenvlprop-l-vl)cvclotetradecane
Ruthenium(III) chloride (7.2 mg, 0.04 eguiv.) and soaium periodate (0.74 g, 4 equiv.) were added sequentially to a mixture cf 2900 (f) (0.45 g, 0.866 mmol), acetonitrile (8 mL), carbcn tetrachloride (8 mL) and water (12 mL).
After 2 h at room temperature, chloroform (60 mL) was added. The agueous layer was separated and extracted with chloroform (5 x 30 mL). The combined organic phase was dried (Mg304), and filtered through a pad of celite to give the desired carboxylic acid (0.43 g, 93%). ESI-MS (M-rH}*: calcd 534.4, found 534.3. 2900 (h). 2.S, 3-L_5S-2- (N-Benzvloxvcarbcxamido)-10-t-but.axycarbonvl-5,10-diaza-6- (N-methvlcarboxamido) -l-oxa-4-ΟΧΟ-3-f3-ohenvlprop-l-vl)cvclotetradecane A 1.0 M dichloromethane solution of dieveio'nexylcarbodi:mide (0.038 mL, 1 eq.) was added to a solution cf 2900(g) (20.1 mg, 0.0377 mmol), 0-benzylhydroxyamine hvdrochloride (7.2 mg, 1.2 eq), 1-hvdroxybenzotriazcle hydrate (5.1 mg, 1.0 eq.) and diisopropylethviamine (0.0079 mL, 1.2 eqi in tetrahvdrcfurar. (2 mL: . The mixture was stirred until startmg material disappeared as monitered by TLC ther. qusr.ched vcch satur atēd ammor.ium chlcnde. Following -irj- excracticn with ethyl acetate, the combined extracts were washed wich brine, dried (MgS04) and concencrated. Preparacive thin layer chromatography (methanol-chloroform, 5:95) yielded the desired product (12.8 mg, 53%) as a white solid. ESI-MS (M+H)+: calcd 639.4, found 639.3. 2900: 2S.3R.6S-10-t-Butoxvcarbonvl-5.10-diaza-2-(N-hvdroxvcarboxamido) -6- (N-methvlcarboxamido) -l-oxa-4-oxo-3-(3-phenvlprop-l-vl)cvclotetradecane A mixture of 2900(h) (34.0 mg, 0.0532 mmol) and 5% Pd or. BaS04 (56.7 mg) in ethanol (4 mL) was stirred under balloon-pressure hydrogen ac room temperature. Additional Pd on BaS04 (115.3 mg) was added 1 h later. After a total of 2 h, the catalyst was removed by filtration. The filtrate was concencrated to give the desired hydroxamate (26.7 mg, 51%) as a white solid. ESI-MS (M+H) + : calcd 549.3, found 549.3.
Exampie 2910: 2910 1a). 2S,3R, 6S-2-(N-BenzvloxvcarboxamidQ_)-5,10-diaza-6-(N-methvlcarboxamido) -l-oxa-4-oxo-3- f3-phenvlprop-l-vl)cvclotetradecane nvdrochloride A mixture of 2900 (36.1 mg, 0.0565 mmol) and 4 N dioxane solution of HC1 (1.0 mL! was stirred at room temperacure for 3 0 min. Removai of solvent in vacuo gavē the desired product as a white solid. The crude material was taken tc the next step without purification. ESI-MS (M+K)*: calcd 539.3, found 539.3. 2910 (b) . 2S. 3R. 6S-S. 10-Diaza-2- (N-hvdroxvcarboxamidc) -6--(N-methv 1 carboxamidoi -l-oxa-4-_oxor-3-13-chenvlpros-lr vllcvclotetradecane nvdrochloride
FolIowing a prccedure analogous to the conversion of 2900(h) to 2900 (i), 2900(a) converted to the desired product (26.3 mg, (95%, for two steps). ESI-MS (M+H)+: calcd 449.3, found 449.4. -194- LV 12167
Example 2920:
2920 (a) . 25.. 3R, 6S-10-Aegryl-2- (N-Benzvloxvcarboxamido) -.5 UO-diaza^S- CK-methvlcarboxamido) -l-oxa-4-oxo-3- (3-DhenvlPrQP-l-vl)cvclQt6r.rartPranP A crude material of 2910(a) derived from 2900(h) (45.4 mg, C.071 mmol) was treated with acecic anhydride (1.5 mL) and diisopropylethylamine (0.040 mL, 3.2 equiv.) . 10 min later, che reaction mixture was quenched with saturaced ammonium chloride and extracted with ethyl acetate. The combined excracts were washed with saturaced sodium bicarbonate, brine dried (MgS04) and concentrated. Silica gel chromatographv (methanol-chloroform, 5:95 then 7.5:92.5) furnished the desired product (32.9 mg, 80% for two steps). ESI-MS (M*K)·-: calcd 581.4, found 581.5. 2920: 2S. 3R. 6S-lQ-Acer.vl-5 .lQ-diaza-2- (N-hvdroxvcarboxamido'-fi-fN-methvlcarboxamido)-l-oxa-4-oxo-3-(3-nhenvlprop-1 -vi) cvclotetradecane
Following a procedure analogous to the conversion of 2900 (h) to 2900(i), 2920(a) (31.8 mg, 0.0548 mmol) was converted to the desired product (24.0 mg, 89%). ESI-MS (M+H)τ: calcd 491.3, found 491.4.
Example 253 0: 2S, 13β.-.:4Ε-Ι^-7-6ΐ&Ζζ-8 , li-diQXa-9-QXarl.4- i snhnr.vl - Γπΐ vc: np-w-hvdroxvDiperidinei -cvclopentadecane-13 -N-hvdroxvrarbcxamid& T'nis compound was preps-sd using the procedures analogous to those above. ESI-MS: found 527.6.
Example 2931: 2S,: 3S ,1 4R-1,7-Qiaz.a-8,15-dioxo-9-oxa-14- •isnhutvl-7- ļ- rvri 13 -N-hvdroarearboremide ^his comocur.d was prep*red ^sing the procedures analogous to thcse abcve. ESI-MS-· touna 5*_./. -195-
Example 2940: 2940(a)- 2S.3R.6S-2-(N-Benzvloxvcarboxamido)-lQ-benzen.esulfonvl-5.lO-diaza-6-(N-methvlcarboxarnido)-l-oxa-4-ΟΧΡ-3-(3-phenvlproD-l-vl)cvclotetradecane 3enzenesulfonyl chloride (0.13 mL, 25 equiv.) was added to 2910 (a) (23.2 mg, 0.0403 mmol), and 4-(N,N-dimethylamino)pyridine (0.5 mg, 0.1 eguiv.) in pyridine (1 mL}. After 30 min at room temperature, saturated ammonium chloride (2 mL) was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (MgS04) and concentrated. Preparative thin layer chromatography (methanol-methylene chloride, 10:90) yielded the desired product (11.1 mg, 41%). ESI-MS (M+H!*: calcd 679.4, found 679.3.
Example 2940: 2S,3R,6S-10-Benzenesulfonvl-5,10-diaza-2-(N-hvdroxvcarboxamido)-6-(N-methvlcarboxamido)-l-oxa-4-oxo-3-(3-Dhenvlproo-l-vl)cvclotetradecane
Following a procedure analogous to the conversion of 2900(h) to 2900(i), 2940(a) (14 mg, 0.021 mmol) was converted to the desired product (12.7 mg, 100%) as a white solid. ESI-MS (M+H)+: calcd 589.3, found 589.4.
Example 2950: 2950 (a) . 2R, 3S-4-Benzvloxv-3- (2-bromomer.hvl-2-propen-l-v1) -2 - (2E-3 - phenvl-2 -proūen-l-vl) butvrvl-NS-t-butoxvcarbcr.vl-L-gmiwhir.'g N-ir.gUaoI-ainide
Foliovir.g a procedure analogous to the conversion of 2900(0 to 2900(d), 2900(c) (1.12 g, 2.03 mmol) was reacted with 3-bromc-2-bromcmethylpropene to give the desireē fcromide (0.92 g, 67%) as a white solid. ESI-MS (M+H'-: calcd 688.3, found 688.2. 2950(b). 2R.3S-4-Benzvloxv-3-?2-bromomethvl-2-proper-l-vl)-2- (2E-3-oher.vl-2-propen-l-vl!butvrvl-L-omithine Ν-τηΡ-hvi amids. iiv-drocnldiiag -196- LV 12167
Following a procedure analogous to the synthesis of 2900(e) , 2950 (a) (0.33 g, 0.48 mmol) was deprotected to give the desired product. The crude white solid was used in the next step without purification. ESI-MS (M+H)+: caicd 588.3, found 588.1. 2950(0. 2S.3R«_6SrlO-Acetvlr2-Benzvloxvmethvl-5.10-diaza-6-(N-methvlcarboxamido)-12-methvlene-l-oxa-4-oxo-3-(2E-3-Dhenvl-2-oropen-l-vl)cvclotridecane
Following a procedure analogous to the conversion of 2900(d) to 2900(e), crude 2950(b) was cyclized and reacted with acetic anhvdride to give the desired product (0.202 g, 76% for two steps) as a white solid. ESI-MS (M+H)+: caicd 548.3, found 548.4. 2950(d). 2S.3R.6S.12(R.-10-Acetvl-5,10-diaza-2-hvdroxvmethvl-6-(N-methvlcarboxamido)-12-methvl-l-oxa-4-ΟΧΟ-3-(3-phenvlDrop-l-vl)cvclotridecane
Following a procedure analogous to the conversion of 2900(e) to 2900(f), 2950(c) (0.20 g, 0.365 mmol) was reduced with hydrogen to give the desired product (0.14 g, 83%) was ar. inseparable 1:1 mixture of two diastereomers. ESI-MS (M-i-K)·": caicd 452.3, found 462.4. 2950(e). 2S.3R.6S.12(R.5)-10-Acetvl-5,lQ-diaza-2-hvdroxycarbonvl-6-(N-methvlcarboxamido)-12-methvl-l-oxa-4-ΟΧΟ-3-(3-ohenvlcroo-l-vl1 cvclotridecane
Following a procedure analogous to the conversion of 2900(f) to 2900(g), 2950(d) (0.14 g, 0.303 mmol) was oxidized to the desired acid (0.113 g, 78%). ESI-MS (M+K)*: caicd 475.3, found 475.3. 2950 (f). 2S.3R.6S,12(R, S = -lO-Acetvl-2-(N-benzvloxvcarboxamidcI-5,13-diaza-S-(N-methvlcarboxamido)-12-methvl-l-oxa-4-oxo-3- ' 3-ohenvltrop- 1-vl) cvclotridecane Following a procedure analogous to the conversion of 2900(g) to 2900(h:, 2950,e) (0.113 g, 0.237 mmol) was -137- 'converted to t'ne desired proauct (46 mg, 33%) as a white solic. ESI-MS (M+H)*: calcd 581.3, found 581.2. 2950(g). 2S.3R.6S,12(R,S)-10-Acetvl-5.10-dia2a-2-(N-hvdrnxvcarboxamirio)-6-(N-methvlcarboxamido)-12-methvl-l-nxa-4-oxo-3-'3-phenvlprop-l-vl)cvclotridecane
Following a procedure analogous to the conversion of 2900(h) to 2900(i), 2950(f) (51 mg, 0.088 mmol) was converted to the desired product (33 mg, 76%). ESI-MS (M+H)*: calcd 491.3, found 491.2.
Example 2960: 2S,5S.12R-12-carboxv-3.10-dioxo-5-N- methv 1 carboxamido-2-nnenet hv 1-1.4.9-r_riaza-cvclotridecane trifluoroacetate 2960. 2S.5S.12R-12-carboxv-3.10-dioxo-5-N- methvlcarboxamido-2-phenethvl-l.4.9-triaza-cvclotridecane rrifluoroacetate
The compound 2960(d) (100 mg, 0.2 mmol) was dissolved ir. methvlene chloride prior to the addition of TFA (1.7 ml) . The reaction was stirred 4 hrs at RT. The soiution was cor.cer.crated to give the title compound (80 mg, 75%) . M3 (CI) m/e 419 (Μ i· 1)-. 2960 (a) . M- [g--Fluorenvlmethoxvcarbonvl) -D- (Sl-aspartic-t-butvl eater Ng- (benrvloxvcarhQnvl) -L- (eVlvsine N-methvlair.ide. N- (9-Fluorenylnethoxycarbonyl) -D-Aspartic-a-t-butyl ester (5 g, 12.1 mmcl! was dissolved in methylene chloride and cooled tc 0°C. in succession, HOBt (1.8 g, 13.3 mmol), 4-methyimorphcline ;4.4 ml, 39.9 mmol) , Na-(benzyloxycarscnyl)-1-Lysine N-methylamide (4.8 g, 14.5 mmol), and EBC (3.0 g, 15.7 mmol) wers added. The reaction was warmed tc RT and stirred 15 hrs. The soiution was washed with agueous sodium bicarbonate, 10% agueous citric acid, and brir.e soiution. The organio layer was dried and concentrated. The resulting material was purified ty
LV 12167 chromatography to yield the desired amide (3.1 g, 47%). MS(CI) m/e 687 (M + 1)-. 2960(b). D-(B)-asnartic-t-butvl ester Nfl-(ber.zvlo^/carbonvi ) -L- (el-lvsine N-methvlamide-
The compound of 2960 (a) (3.1 g, 4.6 inmol) was dissolved in DMF prior to the addition of diethylainine (7 ml) . The reactior. was stirred for 20 min. The solution was concentrated and purified by chromatography to afford the desired amine (1.9 g, 86%). MS (CI) m/e 465 (M + 1)+. 2960(0. N^2 ' - (benzvl .4^.phenvlbutanoate) -D- (β) -aspartio- t-butvl ester Nc- (benzvloxvcarbonvl) -L- (E)-lvsine N-methvlamide.
The compound of 2960(b) (220 mg, 0.5 mmol) was dissolved ir. methyiene chloride prior to the addition of Hur.ig's base (0.09 ml, 0.5 mmol) and (R)-benzyl 2-(triflucromethyl)suifcnyloxy-4-phenylbutanoate (190 mg, 0.5 mmol) (3ennion, C.; 3rown, R.C.; Cook, A.R.; Manners, C.N.; Pavling, D.W.; Robinson, D.H. J. Med. Chem. 1991, 34, 439). Afoer 15 hrs, the solution was concentrated and purified by chromatographv to give the desired secondary amine (290 mg, 86%). MS (CI) m/e 71" (M + D*. 2960(a). 25.55.12R-12-t-butvlcarboxv-3.10-dioxo-5-N- methvl.carboxar.ido-2 -phenethvl-1,4.9-triaza-cvclotridecar.e
The compound 2960(0 (270 mg, 0.4 mmol) was placed ur.der a nydroger. atmcspnere in methanol with 10% Pd/C (60 mg). After 5 hrs, 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 ( C.l ml, 0.8 mmol) in DMF. This mixture was stirred 24 hrs. The solution was concentrated and purified bv chromatography to give the desired triamide (55 mg, 30%). MS (CI) m/e 475 (M -r 1)-. -199-
Example 2951: 2S.5S,13R-13-carboxv-3.10-dioxo-5-N- methylcarboxamido-2-phenethvl-l, 4.9-triaza-cvclotetradecane trifluoroacetate 2961. 2S.5S,13R-13-carboxv-3,10-dioxo-5-N- methvIcarboxamido-2-phenethvI-l,4,9-triaza-cvclotetradecane trifluoroacetate
The compound 2961 (d) (60 mg, 0.1 inmol) was dissolved in methylene chloride prior to the addition of TFA (1 ml). The reaction was stirred 4 hrs at RT. The solution was concentrated to give the title compound (50 mg, 74%). MS (CI) m/e 433 (M + 1)+. 2961(a). N-f9-Fluorenvlmethoxvcarbonvl)-D-(B)-crl utainie-1-butvl ester %- (benzvloxvcarbonvi) -L- (e)-lvsine N- methYlanvi.de N-Fmoc-D-Glutamic-a-t-butyl ester (5 g, 11.8 mmcl) was dissolved ir. DMF and cooled to 0°C. In succession, HOBt (1.8 g, 13.3 mmol), 4-methylmorpholine (4.0 ml, 36.6 mmol), NorCbz-L-Lysine-N-methylcarboxamido»HCl (5 g, 12.9 mmol), and BOP (6.8 g, 15.3 mmol) were added. The reaction was warmed to RT and stirred 15 hrs. The solution was diluted with ethvi acetate and washed with aqueous sodium bicarbonace, 10% aqueous citric acid, and brine solution. The organic layer was dried and concentrated. The resulting material was purified by chromatography to vield the desired amide (8 g, quant) . MS(CI) m/e 701 (M + 1)". 2961 (b). D-(B· -clutamic-t-butvl ester Nfl-(ber.zvloxvcarbonvl) -L- (D-lvsine N-methvlamide
The compound 2951(a) (8 g, 11.8 mmol) was dissolved in DMF prior to the addition of diethylamine (36 ml) . The reaction was stirred for 45 min. The solution was concentrated and purified by chromatography to afford the desired amir.e (2.9 g, 49%). MS (CI) m/e 479 (M -r 1) + . -200- LV 12167 2961(0. N-2 ' - (benzvl 4 ’ -phenvlbutanoate) -D- (β) -olutamic- t-butvl esr^r Nc- (benzyloxvcarbonvl ī -L- (fO-lvsine N-methvlamidfr.
The compound 2961(b) (1 g, 2.1 iranol) was dissolved in methylene chloride prior to the addition of Hunig's base (0.4 ml, 2.1 mmcl! and (R)-benzyl 2- (triflucromethvl)sulfonyloxy-4-phenylbutanoate (0.6 mg, 2.1 mmol) (3ennion, C.; Brown, R.C.; Cook, A.R.; Manners, C.N.; Payling, D.W.; Robinson, D.H. J. Med. Chem. 1991, 34, 439). After 15 hrs, the solution was concentrated and purified by chromatograpny to give the desired secondary amine (2.3 g, 78%). MS (CI) m/e 731 (M + 1)+. 2961(d). 2S,5S.13R-13---butvloarboxv-3.10-dinxo-5-N-methvlcarboxamido-2-phenethvl-l, 4.9-triaza-cvclotetradecane
The compound 2961(c) (2.1 g, 2.9 mmol) was placed under a hvdrogen atmosphere in methanol with 10% Pd/C (430 mg). After 4.5 hrs, the solution was filtered and concentrated. A portion of the resulting material (400 mg, 0.8 mmol) was dissolved in DMF and adaed to a solution cf BO? (454 mc, 1 mmcl) ar.d Hunig’s base ( 0.3 ml, 1.6 mmcl) in DMF. This mixture was stirred 24 hrs. The solution was concentrated and purified by chromatography to give the desired triamide (60 mg, 16%). MS (CI) m/e 489 (M + 1)*. -2C1- TABLE 1
For the cyciophane:
R2 E X R2 (CI-MS) m Ex R2 (CI-MS) ms 2 C02Me 406 2 CONH-cyclopentyl 3 C02Et 4 CONH2 5 C02iPr 6 CONHiPr 7 C02(CH2)20Me 8 CONK-tert-bucyl 9 C02(CH2)2Ph 10 CONMe2 i: C02~tBu 12 CONEt2 13 C02CH2C0NHMe 14 CONH-3-indazolyl 15 CH20H 379 16 CONH-adaraancyl 17 CH2OCH2CH3 18 CONHCH2(P-SO2NH2-Ph) 19 CH2OCH2CH2CO2CH; 20 C0NH(CH2)3-1-imidazolvl 500 21 CHOBn 22 CONHSO2NH2 23 CONH(CH2)2-2-pyridyl 497 24 CONHSO2CH3 25 CO(N-morpholinyl! 26 C0NHS02Ph 27 CO(N-Me-N-DiDerazinvl1 475 28 C0NHS02BH 29 CONH(CH2)2-(N-Me-N-Dioerazinvl1 30 CGNHS02-N-Me- imidazolvl 31 C0NK-cycl3propyl 32 C0NHS02-p-NH2Ph 33 CONH-cyciobucyl 34- CCNHSO2-p-MeOPh 3 5 CONHS02-p-r-Ph 3 6 CONH-S-CH [CHpCH(CH3)21CONHMe 37 CONH 'CH'2 ) 2NHSC2Me 38 CONH:CH2)4NHS02Me LV 12167 39 CONK-cyclohexyl 40 CONHCCH2!gNHS02Me 41 CCNK-2-imidazolyl 457 42 CONH-R-CH [ CH2CH(CH3)2]CONHMe 43 CH2SO2NHCH3 44 CONH-S-CH [(CH2)4NH2]CONHMe 45 CH2S02NHPh 46 CONH-S- CH! !CH2)3NH2]CONHMe 47 CH2SO2NH-[4-NH2?h] 48 CONH-S- CH! (CH2)2NH2]CONHMe 49 2-imidazolyl 50 CONHMe 406 51 2-oxazoly 52 CONHCH2CONMe2 53 2-chiazolyl 54 CONHCH2CONHEt 55 2-benzinudazolyi 465 56 CONHCH2CONEC2 57 CONH-R-CH;CH3)Ph 58 CONHCH2CONH- cvcloproūvl 59 CONH-S-CH(CH3)Ph 60 CONHCH2CONH- cvclobutvl 0 1 CONHCH2CONHMe 463 62 CONHCH2CONH- cvcloDentvi 63 CONH-S-CH(CH3)CONHMe 477 64 CONHCH2CONK- cvclohexvl €5 CONH-R-CH(CH3)CONHMe 477 66 CONKCH2CONH-Cerc- butvl 6 7 CONH-S-CH!2 -propvl)CONHMe 505 68 CONH-S- CH (CH2Ph) CONHMe 69 CONH-S- CH (CH2SH!CONHMe 70 CONH-S-CH(CH2-P-MeOPh)CONHMe 583 71 CONH-S- CH (CH2OH)CONHMe 433 72 CONHCH2CH2CONHMe 499 73 CONH-R- CH (CHoOK) CONHMe 493 74 CONHCH2CH2CH2CONHMe 75 CONH-S-CHiCH20-L-Bu)CONHMe 543 76 CONH-S- CH ! CH2CH2OH)CONHMe 77 CONH-R-CH'CH2O-C-' Bu)CONHMe 549 78 CONK-S- (CH(CH2)3CH3)CONHMe 79 CONK-CH:Phj2 80 CONH(CH2>2C02Me 8 i CO-L>-proline-NHMe 82 CONH(CH2)2CO2H 83 CONHCH2CO(N-oiDerazir.vl' 34 CONH-S- CH! ! CH2)3NHBOC]COoMe 85 CONHCH2CO (N-.Tie-hy: -N-oiDerazznvl) 86 CONH-S- CH [ (CH2)3NHBOC]CONHMe 87 CONHCH2CO (2i-acezyl-N-Dizserazznvl) 88 CONH-S-CH- [ (CH?)3NH2]CO^Me 89 CONHCH2CO-N- morobclinc 90 CONH-S- CH! 'CH2)4NH2]CONHj 520 91 CONKCH2CC- ;n- ;.4-hvdrcx'/oiDerzdinvl 1 9 2 C0NH1CH2)2?h 93 co;:-: 34 CONH: CH2 )2-(3,4,-diz;ezhoxvOhenvl) 95 CONHBn 482 96 CONH(CH2)2-<N-morpholinvl) 97 CONH-2-pyridyl 98 CONH(CH2)3 -(N-morpholino) 99 CONH-Ph 100 CONHCH2CONH-(2-pvridvl) 101 CONK-3-pyridyl 102 CONHCH2CONH-(3-pvridvl) 103 CONH-4-pyridyl 104 CONHCH2CONH-(4-pvridvl) 105 CONH-CHjCH (Ph) 2 600.6 106 C0NH(CHj)2(P-S02NH2- Ph) 575 107 CONHCHj-2- benzimidazole 522 108 CONH-2-benzimidazole 508 LV 12167 TABLE2
For the cvclophane:
2 X R2 (Cl-MS) ai 2 X R2 (CI-MS) as 120 C02Me 435.3 121 CONH-cyc1openty1 122 C02Et 123 CONH2 124 C02iPr 125 CONHiPr 126 C02(CH2)20Me 479.4 127 CONH-terc-bucyl 128 C02(CH2)2Ph 525.4 129 CONMe2 448.5 13 C C02-CBu 131 CONEt2 132 C02CH2C0NHMe 429.4 133 CONK-3-indazolyl 134 CH2OH 135 CONH-adamantyl 13 6 CH2OCK2CH3 137 CONHCH2(p-S02NH2-Ph) 13 8 CH20CH2CH2C02CH3 139 CONH(CH2)3-1-imidazolvl 528.5 140 CHOBn 141 C0NHS02NH2 142 CONH(CH2)2-2-pyridyl 525.5 143 CONHSO2CH3 144 C 0(N-mo rpho1i ny1; 145 CONHS02Ph 146 CO(N-Me-N-DiDerazinvl) 503.6 147 CONHS02Bn 148 CONH C CH2)2-(N-Me-N-PĪDerazinvl) 149 CCNHS02-N-Me-imidazolvl 150 CONH-cyclopropyl 151 C0NHS02-p-NH2Ph 152 CONK-cyclobuzyl 153 C0NK302-p-MeOPh 154 C0NHS02-p-F-Ph 155 CONH-S-CH (CH2CH(CH3)2]CONHMe 156 CONH ;CH2'2NHS02Me 541.5 157 CONH;CH2)4NHS02Me 569.5 158 COi3H-cyclohexyl 502.5 159 CON"H CH2) gNHS02Me 597.6 160 CONH-2-imidozolyl 161 | CONH-R-CH (CHoCH(CH3)2]CONHMe 162 CH2SO2NHCH3 163 CONH-S-CH [ (CH2)4NH2]CONHMe 164 CH2S02NHPh 165 CONH-S- CH i (CH2)3NH2lCONHMe 548.5 166 CH2SO2NH-[4-NH2Ph] 167 CONH-S- CH [(CH?)2NH2]CONHMe 168 2-iiaidazolyl 169 CONHMe 434.4 170 2-oxazoly 171 CONHCH2CONMe2 172 2-thiazolyl 173 CONHCH2CONHEt 174 2-benzimidazolyl 175 CONHCH2CONEC2 176 CONH-R-CH(CH3)Ph 177 CONHCH2CONH- cvclooropvl 178 CONH-S-CH(CH3)Ph 179 CONHCH2CONH- cvclobucvl 180 CONHCH2CONHMe 491.5 181 CONHCH2CONH- cvclopentvl 182 CONH-S-CH i CH3)CONHMe 505.6 183 CONHCH2CONH- cyclohexvl 184 CONH-R-CH!CH3)CONHMe 505.5 185 CONHCH2CONH-terc-butvl 186 CONH-S-CH(2-propvl;CONHMe 187 CONH-S- CH (CH2Ph) CONHMe 188 CONH-S- CH (CH?SH) CONHMe 189 CONH-S-CH(CH2-p-MeOPh)CONHMe ISO CONH-S- CH (CH2OH) CONHMe 191 CONHCH2CH2CONHMe 192 CONH-R- CH (CHjCH; CONHMe 193 CONHCH2CH2CH2CONHMe 194 CONH-S-CH(CH20-t-Bu) CONHMe 577.6 195 CONH-S- CK!CH2CH20H)CONHMe 196 CONH-R-CHCCH2O-C-Bu)CONHMe 197 CONH-S- (CH(CH2)3CH3)CONHMe 198 CONH-CK(Ph)2 199 CONH(CH2)2C02Me 506.4 200 CO-L-prolme-NHMe 201 C0NH(CH2)2cO2h 492.3 202 CONHCH2CO(N-piperazinvl) 203 CONH-S- CH : (CH2)3NHBOC]C02Me 649.5 204 CONHCH2CO{N-mechy1-N-oiDerazinvl) 205 CONH-S-CH [ (CH2)3NHBOC]CONHMe 648.6 206 CONHCH2CO(N-acetyl-N-oioerazinvl) 207 CONH-S-CH-[:CH2)3NH2]C02Me 549.5 208 CONHCK-CO-N- morphciinoi 209 CONH-S- CH [ (CH2)4NH2]CONH^ 548.5 210 CONHCHiCO-[N-(4 -hvdroxvpiceridinvl'] 211 CONH(CH2)2P^ 524.5 212 CC-H 421.4 213 CCNH (CH.2 ) 2 “ (3,4 , -dzmethcDcvphenvi) 584.6 214 CONHBn 510.5 215 C0NH(CH2)2-(N- morsholinoi 533 .5 06- LV 12167 216 CONH-2-pyridyl 217 CONH(CH2)3-(N-morDholi.no) 547.5 218 CONH-Ph 219 CONHCH2CONH-(2-Dvridvl) 220 CONK-3-pyridyl 221 CONHCH2CONH-(3 -Dvridvl) 222 CONH-4 -pyridy1 223 CONHCH2CONH-(4-ovridvl) 224 CONH-CHjCH(Ph), 600.6 225 CONH (CH2) 2 (P-SOjNH;-Ph) 603.6 -207- TABLE3
Fcr the cyclcphane:
E X R2 (CI-MS) m s B x R2 (CI-MS) ne 240 C02Me 241 CONH-cyc1openty1 242 CO2EC 243 CONH2 244 C02iPr 245 CONHiPr 246 CO2 (CH.2) 2°Me 247 CONH -cērt-bucyl 248 CO2 (CH;ļ) 2Ph 249 CONMe2 250 C02~cBu 251 CONEt2 252 C02CH2C0NHMe 253 CCNH-3-indazolyl 254 CH2OK 255 CONH-adamantv1 256 CH2CCH2CH3 257 CONHCH2(p-S02NH2-Ph) 258 CH2OCH2CH2CO2CH2 259 CONH(CH2)3-1-imidazolvi 260 CHOBn 261 CONHSO2NH2 262 CONH(CH2)2-2-pyridvl 263 CONHSO2CH3 264 CO;N-mcrphoiinyl) 265 CONHS02Ph 2 66 CO (N-Me-N-piperazir.v 1) 267 CONHS02Bn 268 CONH(CH2i2“(N-Me-N-DiDerazinvl) 269 CONHS02-N-Me- imidazolyl 270 CONH-cyciopropyl 271 C0NHS02-p-NH2Ph 272 CONH-cy c i obuc y1 273 C0NHS02-p-MeOPh -208- LV 12167 274 C0NHS02-p-F-Ph 275 CONH-S-CH (CH?CH(CH3)21CONHMe 276 CONH(CH2)2NHS02Me 277 CONH(CH2)4NHS02Me 278 CONK-cvclohexyl 279 CONH(CH2)6NHS02Me 280 CONH-2-imidozolyl 281 CONH-R-CH [CH2CH(CH3)2lCONHMe 282 CH2SO2NHCH3 283 CONH-S-CH [(CH2)4NH2)CONHMe 284 CH2S02NHPh 285 CONH-S- CH ! (CH2)3NH2]CONHMe 286 CH2S02NK-[4-NH2Ph] 287 CONH-S- CH [ (CH?)2NH2JCONHMe 288 2-imidazolyl 289 CONHMe 290 2-oxazoly 291 CONHCH2CONMe2 292 2-thiazolyl 293 CONHCH2CONHEt 294 2-benzimidazoly1 295 CONHCH2CONEC2 296 CONH-R-CH(CH3)Ph 297 CONHCH2 CONH-cvclooroDvl 293 CONH-S-CH(CH3) Ph 299 CONHCH2CONH- cvclobutvl 300 CONHCH2CONHMe 301 CONHCH2CONH- cvcloDencvl 302 CONH-3-CH:CH3)CONHMe 303 CONHCH2CONH- cvclohexvl 3C4 CONH-R-CH!CH3)CONHMe 305 CONHCH2CONH-terz-bucvl 306 CONH-S-CH(2-propyl'CONHMe 307 CONH-S- CH (CH -5 Ph) CONHMe 308 CONH-S- CH (CH?SHi CONHMe 309 CONH-S-CH(CH2-P-MeOPh)CONHMe 310 CONH-S- CH (CH2OH;CONHMe 311 CONHCH2CH2CONHMe 312 CONH-R- CH (CH?OK)CONHMe 313 CONHCH2CH2CH2CONHMe 314 CONH-S-CHiCH20-t-Bu)CONHMe 315 CONH-S- CH ! CH2CH2OH)CONHMe 316 CONH-R-CH(CH2O-C-Bu)CONHMe 317 CONK-S- (CHiCH2)3CH3)CONHMe 318 CONH-CHi Ph)2 319 CCNH(CH2)2C02Me 320 CO-L-prslme-NHMe 321 C0NH(CH2)2CO2H 322 CONHCHiCO(N-DiDerazinvl) 323 CONH-S- CH ; iCH2)3NHBOC]CQ2Me 324 CONHCH2CO(N-mechyl-N-Oioerazinvl) 325 CONH-S- CH [ (CH2)3NHBOC]CONHMe 326 CONHCH2 CO(N-ace cy1-N-zjioerazinvl) 327 CONH-S-CH-: :CH2)3NH2!C02Me 323 CONHCH-CO-N* morOhclīnc 329 CONH-S- CH ; ·:CH2) 4NH0 ] CONH2 -209- 330 CONHCH2CO-[N-(4- hvdroxvpioeridinvl)) 331 CONH(CH2)2Ph 332 C02H 333 CONH(CH2)2-(3 - 4,-dimethoxvphenvl) 334 CONHBn 335 CONH(CH2)2-<N- morpholino) 336 C0NH-2-pyridyl 337 CONH(CH2)3~(N-morpholino) 338 CONH-Ph 339 CONHCH2CONH-(2-pvridvl) 340 CONH-3-pyridyl 341 CONHCH2CONH-(3 -pvridvl) 342 CONH-4-pyridyl 343 CONHCH2CONH-(4-pvridvl) 344 CONK-CH2CH(Ph)2 600.6 345 CONH (CHj) 2 (P-S02NH2-Ph) 603.6 -210- LV 12167 TABLE.4
Fcr the cyclophane:
R2
E x R2 (CI-MS) me Ex R2 (CI-MS) as 35C C02Me 351 CONH-cyc1openty1 252 CO2EC 3 53 CONH2 254 C02iPr 355 CONHiPr 356 CO2(CH2)20Me 357 CONH-cērt-butyl 358 CO2(CH2)2?n 359 CONMe2 360 C02-tĒu 361 CONEc2 3 62 C02CH2C0NKMe 3 55 CONH-3-indazolvl 364 CH2OH 365 CONH-adamantyl 366 CH2OCH2CH2 357 CONHCH2(p-S02NH2-Ph) 363 CH2OCH2CH2CO2CH3 3 5? CONK(CH2)3-1-imidazolvl 370 CHOBn 3 71 CONHSO2NH2 372 CONH(CH2)2-2-?yridyl 372 CONHSO2CH3 374 CO (N-mcrphcl;.nyl, 3 75 C0NKS02Ph 3 76 CO(N-Me-N-Oioerazinvl) 3~" C0NHS02Bn 378 CONH (CH2 ) 2 - ! N-Me-N-DĪDerazir.vl l 3"9 C0NHS02-N-Me-imidazolvl 380 CONH-cyclocrspyl 381 CONHSC2-p-NH2Ph 382 CONK - cy c 1 oč'-zv 1 362 CONHSC2-p-MeOPh 1 - 384 CONKSCo-p-F-Ph 385 CONH-S-CH [CH2CH(CH3)?]CONHMe 386 C0NH(CH?)2NHS02Me 387 C0NH(CH2)4NHS02Me 388 CONH-cvc1o hexy1 389 CONH(CH2)6NHS02Me 3 9 C C0NK-2-irru.dozolyl 391 CONH-R-CH [CH2CH(CH3)2)CONHMe 392 CK2SO2NHCH3 393 CONH-S-CH ((CH2)4NH2]CONHMe 394 CH2S02NHPh 395 CONH-S- CH [ (CH2)3NH2]CONHMe 396 CH2S02NK-[4-NH2Ph] 397 CONH-S- CH [ (CH2)2NH2lCONHMe 398 2-imidazolyi 399 CONHMe 400 2-oxazoly 401 CONHCH2CONMe2 402 2-chiazolyl 403 CONHCH2CONHEC 404 2-benzimidazolyl 405 CONHCH2CONEC2 406 CONH-R-CH(CH3)Ph 407 CONHCH2CONH- cvcloDroovl 408 CONK-S-CH(CH3)Ph 409 CONHCH2CONH- cvclobucvl 410 C0NKCH.2C0NHMe 411 CONHCH2CONH- cvcloDencvl 412 CONK-S-CH ,'CH3 ) CONHMe 413 CONHCH2CONH- cvclohexvl 414 CONK-R-CH{CH3)CONHMe 415 CONHCH2CONH-cerc- butvl 416 CONK-S-CH(2-ņroņvlCONHMe 417 CONH-S- CH !CH2?h)CONHMe 418 CONK-S- CH (CH 2 SH) CONHMe 419 CONH-S-CH(CH2-P-MeOPh)CONHMe 420 CONK-S- CH (CH?OH i CONHMe 421 CONHCH2CH2CONHMe 422 CONH-R- CH ( CH?OH)CONHMe 423 CONKCH2 CH2CH2CONHMe 424 CONK-S-CH(CH20-C-Bu)CONHMe 425 CONH-S- CH (CH2CH2OH) CONHMe 426 CONH-R-CH(CH2O-C-Bu)CONHMe 427 CONH-S- (CH(CH2)3CH3)CONHMe 428 CONH-CK(Ph)2 429 CONK(CH2)2C02Me 430 CO-L-prolme-NHMe 431 CCNH(CH2>2C02H 432 CONKCH2CO(N-Oioerazinvl) 433 CONH-S- CH [(CH?)3NHECC]C02Me 434 CONHCH2CO(N-mechyl-N-cioerazinvl) 435 CONH-S- CH [ (CH?)3NHBCC]CONHMe 436 CONHCK2CO(N-acezyl-N-sioerazinvl> 437 CONH-S-CH- f(CH? ' 3NH2C02Me 438 CONHCH?CO-M-mcrohclinc 439 CONH-S- CH (:CH?)4NK?;CONH2 LV 12167 440 CONHCH2CO-[N-(4 -bvdroxvpioeridinvl) 1 441 CONH(CH2)2Ph 442 CO2H 443 CONH(CH2)2-(3,4, -dimēthoxvphenvl) 444 CONHEn 445 CONH(CH2)2"(N-morpholino) 446 CONK-2-pyridyl 447 CONH(CH2)3 -{N-morpholino) 448 CONK-Ph 449 CONHCH2CONH-(2-pvridvl) 450 CONH-3-pyridyl 451 CONHCH2CONH-(3 -pvridvl) 452 CONK-4-pyridyl 453 CONHCH2CONH-(4-Dvridvl) 454 CONK-CHjCH (Ph) 2 455 C0NH(CH2)2(P-S03NH2- Ph) -213- TABLE5
For the cyclop'nane:
E x R2 (CI-MS) m s B X R2 (CI-MS) ne 470 C02Me 471 CONH-cyclopentyl 472 C022t 473 CONH2 474 C02i?r 475 CONHiPr 476 C02(CH2)2OMe 477 CONH-cert-butvl 47Π CC2 iCH2)2ph 479 CONMe2 480 C02-C3U 481 CONEZ2 432 CC2CH2CCNHMe 483 CCNH-3-indazolyl 484 CH2OH 485 CCNH-adamanty1 486 ch2oc:-:2cH3 487 CONKCH2(p-S02NH2-Ph) 488 CH20CH2CH2C02CH3 489 CONH(CH2)3-1-imidazolvl 490 CHC3n 491 - C0NHS02NH2 492 CONH(CH2)2'2-pvridyl 493 CONHSO2CH3 494 CO (N-morpholmyl) 495 CONHS02Ph 496 CO(N-Me-N-oioerazinvl) 497 CONHS02Bn 498 CONH(CK2)2-(N-Me-N-pioerazinvl) 499 CONHSO2-N-Me-imidazolvl 500 CONK-cycis?ropyi 501 CCNHS02-p-NH2Ph 502 CONH-cvc1:buz y1 503 CONHSO2-p-MeOPh -214- LV 12167 504 CONHSC>2-p-F-Ph 505 CONH-S-CH [CH?CH(CH3)21CONHMe 505 CONH{CH2)2NHS02Me 507 CONH(CH2)4NHS02Me 508 CONK-cyclohexyl 509 CONH;CK2)6NHS02Me 510 CONH-2-imidezolyl 511 CONH-R-CH [CH2CH(CH3)21CONHMe 512 CH2SO2NHCH3 513 CONH-S-CH ( (CH2)4NH2]CONHMe 514 CH2302NHPn 515 CONH-S- CH [(CH2)3NH21CONHMe 516 CH2S02NH-(4-NH2Ph] 517 CONH-S- CH ( (CH2)2NH21CONHMe 518 2-iiriidazoiyl 519 CONHMe 520 2-oxazoly 521 CONHCH2CONMe2 522 2-thiazolyl 523 CONHCH2CONHEC 524 2-benziirudazolyl 525 CONHCH2CONEt2 52 6 CONK-R-CH (CH3 ) Ph 527 CONHCH2CONK- cvciooropvl 528 CONK-3-CH(CH3)Ph 529 CONHCH2CONH- cvclobucvl 530 CONKCH2CONHMe 531 CONKCH2CONH- cvclopencvl 532 CONK-S-CH(CH3/CONHMe 533 CCNKCH2CONH- cvclohexvl 534 CONH-R-CK(CH3)CONHMe 535 CONHCH2CONH-cert-bucvl 53 6 CONK-S-CH(2-propvl)CONHMe 537 CONH-S- CH (CKoPh) CONHMe 538 CONK-S- CH (CH2SH)CONHMe 539 CONH-S-CH(CH2-p-MeOPh)CONHMe 540 CONK-S- CH {CHoOH)CONHMe 541 CONHCK2CH2CONHMe 542 CONK-R- CH (CH2OH) CONHMe 543 CONHCH-2 OH2CH2CONHMe 544 CONK-S-CH(CK20-c-Eu)CONHMe 545 CONK-S- CH (CH2CK2OH)CONHMe 546 CONH-R-CH(CH20-C-Bu)CONHMe 547 CCNH-S- (CH(CH?:3CH3)CONHMe 548 CONK-CH{Ph)2 549 C0NK:CH2) >C02Me 550 CO-L-proiine-NHMe 551 CONK;CH2)2CO2K 552 CONHCH2CO(N-DiDerazinvl> 553 CCNH-S- CH[(CH-'3NHBOC]CO?Me 554 CONHCH2CO(N-merhy1-N-oiūerazinvl) 555 CCNH-S- CH [ (CH?. i 3 NHBOC ] CONHMe 555 CONHCH2CO(N-acezyl-N-oioerazinvl 557 CONH-S-CH- [ (- jNK-j ] COoMe 553 conhch2cc-n- mcr"3holir.cl 559 CONH-S- CH [(CH- 4NK0]CONH2 -215- 560 CONHCH2CO-(N-(4-hvdroxvpiperidinvl)1 561 CONH(CH2)2Ph 562 CO2H 563 CONH(CH2)2-<3,4,-dimechoxvphenvl) 564 CONKBn 565 CONH(CH2)2“(N-morpholino) 566 CONH-2-pryidyl 567 CONH (CH2)3 -(N-moroholino) 568 CONH-Ph 569 CONHCH2CONH-(2-ovridvl) 570 CONH-3-pyridyl 571 CONHCH2CONH-{3 -pvridvl) 572 CONK-4-pyridyl 573 CONHCH2CONH-(4-pvridvl) 574 CONH-CHjCH{Ph)j 575 CONH(CH3)j(P-SOjNHj- Ph) -216- LV 12167 TABLE6
For the cyclophane:
E X R2 (CI-MS) me 2x R2 (CI-MS) na 600 C02Me 601 CONH-cyclopentyl 602 CO2EC 603 CONH 2 604 C02iPr 505 CONHiPr 606 CO2(CH2>20Me 607 CONH-tert-bucyl 608 CO2(CH2)2Ph 609 CONMe2 610 C02“CBu 611 CONEt2 612 C02CK2C0NHMe 613 CONH-3-indazolyl 614 CH2OH 515 CONH-adamancy1 616 CH2OCH2CH3 617 CONHCH2 ip-S02NH2-Ph) 618 CH2OCH2CH2CO2CH3 519 CONH(CH2)3-l-imidazolvl 620 CHOBn 621 CONHSO2NH2 622 CONH(CH2)2-2-pyridyl 623 -CONHSO2CH3 524 CO(N-morphoiinyl) 525 C0NHSO2Ph 626 CO(N-Me-N-oicerazir.vl) 627 C0NHSO2Bn 62 8 CONH (Cr*2 ) 2- iN-Me-N-DiDerazinvl) 529 CONHS02-N-Me-imidazolvl 630 CONH-cyclopropyl 531 C0NHS02-p-NH2Ph 632 CONH-cyclcbucy1 633 CONHSG2-p-MeOPh 634 CONHS02-p-?-Pl~ 53 5 CONH-S-CH [CH?CH:CH3)21CONHMe 63 6 C0NH(CH2)2NHS02Me 637 CONH(CH2)4NHS02Me 638 CONH-cyclohexyl 639 C0NH(CH2)6NHSO2Me 640 CONH-2-imidozoly1 641 CONH-R-CH [CHjCH(CH3)2]CONHMe 642 CH2SO2NHCH3 643 CONH-S-CH [(CH2)4NH2lCONHMe 644 CH2SC>2NHPh 645 CONH-S- CH [(CH2)3NH21CONHMe 646 CH2S02NH-[4-NH2Ph] 647 CONH-S- CH [(CH2)2NH2]CONHMe 648 2-imidazolyl 649 CONHMe 6SO 2-oxazoly 651 CONHCH2CONMe2 652 2-chiazolyl 653 CONHCH2CONHEt 654 2-benzimidazolyi 655 CONHCH2CONEC2 656 CONH-R-CH(CH3 > Ph 657 CONHCH2CONH- cvcloūropvl 658 CONH-S-CH (CH'3) Ph 659 CONHCH2CONH- cvclobutvl 660 CONHCH2CONHMe 661 CONHCH2CONH- cvcloDentvl 662 CONK-S-CH(CH3)CONHMe 663 CONHCH2CONH- cvclohexvl 664 CONH-R-CH;CH3)CONHMe 665 CONHCH2CONH-Cert- bucvl 666 CONH-S-CH(2-propvl)CONHMe 667 CONH-S- CH (CH -j Ph) CONHMe 668 CONH-S- CH (CH2SH) CONHMe 669 CCNH-S-CH(CH2-p-MeOPh)CONHMe 670 CONH-S- CH (CH2OH) CONHMe 671 CONHCH2CH2CONHMe 672 CONH-R- CH (CH2OH) CONHMe 673 CONHCH2CH2CH2CONHMe 674 CONH-S-CH(CH20-:-’ Bu)CONHMe 675 CONH-S- CH (CH2CH2OH!CONHMe 676 CONH-R-CH(CH2O-:-Bu)CONHMe 677 CONH-S- (GK;CH2)3CH3)CONHMe 678 CONH-CH(Ph)2 679 CCNH(CH2)2C02Me 680 CO-L-prciine-NHMe 681 CONH(CH2)2CO2H 582 CONHCH2CC(N-oioerazinvl) 683 CONH-S- CH [ ; CH.2) 3NHEOC ] C02Me 684 CONHCH2CO(N-methyI-N-DiDerazinvl) 685 CONH-S- CH [ί CH2)3NHBOC)CONHMe 686 CONHCH2CO(N-acetyI-N-ūiDerazinvl' 687 CONH-S-CH-[;CH2)3NH2lCO?Me 638 CONHCH2CO-N- morchsimc 689 CCNK-S- CH;.CH2)4NH2ICONH2 690 CONHCH2CO-Γ N-(4 -hvdroxv-)icer i dinvl ’ ' 691 CONH:CH2!2Pn -218- LV 12167 692 co2h 693 CONH (CH2) 2*0,4,-dimechoxvphenvl) 694 CONHBr, 695 CONH(CH2)2-(N- morpholino) 696 CONH-2-pyridyl 697 CONH(CH2)3-(N- morpholino) 698 CONH-Ph 699 CONHCH2CONH-(2-pvridvl) 700 CONH-3-pyridyl 701 CONHCH2CONH-(3 -pvridvl) 702 CONH-4-pyridyl 703 CONHCH2CONH-(4 -pvridvl) 704 CONK-CHjCH(Ph) j 705 C0NH (CHj) 2 (P-S0jNHj-Ph) -215- TABLE7
For the cyclo?hane:
Ex R2 (CI-MS) me īx R2 (CI-MS) me 710 C02Me 435 711 CONH-cyclopencyl 712 C02Et: 713 conh2 714 C02iPr 715 CONHiPr 716 C02(CH2)2OMe 717 CONH-cert-buc.yl 713 C02(CH2)2Ph 719 CONMe2 720 C02-tBu 721 CONEt2 722 C02CH2C0NHMe 723 CONH-3-indazolyl 724 CH2OH 725 CONH-adamantyl 726 CH2CCH2CH3 727 CONHCH2(p-S02NH2-Ph) 728 CH20CH2CH2C02CH3 729 CONH(CH2)3-l- imidazolvl 730 CHOBn 731 conhso2nh2 732 CONK(CH2)2-2-pyridyl 733 C0NKS02CH3 734 CO(N-mcrphoIinyl) 735 C0NHS02Ph 736 CO(N-Me-N-OiDerazinvl) 737 C0NHS02Bn 738 CONH(CH2i 2~(N-Me-N-oiDerazinvl) 73 9 C0NHSO2-N-Me- imidazolvl 740 CONH-ci'dopropyl 741 C0NHSO2-p-NH2Ph 742 CCNH-cyclofcutyl 743 C0NKSO2-p-MeOPh 744 C0NKS02-?-?-Ph 745 CCNH-S-CH [CH-CH!CH3)2]CONHMe LV 12167 746 CONH(CH2)2NHS02Me 747 CONH(CH2)4NHS02Me 748 CONK-cyclohexyl 749 C0NH(CH2)6NHS02Me 750 CONK-2-imidozoiyl 751 CONH-R-CH [CH?CH(CH3)2]CONHMe 752 CH2SO2NHCH3 753 CONH-S-CH [(CH2)4NH2)CONHMe 754 CH2S02NHPh 755 CONH-S- CH [ (CH2)3NH2]CONHMe 756 CH2S02NH-[4-NH2Ph] 757 CONH-S- CH [ (CH2)2NH2]CONHMe 758 2-irmdazolyl 759 CONHMe 434 760 2-oxazoly 761 CONHCH2 CONMe2 762 2-chiazciyl 763 CONHCH2CONHEt 764 2-benzinu.dazolyl 765 CONHCH2CONEt2 766 CONH-R-CH(CH3)Ph 767 CONHCH2CONH- cvcloDropvl 768 CONH-S-CK (CH3 > Ph 769 CONHCH2CONH- cvclobutvl 770 CONHCH2CONHMe 771 CONHCH2CONH- cvcloDentvl 772 CONH-S-CK ί CH3)CONHMe 773 CONHCH2CONH- cvclohexvl 774 CONH-R-CH (CH3} CONHMe 775 CONKCH2CONH-cert- bucvl 776 CONK-S-CH(2 -propvl)CONHMe 777 CONH-S- CH (CH2Ph) CONHMe 778 CONK-S- CH (CH2SH'CONHMe 779 CONK-S-CH(CH2-P-MeCPh)CONHMe 780 CONH-5- CK(CH9OH'CONHMe 781 CONKCH2 C H 2CONHMe 782 CONK-R- CK(CH?OHiCONHMe 783 CONHCK2CH2CH2CONHMe 784 CONH-S-CH;CH2O-t-' 3u)CCNHMe 785 CONH-S- CH (CK7CH2OH)CONHMe 786 CONH-R-CH(CH2O-C-Bu) CONHMe 787 CONK-S- (CH(CK2) 3CH3)CONHMe 788 CONH-CH(Phi2 789 C0NK(CH2)2C02Me 790 CO-L-proline-NHMe 791 CONH(CH2)2CO2H *? ο CONHCH2CO(N-oiDerazinvl: 793 CONH-S- CH f(CH~)3NHBOC]C02Me 794 CONKCK2CO (N-mecr.yl-N-Dioerazinvl' 795 CONK-S- CH [ (CK213NHBOC]CONHMe 79 6 CONHCH2CO<N-acecyl-N-piDeraiinvi < 797 C0NH-S-CH-[(CK2)3NH2]CO^Me 798 CCNKCK2CO-N-mc rshīlmc 799 CONH-S- CH [ i c:-:->) 4NH2 ]conh? 800 conkch2c:-;n-'4- hvdrox'vT3ioerxdxrjvl! ' 301 CCNK(CH2)2Ph 802 co2h 803 CONH(CH2)2-(3,4,-dimethoxvphenvl) 804 CONHBn 805 CONH(CH2)2-(N- morpholino) 806 CONH-2-pyridyl 807 CONH(CH2)3 -(N-morpholino) 808 CONH-Ph 809 CONHCH2CONH-{2 -pvridvl) 810 CONH-3-pyridyl 811 CONHCH2CONH-(3 -pvridvl) 812 CONH-4-pyridyl 813 CONHCH2CONH-(4 -pvridvl) 814 CONH-CHjCH (Ph) j 815 CONH(CHj) j(P-S02NH2-Ph) -222- LV 12167
TABLES
Fcr t'ne cyclic carbamate:
O
E X *2 (CI-HS) Bl B x R2 (CI-MS) ae 820 C02Me 821 CONH-cyclopentyl 822 C02Eī. 823 CONH2 824 C02iPr 825 CONHiPr 826 CO2(CK2)2OMe 827 CONH-cērt-bucyl 828 C02(CH2>2Ph 825 CONMe2 830 CO2-CBU 831 CONEC2 832 C02CH2C0NHMe 833 CONH-3-indazolyl 834 CH2OH 835 CONH-adamantyl 836 CH2OCH2CH3 83“ CONHCH2(p-S02NH2-Ph) 838 CH2OCH2CK2CC2CH2 839 CCNH(CH2)3-1-imidazolvl 840 CHOBn 841 CONHSO2NH2 842 CONH(CH2)2~2-pvridyl 843 CONHSO2CH3 844 CO(N-morpholino) 845 C0NHSO2Ph 846 COtN-Me-N-DiDerazinvI) 84" C0NHS02Bn 848 CONH (CH’2) 2" (N-Me-N-oiDerazinvl) 849 CONHSO2-N-Me-i.Tiidazolvl 850 CONH-cyc1opr opy1 851 C0NHS02-p-NH2Ph 8 52 CONH-cyclo£ucyl 853 CONHSO2-p-MeOPh 854 C0NHS02-D-r-?h 855 CCNH-3-CH [CH2CH :CH3 ) ? ] CONHMe -223- 8 55 CONH(CHt)2NHS02Me 857 C0NH(CH2)4NHS02Me 858 CONH-(4- hydroxycyc1ohexy1 542.5 859 CONH(CH2)6NHS02Me 850 C0Nn-2-imidozolyi 861 CONH-R-CH [CH2CH(CH3)2]CONHMe 8 62 CH2SO2NHCH3 863 CONH-S-CH [(CH2)4NH2]CONHMe 854 CH2S02NHPh 865 CONH-S- CH ( (CH2)3NH2]CONHMe 866 CH2SO2NK- [4-NH2ī>h] 867 CONH-S- CH [ (CH2)2NH2]CONHMe 868 2-iiaidazolyl 869 CONHMe 429.3 870 2-oxazoly 871 CONHCH2CONMe2 500.3 872 2-chiazolyl 873 CONHCH2CONHEt 874 2-benzimidazolyl 875 CONHCH2CONEt2 876 CONH-R-CH(CH3)Ph 877 CONHCH2CONH- cvcloDropvl 878 CONH-S-CH(CH3)Ph 879 CONHCH2CONH- cvclobutvl 880 CONHCH2CONHMe 486.5 881 CONHCH2CONH- cvcloDencyl 1 00 00 Μ CONK-S-CK;CH3)CONHMe 883 CONHCH2CONK- cvclohexvl 884 CONH-R-CH:CH3)CONHMe 885 CONHCH2CONH-cert- butvl 886 CONH-S-CH(2-propvl'CONHMe 887 CONH-S- CH (CH2Ph) CONHMe 888 CONH-S- CH (CH2SH)CONHMe 889 CONH-S-CH(CH2-P-MeOPh)CONHMe 890 CONH-S- CH (CH?OH) CONHMe 891 CONKCH2CH2CONHMe 892 CONH-R- CH (CH 2 OH) CONHMe 893 CONKCH2CH2CH2CONHMe 894 CONH-S-CH!CH20-t-Bu)CONHMe 895 CONH-S- CH (CH2CH2OH) CONHMe 896 CONH-R-CH(CH20-t-Bu)CONHMe 897 CONH-S- (CH(CH2)3CH3)CONHMe 898 CO-L-prciinoi 556.5 899 C0NH(CH2)2C02Me 900 CO-L-prclme-NHMe 901 C0NH(CH2)2C02H 902 CONKCH2CO(N-DiDerazinvl) 903 CONH-S- CH ( (CH2)3NHB0C]C02Me 904 CONHCH2CO(N-mechy1-N-oioerazinvi) 555.5 905 CONH-S- CH { (CH.2) 3NHBOC ] CONHMe 906 CONHCH2CO!N-echyl-N-DiDerazinvl) 569.6 907 C0NH-S-CH- [ f CH*>) 3NH2 ] CO?Me 908 CCNHCH2CO-!3- mcrOhclinc 542.5 909 CONH-S- CH [ (CH2)4NH2]CONH2 LV 12167 910 CONHCH2CO-[N-(4 -hvdroxvmoeridinvl) } 555.7 911 CONH(CH2)2Ph 912 co2h 913 CONH(CH2)2“(3,4 »-dimechoxvphenvl) 914 CONHBn 915 CONH(CH2)2-(N“ morDholi.no) 916 CONK-2-pryidyi 496.5 917 CONH(CH2)3 -(N-morDholinc) 918 CONH-Ph 919 CONHCH2CONH-(2 -Dvridvl) 549.5 920 CONH-3-pyridyl 921 CONHCH2CONH-(3-•pyridvl) 922 CONH-4-pyridyl 923 CONHCH2CONH-(4-Dvridvl) 924 CONK-CHjCH (Ph) j 925 CONH-4-(N-ethoxy carbonvlDioeridinvl 570.5 926 CONH-2-(3-mechyl)Thiazolyl 512.4 927 CONHCHjCNH-2- (3,4,5,6- tetrahvdropvridinvl) 553.6 928 CONHCHjCO-2 - (3 -methvDThiazolvl 569.3 929 CONHCH:-2-pyridyl 506.5 -225- TABLE 9
E X R2 (CI-MS) ne E χ R2 (CI-MS) me 930 C02Me 931 CONH-cyclopentyl 932 C02EC 933 CONH2 934 C02iPr 935 CONHiPr 936 C02(CH2)20Me 937 CONH-tert-bucyl 938 C02(CH2) 939 CONMe2 9 4 0 C02-CBU 941 CONEC2 942 C02CH2C0NHMe 943 CONH-3-indazolyi 944 2H20H 945 CONH-adamanty1 946 CH2OCH2CH3 947 CONHCH2(p-S02NH2-?h) 948 CH2OCH2CH2CO2CH3 949 CONH(CH2)3-1-iroidazolvl 950 CHOBn 951 CONHSO2NH2 952 CONK (C’r.2'2“2-pyridyl 953 CONHSO2CH3 954 CO (N-n;crpholinyl) 955 C0NHS02Ph 955 CC!N-Me-N-Dioerazinvl' 957 C0NHS02Bn 958 CONH (CH.2; 2" !N-Me-N-Dicerazinvl5 959 C0NHS02-N-Me- imidazolvl 960 CONK-cvc i cpropv1 961 CONHSO2-P-NH2 Ph 952 CONH-cyclobutyl 963 CONHS02-p-MeOPh 964 CONKSC2“F-F-Ph 955 CONH-S-CH CH2CH(CH3)2!CONKMe 965 CONH (CK;; 2'ĪHS02Me 967 CONH(CH2)4NHS02Me -226- LV 12167 963 CONH-cyclohexyl 969 C0NH(CH2)6NHSO2Me 970 CONH-2-inu.dozolyl 971 CONH-R-CH [CH2CH(CH3)2]CONHMe 972 CH2SO2NHCH3 973 CONH-S-CH [<CH2>4NH?]CONHMe 974 CH2S02NHPh 975 CONH-S- CH [<CH?)3NH?]CONHMe 976 CH2SO2NH-[4-NH2Ph] 977 CONH-S- CH [ (CH7J2NH?]CONHMe 978 2-imidazolyl 979 CONHMe 980 2-oxazoly 981 CONHCH2CONMe2 982 2-chiazolyi 983 CONHCH2CONHEC 984 2-benzimidazolyl 985 CONHCH2CONEt2 986 CONH-R-CH(CH3)Ph 987 CONHCH2CONH- CVClODrODVl 988 CONH-5-CH(CH3)Ph 989 CONHCH2CONH- cvclobucvl 990 CONHCH2CONHMe 991 CONHCH2CONH- cycloDencvl 992 CONK-S-CK(CH3)CONHMe 993 CONHCH2CONH- cyclohexvl 994 CONH-R-CH(CH3)CONHMe 995 CONHCH2CONH-terc- butvl 996 CONH-S-CH(2 -propvl)CONHMe 997 CONH-S- CH (CH2Ph) CONHMe 998 CONH-S- CH(CH2SH)CONHMe 999 CONH-S-CH(CH2-P-MeOPh)CONHMe 1000 CONH-S- CH (CH2OH)CONHMe 1001 CONHCH2CH2CONHMe 10C2 CONK-R- CH (CHjOH) CONHMe 1003 CONHCH2CH2CH2CONHMe 1004 CONH-S-CH(CH20-t-Bu) CONHMe 1005 CONH-S- CH ! CH2CH2OH)CONHMe 1006 CONH-R-CHiCH20-t-Bu)CONHMe 1007 CONH-S- <CH'CH2)3CH1)CONHMe 1008 CONH-CHiPh)2 1009 C0NH(CH2>2CO2Me 1010 CO-L-proline-NHMe 1011 CONH(CH2)2CO2H 1012 CONHCH2CO(N-DlDerazinvl) 1013 CONH-S- CH [ (CH2)3NHB0C]C02Me 1014 CONHCK2CO vN-inecir/i-N-Diperazi.nvl} 1015 CONH-S-CH [ (CH2)3NHBOC!CONHMe 1015 CONHCH2CO ·, N-acecyl -N-oiDerazinvl) 1017 CONH-S-CH- [ ;CH2)3NH2]C02Me 1018 CONKCH2CO-N- morDhclinc 1019 CONH-S- CH [;ch2)4NH2]CONH2 1020 CONHCH2CO-[N-(4-bvdrcxvr>i:ierid;.nvl ' 1021 CONH(CH2)2Ph 1022 CO2H 1023 CCNH (CH2)2"!3,4,-dir.eChoxvOhenvl! -22 1024 CONHBn 1025 CONH(CH2>2-(N- mornholino) 1026 CONH-2-pyridyl 1027 CONH(CH2)3-(N-morpholino) 1028 CONH-Ph 1029 CONHCH2CONH-(2-pvridvl) 1030 CONH-3-pyridyl 1031 CONHCH2CONH-(3-Dvridvl) 1032 CONH -4-pyr i dy1 1033 CONHCH2CONH-(4-pvridvl) 1034 CONK-CHjCH (Ph) 2 1035 CONH(CH2)2(P-S02NHj- Ph) -22S- LV 12167 TABLE 10
For che cyclic carbamace:
O
B x R2 (CI-MS) aa B x R2 (CI-MS) as 1050 C02Me 1065 CONH-cyclopency1 1051 co2ec 1066 CONH2 1052 C02iPr 1067 CONHiPr 1053 C02(CH2)2OMe 1068 CONH-tert-buty1 1054 C02(CH2 > 2Ph 1069 CONMe2 1055 C02_-Bu 1070 CONEt2 1056 C02CH2C0NHMe 1071 CONH-3-indazoiyl 1057 CH2OH 1072 CONH - adaLmanc y 1 1058 CH2CCH2CH3 1073 CONHCH2(p-S02NH2-Ph) 1059 CH20CH2CH2C02CHj 1074 CONH(CH2)3-1-imidazolvl 1060 CKOBn 1075 C0NHS02NH2 1061 CONH (CJi2) 2 - 2-ovridvl 1076 C0NHS02CH3 1062 CO(N-morphoiinyl· 1077 CONHS02Ph 1063 CO(N-Me-N-DiDerazinvl) 1078 CONHS02Bn 1064 CONH(CH2)2-(N-Me-N-Diūerazinvl) 1079 CONHS02-N-Me- imidazolvl 1080 CONH-cyclopropyl 1107 C0NHSO2-p-NH2Ph 1081 CONK-cyclobutyl 1108 CONHSO2-p-MeOPh 1082 C0NHS02-p-F-Ph 1109 CONH-S-CH [CH?CH(CH3)2]CONHMe 1085 CONH(CH2)2NHS02Me 1110 CONH(CH2)4NHS02Me 1084 CONH-cyc1ohexy1 1111 CONH(CH2)6NHS02Me 1085 CONH-2-iiru.dozolyl 1112 CONH-R-CH [CHjCH(CH3)2]CONHMe 1086 CH2302NHCH3 1113 CONH-S-CH [ (CH2UNH2] CONHMe 1087 CH2S02NHPh 1114 CONH-S- CH t(CH2)3NH2]CONHMe 1068 CH2SO2NH-[4-NH2Ph] 1115 CONH-S- CH [ (CH2)2NH2lCONHMe 1089 2-inudazolyl 1116 CONHMe 1090 2-oxazolv 1117 CONHCH2CONMe2 1091 2-zhiazolyI 1118 CONHCH2CONHEC 1092 2-benzimidazolyI 1119 CONHCH2CONEP2 1093 CONH-R-CH(CHi)Ph 1120 CONHCH2CONH- cvcloproDvl 1094 CONH-5-CH(CH3)Ph 1121 CONHCH2CONK- evclobucvl 1095 CONHCH2CONKMe 1122 CONHCH2CONK- cvclopencvl 1096 CONH-S-CH (CH3 )CONHMe 1123 CONHCH2CONH- cvclohexvi 1097 CCNK-R-CK ' CH3)CONHMe 1124 CONHCH2CONH-cērt-bucvl 1098 CONH-S-CH(2-propvl)CONHMe 1125 CONH-S- CH (CH2Ph) CONHMe 1099 CONH-S- CH (CH^SH) CONHMe 1126 CONH-S-CH(CH2-0-MeOPh)CONHMe 1100 C0NH-3- ČH(CH?OH)CONHMe 1127 CONHCH2CH2CONHMe 1101 CONH-R- CH (CHiOH)CONHMe 1128 CONHCH2CH2CH2CONHMe 1102 CONH-S-CH(CH2O-C-Bu'CONHMe 1129 CONH-S- CH ( CH2CH2OH ) CONHMe 1103 CONH-R-CH(CH20-t-Bu'CONHMe 1130 CONH-S- : CH(CH2)3CH3)CONHMe 1104 CONr>CH(Ph)2 1131 CONH(CH2)2C02Me 1105 CO-L-prsline-NHMe 1132 CONH(CH2)2CO2H 1106 CONKCH2CO(N-Dizerazinvl' 1.133 CONH-S- CH [ (CH2)3NHBOC]CC?Me 1134 CONHCH2O3(N-mezhvl-N-oizera2invl' 1144 CONH-S-CK ; 1CH2)3NHBOC]CONHMe 1125 CONHCH2CO(N-ace^yl-N-cirerazinvl' 1145 CONH-S-CH- [{CH2)3NH2]C02“e -230- LV 12167 1136 CONHCH2CO-N- morpholino 1146 CONH-S- CH[(CH2)4NH23CONH? 1137 CONHCH CO-[N-(4-hvdrcxvPiDeridinvi; 1 1147 CONH(CH2)2Ph 1138 co2h 1148 CONH(CH2)2-(3,4,-dimechojcvDhenvl) 1139 CONHBn 1149 CONH(CH2)2-(N-morpholino) 1140 CONH-2-pyridyi 1150 CONH(CH2)3-(N-morpholino) 1141 CONH-Ph 1151 CONHCH2CONH-(2-pvridvl) 1142 CONK-3-pyridyl 1152 CONHCH2CONH-(3-pvridvl) 1143 CONK-4-pyridyl 1153 CONHCH2CONH-(4- pvridvl) 1144 CONH-CH2CH(Ph): 1154 CONH(CHj) j(P-SOjNHj-Ph) -23
For the cyclic carbamate: TABLE-11
E X R2 (CI-KS) ms iz R2 (CI-MS) ms 1163 CC>2Me 1177 CONH-cyclopentyi 1164 co2e- 1178 conh2 1165 C02iPr 1179 CONHiPr 1166 C02(CH2)2OMe 1180 CONH-tert-bucyl 1167 C02(CH2)2Ph 1181 CONMe2 1168 C02-tBu 1182 CONEc2 1169 C02CH2C0NHMe 1183 CONH-3 -inda2ο1y1 1170 CH2OH 1184 CONK-adamancy1 1171 CH2OCH2CH3 1185 C0NHCH2(p-S02NH2-Ph) 1172 CH2OCH2CH2C02CH3 1186 CONH(CH2)3-1-imidazolvl 1173 CHOBn 1187 conhso2nh2 1174 CONH(CH2)2-2-pyridyl 1188 C0NHS02CH3 1175 CO(N-mcrpholinyi; 547.4 1189 CONHS02Ph 1176 CO(N-Me-N-oiDerazinvlι 560.4 1190 C0NHS02Bn -232- LV 12167
1191 CONK(CH2)2-(N-Me-N-Diūerazinvl) 1218 CONHSO2-N-Me-imidazolvl 1192 CONH-cyc1opropy1 1219 C0NHS02-p-NH2Ph 1193 CONH-cyciobutyi 1220 CONHSO2-p-MeOPh 1194 CONHSO2-p-F-Ph 1221 CONH-S-CH [CH2CH(CH3)2]CONHMe 1195 C0NH(CH2)2NHSO2Me 1222 CONH(CH2)4NHS02Me 1195 CONH-cyciohexyl 1223 C0NH(CH2)6NHS02Me 1197 CONH-2-imidozolyl 1 1224 CONH-R-CH [CH2CH(CH3)2)CONHMe 1193 CH2SO2NHCH3 1225 CONH-S-CH [(CH2)4NH2]CONHMe 1199 CH2S02NHPh 1226 CONH-S- CH [ CCH2)3NH2]CONHMe 1200 CH2SO2NH-(4-NH2Ph] 1227 CONH-S- CH [ (CH2)2NH2]CONHMe 12 01 2-imidazolyl 1228 CONHMe 491.5 1202 2-oxazoly 1229 CONHCH2CONMe2 1203 2-thiazolyl 1230 CONHCH2CONHEC 1204 2-benzimidazolvl 1231 CONHCH2CONEt2 1205 CONH-R-CH(CH3)Ph 1232 CONHCH2CONH- cvcloDroDvl 1205 CONH-S-CH(CH3)Ph 1233 CONHCH2CONH- cvclobutvl 1207 CONHCH2CONHMe 1234 CONHCH2CONH- cvcloūencvl 1208 CONH-S-CH i CH3)CONHMe 1235 CONHCH2CONH- cvclohexvl 1209 CONH-R-CH(CH3)CONHMe 1236 CONHCH2CONH-cerz- bucvl 1210 CONH-S-CH(2-' propvi)CONHMe 1237 CONH-S- CH (CH2Ph) CONHMe 1211 CONH-S- CH (CH2SH) CONHMe 1238 CONH-S-CH(CH2-P-MeOPh)CONHMe 1212 CONH-S- CH (CH-20H) CONHMe 1239 CONHCH2CH2CONHMe 1213 CONH-R- CH (CH2OH)CONHMe 1240 CONHCH2CH2CH2CONKMe 1214 CONK-S-CH(CH20-c-Bu)CONHMe 1241 CONH-S- CH (CH2CH2OH ) CONHMe 1215 CONH-R-CH(CH2O-C-Bu:CONHMe 1242 CONH-S- ;CH(CH2)3CH3)CONHMe 1215 CONK-CH(Ph)2 1243 C0NH(CH2)2C02Me 1217 CC-L-prcline-NHMe 1244 C0NH(CH2>2C02H -233- 1245 CONHCH2CO(N-piperazinyl) 1256 CONH-S- CH[(CH2)3NHBOC]CO2M e 1245 CONHCH2CO(N-methyl-N-piperazinyl) 1257 CONH-S- CH[(CH2)3NHBOC]CONH Me 1247 CONHCH2CO(N-acety1-N-oinerazinvl) 1258 CONH-S-CH- [(CH2)3NH2]CO?Me 1248 CONHCH2CO-N- morOholinol 1259 CONH-S- CH[(CH2)4NH2]CONH? 1249 CONHCH2CO-[N-(4-hvdroxvpiDeridinvl) 1 1260 CONH(CH2)2Ph 1250 co2h 1261 CONH(CH2)2-(3,4,-dimethoxvohenvl) 1251 CONHBn 1262 CONH(CH2)2“(N-morpholino) 1252 CONH-2-pyridyl 1263 CONH(CH2)3 ~(N— morpholi.no) . 1253 CONH-Ph 1264 CONHCH2CONH-(2- pvridvl) 1254 CONH-3-pyridyl 1265 CONHCH2CONH-(3 -Dvridvl) 1255 CONH-4-pyridyI 1266 CONHCH2CONH-(4-pvridvl) 1256 CONH-CH:CH (Ph) 2 1267 C0NH(CH2)j(P-S02NK2- Ph) -234- LV 12167 TABLE.12
For “he cyclic carbairate:
Ex R2 (CI-MS) me 8 x R2 (CI-MS) ma 1277 C02Me 1292 CONH-cyclopencyl 1278 CO2EC 1293 CONH2 1279 C02iPr 1294 CONHiPr 1280 C02(CH2)20Me 1295 CONH-cērt-butyl 1281 CC2(CH2)2Ph 1296 C0NMe2 1282 C02-CBU 1297 CONEC2 1283 C02CH2C0NHMe 1298 CONH-3-indazolyl 1284 CH2OH 1299 CONH-adamant y1 1285 CH2OCH2CH2 1300 CONHCH2(P-SO2NH2-Ph) 1286 CH2OCH2CH2CO2CH3 1301 CONH(CH2)3-1-imidazolvl 1287 CHOBn 1302 CONHSO2NH2 1288 CONH(CH2)2~2-pyridyl 1303 CONHSO2CH3 1289 CO(N-morpholinyl) 1304 CONHS02Ph 1290 CO(N-Me-N-DiDerazinvl) 1305 C0NHS02Bn 1291 CONH(CH2)2-(N-Me-N-cioerazinvl) 1306 C0NHS02-N-Me- imidazolvl 1307 CONH-cyclopropyl 1333 C0NHS02-p-NH2Ph -235- 1308 CONK-cyclobucyl 1334 CONHSO2-p-MeOPh 1309 CONHSO2-p-F-Ph 1335 CONK-S-CH [CH2CH(CH3)2]CONHMe 1310 CONH iCH2)2NHS02Me 1336 CONH(CH2)4NHS02Me 1311 CONH-cyclohexyl 1337 C0NH(CH2)6NHS02Me 1312 CONH-2-iiru.dozolyl 1338 CONH-R-CH [CH2CH(CH3)2]CONHMe 1313 CH2SO2NHCH3 1339 CONH-S-CH [(CH2)4NH2]CONHMe 1314 CH2S02NHPh 1340 CONH-S- CH [ (CH2)3NH2]CONHMe 1315 CH2SO2NH-[4-NH2Ph] 1341 CONH-S- CH [ (CH2)2NH2lCONHMe 1316 2-iniidazolyi 1342 CONHMe 1317 2-oxazoly 1343 CONHCH2CONMe2 1318 2-thiazolyl 1344 CONHCH2CONHEC 1319 2-benzimidazolyl 1345 CONHCH2CONEt2 1320 CONH-R-CH(CH3)Ph 1346 CONHCH2CONH- cvclopropvl 1321 CONK-S-CH{CH3)Ph 1347 CONHCH2CONH- cyclobutyl 1322 CONHCH2CONHMe 1348 CONHCH2CONH- cvcloDencvl 1323 CONH-S-CH(CH3)CONHMe 1349 CONHCH2CONH- cyclohexvl 1324 CONH-R-CH(CH3(CONHMe 1350 CONHCH2CONH-cerz-butvl 1325 CONH-5-CH(2-propvl)CONHMe 1351 CONH-S- CH (CH2Ph)CONHMe 1326 CONH-S- CH !CH2SH)CONHMe 1352 CONH-S-CH(CH2-P-MeOPh)CONHMe 1327 CONH-S- ČH(CH?OH)CONHMe 1353 CONHCH2CH2CONHMe 1328 CONH-R- CH (CH?OH)CONHMe •1354 CONHCH2CH2CH2CONHMe 1329 CONH-S-CH(CH20-t-Bu)CONHMe 1355 CONH-S- CH (CH2CH2OH) CONHMe 1330 CONH-R-CH(CH2O-C-3u)CONHMe 1356 CONK-S- (CH(CH2)3CH3)CONHMe 1331 CONH-CH(Ph)2 1357 CONH(CH2)2C02Me 1332 CO-L-proline-NHMe 1358 CONH(CH2!2C02K 1359 CONHCH2CO(N-DiDerazinvl) 1370 CONH-S-CH [ (CH2) 3NHBOC]COz>Me 1360 CONHCH2CO(N-mechyl-N-ciDerazinvl 1371 CONH-S-CH ; ;CH2 ) 3NHBOC) CONHMe 13 € 1 CONHCH2CO(N-acec/l-N-D;oerazinvl) 1372 CONH-S-CH- [(CH2)3NH2)C0?Me -236- LV 12167 1362 C0NHCH.2C0-N- morpholino 1373 CONH-S- CH[(CH2)4NH2]CONH2 1363 CONHCH2CO-[N-(4-hvdroxv-DiDeridinvl) 1 1374 CONH(CH2)2?h 1364 CO2H 1375 CONH(CH2)2-(3,4,-dimethoxvDhenvl) 1365 CONHBn 1376 CONH(CH2)2“(N-morDholino) 1366 CONH-2-pryidyl 1377 CONH(CH2)3 — t N— morpholino) 1367 CONK-Ph 1378 CONHCH2CONH-(2-pvri-dvl) 1368 CONH-3-pyridyl 1379 CONHCH2CONH-(3 -ovridvl) 1369 CONH-4-pyr idy1 1380 CONHCH2CONH-(4-pvridvl) 1381 CONH-CH:CH ( Ph) 5 1382 C0NH(CHj)2{P-S02NH2- Ph) -237- TABLE 13 :cr the lactam:
E X R2 (CI-MS) ne B x R2 (CI-MS) m 8 1395 C02Me 1412 CONH-cyc1openty1 13 9 6 CO2EC 1413 CONH2 12 57 C02iPr 1414 CONHiPr 1398 C02(CH2)20Me 1415 CONH-cert-bucyl 13 9 9 CC2(CH2)2P- 1416 CONMe2 1400 CO2-CBu 1417 CONEC2 1401 CC2CH2CONHMe 1418 CONH-3-indazolvl 1402 CH2OH 1419 CONH-adarnancyl 1403 CH2OCH2CH2 1420 CONHCH2(P-SO2NH2-Ph) 1404 CH2OCH2CH2CO2CH3 1421 CONH(CH2)3-1-imidazolvl 1405 CHOBn 1422 CONHSO2NH2 1406 CONK C CH2)2-2-pyridyl 1423 CONHSO2CH3 1407 CO(N-mcrpholinvi) 1424 CONHS02Ph 1408 CCiN-Me-N-Dizerazinvl> 1425 C0NHS02Bn 1409 CONH (CH2)2"(N-Me-N-pioerazinvl ’ 1426 CONHSO2-N-Me-imidazolyl 1410 CONK-cvclopropvl 1427 C0NHS02-p-NH2Fb 1411 CONH-cyc1obuzv1 1428 C0NHS02-p-MeCPh -238- LV 12167 1429 CONHSC2-p-r-Ph 1455 CONH-S-CH [CH2CH(CH3)2]CONHMe 1430 CONH(CH2)2NHS02Me 1456 C0NH(CH2)4NHS02Me 1431 CONH-cyclohexyi 1457 CONH(CH2)gNHS02Me 1432 CONH-2-iiaidozolyl 1458 CONH-R-CH [CH2CH(CH3)21CONHMe 1433 CH2SO2NHCH3 1459 CONH-S-CH [(CH2)4NH2lCONHMe 1434 CH2S02NHPh 1460 CONH-S- CH '(CH2)3NH2]CONHMe 1435 CH2S02NK-[4-NH2Ph] 1461 CONH-S- CH [ <CH2)2NH2]CONHMe 1436 2-imidazolyl 1462 CONHMe 385.4 1437 2-oxazoly 1463 CONHCH2CONMe2 1438 2-thiazolyl 1464 CONHCH2CONHE!: 143 9 2-benzīnu dazolyl 1465 CONHCH2 CONEt 2 1440 CONH-R-CK(CH3)Ph 1466 CONHCH2 CONH-cvcloproDvl 1441 CONH-S-CH(CH3)Ph 1467 CONHCH2CONH- cvclobucvl 1442 CONHCH2CONHMe 442.4 1468 CONHCH2CONH-cvcloDencvl 1443 CONH-S-CH;CH3)CONHMe 456.4 1469 CONHCH2CONH- cvclohexvl 1444 CONH-R-CK ί CH3)CONHMe 1470 CONHCH2CONH-cerc-bucyl 1445 CONH-S-CH(2-propvl!CONHMe 1471 CONH-S- CH (CH2Ph)CONHMe 1446 CONH-S- CH tCH?SH)CONHMe 1472 CONH-S-CH(CH2-p-MeOPh)CONHMe 1447 CONK-S- CH ; CH?OH'CONHMe 472.4 1473 CONHCH2CH2CONHMe 456.4 1448 CONH-R- ČH(CH20H)CONHMe 1474 CONHCH2CH2CH2CONHMe 1449 CONH-S-CK(CH2O-Ū-Bu)CONHMe 1475 CONH-S- CH ( CH2CH2OH) CONHMe 1450 CONH-R-CK(CH2O-C-Bu)CONHMe 1476 CONH-S- fCH(CH2)3CH3)CONHMe 145 . CONH-CH i Ph)2 1477 CONH(CH2)2 CO2 Me 1452 CO-L-prolme-NHMe 1478 CONH(CH2)2CO2H 1453 CONHCK2CO(N-oiperazinvl) 1479 CONH-S-CH Γ(CH2)3NHBOC]CO?Me 1454 CONHCK2CC.N-mezhyi-N-piperazinyl) 1480 CONH-S- CH [(CH2)3NHBCC]CONH Me 14 81 CONHCH2CC N-acetyl-N-Oi.oerazir.vl' 1490 CONH-S-CK-; (CH2 ) 3NH0 '1 COoMe -239- 1482 CONHCH2CO-N- morpholi.no 1491 CONH-S- CH[(CH2)4NH2]CONH2 1483 C0NHCH2C0-[N-(4-hvdroxvpiperidinvl)] 1492 CONH(CH2)2Ph 1484 co2h 1493 CONH{CH2)2-n,4,-dimethoxvphenvl) 1485 CONHBn 1494 CONH(CH2)2-(N- morpholino) 1486 C0NH-2-pyridyl 1495 CONH(CH2)3 —(N— morpholino) 1487 CONH-Ph 1496 CONHCH2CONH-(2-Dvridvl) 1488 C0NK-3-pyridyl 1497 CONHCH2CONH-(3- pvridvl) 1489 C0NH-4-pyridyl 1498 CONHCH2CONH-(4-pvridvl) 1490 CONH-CH2CH (Ph)j 1499 C0NH(CH2)j(P-S02NH2- Ph) -240- LV 12167 TABLE 13
E x R2 (CI-HS) me B x R2 (CI-MS) me 1511 C02Me 1529 CONH-cyclopency1 1512 C02EC 1530 CONH2 1513 CC2iPr 1531 CONHiPr 1514 CO2(CH2>2°Me 1532 CONH-cerc-butyl 1515 CO2'CH2)2Ph 1533 CONMe2 1516 CO2-CBU 1534 C0NEZ2 1517 C02CH2C0NHMe 1535 CONH-3-indazolvl 1518 CH2OH 1536 CONH-adamantyl 1519 CH2OCH2CH3 1537 CONHCH2(P-SO2NH2-Ph) 1520 CH2OCH2CH2CO2CH3 1538 CONH(CH2)3-1-imidazolvl 1521 CHOBn 1539 CONHSO2NH2 1522 CONH(CH2)2~2-pyridyl 1540 CONHSO2CH3 1523 CO(N-mcrphc1iny1) 1541 CONHS02Ph 1524 CO(N-Me-N-DĪDerazinv1) 1542 C0NHS02Bn 1525 CONH(CH2'2"(N-Me-N- DĪDerazinvl) 1543 C0NHS02-N-Me- imidazolvl 1526 CONH-cvc1opropv1 1544 C0NHS02-p-NF.2Ph 1527 CONH-cyclcbucyi 1545 CONHSO2-p-MeOPh 1528 C0NHS02-P-F-Ph 1546 CONH-S-CH f CH2CH(CH3)21CONHMe 1547 CONH ; CH? 1 2502Με 1573 CONH{CH2 > 4NHS02Me 1548 CONH-cyc1ohexy1 1574 C0NH(CH2)6NHS02Me 154 9 CONH-2-imidozolyl 1575 CONH-R-CH [CH2CH(CH3)21CONHMe 1550 CH2SO2NHCH3 1576 CONH-S-CH ((CH2 >4NH2]CONHMe 1551 CH.2S02NHPh 1577 CONH-S- CH [(CH2)3NH2lCONHMe 1552 CH2S02NH-(4-NH2Ph] 1578 CONH-S- CH [(CH2)2NH2]CONHMe 1553 2-imidazolyl 1579 CONHMe 1554 2-oxazoly 1580 CONHCH2CONMe2 1555 2-chiazolyl 1581 CONHCH2CONHEt 1556 2-benzimidazolyl 1582 CONHCH2CONEt2 1557 CONH-R-CH (CH3) Ph 1583 CONHCH2CONH- cvcloproDvl 1558 CONH-5-CH(CH3)Ph 1584 CONHCH2 CONH-cvclobuevl 1559 CONHCH2CONHMe 1585 CONHCH2CONH- cvcloDentvl 1560 CONH-S-CH(CH3)CONHMe 1586 CONHCH2CONH- cvclohexvl 1561 CONK-R-CH(CH3)CONHMe 1587 CONHCH2CONH-cert- butvl 1562 CONH-S-CH(2-propvi)CONHMe 1588 CONH-S- CH (CH2Ph)CONHMe 1563 CONH-S- CH ;CH23H) CONHMe 1589 CONH-S-CH(CH2-P-MeOPh)CONHMe 1564 CONH-S- CH ;CH20H) CONHMe 1590 CONHCH2CH2CONHMe 1565 CCNH-R- CH(CH20H)CONHMe 1591 CONHCH2CH2CH2CONHMe 156 6 CONH-S-CH(CH20-C-Bu!CONHMe 1592 CONH-S- CH (CH2CH2OH)CONHMe 1557 CONH-r.-CH (CH2O-C-Bu;CONHMe 1593 CONH-S- (CHCCH2)3CH3(CONHMe 1568 CONH-CH(Ph)2 1594 CONH(CH2)2C02Me 1565 CO-L-proline-NHMe 1595 CONH(CH2)2CO2H 1570 CONHCH2CO(N-Dicerazinvl) 1596 CONH-S-CH [(CH2)3NHBOC]C02Me 1571 CONHCH2CO(N-methyl-N-cicerazinvl) 1597 CONH-S-CH f{CH2)3NHBOC]CONHMe 1572 CONHCHtCO{N-acecyl-N-ūicerazinvl) 1598 CONH-S-CH- [(CH2)3NH2]C02Me 1599 CGNHCH2CO-N- mcrzholi.no 1607 CONH-S- CH [(CH2)4NH2]CONH? 1600 CONKCH':CO- [N- (4-hvdroxv— izeridinvl)ļ 1608 CONH(CH2)2Ph 1601 002H 1609 CONH(CH2)2-(3,4,-dimethoxvOhenvl -242- LV 12167 1602 CONHBr. 1610 CONH(CH2)2-(N-morpholino) 1603 CONK-2-pyridyl 1611 CONH(CH2)3-(N- morpholino) 1604 CONH-Ph 1612 CONHCH2CONH-(2-pvridvl) 1605 CONH-3-pvridyl 1613 CONHCH2CONH-(3-pvridvll 1606 CONH-4-pyridyl 1614 CONHCH2CONH-(4-pvridvl) CONH-CH3CH (Ph) 2 CONH(CH})2(P-SOjNHj- Ph) -243- IABLEJ4 ror the lactam:
Ex R2 (CI-KS) m e B x R2 (CI-MS) m e 1625 C02Me 1642 CONH-cyclopentyi 1626 CC>2Et 1643 CONH2 1627 C02iPr 1644 CONHiPr 1628 C02 !CH2) 2<3Me 1645 CONK-tert-bucyl 1629 C02(CH2)2Ph 1646 CONMe2 1630 C02-cBu 1647 CONEC2 1631 C02CH2C0NHMe 1648 CONH-3-indazolyi 1632 ch2oh 1649 CONH-adamantyl 1633 CH2OCH2CH3 1650 CONHCH2(p-S02NH2-?h} 1634 CH2OCH2CH2CO2CH3 1651 CONH(CH2)3-1-imidazolvl 1635 CHOBn 1652 CONHSO2NH2 1637 CONH (CH;'_ i 2~2-pyridyl 1653 CONHSO2CH3 1638 CC{N-morpholinyi) 1654 C0NHS02Ph 1539 COiN-Me-N-oiDerazinvl) 1655 C0NHS02Bn 1640 CONH(CH2>2-(N-Me-N- Diz>erazinvl) 1656 CONHSO2-N-Me-imidazolvl 1641 CONK-cyciopropyi 1657 C0NHS02-p-NH2Ph 1658 CONH-cyzlobutyI 1686 CCNHS02 -p-MeOPr. -244- LV 121 1659 C0NHS02-p-F-Ph 1687 CONH-S-CH (CH;CH(CH3)21CONHMe 1660 CONH(CH2)2NHS02Me 1688 C0NH(CH2)4NHS02Me 16 61 CONK-cyciohexyl 1689 CONH(CH2)6NHS02Me 1652 CONH-2-iitudozolyl 1690 CONH-R-CH f CH2CH(CH3)2]CONHMe 1663 CH2SO2NHCH3 1691 CONH-S-CH [(CH2)4NH2]CONHMe 1664 CH2S02NHPh 1692 CONH-S- CH [ (CH2)3NH2]CONHMe 1665 CH2SO2NH-i4-NH2Phi 1693 CONH-S- CH [(CH2)2NH2]CONHMe 1666 2-imidazolyl 1694 CONHMe 1667 2-oxazoiy 1695 CONHCH2CONMe2 1668 2-thiazclyl 1696 CONHCH2CONHEt 1669 2-benzīnidazolyl 1697 CONHCH2CONEC2 1670 CONK-R-CH(CH3)Ph 1698 CONHCH2CONK- cvclooroDvl 1671 CONH-S-CH!CH3)Ph 1699 CONHCH2CONH-cyclobucyl 1672 CONHCH^CONHMe 1700 CONHCH2CONK- cvclopentvi 1673 CONK-S-CH;CH3)CONHMe 1701 CONHCH2CONH-cyclohexyl 1674 CONK-R-CH!CH3)CONHMe 1702 CONHCH;CONH-tert-butvl 1675 CONH-S-CH(2-Prcnvl:CONHMe 1703 CONH-S-CH(CH2Ph)CONHMe 16 7 6 CONH-S- CH {CH;SH CONHMe 1704 CONH-S-CH(CH2-P-MeOPh)CONHMe 1677 CONH-S- CH (CH2OH: CONHMe 1705 CONHCH2CH2CONKMe 1678 CONH-R- CH(CH20H', CONHMe 1706 CONHCH2CH2CH2CONHMe 1679 CONK-S-CHiCH20-t-Bu) CONHMe 1707 CONH-S- CH ! CH2CH7OH)CONHMe 1680 CONH-R-CH(CH20-t-Bu)CONHMe 1708 CONK-S- (CHCCH2)3CH3)CONHMe 1631 CONH-CHiPh)2 1709 ' CONH(CH2)2C02Me 1682 CO-L-proime-NHMe 171C CONH CCH2)2CO2H 1683 CCNHCH2CO(N-Diperazinvl) 1711 conh-s- ch ; :CH2)3NHBOC]CO;Me 1634 CONHCH2CO ;N-mechyI-N-ciPerazinvl) 1712 CONH-S- CH; CH2)3NHSOC]CONHMe 1685 CONHCH2CC;N-acecyl-N-Diperazinvl) 1713 CONH-S-CH-• iCH2)3NK2]CO?Me 1714 C C NK C H 2 - 0 - N -re h cl 1 π c 1722 conh-s- ch: (CH;)4NH;]CONH; 171 ; ~ ^ N- ( 4 ~ hvdrcx*/oicer :d:nvi ’ ' 1723 C0NH(CH2)2Pn -245- 1716 C02H 1724 CONH(CH2)2-(3,4,-dimechoxvphenvl) 1717 CONHBn 1725 CONH (CH2 >2-(N-morDholino) 1718 CONH-2-pyridyl 1726 CONH(CH2)3-(N- morpholino) 1719 CONK-Ph 1727 CONHCH2CONH-(2-pvridvl) 1720 CONH-3-pyridyl 1728 CONHCH2CONH-(3 -pvridvl) 1721 CONH-4-pyridyl 1729 CONHCH2CONH-(4-pvridvl) 1722 CONH-CH2CH (Ph) j 1730 CONH (CH2) 3 (P-SOsNH2-Ph) -246- LV 12167 TABLE 15
Ex R2 (CI-MS) na B X R2 (CI-MS) me 1740 C02Me 1758 CONH-cyclopencyl 1741 CO2EC 1759 CONH 2 1742 CO21P- 1760 CONHiPr 1743 CO2(CH2)20Me 1761 CONH-Cert-butyl 1744 CO2(CH2)2Ph 1752 CONMe2 1745 CO2-CBU 1763 CONEC2 1746 C02CH2C0NHMe 1764 CONH-3-indazolvl 1747 CH2OH 1765 CONH-adčmiantyl 1748 CH2OCH2CH3 1766 CONHCH2(p-S02NH2-?h) 1749 CH2OCH2CH2CO2CH3 1767 CONH(CH2)3-1-imidazolvl 1750 CKOBn 1768 CONHSO2NH2 1751 CONH(CH2)2-2-pyridyl 1769 CONHSO2CH3 1752 CO(N-mcr?holinyl! 1770 C0NHS02Ph 1753 CO(N-Me-N- DiDerazinvl) 1771 CONHSO2B11 1754 CONH(CH2)2 * <N-Me-N-OiDerazinvl) 1772 CONHSO2-N-Me-imidazolvl 1755 CONH-cyclopropy1 1773 C0NHS02-p-NH2Ph 1756 CONH-cyclobutyi 1774 CONHSO2-p-MeOPh 1757 CONHSCl“p-?-Ph 1775 CONH-S-CH '.CH^CH ( CH3 > 2 ] CONHMe -247- 1776 CONH(CH2)2NHS02Me 1804 CONH(CH2)4NHS02Me 1777 CONH-cyclohexyl 1805 CONH(CH2)6NHS02Me 1778 CONK-2-irrudozolyl 1806 CONH-R-CH [CH2CH(CH3)2ICONHMe 1^7 9 CH2SO2NHCH3 1807 CONH-S-CH [(CH2)4NH2lCONHMe 1780 CH2SO2NHPI1 1808 CONH-S- CH [ (CH2)3NH23CONHMe 1781 CH2SO2NK-[4-NH2Ph] 1809 CONH-S- CH [ (CH2)2NH7lCONHMe 1782 2-imidazolyl 1810 CONHMe 1783 2-oxazoly 1811 CONHCH2CONMe2 1784 2-chiazolyi 1812 CONHCH2CONHEC 1785 2-benzimidazolyl 1813 CONHCH2CONEt2 1786 CONH-R-CH(CH3)Ph 1814 CONHCH2CONH- cvclooropvl 1787 CONK-S-CH(CH3)Ph 1815 CONHCH2 CONH-cyc1obuc y 1 1788 CONKCH2 CONHMe 1816 CONHCH2CONH- cvclopentvl 1789 CONK-S-CH(CH3)CONHMe 1817 CONHCH2CONH-cyclohexvl 1790 CONH-R-CH(CH3)CONHMe 1818 CONHCH2CONH-tert-but:yl 1791 CONH-3-CH(2-Droovl)CONHMe 1819 CONH-S-CH(CH2Ph)CONHMe 1792 CONH-S- CH (CH^SH) CONHMe 1820 CONH-S-CH(CH2-P-MeOPh)CONHMe 1793 CONH-S- CH iCH-OH) CONHMe 1821 CONHCH2CH2CONHMe 1794 CONH-R- CH (CH-OH)CONHMe 1822 CONHCH2CH2CH2CONHMe 1795 CONK-S-CH(CH2O-C-Bu'i CONHMe 1823 CONH-S- CH (CH2CH2OH)CONHMe 1796 CONH-R-CH(CH2O-C-Bu)CONHMe 1824 CONK-S- (CH(CH2)3CH3)CONHMe 1797 CONK-CH(Ph)2 1825 CONHCCH2)2C02Me 1798 CO-L-prolme-NHMe 1826 CONH(CH2)2CO2H 1799 CONHCH2CO(N-ūiDerazinvl> 1827 CONH-S- CH [(CH2)3NHBOC]C02Me 1800 CONHCH2CO(N-mezhyl-N-Di~erazinvl) 1828 CONH-S- CH [(CH2)3NHBOC]CONHMe 1801 CONHCH2CC(N-acecvl-N-oiserazinvl '* 1829 CONH-S-CH-[(CH2)3NH2]C02Me 1302 CONHCH2CO-N- morzholino 1830 CONK-S- CH [ (CHp) 4NH2 ] CONH-2 1803 CONHCH'CO-[N-(4-hvdrox\—loeridinvl) 1 1831 CONH(CH2)2Ph 13 2 2 - - 2 r* 1838 CONHiCH2)2 _ t 3,4 , -di:ne~hoxvphenvl' LV 12167 1833 CONHBn 1839 CONH(CH2)2”(N-morpholino) 1834 CONH-2-pyndyl 1840 CONH(CH2)3 — < N— morpholino) 1835 CONH-Ph 1841 CONHCH2CONH-(2-pvridvl) 1836 CONH-3-pyridyl 1842 CONHCH2CONH-(3-pvridvl) 1837 CONH-4-pvridyl 1843 CONHCH2CONH-(4-pvridvl) 1838 CONH-CHjCH (Ph) · 1844 CONH (CHj) 3 (P-SOjNHj - Ph) -249- TABLE 16
For the cyclic amine:
Ex R3 (CI-Mfl) ĪX R3 (CI-MS) ne 1860 C02Me 1878 CONH-cyclopentyl 1861 C02Et 1879 CONH2 1862 C02iPr 1880 CONHiPr 1863 C02(CH2)20Me 1881 CONH-cert-bucyl 1864 C02(CH2)2Ph 1882 CONMe2 1865 C02-tBu 1883 CONEt2 1866 C02CH2C0NHMe 1884 CONH-3-indazolvl 18 67 CH2OH 1885 CONH-adamanty1 1868 CH2OCH2CH3 1886 CONHCH2(p-S02NH2-Ph) 1869 CH20CH2CH2C02CH3 1887 CONH(CH2)3-1-imidazolvl 1870 CHOBn 1888 C0NHS02NH2 1871 CONH(CH2)2-2-pyridyl 1889 CONHSO2CH3 1872 CO(N-morpholinyl) 1890 CONHS02Ph 1873 CO(N-Me-N-oiDerazinvl) 1891 CONHS02Bn 1874 CONH(CH2)2-(N-Me-N-ūioerazinvl] 1892 CONHS02-N-Me- imidazolvl 1875 CONH-cyclopropyl 1893 C0NHS02-p-NH2Ph 1876 CONH-cyclobutyl 1894 C0NHS02-p-MeOPh 1377 CONHSC2-p-F-Ph 1895 CONH-S-CH rCH2CH(CH3)2]CONKMe 1896 CONH(CH2i2NKS02Me 1924 CONH(CH2)4NHS02Me -250- LV 12167 1697 CONH-cyalohexyl 1925 CONH(CH2)6NHS02Me 1898 CONH-2-imidozolyl 1926 CONH-R-CH [CH2CH(CH3)2]CONHMe 1899 CH2SO2NHCH3 1927 CONH-S-CH ( (CH2)4NH7]CONHMe 1900 CH2S02NHPh 1928 CONH-S-’ CH[(CH2)3NH2]CONHMe 1501 CH2SO2NH-ί 4-NH2Ph] 1929 CONH-S- CH [ (CH2)2NH?.) CONHMe 1902 2-imidazolyl 1930 CONHMe 471.4 1903 2-oxazoly 1931 CONHCH2CONMe2 1904 2-chiazolyl 1932 CONHCH2CONHEt 1905 2-benziirj.dazolyl 1933 CONHCH2CONEC2 1906 CONK-P.-CH {CH3) Ph 1934 CONHCH2CONH- cvclopropvl 1907 CONH-S-CH(CH3)Ph 1935 CONHCH2CONH-cyclobucyl 1908 CONHCH2CONHME 1936 CONHCH2CONH- cvclopencyl 1909 CONH-5-CH{CK3)CONHMe 1937 CONHCH2CONH-cyclohexvl 1910 CONH-R-CH '.CH3 ) CONHMe 1938 CONHCH2CONH-tert-butyl 1911 CONH-S-CH(2-orcpvl!CONHMe 1939 CONH-S-CH(CH2Ph)CONHMe 1912 CONH-S- CH (CH2SK) CONHMe 1940 C0NH-S-CH(CH2-P-MeOPh)CONHMe 1913 CONH-S- CH {CH2OK) CONHMe 1941 CONHCH2CH2CONHMe 1914 CONH-R- CH :CH2CH!CONHMe 1942 CCNHCH2CH2CH2CONHMe 1915 CONH-S-CH(CH20-C-Bu) CONHMe 1943 CONH-S- CH ;CH2CH20H)CONHMe 1916 CONH-R-CH i CH2O-C-Bu)CONHMe 1944 CONK-S- (CH(CH2)3CH3)CONHMe 1917 CONK-CHlPh)2 1945 C0NK(CH2)2C02Me 1918 CO-L-prcline-NHMe 1946 CONH(CH2)2C02H 1919 CONHCH2CO(N-piperazinvl) 1947 CONH-S- CH i i CH2)3NHBOC]C02Me 1920 CONHCH2CO(N-mechyi-N-oiperazi īvi) 1948 CONH-S- CH :'CH?)3NHBOC]CONHMe 1921 CONHCH2CO;N-acecyl-N-Piperazinvl) 1949 CONH-S-CH-;:CH2)3NH2]C02Me 1922 CONHCH2CO-N- morDhclincl 1950 CONH-S- CH ; (CH2)4NH2]CONH2 1923 CONHCH2CC-[N-(4-hvdroxvmorzholi.nvl) 1 1551 CONH(CH2)2Ph 1952 C0:H 1958 CONH(CH2)2-(3,4,-dimechoxyphenvl) 1953 CGNHBr 1959 :onh;ch2)2-<n- morpholinvl1 -251- 1954 C0NH-2-pryidyl 1960 CONH{CH2)3 —{N— morDholi.no) 1955 CONH-Ph 1961 CONHCH2CONH-(2-pvridvl) 1956 CONH-3-pyrldyl 1962 CONHCH2CONH-(3 -pvridvl) 1957 CONH-4-pyridyl 1963 CONHCH2CONH-(4-pvridvl) CONH-CH2CH(Ph)2 CONH(CH2)2 -(P-S02NH2-Ph) -252- LV 12167 TABLE 17
For the cyclic sulfonamide: S02Ph
2 x R2 (CI-MS) AB īx R2 (CI-MS) AB 1975 C02Me 1992 CONH-cyclopentyl 1976 C02Et 1993 conh2 1977 C02iPr 1994 CONHiPr 1973 C02(CH2)2OMe 1995 CONH-cert-bucyl 1979 C02(CH2)2Ph 1996 CONMe2 1980 C02-CBu 1997 CONEt2 1981 C02CH2C0NHMe 1998 CONH-3-indazolyl 1932 ch2oh 1999 CONH-adamancy1 1983 CH2OCH2CH.3 2000 CONHCH2(p-S02NK2-Ph! 1984 CH20CH2CH2C02CH3 2001 CONH(CH2)3-1-imidazolvl 1985 CHOBn 2002 conhso2nh2 1986 CONH(CH2)2-2-pyridvl 2003 CONHSO2CH3 1987 CO(N-mcrpholinylt 2004 CONHS02Ph 1988 CO(N-Me-N- Oiūerazinvl) 2005 CONHS02Bn 1989 CONK;CH2)2-(N-Me-N-DiDerazinvl) 2006 CONHS02-N-Me- imidazolvl 1990 CONH-cvc1opropy1 2007 CONKS02-p-NH2 Ph 1991 CONH-cyclobucyl 2008 CONHS02-p-MeOPn 2009 C0NHS02-p-?-Ph 2031 CONK-S-CH :CH2CH CCH:·' 2 ! CONHMe
201G CONH(CH2)2NHS02Me 2032 CONH(CH2)4NHS02Me 2 C11 CONH-cyclohexyl 2033 CONH(CH2)6NHSO2ME 2012 CONH-2-imidozolyl 2034 CONH-R-CH [CH9CH(CH3)21CONHMe 2013 CH2SO2NHCH3 2035 CONH-S-CH t(CH2)4NH2]CONHMe 2014 CH2S02NHPh 2036 CONH-S- CH [(CH2)3NH?JCONHMe 2015 CH2S02NK-[4-NH2PH] 2037 CONH-S- CH [ (CH2)2NH2lCONHMe 2016 2-imidazolyl 2038 CONHMe 511.3 2017 2-oxazoly 2039 CONHCH2CONMe2 2018 2-thiazolyi 2040 CONHCH2CONHEC 2019 2-benzimidazolyl 2041 CONHCH2CONHEt2 2020 CONH-R-CH(CH3)Ph 2042 CONHCH2CONH- cvclopropvl 2021 CONH-S-CH(CH3)Ph 2043 CONHCH2CONH-cyclobucyl 2022 CONHCH2CONHMe 2044 CONHCH2CONK- cyclopentyl 2023 CONH-S-CH(CH3)CONHMe 2045 CONHCH2CONH-cyclohexyl 2024 CONH-R-CH(CH3)CONHMe 2046 C0NHCH2C0NH-tert-bucyl 2025 CONH-S-CH(2-oroDvl)CONHMe 2047 CONH-S-CH(CH2Ph)CONHMe 2026 CONH-S- CH (CH2SH) CONHMe 2048 CONH-S-CH(CH2-P-MeOPh)CONHMe 2027 CONH-S- CH iCH-CH)CONHMe 2049 CONHCH2CH2CONHMe 2028 CONH-R- CH ĪCHjOH)CONHMe 2050 CONHCH2CH2CH2CONHMe 2029 CDNH-S-CH(CH20-c-Bu'· CONHMe 2051 CONHH-S- CH(CH2CH2OH)CONHMe 2030 CONH-R-CH(CH2O-0-Bu1CONHMe 2052 CONH-S- CH (CH2)3CH3)CONHMe -2 *± ~ LV 12167
TABLE ĪS
Fcr the cyclic sulfonamide: SO2CF3
Ex R2 (CI-MS) ae E x R2 (CI-MS) as 2072 C02Me 2089 CONH-cyclopencyl 2073 C02Et 2090 CONH2 2074 C02iPr 2091 CONHiPr 2075 CO2(CH2)20Me 2092 CONH-cert-butyl 2076 CO2(CH2)2Ph 2093 CONMe2 2077 CO?-CBu 2094 CONEC2 2078 C02CH2C0NHMe 2095 CONH-3-indazolyl 2079 CH2OH 2096 CONK-adamancyi 2080 CH2CCH2CH2 2097 CONHCH2(p-S02NH2-?b; 2081 CH2OCH2OH2CO2CH3 2098 CONH(CH2)3-1-imidazolvl 2082 CHCSr. 2099 CONHSO2NK2 2083 conh;ch2;~-2-pyridyi 2100 CONHSO2CH3 2084 CO(N-morphoiinyl) 2101 CONHS02Ph 2085 CO(N-Me-N-oiDerazinvl' 2102 C0NHS02Bn 2086 CONH(CH- 2"(N-Me-N- oiDerazinvl) 2103 CONHS02-N-Me- iroidazolvl 2087 CQNH-cy:lopropvl 2104 C0NHS02-p-NH2Ph 2088 CONH-cyciobucyI 2105 C0NHSO2~p-MeOPh 2106 CONHSC- -p-F-Ph 2128 CONH-S-CH [CH2CH'CHi)21CONHMe -255- 2107 CONH(CH2)2NHS02Me 2129 CONH(CH2)4NHS02Me 2108 CONH-cyclohexyl 2130 CONH(CH2> 6NHSO2ME 2109 CONK-2-zmidozolyl 2131 CONH-R-CH [CH2CH(CH3)2]CONHMe 2110 CH2SO2NHCH3 2132 CONH-S-CH [(CH2)4NH2]CONHMe 2111 CH2S02NHPh 2133 CONH-S- CH [ (CH2)3NH2]CONHMe 2112 CH2S02NH-[4-NH2pH] 2134 CONH-S- CH [0CH2)2NH2]CONHMe 2113 2-irrudazolyl 2135 CONHMe 503.3 2114 2-oxazoly 2136 CONHCH2CONMe2 2115 2-chiazolyl 2137 CONHCH2CONHEt 2116 2-benzimidazolyl 2138 CONHCH2CONHEt2 2117 CONH-R-CH(CH3)Ph 2139 CONHCH2CONH- cvcloDroDvl 2118 CONH-S-CH(CH3)Ph 2140 CONHCH2CONH-cyc1očucyl 2119 CONHCH2CONHMe 2141 CONHCH2CONH- cvcloDenZvl 2120 CONH-S-CH(CH3(CONHMe 2142 CONHCH2CONH-cyclohexyl 2121 CONH-R-CH(CH3)CONHMe 2143 CONH.CH2CONH-Cerc-bu.zyl 2122 CONH-S-CH(2-DroDvl)CONHMe 2144 CONH-S-CH(CH2?h)CONHMe 2123 CONH-S- CH (CH25H)CONHMe 2145 CONH-S-CH(CH2-?-MeOPh)CONHMe 2124 CONH-S- CH (CH2OH) CONHMe 2146 CONHCH2CH2CONHMe 2125 CONH-R- CH (CH2OH)CONHMe 2147 CONHCH2CH2CH2CONHMe 2126 CONH-S-CH(CH2O-C-Bu'CONHMe 2148 CONHH-S- CH(CH2CH2OH)CONHMe 2127 CONH-R-CH(CH20-C-Bu;CONHMe 2149 CONH-S- CH ·CH2)3CH3)CONHMe -255-
Fcr he cycli TAB LE-12 sulfonamide:
LV 12167 E X R2 (CI-HS) B> Bx R2 (CI-HS) me 2164 C02Me 2180 CONH-cyclopentyl 2165 C02EC 2181 CONH 2 2166 CC2iPr 2182 CONHiPr 2167 C02(CH2)20Me 2183 CONH-tert-butyl 2168 co2 (c:-:2) 2?h 2184 CONMe2 2169 co2-;Bu 2185 CONEC2 2170 C02CH2C0NHMe 2186 CONH-3-indazoiyl 2171 CH20H 2187 CONH-adamanty1 2172 CH2CCH2CK3 2188 CONHCH2(p-S02NH2-Ph! 2173 CH2OCH2CH2CO2CH3 2189 CONH(CH2)3-l-imidazolvl 2174 CHOBn 2190 CONHSO2NH2 2175 CONH(CH2 i 2- 2-pyridy1 2191 CONHSO2CH3 2176 CO(N-morpholinyl) 2192 C0NHS02Pb 2177 CO(N-Me-N-Diuerazinvl) 2193 C0NHS02Bn 2178 CONH (CH2 2" (N-Me-N-ciuerazinvl) 2194 C0NHS02-N-Me- iraidazolvl 2179 CONH-cyclopropyl 2195 C0NKS02-p-NH2Ph 2196 CONH-cyclobucyl 2219 C0NHSO2-p-MeOPh 2197 C0NHS02-p-F-Ph 2220 CONH-S-CH [CH2CH(CH3)2]CONHMe 2198 CONH(CH2)2NHS02Me 2221 C0NH(CH2)4NHS02Me 2199 CONH-cyciohexyl 2222 CONH(CH2)6NHSO2ME 2200 CONH-2-imidozolyl 2223 CONH-R-CH [CH2CH(CH3)21CONHMe 2201 CH2SO2NHCH2 2224 CONH-S-CH [(CH2)4NH2)CONHMe 2202 CH2S02NHPh 2225 CONH-S- CH [(CH2)3NH2lCONHMe 2203 CH2SO2NŪ-[4-NH2PH] 2226 CONH-S- CH [(CH2)2NH2lCONHMe 2204 2-iraidazolyl 2227 CONHMe 526.3 2205 2-oxazoly 2228 CONHCH2CONMe2 2206 2-chiazolyl 2229 CONHCH2CONHEC 2207 2-benzimidazolyl 2230 CONHCH2CONHEC2 2208 CONH-R-CH(CH3)Ph 2231 CONHCH2CONH- cvcloOronvl 2209 CONH-S-CH(CH3)Ph 2232 CONHCHjCONH-cyc1obucv1 2210 CONHCH2CONHMe 2233 CONHCH2CONH- cvcloDencvl 2211 CONH-S-CH(CH3)CONHMe 2234 CONHCH2CONH-cyclohexyl 2212 CONH-R-CH (CH'3 ) CONHMe 2235 CONHCH2CONH-tert-butyl 2213 CONH-S-CH(2-oroūvl)CONHMe 2236 CONH-S-CH(CH2Ph)CONHMe 2214 CONH-S- CH (CH^SH) CONHMe 2237 CONH-S-CH(CH2-P-MeOPh)CONHMe 2215 CONH-S- CH (CHiOH)CONHMe 2238 CONHCH2CH2CONHMe 2216 CONH-R- CH (CH2OH)CONHMe 2239 CONHCH2CH2CH2CONKMe 2217 CONH-S-CH(CH2O-C-BulCONHMe 2240 CONHH-ΒΟΗ (CH2CH2OH)CONHMe 2218 CONH-R-CH(CH2O-Z-Bu!CONHMe 2241 CONH-S- CH(CH2)3CH3)CONHMe -258- LV 12167 TABLE 20
For the cyclic sulfonamide:
HOHNOC
S x R2 (CI-MS) ma Ex R2 (CI-MS) ma 2260 C02Me 2276 CONH-cyc1openty1 2261 CO2EC 2277 CONH2 2262 C02iPr 2278 CONHiPr 2263 CO2(CH2)2°Me 2279 CONH-cerc-bucyl 2264 CO2(CH2)2Ph 2280 CONMe2 2265 C02-c3u 2281 CONEC2 2266 CO2CH2C0NHMe 2282 CONH-3-indazolyl 2267 CH2CH 2283 C ONK - adaman t y 1 2268 CH2CCH2CH3 2284 CONHCH2(p-S02NH2-Ph! 2269 CH2OCH2CH2CO2CH3 2285 CONH(CH2)3-l-imidazolvl 2270 CHOSn 2286 CONHSO2NH2 2271 CONH{CH2)2-2-pyridvl 2287 CONHSO2CH3 2272 CO(N-morpholinyl) 2288 CONHS02Ph 2273 CO(N-Me-N-DiDerazinvl) 2289 C0NHS02Bn 2274 CONK{CH2'2 *(N-Me-N-ciDerazinvi) 2290 C0NHS02-N-Me- imidazolvl 2275 CONH-cy=lopropyl 22 91 C0NHS02-p-NH2Ph -253- 2292 CONK-cyclobucyl 2315 CONHSO2-p-MeOPh 2293 C0NHS02-p-F-Ph 2316 CONH-S-CH [CH2CH(CH3)21CONHMe 2294 CONH(CH2)2NHS02Me 2317 CONH(CH2)4NHS02Me 2295 CONH-cyclohexyl 2318 CONH(CH2)6NHSO2ME 2295 CONH-2-imidozoiyl 2319 CONH-R-CH [CHpCH(CH3)2]CONHMe 2297 CH2SO2NHCH3 2320 CONH-S-CH [ (CH2UNH2] CONHMe 2298 CK2S02NHPh 2321 CONH-S- CH [ (CH2)3NH2]CONHMe 2299 CH2SO2NH-[4-NH2PH] 2322 CONH-S- CH [ (CH2)2NH2lCONHMe 2300 2-imiaazolyi 2323 CONHMe 553.5 2301 2-oxazoly 2324 CONHCH2CONMe2 2302 2-thiazolvl 2325 CONHCH2CONHEC 2303 2 -benzinu.dazolyl 2326 CONHCH2CONHEZ2 2304 CONH-R-CH(CH3)Ph 2327 CONHCH2CONH- cycloOroDvl 2305 CONH-S-CH(CH3)Ph 2328 CONHCH2CONH-cyclobuzyl 2306 CONHCH2CONHMe 2329 CONHCH2CONH- cvclopencvl 2307 CONK-S-CH;CH3}CONHMe 2330 CONHCH2CONH-cyclohexyl 2308 CONH-R-CH!CH3)CONHMe 2331 CONHCH2CONH-Cert-bucyl 2309 CONH-S-CH(2-crocvl)CONHMe 2332 CONH-S-CH(CH2 Ph)CONHMe 2310 CONH-S- CH !CHjSH)CONHMe 2333 CONH-S-CH(CH2-P-MeOPh)CONHMe 2311 CONH-S- CH (CH2OH) CONHMe 2334 CONHCH2CH2CONHMe 2312 CONH-R- CH (CK?OH) CONHMe 2335 CONHCH2CH2CH2CONHMe 2213 C'ONH-S-CH (CH2O-C-Bu'CONHMe 2336 CONHH-S- CH C CH2CH2OH)CONHMe 2314 CONH-R-CH(CH2O-C-B-1 CONHMe 2337 CONH-S- CH (CH2)3CH3)CONHMe -260 — LV 12167 TABLE 21
E X R2 (CI-MS) BS B x R2 (CI-MS) m 0 2350 CC2Me 2368 CONK-cyclopencyi 2351 CO2EC 2369 CONH2 2352 C02iPr 2370 CONHiPr 2353 C02(CH2)20«e 2371 CONH-terc-butyl 2354 CO2(CH2)2?h 2372 CONMe2 2355 C02~CBu 2373 C0NEC2 23 5 6 C02CH2CONHMe 2374 CONK-3-indazolyl 2357 CH2OH 2375 CONH-adamantyl 2358 CH2CCH2CH3 2376 CONHCH2 (P-SO2NH2-P.1:) 2359 CH2OCH2CH2CO2CH3 2377 CONH(CH2)3-1-imidazolvl 2360 CHOBn 2378 CONHSO2NH2 23 61 CONKi CH2i 2 -2-pyridy1 2379 CONHSO2CH3 2362 CO !N-iī!orpholinyl) 2380 C0NHS02Ph 23 63 CO;N-Me-N- cit>arazinvl) 2381 C0NKS02Bn 2364 CONK(CH2/2-iN-Me-N-cicerazinvl1 2382 CONHS02-N-Me- imidazolvl 2365 CCNK-cyc1opropy1 2383 CONHSO2-D-NH2 Ph 2366 CONH-cyclcbucyi 2384 CONHSO2-p-MeOPh 23 6' CONK5C2-p-F-?h 2385 CONH-S-CH 'CH2CH(CH3)21CONKMe -251- 2386 CONH(CH2)2NHS°2Me 2407 CONH(CH2)4NHS02Me 2387 CONH-cyci ohexy1 2408 CONH(CH2)6NHSO2ME 2388 CONH-2-inu.dozoiyl 2409 CONH-R-CH [CH2CH(CH3)2]CONHMe 2385 CH2SO2NHCH3 2410 CONH-S-CH [(CH2)4NH2]CONHMe 2390 CH2SC>2NHPh 2411 CONH-S- CH [ <CH2)3NH2ICONHMe 2391 CH2SO2NH-[4-NH2PH] 2412 CONH-S- CH [ (CH2)2NH2ICONHMe 2392 2-imidazolyi 2413 CONHMe 372.3 2393 2-oxazoly 2414 CONHCH2CONMe2 2394 2-zhiazolyl 2415 CONHCH2CONHEC 2395 2 -benzīnu. dazolyl 2416 CONHCH2CONHEt2 2395 CONH-R-CH{CH3)Ph 2417 CONHCH2CONH- cvcloDropvl 2397 CONH-3-CH(CH3)Ph 2418 CONHCH2CONH-cyc1obucy1 2398 CONHCH2CONHMe 2419 CONHCH2CONH- cvcloDentvl 2399 CONH-S-CK(CH3)CONHMe 2420 CONHCH2CONH-cyclohexyl 2400 CONH-R-CH(CH3ICONHMe 2421 CONHCH2CONH-tert-buty1 2401 CONH-S-CH(2-uroDvl)CONHMe 2422 CONH-S-CH(CH2Ph)CONHMe 2402 CONH-S- CH(CH2SH)CONHMe 2423 CONH-S-CH{CH2-P-MeOPh)CONHMe 2403 CONH-S- CH(CH.20H) CONHMe 2424 CONHCH2CH2CONHMe 2404 CONH-R- CH (CH 2 OH) CONHMe 2425 CONHCH2CH2CH2CONHMe 2405 CONH-S-CH(CH20-C-Bu)CONHMe 2426 CONHH-S- CH(CH2CH2OH)CONHMe 2406 CONH-R-CH(CH2O-Z-Bu)CONHMe 2427 CONH-S- CH (CH2)3CH3)CONHMe -252- LV 12167 TABLE22
Fcr the lactam:
O. H
____N
HOHNOC
N H R2
Sx R2 (CI-HS) me E X R2 (CI-MS) me 2440 C02Me 2458 CONH-cyc1opency1 2441 C02EC 2459 CONH 2 2442 C02iPr 2460 CONHiPr 2442 CO2(CH2)2®Me 2461 CONH-tert-bucyl 2444 C02 (CH2i2?-7 2462 CONMe2 2445 C02-ZE-J 2463 CONEt2 2446 C02CH2CCNHMe 2464 CONH-3-indazolyl 2447 CH2CH 2465 CONH-adamaney1 2448 CH2OCH2CH3 2466 CONHCH2(p-S02NH2-Phi 2449 CH2OCH2CH2CO2CH3 2467 C0NH(CH2)3-1-imidazolvl 2450 CHCEr. 2468 CONHSO2NH2 2451 CONH (CH.2) 2-2-pyridyl 2469 CONHSO2CH3 2452 CO(N-morphciinyl) 2470 C0NHS02Ph 2453 CO(N-Me-N-oioerazinvl' 2471 C0NHS02Bn 2454 CONH(CH2)2“iN-Me-N-pioerazinvl) 2472 CONHSO2-N-Me-imidazolvl 2455 CONH-cyclc?ropyl 2473 C0NHSO2-p-NH2Ph 2456 CONH-cyclsaucyl 2474 CONHSO2-p-MeOPh 2457 CONHSO2-?-?-?h 2475 CONH-S-CH fCr>CH(CH3)2]CONHMe 2476 CONH : CH2 ) 2-<Ή5θ2Με 2497 C0NH(CH2)4NHSC2Me -253- 2477 CONH-cyclohexyl 2498 CONH(CH2)6NHSO2ME 2478 CONH-2-imidozolyl 2499 CONH-R-CH [CH2CH(CH3)21CONHMe 2479 CK2SO2NHCH3 2500 CONH-S-CH [(CH2)4NH2]CONHMe 2480 CH2S02NHPh 2501 CONH-S- CH { (CH3)3 NH?]CONHMe 2481 CH2SO2NH-Ī4-NH2PH] 2502 CONH-S- CH [ (CH2)2NH?]CONHMe 2482 2-imidazolyl 2503 CONHCH2CONHMe 2483 2-oxazoly 2504 CONHCH2CONMe2 2484 2-cruazolyl 2505 CONHCH2 CONHEt 2485 2 - benzīnu. dazoly 1 2506 CONHCH2CONHEt2 2486 CONH-R-CH(CH3)Ph 2507 CONHCH2 CONH-cvclODroDvl 2487 CONH-S-CH(CH3)Ph 2508 CONHCH2CONH-cyclobucyl 2488 C ONH C H 2 C ONHMe 2509 CONHCH2CONH- cvclopentvl 2489 CONH-S-CH'CH3)CONHMe 2510 C0NHCH2.C0NH-cyclohexyl 2490 CONH-R-CH(CH3)CONHMe 2511 CONHCH2CONH-tert-bucyl 2491 CONK-3-CH(2-nroDvl)CONHMe 2512 CONH-S-CH(CH2Ph)CONHMe 2492 CONH-S- CH (CH?SH) CONHMe 2513 CONH-S-CH(CH2-p-MeOPh)CONHMe 2493 CONH-S- CH (CH?OH) CONHMe 2514 CONHCH2CH2CONKMe 2494 CONH-R- CH (CKņOH)CONHMe 2515 CONHCH2CH2CH2CONHMe 2495 CONH-S-CH(CH20-Ī-Bu' CONHMe 2516 CONHH-S- CH(CH2CH2OH)CONHMe 2496 CONH-R-CH(CH20-C-Bu1 CONHMe 2517 CONH-S- CH (CH2 ) 3CH3 ) CONHMe 2518 CONHMe 387.3 2519 CONHPh 449.3 -264- LV 12167
For che lactam:
E X R2 (CI-HS) ms E X R2 (CI-MS) m b 2530 C02Me 2547 CONH-cyclopentyl 2531 - CO2EC 2548 CONH2 2532 C02iPr 2549 CONHiPr 2533 CO2(CH2 i20Me 2550 CONH-cerc-bucyl 2534 CO2(CH2)2ph 2551 CONMe2 2535 C02-C3U 2552 CONEC2 2536 C02CH2C0NHMe 2553 CONK-3-indazolyl 2537 ch2oh 2554 CONH-adamant y1 2538 CH20CH2CH3 2555 CONHCH2(p-S02NK2~Ph; 2539 CH20CH2CH2C02CH3 2556 CONH(CH2)3-l-imidazolvl 2540 CHOSr. 2557 CONHSO2NH2 2541 CONH(CH2)2-2-pyridyI 2558 CONHSO2CH3 2542 CO(N-mcrphclinvl) 2559 C0NHS02Ph 2543 CO(N-Me-N-uioerazinvl) 2560 C0NHS02Bn 2544 CONH (CH2) 2- : N-Me-N-oiDerazir.vl · 2561 CONKSO2-N-Me-imidazolvl 2545 CCNH-cvcispropvl 2562 CONHSO2-D-NK2 Ph 2546 CONH-cyc1sauc vI 2563 C0NHSO2-p-MeOPh 2564 co:rr:so2-c-7-?h 2586 CONH-S-CH [CH-CH'CH3'2]CONHMe -255- 2565 CONH(CH2)2NHS02Me 2587 CONH(CH2)4 NHSO2 Me 2566 CONH-cyclohexyl 2588 C0NH(CH2)6NHS02ME 2567 CONH-2-iniidozolyi 2589 CONH-R-CH !CH2CH(CH3)2]CONHMe 2568 CH2SO2NHCH3 2590 CONH-S-CH '!CH2)4NH2]CONHMe 2565 CH2S02NHPh 2591 CONH-S- CH [(CH2)3NH2]CONHMe 2570 CH2SO2NK-[4-NH2PH] 2592 CONH-S- CH [ (CH2)2NH2]CONHMe 2571 2-imidazolyl 2593 CONHCH2CONHMe 2572 2-oxazoly 2594 CONHCH2CONMe2 2573 2-thiazolyl 2595 CONHCH2CONHEC 2574 2-benzimidazolyi 2596 CONHCH2CONHEt2 2575 CONH-R-CH(CH3)Pil 2597 CONHCH2CONH- cvcloproDvl 2576 CONH-S-CH(CH3)Pn 2598 CONHCH2CONH-cyclobucyl 2577 CONKCH2CONHMe 2599 CONHCH2 CONH-cvcloDentvl 2578 CONH-S-CH{CH3)CONHMe 2600 CONHCH2CONH-cyclohexyl 2579 CONH-R-CH(CH3)CONHMe 2601 CONHCH2CONH-terc-bucyl 2580 CONH-S-CH(2-oroDvl)CONHMe 2602 CCNH-S-CH(CH2Ph)CONHMe 2581 CONH-S- CH ( CH2 SK ) CONHMe 2603 CONH-S-CH(CH2-P-MeOPh)CONHMe 2582 CONH-S- CH {CH7OH)CONHMe 2604 CONHCH2CH2CONHMe 2583 CONH-R- CH (CH7OH)CONHMe 2605 CONHC H 2 C H 2 C H. 2 CONHMe 2584 CONH-S-CH(CH20-t-3u) CONHMe 2606 CONHH-S- CH(CH2CH2OH)CONHMe 2585 CONH-R-CH (CH2O-::-Eu)CONHMe 2607 CONH-S- CH (CH2)3CH2!CONHMe -256- LV 12167 TAPLE-2-4
Ex R2 (CI-MS) me IX R2 (CI-MS) me 2630 C02Me 2647 CONH-cyclopenty1 2631 C02EC 2648 CONH2 2632 C02iPr 2649 CONHiPr 2633 CO2(CH2)2°Me 2650 CONH-tert-bucyl 2634 C02(CH2)2Ph 2651 CONMe2 2635 CO2-CBU 2652 CONEt2 2636 C02CK2C0NHMe 2653 CONK-3-indazolyi 2637 CH2OH 2654 CONH - adamaunc y 1 2638 CH2OCH2CH3 2655 CONHCH2(p-S02NH2-?b) 2639 CH2OCH2CH2CO2CH3 2656 CONH(CH2)3-1-imidazolvl 2640 CHCBn 2657 CONHSO2NH2 2641 CONK{CH2)2'2-pyridyl 2658 CONHSO2CH3 2642 CO(N-mcrphoiinyl) 2659 C0NHS02Ph 2643 CO(N-Me-N-Dioerazinvl) 2660 C0NHS02Bn 2644 CONK;CH212 -< N-Me-N-ciDerazinvl) 2661 C0NHS02-N-Me- imidazolvl 2545 COKH-cyclopropyl 2662 C0NHS02-p-NH2Pri 2646 CCi-ΓΗ - cy : 1 obuty 1 2663 C0NHS02-p-Me0P'r. 2564 CONHSO:-?-F-Ph 2686 CONH-S-CH [CH2CH(CH3)2]CONHMe 2665 CONH(CH2)2NHS02Me 2687 CONH(CH2)4NHS02Me 2666 CONH-cyciohexyl 2688 CONH(CH2)6NHSO2ME 2 6 67 CONK-2-inudozolyl 2689 CONH-R-CH [CH2CH(CH3)21CONHMe 2668 CH2SO2NHCH3 2690 CONH-S-CH [(CH2)4NH2)CONHMe 2669 CH2S02NHPh 2691 CONH-S- CH [ (CH2)3NH2lCONHMe 2670 CH2SO2NH-i 4-NH2pH] 2692 CONH-S- CH [ (CH2)2NH2lCONHMe 267i 2-inu.dazolyl 2693 CONHCH2CONHMe 2672 2-oxazoly 2694 CONHCH2CONMe2 2673 2-chiazolyl 2695 CONHCH2CONHEC 2674 2-benzimidazolyl 2696 CONHCH2CONHEt2 2675 CONH-R-CH(CH3)Ph 2697 CONHCH2CONH- cvcloDropvl 2676 CONH-S-CH(CH3)Ph 2698 CONHCH2CONH-cyclobucyl 2577 CONHCHjCONHMe 2699 CONHCH2CONH- cvclopentvl 2678 CONH-S-CK!CH3)CONHMe 2700 CONHCH2CONH-cyclohexyl 2679 CONH-R-CHICH3 )CONHMe 2701 CONHCH2CONH-cerc-but:yl 2680 CONH-S-CH(2-DroDvi!CONHMe 2702 CONH-S-CH(CH2Ph)CONHMe 253i CONH-S- CH (CHjSH) CONHMe 2703 CONH-S-CH(CH2-0-MeOPh)CONHMe 2682 CONH-S- CH i CH^CH)CONHMe 2704 CONHCH2CH2CONHMe 2683 CONH-R- CH (CHjCH)CONHMe 2705 CONHCH2CH2CH2CONHMe 2684 CONH-S-CH(CH2O-Z-Bu)CONHMe 2705 CONHH-S- CH(CH2CH2OH)CONHMe 2685 CONH-R-CH(CH2O-Z-Bu)CONHMe 2707 CONH-S- CH (CH2)3CH3)CONHMe 2708 CONHMe 401.6 8- LV 12167 TABLE 25
For the iactair.:
E x R2 (CI-MS) ae Sl R2 (CI-HS) aa 2730 C02Me 2747 CONH-cyclopentyl 2731 CO2EC 2748 CONH 2 2732 C02iPr 2749 CONHiPr 2733 C02(CH2)20Me 2750 CONH-Cert-butyl 2734 CC2(CH2)2Ph 2751 CONMe2 2735 C02~w3u 2752 CONEt2 2736 CO2CH2C0NHMe 2753 CONH-3-indazolyl 2737 CH2CH 2754 •CONH-adamantyl 2733 CH2OCH2CH3 2755 CONHCH2 (P-SO2NH2-P:-.·· 2739 CH2OCH2CH2CO2CH3 2756 CONH(CH2)3-l-imidazolvl 2740 CHOEr. 2757 CONHSO2NH2 2741 CONH(CH2)2-2-pyridyl 2758 CONHSO2CH3 2742 C <(N-morphciinyl) 2759 C0NHS02?h 2743 CC(N-Me-N-Dioerazmvl) 2760 C0NHS02Bii 2744 CONH (C«2) 2 - ; N-Me-N-oioerazinvl) 2761 CONHSO2-N-Me-imidazolvi 2745 CONK-cyelspropyl 2762 C0NHS02-p-NH2Ph 2746 CONH-cycl=bucyl 2763 C0NHS02-p-Me0Ph 2764 C0NHSC2-?-F-?h 27 8 6 CONH-S-CH OH2CH(CH3)2 1 CONHMe -26?- 2765 CONH(CH2)2NHS02Me 2787 CONH(CH2)4NHS02Me 2766 CONH-cyclohexyl 2789 CONH(CH2)6NHSO2ME 27 57 CONH-2-imidozolyl 2790 CONH-R-CH [CH2CH(CH3)2]CONHMe 2768 CH2SO2NHCH3 2791 CONH-S-CH [(CH2)4NH2lCONHMe 2769 CH2S02NHPh 2792 CONH-S- CH [ (CH2)3NH2]CONHMe 2770 CH2S02NH-[4-NH2pH] 2793 CONH-S- CH [(CH2)2NH2]CONHMe 2771 2-imidazolyl 2794 CONHCH2CONHMe 2772 2-oxazoly 2795 CONHCH2CONMe2 2773 2-chiazolyl 2796 CONHCH2 CONHEt 2774 2-benziinidazolyl 2797 CONHCH2CONHEC2 2775 CONH-R-CH(CH3)Ph 2798 CONHCH2CONH- cvcloDropvl 2776 CONH-S-CH(CH3)Ph 2799 CONHCH2CONH-cyclobutyl 2777 C ONHC H 2 C ONHMe 2800 CONHCH2CONH- cvcloDencvl 2778 CONK-S-CH(CH3)CONHMe 2801 CONHCH2CONH-cyclohexyl 2779 CONH-R-CH{CH3)CONHMe 2802 CONHCH2CONH-tert-bucyl 2780 CONH-S-CH(2-oroDvl)CONHMe 2803 CONH-S-CH(CH2 Ph)CONHMe 2781 CONH-S- CH (CH2SH) CONHMe 2804 CONH-S-CH(CH2-?-MeOPh)CONHMe 2782 CONH-S- CH (CHiOH) CONHMe 2805 CONHCH2CH2CONKMe 2783 CONH-R- CH (CH2OH) CONHMe 2806 CONHCH2CH2CH2CC!4HMe 2784 C0NH-S-CH(CH20-t-Bu!CONHMe 2807 CONHH-S- CH(CH2CH2OH)CONHMe 2785 CONH-R-CH(CH20-t-BulCONHMe 2808 CONH-S- CH (CH2) 3 CH3) CONHMe 2809 CONHMe 475 ί -210-
I LV 12167 TABLE 26
For the lactair.
HOHNOC
E X R2 (CI-MS) Bi Bx R2 (CI-MS) &8 2820 C02Me 2837 CONH-cyclopencyl 2821 C02Et: 2838 CONH 2 2822 C02i?r 2839 CONHiPr 2323 CO2 CCH2)20Me 2840 CONH-cert-butyl 2824 CO2(CH2:2?“ 2841 CONMe2 2825 C02--3u 2842 CONEC2 2826 C02CH2C0NHMe 2843 CONH-3-indazoiyi 2827 ch2oh 2844 CONH-adamantyl 2828 ch2oc:-:2ch3 2845 CONHCH2(p-S02NH2-Ph, 2829 CH2CCH2CH2CO2CH3 2846 CONH(CH2)3-1-imidazolvl 2830 CHOBr. 2847 CONHSO2NH2 2831 conh(ch2)2-ī-py-idy3 2843 CONHSO2CH3 2332 CO (N-:norphoiinyl) 2849 C0NHS02Ph 2833 CO(N-Me-N-DiOerazinvl1 2850 C0NHS02Bn 2334 CONH (CH2 ) 2* '.N-Me-N-Dioerazmvi) 2851 C0NHS02-N-Me- imidazolvl 2835 CONH-cvcic?ropyl 2852 CONHS02-p-NK2Ph 2836 CONH-cy=1:2u:y1 2853 CONHSO2-p-MeOPh 2854 C0NK=02-r-F-?h 2876 CONH-S-CH (CH2CH(CH3)2]CONHMe 2855 C0NH(CH2)2NHS02Me 2877 C0NH(CH2)4NHS02Me 2956 CONH-cyc1ohexy1 2878 CONH(CH2)6NHSO2ME 2857 CONH-2-imidozolyl 2879 CONH-R-CH [CH2CH(CH3)2 J CONHMe 2 8 5 8 CH2SO2NHCH3 2859 CH2S02NHPh 2860 CH2SO2NK-[4-NH2PH} 2861 2-imida2olyl 2862 2-oxazoly 2863 2-thiazolyl 2864 2-benzimidazolyl 2865 CONH-R-CH(CH3)Ph 2866 CONH-S-CH(CH3)Ph 2867 CONHCH2CONHMe 2868 CONH-S-CH(CH3)CONHMe 2869 CONH-R-CH(CHs)CONHMe 2870 CONH-S-CH(2-Dropvl)CONHMe 2871 CONH-S- CH (CH2SH) CONHMe 2672 CONH-S- CH (CH2OH) CONHMe 2873 CONH-R- CH (CH2OH)CONHMe 2874 CONH-S-CH(CH20-C-Bu)CONHMe 2875 CONH-R-CH(CH2O-L-Bu'CONHMe LV 12167 TABLE 27
BOC
I
E X R2 (CI-MS) ms B X R2 (CI-MS) ms 2880 CONHMe 471.5 TABLE 23
B X R2 (CI-MS) as B x R2 (CI-MS) ms 28 90 CONHMe 515.4 -273- TABLE 29 ΗΟΗΝ
BOC
R2 B X R2 (CI-MS) VLB lx R2 (CI-MS) m e 2900 CONHMe 549.3 TABLE 30
O (CHgJaPh B x R2 (CI-MS) IBS Bx R2 (CI-MS) m s 2910 CCNHMe 449.4 - -274- LV 12167
TABLE.JLL
HOHNL JL JL X. „ ΥΤΊΙ "* O (CH2)3Ph
Ex R2 (CI-MS) B8 Bx R2 (CI-HS) Bt 2920 CONHMe 491.4 TABLE 32
Ex R2 (CI-MS) ms B x R2 (CI-KS) ms 2930 CONHCHiCON-monohol ino 527.6 2931 CONHCH;CO (N-hvdroxvūioeridinel 541.7
HOHN
TABLE 33Ph02S I
(CH2)3Ph
E X R2 (CI-MS) me B x R2 (CI-MS) BS 2940 CONHMe 589.4 TABLE 34
Ac
E X R2 (CI-MS) me B X R2 (CI-MS) ms 2 95C CONHMe 491.2 -276- LV 12167 TABLE 35
HOHN
Ex R2 (CI-KS) me E x R2 (CI-HS) me 4000 C02Me 4054 CONH-cyclopentyl 4001 C02Et 4055 CONH2 4002 CC2iPr 4056 CONHiPr 4003 C02<CH2>20Me 4057 CONK-cerc-but;yl 4004 CO2(CH2)2?h 4058 CONMe2 4005 CC'2-tBu 4059 CONEC2 4006 C02CH2C0NHMe 4060 CONH-3-indazolyl 4007 CH2OH 4061 CONH-adamancv1 4008 • CH2CCH2CH3 4062 CONHCH2(p-S02NH2-Phi 4009 CH2OCH2CH2CO2CH3 4063 CONH(CH2)3-1-imidazolvi 4010 CHOBn 4064 CONHSO2NH2 4011 CONH (CH2 :'2-2-pyridyl 4065 CONHSO2CH3 4 012 CO(N-mcr?holinyl) 4066 CONHS02Ph 4013 CO(N-Me-N-DiDerazinvl) 4067 C0NHS02Bn 4014 CONH(CH2?2"(N-Me-N-ciDerazinvl) 4068 CONHSO2-N-Me-imidazolvl 4 015 CONH-cyc1opropy1 4069 CONHSO2-p-NH2 Ph -277- 4016 CONH-cyclobutyl 4070 CONHSO2-p-MeOPn 4017 C0NHS02-p-F-Ph 4071 CONH-S-CH [CH2CH<CH3)2]CONHMe 4018 CONH(CH2)2NHS02Me 4072 CONH(CH2)4NHS02Me 4 C19 CONH-cyclohexyi 4073 CONH(CH2)gNHS02Me 4020 C0NK-2-inu.dozolyl 4074 CONH-R-CH (CH2CH(CH3)2]CONHMe 4021 CH2SO2NHCH3 4075 CONH-S-CH [(CH2)4NH21CONHMe 4022 CH2S02NHPh 4076 CONH-S- CH [(CH2)3NH2]CONHMe 4023 CH2SO2NH-[4-NH2Ph] 4077 CONH-S- CH [ <CH2)2NH2]CONHMe 4024 2-imidazolyi 4078 CONHMe 4025 2-oxazoly 4079 CONHCH2CONMe2 4026 2-chiazolyl 4080 CONHCH2CONHEZ 4027 2-benzimidaz01y1 4081 CONHCH2CONEC2 4028 CONH-R-CH(CH3)Ph 4082 CONHCH2CONK- cvclooropvl 4029 CONH-3-CH(CH3)Ph 4083 CONHCH2CONH-cyclobutyl 4031 CONKCH2CONHMe 4084 CONHCH2CONH- cvcloDencvl 4032 CONH-S-CHiCHs)CONHMe 4085 CONHCH2.CONH-cyclor.exyl 4033 CONH-R-CH(CH3)CONHMe 4086 CCNHCH2CONH-Cert-bucv1 4034 CONH-S-CH(2-orocvl1CONHMe 4087 CCNH-5-CH(CH2Ph)CONHMe 4035 CONH-S- CH (CH?SH)CONHMe 4088 CONH-S-CH(CH2-P-MeOPh)CONHMe 4 03 6 CONH-S- CH (CH2OH) CONHMe 4089 CONHCH2CH2CONHMe 4037 CONH-R- CH (CH2OH} CONHMe 4090 CONHCH2CH2CH2CONHMe 4038 CONH-S-CH(CH20-t-BulCONHMe 4091 CONH-S- CH (CH2CH2OH)CONHMe 4039 CONH-R-CH(CH20-t-BulCONHMe 4092 CONH-S- (CH(CH2)3CH3)CONHMe 4040 CONH-CH(Ph)2 4093 C0NH(CH2)2C02Me 4041 CO-L-proiine-NHMe 4094 CONH(CHo)2CO2H 4042 CONHCH2CO(N-oiDerazinvl) 4095 CONH-S- CH [(CH2)3NHBOC]CC? Me 4043 CONHCH2CO (N-methyl-N-Dioerazinvl) 4096 CONH-S- CH [{CH2)3NHBOC]CONHMe 4044 CONHCH2CC(N-acecyl-N-oicerazinvl) 4097 CONH-S-CH-[(CH2)3NH2]C02Me 4 04 5 CCNHCHoCO-N-mcrrholino 4098 CONH-S- CH : (CH2)4NH2]CCNH* LV 12167 4046 CONHCH2CO-[N-(4-hvdroxvpiperidinvl)1 4099 CONH(CH2)2Ph 4047 CO2H 4100 CONH(CH2)2-(3,4,-dimethoxyphenvl) 4048 CONHBn 4111 CONH(CH2)2-(N- morDholino) 4049 CONH-2-pyridyl 4112 CONH(CH2)3 -(N-morpholino) 4050 CONH-Ph 4113 CONHCH2CONH-(2-ovridvl) 4051 CONH-3-pyridyl 4114 CONHCH2CONH-(3 -pvridvl) 4052 CONH-4-pyridyl 4115 CONHCH2CONH-(4-pvridvl) 4053 CONH-CHjCH(Ph)2 4116 CONH (CH3) j (P-SOjNHj-Ph) -275-
UTILITY
The compounds of formula I possess metalloproteinase and aggrecanase and TNF inhibitory activicy. The MMP-3 inhibitory activity of the compounds of the present invention is demonstrated using assays of MMP-3 activicy, for example, using the assay described below for assaying inhibitors of MMP-3 activity. The compounds of the present invention are bioavailable in vivo as demonstrated, for exampīe, using the ex vivo assay described below. The compounds of formula I have the ability to suppress/inhibit cartilage degradation in vivo, for example, as demonstrated using the animal modei of acute cartilage degradation described below.
The compounds provided by this invention are also useful as standards and reaģents in determining the ability of a potential pharmaceutical to inhibit MPs. These would be provided in commercial kits comprising a compound of this invention.
Metalloproteinases have also been implicated in the degradation of basemenr membrances to allow infiltration of cancer celis into the circulation and subsequent penetratior. into other tissues leading to tumor metastasis. (Stecler-Stevenson, Cancer and Metastasis Reviews, 9, 289-303, 1990.) The compounds of the present invention should be useful for the prevention and treatment of invasive tumcrs by inhibition of this aspect of metastasis.
The compounds of the present invention would also have utility fcr the prevention and treatment of osteopenia associated with matrixmetalloproteinase-mediated breakdown of cartilage and bone which occurs in csteoporosis pacients.
Compounds which inhibit the productior. or acticn of TNF and/cr Aggrecanase and/or MP's are potentially useful for the treatment or prophylaxis of various infiammatory. -280- LV 12167 infectious, immunological or malignant aiseases. These include, but are not liir.ited to inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, an acute infection, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, periodontits, gingivitis, congestive heart failure, fibrotic disease, cachexia, and aneroxia, graft rejection, cancer, corneal ulceration or tumor invasion by secondary metastases, autoiīnmune disease, skin inflammatory diseases, multiple osteo and rheuinatoid arthritis, multiple sclerosis, radiation damage, HIV, and hyperoxic alveolar injury.
The compounds of the present invention have been shown to inhibit TNF production in lipopolysacharride stimulated mice, for example, using the assay for TNF Induction in Mice and in human whole blood asdescribed below.
The compounds of the present invention have been shown to inhibit aggrecanase a key enzyme in cartilage breakdown as detemined by the aggrecanase assav aescribed below.
As used herein ^g" denotes micrcgram, “mg’' denctes milligram, "g" denotes gram, "μΐ," denotes microliter, "mL" denotes milliliter, "L" denotes liter, ‘nM" denotes nanomolar, "μΜ" denotes micromolar, "irM" denotes millimolar, "M" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Ccrp. of St. Louis, MO. A compound is considered to be active if it has an IC50 or Ki value of less than about 1 irM for the inhibition of MMP-3. ACTcrecanase Enzvmatic Assav A novel enzymatic assay was develcped to detect potential inhibitors of aggrecanase. The assay uses active aggrecanase accumulated in media from stimulated bovir.e nasal cartilage (3NC) or related cartilage sources ar.č -281- purified cartilage aggrecan monomer or a fragment thereof as a substrātā.
The substrate concentration, amount of aggrecanase time cf incubation and amount of product loaded for Western analvsis were optimized for use of this assay in screening putative aggrecanase inhibitors. Aggrecanase is generated by stimulation of cartilage slices with interleukin-1 (IL-1; , tumor necrosis factor alpha (TNFS) or other stimuli. Matrix metalloproteinases (MMPs) are secreted from cartilage in an inactive, zymogen form following stimulation, although active enzymes are present within the matrix. We have shown that following depletion of the extracellular aggrecan matrix, active MMPs are released into the culture media. (Tortorella, M.D. et. al. Trans. Ort'no. Res. Soc. 20, 34i, 1995). Therefore, in order to accumulate BNC aggrecanase in culture media, cartilage is first depleted of endogenous aggrecan by stimulation with 500 ng/ml human recombinant IL-β for 6 days with media changes ever/ 2 aays. Cartilage is then stimulated for an addicional 8 days without media change to allow accumuiation of soluble, active aggrecanase in the culture media. In crder to decrease the amounts of other matrix metalloproteinases released into the media during aggrecanase aocumulation, aģents wnich inhibit MMP-1, -2, -3, and -9 biosvnthesis are included during stimulation. This BNC conditioned media, containing aggrecanase aotivity is then used as the source cf aggrecanase for the assay. Aggrecanase enzymatic activitv is detected by monitcring producticn cf aggrecan fragments prcduced exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core proteir. ry Westem analvsis using the monoclonal antibocv, BC-3 (Hughes, CE, et ai., Biochem J 306:799-804, 1995) . This antibocv recogr.izes aggrecan fragments vith the N-terminus, 374ARGSVTL.., generated upon cleavage by aggrecanase. The BC-3 antibocv recccnizes this neoepitope only wher. it is at the N-tercenus and not when it is preser.t internallv vtthir. aggrecan fragments or withi.n the -232- LV 12167 aggrecan protein core. Other proteases produced by cartiiage in response co IL-1 do not cleave aggrecan at the GIu373-AIa374 aggrecanase site; therefore, only products prcduced upon cleavage by aggrecanase are detected.
Kinetic studies using this assay yield a Km of 1.5 +/- 0.35 uM fcr aggrecanase.
To evaluate inhibition of aggrecanase, compounds are prepared as 10 mM stocks in DMSO, wacer or other solvents and diluted to appropriate concentrations in water. Drug (50 ul) is added to 50 ul of aggrecanase-containing media and 50 ul of 2 mg/ml aggrecan substrate and brought to a fmal voiume of 200 ul in 0.2 M Tris, pH 7.6, containing 0.4 M NaCl and 40 mM CaC12. The assay is run for 4 hr at 37oC, quenched with 20 mM EDTA and analyzed for aggrecanase-generated products. A sample containing enzyme and substrate without drug is included as a positive contrcl and enzyme incubated in the absence of substrate serves as a measure of background.
Removal cf the glycosaminoglycan side chains from aggrecan is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the core proteir.. Therefore, for analysis of aggrecan fragments generated by cleavage at the Glu373-Aia374 site, proteoglycans and proteoglycan fragments are enzvmatically aeglycosylated with chcndroitinase ABC (0.1 units/10 ug GAG) for 2 hr at 37oC and then with keratanase (0.1 units/10 ug GAG) and keratan.ase II (0.002 units/10 ug GAG) for 2 hr at 37oC in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH 6.5. After digestion, aggrecan in the samples is precipitated with 5 volumes of acetone and resuspended in 30 ul of Trīs glycine SDS sample buffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loaded and then separated by SB3-FAGE unaer reducing conditions with 4-12% gradient gels, transferred to nitrocellulose and immunoiocated wtth 1:500 dilution of antibody BC3. Subsequently, membranes are incubated with a 1:5000 dilution cf gcat anti-mouse IgG alkaline phosphatase second -2 antiboay and aggrecan catabolites visualized by incubation with appropriate substrace for 10-30 minūtes to achieve optimal color development. Blots are quantitated by scanning densitometry and inhibition of aggrecanase determined by comparing the amount cf product produced in the presence versus absence of compound.
Sisacetvlated.Substance P / MMP-3 fluorescent Assav A high capacity enzymatic assay was developed to detect potential inhibitors of MMP-3. The assay uses a derivative of a peptide substrate, substance P (Arg-Pro-Lys-Pro-Gln-Gin-Phe-Phe-Gly-Leu-Met), which is cleaved by MMP-3 exclusively at the glutamine-phenylalanine bond. In order to adapc this assay for high throughput screening, we have developed a fluorimetric method of product detection. The production of the hydrolysis product, substance P 7-11, is measured bv reaction with fluorescamine, a fluorogenic compound which reacts with the primary amine of this fragment. The substance P substrate is bisacetylated to block the primarv amines of the intact substrate. Thus, the resulting fluorescence represents generation of product '7-11 peptide; formed upon cleavage by MMP-3, and is cuantitated using a Standard curve prepared with known concentraticns of 7-u peptide. Kinetic studies using the bisacetylated substrate yield the foliowing parameters for MMP-3: Km =759 +/- 52 uM? Vmax = 0.090 + /- 0.003 nmoies 7-11 peptide/min.
To evaluate inhibition of MMP-3, compounds were prepared at a concer.tration of 10 mM in 100% methanol, and then further diluted to a 20Χ molar stcck. .Five microliters cf each drug stock was added to the assav in the presence of 20 nM truncated MMP-3 in 67.5 mM tricine (pK 7.5), 1C mM CaCl2, 40 mM NaCl, and 0.005% Brij 35 in a final vclume of 100 microliters. Bisacetylated substance P (1000 mM) was added, and the assav was run for 1 hour at 25°C. The reaction was guer.ched with EDTA (20 mM) and product was detected fluorometricallv following addition of -284- LV 12167 fiuorescamine (0.075 mg/ml). Fluorescence of each sample was converted to an amount of product formed using a substance P 7-11 Standard curve. Under these conditions, the assav is linear with respect to MMP-3 amount up to 10 pmoies. Inhibition of MMP-3 was determined by comparing the amount of product generated in the presence and absence of compound.
Selected compounds of the present invention were tested and s'nown to have activity in the above assay.
Ex vivo assav for bioavailabilitv of MMP-3 inhibitors
Blood was collected by cardiac puncture from rats at different times after dosing I.V., I.P., or P.O. with compound in order to determine the Ievels of inhibitor present. Plasma was extracted with 10% TCA in 95% methancl, and placed on ice for 10 minūtes. The plasma was then centrifuged for 15 minūtes at 14,000 rpm in an Eppenaorf microcentrifuge. The supernatant was removed, recer.trifuged, and the resulting supernatant was diluted 1:10 in 50 mM tricina, pH 8.5. The pH of the sample was adjusted to 7.5, and then assayed in the MMP-3 substance P fluorescent enzvmatic assay. Plasma from naive rats was extracted by the same methoa and used as a negative control. Thts plasma was also used to prepare a sņikad plasma curve cf the compound of interese. Known concentraticr.s of the compound were acded to control plasma, the plasma was extracted by the same method, and then assayed in the MMP-3 enzymatic assay. A Standard curve was prepared that relatea percent inhbition ir. the MMP-3 assay to the concentration of drug added in the spiked samples. Based on the percent inhibition in the presence of plasma from dosed rats, the concentration of compound was determined using the Standard curve.
Adute tte: Mods; -285- A novel in vivo modei of acute cartilage degradation in rats has been characterized as a method to determine the proteoglycan content in the synovial fluid after the induction cf cartilage degradation. Experimental groups exhibit increasea Ievels of proteoglycan content in their svnovial fluid versus control rats. The criteria to dēmonstrāte a compound's activity in this modei, is the ability to inhibit the demonstration of cartilage degradation, as measured by increased proteoglycan content in the synovial fluid of rats after compound ādministration. Indomethacin, a non-steroidal anti-inflammatory drug is inactive in this modei. Indomethacin administration does not inhibit the demonstration of cartilage degradation in experimental animals. In contrast, administration of a compound of this invention significantlv inhibited the demonstration of cartilage degradation in this modei. TNr Human Whole Blood Assav
Biood is drawn from normai donors into tubes containing 143 USP units of heparin/lOml. 225ul of blood is plated directlv into sterile polypropylene tubes. Compounds are diluted in DMSO/serum free media and added to the blood samples sc the final concentration of compounds are 50,10,5,1,.5,.1, and . OluM. The final concentration of DMSO does nct exceed .5%. Compounds are preincubated for 15 minūtes before the addition of lOOng/ml LPS. Plates are incubated fcr 5 hours in an atmosphere of 5% C02 in air.
At the end of 5 hours, 750ul of serum free media is added to each tube and the samples are sdut. at 1200RPM for 10 minūtes.
The supernatant is collected off the top and assayed for TNF-alpha prcduction by a Standard sandwich ELISA. The ability of compounds to inhibit TNF-alpha production by 50% compared to DMSC treated cultures is given by the IC50 value. -235- LV 12167 INF .Induction In Mice Tēst compounds are administered to mice either I.P. or P.O. at time zero. Immediately following compound administration, mice receive an I.P. injection of 20 mg of D-galactosamine plus 10 μg of lipopolysaccharide. One hour later, animals are anesthetized and bled by cardiac puncture. Blood plasma is evaluated for TNF Ievels by an ELISA specific for mouse TNF. Administration of representative compounds of the present invention to mice results in a dose-dependent suppression of plasma TNF Ievels at one hour iri the above assay.
Dosaae and Formulation
The compounds of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generallv administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (eacn of which includes sustained release cr timed release formulations), pilis, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they mav also be administered in intravenous (bolus or infusion', , intraperitoneal, subcutaneous, or intramuscuiar form, ali using dosage forms well known to those of ordinarv skiil in the pharmaceutical arts. An effective but non-tcxic amount of the compound desired can be employed as an antiinflammatory and anttarthritic aģent. -287-
The compounds of this invention can be administered by ar.y means that producēs contact of the active aģent with the aģent’s site of action, MMP-3, in the body of a mammai. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic aģents or in a combination of therapeutic aģents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of ādministration and Standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular aģent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the svmptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the rēnai and nepatic function of the patient,and the effect desired. An crcinarilv skilled physician or veterinarian can readilv determine and prescribe the effective amount of the drug required to ņrevent, counter, or arrest the progress cf the condition.
Bv wav cf general guidance, the daiiy oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of bodv weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferabiy between about 1.0 tc 20 mg/kg/day. For a normai male adult human of approximately 70 kg of boay weight, this translates into a dosage of 7C to 1400 mg/day. Intravenously, the most preferred dcses will range from about 1 to about 10 mg/kg/minūte during a constant rāte infusion. Advantageouslv, compounds of the present invention may be administered in a single dailv dose, cr the total dailv dosage mav be administered in divided dcses of two, three, cr four times daily. -288- LV 12167
The compounds for the present invention can be administered in intranasal form via topical use of suitable intrar.asal vehicles, or via transdermal routes, using those forms of trar.sdermal skin pacches wall known to those of ordinary skill ir. that art. To be administered in the form of a trar.sdermal delivery system, the dosage administration will, cf course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typicaily administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materiāls) suitablv selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, svrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be ccmbined with an oral, non-toxic, pnarmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methvl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug compcnents car. be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethancl, giycerol, water, and the like. Moreover, when desired or r.ecessary, suitable binders, lubricants, disintegrating aģents, and coloring aģents can also be incorporated into the mixture. Suitable binders include starch, geJatin, natūrai sugars such as glucose or beta-lactose, corn sweeteners, natūrai and synthetic gums such as acacia, tragacanth, cr scdium alginate, carboxymethylcellulose, poiyethyiene giycol, waxes, and the like. Lubricants used ir. these dosage forms include sodium oleate, sodium stearate, macr.esium stearate, sodium benzoate, sodium. acetate, sodium chlcride, and the like. Disintegratcrs -2S9- include, without limitation, starch, mechyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome deliverv systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Coiapounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, pclyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds of the present invention mav be coupled to a class of biodegradable polvmers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of ņolylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polvorthoesters, polyacetals, polydihyaropyrans, polycyanoacylates, and crossiinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compcsitions) suitable for administration mav contain from about 1 milligram to about 100 milligrams cf active ingredier.t per dosage unit. In these pharmaceutical compositions the active ingreaient will ordinarily be present in an amount of about 0.5-95% by weight based cn the total weight of the composition.
The active ingreaient can be administered orally in solid dosage fcrms, such as capsules, tablets, and powders, cr in licuid dosage forms, such as elixirs, svrups, and suspensions. It can also be administered parenterallv, in sterile liguid dosage forms.
Gelatin capsules may contain the active ingredier.t and ņowdered carriers, such as lactose, staroh, cellulose derivatives, magnesium stearate, stearic acid, and the lika. Sirdlar diluerts can be used to make compressed LV 12167 tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpieasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and fiavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (giucose), and related sugar Solutions and glycols such as propylene glyccl or polyethylene glycols are suitable carriers for parenteral Solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing aģents, and if necessary, buffer substances. Antioxidizing aģents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing aģents. Also used are citric acid and its salts and sodiem EDTA. In addition, parenteral Solutions car. contain preservatives, such as benzaikonium chlortde, methvl- or propvl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are deseribed ir. Remington's Pharmaceutical Sciences, Mack Publishing Company, a Standard reference text in this field.
Useful pharmaceutical dosage-ferms for administration cf the compounds cf this invention can be illustrated as follows:
Capsules
Capsules are prepared by conventional procedures sc chat the dosage unit is 500 milligrams cf active ingredient, 1GC milligrams of cellulose and 10 milligrams of magnesium stearate. A large r.unber cf unit capsules may also prepared by filling seandart two-piece hard gelatir. capsules each vith 100 milligrams of powdered active ingredient, 150 -291- miligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Svmp m, 3 10 50 20 5 as required as reguired
Active Ingredienc Liquid Sugar Sorbitol Glvcerine
Flavor, Colorant and
Preservative
Wacer
The final volume is brought up co 100% by the addition of discilled wacer.
Acrueous Suspension
Wt. % 10 0.01 0.2 5 required required
Active Ingredienc Sodium Saccharin
Keltrol® (Food Grade Xanthan Gum) Liquid Sugar
Flavor, Colorant and as
Preservative
Water as
Xar.thar. gum is slowly added into distilled water before adding the active ingredient and the rest of the formulation ingredients. The final suspension is passed through a homogenizer to assure the elegance of the final products.
Resusoendable Powder
Wt. %
Active Ingredient 50.0 Laccose 35.0 Sugar 10.0 Acacia 4.7 Sodium Carboxylmethvicellulose 0.3
Each ingredient is finelv pulverized and then uniformlv mixed togetner. Alternatively, the powaer car. be prepared as a suspension and then spray dned.
Semi-Solid Gel
Wt. % 10 0.02 2 as reguired as reguired
Acttve Ingredient Sodium Saccharin Gelatin
Flavor, Colorant and
Preservative
Water LV 12167
Gelatin is prepared in hot water. The finely pulverized active ingredient is suspended in the gelatin solution and then the rest of the ingredients are mixed in. The suspension is filled into a suitable packaging Container and cooled down to form the gel.
Semi-Solid Paste
Wt. % 10 1 0.01 2 as required as reguired
Active Ingredient Gelcarin® (Carrageenin gum) Scdium Saccharin Gelatin
Flavor, Colorant and
Preservative
Water
Gelcarin® is dissolved in hot water (around 80°C) and then the fine-powder active ingredient is suspended in this solution. Sodium saccharin and the rest of the formulation ingredients are added to the suspension while it is stili warm. The suspension is homogenized and then filled into suitable containers.
Emulsifiable Paste
Active Ingredient Wt. % 30 Tween® 80 and Span® 80 6 Keltrol® 0.5 Mineral Oil 63.5
Ali the ingredients are carefully mixed together to make a homogenous paste.
Soft Gelatin Capsuies A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected bv means of a positive displacement pump into gelatin to form soft gelatin capsuies containing 10G milligrams of the active ingredient. The capsuies are washed and dried.
Tablets
Tablets may be prepared by conventional procedures so Chat the dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of celluiose and 10 milligrams of magnesium stearate. -293- A large number of tablets may also be prepared by conver.tional procedures so chac the dosage unit was 100 milligrams cf active ingredient, 0.2 milligraiņs of collcidai Silicon dioxide, 5 miligrams of magnesium stearate, 275 milligrams of microcrvstalline cellulose, 11 miligrams cf starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palacabilicy or delay absorption.
Injeccable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of accive ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Susper.sior.
Ar. agueous suspension is prepared for oral ādministraticr. so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitcl solution, υ.Ξ.Ρ., and 0.025 irL of var.illin.
The compcunds of the present invention may be administered in coirbination with a second therapeutic ager.t, especiallv ncn-steroidal anti-inflammatory drugs (NSAID's; . The compcund of Formula I and such second therapeutic acent car be administered saparately or as a pnysical comb-ination in a single dosage- unit, in any dosage fcrm and by various routes of administration, as described above.
The compcund cf Formula I may be formulated together with the second therapeutic aģent in a single dosage unit (that is, ccmbined together in one capsule, tablet, pcwder, or liguid, eto.i . When the ccmpound of Formula I and the second therapeutic aģent are r.ot formulated together in a single dosage unit, the compcund of Formula I and the second therapeutic aģent may be administered essentiallv at -254- LV 12167 the same time, or in any order; for example che compound of Formula I may be administered first, followed by administration of the second aģent. When not administered at the same time, preferably the administration of the compound of Formula I and the second therapeutic aģent occurs less than about one hour apart, more preferably less than about 5 to 30 minūtes apart.
Preferably the route of administration of the compound of Formula I is oral. Aithough it is preferable that the compound of Formula I and the second therapeutic aģent are both administered by the same route (that is, for example, both orally), if desired, they mav each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product mav be administered orally, and another component may be administered intravenousiy).
The dosage cf the compound of Formula I w'nen administered alcne or in combination with a second therapeutic aģent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular aģent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symņtoms, the kind cf concurrent treatment, the frequency of treatment, and the effect desired, as described above.
Particuiarly wher. provided as a single dosage unit, the potential exists for a Chemical interaction between the combined active ingredients. For this reason, w'nen the compound of Formula I and a second therapeutic aģent are combined in a single dosage unit they are formulated such that aithough the active ingredients are combined in a single dosage unit, the ņhysical contact between the active ingredients is minimized (that is, reduced}. For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not oniy to minimizē the contact betveen the combined active ingredients, but alsc, it is possible to ccntrol the -295- release of one of chese components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustamed-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimizē physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Stili another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or cther appropriate materiāls as known in the art, in order to further separate the active components. The pcivmer coating serves to fona an additional barrier to interaction with the other component.
These as weil as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage fona cr administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled ir. the art, cnce armed with the present disclosure.
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of osteoarthritis or rneumatoid arthritis, wnich comprise one or more containers ccntaining a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of varicus conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etr., as will be readily apparent to those skilled ir. the art. Instructicns, either as inserts cr as labels, indicating ouantities of the components to be -295- LV 12167 administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
In the present disclosure it shoula be understood that the specified materiāls and conditions are important in practicing the invention but that unspecified materiāls and conditions are not excluded so long as they do not prevent the benefits of. the invention from being realized.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention. -297- LV 12167
CLAIMS WKAT IS CLAIMED: 1. A compound of formula I:
or pharmaceutically acceptable salts cr prodrug forms thereof, wherein: U is selected from: -C02H, -CONHOH, -CONHOR11, -SH, -NK- COR11, -N(OH)COR11, -SN2K2R6, -SONKR6,CH2C02H, ?0(0H)2, PO (OH) NHR® , CH2SK, -C(0)NH0R12, -C02R12, and consmon prodruc derivatives; H, - (C0-C6) aikyi-S (0) p- {Ci-Ce) allcyl, - (Co-Cg) alkyl-0- (Ci-C6)aikyi, - (Co-Cs!alkyl-S (0)p- (Co-Cg)alkyl-aryl, - (Co-Ce'. alkyl-0- (Co-Cg)alkyl-aryl, alkyl cf from 1 to 20 carbon atoms which include branched, cvcl.c and unsaturated alkvl groups, substituted alkvl whereir. the substituent is selected from; hydrogen, halo, hydroxy, alkoxy, arylcxy, (such as pher.oxy' , amino, mono- alkylaru.no, di-alkylaminc, acylamino (such as acetamido and benzamidc) , arylamino, guanidino, N- 38- methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, - (Co-Cg)aikyl-aryl, -(Co-Cg)alkyl-substituted aryl, -(Co-Cg)aryl-(C1-C4)alkyl-aryl, -(Ci-Cg)alkyl-biaryl, - (Co-Cg)alkyl-S (O)p- (Co-Cg )alkyl-aryl, - (Co-Cg) alkyl-S (0)p— (Co-Cg)alkyl-substituted aryl, - (C1-C4)alkyl-aryl- (Co-Cg)alkyl-aryl- [S(0)p- (C0-
Cg)alkyl] , - (Co-Cg) alkyl-S (0) p- (Co-Cg)alkyl-biaryl, - (Co-Cg) alkyl-0- (Co-Cg)alkyl-aryl, - (C0-C8) alkyl-S (0) p- (Co-Cg) alkyl-subscituted aryl, - (C1-C4) aikyl-aryl- (Co-Cg)alkyl-aryl- [0- (Co-Cg)alkyi], - (Co-Cg) alkyl-0- (Co-Cg)alkyl-biaryl, - (Cņ-Cg) alkyl-0- (Co-Cg >alkyi-substicuced aryl, wherein rhe substituent is selecced from; hydrcgen, C1-C5 alkyl, hydroxy, halo, alkoxy, amir.c, mono-alkylamino, di-alkylaitd.no, acyland.no, thio, thioalkyl, carboxy, carboamido or aryl; R2 is seiec-eč from H, -C02R5, -CONR6R5, -CONR6(OR5), -alkvl, -alkvlarvl, -alkviheteroarvl, -alkyihecerocyclic, -aryl, -heteroarvl or -heterocyclic which is substicuted with one or mcre substituer.es selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkyiand.no, di-allc/lainino, acylaminc (such as acetamido and ber.zamido), arylamino, guanidino, N-methyl imidazolyl, imidazolvl, indolvl, mercapto, icwer alkvlchio, arylthio (such as phenylthio), carccxy, sulfonamido, carboxaru.de, or carbcalkoxy; -2 LV 12167 R3 is selected from: -H, -OH, -OR6 -NK2, -NHR6, -N(R6)2, - (0χ-06) alkyl, --(Ci-Cg)alkyl-aryl, -SR6, halide, or nitrile;
Alternativelv R2 and R3 can form a 3 to 8 membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; R4 is selected from: K, -OH, -OR6 -NK2, -NHR6, -N(R6)2, - (Ci-C6) alkyl, -(Ci-C6)alkyl-aryl, -S(0)p- (Ci-C6)alkyl, halide, or nitrile; R5 is selected from: - (CHR^ln-R9' -C(R7R8)n-W-C(R7R8)m-R9, -C(R7R8)m-R9, -C(R7R8)m-aryl, -C(R7R8)mC:0NR7R8, -C (R7R8ī m-substituted heteroaryl, -C (R7R8) rr;-substituted heterocyclic, wherein the substituent is selected from; hvdrogen, C:~Cs alkyl, hydroxy, halo, alkoxy, amir.c, mono-alkyiamino, di-alkylaird.no, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R6 is selected from: H, alkvl, -(Ci-C6)alkyl-aryl, - (Ci-Ce) alkyl-heteroaryl, - (Ci-Cg)alkyl-heterocyclic, - (Ci-Cg)alkyl-acyi;
Alternatively, R5 and R6 may form a 3 to 8 membered ring optionallv unsaturated containing from 1 to 3 neteroatcirs selected from -0, -NR6, -S(0)p, or ar. acvi grcup, optionally fused to ar. aryl ring; -300- R7 and R8 may be selected independently from: H, R1, or form a 3 co 7 membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from; hydrogen, C1-C5 alkyi, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylairu.no, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing -0-, -S(0)p, -NR6, optionally fused to a substituted aryl ring, wherein the substituent is selected from; hydrogen, Ci-Cs alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R5 is H, alkyi, cycloalkyl 5 or 6 membered ring optionallv containing from 1 to 2 N, 0 or S(0)p, optionaliv substituted with -OK, -0-{C1-C6)alkyl, -0-acyl-alkyl, NHR10, or aryl; R1C is H or ar. cptionally substituted alkvl group; R11 is hydroger., alkyl of from 1 to 10 C atoms which ir-clude cranched, cyclic and unsaturated alkyl groups, s'dbstituted alkyl w’nerein the substituent is selected frcm: hydrcgen, halo, hydroxy, alkoxy, aryloxy, such as phencxy, amino, di-alkylaminc, acylamino such as acetamido and benzetido, arylamino, guanidir.c, imicazoiyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio) carboxy, cartcxamido, carbo-aikoxy, or sulfonamide, - (Ci-C4)alkyl-aryl, - (C1-C4) alkvl- (Ci-Cg) alkyl-aryl - (Ci-Ce) alkvl-biarvl, substituted - (Ci-Ce)alkyl-aryl. -301- LV 12167 wherein the substituent is selecced from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arvlthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;
Rlla is H, -S02~Ci-C6-alkyl, -S02-Ci-C6-alkyl-subscituted aryl, -S02-aryi, -S02-substituted heteroaryl, -COR9, -CO2C-Bu, -CC^Bn, or -alkyl-substituted aryl wherein che substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, airu.no, mono-alkylamino, di-alkylamino, acvlaminc, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selecced from: H, aryl, (Ci to Cio)alkyl-, aryl (C: to Cg)alkyl-, C3 to C:i cvcloalkyl, C3 to Cic alkylcarbonylcxyaikyl, C3 to Ci; alkoxycarbonyloxyalkyl, C2 to Ci; alkoxycarbonyl, C5 to C:c cycloalkylcarbonyloxyalkyl, C5 to Ci;· cyclcalkoxycarbonyloxyalkyl, C3 to Cic cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy(Ci to Cg aikyl)-, arylcarbonyloxy (Ci to Cg alkyi)-, C5 to C12 alkoxyalkylcarbonyioxyalkyl, [5-(C1-C3 aikyl)-1,3-dicxa-cyclopenten-2-one-yi]methy:, (5-aryl-l, 3-dioxa-cyclopenten-2-one-yl)methyl, (R17) (R*-‘a)N- (C1-C10 alkvl) -, -CH(R13)OC (=0)R14, -CH (R13 ) CC (=0) OR-5, or
R13 is H or C1-C4 linear alkyl; R14 is selected from: H,
Ci-Cg alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl C1-C5 alkoxy, aryl substituted with 0-2 groups independently selected from: haloger., phenyl, Ci-Cg alkyl, Ci-Cg alkoxy, NO2, -S(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -802(03-05 alkyli, -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R17a), or -CVFW where v = 1 r0 3 and w = 1 tc (2v+l), aryl substituted with 0-2 groups independently selected from: haloger., phenyl, C’-Cg alkyi, C--C6 alkoxy, N02, -S(Cļ-Cs alkyl). -8(=0)(03-05 alkyl), -S02(Ci-C5 alkyl), -OH, -N(Rl7) (R37a) , -C02R17a, -C(=0)N(R17) (Rl7a) , or -CVFW where v = l to 3 and w = 1 to (2v+l); R15 is selected from:
Ci-Ce alkvl, 03-03 cycloalkyl, said alkyl or cycloalkyl beir.g substituted with 1-2 grtups independer.tly selected from: -303- LV 12167 C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independencly selected from: halogen, phenyl, Ci-Cg alkyl, Ci-C6 alkoxy, N02, -S(Ci-C5 alkyl), -S(=0)(C1-C5 alkyl), -S02(Ci-Cs alkyl) , -OH, -N(Ri7) (Ri7a), -C02R17a, -C(=0)N(R17) (R17a), or -CvFw where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(Ci-C5 alkyi), -S02(Ci-C5 alkyl), -OH, -N(R*7) (R17a) , -C02R17a, -C(=0)N(R17) (R17a) , or -CvFw w'nere v = 1 to 3 and w = 1 tc (2v+l); R16 is C:-C4 alkyl, benzyl, cr phenyl, R17 and P.17a is independently selected from: H, Ci-Cic alkvl,C2-C6 alkenyl, C4-C11 cycloalkylalkyi, and aryl (C1-C5 alkyi);
Combinations cf A, 3 and D, and/or variables are permissabie cr.ly if such combinations rssult in stable compounds (as defined herein) A can be abser.t, -(CHR6)m-, -0(CHRs)m-, -NR6 (CHR6;m-, - S(0)p(CHRS)m-, or selected from an alkyl from 1 to 10 carbon atoms which include brar.ched, cvclic and unsaturated alkyl groups or - (C:-C0'alkyl-aryl; -304- B can be a bond or selected from -NH-, -NR11-, - NRlla- -0--S(0)p- (Ci-C6)alkyl-NH- (Ci-C6)alkyl-, (Ci-C6)alkyl-NRH- (Ci-C6) alky-, -Ci-C6-NH-aryl-, -0-(Ci-Cg)alkyl-, -(Ci-Ce)alkyl-0-aryl-, -S-(Ci-Ce)alkyl-, - (Ci-C6)alkyl-S-aryl-, -(Ci-C6)alkyl-, -(Ci~C6)alkenyl-,-(C1-C6)alkynyl-, -CONH-, -CONR11, -NHCO-, -NRnCO-, -OCO-, -COO-, -0C02 -R11NCONR11-, HNCONH-, -OCONR11-, -NR^COO-, -HNS02-, -SO2NK-, aryl, cycloalkyl, heterocycloalkyl, -R^NCSNR11-, -HNCSNH, -OCSNR11-, -NRUCSO-, -HNCNNH-, and a pepcide bond mimic;
D can be absent or an aikyl from 1 to 10 carbon atoms optionaliv containing 0, S or NR6, which include branched and cyclic and unsaturated alkyl groups and aryl C1-C5 alkyl-; p can be 0, 1 or 2; m is an integer from C to 5; n is an integer from 1 to 5; W is -O-, -S(G!p- or -NR10-; Y is selected from: -CONR10-, -NR10CO-, -SO2NR10-, -NR1CS02-, a peptide bond mimic, a 5 membered heterocvclic ring saturated, unsaturated or partrally unsaturated containing from 1 to 4 heteroatoms selected from N,0 or S, LV 12167 with the proviso that the size of the macrocycle encompased in formula I by -A-B-D-C(R2) (R3)-Y-C(RM-C(U)(R4)-, be connected by no less chan 11 atoms and no more than 22 atoms to form the cycle. 2. A compound of formula II:
B
Formula II or pharmaceuoicallv acceptable salts or prodrug forms thereof,wnerein; X is selected from CK2, NK, NR5, S(0)p, or 0;
R1-' R14' Ris, £16 £i" £i7a and P/ B, D and W are as specified previouslv in Formula I and cefined as stable compounds; with the proviso that the size of the iracrocvcle encompased in formula I by -A-B-D-C (R2) (R3)-Y-C {R1! -X-C (U) (R4) -, be connected by no less than 11 atoms and no more than 22 atoms to form. the cvcle. -306- 3. A compound of formula III:
Formula III or pharmaceuticaily acceptable salts or prodrug forms thereof,wherein; U is selected from; -C02H, -CONHOH, -CONHOR11, -SK, -NH- COR11, -N(OH) COR11, -SN2H2R6, -SONHR6,CH2C02H, PO(OH)2, PO(OH)NHR5, CH2SK, and common prodrug derivatives -C(C)NHOR12 and -C02R12; Z is selected from: N or CH; R-, R<, R6, R11, Rlla, Rl2, Rl3, r14, R15, Ri6( r17 R17a, A; B, C, are as specified previously in Formula I and defined as stabie compounds; 4. A compound of Claim 1 wherein: U is selected from; -CONHOH, -CONHOR1-, NCOHļCOR11, -SN2H2R6, -SONHR6, -C02H, -CH2SH, -C (O) NHOR12-' and common prodrug derivatives; R1 is selected from:
V
** I -(Co-C6)ai3cyl-S(0)p- (Ci-C6)alkyl, - (Co-C6) alicyl-0- (Ci-C6) alkyl, - (Cc-C6) alkyl-S (0) p- (C0-C6) alkyl-aryl, -(Co-Ce)alkyl-0- (Co-Cg)alkyl-aryl, alkyl of from 1 to 20 carbon atoms which include brancheo, cvcltc and unsaturated alkyi groups, LV 12167 substituted alkyl whereir. the substituent is selected from; hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono- alkylarru.no, di-alkylairu.no, acylamino (such as acetamido and benzajnido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio), carboxy, carboxaxnido, carbo alkoxy, or sulfonamido, - (Co-Ca) alkyl-aryl, - (Co-Ce)alkyl-substituted aryl, - (Co-Ce) s.ryl- (C1-C4) alkyl-aryl, - (Ci-Cb) alkyl-biaryl, - (Co-Cg) alkyl-S (0)p- (Co-Ce) alkyl-aryl, - (Co-Ca) alkyl-S (0) p- (Co-Cs)alkyl-substituted aryl, - (Ci-C4)alkyl-aryl- (Co-C8)alkyl-aryl- [S(0)p- (Cc-
Cg)alkyl], - (C0-C3 i alkyl-S (0) p- (Co-Ce)alkyl-biaryl, - (Cc-Ca) alkyl-C- (Cc-C8)alkyl-aryi, - (C0-C8) alkyl-S (0) p- (Co-Ca)alkyl-substituted aryl, - (C1-C4) alkyl-aryl- (Co-Ca) alkyl-arvl- [0- (Co-Ce) alkvl] , - (C0-C8 i alkyl-0- (Co-Ce)aIkyl-biaryl, - (Co-Cs)alkyl-C- (Co-Ca)alkyl-subscituted aryl, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylaitu.no, di-alkylanu.no, acvlamino, thio, thioalkyl, carboxy, carboamido or aryl; R2 is selected from H, -CO2R5, -CONR°R5, -CONR6(OR5), -alkyl, -alkyiaryl, -alkylheteroaryl, -alkylheterocyclic, -aryl,' -heteroaryl or -heterocvclic which is substituted with one or more substituents selected from: -308- hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono-alkylamino, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl iir.idazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylchio (such as pher.ylthio), carboxy, sulfonamido, carboxamiao, or carboalkoxy; r3 is selected from H, -0H, and -NH2;
Alternativelv R2 and R3 can form a 3 to 6 membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; R4 is selected from: K, -OH, and -NK2; R= is selected from: - (CHR^in-R9' -C(R7R8)n-W-C(R7Ra)m-R?, -C(R7R8)m-R9, -C(R7R8)m-ar\'l, -C (R7R8) inC0NR7R8, -C (R7R8)m-5ubstituted heteroaryl, -C (R7R8) m-substituted heterocyclic wnereir. the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkvlaminc, di-aikylaminc, acylamino, thio, thioalkyl, carboxy, carbcxamido or aryl; R6 is selected from: K, alkyl-, - (Ci-Cs)alkyl-aryl, - (C--C6) aikyl-heteroaryl, - (C:-Cg)alkyl-heterocyclic, - (C:-C6)alkyl-acyl; -30?- LV 12167
Alternativeiy, R5 and R6 may form a 3 to 8 membered ring opcionally unsaturated containing from 1 to 3 heteroatoms selected from -0, -NR6, -S(0)p, or an acyl group, optionally fused to an aryl ring; R7 and R8 may be selected independently from: H, R1, or form a 3 to 7 membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acylamino, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing -0-, -S(0)p, -NR6, optionally fused to a substituted aryl ring, wherein the substituent is selected from; hvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acvlaminc, thio, thioalkyl, carboxy, carboxamidc or aryl; F.9 is H, alkvrl, cycloalkyl, 5 or 6 membered ring optionallv containing from 1 to 2 N, 0 or S(0)p, optionaliy substituted with -0H, -0- (C1-C6)alkyl, -0-acvl-alkyl, NHR10, or aryl; R1C is H cr an optionally substituted aikyl group; R11 is hydrogen, alkvl of from 1 to 10 C atoms which include branchec, cyclic and unsaturated alkyl groups, substituted alkyl whereir. the substituent is selected from: hvdrogen, halo, hydroxy, alkoxy, aryloxy, such as phenox>', amino, di-alkylaminc, acylamino sucr. as acetamido and benzamido, arylamino, guanicinc, imidazolyl, indolvl, mercaptc. alkylthic. -310- arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide, - (Ci-C4>alkyl-aryl, - (C1-C4) alkyl- (Ci-Ce) alkyi-aryi - (Ci-Ce) alkyl-biaryl, substituted - (Ci-Ce) alkyl-aryl, wherein the substituent is selected from: nydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylaitu.no, acyīamiiīo~'šuch as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercaptc, alkylthio, arylthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, or sulfonamide;
Rlla is K, -S02-Ci-Ce-alkyl/ -SC>2-Ci-C6-alkyl-substituted aryl, -S02~aryl, -S02-substituted heteroaryl, -COR9, -C02“-3u, -C02Bn, or -alkyl-substituted aryl wnerein the substicuent is selected from: hvarogen, C1-C5 alkyl, hydroxy, nalo, alkoxy, aminc, mono-alkylamino, di-aikvlamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: H, aryl, (Ci to Cio)alkyl-, arvl (Ci to Cg)alkyl-, C3 to C11 cycloalkyl, C3 to C10 alkylcarbonylo^alkyl, C3 to C10 alkoxycarbonyloxyalkyl, C2 to C10 alkoxycarbonyl, C5 to Cic cycloalkylcarbonyloxyalkyl, C5 to Cic cycloalkoxycarbcnyloxyalkyl, C5 to Cio cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (Ci to C6 alkvU-arylcarbcnvloxy(Ci to Cg alkyl)-, C5 to C12 alkoxyalkylcarbonyioxyalkyl, [5 - (C1-C3 alkyl) -1,3 -dioxa-cycloper.ten-2-one-yl]methyl, -3 LV 12167 (5-aryl-l,3-dioxa-cyclopenten-2-one-yl)methyl, (R17) (R17a)N- (C1-C10 alkyl) -, -CH(R13)0C(=0)R14, -CH(R13)OC(=0)0R15, or 0
wherein R13 is K or Ci~Cļ linear alkyi; R14 is selected from:
V /
Ci-Cg alkvl or C3~Cg cycloalkyl, said alkyl or cvcloalkyl being substituted with 1-2 groups independently selected from: C1-C4 alkyl, C3-Cg cycloalkvl C1-C5 alkcxy, aryl substituted with 0-2 groups independentlv selected from: haloger., phenvl, Cļ-Cg alkvl, C--Cg alkoxy, NO2, -S(Ci-Cs alkyl), -£{=0) (C1-C5 alkyl) , -SC'2(Cļ_-C5 alkvl: , -OK, -N(R17) (R17a) , -C02R17a, -C (=0/ N(R-"7) (R:7a) , or -CVFW where v = 1 to 3 and w = 1 to (2v-l), aryl substituted with 0-2 groups ir.dependently selected from: haloger., phenvl, C1-C6 alkyl, Ci-Cg alkoxy, NC'2, -£(Ci-C5 alkvl) , -S(= 0) (C-.-C5 aikyl), -S02(C:~C5 alkylī, -OH, -N(R17' (R17a) , -C02R17a, -C(=0)N(R17) (R-~a; , cr -Cv"w where v = 1 to 2 and w = 1 tc v27t1i ; R15 is selecced from:
Ci-Cg alkyl, C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloālkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independently selecced from: halogen, phenyl, Ci-C6 alkyl, Ci-Cg alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -S02(Ci-C5 alkyl) , -OH, -N(R17) (Rl7a), -C02R17a, -C(=0)N(R17) (R17a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l), arvl substituted with 0-2 groups independently selected from: halogen, pnenyl, Ci-Cg alkyl, Ci-Cg alkoxy, N02, -5(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -S02(Ci-C5 alkyl) , -OH, -N(Rl?) (R17a) , -C02R17a, -C(=0)N(R17) (R-7a) , cr -CVFW where v = 1 to 3 and w = 1 to (2v+l);
Ri6 is C1-C4 alkyl, benzyl, or phenyl; - R17 and R17a is independently selected from: H, C--C:c alkyi,C2-Cs alkenyl, C4-C11 cyclcalkylalkyl, and aryl(Ci-C5 alkyl);
Combinations cf A, B and D, ar.d/or variables are permissable cr.ly if such combinations result in stable compounds (as def ined herein) . -313- LV 12167 A can be absent, -(CHR6)m-, -0(CHR6)m-, -NR6(CHR6)m-, - S (0) p(CHR6)m-> or selected from an alkvl from 1 to 10 carbon atoms which include brar.ched, cyclic and unsaturated alkyl groups or - (Ci-C6>alkvl-aryl; B can be a bond or selected from -NH-, -NR11-, - NRlla--0-, -S(0)p- (Ci-C6)alkyl-NH-(Ci-C6)alkyl-, {Ci-Cs)alkyl-NR11-(Cļ-Ce)alky-, -Ci-C6-NH-aryl-, -0-(Ci—C6)alkyl-, -(Ci-Cg) alkyl-0-aryl-, -S-(Ci-Cg)alkyl-, -(Ci-Cg)alkyl-S-aryl-, - (Ci-Cg)alkyl-, -(Cļ-Cg)alkenyl-,- (Ci-Cg)alkynyl-, -CONK-, -CONR11, -NHCO-, -NR1:1C0-, -0C0-, -COO-, -0C02-, -R11NC0NR11-, HNCONH-, -OCONR11-, -NR11^»-, -HNS02-, -SO2NH-, aryl, cycloalkyl, heterocycloalkyl, -R11NCSNR11-, -HNCSNK, -OCSNR11-, -NRiiCSO-, -HNCNNH-, and a peptide bond mimic;
D can be absent or an alkyl from 1 to 10 carbon atoms optionaliv interupted by 0, S or NR6, which include branched and cvclic and unsaturated alkyl groups and - (Ci-Cg) -alkyl-aryl; p can be 0, 1 or 2; m is an integer from 0 to 5; n is an integer fron 1 to 5; W is -0-, -S(Ci p- or -NR10-; -314- Υ is selected from: -CONR10-, -NR10CO-, -SO2NR10-, -NR10SO2-, a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,0 or S, with the proviso that the size of the macrocycle encompased in formula I fcy -A-B-D-C(R2)(R3)-Y-C(R1)-C(U)(R4) -, be connected by nc less than 11 atoms and no more than 22 atoms to form the cycle. 5. A compound of Claim 2 wherein: X is selected from CH2, NH, S and 0; U, Y, R1, R2, R3, R4, R5 R6, R7, R8, R9, RlO, Rll, Rlla r!2, Rlo, Rl4, Rl5, Ris, Rl7, Rl7a and p/ mi Π/ p and W are as specified previously in Formula I and defined as stable compou^as / with the proviso that the size of the macrocycle encompased in formula I by -A-B-D-C(R2)(R3)-Y-C(R1)-X-C(U)(R4)-, be connected by nc less than 11 atoms and no more than 22 atoms to form. the cycle. 6. A compc-und of Claim 1 wherein: U is selected from: -CONHOH, -C(0)NH0R12' -C02H and commcn prcdrug derivatives; R1 is selected from: H, - (C0-C6) 2.1 1 -S (0) p- (Ci-Cg)alkyl, - (Co-Cg)alkyl-0- (C^-Og) alhyl, - (Co-Cg) aljcyl-S (0)p- (Co-Cg) alkyl-aryl, - (Co-Cg) ah<yl-0- (C0-Cg) alkyl-aryl, -315- LV 12167 alkyl of from 1 to 20 carbon atoms which include branc'ned, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from; hydrcgen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono- alkylaitu.no, di-alkylamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methvl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenvlthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, - (Co-Ce)alkyl-aryl, - (Co-Ce)alkyl-substituted aryl, - (Co-Ce)aryl- (C1-C4) alkyl-aryl, -(Ci-Cs)alkyl-biaryl, -(Cc-Ce)alkvl-S(0)p-(Co-Ce) alkyl-aryl, - (Co-Ce)aikyl-S(0)p-(Co-Ce)alkyl-substituted aryi, - (C-.-C4) alkyl-aryl- (Co-Ce)alkyl-aryl- [S(0)p- (Co-
Ce)alkyl], - (Co-Ce!alkvl-S (0)p- (Co-Ce)alkyl-biaryl, - (Co-Ce)alkyl-0- (Co-Ce)alkyl-aryl, - (Co-Ce) alkyl-S ;0)p- (Co-Ce)alkyl-substituted aryl, - (C1-C4) alkyi-aryl- (C0-C8) alkyl-aryl- (0-(C0-C8)alkvl], - (Co-Ce)alkyi-C- (Co-Ce)alkyl-biaryi, - (Co-Ce) alkyl-0- ;Co-C8)alkyl-substituted aryl, wherein the substituent is selected from; hydrogen, C-.-Cs alkyl, hydroxy, halo, alkoxy, amir.c, monc-alkvlamino, di-alkvlamino, acvlamino, thic, thioalkyl, carboxy, carboanidc cr aryl; 2 is selected from:-:, -CO2R5, -CONR6Rs, -CONR6(OR5), -alkvl, - alkvl ar/l, -alkvlheteroarvl, -alkyiheterccyclic, -aryl, -hetercaryl or -316- -heterocvclic which is substituted with one or more substituer.ts selected froir.: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy) , amino, raono-alkylaiTu.no, di-aikvlamino, acylamino (such as acetamido and benzamido) , arylairu.no, guanidino, N-methyl imidazolyl, iraidazolyl, indolyl, mercapto, iowe alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R3 and R4 are K; F,5 is selected from: - (CHR^n-H5- -C(R7R8)n-W-C(R7R8)m-R3, -C(R7R8)ir-R9, -C (R7R8} m-aryl, -C (R7R8 ) irCONR7R8, -C (R7R8) π-.-substituted heteroaryl, -C (R7R8)m-substituced heterocyclic, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxv, halo, alkoxy, amino, monc-alkylamino, di-alkylaitu.no, acvlamino, thio, thioalkvl, carboxy, carbcxamidc or aryl; R° is selected from: H, alkyl-, - (C1-C6)alkyl-aryl, - (C1-C5)aikyl-heteroaryl, -(C1-C6)alkyl-heterocyclic, - 'Ci-C6)alkyl-acyl;
Alternatively, R5 and R5 may forra a 3 to 8 merabered rmc optionaliv unsaturated cor.taining from 1 to 3 heteroatoms selected from -0, -NR5, -S(0)p, or ar. acvl group, opticrallv fused to an aryl ring; R~ and R8 may be selected indep-endentiv from: LV 12167 H, R1, or form a 3 to 7 membered substituted ring with 0-3 unsaturations, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkvlamino, di-alkylanu.no, acylaiiu.no, thio, thioalkyl, carboxy, carboamido or aryl, optionally containing -O-, -S(0)p, -NR6, optionaliy fused to a substituted aryl ring, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylairu.no, di-alkylamino, acvlamino, thio, thioalkyl, carboxy, carboxamido or aryl; R5 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionallv containing from 1 to 2 N, 0 or S(0)p, oņtionallv substituted with -OH, -0- (Ci-Cg)alkyl, -C-acvi-alkvl, NHR10, or aryl; R1C is H or an optionally substituted alkyl group; R1: is hydroger., alkvl of from 1 to 6 C atoms which inciude branched, cyclic and unsaturated alkv'l groups, substituted alkyi; wherein the substituent is selected from: hvdrogen, halo, hydroxy, alkcxy, aryloxv', such as pher.or/, amino, di-alkylaminc, acylairu.no such as acetamido and benzamido, arylanu.no, guar.idino, imidazolyi, indolyl, mercaptc, loweralkylthio, ar/lthio (such as pnenylthio) carboxy, carboxamido, carbo-alkoxy, and sulfonamide; - (C:-C4>alkyl-aryl, - (C1-C8)alkyl-substituted aryl, wherein the substituent is selected from: hvdrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxi··, amino, di-alkylamir.c, acyiamino such as -318- acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio (such as phenylthio) carboxy, carbcxamldo, carbo-alkoxy, and sulfonamide;
Rlia iS h, -S02-Ci-C6-ālkyl, -S02-Ci-C6-alkyl-subscituted aryl, -SC>2-aryl, -SC>2-substituted heteroaryl, -COR9, -CO2C Bu, -CC>2Bn, wherein che substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylamino, acyiamino, thio, thioalkyl, carboxy, carboxamido or aryl; R12 is selected from: K, aryl, (Ci to Cio)alkyl-, aryl (Ci to C6)alkyl-, C3 to Cn cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 alkoxycarbonyloxyalkyl, C2 to Cio aikoxycarbonyl, C5 to C:c cycloaikylcarbonyioxyalkyl, C5 tc CiG cycloalkoxycarbonyloxyalkyl, C5 to Cij cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (Ci to C6 alkvi) aryicarbonyloxv·iCļ to C6 alkyl)-, C5 to C12 aikoxyalkylcarbonyloxyalkvl, [5-'(Ci-C5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl3methyl, (5-aryl-l,3-dioxa-cyclopenten~2-one-yl)methyl, (R17) (Rl7a;N-(C1-C10 alkyl)-, -CH(R13!OC (=0)R14, -CHtR^jocisOOR-, or
-3 LV 12167 R13 is H or C1-C4 linear alkyl; R14 is selected from: K,
Ci-Ce alkvl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C1-C4 alkyl, C3-C8 cycloalkyl C1-C5 alkoxy, aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, Ci-Cģ alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(C1-C5 alkyl), -S02{Ci-C5 alkyl), -OK, -N(R17)(R17a), -C02R17a, -C (=0)N{R17) (R17a) , or -CvFw where v = 1 to 3 and w = 1 to (2v+l), arvl substituted with 0-2 groups independently selected from: halogen, phenvl, Ci-Cg alkvl, Ci-Cg alkoxy, N02, -S(Ci-Cs alkyl), -S(=0) iCi-Cs alkyi), -S02 (C1-C5 alkyl), -OH, -N(R1_) (R17a) , -C02R17a, C(=0)N(R17) (R17a) , or -CvFw where v = 1 to 3 and w = 1 to (2v+l); R15 is selected from:
Ci-Cg alkvl, C3-C8 cycloalkyl, said alkyl or cycloalkyl beir.g substituted with 1-2 groups independentlv selected from: C1-C4 alkyl, C3-C8 cycloalkyl, C--C5 alkoxy, aryl substituted with 0-2 groups independentlv selected from: -320- halogen, phenyl, Cļ-Cg alkyl, C1-C5 alkoxy, N02, -S(Ci-Cs alkyl), -S(=0) (C1-C5 alkyl) , -S02(Ci-C5. alkyl) , -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (R17a) , or -CvFw where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups independently seiected from: halogen, phenyl, Ci-Cg alkyl, Ci-Cg alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(Ci-Cs alkyl), -S02(Ci-C5 alkyl), -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R17) (Rl7a) f cr -CVFW where v = 1 to 3 and w = 1 to (2v+l); R16 is C1-C4 alkvl, benzvl, or phenyl; R-1 2 3 4 5 and R17a is ir.dependently seiected from: H, Ci-Cio alkyl,C2-C5 aikenvl, C4-C11 cycloalkvlalkyl, and aryl(C:-C6 alkvl);
Combinations of A, 5 and D, and/or variables are permissable cnlv if such combinations resuit in stable compounds (as defined herein). A can be absent, -(CHRs;m-, -0(CHR6)m-, -NR6 {CHR6)m-, - S (C; p (CHR5)m- , or seiected from an alkyl from 1 to 10 carbon atoms which include branched, cyclic and unsaturated a.lkvl groups or -(C1-Cg)alkvl-aryl; -321- 1 can be a bond cr seiected from -NK-, -NR11-, -NRlla-, -0-, 2 -S(Ū)p-Ci-C6alkyl-NH-Ci-C6alkyl-, C:-C6alkyl-NR11-Ci- 3 C6alky-, Ci-Cg-NH-a=yl-, -0-Ci-C6alkyl-, Ci-C6alkyl-C- 4 aryl-, -S-Cl-CSalkvl-, Cl-C6alkyl-S-aryl-, Ci-C6alkyl- 5 , Ci-C5alker.yl-, C:-C6alkynyl-, -C0NH-, -CONR11, -NKCO- LV 12167 , -NRllCO-, -OCO-, -COO-, -OC02-, -RŪNCONR11-, HNCONK- , -0C0NR11-, -nrucoo-, -hnso2-, -so2nh- / aryl, cycloalkyl, heterocycloalkyl, -RUNCSNR11-, -HNCSNK, -OCSNR1^·-, -NR^^-CSO-, -HNCNNK-, and a peptide bond mimic;
D can be absent or an alkyl of from 1 to 6 carbon atoms which inciude branched and cyclic and unsaturated alkvl groups cr - (Ci-C6)alkyl-aryl; p can be 0, 1 or 2; m is an integer from 0 to 3; n is ar. integer from 1 to 4; W is -0-, S (C'< p or NR1Q; Y is seiected from: -CONR10-, -NR10CO-, -S02NRlc-, -NR10SO2-, a peptide bond mimic, a 5 membered heterocvclic ring saturated, unsaturated or partiailv unsaturated containing from 1 tc 4 heteroatoms seiected from N,0 or S, with the proviso that the size of the macrocycle enccmpased in formula I bv -A-B-D-C (R2) (R3)-Y-C (?.*-} -C (U) (R4) -, be connected by r.o less than 11 atoms and no more t'nan 22 atoms to form the cycle.
Cniy substituencs that form stable ccmpounds are clarmed for formula I. -322- 7. A compound of Claim 2 wherein: X is selected from CK2, NH, S and 0; ϋ is selected from; -CO2H, -CO2R12 and common prodrug derivatives ; Y, Rl, R2, R3, R4, R5 R6, R7, R8, R9, Rl°, r11·- , R14,
Ris, Rle, R17. and pf mf n# fiL/ p an(jļ are as specified previously in Formula I and defined as stable compounds; with the proviso that the size of the macrocycle encompased in formula I by -A-B-D-C (R2) (R3)-Y-C (R1) -X-C <U) (R4) -, be connecced by nc less than 11 atoms and no more than 22 atoms to form the cycle. S. A compound of Claim 1 wherein: U is selected from: -C0NH0H, -C(0)NH0R12, -C02H, and common prodrug derivatives; R- is selected from: - (Co-Cg)aikyi-s (0) p- (Ci-Cg) alkyl, - (C0-C6)alkyl-o- (Ci-Cg) alkyl, - (Cc-Cg) alkyl-s (0) p- (Co-Cg)alkyl-aryl, - (Co-Cg) alkyl-o- (Co-Cg) alkyl-aryl, alkyl of from 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl wherein the substituent is selected from; hydrogen, halo, nydroxy, alkoxy, aryloxy, isuch as phenoxy) , aminc, mono- alkylairu.no, di-alkylamino, acylamino (such as acetamido ar.d benzamido) , arylaminc, guanidino, N- -323- LV 12167 methyi imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, "alkyl-aryl, - (Cq-c8)alkyl-substituted aryl, - (Co~C8) aryl- (C1-C4) alkyl-aryl, -(Ci-c8) alkyl-biaryl, -(cQ~C8}alkyl-S(O)p- (Co-Cs)alkyl-aryl, - (Co~Cg)alkvl-S(O)p-(Co-Cs)alkyl-substituted aryl, - (C1-C4) alkyl-aryl- (Co-Cs) alkyl-aryl- [S (0) p- (Co-
Cs) alkyl] , - (Co-C8)alkyl-S (0)p- (Co-Cs)alkyl-biaryl, * (co~Cg)alkyl-0- (Co-Cs) alkyl-aryl, - (Co-Cg) alkyl-S (0)p- (Co-Cs)alkyl-substituted aryl, _ (cl~C4)alkyl-aryi- (Co-Cs)alkyl-aryl- [0- (Co-Cs)alkyl] , - (Co-Cg)alkyl-0- (Co-Cs)alkyl-biaryl, - (Cc-Cg) alkyl-0- (Co-Cs)alkyl-substituted aryl, wherein t'ne substituent is selected from; hvdrogen, C1-C5 alkyl, nydroxy, halo, alkoxy, aninc, mono-alkylaminc, di-alkylaird.no, acvlaminc, thio, thioa!kyl, carboxy, carboamido or aryl; R2 is selected froir. H, -CO2R5, -CONR6R5, -CONR6(OR5;, -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryi, -heteroaryl or -heterccyclic which is substituted with one or more substituents selected from: hvdrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy) , aminc, mono-alkylamino, di-alkvlamino, acyiaird.no (such as acetamido and benzamido) , arylaru.no, guanidino, N-methyl imidazolvi, imidazolyl, inaolyl, mercapto, lower alkvithic, arylthio (such as phenylthio), -324- carboxy, sulfonamido, carboxamido, or carboalkoxy; R3 and R4 are H; R5 is selecced from: - (CHR^Jn-R9' -C(R7R8)n-W-C(R7R8)m-R9, -C (R7R8) m-R9/ C (R7R8) m-aryl, -C (R7R8) m-heteroaryl, -C (R7R8)m-heterocyclic; R6 is selected from: H, alkvl-, - (Ci-Cg)alkyl-aryl, -(Ci-Ce)alkyl-heteroaryl, - (Ci-Ce)alkyl-heterocyclic, -(Ci-Cg)alkyi-acyl;
Alternatively, R5 and R® may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from -0, -NR6, -S(0)p, or ar. acyi group, optior.ally fused to an aryl ring; R7 and Rs may be selected independently from: H, R1, or form a 3 to 7 membered substituted ring with 0-3 unsaturations, wherein the substicuent is selected from; nydrogen/ C1-C5 alkyi, hydroxy, halo, alkoxy, amino, mono-aikylamino, di-alkylamino, acviamino, thio, thioalkyl, cārboxy, carboamido cr aryl, optionallv containing -0-, -S(C)p, -NR6, optionallv fused to a substituted aryl ring, wherein the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, aikoxy, amino, mcno-alkylaminc, di-alkvlamino, acylarinc, thio, thioalkyl, carboxy, carbcxamido cr aryl; -325- LV 12167 R9 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, 0 or S(0)p, optionally substituted with -0H, -0- (Ci-Cg)alkyl, -0-acyi-alkyl, NHR10, or aryl? R10 is H or an optionally substituted alkyl group; R11 is hydrogen, alkyl of from 1 to 6 C atoms— include branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; wherein t’ne substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arvlthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, and sulfonamide; - (Ci-C4)aikyl-aryl, - (Ci-Ce)alkyl-substituted aryl, wherein the substituent is selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, such as p'ner.oxy, amino, di-alkylamino, acylamino such as acetamido and benzamido, arvlamino, guanidino, imidazolyi, indolyl, mercapto, loweralkylthic, arvlthio (such as p'nenylthio) carboxy, carhoxamidc, carbo-alkoxy, and sulfonamide; R-la is K, -SCf (Ci-Cs)alkyl, -SO2- (Ci-Cg) alkyl substituted aryl, -SC>2-aryl, -SOs-substituted heteroaryl, -COR9, -CC>2t-3u, -C02Bn, vnerein the substituent is selected from: hvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylamino, di-alkylaiiu.no, acvlamino, thio, thioaikyl, carboxy, carhoxamido or aryl ; -326- R12 is selected from: H, aryl, (Ci to Cio)alkyl-, aryl -(Ci to C6)alkyl, C3 to Cn cycloalkyl, C3 to C10 alkylcarbonyloxyalkyl, C3 to C10 alkoxycarbonyloxyalkyl, C2 to C10 alkoxycarbonyl, C5 to C10 cycloalkylcarbonyloxyalkyl, C5 to C10 cycloalkoxycarbonyloxyalkyl, C5 tc C10 cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy(Ci to Cg alkyl), arvIcarbonyioxy(Ci to C6 alkyl), C5 to C12 aikoxyalkylcarbonyloxyalkyl, [5-(C1-C5 alkvl)-1,3-dioxa-cyclopenten-2-one-yi]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl) methyl, (Rl7) (Rl7a;N_ (Ci_Cio alkyl) - , -CH(R13)OC (=0)R14, -CH(R13)0C(=O)OR15, or 0
R13 is H or C:-C4 linear alkyl; R14 is selected from: K,
Ci-Ce alkyl cr Ci-Ce cycloalkyl, said alkyl or cycloalkyl beir.g substituted with 1-2 groups indepandentlv selected from: C1-C4 alkyl, C3-C8 cv*cloalkyl C1-C5 alkoxy, aryl substituted with 0-2 groups independentlv selected from: -32"- LV 12167 halogen, phenyl, Ci-Cg alkyl, C1-C6 alkoxy, N02, -SiCi-Cs alkyl), -S(=0)(C1-C5 alkyl), -S02(Ci-C5 alkyi) , -OH, -N(Rl7) (Rl?a) , -C02R17a, -C(=0)N(R17) (Ri7a), or -CvFw where v * 1 to 3 and w = 1 to (2v+l), aryi substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, C\-Cs alkoxy, N02, -S(Ci-Cs alkyl), -S(=0)(Ci-C5 alkyl), -S02(C1-C5 alkyl), -OH, -N(R17) (R17a) , -C02R17a, -C(=0)N(R1·7) (Rl7») , or -CVFW where v = 1 to 3 and w = 1 to (2v+l); R15 is selected from:
Ci-C8 aikvl, C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independentlv selected from: C1-C4 aikyl, C3-C8 cycloalkyl, C1-C5 alkoxy, aryl substituted with 0-2 groups independentlv selected from: halocen, phenvl, Ci-Cg alkyl, C:-Cg aikoxy, N02, -S(Ci-C5 alkyl) , -3(sC. :Ci-C5 alkyl), -S02(Ci-C5 alkyl: , -OH, -N(R17) (R17a) , -C02R17a, -C (=C:N(R17) (R17a) , or -CVFW where v = 1 to 3 and w = 1 to (2v+l), aryl substituted with 0-2 groups inaependently selected from: halocen, phenvl, C3.-C0 alkyl, Ci-Cg alkcxy. N02, -S(Ci-C5 alkyl) , -S(=0)(Ci-C5 aikvl , -S02(C1-C5 aikvl), -OH,· -N;R-" (R17a) , -CC2R17a, -329- -C(=0)N(Ri7) (Ri7a) , or -CVFW where v = i to 3 and w = 1 to (2v+l); R16 is C1-C4 alkyl, benzyl, or phenyl;
Combinations of A, 3 and D, and/or variables are permissable onīy if such combinations result in stable compounds (as defined herein). A can be; -(CH2)m“' -0-(CH2)m-, -S-(CH2)m-, -NR^-(CH2)m-? B can be a bond or selected from -NH-, -NR11-, -NRlla-, -O-, -S(0)p-Ci-C6alkyl-NH-Ci-C6alkyl-, Ci-C6alkyl-NRH-Ci-C6alky-, Ci-C6~NK-aryl-, -0-Ci-C6alkyl-, Ci-C6alkyl-0-aryl-, -S-Cl-C6alkyl-, Cl-C6alkyi-S-aryl-, Ci-CgaDo/l-, Ci-C6alkenyl-, Ci-C6alkynyl-, -CONH-, -CONR11, -NKCO-, -NRUCO-, -OCO-, -COO-, -0C02-, -R11NCONR11-, HNCONH-, -OCONR11-, -NRnCOO-, -HNS02-, -S02NH-, aryl, cycioalkyl, heterocycloalkyl, -RiiNCSNR11-, -HNCSNH, -OCSNR11-, -NR11CSO-, -HNCNNK-, and a peptide bond mimic;
D is -(CH2)m~; p can be C, 1 or 2; m is an integer from 0 to 3; n is an integer from 1 to 4; r*« - LV 12167 W is -0-, S (0) p or NRlc; Y is selectec from: -CONR10-, -NR10CO-, -SO2NRIŪ-, -NR1ūSC>2-, a peptide bona mimic, a 5 membered heterocvclic ring saturated, unsaturated or partially unsaturacea containing from 1 to 4 heteroatoms selectec from N,0 or S, with the proviso Chat the size of the macrocycle encompased in formula I by -A-3-D-C (R2) (R3)-Y-C (R1) -C (U) (R4) -, be connectea by no less than 11 atoms and no more than 22 atoms to form the cycle. -330- 9. A compound of Claim 1, or a pharmaceutically acceptable salt therof, of the formula IVa, or the formula IVb, or the formula IVc, or the formula IVa wherin:
IVc IVd or pharmaceutically acceptable salts or prodrug forms thereof, wherein; r* is selected from: H, - (C0-C6) al:<yl-S (0) p- (Ci-Ce) alkyl, - (C0-C6)ai:<yl-O- (C1-C6)alkyl, - (C0-C5) aikvl-S (0)p- (C0-C5) aikyl-aryl, - (Cc-Cs) ai:<yl-0- (Co-C6)alkyI-aryl, -331- LV 12167 alkyl of from 1 to 20 carbon atoms which include branched, cyclic and unsaturated alkyl groups, substituted al)cyl wherein the substituent is selected from; hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy), amino, mono- alkylaitu.no, di-alkylamino, acylanu.no (such as acetamido and benzamido) , arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (such as phenylthio), carboxy, carboxamido, carbo alkoxy, or sulfonamido, - (Co-C8)alkyl-aryl, - (Co-Ca )alkyl-substituted aryl, - (Co-C8)aryl- (Ci-C4)alkyl-aryl, - (Ci-Ce) alkyl-biaryl, - (CG-C8!alkyi-S(0)p- (C0-C8)alkyl-aryl, - (C0-C8)alJcyl-S(O)p- (Co-Cs)alkyl-substituted aryl, - (C1-C4; alkyl-aryl- (Co-Ca) alkyl-aryl- [S (0) p- (Co-
Cs '1 alkyl], - (Co-Ca ;alkyl-S (0)p- (Co-Cs)alkyl-fciaryi, - (Co—C8; alkyl-0- (Co-C8)alkyl-aryl, - (Cc-Cs, alkyl-S (0) p- (Co-Cs)alkyl-substituted aryl, - (C1-C4: alkyl-aryl- (Co-C8)alkyl-aryl- [0- (Co~Ce)alkyl], - (Cc-Cs; alkyl-0- (Co-C8)alkyl-biaryl, - (Cc-C8: alkyl-0- (Co-C8)alkyl-substituted aryl, whereir. the substituent is selected from; hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylairu.no, di-alkylauru.no, acvlaminc, thio, thioalkyl, carboxy, carboamidc or aryl; R2 is selected from H, -CO2R5, -CONR6R5, -CONR6(OR5), -alkvl, -alkyiaryl, -alkylheteroarvl, -alkylheterocyclic, -aryl, -netercarvl or -332- -heterocyclic which is substituted with one or more substituents selected from: hydrogen, halo, hydroxy, alkoxy, aryloxy, (such as phenoxy) , amino, mono-alkylanu.no, di-alkvlamino, acylamino (such as acetamido and benzamido), arylamino, guanidino, N-methyl imidazolyl, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (such as phenylthio), carboxy, sulfonamido, carboxamido, or carboalkoxy; R5 is selected from: - (CHR^n-R9- -C (R7R8)n-W-C(R7R8)m-R9, -C(R7R8)m-R9, -C (R7R8) m-aryl, -C(R7R8)mCONR7R8' -C(R7R8)m-heteroaryl, -C (R~R8) m-heterocyclic; R6 is selected from: K, alkyi-, - [ (Ci-Ce)alkyl-aryl, - (C1-C6) alkyl-heteroaryl, -(Ci-Cg)alkyl-heterocyclic, -(Ci-Cs'alkyl-acyl;
Alternativeiv, R5 and R6 may form a 3 to 8 membered ring optionaliv unsaturated containing from 1 to 3 neteroatoms selected from -0, -NR®, -S(0)p, or ar. acyl group, optionally fused to an- arvl ring; R7 and R8 may be selected independentlv from: K, R1, cr form a 3 to 7 membered substituted ring with 0-3 unsaturations, whereir. the substituent is selected from; hydrogen, Ci-Cs alkyl, hydroxy', halo, alkoxy, amino, mono-alkylamino, di-aikylamino, acylamino, thio, thioalkyl, carboxy, carboamidc or aryl, -333- LV 12167 optionally containing -0-, -S(0)p, -NR6, optionally fused to a substituted aryl ring, wherein che substituent is selecced from; nvdrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amino, mono-alkylaminc, di-alkylanu.no, acylaitu.no, thio, thioalkyi, carboxy, carboxaiaido or aryl; R9 is H, alkyl, cycloalkyl, 5 or 6 membered ring opcionally containing from 1 to 2 N, 0 or S(0}p, optionally substituted with -OH, -0-(Ci-Ce)alkyl, -0-acyl-alkyl( NHR10, or aryl; R10 is H cr an optionally substituted alkyl group; R11 is hydrogen, alkyl of from 1 to 6 C atoms which incluae branc'ned, cyclic and unsaturated alkyi groups, substituted lower alkyl; wherein the substituent is selected from: nvdrogen, halo, hydroxy, alkoxy, aryloxy, such as phenoxy, arrdno, di-alkylamino, acylamino such as acetamido and benzamido, arylamino, guanidino, imidazolvl, indolyl, mercapto, loweraikylthio, arvlthio (such as phenylthio) carboxy, carboxamido, carbo-alkoxy, and sulfonamide; - (Ci-Cj:alkyl-aryl, - (Ci-C8'alkyl-substituted aryl, whereir. the substituent is selected from: hvdrogen, halo, hydroxy, alkoxy, aryloxy, such as phanoxy, amino, di-alkylamino, acylaitu.no such as acetamido and benzamido, arylamino, guanidtnc, imidazolvl, indolvl, mercapto, loweralkylthio, ar/lthio (such as p'nenylthio) carboxy, carbcxamido, carbc-alkoxy, and sulfonamide; -334-
Rlla is H, -SO2- (Ci-Ce) alkyl, -SO2- (Ci-C6>alkyl subscicuted aryl, -SC>2-aryl, -S02-substituted heteroaryl, -COR9, -C02t-3u, -C02Bn, w'nerein t'ne substituent is selected from: hydrogen, C1-C5 alkyl, hydroxy, halo, alkoxy, amrno, mono-alkylainino/ di-alkylairu.no, acylanu.no, thio, thioalkyl, carboxy, carboxamido or aryl; m is an integer from 0 to 5; n is an inceger from 1 to 5; p can be 0, 1 or 2; W is -0-, S(0)p or NR10; Z is CK2 or 0 Y is selected from: -CONR10-, -NR10CO-, -SO2NR10-, -NR10SO2-, a peptide bond mimic, a 5 membered heterocvclic ring saturated, unsaturated or partiailv unsaturated containing from 1 to 4 heteroatoms selected from N,0 or S, 10. A ccmpcund of Claim 1 selected from t'ne group consisting of: 2S,5R,6S-3-aza-4-oxc-10-oxa-5-isobutyl-2-(N-methylcarbcxarc.de) - [103paracyclop.nane-6-N-hvdroxyc arboxanide; 2S,5R,6S-3-a2a-4-oxo-10-oxa-5-isobutyl-2-(carboxymethyl)-[10]paracycicphane-5-N-hydroxycarboxamide? -335- LV 12167 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-benzylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyi-2-(hydroxymethyl)-ί10]paracyciophane-6-N-hydroxycarboxamide; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-alanine-N-methylamide) - [10] paracyclophane-6-N-hydroxycarboxainide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L-(0-methyl)tyrosine-N-mechylaiuide]-[10]paracyclophane-6-N-hydroxyc arboxainide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[L-(O-tert-bucvl) s erine-N-methylaitu.de ] - [10]paracvclophane-6-N-hydroxycarbcxamide ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-serine-N-methvlamideί-[10]paracvclophane-6-N-hydroxycarboxairu.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(glycine-N-methylamide)-[10] paracyclophane-6-N-hydroxycarboxairu.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-alanine-N-mecnvlaride; - [10] paracyclophane-5-N-hydroxycarboxarru.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(beta-alanine-N-mechvlamide)-[10] paracyclop'nane-6-N-hydroxycarboxamide; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[D-(O-tert-bucyl) serine-N-methvlainide] - [10]paracvclophane-6-N-hydroxycarbcxamide; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(D-serine-N-mezhylarc.de .-[10] paracvclophane- 6 -N-hydroxycarboxamide; -336- 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-lysine-N-methylaiiu.de) - [10] paracyclophane-6-N-hydroxycarboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(L-valine-N-mezhylairri.de)-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobucyl-2-[(2-pyridyl)ethylcarboxamido]-[10]paracyclophane-6-N-hyaroxycarboxamide t ri fluoroacetate; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(4- methyl) piperazinylcarboxamido] - [10] paracyclophane-6-N- hydroxycarboxamide ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(2-beriZimidazolyl) - [10] paracyclophane-6-N-hydroxycarboxarrri.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-iir.idazolvl) carbcxamido] - [10]paracvclophane-6-Ν-hydroxycarboxamide ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[(2-benzimidazolvl)nezhylcarboxamido]-[10]paracyclophane-6-N-hydroxycarboxaini de ; 2S, 5R, 6S-3-aza-4-oxo-lG-oxa-5-isobutyl-2-[(3-imidazolyl) propylcarboxamido] - [10]paracyclopnane-6-N-hydroxycarboxairri.de ; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[2-(4-aminosulfor.ylpher.yl) eth\'lcarboxamido] - [10]paracyclophane-6-N-hydroxycarboxarri.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-iscbutyl-2-(glycine-N,N-dimechylamide) - [10] paracyclophane-6-N-hydroxycarboxamide: -337- LV 12167 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(1-adamantylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxami de; 2S, 5R, 6S-3-a2a-4-oxo-10-oxa-5-isobutyl-2-[(4-aminoindazolyi)carboxamido]-[10]paracyclophane-6-N-hydroxycarbcxami de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N, N-diethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarbcxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobucyl-2-(N-isopropylcarboxamido)-[10]paracyclophane-6-N-hydroxyc arboxamide; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-(N-cvclopropylcarboxamido)-[10]paracyclophane-6-N-hydroxycarbc xaiiu.de ; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyi-2-(N-tert-butylcarboxar.ido) - [10]paracyclophane-6-N-hydroxycarbcxamide; 2S, 5R, 6S-3-a~a-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-isopropvl; arude] - [10] paracyclophane-6-N-hydroxycarboxairu.de; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethyl) amide] -[10] paracyclophane-6 -.N-hydroxycarboxairu.de ; 2S, 5R,6S-3-aza-4-cxo-10-oxa-5-isobutvl-2-[glycine-(N-cvclopropvl)azride]-[10]paracyclopnane-6-N-hydroxvcarbcxami de ; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cert-bucvl i amide[ - [ 10 [ paracyclophane- 5-N-hydrcxycarboxasu.de; -338- 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-cyclobuzyl)amide]-[10]paracyclophane-6-N-hydroxycarbcxamide ; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-morpholino)amide]-[10]paracyclophane-6-N-hyaroxycarboxamide ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-2-hydroxydimethylethyl)amide]-[10]paracyclophane-6-N-hydroxycarboxamide ; 2S,5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N-ethylmet'nylpropyl) amide] - [10] paracyclophane-6-N-hydroxycarboxaxrd de 2S, 5R,6S-3-aza-4-oxo-iO-oxa-5-isobutyl-2-[glycine-(N-dimechylpropyl)amide]-[10]paracyclophane-6-N-hvdroxycarboxamide ; 2S, 5R, 6S~3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(N- (di-2-hydroxymethyl)ezbylamide]-[10]paracyclcphane-6-N-hydroxycarboxamide ; 2S, 5R,6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[glycine-(4-hydroxypiperidir.e) amide] - [10]paracycIophane-6-N-hydroxycarboxamide; 25, 5R,6S-3-aza-4-oxo-10-oxa-5-isobucyl-2-(2-benzimidazoIecarboxamido)-[10]paracyclophane-6-N-hvdroxycarboxamide ; 2S, 5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2-[S-(methyl)-2-phenylmethylcarzoxamido] - [10] paracyclophane-6-N-hvdroxvcarboxamide -339- LV 12167 4S,7R,8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(carboxymethyl) -[12]paracyclophane-8-N-hydroxycarboxamide; 4S,7R,8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(N-methylcarboxamido)-[12]paracyclophane-8-N-hydroxycarboxamide ; 4S,7R,8S-5-aza-6-oxo-12-oxa-7-isobutyl-2-(glycine-N-mechlamide)-[12]paracyclophane-8-N-hydroxycarboxamide; 2S,3R,6S-10-t-Butoxycarbonyl-5,10-diaza-2-(N-hydroxycarboxamido) -6-(N-mechylcarboxamido)-l-oxa-4-oxo-3-(3-phenylprop-l-yl) cyclotetradecane; 2S,3R,6S-5,10-Diaza-2-(N-hydroxycarboxamido)-6-(N-methylcarboxamido)-l-oxa-4- 0X0-3-(3-phenylprop-l-yl)cyc!otetradecane hvdrochloride; 2S, 3R, 6S-10-Aoetyl-5,10-diaza-2-(N-hydroxvcarboxamidc)-6-(N-methylcarbcxamido)-l-oxa-4-oxo-3-(3-phenylprop-i-yi)cycloteoradecane? 2S,3R,6S-10-3enzenesulfonyi-5,10-diaza-2-(N-hydroxycarbcxamido) -6- (N-meohylcarboxaiaido) -i-oxa-4-cxo-3-(3-phenylprop-1-y1)cyclotec radecane; 2S,3R,6S,12 iR, S)-10-Acetyi-5,10-diaza-2- (N-hydroxycarbcxamido) -6- (N-methylcarboxantido) -12-methyL-l-cxa-4-oxo-3-;3-phenylprop-l-yi)cvclocridecane; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(carboxymethyl -[ 10 ] paracyclcphane-6-N-hydrcxycarboxaride ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2- (hydrcxycarboxyi) -[ 10 ] paracyclcphane- 6 -N-hydroxycarboxarjLde; -340- 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-((2-mechoxylethyloxy)carboxyl)-[10]paracyclophane-6-N-hydroxycarboxairu.de; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-((2-phenylechyloxy)carboxy)-[10]paracyclophane-6-N-hydroxycarboxairu.de ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyi-2-(1-(n-methylcarboximido)methylcarboxyl) - [10] paracyclophane-6-N-hydroxycarboxamide ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(N-methylaminosulfonyl)ethylcarboxamido)-[10]paracyclophane-6 N-hydroxycarboxami de ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4-(N-methyiaminosulfonyl)butylcarboxamido)-[10]paracyclophane-6 N-hydroxycarboxamide ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(N-methylamir.osulfonyl) hexyllcarboxairu.do) - [10]paracyclcphane-6-N-hydrcxycarboxaru.de; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-!carbcme~hoxy)ethylcarboxamido) - [10] paracyclophane-5-N-hydroxycarbcxamide; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(hydroxycarbcnyl)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarbcxairlae ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2 - (L-omithine (4-c-bu::oxycarboπy i )carbcxymechv1)-(10]paracyclophane-6 -N-hv d r o xy c ar bc :<ajni de ; -341- LV 12167 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithinecarboxymethyl)-[10]paracyclophane-6-N-hydroxycarboxamide hydrochloride; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithine(4-t-butoxycarbonyl)-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxairu.de ; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-ornithine-N-methvlamide) - [ 10 ] paracyclophane-6-N-hydroxycarboxairu.de hvdrochlor ide ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyi-2-(L-Iysinecarboxamide)-[10]paracyclophane-6-N-hydroxycarboxanu.de ; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(L-serine(O-tert-butyl)-N-methylamide)-[10]paracyclophane-6-N-hydroxycarboxanu.de ; 2S, 3R, 6S-3-aza-4-cxo-10-oxa-5-hexyl-2-(L-alanine-N-methylarru.de - [10]paracyclophane-6-N-hydroxycarboxamide; 2S,3R,6S-3-aza-4-cxo-10-oxa-5-hexyl-2-(D-alanine-N-methylamide - [10]paracyclophane-6-N-hydroxycarboxanride; 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(glycine-N-methvlamide.-[10]paracyclophane-6-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(benzylcarboxamido)-[1C]paracyclcphane-6-N-hydroxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(phenylethylcarboxamido) - [10]paracyclophane-6-N-hydroxycarbcxamide; -342- 2S,3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(diphenylethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxairu.de ; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(2 -pyridyl)ethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxazu.de 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(4-sulfonylaminophenyl)ethylcarboxamido) - [10]paracyclophane-6-N-hydroxycarboxamide ; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(3,4-dimethoxyphenyl) ethylcarboxamido) - [10] paracyclophane-6-N-hydroxycarboxazu.de ; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(2-(4-morpholino)ethylcarboxamido)-[10]paracyclophane-6 -N-hydroxycarboxami de ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(3- (4-morpholino) prcpylcarboxamido) - [10] paracyclophane-6-N-hydroxycarboxazu.de hydrochloride; 2S, 3R,6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(3-(1-imidazolyl) prcpylcarboxamido) - [10]paracyclophane-6-N-hydroxycarboxazu.de ; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(3-(1-imidazolyl) prcpylcarboxamido) - [ 10 ] paracyclophane-6-N-hydroxycarboxazu.de trifluoroacetate; 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(cy clohexy 1 carboxamido) - [10] par acyc lophane - 6 -N-hydr oxycar boxazd de; -343- LV 12167 2S, 3R, 6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(4-methylpiperazin-l-ylcarboxasr.ido) - [10] paracyclophane-6-N-hydroxycarboxamide; 2S,3R.6S-3-aza-4-oxo-10-oxa-5-hexyl-2-(dimethylcarboxamido)-[10]paracyclophane-6-N-hydroxycarboxamide ; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-(N-methylcarboxamido)-cyclopentadecane-13-N-hydroxycarboxamide 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl·-2- [N- (2-pyridy 1)methylcarboxamido] -cyclopentadecane-13-N-hydroxycarboxamide crifluoroacetate; 2S, 13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[2-(5-meūhylthiazolyl)carboxajnido]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [ (2-pyridyl)carboxamido] -cycioper.tadecane-13-N-hvdrcxyc arboxami de ; 2S, 13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[(3-pyridyl)carbcxamido]-cyclopentadecane-13-N-hyčrcxycarboxaiīii de ; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [ (4 -pyridyl) carbcxamido] -cyclopencadecane-13-N-hyaroxycarboxamide ; 2S,13S,14R-1,7-diaza-8,15-aioxo-9-oxa-14-isobutyl-7-methyl-2 - [4 - (N-ethoxycarbonyl)piperidinecarboxamido] -cyclopentadecane-13 -N-hydroxycarboxamide; -344- 2S, 13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[4-hydroxycyclohexylcarboxamido]-cyclopentadecane-13-N-hydroxycarboxanu.de; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyi-7-methyi-2-(giycine-N-methylamide)-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-met:hyl-2- (g!ycine-N, N-dimethylaiiu.de) -cyclopentadecane-13-N-hydroxycarboxairu.de ; 2S,13S,14R-l,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (glycine-2-pyridylaxnide) -cyclopentadecane-13-N-hydroxycarboxamide ; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[giycine-2-(3,4,5,6-tetrahydropyridyl)amide]-cyc1opentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-(4-hydroxy)piperidineamiae]-cyclopentadecane-13-N-hvdroxycarboxami de ; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-pyrolidineamide]-cyclopentadecane-13-N-hydroxycarbcxamide; 2S,13S,14R-1,7-diaza-8,l5-dioxo-9-oxa-14-isobutyl-7-methyl-2-[glycine-N-morpholinoamide]-cyclopentadecane-13-N-hydrcxycarbcxamide; 2S, 13S, 14R-1,7-diaza-8, l5-dioxo-9-oxa-14-isobutyl-7-mechyl-2-[glycine-(4-methyl)N-piperazinylamide]-cyclopentadecane-13-N-hydroxycarboxamide trifluoroacetate; -345- LV 12167 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [glycine-2- (5-methyl) thiazolylamide] -cyclopentadecane-13-N-hydroxycarboxamide trifluoroacetate; 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[ glycine-N-morpholinoaird.de} -cyclopentadecane-13-N-hy droxycarboxaird.de ; 2S,11S,12R-1,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-12-isobucylcyclotridecane-ll- (N-hydroxycarboxajnide) j 2S,11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(glycine N-methyl amide)-11-(N-hydroxycarboxamide); 2S, 11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotriaecane-2- (N^-H-L-ivcine-a-N-K-amide trifluoroacetace)-11-(N- hydroxycarboxamide) ; 2S, 11S,12R-1,7-Diaza-S,13-dioxo-12-isobutylcyclotridecane-2- (L-alanir.e-a-N-methyl amide) -11- (N-hydroxycarboxaru.de) ; 2 S, 11S, 12R-1,7-Diaza-8 f 13-dioxo-12-isobutylcyclotridecane-2- (β-alanine N-methyl amide) -11- (N-hydroxycarboxamide) ; 2S,11S,12R-i,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido) -7-N-mes itvIenes ulfony1-12-isobuty1cyclotridecane-11-(N-hydroxycarboxamide); 2S, 11S, 12R-l,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido>-7-N-t-butyloxycarbonyl-12-isobutylcyclotridecane-ll-(N-hydroxycarboxamide); 2S,11S,12R-l,7-Diaza-8,13-dioxo-2-(N-methylcarboxamddo)-12-isobutyicyclotriaecane-ll-(N-hydroxycarboxamide) hydrogen chloriae; -346- 5S, 8R, 9S-6-Aza-2,7-dioxo-5-(N-methylcarboxamido)-l-oxa-8-isobutylcyclododecane-9-(N-hydroxycarboxanu.de) ; 2S,11S,12R-7-N-Ben2enesulfonyi-l,7-Diaza-8,13-dioxo-2-(N-meznyIcarboxamido) -12-isobutylcyclocridecane-ll- (N-hydroxycarboxanu.de) ; 2S,11S,12R-1,7-Diaza-8,13-dioxo-2-(N-mechylcarboxamido)-7-(p-amino-N-benzenesulfonyl)-12-isobutylcyclotridecane-ll-(N-hydroxycarboxanu.de) ; 2S,11S,12R-1,7-Diaza-8,13-dioxo-2-(N-methylcarboxamido)-7-N-zrifluoroir.echanesulfonyl-12-isobutylcyclotridecane-ll-(N-hydroxycarboxamide); 2S, ilS# 12R-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -7-N-(N-met:hyl-imidazolesulfon-4-yl) -12-isobucvlcvclotridecane-ll- (N-hydroxycarboxanu.de) ; 2S, 11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-norleucir.e-a-N-methyi amide) -11- (N- hydroxycarboxanu.de) ; 2S, 11S, 12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-serine-a-N-met'nvl amide) -11- {N-hydroxycarboxairu.de) ; 2S, HS, 12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (glycine N-dimerhyi amide) -11- (N-hydroxycarboxamide) ? 2S,11S,12R-1,7-Diaza-8,13-dioxo-12(R)- isobucylcyclo”ridecar.e-2 (S) - (glycine N-l,2-ethylenediamine-N', N’ -dimethyl amide) -11 (S) - (N-hydroxycarboxamide) ; 2S, 11S, 12R-1,7-Diaza-S, 13-dicxo-12-isobutylcyclotridecane-2- (glycine N-mcrpholino amide) -11- (N-hydroxycarboxairu.de) ; -347- LV 12167 2S, 11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(L-leucine-a-N-methyl amide)-11-(N-hydroxycarboxamide) ; 2S,11S,12R-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2-(l-threonine-a-N-methyl amide)-11-(N-hydroxycarboxamide) ; 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound.of Claim 1. 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 2. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a conpound of Claim 3. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 4. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a corpound of Claim 5. 16. A pharmaceutical composition comprising a pharmaceutīcally acceptable carrier and a therapeutically effective amount of a compound of Claim 6. 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 7. 18. A pharmaceutical composition conprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 8. -348- 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 9. 20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 10. 21. A method of treating an inflaimnatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound of Claim 1. 22. A method cf treating an inflammatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound of Claim 2. 23. A method cf treating an inflammatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound of Claim 3. 24. A method cf treating an inflammatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound cf Claim 4. 25. A method cf treating an inflammatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound of Claim 5. 26. A method cf treating an inflamnatory disease in a mammai comprising administering to the mammai in need of -349- LV 12167 such treatment a therapeutically effective amount of a compound of Claim 6. 27. A method of treating an inflammatory disease in a mammai comprising administering to c'ne mammai in need of such treatment a therapeutically effective amount of a compound of Claim 7. 28. A method of treating an inflammatory disease in a mammai comprising ādministering to the mammai in need of such treatment a therapeutically effective amount of a compound of Claim 8. 23. A method of treating an inflammatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound cf Claim 9. 3G. A mechod of treating an inflammatory disease in a mammai comprising administering to the mammai in need of such treatment a therapeutically effective amount of a compound of Claim 10. 31. A method as in any of claims 21-30, in which administrētion is oral. 32. An assay for detecting inhibitors of aggrecanase, which comprises: (a) generating soluble aggrecanase, by stimulation of cartiiage sūces; (b) detecting aggrecanase enzymatic activity by using the soluble aggrecanase generated in (a) and monitcring productior. of aggrecan fragments containing the end terminus AP.3SVTL; -350- (c) evaluating inhibition of aggrecanase by comparing the amount of product produced in the presence versus absence of compound. -351-

Claims (32)

LV 12167 IZGUDROJUMA FORMULA 1. Savienojums ar formulu (I)1. A compound of formula (I): vai šī savienojuma farmaceitiski pieņemami sāļi, vai pirmsarstnieciskas formas, kur: U izvēlas no: -C02H, -CONHOH, -CONHOR11, -SH, -NH-COR11, -N(OH)COR11, -SN2H2R8, -SONHR6, -CH2C02H, -PO(OH)2i -PO(OH)NHR6, -CH2SH, -C(0)NH0R12, -C02R12 grupām un parastiem pirmsārstnieciskiem atvasinājumiem; R1 izvēlas no: ūdeņraža atoma, -(C0-Ce)alkil-S(O)p-(CrCe)alkil-; -(C0-Cs)alkil-O-(CrC6)alkil-; -(C0-C6)alkil-S(O)p-(C0-C6)alkil-aril-; -(C0-Cs)alkil-O-(C0-Cs)alkil-ariigrupām; alkilgrupas ar 1 līdz 20 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietotas alkilgrupas, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino-(piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; -(CQ-Ca)alkil-aril-; -(C0-C3)alkil- aizvietotas aril-; -(C0-Ca)aril- (C,-C^)alkil-aril-; -(C1-Ca)alkil-biaril-; -(C0-C6)alkil-S(O)p-(C0-C8)alkil-aril-; -(C0-Cs)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(C1-C4)alkil-aril-(C0-C8)alkil-aril-[S(O)p-(C0-C8)alkil]-; -(C0-C3)alkil-S(O)p-(C0-C8)alkil-biaril-; -(C0-C8)alkil-O-(C0-C8)alkil-aril-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(CrC4)alkil-aril-(C0-C8)alkil-aril-[O-(C0-C8)alkil]-; -(C0-C8)alkil-O-(C0-C8)alkil-biaril-; -(C0-C8)alkil-O-(C0-C8)alkil-aizvietotām arilgrupām; kurās aizvietotāju izvēlas no: ūdeņraža atoma, C-,-C5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido- vai arilgrupas; R2 izvēlas no: ūdeņraža atoma, -C02R5, -CONR5R5, -CONR6(OR5), alkil-, alkilaril-, alkilheteroaril-, alkilheterocikliskas, aril-, heteroaril- vai heterocikliskas grupas, kura aizvietota ar vienu vai vairākiem aizvietotājiem, kurus izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino-(piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, zemākas alkiltio-, ariltio-(piemēram feniltio-), karboksi-, sulfonamido-, karboksamido- vai karbalkoksigrupas; R3 izvēlas no: ūdeņraža atoma, -OH, -ORs, -NH2, -NHRS, -N(RS)2, -(C,- Cs)alkil-, -(Cļ-Cgjalkil-aril-, -SRs-grupām, halogēna atoma vai nitrilgrupas; vai R2 un R3 var veidot 3-8-locekļu piesātinātu, nepiesātinātu aril-, heteroaril-vai heterociklisku gredzenu; LV 12167 R4 izvēlas no: ūdeņraža atoma, -OH, -ORs, -NH2, -NHR6, -N(R6)2, -(C,-C6)alkil-, -(Ct-Cs)alkil-aril-, -SiOjp-iCļ-Cgjalkilgrupām, halogēna atoma vai nitrilgrupas; R5 izvēlas no: -(CHR'Y)n-R9, -C(R7R8)n-W-C(R7R8)m-R9, -C(R7R8)m-R9, -C(R7R8)m-aril, -C(R7R8)m-CONR7R3grupām; -C(R7R8)m-aizvietotas heteroarilgrupas; C(R7R8)m-aizvietotas heterocikliskas grupas, kurās aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Cgalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; Rs izvēlas no: ūdeņraža atoma, alkil-, -(CVCsjalkil-aril, -(Cļ-Csjalkil-heteroarilgrupām, -(C-|-Ce)alkil-heterocikliskas grupas, -(CVCsjalkil-acilgrupas; vai R3 un R3 var veidot 3-8-locekļu gredzenu iespējams nepiesātinātu, kas satur no 1 līdz 3 heteroatomiem, kurus izvēlas no skābekļa atoma, -NR6, -S(0)p vai acilgrupas, iespējams pievienotas arilgredzenam; R7 un R3neatkārīgi izvēlas no: ūdeņraža atoma, R1, vai šīs grupas (R7 un R8) var veidot 3-7-locekļu aizvietotu gredzenu ar 0-3 nepiesātinātām saitēm, kurā aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Cgalkil- oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas, kas iespējams satur -O-, -S(0)p, -NRsgrupas, iespējams pievienotas aizvietotam arilgredzenam, kurā aizvietotāju izvēlas no: ūdeņraža atoma, CVCgalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; 4 R9 ir ūdeņraža atoms, 5- vai 6-locekļu cikloalkilgredzens, kas iespējams satur no 1 līdz 2 slāpekļa, skābekļa atomiem vai S(0)p grupu, iespējams aizvietotu ar -OH, -0-(C1-C6)alkil-, -O-acil-alkil, NHR10- vai arilgrupu; R10 ir ūdeņraža atoms vai iespējams aizvietota alkilgrupa; R11 ir ūdeņraža atoms; alkilgrupa ar 1-10 oglekļa atomiem, šī alkilgrupa var but sazarota, cikliska un nepiesātināta; aizvietota alkilgrupa, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido, karbalkoksi- vai sulfonamidogrupas; -(C^CJalkil-aril-; -(C1-C4)alkil-(C1-C8)aikil-aril-; (CrCg)alkil-biaril-; aizvietotas -(C^Cgjalkil-arilgrupas; kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; R11a ir ūdeņraža atoms, -SCVCVCg-alkil-, -SCVCVCg-alkil-aizvietota arilgrupa; -S02-aril-, -S02-aizvietota heteroarilgrupa, -COR9, -C02terc-Bu, -C02Bn vai alkil-aizvietota arilgrupa, kurās aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Csalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; 5 LV 12167 R’2 izvēlas no: ūdeņraža atoma, aril-, -(Cļ-C^alkil-, aril(C-,-C6)alkil-, (C3-Cnļcikloalkil-, C3-C10alkilkarboniloksialkil-, C3-C10alkoksikarboniloksialkil-, C2-C10alkoksikarbonil-, C5-C10cikloalkilkarboniloksialkil-, C5-C10cikloalkoksikarboniloksi-alkil-, C5-C,oCikloalkoksikarbonil-, ariloksikarbonil-, ariloksikarboniloks^CVCgalkil-), arilkarboniloksKCVCgalkil)-, C5-C12alkoksialkilkarboniloksialkil-, [S-CCļ-CsalkilJ-l,3-dioksaciklopenten-2-on-il]metil-, (5-aril-1,3-dioksaciklopenten-2-on-il]metil-, (R17)(R17a)N-(CrC10alkil)-, -CH(R13)OC(=0)R14, -CH(R13)0C(=0)0R15grupām, vaior pharmaceutically acceptable salts or prodrugs thereof, wherein: U is selected from: -CO2H, -CONHOH, -CONHOR11, -SH, -NH-COR11, -N (OH) COR11, -SN2H2R8, -SONHR6, -CH2C02H, -PO (OH) 2i -PO (OH) NHR6, -CH2SH, -C (O) NH0R12, -CO2R12 and conventional pre-medicated derivatives; R 1 is selected from: hydrogen, - (C 0 -C 6) alkyl-S (O) p - (C 1 -C 6) alkyl-; - (C0-C8) alkyl-O- (C1-C6) alkyl; - (C0-C6) alkyl-S (O) p- (C0-C6) alkylaryl; - (C0-C8) alkyl-O- (C0-C8) alkylaryl; alkyl having 1 to 20 carbon atoms, this alkyl may be branched, cyclic, and unsaturated; substituted alkyl in which the substituent is selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, N-methylimidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy or sulfonamide; - (CQ-Ca) alkyl-aryl; - (C0-C3) alkyl-substituted aryl; - (C0-Ca) aryl- (C1 -C4) alkylaryl; - (C 1 -C 5) alkyl-biaryl; - (C0-C6) alkyl-S (O) p- (C0-C8) alkylaryl; - (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl; - (C 1 -C 4) alkylaryl- (C 0 -C 8) alkylaryl- [S (O) p - (C 0 -C 8) alkyl] -; - (C0-C3) alkyl-S (O) p- (C0-C8) alkyl-biaryl; - (C0-C8) alkyl-O- (C0-C8) alkylaryl; - (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl; - (C 1 -C 4) alkyl-aryl (C 0 -C 8) alkylaryl- [O- (C 0 -C 8) alkyl] -; - (C0-C8) alkyl-O- (C0-C8) alkyl-biaryl; - (C0-C8) alkyl-O- (C0-C8) alkyl-substituted aryl; wherein the substituent is selected from: hydrogen, C, - C5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, urea or aryl; R2 is selected from: hydrogen, -CO2R5, -CONR5R5, -CONR6 (OR5), alkyl, alkylaryl, alkylheteroaryl, alkylheterocyclic, aryl, heteroaryl or heterocyclic, substituted with one or more substituents selected from : hydrogen, halogen, oxy, alkoxy, aryloxy (eg phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, N-methylimidazolyl , imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (e.g., phenylthio), carboxy, sulfonamide, carboxamido or carbalkoxy; R3 is selected from: hydrogen, -OH, -ORs, -NH2, -NHRS, -N (RS) 2, - (C1-C8) alkyl, - (C1-C8-alkyl-aryl, -SRs, halogen or nitrile, or R2 and R3 may form a 3-8 membered saturated, unsaturated aryl, heteroaryl or heterocyclic ring; LV 12167 R4 is selected from: hydrogen, -OH, -ORs, -NH2, -NHR6, - N (R 6) 2, - (C 1 -C 6) alkyl, - (C 1 -C 8) alkyl-aryl, -SiO j p -C 1-4 alkylcarbyl, halogen or nitrile, R 5 is selected from: - (CHR'Y) n -R9, -C (R7R8) nWC (R7R8) m-R9, -C (R7R8) m -R9, -C (R7R8) m-aryl, -C (R7R8) m-CONR7R3; -C (R7R8) m- C (R 7 R 8) m-substituted heterocyclic groups in which the substituent is selected from: hydrogen, C 1 -C 6 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl -, carboxy, carboxamido- or aryl; R 5 is selected from: hydrogen, alkyl, - (C 1 -C 6 -alkyl-aryl, - (C 1 -C 6 -alkyl-heteroaryl, - (C 1 -C 6) -alkyl-heterocyclic) s, - (CVCsalkyl-acyl; or R3 and R3 may form a 3-8-membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from oxygen, -NR6, -S (O) p or acyl, optionally attached to the aryl ring; R7 and R3 are optionally selected from: hydrogen, R1, or these groups (R7 and R8) can form a 3- to 7-membered ring with 0-3 unsaturated bonds selected from: hydrogen, C1-C6alkyl, halogen atom, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carbamido, or aryl, optionally containing -O-, -S (O) p, -NR 5, optionally attached a substituted aryl ring in which the substituent is selected from: hydrogen, CVC6alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; 4 R 9 is hydrogen, a 5- or 6-membered cycloalkyl ring optionally containing 1 to 2 nitrogen, oxygen, or S (O) p groups may be substituted by -OH, -O- (C 1 -C 6) alkyl, -O-acylalkyl, NHR10- or aryl; R10 is hydrogen or optionally substituted alkyl; R11 is hydrogen; alkyl having 1-10 carbon atoms, this alkyl may be branched, cyclic and unsaturated; substituted alkyl in which the substituent is selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidine, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g. phenylthio), carboxy, carboxamido, carbalkoxy or sulfonamide; - (C 1 -C 4 alkyl-aryl; - (C 1 -C 4) alkyl- (C 1 -C 8) alkyl-aryl; (C 1 -C 8) alkyl-biaryl- substituted - (C 1 -C 6 -alkyl-aryl; wherein the substituent is selected from: hydrogen) , halogen atoms, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidine, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido-, carbalkoxy or sulfonamido; R11a is hydrogen, -SCVCVC8alkyl, -SCVCVC8alkyl-substituted aryl, -SO2-aryl, -SO2- substituted heteroaryl, -COR9, -CO2terc-Bu, -C02Bn or alkyl-substituted aryl selected from: hydrogen, C1-C6alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino -, thio, thioalkyl, carboxy, carboxamido or aryl; selected from: hydrogen, aryl, - (C 1 -C 6 alkyl, aryl (C 1 -C 6) alkyl) , (C3-Cycloalkyl, C3-C10alkylcarb nyloxyalkyl, C3-C10alkoxycarbonyloxyalkyl, C2-C10alkoxycarbonyl, C5-C10cycloalkylcarbonyloxyalkyl, C5-C10cycloalkoxycarbonyloxyalkyl, C5-C10cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy-CVCgalkyl), arylcarbonyloxyCalcylalkyl, C5-C12 alkoxyalkylcarbonyloxy, C5-C12alkoxyalkylcarbonyloxy, [S-CCl-Calkalkyl-1,3-dioxacyclopenten-2-on-yl] methyl, (5-aryl-1,3-dioxacyclopenten-2-on-yl) methyl, (R17) (R17a) N- (C 1 -C 10 alkyl) -, -CH (R 13) OC (= O) R 14, -CH (R 13) 0 C (= O) 0 R 15, or R16 grupas, kur R13 ir ūdeņraža atoms vai CrC4 lineāra alkilgrupa; R14 izvēlas no: ūdeņraža atoma, Cļ-Cgaikii- vai C3-C8cikloalkilgrupas, pie kam šī alkil- vai cikloalkilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: C,-C4alkil-, C3-C8cikloalkil-, C,-C5alkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, CrCsalkil, CVCgalkoksi-, -N02, -SiCļ-Cgalkil)-, -S(=0)(CrC5alkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(Rl7a)-, -C02R17a, -C(=0)N(R17)(R,7a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, (VCgalkil-, Cļ-Cgalkoksi-, -N02, -SiCļ-Cgalkil)-, S(=0)(CrC3alkil)-, -SCķOrCgalkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)('R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R15 izvēlas no: 6 Cļ-Cgalkil-, C3-Cacikloalkilgrupām, pie kam šī alkil- vai cikioalkilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: CrC4alkih C3-C8cikloalkil-, C,-C5alkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, C,-C6alkil-, (VCsalkoksi-, -N02, -SiCVCsalkil)-, -S(=0)(C1-C5alkil)-, -SO^CVCsalkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17),(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, CVCsalkil-, C.,-Csalkoksi-, -N02, -S(C-,-Csalkil)-t -S(=0)(CrC5alkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)(Rl7a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R16 ir C-,-C4alkil-, benzil- vai fenilgrupa; R17 un R17a neatkarīgi izvēlas no: ūdeņraža atoma, C^C^alM-, C2-C6alkenil-, C4-C11cikloalkilaikil- un aril(C1-C6alkil)grupām; rada A, B un D kombinācijas un/vai izmaiņas pieņemamas tikai ja šīs kombinācijas veido stabilus savienojumus (kā norādīts šajā izgudrojumā) A var nebūt, -(CHR6)m-, -0(CHRs)m-, -NR6(CHRs)m-, -S(0)p(CHRs)m- vai izvēlas no: alkilgrupas, kura satur no 1 līdz 10 oglekļa atomiem, kura var būt sazarota, cikliska un nepiesātinātā, vai -(C^CeJalkil-arilgrupas; B var būt saite vai izvēlas no: -NH-, -NR11-, -NR11a-, -0-, -S(0)p-(CrC6)alkil-NH-(CrCs)aikil-, (C,-C3)alkil-NR11-(C1-C6)alkil-, (CrCgjalkil-NH-aril-, -O-CCVCgjalkil-; -(CrCsjalkil-O-aril, -S-(C.,-C6)alkil-, -(Cļ-CsJalkil-S-aril-, -(Cļ-Csjalkil-, -(Cļ-Cgjalkenil-, -(Cļ-Csjalkinil-, -CONH-, -CONR11, -NHCO-, -NR11CO-, -OCO-, -COO-, -0C02-, -R11NCONR11-, -HNCONH-, -OCONR11-, -NR11COO-, -HNS02-, -S02NH-, arii-, cikloalkil-, heterocikloalkil-, -R11NCSNR11-, -HNCSNH, -OCSNR11-, -NR11CSO-, -HNCNNH- un peptīda veida saites; 7 LV 12167R 16 groups wherein R 13 is hydrogen or C 1 -C 4 linear alkyl; R 14 is selected from: hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, wherein said alkyl or cycloalkyl is substituted with 1-2 groups independently selected from: C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy groups ; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO 2, -SiC 1 -C 8 alkylalkyl, -S (= O) (C 1 -C 5 alkyl), -SO 2 (C 1 -C 5 alkyl) ) -, -OH, -N (R17) (R17a) -, -CO2R17a, -C (= O) N (R17) (R, 7a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v + 1); aryl substituted with 0-2 groups independently selected from: halogen, phenyl, (C1-C6alkyl, C1-C6alkoxy, -NO2, -SiCl-C8alkyl), S (= O) (C1-C3 alkyl) -, - SCOrCgalkyl), -OH, -N (R17) (R17a) -, -CO2R17a, -C (= O) N (R17) ('R17a) or -CVFW, where v is from 1 to 3 and w is from 1 to (2v + 1); R 15 is selected from: 6 C 1 -C 6 alkyl, C 3 -Cacycloalkyl, wherein said alkyl or cycloalkyl is substituted with 1-2 groups independently selected from: C 1 -C 4 alkylc3 C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, (C 1-4 alkoxy, -NO 2, -C 1 -C 5 Cl 2 alkyl) -, -S (= O) (C 1 -C 5 alkyl) - , -SO 2 CVCsalkyl), -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17), (R 17a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v + 1); aryl substituted with 0-2 groups independently selected from: halogen, phenyl, CVCalkyl, C, -Calkoxy, -NO2, -S (C-, --Calalkyl) -t -S (= O) (C 1 -C 5 alkyl) -, -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17) (R 17a) or -CVFW wherein v is from 1 to 3 and w are from 1 to (2v + 1); R 16 is C, - C 4 alkyl, benzyl or phenyl; R 17 and R 17a are independently selected from: hydrogen, C 1 -C 6 alM-, C 2 -C 6 alkenyl, C 4 -C 11 cycloalkylalkyl, and aryl (C 1 -C 6 alkyl); generates A, B and D combinations and / or changes are acceptable only if these combinations form stable compounds (as indicated in the present invention) A may be absent, - (CHR6) m-, -O (CHRs) m-, -NR6 (CHRs) m -, -S (0) p (CHRs) m- or selected from: alkyl having from 1 to 10 carbon atoms which may be branched, cyclic and unsaturated, or - (C 1 -C 6 alkylalkyl; B may be a bond or selected from: -NH-, -NR 11 -, -NR 11α, -O-, -S (O) p - (C 1 -C 6) alkyl-NH- (C 1 -C 8) alkyl, (C 1 -C 3) alkyl-NR 11 - (C 1 -C 6) alkyl, (C 1 -C 6 alkyl-NH-aryl, -O-CCVC 6 -alkyl-; - (C 1 -C 6 -alkyl-O-aryl, -S- (C 1 -C 6 -alkyl) - - (C 1 -C 8 -alkyl-S -aryl, - (C 1 -C 6 -alkyl, - (C 1 -C 6 -alkyl, - (C 1 -C 6 -alkyl, -CONH-, -CONR 11, -NHCO-, -NR 11 CO-, -OCO-, -COO-, -O-CO 2 - -, -R11NCONR11-, -HNCONH-, -OCONR11-, -NR11COO-, -HNSO2-, -SO2NH-, aryl, cycloalkyl, heterocycloalkyl, -R11NCSNR11-, -HNCSNH, -OCSNR11-, -NR11CSO-, -HNCNNH- and peptide linkages; 7 LV 12167 D var nebūt vai var būt alkilgrupa, kura satur no 1 līdz 10 oglekļa atomiem, kas iespējams satur skābekļa, sēra atomus vai NRsgrupu; šī alkilgrupa var būt sazarota un cikliska, un nepiesātināta; un ariKCVCgļalkilgrupa; p var būt 0,1 vai 2; m ir vesels skaitlis no 0 līdz 5; n ir vesels skaitlis no 1 līdz 5; W ir -0-, *S(0)P- vai -NR10-grupa; Y izvēlas no: -CONR10-, -NR10CO-, -S02NR10-, -NR10SO2-, peptīda veida saites, 5-locekļu heterocikliska piesātināta, nepiesātināta vai daļēji nepiesātināta gredzena, kas satur no 1 līdz 4 heteroatomiem, kurus izvēlas no slāpekļa, skābekļa vai sēra atoma; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R1)-C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā.D may or may not be an alkyl group containing from 1 to 10 carbon atoms which may contain oxygen, sulfur or NRs; this alkyl may be branched and cyclic and unsaturated; and aralkylcycloalkyl; p may be 0.1 or 2; m is an integer from 0 to 5; n is an integer from 1 to 5; W is -O-, * S (O) P- or -NR 10; Y is selected from: -CONR10-, -NR10CO-, -SO2NR10-, -NR10SO2-, peptide bond, 5-membered heterocyclic saturated, unsaturated or partially unsaturated ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; provided that the size of the macrocycle from which Formula I is composed -A-B-D-C (R 2) (R 3) -Y-C (R 1) -C (U) (R 4) - contains not less than 11 atoms and not more than 22 atoms per cycle. 2. Savienojums ar formulu (II)2. A compound of formula (II) vai šī savienojuma farmaceitiski pieņemami sāļi, vai pirmsārtnieciskas formas, kur: X izvēlas no: CH2-, NH-, NR5-, S(0)p-, grupām vai skābekļa atoma; 8or pharmaceutically acceptable salts or prodrugs thereof, wherein: X is selected from: CH2-, NH-, NR5-, S (O) p-, groups or oxygen; 8 R17, R17a un p, m, η, A, B, D, un W ir tādi, kā iepriekš norādīts formulā I un šie savienojumi definēti ka stabilie savienojumi; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R1)-X-C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā.R17, R17a and p, m, η, A, B, D, and W are as defined in formula I above and these compounds are defined as stable compounds; with the proviso that the size of the macrocycle from which the formula I -A-B-D-C (R 2) (R 3) -Y-C (R 1) -X-C (U) (R 4) - contains not less than 11 atoms and not more than 22 atoms per cycle. 3. Savienojums ar formulu (III)3. A compound of formula (III) / (III)/ (III) vai šī savienojuma farmaceitiski pieņemami sāļi, vai pirmsārstnieciskas formas, kur: U izvēlas no: -C02H, -CONHOH, -CONHOR11, -SH, -NH, -COR11, -N(OH)COR11, -SN2H2R6, -SONHR6, -CH2C02H, -PO(OH)2, -PO(OH)NHRs, -CH2SHgrupām un parastiem pirmsārstnieciskiem atvasinājumiem ar -C(0)NH0R12 un -C02R12grupām; Z izvēlas no: slāpekļa atoma vai -CH-grupas; R1, R4, R6, R11, R11a, R12, R13, R14, R15, R1S, R17, R17a, A, B, C ir tādi, kā norādīts formulā I un šie savienojumi definēti ka stabilie savienojumi;or the pharmaceutically acceptable salts or prodrugs thereof, wherein: U is selected from: -CO2H, -CONHOH, -CONHOR11, -SH, -NH, -COR11, -N (OH) COR11, -SN2H2R6, -SONHR6, -CH2C02H , -PO (OH) 2, -PO (OH) NHRs, -CH2SH groups and conventional pre-medicated derivatives with -C (O) NHOR12 and -CO2R12; Z is selected from: nitrogen or -CH; R 1, R 4, R 6, R 11, R 11a, R 12, R 13, R 14, R 15, R 1, R 17, R 17a, A, B, C are as defined in formula I and these compounds are defined as stable compounds; 4. Savienojums saskaņā ar 1. punktu, kur U izvēlas no: -CONHOH, -CONHOR11, -N(OH)COR11, -SN2H2R6, -SONHR8, -C02H, -CH2SH, -C(0)NH0R12grupām un parastiem pirmsārstnieciskiem atvasinājumiem; R1 izvēlas no: ūdeņraža atoma, « » -(C0-C6)aikil-S(O)p-(C,-Ce)alkil-; 9 LV 12167 -(C0-Cs)alkil-O-(C0-C8)alkil-; -(C0-Cs)alkil-S(O)p-(C,-Cs)alkil-aril-; -(C0-C3)alkil-O-(C0-Cs)alkil-arilgrupām; alkilgrupas, kura satur no 1 līdz 20 oglekļa atomiem, kura var būt sazarota, cikliska un nepiesātināta; aizvietotas alkilgrupas, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidino-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio- (piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; -(Co-Ca)alkil-aril-; -(C0-C8)alkil- aizvietotas aril-; -(C0-C8)aril- (Cļ-CJalkil-aril-; -(CrCg)alkil-biaril-; -(CQ-C8)alkil-S(0)p-(Co-C8)alkil-aril; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(CrC4)alkil-aril-(C0-C3)alkil-aril-[S(O)p-(C0-C8)alkil]-; -(C0-C3)alkil-S(O)p-(C0-C3)alkil-biaril-; -(C0-C3)alkil-O-(C0-C8)alkii-aril-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(Cļ-cjaikil-ariKCo-Cajaikil-ariKO-iCo-Cajaikii]-; -(C0-C8)alkil-O-(C0-C3)alkil-biaril-; -(C0-C3)alkil-O-(C0-C3)alkil-aizvietotas arilgrupām; kurās aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Csalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas; R2 izvēlas no ūdeņraža atoma, -C02R5, -CONRsR5, -CONRs(ORs), alkil-, alkilaril-, alkilheteroaril-, alkilheterocikliskas, aril-, heteroaril- vai heterocikliskas grupas, kura aizvietota ar vienu vai vairākiem aizvietotājiem, kurus izvēlas no: 10 ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, zemākas alkiltio-, ariltio- (piemēram feniltio-), karboksi-, sulfonamido-, karboksamido- vai karbalkoksigrupas; R3 izvēlas no: ūdeņraža atoma, -OH un NH2grupām; vai R2 un R3 var veidot 3-6-locekļu piesātinātu, nepiesātinātu aril-, heteroaril-vai heterociklisku gredzenu; R4 izvēlas no: ūdeņraža atoma, -OH, -ORe un NH2grupām; Rs izvēlas no: -(CHR1Y)n-R9, -C(R7R8)n-W-C(R7R3)m-R9, -C(R7R8)m-R9, -C(R7R8)m-aril, -C(R7R8)m-CONR7R8grupārn; C(R7R8)m-aizvietotas heteroaril-; C(R7R8)m-aizvietotārn heterocikliskām grupām, kurās aizvietotāju izvēlas no: ūdeņraža atoma, CrC5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; R6 izvēlas no: 'ūdeņraža atoma, alkil-, -(Cļ-Csjalkil-aril-, -(C-,-Ce)alkil-heteroaril-, -(CrCsjalkil-heterocikliskas, -(CVCsjalkil-acilgrupām; vai R5 un Rs var veidot 3-8-locekļu gredzenu iespējams nepiesātinātu, kas satur no 1 līdz 3 heteroatomiem, kurus izvēlas no skābekļa atoma, -NR6, -S(0)p vai acilgupas, iespējams pievienotas arilgredzenam; R7 un R8 neatkārīgi izvēlas no: ūdeņraža atoma. R1, vai šīs grupas (R7 un R8) var veidot 3-7-locekļu aizvietotu gredzenu ar 0-3 nepiesātinātiem saitēm, kurā aizvietotāju izvēlas no: ūdeņraža atoma, C^Cgalkil- oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, I [ LV 12167 karbamido- vai arilgrupas, kas iespējams satur -O-, -S(0)p, -NR6grupas, iespējams pievienotas aizvietotam arilgredzenam, kurā aizvietotāju izvēlas no: ūdeņraža atoma, C^Cgalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksiamido- vai arilgrupas; R9 ir ūdeņraža atoms, cikloalkilgrupa, 5-6 locekļu gredzens, kas iespējams satur no 1 līdz 2 slāpekļa, skābekļa atomiem vai S(0)pgrupu, iespējams aizvietotu ar -OH, -0-(Cn-C6)alkil-, -O-acil-alkil-, NHR10- vai arilgrupu; R10 ir ūdeņraža atoms vai iespējams aizvietota alkilgrupa; R11 ir ūdeņraža atoms; alkilgrupa ar 1-10 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietota alkilgrupa, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio-(piemēram feniitio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; -(Cļ-CJalkil-aril-; -(Cļ-CJalkiHCrCgjalkil-aril-; -(Cļ-Cajalkil-biarilgrupām; aizvietotas -(Cļ-Cgjalkil-arilgrupas, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio-(piemēram feniitio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; R11a ir ūdeņraža atoms, -SOs-Cļ-Cg-alkil-, -SCVCVCs-alkil-aizvietota aril-; 12 -S02-aril-, -S02-aizvietota heteroaril-, -COR9, -C02terc-Bu, -C02Bn vai alkil-aizvietotas arilgrupas, kurās aizvietotāju izvēlas no: ūdeņraža atoma, CrC5alkih oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; R12 izvēlas no: ūdeņraža atoma, aril-, -(Cļ-C^alkil-, ariKCr^alkil-, (C3-Cnjcikloalkil-, C3-C10alkilkarboniloksialkil-, C3-C10alkoksikarboniloksialkil-, C2-C10alkoksikarbonil-, C5-C10cikloalkilkarboniloksialkil-, C5-C10cikloalkoksikarboniloksi-alkil-, C5-C10cikloalkoksikarbonil-, ariloksikarbonil-, ariloksikarboniloks^CVCgJalkil-, arilkarboniloksiiC^Csalkil)-, C5-C12alkoksialkilkarboniloksialkil-, [5-(0-,-053^11)-1,3-dioksaciklopenten-2-on-il]metil-, (5-aril-1,3-dioksaciklopenten-2-on-il]metil-, (R17)(R17a)N-(CrCl0alkil)-, -CH(R13)0C(=0)R14, -CH(R13)0C(=0)R15grupām, vaiA compound according to claim 1, wherein U is selected from: -CONHOH, -CONHOR11, -N (OH) COR11, -SN2H2R6, -SONHR8, -CO2H, -CH2SH, -C (O) NH0R12groups and conventional prodrugs; R 1 is selected from: - hydrogen, -, - (C 0 -C 6) alkyl-S (O) p - (C 1 -C 6) alkyl-; 12 LV716 - (C0-C8) alkyl-O- (C0-C8) alkyl; - (C0-C8) alkyl-S (O) p- (C1-C6) alkylaryl; - (C0-C3) alkyl-O- (C0-C8) alkyl-aryl; an alkyl group containing from 1 to 20 carbon atoms, which may be branched, cyclic and unsaturated; substituted alkyl in which the substituent is selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, N-methylimidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy or sulfonamide; - (Co-Ca) alkyl-aryl; - (C0-C8) alkyl-substituted aryl; - (C0-C8) aryl- (C1-C6alkyl-aryl-; - (C1-C8) alkyl-biaryl; - (CQ-C8) alkyl-S (O) p- (Co-C8) alkylaryl; C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl- (C 1 -C 4) alkyl-aryl- (C 0 -C 3) alkyl-aryl- [S (O) p - (C 0- C8) alkyl] -; - (C0-C3) alkyl-S (O) p- (C0-C3) alkyl-biaryl; - (C0-C3) alkyl-O- (C0-C8) alkylaryl; - (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl- (C 1 -C 4 -cycloalkyl-C 1 -C 6 -cycloalkyl-arkoxy-C 1 -C 6 -alkyl) -; - (C 0 -C 8) alkyl -O- (C0-C3) alkyl-biaryl-; - (C0-C3) alkyl-O- (C0-C3) alkyl-substituted aryl; in which the substituent is selected from the group consisting of: hydrogen, C-Calkalkyl, oxo, halogen; , alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carbamido, or aryl; R2 is selected from hydrogen, -CO2R5, -CONR5R5, -CONRs (ORs), alkyl- , an alkylaryl, alkylheteroaryl, alkylheterocyclic, aryl, heteroaryl or heterocyclic group substituted with one or more substituents selected from: hydrogen, halogen, oxy, alk ksi, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidine, N-methylimidazolyl, imidazolyl, indolyl, mercapto- , lower alkylthio, arylthio (e.g., phenylthio), carboxy, sulfonamido, carboxamido or carbalkoxy; R3 is selected from: hydrogen, -OH and NH2; or R2 and R3 may form a 3-6-membered saturated, unsaturated aryl, heteroaryl or heterocyclic ring; R4 is selected from: hydrogen, -OH, -ORe and NH2; R 5 is selected from: - (CHR 1 Y) n -R 9, -C (R 7 R 8) nWC (R 7 R 3) m -R 9, -C (R 7 R 8) m -R 9, -C (R 7 R 8) m -aryl, -C (R 7 R 8) m - CONR7R8group; C (R 7 R 8) m-substituted heteroaryl; C (R7R8) m-substituent for heterocyclic groups in which the substituent is selected from: hydrogen, C1-C5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido- or aryl; R6 is selected from the group consisting of: 'hydrogen, alkyl, - (C 1 -C 6 -alkyl-aryl, - (C 1 -C 6) alkyl-heteroaryl, - (C 1 -C 6 -alkyl-heterocyclic, - (C 6 -C 6 -alkyl-acyl; or R 5 and R 5 may be) to form a 3-8-membered ring optionally unsaturated, containing from 1 to 3 heteroatoms selected from oxygen, -NR 6, -S (O) p or acyl, optionally attached to an aryl ring, R 7 and R 8 are independently selected from: hydrogen. R1, or these groups (R7 and R8) may form a 3- to 7-membered ring with 0-3 unsaturated bonds selected from: hydrogen, C1-C6alkyloxy, halogen, alkoxy, amino, monoalkylamino -, dialkylamino, acylamino, thio, thioalkyl, carboxy, I [LV 12167 urea or aryl group optionally containing -O-, -S (O) p, -NR 6 -, optionally attached to a substituted aryl ring selected from: hydrogen, C 1 -C 6 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, ac ilamino, thio, thioalkyl, carboxy, carboxyamid or aryl; R9 is hydrogen, cycloalkyl, 5-6 membered ring, optionally containing 1 to 2 nitrogen, oxygen, or S (O) p, optionally substituted with -OH, -O- (C1-C6) alkyl, -O -acylalkyl, NHR10- or aryl; R10 is hydrogen or optionally substituted alkyl; R11 is hydrogen; alkyl having from 1 to 10 carbon atoms, this alkyl may be branched, cyclic, and unsaturated; substituted alkyl in which the substituent is selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidine, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy or sulfonamide; - (C 1 -C 4 alkyl-aryl-; - (C 1 -C 4 alkylcHCl-C 6 -alkyl-aryl-; - (C 1 -C 6 -alkyl-biaryl; substituted - (C 1 -C 6 -alkyl-aryl- wherein the substituent is selected from: hydrogen, halogen, oxy, alkoxy) , aryloxy (eg phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g. ), carboxy, carboxamido-, carbalkoxy or sulfonamido; R11a is hydrogen, -SO5-C8-C8-alkyl, -SCVCVC5-alkyl-substituted aryl; 12SO2-aryl-, -SO2-substituted heteroaryl- , -COR9, -C02terc-Bu, -CO2Bn or alkyl-substituted aryl groups in which the substituent is selected from: hydrogen, CrC5alkih, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl -, carboxy, carboxamido- or aryl; R12 is selected from: hydrogen, aryl, - (C1-C6 alkyl, arylC1-6alkyl, (C3-C12cycloalkyl, C3-C10 alkylcarbonyloxyalkyl) , C3-C10alkoxycarbonyloxyalkyl, C2-C10alkoxycarbonyl, C5-C10cycloalkylcarbonyloxyalkyl, C5-C10cycloalkoxycarbonyloxyalkyl, C5-C10cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy-CVC8alkyl, arylcarbonyloxyC1-6alkyl), C5-C12alkoxyalkylcarbonyloxyalkyl, [5- (0-,? 053? 11) -1,3-dioxacyclopenten-2-on-yl] methyl, (5-aryl-1,3-dioxacyclopenten-2-on-yl) methyl, (R17) (R17a) ) N- (C 1 -C 10 alkyl) -, -CH (R 13) 0 C (= O) R 14, -CH (R 13) 0 C (= O) R 15, or R16 grupas, kur R13 ir ūdeņraža atoms vai CVC4 lineāra alkilgrupa; R14 izvēlas no: ūdeņraža atoma, CrCaalkil- vai C3-Cacikloalkilgrupas, pie kam šī alkil- vai cikloalkilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: Cļ-C^alkil-, C3-Cacikloalkil-, CrCsalkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izveļas no: halogēna atoma, fenil-, CrCsalkil-, Cļ-Cgalkoksi-, N02, -S(C,-C5alkil)-, -S(=0)(C1-C5aikil)-f -S02(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, CVCgalkil-, Cļ-Cgalkoksi-, N02, -SiCļ-Csalkil)-, 13 LV 12167 -S(=0)(CrC5alkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R15 izvēlas no: C,-C8alkil-, C3-C8cikloalkilgrupām, pie kam šī alkil- vai cikloalkilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: Cļ^alkil-, C3-C8cikloalkil-, Cļ-Csalkoksi-grupām; arilgrupas, aizvietotas ar 0-2 grupām kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, C^Cgalkil-, CrC6alkoksi-, -N02, -SiCļ-Cgalkil)-, -S^OKCrCsalkil)-, -SO^CrCgalkil)-, -OH, -N(R17) (R17a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, C-,-C6alkil-, Ο,-Csalkoksi-, -N02, -S^-Csalkil)-, -S(=0)(C,-C5alkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R1S ir Cļ^alkil-, benzil- vai fenilgrupa; R17 un R17a neatkarīgi izvēlas no: ūdeņraža atoma, C-,-C10alkil-, C2-Csalkenil-, C^CnCikloalkilalkil- un ariKC^CsalkiOgrupām; A, B un D kombinācijas un/vai izmaiņas pieņemamas tikai ja šīs kombinācijas veido stabilus savienojumus (kā norādīts šajā izgudrojumā) A var nebūt, vai var būt -(CHRs)m-, -0(CHRs)m-, -NRs(CHRs)m-, -S(0)p(CHRs)m-grupas vai izvēlas no alkilgrupas, kura satur no 1 līdz 10 oglekļa atomiem un kura var būt sazarota, cikliska un nepiesātināta; vai -(C-,-Ce)alkil-arilgrupa; B var būt saite vai izvēlas no -NH-, -NR11-, -NR11a-, -0-, -SiOJp-iC^CgJalkil-NH(CrCe)alkil-, (CrCgJalkil-NR^-iCrCajalkil-, (CrCeJalkil-NH-aril-, -0-(CrCs)alkil-; 14 -(Cļ-C^alkil-O-aril, -S-iCVCjJalkil-, -(Cļ-CeJalkil-S-aril, -(Cļ-Cgjalkil-, -(CrC6)alkenil-, -(CrC6)alkinil-, -CONH-, -CONR11, -NHCO-, -NR11CO-, -OCO-, -COO-, -0C02-, -R11NCONR11-, HNCONH-, -OCONR11-, NR11COO-, -HNS02-, -S02NH-, aril-, cikloalkil-, heterocikloalkil-, -R11NCSNR11-, -HNCSNH, -OCSNR11-, -NR11CSO-, -HNCNNH- un peptida veida saites;R16 groups wherein R13 is hydrogen or a linear alkyl group of CVC4; R 14 is selected from: hydrogen, C 1 -C 6 alkyl or C 3 -Cacycloalkyl, wherein said alkyl or cycloalkyl is substituted with 1 to 2 groups independently selected from: C 1 -C 6 alkyl, C 3 -Cacycloalkyl, C 1 -C 6 alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, C 1 -C 8 alkoxy, NO 2, -S (C 1 -C 5 alkyl) -, -S (= O) (C 1 -C 5 alkyl) ) -f -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17) (R 17a) or -CVFW wherein v is from 1 to 3 and w are from 1 to (2v + 1); aryl substituted with 0-2 groups independently selected from: halogen, phenyl, CVCgalkyl, C1-C8alkoxy, NO2, SiC1-Calkalkyl), 13L12167-S (= O) (CrC5alkyl) - , -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17) (R 17a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v + 1); R 15 is selected from: C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, wherein said alkyl or cycloalkyl is substituted with 1-2 groups independently selected from: C 1-4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO 2, -SiC 1 -C 8 alkylalkyl, -S 2 -COC 1 -C 8 alkylalkyl,, -SO 2 CrC 6 alkyl) - , -OH, -N (R17) (R17a) -, -CO2R17a, -C (= O) N (R17) (R17a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v) +1; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C -, - C 6 alkyl, Ο, -C 1-4 alkoxy, -NO 2, -S 2 -C 6 alkyl -, -S (= O) (C 1 -C 5 alkyl) -, -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17) (R 17a) or -CVFW groups wherein v is from 1 to 3 and w is from 1 to (2v + 1); R 1 S is C 1-4 alkyl, benzyl or phenyl; R 17 and R 17a are independently selected from: hydrogen, C, - C 10 alkyl, C 2 -C 6 alkenyl, C 1 -C 7 cycloalkylalkyl, and arylC 1-4 alkyl; Combinations A, B and D and / or changes are acceptable only if these combinations form stable compounds (as indicated in the present invention) A may or may not be - (CHRs) m-, -O (CHRs) m-, -NRs (CHRs) ) m-, -S (O) p (CHRs) m-groups or selected from alkyl having from 1 to 10 carbon atoms and which may be branched, cyclic and unsaturated; or - (C 1 -C 6) alkyl-aryl; B may be a bond or selected from -NH-, -NR11-, -NR11a, -O-, -SiOJp-C1-6C8alkyl-NH (C1-C6) alkyl-, (C1-C8alkyl-NR1-C11Crkkalkyl, (CrCl3alkyl-NH -aryl, -O- (C 1 -C 8) alkyl-; - 14 - (C 1 -C 6 alkyl-O-aryl, -S-C 1 -C 8 Cl 1 -alkyl-, - (C 1 -C 6 alkylalkyl-S-aryl, - (C 1 -C 8 -alkyl, - (C 1 -C 6) alkenyl, - (C 1 -C 6) alkynyl, -CONH-, -CONR 11, -NHCO-, -NR 11 CO-, -OCO-, -COO-, -CO 2 -, -R 11 NRCR 11 -, HNCONH-, -OCONR 11- , NR11COO-, -HNSO2-, -SO2NH-, aryl-, cycloalkyl-, heterocycloalkyl-, -R11NCSNR11-, -HNCSNH, -OCSNR11-, -NR11CSO-, -HNCNNH- and peptidic bond; D var nebūt vai var būt alkilgrupa, kura satur no 1 līdz 10 oglekļa atomiem, kas iespējams satur skābekļa, sēra atomus vai NR6grupu, šī alkilgrupa var būt sazarota un cikliska, un nepiesātināta; un (CrCs)alkil-arilgrupa; p var būt 0, 1 vai 2; m ir vesels skaitlis no 0 līdz 5; n ir vesels skaitlis no 1 līdz 5; W ir -O-, -S(0)p- vai -NR10-grupa; Y izvēlas no: -CONR10-, -NR10CO-, -S02NR1°-, -NR10SO2-, peptīda veida saites, 5-locekļu heterocikliska piesātināta, nepiesātināta vai daļēji nepiesātināta gredzena, kas satur no 1 līdz 4 heteroatomiem, kurus izvēlas no slāpekļa, skābekļa vai sēra atoma; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R’)-C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā.D may or may not be an alkyl group containing from 1 to 10 carbon atoms, which may contain oxygen, sulfur atoms or NR6, this alkyl may be branched and cyclic and unsaturated; and (C 1 -C 8) alkyl-aryl; p can be 0, 1 or 2; m is an integer from 0 to 5; n is an integer from 1 to 5; W is -O-, -S (O) p- or -NR 10; Y is selected from: -CONR10-, -NR10CO-, -SO2NR1 ° -, -NR10SO2-, peptide bond, 5-membered heterocyclic saturated, unsaturated or partially unsaturated ring containing 1 to 4 heteroatoms selected from nitrogen; oxygen or sulfur; provided that the size of the macrocycle from which the formula I -A-B-D-C (R 2) (R 3) -Y-C (R ') - C (U) (R 4) - contains not less than 11 atoms and not more than 22 atoms per cycle. 5. Savienojums saskaņā ar 2. punktu, kur: X izvēlas no: CH2, NH-grupām, sēra un skābekļa atomiem; 15 LV 12167 U, Υ, R1, R2, R3, R4, R5, Rs, R7, R8, R9, R10, R11, R11a, R12, R13, R14, R1S, R1S, R17, R17a un p, m, π, A, B, D, un W ir tādi, kā iepriekš norādīts formulā I un šie savienojumi definēti ka stabilie savienojumi; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R1)-X-C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā.A compound according to claim 2, wherein: X is selected from: CH 2, NH-groups, sulfur and oxygen atoms; 15, 12167 U, Υ, R1, R2, R3, R4, R5, R5, R7, R8, R9, R10, R11, R11a, R12, R13, R14, R1S, R1S, R17, R17a and p, m, π , A, B, D, and W are as defined in formula I above and these compounds are defined as stable compounds; with the proviso that the size of the macrocycle from which the formula I -A-B-D-C (R 2) (R 3) -Y-C (R 1) -X-C (U) (R 4) - contains not less than 11 atoms and not more than 22 atoms per cycle. 6. Savienojums saskaņā ar 1. punktu, kur: U izvēlas no: -CONHOH, -C(0)NH0R12, -C02H un parastiem pirms-ārstnieciskiem atvasinājumiem; R1 izvēlas no: ūdeņraža atoma, -(C0-C6)alkil-S(O)p-(CrC6)alkil-; -(Co-Csjalkil-O-iCrCsjalkil-; -(C0-C6)alkil-S(O)p-(C0-Cs)alkil-aril·; -(C0-Cs)alkil-O-(C0-Cs)alkil-arilgrupām; alkilgrupas, kura satur no 1 līdz 20 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietotas alkilgrupas, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolii-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio- (piemēram feniltio-), karboksi-, karboksamido, karbalkoksi- vai sulfonamidogrupas; -(C0-C8)alkil-aril-; -(C0-C8)alkil- aizvietotas aril-; -(C0-C8)aril- (CrC4)alkil-aril-; -(Cļ-Cgjalkil-biaril-; -(C0-Cg)alkil-S(O)p-(C0-Cg)alkil-aril-; -(C0-C8)alkil-S(O)p-(C0-Cg)alkil-aizvietotas aril-; 16 -(C1-C4)alkil-aril-(C0-C8)alkil-aril-[S(O)p-(C0-Ca)alkil]-; -(C0-Ca)alkil-S(O)p-(C0-C3)alkil-biaril-; *(Co-C8)alkil-0-(C0-Ca)alkil-aril-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(C1-C4)alkil-aril-(Ca-Cs)alkil-aril-[0-(Co-C8)alkil]-; -(C0-Ca)alkil-O-(C0-C8)alkil-biaril-; -(C0-C8)alkil-O-(C0-C8)alkil-aizvietotām arilgrupām; kurās aizvietotāju izvēlas no: ūdeņraža atoma, CrC5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido- vai arilgrupas; R2 izvēlas no ūdeņraža atoma, -C02Rs, -CONR6R5, -CONR6(OR5), alkil-, alkilaril-, alkilheteroaril-, alkilheterocikliskas, aril-, heteroaril- vai heterocikliskas grupas, kura aizvietota ar vienu vai vairākiem aizvietotājiem, kurus izvēlas no: ūdeņraža, halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, zemākas alkiltio-, ariltio- (piemēram feniltio-), karboksi-, sulfonamido-, karboksamido- vai karbalkoksigrupas; R3un R* ir ūdeņraža atomi; R5 izvēlas no: -(CHR’V^-R9, -C(R7R8)n-W-C(R7R8)m-R9, -C(R7R8)m-R9, -C(R7R8)m-aril, -C(R7R8)m-CONR7R8grupārn; -C(R7R8)m-aizvietotas heteroarilgrupas; -C(R7R8)m-aizvietotas heterocikliskas grupas, kurās aizvietotāju izvēlas no: ūdeņraža atoma, C-,-C5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; R6 izvēlas no: 17 LV 12167 ūdeņraža atoma, alkil-, -(C1-C6)alkil-aril, -(C1-C6)alkil-heteroaril-, -(C1-Ce)alkil-heterocikliskas grupas, -(C1-Cs)alkil-acilgrupas-; vai R5 un Rs var veidot 3-8-locekļu iespējams nepiesātinātu gredzenu, kas satur no 1 līdz 3 heteroatomiem, kurus izvēlas no skābekļa atoma, -NRS, -S(0)p vai acilgrupas, iespējams pievienotas arilgredzenam; R7 un R8 neatkārīgi izvēlas no: ūdeņraža atoma, R1, šīs grupas (R7 un R8) var veidot 3-7-locekļu aizvietotu gredzenu ar 0-3 nepiesātinātām saitēm, kurā aizvietotāju izvēlas no: ūdeņraža atoma, C^Cgalkil- oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido- vai arilgrupas, kas iespējams satur -0-, -S(0)p, -NR6grupas, iespējams pievienotas aizvietotam arilgredzenam, kurā aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Cgalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas; R9 ir ūdeņraža atoms, alkil-, cikloalkilagrupas; 5- vai 6-locekļu gredzens, kas iespējams satur no 1 līdz 2 slāpekļa, skābekļa atomiem vai S(0)p grupu, iespējams aizvietotu ar -OH, -CHCVC^alkil-, -O-acil-alkil, NHR10- vai arilgrupu; R10 ir ūdeņraža atoms vai iespējams aizvietota alkilgrupa; R11 ir ūdeņraža atoms; alkilgrupa ar 1-10 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietota alkilgrupa, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto- un zemākas alkiltio-, ariltio- (piemēram feniltio-), karboksi-, karboksamido, karbalkoksi- un sulfonamidogrupām; -(CrCJalkil-aril-; 18 -(CrC3)alkil-aizvietotām arilgrupām; kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, zemākas alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; R11a ir ūdeņraža atoms, -SOg-Cļ-Cg-alkil-, -SCVCļ-Cg-alkil-aizvietota aril-; -S02-arii-, -S02-aizvietota heteroaril-, -COR9, -C02terc-Bu, -C02Bn grupām; kurās aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Csalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; R12 izvēlas no: ūdeņraža atoma, aril-, -(C-,-C10)aIkil-, ariKCļ-CsJalkil-, (C3-Cnjcikloalkil-, C3-C10alkilkarboniloksialkil-, C3-C10alkoksikarboniloksialkil-, C2-C10alkoksikarbonil-, C5-C10cikloalkilkarboniloksialkil-, C3-C12cikloalkoksikarboniloksi-alkil-, C5-C10cikloalkoksikarbonil-, ariloksikarbonil-, ariloksikarboniloksi(CrC3)alkil-, arilkarboniloksiiCļ-Cgalkil)-, C5-C12alkoksialkilkarboniloksialkil-, ^-(Cļ-Cgalkilj-1,3-dioksaciklopenten-2-on-il]metil-, (5-aril-1,3-dioksaciklopenten-2-on-il]metil-, '(R17)(R17a)N-(C-,-Cl0alkil)-, -CH(R13)0C(=0)R14, -CH(R13)0C(=O)0R15grupām, vai OThe compound of claim 1, wherein: U is selected from: -CONHOH, -C (O) NH0R12, -CO2H, and conventional pre-treatment derivatives; R 1 is selected from: hydrogen, - (C 0 -C 6) alkyl-S (O) p - (C 1 -C 6) alkyl-; - (C 0 -C 6 -alkyl-O-C 1 -C 6 -alkyl; - (C 0 -C 6) alkyl-S (O) p - (C 0 -C 8) alkylaryl; - (C 0 -C 8) alkyl-O- (C 0 -C 8) an alkyl group containing from 1 to 20 carbon atoms, this alkyl may be branched, cyclic, and unsaturated; substituted alkyl in which the substituent is selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy) ), amino, monoalkylamino, dialkylamino, acylamino (eg acetamido- and benzamido-), arylamino, guanidine, N-methylimidazole, imidazolyl, indolyl, mercapto, alkylthio, arylthio (eg phenylthio) -), carboxy, carboxamido, carbalkoxy or sulfonamido; - (C0-C8) alkyl-aryl- (C0-C8) alkyl-substituted aryl- (C0-C8) aryl- (C1-C4) alkyl aryl -; - (C 1 -C 8 -alkyl-biaryl; - (C 0 -C 8) alkyl-S (O) p - (C 0 -C 8) alkyl-aryl- (C 0 -C 8) alkyl-S (O) p - ( C0-C8) alkyl-substituted aryl; 16 - (C1-C4) alkyl-aryl- (C0-C8) alkylaryl- [S (O) p- (C0-Ca) alkyl] -; Ca) alkyl-S (O) p- (C0-C3) alkyl biaryl; * (C0-C8) alkyl-O- (C0-Ca) alkyl aryl 1- (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl; - (C 1 -C 4) alkylaryl- (C 1 -C 8) alkylaryl- [O- (C 0 -C 8) alkyl] -; - (C0-Ca) alkyl-O- (C0-C8) alkyl-biaryl; - (C0-C8) alkyl-O- (C0-C8) alkyl-substituted aryl; wherein the substituent is selected from: hydrogen, C 1 -C 5 alkyl, oxo, halo, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, urea or aryl; R 2 is selected from hydrogen, -CO 2 R 5, -CONR 6 R 5, -CONR 6 (OR 5), alkyl, alkylaryl, alkylheteroaryl, alkylheterocyclic, aryl, heteroaryl or heterocyclic substituted with one or more substituents selected from: hydrogen, halogen; oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, N-methylimidazolyl, imidazolyl, indolyl , mercapto, lower alkylthio, arylthio (e.g., phenylthio), carboxy, sulfonamide, carboxamido or carbalkoxy; R3 and R * are hydrogen; R5 is selected from: - (CHR'V1-R9, -C (R7R8) nWC (R7R8) m-R9, -C (R7R8) m -R9, -C (R7R8) m-aryl, -C (R7R8) m -CONR7R8group; -C (R7R8) m-substituted heteroaryl; -C (R7R8) m-substituted heterocyclic group wherein the substituent is selected from: hydrogen, C, - C5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R6 is selected from: 17 LV 12167 hydrogen, alkyl, - (C 1 -C 6) alkyl aryl, - (C 1-6) C 6) alkyl-heteroaryl, - (C 1 -C 6) alkyl-heterocyclic, - (C 1 -C 8) alkyl-acyl-, or R 5 and R 8 may form a 3-8-membered unsaturated ring containing 1 to 3 heteroatoms selected from an oxygen atom, -NRS, -S (O) p or an acyl group optionally attached to an aryl ring; R7 and R8 are independently selected from: hydrogen, R1, these groups (R7 and R8) can form 3-7-membered members a substituted ring with 0-3 unsaturated bonds in which the substituent is selected from: ū denier atom, C 1 -C 6 alkyl oxy groups, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, urea, or aryl optionally containing -O-, -S (0) p, -NR 6, optionally attached to a substituted aryl ring in which the substituent is selected from: hydrogen, C 1 -C 6 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl - carboxy, urea or aryl; R9 is hydrogen, alkyl, cycloalkyl; A 5- or 6-membered ring optionally containing 1 to 2 nitrogen, oxygen, or S (O) p groups may be substituted by -OH, -CHCVC1-4alkyl, -O-acylalkyl, NHR10- or aryl ; R10 is hydrogen or optionally substituted alkyl; R11 is hydrogen; alkyl having from 1 to 10 carbon atoms, this alkyl may be branched, cyclic, and unsaturated; substituted alkyl wherein the substituent is selected from: hydrogen, halogen; oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, imidazolyl, indolyl, mercapto- and lower alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy, and sulfonamido; - (C 1 -C 19 alkyl-aryl; 18 - (C 1 -C 3) alkyl-substituted aryl) wherein the substituent is selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino ( for example acetamido- and benzamido-), arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (e.g. phenylthio), carboxy, carboxamido-, carbalkoxy or sulfonamide; R11a is hydrogen , -SO8-C8-C8-alkyl-, -SCVC1-C8-alkyl-substituted aryl-, -SO2-aryl, -SO2-substituted heteroaryl-, -COR9, -CO2terc-Bu, -CO2Bn; of: hydrogen atom, C 1 -C 6 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido- or aryl; R 12 is selected from: hydrogen atom , aryl, - (C, - C10) alkyl, aralkylcycloalkyl, (C3-C12cycloalkyl, C3-C10alkylcarbonyloxyalkyl, C3-C10alkoxycarbonyloxyalkyl, C2-C10alkoxycarbonyl, C5-C10cycloalkyl) alkylcarbonyloxyalkyl, C3-C12cycloalkoxycarbonyloxyalkyl, C5-C10cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxy (C1-C3) alkyl, arylcarbonyloxyC1-C8alkyl), C5-C12alkoxyalkylcarbonyloxyalkyl, 1- (C1-C6alkyl-1,3-dioxacyclopenten-2 -on-yl] methyl, (5-aryl-1,3-dioxacyclopenten-2-on-yl) methyl, '(R17) (R17a) N- (C, - Cl-alkyl) -, -CH (R13) ) 0C (= O) R14, -CH (R13) 0C (= O) 0R15, or O kur: R16 grupas R13 ir ūdeņraža atoms vai C,-C4 lineāra alkilgrupa; R14 izvēlas no: 19 LV 12167 ūdeņraža atoma, C,-C8alkil- vai C3-C8cikloalkilgrupas, pie kam šī alki!- vai cikloaikilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: C1-C4alkil-, C3-CgCikloalkil-, Cļ-Csalkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, - CVCgalkil-, CVCgalkoksi-, -N02, -SiCļ-Csalki!)-, -S(=0)(C,-C5alkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, C-|-C6aikil-, CrCgalkoksi-, -N02, -SiC^Cgalkil)-, S(=0)(CrCsalkil)-, -S02(CrC5alkil)-, -OH, -N(R17),(R17a)-, -C02R17a, -C(=0)N(R17),(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R15 izvēlas no: CrCsalkil-, C3-C3cikloalkilgrupām, pie kam šī alkil- vai cikloaikilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: Cļ^alkil-, C3-C3cikloalkil-, C,-C5alkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, CrCsalkil-, Cļ-Cgalkoksi-, -NO,, -S(CrC5alkil)-, -S(=0)(CrC5alkil)-, -SO^CVCgalkil)-, -OH, -N(R17)(Rl7a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, CVCgalkil-, Cļ-Cgalkoksi-, -N02, -SiC^Cgaikil)-, -S(=0)(CrC5alkil)-, -SO,(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C0,R17a, -C(=0)N(R17)(R17a) vai -C,,FW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R1S ir CrC4alkil-, benzil- vai fenilgrupa; 20 R17 un R17a neatkarīgi izveļas no: ūdeņraža atoma, Cļ-C^alkil-, C2-C6alkenil-, Cj-Cndkloalkilalkil- un aril(CrC6alkil)grupām; A, B un D kombinācijas un/vai izmaiņas pieņemamas tikai ja šis kombinācijās veido stabilus savienojumus (kā norādīts šajā izgudrojumā) A var nebūt, vai var būt -(CHR6)m-, -0(CHR6)m-, -NR6(CHR6)m-, -S(0)p(CHRs)m- vai izvēlas no alkilgrupas, kura satur no 1 līdz 10 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; vai -(CVCsjalkil-arilgrupa; B var but saite vai izvēlas no -NH-, -NR11-, NR11a-, -0-, -S(0)p-(C-,-Ce)alkil-NH(CrCs)alkil-, (CrC6)alkil-NR11-(CrCs)alkil-, (CrCs)alkil-NH-aril·, -O-iC^CeJalkil-; -(Cļ-Cejalkil-O-aril, -S-iCVCgjalkil-, -((VCgjalkil-S-aril, -(Ci~Cs)alkil-, -(CrC6)alkenil-, -(CrCs)alkinil-, -CONH-, -CONR11, -NHCO-, NR11CO-, -OCO-, -COO-, -0C02-, -R11NCONR11-, -HNCONH-, -OCONR11-, NR11COO-, -HNS02-, -S02NH-, aril-, cikloalkii-, heterocikloalkil-, -R11NCSNR11-, -HNCSNH-, -OCSNR11-, -NR11CSO-, -HNCNNH- un peptīda veida saites;wherein: R 16 is R 13 is hydrogen or C 1 -C 4 linear alkyl; R14 is selected from: 19 LV 12167 hydrogen atom, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, wherein the alkyl or cycloalkyl group is substituted with 1-2 groups independently selected from: C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, Chalk-alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, CVCgalkyl, CVCgalkoxy, -NO2, -SiCl-Calkoe), -S (= O) (C 1 -C 5 alkyl) -, -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17) (R 17a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v + 1); aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1-6 alkyl, C 1 -C 6 alkoxy, -NO 2, -Si C 1 -C 6 alkyl, S (= O) (C 1 -C 6 alkyl) -, -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17), (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17), (R 17a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v + 1); R15 is selected from: C1-C6alkyl, C3-C3cycloalkyl, wherein said alkyl or cycloalkyl is substituted with 1-2 groups independently selected from: C1-6alkyl, C3-C3cycloalkyl, C1-C5alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, C 1 -C 8 alkoxy, -NO ,, -S (C 1 -C 5 alkyl) -, -S (= O) (C 1 -C 5 alkyl) -, -SO 2 - CVCgalkyl), -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17) (R 17a) or -CVFW where v is from 1 to 3 and w is from 1 to (2v + 1); aryl substituted with 0-2 groups independently selected from: halogen, phenyl, CVCgalkyl, C1-C8 alkoxy, -NO2, -SiC1C6alkyl), -S (= O) (C1-C5 alkyl) -, - SO, (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -C 0, R 17a, -C (= O) N (R 17) (R 17a) or -C ,, FW where v is from 1 to 3 and w are from 1 to (2v + 1); R 1 S is C 1 -C 4 alkyl, benzyl or phenyl; R 17 and R 17a are independently selected from: hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 cycloalkylalkyl and aryl (C 1 -C 6 alkyl); Combinations and / or variations of A, B and D are only acceptable if this combination produces stable compounds (as indicated in the present invention) A may or may not be - (CHR6) m-, -O (CHR6) m-, -NR6 (CHR6) ) m-, -S (O) p (CHRs) m- or is selected from alkyl having from 1 to 10 carbon atoms, this alkyl may be branched, cyclic, and unsaturated; or - (C 6 -C 6 -alkyl-aryl; B may be a bond or selected from -NH-, -NR 11 -, NR 11a -, -O-, -S (O) p - (C 1 -C 6) alkyl-NH (C 1 -C 8) alkyl -, (C 1 -C 6) alkyl-NR 11 - (C 1 -C 5) alkyl-, (C 1 -C 8) alkyl-NH-aryl ·, -O-C 1 -C 6 Cl 2 alkyl -; - (C 1 -C 6 alkyl-O-aryl, -S-iCV C 6 -alkyl, - ((C 1 -C 6 alkyl-S-aryl, - (C 1 -C 8) alkyl, - (C 1 -C 6) alkenyl, - (C 1 -C 8) alkynyl, -CONH-, -CONR 11, -NHCO-, NR 11 CO-, -OCO-, - COO-, -CO2-, -R11NCONR11-, -HNCONH-, -OCONR11-, NR11COO-, -HNSO2-, -SO2NH-, aryl, cycloalkyl, heterocycloalkyl, -R11NCSNR11-, -HNCSNH-, -OCSNR11- , -NR11CSO-, -HNCNNH- and peptide-type bonds; D var nebūt vai var būt alkilgrupa, kura satur no 1 līdz 6 oglekļa atomiem, šī alkilgrupa var būt sazarota un cikliska, un nepiesātināta; vai (CrC6)alkil-arilgrupa; p var būt 0, 1 vai 2; m ir vesels skaitlis no 0 līdz 3; n ir vesels skaitlis no 1 līdz 4; W ir -O-, -S(0)p- vai -NR10-grupa; 21 LV 12167 Y izvēlas no -CONR10-, -NR10CO-, -S02NR10-, -NR10SO2-grupām, peptīda veida saites, 5-locekļu heterocikliska piesātināta, nepiesātināta vai daļēji nepiesātināta gredzena, kas satur no 1 līdz 4 heteroatomiem, kurus izvēlas no slāpekļa, skābekļa vai sēra atoma; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R1)-C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā. Tikai aizvietotāji, kas veido stabilus savienojumus, iekļauti formulā I.D may or may not be an alkyl group containing from 1 to 6 carbon atoms, this alkyl may be branched and cyclic, and unsaturated; or (C 1 -C 6) alkyl-aryl; 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 -O-, -S (O) p- or -NR 10; 21127 Y is selected from -CONR10-, -NR10CO-, -SO2NR10-, -NR10SO2-, peptide-type bonds, 5-membered heterocyclic saturated, unsaturated or partially unsaturated ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; provided that the size of the macrocycle from which Formula I is composed -A-B-D-C (R 2) (R 3) -Y-C (R 1) -C (U) (R 4) - contains not less than 11 atoms and not more than 22 atoms per cycle. Only substitutes that form stable compounds are included in Formula I. 7. Savienojums saskaņā ar 2. punktu, kur X izvēlas no: ~CH2-, NH-grupām; sēra un skābekļa atomiem; U izvēlas no -C02H, -C02R,2grupām un parastiem pirmsārstnieciskiem atvasinājumiem; ,12 Γΐ13 r->14 (—,15 η16 ι-> 17 —>17a V P1 Pz Q3 Π4 P5 Rs P7 Π8 R3 P10 P11 Rlz R13 R14 R13 R16 Ru R τ,π,π,π,η,π,π,η,η,π,η , n ,n , π , π , π ,π ,π ,π un ρ, m, η, Α, Β, D un W ir tādi, kā iepriekš norādīts formulā I un šie savienojumi definēti ka stabilie savienojumi; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R1)-X*C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā.A compound according to claim 2 wherein X is selected from: -CH2-, NH-; sulfur and oxygen atoms; U is selected from -C02H, -CO2R, 2, and conventional pre-medicated derivatives; , 12 Γΐ13 r- > 14 (-, 15 η16 ι- > 17 - > 17a V P1 Pz Q3 Π4 P5 Rs P7 Π8 R3 P10 R11 R13 R14 R13 R16 Ru R τ, π, π, π, η , π, π, η, η, π, η, n, n, π, π, π, π, π, π, ρ, m, η, Α, Β, D and W are as given in formula I above and these compounds are defined as stable compounds, provided that the size of the macrocycle from which the formula I -ABDC (R2) (R3) -YC (R1) -X * C (U) (R4) is composed - contains not less than 11 atoms and not more than 22 atoms per cycle. 8. Savienojums saskaņā ar 1. punktu, kur U izvēlas no: -CONHOH, -C(0)NH0R12, -C02H-grupām un parastiem pirmsārstnieciskiem atvasinājumiem; R1 izvēlas no: ūdeņraža atoma, » * -(C0-Cs)alkil-S(O)p-(CrC3)alkil-: -(Co-Csjalkil-O-iCļ-Cjjalkil-; -(CQ-Cs)alkil-S(0)p-(Ca-C3)alkil-āril-; -(C0-C6)alkil-O-(C0-Cs)alkil-arHgrupām; aikilgrupas, kura satur no 1 līdz 20 oglekļa atomiem, sī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietotas aikilgrupas, kurā aizvietotāju izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio- (piemēram feniltio-), karboksi-, karboksamido, karbalkoksi- vai sulfonamidogrupas; -(C0-C8)alkil-aril-; -(C0-C8)alkil- aizvietotas aril-; -(C0-C8)aril- (C-,-C4)alkil-aril-; -(C^Cgjalkil-biaril-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aril-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aizvietotas arilgrupas; -(CrCJalkil-aril-iCo-CeJalkil-aril-CSiOJp-iCo-Cejalkil]-; -(Co-C8)alkil-S(0)p-(C0-C8)alkil-biaril-; -(C0-C8)alkil-O-(C0-C8)alkil-aril-; -(C0-C8)aIkil-S(O)p-(Ca-C8)alkil-aizvietotas aril-; -(C^CJalkil-aril-iCo-Cgjalkil-aril-tO-iCo-Cgjalkil]-; -(C0-C8)alkil-O-(C0-C8)alkil-biaril-; -(C0-C8)alkil-O-(C0-C8)alkil-aizvietotām arilgrupām; kurās aizvietotāju izvēlas no: ūdeņraža atoma, CrC5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas; R2 izvēlas no: ūdeņraža atoma, -C02R5, -CONR6R5, -CONRs(OR5), alkil-, alkilaril-, alkilheteroaril-, alkilheterocikliskas, aril-, heteroaril- vai heterocikliskas grupas, kura aizvietota ar vienu vai vairākiem aizvietotājiem, kurus izvēlas no: ūdeņraža, halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, 23 LV 12167 merkapto-, zemākās alkiltio-, ariltio- (piemēram feniltio-), karboksi-, sulfonamido-, karboksamido- vai karbalkoksigrupas; R3un R4 ir ūdeņraža atomi; R5 izvēlas no: -(CHR1Y)n-R9, -CiR'RVvV-C^RVR9, -C(R7R8)m-R9, -C(R7R8)m-aril, -C(R7R8)m-heteroaril-; -C(R7R8)m- heterocikliskām grupām; R6 izvēlas no: ūdeņraža atoma, alkil-, -(Cļ-C^alkil-aril-, -(CT^alkil-heteroaril-, -(C1-Cs)alkil-heterocikliskas, -(CVC^alkil-acilgrupām; vai R5 un R6 var veidot 3-8-locekļu iespējams nepiesātinātu gredzenu, kas satur no 1 līdz 3 heteroatomiem, kurus izvēlas no skābekļa atoma, -NR6, -S(0)p grupām vai šīs gredzens satur acilgrupu, iespējams pievienotu arilgredzenam; R7 un Raneatkārīgi izvēlas no: ūdeņraža atoma, R1-grupas, vai (R7 un R8) var veidot 3-7-locekļu aizvietotu gredzenu ar 0-3 nepiesātinātām saitēm, pie kam šo aizvietotāju izvēlas no: ūdeņraža atoma, Cļ-Csalkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas, kas iespējams satur-0-, -S(0)p, -NRsgrupas, iespējams pievienotas arilgredzenam, šo gredzena aizvietotāju izvēlas no: ūdeņraža atoma, CrC5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; R9 ir ūdeņraža atoms, alkil-, cikloalkilgrupas, 5-6 locekļu gredzens, iespējams aizvietots ar 1 vai 2 slāpekļa, skābekļa atomiem vai S(0)pgrupu, iespējams aizvietotu ar -OH, -0-(CrCs)alkil-, -O-acil-alkil-NHR10- vai arilgrupu; R10 ir ūdeņraža atoms vai iespējams aizvietota alkilgrupa; 24 R11 ir ūdeņraža atoms; alkilgrupa, kura satur no 1 līdz 6 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietota zemākā alkilgrupa; šīs grupas aizvietotāju izvēlas no: ūdeņraža un halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, zemākās alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- un sulfonamidogrupām; -(CrCJalkil-arilgrupas; -(CrCgJalkil-aizvietotas arilgrupas; šo grupas aizvietotāju izvēlas no: ūdeņraža un halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, zemākās alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- un sulfonamidogrupām; R11a ir ūdeņraža atoms, -S02-(C,-Cs)-alkil-, -S02-(C,-Cs)-alkil-aizvietota aril-; -S02-aril-, -S02-aizvietota heteroaril-, -COR9, -C02terc-Bw, C02Bn-grupām, šo grupu aizvietotāju izvēlas no: ūdeņraža atoma, C,-C3alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; R12 izvēlas no: ūdeņraža atoma, aril-, -(C,-C10)alkil-, aril(C,-C6)alkil-, (Ca-Cnļcikloalkil-, C3-C10alkilkarboniloksialkil-, C3-C,calkoksikarboniloksialkil-, C2-C10alkoksikarbonil-, C5-C10cikloalkilkarboniloksialkil-, C=-C1Qcikloalkoksikarboniloksialkil-, C5-C,0cikloalkoksi-karbonil-, ariloksikarbonil-, ariloksikarboniloksKC^CeJalkil-, arilkarboniloksi(C,-C6alkil)-, C5-C12alkoksialkilkarboniIoksialkil-, [5-(0,-053ΜΙ)-1,3-dioksaciklopenten-2-on-il]metil-, (5-aril-1,3-dioksaciklopenten-2-on-il)metil-, (R17)(R17a)N-(C,-C10alkil)-, -CH(R13)0C(=0)R14, -CH(R13)0C(=0)0R1svai 25 LV 12167A compound according to claim 1, wherein U is selected from: -CONHOH, -C (O) NH0R12, -CO2H- and conventional pre-medicated derivatives; R1 is selected from the group consisting of: a hydrogen atom, a * - (C0-C8) alkyl-S (O) p- (C1-C3) alkyl-: - (C 0 -C 6 -alkyl-O-C 1-4 C 1-6 alkyl-; - (CQ-C 8) alkyl- S (O) p- (Ca-C3) alkyl-aryl-; - (C0-C6) alkyl-O- (C0-C8) alkyl-arH; alkyl containing from 1 to 20 carbon atoms may be alkyl branched, cyclic and unsaturated; substituted alkyl substituted with: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido and benzamide) -), arylamino, guanidino, N-methylimidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy or sulfonamide; - (C0-C8) alkyl-aryl- (C0-C8) alkyl-substituted aryl- (C0-C8) aryl- (C, - C4) alkyl-aryl- (C 1 -C 6 -alkyl-biaryl; - (C 0- C8) alkyl-S (O) p- (C0-C8) alkyl-aryl- (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl; C1-C6alkyl-aryl-CSiOp-iCo-Ceoyl] -; - (C 0 -C 8) alkyl-S (O) p - (C 0 -C 8) alkyl biaryl; - (C0-C8) alkyl-O- (C0-C8) alkylaryl; - (C0-C8) alcyl-S (O) p- (Ca-C8) alkyl-substituted aryl; - (C 1 -C 4 alkyl-aryl-C 1 -C 8 -alkyl-aryl-O-C 0 -C 8 -alkyl) -; - (C 0 -C 8) alkyl-O- (C 0 -C 8) alkyl-biaryl; - (C 0 -C 8) alkyl- O- (C0-C8) alkyl-substituted aryl groups in which the substituent is selected from: hydrogen, C1-C5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy -, urea or aryl; R2 is selected from: hydrogen, -CO2R5, -CONR6R5, -CONRs (OR5), alkyl, alkylaryl, alkylheteroaryl, alkylheterocyclic, aryl, heteroaryl or heterocyclic substituted with one or several substituents selected from: hydrogen, halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, N-methylimidazolyl, imidazolyl, indolyl, 23 LV 12167 mercapto, lower alkylthio, arylthio (e.g. phenylthio), carboxy, sulfonamide, carboxamido- or carbalkoxy; is hydrogen, R5 is selected from: - (CHR1Y) n-R9, -C1R'RVvV-C4RVR9, -C (R7R8) m -R9, -C (R7R8) m-aryl, -C (R7R8) m- heteroaryl; -C (R7R8) m-heterocyclic groups; R 6 is selected from: hydrogen, alkyl, - (C 1 -C 6 alkylaryl, - (C 1 -C 6 alkyl heteroaryl, - (C 1 -C 5) alkyl-heterocyclic, - (C 6 -C 6 alkyl acyl; or R 5) and R6 may form a 3-8-membered unsaturated ring containing from 1 to 3 heteroatoms selected from oxygen, -NR6, -S (O) p, or an acyl group optionally attached to an aryl ring; selected from: hydrogen, R1, or (R7 and R8) can form a 3- to 7-membered ring with 0-3 unsaturated bonds, wherein the substituent is selected from: hydrogen, C1-C6alkyl, oxo, halo atom, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carbamido, or aryl, optionally containing -O-, -S (O) p, -NR 5, optionally attached aryl ring, this ring substituent is selected from: hydrogen, C 1 -C 5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is hydrogen, alkyl, cycloalkyl, 5-6 membered ring, optionally substituted with 1 or 2 nitrogen, oxygen, or S (O) p, optionally substituted with -OH, -O- (C1-C6) alkyl, -O -acylalkyl-NHR10- or aryl; R10 is hydrogen or optionally substituted alkyl; 24 R11 is hydrogen; an alkyl group having 1 to 6 carbon atoms, this alkyl group may be branched, cyclic, and unsaturated; substituted lower alkyl; this group substituent is selected from: hydrogen and halogen; oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy, and sulfonamido; - (C 1 -C 7 alkyl-aryl; - (C 1 -C 8 alkylalkyl-substituted aryl; this group substituent is selected from: hydrogen and halogen; oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (e.g. phenylthio), carboxy, carboxamido-, carbalkoxy, and sulfonamido; R11a is hydrogen, -SO2 - (C 1 -C 8) -alkyl, -SO 2 - (C 1 -C 8) -alkyl-substituted aryl-, -SO 2 -aryl-, -SO 2 -substituted heteroaryl-, -COR 9, -C02 -terc-Bw, CO 2 Bn- for these groups, the substituent for these groups is selected from: hydrogen, C 1 -C 3 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; ; R12 is selected from: hydrogen, aryl, - (C 1 -C 10) alkyl, aryl (C 1 -C 6) alkyl, (C 1 -C 6 cycloalkyl, C 3 -C 10 alkylcarbonyloxyalkyl, C 3 -C 6, alkoxycarbonyloxyalkyl, C 2) -C10 alkoxycarbonyl, C5-C10cycloalkylcarbonyloxyalkyl, C = -C1cycloalkoxycarbonyloxyalkyl, C5-C10cycloalkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyloxyC1-6alkylalkyl, arylcarbonyloxy (C1-C6alkyl) -, C5-C12alkoxyalkylcarbonylIoxyalkyl-, [5- (0, -053ΜΙ ) -1,3-dioxacyclopenten-2-on-yl] methyl, (5-aryl-1,3-dioxacyclopenten-2-on-yl) methyl, (R17) (R17a) N- (C, -C10 alkyl) ) -, -CH (R 13) 0 C (= O) R 14, -CH (R 13) 0 C (= O) 0 R 1 or 25 LV 12167 R16 grupas, kur: R13 ir ūdeņraža atoms vai C,-C4 lineāra alkilgrupa; R14 izvēlas no: ūdeņraža atoma, C,-Csalkil- vai C3-Cscikloalkilgrupas, pie kam šī alkil- vai cikloalkilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: Ci-C4alkil-, C3-Cacikloalkil-, Cr C5alkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, C-,-C6alkil-, (VCsalkoksi-, -N02, -S(C-,-C5alkil)-, -,S(=0)(CrC5alkil)-, -S02(C,-C5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17),(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, C^Cgalkil-, C^Csalkoksi-, -N02, -SiC^Cgalkil)-, -S(=0)(CrCsalkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(R17a)-, -C02R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+i): R15 izvēlas no: Cļ-Cgalkil-, C3-Cacikloalkilgrupām, pie kam šī alkil- vai cikloalkilgrupa aizvietota ar 1-2 grupām, kuras neatkarīgi izvēlas no: C-,-C4alkil-, C3-C3cikloalkil-, C-|-C5alkoksigrupām; arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izvēlas no: halogēna atoma, fenil-, CVCsalkoksi-, -NO,, -StC^Csalkil)-, -S(=0)(CrC5alkil)-, -S02(C,-C5alkil)-, -OH, -N(R17)(R17a)-, -CO,R17a, -C(=0)N(R17)(R17a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); 26 arilgrupas, aizvietotas ar 0-2 grupām, kuras neatkarīgi izveļas no: halogēna atoma, fenil-, CrC6alkil-, CVCealkoksi-, -N02, -SiCrCsalkil)-, -S(=0)(CrC5alkil)-, -S02(CrC5alkil)-, -OH, -N(R17)(Ri7a)-, -C02R17a, -0(=O)N(R17)(R,7a) vai -CVFW grupas, kur v ir no 1 līdz 3 un w ir no 1 līdz (2v+1); R1S ir C^C^alkil-, benzil- vai fenilgrupa; A, B un D kombinācijas un/vai izmaiņas pieņemamas tikai ja šīs kombinācijas veido stabilus savienojumus (kā norādīts šajā izgudrojumā); -NRs-( CH2)m- grupas; A var būt -(CH2)m-, -0(CH2)m-, -S(CH2)m-, B var būt saite vai B izvēlas no -NH-, -NR11-, NR11a-, -O-, -SiOjp-iC^Cejalkil-NH-(CrCe)alkil-, (CrCeJalkil-NR^-iCrCeJalkil-, (CrCeJalkil-NH-aril-, -0-(CrC6)alkil-; -(C^CeJalkil-O-aril, -S-iCļ-CeJalkil-, -(Cļ-Cgjalkil-S-aril, -(C^Csjalkil-, -(CVCgjalkenil-, -(CrC6)alkinil-, -CONH-, -CONR11, -NHCO-, NR11CO-, -OCO-, -COO-, -0C02-, -R11NCONR11-, HNCONH-, -OCONR11-, -NR11COO-, -HNS02-, -S02NH-, aril-, cikloalkil-, heterocikloalkil-, -R11NCSNR11-, -HNCSNH-, -OCSNR11-, NR11CSO-, -HNCNNH-grupām un peptīda veida saites;R16 groups wherein: R13 is hydrogen or C1-C4 linear alkyl; R 14 is selected from: hydrogen, C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl, wherein said alkyl or cycloalkyl is substituted with 1-2 groups independently selected from: C 1 -C 4 alkyl, C 3 -Cacycloalkyl, C 1 -C 5 alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C, -C6 alkyl, (C 1-4 alkoxy, -NO 2, -S (C 1 -C 5 alkyl), -, S (= 0) (C 1 -C 5 alkyl) -, -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O) N (R 17), (R 17a) or -CVFW groups where v is from 1 to 3 and w is from 1 to (2v + 1); aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, C 1-4 alkoxy; , -NO 2, -Si C 1 -C 6 alkyl) -, -S (= O) (C 1 -C 6 alkyl) -, -SO 2 (C 1 -C 5 alkyl) -, -OH, -N (R 17) (R 17a) -, -CO 2 R 17a, -C (= O ) N (R17) (R17a) or -CVFW groups where v is from 1 to 3 and w is from 1 to (2v + i): R15 is selected from: C1-C8 alkyl, C3-Cycloalkyl, wherein said alkyl or cycloalkyl substituted with 1 to 2 groups independently selected from: C -, - C 4 alkyl, C 3 -C 3 cycloalkyl, C 1 -C 5 alkoxy; aryl substituted with 0-2 groups independently selected from: halogen, phenyl, CVCalkoxy, -NO1, -StC1Calkyl), -S (= O) (C1-C5 alkyl), -SO2 (C -C5alkyl), -OH, -N (R17) (R17a) -, -CO, R17a, -C (= O) N (R17) (R17a) or -CVFW, where v is 1 to 3 and w is from 1 to (2v + 1); 26 aryl groups substituted with 0-2 groups independently selected from: halogen, phenyl, C 1 -C 6 alkyl, CVCealkoxy, -NO 2, -Si C 1 -C 8 alkylalkyl, -S (= O) (C 1 -C 5 alkyl), -SO 2 (C 1 -C 5 alkyl) ) -, -OH, -N (R17) (Ri7a) -, -CO2R17a, -O (= O) N (R17) (R, 7a) or -CVFW, where v is from 1 to 3 and w is from 1 to (2v + 1); R 1 S is C 1 -C 4 alkyl, benzyl or phenyl; Combinations and / or changes of A, B and D are only acceptable if these combinations form stable compounds (as indicated in the present invention); -NR 5 - (CH 2) m -; A can be - (CH2) m-, -O (CH2) m-, -S (CH2) m-, B can be a bond or B is selected from -NH-, -NR11-, NR11a, -O-, - SiOjpCCC ^jalalkyl-NH- (C 1 -C 6) alkyl-, (C 1 -C 12 alkyl-NR 1 -C 1 ClCealkyl-, (C 1 -C 6 alkylalkyl-NH-aryl, -O- (C 1 -C 6) alkyl-; - (C 1 -C 6 alkylalkyl-O-aryl, -S-ICl-CeJalkyl-, - (C 1 -C 6 -alkyl-S-aryl, - (C 1 -C 6 -alkyl, - (C 6 -C 6 alkenyl, - (C 1 -C 6) alkynyl, -CONH-, -CONR 11, -NHCO-, NR 11 CO- , -OCO-, -COO-, -OCO2-, -R11NCONR11-, HNCONH-, -OCONR11-, -NR11COO-, -HNSO2-, -SO2NH-, aryl, cycloalkyl, heterocycloalkyl, -R11NCSNR11-, - HNCSNH-, -OCSNR11-, NR11CSO-, -HNCNNH- and peptide-type bonds; D ir -(CH2)m-grupa; p var but 0, 1 vai 2; m ir vesels skaitlis no 0 līdz 3; n ir vesels skaitlis no 1 līdz 4; 27 LV 12167 W ir -0-, -S(0)p- vai -NR10-grupa; Y izvēlas no -CONR10-, -NR10CO-, -S02NR1°-, -NR10SO2-grupām; peptīda veida saites, 5-locekļu heterocikliska piesātināta, nepiesātināta vai daļēji nepiesātināta gredzena, kas satur no 1 līdz 4 heteroatomiem, kurus izvēlas no slāpekļa, skābekļa vai sēra atoma; ar nosacījumu, ka makrocikla izmērs, no kura sastāv formula I -A-B-D-C(R2)(R3)-Y-C(R1)-C(U)(R4)- satur ne mazāk par 11 atomiem un ne vairāk par 22 atomiem ciklā.D is - (CH 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; 27 LV 12167 W is -O-, -S (O) p - or -NR 10; Y is selected from -CONR10-, -NR10CO-, -SO2NR1 ° -, -NR10SO2-; a peptide bond, a 5-membered heterocyclic saturated, unsaturated or partially unsaturated ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; provided that the size of the macrocycle from which Formula I is composed -A-B-D-C (R 2) (R 3) -Y-C (R 1) -C (U) (R 4) - contains not less than 11 atoms and not more than 22 atoms per cycle. 9. Savienojums saskaņā ar 1. punktu vai šī savienojuma farmaceitiski pieņemams sāls, kas atbilst formulām IVa, IVb, IVc vai IVd9. A compound according to claim 1 or a pharmaceutically acceptable salt of said compound of formula IVa, IVb, IVc or IVd. rvb IVarvb IVa // R1 R11R1 R11 R2 IVc IVd vai šo savienojumu farmaceitiski pieņemami sāļi, vai pirmsārstnieciskas formas, kur: R1 izveļas no: 28 ūdeņraža atoma, -(C0-C6)alkil-S(O)p-(CrC6)alkil-; -(C0-C6)aikil-O-(CrC6)alkil-; -(C0-Cs)alkil-S(O)p-(C,-Cs)alkil-aril-; -(C0-Cs)alkil-O-(C0-Cs)alkil-arilgrupām; alkilgrupas, kura satur no 1 līdz 20 oglekļa atomiem, pie kam šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietotas alkilgrupas, šīs grupas aizvietotāju izvēlas no: ūdeņraža un halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolil-, indolil-, merkapto-, alkiltio-, ariltio- (piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupas; -(C0-Ca)alkil-aril-; -(C0-C8)alkil- aizvietotas aril-; -(C0-C8)aril- (C1-C4)alkil-ariI-; -(CrC8)alkil-biaril-; -(C0-C8)alkil-S(O)p-(C0-Cs)alkil-aril-; -(CVCa)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(C1-C4)alkil-aril-(C0-Ca)alkil-aril-[S(O)p-(C0-C3)alkil]-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-biaril-; -(C0-C8)alkil-O-(C0-C8)alkil-aril-; -(C0-C8)alkil-S(O)p-(C0-C8)alkil-aizvietotas aril-; -(C1-C4)alkil-aril-(C0-C3)alkil-ari]-[O-(C0-Ca)alkil]-; -(C0-C8)alkil-O-(C0-C8)alkil-biaril-; -(C0-C3)alkil-O-(C0-Cs)alkil-aizvietotām arilgrupām; kurās aizvietotāju izvēlas no: ūdeņraža atoma, CrC5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas; 29 LV 12167 R2 izvēlas no: ūdeņraža atoma, -C02R5, -CONRsR5, -CONRs(OR5), alkil-, alkilaril-, alkilheteroaril-, alkilheterocikliskas, aril-, heteroaril- vai heterocikliskas grupas, kura aizvietota ar vienu vai vairākiem aizvietotājiem, kurus izvēlas no: ūdeņraža un halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, monoalkilamino-, dialkilamino-, acilamino-, (piemēram aceramido- un benzamido-), arilamino-, guanidīno-, N-metilimidazolil-, imidazolii-, indolil-, merkapto-, zemākas alkiltio-, ariltio- (piemēram feniltio-), karboksi-, sulfonamido-, karboksamido- vai karbalkoksigrupas; Rs izvēlas no: -(CHR1Y)n-R9, -C(R7R8)n-W-C(R7R8)m-R9, -C(R7R8)m-Rs, -C(R7R8)m- aril, -C(R7R8)m-CONR7R8; -C(R7R8)m-aizvietotas heteroaril-; -C(R7R8)m- heterocikliskas grupām; R6 izvēlas no: ūdeņraža atoma, alkil-, -(C-,-C6)alkil-aril, -(C^Cgjalkil-heteroaril-, -(C-,-C6)alkil-heterocikliskas, -(CVCsjalkil-acilgrupām; vai R5 un Rs var veidot 3-8-locekļu iespējams nepiesātinātu gredzenu, kas satur no 1 līdz 3 heteroatomiem, kurus izvēlas no skābekļa atoma, -NR6, -S(0)p-grupām vai ši gredzens satur acilgupu, iespējams pievienotu arilgredzenam; R7 un R8 neatkārigi izvēlas no: ūdeņraža atoma, R1-grupas, vai R7 un R8 var veidot 3-7-locekļu aizvietotu gredzenu ar 0-3 nepiesātinātām saitēm, šī gredzena aizvietotāju izvēlas no: ūdeņraža atoma, C^Cgalkil- oksigrupām, halogēna atoma alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karbamido-vai arilgrupas, kas iespējams satur-0-, -S(0)p, -NRsgrupas, iespējams pievienotas aizvietotam arilgredzenam, šī gredzena aizvietotāju izvēlas no: ūdeņraža atoma, C,-C5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; 30 R9 ir ūdeņraža atoms, alkil-, cikloalkil-, 5- vai locekļu gredzens, kas iespējams satur 1 vai 2 slāpekļa, skābekļa atomus vai S(0)pgrupu, iespējams aizvietotu ar -OH, -CHCVC^alkil-, -O-acil-alkil-, NHR10- vai arilgrupu; R10 ir ūdeņraža atoms vai iespējams aizvietota alkilgrupa; R11 ir ūdeņraža atoms; alkilgrupa, kas satur no 1 līdz 6 oglekļa atomiem, šī alkilgrupa var būt sazarota, cikliska un nepiesātināta; aizvietota zemākā alkilgrupa; kurā aizvietotāju izvēlas no: ūdeņraža un halogēna atomiem, oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, zemākās alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido, karbalkoksi- un sulfonamidogrupām; -(C1-C4)a(kil-aril-; -(C1-Cs)alkil-aizvietotas arilgrupas; šīs grupas aizvietotāju izvēlas no: ūdeņraža un halogēna atomiem; oksi-, alkoksi-, ariloksi- (piemēram fenoksi-), amino-, dialkilamino-, acilamino- (piemēram acetamido- un benzamido-), arilamino-, guanidīno-, imidazolil-, indolil-, merkapto-, zemākās alkiltio-, ariltio-(piemēram feniltio-), karboksi-, karboksamido-, karbalkoksi- vai sulfonamidogrupām; R11a ir ūdeņraža atoms, -S02-(CrC3)-alkil-, -S02-(C1-Cs)-alkil-aizvietota arti-; -S02-aril-, -S02-aizvietota heteroaril-, -COR9, -C02terc-Bu, C02Bn grupām, šo grupu aizvietotāju izvēlas no: ūdeņraža atoma, C,-C5alkil-, oksigrupām, halogēna atoma, alkoksi-, amino-, monoalkilamino-, dialkilamino-, acilamino-, tio-, tioalkil-, karboksi-, karboksamido- vai arilgrupas; m ir vesels skaitlis no 0 līdz 5; 31 LV 12167 π ir vesels skaitlis no 1 līdz 5; p var būt 0, 1 vai 2; W ir -0-, -S(0)p- vai *NR10-grupa; Z ir CH2-grupa vai skābekļa atoms; Y izvēlas no -CONR10-, -NR10CO-, -S02NR1°-, -NR10SO2-grupām peptīda veida saites, 5-locekļu heterocikliska piesātināta, nepiesātināta vai daļēji nepiesātināta gredzena, kas satur no 1 līdz 4 heteroatomiem, kurus izvēlas no slāpekļa, skābekļa vai sēra atoma.R2 IVc IVd or pharmaceutically acceptable salts of these compounds, or pre-treatment forms, wherein: R1 is from: 28, - (C0-C6) alkyl-S (O) p- (C1-C6) alkyl-; - (C0-C6) alkyl-O- (C1-C6) alkyl; - (C0-C8) alkyl-S (O) p- (C1-C6) alkylaryl; - (C0-C8) alkyl-O- (C0-C8) alkyl-aryl; an alkyl group containing from 1 to 20 carbon atoms, wherein the alkyl group may be branched, cyclic, and unsaturated; substituted alkyl groups, the substituent of this group is selected from: hydrogen and halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino- , guanidino, N-methylimidazolyl, imidazolyl, indolyl, mercapto, alkylthio, arylthio (e.g., phenylthio), carboxy, carboxamido, carbalkoxy or sulfonamide; - (C0-Ca) alkyl-aryl; - (C0-C8) alkyl-substituted aryl; - (C0-C8) aryl- (C1-C4) alkyl aryl; - (C 1 -C 8) alkyl-biaryl; - (C0-C8) alkyl-S (O) p- (C0-C8) alkylaryl; - (CVCa) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl; - (C 1 -C 4) alkylaryl- (C0-Ca) alkylaryl- [S (O) p- (C0-C3) alkyl] -; - (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-biaryl; - (C0-C8) alkyl-O- (C0-C8) alkylaryl; - (C0-C8) alkyl-S (O) p- (C0-C8) alkyl-substituted aryl; - (C1-C4) alkylaryl- (C0-C3) alkylaryl] - [O- (C0-Ca) alkyl] -; - (C0-C8) alkyl-O- (C0-C8) alkyl-biaryl; - (C0-C3) alkyl-O- (C0-C8) alkyl-substituted aryl; wherein the substituent is selected from: hydrogen, C 1 -C 5 alkyl, oxo, halo, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carbamido, or aryl; R2 is selected from: hydrogen, -CO2R5, -CONRsR5, -CONRs (OR5), alkyl, alkylaryl, alkylheteroaryl, alkylheterocyclic, aryl, heteroaryl or heterocyclic, substituted with one or more substituents; selected from: hydrogen and halogen; oxy, alkoxy, aryloxy (e.g. phenoxy), amino, monoalkylamino, dialkylamino, acylamino, (e.g. aceramido- and benzamido-), arylamino, guanidine, N-methylimidazolyl, imidazolyl, indole - mercapto, lower alkylthio, arylthio (e.g., phenylthio), carboxy, sulfonamide, carboxamido or carbalkoxy; R8 is selected from: - (CHR1Y) n-R9, -C (R7R8) nWC (R7R8) m-R9, -C (R7R8) m -R5, -C (R7R8) m-aryl, -C (R7R8) m- CONR7R8; -C (R7R8) m-substituted heteroaryl; -C (R7R8) m-heterocyclic groups; R6 is selected from: hydrogen, alkyl, - (C, - C6) alkyl-aryl, - (C 1 -C 6 -alkyl-heteroaryl, - (C, - C 6) alkyl-heterocyclic, - (C 6 -C 6 -alkyl-acyl); R5 and R5 may form a 3-8-membered unsaturated ring containing from 1 to 3 heteroatoms selected from oxygen, -NR6, -S (O) p-groups, or this ring contains an acyl group, optionally attached to the aryl ring; and R8 is repeatedly selected from: hydrogen, R1, or R7 and R8 may form a 3-7 membered substituted ring with 0-3 unsaturated bonds, the ring substituent is selected from: hydrogen, C1-C6alkyl, halogen alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy, carbamido, or aryl, optionally containing -O-, -S (O) p, -NR 5, optionally attached to a substituted aryl ring , this ring substituent is selected from: hydrogen, C 1 -C 5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dial kilamino, acylamino, thio, thioalkyl, carboxy, carboxamido or aryl; R9 is hydrogen, alkyl, cycloalkyl, 5- or membered ring, optionally containing 1 or 2 nitrogen, oxygen or S (O) p, optionally substituted with -OH, -CHCVC1-4alkyl, -O- acylalkyl, NHR10- or aryl; R10 is hydrogen or optionally substituted alkyl; R11 is hydrogen; an alkyl group having 1 to 6 carbon atoms, this alkyl group may be branched, cyclic, and unsaturated; substituted lower alkyl; wherein the substituent is selected from: hydrogen and halogen, oxy, alkoxy, aryloxy (e.g. phenoxy), amino, dialkylamino, acylamino (e.g. acetamido- and benzamido-), arylamino, guanidine, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (e.g. phenylthio), carboxy, carboxamido, carbalkoxy, and sulfonamide; - (C 1 -C 4) a (aryl; - (C 1 -C 5) alkyl-substituted aryl; the substituent of this group is selected from: hydrogen and halogen; oxy, alkoxy, aryloxy (eg phenoxy), amino -, dialkylamino, acylamino (for example, acetamido- and benzamido-), arylamino, guanidino, imidazolyl, indolyl, mercapto, lower alkylthio, arylthio (eg phenylthio), carboxy, carboxamido, carbalkoxy \ t - or for sulfonamido groups, R11a is hydrogen, -SO2- (C1-C3) -alkyl, -SO2- (C1-C8) -alkyl-substituted aryl, -SO2-aryl, -SO2-substituted heteroaryl, -COR9, -C02terc-Bu, CO 2 Bn groups, the substituents of these groups are selected from: hydrogen, C 1 -C 5 alkyl, oxo, halogen, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, thio, thioalkyl, carboxy - carboxamido- or aryl; m is an integer from 0 to 5; 31 LV 12167 π is an integer from 1 to 5; p can be 0, 1 or 2; W is -O-, -S (O) p- or * NR10, Z is CH2 or oxygen; wishes from the -CONR10-, -NR10CO-, -SO2NR1 ° -, -NR10SO2-groups peptide-type bonds, 5-membered heterocyclic saturated, unsaturated or partially unsaturated ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen or \ t sulfur atom. 10. Savienojums saskaņā ar 1. punktu, kuru izvēlas no grupas, kura sastāv no: 25,5/?,65-3-aza-4-okso-10-oksa-5-izobutil-2-(N-metilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 2 5,5 R,6 S-3-aza-4-okso-10-oksa-5-izobutil-2-(karboksimetil)-[10]paraciklofan-6-N-oksikarboksamīda; 2S,5/?,65-3-aza-4-okso-10-oksa-5-izobutil-2-(N-benzilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/?,65-3-aza-4-okso-10-oksa-5-izobutil-2-(oksimetil)-[10]paraciklofan-6-N- oksikarboksamīda; 25,5ff,6S-3-aza-4-okso-10-oksa-5-izobutii-2-(L-alanīn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamīda; 25,5/c?,65-3-aza-4-okso-10-oksa-5-izobutil-2-[L-(0-metil)tirozīn-N-metilamid]- [10]paraciklofan-6-N-oksikarboksamida; 32 25,5/?,65L3-aza-4-okso-10-oksa-5-izobuiil-2-[L-(0-terc-butil)serin-N-metilamid]- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/c?,66;-3-aza-4-okso-10-oksa-5-izobutil-2-(L-senn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamīda; 2S',5yc?,6S-3-aza-4-okso-10-oksa-5-izobutil-2'(glicin-N-metilamid)-[10]paraciklofan-6- N-oksikarboksamida; 2$5#,6S3-aza-4-okso-10-oksa-5-izobutil-2-(D-alanin-N-metilamid)- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/7,65L3-aza-4-okso-10-oksa-5-izobutil-2-(p-alanīn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamida; i?Sr5/?,6S-3-aza-4-okso-10-oksa-5-izobutil-2-[D-(0-terc-butil)serīn-N-metilamid]- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/7,6S-3-aza-4-okso-10-oksa-5-izobutil-2-(D-senn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamīda; 2S,5/9,6S3-aza-4-okso-10-oksa-5-izobutil-2'(L-lizīn-N-metilamid)-[10]paraciklofan-6- N-oksikarboksamīda; 25,5/c?,6S-3-aza-4-okso-10-oksa-5-izobutil-2-(L-valīn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamida; 2S,5/9,6S3-aza-4-okso-10-oksa-5-izobutil-2-[(2-piridil)etilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda-trifluoracetāta; 25,5/?,65L3-aza-4-okso-10-oksa-5-izobuĪil-2-[(4-metil)-piperazinilkarboksamidoj- [10]paraciklofan-6-N-oksikarboksamīda; LV 12167 2S,5/?,6S-3-aza-4-okso-10-oksa-5-izobutil-2-(2-benzimidazolil)-[10]paraciklofan-6-N- oksikarboksamīda; 2S, 5/9,6 S-3-aza-4-okso-10-oksa-5-izobutil-2-[(2-imidazolil)karboksamido]-[IOjparaciklofan-6-N-oksikarboksamīda; 25,5/?,65L3-aza-4-okso-10-oksa-5-izobutil-2-[(2-benzimidazolil)metilkarboksamido]-[10]paraciklofan-6-N-oksikarboksamīda; - 2S',5/ī’,65:-3-aza-4'Okso-10-oksa-5-izobuti[-2-[(3-imidazolil)propilkarboksamido]- [10]paraciklofan-6-N-oksikarboksamida; 2 S, 5 R, 6 S-3-aza-4-okso-10-oksa-5-izobutil-2-[2-(4- aminosulfonilfenil)etilkarboksamido]-[10]paraciklofan-6-N-oksikarboksamida; 25,5/7l65L3-aza-4-okso-10-oksa-5-izobutil-2-(glicīn-N,N-dimetilamid)- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/?,6SL3-aza-4-okso-10-oksa-5-izobutil-2-(1-adamantilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 2S‘,5/9,65:-3-aza-4-oksO'10-oksa-5-izobutil-2-[(4-aminoindazolil)karboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/?,6S-3-aza-4-okso10-oksa-5-izobutil-2-(N,N-dietilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda; 25,5/?,6S-3-aza-4-okso-10-oksa-5-izobutil-2-(N-izopropilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 34 2S,5/c?,6S-3-aza-4-okso-10-oksa-5-izobutil-2-(N-ciklopropilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/?,65-3-aza-4-okso-10-oksa-5-izobutil-2-(N-terc-butilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/?,6S3-aza-4-okso-10-oksa-5-izobutil-2-[glicīn-(N-izopropil)amido]- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/c?,6S:-3-aza-4-okso-10-oksa-5-izobutil-2-[glicīn-(N-etil)amid]-[10]paraciklofan-6- N-oksikarboksamīda; 2S,5/?,6SL3-aza-4-okso-10-oksa-54zobutil-2-[glicīn-(N-ciklopropil)amido]- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/?,6SL3-aza-4-okso-10-oksa-5-izobutil-2-[glicin-(N-terc-butil)amido)- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/?,6S-3-aza-4-okso-10-oksa-5-izobutil-2-[glicīn-(N-ciklobuĪil)amido]- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/i?,65l-3-aza-4-okso-10-oksa-5-izobutil-2-(glicīn-(N-morfolino)amido]- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/c?,6SL3-aza-4-okso-10-oksa-5-izobutiI-2-[glicīn-(N-2-oksidimetiletil)amid- [10]paraciklofan-6-N-oksikarboksamīda; 25;5/c?,6S3-aza-4-okso-10-oksa-5-izobutil-2-[glicīn-(N-etilmetilpropii)amid- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/7,65-3-aza-4-okso-10-oksa-5-izobutil-2-[glicīn-(N-dimetilpropil)amid)- [10]paraciklofan-6-N-oksikarboksamīda; 35 LV 12167 25,5/?,65-3-aza-4-okso-10-oksa-54zobutil4Hglicīn-(N-(di-2-oksimetil)etilamid]- [10]paraciklofan-6-N-oksikarboksamīda; 25,5/9,6S-3-aza-4-okso-10-oksa-5-izobutil-2-[glicīn-4-(oksipiperidīn)amid)- [10]paraciklofan-6-N-oksikarboksamīda; 2S,5/£?,65:-3-aza-4-okso-10-oksa-5-izobūtil-2-(2-benzimidazolkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 2S',5/£?,65L3-aza-4-okso-10-oksa-5-izobūtil-2-[S-(metil)-2-fenilmetilkarboksamido]- [10]paraciklofan-6-N-oksikarboksamīda; 45)7/?-8S-5-aza-6-okso-12-oksa-7-izobutil-2-(karboksimetil)-[12]paraciklofan-8-N- oksikarboksamīda; 45,7/7-8 S-5-aza-6-okso-12Όksa-7-ίzobutil·2-(N-metilkarboksam ido)-[12]paracikiofan-8-N-oksikarboksamīda; 45,7/7-85-5-aza-6-okso-12Oksa-7-izobutil-2-(glicīn-N-metilamid)-[12]paraciklofan-8- N-oksikarboksamida; 25,3/716S-10-terc-butoksikarbonil-5>10-diaza-2-(N-oksikarboksamido)-6-(N- metilkarboksamido)-1-oksa-4-okso-3-(3-fenilprop-1-il)ciklotetradekāna; 25,3/?l65-5,10-diaza-2-(N-oksikarboksamido)-6-(N-metilkarboksarnido)-1-oksa-4-okso-3-(3-fenilprop-1 -il)ciklotetradekāna hidrohlorīda; 25,3/7,65-10-aceti1-5,10-diaza-2-(N-oksikarboksamido)-6-(N-metilkarboksamido)-1- oksa-4-okso-3-(3-fenilprop-1-il)cikiotetradekāna; 36 2S,3/7,6S-10-benzosulfonil -5,10-diaza-2-(N-oksikarboksamido)-6-( N-metilkarboksamido)-1-oksa-4-okso-3-(3-fenilprop-1-il)ciklotetradekāna; 2S,3/?f6S, 12(/7,5)-10-acetil-5,10-diaza-2-(N-oksikarboksamido)-6-(N-metilkarboksamido)-12-metil-1-oksa-4-okso-3-(3-fenilprop-1-il)ciklotridekāria; 25,3/£?,6S:-3-aza-4-okso-10-oksa-5-heksil-2-(karboksimetil)-[10]paraciklofan-6-N- oksikarboksamida; 2S’,3/c?,65:-3-aza-4-okso-10-oksa-5-heksil-2-(oksikarbonil)-[10]paraciklofan-6-N- oksikarboksamīda; 2S,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-((2-metoksietiloksi)karboksil)- [10]paraciklofan-6-N-oksikarboksamīda; 2S,3/c?l65L3-aza-4-okso-10-oksa-5-heksil-2-((2-fenileti!oksi)karboksi)- [10]paraciklofan-6-N-oksikarboksamīda; 2S,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(1-(n-metilkarboksimido)metilkarboksil- [10]paraciklofan-6-N-oksikarboksamida; 2S,3fl,6S-3-aza-4-okso-10-oksa-5-heksil-2-(2-(N- metilaminosulfonil)etilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda; 2S,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(4-(N- metilaminosulfonil)butilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda; 25,3/7,6S-3-aza-4-okso-10-oksa-5-heksil-2-(2-(karbometoksi)etilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 25,3^?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(2-(oksikarbonii)etilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 37 LV 12167 2SI3/9,6S-3-aza-4-okso-10-oksa-5-h8ksil-2-(L-omitīn(4-terc- butoksikarbonil)karboksimetil)-[10]paraciklofan-6-N-oksikarboksamīda; 2S,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(L-ornitīnkarboksimetil)-[10]paraciklofan-6-N-oksikarboksamīda hidrohlorīda; 2S,3/7,6S-3-aza-4-okso-10-oksa-5-heksil-2-(L-ornitīn(4-terc-butoksikarbonil)-N- metilamid)-[10]paraciklofan-6-N-oksikarboksamīda; 2S,3/?,6SL3-aza-4-okso-10-oksa-5-heksil-2-(L-ornitīn-N-metilamid)-[10]paraciklofan-6-N-oksikarboksamīda hidrohlorīda; 2S,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(L-lizīnkarboksamid)-[10]paraciklofan-6- N-oksikarboksamīda; 2S,3R, 6S-3-aza-4-okso-10-oksa-5-heksil-2-(L-serīn(0-terc-butil)-N-metilamid)-[10]paraciklofan-6-N-oksikarboksamīda; 2S,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(L-alanīn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamīda; 2S,3/9,6S-3-aza-4-okso-10-oksa-5-heksii-2-(D-alanīn-N-metilamid)-[10]paraciklofan- 6-N-oksikarboksamida; 2S,3/?,6S3-aza-4-okso-10-oksa-5-heksil-2-(glicīn-N-metilamid)-[10]paraciklofan-6- N-oksikarboksamīda; 25,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(benzilkarboksamido)-[10]paraciklofan-6- N-oksikarboksamīda; 38 25,3/7,6SL3-aza-4-okso-10-oksa-5-heksil-2-(feni!etilkarboksamido)-[10]paraciklofan 6-N-oksikarboksamida; 2S,3/7,65-3-aza-4-okso-10-oksa-5-heksil-2-(difeniletilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda; 25,3/?,65-3-aza-4-oksQ-10-oksa-5-heksil-2-(2-(2-piridil)etilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 25,3/c?,65L3-aza-4-okso-10-oksa-5-heksil-2-(2-(4- sulfonilaminofenil)etilkarboksamido-[10]paraciklofan-6-N-oksikarboksamīda; 25,3/?,6S3-aza-4-okso-10-oksa-5-heksil-2-(2-(3,4-dimetoksifenil)etilkarboksamido) [10]paraciklofan-6-N-oksikarboksamīda; 25,3/?,6SL3-aza-4-okso-10-oksa-5-heksil-2-(2-(4-morfolino)etilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda; 25,3/?,6S-3-aza-4-okso-10-oksa-5-heksil-2-(3-(4-morfolino)propilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda hidrohlorīda; •2 5, 3/7, 6 S-3-aza-4-okso-10-oksa-5-heksil-2-(3-(1 -imidazolil)propilkarboksamido)-[10]paraciklofan-6-N-oksikarboksamīda; 25,3/7,6S-3-aza-4-okso-10-oksa-5-heksil-2-(3-(1-imidazolil)propilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda triftoracetāta; 25,3/?,65-3-aza-4-okso-10-oksa-5-heksil-2-(cikloheksilkarboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 25,3/7,6S-3-aza-4-okso-10-oksa-5-heksii-2-(4-metilpiperazin-1-il-karboksamido)- [10]paraciklofan-6-N-oksikarboksamīda; 39 LV 12167 25,3/7,65-3-aza-4-okso-10-oksa-5-heksil-2-(dimetilkarboksamido)-[10]paraciklofan- 6-N-oksikarboksamīda; 25, 135, 14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-(N-metilkarboksamido)-ciklopentadekān-13-N-oksikarboksamīda; 2 5, 135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[N-(2-piridil)metilkarboksamido)-ciklopentadekān-13-N-oksikarboksamida trifluoracetāta; 2 5, 135,14/?-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[2-(5-metiltiazolil)karboksamido]-ciklopentadekān-13-N-oksikarboksamīda; 2 5,13 5,14/7-1,7-diaza-8,15-diokso-9-oksa-14*izobutil-7-metil-2-[(2-piridil)karboksamido]-ciklopentadekān-13-N-oksikarboksamida; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[(3-piridil)karboksamido]-ciklopentadekān-13-N-oksikarboksamīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[(4-piridil)karboksamido]-ciklopentadekān-13-N-oksikarboksamīda; 2 5,13 5,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[4-(N-etoksikarbonil)pipendīnkarboksamido]-ciklopentadekān-13-N-oksikarboksamīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[4- oksicikloheksilkarboksamido]-ciklopentadekān-13-N-oksikarboksamida; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-(glicīn-N-metilamīd)-ciklopentadekān-13-N-oksikarboksamīda; 40 2 5, 135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-(glicīn-N,N-dimetilamid)-ciklopentadekān-13-N-oksikarboksamīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-(glicīn-2-piridilamīd)-ciklopentadekān-13-N-oksikarboksannīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-(glicīn-2-(3,4,5,6-tetrahidropiridil)amīd]-ciklopentadekān-13-N-oksikarboksamīda; 25,13 5,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[glicīn-N-(4-oksi)piperidīnamid]-cikIopentadekān-13-N-oksikarboksamīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[glicīn-N-pirolidīnamid]-ciklopentadekān-13-N-oksikarboksamīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[glicīn-N-morfolinamīd]-ciklopentadekān-13-N-oksikarboksamīda; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[glicin-(4-metil)-N-piperazinilamīd]-ciklopentadekān-13-N-oksikarboksamīda trifluoracetāta; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-7-metil-2-[glicīn-2-(5-metil)tiazolilamīd]-ciklopentadekān-13-N-oksikarboksamida trifluoracetāta; 25,135,14/7-1,7-diaza-8,15-diokso-9-oksa-14-izobutil-2-[glicīn-N-morfolinoamid]-ciklopentadekān-13-N-oksikarboksamīda; 25,115,12/7-1,7-diaza-8,13-diokso-2-(N-metilkarboksamīdo)-12-izobutilciklotridekān-1 l-(N-oksikarboksamīda); 25,115,12/7-1,7-diaza-8,13-dioksO'12-izobutilciklotridekān-2-(glicin-N-metilamid)-11-(N-oksikarboksamīda); 41 LV 12167 25,115,12/9-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(NK-H-L-lizīn-a-N-H-amīdtrifluoracetāt)-11 -(N-oksikarboksamīda); 25,115,12/9-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(L-alanīn-a-N-metilamīd)-11 -(N-oksikarboksamīda); 25,115,12/9-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(p-alanīn-N-metilamīd)- 11- (N-oksikarboksamīda); 25,115,12/9-1,7-diaza-8,13-diokso-2-(N-metilkarboksamido)-7-N-mezitilēnsuIfonil- 12- izobutilciklotridekān-11 -(N-oksikarboksamida); 2 5,11 5,12 /9-1,7-diaza-8,13-diokso-2-(N-m8tilkarboksamido)-7-N-terc-butiloksikarbonil-12-izobutilciklotridekān-11 -(N-oksikarboksamīda); 25,115,12/9-1,7-diaza-8,13-diokso-2-(N-metilkarboksamido)-12-izobutilciklotridekān--11-(N-oksikarboksamīda) hidrohlorīda; 55,8/9,95-6-aza-2,7-diokso-5-(N-metilkarboksamido)-1-oksa-8- izobutilciklotridekān--9-(N-oksikarboksamīda); 25,115,12/9-7-N-benzolsulfonil-1,7-diaza-8,13-diokso-2-(N-metilkarboksamido)-12-izobutilciklotridekān-11 -(N-oksikarboksamīda); 25,115,12/7-1,7-diaza-8,13-diokso-2-(N-metilkarboksamido)-7-(p-amino-N-benzolsulfonil)-12-izobutilciklotridekān-11 -(N-oksikarboksamīda); 2 5,115,12/9-1,7-diaza-8,13-diokso-2-(N-metilkarboksamido)-7-N-trifluormetānsulfonil)-12-izobutilciklotridekān-11-(N-oksikarboksamīda); 42 25,115,12/7-1,7-diaza-8,13-diokso-2-(N-metilkarboksamido)-7-N-(N-metilimidazolsulfon-4-il)-12-izobutilciklotridekān-11-(N-oksikarboksamīda); 2 5,115,12/7-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(L-norleicin-a-N-metilamid)-11 -(N-oksikarboksamīda); 25,115,12/?-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(L-serīn-a-N-metilamid)-11 -(N-oksikarboksamida); 25,115,12/7-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(glicīn-N-metilamid)-11 -(N-oksikarboksamīda); 25,115,12/7-1,7-diaza-8,13-diokso-12(R)-izobuti!ciklotridekān-2(S)-(glicīn-N-1,2-etilēndiamin-N',N'-dimetilamīd)-11 (S)-(N-oksikarboksamīda); 2 5,115,12 /7-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(glicīn-N-morfolīnoamīd)-11 -(N-oksikarboksamīda); 25,11 5,12/7-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(L-leicīn-a-N-metilamid)-11 -(N-oksikarboksamīda); 25,115,12/7-1,7-diaza-8,13-diokso-12-izobutilciklotridekān-2-(L-treonīn-a-N-metilamid)-11 -(N-oksikarboksamīda);10. A compound according to claim 1 selected from the group consisting of: 25.5 [alpha], 65-3-aza-4-oxo-10-oxa-5-isobutyl-2- (N-methylcarboxamide) - [10] paracyclofan-6-N-oxycarboxamide; 5,5R, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2- (carboxymethyl) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5β, 65-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (N-benzylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5β, 65-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (oxymethyl) - [10] paracyclofan-6-N-oxycarboxamide; 25,5ff, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (L-alanine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 25.5 / c, 65-3-Aza-4-oxo-10-oxa-5-isobutyl-2- [L- (O-methyl) tyrosine-N-methylamide] - [10] paracyclofan-6-N oxycarboxamide; 32 25,5?, 65 L3-Aza-4-oxo-10-oxa-5-isobutyl-2- [L- (O-tert-butyl) serine-N-methylamide] - [10] paracyclofan-6-N oxycarboxamide; 25.5 / c, 66; -3-Aza-4-oxo-10-oxa-5-isobutyl-2- (L-senn-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S ', 5yc, 6S-3-aza-4-oxo-10-oxa-5-isobutyl-2' (glycine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2 $ 5 # 6S3-Aza-4-oxo-10-oxa-5-isobutyl-2- (D-alanine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 25,5 / 7,65L3-Aza-4-oxo-10-oxa-5-isobutyl-2- (p-alanine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; Sr5, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- [D- (O-tert-butyl) serine-N-methylamide] - [10] paracyclofan-6- N-oxycarboxamide; 2S, 5,7,6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (D-senn-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5 / 9,6S3-Aza-4-oxo-10-oxa-5-isobutyl-2 '(L-lysine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 25.5 / c, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (L-valine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5,9,6S3-Aza-4-oxo-10-oxa-5-isobutyl-2 - [(2-pyridyl) ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide trifluoroacetate; 25,5β, 65L3-Aza-4-oxo-10-oxa-5-isobutyl-2 - [(4-methyl) -piperazinylcarboxamide [10] paracyclofan-6-N-oxycarboxamide; LV 12167 2S, 5R, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (2-benzimidazolyl) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5 / 9,6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2 - [(2-imidazolyl) carboxamido] - [10] paracyclofan-6-N-oxycarboxamide; 25,5β, 65L3-Aza-4-oxo-10-oxa-5-isobutyl-2 - [(2-benzimidazolyl) methylcarboxamido] - [10] paracyclofan-6-N-oxycarboxamide; 2S ', 5', 65: -3-Aza-4'-oxo-10-oxa-5-isobutyl [-2 - [(3-imidazolyl) propylcarboxamido] - [10] paracyclofan-6-N-oxycarboxamide ; 2 S, 5R, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- [2- (4-aminosulfonylphenyl) ethylcarboxamido] - [10] paracyclofan-6-N-oxycarboxamide; 25,5 / 7,665L3-Aza-4-oxo-10-oxa-5-isobutyl-2- (glycine-N, N-dimethylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 6SL3-Aza-4-oxo-10-oxa-5-isobutyl-2- (1-adamantylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 2S ', 5,9,65: -3-Aza-4-oxo-10-oxa-5-isobutyl-2 - [(4-aminoindazolyl) carboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (N, N-diethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25,5β, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (N-isopropylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 34 2S, 5β, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (N-cyclopropylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25,5β, 65-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (N-tert-butylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25,5β, 6S3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine- (N-isopropyl) amido] - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 6S: -3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine- (N-ethyl) amide] - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 6SL3-Aza-4-oxo-10-oxa-54zobutyl-2- [glycine- (N-cyclopropyl) amido] - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 6SL3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine (N-tert-butyl) amido) - [10] paracyclofan-6-N-oxycarboxamide; 25,5β, 6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine- (N-cyclobutyl) amido] - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 6,5-3-Aza-4-oxo-10-oxa-5-isobutyl-2- (glycine- (N-morpholino) amido] - [10] paracyclofan-6-N-oxycarboxamide; , 5β, 6SL3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine- (N-2-oxydimethylethyl) amide- [10] paracyclofan-6-N-oxycarboxamide; cis, 6S3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine- (N-ethylmethylpropyl) amide- [10] paracyclofan-6-N-oxycarboxamide; 25.5 / 7.65 -3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine- (N-dimethylpropyl) amide] - [10] paracyclofan-6-N-oxycarboxamide; 35 EN 12167 25,5 /, 65-3-Aza-4-oxo-10-oxa-54zobutyl-4H-glycine- (N- (di-2-oxymethyl) ethylamide] - [10] paracyclofan-6-N-oxycarboxamide; 5, 9,6S-3-Aza-4-oxo-10-oxa-5-isobutyl-2- [glycine-4- (oxypiperidine) amide] - [10] paracyclofan-6-N-oxycarboxamide; 2S, 5R, 65: -3-Aza-4-oxo-10-oxa-5-isobutyl-2- (2-benzimidazolecarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 2S ', 5β, 65L3-Aza-4-oxo-10-oxa-5-isobutyl-2- [S- (methyl) -2-phenylmethylcarboxamido] - [10] paracyclofan-6-N-oxycarboxamide; 45) 7β-8S-5-aza-6-oxo-12-oxa-7-isobutyl-2- (carboxymethyl) - [12] paracyclofan-8-N-oxycarboxamide; 45.7 / 7-8-S-5-Aza-6-oxo-12-oxa-7-oxobutyl · 2- (N-methylcarboxamido) - [12] paracyclofan-8-N-oxycarboxamide; 45.7 / 7-85-5-Aza-6-oxo-12-oxa-7-isobutyl-2- (glycine-N-methylamide) - [12] paracyclofan-8-N-oxycarboxamide; 25,3 / 716S-10-tert-butoxycarbonyl-5 > 10-diaza-2- (N-oxycarboxamido) -6- (N-methylcarboxamido) -1-oxa-4-oxo-3- (3-phenylprop-1) -yl) cyclotetradecane; 25.3-1665-5,10-Diaza-2- (N-oxycarboxamido) -6- (N-methylcarboxadido) -1-oxa-4-oxo-3- (3-phenylprop-1-yl) cyclotetradecane hydrochloride ; 25,3 / 7,65-10-Acetyl-5,10-diaza-2- (N-oxycarboxamido) -6- (N-methylcarboxamido) -1-oxa-4-oxo-3- (3-phenylprop-1) -yl) cyclotetradecane; 36 2S, 3 / 7,6S-10-Benzosulfonyl -5,10-diaza-2- (N-oxycarboxamido) -6- (N-methylcarboxamido) -1-oxa-4-oxo-3- (3-phenylprop- 1-yl) cyclotetradecane; 2S, 3R, 6S, 12 (7.5) -10-Acetyl-5,10-diaza-2- (N-oxycarboxamido) -6- (N-methylcarboxamido) -12-methyl-1-oxa-4 -oxo-3- (3-phenylprop-1-yl) cyclotridecare; 25.3 (R), 6S: -3-Aza-4-oxo-10-oxa-5-hexyl-2- (carboxymethyl) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3β, 65: -3-Aza-4-oxo-10-oxa-5-hexyl-2- (oxycarbonyl) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3R, 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2 - ((2-methoxyethyloxy) carboxyl) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3R, 1665L3-Aza-4-oxo-10-oxa-5-hexyl-2 - ((2-phenylethoxy) carboxy) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3R, 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (1- (n-methylcarboximido) methylcarboxyl- [10] paracyclofan-6-N-oxycarboxamide; 2S, 3F 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (2- (N-methylaminosulfonyl) ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3 /? -3-Aza-4-oxo-10-oxa-5-hexyl-2- (4- (N-methylaminosulfonyl) butylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25.3 / 7.6S-3 -aza-4-oxo-10-oxa-5-hexyl-2- (2- (carbomethoxy) ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25.3 ^, 6S-3-aza-4 oxo-10-oxa-5-hexyl-2- (2- (oxycarbonyl) ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 37 LV 12167 2SI3 / 9,6S-3-aza-4-oxo 10-oxa-5-h8cyl-2- (L-omitine (4-tert-butoxycarbonyl) carboxymethyl) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3R, 6S-3-aza-4-oxo -10-oxa-5-hexyl-2- (L-ornithine carboxymethyl) - [10] paracyclofan-6-N-oxycarboxamide hydrochloride; 2S, 3 / 7,6S-3-aza-4-oxo-10-oxa-5 -hexyl-2- (L-ornithine (4-tert-butoxycarbonyl) -N-methylamide) - [10] paracyclofan -6-N-oxycarboxamide; 2S, 3R, 6SL3-Aza-4-oxo-10-oxa-5-hexyl-2- (L-ornithine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide hydrochloride; 2S, 3R, 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (L-lysine carboxamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3R, 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (L-serine (O-tert-butyl) -N-methylamide) [10] paracyclofan-6-N- oxycarboxamide; 2S, 3R, 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (L-alanine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3,9,9S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (D-alanine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3R, 6S3-Aza-4-oxo-10-oxa-5-hexyl-2- (glycine-N-methylamide) - [10] paracyclofan-6-N-oxycarboxamide; 25,3, 6S-3-Aza-4-oxo-10-oxa-5-hexyl-2- (benzylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 38 25,3 / 7,6SL3-Aza-4-oxo-10-oxa-5-hexyl-2- (phenyl-ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 2S, 3,7,75-3-Aza-4-oxo-10-oxa-5-hexyl-2- (diphenylethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25,3,6,5,5-Aza-4-oxo-10-oxa-5-hexyl-2- (2- (2-pyridyl) ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25.3 / c, 65L3-Aza-4-oxo-10-oxa-5-hexyl-2- (2- (4-sulfonylaminophenyl) ethylcarboxamido- [10] paracyclofan-6-N-oxycarboxamide; 6, 6S3-Aza-4-oxo-10-oxa-5-hexyl-2- (2- (3,4-dimethoxyphenyl) ethylcarboxamido) [10] paracyclofan-6-N-oxycarboxamide; -aza-4-oxo-10-oxa-5-hexyl-2- (2- (4-morpholino) ethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25.3 / 6S-3-aza -4-Oxo-10-oxa-5-hexyl-2- (3- (4-morpholino) propylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide hydrochloride • 2 5, 3/7, 6 S-3 -aza-4-oxo-10-oxa-5-hexyl-2- (3- (1-imidazolyl) propylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25.3 / 7.6S-3-aza -4-Oxo-10-oxa-5-hexyl-2- (3- (1-imidazolyl) propylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide triftoracetate; 4-Oxo-10-oxa-5-hexyl-2- (cyclohexylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25.3 / 7.6S-3-Aza-4-oxo-10-oxa-5 -hexi-2- (4-methylpiperazin-1-yl-carboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 39 LV 12167 25,3 / 7,65-3-Aza-4-oxo-10-oxa-5-hexyl-2- (dimethylcarboxamido) - [10] paracyclofan-6-N-oxycarboxamide; 25,135,14,7,7,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (N-methylcarboxamido) -cyclopentadecane-13-N-oxycarboxamide; 2,5,135,14,7,7,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [N- (2-pyridyl) methylcarboxamido) -cyclopentadecan-13-one N-oxycarboxamide trifluoroacetate; 2,5,135,14,11,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [2- (5-methylthiazolyl) carboxamido] -cyclopentadecan-13-one N-oxycarboxamide; 2,5,13,14,14,7,7-Diaza-8,15-dioxo-9-oxa-14 * isobutyl-7-methyl-2 - [(2-pyridyl) carboxamido] -cyclopentadecan-13-N oxycarboxamide; 25,135,14 / 7-1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2 - [(3-pyridyl) carboxamido] -cyclopentadecane-13-N-oxycarboxamide; 25,135,14 / 7-1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2 - [(4-pyridyl) carboxamido] -cyclopentadecane-13-N-oxycarboxamide; 2,5,13,14,14,7,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [4- (N-ethoxycarbonyl) pipendinecarboxamido] -cyclopentadecan-13 -N-oxycarboxamide; 25,135,14,7,7,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [4-oxycyclohexylcarboxamido] -cyclopentadecane-13-N-oxycarboxamide; 25,135,14 / 7-1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (glycine-N-methylamide) -cyclopentadecane-13-N-oxycarboxamide; 40.25, 135.14-7-1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (glycine-N, N-dimethylamide) -cyclopentadecane-13- N-oxycarboxamide; 25,135,14 / 7-1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (glycine-2-pyridylamide) -cyclopentadecane-13-N-oxycarboxannide; 25,135,14,7,7,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- (glycine-2- (3,4,5,6-tetrahydropyridyl) amide] -cyclopentadecane-13-N-oxycarboxamide; 25.13 5.14-7-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [glycine-N- ( 4-oxypiperidine amide] -cyclopentadecane-13-N-oxycarboxamide; 25,135,14 / 7,1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [glycine] N-pyrrolidinamide] -cyclopentadecane-13-N-oxycarboxamide; 25,135,14 / 7,1,7-Diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [glycine-N- morpholinamide] -cyclopentadecane-13-N-oxycarboxamide; 25,135,14,7,7,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2 - [glycine (4-methyl) ) -N-piperazinylamide] -cyclopentadecane-13-N-oxycarboxamide trifluoroacetate; 25,135,14,7,7,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-7-methyl-2- [glycine -2- (5-Methyl) thiazolylamide] -cyclopentadecane-13-N-oxycarboxamide trifluoroacetate; 25,135,14,7,7,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2- [glycine -N-morpholinoamide] -cyclopentadecane-13-N-oxycarboxamide; 12/7-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamide) -12-isobutylcyclotridecane-1-N- (N-oxycarboxamide); 25,155,12,7,7,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (glycine-N-methylamide) -11- (N-oxycarboxamide); 41 LV 12167 25,155,12 / 9-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecan-2- (NK-H-L-lysine-a-N-H-amide trifluoroacetate) -11- (N-oxycarboxamide); 25,115,12 / 9-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-alanine-α-N-methylamide) -11- (N-oxycarboxamide); 25,115,12 / 9-1,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (p-alanine-N-methylamide) -11- (N-oxycarboxamide); 25,115,12 / 9-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -7-N-mesitylsulfonyl-12-isobutylcyclotridecane-11- (N-oxycarboxamide); 2 5,11 5,12-9,1,7-Diaza-8,13-dioxo-2- (N-mtylcarboxamido) -7-N-tert-butyloxycarbonyl-12-isobutylcyclotridecan-11 - (N-oxycarboxamide); 25,115,12 / 9-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -12-isobutylcyclotridecane-11- (N-oxycarboxamide) hydrochloride; 55,8 / 9,95-6-Aza-2,7-dioxo-5- (N-methylcarboxamido) -1-oxa-8-isobutylcyclotridecane-9- (N-oxycarboxamide); 25,115,12 / 9-7-N-Benzenesulfonyl-1,7-diaza-8,13-dioxo-2- (N-methylcarboxamido) -12-isobutylcyclotridecan-11 - (N-oxycarboxamide); 25,115,12 / 7-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -7- (p-amino-N-benzenesulfonyl) -12-isobutylcyclotridecan-11 - (N-oxycarboxamide); 2,5,155,12 / 9-1,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -7-N-trifluoromethanesulfonyl) -12-isobutylcyclotridecane-11- (N-oxycarboxamide); 42 25,155,12,7,7,7-Diaza-8,13-dioxo-2- (N-methylcarboxamido) -7-N- (N-methylimidazole sulfon-4-yl) -12-isobutylcyclotridecan-11- (N- oxycarboxamide); 2,5,155,12,7,7,7-diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-norleucine-α-N-methylamide) -11- (N-oxycarboxamide); 25,155,12-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-serine-a-N-methylamide) -11- (N-oxycarboxamide); 25,115,12 / 7,1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecan-2- (glycine-N-methylamide) -11- (N-oxycarboxamide); 25,155,12,7,7,7-Diaza-8,13-dioxo-12 (R) -isobutylcyclotridecan-2 (S) - (glycine-N-1,2-ethylenediamine-N ', N'-dimethylamide) ) -11 (S) - (N-oxycarboxamide); 2,5,155,12,7,7,7-Diaza-8,13-dioxo-12-isobutylcyclotridecan-2- (glycine-N-morpholinoamide) -11- (N-oxycarboxamide); 25,11 5,12,7,7,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-leucine-α-N-methylamide) -11- (N-oxycarboxamide); 25,115,12 / 7-1,7-Diaza-8,13-dioxo-12-isobutylcyclotridecane-2- (L-threonine-a-N-methylamide) -11- (N-oxycarboxamide); 11. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 1. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1. 12. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 2. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2. 13. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 3. punktu terapeitiski efektīvo daudzumu. 43 LV 12167A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3. 43 LV 12167 14. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 4. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4. 15. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 5. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5. 16. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 6. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 6. 17. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 7. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7. 18. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 8. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8. 19. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 9. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 9. 20. Farmaceitiska kompozīcija, kura satur farmaceitiski pieņemamu nesēju un savienojuma saskaņā ar 10. punktu terapeitiski efektīvo daudzumu.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 10. 21. Savienojuma saskaņā ar 1. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 1 for the preparation of a medicament for the treatment of inflammation in mammals. 22. Savienojuma saskaņā ar 2. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 2 for the preparation of a medicament for the treatment of inflammation in mammals. 23. Savienojuma saskaņā ar 3. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai. 44Use of a compound according to claim 3 for the preparation of a medicament for treating inflammation in mammals. 44 24. Savienojuma saskaņa ar 4. punktu pielietojums ārstnieciskā preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound of claim 4 for the preparation of a medicament for treating inflammation in mammals. 25. Savienojuma saskaņā ar 5. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 5 for the preparation of a medicament for treating inflammation in mammals. 26. Savienojuma saskaņā ar 6. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 6 for the preparation of a medicament for treating inflammation in mammals. 27. Savienojuma saskaņā ar 7. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 7 for the preparation of a medicament for treating inflammation in mammals. 28. Savienojuma saskaņā ar 8. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 8 for the preparation of a medicament for the treatment of inflammation in mammals. 29. Savienojuma saskaņā ar 9. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.The use of a compound according to claim 9 for the preparation of a medicament for the treatment of inflammation in mammals. 30. Savienojuma saskaņā ar 10. punktu pielietojums ārstnieciska preparāta iegūšanā, kas paredzēts zīdītāju iekaisumu ārstēšanai.Use of a compound according to claim 10 for the preparation of a medicament for the treatment of inflammation in mammals. 31. Pielietojums saskaņā ar vienu no 21.-30. punktiem, kas atšķiras ar to, ka ārstniecisku preparātu ievada orāli.Use according to one of claims 21 to 30. wherein the medicament is administered orally. 32. Analīze, kurā ietilpst: (a) Šķīstošas aggrekanāzes ģenerēšana, stimulējot skrimšļa griezumu; (b) aggrekanāzes fermentatīvas aktivitātes noteikšana, izmantojot šķīstošo aggrekanāzu, kas ģenerēta (a) apakšpunktā, un kontrolējot aggrekāna fragmentu kas satur ARGSVIL gala secības, producēšanu; (c) aggrekanāzes inhibēšanas novērtēšana, salīdzinot produkta, kas producēts savienojuma klātbūtnē un tam iztrūkstot, daudzumu; aggrekanāzes inhibitoru noteikšanai.32. An analysis comprising: (a) Generating soluble aggrecanase by stimulating the cartilage cut; (b) determining the enzymatic activity of aggrecanase using the soluble aggrecanase generated in (a) and controlling the aggrecan fragments containing the final sequences of ARGSVIL; (c) evaluating the inhibition of aggrecanase by comparing the amount of product produced in the absence and absence of the compound; aggrecanase inhibitors.
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