MX2008008517A - Pdf inhibitors - Google Patents
Pdf inhibitorsInfo
- Publication number
- MX2008008517A MX2008008517A MXMX/A/2008/008517A MX2008008517A MX2008008517A MX 2008008517 A MX2008008517 A MX 2008008517A MX 2008008517 A MX2008008517 A MX 2008008517A MX 2008008517 A MX2008008517 A MX 2008008517A
- Authority
- MX
- Mexico
- Prior art keywords
- general procedure
- pyrrolidin
- ester
- pharmaceutically acceptable
- prodrug
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 32
- 239000003112 inhibitor Substances 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 283
- 238000002360 preparation method Methods 0.000 claims abstract description 203
- 125000001151 peptidyl group Chemical group 0.000 claims abstract description 23
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims abstract description 8
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 6
- 230000003115 biocidal Effects 0.000 claims abstract description 6
- 229940064005 Antibiotic throat preparations Drugs 0.000 claims abstract description 5
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 claims abstract description 5
- 229940042052 Antibiotics for systemic use Drugs 0.000 claims abstract description 5
- 229940042786 Antitubercular Antibiotics Drugs 0.000 claims abstract description 5
- 229940093922 Gynecological Antibiotics Drugs 0.000 claims abstract description 5
- 102000005741 Metalloproteases Human genes 0.000 claims abstract description 5
- 108010006035 Metalloproteases Proteins 0.000 claims abstract description 5
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 claims abstract description 5
- 230000000845 anti-microbial Effects 0.000 claims abstract description 5
- 229940079866 intestinal antibiotics Drugs 0.000 claims abstract description 5
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 claims abstract description 5
- 239000004599 antimicrobial Substances 0.000 claims abstract description 3
- -1 2-perimidinyl Chemical group 0.000 claims description 130
- 239000000203 mixture Substances 0.000 claims description 68
- 239000011780 sodium chloride Substances 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 49
- 239000000651 prodrug Substances 0.000 claims description 44
- 229940002612 prodrugs Drugs 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 37
- 150000002148 esters Chemical class 0.000 claims description 31
- 201000010099 disease Diseases 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 206010060945 Bacterial infection Diseases 0.000 claims description 7
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229940010383 Mycobacterium tuberculosis Drugs 0.000 claims description 6
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
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- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 206010062207 Mycobacterial infection Diseases 0.000 claims 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 58
- LJTYNLPHQVDDKN-CQSZACIVSA-N (2R)-2-[[formyl(phenylmethoxy)amino]methyl]hexanoic acid Chemical compound CCCC[C@@H](C(O)=O)CN(C=O)OCC1=CC=CC=C1 LJTYNLPHQVDDKN-CQSZACIVSA-N 0.000 description 55
- SJOVAZAFDANSON-SVRRBLITSA-N 2-[(2S,4R)-4-fluoropyrrolidin-2-yl]-3H-imidazo[4,5-c]pyridine Chemical compound C1[C@@H](F)CN[C@@H]1C1=NC2=CC=NC=C2N1 SJOVAZAFDANSON-SVRRBLITSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 44
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- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
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- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 230000002829 reduced Effects 0.000 description 33
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- 238000006243 chemical reaction Methods 0.000 description 30
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- 125000004432 carbon atoms Chemical group C* 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
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- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
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- 229910052786 argon Inorganic materials 0.000 description 20
- 201000009910 diseases by infectious agent Diseases 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
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- 239000012044 organic layer Substances 0.000 description 19
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- 239000008079 hexane Substances 0.000 description 11
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
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- XKEVDZMTMKDMAT-VIFPVBQESA-N 2-[(2S)-pyrrolidin-2-yl]-1,3-benzoxazole Chemical compound C1CCN[C@@H]1C1=NC2=CC=CC=C2O1 XKEVDZMTMKDMAT-VIFPVBQESA-N 0.000 description 6
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- NRBPDHRILYXIDY-HIFRSBDPSA-N (3R)-3-[(2S)-2-(1,3-benzoxazol-2-yl)pyrrolidine-1-carbonyl]heptanoic acid Chemical compound CCCC[C@H](CC(O)=O)C(=O)N1CCC[C@H]1C1=NC2=CC=CC=C2O1 NRBPDHRILYXIDY-HIFRSBDPSA-N 0.000 description 5
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Abstract
The invention relates to novel compounds that are inhibitors of peptidyl deformylase (PDF). The compounds are useful as antimicrobials and antibiotics. The compounds of the invention display selective inhibition of peptidyl deformylase versus other metalloproteinases such as MMPs. Methods of preparation and uses of the compounds are also disclosed.
Description
PEPTIDIL-DEFORMILAS INHIBITORS A (PDF)
TECHNICAL FIELD This invention is directed to novel compounds, to the uses of these compounds in various medical applications, including the treatment of disorders sensitive to treatment through inhibitors of peptidyl deformylase, such as the treatment of bacterial infections such as tuberculosis, and to compositions pharmaceuticals comprising these compounds.
BACKGROUND OF THE INVENTION Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects one third of the world's population, resulting in nine million new cases of active tuberculosis and two million deaths each year (Kremer, et al Expert Opin Research Drugs, 11 (2002), 1033-1049)). TB is currently treated with a combination of four drugs (isoniazid, rifampin, pyrazinamide, ethambutol) that imposes a very long course of treatment of 6-9 months, usually under the direct observation of a health care provider ( Davies, et al., Expert Opin, Investigation Drugs, 12 (2003), 1297-1312). The main disadvantage of this regimen is the long treatment time, which makes patient comfort and proper implementation a challenge. More than two thirds of patients with tuberculosis do not receive complete and appropriate tuberculosis treatment, which results in a high rate of relapse and emergence of drug resistance. At present, approximately 4% of cases with tuberculosis in the world are resistant to multiple drugs (MDR), that is, resistant to both isoniazid and rifampicin. The tuberculosis of M DR is difficult to cure, with a treatment time of up to 2 years and a high failure rate. Newer tuberculosis drugs are much needed to shorten the treatment time and to treat multidrug-resistant tuberculosis in a more effective way. The treatment of microbial infection in host organisms requires an effective means to kill the microbe while doing very little damage to the host. As a result, agents that aim for unique characteristics for a micro organism that causes pathology are desired for the treatment. Metalloproteinases are critical for many aspects of normal metabolism. The class known as matrix metalloproteinases (M MPs) are involved in tissue remodeling, such as degradation of the extracellular matrix. Disorders involving metalloproteinases have been implicated in several diseases such as cancer, arthritis and autoimmune diseases. Due to the importance of M M PS in normal physiological procedures, it may be preferable to develop agents that inhibit peptidyl deformylase (PDF) while avoiding a significant inhibition of MMPs.
Alternatively, PDF inhibitors, which also inhibit MM Ps, may be of use when the therapeutic benefits for inbreeding PDF exceed the risk of side effects of MMP inhibition. In this way, compounds using hydroxyamic acid or N-formyl-hydroxylamine as chelators exhibit appreciable antibacterial activity and in vivo efficacy, include oral activity. The N-formyl hydroxylamine derivatives are described in International Patent Application WO 99/39704 and WO 02/102790. As expected, PDF inhibitors can treat infections caused by bacteria resistant to currently available drugs. However, resistance to PDF inhibitors has also been extensively studied (Clements, et al., Antimicrob Agents Chemother 45 (2001), 563-570; Margolis et al., Antimicrob., Agents Chemother., 44 (2000), 1825). - 1831, and Margolis, et al., Antimicrob Agents Chemother, 45 (2001) 2432-2435). The in vitro frequency of mutation to resistance is low for Streptococcus pneumoniae and Haemphilus influenzae, the two main respiratory infection pathogens. For Staphylococcus aureus, a higher resistance frequency is observed, but these resistant mutants appear to be less virulent in vivo. In view of the importance of identifying new antibiotics to treat bacteria resistant to existing antibiotics, it is desirable to develop novel PDF inhibitors for evaluation and use as antibacterial and antimicrobial agents. The present invention satisfies this need.
BRIEF DESCRIPTION OF THE INVENTION
In a first aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:
where n is 1 or 2; X is CH2, S or CHF; R1 is -N (OH) CHO or -C (O) NH (OH) R2 is alkyl, alkylcycloalkyl or alkylaryl, or R2 represents a cycloalkyl group, wherein the carbon adjacent to the carbonyl group forms part of the cycloalkyl ring; R3 is a substituent of formula (a) or (b), or tetrazolyl, 2-perimidinyl or 4-phenylimidazol-2-yl;
(a) (b)
where Y is NH, O, S or NR4; A, B, D and E each independently are selected from CH, N or CR5; or A and E are CH and B and D are fused to and form part of an aryl ring or a nitrogen heterocycle with 5 or 6 members; R 4 is hydroxy alkyl, alkyl or heteroalkyl; R5 is haloalkyl, heterocycle optionally substituted by an alkyl, halogen, alkyl, amino, cyano, nitro, aryl, alkoxy, haloalkoxy, -CO2R7, -SO2R8, NHC (O) R9 or -NHSO2R9 group; or two R5 groups together form a 6-membered oxygen-containing heterocycle, optionally substituted with one or more halogens and fused to the 6-membered ring of substituents (a); R6 is amino or alkoxy; R7 is H, alkyl, NHR10, NR10R11 or NH2; R8 is aryl, heterocycle, alkyl or amino; R9 is heteroaryl or aryl; and R 10 and R 11 each independently is an alkyl, alkenyl, alkynyl or aryl group. Preferably n is 1. It is also preferred that X is CH2 or CHF. Preferably, R1 is -N (OH) -CHO. It is also preferred that R3 is a substituent of formula (a). It is also preferred that R3 is a substituent of formula (a) and Y is O, or NH. Most preferably, R3 is a substituent of the formula (a) and R5 is trifluoromethyl, 4-Me-piperizin-1-yl, fluoro, chloro, methoxy, amino, methyl, cyano, t-butyl, phenyl, nitro, trifluorimethoxy, -SO2NH2, -SO2 (morpholino), -SO2Et, -CO2Me, -CO2Et, -NHC (O) (2-pyrazinyl) or -NHSO2Ph, or two groups R5 together form a substituent (i) or (ii): (» )
Preferably, R2 is lower alkyl, lower alkylcycloalkyl or lower alkylaryl. Most preferably, R 2 is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl or benzyl, or R 2 is a cycloalkyl group, wherein the carbon adjacent to the carbonyl group forms part of the cyclohexyl ring. Most preferably R2 is n-butyl. It is preferred that B and D are fused to a phenyl ring or a pyrazole ring. Alternatively, it is preferred that R3 is a substituent of formula (b) and R6 is amino or ethoxy. It is preferred that R 4 is heteroalkyl, most preferably an alkyl group having an alkoxy substituent. Most preferably R 4 is hydroxyethyl, methoxyethyl or methyl. In one embodiment, the invention provides a compound of the formula (I '), or a pharmaceutically acceptable salt, ester or prodrug thereof:
wherein R2 is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl or benzyl;
X is CH2, or CHF; And it's NH, O, or S; and A, B, D and E are each independently CH, N or CR5; wherein R5 is as defined in claim 10. Preferably, R2 in the compound of the formula (I ') is n-butyl. It is also preferred that Y in the compound of the formula (I ') is NH or O. In some preferred embodiments, A in the compound of the formula (I) or (I') is N. It is also preferred that B and E both are N. Preferably, X in the compound of the formula (I) or (I ') is
CH2 Alternatively, preferably X in the compound of the formula (I) or (I ') is CHF. In another aspect, the invention provides a pharmaceutical composition comprising a compound of the formula (I) or (I ') as defined above, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with an excipient, diluent or pharmaceutically acceptable vehicle. In yet another aspect, the invention provides a method for treating and / or preventing a disease or disorder responsive to treatment by inhibitors of peptidyl deformylase, which comprises administering a subject in need thereof., an effective inhibitory amount of peptidyl deformylase of a compound of the formula (I) or (I ') as defined above, a pharmaceutically acceptable salt, ester or prodrug thereof. In still another aspect, the invention provides the use of an effective inhibitory amount of peptidyl deformylase of a compound of the formula (I) or (T) as defined above, a pharmaceutically acceptable salt, ester or prodrug thereof, in the manufacture of a medicament for treating and / or preventing a disease or disorder responsive to treatment through peptidyl deformilase inhibitors. In another aspect, the invention provides a pharmaceutical composition for treating and / or preventing a disease or disorder responsive to treatment by inhibitors of peptidyl deformylase, comprising a compound of formula (I) or (I ') as defined above, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable excipient, diluent or carrier. Preferably, the disease or disorder is a bacterial infection. Most preferably, the bacterial infection is an infection by microbacteria. Even more preferably, infection by mycobacteria is caused by Mycobacterium tuberculosis. Preferably, infection by mycobacteria is caused by a multi-drug resistant form of Mycobacterium tuberculosis.
DETAILED DESCRIPTION Definitions Unless otherwise indicated, the following terms as used in the specification have the following meanings. The term "aliphatic group" refers to unsaturated or saturated unsaturated groups, such as alkyl, alkenyl or alkynyl, cycloalkyl or substituted alkyl including straight or branched chain groups and cyclic groups having 1 to 10 carbon atoms. The term "alkyl" or "alk" as used herein, refers to a straight or branched chain, saturated aliphatic group of 1-10 carbon atoms. The term "lower alkyl" refers to alkyl of 1 to 6 carbon atoms. Preferably, the alkyl groups are alkyl of 1 to 7 carbon atoms, in particular alkyl of 1 to 4 carbon atoms. Examples of "alkyl" or "alk" include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, / -butyl, sec-butyl, f-butyl, n-pentyl, neopentyl, n -hexyl, n-heptyl, cyclopropyl, especially n-butyl. The term "cycloalkane" or "cycloalkyl" refers to a saturated or partially saturated (non-aromatic) ring preferably comprising from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The "cycloalkane" or "cycloalkyl" groups preferably contain from 3 to 7 carbon atoms in the ring. Any alkyl group as defined above may be substituted with one or more substituents, preferably 1 to 3 substituents, including, but not limited to, substituents such as halogen, lower alkoxy, hydroxy, mercapto, carboxy, cycloalkyl, aryl, heteroaryl and Similar. Examples of such substituted alkyl groups include, but are not limited to, haloalkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl and pentafluoroethyl or other substituted alkyl groups such as hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2-carboxyethyl and the like. The term "aryl" or "Ar" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having an individual ring (including, but not limited to, groups such as phenyl) or multiple fused rings (including, but not limited to) limited to, groups such as naphthyl or anthryl), and especially phenyl. The term "carbonylamine" as used herein refers to a group -NHC (O) -, wherein the amino portion of the group is linked to the aryl / heteroaryl and the carbonyl portion of the group is linked to the azacyclo-alkane of 4 to 7. carbon atoms, thiazacycloalkane of 4 to 7 carbon atoms or imidazacycloalkane of 4 to 7 carbon atoms. The term "heteroaryl" or "HetAr" refers to a 4- to 7-membered monocyclic aromatic heterocycle or a bicyclo which is composed of a 4 to 7 membered monocyclic aromatic heterocycle and a fused benzene ring. The heteroaryl has at least one heterogeneous atom, preferably at least two heterogeneous atoms including, but not limited to, heterogeneous atoms such as N, O, and S, within the ring. A preferred heteroaryl portion is a 5- or 6-membered monocyclic heterocycle, having 1, 2, 3 or 4 heterogeneous nitrogen atoms in the ring. Examples of heteroaryl groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazinyl piperizinyl N-oxide, benzodioxolanyl, morpholino, triazine, thiazolyl or tetrazolyl. An aryl or heteroaryl group may be unsubstituted or substituted by one or more substituents including, but not limited to, alkyl of 1 to 7 carbon atoms, in particular alkyl of 1 to 4 carbon atoms such as methyl, hydroxy, alkoxy, acyl, acyloxy, SCN, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl, halogen and formyl. The term "heteroalkyl" refers to alkyl of 1 to 8 carbon atoms saturated or unsaturated as defined above, and especially heteroalkyl of 1 to 4 carbon atoms containing one or more heterogeneous atoms, as part of the main chains, branched or cyclical in the group. The heterogeneous atoms can independently be selected from the group consisting of -NR-, wherein R is hydrogen or alkyl, -S-, -O- and -P; preferably -NR- wherein R is hydrogen or alkyl, and / or -O-. Heteroalkyl groups can be attached to the rest of the molecule either in a heterogeneous atom (if a valence is available) or to a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups such as -O-CH3, -CH2-O-CH3, -CH2-CH2-O-CH3, -S-CH2-CH2-CH3, -CH2-CH ( CH3) -S-CH3, and -CH2-CH2-NH-CH2-CH2-, The heteroalkyl group may be unsubstituted or substituted with one or more substituents, preferably one to three substituents, including, but not limited to, alkyl, halogen, alkoxy, hydroxyl, mercapto, carboxy, and especially phenyl. The heterogeneous atom (s) as well as the carbon atoms of the group may be substituted. The heterogeneous atom (s) may also be in an oxidized form. The term "alkoxy" as used herein, refers to an alkyl of 1 to 10 carbon atoms or alkenyl linked to an oxygen atom. Alkoxy is preferably alkoxy of 1 to 7 carbon atoms, most preferably alkoxy of 1 to 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, n-butoxy, re-butoxy and ali loxy. The term "acyl" as used herein refers to the group -C (O) R wherein R is alkyl, especially alkyl of 1 to 7 carbon atoms, such as methyl. Examples of acyl groups include, but are not limited to, acetyl, propanoyl and butanoyl. The term "acyloxy" as used herein refers to the group -OC (O) R, wherein R is hydrogen, alkyl, especially alkyl of 1 to 7 carbon atoms such as methyl or ethyl, or phenyl or substituted alkyl as defined previously. The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, iodine, and especially is fluorine or chlorine. The term "thioalkoxy" as used herein means a group -SR, wherein R is an alkyl as defined above, for example, methylthio, ethylthio, propylthio, butylthio, and the like. The term "heteroarylalkyl" as used herein means a heteroalkyl group, for example, -O-CH2- substituted with an aryl group, especially phenyl. The same phenyl group may also be substituted with one or more substituents such as halogen, especially fluoro or chloro, and alkoxy such as methoxy. The term "alkylsulfonyl" as used herein means a group -SO2R, wherein R is alkyl, especially alkyl of 1 to 7 carbon atoms, such as methylsulfonyl. The term "alkylcycloalkyl" as used herein represents -R-cycloalkyl, wherein R is an alkyl group as defined above. Examples include cyclopentylmethyl. The term "alkylaryl" as used herein represents -R-aryl wherein R is alkyl group as defined above. Examples include benzyl. "Protective group" refers to a chemical group that exhibits the following characteristics: 1) selectively reacts with the desired functionality in a good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to produce the desired functionality and 3) is removable in good yield through reagents compatible with the other functional groups present or generated in said projected reactions. Examples of suitable protecting groups can be found in the publication of Greene et al. , "Protective Groups in Organic Synthesis", 2nd Ed. , John Wiley & Sons, I nc. , New York (1 991). Preferred protective protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBDMS), 9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such such as 6-nitroveratryloxycarbonyl (Nvoc), nitropiperonil, pyrenylmetroxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzyl, 5-bromo-7-nitroindolinyl, and the like. Preferred hydroxy-protecting groups include Fmoc, TBDMS, photolabile protective groups (such as nitroveratril oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether). Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy-methyloxycarbonyl). It will be appreciated that the compounds of the formula (I) may exist in the form of optical isomers, racemates or diastereoisomers, for example, optical isomers in the R- or S- configuration. It should be understood that the present invention encompasses all enantiomers and mixtures thereof. Similar considerations apply in relation to starting materials that exhibit symmetric carbon atoms as mentioned. The compounds of the invention can exist in the form of solid crystalline salts. Preferably, the crystalline salts are metal salts, preferably divalent metals, although for some compounds it is possible to form crystalline solids using monovalent ions, such as Na. The counter ion is preferably Mg, Ca or Zn.
The compounds of the invention can typically be in the form of a mixed hydrate or solvate / hydrate. Typically, the crystalline salt of the invention contains about 2 to 8 hydration waters, more typically about 2 to 6 hydration waters, and even more preferably 2 to 4 hydration waters. In this manner, the crystalline salt of the invention typically contains more than 2% water, approximately more than 4 to about 12% water, and most preferably about 8 to about 9% water. The solvates can be from one or more organic solvents, such as lower alkyl alcohols, such as methanol, ethanol, isopropanol, butanol or mixtures thereof. The compounds of the invention, for example, the compounds of the formula (I), can exist in free form or in salt form, for example, in the form of a pharmaceutically acceptable salt. A "pharmaceutically acceptable salt" of a compound means a physiologically and pharmaceutically acceptable salt that possesses the desired pharmacological activity of the parent compound and does not impart undesirable toxicological effects. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1-2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid , 2-toluenesulfonic acid, camphor-lonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. A compound of the invention, for example, the compounds of the formula (I), can act as a prodrug. "Prodrug" means any compound that releases a drug of active origin according to formula (I) in vivo when said prodrug is admistrated to a mammal. The prodrugs of a compound in the formula (I) are prepared by modifying functional groups present in the compound of the formula (I) in such a way that the modifications can be divided in vivo to release the parent compound. Prodrugs include compounds of the formula (I), wherein a hydroxy, amino or sulfhydryl group is attached to any group that can be divided in vivo to regenerate the free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives), carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy-functional groups in the compounds of the invention. Formula (I) and the like. Functional derivatives of the compounds of the formula (I) include, for example, acid chloride, acid anhydride, or activated ester.
Compounds of the Invention The compounds of the present invention can be used for the treatment or prevention of infectious disorders caused by a variety of prokaryotic / eukaryotic bacteria and organism. The compounds of the present invention are especially useful for the treatment of patients infected with Mycobacterium tuberculosis, including strains that are resistant to multiple drugs. Other diseases, less known and usually not taken into account, can also be treated with the compounds of the present invention. Examples include, but are not limited to, Mycobacterium avium (usually a secondary infection in patients with AIDS); Mycobacterium ulcerans (Buruli ulcer). Parasitic diseases caused by eukaryotic protists such as Plasmodium flaciparum (malaria), Plasmodium vivax (malaria), Trypanosoma brucei (sleeping sickness), Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kalazar), and Leishmania major (Leishmaniosis), are other diseases that can be treated using the compounds of the present invention. The compounds of the present invention have optimal PK properties and are particularly suitable for chronic treatment. In addition, the compounds have a reduced or eliminated inhibition of CYP450 and MMP, as well as a reduced release of aromatic amines in vivo, an important feature to avoid methemoglobinemia. The compounds of the invention also preferably have improved safety, toxicity and pharmacokinetic properties, for example, a reduction or elimination of potential adverse events in humans relative to the prior art compounds. The IC 50 values of the compounds of the formula (I) determined for zinc containing peptidyl deformylase range from about 0.001 μM to about 0.2 μM. Preferably, the IC 50 values of the compounds of the formula (I) are below 0.2 μM, preferably below 0.1 μM, still most preferably below 0.05 μM, and preferably below 0.01 μM. The IC 50 values of the compounds of the formula (I) determined for nickel-containing peptidyl deformylase range from about 0.005 μM to about 3 μM. Preferably the IC 50 values of the compounds of the formula (I) are below 3 μM, preferably below 2 μM, preferably below 1.5 μM, most preferably below 1 μM, preferably below 0.5 μM, preferably below 0.1 μM and most preferably below 0.01 μM. In one aspect, compositions are provided for treating or preventing infectious disorders, comprising a compound of the invention, a pharmaceutically acceptable salt thereof or a prodrug thereof, as described herein in combination with a pharmaceutically acceptable carrier. In another embodiment, said compositions further include another therapeutic agent. In one aspect, a dose amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a prodrug thereof is provided, as described herein in an amount effective for the treatment, prevention or amelioration of a disorder, such as an infectious disorder These compounds or their derivatives can be classified for activity against different microbial agents and the appropriate doses can be determined using methods available in the art. The compounds of the invention can be used to treat a subject, to treat, prevent or reduce the severity of an infection. The subjects include animals, plants, blood products, crops and surfaces such as those of medical or research equipment, such as glasses, needles, surgical equipment and tubing, and objects intended for temporary or permanent implantation in an organism. Preferred animals include mammals, for example, mice, rats, cats, dogs, cows, sheep, pigs, horses, primates, such as monkeys, rhesus, chimpanzees, gorillas and most preferably humans. The treatment of a subject includes, but is not limited to, preventing, reducing, or eliminating the clinical symptoms caused by an infection of a subject by an organism; preventing, reducing or eliminating an infection of a subject by a microorganism; or prevent, reduce or eliminate the contamination of a subject by a microorganism. The microorganism involved is preferably a prokaryote, most preferably a bacterium or a eukaryotic protista. In one aspect, methods are provided for treating or preventing an infectious disorder in a subject, such as a human or other animal., which is sensitive to the inhibition of peptidyl deformylase, by administering to the subject an effective inhibitory amount of peptidyl deformylase of a compound of the invention, a pharmaceutically acceptable salt thereof or a prodrug thereof. In one embodiment, the compound or its derivative is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier. The compound of the invention, its pharmaceutically acceptable salt or its prodrug can be administered alone or in combination with another therapeutic agent. Examples of such therapeutic agents include, but are not limited to β-lactam, quinolone, macrolide, glycopeptide and oxazolidinone. As used herein, an "infectious disorder" and any disorder characterized by the presence of a microbial infection, such as the presence of bacteria. Such infectious disorders include, for example, tuberculosis and multidrug-resistant tuberculosis, infections of the central nervous system, infections of the outer ear, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, infections of the eyes, infections of the the oral cavity, such as infections of teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, infections of bones and joints, infections of the skin and skin structure, bacterial endocarditis, burns, antibacterial prophylaxis surgery antibacterial prophylaxis in immunosuppressed patients, such as patients receiving chemotherapy for cancer, or patients with organ transplantation and chronic diseases caused by infectious organisms, for example, arterioscle rosis The compounds and compositions comprising the compounds can be administered through routes such as topically, locally or systemically. Systemic application includes any method for introducing the compound into the tissues of the body, for example, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, nasal, vaginal, rectal and oral. The specific dose of the antimicrobial that will be administered, as well as the duration of the treatment, can be adjusted as necessary. In another aspect of the present invention, methods for inhibiting peptidyl deformylase are provided. In one embodiment, the method comprises administering to a subject in need thereof an inhibitory amount of effective peptidyl deformylase of a compound of the formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof. The terms "subject" and "effective inhibitory amount of peptidyl deformylase" are as defined above. In still another aspect of the invention, there is also provided the use of a compound of the formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof in the preparation of a medicament for use in the treatment of diseases mediated by agents Infectious agents that express biologically active peptidyl deformilase.
Other aspects The present invention also provides pharmaceutical compositions comprising a bioactive compound of the formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier. Compositions of the invention include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in a subject such as animals, preferably mammals, most preferably humans. The pharmaceutical compositions may also include another therapeutic agent as described below. Antibiotic compounds, also referred to herein as antimicrobial compounds, according to the invention can be formulated to be administered in any convenient form for use in human or veterinary medicine, through analogy with other antibiotics. Such methods are known in the art (see, for example, Remington's Pharmaceutical Sciences, Easton, PA: Mack Publishing Co.) and are not described in detail here. The composition can be formulated to be administered through any route known in the art, such as subdermal, inhalation, oral, topical or parenteral. The compositions may be in any form known in the art, including, but not limited to tablets, capsules, wafers, rapid fusions (without wafers), powders, granules, troches, creams or liquid preparations, such as oral or parenteral solutions or suspensions. sterile The compounds can also be administered in liposomal, micellar or microemulsion formulations. The compounds can also be administered as prodrugs, wherein the experimentally administered prodrug biotransformation in the treated mammal into a form that is biologically active. Topical formulations of the present invention can be presented, for example, as ointments, creams or lotions, solutions, balms, emulsions, plasters, eye ointments and drops for the eyes or ears, impregnated bandages, transdermal patches, sprays and aerosols , and may contain appropriate conventional additives such as preservatives, solvents, to aid penetration of the drug, and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such vehicles may be present, for example, from about 1% to about 99% of the formulation. For example, they can form up to about 80% of the formulation. Tablets and capsules for oral administration may be in a unit dose presentation form, and may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet-forming lubricants, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegration agents, for example, potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in standard pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily ethers such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or ascorbic acid, and, if desired, conventional flavoring or coloring agents. For parenteral administration, fluid unit dose forms are prepared using the compound of a sterile vehicle, water is preferred. The compound, depending on the vehicle in the concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. To prepare solutions, the compound can be dissolved in water for injection and filtered in sterile form before filling in a suitable vial or ampoule and sealed. Advantageously, agents such as a local anesthetic preservative and pH regulating agents can be dissolved in the vehicle. To improve the stability, the composition can be frozen after filling in the flask and the water is removed under vacuum. The dried lyophilized powder is then filled into the bottle and an attached water bottle for injection can be supplied to reconstitute the liquid before use. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization can not be achieved through filtration. The compound can be sterilized through exposure to ethylene oxide before being suspended in the sterile vehicle. Advantageously, an active surfactant and wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain, for example, from about 0.1% by weight to about 99% by weight, for example about 10-60% by weight of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will contain, for example, about 1-1000 mg of the active ingredient. The dose of the compound of the invention will vary with the compound employed, the mode of administration, the treatment desired and the indicated disease, as well as other factors such as age, body weight, general health and sex of the patient. For example, the dose as employed for treatment of an adult human will vary, for example from about 1-3000 mg per day, for example 1500 mg per day, depending on the route and frequency of administration. Said dose corresponds to approximately 0.015-50 mg / kg per day. Conveniently, the dose is, for example, about 5-20 mg / kg per day.
Representative pharmaceutical formulations containing a compound of the formula (I) are described below. The present invention also provides a method for preparing a compound of the invention, for example, a compound of the formula (I), said process comprises reacting a compound of the formula (A7):
A-7
wherein R2 is as defined herein, with a compound of the formula (E5):
(E-5)
wherein X is CH2 or C H F; and A, B, D, E, is CH, N, or CR5 as defined herein. The present invention also provides a method for preparing a compound of the invention, for example, a compound of the formula (I), said process comprising reacting a compound of the formula (A7): A-7
with one of the following compounds:
wherein X is CH2 or CHF; and A, B, D, E is CH, N, or CR5 as defined herein. The above reactions can be carried out according to methods known in the art or as described in the Examples below. The reaction can conveniently be carried out in the presence of a base and then followed by hydrogenation, preferably in the presence of a hydrogenation catalyst. Suitable bases include, for example, Hunig's base (ie, diisopropylethylamine) and inorganic bases such as sodium bicarbonate. The hydrogenation catalyst, preferably and palladium catalyst, for example, palladium on carbon or palladium black, can then be added to the resulting product, for example, after concentration and stirred under a hydrogen atmosphere, for example for about 16 hours. to approximately 24 hours. The palladium catalyst can be added preferably from about 5 mol% to about 10 mol% of the concentrated product. The invention also contemplates other peptide deformylase inhibitors which are described below. The compound N-. { (R) -2-Cyclopentylmethyl-3-oxo-3 - [(S) -2 (1 H -tetrazol-3-yl) -pyrrolidin-1-yl] -propyl} -N-Hydroxy-formamide that has the structural formula:
and a method for making the same, said process comprises reacting (R) -2 - [(benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-pripionic acid A-7 (preparation described in general procedure A) and (S) -5-pyrrolidin-2-yl-1 H-tetrazole H-2 (the preparation is described in General Procedure H) according to General Procedure B. The N-hydroxy-N- compound. { (R) -2 - [(S) -2 - [(S) -2- (1 H -tetrazol-5-yl) -pyrrolidin-1-carbonyl] -heptyl} -formamide that has the structural formula:
and a method for doing the same, which comprises reacting (R) -2 - [(benzyloxy-form-yl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S (-5-pyrrolidin-2-yl-1 H-tetrazole H-2 (the preparation is described in General Procedure H) in accordance with General Procedure B. The hydroxyamide compound of acid (R) -3 - [(S) -2- (1 H-benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] -heptanoic having the chemical structure:
and a process for preparing the same, said process comprises reacting a compound of the formula (D 1) with a compound of the formula (E5) according to General Procedure D. The hydroxyamide compound of acid (R) -3 - ((S) -2-benzooxazol-2-yl-pyrrolidin-1 -carbonyl) -heptanoic having the chemical structure:
and a process for preparing the same, said process comprises reacting a compound of the formula (D 1) with a compound of the formula (F5) according to General Procedure D. The acid compound (R) -3- ( (S) -2-benzooxazol-2-yl-pyrrolidin-1 -carbonyl) -heptanoic having the chemical structure:
with a compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and (S) -2-pyrrolidin-2-yl-benzooxacol F -5 (the preparation is described in general procedure F) according to General Procedure D. The methoxy-methyl-amide compound of R) -3 - ((S) -2-benzooxazol-2-yl-pyrrolidin- 1 -carbonyl) -heptanoic having the chemical structure:
said compound is prepared from (R) -3 - ((S) -2-benzooxazol-2-yl-pyrrolidin-1-carbonyl) -heptanoic acid (the preparation is described in Example 61) and O, N- dimethyl hydroxylamine commercially available through treatment with EDC / HOBt in DMF. The amide compound of (R) -3 - ((S) -2- (1 H -benzomidazol-2-yl-pyrrolidin-1-carbonyl) -heptanoic acid having the chemical structure:
which is prepared through the treatment of (R) -3 - [(S) -2- (1 H-benzoimidazol-2-yl) -pyrrolidin-1-carbonyl] -heptanoic acid (the preparation is described in the example 60) with ammonia in methanol. The amide compound of (R) -3 - ((S) -2-benzooxazol-2-yl-pyrrolidin-1-carbonyl) -heptanoic acid having the chemical structure:
said compound is prepared through treatment of (R) -3 - ((S) -2-benzooxazol-2-yl-pyrrolidin-1 -carbonyl) -heptanoic acid (the preparation is described in example 61) with ammonia in methanol.
The compound N-hydroxy-N-. { (R) -2 - [(S) -2- (5-phenyl-1 H -imidazol-2-yl) -pyrrolidin-1 -carbonyl] -hexy} -formam that has the structure q u mmica:
said compound is prepared from (R) -2 - [(benzyloxy-form-yl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in
General Procedure A) and 5-Phenyl-2- (S) -pyrrolidin-2-yl-1 H-imidazole
G2 (the preparation is described in General Procedure G) according to General Procedure B. Compound N-. { (R) -2-Cyclopentylmethyl-3-oxo-3 - [(S) -2- (5-phenyl-1 H-im-idazol-2-yl) -pyrrolidin-1-yl] -propyl} -N-Hydroxy-formamide that has the chemical structure:
said compound is prepared from (R) -2 - [(benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and 5-Phenyl- 2- (S) -pyrrolidin-2-yl-1 H-imidazole G2 (the preparation is described in General Procedure G) according to General Procedure B. The amide compound of 2 - ((S) -1- {. (R) -2 - [(formyl-hydroxy-amino) -methyl] -hexanoyl.} - pyrrolidin-2-yl) -thiazole-4-carboxylic acid having the chemical structure:
said compound is prepared from (R) -2 - [(benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2-acid amide -Pyrrolidin-2-yl-thiazole-4-carboxylic acid J-4 (the preparation is described in General Procedure J) according to General Procedure C. The ethyl ester compound of 2 - ((S) -1- { (R) -2 - [(formyl-hydroxy-amino) -methyl] -hexanoyl.} - pyrrolidin-2-yl) -thiazole-4-carboxylic acid, which has the chemical structure:
said compound is prepared from (R) -2 - [(benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and ethyl ester of (S) - 2-pyrrolidin-2-yl-thiazole-4-carboxylic acid J-4 (the preparation is described in General Procedure J) according to General Procedure C. Since the production of the starting materials is not particularly described, the Compounds of the starting material are known or can be prepared analogously to methods known in the art, or as the examples presented hereinafter are described. All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same degree as if each individual patent, patent application or publication were thus individually observed.
Abbreviations AcOH, HOAc = acetic acid Ac2O = acetic anhydride BOC, Boc = t-butyloxycarbonyl DCM = dichloromethane DIEA = diisopropylethylamine DMF = dimethylformamide DMSO = dimethyl sulfoxide Et = ethyl EtOAc = ethyl acetate Fmoc, FMOC = 9 fluorenylmethyloxycarbonyl HATU = O- (7-aza-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate MCPBA = meta-chloroperoxy-benzoic acid Me = methyl Ph = phenyl MeOH = methanol MMP = matrix metalloproteinase NVOM = nitroveratryloxymethyl ether p-TSA = p-toluenesulfonic acid RT = room temperature TFA = trifluoroacetic acid tBu = t-butyl THF = tetrahydrofuran THP = 2-tetrahydropyranyl TsOH or p-TSA = toluenesulfonic acid
GENERAL SYNTHETIC METHODS The compounds of this invention can be made by the methods illustrated in the reaction schemes presented below. The starting materials and reagents used to prepare these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA) or are prepared by methods known to those skilled in the art following the procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) , and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications can be made to these schemes and will be suggested to those skilled in the art having reference to this disclosure. The starting materials and intermediates of the reaction can be isolated or purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectrum data.
Preparation of the compounds of the formula (I) The compounds of the formula (I) can be prepared by methods well known in the art of organic chemistry. Representative synthetic procedures for preparing compounds of the present invention are illustrated and described in detail below. For example, the compounds of the present invention can be prepared using the various starting compounds, intermediates or final products as described in schemes A-N which are presented below.
GENERAL PROCEDURE A: Synthesis of 2 - [(benzyloxy formyl-amino) -methyl] -hexanoic acid (A-7)
BnO-NH,
A ^ A-5 A-6
A-7
Step 1: 2-n-butyl acrylic acid (A-2) To a solution of alkyl malonic acid A-1 (R 2 = n-butyl (107.4 mmoles) in ethanol (200 ml) was added piperidine (12.7 ml, 128.8 mmoles , 1.2 equivalents) and 37% aqueous formaldehyde (40.0 ml, 536.9 mmol, 5 equivalents) The solution was heated to 80 ° C, during this time a precipitate appeared, and then gradually dissolved again for 1 hour. it was stirred at 80 ° C overnight, then cooled to room temperature (rt) The solvents were removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with 1 MHC1 and brine, dried over Na 2 SO 4 anhydrous and filtered The filtrate was concentrated to give the title compound A-2 as a clear oil.
Step 2: 4-benzyl-3- (2-butyl-acryloyl) -oxazolidin-2-one (A-3) 2-n-Butyl acrylic acid (9.90 g, 77.2 mmol, and 1 equivalent) was dissolved in 260 ml of dry THF and cooled to -78 ° C under a blanket of nitrogen. The Hunig's base (17.5 ml, 100.4 mmol, 1.3 equivalent) and pivaloyl chloride (9.5 μl, 77.2 mmol, 1 equivalent) were added at such a rate that the temperature remained below -60 ° C. The mixture was stirred at -78 ° C for 30 minutes, warmed to room temperature for 2 hours, and finally cooled again to -78 ° C. In a separate flask, (S) - (-) - 4-benzyl-2-oxazolidinone (13.49 g, 77.24 mmoles) was dissolved in 150 ml of dry THF and cooled to -78 ° C under a blanket of nitrogen. N-Butyl lithium (2.5M solution in hexanes, 30.9 mL, 77.2 mmol, 1 equivalent) was slowly added at -78 ° C, and the mixture was stirred for 30 minutes at room temperature. The resulting anion was slowly transferred through a cannula to the original reaction vessel. The mixture was allowed to warm to room temperature and was stirred overnight at room temperature. The reaction was quenched with 1 M KH CO3, and the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was purified through flash chromatography (hexane: ethyl acetate = 4: 1) to produce the compound of the title A-3 as a white solid (15.0 g, 52.2 mmol, 68%).
Step 3: 4- benzyl-3- [2- (benzyl-oxyamino-meth] l) -hexanoyl] -oxazlidin-2-one (p-toluenesulfonic acid salt) Compound A-3 (8.25 g, 28.7 mmol ) was mixed with O-benzylhydroxylamine (7.07 g, 57.4 mmol, 2 equivalents) and stirred for 40 hours at room temperature under nitrogen. The mixture was dissolved in ethyl acetate and p-toluenesulfonic acid was added
(21.84 g, 114.8 mmol, and 4 equivalents) to precipitate the excess of O-benzylhydroxylamine as a white solid. The white solid was filtered, and the filtrate was concentrated to give a crude yellow oil (HPLC analysis indicated a small footprint of the starting material).
Charging the crude yellow oil with an excess of diethyl ether and cooling to 0 ° C for 30 minutes provided a solid, which was collected through filtration and dried in vacuo to give the title compound as a white crystalline solid.
(individual diastereomer).
Step 4: 4-benzyl-3- [2- (benzyloxy-amino-methyl) -hexanoyl] -oxazlidin-2-one (A-5) To a solution of the salt p-TSA (22.9 g, 39 3 mmol) dissolved in 400 ml of ethyl acetate, 1 M Na2CO3 (200 ml, 5 equivalents) was added and stirred at room temperature for 30 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO, filtered and concentrated to give the title compound as a pale opaque oil (15.8 g, 38.6 mmol, 98%).
Step 5:? / - [2- (4-benzyl-2-oxo-oxozalidin-3-carbonyl) -hexyl] -? / - benzyloxy-formamide (A-6) A solution of compound A-5 (5.38 g, 12.1 mmoles, 1 equivalent) in formic acid (7.4 ml, 196.6 mmoles, 15 equivalents) was cooled to 0 ° C under a blanket of nitrogen. In a separate flask, the formic acid (7.4 ml, 196.6 mmol, 15 equivalents) was cooled to 0 ° C under a blanket of nitrogen, and acetic anhydride (2.47 ml, 26.2 mmol, 2 equivalents) was added dropwise. The solution was stirred at 0 ° C for 15 minutes. The resulting mixed anhydride was transferred slowly through a syringe to the original reaction vessel. The mixture was stirred at 0 ° C for 1 hour, then at room temperature for 3 hours. The mixture was concentrated, taken up in dichloromethane, and washed successively with saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give an opaque oil, which was purified by flash chromatography (hexane: ethyl acetate = 2: 1 then dichloromethane / acetone = 9: 1) to produce the title compound as a colorless oil.
Step 6: 2 - [(benzyloxy-formyl-amino) -methyl] -hexanoic acid (A-7) Compound A-6 (0.163 g, 0.372 mmol, 1 equivalent) was dissolved in 4.5 mL of THF and 1.5 mL of water and cooled to 0 ° C. Hydrogen peroxide (30% in water, 228 μL, 2.23 mmol, 6 equivalents) was added dropwise followed by the slow addition of a lithium hydroxide solution (0.019 g, 0.446 mmol, 1.2 equivalents) in water (350 μL). ). The resulting mixture was stirred at 0 ° C for 1.5 hours. The basic reaction mixture was quenched with the Amberlite IR-120 (H +) resin at a pH of 4-5 at 0 ° C. The resin was filtered and rinsed with ethyl acetate. The mixture was concentrated to remove the THF, and then taken up in ethyl acetate. The aqueous layer was separated and the organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated to give an opaque oil, which was purified by flash chromatography (dichloromethane: acetone = 4: 1 then acetone: methanol = 99: 1) to produce the title compound A-7 as a colorless oil.
GENERAL PROCEDURE B: Synthesis of N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -formamide
A-7 B-1 B-2 B-3 Step 1: N-Benzyloxy-N-. { (R) -2 - [(S) -2- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -pyrolidine-1-carbonyl] -hexyl} -formamide (B-2) To a mixture of A-7 (0.110 g, 0.39 mmoles) and B-1 (0.135 g, 0.53 mmoles) in anhydrous DCM at 0 ° C under argon, DIEA (0.65ml, 2.94 mmoles) was added followed by HATU (0.225g, 0.6 mmoles). The reaction mixture was stirred overnight while the temperature was gradually warmed to room temperature. The excess DCM was first evaporated under reduced pressure. The remaining crude material was diluted with ethyl acetate and washed with 10% citric acid (2.5 ml) and saturated NaHCO3 (2x15 ml). The organic layers were dried over anhydrous MgSO 4, filtered and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to yield the title compound B-2 (0.175 g, 86%).
Step 2: N-Hydroxy-N-. { (R) -2 - [(S) -2- (r-trifluoromethyl-1 H -benzimidazol-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -formamide To a solution of B-2 (0.175g, 0.34 mmole) in 10 ml of EtOH / EtOAc (1: 1) was added a catalytic amount of 10% Pd / C (0.018g, 0.169 mmole) under Argon. The argon was replaced by hydrogen bubbling through the solvent. After stirring under an atmosphere of H2 for about 4 hours, the reaction mixture is filtered on a pad of celite. The celite pad was washed several times with EtOH and the combined filtrate was evaporated to dryness through reduced pressure. The residue was purified through silica gel column chromatography to produce B-3 (0.087 g, 53%).
GENERAL PROCEDURE C: Synthesis of N - [(R) -2 - ((S) -2-Benzothiazol-2-yl-pyrrolidin-1 -carbonyl) -hexyl] -N-hydroxy-formamide (B-3)
A-7 C-1 B-3
Step 1: acid (R) -2-. { [formyl- (tetrahydro-pyran-2-yloxy) -amino] -methyl} -hexanoic (C-1) To a solution of A-7 (6.36g, 22.8 mmol) in EtOH / EtOAc (1: 1) was added a catalytic amount of 10% Pd / C (1.2g, 0.5 equivalents) under Argon, and Argon is replaced by Hydrogen by bubbling through the solvent. After stirring under an atmosphere of H2 for about 3 hours, the reaction mixture was filtered on a pad of celite. The celite pad was washed several times with EtOH and the collected filtrate was evaporated to dryness through reduced pressure to produce the reverse hydroxamate form of A-7. The compound was taken without any purification. A solution of the reverse hydroxamate (0.714g,
3. 78 mmole) in 12 ml of dichloromethane was cooled to 0 ° C, then 3,4-dihydro-2H-pyran (0.689 ml, 7.56 mmole) was added followed by p-toluenesulfonic acid monohydrate (0.072 mmole, 0.1 eq.) The reaction mixture was stirred at 0 ° C for 2 hours. A solution of ice-cold saturated NaCl was added to the stirring reaction mixture. The two phases were partitioned with dichloromethane and extracted through excess dichloromethane. The combined organic layers were dried over MgSO 4, filtered and concentrated to give a light brown oil. The crude material was purified through liquid column chromatography to yield 0.752g, 73% C1.
Step 2: N - [(R) -2 - ((S) -2-Benzothiazol-2-yl-pyrrolidin-1 -carbonyl] -hexyl] -N-hydroxy-formamide (B-3) To a solution of C-1 (0.083 g, 0.275 m moles) in 5 ml of anhydrous dichloromethane and 1 ml of anhydrous DMF was added DI EA (0.3 ml, 1.375 mmoles) followed by a solution of B-1 (54 mg, 0.25 mmoles) ) and then the addition of HATU (105 mg, 0.275 mmol). The reaction mixture was stirred overnight under Argon. After completion of the reaction, the excess dichloromethane was evaporated through reduced pressure, followed by the addition of water and ethyl acetate to the reaction mixture. The two layers were divided and the extractions were carried out again in the aqueous layer with more ethyl acetate. The combined organic layers were washed sequentially, with 10% citric acid, saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification with flash chromatography produced the protected compound (0.094g, 82%). The removal of the protecting group i was carried out by stirring the obtained material (0.094 g, 0.2 mmol) in 30% TFA in 8 ml of dichloromethane for about 2 hours. The excess solvents were evaporated through reduced pressure to produce crude B-3. Final purification with HPLC preparation produced B-3 (20 mg, 27%).
GENERAL PROCEDURE D: Synthesis of Acid Hydroxyamide 3- [2- (1H-Benzoimidazol-2-yl) -Pyrrolidin-1-carbonyl] -heptanoic (D-4)
D-1 B-1 D-2
D-3 D-? Step 1: 3- [2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1-carbonyl] -heptanoic acid (D-2) 2- (2-Oxo-propyl) -hexanoic acid was dissolved ( D-1, 160 mg, 0.70 mmol) (preparation as in General Procedure E) in 5 ml of anhydrous DMF and stirred under Argon protection at room temperature. Then HATU (400mg) was added, 1.04 mmole, 1.5 eq) and stirred at room temperature for approximately 10 minutes. Then 2-pyrrolidin-2-yl-1H-benzoimidazole (B-1, 170 mg, 0.90 mmol, 1.3 equivalents) was added to the mixture and the stirring was continued for 10 minutes at room temperature before it was add DI EA (1 .28ml, 6.9 mmoles, 10 equivalents) through a syringe. The reaction mixture was stirred for 2 hours at room temperature and then tested for reaction by TLC and LC-MS. When the reaction was complete, citric acid (5%, 1.5 ml) was added with stirring, CH2Cl2 was added and the phase separated. The aqueous layer was extracted with CH2Cl2 (3x) and the combined organic layers were washed with 5% citric acid, a saturated sodium bicarbonate solution, salted and dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure to obtain a crude product such as brown oil, which was purified through flash column chromatography (Methanol: CH2Cl2 = 1: 9) to obtain tert-butyl ester of 3- [2- (1 H-Benzoimidazol-2-yl) -pyrrolidino-1 -carbonylj-heptanoic acid as a light brown solid (210 mg, 0.53 mmol, 75%). 3- [2- (1 H-Benzoimidazol-2-yl) -pyrrlidino-1 -carbonyl] -heptanoic acid tert -butyl ester (210 mg, 0.53 mmol) was dissolved in TFA in CH2CI2 (7.5 ml of TFA in 2.5). ml of CH 2 Cl 2), the reaction mixture was stirred at room temperature for 3 hours and then tested for reaction by TLC and LC-MS. When the reaction was complete, the solvent was removed under reduced pressure to yield an orange oil, which was purified by flash column chromatography (Methanol: CH 2 Cl 2 = 1: 9) to obtain the title compound (D -2) as a white solid (150 mg, 0.44 mmol, 83%).
Step 2: 3- [2- (1 H-Benzoimidazol-2-yl) -pyrrolidine-1-carbonyl] -heptanoic acid benzyloxy-acid (D-3) D-2 (150 mg, 0.44 mmol, 1 equivalent) was dissolved ) in 5 ml of anhydrous DMF and stirred under argon protection at room temperature. Successively added to HOBt (89.18 mg, 0.66 mmol, 1.5 equivalent) and EDC (126.52 mg, 0.66 mmol, 1.5 equivalent) and stirred at room temperature for approximately 5 minutes. Then O-Benzylhydroxylamine hydrochloride (91.30 mg, 0.57 mmol, 1.3 equivalents) was added with stirring to the reaction mixture and stirring was continued for another 10 minutes at room temperature before adding DIEA (0.41 ml, 2.20 mmoles, 5 equivalents ) through a syringe. The reaction mixture was stirred overnight at room temperature and then tested for reaction term through TLC and LCMS. When the reaction was complete, citric acid (5%, 15 ml) was added with stirring, CH2Cl2 was added and the phase was separated. The aqueous layer was extracted with CH2Cl2 (3x) and the combined organic layers were washed with citric acid (5%), a saturated sodium bicarbonate solution, brine and dried over magnesium sulfate, filtered and concentrated to obtain a Brown oil, which was further purified through column chromatography (Methanol: CH2CI2 = 1: 9) to yield the title compound (D-3) as a brown solid (89.6mg, 0.19mmol, 44%).
Step 3: 3- [2- (1 H-Benzoimidazol-2-yl) -pi rrol id i n-1 -carbon i I] -heptanoic acid (D-4) hydroxy acid D-3 (89.6mg, 0.19mmol, 1 equivalent) in ethanol and ethyl acetate (1: 1) under argon protection at room temperature and added to a slurry of Pd / C (10%, 10mg, O.Ommol, 0.5 equivalent) in ethanol and ethyl acetate (1ml, 1: 1) under Argon. Hydrogen gas was bubbled through the mixture and the reaction mixture was stirred under a hydrogen atmosphere for 6 hours and then tested for reaction term through TLC and LC-MS. When the reaction was complete, the mixture was filtered through celite, the celite pad was washed with 50 ml of ethanol, and the ethanol solution was concentrated under reduced pressure to a light brown oil which was first purified through water. column chromatography (Methanol: CH2CI2 = 2: 8), then through reverse phase HPLC preparation to produce the title compound (D-4) as white crystals (44.2mg, 0.12mmol, 65%).
GENERAL PROCEDURE E: Synthesis of 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -1 H -imidazo [4,5-c] pyridine (E-5)
E-1 E-2 E-3 E-4 EN Step 1: (2S, 4R) -2- (3-Amino-pyridin-2-ylcarbamoyl) -4-f luoro -pyr rolidin- tert -butyl ester 1 -carboxylic (E -3) To a mixture of E-1 (1.17g, 5.0 mmoles) and E-2 (0.71g, 6.5 mmoles) in anhydrous DMF / DCM (1: 1) at 0 ° C under argon, DIEA was added (4.0ml, 5.0 equivalent) followed by HATU (2.47g, 1.2 equivalent). The reaction mixture was stirred for another 4 hours while the temperature was gradually warmed to room temperature. The LCMS showed that the reaction was complete. The excess of DCM was first evaporated through reduced pressure. The remaining crude material was diluted with ethyl acetate and partitioned with water. The extractions were repeated twice with more ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated. The crude was purified through liquid column chromatography and yielded the desired product.
Step 2: (2S, 4R) -4-Fluoro-2- (1 H -imidazol [4,5-c] pyridin-2-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (E-4) E-3 (1.3g, 4.0 mmol) was dissolved in 40 ml of glacial acetic acid and refluxed at 60 ° C overnight. The acid was then evaporated through reduced pressure. The purification of the raw material was done through master flash to produce the pure E-4 (0.693g, 57%).
Step 3: 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -1 H -imidazo [4,5-c] pyridine (E-5) The removal of the tert-butyl protecting group in E -4 (0.346, 1.13 mmol) was performed by stirring E-4 (346mg, 1.13 mmol) in a solution of 4N HCl in 5 ml of 1,4-dioxane. The reaction mixture was stirred for about 30 minutes before evaporating the excess solvents under reduced pressure to produce the target molecule E-5.
GENERAL PROCEDURE F: Synthesis of 2-pyrrolidin-2-yl-oxazolo [4,5-b] pyridine (F-5)
E-1 F-1 F-2 F-3
F-4 F-5
Step 1: 2- benzyl ester. { 1- [2- (tert-Butyl-dimethyl-s Man i I oxy) -eti l] -1 H -benzoimidazol-2-yl) -pyrrolidin-1 -carboxylic acid (F-1) 1-benzyl ester was dissolved pyrrolidin-1,2-dicarboxylic acid E-1 (10.0 g, 40 mmol) in 40 ml of CH2Cl2 and cooled under ice. SOCI2 (29.3 ml, 400 mmol, 10 equivalents) was added slowly and the mixture was heated at 50 ° C for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give a slightly yellow oil. The oil intermediate was dissolved in 25 ml of THF, cooled to 0 ° C, and a solution of ammonia (38 ml, 96 mmol, 2.3 equivalents) was added. The mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The residue was partitioned between CH2Cl2 (150 ml) and water (30 ml). The layers were separated, and the organic phase was washed with brine, dried over MgSO0, filtered, concentrated under reduced pressure to yield 2-Carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester F-1 as a yellowish oil. (12.0 g).
Step 2: 2-Cyano-pyrrolidin-1-carboxylic acid benzyl ester (F-2) 2- Benzyl ester was dissolved. { 1- [2- (tert-Butyl-dimethyl-silanyloxy) -ethyl] -1H-benzoimidazol-2-yl} -pyrrolidine-1-carboxylic acid F-1
(12. Og) in 30 ml of pyridine and cooled under ice. POCI3 (3.6 mL) was added slowly and the mixture was stirred at 0 ° C for 1 hour. The pyridine was removed under reduced pressure, the crude mixture was dissolved in 150 ml of ethyl acetate and washed with a solution of 1N CHI (3 x 30 ml), concentrated under reduced pressure, dissolved in 50 ml of ethyl acetate. again, it was washed with a solution of 1N HCl (50 ml) to completely remove the pyridine. The ethyl acetate solution was dried over MgSO 4, filtered, concentrated under reduced pressure to yield 2-Cyano-pyrrolidin-1-carboxylic acid benzyl ester F-2 as a slightly yellow oil (6.1 g, 26.5 mmol, 66%).
Step 3: 2-Ethoxycarbonimidoyl-pirorolidin-1-carboxylic acid benzyl ester (F-3) A mixture of EtOH (1.5 ml) and CH2Cl2 (20 ml) was cooled to 0 ° C and CH3COCI was added slowly. followed by a solution of 2-cyano-pyrrolidin-1-carboxylic acid benzyl ester F-2 (2.0g, 8.7 mmoles) in CH2Cl2 (20 ml). The reaction was stirred at room temperature for 2 hours and the solvent was removed under reduced pressure to give 2-ethoxycarbonyl idoyl-pyrrolidin-1-carboxylic acid benzyl ester F-3 as a sticky solid.
Step 4: 2-Oxazolo [4,5-b] pyridin-2-l-pyrrolidin-1-carboxylic acid benzyl ester (F-4) 2-Ethoxycarbonimidoyl-pyrrylidin-1-carboxylic acid benzyl ester F was dissolved -3 in 15 ml of EtOH and 2-ami no-pyridin-3-ol (1.1 g, 9.6 mmol, 1.1 equivalents) was added. The mixture was heated at 95 ° C for 16 hours, then cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified via flash chromatography to yield the title compound as a pale opaque oil (1.2 g, 3.7 mmol, 43%) Step 5: 2-Pyrrolidin-2-yl-oxazolo [4.5 -b] pyridine (F-5) 2-Oxazolo [4,5-b] pyridin-2-yl-pyrrolidine-1-carboxylic acid benzyl ester F-4 (330 mg, 1.0 mmol) was dissolved in a solution of ethyl acetate / MeOH (1: 1, 15 ml) and added slowly to 10% Pd / C (65 mg, 0.2 equivalents). H2 gas was bubbled through the mixture for 6 hours until the LC-MS showed that the reaction was complete. Pd / C was filtered and the filtrate was concentrated to dryness to yield the title compound, 2-pyrrolidin-2-yl-oxazolo [4,5-b] pyridine F-5 as a slightly yellow oil (143.6 mg, 0.76 g. mmoles, 76%).
GENERAL PROCEDURE G: Synthesis of 5-f e n i I -2-p i rro I i d i n -2-i I -1 H-imidazole (G-2)
F-3 G-1 G-2 Step 1: 2- (5-phenyl-1 H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid benzyl ester (G-1) To a solution of the compound F- 3 (1.00 g, 3.62 mmol, 1 equivalent) dissolved in 20 ml of methanol, potassium acetate (1.42 g, 14.5 mmol, 4 equivalents) was added and the mixture was heated to 78 ° C under a blanket of argon. A solution of 2-aminoacetophenone (R = Ph) (1.24 g, 7.24 mmol, 2 equivalents) in 10 ml of methanol was added dropwise to the reaction mixture over a period of 3 minutes. The reaction mixture was stirred at 78 ° C for 17 hours and allowed to cool to room temperature. The mixture was concentrated under reduced pressure, taken up in dichloromethane, and washed successively with saturated NaHCO3. The organic layer was dried over anhydrous MgSO, filtered and concentrated under reduced pressure to give a brown residue. The residue was triturated with ether, and filtered, the filtrate was concentrated to give a brown residue, which was then triturated with ice-cold acetonitrile, and filtered. The solid was further triturated with ether and filtered. The combined filtrates from both ether and acetonitrile triturates were concentrated to give a brown solid, which was purified by flash chromatography (hexane.ethyl acetate = 1: 1) to give the title compound G- 1 as a brown solid (0.505g, 1.45mmol, 40%). Literature references: Breslin, HJ, Miskowski, TA, Kukla, MJ, Leister, WH, De Winter, HL, Gauthier, DA, Somers, MVF, Peeters, DCG, Roevens, PWMJ Med. Chem., 2002, 45, 5303 -5310.
Step 2: 5-phenyl-2-pyrrolidin-2-yl-1 H-imidazole (G-2) Compound G-1 (0.50 g, 1.44 mmol, 1 equivalent) and palladium-on-charcoal 10% (16 mg) in 15 ml of methanol was stirred under a blanket of hydrogen at room temperature for 46 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give a brown residue, which was purified by flash chromatography.
(dichloromethane: methanol: aqueous ammonia = 1: 9: a few drops) to yield the title compound G-2 as a yellow solid (0.2103 g, 0.99 mmol, 98%).
GENERAL PROCEDURE H: Synthesis of 5-pyrrolidin-2-yl-1 H-tetrazole (H-2)
PG- F-2 H-1 H-2
Step 1: 2- (1H-Tetrazol-5-yl) -pyrrolidine-1-carboxylic acid benzyl ester (H-1) To a solution of compound F-2 (PG = Cbz) (0.377 g, 1.64 mmol, 1 equivalent) in 1.5 ml of DMF was added sodium azide (0.111 g, 1.71 mmoles, 1.04 equivalents) and ammonium chloride (0.097 g, 1.80 mmoles, 1.1 equivalents). The solution was heated to 90-95 ° C under a blanket of argon and stirred for 4 hours. The reaction mixture was emptied on ice (10 g.) And acidified to a pH of 2 with 1 M HCL. The acidic reaction mixture was extracted with dichloromethane and the layers were separated. The combined organic layers were washed successively with water and brine. The organic layer was dried over anhydrous MgSO, filtered and concentrated to give the title compound H-1 as a colorless oil (0.420g, 1.54 mmoles, 94%) Literature Reference: Almquist, RG, Chao, WR, Jennings -White, CJ Med. Chem., 1985, 28, 1067.
Step 2: 5-Pyrrolidin-2-yl-1 H-tetrazole (H-2) Compound H-1 (0.401 g, 1.49 mmol, 1 equivalent) and palladium on charcoal 10% (16 mg) in acetate were stirred. of ethyl / ethanol (1: 1, 5 ml) under a blanket of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give the title compound H-2 as a white solid (0.168 g, 1.21 mmol, 81%) which was only soluble in the presence of acetic acid.
GENERAL PROCEDURE J: Synthesis of 4-Phenyl-2- (S) -pyrrolidin 2-yl-thiazole (J-4)
E-1 J-1 J-3 J-4
Step 1: (S) -2-Thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (J-1) E-1 (1.0 g, 4.7 mol) was dissolved in 20 ml of anhydrous DME and added to another Round bottom flask containing a slurry of Lawesson's reagent (1.89 g, 4.7 mmol) in 5 ml of anhydrous DME under Argon at room temperature. The reaction mixture was refluxed at 80 ° C for about 2.5 hours and the completion of the reaction was verified through LCMS. The excess solvents were evaporated under reduced pressure and the obtained crude residue was kept at a low temperature away from direct light. The crude material was purified through liquid column chromatography to produce the desired product J-1 (50%).
Step 2: (S) -2- (4-Phenyl-thiazol-2-yl) -pyrrolidin-1-carboxylic acid ester (J-3) A mixture of J-1 (1.92 mmol) and sodium bicarbonate Potassium (15.4 mmol) was stirred vigorously in 15 ml of anhydrous DME. After stirring at room temperature for 8 minutes, J-2 (5.77 mmoles) was added and stirring was continued for 45 minutes. The reaction mixture was cooled to 0 ° C and trifluoroacetic anhydride (0.7 ml, 7.69 mmol) was added dropwise to the reaction mixture and stirring was continued for an additional hour at 0 ° C. The mixture was allowed to warm slowly to room temperature. The excess solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was collected and the extraction was repeated twice more with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated through reduced pressure. The crude material was purified through liquid column chromatography to produce the desired product J-3 (62%).
Step 3: 4-Phenyl-2- (S) -pyrrolidi n-2-yl-thiazole (J-4) To a solution of J-3 (1-1.8 mmol) in 1 5 mL of dichloromethane, drop was added drop 4.5 ml of trifluoroacetic acid at 0 ° C. The reaction mixture was stirred for about 2 hours at low temperature, then slowly warmed to room temperature. The excess solvent evaporated through reduced pressure and produced the raw material. The crude was purified by liquid column chromatography to produce the desired product J-4 (20%).PROC EDIMI ENTO GEN ERAL K: Synthesis of (S) -2-Pi rrol id i n-2-i I benzothiazole (K-4)
K-1 K-2 K-3 K-4
Step 1: (S) -2- (2,3-Dihydro-benzothiazol-2 -i I) -pyr rolidin-1 -carboxylic acid ester (K-3) A mixture of K-1 (0.400 g) , 2.0 mmole) and K-2 (432uL, 4.0 mmole) in dry THF were subjected to ammonia at 100 ° C for 10 m inutes. The solvent was evaporated to dryness to produce the product K-3 (0.612 g). The crude compound K-3 was taken without further purification.
Step 2: (S) -2-Pi Rrolidin-2-yl-benzothiazole (K4) To a solution of K-3 (0.612 mg, 0.31 mmol) from the previous step in 20 ml of toluene was added MnO2 (8 g, 100 mmol ) and the mixture was refluxed at 120 ° C under Argon overnight. The MnO2 was filtered on a pad of celite to give a brown oil after evaporation of the solvent. The residue was then dissolved in 20 μl of ethyl acetate and washed three times with a solution of 1 N HCl to remove the by-products formed during the reaction. The organic phase collected from the workup was evaporated to dryness under vacuum to produce the desired product K-4. The crude material was purified through silica gel column chromatography, K-4 N-Boc-protected (0.214g, 35%). K-4 N-Boc-protected (0.1 09 g) was deprotected by stirring in a solution of 4 N CHI in 1.5 ml of 1,4-dioxane for 2 hours at room temperature. The solvent was removed under reduced pressure to yield the title compound K-4 (0.073 g).
PROC EDIM I ENTO ER ERAL L: Synthesis of 2-p i r rol i d i n -2-i 1-1 H perimidine (L-2)
Step 1: 2- (1 H -perimidin-2-yl) -pyrrolidine-1-carboxylic acid benzyl ether (L-2) N- (benzyloxycarbonyl) -L-proline E-1 (2.00 g, 8.00 mmol) was dissolved , 1 equivalent) in 30 ml of DMF and cooled to 0 ° C and stirred under an argon blanket. HATU (3.65 g, 9.60 mmol, 1.2 equivalents), 1, 8-diaminonaptalene L-1 (1.51 g, 9.60 mmol, 1.2 equivalents) and DIEA (6.63 ml, 40.0 mmol, 5 equivalents) were added to the solution at 0 °. C. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was concentrated, taken up in dichloromethane and washed successively with 5% citric acid and saturated NaHCO3. The organic layer was dried over anhydrous MgSO, filtered and concentrated to a brown oil, which was purified by flash chromatography (dichloromethane: methanol = 49: 1) to yield the title compound L-2 as a solid coffee (2.93 g, 7.89 mmoles, 98%).
Step 2: 2- pi rro I idin -2-i I -1 H-perimidine (L-2) Compound L-22.93 g, 7.90 mmol, 1 equivalent) and palladium on charcoal 10% (84 mg) were stirred in ethyl acetate / ethanol (1: 1 50 ml) under a blanket of hydrogen at room temperature for 15 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give a brown residue, which was purified by flash chromatography (hexane: ethyl acetate = 1: 1, then dichloromethane: methanol = 9: 1) to produce the title compound H-2 as a yellow solid (0.613 g, 2.58 mmol, 54%).
GENERAL PROCEDURE M: Synthesis of 1 - [(benzyloxy form il-amino) -m ethyl] -cyclopanecarboxylic acid (M-5)
M-1 M-2 M-S
Step 1: Cyclohexylidene-methoxy, methoxytrimethylsilane (M-2) Lithium diisopropylamine (2M solution in THF, 35.2 ml, 70.3 mmole, 2 equivalents) was diluted in 70 ml of THF and cooled to 78 ° C . Methyl cyclohexanecarboxylic acid methyl ether M-1 (5.00 g, 35.2 mmol, 1 equivalent) was added dropwise. The solution was stirred at -78 ° C for 30 minutes, followed by the addition of trimethylchlorosilane (8.88 ml, 70.3 mmol, 2 equivalents). The resulting mixture was stirred at -78 ° C for 30 minutes, then at room temperature for 17 hours, during this time a white precipitate appeared and a smoking action occurred and then the smoking action gradually ceased for 17 hours. The mixture was concentrated under reduced pressure, taken up in hexane and filtered. The filtrate was concentrated to an orange oil, which was purified by distillation (110 ° C, 10 mbar) to yield the title compound M-2 as a clear oil (4.673 g, 21.8 mmol, 62%). Literature references: (1) Ikeda, K., Achiwa, K., Sekiya M., Tetrahedron Lett., 1983, 24, 4707-4710; (2) Malak, V., Matovic, R., Saicic, R.N., Tetrahedron, 2004, 60, 8957-8966.
Step 2: Formaldehyde-O-Benzyl-Oxime (M-3) To a solution of a 36.6% aqueous solution of formaldehyde (2.21 ml, 27.0 mmol, 1 equivalent) in 15 ml of water was added pyridine (6.50 ml, 81.0 mmoles, 3 equivalents) and O-benzylhydroxylamine hydrochloride (4.31 g, 27.0 mmol, 1 equivalent). The mixture was heated at 70 ° C for 1 hour, and allowed to cool to room temperature. The mixture was acidified with 3N HCl (15 ml) and extracted with ether. The organic layers were combined, dried over anhydrous MgSO 4, filtered and concentrated to give a colorless oil, which was purified by flash chromatography (hexane: ethyl acetate = 4: 1) to yield the compound of the title M-3 as a colorless oil (3.00 g, 22.2 mmol, 82%).
Step 3: 1 - (Benzyloxyamino-methyl) -cyclohexanecarboxylic acid methyl ester (M-4) To a solution of compound M-3 (0.636 g, 4.70 mmol, 1 equivalent) dissolved in 15 ml of dichloromethane, the compound was added M-2 (1.00 g, 4.70 mmol, 1 equivalent), cooled to 0 ° C and stirred under a blanket of argon. Trimethylsilyl triflate (0.085 mL, 0.47 mmol, 0.1 equivalent) was added dropwise at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The mixture was washed with 10% potassium carbonate (50 ml), dried over anhydrous MgSO, filtered and concentrated to give a yellow oil, which was purified by flash chromatography (hexane: ethyl acetate = 9: 1) to yield the title compound M-4 as a clear oil (0.961 g, 3.46 mmol, 74%). Literature references: Maslak, V., Matovic, R., Saicic, R.N., Tetrahedon, 2004, 60, 8957-8966.
Step 3: 1 - [(benzyloxy-formyl-amino) -methyl] -cyclohexanecarboxylic acid (M-5) Compound M-5 (0.166 g, 0.60 mmol, 1 equivalent) was dissolved in 6 ml of THF and added drop drop lithium hydroxide (3 N solution in water, 2 ml, 10 equivalents) under a blanket of argon, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was heated to 50 ° C and stirred for 50 hours. 10 ml of water was added to the mixture and extracted with ethyl acetate. The combined organic layer was dried over anhydrous MgSO 4, filtered and concentrated to give a pink oil, which was purified by flash chromatography (hexane: ethyl acetate = 1: 1) to yield the free acid (acid). 1- (benzyloxyamino-methyl) -cyclohexanecarboxylic acid) as a white solid (0.134 g, 0.51 mmol, 85%). A solution of the free acid (l- (benzyloxyamino-methyl) -cyclohexancarboxylic acid) (0.133 g, 0.504 mmol, 1 equivalent) in 3 ml of dichloromethane was cooled to 0 ° C under a blanket of argon. In a separate flask, formic acid (0.19 ml, 5.04 mmol, 10 equivalents) was cooled to 0 ° C under a blanket of argon, and acetic anhydride (0.1 ml, 1.01 mmol, 2 equivalents) was added dropwise. The solution was stirred at 0 ° C for 15 minutes. The resulting mixed anhydride was transferred slowly through a syringe to the original reaction vessel. The mixture was stirred at 0CC for 30 minutes, then warmed to room temperature. 10 ml of water was added to the mixture, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous MgSO 4, filtered and concentrated to give a yellow solid, which was purified through flash chromatography (hexane: ethyl acetate = 1: 1) to yield the title compound M -5 as a white solid (0.133 g, 0.46 mmol, 90%).
GENERAL PROCEDURE N: Synthesis of 1 - [2-tert-Butyl-dimethyl silanyloxy) -ethyl] -2-pyrrolidin-2-yl-1 H-benzoimidazole (N-3)
E-4 N-2 N-3 Step 1: 2-benzyl ester. { 1- [2-tert-Butyl-dimethyl-s i lan loxi) -eti I] -1 H-benzoimidazol-2-yl} -pyrrole di-1 -carboxylic acid (N-2) 2- (1 H-Benzoimidazol-2-yl) -pyrrolidine-1-carboxylic acid benzyl ester E-4 (4.0 mmol) was dissolved in 15 ml of acetonitrile , (2-Bromo-ethoxy) -tert-butyl-dimethyl-silane (1.91 g) was added., 8.0 mmoles, 2 equivalents) and Cs2CO3 (3.9 G, 12.0 mmoles, 3 equivalents) and the reaction was heated at 60 ° C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residues were dissolved in 100 ml of ethyl acetate and washed with 30 ml of brine. The crude product was purified by flash chromatography (hexane: ethyl acetate = 70:30) to yield the title compound N-2 as a slightly yellow paste (1.3 g, 2.7 mmol, 67.8%).
Step 2: 1- [2- (tert-Butyl-dimethyl-s-alanoxo) -ethyl] -2-pyrrolidin-2-yl-1H-benzoimidazole (N-3) 2- Benzyl ester was dissolved. { 1- [2- (tert-Butyl-dimethyl-silanyloxy) -ethyl] -1H-benzoimidazol-2-yl} -pyrrolidine-1-carboxylic acid N-2
(1.3g, 2.7 mmol) in ethyl acetate / MeOH (1: 1, 15 ml) and added slowly to 10% Pd / C / 130 mg, 0.1 equivalent). H2 gas was bubbled through the mixture for 1 hour until LC-MS showed that the reaction was complete. The Pd / C was filtered and the filtrate was concentrated under reduced pressure to yield the title compound 1- [2- (tert-Butyl-dimethyl-silanyloxy) -ethyl] -2-pyrrolidin-2-yl-1H-benzimidazole N -3 as a slightly yellow oil (818 mg, 2.4 mmol, 88.9%).
Examples
Example 1 N-. { (R) -2 - [(S) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] hexyl} -N-hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.30H), 7.86-7.84 (d,
0. 45H), 7.77 (s, 0.25H), 7.65-7.40 (m, 2H), 7.30-7.12 (m, 2H), 5.48 (s, 1H), 5.42 (d, 0.33H), 5.28-5.15 (m, 0.67H), 3.93-3.78 (m, 1.33H), 3.80-3.50 (m, 1.70H), 3.47-3.35 (m, 0.95H), 3.15-3.00 (m, 0.71H), 2.88-2.74 (m, 0.31H), 2.55-1.90 (m, 4H), 1.65-1.05 (m, 6H), 0.93-0.90 (m, 1.15H), 0.84-0.80 (m, 1.85H).
13C-NMR (MeOH-d4, rotamers): d 163.4, 159.9, 159.7, 123.5, 115.2, 57.6, 56.8, 53.4, 53.3, 51.2, 47.7, 44.3, 43.1, 43.0, 34.4, 32.4, 30.9, 30.2, 25.8, 23.8, 23.3, 14.2. ES-MS: cale, for C19H26N O3 (358.44); found (pos.): 359.7 [M + H]; found (neg.): 357.4 [M-H].
Example 2 N-. { (R) -2 - [(S) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] heptyl} -N-hydroxy form amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -heptanoic acid A-7 (R2 = n-pentyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 7.87 (s, 0.64H), 7.84 (s, 0.36H), 7.70-7.90 (m, 0.68H), 7.51-7.49 (m, 1.60H), 7.25- 7.18 (m, 1.72H), 5.50-5.30 (m, 1H), 5.22-5.19 (m, 1H), 3.90-3.87 (m, 1.84H), 3.74-3.65 (m, 2.08H), 3.47-3.42 (m, m, 1.07H), 2.40-2.10 (m, 2.61H), 2.10-1.95 (m, 1H), 1.95-1.75 (m, 0.39H), 1.70-1.05 (m, 8H), 1.05-0.85 (m, 1.13H), 0.85-0.70 (m, 1.87H).
13 C-NMR (MeOH-d 4, rotamers): 175.5, 1 75.1, 164.0, 163.4, 159.9, 159.7, 157.0, 125.9, 124.2, 124.0, 123.5, 115.7, 57.6, 56.7, 53.3, 47.7, 43.0, 34.4, 34.2, 33.1, 33.0, 32.3, 31.5, 31.1, 27.6, 25.8, 23.4, 23.3, 14.3. ES-MS: cale, for C2oH28N4? 3 (372.47); found (pos.): 374.0 [M + H]; found (neg.): 371.6 [M-H].
Example 3 N-. { (R) -3 - [(S) -2- (1H-Benzoimidazol-2-yl) -pyrrolidin-1-yl] -2-benzyl-3-oxo-propyl} -N-hydroxyformamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -3-phenylpropionic acid A-7 (R2 = benzyl, the preparation is described in General Procedure A) and (S) -2-Pi rrol id i n-2-i I- 1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B. 1H-NMR (MeOH-d4, rotamers): d 8.28 (s, 0.15H), 7.96 (s, 0.33H), 7.85 (s, 0.52H), 7.70-7.45 (m, 1.95H), 7.35-7.15 (m, 5.39 H), 7.10-6.80 (m, 1.66H), 5.47 (s, 1.75H), 5.15-5.30 (m, 0.25H), 4.34 (t, 0.62H), 4.00 (d, 0.34H), 3.90-3.80 (m, 0.63H), 3.80-3.65 (m, 0.39H), 3.65-3.35 (m, 2.63H), 3.20-3.00 (m, 0.40H), 3.00-2.58 (m, 2.04H), 2.30-2.20 (m, 0.52H), 2.20-2.05 (m, 0.59H), 2.04-1.88 (m, 0.85H), 1.85-1.68 (m, 0.51H), 1.65-1.45 (m, 1.10H), 0.35-0.20 (m, 0.39H).
13C-NMR (MeOH-d4, rotamers): d 175.2, 174.8, 174.3, 164.1, 163.5, 160.0, 159.8, 156.1, 155.8, 155.3, 139.6, 139.3, 130.2, 130.0, 129.8, 129.5, 129.3, 128.2, 128.1, 127.6, 127.5, 124.1, 123.9, 123.6, 57.1, 56.3, 54.8, 53.7, 47.3, 47.1, 46.9, 38.8, 38.3, 33.7, 33.4, 23.2, 23.1. ES-MS: Cale, for C22H24N4O3 (392.46); found (pos.): 394.0 [M + 1]; found (neg.): 391.4 [M-1].
Example 4 N-. { (R) -3 - [(S) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1-yl] -2-cyclopentylmethyl-3-oxopropyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7
(R2 = cyclopentylmethiol, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.17H), 8.20 (s, 0.08H) 7.83 (0.59H), 7.75 (s, 0.16H), 7.63-7.47 (m, 2H), 7.30-7.16 (m, 2H)
. 41 (d, J = 6.5, 0.35H), 5.26-5.18 (m, 0.65H), 3.95-3.82 (m, 1.49H) 3.80-3.58 (m, 1.75H), 3.49-3.35 (m, 0.85H) , 3.17-3.08 (m, 0.23H)
2. 93-2.85 (m, 0.18H), 2.69-2.60 (m, 0.20H), 2.53-2.40 (m, 0.38H)
2. 40-2.15 (m, 2.35H), 2.13-1.97 (m, 1.06H), 1.94-1.28 (m, 9.46H) 1.25-0.92 (m, 2.11H).
13 C-NMR (MeOH-d4, rotamers): d 176.3, 175.7, 175.2, 174.9, 163.9, 163.4, 159.9, 159.7, 156.8, 156.1, 139.2, 124.2, 123.9, 123.5, 115.7, 57.6.56.7, 53.4, 47.9 , 43.9, 43.3, 42.5, 42.4, 38.8, 38.2, 37.6, 37.2, 34.6, 34.4, 34.3, 33.9, 33.8, 32.2, 26.3, 26.1, 25.9, 23.3, 23.2. ES-MS: cale, for C21H28N4O3 (384.48); found (pos.): 385.7 [M + H]; found (neg.): 383.3 [M-H], 497.5 [M + CF3CO2].
Example 5 N-. { (R) -2 - [(S) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] pentyl} -N-hydroxy form amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -pentanoic acid A-7 (R2 = propyl, the preparation is described in General Procedure A) and (S) ) -2-Pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.16H), 8.20 (s, 0.07H),
7. 87 (0.18H), 7.84 (s, 0.39H), 7.77 (s, 0.17H), 7.65-7.47 (m, 1.77H), 7.29-7.16 (m, 1.91H), 5.43 (d, J = 7.6, 0.36H), 5.25-5.17 (m, 0.61H), .96-3.80 (m, 1.42H), 3.78-3.59 (m, 1.75H), 3.49-3.39 (m, 0.84H), 3.15-3.06 (m , 0.26H), 2.97-2.85 (m, 0.24H), 2.80 (S, 1.13H), 2.72-2.62 (m, 0.22H), 2.53-1.98 (m, 3.65H), 1.94-1.66 (m, 0.39 H), 1.64-1.21 (m, 4.05H), 0.97-0.82 (m, 3. OH).
13 C-NMR (MeOH-d 4, rotamers): d 176.3, 175.7, 175.2, 164.0, 163.4, 159.9, 159.7, 157.1, 156.1, 155.7, 139.2, 124.2, 123.9, 123.5, 115.7, 57.6, 56.7, 56.9, 53.2, 47.7, 42.8, 38.9, 34.8, 34.2, 33.2, 32.5, 25.8, 21.3, 21.2, 14.6, 14.4. ES-MS: cale, for C18H24N4O3 (344.18); found (pos.): 346.1 [M + H]; found (neg.): 343.5 [M-H], 457.7 [M + CF3CO2].
Example 6 N-. { (R) -2 - [(2S, 4R) -2- (1H-Benzoimidazol-2-yl) -4-fuoro-pyrrolidin-1 ca r bo n i I] -h ex i l} -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B. 1H -NMR (MeOH-d4, rotamers): d 8.24 (s, 0.27H), 8.11 (s, 0.21H), 7.83 (0.41H), 7.66 (s, 0.11H), 7.63 (s, 0.13H), 7.59 -7.48 (m, 2H), 7.28-7.18 (m, 2H), 5.54-5.47 (m, 0.63H), 5.44-5.37 (br.s, 0.50H), 5.29 (t, J = 8.5, 0.87H) , 4.40-3.98 (m, 1.81H), 3.82-3.64 (m, 1.09H), 3.54-3.44 (m, 0.44H), 3.42-3.40 (m, 0.25H), 3.39-3.35 (m, 0.28H) , 3.35-3.32 (m, 0.12H), 3.22-3.13 (m, 0.46H), 3.11-3.03 (m, 0.31H), 3.00-2.85 (m, 0.41H), 2.81-2.67 (m, 0.90H) , 2.62-2.52 (m, 0.42H), 2.52-2.36 (m, 0.63H), 1.56-1.28 (m, 3.07H), 1.25-1.08 (m, 2.91H), 0.95-0.87 (m, 0.78H) , 0.80-0.71 (m, 2.23H).
13C-NMR (MeOH-d4, rotamers): d 175.1, 165.0, 163.0, 160.5, 158.6, 156.2, 139.0, 124.4, 122.9, 116.6, 115.0, 55.9, 54.4, 43.5, 42.2, 31.0, 30.0, 23.7, 14.8, 13.6. ES-MS: cale, for C19H25FN4O3 (376.19); found (pos.): 377.7 [M + H]; found (neg.): 375.6 [M-H].
Example 7 N-. { (R) -2 - [(S) -2- (1 H-Benzoimidazol-2-yl) -4-fluoro-pyrrolidin-1 carbonyl] -heptyl} -N-hydroxyform amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -heptanoic acid A-7 (R2 = n-pentyl, the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.22 (s, 0.41H), 7.78 (s, 0.59H), 7.70-7.45 (m, 2H), 7.35-7.12 (m, 2H), 5.55-5.44 (d. m, 1.15H), 5.44-5.32 (m, 0.67H), 5.32-5.23 (m, 1.18H), 1.68-1.05 (m, 8H), 0.95-0.82 (m, 1H), 0.82-0.65 (m, 2H). ES-MS: cale, for C2oH27FN4? 3 (390.46); found (pos.): 391.7 [M + H]; found (neg.): 389.5 [M-H].
Example 8 N-. { (R) -3 - [(2S, 4R) -2- (1H-Benzoimidazol-2-yl) -4-fluoro-pyrrolidin-1-yl] -2-cyclopentylmethyl-3-oxo-propyl} -N-hydroxy-formamida
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (R2 = cyclopentylmethyl, the preparation is described in General Procedure A ) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B .
1 H-NMR (MeOH-d 4, rotamers): d 8.23 (s, 0.30H), 8.17 (s, 0.06H), 7.83 (0.42H), 7.63 (s, 0.22H), 7.59-7.48 (m, 1.93H) ), 7.28-7.17 (m, 1.97H), 5.54-5.45 (m, 0.62H), 5.43-5.37 (br.s, 0.51H), 5.31 (t, J = 8.5, 8.3, 0.88H), 4.38- 4.15 (m, 1.0H), 4.15-3.94 (m, 0.79H), 3.87-3.68 (m, 1.13H), 3.49-3.32 (m, 1.29H), 3.25-3.13 (m, 0.58H), 3.13- 3.04 (m, 0.34H), 3.00-2.84 (m, 0.39H), 2.84-2.58 (m, 1.30H), 2.58-2.43 (m, 0.54H), 2.43-2.37 (m, 0.13H), 1.87- 1.14 (m, 9.50H), 1.11-0.81 (m, 1.91H).
13 C-NMR (MeOH-d 4, rotamers): d 175.2, 163.0, 160.4, 155.9, 124.4, 122.8, 115.1, 55.8, 54.3, 50.0, 43.0, 41.7, 39.3, 38.1, 34.0, 32.6, 27.3, 26.0, 24.7. ES-MS: cale, for C21H27FN4O3 (402.21); found (pos.): 403.4 [M + H]; found (neg.): 401.3 [M-H].
Example 9 N-Hydroxy-N-. { (R) -2 - [(S) -2- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -forward
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-3H-imidazo [4,5-c] pyridine E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 8.89 (s, 0.14H), 8.84 (s, 0.11H), 8.79 (s, 0.61H), 8.31-8.25 (d, 0.94H), 8.24-8.2 ( d, 0.17H), 7.86-7.8 (m, 0.56H), 7.76 (s, 0.15H), 7.74-7.70 (m, 0.17H), 7.69-7.65 (m, 0.13H), 7.59-7.55 (d, 0.64H), 5.49-5.45 (m, 0.29H), 5.28-5.2 (m, 0.71H), 4.68-4.6 (dd, J = 0.04, 0.58H), 8.7-8.6 (m, 1.3H), 3.81- 3.63 (m, 1.67H), 3.5-3.4 (m, 0.9H), 3.78-3.7 (m, 0.43H), 2.91-2.83 (m, 0.26H), 2.73-2.65 (m, 0.18H), 2.35- 2.51 (m, 1.3H), 2.37-2.25 (m, 0.9), 2.26-2.06 (m, 1.7), 1.64-1.5 (m, 1.2H), 1.52-1.4 (m, 1.1H), 1.42-1.2 ( m, 4.8H), 0.96-0.9 (m, 1.1H), 0.9-0.78 (2H).
ES-MS: cale, for C18H25N5? 3 (359.4); found (pos.): 360.6 [M + H].
Example 10 N-. { (R) -2-Cyclopentylmethyl-3 - [(S) -2- (3 H -imidazo [4,5-c] pyridin-2-yl) -pyrrolidin-1-yl] -3-oxo-propyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7
(R2 = cyclopentylmethyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-3H-imidazo [4,5-c] pyridine E-5 (the preparation is described in the Procedure General E; PG = CBz) according to General Procedure B. 1 H-NMR (MeOH-d 4, rotamers): d 8.38-8.19 (m, 1.57H), 7.83 (s, 0.74H), 7.74 (s, 0.49 H), 7.65 (br.s, 0.86H), 5.30-5.22 (m, 1.0H), 3.98-3.83 (m, 2.05H), 3.83-3.58 (m, 2.63H), 3.53-3.41 (m, 1.09) H), 3.34 (s, 1.28H), 3.17-3.07 (m, 0.41H), 2.45-2.00 (m, 5.07H), 1.89-1.72 (m, 2.92H), 1.68-1.23 (m, 0.75H) , 1.23-0.90 (m, 2.87H).
1dC-NMR (MeOH-d4, rotamers): d 175.3, 164.0, 159.7, 56.8, 53.5, 42.4, 38.8, 37.3, 33.9, 33.7, 32.3, 26.3, 26.1, 25.9, 23.4.
Example 11 N-. { (R) -2-Cyclopentylmethyl-3 - [(2S, 4R) -4-fluoro-2- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolidin-1-yl] -3- oxo-propyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7
(R2 = cyclopentylmethyl, the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -3H-imidazo [4,5-c] pyridine E-5 (the preparation is described in General Procedure E; PG = CBz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.88 (s, 0.08H), 8.85 (s, 0.71H), 8.32 (d, J = 5.9, 0.71H), 8.30-8.23 (m, 0.54H), 8.15 (s, 0.74H), 7.82 (s, 0.36H), 7.76-7.63 (m, 1.10H), 5.55 (br.s, 0.62H), 5.42 (br.s, 0.54H), 5.34 (t, J = 9.1, 8.5, 0.85H), 4.40-4.19 (m, 1.04H), 4.19-3.97 (m, 0.89H), 3.90-3.78 (m, 0.46H), 3.78-3.66 (m, 0.69H), 3.54-3.38 (m, 0.98H), 3.26-3.16 (m, 0.51H), 3.16-3.06 (m, 0.36H), 2.84-2.67 (m, 0.45H), 2.57-2.44 (m, 0.55H), 1.92-1.70 (m, 1.52H), 1.70-1.24 (m, 7.46H), 1.24-1.15 (m, 0.27H), 1.15-1.00 (m, 1.02H), 1.00-0.83 (m, 0.80H).
13C-NMR (MeOH-d4, rotamers): d 175.5, 175.3, 165.5, 164.0, 161.2, 159.6, 159.4, 140.5, 140.4, 138.1, 112.4, 111.0, 94.3, 94.0, 92.5, 92.3, 57.0, 55.2, 42.4, 38.9, 38.6, 37.4, 33.9, 26.0. ES-MS: cale, for C20H26FN5O3 (403.20); found (pos.): 404.8 [M + H]; found (neg.): 402.4 [M-H].
Example 12 N-. { (R) -2 - [(2S, 4R) -4-Fluoro-2- (3H-imidazo [4,5-c] pyridin-2-yl) -pi rrol id in -1-carbon I I] -hexyl } -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -3H-imidazo [4,5-c] pyridine E-5 (the preparation is described in General Procedure E; PG = CBz) of according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.86 (s, 0.77H), 8.32 (d, J = 5.88, 0.72H), 8.32-8.28 (m, 0.14), 8.28-8.24 (m, 0.41H) , 8.19 (s, 0.80H), 7.82 (s, 0.37H), 7.80-7.70 (d, J = 6.1, 0.13H), 7.70-7.56 (m, 1.02H), 5.66-5.50 (m, 0.59H) , 5.41 (bs, 0.47H), 5.36-5.20 (m, 0.83H), 4.50-3.94 (m, 1.79H), 3.90-3.66 (m, 1.13H), 3.66-3.44 (m, 0.55H), 3.44 -3.34 (m, 0.53H), 3.24-3.14 (m, 0.46), 3.14-3.04 (m, 0.32H), 3.04-2.84 (m, 0.41H), 2.84-2.66 (m, 0.86H), 2.64- 2.52 (m, 0.49H), 2.52-2.36 (m, 0.49H), 1.60-1.04 (m, 6.84H), 1.0-0.84 (m, 0.83H), 0.84-0.70 (m, 2.16H). ES-MS: cale, for C18H24FN5O3 (377.42); found (pos.): 378.9 [M + H].
Example 13 N-. { (R) -2 - [(S) -2- (6,7-Dihydro-1 H -5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-2-yl) -pyrrolidin-1 - carbon il] -hexyl} -N-hydroxy -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-6,7-dihydro-1 H-5,8-dioxa-1,3-diaza-cyclopenta [b] -naphthalene E-5 (the preparation is described in the Procedure General E; PG = CBz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.14H), 8.23 (s, 0.14H), 7.89 (s, 0.23H), 7.83 (s, 0.39H), 7.77 (s, 0.15H) ), 7.04 (s, 0.30H), 6.97 (s, 0.37H), 6.93 (s, 0.98H), 5.34 (d, J = 7.5, 0.41H), 5.19-5.11 (m, 0.59H), 3.92- 3.79 (m, 1.41H), 3.77-3.55 (m, 1.87H), 3.48-3.38 (m, 0.88H), 3.25-3.17 (m, 0.45H), 3.12-3.02 (m, 0.22H), 2.67- 2.59 (m, 0.23H), 2.44-2.10 (m, 2.67H), 2.10-1.96 (m, 1.08H), 1.89-1.77 (m, 0.42H), 1.63-1.16 (m, 6.74H), 0.97- 0.79 (m, 3.33H).
13C-NMR (MeOH-d4, rotamers): d 176.2, 175.6, 175.1, 164.0, 163.4, 159.9, 159.7, 156.5, 155.6, 155.1, 142.9, 142.8, 142.5, 102.5, 65.5, 56.7, 53.3, 42.9, 32.2, 30.9, 30.2, 30.1, 25.8, 24.0, 23.9, 23.8, 14.2, 14.2. ES-MS: cale, for C21H28N4O5 (416.21); found (pos.): 417.0 [M + H]; found (neg.): 415.5 [M-H].
Example 14 N-. { (R) -2 - [(S) -2- (7-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 7-Chloro-2- (S) -pyrrolidin-2-yl-5-trifluoromethyl-1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.54 (s, 0.03H), 8.28 (s, 0.22H), 7.89-7.71 (m, 1.59H), 7.57-7.47 (m, 0.80H), 7.42 ( s, 0.06H), 7.32 (s, 0.06H), 5.46-5.39 (d, 0.23H), 5.25-5.17 (m, 0.77H), 3.97-3.75 (m, 2.03H), 3.75-3.55 (m, 1.71H), 3.49-3.33 (m, 1.11 H), 3.14-3.08 (m, 0.40H), 2.47-1.88 (m, 4.52H), 1.65-1.18 (m, 7.15H), 1.01-0.77 (m, 3.29H).
13 C-NMR (MeOH-d4, rotamers): d 175.1, 164.0, 161.0, 159.7, 159.7, 126.5, 126.2, 119.8, 56.8, 53.3, 43.1, 43.0, 32.6, 31.0, 30.1, 25.9, 24.0, 23.8, 14.2 . ES-MS: cale, for C2oH2 CIF3N? 3 (460.15); found (pos.): 461.2 [M + H]; found (neg.): 459.6 [M-H].
Example 15 N-Hydroxy-N - ((R) -2- { (S) -2- [5- (4-methyl-piperazin-1-yl) -1H-benzoimidazol-2-yl] -pyrrolidin- 1-carbon i l.}. -hexyl) -formam ida
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5- (4-Methyl-piperazin-1-yl) -2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.35 (s, 0.86H), 8.22 (s, 0.14H), 7.85-7.70 (m, 0.65H), 7.50-7.35 (m, 0.84H), 7.13- 6.90 (m, 1.52H), 5.40-5.30 (m, 0.40H), 5.20-5.08 (m, 0.60H), 3.90-3.79 (m, 1.77H), 3.79-3.60 (m, 2.39H), 3.50- 3.38 (m, 1.20H), 3.25-3.07 (m, 5.67H), 2.90-2.68 (m, 3.63H), 2.48-2.17 (m, 3.42H), 2.10-1.98 (m, 1.41H), 1.90- 1.73 (m, 0.54H), 1.60-1.18 (m, 6H), 0.98-0.86 (m, 1.24H), 0.86-0.72 (m, 1.76H).
13 C-NMR (MeOH-d 4, rotamers): d 175.8, 175.1, 168.5, 164.0, 163.3, 160.0, 159.7, 156.9, 148.3, 116.9, 116.8, 116.5, 116.4, 103.5, 55.4, 55.3, 44.4, 43.0, 32.3, 30.9, 30.2, 25.8, 23.8, 14.3, 14.2. ES-MS: cale, for C2 H36N6? 3 (456.59); found (pos.): 457.6 [M + H]; found (neg.): 455.5 [M-H].
Example 16 N-. { (R) -2 - [(S) -2- (5-Fluoro-1 H -benzoimidazol-2-yl) -pyrrolidin-1-ca r bo n I I -hexyl} -N-hydroxy -forma my da
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5-Fluoro-2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): 8.28 (s, 0.18H), 8.10 (s, 0.17H), 7.90-7.70 (m, 0.65H), 7.53-7.32 (m, 1H), 7.20-7.15 ( m, 1H), 6.98-6.90 (m, 1H), 5.45-5.30 (m, 0.34H), 5.20-5.07 (m, 0.66H), 3.90-3.78 (m, 1.46H), 3.78-3.53 (m. m, 1.86H), 3.50-3.35 (m, 0.87H), 3.15-3.00 (m, 0.29H), 2.95-2.80 (m, 0.23H), 2.57-1.78 (m, 4.29H), 1.68-1.10 ( m, 6H), 1.00-0.75 (m, 3H).
13C-NMR (MeOH-d4, rotamers): d 175.1, 162.1, 158.7, 112.4, 110.8, 110.5, 57.5, 56.1, 53.3, 51.9, 47.4, 43.6, 32.3, 30.9, 30.2, 27.1, 25.8, 23.8, 23.3, 16.1, 14.9, 13.6. ES-MS: cale, for C? 9H25FN4O3 (376.43); found (pos.): 377.8 [M + H]; found (neg.): 375.2 [M-H], 489.2 [M + CF3CO2].
Example 17 N-. { (R) -2 - [(S) -2- (5-Chloro-1H-benzoimidazol-2-yl) -pyrrolidin-1 ca rbo n i I] -hexyl} -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A ) and 5-Chloro-2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E, PG = Boc) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.23 (s, 0.30H), 8.17 (s, 0.06H), 7.83 (0.42H), 7.63 (s, 0.22H), 7.59-7.48 (m, 1.93H) ), 7.28-7.17 (m, 1.97H), 5.54-5.45 (m, 0.62H), 5.43-5.37 (br.s, 0.51H), 5.31 (t, J = 8.5, 8.3, 0.88H), 4.38- 4.15 (m, 1.0H), 4.15-3.94 (m, 0.79H), 3.87-3.68 (m, 1.13H), 3.49-3.32 (m, 1.29H), 3.25-3.13 (m, 0.58H), 3.13- 3.04 (m, 0.34H), 3.00-2.84 (m, 0.39H), 2.84-2.58 (m, 1.30H), 2.58-2.43 (m, 0.54H), 2.43-2.37 (m, 0.13H), 1.87- 1.14 (m, 9.50H), 1.11-0.81 (m, 1.91H).
3C-NMR (MeOH-d4, rotamers): d 175.2, 163.0, 160.4, 155.9, 124.4, 122.8, 115.1, 55.8, 54.3, 50.0, 43.0, 41.7, 39.3, 38.1, 34.0, 32.6, 27.3, 26.0, 24.7. ES-MS: cale, for Ci9H25CIN O3 (392.16); found (pos.): 394.0 [M + H]; found (neg.): 391.3 [M-H]; 505.5 [M + CF3CO2].
Example 18 N-. { (R) -2 - [(S) -2- (5,6-Difluoro-1H-Benzoimidazol-2-yl) -pyrrolidin-1 ca r bo n i I] -hexyl} -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5,6-Difluoro-2- (S) -pyrrolidin-2-yl-1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 7.88-7.78 (m, 0.46H), 7.70 (s, 0.13H), 7.52-7.30 (m, 1.41H), 5.48 (s, 0.27H), 5.40- 5.35 (m, 0.21H), 5.28-5.08 (m, 0.52H), 3.92-3.77 (m, 1.57H), 3.77-3.60 (m, 1.73H), 3.57-3.35 (m, 0.93H), 3.20- 3.04 (m, 0.38H), 2.90-2.78 (m, 0.22H), 2.70-2.58 (m, 0.16H), 2.50-1.95 (m, 4H), 1.65-1.10 (m, 6H), 0.95-0.72 ( m, 3H). ES-MS: cale, for C19H24F2N4O3 (394.42); found (pos.): 395.5 [M + H]; found (neg.): 393.5 [M-H].
Example 19 N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-methoxy-1H-benzoimidazol-2-yl) -pyrrolidine-1-carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5-Methoxy-2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.17H), 7.89 (s, 0.17H), 7.84 (s, 0.36H), 7.78 (s, 0.17H), 7.51-7.35 (m, 1H), 7.09-7.0 (m, 0.79H), 6.93-6.8 (m, 1H), 5.45-5.38 (m, 0.4H), 3.94-3.85 (m, 1.24H), 3.86-3.79 (m, 3.3H) ), 3.8-3.6 (m, 2H), 3.53-3.4 (m, 0.88H), 3.29-3.2 (m, 0.45H), 3.16-3.05 (m, 0.23H), 2.94-2.85 (m, 0.22H) , 2.69-2.6 (m, 0.22H), 2.51-2.15 (m, 2.8H), 2.14-2.0 (m, 1H), 1.95 (m, 0.03H), 1.92-1.78 (m, 0.44H), 1.67- 1.15 (m, 7H), 0.97-0.88 (m, 1.6H), 0.86-0.75 (m, 1.9H). ES-MS: cale, for C20H28N4O4 (388.47); found (pos.): 389.7
[M + H]
EXAMPLE 20 2 - ((S) -1- { (R) -2 - [(Formyl-hydroxy-amino) -methyl] -hexanoyl} -pyrrolidin-2-yl) -1 H methyl ester -benzoimidazole-5-carboxylic acid
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-1 H-benzoimidazole-5-carboxylic acid methyl ester E-5 (the preparation is described in General Procedure E; PG = CBz) according to the General Procedure Procedure B .
1 H-NMR (MeOH-d 4, rotamers): d 8.29-8.2 (m, 0.8H), 7.99-7.9 (m, 0.7H), 7.85-7.8 (m, 0.2H), 7.76 (s, 0.1H), 7.61-7.52 (m, 0.6H), 5.45-5.4 (m, 0.2H), 5.32-5.25 (m, 0.4H), 5.22-5.15 (m, 0.7H), 4.57-4.55 (m, 0.2H), 3.91 (s, 2.8H), 3.82-3.6 (m, 1H), 3.51-3.4 (m, 0.6H), 3.2-3.02 (m, 0.2H), (s, 0.1H), 2.93-2.8 (m, 0.4H), 2.8 (s, 0.12H), 3.63-3.5 (m, 0.77H), 2.31-2.2 (m, 0.7H), 2.27-2.05 (m, 1.4H), 1.98 (s, 0.3H), 1.74-1.15 (m, 5.2H), 0.99-0.9 (m, 0.8H), 0.94-0.8 (m, 1.4). ES-MS: cale, for C21H28N4O5 (416.48); found (pos.): 417.5 [M + H].
Example 21 N-. { (R) -2 - [(S) -2- (5-Chloro-6-fluoro-1H-benzoimidazol-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5-Chloro-6-fluoro-2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = Boc) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.45 (s, 0.17H), 8.27 (s, 0.18H), 7.83-7.8 (m, 0.51H), 7.77 (s, 0.16H), 7.61-7.55 (s m, 0.45H), 7.35-7.3 (m, 0.52H), 5.4-5.35 (m, 0.31H), 5.24-5.15 (m, 0.69H), 3.89-3.8 (m, 1.4H), 3.77-3.6 ( m, 1.9H), 3.47-3.35 (m, 1H), 3.27-3.2 (m, 0.66H), 3.14-3.05 (m, 0.42H), 3.0 (s, 0.07H), 2.9-2.85 (m, 0.24) H), 2.49-2.4 (m, 0.42H), 2.39-2.2 (m, 1.8H), 2.19-2.0 (m, 1.9H), 1.62-1.5 (m, 1H), 1.49-1.4 (m, 1H) , 1.4-1.2 (m, 4.7H), 0.97-0.9 (m, 1H), 0.87-0.8 (m, 1.7H). ES-MS: cale, for d9H2 CIFN4O3 (410.88); found (pos.): 411.5 [M + H].
Example 22 N-. { (R) -2 - [(S) -2- (5-Amino-1H-benzoimidazol-2-yl) -pyrrolidin-1 ca r bo n i I] -h ex i l} -N-hydroxy -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5-amino-2- (S) -pyrrolidin-2-yl-1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = X) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.00-7.64 (m, 0.85H), 7.34-7.2 (m, 0.77H), 6.85 (s, 7.12H), 6.80-6.65 (m, 0.95H), 5.40-5.30 (m, 0.42H), 5.24-5.05 (m, 0.58H), 3.97-3.77 (m, 1.34H), 3.77-3.54 (m, 1.86H), 3.54-3.33 (m, 0.93H), 3.15-3.0 (m, 0.39H), 3.0-2.84 (m, 0.30H), 2.67-2.54 (m, 0.35H), 2.47-2.10 (m, 2.75H), 2.10-2.02 (m, 1H), 1.67 -1.17 (m, 7.28H), 0.97-0.85 (m, 1.29H), 0.85-0.70 (m, 1.57H). ES-MS: cale, for C19H27N5? 3 (373.46); found (pos.): 374.7 [M + H].
Example 23 N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-methyl-1H-benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5-Methyl-2- (S) -pyrrolidin-2-yl-1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.03 (s, 0.19H), 7.87 (s, 0.40H), 7.83 (s, 0.17H), 7.70-7.60 (d, J = 8.19, 0.18H), 7.46-7.30 (m, 1.18H),
7. 29 (s, 0.74H), 7.26-7.16 (m, 0.34H), 7.16-6.94 (m, 1.05H), 5.46- 5.30 (m, 0.39H), 5.26-5.12 (m, 0.61H), 3.96- 3.78 (m, 1.45H), 3.78-3.55 (m, 2.08H), 3.50-3.36 (m, 0.91H), 3.28-3.15 (m, 0.70H), 2.42 (s,
3. 44H), 2.40-2.14 (m, 2.72H), 2.14-1.95 (m, 1.4H), 1.65-1.48 (m, 1.39H), 1.48-1.10 (m, 7.43H), 0.95-0.85 (m, 1.52) H), 0.85-0.75 (m, 1.98H). ES-MS: cale, for C20H28N4O3 (372.47); found (pos.): 373.6 [M + H].
Example 24 N-Hydroxy-N-. { 2- [2- (5-Trifluoromethyl-1H-Benzoimidazol-2-yl) pyrrolidin-1 -carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 2- (S) -Pyrrol idin-2-yl-5-trifluoromethil-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = Boc) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.20H), 7.90-7.60 (m, 2.40H), 7.60-7.40 (m, 0.93H), 5.55-5.40 (m, 0.37H), 5.30-5.13 (m, 0.63H), 3.90-3.55 (m, 3.31H), 3.55-3.33 (m, 0.93H), 3.17-3.0 (m, 0.29H), 3.0-2.85 (m, 0.23H), 2.80 ((s, 2.70H), 2.73-2.55 (m, 0.18H), 2.55-2.42 (m, 0.28H), 2.42-2.33 (m, 0.98H), 2.33-2.23 (m, 0.89H), 2.23 -2.13 (m, 0.93H), 2.13-2.0 (m, 1.27H), 1.70-1.03 (m, 7.90H), 1.0-0.83 (m, 1.31H), 0.83-0.70 (m, 1.89H). -MS: cale, for C2oH25F3N4? 3 (426.44), found (pos.): 427.6 [M + H].
Example 25 [2 - ((S) -1- { (R) -2 - [(formyl-hydroxy-amino) -methyl] -hexanoyl.} - pyrrolidin-2-yl) -1 H -benzoimidazole- 5-yl] - pyrazine-2-carboxylic acid amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and ((S) -2-pyrrolidin-2-yl-3H-benzoimidazol-5-yl) -amide of pyrazine-2-carboxylic acid E-5 (the preparation is described in General Procedure E; PG = CBz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 9.34 (s, 1.19H), 8.81 (s, 1.21H), 8.74 (s, 1.24H), 8.34-8.14 (m, 1.22H), 7.84 (s, 0.53H), 7.80-7.70 (m, 0.30H), 7.70-7.60 (m, 0.18H), 7.60-7.40 (m, 1.87H), 5.54-5.34 (m, 0.35H), 5.34-5.10 (m, 0.65H), 4.0-3.80 (m, 1.58H), 3.80-3.55 (m, 2.17H), 3.55-3.36 (m, 0.93H), 3.17-3.04 (m, 0.31H), 2.98-2.84 (m, 0.20H), 2.76-2.60 (m, 0.21H), 2.54-1.94 (m, 4.63H), 1.70-1.10 (m, 7.74H), 1.0-0.64 (m, 3.63H). ES-MS: cale, for C 24 H 29 N 7 O (479.54); found (pos.): 480.5 [M + H].
Example 26 N- [2 - ((S) -1- { (R) -2 - [(Formyl-hydroxy-amino) -methyl] -hexanoyl.} - pyrrolidin-2-yl) -3H-benzoimidazole -5-yl] -benzenesulfonamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and N - ((S) -2-Pyrrolidin-2-yl-3H-benzoimidazol-5-yl) -benzenesulfonamide E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B .
1 H-NMR (MeOH-d 4, rotamers): d 8.36 (s, 0.17H), 7.82 (s, 0.43H),
7. 76-7.60 (m, 1.94H), 7.46-7.14 (m, 3.49H), 7.04-6.80 (m, 0.91H), 5.48-5.30 (m, 0.30H), 5.24-5.0 (m, 0.70H), 3.96-3.74 (m, 1.66H),
3. 74-3.52 (m, 1.86H), 3.52-3.34 (m, 0.99H), 3.17-3.04 (m, 0.31H),
2. 98-2.84 (m, 0.20H), 2.76-2.60 (m, 0.21H), 2.50-1.94 (m, 4.13H),
1. 94-1.66 (m, 0.49H), 1.66-1.06 (m, 6.87H), 1.0-0.84 (m, 1.09H), 0.84-0.64 (m, 1.90H). ES-MS: cale, for C25H31N5? 5S (513.62); found (pos.): 514.3 [M + H].
Example 27 N-. { (R) -2 - [(S) -2- (2, 2-difluoro-5H- [1,3] dioxolo [4 \ 5X4,5] benzo [1,2-d] im-idazol-6-yl ) -pyrrolid i n-1 -car bon i I] -hexyl} -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 2,2-Difluoro- 6- (S) -pyrrolidin-2-yl-5H- [1,3] dioxolo [4,, 5,: 4,5] benzo [1,2-d] imidazole E-5 (the preparation is described in General Procedure E, PG = CBz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.15H), 7.93-7.80 (m, 0.50 H), 7.77 (s, 0.17H), 7.50-7.34 (m, 0.45H), 7.31 ( s, 1.04H), 5.44-5.30 (m, 0.31H), 5.26-5.03 (m, 0.68H), 3.96-3.74 (m, 1.72H), 3.74-3.54 (m, 1.80H), 3.50-3.33 ( m, 0.94H), 2.50-2.13 (m, 3.03H), 2.13-2.03 (m, 0.96H), 1.66-1.50 (m, 1.38H), 1.50-1.34 (m, 1.24H), 1.34-1.14 ( m, 5.56H), 1.0-0.86 (m, 1.21H), 0.86-0.73 (m, 1.88H). ES-MS: cale, for C2oH24F2N4? 5 (438.43); found (pos.): 439.6 [M + H].
Example 28 N-Hydroxy-N - ((R) -2- { (S) -2- [6- (morpholin-4-sulfonyl) -1H-benzoimidazol-2-yl] -pyrrolidine-1-carbonyl}-hexyl) -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 6- (Morpholin-4) -sulfonyl) -2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E, PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.21H), 7.95 (s, 0.68H), 7.83 (s, 0.49), 7.75-7.50 (m, 2.13H), 5.64-5.34 (m , 0.25H), 5.30-5.10 (m, 0.75H), 3.90 (t, J = 6.63, 1.51H), 3.80-3.60 (m, 5.72H), 3.55-3.34 (m, 0.83H), 3.16-3.03 (m, 0.31H), 3.00-2.84 (m, 3.83H), 2.50-2.24 (m, 1.80H), 2.24-2.00 (m, 1.87H), 1.66-1.50 (m, 1.17H), 1.50-1.35 (m, 1.12H), 1.35-1.10 (m, 4.93H), 1.00-0.85 (m, 0.77H), 0.854-0.70 (m, 2.17H). ES-MS: cale, for C ^ HssNsOeS (507.61); found (pos.): 508.6 [M + H].
EXAMPLE 29 N - ((R) -2 - [(S) -2- (1,7-Dihydro-imidazo [4,5-f] indazol-6-yl) -pyrrolidine 1 -ca r bon i I] - hexyl.}. -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -6- Pyrrolidin-2-yl-1, 7-Dihydro-imidazo [4,5-f] indazole E-5 (the preparation is described in General Procedure E, PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.18-8.02 (m, 0.84H), 7.98-7.80 (m, 1.37H), 7.65-7.40 (m, 0.79H), 5.50-5.38 9m, 0.36H) , 5.28-5.10 (m, 0.64H), 3.95-3.60 (m, 4.76H), 3.55-3.38 (m, 1.24H), 2.50-2.00 (m, 3.58H), 2.00-1.80 (m, 0.42H) , 1.68-1.18 (m, 6H), 1.00-0.80 (m, 3H). ES-MS: cale, for C20H26N6O3 (398.47); found (pos.): 399.1 [M + H]; found (neg.): 397.4 [M-H], 511.4 [M + CF3CO2].
Example 30 N-Hydroxy-N-. { (R) -2 - [(S) -2- (9H-purin-8-yl) -pyrrolidin-1-carbon and I] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -8- Pyrrolidin-2-yl-9H-purine E-5 (the preparation is described in General Procedure E, PG = CBz) according to General Procedure B. 1 H-NMR (MeOH-d 4, rotamers): d 9.00-8.95 (m, 0.19H), 8.95-8.70 (m, 1.96H), 8.28 (s, 0.23H), 7.89-7.78 (m, 0.62H), 5.50-5.38 (m, 0.18H), 5.30-5.10 (m , 0.82H), 3.95-3.78 (m, 1.39H), 3.78-3.50 (m, 1.87H), 3.50-3.35 (m, 0.74H), 3.18-3.05 (m, 0.26H), 2.90-2.78 (m, 0.16H), 2.60-1.80 (m, 4.58H), 1.70-1.15 (m, 6H), 1.00-0.70 (m, 3H).
Example 31 N-. { (R) -2 - [(S) -2- (6-Cyano-1H-benzoimidazol-2-yl) -pyrrolidin-1 ca rbo n i I] -hexyl} -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-3H-benzoimidazole-5-carbonitrile E-5 (the preparation is described in General Procedure E, PG = Boc) according to General Procedure B.
1 H-NMR (MeOH-d 4> rotamers): d 7.90-7.45 (m, 3H), 5.42 (s, 1H), 3.76-3.64 (m, 3H), 3.28-3.18 (m, 2H), 2.75-2.58 (m, 4H), 1.45-1.20 (m, 6H), 0.98-0.72 (m, 3H). ES-MS: Cale, for C? O H ^ NsOs (383.45); found (pos.): 384.5 [M + H]; found (neg.): 382.4 [M-H], 496.2 [M + CF3CO2].
Example 32 N-Hydroxy-N - ((R) -2- { (S) -2- [1- (2-methoxy-ethyl) -1H-benzoimidazol-2-yl] -pyrrolidine-1-carbonyl}-hexyl) -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 1- (2-Methoxy) ethyl) -2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole N-3 (the preparation is described in General Procedure N, PG = CBz) according to General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 11.4-11.2 (br, 0.5H), 8.29 (s, 0.090H),
8. 12 (s, 0.10H), 7.83-7.60 (m, 1.90H), 7.30-7.24 (m, 4.20H), 5.59 (d, 0.92H), 4.40-4.20 (m, 2.25H), 4.00-3.55 ( m, 6.38H), 3.50-3.30 (m, 1.04H), 3.26 (s, 0.72H), 3.22 (s, 2.97H), 2.55-2.30 (m, 2.37H), 2.15-2.05 (m, 1.11 H) ), 2.00-1.80 (m, 2.36H), 1.60-1.40 (m, 1.14H), 1.45-1.10 (m, 6.53H), 0.90-0.80 (m, 2.95H), 1.80-1.65 (m, 0.72H) ). 13 C-NMR (CDCl 3, rotamers): d 200.68, 174.39, 161.62, 155.84, 155.56, 140.60, 134.69, 123.79, 123.38, 122.94, 122.43, 119.01, 109.47, 70.83, 70.70, 70.14, 59.27, 59.06, 59.01, 54.68, 52.70, 50.46, 48.60, 46.89, 44.41, 43.85, 33.42, 31.82, 28.89, 28.70, 25.17, 22.94, 22.63, 21.82, 13.90, 13.78. ESI-MS: cale, for C22H32N4O4 (416.52); found (pos.): 417.2 [M + H]. Found (neg.): 415.5 [M-H].
Example 33 N-Hydroxy-N - ((R) -2- { (S) -2- [1 - (2-Hydroxy-ethyl) -1 H -benzoim idazol-2-yl] -pyrrolidin-1 -carbonyl.}. -hexyl) -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 2 - ((S) -2-Pyrrolidin-2-yl-benzoimidazol-1-yl) -ethanol N-3 (the preparation is described in General Procedure N, PG = CBz) according to General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 10.48 (s, 0.50H), 8.22 (s, 0.97H),
7. 70-7.60 (m, 1.03H), 7.30-7.05 (m, 3H), 6.86 (s 0.55H), 5.68 (d,
0. 68H), 5.55-5.30 (m, 0.27H), 5.90-5.75 (br, 0.13H), 4.40-4.15 (m,
1. 88H), 4.15-3.50 (m, 5.47H), 3.42-3.25 (m, 0.80H), 3.18-3.05 (m,
0. 18H), 3.04-2.87 (m, 0.11H), 2.77-2.62 (m, 0.62H), 2.42-2.20 (m,
1. 42H), 2.10-1.75 (m, 2.63H), 1.64-1.05 (m, 5.91H), 0.90-0.74 (m, 2.84H).
13 C-NMR (CDCl 3, rotamers): d 173.94, 172.56, 162.07, 161.72, 156.62, 156.25, 155.92, 142.75, 140.76, 134.67, 134.31, 123.79, 123.35, 122.76, 122.69, 122.29, 122.14, 119.46, 119.20, 109.84, 109.43, 109.26, 61.94, 61.84, 59.64, 55.13, 53.71, 51.10, 49.79, 47.94, 47.30, 47.24, 46.64, 46.33, 43.21, 41.62, 33.15, 31.98, 31.38, 29.86, 29.16, 28.99, 28.67, 25.02, 22.81, 22.73, 22.62, 21.54, 13.89. ESI-MS: cale, for C21H30N4O (402.50); found (pos.): 403.3 [M + H]. Found (neg.): 401.5 [M-H].
Example 34 N-. { (R) -2-Cyclopentylmethyl-3 - [(S) -2- (1H-naphtho [2,3-d] imidazol-2-yl). pyrrolidin-1-yl] -3-oxo-propyl} -N-idroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and (S) ) -2-Pyrrolidin-2-yl-1 H-naphtho [2,3-d] imidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1H-NMR (DMSO-d4, rotamers): d 9.07 (s, 0.25H), 8.92-8.66 (m, 4.09 H), 8.70 (s, 0.51H), 8.60 (s, 0.14H), 8.20-8.00 (s) m, 1.97H), 6.22-6.14 (m, 0.28H), 5.98 (br.s, 0.72H), 4.91-4.76 (m, 1.58H), 4.64-4.47 (m, 1.69H), 4.47-4.28 ( m, 1.75H), 3.13-2.94 (m, 1.58H), 2.94-2.65 (m, 2.10H), 2.65-2.46 (m, 2.63H), 2.46-2.10 (m, 6.68H), 2.09-2.00 ( m, 0.73H), 1.95-1.62 (m, 2.56H), 1.46-1.32 (m, 1.03H), 1.26-1.00 (m, 2.06H).
13C-NMR (DMSO-d4, rotamers): d 172.0, 157.3, 143.8, 135.0, 129.8, 128.0, 127.3, 123.5, 122.8, 114.6, 106.4, 54.9, 51.7, 48.6, 46.9, 46.3, 36.9, 32.6, 32.3, 30.9, 24.8, 24.4. ES-MS: cale, for C25H3oN4? 3 (434.23); found (pos.): 436.0 [M + H]; found (neg.): 433.4 [M-H].
Example 35 N-Hydroxy-N-. { (R) -2 - [(S) -2- (1H-naphtho [2,3-d] imidazol-2-yl) -pyrrolidin-1 carbonyl] -pentyl} -forward
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -pentanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-1 H-naphtho [2,3-d] imidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 8.29 (s, 0.21H), 8.15 (s, 0.17H), 8.08-7.83 (m, 4.28H), 7.81-7.72 (m, 0.19H), 7.42- 7.27 (m, 1.86H), 5.51-5.43 (m, 0.35H), 5.23-5.21 (m, 0.65H), 4.00-3.82 (m, 1.46H), 3.82-3.60 (m, 2.02H), 3.51- 3.38 (m, 0.83H), 3.18-3.09 (m, 0.23H), 2.99-2.84 (m, 0.29H), 2.76-2.65 (m, 0.19H), 2.58-2.00 (m, 3.67H), 1.98- 1.76 (m, 0.52H), 1.67-1.23 (m, 4.12H), 0.99-0.84 (m, 3H). 13 C-NMR (MeOH-d 4, rotamers): d 131.9, 129.7, 128.2, 125.7, 125.6, 124.1, 49.9, 47.0. ES-MS: cale, for C22H26N4? 3 (394.20); found (pos.): 395.9 [M + H]; found (neg.): 393.6 [M-H].
Example 36 N-Hydroxy-N-. { (R) -2 - [(S) -2- (1H-naphtho [2,3-d] imidazol-2-yl) -pyrrolidin-1 -carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-1 H-naphtho [2,3-d] imidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.20 (s, 0.19H), 8.03 (s, 0.32H), 7.90 (s, 1.62H), 7.89-7.82 (m, 1.92H), 7.75 (s, 0.49H), 7.68 (s, 0.15H), 7.34-7.25 (m, 1.93H), 5.39 (d, J = 7.8, 0.29H), 5.25-5.05 (m, 0.71H), 3.89-3.75 (m, 1.52H), 3.72-3.52 (m, 1.73H), 3.45-3.29 (m, 0.73H), 3.10-2.97 (m, 0.19H), 2.89-2.75 (m, 0.34H), 2.67-2.53 (m, 0.15H), 2.51-2.30 (m, 1.28H), 2.29-2.00 (m, 2.39H), 1.99-1.87 (m, 0.32H) 1.87-1.77 (m, 0.30H), 1.76-1.68 (m, 0.24) H), 1.6-1.47 (m, 1.05H), 1.45-1.31 (m, 1.28H), 1.29-1.11 (m, 5H), 0.87-0.81 (m, 1.15H), 0.77-0.70 (m, 1.98H) ). ES-MS: cale, for C23H26 4? 3 (408.50); found (pos.): 409.9 [M + H].
Example 37 N-Hydroxy-N-. { (R) -2 - [(S) -2- (1H-naphtho [2,3-d] imidazol-2-yl) -pyrrolidine-1-carbonyl] -heptyl} -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -heptanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-1 H- naphtho [2,3-d] imidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.00-7.65 (m, 4H), 7.35-7.17 (m, 2H), 5.40-5.30 (m, 0.32H), 5.24-5.08 (m, 0.68H), 3.88-3.75 (m, 1.82H), 3.70-3.50 (m, 2.13H), 3.45-3.27 (m, 1.05H), 2.45-2.28 (m, 1.39H), 2.28-1.90 (m, 2.61H), 1.56-0.98 (m, 8H), 0.90-0.60 (m, 3H). 13C-NMR (MeOH-d4, rotamers): d 173.9, 162.6, 162.0, 161.5, 160.2, 158.3, 137.6, 130.6, 127.5, 123.7, 116.2, 110.5, 102.2, 56.4, 55.5, 51.9, 47.8, 47.0, 46.5, 41.6, 31.7, 31.4, 29.7, 26.2, 24.6, 22.3, 22.1, 13.0, 12.9. ES-MS: cale, for C24H30N4O3 (422.53); found (pos.): 423.6 [M + H]; found (neg.): 421.6 [M-H], 535.6 [M + CF3CO2].
Example 38 N-. { (R) -2-Benzyl-3 - [(S) -2- (1H-naphtho [2,3-d] imidazol-2-yl) -pyrrolidin-1-yl] -3-oxopropyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-phenylpropionic acid A-7 (the preparation is described in General Procedure A) and (S) - 2-Pyrrolidin-2-yl-1 H-naphtho [2,3-d] imidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamer): d 8.18 (m, 1H), 7.97-7.68 (m, 3.38H), 7.35-7.00 (m, 6.01H), 7.00-6.78 (m, 1.60H), 5.25 -5.18 (m, 1H), 4.35-4.20 (m, 0.53H), 3.98-3.88 (d, 0.33H), 3.85-3.60 (m, 1.30H), 3.60-3.22 (m, 2.83H), 2.90- 2.50 (m, 4H), 1.30-1.00 (m, 2H). ES-MS: cale, for C 26 H 26 N 4 O 3 (442.52); found (pos.): 444.1 [M + 1]; found (neg.): 442.3 [M-1], 556.1 [M + CF3CO2].
Example 39 N - [(R) -2 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1-carbonyl) -hexyl] -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.25 (s, 0.24H), 0.78 (s, 0.76H), 7.65-7.55 (m, 1.02H), 7.55-7.47 (m, 0.86H), 7.40- 7.25 (m, 2.13H), 5.30-5.15 (m, 1H), 3.95-3.78 (m, 2.15H), 3.78-3.60 (m, 1.89H), 3.50-3.37 (m, 0.96H), 2.55-2.30 (m, 1.11 H), 2.30-1.95 (m, 2.90H), 1.70-1.18 (m, 6H), 1.00-0.80 (m, 3H).
13C-NMR (MeOH-d4, rotamers): d 175.3, 175.1, 168.2, 163.0, 160.7, 158.7, 151.8, 141.9, 127.2, 127.1, 126.6, 126.5, 125.6, 125.0, 124.9, 121.3, 119.7, 112.5, 112.4, 110.8, 57.2, 55.8, 53.4, 47.3, 43.5, 42.3, 31.8, 31.2, 30.5, 30.1, 25.7, 23.9, 15.0, 13.8. ES-MS: cale, for C? 9H25N3O4 (359.43); found (pos.): 360.8 [M + H].
Example 40 N - [(R) -2 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1 -carbonyl] -heptyl] -N-hydroxyformamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -heptanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.32H), 7.83 (s, 0.68H), 7.67-7.55 (m, 1.02H), 7.55-7.42 (m, 0.87H), 7.42- 7.25 (m, 2.11H), 5.50-5.40 (m, 0.19H), 5.28-5.17 (m, 0.81H), 3.97-3.82 (m, 2.16H), 3.82-3.60 (m, 1.87H), 3.50- 3.35 (m, 0.97H), 2.54-2.34 (m, 1.14H), 2.34-2.00 (m, 2.86H), 1.70-1.15 (m, 8H), 0.97-0.80 (m, 3H). 13 C-NMR (MeOH-d 4, rotamers): d 175.1, 168.2, 160.7, 158.7, 142.1, 127.2, 126.6, 126.5, 125.5, 125.0, 124.9, 121.3, 119.7, 112.5, 110.8, 107.5, 57.2, 55.8, 47.31, 43.6, 42.3, 33.1, 31.8, 27.5, 25.7, 23.6, 15.0, 13.7. ES-MS: cale, for C2oH27N3O (373.46); found (pos.): 375.0 [M + H]; found (neg.): 373.0 [M-H].
Example 41 N - [(R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1-yl) -2-benzyl-3-oxo-propyl] -N-hydroxy form amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-phenylpropionic acid A-7 (the preparation is described in General Procedure A) and (S) - 2-Pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) according to General Procedure B. 1 H-NMR (MeOH-d 4, rotamers): d 8.18 (s, 0.22H) , 7.78-7.68 (d, 0.78H), 7.67-7.37 (m, 1.98H), 7.35-7.15 (m, 3.92H), 7.15-6.95 (m, 3.09H), 5.39 (s, 0.38H), 5.18 -5.08 (m, 0.62H), 4.28-4.17 (d, 0.42H), 3.80-3.55 (m, 1.71H), 3.55-3.35 (m, 1.75H), 3.35-3.26 (m, 1.12H), 2.87 -2.70 (m, 0.94H), 2.70-2.55 (m, 0.96H), 2.10-1.95 (m, 2.10H), 1.80-1.60 (m, 1.26H), 1.55-1.35 (m, 0.74H).
13 C-NMR (MeOH-d 4, rotamers): d 174.1, 167.8, 163.8, 159.8, 151.9,
141. 9, 139.7, 130.2, 130.1, 129.9, 129.8, 129.6, 129.5, 128.2, 127.7,
127. 6, 126.9, 126.4, 126.1, 126.0, 125.8, 120.9, 120.6, 112.1, 111.9,
56. 6, 56.3, 53.4, 47.3, 46.3, 45.2, 38.3, 37.4, 37.0, 32.2, 31.5, 25.5,
23. 2. ES-MS: cale, for C22H23N3O (393.45); found (pos.): 395.1
[M + H]
Example 42 N - [(R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1-yl) -2-cyclopentylmethyl
3-oxo-propyl] -N-hydroxy-formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amine) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) according to General Procedure B. 1 H-NMR (MeOH-d 4, rotamers): d 8.19 (s) , 0.24H), 7.74 (s, 0.58H), 7.69 (s, 0.07H), 7.65-7.58 (m, 0.17H), 7.55-7.47 (m, 0.94H), 7.45-7.38 (m, 0.84H) , 7.35-7.22 (m, 1.97H), 5.40-5.30 (m, 0.15H), 5.18-5.11 (m, 0.85H), 3.87-3.71 (m, 1.76H), 3.71-3.47 (m, 1.56H) , 3.42-3.32 (m, 0.78H), 3.27-3.21 (m, 1.17H), 3.12-2.99 (m, 0.36H), 2.44-2.26 (m, 1.13H), 2.18-1.90 (m, 2.96H) , 1.86-1.49 (m, 2.09H), 1.49-1.24 (m, 6.16H), 1.14-0.89 (m, 2.12H).
13C-NMR (MeOH-d4, rotamers): d 175.2, 168.1, 159.6, 151.8, 142.0, 126.4, 125.8, 120.5, 111.6, 99.5, 56.5, 53.8, 42.5, 38.8, 37.4, 34.2, 33.7, 31.8, 26.2, 25.7. ES-MS: cale, for C2iH27N4O3 (385.20); found (pos.): 386.5
[M + H]; found (neg.): 384.4 [M-H], 769.7 [2M].
Example 43 N - [(R) -2 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1 -carboni I) -pentl] -N-hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -pentanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in the Procedure
General F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.19 (s, 0.24H), 7.76-7.67 (m, 0.68H), 7.67-7.58 (m, 0.16H), 7.58-7.50 (m, 0.89H), 7.49-7.43 (m, 0.76H), 7.37-7.24 (m, 1.84H), 5.40-5.35 (m, 0.19H), 5.16-5.10 (m, 0.81H), 3.86-3.71 (m, 1.66H), 3.71-3.48 (m, 1.53H), 3.42-3.31 (m, 0.84H), 3.25 (s, 1.47H), 3.12-2.94 (m, 0.40H), 2.42-2.24 (m, 1.13H), 2.17- 1.91 (m, 2.70H), 1.56-1.18 (m, 3.87H), 0.90-0.80 (m, 2.79H).
13C-NMR (MeOH-d4, rotamers): d 159.7, 151.8, 141.9, 126.3, 125.8, 120.5, 111.6, 56.5, 53.3, 42.8, 33.5, 31.8, 25.7, 21.1, 14.5. ES-MS: cale, for C18H23N3O4 (345.17); found (pos.): 346.8 [M + H]; found (neg.): 344.6 [M-H].
Example 44 N-. { (R) -2 - [(S) -2- (5-Ethanesulfonyl-benzooxazol-2-yl) -pyrrolidin-1-car bon i I] -hexyl} - N-hydroxy-form my day
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 5-Etanesulfonyl-2- (S) -pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.38H), 8.10 (s, 0.62H),
7. 98-7.80 (m, 1.20H), 7.80-7.70 (m, 1.80H), 5.30-5.10 (m, 1H), 3.94-3.80 (m, 2.19H), 3.80-3.63 (m, 2.27H), 3.50 -3.37 (m, 1.27H), 3.15-3.00 (m, 1.27H), 2.55-2.30 (m, 1.13H), 2.28-2.02 (m, 2.87H), 1.67-1.23 (m, 6H), 1.23- 1.14 (m, 3H), 0.97-0.82 (m, 3H). ES-MS: cale, for C21H29N3O6S (451.55); found (pos.): 452.8 [M + H]; found (neg.): 450.7 [M-H].
Example 45 N-. { (R) -2 - [(S) -2- (5-tert-Butyl-benzooxazol-2-yl) -pyrrolidin-1 carbonyl] -hexyl} -N-hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 5-tert-Butyl- 2- (S) -pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) according to General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 8.28 (s, 0.27H), 7.83 (s, 0.79H), 7.62 (1H), 7.55-7.50 (m, 0.32H), 7.44 (s, 2.21H) , 5.30-5.15 (m, 1.05H), 3.95-3.85 (m, 2.28H), 3.70-3.65 (m, 1.83H), 3.50-3.40 (m, 0.98H), 2.50-2.34 (m, 1.40H) , 2.30-2.05 (m, 3.87H), 1.65-1.43 (m, 2.87H), 1.43-1.25 (m, 17.89H), 0.94-0.83 (m, 4. OOH).
13C-NMR (MeOH-d4, rotamers): d 175.01, 168.33, 164.01, 159.70, 149.84, 149.54, 141.85, 124.73, 124.06, 117.44, 116.85, 110.81, 110.81, 56.54, 53.37, 42.90, 35.77, 32.14, 31.81, 31.12, 30.07, 25.69, 23.88, 14.39. ESI-MS: cale, for C23H33N3O4 (415.25); found (pos.): 416.4 [M + H]; found (neg.): 414.6 [M-H].
Example 46 N-. { (R) -2 - [(S) -2- (6-Chloro-benzooxazol-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -N-hydroxy form amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanolco A-7 acid (the preparation is described in General Procedure A) and 6-Chloro-2- (S) -pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure C.
1 H-NMR (CDCl 3, rotamers): d 9.94 (s, 0.13H), 9.40-8.98 (br, 0.49H), 8.26 (0.17H), 8.12 (s, 0.12H), 7.86-7.71 (m, 0.71H ), 7.54-7.42 (m, 0.95H), 7.42-7.32 (m, 0.50H), 7.32-7.15 (m, 1.10H), 5.30-5.18 (m, 0.72H), 5.18-5.15 (d, J = 7.68, 0.25H), 3.94-3.53 (m, 3.31H), 3.39-3.23 (m, 0.64H), 3.21-3.10 (m, 0.52H), 3.00-2.82 (m, 0.29H), 2.55-1.94 ( m, 3.88H), 1.94-1.05 (m, 7.67H), 0.90-0.65 (m, 3.14H).
13 C-NMR (CDCl 3, rotamers): d 175.68, 172.37, 167.17, 166.30, 161.75, 161.44, 156.89, 156.62, 150.74, 139.96, 130.71, 130.39, 126.30, 125.83, 125.17, 124.93, 121.02, 120.56, 120.44, 119.91, 111.89, 111.49, 111.26, 111.20, 55.57, 55.16, 54.80, 51.27, 47.69, 47.12, 46.45, 46.42, 44.04, 43.28, 41.01, 31.37, 30.68, 30.54, 30.01, 29.91, 29.26, 28.89, 28.80, 24.74, 22.80, 22.76, 22.72, 13.96, 13.85. ESI-MS: cale, for C19H24CIN3O (393.14); found (pos.): 394.8 [M + H].
Example 47 N-. { (R) -2 - [(S) -2- (5,6-Difluoro-benzooxazol-2-yl) -pyrrolidin-1 ca r bo n i I] -hex i l} -N-hydroxy -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 5,6-Difluoro- 2- (S) -pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) according to General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 10.15-9.53 (br, 0.46H), 9.15 (br, 0.10H), 8.33 (s, 0.12H), 8.18 (s, 0.06H), 7.75 (s, 0.97H) ), 7.64-7.53 (m, 0.08H), 7.53-7.38 (m, 0.90H), 7.38-7.25 (m, 0.76H), 5.38-5.30 (m, 0.80H), 5.30-5.22 (m, 0.15H) ), 3.97-3.62 (m, 3.21H), 3.48-3.32 (m, 0.77H), 3.32-3.19 (m, 0.23H), 2.62-2.30 (m, 1.28H), 2.29-1.98 (m, 3.01H) ), 1.93-1.80 (br, 0.1H), 1.70-1.52 (m, 1.20H), 1.54-1.27 (m, 4.95H), 0.97-0.83 (t, J = 6.8Hz).
13 C-NMR (CDCl 3, rotamers): d 172.42, 168.32, 168.29, 161.55, 157.38, 156.94, 149.92, 149.77, 147.47, 147.42, 147.31, 147.27, 145.58, 145.57, 145.46, 145.45, 136.67, 136.56, 107.56, 107.46, 107.35, 99.88, 99.79, 99.65, 99.56, 55.27, 55.09, 54.77, 51.61, 47.63, 47.35, 47.06, 46.42, 43.10, 40.90, 30.71, 30.63, 30.54, 30.00, 29.96, 29.14, 29.85, 29.14, 28.85, 28.74, 24.68, 22.78, 22.74, 22.70, 22.67, 13.92, 13.80. ESI-MS: cale, for C19H23F2N3O4 (395.17); found (pos.): 396.5 [M + H]. Found (neg.): 394.8 [M-H].
Example 48 N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-phenyl-benzooxazol-2-yl) -pyrrolidin-1 carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 5-phenyl-2- (S) -pyrrolidin-2-yl-benzooxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 8.33 (s, 0.18H), 8.21 (s, 0.26H), 8.04 (s, 0.14H), 7.85-7.78 (m, 1.22H), 7.65-7.30 (m, 6.53H), 5.32-5.22 (m, 0.53H), 5.26 (d, J = 7.5, 0.47H), 4.00-3.65 (m, 3.38H), 3.48-3.34 (m, 0.52H), 3.27-3.18 ( m, 0.35H), 3.06-2.92 (m, 0.37H), 2.64-2.01 (m, 4.26H), 2.00-1.20 (m, 8.38H), 0.94-0.82 (m, 2.89).
13 C-NMR (CDCl 3, rotamers): d 172.3, 167.1, 161.8, 161.3, 156.1,
150. 1, 141.6, 139.8, 138.3, 129.0, 128.9, 128.8, 127.7, 127.5, 127.2, 125.9, 124.7, 124.5, 118.6, 118.5, 117.7, 111.2, 110.6, 55.7, 54.9, 50.8, 48.0, 47.2, 46.4, 44.1, 41.2, 32.2, 31.5, 30.8, 30.6, 30.1, 29.9, 29.3, 28.9, 28.9, 24.8, 22.8, 22.3. ES-MS: cale, for C25H29N3O (435.22); found (pos.): 436.7 [M + H]; found (neg.): 434.5.
Example 49 N-Hydroxy-N - [(R) -2 - ((S) -2-oxazolo [4,5-b] pyridin-2-i I -pyr ro I idin -1 carboni I) -hexyl] - formam ida
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-oxazolo [4,5-b] pyridine F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 8.61-8.48 (m, 0.83H), 8.35 (d, J = 13.0, 0.24H), 7.90-7.71 (m, 1.01H), 7.40-7.27 (m, 0.43H ), 4.97-4.71 (m, 1H), 4.12-3.55 (m, 3.15H), 3.51-3.40 (m, 0.61H), 3.25-3.10 (m, 0.23H), 2.62-1.98 (m, 3.86H) , 1.20-1.94 (m, 14.19H), 0.94-0.82 (m, 2.40).
13 C-NMR (CDCl 3, rotamers): d 173.8, 172.5, 169.9, 169.8, 163.5, 161.4, 156.2, 147.1, 146.6, 146.4, 120.6, 120.2, 119.9, 118.8, 118.4, 118.3, 55.4, 55.0, 54.8, 52.3, 50.7, 47.5, 47.1, 42.6, 41.1, 30.7, 30.6, 30.3, 29.9, 29.7, 29.6, 29.0, 28.9, 24.7, 24.4, 22.8, 22.7. ES-MS: cale, for C18H24N4O4 (360.18); found (pos.): 361.2 [M + H]; found (neg.): 359.2.
Example 50 N-Hydroxy-N - [(R) -2 - ((S) -2-naphtho [2,3-d] oxazol-2-yl-pyrrolidin-1 carbonyl) -hexyl] -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-naphtho [2,3-d] oxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.54-8.46 (m, 0.19H), 8.32-8.23 (m, 0.36H), 8.10-7.91 (m, 4.57H), 7.85 (s, 0.82H), 7.79 (s, 0.17H), 7.54-7.42 (m, 1.85H), 7.14 (s, 0.21H), 5.31-5.22 (m, 1.0H), 3.98-3.85 (m, 2.01H), 3.85-3.61 ( m, 2.56H), 3.52-3.41 (m, 1.07H), 2.56-2.39 (m, 1.36H), 2.31-2.00 (m, 4.29H), 1.68-1.27 (m, 8.63H), 1.00-0.82 ( m, 4.27H).
13 C-NMR (MeOH-d 4, rotamers): d 175.1, 170.5, 164.0, 159.7, 150.7, 141.9, 133.1, 132.9, 129.5, 129.0, 126.7, 126.0, 117.8, 107.5, 56.7, 53.4, 42.9, 31.7, 31.1, 30.1, 25.8, 23.9, 14.4, 14.2. ES-MS: cale, for C23H27N3O4 (409.20); found (pos.): 411.0 [M + H]; found (neg.): 408.6 [M-H].
Example 51 N-Hydroxy-N - [(R) -2 - ((S) -2-naphtho [2,3-d] oxazol-2-yl-pyrrolidin-1 carbon i) -heptyl] -formam ida
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-naphtho [2,3-d] oxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 8.40 (s, 0.34H), 8.28 (s, 0.66H), 8.08-7.92 (m, 3.24H), 7.92-7.87 (m, 0.61H), 7.53- 7.40 (m, 1.60H), 7.28-7.18 (m, 0.56H), 5.48 (s, 0.45H), 5.30-5.20 (m, 0.55H), 3.97-3.83 (m, 1.80H), 3.82-3.65 ( m, 2.20H), 3.52-3.40 (m, 1.02H), 2.55-2.35 (m, 1H), 2.35-2.07 (m, 3H), 1.68-1.17 (m, 8H), 0.97-0.75 (m, 3H) ).
13 C-NMR (MeOH-d 4, rotamers): d 175.1, 170.5, 159.7, 150.7, 141.9, 133.1, 132.9, 129.5, 129.0, 126.7, 126.0, 117.9, 107.5, 56.7, 53.4, 42.9, 33.0, 31.7, 31.4, 27.5, 25.8, 23.6, 23.4, 14.4. ES-MS: cale, for C 24 H 29 N 3 O 4 (423.52); found (pos.): 425.0 [M + H]; found (neg.): 422.6 [M-H], 536.6 [M + CF3CO2].
Example 52 N - [(R) -2-Benzyl-3 - ((S) -2-naphtho [2,3-d] oxazol-2-yl-pyrrolidin-1-yl] -3-oxo-prop i I ] -N-hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-phenylpropionic acid A-7 (the preparation is described in General Procedure A) and (S) - 2-Pyrrolidin-2-yl-naphtho [2,3-d] oxazole F-5 (the preparation is described in General Procedure F) according to General Procedure B. 1 H-NMR (MeOH-d 4, rotamers): d 8.55 (s, 0.34H), 8.20-8.05 (m, 0.66H), 8.05-7.90 (m, 1.52H), 7.90-7.78 (m, 1.60H), 7.70-7.62 (m, 0.71H), 7.62 -7.55 (m, 0.73H), 7.55-7.40 (m, 1.03H), 7.40-7.10 (m, 5.04H), 7.06-6.95 (m, 0.37H), 5.48 (s, 0.71H), 5.27-5.15 (m, 0.29H), 3.32-3.17 (m, 5H), 2.20-1.75 (m, 6H).
13 C-NMR (MeOH-d 4, rotamers): d 150.2, 139.5, 133.4, 132.9, 130.9,
130. 2, 129.9, 129.6, 129.1, 128.8, 128.4, 127.8, 126.7, 126.0, 125.6, 124.9, 117.9, 111.8, 107.8, 105.6, 56.5, 54.8, 53.1, 47.4, 45.1, 37.9, 31.5, 25.6. ES-MS: cale, for C 26 H 25 N 3 O 4 (443.51); found (pos.): 444.8
[M + H]; found (neg.): 442.6 [M-H], 556.6 [M + CF3CO2].
Example 53 N - [(R) -2-Cyclopentylmethyl-3 - ((S) -2-naphtho [2,3-d] oxazol-2-yl-pyrrolidin-1-yl) -3-oxopropyl] -N- hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and (S) ) -2-Pyrrolidin-2-yl-naphtho [2,3-d] oxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.54-8.49 (m, 0.15H), 8.31-8.25 (m, 0.24H), 8.21-8.13 (m, 0.12H), 8.10-8.03 (m, 0.83H) ), 8.01-7.91 (m, 2.27H), 7.84 (s, 0.59H), 7.79-7.75 (m, 0.07H), 7.74-7.70 (m, 0.06H), 7.67-7.63 (m, 0.17H), 7.60-7.54 (m, 0.18H), 7.54-7.43 (m, 1.60H), 7.34-7.20 (m, 0.38H), 7.17-7.11 (m, 0.17H), 5.47-5.44 (m, 0.30H), 5.32-5.24 (m, 0.70H), 4.00-3.87 (m, 1.42H), 3.82-3.62 (m, 1.65H),
3. 52-3.41 (m, 0.77H), 3.41-3.31 (m, 1.16H), 2.55-2.37 (m, 0.94H),
2. 34-2.04 (m, 3.06H), 1.98-1.48 (m, 7.91H), 1.46-1.32 (m, 1.03H), 1.26-1.00 (m, 2.06H).
13C-NMR (MeOH-d4, rotamers): d 175.5, 175.2, 170.5, 159.7, 150.7, 144.7, 141.9, 133.1, 132.9, 129.5, 129.0, 126.7, 125.9, 117.9, 107.5, 56.7, 54.8, 53.8, 42.5, 38.8, 37.9, 37.9, 37.5, 34.2, 33.7, 31.7, 26.3, 26.2, 25.8. ES-MS: cale, for C25H29 3O4 (435.22); found (pos.): 437.0 [M + H]; found (neg.): 434.5 [M-H].
Example 54 N-Hydroxy-N - [(R) -2 - ((S) -2-naphtho [2,3-d] oxazol-2-yl-pyrrolidin-1 carbonyl) -pentyl] -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -pentanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-naphtho [2,3-d] oxazole F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.54-8.46 (m, 0.19H), 8.30-8.25 (m, 0.31H), 8.22-8.16 (m, 0.18H), 8.12-7.91 (m, 4.49H) ), 7.84 (s, 0.80H), 7.69-7.62 (m, 0.22H), 7.62-7.53 (m, 0.22H), 7.53-7.44 (m, 2.33H), 7.32-7.20 (m, 0.51H), 7.14 (s, 0.21H), 5.30-5.22 (m, 1.0H), 4.00-3.83 (m, 1.99H), 3.83-3.62 (m, 2.52H), 3.54-3.49 (m, 1.08H), 2.56- 2.38 (m, 1.38H), 2.31-2.00 (m, 4.32H), 1.69-1.32 (m, 5.62H), 1.01-0.91 (m, 4.14H).
13 C-NMR (MeOH-d 4, rotamers): d 175.1, 170.5, 159.7, 150.7, 141.9, 133.1, 132.9, 129.5, 129.0, 126.7, 126.0, 117.8, 107.5, 56.7, 54.8, 53.4, 42.8, 33.8, 33.5, 31.8, 25.8, 21.1, 14.5. ES-MS: cale, for C22H25N3O (395.18); found (pos.): 396.7 [M + H]; found (neg.): 394.7 [M-H].
Example 55 N - [(R) -2 - ((S) -2-Benzothiazol-2-yl-pyrrolidin-1-carbonyl) -hexyl] -N-hydroxy-formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-benzothiazole K-4 (the preparation is described in General Procedure K) according to General Procedure C. 1 H-NMR (MeOH-d 4, rotamers): d 8.28 (s, 0.24H), 8.04 -7.96 (m, 0.29), 7.96-7.80 (m, 2.30H), 7.76 (s, 0.11H), 7.44-7.24 (m, 0.96H), 5.76-5.64 (m, 0.03), 5.64-5.50 (m , 0.11H), 5.50-5.34 (m, 0.86H), 4.10-3.94 (m, 0.09H), 3.94-3.70 (m, 3.32H), 3.70-3.54 (m, 0.33H), 3.54-3.34 (m , 0.80H), 3.20-3.08 (m, 0.31H), 3.08-2.97 (m, 0.07), 2.97-2.80 (m, 0.06H), 2.60-2.46 (m, 0.16H), 2.46-2.30 (m, 1.06H), 2.30-1.90 (m, 3.42H), 1.76-1.57 (m, 0.98H), 1.57-1.14 (m, 5.97H), 1.0-0.82 (m, 3.27H). ES-MS: cale, for C19H25 3? 3S (375.49); found (pos.): 376.4 [M + H].
Example 56 N - [(R) -3 - ((S) -2-Benzothiazol-2-yl-pyrrolidin-1-yl) -2-cyclopentylmethyl-3-oxo-propyl] -N-hydroxy-formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and (S) ) -2- Pyrrolidin-2-yl-benzothiazole K-4 (the preparation is described in General Procedure K) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.53 (s, 0.02H), 8.28 (s, 0.25H), 8.02-7.82 (m, 2.40H), 7.75 (s, 0.07H), 7.56-7.34 ( m, 1.88H), 5.59-5.53 (m, 0.17H), 5.49-5.42 (m, 0.83H), 3.95-3.81 (m, 1.80H), 3.81-3.58 (m, 1.57H), 3.52-3.40 ( m, 0.76H), 3.20-3.10 (m, 0.29H), 3.07-2.84 (m, 0.25H), 2.67 (s, 0.02H), 2.60-2.47 (m, 0.17H), 2.47-2.32 (m, 0.97H), 2.30-1.98 (3.05H), 1.98-1.45 (m, 8.26H), 1.45-1.01 (m, 3.53H), 0.92-0.80 (m, 0.02H).
13C-NMR (MeOH-d4, rotamers): d 175.7, 175.6, 164.0, 159.6, 154.2, 135.8, 127.7, 127.4, 126.4, 123.8, 123.5, 122.9, 60.9, 60.8, 42.4, 38.8, 37.6, 34.2, 33.6, 33.5, 33.3, 16.3, 26.1, 25.4. ES-MS: cale, for C2iH27 3? 3S (401.18); found (pos.): 402.8 [M + H]; found (neg.): 400.4 [M-H].
Example 57 N-. { (R) -2-Cyclopentylmethyl-3-oxo-3 - [(S) -2- (1 H -tetrazol-5-yl) -pyr rolidin-1-yl] -propyl} -N-hydroxyform amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and (S) ) -5-Pyrrolidin-2-yl-1 H-tetrazole H-2 (the preparation is described in General Procedure H) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.28H), 8.04-7.98 (m, 0.11H), 7.82 (s, 0.62H), 7.77 (s, 0.09H), 5.42-5.30 ( m, 1.0H), 3.92-3.75 (m, 2.06H), 3.75-3.66 (m, 1.13H), 3.66-3.52 (m, 0.87H), 3.50-3.32 (m, 0.88H), 3.14-2.98 ( m, 0.41H), 2.52-2.18 (m, 2.28H), 2.18-1.92 (m, 2.35H), 1.92-1.73 (m, 1.45H), 1.73-1.43 (m, 7.90H), 1.41-1.25 ( m, 1.29H), 1.23-0.85 (m, 2.57H).
13 C-NMR (MeOH-d 4, rotamers): d 174.1, 173.7, 163.6, 159.3, 158.3, 157.3, 138.5, 51.8, 50.4, 46.9, 45.8, 41.6, 40.3, 30.6, 24.7, 24.3, 23.5, 23.0.
ES-MS: cale, for C15H24N6? 3 (336.19); found (pos.): 337.6 [M + H]; found (neg.): 335.4 [M-H].
Example 58 N-Hydroxy-N-. { (R) -2 - [(S) -2- (1 H -tetrazol-5-yl) -pyrrolidin-1 -carbonyl] -heptyl} -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -5- Pyrrolidin-2-yl-1 H-tetrazole H-2 (the preparation is described in the General Procedure
H) in accordance with General Procedure B. 1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.33H), 7.83 (s, 0.67H),
. 46 (s, 0.34H), 5.38-5.25 (m, 0.66H), 3.88-3.75 (m, 1.92H), 3.75-3.65 (m, 1.08H), 3.58-3.35 (m, 0.86H), 3.25- 3.14 (m, 0.73H), 3.10- 2.98 (m, 0.42H), 2.40-2.18 (m, 2H), 2.18-2.00 (m, 2H), 1.65-1.09 (m,
8H), 0.92-0.73 (m, 3H).
13C-NMR (MeOH-d4, rotamers): d 175.0, 165.0, 163.0, 160.7, 158.8, 53.3, 47.1, 43.5, 42.2, 33.0, 32.0, 31.2, 27.5, 25.7, 23.4, 22.2, 14.9, 13.7. ES-MS: cale, for C 14 H 24 N 6 O 3 (324.39); found (pos.): 325.8
[M + H]; found (neg.): 323.6 [M-H], 437.7 [M + CF3CO2].
Example 59 (R) -3 - [(S) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] -heptanoic acid hydroxyamide
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 and (S) -2-Pyrrolidin-2-yl-1 H-benzoimidazole E-5 ( the preparation is described in General Procedure E) in accordance with General Procedure D.
1 H-NMR (MeOH-d 4, rotamers): d 7.50-7.40 (m, 2H), 7.25-7.10 (m, 2H), 5.50 (s, 0.11H), 5.28-5.15 (m, 0.89H), 4.00- 3.80 (m, 2H), 3.18-3.02 (m, 1H), 2.40-2.00 (m, 6H), 1.50-1.10 (m, 6H), 0.95-0.74 (m, 3H).
13 C-NMR (MeOH-d 4, rotamers): d 176.7, 171.1, 157.3, 124.3, 122.7, 116.5, 114.9, 57.5, 56.0, 36.0, 32.5, 23.8, 14.9, 13.7.
ES-MS: cale, for C? 9H26N4? 3 (358.44); found (pos.): 359.8 [M + H]; found (neg.): 357.2 [M-H], 471.5 [M + CF3CO2].
EXAMPLE 60 (R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidine-1-carbonyl) -heptanoic acid hydroxyamide
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 and (S) -2-Pyrrolidin-2-yl-benzooxazole F-5 (the preparation was described in General Procedure F) in accordance with General Procedure D.
1 H-NMR (MeOH-d 4, rotamers): d 7.68-7.57 (m, 1.03H), 7.57-7.45 (m, 0.90H), 7.42-7.27 (m, 2.07H), 5.55 (s, 0.84H), 5.30-5.16 (m, 1.16H), 4.05-3.80 (m, 2H), 3.20-3.10 (m, 1H), 2.50-2.05 (m, 6H), 1.65-1.20 (m, 6H), 1.00-0.80 ( m, 3H).
13 C-NMR (MeOH-d 4, rotamers): d 176.5, 170.9, 168.4, 151.8, 141.9, 126.3, 125.7, 120.4, 111.6, 56.4, 54.8, 41.1, 36.3, 33.6, 31.9, 30.1, 25.7, 23.9, 14.4.
ES-MS: cale, for C? 9H25N3O4 (359.43); found (pos.) 360.8 [M + H]; found (neg.): 358.6 [M-H], 472.3 [M + CF3CO2].
Example 61: Acid (R) -3 - [(S) -2- (1H-Benzoimidazol-2-yl) -pyrrolidine-1-carbonyl] -heptanoic acid
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and (S) -2-Pyrrolidin-2-yl-1 H -benzoimidazole E-5 (the preparation is described in General Procedure E) according to General Procedure D.
1 H-NMR (MeOH-d 4, rotamers): d 7.80-7.65 (m, 2H), 7.60-7.48 (m, 2H), 5.30-5.18 (m, 1H), 4.15-4.00 (m, 1H), 3.96- 3.80 (m, 1H), 3.10-3.00 (m, 1H), 2.68-2.54 (m, 2H), 2.35-2.14 (m, 2H), 2.04-1.98 (m, 2H), 1.45-1.15 (m, 6H) ), 0.96-0.77 (m, 3H).
13C-NMR (MeOH-d4, rotamers): d 177.3, 176.1, 157.3, 139.1, 124.6, 124.5, 124.3, 122.8, 116.5, 114.7, 57.4, 55.9, 41.6, 40.2, 37.2, 33.1, 32.4, 30.1, 25.9, 24.6, 23.8, 14.9, 13.6. ES-MS: Cale, for C? 9H25N3O3 (343.43); found (pos.): 344.7
[M + H]; found (neg.): 342.6 [M-H], 456.6 [M + CF3CO2].
Example 62: Acid (R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1 -carboni I) -heptanoic acid
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and (S) -2-Pyrrolidin-2-l-benzooxazole F -5 (the preparation is described in General Procedure F) in accordance with General Procedure D.
1 H-NMR (MeOH-d 4, rotamers): d 7.72-7.58 (m, 1.02H), 7.58-7.45 (m, 0.91H), 7.40-7.20 (m, 2.07H), 5.47 (s, 0.09H), 5.40-5.35 (d, 0.09H), 5.28-5.15 (m, 0.82H). 4.00-3.90 (m, 1H), 3.90-3.78 (m, 1H), 3.18-3.00 (m, 1H), 2.72-2.58 (m, 0.91H), 2.50-2.30 (m, 2.07H), 2.30-2.00 (m, 3.02H), 1.68-1.19 (m, 6H), 0.95-0.80 (m, 3H).
13C-NMR (MeOH-d4, rotamers): d 177.0, 175.9, 168.5, 151.8, 142.0, 126.3, 125.7, 120.5, 111.6, 55.4, 40.8, 37.5, 33.5, 31.9, 30.0, 25.8, 23.9, 14.4. ES-MS: cale, for C19H24N2O (344.41); found (pos.): 345.9 [M + H]; found (neg.): 343.6 [M-H], 457.4 [M + CF3CO2].
EXAMPLE 63 (R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1-carbonyl) -heptanoic acid methoxymethyl-amide
The title compound was prepared from (R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1-carbonyl) -heptanoic acid (the preparation is described in Example 61) and O, N-Dimethyl-hydroxylamine comrcially available through treatment with EDC / HOBt in DMF.
1H-NMR (MeOH-d4, rotamers): d 7.60-7.52 (m, 1.02H), 7.52-7.40 (m, 0.89H), 7.37-7.20 (m, 2.09H), 5.48 (s, 0.33H), 5.25-5.10 (m, 0.67H), 4.05-3.92 (m, 1H), 3.92-3.80 (m, 1H), 3.75-3.58 (m, 3H), 3.20-3.00 (m, 4H), 2.95-2.80 ( m, 1H), 2.60-2.45 (m, 1H), 2.45-2.30 (m, 1H), 2.30-2.00 (m, 3H), 1.68-1.54 (m, 0.98H), 1.54-1.20 (m, 5.02H) ), 1.00-0.80 (m, 3H).
13 C-NMR (MeOH-d 4, rotamers): d 177.3, 168.5, 151.8, 142.0, 126.3, 125.7, 120.4, 111.6, 61.7, 56.4, 40.4, 35.9, 33.6, 31.9, 30.1, 25.8, 23.9, 14.4. ES-MS: cale, for C2iH29N3O4 (387.48); found (pos.): 388.9 [M + H].
EXAMPLE 64 (R) -3 - [(S) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1-car bon i I] -heptane ico acid amide
The title compound was prepared through the treatment of (R) -3 - [(S) -2- (1H-Benzoimidazol-2-yl) -pyrrole idin-1-carbon and I] -heptanoic acid (the preparation was described in Example 60) with ammonia in methanol.
1 H-NMR (MeOH-d 4, rotamers): d 7.67-7.50 (m, 2H), 7.40-7.30 (m, 2H), 5.50-5.40 (m, 0.21H), 5.27-5.15 (m, 0.79H), 4.03-3.95 (m, 1.02H), 3.95-3.78 (m, 1.06H), 3.68-3.57 (m, 0.44H), 3.15-3.00 (m, 1.12H), 3.00-2.85 (m, 0.28H), 2.65-2.06 (m, 7.37H), 1.48-1.10 (m, 6H), 0.92-0.75 (m, 3H).
13 C-NMR (MeOH-d 4, rotamers): d 176.9, 163.7, 156.8, 150.5, 135.7, 126.4, 124.8, 116.1, 114.5, 56.8, 55.4, 41.7, 38.3, 33.0, 32.5, 31.5, 30.0, 14.9. ES-MS: cale, for C19H26N4O2 (342.44); found (pos.): 343.9 [M + H]; found (neg.): 341.4 [M-H], 455.5 [M + CF3CO2].
Example 65 (R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1 carbonyl) -heptanoic acid amide
The title compound was prepared through the treatment of (R) -3 - ((S) -2-Benzooxazol-2-yl-pyrrolidin-1-carbonyl) -heptanoic acid (the preparation is described in Example 61) with ammonia in methanol.
1 H-NMR (MeOH-d 4, rotamers): d 7.65-7.55 (m, 1.05H), 7.55-7.45 (m, 0.91H), 7.40-7.24 (m, 2.03H), 5.30-5.12 (m, 1H) , 4.02-3.90 (m,
1. 10H), 3.90-3.80 (m, 1.19H), 3.20-3.03 (m, 1.22H), 2.62-2.48 (m,
1. 21H), 2.48-2.25 (m, 2.55H), 2.25-2.02 (m, 3.74H), 1.60-1.18 (m, 6H), 0.95-0.75 (m, 3H).
13C-NMR (MeOH-d4, rotamers): d 176.8, 168.5, 142.0, 127.1, 126.6, 126.5, 125.4, 124.9, 121.3, 119.7, 112.4, 110.8, 57.2, 55.7, 41.7, 40.4, 38.7, 33.5, 31.9, 25.8, 23.9, 15.0, 13.8. ES-MS: cale, for C19H25N3O3 (343.43); found (pos.): 344.8 [M + H].
Example 66 N-Hydroxy-N-. { (R) -2 - [(S) -2- (1 H -perimidin-2-yl) -pyrrolidin-1 carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (S) -2- Pyrrolidin-2-yl-1 H -perimidine L-3 (the preparation is described in General Procedure L) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.53 (s, 0.24H), 8.27 (s, 0.20H), 7.87 (s, 0.13H), 7.82 (s, 0.57H), 7.15-6.96 (m, 4.71H), 6.43 (br.s, 2.31H), 4.49-4.38 (m, 0.99H), 3.90-3.80 (t, J = 13.4, 8.1, 1.51H), 3.80-3.65 (m, 1.56H), 3.49-3.40 (m, 0.94H), 2.36-1.90 (m, 4.65H), 1.71-1.23 (m, 5.86H), 0.95-0.84 (m, 2.84H).
13C-NMR (MeOH-d4, rotamers): d 175.0, 160.6, 159.9, 159.7, 158.7, 140.0, 137.0, 130.0, 128.4, 123.5, 120.9, 62.1, 60.6, 43.6, 42.3, 31.5, 30.2, 24.0, 22.7, 14.9, 13.7. ES-MS: cale, for C23H28N4? 3 (408.22); found (pos.): 409.9 [M + H]; found (neg.): 407.5 [M-H], 521.5 [M + CF3CO2].
Example 67 N-. { (R) -2-Cyclopentylmethyl-3-oxo-3 - [(S) -2- (1 H -perimidin-2-yl) -pyrrolidin-1-yl] -propyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and (S) ) -2- Pi rrol idin-2-i I-1 H-perimidine L-3 (the preparation is described in General Procedure L) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.19H), 8.21 (s, 0.27H), 7.87 (s, 0.11H), 7.82 (s, 0.60H), 7.17-6.97 (m, 3.88H), 6.53 (d, J = 7.1, 0.48H), 6.45-6.38 (m, 1.48H), 4.66-4.57 (m, 0.22H), 4.47-4.39 (m, 0.78H), 4.02-3.95 ( m, 0.16H), 3.92-3.55 (m, 3.22H), 3.51-3.40 (m, 0.78H), 3.17-3.08 (m, 0.31H), 2.34-1.86 (m, 5.64H), 1.84-1.45 ( m, 6.68H), 1.43-1.28 (m, 0.87H), 1.25-1.02 (m, 2.05H).
13C-NMR (MeOH-d4, rotamers): d 175.1, 160.6, 159.8, 158.6, 142.0, 137.0, 130.0, 128.4, 123.4, 121.0, 119.4, 109.6, 108.2, 61.9, 60.4, 43.1, 41.8, 39.3, 38.0, 34.4, 31.4, 27.6, 26.3, 25.8, 25.0. ES-MS: cale, for C25H3oN4? 3 (434.23); found (pos.): 436.0 [M + H]; found (neg.): 433.1 [M-H], 547.6 [M + CF3CO2].
Example 68 N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-phenyl-1H-imidazol-2-yl) -pyrrolidin-1 carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 5-Phenyl-2- (S) -pyrrolidin-2-yl-1 H-imidazole G-2 (the preparation is described in General Procedure G) in accordance with General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 8.28 (s, 0.16H), 7.84 (s, 0.42H), 7.78 (s, 0.21H), 7.63 (d, J = 7.4, 2.08H), 7.40- 7.29 (m, 2.45H), 7.29-7.18 (m, 1.67H), 5.30-5.24 (m, 0.41H), 5.15-5.08 (m, 0.59H), 3.93- 3.78 (m, 1.35H) 3.78-3.65 (m, 1.32H), 3.65-3.53 (m, 0.70H), 3.48-3.35 (m, 0.75H) 3.25-3.14 (m, 0.50H), 3.14-3.02 (m, 0.27H), 2.93- 2.82 ( m, 0.22H) 2.67-2.57 (m, 0.24H), 2.45-2.32 (m, 0.47H), 2.32-2.10 (m, 2.26H) 2.10-1.93 (m, 0.45H), 1.93-1.80 (m, 0.45H), 1.66-1.17 (m, 6.47H), 0.96-0.87 (m, 1.36H), 0.87-0.79 (m, 1.82H).
13C-NMR (MeOH-d4, rotamers): d 160.7, 158.8, 130.5, 128.9, 126.7, 125.1, 55.5, 50.4, 47.3, 43.8, 32.6, 30.9, 30.2, 14.8, 13.6, 13.0. ES-MS: cale, for C2? H28N4O3 (384.22); found (pos.): 385.6 [M + H]; found (neg.): 383.2 [M-H], 497.3 [M + CF3CO2].
Example 69 N-. { (R) -2-Cyclopentylmethyl-3-oxo-3 - [(S) -2- (5-phenyl-1H-imidazol-2-yl) -pyr rolidin-1-yI] -propyl} -N-hydroxyformamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7 (the preparation is described in General Procedure A) and feni I-2- (S) -pyrrolidin-2-yl-1 H-imidazole G-2 (the preparation is described in General Procedure G) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.16H), 8.22 (s, 0.30H), 7.83 (s, 0.39H), 7.77 (s, 0.15H), 7.74-7.60 (m, 2.17H), 7.47 (s, 0.04H), 7.39-7.28 (m, 2.92H), 7.28-7.20 (m, 0.95H), 5.30-5.25 (m,
0. 35H) 5.19-5.08 (m, 0.65H) 3.95-3.79 (m, 1.45H) 3.79-3.67 (m, 0.95H) 3.67-3.51 (m, 0.74H) 3.50-3.39 (m, 0.67H) 3.16-3.06 (m, 0.22H) 2.91-2.82 (m, 0.16H) 2.67-2.56 (m, 0.20H) 2.49-2.10 (m, 2.77H) 2.00-1.95 (m, 1.14H) 1.94-1.30 (m, 9.73H) ) 1.24-0.96 (m, 2.12H).
13 C-NMR (MeOH-d 4, rotamers): d 175.2, 167.3, 165.3, 164.9, 164.6,
162. 6, 160.6, 158.6, 150.9, 137.8, 133.4, 130.6, 130.5, 128.9, 125.4,
125. 1, 118.5, 116.6, 56.8, 55.3, 43.1, 41.8, 39.4, 32.1, 27.4, 26.1,
24. 9. ES-MS: cale, for C23H3oN4? 3 (410.23); found (pos.): 412.0
[M + H]; found (neg.): 409.6 [M-H], 523.8 [M + CF3CO2].
Example 70 N-. { 1 - [(S) -2- (1H-Benzoimidazol-2-yl) -pyrrolidine-1-carbonyl] -cydohexylmethyl} -N-hydroxyform amide
The title compound was prepared from 1 - [(Benzyloxy-formyl-amino) -methyl] -cyclohexanecarboxylic acid M-5 (the preparation is described in General Procedure M) and (S) -2-Pyrrolidin-2- il-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.39 (s, 0.62H), 7.92 (s, 0.40H),
7. 48 (br.s, 1.80H), 7.22-7.14 (m, 2.24H), 5.31 (br.s, 1.0H), 4.28-4.14 (m, 1.11 H), 4.07-3.97 (m, 0.68H), 3.90-3.70 (m, 2.76H), 2.37-1.95 (m, 7.10H), 1.67-1.23 (m, 9.58H).
13 C-NMR (MeOH-d 4, rotamers): d 174.9, 168.1, 164.9, 157.8, 124.3, 122.7, 60.1, 58.6, 36.0, 32.3, 31.3, 28.1, 26.8, 25.2, 23.9, 22.8, 5.2. ES-MS: cale, for C2oH26N4O3 (370.20); found (pos.): 371.9 [M + H]; found (neg.): 369.2 [M-H].
Example 71 N-. { (R) -2 - [(S) -2- (1 H-Benzoxydazol-2-yl) -p-penylene n-1-carbonyl] -hexyl} -N-hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 5 (S) -2 -Piperidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.1-8.0 (m, 0.42H), 7.98-7.84 (m,
0. 53H), 7.6-7.44 (bs, 1.83H), 7.30-7.10 (m, 2.20H), 6.1-6.01 (d, J = 3.76, 0.46H), 5.80-5.72 (d, J = 4.64, 0.24H) , 5.72-5.62 (d, J = 3.64, 0.29H), 4.75-4.55 (m, 0.70H), 7.34-7.25 (m, 1.93H), 5.39 (d, J = 7.8, 0.29H), 5.25-5.05 (m, 0.71H), 3.70-3.40 (m, 1.30H), 3.40-3.30 (m, 1.30H), 3.23-3.03 (m, 0.84H), 2.75-2.60 (m, 0.89H), 2.60-2.30 (m, 0.78H), 1.95-1.80 (m, 1H), 1.80-1.44 (m, 6.36H), 1.44-1.25 (m, 5.84H), 1.00-0.8 (m, 3.39H). ES-MS: cale, for C20H28N4O3 (372.47); found (pos.): 373.9 [M + H].
Example 72 N-. { (R) -2 - [(R) -4- (1 H-Benzoimidazol-2-yl) -thiazolidin-3-carbonyl] hexyl} -N-hydroxyformamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and (R) -2- Thiazolidin-4-yl-1 H-benzoimidazole E-5 (the preparation is described in the Procedure
General E) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.52 (s, 0.07H), 8.21 (m, 0.23H), 7.9-7.8 (m, 0.88H), (s, 1.8H), (m, 2.2H ), 5.89 (m, 0.72H), 5.66 (m, 0.55H), (m, H), (dd, J = 0.04, 0.38H), 3.84-3.7 (m, 1.2H), 3.67-3.45
(m, 3.2H), 3.14-3.1 (m, 0.49H), 1.79-1.25 (m, 8H), 0.97-0.75 (m,
3. 6H). ES-MS: cale, for C18H24N4O3S (376.5); found (pos.): 377.1
[M + H]
EXAMPLE 73 2 - ((S) -1-. {(R) -2 - [(Formyl-hydroxy-amino) -methyl] -hexanoyl}. Pyrrolidin-2-yl) -thiazole-4 acid amide -carboxylic
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and acid amide (S) -2-Pyrrolidin-2-ylthiazole-4-carboxylic acid J-4 (the preparation is described in General Procedure J) according to General Procedure C. 1H-NMR (MeOH-d4, rotamers): d 8.30-8.15 ( m, 0.40H), 8.15-8.0 (m, 0.80H), 7.90-7.75 (m, 0.52H), 7.73 (s, 0.08H), 5.70-5.60 (m, 0.06H), 5.60-5.46 (m, 0.17H), 5.46-5.25 (m, 0.78H), 4.0-3.90 (m, 0.18H), 3.90-3.52 (m, 3.10H), 3.52-3.30 (m, 0.69H), 3.20-3.00 (m, 0.38H), 2.60-2.40 (m, 0.16H), 2.40-2.20 (m, 1.68H), 2.20-1.90 (m, 2.14H), 1.76-1.40 (m, 2.32H), 1.40-1.15 (m, 4.25H), 1.0-0.80 (m, 3H). ES-MS: cale, for C? ßH24N4O4S (368.46); found (pos.): 369.20 [M + H].
EXAMPLE 74 Ethyl ester of 2 - ((S) -1- { (R) -2 - [(Formyl-hydroxy-amino) -methyl] -hexanoyl.} - pyrrolidin-2-yl) -thiazole- 4-carboxylic
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and ethyl ester (S) ) -2-Pyrrolidin-2-ylthiazole-4-carboxylic acid J-4 (the preparation is described in General Procedure J) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 1.1H), 7.84 (s, 0.52H),
. 44-5.26 (m, 1H), 4.36 (q, J = 7, 2.36H), 3.90-3.60 (m, 3.46H), 3.54-3.34 (m, 0.83H), 3.20-3.00 (m, 0.36), 2.40-2.20 (m, 2.32H), 2.20-2.04 (m, 2.44H), 1.74-1.42 (m, 2.84H), 1.42-1.26 (m, 8.10H), 1.0-0.74 (m,
3. 56H). ES-MS: cale, for C18H27N3O5S (397.50); found (pos.): 398.6
[M + H]
Example 75 N-. { (R) -2 - [(R) -2- (1 H-Benzoimidazol-2-yl) -pyrrolidin-1 -carbonyl] -hexyl} -N-hydroxy formamide
The title compound was prepared as a mixture with N-. { (R) -2 - [(S) -2- (1H-Benzoimidazol-2-yl) -pyrrole idin-1-carbon I] -hexyl} -N-hydroxyformamide (the preparation is described in Example 1) and was isolated through purification by preparative HPLC.
1 H-NMR (MeOH-d 4, rotamers): d 8.64-8.6 (m, 0.04H), 8.35 (s, 0.23H), 8.33-8.25 (m, 0.16H), 8.01-7.95 (m, 0.07H), 7.81 (s, 0.25H), 7.72 (s, 0.26H), 7.64-7.6 (m, 0.06H), 7.61-7.45 (m, 1.7H), 7.51-7.45 (m, 0.07H), 7.29-7.15 ( m, 1.8H), 5.58-5.5 (m, 0.29H), 5.44-5.5 (m, 0.12H), 5.43-5.35 (m, 0.27H), 5.35-5.25 (m, 0.33H), 4.12-4.0 ( m, 0.32H), 3.98-3.8 (m, 1H), 3.62-3.8 (m, 1.5H), 3.62-3.5 (m, 0.23H), 3.5-3.46 (m, 0.18H), 3.44-3.4 (m , 0.18H), 3.4-3.36 (m, 0.15H), 3.25-3.15 (m, 0.44H), 3.16-3.1 (m, 0.07H), 3.07-2.95 (m, 0.5H), 2.85 (s, 0.2 H), 2.80 (s, 0.6H), 2.61-2.45 (m, 0.47H), 2.45-2.31 (m, 0.6H), 2.29-1.95 (m, 3H), 1.73-1.55 (m, 0.76H), 1.55-1.43 (m, 0.65H), 1.45-1.19 (m, 4H), 1.25-1.05 (m, 1.4H), 0.99-0.85 (m, 1.88H), 0.82-0.6 (m, 1.14H), 0.45 -0.29 (m, 1.4H). ES-MS: cale, for C19H26N O3 (358.4); found (pos.): 359.6 [M + H].
Example 76 N - [(R) -2 - ((R) -2-Benzooxazol-2-yl-pyrrolidin-1-carbon l) -hexyl] -N-hydroxy-formamide
The title compound was prepared as a mixture with N - [(R) -2 - ((R) -2-Benzooxazol-2-yl pyrrolidin-1-carbonyl) -hexy I] - N -hid rox i -formamide (the preparation is described in Example 38) and quenched through purification by preparative HPLC.
1 H-NMR (CDCl 3, rotamers): d 8.50 (s, 0.74H), 8.37-8.20 (m, 0.09H), 7.87-7.80 (m, 0.30H), 7.51 (s, 0.21H), 7.60-7.42 ( 1.83H), 7.38-7.22 (m, 2.18H), 5.50-5.38 (m, 1.03H), 5.28 (s, 0.12H), 4.18-4.07 (dd, J = 13.9, 4.5, 0.79H), 4.07- 4.00 (m, 0.23H), 3.87-3.78 (m, 1.12H), 3.77-3.40 (m, 2.84H), 3.32-3.22 (m, 0.28H), 3.18-3.07 (m, 0.84H), 2.44- 2.18 (m, 2.71H), 2.14-1.88 (m, 2.64H), 1.87-1.80 (m, 0.25), 1.78-1.60 (m, 1.87H), 1.52-1.20 (m, 6.10H), 0.98-0.85 (m, 3.3H), 0.43-0.37 (t, 0.17H).
13 C-NMR (CDCl 3, rotamers): d 173.49, 166.27, 163.08, 156.80,
150. 83, 139.06, 125.58, 125.14, 124.98, 124.70, 120.34, 119.10, 110.90, 110.65, 54.62, 54.46, 52.48, 51.53, 47.45, 47.19, 42.57,
41. 58, 30.50, 30.15, 29.68, 29.60, 29.55, 24.25, 24.14, 22.78, 22.74,
13. 90. ESI-MS: cale, for C? 9H25N3O4 (359.18); found (pos.): 360.5
[M + H] Found (neg.): 358.4 [M-H].
Example 77 N - [(R) -3 - ((R) -2-Benzothiazol-2-yl-pyrrolidin-1-yl) -2-cyclopentylmethyl-3-oxo-propyl] -N-hydroxy-formamide
The title compound was prepared as a mixture with N- [(R) -3 - ((R) -2-Benzothiazol-2-ylpyrrolidin-1-yl) -2-cyclopentylmethyl-3-oxo-propyl] -N- hydroxyformamide (the preparation is described in Example 53) and asylated through purification by preparative HPLC.
1 H-NMR (MeOH-d 4, rotamers): d 8.19 (s, 0.24H), 7.74 (s, 0.58H),
7. 69 (s, 0.07H), 7.65-7.58 (m, 0.17H), 7.55-7.47 (m, 0.94H), 7.45- 7.38 (m, 0.84H), 7.35-7.22 (m, 1.97H), 5.40- 5.30 (m, 0.15H), 5.18- 5.11 (m, 0.85H), 3.87-3.71 (m, 1.76H), 3.71-3.47 (m, 1.56H), 3.42- 3.32 (m, 0.78H), 3.27- 3.21 (m, 1.17H), 3.12-2.99 (m, 0.36H), 2.44-2.26 (m, 1.13H), 2.18-1.90 (m, 2.96H), 1.86-1.49 (m, 2.09H), 1.49- 1.24 (m, 6.16H), 1.14-0.89 (m, 2.12H).
13C-NMR (MeOH-d4, rotamers): d 175.2, 168.1, 159.6, 151.8, 142.0, 126.4, 125.8, 120.5, 111.6, 99.5, 56.5, 53.8, 42.5, 38.8, 37.4, 34.2, 33.7, 31.8, 26.2, 25.7. ES-MS: cale, for C21H27N3O3S (401.18); found (pos.): 402.4 [M + H]; found (neg.): 400.3 [M-H].
Example 78 N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-Nitro-1H-benzoimidazol-2-y1) -pyrrolidin-1-carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R1 = n-butyl, the preparation is described in General Procedure A) and 5-Nitro-2- (S) -pyrrolidin-2-yl-1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = Boc) according to General Procedure C.
1 H-NMR (MeOH-d 4, rotamers): d 8.43 (s, 0.67H), 8.27 (s, 0.20H), 8.25-8.10 (m, 0.94H), 7.85-7.55 (m, 1.6H), 5.52- 5.35 (m, 0.21H), 5.30-5.13 (m, 0.71H), 4.0-3.83 (m, 1.5H), 3.83-3.55 (m, 1.71H), 3.55-3.33 (m, 0.70H), 2.50- 2.0 (m, 3.73H), 1.65-1.10 (m, 6.5H), 1.0-0.72 (m, 3.13H). ES-MS: cale, for Ci9H25N5? 5 (403.44); found (pos.): 404.7 [M + H].
Example 79 N-Hydroxy-N-. { (R) -2 - [(S) -2- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -pyrrolidine-1-carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 5-Trifluoromethoxy-2- (S) -pyrrolidin-2-yl-1 H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = Cbz) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.20H), 7.9-7.74 (m,
0. 70H), 7.69-7.50 (m, 1.10H), 7.50-7.36 (m, 0.83H), 7.25-7.06 (m,
0. 99H), 5.50-5.34 (m, 0.29H), 5.28-5.08 (m, 0.75H), 3.86-3.53 (m,
3. 24H), 3.53-3.33 (m, 0.85H), 2.60-2.0 (m, 4.18H), 1.64-1.10 (m, 6.4H), 1.0-0.70 (m, 3. OH). ES-MS: cale, for C2oH25F3N4O4 (442.44); found (pos.): 443.4 [M + H].
EXAMPLE 80 Amide of 2 - ((S) -1- { (R) -2 - [(Formyl-hydroxy-amino) -methyl] -hexanoyl}. - pyrrolidin-2-yl) -1H- acid nzoimidazole -5-sulphonic
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-3H-benzoimidazole-5-sulfonic acid amide E-5 (the preparation is described in General Procedure E; PG = Cbz) according to General Procedure B.
1H-NMR (MeOH-d4, rotamers): d 8.27 (s, 0.20H), 8.13 (s, 0.23H), 8.10 (s, 0.61H), 7.9-7.74 (m, 1.70H), 7.74-7.66 ( m, 0.24H), 7.63 (d, J = 8.5 Hz, 0.72H), 5.50-5.30 (m, 0.279H), 5.30-5.10 (m, 0.78H), 4.0-3.80 (m, 1.6H), 3.80 -3.60 (m, 1.73H), 3.55-3.35 (m, 0.82H), 3.20-3.05 (m, 0.34H), 2.95-2.80 (m, 0.26H), 2.75-2.60 (m, 0.16H), 2.60 -2.45 (m, 0.29H), 2.45-2.23 (m, 1.79H), 2.23-1.97 (m, 2.59H), 1.97-1.80 (m, 0.34H), 1.66-1.49 (m, 1.19H), 1.49 -1.38 (m, 1.1H), 1.38-1.12 (m, 4.25H), 1.0-0.89 (m, 0.84H), 0.89-0.72 (m, 2.28H).
ES-MS: cale, for C19H27N5O5S (437.52); found (pos.): 438.6 [M + H].
Example 81 N - ((R) -2 - [(2S, 4R) -2- (6,7-Dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-2-yl) ) -4-fluoro-pyrrolidin-1 -carbonyl] -hexyl}. -hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -6,7-Dihydro-1 H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalene E-5 ( the preparation is described in General Procedure E, PG = Boc) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.23 (s, 0.27H), 8.14 (s, 0.095H),
7. 82 (s, 0.41H), 7.18 (s, 0.15H), 7.67 (s, 0.15H), 7.00 (s, 0.27H), 6.95 (s, 0.30H), 6.93 (s, 1.15H), 5.49 ( s, 0.40H), 5.46-5.31 (m, 0.92H), 5.31-5.17 (m, 0.96H), 4.23 (s, 4H), 4.15-3.92 (m, 1.05H),
3. 84-3.56 (m, 1.37H), 3.56-3.33 (m, 1.17H), 3.22-3.10 (m, 0.54H),
3. 10-2.96 (m, 0.34H), 2.96-2.76 (m, 0.55H), 2.76-2.60 (m, 0.97H),
2. 60-2.49 (m, 0.44H), 2.49-2.30 (m, 0.58H), 1.6-1.24 (m, 3.67H), 1.24-1.02 (m, 3.1H), 0.96-0.83 (m, 1H), 0.83 -0.66 (m, 2.2H). ES-MS: cale, for C2? H2 FN4O5 (434.47); found (pos.): 435.6 [M + H].
Example 82 N-. { (R) -2-Cyclopentylmethyl-3 - [(2S, 4R) -2- (6,7-Dihydro-1H-5,8-dioxa-1,3-diazacyclopenta [b] naphthalen-2-yl) -4 -fluoro-pyrrolidin-1-yl] -3-oxo-propyl} -N-hydroxyform amide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7
(R2 = cyclopentylmethyl, the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -6,7-Dihydro-1 H-5,8-dioxa -1, 3-diaza-cyclopenta [b] naphthalene E-5 (the preparation is described in General Procedure E; PG = Boc) according to General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.22 (s, 0.27H), 8.11 (s, 0.22H), 7.82 (s, 0.38H), 7.72 (s, 0.12H), 7.64 (s, 0.12H) ), 7.0 (s, 0.2H), 6.97 (s, 0.2H), 6.93 (s, 1.05H), 5.50 (s, 0.38H), 5.44-5.32 (m, 0.78H), 5.32-5.16 (m, 0.84H), 4.23 (s, 4.6H), 4.15-3.88 (m, 0.76H), 3.88-3.65 (m, 1.16H), 3.50-3.34 (m, 1.12H), 3.25-2.85 (m, 0.98H) ), 2.80-2.53 (m, 1.24H), 2.53-2.40 (m, 0.5H), 2.40-2.30 (m, 0.14H), 1.90-1.70 (m, 1.73H), 1.70-1.40 (m, 6.1H) ), 1.40-1.28 (m, 1.41H), 1.28-1.14 (m, 0.28H), 1.14-0.97 (m, 1.03H), 0.97-0.80 (m, 0.69H). ES-MS: cale, for C23H29FN4O5 (460.51); found (pos.): 461.4 [M + H].
Example 83 N-. { 2 Cyclopentylmethyl-3- [2- (6,7-Dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-2-yl) -pyrrolidin-1-yl] -3-oxo- propyl} -N-hydroxy formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7
(R2 = cyclopentylmethyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-6,7-Dihydro-1 H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalene E-5 (the preparation is described in General Procedure E; PG = Cbz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.15H), 8.21 (s, 0.19H), 7.86 (s, 0.17H), 7.83 (s, 0.37H), 7.75 (s, 0.16H) ), 7.03 (s, 0.24H), 6.98 (s, 0.30H), 6.93 (s, 0.90H), 5.33 (d, J = 6.9, 0.40H), 5.19-5.11 (m, 0.60H), 4.23 ( s, 4. OH), 3.93-3.79 (m, 1.48H), 3.76-3.65 (m, 1.20H), 3.65-3.55 (m, 0.71H), 3.48-3.35 (m, 0.98H), 3.15-3.05 (m, 0.29H), 2.95-2.84 (m, 0.23H), 2.67-2.59 (m, 0.24H), 2.49-2.37 (m, 0.48H), 2.37-2.11 (m, 2.47H), 2.11-1.97 (m, 1.18H), 1.87-1.31 (m, 9.90H), 1.23-0.93 (m, 2.24H).
13C-NMR (MeOH-d4, rotamers): d 176.3, 175.7, 175.2, 166.2, 163.9, 163.4, 159.9, 159.6, 156.3, 155.1, 142.9, 142.8, 142.5, 102.5, 65.5, 57.6, 56.6, 53.4, 38.9, 33.9, 33.8, 32.1, 26.3, 26.2, 26.1, 25.9, 23.2. ES-MS: cale, for C23H3oN4O5 (442.22); found (pos.): 443.6 [M + H]; found (neg.): 441.7 [M-H].
Example 84 N-. { 2- [2- (7,8-Dihydro-3 H -6,9-dioxa-1,3-diaza-cyclopenta [a] naphthalene 2-yl) -pyrrolidin-1-carbonyl] -hexyl} -N-hydroxy-formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-7,8-Dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta [a] naphthalene E-5 (the preparation is described in General Procedure E; PG = Cbz) in accordance with General Procedure B.
1 H-NMR (MeOH-d 4, rotamers): d 8.27 (s, 0.16H), 8.15 (s, 0.18H),
7. 94 (s, 0.20H), 7.83 (s, 0.38H), 7.72 (s, 0.12H), 7.10-7.05 (m, 0.12H), 7.01-6.93 (m, 0.79H), 6.73-6.62 (m, 0.91H), 5.39-5.31 (m,
0 39H), 5.21-5.13 (m, 0.61H), 4.37-4.22 (m, 4. OH), 3.96-3.78 (m,
1 58H), 3.78-3.55 (m, 1.81H), 3.48-3.37 (m, 0.92H), 3.27-3.16 (m,
0 54H), 3.12-3.03 (m, 0.30H), 2.95-2.81 (m, 0.25H), 2.63-2.56 (m,
0 • 25H), 2.48-2.13 (m, 2.74H), 2.11-1.95 (m, 1.15H), 1.91-1.72 (m, 0 0..4400HH)) ,, 1.63-1.14 (m, 6.64H), 0.95-0.79 (m, 3.07H).
3C-NMR (MeOH-d4, rotamers): d 176.4, 175.5, 175.1, 165.6, 164.0,
163. 7, 159.9, 159.7, 156.2, 155.3, 140.0, 133.0, 115.0, 114.6, 114.3,
107. 8, 66.0, 66.0, 65.7, 56.7, 53.2, 43.0, 32.4, 30.9, 30.2, 30.1, 25.8, 24.0, 23.8, 14.2. ES-MS: cale, for C2? H28 4O5 (416.21); found (pos.): 417.1 [M + H]; found (neg.): 415.5 [M-H].
Example 85 N-Hydroxy-N-. { 2- [2- (3-methyl-3H-imidazo [4,5-c] pyridin-2-yl] -pyrrolidine 1-carbonyl.] -hexyl) -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 3-Methyl-2- (S) -pyrrolidin-2-yl-3H-imidazo [4,5-c] pyridine N-3 (the preparation is described in General Procedure N; PG = Cbz) according to the Procedure General B.
1 H-NMR (CDCl 3, rotamers): d 8.92 (s, 0.65H), 8.62-8.22 (m, 4.95H), 8.10 (s, 0.37H), 7.87 (d, J = 6.7, 0.70H), 7.80- 7.67 (m, 2.14H), 5.38- 5.30 (m, 1H), 4.35-4.20 (m, 3.33H), 4.09-3.90 (m, 1.30H), 3.76-3.53 (m, 2.63H), 3.38-3.30 (m, 0.70H), 2.84-2.72 (m, 1.36H), 2.66-2.58 (m, 0.39H), 2.52-2.33 (m, 1.87H), 2.00-1.86 (m, 1.12H), 1.80-1.52 (m, 2.30H), 1.52-1.15 (m, 6.49H), 0.94-0.74 (m, 3.70H).
13 C-NMR (CDCl 3, rotamers): d 175.2, 174.3, 173.8, 173.5, 165.1, 161.5, 157.5, 154.0, 143.4, 142.6, 133.3, 131.9, 131.6, 113.7, 113.3, 58.1, 57.8, 53.1, 48.0, 47.0, 46.8, 46.5, 46.3, 43.8, 43.6, 33.8, 32.8, 31.6, 31.4, 29.2, 29.1, 22.9, 22.8, 22.4, 13.9, 13.8. ES-MS: cale, for C19H27N5? 3 (373.21); found (pos.): 374.3 [M + H].
Example 86 N-Hydroxy-N- (2- { 2- [3- (2-hydroxy-ethyl) -3H-imidazo [4,5-c] pyridin-2-yl] pyrrole idin-1 -carboni .}.-hexyl) -forward
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 2 - ((S) -2-Pyrrolidin-2-yl-imidazo [4,5-c] pyridin-3-yl) -ethanol N-3 (the preparation is described in General Procedure N; PG = Cbz) of according to General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 9.07 (s, 0.37H), 8.95-8.90 (m, 0.59H), 8.42 (d, J = 6.3, 0.39H), 8.36 (s, 0.45H), 8.28 ( s, 0.13H), 8.22-8.13 (m, 0.57H), 8.00 (s, 0.18H), 7.94 (d, J = 6.7, 0.39H), 7.87-7.78 (m, 0.86H), 7.74 (s, 0.36H), 5.46-5.40 (m, 0.57H), 5.34-5.25 (m, 0.43H), 4.69-4.53 (m, 2.01H), 4.03-3.82 (m, 319H), 3.82-3.60 (m, 2.25 H), 3.52-3.41 (m, 0.89H), 318-3.07 (m, 0.17H), 2.98-2.80 (m, 0.40H), 2.68-2.59 (m, 0.58H), 2.53-2.36 (m, 1.27) H), 2.39-2.24 (m, 0.44H), 2.19-2.06 (m, 0.89H), 2.06-1.95 (m, 0.64H), 1.87-1.72 (m, 0.62H), 1.64-1.24 (m, 6.38) H), 0.96-0.75 (m, 3.13H).
13C-NMR (CDC, rotamers): d 176.1, 175.9, 175.0, 174.2, 167.9, 163.5, 159.7, 155.1, 143.7, 136.9, 135.8, 134.7, 134.6, 134.4, 134.2, 113.7, 113.5, 112.5, 63.4, 62.3, 62.1, 59.6, 57.6, 53.8, 47.7, 44.6, 42.9, 34.2, 32.6, 32.1, 30.1, 24.0, 23.9, 23.8, 14.3, 14.2. ES-MS: cale, for C2oH29N5O (403.22); found (pos.): 404.7 [M + H]; found (neg.): 402.6.
Example 87 N-Hydroxy-N- (2- {2- [3- (2-methoxy-ethyl) -3H-imidazo [4,5-c] pyridin-2-yl] -pyrrolidin-1-carbonyl}-hexyl) -formamide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 3- (2-Methoxyethyl) -2- (S) -pyrrolidin-2-yl-3H-imidazo [4,5-c] pyridine N-3 (the preparation is described in General Procedure N; PG = Cbz) of according to General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 8.89 (s, 0.37H), 8.51 (s, 0.27H), 8.39-8.30 (m, 0.19H), 8.16-8.07 (m, 0.30H), 7.89-7.70 ( m, 2.03H), 5.40-5.26 (m, 1H), 4.53-4.39 (m, 1.85H), 4.12-3.95 (m, 1.41H), 3.87-3.50 (m, 5.83H), 3.38-3.20 (m , 4.40H), 2.98-2.77 (m, 1.33H), 2.72-2.62 (m, 0.64H), 2.53-2.24 (m, 1.93H), 2.03-1.85 (m, 1.43H), 1.81-1.55 (m , 2.52H), 1.50-1.12 (m, 7.07H), 0.94-0.75 (m, 3.79H).
13 C-NMR (CDCl 3, rotamers): d 174.7, 174.3, 173.5, 161.4, 157.3, 155.4, 143.1, 132.3, 131.4, 131.2, 131.0, 113.1, 112.9, 71.2, 71.0, 60.2, 60.0, 59.3, 59.2, 58.4, 58.1, 53.2, 48.0, 46.5, 46.3, 43.8, 43.7, 33.8, 32.6, 31.8, 31.5, 29.3, 29.2, 22.2, 22.5, 22.4, 13.9. ES-MS: cale, for C2? H31N5O (417.24); found (pos.): 418.7 [M + H].
Example 88 N-Hydroxy-N- (2- {2- [1- (2-methoxy-ethyl) -1H-imidazo [4,5-c] pyridin-2-yl] -pyrrole id i n-1 -carbon il.}.-hexyl) -forward
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (R2 = n-butyl, the preparation is described in General Procedure A) and 3- (2-Methoxyethyl) -2- (R) -pyrrolidin-2-yl-3H-imidazo [4,5-c] pyridine N-3 (the preparation is described in General Procedure N; PG = Cbz) of according to General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 8.84 (s, 0.69H), 8.48 (d, J = 5.6, 0.20H), 8.44-8.22 (m, 1.56H), 7.81 (s, 0.56H), 7.74 ( s, 0.18H), 7.63 (d, J = 5.6, 0.68H), 5.65-5.04 (m, 4.99H), 4.94-4.74 (m, 1H), 4.50-4.40 (m, 1.03H), 4.36-4.25 (m, 0.30H), 4.03-3.60 (m, 5.83H), 3.55-3.34 (m, 1.11H), 3.34-3.13 (m, 3.87H), 3.02-2.93 (m, 0.31H), 2.60-1.92 (m, 4.50H), 1.72-1.56 (m, 0.88H), 1.56-1.06 (m, 6.85H), 0.93-0.69 (m, 3.24H).
13 C-NMR (CDCl 3, rotamers): d 174.4, 172.3, 165.3, 161.6, 161.3,
156. 2, 148.5, 142.6, 140.1, 139.7, 132.6, 132.4, 131.8, 131.6, 114.4,
113. 7, 70.7, 59.3, 59.1, 54.7, 52.8, 51.0, 48.7, 47.8, 44.5, 43.9, 41.2,
33. 4, 31.9, 31.8, 31.7, 30.0, 28.9, 28.7, 25.3, 22.9, 22.6, 21.9, 13.9,
13. 8. ES-MS: cale, for C2? H31N5O4 (417.24); found (pos.): 418.6
[M + H]; found (neg.): 416.2 [M-H].
EXAMPLE 89 N- [2-Cyclopentylmethyl-3- (2-oxazolo [4,5-b] pyridin-2-yl) -pyrrolidin-1-i I) -3-oxop ro p i I] -N-hydroxyformamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -3-cyclopentyl-propionic acid A-7
(R2 = cyclopentylmethyl, the preparation is described in General Procedure A) and (S) -2-Pyrrolidin-2-yl-oxazolo [4,5-b] pyridine F-5 (the preparation is described in General Procedure F ) in accordance with General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 10.26 (s, 0.17H), 9.72 (s, 0.09H), 8.55-8.41 (m, 1.06H), 8.30-8.25 (m, 0.26H), 8.18 (s, 0.08H), 7.88-1.60 (m, 1.78H), 7.36-7.16 (m, 1.27H), 5.40-5.21 (m, 1H), 4.91-4.76 (m, 0.09H), 4.48-4.36 (m, 0.20 H), 4.18-3.92 (m, 0.65H), 3.92-3.50 (m, 4.58H), 3.50-3.26 (m, 1.12H), 3.25-3.08 (m, 0.90H), 3.08-2.84 (m, 0.37) H), 2.45-1.29 (m, 19.75H), 1.29-0.90 (m, 3.65H).
13 C-NMR (CDCl 3, rotamers): d 175.8, 173.7, 172.6, 169.8, 163.6, 162.4, 161.5, 156.8, 155.6, 147.5, 147.1, 146.5, 146.3, 142.7, 121.3, 120.6, 120.1, 119.9, 119.1, 118.8, 118.4, 118.3, 61.0, 58.9, 55.0, 54.8, 51.3, 47.1, 40.5, 37.9, 37.4, 37.2, 36.3, 36.1, 33.1, 33.0, 32.9, 32.7, 30.7, 25.2, 25.1, 24.7, 14.1. ES-MS: cale, for C o H26N4O4 (386.20); found (pos.): 387.7 [M + H]; found (neg.): 385.3.
Example 90 N-Hydroxy-N- [2- (4-fluoro-2-oxazolo [4,5-b] pyridin-2-yl) -pyrrolidin-1-carbonyl] -hexyl} -formamide
The title compound was prepared from (R) -2 - [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and 2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -oxazolo [4,5-b] pyridine F-5 (the preparation is described in General Procedure F) in accordance with General Procedure B.
1 H-NMR (CDCl 3, rotamers): d 10.82 (s, 0.19H), 8.65-.8. 9 (m, 1.41H), 8.34 (s, 0.20H), 8.21 (s, 0.08H), 8.08 (s, 0.07H), 8.00-7.96 (m, 0.07H), 7.92-7.70 (m, 2.11H) ), 7.41-7.22 (m, 1.64H), 7.05-6.99 (m, 0.06H), 5.78-5.64 (m, 0.27), 5.58-5.23 (m, 2.60H), 4.60-4.25 (m, 1H), 4.22-3.55 (m, 4.22H), 3.48-3.28 (m, 0.95H), 3.28-2.94 (m, 1.56H), 2.94-2.70 (m, 1.39H), 2.70-2.35 (m, 1.80H) 1.89 -1.21 (m, 10.56H), 0.95-0.78 (m, 4.23H), 0.64-0.55 (m, 0.11H).
13 C-NMR (CDCl 3, rotamers): d 173.8, 172.7, 169.5, 168.3, 163.9, 161.7, 157.1, 155.3, 147.7, 147.2, 146.7, 146.6, 142.7, 122.4, 120.7, 120.4, 120.2, 118.7, 118.6, 92.9, 92.5, 90.7, 90.5, 54.2, 54.1, 54.0, 53.5, 53.5, 53.5, 53.4, 53.3, 52.5, 52.5, 52.5, 53.5, 53.5, 52.5, 52.5, 53.5, 52.5, 53.5, 53.5, 53.5, 53.5, 52.5, 52.5, 50.2, 43.3, 42.6, 42.6 13.8. ES-MS: cale, for C18H23FN4O4 (378.17); found (pos.): 379.4 [M + H]; found (neg.): 377.6.
EXAMPLE 91 2- (1- {2 - [(Formyl-hydroxy-amino) -methyl] -hexanoyl} - pyrrolidin-2-yl) -benzo-oxazole-5-sulphonic acid amide
The title compound was prepared from (R) -2- [(Benzyloxy-formyl-amino) -methyl] -hexanoic acid A-7 (the preparation is described in General Procedure A) and acid amide (S) -2-Pyrrolidin-2-ylbenzooxazole-5-sulfonic acid F-5 (the preparation is described in General Procedure F) according to General Procedure B. ESI-MS: cale, for C? 9H26N4O6S (438.51); found (pos.): 439.4 [M + H]. Found (neg.): 437.5 [M-H].
EXAMPLE 92 (R) -3 - [(2S, 4R) -4-Fluoro-2- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolidine-1-carbonyl] -heptanoic acid hydroxyamide
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and
2 - ((2S, 4R) -4-Fluoro-pyrrolidin-2-yl) -3H-imidazo [4,5-c] pyridine E-5 (the preparation is described in General Procedure E) according to the Procedure General D.
1H-NMR (MeOH-d4, rotamers): d 8.89-8.87 (s, 0.13H), 8.87-8.86 (s, 0.87H), 8.36-8.28 (m, 1.3H), 7.78-7.62 (dd, J = 0.08, 1.31H), 5.6-5.52 (m, 0.65H), 5.5-5.4 (m, 0.73H), 5.38-5.28 (m, 1.27H), 4.42-4.2 (m, 1.33H), 4.2-4.02 ( m, 1.3H), 3.17-3.04 (m, 1.28H), 2.85-2.69 (m, 1.48H), 2.63-2.52 (m, 0.85H), 2.52-2.41 (m, 0.82H), 2.41-2.32 ( m, 1.18H), 2.22-2.13 (m, 1.05H), 1.59-1.46 (m, 1.58H), 1.46-1.28 (m, 2.4H), 1.28-1.07 (m, 4.87H), 0.96-0.87 ( m, 0.76H), 0.85-0.65 (m, 3.5H). ES-MS: cale, for C18H24FN5O3 (377.4); found (pos.): 378.4 [M + H];
Example 93 3- [2- (1 H-Benzoimidazol-2-yl) -4-fluoro-pyrrolidin-1-carbonyl] -heptanoic acid hydroxyamide
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and 2 - ((2S, 4R) -4-Fluoro- pyrrolidin-2-yl) -1H-benzoimidazole E-5 (the preparation is described in General Procedure E) according to General Procedure D.
1 H-NMR (MeOH-d 4, rotamers): d 8.21 (s, 0.03H), 7.59-7.45 (m,
1. 88H), 7.26-7.15 (m, 1.96H), 5.56-5.48 (m, 0.57H), 5.43-5.36 (m,
0. 52H), 5.28 (t, J = 8.6, 8.6, 0.92H), 4.37-4.24 (m, 0.96H), 4.13 (dd, J = 3.1, 12.4, 0.45H), 4.04 (dd, J = 3.2, 12.4 , 0.45H), 3.76-3.62 (m,
0. 25H), 3.25-3.18 (m, 0.17H), 3.13-3.02 (m, 0.91H), 2.99-2.84 (m,
0. 43H), 2.79-2.65 (m, 1.01H), 2.63-2.49 (m, 1.31H), 2.49-2.28 (m,
0. 87H), 2.19-2.08 (m, 0.85H), 2.08-1.96 (m, 0.32H), 1.59-1.44 (m,
1. 13H), 1.44-1.26 (m, 2.26H), 1.26-1.04 (m, 3.56H), 0.95-0.85 (m, 0.53H), 0.81-0.72 (m, 2.55H).
13 C-NMR (MeOH-d 4, rotamers): d 176.6, 170.8, 156.4, 123.9, 123.6,
115. 9, 94.1, 92.4, 55.3, 55.2, 41.3, 39.7, 39.4, 35.7, 33.1, 30.0, 23.7,
14. 2. ES-MS: cale, for C19H25FN4O3 (376.19); found (pos.): 377.4
[M + H]; found (neg.): 375.5 [M-H].
Example 94 (R) -3 - [(S) -2- (3H-lmidazo [4,5-c] pyridin-2-yl) -pyrrolidine-1-carbonyl] -heptanoic acid hydroxyamide
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and (S) -2-Pyrrolidin-2-yl-3H -imidazo [4,5-c] pyridine E-5 (the preparation is described in General Procedure E) in accordance with General Procedure D.
1H-NMR (MeOH-d4, rotamers): d 8.95-8.9 (s, 0.2H), 8.9-8.6 (s, 0.77H), 8.4-8.3 (d, 1.14H), 8.2-8.1 (s, 0.48H ), 7.8-7.6 (dd, 1.2H), 5.5-5.3 (m, 0.36H), 5.3-5.2 (m, 1.1H), 4.08-3.85 (m, 2.2H), 3.75-3.55 (m, 0.81H) ), 3.5-3.43 (m, 0.3H), 3.18-3.03 (m, 1.29H), 2.5-2.33 (m, 2.2H), 2.33-2.23 (m, 1.28H), 2.23-2.03 (m, 3H) , 1.67-1.5 (m, 1.48H), 1.5-1.17 (m, 5.9H), 1.0-0.88 (m, 0.72H), 0.88-0.73 (m, 2.91H). ES-MS: cale, for C18H25N5O3 (359.4); found (pos.): 360.3 [M + H];
EXAMPLE 95 3- [2- (5-Sulfamoyl-benzooxazol-2-yl) -pi rrol id i-1 -carbonyl] -heptanoic acid hydroxyamide
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and (S) -2-Pyrrolidin-2-amide il-benzooxazole-5-sulphonic F-5 (the preparation is described in General Procedure F) according to General Procedure D. ESI-MS: cale, for C19H26N O6S (438.51); found (pos.): 439.4 [M + H]. Found (neg.): 437.5 [M-H].
Example 96: 3- [2- (1H-Benzoimidazol-2-yl) -4-fluoro-pyrrolidine-1-carbonyl] -heptanoic acid
The title compound was prepared from 4-tert-butyl ester of (R) -2-Butyl-succinic acid D-1 (as described in D) and 2 - ((2S, 4R) -4-Fluoro- pyrrolidin-2-yl) -1H-benzoimidazole E-5 (the preparation is described in General Procedure E; PG = CBz) according to General Procedure D.
1H-NMR (MeOH-d4, rotamers): d 7.77-7.72 (m, 1.71H), 7.72-7.65 (m, 0.12H), 7.57-7.51 (m, 1.89H), 7.47-7.41 (m, 0.10H ), 5.70-5.64 (m, 0.04H), 5.62-5.56 (m, 0.49H), 5.48-5.43 (m, 0.50H), 5.48-5.43 (m, 0.97H), 4.53-4.39 (m, 0.96H) ), 4.18 (dd, J = 3.1, 12.4, 0.51H), 4.09 (dd, J = 3.2, 12.4, 0.50H), 3.09-3.00 (m, 1.04H), 2.97-2.84 (m, 1.01H), 2.67-2.40 (m, 3.12H), 1.99-1.96 (m, 0.04H), 1.58-1.46 (m, 1.12H), 1.46-1.04 (m, 5.31H), 0.94-0.88 (m, 0.21H), 0.86-0.77 (m, 2.81H).
13 C-NMR (MeOH-d 4, rotamers): d 178.3, 175.6, 155.2, 133.0, 127.3, 115.1, 94.0, 92.2, 55.5, 55.2, 54.2, 41.1, 39.6, 39.4, 36.9, 33.0, 30.1, 23.7, 14.2. ES-MS: cale, for C19H24FN3O3 (361.18); found (pos.): 362.2 [M + H]; found (neg.): 360.6 [M-H].
Example 97: Inhibition of Peptide-Deformilase Activity A PDF / FDH coupled assay (Lazennec et al., Anal. Biochem., Vol. 224, pp. 180-182 (1997)) was used. In this coupled assay, the formeate released through PDF from its fMAS substrate was oxidized through the above FDH coupling, reducing one molecule of NAD * to NADH, which caused an increase in absorption at 340 nM. All tests are carried out at room temperature in a pH regulator of 50 nM HEPES, pH 7.2, 10 μM NaCl, 0.2 mg / ml BSA, in 96-well medium-area microtiter plates (Corning). The reaction was started by adding a mixture of 0.5 Units / μl of FDH, 1 mM NAD *, and fMAS at the desired concentration. To determine the I50 values (the concentration needed to inhibit 50% of the activity of the enzyme), the PDF was pre-incubated for 10 minutes with varying concentrations of the inhibitor, and the deformilation reaction was initiated through the addition of a reaction mixture containing 4 mM fMAS. The initial reaction rate, y, was measured as the initial rate of absorption increase at 340 nM using a SpectraMax plate reader (Molecular Devices, Sunnyvale, CA). The concentration of inhibitor [I n] at which 50% of the enzyme activity, I C50, is inhibited, was calculated using the following formula: y = y0 / (1 + [ln] / IC5o) where y0 is the reaction rate in the absence of the inhibitor. The resolution of this equation for IC50 to [I n] when y = y0 / 2 produces the value of I C50. The IC50 is calculated based on a non-linear least squares regression, using a commercial software package (Deltapoint, I nc., Chicago, I L.). Using this assay, the I C5o values of several compounds are determined. The I C50 for the various compounds was determined against the deformilase containing nickel and zinc as the metallic hyphen. The IC 50 values of the preferred compounds of the formula (I) determined for the zinc-containing deformilaza range from about O.OOlμM to about 0.2μM. The IC 0 values of the preferred compounds of the formula (I) determined for the nickel-containing deformylase range from about 0.005 μM to about 3 μM.
Example 98: Assay for Testing Antimicrobial Activity Minimum inhibitory concentrations (MICs) were determined using the microdilution method in 96-well format plates. The compounds were suspended in DMSO at 5 or 10 mg / ml and stored at 4 ° C until used. They were diluted in a Mueller-Hinton broth (MHB) or a Tripticase Soy broth (TSB) and used for the determination of MIC. The scale of concentrations tested is 64-0.0625 μg / ml as the final concentration using a double dissolution system. The inoculum was prepared from cells grown in Trypticase Soy Agar (TSA) and incubated overnight at 35 ° C, 5-10 colonies were used to inoculate the MHB or TSB broths, and the culture was incubated for the night at 35 ° C. The overnight culture was diluted 1:10, incubated for 1 hour at 35 ° C, diluted to the appropriate inoculum size and applied to the cavities containing the broth and the test compound. The inoculum sizes are 2x104 CFU / ml. The plates were incubated at 35 ° C for 48 hours and the MIC values were recorded after 18 hours of incubation for bacteria. MIC was defined as the lowest concentration of the compound that does not produce visible growth after incubation. The above deformylase was obtained from E. coli. The MICs for the compounds of the formula (I) are below 2 μg / ml, preferably below 1.5 μg / ml, preferably below 1 μg / ml, most preferably below 0.5 μg / ml. The following are representative pharmaceutical formulations containing a compound of the present invention:
Example 99: Tablet Formulation The following ingredients were intimately mixed and compressed into individual labeled tablets: Ingredient Amount (mg) Compound of this invention 400 Corn starch 50 Croscarmellose sodium 25 Lactose 120 Magnesium stearate 5
Example 100: Capsule Formulation The following ingredients were intimately mixed and loaded into a hard shell gelatin capsule: Ingredient Amount (mg) Copper of this invention 200 Lactose, sprinkled 148 Magnesium stearate 2
Example 101: Suspending Formulation The following ingredients were mixed to form a suspension for oral administration: Ingredient Amount (go ml) Compound of this invention 1.0 g fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulated sugar 25.0 g Sorbitol (70% solution) 13.00 g Veegum K (Vanderbilt Co.) 1.0 g Flavor 0.035 ml Color 0.5 mg Distilled water qs. for 100 ml
Example 102: Injectable Formulation The following ingredients were mixed to form an injectable formulation: Ingredient Quantity (mg) Compound of this invention 0.2-20 mg pH regulation solution of sodium acetate, 0.4 M 20 ml HCl (1N) or NaOH ( 1N) cs for suitable pH Water (distilled, sterile) q.s. for 20 ml
Example 103: Suppository Formulation A suppository with a total weight of 2.5 g was prepared by mixing the compound of the invention with Witepsol® H-5 (triglycerides of saturated vegetable fatty acid, Riches-Nelson, Inc., New York), and the following composition: Ingredient Quantity (mg) Compound of this invention 500 mg Witepsol® H-15 Rest
INDUSTRIAL APPLICABILITY The N-formyl hydroxylamine compounds of this invention are inhibitors of peptidyl deformylase and, therefore, can be used in various medical applications, including the treatment of disorders sensitive to treatment by peptidyl deformilase inhibitors, by example the treatment of bacterial infections, such as tuberculosis.
Claims (27)
1. A compound of the formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof: (") where n is 1 or 2, X is CH2, S or CHF, R1 is -N (OH) CHO or -C (O) NH (OH) R2 is alkyl, alkylcycloalkyl or alkylaryl, or R2 represents a group cycloalkyl, wherein the carbon adjacent to the carbonyl group forms part of the cycloalkyl ring, R3 is a substituent of the formula (a) or (b), or tetrazolyl, 2-perimidinyl or 4-phenylimidazol-2-yl; (b) where Y is NH, O, S or NR4; A, B, D and E each independently are selected from CH, N or CR5; or A and E are CH and B and D are fused to and form part of an aryl ring or a nitrogen heterocycle with 5 or 6 members; R 4 is hydroxy alkyl, alkyl or heteroalkyl; R5 is haloalkyl, heterocycle optionally substituted by an alkyl, halogen, alkyl, amino, cyano, nitro, aryl, alkoxy, haloalkoxy, -CO2R7, -SO2R8, NHC (O) R9 or -NHSO2R9 group; or two R5 groups together form a 6-membered oxygen-containing heterocycle, optionally substituted with one or more halogens and fused to the 6-membered ring of substituents (a); R6 is amino or alkoxy; R7 is H, alkyl, NHR10, NR10R11 or NH2; R8 is aryl, heterocycle, alkyl or amino; R9 is heteroaryl or aryl; and R 10 and R 11 each independently is an alkyl, alkenyl, alkynyl or aryl group.
2. A compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein n is 1.
3. A compound according to claim 1 or claim 2, or a salt, ester or prodrug. pharmaceutically acceptable thereof, wherein R1 is -N (OH) CHO.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is CH2 or CHF.
5. A compound according to any of claims 1 to 4, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R3 is a substituent of the formula (a).
6. A compound according to any of claims 1 to 5, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R2 is lower alkyl, lower alkylcycloalkyl or lower alkylaryl.
7. A compound according to claim 6, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R2 is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl or benzyl, or wherein R2 is a group cyclohexyl, wherein the carbon adjacent to the carbonyl group forms part of the cyclohexyl ring.
8. A compound according to claim 7, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R2 is n-butyl.
9. A compound according to any of claims 1 to 8, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R3 is a substituent of formula (a) and Y is O or NH.
10. A compound according to any of claims 1 to 9, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R3 is a substituent of the formula (a) and R5 is trifluoromethyl, 4-Me-piperizin- 1 -yl, fluoro, chloro, methoxy, amino, methyl, cyano, t-butyl, phenyl, nitro, trifluoromethoxy, -SO2NH2, -SO2 (morpholino), -SO2Et, -CO2Me, -CO2Et, -NHC (O) ( 2-pyrazinyl) or -NHSO2Ph, or two groups R5 together form a substituent (i) or (ii): (l) (ll)
11. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester or prodrug, wherein B and D are fused to a phenyl ring or a pyrazole ring.
12. A compound according to any of claims 1 to 8 or a pharmaceutically acceptable salt, ester or prodrug, wherein R3 is a substituent of the formula (b) and R6 is amino or ethoxy.
13. A compound according to any of claims 1 to 12 or a pharmaceutically acceptable salt, ester or prodrug, wherein R4 is an alkyl group having an alkoxy substituent.
14. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, ester or prodrug, wherein R4 is hydroxyethyl, methoxyethyl or methyl.
15. A compound of the formula (I '), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein: R2 is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl or benzyl; X is CH2 or CHF; And it's NH, O, or S; and A, B, D and E are each independently CH, N, or CR5; wherein R5 is as defined in claim 1.
16. A compound according to claim 15, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R2 is n-butyl.
17. A compound according to claim 15 or claim 16, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y is NH or O.
18. A compound according to any of claims 1 to 17 or a A pharmaceutically acceptable salt, ester or prodrug thereof, wherein A is N.
19. A compound according to any one of claims 1 to 10 or 12 to 17 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein B and E both are N.
20. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is CH2.
21. A compound according to any of claims 1 to 19 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X is CHF.
22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable excipient, diluent or carrier.
23. A method for treating and / or preventing a disease or disorder responsive to treatment by inhibitors of peptidyl deformylase, comprising administering to a subject in need thereof, an effective inhibitory amount of peptidyl deformylase of a compound of according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, ester or prodrug thereof.
24. A method according to claim 23, wherein the disease or disorder is a bacterial infection.
25. A method according to claim 24, wherein the bacterial infection is a mycobacterial infection.
26. A method according to claim 25, wherein the mycobacterial infection is caused by Mycobacterium tuberculosis.
27. A method according to claim 26, wherein the mycobacterial infection is caused by a multi-drug resistant form of Mycobacterium tuberculosis. SUMMARY The invention relates to novel compounds that are inhibitors of peptidyl deformylase (PDF). The compounds are useful as antimicrobials and antibiotics. Compounds of the invention exhibit selective inhibition of peptidyl deformylase against other metalloproteinases such as MMPs. Methods of preparation and uses of the compounds are also described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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SG200508608-7 | 2005-12-30 |
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MX2008008517A true MX2008008517A (en) | 2008-09-26 |
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