Benzylamine derivatives as plasma kallikrein inhibitors, their use, and pharmaceutical composition

专利摘要:
BENZYLAMINE DERIVATIVES AS PLASMAKALKREIN INHIBITORS, THEIR USE, AND PHARMACEUTICAL COMPOSITION. The present invention relates to compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example, in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and to methods of treating patients with such compounds; wherein R1 to R9 are as defined herein.
公开号:BR112014000240B1
申请号:R112014000240-1
申请日:2012-07-06
公开日:2022-02-01
发明作者:David Michael Evans；Rebecca Louise Davie；Hannah Joy Edwards；David Philip Rooker
申请人:Kalvista Pharmaceuticals Limited；
IPC主号:

专利说明:

[0001] The present invention relates to benzylamine derivatives and pharmaceutical compositions containing, and uses of, such derivatives. Background to the Invention
[0002] The benzylamine derivatives of the present invention are inhibitors of plasma kallikrein and have diverse therapeutic applications, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
[0003] Plasma kallikrein is a trypsin-like serine protease that can release kinins from kininogens (see KD Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; JW Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009; KD Bhoola et al., Pharmacological Rev., 1992, 44, 1; and DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). It is an essential member of the intrinsic blood clotting cascade although its role in this cascade does not involve bradykinin release or enzymatic cleavage. Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a high molecular weight kininogen-bound heterodimer complex that is activated to provide active plasma kallikrein. Kinins are potent mediators of inflammation that act through G protein-coupled receptors, and kinin antagonists (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents for the treatment of various disorders (F. Marceau and D. Regoli, Nature). Rev., Drug Discovery, 2004, 3, 845-852).
[0004] Plasma kallikrein is believed to play a role in several inflammatory disorders. The main inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1 esterase inhibitor suffer from hereditary angioedema (HAE) that results in intermittent dilatation of the face, hands, throat, gastrointestinal tract, and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen releasing bradykinin leading to increased vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the release of bradykinin that causes increased vascular permeability (A. Lehmann's Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in cardiothoracic pump surgery" Expert Opin. Biol. Ther. 8, p1187-99).
[0005] The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It was recently published that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasm Kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, p1590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 improved both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Furthermore, a plasma kallikrein inhibitor may have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
[0006] Synthetic plasma and small molecule kallikrein inhibitors, eg by Garrett et al. ("Peptide aldehyde...." J. Peptide Res. 52, p62-71 (1998)), T. Griesbacher et al. ("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous Kinins in acute pancreatitis in rats" British Journal of Pharmacology 137, p692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/ 076458), Szelke et al. ("Kininogenase inhibitors" WO92/04371), D.M. Evans et al. (Immunolpharmacology, 32, p115-116 (1996)), Szelke et al. ("Kininogen inhibitors" WO95/07921), Antonsson et al. ("New peptides derivatives" WO94/29335), J. Stürzbecher et al. (Brazilian J. Med. Biol. Res 27, p1929-34 (1994)), Kettner et al. (US 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, p1079-1090 (1993)), W.B. Young et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 (2006)), Okada et al. ("Development of potent and selective plasmin and inhibitor of plasma kallikreins and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, p1964-72 (2000)), Steinmetzer et al. ("tripsin-like serine protease inhibitors and their preparation and use" WO08/049595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors" Medicinal Chemistry 2, p545-553 (2006)), Sinha et al. ("Inhibitors of plasma kallikrein" WO08/016883), and Brandl et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein" WO2012/017020 ). Furthermore, Steinmetzer et al. ("Serine protease inhibitors" WO2012/004678 ) describe cyclized peptide analogues which are inhibitors of human plasmin and plasma kallikrein.
[0007] To date, no synthetic small molecule inhibitor of plasma kallikrein has been approved for medical use. Molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. Large protein plasma kallikrein inhibitors carry risks of anaphylactic reactions, as has been reported for Ecalantide. Thus, there remains a need for compounds that selectively inhibit plasma kallikrein, that do not induce anaphylaxis, and that are orally available. Furthermore, molecules in the known art represent an ionizable and highly polar guanidine or amidine functionality. It is well known that such functionalities can be limiting for gut permeability and therefore oral availability.
[0008] Oral complications of diabetes, such as cerebral hemorrhage, nephropathy, cardiomyopathy, and neuropathy, all of which have associations with plasma kallikrein, may also be considered targets for a plasma kallikrein inhibitor. Summary of the invention
[0009] The present invention relates to a series of benzylamines that are inhibitors of plasma kallikrein. These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of impaired visual acuity, diabetic retinopathy, macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation , septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery, and bleeding after operative surgery. The invention also relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.
[00010] In one aspect, the present invention provides compounds of Formula I
wherein: R1 is selected from H, alkyl, -COalkyl, -COaryl, -COheteroaryl, -CO2alkyl, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alkyl, -SO2aryl, -SO2( CH2)hR13, -CO(CH2)iR14, -COcycloalkyl, -COCH=CHR15, -CO(CH2)jNHCO(CH2)kR16 and -CONR17R18; R2 is selected from H and alkyl; R3 is selected from H, alkyl, -(CH2)daryl, -(CH2)eheteroaryl, -(CH2)fcycloalkyl, -(CH2)gheterocycloalkyl, -CH(cycloalkyl)2, -CH(heterocycloalkyl)2 and -(CH2) laryl-O-(CH2 )m-aryl; R4 and R6 are independently selected from H and alkyl; R5 is selected from H, alkyl, alkoxy and OH; or R4 and R5, together with the atoms to which they are attached, may join to form a 5- or 6-membered azacycloalkyl structure; R7 and R8 are independently selected from H, alkyl, alkoxy, CN, halo and CF3; R9 is aryl or heteroaryl; R10 is H or alkyl; a, b, c, d, e, f, g, h, i, j, m and m are independently 1, 2 or 3; k is 0, 1, 2 or 3; *1 and *2 denote chiral centers; alkyl is a saturated straight hydrocarbon having up to 10 carbon atoms (C1-C10) or a saturated hydrocarbon branched between 3 and 10 carbon atoms (C3-C10); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR11, fluorine and NR11R12; cycloalkyl is a saturated mono- or bicyclic hydrocarbon of between 3 and 10 carbon atoms; cycloalkyl may optionally be fused to an aryl group; or cycloalkyl is adamantyl; heterocycloalkyl is a C-linked or N-linked saturated 3- to 10-membered mono- or bicyclic ring, wherein said heterocycloalkyl ring contains, where possible, 1, 2 or 3 heteroatoms independently selected from N, NR11 and O; alkoxy is a linear O-linked hydrocarbon of 1 to 6 carbon atoms (C1-C6) or branched O-linked hydrocarbon of 3 to 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, OH, CN, CF3, COOR11, fluorine and NR11R12; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with up to 5 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12; heteroaryl is a 5, 6, 9 or 10 membered mono- or bicyclic aromatic ring containing, where possible, 1, 2 or 3 ring members independently selected from N, NR11, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3, NR11R12 and NHR19; R11 and R12 are independently selected from H and alkyl; R13 is aryl or heteroaryl; R14 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R15 is H, alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R16 is H, aryl or heteroaryl; R17 is H, alkyl, aryl, heteroaryl or heterocycloalkyl; R18 is -(CH2)mR21, where m is 0, 1, 2 or 3 and R21 is H, aryl or heteroaryl; R19 -COalkyl, -COaryl or -COheteroaryl; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
[00011] In another aspect the present invention provides a prodrug of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.
[00012] However, in another aspect the present invention provides an N-oxide of a compound of Formula (I) as defined herein, or a prodrug or pharmaceutically acceptable salt thereof.
[00013] It will be understood that certain compounds of the present invention may exist in solvated, e.g., hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms.
[00014] In one aspect, the invention comprises a subgroup of the compounds of Formula (I) wherein: R1 is selected from H, alkyl, -COalkyl, -COaryl, -COheteroaryl, -CO2alkyl, -(CH2)aOH, -( CH2)bCOOR10, -(CH2)cCONH2, -SO2alkyl and -SO2aryl; R2 is selected from H and alkyl; R3 is selected from H, alkyl, -(CH2)daryl, -(CH2)eheteroaryl, -(CH2)fcycloalkyl, -(CH2)geterocycloalkyl, -CH(cycloalkyl)2 and -CH(heterocycloalkyl)2; R4 and R6 are independently selected from H and alkyl; R5 is selected from H, alkyl, alkoxy and OH; or R4 and R5, together with the atoms to which they are attached, may join to form a 5- or 6-membered azacycloalkyl structure; R7 and R8 are independently selected from H, alkyl, alkoxy, CN and halo; R9 is aryl or heteroaryl; R10 is H or alkyl; a, b, c, d, e, f and g are independently 1, 2 or 3; *1 and *2 denote chiral centers; alkyl is a saturated straight hydrocarbon having up to 10 carbon atoms (C1-C10) or a saturated hydrocarbon branched between 3 and 10 carbon atoms (C3-C10); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR11, fluorine and NR11R12; cycloalkyl is a saturated mono- or bicyclic hydrocarbon of between 3 and 10 carbon atoms; cycloalkyl may optionally be fused to an aryl group; heterocycloalkyl is a C-linked or N-linked saturated 3- to 10-membered mono- or bicyclic ring, wherein said heterocycloalkyl ring contains, where possible, 1, 2 or 3 heteroatoms independently selected from N, NR11 and O; alkoxy is a linear O-linked hydrocarbon of 1 to 6 carbon atoms (C1-C6) or branched O-linked hydrocarbon of 3 to 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, OH, CN, CF3, COOR11, fluorine and NR11R12; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with up to 5 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12; heteroaryl is a 5, 6, 9 or 10 membered mono- or bicyclic aromatic ring containing, where possible, 1, 2 or 3 ring members independently selected from N, NR11, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12; R11 and R12 are independently selected from H and alkyl; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
[00015] In another aspect, the invention comprises a subgroup of compounds of Formula (I) wherein: R1 is selected from H, alkyl, -COalkyl, -COaryl, -CO2alkyl, -CH2CH2OH, -CH2COOR10, -CH2CONH2, -SO2alkyl and -SO2aryl; R2 is selected from H and alkyl; R3 is selected from alkyl, -CH2aryl, -CH2cycloalkyl and -CH(cycloalkyl)2; R4 and R6 are independently selected from H and alkyl; R5 is selected from H, alkyl, and OH; or R4 and R5, together with the atoms to which they are attached, may join to form a 5- or 6-membered azacycloalkyl structure; R7 and R8 are independently selected from H, F, and Cl; R9 is aryl; R10 is H or alkyl; *1 and *2 denotes chiral centers; alkyl is a linear saturated hydrocarbon having up to 6 carbon atoms (C1-C6) or a saturated hydrocarbon branched between 3 and 6 carbon atoms (C3-C6); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR11, fluorine and NR11R12; cycloalkyl is a saturated mono- or bicyclic hydrocarbon of between 3 and 10 carbon atoms; alkoxy is a linear O-linked hydrocarbon of 1 to 6 carbon atoms (C1-C6) or branched O-linked hydrocarbon of 3 to 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, OH, CN, CF3, COOR11, fluorine and NR11R12; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with up to 5 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12; R11 and R12 are independently selected from H and alkyl; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
[00016] The present invention also comprises the following aspects and combinations thereof:
[00017] In one aspect of the invention, R1 is selected from H, alkyl, -COalkyl, -COaryl, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alkyl and -SO2aryl.
[00018] In one aspect of the invention, R1 is selected from H, alkyl, -COalkyl, -COaryl, -(CH2)aOH, -CH2COOR10, -CH2CONH2, -SO2alkyl and -SO2aryl; where a is 1 or 2.
[00019] In one aspect of the invention, R1 is selected from H, -COaryl, -COalkyl, -CH2COOH, -SO2Ph and -SO2CH3.
[00020] In one aspect of the invention, R1 is selected from H, -COethyl, methyl, methylsulfonyl, -COphenyl, phenylsulfone, -CH2COOH, -CO-ipropyl, propyl, -CH2COOCH3, -CH2CONH2, -CH2CH2OH and -COnaphthyl.
[00021] In one aspect of the invention, R1 is selected from -COalkyl and -COphenyl.
[00022] In one aspect of the invention, R1 is selected from H, -COaryl, COheteroaryl, -COalkyl, -CH2COOH, -SO2Ph and -SO2CH3.
[00023] In one aspect of the invention, R1 is selected from -COalkyl, COheteroaryl and -COaryl.
[00024] In one aspect of the invention, R2 is selected from H and methyl.
[00025] In one aspect of the invention, R2 is H.
[00026] In one aspect of the invention, R3 is selected from alkyl, -(CH2)daryl,-(CH2)fcycloalkyl, and -CH(cycloalkyl)2; where d and f are independently 1 or 2.
[00027] In one aspect of the invention, R3 is selected from alkyl, -CH2aryl, -CH2cycloalkyl, and -CH(cycloalkyl)2.
[00028] In one aspect of the invention, R3 is selected from -CH2aryl, -CH2cycloalkyl, and -CH(cycloalkyl)2.
[00029] In one aspect of the invention, R3 is selected from:

[00030] In one aspect of the invention, R4 is selected from H and methyl.
[00031] In one aspect of the invention, R4 is H.
[00032] In one aspect of the invention, R5 is selected from H, alkyl and OH.
[00033] In one aspect of the invention, R5 is selected from H and OH.
[00034] In one aspect of the invention, R5 is H.
[00035] In one aspect of the invention, R4 and R5, together with the atoms to which they are attached, unite to form a pyrrolidine moiety.
[00036] In one aspect of the invention, R4 and R5, together with the atoms to which they are attached, unite to form a piperidine moiety.
[00037] In one aspect of the invention, R6 is selected from H and methyl.
[00038] In one aspect of the invention, R6 is H.
[00039] In one aspect of the invention, R7 is selected from H, methyl and halo.
[00040] In one aspect of the invention, R7 is selected from H, F and Cl.
[00041] In one aspect of the invention, R7 is H.
[00042] In one aspect of the invention, R8 is selected from H, methyl and halo.
[00043] In one aspect of the invention, R8 is selected from H, F and Cl.
[00044] In one aspect of the invention, R8 is selected from H and F.
[00045] In one aspect of the invention, R8 is H.
[00046] In one aspect of the invention, R9 is aryl.
[00047] In one aspect of the invention, R9 is selected from phenyl and naphthyl, wherein phenyl may be optionally substituted by up to 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12.
[00048] In one aspect of the invention, R9 is phenyl, wherein phenyl may be optionally substituted by up to 2 substituents independently selected from alkyl, halo and CF3.
[00049] In one aspect of the invention, R9 is selected from phenyl, 1-naphthalene, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-ethoxyphenyl.
[00050] In one aspect of the invention, R9 is selected from phenyl, heteroaryl and naphthyl, wherein phenyl may be optionally substituted by up to 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12.
[00051] In one aspect of the invention, R9 is selected from phenyl, 1-naphthalene, 3,4-dichlorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-trifluoromethylphenyl, pyrid-3 -yl, pyrid-2-yl, pyrid-4-yl, benzothiophen-3-yl, thiophen-2-yl, thiophen-3-yl, indole-3-yl, and thiazol-4yl.
[00052] In one aspect of the invention, R10 is H or methyl.
[00053] In one aspect of the invention, the stereochemical configuration about the *1 chiral center is R.
[00054] In one aspect of the invention, the stereochemical configuration about the *2 chiral center is S.
[00055] In one aspect of the invention, a is 2 and b, c, d, e, f and g are 1.
[00056] In one aspect of the invention, a is 2 and b, c, d, e, f, g, h, j, l and m are 1.
[00057] In one aspect of the invention, k is 0 or 1.
[00058] In one aspect, the invention comprises a compound selected from:
[00059] (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide;
[00060] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide;
[00061] {(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid;
[00062] (S)-N-(4-Aminomethyl-3-fluoro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide ;
[00063] (S)-N-(4-Aminomethyl-2-chloro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide ;
[00064] (S)-N-(4-Aminomethyl-benzyl)-3-(3,4-dichloro-phenyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino- propionylamino]-propionamide;
[00065] (S)-N-(4-Aminomethyl-3-chloro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide ;
[00066] (S)-N-(4-Aminomethyl-benzyl)-2-{[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionyl]-methyl-amino}-3-phenyl -propionamide;
[00067] ({(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-methyl-amino)-acetic acid;
[00068] (S)-N-(4-Aminomethyl-3-fluoro-benzyl)-2-{[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionyl]-methyl-amino} -3-phenyl-propionamide;
[00069] N-[(R)-1-{[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-methyl-carbamoyl}-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[00070] N-[(R)-1-{[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-methyl-carbamoyl}-2-(4-ethoxy-phenyl)- ethyl]-isobutyramide;
Naphthalene Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide [00071] 1- carboxylic;
[00072] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-chloro -benzamide;
[00073] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,4 -dichlorobenzamide;
[00074] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4 -difluoro-benzamide;
[00075] (R)-2-Amino-N-[(1S,2S)-1-(4-aminomethyl-benzylcarbamoyl)-2-hydroxy-2-phenyl-ethyl]-3-(4-ethoxy-phenyl) -propionamide;
[00076] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-nicotinamide;
[00077] (2S,3S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-hydroxy-3-phenyl -propionamide;
[00078] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide;
[00079] Thiophen-acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 3-carboxylic;
[00080] Thiophen-acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 2-carboxylic;
[00081] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide hexanecarboxylic;
[00082] Ioxazol-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 5-carboxylic;
[00083] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide pyridine- 2-carboxylic;
[00084] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide benzo[ b]thiophene-2-carboxylic acid;
[00085] (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-2-(4-chloro-benzenesulfonylamino)-3-(4-ethoxy-phenyl) -propionamide;
[00086] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3-chloro -benzamide;
[00087] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2-chloro -benzamide
[00088] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3-trifluoromethyl -benzamide;
[00089] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methyl -benzamide;
[00090] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4 -dichlorobenzamide;
[00091] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methoxy -benzamide;
[00092] (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-(2-phenylacetylamino-acetylamino)-propionylamino]-3-phenyl -propionamide;
[00093] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-fluor -benzamide;
[00094] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-6-methyl -nicotinamide;
[00095] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2-methyl -nicotinamide;
[00096] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,6 -dichloro-nicotinamide;
[00097] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-5,6 -dichloro-nicotinamide;
[00098] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,3 ,6-trifluoro-isonicotinamide;
[00099] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,3 ,3-trifluoro-propionamide;
[000100] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 2, 4-dimethyl-thiazole-5-carboxylic acid;
[000101] 2-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide methyl-thiazole-5-carboxylic acid;
[000102] 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000103] 4-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide methyl-thiazole-5-carboxylic acid;
[000104] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide furan- 2-carboxylic;
[000105] 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000106] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2-methoxy -isonicotinamide;
[000107] 3-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide methyl-1H-pyrrole-2-carboxylic acid;
[000108] 3-Amino-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000109] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-propoxy-phenyl)-ethyl]-benzamide;
[000110] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000111] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl) )-ethyl]-benzamide;
[000112] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-chloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000113] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000114] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000115] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-methoxy-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000116] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000117] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000118] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000119] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-3-yl-ethylcarbamoyl-2-(4-ethoxy-phenyl)-ethyl]- benzamide;
[000120] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000121] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000122] N-[(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000123] N-[(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000124] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of pyridine-2-carboxylic acid;
[000125] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methoxy-benzamide;
[000126] [(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of pyridine-2-carboxylic acid;
[000127] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methoxy-benzamide;
[000128] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-isonicotinamide;
[000129] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000130] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-chloro-benzamide;
[000131] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methyl-benzamide;
[000132] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- pyridine-2-carboxylic acid ethyl]-amide;
[000133] (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethyl]-3-(4-ethoxy-phenyl)-2-propionylamino-propionamide ;
[000134] N-[(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -isonicotinamide;
[000135] [(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of pyridine-2-carboxylic acid;
[000136] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- thiophene-2-carboxylic acid ethyl]-amide;
[000137] (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethyl]-3-(4-ethoxy-phenyl)-2-propionylamino-propionamide ;
[000138] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl) )-ethyl]-isonicotinamide;
[000139] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-3,3,3-trifluoropropionamide;
[000140] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-chloro-benzamide;
[000141] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of isoxazole-5-carboxylic acid;
[000142] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methyl-benzamide;
[000143] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000144] 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- thiophene-2-carboxylic acid ethyl]-amide;
[000145] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000146] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-isonicotinamide;
[000147] 3-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide acetylamino-thiophene-2-carboxylic acid;
[000148] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(2-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000149] 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- thiophene-2-carboxylic acid ethyl]-amide;
[000150] N-[(R)-1-[(S)-1-(4-aminomethyl-3-methyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000151] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of 3-amino-thiophene-2-carboxylic acid;
[000152] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of 3-chloro-thiophene-2-carboxylic acid;
[000153] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methyl-benzamide;
[000154] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- 3-methyl-1H-pyrrole-2-carboxylic acid ethyl]-amide;
[000155] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of 3-amino-thiophene-2-carboxylic acid;
[000156] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- 3-acetylamino-thiophene-2-carboxylic acid ethyl]-amide;
[000157] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -3-methyl-benzamide;
[000158] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -2-methyl-benzamide;
[000159] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 3, 5-dimethyl-1H-pyrrole-2-carboxylic acid;
[000160] N-[(R)-1-[(S)-1-(4-aminomethyl-3-methyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000161] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of 3-acetylamino-thiophene-2-carboxylic acid;
[000162] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- 3-amino-thiophene-2-carboxylic acid ethyl]-amide;
[000163] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- 3-acetylamino-thiophene-2-carboxylic acid ethyl]-amide;
[000164] [(R)-1-{[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-methyl-carbamoyl}-2-(4-ethoxy-phenyl)-ethyl] 3-chloro-thiophene-2-carboxylic acid amide;
[000165] N-[(R)-1-[(1S,2R)-1-(4-Aminomethyl-benzylcarbamoyl)-2-hydroxy-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000166] [(R)-1-[(1S,2R)-1-(4-aminomethyl-benzylcarbamoyl)-2-hydroxy-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] 3-chloro-thiophene-2-carboxylic acid amide;
[000167] N-{(R,S)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-[4-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-benzamide;
[000168] and pharmaceutically acceptable salts and solvates thereof.
[000169] In one aspect, the invention comprises a compound selected from:
[000170] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide;
[000171] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of naphthalene- 1- carboxylic;
[000172] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-chloro -benzamide;
[000173] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,4 -dichlorobenzamide;
[000174] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4 -difluoro-benzamide;
[000175] and pharmaceutically acceptable salts and solvates thereof.
[000176] In one aspect, the invention comprises a compound selected from:
[000177] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide;
[000178] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide naphthalene- 1- carboxylic;
[000179] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-chloro -benzamide;
[000180] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,4 -dichlorobenzamide;
[000181] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-nicotinamide;
[000182] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4 -difluoro-benzamide;
[000183] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide;
[000184] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 3-carboxylic;
[000185] Thiophen-acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide 2-carboxylic;
[000186] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide hexanecarboxylic;
[000187] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of ioxazol- 5-carboxylic;
[000188] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide pyridine- 2-carboxylic;
[000189] (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-2-(4-chloro-benzenesulfonylamino)-3-(4-ethoxy-phenyl) -propionamide;
[000190] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methyl -benzamide;
[000191] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4 -dichlorobenzamide;
[000192] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3-chloro -benzamide;
[000193] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methoxy -benzamide;
[000194] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-fluor -benzamide;
[000195] 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000196] 3-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide methyl-1H-pyrrole-2-carboxylic acid;
[000197] 3-Amino-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000198] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-propoxy-phenyl)-ethyl]-benzamide;
[000199] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000200] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl) )-ethyl]-benzamide;
[000201] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- ethyl]-benzamide;
[000202] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000203] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000204] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-3-yl-ethylcarbamoyl-2-(4-ethoxy-phenyl)-ethyl]- benzamide;
[000205] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000206] N-[(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000207] N-[(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -benzamide;
[000208] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of pyridine-2-carboxylic acid;
[000209] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methoxy-benzamide;
[000210] [(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of pyridine-2-carboxylic acid;
[000211] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methoxy-benzamide;
[000212] [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000213] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] -4-methyl-benzamide;
[000214] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000215] 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide of thiophene-2-carboxylic acid;
[000216] 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- thiophene-2-carboxylic acid ethyl]-amide;
[000217] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-benzamide;
[000218] N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl )-ethyl]-isonicotinamide;
[000219] 3-Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide acetylamino-thiophene-2-carboxylic acid;
[000220] 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)- thiophene-2-carboxylic acid ethyl]-amide;
[000221] and pharmaceutically acceptable salts and solvates thereof. therapeutic applications
[000222] As previously mentioned, the compounds of the present invention are potent and selective inhibitors of plasma kallikrein. They are therefore useful in the treatment of disease conditions for which plasma kallikrein overactivity is a causative factor.
[000223] Accordingly, the present invention provides a compound of Formula (I) for use in medicine.
[000224] The present invention also provides the use of a compound of Formula (I) in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
[000225] The present invention also provides a compound of Formula (I) for use in treating or preventing a disease or condition in which plasma kallikrein activity is implicated.
[000226] The present invention also provides a method of treating a disease or condition in which plasma kallikrein activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) .
[000227] In one aspect, the disease or condition, in which plasma kallikrein activity is implicated, is selected from diseases or conditions, in which plasma kallikrein activity is implicated, include impaired visual acuity, diabetic retinopathy, diabetic macular edema , hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery, and bleeding after operative surgery.
[000228] In another aspect, the disease or condition, in which plasma kallikrein activity is implicated, is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. combination therapy
[000229] The compounds of the present invention may be administered in combination with other therapeutic agents. Suitable combination therapies include a compound of Formula (I) combined with one or more agents selected from agents that inhibit platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), alpha5beta1 integrin, steroids, other agents that inhibit plasma kallikrein and other inhibitors of inflammation. Specific examples of therapeutic agents that can be combined with the compounds of the present invention include those described in EP2281885A and by S. Patel in Retina, 2009 Jun; 29(6 Suppl):S45-8.
[000230] When combination therapy is employed, the compounds of the present invention and said combination agents may exist in the same or different pharmaceutical compositions, and may be administered separately, sequentially or simultaneously. Definitions
[000231] The term "alkyl" includes saturated hydrocarbon residues including: - linear groups of up to 10 carbon atoms (C1-C10), or of up to 6 carbon atoms (C1-C6), or of up to 4 carbon atoms ( C1C4). Examples of such alkyl groups include, but are not limited to, C1-methyl, C2-ethyl, C3-propyl and C4-n-butyl. - branched groups between 3 and 10 carbon atoms (C3C10), or up to 7 carbon atoms (C3-C7), or up to 4 carbon atoms (C3-C4). Examples of such alkyl groups include, but are not limited to, C3 - iso-propyl, C4 - sec-butyl, C4 - iso-butyl, C4 - tert-butyl and C5 - neo-pentyl. each optionally substituted as set forth above.
[000232] The term "alkoxy" includes O-linked hydrocarbon residues including: - linear groups between 1 and 6 carbon atoms (C1-C6), or between 1 and 4 carbon atoms (C1-C4). Examples of such alkoxy groups include, but are not limited to, C1 -methoxy, C2 -ethoxy, C3 -n-propoxy and C4-n-butoxy. - groups branched between 3 and 6 carbon atoms (C3-C6) or between 3 and 4 carbon atoms (C3-C4). Examples of such alkoxy groups include, but are not limited to, C3 - iso-propoxy, and C4 - sec-butoxy and tert-butoxy. each optionally substituted as set forth above.
[000233] Unless otherwise stated, halo is selected from Cl, F, Br and I.
[000234] Cycloalkyl is as defined above. Cycloalkyl groups may contain from 3 to 10 carbon atoms, or from 4 to 10 carbon atoms, or from 5 to 10 carbon atoms, or from 4 to 6 carbon atoms. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of suitable bicyclic cycloalkyl groups include decahydronaphthalene and octahydro-1H-indene. Examples of suitable cycloalkyl groups when fused to aryl include indanyl and 1,2,3,4-tetrahydronaphthyl.
[000235] Heterocycloalkyl is as defined above. Examples of suitable heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, piperazinyl, N-methylpiperazinyl, azepanyl, oxazepanil and diazepanyl.
[000236] Arila is as defined above. Typically, aryl will be optionally substituted with 1, 2 or 3 substituents. Optional substituents are selected from those set out above. Examples of suitable aryl groups include phenyl and naphthyl (each optionally substituted as set forth above).
[000237] Heteroaryl is as defined above. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl ( optionally substituted as set forth above).
[000238] The term "C-linked", as in "C-linked heterocycloalkyl", means that the heterocycloalkyl group is linked to the remainder of the molecule via a ring carbon atom.
[000239] The term "N-linked", as in "N-linked heterocycloalkyl", means that the heterocycloalkyl group is linked to the remainder of the molecule via a ring nitrogen atom.
[000240] The term "O-linked", as in "O-linked hydrocarbon residue", means that the hydrocarbon residue is linked to the remainder of the molecule via an oxygen atom.
[000241] In groups such as -COalkyl and -(CH2)bCOOR10, "-" denotes the point of attachment of the substituent group to the remainder of the molecule.
[000242] "Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, where appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example, (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts which may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or with organic amines such as diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where a compound of the invention contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates , oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulfonates, maleates, adipates, fumarates, hipurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.
[000243] Hemissals of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
[000244] For a review of suitable salts, see the "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[000245] "Prodrug" refers to a compound that is convertible in vivo by metabolic methods (eg, by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for prodrug formation are described in 'The Practice of Medicinal Chemistry, 2nd Ed. pp561-585 (2003) and in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.
[000246] The compounds of the invention can exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example ethanol. The term 'hydrate' is used when the solvent is water.
[000247] Where the compounds of the invention exist in one or more geometric, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis and trans forms, E and Z forms, R-, S- and meso forms, keto, and enol. Unless otherwise stated, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate, such isomers can be separated from their mixtures by the application or adaptation of known methods (eg, chromatographic techniques and recrystallization techniques). Where appropriate, such isomers can be prepared by the application or adaptation of known methods (eg, asymmetric synthesis).
[000248] In the context of the present invention, references herein to "treatment" include references to curative, palliative and prophylactic treatment. general methods
[000249] Compounds of Formula (I) should be evaluated for their biopharmaceutical properties, such as solubility and solution stability (via pH), permeability, etc., in order to select the most appropriate and routine dosage form administration for the treatment of the proposed indication. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention that may confer a functional (i.e., drug release rate control) and/or non-functional (i.e. , processing aid or diluent) to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
[000250] Compounds of the invention intended for pharmaceutical use may be administered as a solid or liquid, such as a tablet, capsule or solution. Pharmaceutical compositions suitable for delivering compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19a. Edition (Mack Publishing Company, 1995).
[000251] Accordingly, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
[000252] For the treatment of conditions, such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema, the compounds of the invention may be administered in a form suitable for injection into the ocular region of a patient, in particular, in a form suitable for intravitreal injection. It is envisaged that formulations suitable for such use will take the form of sterile solutions of a compound of the invention in a suitable aqueous vehicle. The compositions may be administered to the patient under the supervision of the attending physician.
[000253] The compounds of the invention can also be administered directly into the bloodstream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Devices suitable for parenteral administration include needle injectors (including microneedle), needleless injectors and infusion techniques.
[000254] Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), however, for some In applications, they may most suitably be formulated as a sterile nonaqueous solution or as a dry form to be used in conjunction with a suitable vehicle, such as pyrogen-free water.
[000255] Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycaprolactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations can be administered through a surgical incision into subcutaneous tissue, muscle tissue, or directly into specific organs.
[000256] The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can easily be carried out using standard pharmaceutical techniques well known to those skilled in the art.
[000257] The solubility of compounds of Formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility enhancing agents such as surfactants, micelle and cyclodextrins.
[000258] In one embodiment, the compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration, whereby the compound enters the blood stream directly from the mouth.
[000259] Formulations suitable for oral administration include solid buffers, solid microparticulates, semi-solids and liquids (including multiple phases or dispersed systems), such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including filled with liquid); chewables; gels; fast-dispersing dosage forms; films; eggs; sprays; and oral/mucoadhesive plasters.
[000260] Formulations suitable for oral administration may also be designed to release the compounds of the invention in an immediate release manner or in a rate maintenance manner, wherein the release profile may be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a way as to optimize the therapeutic efficacy of said compounds. Methods for releasing compounds in a rate-maintaining manner are known in the art and include slow-release polymers that can be formulated with said compounds to control their release.
[000261] Examples of rate-maintaining polymers include degradable and non-degradable polymers, which can be used to release said compounds by diffusion or a combination of diffusion and polymer erosion. Examples of rate-maintaining polymers include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthan gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
[000262] Liquid formulations (including multi-phase and disperse systems) include emulsions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, of gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example a sachet.
[000263] The compounds of the invention can also be used in fast-dissolving, fast-disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11(6), 981-986.
[000264] The Tablet formulation is described in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
[000265] For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.01 mg to 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg, depending, in fact, from the mode of administration. For example, if administered by intravitreal injection, it is envisaged that the compound of the invention will be dosed infrequently, for example once a month. In this circumstance, a dose between 0.5 mg and 20 mg, such as between 1 mg and 10 mg, is considered. If dosed more frequently, for example once daily, a much smaller dose between 0.005 mg and 0.02 mg is considered.
[000266] The total dose may be administered in single dose or divided doses and may, at the discretion of the physician, be excluded from the typical range mentioned here. These dosages are based on an average human individual who weighs around 60kg to 70kg. The physician will easily be able to determine doses for individuals whose weight falls outside this range, such as children and the elderly. Synthetic Methods
[000267] The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are also exemplified by the specific examples provided hereinbelow. Furthermore, using the procedures described herein, one skilled in the art can easily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples should not, however, be construed as forming the only genus that is considered to be the invention. The examples also illustrate details for preparing the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
[000268] The compounds of the invention can be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
[000269] It may be necessary to protect reactive functional groups (eg hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to prevent their undesired participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T.W. Greene and P.G.M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 4th Edition, 2006, can be used. For example, a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is easily removed by treatment with an acid, such as trifluoroacetic acid or hydrogen chloride in an organic solvent, such as dichloromethane. Alternatively the amino protecting group can be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a palladium catalyst under an atmosphere of hydrogen or 9-fluorenylmethyloxycarbonyl (Fmoc) which can be removed by solutions of secondary organic amines such as such as diethylamine or piperidine in an organic solvent. Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by hydrolysis in the presence of bases such as sodium or lithium hydroxide. Benzyl protecting groups can also be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere, although tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively, a trichloroethyl ester protecting group is removed with zinc in acetic acid. A common hydroxy protecting group suitable for use herein is a methyl ether, deprotection conditions comprise refluxing in 48% aqueous HBr for 1 to 24 hours, or stirring with borane tribromide in dichloromethane for 1 to 24 hours. Alternatively where a hydroxy group is protected as a benzyl ether, the deprotection conditions comprise hydrogenation with a palladium catalyst under a hydrogen atmosphere.
[000270] Compounds according to general Formula I can be prepared using conventional synthetic methods, for example, but not limited to the routine outlined in scheme 1. In a typical first step the amine (2) is coupled using standard coupling conditions from peptide to an activated alpha amino acid (1) protected by amino suitably with a standard protecting group, such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc). The activating group (X) may be N-hydroxysuccinimide. The use of such groups is well known in the art. Where R5 or R9 (shown as 'Aryl' in Scheme 1) has a reactive functional group, such as an amine or a carboxylic acid, this group will also be protected. Other standard peptide coupling methods include the reaction of acids with amines in the presence of hydroxybenzotriazole and carbodiimide, such as a water-soluble carbodiimide, or hexafluorophosphate 2-(1H-benzotriazol-1-yl)-1,1, 3,3-tetramethylamino or benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate or bromo-trispyrrolidine-phosphonium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine. In a typical second step the protection group is removed using standard methods as previously described.
[000271] The routine exemplified in Scheme 1 then proceeds to the third step through another standard peptide coupling and to the fourth step through removal of the Boc protecting group, using standard conditions as previously described. The amine disclosed in 7 may, in a fifth step, then typically be alkylated or acylated with the R1 group. The acylation may be carried out by treatment with an acylating agent, such as an acyl chloride, for example, acetyl chloride or benzoyl chloride, in the presence of a base, typically a tertiary amine base, such as triethylamine or diisopropylethylamine. . Alkylation can typically be carried out by treatment with an alkyl halide or by reductive alkylation. Typically, in a reductive alkylation procedure the amine is allowed to react with an aldehyde or ketone in the presence of a suitable reducing agent, such as sodium cyanoborohydride or sodium acetoxyborohydride in a suitable solvent, such as methanol, at room temperature. The resulting nitrile compound 8 can then be reduced by hydrogenation. The conversion of 8 to 10 can be achieved in a single step or by direct reduction of the nitrile by hydrogenation in a suitable solvent, such as methanol in the presence of a suitable catalyst, such as palladium on charcoal in the presence of an acid, such as hydrochloric acid or reduction with a suitable borohydride in the presence of a suitable transition metal, such as cobalt or nickel chloride in a suitable solvent, such as methanol at room temperature. Alternatively, the tert-butoxycarbonyl (Boc) protected amine 9 can be isolated (using, for example, the method as described in S. Caddick et al., Tetrahedron Lett., 2000, 41, 3513) and subsequently deprotected by standard methods. described previously to provide amine 10. Scheme 1
Brief description of drawings
[000272] Figure 1 shows the inhibitory effect of example 3 and CH-3457 (positive control; plasma kallikrein inhibitor) on CA-I-stimulated RVP in Sprague Dawley rats.
[000273] Figure 2 shows the eye tissue concentrations of example 3 after administration of IVT of 4.2 μg/mL (210ng/eye). Examples
[000274] The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:


[000275] All reactions were carried out under an atmosphere of nitrogen unless otherwise specified.
[000276] The 1H NMR spectra were recorded on a Brucker Avance III spectrometer (400 MHz) with reference to the deuterium solvent and at room temperature.
[000277] Molecular ions were obtained using LCMS which was performed using a Cromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient from 10% to 90%, 0.1% HCO2H/MeCN at 0. 1% HCO2H/H2O for 11 minutes, flow rate 1.5 mL/min. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization in conjunction with a Thermofinnigan Surveyor LC system.
[000278] Chemical names were generated using Autonom software provided as part of the ISIS draw package from MDL Information Systems.
[000279] Where products were purified by flash chromatography, 'silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen to 0.70 km/cm2 (10 psi) accelerated the elution of the column. Reverse-phase preparative HPLC purifications were performed using a Waters 2525 binary Gradient pump system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.
[000280] All commercial solvents and reagents were used as received. EXAMPLE 1 (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide
A. (S)-2-[(R)-2-tert-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionic acid methyl ester
[000281] H-Fe-OMe.HCl (2.3g, 10.7mmol) was dissolved in CH2Cl2 (100 mL) and DMF (10 mL). This solution was cooled to 0°C. (R)-2-Butoxyloxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid (3.0 g, 9.7 mmol) was added followed by HOBt (1.57 g, 11.6 mmol) and triethylamine ( 2.9g, 29.0mmol). Water-soluble carbodiimide (2.04 g, 10.6 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1 x 30 mL), water (1 x 30 mL), saturated sodium chloride solution in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was purified by flash chromatography (silica), eluent 20% petroleum ether (60 to 80°C), 80% EtOAc, the fractions combined and evaporated in vacuo to give a colorless oil identified as acid methyl ester ( S)-2-[(R)-2-tert-butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionic acid (4.25 g, 9.03 mmol, 93%).[ M+H]+ = 471.27. B. (S)-2-[(R)-2-tert-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionic acid
[000282] (S)-2-[(R)-2-tert-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionic acid methyl ester (2.5 g, 5, 3 mmol) was dissolved in THF (100 mL). Lithium hydroxide monohydrate (668 mg, 15.9 mmol) in water (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hours after which time the reaction mixture was diluted with EtOAc (150 mL). This solution was washed with 0.3M KHSO4 (1 x 50 mL), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as (S)-2-[(R)-2-tert-butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionic acid (2.095 g, 4.58 mmol , 86%). [M+H]+ = 457.25. C. [(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-acid tert-Butyl ester carbamic
[000283] 4-(aminomethyl)benzonitrile hydrochloride (303 mg, 1.80 mmol) was dissolved in CH 2 Cl 2 (50 mL) and DMF (5 mL). This solution was cooled to 0°C. (S)-2-[(R)-2-tert-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionic acid (745 mg, 1.63mmol) was added followed by HOBt ( 265 mg, 1.96 mmol) and triethylamine (495 mg, 4.9 mmol). Water-soluble carbodiimide (344 mg, 1.8 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1 x 30 mL), water (1 x 30 mL), saturated sodium chloride solution in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was purified by flash chromatography (silica), eluent 20% petroleum ether (60 to 80°C), 80% EtOAc, the fractions combined and evaporated in vacuo to give a colorless oil identified as tert-butyl ester of [(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-carbamic acid (493 mg, 0. 86 mmol, 53%). [M+H]+ = 571.29 D. (R)-2-Amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-propionamide hydrochloride
[000284] [(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl] acid tert-Butyl ester -carbamic (225 mg, 0.39 mmol) was treated with 4M HCl/dioxane (50 mL). After one hour at room temperature the solvent was removed to give a white solid identified as (R)-2-amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl] hydrochloride -3-(4-ethoxy-phenyl)-propionamide (200 mg, 0.39 mmol, 100%).[M+H]+ = 471.26 E. (S)-N-(4-Cyano-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide
[000285] (R)-2-Amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-propionamide hydrochloride (200 mg, 0.37 mol) was dissolved in dichloromethane (50 mL), this solution was cooled to 0°C. Triethylamine (111 mg, 1.1 mmol) was added followed by propionyl chloride (39 mg, 0.40 mmol). After 18 hours at 0°C at room temperature the reaction mixture was diluted with CHCl3 (50 mL), this solution was washed with sat. (1 x 20 ml), water (1 x 20 ml), brine in water (1 x 20 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 2% MeOH, 98% CHCl 3 , the fractions combined and evaporated in vacuo to give a colorless oil identified as (S)-N-(4-cyano-benzyl)- 2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide (189 mg, 0.36 mmol, 98%). [M+H]+ = 527.27 F. [4-({(S)-2-[(R)-3-(4-Ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionylamino}-methyl) tert-Butyl ester - benzyl]-carbamic
[000286] (S)-N-(4-Cyano-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide (100 mg, 0.19 mmol) was dissolved in methanol (50 mL). This solution was cooled to 0°C. Nickel(II) chloride hexahydrate (4.5mg, 0.0192mmol) and di-tertbutyl dicarbonate (83mg, 0.38mmol) were added followed by sodium borohydride (50mg, 1.33mmol) portion the portion. The reaction mixture was stirred at 0°C at room temperature for 18 hours. Methanol was removed by evaporation. The residue was dissolved in CHCl3 (70 mL), washed with sat. (1 x 30 mL), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, eluent 1% MeOH, 99% CHCl3 to give a colorless oil identified as [4-({(S)-2-[(R)-3-(4-ethoxy) tert-butyl ester -phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionylamino}-methyl)-benzyl]-carbamic (89 mg, 0.14 mmol, 74%).[M+H]+ = 631.39 G. (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide trifluoroacetate
[000287] [4-({(S)-2-[(R)-3-(4-Ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionylamino}-methyl acid tert-Butyl ester )-benzyl]-carbamic (89 mg, 0.13mmol) was dissolved in trifluoroacetic acid (20 mL). This solution was stirred at room temperature for one hour after which time the solvent was removed in vacuo to give a yellow oil. The residue was purified by preparative HPLC (Sunfire prep C18 OBD column. 19 x 250 mm, 10 µ). 10 to 90% 0.1% TFA/MeCN in 0.1% TFA/H 2 O for 35 min at 20 mL/min. Fractions combined and freeze-dried to give a white solid identified as (S)-N-(4-aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-trifluoroacetate. propionylamino]-3-phenyl-propionamide (38 mg, 0.056 mmol, 42%) [M+H]+ = 531.31 1H NMR: (CD3OD) 1.02 (3H, t, J=7.7Hz), 1 .42 (3H, t, J=7.0Hz), 2.132.21 (2H, m), 2.71-2.77 (1H, m), 2.81-2.92 (2H, m), 3 .12-3.16 (1H, m), 4.05 (2H, q, J=6.9Hz), 4.13 (2H, s), 4.37-4.50 (3H, m), 4 .57-4.69 (1H, m), 6.82 (2H, d, J=8.6Hz), 7.05 (2H, d, J=8.6Hz), 7.17-7.19 ( 2H, m), 7.24-7.31 (5H, m), 7.41 (2H, d, J=8.1Hz).EXAMPLE 2 (R)-N-[(S)-1-(4 -Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide
A. (R)-N-[(S)-1-(4-Cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide
[000288] (R)-2-Amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-propionamide hydrochloride (150 mg, 0.30 mmol) was dissolved in CH2Cl2 (20 mL). This solution was cooled to 0°C. Methanesulfonyl chloride (37mg, 0.33mmol) was added followed by triethylamine (90mg, 0.89mmol). After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (50 mL) and washed with NaHCO3 (1 x 20 mL), water (1 x 20 mL), saturated sodium chloride solution in water (1 x 20 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was purified by flash chromatography (silica), 2% MeOH, 98% CHCl 3 element, the fractions combined and evaporated in vacuo to give a white solid identified as (R)-N-[(S)-1-( 4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide (110 mg, 0.20 mmol, 68%).[M+H]+ = 549 ,11 B. [4-({(S)-2-[(R)-3-(4-Ethoxy-phenyl)-2-methanesulfonylamino-propionylamino]-3-phenyl-propionylamino}-methyl) tert-Butyl ester -benzyl]-carbamic
[000289] (R)-N-[(S)-1-(4-Cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide (110 mg, 0.20 mmol) was dissolved in methanol (50 mL). This solution was cooled to 0°C. Nickel(II) chloride hexahydrate (4.8 mg, 0.02 mmol) and di-tertbutyl dicarbonate (88 mg, 0.4 mmol) were added followed by sodium borohydride (53 mg, 1.4 mmol) portion by portion. The reaction mixture was stirred at 0°C at room temperature for 18 hours. The MeOH was removed by evaporation. The residue was dissolved in CHCl3 (70 mL), washed with sat. (1 x 30 mL), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, eluent 2% MeOH, 98% CHCl3 to give white solid identified as [4-({(S)-2-[(R)-3-(4-ethoxy- phenyl)-2-methanesulfonylamino-propionylamino]-3-phenyl-propionylamino}-methyl)-benzyl]-carbamic (86 mg, 0.13 mmol, 66%). [M+H]+ = 653.23, 675.19 (M+Na). C. (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide trifluoroacetate
[000290] [4-({(S)-2-[(R)-3-(4-Ethoxy-phenyl)-2-methanesulfonylamino-propionylamino]-3-phenyl-propionylamino}-methyl acid tert-Butyl ester )-benzyl]-carbamic (86 mg, 0.13 mmol) was treated with trifluoroacetic acid (20 mL). After one hour at room temperature the solvent was evaporated in vacuo. The residue was purified by preparative HPLC (Sunfire prep C18 OBD column. 19 x 250 mm, 10 µ). 10 to 90% 0.1% TFA/MeCN in 0.1% TFA/H 2 O for 35 min at 20 mL/min. Fractions combined and freeze-dried to give a white solid identified as (R)-N-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy- phenyl)-2-methanesulfonylamino-propionamide (28 mg, 0.042 mmol, 32%) [M+H]+ = 553.08 D. NMR: (CD3OD) 1.41 (3H, t, J=7.0Hz), 2.60 (3H, s), 2.69-2.75 (1H, m), 2.81-2.91 (2H, m), 3.09 (1H, dd, J=13.7, 6 .5Hz), 4.04 (2H, q, J=7.0Hz), 4.13 (3H, m), 4.39 (2H, s), 4.62 (1H, dd, J=8.1 , 6.6Hz), 6.87 (2H, d, J=8.6Hz), 7.13 (2H, d, J=8.6Hz), 7.23 (2H, t, J=6.6Hz) , 7,257.32 (5H, m), 7.41 (2H, d, J=8.1Hz). EXAMPLE 3 N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide
A. {(S)-1-[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester
[000291] (S)-2-Benzyloxycarbonylamino-3-phenyl-propionic acid 2,5-Dioxo-pyrrolidin-1-yl ester (4.25 g, 10.72 mmol) was dissolved in CH 2 Cl 2 (100 mL). This solution was cooled to 0°C. 1-(N-Boc-Aminomethyl)-4-(aminomethyl)benzene (2.79 g, 11.79 mmol) was added followed by triethylamine (3.25 g, 32.16 mmol). After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1 x 30 mL), water (1 x 30 mL), saturated sodium chloride solution in water (1 x 30 mL), dried (Na2SO4) evaporated in vacuo yielding a yellow oil. The residue was triturated with petroleum ether (60 to 80°C) and EtOAc to give a white solid identified as {(S)-1-[4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-2 acid benzyl ester -phenyl-ethyl}-carbamic (3.88 g, 7.49 mmol, 70%).[M+H]+ = 518.28, 540.32 (M+Na). B. {4-[((S)-2-Amino-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester
[000292] {(S)-1-[4-(tert-Butoxycarbonylaminomethyl)-benzylcarbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester (3.66 g, 7.08 mmol) was dissolved in methanol (200 ml). This solution was hydrogenated over 10% Pd/C (500 mg) at atmospheric pressure and room temperature for one hour after which time the catalyst was filtered through celite and the residue washed with methanol (30 mL), the combined filtrates were evaporated in vacuo to give a white solid identified as {4-[((S)-2-amino-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (2.627 g, 6.85 mmol, 97%). [M+H]+ = 384.37 C. (R)-2-Amino-3-(4-ethoxy-phenyl)-propionic acid
[000293] (R)-2-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid (4.0 g, 12.93 mmol) was dissolved in 4M HCl in dioxane (150 mL). After one hour at room temperature the solvent was removed in vacuo to give a white solid identified as (R)-2-amino-3-(4-ethoxy-phenyl)-propionic acid hydrochloride (3.18 g, 12.9 mmol, 100%).[M+H]+ = 210.18 D. (R)-2-Benzyloxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid
[000294] (R)-2-Amino-3-(4-ethoxy-phenyl)-propionic acid hydrochloride (3.17 g, 12.9 mmol) was dissolved in a solution of sodium hydroxide (1.14 g , 28.38 mmol) in water (100 mL). Benzyl chloroformate (2.64 g, 15.48 mmol) in dioxane (100 mL) was added. The reaction mixture was stirred at room temperature for 18 hours after which time the dioxane was removed in vacuo. The aqueous residue was washed with diethyl ether (1 x 100 mL), acidified to pH 2 with 1M HCl and extracted with chloroform (2 x 200 mL). The combined extracts were washed with water (1 x 50 mL), brine in water (1 x 50 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as (R)-2 acid. -benzyloxycarbonylamino-3-(4-ethoxy-phenyl)-propionic (4.0 g, 11.65 mmol, 90%). [M+H]+ = 344.20. E. [(R)-1-{(S)-1-[4-(tert-Butoxycarbonylaminomethyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-(4-ethoxy-phenyl) acid benzyl ester -ethyl]- carbamic
[000295] {4-[((S)-2-Amino-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-Butyl ester (2.63 g, 6.86 mmol) was dissolved in CH2Cl2 (100 mL) and DMF (5 mL). This solution was cooled to 0°C. (R)-2-Benzyloxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid (2.59 g, 7.54 mmol) was added followed by HOBt (1.11 g, 8.23 mmol) and triethylamine ( 2.08 g, 20.57 mmol). Water-soluble carbodiimide (1.45 g, 7.54 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (200 mL) and washed with NaHCO3 (1 x 50 mL), water (1 x 50 mL), saturated sodium chloride solution in water (1 x 50 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was triturated with ethyl acetate and petroleum ether (60 to 80°C) to give a white solid identified as [(R)-1-{(S)-1-[4-(tert- Butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-(4-ethoxy-phenyl)-ethyl]-carbamic (3.55 g, 5.01 mmol, 73%). [M+H]+ = 709.34. F. [4-({(S)-2-[(R)-2-Amino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionylamino}-methyl) tert-Butyl ester -benzyl]-carbamic
[000296] [(R)-1-{(S)-1-[4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-(4-ethoxy-phenyl) benzyl ester )-ethyl]-carbamic (3.55 g, 5.00 mmol) was dissolved in methanol (200 mL). This solution was hydrogenated over 10% Pd/C (500 mg) at atmospheric pressure and room temperature for one hour after which time the catalyst was filtered through celite and the residue washed with methanol (30 mL), the combined filtrates were evaporated in vacuo to give a white solid identified as [4-({(S)-2-[(R)-2-amino-3-(4-ethoxy-phenyl)-propionylamino]-3 acid tert-butyl ester -phenyl-propionylamino}-methyl)-benzyl]-carbamic (2.8 g, 4.87 mmol, 97%). [M+H]+ = 575.37. G. [4-({(S)-2-[(R)-2-Benzoylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionylamino}-methyl) tert-Butyl ester -benzyl]- carbamic
[000297] [4-({(S)-2-[(R)-2-amino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionylamino}-methyl acid tert-Butyl ester )-benzyl]-carbamic (3.45 g, 5.99 mmol) was dissolved in dichloromethane (150 mL). Benzoyl chloride (1.01g, 7.19mmol) was added followed by triethylamine (1.82g, 17.98mmol). The reaction mixture was stirred at room temperature for 5 hours and diluted with CHCl3 (150 mL), this solution was washed with 0.3 M KHSO4 (1 x 50 mL), sat. (1 x 50 ml), water (1 x 50 ml), brine in water (1 x 50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with petroleum ether (60 to 80°C) and EtOAc to give a white solid identified as [4-({(S)-2-[(R)-2-benzoylamino- 3-(4-Ethoxy-phenyl)-propionylamino]-3-phenyl-propionylamino}-methyl)-benzyl]-carbamic (3.06 g, 4.51 mmol, 75%). [M+H]+ = 679.34. H. N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide hydrochloride
[000298] [4-({(S)-2-[(R)-2-Benzoylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionylamino}-methyl acid tert-Butyl ester )-benzyl]-carbamic (2.86 g, 4.21 mmol) was dissolved in 4M HCl in dioxane (150 mL). After one hour at room temperature the solvent was removed in vacuo. The residue was precipitated from ethanol to give a white solid identified as N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4 -ethoxy-phenyl)-ethyl]-benzamide (2.1 g, 3.41 mmol, 81%).[M+H]+ = 579.34 1H NMR: (CD3OD), 1.40 (3H, t, J= 6.9 Hz), 2.91-2.99 (3H, m), 3.143.19 (1H, m), 4.02 (2H, q, J= 6.9 Hz), 4.08 ( 2H, s), 4.41 (1H, d, J= 15.5 Hz), 4.51 (1H, d, J= 15.5 Hz), 4.66-4.69 (2H, m), 6.82 (2H, d, J= 8.4 Hz), 7.10 (2H, d, J= 8.2 Hz), 7.18-7.20 (2H, m), 7.25-7 .38 (7H, m), 7.44-7.59 (3H, m), 7.72 (2H, d, J=7.8 Hz). EXAMPLE 3b N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide hydrochloride
[000299] [4-({(S)-2-[(R)-2-Benzoylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-phenyl-propionylamino}-methyl acid tert-Butyl ester )-benzyl]-carbamic (10.0 g, 14.7 mmol) was stirred in hydrogen chloride/ethyl acetate (3.7 M, 250 mL) at room temperature. After two hours the mixture was filtered, washed with ethyl acetate (2 x 50 mL) and dried to provide a solid (7.9 g). A portion of the solid (0.106 g) was suspended in a mixture of acetonitrile (2.1 mL) and water (0.32 mL), stirred, and heated to 77°C. More aliquots of water (0.05 mL) were successively added to the mixture until dissolution was observed. The stirred mixture was then cooled to room temperature overnight. The resulting solid was isolated by filtration and dried in vacuo at 40°C to provide N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide (0.067 g, 3.41 mmol, 81%). 1H NMR (CD3OD) was identical to that of example 3, step H. EXAMPLE 4 {(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cycloacid -hexyl-ethylamino}-acetic
A. [(S)-1-(4-Cyano-benzylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-Butyl ester
[000300] 4-Aminomethylbenzonitrile hydrochloride (1.53 g, 9.1 mmol) was dissolved in CH2Cl2 (100 mL). This solution was cooled to 0°C. (S)-2-tert-Butoxycarbonylamino-3-phenylpropionic acid 2,5-Dioxo-pyrrolidin-1-yl ester (3.00 g, 8.3 mmol) was added followed by triethylamine (2.51 g, 25 mmol). After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1 x 30 mL), water (1 x 30 mL), saturated sodium chloride solution in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was crystallized from EtOAc/petroleum ether (60 to 80°C) to give a white solid identified as [(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl acid tert-butyl ester ]-carbamic (2.71 g, 7.1 mmol, 86%). [M+H]+ = 380.13 B. (S)-2-Amino-N-(4-cyano-benzyl)-3-phenyl-propionamide hydrochloride
[000301] [(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-Butyl ester (2.71 g, 7.1 mmol) was treated with 4M HCl /dioxane (150 mL). After one hour at room temperature the solvent was removed to give a white solid identified as (S)-2-amino-N-(4-cyano-benzyl)-3-phenyl-propionamide hydrochloride (2.24 g, 7. 1 mmol, 99%).[M+H]+ = 280.14 C. {(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester
[000302] (S)-2-Amino-N-(4-cyano-benzyl)-3-phenyl-propionamide hydrochloride (500 mg, 1.58 mmol) was dissolved in CH2Cl2 (30 mL) and DMF (3 mL ). This solution was cooled to 0°C. Boc-DCa-OH (473 mg, 1.74 mmol) was added followed by HOBt (257 mg, 1.74 mmol) and triethylamine (481 mg, 4.75 mmol). Water-soluble carbodiimide (339 mg, 1.74 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1 x 30 mL), water (1 x 30 mL), saturated sodium chloride solution in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was purified by flash chromatography (silica), eluent 60% cyclohexane, 40% EtOAc, the combined fractions and evaporated in vacuo to give a white foamy solid identified as {(R)- 1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic (799 mg, 1.50 mmol, 95%). [M+H]+ = 533.18 D. (R)-2-Amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-cyclohexyl-propionamide hydrochloride
[000303] {(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester (799 mg, 1.5 mmol) was treated with 4M HCl/dioxane (50 mL). After one hour at room temperature the solvent was removed to give a white solid identified as (R)-2-amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl] hydrochloride -3-cyclohexyl-propionamide (703 mg, 1.5 mmol, 100%). [M+H]+ = 433.06 E. {(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid tert-butyl ester
[000304] (R)-2-Amino-N-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethyl]-3-cyclohexyl-propionamide hydrochloride (290 mg, 0. 62 mmol) was dissolved in acetonitrile (10 mL). tert-Butylbromoacetate (144mg, 0.74mmol) was added followed by diisopropylethylamine (160mg, 1.24mmol). The reaction mixture was stirred at 60°C for 2 days after which time it was diluted with chloroform (100 ml), washed with water (1 x 30 ml), saturated sodium chloride solution in water (1 x 30 ml ), dried (Na2SO4) and evaporated in vacuo yielding a yellow oil. The residue was purified by flash chromatography (silica), eluent 25% petroleum ether (60 to 80°C), 75% EtOAc, the fractions combined and evaporated in vacuo to give a colorless oil identified as tert-butyl ester of {(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid (240 mg, 0.44 mmol, 71 %).[M+H]+ = 547.30. F. ((R)-1-{(S)-1-[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-cyclohexyl-ethylamino acid tert-Butyl ester )-acetic
[000305] {(R)-1-[(S)-1-(4-cyano-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid tert-butyl ester (240 mg, 0.44 mmol) was dissolved in methanol (25 mL). This solution was cooled to 0°C. Nickel(II) chloride hexahydrate (10.4 mg, 0.44 mmol) and di-tertbutyl dicarbonate (192 mg, 0.88 mmol) were added followed by sodium borohydride (116 mg, 3.1 mmol) portion by portion. The reaction mixture was stirred at 0°C at room temperature for 3 days. The MeOH was removed by evaporation. The residue was dissolved in CHCl3 (70 mL), washed with sat. (1 x 30 mL), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, eluent 40% petroleum ether (60 to 80°C), 60% EtOAc to give white solid identified as acid tert-butyl ester ((R)-1-{(S)-1- [4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-cyclohexyl-ethylamino)-acetic acid (65 mg, 0.10 mmol, 23%).[M+H]+ = 651.44. G. {(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid ditrifluoroacetate
[000306] Acid tert-Butyl ester ((R)-1-{(S)-1-[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-cyclohexyl- ethylamino)-acetic acid (65 mg, 0.1 mmol) was treated with trifluoroacetic acid (4 mL) and CH2Cl2 (2 mL). After one hour at room temperature the solvent was evaporated in vacuo. The residue was purified by preparative HPLC (Sunfire prep C18 OBD column. 19 x 250 mm, 10 µ). 10 to 90% 0.1% TFA/MeCN in 0.1% TFA/H 2 O for 35 min at 20 mL/min. The fractions combined and freeze-dried to give a white solid identified as {(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclocarbamoyl acid ditrifluoroacetate. hexyl-ethylamino}-acetic acid (46 mg, 0.064 mmol, 64%). [M+H]+ = 495.28 1H NMR: (CD3OD) 0.78-0.98 (2H, m), 1.10-1.25 (4H, m), 1.53-1.70 ( 7H, m), 2.97 (1H, dd, J=14.0, 10.5Hz), 3.25 (1H, dd, J=14.1, 5.2Hz), 3.74 (2H, s ), 4.01 (1H, dd, J=8.1, 6.1Hz), 4.15 (2H, s), 4.47 (2H, s), 4.76 (1H, dd, J=10 .5, 5.2Hz), 7.28-7.38 (7H, m), 7.45 (2H, d, J=8.2Hz), 8.83 (1H, t, J=5.9Hz) .
[000307] Compounds in Tables 1 to 5 were synthesized as described by Examples 1 to 4 (above) and 199 to 201 (below).Table 1





























































EXAMPLE 199 N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-ylethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methyl benzamide
A. [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid benzyl ester
[000308] tert-Butyl 4-(Aminomethyl)benzylcarbamate (7.5 g, 31.74 mmol) was dissolved in dichloromethane (250 mL). This solution was cooled to 0°C and triethylamine (9.63g, 93.2mmol) was added followed by carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester benzyl ester (9.5g, 38, 09 mmol). The reaction mixture was stirred at 0°C at room temperature for 18 hours and diluted with CHCl3 (200 mL), the filtrate was washed with 0.3 M KHSO4 (1 x 50 mL), sat. (1 x 50 mL), water (1 x 50 mL), brine in water (1 x 50 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was triturated with EtOAc/petroleum ether at 60 to 80°C to give a white solid identified as [4-(tert-butoxycarbonylamino-methyl)-benzyl]-carbamic acid benzyl ester (11.3 g, 30. 5 mmol, 96%).[M+H]+ = 392.98 (M+ Na) B. (4-Aminomethyl-benzyl)-carbamic acid benzyl ester hydrochloride
[000309] [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid benzyl ester (10.8 g, 29.15 mmol) was dissolved in 4M HCl in dioxane (400 mL). After one hour at room temperature the solvent was removed in vacuo. The residue was suspended in acetone and the solid filtered to give a white solid identified as (4-aminomethyl-benzyl)-carbamic acid benzyl ester hydrochloride (11.9 g, 30.135 mmol, 99%).[M+H ]+ = 359.15 C. {(S)-1-[4-(Benzyloxycarbonylamino-methyl)-benzylcarbamoyl]-2-pyridin-3-yl-ethyl}-carbamic acid tert-butyl ester
[000310] (S)-2-tert-Butoxycarbonylamino-3-pyridin-3-yl-propionic acid (2.12 g, 7.96 mmol) was dissolved in CH 2 Cl 2 (100 mL), HBTU (3.29 g, 8.68 mmol) and triethylamine (2.20 g, 21.71 mmol) were added. After 20 minutes at room temperature the reaction mixture was cooled to 0°C and (4-aminomethyl-benzyl)-carbamic acid benzyl ester hydrochloride (1.96 g, 7.24 mmol) was added. After 2 hours at 0°C the reaction mixture was diluted with CHCl3 (200 mL), this solution was washed with 0.3 M KHSO4 (1 x 50 mL), sat. (1 x 50 mL), water (1 x 50 mL), brine in water (1 x 50 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was triturated with EtOAc/petroleum ether at 60 to 80°C to give a white solid identified as {(S)-1-[4-(benzyloxycarbonylamino-methyl)-benzylcarbamoyl]-2-pyridin acid tert-butyl ester -3-yl-ethyl}-carbamic (2.53 g, 4.88 mmol, 67%). [M+H]+ = 519.16 D. {4-[((S)-2-Amino-3-pyridin-3-yl-propionylamino)-methyl]-benzyl}-carbamic acid benzyl ester dihydrochloride
[000311] {(S)-1-[4-(Benzyloxycarbonylaminomethyl)-benzylcarbamoyl]-2-pyridin-3-yl-ethyl}-carbamic acid tert-butyl ester (2.52 g, 4.89 mmol) was treated with 4M HCl/dioxane (50 mL). After one hour at room temperature the solvent was removed to give a white solid identified as {4-[((S)-2-amino-3-pyridin-3-yl-propionylamino)-methyl]-acid benzyl ester dihydrochloride. benzyl}-carbamic (2.31 g, 4.71 mmol, 97%).[M+H]+ = 419.18 1H NMR: (d6-DMSO) δ: 9.38 (1H, t, J = 5 .7Hz), 8.87 (1H, s), 8.81 (1H, d, J = 5.4Hz), 8.42-8.49 (2H, br s), 8.41 (1H, d, J=8.0Hz), 7.93 (1H, dd, J=7.9, 5.8Hz), 7.87 (1H, t, J=6.2Hz), 7.28-7.38 (4H , m), 7.167.25 (4H, m), 5.03 (2H, s), 4.22-4.43 (4H, m), 4.18 (2H, d, J = 6.1Hz), 3.39 (1H, dd, J=14, 5.6Hz), 3.26 (1H, dd, J=14.0, 8.2Hz). E. [(R)-1-{(S)-1-[4-(Benzyloxycarbonylaminomethyl)-benzylcarbamoyl]-2-pyridin-3-yl-ethylcarbamoyl}-2-(4- ethoxy-phenyl)-ethyl]-carbamic
[000312] (R)-2-Benzyloxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid (870 mg, 2.80 mmol) was dissolved in CH 2 Cl 2 (100 mL), HBTU (1.21 g, 3. 20 mmol) and triethylamine (1.35 g, 13.33 mmol) were added. After 20 minutes at room temperature the reaction mixture was cooled to 0°C and {4-[((S)-2-amino-3-pyridin-3-yl-propionylamino)-methyl]-acid benzyl ester dihydrochloride benzyl}-carbamic (1.31 g, 2.67 mmol) was added. After 2 hours at 0°C the reaction mixture was diluted with CHCl3 (200 mL), this solution was washed with 0.3 M KHSO4 (1 x 50 mL), sat. (1 x 50 mL), water (1 x 50 mL), brine in water (1 x 50 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was triturated with EtOAc/petroleum ether at 60 to 80°C to give a white solid identified as [(R)-1-{(S)-1-[4-(benzyloxycarbonylamino-methyl) acid tert-butyl ester )-benzylcarbamoyl]-2-pyridin-3-yl-ethylcarbamoyl}-2-(4-ethoxy-phenyl)-ethyl]-carbamic (2.40 g, 1.70 mmol, 90%).[M+H] + = 710.18 F. [4-({(S)-2-[(R)-2-Amino-3-(4-ethoxy-phenyl)-propionylamino]-3-pyridin-3-yl-propionylamino]-3-pyridin-3-yl-propionylamino acid benzyl ester dihydrochloride }-methyl)-benzyl]-carbamic
[000313] [(R)-1-{(S)-1-[4-(Benzyloxycarbonylamino-methyl)-benzylcarbamoyl]-2-pyridin-3-yl-ethylcarbamoyl}-2-(4 -ethoxy-phenyl)-ethyl]-carbamic (1.70, 2.42 mmol) was treated with 4M HCl/dioxane (100 mL). After one hour at room temperature the solvent was removed to give a white solid identified as [4-({(S)-2-[(R)-2-amino-3-(4-ethoxy- phenyl)-propionylamino]-3-pyridin-3-yl-propionylamino}-methyl)-benzyl]-carbamic (1.50 g, 2.32 mmol, 97%). [M+H]+ = 609.99 1H NMR: (d6-DMSO) δ: 9.29 (1H, d, J = 8.4Hz), 8.96 (1H, t, J = 5.8Hz), 8.83 (1H, s), 8.77 (1H, d, J = 5.4Hz), 8.39 (1H, d, J = 8.2Hz), 8.28-7.98 (2H, br s), 7.92 (1H, dd, J = 8.0, 5.7Hz), 7.86 (1H, t, J = 6.2Hz), 7.287.38 (4H, m), 7.11- 7.20 (4H, m), 6.95 (2H, d, J = 8.6Hz), 6.79 (2H, d, J = 8.6Hz), 5.02 (2H, s), 4, 68-4.75 (1H, m), 4.23-4.25 (2H, m), 4.16 (2H, d, J = 6.1Hz), 3.83-4.13 (4H, m ), 3.22 (1H, dd, J = 14.0, 4.4Hz), 3.03 (1H, dd, J = 13.7, 9.7Hz), 2.84 (1H, dd, J = 14.0, 5.9Hz), 2.63 (1H, dd, J=13.8, 6.1Hz), 1.29 (3H, t, J=7.0Hz). G. [4-({(S)-2-[(R)-3-(4-Ethoxy-phenyl)-2-(4-methyl-benzoylamino)-propionylamino]-3-pyridin-3 acid benzyl ester -yl-propionylamino}-methyl)-benzyl]-carbamic
[000314] [4-({(S)-2-[(R)-2-Amino-3-(4-ethoxy-phenyl)-propionylamino]-3-pyridin-3-yl- propionylamino}-methyl)-benzyl]-carbamic (150 mg, 0.23 mol) was dissolved in dichloromethane (50 mL), this solution was cooled to 0°C. Triethylamine (70 mg, 0.70 mmol) was added followed by p-toluoyl chloride (39 mg, 0.26 mmol). After 18 hours at 0°C at room temperature the reaction mixture was diluted with CHCl3 (50 mL), this solution was washed with sat. (1 x 20 ml), water (1 x 20 ml), brine in water (1 x 20 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 2% MeOH, 98% CHCl 3 , the fractions combined and evaporated in vacuo to give a colorless oil identified as [4-({(S)-2 -[(R)-3-(4-ethoxy-phenyl)-2-(4-methyl-benzoylamino)-propionylamino]-3-pyridin-3-yl-propionylamino}-methyl)-benzyl]-carbamic (130 mg , 0.18 mmol, 77%).[M+H]+ = 728.14 H. N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl dihydrochloride ]-4-methyl-benzamide
[000315] [4-({(S)-2-[(R)-3-(4-Ethoxy-phenyl)-2-(4-methyl-benzoylamino)-propionylamino]-3-pyridin- 3-yl-propionylamino}-methyl)-benzyl]-carbamic (98 mg, 0.13 mmol) was dissolved in methanol (100 mL), 1M hydrochloric acid (0.263 mL, 0.263 mmol) was added and the mixture of The reaction was hydrogenated over 10% Pd/C (50 mg) at atmospheric pressure for 2 hours after which time the catalyst was filtered and washed with methanol (100 mL), the combined filtrates were evaporated in vacuo to give a white solid which was recrystallized from ethanol to give a white solid identified as N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2- (4-ethoxy-phenyl)-ethyl]-4-methyl-benzamide. Yield = 340 mg, 0.498 mmol, 57% [M+H]+ = 593.99 1H NMR: (d6-DMSO) δ: 1.28 (3H, t, J = 7.05Hz), 2.34 (3H , s), 2.72 (2H, d, J = 8.16Hz), 3.01-3.06 (1H, m), 3.25-3.28 (1H, m), 3.91-3 .98 (4H, m), 4.32-4.38 (2H, m), 4.54-4.57 (1H, m), 4.70-4.73 (1H, m), 6.75 (2H, d, J = 6.83Hz), 7.18 (2H, d, J = 8.56Hz), 7.24 (2H, d, J = 7.56Hz), 7.25-7.27 ( 1H, m), 7.28 (2H, d, J=6.78Hz), 7.39 (2H, d, J=7.51Hz), 7.67 (1H, d, J=7.51Hz), 7.76 (1H, s, br), 8.22 (1H, d, J = 7.56Hz), 8.33 (3H, s, br), 8.71-8.77(4H, m). EXAMPLE 200 N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluorophenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl) -ethyl]-benzamide
A. [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid 9H-Fluoren-9-ylmethyl ester
[000316] tert-Butyl 4-(Aminomethyl)benzylcarbamate (7.5 g, 31.74 mmol) was dissolved in dichloromethane (250 mL). This solution was cooled to 0°C and triethylamine (9.63 g, 93.2 mmol) was added followed by 2,5-dioxo-pyrrolidin-1-yl carbonic acid 9H-fluoren-9-ylmethyl ester ( 12.85 g, 38.09 mmol). The reaction mixture was stirred at 0°C at room temperature for 3 hours and diluted with CHCl3 (200 mL), the filtrate was washed with 0.3 M KHSO4 (1 x 50 mL), sat. (1 x 50 mL), water (1 x 50 mL), brine in water (1 x 50 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was triturated with EtOAc/petroleum ether at 60 to 80°C to give a white solid identified as [4-(tert-butoxycarbonylamino-methyl)-benzyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (13 .96 g, 30.44 mmol, 96%). [M+H]+ = 359.14 (M-Boc) B. 9H-Fluoren-9-ylmethyl (4-aminomethyl-benzyl)-carbamic acid ester hydrochloride
[000317] [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid 9H-Fluoren-9-ylmethyl ester (13.9 g, 31.41 mmol) was dissolved in 4M HCl in dioxane (400 mL). After one hour at room temperature the solvent was removed in vacuo. The residue was triturated with acetone, the solid filtered to give a white solid identified as (4-aminomethyl-benzyl)-carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride (11.9 g, 30.135 mmol, 99% ) [M+H]+ = 359.15 C. ((S)-2-(3,4-Difluoro-phenyl)-1-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-benzylcarbamoyl}-ethyl)- tert -butyl ester carbamic
[000318] (S)-2-tert-Butoxycarbonylamino-3-(3,4-difluoro-phenyl)-propionic acid (2.1 g, 6.96 mmol) was dissolved in CH2Cl2 (250 mL) and DMF (25 mL). This solution was cooled to 0°C. (4-Aminomethyl-benzyl)-carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride (2.5 g, 6.33 mmol) was added followed by HOBt (940 mg, 6.96 mmol) and triethylamine (1 .92g, 18.99mmol). Water-soluble carbodiimide (1.45 g, 7.6 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (400 mL), washed with 0.3 M KHSO4 (1 x 30 mL), NaHCO3 (1 x 30 mL), water (1 x 30 mL). mL), saturated sodium chloride solution in water (1 x 30 mL) and evaporated in vacuo to give a white solid. The residue was triturated with ethyl acetate / petroleum ether at 60 to 80°C to give a white solid identified as ((S)-2-(3,4-difluoro-phenyl)-1- {4-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-benzylcarbamoyl}-ethyl)-carbamic (2.60 g, 4.05 mmol, 64%).[M+H]+ = 641.9, 664.07 (M+Na) D. (4-{[(S)-2-amino-3-(3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride
[000319] ((S)-2-(3,4-Difluoro-phenyl)-1-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-benzylcarbamoyl}-ethyl) tert-Butyl ester - carbamic (2.5 g, 3.90 mmol) was dissolved in 4M HCl in dioxane (150 mL). After one hour at room temperature the solvent was removed in vacuo to give a white solid identified as 9H-fluoren-9-ylmethyl ester hydrochloride (4-{[(S)-2-amino-3-(3,4 - difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic (2.25 g, 3.89 mmol, 100%).[M+H]+ = 542.12 E. [(R)-1-((S)-2-(3,4-Difluoro-phenyl)-1-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl] acid tert-Butyl ester -benzylcarbamoyl}-ethylcarbamoyl)-2-(4-ethoxy-phenyl)-ethyl]-carbamic
[000320] (R)-2-tert-Butoxycarbonylamino-3-(4-ethoxy-phenyl)-propionic acid (895 mg, 2.90 mmol) was dissolved in CH 2 Cl 2 (250 mL) and DMF (25 mL). This solution was cooled to 0°C. (4-{[(S)-2-Amino-3-(3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride (1, 5g, 2.63mmol) was added followed by HOBt (391mg, 2.90mmol) and triethylamine (800mg, 7.89mmol). Water soluble carbodiimide (605 mg, 3.16 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (200 mL), washed with 0.3 M KHSO4 (1 x 30 mL), NaHCO3 (1 x 30 mL), water (1 x 30 mL). mL), saturated sodium chloride solution in water (1 x 30 mL) and evaporated in vacuo to give a white solid. The residue was triturated with ethyl acetate / petroleum ether at 60 to 80°C to give a white solid identified as [(R)-1-((S)-2-(3,4- difluoro-phenyl)-1-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-benzylcarbamoyl}-ethylcarbamoyl)-2-(4-ethoxy-phenyl)-ethyl]-carbamic (2.1 g, 2.52 mmol, 96%).[M+H]+ = 733.15 (M-Boc) F. (4-{[(S)-2-[(R)-2-amino-3-(4-ethoxy-phenyl)-propionylamino]-3-(acid) 9H-fluoren-9-ylmethyl ester hydrochloride 3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic
[000321] [(R)-1-((S)-2-(3,4-Difluoro-phenyl)-1-{4-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl acid tert-Butyl ester ]-Benzylcarbamoyl}-ethylcarbamoyl)-2-(4-ethoxy-phenyl)-ethyl]-carbamic (2.1 g, 2.52 mmol) was dissolved in 4M HCl in dioxane (150 mL). After one hour at room temperature the solvent was removed in vacuo and the residue triturated with acetone to give a white solid identified as 9H-fluoren-9-ylmethyl ester hydrochloride (4-{[(S)-2-[( R)-2-amino-3-(4-ethoxy-phenyl)-propionylamino]-3-(3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic (1.9 g, 2, 47 mmol, 98%).[M+H]+ = 73.12 G. (4-{[(S)-2-[(R)-2-benzoylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-(3, 4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic
[000322] 9H-Fluoren-9-ylmethyl ester hydrochloride (4-{[(S)-2-[(R)-2-amino-3-(4-ethoxy-phenyl)-propionylamino]-3- (3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic (410 mg, 0.53 mmol) was dissolved in dichloromethane (50 mL). This solution was cooled to 0°C and triethylamine (162 mg, 1.60 mmol) was added followed by benzoyl chloride (82 mg, 0.59 mmol). The reaction mixture was stirred at 0°C at room temperature for 3 hours and diluted with CHCl3 (100 mL), the filtrate was washed with 0.3 M KHSO4 (1 x 30 mL), sat. (1 x 30 mL), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was triturated with hot ethanol, the cooled suspension was filtered to give a white solid identified as (4-{[(S)-2-[(R)-2-benzoylamino- 3-(4-Ethoxy-phenyl)-propionylamino]-3-(3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic (240 mg, 0.34 mmol, 99%).[M +H]+ = 697.18 H. N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy- phenyl)-ethyl]-benzamide
[000323] (4-{[(S)-2-[(R)-2-Benzoylamino-3-(4-ethoxy-phenyl)-propionylamino]-3-(3) Acid 9H-Fluoren-9-ylmethyl ester ,4-Difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic (180 mg, 0.215 mmol) was dissolved in diethylamine/THF (1:1, 100 mL), the reaction mixture was stirred at room temperature for 3 hours time after which the solvent was removed in vacuo and the residue was triturated with ethyl acetate/petroleum ether at 60 to 80°C to give an identified white solid which was treated with 4M HCl in dioxane (20 mL ), the solvent was removed in vacuo and the residue recrystallized from EtOH to give a white solid identified as N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-( 3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide (62 mg, 0.095 mmol, 44%).[M+H]+ = 614.68 1H NMR: (d6-DMSO) δ: 1.26(3H, t, J=6.79Hz), 2.65-2.84(3H, m), 3.033.08(1H, m), 3.92(2H, m) q, J=6.11Hz), 3.96(2H, s), 4.27-4.35(2H,m), 4.57-4.63(2H, m), 6.75(2H, m), d , J=8.03Hz), 7.16(2H, d, J=8.76Hz), A. 23-7.25(1H, m), 7.26-7.27(2H, m), 7 .37-7.51(6H, m), 7.43(1H, d, J=7.3Hz), 7.73-7.75(2H, m), 8.24 (2H, s), 8 .50(1H, d, J=7.40Hz), 8.678.71(2H, m). EXAMPLE 201N-{(R,S)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-[4-(2,2,2-trifluoro-ethoxy) -phenyl]-ethyl}-benzamide
A. (R,S)-2-Benzyloxycarbonylamino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid
[000324] (R)-2-Benzyloxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid (1.0 g, 3.17 mmol) was dissolved in THF (70 mL), 2,22-trifluoroethyl trifluoromethanesulfonate (883 mg, 3.81 mmol) and cesium carbonate (3.1 g, 9.51 mmol) were added. The reaction mixture was stirred at 65°C for 18 hours after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100 ml), this solution was washed with 1M HCl (1 x 30 ml), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 1% AcOH, 5% MeOH, 94% CHCl3, the fractions combined and evaporated in vacuo to give a colorless oil identified as (R,S)-2-acid. benzyloxycarbonylamino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid (380 mg, 0.96 mmol, 30%). [M+H]+ = 395.11 B. {(R,S)-1-{(S)-1-[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-[4-(2) Acid Benzyl Ester ,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-carbamic
[000325] (R,S)-2-Benzyloxycarbonylamino-3-[4-(2,2,2-trifluoroethoxy)-phenyl]-propionic acid (200 mg, 0.50 mmol) was dissolved in CH2Cl2 (50 mL) and DMF (2.5mL). This solution was cooled to 0°C. {4-[((S)-2-Amino-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (231 mg, 0.60 mmol) was added followed by HOBt (75 mg , 0.55 mmol) and triethylamine (153 mg, 1.51 mmol). Water soluble carbodiimide (116 mg, 0.60 mmol) was then added. After 18 hours at 0°C at room temperature the reaction mixture was diluted with chloroform (400 mL), washed with 0.3 M KHSO4 (1 x 30 mL), NaHCO3 (1 x 30 mL), water (1 x 30 mL). mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to a yellow oil. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl 3 , the fractions combined and evaporated in vacuo to give a white solid identified as {(R,S)-1-{ acid benzyl ester (S)-1-[4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}- carbamic (350 mg, 0.46 mmol, 92%). [M+H]+ = 663.43 (M-Boc), 785.44 (M+Na) C. {4-[((S)-2-{(R,S)-2-Amino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-Acid tert-Butyl ester propionylamino}-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic
[000326] {(R,S)-1-{(S)-1-[4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-2-phenyl-ethylcarbamoyl}-2-[4-( 2,2,2-Trifluoro-ethoxy)-phenyl]-ethyl}-carbamic (350 mg, 0.46 mmol) was dissolved in methanol (100 mL). This solution was hydrogenated over 10% Pd/C (50mg) at atmospheric pressure for 2 hours after which time the catalyst was filtered and washed with methanol (100ml), the combined filtrates were evaporated in vacuo to give an identified white solid as {4-[((S)-2-{(R,S)-2-amino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino acid tert-butyl ester }-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic (270 mg, 0.43 mmol, 94%). [M+H]+ = 629.40 D. {4-[((S)-2-{(R,S)-2-Benzoylamino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-Acid tert-Butyl ester propionylamino}-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic
[000327] {4-[((S)-2-{(R,S)-2-amino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl] acid tert-Butyl ester] -propionylamino}-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic (250 mg, 0.40 mmol) was dissolved in dichloromethane (50 mL). This solution was cooled to 0°C and triethylamine (121 mg, 1.19 mmol) was added followed by benzoyl chloride (61 mg, 0.44 mmol). The reaction mixture was stirred at 0°C at room temperature for 18 hours and diluted with CHCl3 (100 ml), the filtrate was washed with 0.3 M KHSO4 (1 x 30 ml), sat. (1 x 30 mL), water (1 x 30 mL), brine in water (1 x 30 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was triturated with ethyl acetate/petroleum ether at 60 to 80°C to give a white solid identified as {4-[((S)-2-{(R,S)-2 - benzoylamino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino}-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic (190 mg, 0.26 mmol, 65 %).[M+H]+ = 733.357, 755.49 (M+Na) E. N-{(R,S)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-[4-(2,2,2-trifluoro) ditrifluoroacetate -ethoxy)-phenyl]-ethyl}-benzamide
[000328] {4-[((S)-2-{(R,S)-2-benzoylamino-3-[4-(2,2,2-trifluoro-ethoxy)-phenyl] acid tert-Butyl ester] -propionylamino}-3-phenyl-propionylamino)-methyl]-benzyl}-carbamic (190 mg, 0.26 mmol) was treated with 4M HCl/dioxane (50 mL). After one hour at room temperature the solvent was removed. The residue was purified by preparative HPLC (Sunfire prep C18 OBD column. 19 x 250 mm, 10 µ). 10 to 90% 0.1% TFA/MeCN in 0.1% TFA/H 2 O for 35 min at 20 mL/min. The fractions were combined and freeze-dried to provide a white solid identified as N-{(R,S)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-ditrifluoroacetate. 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-benzamide (56 mg, 0.075 mmol, 29%).[M+H]+ = 632.51 1H NMR (d6- DMSO) δ: 2.68 (1H, d, J=7.44Hz), 2.82-3.08 (5H, m), 3.98 (2H, d, J=5.92Hz), 4.31 -4.34 (2H, m), 4.60-4.70 (4H, m), 6.90-6.94 (2H, m), 7.16-7.28 (6H, m), 7 .34-7.37 (2H, m), 7.43-7.52 (3H, m), 7.74-7.79 (2H, m), 8.09 (3H, s, br), 8 .47 (1H, d, J=8.45Hz), 8.588.62 (2H, m). Determination of kinetic solubility in phosphate buffer
[000329] Solubility was determined turbidimetrically using standard published methods (Lipinski et.al. Advanced Drug Delivery Reviews 23 (1997) 3-25). A 10 mM stock of compound was prepared in DMSO, which was added to 25 mM sodium phosphate buffer pH 7.0, to yield concentrations ranging from 12 to 235 μM. After stirring for approximately 30 seconds, the reduction in light transmission of these samples, at 650 nm, was measured (Molecular Devices Spectromax UV/Visible Spectrophotometer). A second measurement was taken approximately 30 seconds later. Absorbance greater than 0.005 is taken to indicate that some precipitation of the compound has occurred and therefore the compound is not soluble at that concentration.
[000330] The data acquired from these determinations are shown in Table 8 below: Table 8

Determination of thermodynamic solubility in phosphate buffer
[000331] The thermodynamic solubility of compound was determined in ammonium phosphate buffer (pH 7.4, 290 mOsm). Compounds were prepared at a nominal concentration of 1 mg/mL, vortexed, then shaken for 1 hour at 37°C at approximately 950 rpm. After incubation the samples were transferred to Eppendorf tubes and centrifuged at 15,000 g (r.c.f.) for 10 minutes at 37°C. The concentration of compound in the supernatant was determined by LC-MS/MS analysis using a calibration line prepared from a DMSO stock.
[000332] The data acquired from these determinations are shown in Table 9 below: Table 9

Biological Methods
[000333] The ability of compounds of Formula (I) to inhibit plasma kallikrein can be determined using the following biological assay: Determination of IC50 for plasma kallikrein
[000334] In vitro plasma kallikrein inhibitory activity was determined using standard published methods (see for example, Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol. , 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated at 37°C with the fluorogenic substrate H-DPro-Fe-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial reaction rate) was determined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
[000335] The data acquired from this test are shown in tables 10 and 11 below: Table 10





[000336] Selected compounds were also analyzed for inhibitory activity compared to the related enzyme KLK1. The ability of compounds of Formula (I) to inhibit KLK1 can be determined using the following biological assay: Determination of IC50 for KLK1
[000337] KLK1 inhibitory activity in vitro was determined using standard published methods (see, for example, Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol. , 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated at 37oC with the fluorogenic substrate H-DVal-Leu-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial reaction rate) was determined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
[000338] The data acquired from this test are shown in tables 12 and 13 below:Table 12






[000339] The selected compounds were also analyzed for inhibitory activity compared to the related enzymes plasmin, thrombin, trypsin, Factor Xa and Factor XIIa. The ability of compounds of Formula (I) for these enzymes can be determined using the following biological assays: Determination of enzyme selectivity
[000340] The human serine protease enzymes plasmin, thrombin, trypsin, Factor Xa and Factor XIIa were assayed for enzymatic activity using an appropriate fluorogenic substrate. Protease activity was measured by monitoring the accumulation of fluorescence released from the substrate for 5 minutes. The linear rate of increase in fluorescence per minute was expressed as percent activity (%). The Km for cleavage of each substrate was determined by the standard transformation of the Michaelis-Menten equation. Compound inhibitor assays were performed at Km concentration of substrate and activities were calculated as the concentration of inhibitor providing 50% inhibition (IC50 ) of uninhibited (100%) enzyme activity.
[000341] The data acquired from these tests are shown in Table 14 below: Table 14 (Selectivity data)
Table 15 (selectivity data: Factor XIIa)
Model of carbonic anhydrase I-induced retinal vascular permeability
[000342] Example 3 activity was established using this in vivo mouse model. Rats received an intravitreal injection (5μL) of phosphate-buffered saline (PBS), CH-3457 (a positive control plasma kallikrein inhibitor) (10μM) or Example 3 (1μM) at time 0. After 30 minutes, a second intravitreal injection (5 μL) of PBS or CA-I (200 ng/eye) was administered. After 15 minutes, 10% sodium fluorescein was infused and retinal vascular permeability (RVP) was measured by vitreous fluorophotometry 75 minutes after the initial IVT injections. Data for example 3 are shown in Figure 1, where the lower dashed line indicates baseline PVR after PBS/PBS and the upper dashed line indicates maximum stimulation. Intravitreal injection of 1μM of example 3 alone had no effect on baseline PVR compared to PBS alone (3.29 ± 0.21 vs. 3.64 ± 0.48). Example 3 intravitreal injection reduced PVR (stimulated by CA-I injection) by 53 ± 21%. Pharmacokinetics
[000343] An example 3 pharmacokinetic study was performed to estimate ocular and systemic pharmacokinetics after a single dose of IVT in pigmented (Dutch-belted) rabbits. Six rabbits per dose level were given a single, bilateral, 50 μL IVT injection of a 4.2 μg/mL (210 ng per eye). Example 3 formulated in phosphate buffered saline. One rabbit was euthanized at each time point (4, 8, 24, 48, 96 and 168 hours after IVT administration) and concentrations of example 3 ocular tissue in the vitreous, retina/choroid and aqueous humor were measured. Serial blood samples were collected from surviving rabbits.
[000344] Ocular tissue concentration data are shown in Figure 2, where the solid line for each ocular tissue concentration is the average of the left and right eye of each rabbit. The decline in eye tissue concentrations from example 3 was minimal for 7 days. Example 3 plasma concentrations after IVT administration were below 1 ng/mL at all time points.

权利要求:
Claims (15)
[0001]
1. Compound, characterized by the fact that it presents Formula (I),
[0002]
2. Compound according to claim 1, characterized in that R9 is selected from phenyl and naphthyl, and the phenyl may be optionally substituted by up to 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11 , CF3 and NR11R12.
[0003]
3. Compound according to claim 1 or 2, characterized in that R9 is selected from phenyl, 1-naphthalene, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-ethoxyphenyl.
[0004]
4. Compound according to any one of claims 1 to 3, characterized in that R1 is selected from H, -COaryl, -COalkyl, -CH2COOH, -SO2Ph and -SO2CH3.
[0005]
5. Compound according to any one of claims 1 to 4, characterized in that R3 is selected from:
[0006]
6. Compound according to any one of claims 1 to 5, characterized in that R4 and R6 are selected from H and CH3.
[0007]
7. Compound according to any one of claims 1 to 6, characterized in that the stereochemical configuration over the chiral center *1 is R.
[0008]
8. Compound according to any one of claims 1 to 7, characterized in that the stereochemical configuration over the chiral center *2 is S.
[0009]
9. Compound according to any one of claims 1 to 8, characterized in that: a is 2, and b, c, d, e, f, g, h, j, l and m are 1.
[0010]
10. Compound according to claim 1, characterized in that it is selected from: (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl) -2-propionylamino-propionylamino]-3-phenyl-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; {(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethylamino}-acetic acid; (S)-N-(4-Aminomethyl-3-fluoro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide; (S)-N-(4-Aminomethyl-2-chloro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide; (S)-N-(4-Aminomethyl-benzyl)-3-(3,4-dichloro-phenyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]- propionamide; (S)-N-(4-Aminomethyl-3-chloro-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-phenyl-propionamide; (S)-N-(4-Aminomethyl-benzyl)-2-{[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionyl]-methyl-amino}-3-phenyl-propionamide; ({(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-methyl-amino)-acetic acid; (S)-N-(4-Aminomethyl-3-fluoro-benzyl)-2-{[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionyl]-methyl-amino}-3- phenyl-propionamide; N-[(R)-1-{[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-methyl-carbamoyl}-2-(4-ethoxy-phenyl)-ethyl]- benzamide; N-[(R)-1-{[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-methyl-carbamoyl}-2-(4-ethoxy-phenyl)-ethyl]- isobutyramide; Naphthalene-1-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-chloro-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,4-dichloro- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4-difluoro- benzamide; (R)-2-Amino-N-[(1S,2S)-1-(4-aminomethyl-benzylcarbamoyl)-2-hydroxy-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-nicotinamide; (2S,3S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylamino-propionylamino]-3-hydroxy-3-phenyl-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; Thiophene-3-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; Thiophene-2-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; cyclohexanecarboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide; Ioxazole-5-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; Pyridine-2-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; Benzo[b]thiophene acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-2-(4-chloro-benzenesulfonylamino)-3-(4-ethoxy-phenyl)-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3-chloro-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2-chloro-benzamide N -[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3-trifluoromethyl-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methyl-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4-dichloro- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methoxy-benzamide; (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-(2-phenylacetylamino-acetylamino)-propionylamino]-3-phenyl-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-fluoro-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-6-methyl-nicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2-methyl-nicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,6-dichloro- nicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-5,6-dichloro- nicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,3,6- trifluoro-isonicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,3,3- trifluoro-propionamide; 2,4-Dimethyl Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -thiazole-5-carboxylic acid; 2-Methyl-thiazole Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -5- carboxylic; Thiophene Acid 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; 4-Methyl-thiazole acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -5- carboxylic; Furan-2-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; Thiophene Acid 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2-methoxy-isonicotinamide; 3-Methyl-1H Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -pyrrole-2-carboxylic acid; Thiophene Acid 3-Amino-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-propoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-chloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-methoxy-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-3-yl-ethylcarbamoyl-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; Pyridine acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methoxy-benzamide; Pyridine acid [(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methoxy-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-isonicotinamide; Thiophene acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- chloro-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methyl benzamide; [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- pyridine-2-carboxylic acid amide; (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethyl]-3-(4-ethoxy-phenyl)-2-propionylamino-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; Pyridine acid [(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- thiophene-2-carboxylic acid amide; (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethyl]-3-(4-ethoxy-phenyl)-2-propionylamino-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-isonicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-3,3,3-trifluoropropionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- chloro-benzamide; Isoxazole acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -5- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methyl benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- thiophene-2-carboxylic acid amide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-isonicotinamide; 3-Acetylamino-thiophene acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2-carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(2-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- thiophene-2-carboxylic acid amide; N-[(R)-1-[(S)-1-(4-aminomethyl-3-methyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -amino-thiophene-2-carboxylic acid; Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -chloro-thiophene-2-carboxylic acid; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methyl benzamide; [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- 3-methyl-1H-pyrrole-2-carboxylic acid amide; Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiazol-4-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -amino-thiophene-2-carboxylic acid; [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- 3-acetylamino-thiophene-2-carboxylic acid amide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3- methyl benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2- methyl benzamide; 3,5-Dimethyl Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -1H-pyrrole-2-carboxylic acid; N-[(R)-1-[(S)-1-(4-aminomethyl-3-methyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -acetylamino-thiophene-2-carboxylic acid; [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- 3-amino-thiophene-2-carboxylic acid amide; [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- 3-acetylamino-thiophene-2-carboxylic acid amide; [(R)-1-{[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-methyl-carbamoyl}-2-(4-ethoxy-phenyl)-ethyl]-amide from 3-chloro-thiophene-2-carboxylic acid; N-[(R)-1-[(1S,2R)-1-(4-Aminomethyl-benzylcarbamoyl)-2-hydroxy-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; [(R)-1-[(1S,2R)-1-(4-aminomethyl-benzylcarbamoyl)-2-hydroxy-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide from 3-chloro-thiophene-2-carboxylic acid; N-{(R,S)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-[4-(2,2,2-trifluoro-ethoxy)- phenyl]-ethyl}-benzamide; and pharmaceutically acceptable salts and solvates thereof.
[0011]
11. Compound according to claim 1, characterized in that it is selected from: N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl] -2-(4-ethoxy-phenyl)-ethyl]-benzamide; Naphthalene-1-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-chloro-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-2,4-dichloro- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-nicotinamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4-difluoro- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; Thiophene-3-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; Thiophene-2-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; cyclohexanecarboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide; Ioxazole-5-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; Pyridine-2-carboxylic acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide ; (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-2-(4-chloro-benzenesulfonylamino)-3-(4-ethoxy-phenyl)-propionamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methyl-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3,4-dichloro- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-3-chloro-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-methoxy-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4-fluoro-benzamide; Thiophene Acid 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; 3-Methyl-1H Acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -pyrrole-2-carboxylic acid; Thiophene Acid 3-Amino-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-propoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-3-yl-ethylcarbamoyl-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-3-fluoro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-benzamide; Pyridine acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-thiophen-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-2-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methoxy-benzamide; Pyridine acid [(R)-1-[(S)-1-(4-aminomethyl-3-chloro-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methoxy-benzamide; Thiophene acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-4- methyl benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; Thiophene Acid 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2- carboxylic; 3-Chloro-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- thiophene-2-carboxylic acid amide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-benzamide; N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-benzo[b]thiophen-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl ]-isonicotinamide; 3-Acetylamino-thiophene acid [(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide -2-carboxylic; 3-Methyl-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-pyridin-3-yl-ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]- thiophene-2-carboxylic acid amide; and pharmaceutically acceptable salts and solvates thereof.
[0012]
12. Compound according to claim 1, 10 and 11, characterized in that it is N-[(R)-1-[(S)-1-(4-aminomethyl-benzylcarbamoyl)-2-phenyl- ethylcarbamoyl]-2-(4-ethoxyphenyl)-ethyl]-benzamide,
[0013]
13. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 12, and a pharmaceutically acceptable carrier, diluent or excipient.
[0014]
14. Use of a compound, as defined in any one of claims 1 to 12, characterized in that it is in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated, which is selected from impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, respiratory distress syndrome in adults, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding after operative surgery.
[0015]
15. Use according to claim 14, characterized in that the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112014000240B1|2022-02-01|Benzylamine derivatives as plasma kallikrein inhibitors, their use, and pharmaceutical composition

---

EP3224256B1|2019-07-03|N-|arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors,

---

EP3464271B1|2020-05-13|Pyrazole derivatives as plasma kallikrein inhibitors

---

ES2623895T3|2017-07-12|Benzylamine derivatives

---

EP2870137B1|2018-05-16|Polymorphs of n-[|-1-[|-1-|-2-phenyl-ethylcarbamoyl]-2-|-ethyl]-benzamide hydrochloride

---

BR112020009975A2|2020-11-03|solid forms of a plasma kallikrein inhibitor and salts thereof

---

NZ620271B2|2015-09-01|Benzylamine derivatives as inhibitors of plasma kallikrein

---

AU2020293614A1|2022-01-27|Treatments of hereditary angioedema

---

BR112016003040B1|2022-01-25|BICYCLIC PLASMAKALKREIN INHIBITOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AND THEIR USES

同族专利:

---

公开号 | 公开日

---

PT2729443E|2016-03-31|

---

PL2729443T6|2020-07-13|

---

GB201111682D0|2011-08-24|

---

HUE027482T2|2016-11-28|

---

ME02308B|2016-06-20|

---

CL2014000032A1|2014-08-01|

---

CN103687846B|2016-06-22|

---

ES2560612T7|2020-10-08|

---

MX2014000073A|2014-10-24|

---

WO2013005045A1|2013-01-10|

---

AR087102A1|2014-02-12|

---

IL230332A|2017-02-28|

---

RU2014104226A|2015-08-20|

---

EP2729443B1|2015-11-25|

---

DK2729443T6|2020-04-20|

---

ZA201400682B|2014-11-26|

---

HRP20160101T4|2020-03-20|

---

IL230332D0|2014-03-06|

---

JP2014523897A|2014-09-18|

---

AU2012280064A1|2014-02-27|

---

KR20140074275A|2014-06-17|

---

PL2729443T3|2016-05-31|

---

TWI537238B|2016-06-11|

---

HK1197055A1|2015-01-02|

---

BR112014000240A2|2017-06-13|

---

CA2841042A1|2013-01-10|

---

US9051249B2|2015-06-09|

---

UA115427C2|2017-11-10|

---

US9234000B2|2016-01-12|

---

EP2729443A1|2014-05-14|

---

RS54509B2|2020-09-30|

---

CA2841042C|2019-03-19|

---

RS54509B1|2016-06-30|

---

DK2729443T3|2016-01-04|

---

US20140213611A1|2014-07-31|

---

ES2560612T3|2016-02-22|

---

TW201307259A|2013-02-16|

---

GB2494851A|2013-03-27|

---

SMT201600020B|2016-02-25|

---

AU2012280064B2|2016-09-08|

---

JP5921679B2|2016-05-24|

---

KR101999195B1|2019-07-11|

---

HRP20160101T1|2016-02-26|

---

RU2607045C2|2017-01-10|

---

EP2729443B3|2020-02-12|

---

CY1117200T1|2017-04-05|

---

MX343740B|2016-11-22|

---

NZ620271A|2015-05-29|

---

SI2729443T1|2016-02-29|

---

US20150225450A1|2015-08-13|

---

CO6940413A2|2014-05-09|

---

CN103687846A|2014-03-26|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US5187157A|1987-06-05|1993-02-16|Du Pont Merck Pharmaceutical Company|Peptide boronic acid inhibitors of trypsin-like proteases|

---

GB9019558D0|1990-09-07|1990-10-24|Szelke Michael|Enzyme inhibitors|

---

SE9301911D0|1993-06-03|1993-06-03|Ab Astra|NEW PEPTIDE DERIVATIVES|

---

US5589467A|1993-09-17|1996-12-31|Novo Nordisk A/S|2,5',N6-trisubstituted adenosine derivatives|

---

US5914319A|1995-02-27|1999-06-22|Eli Lilly And Company|Antithrombotic agents|

---

IL112795A|1994-03-04|2001-01-28|Astrazeneca Ab|Peptide derivatives as antithrombic agents their preparation and pharmaceutical compositions containing them|

---

AU698911B2|1995-04-04|1998-11-12|Merck & Co., Inc.|Thrombin inhibitors|

---

EP1364960A4|2001-02-02|2005-05-18|Chugai Pharmaceutical Co Ltd|Peptide derivatives|

---

GB0205527D0|2002-03-08|2002-04-24|Ferring Bv|Inhibitors|

---

DE10301300B4|2003-01-15|2009-07-16|Curacyte Chemistry Gmbh|Use of acylated 4-amidino- and 4-guanidinobenzylamines for the inhibition of plasma kallikrein|

---

NZ617083A|2003-08-27|2015-04-24|Ophthotech Corp|Combination therapy for the treatment of ocular neovascular disorders|

---

ES2365815T3|2005-12-14|2011-10-11|Bristol-Myers Squibb Company|ANALOGS OF ARILPROPIONAMIDA, ARILACRILAMIDA, ARILPROPINAMIDA OR ARILMETILUREA AS INHIBITORS OF THE XIA FACTOR.|

---

WO2008016883A2|2006-07-31|2008-02-07|Activesite Pharmaceuticals, Inc.|Inhibitors of plasma kallikrein|

---

DE102006050672A1|2006-10-24|2008-04-30|Curacyte Discovery Gmbh|New glycylglycine derivatives with a benzylsulfonylamido group and an amidino-organylamido group at the opposite chain ends, used in drugs for reducing loss of blood, e.g. in operations|

---

EP2152664B1|2007-06-13|2014-09-03|Bristol-Myers Squibb Company|Dipeptide analogs as coagulation factor inhibitors|

---

ES2380648T3|2008-03-13|2012-05-17|Bristol-Myers Squibb Company|Pyridazine derivatives as XIA factor inhibitors|

---

US8609866B2|2009-12-18|2013-12-17|Activesite Pharmaceuticals, Inc.|Prodrugs of inhibitors of plasma kallikrein|

---

EA022121B1|2010-01-28|2015-11-30|Зе Медисинс Компани Гмбх|Trypsin-like serine protease inhibitors, and their preparation and use|

---

JP2013121919A|2010-03-25|2013-06-20|Astellas Pharma Inc|Plasma kallikrein inhibitor|

---

WO2012004678A2|2010-07-07|2012-01-12|The Medicines Company Gmbh|Serine protease inhibitors|

---

US9290485B2|2010-08-04|2016-03-22|Novartis Ag|N-methyl)-heteroaryl-carboxamides|

---

EP2697196A1|2011-04-13|2014-02-19|Activesite Pharmaceuticals, Inc.|Prodrugs of inhibitors of plasma kallikrein|RS58111B1|2011-10-26|2019-02-28|Allergan Inc|Amide derivatives of n-urea substituted amino acids as formyl peptide receptor like-1receptor modulators|

---

GB201212081D0|2012-07-06|2012-08-22|Kalvista Pharmaceuticals Ltd|New polymorph|

---

GB2510407A|2013-02-04|2014-08-06|Kalvista Pharmaceuticals Ltd|Aqueous suspensions of kallikrein inhibitors for parenteral administration|

---

TWI636047B|2013-08-14|2018-09-21|英商卡爾維斯塔製藥有限公司|Heterocyclic derivatives|

---

ES2748434T3|2014-01-10|2020-03-16|Univ Cornell|Dipeptides as inhibitors of human immunoproteasomes|

---

WO2016028571A2|2014-08-18|2016-02-25|Cornell University|Dipeptidomimetics as inhibitors of human immunoproteasomes|

---

GB201421083D0|2014-11-27|2015-01-14|Kalvista Pharmaceuticals Ltd|Enzyme inhibitors|

---

GB201421085D0|2014-11-27|2015-01-14|Kalvista Pharmaceuticals Ltd|New enzyme inhibitors|

---

EP3362754B1|2015-10-15|2021-12-22|Cornell University|Proteasome inhibitors and uses thereof|

---

RU2739447C2|2016-05-31|2020-12-24|Калвиста Фармасьютикалз Лимитед|Pyrazole derivatives as kallikrein inhibitors|

---

GB201609607D0|2016-06-01|2016-07-13|Kalvista Pharmaceuticals Ltd|Polymorphs of N-methyl)-3--1-methyl)phenyl}methyl)pyrazole-4-carboxamide and salts|

---

GB201609603D0|2016-06-01|2016-07-13|Kalvista Pharmaceuticals Ltd|Polymorphs of N-[Methyl]-3--1-Methyl]phenyl}methyl)pyrazole-4-carboxamide|

---

GB201713660D0|2017-08-25|2017-10-11|Kalvista Pharmaceuticals Ltd|Pharmaceutical compositions|

---

US11203613B2|2017-10-11|2021-12-21|Cornell University|Peptidomimetic proteasome inhibitors|

---

RU2020121151A|2017-11-29|2021-12-29|Калвиста Фармасьютикалз Лимитед|DOSAGE FORMS CONTAINING PLASMA KALLIKREIN INHIBITOR|

---

AU2019234670A1|2018-03-13|2020-09-03|Takeda Pharmaceutical Company Limited|Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof|

---

CN111217670B|2018-11-25|2021-04-09|中国科学院大连化学物理研究所|Method for catalytically reducing carbonyl in compound into methylene|

---

CN113474318A|2019-04-22|2021-10-01|南京明德新药研发有限公司|Bicycloalkanes as plasma kallikrein inhibitors|

---

GB201910125D0|2019-07-15|2019-08-28|Kalvista Pharmaceuticals Ltd|Treatments of angioedema|

---

GB201910116D0|2019-07-15|2019-08-28|Kalvista Pharmaceuticals Ltd|Treatments of hereditary angioedema|

---

WO2021028645A1|2019-08-09|2021-02-18|Kalvista Pharmaceuticals Limited|Plasma kallikrein inhibitors|

---

GB2591730A|2019-12-09|2021-08-11|Kalvista Pharmaceuticals Ltd|New polymorphs|

---

GB201918994D0|2019-12-20|2020-02-05|Kalvista Pharmaceuticals Ltd|Treatments of diabetic macular edema and impaired visual acuity|

---

WO2021198534A1|2020-04-04|2021-10-07|Oxurion NV|Plasma kallikrein inhibitors for use in the treatment of coronaviral disease|

法律状态:
2019-04-30| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2020-06-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

---

2021-07-06| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2021-07-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-09-21| B350| Update of information on the portal [chapter 15.35 patent gazette]|

---

2021-11-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2022-02-01| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 06/07/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201161505305P| true| 2011-07-07|2011-07-07|

---

GB1111682.9|2011-07-07|

---

GB1111682.9A|GB2494851A|2011-07-07|2011-07-07|Plasma kallikrein inhibitors|

---

US61/505,305|2011-07-07|

---

PCT/GB2012/051588|WO2013005045A1|2011-07-07|2012-07-06|Benzylamine derivatives as inhibitors of plasma kallikrein|

---