NZ620271B2 - Benzylamine derivatives as inhibitors of plasma kallikrein - Google Patents

Benzylamine derivatives as inhibitors of plasma kallikrein Download PDF

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Publication number
NZ620271B2
NZ620271B2 NZ620271A NZ62027112A NZ620271B2 NZ 620271 B2 NZ620271 B2 NZ 620271B2 NZ 620271 A NZ620271 A NZ 620271A NZ 62027112 A NZ62027112 A NZ 62027112A NZ 620271 B2 NZ620271 B2 NZ 620271B2
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New Zealand
Prior art keywords
phenyl
benzylcarbamoyl
ethyl
aminomethyl
ethoxy
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NZ620271A
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NZ620271A (en
Inventor
Rebecca Louise Davie
Hannah Joy Edwards
David Michael Evans
David Philip Rooker
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Kalvista Pharmaceuticals Limited
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Priority claimed from GB1111682.9A external-priority patent/GB2494851A/en
Application filed by Kalvista Pharmaceuticals Limited filed Critical Kalvista Pharmaceuticals Limited
Publication of NZ620271A publication Critical patent/NZ620271A/en
Publication of NZ620271B2 publication Critical patent/NZ620271B2/en

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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract

Disclosed herein are benzylamide compounds of formula (I), wherein the substituents are as defined in the specification. Also disclosed are pharmaceutical compositions comprising a compound of formula (I) for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated selected from impaired visual acuity, diabetic retinopathy, diabetic macular oedema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post-operative surgery. Examples of a compound of formula (I) are: (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylaminopropionylamino]-3-phenyl-propionamide (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide N-[(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyll-2-(4-ethoxyphenyl)-ethyl]-benzamide {(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyll-2-cyclohexyl-ethylamino}-acetic acid s implicated selected from impaired visual acuity, diabetic retinopathy, diabetic macular oedema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post-operative surgery. Examples of a compound of formula (I) are: (S)-N-(4-Aminomethyl-benzyl)-2-[(R)-3-(4-ethoxy-phenyl)-2-propionylaminopropionylamino]-3-phenyl-propionamide (R)-N-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethyl]-3-(4-ethoxy-phenyl)-2-methanesulfonylamino-propionamide N-[(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyll-2-(4-ethoxyphenyl)-ethyl]-benzamide {(R)-1-[(S)-1-(4-Aminomethyl-benzylcarbamoyl)-2-phenyl-ethylcarbamoyll-2-cyclohexyl-ethylamino}-acetic acid

Description

BENZYLAMINE DERIVATIVES This invention relates to benzylamine derivatives and to pharmaceutical compositions containing and the uses of, such derivatives.
Background to the Invention The benzylamine derivatives of the present invention are inhibitors of plasma kallikrein and have a number of therapeutic applications, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular oedema.
Plasma kallikrein is a trypsin-like serine se that can liberate kinins from kininogens (see K.
D. Bhoola et al., "Kallikrein-Kinin e", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological ch 2000, 33, 665-677). It is an ial member of the intrinsic blood coagulation cascade although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage. Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is ed by hepatocytes as an inactive plasma likrein that circulates in plasma as a heterodimer complex bound to high molecular weight kininogen which is activated to give the active plasma kallikrein. Kinins are potent mediators of mation that act through G protein-coupled receptors and antagonists of kinins (such as bradykinin antagonists) have previously been investigated as ial therapeutic agents for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
Plasma kallikrein is t to play a role in a number of matory ers. The major 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) which results in intermittent swelling of face, hands, , gastro-intestinal tract and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin leading to increased vascular permeability.
Treatment with a large protein plasma kallikrein inhibitor has been shown to ively treat HAE by preventing the release of bradykinin which causes increased vascular permeability (A. n "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin.
Biol. Ther. 8, p1187-99).
The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular oedema. It has been recently published that plasma kallikrein butes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma rein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" es, 2011, 60, p1590- 98). Furthermore, administration of the plasma kallikrein inhibitor ASP -440 ameliorated both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular oedema.
Synthetic and small le plasma kallikrein inhibitors have been described previously, for example by Garrett et al. ("Peptide aldehyde…." J. Peptide Res. 52, p62 -71 (1998)), T. acher et al. lvement of tissue kallikrein but not plasma kallikrein in the pment of symptoms mediated by endogenous kinins in acute pancreatitus in rats" British Journal of Pharmacology 137, p692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/076458), Szelke et al. ("Kininogenase tors" WO92/04371), D. M. Evans et al. olpharmacology, 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, 1090 ), W. B. Young et al. l molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, 2036 (2006)), Okada et al.
("Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, p1964-72 (2000)), Steinmetzer et al.
("Trypsin-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, 53 (2006)), Sinha et al. ("Inhibitors of plasma kallikrein" WO08/016883), and Brandl et al. (“ N-((6-amino-pyridinyl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” WO2012/017020). Also, etzer et al. (“Serine protease inhibitors” WO2012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kallikrein.
To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The 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. The large protein plasma kallikrein inhibitors present risks of anaphylactic reactions, as has been ed for Ecallantide. Thus there remains a need for compounds that selectively inhibit plasma kallikrein, that do not induce anaphylaxis and that are orally available.
Furthermore, the molecules in the known art e a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability.
Other complications of diabetes such as cerebral haemorrhage, nepropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.
Summary of the Invention The t invention relates to a series of benzylamines that are inhibitors of plasma rein.
These nds demonstrate good selectivity for plasma kallikrein and are ially useful in the treatment of impaired visual acuity, ic retinopathy, macular oedema, hereditary angioedema, diabetes, atitus, cerebral haemorrhage, nepropathy, cardiomyopathy, neuropathy, inflammaotory bowel disease, tis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, pulmonary bypass surgery and bleeding from post ive surgery. The invention further relates to pharmaceutical itions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.
In an aspect, the present invention provides compounds of formula I 1 2 R R 4 7 N R O R *1 8 3 N *2 R R N O 5 9 R NH2 R R wherein: R1 is selected from H, alkyl, -COalkyl, -COaryl, eroaryl, -CO2alkyl, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alkyl, -SO2aryl, -SO2(CH2)hR13, -CO(CH2)iR14, -COcycloalkyl, -COCH=CHR15, -CO(CH2)jNHCO(CH2)kR16 and 7R18; 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-memebered 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, l and m are independently 1, 2 or 3; k is 0, 1, 2 or 3; *1 and *2 denote chiral centres; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a ed saturated hydrocarbon of n 3 and 10 carbon atoms 0); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C3- C10)cycloalkyl, )alkoxy, OH, CN, CF3, COOR11, fluoro and NR11R12; cycloalkyl is a mono- or bi-cyclic saturated 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 3 to 10 membered saturated, mono- or bicyclic ring, n 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 between 1 and 6 carbon atoms (C1-C6) or a ed O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2 substituents ndently ed from (C3- C10)cycloalkyl, OH, CN, CF3, COOR11, fluoro 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 lic 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 tuents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3, NR11R12 and NHR19; R11 and R12 are ndently selected from H and alkyl; R13 is aryl or heteroaryl; R14 is aryl, aryl, 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 es thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect the present invention provides a prodrug of a nd of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
In yet another aspect the present invention es an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
It will be understood that certain nds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms.
In an aspect, the invention comprises a subset of the compounds of a (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)gheterocycloalkyl, -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, er with the atoms to which they are attached, may join to form a 5- or 6-memebered 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 centres; alkyl is a linear ted hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10); alkyl may ally be substituted with 1 or 2 substituents independently selected from (C3- C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR11, fluoro and NR11R12; cycloalkyl is a mono- or bi-cyclic saturated hydrocarbon of between 3 and 10 carbon atoms; cycloalkyl may ally be fused to an aryl group; heterocycloalkyl is a C-linked or N-linked 3 to 10 membered saturated, 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 between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2 tuents independently selected from (C3- cloalkyl, OH, CN, CF3, , fluoro and 2; aryl is phenyl, biphenyl or naphthyl; aryl may be ally substituted with up to 5 substituents independently selected from alkyl, alkoxy, OH, halo, CN, , CF3 and NR11R12; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic 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 ed from H and alkyl; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and c and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect, the invention ses a subset of the compounds of formula (I) wherein: R1 is selected from H, alkyl, -COalkyl, -COaryl, -CO2alkyl, -CH2CH2OH, -CH2COOR10, NH2, -SO2alkyl and -SO2aryl; R2 is ed 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 ed, may join to form a 5- or bered azacycloalkyl structure; R7 and R8 are independently selected from H, F, and Cl; R9 is aryl; R10 is H or alkyl; *1 and *2 denote chiral centres; alkyl is a linear ted hydrocarbon having up to 6 carbon atoms (C1-C6) or a branched saturated hydrocarbon of 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, fluoro and NR11R12; cycloalkyl is a mono- or bi-cyclic saturated hydrocarbon of between 3 and 10 carbon atoms; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 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, fluoro 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 R11 and R12 are independently selected from H and alkyl; and tautomers, isomers, stereoisomers (including enantiomers, reoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
The present invention also comprises the following aspects and ations thereof: In an aspect of the invention, R1 is selected from H, alkyl, yl, -COaryl, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alkyl and -SO2aryl.
In an aspect of the invention, R1 is selected from H, alkyl, yl, -COaryl, aOH, -CH2COOR10, -CH2CONH2, -SO2alkyl and -SO2aryl; wherein a is 1 or 2.
In an aspect of the invention, R1 is selected from H, -COaryl, -COalkyl, OH, -SO2Ph and -SO2CH3.
In an aspect of the invention, R1 is selected from H, -COethyl, methyl, methylsulfonyl, -COphenyl, sulfone, -CH2COOH, -CO-ipropyl, propyl, -CH2COOCH3, -CH2CONH2, -CH2CH2OH and –COnaphthyl.
In an aspect of the invention, R1 is selected from -COalkyl and –COphenyl.
In an aspect of the invention, R1 is selected from H, -COaryl, COheteroaryl, -COalkyl, OH, -SO2Ph and -SO2CH3.
In an aspect of the invention, R1 is selected from -COalkyl, roaryl and –COaryl.
In an aspect of the invention, R2 is selected from H and methyl.
In an aspect of the invention, R2 is H.
In an aspect of the invention, R3 is selected from alkyl, -(CH2)daryl, -(CH2)fcycloalkyl, and -CH(cycloalkyl)2; n d and f are, independently, 1 or 2.
In an aspect of the invention, R3 is selected from alkyl, -CH2aryl, -CH2cycloalkyl, and -CH(cycloalkyl)2.
In an aspect of the invention, R3 is selected from -CH2aryl, -CH2cycloalkyl, and -CH(cycloalkyl)2.
In an aspect of the invention, R3 is selected from: O CH2 H3C and .
In an aspect of the invention, R4 is selected from H and methyl.
In an aspect of the invention, R4 is H.
In an aspect of the ion, R5 is selected from H, alkyl and OH.
In an aspect of the invention, R5 is selected from H and OH.
In an aspect of the invention, R5 is H.
In an aspect of the invention, R4 and R5, together with the atoms to which they are attached, join to form a pyrrolidine moiety.
In an aspect of the invention, R4 and R5, together with the atoms to which they are attached, join to form a piperidine moiety.
In an aspect of the invention, R6 is selected from H and methyl.
In an aspect of the ion, R6 is H.
In an aspect of the invention, R7 is selected from H, methyl and halo.
In an aspect of the ion, R7 is ed from H, F and Cl.
In an aspect of the invention, R7 is H.
In an aspect of the invention, R8 is selected from H, methyl and halo.
In an aspect of the invention, R8 is selected from H, F and Cl.
In an aspect of the invention, R8 is selected from H and F.
In an aspect of the invention, R8 is H.
In an aspect of the invention, R9 is aryl.
In an aspect of the invention, R9 is selected from phenyl and naphthyl, wherein phenyl may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12.
In an aspect of the invention, R9 is , wherein phenyl may be optionally substituted with up to 2 substituents independently selected from alkyl, halo and CF3.
In an aspect of the invention, R9 is selected from phenyl, 1-naphthalene, 2,4-dichlorophenyl, 3,4- rophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4- ethoxyphenyl.
In an aspect of the invention, R9 is selected from phenyl, heteroaryl and naphthyl, n phenyl may be optionally substituted with up to 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12.
In an aspect of the invention, R9 is selected from phenyl, 1-naphthalene, 3,4-dichlorophenyl, 3,4- difluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, luoromethylphenyl, pyrid- 3-yl, 2-yl, pyridyl, benzothiophenyl, thiophenyl, thiophenyl, indolyl, and thiazol-4yl.
In an aspect of the invention, R10 is H or methyl.
In an aspect of the invention, the stereochemical configuration about chiral centre *1 is R.
In an aspect of the invention, the stereochemical configuration about chiral centre *2 is S.
In an aspect of the invention, a is 2 and b, c, d, e, f and g are 1.
In an aspect of the ion, a is 2 and b, c, d, e, f, g, h, j, l and m are 1.
In an aspect of the invention, k is 0 or 1.
In an aspect, the invention ses a compound selected from: (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide; {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexylethylamino }-acetic acid; (S)-N-(4-Aminomethylfluoro-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; (S)-N-(4-Aminomethylchloro-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; (S)-N-(4-Aminomethyl-benzyl)(3,4-dichloro-phenyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]-propionamide; (S)-N-(4-Aminomethylchloro-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; (S)-N-(4-Aminomethyl-benzyl){[(R)(4-ethoxy-phenyl)propionylamino-propionyl]- methyl-amino}phenyl-propionamide; ({(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexylethyl }-methyl-amino)-acetic acid; (S)-N-(4-Aminomethylfluoro-benzyl){[(R)(4-ethoxy-phenyl)propionylaminopropionyl ]-methyl-amino}phenyl-propionamide; N-[(R){[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methyl-carbamoyl} (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R){[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methyl-carbamoyl} (4-ethoxy-phenyl)-ethyl]-isobutyramide; alenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-difluoro-benzamide; (R)Amino-N-[(1S,2S)(4-aminomethyl-benzylcarbamoyl)hydroxyphenyl-ethyl] (4-ethoxy-phenyl)-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxyphenyl )-ethyl]-nicotinamide; (2S,3S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]hydroxyphenyl-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] oxyphenyl )-ethyl]-isonicotinamide; enecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; enecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; exanecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Isoxazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Benzo[b]thiophenecarboxylic acid[(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-chlorobenzenesulfonylamino )(4-ethoxy-phenyl)-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]trifluoromethyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methoxy-benzamide; (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)(2-phenylacetylaminoacetylamino )-propionylamino]phenyl-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]fluoro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,6-dichloro-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-5,6-dichloro-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,3,6-trifluoro-isonicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,3,3-trifluoro-propionamide; 2,4-Dimethyl-thiazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 2-Methyl-thiazolecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 4-Methyl-thiazolecarboxylic acid[(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; Furancarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; 3-Methyl-thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methoxy-isonicotinamide; 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; o-thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-propoxyphenyl )-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- thoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-chloro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-fluoro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-methoxy-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)(3-fluoro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl(4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethylchloro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methoxy-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethylchloro-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methoxy-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; Thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl -ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl lcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethyl](4-ethoxy-phenyl) propionylamino-propionamide; N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-isonicotinamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethylfluoro-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl )-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethyl](4-ethoxy-phenyl) propionylamino-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-3,3,3-trifluoro-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]chloro-benzamide; Isoxazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(1H-indolyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; 3-Acetylamino-thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(2-fluoro-phenyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethylmethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) lyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; o-thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Acetylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- -phenyl)-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; 3,5-Dimethyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethylmethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; ylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Acetylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; ro-thiophenecarboxylic acid [(R){[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethyl]-methyl-carbamoyl}(4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(1S,2R)(4-Aminomethyl-benzylcarbamoyl)hydroxyphenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; 3-Chloro-thiophenecarboxylic acid [(R)[(1S,2R)(4-aminomethyl-benzylcarbamoyl) hydroxyphenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-{(R,S)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl][4-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-benzamide; and pharmaceutically acceptable salts and solvates thereof.
In an , the invention comprises a compound selected from: N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide; Naphthalenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-difluoro-benzamide; and pharmaceutically acceptable salts and solvates thereof.
In an aspect, the invention comprises a compound selected from: N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide; Naphthalenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl -ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxy- phenyl)-ethyl]-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-difluoro-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxyphenyl )-ethyl]-isonicotinamide; Thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Cyclohexanecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenyl- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; Isoxazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl -ethoxy-phenyl)-ethyl]-amide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-chlorobenzenesulfonylamino )(4-ethoxy-phenyl)-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methoxy-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]fluoro-benzamide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-propoxyphenyl l]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl] oxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-fluoro-phenyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl(4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; [(S)(4-Aminomethylchloro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- -phenyl)-ethyl]methoxy-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethylchloro-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methoxy-benzamide; enecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; [(S)(4-Aminomethyl-benzylcarbamoyl)(1H-indolyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; 3-Acetylamino-thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; and pharmaceutically acceptable salts and solvates thereof.
Therapeutic Applications As previously mentioned, the compounds of the present invention are potent and selective inhibitors of plasma kallikrein. They are ore useful in the treatment of disease conditions for which over-activity of plasma kallikrein is a causative factor.
Accordingly, the present invention provides a nd of formula (I) for use in medicine.
The present ion also provides for the use of a nd of formula (I) in the manufacture of a medicament for the ent or prevention of a disease or condition in which plasma kallikrein activity is implicated.
The present invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition in which plasma kallikrein ty is implicated.
The present invention also provides a method of treatment of a disease or condition in which plasma kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
In one aspect, the disease or condition in which plasma kallikrein ty is implicated is selected from Diseases or conditions in which plasma kallikrein activity is implicated include impaired visual acuity, diabetic pathy, diabetic macular oedema, hereditary angioedema, diabetes, pancreatitus, cerebral haemorrhage, nepropathy, cardiomyopathy, neuropathy, inflammaotory bowel e, arthritis, inflammation, septic shock, hypotension, cancer, adult atory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and ng from post operative surgery.
In another aspect, the disease or condition in which plasma kallikrein activity is implicated is retinal vascular bility associated with diabetic retinopathy and diabetic macular oedema.
Combination y 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 t platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), integrin alpha5beta1, steroids, other agents that inhibit plasma kallikrein and other inhibitors of inflammation. Specific examples of therapeutic agents that may be combined with the compounds of the present invention include those disclosed in EP2281885A and by S. Patel in Retina, 2009 Jun;29(6 Suppl):S45-8.
When combination therapy is employed, the compounds of the present invention and said combination agents may exist in the same or ent pharmaceutical compositions, and may be administered separately, sequentially or simultaneously.
Definitions The term "alkyl" includes saturated hydrocarbon residues including: - linear groups up to 10 carbon atoms 0), or of up to 6 carbon atoms ), or of up to 4 carbon atoms (C1-C4). Examples of such alky l groups include, but are not d, to C1 - methyl, C2 - ethyl, C3 - propyl and C4- n-butyl. - branched groups of between 3 and 10 carbon atoms (C3-C10), or of up to 7 carbon atoms (C3- C7), or of 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 stated above.
The term y" includes O-linked hydrocarbon residues including: - linear groups of n 1 and 6 carbon atoms (C1-C6), or of between 1 and 4 carbon atoms (C1-C4). es of such alkoxy groups include, but are not limited to, C 1 - methoxy, C2 - ethoxy, C3 - n-propoxy and C4 - n-butoxy. - branched groups of between 3 and 6 carbon atoms (C3-C6) or of n 3 and 4 carbon atoms ). Examples of such alkoxy groups e, but are not limited to, C 3 - iso- propoxy, and C4 - sec-butoxy and tert-butoxy. each optionally substituted as stated above.
Unless otherwise stated, halo is selected from Cl, F, Br and I.
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 with aryl, include indanyl and 1,2,3,4-tetrahydronaphthyl.
Heterocycloalkyl is as defined above. Examples of suitable heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, ydropyranyl, piperidinyl, N-methylpiperidinyl, morpholinyl, N-methyl linyl, piperazinyl, N-methylpiperazinyl, azepanyl, oxazepanyl and diazepanyl.
Aryl is as defined above. Typically, aryl will be optionally substituted with 1, 2 or 3 substituents. Optional substituents are selected from those stated above. Examples of le aryl groups include phenyl and yl (each optionally tuted as stated above).
Heteroaryl is as defined above. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, olyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, azolyl, tetrazolyl, nyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, inyl and isoquinolinyl (optionally substituted as stated above).
The term "C-linked", such as in "C-linked cycloalkyl", means that the heterocycloalkyl group is joined to the der of the molecule via a ring carbon atom.
The term "N-linked", such as in "N-linked heterocycloalkyl", means that the heterocycloalkyl group is joined to the remainder of the molecule via a ring nitrogen atom.
The term "O-linked", such as in "O-linked hydrocarbon residue", means that the hydrocarbon residue is joined to the remainder of the molecule via an oxygen atom.
In groups such as -COalkyl and -(CH2)bCOOR10, "-" denotes the point of ment of the substituent group to the remainder of the molecule.
"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when 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 that can be formed include sodium, potassium, calcium, magnesium and um salts, or salts with organic , such as, diethylamine, N-methyl- glucamine, diethanolamine or amino acids (e.g. ) 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 can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, ates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, rates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, ates and the like.
Hemisalts of acids and bases can also be formed, for example, hemisulfate and lcium salts.
For a review of le salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, y, 2002).
“Prodrug” refers to a compound which is convertible in vivo by lic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in ‘The Practice of Medicinal Chemistry, 2nd Ed. pp561-585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. .
The compounds of the invention can exist in both ated 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 les, for example, ethanol. The term 'hydrate' is employed when the solvent is water.
Where compounds of the invention exist in one or more geometrical, 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-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures f. Where appropriate such isomers can be separated from their es by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
In the context of the present ion, references herein to "treatment" include references to curative, palliative and prophylactic treatment.
General Methods The nds of formula (I) should be assessed for their biopharmaceutical properties, such as lity and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed tion.
They may be administered alone or in combination with one or more other compounds of the ion 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 ceutically acceptable excipients. The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of stration, the effect of the excipient on lity and stability, and the nature of the dosage form.
Compounds of the invention intended for pharmaceutical use may be administered as a solid or liquid, such as a tablet, capsule or solution. ceutical compositions suitable for the ry of compounds of the present invention and methods for their ation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ton’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
For the treatment of conditions such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular oedema, 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 intra-vitreal 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 ision of the attending physician.
The compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable means for parenteral stration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle ding microneedle) injectors, free injectors and on ques.
Parenteral ations are typically aqueous or oily ons. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and ing agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile ueous solution or as a dried form to be used in conjunction with a suitable e such as sterile, pyrogen-free water.
Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, pro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may y be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be sed by the use of appropriate formulation techniques, such as the incorporation of co- solvents and/or solubility-enhancing agents such as surfactants, e structures and cyclodextrins.
In one ment, 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 by which the nd enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid plugs, solid microparticulates, semi- solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an ate release manner or in a rate-sustaining manner, wherein the e profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which ses the therapeutic efficacy of the said nds. Means to deliver compounds in a rate-sustaining manner are known in the art and e slow release polymers that can be formulated with the said compounds to control their release.
Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by ion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl methylcellulose, ypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, thacrylates, polyethylene oxide and polyethylene glycol.
Liquid (including multiple phases and dispersed systems) formulations e emulsions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, ene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or ding agents.
Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in eutic Patents, 2001, 11 (6), 981-986.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H.
Lieberman and L. Lachman l Dekker, New York, 1980).
For administration to human patients, the total daily dose of the compounds of the invention is lly in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or n 1 mg and 50 mg depending, of course, on the mode of stration. For example, if administered by vitreal injection it is envisaged that the compound of the invention will be dosed infrequently, e.g. once a month. In this circumstance, a dose of between 0.5 mg and 20 mg, such as between 1 mg and 10 mg, is envisaged. If dosed more frequently, e.g. once daily, a much lower dose of between 0.005 mg and 0.02 mg is envisaged.
The total dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the Synthetic Methods The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the specific es provided herein below. Moreover, by utilising the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed . The compounds illustrated in the examples are not, r, to be construed as forming the only genus that is considered as the invention.
The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the ions and processes of the ing preparative procedures can be used to e these compounds.
The compounds of the ion may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
It may be necessary to protect reactive onal groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted 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, may be used. For example, a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily d by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic amines such as diethylamine or piperidine in an organic solvents. Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by ysis in the presence of bases such as lithium or sodium hydroxide. Benzyl protecting groups can also be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere whilst 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, ection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by ng with borane mide in dichloromethane for 1-24 hours. Alternatively where a hydroxy group is ted as a benzyl ether, deprotection conditions comprise hydrogenation with a palladium catalyst under a hydrogen here.
The compounds according to general formula I can be prepared using conventional synthetic methods for example, but not limited to, the route outlined in Scheme 1. In a typical first step the amine (2) is coupled using standard e coupling conditions to an activated alpha amino acid (1) suitably amino -protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc). The ting 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 ve 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 water soluble carbodiimide, or 2-(1H-benzotriazoleyl)-1,1,3,3- tetramethylaminium hexafluorophosphate or benzotriazoleyl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo-trispyrolidino-phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine. In a typical second step the protecting group is removed using standard methods as previously described.
The route exemplified in Scheme 1 then proceeds in the third step via a further standard peptide ng and in the fourth step via removal of the Boc ting group using standard conditions as previously described. The amine ed in 7 may, in a fifth step, then typically be alkylated or ed with the group R1. Acylation may be d 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 may typically be carried 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 ng agent such as sodium cyanoborohydride or sodium acetoxyborohydride in a suitable solvent such as methanol, at room ature. The resulting nitrile compound 8 may then be reduced by enation. sion from 8 to 10 may be achieved in a single step either by direct ion 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 le 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 may be isolated (using, for example, the method as described in S. Caddick et al., Tetrahedron Lett., 2000, 41, 3513) and subsequently deprotected by standard means described previously to give the amine 10.
Scheme 1 R5 Aryl O O R8 O R7 X R7 HN R8 HN + N O H N O O R5 Aryl 1 2 3 R3 O R7 O R7 H N R8 H N R8 O O HN N 2 N O H H + O HN O O R5 Aryl R5 Aryl OH N 4 5 6 R3 O R7 R3 O R7 H H N R8 N R8 2 N HN N H H O R1 O R5 Aryl R5 Aryl N N 7 8 R3 O R7 H R3 O R7 N R8 H HN N N R8 H HN N R1 O R5 Aryl H R1 O R5 Aryl HN O 9 10 Brief description of drawings Figure 1 shows the tory effect of Example 3 and CH-3457 (positive control; plasma kallikrein inhibitor) upon CA-I stimulated RVP in Sprague Dawley rats.
Figure 2 shows the ocular tissue concentrations of Example 3 following IVT administration of 4.2 µg/mL /eye).
Examples The invention is rated by the following non-limiting examples in which the following abbreviations and definitions are used: Cha 3-Cyclohexylalanine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Et Ethyl EtOAc Ethyl Acetate hrs Hours HOBt Hydroxybenzotriazole LCMS Liquid chromatography mass spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol min Minutes MS Mass spectrum m/z Mass charge ratio (of parent, MH+, ion unless otherwise stated) Nuclear magnetic resonance spectrum – NMR spectra were recorded at a frequency of 400MHz unless otherwise indicated Pet. Ether Petroleum ether fraction boiling at 60-80°C Ph Phenyl Phe alanine n-Pr n-Propyl THF ydrofuran TFA Trifluoroacetic acid All reactions were carried out under an here of nitrogen unless specified otherwise. 1H NMR spectra were recorded on a Brucker Avance III (400MHz) spectrometer with reference to ium solvent and at room temperature.
Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCO2H/MeCN into 0.1% HCO2H/H2O over 11 min, flow rate 1.5 mL/min. Data was ted using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.
Chemical names were generated using the Autonom software provided as part of the ISIS draw package from MDL Information Systems.
Where products were purified by flash chromatography, ‘silica’ refers to silica gel for tography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an d pressure of nitrogen up to 10 p.s.i accelerated column elution. Reverse phase preparative HPLC purifications were carried out using a Waters 2525 binary nt pumping system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.
All solvents and cial reagents were used as received.
EXAMPLE 1 (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide O NH H 2 HN N O A. (S)[(R)tert-Butoxycarbonylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionic acid methyl ester H-Phe-OMe.HCl (2.3g, 10.7mmol) was dissolved in CH2Cl2 (100 mL) and DMF (10 mL). This solution was cooled to 0°C. (R)Butoxyloxycarbonylamino(4-ethoxy-phenyl)-propionic acid (3.0g, 9.7mmol) was added followed by HOBt (1.57g, 11.6mmol) and triethylamine (2.9g, 29.0mmol). Water soluble carbodiimide (2.04g, 10.6mmol) was then added. After 18 hrs at 0°C to room temperature reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent 20% Pet. Ether (60-80°C), 80% EtOAc, fractions combined and ated in vacuo to give a colourless oil identified as (S)[(R)tert-butoxycarbonylamino(4-ethoxy-phenyl)- nylamino]phenyl-propionic acid methyl ester (4.25g, 9.03mmol, 93%).
[M+H]+ = 471.27.
B. (S)[(R)tert-Butoxycarbonylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionic acid (S)[(R)tert-Butoxycarbonylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionic acid methyl ester (2.5g, 5.3mmol) was dissolved in THF (100 mL). Lithium hydroxide monohydrate (668mg, ol) in water (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hrs after which time the reaction e was diluted with EtOAc (150 mL). This solution was washed with 0.3M KHSO 4 (1x50 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as (S) -tert-butoxycarbonylamino(4-ethoxy-phenyl)-propionylamino]phenyl-propionic acid (2.095g, 4.58mmol, 86%).
[M+H]+ = 457.25.
C. [(R)[(S)(4-Cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-carbamic acid tert-butyl ester nomethyl)benzonitrile hydrochloride (303mg, 1.80mmol) was dissolved in CH2Cl2 (50 mL) and DMF (5 mL). This solution was cooled to 0°C. [(R)tert-butoxycarbonylamino- 3-(4-ethoxy-phenyl)-propionylamino]phenyl-propionic acid (745mg, 1.63mmol) was added followed by HOBt , 1.96mmol) and triethylamine (495mg, 4.9mmol). Water soluble carbodiimide (344mg, 1.8mmol) was then added. After 18 hrs at 0°C to room temperature reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO 3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil.
The residue was purified by flash tography (silica), eluent . Ether (60-80°C), 80% EtOAc, fractions combined and evaporated in vacuo to give a colourless oil identified as [(R) [(S)(4-cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- ic acid tert-butyl ester (493mg, 0.86mmol, 53%).
[M+H]+ = 571.29 D. Amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl)- propionamide Hydrochloride [(R)[(S)(4-Cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxy-phenyl)- ethyl]-carbamic acid tert-butyl ester (225mg, 0.39mmol) was treated with 4M HCl/dioxan (50 mL). After one hour at room temperature the solvent was removed to give a white solid identified as (R)amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl](4-ethoxy- phenyl)-propionamide hydrochloride (200mg, 0.39mmol, 100%).
[M+H]+ = 471.26 E. (S)-N-(4-Cyano-benzyl)[(R)(4-ethoxy-phenyl)propionylamino-propionylamino]- 3-phenyl-propionamide (R)Amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl)- namide hydrochloride (200mg, 0.37mol) was dissolved in dichloromethane (50 mL), this solution was cooled to 0°C. Triethylamine (111mg, 1.1mmol) was added followed by propionyl chloride (39mg, ol). After 18 hrs at 0°C to room temperature the reaction e was diluted with CHCl3 (50 mL), this solution was washed with sat. NaHCO3 (1x20 mL), water (1x20 mL), brine (1x20 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 2% MeOH, 98% CHCl3, fractions combined and evaporated in vacuo to give a less oil identified as (S)-N-(4-cyano-benzyl)[(R)(4- ethoxy-phenyl)propionylamino-propionylamino]phenyl-propionamide (189mg, 0.36mmol, 98%).
[M+H]+ = 527.27 F. [4-({(S)[(R)(4-Ethoxy-phenyl)propionylamino-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester (S)-N-(4-Cyano-benzyl)[(R)(4-ethoxy-phenyl)propionylamino-propionylamino] phenyl-propionamide (100mg, 0.19mmol) 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) portionwise. The reaction mixture was stirred at 0°C to room temp for 18hrs. The methanol was removed by evaporation. The e was dissolved in CHCl3 (70 mL), washed with sat NaHCO3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. Purified by flash tography, eluant 1% MeOH, 99% CHCl3 to give a colourless oil identified as [4-({(S)[(R)(4-ethoxy-phenyl)propionylamino- propionylamino]phenyl-propionylamino}-methyl)-benzyl]-carbamic acid tert-butyl ester (89mg, 0.14mmol, 74%).
[M+H]+ = 631.39 G. (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylamino- propionylamino]phenyl-propionamide Trifluoroacetate [4-({(S)[(R)(4-Ethoxy-phenyl)propionylamino-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester (89mg, 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 d in vacuo to give a yellow oil. The residue was ed by Prep HPLC (Sunfire prep C18 OBD column. 19x250mm, 10µ). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H2O over 35 min at 20 mL/min. Fractions combined and freeze dried to give a white solid fied as (S)-N-(4-aminomethyl-benzyl)[(R)(4-ethoxyphenyl )propionylamino-propionylamino]phenyl-propionamide trifluoroacetate (38mg, 0.056mmol, 42%) [M+H]+ = 531.31 1H NMR: (CD3OD) 1.02 (3H, t, J=7.7Hz), 1.42 (3H, t, J=7.0Hz), .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).
(R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl) methanesulfonylamino-propionamide S O NH H 2 HN N A. [(S)(4-Cyano-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl) esulfonylamino-propionamide (R)Amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl)- propionamide hydrochloride (150mg, 0.30mmol) was dissolved in CH2Cl2 (20 mL). This solution was cooled to 0°C. Methanesulfonyl chloride (37mg, 0.33mmol) was added followed triethylamine (90mg, 0.89mmol). After 18 hrs at 0°C to room ature reaction mixture was diluted with chloroform (50 mL) and washed with NaHCO3 (1x20 mL), water (1x20 mL), brine (1x20 mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluant 2%MeOH, 98% CHCl3, fractions combined and evaporated in vacuo to give a white solid identified as (R)-N-[(S)(4-cyano-benzylcarbamoyl)- 2-phenyl-ethyl](4-ethoxy-phenyl)methanesulfonylamino-propionamide (110mg, 0.20mmol, 68%).
[M+H]+ = 549.11 B. [4-({(S)[(R)(4-Ethoxy-phenyl)methanesulfonylamino-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester [(S)(4-Cyano-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl) esulfonylamino-propionamide (110mg, 0.20mmol) was dissolved in methanol (50 mL).
This solution was cooled to 0°C. Nickel (II) chloride hexahydrate (4.8mg, 0.02mmol) and ditertbutyl dicarbonate (88mg, 0.4mmol) were added followed by sodium borohydride (53mg, 1.4mmol) portionwise. The reaction mixture was stirred at 0°C to room temp for 18hrs. The MeOH was removed by evaporation. The residue was dissolved in CHCl3 (70 mL), washed with sat NaHCO3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried 4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, eluant 2% MeOH, 98% CHCl3 to give white solid identified as [4-({(S)[(R)(4-ethoxy-phenyl)methanesulfonylamino- propionylamino]phenyl-propionylamino}-methyl)-benzyl]-carbamic acid tert-butyl ester (86mg, 0.13mmol, 66%).
[M+H]+ = 653.23, 675.19 (M+Na).
C. (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxy-phenyl) methanesulfonylamino-propionamide Trifluoroacetate [4-({(S)[(R)(4-Ethoxy-phenyl)methanesulfonylamino-propionylamino]phenylpropionylamino yl)-benzyl]-carbamic acid tert-butyl ester (86mg, 0.13mmol) was treated with trifluoroacetic acid (20 mL). After one hour at room temp the solvent was evaporated in vacuo. The residue was purified by Prep HPLC (Sunfire prep C18 OBD column. 19x250mm, 10µ). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 mL/min. Fractions combined and freeze dried to give a white solid identified as (R)-N-[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethyl](4-ethoxy-phenyl)methanesulfonylamino-propionamide trifluoroacetate (28mg, 0.042mmol, 32%) [M+H]+ = 553.08 1H NMR: (CD3OD) 1.41 (3H, t, J=7.0Hz), 2.60 (3H, s), .75 (1H, m), 2.81-2.91 (2H, m), 3.09 (1H, dd, J=13.7, , 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), 7.25-7.32 (5H, m), 7.41 (2H, d, J= 8.1Hz).
EXAMPLE 3 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide O NH H 2 HN N O A. {(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenyl-ethyl}- carbamic acid benzyl ester (S)Benzyloxycarbonylaminophenyl-propionic acid 2,5-dioxo-pyrrolidinyl ester (4.25g, .72mmol) was dissolved in CH2Cl2 (100 mL). This solution was cooled to 0°C. 1 -(N-Boc- Aminomethyl)(aminomethyl)benzene (2.79g, mol) was added followed by triethylamine (3.25g, 32.16mmol). After 18 hrs at 0°C to room temperature reaction mixture was d with chloroform (100 mL) and washed with NaHCO3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) evaporated in vacuo giving a yellow oil. The residue was triturated with Pet. Ether (60-80°C) and EtOAc to give a white solid identified as {(S)[4-(tertbutoxycarbonylamino-methyl )-benzylcarbamoyl]phenyl-ethyl}-carbamic acid benzyl ester (3.88g, 7.49mmol, 70%).
[M+H]+ = 518.28, 540.32 (M+Na).
B. {4-[((S)Aminophenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester {(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenyl-ethyl}-carbamic acid benzyl ester (3.66g, 7.08mmol) was dissolved in methanol (200 mL). This on was hydrogenated over 10% Pd/C (500mg) at atmospheric pressure and room temperature for one hour after which time the catalyst was filtered off through celite and the e washed with ol (30 mL), the combined filtrates were ated in vacuo to give a white solid identified as {4-[((S)aminophenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert- butyl ester (2.627g, 6.85mmol, 97%).
[M+H]+ = 384.37 C. (R)Amino(4-ethoxy-phenyl)-propionic acid (R)Butoxycarbonylamino(4-ethoxy-phenyl)-propionic acid (4.0g, 12.93mmol) was dissolved in 4M HCl in dioxan (150 mL). After one hour at room temperature the solvent was removed in vacuo to give a white solid identified as (R)amino(4-ethoxy-phenyl)-propionic acid hydrochloride (3.18g, 12.9mmol, 100%).
[M+H]+ = 210.18 D. (R)Benzyloxycarbonylamino(4-ethoxy-phenyl)-propionic acid (R)Amino(4-ethoxy-phenyl)-propionic acid hydrochloride (3.17g, 12.9mmol) was dissolved in a solution of sodium ide (1.14g, mol) in water (100 mL). Benzyl chloroformate (2.64g, 15.48mmol) in dioxan (100 mL) was added. The reaction mixture was stirred at room ature for 18 hrs after which time the dioxan was removed in vacuo. The aqueous residue was washed with diethyl ether (1x 100 mL), acidified to pH 2 with 1M HCl and extracted with chloroform (2x200 mL). The combined ts were washed with water (1x50 mL), brine (1x50 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as (R)benzyloxycarbonylamino(4-ethoxy-phenyl)-propionic acid (4.0g, 11.65mmol, 90%).
[M+H]+ = 344.20.
E. [(R){(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenylethylcarbamoyl }(4-ethoxy-phenyl)-ethyl]-carbamic acid benzyl ester {4-[((S)Aminophenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (2.63g, 6.86mmol) was dissolved in CH2Cl2 (100 mL) and DMF (5 mL). This solution was cooled to 0°C. Benzyloxycarbonylamino(4-ethoxy-phenyl)-propionic acid (2.59g, 7.54mmol) was added followed by HOBt (1.11g, 8.23mmol) and triethylamine (2.08g, .57mmol). Water soluble carbodiimide (1.45g, 7.54mmol) was then added. After 18 hrs at 0°C to room temperature reaction e was diluted with chloroform (200 mL) and washed with NaHCO3 (1x50 mL), water (1x50 mL), brine (1x50 mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was triturated with ethyl acetate and Pet. Ether (60-80°C) to give a white solid identified as [(R){(S)[4-(tert-butoxycarbonylamino-methyl)- benzylcarbamoyl]phenyl-ethylcarbamoyl}(4-ethoxy-phenyl)-ethyl]-carbamic acid benzyl ester (3.55g, 5.01mmol, 73%).
[M+H]+ = 709.34.
F. [4-({(S)[(R)Amino(4-ethoxy-phenyl)-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester [(R){(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenylethylcarbamoyl }(4-ethoxy-phenyl)-ethyl]-carbamic acid benzyl ester , 5.00mmol) was dissolved in methanol (200 mL). This solution was hydrogenated over 10% Pd/C (500mg) at atmospheric pressure and room temperature for one hour after which time the catalyst was filtered off through Celite and the residue washed with methanol (30 mL), the combined filtrates were evaporated in vacuo to give a white solid identified as S)[(R)amino(4- -phenyl)-propionylamino]phenyl-propionylamino}-methyl)-benzyl]-carbamic acid tertbutyl ester (2.8g, ol, 97%).
[M+H]+ = 575.37.
G. [4-({(S)[(R)Benzoylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester [4-({(S)[(R)Amino(4-ethoxy-phenyl)-propionylamino]phenyl-propionylamino}- )-benzyl]-carbamic acid tert-butyl ester (3.45g, 5.99mmol) was dissolved in dichloromethane (150 mL). Benzoyl de (1.01g, 7.19mmol) was added followed by triethylamine (1.82g, 17.98mmol). The reaction mixture was stirred at room temperature for 5 hrs and diluted with CHCl3 (150 mL), this solution was washed with 0.3M KHSO4 (1x50 mL), sat. NaHCO3 (1x50 mL), water (1x50 mL), brine (1x50 mL), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with Pet Ether (60-80°C) and EtOAc to give a white solid identified as [4-({(S)[(R)benzoylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid utyl ester (3.06g, 4.51mmol, 75%).
[M+H]+ = 679.34.
H. N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide hydrochloride [4-({(S)[(R)Benzoylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester (2.86g, ol) was dissolved in 4M HCl in dioxan (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)[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide hydrochloride (2.1g, 3.41mmol, 81%).
[M+H]+ = 579.34 1H NMR: (CD 3OD), 1.40 (3H, t, J= 6.9 Hz), 2.91-2.99 (3H, m), .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 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide hydrochloride S)[(R)Benzoylamino(4-ethoxy-phenyl)-propionylamino]phenylpropionylamino }-methyl)-benzyl]-carbamic acid tert-butyl ester (10.0g, 14.7mmol) was stirred in en chloride / ethyl acetate (3.7M, 250 mL) at room temperature. Aft er two hours the mixture was ed, washed with ethyl acetate (2 x 50 mL) and dried to afford a solid (7.9g). A portion of the solid (0.106g) was suspended in a mixture of acetonitrile (2.1 mL) and water (0.32 mL), stirred, and heated to 77°C. onal aliquots of water (0.05 mL) were added successively 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 afford N-[(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide hydrochloride (0.067g, 3.41mmol, 81%). 1H NMR ) was identical to that of Example 3, Step H.
EXAMPLE 4 {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexyl- ethylamino}-acetic acid O O NH H 2 HN N A. [(S)(4-Cyano-benzylcarbamoyl)phenyl-ethyl]-carbamic acid tert-butyl ester 4-Aminomethylbenzonitrile hydrochloride (1.53g, 9.1mmol) was dissolved in CH2Cl2 (100 mL).
This solution was cooled to 0°C. (S)tert-Butoxycarbonylaminophenylpropionic acid 2,5- pyrrolidinyl ester (3.00g, 8.3mmol) was added followed triethylamine (2.51g, 25mmol). After 18 hrs at 0°C to room temperature reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO 3 ( 1x30 mL), water ( 1x30 mL), brine ( 1x30 mL), dried 4) and evaporated in vacuo giving a yellow oil. The residue was crystallised from EtOAc/Pet. Ether (60-80°C) to give a white solid identified as [(S)(4-cyanobenzylcarbamoyl )phenyl-ethyl]-carbamic acid tert-butyl ester (2.71g, 7.1mmol, 86%).
[M+H]+ = 380.13 B. (S)Amino-N-(4-cyano-benzyl)phenyl-propionamide Hydrochloride [(S)(4-Cyano-benzylcarbamoyl)phenyl-ethyl]-carbamic acid tert-butyl ester (2.71g, 7.1mmol) was treated with 4M HCl/dioxan (150 mL). After one hour at room temperature the solvent was removed to give a white solid identified as (S)amino-N-(4-cyanobenzyl )phenyl-propionamide hydrochloride (2.24g, 7.1mmol, 99%).
[M+H]+ = 280.14 C. {(R)[(S)(4-Cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexyl- ethyl}-carbamic acid tert-butyl ester (S)Amino-N-(4-cyano-benzyl)phenyl-propionamide hydrochloride (500mg, 1.58mmol) was dissolved in CH2Cl2 (30 mL) and DMF (3 mL). This solution was cooled to 0°C. Boc-DCha- OH (473mg, 1.74mmol) was added followed by HOBt (257mg, 1.74mmol) and triethylamine (481mg, ol). Water soluble carbodiimide (339mg, 1.74mmol) was then added. After 18 hrs at 0°C to room temperature reaction mixture was diluted with chloroform (100 mL) and washed with NaHCO3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent 60% cyclohexane, 40% EtOAc, ons combined and evaporated in vacuo to give a foamy white solid identified as {(R)[(S)(4-cyano-benzylcarbamoyl)phenyl- ethylcarbamoyl]cyclohexyl-ethyl}-carbamic acid tert-butyl ester (799mg, 1.50mmol, 95%).
[M+H]+ = 533.18 D. (R)Amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl]cyclohexylpropionamide hloride {(R)[(S)(4-Cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexyl-ethyl}- carbamic acid tert-butyl ester (799mg, 1.5mmol) was treated with 4M HCl/dioxan (50 mL).
After one hour at room ature the t was removed to give a white solid fied as (R)amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl]cyclohexyl-propionamide hydrochloride (703mg, 1.5mmol, 100%).
[M+H]+ = 433.06 E. {(R)[(S)(4-Cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexylethylamino }-acetic acid tert-butyl ester (R)Amino-N-[(S)(4-cyano-benzylcarbamoyl)phenyl-ethyl]cyclohexyl-propionamide hydrochloride (290mg, 0.62mmol) was ved in acetonitrile (10 mL). tert-Butylbromoacetate (144mg, 0.74mmol) was added ed diisopropylethylamine (160mg, 1.24mmol). The reaction e was stirred at 60°C for 2 days after which time it was diluted with chloroform (100 mL), washed with water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent %Pet. Ether (60-80°C), 75% EtOAc, fractions combined and evaporated in vacuo to give a colourless oil identified as {(R)[(S)(4-cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-cyclohexyl-ethylamino}-acetic acid tert-butyl ester (240mg, 0.44mmol, 71%).
[M+H]+ = 547.30.
F. ((R){(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenylethylcarbamoyl }cyclohexyl-ethylamino)-acetic acid tert-butyl ester {(R)[(S)(4-Cyano-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexyl- ethylamino}-acetic acid utyl ester (240mg, 0.44mmol) was dissolved in methanol (25 mL).
This solution was cooled to 0°C. Nickel (II) chloride hexahydrate (10.4mg, 0.44mmol) and ditertbutyl dicarbonate (192mg, 0.88mmol) were added followed by sodium borohydride (116mg, l) nwise. The reaction mixture was stirred at 0°C to room temp for 3 days. The MeOH was removed by evaporation. The residue was dissolved in CHCl3 (70 mL), washed with sat NaHCO3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. ed by flash chromatography, eluant 40% Pet. Ether (60-80°C), 60% EtOAc to give white solid identified as ((R){(S)[4-(tert-butoxycarbonylaminomethyl )-benzylcarbamoyl]phenyl-ethylcarbamoyl}cyclohexyl-ethylamino)-acetic acid tertbutyl ester (65mg, 0.10mmol, 23%).
[M+H]+ = 651.44.
G. {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] cyclohexyl-ethylamino}-acetic acid Ditrifluoroacetate ((R){(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenyl- ethylcarbamoyl}cyclohexyl-ethylamino)-acetic acid utyl ester (65mg, 0.1mmol) was treated with trifluoroacetic acid (4 mL) and CH 2Cl2 (2 mL). After one hour at room temp the solvent was evaporated in vacuo. The residue was ed by Prep HPLC (Sunfire prep C18 OBD column. 19x250mm, 10µ). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 mL/min. Fractions combined and freeze dried to give a white solid identified as {(R) [(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexyl-ethylamino}- acetic acid ditrifluoroacetate (46mg, 0.064mmol, 64%).
[M+H]+ = 495.28 1H NMR: (CD3OD) 0.78-0.98 (2H, m), 1.10-1.25 (4H, m), .70 (7H, m), 2.97 (1H, dd, , 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).
Compounds in Tables 1 to 5 were synthesised as described for Examples 1 to 4 (above) and 199 to 201 (below).
Table 1 Ex. R1 R2 R3 R4 Aryl R6 R7 R8 m/z H H H phenyl H H H 475.3 6 H H H phenyl H H F 493.3 7 CO H H phenyl H H F 549.3 8 H H H phenyl H H H 315.2 9 CH3 CH3 H phenyl H H H 465.3 CH3CH2CO H H phenyl H H H 493.2 11 CH3SO2 H H phenyl H H H 515.2 12 CO H H phenyl H Cl H 565.1 13 CH3 CH3 H phenyl H H H 503.2 14 H H H H H H 543.2 545.2 PhSO2 H H phenyl H H H 615.2 16 CH3CH2CO H H H H H 599.1 601.2 17 HOOCCH2 H H phenyl H H H 533.2 18 H H H H H H 567.1 569.1 19 CO H H H H H 623.2 625.2 H H H H H H 505.2 507.2 21 CH3CH2CO H H H H H 561.2 563.2 22 PhCO H CH3 H phenyl H H H 459.2 23 CH3CH2CO H H phenyl H H Cl 565.1 24 CO H H phenyl CH3 H H 545.3 H H CH phenyl H H H 489.2 26 CH3CH2CO H CH phenyl H H H 545.2 27 CH3 H H phenyl H H H 489.3 28 HOOCCH2 H (CH3)2CHCH2 H phenyl H H H 455.3 29 HOOCCH2 CH3 H phenyl H H H 509.3 HOOCCH2 H CH phenyl H H H 509.3 31 CO CH3 H phenyl H H H 545.3 32 CH3CH2CO H CH phenyl H H F 563.3 33 CH3 H H phenyl H H H 451.4 34 HOOCCH2 H CH phenyl H H F 527.3 n-Pr H CH phenyl H H H 531.4 36 2 H H phenyl CH3 H H 509.3 37 n-Pr H H phenyl H H H 479.4 38 PhCO H CH phenyl H H H 593.3 39 CH3CO H CH phenyl H H H 531.3 40 CH3 H H phenyl H H F 469.3 41 CH3 H H H H F 537.2 539.2 42 HOOCCH2 CH3 H phenyl H H F 527.3 43 HOOCCH2 CH3 H H H F 595.3 597.3 44 (CH3)2CHCO H CH phenyl H H H 559.3 45 n-Pr CH3 H phenyl H H H 493.4 46 CH2 H H phenyl H H H 509.3 47 CH3OCOCH2 CH3 H phenyl H H H 523.3 48 NH2COCH2 CH3 H phenyl H H H 508.3 49 HOCH2CH2 CH3 H phenyl H H H 495.4 50 H2 H H phenyl H H H 494.3 51 HOCH2CH2 H H phenyl H H H 481.3 52 H H H phenyl H H H 519.3 53 n-Pr n-Pr H phenyl H H H 521.3 54 1-NaphCO H H phenyl H H H 629.3 55 4-Cl-PhCO H H phenyl H H H 613.3 56 PhCO H H phenyl H H H 647.3 57 4-Ph-PhCO H H phenyl H H H 655.3 58 2,4-diCl- H H phenyl H H H 647.3 PhCO 59 3,4-diF- H H phenyl H H H 615.3 PhCO Table 2 Example * & R1 R2 R4 R5 m/z 60 ted but R H H H OH 491.2 not confirmed 61 R H H H OH 491.2 62 separated but R CH3CH2CO H H OH 547.2 63 not confirmed R CH3CH2CO H H OH 547.3 64 separated but R CH3CH2CO H CH3CH2 H 559.3 65 not confirmed R CH3CH2CO H CH3CH2 H 559.3 66 S S CH3CH2CO CH3 H H 545.3 Table 3 e m/z 67 557.17 Table 4 Example R1 R3 R4 R8 R9 m/z H H 607.99 H H 594.04 H H 580.19 H H 580.18 H H 585.15 H H 585.15 H H 542.95 H H H H 572.99 H H 560.28 H H 602.26 H H 570.13 H H 663.12 H H 580.18 H H 597.2 H H 635.14 H H 649.13 H H 594.10 H H 607.18 H H 621.2 H H 613.1 H H 613.1 H H 647.1 H H 637.21 H H 594.12 H H 647.05 H H 647.05 H H 610.11 H H 605.17 H H 650.16 H H 636.16 H H 597.14 H H 629.15 H H 686.14 H H 628.1 H H 636.1 H H 594.04 H H 594.06 H H 648.09 H H 648.07 H H 633.87 H H 585.12 H H 110 649.92 (M+Na) H H 613.95 H H 599.92 H H 597.75 H H 644.13 H H 664.06 H H 618.97 H H 600.06 H H 569.04 H H 599.04 H H 610.01 H H 610.06 H H 615.05 H H 610.07 H H 582.06 H H 600.57 H H 541.21 H H 569.11 H H 675.1 H H 551.15 H H 659.12 H H 594.05 H H 642.12 H H 501.21 H H 709.12 H H 548.94 H H 659.12 H H 566.09 H H 565.1 H H 535.11 H H 580.06 H H 647.04 141 and 649.06 H H 612.94 H H 596.93 H H 646.96 H H 580.13 H H 608.97 H H 579.95 H H 646.97 H H 618.93 (M+Na) H H 606.88 (M+Na) H H 584.98 H H 586.03 H H 635.05 H F 596.93 H Cl 612.92 H CF3 646.9 H H 586.26 H H 610.02 H Cl 614.29 H H 610.35 H H 616.03 H H 585.98 H H 614.05 H H 616.05 H H 648.04 165 and 650.04 H H 532.04 H F 598.03 H F 598.04 H H 653.00 169 and 654.99 H H 532.04 H H 648.02 171 and 650.04 H H 653.02 H H 614.30 H H 571.02 H H 620.26 H H 641.37 (M+Na) H H 569.48 H H 636.36 H H 642.38 H H 597.35 H H 600.32 H Me 593.29 H H 607.26 H H 625.22 H H 600.32 H H 638.19 H H 588.09 H H 698.15 H H 594.02 H H 594.07 H H 596.18 H Me 594.05 H H 648.16 H H 656.47 H H 605.52 Me H 633.18 Table 5 Example R1 m/z 594.48 635.06 Table 6 Example Name (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethyl](4- ethoxy-phenyl)-propionamide 6 (R)Amino-N-[(S)(4-aminomethylfluoro-benzylcarbamoyl)phenylethyl ](4-ethoxy-phenyl)-propionamide 7 (S)-N-(4-Aminomethylfluoro-benzyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]phenyl-propionamide 8 (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethyl] cyclohexyl-propionamide 9 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- thylamino-propionamide (S)-N-(4-Aminomethyl-benzyl)((R)cyclohexylpropionylaminopropionylamino )phenyl-propionamide 11 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- 2-methanesulfonylamino-propionamide 12 (S)-N-(4-Aminomethylchloro-benzyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]phenyl-propionamide 13 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl] dimethylamino(4-ethoxy-phenyl)-propionamide 14 (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl )-ethyl](4-ethoxy-phenyl)-propionamide (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl] benzenesulfonylamino(4-ethoxy-phenyl)-propionamide 16 (S)-N-(4-Aminomethyl-benzyl)(3,4-dichloro-phenyl)[(R)(4-ethoxyphenyl )propionylamino-propionylamino]-propionamide 17 [(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxy-phenyl)-ethylamino]-acetic acid 18 (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl )-ethyl](4-trifluoromethyl-phenyl)-propionamide 19 ((R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)- ethyl]propionylamino(4-trifluoromethyl-phenyl)-propionamide (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl l]cyclohexyl-propionamide 21 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethyl]- 3-cyclohexylpropionylamino-propionamide 22 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- ethyl}-benzamide 23 (S)-N-(4-Aminomethylchloro-benzyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]phenyl-propionamide 24 (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]-N-methylphenyl-propionamide (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethyl](4- -phenyl)-N-methyl-propionamide 26 (S)-N-(4-Aminomethyl-benzyl){[(R)(4-ethoxy-phenyl)propionylaminopropionyl ]-methyl-amino}phenyl-propionamide 27 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxyphenyl )methylamino-propionamide 28 {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] methyl-butylamino}-acetic acid 29 ({(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] cyclohexyl-ethyl}-methyl-amino)-acetic acid -{[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methylcarbamoyl }cyclohexyl-ethylamino)-acetic acid 31 (4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)(methylpropionyl-amino )-propionylamino]phenyl-propionamide 32 (S)-N-(4-Aminomethylfluoro-benzyl){[(R)(4-ethoxy-phenyl) propionylamino-propionyl]-methyl-amino}phenyl-propionamide 33 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- 2-methylamino-propionamide 34 ((R){[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethyl]- methyl-carbamoyl}cyclohexyl-ethylamino)-acetic acid (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxyphenyl )-N-methylpropylamino-propionamide 36 ((R){(S)[(4-Aminomethyl-benzyl)-methyl-carbamoyl]phenylethylcarbamoyl }cyclohexyl-ethylamino)-acetic acid 37 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- 2-propylamino-propionamide 38 N-[(R){[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methylcarbamoyl }(4-ethoxy-phenyl)-ethyl]-benzamide 39 (R)Acetylamino-N-[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethyl]- 3-(4-ethoxy-phenyl)-N-methyl-propionamide 40 (R)-N-[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethyl] cyclohexylmethylamino-propionamide 41 [(S)(4-Aminomethylfluoro-benzylcarbamoyl)(3,4-dichlorophenyl )-ethyl]cyclohexylmethylamino-propionamide 42 ({(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenylethylcarbamoyl ]cyclohexyl-ethyl}-methyl-amino)-acetic acid 43 ({(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)(3,4-dichlorophenyl )-ethylcarbamoyl]cyclohexyl-ethyl}-methyl-amino)-acetic acid 44 N-[(R){[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methylcarbamoyl }(4-ethoxy-phenyl)-ethyl]-isobutyramide 45 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- hyl-propyl-amino)-propionamide 46 {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] cyclohexyl-ethylamino}-acetic acid methyl ester 47 {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] cyclohexyl-ethylamino}-acetic acid methyl ester 48 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl] (carbamoylmethyl-methyl-amino)cyclohexyl-propionamide 49 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- 2-[(2-hydroxy-ethyl)-methyl-amino]-propionamide 50 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl] (carbamoylmethyl-amino)cyclohexyl-propionamide 51 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- 2-(2-hydroxy-ethylamino)-propionamide 52 (R)Amino-N-[(S)(4-aminomethyl-benzylcarbamoyl)phenyl-ethyl]-3,3- dicyclohexyl-propionamide 53 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]cyclohexyl- 2-dipropylamino-propionamide 54 Naphthalenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 55 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]chloro-benzamide 56 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]trifluoromethyl-benzamide 57 Biphenylcarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) -ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 58 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-2,4-dichloro-benzamide 59 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- thoxy-phenyl)-ethyl]-3,4-difluoro-benzamide 60 (R)Amino-N-[(1R,2S)(4-aminomethyl-benzylcarbamoyl)hydroxy phenyl-ethyl](4-ethoxy-phenyl)-propionamide 61 (R)Amino-N-[(1S,2S)(4-aminomethyl-benzylcarbamoyl)hydroxy phenyl-ethyl](4-ethoxy-phenyl)-propionamide 62 (2R,3S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]hydroxyphenyl-propionamide 63 (2S,3S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]hydroxyphenyl-propionamide 64 (R)-N-(4-Aminomethyl-benzyl){[(R)(4-ethoxy-phenyl)propionylaminopropionyl l-amino}phenyl-propionamide 65 (S)-N-(4-Aminomethyl-benzyl){[(R)(4-ethoxy-phenyl)propionylaminopropionyl ]-ethyl-amino}phenyl-propionamide 66 (S)-N-(4-Aminomethyl-benzyl)[(S)(4-ethoxy-phenyl)(methyl-propionylamino )-propionylamino]phenyl-propionamide 67 (2S,3R)[(R)(4-Ethoxy-phenyl)propionylamino-propionyl]pheny - pyrrolidinecarboxylic acid 4-aminomethyl-benzylamide 68 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](3-benzylureido ) (4-ethoxy-phenyl)-propionamide 69 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxyphenyl )(3-phenyl-ureido)-propionamide 70 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2- oxy-phenyl)-ethyl]-nicotinamide 71 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2- (4-ethoxy-phenyl)-ethyl]-isonicotinamide 72 Thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 73 Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 74 Cyclopropanecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 75 Cyclohexanecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 76 Hexanoic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide 77 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxyphenyl )(3-isopropyl-ureido)-propionamide 78 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxyphenyl )(3-hexyl-ureido)-propionamide 79 olecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 80 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]trifluoromethoxy-benzamide 81 Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 82 2,5-Dimethyl-2H-pyrazolecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-amide 83 Benzo[b]thiophenecarboxylic acid[(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-amide 84 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-chlorobenzenesulfonylamino )(4-ethoxy-phenyl)-propionamide 85 (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl) phenylacetylamino-propionylamino]phenyl-propionamide 86 (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)(3-phenylpropionylamino )-propionylamino]phenyl-propionamide 87 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]phenyl-butyramide 88 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]chloro-benzamide 89 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]chloro-benzamide 90 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]trifluoromethyl-benzamide 91 Adamantanecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 92 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]methyl-benzamide 93 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-3,4-dichloro-benzamide 94 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoy] (4-ethoxy-phenyl)-ethyl]-3,5-dichloro-benzamide 95 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]methoxy-benzamide 96 (E)-N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl -ethoxy-phenyl)-ethyl]phenyl-acrylamide 97 (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)(2- phenylacetylamino-acetylamino)-propionylamino]phenyl-propionamide 98 N-{[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethylcarbamoyl]-methyl}-benzamide 99 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]fluoro-benzamide 100 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-ethoxyphenyl )phenylmethanesulfonylamino-propionamide 101 (S)-N-(4-Aminomethyl-benzyl){(R)(4-ethoxy-phenyl)[2-(toluene sulfonylamino)-acetylamino]-propionylamino}phenyl-propionamide 102 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl][3-(4-chlorophenyl )-ureido](4-ethoxy-phenyl)-propionamide 103 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](3-benzyl ethyl-ureido)(4-ethoxy-phenyl)-propionamide 104 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]methyl-nicotinamide 105 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]methyl-nicotinamide 106 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-2,6-dichloro-nicotinamide 107 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-5,6-dichloro-nicotinamide 108 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- thoxy-phenyl)-ethyl]-2,3,6-trifluoro-isonicotinamide 109 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-3,3,3-trifluoro-propionamide 110 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]chloromethyl-isonicotinamide 111 2,4-Dimethyl-thiazolecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 112 2-Methyl-thiazolecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 113 2,5-Dimethyl-oxazolecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl enyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 114 2-Methyl-quinolinecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 115 7-Chloro-quinolinecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 116 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl enyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 117 4-Methyl-thiazolecarboxylic acid[(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 118 Furancarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 119 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 120 oxy-pyridinecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 121 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]methoxy-nicotinamide 122 3-Methoxy-thiophenecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 123 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]methoxy-isonicotinamide 124 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 125 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 126 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-cyclohexyl-ethyl}-benzamide 127 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-chloro-phenyl)-ethyl]-benzamide 128 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-benzamide 129 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-hydroxy-phenyl)-ethyl]-benzamide 130 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-[4-(4-fluoro-benzyloxy)-phenyl]-ethyl}-benzamide 131 [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-propoxy-phenyl)-ethyl]-benzamide 132 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(4-benzyloxy-phenyl)-ethyl]-benzamide 133 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 3-methyl-butyl}-benzamide 134 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-ethyl}-benzamide 135 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-p-tolyl-ethyl}-benzamide 136 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethyl}-benzamide 137 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-(6-methoxy-pyridinyl)-ethyl]-benzamide 138 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- ethoxy-phenyl)-ethyl]-benzamide 139 N-{(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]- 2-phenyl-ethyl}-benzamide 140 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 141 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 142 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-chloro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 143 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-fluoro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 144 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3-trifluoromethylphenyl )-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 145 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 146 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-methoxy-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 147 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 148 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-trifluoromethylphenyl )-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 149 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3-fluoro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 150 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 151 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenylethylcarbamoyl (4-ethoxy-phenyl)-ethyl]-benzamide 152 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiazolylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 153 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 154 N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenylethylcarbamoyl -ethoxy-phenyl)-ethyl]-benzamide 155 N-[(R)[(S)(4-Aminomethylchloro-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 156 N-[(R)[(S)(4-Aminomethyltrifluoromethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide 157 Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) enyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 158 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]methoxy-benzamide 159 Pyridinecarboxylic acid [(R)[(S)(4-aminomethylchlorobenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 160 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]methoxy-benzamide 161 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-isonicotinamide 162 enecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 163 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]chloro-benzamide 164 [(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]methyl-benzamide 165 Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) (3,4-dichloro-phenyl)-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 166 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethyl](4- ethoxy-phenyl)propionylamino-propionamide 167 N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-isonicotinamide 168 Pyridinecarboxylic acid [(R)[(S)(4-aminomethylfluorobenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 169 Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) (3,4-dichloro-phenyl)-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 170 (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethyl](4- ethoxy-phenyl)propionylamino-propionamide 171 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-isonicotinamide 172 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-3,3,3-trifluoro-propionamide 173 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]chloro-benzamide 174 Isoxazolecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide 175 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethylbenzylcarbamoyl )pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- amide 176 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(1H-indolyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 177 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(1H-imidazolyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 178 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-isonicotinamide 179 3-Acetylamino-thiophenecarboxylic acid-[(R)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(2-fluoro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl- 181 benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- amide N-[(R)[(S)(4-Aminomethylmethyl-benzylcarbamoyl)phenyl- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl- 183 benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- amide ro-thiophenecarboxylic acid -[(S)(4-aminomethyl- 184 benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- amide [(S)(4-Aminomethyl-benzylcarbamoyl)thiazolyl- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]methyl-benzamide 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl- 186 benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-amide 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl- 187 benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- amide 3-Acetylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl- 188 benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-amide N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]methyl-benzamide N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]methyl-benzamide 3,5-Dimethyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl- benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide N-[(R)[(S)(4-Aminomethylmethyl-benzylcarbamoyl)pyridinyl- arbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 3-Acetylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl 193 -benzylcarbamoyl)thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- amide 3-Amino-thiophenecarboxylic acid -[(S)(4-aminomethyl- 194 benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-amide ylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl- 195 benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-amide 3-Chloro-thiophenecarboxylic acid [(R){[(S)(4-aminomethyl- 196 benzylcarbamoyl)phenyl-ethyl]-methyl-carbamoyl}(4-ethoxy-phenyl)- ethyl]-amide N-[(R)[(1S,2R)(4-Aminomethyl-benzylcarbamoyl)hydroxyphenyl- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide 3-Chloro-thiophenecarboxylic acid [(R)[(1S,2R)(4-aminomethyl- 198 benzylcarbamoyl)hydroxyphenyl-ethylcarbamoyl](4-ethoxy-phenyl)- ethyl]-amide Table 7 NMR data of examples Example t NMR (ppm) CD3OD δ 1.42 (3H, t, J=7.0Hz), 2.80-2.91 (2H, m), 2.94-2.99 (1H, m), 3.08- 3.13 (1H, m), 3.96-4.10 (3H, m), 4.14 (2H, s), 4.31-4.36 (1H, m), 4.47- 4.52 (1H, m), 4.66-4.70 (1H, m), 6.88 (2H, d, J=8.6Hz), 7.02 (2H, d, J=8.6Hz), 7.25-7.40 (7H, m), 7.42 (2H, d, J= 8.1Hz), .76(1H, m) 6 CD3OD δ1.42 (3H, t, J=7.0Hz), 2.80-2.89 (2H, m), 2.95-3.00 (1H, m), 3.08-3.13 (1H, m), .13 (3H, m), 4.21 (2H, s), 4.32-4.38 (1H, m), 4.46-4.51 (1H, m), 4.65-4.69 (1H, m), 6.88 (2H, d, J=8.6Hz), 7.03 (2H, d, J= 8.6Hz), 7.05-7.09 (2H, m), 7.26-7.37 (5H, m), 7.41-7.47 (1H, m), 8.78- 8.80 (1H, m) 7 CD3OD δ 1.02 (3H, t, z), 1.42 (3H, t, J=7.0Hz), 2.13-2.21 (2H, m), 2.71- 2.77 (1H, m), 2.81-2.92 (3H, 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, z), 7.05 (2H, d, J= 8.6Hz), 7.17-7.27 (4H, m), 7.30-7.35 (3H, m), 7.46-7.49 (1H, m) 8 CD3OD δ 0.82-0.94 (2H, m), 1.19-1.28 (4H, m), 1.42-1.48 (2H, m), 1.64-1.71 (5H, m), 2.92-2.98 (1H, m), 3.23-3.28 (1H, m), 3.88 (1H, q, J=7.6Hz), 4.15 (2H, s), 4.39 (1H, d, Hz), 4.52 (1H, d, Hz), 4.76-4.79 (1H, m), 7.33-7.37 (7H, m), 7.44 (2H, d, J= 8.1Hz) 9 CD3OD δ 0.84-1.03 (4H, m), 1.13-1.23 (2H, m), 1.52-1.77 (7H, m), 2.93 (6H, s), 2.96-3.02 (1H, m), 3.20-3.30 (1H, m), 3.81 (1H, q, J=3.9Hz), 4.15 (2H, s), 4.47 (2H, q, J=15.4Hz), 4.76 (1H, dd, J=5.3, 10.5Hz), 7.29-7.40 (7H, m), 7.45 (2H, d, J= 8.2Hz) CD3OD δ 0.84-0.92 (2H, m), 1.03 (3H, t, J=7.7Hz), 1.11-1.20 (4H, m), 1.35- 1.39 (2H, m), 1.64-1.67 (5H, m), 2.15-2.26 (2H, m), 2.87-2.93 (1H, m), 3.39-3.42 (1H, m), 4.14 (2H, s), 4.21-4.26 (1H, m), 4.41-4.42 (1H, m), 4.44-4.57 (1H, m), 4.69-4.75 (1H, m), 7.27-7.44 (9H, m), 8.08(1H, d, z), 8.49 (1H, d, J= 8.3Hz), 8.63-8.70 (1H, m) 11 CD3OD δ 0.85-0.95 (2H, m), 1.21-1.40 (6H, m), 1.70-1.79 (5H, m), 2.85 (3H, s), 2.95 (1H, dd, J=10.0, 14.0Hz), 3.29 (1H, dd, J=5.5, 14.0Hz), 3.98 (1H, dd, J= 5.6, 8.8Hz), 4.14 (2H, s), 4.43 (2H, s), 4.71 (1H, dd, J=5.4, .0Hz), 7.27-7.35 (7H, m), 7.42 (2H, d, J= 8.1Hz) 12 CD3OD δ 1.04 (3H, t, J=7.5Hz), 1.40 (3H, t, J=7.0Hz), 2.15-2.23 (2H, m), 2.74- 2.90 (3H, m), 2.97-3.21(2H, m), 3.98-4.13 (2H, m), 4.14 (2H, s), 4.35- 4.58 (3H, m), 4.61-4.68 (1H, m), 6.82 (2H, d, J=8.6Hz), 7.04-7.08 (1H, m), 7.12-7.42 (9H, m), 7.55 (1H, d, J= 1.6Hz) 13 CD3OD δ 1.42 (3H, t, J=7.0Hz), 2.61-2.66 (1H, m), 2.83-2.88 (1H, m), 3.00 (6H, s), .08 (1H, m), 3.29 (1H, dd, J= 12.9, 4.9Hz), 3.98-4.06 (3H, m), 4.14 (2H, s), 4.19-4.21 (1H, m), 4.33-4.45 (2H, m), 6.87 (2H, d, J=8.6Hz), 6.89-7.05 (2H, m), 7.12 (2H, d, J= 8.6Hz), 7.22-7.27 (5H, m), 7.40 (2H, d, J= 8.2Hz), 8.61-8.64 (1H, m) 14 CD3OD δ 1.42 (3H, t, z), 2.82-2.92 (2H, m), 3.03-3.09 (2H, m), 4.04- 4.13 (3H, m), 4.15 (2H, s), 4.30-4.35 (1H, m), .53 (1H, m), 4.65- 4.69 (1H, m), .91 (2H, m), 7.02-7.06 (2H, m), 7.15 (1H, dd, J=8.3, 2.0Hz), 7.29 (2H, d, J= 8.1Hz), 7.43-7.46 (4H, m), 8.74 (1H, t, J= .8Hz) CD3OD δ 1.42 (3H, t, J=7.0Hz), 2.54-2.60 (1H, m), 2.67-2.72 (1H, m), 2.78- 2.83 (1H, m), 3.06-3.11 (1H, m), 3.91-3.95 (1H, m), 3.98-4.04 (2H, m), 4.14 (2H, s), 4.36-4.49 (2H, m), 4.54-4.58 (1H, m), 6.69-6.72 (2H, m), 6.91 (2H, d, J= , 7.19-7.21 (2H, m), 7.24-7.32 (5H, m), 7.41-7.45 (4H, m), 7.55-7.59 (1H, m), 7.64-7.66 (2H, m). 16 CD3OD δ 1.03 (3H, t, J=7.6Hz), 1.42 (3H, t, J=7.0Hz), 2.14-2.24 (2H, m), 2.75- 2.94 (3H, m), 3.07-3.12 (1H, m), 4.04 (2H, q, J=7.0Hz), 4.14 (2H, s), 4.36-4.51 (3H, m), 4.61-4.65 (1H, m), 6.81-6.84 (2H, m), .09 (3H, m), 7.33 (2H, d, J= 8.1Hz), .43 (4H, m) 17 CD3OD δ 1.17 (3H, t, J=7.0Hz), 2.49-2.54 (1H, m), 2.74-2.83 (3H, m), 3.32 (2H, s), 3.81 (2H, q, J=7.0Hz), 3.88 (2H, s), 3.90-3.94 (1H, m), .21 (2H, m), 4.30-4.34 (1H, m), 6.60-6.65 (2H, m), 6.77-6.82 (2H, m), 6.94- 6.96 (2H, m), 7.01-7.11 (5H, m), 7.17 (2H, d, J= 8.2Hz), 8.43 (1H, t, J= 6.0Hz) 18 CD3OD δ 2.82-2.88 (1H, m), 3.02-3.09 (2H, m), 3.20-3.26 (1H, m), 4.15 (2H, s), 4.21-4.34 (2H, m), 4.49-4.54 (1H, m), 4.68-4.72 (1H, m), 7.19 (1H, dd, J=8.2, 2.0Hz), 7.29 (2H, d, J=8.1Hz), 7.34 (2H, d, J=8.0Hz), 7.43-7.48 (4H, m), 7.68 (2H, d, J=8.2Hz), 8.76 (1H, t, J=5.8Hz) 19 CD3OD δ 1.02 (3H, t, J=7.6Hz), 2.19 (2H, q, J=7.6Hz), 2.86-2.94 (2H, m), 3.06- 3.16 (2H, m), 4.14 (2H, s), .50 (2H, m), 4.61-4.70 (2H, m), 7.13 (1H, dd, J= 8.3, 2.0Hz), 7.32-7.37 (4H, m), .45 (4H, m), 7.60 (2H, d, J=8.2Hz) CD3OD δ 0.82-0.99 (2H, m), 1.15-1.30 (4H, m), 1.44-1.54 (2H, m), 1.62-1.73 (5H, m), 2.91-2.97 (1H, m), 3.22-3.27 (1H, m), 3.90 (1H, t, J=7.1Hz), 4.16 (2H, s), 4.38-4.55 (2H, m), 4.77-4.81 (1H, m), 7.26 (1H, dd, J=8.2, , 7.37 (2H, d, J=8.1Hz), 7.43-7.52 (4H, m) 21 CD3OD δ 0.85-0.94 (2H, m), 1.02-1.22 (7H, m), 1.34-1.42 (2H, m), 1.62-1.69 (5H, m), 2.16-2.27 (2H, m), 2.85-2.92 (1H, m), 3.39-3.44 (1H, m), 4.14 (2H, s), 4.18-4.24 (1H, m), 4.40-4.45 (1H, m), 4.53-4.58 (1H, m), 4.73- 4.79 (1H, m), 7.24 (1H, dd, J=8.2, 2.0Hz), 7.38-7.51 (6H, m), 8.11 (1H, d, J=5.6Hz), 8.59 (1H, d, z), 8.69 (1H, t, J=6.0Hz) 22 CD3OD δ 1.30 (3H, d, J=7.1Hz), 2.92-2.98 (1H, m), 3.40 (1H, d, z), 4.09 (2H, s), 4.41-4.48 (2H, m), 4.54-4.60 (1H, m), 4.68-4.74 (1H, m), 7.24- 7.34 (5H, m), 7.38 (4H, s), 7.43-7.49 (2H, m), 7.56-7.60 (1H, m), 7.80- 7.82 (2H, m), 8.51 (1H, d, J=8.2Hz), 8.56 (1H, d, J=5.3Hz), 8.66 (1H, t, J=6.0Hz) 23 CD3OD δ 1.03 (3H, t, J=7.6Hz), 1.42 (3H, t, J=7.0Hz), 2.16-2.22 (2H, m), 2.73- 2.93 (3H, m), 3.11-3.16 (1H, m), 4.05 (2H, q, J=6.9Hz), ), 4.28 (2H, s), 4.37-4.48 (3H, m), 4.60-4.64 (1H, m), 6.82 (2H, d, J=8.6Hz), 7.05 (2H, d, J= 8.7Hz), 7.17 (2H, t, z), 7.29-7.33 (4H, m), 7.46 (2H, dd, J=9.6,1.4Hz) 24 CD3OD δ 1.08 (3H, t, J=7.7Hz), 1.38-1.42 (3H, m), 2.18-2.25 (2H, m), 2.71- 3.07 (7H, m), 4.00-4.07 (2H, m), 4.14 (2H, s), 4.54-4.58 (2H, m), 4.62- 4.66 (1H, m), 5.09-5.15 (1H, m), .88 (2H, m), 7.08-7.21 (4H, m), 7.26-7.38 (4H, m), 7.42 (2H, d, J= 8.1Hz), 8.29 (1H, d, J= 7.8Hz), 8.35 (1H, d, J= 8.3Hz) CD3OD δ 1.41 (3H, t, J= 7.0Hz), 2.56-2.68 (2H, m), 2.94-2.98 (1H, m), 3.01 (3H, s), .41 (1H, m), 4.05 (2H, q, J= 7.0Hz), 4.14 (2H, s), 4.33- 4.38 (1H, m), 4.49-4.55 (2H, m), 5.52-5.56 (1H, m), 6.86-6.89 (2H, m), 7.02 (2H, d, J= 8.6Hz), 7.28-7.39 (7H, m), 7.43 (2H, d, J= 8.1Hz), 8.53 (1H, t, J= 5.8Hz) 26 CD3OD δ 1.05 (3H, t, J= , 1.39 (3H, t, J= , .23 (2H, m), 2.51-2.63 (2H, m), 2.83-2.90 (1H, m), 2.96 (3H, s), 3.39-3.41 (1H, m), 4.01 (2H, q, J= , 4.13 (2H, s), 4.38-4.50 (2H, m), 4.83-4.87 (1H, m), 5.47-5.51 (1H, m), 6.78-6.82 (2H, m), 7.01 (2H, d, J= 8.6Hz), 7.22- 7.40 (7H, m), 7.43 (2H, d, J= 8.1Hz), 8.19 (1H, d, J= 6.8Hz), 8.34 (1H, t, J= 6.0Hz) 27 CD3OD δ 1.42 (3H, t, J= 7.0Hz), 2.66 (3H, s), .90 (1H, m), 3.01-3.15 (3H, m), 4.02-4.10 (3H, m), 4.14 (2H, s), 4.34-4.47 (2H, m), 4.59-4.70 (1H, m), 6.83-6.88 (2H, m), 6.97-7.02 (2H, m), 7.20-7.22 (2H, m), 7.26-7.34 (5H, m), 7.42 (2H, d, J= 8.1Hz), 8.69 (1H, t, J= 5.8Hz) 28 CD3OD δ 0.81-0.83 (6H, m), 1.10-1.18 (1H, m), 1.48-1.55 (1H, m), .65 (1H, m), 2.92-2.98 (1H, m), 3.25-3.30 (1H, m), 3.75 (2H, s), 3.92-3.96 (1H, m), 4.15 (2H, s), 4.48-4.53 (2H, m), 4.75-4.79 (1H, m), 7.27-7.40 (7H, m), 7.46 (2H, d, J= 8.2Hz), 8.83 (1H, t, J= 5.9Hz) 29 CD3OD δ 0.70-1.03 (6H, m), 1.37-1.69 (7H, m), 2.81-2.87 (4H, m), 3.06-3.11 (1H, m), 3.72-3.96 (3H, m), 3.99 (2H, s), 4.26-4.37 (2H, m), 4.58-4.62 (1H, m), 7.13-7.24 (7H, m), 7.30 (2H, d, J= 8.1Hz), 8.72 (1H, t, J= .9Hz) CD3OD δ 0.75-0.93 (3H, m), 1.20-1.31 (5H, m), 1.54-1.81 (5H, m), 3.02 (3H, s), 3.08-3.17 (1H, m), 3.43-3.48 (1H, m), 3.81 (2H, s), 4.15 (2H, s), 4.45- 4.53 (3H, m), 5.65-5.71 (1H, m), 7.27-7.39 (5H, m), 7.41 (2H, d, J= 8.1Hz), 7.48 (2H, d, J= 8.2Hz), 8.67 (1H, t, J= 5.9Hz) 31 CD3OD δ 0.67-0.71 and 0.77-0.80 (3H, m), 1.19-1.24 (3H, m), 1.99-2.11 (2H, m), 2.65-2.83 (5H, m), 2.91-3.09 (2H, m), 3.81-3.88 (2H, m), 3.95 (2H, s), 4.17-4.32 (2H, m), 4.43-4.54 (1H, m), 4.77-4.82 (1H, m), 6.62-6.69 (2H, m), 6.90-6.94 (2H, m), 6.98-7.20 (7H, m), 7.21-7.26 (2H, m), 7.69 (1H, d, J= 7.9Hz), 8.26-8.29 and 8.40-8.43 (1H, m) 32 CD3OD δ 1.02-1.10 (3H, m), 1.40 (3H, t, J= , 2.11-2.24 (2H, m), 2.51- 2.63 (2H, m), 2.82-2.90 (1H, m), 2.95 (3H, s), 3.36-3.41 (1H, m), 3.98- 4.03 (2H, m), 4.20 (2H, s), 4.38-4.51 (2H, m), 4.85 (1H, t, J= 7.3Hz), .46-5.50 (1H, m), 6.77-6.85 (2H, m), .08 (2H, m), 7.11-7.18 (2H, m), 7.21-7.36 (5H, m), 7.42-7.48 (1H, m), 8.43 (1H, t, J= 6.1Hz) 33 CD3OD δ 0.63-0.80 (2H, m), 0.87-1.08 (4H, m), 1.32-1.54 (7H, m), 2.50 (3H, s), .85 (1H, m), 3.08-3.13 (1H, m), 3.66-3.70 (1H, m), 3.99 (2H, s), 4.27-4.36 (2H, m), 4.59-4.65 (1H, m), 7.13-7.24 (7H, m), 7.30 (2H, d, J= 8.2Hz), 8.71 (1H, t, J= 5.9Hz), 8.80 (1H, d, J= 7.6Hz) 34 CD3OD δ 0.75-0.91 (3H, m), 1.20-1.33 (5H, m), 1.55 (1H, d, J= ), 1.62- 1.71 (3H, m), 1.80 (1H, d, J= 12.5Hz), 3.02 (3H, s), 3.08-3.18 (1H, m), .50 (1H, m), 3.83-3.87 (2H, m), 4.23 (2H, s), 4.46-4.52 (3H, m), .66-5.72 (1H, m), 7.21-7.41 (7H, m), 7.52 (1H, t, J= 7.8Hz), 8.77 (1H, t, J= 6.0Hz) CD3OD δ 0.83 (3H, t, J= 7.4Hz), 1.24-1.30 (3H, m), 1.51-1.62 (2H, m), 2.64 (3H, s), 2.65-2.89 (5H, m), 3.09-3.14 (1H, m), 3.85-3.96 (2H, m), 3.98 (2H, s), 4.16-4.22 (1H, m), 4.28-4.37 (1H, m), 4.47-4.50 (1H, m), 5.29 (1H, t, J= 8.1Hz), 6.67-6.75 (2H, m), 6.87-6.90 (2H, m), 7.09 (2H, d, J= 8.2Hz), 7.15-7.29 (7H, m), 8.42 (1H, t, J= 6.0Hz) 36 CD3OD δ 1.15-1.30 (6H, m), 1.52-1.76 (7H, m), 2.89-3.02 (4H, m), 3.10-3.19 (1H, m), .80 (2H, m), 3.99-4.05 (1H, m), 4.12-4.14 (2H, m), 4.48- 4.59 (1H, m), 4.71-4.80 (1H, m), 5.08-5.16 (1H, m), 7.19-7.49 (9H, m) 37 CD3OD δ 0.62-1.08 (9H, m), 1.34-1.66 (9H, m), 2.71-2.86 (3H, m), 3.07-3.11 (1H, m), 3.69-3.73 (1H, m), 4.00 (2H, s), 4.27-4.37 (2H, m), 4.59-4.63 (1H, m), 7.13-7.27 (7H, m), 7.30 (2H, d, J= 8.1Hz), 8.68 (1H, t, J= .9Hz) 38 CD3OD δ 1.39 (3H, t, J= 7.0Hz), 2.66-2.71 (1H, m), 2.79-2.94 (2H, m), 3.01 (3H, s), .43 (1H, m), 3.97-4.03 (2H, m), 4.07-4.14 (2H, m), 4.40- 4.50 (2H, m), 5.03-5.09 (1H, m), 5.52-5.56 (1H, m), 6.78-6.86 (2H, m), 7.05-7.18 (2H, m), .71 (12H, m), 7.73-7.81 (2H, m), 8.37 (1H, t, J= 6.0Hz), 8.58 (1H, d, J= 6.7Hz) 39 CD3OD δ 1.39 (3H, t, J= 7.0Hz), 1.93 (3H, s), 2.50-2.63 (2H, m), 2.81-2.90 (1H, m), 2.95 (3H, s), 3.34-3.41 (1H, m), .05 (2H, m), 4.13 (2H, s), 4.33-4.51 (2H, m), 4.82-4.89( 1H, m), 5.46-5.50 (1H, m), 6.78-6.85 (2H, m), 7.00-7.05 (2H, m), 7.09-7.36 (7H, m), 7.39-7.43 (2H, m), 8.29 (1H, t, J= 6.0Hz) 40 CD3OD δ 0.61-0.81 (2H, m), 0.88-1.05 (4H, m), 1.34-1.54 (7H, m), 2.51 (3H, s), 2.80-2.86 (1H, m), 3.08-3.13 (1H, m), 3.67-3.70 (1H, m), 4.07 (2H, s), 4.27-4.37 (2H, m), 4.59-4.63 (1H, m), 6.99-7.04 (2H, m), 7.13-7.24 (5H, m), 7.34 (1H, t, J= 7.9Hz), 8.73 (1H, t, J= 6.0Hz) 41 CD3OD δ 0.73-1.25 (6H, m), 1.50-1.69 (7H, m), 2.67 (3H, s), 2.94-3.00 (1H, m), 3.24-3.29 (1H, m), 3.81-3.85 (1H, m), 4.23 (2H, s), 4.44-4.54 (2H, m), 4.76-4.80 (1H, m), 7.18-7.23 (2H, m), 7.31 (1H, dd, J= 8.3, 2.0 Hz), 7.45-7.56 (3H, m), 8.91 (1H, t, J= 5.9Hz), 8.97 (1H, d, J= 7.7Hz) 42 CD3OD δ 0.83-1.19 (6H, m), 1.53-1.85 (7H, m), 2.94-3.08 (4H, m), .26 (1H, m), 3.87-4.08 (3H, m), 4.22 (2H, s), 4.38-4.55 (2H, m), 4.72-4.76 (1H, m), .22 (2H, m), 7.28-7.39 (5H, m), 7.47-7.51 (1H, m), 8.93 (1H, t, J= 6.0Hz), 9.05 (1H, d, J= 7.2Hz) 43 CD3OD δ 0.78-0.97 (4H, m), 1.03-1.20 (2H, m), 1.47-1.50 (1H, m), 1.54-1.63 (5H, m), 1.75-1.82 (1H, m), 2.92-2.95 (1H, m), 2.98 (3H, s), 3.19-3.24 (1H, m), 3.98-4.13 (3H, m), 4.19 (2H, s), 4.38-4.52 (2H, m), .74 (1H, m), 7.17-7.20 (2H, m), 7.27 (1H, dd, J= 8.3, 2.0 Hz), 7.37-7.52 (3H, m), 8.92 (1H, t, J= 5.9Hz), 9.08 (1H, d, J= 7.3Hz) 44 CD3OD δ .05 (6H, m), 1.40 (3H, t, J=7.0Hz), 2.36-2.62 (3H, m), 2.85- 2.91 (1H, m), 2.96 (3H, s), 3.37-3.42 (1H, ,m), 3.98-4.04 (2H, m), 4.13 (2H, s), 4.39-4.50 (2H, m), 4.82-4.86 (1H, ,m), 5.48-5.52 (1H, m), 6.77-6.85 (2H, m), 6.99-7.04 (2H, m), 7.22-7.36 (7H, m), 7.39-7.44 (2H, m), 8.37 (1H, t, J= 6.0Hz) 45 CD3OD δ 0.71-1.03 (9H, m), .63 (9H, m), 2.75 (3H, s), 2.81-3.11 (4H, m), 3.71-3.74 (1H, m), 4.00 (2H, s), 4.31-4.33 (2H, m), 4.59-4.63 (1H, m), 7.14-7.24 (7H, m), 7.30 (2H, d, J= 8.2Hz), 8.71 (1H, t, J= 5.8Hz) 46 CD3OD δ 0.78-0.97 (2H, m), 1.09-1.25 (4H, m), 1.54-1.69 (7H, m), 2.93-2.99 (1H, m), 3.24-3.29 (1H, m), 3.87 (3H, s), 3.94 (2H, d, J= , 3.99- 4.04 (1H, m), 4.15 (2H, s), .53 (2H, m), 4.73-4.77 (1H, m), 7.25- 7.38 (7H, m), 7.46 (2H, d, J= 8.1Hz), 8.83 (1H, t, J= 5.9Hz) 47 CD3OD δ 0.72-1.14 (6H, m), 1.40-1.73 (7H, m), 2.85-2.91 (4H, m), 3.11-3.16 (1H, m), 3.77 (3H, s), .96 (1H, m), 4.04 (2H, s), 4.07-4.18 (2H, m), 4.36 (2H, s), 4.63-4.67 (1H, m), 7.17-7.27 (7H, m), 7.35 (2H, d, J= 8.1Hz), 8.73 (1H, t, J= 5.9Hz), 8.92 (1H, d, J= 7.3Hz) 48 CD3OD δ 0.87-1.17 (6H, m), 1.54-1.79 (7H, m), 2.89 (3H, s), 2.95-3.02 (1H, m), 3.21-3.27 (1H, m), 3.79-3.99 (3H, m), 4.15 (2H, s), 4.47 (2H, s), 4.74- 4.78 (1H, m), 7.29-7.39 (7H, m), 7.46 (2H, d, J= 8.1Hz), 8.84 (1H, t, J= 5.8Hz) 49 CD3OD δ 0.75-1.08 (6H, m), .76 (7H, m), 2.85-2.91 (4H, m), 3.11-3.36 (3H, m), .90 (3H, m), 4.04 (2H, s), 4.31-4.41 (2H, m), .67 (1H, m), 7.18-7.29 (7H, m), 7.35 (2H, d, J= 8.2Hz), 8.76(1H, t, J= .9Hz) 52 CD3OD δ, 0.74-0.88 (4H 0.78-2.10 (23H, m), .08 (1H, m), 3.12-3.30 (1H, m), 4.07 (1H, d, 4.2Hz), 4.15 (2H, s), 4.42 (1H, dd, J=15.3, 5.5Hz), 4.52 (1H, dd, , 6.0Hz), 4.66 (1H, dd, J=10.2, 5.2Hz), 7.20-7.48 (9H, m), 8.87 (1H, t, J=6.0Hz) 53 CD3OD δ 0.83-1.19 (12H, m), 1.50 (1H, d, J=12.2 Hz), 1.60-1.79 (10H, m), 2.98 (1H, dd, J=10.6, 14.2 Hz), 3.14-3.28 (5H, m), 3.91 (1H, dd, J=3.4, 11.7 Hz), 4.15 (2H, s), 4.47-4.49 (2H, m), 4.77 (1H, dd, J=5.2, 10.5 Hz), H, s7.36-7.41(6H (7H, m), 7.45 (2H, d, J=8.1 Hz), 8.89-8.92 (1H, m) 54 CD3OD δ 1.44 (3H, t, J= 7.0 Hz), 2.81-2.87 (1H, m), 2.95-3.02 (2H, m), 3.19- 3.24 (1H, m), 4.03-4.09 (4H, m), 4.46 (2H, d, J = 6.0 Hz), 4.84-4.89 (1H, m), 6.88 (2H, d, J = 8.5 Hz), 7.04 (2H, d, J = 8.5 Hz), 7.17-7.51 (13H, m), 7.85 (1H, d, J= 8.5 Hz), 7.93 (1H, d, J= 8.5 Hz), 7.90 and 8.00 (total 1H, each dd, J= each 7.2 Hz), 8.43 (1H, d, J= 8.1 Hz), 8.63 (1H, t, J= 5.9 Hz), 8.75 (1H, t, J= 7.0 Hz) 55 CD3OD δ 1.25 (3H, t, J= 7.0 Hz), 2.77-2.83 (H3H, m), 2.96-3.02 (1H, m), 3.85- 3.97 (4H, m), 4.22-4.26 (1H, m), 4.27-4.39 (1H, m), 4.48-4.54 (2H, m), 6.66-6.68 (2H, m), 6.94 (2H, d, J = 8.6 Hz), 7.01-7.03 (2H, m), 7.11- 7.29 (9H, m), 7.31 (1H, d, J= 1.8 Hz), 7.53 (1H, d, J= 8.6 Hz), 8.22 (1H, d, J= 8.0 Hz), 8.36-8.44 (2H, m) 56 CD3OD δ 1.25 (3H, t, J= 7.0 Hz), 2.75-2.83 (4H, m), 2.87-2.99 (1H, m), 3.85- 3.89 (2H, m), 3.97 (2H, s), 4.22-4.39 (2H, m), 4.53-4.57 (H1H, m), 6.67 (2H, d, J = 8.5 Hz), 6.95 (2H, d, J = 8.5 Hz), 7.02-7.04 (2H, m), 7.11- 7.22 (7H, m), 7.60 (2H, d, J= 8.3 Hz), 7.71 (2H, d, J= 8.2 Hz), 8.25 (1H, d, J= 8.0 Hz), 8.42 (1H, t, J= 5.8 Hz) 57 CD3OD δ 1.41 (3H, t, J= 7.0 Hz), 2.91-3.04 (4H, m), 3.15-3.20 (1H, m), 4.01- 4.07 (4H, m), 4.40 (1H, d, J= 15.4 Hz), 4.53 (1H, d, J= 15.4 Hz), 4.67- 4.71 (2H, m), 6.84 (2H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.19- 7.24 (2H, m), 7.27-7.37 (9H, m), 7.44-7.54 (2H, m), 7.70-7.73 (4H, m), 7.80-7.82 (1H, m) 58 CD3OD δ 1.42 (3H, t, J= 7.0 Hz), .98 (4H, m), 3.02-3.06 (1H, m), 4.05 (2H, d, J = 7.0 Hz), 4.12 (2H, s), 4.39-4.46 (2H, m), 4.68-4.76 (2H, m), 6.85 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.20-7.22 (2H, m), 7.26-7.32 (6H, m), 7.39-7.41 (3H, m), 7.54 (1H, d, J = 1.9 Hz), 8.54 (1H, t, J = 5.9 Hz) 59 CD3OD δ 1.25 (3H, t, J= 7.0 Hz), 2.77-2.81 (4H, m), 2.97-3.02 (1H, m), 3.87 (2H, q, J = 7.0 Hz), 3.93 (2H, s), 4.26-4.30 (1H, m), 4.35-4.40 (1H, m), 4.48-4.55 (2H, m), 6.68 (2H, d, J = 8.6 Hz), 6.94 (2H, d, J = 8.6 Hz), 7.01-7.03 (2H, m), 7.09-7.22 (8H, m), 7.42-7.45 (2H, m), 8.22 (1H, d, J= 8.1 Hz), 8.41 (1H, t, J= 5.8 Hz) 60 CD3OD δ 1.23 (3H, t, J= , 2.81-2.87 (1H, m), .06 (1H, m), 3.85- 3.91 (2H, m), 3.94 (2H, s), 3.96-4.04 (2H, m), 4.18-4.24 (1H, m), 4.53 (1H, d, J= 7.0Hz), 4.84 (1H, d, J= 7.1Hz), 6.70-6.74 (2H, m), 6.88 (2H, d, J= 8.0Hz), 7.01-7.04 (2H, m), 7.13-7.23 (5H, m), 7.27-7.31 (2H, m) 61 CD3OD δ 1.43 (3H, t, J= , 2.68-2.74 (1H, m), 2.98-3.03 (1H, m), 4.06 (2H, q, J= 7.0Hz), 4.14 (2H, s), 4.21-4.24 (1H, m), 4.42-4.50 (2H, m), 4.75 (1H, d, J= 4.4Hz), 5.28 (1H, d, J= 4.4Hz), 6.85-6.89 (2H, m), 6.97-7.00 (2H, m), 7.30-7.35 (4H, m), 7.38-7.43 (3H, m), 7.5 (2H, d, J= 7.3Hz) 62 CD3OD δ 0.93 (3H, t, J= 7.7Hz), 1.25 (3H, t, J= 7.0Hz), 2.01-2.11 (2H, m), .66 (1H, m), 2.79-2.84 (1H, m), 3.86 (2H, q, J= 7.0Hz), 3.99 (2H, s), 4.22-4.32 (2H, m), 4.41-4.43 (1H, m), 4.46 (1H, d, J= 4.0Hz), 5.13 (1H, d, J= 4.0Hz), 6.64-6.67 (2H, m), 6.91-6.95 (2H, m), 7.14-7.33 (9H, m) 63 CD3OD δ 1.00 (3H, t, J= , 1.43 (3H, t, J= 7.0Hz), 2.13-2.19 (2H, ,m), 2.61-2.66 (1H, m), 2.78-2.83 (1H, m), 4.04 (2H, q, J= 7.0Hz), 4.14 (2H, s), 4.45-4.65 (4H, m), 5.37 (1H, d, J= 3.0Hz), 6.77-6.81 (2H, m), 7.01 (2H, d, J= 8.6Hz), .45 (9H, ,m), 8.00 (1H, d, J= 6.9Hz), 8.23 (1H, d, J= 8.4Hz), 8.51 (1H, t, J= 6.0Hz) 64 CD3OD δ 0.98 (3H, t, J= 7.2Hz), 1.06-1.13 (3H, m), 1.40 (3H, t, J= 7.0Hz), 2.19-2.24 (2H, m), 2.71-2.82 (2H, ,m), 2.98-3.05 (1H, m), 3.14-3.22 (1H, m), 3.29-3.35 (1H, ,m), 3.51-3.60 (1H, m), 3.98-4.04 (2H, m), 4.13 (2H, s), 4.35-4.48 (2H, m), 4.78-4.89 (1H, m), 5.12-5.21 (1H, m), 6.79-6.83 (2H, m), .16 (2H, m), 7.26-7.38 (7H, m), 7.41 (2H, d, J= 8.1Hz), 8.21 (1H, t, J= 6.1Hz) 65 CD3OD δ 0.96-1.10 (6H, m), 1.33-1.44 (3H, m), .27 and .46 (total 3H, m), 2.74-2.97 (2H, m), 3.12-3.23 (1H, m), 3.28-3.34 (1H, m), 3.41- 3.50 (1H, m), 3.92-4.08 (2H, m), 4.12 (2H, s), 4.34-4.50 (2H, m), 4.60- 4.64 and 4.78-4.82 (1H, m), 4.94-4.98 and 5.08-5.12(total 1H, m), 6.80- 6.89 (2H, m), .42 (11H, m), 8.11 (1H, t, J=6.0 Hz), 8.20 (1H, d, J=6.5 Hz), 8.45 (1H, d, J=7.2 Hz), 8.77 (1H, t, J=5.8 Hz) 66 CD3OD δ 0.82-0.86 and .00 (total 3H, m), 1.38-1.43 (3H, m), 2.18-2.30 (2H, m), 2.63 (3H, s), 2.84-3.02 (2H, m), 3.11-3.28 (2H, m), 3.99-4.06 (2H, m), 4.15 (2H, s), 4.39-4.51 (2H, m), 4.64-4.79 (1H, m), 5.22-5.26 (1H, m), 6.81-6.87 (2H, m), 7.09-7.13 (2H, m), 7.22-7.37 (7H, m), 7.42- 7.46 (2H, m), 7.76 (1H, d, J= 7.9Hz), 8.45-8.47 and 8.59-8.62 (total 1H, m) 67 CD3OD δ 1.00 (3H, t, J=7.7Hz), 1.44 (3H, t, J=7.0Hz), 1.64-1.72 (1H, m), 2.08- 2.31 (3H, m), 2.98-3.09 (2H, m), 3.30-3.36 (1H, m), 3.39-3.44 (1H, m), 3.91-3.97 (1H, m), 4.03-4.07 (2H, m), 4.14 (2H, s), 4.10-4.16 (1H, m), 4.31-4.34 (1H, m), 4.37 (1H, d, J=4.9Hz), 4.51-4.57 (1H, m), 4.82-4.86 (1H, m), H, s6.91-6.97 (4H, m), 7.25-7.36 (7H, m), 7.42 (2H, d, J=8.2Hz), 8.35-8.50 (1H, m) 68 d6- δ: 1.29 (3H, t, J = 7.0Hz), 2.43 (1H, dd, J = 13.7, 8.0Hz), 2.63 (1H, dd, J DMSO = 13.8, 4.7Hz), 2.77 (1H, dd, J = 13.6, 10.4Hz), 3.06 (1H, dd, J = 13.7, 4.4Hz), 3.91-3.96 (4H, m), 4.07 (1H, dd, J = 15.4, , 4.15 (1H, dd, J = 15.4, 6.0Hz), 4.23-4.26 (2H, m), 4.32-4.37 (1H, m), .50 (1H, m), 6.09 (1H, d, J = 7.7Hz), 6.58 (1H, t, J = 6.0Hz), 6.67 (2H, d, J = 8.7Hz), 6.76 (2H, d, J = 8.6Hz), 7.08-7.38 (11H, m), 7.45 (2H, d, J = 7.5Hz), 8.28 (3H, br s), 8.48 (1H, d, J = 8.5Hz), 8.62 (1H, t, J = 6.0Hz). 69 d6- δ: 1.28 (3H, t, J = 7.0Hz), 2.47-2.50 (1H, m), 2.67 (1H, dd, J = 13.9, DMSO 4.6Hz), 2.79 (1H, dd, J = 13.6, 10.5Hz), 3.07 (1H, dd, J = 13.7, 4.3Hz), 3.90-3.97 (4H, m), 4.23-4.33 (2H, m), 4.43-4.53 (2H, m), 6.24 (1H, d, J = 7.7Hz), 6.66 (2H, d, J = 8.7Hz), 6.72 (2H, d, J = , 6.86 (1H, t, J = 7.4Hz), 7.13-7.32 (11H, m), 7.36 (2H, d, J = 8.1Hz), 8.23 (2H, br s), 8.58-8.63 (2H, m), 8.77 (1H, s). 70 d6- δ: 1.26 (3H, t, J = 7.0Hz), 2.66 (1H, dd, J = 13.5, 10.6Hz), 2.73 (1H, DMSO dd, J = 13.8, 4.0Hz), 2.82 (1H, dd, J = 13.5, 10.2Hz), 3.05 (1H, dd, J = 13.6, 4.9Hz), 3.89-4.01 (4H, m), 4.27 (1H, dd, J = 15.4, 5.8Hz), 4.34 (1H, dd, J = 15.4, 6.1Hz), 4.55-4.68 (2H, m), 6.75 (2H, d, J = 8.6Hz), 7.07-7.32 (8H, m), 7.39 (2H, d, J = 8.1Hz), 7.73 (1H, dd, J = 7.9, .2Hz), 8.13-8.59 (4H, m), 8.63 (2H, m), 8.81 (1H, dd, J = 5.1, 1.3Hz), 8.99-9.01 (2H, m). 71 d6- δ: 1.26 (3H, t, J = 6.9Hz), 2.64 (1H, dd, J = 13.5, ), 2.72 (1H, DMSO dd, J = 13.6, , 2.82 (1H, dd, J = 13.5, 10.2Hz), 3.05 (1H, dd, J = 13.6, 4.7Hz), 3.80-4.01 (4H, m), 4.27 (1H, dd, J = 15.4, 5.8Hz), 4.34 (1H, dd, J = 15.4, 6.0Hz), 4.58-4.68 (2H, m), 6.75 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.7Hz), 7.17-7.27 (6H, m), 7.38 (2H, d, J = 8.1Hz), 7.85 (2H, d, J = 5.9Hz), 8.14-8.50 (3H, m), 8.64 (1H, d, J = 6.2Hz), 8.67 (1H, d, J = 8.6Hz), 8.80 (2H, d, J = 6.0Hz), 9.03 (1H, d, J = 8.3Hz). 72 d6- δ: 1.26 (3H, t, J = , 2.62 -2.64 (2H, m), 2.81 (1H, dd, J = 13.6, DMSO 10.0Hz), 3.03 (1H, dd, J = 13.4, 4.5Hz), 3.92 (2H, q, J = 7.0Hz), 3.96 (2H, s), 4.25-4.35 (2H, m), .61 (2H, m), 6.74 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.7Hz), 7.16-7.25 (7H, m), 7.35 (2H, d, J = 8.1Hz), 7.43 (1H, dd, J = 5.0, 1.3Hz), 7.53 (1H, dd, J = 5.0, 3.0Hz), 8.11 (1H, dd, J = 2.8, 1.0), 8.20 (2H, br s), 8.33 (1H, d, J = 8.2Hz), 8.54 (1H, d, J = 8.7Hz), 8.60 (1H, t, J = 6.0Hz). 73 d6- δ: 1.26 (3H, t, J = , .68 (2H, m), 2.81 (1H, dd, J = 13.6, DMSO 10.1Hz), 3.03 (1H, dd, J = 13.6, 4.7Hz), 3.89-3.96 (4H, m), 4.24-4.34 (2H, m), 4.53-4.62 (2H, m), 6.74 (2H, d, J = 8.6Hz), 7.10-7.27 (9H, m), 7.37 (2H, d, J = 8.1Hz), 7.71 (1H, dd, J = 4.9, 0.9Hz), 7.82 (1H, dd, J = 3.6, 2.8Hz),8.20 (3H, br s), 8.56 (2H, dd, J = 10.5, 9.1Hz), 8.62 (1H, t, J = 6.0Hz). 74 d6- δ: 0.48-0.57(4H,m), H,t,J= 7.0Hz), 1.56-1.62(1H,m), 2.43- DMSO 2.49(1H,m), 2.54-2.59(1H,m), 2.73-2.79(1H,m), 3.00-3.05(1H,m), 3.92- 3.97(4H,m), 4.20-4.33(2H,m), 4.38-4.43(1H,m), 4.47-4.53(1H,m), 6.73(2H,d,J= 8.6Hz), 6.98(2H,d,J= 8.6Hz), 7.16-7.26(7H,m), 7.38(2H,d,J= 8.1Hz), 8.23(1H,d,J= 7.7Hz), 8.28(2H,s), 8.48(1H,d,J= 8.6Hz), 8.54(1H,t,J =6.0Hz). 75 d6- δ: 0.96-1.15(5H,m), H,t,J= 7.0Hz), .55(5H,m), 1.96- DMSO 2.01(1H,m), 2.34-2.41(1H,m), 2.51-2.56(1H,m), 2.67-2.73(1H,m), 2.92- 2.97(1H,m), 3.86(2H,q,J= 7.0Hz), 3.90(2H,s), 4.15-4.24(2H,m), 4.27- 4.32(1H,m), 4.41-4.47(1H,m), H,d,J= 8.6Hz), 6.88(2H,d,J= 8.6Hz), 7.08-7.18(7H,m), 7.30(2H,d,J= 8.1Hz), 7.66(1H,d,J= 8.0Hz), 8.17(2H,s), 8.29(1H,d,J= 8.5Hz), 8.51(1H,t,J =6.0Hz). 76 d6- δ: 0.78(3H,t,J= 7.3Hz), 0.99-1.05(2H,m), 1.12-1.21(2H,m), 1.26- DMSO 1.36(5H,m), 1.91-2.03(2H,m), 2.38-2.44(1H,m), 2.56-2.61(1H,m), 2.74- 2.80(1H,m), 2.99-3.04(1H,m), 3.93(2H,q,J= 7.0Hz), 3.97(2H,s), 4.23- 4.33(2H,m), 4.39-4.44(1H,m), .56(1H,m), 6.72(2H,d,J= 8.6Hz), 6.98(2H,d,J= 8.6Hz), 7.15-7.26(7H,m), 7.38(2H,d,J= 8.1Hz), 7.88(1H,d,J= 8.0Hz), H,s), 8.42(1H,d,J= 8.6Hz), 8.58(1H,t,J =6.0Hz). 77 d6- δ: 0.93 (3H, d, J = 4.2Hz), 0.95 (3H, d, J = 4.1Hz), 1.28 (3H, t, J = DMSO 7.0Hz), 2.41 (1H, dd, J = 13.7, 8.0Hz), 2.58 (1H, dd, J = 13.8, 4.7Hz), 2.77 (1H, dd, J = 13.6, 10.5Hz), 3.06 (1H, dd, J = 13.7, 4.2Hz), 3.50- 3.58 (1H, m), .01 (4H, m), 4.25-4.30 (3H, m), 4.41-4.47 (1H, m), .82 (1H, d, J = 7.6Hz), 5.99 (1H, d, J = 7.6Hz), 6.67 (2H, d, J = 8.6Hz), 6.76 (2H, d, J = 8.6Hz), 7.16-7.26 (7H, m), 7.39 (2H, d, J = 8.1Hz), 8.37 (2H, br s), 8.46 (1H, d, J = 8.5Hz), 8.65 (1H, t, J = 6.0Hz). 78 d6- δ: 0.83 (3H, t, J = 7.0Hz), 1.16-1.30 (11H, m), 2.41 (1H, dd, J = 13.8, DMSO 8.0Hz), 2.59 (1H, dd, J = 13.6, 4.6Hz), 2.77 (1H, dd, J = 13.7, .5Hz), 2.83-2.90 (2H, m), 3.05 (1H, dd, J = 13.7, 4.2Hz), 3.93 (2H, q, J = 7.0Hz), 3.95 (2H, m), 4.26-4.32 (3H, m), 4.42-4.46 (1H, m), 5.91 (1H, d, J = 7.6Hz), 6.09 (1H, t, J = 5.6Hz), 6.67 (2H, d, J = 8.7Hz), 6.76 (2H, d, J = 8.6Hz), 7.16-7.26 (7H, m), 7.39 (2H, d, J = 8.1Hz), 8.35 (2H, br s), 8.45 (1H, d, J = 8.5Hz), 8.65 (1H, t, J = 6.0Hz). 79 d6- δ: 1.34(3H,t,J= 7.0Hz), 2.65-2.79(2H,m), 2.85-2.91(1H,m), 3.09- DMSO H,m), 3.99(2H,q,J= 7.0Hz), 4.04(2H,s), 4.32-4.42(2H,m), 4.65- H,m), 6.80(2H,d,J= 8.6Hz), 7.15(2H,d,J= 1.9Hz), 7.16(1H,s), 7.22-7.34(7H,m), 7.44(2H,d,J= 8.1Hz), 8.29(2H,s), 8.68-8.72(2H,m), 8.77(1H,d,J= 1.8Hz), H,d,J = 8.6Hz). 80 d6- δ: H,t,J= , 2.61-2.72(2H,m), 2.79-2.84(1H,m), 3.02- DMSO 3.07(1H,m), 3.92(2H,q,J= 7.0Hz), 3.96(2H,s), .37(2H,m), 4.56- 4.63(2H,m), H,d,J= 8.6Hz), 7.14(2H,d,J= 8.6Hz), 7.16- 7.25(7H,m), 7.37(2H,d,J= 8.1Hz), 7.42(2H,d,J= 8.2Hz), 7.85- 7.88(2H,m), 8.21(2H,s), 8.56-8.64(3H,m). 81 d6- δ: 1.25 (3H, t, J = 7.0Hz), 2.68 (1H, m), 2.78-2.85 (2H, m), 3.06 (1H, DMSO dd, J = 13.6, 4.4Hz), 3.86-4.01 (4H, m), 4.28 (2H, d, J = 6.0Hz), 4.50- 4.56 (1H, m), 4.74-4.79 (1H, m), 6.59 (2H, d, J = 8.7Hz), 6.65 (2H, d, J = 8.8Hz), .38 (8H, m), 7.59-7.61 (1H, m), 7.96-7.99 (2H, m), 8.33 (3H, br s), 8.48 (1H, d, J = 8.2Hz), 8.61 (1H, dt, J = 4.7, 1.2Hz), 8.66 (1H, t, J = 6.0Hz), 8.71 (1H, d, J = 8.5Hz). 82 d6- δ: 1.27 (3H, t, J = , 2.13 (3H, s), 2.57-2.69 (2H, m), 2.82 (1H, dd, DMSO J = 13.6, 10.0Hz), 3.05 (1H, dd, J = 13.6, 4.7Hz), 3.78 (3H, s), 3.91 (2H, q, J = 7.0Hz), 3.92-3.99 (2H, m), 4.25-4.36 (2H, m), 4.50-4.62 (2H, m), 6.63 (1H, s), 6.74 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.7Hz), 7.17-7.25 (7H, m), 7.37 (2H, d, J = 8.2Hz), 8.25 (2H, br s), 8.35 (1H, d, J = 8.4Hz), 8.55 (1H, d, J = 8.6Hz), 8.60 (1H, t, J = 6.0Hz). 83 d6- δ: 1.25 (3H, t, J = 7.0Hz), 2.61-2.70 (2H, m), 2.82 (1H, dd, J = 13.5, DMSO ), 3.05 (1H, dd, J = 13.6, 4.7Hz), 3.91 (2H, q, J = 7.0Hz), 3.94 (2H, s), 4.25-4.35 (2H, m), .64 (2H, m), 6.75 (2H, d, J = 8.6Hz), 7.14-7.25 (9H, m), 7.38 (2H, d, J = 8.2Hz), 7.42-7.45 (2H, m), 7.93- 7.99 (2H, m), 8.18 (1H, s), 8.27 (2H, br s), 8.63-8.67 (2H, m), 8.84 (1H, d, J = 8.4Hz). 84 d6- δ: 1.31(3H,t,J= 7.0Hz), 2.21-2.27(1H,m), 2.35-2.39(1H,m), 2.67- DMSO 2.72(1H,m), 2.90-2.95(1H,m), 3.94(2H,q,J= 7.0Hz), H,s), 4.22- 4.27(1H,m), 4.38-4.44(1H,m), 4.49-4.55(1H,m), H,d,J= , 6.93(2H,d,J= 8.6Hz), 7.13-7.25(7H,m), 7.31-7.34(2H,m), 7.38- 7.42(4H,m), 8.10(1H,s), 8.20(2H,s), 8.48(1H,d,J= 8.8Hz), 8.56(1H,t,J = 6.0Hz). 85 d6- δ: 1.30 (3H, t, J= 6.96Hz), 2.38-2.42 (1H, m), 2.58-2.62 (1H, m), 2.73- DMSO 2.79 (1H,m), .03 (1H,m), 3.91-3.95 (4H, m), 4.24-4.25 (2H, m), 4.41-4.46 (1H,m), .57 , 6.67 (2H, d, J= 8.69Hz), 6.89 (2H, d, J= 8.64Hz), 7.07 (2H, d, J= 1.8Hz), 7.17-7.25 (10H,m), 7.37 (2H, t, J= 8.08Hz), 8.14 (1H, t, J= 8.12Hz), 8.26 (3H,s, br), 8.49 (1H, d, J = 8.57Hz), 8.56-8.59 (1H, m). 86 d6- δ: 1.28 (3H, t, J= 6.92Hz), 2.26-2.35 (2H, m), 2.39-2.45 (1H, m), 2.49 DMSO (2H, s), 2.56-2.65 (2H,m), 2.74-2.80 (1H, m), 3.00-3.05 (1H, m), 3.93- 3.96 (3H, m), 4.25-4.32 (2H, m), 4.41-4.46 (1H,m), 4.49-4.55 (1H, m), 6.70 (2H, d, J= 8.48Hz), 6.92 (2H, d, J= 8.48Hz), 7.08 (2H, d, J= 7.16Hz), 7.18-7.24 (10H, m), 7.38 (2H, t, J= 8.0Hz), 8.00 (1H, d, J= 8.00Hz), 8.28 (3H,s, br), 8.46 (1H, d, J = 8.48Hz), 8.57 (1H, t, J= .92Hz). 87 d6- δ: 1.28 (3H, t, J= 6.92Hz), 1.51-1.58 (2H, m), 1.73-1.86 (2H, m), 2.39- DMSO 2.45 (2H, m), 2.49 (2H, s), 2.56-2.65 (2H, m), 2.95-3.03 (1H, m), 3.86- 3.97 (4H, m), 4.29-4.34 (3H, m), 4.47-4.53 (1H, m), 6.66 (2H, d, J= 8.21Hz), 6.96 (2H, d, J= 8.17Hz), 7.17-7.34 (10H, m), 7.36-7.40 (2H, m), 8.02-8.11 (1H, m), 8.26 (3H,s, br), .56 (2H, m). 88 d6- δ: 1.33 J= 6.93Hz), 2.71-2.75 (2H, m), 2.86-2.92 (1H, m), 3.09- DMSO 3.14 , 3.98-4.03 (4H, m), 4.32-4.43 (2H, m), 4.63-4.69 (2H,m), 6.82 (2H, d, J= 8.52Hz), 7.21 (2H, d, J= ), 7.27-7.31 (7H,m), 7.44 (2H, d, J = 8.07Hz), 7.51-7.54 (1H,m), 7.63-7.65 , 7.77 (1H, d, J= 7.84Hz), 7.86 (1H, d, J= 1.68Hz), 8.35 (3H,s, br), 8.63-8.74 (3H, m). 89 d6- δ: 1.29 (3H, t, J= 6.88Hz), 2.52-2.58 (1H, m), 2.71-2.79 (1H, m), 2.81- DMSO 2.84 (1H, m), 3.02-3.07 (1H,m), 3.95-3.98 (4H, m), 4.24-4.36 (2H, m), 4.58-4.63 (2H,m), 6.76 (2H, d, J= 8.56Hz), 7.08 (2H, d, J= 8.56Hz), 7.14-7.25 (9H, m), 7.33-7.43 (4H,m), 8.285 (3H,s, br), 8.47 (2H, t, J= 7.84Hz), 8.62 (1H, t, J= 5.764Hz). 90 d6- δ: 1.26 (3H,t,J= 6.89Hz), 2.61-2.74 (2H, m), 2.79-2.85 (1H, m), 3.02- DMSO 3.07 (1H, m), 3.91-3.96 (4H, m), 4.25-4.36 (2H, m), 4.58-4.67 (2H,m), 6.74 (2H, d, J= 8.56Hz), 7.15-7.24 (9H, m), 7.37 (2H, d, J= 8.12Hz), 7.68 (1H, t, J= 7.80Hz), 7.87 (1H, d, J= 7.89Hz), 8.03 (1H, d, J= 7.89Hz), 8.09 (1H, s) 8.28 (3H,s, br), 8.48-8.65 (2H, m), 8.82 (1H, d, J= 8.28Hz). 91 d6- δ: 1.27 (3H, t, J= 6.88Hz), 1.55-1.61 (11H, m), 1.89 (2H, s), 2.49 (2H, DMSO s), 2.62-2.72 (2H, m), 2.79-2.84 (1H, m), .05 , 3.91-3.96 (4H, m), 4.23-4.39 (3H, m), 4.49-4.54 (1H,m), 6.69 (2H, d, J= 8.36Hz), 6.88 (2H, d, J= 8.37Hz), 7.19-7.25 (8H, m), 7.39 (2H, d, J = 7.84Hz), 8.32-8.38 (3H,m), 8.65-8.68 (1H, m). 92 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.32 (3H, s), 2.67 (2H,d, J = 7.20Hz), 2.78- DMSO 2.84 (1H,m), 3.02-3.07 (1H,m), 3.91-3.97 (4H, m), 4.27-4.36 (2H, m), .60 (2H,m), 6.73 (2H, d, J= 8.57Hz), 7.12 (2H, d, J= ), 7.21-7.24 (9H,m), 7.36 (2H, t, J= 8.08Hz), 7.65 (2H, t, J= 8.17Hz), 8.25 (3H,s, br), 8.37 (1H, d, J = 8.08Hz), 8.54 (1H, d, J= 8.60Hz), 8.59- 8.62 (1H, m). 93 d6- δ: 1.33 (3H,t,J= 6.97Hz), .79 (2H,m), 2.86-2.91 (1H,m), 3.093- DMSO 3.14 (1H, m), 3.98-4.04 (4H, m), .44 (2H, m), 4.63-4.70 (2H, m), 6.81 (2H, d, J= 8.57Hz), 7.21 (2H, d, J= 8.60Hz), 7.27-7.32 (8H,m), 7.44 (2H, t, J= 8.08Hz), 7.79 (2H, s), 8.06 (1H, s), 8.38 (3H,s, br), 8.63- 8.70 (1H, m), 8.83 (1H, d, J= 8.28Hz). 94 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.61-2.71 (2H, m), 2.71-2.84 (1H, m), 3.02- DMSO 3.06 (1H, m), 3.92-3.96 (4H, m), 4.25-4.35 (2H, m), 4.57-4.64 (2H, m), 6.75 (2H, d, J= 8.64Hz), 7.14 (2H, d, J= 8.56Hz), 7.21-7.25 (8H,m), 7.36 (2H, d, J = 8.08Hz), 7.76-7.79 (3H,m), 8.24 (3H,s, br), 8.59 (1H, t, J = 6.32Hz), 8.78 (1H, d, J= 8.24Hz). 95 d6- δ: 1.26 (3H, t, J= 6.97Hz), 2.65-2.69 (2H, m), 2.79-2.84 (1H, m), 3.03- DMSO 3.07 (1H, m), 3.797 (3H, s), .95 (4H, m), 4.25-4.34 (2H, m), 4.53- 4.59 (2H,m), 6.73 (2H, d, J= 8.57Hz), 6.95 (2H, d, J= 8.88Hz), 7.13 (2H, d, J= 8.64Hz), 7.18-7.24 (7H,m), 7.37 (2H, d, J= 8.12H), 7.74 (2H, t, J= 8.85Hz), 8.29 (3H,s, br), 8.34 (1H, d, J = 8.60Hz), 8.54 (1H, d, J= ), 8.61 (1H, t, J= 5.96Hz). 96 d6- δ: 1.27 (3H, t, J= 6.92Hz), 2.61-2.66 (2H, m), 2.76-2.82 (1H, m), 3.01- DMSO 3.06 (1H, m), 3.90-3.95 (4H, m), 4.28-4.31 (2H, m), 4.52-4.62 (2H, m), 6.67-6.73 (3H, m), 6.97 (2H, d, J= ), 7.18-7.27 (10H, m), 7.35- 7.41 (3H, m), 7.50 (2H, d, J= 6.73Hz), 8.21 (4H, d, J= 8.00Hz), 8.59 (2H, t, J = 7.24Hz). 97 d6- δ: 1.28 (3H, t, J= 6.88Hz), .46 (1H, m), 2.59-2.64 (1H, m), 2.73- DMSO 2.79 (1H,m), 2.98-3.03 (1H,m), 3.43 (2H, s), 3.51-3.57 (1H,m), 3.67- 3.73 (1H, m), 3.92-3.97 (4H, m), 4.24-4.33 (2H, m), 4.43-4.54 (2H,m), 6.68 (2H, d, J= 8.56Hz), 6.88 (2H, d, J= 8.57Hz), 7.20-7.26 (12H, m), 7.37 (2H, d, J = 8.08Hz), 7.96 (1H, d, J= ), 8.20-8.27 (4H, m), 8.47 (1H, d, J = 8.50Hz), 8.57 (1H, t, J= 5.97Hz). 98 d6- δ: 1.27 (3H, t, J= 6.93Hz), 2.47-2.49 (1H, m), 2.62-2.66 (1H, m), 2.76- DMSO 2.82 (1H, m), 3.01-3.06 (1H, m), 3.72-3.77 (1H, m), 3.85-3.91 (3H, m), 3.94-3.98 (2H, m), 4.26-4.30 (2H, m), 4.44-4.54 (2H,m), 6.61 (2H, d, J= 8.64Hz), 6.83 (2H, d, J= 8.60Hz), 7.18 (2H, d, J= 8.05Hz), .27 (5H,m), 7.36 (2H, d, J= 8.12Hz), 7.46 (2H, d, J= 7.68Hz), 7.51-7.55 , 7.84 (2H, t, J= 7.126Hz), 7.92 (1H, d, J= 8.08Hz), 8.30 (3H,s, br), 8.50 (1H, d, J = 8.53Hz), 8.57 (1H, t, J= 5.93Hz), 8.73 (1H, t, J = .84). 99 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.65-2.67 (2H, m), 2.78-2.84 (1H, m), 3.03- DMSO 3.07 (1H, m), .96 (4H, m), 4.25-4.36 (2H, m), 4.55-4.61 (2H, m), 6.74 (2H, d, J= 8.60Hz), 7.14 (2H, d, J= 8.64Hz), 7.21-7.28 (9H,m), 7.36 (2H, d, J = 8.12Hz), 7.80-7.83 (2H, m), 8.23 (3H,s, br), .583 (3H, m). 100 d6- δ: 1.36(3H,t,J= 7.0Hz), 2.50-2.56(1H,m), 2.59-2.63(1H,m), 2.82- DMSO 2.88(1H,m), 3.02-3.07(1H,m), .85(1H,m), 3.97(2H,s), 4.03(2H,q,J= 7.0Hz), 4.16-4.21(2H,m), 4.32(2H,d,J= 5.8Hz), 4.63- 4.69(1H,m), 6.87(2H,d,J= 8.6Hz), 7.15(2H,d,J= , 7.20- 7.35(14H,m), 7.47-7.57(1H,m), 7.73-7.81(2H,m), 8.61-8.66(2H,m). 101 d6- δ: 1.28 (3H, t, J= 6.92Hz), 2.36 (3H, s), 2.38-2.42 (1H, m), 2.56-2.60 DMSO (1H, m), 2.73-2.78 (1H, m), 2.98-3.03 (1H, m), 3.23-3.28 (1H, m), 3.92- 3.98 (4H, m), .32 (2H, m), 4.41-4.46 (1H, m), 4.49-4.55 (1H, m), 6.66 (2H, d, J= 8.61Hz), 6.79 (2H, d, J= 8.60Hz), 7.20 (2H, d, J= 6.21Hz), 7.26-7.29 (6H,m), 7.32-7.40 (4H,m), 7.62 (2H, d, J= 8.28Hz), 7..80-7.88 (2H, m), 8.29 (3H,s, br), 8.52 (1H, d, J = 8.52Hz), 8.59-8.62 (1H, m). 102 d6- δ: 1.27(3H,t,J= 7.0Hz), 2.42-2.47(1H,m), 2.64-2.69(1H,m), 2.75- DMSO 2.81(1H,m), 3.04-3.08(1H,m), 3.92(2H,q,J= , 3.96(2H,s), 4.28(2H,d,J= 5.8Hz), 4.43-4.53(2H,m), 6.23(1H,d,J= , 6.65(4H,s), 7.17-7.23(5H,m), 7.26-7.36(8H,m), 8.19(2H,s), 8.63- 8.65(2H,m), 8.91(1H,s). 103 d6- δ: 1.26 (3H, t, J= 6.93Hz), 1.31-1.43 (7H, m), 2.68 (2H, d, J= 7.47Hz), DMSO 2.79-2.84 (1H, m), 3.02-3.07 (1H, m), 3.90-3.95 (2H, m), 4.06 (2H, d, J= 6.40Hz), 4.25-4.32 (2H, m), 4.56-4.63 (2H,m), 6.75 (2H, d, J= 8.52Hz), 7.13-7.22 (12H, m), 7.32-7.35 (1H, m), 7.40-7.43 (2H, m), 7.59-7.63 (1H, m), 7.74 (2H, d, J = 7.90Hz), 8.45-8.52 (3H, m). 104 d6- δ:1.26 (3H,t,J= ), .75 (2H, m + 3H, s), 2.82-2.86 (1H, m), DMSO 3.04-3.08 (1H,m), 3.91-3.96 (4H, m), 4.24-4.36 (2H, m), 4.57-4.69 (2H,m), 6.73 (2H, d, J= 8.52Hz), 7.14 (2H, d, J= 8.68Hz), 7.17-7.24 (6H,m), 7.39 (2H, d, J = 8.07Hz), 7.79 (1H, d, J= 7.84Hz), 8.44 (3H,s, br), 8.49-8.52 (1H, m), 8.65-8.69 (2H, m), 9.00 (1H, d, J= 1.68Hz), 9.14 (1H, d, J= 1.68Hz). 105 d6- δ: 1.29 (3H,t,J= ), 2.42 (3H, s), 2.75-2.86 (3H, m), 3.05-3.09 DMSO (1H,m), .97 (4H, m), 4.25-4.37 (2H, m), 4.61-4.74 (2H,m), 6.78 (2H, d, J= 8.52Hz), 7.09 (2H, d, J= ), 7.21-7.27 (6H,m), 7.40 (2H, d, J = 8.07Hz), 7.76-7.80 (1H, m), 8.07-8.13 (1H, m), 8.42 (3H,s, br), 8.67-8.73 (3H, m), 8.94 (1H, d, J= 1.68Hz). 106 d6- δ: 1.13 (3H,t,J= 6.93Hz), 2.70-2.84 (3H, m), 3.01-3.06 (1H,m), 3.95- DMSO 3.98 (4H, m), 4.24-4.36 (2H, m), 4.59-4.69 (2H,m), 6.76 (2H, d, J= ), 7.04 (2H, d, J= 8.68Hz), 7.16-7.26 (6H,m), 7.38 (2H, d, J = 8.07Hz), 7.61 (2H, s), 8.33 (3H,s, br), 8.58-8.60 (1H, m), 8.64-8.67 (1H, m), 8.78 (1H, d, J= 1.68Hz). 107 d6- δ: 1.24 (3H,t,J= 6.93Hz), 2.56-2.62 (1H, m), .73 (1H, m), 2.78- DMSO 2.84 (1H, m), 3.02-3.07 (1H,m), 3.89-3.95 (4H, m), 4.24-4.37 (2H, m), 4.58-4.67 (2H,m), 6.75 (2H, d, J= 8.52Hz), 7.13 (2H, d, J= 8.68Hz), 7.16-7.25 (8H, m), 7.36 (2H, d, J = 8.07Hz), 8.26 (3H,s, br), 8.59-8.64 (1H, m), 8.65 (1H, d, J= 1.68Hz), 8.94 (1H, d, J= 1.68Hz). 108 d6- δ: 1.28 (3H,t,J= 6.93Hz), 2.69-2.82 (2H, m), .09 (2H,m), 3.92- DMSO 3.98 (4H, m), 4.26-4.33 (2H, m), 4.59-4.62 , 6.74 (2H, d, J= 8.52Hz), 6.98 (2H, d, J= 8.68Hz), 7.23-7.29 (7H, m), 7.37-7.40 (2H, m), 8.05 (1H,s, br), 8.23 (3H,s, br), .69 (1H, m), 8.85 (1H, d, J= 1.68Hz). 109 d6- δ: 1.28 (3H,t,J= 6.93Hz), 2.36-2.40 (1H, m), 2.59-2.63 (1H, m), 2.73- DMSO 2.79 (1H, m), 3.00-3.03 (1H, m), 3.19-3.27 (1H, m), 3.91-3.97 (4H, m), 4.28-4.36 (2H, m), .54 (2H,m), 6.68 (2H, d, J= 8.52Hz), 6.84 (2H, d, J= 8.68Hz), 7.19-7.24 , 7.38 (2H, d, J = 8.07Hz), 8.35 (3H,s, br), 8.59-8.63 (2H, m). 110 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.47 (3H, s), 2.49-2.50 (1H, m), 2.59-2.63 DMSO (1H, m), 2.69-2.74 (1H, m), 3.02-3.07 (1H,m), 3.91-3.95 (4H, m), 4.28- 4.37 (2H, m), 4.57-4.66 (2H,m), 4.79-4.80 (2H,m), 6.74 (2H, d, J= 8.52Hz), 7.14 (2H, d, J= 8.68Hz), 7.16-7.23 (6H, m), 7.38 (2H, d, J = 8.07Hz), 7.55 (2H, d, J= 7.84Hz), 8.40 (2H,s, br), 8.63-8.67 (1H, m), 8.91 (1H, d, J= 1.68Hz). 111 d6- δ: 1.27 (3H, t, J= 6.93Hz), 2.30 (3H, s), 2.59 (3H, s), 2.61-2.72 (2H, DMSO m), 2.79-2.84 (1H, m), 3.04-3.09 (1H,m), 3.91-3.96 (4H, m), 4.29-4.35 (2H, m), 4.50-4.60 (2H, m), 6.73 (2H, d, J= 8.52Hz), 7.03 (2H, d, J= 8.68Hz), 7.15-7.27 (7H, m), 7.39 (2H, d, J = 8.07Hz), 8.07 (1H, d, J= 7.84Hz), 8.42 (2H,s, br), 8.62-8.66 (2H, m). 112 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.66 (3H, s), 2.77-2.84 (3H, m), 3.03-3.08 DMSO (1H, m), 3.87-3.97 (4H, m), 4.28 (2H, d), .55 (1H, m), .75 (1H, m), 6.61 (2H, d, J= 8.52Hz), 6.67 (2H, d, J= 8.68Hz), 7.19-7.30 (7H, m), 7.38 (2H, d, J = 8.07Hz), 7.89 (1H, d, J= 7.84Hz), 8.06 (1H, s), 8.41 (2H,s, br), 8.65-8.70 (2H, m). 113 d6- δ: 1.27 (3H, t, J= 6.93Hz), 2.36 (3H, s), 2.45 (3H, s), 2.63-2.68 (1H, DMSO m), 2.75-2.84 (2H, m), 3.04-3.08 (1H,m), 3.88-3.96 (4H, m), 4.29 (2H, d), .54 (1H, m), 4.64-4.69 (1H, m), 6.62 (2H, d, J= ), 6.65 (2H, d, J= 8.68Hz), 7.17-7.24 (6H, m), 7.39 (2H, d, J = 8.07Hz), 7.54 (1H, d, J= ), 8.40 (3H,s, br), 8.64-8.66 (2H, m). 114 d6- δ: 1.26 (3H, t, J= 7.07Hz), 2.09 (3H, s), 2.67-2.77 (2H, m), 2.78—2.88 DMSO (1H, m), 3.05-3.09 (1H, m), 3.92-3.97 (4H, m), 4.31-4.40 (2H, m), 4.59- 4.63 (1H, m), 4.64-4.74 (1H, m), 6.77 (2H, d, J= ), 7.17-7.29 (10H, m), 7.39 (2H, d, J = 8.36Hz), 7.87 (1H, d, J= 8.55Hz), 8.26-8.36 (4H, m), 8.62 (1H, s), 8.68-8.71 (2H, m), 8.88-8.95 (1H, m). 115 d6- δ: 1.26 (3H, t, J= 6.36Hz), 2.66-2.87 (3H, m), 3.05-3.10 (1H,m), 3.92- DMSO 3.97 (4H, m), 4.31-4.38 (2H, m), 4.38-4.40 (2H, m), 4.59-4.63 (1H,m), 4.69-4.75 (1H,m), 6.77 (2H, d, J= 7.95Hz), 7.14 (2H, d, J= 7.95Hz), 7.16-7.23 (6H, m), 7.38 (2H, d, J = 7.82Hz), 7.55 (2H, d, J= 7.95Hz), 7.74 (1H, d, J= 11.13Hz), 8.40 (3H,s, br), 8.63-8.67 (1H, m), 8.91 (1H, d, J= ), 9.05 (1H, J = 8.68Hz), 9.20 (1H, d, J = 2.2Hz). 116 d6- δ: 1.28(3H, t, J= 6.57Hz), 2.61-2.67 (1H, m), 2.79-2.85 (2H, m), DMSO 3.08-3.12 , 3.92-3.98 (4H, m), 4.31 (2H, d, J = 6.57Hz), 4.53- 4.58 (1H,m), 4.67-4.71 (1H, m), 6.66 (2H, d, J= 8.09Hz), 6.74 (2H, d, J= 8.23Hz), 7.14 (1H, d, J= 5.47Hz), .25 (2H, m), 7.30-7.35 (4H, m),7.39 (2H, d, J = 8.09Hz), 7.82 (1H, d, J= 7.66Hz), 7.86 (1H, d, J= ), 8.35 (3H,s, br), 8.69(1H, t, J = 6.57Hz), 8.76 (1H, d, J= 8.21Hz). 117 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.38 (3H, s), 2.62 (1H, d, J = 10.3 Hz), 2.70 DMSO (1H, dd, J = 14.3 Hz, 4.2 Hz), 2.82 (1H, dd, J = 13.5 Hz, 10.1 Hz), 3.07 (1H, dd, J = 13.6 Hz, 4.5 Hz), 3.95 (2H, q, J = 7.0 Hz), 3.98 (2H, d, J = 4.8 Hz), 4.26 - 4.37 (2H, m), 4.52 - 4.62 (2H, m), 6.75 (2H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.6 Hz), 7.18 - 7.12 (1H, m), 7.23 - 7.28 (6H, m), 7.38 (2H, d, J = 8.1 Hz), 8.21 (1H, d, J = 8.3 Hz), 8.26 (2H, br.s), 8.62 (2H, d, J = 7.6 Hz), 9.01 (1H, s) 118 d6- δ: 1.27 (3H, t, J = 7.0 Hz), 2.64 - 2.67 (2H, m), 2.81(1H, dd, J = 13.5 DMSO Hz, 10.1 Hz), 3.04 (1H, dd, J = 13.5, 4.6 Hz), 3.93 (2H, q, J = 7.0 Hz), 3.97 (2H, d, J = 5.4 Hz), 4.30 (2H, dd, J = 5.5 Hz, 3.5 Hz), 4.54 - 4.63 (2H, m), 6.60 (1H, dd, J = 3.5 Hz, 1.9 Hz), 6.7 (2H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.11 (1H, d, J = 3.5 Hz), 7.16 - 7.28 (7H, m), 7.38 (2H, d, J = 8.1 Hz), 7.81 (1H, d, J = 1.1 Hz), 8.18 (1H, d, J = 8.4 Hz), 8.28 (2H, br.s), 8.60 (1H, d, J = 8.6 Hz), 8.64 (1H, t, J = 6.0 Hz) 119 d6- δ: 1.28 (3H, t, J = 6.9 Hz), 2.22 (3H, s), 2.65 (1H, dd, J = 13.6 Hz, 9.3 DMSO Hz), 2.72 (1H, dd, J = 13.8 Hz, 4.2 Hz), 2.82 (1H, dd, J = 13.5 Hz, 10.2 Hz), 3.08 (1H, dd, J = 13.5 Hz, 4.5 Hz), 3.94 (2H, q, J = 7.0 Hz), 3.98 (2H, br.s), 4.31 (2H, d, J = 5.8 Hz), 4.52 - 4.59 (2H, m), 6.73 (2H, d, J = 8.6 Hz), 6.91(1H, d, J = 5.0 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.18 - 7.21 (1H, m), 7.23 - 7.30 (6H, m), 7.38 (2H, d, J = 7.9 Hz), 7.55 (1H, d, J = .0 Hz), 7.72 (1H, d, J = 7.8 Hz), 8.23 (2H, br.s), 8.62 (2H, d, J = 9.6 120 d6- δ: 1.27(3H,t,J= 7.0Hz), 2.70-2.75(1H,m), 2.80-2.86(2H,m), 3.07- DMSO 3.11(1H,m), 3.88(3H,s), 3.92(2H,q,J= 6.9Hz), 3.97(2H,q,J= 5.7Hz), 4.31(2H,d,J= , 4.52-4.58(1H,m), 4.67-4.72(1H,m), 6.65(2H,d,J= 8.6Hz), 6.76(2H,d,J= 8.4Hz), 7.02-7.04(1H,m), 7.21-7.34(7H,m), 7.37(2H,d,J= 8.1Hz), 7.53-7.55(1H,m), 7.85-7.88(1H,m), 8.23(2H,s), 8.27(1H,d,J= 8.1Hz), 8.67(1H,t,J= 5.9Hz), 8.71(1H,d,J= 8.4Hz). 121 d6- δ: 1.28(3H,t,J= 6.9Hz), 2.66-2.75(2H,m), 2.80-2.86(1H,m), 3.03- DMSO 3.08(1H,m), 3.87(3H,s), 3.91-4.00(4H,m), 4.30-4.38(2H,m), 4.59- 4.68(2H,m), 6.77(2H,d,J= 8.6Hz), 7.16(1H,s), 7.18-7.21(2H,m), 7.23- 7.27(6H,m), H,d,J= 8.2Hz), H,t,J= 4.2Hz), 8.24(2H,s), 8.44(1H,d,J= 2.9Hz), 8.51(1H,d,J= 1.6Hz),, 8.62-8.64(2H,m), 8.79(1H,d,J= 8.4Hz). 122 d6- δ: 1.29(3H,t,J= 7.0Hz), .62(1H,m), 2.73-2.84(2H,m), 3.07- DMSO 3.11(1H,m), 3.89(3H,s), 3.94(2H,q,J= 7.0Hz), 3.98(2H,s), 4.30(2H,d,J= 6.0Hz), 4.55(1H,m), 4.65-4.70(1H,m), H,s), 7.11(1H,d,J= 5.4Hz), 7.20-7.25(3H,m), .35(4H,m), 7.37(2H,d,J= 8.1Hz), 7.47(1H,d,J= 7.4Hz), 7.72(1H,d,J= 5.5Hz), H,s), 8.63(1H,t,J= 6.0Hz), 8.67(1H,d,J= 8.5Hz). 123 d6- δ: 1.28(3H,t,J= 7.0Hz), 2.58-2.70(2H,m), 2.79-2.85(1H,m), 3.03- DMSO 3.08(1H,m), 3.87(3H,s), 3.93(2H,q,J= 7.0Hz), 3.99(2H,q,J= 5.5Hz), 4.26-4.38(2H,m), 4.59-4.65(2H,m), 6.76(2H,d,J= 8.6Hz), 7.08(1H,s), 7.15(2H,d,J= 8.3Hz), 7.18-7.27(8H,m), 7.36(2H,d,J= 8.0Hz), 8.19(2H,s), 8.25(1H,d,J= 5.2Hz), 8.59-8.62(2H,m), H,d,J= 8.1Hz). 124 d6- δ: 1.28(3H, t, J= 6.84Hz), 2.13 (3H, s), 2.56-2.59 (1H, m), .74 DMSO (1H, m), 2.78-2.84 (1H, m), 3.05-3.10 (1H,m), 3.91-4.00 (4H, m), 4.30 (2H, d, J = 5.82Hz), 4.52-4.64 (2H,m), 5.91 (1H, s) 6.71 (2H, d, J= 8.66Hz), 6.77 (1H, t, J= ), 6.92 (2H, d, J= 7.78Hz), 7.18-7.28 (8H, m), 7.34 (2H, d, J = 8.49Hz), 8.09 (3H,s, br), 8.60-8.64(2H, m). 125 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.67 - 2.69 (2H, m), 2.82 (1H, dd, J = 13.5 DMSO Hz, 10.0 Hz), 3.05 (1H, dd, J = 13.6 Hz, 6.4 Hz), 3.93 (2H, q, J = 7.0 Hz), 3.97 (2H, d, J = 5.6 Hz), 4.31 (2H, d, J = 5.8 Hz), 4.47 - 4.57 (2H, m), 6.57 (1H, d, J = 5.4 Hz), 6.71 (2H, d, J = 8.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.18 - 7.27 (10H m), 7.38 (2H, d, J = 6.0 Hz), 7.40 (1H, d, J = 3.1 Hz), 8.28 (2H, br.s), 8.51 (1H, d, J = 8.5 Hz), 8.61 (1H, t, J = 6.0 126 d6- δ: .85(2H,m), 1.02-1.12(4H,m), 1.22-1.32(1H,m), 1.41- DMSO 1.48(1H,m), 1.53-1.62(5H,m), 2.76-2.82(1H,m), 3.09-3.13(1H,m), 3.95(2H,s), 4.28-4.35(2H,m), 4.37-4.43(1H,m), 4.46-4.52(1H,m), 7.15- H,m), 7.34-7.37(2H,m), .46(2H,m), 7.48-7.54(1H,m), 7.80- 7.83(2H,m), 8.21(2H,s), 8.51(2H,d,J= 7.8Hz), 8.59(1H,t,J= 6.1Hz). 127 d6- δ: 2.62-2.69 (2H, m), 2.71-2.77 (1H, m), 2.96-3.01(1H, m), 3.87 (2H, d, DMSO J= 4.56Hz), 4.22-4.25 (2H, m), 4.49-4.61 (2H,m), 7.10-7.22 (10H, m), 7.30-7.36 (4H, m), 7.40-7.48 (1H, m), 7.67 (2H, d, J = 6.61Hz), 8.30 (3H,s, br), 8.47 (1H, d, J= 8.82Hz), 8.56-8.62 (2H, m). 128 d6- δ: 2.70 (2H, d, J = 7.21Hz), 2.78-2.85 (1H, m), 3.03-3.07 (1H, m), 3.95 DMSO (2H, d, J= 8.78Hz), 4.27-4.36 (2H, m), 4.55-4.63 (2H,m), 6.84 (2H, d, J= ), 7.05-7.29 (12H, m), 7.37-7.44 (6H, m), 7.74 (2H, d, J= 7.52Hz), 8.34 (3H,s, br), 8.50 (1H, d, J= ), 8.58 (1H, d, J= 8.77Hz), 8.63-8.66 (2H, m). 129 d6- δ: 2.61-2.63 (2H, m), 2.70-2.77 (1H, m), 2.95-3.00 (1H, m), 3.88 (2H, d, DMSO J= 6.26Hz), 4.18-4.29 (2H, m), 4.47-4.54 (2H,m), 4.91 (1H, s), 6.76 (2H, d, J= 8.18Hz), 7.07-7.18 (9H, m), 7.26-7.36 (4H, m), 7.66-7.68 (2H, m), 8.24 (3H,s, br), 8.42 (1H, d, J= 8.17Hz), 8.50 (1H, d, J= 8.02Hz), 8.53-8.58 (1H, m). 130 d6- δ: 2.65 (2H, d, J = 5.97Hz), 2.79-2.85 (1H, m), 3.03-3.06 (1H, m), 3.95 DMSO (2H, s), 4.31 (2H, s), 4.55 (2H, s, br), 6.58 (2H, d, J= 7.55Hz), 7.01 (2H, d, J= 7.12Hz), 7.18-7.24 (10H, m), .50 (7H, m), 7.74 (2H, d, J= 7.10Hz), 8.32 (3H,s, br), 8.46 (1H, d, J= 9.60Hz), 8.53 (1H, d, J= 9.60Hz), 8.61 (1H, s). 131 d6- δ: 1.43 (3H, t, J= ), 2.88 (2H, d, J= 6.67Hz), 2.95-3.06 (2H, m), DMSO 3.14-3.23 (2H, m), 4.06-4.12 (2H, m), 4.39-4.49 (2H, m), 4.75-4.78 (2H, m), 6.91 (2H, d, J= 8.95Hz), 7.31 (2H, m), 7.37-7.46 (9H, m), 7.54-7.67 (5H, m), 7.89-7.98 (2H, m), 8.46 (2H, s, br), 8.65-8.81 (3H, 132 d6- δ: 2.68 (2H, d, J = 7.36Hz), 2.79-2.98 (1H, m), 3.03-3.06 (1H, m), 3.96 DMSO (2H, s), 4.21-4.32 (2H, m), 4.59-4.61 (2H,m), 5.00 (2H, s), 6.84 (2H, d, J= 8.15Hz), 7.14-7.24 (12H, m), 7.35-7.40 (5H, m), 7.67-7.76 (2H, m), 7.82-7.88 (2H, m), 8.24 (1H,s, br), 8.47-8.64 (4H, m). 133 d6- δ: 0.81(3H,d,J= 6.3Hz), 0.87(3H,d,J= 6.3Hz), 1.27-1.39(2H,m), 1.45- DMSO 1.52(1H,m), 2.81-2.87(1H,m), .24(1H,m), 4.02(2H,s), 4.35- 4.44(3H,m), 4.52-4.58(1H,m), 7.22-7.35(7H,m), 7.43(2H,d,J= 8.1Hz), 7.48-7.52(2H,m), 7.58-7.64(1H,m), .89(2H,m), H,s), 8.59- 8.69(3H,m). 134 d6- δ: 2.70 (2H, d, J = 7.36Hz), 2.78-2.84 (1H, m), 3.03-3.06 (1H, m), 3.97 DMSO (2H, s), 4.11-4.34 (2H, m), 4.59-4.63 (2H,m), 5.14 (2H, s), 6.90 (2H, d, J= 8.21Hz), .30 (11H, m), 7.36-7.54 (5H, m), 7.67-7.75 (2H, m), 7.80-7.88 (2H, m), 8.47-8.58 (4H, m). 135 d6- δ: 2.20 (3H, s), 2.71 (2H, d, J = 7.81Hz), 2.79-2.85 (1H, m), 3.03- DMSO 3.07(1H,m), 3.93-3.96 (2H, m), 4.25-4.36 (2H, m), 4.55-4.65 (2H,m), 7.00 (2H, d, J= 9.01Hz), 7.12 (2H, d, J= 7.78Hz), 7.18 (2H, d, J= 7.79Hz), 7.22-7.24 (4H, m), 7.38 (2H, d, J= 6.49Hz), 7.42 (2H, d, J= 7.79Hz), .50 (1H, m), 7.74-7.76 (2H,m), 8.33 (3H,s, br), 8.51 (1H, d, J= ), 8.58 (1H, d, J= 7.79Hz), 8.62-8.65 (1H, m). 136 d6- δ: 2.70 (2H, d, J = 7.28Hz), .85 (1H, m), .08 (1H, m), 3.95 DMSO (2H, s), 4.27-4.36 (2H, m), 4.58-4.62 (2H,m), 5.03 (2H, s), 6.85 (2H, d, J= 8.21Hz), 7.15-7.24 (11H, m), .52 (5H, m), 7.56-7.61 (1H, m), 7.75 (2H, d, J = 8.22Hz), 8.34 (3H, s, br), 8.50(1H, d, J= 7.02Hz), H, d, J= 9.38Hz), 8.62-8.65 (1H, m). 137 d6- δ: 2.66-2.69 (2H, m), 2.81 (1H, dd, J = 13.5, 10.0Hz), 3.05 (1H, dd, J = DMSO 13.6, , 3.69 (2H, s), 3.77 (3H, s), 4.23-4.33 (2H, m), 4.58-4.67 (2H, m), 6.68 (1H, d, J = 8.5Hz), 7.07-7.25 (11H, m), 7.43 (2H, t, J = 7.3Hz), 7.49-7.55 (2H, m), 7.75 (2H, d, J = 7.2Hz), 8.00 (1H, d, J = 1.8Hz),8.49-8.57 (3H, m). 138 d6- δ: 2.69-2.71 (1H, m), 2.79-2.85 (1H, m), 3.03-3.07(1H,m), 3.67 (3H, s), DMSO 3.96 (2H, s), 4.26-4.32 (2H, m), 4.55-4.63 (2H,m), 6.76 (2H, d, J= 8.52Hz), 7.14-7.25 (9H, m), 7.36-7.44 (4H, m), 7.48-7.52 (1H,m), 7.74-7.76 (2H,m), 8.29 (3H,s, br), 8.56 (1H, d, J= 1.68Hz), 8.613-8.64 (2H, m). 139 d6- δ: 2.82-2.85 (3H, m), 3.03-3.08 (1H,m), 3.93-3.98 (2H, m), 4.26-4.31 DMSO (2H, m), 4.56-4.69 (2H,m), 7.11-7.26 (12H, m), 7.37-7.43 (4H, m), 7.48-7.51 (1H,m), 7.73-7.75 (2H,m), 8.32 (3H,s, br), 8.53-8.65 (2H, m). 140 d6- δ: 1.09 (3H, t, J = 7.0Hz), 2.50-2.66 (2H, m), 3.05 (1H, dd, J = 13.4, DMSO 10.4Hz), 3.26-3.32 (1H, m), 3.45-3.54 (2H, m), 3.74 (2H, q, J = , 4.09-4.15 (2H, m), .38 (1H, m), 4.65-4.71 (1H, m), 6.57 (2H, d, J = 8.6Hz), 7.00 (2H, d, J = 8.5Hz), 7.09 (2H, d, J = 8.0Hz), 7.16-7.35 (5H, m), 7.53-7.58 (4H, m), 7.95-8.20 (3H, br m), 8.48-8.56 (3H, m), 8.64 (1H, d, J = . 141 d6- δ: 1.26(3H,t,J= 7.0Hz), 2.65-2.84(3H,m), 3.03-3.08(1H,m), DMSO 3.92(2H,q,J= 7.0Hz), 3.96(2H,s), 4.27-4.35(2H,m), 4.57-4.63(2H,m), H,d,J= 8.7Hz), 7.16(2H,d,J= 8.6Hz), 7.23(1H,dd,J= 8.3,1.7Hz), 7.27(2H,d,J= 8.1Hz), 7.37-7.51(6H,m), 7.55(1H,d,J= 1.8Hz), 7.73- 7.75(2H,m), 8.24(2H,s), 8.50(1H,d,J= 8.1Hz), 8.67-8.71(2H,m). 142 d6- δ: 1.26(3H,t,J= 6.9Hz), 2.67-2.83(3H,m), 3.01-3.05(1H,m), 3.89- DMSO 3.95(4H,m), 4.27-4.35(2H,m), 4.53-4.63(2H,m), 6.75(2H,d,J= 8.5Hz), 7.14(2H,d,J= 8.5Hz), 7.20-7.26(5H,m), 7.37-7.44(4H,m), 7.50(1H,t,J= 7.3Hz), 7.66-7.72(1H,m), 7.75(2H,d,J= 7.4Hz), 8.31(2H,s), 8.53(1H,d,J= 8.1Hz), 8.62(1H,d,J= 8.7Hz), 8.69(1H,t,J= 5.9Hz). 143 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.70 (2H, d, J= 7.52Hz), 2.89-2.95 (1H, m), DMSO 3.12-3.17 (1H, m), 3.89-3.94 (2H, m), 3.95 (2H, s), 4.31 (2H, d, , J= .38Hz), 4.56-4.66 (2H,m), 6.74 (2H, d, J= 8.52Hz), 7.12 (2H, d, J= ), 7.26 (2H, d, J= 9.72Hz), 7.38-7.44 (5H, m), 7.50-7.54 (3H, m), 7.75 (2H, d, J = ), 8.34 (3H, s, br), 8.51 (1H, d, J= 8.32Hz), 8.62 (1H, d, J= 8.32Hz), 8.68-8.71 (1H, m). 144 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.65 (2H, d, J= 6.98Hz), 2.89-2.95 (1H, m), DMSO 3.16-3.21 (1H, m), 3.91-3.96 (2H, m), 4.32 (2H, J= 5.82Hz), 4.57-4.66 (2H, m), 6.73 (2H, d, J= 8.54Hz), 7.13 (2H, d, J= 9.08Hz), 7.27 (2H, d, J= 8.01Hz), .44 (8H, m), 7.50-7.57 (1H, m), 7.68-7.71 (1H, m), 7.73-7.75 (2H, m), 8.44-8.50 (4H, m), .76 (2H, m). 145 d6- δ: 1.26 (3H, t, J = 7.0Hz), 2.64 (2H, d, J = 7.2Hz), 2.82 (1H, dd, J = DMSO 13.5, 10.3Hz), 3.07 (1H, dd, J = 13.6, 4.2Hz), 3.81 (2H, s), 3.92 (2H, q, J = 7.0Hz), .35 (2H, m), .65 (2H, m), 5.70-6.60 (2H, br s), 6.75 (2H, d, J = 8.6Hz), 7.14-7.34 (7H, m), .51 (3H, m), 7.62 (1H, d, J = 7.7Hz), 7.73 (2H, d, J = 7.2Hz), 8.39 (1H, dd, J = 4.8, 1.4Hz), 8.46 (1H, d, J = 1.6Hz), 8.52 (1H, d, J = 8.0Hz), 8.62 (1H, t, J = 6.0Hz), 8.68 (1H, d, J = 8.8Hz). 146 d6- δ: 1.26(3H,t,J= 7.0Hz), 2.69-2.77(3H,m), 2.94-2.99(1H,m), 3.65(3H,s), DMSO 3.92(2H,q,J= , 3.96(2H,s), 4.25-4.35(2H,m), 4.49-4.54(1H,m), 4.57-4.63(1H,m), H,dd,J= 8.6,1.7Hz), 7.13-7.18(4H,m), 7.25(2H,d,J= , 7.36(2H,d,J= 8.1Hz), 7.40-7.44(2H,m),7.48- 7.52(1H,m), 7.72-7.75(2H,m), 8.19(2H,s), 8.48-8.53(2H,m), 8.62(1H,t,J= 6.0Hz). 147 d6- δ: 1.26 (3H, t, J = 7.0 Hz), 2.69 (2H, d, J = 7.2 Hz), 2.83 (1H, dd J = DMSO 13.6, 10.0 Hz), 3.06 (1H, dd, J = 13.7, 4.5 Hz), 3.87 (2H,s), 3.92 (2H, q, J = 7.0 Hz), 4.26-4.31(2H, m), 4.55-4.60 (1H, m), 4.62-4.67 (1H, m), 6.51-6.79 (1H, m), 6.75 (2H, d, J = 8.6Hz), 7.13-7.19 (3H, m), 7.20- 7.22 (4H, m), 7.31 (1H, d, J = 8.1Hz), 7.40-7.44 (3H, m), 7.45-7.52 (1H, m), 7.71-7.75 (2H, m), 8.36-8.39 (2H, m), .61 (3H, m). 148 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.70 (2H, d, J= 7.09Hz), 2.89-2.95 (1H, m), DMSO 3.12-3.17 (1H, m), 3.89-3.94 (2H, m), 3.95 (2H, s), 4.31-4.32 (2H, m), 4.56-4.66 (2H,m), 6.74 (2H, d, J= 7.19Hz), 7.12 (2H, d, J= 8.40Hz), 7.26 (2H, d, J= 8.40Hz), 7.38-7.44 (5H, m), 7.50-7.54 (3H, m), 7.74- 7.76 (2H, m), 8.35 (3H, s, br), 8.51 (1H, d, J= , 8.62 (1H, d, J= 8.40Hz), 8.68-8.71 (1H, m). 149 d6- δ: 1.26 (3H, t, J= 6.93Hz), 2.67-2.69 (2H, m), .87 (1H, m), 3.06- DMSO 3.10 (1H,m), 3.59 (2H, s, br), 3.89-3.98 (4H, m), 4.22-4.33 (2H, m), 4.57-4.62 , 6.74 (2H, d, J= 8.52Hz), 7.13-7.16 (7H, m), 7.22- 7.27 (2H,m), 7.35-7.41 (3H,m), 7.43-7.51 (1H, m), 7.72-7.81 (2H,m), 8.29-8.32 (1H,m), 8.48-8.53 (1H, m), 8.54-8.64 (1H, m). 150 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.80 - 2.87 (2H, m), 3.07 (1H, dd, J = 14.7, DMSO 9.4 Hz), 3.27 (2H, dd, J = 14.8, 4.3 Hz), 3.32 (2H, br.s), 3.69 (1H, s), 3.94 (2H, q, J = 6.9 Hz), 4.27 - 4.30 (2H, m), 4.53 - 4.58 (1H, m), 4.60 - 4.66 (1H, m), 6.78 (2H, d, J = 8.6 Hz), 6.86 - 6.90 (2H, m), 7.12 - 7.24 (6H, m), 7.31 (1H, d, J = 5.0 Hz), 7.42 (2H, t, J = 7.4 Hz), 7.50 (1H, q, J = 7.3 Hz), 7.73 (2H, d, J = 7.1 Hz), 8.51 (1H, t, J = 5.5 Hz), 8.57 (2H, 151 d6- δ: 1.28 (3H, t, J = 6.9 Hz), 2.77 (2H, br.s), 2.89 (1H, dd, J = 14.1, 9.8 DMSO Hz), 3.07 (1H, dd, J = 14.1, 4.4 Hz), 3.33 (3H, br.s), 3.65 (1H, br.s), 3.94 (2H, q, J = 6.9 Hz), 4.28 (2H, t, J = 5.8 Hz), 4.52 - 4.58 (1H, m), 4.60 - 4.65 (1H, m), 6.78 (2H, d, J = 8.5 Hz), 6.98 (1H, d, J = 4.6 Hz), 7.15 (3H, br.s), 7.18 - 7.23 (4H, m), 7.38 - 7.41 (1H, m), 7.44 (2H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.2 Hz), 7.75 (2H, d, J = 7.2 Hz), 8.50 (1H, br.s), 8.57 (2H, d, J = 6.2 Hz) 152 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.67 (1H, t, J = 1.6 Hz), 2.77 (1H, d, J = 7.3 DMSO Hz), 3.06 (1H, dd, J = 14.5 Hz, 9.7 Hz), 3.23 (1H, dd, J = 14.6 Hz, 4.7 Hz), 3.94 (2H, q, J = 7.0 Hz), 3.96 - 3.99 (2H, m), 4.31(2H, t, J = 5.7 Hz), 4.58 (1H, q, J = 7.5 Hz), 4.70 (1H, td, J = 9.1 Hz, 4.6 Hz), 6.77 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.26 (1H, d, J = 1.5 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.43 (2H, t, J = 7.5 Hz), 7.52 (1H, t, J = 7.4 Hz), 7.42 (2H, d, J = 7.1 Hz), 8.05 (2H, br.s), 8.55 (2H, d, J = 7.6 Hz), 8.59 (1H, d, J = 8.6 Hz), 8.95 (1H, d, J = 1.8 153 d6- δ: 1.27 (3H, t, J = 7.0 Hz), 2.66 - 2.72 (3H, m), 3.10 (1H, dd, J = 14.4 DMSO Hz, 9.8 Hz), 3.91 (2H, q, J = 7.0 Hz), 3.98 (2H, d, J = 5.2 Hz), 4.33 (2H, qd, J = 14.5 Hz, 6.0 Hz), 4.61 (1H, td, J = 8.7 Hz, 4.9 Hz), 4.72 (1H, td, J = 9.1 Hz, 4.7 Hz), 6.71 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.35 (3H, d, J = 7.7 Hz), 7.38 - 7.40 (2H, m), 7.42 (2H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.4 Hz), 7.73 (2H, d, J = 7.2 Hz), 7.97 (2H, d, J = 8.0 Hz), 8.06 (2H, br.s), 8.45 (1H, d, J = 7.8 Hz), 8.66 - 8.72 (2H, m) 154 d6- δ: 1.26(3H,t,J= 7.0Hz), 2.70(2H,d,J= 7.3Hz), 2.79-2.85(1H,m), 3.03- DMSO 3.08(1H,m), H,q,J= 7.0Hz), 4.00(2H,s), 4.27-4.39(2H,m), 4.54- 4.62(2H,m), 6.75(2H,d,J= 8.6Hz), 7.07-7.25(9H,m), 7.41-7.52(4H,m), 7.70-7.74(2H,m), 8.26(2H,s), 8.49(1H,d,J= 8.1Hz), 8.58(1H,d,J= 8.6Hz), 8.66(1H,t,J= 6.0Hz). 155 d6- δ: 1.26(3H,t,J= 6.9Hz), 2.72(2H,d,J= 7.2Hz), 2.80-2.86(1H,m), 3.03- DMSO 3.08(1H,m), 3.92(2H,q,J= 6.9Hz), 4.06(2H,s), 4.26-4.37(2H,m), 4.53- 4.62(2H,m), 6.74(2H,d,J= 8.5Hz), 7.13(2H,d,J= 8.5Hz), 7.15- 7.23(6H,m), .43(3H,m), 7.48-7.53(2H,m), 7.75(2H,d,J= 7.3Hz), 8.49(2H,s), 8.52(1H,d,J= 8.2Hz), 8.59(1H,d,J= 8.5Hz), 8.71(1H,t,J= 5.9Hz). 156 d6- δ: 1.26(3H,t,J= 7.0Hz), 2.70(2H,d,J= 7.2Hz), 2.79-2.85(1H,m), 3.03- DMSO 3.07(1H,m), H,q,J= 7.0Hz), 4.11(2H,s), 4.33-4.46(2H,m), 4.54- 4.62(2H,m), 6.74(2H,d,J= 8.6Hz), H,d,J= , 7.16- H,m), 7.39-7.43(2H,m), 7.47-7.56(2H,m), 7.67-7.74(4H,m), 8.48(1H,d,J= 8.0Hz), H,d,J= 8.5Hz), 8.75(1H,t,J= 6.0Hz). 157 d6- δ: 1.27(3H,t,J= 7.0Hz), .86(1H,m), 2.93-2.97(1H,m), 3.06- DMSO H,m), .29(1H,m), 3.90-3.99(4H,m), 4.30(2H,d,J= 5.8Hz), 4.50-4.56(2H,m), .83(2H,m), 6.69(2H,d,J= 8.6Hz), 6.86(2H,d,J= 8.6Hz), 6.91-6.94(2H,m), 7.23(2H,d,J= 8.1Hz), 7.35-7.38(3H,m), 7.60- 7.63(1H,m), 7.96-8.00(2H,m), 8.20(2H,s), 8.56(1H,d,J= 8.3Hz), 8.63(1H,d,J= 4.8Hz), 8.67(1H,d,J= 6.0Hz), H,d,J= 8.3Hz). 158 d6- δ: 1.28 (3H, t, J = 6.9 Hz), 2.74 (2H, d, J = 7.2 Hz), 3.02 (2H, dd, J = DMSO 13.9 Hz, 9.4 Hz), 3.18 (1H, d, J = 13.9 Hz, 4.6 Hz), 3.66 (1H, s), 3.80 (3H, s), 3.93 (2H, q, J = 6.9 Hz), 4.27 (2H, d, J = 6.0 Hz), 4.52 (1H, q, J = 7.4 Hz), 4.73 - 4.79 (1H, m), 6.74 (2H, d, J = 8.6 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.2 Hz), 7.13 (2H, d, J =8.6 Hz), 7.17 - 7.21 (3H, m), 7.34 (1H, d, J = 7.8 Hz), 7.63 (1H, td, J = 7.6 Hz, 1.7 Hz), 7.7 (2H, d, J = 8.8 Hz), 8.36 (1H, d, J = 4.0 Hz), 8.41 (2H, d, J = 6.6 Hz), 8.60 (1H, d, J = 8.4 Hz) 159 d6- δ: 1.27(3H,t,J= 7.0Hz), 2.68-2.74(1H,m), 2.82-2.88(2H,m), 3.05- DMSO 3.10(1H,m), 3.90(2H,q,J= 7.0Hz), H,q,J= 5.7Hz), 4.31(2H,d,J= .9Hz), 4.50-4.55(1H,m), 4.76-4.81(1H,m), 6.59-6.65(4H,m), 7.19- 7.23(2H,m), 7.28(2H,t,J= 7.4Hz), 7.33(2H,d,J= 7.2Hz), 7.37(1H,d,J= 1.0Hz), 7.50(1H,d,J= 8.0Hz), 7.59-7.63(1H,m), 7.98- 8.02(2H,m), 8.38(2H,s), H,d,J= 8.2Hz), 8.61(1H,d,J= 4.7Hz), 8.71-8.74(2H,m). 160 d6- δ: 1.28 (3H, t, J = 7.66Hz), 2.70 (2H, d, J = 7.60Hz), 2.94-3.00 (1H, m), DMSO 3.21-3.24 (1H, m), 3.80 (3H, s), 3.92-4.00 (4H, m), 4.33 (2H, d, J= ), 4.52 (1H, q, J = 7.45Hz), 4.66-4.69 (2H, m), 6.75 (2H, d, J = 7.79Hz), 6.96 (2H, d, J = 8.68Hz), 7.17 (2H, d, J = 8.45Hz), 7.27 (2H, d, J = 7.82Hz), 7.38 (2H, d, J = 7.82Hz), 7.67 (1H, s, br), 7.74 (1H, d, J = 9.03Hz), 8.11 (1H, s, br), 8.22 (2H, s, br), 8.45 (1H, d, J = 8.34Hz), 8.68-8.69 (4H, m). 161 d6- δ: 1.28 (3H, t, J= 6.94Hz), 2.62-2.84 (3H, m), 2.96-3.07 (1H, m), 3.90- DMSO 4.02 (4H, m), 4.32 (2H, d, J= 5.8Hz), 4.60-4.67 (2H, m), 6.77(2H, d, J = 8.88Hz), 7.16 – 7.22 (1H, m), 7.26 (2H, d, J= 8.32Hz), 7.29-7.35(5H, m), 7.36 (2H, d, J= 8.32Hz), 7.64 (1H, d, J= 6.53Hz), 8.08 (3H,s, br), 8.58-8.71(3H, m), 8.82 (1H, d, J= 7.71Hz). 162 d6- δ: 1.27 (3H, t, J = 7.0 Hz), 2.61 (2H, dd, J = 14.0 Hz, 4.3 Hz), 2.86 (1H, DMSO dd, J = 13.7 Hz, 10.3 Hz), 3.10 (1H, dd, J = 13.7 Hz, 4.5 Hz), 3.93 (2H, q, J = 7.0 Hz), 3.98 - 4.00 (2H, m), 4.3 (2H, d, J = 5.8 Hz), 4.56 (1H, td, J = 9.0 Hz, 5.0 Hz), 4.66 (1H, td, J = 9.0 Hz, 4.8 Hz), 6.75 (2H, d, J = 8.6 Hz), 7.12 (1H, dd J = 4.9, 3.7 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.36 (3H, d, J = 8.1 Hz), 7.72 (1H, dd, J = 5.0 Hz, 0.7 Hz), 7.76 (1H, br.s), 7.81 (1H, d, J = 3.2 Hz), 8.07 (2H, br.s), 8.47 - 8.55 (3H, m), 8.64 (2H, t, J = 9.0 Hz) 163 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.67 - 2.75 (2H, m), 3.03 (2H, dd, J = 13.8 DMSO Hz, 9.5 Hz), 3.21 (2H, dd, J = 14.0 Hz, 4.7 Hz), 3.93 (2H, q, J = 7.0 Hz), 3.99 (2H, q, J = 5.8 Hz), 4.20 - 4.40 (3H, m), 4.53 - 4.58 (1H, m), 4.77 - 4.83 (1H, m), 6.75 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.1Hz), 7.34 (2H, d, J = 8.2 Hz), 7.52 (2H, d, J =8.6 Hz), 7.76 (2H, d, J = 8.6 Hz), 8.07 (2H, br.s), 8.44 (1H, d, J = 4.5 Hz), 8.53 (1H, br.s), 8.66 (2H, d, J = 7.6 Hz) 164 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.34 (3H, s), 2.74 (2H, d, J = 8.2 Hz), 3.05 DMSO (1H, dd, J = 13.9, 9.5 Hz), 3.23 (1H, dd, J = 14.0, 4.7 Hz), 3.93 (2H, q, J = 7.0 Hz), 3.99 (2H, q, J = 5.8 Hz), 4.26 - 4.36 (2H, m), 4.54 (1H, dd, J = 14.5, 7.7 Hz), 4.79 (1H, td, J = 8.9 Hz, 4.8 Hz), 6.75 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.24 (4H, d, J = 8.0 Hz), 7.30 (1H, br.s), 7.34 (3H, d, J = 8.0 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.76 (1H, br.s), 8.09 (2H, br.s), 8.45 (2H, t, J = 6.0 Hz), 8.54 (1H, t, J = 6.0 Hz), 8.64 (1H, d, J = 8.3 Hz) 165 d6- δ: 1.28(3H,t,J= , 2.71-2.92(3H,m), 3.06-3.10(1H,m), DMSO 3.92(2H,q,J= 6.9Hz), 3.96-4.01(2H,m), H,d,J= 5.8Hz), 4.53- 4.59(1H,m), .80(1H,m), 6.57-6.72(4H,m), 7.27(2H,d,J= 8.0Hz), 7.30-7.33(1H,m), 7.37(2H,d,J= 8.0Hz), 7.55(1H,d,J= 8.2Hz), 7.59- 7.63(1H,m), 7.64(1H,s), 7.98-8.01(2H,m), 8.13(2H,s), 8.47(1H,d,J= 8.2Hz), 8.62(1H,d,J= 4.7Hz), 8.65-8.67(1H,m), 8.77(1H,d,J= 8.2Hz). 166 d6- δ: 0.85 (3H, t, J = 7.6 Hz), 1.30 (3H, t, J = 7.0 Hz), 2.02 (2H, q, J = 7.6 DMSO Hz), 2.63 - 2.68 (1H, m), 2.99 (2H, dd, J = 14.0 Hz, 9.6 Hz), 3.20 (1H, dd, J = 13.9, 4.8 Hz), 3.95 (2H, q, J = 7.0 Hz), 4.00 (2H, q, J = 6.0 Hz), 4.28 (2H, t, J = 7.2 Hz), 4.32 - 4.35 (1H, m), 4.74 (1H, td, J = 8.9 Hz, 4.8 Hz), 6.73 (2H, d, J = 8.6 Hz), 7.00 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 7.24 Hz), 7.36 (2H, d, J = 8.12 Hz), 7.74 (1H, br.s), 7.97 (1H, d, J = 5.2 Hz), 8.08 (2H, br.s), 8.51 (3H, d, J = 4.2 167 d6- δ: 1.27(3H,t,J= 6.9Hz), 2.65-2.89(3H,m), 3.05- DMSO 3.10(1H,m), 3.93(2H,q,J= 6.9Hz), 4.00(2H,q,J= 5.4Hz), 4.27- 4.40(2H,m), 4.58-4.70(2H,m), 6.76(2H,d,J= 8.5Hz), 7.08(1H,s), 7.11(1H,d,J= 2.8Hz), 7.16-7.29(7H,m), H,t,J= 8.0Hz), 7.95(2H,s), 8.47(2H,s), 8.72-8.78(2H,m), 8.87(2H,s), 9.19(1H,d,J= 7.7Hz). 168 d6- δ: 1.27(3H,t,J= 7.0Hz), 2.69-2.74(1H,m), 2.82-2.93(2H,m), 3.05- DMSO 3.10(1H,m), 3.90(2H,q,J= 7.0Hz), H,q,J= , 4.32(2H,d,J= 6.0Hz), 4.51-4.56(1H,m), 4.76-4.79(1H,m), .67(3H,m), 7.06- 7.09(2H,m), 7.18-7.22(2H,m), 7.28(2H,t,J= 7.4Hz), 7.33(2H,d,J= 3.8Hz), 7.46(1H,t,J= , 7.59-7.63(1H,m), 7.96- 7.99(2H,m), H,s), 8.50(1H,d,J= 8.2Hz), 8.60-8.62(1H,m), 8.71- 8.74(2H,m). 169 d6- δ: 1.26-1.30(3H,m), 2.60-2.84(3H,m), .07(1H,m), 3.93(2H,q,J= DMSO 7.0Hz), 4.00(2H,q,J= 5.4Hz), 4.32(2H,d,J= 5.8Hz), 4.56-4.66(2H,m), 6.76(2H,d,J= 8.6Hz), 7.11-7.13(1H,m), 7.16(2H,d,J= 8.5Hz), 7.23(1H,dd,J= 8.3,1.8Hz), 7.28(2H,d,J= 8.0Hz), 7.38(2H,d,J= 8.0Hz), 7.48(1H,d,J= 8.2Hz) 7.55(1H,d,J= 1.7Hz), 7.73(1H,dd,J= 5.0,0.7Hz), 7.81(1H,d,J= 3.2Hz), 8.17(2H,s), 8.53(1H,d,J= 8.3Hz), 8.63- 8.66(2H,m). 170 d6- δ: 0.84 (3H, t, J = 7.6 Hz), 1.30 (3H, t, J = 7.0 Hz), 2.00 (2H, q, J = 7.6 DMSO Hz), 2.43 - 2.47 (1H, m), 2.61 (1H, dd, J = 13.7 Hz, 4.8 Hz), 2.94 (1H, dd, J = 13.6 Hz, 10.2 Hz), 3.20 (1H, dd, J = 13.8 Hz, 4.4 Hz), 3.97 (2H, q, J = 7.0 Hz), 3.99 (2H, q, J = 5.5 Hz), 4.30 (2H, d, J = 5.6 Hz), 4.35 (1H, td, J = 8.4, 5.2 Hz), 4.62 (1H, td, J = 9.3, 4.6 Hz), 6.73 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.40 (2H, d, J = 8.1 Hz), 7.71 (1H, br.s), 8.00 (1H, d, J = 7.6 Hz), 8.12 (1H, d, J = 6.4 Hz), 8.27 (2H, br.s), 8.58 (1H, d, J = 8.4 Hz), 8.65 (1H, br.s), 8.66 (2H, br.s) 171 d6- δ: 1.28(3H,t,J= 7.0Hz), 2.62-2.68(1H,m), 2.75-2.85(2H,m), 3.03- DMSO 3.08(1H,m), 3.94(2H,q,J= , 3.97-4.02(2H,m), 4.28-4.38(2H,m), 4.63-4.67(2H,m), 6.77(2H,d,J= 8.6Hz), 7.17(2H,d,J= 8.5Hz), 7.22- 7.25(1H,m), 7.28(2H,d,J= , 7.38(2H,d,J= 8.0Hz), 7.50(1H,d,J= 8.2Hz), H,d,J= , 7.65(2H,d,J= 5.8Hz), 7.71-7.78(1H,m), 8.12(2H,s), 8.62-8.73(3H,m), H,d,J= 8.4Hz). 173 d6- δ: 1.28 (3H, t, J = 6.82Hz), 2.61-2.71 (2H, m), 2.85-2.91 (1H, m), 3.02- DMSO 3.14 (1H, m), 3.93-4.01 (4H, m), 4.32-4.34 (2H, m), 4.56-4.69 (2H, m), 6.76 (2H, d, J = 8.67Hz), 7.16 (2H, d, J = 8.67Hz), 7.26 (2H, d, J = 8.67Hz), 7.36 (2H, d, J = 7.51Hz), 7.40-7.47 (1H, m), 7.51 (2H, d, J = 8.48Hz), 7.56 (1H, d, J = 7.51Hz), 7.76 (2H, d, J = 8.09Hz), 8.12 (2H, s, br), 8.48-8.58 (2H, m), 8.62-8.68(3H, m). 174 d6- δ: 1.28(3H, t, J= 7.05Hz), 2.65-2.71 (1H, m), 2.79-2.82 (1H, DMSO m), 3.04-3.07 (1H, m), 3.28-3.31 (1H,m), 3.91-3.99 (4H, m), 4.31 (2H, s), 4.58-4.60 (1H,m), 4.74-4.75 (1H,m), 6.75 (2H, d, J= 8.13Hz), 7.14 (2H, d, J= 9.73Hz), 7.27 (2H, d, J= 8.41Hz), 7.41 (2H, d, J = 8.41Hz), 7.85-7.88 (1H, m),8.34-8.42 (4H, m), .83 (5H, m), 9.08 (1H, d, J= 8.41Hz). 175 d6- δ: 1.29 (3H, t, J = 6.75 Hz), 2.61-2.64 (1H, m), 2.78-2.83 (1H, m), 2.87- DMSO 2.93 (1H, m), 3.14-3.19 (1H, m), 3.92-4.00 (4H, m), 4.32 (2H, d, J = .78Hz), 4.60-4.65 (2H, m), 6.71 (2H, d, J = 8.18 Hz), 6.87 (2H, d J = 8.56 Hz), 7.14 (1H, d, J = 5.45 Hz), 7.26 (2H, d, J = 8.56 Hz), 7.37 (2H, d, J = 7.78 Hz), 7.49-7.52 (1H, m), 7.83-7.90 (2H, m), 8.10 (3H, s, br), 8.54 (1H, d, J = 4.69Hz), 8.60 - 8.66 (2H, m), 8.77 (1H, d, J = 8.63 Hz). 176 d6- δ: 1.27 (3H, t, J = 7.0 Hz), 2.66 - 2.77 (2H, m), 2.98 (1H, dd, J = 14.5 DMSO Hz, 9.6 Hz), 3.19 (1H, dd, J = 14.5 Hz, 4.6 Hz), 3.91 (2H, q, J = 7.0 Hz), 3.98 (2H, q, J = 5.7 Hz), 4.32 (2H, d, J = 5.9 Hz), 4.62 (2H, qd, J = 9.3 Hz, 4.6 Hz), 6.69 (2H, d, J = 8.6 Hz), 6.99 (1H, t, J = 6.9 Hz), 7.08 (3H, d, J = 8.7 Hz), 7.16 (1H, d, J = 2.1 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.33 (3H, dd, J = 8.0 Hz, 6.1 Hz), 7.42 (2H, t, J = 7.5 Hz), 7.51 (1H, t, J = 7.4 Hz), 7.66 (1H, d, J = 7.8 Hz), 7.73 (2H, d, J = 7.2 Hz), 8.06 (2H, br.s), 8.39 (1H, d, J = 7.8 Hz), 8.52 (1H, d, J = 6.5 Hz), 8.61 (1H, t, J = 4.9 Hz), 10.82 (1H, br.s) 177 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.32 - 2.34 (1H, m), 2.66 (2H, t, J = 1.7 Hz), DMSO 2.85 (1H, d, J = 7.44 Hz), 2.91 - 3.03 (1H, m), 3.17 (1H, dd, J = 15.2 Hz, 5.0 Hz), 3.94 (2H, q, J = 7.0 Hz), 3.98 - 4.00 (1H, br.m), 4.20 (1H, d, J = 6.2 Hz), 4.55 (1H, q, J = 7.4 Hz), 4.62 - 4.68 (1H, m), 6.78 (2H, d, J = 8.5 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.34 - 7.38 (2H, m), 7.44 (2H, q, J = 8.0 Hz), 7.51 - 7.56 (1H, m), 7.72 - 7.78 (2H, m), 8.08 (2H, br.s), 8.52 (1H, t, J = 6.6 Hz), 8.59 - 8.66 (2H, m), 8.97 (1H, br.s), 14.02 (1H, br.s), 14.18 (1H, br.s) 178 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.66 (1H, d, J = 11.0 Hz), 2.73 (1H, dd, J = DMSO 13.5, 3.6 Hz), 3.10 (1H, dd, J = 14.4, 9.8 Hz), 3.29 (1H, d, J = 4.9 Hz), 3.66 (2H, s), 3.92 (2H, q, J = 7.0 Hz), 4.30 (2H, qd, J = 15.2, 5.7 Hz), 4.66 (1H, td, J = 9.1, 4.4 Hz), 4.75 (1H, td, J = 9.0, 5.0 Hz), 6.73 (2H, d, J = 8.6 Hz), 7.14 (5H, dd, J = 8.3, 5.1 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.35 - 7.44 (4H, m), 7.61 (2H, dd, J = 4.5, 1.5 Hz), 7.97 (2H, t, J = 9.4 Hz), 8.62 (1H, br, s), 8.67 (2H, dd, J = 4.5, 1.5 Hz), 8.71 (1H, br,s), 8.80 (1H, br,s) 179 d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.02 (3H, s), 2.68 - 2.74 (2H, m), 2.83 (1H, DMSO dd, J = 13.6, 10.0 Hz), 3.05 (1H, dd, J = 13.5, 4.6 Hz), 3.93 (2H, q, J = 7.0 Hz), 3.98 (2H, d, J = 5.8 Hz), 4.32 (2H, qd, J = 15.3, 6.0 Hz), 4.55 - 4.64 (2H, m), 6.73 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz), 7.19 - 7.27 (7H, m), 7.38 (2H, d, J = 8.1 Hz), 7.69 (1H, d, J = 5.4 Hz), 7.85 (1H, d, J = 5.4 Hz), 8.11 (1H, d, J = 8.1 Hz), 8.22 (2H, br.s), 8.58 (1H, d, J = 8.5 Hz), 8.65 (1H, t, J = 5.7 Hz), 10.70 (1H, s) d6- δ: 1.27 (3H, t, J= 7.09Hz), 2.72-2.74 (2H, m), 2.84-2.90 (1H, m), 3.09- DMSO 3.16 (1H,m), 3.59 (2H, s, br), 3.91-3.98 (4H, m), 4.29-4.33 (2H, m), 180 4.57-4.67 (2H,m), 6.76 (2H, d, J= 8.79Hz), 7.01-7.16 (7H, m), 7.22- 7.27 (2H,m), 7.35-7.41 (3H,m), .51 (1H, m), 7.76 (2H, d, J = 7.19Hz), 8.37 (3H, s, br), 8.57 (1H, d, J = 7.97Hz), 8.64-8.69 (1H, m). d6- δ: 1.30 (3H, t, J = 7.21 Hz), 2.22 (3H, s), 2.56-2.78 (2H, m), 2.96-3.08 DMSO (1H, m), 3.23-3.28 (1H, m), 3.95-4.00 (4H, m), 4.32 (2H, d, J = .60Hz), 4.49-4.54 (1H, m), .72 (1H, m), 6.76 (2H, d, J = 8.32 181 Hz), 6.91 (1H, d J = 5.14 Hz), 7.05 (2H, d, J = 8.69Hz), 7.27 (2H, d, J = 7.90 Hz), 7.39 (2H, d, J = 8.30 Hz), 7.56 (1H, d, J = 5.14Hz), 7.72 (1H, s, br), 7.88 (1H, d, J = 7.61?Hz), 8.16 (1H, d, J = 7.61Hz ), 8.27 (3H, s, br), 8.67 - 8.74 (3H, m). d6- δ: 1.28(3H,t,J= 7.0Hz), 2.29(3H,s), 2.69(2H,d,J= 7.2Hz), 2.80- DMSO 2.86(1H,m), 3.04-3.09(1H,m), .97(4H,m), 4.24-4.34(2H,m), 4.56- 182 4.63(2H,m), 6.76(2H,d,J= 8.7Hz), 7.08-7.31(10H,m), .45(2H,m), 7.50-7.53(1H,m), 7.74-7.76(2H,m), 8.15(2H,s), 8.48(1H,d,J= 8.0Hz), 8.57-8.61(2H,m) d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.76 (2H, d, J = 5.8 Hz), 3.06 (2H, dd, J = DMSO 14.5, 9.5 Hz), 3.22 (1H, dd, J = 14.5, 4.5 Hz), 3.94 (2H, q, J = 7.0 Hz), 3.98 (1H, d, J = 5.7 Hz), 4.29 (2H, d, J = 6.0 Hz), 4.44 - 4.50 (1H, m), 4.65 (1H, td, J = 8.8, 4.9 Hz), 6.33 (2H, br.s), 6.55 (1H, d, J = 5.3 Hz), 6.74 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.27 (1H, d, J = 1.4 Hz), 7.29 (1H, s), 7.34 (2H, d, J = 8.0 Hz), 7.39 (1H, d, J = 5.4 Hz), 8.07 (2H, br.s), 8.52 (1H, s), 8.53 (1H, s), 8.97 (1H, d, J = 1.8 Hz) d6- δ: 1.28 (3H, t, J = 7.0 Hz), 1.35 (1H, s), 1.89 (3H, s), 2.72 (1H, dd, J = DMSO 14.7, 7.9 Hz), 2.86 (1H, dd, J = 13.7, 4.7 Hz), 3.05 (1H, dd, J = 14.4, 9.8 Hz), 3.24 (1H, dd, J = 14.7, 4.6 Hz), 3.67 (2H, s), 3.94 (2H, q, J = 7.0 Hz), 4.25 (2H, d, J = 5.2 Hz), 4.65-4.70 (2H, m), 6.72 (2H, d, J = 8.6 Hz), 6.88 (2H, d, J = 8.7 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.14 (1H, d, J = .2 Hz), 7.22 (2H, d, J = 7.8 Hz), 7.34 (1H, d, J = 1.7 Hz), 7.85 (1H, d, J = 5.2 Hz), 7.89 (2H, d, J = 7.5 Hz), 8.51 (1H, t, J = 6.0 Hz), 8.68 (1H, d, J = 8.6 Hz), 9.04 (1H, d, J = 1.9 Hz) d6- δ: 1.28(3H,t,J= 6.9Hz), 2.34(3H,s), 2.77(2H,d,J= 7.3Hz), DMSO 3.05(1H,dd,J=14.6,9.6Hz), H,dd,J=14.6,4.7Hz), 3.93(2H,q,J=7.0Hz), 3.97(2H,m), 4.3(2H,dd,J=5.0,4.9Hz), 185 4.56(1H,dd,J=14.8,7.6), .71(1H,m), 6.76(2H,d,J= 8.7Hz), 7.15(2H,d,J=8.6Hz), .26(4H,m), 7.34(2H,d,J=8.2Hz), 7.66(2H,d,J=8.2Hz), 8.08(3H,br s), 8.47(1H,d,J=7.8Hz), 8.54(1H,d,J=6.0), 8.58(1H,d,J= 8.3Hz), 8.95(1H,d,J=2.0Hz). d6- δ: 1.26 (3H, t, J = 7.0 Hz), 2.12 (3H, s), 2.26-2.67 (1H, m), 2.74 (1H, DMSO dd, J = 13.7, 4.7 Hz), 3.09 (1H, dd, J = 14.5, 10.1 Hz), 3.35 (1H, d, J = .6 Hz), 3.65 (2H, s), 3.89 (2H, q, J =7.0 Hz), 4.27 (2H, d, J = 6.0 Hz), 4.64 (2H, dd, J = 7.5, 4.7 Hz), 5.90 (1H, br.s), 6.59 (2H, d, J = 8.6 Hz), 6.76 (1H, t, J = 2.5 Hz), 6.86 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 7.3 Hz), 7.20 (2H, d, J = 8.1 Hz), 7.24 (1H, br.s), 7.36-7.45 (3H, m). 7.97 (2H, d, J = 8.2 Hz), 8.64 (1H, br.s), 8.68 (1H, d, J = 7.2 Hz), 11.12 (1H, br.s) d6- δ: 1.29 (3H, t, J = 7.0 Hz), 2.14 (3H, s), 2.66 (1H, dd, J = 13.1, 9.0 Hz), DMSO 2.78 (1H, dd, J = 13.7, 4.5 Hz), 2.86 (1H, dd, J = 14.2, 10.0 Hz), 3.07 (1H, dd, J = 14.2, 4.4 Hz), 3.66 (2H, s), 3.95 (2H, q, J = 7.0 Hz), 4.26 (2H, d, J = 4.6 Hz), 4.51 (1H, td, J = 9.0, 4.8 Hz), 4.61-4.67 (1H, m), .91 (1H, s), 6.75 (2H, d, J = 8.6 Hz), 6.77 (1H, d, J = 2.7 Hz), 7.02 (3H, d, J = 8.5 Hz), 7.12 (2H, d, J = 7.6 Hz), 7.15 (2H, br.s), 7.21 (2H, d, J = 8.3 Hz), 7.29 (1H, d, J = 7.4 Hz), 7.42 (1H, dd, J = 4.8, 2.9 Hz), 8.32 (1H, s), 8.49 (1H, br.s), 8.57 (1H, d, J = 7.0 Hz), 11.11 (1H, s) d6- δ: 1.26 (3H, t, J = 7.0 Hz), 2.01 (3H, s), 2.08 (1H, s), 2.66-2.72 (1H, DMSO m), 2.76-2.80 (1H, m), 3.12 (1H, dd, J = 14.4, 9.6), 3.67 (1H, s), 3.90 (2H, q, J = 7.0 Hz), 4.10 (1H, dd, J = 17.3, 6.1 Hz), 4.28-4.31 (2H, m), 4.35 (1H, dd, J = 13.5, 6.8 Hz), 4.59 (1H, br.s), 4.71-4.76 (1H, m), 6.66 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.5 Hz), 7.14 (3H, d, J = 7.6 Hz), 7.22 (1H, d, J = 8.2 Hz), 7.31-7.42 (4H, m), 7.67 (1H, d, J = 5.2 Hz), 7.84 (1H, d, J = 5.4 Hz), 7.97 (2H, dd, J = 12.2, 8.0 Hz), 8.05 (br.s, 1H), 8.60 (2H, br.d, J = 7.1 Hz), 10.66 (1H, br.s) d6- δ: 1.28 (3H, t, J = 6.70Hz), 2.33 (3H, s), 2.69 (2H, d, J = 7.51Hz), 2.91- DMSO 2.99 (1H, m), 3.13-3.18 (1H, m), 3.92-4.00 (4H, m), 4.33 (2H, d, J = .94Hz), 4.52-4.61 (1H, m), 4.63-4.69 (1H, m), 6.76 (2H, d, J = 189 8.67Hz), 7.15 (2H, d, J = 7.86Hz), 7.27 (2H, d, J = 8.096Hz), 7.31 (2H, d, J= 6.36Hz), 7.36 (2H, d, J = 7.51Hz), 7.47-7.53 (1H, m), 7.56 (1H, d, J = 7.51Hz), 7.87 (1H, d, J = z), 8.11 (3H, s, br), 8.45 (1H, d, J = 7.86Hz), 8.53 (2H, d, J = 4.72Hz), 8.57-8.65(2H, m). d6- δ: 1.31 (3H, t, J = 6.88Hz), 2.08 (3H, s), .71 (1H, m), 2.74-2.75 DMSO (1H, m), 2.88-2.94 (1H, m), 3.13-3.18 (1H, m), 3.90-4.01 (4H, m), 4.33 (2H, d, J = 6.21?Hz), 4.57-4.62 (1H, m), .71 (1H, m), 6.80 (2H, d, 190 J = 8.06Hz), 7.09-7.11 (5H, m), 7.14-7.31 (2H, m), 7.36 (2H, d, J = 8.056Hz), 7.45-7.48 (1H, m), 7.84 (1H, d, J = 7.051Hz), 8.11 (3H, s, br), 8.34 (1H, d, J = 8.06Hz), 8.52-8.53(1H, m), 8.56 (1H, d, J = .021Hz), 8.63-8.65(2H, m). d6- δ: 1.29 (3H, t, J= 6.84Hz), 2.07 (3H, s), 2.14 (3H, s), 2.53-2.59 (1H, DMSO m), 2.69-2.74 (1H, m), 2.77-2.83 (1H, m), 3.05-3.09 (1H,m), 3.91-4.01 (4H, m), 4.30 (2H, d, J = 5.98Hz), 4.51-4.65 (2H, m), 5.63 (1H, d, J = 1.50Hz) 6.71 (2H, d, J= 8.88Hz), 6.90 (2H, t, J= 8.88Hz), 7.04 (1H, d, J= 8.17Hz), 7.18-7.28 (8H, m), 7.34 (2H, d, J = 7.35Hz), 8.10 (2H, s, br), 8.57-8.64(2H, m). d6- δ: 1.28 (3H, t, J= 6.82Hz), 2.30 (3H,s), .74 (2H, m), 2.80- DMSO 2.86(1H,m), 3.04-3.09(1H,m), 3.91-3.95 (4H,m), 4.25-4.30 (2H,m), 192 4.54-4.59(1H,m), 4.69-4.74 (1H,m), 6.76 (2H, d, J= z), 7.08- 7.31(10H, m), 7.41-7.45(2H,m), 7.50-7.53(1H,m), 7.74-7.76(2H,m), 8.31-8.39 (3H, m), H, d, J= 7.88Hz), 8.75-8.78(3H,m). d6- δ: 1.27 (3H, t, J = 7.0 Hz), 2.01 (3H, s), 2.32-2.34 (1H, m), 2.67 (1H, t, J DMSO = 1.7 Hz), 2.76-2.78 (2H, m), 2.88 (2H, dd, J = 14.1, 9.6 Hz), 3.04 (2H, dd, J = 14.2, 4.6 Hz), 3.67 (1H, s), 3.93 (2H, q, J = 7.0 Hz), 4.28 (2H, t, J = 6.4 Hz), 4.56-4.62 (2H, m), 6.75 (2H, d, J = 8.6 Hz), 6.99 (1H, d, J = .8 Hz), 7.12 (3H, t, J = 8.3Hz), 7.15 (1H, d, J = 3.5 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.39 (1H, dd, J = 4.8, 3.0 Hz), 7.69 (1H, d, J = 5.4 Hz), 7.85 (1H, d, J = 5.4 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.50 (2H, t, J = 8.0 Hz), .69 (1H, br.s) d6- (DMSO) δ: 1.27 (3H, t, J = 7.0 Hz), 7.00 (2H, d, J = 7.0 Hz), 3.10 (2H, DMSO dd, J = 14.5, 10.0 Hz), 3.90 (2H, q, J= 7.0 Hz), 4.00 (2H, q, J = 5.5 Hz), 4.33 (2H, d, J = 6.1 Hz), 4.52 (1H, q, J = 6.6 Hz), 4.67 (1H, td, J = 9.6 Hz, 4.1 Hz), 6.35 (1H, br.s), 6.56 (1H, d, J = 5.4 Hz), 6.61 (2H, d, J = 8.6 Hz), 6.91 (2H, d, J = 8.6 Hz), 7.14 (1H, d, J = 7.7 Hz), 7.26 (2H, d, J = 7.5 Hz), 7.36 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 5.3 Hz), 7.46-7.41 (3H, m), 7.98 (2H, d, J = 8.8 Hz), 8.06 (2H, br.s), 8.60 (1H, d, J = 8.12 Hz), 8.70 (1H, br.s) d6- δ: 1.28 (3H, t, J = 7.0 Hz), 2.76 (2H, d, J = 5.8 Hz), 3.06 (2H, dd, J = DMSO 14.5, 9.5 Hz), 3.22 (1H, dd, J = 14.5, 4.5 Hz), 3.94 (2H, q, J = 7.0 Hz), 3.98 (1H, d, J = 5.7 Hz), 4.29 (2H, d, J = 6.0 Hz), 4.44 - 4.50 (1H, m), 4.65 (1H, td, J = 8.8, 4.9 Hz), 6.33 (2H, br.s), 6.55 (1H, d, J = 5.3 Hz), 6.74 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.27 (1H, d, J = 1.4 Hz), 7.29 (1H, s), 7.34 (2H, d, J = 8.0 Hz), 7.39 (1H, d, J = 5.4 Hz), 8.07 (2H, br.s), 8.52 (1H, s), 8.53 (1H, s), 8.97 (1H, d, J = 1.8 Hz) d6- δ: 1.29(3H, t, J= 6.91Hz), 2.42-2.46 (1H, m), 2.76-3.00 (3H, m), 3.05 DMSO (3H, s), 3.27-3.31 (1H,m), .00 (4H, m), 4.29 (2H, d, J = 6.28Hz), 4.89-4.99 (1H, m), 5.34-5.38 (1H, m), 6.67 (2H, d, J= 8.78Hz), 6.74 (2H, d, J= 8.21Hz), 6.98-7.01 (1H, m), 7.14 (1H, d, J= 5.67Hz), 7.19- 7.38 (7H, m), 7.86 (1H, d, J= 5.67Hz), 7.88 (1H, d, J= 7.09Hz), 8.09 (3H,s, br), 8.41-8.48 (1H, m). d6- δ: 1.28 (3H, t, J= 7.15Hz), 2.72-2.74 (2H, m), 3.92-3.99 (4H, m), 4.36 DMSO (2H, d, J = 6.40Hz), 4.47-4.50 (1H, m), .73 (1H, m), 5.22 (1H, s, 197 br), 5.83 (1H, s, br), 6.76 (2H, d, J= 8.51Hz), 7.17-7.30 (6H, m), 7.37- 7.45 (5H, m), .53 (1H, m), 8.30 (4H,s, br), 8.38-8.44 (2H, m), 8.60 (1H, d, J = 7.64Hz). d6- δ: 1.28(3H, t, J= 6.70Hz), 2.61-2.64 (1H, m), 2.79-2.83 (1H, m), , DMSO 3.91-4.00 (4H, m), 4.34-4.36 (2H, m), 4.45-4.48 (1H, m), 4.82-4.85 (1H, m), 5.26-5.28 (1H, m), 5.85-5.86 (1H, m), 6.54 (1H,s, br), 6.65 (2H, d, J= 8.21Hz), 6.71 (2H, d, J= 8.213Hz), 7.13 (1H, d, J= 5.47Hz), 7.23-7.36 (4H, m), 7.49 (2H, d, J = 7.11Hz), .86 (3H, m), 8.07 (3H,s, br), 8.36(1H, t, J = 5.81Hz), 8.53 (1H, d, J= 8.92Hz).
EXAMPLE 199 N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide N O A. [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid benzyl ester tert-Butyl 4-(Aminomethyl)benzylcarbamate (7.5g, 31.74mmol) was dissolved in dichloromethane ). This solution was cooled to 0°C and ylamine (9.63g, 93.2mmol) was added followed by ic acid benzyl ester 2,5-dioxo-pyrrolidinyl ester (9.5g, 38.09mmol). The reaction mixture was stirred at 0°C to room temperature for 18 hours and diluted with CHCl3 (200mL) the filtrate was washed with 0.3M KHSO4 (1x50mL), sat. NaHCO3 (1x50mL), water (1x50mL), brine (1x50mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid were triturated with EtOAc/Pet Ether 60-80°Cto give a white solid identified as [4-(tert-butoxycarbonylamino-methyl)-benzyl]-carbamic acid benzyl ester (11.3g, .5mmol, 96%).
[M+H]+ = 392.98 (M+ Na) B. (4-Aminomethyl-benzyl)-carbamic acid benzyl ester hydrochloride [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid benzyl ester , 29.15mmol) was ved in 4M HCl in dioxan (400mL). After one hour at room temperature the solvent was removed in vacuo. The residue was slurried with acetone and the solid was filtered off to give a white solid identified as (4-aminomethyl-benzyl)-carbamic acid benzyl ester hydrochloride , 30.135mmol, 99%).
[M+H]+ = 359.15 C. {(S)[4-(Benzyloxycarbonylamino-methyl)-benzylcarbamoyl]pyridinyl-ethyl}- carbamic acid tert-butylester (S)tert-Butoxycarbonylaminopyridinyl-propionic acid (2.12g, 7.96mmol) was dissolved in CH2Cl2(100mL), HBTU (3.29g, 8.68mmol) and triethylamine (2.20g, 21.71mmol) were added. After 20 mins at room temperature the on mixture was cooled to 0°C and (4- ethyl-benzyl)-carbamic acid benzyl ester hydrochloride , 7.24mmol) was added.
After 2 hours at 0°C the reaction mixture was diluted with CHCl3 (200mL), this solution was washed with 0.3M KHSO4 (1x50mL), sat NaHCO3 (1x50mL), water (1x50mL), brine (1x50mL), dried (Na2SO4) and ated in vacuo to give a white solid. The solid was triturated with EtOAc/Pet Ether 60-80°C to give a white solid identified as {(S)[4- (benzyloxycarbonylamino-methyl)-benzylcarbamoyl]pyridinyl-ethyl}-carbamic acid tertbutylester (2.53g, 4.88mmol, 67%).
[M+H]+ = 519.16 D. {4-[((S)Aminopyridinyl-propionylamino)-methyl]-benzyl}-carbamic acid benzyl ester Dihydrochloride -[4-(Benzyloxycarbonylamino-methyl)-benzylcarbamoyl]pyridinyl-ethyl}-carbamic acid tert-butylester (2.52g, 4.89mmol) was treated with 4M HCl/dioxan (50 mL). After one hour at room temperature the solvent was removed to give a white solid identified as {4-[((S) aminopyridinyl-propionylamino)-methyl]-benzyl}-carbamic acid benzyl ester dihydrochloride (2.31g, 4.71mmol, 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, , 7.87 (1H, t, J = 6.2Hz), 7.28- 7.38 (4H, m), 7.16-7.25 (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){(S)[4-(Benzyloxycarbonylamino-methyl)-benzylcarbamoyl]pyridinylethylcarbamoyl }(4-ethoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (R)Benzyloxycarbonylamino(4-ethoxy-phenyl)-propionic acid (870mg, 2.80mmol) was dissolved in CH2Cl2(100mL), HBTU (1.21g, ol) and triethylamine (1.35g, 13.33mmol) were added. After 20 mins at room temperature the reaction mixture was cooled to 0°C and {4- [((S)aminopyridinyl-propionylamino)-methyl]-benzyl}-carbamic acid benzyl ester dihydrochloride (1.31g, 2.67mmol) was added. After 2 hours at 0°C the reaction mixture was diluted with CHCl3 (200mL), this on was washed with 0.3M KHSO4 (1x50mL), sat NaHCO3 (1x50mL), water (1x50mL), brine (1x50mL), dried 4) and evaporated in vacuo to give a white solid. The solid was triturated with EtOAc/Pet Ether 60-80°C to give a white solid identified as -{(S)[4-(benzyloxycarbonylamino-methyl)-benzylcarbamoyl] pyridinyl-ethylcarbamoyl}(4-ethoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.40g, ol, 90%).
[M+H]+ = 710.18 F. S)[(R)Amino(4-ethoxy-phenyl)-propionylamino]pyridinyl- propionylamino}-methyl)-benzyl]-carbamic acid benzyl ester Dihydrochloride [(R){(S)[4-(Benzyloxycarbonylamino-methyl)-benzylcarbamoyl]pyridinylethylcarbamoyl }(4-ethoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.70, 2.42mmol) was treated with 4M HCl/dioxan (100 mL). After one hour at room temperature the solvent was removed to give a white solid identified as [4-({(S)[(R)amino(4-ethoxy-phenyl)- propionylamino]pyridinyl-propionylamino}-methyl)-benzyl]-carbamic acid benzyl ester dihydrochloride (1.50g, 2.32mmol, 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, , 7.86 (1H, t, J = 6.2Hz), 7.28-7.38 (4H, m), 7.11-7.20 (4H, m), 6.95 (2H, d, J = , 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, .9Hz), 2.63 (1H, dd, J = 13.8, 6.1Hz), 1.29 (3H, t, J = 7.0Hz).
G. [4-({(S)[(R)(4-Ethoxy-phenyl)(4-methyl-benzoylamino)-propionylamino] pyridinyl-propionylamino}-methyl)-benzyl]-carbamic acid benzyl ester [4-({(S)[(R)Amino(4-ethoxy-phenyl)-propionylamino]pyridinylpropionylamino }-methyl)-benzyl]-carbamic acid benzyl ester dihydrochloride (150mg, 0.23mol) was dissolved in dichloromethane (50 mL), this solution was cooled to 0°C. Triethylamine (70mg, 0.70mmol) was added followed by p-toluoyl de (39mg, 0.26mmol). After 18 hrs at 0°C to room ature the reaction mixture was diluted with CHCl3 (50 mL), this solution was washed with sat. NaHCO3 (1x20 mL), water (1x20 mL), brine (1x20 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 2% MeOH, 98% CHCl3, fractions combined and evaporated in vacuo to give a less oil fied as [4-({(S)[(R)(4-ethoxy-phenyl)(4-methyl-benzoylamino)-propionylamino]- 3-pyridinyl-propionylamino}-methyl)-benzyl]-carbamic acid benzyl ester (130mg, 0.18mmol, 77%).
[M+H]+ = 728.14 H. N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide Dihydrochloride [4-({(S)[(R)(4-ethoxy-phenyl)(4-methyl-benzoylamino)-propionylamino]pyridin yl-propionylamino}-methyl)-benzyl]-carbamic acid benzyl ester (98mg, 0.13mmol) was dissolved in methanol (100mL) , 1M hydrochloric acid (0.263mL, 0.263mmol) was added and the reaction mixture was hydrogenated over 10% Pd/C (50mg) at atmospheric pressure for 2 hours after which time the catalyst was filtered off and washed with methanol (100mL), the combined filtrates were evaporated in vacuo to give a white solid which was tallised from l to give a white solid identified as N-[(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]methyl-benzamide dihydrochloride.
Yield = 340mg, mol, 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)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide N O A. [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid 9H-fluorenylmethyl ester tert-Butyl nomethyl)benzylcarbamate (7.5g, 31.74mmol) was dissolved in dichloromethane (250mL). This solution was cooled to 0°C and triethylamine (9.63g, ol) was added followed by carbonic acid 2,5-dioxo-pyrrolidinyl ester 9H-fluorenylmethyl ester (12.85g, 38.09mmol). The reaction mixture was stirred at 0°C to room temperature for 3 hours and diluted with CHCl3 (200mL) the filtrate was washed with 0.3M KHSO 4 (1x50mL), sat.
NaHCO3 (1x50mL), water (1x50mL), brine (1x50mL), dried 4) and evaporated in vacuo to give a white solid. The solid was triturated with EtOAc/Pet Ether 60-80°C to give a white solid identified as [4-(tert-butoxycarbonylamino-methyl)-benzyl]-carbamic acid 9H-fluoren yl ester (13.96g, 30.44mmol, 96%).
[M+H]+ = 359.14 (M-Boc) B. (4-Aminomethyl-benzyl)-carbamic acid 9H-fluorenylmethyl ester Hydrochloride [4-(tert-Butoxycarbonylamino-methyl)-benzyl]-carbamic acid 9H-fluorenylmethyl ester (13.9g, 31.41mmol) was dissolved in 4M HCl in dioxan (400mL). After one hour at room temperature the solvent was removed in vacuo. The residue was triturated with acetone, the solid was ed off to give a white solid fied as (4-aminomethyl-benzyl)-carbamic acid 9H- fluorenylmethyl ester hydrochloride ( 11.9g, 30.135mmol, 99%) [M+H]+ = 359.15 C. ((S)(3,4-Difluoro-phenyl){4-[(9H-fluorenylmethoxycarbonylamino)-methyl]- benzylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester (S)tert-Butoxycarbonylamino(3,4-difluoro-phenyl)-propionic acid (2.1g, 6.96mmol) was dissolved in CH2Cl2(250mL) and DMF(25 mL). This solution was cooled to 0 °C. (4- Aminomethyl-benzyl)-carbamic acid 9H-fluorenylmethyl ester hydrochloride (2.5g, 6.33mmol) was added followed by HOBt (940mg, 6.96mmol) and triethylamine (1.92g, 18.99mmol). Water soluble carbodiimide , 7.6mmol) was then added. After 18 hours at 0°C to room temperature reaction mixture was diluted with chloroform (400mL) washed with 0.3MKHSO4 (1x30mL), NaHCO3 (1x30mL), water (1x30mL), brine (1x30mL) and evaporated in vacuo giving a white solid. The residue was ated with ethyl acetate/pet ether 60-80°C to give a white solid fied as ((S)(3,4-difluoro-phenyl){4-[(9H-fluoren ylmethoxycarbonylamino)-methyl]-benzylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester , 4.05mmol, 64%).
[M+H]+ = 641.9, 664.07 (M+Na) D. (4-{[(S)Amino(3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluorenylmethyl ester hydrochloride ((S)(3,4-Difluoro-phenyl){4-[(9H-fluorenylmethoxycarbonylamino)-methyl]- benzylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester (2.5g, ol) was dissolved in 4M HCl in dioxan (150mL). After one hour at room temperature the t was removed in vacuo to give a white solid identified as (4-{[(S)amino(3,4-difluoro-phenyl)-propionylamino]- methyl}-benzyl)-carbamic acid orenylmethyl ester hydrochloride (2.25g, 3.89mmol, 100%).
[M+H]+ = 542.12 E. [(R)((S)(3,4-Difluoro-phenyl){4-[(9H-fluorenylmethoxycarbonylamino)- methyl]-benzylcarbamoyl}-ethylcarbamoyl)(4-ethoxy-phenyl)-ethyl]-carbamic acid tertbutyl ester (R)tert-Butoxycarbonylamino(4-ethoxy-phenyl)-propionic acid (895mg, ol) was dissolved in CH2Cl2(250mL) and DMF(25 mL). This solution was cooled to 0 °C. (4-{[(S) Amino(3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluoren ylmethyl ester hydrochloride (1.5g, 2.63mmol) was added followed by HOBt (391mg, 2.90mmol) and triethylamine (800mg, 7.89mmol). Water soluble carbodiimide (605mg, 3.16mmol) was then added. After 18 hours at 0°C to room temperature reaction mixture was d with chloroform (200mL) washed with 0.3MKHSO4 (1x30mL), NaHCO3 (1x30mL), water (1x30mL), brine (1x30mL) and evaporated in vacuo giving a white solid. The residue was triturated with ethyl acetate/pet ether 60-80°C to give a white solid identified [(R)((S)(3,4- difluoro-phenyl){4-[(9H-fluorenylmethoxycarbonylamino)-methyl]-benzylcarbamoyl}- arbamoyl)(4-ethoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.1g, 2.52mmol, 96%).
[M+H]+ = 733.15 (M-Boc) F. (4-{[(S)[(R)Amino(4-ethoxy-phenyl)-propionylamino](3,4-difluoro-phenyl)- nylamino]-methyl}-benzyl)-carbamic acid 9H-fluorenylmethyl ester hloride [(R)((S)(3,4-Difluoro-phenyl){4-[(9H-fluorenylmethoxycarbonylamino)-methyl]- benzylcarbamoyl}-ethylcarbamoyl)(4-ethoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.1g, 2.52mmol) was dissolved in 4M HCl in dioxan (150mL). 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 (4-{[(S)[(R)amino(4-ethoxy-phenyl)-propionylamino](3,4- difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluorenylmethyl ester hydrochloride (1.9g, 2.47mmol, 98%).
[M+H]+ = 73.12 G. S)[(R)Benzoylamino(4-ethoxy-phenyl)-propionylamino](3,4-difluorophenyl )-propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluorenylmethyl ester (4-{[(S)[(R)Amino(4-ethoxy-phenyl)-propionylamino](3,4-difluoro-phenyl)- nylamino]-methyl}-benzyl)-carbamic acid 9H-fluorenylmethyl ester hydrochloride (410mg, 0.53mmol) was dissolved in dichloromethane (50mL). This solution was cooled to 0°C and triethylamine (162mg, 1.60mmol) was added followed by benzoyl chloride (82mg, 0.59mmol). The reaction mixture was d at 0°C to room temperature for 3 hours and diluted with CHCl3 (100mL) the filtrate was washed with 0.3M KHSO 4 (1x30mL), sat. NaHCO3 (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid were triturated with hot ethanol, the cooled suspension was ed to give a white solid identified as (4-{[(S)[(R)benzoylamino(4-ethoxy-phenyl)- propionylamino](3,4-difluoro-phenyl)-propionylamino]-methyl}-benzyl)-carbamic acid 9H- fluorenylmethyl ester (240mg, 0.34mmol, 99%).
[M+H]+ = 697.18 H. N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)- ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-benzamide Hydrochloride (4-{[(S)[(R)Benzoylamino(4-ethoxy-phenyl)-propionylamino](3,4-difluoro-phenyl)- propionylamino]-methyl}-benzyl)-carbamic acid 9H-fluorenylmethyl ester , mol) was dissolved in diethylamine/THF (1:1, 100mL) the reaction mixture was stirred at room ature for 3 hours after which time the solvent was removed in vacuo and the residue was triturated with ethyl acetate/pet ether 60-80°C to give a white solid identified which was treated with 4M HCl in dioxan (20mL), the solvent was removed in vacuo and the e recrystallised from EtOH to give a white solid identified as N-[(R)[(S)(4-aminomethylbenzylcarbamoyl )(3,4-difluoro-phenyl)-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]- benzamide hydrochloride (62mg, 0.095mmol, 44%).
[M+H]+ = 614.68 1H NMR: (d6-DMSO) δ: 1.26(3H, t, J= 6.79Hz), 2.65-2.84(3H, m), 3.03-3.08(1H, m), 3.92(2H, q, J= ), 3.96(2H, s), 4.27-4.35(2H,m), 4.57-4.63(2H, m), 6.75(2H, d, J= 8.03Hz), 7.16(2H, d, J= 8.76Hz), 7.23-7.25(1H, m), .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), 8.67-8.71(2H, m).
EXAMPLE 201 N-{(R,S)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl][4-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-benzamide O NH H 2 HN N A. (R,S)Benzyloxycarbonylamino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid (R)Benzyloxycarbonylamino(4-hydroxy-phenyl)-propionic acid (1.0g, ol) was dissolved in THF (70mL), 2,22-trifluoroethyl trifluoromethanesulfonate (883mg, 3.81mmol) and cesium carbonate (3.1g, 9.51mmol) 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 (100mls), this solution was washed with 1M HCl (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 1% AcOH, 5%MeOH, 94% CHCl3, fractions ed and evaporated in vacuo to give a colourless oil identified as (R,S)benzyloxycarbonylamino[4-(2,2,2-trifluoroethoxy )-phenyl]-propionic acid (380mg, 0.96mmol, 30%).
[M+H]+ = 395.11 B. {(S)[4-(tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]phenylethylcarbamoyl }[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-carbamic acid benzyl ester (R,S)Benzyloxycarbonylamino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionic acid , 0.50mmol) was dissolved in CH2Cl2(50mL) and DMF(2.5mL). This solution was cooled to 0°C.
S)aminophenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (231mg, 0.60mmol) was added followed by HOBt (75mg, ol) and triethylamine (153mg, 1.51mmol). Water soluble carbodiimide (116mg, 0.60mmol) was then added. After 18 hours at 0°C to room temperature on mixture was diluted with chloroform (400mL) washed with 0.3M KHSO4 (1x30mL), NaHCO3 (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent 3%MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a white solid fied as {(R,S){(S)[4-(tert-butoxycarbonylamino-methyl)- benzylcarbamoyl]phenyl-ethylcarbamoyl}[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}- carbamic acid benzyl ester (350mg, 0.46mmol, 92%).
[M+H]+ = 663.43 (M-Boc), 785.44 (M+Na) C. {4-[((S){(R,S)Amino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino} phenyl-propionylamino)-methyl]-benzyl}-carbamic acid utyl ester {(R,S){(S)[4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]phenylethylcarbamoyl }[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-carbamic acid benzyl ester (350mg, 0.46mmol) was dissolved in methanol (100mL) This solution was hydrogenated over % Pd/C (50mg) at atmospheric for 2 hours after which time the catalyst was filtered off and washed with methanol (100mls), the combined filtrates were ated in vacuo to give a white solid identified as {4-[((S){(R,S)amino[4-(2,2,2-trifluoro-ethoxy)-phenyl]- propionylamino}phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (270mg, 0.43mmol, 94%).
[M+H]+ = 629.40 D. {4-[((S){(R,S)Benzoylamino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino}- 3-phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester {4-[((S){(R,S)Amino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino}phenylpropionylamino )-methyl]-benzyl}-carbamic acid tert-butyl ester (250mg, ol) was dissolved in dichloromethane (50mL). This solution was cooled to 0°C and triethylamine (121mg, 1.19mmol) was added followed by benzoyl chloride (61mg, 0.44mmol). The reaction mixture was d at 0°C to room temperature for 18 hours and diluted with CHCl3 (100mls) the filtrate was washed with 0.3M KHSO4 (1x30mL), sat. NaHCO3 (1x30mL), water L), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo to give a white solid. The solid was ated with ethyl acetate/pet ether 60-80°C to give a white solid identified as {4-[((S) {(R,S)benzoylamino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino}phenylpropionylamino )-methyl]-benzyl}-carbamic acid tert-butyl ester (190mg, 0.26mmol, 65%).
[M+H]+ = 733.357, 755.49 (M+Na) E. N-{(R,S)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl][4- (2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-benzamide Ditrifluoroacetate {4-[((S){(R,S)Benzoylamino[4-(2,2,2-trifluoro-ethoxy)-phenyl]-propionylamino} phenyl-propionylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (190mg, ol) was treated with 4M HCl/dioxan (50 mL). After one hour at room temperature the solvent was removed. The residue was purified by Prep HPLC (Sunfire prep C18 OBD column. 19x250mm, 10µ). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H2O over 35 min at 20ml/min. Fractions were combined and freeze dried to give a white solid identified N-{(R,S)[(S)(4-aminomethylbenzylcarbamoyl )phenyl-ethylcarbamoyl][4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}- ide luoroacetate (56mg, 0.075mmol, 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), .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= ), .62 (2H, m).
Determination of the kinetic solubility in phosphate buffer The solubility was determined turbidimetrically using standard published methods (Lipinski et.al. Advanced Drug Delivery Reviews 23 (1997) 3-25). A 10mM compound stock was prepared in DMSO, which was added to 25mM pH 7.0 sodium phosphate buffer to produce concentrations ranging from 12 to 235μM. After shaking for imately 30 seconds the reduction in light transmission of these samples, at 650nm, was measured (Molecular Devices Spectromax UV/visible spectrophotometer). A second measurement was taken at approximately seconds later. Absorbance of greater than 0.005 is taken to indicate that some precipitation of compound has occurred and therefore the compound is not soluble at that concentration.
Data acquired from these determinations are shown in Table 8 below: Table 8 Example solubility Example solubility Example solubility No in No in No in PO4buffer PO4buffer PO4buffer (μM) (μM) (μM) 1 235 26 235 51 235 2 235 27 235 52 235 3 12 29 235 53 235 4 235 30 235 54 12 235 31 235 55 36 6 235 32 235 56 36 8 235 33 235 57 36 9 235 34 235 58 36 235 35 235 59 36 11 235 36 235 61 235 12 235 37 235 63 235 14 235 38 235 64 235 235 39 235 67 235 17 235 40 235 18 235 41 235 235 42 235 21 12 43 235 24 235 44 235 235 45 235 Determination of thermodynamic solubility in phosphate buffer The thermodynamic solubility of compound was determined in Ammonium Phosphate Buffer (pH7.4, m). Compounds were made up at a nominal concentration of 1 mg/mL, vortexed then placed on a shaker for 1h, 37°C at approximately 950 rpm. Following incubation samples were transferred to orf tubes and centrifuged at 15,000 g (r.c.f.) for 10 s at 37°C.
The concentration of nd in the supernatant was determined by LC-MS/MS analysis using a calibration line prepared from a DMSO stock.
Data acquired from these determinations are shown in Table 9 below: Table 9 Example No lity in PO4 buffer (μg/ml) 3 10 38 14.55 54 0.8 55 1.5 56 0.9 58 4.1 59 7.7 70 11.53 71 22.1 72 6.9 73 5.1 75 1.06 79 2.4 81 1.3 84 0.5 88 0.2 92 0.2 93 0.01 95 2.05 99 2.88 116 1.39 119 1.61 124 64.45 125 43.60 131 0.56 140 79.63 141 0.15 143 2.86 145 68.91 150 0.12 151 4.31 152 122.19 153 0.19 154 3.14 155 0.44 157 4.77 158 70.56 159 1.15 160 20.4 162 69.69 173 2.38 174 232.69 175 23.4 176 2.28 178 1.54 179 17.72 181 61.65 199 15.88 200 0.22 Biological s The y of the compounds of formula (I) to inhibit plasma kallikrein may be determined using the following biological assay: Determination of the IC50 for plasma kallikrein Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g. 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-Phe-Arg- AFC and s concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
Data acquired from this assay are shown in Tables 10 and 11 below: Table 10 Example IC50 Example IC50 Example IC50 No (human No (human No (human PKal) PKal) PKal) μM μM μM 1 0.089 24 0.45 47 2.1 2 0.82 25 0.34 48 4.7 3 0.022 26 0.081 49 2.2 4 0.23 27 1.3 50 4.3 0.46 28 8.9 51 1.0 6 1.0 29 0.30 52 0.86 7 0.074 30 0.58 53 0.65 8 0.74 31 4.3 54 0.083 9 2.0 32 0.20 55 0.031 7.2 33 1.1 56 0.50 11 1.7 34 1.4 57 10 12 0.29 35 2.0 58 0.17 13 10 36 8.2 59 0.078 14 0.40 37 0.91 60 10 0.47 38 0.047 61 0.22 16 0.053 39 0.31 62 10 17 5.8 40 1.8 63 0.052 18 8.8 41 1.3 64 3.4 19 10 42 0.53 65 10 0.73 43 1.3 66 10 Example IC50 Example IC50 e IC50 No (human No (human No (human PKal) PKal) PKal) μM μM μM 21 5.1 44 0.18 67 1.6 22 10 45 0.79 23 0.031 46 1.2 Table 11 Example No IC50 (human PKal)(µM) 68 0.861 69 0.621 70 0.126 71 0.077 72 0.046 73 0.025 74 0.545 75 0.270 76 0.452 77 1.959 78 10.000 79 0.038 80 0.398 81 0.040 82 0.539 83 0.254 84 0.219 85 0.485 86 0.423 87 0.755 88 0.090 89 0.099 90 0.276 91 2.083 92 0.032 93 0.175 94 1.080 95 0.046 96 0.764 97 0.241 98 0.576 99 0.095 100 0.474 101 1.113 102 10.000 103 10.000 104 0.159 105 0.185 106 0.256 107 0.133 108 0.232 109 0.155 110 0.598 111 0.058 112 0.298 113 0.455 114 0.427 115 0.417 116 0.018 117 0.048 118 0.061 119 0.015 120 0.540 121 0.310 122 0.519 123 0.214 124 0.020 125 0.010 126 4.013 127 0.521 128 2.009 129 10.000 130 2.491 131 0.040 132 1.209 133 10.000 134 10.000 135 0.424 136 1.017 137 7.540 138 0.310 139 1.141 140 0.045 141 0.055 142 0.096 143 0.083 144 0.340 145 0.025 146 0.232 147 0.284 148 0.934 149 0.091 150 0.051 151 0.009 152 0.023 153 0.010 154 0.021 155 0.022 156 1.083 157 0.036 158 0.047 159 0.015 160 0.010 161 0.049 162 0.010 163 0.064 164 0.050 165 0.070 166 0.262 167 0.080 168 0.076 169 0.044 170 0.051 171 0.123 172 0.881 173 0.213 174 0.045 175 0.003 176 0.028 177 0.457 178 0.042 179 0.022 180 0.073 181 0.010 182 0.015 183 0.016 184 0.010 185 0.049 186 0.014 187 0.007 188 0.036 189 0.023 190 0.028 191 0.020 192 0.012 193 0.025 194 0.013 195 0.014 196 0.032 197 0.012 198 0.007 199 0.010 200 0.045 201 0.012 Selected compounds were further screened for inhibitory activity t the related enzyme KLK1. The ability of the compounds of a (I) to inhibit KLK1 may be determined using the following biological assay: Determination of the IC50 for KLK1 KLK1 inhibitory activity in vitro was ined using standard published methods (see e.g.
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 -Leu-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
Data acquired from this assay are shown in Tables 12 and 13 below: Table 12 Example IC50 Example IC50 e IC50 No (human No (human No (human KLK1) KLK1) KLK1) μM μM μM 1 >1 24 >10 42 >10 3 >10 25 6.3 43 >10 4 >10 26 >10 44 >10 0.16 27 4.0 45 >10 6 >1 28 >10 46 >10 7 >1 29 >10 47 >10 8 >1 30 >10 48 >10 9 >1 31 9.6 49 >10 14 3.7 32 >10 50 5 2.2 33 >10 51 >10 16 4.9 34 7.7 52 9.5 17 >10 35 >10 53 >10 18 1.6 36 >10 66 8.4 19 >10 37 >10 67 >10 3.7 38 >10 21 10 39 >10 22 9.6 40 >10 23 5.6 41 2.5 Table 13 Example No IC50 (human KLK1) (µM) 68 >10 69 >10 70 7.5 71 >10 72 9.1 73 9.3 74 >10 75 >10 76 3.6 77 >10 78 >10 79 8.6 80 >10 81 >10 82 >10 83 >10 84 1.2 85 2.9 86 >10 87 3.4 88 >10 89 3.7 90 >10 91 >10 92 >10 93 >10 94 >10 95 >10 96 >10 97 4.7 98 5.1 99 >10 100 2.9 101 >10 102 9.0 103 >10 104 >10 105 >10 106 8.4 107 7.5 108 >10 109 >10 110 >10 111 >10 112 >10 113 >10 114 >10 115 9.0 116 6.3 117 6.1 118 >10 119 6.1 120 >10 121 >10 122 4.8 123 >10 124 8.4 125 7.0 126 >10 127 >10 128 >10 129 >10 130 >10 131 9.5 132 >10 133 >10 134 >10 135 >10 136 >10 137 >10 138 >10 139 >10 140 >10 141 >10 142 >10 143 >10 144 >10 145 >10 146 >10 147 >10 148 >10 149 >10 150 >10 151 >10 152 >10 153 >10 154 >10 155 >10 156 >10 157 >10 158 >10 159 >10 160 >10 161 6.9 162 >10 163 >10 164 >10 165 >10 166 >10 167 >10 168 >10 169 9.9 170 >10 171 9.4 172 >10 173 >10 174 >10 175 >10 176 >10 177 >10 178 >10 179 7.2 180 >10 181 >10 182 >10 183 >10 184 >10 185 >10 186 3.8 187 >10 188 >10 189 >10 190 >10 191 >10 192 >10 193 >10 194 7.1 195 >10 196 9.9 197 >10 198 9.1 199 >10 200 7.6 201 >10 Selected compounds were further screened for inhibitory activity t the related enzymes plasmin, thrombin, trypsin, Factor Xa and Factor XIIa. The ability of the compounds of formula (I) to these enzymes may be determined using the following biological assays: Determination of enzyme selectivity Human serine protease s 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 lation of liberated fluorescence from the substrate over 5 minutes. The linear rate of fluorescence increase per minute was expressed as percentage (%) activity. The Km for the cleavage of each substrate was determined by standard transformation of the Michaelis-Menten equation. The compound inhibitor assays were performed at substrate Km tration and activities were calculated as the concentration of tor giving 50% inhibition (IC50) of the uninhibited enzyme activity (100%).
Data acquired from these assays are shown in Table 14 below: Table 14 (Selectivity data) Example IC50 (µM) No Thrombin Trypsin n Factor Xa 3 >40 10.8 3.5 >10 Table 15 (Selectivity data: Factor XIIa) Example No IC50 (Factor XIIa) (µM) 3 >10 85 >10 91 >10 92 >10 93 >10 94 >10 95 >10 96 >10 157 >10 182 >10 183 >10 184 >10 185 >10 186 >10 187 >10 188 >10 189 >10 190 >10 191 >10 192 >10 193 >10 194 >10 195 >10 196 >10 197 >10 198 >10 199 >10 201 >10 Carbonic ase I induced Retinal Vascular Permeability Model The activity of Example 3 has been established using this in vivo model in the rat. Rats received an intravitreal injection (5µL) of phosphate buffered saline (PBS), 7 (a plasma kallikrein inhibitor positive l) (10µM) or Example 3 (1µM) at time 0. After 30mins, a second intravitreal injection (5µL) of PBS or CA-I (200ng/eye) was given. After 15 minutes, 10% sodium scein was infused and retinal vascular permeability (RVP) was measured by vitreous fluorophotometry 75 minutes following the initial IVT injections. Data for Example 3 are presented in Figure 1, in which the lower dashed line indicates basal RVP following PBS/PBS and upper dashed line indicates maximal stimulation. Intravitreal injection of 1M Example 3 alone had no effect upon basal RVP compared to PBS alone (3.29±0.21 vs. 3.64±0.48). Intravitreal injection of Example 3 reduced RVP lated by CA-I injection) by 53±21%.
Pharmacokinetics A pharmacokinetic study of Example 3 was performed to assess the ocular and systemic pharmacokinetics following a single IVT dose in pigmented -belted) rabbits. Six rabbits per dose level were given a single, bilateral, IVT injection of 50µL of a 4.2 µg/mL (210ng 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 ocular tissue concentrations of e 3 in the vitreous, retina/choroid and aqueous humour were measured. Serial blood samples were ted in surviving rabbits.
Ocular tissue concentration data are presented in Figure 2, in which the solid line for each ocular tissue concentration is the average of the left and right eye of each rabbit. The decline in ocular tissue concentrations of Example 3 was l over 7 days. Plasma trations of Example 3 following IVT administration were below 1 ng/mL at all time points.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this ication to any prior ation (or information derived from it) or to any matter which is known, is not, and should not be taken as an ledgement or admission or any form of suggestion that that prior publication (or information d from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.

Claims (22)

Claims
1. A compound of formula I 1 2 R R 4 7 N R O R 3 *1 N *2 R R N O 5 9 R NH2 R R wherein: R1 is selected from H, alkyl, -COalkyl, -COaryl, -COheteroaryl, kyl, -(CH2)aOH, -(CH2)bCOOR10, cCONH2, kyl, -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, 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- memebered azacycloalkyl ure; R7 and R8 are independently selected from H, alkyl, alkoxy, CN, halo and CF3; R9 is aryl or aryl; R10 is H or alkyl; a, b, c, d, e, f , g, h, i, j, l and m are independently 1, 2 or 3; k is 0, 1, 2 or 3; *1 and *2 denote chiral centres; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of 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, fluoro and NR11R12; cycloalkyl is a mono- or bi-cyclic saturated 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 3 to 10 membered saturated, mono- or bi-cyclic ring, wherein said heterocycloalkyl ring contains, where possible, 1, 2 or 3 heteroatoms independently selected from N, NR11 and O; alkoxy is a linear ed hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched ed hydrocarbon of between 3 and 6 carbon atoms ); alkoxy may optionally be substituted with 1 or 2 tuents independently selected from (C3-C10)cycloalkyl, OH, CN, CF3, COOR11, fluoro and NR11R12; aryl is phenyl, biphenyl or yl; aryl may be optionally substituted with up to 5 substituents independently selected from alkyl, , OH, halo, CN, COOR11, CF3 and NR11R12; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic 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 ed from H and alkyl; R13 is aryl or heteroaryl; R14 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R15 is H, alkyl, aryl, heteroaryl, cycloalkyl or cycloalkyl; 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, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
2. A compound as claimed in claim 1, wherein R9 is selected from phenyl and naphthyl, wherein phenyl may be optionally substituted with up to 3 substituents ndently selected from alkyl, , OH, halo, CN, COOR11, CF3 and NR11R12.
3. A compound as claimed in claim 1 or claim 2, n R9 is selected from phenyl, 1- naphthalene, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4- trifluoromethylphenyl and 4-ethoxyphenyl.
4. A nd as claimed in any one of claims 1 to 3, wherein R1 is selected from H, - , -COalkyl, -CH2COOH, -SO2Ph and -SO2CH3.
5. A compound as claimed in any one of claims 1 to 4, wherein R1 is selected from -COalkyl and –COaryl.
6. A compound as claimed in any one of claims 1 to 5, wherein R3 is selected from: O CH2 H3C and .
7. A compound as d in any one of claims 1 to 6, wherein R4 and R6 are selected from H and CH3.
8. A compound as claimed in any one of claims 1 to 7, wherein the chemical configuration about chiral centre *1 is R.
9. A compound as claimed in any one of claims 1 to 8, wherein the stereochemical configuration about chiral centre *2 is S.
10. A compound as claimed in any one of claims 1 to 9, wherein a is 2 and b, c, d, e, f, g, h, j, l and m are 1.
11. A compound as claimed in claim 1, selected from (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide; {(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexylethylamino }-acetic acid; (S)-N-(4-Aminomethylfluoro-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; (S)-N-(4-Aminomethylchloro-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; (S)-N-(4-Aminomethyl-benzyl)(3,4-dichloro-phenyl)[(R)(4-ethoxy-phenyl) propionylamino-propionylamino]-propionamide; (S)-N-(4-Aminomethylchloro-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]phenyl-propionamide; (S)-N-(4-Aminomethyl-benzyl){[(R)(4-ethoxy-phenyl)propionylamino-propionyl]- methyl-amino}phenyl-propionamide; ({(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl]cyclohexylethyl }-methyl-amino)-acetic acid; (S)-N-(4-Aminomethylfluoro-benzyl){[(R)(4-ethoxy-phenyl)propionylaminopropionyl ]-methyl-amino}phenyl-propionamide; N-[(R){[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methyl-carbamoyl} (4-ethoxy-phenyl)-ethyl]-benzamide; {[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl]-methyl-carbamoyl} (4-ethoxy-phenyl)-ethyl]-isobutyramide; Naphthalenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-difluoro-benzamide; (R)Amino-N-[(1S,2S)(4-aminomethyl-benzylcarbamoyl)hydroxyphenyl-ethyl] (4-ethoxy-phenyl)-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxyphenyl l]-nicotinamide; (2S,3S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)propionylaminopropionylamino ]hydroxyphenyl-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxyphenyl )-ethyl]-isonicotinamide; Thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl)- 2-phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; exanecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; olecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Benzo[b]thiophenecarboxylic acid[(R)[(S)(4-aminomethyl-benzylcarbamoyl) -ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-chlorobenzenesulfonylamino )(4-ethoxy-phenyl)-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]trifluoromethyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methoxy-benzamide; (S)-N-(4-Aminomethyl-benzyl)[(R)(4-ethoxy-phenyl)(2-phenylacetylaminoacetylamino )-propionylamino]phenyl-propionamide; [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]fluoro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,6-dichloro-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-5,6-dichloro-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,3,6-trifluoro-isonicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,3,3-trifluoro-propionamide; 2,4-Dimethyl-thiazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 2-Methyl-thiazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; yl-thiazolecarboxylic acid[(R)[(S)(4-aminomethyl-benzylcarbamoyl) -ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; Furancarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methoxy-isonicotinamide; 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; o-thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-propoxyphenyl )-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-chloro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-fluoro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-methoxy-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- -phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3-fluoro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl(4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; [(S)(4-Aminomethylchloro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methoxy-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethylchloro-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- -phenyl)-ethyl]methoxy-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl )-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethyl](4-ethoxy-phenyl) propionylamino-propionamide; N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- -phenyl)-ethyl]-isonicotinamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethylfluoro-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)(3,4-dichlorophenyl )-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethyl](4-ethoxy-phenyl) propionylamino-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; [(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-3,3,3-trifluoro-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]chloro-benzamide; Isoxazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; [(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(1H-indolyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl]- thoxy-phenyl)-ethyl]-isonicotinamide; 3-Acetylamino-thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(2-fluoro-phenyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethylmethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) lyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiazolyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) thiazolyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Acetylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- -phenyl)-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; 3,5-Dimethyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethylmethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; 3-Acetylamino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Acetylamino-thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl) benzo[b]thiophenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid [(R){[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethyl]-methyl-carbamoyl}(4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(1S,2R)(4-Aminomethyl-benzylcarbamoyl)hydroxyphenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; 3-Chloro-thiophenecarboxylic acid [(R)[(1S,2R)(4-aminomethyl-benzylcarbamoyl) hydroxyphenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-{(R,S)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl][4-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-benzamide; and pharmaceutically acceptable salts and solvates thereof.
12. A compound as claimed in claim 1, selected from N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-benzamide; Naphthalenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; [(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-2,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxyphenyl )-ethyl]-nicotinamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-difluoro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl] (4-ethoxyphenyl l]-isonicotinamide; Thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl)- ylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Thiophenecarboxylic acid -[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Cyclohexanecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Isoxazolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; (R)-N-[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethyl](4-chlorobenzenesulfonylamino -ethoxy-phenyl)-propionamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]-3,4-dichloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]chloro-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]methoxy-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-ethoxyphenyl )-ethyl]fluoro-benzamide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Methyl-1H-pyrrolecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Amino-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)phenyl-ethylcarbamoyl](4-propoxyphenyl )-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-dichloro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(4-fluoro-phenyl)-ethylcarbamoyl] (4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- -phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl](4- -phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)thiophenyl-ethylcarbamoyl(4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethylfluoro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethylchloro-benzylcarbamoyl)phenyl-ethylcarbamoyl](4- -phenyl)-ethyl]-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)thiophenylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methoxy-benzamide; Pyridinecarboxylic acid [(R)[(S)(4-aminomethylchloro-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methoxy-benzamide; Thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl)pyridinylethylcarbamoyl ](4-ethoxy-phenyl)-ethyl]-amide; [(S)(4-Aminomethyl-benzylcarbamoyl)pyridinyl-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]methyl-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)(3,4-difluoro-phenyl)-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-benzamide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Chloro-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; [(S)(4-Aminomethyl-benzylcarbamoyl)(1H-indolyl)-ethylcarbamoyl](4- ethoxy-phenyl)-ethyl]-benzamide; N-[(R)[(S)(4-Aminomethyl-benzylcarbamoyl)benzo[b]thiophenyl-ethylcarbamoyl]- 2-(4-ethoxy-phenyl)-ethyl]-isonicotinamide; 3-Acetylamino-thiophenecarboxylic acid-[(R)[(S)(4-aminomethyl-benzylcarbamoyl) phenyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; 3-Methyl-thiophenecarboxylic acid [(R)[(S)(4-aminomethyl-benzylcarbamoyl) pyridinyl-ethylcarbamoyl](4-ethoxy-phenyl)-ethyl]-amide; and pharmaceutically acceptable salts and solvates thereof.
13. A ceutical composition comprising a compound as claimed in any one of claims 1 to 12 and a pharmaceutically acceptable carrier, t or excipient.
14. A compound as claimed in any one of claims 1 to 12 for use in medicine.
15. The use of a compound as claimed in any one of claims 1 to 12 in the cture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
16. A compound as claimed in any one of claims 1 to 12 for use in a method of treatment of a disease or condition in which plasma kallikrein activity is implicated.
17. The use of claim 15 or a compound as claimed in claim 17, wherein the disease or ion in which plasma kallikrein activity is implicated is selected from impaired visual acuity, diabetic retinopathy, diabetic macular oedema, hereditary angioedema, es, pancreatitis, cerebral haemorrhage, nephropathy, myopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery.
18. The use of claim 15 or a compound as claimed in claim 17, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular .
19. A nd according to claim 1 ntially as hereinbefore bed with reference to any one of the examples.
20. A ition according to claim 13 substantially as hereinbefore described with reference to any one of the examples.
21. A compound for use in medicine according to claim 14 or a compound for use in the method according to claim 16 substantially as hereinbefore described with reference to any one of the examples.
22. Use according to claim 15 substantially as hereinbefore described with reference to any one of the examples.
NZ620271A 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein NZ620271B2 (en)

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US201161505305P 2011-07-07 2011-07-07
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GB1111682.9A GB2494851A (en) 2011-07-07 2011-07-07 Plasma kallikrein inhibitors
PCT/GB2012/051588 WO2013005045A1 (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein

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