Benzylamine Derivatives

Abstract

The present invention provides compounds of formula (I):

##STR00001##

compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R1 to R3, R5 to R9, A, P, V, W, X, Y and Z are as defined herein.

Claims

1. A method of treating 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): ##STR00154## wherein: V is C or N such that the aromatic ring containing V is phenyl or pyridine; R2 is absent when V is N; or, when present, R2 is H, alkyl, alkoxy, CN, halo or CF.sub.3; R1 and R3 are, independently, H, alkyl, alkoxy, CN, halo or CF.sub.3; W, X, Y and Z are, independently, C, N, O, or S, such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle; R5, R6 and R7 are, independently, absent, H, alkyl, halo, aryl, heteroaryl, or CF.sub.3; P is —C(R10)(R11)NH.sub.2; R8 and R9 are, independently, H or alkyl, or may together form a cycloalkyl ring; R10 and R11 are, independently, H or alkyl, or may together form a cycloalkyl ring or a cyclic ether; A is N-linked morpholine, aryl, or heteroaryl; and wherein alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C.sub.1-C.sub.10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C.sub.3-C.sub.10); alkyl is optionally substituted with 1 or 2 substituents which are, independently, (C.sub.1-C.sub.6)alkoxy, OH, CN, CF.sub.3, —COOR12, —CONR12R13, H(CH.sub.2).sub.1-3CON(R12)(CH.sub.2).sub.1-3—, fluoro and —NR12R13; cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms; wherein cycloalkyl is optionally substituted with a substituent which is alkyl, alkoxy or NR12R13; a cyclic ether is a monocyclic saturated hydrocarbon of between 4 and 7 carbon atoms, wherein one of the ring carbons is replaced by an oxygen atom; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C.sub.1-C.sub.6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C.sub.3-C.sub.6); alkoxy is optionally substituted with 1 or 2 substituents which are, independently, aryl, OH, CN, CF.sub.3, —COOR12, —CONR12R13, fluoro, or NR12R13; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, OH, halo, CN, -morpholinyl, -piperidinyl, heteroaryl, aryl.sup.b, —O-aryl.sup.b, —(CH.sub.2).sub.1-3-aryl.sup.b, —(CH.sub.2).sub.1-3-heteroaryl, —COOR12, —CONR12R13, —(CH.sub.2).sub.1-3—NR14R15, CF.sub.3 and NR12R13; aryl.sup.b is phenyl, biphenyl or naphthyl, which is optionally substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, —COOR12, —CONR12R13, CF.sub.3, or NR12R13; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members which are, independently, N, NR12, S or O; heteroaryl is optionally substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, aryl, —(CH.sub.2).sub.1-3-aryl, heteroaryl.sup.b, —COOR12, —CONR12R13, CF.sub.3 or NR12R13; heteroaryl.sup.b is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members which are, independently, N, NR12, S or O; wherein heteroaryl.sup.b is optionally substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, aryl, —(CH.sub.2).sub.1-3-aryl, —COOR12, —CONR12R13, CF.sub.3 or NR12R13; R12 and R13 are, independently, H or alkyl; or R12 and R13 together with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring which is saturated or unsaturated with 1 or 2 double bonds; R14 and R15 together with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring which is saturated or unsaturated with 1 or 2 double bonds, and optionally is oxo substituted; wherein, when R5, R6 and R7 are absent or H, then: either R10 and R11 together form a cycloalkyl ring or a cyclic ether; or A is aryl and aryl is phenyl, biphenyl or naphthyl substituted with 1, 2 or 3 substituents which are, independently, OH, heteroaryl, aryl.sup.b, —O-aryl.sup.b, —(CH.sub.2).sub.1-3-aryl.sup.b, —(CH.sub.2).sub.1-3-heteroaryl, —COOR12, —CONR12R13, or —(CH.sub.2).sub.3—NR14R15; wherein, aryl.sup.b is phenyl, biphenyl or naphthyl, wherein aryl.sup.b is substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, —COOR12, —CONR12R13, CF.sub.3 or NR12R13; and heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members which are, independently, N, NR12, S or O, wherein heteroaryl is substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, halo, CN, aryl, morpholinyl, piperidinyl, —(CH.sub.2).sub.1-3-aryl, heteroaryl.sup.b, —COOR12, —CONR12R13, CF.sub.3 or —NR12R13; or A is heteroaryl and heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members which are, independently, N, NR12, S and O, wherein heteroaryl is substituted with 1, 2 or 3 substituents which are, independently, aryl, —(CH.sub.2).sub.1-3-aryl, heteroaryl.sup.b, —COOR12, or —CONR12R13; wherein, aryl is phenyl, biphenyl or naphthyl, wherein aryl is substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, heteroaryl, aryl.sup.b, —O-aryl.sup.b, —(CH.sub.2).sub.1-3-aryl.sup.b, —(CH.sub.2).sub.1-3-heteroaryl, —COOR12, —CONR12R13, —COR12R13, —(CH.sub.2).sub.1-3—NR14R15, CF.sub.3 or —NR12R13; and heteroaryl.sup.b is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members which are, independently, N, NR12, S or O, wherein heteroaryl.sup.b is substituted with 1, 2 or 3 substituents which are, independently, alkyl, alkoxy, halo, CN, morpholinyl, piperidinyl, aryl, —(CH.sub.2).sub.1-3-aryl, —COOR12, —CONR12R13, CF.sub.3 or NR12R13; or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof; wherein the disease or condition in which plasma kallikrein activity is implicated is cerebral haemorrhage, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from post operative surgery.

2. The method of claim 1, wherein at least one of R5, R6 and R7 is alkyl, halo, aryl, heteroaryl or CF.sub.3.

3. The method of claim 1, wherein A is: ##STR00155##

4. The method of claim 1, wherein A is: ##STR00156##

5. The method of claim 1, wherein R5, R6 and R7 are absent or H; and A is: ##STR00157##

6. The method of claim 1, wherein, X is N and W, Y and Z are C.

7. The method of claim 6, wherein R5 is H, and R6 and R7 are methyl.

8. The method of claim 1, wherein, X and Y are N and W and Z are C.

9. The method of claim 1, wherein, X, Y and Z are N and W is C.

10. The method of claim 1, wherein R8 and R9 are H.

11. The method of claim 1, wherein: W is C; X is N; Y is C; Z is C; R5 is H; R6 and R7 are CH.sub.3; R8 and R9 are H; and R10 and R11 are both H or together form a cyclopropane ring.

12. The method of claim 1, wherein V is C.

13. The method of claim 1, wherein R1 is alkyl, alkoxy, CN, halo or CF.sub.3.

14. The method of claim 1, wherein R1 is alkyl.

15. The method of claim 1, wherein R3 is alkyl.

16. The method of claim 1, wherein the compound of formula (I) is: 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide; 2,5-Dimethyl-1-(6-phenyl-pyridin-2-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide; 1-[2-(3-Fluoro-phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide; 2,5-Dimethyl-1-(2-thiophen-3-yl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (6-aminomethyl-pyridin-3-ylmethyl)-amide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-3-fluoro-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-fluoro-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-chloro-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-trifluoromethyl-benzylamide; 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methoxy-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide; 1-[4-(3,5-Dimethyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide; 2,5-Dimethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide; 2,5-Dimethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrrole-2-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 2,5-Dimethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrrole-2-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide; 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrrole-2-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrrole-2-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4-carboxylic acid 4-aminomethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid 4-aminomethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid 4-aminomethyl-2-methyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrrole-2-carboxylic acid 4-aminomethyl-benzylamide; 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrrole-2-carboxylic acid 4-aminomethyl-benzylamide; 5-Methyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 4-aminomethyl-3-fluoro-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 4-aminomethyl-3-fluoro-2-methyl-benzylamide; 3-Methyl-1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 5-Methyl-1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-(2-Methyl-quinolin-6-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; 1-(2-Pyrrolidin-1-yl-pyridin-4-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide; or a pharmaceutically acceptable salt or solvate thereof.

17. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is cerebral haemorrhage.

18. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is cerebral haemorrhage in hyperglycemic patients.

19. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is disseminated intravascular coagulation.

20. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is blood coagulation during cardiopulmonary bypass surgery.

21. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is bleeding from post-operative surgery.

Description

EXAMPLES

[0326] The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

TABLE-US-00001 DMF N,N-Dimethylformamide EtOAc Ethyl Acetate hrs Hours HOBt Hydroxybenzotriazole LCMS Liquid chromatography mass spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol Min Minutes MS Mass spectrum NMR Nuclear magnetic resonance spectrum - NMR spectra were recorded at a frequency of 400 MHz unless otherwise indicated Pet. Ether Petroleum ether fraction boiling at 60-80° C. THF Tetrahydrofuran TFA Trifluoroacetic acid

[0327] All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.

[0328] .sup.1H NMR spectra were recorded on a Bruker Avance III (400 MHz) spectrometer with reference to deuterium solvent and at room temperature.

[0329] Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50×4.6 mm, with a linear gradient 10% to 90% 0.1% HCO.sub.2H/MeCN into 0.1% HCO.sub.2H/H.sub.2O over 11 min, flow rate 1.5 mL/min. Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.

[0330] Chemical names were generated using the Autonom software provided as part of the ISIS Draw package from MDL Information Systems.

[0331] Where products were purified by flash chromatography, ‘silica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution. Reverse phase preparative HPLC purifications were carried out using a Waters 2525 binary gradient pumping system at flow rates of typically 20 ml/min using a Waters 2996 photodiode array detector.

[0332] All solvents and commercial reagents were used as received.

Compound A

4-Bromo-2-fluoro-3-methyl-benzonitrile

[0333] ##STR00022##

[0334] To a solution of diisopropylamine (4.2 mL, 30 mmol) in dry THF (5 ml) was added a solution of nBuLi in THF (2.5M, 11 mL, 27.5 mmol) dropwise at −78° C. Once addition was complete, the reaction was allowed to warm to 0° C. and stirred in an ice-salt bath for 40 mins. The resulting solution was added dropwise to a solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) in dry THF (50 ml) at −78° C. and the mixture stirred for 2.5 hrs. The reaction mixture was then cooled to −78° C. and methyl iodide added in one portion and the mixture slowly allowed to warm to room temperature. The reaction was quenched with aqueous NH.sub.4C1 and extracted with EtOAc (3×40 ml). The combined organics were washed with water (40 ml) and brine (40 ml). The organics were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography eluting with 9:1 pet ether:ethyl acetate to afford 4-bromo-2-fluoro-3-methyl-benzonitrile as an off white solid (2.40 g, 45% yield).

Compound B

4-Bromo-2-fluoro-3,5-dimethyl-benzonitrile

[0335] ##STR00023##

[0336] Following a similar procedure to that described for the preparation of Compound A, 4-bromo-2-fluoro-3-methyl-benzonitrile was converted to 4-bromo-2-fluoro-3,5-dimethyl-benzonitrile which was isolated as a lime green oil.

Example 1

2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide

[0337] ##STR00024##

A. 2-Acetyl-4-oxo-pentanoic acid ethyl ester

[0338] Ethylacetoacetate sodium salt (17.10 g, 112 mmol) was suspended in acetone (500 mls) Potassium carbonate (15.54 g, 112 mmol) and potassium iodide (3.73 g, 22.48 mmol) were added and the resulting solution was refluxed. Chloroacetone (11.41 g, 124 mmol) was added dropwise over a period of 5 mins). Once the addition was complete the mixture was heated under reflux for a further 2 hours. The reaction mixture was allowed to cool to room temperature and the solid material was filtered off and washed with acetone. The resultant filtrate was evaporated and purified by flash chromatography (silica), eluant 75% Pet. Ether (60-80° C.), 25% EtOAc, fractions combined and evaporated in vacuo to give a yellow oil identified as 2-acetyl-4-oxo-pentanoic acid ethyl ester (10.1 g, 54.2 mmol, 48%).

B. 1-[2-phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester

[0339] 2-Acetyl-4-oxo-pentanoic acid ethyl ester (1.8 g, 9.66 mmol) was dissolved in toluene (35 mls), 2-phenyl-thiazoyl-4-methylamine (2.02 g, 10.62 mmol) and p-toluenesulphonic acid (183 mg, 0.966 mmol) were added. The reaction mixture was heated at reflux for 4 hours after which time it was diluted with ethyl acetate and washed with NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 85% Pet. Ether (60-80° C.), 15% EtOAc, fractions combined and evaporated in vacuo to give a colourless oil identified as 1-[2-phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.26 g, 3.69 mmol, 38%).

[0340] [M+H]+=341.27

C. 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid

[0341] 1-[2-Phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.07 g, 3.14 mmol) was dissolved in ethanol (50 mls). Sodium hydroxide (629 mg, 15.72 mmol) in water (5 mls) was added. The reaction mixture was heated at 90° C. for 3 days after which time the solvent was removed in vacuo. The residue was diluted with water and acidified to pH1 with 1M HCl and extracted with ethyl acetate (3×50 mls). The combined extracts were washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give an off white solid identified as 2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (980 mg, 3.14 mmol, 100%).

[0342] [M+H]+=313.23

D. [4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester

[0343] 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (1.60 g, 5.12 mmol) was dissolved in CH.sub.2Cl.sub.2(100 mls) and DMF(5 mls). This solution was cooled to 0° C. 1-(N-Boc-aminomethyl)-4-(aminomethyl) benzene (1.21 g, 5.12 mmol) was added followed by HOBt (830 mg, 6.14 mmol) and triethylamine (2.59 g, 25.6 mmol). Water soluble carbodiimide (1.37 g, 4.33 mmol) was then added. After 18 hrs at 0° C. to room temperature reaction mixture was diluted with chloroform (200 mls) and washed with NaHCO.sub.3 (1×50 mls), water (1×50 mls), brine (1×50 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 50% Pet. Ether (60-80° C.), 50% EtOAc, fractions combined and evaporated in vacuo to give a white solid identified as [4-({[2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (2.30 g, 4.33 mmol, 85%).

[0344] [M+H].sup.+=531.29.

E. 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide

[0345] [4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (2.30 g, 4.33 mmol) was dissolved in methanol (40 mls) to which 4M HCl in dioxan (10 mls) was added. After three hours at room temperature the solvent was removed in vacuo and the residue was azeotroped from toluene. The free base was liberated with a mixture of dichloromethane, MeOH and NH.sub.3 then evaporated. The residue was purified by flash chromatography (silica), eluant dichlromethane:MeOH:NH.sub.3 (100:10:1). The residue was triturated with EtOAc/Pet Ether 60-80° C. to give an off white solid identified as 2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide (1.2 g, 2.79 mmol, 64%).

[0346] [M+H]+=431.20

[0347] .sup.1H NMR: (d6-DMSO), δ: 2.26 (3H, s), 2.56 (3H, s), 3.33 (2H, br s), 3.68(2H, s), 4.33 (2H, d, J=6.1 Hz), 5.17 (2H, s), 6.29 (1H, s), 7.19-7.26 (5H, m), 7.48 (3H, m), 7.90-7.92 (2H, m), 8.05 (1H, t, J=6.1 Hz).

Example 2

2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide

[0348] ##STR00025##

A. (4-Cyano-2-methyl-benzyl)-carbamic acid benzyl ester

[0349] 4-Aminomethyl-3-methylbenzonitrile (1.0 g, 5.48 mmol) was dissolved in dichloromethane (50 mls) and the solution was cooled to 0° C. N,N-Diisopropylethylamine (1.56 g, 12.05 mmol) was added followed by benzyl chloroformate 1.12 g, 6.57 mmol) was added. After 3 days at 0° C. to room temperature the reaction mixture was diluted with chloroform, this solution was washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a brown oil identified as (4-cyano-2-methyl-benzyl)-carbamic acid benzyl ester (1.50 g, 5.35 mmol, 98%).

[0350] [M+H].sup.+=281.25

B. [4-(tert-Butoxycarbonylamino-methyl)-2-methyl-benzyl]-carbamic acid benzyl ester

[0351] (4-Cyano-2-methyl-benzyl)-carbamic acid benzyl ester (1.5 g, 5.35 mmol) was dissolved in methanol (75 mls). This solution was cooled to 0° C. Nickel (II) chloride hexahydrate (127 mg, 0.54 mmol) and di-tertbutyl dicarbonate (2.34 g, 10.70 mmol) were added followed by sodium borohydride (1.42 g, 37.56 mmol) portionwise. 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 CHCl.sub.3 (70 mls), washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, (silica), eluant 40% Pet. Ether (60-80° C.), 60% EtOAc to give white solid identified as [4-(tert-butoxycarbonylamino-methyl)-2-methyl-benzyl]-carbamic acid benzyl ester (1.11 g, 2.38 mmol, 54%).

[0352] [M+h].sup.+=285.32.

C. (4-Aminomethyl-3-methyl-benzyl)-carbamic acid tert-butyl ester

[0353] [4-(tert-Butoxycarbonylamino-methyl)-2-methyl-benzyl]-carbamic acid benzyl ester (130 mg, 0.34 mmol) was dissolved in methanol (40 mls). This solution was hydrogenated over 10% Pd/C (40 mg) at atmospheric pressure and room temperature for one hour after which time the catalyst was filtered off and washed with methanol (30 mls), the combined filtrates were evaporated in vacuo to give a white solid identified as (4-aminomethyl-3-methyl-benzyl)-carbamic acid tert-butyl ester (80 mg, 0.32 mmol, 95%).

D. [4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-3-methyl-benzyl]-carbamic acid tert-butyl ester

[0354] 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (100 mg, 0.32 mmol) was dissolved in CH.sub.2Cl.sub.2(20 mls). This solution was cooled to 0° C. (4-Aminomethyl-3-methyl-benzyl)-carbamic acid tert-butyl ester (80 mg, 0.32 mmol) was added followed by HOBt (52 mg, 0.38 mmol) and triethylamine (162 mg, 1.60 mmol). Water soluble carbodiimide (86 mg, 0.45 mmol) was then added. After 18 hrs at 0° C. to room temperature reaction mixture was diluted with chloroform (200 mls) and washed with NaHCO.sub.3 (1×50 mls), water (1×50 mls), brine (1×50 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 50% Pet. Ether (60-80° C.), 50% EtOAc, fractions combined and evaporated in vacuo to give a white solid identified as [4-({[2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-3-methyl-benzyl]-carbamic acid tert-butyl ester (105 mg, 0.19 mmol, 60%).

[0355] [M+H].sup.+=567.14.

E. 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide

[0356] [4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-3-methyl-benzyl]-carbamic acid tert-butyl ester (105 mg, 0.93 mmol) was dissolved in methanol (20 mls) to which 4M HCl in dioxan (5 mls) was added. After three hours at room temperature the solvent was removed in vacuo and the residue was azeotroped from toluene. The free base was liberated with a mixture of dichloromethane, MeOH and NH.sub.3 then evaporated. The residue was purified by flash chromatography (silica), eluant dichlromethane:MeOH:NH.sub.3 (100:10:1). The residue freeze dried from acetonitrile and water to give an off white solid identified as 2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide (58 mg, 0.13 mmol, 68%).

[0357] [M+H]+=445.17

[0358] .sup.1H NMR: (d6-DMSO), δ: 2.26 (3H, s), 2.27 (3H, s), 2.55 (3H, s), 3.32 (2H, br s), 3.65 (2H, s), 4.30 (2H, s), 5.16 (2H, s), 6.31 (1H, s), 7.08-7.13 (3H, m), 7.27 (1H, s), 7.48-7.54 (3H, m), 7.87-7.92 (3H, m).

Example 3

2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide

[0359] ##STR00026##

A. (4-Bromo-2,6-dimethyl-benzyl)-carbamic acid tert-butyl ester

[0360] 4-Bromo-2,6-dimethylbenzonitrile (2.5 g, 11.9 mmol) was dissolved in methanol (150 mls). This solution was cooled to 0° C. Nickel (II) chloride hexahydrate (238 mg, 1.19 mmol) and di-tertbutyl dicarbonate (5.19 g, 23.80 mmol) were added followed by sodium borohydride (3.15 g, 83.30 mmol) portionwise. 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 CHCl.sub.3 (70 mls), washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a colourless oil identified as (4-bromo-2,6-dimethyl-benzyl)-carbamic acid tert-butyl ester (3.0 g, 9.55 mmol, 80%).

B. (4-Cyano-2,6-dimethyl-benzyl)-carbamic acid tert-butyl ester

[0361] To a degassed solution of (4-bromo-2,6-dimethyl-benzyl)-carbamic acid tert-butyl ester (3.0 g, 9.55 mmol) in N,N-dimethylacetamide (30 mls) was added zinc powder (75 mg, 1.15 mmol), zinc acetate (210 mg, 1.15 mmol), 1,1′-bis(diphenylphosphino) ferrocine (635 mg, 1.15 mmol), zinc cyanide (560 mg, 4.77 mmol), and tris(dibenzylideneacetone) dipalladium(0) (524 mg, 0.57 mmol). The reaction was heated at 120° C. for 4 hrs. After which the reaction mixture was cooled to room temperature and extra 1,1′-bis(diphenylphosphino) ferrocine (423 mg, 0.77 mmol) and tris(dibenzylideneacetone) dipalladium(0) (350 mg, 0.38 mmol) were added and the reaction was heated at 120° C. for a further 28 hrs. The reaction mixture was cooled to RT filtered through celite and washed with ethyl acetate (250 mls). The filtrate washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography, (silica), eluant 80% Pet. Ether (60-80° C.), 20% EtOAc to give an off white solid identified as (4-cyano-2,6-dimethyl-benzyl)-carbamic acid tert-butyl ester (630 mg, 2.42 mmol, 25%).

[0362] [M+H].sup.+=261.06.

C. 4-Aminomethyl-3,5-dimethyl-benzonitrile Hydrochloride

[0363] (4-Cyano-2,6-dimethyl-benzyl)-carbamic acid tert-butyl ester (630 mg, 2.42 mmol) was dissolved in 4M HCl in dioxan (10 mls). After one hour at room temperature the solvent was removed in vacuo to give a pale brown solid identified as 4-aminomethyl-3,5-dimethyl-benzonitrile hydrochloride (470 mg, 2.39 mmol, 99%).

D. (4-Cyano-2,6-dimethyl-benzyl)-carbamic acid benzyl ester

[0364] 4-Aminomethyl-3,5-dimethyl-benzonitrile hydrochloride (470 mg, 2.39 mmol) was dissolved in dichloromethane (50 mls) and the solution was cooled to 0° C. N,N-Diisopropylethylamine (679 mg, 5.26 mmol) was added followed by benzyl chloroformate (489 mg, 2.87 mmol) was added. After one hour at 0° C. to room temperature the reaction mixture was diluted with chloroform, this solution was washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a brown oil identified as (4-cyano-2,6-dimethyl-benzyl)-carbamic acid benzyl ester (700 mg, 2.38 mmol, 99%).

[0365] [M+H].sup.+=295.04

E. [4-(tert-Butoxycarbonylamino-methyl)-2,6-dimethyl-benzyl]-carbamic acid benzyl ester

[0366] (4-Cyano-2,6-dimethyl-benzyl)-carbamic acid benzyl ester (700 mg, 2.38 mmol) was dissolved in methanol (75 mls). This solution was cooled to 0° C. Nickel (II) chloride hexahydrate (57 mg, 0.24 mmol) and di-tertbutyl dicarbonate (1.04 g, 4.76 mmol) were added followed by sodium borohydride (630 mg, 16.65 mmol) portionwise. 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 CHCl.sub.3 (70 ml), washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography, (silica), eluant 65% Pet. Ether (60-80° C.), 35% EtOAc to give an off white solid identified as [4-(tert-butoxycarbonylamino-methyl)-2,6-dimethyl-benzyl]-carbamic acid benzyl ester (600 mg, 1.51 mmol, 63%).

[0367] [M+H].sup.+=421.05 (M+Na).

F. (4-Aminomethyl-3,5-dimethyl-benzyl)-carbamic acid tert-butyl ester

[0368] [4-(tert-Butoxycarbonylamino-methyl)-2,6-dimethyl-benzyl]-carbamic acid benzyl ester (600 mg, 1.51 mmol) was dissolved in methanol (60 mls). This solution was hydrogenated over 10% Pd/C (100 mg) at atmospheric pressure and room temperature for one hour after which time the catalyst was filtered off and washed with methanol (30 mls), the combined filtrates were evaporated in vacuo to give a white solid identified as (4-aminomethyl-3,5-dimethyl-benzyl)-carbamic acid tert-butyl ester (350 mg, 1.32 mmol, 88%).

[0369] [M+H].sup.+=287.07 (M+Na).

G. [4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-3,5-dimethyl-benzyl]-carbamic acid tert-butyl ester

[0370] 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (118 mg, 0.38 mmol) was dissolved in CH.sub.2Cl.sub.2(20 mls). This solution was cooled to 0° C. (4-(4-Aminomethyl-3,5-dimethyl-benzyl)-carbamic acid tert-butyl ester (100 mg, 0.38 mmol) was added followed by HOBt (61 mg, 0.45 mmol) and triethylamine (191 mg, 1.89 mmol). Water soluble carbodiimide (102 mg, 0.53 mmol) was then added. After 18 hrs at 0° C. to room temperature reaction mixture was diluted with chloroform (200 mls) and washed with NaHCO.sub.3 (1×50 mls), water (1×50 mls), brine (1×50 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 50% Pet. Ether (60-80° C.), 50% EtOAc, fractions combined and evaporated in vacuo to give a white solid identified as [4-({[2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-3,5-dimethyl-benzyl]-carbamic acid tert-butyl ester (110 mg, 0.20 mmol, 52%).

[0371] [M+H].sup.+=567.14.

H. 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide

[0372] [4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-3,5-dimethyl-benzyl]-carbamic acid tert-butyl ester (110 mg, 0.20 mmol) was dissolved in methanol (20 mls) to which 4M HCl in dioxan (5 mls) was added. After three hours at room temperature the solvent was removed in vacuo and the residue was azeotroped from toluene. The free base was liberated with a mixture of dichloromethane, MeOH and NH.sub.3 then evaporated. The residue was purified by flash chromatography (silica), eluant dichloromethane:MeOH:NH.sub.3 (100:10:1). The residue freeze dried from acetonitrile and water to give an off white solid identified as 2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide (77 mg, 0.17 mmol, 85%).

[0373] [M+H].sup.+=459.09

[0374] .sup.1H NMR: (d6-DMSO), δ: 2.22 (3H, s), 2.34 (6H, s), 2.54 (3H, s), 3.74 (2H, s), 4.34 (2H, d, J=5.0 Hz), 5.15 (2H, s), 5.44 (2H, br s), 6.24 (1H, s), 7.00 (2H, s), 7.25 (1H, s), 7.45 (1H, t, J=5.1 Hz), 7.49-7.51 (3H, m), 7.88-7.91 (2H, m).

Example 4

2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide

[0375] ##STR00027##

A. 4-(1-Amino-cyclopropyl)-benzonitrile

[0376] In oven dried glassware under an atmosphere of nitrogen a solution of 1,4-dicyanobenzene (2.50 g, 20 mmol) in anhydrous dichloromethane (80 mls) was cooled to −70° C. Titanium isopropoxide (6.1 g, 21.46 mmol) was added followed by dropwise addition of 3M solution of ethyl magnesium bromide in diethyl ether (14.37 mls, 43 mmol). The reaction was stirred at −70° C. for 10 min and then allowed to warm to room temperature). After 1 hour boron trifluoride etherate (5.54 g, 39.02 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was quenched with NH.sub.4C1 and then the pH adjusted to 9-10 with 1M NaOH. The layers were separated and the aqueous extracted dichloromethane (5×20 mls) then with ethyl acetate (3×20 mls). Organic layers were combined and dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography (silica), eluant dichloromethane/MeOH/NH.sub.4OH (99:1:1, 98:2:1, 97:3:1, 95:5:1) giving a yellow oil identified as 4-(1-amino-cyclopropyl)-benzonitrile (1.61 g, 10 mmol, 52%).

[0377] .sup.1H NMR: (CDCl.sub.3), δ: 1.07-1.10 (2H, m), 1.21-1.24 (2H, m), 1.86 (2H, br, s), 7.39 (2H, dt, J=8.4, 1.9 Hz), 7.61 (2H, dt, J=8.4, 1.9 Hz).

B. [1-(4-Cyano-phenyl)-cyclopropyl]-carbamic acid benzyl ester

[0378] 4-(1-Amino-cyclopropyl)-benzonitrile (1.61 g, 10.18 mmol) was dissolved in dichloromethane (250 mls) and the solution was cooled to 0° C. N,N-Diisopropylethylamine (2.89 g, 22.39 mmol) was added followed by benzyl chloroformate 2.08 g, 12.21 mmol) was added. After 18 hours at 0° C. to room temperature the reaction mixture was diluted with chloroform, this solution was washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 90% Pet. Ether (60-80° C.), 10% EtOAc, fractions combined and evaporated in vacuo to give a to give a yellow oil identified as [1-(4-cyano-phenyl)-cyclopropyl]-carbamic acid benzyl ester (1.33 g, 4.55 mmol, 45%).

[0379] [M+H].sup.+=293.04

[0380] .sup.1H NMR: (CDCl.sub.3), δ: 1.24 (6H, t, J=7.2 Hz), 3.02 (4H, q, J=7.2 Hz), 4.70 (2H, s), 7.34-7.37 (5H, m), 7.77 (2H, d, J=8.4 Hz), 8.04 (2H, d, J=8.6 Hz).

C. {1-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-cyclopropyl}-carbamic acid benzyl ester

[0381] [1-(4-Cyano-phenyl)-cyclopropyl]-carbamic acid benzyl ester (1.33 g, 4.55 mmol) was dissolved in methanol (100 mls). This solution was cooled to 0° C. Nickel (II) chloride hexahydrate (108 mg, 0.46 mmol) and di-tertbutyl dicarbonate (1.99 g, 9.10 mmol) were added followed by sodium borohydride (1.21 g, 31.85 mmol) portionwise. The reaction mixture was stirred at 0° C. to room temp for 18 hours. The MeOH was removed by evaporation. The residue was dissolved in CHCl.sub.3 (70 mls), washed with sat NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, (silica), eluant 30% Pet. Ether (60-80° C.), 70% EtOAc to give white solid identified as {1-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-cyclopropyl}-carbamic acid benzyl ester (1.06 g, 2.67 mmol, 59%).

[0382] [M+H].sup.+=419.2 (M+Na).

D. [1-(4-Aminomethyl-phenyl)-cyclopropyl]-carbamic acid benzyl ester Hydrochloride

[0383] {1-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-cyclopropyl}-carbamic acid benzyl ester (90 mg, 0.23 mmol) was dissolved in 4M HCl in dioxan (10 mls). After 3 hours at room temperature the solvent was removed in vacuo to give a yellow solid identified as [1-(4-aminomethyl-phenyl)-cyclopropyl]-carbamic acid benzyl ester hydrochloride (84 mg, 0.23 mmol, 100%).

[0384] [M+H].sup.+=318.97 (M+Na).

E. {1-[4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-phenyl]-cyclopropyl}-carbamic acid benzyl ester

[0385] 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (78 mg, 0.25 mmol) was dissolved in CH.sub.2Cl.sub.2(20 mls). This solution was cooled to 0° C. [1-(4-Aminomethyl-phenyl)-cyclopropyl]-carbamic acid benzyl ester hydrochloride (84 mg, 0.23 mmol) was added followed by HOBt (37 mg, 0.27 mmol) and triethylamine (115 mg, 1.14 mmol). Water soluble carbodiimide (61 mg, 0.32 mmol) was then added. After 18 hrs at 0° C. to room temperature reaction mixture was diluted with chloroform (100 mls) and washed with NaHCO.sub.3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 50% Pet. Ether (60-80° C.), 50% EtOAc, fractions combined and evaporated in vacuo to give a white solid identified as {1-[4-({[2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-phenyl]-cyclopropyl}-carbamic acid benzyl ester (66 mg, 0.11 mmol, 49%).

[0386] [M+H].sup.+=613.02 (M+Na).

F. 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide

[0387] {1-[4-({[2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carbonyl]-amino}-methyl)-phenyl]-cyclopropyl}-carbamic acid benzyl ester (70 mg, 0.12 mmol) was dissolved in methanol (40 mls). This solution was hydrogenated over 10% Pd/C (10 mg) at atmospheric pressure and room temperature for 5 hours after which time the catalyst was filtered off and washed with methanol (30 mls), the combined filtrates were evaporated in vacuo and freeze dried from acetonitrile and water to give a white solid identified as 2,5-dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide (21 mg, 0.046 mmol, 38%).

[0388] [M+H].sup.+=480.16.

[0389] .sup.1H NMR: (d6-DMSO) δ: 0.75 (2H, t, J=7.4 Hz), 1.45-1.57 (2H, m), 2.25 (3H, s), 2.55 (3H, s), 3.63 (1H, t, J=6.7 Hz), 4.32 (2H, d, J=6.1 Hz), 5.16 (2H, s), 6.29 (2H, s), 7.18 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.0 Hz), 7.25 (1H, s), 7.49 (2H, d, J=1.8 Hz), 7.50-7.51 (1H, m), 7.89 (1H, d, J=1.7 Hz), 7.91 (1H, d, J=2.6 Hz), 8.03 (1H, t, J=6.1 Hz).

Reference Example 5

1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide

[0390] ##STR00028##

A. 1-(4-Chloromethyl-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0391] Polymer-supported triphenylphosphine (3.0 mmol/g, 3 equiv, 1.0 g) was swollen in THF/dichloromethane (1:1, 100 mls) under a nitrogen atmosphere. Ethyl 1H-pyrazole-4-carboxylate (500 mg, 3.57 mmol) and 4-(chloromethyl)benzyl alcohol (671 mg, 4.28 mmol) were added followed by a solution of diisopropyl azodicarboxylate (1.08 g, 5.35 mmol) in THF/dichloromethane (1:1, 10 mls) over a period of 30 mins. The reaction mixture was stirred at room temperature for 18 hours, the mixture was filtered through celite and the resin was washed with 3 cycles of dichloromethane/methanol (15 mls). The combined filtrates were evaporated in vacuo and triturated with ethanol to give a white solid identified as 1-(4-chloromethyl-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (741 mg, 2.66 mmol, 75%).

[0392] [M+H].sup.+=279.05

B. 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester

[0393] 1-(4-Chloromethyl-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (300 mg, 1.076 mmol) was dissolved in acetone (50 mls) 2-hydroxypyridine (123 mg, 0.001 mmol) and potassium carbonate (446 mg, 0.003 mmol) were added and the reaction mixture was stirred at 50° C. for 3 hours after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100 mls), this solution was washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCl.sub.3, fractions combined and evaporated in vacuo to give a colourless oil identified as 1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester (310 mg, 0.92, 85%).

[0394] [M+H].sup.+=337.78, 350.84 (M+Na).

C. 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid

[0395] 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester (310 mg, 0.92 mmol) was dissolved in THF (50 mls) and water (5 mls) lithium hydroxide (110 mg, 4.6 mmol) was added. The reaction mixture was stirred at 50° C. for 18 hours after which time the solvent was concentrated in vacuo and the residue taken up in EtOAc (50 mls), the aqueous layer was separated, acidified with 1M HCl to pH2 and extracted CHCl.sub.3 (3×50 mls) the combined extracts were washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCl.sub.3, fractions combined and evaporated in vacuo to give a colourless oil identified as 1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (140 mg, 0.453 mmol, 49%).

[0396] [M+H].sup.+=309.93

D. {4-[({1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carbonyl}-amino)-methyl]-benzyl}-carbamic acid tert-butyl ester

[0397] 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (130 mg, 0.42 mmol) was dissolved in CH.sub.2Cl.sub.2 (50 mls) and DMF (2.5 mls). This solution was cooled to 0° C. tert-Butyl 4-(Aminomethyl)benzylcarbamate (119 mg, 0.50 mmol) was added followed by HOBt (62 mg, 0.46 mmol) and triethylamine (128 mg, 1.27 mmol). Water soluble carbodiimide (97 mg, 0.50 mmol) was then added. After 18 hours at 0° C. to room temperature reaction mixture was diluted with chloroform (400 mls) washed with 0.3M KHSO.sub.4 (1×30 mls), NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 6% MeOH, 94% CHCl.sub.3, fractions combined and evaporated in vacuo to give a white solid identified as {4-[({1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carbonyl}-amino)-methyl]-benzyl}-carbamic acid tert-butyl ester (156 mg, 0.296 mmol, 70%).

[0398] [M+H].sup.+=550.45

E. 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide Hydrochloride

[0399] {4-[({1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carbonyl}-amino)-methyl]-benzyl}-carbamic acid tert-butyl ester (52 mg, 0.10 mmol) was dissolved in 4M HCl in dioxan (25 mls). 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 1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide hydrochloride (89 mg, 0.19 mmol, 47%).

[0400] [M+H].sup.+=428.32

[0401] .sup.1H NMR: (d6-DMSO), δ: 3.97 (2H, q, J=5.72 Hz), 4.38 (2H, dq, J=6.06 Hz), 5.08 (2H, s), 5.31 (2H, s), 6.23 (1H, q, J=6.34 Hz), 6.40 (1H, d, J=5.72 Hz), 7.22-7.32 (6H, m), 7.41-7.44 (2H, m), 7.77 (1H, d, J=6.62 Hz), 7.91 (1H, s), 8.27 (1H, s), 8.39 (3H, s, br), 8.71-8.74 (1H, m).

Reference Example 6

1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4-carboxylic acid 4-aminomethyl-benzylamide

[0402] ##STR00029##

A. 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one

[0403] 4-(Chloromethyl)benzylalcohol (1.0 g, 6.38 mmol) was dissolved in acetone (50 mls) 2-hydroxypyridine (729 mg, 7.66 mmol) and potassium carbonate (2.65 g, 19.20 mmol) were added and the reaction mixture was stirred at 50° C. for 3 hours after which time the solvent was removed in vacuo and the residue taken up in chloroform (100 mls), this solution was washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCl.sub.3, fractions combined and evaporated in vacuo to give a white solid identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (1.10 g, 5.11, 80%)

[0404] [M+H].sup.+=238.09 (M+Na)

B. 1-(4-Azidomethyl-benzyl)-1H-pyridin-2-one

[0405] 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (570 mg, 2.65 mmol) and DBU (806 mg, 5.30 mmol) were dissolved in DMF (20 mls). Diphenylphosphoryl azide (1.09 g, 3.97 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours after which time the reaction mixture was diluted with EtOAc (100 mls), this solution was washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCl.sub.3, fractions combined and evaporated in vacuo to give a white foamy solid identified as 1-(4-azidomethyl-benzyl)-1H-pyridin-2-one (430 mg, 1.79 mmol, 68%).

[0406] [M+H].sup.+=360.90 (M+Na).

C. 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid ethyl ester

[0407] 1-(4-Azidomethyl-benzyl)-1H-pyridin-2-one (340 mg, 1.41 mmol), ethyl propiolate (139 mg, 1.41 mmol), (+)-sodium L-ascorbate (280 mg, 1.41 mmol) and copper (II) sulphate pentahydrate (71 mg, 0.28 mmol) were dissolved in tert-butanol (20 mls) and water (5 mls). The reaction mixture was stirred at room temperature for 18 hours after which time the reaction mixture was diluted with chloroform (100 mls), this solution was washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was triturated with ethyl acetate and pet ether 60-80 to give a white solid identified as 1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid ethyl ester (110 mg, 0.33 mmol, 23%).

[0408] [M+H].sup.+=486.18

D. 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid

[0409] 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid ethyl ester (110 mg, 0.32 mmol) was dissolved in THF(50 mls) and water (5 mls), lithium hydroxide (39 mg, 1.62 mmol) was added. The reaction mixture was stirred at 50° C. for 18 hours after which time the solvent was concentrated in vacuo and the residue taken up in EtOAc (50 mls), the aqueous layer was separated, acidified with 1M HCl to pH2 and extracted CHCl.sub.3 (3×50 mls) the combined extracts were washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCl.sub.3, fractions combined and evaporated in vacuo to give a colourless oil identified as 1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid (80 mg, 0.26 mmol, 79%).

E. {4-[({1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carbonyl}-amino)-methyl}-benzyl]-carbamic acid tert-butyl ester

[0410] 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid (80 mg, 0.26 mmol) was dissolved in CH.sub.2Cl.sub.2(50 mls) and DMF(2.5 mls). This solution was cooled to 0° C. tert-Butyl 4-(aminomethyl)benzylcarbamate (73 mg, 0.31 mmol) was added followed by HOBt (38 mg, 0.28 mmol) and triethylamine (78 mg, 0.77 mmol). Water soluble carbodiimide (59 mg, 0.31 mmol) was then added. After 18 hours at 0° C. to room temperature reaction mixture was diluted with chloroform (400 mls) washed with 0.3M KHSO.sub.4 (1×30 mls), NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluant 6% MeOH, 94% CHCl.sub.3, fractions combined and evaporated in vacuo to give a white solid identified as {4-[({1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4-carbonyl}-amino)-methyl]-benzyl}-carbamic acid tert-butyl ester (85 mg, 0.166 mmol, 62%).

[0411] [M+H].sup.+=550.45

F. 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid 4-aminomethyl-benzylamide Hydrochloride

[0412] {4-[({1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carbonyl}-amino)-methyl]-benzyl}-carbamic acid tert-butyl ester (85 mg, 0.16 mmol) was dissolved in 4M HCl in dioxan (25 mls). 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 1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H[1,2,3]triazole-4-carboxylic acid 4-aminomethyl-benzylamide hydrochloride (76 mg, 0.18 mmol, 60%).

[0413] [M+H].sup.+=429.10

[0414] .sup.1H NMR: (d6-DMSO), δ: 4.00 (2H, q, J=5.72 Hz), 4.43 (2H, q, J=6.25 Hz), 5.08 (2H, s), 5.31 (2H, s), 6.23 (1H, q, J=6.52 Hz), 6.40 (1H, d, J=8.92 Hz), 7.27-7.48 (7H, m), 7.77 (1H, q, J=8.82 Hz), 7.91 (1H, s), 8.21 (3H, s, br), 8.64 (1H, s), 9.12 (1H, t, J=5.83 Hz).

Reference Example 7

1-(2-Methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide

[0415] ##STR00030##

A. (4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester

[0416] 4-Pyrazolecarboxylic acid (400 mg, 3.57 mmol) was dissolved in CH.sub.2Cl.sub.2 (50 mls) and DMF (2.5 mls). This solution was cooled to 0° C. tert-Butyl 4-(aminomethyl)benzylcarbamate (1.01 g, 4.28 mmol) was added followed by HOBt (530 mg, 3.93 mmol) and triethylamine (1.08 g, 10.71 mmol). Water soluble carbodiimide (821 mg, 4.28 mmol) was then added. After 18 hours at 0° C. to room temperature reaction mixture was diluted with chloroform (400 mls) washed with 0.3M KHSO.sub.4 (1×30 mls), NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluant 7% MeOH, 93% CHCl.sub.3, fractions combined and evaporated in vacuo to give a white solid identified as (4-{[(1H-pyrazole-4-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (1.10 g, 3.33 mmol, 93%).

[0417] [M+H].sup.+=352.95 (M+Na)

B. (2-Methyl-quinolin-6-yl)-methanol

[0418] 2-Methyl-quinoline-6-carboxylic acid (1.0 g, 5.34 mmol) was dissolved in THF (100 mls), this solution was cooled to −20° C., to this solution was added triethylamine (1.62 g, 16.03 mmol) and isobutyl chloroformate (875 mg, 6.41 mmol). The reaction mixture was stirred at −20° C. for 20 mins and then poured into a solution of sodium borohydride (1.0 g, 26.71 mmol) in water (10 mls) at 0° C. The reaction mixture was stirred at 0° C. to room temperature for 18 hours and diluted with EtOAc (200 mls) 0.3M KHSO.sub.4 (1×50 mls), water (1×50 mls), brine (1×50 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a white solid. The solid were triturated with EtOAc/Pet Ether 60-80° C. to give a white solid identified as (2-methyl-quinolin-6-yl)-methanol (890 mg, 5.14 mmol, 96%).

[0419] [M+H].sup.+=174.24

C. 6-Bromomethyl-2-methyl-quinoline

[0420] (2-Methyl-quinolin-6-yl)-methanol (150 mg, 0.87 mmol) was dissolved in dichloromethane (50 mls). To this solution was added phosphorous tribromide (215 mg, 2.13 mmol) The reaction mixture was stirred at room temperature for 18 hours and diluted with CHCl.sub.3 (100 mls) the filtrate was washed with sat. NaHCO.sub.3 (1×30 mls), water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo to give a white solid which was identified as 6-bromomethyl-2-methyl-quinoline (180 mg, 0.76 mmol, 88%).

[0421] [M+H].sup.+=235.96

D. [4-({[1-(2-Methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester

[0422] 6-Bromomethyl-2-methyl-quinoline (180 mg, 0.76 mmol) was dissolved in DMF (10 mls). (4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (302 mg, 0.915 mmol) and cesium carbonate (745 mg, 2.29 mmol) were added and the reaction mixture was stirred at 50° C. for 18 hours after which time the reaction mixture was diluted with EtOAc (100 mls), this solution was washed with water (1×30 mls), brine (1×30 mls), dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCl.sub.3, fractions combined and evaporated in vacuo to give a white foamy solid identified as [4-({[1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (145 mg, 0.30 mmol, 39%).

[0423] [M+H].sup.+=486.18

E. 1-(2-Methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide Hydrochloride

[0424] [4-({[1-(2-Methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (145 mg, 0.30 mmol) was dissolved in 4M HCl in dioxan (25 mls). 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 1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide hydrochloride (76 mg, 0.18 mmol, 60%).

[0425] [M+h].sup.+=385.94

[0426] .sup.1H NMR: (d6-DMSO), δ: 2.97 (3H, s), 3.98 (2H, q, J=5.53 Hz), 4.40 (2H, d, J=6.00 Hz), 5.66 (2H, s), 7.32 (2H, d, J=8.02 Hz), 7.42 (2H, d, J=8.30 Hz), 7.94-7.99 (1H, m), 8.00 (1H, s), 8.10 (1H, s), 8.37-8.43 (5H, m), 8.82 (1H, t, J=6.09 Hz), 9.00 (1H, d, J=8.60 Hz).

[0427] The compounds in the following tables were synthesised as described for Examples 1 to 4 and reference examples 5-7.

TABLE-US-00002 TABLE 1 [00031] Example Free No A Base MW [M + H].sup.+ 8 [00032] 430.6 431.29 9 [00033] 429.6 430.1 10 [00034] 429.6 430.16 11 [00035] 414.5 437.2 (M + Na) 12 [00036] 404.5 405.19 13 [00037] 430.6 431.17 14 [00038] 430.6 431.36 15 [00039] 433.5 434.24 16 [00040] 424.5 425.35 17 [00041] 425.5 426.23 18 [00042] 414.5 415.24 19 [00043] 428.5 429.42

TABLE-US-00003 TABLE 2 [00044] Example No. G6 Free Base MW [M + H].sup.+ 20 H 353.5 353.87 21 [00045] 430.6 431.16 22 [00046] 429.6 430.15 23 [00047] 450.6 451.16

TABLE-US-00004 TABLE 3 [00048] Free Base Example No G7 R6 R7 MW [M + H].sup.+ 24 [00049] [00050] CH.sub.3 492.6 493.19 25 [00051] CH.sub.3 H 416.5 416.83 26 [00052] CH.sub.3 CH.sub.3 436.6 437.14 27 [00053] CH.sub.3 CH.sub.3 465.0 465.13 28 [00054] CH.sub.3 CH.sub.3 465.0 465.14 29 [00055] CH.sub.3 CH.sub.3 448.6 449.16 30 [00056] CH.sub.3 CH.sub.3 444.6 445.32 31 [00057] CH.sub.3 CH.sub.3 431.6 454.18 (M + Na) 32 [00058] CH.sub.3 CH.sub.3 431.6 432.38 33 [00059] CH.sub.3 CH.sub.3 460.6 461.36 34 [00060] CH.sub.3 CH.sub.3 460.6 461.37 35 [00061] CH.sub.3 CH.sub.3 444.6 445.37 36 [00062] CH.sub.3 CH.sub.3 431.6 432.39 37 [00063] CH.sub.3 CH.sub.3 436.6 437.32 38 [00064] CH.sub.3 CH.sub.3 444.6 445.36 39 [00065] CH.sub.3 CH.sub.3 420.5 421.19 40 [00066] CH.sub.3 CH.sub.3 432.5 433.21 41 [00067] CH.sub.3 CH.sub.3 474.6 475.26

TABLE-US-00005 TABLE 4 [00068] Example No B R8 R9 G8 Free Base MW [M + H].sup.+ 42 [00069] (R)-CH.sub.3 H H 444.6 445.15 43 [00070] H H H 431.6 432.22 44 [00071] H H F 449.5 450.18 45 [00072] H H H 448.6 449.14 46 [00073] H H H 444.6 445.18 47 [00074] H H H 448.6 449.07 48 [00075] H H H 444.593 467.15 (M + Na) 49 [00076] H H H 465.01 465.00 50 [00077] H H H 498.564 499.04 51 [00078] H H H 444.593 467.03 (M + Na) 52 [00079] —CH.sub.2—CH.sub.2— (so as to form spiro-cyclo- propyl) H 456.604 53 [00080] H H H 460.592 483.21 (M + Na) 54 [00081] H H H 460.592 483.29 (M + Na)

TABLE-US-00006 TABLE 5 [00082] Example No G9 G10 R3 R7 Free Base MW [M + H].sup.+ 55 H H H H 347.5 348.24 56 H H Cl H 381.9 382.15 57 H H H [00083] 409.5 410.24 58 CH.sub.3CH.sub.2O H H CH.sub.3 391.5 392.21 59 H CH.sub.3CH.sub.2O H CH.sub.3 391.5 392.21 60 H [00084] H CH.sub.3 453.6 454.2 61 H CH.sub.3O H CH.sub.3 377.5 378.71 62 H.sub.2NCO H H CH.sub.3 390.5 391.15 63 H H.sub.2NCO H CH.sub.3 390.5 391.13 64 NC H H CH.sub.3 372.5 373.14 65 H NC H CH.sub.3 372.5 373.13 66 H.sub.2NCH.sub.2 H H CH.sub.3 376.5 377.18 67 H H.sub.2NCH.sub.2 H CH.sub.3 376.5 377.19 68 H H.sub.3CCONHCH.sub.2 H CH.sub.3 418.5 419.16 69 [00085] H H CH.sub.3 423.5 424.28 70 H [00086] H CH.sub.3 423.5 424.33 71 [00087] H H CH.sub.3 424.5 425.41 72 [00088] H H CH.sub.3 424.5 425.36 73 [00089] H H CH.sub.3 432.6 433.24 74 [00090] H H CH.sub.3 430.6 431.28

TABLE-US-00007 TABLE 6 [00091] Example No R7 R6 Free Base MW [M + H].sup.+ 75 CH.sub.3 CH.sub.3 347.5 348.2  76 H CH.sub.3 333.4 334.17 77 CH.sub.3CH.sub.2CH.sub.2 CH.sub.3 361.5 362.19 78 CH.sub.3CH.sub.2 CH.sub.3 375.5 376.21

TABLE-US-00008 TABLE 7 [00092] Free Example Base No A R7 R5 W Z Y MW [M + H].sup.+ 79 [00093] H H C C N 405.5 80 [00094] CH.sub.3 H C C N 417.5 418.16 81 [00095] H CH.sub.3 C C N 417.5 418.14 82 [00096] CF.sub.3 H C C N 471.5 494.06 (M + Na) 83 [00097] H CF.sub.3 C C N 471.5 494.04 (M + Na) 84 [00098] H [00099] C C N 396.5 397.21 85 [00100] H H C C N 414.5 437.32 (M + Na) 86 [00101] H H C C N 428.5 429.31 87 [00102] H H C C N 431.53 432.24 88 [00103] absent absent N N CH 413.48 455.06 (M + MeCN)

TABLE-US-00009 TABLE 8 [00104] Free Base Example No G12 MW [M + H].sup.+ 89 [00105] 453.5 454.3 90 [00106] 454.6 455.3 91 [00107] 468.6 469.3 92 [00108] 482.6 483.2 93 [00109] 494.6 495.2 94 [00110] 482.6 483.3 95 [00111] 496.6 497.4

TABLE-US-00010 TABLE 9 [00112] Free Base Example No G13 MW [M + H].sup.+  96 [00113] 441.6 442.3  97 [00114] 455.6 456.3  98 [00115] 467.6 468.3  99 [00116] 469.6 470.2 100 [00117] 481.6 482.3 101 [00118] 469.6 470.3 102 [00119] 483.7 484.3 103 [00120] 440.54 441.2 104 [00121] 414.50 415.3 105 [00122] 440.54 441.3 106 [00123] 428.53 429.3 107 [00124] 428.53 429.3 108 [00125] 415.49 416.3 109 [00126] 429.52 430.3 110 [00127] 441.53 442.2 111 [00128] 442.56 443.3 112 [00129] 442.56 443.3 113 [00130] 443.54 444.3 114 [00131] 456.58 457.05 115 [00132] 456.58 457.05 116 [00133] 470.61 471.07 117 [00134] 500.49 500.96 118 [00135] 510.55 511.00 119 [00136] 514.52 514.98 120 [00137] 528.54 528.90

TABLE-US-00011 TABLE 10 [00138] Example Free Base No G14 MW [M + H].sup.+ 121 [00139] 455.6 456.2 122 [00140] 468.6 469.2 123 [00141] 444.6 445

TABLE-US-00012 TABLE 11 [00142] Free Base Example No G15 MW [M + H].sup.+ 124 [00143] 427.55 428.00 125 [00144] 427.55 428.01 126 [00145] 481.53 481.88 127 [00146] 481.53 481.89 128 [00147] 440.58 441.07

TABLE-US-00013 TABLE 12 [00148] Ex- Free ample Base No G16 R5 R7 MW [M + H].sup.+ 129 [00149] CF.sub.3 H 486.54 487.03 130 [00150] CF.sub.3 H 486.54 131 [00151] H CH.sub.3 432.57 432.99 132 [00152] CH.sub.3 H 432.57 133 [00153] CH.sub.3 H 432.57 432.99

TABLE-US-00014 TABLE 13 Example No Name 8 2,5-Dimethyl-1-(5-pyridin-3-yl-thiophen-3-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 9 2,5-Dimethyl-1-(4-phenyl-thiophen-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 10 2,5-Dimethyl-1-(5-phenyl-thiophen-3-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 11 2,5-Dimethyl-1-(3-phenyl-isoxazol-5-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 12 1-Benzothiazol-2-ylmethyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 13 2,5-Dimethyl-1-(4-pyridin-3-yl-thiophen-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 14 2,5-Dimethyl-1-(4-pyridin-4-yl-thiophen-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 15 2,5-Dimethyl-1-(6-morpholin-4-yl-pyridin-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 16 2,5-Dimethyl-1-(6-phenyl-pyridin-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 17 1-[2,3′]Bipyridinyl-6-ylmethyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 18 2,5-Methyl-1-(2-phenyl-oxazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 19 2,5-Dimethyl-1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-pyrrole- 3-carboxylic acid 4-aminomethyl-benzylamide 20 2,5-Dimethyl-1-thiophen-2-ylmethyl-1H-pyrrole-3-carboxylic acid 4-amidomethyl-benzylamide 21 2,5-Dimethyl-1-(5-pyridin-4-yl-thiophen-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 22 2,5-Dimethyl-1-(5-phenyl-thiophen-2-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 23 2,5-Dimethyl-1-[5-(2-methyl-thiazol-4-yl)-thiophen-2-ylmethyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 24 5-Methyl-2-phenyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 25 2-Methyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 26 2,5-Dimethyl-1-[2-(2-thienyl)-thiazol-4-ylmethyl]-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 27 2,5-Dimethyl-1-[2-(3-chlorophenyl)-thiazol-4-ylmethyl]-1H-pyrrole- 3-carboxylic acid 4-aminomethyl-benzylamide 28 2,5-Dimethyl-1-[2-(4-chlorophenyl)-thiazol-4-ylmethyl]-1H-pyrrole- 3-carboxylic acid 4-aminomethyl-benzylamide 29 1-[2-(3-Fluoro-phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H- pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 30 2,5-Dimethyl-1-(2-m-tolyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 31 2,5-Dimethyl-1-(2-pyridin-3-yl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 32 2,5-Dimethyl-1-(2-pyridin-4-yl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 33 2,5-Dimethyl-1-(3-methoxyphenyl-thiazol-4-ylmethyl)-1H-pyrrole- 3-carboxylic acid 4-aminomethyl-benzylamide 34 2,5-Dimethyl-1-(4-methoxyphenyl-thiazol-4-ylmethyl)-1H-pyrrole- 3-carboxylic acid 4-aminomethyl-benzylamide 35 2,5-Dimethyl-1-(2-p-tolyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 36 2,5-Dimethyl-1-(2-pyridin-2-yl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 37 2,5-Dimethyl-1-(2-thiophen-3-yl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 38 1-(2-Benzyl-thiazol-4-ylmethyl)-2,5-dimethyl-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 39 2,5-Dimethyl-1-(2-furan-3-yl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 40 2,5-Dimethyl-1-(2-pyrazin-2-yl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 41 1-[2-(4-Ethoxy-phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H- pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 42 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid [(R)-1-(4-aminomethyl-phenyl)-ethyl]-amide 43 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid (6-aminomethyl-pyridin-3-ylmethyl)-amide 44 1-[2-(3-Fluoro-phenyl)-thiazol-4-ylmethyl]-2,5-dimethyl-1H- pyrrole-3-carboxylic acid (6-aminomethyl-pyridin-3-ylmethyl)- amide 45 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-3-fluoro-benzylamide 46 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-3-methyl-benzylamide 47 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-2-fluoro-benzylamide 48 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-((R)-1-amino-ethyl)-benzylamide 49 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-2-chloro-benzylamide 50 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-2-trifluoromethyl-benzylamide 51 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid-4-((S)-1-amino-ethyl)-benzylamide 52 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid [1-(4-aminomethyl-phenyl)-cyclopropyl]-amide 53 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-3-methoxy-benzylamide 54 2,5-Dimethyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-2-methoxy-benzylamide 55 1-Benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-benzylamide 56 1-Benzyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-2-chloro-benzylamide 57 1-Benzyl-5-methyl-2-phenyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-benzylamide 58 1-(3-Ethoxy-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-benzylamide 59 1-(4-Ethoxy-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-benzylamide 60 1-(4-Benzyloxy-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 61 1-(4-Methoxy-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 62 1-(3-Carbamoyl-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 63 1-(4-Carbamoyl-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 64 1-(3-Cyano-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-benzylamide 65 1-(4-Cyano-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4- aminomethyl-benzylamide 66 1-(3-Aminomethyl-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 67 1-(4-Aminomethyl-benzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 68 1-[4-(Acetylamino-methyl)-benzyl]-2,5-dimethyl-1H-pyrrole-3- carboxylic acid 4-aminomethyl-benzylamide 69 1-Biphenyl-3-ylmethyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 70 1-Biphenyl-4-ylmethyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 71 2,5-Dimethyl-1-(3-pyridin-3-yl-benzyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 72 2,5-Dimethyl-1-(3-pyridin-4-yl-benzyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 73 2,5-Dimethyl-1-(3-morpholin-4-yl-benzyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 74 2,5-Dimethyl-1-(3-piperidin-1-yl-benzyl)-1H-pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 75 5-Benzyl-1,4-dimethyl-1H-pyrrole-2-carboxylic acid 4- aminomethyl-benzylamide 76 5-Benzyl-4-methyl-1H-pyrrole-2-carboxylic acid 4-aminomethyl- benzylamide 77 5-Benzyl-1-ethyl-4-methyl-1H-pyrrole-2-carboxylic acid 4- aminomethyl-benzylamide 78 5-Benzyl-4-methyl-1-propyl-1H-pyrrole-2-carboxylic acid 4- aminomethyl-benzylamide 79 1-(4-Isopropylcarbamoyl-benzyl)-1H-pyrazole-4-carboxylic acid 4- aminomethyl-benzylamide 80 5-Methyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide 81 3-Methyl-1-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide 82 1-(2-Phenyl-thiazol-4-ylmethyl)-5-trifluoromethyl-1H-pyrazole-4- carboxylic acid 4-aminomethyl-benzylamide 83 1-(2-Phenyl-thiazol-4-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4- carboxylic acid 4-aminomethyl-benzylamide 84 1-Benzyl-3-phenyl-1H-pyrazole-4-carboxylic acid 4-aminomethyl- benzylamide 85 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid 4-aminomethyl-benzylamide 86 1-[4-(3,5-Dimethyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid 4-aminomethyl-benzylamide 87 1-[4-(Piperidine-1-carbonyl)-benzyl]-1H-pyrazole-4-carboxylic acid 4-aminomethyl-benzylamide 88 1-(4-Phenoxy-benzyl)-1H-[1,2,4]triazole-3-carboxylic acid 4- aminomethyl-benzylamide 89 1-[4-(2-Oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 90 2,5-Dimethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 91 2,5-Dimethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide 92 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-aminomethyl-2-methyl-benzylamide 93 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 94 2,5-Dimethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 95 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 96 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-benzylamide 97 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-2-methyl-benzylamide 98 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 99 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-aminomethyl-2-methyl-benzylamide 100 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 101 2,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-3-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 102 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 103 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 104 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4- carboxylic acid 4-aminomethyl-benzylamide 105 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4- carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 106 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2-methyl-benzylamide 107 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4- carboxylic acid 4-aminomethyl-2-methyl-benzylamide 108 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4- carboxylic acid 4-aminomethyl-benzylamide 109 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4- carboxylic acid 4-aminomethyl-2-methyl-benzylamide 110 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4- carboxylic acid 4-(1-amino-cyclopropyl)-benzylamide 111 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 112 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-imidazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 113 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 114 3-Methyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole- 4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 115 5-Methyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole- 4-carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 116 3,5-Dimethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 117 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid 4-aminomethyl-3-fluoro-benzylamide 118 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 119 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid 4-aminomethyl-3-fluoro-2-methyl- benzylamide 120 1-[4-(4-Methyl-pyrazol-1-ylmethyl)-benzyl]-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid 4-aminomethyl-3-fluoro-2,6-dimethyl- benzylamide 121 1-Ethyl-4-methyl-5-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-aminomethyl-benzylamide 122 1-Ethyl-4-methyl-5-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H- pyrrole-2-carboxylic acid 4-aminomethyl-benzylamide 123 1-Ethyl-4-methyl-5-(2-phenyl-thiazol-4-ylmethyl)-1H-pyrrole-2- carboxylic acid 4-aminomethyl-benzylamide 124 3-Methyl-1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 125 5-Methyl-1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 126 1-(2-Methyl-quinolin-6-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 127 1-(2-Methyl-quinolin-6-ylmethyl)-5-trifluoromethyl-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 128 2,5-Dimethyl-1-(2-methyl-quinolin-6-ylmethyl)-1H-pyrrole-3- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 129 1-(2-Pyrrolidin-1-yl-pyridin-4-ylmethyl)-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 130 1-(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid 4-aminomethyl-2,6-dimethyl- benzylamide 131 5-Methyl-1-(2-pyrrolidin-1-yl-pyridin-4-ylmethyl)-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 132 3-Methyl-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide 133 3-Methyl-1-(2-pyrrolidin-1-yl-pyridin-4-ylmethyl)-1H-pyrazole-4- carboxylic acid 4-aminomethyl-2,6-dimethyl-benzylamide

TABLE-US-00015 TABLE 14 NMR data of examples Example No Solvent Chemical Shift (ppm) 8 d6- 2.16 (3H, s), 2.46 (3H, s), 3.20-3.38 (2H, s, br), DMSO 3.66 (2H, s), 4.32 (2H, d, J = 6.0 Hz), 5.03 (2H, s), 6.30 (1H, s), 7.00 (1H, d, J = 0.8 Hz), 7.15-7.25 (4H, m), 7.38 (1H, d, J = 1.3 Hz), 7.40-7.43 (1H, m), 7.98- 8.01 (1H, m), 8.04 (1H, t, J = 6.1 Hz), 8.49 (1H, dd, J = 4.8, 1.5 Hz), 8.84 (1H, d, J = 2.4 Hz). 9 CD.sub.3OD 2.24 (3H, s), 2.54 (3H, s), 3.77 (2H, s), 4.48 (2H, s), 5.27 (2H, s), 6.23 (1H, d, J = 0.7 Hz), 7.13 (1H, d, J = 1.2 Hz), 7.24-7.37 (7H, m), 7.48 (1H, d, J = 1.5 Hz), 7.57 (2H, d, J = 1.2 Hz). 10 CD.sub.3OD 2.19 (3H, s), 2.48 (3H, s), 3.80 (2H, s), 4.48 (2H, s), 5.07 (2H, s), 6.24 (1H, d, J = 0.7 Hz), 6.70 (1H, d, J = 0.9 Hz), 7.11 (1H, d, J = 1.2 Hz), 7.25-7.37 (7H, m), 7.56 (2H, d, J = 7.5 Hz). 11 CD.sub.3OD 2.28 (3H, s), 2.55 (3H, s), 4.08 (2H, s), 4.50 (2H, d, J = 4.9 Hz), 5.29 (2H, s), 6.24 (1H, d, J = 0.6 Hz), 6.57 (1H, s), 7.39 (2H, d, J = 8.7 Hz), 7.42 (2H, d, J = 8.9 Hz), 7.44-7.50 (3H, m), 7.77-7.80 (2H, m). 12 CD.sub.3OD 2.23 (3H, s), 2.52 (3H, s), 3.78 (2H, s), 4.48 (2H, s), 5.50 (2H, s), 6.29 (1H, d, J = 0.7 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.41 (1H, ddd, J = 8.0, 8.0, 1.0 Hz), 7.51 (1H, ddd, J = 8.2, 8.2, 1.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.96 (1H, d, J = 8.2 Hz). 13 d6- 2.48-2.50 (6H, m) 3.89 (2H, s) 4.34 (2H, d, J = 8.0 Hz) DMSO 5.26 (2H, d, J = 8.0 Hz) 6.29 (1H, s) 7.17-7.43 (8H, m) 7.91 (1H, d, J = 4.0 Hz) 8.48 (1H, dd, J = 8.0, 4.0 Hz) 8.90 (1H, s) 14 CD.sub.3OD 2.16 (3H, s) 2.43 (3H, s) 3.72 (2H, s) 4.36 (2H, s) 5.21 (2H, s) 6.19 (1H, s) 7.16-7.33 (5H, m) 7.48-7.59 (2H, m) 7.76-7.79 (1H, m) 8.39-8.44 (2H, m) 15 d6- 2.12 (3H, s), 2.40 (3H, s), 2.62-2.85 (2H, s, br), 3.21- DMSO 3.37 (2H, br), 3.41 (4H, t, J = 5.0 Hz), 3.65-3.69 (4H, m), 4.32 (2H, d, J = 6.0 Hz), 4.93 (2H, s), 5.99 (1H, d, J = 7.3 Hz), 6.29 (1H, d, J = 0.6 Hz), 6.70 (1H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.48 (1H, dd, J = 7.5, 8.5 Hz), 8.02 (1H, t, J = 6.0 Hz) 16 d6- 2.17 (3H, s), 2.46 (3H, s), 3.28-3.48 (2H, s, br), 3.73 DMSO (2H, s), 4.33 (2H, d, J = 6.0 Hz), 5.21 (2H, d), 6.34 (1H, d, J = 0.5 Hz), 6.67-6.72 (1H, m), 7.23 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 9.2 Hz), 7.41-7.52 (3H, m), 7.82-7.89 (2H, m), 8.06-8.08 (2H, m), 8.14 (1H, t, J = 6.0 Hz) 17 d6- 2.17 (3H, s), 2.46 (3H, s), 3.28-3.45 (2H, s, br), 3.68 DMSO (2H, s), 4.33 (2H, d, J = 6.1 Hz), 5.24 (2H, s), 6.34 (1H, d, J = 0.6 Hz), 6.79 (1H, d, J = 7.5 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.51-7.54 (1H, m), 7.89 (1H, t, J = 7.7 Hz), 7.97 (1H, d, J = 7.5 Hz), 8.11 (1H, t, J = 6.1 Hz), 8.39 (1H, dt, J = 1.9, 7.9 Hz), 8.64 (1H, dd, J = 1.6, 5.0 Hz), 9.23-9.26 (1H, m) 18 CD.sub.3OD 2.26 (3H, s), 2.56 (3H, s), 3.73 (2H, s), 4.41 (2H, s), 4.91 (2H, s), 6.20 (1H, s), 7.24-7.30 (4H, m), 7.42-7.45 (3H, m), 7.51 (1H, s), 7.93-7.97 (2H, m). 19 d6- 2.25 (3H, s), 2.26 (3H, s), 2.55 (3H, s), 3.97 (2H, dt, J = DMSO 11.4, 5.6 Hz), 4.33 (2H, d, J = 5.9 Hz), 4.94 (2H, s), 6.26 (1H, s), 7.30 (2H, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.48-7.51 (3H, m), 7.86-7.89 (2H, m), 8.11 (1H, t, J = 6.0 Hz), 8.20-8.45 (2H, s, br) 20 CD.sub.3OD 7.52-7.42 (4H, m), 7.36 (1H, dd, J = 5.0, 1.0 Hz), 7.00 (1H, dd, J = 5.0, 3.0 Hz), 6.85 (1H, dd, J = 3.0, 1.0 Hz), 6.27 (1H, s), 5.31 (2H, d, J = 0.6 Hz), 4.57 (2H, s), 4.14 (2H, s), 2.55 (3H, s), 2.28 (3H, s). 21 CD.sub.3OD 2.22 (3H, s), 2.52 (3H, s), 3.76 (2H, s), 4.46 (2H, s), 5.23 (2H, s), 6.24 (1H, d, J = 0.7 Hz), 6.80 (1H, d, J = 3.7 Hz), 7.24-7.31 (5H, m), 7.36-7.40 (1H, m), 7.92 (1H, dd, J = 8.0, 1.6 Hz), 8.38 (1H, dd, J = 5.0, 1.5 Hz), 8.68 (1H, dd, J = 1.6, 0.7 Hz). 22 CD.sub.3OD 2.23 (3H, s), 2.52 (3H, s), 3.78 (2H, s), 4.47 (2H, s), 5.20 (2H, s), 6.22 (1H, s), 6.73 (1H, d, J = 3.6 Hz), 7.18 (1H, d, J = 3.8 Hz), 7.21-7.36 (7H, m), 7.57 (2H, d, J = 7.3 Hz). 23 CD.sub.3OD 2.23 (3H, s), 2.52 (3H, s), 2.66 (3H, s), 3.94 (2H, s), 4.48 (2H, s), 5.22 (2H, s), 6.23 (1H, d, J = 0.8 Hz), 6.75 (1H, d, J = 3.8 Hz), 7.27 (1H, d, J = 3.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.6 Hz), 7.40 (1H, s). 24 CD.sub.3OD 2.28 (3H, s), 3.80 (2H, s), 4.32 (2H, s), 5.03 (2H, d, J = 0.7 Hz), 6.41 (1H, d, J = 0.7 Hz), 6.69 (1H, s), 7.08 (2H, d, J = 8.0 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.32-7.36 (5H, m), 7.41-7.43 (3H, m), 7.84-7.86 (2H, m). 25 d6- 2.53(3H, s), 3.28(2H, br s), 3.66(2H, s), 4.33(2H, d, J = DMSO 6.1 Hz), 5.21(2H, s), 6.53(1H, d, J = 3.1 Hz), 6.79(1H, d, J = 3.1 Hz), 7.15-7.24(4H, m), 7.30(1H, s), 7.47-7.51 (3H, m), 7.88-7.93(2H, m), 8.13(1H, t, J = 6.1 Hz). 26 CD.sub.3OD 2.25 (3H, s), 2.52 (3H, s), 4.06 (2H, s), 4.50 (2H, s), 5.16 (2H, d, J = 0.7 Hz), 6.24 (1H, s), 6.73 (1H, s), 7.11 (1H, d, J = 5.0, 3.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.55 (1H, dd, J = 5.0, 1.0 Hz), 7.41 (1H, dd, J = 3.5, 1.0 Hz). 27 CD.sub.3OD 2.27 (3H, s), 2.54 (3H, s), 4.05 (2H, s), 4.50 (2H, s), 5.22 (2H, d, J = 0.7 Hz), 6.24 (1H, d, J = 0.7 Hz), 6.84 (1H, s), 7.38 (2H, d, J = 8.5 Hz), 7.41 (2H, d, J = 8.5 Hz), 7.45-7.47 (2H, m), 7.82-7.85 (1H, m), 7.95 (1H, dd, J = 2.2, 1.4 Hz). 28 CD.sub.3OD 2.25 (3H, s), 2.54 (3H, s), 3.79 (2H, s), 4.47 (2H, s), 5.20 (2H, s), 6.23 (1H, d, J = 0.7 Hz), 6.88 (1H, s), 7.28 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.6 Hz). 29 d6- 2.24(3H, s), 2.53(3H, s), 3.10-3.43 (2H, s, br), DMSO 3.66(2H, s), 4.31(2H, d, J = 6.0 Hz), 5.16(2H, s), 6.28(1H, s), 7.15-7.24(4H, m), 7.30(1H, s), 7.33- 7.35(1H, m), 7.52-7.57(1H, m), 7.66-7.69(1H, m), 7.73- 7.75(1H, m), 8.02(1H, t, J = 6.1 Hz). 30 d6- 2.24(3H, s), 2.37(3H, s), 2.54(3H, s), 2.80-3.38 (2H, br DMSO s), 3.66(2H, s), 4.32(2H, d, J = 6.0 Hz), 5.15(2H, s), 6.29(1H, s), 7.15-7.24(5H, m), 7.29(1H, d, J = 7.6 Hz), 7.37(1H, t, J = 7.6 Hz), 7.69(2H, d, J = 9.2 Hz), 8.03(1H, t, J = 6.1 Hz). 31 d6- 2.26 (3H, s), 2.54 (3H, s), 2.80 (2H, s), 4.33 (2H, d, J = DMSO 6.0 Hz), 5.19 (2H, s), 5.20-5.55 (2H, s, br), 6.29 (1H, s), 7.24 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.36 (1H, s), 7.54 (1H, ddd, J = 8.0, 4.9, 0.6 Hz), 8.08 (1H, t, J = 6.1 Hz), 8.26 (1H, dt, J = 8.2, 1.8 Hz), 8.67 (1H, dd, J = 4.8, 1.6 Hz), 9.09 (1H, d, J = 1.8 Hz). 32 CD.sub.3OD 2.25 (3H, s), 2.55 (3H, s), 3.77 (2H, s), 4.47 (2H, s), 5.21 (2H, s), 6.24 (1H, s), 7.09 (1H, s), 7.26-7.32 (4H, m), 7.87 (2H, dd, J = 4.8, 1.4 Hz), 8.60 (2H, dd, J = 4.7, 1.5 Hz). 33 CD.sub.3OD 2.25 (3H, s), 2.54 (3H, s), 3.20-3.45 (2H, br s), 3.66 (2H, s), 3.82 (3H, s), 4.32 (2H, d, J = 6.1 Hz), 5.16 (2H, s), 6.29 (1H, s), 7.05-7.08 (1H, m), 7.18-7.25 (5H, m), 7.38-7.48 (3H, m), 8.04 (1H, t, J = 6.1 Hz). 34 d6- 2.25 (3H, s), 2.54 (3H, s), 3.20-3.40 (2H, br s), 3.71 DMSO (2H, s), 3.81 (3H, s), 4.32 (2H, d, J = 6.0 Hz), 5.13 (2H, s), 6.28 (1H, s), 7.05 (2H, dt, J = 8.9, 2.9 Hz), 7.14 (1H, s), 7.20 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.84 (2H, dt, J = 8.9, 2.9 Hz), 8.04 (1H, t, J = 6.1 Hz). 35 d6- 2.08(2H, br s), 2.24(3H, s), 2.34(3H, s), 2.54(3H, s), DMSO 3.65(2H, s), 4.31(2H, d, J = 6.1 Hz), 5.14(2H, s), 6.28(1H, s), 7.17-7.24(5H, m), 7.30(2H, d, J = 8.1 Hz), 7.78(2H, d, J = 8.1 Hz), 8.02(1H, t, J = 6.0 Hz). 36 CD.sub.3OD 2.24 (3H, s), 2.55 (3H, s), 3.78 (2H, s), 4.47 (2H, s), 5.18 (2H, s), 6.23 (1H, d, J = 0.7 Hz), 6.95 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.37-7.40 (1H, m), 7.86 (1H, dt, J = 7.8, 6.1 Hz), 8.10 (1H, d, J = 8.0 Hz), 8.51-8.53 (1H, m). 37 CD.sub.3OD 2.26 (3H, s), 2.56 (3H, s), 3.88 (2H, s), 4.52 (2H, s), 5.21 (2H, s), 6.28 (1H, s), 6.73 (1H, s), 7.34 (2H, d, J = 8.3 Hz), 7.37 (2H, d, J = 8.3 Hz), 7.54-7.59 (2H, m), 7.99 (1H, dd, J = 2.8, 1.4 Hz). 38 d6- 2.18 (3H, s), 2.48 (3H, s), 3.22-3.36 (2H, br s), 3.68 DMSO (2H, s), 4.28 (2H, s), 4.31 (2H, d, J = 6.1 Hz), 5.10 (2H, s), 6.25 (1H, d, J = 0.6 Hz), 6.98 (1H, s), 7.18-7.28 (5H, m), 7.31-7.35 (4H, m), 8.02 (1H, t, J = 6.1 Hz) 39 d6- 2.22 (3H, s), 2.51 (3H, s), 3.78 (2H, s), 4.33 (2H, d, J = DMSO 6.0 Hz), 4.72-5.10 (2H, br s), 5.12 (2H, s), 6.29 (1H, s), 6.89 (1H, dd, J = 1.1, 0.9 Hz), 7.05 (1H, s), 7.24 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.82 (1H, dd, J = 1.8, 1.6 Hz), 8.07 (1H, t, J = 6.1 Hz), 8.36 (1H, dd, J = 1.2, 1.0 Hz). 40 d6- 2.26 (3H, s), 2.54 (3H, s), 3.96 (2H, s), 4.35 (2H, d, J = DMSO 6.1 Hz), 5.22 (2H, s), 6.32 (1H, s), 7.30 (2H, d, J = 8.1 Hz), 7.41 (2H, d, J = 8.1 Hz), 7.46 (1H, s), 7.46-7.70 (2H, br s), 8.17 (1H, t, J = 6.1 Hz), 8.71 (1H, d, J = 1.8 Hz), 8.74 (1H, dd, J = 14.3, 1.5 Hz), 9.24(1H, d, J = 1.4 Hz). 41 d6- 1.34 (3H, t, J = 7.0 Hz), 2.25 (3H, s), 2.54 (3H, s), 3.26- DMSO 3.46 (2H, br), 3.69 (2H, s), 4.08 (2H, q, J = 7.0 Hz), 4.32 (2H, d, J = 6.0 Hz), 5.12 (2H, s), 6.28 (1H, s), 7.02 (2H, d, J = 8.8 Hz), 7.15 (1H, s), 7.20 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.82 (2H, d, J = 8.8 Hz), 8.03 (1H, t, J = 6.0 Hz) 42 d6- 1.38 (3H, d, J = 7.0 Hz), 2.26 (3H, s), 2.33 (3H, t, J = DMSO 2.0 Hz), 2.67 (1H, t, J = 1.7 Hz), 3.28 (2H, d, J = 10.5 Hz), 3.37 (1H, s), 3.65 (2H, s), 5.15 (2H, s), 6.39 (1H, s), 7.22-7.28 (5H, m), 7.49 (2H, d, J = 1.8 Hz), 7.50 (1H, d, J = 2.6 Hz), 7.88 (1H, d, J = 1.7 Hz), 7.90 (1H, d, J = 3.0 Hz) 43 d6- 2.25(3H, s), 2.53(3H, s), 3.32(2H, s, br), 3.82(2H, s), DMSO 4.33(2H, d, J = 6.0 Hz), 5.15(2H, s), 6.26(1H, s), 7.25(1H, s), 7.35(1H, d, J = 8.0 Hz), 7.47-7.52(3H, m), 7.63(1H, dd, J = 8.0, 2.1 Hz), 7.88-7.92(2H, m), 8.12 (1H, t, J = 6.1 Hz), 8.41(1H, s). 44 d6- 2.10(2H, br s), 2.24(3H, s), 2.53(3H, s), 3.74(2H, s), DMSO 4.37(2H, d, J = 6.4 Hz), 5.16(2H, s), 6.26(1H, s), 7.30(1H, s), 7.34(2H, d, J = 7.7 Hz), 7.52-7.57(1H, m), 7.62(1H, dd, J = 8.0, 2.2 Hz), 7.65-7.75(2H, m), 8.10(1H, t, J = 6.0 Hz), 8.38(1H, d, J = 1.8 Hz). 45 CD.sub.3OD 2.23(3H, s), 2.54(3H, s), 3.81(2H, s), 4.46(2H, s), 5.17(2H, s), 6.25(1H, d, J = 0.8 Hz), 6.79(1H, s), 7.06(1H, dd, J = 11.1, 1.2 Hz), 7.12(1H, dd, J = 7.9, 1.3 Hz), 7.32(1H, t, J = 7.8 Hz), 7.42-7.45(3H, m), 7.89- 7.91(2H, m). 46 d6- 2.27(3H, s), 2.31(3H, s), 2.55(3H, s), 3.99(2H, q, J = DMSO 5.7 Hz), 4.31(2H, d, J = 6.0 Hz), 5.16(2H, s), 6.28(1H, s), 7.14-7.15(2H, m), 7.26-7.29(2H, m), 7.49-7.53(3H, m), 7.89-7.91(2H, m), 8.03(2H, s, s, br), 8.09(1H, t, J = 6.0 Hz). 47 d6- 2.27(3H, s), 2.54(3H, s) 3.33(2H, S), 3.89(2H, s), DMSO 4.37(2H, d, J = 5.9 Hz), 5.17(2H, s), 6.31(1H, s), 7.17(1H, d, J = 7.9 Hz), 7.23-7.32(3H, m), 7.49-7.52(3H, s), 7.88-7.91(2H, m), 8.09(1H, t, J = 5.6 Hz). 48 d6- 1.46 (3H, d, J = 6.8 Hz), 2.27 (3H, s, br), 2.32-2.33 (2H, DMSO m), 2.66-2.68 (1H, m), 4.35 (3H, d, J = 6.1 Hz), 5.16 (2H, s), 6.28 (1H, s), 7.29 (1H, s), 7.32 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.50 (3H, dd, J = 5.2 Hz, 1.9 Hz), 7.89-7.91 (2H,. m), 8.12 (3H, s, s, br) 49 d6- 2.28(3H, s), 2.55(3H, s), 2.77(2H, br s), 3.69(2H, s), DMSO 4.38(2H, d, J = 6.0 Hz), 5.18(2H, s), 6.34(1H, d, J = 0.6 Hz), 7.21(2H, s), 7.30(1H, s), 7.41(1H, s), 7.49- 7.55(3H, m), 7.90-7.92(2H, m), 8.07(1H, t, J = 6.0 Hz). 50 d6- 2.29(3H, s), 2.56(3H, s), 3.07(2H, br s), 3.78(2H, s), DMSO 4.51(2H, d, J = 5.6 Hz), 5.18(2H, s), 6.35(1H, s), 7.32(1H, s), 7.39(1H, d, J = 8.0 Hz), 7.49-7.55(4H, m), 7.69(1H, s), 7.90-7.92(2H, m), 8.13(1H, t, J = 5.8 Hz). 51 d6- 1.46 (3H, d, J = 6.8 Hz), 2.27 (3H, br.s), 2.32-2.33 (1H, DMSO m), 2.59-2.60 (1H, m), 2.66-2.68 (1H, m), 4.35 (3H, d, J = 6.1 Hz), 5.17 (2H, s), 6.28 (1H, s), 7.29 (1H, s), 7.32 (2H, d, J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz), 7.50 (3H, dd, J = 5.1 Hz, 1.9 Hz), 7.89-7.92 (2H . m), 8.12 (3H, s, br) 52 d6- 0.85 (2H, t, J = 7.2 Hz), 1.66-1.81 (2H, m), 2.26 (3H, s), DMSO 3.28 (1H, d, J = 11.0 Hz), 3.65 (2H, s), 4.79 (1H, q, J = 8.8 Hz), 5.14 (2H, s), 6.40 (1H, s), 7.21-7.27 (5H, m), 7.48 (2H, d, J = 1.8 Hz), 7.50 (1H, d, J = 2.3 Hz), 7.66 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 1.6 Hz), 7.90 (1H, d, J = 2.8 Hz) (3H, s, obscured by DMSO) 53 d6- 2.26 (3H, s), 2.55 (3H, s), 3.75-3.80 (2H, s, brs), 3.78 DMSO (3H, s), 4.33-4.35 (2H, d, J = 6.0 Hz), 5.16 (2H, s), 6.29 (1H, s), 6.83-6.85 (1H, d, J = 7.6 Hz), 6.95 (1H, s), 7.22-7.24 (1H, d, J = 7.7 Hz), 7.28 (1H, s), 7.48- 7.52 (3H, m), 7.89-7.91 (2H, m), 8.06-8.09 (1H, t, J = 6.0 Hz) 54 d6- 2.27 (3H, s), 2.54 (3H, s), 3.68 (2H, s, br), 3.81 (3H, s), DMSO 4.29-4.30 (2H, d, J = 5.9 Hz), 5.17 (2H, s), 6.32 (1H, s), 6.80-6.82 (1H, d, J = 7.6 Hz), 6.96 (1H, s), 7.04- 7.06 (1H, d, J = 7.6 Hz), 7.27 (1H, s), 7.48-7.52 (3H, m), 7.78-7.85 (1H, m), 7.89-7.92 (2H, m) 55 CD.sub.3OD 2.18 (3H, s), 2.46 (3H, s), 4.14 (2H, s), 4.57 (2H, s), 5.18 (2H, s), 6.31 (1H, s), 6.96 (2H, d, J = 7.5 Hz), 7.29- 7.31 (1H, m), 7.34-7.39 (2H, m), 7.44-7.50 (4H, m). 56 CD.sub.3OD 2.20 (3H, s), 2.46 (3H, s), 4.15 (2H, s), 4.65 (2H, d, J = 5.5 Hz), 5.19 (2H, s), 6.35 (1H, d, J = 0.6 Hz), 6.97 (2H, d, J = 7.2 Hz), 7.28-7.42 (4H, m), 7.51 (1H, d, J = 8.0 Hz), 7.58 (1H, d, J = 1.6 Hz). 57 CD.sub.3OD 2.20 (3H, s), 3.76 (2H, s), 4.22 (2H, s), 4.84 (2H, s), 6.30 (1H, d, J = 0.7 Hz), 6.70 (2H, d, J = 7.1 Hz), 7.00 (2H, d, J = 8.0 Hz), 7.04-7.26 (10H, m). 58 d6- 1.29 (3H, t, J = 7.0 Hz), 2.07 (3H, s), 2.36 (3H, s), 3.46- DMSO 3.89 (2H, br s), 3.74 (2H, s), 3.95 (2H, q, J = 7.0 Hz), 4.34 (2H, d, J = 6.0 Hz), 5.04 (2H, s), 6.33 (1H, s), 6.37 (1H, s), 6.44 (1H, d, J = 7.6 Hz), 6.80 (1H, dd, J = 8.1, 2.3 Hz), 7.17-7.29 (5H, m), 8.12 (1H, t, J = 6.1 Hz). 59 d6- 1.29 (3H, t, J = 7.0 Hz), 2.07 (3H, s), 2.37 (3H, s), 3.74 DMSO (2H, s), 3.74-4.10 (2H, br s), 3.96 (2H, q, J = 7.0 Hz), 4.33 (2H, d, J = 6.0 Hz), 4.99 (2H, s), 6.31 (1H, s), 6.81 (2H, d, J = 8.8 Hz), 6.87 (2H, d, J = 8.7 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 8.10 (1H, t, J = 6.1 Hz). 60 d6- 2.08 (3H, s), 3.37 (2H, s), 3.98 (2H, q, J = 5.6 Hz), 4.35 DMSO (2H, d, J = 6.1 Hz), 5.00 (2H, s), 5.06 (2H, s), 6.32 (1H, s), 6.83 (2H, d, J = 8.6 Hz), 6.96 (2H, d, J = 8.6 Hz), 7.28- 7.35 (4H, m), 7.37-7.45 (6H, m), 8.14 (1H, t, J = 6.1 Hz), 8.27-8.38 (2H, s, br) 61 d6- 2.08 (3H, s), 2.37 (3H, s), 3.71 (3H, s), 3.99 (2H, q, DMSO J = 5.7 Hz), 4.35 (2H, d, J = 6.1 Hz), 5.00 (2H, s), 6.31 (1H, s), 6.83 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.1 Hz), 8.14 (1H, t, J = 6.1 Hz), 8.23-8.35 (2H, s, br) 62 d6- 2.08 (3H, s), 2.37 (3H, s), 3.98 (2H, d, J = 5.8 Hz), 4.36 DMSO (2H, d, J = 6.0 Hz), 5.13 (2H, s), 6.33 (1H, s), 7.32 (2H, d, J = 8.2 Hz), 7.35-7.42 (5H, m), 7.51 (1H, s), 7.74 (1H, d, J = 7.8 Hz), 7.97 (1H, s), 8.19 (1H, t, J = 6.0 Hz), 8.20- 8.29 (2H, s, br) 63 d6- 2.07 (3H, s), 2.36 (3H, s), 3.99 (2H, q, J = 5.8 Hz), 4.24 DMSO (2H, d, J = 6.0 Hz), 5.14 (2H, s), 6.35 (1H, s), 6.94 (2H, d, J = 8.3 Hz), 7.32 (3H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.3 Hz), 7.92 (1H, s), 8.17 (1H, t, J = 6.0 Hz), 8.19-8.27 (2H, s, br) 64 d6- 2.07 (3H, s), 2.36 (3H, s), 3.99 (2H, q, J = 5.6 Hz), 4.36 DMSO (2H, d, J = 6.0 Hz), 5.17 (2H, s), 6.36 (1H, s), 7.19 (1H, d, J = 7.3 Hz), 7.31 (1H, s), 7.32 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 7.7 Hz), 8.15-8.28 (3H, m) 65 d6- 2.05 (3H, s), 2.34 (3H, s), 3.99 (2H, q, J = 5.7 Hz), 4.336 DMSO (2H, d, J = 6.0 Hz), 5.21 (2H, s), 6.36 (1H, s), 7.04 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.81 (2H, d, J = 8.2 Hz), 8.18 (1H, t, J = 6.0 Hz), 8.25-8.34 (2H, s, br) 66 d6- 2.10 (3H, s), 2.39 (3H, s), 3.98 (4H, d, J = 5.2 Hz), 4.36 DMSO (2H, d, J = 6.1 Hz), 5.09 (2H, s), 6.34 (1H, s), 6.83-6.87 (1H, m), 7.13 (1H, s), 7.31 (2H, d, J = 8.1 Hz), 7.36 (2H, d, J = 3.4 Hz), 7.40 (2H, d, J = 8.1 Hz), 8.17 (1H, t, J = 6.1 Hz), 8.24-8.38 (4H, s, br) 67 d6- 2.07 (3H, s), 2.36 (3H, s), 3.70 (4H, s), 4.36 (2H, d, DMSO J = 6.1 Hz), 5.11 (2H, s), 6.35 (1H, s), 6.92 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.1 Hz), 7.43 (2H, d, J = 8.1 Hz), 8.17 (1H, t, J = 6.1 Hz), 8.23-8.36 (4H, s, br) 68 d6- 1.84 (3H, s), 2.07 (3H, s), 2.36 (3H, s), 3.98 (2H, dt, J = DMSO 5.8, 5.7 Hz), 4.19 (2H, d, J = 5.9 Hz), 4.36 (2H, d, J = 6.0 Hz), 5.06 (2H, s), 6.32 (1H, s), 6.84 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.2 Hz), 8.15 (1H, t, J = 6.1 Hz), 8.25 (2H, s, br), 8.31 (1H, d, J = 6.0 Hz). 69 d6- 2.10(3H, s), 2.40(3H, s), 2.72(2H, s, br), 3.69(2H, s), DMSO 4.33(2H, d, J = 6.1 Hz), 5.16(2H, s), 6.34(1H, s), 6.80(1H, d, J = 7.7 Hz), 7.20-7.26(5H, m), 7.34-7.47(4H, m), 7.52-7.63(3H, m), 8.08(1H, t, J = 6.1 Hz). 70 d6- 2.10(3H, s), 2.20(2H, s, br), 2.40(3H, s), 3.67(2H, s), DMSO 4.33(2H, d, J = 6.0 Hz), 5.13(2H, s), 6.34(1H, s), 6.97(2H, d, J = 8.2 Hz), 7.20-7.26(4H, m), 7.32- 7.39(1H, m), 7.41-7.47(2H, m), 7.52-7.63(4H, m), 8.08(1H, t, J = 6.1 Hz). 71 d6- 2.11 (3H, s), 2.41 (3H, s), 3.20-3.40 (2H, s, br), 3.69 DMSO (2H, s), 4.33 (2H, d, J = 6.1 Hz), 5.18 (2H, s), 6.34 (1H, s), 6.82 (1H, d, J = 7.5 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.34 (1H, s), 7.45 (1H, t, J = 7.5 Hz), 7.47- 7.50 (1H, m), 7.61 (1H, d, J = 7.9 Hz), 7.99-8.01 (1H, m), 8.09 (1H, t, J = 6.1 Hz), 8.57 (1H, dd, J = 1.5, 5.0 Hz), 8.81-8.83 (1H, m) 72 d6- 2.11 (3H, s), 2.41 (3H, s), 3.20-3.40 (2H, br s), 3.68 DMSO (2H, s), 4.33 (2H, d, J = 6.1 Hz), 5.19 (2H, s), 6.36 (1H, s), 6.86 (1H, d, J = 7.5 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.43 (1H, s), 7.45 (1H, t, J = 7.5 Hz), 7.62 (2H, dd, J = 1.5, 4.5 Hz), 7.68 (1H, d, J = 7.5 Hz), 8.09 (1H, t, J = 6.1 Hz), 8.63 (2H, dd, J = 1.5, 4.5 Hz) 73 d6- 2.08 (3H, s), 2.37 (3H, s), 3.04 (4H, t, J = 4.9 Hz), 3.23- DMSO 3.37 (2H, s, br), 3.68 (2H, s), 3.71 (4H, t, J = 4.9 Hz), 4.33 (2H, d, J = 6.1 Hz), 5.01 (2H, s), 6.19 (1H, 7.6 Hz), 6.31 (1H, s), 6.61 (1H, s), 6.81 (1H, dd, J = 2.1, 9.2 Hz), 7.12-7.15 (1H, m), 7.20 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 8.2 Hz), 8.05 (1H, t, J = 6.1 Hz) 74 d6- 1.48-1.54 (2H, m), 1.55-1.59 (4H, m), 2.08 (3H, s), 2.37 DMSO (3H, s), 3.05-3.09 (4H, m) 3.25-3.36 (2H, s, br), 3.72 (2H, s), 4.33 (2H, d, J = 6.0 Hz), 5.00 (2H, s)m 6.16 (1H, d, J = 7.5 Hz), 6.31 (1H, s), 6.55 (1H, s), 6.78 (1H, dd, J = 2.0, 8.2 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.22 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.2 Hz), 8.06 (1H, t, J = 6.0 Hz) 75 CD.sub.3OD 2.05 (3H, s), 3.61 (3H, s), 3.91 (2H, s), 3.97 (2H, s), 4.46 (2H, s), 6.65 (1H, s), 7.03 (2H, d, J = 7.2 Hz), 7.15 (1H, d, J = 7.3 Hz), 7.22 (2H, d, J = 7.6 Hz), 7.34 (4H, s). 76 d6- 1.92 (3H, s), 3.19-3.42 (2H, s, br), 3.67 (2H, s), 3.85 DMSO (2H, s), 4.36 (2H, d, J = 6.1 Hz), 6.57 (1H, d, J = 2.3 Hz), 7.12-7.30 (9H, m), 8.25 (1H, t, J = 6.0 Hz), 11.10 (1H, s, br). 77 d6- 0.91 (3H, t, J = 7.0 Hz), 2.01 (3H, s), 3.69 (2H, s), 3.96 DMSO (2H, s), 4.15 (2H, q, J = 7.0 Hz), 4.33 (2H, d, J = 6.1 Hz), 6.69 (1H, s), 7.07 (2H, d, J = 7.2 Hz), 7.14-7.22 (4H, m), 7.25-7.31 (5H, m), 8.36 (1H, t, J = 6.1 Hz) 78 d6- 0.67 (3H, t, J = 7.6 Hz), 1.24-1.34 (2H, m), 2.01 (3H, s), DMSO 3.70 (2H, s), 3.95 (2H, s), 4.09 (2H, t, J = 7.6 Hz), 4.32 (2H, d, J = 6.1 Hz), 6.68 (1H, s), 7.07 (2H, d, J = 7.2 Hz), 7.16-7.22 (4H, m), 7.25-7.31 (5H, m), 8.35 (1H, t, J = 6.1 Hz) 79 d6- 1.15 (6H, d, J = 7.6 Hz), 3.68-3.74 (1H, m), 4.00 (2H, DMSO s), 4.03-4.13 (1H, m), 4.41 (2H, d, J = 6.0 Hz), 5.40 (2H, s), 7.31-7.41 (6H, m), 7.82 (2H, d, J = 8.2 Hz), 7.93 (1H, s), 8.15 (2H, br.s + HCl salt), 8.28 (1H, s), 8.69 (1H, t, J = 6.0 Hz) 80 CD.sub.3OD 2.68 (3H, s), 3.89 (2H, s), 4.50 (2H, s), 5.46 (2H, s), 7.21 (1H, s), 7.33 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.7 Hz), 7.39-7.46 (3H, m), 7.89-7.92 (3H, m). 81 CD.sub.3OD 2.40 (3H, s), 3.97 (2H, s), 4.48(2H, s), 5.40 (2H, s), 7.36 (4H, s), 7.41-7.46 (4H, m), 7.89-7.93 (2H, m), 8.16 (1H, s). 82 d6- 3.98 (2H, q, J = 5.7 Hz), 4.39 (2H, d, J = 6.0 Hz), 5.61 DMSO (2H, s), 7.33 (2H, d, J = 8.1 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.49-7.53 (3H, m), 7.76 (1H, s), 7.91-7.94 (2H, m), 8.15-8.40 (2H, s, br), 8.55 (2H, s), 8.94 (1H, t, J = 5.8 Hz) 83 d6- 3.98 (2H, q, J = 5.64 Hz), 4.39 (2H, d, J = 5.96), 5.61 DMSO (2H, s), 7.32 (2H, d, J = 8.16), 7.42 (2H, d, J = 8.16 Hz), 7.50 (3H, m), 7.76 (1H, s), 7.93 (2H, d.d, J = 2.44, 7.16 Hz), 8.33 (2H, s, br), 8.56 (1H, s), 8.96 (1H, t) 84 CD.sub.3OD 4.05 (2H, s) 4.44 (2H, s) 5.25 (2H, s) 6.96-7.03 (2H, m) 7.22-7.36 (4H, m) 7.39-7.57 (7H, m) 7.66-7.68 (1H, m) 8.09 (1H, s) 85 d6- 1.98 (3H, s), 3.98 (2H, q, J = 5.68 Hz), 4.38 (2H, d J = DMSO 5.92 Hz), 5.21 (2H, s), 5.31 (2H, s), 7.15 (2H, d, J = 5.68 Hz), 7.20 (2H, d, J = 8.16 Hz), 7.22 (2H, d, J = 7.60 Hz), 7.31 (2H, d, J = 8.08), 7.39 (2H, d, J = 8.04 Hz), 7.51 (1H, s), 7.53 (1H, s), 7.89 (1H, s), 8.25 (1H, s), 8.68 (1H, t, J = 6.08 Hz) 86 d6- 2.08 (3H, s), 2.14 (3H, s), 3.98 (2H, q, J = 5.82 Hz), DMSO 4.39 (2H, d, J = 6.79 Hz), 5.16 (2H, s), 5.31 (2H, s), 7.07 (2H, d, J = 8.01 Hz), 7.22 (2H, d, J = 8.01 Hz), 7.32 (2H, d, J = 8.33 Hz), 7.38 (2H, d, J = 8.33 Hz), 7.89 (1H, s), 8.08 (3H, s, br), 8.24 (1H, s), 8.67(1H, t, J = 5.90 Hz). 87 d6- 3.23 (2H, s, br), 3.55 (2H, s, br), 3.88 (6H, s, br), 3.98 DMSO (2H, q, J = 5.8 Hz), 4.40 (2H, d, J = 6.0 Hz), 5.39 (2H, s), 7.27-7.36 (6H, m), 7.40 (2H, d, 8.1 Hz), 7.94 (1H, s), 8.25 (2H, s, br), 8.31 (1H, s), 8.71 (1H, s) 88 d6- 3.99 (2H, q, J = 5.19 Hz), 4.41 (2H, d, J = 6.136 Hz), DMSO 5.45 (2H, s), 7.00-7.03 (4H, m), 7.14-7.18 (1H, m), 7.33-7.39 (7H, m), 8.07 (3H, s, br), 8.81 (1H, s), 9.07- 9.10 (1H, m). 89 d6- 0.88-0.95 (2H, m), 0.97-1.04 (2H, m), 2.50-2.70 DMSO (2H, br s), 4.33 (2H, d, J = 6.0 Hz), 5.07 (2H, s), 5.31 (2H, s), 6.21 (1H, td, J = 1.4, 6.7 Hz), 6.40 (1H, d, J = 9.2 Hz), 7.16-7.31 (8H, m), 7.40 (1H, ddd, J = 2.1, 6.6, 8.8 Hz), 7.75 (1H, dd, J = 1.5, 6.8 Hz), 7.87 (1H, s), 8.23 (1H, s), 8.55 (1H, t, J = 6.0 Hz). 90 d6- 2.06 (3H, s), 2.35 (3H, s), 3.86 (2H, s), 4.35 (2H, d, J = DMSO 6.1 Hz), 5.06 (4H, s), 6.23 (1H, dt, J = 1.4, 6.7 Hz), 6.32 (1H, s), 6.40 (1H, d, J = 6.8 Hz), 6.86-6.88 (2H, m), 7.23-7.25 (2H, m), 7.27-7.29 (2H, m), 7.32-7.34 (2H, m), 7.42 (1H, ddd, J = 2.1, 6.6, 9.2 Hz), 7.75 (1H, ddd, J = 0.4, 2.0, 6.8 Hz), 8.11 (1H, t, J = 6.0 Hz). 91 d6- 2.07 (3H, s), 2.28 (3H, s), 2.38 (3H, s), 3.67 (2H, s), DMSO 4.31 (2H, d, J = 5.8 Hz), 5.07 (4H, s), 6.24 (1H, td, J = 1.4, 6.7 Hz), 6.32-6.37 (1H, m), 6.42 (1H, dd, J = 0.7, 9.1 Hz), 6.87 (2H, d, J = 8.2 Hz), 7.09 (2H, m), 7.17 (1H, d, J = 7.7 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.42 (1H, ddd, J = 2.1, 6.6, 8.8 Hz), 7.72-7.79 (1H, m), 7.93 (1H, t, J = 5.9 Hz). 92 d6- 0.94 (3H, t, J = 7.0 Hz), 1.98 (3H, s), 2.28 (3H, s), 3.67 DMSO (2H, s), 3.92 (2H, s), 4.14 (2H, q, J = 7.0 Hz), 4.31 (2H, d, J = 5.8 Hz), 5.03 (2H, s), 6.21 (1H, td, J = 6.7, 1.4 Hz), 6.39 (1H, d, J = 9.1 Hz), 6.70 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.06-7.16 (3H, m), 7.20 (2H, d, J = 8.2 Hz), 7.40 (1H, ddd, J = 8.9, 6.6, 2.1 Hz), 7.73 (1H, dd, J = 6.8, 1.6 Hz), 8.23 (1H, t, J = 5.9 Hz). 93 d6- 0.80-0.88 (2H, m), 0.88-0.98 (5H, m), 1.98 (3H, s), 3.92 DMSO (2H, s), 4.13 (2H, q, J = 6.9 Hz), 4.31 (2H, d, J = 6.1 Hz), 5.03 (2H, s), 6.21 (1H, td, J = 6.7, 1.4 Hz), 6.39 (1H, d, J = 9.1 Hz), 6.67 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.11- 7.28 (6H, m), 7.40 (1H, ddd, J = 8.9, 6.6, 2.1 Hz), 7.73 (1H, dd, J = 6.8, 1.6 Hz), 8.32 (1H, t, J = 6.1 Hz). 94 d6- 1.87 (1H, s), 1.96 (1H, t, J = 1.2 Hz), 2.01 (3H, s), 2.32- DMSO 2.35 (8H, m), 3.69 (1H, s), 4.28 (1H, s), 4.34 (2H, d, J = 4.8 Hz), 5.03-5.04 (4H, m), 6.22 (1H, dt, J = 1.4, 6.7 Hz), 6.28-6.29 (1H, m), 6.38-6.40 (1H, m), 6.83- 6.85 (2H, m), 6.92-6.93 (1H, m), 6.98 (1H, s), 7.21- 7.23 (2H, m), 7.40 (1H, ddd, J = 2.1, 6.6, 9.2 Hz), 7.75 (1H, ddd, J = 0.4, 2.0, 6.8 Hz) ppm. NH2 not observed 95 d6- 0.95 (3H, t, J = 6.8 Hz), 1.87 (2H, s), 1.94 (3H, s), 1.96 DMSO (2H, t, J = 1.24 Hz), 2.31 (6H, s), 3.91 (2H, s), 4.15 (2H, q, J = 6.8 Hz), 4.35 (2H, d, J = 4.9 Hz), 5.04 (2H, s), 6.21 (1H, dt, J = 1.4, 6.7 Hz), 6.38-6.41 (1H, m), 6.21-6.22 (1H, m), 6.89-6.96 (2H, m, 7.01-7.03 (2H, m), 7.19-7.21 (2H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 9.1 Hz), 7.73-7.78 (2H, m) 96 d6- 1.98 (3H, s), 2.07 (3H, s), 2.35 (3H, s), 2.69-3.03 (2H, DMSO br s), 3.69 (2H, s), 4.34 (2H, d, J = 6.1 Hz), 5.06 (2H, s), 5.19 (2H, s), 6.26-6.36 (1H, m), 6.85 (2H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.18-7.31 (5H, m), 7.46-7.55 (1H, m), 8.07 (1H, t, J = 6.2 Hz). 97 d6- 2.04 (3H, s), 2.11 (3H, s), 2.34 (3H, s), 2.41 (3H, s), DMSO 3.23 (2H, br s), 3.70 (2H, s), 4.36 (2H, d, J = 5.8 Hz), 5.11 (2H, s), 5.25 (2H, s), 6.40 (1H, s), 6.91 (2H, d, J = 8.0 Hz), 7.08-7.15 (2H, m), 7.19-7.22 (3H, m), 7.29 (1H, s), 7.58 (1H, s), 7.98 (1H, t, J = 5.5 Hz). 98 d6- 0.82-0.90 (2H, m), 0.90-0.96 (2H, m), 1.97 (3H, s), DMSO 2.05 (3H, s), 2.35 (3H, s), 2.55 (2H, br s), 4.31 (2H, d, J = 6.1 Hz), 5.05 (2H, s), 5.19 (2H, s), 6.31 (1H, s), 6.84 (2H, d, J = 8.2 Hz), 7.11-7.21 (4H, m), 7.21-7.27 (3H, m), 7.52 (1H, s), 8.05 (1H, t, J = 6.1 Hz). 99 d6- 0.94 (3H, t, J = 7.0 Hz), 1.82 (2H, s, br), 1.98 (6H, m), DMSO 2.27 (3H, s), 3.64 (2H, s), 3.92 (2H, s), 4.14 (2H, q, J = 6.9 Hz), 4.30 (2H, d, J = 5.9 Hz), 5.17 (2H, s), 6.70 (1H, s), 7.02 (2H, d, J = 8.2 Hz), 7.04-7.17 (5H, m), 7.22 (1H, s), 7.49 (1H, s), 8.21 (1H, t, J = 5.9 Hz). 100 d6- 0.82-0.88 (2H, m), 0.88-0.98 (5H, m), 1.98 (6H, s), 3.92 DMSO (2H, s), 4.13 (2H, q, J = 6.9 Hz), 4.31 (2H, d, J = 6.1 Hz), 5.17 (2H, s), 6.67 (1H, s), 7.01 (2H, d, J = 8.2 Hz), 7.11 (2H, d, J = 8.2 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.19-7.26 (3H, m), 7.49 (1H, s), 8.32 (1H, t, J = 6.1 Hz). 101 d6- 1.98 (3H, s), 2.01 (3H, s), 2.02-2.14 (2H, s, br), 2.32 DMSO (6H, s), 2.34 (3H, s), 3.61 (2H, s), 4.33 (2H, d, J = 5.0 Hz), 5.03 (2H, s), 5.18 (2H, s), 6.29 (1H, s), 6.83 (2H, d, J = 8.2 Hz), 6.95 (2H, s), 7.14 (2H, d, J = 8.2 Hz), 7.22 (1H, s), 7.42 (1H, t, J = 5.0 Hz), 7.51 (1H, s). 102 d6- 0.94 (3H, t, J = 7.0 Hz), 1.94 (3H, s), 1.98 (3H, s), 2.32 DMSO (6H, s), 3.66 (2H, s), 3.90 (2H, s), 4.14 (2H, q, J = 6.9 Hz), 4.35 (2H, d, J = 5.0 Hz), 5.17 (2H, s), 6.61 (1H, s), 6.97-7.01 (m, 4H), 7.10 (2H, d, J = 8.2 Hz), 7.22 (1H, s), 7.49 (1H, s), 7.78 (1H, t, J = 5.0 Hz). 103 0.79-0.95 (4H, m), 1.98 (3H, s), 2.36 (2H, br s), 4.34 (2H, d, J = 5.9 Hz), 5.20 (2H, s), 5.30 (2H, s), 7.12- 7.27 (9H, m), 7.51 (1H, s), 7.87 (1H, s), 8.22 (1H, s), 8.53 (1H, t, J = 6.0 Hz). 104 1.98 (3H, s), 3.20-3.40 (2H, br s), 3.70 (2H, s), 4.35 (2H, d, J = 6.4 Hz), 5.19 (2H, s), 5.21 (2H, s), 7.12- 7.32 (9H, m), 7.52 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 1.3 Hz), 7.81 (1H, d, J = 1.3 Hz), 8.38 (1H, t, J = 6.4 Hz). 105 0.81-0.89 (2H, m), 0.89-0.96 (2H, m), 1.98 (3H, s), 2.66 (2H, br s), 4.32 (2H, d, J = 6.4 Hz), 5.17 (2H, s), 5.21 (2H, s), 7.13-7.24 (7H, m), 7.27 (2H, d, J = 8.1 Hz), 7.51 (1H, s), 7.67 (1H, d, J = 1.3 Hz), 7.82 (1H, d, J = 1.2 Hz), 8.35 (1H, t, J = 6.4 Hz). 106 1.98 (3H, s), 2.27 (3H, s), 3.32 (2H, br s), 3.65 (2H, s), 4.34 (2H, d, J = 5.6 Hz), 5.21 (2H, s), 5.30 (2H, s), 7.05-7.25 (8H, m), 7.52 (1H, s), 7.89 (1H, s), 8.24 (1H, s), 8.38 (1H, t, J = 5.7 Hz). 107 1.98 (3H, s), 2.27 (3H, s), 2.19-2.41 (2H, br s), 3.64 (2H, s), 4.34 (2H, d, J = 6.2 Hz), 5.19 (2H, s), 5.21 (2H, s), 7.05 (1H, d, J = 7.9 Hz), 7.08-7.14 (2H, m), 7.18 (2H, d, J = 8.1 Hz), 7.23 (1H, s), 7.28 (2H, d, J = 8.1 Hz), 7.52 (1H, s), 7.69 (1H, d, J = 1.2 Hz), 7.82 (1H, d, J = 1.2 Hz), 8.17 (1H, t, J = 6.2 Hz). 108 1.98 (3H, s), 2.89 (2H, br s), 3.70 (2H, s), 4.39 (2H, d, J = 6.3 Hz), 5.22 (2H, s), 5.61 (2H, s), 7.11-7.36 (9H, m), 7.52 (1H, s), 8.61 (1H, s), 9.02 (1H, t, J = 6.2 Hz). 109 1.91 (2H, br s), 1.98 (3H, s), 2.28 (3H, s), 3.63 (2H, s), 4.38 (2H, d, J = 6.1 Hz), 5.22 (2H, s), 5.61 (2H, s), 7.01-7.16 (3H, m), 7.17-7.26 (3H, m), 7.31 (2H, d, J = 8.2 Hz), 7.52 (1H, s), 8.62 (1H, s), 8.85 (1H, t, J = 6.1 Hz). 110 0.87-1.11 (4H, m), 1.99 (3H, s), 4.39 (2H, d, J = 6.3 Hz), 4.80 (2H, s), 5.22 (2H, s), 5.62 (2H, s), 7.12- 7.38 (9H, m), 7.53 (1H, s), 8.62 (1H, s), 9.03 (1H, t, J = 6.3 Hz). 111 d6- 1.97 (3H, s), 2.14-2.30 (2H, s, br), 2.29 (6H, s), 3.62 DMSO (2H, s), 4.36 (2H, d, J = 4.8 Hz), 5.20 (2H, s), 5.27 (2H, s), 6.97 (2H, s), 7.16 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.3 Hz), 7.22 (1H, s), 7.51 (1H, s), 7.86 (1H, s), 7.95 (1H, t, J = 4.7 Hz), 8.23 (1H, s). 112 d6- 1.82-2.00 (2H, s, br), 1.98 (3H, s), 2.31 (6H, s), 3.60 (s, DMSO 2H), 4.39 (2H, d, J = 5.5 Hz), 5.17 (2H, s), 5.20 (2H, s), 6.95 (2H, s), 7.17 (2H, d, J = 8.3 Hz), 7.22 (s, 1H), 7.25 (2H, d, J = 8.2 Hz), 7.45 (1H, t, J = 5.4 Hz), 7.51 (1H, m), 7.69 (1H, d, J = 1.3 Hz), 7.77 (1H, d, J = 1.3 Hz). 113 d6- 1.91-2.04 (2H, s, br), 1.98 (3H, s), 2.32 (6H, s), 3.60 DMSO (2H, s), 4.43 (2H, d, J = 5.3 Hz), 5.21 (2H, s), 5.59 (2H, s), 6.95 (2H, s), 7.18 (2H, d, J = 8.2 Hz), 7.22 (1H, s), 7.28 (2H, d, J = 8.2 Hz), 7.52 (1H, s), 8.29 (1H, t, J = 5.2 Hz), 8.59 (1H, s). 114 d6- 1.98 (3H, s), 2.28 (3H, s), 2.36 (6H, s), 3.93 (2H, d, J = DMSO 5.5 Hz), 4.37 (2H, d, J = 5.0 Hz), 5.18 (2H, s), 5.20 (2H, s), 7.09 (2H, s) 7.14-7.20 (4H, m) 7.23 (1H, s), 7.52 (1H, s), 7.86 (1H, t, J = 4.9 Hz), 8.08 (3H, br s), 8.14 (1H, s). 115 d6- 1.98 (3H, s), 2.38 (6H, s), 2.43 (3H, s), 3.94 (2H, d, J = DMSO 5.8 Hz), 4.40 (2H, d, J = 5.0 Hz), 5.20 (2H, s), 5.27 (2H, s), 7.06-7.09 (4H, m), 7.15-7.18 (2H, m) 7.23 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 7.99 (1H, t, J = 4.9 Hz), 8.08 (2H, br s), 8.14 (1H, s). 116 d6- 1.98 (3H, s), 2.38 (6H, s), 2.43 (3H, s), 3.94 (2H, d, J = DMSO 5.8 Hz), 4.40 (2H, d, J = 5.0 Hz), 5.20 (2H, s), 5.27 (2H, s), 7.06-7.09 (4H, m), 7.15-7.18 (2H, m) 7.23 (1H, s), 7.52 (1H, s), 7.89 (1H, s), 7.99 (1H, t, J = 4.9 Hz), 8.08 (2H, br s), 8.14 (1H, s). 117 d6- 1.99 (3H, s), 2.09 (2H, br s), 3.71 (2H, s), 4.36 (2H, d, DMSO J = 5.9 Hz), 5.23 (2H, s), 5.41 (2H, s), 7.02 (1H, d, J = 11.2 Hz), 7.08 (1H, d, J = 7.9 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.24 (1H, s), 7.29 (2H, d, J = 8.1 Hz), 7.42 (1H, t, J = 7.9 Hz), 7.54 (1H, s), 8.44 (1H, s), 8.80 (1H, t, J = 5.9 Hz). 118 d6- 1.98 (3H, s), 2.30 (6H, s), 3.61 (2H, s), 4.36 (2H, d, J = DMSO 4.7 Hz), 5.21 (2H, s), 5.36 (2H, s), 6.98 (2H, s), 7.17- 2.26 (5H, m), 7.53 (1H, s), 8.20 (1H, t, J = 4.6 Hz), 8.38 (1H, s) 119 d6- 1.70-2.20 (2H, br s), 1.99 (3H, s), 2.18 (3H, d, J = DMSO 1.6 Hz), 3.71 (2H, s), 4.36 (2H, d, J = 5.2 Hz), 5.23 (2H, s), 5.40 (2H, s), 7.05 (1H, d, J = 8.0 Hz), 7.21-7.29 (6H, m), 7.54 (1H, s), 8.44 (1H, s), 8.65 (1H, t, J = 5.2 Hz). 121 d6- 0.94 (3H, t, J = 7.0 Hz), 1.98 (8H, m), 3.67 (2H, s), 3.92 DMSO (2H, s), 4.14 (2H, q, J = 6.9 Hz), 4.33 (2H, d, J = 6.1 Hz), 5.17 (2H, s), 6.68 (1H, s), 7.01 (2H, d, J = 8.2 Hz), 7.11 (2H, d, J = 8.2 Hz), 7.15-7.29 (5H, m), 7.49 (1H, s), 8.34 (1H, t, J = 6.1 Hz). 122 d6- 0.94 (3H, t, J = 7.0 Hz), 1.98 (3H, s), 3.71 (2H, s), 3.92 DMSO (2H, s), 4.13 (2H, q, J = 6.9 Hz), 4.33 (2H, d, J = 6.1 Hz), 5.03 (2H, s), 6.21 (1H, td, J = 6.7, 1.4 Hz), 6.39 (1H, d, J = 9.1 Hz), 6.68 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.17- 7.23 (4H, m), 7.26 (2H, d, J = 8.2 Hz), 7.40 (1H, ddd, J = 8.8, 6.6, 2.1 Hz), 7.70-7.76 (1H, m), 8.35 (1H, t, J = 6.2 Hz). 123 d6- 1.11 (3H, t, J = 6.9 Hz), 2.05 (3H, s), 3.67 (2H, s), 4.10 DMSO (2H, s), 4.34 (2H, d, J = 6.1 Hz), 4.40 (2H, q, J = 6.9 Hz), 6.66 (1H, s), 7.15-7.28 (5H, m), 7.44-7.53 (3H, m), 7.86-7.93 (2H, m), 8.34 (1H, t, J = 6.2 Hz). 124 d6- 2.31 (3H, s), 2.36 (6H, s), 2.80 (3H, s), 3.92 (2H, d, J = DMSO 5.72 Hz), 4.39 (2H, d, J = 5.0 Hz), 5.46 (2H, s), 7.09 (2H, s), 7.68-7.75 (2H, m), 7.91-7.92 (1H, m), 7.98-8.07 (1H, m), 8.27 (1H, s), 8.37 (3H, s), 8.62 (1H, d, J = 7.56 Hz). 126 d6- 2.36 (6H, s), 2.87 (3H, s), 3.91 (2H, d, J = 5.6 Hz), 4.41 DMSO (2H, d, J = 4.8 Hz), 5.68 (2H, s), 7.13 (2H, s), 7.81 (1H, s), 7.86 (1H, d, J = 8.1 Hz), 8.17-8.34 (4H, m), 8.39 (1H, s), 8.53 (1H, s), 8.78 (1H, br, s). 127 d6- 2.37 (6H, s), 2.89 (3H, s), 3.92 (2H, d, J = 5.36 Hz), 4.43 DMSO (2H, d, J = 4.9 Hz), 5.80 (2H, s), 7.14 (2H, s), 7.76-7.82 (1H, m), 7.92 (1H, s), 7.99 (1H, s), 8.27 (1H, d, J = 8.1 Hz), 8.37 (3H, s), 8.64 (1H, s), 8.81 (1H, br, s). 128 d6- 2.07 (3H, s), 2.35 (6H, s), 2.41 (3H, s), 2.63 (3H, s), DMSO 3.65 (2H, s), 4.35 (2H, d, J = 4.7 Hz), 5.25 (2H, s), 6.35 (1H, s), 6.97 (2H, s), 7.30-7.34 (2H, m), 7.38 (1H, d, J = 8.1 Hz), 7.51 (1H, br s), 7.89 (1H, d, J = 8.1 Hz), 8.15 (1H, d, J = 8.1 Hz). 129 d6- 2.01 (4H, s), 2.37 (6H, s), 3.65-3.72 (4H, m), 3.91 (2H, DMSO d, J = 5.6 Hz), 4.41 (2H, d, J = 4.9 Hz), 5.55 (2H, s), 6.55 (1H, d, J = 6.4 Hz), 7.03 (1H, s), 7.16 (2H, s), 7.92 (1H, d, J = 6.5 Hz), 8.42 (2H, s), 8.49 (1H, s), 8.58 (1H, s).

Biological Methods

[0428] The ability of the compounds of formula (I) to inhibit plasma kallikrein may be determined using the following biological assays:

Determination of the IC.SUB.50 .for Plasma Kallikrein

[0429] 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 various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410 nm and the IC.sub.50 value for the test compound was determined.

[0430] Data acquired from these assays are shown in Table 15 below. Generally, but not exclusively, preferred compounds demonstrate an IC.sub.50 of less than 200 nM.

TABLE-US-00016 TABLE 15 Example No IC.sub.50 (human PKal) nM 1 63 2 15 3 6 4 121 8 348 9 543 10 571 11 2419 12 5119 13 2383 14 2295 15 5694 16 186 17 492 18 435 19 768 20 4947 21 4522 22 3269 23 1596 24 431 25 1327 26 437 27 848 28 1326 29 140 30 773 31 251 32 732 33 919 34 3599 35 2100 36 203 37 170 38 2311 39 1092 40 1661 41 4704 42 953 43 196 44 355 45 135 46 1164 47 74 48 624 49 89 50 56 51 341 52 475 53 677 54 30 55 3267 56 3856 57 7178 58 4915 59 2742 60 3115 61 2990 62 6034 63 7338 64 6253 65 4558 66 5383 67 3503 68 2093 69 689 70 4593 71 702 72 3021 73 7580 74 1584 75 4499 76 8767 77 3722 78 4133 79 5546 80 2340 81 695 82 488 83 452 84 8379 85 11 86 7 87 5480 88 6989 89 226 90 114 91 29 92 40 93 2845 94 11 95 16 96 63 97 28 98 701 99 38 100 2321 101 4 102 11 103 694 104 30 105 941 106 2 107 3 108 33 109 5 110 2584 111 1 112 2 113 2 114 0.6 115 8 116 11699 117 51 118 1 119 9 121 155 122 151 123 2149 124 2 125 3 126 3 127 731 128 934 129 24

[0431] Selected compounds were further screened for inhibitory activity against the related enzyme KLK1. The ability of the compounds of formula (I) to inhibit KLK1 may be determined using the following biological assay:

Determination of the IC.SUB.50 .for KLK1

[0432] KLK1 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 KLK1 (Callbiochem) was incubated at 37° C. with the fluorogenic substrate H-DVal-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 410 nm and the IC.sub.50 value for the test compound was determined.

[0433] Data acquired from this assay are shown in Table 16 below:

TABLE-US-00017 TABLE 16 (KLK1 Activity) Example No IC.sub.50 (human KLK1) nM 1 >10,000 2 >10,000 3 >10,000 4 >10,000 8 6360 9 >10,000 10 >10,000 11 >10,000 12 >10,000 13 >10,000 14 6370 15 >10,000 16 >10,000 17 >10,000 18 >10,000 19 >10,000 20 2400 21 7500 22 >10,000 23 >10,000 24 >10,000 25 >10,000 26 >10,000 27 >10,000 28 >10,000 29 >10,000 30 >10,000 31 8080 32 >10,000 33 >10,000 34 >10,000 35 >10,000 36 >10,000 37 >10,000 38 >10,000 39 >10,000 40 >10,000 41 >10,000 42 >10,000 43 >10,000 44 >10,000 45 >10,000 46 4890 47 >10,000 48 >10,000 49 >10,000 50 >10,000 51 >10,000 52 >10,000 53 >10,000 54 >10,000 56 5480 57 >10,000 58 >10,000 59 >10,000 60 >10,000 61 >10,000 62 >10,000 63 >10,000 64 >10,000 65 >10,000 66 4230 67 6970 68 >10,000 69 >10,000 70 >10,000 71 >10,000 72 >10,000 73 >10,000 74 >10,000 75 >10,000 76 >10,000 77 >10,000 78 >10,000 79 >10,000 80 >10,000 81 >10,000 82 >8660 83 >10,000 84 >10,000 85 >8510 86 >10,000 87 >10,000 88 >10,000 89 >10,000 90 >10,000 91 >10,000 92 10,000 93 >10,000 94 10900 95 3900 96 >10,000 97 >10,000 98 >10,000 99 >10,000 100 >10,000 101 6310 102 4270 103 >10000 104 >10000 105 >10000 106 >10000 107 >10000 108 >10000 109 >10000 110 >10000 111 >10000 112 >10000 113 >10000 114 >10000 115 >10000 116 >10000 117 >10000 118 >10000 119 >10000 121 >10,000 122 >10,000 123 >10,000 124 301 125 657 126 566 127 >10,000 128 2660 129 >10,000

[0434] Selected compounds were further screened for inhibitory activity against 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

[0435] Human serine protease enzymes plasmin, thrombin, trypsin, Factor Xa and Factor XIIa were assayed for enzymatic activity using an appropriate fluorogenic substrate. Protease activity was measured by monitoring the accumulation of 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 concentration and activities were calculated as the concentration of inhibitor giving 50% inhibition (IC.sub.50) of the uninhibited enzyme activity (100%).

[0436] Data acquired from these assays are shown in Table 17 below:

TABLE-US-00018 TABLE 17 (Selectivity data) Example IC.sub.50 (nM) No Thrombin Trypsin Plasmin Factor XIIa 1 >40000 >40000 >40000 >10000 2 >40000 >40000 24805 >10000 83 >40000 26565 27242 >8510 84 >40000 >40000 >40000 >10000 101 >10000 119 >40000 124 >40000 125 >40000 126 >40000 127 >40000

Pharmacokinetics

[0437] Pharmacokinetic studies of selected examples were performed to assess the pharmacokinetics following a single oral dose in male Sprague-Dawley rats. Typically, either two or three rats were given a single po dose of 5 mL/kg of a nominal 2 mg/mL (10 mg/kg) composition of test compound in either 5% cremophor:5% ethanol:90% phosphate buffered saline or 20% Labrasol:80% water. Following dosing, blood samples were collected over a period of 8 hours. Typical sample times include 5, 15 and 30 minutes then 1, 2, 4, 6 and 8 hours. Following collection, blood samples were centrifuged and the plasma fraction analysed for concentration of test compound by LCMS. Oral exposure data acquired from these studies are shown below:

TABLE-US-00019 TABLE 18 (Oral exposure data) Example Dose po Cmax Tmax No. (mg/kg) (ng/mL) (mins) 1 11 81 280 2 11 59 300 37 10 171 210 43 8.9 71 240 45 10 228 155 101 9.7 67 300