Related Applications

This application claims the benefit of Indian Provisional Application Nos. 2129/MUM/2012 filed on 25 July 2012; 3014/MUM/2012 filed on 16 October 2012; and 1833/MUM/2013 filed on 24 May 2013; and U.S. Provisional Application Nos. 61/691,918 filed on 22 August, 2012; and 61/729,220 filed on 21 November, 2012, each of which is hereby incorporated by reference in its entirety.

Technical Field

The present application relates to guanidine derivatives as TRPC modulators, the TRP channel may be selected from TRPCl, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7. The compounds of present application are particularly modulators of TRPC3 and/or TRPC6 and/or TRPC7, more particularly modulators of TRPC6.

Background of the Invention

Transient receptor potential (TRP) family of ion channels act as sensors of the physical and chemical environment (Clapham, Nature, 2003, 426, 517-524). These channels are activated by temperature, light and touch etc. They have been classified into seven subfamilies: TRPC ('Canonical', short), TRPV (vanilloid), TRPM (long, melastatin), TRPP (polycystins), TRPML (mucolipins), TRP A (ANKTM1, Ankyrin) and TRPN (WOMPC) families. The TRPC channels all appear to be activated in response to phospholipase C (PLC)-coupled receptors. The TRPC family has two structurally divided subgroups: TRPC3, TRPC6, and TRPC7 channels (TRPC3/6/7) and TRPCl, TRPC4, and TRPC5 (TRPCl/4/5). One functional characteristic distinguishing these two subgroups is the ability of diacylglycerol (DAG) to activate TRPC3/6/7 channels but not TRPCl/4/5 channels. DAG also activates TRPC2 channels; however, this channel is not expressed in higher mammals and is restricted mostly to the vomeronasal organ (Soboloff et al., J. Biol. Chem., 2005, 280 (48), 39786-39794).

Canonical TRPC6 (transient receptor potential channel 6) channels are Ca ²⁺ permeable non-selective cation channels. The channels are ubiquitously expressed and play diverse functional roles, including vascular smooth muscle contraction, cell proliferation, and kidney glomerular filtration (Bing Shen et al., J. Biol. Chem., 2011, 286 (22), 19439-19445). Mutation in TRPC6 causes familial focal segmental glomerulosclerosis, which is characterized by proteinuria and a progressive decline in renal function. Down-regulation of TRPC6 by antisense sequences in pulmonary vascular smooth muscle cells result in reduction of store-operated Ca ²⁺ entry (Ying Yu et al., Am. J. Physiol. Cell Physiol, 2003, 284, C316-C330).

TRPC6 gets activated by several inflammatory stimuli such as FP3, Protease Activated Receptor-1 (PAR-1) (Singh BB et al., Mol. Cell, 2002, 9, 739-750), IL-IR (Beskina O et al., Am. J Physiol Cell Physiol, 2007, 293, CI 103-1111) and H ₂ 0 ₂ (Graham S et al., J. Biol Chem., 2010, 285, 23466-23476). It also gets activated by bronchoconstrictors such as histamine Hi (Hofmann T. et al., Nature, 1999, 397, 259- 263), BK-2 (Delmas P et al., Neuron, 2002, 34, 209-220) and serotonin (5-HT) (Jung S. et al., Am. J. Physiol. Cell Physiol, 2002, 282, C347-359). TRPC6 is also a mechanosensor (Spassova MA et al., Proc. Natl. Acad. Sci. USA., 2006, 103, 16586- 16591). TRPC6 knockout mice are protected against asthma and exhibit decreased airway eosinophilia, T _h 2 cells IL-5 and IL-13 levels in BAL fluid in ovalbumin induced asthma model (Sel S. et al., Clin. Exp. Allergy., 2008, 38, 1548-1558). TRPC6 expression is found to be elevated in smokers and COPD patients compared to non-smokers (Finney-Hayward TK et al., Am. J. Respir. Cell Mol. Biol, 2010, 43, 296-304).

TRPC6 has been associated with skeletal muscle dysfunction (Millay et al., Proc Natl Acad Sci USA., 2009, 106, 19023-19028), renal failure, atherosclerosis, heart failure (Kuwahara et al., J. Clin. Invest. 2006, 116, 3114-26), cancer such as oesophageal cancer, breast cancer (Aydar et al., Cancer Cell Int., 2009, 9, 23, Cai et al., Int. J. Cancer., 2009, 125, 2281-2287), chronic obstructive pulmonary disease (Sel et al., Clin. Exp. Allergy., 2008, 38, 1548-1558), pain (Alessandri-Haber et al., J. Neuroscl, 2009, 29, 6217-6228), pulmonary hypertension (Yu et al., Circulation, 2009, 119, 2313-2322), ischemic stroke, myocardial infarction (Varga-Szabo et al., Journal of Thrombosis and Haemostasis, 2009, 7, 1057-1066), inflammation or peripheral arterial occlusive disease.

TRPC6 may also contribute to the hypersecretion of mucus, allergic airway inflammation, making this cation channel a potential new drug target in asthma and COPD (Fabrice Antigny et al, Am. J. Respir. Cell Mol. Biol, 2011, 44(1), 83-90). TRPC6 is highly expressed in the lung, and involved in airway hyperresponsiveness (AHR) and allergic inflammation of the lung (Sel S. et al., Clin Exp Allergy., 2008, 38(9), 1548-1558).

TRPC6 is activated by diverse cellular signals, including agonists at Gq protein-coupled receptors and diacylglycerol. Various protein phosphorylations have complex regulation effects on the channel. Calcium/calmodulin dependent protein kinase II and the Src family receptor tyrosine kinase Fyn activate TRPC6, whereas PKC (protein kinase C) and PKG (protein kinase G) inactivate the channel. PKA (protein kinase A) can also phosphorylate TRPC6, although the phosphorylation does not appear to affect cation permeation (Bing Shen et al., J. Biol. Chem., 2011, 286 (22), 19439-19445).

International Publication No. WO2011/107474 Al describes aminoindanes as TRPC6 antagonists. WO2012/037351 Al and WO2012/037349 Al describe 2- (amino)-thiazole-4-carboxamide compounds as TRPC3 and/or TRPC6 ion channel blockers.

The present application is directed to compounds that act as modulators of TRPC activity, the TRP channel may be selected from TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7. The compounds of present application are particularly modulators of TRPC3 and/or TRPC6 and/or TRPC7 activity, more particularly modulators of TRPC6 activity.

Summary of the Invention

aspect, the present invention relates to a compound of formula (I)

(I)

stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein,

ring A is phenyl, naphthyl or benzodioxole;

ring B is phenyl, naphthyl, benzodioxole, indolyl or indolinyl;

R ¹ is selected from hydrogen, Ci_ ₈ alkyl and -(CH ₂ ) _n C(0)R ^b ;

R is selected from hydrogen and Ci_ ₈ alkyl; R is selected from hydrogen and Ci_ ₈ alkyl; R ⁴ is hydrogen;

R ⁵ is selected from hydrogen, halogen and Ci_ ₈ alkyl; at each occurrence, R ⁶ is independently selected from halogen, cyano, Ci_ galkyl, Ci_ ₈ alkoxy, haloCi_ ₈ alkyl, haloCi_ ₈ alkoxy, C6-i ₄ aryl, -(CH ₂ ) _n C(0)R ^b and - (CH ₂ ) _n NR ^b C(0)R ^c ;

at each occurrence, R is independently selected from halogen, cyano, Ci_ ₈ alkyl, Ci_ ₈ alkoxy, haloCi_ ₈ alkyl, haloCi_ ₈ alkoxy, C ₆ -i ₄ aryl and -(CH ₂ ) _n NR ^b C(0)R ^c ; at each occurrence, R ^b and R ^c are independently selected from hydrogen and Ci_ ₈ alkyl; n is selected from '0' to '3', both inclusive; p is selected from '0' to '5', both inclusive; and q is selected from '0' to '5', both inclusive.

The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (la), as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above, wherein A is phenyl, 1 -naphthyl, 2-naphthyl or benzodioxole (according to one embodiment defined below), B is phenyl, 1 -naphthyl, 2-naphthyl, benzodioxole, indolyl or indolinyl (according to another embodiment defined below), R ¹ is hydrogen (according to yet another embodiment defined below), R is hydrogen or methyl (according to yet another embodiment defined below), R is hydrogen or methyl (according to yet another embodiment defined below).

According to another embodiment, specifically provided are compounds of formula (I), in which A is phenyl, 1-naphthyl, 2-naphthyl or benzodioxole.

According to yet another embodiment, specifically provided are compounds of formula (I), in which B is phenyl, 1-naphthyl, 2-naphthyl, benzodioxole, indolyl or indolinyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is hydrogen or Ci_ ₈ alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is -(CH ₂ ) _n C(0)R ^b . In this embodiment, R ^b is Ci_ ₈ alkyl (e.g. methyl), and 'n' is 0.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is -C(0)CH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is hydrogen, methyl or -C(0)CH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or Ci_ ₈ alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or C _1-8 alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁵ is hydrogen, halogen (e.g. fluorine) or Ci_ ₈ alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁵ is hydrogen, fluorine or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R ⁶ is independently selected from halogen (e.g. fluorine or chlorine), cyano, C _1-8 alkyl (e.g. methyl, ethyl or isopropyl), Ci_ galkoxy (e.g. methoxy), haloCi-salkyl (e.g. trifluoromethyl), haloCi-salkoxy (e.g. difluoromethoxy, trifluoromethoxy), C6-i ₄ aryl (e.g. phenyl), -(CH ₂ ) _n C(0)R ^b and - (CH ₂ ) _n NR ^b C(0)R ^c . In this embodiment R ^b is independently selected from hydrogen and Ci_galkyl (e.g. methyl); R ^c is Ci_galkyl (e.g. methyl), and 'n' is 0.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R ⁶ is independently selected from fluorine, chlorine, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, -C(0)CH ₃ and -NHC(0)CH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'p' is '0' to '5' .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'p' is 0, 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R is independently selected from halogen (e.g. chlorine or fluorine), cyano, (e.g. methoxy), haloCi_ ₈ alkyl (e.g. trifluoromethyl), (e.g. trifluoromethoxy), C ₆ -i ₄ aryl (e.g. phenyl) and -(CH ₂ ) _n NR ^b C(0)R ^c . In this embodiment R ^b is hydrogen; R ^c is Ci_ galkyl (e.g. methyl), and 'n' is 0.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R is independently selected from chlorine, fluorine, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl and - NHC(0)CH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'q' is '0' to '5' .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'q' is 0, 1 or 2.

According to an embodiment, specifically provided are compounds of formula (I) with that exhibit an IC ₅₀ value of less than 5000 nM, preferably less than 1000 nM, more preferably less than 100 nM, with respect to TRPC6 inhibition.

Further embodiments relating to groups R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , p and q (and groups defined therein) are described hereinafter in relation to the compounds of formula (la). It is to be understood that these embodiments are not limited to use in conjunction with formula (la), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (la), in which 'p' is 0, 1 or 2, and consequently, there is also provided a compound of formula (I) in which 'p' is 0, 1 or 2.

The invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (la)

stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof,

wherein,

R ³ is selected from hydrogen and Ci_ ₈ alkyl; R ⁴ is hydrogen;

R ⁵ is selected from hydrogen, halogen and C _1-8 alkyl; at each occurrence, R ⁶ is independently selected from halogen, cyano, Ci_ ₈ alkyl, Ci_ ₈ alkoxy, haloCi_ ₈ alkyl, haloCi_ ₈ alkoxy, C ₆ -i ₄ aryl and -(CH ₂ ) _n NR ^b C(0)R ^c ; at each occurrence, R is independently selected from halogen, cyano, Ci_ galk l, Ci_ ₈ alkoxy, haloCi_ ₈ alkyl, haloCi_ ₈ alkoxy, C ₆ -i ₄ aryl and -(CH ₂ ) _n NR ^b C(0)R ^c ;

R 8 and R 9 are absent or together with the phenyl ring to which they are attached form naphthyl, benzodioxole or indolyl ring;

R ¹⁰ and R ¹¹ are absent or together with the phenyl ring to which they are attached form naphthyl or benzodioxole ring; at each occurrence, R ^b and R ^c are independently selected from hydrogen and Ci_ ₈ alkyl; n is selected from '0' to '3', both inclusive; p is selected from '0' to '5', both inclusive; and q is selected from '0' to '5', both inclusive.

The compounds of formula (la) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition of any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (la) as defined above wherein R is hydrogen or methyl (according to one embodiment defined below), R ⁴ is hydrogen (according to another embodiment defined below), R ⁵ is hydrogen (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or Ci_ ₈ alkyl (e.g. methyl).

According to another embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁵ is hydrogen, halogen (e.g. fluorine) or Ci_ ₈ alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ⁵ is hydrogen, fluorine or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R ⁶ is independently selected from halogen (e.g. chlorine or fluorine), cyano, Ci_ ₈ alkyl (e.g. methyl, ethyl or isopropyl), Ci_ galkoxy (e.g. methoxy), haloCi_ ₈ alkyl (e.g. trifluoromethyl), haloCi_ ₈ alkoxy (e.g. difluoromethoxy, trifluoromethoxy), C6-i ₄ aryl (e.g. phenyl) and -(CH ₂ ) _n NR ^b C(0)R ^c . In this embodiment R ^b is hydrogen; R ^c is Ci_ ₈ alkyl (e.g. methyl), and 'n' is 0.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R ⁶ is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, and -NHC(0)CH ₃ . According to yet another embodiment, specifically provided are compounds of formula (I), in which 'p' is '0' to '5' .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'p' is 0, 1 or 2.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R is independently selected from halogen (e.g. chlorine or fluorine), cyano, Ci_ ₈ alkyl (e.g. methyl), (e.g. methoxy), haloCi_galkyl (e.g. trifluoromethyl), haloCi_galkoxy (e.g. trifluoromethoxy), C6-i ₄ aryl (e.g. phenyl) and -(CH ₂ ) _n NR ^b C(0)R ^c . In this embodiment R ^b is hydrogen; R ^c is Ci_ galkyl (e.g. methyl), and 'n' is 0.

According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R is independently selected from chlorine, fluorine, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl and - NHC(0)CH ₃ .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'q' is '0' to '5' .

According to yet another embodiment, specifically provided are compounds of formula (I), in which 'q' is 0, 1 or 2.

According to yet another embodiment, specifically provided compounds of formula (la), in which R 8 and R 9 are absent.

According to yet another embodiment, specifically provided compounds of formula (la), in which R 8 and R 9 together with the phenyl ring to which they are attached form 1-naphthyl or 2-naphthyl ring.

According to yet another embodiment, specifically provided compounds of formula (la), in which R 8 and R 9 together with the phenyl ring to which they are attached form benzodioxol, 4-indolyl or 6-indolyl ring.

According to yet another embodiment, specifically provided compounds of formula (la), in which R 8 and R 9 together with the phenyl ring to which they are attached form 1-naphthyl, 2-naphthyl, benzodioxol, 4-indolyl or 6-indolyl ring.

According to yet another embodiment, specifically provided compounds of formula (la), in which R ¹⁰ and R ¹¹ are absent.

According to yet another embodiment, specifically provided compounds of formula (la), in which R ¹⁰ and R ¹¹ together with the phenyl ring to which they are attached form 1-naphthyl or 2-naphthyl ring. According to yet another embodiment, specifically provided compounds of formula (la), in which R ¹⁰ and R ¹¹ together with the phenyl ring to which they are attached form a benzodioxol ring.

According to yet another embodiment, specifically provided compounds of formula (la), in which R ¹⁰ and R ¹¹ together with the phenyl ring to which they are attached form a 1-naphthyl, 2-naphthyl or benzodioxol ring.

According to an embodiment, specifically provided are compounds of formula (I) with that exhibit an IC ₅₀ value of less than 5000 nM, preferably less than 1000 nM, more preferably less than 100 nM, with respect to TRPC6 inhibition.

Below are the representative compounds, which are illustrative in nature only and are not intended to limit the scope of the invention.

(±)-N-Carbamimidoyl-2,3-diphenylpropanamide;

(2R)-N-Carbamimidoyl-2,3-diphenylpropanamide;

(2S)-N-Carbamimidoyl-2,3-diphenylpropanamide;

(±)-N-Carbamimidoyl-2-phenyl-3-(2-methylphenyl)propanami de;

(2R)-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanami de;

(2 _l S')-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropana mide;

(+)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamid e;

(2R)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanami de;

(2 _l S')-N-Carbamimidoyl-3-(3-methylphenyl)-2-phenylpropana mide;

(±)-N-Carbamimidoyl-2-phenyl-3-(4-methylphneyl)propanami de;

(2R)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanami de;

(2S)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanami de;

(±)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamid e;

(2R)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamid e;

(2S)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamid e;

(±)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropan amide;

(2R)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropan amide;

(2 _l S')-N-Carbamimidoyl-2-phenyl-3-[4-(propan-2-yl)phenyl] propanamide;

(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanami de;

(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanami de;

(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanami de;

(+)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamid e;

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanami de; (25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide;

(+)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-phenylpropanamid e;

(2R)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-phenylpropanami de;

(25)-N-Carbaimimdoyl-3-(4-chlorophenyl)-2-phenylpropanami de;

(+)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamid e;

(2R)-N-Carbaimmidoyl-3-(2-fluorophenyl)-2-phenylpropanami de;

(25 ^, )-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanami de;

(+)-N-Carbaimimdoyl-3-(3-fluorophenyl)-2-phenylpropanamid e;

(2R)-N-Carbaimmidoyl-3-(3-fluorophenyl)-2-phenylpropanami de;

(25 ^, )-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanami de;

(+)-N-Carbaimimdoyl-3-(4-fluorophenyl)-2-phenylpropanamid e;

(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2-phenylpropanamide ;

(25 ^, )-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanami de;

(+)-N-Carbaimimdoyl-3-(2-methoxyphenyl)-2-phenylpropanami de;

(2R)-N-Carbaimimdoyl-3-(2-methoxyphenyl)-2-phenylpropanam ide;

(2 _l S')-N-Carbamimidoyl-3-(2-methoxyphenyl)-2-phenylpropan amide;

(+)-N-Carbaimimdoyl-3-(3-methoxyphenyl)-2-phenylpropanami de;

(2R)-N-Carbaimimdoyl-3-(3-methoxyphenyl)-2-phenylpropanam ide;

(2 _l S')-N-Carbamimidoyl-3-(3-methoxyphenyl)-2-phenylpropan amide;

(+)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-phenylpropanami de;

(2R)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-phenylpropanam ide;

(2 _l S')-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropan amide;

(+)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl ]propanamide; (2R)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]p ropanamide; (2 _l S ^, )-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethyl)pheny l]propanamide; (+)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]pr opanamide; (2R)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]p ropanamide; (2 _l S ^, )-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethyl)pheny l]propanamide; (+)-N-Carbaimimdoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpr opanaim (2R)-N-Carbaimimdoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylp ropanaim (25 ^, )-N-Carbamimidoyl-3-[4-(difluoromethoxy)phenyl]-2-phen ylpropanamide; (+)-N-Carbaimimdoyl-2-phenyl-3-(2-(trifluoromethoxy)phenyl)p ropanamide; (2R)-N-Carbaimimdoyl-2-phenyl-3-[2-(trifluoromethoxy)phenyl] propanamide; (25)-N-Carbamimidoyl-2-phenyl-3-[2-(trifluoromethoxy)phenyl] propanamide; (+)-N-Carbairnirndoyl-2-phenyl-3-[3-(trffl^

(2R)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl] propanamid

(25)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phen yl]propanamid

(+)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethoxy)pheny l]propanamide;

(2R)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethoxy)phen yl]propanamid

(25)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phen yl]propanamid

(+)-N-Carbaimimdoyl-3-(3-cyanophenyl)-2-phenylpropanamide ;

(2R)-N-Carbaimimdoyl-3-(3-cyanophenyl)-2-phenylpropanamide;

(2S)-N-Carbamimidoyl-3-(3-cyanophenyl)-2-phenylpropanamide;

(+)-N-Carbaimimdoyl-3-(4-cyanophenyl)-2-phenylpropanamide;

(2R) -N-Carbamimidoyl- 3 - (4-cy anophenyl) -2-phenylpropanamide ;

(2S)-N-Carbamimidoyl-3-(4-cyanophenyl)-2-phenylpropanamide;

(+)-3-(4-Acetamidophenyl)-N-carbamimidoyl-2-phenylpropanamid e;

(2R)-3-(4-Acetamidophenyl)-N-carbamimidoyl-2-phenylpropanami de;

(25)-3-(4-Acetamidophenyl)-N-carbaimimdoyl-2-phenylpropanami de;

(+)-N-Carbaimimdoyl-3-(2,4-dichlorophenyl)-2-phenylpropanami de;

(2R)-N-Carbaimmidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanam ide;

(25)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanam ide;

(+)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylprop anamide;

(2R)-N-Carbaimimdoyl-3-(4-chloro-2-fluorophenyl)-2-phenyl propanamide;

(2 _l S')-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phen ylpropanamide;

(+)-N-Carbaimmidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylp ropanamide;

(2R)-N-Carbaimimdoyl-3-(4-chloro-3-fluorophenyl)-2-phenyl propanamide;

(2 _l S')-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phen ylpropanamide;

(+)-N-Carbaimimdoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropa namide;

(2R) -N-Carbamimidoyl- 3 - (2, 3 -dimethoxyphenyl) -2-phenylpropanamide ;

(25)-N-Carbamimidoyl-3-(2,3-dimethoxyphenyl)-2-phenylprop anamide;

(±)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylprop anamide;

(2R)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropana mide;

(25)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylprop anamide;

(±)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpro panamide;

(2R)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropan amide;

(25)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpro panamide;

(±)-N-Carbamimidoyl-3-phenyl-2-(4-methylphenyl)propanami de; (2R)-N-Carbaimimdoyl-2-(4-methylphenyl)-3-phenylpropanamide;

(25)-N-Carbamimidoyl-2-(4-methylphenyl)-3-phenylpropanamide;

(+)-N-Carbaimmidoyl-2-(2-chlorophenyl)-3-phenylpropanamide;

(2R)-N-Carbaimmidoyl-2-(2-chlorophenyl)-3-phenylpropanamide;

(25)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-phenylpropanamide;

(+)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-phenylpropanamide;

(2R)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-phenylpropanamide;

(25)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-phenylpropanamide;

(+)-N-Carbaimmidoyl-2-(4-chlorophenyl)-3-phenylpropanamide;

(2R)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-phenylpropanamide;

(25)-N-Carbaimmidoyl-2-(4-chlorophenyl)-3-phenylpropanamide;

(+)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-phenylpropanamide;

(2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-phenylpropanamide;

(25 ^, )-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanami de;

(+)-N-Carbaimimdoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;

(2R)-N-Carbaimimdoyl-2-(3-methoxyphenyl)-3-phenylpropanamide ;

(2 _l S')-N-Carbamimidoyl-2-(3-methoxyphenyl)-3-phenylpropan amide;

(+)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;

(2R)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-phenylpropanamide ;

(2 _l S')-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropan amide;

(+)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]pr opanamide;

(2R) -N-Carbamimidoyl- 3 -phenyl-2- [4- (trifluoromethyl)phenyl] propanamide ;

(2 _l S ^, )-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethyl)pheny l]propanamide;

(+)-N-Carbaimimdoyl-3-phenyl-2-[3-(trifluoromethoxy)pheny l]propanamide;

(2R)-N-Carbaimimdoyl-3-phenyl-2-[3-(trifluoromethoxy)phen yl]propanamid

(25)-N-Carbaimmidoyl-3-phenyl-2-[3-(trifluoromethoxy)phen yl]propanamid

(+)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethoxy)pheny l]propanamide;

(2R)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethoxy)phen yl]propanamid

(25)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethoxy)phen yl]propanamid

(+)-N-Carbaimimdoyl-2-(4-cyanophenyl)-3-phenylpropanamide ;

(2R)-N-Carbaimimdoyl-2-(4-cyanophenyl)-3-phenylpropanamide;

(2S)-N-Carbamimidoyl-2-(4-cyanophenyl)-3-phenylpropanamide;

(+)-N-carbaimmidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanami de;

(2R)-N-carbaimmidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanam ide; (25)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanam ide;

(+)-N-Carbaimmidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanam ide;

(2R)-N-Carbaimmidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropana mide;

(25)-N-Carbamimidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropana mide;

(+)-2-(l,3-Benzodioxol-5-yl)-N-carbaimimdoyl-3-phenylpropana mide;

(2R)-2-(l,3-Benzodioxol-5-yl)-N-carbamiimdoyl-3-phenylpropan amide;

(25)-2-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-3-phenylpropan amide;

(+)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamid e;

(2R)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanami de;

(25)-2-(4-Acetamidophenyl)-N-carbaimimdoyl-3-phenylpropanami de;

(+)-N-Carbaimimdoyl-2,3-bis(4-methylphenyl)propanamide;

(2R)-N-Carbaimmidoyl-2,3-bis(4-methylphenyl)propanamide;

(25)-N-Carbamimidoyl-2,3-bis(4-methylphenyl)propanamide;

(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-methylphenyl)propanamide ;

(2R)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-(4-methylphenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methylphen yl)propanamide;

(+)-N-Carbaimimdoyl-3-(4-fluorophenyl)-2-(4-methylphenyl) propanamide;

(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- (4-methylphenyl)propanamide ;

(25 ^, )-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methylphenyl )propanamide;

(+)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-(4-methylphenyl )propanamide;

(2R)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-(4-methylpheny l)propanaim

(2 _l S ^, )-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-(4-methylpheny l)propanamide;

(+)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-methylphenyl) propanamide;

(2R)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-methylphenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-methylphen yl)propanamide;

(+)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl) propanamide;

(2R)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-chlorophen yl)propanamide;

(+)-N-Carbaimmidoyl-2-(2-chlorophenyl)-3-(3-fluorophenyl) propanamide;

(2R)-N-Carbaimmidoyl-2-(2-chlorophenyl)-3-(3-fluorophenyl )propanamide;

(25)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-fluorophenyl )propanamide;

(+)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-methylphenyl) propanamide;

(2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-methylphenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-methylphen yl)propanamide; (+) -N-Carbaimimdoyl- 3 - (2-chlorophenyl) -2- ^

(2R)-N-Carbaimimdoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)pr opanamide;

(2 _l S')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(3-chlorophen yl)propanamide;

(+)-N-Carbaimimdoyl-2,3-bis(3-chlorophenyl)propanamide;

(2R)-N-Carbaimimdoyl-2,3-bis(3-chlorophenyl)propanamide;

(2 _l S')-N-Carbamimidoyl-2,3-bis(3-chlorophenyl)propanamide ;

(+)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)pro panamide;

(2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-chlorophen yl)propanamide;

(+)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-(3-fluorophenyl) propanamide;

(2R)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-(3-fluorophenyl )propanamide;

(25)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(3-fluorophenyl )propanamide;

(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-methylphenyl)propanamide ;

(2R)-N-Carbaimmidoyl-2-(4-chlorophenyl)-3-(4-methylphenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methylphen yl)propanamide;

(+)-N-Carbaimimdoyl-2,3-bis(4-chlorophenyl)propanamide;

(2R)-N-Carbaimimdoyl-2,3-bis(4-chlorophenyl)propanamide;

(2 _l S')-N-Carbamimidoyl-2,3-bis(4-chlorophenyl)propanamide ;

(+)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)pro panamide;

(2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-fluorophen yl)propanamide;

(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-methoxyphenyl)propanamide ;

(2R)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxypheny l)propanamide;

(25)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxypheny l)propanamide;

(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-fluorophenyl)propanamide ;

(2R)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-fluorophenyl )propanamide;

(25)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-fluorophenyl )propanamide;

(±)-N-Carbamimidoyl-2-(3-fluorophenyl)-3-(3-methylphenyl )propanamide;

(2R)-N-Carbamimidoyl-2-(3-fluorophenyl)-3-(3-methylphenyl )propanamide;

(2 _l S')-N-Carbamimidoyl-2-(3-fluorophenyl)-3-(3-methylphen yl)propanamide;

(±)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanamide;

(2R)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanarriide;

(2 _l S')-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanamide ;

(+)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)pro panamide; (2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)pr opanamide;

(25)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)pr opanamide;

(+)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)pro panamide;

(2R)-N-Carbaimmidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)pr opanamide;

(25 ^, )-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl )propanamide;

(+)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)pro panamide;

(2R)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)pr opanamide;

(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)pr opanamide;

(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-fluorophenyl)propanamide ;

(2R)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)pr opanamide;

(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)pr opanamide;

(+)-N-Carbaimmidoyl-2,3-bis(4-fluorophenyl)propanamide;

(2R)-N-Carbaimimdoyl-2,3-bis(4-fluorophenyl)propanamide;

(2S)-N-Carbamimidoyl-2,3-bis(4-fluorophenyl)propanamide;

(+)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)pr opanamide;

(2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)p ropanamide;

(25 ^, )-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methoxypheny l)propanamide;

(+)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)pr opanamide;

(2R)-N-Carbairnirndoyl-2-(4-memoxyphenyl)-3-(4-m

(2 _l S ^, )-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-(4-methylpheny l)propanamide;

(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-methoxyphenyl)propanamide ;

(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)p ropanamide;

(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)p ropanamide;

(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)pr opanamide;

(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- (4-methoxyphenyl)propanamide ;

(2 _l S')-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphe nyl)propanamide;

(+)-N-Carbamimidoyl-2,3-bis(4-methoxyphenyl)propanamide;

(2R)-N-Carbamimidoyl-2,3-bis(4-methoxyphenyl)propanamide;

(25)-N-Carbamimidoyl-2,3-bis(4-methoxyphenyl)propanamide;

(+)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[4-trifluoromethyl) phenyl]propanamide;

(2R)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[4-(trifluorome thyl)phenyl] propanamide;

(2 _l S')-N-Carbamimidoyl-3-(4-methylphenyl)-2-[4-(trifluoro methyl)phenyl]

propanamide; (+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- [4- (trifluoromethyl)phenyl] propanamid

(2R)-N-Carbaimimdoyl-3-(4-chlorophenyl)-2-[4-(trifluorome thyl)phenyl] propanamide;

(2 _l S')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-[4-(trifluoro methyl)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[4-(trifluoromethyl )phenyl]propanam (2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- [4- (trifluoromethyl)phenyl] propanamide;

(25 ^, )-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[4-(trifluorome thyl)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethy l)phenyl] propanamide;

(2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluorometh yl)phenyl] propanamide;

(25)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluorometh yl)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethyl )phenyl]propanamid (2R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2- [2- (trifluoromethyl)phenyl] propanamide;

(25 ^, )-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluorome thyl)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethyl )phenyl]propanamid (2R) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethyl)phenyl] propanamide;

(25 ^, )-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluorome thyl)phenyl] propanamide;

(+) -N-Carbamimidoyl- 3 - (3 -chlorophenyl) -2- [2- (trifluoromethyl)phenyl] propanamid

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluorome thyl)phenyl] propanamide;

(2 _l S')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoro methyl)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl )phenyl] propanamide; (2R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethy l)phenyl] propanamide;

(2 _l S')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoro methyl)phenyl] propanamide;

(+) -N-Carbamimidoyl- 3 - (2-chlorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;

(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluorometho xy)phenyl] propanamide;

(2 _l S')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoro methoxy)phenyl] propanamide;

(+) -N-Carbamimidoyl- 3 - (3 -chlorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluorometho xy)phenyl] propanamide;

(2 _l S')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoro methoxy)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethox y)phenyl] propanamide;

(2R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;

(25 ^, )-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluorome thoxy)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethox y)phenyl] propanamide;

(2R) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;

(2 _l S ^, )-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluorome thoxy)phenyl] propanamide;

(+)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethox y)phenyl] propanamide;

(2R)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluorometho xy)phenyl] propanamide;

(25)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluorometho xy)phenyl] propanamide; (+)-N-Carbairnirndoyl-3-(4-fluorophenyl)-2^

propanamide;

(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- [3 - (trifluoromethoxy )phenyl] propanamide;

(25 ^, )-N-Carbamimidoyl-3-(4-f uorophenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide;

(±)-N-carbamimidoyl-2-(2,4-dichloiOphenyl)-3-(4-methylpheny l)propanamide;

(2R)-N-carbarmmidoyl-2-(2,4-dichlorophenyl)-3-(4-methylph enyl)propanamide;

(25 N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)pro panamide;

(+)-N-Carbarmrmdoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophe nyl)propanarmde;

(2R)-N-Carbarmmidoyl-2-(2,4-dichlorophenyl)-3-(4-fluoroph enyl)propanamide;

(2S)-N-Carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-fluoroph enyl)propanamide;

(±)-N-(N, N-Dimethylcarbamimidoyl)-2,3-diphenylpropanamide;

(2R)-N-(N, N-Dimethylcarbamimidoyl)-2,3-diphenylpropanamide;

(2S)-N-(N, N-Dimethylcarbamimidoyl)-2,3-diphenylpropanamide;

(+)-N-(N,N-DimethylcarbaiTdmidoyl)-3-(4-methoxyphenyl)-2-phe nylpropanamide;

(2R)-N-(N,N-Dimethylcarbamirmdoyl)-3-(4-methoxyphenyl)-2- phenylpropanamide;

(25)-N-(N,N-DimethylcarbaiTiimidoyl)-3-(4-methoxyphenyl)- 2-phenylpropanamide;

(+)-N-Carbarmmidoyl-3-(lH-indol-3-yl)-2-phenylpropanamide ;

(2R)-N-Carbarmmidoyl-3-(lH-indol-3-yl)-2-phenylpropanaiTiide ;

(25)-N-Carbamimidoyl-3-(lH-indol-3-yl)-2-phenylpropanamide;

(+)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropa namide;

(2R)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylprop anamide;

(2S)-3-(l -Acetyl- lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide;

(+)-3-(l-Acetylindolin-3-yl)-N-Carbarmrmdoyl-2-phenylpiOpana mide;

(2R)-3-(l-Acetylindolin-3-yl)-N-Carbarmrmdoyl-2-phenylpropan amide;

(25 ^, )-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpro panamide;

(+)-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanamide;

(2R)-N-Carbarmrmdoyl-3-(lH-indol-6-yl)-2-phenylpiOpanamide;

(2 _l S')-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanam ide;

(+)-N-Carbamimidoyl-3-(lH-indol-4-yl)-2-phenylpropanamide;

(2R)-N-Carbarmrmdoyl-3-(lH-indol-4-yl)-2-phenylpropanamide;

(25 ^, )-N-Carbamimidoyl-3-(lH-indol-4-yl)-2-phenylpropanamid e;

(+)-N-(N-Acetylcarbamimidoyl)-2,3-diphenylpropanarnide; (2R)-N-(N-Acetylcarbamimidoyl)-2,3-diphenylpropanamide;

(25)-N-(N-Acetylcarbamiimdoyl)-2,3-diphenylpropanamide;

(+) -N-Carbamimidoyl-2- (naphthalen- 1 -yl) - 3 -phenylpropanamide ;

(2R)-N-Carbaimimdoyl-2-(naphthalen-l-yl)-3-phenylpropanamide ;

(2 _l S')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropan amide;

(+) -N-Carbamimidoyl-2- (naphthalen- 1 -yl) - 3 -phenylpropanamide ;

(2R)-N-Carbarrdmidoyl-2-(naphthalen-l-yl)-3-phenylpropanamid e;

(2 _l S')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropan amide;

(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)p ropanamide;

(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-y l)propanamid

(2 _l S')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l -yl)propanamide

(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-y l)propanamide;

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-y l)propanamid

(2 _l S')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l -yl)propanamide

(±)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-y l)propanamide;

(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-y l)propanamid

(2 _l S')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l -yl)propanamide

(±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-y l)propanamide;

(2R)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-y l)propanamide

(25)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-y l)propanamide

(±)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanam ide;

(2R)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide ;

(2 _l S')-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropan amide;

(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)p ropanamide;

(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-y l)propanamid

(2 _l S')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2 -yl)propanamide

(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-y l)propanamide;

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-y l)propanamid

(2 _l S')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2 -yl)propanamide

(±)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-y l)propanamide;

(2R)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-y l)propanamid

(2 _l S')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l -yl)propanamid(

(±)-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanam ide;

(2R)-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide ; (2S)-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide ;

(+)-N-Carbamimidoyl-2,3-di(naphthalen- 1 -yl)propanamide;

(2R)-N-Carbamimidoyl-2,3-di(naphthalen- 1 -yl)propanamide;

(2S)-N-Carbamimidoyl-2,3-di(naphthalen- 1 -yl)propanamide;

(+)-N-Carbaimimdoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)p ropanamide;

(2R)-N-Carbaimmidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2- yl)propanamide;

(2 _l S')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-(naphthalen- 2-yl)propanamide;

(+)-N-Carbaimimdoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-y l)propanamide;

(2R)-N-Carbaimmidoyl-3-(naphthalen-l-yl)-2-(naphthalen-2- yl)propanamide;

(2 _l S')-N-Carbamimidoyl-3-(naphthalen-l-yl)-2-(naphthalen- 2-yl)propanamide;

(+)-N-Carbaimmidoyl-2,3-di(naphthalen-2-yl)propanamide;

(2R)-N-Carbaimimdoyl-2,3-di(naphthalen-2-yl)propanamide;

(2S)-N-Carbamimidoyl-2,3-di(naphthalen-2-yl)propanamide;

(+)-N-Carbamimidoyl-2,3-diphenylbutanamide;

(2R,3R)-N-Carbamimidoyl-2,3-diphenylbutanamide;

(2S,3S)-N-Carbamimidoyl-2,3-diphenylbutanamide;

(+) -N-Carbamimidoyl- 3 - (2-chlorophenyl) -2-phenylbutanamide ;

(2R,3R)-N-Carbaimimdoyl-3-(2-chlorophenyl)-2-phenylbutanamid e;

(25,35)-N-Carbaimmidoyl-3-(2-chlorophenyl)-2-phenylbutanamid e;

(+)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylbutanamide;

(2R,3R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylbutanamid e;

(25,35)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-phenylbutanamid e;

(+)-N-Carbaimmidoyl-3-(2-fluorophenyl)-2-phenylbutanamide;

(2R,3R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2-phenylbutanamide ;

(25,35)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylbutanamid e;

(+)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;

(2R,3R)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamid e;

(25,35)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamid e;

(+)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbuta namide;

(2R,3R)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phe nylbutanamide;

(25,35)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phe nylbutanamide;

(+)-N-Carbamimidoyl-2-fluoro-2,3-diphenylpropanamide;

(2R)-N-Carbamimidoyl-2-fluoro-2,3-diphenylpropanamide;

(25 ^, )-N-Carbamimidoyl-2-fluoro-2,3-diphenylpropanamide; (±)-N-Carbarrdmidoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylp ropanamide;

(2R)-N-Carbamimidoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpr opanamide;

(2 _l S ^, )-N-Carbamimidoyl-2-fluoro-3-(4-methoxyphenyl)-2-pheny lpropanamide;

(±)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpr opanamide;

(2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpr opanamide;

(2 _l S ^, )-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-pheny lpropanamide;

(±)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide;

(2R)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide;

(25)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide;

(±)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide

(2R)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide

(25)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide;

(±)-3-(Biphenyl-2-yl)-N-carbamimidoyl-2-phenylpropanamide;

(2R)-3-(Biphenyl-2-yl)-N-carbamimidoyl-2-phenylpropanamide;

(25)-3-(Biphenyl-2-yl)-N-carbamimidoyl-2-phenylpropanamide;

(±)-3-(Biphenyl-3-yl)-N-carbamimidoyl-2-phenylpropanamide;

(2R)-3-(Biphenyl-3-yl)-N-carbamimidoyl-2-phenylpropanamide;

(25)-3-(Biphenyl-3-yl)-N-carbamimidoyl-2-phenylpropanamide;

or pharmaceutically acceptable salts thereof.

It should be understood that the formulas (I) and (la) structurally encompass racemic mixtures, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

Compounds of the present invention include the compounds in Examples 1-

175.

According to an embodiment, the compounds of formula (I) or formula (la) structurally encompass all tautomeric forms whether such tautomer exists in equilibrium or predominantly in one form. Such tautomeric form may be different or the same when the compound is bound to the TRPC channel.

The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of TRPC, the TRP channel may be selected from TRPCl, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7. The compounds of the present invention are particularly modulators of TRPC3 and/or TRPC6 and/or TRPC7 activity, more particularly modulators of TRPC6 activity, which is related to a variety of disease states.

The present invention further provides a method of inhibiting TRPC1/TRPC3/TRPC4/TRPC5/TRPC6/TRPC7 activity, particularly

TRPC3/TRPC6/TRPC7 activity, and the treatment of disorders associated therewith using compound of formula (I) or a pharmaceutically acceptable salt, racemic mixture, stereoisomer, diastereoisomer, enantiomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, racemic mixture, stereoisomer, diastereoisomer, enantiomer thereof . More particularly, the invention is further directed to methods of inhibiting TRPC6 activity and treatment of disorders associated therewith using a compound of formula (I) or a pharmaceutically acceptable salt, racemic mixture, stereoisomer, diastereoisomer, enantiomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, racemic mixture, stereoisomer, diastereoisomer, enantiomer thereof.

Furthermore, the present invention includes all racemic mixtures, stereoisomers, diastereoisomers, enantiomers and enantiomerically enriched compounds of formula (I) and (la).

All stereoisomers of the compounds of present invention are contemplated, either in racemic mixture or in pure or substantially pure form or in enantiomerically enriched form. The processes for preparation of compounds of present invention can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

Detailed Description of the Invention

Definitions

The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).

The term "alkyl" refers to a straight or branched hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_ ₈ alkyl), and which is attached to the rest of the molecule by a single bond. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 2- methylpropyl (isobutyl), n-pentyl, 1,1-dimethylethyl (t-butyl), and 2,2- dime thy Ipropyl. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C ₂ - ₁₀ alkenyl) and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2- propenyl (allyl), zsopropenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C _2-10 alkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Representative examples of such groups are -OCH ₃ and -OC ₂ H ₅ . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci_ galkoxyCi_ ₈ alkyl or Ci_ ₈ alkyloxyCi_ ₈ alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH ₂ OCH ₃ and -CH ₂ OC ₂ H ₅ . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi_galkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, trifluoroethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_galkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "hydroxyalkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi-salkyl). Examples of hydroxyalkyl moiety include, but are not limited to -CH ₂ OH, -C ₂ H ₄ OH and -CH(OH)C ₂ H ₄ OH. Unless set forth or recited to the contrary, all hydroxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C ₃ _i ₂ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2- yl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a non-aromatic cyclic ring-containing radical having 3 to about 12 carbon atoms directly attached to an alkyl group, for example C ₃ _i ₂ cycloalkylCi_ ₈ alkyl. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a non-aromatic cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, for example C ₃ _ ₈ cycloalkenyl, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.

The term "cycloalkenylalkyl" refers to a non-aromatic cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C ₃ _ ₈ cycloalkenylCi_ ₈ alkyl. Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-i ₄ aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted. The term "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C ₆ -i ₄ aryloxy). Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C ₆ -i ₄ arylCi_ ₈ alkyl, such as -CH ₂ C ₆ H ₅ and - C ₂ H ₄ C ₆ H ₅ . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclyl" or "heterocyclic ring" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylCi_ ₈ alkyl). Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroaryl" unless otherwise specified refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "bicyclic heteroaryl" unless otherwise specified refers to substituted or unsubstituted bicyclic aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to indolyl, isoindolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, 1,3- Benzodioxolyl, 1,4-Benzodioxanyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, benzothiadiazolyl, thienothiadiazolyl, indolizinyl and phthalazinyl. Unless set forth or recited to the contrary, all bicyclic heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. heterarylCi_ ₈ alkyl). Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR ^x , - C(0)R ^x , -C(S)R ^X , -C(0)NR ^x R ^y , -C(0)ONR ^x R ^y , -NR ^x CONR ^y R ^z , -N(R ^x )SOR ^y , - N(R ^x )S0 ₂ R ^y , -NR ^x C(0)OR ^y , -NR ^x R ^y , -NR ^x C(0)R ^y , -NR ^x C(S)R ^y , -NR ^x C(S)NR ^y R ^z , - SONR ^x R ^y , -S0 ₂ NR ^x R ^y , -OR ^x , -OC(0)NR ^y R ^z , -OC(0)OR ^y , -OC(0)R ^x , -OC(0)NR ^x R ^y , -SR ^X , -SOR ^x , -S0 ₂ R ^x and -ON0 ₂ , wherein R ^x , R ^y and R ^z are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" can be unsubstituted alkenyl but cannot be "substituted alkenyl".

The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.

The term "substantially pure" refers to the guanidine derivatives of present invention having a total purity, including both stereochemical and chemical purity, of greater than about 95%, specifically greater than about 98%, more specifically greater than about 99%, and still more specifically greater than about 99.5%. The purity is preferably measured by High Performance Liquid Chromatography (HPLC). For example, the purity of the guanidine derivatives obtained by the process disclosed herein is about 95% to about 99%, or about 98% to about 99.5%, as measured by HPLC.

The term "enantiomerically enriched" refers to the guanidine derivatives of present invention comprising more than 75% of one stereoisomer, preferably more than 80%, preferably more than 85%, preferably more than 90%, preferably more than 95%.

The term "racemic mixture" refers to the guanidine derivatives of present invention comprising 30-70% of each of the two stereoisomers.

The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

The compound described in the present patent application may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.

Compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) and formula (la), the present invention extends to all these stereoisomeric forms and to mixtures thereof. The different stereoisomeric forms of the compounds described herein may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. It is also to be understood that compounds described herein may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.

Pharmaceutical Compositions

The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, and solvents.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene. The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide a desired release profile.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, and impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.

The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 ^th Ed., 2003 (Lippincott Williams & Wilkins).

Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from animal studies. Doses are generally sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.

In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound as described herein, a second therapeutic agent, and optionally a pharmaceutically- acceptable excipient. In one embodiment, the pharmaceutical composition includes a compound as described herein and a second therapeutic agent, wherein each of the compounds described herein and the second therapeutic agent is formulated in admixture with a pharmaceutically-acceptable excipient.

Methods of Treatment

The present invention provides compounds and pharmaceutical compositions which inhibit TRPC activity, particularly TRPC3 and/or TRPC6 and/or TRPC7 activity. More particularly, the present invention provides compounds which are inhibitors of the TRPC6 activity and are thus useful in the treatment or prevention of disorders associated with TRPC6. Compounds and pharmaceutical compositions of the present invention selectively inhibit TRPC6 and are thus useful in the treatment or prevention of a range of disorders associated with the activation of TRPC6 which includes, but are not limited to respiratory diseases, fibrotic diseases, skeletal muscle dysfunction, renal diseases, atherosclerosis; osteoarthritis, cardiovascular disorders, cancer, inflammatory disorders, pain, ischemic stroke, peripheral arterial occlusive disease and other diseases/disorders associated with TRPC6.

In particular, the compounds of the present invention may be used to prevent or treat one or more diseases, conditions and/or disorders selected from asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example, late asthma and airways hyper-responsiveness), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, bronchitis, cystic fibrosis, emphysema, acute respiratory distress syndrome, restrictive lung diseases, pulmonary embolism, pulmonary arterial hypertension, pulmonary edema, acute allergic rhinitis, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; sinusitis, chronic rhinosinusitis, nasosinusal polyposis; pulmonary fibrosis, Wegener's granulomatosis and Goodpasture's syndrome, focal segmental glomerulosclerosis, Duchenne muscular dystrophy, renal failure, atherosclerosis, osteoarthritis, heart failure, myocardial infarction, cardiac hypertrophy, cardiac arrhythmia, essential hypertension, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, glioma, inflammatory pain, ischemic stroke, conjunctivitis, contact dermatitis, inflammatory bowel disease, chronic inflammation, or peripheral arterial occlusive disease.

Compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions may have potential utility in combination with other therapies for the treatment of respiratory diseases, fibrotic diseases, skeletal muscle dysfunction, renal diseases, atherosclerosis, osteoarthritis, cardiovascular disorders, cancer, inflammatory disorders, pain, ischemic stroke and peripheral arterial occlusive disease. Example includes but not limited to co-administration with steroids, leukotriene antagonists, anti-histamines, anti-cancer agents, protein kinase inhibitors, diuretics, angiotensin receptor blockers, ACE inhibitors, adrenergic receptor antagonists, rennin inhibitors, calcium sensitizers and/or TRPV4 blocker, which may be administered in effective amounts. One or more compounds from a given class or from different classes may be used in combination with a compound of the invention. Use in combination includes combination products (e.g. dosage forms) as well as regimens. Accordingly, the compounds may be combined in a single composition, or may be in different compositions which are administered to a patient concurrently or at different times.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg. General Methods of Preparation

The compounds described herein, including compounds of general formula (I) and (la) and specific examples can be prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes 1 to 9, as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.

The starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention may be prepared through the reaction schemes as follows.

A general approach for the preparation of guanidine amides of the general formula (I) is depicted in scheme 1, wherein A, B, R 1, R 2, R 3, R 4, R 5, R 6, R V, p and q are as defined in the general formula (I). Thus, reaction of carboxylic acid of general formula (1) with thionyl chloride yields the corresponding acid chloride which on reaction with a functionalized guanidine of the formula (2) in presence of a base such as triethylamine, diisopropylethylamine or pyridine gives compounds of the invention represented by the general formula (I).

Scheme 1:

Compound of general formula (la) and its acid addition salt of the formula

(la- A) (where R 3 - R 11 , p and q are as defined in the general formula (I)) can be prepared as described in scheme 2. Thus, propanoic acid derivative (3) is coupled with guanidine base, which is obtained by neutralization of guanidine hydrochloride with sodium iert-butoxide. The coupling reaction can be mediated by CDI (Ι,Γ- carbonyldiimidazole) as shown in scheme 2. The coupled product can further be transformed to an appropriate salt (Ia-A), such as, but not limited to, hydrochloride, sulfate, hemisulfate, hydrobromide, citrate, benzoate, benzenesulfonate and methanesulfonate by reaction of (la) with acids such as, but not limited to, hydrochloric acid, sulfuric acid, hemisulfuric acid, hydrobromic acid, citric acid, benzoic acid, benzenesulfonic acid and methanesulfonic acid.

Scheme 2:

Compound of general formula (10) is prepared as described in scheme 3 (wherein R ⁶ , R ⁷ , p and q are as defined in the general formula (I)). The Perkin reaction of phenyl acetic acid derivative of formula (4) and benzaldehyde of formula (5), using acetic anhydride and an appropriate base such as triethylamine, diisopropylmethylamine or pyridine gives the corresponding cinnamic acid derivative which on double bond reduction using palladium catalyst in the presence of hydrogen gas gives the corresponding propanoic acid derivative of formula (6). The N,N'-di- iert-butoxycarbonyl intermediate of formula (8) is synthesized by reaction of in-situ generated acid chloride (using thionyl chloride) of intermediate (6) with protected guanidine of formula (7) in presence of an appropriate base such as triethylamine, diisopropylmethylamine, or pyridine and an appropriate solvent such as, but not limited to, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2- dichloroethane. The removal of both the BOC (ie/t-butoxycarbonyl) protecting groups of intermediate of formula (8) is carried out using acids such as, but not limited to, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, formic acid or methanesulfonic acid to give the corresponding free guanidine derivative (9). The acid (HX) addition salt of compound of general formula (10), such as, but not limited to, hydrochloride, sulfate, hemisulfate, hydrobromide, citrate, benzoate, benzenesulfonate and methanesulfonate salt is prepared by reaction of intermediate (9) with, but not limited to, hydrochloric acid, sulfuric acid, hemisulfuric acid, hydrobromic acid, citric acid, benzoic acid, benzenesulfonic acid and methanesulfonic acid. Alternatively, compound of general formula (9) can be prepared by directly coupling propanoic acid derivative of formula (6) with free guanidine base. The coupling reaction of carboxylic acid with guanidine can be mediated by CDI as shown in scheme 3. The coupled product can further be transformed to an appropriate salt (10), such as, but not limited to, hydrochloride, sulfate, hemisulfate, hydrobromide, citrate, benzoate, benzenesulfonate and methanesulfonate.

Scheme 3:

Compound of general formula (14) can be prepared as shown in scheme 4. Thus, phenyl acetic acid of formula (4) on Perkin reaction with naphthaldehyde (11) yields the corresponding cinnamic acid (12) which on double bond reduction gives Intermediate of formula (13). Coupling of Intermediate of formula (13) with guanidine in presence of the coupling agent such as CDI followed by salt formation using acids such as, but not limited to, hydrochloric acid, sulfuric acid, hemisulfuric acid, hydrobromic acid, citric acid, benzoic acid, benzenesulfonic acid and methanesulfonic acid, gives the final compound of general formula (14). Scheme 4

(13) (14)

Similarly, compound of general formula (18) can be prepared as shown in scheme 5. Thus, 2-(naphthalen-l-yl)acetic acid or 2-(naphthalen-2-yl)acetic acid of the formula (15) is coupled with substituted benzaldehyde (5) under Perkin reaction conditions followed by reduction to yield Intermediate of formula (17). Intermediate of formula (17) is coupled with guanidine in presence of coupling agent such a CDI followed by salt formation using acids such as, but not limited to, hydrochloric acid, sulfuric acid, hemisulfuric acid, hydrobromic acid, citric acid, benzoic acid, benzenesulfonic acid and methanesulfonic acid, to yield final compound of general formula (18).

Scheme 5

(17) (18)

Compound of the general formula (10) having an asymmetrically substituted carbon atom can exist as a mixture of enantiomers. Thus, a method has been developed for the preparation of (10) in high optical purity (>95%) by using chiral oxazolidinones. By this approach, both enantiomers of the desired propanoic acids are prepared and then coupled with guanidine to give the optically pure isomers of compound of general formula (10).

The (R)-isomer of (10) is prepared as shown in scheme 6 (wherein R ⁶ , R ⁷ , p and q are as defined in formula (I)). Thus, phenyl acetic acid of formula (4) is coupled with (4R)-l,3-oxazolidin-2-one (19) (wherein R is benzyl group) in presence of pivaloyl chloride and triethylamine to give (R)-intermediate of formula (20). Alkylation of (R)-intermediate of formula (20) with benzyl halide of formula (21) (wherein X is halogen) in presence of strong base like n-butyl lithium, lithium diiospropylamide (LDA), sodium or potassium hexamethyldisilazide (NaHMDS or KHMDS) gives (R),(R)-diastereoisomer of formula (22). The cleavage of the chiral auxiliary from (R),(R)-diastereoisomer of formula (22) using in-situ generated lithium hydroperoxide (LiOH and H ₂ 0 ₂ ) gives optically pure (R)-carboxylic acid of formula (6) in good chemical yield and optical purity. The (R)-isomer of compound of formula (6) is then coupled with guanidine using coupling agent such as CDI which yields the final (R)- isomer compound of the present invention ((R)-(10)).

Scheme 6

(R),(R)-22 (R)-6 (R)-(10)

Similarly, optically pure (^-isomer of compound of general formula (S)-(10) is synthesized by following the above reaction sequence using (^-l^-oxazolidin-l- one (S)-19 as shown in scheme 7 (wherein R ⁶ , R ⁷ , p and q are as defined in formula (I)). Thus, reaction of (^-intermediate of formula (20) prepared by coupling carboxylic acid (4) with (^-l^-oxazolidin-l-one (19) (wherein R is benzyl group), on alkylation with (21) (wherein X is halogen), and cleavage of the resultant diastereomer ((S),(S)-(22)) with lithium hydroperoxide gives the optically pure (S) acid of formula (6). The (^-isomer of compound of formula (6) is then coupled with guanidine in the presence of CDI to give the final (^-isomer compound of the present invention (S)-(10). Scheme 7

(S),(S)-22 (S)-6 (S)-(10)

The optically enriched carboxylic acids of the formula 2(R),3(R)-(28) and 2(5 ^, ),3(5 ^, )-(29) are obtained by resolution of racemic Intermediate of formula (24) using chiral resolving agents such as R and S isomers of 4-benzyl-5,5-dimethyl-2- oxazolidinone, 4-benzyl-2-oxazolidinone, 4-ie/t-butyl-2-oxazolidonone, 5,5- dimethyl-4-phenyl-2-oxazolidinone, 4-(diphenylmethyl)-2-oxazolidinone or 5,5- diphenyl-4-methyl-2-oxazolidinone shown in scheme 8 (wherein R ⁶ , R ⁷ , p and q are as defined in formula (I)).

Thus, alkylation of substituted phenylacetic acid (4) by substituted (1- bromoethyl)benzene of formula (23) using a strong base like n-butyl lithium, lithium diiospropylamide (LDA), sodium or potassium hexamethyldisilazide (NaHMDS or KHMDS) gives the propionic acid (24) as an inseparable mixture of two trans isomers. Intermediate of formula (24) is treated with (R)-(+)-l-phenylethylamine (PEA) to form a diasteromeric salt. The salt is isolated and crystallized twice from isopropyl alcohol. The optically active acid 2(R),3(R)-(26) is regenerated by acidification of the diastereomeric adduct followed by normal work-up and isolation. The 2(S),3(S)-(27) isomer is similarly obtained by using (S)-(-)-l-phenylethylamine (PEA) as the resolving agent. The optically active acids 2(R),3(R)-(26) and 2(S),3(S)- (27) are coupled with guanidine using CDI to give the corresponding final compounds of general formula 2(R),3(R)-(28) and 2(S),3(S)-(29) respectively. Scheme 8

ion)

2(S),3(S)-(29) 2S,3S-(27) 2(R),3(R)-(28)

Compound of formula (32) and (35) (wherein R ⁵ , R ⁶ , R ⁷ p and q are as defined above) were prepared as shown in scheme 9. Thus, phenylpropanoic acid derivative (6) is subjected to esterification with ethanol in presence of catalytic H ₂ SO ₄ to give Intermediate of formula (30). Fluorination of Intermediate of formula (30) by N- fluorobenzenesulfonimide using a strong base such as LDA followed by ester hydrolysis gives Intermediate of formula (31). The CDI mediated coupling of acid (31) with guanidine followed by salt formation using an appropriate acid of formula HX, yields the final compound of general formula (32). Similarly, alkylation of ester derivative (30) by alkyl halide derivative (33) (wherein L is a leaving group such as bromine or iodine and R ⁵ is using a strong base such as LDA followed by hydrolysis gives Intermediate of formula (34). Coupling of acid of formula (34) with free guanidine using CDI followed by salt formation using an appropriate acid (HX), gives the final compound of general formula (35).

Scheme 9

Experimental

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.

The abbreviations, symbols and terms used in the examples and assays have the following meanings throughout: DMSO-<i6: Hexadeuterodimethyl sulfoxide; CDCI ₃ : Deuterated chloroform; 1H NMR: Proton Nuclear Magnetic Resonance; DMF: N,N-dimethyl formamide; HC1: Hydrochloric acid; H ₂ S0 ₄ : Sulfuric acid; H ₂ 0 ₂ : Hydrogen peroxide; TEA: Trie thy lamine; THF: Tetrahydofuran; LiOH: Lithium hydroperoxide; CDI: Ι,Γ-Carbonyldiimidazole; LDA: Lithium diiospropylamide; PEA: Phenylethylamine; NaHMDS: Sodium hexamethyldisilazide; KHMDS: Potassium hexamethyldisilazide; EtOH: Ethanol; DCM: Dichlorome thane; Na ₂ S0 ₄ : Sodium sulfate; /: Coupling constant in units of Hz; h: hour(s); RT or rt: Room temperature (22-26°C); APCI-MS: Atmospheric Pressure Chemical Ionization Mass Spectrometry; ESI-MS: Electrospray ionization Mass Spectroscopy; BOC: tert- butoxycarbonyl; Pd: Palladium; MHz: Megahertz; Hz: Hertz; HPLC: High- performance liquid chromatography.

Intermediates

Intermediate 1

(+)-2,3-Diphenylpropanoic acid

Step 1: (E)-2,3-Diphenylacrylic acid: To a well stirred solution of phenylacetic acid (6 g, 44.06 mmol) in acetic anhydride (30 ml) was added triethylamine (12.3 ml, 88.12 mmol) followed by benzaldehyde (4.5 ml, 44.06 mmol) and the reaction mixture was heated at 160 °C for 4 h. To this reaction mixture water (100 ml) was slowly added and it was further refluxed for 30 mins. The reaction mixture was cooled to room temperature and the precipitate formed was filtered and dissolved in chloroform (500 ml). The organic layer was dried over Na ₂ S0 ₄ and concentrated under reduced pressure to yield 4.5 g of (E)-2,3-Diphenylacrylic acid as a white solid. 1H NMR (300 MHz, OMSO-d ₆ ) δ 7.04 (d, / = 6.9 Hz, 2H), 7.16-7.21 (m, 5H), 7.38 (br s, 3H), 7.75 (s, 1H), 12.75 (br s, 1H).

Step 2: 2,3-Diphenylpropanoic acid: To a well stirred solution of step 1 intermediate (500 mg, 2.23 mmol) in methanol (25 ml) was added palladium (50 mg) and the reaction mixture was stirred under hydrogen atmosphere at about 50 psi pressure for 1 h. The reaction mixture was filtered and excess of methanol was concentrated under reduced pressure to give 459 mg of the title product as an off-white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.93-3.00 (m, 1H), 3.24-3.31 (m, 1H), 3.86 (br s, 1H), 7.14- 7.23 (m, 6H), 7.25-7.32 (m, 4H), 12.37 (br s, 1H).

The intermediates 2 to 72 were prepared from corresponding phenyl acetic acid and benzaldehyde derivatives by the Perkin reaction followed by olefinic bond reduction using palladium as catalyst as described in synthetic procedure of intermediate 1. Their structure, chemical names and 1H NMR data are given in Table 1.

Table 1: Structures, chemical names and 1H NMR data of Intermediates 2-72.

Intermediate Structure Chemical name and 1H NMR data No.

Intermediate 4 IH), 3.82 (t, / = 7.2 Hz, IH), 7.00-7.07

(m, 4H), 7.22-7.31 (m, 5H), 12.30 (br s, IH).

5. o (+)-3-(4-Ethylphenyl)-2-phenylpropanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 1.10 (t, / = 5.4 Hz, 3H), 2.49-2.56 (m, 2H), 2.83-

Intermediate 5

2.89 (m, IH), 3.18-3.30 (m, IH), 3.80 (t, / = 5.7 Hz, IH), 7.02 (d, / = 6.0 Hz, 2H), 7.06 (d, / = 6.0 Hz, 2H), 7.20-7.29 (m, 5H), 12.26 (br s, IH).

6. o (+)-2-Phenyl-3-r4-(propan-2-yl)phenyll propanoic acid;

CH ₃ 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.14 (d,

/ = 5.1 Hz, 6H), 2.78-2.90 (m, 2H), 3.20-

Intermediate 6

3.30 (m, IH), 3.81-3.85 (m, IH), 7.09 (s, 4H), 7.22-7.25 (m, IH), 7.28-7.34 (m, 4H), 12.37 (br s, IH).

7. CI o (+) -3 - (2-Chlorophenyl) -2-phenyl

propanoic acid;

1H NMR (400 MHz, DMSO-A δ 3.02- 3.07 (m, IH), 3.34-3.40 (m, IH), 3.90 (t, / Intermediate 7

= 6.0 Hz, IH), 7.17-7.25 (m, 4H), 7.26- 7.32 (m, 4H), 7.37-7.40 (m, IH), 12.46 (br s, IH).

8. o (+) -3 - (3 -Chlorophenyl) -2-phenyl

propanoic acid;

1H NMR (400 MHz, DMSO-A δ 2.92- 2.97 (m, IH), 3.23-3.30 (m, IH), 3.86-

Intermediate 8

3.89 (m, IH), 7.13-7.24 (m, 5H), 7.25- 7.31 (m, 4H), 12.38 (br s, IH).

9. o ( + - 3- 4-Chlorophenyl -2-phenyl

propanoic acid;

1H NMR (300 MHz, DMSO-A δ 2.96- 3.03 (m, IH), 3.32-3.39 (m, IH), 3.80 (t, /

Intermediate 9

= 7.8 Hz, IH), 7.01 (d, / = 8.4 Hz, 2H), 7.18 (d, / = 8.1 Hz, 2H), 7.25-7.31 (m, 5H), 12.42 (br s, IH). Intermediate Structure Chemical name and 1H NMR data No.

65. o +)-3- 4-Methoxyphenyl)-2- Γ4- (trifluoromethyl)phenyllpropanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 2.90-

F ₃ C 2.95 (m, IH), 3.21-3.27 (m, IH), 3.68 (s.

Intermediate 65 3H), 3.98 (t, / = 5.7 Hz, IH), 6.78 (d, / =

5.7 Hz, 2H), 7.10 ( d, / = 5.7 Hz, 2H), 7.54 (d, / = 5.7 Hz, 2H), 7.67 (d, / = 5.7 Hz, 2H) 12.55 (s, IH).

66. o +)-3- 4-Methylphenyl)-2-r3- (trifluoromethoxy)phenyll propanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.89-2.95 (m, IH), 3.20-3.26 (m,

Intermediate 66

IH), 3.95 (t, / = 6.0 Hz, IH), 7.01 (d, / = 6.3 Hz, 2H), 7.05 (d, / = 6.3 Hz, 2H), 7.23 (d, / = 6.3 Hz, IH), 7.28 (s, IH), 7.34 (d, / = 6.0 Hz, IH), 7.43 (t, / = 6.0 Hz, IH), 12.56 (br s, IH).

67. (+ -3-(4-FluoroDhenyl -2-r3- (trifluoromethoxy)phenyll propanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 2.92- 2.97 (m, IH), 3.22-3.28 (m, IH), 3.95 (t, / Intermediate 67

= 6.0 Hz, IH), 7.01 (t, / = 6.6 Hz, 2H), 7.16-7.25 (m, 4H), 7.32 (d, / = 6.0 Hz, IH), 7.39-7.45 (m, IH), 12.61 (br s, IH).

68. o (+ -2- NaDhthalen- 1 -yl -3-Dhenyl

propanoic acid;

1H NMR (300 MHz, CDC1 ₃ ) δ 3.12-3.19 (m, IH), 3.54-3.62 (m, IH), 4.67-4.72 (m,

Intermediate 68

IH), 7.19 (br s, 5H), 7.42-7.57 (m, 4H), 7.79 (d, / = 7.8 Hz, IH), 7.87 (d, / = 7.5 Hz, IH), 8.11 (d, / = 8.7 Hz, IH), 12.32 (br s, IH).

69. o + -2- NaDhthalen-2-yl -3-Dhenyl

propanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) δ 3.06- 3.12 (m, IH), 3.35-3.40 (m, IH), 4.05 (t, / = 7.5 Hz, IH), 7.14 (br s, 2H), 7.21 (br s,

Intermediate 69

4H), 7.49-7.55 (m, 3H), 7.82-7.88 (m, 3H), 12.45 (br s, IH).

Intermediate 73

(2R)-2,3-Diphenylpropanoic acid

Step 1 : (4R)-4-Benzyl-3-(phenylacetyl)-l,3-oxazolidin-2-one: The title compound was prepared by the reaction of phenyl acetic acid (1.5 g, 11.28 mmol) and (4R)-4- benzyl-l,3-oxazolidin-2-one (1 g, 5.64 mmol) using triethylamine (3.15 ml, 22.57 mmol) and pivaloyl chloride (1.39 ml, 11.28 mmol) in presence of toluene (20 ml) at 110 °C for 6.5 h to yield the product which was further purified by column chromatography to yield 1.1 g of the product as off-white solid. 1H NMR (300 MHz, CDCI3) δ 2.73-2.79 (m, 1H), 3.24-3.30 (m, 1H), 4.15-4.21 (m, 2H), 4.24-4.37 (m, 2H), 4.65-4.71 (m, 1H), 7.13 (d, / = 5.7 Hz, 2H), 7.26-7.34 (m, 8H).

Step 2: (4R)-4-Benzyl-3-[(2R)-2,3-diphenylpropanoyl]-l,3-oxazolidin- 2-one: Step 1 intermediate (550 mg, 1.864 mmol) on reaction with benzyl bromide (0.26 ml, 2.23 mmol) using NaHMDS (2.2 ml, 2.23) in presence of dry THF (15 ml) yielded a product which was further purified by column chromatography to yield 320 mg of product as off-white solid. 1H NMR (300 MHz, CDC1 ₃ ) δ 2.51-2.59 (m, 1H), 2.95- 3.08 (m, 2H), 3.49-3.57 (m, 1H), 4.01 (d, / = 5.1 Hz, 2H), 4.54-4.58 (m, 1H), 5.47- 5.52 (m, 1H), 6.94 (t, / = 5.1 Hz, 2H), 7.22-7.34 (m, 11H), 7.45 (d, / = 7.5 Hz, 2H). Step 3: (2R)-2,3-Diphenylpropanoic acid: The step 2 intermediate (1.18 g, 3.06 mmol) on hydrolysis using lithium hydroxide (128 mg, 3.06 mmol) and hydrogen peroxide (14 ml) in presence of THF (50 ml) and water (15 ml) yielded product which was further purified by cloumn chromatography to yield 450 mg of the product as off- white solid. 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.90-2.96 (m, 1H), 3.24-3.30 (m, 1H), 3.85 (t, / = 7.8 Hz, 1H), 7.14-7.22 (m, 6H), 7.25-7.32 (m, 4H), 12.35 (br s, 1H). HPLC: Chiracel OD-H, retention time: 13.95 min (hexane/EtOH, 98:2, 99.70 %).

Intermediate 74

(25 ^, )-2,3-Diphenylpropanoic acid

Step 1 : (4S)-4-Benzyl-3-(phenylacetyl)-l,3-oxazolidin-2-one: To a well stirred solution of (4S)-4-benzyl-l,3-oxazolidin-2-one (2 g, 11.286 mmol) in dry toluene (40 ml) was added phenylacetic acid (3.7 g, 22.573 mmol) and TEA (6.3 ml, 45.146 mmol) and the reaction mixture was heated at 80 °C for 10 mins. Pivaloyl chloride (2.8 ml, 22.573 mmol) was added to the reaction mixture at the same temperature and it was further heated at 110 °C overnight. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic layer was washed with water (3 x 100 ml), brine (100 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield the product which was further purified by column chromatography to yield 2.4 g of the product as off-white solid. 1H NMR (300 MHz, CDCI3) δ 2.72-2.79 (m, 1H), 3.24-3.30 (m, 1H), 4.15-4.21 (m, 2H), 4.24-4.37 (m, 2H), 4.65-4.69 (m, 1H), 7.13 (d, / = 5.7 Hz, 2H), 7.25-7.34 (m, 8H).

Step 2: (4 _l S ^, )-4-Benzyl-3-[(25 ^, )-2,3-diphenylpropanoyl]-l,3-oxazolidin-2-one: To a well stirred solution of step 1 intermediate (1.6 g, 5.423 mmol) in dry THF (25 ml) was added NaHMDS (6.5 ml, 6.508 mmol) at -78 °C and it was stirred at the same temperature. After 1 h, benzyl bromide (0.7 ml, 6.508 mmol) was added to it at -78°C and it was further stirred for 4.5 h along with gradual increase of temperature to room temperature. The reaction mixture was quenched with water (250 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic layer was washed with water (3 x 100 ml), brine (100 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield the product which was further purified by column chromatography to yield 1.3 g of the product as off-white solid. 1H NMR (300 MHz, CDC1 ₃ ) δ 2.52-2.59 (m, 1H), 2.95- 3.10 (m, 1H), 3.49-3.57 (m, 1H), 4.01 (d, / = 5.1 Hz, 2H), 4.54-4.58 (m, 1H), 5.47- 5.52 (m, 1H), 6.94 (br s, 2H), 7.17-7.25 (m, 5H), 7.26-7.34 (m, 6H), 7.45 (d, / = 7.5 Hz, 2H).

Step 3: (25 ^, )-2,3-Diphenylpropanoic acid: To a well stirred solution of step 2 intermediate (1.3 g, 3.376 mmol) in a mixture of THF (80 ml) and water (20 ml) was added hydrogen peroxide (10 ml) and lithium hydroxide monohydrate (142 mg, 3.376 mmol) at 0 °C and was stirred for 4.5 h at room temperature. The reaction mixture was acidified with dilute HC1, diluted with water (150 ml) and extracted with ethyl acetate (2 x 250 ml). The combined organic layer was washed with water (3 x 100 ml), brine (100 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield the product which was further purified by column chromatography to yield 500 mg of the product as off-white solid; 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.90-2.97 (m, 1H), 3.23-3.29 (m, 1H), 3.86 (t, / = 7.2 Hz, 1H), 7.14-7.22 (m, 6H), 7.25-7.32 (m, 4H), 12.34 (br s, 1H). HPLC: Chiracel OD-H, retention time: 15.09 min (hexane/EtOH, 98:2, 99.52 %).

Intermediates 75-151 were prepared from their respective phenyl acetic acids as described in Intermediate 73 or 74. Their structure, chemical names and 1H NMR data are given in Table 2.

Table 2: Structures, chemical names and 1H NMR data of Intermediates 75-151.

112. 2R -2- 2-ChloroDhenvl -3- 3- chlorophenvDpropanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 2.98-

3.04 (m, IH), 3.29-3.32 (m, IH), 4.32 (d, /

Intermediate 112

= 5.7 Hz, IH), 7.09 (d, / = 5.4 Hz, IH), 7.19-7.28 (m, 4H), 7.30-7.34 (m, IH), 7.39-7.45 (m, 2H) 12.85 (s, IH).

113. o 2R -2- 2-ChloroDhenvl -3- 3- fluorophenvDpropanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 2.98- 3.04 (m, IH), 3.29-3.34 (m, IH), 4.31 (t, /

Interaiediate 113

= 6.0 Hz, IH), 6.93-6.97 (m, 3H), 7.20- 7.26 (m, 2H), 7.30 (t, J = 5.7 Hz, IH), 7.38 (br s, IH), 7.41 (t, / = 5.7 Hz, IH), 12.63 (br s, IH).

114. CI o 2S)-3- 2-ChloroDhenyl)-2-(3- chlorophenvDpropanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) 3.07-3.12 (m, IH), 3.35-3.41 (m, IH), 3.97 (t, / = 7.5 Interaiediate 114

Hz, IH), 7.18-7.26 (m, 4H), 7.32-7.39 (m, 4H), 12.69 (br s, IH).

115. o (2S)-2,3-bis(3-Chlorophenyl)propanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) 2.94-3.01 (m, IH), 3.22-3.30 (m, IH), 3.97 (t, / = 8.4

Interaiediate 115

Hz, IH), 7.16 (d, / = 6.9 Hz, IH), 7.21- 7.26 (m, 2H), 7.29-7.38 (m, 4H), 7.40 (s, IH), 12.59 (br s, IH); APCI-MS (m/z) 292 (M-H) ⁺ .

116. 2S)-2-(3-Chlorophenyl)-3- 3-

^F" CQ ^0H fluorophenyDpropanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) 2.96-3.03 (m, IH), 3.24-3.29 (m, IH), 3.97 (t, / = 7.8

Interaiediate 116

Hz, IH), 6.95-7.07 (m, 3H), 7.22-7.34 (m, 4H), 7.39 (s, IH), 12.58 (br s, IH).

117. o 2R -2- 3-FluoroDhenvl -3- 3- methylphenyDpropanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 2.23 (s, 3H), 2.88-2.93 (m, IH), 3.20-3.26 (m, IH),

Interaiediate 117

3.91 (t, / = 5.4 Hz, IH), 6.97 (d, / = 5.4 Hz, 2H), 7.01 (s, IH), 7.05-7.13 (m, 2H), 7.16 (d, / = 5.7 Hz, 2H), 7.32-7.38 (m, IH), 12.52 (s, IH). 135. CI 0 (25) -3 - (2-Chlorophenyl) -2- (naphthalen- 1 - yl) propanoic acid;

1H NMR (300 MHz, DMSO-d ₆ ) 3.20-3.27 (m, IH), 3.56-3.61 (m, IH), 4.75 (t, / = 7.5 Intermediate 135

Hz, IH), 7.12-7.22 (m, 4H), 7.37 (d, / = 7.8 Hz, IH), 7.49-7.58 (m, 3H), 7.84 (d, / = 8.4 Hz, IH), 7.92 (d, / = 7.2 Hz, IH), 8.13 (d, / = 8.4 Hz, IH), 12.58 (br s, IH).

136. (2S)-3-(3-Chlorophenyl)-2-(naphthalen-l- yl) propanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) 3.10-3.17 (m, IH), 3.44-3.49 (m, IH), 4.74 (t, / = 6.9

Intermediate 136

Hz, IH), 7.20 (br s, 3H), 7.33 (s, IH), 7.46- 7.56 (m, 4H), 7.83 (d, / = 7.2 Hz, IH), 7.93 (d, / = 7.8 Hz, IH), 8.23 (d, / = 8.4 Hz, IH), 12.51 (br s, IH).

137. (2S)-3-(4-Chlorophenyl)-2-(naphthalen-l- yl) propanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) 3.08-3.15

(m, IH), 3.41-3.48 (m, IH), 4.70 (t, / = 7.5

Intermediate 137

Hz, IH), 7.25 (br s, 4H), 7.45-7.58 (m, 4H), 7.83 (d, / = 7.8 Hz, IH), 7.93 (d, / = 7.8 Hz, IH), 8.20 (d, / = 8.1 Hz, IH), 12.51 (br s, IH).

138. (25) -3 - (3 -Fluorophenyl) -2- (naphthalen- 1 - yDpropanoic acid

1H NMR (300 MHz, OMSO-d ₆ ) δ 3.11- 3.18 (m, IH), 3.43-3.51 (m, IH), 4.74 (t, /

Intermediate 138

= 7.8 Hz, IH), 6.94 (t, / = 8.4 Hz, IH), 7.05-7.11 (m, 2H), 7.19-7.26 (m, IH), 7.46-7.58 (m, 4H), 7.83 (d, / = 7.8 Hz, IH), 7.92 (d, / = 7.5 Hz, IH), 8.22 (d, / = 7.8 Hz, IH), 12.49 (br s, IH).

139. CI o (25) -3 - (2-Chlorophenyl) -2- (naphthalen-2- yl) propanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) 3.16-3.23

I) (m, IH), 3.45-3.52 (m, IH), 4.10 (t, / = 6.9

Hz, IH), 7.16-7.22 (m, 3H), 7.40 (d, / =

Intermediate 139

8.7 Hz, IH), 7.49 (br s, 3H), 7.79 (s, IH), 7.87 (d, / = 8.7 Hz, 3H), 12.60 (br s, IH). = 8.4 Hz, 1H), 7.19 (d, / = 7.2 Hz, 2H),

7.24-7.37 (m, 6H), 7.46 (br s, 4H), 7.58 (d, J = 7.5 Hz, 2H), 12.38 (s, 1H).

Intermediate 152

(±)-2,3-Diphenylbutanoic acid

To a well stirred solution of phenyl acetic acid (200 mg, 1.468 mmol) in dry THF (5 ml) was added sodium hexamethyldisilazide (NaHMDS; 0.36 ml, 3.672 mmol) at -78 °C and the reaction mixture was stirred for 30 mins at the same temperature. After 30 mins (1-bromoethyl) benzene (0.24 ml, 1.762 mmol) was added to the reaction mixture and it was further stirred for 3 h with gradual increase of temperature from - 78 °C to 0 °C. The reaction mixture was diluted with water (50 ml), acidified with dil. HC1 and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water (2 x 50 ml), brine (50 ml) and dried (Na ₂ S0 ₄ ). The excess of solvent was distilled under reduced pressure and the product was purified by silica gel column chromatography to yield 60 mg of the compound as white solid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 0.88 (d, / = 5.4 Hz, 3H), 3.30-3.37 (m, 1H), 3.78 (d, / = 8.7 Hz, 1H), 7.31 (t, / = 6.0 Hz, 1H), 7.31 (t, / = 6.0 Hz, 3H), 7.35-7.41 (m, 4H), 7.47 (d, / = 6.6 Hz, 2H), 12.01 (br s, 1H).

Intermediates 153-157 were prepared from respective phenyl acetic acid and (1- bromoethyl) benzene using NaHMDS as described in Intermediate 152. Their structure, chemical names and 1H NMR data are given in Table 3.

Table 3: Structures, chemical names and 1H NMR data of Intermediates 153-157.

154. CH ₃ 0 (+) - 3 - (3 -Chlorophenyl) -2-phenylbutanoic acid;

1H NMR (400 MHz, OMSO-d ₆ ) δ 0.92 (d, / = 7.8 Hz, 3H), 3.37-3.43 (m, 1H), 3.83 Intermediate 154

(d, / = 8.7 Hz, 1H), 7.25-7.31 (m, 2H), 7.32-7.40 (m, 4H), 7.44-7.50 (m, 3H), 12.12 (br s, 1H).

155. F CH ₃ 0 (±) - 3 - (2-Fluorophenyl) -2-phenylbutanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) δ 0.88 (d, / = 7.5 Hz, 3H), 3.61-3.67 (m, 1H), 3.90 Intermediate 155

(d, / = 11.7 Hz, 1H), 7.11-7.19 (m, 2H), 7.22-7.27 (m, 1H), 7.29-7.39 (m, 3H), 7.41-7.51 (m, 3H), 12.14 (br s, 1H).

156. H ₃ c 0 (+)-2-(2-Fluorophenyl)-3-phenylbutanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) δ 0.92 (d, / = 7.5 Hz, 3H), 3.34-3.42 (m, 1H), 4.09 Intermediate 156

(d, / = 11.1 Hz, 1H), 7.21-7.25 (m, 4H), 7.27-7.35 (m, 4H), 7.59 (t, J = 6.9 Hz, 1H), 12.25 (br s, 1H).

157. H ₃ c 0 (+ -2-(4-Chloro-2-fluoroDhenyl -3- phenylbutanoic acid;

1H NMR (300 MHz, OMSO-d ₆ ) δ 0.93 (d,

CI / = 6.6 Hz, 3H), 3.35-3.42 (m, 1H), 4.06

Intermediate 157 (d, / = 11.4 Hz, 1H), 7.18-7.24 (m, 1H),

7.30-7.37 (m, 5H), 7.48 (d, / = 9.9 Hz, 1H), 7.61 (t, / = 8.1 Hz, 1H), 12.37 (br s, 1H).

Intermediate 158

3-(lH-Indol-4-yl)-2-phenylpropanoic acid

Step 1 : (2E)-3-(l-Acetyl-lH-indol-4-yl)-2-phenylprop-2-enoic acid: The title compound was prepared from phenyl acetic acid (937 mg, 6.882 mmol) and Indole-4- carboxaldehyde (998 mg, 6.882 mmol) under Perkin reaction conditions to yield 700 mg of product as off-white solid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.65 (s, 3H), 6.63 (d, / = 5.7 Hz, 1H), 6.82 (br s, 1H), 7.00 (t, / = 6.0 Hz, 1H), 7.11-7.16 (m, 2H), 7.26- 7.35 (m, 3H), 7.90 (br s, 1H), 8.07 (s, 1H), 8.19 (d, / = 6.3 Hz, 1H), 12.85 (br s, 1H). Step 2: (2E)-3-(lH-Indol-4-yl)-2-phenylprop-2-enoic acid: To the well stirred solution of Step 1 intermediate (350 mg, 1.147 mmol) in acetonitrile (15 ml) was added aqueous solution of sodium hydroxide (92 mg, 2.295 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (100 ml) and acidified with dil. HC1. The product was extracted with ethyl acetate (3 x 100 ml) and the combined organic layer was dried and excess of solvent was distilled under reduced pressure to yield 300 mg of the product as white solid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 6.41 (d, / = 5.7 Hz, 1H), 6.54 (br s, 1H), 6.76 (t, / = 6.0 Hz, 1H), 7.18 (d, / = 5.4 Hz, 2H), 7.28-7.36 (m, 5H), 7.42 (br s, 1H), 11.27 (br s, 1H), 12.64 (br s, 1H).

Step 3: 3-(lH-Indol-4-yl)-2-phenylpropanoic acid: The step 2 intermediate (300 mg, 1.140 mmol) was reduced using palladium catalyst in methanol (20 ml) to yield 180 mg of the title compound as off-white solid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.14- 3.19 (m, 1H), 3.53-3.59 (m, 1H), 4.01 (t, / = 6.6 Hz, 1H), 6.49 (br s, 1H), 6.77 (d, / = 5.4 Hz, 1H), 6.93 (t, / = 5.7 Hz, 1H), 7.21-7.26 (m, 2H), 7.31 (t, / = 5.7 Hz, 3H), 7.37 (d, / = 5.1 Hz, 2H), 11.06 (s, 1H), 12.30 (br s, 1H).

Intermediates 159 and 160 were prepared from respective phenyl acetic acid and indole carboxaldehyde under Perkin reaction conditions followed by deacetylation and reduction as described in Intermediate 158. Their structure, chemical names and 1H NMR data are given in Table 4.

Table 4: Structures, chemical names and 1H NMR data of Intermediates 159 and 160.

160. o 3-(lH-indol-6-yl)-2-phenylpropanoic acid;

ΌΗ 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.96-3.01 (m, 1H), 3.32-3.37 (m, 1H), 3.87 (t, / = 5.1 Hz, 1H), 6.31 (s, 1H), 6.93 (d, / = 5.7 Hz,

Intermediate 160

1H), 7.21-7.29 (m, 4H), 7.31-7.36 (m, 4H), 10.94 (s, 1H), 12.31 (br s, 1H).

Intermediate 161

2-Fluoro-2,3-diphenylpropanoic acid

Step 1 : 2,3-Diphenylpropanoic acid: The title compound was prepared from phenyl acetic acid and benzaldehyde under perkin reaction conditions followed by double bond reduction as described in Intermediate 1. 1H NMR (300 MHz, DMSO-<i ₆ ) δ 2.93-3.00 (m, 1H), 3.24-3.31 (m, 1H), 3.86 (br s, 1H), 7.14-7.23 (m, 6H), 7.25-7.32 (m, 4H), 12.37 (br s, 1H).

Step 2: Ethyl 2,3-diphenylpropanoate: To the well stirred solution of Step 1 intermediate (500 mg, 2.212 mmol) in ethanol (20 ml) was added catalytic amount of cone. H ₂ SO ₄ and the reaction mixture was refluxed overnight. The excess of solvent was distilled under reduced pressure. The residue obtained was diluted with water (150 ml) and neutralized with sodium bicarbonate. The product was extracted with ethyl acetate (3 x 100 ml) and the combined organic layer was washed with water (2 x 100 ml), brine (100 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield 500 mg of the product as off-white solid. 1H NMR (400 MHz, CDC1 ₃ ) δ 1.12 (t, / = 5.4 Hz, 3H), 3.01-3.06 (m, 1H), 3.39-3.44 (m, 1H), 3.82-3.87 (m, 1H), 4.00-4.07 (m, 2H), 7.13- 7.19 (m, 3H), 7.22-7.28 (m, 3H), 7.29-7.32 (m, 4H).

Step 3: Ethyl 2-fluoro-2,3-diphenylpropanoate: To the well stirred and cooled (-78 °C) solution of step 2 intermediate (200 mg, 0.787 mmol) in dry THF (10 ml) was added LDA (0.59 ml, 1.180 mmol) and the reaction mixture was stirred for 30 mins at the same temperature. N-fluorobenzenesulfonimide (323 mg, 1.023 mmol) was added to the reaction mixture and it was further stirred for 4 h with gradual increase to room temperature. After the completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with water (3 x 25 ml), brine (25 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield 150 mg of the product as colorless liquid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.19 (t, / = 5.4 Hz, 3H), 3.38-3.46 (m, 1H), 3.62-3.73 (m, 1H), 4.14-4.20 (m, 2H), 7.23-7.29 (m, 5H), 7.35-7.43 (m, 3H), 7.59 (d, / = 6.3 Hz, 2H).

Step 4: 2-Fluoro-2,3-diphenylpropanoic acid: To the well stirred solution of above intermediate (140 mg, 0.514 mmol) in ethanol (10 ml) was added aqueous potassium hydroxide solution (115 mg, 2.058 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water (50 ml), acidified with dil. HCl (20 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with water (3 x 25 ml), brine (25 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield 60 mg of the product as off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 3.32-3.42 (m, 1H), 3.60-3.72 (m, 1H), 7.19-7.26 (m, 5H), 7.34-7.42 (m, 3H), 7.53 (d, / = 6.3 Hz, 2H), 13.56 (br s, 1H).

Intermediate 162

2-Fluoro-3-(4-methoxyphenyl)-2-phenylpropanoic acid

The title compound was prepared from 4-methoxy phenyl acetic acid, benzaldehyde and N-fluorobenzenesulfonimide as described in Intermediate 151. 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.27-3.35 (m, 1H), 3.54-3.65 (m, 1H), 3.71 (s, 3H), 6.81 (d, / = 6.3 Hz, 2H), 7.12 (d, / = 6.3 Hz, 2H), 7.35-7.43 (m, 3H), 7.53 (d, / = 5.4 Hz, 2H), 13.61 (br s, 1H).

Intermediate 163

3-(4-Methoxyphenyl)-2-methyl-2-phenylpropanoic acid

Step 1 : 3-(4-Methoxyphenyl)-2-phenylpropanoic acid: The title compound was prepared from 4-methoxy phenyl acetic acid and benzaldehyde under Perkin reaction conditions followed by double bond reduction as described in Intermediate 1. 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.83-2.90 (m, 1H), 3.17-3.24 (m, 1H), 3.69 (s, 3H), 3.79 (t, / = 8.7 Hz, 1H), 6.78 (d, / = 8.4 Hz, 2H), 7.09 (d, / = 8.4 Hz, 2H), 7.24-7.31 (m, 5H), 12.29 (br s, 1H).

Step 2: Ethyl 3-(4-methoxyphenyl)-2-phenylpropanoate: To the well stirred solution of Step 1 intermediate (900 mg, 3.515 mmol) in ethanol (20 ml) was added catalytic amount of cone. H ₂ SO ₄ and the reaction mixture was refluxed overnight. The excess of solvent was distilled under reduced pressure. The residue obtained was diluted with water (150 ml) and neutralized with sodium bicarbonate. The product was extracted with ethyl acetate (3 x 100 ml) and the combined organic layer was washed with water (2 x 100 ml), brine (100 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated to yield 900 g of the product as colorless liquid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.54 (t, / = 5.1 Hz, 3H), 2.95-3.01 (m, 1H), 3.33-3.39 (m, 1H), 3.78 (s, 3H), 3.80-3.85 (m, 1H), 4.03-4.13 (m, 2H), 6.79 (d, / = 6.3 Hz, 2H), 7.06 (d, / = 8.4 Hz, 2H), 7.25-7.32 (m, 3H), 7.33 (d, / = 6.9 Hz, 2H).

Step 3: Ethyl 3-(4-methoxyphenyl)-2-methyl-2-phenylpropanoate: To the well stirred and cooled (-78 °C) solution of step 2 intermediate (300 mg, 1.056 mmol) in dry THF (10 ml) was added LDA (0.79 ml, 1.584 mmol) and the reaction mixture was stirred for 30 mins at the same temperature. Methyl iodide (0.08 ml, 1.372 mmol) was added to the reaction mixture and it was further stirred for 4 h with gradual increase to room temperature. After the completion of the reaction, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with water (3 x 25 ml), brine (25 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated. The product was purified by silica gel column chromatography to yield 250 mg of the product as colorless liquid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.21 (t, / = 5.4 Hz, 3H), 1.46 (s, 3H), 3.13 (d, / = 9.9 Hz, 1H), 3.38 (d, / = 9.9 Hz, 1H), 3.78 (s, 3H), 4.11-4.21 (m, 2H), 6.72 (d, / = 6.6 Hz, 2H), 6.83 (d, / = 6.6 Hz, 2H), 7.25-7.35 (m, 5H).

Step 4: 3-(4-Methoxyphenyl)-2-methyl-2-phenylpropanoic acid: To the well stirred solution of above intermediate (250 mg, 0.838 mmol) in ethanol (20 ml) was added aqueous sodium hydroxide solution (168 mg, 4.190 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction was diluted with water (50 ml), acidified with dil. HC1 (20 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with water (3 x 25 ml), brine (25 ml), dried (Na ₂ S0 ₄ ), filtered and concentrated. The product was purified by silica gel column chromatography to yield 160 mg of the product as off-white solid. 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.31 (s, 3H), 3.04 (d, / = 9.9 Hz, 1H), 3.27 (d, / = 9.9 Hz, 1H), 3.69 (s, 3H), 6.74 (d, / = 6.3 Hz, 2H), 6.90 (d, / = 6.3 Hz, 2H), 7.23-7.28 (m, 1H), 7.30-7.36 (m, 4H), 12.55 (br s, 1H).

Examples

The following examples illustrate the present invention. However, these examples are not intended to limit the scope of the present invention. The person skilled in the art can readily recognize a variety of non-critical parameters which can be modified or altered to yield similar results.

The following representative examples described below were prepared by coupling appropriate carboxylic acid intermediates (1-163) with guanidine or a substituted guanidine using methods described in the schemes. Three different methods (Method A-C) were developed for the coupling reaction and the details are given below.

Preparation of guanidine amides: Method A

Step 1 : To a well stirred solution of propanoic acid derivative (1 equiv.) in DCM, were added oxalyl chloride (1.5 equiv.) and catalytic amount of DMF (1-2 drops) at 0 °C and the reaction mixture was stirred for 1.5 h. The excess of solvent was distilled under reduced pressure and the acid chloride thus formed was dissolved in fresh DCM. This acid chloride in DCM solution was added to a well stirred solution of tert- butyl [N-(ieri-butoxycarbonyl)carbamimidoyl] carbamate (0.85 equiv.) and triethylamine (2 equiv.) in DCM at 0 °C and the reaction mixture was further stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with chloroform, washed with water, brine and dried over Na ₂ S0 ₄ . The solvent was distilled off under reduced pressure to give Boc-protected propanamide derivative. Step 2: The step 1 intermediate (1 equiv) was added to trifluoro acetic acid (excess) at 0 °C and the reaction mixture was stirred for 2.5 h. The excess of TFA was distilled out and the residue obtained was diluted with water, basified with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ and distilled under reduced pressure to yield the free amine. To this free amine in ethyl acetate was added HC1 in ethylacetate and the solid thus obtained was filtered and triturated with w-pentane to yield the final product. Preparation of guanidine amides: Method B

Step 1: To the well stirred and cooled (-30°C) solution of propanoic acid derivative (1 equiv.) in dry THF was added TEA (1.4 equiv.) followed by isobutyl chloroformate (2 equiv.) and the reaction mixture was stirred at the same temperature. After 20 mins a solution of ie/t-butyl [N-(ieri-butoxycarbonyl)carbamimidoyl] carbamate (0.8 equiv.) in dry THF was added to the reaction mixture and it was further stirred for 30 mins at -30 °C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried (Na ₂ S0 ₄ ) and concentrated to yield the product. The product was further purified by silica gel column chromatography to yield Boc-protected propanamide derivative as off-white solid.

Step 2: The step 1 intermediate (1 equiv.) was added to trifluoroacetic acid (3 ml) at 0 °C and the reaction mixture was stirred for 2.5 h. The excess of TFA was distilled out and the residue obtained was diluted with water, basified with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ and distilled under reduced pressure to yield the free amine. To this free amine in ethyl acetate was added HC1 in ethylacetate and the solid thus obtained was filtered and triturated with w-pentane to yield final product as its hydrochloride salt.

Preparation of guanidine amides: Method C

To a well stirred solution of propanoic acid derivative (1 equiv.) in DMF was added Ι,Γ-carbonyldiimidazole (1.1 equiv.) and the mixture was stirred at RT for 1 h to form the active ester. The reaction mixture was then cooled to 0°C and excess of free guanidine (2.0-2.5 equiv) in a mixture of DMF and dioxane was added to this reaction mixture and further stirred at 0°C for 1 h. The required guanidine base was prepared by careful addition of sodium ie/t-butoxide to a suspension of guanidine hydrochloride in a 1:1 mixture of DMF and dioxane. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine and excess of solvent was evaporated under reduced pressure to give the product. The product was dissolved in minimum quantity of ethyl acetate and treated with excess hydrochloric acid in ethyl acetate (1.5-2.0 equiv) to yield final product as off-white solid. Example 1

(±)-N-Carbamimidoyl-2,3-diphenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 1 and iert-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCI salt formation as described in general procedure (Method A). 1H NMR (300 MHz, DMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.35 (br s, 1H), 4.10 (br s, 1H), 7.16-7.23 (m, 5H), 7.28-7.38 (m, 5H), 8.27 (br s, 4H), 12.07 (br s, 1H); APCI-MS (m/z) 268 (M+H) ⁺ .

Example 2

(2R)-N-Carbamimidoyl-2,3-diphenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 73 and ie/t-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCI salt formation as described in general procedure (Method B). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.00-3.07 (m, 1H), 3.38-3.46 (m, 1H), 4.11 (t, / = 7.8 Hz, 1H), 7.16-7.24 (m, 5H), 7.26-7.42 (s, 5H), 8.32 (br s, 4H), 12.28 (br s, 1H); APCI-MS (m z) 268 (M+H) ⁺ .

Example 3

(2S)-N-Carbamimidoyl-2,3-diphenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 74 and ie/t-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCI salt formation as described in general procedure (Method B). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.99-3.06 (m, 1H), 3.40-3.46 (m, 1H), 4.10 (t, / = 7.8 Hz, 1H), 7.16-7.26 (m, 5H), 7.28-7.40 (m, 5H), 8.27 (m, 4H), 12.11 (br s, 1H); ESI-MS (m z) 268 (M+H) ⁺ .

Example 4 (+)-N-Carbamimidoyl-2-phenyl-3-(2-methylphenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 2 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.24 (s, 3H), 2.95-3.30 (m, 1H), 3.34-3.40 (m, 1H), 4.11 (t, / = 6.0 Hz, 1H), 7.03-7.10 (m, 4H), 7.27-7.38 (m, 5H), 8.24 (br s, 4H), 12.09 (br s, 1H); APCI-MS (m/z) 282 (M+H) ⁺ .

Example 5

(2R)-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 75 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.25 (s, 3H), 2.97-3.02 (m, 1H), 3.31-3.42 (m, 1H), 4.14 (t, / = 6.0 Hz, 1H), 7.05-7.13 (m, 4H), 7.29-7.41 (m, 5H), 8.30 (br s, 4H), 12.29 (br s, 1H); ESI-MS (m/z) 282 (M+H) ⁺ .

Example 6

(2 _l S')-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropana mide hydrochloride

The title compound was synthesized from Intermediate 76 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.25 (s, 3H), 2.95-3.02 (m, 1H), 3.35-3.42 (m, 1H), 4.14 (t, / = 6.9 Hz, 1H), 7.05-7.11 (m, 4H), 7.29-7.40 (m, 5H), 8.26 (br s, 4H), 12.30 (br s, 1H); ESI-MS (m/z) 282 (M+H) ⁺ .

Example 7

(+)-N-Carbamimidoyl-2-phen l-3-(3-methylphenyl)propanamide hydrochloride The title compound was synthesized from Intermediate 3 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.95-3.00 (m, 1H), 3.32-3.39 (m, 1H), 4.09 (t, J = 5.7 Hz, 1H), 6.96 (t, / = 5.7 Hz, 2H), 7.00 (s, 1H), 7.10 (t, / = 5.7 Hz, 1H), 7.26-7.29 (m, 1H), 7.33 (t, / = 5.4 Hz, 2H), 7.39 (t, / = 5.4 Hz, 2H), 8.29 (br s, 4H), 12.15 (br s, 1H); APCI-MS (m/z) 282 (M+H) ⁺ .

Example 8

(2R)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 77 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.95-3.00 (m, 1H), 3.34-3.40 (m, 1H), 4.09 (t, J = 5.7 Hz, 1H), 6.96 (t, / = 5.4 Hz, 1H), 7.00 (s, 1H), 7.10 (t, / = 5.7 Hz, 1H), 7.25-7.30 (m, 1H), 7.33 (t, / = 5.4 Hz, 3H), 7.40 (t, / = 5.4 Hz, 2H), 8.28 (br s, 4H), 12.21 (s, 1H); ESI-MS (m/z) 282 (M+H) ⁺ .

Example 9

(2 _l S')-N-Carbamimidoyl-3-( -methylphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 78 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.23 (s, 3H), 2.94-2.99 (m, 1H), 3.35-3.38 (m, 1H), 4.09 (t, / = 7.8 Hz, 1H), 6.94-7.09 (m, 3H), 7.14 (t, / = 7.8 Hz, 2H), 7.32-7.38 (m, 4H), 8.25 (br s, 4H), 12.01 (br s, 1H); APCI-MS (m/z) 282

(M+H) ⁺ .

Example 10

(+)-N-Carbamimidoyl-2-phen l-3-(4-methylphneyl)propanamide hydrochloride The title compound was synthesized from Intermediate 4 and iert-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.20 (m, 3H), 2.92-2.99 (m, 1H), 3.30-3.37 (m, 1H), 4.05 (t, / = 7.8 Hz, 1H), 7.03 (s, 4H), 7.26-7.34 (m, 5H), 8.23 (br s, 4H), 12.09 (br s, 1H); APCI- MS (m/z) 282 (M+H) ⁺ .

Example 11

(2R)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 79 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.21 (s, 3H), 2.94-2.99 (m, 1H), 3.32-3.37 (m, 1H), 4.05 (t, / = 5.7 Hz, 1H), 7.01-7.06 (m, 4H), 7.27-7.38 (m, 5H), 8.32 (br s, 4H), 11.95 (br s, 1H); APCI-MS (m/z) 282 (M+H) ⁺ .

Example 12

(2 _l S')-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propana mide hydrochloride

The title compound was synthesized from Intermediate 80 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.21 (s, 3H), 2.94-3.00 (m, 1H), 3.31-3.38 (m, 1H), 4.06 (t, / = 5.7 Hz, 1H), 7.02 (d, / = 6.0 Hz, 2H), 7.05 (d, / = 5.4 Hz, 2H), 7.27-7.39 (m, 5H), 8.27 (br s, 4H), 12.15 (br s, 1H); ESI-MS (m/z) 282 (M+H) ⁺ .

Example 13

(±)-N-Carbamimidoyl-3- -ethylphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 5 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 1.12 (t, / = 5.7 Hz, 3H), 2.49-2.53 (m, 1H), 2.95-3.01 (m, 2H), 3.30-3.35 (m, 1H), 4.07 (t, / = 7.8 Hz, 1H), 7.24-7.29 (m, 4H), 7.34-7.39 (m, 5H), 8.22 (br s, 4H), 11.90 (br s, 1H); ESI-MS (m/z) 296 (M+H) ⁺ .

Example 14

(+)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropanamid e hydrochloride

The title compound was synthesized from Intermediate 6 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 1.11 (d, / = 5.4 Hz, 6H), 2.74-2.80 (m, 1H), 2.92-2.97 (m, 1H), 3.34-3.37 (m, 1H), 4.04-4.09 (m, 1H), 7.05- 7.10 (m, 2H), 7.26 (d, / = 5.7 Hz, 2H), 7.32 (t, / = 5.4 Hz, 3H), 7.66 (d, / = 5.1 Hz, 2H), 8.21 (br s, 4H), 12.10 (br s, 1H); ESI-MS (m/z) 310 (M+H) ⁺ .

Example 15

(25)-N-Carbamimidoyl-2-phenyl-3-[4-(propan-2-yl)phenyl]propa namide

hydrochloride

The title compound was synthesized from Intermediate 81 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 1.15 (d, / = 6.6 Hz, 6H), 2.76-2.83 (m, 1H), 2.97-3.01 (m, 1H), 3.34-3.43 (m, 1H), 4.10 (t, / = 6.9 Hz, 1H), 7.10 (s, 4H), 7.28-7.37 (m, 3H), 7.45 (d, / = 7.2 Hz, 2H), 8.28 (br s, 4H), 12.28 (br s, 1H); APCI-MS (m/z) 310 (M+H) ⁺ .

Example 16

(+)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 7 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.11-3.16 (m, 1H), 3.45- 3.50 (m, 1H), 4.20 (t, / = 5.4 Hz, 1H), 7.19-7.23 (m, 3H), 7.27-7.34 (m, 3H), 7.35- 7.41 (m, 3H), 8.30 (br s, 4H), 12.19 (br s, 1H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 17

(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide

The title compound was synthesized from Intermediate 82 and free guanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.11-3.16 (m, 1H), 3.45-3.50 (m, 1H), 4.19 (t, / = 5.7 Hz, 1H), 7.20-7.24 (m, 3H), 7.27-7.32 (m, 2H), 7.34-7.41 (m, 4H), 8.29 (br s, 4H); APCI- MS (m/z) 302 (M+H) ⁺ .

Example 18

(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide hydrochloride

The treatment of compound of Example 17 with excess of hydrochloric acid in ethyl acetate yields the title compound as a hydrochloride salt. 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.11-3.16 (m, 1H), 3.45-3.50 (m, 1H), 4.19 (t, / = 5.7 Hz, 1H), 7.20-7.24 (m, 3H), 7.27-7.32 (m, 2H), 7.34-7.41 (m, 4H), 8.29 (br s, 4H), 12.15 (s, 1H); APCI- MS (m/z) 302 (M+H) ⁺ .

Example 19

(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide

The title compound was synthesized from Intermediate 83 and guanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.08-3.16 (m, 1H), 3.42-3.50 (m, 1H), 4.18 (t, / = 7.5 Hz, 1H), 7.19-7.22 (m, 3H), 7.29-7.40 (m, 6H), 8.33 (br s, 4H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 20

(2S)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide hydrochloride

The treatment of compound of Example 19 with excess of hydrochloric acid in ethyl acetate yields the title compound as a hydrochloride salt. 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.08-3.16 (m, 1H), 3.42-3.50 (m, 1H), 4.18 (t, / = 7.5 Hz, 1H), 7.19-7.22 (m, 3H), 7.29-7.40 (m, 6H), 8.33 (br s, 4H), 12.09 (br s, 1H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 21

(+)-N-Carbamimidoyl-3-(3-chloro henyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 8 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.03-3.08 (m, 1H), 3.38- 3.43 (m, 1H), 4.11 (t, / = 5.7 Hz, 1H), 7.11 (d, / = 5.4 Hz, 1H), 7.19-7.23 (m, 2H), 7.25-7.30 (m, 2H), 7.33 (t, / = 5.7 Hz, 2H), 7.37-7.41 (m, 2H), 8.30 (m, 4H), 12.15 (br s, 1H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 22

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 84 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.04-3.09 (m, 1H), 3.41- 3.45 (m, 1H), 4.12 (t, / = 5.7 Hz, 1H), 7.13 (d, / = 5.4 Hz, 1H), 7.21-7.25 (m, 2H), 7.27-7.31 (m, 3H), 7.33-7.40 (m, 3H), 8.30 (br s, 4H), 12.14 (s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 23

(2S)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 85 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.04-309 (m, 1H), 3.39- 3.44 (m, 1H), 4.12 (t, / = 6.0 Hz, 1H), 7.13 (d, / = 5.4 Hz, 1H), 7.22-7.31 (m, 4H), 7.33-7.41 (m, 4H), 8.29 (br s, 4H), 12.14 (s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 24

(+)-N-Carbamimidoyl-3-(4-chloro henyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 9 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.96-3.03 (m, 1H), 3.37- 3.44 (br s, 1H), 3.89 (t, / = 7.2 Hz, 1H), 7.01 (d, / = 8.4 Hz, 2H), 7.18 (d, / = 8.1 Hz, 2H), 7.26-7.31 (m, 5H), 8.05 (br s, 2H), 8.26 (br s, 2H), 11.52 (br s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 25

(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide

The title compound was synthesized from Intermediate 86 and free guanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR

(300 MHz, OMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.36-3.41 (m, 1H), 4.07 (t, / = 5.7 Hz, 1H), 7.18 (d, / = 6.3 Hz, 2H), 7.27-7.37 (m, 7H), 8.26 (br s, 4H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 26

(2R)-N-Carbamimidoyl-3-( -chlorophenyl)-2-phenylpropanamide hydrochloride The treatment of compound of Example 25 with excess of hydrochloric acid in ethyl acetate yields the title compound as a hydrochloride salt. 1H NMR (300 MHz,

DMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.36-3.41 (m, 1H), 4.07 (t, / = 5.7 Hz, 1H), 7.18 (d, / = 6.3 Hz, 2H), 7.27-7.37 (m, 7H), 8.26 (br s, 4H), 12.13 (br s, 1H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 27

(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide

The title compound was synthesized from Intermediate 87 and free guanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR

(300 MHz, OMSO-d ₆ ) δ 3.01-3.06 (m, 1H), 3.32-3.42 (m, 1H), 4.08 (t, / = 5.7 Hz, 1H), 7.17-7.27 (m, 2H), 7.33-7.38 (m, 7H), 8.33 (br s, 4H); ESI-MS (m z) 302 (M+H) ⁺ .

Example 28

(2S)-N-Carbamimidoyl-3-( -chlorophenyl)-2-phenylpropanamide hydrochloride

The treatment of compound of Example 27 with excess of hydrochloric acid in ethyl acetate yields the title compound as a hydrochloride salt. 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.01-3.06 (m, 1H), 3.32-3.42 (m, 1H), 4.08 (t, / = 5.7 Hz, 1H), 7.17-7.27 (m, 2H), 7.33-7.38 (m, 7H), 8.33 (br s, 4H), 12.24 (br s, 1H); ESI-MS (m z) 302 (M+H) ⁺ .

Example 29

(2 _l S')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropana mide hydrogen sulphate

The treatment of compound of Example 27 with excess of sulphuric acid in ethanol yields the title compound as the hydrogen sulphate salt. 1H NMR (300 MHz, DMSO- d ₆ ) δ 2.95-3.01 (m, 1H), 3.34-3.40 (m, 1H), 4.08 (br s, 1H), 7.17-7.28 (m, 7H), 7.38 (d, / = 7.5 Hz, 2H), 7.95 (br s, 2H), 8.51 (br s, 2H), 11.92 (br s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 30

(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide methane sulphate

The treatment of compound of Example 27 with excess of methanesulfonic acid in ethanol yields the title compound as the hydrogen sulphate salt. 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.39 (s, 3H), 2.98-3.05 (m, 1H), 3.33-3.38 (m, 1H), 4.13 (t, J = 7.8 Hz, 1H), 7.17 (d, / = 8.4 Hz, 2H), 7.27-7.32 (m, 7H), 8.25 (s, 4H), 11.38 (s, 1H); APCI- MS (m/z) 302 (M+H) ⁺ .

Example 31

(±)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 10 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.05-3.12 (m, 1H), 3.35- 3.43 (m, 1H), 4.13 (t, / = 7.5 Hz, 1H), 7.03-7.13 (m, 2H), 7.18-7.23 (m, 2H), 7.30- 7.36 (m, 5H), 8.29 (br s, 4H), 12.09 (br s, 1H); ESI-MS (m/z) 286 (M+H) ⁺ .

Example 32

(2 _l S ^, )-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanami de hydrochloride

The title compound was synthesized from Intermediate 88 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.06-3.13 (m, 1H), 3.39- 3.43 (m, 1H), 4.14 (t, / = 7.5 Hz, 1H), 7.04-7.10 (m, 2H), 7.21 (t, / = 6.6 Hz, 2H), 7.27-7.36 (m, 5H), 8.23 (br s, 4H), 11.96 (br s, 1H); APCI-MS (m/z) 285 (M+H) ⁺ .

Example 33

(±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 11 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.03-3.09 (m, 1H), 3.39- 3.45 (m, 1H), 4.12 (t, J = 5.7 Hz, 1H), 6.96- 7.02 (m, 3H), 7.23-7.39 (m, 6H), 8.28 (br s, 4H), 12.19 (br s, 1H); APCI-MS (m/z) 286 (M+H) ⁺ .

Example 34

(2 _l S ^, )-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanami de hydrochloride

The title compound was synthesized from Intermediate 89 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.01-3.10 (m, 1H), 3.54- 3.60 (m, 1H), 4.12 (t, / = 7.8 Hz, 1H), 7.00-7.06 (m, 3H), 7.30-7.39 (m, 6H), 8.33 (br s, 4H), 12.17 (br s, 1H); APCI-MS (m/z) 286 (M+H) ⁺ .

Example 35

(±)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 12 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.00-3.07 (m, 1H), 3.38- 3.45 (m, 1H), 4.09 (t, / = 7.8 Hz, 1H), 7.05 (t, / = 8.7 Hz, 2H), 7.18-7.25 (m, 2H), 7.27-7.39 (m, 5H), 8.29 (br s, 2H), 8.46 (br s, 2H), 12.44 (br s, 1H); APCI-MS (m/z) 286 (M+H) ⁺ .

Example 36

(2 _l S ^, )-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanami de hydrochloride The title compound was synthesized from Intermediate 90 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.98-3.05 (m, 1H), 3.35- 3.42 (m, 1H), 4.06 (t, / = 7.8 Hz, 1H), 7.04 (t, / = 8.7 Hz, 2H), 7.16-7.22 (m, 2H), 7.26-7.38 (m, 5H), 8.24 (br s, 2H), 8.29 (br s, 2H), 12.22 (s, 1H); APCI-MS (m/z) 286

(M+H) ⁺ .

Example 37

(+)-N-Carbamimidoyl-3-(2-methoxyphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 13 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.96-3.02 (m, 1H), 3.26- 3.30 (m, 1H), 3.78 (s, 3H), 4.14 (t, / = 5.1 Hz, 1H), 6.77 (t, / = 5.4 Hz, 1H), 6.93 (d, / = 6.0 Hz, 1H), 7.01 (d, / = 5.1 Hz, 1H), 7.14-7.18 (m, 1H), 7.25-7.37 (m, 4H), 8.30 (br s, 4H), 12.10 (br s, 1H); ESI-MS (m/z) 298 (M+H) ⁺ .

Example 38

(+)-N-Carbamimidoyl-3-(3-methoxyphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 14 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.97-3.04 (m, 1H), 3.35- 3.39 (m, 1H), 3.68 (s, 3H), 4.13 (t, / = 7.2 Hz, 1H), 6.76 (br s, 3H), 7.14 (d, / = 7.8 Hz, 1H), 7.28-7.37 (m, 3H), 7.41 (d, / = 7.5 Hz, 2H), 8.30 (br s, 4H), 12.40 (br s, 1H); APCI-MS (m/z) 298 (M+H) ⁺ .

Example 39

(2 _l S')-N-Carbamimidoyl-3-( -methoxyphenyl)-2-phenylpropanamide hydrochloride The title compound was synthesized from Intermediate 91 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.97-3.04 (m, 1H), 3.36- 3.43 (m, 1H), 3.68 (s, 3H), 4.12 (t, / = 8.4 Hz, 1H), 6.71-6.77 (m, 3H), 7.15 (t, 7 = 7.8 Hz, 1H), 7.28-7.33 (m, 2H), 7.35-7.42 (m, 3H), 8.30 (br s, 4H), 12.24 (br s, 1H); APCI-MS (m/z) 298 (M+H) ⁺ .

Example 40

(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 15 and tert-b tyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.93-3.00 (m, 1H), 3.37 (br s, 1H), 3.68 (s, 3H), 4.06 (t, / = 7.8 Hz, 1H), 6.79 (d, / = 8.4 Hz, 2H), 7.09 (d, / = 8.4 Hz, 2H), 7.27-7.34 (m, 3H), 7.36- 7.42 (m, 2H), 8.29 (br s, 2H), 8.45 (br s, 2H), 12.45 (br s, 1H); ESI-MS (m/z) 298 (M+H) ⁺ .

Example 41

(2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 92 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.92-2.99 (m, 1H), 3.32- .335 (m, 1H), 3.69 (s, 3H), 4.05 (br s, 1H), 6.79 (d, / = 7.8 Hz, 2H), 7.09 (d, / = 8.4 Hz, 2H), 7.28-7.37 (m, 5H), 8.27 (br s, 4H), 12.05 (br s, 1H); ESI-MS (m/z) 298 (M+H) ⁺ .

Example 42

(2 _l S')-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropan amide hydrochloride The title compound was synthesized from Intermediate 93 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.92-2.99 (m, 1H), 3.35- 3.41 (m, 1H), 3.69 (s, 3H), 4.04 (t, J = 7.8 Hz, 1H), 6.79 (d, / = 8.4 Hz, 2H), 7.09 (d, / = 8.4 Hz, 2H), 7.32-7.37 (m, 5H), 8.27 (br s, 4H), 12.08 (br s, 1H); APCI-MS (m/z) 298 (M+H) ⁺ .

Example 43

(+)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]pr opanamide

hydrochloride

The title compound was synthesized from Intermediate 16 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.15-3.20 (m, 1H), 3.49- 3.54 (m, 1H), 4.15 (t, / = 5.7 Hz, 1H), 7.27-7.31 (m, 1H), 7.34 (t, / = 5.7 Hz, 2H), 7.39 (d, / = 5.4 Hz, 2H), 7.47-7.51 (m, 4H), 8.35 (br s, 4H), 12.30 (br s, 1H); ESI-MS (m/z) 336 (M+H) ⁺ .

Example 44

(+)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]pr opanamide

hydrochloride

The title compound was synthesized from Intermediate 17 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.14-3.21 (m, 1H), 3.49- 3.56 (m, 1H), 4.18 (t, / = 7.8 Hz, 1H), 7.27-7.34 (m, 3H), 7.36-7.42 (m, 4H), 7.60 (d, / = 8.1 Hz, 2H), 8.31 (br s, 2H), 8.62 (br s, 2H), 12.70 (br s, 1H); APCI-MS (m/z) 336 (M+H) ⁺ .

Example 45

(±)-N-Carbamimidoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylp ropanamide hydrochloride

The title compound was synthesized from Intermediate 18 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.00-3.07 (m, 1H), 3.39- 3.45 (m, 1H), 4.09 (t, / = 7.8 Hz, 1H), 7.04 (d, / = 7.8 Hz, 2H), 7.17-7.24 (m, 3H), 7.28-7.8 (m, 5H), 8.28 (br s, 4H), 12.12 (br s, 1H); ESI-MS (m/z) 334 (M+H) ⁺ .

Example 46

(+)-N-Carbamimidoyl-2-phenyl-3-(2-(trifluoromethoxy)phenyl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 19 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.40- 3.46 (m, 1H), 4.15 (t, / = 5.7 Hz, 1H), 7.25-7.37 (m, 9H), 8.27 (br s, 4H), 12.02 (br s, 1H); ESI-MS (m/z) 352 (M+H) ⁺ .

Example 47

(2R)-N-Carbamimidoyl-2-phenyl-3-[2-(trifluoromethoxy)phenyl] propanamide hydrochloride

The title compound was synthesized from Intermediate 94 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.40- 3.346 (m, 1H), 4.15 (t, / = 5.7 Hz, 1H), 7.26-7.31 (m, 4H), 7.32-7.39 (m, 5H), 8.24 (br s, 2H), 8.34 (br s, 2H), 12.07 (s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 48

(+)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]p ropanamide hydrochloride

The title compound was synthesized from Intermediate 20 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.01-3.11 (m, 1H), 3.39- 3.42 (m, 1H), 4.07 (t, / = 7.8 Hz, 1H), 7.08-7.14 (m, 2H), 7.17 (d, / = 5.7 Hz, 2H), 7.25-7.35 (m, 5H), 8.25 (br s, 4H), 12.00 (br s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 49

(2R)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl] propanamide hydrochloride

The title compound was synthesized from Intermediate 95 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.42- 3.48 (m, 1H), 4.10 (t, / = 6.0 Hz, 1H), 7.11-7.16 (m, 2H), 7.20 (d, / = 5.7 Hz, 1H), 7.25-7.37 (m, 6H), 8.28 (s, 4H), 12.08 (br s, 1H); ESI-MS (m/z) 352 (M+H) ⁺ .

Example 50

(2 _l S ^, )-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phen yl]propanamide hydrochloride

The title compound was synthesized from Intermediate 96 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.43- 3.48 (m, 1H), 4.10 (t, / = 6.0 Hz, 1H), 7.13-7.16 (m, 2H), 7.20 (d, / = 5.7 Hz, 1H), 7.25-7.29 (m, 3H), 7.30-7.38 (m, 3H), 8.25 (br s, 2H), 8.34 (br s, 2H), 12.18 (s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 51

(+)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]p ropanamide hydrochloride

The title compound was synthesized from Intermediate 21 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.04-3.11 (m, 1H), 3.35- 3.47 (m, 1H), 4.11 (t, / = 7.8 Hz, 1H), 7.22-7.28 (m, 4H), 7.31-7.37 (m, 5H), 8.28 (br s, 4H), 12.06 (br s, 1H); ESI-MS (m/z) 352 (M+H) ⁺ .

Example 52

(2 _l S ^, )-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phen yl]propanamide hydrochloride

The title compound was synthesized from Intermediate 97 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.04-3.12 (m, 1H), 3.41- 3.48 (m, 1H), 4.12 (t, / = 7.5 Hz, 1H), 7.22-7.29 (m, 3H), 7.31-7.40 (m, 6H), 8.28 (br s, 2H), 8.42 (br s, 2H), 12.18 (s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 53

(+)-N-Carbamimidoyl-3-(3-cyanophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 22 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.09-3.14 (m, 1H), 3.43- 3.47 (m, 1H), 4.13 (t, / = 5.7 Hz, 1H), 7.29-7.38 (m, 5H), 7.43-7.52 (m, 2H), 7.63- 7.67 (m, 2H), 8.28 (br s, 4H), 11.98 (br s, 1H); APCI-MS (m/z) 293 (M+H) ⁺ .

Example 54

(+)-N-Carbamimidoyl-3-(4-cyanophenyl)-2-phenylpropanamide hydrochloride The title compound was synthesized from Intermediate 23 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.12-3.20 (m, 1H), 3.45- 3.53 (m, 1H), 4.15 (t, / = 7.8 Hz, 1H), 7.28-7.39 (m, 7H), 7.71 (d, / = 8.4 Hz, 2H), 8.29 (br s, 4H), 12.15 (br s, 1H); APCI-MS (m/z) 293 (M+H) ⁺ .

Example 55

(+)-3-(4-Acetamidophenyl -N-carbamimidoyl-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 24 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 1.99 (s, 3H), 2.95-2.99 (m, 1H), 3.34-3.39 (m, 1H), 3.98-4.06 (br s, 1H), 7.07 (d, / = 8.4 Hz, 2H), 7.34-7.44 (m, 7H), 8.25 (br s, 4H), 9.86 (br s, 1H), 11.95 (br s, 1H); ESI-MS (m/z) 325 (M+H) ⁺ .

Example 56

(±)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 25 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.12-3.18 (m, 1H), 3.44- 3.49 (m, 1H), 4.19 (t, / = 5.7 Hz, 1H), 7.22 (d, / = 6.3 Hz, 1H), 7.29-7.33 (m, 3H), 7.34-7.39 (m, 3H), 7.58 (s, 1H), 8.33 (br s, 4H), 12.21 (s, 1H); APCI-MS (m/z) 336

(M+H) ⁺ .

Example 57

(2R)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 98 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.12-3.17 (m, 1H), 3.43- 3.49 (m, 1H), 4.19 (t, / = 5.7 Hz, 1H), 7.17 (d, / = 6.0 Hz, 2H), 7.28-32 (m, 2H), 7.33-7.40 (m, 3H), 7.58 (s, 1H), 8.31 (br s, 4H), 12.16 (s, 1H); APCI-MS (m/z) 336 (M+H) ⁺ .

Example 58

(25)-N-Carbamimidoyl-3-(2, -dichlorophenyl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 99 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.12-3.17 (m, 1H), 3.43- 3.49 (m, 1H), 4.19 (t, / = 6.0 Hz, 1H), 7.22 (d, / = 6.0 Hz, 1H), 7.29-7.33 (m, 4H), 7.33-7.37 (m, 2H), 7.58 (br s, 1H), 8.24 (br s, 2H), 8.45 (br s, 2H), 12.17 (s, 1H); ESI- MS (m/z) 336 (M+H) ⁺ .

Example 59

(+)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylprop anamide

hydrochloride

The title compound was synthesized from Intermediate 26 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.06-3.11 (m, 1H), 3.32- 3.39 (m, 1H), 4.11 (t, / = 5.7 Hz, 1H), 7.18 (d, / = 6.0 Hz, 1H), 7.21-7.28 (m, 2H), 7.29-7.35 (m, 5H), 8.25 (br s, 2H), 8.34 (br s, 2H), 12.17 (s, 1H); APCI-MS (m/z) 320

(M+H) ⁺ .

Example 60

(2 _l S ^, )-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenyl propanamide

hydrochloride

The title compound was synthesized from Intermediate 100 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.05-3.13 (m, 1H), 3.32- 3.38 (m, 1H), 4.11 (t, / = 7.8 Hz, 1H), 7.15-7.24 (m, 2H), 7.27-7.36 (m, 6H), 8.26 (br s, 4H), 12.15 (br s, 1H); APCI-MS (m/z) 320 (M+H) ⁺ .

Example 61

(+) -N-Carbamimidoyl- 3 - (4-chloro- 3 -fluorophenyl) -2-phenylpropanamide

hydrochloride

The title compound was synthesized from Intermediate 27 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.04-3.10 (m, 1H), 3.38- 3.44 (m, 1H), 4.11 (t, / = 5.7 Hz, 1H), 7.02 (d, / = 6.0 Hz, 1H), 7.22-7.33 (m, 3H), 7.35-7.45 (m, 4H), 8.26 (br s, 2H), 8.35 (br s, 2H), 12.21 (s, 1H); APCI-MS (m/z) 320

(M+H) ⁺ .

Example 62

(2 _l S ^, )-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenyl propanamide

hydrochloride

The title compound was synthesized from Intermediate 101 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.04-3.11 (m, 1H), 3.40- 3.46 (m, 1H), 4.11 (t, / = 7.8 Hz, 1H), 7.03 (d, / = 8.1 Hz, 1H), 7.23-7.30 (m, 3H), 7.32-7.37 (m, 3H), 7.45 (t, / = 7.8 Hz, 1H), 8.32 (br s, 4H), 12.12 (br s, 1H); APCI- MS (m/z) 320 (M+H) ⁺ .

Example 63

(+)-N-Carbamimidoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 28 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.98-3.04 (m, 1H), 3.31- 3.39 (m, 1H), 3.70 (s, 3H), 3.77 (s, 3H), 4.10 (t, / = 7.8 Hz, 1H), 6.67 (d, / = 6.3 Hz, 1H), 6.88-6.92 (m, 2H), 7.30-7.36 (m, 5H), 8.23 (br s, 4H), 11.94 (br s, 1H); APCI- MS (m/z) 328 (M+H) ⁺ .

Example 64

(+)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 29 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.90-2.98 (m, 1H), 3.31- 3.35 (m, 1H), 3.67 (d, / = 4.5 Hz, 6H), 4.01-4.09 (m, 1H), 6.67 (d, / = 7.8 Hz, 1H), 6.79 (d, / = 8.1 Hz, 2H), 7.29-7.39 (m, 5H), 8.29 (br s, 4H), 12.23 (br s, 1H); APCI- MS (m/z) 328 (M+H) ⁺ .

Example 65

(±)-3-(l,3-Benzodioxol-5-yl)- -carbamimidoyl-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 30 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.91-2.98 (m, 1H), 3.38 (br s, 1H), 4.06 (t, / = 7.8 Hz, 1H), 5.94 (s, 2H), 6.62 (d, / = 7.8 Hz, 1H), 6.76 (d, / = 8.7 Hz, 2H), 7.28-7.34 (m, 3H), 7.36-7.42 (m, 2H), 8.30 (br s, 2H), 8.43 (br s, 2H), 12.44 (br s, 1H); APCI-MS (m/z) 312 (M+H) ⁺ .

Example 66

(+)-N-Carbamimidoyl-3-phenyl-2-(4-methylphenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 31 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.25 (s, 3H), 2.97-3.02 (m, 1H), 3.31-3.41 (m, 1H), 4.05 (t, / = 5.7 Hz, 1H), 7.12-7.20 (m, 5H), 7.22-7.27 (m, 4H), 8.27 (br s, 4H), 12.11 (br s, 1H); ESI-MS (m/z) 282 (M+H) ⁺ .

Example 67

(2R)-N-Carbamimidoyl-2-(4-methylphenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 102 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.26 (s, 3H), 2.98-3.04 (m, 1H), 3.36-3.42 (m, 1H), 4.06 (t, / = 6.0 Hz, 1H), 7.14 (d, / = 6.0 Hz, 2H), 7.17 (d, / = 6.3 Hz, 2H), 7.22-7.29 (m, 5H), 8.27 (br s, 4H), 12.08 (s, 1H); APCI-MS (m/z) 282 (M+H) ⁺ .

Example 68

(2R)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 103 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.05-3.10 (m, 1H), 3.36- 3.41 (m, 1H), 4.54 (t, / = 5.4 Hz, 1H), 7.18-7.27 (m, 5H), 7.30-7.39 (m, 2H), 7.46 (d, / = 6.0 Hz, 1H), 7.51 (d, / = 6.0 Hz, 1H), 8.26 (br s, 2H), 8.37 (br s, 2H), 11.73 (s, 1H); ESI-MS (m/z) 302 (M+H) ⁺ .

Example 69

(+)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 32 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.02-3.07 (m, 1H), 3.34- 3.43 (m, 1H), 4.16 (t, / = 6.0 Hz, 1H), 7.14-7.25 (m, 5H), 7.32-7.39 (m, 3H), 7.45 (m 1H), 8.30 (br s, 4H), 12.32 (s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 70

(2S)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 104 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.02-3.09 (m, 1H), 3.39- 3.46 (m, 1H), 4.17 (t, / = 7.8 Hz, 1H), 7.19-7.26 (m, 5H), 7.36 (br s, 3H), 7.47 (s, 1H), 8.26 (br s, 2H), 8.42 (br s, 2H), 12.45 (br s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 71

(+)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 33 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.43- 3.48 (m, 1H), 4.13 (t, / = 6.0 Hz, 1H), 7.14-7.19 (m, 3H), 7.21-7.27 (m, 2H), 7.37- 7.42 (m, 4H), 8.25 (br s, 4H), 12.05 (br s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ .

Example 72

(2R)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 105 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.01-3.06 (m, 1H), 3.40- 3.45 (m, 1H), 4.15 (t, / = 6.0 Hz, 1H), 7.13-7.19 (m, 3H), 7.21-7.26 (m, 2H), 7.41 (s, 4H), 8.25 (br s, 2H), 8.40 (br s, 2H), 12.36 (s, 1H); APCI-MS (m/z) 302 (M+H) ⁺ . Example 73

(±)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 34 and ie/t-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.99-3.06 (m, 1H), 3.46 (br s, 1H), 4.16 (t, / = 7.2 Hz, 1H), 7.14- 7.23 (m, 7H), 7.42-7.48 (m, 2H), 8.29 (br s, 2H), 8.54 (br s, 2H), 12.66 (br s, 1H); ESI-MS (m/z) 286 (M+H) ⁺ .

Example 74

(2R)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 106 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.38- 3.43 (m, 1H), 4.13 (t, / = 5.7 Hz, 1H), 7.15-7.21 (m, 5H), 7.22-7.28 (m, 2H), 7.40- 7.46 (m, 2H), 8.27 (br s, 4H), 12.24 (br s, 1H); APCI-MS (m/z) 286 (M+H) ⁺ .

Example 75

(2 _l S ^, )-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanami de hydrochloride

The title compound was synthesized from Intermediate 107 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.97-3.04 (m, 1H), 3.33- 3.42 (m, 1H), 4.12 (d, / = 6.0 Hz, 1H), 7.13-7.21 (m, 7H), 7.40 (br s, 2H), 8.25 (br s, 4H), 12.25 (s, 1H); APCI-MS (m/z) 286 (M+H) ⁺ .

Example 76 (±)-N-Carbamimidoyl-2-(3-methoxyphenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 35 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.99-3.06 (m, 1H), 3.34- 3.44 (m, 1H), 3.74 (s, 3H), 4.07 (t, J = 7.8 Hz, 1H), 6.86 (d, / = 7.8 Hz, 1H), 6.97 (s, 2H), 7.17-7.26 (m, 6H) 8.27 (br s, 4H), 12.10 (br s, 1H); APCI-MS (m/z) 298 (M+H) ⁺ .

Example 77

(+)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 36 and ie/t-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.96-3.03 (m, 1H), 3.38-3.43 (m, 1H), 3.72 (s, 3H), 4.05 (t, J = 6.6 Hz, 1H), 6.89 (d, / = 8.4 Hz, 2H), 7.16-7.23 (m, 5H), 7.33 (d, / = 7.8 Hz, 2H), 8.29 (br s, 2H), 8.42 (br s, 2H), 12.44 (br s, 1H); APCI-MS (m/z) 298 (M+H) ⁺ .

Example 78

(2R)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 108 and iert-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.95-3.02 (m, 1H), 3.34-3.41 (m, 1H), 3.72 (s, 3H), 4.03 (t, / = 7.2 Hz, 1H), 6.89 (d, / = 8.4 Hz, 2H), 7.16 (d, / = 6.9 Hz, 3H), 7.22 (d, / = 6.3 Hz, 2H), 7.30 (d, / = 8.4 Hz, 2H), 8.26 (br s, 4H), 11.99 (br s, 1H); ESI-MS (m/z) 298 (M+H) ⁺ . Example 79

(2 _l S ^, )-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 109 and iert-butyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method B). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.95-3.03 (m, 1H), 3.35-3.41 (m, 1H), 3.72 (s, 3H), 4.03 (t, / = 7.2 Hz, 1H), 6.89 (d, / = 9.0 Hz, 2H), 7.15-7.23 (m, 4H), 7.26-7.32 (m, 3H), 8.26 (br s, 4H), 12.10 (br s, 1H); ESI-MS (m/z) 298 (M+H) ⁺ .

Example 80

(+)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]pr opanamide

hydrochloride

The title compound was synthesized from Intermediate 37 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.04-3.10 (m, 1H), 3.41- 3.46 (m, 1H), 4.25 (t, / = 5.7 Hz, 1H), 7.15-7.25 (m, 5H), 7.60 (d, / = 6.0 Hz, 2H), 7.70 (d, / = 6.0 Hz, 2H), 8.27 (br s, 4H), 12.30 (br s, 1H); ESI-MS (m z) 336 (M+H) ⁺ .

Example 81

(+)-N-Carbamimidoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]p ropanamide hydrochloride

The title compound was synthesized from Intermediate 38 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.05-3.10 (m, 1H), 3.40- 3.46 (m, 1H), 4.22 (t, / = 6.0 Hz, 1H), 7.14-7.18 (m, 3H), 7.20-7.26 (m, 2H), 7.29 (d, / = 6.3 Hz, 1H), 7.36 (s, 1H), 7.41 (d, / = 5.7 Hz, 1H), 7.48 (t, / = 6.0 Hz, 1H), 8.25 (br s, 2H), 8.38 (br s, 2H), 12.34 (s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 82

(±)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl] propanamide hydrochloride

The title compound was synthesized from Intermediate 39 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.01-3.06 (m, 1H), 3.39- 3.44 (m, 1H), 4.19 (t, / = 5.7 Hz, 1H), 7.14- 7.20 (m, 3H), 7.21-7.27 (m, 2H), 7.33 (d, / = 6.0 Hz, 2H), 7.51 (d, / = 6.6 Hz, 2H), 8.28 (br s, 4H), 12.30 (s, 1H); ESI-MS (m z) 352 (M+H) ⁺ .

Example 83

(+)-N-Carbamimidoyl-2-(4-cyanophenyl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 40 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.05-3.11 (m, 1H), 3.39- 3.47 (m, 1H), 4.26 (t, / = 5.7 Hz, 1H), 7.17 (d, / = 4.8 Hz, 2H), 7.24 (t, / = 6.0 Hz, 3H), 7.57 (d, / = 6.3 Hz, 2H), 7.82 (d, / = 6.3 Hz, 2H), 8.28 (br s, 4H), 12.22 (s, 1H); APCI-MS (m/z) 293 (M+H) ⁺ .

Example 84

(2R)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 110 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.01-3.06 (m, 1H), 3.32- 3.42 (m, 1H), 4.49 (br s, 1H), 7.12-7.18 (m, 3H), 7.21-7.26 (m, 2H), 7.43 (d, / = 6.3 Hz, 1H), 7.51 (d, / = 6.3 Hz, 1H), 7.60 (s, 1H), 8.21 (br s, 4H), 11.66 (s, 1H); APCI- MS (m/z) 336 (M+H) ⁺ .

Example 85

(+)-N-Carbamimidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanam ide hydrochloride

The title compound was synthesized from Intermediate 41 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.99-3.04 (m, 1H), 3.37- 3.43 (m, 1H), 3.71 (s, 3H), 3.74 (s, 3H), 4.01 (t, / = 5.7 Hz, 1H), 6.89 (s, 2H), 7.04 (s, 1H), 7.13- 7.25 (m, 5H), 8.29 (br s, 4H), 12.18 (s, 1H); APCI-MS (m/z) 328 (M+H) ⁺ .

Example 86

(±)-2-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-3-phenylpropan amide hydrochloride

The title compound was synthesized from Intermediate 42 and tert-b tyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.97-3.04 (m, 1H), 3.36-3.41 (m, 1H), 4.04 (t, / = 7.8 Hz, 1H), 6.00 (s, 2H), 6.86 (s, 2H), 7.01 (s, 1H), 7.17-7.27 (m, 5H), 8.30 (br s, 4H), 12.33 (br s, 1H); APCI-MS (m/z) 312 (M+H) ⁺ .

Example 87

(+)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamid e hydrochloride

The title compound was synthesized from Intermediate 70 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.01 (s, 3H), 2.96-3.02 (m, 1H), 3.31-3.34 (m, 1H), 4.01 (t, / = 5.7 Hz, 1H), 7.12-7.18 (m, 3H), 7.20-7.28 (m, 4H), 7.51 (d, / = 6.3 Hz, 2H), 8.23 (br s, 4H), 9.96 (s, 1H), 11.95 (br s, 1H); ESI-MS (m/z) 325 (M+H) ⁺ .

Example 88

(±)-N-Carbamimidoyl-2, -bis(4-methylphenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 43 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.26 (s, 3H), 2.93-2.98 (m, 1H), 3.31-3.36 (m, 1H), 4.02 (t, / = 6.0 Hz, 1H), 7.03-7.09 (m, 4H), 7.14 (d, / = 5.7 Hz, 2H), 7.27 (d, / = 5.7 Hz, 2H), 8.27 (br s, 4H), 12.10 (br s, 1H); ESI-MS (m/z) 296 (M+H) ⁺ .

Example 89

(+)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methylphenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 44 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.26 (s, 3H), 2.99-3.05 (m, 1H), 3.30-3.40 (m, 1H), 4.04 (t, / = 6.0 Hz, 1H), 7.14 (d, / = 5.7 Hz, 2H), 7.19 (d, / = 6.3 Hz, 2H), 7.26 (d, / = 6.3 Hz, 2H), 7.29 (d, / = 6.3 Hz, 2H), 8.28 (br s, 4H), 12.05 (s, 1H); APCI-MS (m/z) 316 (M+H) ⁺ .

Example 90

(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methylphenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 45 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.26 (s, 3H), 2.98-3.04 (m, 1H), 3.35-3.40 (m, 1H), 4.03 (t, J = 5.7 Hz, 1H), 7.06 (t, J = 6.6 Hz, 2H), 7.14 (d, / = 5.7 Hz, 2H), 7.18-7.22 (m, 2H), 7.27 (d, / = 6.0 Hz, 2H), 8.30 (br s, 4H), 12.11 (s, 1H); APCI-MS (m/z) 300 (M+H) ⁺ .

Example 91

(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-(4-methylphenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 46 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.27 (s, 3H), 2.91-2.96 (m, 1H), 3.30-3.36 (m, 1H), 3.69 (s, 3H), 4.00 (t, / = 5.0 Hz, 1H), 6.80 (d, / = 6.0 Hz, 2H), 7.09 (d, / = 6.0 Hz, 2H), 7.15 (d, / = 6.0 Hz, 2H), 7.27 (d, / = 6.0 Hz, 2H), 8.28 (br s, 4H), 12.10 (s, 1H); ESI-MS (m/z) 312 (M+H) ⁺ .

Example 92

(2R)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 111 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.99-3.07 (m, 1H), 3.29-3.38 (m, 1H), 4.51 (t, 7 = 5.7 Hz, 1H), 6.97-7.00 (m, 2H), 7.00 (s, 1H), 7.11 (t, / = 5.7 Hz, 1H), 7.29-7.38 (m, 2H), 7.45 (d, / = 5.7 Hz, 1H), 7.50 (d, / = 5.7 Hz, 1H), 8.25 (br s, 2H), 8.40 (br s, 2H), 11.80 (br s, 1H); APCI-MS (m/z) 316 (M+H) ⁺ .

Example 93

(2R)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 112 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.38- 3.43 (m, 1H), 4.55 (t, / = 5.7 Hz, 1H), 7.15 (d, / = 5.1 Hz, 1H), 7.20-7.28 (m, 3H), 7.33-7.39 (m, 2H), 7.45 (d, / = 5.1 Hz, 1H), 7.51 (d, / = 5.1 Hz, 1H), 8.26 (br s, 2H), 8.42 (br s, 2H), 11.82 (s, 1H); APCI-MS (m/z) 336 (M+H) ⁺ .

Example 94

(2R)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-fluorophenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 113 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.39- 3.44 (m, 1H), 4.55 (t, / = 5.7 Hz, 1H), 6.96-7.05 (m, 3H), 7.23-7.38 (m, 3H), 7.43 (d, / = 5.7 Hz, 1H), 7.50 (d, / = 5.7 Hz, 1H), 8.26 (br s, 2H), 8.43 (br s, 2H), 11.85 (br s, 1H); APCI-MS (m/z) 319 (M+H) ⁺ .

Example 95

(+)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-methylphenyl)pro panamide

hydrochloride The title compound was synthesized from Intermediate 47 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.21 (s, 3H), 2.97-3.02 (m, 1H), 3.33-3.38 (m, 1H), 4.12 (t, / = 6.0 Hz, 1H), 7.03 (d, / = 6.0 Hz, 2H), 7.06 (d, / = 6.0 Hz, 2H), 7.32-7.39 (m, 3H), 7.45 (s, 1H), 8.28 (br s, 4H), 12.25 (s, 1H); APCI-MS (m/z) 316 (M+H) ⁺ .

Example 96

(2 _l S')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(3-chlorophen yl)propanamide hydrochloride

The title compound was synthesized from Intermediate 114 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.13-3.20 (m, 1H), 3.44- 3.51 (m, 1H), 4.25 (t, / = 7.8 Hz, 1H), 7.18-7.26 (m, 3H), 7.32-7.42 (m, 5H), 8.25 (br s, 2H), 8.41 (br s, 2H), 12.28 (br s, 1H); APCI-MS (m/z) 336 (M+H) ⁺ .

Example 97

(25)-N-Carbamimidoyl-2, -bis(3-chlorophenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 115 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.05-3.12 (m, 1H), 3.39- 3.47 (m, 1H), 4.18 (t, / = 8.1 Hz, 1H), 7.14 (t, / = 6.9 Hz, 1H), 7.24-7.35 (m, 3H), 7.37 (br s, 3H), 7.48 (s, 1H), 8.27 (br s, 2H), 8.42 (br s, 2H), 12.33 (br s, 1H); ESI-MS (m/z) 336 (M+H) ⁺ .

Example 98

(+)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 48 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.03-3.08 (m, 1H), 3.35- 3.41 (m, 1H), 4.13 (t, / = 5.7 Hz, 1H), 7.20 (d, / = 6.3 Hz, 2H), 7.28-7.37 (m, 5H), 7.44 (s, 1H), 8.26 (br s, 4H), 12.50 (br s, 1H); APCI-MS (m/z) 336 (M+H) ⁺ .

Example 99

(25)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(3-fluorophenyl)pr opanamide

hydrochloride

The title compound was synthesized from Intermediate 116 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.06-3.13 (m, 1H), 3.39- 3.46 (m, 1H), 4.19 (t, / = 7.5 Hz, 1H), 6.97-7.08 (m, 3H), 7.25-7.32 (m, 1H), 7.37 (br s, 3H), 7.48 (s, 1H), 8.25 (br s, 2H), 8.40 (br s, 2H), 12.34 (br s, 1H); ESI-MS (m z) 320 (M+H) ⁺ .

Example 100

(+)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methylphenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 49 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.89 (s, 3H), 2.94-2.99 (m, 1H), 3.33-3.36 (m, 1H), 4.09 (t, / = 5.7 Hz, 1H), 7.03 (s, 4H), 7.38 (s, 4H), 8.26 (br s, 4H), 12.15 (s, 1H); ESI-MS (m/z) 316 (M+H) ⁺ .

Example 101

(+)-N-Carbamimidoyl-2,3-bis(4-chlorophenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 50 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.35- 3.40 (m, 1H), 4.10 (t, / = 6.0 Hz, 1H), 7.17 (d, / = 6.3 Hz, 2H), 7.28 (d, / = 6.3 Hz, 2H), 7.35-7.40 (m, 4H), 8.27 (br s, 4H), 12.15 (s, 1H); APCI-MS (m/z) 336 (M+H) ⁺ .

Example 102

(+) -N-Carbamimidoyl-2- (3 -chlorophenyl) - 3 - (4-fluorophenyl)propanamide

hydrochloride

The title compound was synthesized from Intermediate 51 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.01-3.10 (m, 1H), 3.38- 3.42 (m, 1H), 4.13 (t, / = 6.0 Hz, 1H), 7.08 (t, / = 6.6 Hz, 2H), 7.20-7.26 (m, 2H), 7.34-7.38 (m, 3H), 7.45 (s, 1H), 8.24 (br s, 2H), 8.34 (br s, 2H), 12.20 (s, 1H); APCI- MS (m/z) 320 (M+H) ⁺ .

Example 103

(±)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxyphenyl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 52 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.91-2.96 (m, 1H), 3.24- 3.30 (m, 1H), 3.67 (s, 3H), 4.04 (t, J = 5.7 Hz, 1H), 6.78 (d, / = 6.6 Hz, 2H), 7.06 (d, J = 6.6 Hz, 2H), 7.33-7.41 (m, 4H), 8.22 (br s, 4H), 11.70 (s, 1H); ESI-MS (m/z) 332 (M+H) ⁺ . Example 104

(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-fluorophenyl)pro anamide

hydrochloride

The title compound was synthesized from Intermediate 53 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.24- 3.37 (m, 1H), 4.11 (t, / = 5.7 Hz, 1H), 7.06 (t, / = 6.6 Hz, 2H), 7.18-7.21 (m, 2H), 7.37-7.42 (m, 4H), 8.30 (br s, 4H), 12.19 (s, 1H); ESI-MS (m/z) 320 (M+H) ⁺ .

Example 105

(2R)-N-Carbamimidoyl-2-(3-fluorophenyl)-3-(3-methylphenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 117 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.23 (s, 3H), 2.99-3.04 (m, 1H), 3.34-3.40 (m, 1H), 4.16 (t, / = 6.0 Hz, 1H), 6.96 (t, / = 5.4 Hz, 2H), 7.03 (s, 1H), 7.11-7.16 (m, 2H), 7.22-7.27 (m, 2H), 7.37-7.42 (m, 1H), 8.27 (br s, 2H), 8.34 (br s, 2H), 12.25 (s, 1H); APCI-MS (m/z) 300 (M+H) ⁺ .

Example 106

(2R)-N-Carbamimidoyl-2, -bis(3-fluorophenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 118 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.07-3.13 (m, 1H), 3.40- 3.46 (m, 1H), 4.19 (t, / = 5.7 Hz, 1H), 6.98-7.07 (m, 3H), 7.11-7.16 (m, 1H), 7.21- 7.31 (m, 3H), 7.36-7.42 (m, 1H), 8.25 (br s, 2H), 8.35 (br s, 2H), 12.22 (s, 1H); APCI- MS (m/z) 304 (M+H) ⁺ .

Example 107

(25 ^, )-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl )propanamide hydrochloride

The title compound was synthesized from Intermediate 119 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.92-3.00 (m, 1H), 3.28-3.41 (m, 1H), 4.10 (t, / = 8.1 Hz, 1H), 6.92-6.99 (m, 3H), 7.09-7.21 (m, 3H), 7.36-7.43 (m, 2H), 8.23 (br s, 4H), 11.96 (br s, 1H); APCI-MS (m/z) 300 (M+H) ⁺ .

Example 108

(+)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 54 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.21 (s, 3H), 2.94-2.99 (m, 1H), 3.33-3.38 (m, 1H), 4.11 (t, / = 5.7 Hz, 1H), 7.02 (d, / = 6.0 Hz, 2H), 7.04 (d, / = 6.3 Hz, 2H), 7.15 (t, / = 6.6 Hz, 2H), 7.41-7.44 (m, 2H), 8.33 (br s, 4H), 12.42 (s, 1H); APCI-MS (m/z) 300 (M+H) ⁺ .

Example 109

(2 _l S')-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphen yl)propanamide hydrochloride

The title compound was synthesized from Intermediate 120 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 2.93-3.00 (m, 1H), 3.32-3.36 (m, 1H), 4.09 (t, J = 7.8 Hz, 1H), 7.04 (s, 4H), 7.17 (t, / = 8.7 Hz, 2H), 7.39-7.44 (m, 2H), 8.27 (br s, 4H), 12.15 (br s, 1H); APCI-MS (m/z) 300 (M+H) ⁺ .

Example 110

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 121 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.05-3.10 (m, 1H), 3.36- 3.42 (m, 1H), 4.16 (t, J = 6.6 Hz, 1H), 7.10-7.16 (m, 2H), 7.18-7.26 (m, 4H), 7.28 (br s, 1H), 7.35-7.41 (m, 1H), 8.26 (br s, 4H), 12.05 (s, 1H); ESI-MS (m/z) 320 (M+H) ⁺ .

Example 111

(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-fluorophenyl)propanamide

hydrochloride

The title compound was synthesized from Intermediate 55 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.99-3.05 (m, 1H), 3.34- 3.40 (m, 1H), 4.09 (t, / = 6.0 Hz, 1H), 7.14-7.18 (m, 4H), 7.28 (d, / = 6.3 Hz, 2H), 7.36-7.40 (m, 2H), 8.24 (br s, 4H), 12.01 (s, 1H); APCI-MS (m/z) 320 (M+H) ⁺ .

Example 112

(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)pr opanamide

hydrochloride

The title compound was synthesized from Intermediate 122 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.04-3.08 (m, 1H), 3.33- 3.36 (m, 1H), 4.10 (t, / = 7.5 Hz, 1H), 7.16-7.20 (m, 4H), 7.29 (d, / = 6.9 Hz, 2H), 7.39-7.44 (m, 2H), 8.28 (br s, 4H), 12.15 (br s, 1H); APCI-MS (m/z) 320 (M+H) ⁺ .

Example 113

(+)-N-Carbamimidoyl-2,3-bis(4-fluorophenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 56 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.99-3.05 (m, 1H), 3.39- 3.47 (m, 1H), 4.09 (t, / = 5.7 Hz, 1H), 7.06 (t, / = 6.6 Hz, 2H), 7.16-7.21 (m, 4H), 7.38-7.42 (m, 2H), 8.26 (br s, 4H), 12.05 (s, 1H); ESI-MS (m/z) 304 (M+H) ⁺ .

Example 114

(25)-N-Carbamimidoyl-2,3-bis(4-fluorophenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 123 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.01 (s, 1H), 3.35 (br s, 1H), 4.09 (br s, 1H), 7.06 (br s, 2H), 7.18 (br s, 4H), 7.40 (br s, 2H), 8.29 (br s, 4H), 12.13 (br s, 1H); APCI-MS (m/z) 304 (M+H) ⁺ .

Example 115

(±)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 57 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.91-2.97 (m, 1H), 3.30- 3.36 (m, 1H), 3.67 (s, 3H), 4.07 (t, J = 5.7 Hz, 1H), 6.78 (d, / = 6.3 Hz, 2H), 7.07 (d, / = 6.6 Hz, 2H), 7.16 (t, / = 6.6 Hz, 2H), 7.39-7.45 (m, 2H), 8.27 (br s, 4H), 12.32 (s, 1H); APCI-MS (m/z) 316 (M+H) ⁺ .

Example 116

(+)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)pr opanamide hydrochloride

The title compound was synthesized from Intermediate 58 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.89 (s, 3H), 2.90-2.97 (m, 1H), 3.29-3.36 (m, 1H), 3.71 (s, 3H), 3.99 (t, / = 7.8 Hz, 1H), 6.88 (d, / = 8.4 Hz, 2H), 7.00-7.06 (m, 4H), 7.28 (d, / = 8.7 Hz, 2H), 8.28 (br s, 4H), 12.13 (s, 1H); APCI-MS (m/z) 312 (M+H) ⁺ .

Example 117

(±)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 59 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.99-3.04 (m, 1H), 3.37- 3.41 (m, 1H), 3.72 (s, 3H), 4.02 (t, / = 6.0 Hz, 1H), 6.89 (d, / = 6.6 Hz, 2H), 7.21 (d, / = 7.2 Hz, 2H), 7.29 (d, / = 6.3 Hz, 2H), 7.30 (d, / = 6.6 Hz, 2H), 8.31 (br s, 4H), 12.17 (s, 1H); ESI-MS (m/z) 332 (M+H) ⁺ .

Example 118

(±)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 60 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.96-3.01 (m, 1H), 3.31- 3.38 (m, 1H), 3.71 (s, 3H), 3.99 (t, / = 6.0 Hz, 1H), 6.88 (d, / = 6.3 Hz, 2H), 7.04 (t, / = 6.6 Hz, 2H), 7.16-7.20 (m, 2H), 7.28 (d, / = 6.6 Hz, 2H), 8.27 (br s, 4H), 12.09 (br s, 1H); APCI-MS (m/z) 316 (M+H) ⁺ .

Example 119

(±)-N-Carbamimidoyl-2,3-bis(4-methoxyphenyl)propanamide hydrochloride

The title compound was synthesized from Intermediate 61 and tert-b tyl [N-(tert- butoxycarbonyl)carbamimidoyl]carbamate followed by deprotection of boc group and HCl salt formation as described in general procedure (Method A). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.88-2.95 (m, 1H), 3.27 (br s, 1H), 3.68 (s, 3H), 3.72 (s, 3H), 3.97 (t, / = 7.8 Hz, 1H), 6.79 (d, / = 8.4 Hz, 2H), 6.89 (d, / = 8.4 Hz, 2H), 7.08 (d, / = 8.4 Hz, 2H), 7.30 (d, / = 8.4 Hz, 2H), 8.27 (br s, 4H), 12.05 (br s, 1H); APCI-MS (m/z) 328 (M+H) ⁺ .

Example 120

(±)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[4-(trifluoromethy l)phenyl]propanamide hydrochloride

O NH

A .HCl

N NH,

H The title compound was synthesized from Intermediate 62 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.22 (s, 3H), 3.00-3.06 (m, 1H), 3.36-3.42 (m, 1H), 4.22 (t, / = 6.0 Hz, 1H), 7.04 (d, / = 6.3 Hz, 2H), 7.07 (d, / = 6.3 Hz, 2H), 7.60 (d, / = 6.3 Hz, 2H), 7.72 (d, / = 6.0 Hz, 2H), 8.25 (br s, 4H), 12.10 (s, 1H); APCI-MS (m/z) 350 (M+H) ⁺ .

Example 121

(±)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-[4-(trifluoromethy l)phenyl]propanamide hydrochloride

The title compound was synthesized from Intermediate 63 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.07-3.12 (m, 1H), 3.39- 3.47 (m, 1H), 4.24 (t, / = 6.0 Hz, 1H), 7.21 (d, / = 6.3 Hz, 2H), 7.31 (d, / = 6.3 Hz, 2H), 7.59 (d, / = 6.0 Hz, 2H), 7.72 (d, / = 6.0 Hz, 2H), 8.26 (br s, 4H), 12.21 (s, 1H); ESI-MS (m z) 370 (M+H) ⁺ .

Example 122

(±)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[4-(trifluoromethy l)phenyl]propanamide hydrochloride

The title compound was synthesized from Intermediate 64 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.00-3.06 (m, 1H), 3.35- 3.40 (m, 1H), 4.10 (t, / = 6.0 Hz, 1H), 7.17 (d, / = 6.3 Hz, 2H), 7.28 (d, / = 6.3 Hz, 2H), 7.35-7.40 (m, 4H), 8.27 (br s, 4H), 12.15 (s, 1H); APCI-MS (m/z) 354 (M+H) ⁺ .

Example 123

(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethy l)phenyl]

propanamide hydrochloride

The title compound was synthesized from Intermediate 65 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.99-3.04 (m, 1H), 3.36- 3.41 (m, 1H), 3.69 (s, 3H), 4.21 (t, / = 6.0 Hz, 1H), 6.80 (d, / = 6.6 Hz, 2H), 7.10 (d, / = 6.3 Hz, 2H), 7.60 (d, / = 6.0 Hz, 2H), 7.72 (d, / = 6.0 Hz, 2H), 8.30 (br s, 4H), 12.25 (s, 1H); ESI-MS (m/z) 366 (M+H) ⁺ .

Example 124

(25)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethy l)phenyl]propanamide hydrochloride

The title compound was synthesized from Intermediate 124 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.32-3.36 (m, 1H), 3.46- 3.52 (m, 1H), 4.43 (br s, 1H), 7.02-7.08 (m, 2H), 7.17-7.28 (m, 2H), 7.47 (br s, 1H), 7.64-7.71 (m, 2H), 7.89 (d, / = 7.5 Hz, 1H), 8.27 (br s, 2H), 8.46 (br s, 2H), 11.77 (br s, 1H); ESI-MS (m/z) 354 (M+H) ⁺ .

Example 125

(25)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethy l)phenyl]propanamide hydrochloride

The title compound was synthesized from Intermediate 125 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.32-3.36 (m, 1H), 3.52- 3.58 (m, 1H), 4.47 (br s, 1H), 6.95 (t, / = 7.2 Hz, 1H), 7.02-7.11 (m, 2H), 7.22 (br s, 1H), 7.48 (t, / = 7.2 Hz, 1H), 7.65 (d, / = 7.2 Hz, 1H), 7.72 (t, / = 7.5 Hz, 1H), 7.94 (d, / = 8.4 Hz, 1H), 8.31 (br s, 2H), 8.35 (br s, 2H), 12.35 (br s, 1H); APCI-MS (m/z) 354 (M+H) ⁺ .

Example 126

(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trinuoromethyl )phenyl]propanamide hydrochloride

The title compound was synthesized from Intermediate 126 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.26-3.32 (m, 1H), 3.50- 3.57 (m, 1H), 4.46 (br s, 1H), 7.17-7.22 (m, 3H), 7.32 (s, 1H), 7.48 (t, / = 7.2 Hz, 1H), 7.65 (d, / = 9.0 Hz, 1H), 7.73 (t, / = 7.5 Hz, 1H), 7.94 (d, / = 7.8 Hz, 1H), 8.40 (br s, 4H), 12.21 (br s, 1H); APCI-MS (m/z) 370 (M+H) ⁺ .

Example 127

(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethy l)phenyl]

propanamide hydrochloride

The title compound was synthesized from Intermediate 127 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.07-3.15 (m, 1H), 3.35- 3.42 (m, 1H), 4.28 (t, / = 7.4 Hz, 1H), 7.12-7.17 (m, 1H), 7.24-7.31 (m, 3H), 7.58- 7.64 (m, 1H), 7.59-7.71 (m, 3H), 8.29 (br s, 4H), 12.14 (br s, 1H); APCI-MS (m/z) 370 (M+H) ⁺ .

Example 128

(2 _l S ^, )-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluorome thoxy)phenyl] propanamide hydrochloride The title compound was synthesized from Intermediate 128 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.16-3.22 (m, 1H), 3.47- 3.54 (m, 1H), 4.48 (t, J = 6.9 Hz, 1H), 7.15-7.21 (m, 3H), 7.31-7.44 (m, 4H), 7.56 (d, / = 7.8 Hz, 1H), 8.25 (br s, 2H), 8.45 (br s, 2H), 11.56 (br s, 1H); APCI-MS (m/z) 386

(M+H) ⁺ .

Example 129

(2 _l S')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoro methoxy)phi

propanamide hydrochloride

The title compound was synthesized from Intermediate 129 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, 1H), 3.37- 3.42 (m, 1H), 4.43 (br s, 1H), 7.11 (m, 1H), 7.21-7.25 (m, 4H), 7.41 (br s, 2H), 7.63 (m, 1H), 8.29 (br s, 4H), 11.94 (br s, 1H); ESI-MS (m/z) 386 (M+H) ⁺ .

Example 130

(2 _l S ^, )-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluorome thoxy)phenyl]

propanamide hydrochloride

The title compound was synthesized from Intermediate 130 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.11-3.16 (m, 1H), 3.37- 3.45 (m, 1H), 4.42 (t, / = 7.5 Hz, 1H), 7.04-7.12 (m, 2H), 7.23 (t, / = 7.5 Hz, 2H), 7.32-7.43 (m, 3H), 7.55 (d, / = 6.9 Hz, 1H), 8.26 (br s, 2H), 8.47 (br s, 2H), 11.73 (br s, 1H); APCI-MS (m/z) 370 (M+H) ⁺ .

Example 131

(2S) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethoxy )phenyl]

propanamide

The title compound was synthesized from Intermediate 131 and free guanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.09-3.15 (m, 1H), 3.36-3.41 (m, 1H), 4.43 (br s, 1H), 6.97- 7.02 (m, 3H), 7.26-7.32 (m, 2H), 7.40 (br s, 2H), 7.61 (br s, 1H), 8.29 (br s, 2H), 8.41 (br s, 2H); ESI-MS (m/z) 370 (M+H) ⁺ .

Example 132

(2S) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethoxy )phenyl]

propanamide hydrochloride

The treatment of compound of Example 131 with excess of hydrochloric acid in ethyl acetate yields the title compound as a hydrochloride salt. 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.09-3.15 (m, 1H), 3.36-3.41 (m, 1H), 4.43 (br s, 1H), 6.97-7.02 (m, 3H), 7.26-7.32 (m, 2H), 7.40 (br s, 2H), 7.61 (br s, 1H), 8.29 (br s, 2H), 8.41 (br s, 2H), 11.95 (br s, 1H); ESI-MS (m/z) 370 (M+H) ⁺ .

Example 133

(+)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethox y)phenyl]

propanamide hydrochloride

The title compound was synthesized from Intermediate 66 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.20 (s, 3H), 2.98-3.03 (m, 1H), 3.32-3.39 (m, 1H), 4.17 (t, / = 6.0 Hz, 1H), 7.02 (d, / = 6.3 Hz, 2H), 7.05 (d, / = 6.3 Hz, 2H), 7.27 (d, / = 6.0 Hz, 1H), 7.35 (s, 1H), 7.39 (d, / = 5.7 Hz, 1H), 7.46 (t, / = 5.7 Hz, 1H), 8.25 (br s, 2H), 8.34 (br s, 2H), 12.33 (s, 1H); APCI-MS (m/z) 366

(M+H) ⁺ . Example 134

(±)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[3-(trifluorometho xy)phi

propanamide hydrochloride

The title compound was synthesized from Intermediate 67 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.03-3.09 (m, 1H), 3.38- 3.43 (m, 1H), 4.17 (t, / = 6.0 Hz, 1H), 7.01-7.07 (m, 2H), 7.16-7.20 (m, 2H), 7.27 (d, / = 6.3 Hz, 1H), 7.33 (s, 1H), 7.38 (d, / = 6.0 Hz, 1H), 7.46 (t, / = 6.0 Hz, 1H), 8.25 (br s, 2H), 8.35 (br s, 2H), 12.33 (s, 1H); APCI-MS (m/z) 370 (M+H) ⁺ .

Example 135

(2R)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylpheny l)propanamide hydrochloride

The title compound was synthesized from Intermediate 132 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.28 (s, 3H), 3.01-3.08 (m, 1H), 3.33-3.39 (m, 1H), 4.51 (t, / = 5.7 Hz, 1H), 7.04 (d, / = 6.0 Hz, 2H), 7.09 (d, / = 6.0 Hz, 2H), 7.45 (d, / = 6.3 Hz, 1H), 7.54 (d, / = 6.3 Hz, 1H), 7.61 (s, 1H), 8.29 (br s, 2H), 8.44 (br s, 2H), 12.00 (s, 1H); APCI-MS (m/z) 350 (M+H) ⁺ .

Example 136

(2R)-N-Carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-fluoropheny l)propanamide hydrochloride

The title compound was synthesized from Intermediate 133 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, CDC1 ₃ ) δ 2.98-3.12 (m, IH), 3.34-3.39 (m, IH), 4.46 (t, / = 6.0 Hz, IH), 6.92-6.96 (m, 2H), 7.10-7.16 (m, 2H), 7.25-7.31 (m, IH), 7.34 (d, / = 6.3 Hz, IH), 7.37 (s, IH), 8.27 (br s, 2H), 8.38 (br s, 2H), 11.43 (br s, IH); ESI-MS (m/z) 354 (M+H) ⁺ .

Example 137

(±)-N-(N, N-Dimethylcarbamimidoyl)-2,3-diphenylpropanamide

The title compound was synthesized from Intermediate 1 and free 1,1- dimethylguanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.84-2.91 (m, 7H), 3.37- 3.42 (m, IH), 3.69 (t, J = 6.9 Hz, IH), 7.09-7.18 (m, 5H), 7.20-7.26 (m, 3H), 7.34 (d, / = 7.5 Hz, 2H), 8.21 (br s, 2H); APCI-MS (m z) 296 (M+H) ⁺ .

Example 138

(+)-N-(N,N-Dimethylcarbamimidoyl)-3-(4-methoxyphenyl)-2-phen ylpropanamide

The title compound was synthesized from Intermediate 15 and free 1,1- dimethylguanidine base using CDI as activating agent as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.91 (br s, 7H), 3.34 (m, IH), 3.67 (s, 4H), 6.74 (d, / = 7.8 Hz, 2H), 7.05 (d, / = 8.4 Hz, 2H), 7.16 (s, IH), 7.22 (t, / = 7.8 Hz, 2H), 7.32 (d, / = 6.3 Hz, 2H), 8.18 (br s, 2H); ESI-MS (m z) 326 (M+H) ⁺ .

Example 139

(+)-N-Carbamimidoyl-3-(lH-indol-3-yl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 159 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.08-3.13 (m, IH), 3.53- 3.59 (m, IH), 4.19 (t, / = 5.7 Hz, IH), 6.98 (t, / = 5.4 Hz, IH), 7.00 (s, IH), 7.06 (t, / = 5.1 Hz, 1H), 7.28-7.32 (m, 2H), 7.37 (t, / = 5.4 Hz, 2H), 7.43 (d, / = 6.0 Hz, 2H), 7.58 (d, / = 6.0 Hz, 1H),8.25 (br s, 4H), 10.85 (s, 1H), 11.95 (br s, 1H); ESI-MS (m/z) 307 (M+H) ⁺ .

Example 140

(±)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylprop anamide

hydrochloride

The title compound was synthesized from Intermediate 71 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.25 (s, 3H), 2.87-2.92 (m, 1H), 3.37-3.43 (m, 1H), 3.81-3.85 (m, 1H), 7.15-7.21 (m, 1H), 7.22-7.29 (m, 5H), 7.37 (d, / = 5.4 Hz, 2H), 7.46 (s, 1H), 7.56 (d, / = 5.4 Hz, 1H), 8.24 (d, / = 5.7 Hz, 1H); APCI-MS (m/z) 349 (M+H) ⁺ .

Example 141

(±)-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpropan amide hydrochloride

The title compound was synthesized from Intermediate 72 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.15 (s, 3H), 2.29-2.36 (m, 2H), 2.59-2.67 (m, 1H), 3.03-3.06 (m, 1H), 3.88-3.92 (m, 1H), 4.11-4.17 (m, 1H), 6.97-7.03 (m, 1H), 7.14-7.19 (m, 1H), 7.25-7.35 (m, 3H), 7.36-7.47 (m, 3H), 8.01 (d, / = 5.7 Hz, 1H), 8.29 (br s, 4H), 12.03 (br s, 1H); APCI-MS (m/z) 351 (M+H) ⁺ .

Example 142

(+)-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 160 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 2.85-2.90 (m, 1H), 3.30- 3.41 (m, 1H), 3.77 (t, / = 5.4 Hz, 1H), 6.26 (s, 1H), 6.87 (d, / = 6.0 Hz, 2H), 7.13- 7.20 (m, 1H), 7.21-7.26 (m, 4H), 7.32 (d, / = 5.4 Hz, 2H), 8.28 (br s, 4H), 7.77 (br s, 1H), 10.87 (br s, 1H); APCI-MS (m/z) 307 (M+H) ⁺ .

Example 143

(+)-N-Carbamimidoyl-3-( -indol-4-yl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 158 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.01-3.06 (m, 1H), 3.54- 3.60 (m, 1H), 3.89 (t, / = 6.3 Hz, 1H), 6.44 (s, 2H), 6.72 (d, / = 5.4 Hz, 1H), 6.88 (t, / = 5.7 Hz, 1H), 7.16 (t, / = 5.7 Hz, 2H), 7.21-7.27 (m, 3H), 7.33 (d, / = 5.4 Hz, 2H), 7.80 (br s, 4H), 10.99 (br s, 1H); ESI-MS (m z) 307 (M+H) ⁺ .

Example 144

(±)-N-(N-Acetylcarbamimidoyl)-2,3-diphenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 1 and 1 -acetyl guanidine using CDI as activating agent as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 2.00 (s, 3H), 2.84-2.90 (m, 1H), 3.30-3.36 (m, 1H), 3.90 (br s, 1H), 7.16-7.21 (m, 5H), 7.25-7.31 (m, 5H), 9.16 (br s, 1H), 9.54 (br s, 1H), 10.92 (br s, 1H); APCI-MS (m/z) 310 (M+H) ⁺ .

Example 145

(+)-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 68 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.13-3.19 (m, 1H), 3.45- 3.57 (m, 1H), 4.98 (d, / = 7.5 Hz, 1H), 7.14-7.7.20 (m, 2H), 7.22-7.29 (m, 4H), 7.53- 7.59 (m, 3H), 7.63-7.70 (m, 1H), 7.89 (d, / = 7.8 Hz, 1H), 7.96 (d, / = 7.8 Hz, 1H), 8.24 (d, / = 7.5 Hz, 2H), 8.31 (br s, 2H), 11.95 (br s, 1H); APCI-MS (m/z) 318 (M+H) ⁺ .

Example 146

(25)-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 134 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.12-3.17 (m, 1H), 3.48- 3.54 (m, 1H), 4.98 (br s, 1H), 7.17-7.26 (m, 5H), 7.55-7.63 (m, 4H), 7.88-7.94 (s, 2H), 8.25 (br s, 1H), 8.28 (br s, 4H), 11.90 (br s, 1H); APCI-MS (m/z) 318 (M+H) ⁺ .

Example 147

(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 135 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.20-3.25 (m, 1H), 3.60- 3.66 (m, 1H), 5.05 (br s, 1H), 7.16-7.25 (m, 3H), 7.37 (br s, 1H), 7.54 (br s, 3H), 7.63 (br s, 1H), 7.92 (br s, 2H), 8.24 (br s, 1H), 8.29 (br s, 4H), 11.86 (br s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 148

(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 136 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.15-3.18 (m, 1H), 3.49- 3.53 (m, 1H), 5.01 (br s, 1H), 7.21 (br s, 3H), 7.34 (br s, 1H), 7.54-7.63 (m, 5H), 7.90- 7.96 (m, 2H), 8.24 (br s, 2H), 8.35 (br s, 2H), 11.88 (br s, 1H); ESI-MS (m/z) 352 (M+H) ⁺ .

Example 149

(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 137 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (30 0 MHz, OMSO-d ₆ ) δ 3.15-3.22 (m, 1H), 3.49- 3.57 (m, 1H), 4.97 (t, / = 7.8 Hz, 1H), 7.28 (br s, 4H), 7.50-7.57 (m, 3H), 7.63 (d, / = 6.3 Hz, 1H), 7.89 (d, / = 7.8 Hz, 1H), 7.95 (d, / = 7.5 Hz, 1H), 8.24 (d, / = 8.7 Hz, 1H), 8.25 (br s, 2H), 8.39 (br s, 2H), 12.04 (br s, 1H); ESI-MS (m/z) 352 (M+H) ⁺ .

Example 150

(2 _l S ^, )-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-y l)propanamide hydrochloride

The title compound was synthesized from Intermediate 138 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.18-3.23 (m, 1H), 3.51- 3.59 (m, 1H), 5.01 (t, / = 7.8 Hz, 1H), 6.99 (t, / = 6.3 Hz, 1H), 7.07-7.14 (m, 2H), 7.21-7.27 (m, 1H), 7.53-7.64 (m, 4H), 7.90 (d, / = 7.8 Hz, 1H), 7.95 (d, / = 8.1 Hz, 1H), 8.23 (d, / = 7.8 Hz, 1H), 8.32 (br s, 4H), 11.90 (br s, 1H); APCI-MS (m/z) 337 (M+H) ⁺ .

Example 151

(+)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 69 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.13-3.20 (m, 1H), 3.48- 3.55 (m, 1H), 4.29 (d, / = 7.2 Hz, 1H), 7.16 (br s, 1H), 7.21 (br s, 4H), 7.48-7.53 (m, 2H), 7.57 (d, / = 8.1 Hz, 1H), 7.84-7.92 (m, 4H), 8.32 (br s, 4H), 12.25 (br s, 1H); ESI-MS (m/z) 318 (M+H) ⁺ .

Example 152

(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 139 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.21-3.26 (m, 1H), 3.55- 3.60 (m, 1H), 4.38 (t, J = 7.8 Hz, 1H), 7.17-7.23 (m, 3H), 7.40 (br s, 1H), 7.50-7.55 (m, 3H), 7.86-7.92 (m, 4H), 8.27 (br s, 4H), 12.03 (s, 1H); APCI-MS (m/z) 352

(M+H) ⁺ .

Example 153

(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)p ropanamide hydrochloride

The title compound was synthesized from Intermediate 140 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.18-3.23 (m, 1H), 3.46- 3.52 (m, 1H), 4.30 (t, / = 7.8 Hz, 1H), 7.13-7.18 (m, 1H), 7.22-7.27 (m, 2H), 7.33 (s, 1H), 7.52-7.57 (m, 3H), 7.86-7.93 (m, 4H), 8.27 (br s, 4H), 11.96 (s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 154 (25)-N-Carbarrdmidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl) propanamide hydrochloride

The title compound was synthesized from Intermediate 141 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.44-3.52 (m, 1H), 3.90- 3.97 (m, 1H), 4.31 (t, / = 7.2 Hz, 1H), 7.21 (d, / = 7.2 Hz, 1H), 7.31-7.37 (m, 4H), 7.43 (s, 1H), 7.50-7.60 (m, 2H), 7.76 (d, / = 7.8 Hz, 1H), 7.92 (d, / = 6.9 Hz, 1H), 8.19 (d, / = 8.1 Hz, 1H), 8.22 (br s, 2H), 8.42 (br s, 2H), 12.21 (br s, 1H); APCI-MS (m/z) 352 (M+H) ⁺ .

Example 155

(2R)-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 142 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.20-3.26 (m, 1H), 3.55- 3.62 (m, 1H), 4.25 (br s, 1H), 7.28-7.37 (m, 4H), 7.40-7.47 (m, 4H), 7.68 (s, 1H), 7.79-7.84 (m, 3H), 8.29 (br s, 4H), 12.18 (br s, 1H); APCI-MS (m/z) 318 (M+H) ⁺ .

Example 156

(2 _l S')-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropan amide hydrochloride

The title compound was synthesized from Intermediate 143 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.18-3.24 (m, 1H), 3.56- 3.60 (m, 1H), 4.25 (t, / = 7.5 Hz, 1H), 7.30-7.37 (m, 4H), 7.39-7.46 (m, 4H), 7.68 (s, 1H), 7.78-7.84 (m, 3H), 8.33 (br s, 4H), 12.28 (br s, 1H); ESI-MS (m/z) 318 (M+H) ⁺ .

Example 157 (2S)-N-Carbamimidoyl-2,3-di(naphthalen- 1 -yl)propanamide hydrochloride

The title compound was synthesized from Intermediate 144 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.53-3.59 (m, 1H), 4.04- 4.09 (m, 1H), 5.09 (br s, 1H), 7.21-7.29 (m, 2H), 7.43-7.56 (m, 5H), 7.72 (br s, 2H), 7.88-8.00 (m, 4H), 8.19 (d, / = 7.8 Hz, 1H), 8.28 (br s, 4H), 11.64 (br s, 1H); APCI- MS (m/z) 368 (M+H) ⁺ .

Example 158

(2 _l S ^, )-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2- yl)propanamide hydrochloride

The title compound was synthesized from Intermediate 145 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.32-3.39 (m, 1H), 3.68- 3.74 (m, 1H), 5.13 (br s, 1H), 7.47-7.54 (m, 4H), 7.57-7.62 (m, 3H), 7.68 (d, / = 6.9 Hz, 1H), 7.79-7.83 (m, 4H), 7.90 (d, / = 7.2 Hz, 1H), 7.96 (d, / = 7.8 Hz, 1H), 8.30 (br s, 4H), 11.85 (br s, 1H); APCI-MS (m/z) 368 (M+H) ⁺ .

Example 159

(2 _l S ^, )-N-Carbamimidoyl-3-(naphthalen-l-yl)-2-(naphthalen-2- yl)propanamide hydrochloride

The title compound was synthesized from Intermediate 146 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.59-3.62 (m, 1H), 4.00- 4.15 (m, 1H), 4.42 (br s, 1H), 7.20-7.29 (m, 3H), 7.51-7.57 (br s, 5H), 7.74 (d, / = 8.7 Hz, 1H), 7.84-7.90 (m, 5H), 8.24 (d, / = 7.8 Hz, 4H), 11.83 (br s, 1H); APCI-MS (m/z) 368 (M+H) ⁺ .

Example 160

(2S)-N-Carbairrimidoyl-2,3-di(naphthalen-2-yl)propanamide hydrochloride

The title compound was synthesized from Intermediate 147 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.36-3.42 (m, 1H), 3.64- 3.71 (m, 1H), 4.43 (t, / = 6.3 Hz, 1H), 7.39-7.45 (m, 3H), 7.49-7.52 (br s, 2H), 7.59 (t, / = 8.1 Hz, 1H), 7.72-7.81 (m, 4H), 7.84-7.93 (m, 4H), 8.26 (br s, 4H), 11.99 (br s, 1H); APCI-MS (m/z) 368 (M+H) ⁺ .

Example 161

(+)-N-Carbamimidoyl-2,3-diphenylbutanamide hydrochloride

The title compound was synthesized from Intermediate 152 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 0.92 (d, / = 5.4 Hz, 3H), 3.54-3.59 (m, 1H), 4.06 (d, / = 8.4 Hz, 1H), 7.21 (d, / = 5.4 Hz, 1H), 7.30-7.44 (m, 7H), 7.53 (d, / = 5.4 Hz, 2H), 8.11 (br s, 4H), 12.14 (s, 1H); APCI-MS (m/z) 282 (M+H) ⁺ .

Example 162 (2R,3R)-N-Carbamimidoyl-2,3-diphenylbutanamide hydrochloride

Step 1 : (2R,3R)-2,3-Diphenylbutanoic acid: To a well stirred solution of Intermediate 152 (500 mg, 2.083 mmol) in isopropyl alcohol (15 ml) was added R-(+)-l- phenylethylamine (0.13 ml, 1.041 mmol) and the reaction mixture was heated at 90 °C for 30 min followed by overnight stirring at room temperature. The precipitate obtained was filtered and washed (100 ml) with isopropyl alcohol. The precipitate was then dissolved in water and was acidified with dil. HCl followed by extraction with ethyl acetate (3 x 100 ml). The combined organic layer was dried and solvent was distilled under reduced pressure to yield 130 mg of the title compound as white solid.

Step 2: (2R,3R)-N-Carbamimidoyl-2,3-diphenylbutanamide hydrochloride:

The title compound was synthesized from step 1 intermediate and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 0.92 (d, / = 6.9 Hz, 3H), 3.54-3.59 (m, 1H), 4.08 (d, / = 10.5 Hz, 1H), 7.21-7.27 (m, 1H), 7.30-7.37 (m, 3H), 7.38-7.45 (m, 4H), 7.55 (d, / = 7.8 Hz, 2H), 8.15 (br s, 4H), 12.28 (br s, 1H); APCI- MS (m/z) 282 (M+H) ⁺ .

Example 163

(2 _l S ^, ,35 ^, )-N-Carbamimidoyl-2,3-diphenylbutanamide hydrochloride

The title compound was synthesized by resolution of Intermediate 152 using S(+)-l- phenylethylamine in isopropyl alcohol followed by coupling with free guanidine base using CDI followed by salt formation as described in Example 162. 1H NMR (300

MHz, OMSO-d ₆ ) δ 0.92 (d, / = 6.9 Hz, 3H), 3.52-3.60 (m, 1H), 4.08 (d, / = 11.1 Hz, 1H), 7.24 (t, J = 6.6 Hz, 1H), 7.30-7.35 (m, 3H), 7.38-7.45 (m, 4H), 7.55 (d, / = 8.1 Hz, 2H), 8.16 (br s, 4H), 12.30 (br s, 1H); APCI-MS (m/z) 282 (M+H) ⁺ .

Example 164

(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylbutanamide hydrochloride

The title compound was synthesized from Intermediate 153 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 0.87 (d, / = 6.9 Hz, 3H), 3.95-3.98 (m, 1H), 4.35 (d, / = 11.7 Hz, 1H), 7.25 (t, / = 6.3 Hz, 1H), 7.34-7.39 (m, 2H), 7.41-7.46 (m, 3H), 7.51-7.57 (m, 3H), 8.13 (br s, 4H), 12.43 (br s, 1H); APCI- MS (m/z) 316 (M+H) ⁺ . Example 165

(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylbutanamide hydrochloride

The title compound was synthesized from Intermediate 154 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 0.93 (d, / = 5.1 Hz, 3H), 3.60-3.66 (m, 1H), 4.11 (d, / = 8.7 Hz, 1H), 7.27-7.31 (m, 1H), 7.34-7.86 (m, 3H), 7.43 (t, / = 5.4 Hz, 2H), 7.48 (s, 1H), 7.54 (d, / = 5.4 Hz, 2H), 8.19 (br s, 4H), 12.30 (s, 1H); APCI-MS (m/z) 316 (M+H) ⁺ .

Example 166

(±)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylbutanamide hydrochloride

The title compound was synthesized from Intermediate 155 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 0.91 (d, / = 6.9 Hz, 3H), 3.76-3.82 (m, 1H), 4.21 (t, / = 11.4 Hz, 1H), 7.14-7.21 (m, 2H), 7.27-7.37 (m, 1H), 7.37-7.44 (m, 3H), 7.46-7.54 (m, 3H), 8.13 (br s, 4H), 12.28 (br s, 1H); ESI-MS (m z) 300 (M+H) ⁺ .

Example 167

(±)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide hydrochloride

The title compound was synthesized from Intermediate 156 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 0.98 (d, / = 6.6 Hz, 3H), 3.54-3.60 (m, 1H), 4.33 (t, / = 10.8 Hz, 1H), 7.23-7.32 (m, 5H), 7.35-7.43 (m, 3H), 7.70 (t, / = 7.8 Hz, 1H), 8.15 (br s, 2H), 8.29 (br s, 2H), 11.92 (br s, 1H); APCI-MS (m z) 300 (M+H) ⁺ .

Example 168 (+)-N-Carbarrdmidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbut anamide

hydrochloride

The title compound was synthesized from Intermediate 157 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 0.99 (d, / = 6.6 Hz, 3H), 3.51-3.58 (m, 1H), 4.30 (t, / = 11.1 Hz, 1H), 7.21-7.26 (m, 1H), 7.30-7.42 (m, 5H), 7.54 (d, J = 11.4 Hz, 1H), 7.71 (t, / = 8.4 Hz, 1H), 8.11 (br s, 2H), 8.26 (br s, 2H), 11.97 (br s, 1H); APCI-MS (m/z) 334 (M+H) ⁺ .

Example 169

(+)-N-Carbamimidoyl-2-fluoro-2,3-diphenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 161 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.49-3.59 (m, 1H), 3.77- 3.88 (m, 1H),7.19 (d, / = 5.4 Hz, 2H), 7.24-7.29 (m, 3H), 7.43-7.49 (m, 3H), 7.58 (d, / = 5.1 Hz, 2H), 8.36 (br s, 2H), 8.55 (br s, 2H), 11.48 (s, 1H); ESI-MS (m z) 286 (M+H) ⁺ .

Example 170

(±)-N-Carbamimidoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpr opanamide hydrochloride

The title compound was synthesized from Intermediate 162 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 3.41-3.50 (m, 1H), 3.71 (s, 3H), 3.75-3.83 (m, 1H), 6.83 (d, / = 6.6 Hz, 2H), 7.11 (d, / = 6.3 Hz, 2H), 7.43-7.48 (m, 3H), 7.58 (d, / = 5.1 Hz, 2H), 8.45 (br s, 2H), 8.62 (br s, 2H), 11.47 (s, 1H); ESI- MS (m/z) 316 (M+H) ⁺ .

Example 171

(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpro panamide hydrochloride

The title compound was synthesized from Intermediate 163 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (400 MHz, OMSO-d ₆ ) δ 1.47 (s, 3H), 3.18-3.23 (m, 1H), 3.40-3.45 (m, 1H), 3.69 (s, 3H), 6.72 (d, / = 6.6 Hz, 2H), 6.82 (d, / = 6.6 Hz, 2H), 7.28-7.35 (m, 3H), 7.38-7.42 (m, 2H), 8.44 (br s, 4H), 10.82 (s, 1H); ESI-MS (m/z) 312 (M+H) ⁺ .

Example 172

(25)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 148 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.19-3.26 (m, 1H), 3.50- 3.55 (m, 1H), 4.29 (t, / = 7.8 Hz, 1H), 7.21-7.27 (m, 3H), 7.33-7.38 (m, 1H), 7.40- 7.50 (m, 5H), 7.57-7.65 (m, 4H), 8.28 (br s, 4H), 12.09 (br s, 1H); APCI-MS (m/z) 378 (M+H) ⁺ .

Example 173

(25)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)pro panamide

hydrochloride

The title compound was synthesized from Intermediate 149 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.18-3.24 (m, 1H), 3.48- 3.52 (m, 1H), 4.26 (t, / = 7.8 Hz, 1H), 7.24 (br s, 3H), 7.35-7.40 (m, 1H), 7.47 (br s, 5H), 7.65 (br s, 4H), 8.27 (br s, 4H), 12.02 (br s, 1H); APCI-MS (m/z) 378 (M+H) ⁺ .

Example 174

(25)-3-(Biphenyl-2-yl)-N-carbamimidoyl-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 150 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.01 (m, 1H), 3.28- 3.32 (m, 1H), 3.97 (t, J = 7.8 Hz, 1H), 7.03 (br s, 2H), 7.13 (d, / = 7.2 Hz, 1H), 7.23- 7.29 (m, 8H), 7.37-7.73 (m, 3H), 8.23 (br s, 4H), 12.15 (br s, 1H); APCI-MS (m/z) 344 (M+H) ⁺ .

Example 175

(25)-3-(Biphenyl-3-yl)- -carbamimidoyl-2-phenylpropanamide hydrochloride

The title compound was synthesized from Intermediate 151 and free guanidine base using CDI as activating agent followed by HCl salt formation as described in general procedure (Method C). 1H NMR (300 MHz, OMSO-d ₆ ) δ 3.08-3.14 (m, 1H), 3.48- 3.53 (m, 1H), 4.18 (br s, 1H), 7.19 (br s, 1H), 7.36 (br s, 5H), 7.43-7.52 (m, 6H), 7.57 (br s, 2H), 8.28 (br s, 4H), 12.16 (br s, 1H); APCI-MS (m/z) 344 (M+H) ⁺ .

Pharmacological Activity In-vitro TRPC6 inhibition assay of compounds of the invention:

The illustrative examples of the present invention are screened for TRPC6 antagonist activity according to a modified procedure described in Mukhopadhyay I. et al., J. Recept. Signal Transduct., 2011, 31, 350-358. The screening of the compounds can be carried out by other methods and procedures known to persons skilled in the art.

Screening for TRPC6 antagonist using the fluorescence calcium influx assay:

The inhibition of TRPC6 receptor activation was measured as inhibition of Hyp9 induced cellular influx of calcium ion. Test compounds were dissolved in 100% DMSO (Dimethyl sulfoxide) to prepare 10 mM stock and then diluted using Ca, Mg free PBS (Phosphate buffered saline) to get the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v/v). Human TRPC6 expressing HEK cells were grown in MEM medium (Minimum Essential Medium) with 10% FBS (Fetal bovine serum) and cultured under antibiotic pressure.

Cells were seeded 24 h prior to the assay in black- walled clear bottom 96- well plates so as to get ~ 50,000 cells per well at the time of experiment. On the day of the experiment, medium was removed and cells were loaded with calcium sensitive No Wash plus dye as instructed in the kit manual (HitHunter Calcium No Wash Plus Assay kit, DiscoverX, Fremont, CA, USA). The plate was covered and incubated at 37°C in 5% C0 ₂ (carbon dioxide) for 60 min followed by incubation at 25°C for 30 min. Cells were treated with the test compounds for 10 minutes followed by the addition of Hyp9 at a final concentration of 10 μΜ. Fluorescence readings were recorded using FLUOstar Omega plate reader (BMG Labtech, Offenburg, Germany) at an excitation wavelength of 485 nm and an emission wavelength of 520 nm.

Concentration response curves were plotted as a % of maximal response obtained in the absence of test antagonist. IC ₅₀ values can be calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 5. The percentage inhibition of the compounds of the present invention at concentrations of 1.0 μΜ and 10.0 μΜ is provided below in table 5.

The IC ₅₀ (nM) values of some the compounds are set forth in Table-5 wherein "A" refers to an IC ₅₀ value of less than 100 nM, "B" refers to IC ₅₀ value in range of 100.01 to 200 nM, "C" refers to an IC ₅₀ value in range of 200.01 to 500 nM and "D" refers to an IC ₅₀ value more than 500 nM.

Table 5