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WO2014016766A1 - Guanidine derivatives as trpc modulators - Google Patents

Guanidine derivatives as trpc modulators Download PDF

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Publication number
WO2014016766A1
WO2014016766A1 PCT/IB2013/056030 IB2013056030W WO2014016766A1 WO 2014016766 A1 WO2014016766 A1 WO 2014016766A1 IB 2013056030 W IB2013056030 W IB 2013056030W WO 2014016766 A1 WO2014016766 A1 WO 2014016766A1
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WO
WIPO (PCT)
Prior art keywords
carbamimidoyl
propanamide
phenylpropanamide
chlorophenyl
phenyl
Prior art date
Application number
PCT/IB2013/056030
Other languages
French (fr)
Inventor
V. S. Prasada Rao Lingam
Abraham Thomas
Dnyaneshwar Harishchandra DAHALE
Vijay Eknath RATHI
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
Original Assignee
Glenmark Pharmaceuticals S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals S.A. filed Critical Glenmark Pharmaceuticals S.A.
Publication of WO2014016766A1 publication Critical patent/WO2014016766A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • 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.
  • TRP Transient receptor potential
  • TRPC 'Canonical', short
  • TRPV vanilloid
  • TRPM long, melastatin
  • TRPP polycystins
  • TRPML mucolipins
  • TRP A ANKTM1, Ankyrin
  • TRPN WOMPC
  • TRPC3/6/7 TRPC3/6/7
  • TRPCl TRPC4
  • TRPC5 TRPCl/4/5
  • DAG diacylglycerol
  • 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.
  • PAR-1 Protease Activated Receptor-1
  • IL-IR Beskina O et al., Am. J Physiol Cell Physiol, 2007, 293, CI 103-1111
  • H 2 0 2 Graham S et al., J. Biol Chem., 2010, 285, 23466-23476.
  • bronchoconstrictors such as histamine Hi (Hofmann T
  • 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.
  • 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.
  • 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).
  • AHR airway hyperresponsiveness
  • 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
  • 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.
  • the present invention relates to a compound of formula (I)
  • 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 ;
  • 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.
  • 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).
  • R 1 is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R 1 is -(CH 2 ) n C(0)R b .
  • R b is Ci_ 8 alkyl (e.g. methyl), and 'n' is 0.
  • R 1 is hydrogen, methyl or -C(0)CH 3 .
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R is hydrogen or C 1-8 alkyl (e.g. methyl).
  • R 5 is hydrogen, halogen (e.g. fluorine) or Ci_ 8 alkyl (e.g. methyl).
  • R 5 is hydrogen, fluorine or methyl.
  • 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 .
  • 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.
  • 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 .
  • 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 .
  • R b is hydrogen
  • R c is Ci_ galkyl (e.g. methyl)
  • 'n' is 0.
  • each occurrence of R is independently selected from chlorine, fluorine, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl and - NHC(0)CH 3 .
  • the invention also provides a compound of formula (la), which is an embodiment of a compound of formula (I).
  • 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.
  • 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).
  • R is hydrogen or Ci_ 8 alkyl (e.g. methyl).
  • R 5 is hydrogen, halogen (e.g. fluorine) or Ci_ 8 alkyl (e.g. methyl).
  • R 5 is hydrogen, fluorine or methyl.
  • 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 .
  • R b is hydrogen
  • R c Ci_ 8 alkyl (e.g. methyl)
  • 'n' is 0.
  • 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 .
  • compounds of formula (I) in which 'p' is '0' to '5' .
  • 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 .
  • R b is hydrogen
  • R c Ci_ galkyl (e.g. methyl)
  • 'n' is 0.
  • each occurrence of R is independently selected from chlorine, fluorine, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl and - NHC(0)CH 3 .
  • 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).
  • 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 .
  • 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.
  • 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.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_galkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • 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,
  • 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.
  • heteroaryl 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.
  • 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,
  • bicyclic heteroaryl 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.
  • 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.
  • 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.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids 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, methylsulf
  • 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).
  • HPLC High Performance Liquid Chromatography
  • 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.
  • 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%.
  • racemic mixture refers to the guanidine derivatives of present invention comprising 30-70% of each of the two stereoisomers.
  • 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.
  • 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).
  • domestic animals e.g., household pets including cats and dogs
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein, a second therapeutic agent, and optionally a pharmaceutically- acceptable excipient.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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
  • 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.
  • an appropriate salt 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, benzenes
  • 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.
  • an appropriate base such as triethylamine, diisopropylmethylamine, or pyridine
  • an appropriate solvent such as, but not limited to, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, 1,2- dichloroethane.
  • 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.
  • 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.
  • an appropriate salt (10) such as, but not limited to, hydrochloride, sulfate, hemisulfate, hydrobromide, citrate, benzoate, benzenesulfonate and methanesulfonate.
  • compound of general formula (18) can be prepared as shown in scheme 5.
  • 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).
  • 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)).
  • 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).
  • 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)).
  • 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)).
  • 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.
  • 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.
  • 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).
  • 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 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.
  • 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 ⁇ , ⁇ -Carbonyldiimidazole
  • LDA Lithium diiospropylamide
  • PEA Phenylethylamine
  • NaHMDS Sodium hexamethyldisilazide
  • KHMDS Potassium hexamethyldisilazide
  • EtOH Ethanol
  • DCM Dichlorome thane
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ) ⁇ 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • (+)-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).
  • (+)-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).
  • (+)-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).

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Abstract

The present invention is directed to guanidine derivatives as inhibitors of transient receptor potential canonical channels (TRPC channels), in particular TRPC3 and/or TRPC6 and/or TRPC7 activity, more particularly TRPC6 activity. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders mediated by TRPC channels (Formula (I)).

Description

GUANIDINE DERIVATIVES AS TRPC MODULATORS
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 Ca2+ 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 Ca2+ 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 H202 (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, Th2 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)
Figure imgf000005_0001
(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;
R1 is selected from hydrogen, Ci_8alkyl and -(CH2)nC(0)Rb;
R is selected from hydrogen and Ci_8alkyl; R is selected from hydrogen and Ci_8alkyl; R4 is hydrogen;
R5 is selected from hydrogen, halogen and Ci_8alkyl; at each occurrence, R6 is independently selected from halogen, cyano, Ci_ galkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl, -(CH2)nC(0)Rb and - (CH2)nNRbC(0)Rc;
at each occurrence, R is independently selected from halogen, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl and -(CH2)nNRbC(0)Rc; at each occurrence, Rb and Rc are independently selected from hydrogen and Ci_8alkyl; 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), R1 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 R1 is hydrogen or Ci_8alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is hydrogen or methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -(CH2)nC(0)Rb. In this embodiment, Rb is Ci_8alkyl (e.g. methyl), and 'n' is 0.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -C(0)CH3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is hydrogen, methyl or -C(0)CH3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R is hydrogen or Ci_8alkyl (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 C1-8alkyl (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 R5 is hydrogen, halogen (e.g. fluorine) or Ci_8alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is hydrogen, fluorine or methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R6 is independently selected from halogen (e.g. fluorine or chlorine), cyano, C1-8alkyl (e.g. methyl, ethyl or isopropyl), Ci_ galkoxy (e.g. methoxy), haloCi-salkyl (e.g. trifluoromethyl), haloCi-salkoxy (e.g. difluoromethoxy, trifluoromethoxy), C6-i4aryl (e.g. phenyl), -(CH2)nC(0)Rb and - (CH2)nNRbC(0)Rc. In this embodiment Rb is independently selected from hydrogen and Ci_galkyl (e.g. methyl); Rc 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 R6 is independently selected from fluorine, chlorine, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, -C(0)CH3 and -NHC(0)CH3.
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,
Figure imgf000008_0001
(e.g. methoxy), haloCi_8alkyl (e.g. trifluoromethyl),
Figure imgf000008_0002
(e.g. trifluoromethoxy), C6-i4aryl (e.g. phenyl) and -(CH2)nNRbC(0)Rc. In this embodiment Rb is hydrogen; Rc 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)CH3.
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 IC50 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 R3, R4, R5, R6, R7, R8, R9, R10, R11, 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)
Figure imgf000009_0001
stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof,
wherein,
R3 is selected from hydrogen and Ci_8alkyl; R4 is hydrogen;
R5 is selected from hydrogen, halogen and C1-8alkyl; at each occurrence, R6 is independently selected from halogen, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl and -(CH2)nNRbC(0)Rc; at each occurrence, R is independently selected from halogen, cyano, Ci_ galk l, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl and -(CH2)nNRbC(0)Rc;
R 8 and R 9 are absent or together with the phenyl ring to which they are attached form naphthyl, benzodioxole or indolyl ring;
R10 and R11 are absent or together with the phenyl ring to which they are attached form naphthyl or benzodioxole ring; at each occurrence, Rb and Rc are independently selected from hydrogen and Ci_8alkyl; 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), R4 is hydrogen (according to another embodiment defined below), R5 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_8alkyl (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 R5 is hydrogen, halogen (e.g. fluorine) or Ci_8alkyl (e.g. methyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is hydrogen, fluorine or methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R6 is independently selected from halogen (e.g. chlorine or fluorine), cyano, Ci_8alkyl (e.g. methyl, ethyl or isopropyl), Ci_ galkoxy (e.g. methoxy), haloCi_8alkyl (e.g. trifluoromethyl), haloCi_8alkoxy (e.g. difluoromethoxy, trifluoromethoxy), C6-i4aryl (e.g. phenyl) and -(CH2)nNRbC(0)Rc. In this embodiment Rb is hydrogen; Rc is Ci_8alkyl (e.g. methyl), and 'n' is 0.
According to yet another embodiment, specifically provided are compounds of formula (I), in which each occurrence of R6 is independently selected from chlorine, fluorine, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, and -NHC(0)CH3. 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_8alkyl (e.g. methyl),
Figure imgf000011_0001
(e.g. methoxy), haloCi_galkyl (e.g. trifluoromethyl), haloCi_galkoxy (e.g. trifluoromethoxy), C6-i4aryl (e.g. phenyl) and -(CH2)nNRbC(0)Rc. In this embodiment Rb is hydrogen; Rc 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)CH3.
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 R10 and R11 are absent.
According to yet another embodiment, specifically provided compounds of formula (la), in which R10 and R11 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 R10 and R11 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 R10 and R11 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 IC50 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)propanamide;
(2R)-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide;
(2R)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide;
(2lS')-N-Carbamimidoyl-3-(3-methylphenyl)-2-phenylpropanamide;
(±)-N-Carbamimidoyl-2-phenyl-3-(4-methylphneyl)propanamide;
(2R)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide;
(2S)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide;
(±)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamide;
(2S)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-phenyl-3-[4-(propan-2-yl)phenyl]propanamide;
(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide; (25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-phenylpropanamide;
(25)-N-Carbaimimdoyl-3-(4-chlorophenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(2-fluorophenyl)-2-phenylpropanamide;
(25,)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(3-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(3-fluorophenyl)-2-phenylpropanamide;
(25,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(4-fluorophenyl)-2-phenylpropanamide;
(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2-phenylpropanamide ;
(25,)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(2-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(2-methoxyphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(2-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(3-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(3-methoxyphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(3-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]propanamide; (2R)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]propanamide; (2lS,)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]propanamide; (+)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide; (2R)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide; (2lS,)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide; (+)-N-Carbaimimdoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpropanaim (2R)-N-Carbaimimdoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpropanaim (25,)-N-Carbamimidoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpropanamide; (+)-N-Carbaimimdoyl-2-phenyl-3-(2-(trifluoromethoxy)phenyl)propanamide; (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)phenyl]propanamid
(+)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]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-phenylpropanamide;
(2R)-3-(4-Acetamidophenyl)-N-carbamimidoyl-2-phenylpropanamide;
(25)-3-(4-Acetamidophenyl)-N-carbaimimdoyl-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimmidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropanamide;
(2R) -N-Carbamimidoyl- 3 - (2, 3 -dimethoxyphenyl) -2-phenylpropanamide ;
(25)-N-Carbamimidoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide;
(±)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide;
(2R)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide;
(25)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide;
(±)-N-Carbamimidoyl-3-phenyl-2-(4-methylphenyl)propanamide; (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-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;
(2R)-N-Carbaimimdoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;
(2R)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]propanamide;
(2R) -N-Carbamimidoyl- 3 -phenyl-2- [4- (trifluoromethyl)phenyl] propanamide ;
(2lS,)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]propanamide;
(+)-N-Carbaimimdoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbaimmidoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamid
(+)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]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-phenylpropanamide;
(2R)-N-carbaimmidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanamide; (25)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanamide;
(+)-N-Carbaimmidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide;
(2R)-N-Carbaimmidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide;
(25)-N-Carbamimidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide;
(+)-2-(l,3-Benzodioxol-5-yl)-N-carbaimimdoyl-3-phenylpropanamide;
(2R)-2-(l,3-Benzodioxol-5-yl)-N-carbamiimdoyl-3-phenylpropanamide;
(25)-2-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-3-phenylpropanamide;
(+)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamide;
(2R)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamide;
(25)-2-(4-Acetamidophenyl)-N-carbaimimdoyl-3-phenylpropanamide;
(+)-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;
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methylphenyl)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-methylphenyl)propanaim
(2lS,)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-(4-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)propanamide;
(2lS')-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)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;
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-methylphenyl)propanamide; (+) -N-Carbaimimdoyl- 3 - (2-chlorophenyl) -2- ^
(2R)-N-Carbaimimdoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-2,3-bis(3-chlorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2,3-bis(3-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2,3-bis(3-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)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;
(2lS')-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2,3-bis(4-chlorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2,3-bis(4-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2,3-bis(4-chlorophenyl)propanamide;
(+)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide;
(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-methoxyphenyl)propanamide ;
(2R)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxyphenyl)propanamide;
(25)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxyphenyl)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;
(2lS')-N-Carbamimidoyl-2-(3-fluorophenyl)-3-(3-methylphenyl)propanamide;
(±)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanamide;
(2R)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanarriide;
(2lS')-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanamide;
(+)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide; (2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide;
(25)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide;
(2R)-N-Carbaimmidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide;
(25,)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide;
(+)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide;
(2R)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide;
(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-fluorophenyl)propanamide ;
(2R)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)propanamide;
(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)propanamide;
(+)-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)propanamide;
(2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)propanamide;
(25,)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)propanamide;
(2R)-N-Carbairnirndoyl-2-(4-memoxyphenyl)-3-(4-m
(2lS,)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)propanamide;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-methoxyphenyl)propanamide ;
(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)propanamide;
(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)propanamide;
(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)propanamide;
(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- (4-methoxyphenyl)propanamide ;
(2lS')-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)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-(trifluoromethyl)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(4-methylphenyl)-2-[4-(trifluoromethyl)phenyl]
propanamide; (+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- [4- (trifluoromethyl)phenyl] propanamid
(2R)-N-Carbaimimdoyl-3-(4-chlorophenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-[4-(trifluoromethyl)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-(trifluoromethyl)phenyl] propanamide;
(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(25)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)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-(trifluoromethyl)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-(trifluoromethyl)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (3 -chlorophenyl) -2- [2- (trifluoromethyl)phenyl] propanamid
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethyl)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethyl)phenyl] propanamide;
(+)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl] propanamide; (2R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (2-chlorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (3 -chlorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(+)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(25,)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(+)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2R) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(+)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide;
(25)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethoxy)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-methylphenyl)propanamide;
(2R)-N-carbarmmidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)propanamide;
(25 N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)propanamide;
(+)-N-Carbarmrmdoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophenyl)propanarmde;
(2R)-N-Carbarmmidoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophenyl)propanamide;
(2S)-N-Carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophenyl)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-phenylpropanamide;
(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-phenylpropanamide;
(2R)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide;
(2S)-3-(l -Acetyl- lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide;
(+)-3-(l-Acetylindolin-3-yl)-N-Carbarmrmdoyl-2-phenylpiOpanamide;
(2R)-3-(l-Acetylindolin-3-yl)-N-Carbarmrmdoyl-2-phenylpropanamide;
(25,)-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanamide;
(2R)-N-Carbarmrmdoyl-3-(lH-indol-6-yl)-2-phenylpiOpanamide;
(2lS')-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanamide;
(+)-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-phenylpropanamide;
(+)-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;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide;
(+) -N-Carbamimidoyl-2- (naphthalen- 1 -yl) - 3 -phenylpropanamide ;
(2R)-N-Carbarrdmidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamide
(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamide
(±)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamide
(±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide
(25)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide
(±)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide;
(2R)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamide
(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamide
(±)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl)propanamid(
(±)-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide;
(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)propanamide;
(2R)-N-Carbaimmidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)propanamide;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)propanamide;
(+)-N-Carbaimimdoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-yl)propanamide;
(2R)-N-Carbaimmidoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-yl)propanamide;
(2lS')-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-phenylbutanamide;
(25,35)-N-Carbaimmidoyl-3-(2-chlorophenyl)-2-phenylbutanamide;
(+)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylbutanamide;
(2R,3R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylbutanamide;
(25,35)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-phenylbutanamide;
(+)-N-Carbaimmidoyl-3-(2-fluorophenyl)-2-phenylbutanamide;
(2R,3R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2-phenylbutanamide ;
(25,35)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylbutanamide;
(+)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;
(2R,3R)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;
(25,35)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;
(+)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide;
(2R,3R)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide;
(25,35)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide;
(+)-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-phenylpropanamide;
(2R)-N-Carbamimidoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2lS,)-N-Carbamimidoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpropanamide;
(2lS,)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpropanamide;
(±)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide;
(2R)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide;
(25)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide;
(±)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide
(2R)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide
(25)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide;
(±)-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.
Figure imgf000025_0001
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_8alkyl), 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. C2-10 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. C2-10 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.
Figure imgf000027_0001
Representative examples of such groups are -OCH3 and -OC2H5. 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_8alkyl or Ci_8alkyloxyCi_8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3 and -CH2OC2H5. 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 -CH2OH, -C2H4OH and -CH(OH)C2H4OH. 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 C3_i2cycloalkyl, 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 C3_i2cycloalkylCi_8alkyl. 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 C3_8cycloalkenyl, 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 C3_8cycloalkenylCi_8alkyl. 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-i4aryl), 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. C6-i4aryloxy). 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. C6-i4arylCi_8alkyl, such as -CH2C6H5 and - C2H4C6H5. 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_8alkyl). 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_8alkyl). 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, -COORx, - C(0)Rx, -C(S)RX, -C(0)NRxRy, -C(0)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, - N(Rx)S02Ry, -NRxC(0)ORy, -NRxRy, -NRxC(0)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, - SONRxRy, -S02NRxRy, -ORx, -OC(0)NRyRz, -OC(0)ORy, -OC(0)Rx, -OC(0)NRxRy, -SRX, -SORx, -S02Rx and -ON02, wherein Rx, Ry and Rz 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, 20th 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:
Figure imgf000037_0001
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:
Figure imgf000038_0001
Compound of general formula (10) is prepared as described in scheme 3 (wherein R6, R7, 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:
Figure imgf000039_0001
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
Figure imgf000040_0001
(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
Figure imgf000040_0002
(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 R6, R7, 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 H202) 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
Figure imgf000041_0001
(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 R6, R7, 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
Figure imgf000042_0001
(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 R6, R7, 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 R5, R6, R7 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 H2SO4 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 R5 is
Figure imgf000043_0002
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
Figure imgf000043_0003
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; CDCI3: Deuterated chloroform; 1H NMR: Proton Nuclear Magnetic Resonance; DMF: N,N-dimethyl formamide; HC1: Hydrochloric acid; H2S04: Sulfuric acid; H202: 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; Na2S04: 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
Figure imgf000044_0001
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 Na2S04 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-d6) 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-d6) 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.
Figure imgf000045_0001
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-d6) 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;
CH3 1H NMR (400 MHz, OMSO-d6) 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).
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Intermediate Structure Chemical name and 1H NMR data No.
65. o +)-3- 4-Methoxyphenyl)-2- Γ4- (trifluoromethyl)phenyllpropanoic acid;
1H NMR (400 MHz, OMSO-d6) δ 2.90-
F3C 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-d6) 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-d6) δ 2.92-
Figure imgf000057_0001
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, CDC13) 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-d6) 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).
Figure imgf000058_0001
Intermediate 73
(2R)-2,3-Diphenylpropanoic acid
Figure imgf000058_0002
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, CDC13) 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-d6) 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
Figure imgf000059_0001
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 (Na2S04), 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: (4lS,)-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 (Na2S04), 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, CDC13) 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 (Na2S04), 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-d6) 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.
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
112. 2R -2- 2-ChloroDhenvl -3- 3- chlorophenvDpropanoic acid;
1H NMR (400 MHz, OMSO-d6) δ 2.98-
Figure imgf000067_0001
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-d6) 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-d6) 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-d6) 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-d6) 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-d6) 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).
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
135. CI 0 (25) -3 - (2-Chlorophenyl) -2- (naphthalen- 1 - yl) propanoic acid;
1H NMR (300 MHz, DMSO-d6) 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-d6) 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-d6) 3.08-3.15
Figure imgf000071_0001
(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-d6) 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-d6) 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).
Figure imgf000072_0001
Figure imgf000073_0001
= 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
Figure imgf000074_0001
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 (Na2S04). 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-d6) 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.
Figure imgf000074_0002
154. CH30 (+) - 3 - (3 -Chlorophenyl) -2-phenylbutanoic acid;
1H NMR (400 MHz, OMSO-d6) 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 CH3 0 (±) - 3 - (2-Fluorophenyl) -2-phenylbutanoic acid;
1H NMR (300 MHz, OMSO-d6) 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. H3c 0 (+)-2-(2-Fluorophenyl)-3-phenylbutanoic acid;
1H NMR (300 MHz, OMSO-d6) 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. H3c 0 (+ -2-(4-Chloro-2-fluoroDhenyl -3- phenylbutanoic acid;
1H NMR (300 MHz, OMSO-d6) 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
Figure imgf000075_0001
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-d6) 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-d6) 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-d6) 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.
Figure imgf000076_0001
160. o 3-(lH-indol-6-yl)-2-phenylpropanoic acid;
ΌΗ 1H NMR (400 MHz, OMSO-d6) 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
Figure imgf000077_0001
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-<i6) 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. H2SO4 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 (Na2S04), filtered and concentrated to yield 500 mg of the product as off-white solid. 1H NMR (400 MHz, CDC13) 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 (Na2S04), filtered and concentrated to yield 150 mg of the product as colorless liquid. 1H NMR (400 MHz, OMSO-d6) 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 (Na2S04), filtered and concentrated to yield 60 mg of the product as off-white solid. 1H NMR (400 MHz, DMSO-d6) 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
Figure imgf000078_0001
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-d6) 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
Figure imgf000078_0002
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-d6) 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. H2SO4 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 (Na2S04), filtered and concentrated to yield 900 g of the product as colorless liquid. 1H NMR (400 MHz, OMSO-d6) 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 (Na2S04), 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-d6) 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 (Na2S04), 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-d6) 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 Na2S04. 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 Na2S04 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 (Na2S04) 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 Na2S04 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
Figure imgf000082_0001
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-d6) 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
Figure imgf000082_0002
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-d6) 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
Figure imgf000082_0003
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-d6) 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
Figure imgf000083_0001
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-d6) 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
Figure imgf000083_0002
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-d6) 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
(2lS')-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide hydrochloride
Figure imgf000083_0003
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-d6) 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
Figure imgf000083_0004
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-d6) 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
Figure imgf000084_0001
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-d6) 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
(2lS')-N-Carbamimidoyl-3-( -methylphenyl)-2-phenylpropanamide hydrochloride
Figure imgf000084_0002
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-d6) 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
Figure imgf000084_0003
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-d6) 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
Figure imgf000085_0001
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-d6) 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
(2lS')-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide hydrochloride
Figure imgf000085_0002
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-d6) 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
Figure imgf000085_0003
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000086_0001
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-d6) 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]propanamide
hydrochloride
Figure imgf000086_0002
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-d6) 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
Figure imgf000086_0003
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-d6) 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
Figure imgf000087_0001
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-d6) 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
Figure imgf000087_0002
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-d6) 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
Figure imgf000087_0003
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-d6) 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
Figure imgf000088_0001
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-d6) 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
Figure imgf000088_0002
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-d6) 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
Figure imgf000088_0003
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-d6) 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
Figure imgf000089_0001
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-d6) 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
Figure imgf000089_0002
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-d6) 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
Figure imgf000089_0003
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-d6) 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
Figure imgf000089_0004
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-d6) 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
Figure imgf000090_0001
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-d6) 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
Figure imgf000090_0002
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-d6) 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
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide hydrogen sulphate
Figure imgf000090_0003
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- d6) 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
Figure imgf000091_0001
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-d6) 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
Figure imgf000091_0002
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamide hydrochloride
Figure imgf000091_0003
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-d6) 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
Figure imgf000092_0001
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanamide hydrochloride
Figure imgf000092_0002
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-d6) 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
Figure imgf000092_0003
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanamide hydrochloride
Figure imgf000092_0004
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-d6) 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
Figure imgf000093_0001
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-d6) 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
Figure imgf000093_0002
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-d6) 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
(2lS')-N-Carbamimidoyl-3-( -methoxyphenyl)-2-phenylpropanamide hydrochloride
Figure imgf000093_0003
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-d6) 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
Figure imgf000094_0001
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-d6) 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
Figure imgf000094_0002
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-d6) 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
(2lS')-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride
Figure imgf000094_0003
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-d6) 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]propanamide
hydrochloride
Figure imgf000095_0001
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-d6) 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]propanamide
hydrochloride
Figure imgf000095_0002
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000096_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000096_0002
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-d6) 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
Figure imgf000096_0003
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-d6) 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]propanamide hydrochloride
Figure imgf000097_0001
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-d6) 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
Figure imgf000097_0002
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-d6) 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
(2lS,)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]propanamide hydrochloride
Figure imgf000097_0003
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-d6) 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]propanamide hydrochloride
Figure imgf000098_0001
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-d6) 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
(2lS,)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamide hydrochloride
Figure imgf000098_0002
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-d6) 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
Figure imgf000098_0003
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-d6) 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
Figure imgf000098_0004
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-d6) 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
Figure imgf000099_0001
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000099_0002
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000099_0003
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-d6) 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
Figure imgf000100_0001
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-d6) 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-phenylpropanamide
hydrochloride
Figure imgf000100_0002
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide
hydrochloride
Figure imgf000100_0003
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-d6) 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
Figure imgf000101_0001
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide
hydrochloride
Figure imgf000101_0002
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000101_0003
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000102_0001
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-d6) 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
Figure imgf000102_0002
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-d6) 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
Figure imgf000102_0003
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-d6) 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
Figure imgf000103_0001
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-d6) 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
Figure imgf000103_0002
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-d6) 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
Figure imgf000103_0003
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-d6) 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
Figure imgf000104_0001
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-d6) 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
Figure imgf000104_0002
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-d6) 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
Figure imgf000104_0003
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-d6) 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
Figure imgf000105_0001
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-d6) 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
Figure imgf000105_0002
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-d6) 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
(2lS,)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanamide hydrochloride
Figure imgf000105_0003
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-d6) 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
Figure imgf000106_0001
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-d6) 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
Figure imgf000106_0002
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-d6) 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
Figure imgf000106_0003
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-d6) 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
(2lS,)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide hydrochloride
Figure imgf000107_0001
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-d6) 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]propanamide
hydrochloride
Figure imgf000107_0002
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-d6) 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]propanamide hydrochloride
Figure imgf000107_0003
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-d6) 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
Figure imgf000108_0001
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-d6) 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
Figure imgf000108_0002
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000108_0003
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000109_0001
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000109_0002
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000109_0003
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-d6) 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
Figure imgf000110_0001
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-d6) 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)propanamide
hydrochloride
Figure imgf000110_0002
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-d6) 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)propanamide
hydrochloride
Figure imgf000111_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000111_0002
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-d6) 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)propanamide hydrochloride
Figure imgf000111_0003
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-d6) 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)propanamide hydrochloride
Figure imgf000112_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000112_0002
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-d6) 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)propanamide
hydrochloride
Figure imgf000112_0003
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-d6) 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
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide hydrochloride
Figure imgf000113_0001
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-d6) 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
Figure imgf000113_0002
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-d6) 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)propanamide
hydrochloride
Figure imgf000114_0001
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-d6) 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)propanamide
hydrochloride
Figure imgf000114_0002
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-d6) 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)propanamide
hydrochloride
Figure imgf000114_0003
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-d6) 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
Figure imgf000115_0001
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-d6) 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
Figure imgf000115_0002
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-d6) 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)propanamide hydrochloride
Figure imgf000115_0003
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-d6) 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
Figure imgf000116_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000116_0002
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-d6) 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
Figure imgf000116_0003
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-d6) 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
Figure imgf000117_0001
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-d6) 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)propanamide
hydrochloride
Figure imgf000117_0002
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-d6) 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
(2lS')-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide hydrochloride
Figure imgf000117_0003
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-d6) 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)propanamide hydrochloride
Figure imgf000118_0001
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-d6) 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
Figure imgf000118_0002
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-d6) 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)propanamide
hydrochloride
Figure imgf000119_0001
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-d6) 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
Figure imgf000119_0002
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-d6) 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
Figure imgf000119_0003
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-d6) 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)propanamide hydrochloride
Figure imgf000120_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000120_0002
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-d6) 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)propanamide hydrochloride
Figure imgf000120_0003
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-d6) 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)propanamide hydrochloride
Figure imgf000121_0001
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-d6) 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
Figure imgf000121_0002
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-d6) 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-(trifluoromethyl)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-d6) 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-(trifluoromethyl)phenyl]propanamide hydrochloride
Figure imgf000122_0001
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-d6) 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-(trifluoromethyl)phenyl]propanamide hydrochloride
Figure imgf000122_0002
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-d6) 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-(trifluoromethyl)phenyl]
propanamide hydrochloride
Figure imgf000123_0001
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-d6) 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-(trifluoromethyl)phenyl]propanamide hydrochloride
Figure imgf000123_0002
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-d6) 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-(trifluoromethyl)phenyl]propanamide hydrochloride
Figure imgf000123_0003
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-d6) 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
Figure imgf000124_0001
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-d6) 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-(trifluoromethyl)phenyl]
propanamide hydrochloride
Figure imgf000124_0002
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide hydrochloride
Figure imgf000124_0003
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-d6) 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
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethoxy)phi
propanamide hydrochloride
Figure imgf000125_0001
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl]
propanamide hydrochloride
Figure imgf000125_0002
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-d6) 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
Figure imgf000126_0001
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-d6) 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
Figure imgf000126_0002
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-d6) 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-(trifluoromethoxy)phenyl]
propanamide hydrochloride
Figure imgf000126_0003
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-d6) 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-(trifluoromethoxy)phi
propanamide hydrochloride
Figure imgf000127_0001
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-d6) 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-methylphenyl)propanamide hydrochloride
Figure imgf000127_0002
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-d6) 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-fluorophenyl)propanamide hydrochloride
Figure imgf000127_0003
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, CDC13) 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
Figure imgf000128_0001
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-d6) 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-phenylpropanamide
Figure imgf000128_0002
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-d6) 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
Figure imgf000128_0003
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-d6) 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-phenylpropanamide
hydrochloride
Figure imgf000129_0001
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000129_0002
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-d6) 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
Figure imgf000129_0003
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-d6) 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
Figure imgf000130_0001
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-d6) 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
Figure imgf000130_0002
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-d6) 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
Figure imgf000130_0003
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-d6) 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
Figure imgf000131_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000131_0002
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-d6) 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)propanamide hydrochloride
Figure imgf000131_0003
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-d6) 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)propanamide hydrochloride
Figure imgf000132_0001
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide hydrochloride
Figure imgf000132_0002
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-d6) 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
Figure imgf000132_0003
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-d6) 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)propanamide hydrochloride
Figure imgf000133_0001
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-d6) 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)propanamide hydrochloride
Figure imgf000133_0002
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-d6) 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
Figure imgf000134_0001
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-d6) 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
Figure imgf000134_0002
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-d6) 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
(2lS')-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide hydrochloride
Figure imgf000134_0003
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-d6) 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
Figure imgf000135_0001
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-d6) 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
(2lS,)-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)propanamide hydrochloride
Figure imgf000135_0002
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-d6) 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
(2lS,)-N-Carbamimidoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-yl)propanamide hydrochloride
Figure imgf000135_0003
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-d6) 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
Figure imgf000136_0001
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-d6) 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
Figure imgf000136_0002
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-d6) 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
Figure imgf000136_0003
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-d6) 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
(2lS,,35,)-N-Carbamimidoyl-2,3-diphenylbutanamide hydrochloride
Figure imgf000137_0001
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-d6) 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
Figure imgf000137_0002
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-d6) 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
Figure imgf000138_0001
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-d6) 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
Figure imgf000138_0002
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-d6) 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
Figure imgf000138_0003
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-d6) 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-phenylbutanamide
hydrochloride
Figure imgf000139_0001
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-d6) 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
Figure imgf000139_0002
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000139_0003
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-d6) 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-phenylpropanamide hydrochloride
Figure imgf000140_0001
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-d6) 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)propanamide
hydrochloride
Figure imgf000140_0002
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-d6) 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)propanamide
hydrochloride
Figure imgf000141_0001
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-d6) 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
Figure imgf000141_0002
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-d6) 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
Figure imgf000141_0003
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-d6) 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% C02 (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. IC50 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 IC50 (nM) values of some the compounds are set forth in Table-5 wherein "A" refers to an IC50 value of less than 100 nM, "B" refers to IC50 value in range of 100.01 to 200 nM, "C" refers to an IC50 value in range of 200.01 to 500 nM and "D" refers to an IC50 value more than 500 nM.
Table 5
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of formula
Figure imgf000148_0001
(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;
R1 is selected from hydrogen, Ci_8alkyl and -(CH2)nC(0)Rb;
R is selected from hydrogen and Ci_8alkyl;
R3 is selected from hydrogen and Ci_8alkyl;
R4 is hydrogen;
R5 is selected from hydrogen, halogen and C1-8alkyl; at each occurrence, R6 is independently selected from halogen, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl, -(CH2)nC(0)Rb and - (CH2)nNRbC(0)Rc;
at each occurrence, R is independently selected from halogen, cyano, Ci_ galk l, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl and -(CH2)nNRbC(0)Rc; at each occurrence, Rb and Rc are independently selected from hydrogen and Ci_8alkyl; 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.
2. The compound according to claim 1, wherein R1 is hydrogen, methyl or -C(0)CH3.
3. The compound according to claim 1 or 2, wherein R is hydrogen or methyl.
4. The compound according to any one of claims 1 to 3, wherein R is hydrogen or methyl.
5. The compound according to any one of claims 1 to 4, wherein R5 is hydrogen, fluorine or methyl.
6. The compound according to any one of claims 1 to 5, wherein R6 is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, -C(0)CH3 or -NHC(0)CH3.
7. The compound according to any one of claims 1 to 6, wherein R is fluorine, chlorine, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl or - NHC(0)CH3.
8. The compound according to any one of claims 1 to 7, wherein 'p' is 0, 1 or 2.
9. The compound according to any one of claims 1 to 8, wherein 'q' is 0, 1 or 2.
10. A compound of the formula (la)
Figure imgf000149_0001
stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof,
wherein,
R is selected from hydrogen and Ci_8alkyl;
R4 is hydrogen;
R5 is selected from hydrogen, halogen and Ci_8alkyl;
at each occurrence, R6 is independently selected from halogen, cyano, Ci_ 8alkyl, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl and -(CH2)nNRbC(0)Rc; at each occurrence, R is independently selected from halogen, cyano, Ci_ galk l, Ci_8alkoxy, haloCi_8alkyl, haloCi_8alkoxy, C6-i4aryl and -(CH2)nNRbC(0)Rc;
R 8 and R 9 are absent or together with the phenyl ring to which they are attached form naphthyl, benzodioxole or indolyl ring;
R10 and R11 are absent or together with the phenyl ring to which they are attached form naphthyl or benzodioxole ring;
at each occurrence, Rb and Rc are independently selected from hydrogen and Ci_8alkyl;
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.
11. The compound according to claim 10, wherein R is hydrogen or methyl.
12. The compound according to claim 11 or 12, wherein R5 is hydrogen, fluorine or methyl.
13. The compound according to any one of claims 10 to 12, wherein R6 is chlorine, fluorine, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl or -NHC(0)CH3.
14. The compound according to any one of claims 10 to 13, wherein R is chlorine, fluorine, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl or - NHC(0)CH3.
15. The compound according to any one of claims 10 to 14, wherein R and R together with the phenyl ring to which they are attached form 1-naphthyl, 2-naphthyl, benzodioxol, 4-indolyl or 6-indolyl ring.
16. The compound according to claim 10 to 15, wherein R10 and R11 together with the phenyl ring to which they are attached form 1-naphthyl, 2-naphthyl or benzodioxol ring.
17. The compound according to any one of claims 10 to 16, wherein 'p' is 0, 1 or 2.
18. The compound according to any one of claims 10 to 17, wherein 'q' is 0, 1 or 2.
19. A compound selected from
(±)-N-Carbamimidoyl-2,3-diphenylpropanamide;
(2R)-N-Carbamimidoyl-2,3-diphenylpropanamide;
(2S)-N-Carbamimidoyl-2,3-diphenylpropanamide;
(±)-N-Carbamimidoyl-2-phenyl-3-(2-methylphenyl)propanamide;
(2R)-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide;
(2R)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide;
(2lS')-N-Carbamimidoyl-3-(3-methylphenyl)-2-phenylpropanamide;
(±)-N-Carbamimidoyl-2-phenyl-3-(4-methylphneyl)propanamide;
(2R)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide;
(2S)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide;
(±)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamide;
(2S)-N-Carbamimidoyl-3-(4-ethylphenyl)-2-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-isopropylphenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-phenyl-3-[4-(propan-2-yl)phenyl]propanamide;
(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide; (+)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(4-chlorophenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(2-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(2-fluorophenyl)-2-phenylpropanamide;
(2S)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(3-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(3-fluorophenyl)-2-phenylpropanamide;
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(4-fluorophenyl)-2-phenylpropanamide;
(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2-phenylpropanamide ;
(2S)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(2-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(2-methoxyphenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(2-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(3-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(3-methoxyphenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(3-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimmidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide;
(+) -N-Carbamimidoyl-2-phenyl- 3 - [3 - (trifluoromethyl)phenyl] propanamide ;
(2R)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]propanamide;
(2lS,)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]propanamide;
(+)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide;
(2lS,)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide;
(+)-N-Carbaimimdoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpropanaim
(2R)-N-Carbaimimdoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpropanaim
(2lS,)-N-Carbamimidoyl-3-[4-(difluoromethoxy)phenyl]-2-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-phenyl-3-(2-(trifluoromethoxy)phenyl)propanamide; (2R)-N-Carbaimimdoyl-2-phenyl-3-[2-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-2-phenyl-3-[2-(trifluoromethoxy)phenyl]propanamide
(+)-N-Carbairriirridoyl-2-phenyl-3-[3-(trffl^
(2R)-N-Carbaimimdoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]propanamide
(+)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamide
(+) -N-Carbamimidoyl- 3 - (3 -cy anophenyl) -2-phenylpropanamide ;
(2R)-N-Carbaimimdoyl-3-(3-cyanophenyl)-2-phenylpropanamide;
(2S)-N-Carbamimidoyl-3-(3-cyanophenyl)-2-phenylpropanamide;
(+) -N-Carbamimidoyl- 3 - (4-cy anophenyl) -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-phenylpropanamide;
(2R)-3-(4-Acetamidophenyl)-N-carbamimidoyl-2-phenylpropanamide;
(25)-3-(4-Acetamidophenyl)-N-carbamimidoyl-2-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide;
(2lS,)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide;
(2lS,)-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropanamide;
(2R) -N-Carbamimidoyl- 3 - (2, 3 -dimethoxyphenyl) -2-phenylpropanamide ;
(25)-N-Carbamimidoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide;
(25)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide;
(±)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide;
(2R)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide; (25)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide;
(+)-N-Carbaimmidoyl-3-phenyl-2-(4-methylphenyl)propanamide;
(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-Carbaimimdoyl-2-(2-chlorophenyl)-3-phenylpropanamide;
(25)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-phenylpropanamide;
(+)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-phenylpropanamide;
(2R)-N-Carbaimimdoyl-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;
(2S)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;
(2R)-N-Carbaimmidoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;
(25)-N-Carbamimidoyl-2-(3-methoxyphenyl)-3-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;
(2R)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;
(25)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide;
(+)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]propanamide;
(2R) -N-Carbamimidoyl- 3 -phenyl-2- [4- (trifluoromethyl)phenyl] propanamide ;
(2lS,)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]propanamide;
(+)-N-Carbaimimdoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamid
(+)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]propanamide;
(2R)-N-Carbaimimdoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]propanamid
(25)-N-Carbamimidoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]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-phenylpropanamide;
(2R)-N-carbaimmidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanamide;
(25)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanamide;
(+)-N-Carbaimimdoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide;
(2R)-N-Carbaimmidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide;
(25)-N-Carbamimidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide;
(+)-2-(l,3-Benzodioxol-5-yl)-N-carbaimimdoyl-3-phenylpropanamide;
(2R)-2-(l,3-Benzodioxol-5-yl)-N-carbamiimdoyl-3-phenylpropanamide;
(25)-2-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-3-phenylpropanamide;
(+)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamide;
(2R)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamide;
(25)-2-(4-Acetamidophenyl)-N-carbaimimdoyl-3-phenylpropanamide;
(+)-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;
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-3-(4-fluorophenyl)-2-(4-methylphenyl)propanamide;
(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- (4-methylphenyl)propanamide ;
(2lS,)-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-methylphenyl)propanaim
(2lS,)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-(4-methylphenyl)propanamide;
(+) -N-Carbaimimdoyl-2- (2-chlorophenyl) - 3 - (3 -m
(2R)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)propanamide;
(2lS')-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)propanamide;
(2R)-N-Carbaimmidoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)propanamide;
(25)-N-Carbamimidoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-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-Carbairriirridoyl-2-(3-chlorophenyl)-3-(4-m (2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-methylphenyl)propanamide;
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide;
(2R)-N-Carbaimmidoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide;
(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-2,3-bis(3-chlorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2,3-bis(3-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2,3-bis(3-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)propanamide;
(2R)-N-Carbaimmidoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)propanamide;
(25)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-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;
(2lS')-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2,3-bis(4-chlorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2,3-bis(4-chlorophenyl)propanamide;
(2lS')-N-Carbamimidoyl-2,3-bis(4-chlorophenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide;
(25)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide;
(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-methoxyphenyl)propanamide ;
(2R)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxyphenyl)propanamide;
(25)-N-Carbamimidoyl-2-(4-chlorophenyl)-3-(4-methoxyphenyl)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;
(2lS')-N-Carbamimidoyl-2-(3-fluorophenyl)-3-(3-methylphenyl)propanamide;
(±)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanamide;
(2R)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanarriide; (2lS,)-N-Carbamimidoyl-2,3-bis(3-fluorophenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide;
(25)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide;
(2R)-N-Carbaimmidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide;
(2lS,)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide;
(+)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide;
(2R)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide;
(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-fluorophenyl)propanamide ;
(2R)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)propanamide;
(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)propanamide;
(±)-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)propanamide;
(2R)-N-Carbaimimdoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)propanamide;
(2lS,)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)propanamide;
(+)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)propanamide;
(2R)-N-Carbaimimdoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)propanaim
(2lS,)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)propanamide;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-methoxyphenyl)propanamide ;
(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)propanamide;
(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-methoxyphenyl)propanamide;
(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)propanamide;
(2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- (4-methoxyphenyl)propanamide ;
(2lS')-N-Carbamimidoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)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-Carbaimimdoyl-3-(4-methylphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(2lS,)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- [4- (trifluoromethyl)phenyl] propanamid
(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(±)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[4-(trifluoromethyl)phenyl]propanamid (2R) -N-Carbamimidoyl- 3 - (4-fluorophenyl) -2- [4- (trifluoromethyl)phenyl] propanamide;
(25,)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(±)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide;
(25)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)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-(trifluoromethyl)phenyl] propanamide;
(±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethyl)phenyl]propanamid (2R) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethyl)phenyl] propanamide;
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethyl)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (3 -chlorophenyl) -2- [2- (trifluoromethyl)phenyl] propanamid
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethyl)phenyl] propanamide; (25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethyl)phenyl] propanamide;
(+)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl]propan
(2R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl] propanamide;
(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (2-chlorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(+) -N-Carbamimidoyl- 3 - (3 -chlorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2lS,)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(±)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2lS,)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(2R) -N-Carbamimidoyl- 3 - (3 -fluorophenyl) -2- [2- (trifluoromethoxy )phenyl] propanamide;
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide;
(±)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide; (2R)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide;
(25)-N-Carbaimmidoyl-3-(4-methylphenyl)-2 3-(trifluoi methoxy)phenyl] propanamide;
(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[3-(trifluorornethoxy)phenyl] propanamide;
(2R)-N-Carbamimidoyl-3-(4-fluoiOphenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide;
(2lS N-Carbamimidoyl-3-(4-fluorophenyl)-2-[3-(trifluoiOmethoxy)phenyl] propanamide;
(+)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)propanamide;
(2R)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)propanamide;
(25')-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)propanamide;
(±)-N-Carbarrdrrddoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophenyl)propananiid
(2R)-N-Carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophenyl)propanamide;
(2vS)-N-Carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-fluoiOphenyl)propanamide;
(±)-N-(N, N-Dimethylcarbamimidoyl)-2,3-diphenylpropanamide;
(2R)-N-(N, N-Dimethylcarbamimidoyl)-2,3-diphenylpropanamide;
(2S)-N-(N, N-DimethylcarbaiT iiTiidoyl)-2,3-diphenylpropanaiTiide;
(+)-N-(N,N-DimethylcarbamiiTiidoyl)-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-(N,N-Dimethylcarbarrdmidoyl)-3-(4-methoxyphenyl)-2-phenylpropanaiTiide;
(2lS N-(N,N-Dimethylcarbamimidoyl)-3-(4-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-( lH-indol-3-yl)-2-phenylpropanamide;
(2R)-N-Carbamimidoyl-3-(lH-indol-3-yl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(lH-indol-3-yl)-2-phenylpropanamide;
(+)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide;
(2R)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide;
(25 3-( l -Acetyl- lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide;
(+)-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpropanamide;
(2R)-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpropanamide;
(2lS')-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpropanamide;
(+)-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanaiTiide;
(2R)-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanaiT ide;
(25')-N-Carbamimidoyl-3-( lH-indol-6-yl)-2-phenylpropanamide; (+)-N-Carbaimimdoyl-3-(lH-indol-4-yl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(lH-indol-4-yl)-2-phenylpropanamide;
(2lS')-N-Carbamimidoyl-3-(lH-indol-4-yl)-2-phenylpropanamide;
(+)-N-(N-Acetylcarbaimmidoyl)-2,3-diphenylpropanamide;
(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;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide;
(+) -N-Carbamimidoyl-2- (naphthalen- 1 -yl) - 3 -phenylpropanamide ;
(2R)-N-Carbarrdmidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(±)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamid
(±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamid
(25)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide
(±)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide;
(2R)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide;
(2lS')-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide;
(±)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamid
(±)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamide;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamid
(2lS')-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamid
(±)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl)propanamide (2R)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(napto^
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl)propanamide;
(+)-N-Carbaimmidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-3-(naphthalen-2-yl)-2-phenylpropanamide;
(2lS')-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)propanamide;
(2R)-N-Carbaimmidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)propanamide;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)propanamide;
(+)-N-Carbaimimdoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-yl)propanamide;
(2R)-N-Carbaimmidoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-yl)propanamide;
(2lS')-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-Carbaimmidoyl-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-phenylbutanamide;
(25,35)-N-Carbaimmidoyl-3-(2-chlorophenyl)-2-phenylbutanamide;
(+)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylbutanamide;
(2R,3R)-N-Carbaimimdoyl-3-(3-chlorophenyl)-2-phenylbutanamide;
(25,35)-N-Carbaimmidoyl-3-(3-chlorophenyl)-2-phenylbutanamide;
(±)-N-Carbaimmidoyl-3-(2-fluorophenyl)-2-phenylbutanamide;
(2R,3R) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2-phenylbutanamide ;
(25,35)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylbutanamide;
(+)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;
(2R,3R)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;
(25,35)-N-Carbamimidoyl-2-(2-fluorophenyl)-3-phenylbutanamide;
(±)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide;
(2R,3R)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide; (25,35)-N-Carbaimmidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide;
(±)-N-Carbaimmidoyl-2-fluoro-2,3-diphenylpropanamide;
(2R)-N-Carbaimmidoyl-2-fluoro-2,3-diphenylpropanamide;
(25)-N-Carbamimidoyl-2-fluoro-2,3-diphenylpropanamide;
(+)-N-Carbaimimdoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2R)-N-Carbaimimdoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpropanamide;
(2lS,)-N-Carbamimidoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpropanamide;
(+)-N-Carbairriirridoyl-3-(4-methoxyphenyl)-2-meth^
(2R)-N-Carbaimimdoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpropanaimde;
(2lS,)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpropanamide;
(+)-2-(Biphenyl-3-yl)-N-carbaimmidoyl-3-(2-chlorophenyl)propanamide;
(2R)-2-(Biphenyl-3-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide;
(25)-2-(Biphenyl-3-yl)-N-carbamiimdoyl-3-(2-chlorophenyl)propanamide;
(+)-2-(Biphenyl-4-yl)-N-carbaimmidoyl-3-(2-chlorophenyl)propanamide
(2R)-2-(Biphenyl-4-yl)-N-carbamimidoyl-3-(2-chlorophenyl)propanamide
(25)-2-(Biphenyl-4-yl)-N-carbamiimdoyl-3-(2-chlorophenyl)propanamide;
(+)-3-(Biphenyl-2-yl)-N-carbaimmidoyl-2-phenylpropanamide;
(2R)-3-(Biphenyl-2-yl)-N-carbamimidoyl-2-phenylpropanamide;
(25)-3-(Biphenyl-2-yl)-N-carbamiimdoyl-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-carbamiimdoyl-2-phenylpropanamide;
or pharmaceutically acceptable salts thereof.
20. A compound selected from
(+)-N-Carbamimidoyl-2,3-diphenylpropanamide hydrochloride;
(2R)-N-Carbamimidoyl-2,3-diphenylpropanamide hydrochloride;
(2S)-N-Carbamimidoyl-2,3-diphenylpropanamide hydrochloride;
(+)-N-Carbamimidoyl-2-phenyl-3-(2-methylphenyl)propanamide hydrochloride; (2R)-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide hydrochloride; (2lS')-N-Carbamimidoyl-3-(2-methylphenyl)-2-phenylpropanamide hydrochloride; (+)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide hydrochloride; (2R)-N-Carbamimidoyl-2-phenyl-3-(3-methylphenyl)propanamide hydrochloride; (2lS')-N-Carbamimidoyl-3-(3-methylphenyl)-2-phenylpropanamide hydrochloride; (+)-N-Carbaimmidoyl-2-phenyl-3-(4-methylphneyl)propanamide hydrochloride; (2R)-N-Carbairdirddoyl-2-phenyl-3-(4-methylphenyl)propanamide hydrochloride; (2lS,)-N-Carbamimidoyl-2-phenyl-3-(4-methylphenyl)propanamide hydrochloride; (+)-N-Carbairdirddoyl-3-(4-ethylphenyl)-2-phenylpropanamide hydrochloride;
(+)-N-Carbairdmidoyl-3-(4-isopropylphenyl)-2-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-2-phenyl-3-[4-(propan-2-yl)phenyl]propanamide
hydrochloride;
(+)-N-Carbairdmidoyl-3-(2-chlorophenyl)-2-phenylpropanamide hydrochloride; (2R)-N-Carbairdirddoyl-3-(2-chlorophenyl)-2-phenylpropanamide hydrochloride; (2S)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-3-(3-chlorophenyl)-2-phenylpropanamide hydrochloride; (2R)-N-Carbairdirddoyl-3-(3-chlorophenyl)-2-phenylpropanamide hydrochloride; (2S)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-3-(4-chlorophenyl)-2-phenylpropanamide hydrochloride; (2R)-N-Carbairdirddoyl-3-(4-chlorophenyl)-2-phenylpropanamide hydrochloride; (2S)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide hydrogen sulphate; (2lS,)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-phenylpropanamide methane sulphate (±)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-phenylpropanarriide hydrochloride; (±)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-phenylpropanarriide hydrochloride; (±)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-phenylpropanarriide hydrochloride; (±)-N-Carbamimidoyl-3-(2-methoxyphenyl)-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-(3-methoxyphenyl)-2-phenylpropanamide hydrochloride; (2lS,)-N-Carbamimidoyl-3-(3-methoxyphenyl)-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride; (2R)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride; (2lS,)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride; (+)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethyl)phenyl]propanamide hydrochloride;
(+)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethyl)phenyl]propanamide hydrochloride; (+)-N-Carbairriirridoyl-3-[4-(difluorometh^
hydrochloride;
(+)-N-Carbairdirddoyl-2-phenyl-3-(2-(trifluoromethoxy)phenyl)propanamide hydrochloride;
(2R)-N-Carbairdirddoyl-2-phenyl-3-[2-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(2R)-N-Carbairdirddoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(25)-N-Carbamimidoyl-2-phenyl-3-[3-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(25)-N-Carbamimidoyl-2-phenyl-3-[4-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(+) -N-Carbamimidoyl- 3 - (3 -cy anophenyl) -2-phenylpropanamide hydrochloride ;
(+) -N-Carbamimidoyl- 3 - (4-cy anophenyl) -2-phenylpropanamide hydrochloride ;
(±)-3-(4-Acetamidophenyl)-N-carbamimidoyl-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide hydrochloride; (2R)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide hydrochloride; (2S)-N-Carbamimidoyl-3-(2,4-dichlorophenyl)-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide
hydrochloride;
(2lS,)-N-Carbamimidoyl-3-(4-chloro-2-fluorophenyl)-2-phenylpropanamide hydrochloride;
(±)-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide
hydrochloride;
(2lS,)-N-Carbamimidoyl-3-(4-chloro-3-fluorophenyl)-2-phenylpropanamide hydrochloride;
(±)-N-Carbamimidoyl-3-(2,3-dimethoxyphenyl)-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-(3,4-dimethoxyphenyl)-2-phenylpropanamide hydrochloride; (±)-3-(l,3-Benzodioxol-5-yl)-N-carbamimidoyl-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-phenyl-2-(4-methylphenyl)propanamide hydrochloride; (2R)-N-Carbaimmidoyl-2-(4-methylphenyl)-3-phenylpropanamide hydrochloride; (2R)-N-Carbairdirddoyl-2-(2-chlorophenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-2-(3-chlorophenyl)-3-phenylpropanamide hydrochloride;
(2S)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-2-(4-chlorophenyl)-3-phenylpropanamide hydrochloride;
(2R)-N-Carbamiirddoyl-2-(4-chlorophenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdirddoyl-2-(4-fluorophenyl)-3-phenylpropanamide hydrochloride;
(2R)-N-Carbairdmidoyl-2-(4-fluorophenyl)-3-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-2-(4-fluorophenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-2-(3-methoxyphenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide hydrochloride; (2R)-N-Carbairdirddoyl-2-(4-methoxyphenyl)-3-phenylpropanamide hydrochloride; (2lS,)-N-Carbamimidoyl-2-(4-methoxyphenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdirddoyl-3-phenyl-2-[4-(trifluoromethyl)phenyl]propanamide hydrochloride;
(+)-N-Carbairdirddoyl-3-phenyl-2-[3-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(+)-N-Carbairdirddoyl-3-phenyl-2-[4-(trifluoromethoxy)phenyl]propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-(4-cyanophenyl)-3-phenylpropanamide hydrochloride;
(2R)-N-carbairdmidoyl-2-(2,4-dichlorophenyl)-3-phenylpropanamide hydrochloride; (+)-N-Carbairdmidoyl-2-(3,4-dimethoxyphenyl)-3-phenylpropanamide hydrochloride; (+)-2-(l,3-Benzodioxol-5-yl)-N-carbairdmidoyl-3-phenylpropanamide hydrochloride; (+)-2-(4-Acetamidophenyl)-N-carbamimidoyl-3-phenylpropanamide hydrochloride; (+)-N-Carbairdirddoyl-2,3-bis(4-methylphenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-3-(4-chlorophenyl)-2-(4-methylphenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-3-(4-fluorophenyl)-2-(4-methylphenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-3-(4-methoxyphenyl)-2-(4-methylphenyl)propanamide hydrochloride;
(2R)-N-Carbairdmidoyl-2-(2-chlorophenyl)-3-(3-methylphenyl)propanamide hydrochloride; (2R)-N-Carbaimmidoyl-2-(2-chlorophenyl)-3-(3-chlorophenyl)propanamide hydrochloride;
(2R)-N-Carbairdirddoyl-2-(2-chlorophenyl)-3-(3-fluorophenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-2-(3-chlorophenyl)-3-(4-methylphenyl)propanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(3-chlorophenyl)propanamide hydrochloride;
(25)-N-Carbamimidoyl-2,3-bis(3-chlorophenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)propanamide hydrochloride;
(2lS')-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(3-fluorophenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-2-(4-chlorophenyl)-3-(4-methylphenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2,3-bis(4-chlorophenyl)propanamide hydrochloride; (+)-N-Carbairdmidoyl-2-(3-chlorophenyl)-3-(4-fluorophenyl)propanamide hydrochloride;
(+) -N-Carbamimidoyl-2- (4-chlorophenyl) - 3 - (4-methoxyphenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-2-(4-chlorophenyl)-3-(4-fluorophenyl)propanamide hydrochloride;
(2R)-N-Carbairdmidoyl-2-(3-fluorophenyl)-3-(3-methylphenyl)propanamide hydrochloride;
(2R)-N-Carbairdmidoyl-2,3-bis(3-fluorophenyl)propanamide hydrochloride; (2lS')-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(3-methylphenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide hydrochloride;
(2lS')-N-Carbamimidoyl-2-(4-fluorophenyl)-3-(4-methylphenyl)propanamide hydrochloride;
(2R)-N-Carbairdirddoyl-3-(3-chlorophenyl)-2-(3-fluorophenyl)propanamide hydrochloride; (±)-N-Carbaimmidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)propanamide hydrochloride;
(2lS')-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(4-fluorophenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-2,3-bis(4-fluorophenyl)propanamide hydrochloride;
(2S)-N-Carbamimidoyl-2,3-bis(4-fluorophenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)propanamide hydrochloride;
(+)-N-Carbairdmidoyl-2-(4-methoxyphenyl)-3-(4-methylphenyl)propanamide hydrochloride;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- (4-methoxyphenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2,3-bis(4-methoxyphenyl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-3-(4-methylphenyl)-2-[4-(trifluoromethyl)phenyl]propanamide hydrochloride;
(+) -N-Carbamimidoyl- 3 - (4-chlorophenyl) -2- [4- (trifluoromethyl)phenyl] propanamide hydrochloride;
(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[4-(trifluoromethyl)phenyl]propanamide hydrochloride;
(+)-N-Carbamimidoyl-3-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl] propanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethyl)phenyl]propanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethyl)phenyl]propanamide hydrochloride;
(2lS,)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethyl)phenyl]propanamide hydrochloride;
(2R)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[3-(trifluoromethyl)phenyl]
propanamide hydrochloride;
(2lS')-N-Carbamimidoyl-3-(2-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide hydrochloride; (25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(2-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide hydrochloride;
(2lS,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-[2-(trifluoromethoxy)phenyl] propanamide hydrochloride;
(+)-N-Carbamimidoyl-3-(4-methylphenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide hydrochloride;
(+)-N-Carbamimidoyl-3-(4-fluorophenyl)-2-[3-(trifluoromethoxy)phenyl] propanamide hydrochloride;
(2R)-N-carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-methylphenyl)propanamide hydrochloride;
(2R)-N-Carbamimidoyl-2-(2,4-dichlorophenyl)-3-(4-fluorophenyl)propanamide hydrochloride;
(±)-N-Carbamimidoyl-3-(lH-indol-3-yl)-2-phenylpropanamide hydrochloride;
(±)-3-(l-Acetyl-lH-indol-3-yl)-N-carbamimidoyl-2-phenylpropanamide
hydrochloride;
(±)-3-(l-Acetylindolin-3-yl)-N-Carbamimidoyl-2-phenylpropanamide hydrochloride; (±)-N-Carbamimidoyl-3-(lH-indol-6-yl)-2-phenylpropanamide hydrochloride;
(±)-N-Carbamimidoyl-3-(lH-indol-4-yl)-2-phenylpropanamide hydrochloride;
(±)-N-(N-Acetylcarbamimidoyl)-2,3-diphenylpropanamide hydrochloride;
(±)-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide hydrochloride; (2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-phenylpropanamide hydrochloride; (25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-l-yl)propanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-l-yl)propanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(4-chlorophenyl)-2-(naphthalen-l-yl)propanamide hydrochloride;
(25,)-N-Carbamimidoyl-3-(3-fluorophenyl)-2-(naphthalen-l-yl)propanamide hydrochloride;
(±)-N-Carbamimidoyl-2-(naphthalen-2-yl)-3-phenylpropanamide hydrochloride;
(25)-N-Carbamimidoyl-3-(2-chlorophenyl)-2-(naphthalen-2-yl)propanamide hydrochloride; (25)-N-Carbamimidoyl-3-(3-chlorophenyl)-2-(naphthalen-2-yl)propanamide hydrochloride;
(25)-N-Carbamimidoyl-2-(3-chlorophenyl)-3-(naphthalen-l-yl)propanamide hydrochloride;
(2R)-N-Carbairdirddoyl-3-(naphthalen-2-yl)-2-phenylpropanamide hydrochloride; (2S)-N-Carbamimidoyl-3-(naphthalen-2-yl)-2-phenylpropanamide hydrochloride; (2S)-N-Carbamimidoyl-2,3-di(naphthalen- 1 -yl)propanamide hydrochloride;
(2lS')-N-Carbamimidoyl-2-(naphthalen-l-yl)-3-(naphthalen-2-yl)propanamide hydrochloride;
(2lS')-N-Carbamimidoyl-3-(naphthalen-l-yl)-2-(naphthalen-2-yl)propanamide hydrochloride;
(2S)-N-Carbamimidoyl-2,3-di(naphthalen-2-yl)propanamide hydrochloride;
(+)-N-Carbairdirddoyl-2,3-diphenylbutanamide hydrochloride;
(2R,3R)-N-Carbairdmidoyl-2,3-diphenylbutanamide hydrochloride;
(25,35)-N-Carbairdmidoyl-2,3-diphenylbutanamide hydrochloride;
(+)-N-Carbairdirddoyl-3-(2-chlorophenyl)-2-phenylbutanamide hydrochloride; (+)-N-Carbairdirddoyl-3-(3-chlorophenyl)-2-phenylbutanamide hydrochloride; (+) -N-Carbamimidoyl- 3 - (2-fluorophenyl) -2-phenylbutanamide hydrochloride ; (+)-N-Carbairdmidoyl-2-(2-fluorophenyl)-3-phenylbutanamide hydrochloride; (+)-N-Carbamimidoyl-2-(4-chloro-2-fluorophenyl)-3-phenylbutanamide hydrochloride;
(+)-N-Carbairdmidoyl-2-fluoro-2,3-diphenylpropanamide hydrochloride;
(+)-N-Carbairdirddoyl-2-fluoro-3-(4-methoxyphenyl)-2-phenylpropanamide hydrochloride;
(+)-N-Carbairdmidoyl-3-(4-methoxyphenyl)-2-methyl-2-phenylpropanamide hydrochloride;
(25)-2-(Biphenyl-3-yl)-N-carbamiirddoyl-3-(2-chlorophenyl)propanamide hydrochloride;
(25)-2-(Biphenyl-4-yl)-N-carbamiirddoyl-3-(2-chlorophenyl)propanamide hydrochloride;
(25)-3-(Biphenyl-2-yl)-N-carbamimidoyl-2-phenylpropanamide hydrochloride; and (2lS,)-3-(Biphenyl-3-yl)-N-carbamimidoyl-2-phenylpropanamide hydrochloride.
21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable excipient.
22. The pharmaceutical composition according to claim 21, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
23. A method of treating a TRPC6 mediated disease, disorder or syndrome in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 20.
24. A method according to claim 23, wherein disease, disorder, syndrome or condition is selected from the group consisting respiratory diseases, fibrotic diseases, skeletal muscle dysfunction, renal diseases, atherosclerosis; osteoarthritis, cardiovascular disorders, cancer, inflammatory disorders, pain, ischemic stroke or peripheral arterial occlusive disease.
25. The method according to claim 24, wherein the disease, disorder, syndrome or condition is selected from asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma, 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.
26. The method according to claim 24, wherein the disease, disorder, syndrome or condition is asthma.
27. The method according to claim 24, wherein the disease, disorder, syndrome or condition is chronic obstructive pulmonary disease (COPD).
28. The method according to claim 24, wherein the disease, disorder, syndrome or condition is inflammation.
29. The method according to claim 24, wherein the disease, disorder, syndrome or condition is pain.
PCT/IB2013/056030 2012-07-25 2013-07-23 Guanidine derivatives as trpc modulators WO2014016766A1 (en)

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