Patent Application: US-57458404-A

Abstract:
the invention relates to arylsulfonylamino based peptidomimetics of formula , wherein r1 , r2 , r3 , a , b , d , q , k and n are defined as disclosed , or a pharmaceutically acceptable salt or ester thereof . compounds of formula possess high affinity and selectivity for the somatostatin receptor subtypes sstr1 and / or sstr4 and can be used for the treatment or diagnosis of diseases or conditions wherein an interaction with sstr1 and / or sstr4 is indicated to be useful .

Description:
the invention relates to the use of compounds having general formula ( i ) and pharmaceutically acceptable salts and esters thereof for the preparation of a medicament for treating a disease or condition in mammals where an interaction with the somatostatin receptor subtypes 1 and / or 4 is indicated to be useful , wherein aryl and heteroaryl can be unsubstituted or substituted with 1 to 4 substituents selected from r a ; or b and b together can form a double or a triple bond between the atoms to which they are attached ; d is aryl or heteroaryl , which can be unsubstituted or substituted with one to four groups selected from r d ; wherein r b and r b together with the atoms to which they are attached can also form a 5 to 6 membered unsaturated or saturated ring ; or r2 and r2 together with the nitrogen to which they are attached form a 5 to 7 membered ring containing 1 to 3 heteroatoms selected from n , o and s , wherein the formed ring can be saturated or unsaturated ; wherein alkyl , alkenyl , alkynyl and cy are each optionally substituted with one to two substituents selected from r d ; wherein aryl and heteroaryl are each optionally substituted with one to two substituents selected from r d ; or r4 and r5 together with the atom to which they are attached form a 3 to 7 membered ring containing 0 to 2 heteroatoms selected from n , o and s , wherein the said ring can be substituted with one to three substituents selected from r d ; or the said ring can be fused to aryl or heteroaryl which can be substituted with one to three substituents selected from r d . wherein alkyl , alkenyl , alkynyl , aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from r c ; “ alkyl ”, as well as other groups having the prefix “ alk ”, such as alkoxy , alkanoyl , means carbon chains which may be linear or branched or combinations thereof . size of the alkyl can further be specified by adding the number of carbons in front of the group , e . g . ( c 1 - c 6 ) alkyl , ( c 1 - c 3 ) alkyl . examples of alkyl groups include methyl , ethyl , propyl , isopropyl , butyl , sec - butyl , tert - butyl , pentyl , neopentyl , hexyl , heptyl , octyl , nonyl , and the like . “ alkenyl ” means carbon chains which contain at least one carbon - carbon double bond , and which may be linear or branched or combinations thereof . size of the alkenyl can further be specified by adding the number of carbons in front of the group , e . g . ( c 2 - c 6 ) alkenyl , ( c 2 - c 8 ) alkenyl . examples of alkenyl groups include vinyl , allyl , isopropenyl , 1 - pentenyl , 2 - pentenyl , hexenyl , heptenyl , 1 - propenyl , 2 - butenyl , 2 - methyl - 2 - butenyl , and the like . “ alkynyl ” means carbon chains which contain at least one carbon - carbon triple bond , and which may be linear or branched or combinations thereof . size of the alkynyl can further be specified by adding the number of carbons in front of the group , e . g . ( c 2 - c 6 ) alkynyl , ( c 2 - c 8 ) alkynyl . examples of alkynyl groups include ethynyl , propargyl , 3 - methyl - 1 - pentynyl , 2 - heptenyl , and the like . “ cycloalkyl ” means mono - or bicyclic saturated carbocyclic rings , each of which having from 3 to 8 carbon atoms . the term also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non - aromatic portion . size of the cycloalkyl can further be specified by adding the number of carbons in front of the group , e . g . ( c 3 - c 7 ) cycloalkyl , ( c 5 - c 10 )- cycloalkyl . examples of cycloalkyl groups include cyclopropyl , cyclopentyl , cyclohexyl , cycloheptyl , tetrahydronaphthyl , decahydronaphthyl , indanyl , and the like . “ aryl ” means mono - or bicyclic aromatic rings containing only carbon atoms . the term also include aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion . size of the aryl can further be specified by adding the number of carbons in front of the group , e . g . ( c 6 - c 12 ) aryl . examples of aryl groups include phenyl , naphthyl , indanyl , indenyl , tetrahydronaphthyl , 2 , 3 - dihydrobenzofuranyl , benzopyranyl , 1 , 4 - benzodioxanyl , and the like . “ heteroaryl ” means a mono - or bicyclic aromatic ring containing at least one heteroatom selected from n , o and s , with each ring containing 5 to 6 atoms . the term also include heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion . examples of heteroaryl groups include pyrrolyl , isoxazolyl , isothiazolyl , pyrazolyl , pyridyl , oxazolyl , oxadiazolyl , thiadiazolyl , thiazolyl , imidazolyl , triazolyl , tetrazolyl , furanyl , triazinyl , thienyl , pyrimidyl , pyridazinyl , pyrazinyl , benzoxazolyl , benzothiazolyl , benzimidazolyl , benzofuranyl , benzothiophenyl , furo ( 2 , 3b ) pyridyl , quinolyl , indolyl , isoquinolyl , and the like . “ heterocyclyl ” means mono - or bicyclic saturated rings containing at least one heteroatom selected from n , o , s , each of said ring having from 5 to 8 atoms in which the point of attachment may be carbon or nitrogen . the term also includes monocyclic heterocycle fused to an aryl or a heteroaryl group in which the point of attachment is on the non - aromatic portion . furthermore , the term also includes partially unsaturated monocyclic rings that are not aromatic , such as 2 - and 4 - pyridones attached through the nitrogen . other examples of heterocyclyl groups include pyrrolidinyl , piperidinyl , piperazinyl , imidazolinyl , 2 , 3 - dihydrofuro ( 2 , 3 - b ) pyridyl , benzoxazinyl , tetrahydroquinolinyl , tetrahydroisoquinolinyl , dihydroindonyl , and the like . the term “ cycloalkyl - alkyl ”, as employed herein , refers to a “ cycloalkyl ”, as defined above , appended to the parent molecular moiety through an alkyl group , as defined above . size of the cycloalkyl and the alkyl can further be specified by adding the number of carbons in front of the group , e . g . ( c 3 - c 7 ) cycloalkyl ( c 1 - c 6 ) alkyl , ( c 3 - c 5 ) cycloalkyl ( c 1 - c 2 ) alkyl . representative examples of cycloalkyl - alkyl include , but are not limited to , cyclohexylmethyl , 1 - cyclohexylethyl , 2 - cyclopentylethyl , and the like . the term “ aryl - alkyl ”, as employed herein , refers to a “ aryl ”, as defined above , appended to the parent molecular moiety through an ( c 1 - c 6 ) alkyl group , as defined above . size of the aryl or alkyl can further be specified by adding the number of carbons in front of the group , e . g . aryl -( c 1 - c 6 ) alkyl , ( c 6 - c 12 ) aryl -( c 1 - c 3 ) alkyl . representative examples of aryl - alkyl include , but are not limited to , 2 - naphthylmethyl , 1 -( 2 - indanyl ) ethyl , 2 - tetrahydronaphthylethyl , and the like . the term “ heteroaryl - alkyl ”, as employed herein , refers to a “ heteroaryl ”, as defined above , appended to the parent molecular moiety through an alkyl group , as defined above . size of the alkyl can further be specified by adding the number of carbons in front of the group , e . g . heteroaryl -( c 1 - c 6 ) alkyl , heteroaryl -( c 1 - c 2 ) alkyl . representative examples of heteroaryl - alkyl include , but are not limited to , 2 -( 2 - pyridyl ) propyl , 2 - benzothiophenylmethyl , 4 -( 2 - quinolyl ) butyl , and the like . the term “ cy - alkyl ”, as employed herein , refers to a “ cy ”, as defined above , appended to the parent molecular moiety through an alkyl group , as defined above . size of the alkyl can further be specified by adding the number of carbons in front of the group , e . g . cy -( c 1 - c 6 ) alkyl , cy -( c 1 - c 3 ) alkyl . representative examples of cy - alkyl include , but are not limited to , benzyl , 1 -( 2 - naphthyl ) ethyl , 2 - cyclohexylethyl , and the like . the term “ halogen ”, as employed herein , refers to chlorine , bromine , fluorine or iodine . the compounds of formula i , as well as the pharmaceutically acceptable salts and esters thereof , are referred to below as the compounds of the invention , unless otherwise indicated . the invention includes within its scope all the possible stereoisomers of the compounds , including geometric isomers , e . g . z and e isomers ( cis and trans isomers ), and optical isomers , e . g . diastereomers and enantiomers . furthermore , the invention includes in its scope both the individual isomers and any mixtures thereof , e . g . racemic mixtures . the individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods . for the separation of optical isomers , e . g . enantiomers , from the mixture thereof the conventional resolution methods , e . g . fractional crystallisation , may be used . some of the compounds of the invention may also exist as tautomers , namely having different points of attachment of hydrogen . for instance , ketones can exist also in their enol form ( keto - enol tautomerism ). the individual tautomers as well as mixtures thereof are encompassed with compounds of invention . pharmaceutically acceptable salts , e . g . acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals . non - limiting examples of these salts include chlorides , bromides , sulfates , nitrates , phosphates , sulfonates , formates , tartrates , maleates , citrates , benzoates , salicylates and ascorbates . pharmaceutically acceptable esters , when applicable , may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form . non - limiting examples of these esters include esters of aliphatic or aromatic alcohols , e . g . methyl , ethyl , propyl , isopropyl , butyl , isobutyl , sec - butyl and tert - butyl esters . the pharmaceutical compositions of the compounds of the invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients . formulations can for instance enable for oral , buccal , topical , intranasal , parenteral ( e . g . intravenous , intramuscular or subcutaneous ) or rectal administration or administration by inhalation or insufflation . compounds of the invention may also be formulated for sustained delivery . for oral administration , forms of suitable compositions include but are not limited to tablets , chewable tablets and capsules . these may be prepared by conventional means with pharmaceutically acceptable excipients , such as binding agents ( e . g . pregelatinized maize starch ), disintegrants ( e . g . potato starch ), fillers ( e . g . lactose ) or lubricants ( e . g . magnesium stearate ). tablets may be coated by methods well known in the art . for oral administration , possible liquid preparations include but are not limited to solutions , syrups or suspensions , or they may exist as dry powder for constitution with water or other suitable vehicle prior use . these liquid preparations may be prepared by conventional means with pharmaceutically acceptable agents , such as suspending agents , non - aqueous vehicles , preservatives and emulsifyiers . a possible dose of the active compounds of the invention for oral , parenteral , buccal or topical dose to the adult human is between 0 . 1 and 500 mg of the active compound per unit dose , which may administered , for instance , 1 to 4 times in a day . it is well recognized that the precise dose , the route of administration and the dosing interval can be determined by those skilled in the art . it is also well recognized that these variables depend on multiple factors including but not restricted to activity of the therapeutic compound , the formulation thereof , pharmacokinetic properties ( such as absorption , distribution , metabolism and excretion ) of the therapeutic compound , the nature and location of the target tissue or organ and the issues connected to the state of a disease or disorder in a patient in need of treatment . additionally , when the compounds of the invention are administered with additional pharmaceutically active ingredients , one or more pharmaceutical compositions may be used for the delivery of all the agents , which may be administered together , or at different times , as determined by those skilled in the art . the compounds of the current invention can be viewed as consisting of three different motifs : an ‘ aromatic part ’, a ‘ carboxylic acid ’ and a ‘ sulfonylamino ’ part . thus , the compounds of the invention are named as amides wherein the ‘ carboxylic acid ’ forms the parent structure that is amidated by the ‘ aromatic part ’ and further substituted by the ‘ sulfonylamino ’ and an additional basic function . naming is exemplified with the following structures : one preferred embodiment of the compounds of formula i are those wherein q is and r5 is — c ( o ) nh 2 . for this purpose r4 is preferably cy or cy -( c 1 - c 3 ) alkyl where cy is optionally substituted with one to three substituents selected from r d ; even more preferred cy is phenyl . preferred substitutients are selected from halogen , ( c 1 - c 3 ) alkyl and — o ( c 1 - c 3 ) alkyl . another preferred embodiment of the compounds of formula i are those wherein q is and r5 is — c ( o ) nh 2 . for this embodiment r4 is preferably benzyl where the benzylic carbon is substituted with an additional phenyl . another preferred embodiment of the compounds of formula i are those wherein q is and r5 is hydrogen or ( c 1 - c 3 ) alkyl and r4 is phenyl or benzyl , optionally substituted at positions 2 or 3 with one to two substituents selected from r d . more preferred substituents are selected from halogen and ( c 1 - c 3 ) alkyl . another preferred embodiment of the compounds of formula i are those where r1 is hydrogen or ( c 1 - c 3 ) alkyl and more preferably hydrogen . yet another preferred embodiment of the compounds of formula i are those where r2 is hydrogen , ( c 1 - c 3 ) alkyl , ( c 3 - c 5 ) cycloalkyl or — c (═ nh ) nh 2 . yet another preferred embodiment of the compounds of formula i are those where r3 is hydrogen or ( c 1 - c 6 ) alkyl . yet another preferred embodiment of the compounds of formula i are those where a is hydrogen . yet another preferred embodiment of the compounds of formula i are those where b is hydrogen . yet another preferred embodiment of the compounds of formula i are those where d is aryl , which is optionally substituted with one to three substituents selected from r d . in a more preferred embodiment d is naphthyl , which is optionally substituted with one to two groups selected from r d and preferred substitutions are selected from halogen , ( c 1 - c 6 ) alkyl , — nr b r b and — or b . even more preferred substitutions are halogen and ( c 1 - c 3 ) alkyl . yet another preferred embodiment of the compounds of formula i are those where n is an integer 1 or 2 . yet another preferred embodiment of the compounds of formula i are those where k is 0 . yet another preferred embodiment of the compounds of formula i are those where the absolute configuration of the carbon containing the group a substitution is s . in another aspect the invention provides novel compounds of formula ii , and pharmaceutically acceptable salts and esters thereof , wherein r1 , r3 , a , b and q are as defined above under formula i , and r2 is independently selected from or symbols r2 together with the nitrogen to which they are attached form a saturated 5 to 7 membered ring containing 1 to 2 heteroatoms selected from n , o and s ; and when q is a group of formula wherein aryl and heteroaryl are each optionally substituted with one to four substituents selected from r d ; or r4 and r5 together with the atom to which they are attached form a 3 to 8 membered ring containing 0 to 2 heteroatoms selected from n , o and s , wherein the said ring may be substituted with one to three substituents selected from r d ; or the said ring may be fused to aryl or heteroaryl which may be substituted with one to three substituents selected from r d . r b and r d are as defined above under formula i . r1 is h ; r2 is independently h or ( c 1 - c 6 ) alkyl ; r3 is h or ( c 1 - c 3 ) alkyl ; r4 is phenyl or benzyl optionally substituted by a group selected from r a as defined above under formula i ; r6 is independently selected from h , halogen , ( c 1 - c 6 ) alkyl or — cf 3 ; t is an integer 0 to 1 ; a is h ; b is h ; l is c ( r6 ), x is c ( r6 ); and r5 and n are as defined above under formula ii . yet another preferred embodiment of the compounds of formula ii are those where the carbon containing the group a has the absolute configuration s . compounds of the invention can be prepared using the following general synthetic schemes . it &# 39 ; s evident for a person skilled in the art that these general schemes can be further modified for example by using different protecting groups ( e . g . those described in t . w . greene and p . g . m . wuts , “ protective groups in organic synthesis ”, 2 nd ed . wiley , 1991 , new york , us ), or adding or removing steps in between or after the described steps , which enables additional synthetic modifications including , but not limited to , examples given . the rink resin was obtained from advanced chemtech , uk . amino acids were purchased from either from advanced chemtech , uk or novabiochem , switzerland unless otherwise specified . dic , hobt , acetic anhydride and piperidine were products of acros organics , belgium . dipea was from fluka a g , germany . all the other reagents or solvents were purchased from aldrich or merck , germany , if not otherwise specified . the reagents were used as such and solvents were purified and dried according the methods described in w . l . f . armareggo and d . d . perrin , “ purification of laboratory chemicals ”, 4 th ed . bufterworth - heinemann , 1996 , bath , great britain . molecular weight of the compound was determined with micromass micro triple quadrupole mass spectrometer . essential ms parameters were : cone voltage 30 v , capillary voltage 3 . 5 kv , low mass resolution on ms1 15 , high mass resolution on ms1 15 , ion energy on ms1 1 . 0 , source temperature 110 ° c ., desolvation temperature 250 ° c . and desolvation gas flow 700 i / h . samples were introduced by waters alliance 2695 hplc . flow rate of 0 . 3 ml / min was formed of 10 % water and 90 % meoh eluent ( containing 0 . 01 % hcooh ). sample volume of 10 μl was injected through a waters symmetry shield 2 . 1 × 10 mm c 18 precolumn . for lc - ms analysis the gradient started from 100 % water ( containing 0 . 01 % hcooh ) ( a ) which changed linearly in ten minutes to 100 % acn ( containing 0 . 01 % hcooh ) ( b ). in addition , a waters symmetry shield 2 . 1 × 50 mm c 18 column with a corresponding precolumn was flushed for two minutes with b . flow rate was 0 . 4 ml / min and 10 μl of sample was injected . some essential ms parameters were increased compared to standard ms analysis : desolvation temperature to 350 ° c . and desolvation gas flow to 900 i / h . uv chromatogram was recorded with waters 996 diode array detector . nmr spectra were recorded on bruker dmx 500 spectrometer operating at 500 . 13 mhz for 1 h . cd 3 od was used as the solvent and tms as internal standard . flash chromatographic purification were conducted with argonaut flashmaster ii automated purification system ( argonaut technologies , uk ) using normal phase columns ( supelco dsc - si 20 g ). flow rate was 7 ml / min and detection wavelength 230 nm . standard elution program was 25 minutes with the following gradient : 100 % dcm for 3 minutes followed by gradual increase up to 25 % meoh during 17 minutes and a gradual increase up to 100 % of meoh during the final 5 minutes . after ms verification , fractions containing the product were combined and evaporated . semi - preparative rp - hplc purifications were done with waters 616 pump , controlled by waters 600 controller unit . instrument was equipped with waters 2487 uv detector and waters fraction collector . xterra prep c 18 rp 10 × 150 mm column with 7 . 8 × 20 mm precolumn was used for purifications . flow rate was 6 . 6 ml / min and the detection wavelength 254 nm . gradient started with water ( containing 0 . 3 % hcooh ) ( a ) which changed linearly to acn ( containing 0 . 3 % hcooh ) ( b ) within ten minutes . in addition column was flushed with b for two minutes . fraction collector was programmed to collect 30 s fractions . the fractions were analysed by ms . hplc purity of the compounds was determined using waters 616 pump , controlled by waters 600 controller unit . instrument was further equipped with waters 2487 uv detector ( detection wavelengths 254 nm and 220 nm ). waters symmetry shield 2 . 1 × 50 mm c 18 column with corresponding precolumn and a flow rate of 0 . 4 ml / min was used . linear gradient starting from water ( containing 0 . 01 % hcooh ) ( a ) to acetonitrile ( containing 0 . 01 % hcooh ) ( b ) over 17 minutes and then 100 % b for 1 minute was applied . fmoc - orn ( boc )- oh ( 70 . 0 mg , 454 . 52 g / mol , 0 . 15 mmol , 1 eq ), dic ( 24 . 1 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 15 mmol , 1 eq ) and hobt ( 20 . 8 mg , 135 . 12 g / mol , 0 . 15 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 5 ml ). after 5 minutes 3 - chlorobenzylamine ( 18 . 8 μl , 141 . 60 g / mol , 1 . 159 g / cm 3 , 0 . 15 mmol , 1 eq , acros ) was added to the reaction mixture . according to tlc analysis , reaction was complete after overnight stirring . solvent was then evaporated and the yellow residue was purified with flash chromatography . 5 -( n - boc - amino )- n ′-( 3 - chlorobenzyl )-( s )- 2 -( n ″- fmoc - amino ) pentanamide as white foam was obtained with quantitative yield . fmoc protection was removed by dissolving the 5 -( n - boc - amino )- n ′-( 3 - chlorobenzyl )-( s )- 2 -( n ″- fmoc - amino ) pentanamide in 5 ml of 20 vol -% piperidine in dmf . after 30 minutes stirring , solvent and excess of piperidine were evaporated . product was used without purification for step iii . ( s )- 2 - amino - 5 -( n - boc - amino )- n ′-( 3 - chlorobenzyl ) pentanamide ( 0 . 15 mmol ) was dissolved in dmf ( 2 . 5 ml , dry ) and 1 - naphthalenesulfonyl chloride ( 45 . 4 mg , 226 . 68 g / mol , 0 . 2 mmol , 1 . 3 eq , acros ) in thf ( 2 . 5 ml , dry ) was added . tea ( 27 . 8 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 2 mmol , 1 . 3 eq , baker ) was then added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with flash chromatography to give 5 -( n - boc - amino )- n ′-( 3 - chlorobenzyl )-( s )- 2 -( n ″-( 1 - naphthalenesulfonyl ) amino ) pentanamide . 5 -( n - boc - amino )- n ′-( 3 - chlorobenzyl )-( s )- 2 -( n ″-( 1 - naphthalenesulfonyl ) amino ) pentanamide was dissolved in 25 % tfa in dcm ( 2 ml ) and mixture was stirred for 30 minutes . solvent evaporation gave 75 . 8 mg of 5 - amino - n -( 3 - chlorobenzyl )-( s )- 2 -( n ′-( 1 - naphthalenesulfonyl ) amino ) pentanamide as brown oil . part of the product was further purified with rp - hplc to give 11 . 5 mg of 5 - amino - n -( 3 - chlorobenzyl )-( s )- 2 -( n ′-( 1 - naphthalenesulfonyl ) amino ) pentanamide as a white powder , overall yield 13 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 70 ( m , 1h ), 8 . 21 ( m , 1h ), 8 . 13 ( d , 1h ), 8 . 01 ( m , 1h ), 7 . 66 - 7 . 60 ( m , 2h ), 7 . 53 ( m , 1h ), 7 . 24 - 7 . 17 ( m , 2h ), 7 . 02 ( m , 1h ), 6 . 84 ( m , 1h ), 3 . 87 ( d , 2h ), 3 . 80 ( m , 1h ), 2 . 82 ( m , 2h ), 1 . 76 - 1 . 57 ( m , 4h ). fmoc - orn ( boc )- oh ( 50 . 0 mg , 454 . 52 g / mol , 0 . 11 mmol , 1 eq ), dic ( 17 . 2 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 11 mmol , 1 eq ) and hobt ( 15 . 0 mg , 135 . 12 g / mol , 0 . 12 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 4 ml ). after 10 minutes aniline ( 10 . 0 μl , 93 . 13 g / mol , 1 . 022 g / cm 3 , 0 . 11 mmol , 1 eq , acros ) was added to the reaction mixture . after overnight stirring , temperature was raised to 40 ° c . and kept there for 2 hours . solvent was then evaporated and residue purified with flash chromatography . 5 -( n - boc - amino )-( s )- 2 -( n ′- fmoc - amino )- n ″-( phenyl ) pentanamide as white powder was obtained with quantitative yield . fmoc protection was removed by dissolving the 5 -( n - boc - amino )( s )- 2 -( n ′- fmoc - amino )- n ″-( phenyl ) pentanamide in 5 ml of 20 vol -% piperidine in dmf . after 45 minutes stirring , solvent and excess of piperidine were evaporated . product was used without purification for step iii . ( s )- 2 - amino - 5 -( n - boc - amino )- n ′-( phenyl ) pentanamide ( 0 . 11 mmol ) was dissolved in dmf ( 1 ml , dry ) and 4 - methyl - 1 - naphthalenesulfonyl chloride ( 26 . 5 mg , 240 . 71 g / mol , 0 . 11 mmol , 1 eq , maybridge ) in thf ( 1 ml , dry ) was added . finally , tea ( 15 . 3 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 11 mmol , 1 eq , baker ) was added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with flash chromatography to give 5 -( n - boc - amino )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- n ″-( phenyl ) pentanamide . 5 -( n - boc - amino )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- n ″-( phenyl ) pentanamide was dissolved in 30 % tfa in dcm ( 3 ml ) and mixture was stirred for 45 minutes . after solvent evaporation and flash chromatography 21 . 8 mg of 5 - amino -( s )- 2 -( n -( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- n ′-( phenyl ) pentanamide was obtained ; yield 48 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 73 ( m , 1h ), 8 . 15 ( d , 1h ), 7 . 99 ( m , 1h ), 7 . 75 - 7 . 60 ( m , 2h ), 7 . 32 ( m , 1h ), 7 . 15 - 7 . 09 ( m , 2h ), 7 . 00 ( m , 1h ), 6 . 80 ( m , 2h ), 3 . 79 ( m , 1h ), 2 . 92 ( m , 2h ), 2 . 50 ( d , 3h ), 1 . 90 - 1 . 60 ( m , 4h ). fmoc - orn ( boc )- oh ( 100 . 2 mg , 454 . 52 g / mol , 0 . 22 mmol , 1 eq ), dic ( 34 . 4 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 22 mmol , 1 eq ) and hobt ( 29 . 7 mg , 135 . 12 g / mol , 0 . 22 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 4 ml ). after 10 minutes ( r )- 1 -( 2 - naphthyl ) ethylamine ( 37 . 7 mg , 171 . 24 g / mol , 0 . 22 mmol , 1 eq , acros ) was added to the reaction mixture . after overnight stirring , temperature was raised to 40 ° c . and kept there for 2 hours . solvent was then evaporated and residue purified with flash chromatography . 5 -( n - boc - amino )( s )- 2 -( n ′- fmoc - amino )- n ″-(( r )- 1 -( 2 - naphthyl ) ethyl ) pentanamide was obtained with quantitative yield . fmoc protection was removed by dissolving the 5 -( n - boc - amino )( s )- 2 -( n ′- fmoc - amino )- n ″-(( r )- 1 -( 2 - naphthyl ) ethyl ) pentanamide in 5 ml of 20 vol -% piperidine in dmf . after 45 minutes stirring , solvent and excess of piperidine were evaporated . product was used without purification for step iii . ( s )- 2 - amino - 5 -( n - boc - amino )- n ′-(( r )- 1 -( 2 - naphthyl ) ethyl ) pentanamide ( 0 . 22 mmol ) was dissolved in dmf ( 1 ml , dry ) and 4 - methyl - 1 - naphthalenesulfonyl chloride ( 53 . 1 mg , 240 . 71 g / mol , 0 . 22 mmol , 1 eq , maybridge ) in thf ( 1 ml , dry ) was added . finally , tea ( 30 . 5 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 22 mmol , 1 eq , baker ) was added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with flash chromatography to give 5 -( n - boc - amino )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- n ″-(( r )- 1 -( 2 - naphthyl ) ethyl ) pentanamide . 5 -( n - boc - amino )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- n ″-(( r )- 1 -( 2 - naphthyl ) ethyl ) pentanamide was dissolved in 30 % tfa in dcm ( 3 ml ) and mixture was stirred for 45 minutes . after solvent evaporation and flash chromatography 11 . 4 mg of 5 - amino -( s )- 2 -( n -( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- n ′-(( r )- 1 -( 2 - naphthyl ) ethyl ) pentanamide was obtained ; overall yield 11 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 68 ( m , 1h ), 8 . 05 - 7 . 94 ( m , 2h ), 7 . 84 ( m , 1h ), 7 . 77 - 7 . 68 ( m , 2h ), 7 . 61 ( m , 2h ), 7 . 48 ( m , 3h ), 7 . 04 ( m , 2h ), 4 . 75 ( m , 1h ), 3 . 90 ( m , 1h ), 2 . 97 - 2 . 83 ( m , 2h ), 2 . 47 ( s , 3h ), 1 . 85 - 1 . 62 ( m , 4h ), 1 . 15 ( d , 3h ). compound was synthesised according the procedure described in example 3 but ( r )- 1 -( 2 - naphthyl ) ethylamine was substituted with 2 -( 3 - chlorophenyl ) ethylamine ( 30 . 6 μl , 155 . 63 g / mol , 1 . 119 g / cm 3 , 0 . 22 mmol , 1 eq ). final boc deprotection and subsequent flash chromatography gave 73 . 3 mg of 5 - amino - n -( 2 -( 3 - chlorophenyl ) ethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide ; yield 68 % 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 72 ( m , 1h ), 8 . 17 ( m , 1h ), 8 . 13 ( d , 1h ), 7 . 70 ( m , 2h ), 7 . 45 ( m , 1h ), 7 . 23 - 7 . 15 ( m , 2h ), 7 . 03 ( m , 1h ), 6 . 92 ( m , 1h ), 3 . 68 ( m , 1h ), 2 . 93 - 2 . 75 ( m , 4h ), 2 . 74 ( d , 3h ), 2 . 28 - 2 . 15 ( m , 2h ), 1 . 75 - 1 . 52 ( m , 4h ). compound was synthesised according the procedure described in example 3 but ( r )- 1 -( 2 - naphthyl ) ethylamine was substituted with 1 , 2 - diphenylethylamine ( 42 . 6 μl , 197 . 28 g / mol , 1 . 020 g / cm 3 , 0 . 22 mmol , 1 eq ). step i gave 118 . 1 mg of 5 -( n - boc - amino )- n ′-( 1 , 2 - diphenylethyl )-( s )- 2 -( n ″- fmoc - amino ) pentanamide ; yield 85 %. after final boc deprotection and subsequent flash chromatography , 27 . 1 mg of 5 - amino - n -( 1 , 2 - diphenylethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide was obtained ; yield 28 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 75 ( m , 1h ), 8 . 67 ( m , 1h ), 8 . 21 - 8 . 08 ( m , 3h ), 7 . 97 ( d , 1h ), 7 . 77 - 7 . 61 ( m , 4h ), 7 . 47 ( m , 2h ), 7 . 25 - 7 . 05 ( m , 12h ), 7 . 00 - 6 . 76 ( m , 8h ), 4 . 54 ( m , 2h ), 3 . 81 ( m , 2h ), 2 . 87 - 2 . 69 ( m , 8h ), 2 . 64 ( d , 3h ), 2 . 58 ( m , 1h ), 2 . 44 ( m , 1h ), 2 . 31 ( m , 1h ), 1 . 75 - 1 . 31 ( m , 8h ). compound was synthesised according the procedure described in example 3 but ( r )- 1 -( 2 - naphthyl ) ethylamine was substituted with 2 - ethoxybenzylamine ( 34 . 1 μl , 151 . 21 g / mol , 1 . 015 g / cm 3 , 0 . 23 mmol , 1 eq ). step i gave 5 -( n - boc - amino )- n ′- 2 - ethoxybenzyl -( s )- 2 -( n ″- fmoc - amino ) pentanamide with quantitative yield . after final boc deprotection and subsequent preparative tlc purification , 24 mg of 5 - amino - n - 2 - ethoxybenzyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide was obtained ; yield 23 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 71 ( m , 1h ), 8 . 17 ( m , 1h ), 8 . 11 ( d , 1h ), 7 . 67 ( m , 2h ), 7 . 40 ( m , 1h ), 7 . 17 ( m , 1h ), 6 . 84 ( d , 1h ), 6 . 80 - 6 . 73 ( m , 2h ), 3 . 98 ( m , 2h ), 3 . 89 ( m , 2h ), 3 . 80 ( m , 1h ), 2 . 85 - 2 . 72 ( m , 5h ), 1 . 70 ( m , 2h ), 1 . 60 ( m , 2h ), 1 . 35 ( t , 3h ). compound was synthesised according the procedure described in example 3 but in step i ( r )- 1 -( 2 - naphthyl ) ethylamine was substituted with cyclohexylamine ( 26 μl , 99 . 18 g / mol , 0 . 867 g / cm 3 , 0 . 23 mmol , 1 eq ) and fmoc - orn ( boc )- oh with fmoc - dbu ( boc )- oh ( 100 . 6 mg , 440 . 5 g / mol , 0 . 23 mmol , 1 eq ). step i gave 4 -( n - boc - amino )- n ′- cyclohexyl -( s )- 2 -( n ″- fmoc - amino ) butanamide with quantitative yield . after final boc deprotection and subsequent preparative tlc purification , 34 mg of 4 - amino - n - cyclohexyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide was obtained ; overall yield 37 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 71 ( m , 1h ), 8 . 20 ( m , 1h ), 8 . 14 ( d , 1h ), 7 . 72 ( m , 2h ), 7 . 46 ( m , 1h ), 3 . 81 ( m , 1h ), 3 . 04 ( m , 2h ), 2 . 94 ( m , 1h ), 2 . 77 ( d , 3h ), 1 . 99 ( m , 1h ), 1 . 86 ( m , 1h ), 1 . 49 ( m , 3h ), 1 . 37 ( m , 1h ), 1 . 17 - 0 . 94 ( m , 4h ), 0 . 58 ( m , 1h ), 0 . 45 ( m , 1h ). fmoc - dbu ( boc )- oh ( 100 mg , 440 . 5 g / mol , 0 . 23 mmol , 1 eq ), dic ( 36 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 23 mmol , 1 eq ) and hobt ( 31 mg , 135 . 12 g / mol , 0 . 23 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 3 ml ). after 5 minutes 1 - naphthylmethylamine ( 33 μl , 157 . 22 g / mol , 1 . 092 g / cm 3 , 0 . 23 mmol , 1 eq , fluka ) was added to the reaction mixture . after overnight stirring at 50 ° c ., solvent was evaporated and the residue was dissolved in 30 ml ethyl acetate and washed three times with 20 ml water . organic phase was dried with na 2 so 4 and evaporated . residue was purified with flash chromatography . 78 . 5 mg of 4 - n - boc - amino -( s )- 2 - n ′- fmoc - amino - n ″− 1 - naphthylmethylbutanamide was obtained , yield 60 %. 4 - n - boc - amino -( s )- 2 - n ′- fmoc - amino - n ″− 1 - naphthylmethylbutanamide was dissolved in 8 ml of 20 vol -% piperidine in dmf . after 45 minutes stirring , solvent and excess of piperidine were evaporated . residue was used without purification for step iii . ( s )- 2 - amino - 4 - n - boc - amino - n ′-( 1 - naphthylmethyl ) butanamide ( 50 . 0 mg , 357 . 46 g / mol , 0 . 14 mmol , 1 eq ) was dissolved in thf ( 4 ml , dry ) and both 4 - methyl - 1 - naphthalenesulfonyl chloride ( 49 mg , 240 . 71 g / mol , 0 . 20 mmol , 1 . 5 eq , maybridge ) in thf ( 4 ml , dry ) was added . tea ( 28 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 1 . 5 eq , baker ) was then added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with flash chromatography . 4 - n - boc - amino -( s )- 2 - n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino - n ″-( 1 - naphthylmethyl ) butanamide was dissolved in 25 % tfa in dcm ( 5 ml ) and mixture was stirred for 30 minutes . solvent evaporation and subsequent rp - hplc purification gave 26 mg of 4 - amino -( s )- 2 - n -( 4 - methyl - 1 - naphthalenesulfonyl ) amino - n ′-( 1 - naphthylmethyl ) butanamide as a white solid , yield 42 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 67 ( m , 1h ), 8 . 13 ( m , 1h ), 8 . 08 ( d , 1h ), 7 . 86 ( d , 1h ), 7 . 78 ( d , 1h ), 7 . 72 ( d , 1h ), 7 . 63 ( m , 2h ), 7 . 48 ( m , 1h ), 7 . 42 ( m , 1h ), 7 . 32 ( m , 2h ), 7 . 06 ( d , 1h ), 4 . 44 ( d , 1h ), 4 . 27 ( d , 1h ), 3 . 90 ( m , 1h ), 2 . 97 ( m , 1h ), 2 . 87 ( m , 1h ), 2 . 73 ( s , 3h ), 2 . 01 ( m , 1h ), 1 . 89 ( m , 1h ). fmoc - dbu ( boc )- oh ( 250 . 8 mg , 440 . 5 g / mol , 0 . 57 mmol , 1 eq ), dic ( 89 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 57 mmol , 1 eq ) and hobt ( 77 . 6 mg , 135 . 12 g / mol , 0 . 57 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 6 ml ). after 5 minutes 2 -( 3 - chlorophenyl ) ethylamine ( 79 μl , 155 . 63 g / mol , 1 . 119 g / cm 3 , 0 . 57 mmol , 1 eq ) was added to the reaction mixture . temperature was raised to 35 ° c . and mixture stirred overnight . solvent was then evaporated and residue dissolved in dcm , which was washed twice with water and once with brine . organic phase was subsequently dried with na 2 so 4 and evaporated . residue was purified with silica column chromatography ( mobile phase starting from dcm up to 5 % meoh in dcm ). 4 -( n - boc - amino )- n ′- 2 -( 3 - chlorophenyl ) ethyl -( s )- 2 -( n ″- fmoc - amino ) butanamide was obtained with quantitative yield . fmoc protection was removed by dissolving the 4 -( n - boc - amino )- n ′- 2 -( 3 - chlorophenyl ) ethyl -( s )- 2 -( n ″- fmoc - amino ) butanamide in 5 ml of 20 vol -% piperidine in dmf . after 30 minutes stirring , solvent and excess of piperidine were evaporated . product was used without purification for step iii . ( s )- 2 - amino - 4 -( n - boc - amino )- n ′-( 2 -( 3 - chlorophenyl ) ethyl ) butanamide ( 0 . 57 mmol ) was dissolved in dmf ( 3 ml , dry ) and 4 - methyl - 1 - naphthalenesulfonyl chloride ( 206 mg , 240 . 71 g / mol , 0 . 86 mmol , 1 . 5 eq , maybridge ) in thf ( 3 ml , dry ) was added . finally , tea ( 119 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 86 mmol , 1 . 5 eq , baker ) was added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with silica column chromatography ( mobile phase 5 % meoh in dcm ) to give 220 mg of 4 -( n - boc - amino )- n ′-( 2 -( 3 - chlorophenyl ) ethyl )-( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide , yield 67 %. 4 -( n - boc - amino )- n ′-( 2 -( 3 - chlorophenyl ) ethyl )-( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide ( 220 mg , 560 . 11 g / mol , 0 . 39 mmol ) was dissolved in 25 % tfa in dcm ( 10 ml ) and mixture was stirred for 45 minutes . after solvent evaporation and silica column chromatography ( mobile phase from dcm up to 10 % meoh in dcm ) 163 mg of 4 - amino - n - 2 -( 3 - chlorophenyl ) ethyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide was obtained ; yield 91 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 72 ( m , 1h ), 8 . 18 ( m , 1h ), 8 . 14 ( d , 1h ), 7 . 76 - 7 . 67 ( m , 2h ), 7 . 46 ( m , 1h ), 7 . 22 - 7 . 15 ( m , 2h ), 7 . 03 ( t , 1h ), 6 . 91 ( m , 1h ), 3 . 76 ( m , 1h ), 2 . 99 - 2 . 84 ( m , 3h ), 2 . 83 - 2 . 73 ( m , 4h ), 2 . 22 ( m , 2h ), 1 . 89 ( m , 1h ), 1 . 79 ( m , 1h ). fmoc - orn ( boc )- oh ( 250 . 9 mg , 454 . 5 g / mol , 0 . 55 mmol , 1 eq ), dic ( 86 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 55 mmol , 1 eq ) and hobt ( 74 . 2 mg , 135 . 12 g / mol , 0 . 55 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 6 ml ). after 5 minutes benzylamine ( 60 μl , 107 . 16 g / mol , 0 . 981 g / cm 3 , 0 . 55 mmol , 1 eq ) was added to the reaction mixture . temperature was raised to 35 ° c . and mixture stirred overnight . solvent was then evaporated and residue dissolved in dcm , which was washed twice with water and once with brine . organic phase was subsequently dried ( na 2 so 4 ) and evaporated . residue was purified with silica column chromatography ( mobile phase from dcm up to 10 % meoh in dcm ). n - benzyl - 5 - n ′- boc - amino -( s )- 2 -( n ″- fmoc - amino ) pentanamide was obtained with quantitative yield . fmoc protection was removed by dissolving the n - benzyl - 5 - n ′- boc - amino -( s )- 2 -( n ″- fmoc - amino ) pentanamide in 5 ml 20 vol -% piperidine in dmf . after 1 . 5 hours stirring , solvent and excess of piperidine were evaporated . product was used without purification for step iii . ( s )- 2 - amino - n - benzyl - 5 -( n ′- boc - amino ) pentanamide ( 0 . 55 mmol ) was dissolved in dmf ( 2 . 5 ml , dry ) and 4 - methyl - 1 - naphthalenesulfonyl chloride ( 200 mg , 240 . 71 g / mol , 0 . 83 mmol , 1 . 5 eq , maybridge ) in thf ( 2 . 5 ml , dry ) was added . finally , tea ( 115 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 83 mmol , 1 . 5 eq , baker ) was added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with silica column chromatography ( mobile phase 10 % meoh in dcm ) to give n - benzyl - 5 -( n ′- boc - amino )-( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide with quantitative yield . n - benzyl - 5 -( n ′- boc - amino )-( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide ( 289 mg , 525 . 67 g / mol , 0 . 55 mmol ) was dissolved in 25 % tfa in dcm ( 10 ml ) and mixture was stirred for 1 hour . after solvent evaporation and rp - hplc purification , 96 . 6 mg of 5 - amino - n - benzyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide was obtained ; yield 41 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 81 ( m , 1h ), 8 . 27 ( m , 1h ), 8 . 19 ( d , 1h ), 7 . 77 ( m , 2h ), 7 . 49 ( d , 1h ), 7 . 28 ( m , 3h ), 6 . 99 ( m , 2h ), 3 . 94 ( d , 2h ), 3 . 87 ( m , 1h ), 2 . 91 ( m , 2h ), 2 . 85 ( s , 3h ), 1 . 80 ( m , 2h ), 1 . 71 ( m , 2h ). h - phe - nh 2 hydrochloride ( 114 . 2 mg , 200 . 7 g / mol , 0 . 57 mmol , 1 eq , advanced chemtech ) was dissolved in 2 ml of dry dmf / dcm ( 1 / 1 ) and tea ( 95 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 68 mmol , 1 . 2 eq ) was added . after 30 minutes , a dmf / dcm ( 1 / 1 , 4 ml ) solution containing fmoc - dbu ( boc )- oh ( 250 . 2 mg , 440 . 5 g / mol , 0 . 57 mmol , 1 eq ), dic ( 89 μl , 126 . 20 g / mol , 0 . 805 g / cm 3 , 0 . 57 mmol , 1 eq ) and hobt ( 77 . 6 mg , 135 . 12 g / mol , 0 . 57 mmol , 1 eq ) was added . after overnight stirring , solvent was evaporated and dcm ( 30 ml ) was added . organic phase was washed three times with water ( 10 ml ) and once with brine ( 10 ml ). part of the product precipitated from the water phase and after filtration it was combined with the evaporated organic phase . 333 mg of 4 -( n - boc - amino )- n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl )-( s )- 2 -( n ″- fmoc - amino ) butanamide was obtained as a white powder with quantitative yield . fmoc protection was removed by treating the 4 -( n - boc - amino )- n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl )-( s )- 2 -( n ″- fmoc - amino ) butanamide with 4 . 5 ml of 20 vol -% piperidine in dmf for 45 minutes . solvent was then evaporated to give ( s )- 2 - amino - 4 -( n - boc - amino )- n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl ) butanamide as a white solid . residue from step ii was dissolved in 9 ml of dry thf / dmf ( 1 / 1 ) solution and 4 - methyl - 1 - naphthalenesulfonylchloride ( 205 . 3 mg , 240 . 71 g / mol , 0 . 85 mmol , 1 . 5 eq , maybridge ) and finally tea ( 120 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 85 mmol , 1 . 5 eq , baker ) were added . after overnight reaction , solvent was evaporated and the residue purified with silica column chromatography ( mobile phase from 5 % meoh in dcm up to 20 % meoh in dcm ). 238 mg of 4 -( n - boc - amino )- n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl )-( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide as a white powder was obtained ; yield 75 %. boc protection was remove by dissolving the product from step iii in 2 . 5 ml of 25 vol -% tfa in dcm and stirring for 1 h . solvent was then evaporated and residue purified with rp - hplc to give 52 . 5 mg of 4 - amino - n -( s )- 1 - carbamoyl - 2 - phenylethyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide ; yield 26 . 8 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 69 ( m , 1h ), 8 . 16 ( m , 1h ), 8 . 07 ( m , 1h ), 7 . 69 ( m , 2h ), 7 . 39 ( d , 1h ), 7 . 25 - 7 . 16 ( m , 3h ), 7 . 06 ( m , 2h ), 4 . 21 ( t , 1h ), 3 . 84 ( m , 1h ), 2 . 84 - 2 . 69 ( m , 6h ), 2 . 49 ( m , 1h ), 1 . 94 - 1 . 74 ( m , 2h ). fmoc - dbu ( boc )- oh ( 1 . 00 g , 440 . 5 g / mol , 2 . 27 mmol , 1 eq ), dic ( 355 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 2 . 27 mmol , 1 eq ) and hobt ( 308 . 2 mg , 135 . 12 g / mol , 2 . 27 mmol , 1 eq ) were dissolved in dry dmf / dcm ( 1 / 1 , 10 ml ). after 5 minutes , benzylamine ( 248 μl , 107 . 16 g / mol , 2 . 27 mmol , 1 eq , acros ) was added to the reaction mixture and temperature raised to 35 ° c . after overnight stirring , solvent was evaporated and residue dissolved in dcm and washed twice with water and once with brine . organic phase was dried with na 2 so 4 and solvent evaporated . residue was purified with silica column chromatography ( mobile phase from dcm up to 5 % meoh in dcm ). n - benzyl - 4 -( n ′- boc - amino )-( s )- 2 -( n ″- fmoc - amino ) butanamide was obtained with quantitative yield . fmoc protection was removed by dissolving the n - benzyl - 4 -( n ′- boc - amino )-( s )- 2 -( n ″- fmoc - amino ) butanamide ( 1 . 12 g , 529 . 64 g / mol , 2 . 1 mmol , 1 eq ) in 10 ml 20 vol -% piperidine in dmf . after 1 . 5 hours stirring , solvent and excess of piperidine were evaporated . product was used without purification for step iii . ( s )- 2 - amino - n - benzyl - 4 -( n ′- boc - amino ) butanamide ( 2 . 1 mmol ) was dissolved in thf ( 7 ml , dry ) and 4 - methyl - 1 - naphthalenesulfonyl chloride ( 761 mg , 240 . 71 g / mol , 3 . 15 mmol , 1 . 5 eq , maybridge ) was added . finally , tea ( 440 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 3 . 15 mmol , 1 . 5 eq , baker ) was added to the solution . after 15 minutes , some precipitate was observed . after overnight stirring , solvent was evaporated and residue purified with silica column chromatography ( mobile phase 5 % meoh in dcm ) to give 860 mg of n - benzyl - 4 -( n ′- boc - amino )-( s )- 2 -(( 4 - methyl - 1 - naphthalene ) amino ) butanamide ; yield 80 %. n - benzyl - 4 -( n ′- boc - amino )-( s )- 2 -(( 4 - methyl - 1 - naphthalene ) amino ) butanamide ( 850 mg , 511 . 64 g / mol , 1 . 66 mmol ) was dissolved in 25 % tfa in dcm ( 10 ml ) and mixture was stirred for 1 hour . after solvent evaporation and silica column chromatography 4 - amino - n - benzyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide was obtained with quantitative yield . 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 69 ( m , 1h ), 8 . 16 ( m , 1h ), 8 . 10 ( d , 1h ), 7 . 66 ( m , 2h ), 7 . 39 ( d , 1h ), 7 . 17 ( m , 3h ), 6 . 88 ( m , 2h ), 3 . 88 ( d , 2h ), 3 . 84 ( m , 1h ), 2 . 91 ( m , 1h ), 2 . 82 ( m , 1h ), 2 . 74 ( s , 3h ), 1 . 96 ( m , 1h ), 1 . 83 ( m , 1h ). 4 - amino - n - benzyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide ( 45 . 9 mg , 411 . 52 g / mol , 0 . 11 mmol ) prepared in example 12 was dissolved in dry meoh and acetic acid ( 32 μl , 60 . 05 g / mol , 1 . 05 g / cm 3 , 0 . 55 mmol , 5 eq , acros ) and molecular sieves ( 3 å ) were added . finally , ( 1 - ethoxycyclopropoxy ) trimethylsilane ( 66 μl , 173 . 42 g / mol , 0 . 867 g / cm 3 , 0 . 33 mmol , 3 eq , acros ) and sodium cyanoborohydride ( 18 mg , 62 . 84 g / mol , 0 . 28 mmol , 2 . 5 eq , acros ) were added . mixture was refluxed overnight , molecular sieves filtered and the filtrate evaporated . residue was dissolved in ethyl acetate and washed with saturated nahco 3 and water . organic phase was then dried with na 2 so 4 and evaporated . residue was purified with preparative tlc ( 10 % meoh in dcm as mobile phase ) and 7 mg of n - benzyl - 4 -( n ′, n ′- dicyclopropyl ) amino -( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide was obtained ; yield 13 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 75 ( m , 1h ), 8 . 18 ( m , 1h ), 8 . 13 ( d , 1h ), 7 . 69 ( m , 2h ), 7 . 43 ( m , 1h ), 7 . 28 - 7 . 18 ( m , 3h ), 7 . 10 ( m , 2h ), 4 . 07 ( d , 2h ), 3 . 70 ( m , 1h ), 2 . 76 ( d , 3h ), 2 . 40 ( m , 1h ), 2 . 30 ( m , 1h ), 1 . 90 ( m , 1h ), 1 . 73 ( m , 1h ), 1 . 55 ( m , 2h ), 0 . 30 - 0 . 13 ( m , 8h ). 4 - amino - n - benzyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide ( 50 . 0 mg , 411 . 52 g / mol , 0 . 12 mmol ) prepared in example 12 was dissolved in tmof and acetone ( 8 . 8 μl , 58 . 08 g / mol , 0 . 79 g / cm 3 , 0 . 12 mmol , 1 eq , prolabo ), acetic acid ( 10 . 3 μl , 60 . 05 g / mol , 1 . 05 g / cm 3 , 0 . 18 mmol , 1 . 5 eq , acros ) and finally sodium triacetoxyborohydride ( 39 mg , 211 . 94 g / mol , 0 . 18 mmol , 1 . 5 eq , acros ) were added . mixture was stirred for 2 hours and additional 0 . 5 eq of acetone was added . after overnight stirring , solvent was evaporated . the residue was dissolved in ethyl acetate and washed with water . after drying with na 2 so 4 , the organic phase was evaporated . product was purified with preparative tlc ( 10 % meoh in dcm as mobile phase ) and 18 mg of n - benzyl - 4 -( n ′- isopropyl ) amino -( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide was obtained , yield 33 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 72 ( m , 1h ), 8 . 20 ( m , 1h ), 8 . 14 ( d , 1h ), 7 . 70 ( m , 2h ), 7 . 44 ( m , 1h ), 7 . 24 - 7 . 19 ( m , 3h ), 6 . 97 ( m , 2h ), 4 . 00 ( m , 2h ), 3 . 87 ( m , 1h ), 3 . 11 ( m , 1h ), 2 . 83 ( m , 1h ), 2 . 77 ( s , 3h ), 2 . 73 ( m , 1h ), 1 . 98 ( m , 1h ), 1 . 85 ( m , 1h ), 1 . 16 ( m , 6h ). 4 - amino - n - benzyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide ( 123 mg , 451 . 59 g / mol , 0 . 27 mmol , 1 eq ) prepared in example 12 was dissolved in 4 ml of dry dcm under argon and tea ( 190 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 82 mmol , 3 eq , baker ) was added to the solution . n , n ′- bis ( tertbutoxycarbonyl )- n ″- triflylguanidine ( 273 mg , 391 . 4 g / mol , 0 . 41 mmol , 1 . 5 eq ) was dissolved in dcm ( 1 ml ) and added dropwise to the reaction mixture . after 18 h stirring , solvent was evaporated and purified with silica column chromatography ( mobile phase from dcm up to 2 . 5 % meoh in dcm ) to give 250 mg of n - benzyl - 4 -( n ′, n ″- diboc - guanidino )-( s )- 2 -( n ′″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide , yield 83 %. boc protections were removed by dissolving the product after step i in 25 vol -% tfa in dcm ( 10 ml ) and the mixture was stirred for 1 hour . subsequent solvent evaporation and flash chromatographic purification gave 172 mg of n - benzyl - 4 - guanidino -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide with quantitative yield . 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 73 - 8 . 71 ( m , 1h ), 8 . 20 - 8 . 18 ( m , 1h ), 8 . 13 - 8 . 11 ( m , 1h ), 7 . 76 - 7 . 71 ( m , 2h ), 7 . 41 - 7 . 39 ( m , 1h ), 7 . 22 - 7 . 20 ( m , 3h ), 6 . 93 - 6 . 70 ( m , 2h ), 4 . 00 - 3 . 95 ( m , 2h ), 3 . 85 - 3 . 82 ( m , 1h ), 3 . 19 - 3 . 07 ( m , 2h ), 2 . 76 ( s , 3h ), 1 . 93 - 1 . 87 ( m , 1h ) 1 . 77 - 1 . 70 ( m , 1h ). boc - orn ( 2 - cl - z )- oh ( 1 . 0 g , 400 . 86 g / mol , 2 . 5 mmol , 1 eq ), dic ( 390 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 2 . 5 mmol , 1 eq ) and hobt ( 339 . 7 mg , 135 . 12 g / mol , 2 . 5 mmol , 1 eq ) were dissolved in dry dmf ( 5 ml ). after 5 minutes , aniline ( 228 μl , 93 . 13 g / mol , 1 . 022 g / cm 3 , 2 . 5 mmol , 1 eq ) in dry dcm ( 5 ml ) was added . temperature was raised to 35 ° c . and solution stirred overnight . solution was then evaporated , dcm added and solution washed twice with water and once with brine . organic phase was dried with na 2 so 4 and evaporated . subsequent silica column chromatography ( 2 % meoh in dcm as mobile phase ) gave 1 . 12 g of 5 - n -( 2 - cl - z ) amino -( s )- 2 -( n ′- boc - amino )- n ″- phenylpentanamide , yield 94 %. 2 - cl - z protection was removed by dissolving the product from step i in meoh ( 60 ml ) and 10 % pd / c ( 200 mg ) was added . reaction vessel was flushed thrice with argon before introduction of hydrogen ( atmospheric pressure ). mixture was stirred for 4 h , catalyst filtered and finally filtrate evaporated . 5 - amino -( s )- 2 -( n - boc - amino )- n ′- phenylpentanamide was used without purification for step iii . 5 - amino -( s )- 2 -( n - boc - amino )- n ′- phenylpentanamide ( 720 mg , 307 . 39 g / mol , 2 . 34 mmol , 1 eq ) was dissolved in dry dmf ( 5 ml ), tea ( 324 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 2 . 34 mmol , 1 eq , baker ) added and the mixture cooled in an ice bath . 2 - nitrobenzenesulfonyl chloride ( 520 . 7 mg , 221 . 62 g / mol , 2 . 34 mmol , 1 eq ) in dry dcm ( 1 ml ) was added , ice bath removed and solution stirred overnight . solvent was then evaporated , dcm added and solution washed twice with saturated nahco 3 and once with water . organic phase was dried ( na 2 so 4 ), evaporated and finally the residue was purified with silica column chromatography ( mobile phase 2 . 5 % meoh in dcm ). 440 mg of ( s )- 2 -( n - boc - amino )- 5 - n ′-( 2 - nitrobenzenesulfonyl ) amino )- n ″- phenylpentanamide was obtained , yield 38 %. ( s )- 2 -( n - boc - amino )- 5 - n ′-( 2 - nitrobenzenesulfonyl ) amino )- n ″- phenylpentanamide ( 200 . 8 mg , 492 . 55 g / mol , 0 . 41 mmol , 1 eq ) was dissolved in dry dmf ( 0 . 5 ml ) and dbu ( 61 μl , 152 . 24 g / mol , 1 . 018 g / cm 3 , 0 . 41 mmol , 1 eq , acros ) was added . solution was then cooled in an ice bath and methyl iodide ( 25 μl , 141 . 94 g / mol , 2 . 28 g / cm 3 , 0 . 41 mmol , 1 eq ) added dropwise . cooling was removed and mixture stirred overnight . additional 0 . 5 eq of methyl iodide and dbu was added and after 2 hours yet another 0 . 5 eq of methyl iodide and dbu . after 2 hours , solvent was evaporated , dcm added and solution washed twice with saturated nahco 3 and once with water . organic phase was dried ( na 2 so 4 ) and evaporated . after preparative tlc purification 135 mg of ( s )- 2 -( n - boc - amino )- 5 -( n ′- 2 - nitrobenzenesulfonyl - n ′- methylamino )- n ″- phenylpentanamide was obtained , yield 65 %. boc protection was removed by dissolving the product after step 1v in 3 ml of 25 vol -% tfa in dcm and stirring the solution for 45 minutes . solvent was then evaporated and product used without purification for step vi . ( s )- 2 - amino - 5 -( n - 2 - nitrobenzenesulfonyl - n - methylamino )- n ′- phenylpentanamide ( 100 mg , 406 . 46 g / mol , 0 . 25 mmol , 1 eq ) was dissolved in dry thf ( 3 ml ), 1 - naphthalenesulfonyl chloride ( 67 . 4 mg , 226 . 68 g / mol , 0 . 30 mml , 1 . 2 eq ) and finally tea ( 87 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 63 mmol , 2 . 5 eq , baker ) were added . after overnight stirring , 0 . 2 eq of 1 - naphthalenesulfonyl chloride and 1 eq of tea were added and reaction temperature raised to 50 ° c . after additional 1 . 5 hours , solvent was evaporated and residue purified with silica column chromatography ( mobile phase 2 % meoh in dcm ). 138 mg of ( s )- 2 -( n - 1 - naphthalenesulfonylamino )- 5 -( n ′- 2 - nitrobenzenesulfonyl - n ′- methylamino )- n ″- phenylpentanamide was obtained , yield 93 %. ( s )- 2 -( n - 1 - naphthalenesulfonylamino )- 5 -( n ′- 2 - nitrobenzenesulfonyl - n ′- methylamino )- n ″- phenylpentanamide ( 67 mg , 596 . 69 g / mol , 0 . 11 mmol , 1 eq ) was dissolved in dry dmf ( 0 . 5 ml ) and a solution containing thiophenol ( 115 μl , 110 . 18 g / mol , 1 . 078 g / cm 3 , 1 . 1 mmol , 10 eq ), k 2 co 3 ( 40 . 4 mg , 138 . 21 g / mol , 0 . 28 mmol , 2 . 5 eq , baker ) and water ( 200 μl ) was added . finally , tea ( 155 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 1 . 1 mmol , 10 eq , baker ) was added and temperature raised to 50 ° c . after 1 . 5 hours , solvent was evaporated , dcm added and solution washed twice with water and once with brine . organic phase was dried ( na 2 so 4 ) and evaporated . flash chromatography gave 18 . 4 mg of 5 - n - methylamino -( s )- 2 - n ′-( 1 - naphthalenesulfonyl ) amino - n ″- phenylpentanamide ; yield 41 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 78 ( m , 1h ), 8 . 22 ( m , 1h ), 7 . 98 ( d , 1h ), 7 . 90 ( d , 1h ), 7 . 68 ( m , 1h ), 7 . 57 ( m , 1h ), 7 . 46 ( m , 1h ), 7 . 13 ( m , 2h ), 7 . 03 - 6 . 96 ( m , 3h ), 3 . 82 ( m , 1h ), 2 . 42 ( m , 2h ), 2 . 28 ( s , 3h ), 1 . 64 ( m , 2h ), 1 . 52 ( m , 1h ), 1 . 40 ( m , 1h ). rink amide resin ( 1 g , 0 . 7 mmol / g , 0 . 7 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 12 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 35 minutes . resin was then washed thrice with dmf , thrice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - phe - oh ( 813 . 6 mg , 387 . 44 g / mol , 2 . 1 mmol , 3 eq ) and dic ( 328 . 8 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 2 . 1 mmol , 3 eq ) were dissolved in dry dmf ( 12 . 5 ml ) and after 10 minutes mixed with the resin . after 18 hours agitation , solvent was filtered out and fresh solution with half of the original amounts of fmoc - phe - oh and dic in dry dmf was introduced . after additional 5 . 5 hours , solvent was again filtered out and resin washed thrice with dmf , thrice with meoh , thrice with dcm and thrice with thf . possibly unreacted amino groups of the resin were acetylated with a solution consisting of acetic anhydride ( 1 ml , 102 . 09 g / mol , 1 . 087 g / cm 3 , 10 . 6 mmol ) and dipea ( 250 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 1 . 46 mmol ) in dry dmf ( 12 ml ) for 45 minutes . resin was then filtered and washed thrice with dmf , thrice with meoh , twice with dcm and twice with thf . fmoc protection of the attached phenylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - arg ( pmc )- oh ( 928 . 0 mg , 662 . 8 g / mol , 1 . 4 mmol , 2 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii . possibly unreacted amino groups of phenylalanine were acetylated using the procedure described in step iii . fmoc protection of the arginine attached in step v was removed according to procedure described in step i but again without any washes prior treatment with piperidine / dmf . 4 - methyl - 1 - naphthalenesulfonyl chloride ( 337 . 0 mg , 240 . 71 g / mol , 1 . 4 mmol , 2 eq , maybridge ) was dissolved in dry thf ( 12 . 5 ml ) and mixed with the resin . tea ( 194 . 1 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 1 . 4 mmol , 2 eq , baker ) was then added to the mixture . after overnight agitation , solvent was filtered and resin washed thrice with thf , thrice with meoh , thrice with dmf , once with meoh and finally thrice with dcm . resin bound product was cleaved and pmc protection removed by treating the resin with 50 vol -% tfa in dcm ( 12 . 5 ml ) for 1 hour . resulting red solution was collected and evaporated . 116 . 5 mg of n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - guanidino -( s )- 2 -( n ′-( 4 - methylnaphthalene - 1 - sulfonyl ) amino ) pentanamide as a dark oil was obtained . product was purified using flash chromatography to give 50 . 8 mg of n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - guanidino -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide as white solid , overall yield 14 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 79 ( m , 1h ), 8 . 23 ( m , 1h ), 8 . 14 ( d , 1h ), 7 . 76 ( m , 2h ), 7 . 47 ( m , 1h ), 7 . 33 - 7 . 18 ( m , 5h ), 4 . 39 ( m , 1h ), 3 . 62 ( m , 1h ), 3 . 03 ( m , 1h ), 2 . 94 - 2 . 78 ( m , 5h ), 2 . 68 ( m , 1h ), 1 . 50 ( m , 2h ), 1 . 35 ( m , 1h ), 1 . 21 ( m , 1h ). rink amide resin ( 200 . 2 mg , 0 . 7 mmol / g , 0 . 14 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc -( s )- 3 - amino - 4 -( naphthyl ) butyric acid ( 124 mg , 451 . 52 g / mol , 0 . 28 mmol , 2 eq , peptech ) and dic ( 44 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 28 mmol , 2 eq ) were dissolved in dry dmf and after 5 minutes mixed with the resin . after 6 hours , solvent was filtered out and fresh solution with same amounts of fmoc -( s )- 3 - amino - 4 -( naphthyl ) butyric acid and dic in dry dmf were introduced . after additional 6 hours , solvent was again filtered out and resin washed twice with dmf , twice with meoh , once with dcm and once with thf . possibly unreacted amino groups were acetylated by treating the resin with a solution consisting of acetic anhydride ( 100 μl , 102 . 09 g / mol , 1 . 087 g / cm 3 , 1 . 06 mmol ) and dipea ( 17 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 0 . 1 mmol ) in dry dmf ( 2 . 1 ml ) for 30 minutes . resin was then filtered and washed twice with dmf , twice with meoh , once with dcm and once with thf . fmoc protection of the attached fmoc -( s )- 3 - amino - 4 -( naphthyl ) butyric acid was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - orn ( boc )- oh ( 197 . 5 mg , 454 . 5 g / mol , 0 . 44 mmol , 3 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the ornithine attached in step v was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . 4 - toluenesulfonyl chloride ( 80 mg , 190 . 65 g / mol , 0 . 42 mmol , 3 eq ) was dissolved in dry thf ( 2 . 5 ml ), mixed with the resin and tea ( 58 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 42 mmol , 3 eq , baker ) was added to the mixture . after overnight agitation , solvent was filtered and resin washed thrice with thf , twice with meoh , twice with dmf , once with meoh and finally thrice with dcm . resin bound product was cleaved and boc protection removed by treating the resin with 25 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . residue was purified with rp - hplc to give 12 mg of 5 - amino - n -(( s )- 1 - carbamoylmethyl - 2 -( 1 - naphthyl ) ethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - benzenesulfonyl ) amino ) pentanamide as white solid , overall yield 17 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 15 - 8 . 07 ( m , 1h ), 7 . 90 - 7 . 86 ( m , 1h ), 7 . 77 - 7 . 76 ( m , 1h ), 7 . 71 - 7 . 69 ( m , 1h ), 7 . 55 - 7 . 48 ( m , 2h ), 7 . 40 - 7 . 37 ( m , 1h ), 7 . 29 - 7 . 21 ( m , 3h ), 4 . 37 - 4 . 31 ( m , 1h ), 3 . 79 - 3 . 77 ( m , 1h ), 3 . 35 - 3 . 34 ( m , 2h ), 2 . 97 - 2 . 80 ( m , 4h ), 2 . 28 - 2 . 19 ( m , 1h ), 2 . 15 ( m , 3h ), 1 . 69 - 1 . 54 ( m , 3h ). rink amide resin ( 208 . 6 mg , 0 . 7 mmol / g , 0 . 15 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - phe - oh ( 114 . 9 mg , 387 . 44 g / mol , 0 . 30 mmol , 2 eq ) was coupled to the resin using the same procedure and coupling agent as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii in example 18 . fmoc protection of the attached phenylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . n - fmoc - l - beta - homo - arginine ( pbf )- oh ( 281 . 0 mg , 662 . 8 g / mol , 0 . 42 mmol , 3 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii in example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii in example 18 . fmoc protection of the attached beta - homo - arginine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . 1 - naphthalenesulfonyl chloride ( 78 . 5 mg , 226 . 7 g / mol , 0 . 34 mmol , 2 . 5 eq , acros ) was introduced according to the procedure described in step viii of example 18 . resin bound product was cleaved and pbf protection removed by treating the resin with 40 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . residue was purified with rp - hplc to give 14 . 9 mg of n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 6 - guanidino -( s )- 3 -( n ′-( 1 - naphthalenesulfonyl ) amino ) hexanamide as white solid , overall yield 19 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 65 - 8 . 63 ( m , 1h ), 8 . 25 - 8 . 23 ( m , 1h ), 8 . 15 - 8 . 13 ( m , 1h ), 7 . 93 - 7 . 92 ( m , 1h ), 7 . 69 - 7 . 56 ( m , 3h ), 7 . 24 - 7 . 14 ( m , 5h ), 4 . 53 - 4 . 48 ( m , 1h ), 3 . 45 - 3 . 41 ( m , 1h ), 3 . 12 - 3 . 08 ( m , 1h ), 2 . 78 - 2 . 67 ( m , 3h ), 2 . 19 - 2 . 15 ( m , 1h ), 2 . 03 - 1 . 98 ( m , 1h ), 1 . 26 - 0 . 95 ( m , 4h ). rink amide resin ( 205 . 8 mg , 0 . 7 mmol / g , 0 . 14 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - trp ( boc )- oh ( 161 . 4 mg , 526 . 6 g / mol , 0 . 31 mmol , 2 eq ) was coupled to the resin using the same procedure and coupling agent as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii of example 18 . fmoc protection of the attached tryptophan was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - lys ( boc )- oh ( 205 . 8 mg , 468 . 54 g / mol , 0 . 44 mmol , 3 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the attached lysine was removed according to procedure described in step i but without any washes prior to treatment with piperidine / dmf . benzenesulfonyl chloride ( 76 . 3 mg , 176 . 6 g / mol , 0 . 43 mmol , 3 eq ) was introduced according to the procedure described in step viii of example 18 . resin bound product was cleaved and boc protection removed by treating the resin with 20 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . residue was purified with rp - hplc to give 17 . 2 mg of 6 - amino -( s )- 2 -( n - benzenesulfonylamino )- n ′-(( s )- 1 - carbamoyl - 2 -( 1h - indol - 3 - yl ) ethyl ) hexanamide as white solid ; overall yield 25 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 7 . 74 - 7 . 72 ( m , 2h ), 7 . 61 - 7 . 59 ( m , 1h ), 7 . 49 - 7 . 46 ( m , 1h ), 7 . 37 - 7 . 34 ( m , 3h ), 7 . 14 - 7 . 10 ( m , 2h ), 7 . 06 - 7 . 03 ( m , 1h ), 4 . 45 - 4 . 43 ( m , 1h ), 3 . 67 - 3 . 64 ( m , 1h ), 3 . 35 ( s , 2h ), 3 . 24 - 3 . 20 ( m , 1h ), 3 . 02 - 2 . 97 ( m , 1h ), 2 . 74 - 2 . 70 ( m , 2h ), 1 . 54 - 1 . 42 ( m , 4h ), 1 . 21 - 1 . 09 ( m , 2h ). rink amide resin ( 219 . 3 mg , 0 . 7 mmol / g , 0 . 15 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - phe - oh ( 119 . 3 mg , 387 . 44 g / mol , 0 . 30 mmol , 2 eq ) was coupled to the resin using the same procedure and coupling agent as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii in example 18 . fmoc protection of the attached phenylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - orn ( boc )- oh ( 140 . 2 mg , 454 . 5 g / mol , 0 . 31 mmol , 2 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the attached ornithine was removed according to procedure described in step i but without any washes prior to treatment with piperidine / dmf . benzenesulfonyl chloride ( 81 . 3 mg , 176 . 62 g / mol , 0 . 46 mmol , 3 eq ) was introduced according to the procedure described in step viii of example 18 . resin bound product was cleaved and boc protection removed by treating the resin with 20 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . residue was purified with rp - hplc to give 16 . 1 mg of 5 - amino -( s )- 2 -( n - benzenesulfonylamino )- n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl ) pentanamide as white solid , overall yield 25 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 7 . 77 ( m , 2h ), 7 . 58 ( m , 1h ), 7 . 47 - 7 . 44 ( m , 2h ), 7 . 30 - 7 . 18 ( m , 5h ), 4 . 31 ( m , 1h ), 3 . 76 ( m , 1h ), 2 . 98 1h ), 2 . 81 - 2 . 48 ( m , 2h ), 2 . 75 ( m , 1h ), 1 . 66 - 1 . 51 ( m , 4h ). rink amide resin ( 218 . 3 mg , 0 . 7 mmol / g , 0 . 15 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - 1 - naphthylalanine ( 134 . 4 mg , 437 . 49 g / mol , 0 . 31 mmol , 2 eq , peptech ) was coupled to the resin using the same procedure and coupling agent as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii in example 18 . fmoc protection of the attached naphthylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - lys ( boc )- oh ( 218 . 0 mg , 468 . 54 g / mol , 0 . 46 mmol , 3 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the attached lysine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . 1 - naphthalenesulfonyl chloride ( 107 . 9 mg , 226 . 68 g / mol , 0 . 48 mmol , 3 eq ) was introduced according to the procedure described in step viii of example 18 . resin bound product was cleaved and boc protection removed by treating the resin with 20 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . the product was purified with rp - hplc to give 10 . 5 mg of 6 - amino - n -(( s )- 1 - carbamoyl - 2 -( 1 - naphthyl ) ethyl )-( s )- 2 -( n ′-( 1 - naphthalenesulfonyl ) amino ) hexanamide as white solid ; overall yield 25 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 71 ( d , 1h ), 8 . 17 ( m , 1h ), 8 . 09 ( d , 1h ), 8 . 00 - 7 . 95 ( m , 2h ), 7 . 85 ( m 1h ), 7 . 75 - 7 . 69 ( m , 2h ), 7 . 62 - 7 . 59 ( m , 1h ), 7 . 55 - 7 . 47 ( m , 3h ), 7 . 36 - 7 . 33 ( m , 1h ), 7 . 30 - 7 . 28 ( m , 1h ), 4 . 49 ( m , 1h ), 3 . 56 ( m , 1h ), 3 . 41 ( m , 1h ), 3 . 01 ( m , 1h ), 2 . 56 - 2 . 52 ( m , 2h ), 1 . 39 - 1 . 21 ( m , 4h ), 1 . 04 ( m , 1h ), 0 . 87 ( m , 1h ). rink amide resin ( 201 . 0 mg , 0 . 7 mmol / g , 0 . 14 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - trp ( boc )- oh ( 147 . 2 mg , 526 . 6 g / mol , 0 . 28 mmol , 2 eq ) was coupled to the resin using the same procedure and coupling agent as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii in example 18 . fmoc protection of the attached tryptophan was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - lys ( boc )- oh ( 199 . 7 mg , 468 . 54 g / mol , 0 . 43 mmol , 3 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the attached lysine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . 1 - naphthalenesulfonyl chloride ( 97 . 9 mg , 226 . 68 g / mol , 0 . 43 mmol , 3 eq , acros ) was introduced according to the procedure described in step viii of example 18 . resin bound product was cleaved and boc protection removed by treating the resin with 20 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . the product was purified with rp - hplc to give 7 . 3 mg of 6 - amino - n -(( s )- 1 - carbamoyl - 2 -( 1h - indol - 3 - yl ) ethyl )( s )- 2 -( n ′-( 1 - naphthalenesulfonyl ) amino ) hexanamide as white solid ; overall yield 10 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 68 ( d , 1h ), 8 . 14 ( m , 1h ), 8 . 06 ( m , 1h ), 7 . 96 ( m , 1h ), 7 . 69 - 7 . 59 ( m , 2h ), 7 . 52 - 7 . 34 ( m , 3h ), 7 . 12 - 7 . 00 ( m , 3h ), 4 . 36 ( m , 1h ), 3 . 60 ( m , 1h ), 3 . 12 ( m , 1h ), 2 . 86 ( m , 1h ), 2 . 55 - 2 . 51 ( m , 2h ), 1 . 49 - 1 . 23 ( m , 4h ), 1 . 11 - 0 . 90 ( m , 2h ). rink amide resin ( 195 . 3 mg , 0 . 7 mmol / g , 0 . 14 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - phe - oh ( 105 . 3 mg , 387 . 4 g / mol , 0 . 27 mmol , 2 eq ) was coupled to the resin using the same procedure and coupling agent as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii of example 18 . fmoc protection of the attached phenylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - lys ( boc )- oh ( 196 . 1 mg , 468 . 54 g / mol , 0 . 42 mmol , 3 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii of example 18 . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the attached lysine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . 4 -( n - butoxy ) benzenesulfonyl chloride ( 106 . 6 mg , 248 . 73 g / mol , 0 . 43 mmol , 3 eq ) was introduced according to the procedure described in step viii of example 18 . resin bound product was cleaved and boc protection removed by treating the resin with 20 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . the product was purified with rp - hplc to give 18 . 3 mg of 6 - amino -( s )- 2 -( n -( 4 - butoxy - 1 - benzenesulfonyl ) amino )- n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl ) hexanamide as white solid , overall yield 35 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 7 . 71 ( m , 2h ), 7 . 29 - 7 . 19 ( m , 5h ), 6 . 98 ( m , 2h ), 4 . 41 ( m , 1h ), 4 . 00 ( m , 2h ), 3 . 62 ( m , 1h ), 3 . 05 ( m , 1h ), 2 . 82 - 2 . 73 ( m , 3h ), 1 . 77 - 1 . 71 ( m , 2h ), 1 . 57 - 1 . 43 ( m , 6h ), 1 . 31 - 1 . 09 ( m , 2h ), 0 . 98 - 0 . 95 ( m 3h ). rink amide resin ( 1 . 5 g , 0 . 7 mmol / g , 1 . 02 mmol ) was washed twice with dmf prior use . washed resin was dissolved in 21 ml of 20 vol -% piperidine in dmf and mixture was agitated for 50 minutes . resin was then washed thrice with dmf , thrice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - l - 3 , 3 - diphenylalanine ( 1 . 41 g , 463 . 53 g / mol , 3 . 05 mmol , 3 eq , peptech ) and dic ( 477 . 3 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 3 . 05 mmol , 3 eq ) were dissolved in dry dmf ( 21 ml ) and after 10 minutes mixed with the resin . after 22 hours agitation , solvent was filtered out and fresh solution with similar amounts of fmoc - l - 3 , 3 - diphenylalanine and dic in dry dmf was introduced . after additional 5 hours , solvent was again filtered out and resin washed thrice with dmf , thrice with meoh , thrice with dcm and thrice with thf . possibly unreacted amino groups of the resin were acetylated with a solution consisting of acetic anhydride ( 700 μl , 102 . 09 g / mol , 1 . 087 g / cm 3 , 7 . 5 mmol ) and dipea ( 119 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 0 . 7 mmol ) in dry dmf ( 16 . 1 ml ) for 45 minutes . resin was then filtered and washed thrice with dmf , thrice with meoh , twice with dcm and twice with thf . fmoc protection of the attached 3 , 3 - diphenylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - arg ( pmc )- oh ( 1 . 34 g , 662 . 8 g / mol , 2 . 03 mmol , 2 eq ) was coupled to resin bound compound using the same coupling agent and procedure as described in step ii . possibly unreacted amino groups of 3 , 3 - diphenylalanine were acetylated using the procedure described in step iii . fmoc protection of the arginine attached in step v was removed according to procedure described in step i but again without any washes prior treatment with piperidine / dmf . 4 - methyl - 1 - naphthalenesulfonyl chloride ( 733 . 7 mg , 240 . 71 g / mol , 3 . 0 mmol , 3 eq , maybridge ) was dissolved in dry thf ( 21 ml ) and mixed with the resin . tea ( 422 . 5 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 3 . 0 mmol , 3 eq , baker ) was then added to the mixture . after overnight agitation , solvent was filtered and resin washed thrice with thf , thrice with meoh , thrice with dmf , once with meoh and finally thrice with dcm . resin bound product was cleaved and pmc protection removed by treating the resin with 50 vol -% tfa in dcm ( 21 ml ) for 1 hour . resulting red solution was collected and evaporated . product was purified with rp - hplc to give 108 . 4 mg of n -(( s )- 1 - carbamoyl - 2 , 2 - diphenylethyl )- 5 - guanidino -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide as white solid , overall yield 16 . 4 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 71 ( m , 1h ), 8 . 17 ( m , 1h ), 7 . 94 ( m , 1h ), 7 . 69 - 7 . 65 ( m , 2h ), 7 . 35 ( m , 1h ), 7 . 27 - 7 . 19 ( m , 9h ), 7 . 17 - 7 . 13 ( m , 2h ), 5 . 11 ( m , 1h ), 4 . 38 ( d , 1h ), 3 . 46 ( m , 1h ), 2 . 77 ( s , 3h ), 2 . 76 - 2 . 65 ( m , 2h ), 1 . 44 - 1 . 02 ( m , 4h ). rink amide resin ( 223 . 6 mg , 0 . 7 mmol / g , 0 . 16 mmol ) was washed twice with dry dmf prior use . washed resin was dissolved in 2 . 5 ml of 20 vol -% piperidine in dmf and mixture was agitated for 30 minutes . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step ii . fmoc - phe - oh ( 184 mg , 387 . 44 g / mol , 0 . 47 mmol , 3 eq ) and dic ( 74 μl , 126 . 20 g / mol , 0 . 806 g / cm 3 , 0 . 47 mmol , 3 eq ) were dissolved in dry dmf and after 5 minutes mixed with the resin . after 6 hours agitation , solvent was filtered out and fresh solution with same amounts of fmoc - phe - oh and dic in dry dmf was introduced . after additional 6 hours solvent was again filtered out and resin washed twice with dmf , twice with meoh , once with dcm and once with thf . possibly unreacted amino groups were acetylated by treating the resin with acetic anhydride ( 100 μl , 102 . 09 g / mol , 1 . 087 g / cm 3 , 1 . 06 mmol ), dipea ( 17 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 0 . 1 mmol ) and dry dmf ( 2 . 1 ml ) for 30 minutes . resin was then filtered and washed twice with dmf , twice with meoh , once with dcm and once with thf . fmoc protection of the phenylalanine was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . fmoc - dbu ( boc )- oh ( 211 . 3 mg , 440 . 5 g / mol , 0 . 47 mmol , 3 eq ) was coupled to resin bound compound using same coupling agents and procedure as described in step ii . possibly unreacted amino groups were acetylated using the procedure described in step iii . fmoc protection of the amino acid attached in step v was removed according to procedure described in step i but without any washes prior treatment with piperidine / dmf . 4 - methyl - 1 - naphthalenesulfonyl chloride ( 115 mg , 240 . 71 g / mol , 0 . 47 mmol , 3 eq , maybridge ) was dissolved in dry thf ( 2 . 5 ml ), mixed with the resin and tea ( 65 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 47 mmol , 3 eq , baker ) was added to the mixture . after overnight agitation , solvent was filtered and resin washed thrice with thf , twice with meoh , twice with dmf , once with meoh and finally thrice with dcm . resin ( 0 . 16 mmol ) was swollen with dry dmf ( 2 . 5 ml ) and dbu ( 240 μl , 152 . 24 g / mol , 1 . 018 g / cm 3 , 1 . 6 mmol , 10 eq , acros ) was added to the mixture . methyl iodide ( 1 . 6 mmol , 141 . 94 g / mol , 2 . 28 g / cm 3 , 1 . 6 mmol , 10 eq , acros ) was then added dropwise to the mixture . after overnight agitation solvent was filtered and resin washed twice with dmf , twice with meoh , twice with dcm and twice with thf . resin bound product was cleaved and boc protection removed by treating the resin with 25 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . residue was purified with rp - hplc to give 10 . 2 mg of 4 - amino - n -(( s )- 1 - carbamoyl - 2 - phenylethyl )-( s )- 2 -( n ′- methyl - n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) butanamide as white solid , overall yield 13 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 64 ( m , 1h ), 8 . 28 ( m , 1h ), 8 . 16 ( d , 1h ), 7 . 75 ( m , 2h ), 7 . 52 ( d , 1h ), 7 . 05 ( m , 1h ), 6 . 98 ( t , 2h ), 6 . 69 ( d , 2h ), 4 . 78 ( m , 1h , shielded ), 4 . 42 ( m , 1h ), 3 . 00 ( m , 1h ), 2 . 82 ( s , 3h ), 2 . 79 ( t , 2h ), 2 . 34 ( m , 1h ), 2 . 23 ( s , 3h ), 2 . 12 ( m , 1h ), 1 . 75 ( m , 1h ). trityl resin ( 129 . 0 mg , 1 . 5 mmol / g , 0 . 19 mmol ) was washed twice with dry dmf prior use . fmoc - phenylalaninol ( 220 . 8 mg , 373 . 45 g / mol , 0 . 58 mmol , 3 eq , advanced chemtech ) and dipea ( 106 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 0 . 58 mmol , 3 eq ) were dissolved in dry dmf and after 5 minutes mixed with the resin . after 4 hours , solvent was filtered out and fresh solution with same amounts of fmoc - phenylalaninol and dipea in dry dmf was introduced . after overnight agitation solvent was again filtered out and resin washed twice with dmf , twice with meoh , once with dcm and once with thf . possibly unreacted chloro groups were capped by treating the resin with methanol ( 300 μl , 32 . 04 g / mol , 0 . 79 g / cm 3 , 7 . 4 mmol ) and dipea ( 100 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 0 . 1 mmol ) in dry dcm ( 1 . 7 ml ) for 30 minutes . resin was then filtered and washed twice with dcm , twice with meoh , once with dmf and once with thf . dissolving the resin in 2 . 5 ml of 20 vol -% piperidine in dmf and agitating the mixture for 30 minutes removed the fmoc protection . resin was then washed thrice with dmf , twice with meoh , twice with dcm and finally twice with thf . resin was used immediately for step 1v . fmoc - dbu ( boc )- oh ( 254 . 7 mg , 440 . 48 g / mol , 0 . 57 mmol , 3 eq ) was coupled to resin bound compound using same coupling agent and procedure as described in step ii of example 26 . possibly unreacted amino groups were acetylated by treating the resin with acetic anhydride ( 100 μl , 102 . 09 g / mol , 1 . 087 g / cm 3 , 1 . 06 mmol ) and dipea ( 17 μl , 129 . 25 g / mol , 0 . 755 g / cm 3 , 0 . 1 mmol ) in dry dmf ( 2 . 1 ml ) for 30 minutes . resin was then filtered and washed twice with dmf , twice with meoh , once with dcm and once with thf . fmoc protection of the amino acid attached in step 1v was removed according to procedure described in step iii . 4 - methyl - 1 - naphthalenesulfonyl chloride ( 115 . 4 mg , 240 . 71 g / mol , 0 . 47 mmol , 3 eq , maybridge ) dissolved in dry thf ( 2 . 5 ml ) was mixed with the resin and tea ( 65 μl , 101 . 19 g / mol , 0 . 73 g / cm 3 , 0 . 47 mmol , 3 eq , baker ) was added to the mixture . after overnight agitation , solvent was filtered and resin washed thrice with thf , twice with meoh , twice with dmf , once with meoh and finally thrice with dcm . resin bound product was cleaved and boc protection removed by treating the resin with 5 vol -% tfa in dcm ( 2 . 5 ml ) for 45 minutes . resulting red solution was collected and evaporated . 14 mg of 4 - amino - n -(( s )- 1 - hydroxymethyl - 2 - phenylethyl )-( s )- 2 -( n ′- 4 - methyl - 1 - naphthalenesulfonylamino ) butanamide as a yellow oil was obtained . the product was further purified with rp - hplc to give 2 . 3 mg of 4 - amino - n -(( s )- 1 - hydroxymethyl - 2 - phenylethyl )( s )- 2 -( n ′- 4 - methyl - 1 - naphthalenesulfonylamino ) butanamide as white solid , overall yield 3 %. 1 h nmr ( 500 mhz , cd 3 od ; δ , ppm ): 8 . 70 ( d , 1h ), 8 . 13 ( d , 1h ), 8 . 11 ( d , 1h ), 7 . 73 - 7 . 63 ( m , 2h ), 7 . 42 ( d , 1h ), 7 . 20 - 7 . 10 ( m , 3h ), 6 . 95 ( d , 2h ), 3 . 83 ( m , 1h ), 3 . 63 ( m , 1h ), 3 . 16 ( m , 1h ), 3 . 05 ( m , 1h ), 2 . 94 - 2 . 81 ( m , 2h ), 2 . 70 ( s , 3h ), 2 . 29 ( m , 1h ), 2 . 00 - 1 . 89 ( m , 2h ), 1 . 81 ( m , 1h ). additional compounds ( including but not restricted to those described below ) were prepared according to methods described in examples 1 - 27 but using the corresponding starting materials . ms - esi + name ( m / z ) example 5 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 483 18 yl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphtha - lenesulfonyl ) amino ) pentanamide ( compound 7 ) 4 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 483 18 yl )-( s )- 2 -( n ′-( 4 - ethyl - 1 - naphtha - lenesulfonyl ) amino ) butanamide ( compound 8 ) 4 - amino - n -(( s )- 1 - carbamoyl - 2 , 2 - diphenyl - 545 18 ethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naph - thalenesulfonyl ) amino ) butanamide ( compound 9 ) 4 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 455 18 yl )-( s )- 2 -( n ′-( 1 - naphthalenesulfo - nyl ) amino ) butanamide ( compound 10 ) n - benzyl - 4 - n ′- cyclohexylamino -( s )- 494 1 , 14 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfo - nyl ) amino ) butanamide ( compound 11 ) ( s )- 2 - n -( 4 - butoxybenzenesulfonyl ) amino - 533 17 n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - guanidinopentanamide ( compound 12 ) 4 - amino - n -(( s )- 1 - carbamoyl - 2 - methylprop - 421 18 yl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphtha - lenesulfonyl ) amino ) butanamide ( compound 13 ) 4 - amino -( s )- 2 - n -( 4 - bromo - 2 - ethylbenzene - 511 , 513 18 sulfonylamino - n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl ) butanamide ( compound 14 ) n - 1 - carbamoyl - 2 - phenylethyl -( s )- 2 - n ′- 540 17 ( 4 - chloro - 3 - nitrobenzenesulfonyl ) amino - 5 - guanidinopentanamide n -( 1 - carbamoyl - 2 - phenylethyl )- 5 - guani - 587 17 dino -( s )- 2 -( n ′-( 2 , 4 , 6 - triisopropyl - benzenesulfonyl ) amino ) pentanamide n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - 511 17 guanidino -( s )- 2 -( n ′-( 2 - naphthalene - sulfonyl ) amino ) pentanamide ( compound 15 ) n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - 537 17 guanidino -( s )- 2 -( n ′-( 3 - phenylben - zenesulfonyl ) amino ) pentanamide ( compound 16 ) 5 - n - isopropylamino -( s )- 2 - n ′-( 4 - meth - 508 1 , 14 yl - 1 - naphthalene - sulfonyl ) amino - n ″- ( 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthyl )- pent - anamide ( compound 17 ) n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 6 - 539 17 guanidino -( s )- 3 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) hexanamide 4 - amino -( s )- 2 - n -( 4 - methyl - 1 - naphtha - 452 1 lenesulfonyl )- amino -( n ′-( 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthyl ) butanamide ( compound 18 ) n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - 537 17 guanidino -( s )- 2 -( n ′-( 4 - phenylben - zenesulfonyl ) amino ) pentanamide 5 - amino - n -( 2 -( 2 - carbamoyl ) indanyl )- 495 18 ( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalene - sulfonyl ) amino ) pentanamide ( compound 19 ) 5 - amino - n -( 2 -( 1h - indol - 3 - yl ) ethyl )- 479 1 ( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalene - sulfonyl ) amino ) pentanamide ( compound 20 ) 5 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyl - 495 18 ethyl )-( s )- 2 -( n ′-( 2 - phenylbenzene - sulfonyl ) amino ) pentanamide 5 - amino - n -(( s )- 1 - carbamoyl - 2 -( 3 - chloro - 517 18 phenyl ) ethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- pent - anamide ( compound 21 ) 5 - amino - n -( 2 -( 2 - carbamoyl )- 1 , 2 , 3 , 4 - te - 509 18 trahydronaphthyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- pentanamide ( compound 22 ) n -( 2 -( 3 - chlorophenyl ) ethyl )- 4 - n ′- 474 1 , 14 methylamino -( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- butanamide ( compound 23 ) n -(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - 512 17 guanidino -( s )- 2 -( n ′-( 8 - quinoline - sulfonyl ) amino ) pentanamide ( s )- 2 - n -( 4 - acetylbenzenesulfonyl ) amino - 503 17 n ′-(( s )- 1 - carbamoyl - 2 - phenylethyl )- 5 - guanidinopentanamide n - benzyl - 5 - n ′, n ′- dimethylamino - 454 1 , 14 ( s )- 2 -( n ″-( 4 - methyl - 1 - naphthalene - sulfonyl ) amino ) pentanamide 5 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 425 18 yl )-( s )- 2 -( n ′-( 3 - thiophenesulfo - nyl ) amino ) pentanamide 5 - amino -( s )- 2 - n -( 3 - benzo [ b ] thio - 475 18 phenesulfonyl ) amino - n ′-(( s )- 1 - car - bamoyl - 2 - phenylethyl ) pentanamide 5 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 492 18 yl )-( s )- 2 -( n ′-( 5 -( 1 , 3 - oxazol - 5 - yl )- 2 - thiophenenesulfonyl ) amino )- pentanamide 5 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 503 18 yl )-( s )- 2 -( n ′-( 5 - chloro - 1 - naphtha - lenesulfonyl ) amino ) pentanamide n -(( s )- 1 - carbamoyl - 2 -( 4 - biphenyl ) ethyl )- 587 17 5 - guanidino ( s )- 2 -( n ′-( 1 - naphthalene - sulfonyl ) amino ) pentanamide 5 - amino - n -(( s )- 1 - carbamoyl - 2 -( 3 - pyridin - 484 18 yl ) ethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino ) pentanamide 5 - amino - n -(( s )- 1 - carbamoyl - 2 - phenyleth - 497 18 yl )- n - methyl -( s )- 2 -( n ′-( 4 - methyl - 1 - naphthalenesulfonyl ) amino )- pentanamide 5 - amino - n -( 2 - benzyloxy -( s )- 1 - carbamoyl - 513 18 ethyl )-( s )- 2 -( n ′-( 4 - methyl - 1 - naph - thalenesulfonyl ) amino ) pentamide 4 - amino -( s )- 2 - n -( 4 - methyl - 1 - naphtha - 448 1 lenesulfonyl )- amino - n ′- 1 - naphthyl - butanamide 4 - amino - n - cyclohexyl -( s )- 2 -( n ′-( 4 - 404 1 methyl - 1 - naphthalene - sulfonyl ) amino ) bu - tanamide 4 - amino -( s )- 2 -( n -( 4 - methyl - 1 - naphtha - 322 18 lenesulfonyl )- amino ) butanamide 5 - amino -( s )- 2 - n -( 4 - methyl - 1 - naphtha - 466 1 lenesulfonyl )- amino - n ′-( 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthyl ) pentanamide 5 - n - methylamino -( s )- 2 - n ′-( 4 - 480 1 , 14 methyl - 1 - naphthalene - sulfonyl ) amino - n ″-( 1 , 2 , 3 , 4 - tetrahydro - 1 - naph - thyl )- pentanamide the affinity of the compounds of the invention for the five human somatostatin receptor subtypes ( sstr1 , sstr2 , sstr3 , sstr4 , and sstr5 ) was determined in competition binding assays with ( 125 i - tyr )-[ leu 8 , dtrp 22 ]- somatostatin - 28 ( 125 i - ltt - sst - 28 ). the biological material for these experiments consisted of membranes from chinese hamster ovary ( cho ) cells stably transfected with one of the five human somatostatin receptor subtypes . membranes ( 3 - 20 μg of total protein per sample ) and trace amount of 125 i - ltt - sst - 28 were incubated in 10 mm hepes , 1 mm edta , 5 mm mgcl 2 , 5 mg / ml of bsa and 30 μg / ml bacitracin , ph 7 . 6 with six concentrations of the compounds . each concentration was run in duplicate . nonspecific binding was defined by 1 μm somatostatin - 14 ( sst - 14 ) and corresponded to 5 - 25 % of total binding . after 60 min at room temperature , incubations were terminated by rapid vacuum filtration through gf / b glass fiber filter mats ( presoaked at 4 ° c . in 200 ml of 10 mm hepes , 1 mm edta , 5 mm mgcl 2 , ph 7 . 6 ) and three 5 ml washes with ice - cold wash buffer ( 20 mm tris , 1 mm edta , 5 mm mgcl 2 , ph 7 . 4 ). the filters were then dried , impregnated with scintillate and their radioactivity was measured by scintillation counting . the analysis of the experiments was carried out by nonlinear least square curve fitting . affinity constants ( k i ) were calculated from the ic 50 values according to the cheng - prusoff &# 39 ; s equation ( cheng and prusoff , 1973 ). experiments were repeated a minimum of three times . compound k i ( sstr1 )/ nm k i ( sstr2 )/ nm k i ( sstr3 )/ nm k i ( sstr4 )/ nm k i ( sstr5 )/ nm compound 17 1 . 0 ± 0 . 4 & gt ; 10 000 & gt ; 2 000 84 ± 23 & gt ; 10 000 compound 2 500 ± 150 & gt ; 5 000 1 400 ± 100 1 . 2 ± 0 . 4 540 ± 80 besides these , a large set of compounds had k i less than 300 nm for sstr1 . among this set were for example : furthermore , another subset of the compounds of the invention had k i less than 300 nm for sstr4 . among this set were for example : aavik et al . 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( 1995 ), classification and nomenclature of somatostatin receptors . tips 16 : 86 - 88 mazarguil et al . ( 2001 ), structure - activity relationships of neuropeptide ff : role of c - terminal regions . peptides 22 : 1471 - 1478 mori et al . ( 1997 ), differential expression of somatostatin receptors in the rat eye : sstr 4 is intensely expressed in the iris / ciliary body . neurosci left 223 : 185 - 188 patel ( 1999 ), somatostatin and its receptor family . front neuroendocrinol 20 : 157 - 198 payza et al . ( 1993 ), neuropeptide ff receptors : structure - activity relationship and effect of morphine . j pharmacol exp ther 267 : 88 - 94 reisine and bell ( 1995 ), molecular biology of somatostatin receptors . endocrinological reviews 16 : 427 - 442 reubi et al ( 1997 ), a selective analog for the somatostatin sst 1 - receptor subtype expressed by human tumors . eur j pharmacol 345 : 103 - 110 reubi et al . ( 2001 ), somatostatin receptor sst 1 - sst 5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype - selective ligands . eur j nucl med 28 : 836 - 846 rivier et al . ( 2001 ), potent somatostatin undecapeptide agonists selective for somatostatin receptor 1 ( sst 1 ). j med chem 44 : 2238 - 2246 rohrer et al . ( 1998 ), rapid identification of subtype - selective agonists of the somatostatin receptor through combinatorial chemistry . science 282 : 737 - 740 sinisi et al . ( 1997 ), different expression patterns of somatostatin receptor subtypes in cultured epithelial cells from human normal prostate and prostate cancer . j clin endocrinol metab 82 : 2566 - 2569 van essen et al . ( 1997 ), effects of octreotide treatment on restenosis after coronary angioplasty : results of the veras study . circulation 96 : 1482 - 1487 yang et al . ( 1985 ), isolation , sequencing , synthesis and pharmacological characterisation of two brain neuropeptides that modulate the action of morphine . proc natl acad sci 82 : 7757 - 7781