The present invention provides compounds of Formula (I): ##STR00001##
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective Factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

A method of increasing a density of carboxylic acids on a surface of a carbon nanoparticle is disclosed. The method includes contacting an oxygen-containing functional group on a surface of a carbon nanoparticle with a reducing agent to provide a hydroxyl group; reacting the hydroxyl group with a diazoacetate ester in the presence of a transition metal catalyst to provide an ester, the diazoacetate ester having the structure wherein R is a C1-8 hydrocarbyl, preferably tert-butyl, methyl, ethyl, isopropyl, allyl, benzyl, pentafluorophenyl, or N-succinimidyl; and cleaving the ester to provide a carboxylic acid group. Surface-functionalized carbon nanoparticles made by the method are also disclosed.

A method of increasing a density of carboxylic acids on a surface of a carbon nanoparticle is disclosed. The method includes contacting an oxygen-containing functional group on a surface of a carbon nanoparticle with a reducing agent to provide a hydroxyl group; reacting the hydroxyl group with a diazoacetate ester in the presence of a transition metal catalyst to provide an ester, the diazoacetate ester having the structure wherein R is a C1-8 hydrocarbyl, preferably tert-butyl, methyl, ethyl, isopropyl, allyl, benzyl, pentafluorophenyl, or N-succinimidyl; and cleaving the ester to provide a carboxylic acid group. Surface-functionalized carbon nanoparticles made by the method are also disclosed.

The disclosure is directed to compounds and methods for preparing purified macrocyclic peptide using catch-release methods. These methods comprise reacting a free amino group of a resin-bound linear peptide with an azide- or alkyne-functionalized cap to form a resin-bound capped linear peptide having an azide- or alkyne-functionalized cap; cleaving said capped linear peptide from the resin to form a free capped linear peptide having an azide- or alkyne-functionalized cap; reacting the free capped linear peptide having an azide-functionalized cap with an alkyne-functionalized catch resin, or reacting the free capped linear peptide having an akynyl-functionalized cap with an azide functionalized catch resin, to form a catch-resin bound capped linear peptide; reacting the catch-resin bound capped linear peptide under conditions sufficient to effect macrocyclization of the linear peptide and release of the macrocyclic peptide from the catch resin.

The disclosure is directed to compounds and methods for preparing purified macrocyclic peptide using catch-release methods. These methods comprise reacting a free amino group of a resin-bound linear peptide with an azide- or alkyne-functionalized cap to form a resin-bound capped linear peptide having an azide- or alkyne-functionalized cap; cleaving said capped linear peptide from the resin to form a free capped linear peptide having an azide- or alkyne-functionalized cap; reacting the free capped linear peptide having an azide-functionalized cap with an alkyne-functionalized catch resin, or reacting the free capped linear peptide having an akynyl-functionalized cap with an azide functionalized catch resin, to form a catch-resin bound capped linear peptide; reacting the catch-resin bound capped linear peptide under conditions sufficient to effect macrocyclization of the linear peptide and release of the macrocyclic peptide from the catch resin.

A branched monodispersed polyethylene glycol represented by the formula (1):

##STR00001##

wherein X.sup.1 is a functional group that forms a covalent bond upon a reaction with a functional group present in a biofunctional molecule; n is an integer of 4 to 50, which represents number of repeating units of ethylene oxide units; and L.sup.1 represents a single bond, NH, -L.sup.2-(CH.sub.2).sub.m1 or -L.sup.2-(CH.sub.2).sub.m1-L.sup.3-(CH.sub.2).sub.2-, L.sup.2 represents an ether bond, an amide bond, an urethane bond or a single bond, L.sup.3 represents an ether bond, an amide bond or an urethane bond, and m1 and m2 represent each independently an integer of 1 to 5.

A desired antibody or antibody composition may be obtained by modifying a thiol group chemically introduced to an antibody to obtain an antibody composition comprising (A) an antibody intermediate or a salt thereof having a bioorthogonal functional group which may be protected, which is represented by the following formula (A):

AbS-L-R].sub.n(A) wherein Ab is a certain antibody, S is a sulfur atom, L is a divalent group, R is a bioorthogonal functional group which may be protected, and n is an integer from 1 to 8, and (B) a thiol group-introduced antibody or a salt thereof, which is represented by the following formula (B):

AbSH].sub.n(B) wherein Ab and n are the same as formulae (A), and SH is a thiol group; and the like.

A desired antibody or antibody composition may be obtained by modifying a thiol group chemically introduced to an antibody to obtain an antibody composition comprising (A) an antibody intermediate or a salt thereof having a bioorthogonal functional group which may be protected, which is represented by the following formula (A):

AbS-L-R].sub.n(A) wherein Ab is a certain antibody, S is a sulfur atom, L is a divalent group, R is a bioorthogonal functional group which may be protected, and n is an integer from 1 to 8, and (B) a thiol group-introduced antibody or a salt thereof, which is represented by the following formula (B):

AbSH].sub.n(B) wherein Ab and n are the same as formulae (A), and SH is a thiol group; and the like.

A method of increasing a density of carboxylic acids on a surface of a carbon nanoparticle is disclosed. The method includes contacting an oxygen-containing functional group on a surface of a carbon nanoparticle with a reducing agent to provide a hydroxyl group; reacting the hydroxyl group with a diazoacetate ester in the presence of a transition metal catalyst to provide an ester, the diazoacetate ester having the structure wherein R is a C1-8 hydrocarbyl, preferably tert-butyl, methyl, ethyl, isopropyl, allyl, benzyl, pentafluorophenyl, or N-succinimidyl; and cleaving the ester to provide a carboxylic acid group. Surface-functionalized carbon nanoparticles made by the method are also disclosed.

A method of increasing a density of carboxylic acids on a surface of a carbon nanoparticle is disclosed. The method includes contacting an oxygen-containing functional group on a surface of a carbon nanoparticle with a reducing agent to provide a hydroxyl group; reacting the hydroxyl group with a diazoacetate ester in the presence of a transition metal catalyst to provide an ester, the diazoacetate ester having the structure wherein R is a C1-8 hydrocarbyl, preferably tert-butyl, methyl, ethyl, isopropyl, allyl, benzyl, pentafluorophenyl, or N-succinimidyl; and cleaving the ester to provide a carboxylic acid group. Surface-functionalized carbon nanoparticles made by the method are also disclosed.