US 10,159,746 B2  11  12  added to cause a unit change in pH. Thus, a buffer is a  substance that assists in regulating the pH of a composition.  Typically, a buffer is chosen based upon the desired pH and  compatibility with other components of a composition. In  general, a buffer has a pKa that is no more than 1 unit less  than or greater than the desired pH of the composition ( or  that the composition will produce upon dissolution).  The term "water" as used herein refers to a liquid solution  of H$_{2}$ 0  having a pH of approximately 7.0.  The terms "carbocycle" and "carbocyclyl", as used  herein, refer to a non-aromatic substituted or unsubstituted  ring in which each atom of the ring is carbon. The terms  "carbocycle" and "carbocyclyl" also include polycyclic ring  systems having two or more cyclic rings in which two or  more carbons are common to two adjoining rings wherein at  least one of the rings is carbocyclic, e.g., the other cyclic  rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,  aryls, heteroaryls, and/or heterocyclyls.  The term "carbonyl" is art-recognized and includes such  moieties as can be represented by the general formulae:  wherein X is a bond or represents an oxygen or a sulfur, and  R 11  represents  a  hydrogen,  an  alkyl,  an  alkenyl,  -(CH$_{2}$)m-R 8  or a pharmaceutically acceptable salt, R 11 ’  represents a hydrogen, an alkyl, an alkenyl or -(CH$_{2}$)m› R 8, where m and R  8  are as defined above. Where X is an  oxygen and R$^{11 }$or R 11 ’ is not hydrogen, the formula repre› sents an "ester". Where X is an oxygen, and R 11  is a  hydrogen, the formula represents a "carboxylic acid".  The term "C$_{1}$ _ $_{6}$heteroaralkyl", as used herein, refers to a  C$_{1}$ _ $_{6}$alkyl group substituted with a heteroaryl group.  The term "heteroaryl" includes substituted or unsubsti› tuted aromatic 5- to 7-membered ring structures, for  example, 5- to 6-membered rings, whose ring structures  include one to four heteroatoms. The term "heteroaryl" also  includes polycyclic ring systems having two or more cyclic  rings in which two or more carbons are common to two  adjoining rings wherein at least one of the rings is heteroaro› matic, e.g., the other cyclic rings can be cycloalkyls,  cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or het› erocyclyls. Heteroaryl groups include, for example, pyrrole,  furan, thiophene, imidazole, oxazole, thiazole, triazole,  pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and  the like.  The term "heteroatom" as used herein means an atom of  any element other than carbon or hydrogen. For example,  heteroatoms include nitrogen, oxygen, phosphorus, and sul› fur.  The term "heterocyclyl" or "heterocyclic group" refers to  substituted or unsubstituted non-aromatic 3- to 10-mem- bered ring structures, for example, 3- to 7-membered rings,  whose ring structures include one to four heteroatoms. The  term "heterocyclyl" or "heterocyclic group" also includes  polycyclic ring systems having two or more cyclic rings in  which two or more carbons are common to two adjoining  rings wherein at least one of the rings is heterocyclic, e.g.,  the other cyclic rings can be cycloalkyls, cycloalkenyls,  cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Het› erocyclyl groups include, for example, piperidine, pipera› zine, pyrrolidine, morpholine, lactones, lactams, and the  like.  The term "C$_{1}$ _ $_{6}$hydroxyalkyl" refers to a C$_{1}$ _ $_{6}$alkyl group  substituted with a hydroxy group.  The term "thioether" refers to an alkyl group, as defined  above, having a sulfur moiety attached thereto. In some  embodiments, the "thioether" is represented by -S-alkyl.  Representative thioether groups include methylthio, ethyl› thio, and the like.  The term "substituted" refers to moieties having substitu› ents replacing a hydrogen on one or more non-hydrogen  atoms of the molecule.  It  will be understood that "substitu- tion" or "substituted with" includes the implicit proviso that  such substitution is in accordance with permitted valence of  the substituted atom and the substituent, and that the sub- stitution results in a stable compound, e.g., which does not  spontaneously undergo transformation such as by rearrange› ment, cyclization, elimination, etc. As used herein, the term  "substituted" is contemplated to include all permissible  substituents of organic compounds. In a broad aspect, the  permissible  substituents  include  acyclic  and  cyclic,  branched and unbranched, carbocyclic and heterocyclic,  aromatic and non-aromatic substituents of organic com- pounds. The permissible substituents can be one or more and  the same or different for appropriate organic compounds.  For purposes of this disclosure, the heteroatoms such as  nitrogen may have hydrogen substituents and/or any per› missible substituents of organic compounds described  herein which satisfy the valences of the heteroatoms. Sub› stituents can include, for example, a halogen, a hydroxyl, a  carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl,  or an acyl), a thiocarbonyl (such as a thioester, a thioacetate,  or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a  phosphonate, a phosphinate, an amino, an amido, an ami› dine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an  alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido,  a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or  heteroaromatic moiety.  It  will be understood by those skilled  in the art that the moieties substituted on the hydrocarbon  chain can themselves be substituted, if appropriate.  In some embodiments, the compounds provided herein, or  salts thereof, are substantially isolated or purified. By "sub› stantially isolated" is meant that the compound is at least  partially or substantially separated from the environment in  which it was formed or detected. Partial separation can  include, for example, a composition enriched in the com- pounds provided herein. Substantial separation can include  compositions containing at least about 50%, at least about  60%, at least about 70%, at least about 80%, at least about  90%, at least about 95%, at least about 97%, or at least about  99% by weight of the compounds, or salt thereof. Methods  for isolating compounds and their salts are routine in the art.  As used herein, the term "peptide" refers to a chain of  amino acids that is about two to about ten amino acids in  length.  As used herein, the term "natural" or "naturally occur› ring" amino acid refers to one of the twenty most common  occurring amino acids. Natural amino acids are referred to  by their standard one- or three-letter abbreviations.  The term "non-natural amino acid" or "non-natural"  refers to any derivative or structural analogue of a natural  amino acid including D forms, and  ~  and y amino acid  derivatives.  It  is noted that certain amino acids, e.g.,  hydroxyproline, that are classified as a non-natural amino  acid herein, may be found in nature within a certain organ› ism or a particular protein. Non-limiting examples of non- natural amino acids include: ~-Alanine (~-Ala), y-Aminobu› tyric Acid (GABA), 2-Aminobutyric Acid (2-Abu),  a,~› Dehydro-2-aminobutyric  Acid  (fl-Abu),  0  II  RI!  ~x,,,,.  or 