US 20160O821 23A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0082123 A1 RAU et al. (43) Pub. Date: Mar. 24, 2016

(54) HYDROGEL-LINKED PRODRUGS (30) Foreign Application Priority Data RELEASING TAGGED DRUGS Apr. 22, 2013 (EP) ...... 13164669.7 (71) Applicant: ASCENDIS PHARMA A/S, Hellerup Oct. 8, 2013 (EP) ...... 13187784.7 (DK) Publication Classification (72) Inventors: Harald RAU, Dossenheim (DE); Nora KALUZA, Heidelberg (DE); Ulrich (51) Int. Cl. HERSEL, Heidelberg (DE); Thomas A647/48 (2006.01) KNAPPE, Heidelberg (DE); Burkhardt (52) U.S. Cl. LAUFER, Dossenheim (DE) CPC. A61 K47/48784 (2013.01); A61K 47/48215 2013.O1 (73) Assignee: Ascendis Pharma A/S, Hellerup (DK) ( ) (21) Appl. No.: 14/786,481 (57) ABSTRACT 1-1. The present invention relates to a process for the preparation (22) PCT Filed: Apr. 16, 2014 of a hydrogel-linked prodrug releasing a tag moiety-biologi (86). PCT No.: PCT/EP2014/057753 releasingcally active a tag moiety moiety-biologically conjugate, to a hydrogel-linked active moiety conjugate prodrug S371 (c)(1), obtainable by Such process, to pharmaceutical compositions (2) Date: Oct. 22, 2015 comprising said prodrug and their use as a medicament. US 2016/00821 23 A1 Mar. 24, 2016

HYDROGEL-LINKED PRODRUGS boxyl (-COOH) or activated carboxyl ( COY, RELEASING TAGGED DRUGS wherein Y is selected from formulas (fi) to (f-vi): FIELD OF THE INVENTION 0001. The present invention relates to a process for the (f-i) preparation of a hydrogel-linked prodrug releasing a tag moi ety-biologically active moiety conjugate, to a hydrogel linked prodrug releasing a tag moiety-biologically active moiety conjugate obtainable by Such process, to pharmaceu tical compositions comprising said prodrug and their use as a medicament. (f-ii) BACKGROUND OF THE INVENTION 0002 Hydrogels are versatile carriers for carrier-linked prodrugs, see for example WO2006003.014A2 and WO2011 012715A1. As at least most of the drugs are con nected to the inside of the hydrogel, they are protected from modifying and/or degrading enzymes present in a patients body which extends the time period over which active drugs (f-iii) are released from Such prodrugs. 0003. However, once the drug is released from the hydro y O gel carrier, it is subject to renal clearance and exposed to modifying and/or degrading enzymes that reduce the half-life of the released drug. NO2, 0004) To avoid this Harris (WO199922770) has devised (f-iv) hydrogel prodrugs which release biologically active moiety Fb. poly(ethylene glycol) (PEG) conjugates. These prodrugs w O have two major disadvantages. On the one hand polymeriza tion of the Harris hydrogel occurs in the presence of drug S molecules which get coupled to the forming hydrogel during polymerization. This may cause drug molecules to be (f-v) entrapped in the hydrogel which may lead to a burst-type release of drug during hydrogel degradation. 0005. On the other hand drug molecules are released upon O F degradation of labile bonds present in the hydrogel matrix. As the degradation process leads to fragments of various sizes, and the exact nature of the PEG tag attached to the released F F biologically active moiety varies between different degrada tion products. The variable size of the PEG tags leads to F different residual activities of the conjugates which are (f-vi) undesired from a pharmacological view point. DETAILED DESCRIPTION OF THE INVENTION 0006. Accordingly, there is a need for hydrogel-linked prodrugs, which at least partially overcome the shortcomings 0011 wherein described before. 0012 the dashed lines indicate attachment to the rest 0007. It is therefore an object of the present invention to of the molecule, overcome at least some of the above-mentioned shortcomings and to provide a hydrogel, which releases drugs with 0013 b is 1, 2, 3 or 4 improved pharmacologic properties, like for example 0014 X is C1, Br, I, or F); extended half-lives. This is achieved by releasing drugs with 00.15 (a-ii) at least one crosslinker reagent, wherein a tag, i.e. tag moiety-biologically active moiety conjugates, the at least one crosslinker reagent has a molecular from the hydrogel-linked prodrugs of the present invention. weight ranging from 0.2 to 40 kDa and comprises at 0008. In one aspect, the present invention relates to a pro least two functional end groups selected from the cess for the preparation of a hydrogel-linked prodrug releas group consisting of activated ester groups, activated ing a tag moiety-biologically active moiety conjugate com carbamate groups, activated carbonate groups, acti prising the steps of: vated thiocarbonate groups and amine groups; 0009 (a) providing a mixture comprising 0016 in a weight ratio of the at least one backbone 0010 (a-i) at least one backbone reagent, wherein the reagent to the at least one crosslinker reagent ranging at least one backbone reagent has a molecular weight from 1:99 to 99:1 and wherein the molar ratio of A' ranging from 1 to 100 kDa, and comprises at least to functional end groups is >1; three functional groups A", wherein each A' is an 0017 (b) polymerizing the mixture of step (a) to a amine ( NH or —NH ), hydroxyl ( OH), car hydrogel; US 2016/00821 23 A1 Mar. 24, 2016

0018 (c) optionally covalently conjugating a spacer cally active moiety conjugate conjugated to the reagent of formula (VI) hydrogel of step (b) or (c); or 10030) (d-vi)areversible prodrug linker reagent to A' Axl-SP2-AX2 (VI), or A' of the hydrogel of step (b) or (c), respectively, 0019 wherein resulting in a reversible prodrug linker moiety conju 10020 SP is Clso alkyl, Clso alkenyl or Clso alky gated to the hydrogel of step (b) or (c), followed by nyl, which Clso alkyl, C-soalkenyland Clso alkynyl covalent conjugation of a tag moiety-biologically is optionally interrupted by one or more group(s) active moiety conjugate reagent to said reversible pro selected from the group consisting of —NH-, drug linker moiety through a functional group of the —N(C. alkyl)-, —O— —S, —C(O)— —C(O) tag moiety; NH, —C(O)N(C. alkyl)-, - O C(O) , 0031 (d-vii) a reversible prodrug linker moiety-tag —S(O)— —S(O) , 4- to 7-membered heterocy moiety conjugate reagent to A' or A' of the hydrogel clyl phenyl and naphthyl; of step (b) or (c), respectively, through a functional I0021 A' is a functional group for reaction with A' group of the reversible prodrug linker moiety, fol of the hydrogel; and lowed by covalent conjugation of a drug to said tag (0022 A' is a functional group; moiety; or 0032 (d-viii) a reversible prodrug linker moiety-tag 0023 to A' of the hydrogel from step (b); and moiety-biologically active moiety conjugate reagent 0024 (d) covalently conjugating to A' or A* of the hydrogel of step (b) or (c), respec I0025 (d-i) a reversible prodrug linker reagent to A' tively, through a functional group of the reversible or A* of the hydrogel of step (b) or (c), respectively, prodrug linker moiety; resulting in a reversible prodrug linker moiety conju wherein the linkage between the reversible prodrug linker gated to the hydrogel of step (b) or (c), followed by moiety and the biologically active moiety in the prodrug covalent conjugation of a drug to said reversible pro according to (d-i), (d-ii), (d-iii) and (d-iv) and the linkage drug linker moiety resulting in a reversible prodrug between the reversible prodrug linker moiety and the tag linker moiety-biologically active moiety conjugate moiety in the prodrug according to (d-V), (d-vi), (d-vii) and conjugated to the hydrogel of step (b) or (c), followed (d-viii) is reversible. by covalent conjugation of a tag reagent to the bio 0033. It was now surprisingly found that such hydrogel logically active moiety resulting in a reversible pro linked prodrugs have a release kinetic that is only governed by drug linker moiety-biologically active moiety-tag the release kinetic of the reversible prodrug linker and the moiety conjugate conjugated to the hydrogel of step released tag moiety-biologically active moiety conjugate has (b) or (c); or improved pharmacologic properties, like for example an (0026 (d-ii) a reversible prodrug linker reagent to A' extended half-life, compared to the corresponding drug with or A* of the hydrogel of step (b) or (c), respectively, out the tag moiety. In contrast to the various conjugates of resulting in a reversible prodrug linker moiety conju Harris (WO199922770) the released tag moiety-biologically gated to the hydrogel of step (b) or (c), followed by active moiety conjugates have a well-defined structure. covalent conjugation of a biologically active moiety 0034. Within the present invention the terms are used with tag moiety conjugate reagent to said reversible pro the meaning as follows. drug linker moiety through a functional group of the 0035. As used herein, the term “hydrogel' means a hydro biologically active moiety resulting in a reversible philic or amphiphilic polymeric network composed of prodrug linker moiety-biologically active moiety-tag homopolymers or copolymers, which is insoluble due to the moiety conjugate conjugated to the hydrogel of step presence of covalent chemical crosslinks. The crosslinks pro (b) or (c); or vide the network structure and physical integrity. Hydrogels 0027 (d-iii) a reversible prodrug linker moiety-bio exhibit a thermodynamic compatibility with water which logically active moiety conjugate reagent to A" or allows them to Swell in aqueous media. A° of the hydrogel of step (b) or (c), respectively, 0036. As used herein, the term “reagent’ means a chemi through a functional group of the reversible prodrug cal compound which comprises at least one functional group linker moiety, followed by covalent conjugation of a for reaction with the functional group of another reagent or tag reagent to said biologically active moiety; or moiety. 0028 (d-iv) a reversible prodrug linker moiety-bio 0037. As used herein, the term “backbone reagent’ means logically active moiety-tag moiety conjugate reagent a reagent, which is suitable as a starting material for forming to A" or A* of the hydrogel of step (b) or (c), respec hydrogels. As used herein, a backbone reagent preferably tively, through a functional group of the reversible does not comprise biodegradable linkages. A backbone prodrug linker moiety; or reagent may comprise a “branching core' which refers to an (0029 (d-v) a reversible prodrug linker reagent to A' atom or moiety to which more than one other moiety is or A' of the hydrogel of step (b) or (c), respectively, attached. resulting in a reversible prodrug linker moiety conju 0038. As used herein, the term “crosslinker reagent' gated to the hydrogel of step (b) or (c), followed by means a linear or branched reagent, which is suitable as a covalent conjugation of a tag reagent to said reversible starting material for crosslinking backbone reagents. Prefer prodrug linker moiety resulting in a reversible pro ably, the crosslinker reagent is a linear chemical compound. A drug linker moiety-tag moiety conjugate conjugated crosslinker reagent comprises at least one biodegradable link to the hydrogel of step (b) or (c), followed by covalent age. conjugation of a drug to said tag moiety resulting in a 0039. As used herein, the term "moiety' means a part of a reversible prodrug linker moiety-tag moiety-biologi molecule, which lacks one or more atom(s) compared to the US 2016/00821 23 A1 Mar. 24, 2016 corresponding reagent. If, for example, a reagent of the for

mula "H X—H' reacts with another reagent and becomes (f-i) part of the reaction product, the corresponding moiety of the reaction product has the structure “H X or “ X ’.99 whereas each “- indicates attachment to another moiety. 0040. Accordingly, the phrase “in bound form is used to refer to the corresponding moiety of a reagent, i.e. “lysine in (f-ii) bound form” refers to a lysine moiety which lacks one or more atom(s) of the lysine reagent and is part of a molecule. 0041. The term “drug” means any substance which can affect one or more physical or biochemical properties of a biological organism, including but not limited to viruses, bacteria, fungi, plants, animals, and humans. In particular, as used herein, the term includes any substance intended for (f-iii) diagnosis, cure, mitigation, treatment, or prevention of dis NO ease in organisms, in particular humans or animals, or to otherwise enhance physical or mental well-being of organ , -0. isms, in particular humans or animals. Instead of the term "drug” also the notation"(A)-D-(A'), is used, wherein D is biologically active moiety, A'and Aare independently NO2, of each other a functional group and a1 and a2 are both 1 in (f-iv) Fi, steps (d-i), (d-ii), (d-iii) and (d-iv) and a1 is 1 and a2 is 0 or 1 w O in steps (d-V), (d-vi), (d-vii) and (d-viii). It is understood that a drug may also have more than two functional groups which >"N-/ for simplification are not explicitly mentioned as they are not w N involved in the process of the present invention. (f-v) 0042. The term “biologically active moiety” refers to the moiety which results after covalently conjugating a drug to one or more other moieties wherein one or more functional O F groups of the drug were conjugated to functional groups of said one or more other moieties which Subsequently form linkages. The term “biologically active moiety” is also referred to as “D’. Accordingly, the corresponding reagent is F F and referred to as “drug’. F 0043. The term “spacer moiety” as used herein refers to (f-vi) any moiety Suitable for connecting two moieties and is known to the person skilled in the art. --X 0044) The term “tag moiety” as used herein refers to a moiety covalently conjugated to the biologically active moi ety and preferably has a molecular weight ranging from 15 Da 0047 wherein to 80 kDa. 0048 the dashed lines indicate attachment to the rest of 0045. As used herein, the term “functional group” means a the molecule; group of atoms which can react with other functional groups. 0049 b is 1, 2, 3 or 4; and Functional groups include but are not limited to the following 0050 X is C1, Br, I, or F. groups: carboxylic acid (—(C=O)OH), primary or second 0051. Accordingly, a preferred activated ester has the for ary amine ( NH, -NH ), maleimide, thiol ( SH), sul mula fonic acid ( (O—S—O)OH), carbonate, carbamate ( O –(C=O) X, (C=O)N<), hydroxy (-OH), aldehyde (-(C=O)H), ketone (—(C=O) ), hydrazine (>N N<), isocyanate, 0052 wherein isothiocyanate, phosphoric acid ( O(P=O)OHOH), phos 0053 X is selected from the group consisting of for phonic acid (—O(P—O)OHH), haloacetyl, alkyl halide, mulas (fi), (f-ii), (f-iii), (fiv), (f-v) and (f-vi). acryloyl, aryl fluoride, hydroxylamine, disulfide, vinyl sul 0054 Accordingly, a preferred activated carbamate has fone, vinyl ketone, diazoalkane, oxirane, and aziridine. the formula 0046. As used herein, the term “activated functional - N (C=O) X, group” means a functional group, which is connected to an 0.055 wherein activating group, i.e. a functional group was reacted with an activating reagent. Preferred activated functional groups I0056 X is selected from the group consisting of for include but are not limited to activated ester groups, activated mulas (fi), (f-ii), (f-iii), (fiv), (f-v) and (f-vi). carbamate groups, activated carbonate groups and activated 0057 Accordingly, a preferred activated carbonate has the thiocarbonate groups. Preferred activating groups are formula selected from the group consisting of formulas ((f-i) to (f-vi): US 2016/00821 23 A1 Mar. 24, 2016

0058 wherein the term “number average molecular weight” means the ordi I0059 X is selected from the group consisting of for nary arithmetic means of the molecular weights of the indi mulas (f-i), (f-ii), (f-iii), (fiv), (f-v) and (f-vi). vidual polymers. 0060 Accordingly, a preferred activated thiocarbamate 0070. As used herein, the term “polymerization” or “poly has the formula merizing” means the process of reacting monomer or mac romonomer reagents in a chemical reaction to form polymer 0061 wherein chains or networks, including but not limited to hydrogels. I0062 X is selected from the group consisting of for (0071. As used herein, the term “macromonomer” means a mulas (f-i), (f-ii), (f-iii), (fiv), (f-v) and (f-vi). molecule that was obtained from the polymerization of 0063. Accordingly, a “functional end group' is a func tional group which is localized at the end of a moiety or monomer reagents. molecule, i.e. is a terminal functional group. 0072. As used herein, the term “condensation polymeriza 0064. As used herein, the term “capping group” means a tion' or “condensation reaction” means a chemical reaction, moiety which is irreversibly, i.e. permanently, connected to a in which the functional groups of two reagents react to form functional group to render it incapable of reacting with func one single molecule, i.e. the reaction product, and a low tional groups of other reagents or moieties. molecular weight molecule, for example water, is released. 0065. As used herein, the term “protecting group” means a moiety which is reversibly connected to a functional group to 0073. As used herein, the term "suspension polymeriza render it incapable of reacting with, for example, another tion” means a heterogeneous and/or biphasic polymerization functional group. Suitable alcohol (-OH) protecting groups reaction, wherein the monomer reagents are dissolved in a are, for example, acetyl, benzoyl, benzyl, B-methoxy first solvent, forming the disperse phase which is emulsified ethoxymethyl ether, dimethoxytrityl, methoxymethyl ether, in a second solvent, forming the continuous phase. In the methoxytrityl, p-methoxybenzyl ether, methylthiomethyl present invention, the monomer reagents are the at least one ether, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert backbone reagent and the at least one crosslinker reagent. butyldimethylsilyl, tri-iso-propylsilyloxymethyl, triisopro Both the first solvent and the monomer reagents are not pylsilyl ether, methyl ether, and ethoxyethyl ether. Suitable soluble in the second solvent. Such emulsion is formed by amine protecting groups are, for example, carbobenzyloxy, stirring, shaking, exposure to ultrasound or MicrosieveTM p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluore emulsification, more preferably by stirring or MicrosieveTM nylmethyloxyarbonyl, acetyl, benzoyl, benzyl, carbamate, emulsification and more preferably by stirring. This emulsion p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, is stabilized by an appropriate emulsifier. The polymerization and tosyl. Suitable carbonyl protecting groups are, for is initiated by addition of a base as initiator which is soluble example, acetals and ketals, acylals and dithianes. Suitable in the first solvent. A suitable commonly known base suitable carboxylic acid protecting groups are, for example, methyl as initiator may be a tertiary base. Such as tetramethylethyl esters, benzyl esters, tert-butyl esters, 2,6-dimethylphenol, enediamine (TMEDA). 2,6-diisopropylphenol. 2.6.-di-tert-butylphenol, silyl esters, 0074 As used herein, the term “immiscible” means the orthoesters, and oxazoline. Suitable phosphate protecting property where two Substances are not capable of combining groups are, for example, 2-cyanoethyl and methyl. to form a homogeneous mixture at ambient temperature and 0066. As used herein, the terms “work-up' and “working pressure, i.e. attemperature and pressure conditions typically up' refer to the series of manipulations required to isolate and present in a typical laboratory environment. purify the product(s) of a chemical reaction, in particular of a polymerization. 0075. As used herein, the term “polyamine” means a 0067. As used herein, the term “polymer means a mol reagent or moiety comprising more than one amine (-NH ecule comprising repeating structural units, i.e. monomers, and/or —NH), e.g. from 2 to 64 amines, from 4 to 48 amines, connected by chemical bonds in a linear, circular, branched, from 6 to 32 amines, from 8 to 24 amines, or from 10 to 16 crosslinked or dendrimeric way or a combination thereof, amines. Particularly preferred polyamines comprise from 2 to which may be of synthetic or biological origin or a combina 32 amines. tion of both. It is understood that a polymer may for example 0076. As used herein, the term “PEG-based comprising at also comprise functional groups or capping moieties. Prefer least X% PEG' in relation to a moiety or reagent means that ably, a polymer has a molecular weight of at least 0.5 kDa, e.g. said moiety or reagent comprises at least X% (w/w) ethylene a molecular weight of at least 1 kDa, a molecular weight of at glycol units (—CH2CH2O ), wherein the ethylene glycol least 2 kDa, a molecular weight of at least 3 kDa or a molecu units may be arranged blockwise, alternating or may be ran lar weight of at least 5 kDa. At most, a polymer preferably has domly distributed within the moiety or reagent and preferably a molecular weight of 1 million Da. all ethylene glycol units of said moiety or reagent are present 0068. As used herein, the term “polymeric' means a in one block; the remaining weight percentage of the PEG reagent or a moiety comprising one or more polymer(s). based moiety or reagent are other moieties especially selected 0069. The person skilled in the art understands that the from the group consisting of polymerization products obtained from a polymerization reaction do not all have the same molecular weight, but rather 0077 Cso alkyl, C2-so alkenyl, C2-so alkynyl, Cso exhibit a molecular weight distribution. Consequently, the cycloalkyl, 4- to 7-membered heterocyclyl, 8- to molecular weight ranges, molecular weights, ranges of num 11-membered heterobicyclyl phenyl; naphthyl; inde bers of monomers in a polymer and numbers of monomers in nyl; indanyl; and tetralinyl; and a polymeras used herein, refer to the number average molecu 0078 linkages selected from the group of linkages con lar weight and number average of monomers. As used herein, sisting of US 2016/00821 23 A1 Mar. 24, 2016

examples of straight-chain and branched Calkyl groups are methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu tyl and tert-butyl. When two moieties of a molecule are linked --O--, --S-H, by the C alkyl group, then examples for such C alkyl groups are CH2—, CH2—CH2—, CH(CH) , —CH2—CH2—CH2—, —CH(CHs)— —C(CH) , --N-H, --N=E, CH2—CH2—CH2—CH2—, and CH, CH, CH RI (CH)—. Each hydrogen atom of a C alkyl group may be replaced by a substituent as defined below. I0083. As used herein, the term "C. alkyl alone or in --S-S-H, --N=N s combination means a straight-chain or branched alkyl group having 1 to 6 carbonatoms. If present at the end of a molecule, ORI examples of straight-chain and branched Calkyl groups are methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu --C-H, --C-H, tyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, O NRI 2,3-dimethylbutyl and 3.3-dimethylpropyl. When two moi --C-H, --C-H, eties of a molecule are linked by the C- alkyl group, then examples for Such Ce alkyl groups are —CH2—, —CH2— CH2—, —CH(CH)—, CH2—CH2—CH2—, CH (CHs)— and —C(CH)—. Each hydrogen atom of a C alkyl group may be replaced by a Substituent as defined below. I0084. Accordingly, as used herein, the term “Coalkyl alone or in combination means a straight-chain or branched alkyl group having 1 to 20 carbon atoms. The term "Css alkyl alone or in combination means a straight-chain or branched alkyl group having 8 to 18 carbon atoms. Accord ingly, as used herein, the term "Clso alkyl alone or in com bination means a straight-chain or branched alkyl group hav ing 1 to 50 carbonatoms. Each hydrogenatom of a Coalkyl group, a Cs-1s alkyl group and Clso alkyl group may be replaced by a substituent. In each case the alkyl group may be present at the end of a molecule or two moieties of a molecule may be linked by the alkyl group. I0085. As used herein, the term “Calkenyl alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to 6 carbonatoms. If present at the end of a molecule, examples are —CH=CH, —CH=CH-CH —CH2— CH=CH, -CH=CHCH-CH and -CH=CH CH=CH2. When two moieties of a molecule are linked by the Calkenyl group, then an example for such Calkenyl is —CH=CH-. Each hydrogen atom of a C- alkenyl group may be replaced by a substituent as defined below. Optionally, one or more triple bond(s) may occur. I0086 Accordingly, as used herein, the term “Coalk enyl alone or in combination means a straight-chain or branched hydrocarbon residue comprising at least one car bon-carbon double bond having 2 to 20 carbon atoms. The term "C-so alkenyl alone or in combination means a straight-chain or branched hydrocarbon residue comprising at least one carbon-carbon double bond having 2 to 50 carbon atoms. If present at the end of a molecule, examples are -CH=CH, -CH=CH-CH, -CH-CH=CH, 0079 wherein -CH=CHCH-CH and -CH=CH-CH=CH. When 0080 dashed lines indicate attachment to the remain two moieties of a molecule are linked by the alkenyl group, der of the moiety or reagent, and R' and R" are then an example is e.g. —CH=CH-. Each hydrogen atom independently of each other H or C. alkyl. of a Coalkenyl or Clso alkenyl group may be replaced by 0081. The term "hyaluronic acid-based comprising at least a substituent as defined below. Optionally, one or more triple X% hyaluronic acid is used accordingly. bond(s) may occur. 0082. As used herein, the term "C. alkyl alone or in I0087 As used herein, the term “C. alkynyl alone or in combination means a straight-chain or branched alkyl group combination means Straight-chain or branched hydrocarbon having 1 to 4 carbonatoms. If present at the end of a molecule, residue comprising at least one carbon-carbon triple bond US 2016/00821 23 A1 Mar. 24, 2016

having 2 to 6 carbonatoms. If present at the end of a molecule, 7-membered heterocyclyl or 4- to 7-membered heterocyclic examples are —C=CH, —CH2—C=CH, CH, CH group may be replaced by a Substituent as defined below. C=CH and CH-C=C CH. When two moieties of a 0093. As used herein, the term “8- to 11-membered het molecule are linked by the alkynyl group, then an example is: erobicyclyl or “8- to 11-membered heterobicycle” means a —C=C-. Each hydrogenatom of a C- alkynyl group may heterocyclic system of two rings with 8 to 11 ring atoms, be replaced by a substituent as defined below. Optionally, one where at least one ring atom is shared by both rings and that or more double bond(s) may occur. may contain up to the maximum number of double bonds 0088 Accordingly, as used herein, the term “Coalky (aromatic or non-aromatic ring which is fully, partially or nyl alone or in combination means a straight-chain or un-saturated) wherein at least one ring atom up to 6 ring branched hydrocarbon residue comprising at least one car atoms are replaced by a heteroatom selected from the group bon-carbon triple bond having 2 to 20 carbon atoms and consisting of sulfur (including —S(O)— —S(O) ), oxy “Clso alkynyl alone or in combination means a straight gen and nitrogen (including=N(O)—) and wherein the ring chain or branched hydrocarbon residue comprising at least is linked to the rest of the molecule via a carbon or nitrogen one carbon-carbon triple bond having 2 to 50 carbonatoms. If atom. Examples for a 8- to 11-membered heterobicycle are present at the end of a molecule, examples are —C=CH, indole, indoline, benzofuran, benzothiophene, benzoxazole, —CH C=CH, CH, CH, C=CH and CH-C=C- benzisoxazole, benzothiazole, benzisothiazole, benzimida CH. When two moieties of a molecule are linked by the Zole, benzimidazoline, quinoline, quinazoline, dihydro alkynyl group, then an example is —C=C-. Each hydrogen quinazoline, quinoline, dihydroquinoline, tetrahydroquino atom of a C2-20 alkynyl or C2-so alkynyl group may be line, decahydroquinoline, isoquinoline, replaced by a substituent as defined below. Optionally, one or decahydroisoquinoline, tetrahydroisoquinoline, dihydroiso more double bond(s) may occur. quinoline, benzazepine, purine and pteridine. The term 8- to 0089. As used herein, the terms “Cs cycloalkyl or “Cs 11-membered heterobicycle also includes spiro structures of cycloalkyl ring means a cyclic alkyl chain having 3 to 8 two rings like 1,4-dioxa-8-azaspiro4.5 decane or bridged carbon atoms, which may be saturated or unsaturated, e.g. heterocycles like 8-aza-bicyclo[3.2.1]octane. Each hydrogen cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex atom of an 8- to 11-membered heterobicyclyl or 8- to enyl, cycloheptyl, cyclooctyl. Each hydrogen atom of a 11-membered heterobicycle carbon may be replaced by a cycloalkyl carbon may be replaced by a substituent as defined substituent as defined below. below. The term "C's cycloalkyl” or “Cs cycloalkyl ring” 0094. The term “substituted” means that one or more—H also includes bridged bicycles like norbonane or norbonene. atom(s) of a molecule or moiety are replaced by a different Accordingly, "Cs cycloalkyl means a cycloalkyl having 3 atom or a group of atoms, which are referred to as 'substitu to 5 carbon atoms and Co cycloalkyl having 3 to 10 carbon ent'. Suitable substituents are halogen; CN; COOR: OR: atOmS. C(O)R’: C(O)N(RR), S(O)N(RR); S(O)N(R'R''); 0090 Accordingly, as used herein, the term “Co S(O).R.: S(O)R’; N(R)S(O)N(RR); SR; N(RR): cycloalkyl means a carbocyclic ring system having 3 to 10 NOOC(O)R’:N(R)C(O)R’; N(R)S(O)R’’; N(R)S(O) carbon atoms, which may be saturated or unsaturated, e.g. R; N(R)C(O)OR; N(R)C(O)N(RR); OC(O)N cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex (R'R''); T: Clso alkyl: Clso alkenyl; or Clso alkynyl, which enyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl. The T: C so alkyl, C2-soalkenyl; and C2-so alkynyl are optionally term “Co cycloalkyl also includes at least partially satu substituted with one or more R', which are the same or rated carbomono- and -bicycles. different and wherein Clso alkyl, C2-so alkenyl; and C2-s 0091. As used herein, the term “halogen' means fluoro, alkynyl are optionally interrupted by one or more group(s) chloro, bromo or iodo. Particularly preferred is fluoro or selected from the group consisting of T. —C(O)O—; —O—; chloro. 0092. As used herein, the term “4- to 7-membered hetero cyclyl or “4- to 7-membered heterocycle” means a ring with 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of Sulfur (including group consisting of H. T. Clso alkyl, C2-soalkenyl; and —S(O)— —S(O) ), oxygen and nitrogen (including Clso alkynyl, which T. Clso alkyl, Clso alkenyl; and —N(O)—) and wherein the ring is linked to the rest of the Clso alkynyl are optionally Substituted with one or more molecule via a carbon or nitrogen atom. Examples for 4- to R", which are the same or different and which Clso 7-membered heterocycles include but are not limited to aze alkyl, Clso alkenyl; and Clso alkynyl are optionally tidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, interrupted by one or more group(s) selected from the imidazole, imidazoline, pyrazole, pyrazoline, oxazole, group consisting of T. —C(O)O—; —O—, —C(O)—; oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, C(O)N(R') : S(O)N(R') : S(O)N(R') : isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahy —S(O) ; –S(O)–: N(R')S(O)N(R') : drofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, S : N(R') ; OC(O)R'': N(R')C(O) ; pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, N(R')S(O) : N(R')S(O) ; N(R')C(O) isothiazolidine, thiadiazolidine, Sulfo lane, pyran, dihydropy O. : N(R')C(O)N(R') ; and OC(O)N ran, tetrahydropyran, imidazolidine, pyridine, pyridazine, (R' IRI la); pyrazine, pyrimidine, piperazine, piperidine, morpholine, tet 0097 T is selected from the group consisting of phenyl: razole, triazole, triazolidine, tetrazolidine, diazepane, naphthyl; indenyl; indanyl, tetralinyl; Co cycloalkyl, azepine and homopiperazine. Each hydrogen atom of a 4- to 4- to 7-membered heterocyclyl; and 8- to 11-membered US 2016/00821 23 A1 Mar. 24, 2016

heterobicyclyl, wherein T is optionally substituted with 0110. In contrast, a “permanent linkage' is non-enzymati one or more R', which are the same or different; cally hydrolytically degradable under physiological condi 0.098 R' is halogen; CN; oxo (=O); COOR: OR; tions (aqueous buffer at pH 7.4, 37° C.) with a half-life of C(O)R2, C(O)N(R2R12); S(O)N(R2R'2); S(O)N more than twelve months. (R'R'2); S(O).R'?: S(O)R'?; N(R')S(O)N 0111. As used herein, the term “traceless prodrug linker' (R2R12); SR2; N(R2R12); NO; OC(O)R'?: means a reversible prodrug linker which upon cleavage leaves N(R'2)C(O)R2; N(R'2)S(O).R'2'; N(R'2)S(O)R'2'; no moiety originally part of the reversible prodrug linker N(R')C(O)OR'2'; N(R')C(O)N(R'R'2); OC(O)N moiety on the released tag moiety-biologically active moiety (R'R''); or C alkyl, which C alkyl is optionally conjugate. substituted with one or more halogen, which are the 0112. As used herein, the term "peptide' means a short same or different; polymer of amino acid monomers linked by peptide bonds. 0099 R'', R''", R', R'', R'' are independently of The term “polypeptide' means a peptide comprising up to each other selected from the group consisting of H; and and including 50 amino acid monomers. The term “protein' C. alkyl, which C alkyl is optionally substituted means a peptide of more than 50 amino acid monomers. with one or more halogen, which are the same or differ 0113. As used herein, the term "oligonucleotide' means a ent. short nucleic acid polymer of up to 200 bases. 10100. In one embodiment R. R. Rare independently 0114. As used herein, the term “pharmaceutical composi of each other H. tion” means one or more active ingredients, i.e. drugs or 0101. In one embodiment R' is C alkyl. prodrugs, and one or more inert ingredients, the so-called 0102. In one embodiment T is phenyl. excipients, as well as any product which results, directly or 0103 Preferably, a maximum of 6 —H atoms of a moiety indirectly, from combination, complexation or aggregation of or molecule are independently replaced by a Substituent, e.g. any two or more of the ingredients, or from dissociation of 5 —H atoms are independently replaced by a Substituent, 4 one or more of the ingredients, or from other types of reac —Hatoms are independently replaced by a substituent, 3 —H tions or interactions of one or more of the ingredients. atoms are independently replaced by a Substituent, 2 —H Accordingly, the pharmaceutical compositions of the present atoms are independently replaced by a Substituent, or 1 —H invention encompass any composition made by admixing the atom is replaced by a Substituent. hydrogel-linked prodrug releasing tag moiety-biologically 0104. As used herein, the term “interrupted means that active moiety conjugates of the present invention and one or between two carbon atoms or at the end of a carbon chain more pharmaceutically acceptable excipient(s). between the respective carbon atom and the hydrogen atom 0.115. As used herein, the term “excipient” refers to a one or more atom(s) are inserted. diluent, adjuvant, or vehicle with which the active ingredient 0105. As used herein, the term “prodrug” means a com is administered. Such pharmaceutical excipient can be sterile pound that undergoes biotransformation before exhibiting its liquids, such as water and oils, including those of petroleum, pharmacological effects. Prodrugs can thus be viewed as animal, vegetable or synthetic origin, including but not lim biologically active moieties connected to specialized non ited to peanut oil, soybean oil, mineral oil, Sesame oil and the toxic protective groups used in a transient manner to alter or like. Water is a preferred excipient when the pharmaceutical to eliminate undesirable properties in the parent molecule. composition is administered orally. Saline and aqueous dex This also includes the enhancement of desirable properties in trose are preferred excipients when the pharmaceutical com the drug and the Suppression of undesirable properties. position is administered intravenously. Saline Solutions and 0106. As used herein, the term “carrier-linked prodrug’ aqueous dextrose and glycerol Solutions are preferably means a prodrug that contains a reversible linkage of a bio employed as liquid excipients for injectable solutions. Suit logically active moiety with a carrier group and which carrier able pharmaceutical excipients include starch, glucose, lac improves the physicochemical orpharmacokinetic properties tose, Sucrose, mannitol, trehalose, gelatin, malt, rice, flour, of the biologically active moiety and which carrier is removed chalk, silica gel, Sodium Stearate, glycerol monostearate, talc, in vivo, usually by a hydrolytic cleavage. Preferably, the Sodium chloride, dried skim milk, glycerol, propylene, gly carrier is a polymer. col, water, ethanol and the like. The pharmaceutical compo 0107 Accordingly, the term “hydrogel-linked prodrug’ sition, if desired, can also contain minor amounts of wetting refers to a carrier-linked prodrug in which the carrier is a or emulsifying agents, pH buffering agents, like, for example, hydrogel. acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2- 0108. As used herein, the term “reversible prodrug linker hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2- moiety' means a moiety which on its one end is attached to a (N-morpholino)ethanesulfonic acid), or can contain deter backbone moiety of the hydrogel either directly or through a gents, like Tween, poloxamers, poloxamines, CHAPS, spacer moiety and on another end is attached to a tag moiety Igepal, or amino acids like, for example, glycine, lysine, or biologically active moiety conjugate through a reversible histidine. These pharmaceutical compositions can take the linkage. form of Solutions, Suspensions, emulsions, tablets, pills, cap 0109 A“biodegradable linkage' or “reversible linkage' is Sules, powders, Sustained-release formulations and the like. a linkage that is enzymatically and/or non-enzymatically The pharmaceutical composition can be formulated as a Sup hydrolytically degradable, i.e. cleavable, under physiological pository, with traditional binders and excipients such as trig conditions (aqueous buffer at pH 7.4, 37°C.) with a half-life lycerides. An oral formulation can include standard excipi ranging from one hour to twelve months. Preferably, a bio ents such as pharmaceutical grades of mannitol, lactose, degradable linkage is non-enzymatically hydrolytically starch, magnesium Stearate, sodium saccharine, cellulose, degradable, i.e. degradable independent of enzymatic activ magnesium carbonate, etc. Examples of Suitable pharmaceu ity, under physiological conditions with a half-life ranging tical excipients are described in “Remington’s Pharmaceuti from one hour to twelve months. cal Sciences” by E. W. Martin. Such compositions will con US 2016/00821 23 A1 Mar. 24, 2016 tain a therapeutically effective amount of the drug or prodrug, I0120 Preferably, the at least one backbone reagent of step together with a Suitable amount of excipient, so as to provide (a) is PEG-based comprising at least 10% PEG or is hyalu the form for proper administration to the patient. The formu ronic acid-based comprising at least 20% hyaluronic acid. lation should suit the mode of administration. I0121. In one preferred embodiment, the at least one back 0116. In general the term “comprise' or “comprising also bone reagent of step (a) is hyaluronic acid-based comprising encompasses "consist of or “consisting of. at least 20% hyaluronic acid, more preferably, comprising at 0117 Some of the backbone and crosslinker reagents, least 40% hyaluronic acid, even more preferably, at least 60% which can be used as starting material in process step (a) are hyaluronic acid, even more preferred at least 80% hyaluronic commercially available. Further, the backbone and acid. crosslinker reagents can be prepared according to a method 0.122 Preferably, in such hyaluronic acid-comprising described in the Examples section. A method for the synthesis backbone reagent of step (a) each A" is an amine. of a suitable backbone reagent is described in example 1 of I0123. In another preferred embodiment, the at least one WO2011/012715A1, which is incorporated by reference backbone reagent of step (a) is PEG-based comprising at least herein. Example 2 of WO2011/012715A1 further provides 10% PEG, preferably at least 20% PEG, even more preferably methods for the synthesis of crosslinker reagents. Based on at least 30%, even more preferably at least 40% PEG, even these methods the person skilled in the art is able to apply more preferably at least 50% PEG, even more preferably at standard chemical knowledge to obtain the backbone and least 60%, even more preferably at least 70% PEG, even more crosslinker reagents described in the present invention. preferably at least 80% PEG and most preferably at least 90% PEG. The Backbone Reagent 0.124 Preferably, in such PEG-based backbone reagent of step (a) each A" is an amine. 0118. In one embodiment the backbone reagent is present I0125. Some of the functional groups A" react with the in the form of its acidic salt, preferably in the form of an acid functional end groups of the crosslinker reagents during poly addition salt, if A' is amine. Suitable acid addition salts are merization in step (b) and the remaining activated functional formed from acids which form non-toxic salts. Examples end groups are used for optionally coupling spacer moieties include but are not limited to acetate, aspartate, benzoate, in step (c) and/or for covalently conjugating the reagents of besylate, bicarbonate, carbonate, bisulphate, Sulphate, steps (d-i), (d-ii), (d-iii), (d-iv), (d-V) (d-vi), (d-vii) or (d-viii). borate, camsylate, citrate, edisylate, esylate, formate, fuma i.e. the molar ratio of A" to functional end groups is >1. rate, gluceptate, gluconate, glucuronate, hexafluorophos 0126. In one embodiment, the at least one backbone phate, hibenzate, hydrochloride, hydrobromide, hydroiodide, reagent is selected from the group consisting of isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, nicotinate, nitrate, orotate, 0.127 (i) a compound of formula (I) oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, B(-(A'), (SP).2-A-P-A’-Hyp'), (I), dihydrogen phosphate, Sacharate, Stearate. Succinate, tartrate 0.128 wherein and tosylate. Particularly preferred, the backbone reagent is I0129 B is a branching core, present in the form of its hydrochloride salt. I0130 SP' is a spacer moiety selected from the group 0119 The at least one backbone reagent of step (a) com consisting of Calkyl, C2-alkenyland C2-alkynyl, prises one or more polymer(s) selected from the group con sisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly I0131 P is a PEG-based polymeric chain comprising (acrylic acids), poly(acrylates), poly(acrylamides), poly at least 80% PEG, preferably at least 85% PEG, more (alkyloxy) polymers, poly(amides), poly(amidoamines), preferably at least 90% PEG and most preferably at poly(amino acids), poly(anhydrides), poly(aspartamides), least 95% PEG, poly(butyric acids), poly(glycolic acids), polybutylene (0132 Hyp' is a moiety comprising an amine ( NH terephthalates, poly(caprolactones), poly(carbonates), poly and/or —NH-) or a polyamine comprising at least (cyanoacrylates), poly(dimethylacrylamides), poly(esters), two amines ( NH and/or NH ), poly(ethylenes), poly(ethyleneglycols), poly(ethylene 0.133 x is an integer from 3 to 16, oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly 0.134 x1, x2 are independently of each other 0 or 1, (glycolic acids), poly(hydroxyethyl acrylates), poly(hy provided that x1 is 0, if x2 is 0, A, A, A are inde droxyethyloxazolines), poly(hydroxymethacrylates), poly pendently of each other selected from the group con (hydroxypropylmethacrylamides), poly(hydroxypropyl sisting of methacrylates), poly(hydroxypropyloxazolines), poly(imi nocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly (methyloxazolines), poly(organophosphaZenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(si loxanes), poly(urethanes), poly(Vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(Vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gela tins, hyaluronic acids and derivatives, functionalized hyalu ronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, Xylans, and copolymers thereof. US 2016/00821 23 A1 Mar. 24, 2016

-continued -continued O O -HO-C-H, --C-O-H-,

-Hé-N-H, --N---,i --O---, ---O-H-, : O --N-C-N-H, ----R1 - - - - 6 - O

RI O -HS RI N , and O and O X -HS

O N O X --N O

O S--, --N

O S--, I0135 wherein R' and R'' are independently of each other H or C. alkyl; 0.136 (ii) a compound of formula (II) Hyp?-A-P-A-Hyp (II), I0141 wherein R' and R" are independently of each other H or C. alkyl; 0.137 wherein 0.138 P is defined as above in the compound of for 0.142 (iii) a compound of formula (III) mula (I), P-A-Hyp' (III), 0.139 Hyp, Hypare independently of each other a 0.143 wherein polyamine comprising at least two amines (—NH I0144 P' is a PEG-based polymeric chain comprising and/or —NH ), and at least 80% PEG, preferably at least 85% PEG, more I0140 A and A'are independently selected from the preferably at least 90% PEG and most preferably at group consisting of least 95% PEG, (0145) Hyp' is a polyamine comprising at least three amines ( NH and/or NH), and

O s S s I0146) A is selected from the group consisting of

--N--, ----, --O--, --S-H, US 2016/00821 23 A1 Mar. 24, 2016 10

-continued -continued --N-H, ----, --N-H, ----, : :

--O-)--, --8-O--, --O-)--, --8-O--, R' ------O O

RI RI O and O and -- S -HS N N O X O \

O O --N --N

O S-H- O S--

0147 wherein R' and R'' are independently of each wherein RandR" are independently of each other Hor other H or C. alkyl; C. alkyl, and 0148 and I0153. T is selected from the group consisting of 0149 (iv) a compound of formula (IV) Clso alkyl, C2-so alkenyl and C2-so alkynyl, which T-A-Hyp (IV), Clso alkyl, Clso alkenyl or Clso alkynyl are option ally interrupted by one or more group(s) selected from 0150 wherein the group consisting of —NH , —N(C. alkyl)-. I0151 Hyp is a polyamine comprising at least three O— —S , —C(O)— —C(O)NH , —C(O)N amines ( NH and/or —NH), and (C. alkyl)-, -O-C(O)— —S(O)— —S(O) , I0152 A is selected from the group consisting of 4- to 7-membered heterocyclyl phenyl and naphthyl. 0154) In the following sections the term “Hyp” refers to Hyp', Hyp, Hyp, Hyp' and Hypcollectively. 0155 Preferably, the backbone reagent is a compound of --O--, --S-H, formula (I), (II) or (III), more preferably the backbone reagent is a compound of formula (I) or (III), and most preferably the backbone reagent is a compound of formula (I). US 2016/00821 23 A1 Mar. 24, 2016

0156. In a preferred embodiment, the backbone reagent is (0161 Preferably, A of formula (II) is selected from the of formula (I) and X is 4, 6 or 8, more preferablyx is 4 or 8 and group consisting of most preferably x is 4. (O157. In a preferred embodiment A, A, A, A, A, A and A of formulas (I) to (IV) are selected from the group consisting of -HC-N-H, and

HN-C-N-H. -HO-H, -HC-N-H, H H

-HN-C-H and (0162 Preferably, A of formula (II) is selected from the group consisting of

HN-C-N-H. HN-C-H and

0158 Preferably, A' of formula (I) is selected from the group consisting of -HN-C-N-H . H H

(0163 Preferably, A of formula (III) is selected from the group consisting of

0159 Preferably, A' of formula (I) is selected from the group consisting of

-HO-H, --C-N-H, and (0164 Preferably, A of formula (IV) is selected from the group consisting of

-HN-C-H.

(0160 Preferably, A of formula (I) is selected from the group consisting of

HN-C-H and (0165 Preferably, in a compound of formula (IV), T is H or C. alkyl. (0166 SP is a spacer moiety selected from the group con HN-C-N-H. sisting of Calkyl, Calkenyl and C-alkynyl. Preferably SP' is —CH2—, —CH2—CH2—, —CH(CH)—, —CH2— H H CH2—CH2—, —CH(CHs)— —C(CH) , -CH=CH- or -CH=CH-, and most preferably SP' is —CH2—, —CH2—CH2—, or —CH=CH-. US 2016/00821 23 A1 Mar. 24, 2016 12

0167. In one embodiment B of formula (I) is selected from -continued the group consisting of (a-X) | (a-i)

-- (a-xi)

(a-ii)

--N s (a-xii)

(a-iii)

(a-xiii)

(a-iv)

(a-xiv)

(a-v)

(a-XV)

(a-vi)

(a-vii) (a-xvi)

(a-viii)

(a-iX) (a-xvii) US 2016/00821 23 A1 Mar. 24, 2016 13

-continued -continued (a-xviii) (a-xxiii)

(a-xix)

(0168 wherein (0169 dashed lines indicate attachment to A' or, if X1 and x2 are both 0, to A', (0170 t is 1 or 2; preferably t is 1, (0171 v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14: preferably, V is 2, 3, 4, 5, 6; more preferably, V is 2, 4 or 6; most preferably, V is 2. 0172. In a preferred embodiment, B has a structure of (a-XX) formula (a-i), (a-ii), (a-iii), (a-iv), (a-V), (a-vi), (a-vii), (a-viii). (a-ix), (a-X), (a-Xiv), (a-XV) or (a-Xvi). More preferably, Bhas a structure of formula (a-iii), (a-iv), (a-V), (a-vi), (a-vii), (a-viii), (a-ix), (a-X) or (a-iv). Most preferably, B has a struc ture of formula (a-xiv). , (0173 A preferred combination of Band A", or, if x1 and x2 are both 0, of B and A', is selected from the group con sisting of the following structures:

(b-i)

-HO O-H-

(a-xxi)

-HO O-H-

(b-ii)

(a-xxii)

(b-iii) US 2016/00821 23 A1 Mar. 24, 2016

-continued 0180. In one embodiment, P of formula (I) or (II) is of A. (b-iv) formula (c-i):

A.

w O w w w w (c-i) w ', O y O

O F

p F A. p 0181 wherein in ranges from 6 to 900, more preferably in ranges from 20 to 700 and most preferably n ranges from 20 to 250. A. A. (b-v) F F F F A. A. (0182. In one embodiment, Pofformula (III) has the struc ' w O w O ture of formula (c-ii):

w F '', O O O ? w p

w F w F (c-ii) A. W F

A. A. (b-vi) f F w A. A. wherein w 0183) O ' O w F w F 0.184 n ranges from 6 to 900, more preferably n ranges , O O w F from 20 to 700 and most preferably n ranges from 20 to w F w w 250; , ? O 0185 T is selected from the group consisting of C. p F alkyl, C- alkenyl and C alkynyl, which Ce alkyl, p Calkenyl and C- alkynyl are optionally interrupted by one or more group(s) selected from the group con sisting of —NH-, -N (C. alkyl)-, —O— —S- (b-vii) —C(O)—, —C(O)NH , —C(O)N(C. alkyl)-. O—C(O)— —S(O)—and —S(O) 0186. In one embodiment, the moiety Hyp' of formulas (I) to (IV) is a polyamine and preferably comprises in bound form and, where applicable, in R- and/or S-configuration, a '', N-N-N-N-N-N-X moiety of formulas (d-i), (d-ii), (d-iii) and/or (d-iv):

0.174 wherein (d-i) (0175 dashed lines indicate attachment to SP' or, if X1 H and X2 are both 0, to P. HN -h-2 N-4N1. (0176 More preferably, the combination of Band A' or, if X1 and x2 are both 0, the combination of B and A', is of formula (b-i), (b-iv), (b-vi) or (b-viii) and most preferably is (d-ii) of formula (b-i). 0177. In one embodiment, x1 and x2 of formula (I) are both 0. HO 3 NH2, 0178. In one embodiment, the PEG-based polymeric NH2 chain Phas a molecular weight from 0.3 kDa to 40 kDa; e.g. from 0.4 to 35 kDa, from 0.6 to 38 kDA, from 0.8 to 30 kDa, from 1 to 25 kDa, from 1 to 15 kDa or from 1 to 10 kDa. Most preferably P has a molecular weight from 1 to 10 kDa. (d-iii) (0179. In one embodiment, the PEG-based polymeric chain P' has a molecular weight from 0.3 kDa to 40 kDa; e.g. HO z4 OH, from 0.4 to 35 kDa, from 0.6 to 38 kDA, from 0.8 to 30 kDa, from 1 to 25 kDa, from 1 to 15 kDa or from 1 to 10 kDa. Most preferably P" has a molecular weight from 1 to 10 kDa. US 2016/00821 23 A1 Mar. 24, 2016 15

-continued a moiety of formula (e-iii)

(e-iii) (d-iv) NH2 lz5 O HO --- NN11 NH,

0187 wherein 0188 Z1, z2, Z3, Z4, Z5, Z6 are independently of each other 1, 2, 3, 4, 5, 6, 7 or 8. 0189 More preferably, Hyp' comprises inbound form and in R- and/or S-configuration lysine, ornithine, diaminoprop rionic acid and/or diaminobutyric acid. Most preferably, Hyp' comprises in bound form and in R- and/or S-configura tion lysine. (0190. Preferably, Hyp has a molecular weight from 40 Da to 30 kDa, preferably from 0.3 kDa to 25 kDa, more prefer ably from 0.5 kDa to 20 kDa, even more preferably from 1 kDa to 20 kDa and most preferably from 2 kDa to 15 kDa. wherein 0191 Hyp is preferably selected from the group consist 01.98 ing of 0199 p5 to p11 are identical or different and each is a moiety of formula (e-i) independently of the others an integer from 1 to 5, pref erably p5 to p11 are 4, and (0200 the dashed line indicates attachment to A if the (e-i) backbone reagent is of formula (I), to A or A if the NH2 backbone reagent is of formula (II), to A if the backbone '', NH2 reagent is of formula (III) and to A if the backbone w pl reagent is of formula (IV); a moiety of formula (e-iv) (0192 wherein 0193 p1 is an integer from 1 to 5, preferably p1 is 4, and (e-iv) (0194 the dashed line indicates attachment to A if the backbone reagent is of formula (I) and to A or A if the backbone reagent is of formula (II): a moiety of formula (e-ii)

(e-ii)

p2

0195 wherein 0.196 p2, p3 and p4 are identical or different and each is independently of the others an integer from 1 to 5, pref erably p2, p3 and p4 are 4, and (0197) the dashed line indicates attachment to A if the backbone reagent is of formula (I), to A or A if the backbone reagentis of formula (II), to A if the backbone is of formula (III) and to A if the backbone reagent is of formula (IV); US 2016/00821 23 A1 Mar. 24, 2016

wherein reagent is of formula (III) and to A if the backbone 0201 p12 to p26 are identical or different and each is reagent is of formula (IV); independently of the others an integer from 1 to 5, pref a moiety of formula (e-vii) erably p12 to p26 are 4, and (0202) the dashed line indicates attachment to A if the (e-vii) backbone reagent is of formula (I), to A or A if the NH2 backbone reagentis of formula (II), to A if the backbone tra is of formula (III) and to A if the backbone reagent is of N NH 2 formula (IV); 13 r Ya16. a moiety of formula (e-v) O ra NH2 ->,', NYa16. N Ya16.NH 2 w O

(e-v) 0210 wherein 0211 p31 to p36 are identical or different and each is independently of the others an integer from 2 to 5, pref erably p31 to p36 are 3, and 0212 the dashed line indicates attachment to A if the backbone reagent is of formula (I), to A or A if the backbone reagentis of formula (II), to A if the backbone reagent is of formula (III) and to A if the backbone 0203 wherein reagent is of formula (IV); 0204 p27 and p28 are identical or different and each is a moiety of formula (e-viii) independently of the other an integer from 1 to 5, pref erably p27 and p28 are 4, (e-viii) 0205 q is an integer from 1 to 8, preferably q is 2 or 6 and most preferably 1 is 6, and r NH2 0206 the dashed line indicates attachment to A if the N NH backbone reagent is of formula (I), to A or A if the 138 r Ya-26 2 backbone reagentis of formula (II), to A if the backbone reagent is of formula (III) and to A if the backbone O NH2 reagent is of formula (IV); H H 1. N N N N NH2 a moiety of formula (e-vi) 1,37 Ya-21 Ya-2, O O raNH2 N NH2 (e-vi) 1645 Ya-2, NH2 O NH2 , Nra. NH 1. -N-1": ->, NYa-6 N Ya16s N Ya-2 NH2 w O O

wherein 0207 wherein 0213 p37 to p50 are identical or different and each is independently of the others an integer from 2 to 5, pref 0208 p29 and p30 are identical or different and each is erably p37 to p50 are 3, and independently of the other an integer from 2 to 5, pref 0214) the dashed line indicates attachment to A if the erably p29 and p30 are 3, and backbone reagent is of formula (I), to A or A if the 0209 the dashed line indicates attachment to A if the backbone reagentis of formula (II), to A if the backbone backbone reagent is of formula (I), to A or A if the reagent is of formula (III) and to A if the backbone backbone reagentis of formula (II), to A if the backbone reagent is of formula (IV); and US 2016/00821 23 A1 Mar. 24, 2016

a moiety of formula (e-ix): 0218. Preferrably, the moiety -A-Hyp' is

(e-ix) H NH2 >''" H rá w O 1653 N.1% 0219) wherein O NH2 0220 the dashed line indicates attachment to P; and H H p? N N N N NH2 0221) E" is selected from formulas (e-i) to (e-ix). 0222 Preferrably, the moiety Hyp’-A is "SSX 6

0223) wherein 0224 the dashed line indicates attachment to P; and 0225 E" is selected from formulas (e-i) to (e-ix). 0226 Preferably, the moiety -A-Hyp is

w H

H H N N N Nr? NH2 >''" 1667 r N-51 N.1% 6 O O NH2 0227 wherein H N Nr? NH2 0228 the dashed line indicates attachment to P; and 1675 N-21 0229 E" is selected from formulas (e-i) to (e-ix). NH2 O 6 0230 Preferably, the moiety -A-Hyp is N N N N NH2 -X N-2 Y-6, S-15 N16 H ' O O O >" w O

0231 wherein wherein 0232 the dashed line indicates attachment to P'; and 0215 p51 to p80 are identical or different and each is 0233 E" is selected from formulas (e-i) to (e-ix). independently of the others an integer from 2 to 5, pref 0234 More preferably, the backbone reagent is of formula erably p51 to p80 are 3, and (I) and B is of formula (a-xiv). 0216) the dashed line indicates attachment to A if the 0235. Even more preferably, the backbone reagent is of backbone reagent is of formula (I), to A or A if the formula (I), B is of formula (a-xiv), x1 and x2 are 0, and A' is backbone reagent is of formula (II), to A if the backbone —O—. reagent is of formula (III) and to A if the backbone 0236 Even more preferably, the backbone reagent is of reagent is of formula (IV); and formula (I), B is of formula (a-xiv), A' is —O , and P is of wherein the moieties (e-i) to (e-v) may at each chiral center be formula (c-i). in either R- or S-configuration, preferably, all chiral centers of 0237 Even more preferably, the backbone reagent is of a moiety (e-i) to (e-V) are in the same configuration. formula (I), B is of formula (a-xiv), x1 and x2 are 0, A' is 0217 Preferably, Hyp is of formula (e-i), (e-ii), (e-iii), —O— and P is of formula (c-i). (e-iv), (e-vi), (e-vii), (e-viii) or (e-ix). More preferably, Hyp' 0238 Even more preferably, the backbone reagent is for is of formula (e-ii), (e-iii), (e-iv), (e-vii), (e-viii) or (e-ix), mula (I), B is of formula (a-xiv), x1 and x2 are 0, A' is —O , even more preferably Hyp is of formula (e-ii), (e-iii), (e-vii) P is of formula (c-i), A is NH-(C=O)—and Hyp' is of or (e-viii) and most preferably Hyp is of formula (e-iii). formula (e-iii). US 2016/00821 23 A1 Mar. 24, 2016

0239 Most preferably, the backbone reagent has the fol lowing formula:

O H N HN NH2 NH2 O HN O NH2 O H N N NH2 H NH2 O HN NH2 O

0240 wherein more preferably at least 80% hyaluronic acid and most pref 0241 n ranges from 10 to 40, preferably from 10 to 30, erably at least 90% hyaluronic acid and further comprises more preferably from 10 to 20. 0242 Equally preferably, in ranges from 20 to 30 kDa and 0246 (i) at least two carbonyloxy groups (—(C=O)— most preferably n is 28. O— or —O—(C=O)—), and additionally 0247 (ii) at least two functional end groups selected The Crosslinker Reagent from the group consisting of activated ester groups, acti 0243 The at least one crosslinker reagent of step (a) com vated carbamate groups, activated carbonate groups, prises one or more polymer(s) selected from the group con activated thiocarbonate groups and amine groups. sisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly 0248. In another preferred embodiment, the at least one (acrylic acids), poly(acrylates), poly(acrylamides), poly crosslinker reagent of step (a) comprises PEG. Preferably, (alkyloxy) polymers, poly(amides), poly(amidoamines), Such PEG-comprising crosslinker reagent of step (a) com poly(amino acids), poly(anhydrides), poly(aspartamides), prises at least 70% PEG, more preferably at least 80% PEG poly(butyric acids), poly(glycolic acids), polybutylene and most preferably at least 90% PEG and further comprises terephthalates, poly(caprolactones), poly(carbonates), poly (cyanoacrylates), poly(dimethylacrylamides), poly(esters), 0249 (i) at least two carbonyloxy groups (—(C=O)— poly(ethylenes), poly(ethyleneglycols), poly(ethylene O— or —O—(C=O)—), and additionally oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly (glycolic acids), poly(hydroxyethyl acrylates), poly(hy 0250 (ii) at least two functional end groups selected droxyethyloxazolines), poly(hydroxymethacrylates), poly from the group consisting of activated ester groups, acti (hydroxypropylmethacrylamides), poly(hydroxypropyl vated carbamate groups, activated carbonate groups, methacrylates), poly(hydroxypropyloxazolines), poly(imi activated thiocarbonate groups and amine groups. nocarbonates), poly(lactic acids), poly(lactic-co-glycolic 0251. The at least one crosslinker reagent preferably com acids), poly(methacrylamides), poly(methacrylates), poly prises at least two carbonyloxy groups (—(C=O)—O— or (methyloxazolines), poly(organophosphaZenes), poly(ortho —O—(C=O)—), which are biodegradable linkages. These esters), poly(oxazolines), polypropylene glycols), poly(si biodegradable linkages render the hydrogel biodegradable loxanes), poly(urethanes), poly(Vinyl alcohols), poly(vinyl which is advantageous. In addition, the at least one amines), poly(vinylmethylethers), poly(Vinylpyrrolidones), crosslinker reagent comprises at least two functional end silicones, celluloses, carbomethyl celluloses, hydroxypropyl groups which during the polymerization of step (b) react with methylcelluloses, chitins, chitosans, dextrans, dextrins, gela tins, hyaluronic acids and derivatives, functionalized hyalu the functional groups A" of the at least one backbone reagent. ronic acids, mannans, pectins, rhamnogalacturonans, 0252. The crosslinker reagent has a molecular weight starches, hydroxyalkyl starches, hydroxyethyl starches and ranging from 0.2 to 40 kDa, more preferably ranging from 0.5 other carbohydrate-based polymers, Xylan, and copolymers to 30 kDa, even more preferably ranging from 0.5 to 20 kDa, thereof. even more preferably ranging from 0.5 to 15 kDa and most 0244 Preferably, the at least one crosslinker reagent of step (a) comprises hyaluronic acid or PEG. preferably ranging from 1 to 10 kDa. 0245. In one preferred embodiment, the at least one 0253 Preferably, the reaction of a functional end group of crosslinker reagent of step (a) comprises hyaluronic acid. a crosslinker reagent with a functional group A" of a back Preferably, Such hyaluronic acid-comprising crosslinker bone reagent leads to the formation of an amide linkage reagent of step (a) comprises at least 70% hyaluronic acid, between a backbone moiety and a crosslinker moiety. US 2016/00821 23 A1 Mar. 24, 2016 19

0254. In one preferred embodiment, the crosslinker reagent is a compound of formula (V-I):

(V-I) O O D Y2 D3 s Y. D D2 P2 * * 3 o1 No O O 3 3a R4 R4a R1 R1a R2 R2a R R S 7 2 ra. s2 sl

0255 wherein 0256 each D', D., D and D are identical or different w (f-i) and each is independently of the others selected from the -O O group comprising -O-, -NR , -S- and - V CRR : , N 0257 each R', R', R, R2, R., R., R, R, R and R" are identical or different and each is independently of the others selected from the group comprising —H. (f-ii) —OR7, NR'R'', SR 7 and C alkyl: optionally, | each of the pair(s) R/R, R/R, R/R, and R/R may independently form a chemical bond and/or each of the pairs R/R1,R2/R2, R/R, R/R, R/R, R/R2, O R/R, R''/R', and R/R" are independently of each other joined together with the atom to which they are attached to form a Cs cycloalkyl or to form a ring A or are joined together with the atom to which they are (f-iii) attached to form a 4- to 7-membered heterocyclyl or 8 to 11-membered heterobicyclyl or adamantyl: O (0258 each R is independently selected from Hand C. alkyl: optionally, each of the pair(s) R'/R. R/R. R/R. R/R and R/R may independently form a NO2, chemical bond and/or are joined together with the atom (f-iv) to which they are attached to form a 4- to 7-membered , Fb, heterocyclyl or 8- to 11-membered heterobicyclyl: w 21 A. 0259 each R', R' is independently selected from H y and C alkyl, N 0260nyl, indanylA is selected and tetralinyl: from the group consisting of inde- | (f-v) 0261 P’ is O

(f-vi) 0262 m ranges from 120 to 920, preferably from 120 to 460 and more preferably from 120 to 230; --X 0263 r1, r2, r7, r8 are independently 0 or 1; 0264 r3, ré are independently 0, 1, 2, 3, or 4: 0265 r4, rS are independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 0268 wherein 10: 0269 the dashed lines indicate attachment to the rest 0266 s1, s2 are independently 1, 2, 3, 4, 5 or 6: of the molecule 0267 Y',Y are identical or different and each is inde pendently of the other selected from formulas (f-i) to 0270 b is 1, 2, 3 or 4 (f-vi): 0271 X is C1, Br, I, or F. US 2016/00821 23 A1 Mar. 24, 2016 20

0272 Preferably, the crosslinker reagent is a compound of formula (V-II):

O O Y D D2 P2 * 3 o1 No O 4 4a O R3 R3a R R 7 R1 R1a 2 R2 R2a S ra. s2 sl

0273 wherein -continued (0274 D", D., D and D are identical or different and (f-ii) each is independently of the others selected from the group comprising —O-, -NR , —S- and CRR O 0275 R', R1, R2, R2, R,R,R,R, R and R5 are identical or different and each is independently of the others selected from the group comprising H and C. NO2, (f-iii) alkyl: optionally, one or more of the pair(s) R/R', NO R2/R2, R/R3, R/R1, R/R2, R/R1, R1/R2, and R/ R" form a chemical bond or are joined together with the , -o atom to which they are attached to form a Cs cycloalkyl or to form a ring A or are joined together with the atom to which they are attached to form a 4- to 7-membered NO, heterocyclyl or 8- to 11-membered heterobicyclyl or (f-iv) , Fb, adamantyl: w O 0276 A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl and tetralinyl; N (0277 P2 is (f-v)

O F

F F or (0278 m ranges from 120 to 920, preferably from 120 to F 460 and more preferably from 120 to 230; (f-vi) (0279 r1, r2, r7, r8 are independently 0 or 1; --X 0280 r3, ré are independently 0, 1, 2, 3, or 4: 0281 ra, rS are independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10: 0284 wherein 0282 s1, s2 are independently 1, 2, 3, 4, 5 or 6: 0285 the dashed lines indicate attachment to the rest (0283 Y', Y are identical or different and each is inde of the molecule, pendently of the other selected from formulas (f-i) to (f-vi): 0286 b is 1, 2, 3 or 4 (0287 X is C1, Br, I, or F. 0288 Preferably,Y and Y of formula (V-I) and (V-II) are (f-i) of formula (f-i), (f-ii) or (f-v). More preferably, Y and Y are of formula (fi) or (f-ii) and most preferably, Y and Y are of formula (f-i). 0289 Preferably, both moieties Y and Y of formula (V-I) and (V-II) have the same structure. More preferably, both Y' and Y are of formula (f-i). US 2016/00821 23 A1 Mar. 24, 2016 21

0290. It is understood that the moieties of formula (V-I) 0295 Preferably, the crosslinker reagent of formula (V-I) and (V-II) and (V-II) is symmetric, i.e. the moiety

y and Y w Y2

O O represent the at least two activated functional end groups. 0291 Preferably, r1 and r8 of formula (V-I) and (V-II) are both 0. 0292 Preferably, r1, r8, s1 and s2 of formula (V-I) and (V-II) are all 0. 0293 Preferably, one or more of the pair(s) R'/R', R2/R2, R3/R3a, R/R4, R/R2, R3/R1, R1a/R2, and R3a/R4 of formula (V-I) and (V-II) form a chemical bond or are joined together with the atom to which they are attached to form a Cs cycloalkyl or a ring A. 0294 Preferably, one or more of the pair(s) R/R, R'/ R", R/R, R/R of formula (V-I) and (V-II) are joined together with the atom to which they are attached to form a 4 to 7-membered heterocyclyl or 8- to 11-membered heterobi 0296 Preferred crosslinker reagents are of formula (V-1) cyclyl. to (V-54):

(V-1) (V-2) O O O O O O O O

Yl lus O O O lul Y2, Yl 2 O iii. O 2 Y2, iii. 1.------

(V-3) (V-4) O O O O O O O O

Yl l 3 O O iii. O ---3 Y2, Yl ls4 O1N-N-n iii. O ---,4 Y2,

(V-5) (V-6) O O O O O O O O

Yl l 5 O O iii. O ---5 Y2, Yl ---6 O O iii. O ---6 Y2,

O O O O O O O O

Yl ls7 O O iii. O ---7 Y2, Yl ---8 O O iii. O ---,8 Y2, (V-10) O O O O O O O O

Yl ul-9 O O iii. O ---9 Y2, Yl 1.O O O iii. O ---10 Y2, (V-11) (V-12) O O O O O O O O

O O

Yl O iii. O Y2, Yl O iii. O Y2,

US 2016/00821 23 A1 Mar. 24, 2016

-continued (V-31) O O O O

O

Yl 4 o-ha- iii.-no 4 Y2

(V-32) O O O O cr's -N- O -no O ~. (V-33) O O O O

O Yl O 2 o-ha- -no 2 ch's

(V-34) O O O O

O Yl 3O 3 O -ha- -no15-is (V-35) O O O O

O Yl 4O 4 O-ha- -no11. 4 Y2 (V-36) (V-37) O O O O O O O O

Y O -ha- O-niii. O Y2 Y O 1N- O-niii. O Y2

trans trans cis cis (V-38) (V-39) O O O O O O O O

Y O1n- O-niii. O Y2 Y O 1n- O-niii. O Y2

trans trans cis cis (V-40) (V-41) O O O O O O O O

Yl o-ha-N-noiii. Y2 Yl o-ha-N-noiii. Y2

trans trans cis cis (V-42) (V-43) O O O O O O O O

Y O -ha-N-niii. O Y2 Y O -ha-N-niii. O Y2

trans trans cis cis (V-44) (V-45) O O O O O O O O

trans trans cis cis US 2016/00821 23 A1 Mar. 24, 2016 24

-continued (V-46) (V-47) O O O O O O O O O O

trans trans cis cis

(V-48) (V-49) O Oh-C'sO O O O Oh-'-O-O O O trans trans cis cis

(V-50) (V-51) O O O O O O O O Yl ch--C'. Y2 Yl ---O's trans trans cis cis (V-52) (V-53) , O Oh--O-O O O s'Oh-'-O-O O O O trails trails cis cis (V-54) O O O O ot O N-No Y2

0297 wherein 0298 each crosslinker reagent may be in the form of its racemic mixture, where applicable; and 0299 m, Y and Y are defined as above. 0300 Even more preferred crosslinker reagents are of for mula (Va-1) to (Va.-54):

(Va-1) (Va.-2) O O O O O O O O

Yl lus O O iii. O lul Y2 Yl ---2 O O iii. O ---,3 y2 (Va.-3) (Va.-4) O O O O O O O O

Yl ------,3 O iii. O 5 y2 Yl------4 O iii. O 1 y2 (Va.-5) (Va.-6) O O O O

Yl ls 5 O O iii. O ---s y2 Yl ---6 O O iii. O ---, Y2 US 2016/00821 23 A1 Mar. 24, 2016 25

-continued (Va.-7) (Va.-8) O O O O O O O O

Yl ------,7 O iii. O 2 y2 Yl------8 O iii. O Y2 (Va.-9) (Va.-10) O O O O O O O O

Yl ---9 O O iii. O ---6 Y2 Yl ---0 O O iii. O ---o Y2 (Va.-11) (Va.-12) O O O O O O O O Yl o-ha-O N-1so Y2 Yl o-ha- O -1. Y2

(Va.-13) (Va.-14) O O O O O O O O

O O Yl O iii. O Y2 Yl O iii. O Y2

(Va.-15) (Va.-16) O O O O O O O O

O O Yl O iii. O Y2 YI O iii. O Y2

(Va.-17) (Va.-18) O O O O O O O O

O O Yl O iii. O Y2 Yl O iii. O Y2

(Va.-19) (Va.-20) O O O O O O O O

O O Yl O iii. O Y2 Yl O iii. O Y2

(Va.-21) (Va.-22) O O O O O O O O

Yl O 1N--n.iii. O Y2 Yl O 1N- iii. -n.O Y2

(Va.-23) (Va.-24) O O O O O O O O Yl 2 o-ha-O -hy Yl 3 o-ha- O -hy

US 2016/00821 23 A1 Mar. 24, 2016 27

-continued (Va.-42) (Va.-43) y-h-'--t Y2 ya-h-'--t Y2 (Va.-44) (Va.-45) sch--So Sch--Nors (Va.-46) (Va.-47) y \{y1.h---t SO1 Y2 !:-(y1, h---SC). Y2 (Va.-48) (Va.-49) s' Chol-O-t Y2 , t C2h -- SO2.t Y2 (Val-50) (Va.-51) 9. ---, Y2 Yl --- or Y2 (Va.-52) (Va.-53) R O O O O 'O-h-'-O- Y2 , O1 h--- SO1. Y2 (Va.-54) O O O O

O 1N-N-Niii. O - '',

0301 wherein 0307. In another embodiment, crosslinker reagents V-1, 0302 each crosslinker reagent may be in the form of its V-2, V-5, V-6, V-7, V-8, V-9, V-10, V-11, V-12, V-13, V-14, racemic mixture, where applicable; and V-15, V-16, V-17, V-18, V-19, V-20, V-21, V-22, V-23, V-24, 0303 m, Y and Y are defined as above. V-25, V-26, V-27, V-28, V-29, V-30, V-31, V-32, V-33, V-34, 0304. It was surprisingly found that the use of crosslinker V-35, V-36, V-37, V-38, V-39, V-40, V-41, V-42, V-43, V-44, reagents with branches, i.e. residues other than H, at the alpha V-45, V-46, V-47, V-48, V-49, V-50, V-51, V-52, V-53 anV-54 carbon of the carbonyloxy group lead to the formation of are preferred crosslinker reagents. More preferably, the at hydrogels which are more resistant against enzymatic degra least one crosslinker reagent is of formula V-5, V-6, V-7. V-8, dation, such as degradation through esterases. V-9, V-10, V-14, V-22, V-23, V-43, V-44, V-45 or V-46, and 0305 Similarly, it was surprisingly found that the fewer most preferably, the at least one crosslinker reagent is of atoms there are between the (C=O) of a carbonyloxy group formula V-5, V-6, V-9 or V-14. and the (C=O) of the adjacent activated ester, activated car 0308. In another embodiment, crosslinker reagents Va-1, bamate, activated carbonate or activated thiocarbamate, the Va-2, Va-5, Va-6, Va-7, Va.-8, Va-9, Va-10, Va-11, Va-12, more resistant against degradation the resulting hydrogels Va-13, Va-14, Va-15, Va-16, Va-17, Va-18, Va-19, Va-20, are, Such as more resistant against degradation through Va-21, Va.-22, Va-23, Va-24, Va-25, Va-26, Va-27, Va.-28, esterases. Va-29, Va.-30, Va-31, Va-32, Va-33, Va-34, Va-35, Va-36, 0306 Accordingly, crosslinker reagents V-11 to V-54, V-1, Va-37, Va-38, Va-39, Va-40, Va-41, Va-42, Va.-43, Va.-44, V-2, Va-11 to Va-54, Va-1 and Va-2 are preferred crosslinker Va-45, Va.-46, Va.-47, Va.-48, Va-49, Va-50, Va-51, Va-52, reagents. Crosslinker reagents Va-11 to Va-54, Va-1 and Va-2 Va-53 anVa-54 are even more preferred crosslinker reagents. are most preferred crosslinker reagents. Most preferred is More preferably, the at least one crosslinker reagent is of crosslinker reagent Va-14. formula Va-5, Va-6, Va-7, Va.-8, Va-9, Va-10, Va-14, Va-22, US 2016/00821 23 A1 Mar. 24, 2016 28

Va-23, Va.-43, Va.-44, Va.-45 or Va-46, and most preferably, the 0317 Step (b) can be performed in a broad temperature at least one crosslinker reagent is of formula Va-5, Va-6, Va-9 range, preferably at a temperature from -10°C. to 100 C., or Va-14. more preferably at a temperature of 0°C. to 80°C., even more 0309 The preferred embodiments of the compound of preferably at a temperature of 10° C. to 50° C. and most formula (V-I) and (V-II) as mentioned above apply accord preferably at ambient temperature. ingly to the preferred compounds of formulas (V-1) to (V-54) 0318 "Ambient temperature” refers to the temperature and to the more preferred compounds of formulas (Va-1) to present in a typical laboratory environment and preferably (Va-54). means a temperature ranging from 17 to 25°C. 0310. The hydrogel resulting from step (b) preferably con 0319 Preferably, the hydrogel obtained from the polymer tains from 0.01 to 1.2 mmol/g primary amine groups ization of step (b) is a shaped article. Such as a coating, mesh, ( NH), more preferably from 0.02 to 1.0 mmol/g primary stent, nanoparticle or a microparticle. More preferably, the amine groups, even more preferably from 0.02 to 0.5 mmol/g hydrogel is in the form of microparticular beads having a primary amine groups and most preferably from 0.05 to 0.3 diameter from 1 to 500 micrometer, more preferably with a mmol/g primary amine groups. diameter from 10 to 300 micrometer, even more preferably 0311. The term “X mmol/g primary amine groups' means with a diameter from 20 and 150 micrometer and most pref that 1 g of dry hydrogel comprises X mmol primary amine erably with a diameter from 30 to 130 micrometer. The afore groups. Measurement of the amine content of the hydrogel is mentioned diameters are measured when the hydrogel micro carried out according to Gude et al. (Letters in Peptide Sci particles are fully hydrated in water. ence, 2002, 9(4): 203-206, which is incorporated by reference 0320 In one preferred embodiment the polymerization in in its entirety) and is also described in detail in the Examples step (b) occurs in a Suspension polymerization, in which case section. the mixture of step (a) further comprises a first solvent and at least a second solvent, which second solvent is immiscible in Polymerization the first solvent. 0321 Said first solvent is preferably selected from the 0312 The polymerization in step (b) is initiated by adding group consisting of dichloromethane, chloroform, tetrahy a base. Preferably, the base is a non-nucleophilic base soluble drofuran, ethyl acetate, dimethylformamide, acetonitrile, in alkanes, more preferably the base is selected from the dimethyl sulfoxide, propylene carbonate, N-methylpyrroli group consisting of N.N.N',N'-tetramethylethylene diamine done, methanol, ethanol, isopropanol, water and mixtures (TMEDA), 1,4-dimethylpiperazine, 4-methylmorpholine, thereof. 4-ethylmorpholine, 1,4-diazabicyclo2.2.2]octane, 1,14.7, 0322 The at least one backbone reagent and at least one 10, 10-hexamethyltriethylenetetramine, 1,4,7-trimethyl-1,4, crosslinker reagent are dissolved in the first solvent, i.e. the 7-triazacyclononane, tris 2-(dimethylamino)ethylamine, disperse phase of the Suspension polymerization. In one triethylamine, DIPEA, trimethylamine, N,N-dimethylethy embodiment the at least one backbone reagent and the at least lamine, N.N.N',N'-tetramethyl-1,6-hexanediamine, N.N.N', one crosslinker reagent are dissolved separately, i.e. in differ N"N"-pentamethyldiethylenetriamine, 1,8-diazabicyclo[5. ent containers, using either the same or different solvent and 4.0]undec-7-ene, 1,5-diazabicyclo4.3.0non-5-ene, and preferably using the same solvent for both reagents. In hexamethylenetetramine. Even more preferably, the base is another embodiment, the at least one backbone reagent and selected from TMEDA, 1,4-dimethylpiperazine, 4-methyl the at least one crosslinker reagent are dissolved together, i.e. morpholine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]oc in the same container and using the same solvent. tane, 1,1,4,7,10,10-hexamethyltriethylenetetramine, 1,4,7- 0323. A suitable solvent for the at least one backbone trimethyl-1,4,7-triazacyclononane, tris 2-(dimethylamino) reagent is an organic solvent. Preferably, the solvent is ethylamine, 1,8-diazabicyclo5.4.0]undec-7-ene, 1.5- selected from the group consisting of dichloromethane, chlo diazabicyclo4.3.0non-5-ene, and hexamethylenetetramine. roform, tetrahydrofuran, ethyl acetate, dimethylformamide, Most preferably, the base is TMEDA. acetonitrile, dimethylsulfoxide, propylene carbonate, N-me 0313 The base is added to the mixture of step (a) in an thylpyrrolidone, methanol, ethanol, isopropanol, water and amount of 1 to 500 equivalents per activated functional end mixtures thereof. More preferably, the backbone reagent is group in the mixture, preferably in an amount of 5 to 50 dissolved in a solvent selected from acetonitrile, dimethyl equivalents, more preferably in an amount of 5 to 25 equiva sulfoxide, methanol and mixtures thereof. Most preferably, lents and most preferably in an amount of 10 equivalents. the backbone reagent is dissolved in dimethylsulfoxide. 0314 Preferably, the polymerization of step (b) is a con 0324. In one embodiment the at least one backbone densation reaction, which preferably occurs under continu reagent is dissolved in the solvent in a concentration ranging ous stirring of the mixture of step (a). Preferably, the tip speed from 1 to 300 mg/ml, more preferably from 5 to 60 mg/mland (tip speed TLXstirrer rotational speedxstirrer diameter) ranges most preferably from 10 to 40 mg/ml. from 0.2 to 10 meter per second (m/s), more preferably from 0325 A suitable solvent for the at least one crosslinker 0.5 to 4 m/s and most preferably from 1 to 2 m/s. reagent is an organic solvent. Preferably, the solvent is 0315. In a preferred embodiment of step (b), the polymer selected from the group consisting of dichloromethane, chlo ization reaction is carried out in a cylindrical vessel equipped roform, tetrahydrofuran, ethyl acetate, dimethylformamide, with baffles. The diameter to height ratio of the vessel pref acetonitrile, dimethylsulfoxide, propylene carbonate, N-me erably ranges from 4:1 to 1:2, more preferably the diameter to thylpyrrolidone, methanol, ethanol, isopropanol, water and height ratio of the vessel ranges from 2:1 to 1:1. mixtures thereof. More preferably, the crosslinker reagent is 0316 Preferably, the reaction vessel is equipped with an dissolved in a solvent selected from dimethylformamide, axial flow stirrer selected from the group consisting of pitched acetonitrile, dimethyl sulfoxide, methanol and mixtures blade stirrers, marine type propellers, and Lightnin A-310. thereof. Most preferably, the crosslinker reagent is dissolved More preferably, the stirrer is a pitched blade stirrer. in dimethylsulfoxide. US 2016/00821 23 A1 Mar. 24, 2016 29

0326 In one embodiment the at least one crosslinker 0334 Preferably, the working-up step comprises all of the reagent is dissolved in the solvent in a concentration ranging following steps from 5 to 500 mg/ml, more preferably from 25 to 300 mg/ml (b-i) removing excess liquid from the polymerization reac and most preferably from 50 to 200 mg/ml. tion, 0327. The at least one backbone reagent and the at least (b-ii) washing the hydrogel to remove solvents used during one crosslinker reagent are mixed in a weight ratio ranging polymerization, from 1:99 to 99:1, e.g. in a ratio ranging from 2:98 to 90:10, in a weight ratio ranging from 3:97 to 88:12, in a weight ratio (b-iii) transferring the hydrogel into a buffer solution, ranging from 3:96 to 85:15, in a weight ratio ranging from (b-iv) size fractionating/sieving of the hydrogel, 2:98 to 90:10 and in a weight ratio ranging from 5:95 to 80:20; (b-V) transferring the hydrogel into a container, particularly preferred in a weight ratio from 5:95 to 80:20, (b-vii) transferring the hydrogel into a specific solvent Suit wherein the first number refers to the at least one backbone able for sterilization, and reagent and the second number to the at least one crosslinker (b-viii) Sterilizing the hydrogel, preferably by gamma radia reagent. tion. 0328 Preferably, the ratios are selected such that the mix Optional Reaction with a Spacer Reagent ture of step (a) comprises a molar excess of functional groups A' from the at least one backbone reagent compared to the 0335) In a preferred embodiment A' is an amine and A' functional end groups of the at least one crosslinker reagent. is CISO. , R' (C=O) , I-, Br , Cl-, SCN- CN-, Consequently, the hydrogel resulting from the process of the O—C=N Y" (C=O) Y. (C=O) NH orY' present invention has free functional groups A" groups (C=O)—O , which can be used to couple other moieties to the hydrogel, 0336 wherein Such as spacer moieties and/or reversible prodrug linker moi 0337) R' is H. C. alkyl, C. alkenyl, C. alkynyl, eties. Cs cycloalkyl, 4- to 7-membered heterocyclyl, 8- to 0329. The at least one second solvent, i.e. the continuous 11-membered heterobicyclyl phenyl, naphthyl, inde phase of the Suspension polymerization, is preferably an nyl, indanyl, or tetralinyl; and organic solvent, more preferably an organic solvent selected 0338 Y is selected from formulas (fi) to (f-vi): from the group consisting of linear, branched or cyclic Cso alkanes; linear, branched or cyclic Cs-so alkenes; linear, branched or cyclic Cso alkynes; linear or cyclic poly(dim (f-i) ethylsiloxanes); aromatic Co-o hydrocarbons; and mixtures thereof. Even more preferably, the at least second solvent is selected from the group consisting of linear, branched or cyclic Cse alkanes; toluene, Xylene; mesitylene; hexameth yldisiloxane; and mixtures thereof. Most preferably, the at least second solvent is a linear C- alkane, Such as heptane, (f-ii) octane, nonane, decane or undecane. 0330 Preferably, the mixture of step (a) further comprises a detergent. Preferred detergents are Cithrol DPHS, Hyper mer 70A. Hypermer B246, Hypermer 1599A, Hypermer 2296, and Hypermer 1083. 0331 Preferably, the detergent has a concentration of 0.1 g to 100 g per 1 L total mixture, i.e. disperse phase and con tinuous phase together. More preferably, the detergent has a (f-iii) concentration of 0.5 g to 10g per 1 L total mixture, and most NO preferably, the detergent has a concentration of 0.5g to 5g per , -0. 1 L total mixture. 0332 Preferably, the mixture of step (a) is an emulsion. 0333. In one embodiment, step (b) further comprises NO, working-up the hydrogel after polymerization, wherein said (f-iv) working-up comprises one or more of the following steps: ', O Fb, (b-i) removing excess liquid from the polymerization reac tion, (b-ii) washing the hydrogel to remove solvents used during N polymerization, (f-v) (b-iii) transferring the hydrogel into a buffer solution, (b-iv) size fractionating/sieving of the hydrogel, (b-V) transferring the hydrogel into a container, (b-vi) drying the hydrogel, (b-vii) transferring the hydrogel into a specific solvent Suit able for sterilization, and/or (b-viii) Sterilizing the hydrogel, preferably by gamma radia tion. US 2016/00821 23 A1 Mar. 24, 2016 30

-continued 0347 b is 1, 2, 3 or 4, (f-vi) 0348 X is C1, Br, I, or F. (0349 Inanotherpreferredembodiment A" is a carboxylic acid (—(C=O)OH) and A' is a primary amine or secondary --x" amine. 0350 Most preferably, A' is an amine and A' is Y (C=O)—. 0339 wherein 0351 Suitable activating reagents to obtain the activated 0340 the dashed lines indicate attachment to the rest carboxylic acid are for example N,N'-dicyclohexyl-carbodi of the molecule, imide (DCC), 1-ethyl-3-carbodiimide (EDC), benzotriazol 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate 0341 b is 1, 2, 3 or 4, (PyBOP), bromotripyrrolidinophosphonium hexafluoro 0342 X is C1, Br, I, or F. phosphate (PyBrOP), 1-cyano-2-ethoxy-2-oxoethylidenami (0343. In another preferred embodiment A' is a hydroxyl nooxy)dimethylamino-morpholino-carbenium hexafluoro group (-OH) and A' is O—C=N , I-, Br , SCN , or phosphate (COMU), 1-hydroxybenzotriazole (HOBT), Y' (C=O) NH 1-hydroxy-7-azabenzotriazole (HOAT), O-(6-chlorobenzot (0344) wherein Y is selected from formulas (fi) to riazol-1-yl)-N.N.N',N'-tetramethyluronium hexafluorophos (f-vi): phate (HCTU), 1-H-benzotriazolium (HBTU), (O-(7-aza benzotriazol-1-yl)-N.N.N',N'-tetramethyluronium hexafluorophosphate (HATU), and O-(benzotriazol-1-yl)-N, (f-i) N,N',N'-tetramethyluronium tetrafluoroborate (TBTU). These reagents are commercially available and well-known --O O, to the skilled person. \N 10352 Preferably, A' is selected from the group consisting of -maleimide, SH, -NH. —SeH, N, -C=CH, CR'—CR'R'', OH, -(CH-X) R', (C=O) O S-R', -(C=O)-H, -NH-NH - O NH. -Ar | (f-ii) X, Ar Sn(R)(R')(R'), Ar B(OH)(OH), Br, I,

O

NO, (f-iii) NO ', O

NO2, F (fiv) y O is

w N (f-v)

O F

and

F F

F (f-vi) --N- O --X ON , and

with optional protecting groups; (0345 wherein 0353 wherein 0346 the dashed lines indicate attachment to the rest 0354 dashed lines indicate attachment to SP': of the molecule, 0355 X is O, S, or NH, US 2016/00821 23 A1 Mar. 24, 2016

0356 X is OH, - NR'R'', SH, or - SeH, carbons such as, for example, petroleum ether, hexane, hep 0357 X is C1, Br, I or F: tane, cyclohexane, methylcyclohexane, benzene, toluene, 0358 Ar is phenyl, naphthyl, indenyl, indanyl, or Xylene or decalin; halogenated hydrocarbons such as, for tetralinyl, and example, chlorobenzene, dichlorobenzene, dichloromethane, 0359 R', R', R'' are independently of each other H, chloroform, carbon tetrachloride, dichloroethane or trichlo Calkyl, Calkenyl, C-alkynyl, C.s cycloalkyl, 4 roethane; alcohols such as methanol, ethanol, n- or i-pro to 7-membered heterocyclyl, 8- to 11-membered hetero panol, n-, i-, Sec- or tert-butanol, ethanediol, propane-1,2- bicyclyl phenyl, naphthyl, indenyl, indanyl, or tetrali diol, ethoxyethanol, methoxyethanol, diethylene glycol nyl. monomethyl ether, dimethylether, diethylene glycol; aceto 0360 More preferably, A' is NH, maleimide or thiol nitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide and most preferably A' is maleimide. (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylaceta 0361) If the hydrogel of step (b) is covalently conjugated mide, nitromethane, nitrobenzene, hexamethylphosphora to a spacer moiety, the resulting hydrogel-spacer moiety con mide (HMPT), 1,3-dimethyl-2-imidazolidinone (DMI), 1,3- jugate is of formula (VIa): dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), ethyl acetate, acetone, butanone; ethers such as diethyl ether, : A SP-A2 (VIa), diisopropyl ether, methyl t-butyl ether, methylt-amyl ether, 0362 wherein dioxane, tetrahydrofuran, 1.2-dimethoxyethane, 1,2-di 0363 the dashed line indicates attachment to the hydro ethoxyethane oranisole; or mixtures thereof. Preferably, the gel of step (b): Solvent is selected from the group consisting of water, aceto 0364 A' is the linkage formed between A' and A'; nitrile and N-methyl-2-pyrrolidone. and 0365 SP and A’are used as in formula (VI). Step (d) 0366 Preferably, A' is a stable linkage. 0367 Preferably, A' is selected from the group consisting 0373 The hydrogel or hydrogel-spacer moiety conjugate of of step (b) or (c) is Subjected to one of steps (d-i), (d-ii), (d-iii), (d-iv), (d-V), (d-vi), (d-vii) or (d-viii). The result of each of these steps is a hydrogel-linked prodrug which releases a tag * , O * , O w moiety-biologically active moiety conjugate. Step (d-i) 0374 Step (d-i) preferably comprises three sub-steps, X--->P H n, X->H H or namely * , O w 0375 (i) covalently conjugating a reversible prodrug linker reagent of formula (VII) Ax3-L-AX4 (VII), X->A. H w 0376 wherein 0368 wherein 0377 A' and A'are independently of each other a 0369 dashed lines marked with an asterisk indicate functional group; and attachment to a backbone moiety; and unmarked dashed 0378 L is a reversible prodrug linker moiety; lines indicate attachment to SP. to A' of the hydrogel of step (b) or to A' of step (c) 0370. Suitable reaction conditions are described in the wherein Areacts with A' or A', respectively; Examples sections and are known to the person skilled in the 0379 (ii) covalently conjugating a drug of formula art. (VIII) 0371 Process step (c) may be carried out in the presence of Axis-D-A-6 a base. Suitable bases include customary inorganic or organic (VIII), bases. These preferably include alkaline earth metal or alkali 0380 wherein metal hydrides, hydroxides, amides, alkoxides, acetates, car 0381 A' and A are independently of each other a bonates or bicarbonates such as, for example, sodium functional group; and D is a biologically active moiety; hydride, Sodium amide, Sodium methoxide, Sodium ethoxide, to the conjugate of step (i), wherein Areacts with A'; potassium tert-butoxide, Sodium hydroxide, potassium and hydroxide, ammoniumhydroxide, Sodium acetate, potassium 0382 (iii) covalently conjugating a tag reagent of for acetate, calcium acetate, ammonium acetate, sodium carbon mula (IX) ate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or ammonium carbonate, and tertiary amines Ax7-T (IX), such as trimethylamine, triethylamine, tributylamine, N.N- dimethylaniline, N,N-dimethylbenzylamine, pyridine, 0383 wherein N-methylpiperidine, N-methylmorpholine, N,N-dimethy (0384) A is a functional group; and laminopyridine, diazabicyclooctane (DABCO), diazabicy 0385 T is a tag moiety; clononene (DBN), N,N-diisopropylethylamine (DIPEA), to the conjugate of step (ii), wherein A7 reacts with A. diazabicycloundecene (DBU) or collidine. 0386 The resulting conjugate of step (iii) has the structure 0372 Process step (c) may be carried out in the presence of of formula (Xa) or (Xb): a solvent. Suitable solvents for carrying out the process step - A-L-A-D-A-T (Xa), (d) of the invention include organic solvents. These prefer ably include water and aliphatic, alicyclic or aromatic hydro US 2016/00821 23 A1 Mar. 24, 2016 32

(0387 wherein 04.05) Y is selected from formulas (fi) to (f-vi): 0388 the dashed line indicates attachment to a back bone moiety; (0389. A' is the linkage formed between A' and A: w (f-i) * -O O 0390 A' is used as in formula (VIa); - V s 0391 A' is the linkage formed between A and A: y N 0392 A is the linkage formed between A and A': 0393 A' is the linkage formed between A and A'; O 0394 SP is used as in formula (VI): (f-ii) 0395 L is used as in formula (VII); 0396 D is used as in formula (VIII); and 0397) T is used as in formula (IX). 0398 Preferably, A is selected from the group consisting of SH, -NH2. —SeH, -maleimide, —C=CH, N, NO, CR'—CR'R'', (C=X) R', OH, -(C=O) S (f-iii) R", NH NH. O. NH – Ar Sn(R)(R')(R'), NO —Air B(OH)(OH), – Ar X, , -o

NO2,

(f-iv) w O Fb,

w N

(f-v)

O F

F F and

F (f-vi) --X

0406 wherein 0407 the dashed lines indicate attachment to the rest of the molecule, 0408 b is 1, 2, 3 or 4, 0399 wherein 04.09 X is C1, Br, I, or F. 04.00 dashed lines indicate attachment to L.; 0410 Preferred combinations of A and A are the fol 04.01 X is O, S, or NH, lowing: 0402 X is OH, - NR'R'', SH, or - SeH; (0403 R', R', R'' are independently of each other H, Calkyl, Calkenyl, C-alkynyl, C.s cycloalkyl, 4 Ax2 Ax3 to 7-membered heterocyclyl, 8- to 11-membered hetero bicyclyl phenyl, naphthyl, indenyl, indanyl, or tetrali -maleimide HS—, H2N-, or HSe— nyl; and —SH, -NH2, or—SeH maleimide 0404 Ar is phenyl, naphthyl, indenyl, indanyl, or tetralinyl. US 2016/00821 23 A1 Mar. 24, 2016

-continued -continued Ax2 Ax3

R—(C=X)—

- OH HN- or

S-N-- | H O NO

-NH2 or HO O I -HN-S ; H || O ON

CR1a- CRIGR1b R1bRIC=CR1- or

0411 wherein R1bRICC CRI 0412 X is O, S, or NH; 0413 X is OH, - NR'R'', SH, or - SeH; 0414) R', R", R'' are independently of each other selected from the group consisting of H. C. alkyl, C alkenyl, C-alkynyl, Css cycloalkyl, 4- to 7-membered

heterocyclyl, 8- to 11-membered heterobicyclyl phenyl, naphthyl, indenyl, indanyl, and tetralinyl; and 0415 Ar is phenyl, naphthyl, indenyl, indanyl, or tetralinyl. 0416) More preferably, A is SH or -maleimide and most preferably A is -SH. 10417. Accordingly, a preferred combination of A/A is -maleimide/-SH and —SH/-maleimide and most preferably, A' is -maleimide and A' is -SH. US 2016/00821 23 A1 Mar. 24, 2016 34

0418 Preferably, A'is selected from the group consisting 0426. It is understood that A and A' are functional of groups of the drug which are independ of each other selected from the group consisting of carboxylic acid, amine, thiol, Sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, O O ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkylhalides, acryloyl, aryl -HOH fluorides, hydroxylamine, disulfides, vinyl sulfone, vinyl > Yl, X-l Yl, s ketone, diazoalkanes, diazoacetyls, oxirane, and aziridine. Preferably, A and Aare independently selected from car boxylic acid, amine, and hydroxyl. HNECEO and F l 0427 Preferably, A7 is selected from the group consisting X Yl of

0419 wherein 0420 dashed lines indicate attachment to L; O , O 0421) Y is selected from formulas (fi) to (f-vi): -HOH as Yl, X-l Yl, s (f-i) F O O O, --N=C=O and l- N x -l,

0428 wherein (f-ii) 0429 dashed lines indicate attachment to T; and 0430 Y is selected from formulas (fi) to (f-vi):

(f-i) -o O, -N (f-iii) , -0. (f-ii)

NO, (fiv) , O Fb.

N (f-iii) (f-v) , -0.

O F and NO, (f-iv) , O Fb. F F 21 A. F (f-vi) N (f-v) --X

F and 0422 wherein 0423 the dashed lines indicate attachment to the rest of the molecule, F F 0424 b is 1, 2, 3 or 4, 0425 X is C1, Br, I, or F. US 2016/00821 23 A1 Mar. 24, 2016 35

-continued -continued (f-vi)

* l 8. 0431 wherein X, >1 0432 the dashed lines indicate attachment to the rest of H w the molecule, 0433 b is 1, 2, 3 or 4 0434 X is C1, Br, I, or F. A H w 0435 The person skilled in the art knows what type of linkage results from the reaction of any two of the above mentioned functional groups. Therefore only preferred link 0444 wherein ages are listed below. 0445 the dashed lines marked with an asterisk indicate 0436 Preferably, A' is a stable linkage. attachment to L; and 0437. Preferably, A'is selected from the group consisting 0446 the unmarked dashed lines indicate attachment to of thioether, ether, amine, amide, ester, OXime, hydrazone, D. carbamate, thioZolidine, carbon-carbon bond and triazole. 0447 More preferably, the linkage A' is selected from the 0438 Preferably, A' is a stable linkage. group consisting of 0439 Preferably, A' is selected from the group consisting of

: O O w A w s w w s F w w is Y w A. ls w w w N w w O O y * H O S-- and F w w w O w & w w and w s w w w w * , O w v, w : N w O w : w w Y w w w W w w O s --S O

NN 0448 wherein 0449 the dashed lines marked with an asterisk indicate attachment to L; and 0450 the unmarked dashed lines indicate attachment to 0440 wherein D. 0441 the dashed lines marked with an asterisk indicate attachment to SP; and 0451. Preferably, A is a stable linkage. 0442 the unmarked dashed lines indicate attachment to 0452 Preferably, A' is selected from the group consisting L of 0443 Preferably, the linkage A' is selected from the group consisting of is is --O--, --N-- O w O & : s s , w : , w w w w w w O N w w w H w --S--, --S-S--, w w w &

* s * O w s O w w A. w -H S O -> Y& O O >1 O F w O w * O w * O w F w s F w s F w F w w p w NNXN : w N 31'', ? N O O N F H w f H w O , US 2016/00821 23 A1 Mar. 24, 2016 36

-continued Step (d-iv) O w 0474 Step (d-iv) preferably comprises the step of ', A. O w w s : ? s covalently conjugating a reversible prodrug linker moiety : '', A. w biologically active moiety-tag moiety conjugate reagent of w to , , no.1 n1 , w H formula (XIII) A. O A*-L-A-D-A-T (XIII), , Q : A. : f 0475 wherein A. w FA. N Y& x1 A. F N N , , H N, 0476 A and L are used as in formula (VII); F H H w f 0477 A' and A'are used as in formula (Xa)/(Xb): A. O * F , Q 0478 D is used as in formula (VIII); and * w ? F w 0479. T is used as in formula (IX):

f F w to A' of step (b) or to A' of step (c), wherein Areacts with F O F and Y{ N O >1 F H w A' or A', respectively. 0480. The resulting conjugate is of formula (Xa) or (Xb). Step (d-v) 0453 wherein 0481 Step (d-v) preferably comprises three sub-steps, 0454 the dashed lines marked with an asterisk indicate namely attachment to D; and 0482 (i) covalently conjugating a reversible prodrug 0455 the unmarked dashed lines indicate attachment to linker reagent of formula (VII) to A' of step (b) or to A' T of step (c), wherein A reacts with A" or A', respec 0456 Preferred embodiments of L., D and T are given tively; below. 0483 (ii) covalently conjugating a tag reagent of for Step (d-ii) mula (XIV) 0457 Step (d-ii) preferably comprises two sub-steps, Ax8-TA-9 (XIV), namely 0484 wherein 0458 (i) covalently conjugating a reversible prodrug 0485 A and A' are independently of each other a linker reagent of formula (VII) to A' of step (b) or to A' functional group; and of step (c), wherein A reacts with A" or A', respec 0486 T is used as in formula (IX): tively; to the conjugate of step (i), wherein Areacts with A'; 0459 (ii) covalently conjugating a biologically active and moiety-tag moiety conjugate reagent of formula (XI) 0487 (iii) covalently conjugating a drug of formula (VIIIa) Ax3-D (VIIIa), wherein 0460) 0488 wherein 0461) A' and D are used as in formula (VIII); 0489. A' and D are used as in formula (VIII): 0462 A' is used as in formula (Xa)/(Xb); and to the conjugate of step (ii), wherein Areacts with A. 0463 T is used as in formula (IX): 0490 The resulting conjugate is of formula (XVa) or 10464) to the conjugate of step (i), wherein A reacts (XVb):

with A. A-L-A-D-A-T- - T - - T - (XVa),8. 0465. The resulting conjugate of step (ii) has the structure of formula (Xa) or (Xb). (XVb), Step (d-iii) 0491 wherein 0466 Step (d-iii) preferably comprises two sub-steps, 0492 the dashed line indicates attachment to the hydro namely gel of step (b): 0467 (i) covalently conjugating a reversible prodrug 0493 A' and Aare used as in formula (Xa)/(Xb): linker moiety-biologically active moiety conjugate 0494 A' is used as in formula (Vla); reagent of formula (XII) 0495 A is the linkage formed between A and A'; 0496 A' is the linkage formed between A' and A': 0497 SP is used as in formula (VI): 0468 wherein 0498 L is used as in formula (VII); 0469 A and L are used as in formula (VII), 0499 T is used as in formula (IX); and 0470 A' is used as in formula (Xa)/(Xb); and (0500 D is used as in formula (VIII). 0501 Preferably, A' is selected from the group consisting 0471 D and Aare used as in formula (VIII); of carboxylic acid, amine, thiol, Sulfonic acid, carbonate, to A" of step (b) or to A' of step (c), wherein Areacts carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyan with A' or A, respectively; and ate, isothiocyanate, phosphoric acid, phosphonic acid, halo 0472 (ii) covalently conjugating a tag reagent of for acetyl, alkylhalides, acryloyl, aryl fluorides, hydroxylamine, mula (IX) to the conjugate of step (ii), wherein Areacts disulfides, vinyl Sulfone, vinyl ketone, diazoalkanes, diaz with A. oacetyls, oxirane, and aziridine. Preferably, A' is selected 0473. The resulting conjugate of step (ii) has the structure from the group consisting of carboxylic acid, amine, and of formula (Xa) or (Xb). hydroxyl. US 2016/00821 23 A1 Mar. 24, 2016 37

0502 Preferably, A'is selected from the group consisting -continued of-maleimide, (f-vi)

O --xh '', X, -- — , O 0506 wherein 0507 the dashed lines indicate attachment to the rest of ... O O the molecule, -- s y 2 s 0508 b is 1, 2, 3 or 4, N 0509 X is C1, Br, I, or F. F H '', 0510 Preferably, A' is selected from the group consisting O , o' of x Y', ' 1s. -HOH, O w O w w : , s w , s

F O Y w w w >1w : w W 31w w O w N w W w H & w w --N=C=O and 1s. w w * s * O w s w O ? w , A &

w O O ', 0503 wherein w O F w * O w : t O w 0504 dashed lines indicate attachment to T; and p w s w s f w F w (0505) Y is selected from formulas (fi) to (f-vi): A. A. w N O , O N F H w F H w * O w p w s F w (f-i) A. O O, S N F w -1\ S N : ', 8. f w A.

O S&F O N 31 F H w (f-ii) * S w A. w A w F w S N H w

0511 wherein 0512 the dashed lines marked with an asterisk indicate (f-iii) attachment to L; and NO 0513 the unmarked dashed lines indicate attachment to T , -o 0514 More preferably, A is selected from the group con sisting of NO2, (fiv) Fb, w O

S US 2016/00821 23 A1 Mar. 24, 2016

0515 wherein Step (d-vii) 0516 the dashed lines marked with an asterisk indicate 0532 Step (d-vii) preferably comprises two sub-steps, attachment to L; and namely 0517 the unmarked dashed lines indicate attachment to 0533 (i) covalently conjugating a reversible prodrug T linker moiety-tag moiety conjugate reagent of formula 0518. Preferably, A' is a stable linkage. (XVII) 0519 Preferably, the linkage A' is selected from the Ax3-L-A-TA-9 (XVII); group consisting of 0534 wherein 0535 A and L are used as in formula (VII); 0536 A' is used as in formula (XVa)(XVb): --O--, --N-H, 0537) T is used as in formula (IX); and 0538 A' is used as in formula (XIV); to A" of step (b) or to A' of step (c), wherein Areacts with A' or A', respectively; and --S--, --S-S-I-, 0539 (ii) covalently conjugating a drug of formula (VIIIa) to the conjugate of step (i) wherein A reacts s with A. -- S O 0540. The resulting conjugate is of formula (XVa) or (XVb). O w Step (d-viii) NN : ,w 31 0541 Step (d-viii) preferably comprises the step of XN N covalently conjugating a reversible prodrug linker moiety-tag O moiety-biologically active moiety conjugate reagent of for O w F O w mula (XVIII) * , >1w s : ? it w s A*-L-A-T-A-D (XVIII), O ,w Yx?' O l N 31y A. H w 0542 wherein O (0543 A and L are used as in formula (VII); F O w * (0544) A and A'are used as informula (XVa)/(XVb): Y{: 31 Y{NN A 0545 T is used as in formula (IX); and N N , , H ? s A H H w (0546 D is used as in formula (VIII): O to A" of step (b) or to A' of step (c), wherein Areacts with : F O w A' or A, respectively. No ? A. and Y{ N l O x1 0547. The resulting conjugate is of formula (XVa) or A H w (XVb). 0548. Depending on the exact nature of the different steps and sub-steps the functional groups A", A', A., A. A. 0520 wherein A, A, A7, A', and A' may be present in their protected 0521 the dashed lines marked with an asterisk indicate form, i.e. reversibly connected to a protection group which attachment to D; and renders said functional group incapable of reacting with for 0522 the unmarked dashed lines indicate attachment to example other chemical functional groups. Such protection T. groups are well known to the person skilled in the art. Step (d-vi) 0549. In one preferred embodiment step (d) is (d-iv). 0523 Step (d-vi) preferably comprises two sub-steps, namely 0550. In another preferred embodiment step (d) is (d-vii). 0524 (i) covalently conjugating a reversible prodrug 0551. In another preferred embodiment step (d) is (d-viii). linker reagent of formula (VII) to A' of step (b) or to A' of step (c), wherein A reacts with A' or A', respec Reversible Prodrug Linker Moiety L tively; and 0552. The reversible prodrug linker moiety L. may have the 0525 (ii) covalently conjugating a tag moiety-biologi structure of any prodrug linker moiety known in the art. cally active moiety conjugate reagent of formula (XVI) 0553 Preferably, L is a traceless prodrug linker moiety. Ax8-TA'6-D (XVI), 0554. Due to the different embodiments of step (d), namely (d-i), (d-ii), (d-iii), (d-iv), (d-V), (d-vi), (d-vii) and 0526 wherein (d-viii), the moiety L is present in different structural con 0527 A is used as in formula (XIV); texts. For simplification, the term 'A'-L-A^* will be used, 0528 T is used as in formula (IX): wherein A' is A, A' or A' and wherein A^* is A, A' or 0529 A' is used as in formula (XVa)/(XVb); and A’s. 0530 D is used as in formula (VIII): 0555. A preferred prodrug linker is disclosed and can be to the conjugate of step (i) wherein A reacts with A. obtained as described in WO 2005/099768A2. Accordingly, 0531. The resulting conjugate is of formula (XVa) or a preferred moiety/reagent A^-L-A5 has the structure of (XVb). formula (L-i) or (L-ii): US 2016/00821 23 A1 Mar. 24, 2016 39

0573 Preferably, R. R. R4, Rs. R. R., and Rs of formula 2 (L-i) (L-i) and (L-ii) are independently selected from the group R4 A. consisting of H. C. alkyl, C2-alkenyl and C2-alkynyl. Y x1 y, 0574 Preferably, Y of formula (L-i) and (L-ii) is Co X-Y, O Y-I-A alkyl, Coalkenyl or Co alkynyl. Nu-W-Y Air R3 (0575 Preferably, Nu of formula (L-i) and (L-ii) is selected from the group of nucleophiles consisting of primary, second (L-ii) ary and tertiary amino groups, thiol, carboxylic acid, AZ1 |R4), X1 hydroxylamine, hydrazine and nitrogen containing het Y R2 Ys eroaryl. (0576 Preferably, W of formula (L-i) and (L-ii) is X-Y, O Y-I-A —(CRR) , wherein R and Ro are independently of Nu-W-Y Air R3 each other selected from the group consisting of H. C. alkyl, Calkenyl and C- alkynyl and wherein b is 1, 2, 3, 4 or 5. 0556 wherein (0577 Preferably, in of formula (L-i) and (L-ii) is 0, 1 or 2, 0557. A7 is A, A or A: more preferably, n is 0 or 1 and most preferably n is 0. 0558 A?? is A, A' or A'; wherein A^* is connected (0578 Preferably, Ar of formula (L-i) and (L-ii) is selected to Tor D through an aromatic amine of the correspond from the group consisting of ing drug or tag reagent; 0559 X is a spacer moiety such as Rs Y, 0560 Y.Y. are independently O, S or NR 0561 Y.Y. are independently O or S, 0562 Y is O, NR or C(R)(Rs), 0563 Y is O, S, NR, succinimide, maleimide, an unsaturated carbon-carbon bonds or any heteroatom DuO containing a free electron pair or is absent, 1. 0564) R, R are independently of each other selected from the group consisting of substituted or non-substi tuted linear, branched or cyclical alkyl or heteroalkyl, OC aryls, substituted aryls, substituted or non-substituted heteroaryl, cyano, nitro, halogen, carboxy, carboxyla lkyl, alkylcarbonyl and carboxamidoalkyl; 0565 R4 is selected from the group consisting of hydro DON O.N gen, Substituted or non-substituted linear, branched or cyclical alkyl or heteroalkyl, aryl, substituted aryl, sub stituted or non-substituted heteroaryl, substituted or non-Substituted linear, branched or cyclical alkoxy, Sub stituted or non-substituted linear, branched or cyclical heteroalkyloxy, aryloxy or heteroaryloxy, cyano, and halogen, 0566 Rs is selected from the group consisting of sub stituted or non-substituted linear, branched or cyclical alkyl or heteroalkyl, aryls, substituted aryls, substituted and non-substituted heteroaryls, WW 0567 R is selected from the group consisting of sub or ) stituted or non-substituted linear, branched or cyclical alkyl or heteroalkyl, aryls, and Substituted or non-Sub stituted heteroaryls, 0568 R2, Rs are independently selected from the group consisting of hydrogen, Substituted or non-substituted linear, branched or cyclical alkyl or heteroalkyl, aryls, substituted aryls, substituted or non-substituted het eroaryls, carboxyalkyl, alkylcarbonyl, carboxami doalkyl, cyano and halogen, 0569 W is selected from the group consisting of sub stituted or non-substituted linear, branched or cyclical 3 alkyl, aryls, Substituted aryls, Substituted or non-substi tuted linear, branched or cyclical heteroalkyl, and sub 0579. It is understood that in formula (L-i) and (L-ii) L stituted or non-substituted heteroaryls, corresponds to the moiety linking A, and Af. (0570 Nu is a nucleophile, 0580. Other preferred reversible prodrug linkers are dis 0571 n is zero or a positive integer, and closed and can be obtained as described in WO 2006/136586 0572 Aris a multi-substituted aromatic hydrocarbon or A2. Accordingly, a preferred moiety/reagent A^-L-A5 has a multi-substituted aromatic heterocycle. the structure of formula (L-iii), (L-iv) or (L-V): US 2016/00821 23 A1 Mar. 24, 2016 40

0592 Another preferred prodrug linker is disclosed and (L-iii) can be obtained as described in WO 2009/095479 A2. Accordingly, a preferred moiety/reagent A?-L-Aff has the structure of formula (L-vi):

R. Rs (L-vi) / X R3a Q RI R la R-O 2 22 2 N X X A4, R8 R6 A. AZ1 R3 Y NN 1 Yx AZ1 (L-iv) R‘Yes | O

R7 X 0593 wherein R-O R4 O 0594 A7 is A, A' or A: R8 R6 22 0595 A?? is A, A or A'; wherein A^* is connected N A. to Tor D through an amine of the corresponding drug or Rs tag reagent by forming an amide linkage; 0596 X is C(R'R''); N(R):O: C(RR) C(RR): R C(RR) C(RR): C(RR) N(R); N(R) C 8 RG (L-v) (RR): C(RR). O: or O C(R'R''); AZ1 0597 X is C; or S(O); l R5 0598 X is C(R', R7); or C(R7, R7), C(R,R); 0599) R", R1a, R°, R2, R, R3a, R, R4, R5, R5, R, R7, R7, R. Rare independently of each other selected H: or C. alkyl, 0600 optionally, one or more of the pair(s) R''/R", R"/R, R/R, R/R, R7/R form a chemical bond; 0601 optionally, one or more of the pair(s) R/R', R/R2, R/R, R/R, R7/R7, R/R are joined together with the atom to which they are attached to form 0581 wherein a C-s cycloalkyl, or 4- to 7-membered heterocyclyl: 0582 A1 is A, A or A2; 10602) 5 optionally, one 9r. Flore of the pair(s) R/R, 0583. A?? is A, A' or A'; wherein A^* is connected R"/R, R"/R, R/R, R'/R, R/R are joined together to Tor D through an amine of the corresponding drug or with the atoms to which they are attached to form a ring A; tag reagent by forming an amide linkage; 0603 optionally, R/R are joined together with the 0584) X is a spacer moiety such as R13-Y1; nitrogen atom to which they are attached to form a 4- to 0585 Y1 is O, S, NR6, succinimide, maleimide, unsat 7-membered heterocycle; urated carbon-carbon bonds or any heteroatom-contain 0604) A is phenyl; naphthyl; indenyl; indanyl; tetrali ing a free electron pair or is absent; nyl; Co cycloalkyl, 4- to 7-membered heterocyclyl; or 0586 R is selected from the group consisting of sub 8- to 11-membered heterobicyclyl: stituted or non-substituted linear, branched or cyclical 0605 providedrOV1ded thatth One hydrogO9 O f RI,s R16,s uwR2, s R2a s alkyl or heteroalkyl, aryls, Substituted aryls, and Substi R, R3a, R, R4, R, R5, R, R7, R7, R8 O Risa is tuted or non-substituted heteroaryls: replaced by A^*. 0587 R and R are independently of each other 0606. It is understood that in formula (L-Vii) L corre Selected from the group consisting of hydrogen, acyl sponds to the moiety linking A, and Af. groups, and protecting groups for hydroxyl groups; 0607 Another preferred prodrug linker is disclosed and 0588 Rato Rare independently of each other selected can be obtained as described in WO 2011/O12721 A1 and WO from the group consisting of hydrogen, Substituted or 2011/012722 A1. Accordingly, a preferred moiety/reagent non-substituted linear, branched or cyclical alkyl or het eroalkyl, aryls, Substituted aryls, Substituted or non-Sub Af'-L-A5 has the structure of formula (L-vii): stituted heteroaryls, cyano, nitro, halogen, carboxy and carboxamide. (L-vii) 0589 Preferably, R. R. R. R. R. R. R. R. R. R. O and R2 of formula (L-iii), (L-iv) and (L-V) are independently 2 ls AZ2 of each other H. C. alkyl, Calkenyl or C. alkynyl. AZ1 RS x21 X s 0590 Preferably, Y1 of formula (L-iii), (L-iv) and (L-v) is l, C-20 alkyl, C2-20 alkenyl or C2-20 alkynyl. R2a O 0591. It is understood that in formula (L-iii), (L-iv) and (L-v) L corresponds to the moiety linking A? and Af. US 2016/00821 23 A1 Mar. 24, 2016 41

0608 wherein 0609 A1 is A, A' or A: R3 R2 V 0610 A5 is A' A' or A'; wherein Aff is connected N s to Tor D through an aromatic amine of the correspond 4. ing drug or tag reagent by forming an amide linkage; R R2a d 0611 X is C(R'R'') or a cyclic fragment selected from the group consisting of Cs cycloalkyl, 4- to 7-mem 0630) R, R, R and R are independently of each bered heterocyclyl phenyl, naphthyl, indenyl, indanyl, other selected from the group consisting of hydrogen, tetralinyl, and 8- to 11-membered heterobicyclyl, substituted or non-substituted linear, branched or cyclic 0612 wherein Calkyl and heteroalkyl: 0613 in case X" is a cyclic fragment, said cyclic 0631 each d is independently 2, 3 or 4: fragment is incorporated into L'via two adjacentring 0632 provided that one hydrogen of R', R. R. R. or atoms and the ring atom of X", which is adjacent to the R" is replaced by A'. 0633 It is understood that in formula (L-viii) L corre carbonatom of the amide bond, is also a carbonatom; sponds to the moiety linking A^* and Af. I0614 X is a chemical bond or selected from the group 0634. Another preferred prodrug linker is disclosed and consisting of C(RR), N(R), O, C(RR) C can be obtained as described in WO 2011/089216 A1. (RR), C(RR) N(R), N(R) C(RR), Accordingly, a preferred moiety/reagent A?-L-Aff has the C(RR) O, and O C(RR), structure of formula (L-ix): 0615 wherein I0616) in caseX' is a cyclic fragment, X is a chemical

bond, C(RR), N(R) or O; (L-ix) 0617 optionally, in case X" is a cyclic fragment and X R4a is C(RR), the order of the X fragment and the X RN t fragment within L' may be changed and the cyclic frag R3a ment is incorporated into L' via two adjacentring atoms; O 3 0618. R', Rand Rare independently of each other H, O R AZ1 Calkyl or N(RR): N R2 0619 R', R. R. R* and R are independently of each other H, or C. alkyl, AZ2 X.X 0620 R is C(O)R: RI 0621 R is C, alkyl: 0622 optionally, one of the pairs R''/R', R/R' or 0635 wherein R"/R' form a chemical bond; 0636) A^* is A, A' or A: 0623 provided that one hydrogen of R', R', R, R*, 0637 A^* is A, A or A'; wherein A^* is connected R, R,R,R,R,R or R is replaced by A1. to Tor D through an aliphatic amine of the correspond 0624. It is understood that in formula (L-Vii) L corre ing drug or tag reagent by forming an amide linkage; sponds to the moiety linking A, and Af. 0638 X is O, S or CH R'"; 0625. Another preferred prodrug linker is disclosed and 0639) R' and R'' are independently of each other H, can be obtained as described in WO 2011/089214 A1. OH, or CH: Accordingly, a preferred moiety/reagent Af'-L-A5 has the 0640 R. R. R. and R“ are independently of each structure of formula (L-viii): other H or C. alkyl, (0641 R and R are independently of each other H, C, alkyl, or R: (L-viii) 0642 R is selected from the group consisting of

AZ1

-HH -H

0626 wherein 0627 A1 is A, A or A2; --( (0628 A^* is A, A' or A'; wherein A^* is connected OH to T or D through an aromatic hydroxyl ( OH) of the corresponding drug or tag reagent by forming a carbam ate linkage; 0629) R' is selected from the group consisting of Ca alkyl; heteroalkyl, C.s cycloalkyl, and US 2016/00821 23 A1 Mar. 24, 2016 42

-continued (L-x) OH O R R3 R3a N R4a 2 AZ2 N1 A. O HN R1 R1a O R 4

0652 wherein 0653 A7 is A, A' or A: 0654) A^* is A' A' or A'; wherein A^* is connected to Tor D through an aromatic amine of the correspond ing drug or tag reagent by forming an amide linkage; 0655 R', R'", R. R. R, R and R* are indepen dently of each other H or C. alkyl: 0656 optionally, any two of R', R'',R,R,R,R and R" may independently form one or more cyclic frag ment(s) selected from the group consisting of Cs cycloalkyl, 4- to 7-membered heterocyclyl phenyl, naphthyl, indenyl, indanyl, tetralinyl, and 8- to 11-mem bered heterobicyclyl: 0657 optionally, R', R', R. R. R, R and R* are further substituted with a substituent selected from the group consisting of C alkyl, C2-alkenyl, C2-alky nyl, Css cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, naphthyl, indenyl, indanyl, tetralinyl, and 8- to 11-membered heterobicyclyl: 0658 provided that one hydrogen of R', R", R. R. R, R and R is replaced by A'. 0659. It is understood that in formula (L-x) L corresponds to the moiety linking A, and Af. 0660 Another preferred prodrug linker is disclosed and can be obtained as described in PCT/EP2012/065748. Accordingly, a preferred moiety/reagent A?-L-Aff has the structure of formula (L-xi): 0643 wherein

0644 dashed lines indicate attachment to the rest of (L-xi) the moiety. (0645 provided that one hydrogen of R', R'', R, R*, R. R. R. R* and R is replaced by A'. 0646. It is understood that informula (L-ix) L corresponds to the moiety linking A, and Af. 0661 wherein (0647 Preferably, R of formula (L-ix) is H and R of 0662 A3 is A, A' or A: formula (L-ix) is R. 0663) A^* is A, A or A'; wherein A^* is connected to Tor D through a carboxylic acid group (—(C=O)— 0648. Preferably, one of R/R“ of formula (L-ix) is H. OH) of the corresponding drug or tag reagent by forming 0649 Optionally, one or more of the pair(s) R/R", an amide linkage; R/R“, R/R of formula (L-ix) may independently form one 0664) R' is selected from the group consisting of unsub or more cyclic fragment(s) selected from the group consisting stituted alkyl; substituted alkyl; unsubstituted phenyl: of Css cycloalkyl, 4- to 7-membered heterocyclyl, and 8- to substituted phenyl; unsubstituted naphthyl; substituted 11-membered heterobicyclyl. naphthyl; unsubstituted indenyl; substituted indenyl: unsubstituted indanyl; Substituted indanyl; unsubsti 0650 Optionally, R. R. RandR' of formula (L-ix) are tuted tetralinyl; substituted tetralinyl; unsubstituted further Substituted with Ce alkyl, Calkenyl, C. alkynyl, Co cycloalkyl; Substituted Co cycloalkyl; unsubsti phenyl, 4- to 7-membered heterocycle or halogen. tuted 4- to 7-membered heterocyclyl; substituted 4- to 0651. Another preferred prodrug linker is disclosed and 7-membered heterocyclyl; unsubstituted 8- to 11-mem can be obtained as described in WO 2011/0892 15 A1. bered heterobicyclyl; and substituted 8- to 11-mem Accordingly, a preferred moiety/reagent Af'-L-A5 has the bered heterobicyclyl: structure of formula (L-x): 0665 R is H, unsubstituted alkyl, or substituted alkyl US 2016/00821 23 A1 Mar. 24, 2016 43

10666 R and R are independently selected from the 0683 T is phenyl; naphthyl; indenyl; indanyl; tetralinyl: group consisting of H, unsubstituted alkyl, and Substi Cocycloalkyl, 4- to 7-membered heterocyclyl; or 8- to tuted alkyl: 11-membered heterobicyclyl, wherein T is optionally 0667 e is 0 or 1: substituted with one or more R, which are the same or 10668) optionally, RandR are joined together with the different; atoms to which they are attached to form a ring A: 0684 R is halogen; –CN; oxo (=O); –C(O)OH: 0669 A is selected from the group consisting of Co - OH: S(O)NH; S(O)NH; S(O)OH:-S(O) cycloalkyl, 4- to 7-membered aliphatic heterocyclyl; OH: —SH; NH; NO; C alkyl, or Co. het and 8- to 11-membered aliphatic heterobicyclyl, eroalkyl; wherein A is unsubstituted or substituted; 0685 optionally, one or more of the pairs R/R', 0670 Q is selected from the group consisting of Clso R/R, R/R6, R/R5, R2/R2, R2/R3, R/R1, R/R5, alkyl, C-soalkenyl and Clso alkinyl, which fragment is R/R, R/R7, R7/R, R/R are joined together with optionally interrupted by one or more group(s) selected the atom to which they are attached to form a ring T: from the group consisting of NH , —N(C. alkyl)-. 0686 optionally, R/R are joined together with the O— —S , —C(O)— —C(O)NH , —C(O)N nitrogen atom to which they are attached to form a 4- to (C. alkyl)-, —O—C(O)— —S(O)— —S(O). , 4 7-membered heterocycle; to 7-membered heterocyclyl phenyl and naphthyl. 0687 provided that one hydrogen of R', R', R, R*, 0671. It is understood that informula (L-xi)L corresponds R, R3a, R*, R4a, R5, R5, R, R7, R7e, R8 O R8a is to the moiety linking A^* and Af. replaced by A". 0672 Another preferred prodrug linker is disclosed and 0688. It is understood that in formula (L-xii) L corre can be obtained as described in EP12165516. Accordingly, a sponds to the moiety linking A, and Af. preferred moiety/reagent A'-L-Af’ has the structure of for mula (L-xii): Biologically Active Moiety/Drug 0689. In step (d) any drug (A')-D-(A) can be used, provided that it comprises at least two functional groups for (L-xii) steps (d-i), (d-ii), (d-iii) and (d-iv) and at least one functional R3a group for steps (d-V), (d-vi), (d-vii) and (d-viii). 0690 Preferably, D is a small molecule biologically active yl X2 X Y AZ2 s moiety, a peptide biologically active moiety, a protein bio A. -> nN.1N1H logically active moiety or an oligonucleotide biologically O active moiety. 0691 Preferably, D has a molecular weight ranging 0673 wherein between 0.05 and 500 kDa, more preferably between 0.2 and 0674) A^* is A, A' or A: 250 kDa, more preferably between 0.5 and 100 kDa and most 0675) A^* is A, A' or A'; wherein A^* is connected preferably between 1 and 60 kDa. to Tor D through a hydroxyl of the corresponding drug 0692. In one embodiment the drug is a small molecule or tag reagent by forming an ester or carbamate linkage; drug. A Small molecule drug preferably has a molecular weight of between 50 Da and 1 kDa, more preferably of 0676 Y is C(R)(R') : or N(R') : between 50 Daand 800 Da and most preferably of between 50 0677 X is C(R)(R') : N(R) ; O : Da and 500 Da. C(R)(R') C(R)(R) ; C(R)(R) N 0693 Suitable small molecule drugs comprising an aro (R) ; N(R) C(R)(R) : C(R)(R) matic amine functional group are, for example, (-)-Carbovir, O. : O C(R)(R') : C(O) N(R) ; or (+)-Hymenin, (+)-Norcisapride, (+)-Picumeterol, (R)-Ami - N(R) C(O)–: noglutethimide, (R)-Clenbuterol, (S)-Aminoglutethimide, 0678 X is (S)-Clenbuterol, 6-p-aminophenylalanine-angiotensin II, 10-Demethoxystreptonigrin, 17-Aminogeldanamycin, 1-Aminoacridine, 1-Deazaadenine, 1-NA-PP 1, 1-NM-PP 1,2,7-Diaminoacridine, 2,7-Dimethylproflavine, 2-Amino-6 -- O -- (5H)-phenanthridinone, 2-Aminoacridine, 2-amino-Carba O nilide, 2-Amino histamine, 2-Aminoperimidine, 2-AMP. 2-Chloroadenosine, 2-Deoxyxylotubercidin, 2-Sulfanilami doimidazole, 3,4-Diaminocoumarin, 3'-Amino-4'-methoxy 0679 X is C(R)(R7) ; or C(R)(R7), C(R) flavone, 3-Aminoacridine, 3-Aminopicolinic acid, 3-Deaza (R) ; guanine, 4'-Aminoflavone, 4-Aminopyridine, 5'-ADP, 0680 X is —O; –S; or=N CN: 5-Aminoacridine, 5-amino-DL-Tryptophan, 5-Aminonicoti 0681 R", R1a, R°, R2, R, R3a, R, R4, R, R5, R°, R7, namide, 5'-AMP, 5'-ATP 5-Chlorodeoxycytidine, 5'-CMP. R7, R, R are independently of each other H. C. 5-Dimethylamiloride, 5'-GDP, 5'-GMP, 5'-GTP 5-Iodotuber alkyl, C2-alkenyl, C2-alkynyl, C-2 heteroalkyl or cidin, 5-Methylcytosine, 6-Aminoflavone, 6-Aminophenan Y-T, and independently none, one or more of the pair(s) thridine, 6-Aminothymine, 6-Benzylthioguanine, 6-Chloro R/R, R/R, R/R, R7/R are absent and the tacrine, 6-Iodoamiloride, 7,8-Dihydroneopterin, corresponding carbon atoms to which they are attached 7-Aminonimetazepam, 7-Methoxytacrine, 7-Methyltacrine, form a cis double bond; 9-Deazaguanine, 9-Phenethyladenine, Abacavir, Acadesine, 0682. Y' is a chemical bond or Calkyl, Calkenyl, Acediasulfone, Acefurtiamine, Acetyl coenzyme A, Aciclo C2-alkynyl, Vir, Actimid, Actinomycin, Acyclovir, Adefovir, Adenallene, US 2016/00821 23 A1 Mar. 24, 2016 44

Adenine, Adenophostin A, Adenosine, Adenosine mono tracid, Gemcitabine, Giracodazole, Gloximonam, Glybuthia phosphate, Adenosine triphosphate, Adenosylhomocysteine, Zol, GSK 3B Inhibitor XII, GSK3BInhibitorxII, Guanine, Aditeren, Afloqualone, Alamifovir, Albofungin, AlfuZosin, Guanine arabinoside, Guanosine, Hexyl PABA, Hydroxym Allithiamine, Alpiropride, Amanozine, Ambasilide, ethylclenbuterol, Hydroxyprocaine, Hydroxytriamterene Ambucaine, Amdoxovir, Ameltolide, Amethopterin, Sulfate, Ibacitabine, Iclaprim, Imanixil, Imiquimod, Indano Amfenac, Amflutizole, Amicycline, Amidapsone, Amifam cine, Iobenzamic acid, Iocetamic acid, Iomeglamic acid, pridine, Amiloride, Aminacrine, Aminoacridine, Aminoan Iomeglamicacid, Ipidacrine, Iramine, Irsogladine, Isatorib tipyrine, Aminobenzoate, Aminogenistein, Aminoglutethim ine, Isobutamben, Isoritmon, IsoSepiapterin, Ketoclen ide, Amino hippurate, Aminoisatin, Aminometradine, buterol, Ketotrexate, Kopexil, Lamivudine, Lamotrigin, Aminonimetazepam, Aminophenylalanine, Aminopotenti Lamotrigine, Lamtidine, Lappaconine, Lavendamycin, dine, Aminopterin, Aminopurvalanol A, Aminoquinuride, L-Cytidine, Lenalidomide, Leucinocaine, Leucovorin, L-g- Aminosalicylic Acid, Amiphenazole, Amiphenosine, Ami Methylene-10-deazaaminopterin, Linifanib, Lintopride, Sometradine, Amisulpride, Amiterol, AmlexanoX, Ammelin, Lisadimate, Lobucavir, Lodenosine, Lomeguatrib, Lometr Amonafide, Amoxecaine, Amphenidone, Amphethinile, exol, Loxoribine, L-S-Adenosylmethionine, Mabuterol, Amphotalide, Amprenavir, Ampurine, Amrinone, AMT, Medeyol, Melarsenoxyd, Melarsoprol B, Mesalazine, Amthamine, Amtizole, Angustmycin A, Anileridine, Apad Metabutethamine, Metabutoxycaine, Metahexamide, Meta enoson, Apraclonidine, Apricitabine, Arafluorocytosine, Zosin, Methioprim, Methotrexate, Methylanthranilate, Aramine, Arazide, Aristeromycin, Arprinocid, Ascamycin, Metioprim, Metoclopramide, Metoprine, Minoxidil, Mirabe Ascensil, Aspiculamycin, Atolide, AZabon, AZacitidine, AZa gron, Mitomycin, Mivobulin, Mocetinostat, Monocain, line B, AZamulin, AZanidazole, AZepexole, Aztreonam, Baq Mosapride, Mutamycin, N-(p-Aminophenethyl)spiroperi uiloprim. Basedol, Batanopride, b-D-Adenosine, Bemitra dol, N6-2-(4-aminophenyl)ethyladenosine Role, NAD+, dine, Benfotiamine, Bentiamine, BenZamil, Benzocaine, NADH, NADH2, NADP+, NADPH2, Naepaine, Naminterol, Betoxycaine, Binodenoson, Biopterin, Bisbentiamine, Blas Naretin, Nebidrazine, NECA, Nelarabine, Nelzarabine, ticidin, Bleomycin, Bleomycin A1, Bleomycin A2, Bleomy Neolamin, Neotropine, Nepafenac, Nerisopam, Neurofort, cin A5, Bleomycin A6, Bleomycin DMA2, Brodimoprim, Nifurprazine, Nimustine, Nitrine, N-Methyltetrahydrofolic Bromfenac, Bromobuterol, Bromopride, Bropirimine, Buci acid, Nolatrexed, Nomifensine, Norcisapride, N-Propionylp clovir, BunaZosin, Butyrylthiamine disulfide, Cadeguomy rocainamide, N-Sulfanilylnorfloxacin, o-Aminophenylala cin, cAMP, Candicidin, Capadenoson, Carbanilide, Carbod nine, Octotiamine, Olamufloxacin, Ormetoprim, Orthocaine, ine, Carbovir, Carbutamide, Carumonam, CDP-dipalmitin, Oximonam, Oxybuprocaine, p-Aminoantipyrine, p-Ami Cefcapenepivoxil, Cefclidin, Cefdaloxime, Cefdinir, Cefdi nobenzoate, p-Amino-D-phenylalanine, Pancopride, toren, Cefenpidone, Cefepime, Cefetamet, Cefetecol, Parsalmide, Pasdrazide, Pathocidine, Pelitrexol, Pemetrexed, Cefixime, Cefluprenam, Cefnmatilen, Cefnmenoxime, Cefodi Penciclovir, Peplomycin, Peralopride, Phenamil, Phenazone, Zime, Cefoselis, Cefotaxime, Cefotiam, Cefozopran, Ce?po Phenazopyridine, Phenyl p-aminobenzoate, Phenyl-PAS doxime, Cefauinome, Cefrom, Ceftazidime, Cefteram, Cef Tebamin, Phleomycin D1, Pibutidine, Picumeterol, Piraz tibuten, Ceftiofur, Ceftiolene, Ceftioxide, Ceftizoxime, monam, Piridocaine, Piritrexim, Porfiromycin, Pralatrexate, Ceftobiprole, Ceftriaxone, CefuZonam, Centazolone, Ceto Pramipexole, Prazobind, Prazosin, Preladenant, Procaina tiamine, c0MP. Chloroprocaine, Cidofovir, Cifostodine, mide, Procaine, Proflavine, Proparacaine, Propoxycaine, Cipamfylline, Cisapride, Cladribine, Clafanone, Claforan, Prosultiamine, Prucalopride, Pseudoisocytidine, Psicofura Clebopride, Clenbuterol, Clenproperol, Clofarabine, Clorsu nine, Pteridoxamine, Pteroyltriglutamic acid, Pyramine, lon, Coelenteramine, Coenzyme A, Colchicamid, Coumarin Pyrimethamine, Questiomycin, Quinelorane, Racivir, 10, Coviracil, Crotonoside, Cyclobut A, Cyclobut G, Cyclo Regadenoson, Renoquid, Renzapride, Residuimod, Resor clenbuterol, Cycotiamine, Cytallene, Cytarabine, Cytarazid, cein, Retigabine, Reverset, Riluzole, Rociclovir, Rufocromo Cytidine, Cytidine diphosphate, Cytidoline, CytosineD-(+)- mycin, S-Adenosylmethionine, Sangivamycin, Sapropterin, Neopterin, Dactinomycin, D-Amethopterin, dAMP, Damvar, S-Doxazosin, Sepiapterine, Silversulfadiazine, Sinefungin, Daniquidone, Dapsone, Daptomycin, Daraprim, Darunavir, Sipatrigine, Sparfloxacin, Sparsomycin, Stearyl-CoA, Stear DATHF, Dazopride, dCMP, dCTP, Debromohymenialdisine, ylsulfamide, Streptonigrin, Succisulfone, Sufamonomethox Decitabine, Declopramide, Deisopropylhydroxyatrazine, ine, Sulamserod, Sulfabromomethazine, Sulfacetamide, Sul Delafloxacin, Delfantrine, Denavir, Deoxyadenosine, fachlorpyridazine, Sulfachrysoidine, Sulfaclomide, Deoxy-ATP, Deoxycytidine, Deoxyguanosine, Dephosphoc Sulfaclorazole, Sulfaclozine, Sulfacytine, Sulfadiasulfone, oenzyme A, Dequalinium, Desbutylbumetanide, Desciclovir, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadimi Desoxyminoxidil, dGMP, dGTP, Diacethiamine, Diami dine, Sulfadoxine, Sulfaethoxypyridazine, Sulfaguanidine, noacridine, Diaveridine, Dichlorobenzamil, Dichlo Sulfaguanole, Sulfalene, Sulfamerazine, Sulfamethazine, romethotrexate, Dichlorophenarsine, Dideoxycytidine, Sulfamethizole, Sulfamethoxazole, Sulfamethoxydiazine, Dihydrobiopterin, Dihydro folic acid, Dimethialium, Dime Sulfamethoxypyridazine, Sulfametomidine, Sulfametopyra thocaine, Dimethyl methotrexate, Dinalin, DL-5,6,7,8-Tet Zine, Sulfametrole, Sulfanilamide, Sulfanilamidoimidazole, rahydrofolic acid, DL-Methotrexate, Dobupride, Dovitinib, Sulfanilylglycine, Sulfaperin, Sulfaphenazole, Sulfaproxy Doxazosin, Draflazine, Edatrexate, Elpetrigine, Elvucitab line, Sulfapyrazole, Sulfapyridine, Sulfasomizole, Sulfasy ine, Emtricitabine, Entecavir, Enviradene, Epcitabine, mazine, Sulfathiadiazole, Sulfatroxazole, Sulfatrozole, Sulfi Epiroprim, Eritadenine, Etanterol, Ethacridine, Ethaden, Eth somidine, Sulfisoxazole, Tacedinaline, Tacrine, Talampanel, ylisopropylamiloride, Etoprine, EtoxaZene, Etravirine, Talipexole, Talisomycin A, Tenofovir, Tenofovir disoproxil, Etriciguat, FAD, Famciclovir, Fazarabine, Fenamol, Feprat Terazosin, Tetrahydrobiopterinm, Tetrahydrofolic acid, set, Fiacitabine, Flucytosine, Fludara, Fludarabine, Fluocy Tetroxoprim, Tezacitabine. Thiamine. Thiazosulfone, tosine, Folic acid, Formycin A, Fosamprenavir, Furalazine, Thioguanine, Tiamiprine, Tigemonam, Timirdine, Tinori Fursultiamine, Furyltriazine, Ganciclovir, Gancyclovir, Gas dine, TiodaZosin, Tirapazamine, Tiviciclovir, Tocladesine, US 2016/00821 23 A1 Mar. 24, 2016

Trancopal, Triacanthine, Triamterene, Triapine, Triciribine, mucillin-A, 5"-Homoneplanocin A, 5-Aminosalicylic Acid, Trimazosin, Trimethoprim, Trimetrexate, Tritoqualine, Trox 9-Aminocamptothecin, Abacavir Succinate, Abacavir Sul acitabine, Tubercidin 5'-diphosphate, Tuvatidine, Tyrphostin fate, Abanoquil Mesilate, Acadesine, Acriflavine, Acyclovir, AG 1112, Valacyclovir, Valganciclovir, Valopicitabine, Val Acyclovir Elaidate. Acyclovir Oleate, Adefovir, Adefovir torcitabine, Velnacrine, Vengicide, Veradoline, Vidarabine, Dipivoxil, Ademetionine Tosylate Sulfate, Adenallene, Viroxime, Vitaberin, Zalcitabine, Zhengguangmycin B2, Adenophostin A, Adenophostin B, Adenosine, Afloqualone, ZinviroXime, Zorbamycin, Zoxazolamine, (t)-Saxitoxin, Ageliferin Diacetate, Ageliferin Dihydrochloride, Alami 2-Aminoperimidine, 6-Formylpterin, 8-13-Neurotensin, fovir, Alfuzosin Hydrochloride, Ambasilide, Ambroxol 8-Thioguanosine, 9-Deazaguanosine, 9-Desarginine-brady Nitrate, Amdoxovir, Ameltolide, Amezinium Methylsulfate, kinin, a4-10-Corticotropin, Afamelanotide, Agmatine, Alare Amfenac Sodium, Amiloride Hydrochloride, Aminoglute lin, Ambazone, Amiloride, Aminopterine, Ampyrimine, thimide, Amisulpride, AmoxanoX, Amprenavir, Ampydin, Angiotensin, Angiotensin I, Angiotensin II, Antibiotic Amrinone, Amselamine Hydrobromide, Amthamine, Anak O-129, Antipain, Arginine, Argiprestocin, Astressin, Atrio inra, Apadenoson, Aplonidine Hydrochloride, Apricitabine, peptin III, Aviptadil, Benzylisothiourea, Betacyamine, Bisin AZacytidine, AZalanstat, Aztreonam, Aztreonam L-Lysine, dolylmaleimide IX, Bivalirudin, Blasticidin S. Bleomycin Balapiravir Hydrochloride, Batracylin, Belactin A, Ben B2, Bombesin 14, Buformin, Camostat, Cariporide, Carper Zocaine, Binodenoson, Bleomycin A2 Sulfate, Brodimoprim, itide, Cecropin P1, Cetrorelix, Cilengitide, Creapure, Cyan Bromfenac Sodium, Bromhexine Hydrochloride, BunaZosin oginosin LR, Cyanoviridin RR, Dalargine, Damvar, Dea Hydrochloride, Capadenoson, Capeserod Hydrochloride, Zaaminopterin, Defensin HNP 1, Deslorelin, Desmopressin, Carbovir, Carboxyamidotriazole, Carumonam Sodium, Cef Dezaguanine, Dichloromethotrexate, Dihydrostreptomycin, capene Pivoxil Hydrochloride, Cefdaloxime, Cefdaloxime Dimaprit, Dimethylamiloride, DiminaZene, DL-Methotrex Pentexil Tosilate, Cefdinir, Cefditoren Pivoxil, Cefepime, ate, D-Methotrexate, Ebrotidine, Edatrexate, Eel Thyrocalci Cefetamet Pivoxil, Cefetecol, Cefixime, Cefluprenam, Cef tonin, Elastatinal, Elcatonin, Enterostatin, Enviomycin, Epti matilen Hydrochloride Hydrate, Cefnmenoxime Hydrochlo fibatide, Ethylisopropylamiloride, Etilamide, Etoprine, ride, Cefodizime, Cefodizime Sodium, Cefoselis Sulfate, Famotidine, Flupirtine, Furterene, Galanin, Galegin, Ghrelin, Cefotaxime Sodium, Cefotiam Hexetil, Cefotiam Hexetil Glucagon, Gonadoliberin A, Guanethidine, Guanfacine, Hydrochloride, Cefotiam Hydrochloride, CefoZopran, Cefo Guanoxan, Guanylthiourea, Gusperimus, Hexamidine, Zopran Hydrochloride, Ce?pirome, Cefpodoxime Proxetil, Histatin 5. Histrelin, Homoarginine, Icatibant, Imetit, Insuli Cefauinome, Ceftaroline, Ceftazidime, Cefteram Pivoxil, notropin, Isocaramidine, Kallidin 10, Kemptide, Ketotrexate, Ceftibuten, Ceftobiprole, Ceftobiprole Medorcaril, Ceftra Kiotorphin, Lactoferricin, Lamifiban, L-Bradykinin, Leu Zonal Bopentil, CeftraZonal Sodium, Ceftriaxone Sodium, coverin, Leucovorin A, Leupeptin, Leuprolide, Lometrexol. Centanamycin, Cibrostatin 1, Cidofovir, Cimaterol, Cinitap Lutrelin, m-Chlorophenylbiguanide, Melagatran, Melanotan ride Hydrogen Tartrate, Cipamfylline, Cisapride Hydrate, II, Melanotropin, Melittin, Metformin, Methotrexate dim Citicoline, Cladribine, Clitocine, Clofarabine, Clopidogrel ethyl ester, Methotrexate monohydrate, Methoxtrexate, Sulfate, Cycallene, Cyclic-Cidofovir, Cygalovir, Cystazosin, Methylisothiourea, Metoprine, Miacalcin, MIBG, Minoxidil, Cytarabine, Cytarabine Ocfosfate, Cytaramycin, Cytochlor, MitoguaZone, Mivobulin, Mivobulin isethionate, Moroxy Dactinomycin, DADME-Immucillin-G, Dapropterin Dihy dine, Nafarelin, Neotine, Nesiritide, Netropsin, Neurotensin, drochloride, Dapsone, Darbufelone Mesilate, Darunavir, N-Methyltetrahydrofo late, Nociceptin, Nolatrexed, Novas Delafloxacin, Denufosol Tetrasodium, Deoxy variolin B, tan, Panamidin, Pathocidine, Pebac, Peldesine, Pelitrexol, Desacetylvinblastinehydrazide/Folate Conjugate, Detivici Pemetrexed, Pentamidine, Peramivir, Phenformine, Phenyl clovir Diacetate, Dexelvucitabine, Dezocitidine, Diadenos biguanide, Pig galanin, Pimagedine, Piritrexim, Pitressin, ine Tetraphosphate, Diaveridine, Dichlorobenzoprim, Porcine angiotensinogen, Porcine gastrin-releasing hormone, Dicloguamine Maleate, Dideoxycytidine, DI-VAL-L-DC, Porcine neuropeptide Y, Porcine PHI, Pralatrexate, Protein Docosyl Cidofovir, Dovitinib Lactate, Doxazosin Mesylate, Humanin, Proteinase inhibitor E 64, Pyrimethamin, Draflazine, DTPA-Adenosylcobalamin, Ecenofloxacin Quinespar, Rat atriopeptin, Rat atriopeptin, Residuimod, Hydrochloride, Eicosyl Cidofovir, Elacytarabine, Elpet Ribamidine, Rimorphin, Saralasin, Saxitoxin, Sermorelin, rigine, Elvucitabine, Emtricitabine, Entecavir, Entinostat, S-Ethylisothiourea, Spantide, Stallimycin, Stilbamidine, Epinastine Hydrochloride, Epiroprim, Epofolate, Ethylthio Streptomycin A. Substance Pfree acid, Sulfaguanidine, Syn DADME-Immucillin-A, Ethynylcytidine, Etravirine, thetic LH-releasing hormone, Tallimustine, Teprotide, Tetra Etriciguat, Famciclovir, Filarizone, Flucytosine, Fludarabine cosactide, Tetrahydrobiopterin, Tetrahydrofo lic acid, Phosphate, Fluorobenzyltriamterene, Fluorominoxidil, Fluo Thrombin receptor-activating peptide-14, Thymopentin, roneplanocin A. Flupiritine Maleate. Folinic Acid, Fosam Tioguanin, Tiotidine, Tirapazamine, Triamteren, Trimetrex prenavir Calcium, Fosamprenavir Sodium, Freselestat, Gan ate, Tryptorelin, Tuberactinomycin B, Tuftsin, Urepearl, Vio ciclovir, Ganciclovir Elaidic Acid, Ganciclovir mycidin, Viprovex, Vitamin M, Xenopsin, Zanamivir, Zeo Monophosphate, Ganciclovir Sodium, Gemcitabine, Gemcit cin, Ziconotide, Zoladex. abine Elaidate, Girodazole, Hepavir B, Heptaminol AMP 0694 Preferably, suitable small molecule drugs compris Amidate, Hexadecyl Cidofovir, Hexadecyloxypropyl-Cido ing an aromatic amine functional group are selected from the fovir, Hydroxyakalone, Iclaprim, Imiquimod, Immunosine, group consisting of (-)-Draflazine, (-)-Indocarbazostatin B, Indanocine, Isobatzelline A, Isobatzelline B, Isobatzelline C, (+)-(R)-Pramipexole, (R)-(+)-Terazosin, (R)-Ganciclovir Isobatzelline D. Lamivudine, Lamotrigine, Lenalidomide, Cyclic Phosphonate, (R)-Sufinosine, (R)-Zacopride, (S)- Leucettamine A, Leucovorin Calcium, Levo leucovorin Cal Sufinosine, (S)-Zacopride Hydrochloride, 17-Ami cium, Liblomycin, Linifanib, Lintopride, Lirexapride, Lobu nogeldanamycin, 2-Aminoaristeromycin, 2-Aminoneplano cavir, Lodenosine, Lomeguatrib, Lometrexol, Loxoribine, cin A, 3-Chloroprocainamide, 3-Deazaadenosine, L-Simexonyl Homocysteine, Lymphostin, Mabuterol Hydro 4-Aminosalicylic Acid, 4-Chlorophenylthio-DADME-Im chloride, Makaluvamine A, Makaluvamine A, Makalu US 2016/00821 23 A1 Mar. 24, 2016 46 vamine B. Makaluvamine C. Managlinat Dialanetil, Merio dine Hydrochloride, Ambasilide, Ambazone, Ambroxol lin-3, Metazosin, Methotrexate, Methylthio-DADME Nitrate, Amdoxovir, Ameltolide, Amelubant, Amezinium Immucillin-A, Metoclopramide Hydrochloride, Midoriamin, Methylsulfate, Amfenac Sodium, Amidox, Amifostine Minoxidil, Mirabegron, Mitomycin, Mivobulin Isethionate, Hydrate, Amikacin, Amiloride Hydrochloride, Amino can Mocetinostat Dihydrobromide. Mosapride Citrate, din, Aminoglutethimide, Aminoguanidine, Amino levulinic Mozenavir Mesilate, Neldazosin, Nelzarabine, Nepafenac, Acid Hexyl Ester, Aminolevulinic Acid Methyl Ester, Nolatrexed Hydrochloride, NO-Mesalamine, Noraristero Amisulpride, Amlodipine, Amlodipine Besylate. Amoxanox, mycin, O6-Benzylguanine, Olamufloxacin, Olamufloxacin Amoxicillin Pulsys. Amphotericin B, Ampicillin Sodium, Mesilate, Omaciclovir. Oxyphenarsine, Palau.Amine, Panco Amprenavir, Ampydin, Amrinone, Amrubicin Hydrochlo pride, Peldesine, Pelitrexol, Pemetrexed Disodium, Penciclo ride, Amselamine Hydrobromide, Amthamine, Anakinra, vir, Penicillin G Procaine, Peplomycin, Picumeterol Fuma Anamorelin Hydrochloride, Anatibant Mesilate, Angiopeptin rate, Pimeloylanilide O-Amino anilide, PMEO-5-ME DAPY. Pralatrexate, Pramipexole Hydrochloride, Prazosin Acetate, Anisperimus, Antagonist-G, Antide, Antide-1. Hydrochloride, Prefolic A. Preladenant, Procainamide Antide-2, Antide-3, Antileukinate, Apadenoson, Apixaban, Hydrochloride, Procaine Hydrochloride, Prucalopride, Pru Aplonidine Hydrochloride, Apoptozole 1, Apoptozole 2, calopride Hydrochloride, Prucalopride Succinate, Pyrifer Apoptozole 3, Apricitabine, Arbekacin, Arbekacin Sulfate, one, Pyrimethamine, Quinelorane Hydrochloride, Razaxa Arborcandin A, Arborcandin B, Arborcandin C, Arborcandin ban Hydrochloride, Regadenoson, Residuimod, Retigabine D. Arborcandin E, Arborcandin F, Argatroban Monohydrate, Hydrochloride, Riluzole, Riociguat, Rociclovir, Rumycin 1, Argimesna, Arginine Butyrate, Argiotoxin-636, Armodafinil, Rumycin 2, Sampirtine, Secobatzelline A, Secobatzelline B. Arotinolol Hydrochloride, Arterolane Maleate, Aspoxicillin, Silver Sulfadiazine, Sipatrigine, Sonedenoson, Sotirimod, Atenolol, Atosiban, Atreleuton, AVorelin, AZacytidine, AZa Sparfloxacin, Styloguanidine, Sufinosine, Surfen, Synad lanstat, AZaromycin SC, AZelnidipine, AZetirelin, AZodicar enol, Synguanol, Tacedinaline, Tacrine Hydrochloride, bonamide, AZOxybacilin, AZtreonam, Aztreonam L-Lysine, Talampanel, Talipexole Dihydrochloride, Talopterin, Teno AZumamide A, Baclofen, Bactobolin, Balapiravir Hydro fovir, Tenofovir DF. Terazosin Hydrochloride, Tetracosyl chloride, Balhimycin, Barusiban, Batracylin, Belactin A, Cidofovir, Tezacitabine, TGP, Timirdine Diethanesulfonate, Belactosin A, Belactosin C, Benanomicin B, Benexate Cyclo Torcitabine, Trantinterol Hydrochloride, Trichomycin A, Tri dextrin, Benzocaine, Besifloxacin Hydrochloride, Beta mazosin Hydrochloride, Trimetrexate Glucuronate, Troxac Amyloid (12-20), Binodenoson, Bleomycin A2 Sulfate, itabine, Trybizine Hydrochloride, Valacyclovir, Valganciclo Boceprevir, Bogorol A, Boholmycin, Brasilicardin A, Bremelanotide, Brivanib Alaninate, Brivaracetam, Brodi vir Hydrochloride, Valomaciclovir Stearate, Valopicitabine, moprim, Bromfenac Sodium, Bromhexine Hydrochloride, Velnacrine Maleate, and Xylocydine. Brostallicin Hydrochloride, Bunazosin Hydrochloride, 0695 Suitable small molecule drugs comprising an amine Buserelin Acetate, Butabindide, Butamidine, Buteranol, functional group are, for example, Aphidicolin Glycinate, Cabin 1, Calcium-Like Peptide 1, Calcium-Like Peptide 2, Cetrorelix Acetate, Picumeterol Fumarate, (-)-Draflazine, Cambrescidin 800, Cambrescidin 816, Cambrescidin 830, (-)-Indocarbazostatin B, (+)-(23.24)-Dihydrodiscoder Cambrescidin 844, Camostat, Canfosamide Hydrochloride, mollide, (+)-(R)-Pramipexole, (R)-(+)-Amlodipine, (R)-(+)- Capadenoson, Capeserod Hydrochloride, Capravirine, Terazosin, (R)-Ganciclovir Cyclic Phosphonate, (R)-Sufi CapraZamycin A, CapraZamycin B, CapraZamycin C, nosine, (R)-Zacopride, (S)-(-)-Norketamine, (S)- CapraZamycin E. CapraZamycin F. Capromorelin, Carafiban Oxiracetam, (S)-Sufinosine, (S)-Zacopride Hydrochloride, Maleate, Carbachol, Carbamazepine, Carbetocin, Carbovir, 90Y-DOTAGA-Substance P. LARG(Me)9 MS-10, Carboxyamidotriazole, Cariporide Hydrochloride, Caris D-TYR1ARG(Me)9] MS-10, D-TYR1AzaGLY7, ARG bamate, Carpipramine, Carumonam Sodium, Caspofungin (Me)9] MS-10, D-TYR1 MS-10, Psi(CH2NH)TPG4Van Acetate, Cefaclor, Cefcanel Daloxate Hydrochloride, Cef comycin Aglycon, TRP19 MS-10, 111 IN-Pentetreotide, capene Pivoxil Hydrochloride, Cefdaloxime, Cefdaloxime 13-Deoxyadriamycin Hydrochloride, 17-Aminogeldanamy Pentexil Tosilate, Cefdinir, Cefditoren Pivoxil, Cefepime, cin, 19-O-Methylgeldanamycin, 1-Methyl-D-Tryptophan, Cefetamet Pivoxil, Cefetecol, Cefixime, Cefluprenam, Cef 21-Aminoepothilone B, 2-Aminoaristeromycin, 2-Aminon matilen Hydrochloride Hydrate, Cefnmenoxime Hydrochlo eplanocin A, 3-Chloroprocainamide, 3-Deazaadenosine, ride, Cefninox Sodium, Cefodizime, Cefodizime Sodium, 3-Matida, 4-Amino salicylic Acid, 4-Chlorophenylthio Cefoselis Sulfate, Cefotaxime Sodium, Cefotetan Disodium, DADME-Immucillin-A, 5,4'-Diepiarbekacin, 5'-Homonepl Cefotiam Hexetil, Cefotiam Hexetil Hydrochloride, Cefo anocin A, 5-Aminosalicylic Acid, 8(R)-Fluoroidarubicin tiam Hydrochloride, Cefoxitin, Cefozopran, CefoZopran Hydrochloride, 99MTC-C(RGDFK*)2Hynic, 9-Ami Hydrochloride, Ce?pirome, Cefpodoxime Proxetil, Cef nocamptothecin, A-42867 Pseudoaglycone, Abacavir Succi prozil, Cefprozil Monohydrate, Cefauinome, Ceftaroline, nate, Abacavir Sulfate, Abanoquil Mesilate, Abarelix, Ceftazidime, Cefteram Pivoxil, Ceftibuten, Ceftobiprole, Acadesine, Acriflavine, Acyclovir, Acyclovir Elaidate, Acy Ceftobiprole Medorcaril, CeftraZonal Bopentil, CeftraZonal clovir Oleate, Acyline, Adefovir, Adefovir Dipivoxil, Ademe Sodium, Ceftriaxone Sodium, Ceftrizoxime Alapivoxil, tionine Tosylate Sulfate, Adenallene, Adenophostin A, Cefuroxime, CefuroximeAxetil, Cefuroxime Pivoxetil, Cen Adenophostin B, Adenosine, Aerothricin 1, Aerothricin 16, tanamycin, Cephalexin Monohydrate, Ceranapril, Ceruletide Aerothricin 41, Aerothricin 45, Aerothricin 5, Aerothricin 50, Diethylamine, Cetefloxacin, Chlorofusin, Chloroorienticin Aerothricin 55, Afloqualone, Ageliferin Diacetate, Ageliferin A, Chloroorienticin B, Chlorotetain, Cibrostatin 1, Cidofovir, Dihydrochloride, Aladapcin, Alamifovir, Alatrofloxacin Cilastatin Sodium, Cilengitide, Cimaterol, Cinitapride Mesilate, Alendronic Acid Sodium Salt, Alestramustine, Hydrogen Tartrate, Cipamfylline, Circinamide, Cisapride Alfuzosin Hydrochloride, Aliskiren Fumarate. Alogliptin Hydrate, Cispentacin, Citicoline, Citrullimycine A, Cladrib Benzoate, Alpha-Methylnorepinephrine, Alpha-Methyltryp ine, Clitocine, Clofarabine, Clopidogrel Sulfate, Compound tophan, Altemecidin, Alvespimycin Hydrochloride, Amanta 3.01029, Coumamidine Gammal, Coumamidine Gamma2, US 2016/00821 23 A1 Mar. 24, 2016 47

Cromoglycate Lisetil Hydrochloride, Cycallene, Cyclic-Ci din B, Hepavir B, Heptaminol AMP Amidate, Hexa-D-Argi dofovir, Cycloserine, Cyclotheonamide A, Cyclothialidine, nine, Hexadecyl Cidofovir, Hexadecyloxypropyl-Cidofovir, Cygalovir, Cypemycin, CySmethynil, Cystamidin A, Cysta Histamine Dihydro chloride. Histaprodifen, Histrelin, Histre mine, CystaZosin, Cystocin, Cytarabine, Cytarabine Ocfos lin Acetate, Human Angiotensin II, Hydrostatin A, Hydroxy fate, Cytaramycin, Cytochlor, Cytomodulin, Dabigatran, akalone, Hydroxyurea, Hypeptin, Ibutamoren Mesilate, Icati Dabigatran Etexilate, Dacopafant, Dactimicin, Dactinomy bant Acetate, Iclaprim, Icofungipen, Idarubicin cin, Dactylocycline A, Dactylocycline B, DADME-Immuci Hydrochloride, Ilatreotide, Ilonidap, Imetit, Imidafenacin, lin-G, Dalargin, Danegaptide Hydrochloride, Dapropterin Imidazenil, Imiquimod, Immunosine, Impentamine, Incyc Dihydrochloride, Dapsone, Darbufelone Mesilate, Darifena linide, Indanocine, Indantadol Hydrochloride, Indoxam, cin Hydrobromide, Darinaparsin, Darunavir, Daunorubicin, Inogatran, Intrifiban, Iobenguane 131I]. Iodorubidazone (P), Davasaicin, Davunetide, Debrisoquine Sulfate, Decahydro Iotriside, Isepamicin Sulfate, Isobatzelline A, Isobatzelline B. moenomycin A, Decaplanin, Deferoxamine, Degarelix Isobatzelline C, Isobatzelline D, Isobutyramide, Isodoxoru Acetate, Delafloxacin, Delta-Aminolevulinic Acid Hydro bicin, Isopropamide Iodide, Ispinesib Mesylate, Istaroxime, chloride, Deltibant, Denagliptin Hydrochloride, Denibulin Janthinomycin A, Janthinomycin B, Janthinomycin C, Jas Hydrochloride, Denufosol Tetrasodium, Deoxymethylsper pine B, Kahalalide F, Kaitocephalin, Kanamycin, Karnami gualin, Deoxynegamycin, Deoxyvariolin B. Desacetylvin cin B1, Katanosin A, Katanosin B. Kistamicin A, L-4-Oxal blastinehydrazide/Folate Conjugate, Des-F-Sitagliptin, Des ysine, Labetalol Hydrochloride, Labradimil, Lagatide, glugastrin Tromethamine, Deslorelin, Desmopressin Lamifiban, Lamivudine, Lamotrigine, Lanicemine 2CS)-Hy Acetate, Detiviciclovir Diacetate, Dexelvucitabine, Dexibu droxysuccinate, Lanicemine Hydrochloride, Lanomycin, profen Lysine, Dextroamphetamine Sulfate, Dezinamide, Larazotide Acetate, Lazabemide Hydrochloride, L-Dopa Dezocitidine, Diadenosine Tetraphosphate, Diaveridine, Methyl Ester Hydrochloride, L-Dopamide, Lecirelin, Lena Dichlorobenzoprim, Dicloguamine Maleate, Didemnin X. lidomide, Lenampicillin Hydrochloride, Leucettamine A, Didemnin Y. Dideoxycytidine, Difurazone, Dilevalol, Dil Leucovorin Calcium, Leuprolide Acetate, Leurubicin, Leus evalol Hydrochloride, Disermolide, Disopyramide Phos troducsin A, LeuStroducsin B. Leustroducsin C. Leustroduc phate, DI-VAL-L-DC, Docosyl Cidofovir, Dolastatin 14, sin H. Levetiracetam, Levodopa, Levodopa 3-O-Glucoside, Dolastatin C, Donitriptan Hydrochloride, Donitriptan Mesi Levodopa 4-O-Glucoside, Levo leucovorin Calcium, L-His late, Dovitinib Lactate. Doxazosin Mesylate, Doxorubicin tidinol, L-Homothiocitrulline, Liblomycin, Linagliptin, Lini Hydrochloride, Doxycycline Hyclate, D-Penicillamine, fanib, Lintopride, Lirexapride, Lirimilast, Lisinopril, Draflazine, Droxidopa, DTPA-Adenosylcobalamin, Ebroti L-Lysine-D-Amphetamine Dimesylate, Lobophorin A, dine, Ecenofloxacin Hydrochloride, Efegatran Sulfate Lobucavir, Lodenosine, Loloatin B, Lomeguatrib, Lometr Hydrate, Eflornithine Hydrochloride, Eglumegad Hydrate, exol, Lonafarnib, Loracarbef Hydrate, Loviride, Loxoribine, Eicosyl Cidofovir, Elacytarabine, Elastatinal B, Elastatinal C. L-Simexonyl Homocysteine, L-Thiocitrulline, Lymphostin, Elpetrigine, Elvucitabine, Emtricitabine, Enalkiren, Enig Lysobactin, Mabuterol Hydrochloride, Makaluvamine A, mol, Eniporide Mesilate, Entecavir, Entinostat, Epinastine Makaluvamine A, Makaluvamine B, Makaluvamine C, Hydrochloride, Epiroprim, Epirubicin Hydrochloride, Epi Managlinat Dialanetil, Matristatin A2, Melagatran, Melano thalon, Epofolate, Epostatin, Epsilon Aminocaproic Acid, tan II, Memantine Hydrochloride, Memno-Peptide A, Mep Eremomycin, Eribulin Mesylate, Erucamide, Esafloxacine robamate, Meriolin-3, Mersacidin, Metaraminol, Metazosin, Hydrochloride, Eslicarbazepine Acetate, Etaquine, Ethanola Metformin Hydrochloride, Methotrexate, Methyl Bestatin, mine, Ethylthio-DADME-Immucillin-A, Ethynylcytidine, Methyldopa, Methylthio-DADME-Immucillin-A, Metoclo Etravirine, Etriciguat. Exalamide, Examorelin, Exatecan pramide Hydrochloride, Metyrosine, Mexiletine Hydrochlo Mesilate, Ezatiostat Hydrochloride, Famciclovir, Famoti ride, Micafungin Sodium, Midaxifylline, Mideplanin, dine, Famotidine Bismuth Citrate, Favipiravir, Feglymycin, Midoriamin, Milacainide Tartrate, Milacemide-2H, Mil Felbamate, Fenleuton, Fidarestat, Fidexaban, Filaminast, nacipran Hydrochloride, Minamestane, Minocycline Hydro Filarizone, Fingolimod Hydrochloride, Flucytosine, Fludara chloride, Minoxidil, Mirabegron, Mitomycin, MivaZerol, bine Phosphate, Fluorobenzyltriamterene, Fluorominoxidil, Mivobulin Isethionate, Mizoribine, Mocetinostat Dihydro Fluoroneplanocin A. Flupiritine Maleate, Fluvirucin B2, Flu bromide, Modafinil, Modafinil Sulfone, Moenomycin A voxamine Maleate, Folinic Acid, Fortimicin A, Fosam Chloride Bismuth Salt, Mofegiline, Mofegiline Hydrochlo prenavir Calcium, Fosamprenavir Sodium, Fosfomycin ride, Monamidocin, Monodansyl Cadaverine, Montirelin Trometamol, Fradafiban, Freselestat, Frovatriptan, Tetrahydrate, Mosapride Citrate, Moxilubant, Moxilubant Fudosteine, Furamidine, G1 Peptide, Gabadur, Gabapentin, Maleate, Mozenavir Mesilate, M-Phenylene Ethynylene, Gabexate Mesilate, GalarubicinHydrochloride, Galmic, Gal Muraminomicin A, Muraminomicin B, Muraminomicin C, non, Ganciclovir, Ganciclovir Elaidic Acid, Ganciclovir MuraminomicinD, Muraminomicin E1, Muraminomicin E2, Monophosphate, Ganciclovir Sodium, Ganirelix, Ganirelix Muraminomicin F. Muraminomicin G, Muraminomicin H, Acetate, Garomefrine Hydrochloride, Gemcitabine, Gemcit Muraminomicin I, Muraminomicin Z1, Muraminomicin Z2, abine Elaidate, Gemifloxacin Mesilate, Gilatide, Girodazole, Muraminomicin Z3, Muraminomicin Z4, Muramyl Dipep Glaspimod, Glucosamine Sulfate, Gludopa, Glutathione tide C. Mureidomycin A. Mureidomycin B. Mureidomycin Monoethylester, Glutathione Monoisopropylester, Glycine C. Mureidomycin D. Mycestericin E. Myriocin, Nafamostat Proline-Melphalan, Glycopin, Glycothiohexide alpha, Golo Mesylate, Nafarelin Acetate, Naglivan, Namitecan, Napsa timod, Goserelin, Growth Factor Antagonist-116, Growth gatran, Nebostinel, Nebracetam Fumarate, Neldazosin, Hormone Releasing Peptid 2, Guanabenz Acetate, Guanadrel Nelzarabine, Nemonoxacin, Neomycin B-Hexaarginine Sulfate, Guanethidine Monosulfate, Guanfacine Hydrochlo Conjugate, Neomycin-Acridine, Nepafenac, Nepicastat ride, Gusperimus Hydrochloride, Halovir A. Halovir B. Hydrochloride, Neramexane Hydrochloride, Neridronic Halovir C. Halovir D. Halovir E. Hayumicin B, Hayumicin Acid, Netamiftide Trifluoroacetate, Netilmicin Sulfate, C1, Hayumicin C2, Hayumicin D, Helvecardin A, Helvecar Nocathiacin I, Nocathiacin II, Nocathiacin III, Nocathiacin US 2016/00821 23 A1 Mar. 24, 2016 48

IV, NO-Gabapentin, Nolatrexed Hydrochloride, NO-Me Sitagliptin Phosphate Monohydrate, S-Nitrosoglutathione, salamine, Noraristeromycin, Nuvanil. 06-Benzylguanine, Sofigatran, Sonedenoson, Sotirimod, Sparfloxacin, Sperabil Ocimumoside A, Octacosamicin A, Octacosamicin B, Oct lin A, Sperabillin B, Sperabillin C, Sperabillin D. Sphingo reother, Octreotide Acetate, Oglufanide Disodium, Olamu fungin F. Spinorphin, Spisulosine, Squalamine Lactate, floxacin, Olamufloxacin Mesilate, Olcegepant, Olradipine Streptomycin, Styloguanidine, Substance P(8-11), Sufi Hydrochloride, Omaciclovir, Ombrabulin, Ombrabulin nosine, Sulcephalosporin, Sulfostin, Sulphazocine, Sultami Hydrochloride, Onnamide A, Opiorphin, Orbofiban Acetate, cilline Tosylate, Sunflower Trypsin Inhibitor-1, Surfen, Syn Orienticin A, Orienticin B, Orienticin C, Orienticin D, Orita adenol, Synguanol, Tabimorelin, Tacedinaline, Tacrine vancin, Oseltamivir Carboxylate, Oseltamivir Phosphate, Hydrochloride, Tageflar, Talabostat, Talaglumetad Hydro chloride, Talampanel, Talipexole Dihydrochloride, Tallimus Otamixaban, Otenabant Hydrochloride. Ovothiol A, Oxazo tine Hydrochloride, Talopterin, Taltirelin, Tanespimycin, furin, Oxcarbazepine, Oxiglutatione Sodium, Oxiracetam, Tanogitran, Targinine, Technetium (99MTC) Depreotide, Oxolide, Oxynor, Oxyphenarsine, Ozarelix, Pachymedusa Teicoplanin-A2-1, Teicoplanin-A2-2, Teicoplanin-A2-3, Dacnicolor Tryptophyllin-1, Paecilaminol, Pafuramidine Teicoplanin-A2-3, Teicoplanin-A2-5, Telavancin Hydro Maleate, Palau.Amine, Paldimycin B, Pamidronate Sodium, Pancopride, Papuamide A, Papuamide B, Papuamide C. Pap chloride, Telinavir, Temozolomide, Temurtide, Tenidap, uamide D, Parasin I, Paromomycin, Pasireotide, Paulomycin, Tenidap Sodium, Tenofovir, Tenofovir DF, Terazosin Hydro Paulomycin A2, Paulomycin B, Paulomycin C, Paulomycin chloride, Tetracosyl Cidofovir, Tetracycline Hydrochloride, D. Paulomycin E, Paulomycin F. PaZufloxacin, PaZufloxacin Tetrafibricin, Texenomycin A, Tezacitabine, TGP. Thioacet, Mesilate, PEG-Vancomycin, Pelagiomicin C, Peldesine, Thiothio. Thrazarine, Thymoctonan, Thymopentin, Tiam Pelitrexol, Pemetrexed Disodium, Penciclovir, Penicillin G dipine, Tigecycline, Tilarginine Hydrochloride, Timirdine Procaine, Pentamidine Gluconate, Pentamidine Isethionate, Diethanesulfonate, Timodepressin, Tipifarnib, TNF-Alpha Pentamidine Lactate, Peplomycin, Peramivir, Perphanazine Protease Enzyme Inhibitor, Tobramycin, Tocainide Hydro 4-Aminobutyrate, Phakellistatin 5, PHE-ARG-Beta-Naph chloride, Tokaramide A, Tomopenem, Topostatin, Torcitab thylamide, Phentermine, Phortress, Phospholine, Pibutidine ine, ToSufloxacin, ToSufloxacin Tosilate, Tranexamic Acid, Hydrochloride, Pimeloylanilide O-Aminoanilide, Piracetam, Trantinterol Hydrochloride, Tranylcypromine Sulfate, Pirarubicin, Pivampicillin, Pixantrone Maleate, Pluraflavin Trelanserin, Tresperimus Triflutate, Trichomycin A, Tricirib A, Pluraflavin B, Plusbacin A1, Plusbacin A2, Plusbacin A3, ine, Triciribine Phosphate, Trientine Hydrochloride, Trima Plusbacin A4, Plusbacin B1, Plusbacin B2, Plusbacin B3, Zosin Hydrochloride, Trimetrexate Glucuronate, Trimexau Plusbacin B4, PMEO-5-ME-DAPY, Pneumocandin A0, tide, Trimidox, Trovafloxacin, Trovafloxacin Hydrate, Pneumocandin B0, Pneumocandin B0 2-Phosphate, Pneu Trovafloxacin Hydrochloride Mesylate, Trovafloxacin Mesi mocandin D0, Polaprezinc, Polydiscamide A, Polymer late, Troxacitabine, Trybizine Hydrochloride, Tubastrine, Bound Human Leukocyte Elastase Inhibitor, Poststatin, Tuftsin, Tyroservatide, Tyrphostin 47, Ubenimex, Valacyclo PPI17-24, Pradimicin E, Pradimicin FA-2, Pralatrexate, vir, Valganciclovir Hydrochloride, Valnemulin, Valomaciclo Pramipexole Hydrochloride, Pranedipine Tartrate, Prazosin vir Stearate, Valonomycin A, Valopicitabine, Valpromide, Hydrochloride, Prefolic A. Pregabalin, Preladenant, Pri Valrocemide, Vamicamide, Vancomycin Hydrochloride, Van maquine Phosphate, Probestin, Procainamide Hydrochlo coresmycin, Vapitadine Hydrochloride, Varespladib, Varesp ride, Procaine Hydrochloride, Pro-Diazepam, Prostatin, Pru ladib Methyl, Varespladib Mofetil, Velnacrine Maleate, calopride, Prucalopride Hydrochloride, Prucalopride Venorphin, Vigabatrin, Vilazodone Hydrochloride, Vin Succinate, Pseudomycin A", Pseudomycin B", Pyloricidin B, desine, Viramidine Hydrochloride, Viranamycin-B, Vitamin Pyradizomycin, Pyrazinamide, Pyrazinoylguanidine, Pyrif B3, W Peptide, Xemilofiban, Xylocydine, Zanamivir, Zileu erone, Pyrimethamine, Quinelorane Hydrochloride, R-(+)- ton, Zoniporide Hydrochloride, Zorubicin Hydrochloride. Aminoindane, Ralfinamide, Ramoplanin A1, Ramoplanin 0696 Suitable small molecule drugs comprising a second A2, Ramoplanin A3. Ramorelix, Ravidomycin N-oxide, ary amine functional group are, for example, (-)-3-O-Ace Razaxaban Hydrochloride, Reblastatin, Regadenoson, Rel tylspectaline hydrochloride, (-)-3-O-tert-Boc-spectaline covaptan, Remacemide Hydrochloride, Residuimod, Restric hydrochloride, (-)-Cicloprolol, (-)-Norchloro-18F fluoro ticin, Retaspimycin Hydrochloride, Retigabine Hydrochlo homoepibatidine, (-)-Salbutamol hydrochloride, (-)-Salme ride, Rhodopeptin C1, Rhodopeptin C2, Rhodopeptin C3, terol, (+)-(S)-Hydroxychloroquine, (+)-Isamoltan, (+)-R- Rhodopeptin C4, Rhodostreptomycin A, Rhodostreptomycin Pramipexole, (R)-(+)-Amlodipine, (R)-Clevidipine, (R)- B, Ribavirin, Ribavirin Eicosenate cis, Ribavirin Eicosenate NSP-307, (R)-Teludipine, (R)-Thionisoxetine, (S)- trans, Ribavirin Elaidate, Ribavirin Oleate, Rilmazafone Clevidipine, (S)-N-Desmethyltrimebutine, (S)- Hydrochloride Dihydrate, Riluzole, Rimacalib Hydrochlo Noremopamil, 99TcDemobesin 4, Glu10.Nle17.Nle30 ride, Rimeporide Hydrochloride, Riociguat, Ritipenem Pancreatic polypeptide(2-36), Nle17.Nle30-Pancreatic Acoxil, RobalZotan Hydrochloride, RobalZotan Tartrate polypeptide(2-36), psiCH2NHITpg4Vancomycin agly Hydrate, Rociclovir, Romurtide, Rotigaptide, Roxifiban con, 15bbeta-Methoxyardeemin, 3-Bromomethcathinone, Acetate, Ruboxyl, Rufinamide, Rumycin 1, Rumycin 2, 4,5-Dianilinophthalimide, 4-Hydroxyatomoxetine. 5-Me Sabarubicin Hydrochloride, Sabiporide Mesilate, Safinamide thylurapidil, 7-Oxostaurosporine, 99mTc-c(RGDfK*) Mesilate, Safingol, Sagamacin, Sampatrilat, Sampirtine, 2HYNIC, A-42867 pseudoaglycone, Abacavir succinate, Saprisartan, Saquinavir, Saquinavir Mesilate, Sardomizide Abacavir sulfate, Abarelix, Acarbose, Acebutolol hydrochlo Hydrochloride, Sardomozide, Saussureamine C. Saxagliptin, ride, Aceclofenac, Acyline, Adaphostin, Adaprolol maleate, Secobatzelline A, Secobatzelline B, Seglitide, Selank, Sele Adaprolol oxalate, Adecypenol, Adirogolide hydrochloride, tracetam, Semapimod Hydrochloride, Senicapoc, Sepimostat Aglaiastatin C, Alchemix, Alinidine, Alkasar-18, Alminopro Mesilate, Seproxetine, Seraspenide, Sevelamer Carbonate, fen, Alniditan, alpha-Methylepinephrine, Alprafenone Sevelamer Hydrochloride. Shepherdin, Sibrafiban, Silo hydrochloride, Alprenolol hydrochloride, Alprenoxime dosin, Silver Sulfadiazine, Sipatrigine, Sitafloxacin Hydrate, hydrochloride, Altromycin A, Altromycin C, Alvespimycin US 2016/00821 23 A1 Mar. 24, 2016 49 hydrochloride, Ambroxol nitrate, Amfebutamone hydrochlo 875, Efaroxan, Efegatran sulfate hydrate, Efepristin, Efonid ride, Amibegron hydrochloride, Amifostine hydrate, ipine hydrochloride ethanol, Elagolix sodium, Elansolid C1, Amineptine, Aminocandin, Aminochinol, Amitivir, Amlo Elaroflban, Elbanizine, Elgodipine hydrochloride, Elinafide dipine, Amlodipine besylate. Amocarzine, Amodiaquine, mesilate, Elinogrel potassium, Elnadipine, Enalapril maleate, Amosulalol hydrochloride, Amoxapine, Amsacrine, Ana Enalapril nitrate, Enalaprilat, EnaZadrem, Enkastin (D), basine hydrochloride, Anisperimus, Antide-1, Aranidipine, Enkastin (D), Enkastin (D), Enkastin AD, Enkastin AE, Araprofen, Arbutamine hydrochloride, Ardeemin, Arformot Enkastin ID, Enkastin IE, Enkastin VD, Enkastin VE, Enoxa erol tartrate, Argatroban monohydrate, Argiopine, Arotinolol cin, Epibatidine, Epostatin, Eremomycin, Ersentilide, Ersen hydrochloride, Asperlicin E, Atenolol, Atevirdine mesylate, tilide hydrochloride, Ertapenem Sodium, Esculeogenin A, Azathioprine, AZelnidipine, AZepino statin, Balamapimod, Esculeoside A, Esmolol hydrochloride, Esperamicin A1, Balhimycin, Balofloxacin, Balofloxacin dihydrate, Bam Etamsylate, Ethoxy-idazoxan, Eugenodilol, Ezlopitant, buterol, Bamirastine hydrate, Banoxantrone, Baogongteng A, Falnidamol, Farglitazar, Fasobegron hydrochloride, Fasudil Barixibat, Barnidipine hydrochloride, Batoprazine, Batzel hydrochloride, Felodipine, Fenoldopam mesilate, Fenoterol line A, Batzelline B. Batzelline C. Becampanel, Bederocin, hydrobromide, Fepradinol, Ferroquine, Ferulinolol, Fina Bedoradrine sulfate. Befunolol hydrochloride, Belactin B, floxacin hydrochloride, Flecainide acetate, Florbetaben, Belotecan hydrochloride, Benazepril hydrochloride, Ben Florbetapir F 18, Flufenoxine, Flumezapine, Fluodipine, Flu droflumethiazide, Benidipine hydrochloride, Berlafenone oxetine hydrochloride, Fluparoxan, Flupirtine maleate, Foe hydrochloride, Betaxolol hydrochloride, Bevantolol hydro tidine 1, Foetidine 2, Folinic acid, Formoterol fumarate, chloride, Biemnidin, Bifemelane hydrochloride, Binospirone Forodesine hydrochloride, Fosaprepitant dimeglumine, mesylate, Bioxalomycin alpha 1, Bis(7)-cognition, Bisant Fosopamine, Frovatriptan, Furnidipine, Furosemide, rene hydrochloride, Bisnafide mesilate, Bisoprolol fumarate, Gaboxadol, Gadobenic acid dimeglumine salt, Gadopen Bitolterol mesylate, Bleomycin A2 sulfate, Boholmycin, tetate dimeglumine, Gadoterate meglumine, Galactomycin I. Bopindolol, Bosutinib, Brinazarone, Brinzolamide, Galactomycin II, Garenoxacin mesilate, Gatifloxacin, Gefi Bulaquine, Bumetanide, Buteranol, Butofilolol, Cadrofloxa tinib. Glucolanomycin, Glutapyrone, Gosogliptin hydrochlo cin hydrochloride, Caldaret hydrate, Calindol Dihydrochlo ride, Grepafloxacin hydrochloride, Gypsetin, Halofuginone ride, Capridine beta, Carmoterol hydrochloride, Carteolol hydrobromide, Helvecardin A, Helvecardin B. Herquline B. hydrochloride, Carvedilol, Caspofungin acetate, Ceftaroline Hesperadin, Himastatin, Hispidospermidin, Homoepibati fosamil acetate, Ceftizoxime sodium, Ceftobiprole, Celip dine, Hydrochlorothiazide, Hydroflumethiazide, Hydroxy rolol hydrochloride, Cerebrocrast, Ceruletide diethylamine, chloroquine sulfate, Ibopamine, Idazoxan hydrochloride, Cevipabulin, Chinoin-169, Chloptosin, Chlordiazepoxide Iganidipine hydrochloride, Imidapril, Imidapril hydrochlo hydrochloride, Chloroorienticin A, Chloroorienticin B, ride, Imidazoacridinone, Imisopasem manganese, Immepip, Cilazapril, Cilnidipine, Ciluprevir, Cimaterol, Cinacalcet Immepyr, Incadronate, Indacaterol, Indantadol hydrochlo hydrochloride, Cinnamycin, Ciprofloxacin hydrochloride, ride, Indeloxazine hydrochloride, Indolmycin, Inogatran, Ciprofloxacin silver salt, Clevidipine butyrate, Clitocine, Intoplicine, Iofetamine hydrochloride I-123. Iptakalim Clopenphendioxan, Cloranolol hydrochloride, Clozapine, hydrochloride, Isavuconazonium chloride hydrochloride, Conantokin-R, Conophylline, Crisinatol mesilate, Cronid Isepamicin Sulfate, Isofagomine tartrate, Isoquine, Isproni ipine, Dabelotine mesilate, Dabigatran, Dabigatran etexilate, cline, Isradipine, Iturelix, Kaitocephalin, Ketamine hydro Dalbavancin, Dapivirine, Dapropterin dihydrochloride, Das chloride, Kopsinine, Korupensamine A, Korupensamine B. antafil. Debromoshermilamine, Decaplanin, Degarelix Korupensamine C, Kosinostatin, Labedipinedilol A, Labe acetate, Delapril hydrochloride, Delavirdine mesilate, Del dipinedilol B, Labetalol hydrochloride, Labradimil, Lacid faprazine hydrochloride, Delucemine hydrochloride, Dem ipine, Ladasten, Ladostigil tartrate, Lagatide, Landiolol. ethylallosamidin, Demexiptiline hydrochloride, Denopam Lapatinib ditosylate, Lenapenem hydrochloride, Lenapenem ine, Deoxymethylspergualin, Deoxyspergualin hydrochloride hydrate, Lerisetron, Leucovorin calcium, Hydrochloride. Desacetylvinblastinehydrazide/folate conju Levobetaxolol hydrochloride, Levobunolol hydrochloride, gate. Desbutylbenflumetol, Desbutylhalofantrine hydrochlo Levo leucovorin calcium, Levonebivolol, Liblomycin, ride, Desferri-salmycin A, Desferri-salmycin B. Desferri-sal Linaprazan, Lisinopril, Litoxetine, Lobenzarit Sodium, mycin C, Desferri-salmycin D. Desipramine hydrochloride, Lodamin, Lofexidine hydrochloride, Lomefloxacin hydro Desloratadine, Dexfenfluramine hydrochloride, Dexketopro chloride, Lorcaserin, Lotrafiban, Loviride, Lubazodone fen meglumine, Dexmethylphenidate hydrochloride, Dex hydrochloride, Lumiracoxib, Mabuterol hydrochloride, niguldipine hydrochloride, DeXSotalol, Diazepinomicin, Makaluvamine D, Makaluvamine E. Makaluvamine F. Dichlorobenzoprim, Diclofenac potassium, Diclofenac Makaluvone, Manidipine hydrochloride, Manifaxine hydro sodium, Diclofenac Zinc salt, Diethylnorspermine, Dihy chloride, Manzamine B. Manzamine D. Maprotiline hydro drexidine, Dilevalol, Dilevalol hydrochloride, Dinapsoline, chloride, Maropitant, Masnidipine hydrochloride, Mecamy Dinoxyline, Dipivefrine hydrochloride, Discodermide, Dis lamine hydrochloride, Meclofenamate sodium, Mefenamic codermide acetate, Discorhabdin D, Discorhabdin P. Dis acid, Mefloquine hydrochloride, Melagatran, Melogliptin, corhabdin S, Discorhabdin T. Discorhabdin U, Dobutamine Meluadrine, Meluadrine tartrate, Memoduin, Mepindolol hydrochloride, Dobutamine phosphate, Dopexamine, sulfate, Mepindolol transdermal patch, Meropenem, Meth Dopexamine hydrochloride, Doripenem, Dorzolamide amphetamine hydrochloride, Methoctramine, Methy hydrochloride, d-Pseudoephedrine hydrochloride, Droxi clothiazide, Methylhistaprodifen, Methylphenidate hydro navir, Duloxetine hydrochloride, Duocarmycin A, Duocar chloride, Metipranolol, Metolazone, Metoprolol fumarate, mycin B1, Duocarmycin B2, Duocarmycin C1, Duocarmycin Metoprolol succinate, Metoprolol tartrate, Mezacopride, C2, Dynemicin A. Dynemicin C. Ebanicline, Ecteinascidin Michellamine B, Microcin J25, Micronomicin sulfate, 1560, Ecteinascidin 722, Ecteinascidin 729, Ecteinascidin Midafotel, Milacemide-2H), Minaprine hydrochloride, 736, Ecteinascidin 745, Ecteinascidin 770, Ecteinascidin Mirabegron, Mitomycin, Mitoxantrone hydrochloride, US 2016/00821 23 A1 Mar. 24, 2016 50

Mivobulin isethionate, Modipafant, Moexipril hydrochlo dipine hydrochloride, Tamsulosin hydrochloride, Tanespi ride, Moexiprilat, Montirelin tetrahydrate, Moranolin, Mote mycin, Tanogitran, Tauropyrone, Tazopsine, Tecalcet hydro sanib diphosphate, Moxifloxacin hydrochloride, Moxonidine chloride, Tecastemizole, Technetium (99mTc) apcitide, hydrochloride hydrate, Muraminomicin I, Mureidomycin E, Technetium (99mTc) bicisate, Telatinib, Telavancin hydro Mureidomycin F. Mureidomycins, N1,N8-Bisnorcymserine, chloride, Temacrazine mesilate, Temafloxacin hydrochlo Nadolol, Naproxen piperazine, Napsamycin A, Napsamycin ride, Temocapril hydrochloride, Terbutaline sulfate, B, Napsamycin C, Napsamycin D. Nardeterol, N-demethy Terodiline hydrochloride, Tertatolol hydrochloride, Tetra lated sildenafil. Nebivolol, Nemonapride, Neomycin-acri caine hydrochloride, Tetrahydrodercitin 1, Tetrindole, dine, Neratinib, Netilmicin sulfate, Nicardipine hydrochlo Tezampanel. Thiamet-G, Thiofedrine, Tiamdipine, Tiameni ride, Nifedipine, Nifekalant hydrochloride, Niguldipine dine, Tianeptine Sodium, Tiapafant, Tienoxolol hydrochlo hydrochloride, Nilvadipine, Nimodipine, Nipradilol, Nisol ride, Tigecycline, Tilisolol hydrochloride, Timolol hemihy dipine, Nitracrine dihydrochloride hydrate, Nitrendipine, drate, Timolol maleate, Tinazoline hydrohloride, Tirofiban Nitrofenac, Nitroso-nifedipine, Noberastine, Noberastine hydrochloride, Tizanidine hydrochloride, Toborinone, Tolfe citrate, NO-ciprofloxacin, N-Octyl-beta-valienamine, Nolo namic acid, Tomatine, Tomoxetine hydrochloride, Topix mirole hydrochloride, Norfloxacin, Norsegoline, Nortopix antrone hydrochloride, Torasemide, Trabectedin, Trandola antrone hydrochloride, Nortriptyline hydrochloride, N-tert pril, Trandolaprilat, Trantinterol hydrochloride, Treprostinil butyl isoquine, Oberadilol, Oberadilol monoethyl maleate, diethanolamine, Tresperimus triflutate, Triacetyl dynemicin Odanacatib, Olanzapine, Olanzapine pamoate, Olradipine C, Trientine hydrochloride, Trifluproxim, Trimetazidine, Tri hydrochloride, Ontazolast, OPC-17083, Orbifloxacin, Orci metrexate glucuronate, Trombodipine, Troxipide, Tulathro prenaline sulphate, Orienticin A. Orienticin B. Orienticin C, mycin A, Tulathromycin B, Tulobuterol hydrochloride, Ufe Oritavancin, Osemozotan hydrochloride, Osutidine, Otena namate, Ulifloxacin, Ulimorelin, Uncialamycin, Urapidil, bant hydrochloride, Ovothiol B, Oxprenolol hydrochloride, Utibapril, Utibaprilat, Vabicaserin hydrochloride, Vancomy Ozenoxacin, Pafenolol, Palau'amine, Palindore fumarate, cin hydrochloride, Vandetanib, Vanidipinedilol, Vaninolol, Panobinostat, Parodilol hemifumarate, Parogrelil hydrochlo Vapitadine hydrochloride, Varenicline tartrate, Varlitinib, ride, Paroxetine, Paroxetine ascorbate, Paroxetine camsilate, Vatalanib succinate, Vatanidipine, Vatanidipine hydrochlo Paroxetine hydrochloride, Paroxetine mesilate, Pazelliptine ride, Vestipitant mesylate, Vicenistatin, Vildagliptin, Vilox trihydrochloride, Pazelliptine trihydrochloride monohydrate, azine hydrochloride, Vofopiitant hydrochloride, Voglibose, Pelitinib, Pelitrexol, Penbutolol sulfate, Pentostatin, Peplo Voreloxin, Xamoterol fumarate, Ximelagatran, Yttrium-90 mycin, Perindopril, Perzinfotel, Phendioxan, Pibutidine edotreotide, Zabicipril hydrochloride, Zabiciprilat hydro hydrochloride, Picumeterol fumarate, Pindolol, Pirbuterol chloride (), Zabofloxacin hydrochloride, Zanapezil fumarate, hydrochloride, Pittsburgh Compound B, Pixantrone maleate, Zelandopam hydrochloride, Zilpaterol, Zolmitriptan. Plerixafor hydrochloride, Polyglutamate camptothecin, 0697 Suitable small molecule drugs comprising an aro Pozanicline hydrochloride, Pradimicin A, Pradimicin B, matic hydroxyl group are, for example, (-)-cis-Resorcylide, Pradimicin D, Pradimicin FA-1, Pradimicin FL, Pradimicin (-)-Indocarbazostatin B, (-)-Salmeterol, (-)-Subersic acid, FS, Pradimicin L. Pradimicin S. Pradofloxacin, Pramipexole (+)-alpha-Viniferin, (+)-Etorphine, (+)-Indocarbazostatin, hydrochloride, Pranedipine tartrate, Pranidipine, Prefolic A. (+)-SCH-351448, (R)-Gossypol, (S)-(+)-Curcuphenol, (S)- Premafloxacin, Premafloxacin hydrochloride, Premafloxacin Methylmaltrexone bromide, 8-Gingerol, Arg(Me)9] magnesium, Primaquine phosphate, Prisotinol, Procaterol MS-10, D-Tyr1Arg(Me)9 MS-10, D-Tyr1AzaGly7. Arg Hydrochloride Hemihydrate, Propafenone hydrochloride, (Me)9 MS-10, D-Tyr1 MS-10, psiCH2NHITpg4Vanco Propranolol hydrochloride, Protriptyline hydrochloride, mycinaglycon, Trp 19 MS-10, 13-Deoxyadriamycin hydro Proxodolol, Pumaprazole, Pyrindamycin A. Pyrindamycin B, chloride, 14-Methoxymetopon, 14-Phenylpropoxymetopon, Quinapril hydrochloride, Quinpramine, rac-Debromoflustra 18, 19-Dehydrobuprenorphine hydrochloride, 2,12-Dimeth mine E. Radezolid, Rafabegron, Ralfinamide, Ramipril, yleurotinone, 2-Hydroxymatteucinol, 2-Methoxyestradiol, Rasagiline mesilate, Razupenem, Reboxetine mesilate, Repi 2-Methyleurotinone, 3,5-Dicaffeoylquinic acid, 3-Bromo notan, Repinotan hydrochloride, Reproterol hydrochloride, diosmetine, 3-Bromodiosmine, 3-Chlorodiosmetime, 3-Chlo Retaspimycin hydrochloride, Retigabine hydrochloride, rodiosmine, 4',7,8-Trihydroxyisoflavone, 4-Aminosalicylic RhodostreptomycinA, Rhodostreptomycin B. Rifabutin, Ril acid, 4-Hydroxyatomoxetine, 4-Iodopropofol, 5-Iodofrederi menidine dihydrogen phosphate, Rimoterol hydrobromide, camycin A, 5Z-7-Oxozeaenol, 6-Carboxygenistein, 6-O- Risotilide, Rivanicline, Robenacoxib, Rolapitant hydrochlo mPEG4-Nalbupine, 6-O-mPEG5-Nalbuphine, 7-Methylcap ride, Safinamide mesilate, Sagandipine, Salbostatin, Salbuta illarisin, 8(R)-Fluoroidarubicin hydrochloride, 8.9'- mol nitrate, Salbutamol sulfate, Salmaterol, Salmeterol Xin Dehydroascochlorin, 8-Carboxy-iso-iantheran A, 8-Paradol, afoate, Sarizotan hydrochloride, Saussureamine C, 8-Prenylapigenin, 8-Prenylmaringenin, 9-Hydroxycrisamicin Sazetidine-A, Selodenoson, Sertraline, Sertraline hydrochlo A, A-42867 pseudoaglycone, Abarelix, Acacetin, Aclarubi ride, Setazindol, Sezolamide hydrochloride, Shishijimicin A, cin, Acolbifene hydrochloride, Acotiamide hydrochloride Shishijimicin B, Shishijimicin C, Sibanomicin, Sibenadet hydrate, Acrovestone, Actinoplanone A, Actinoplanone B. hydrochloride, Silodosin, Sitamaquine hydrochloride, Sive Aculeacin Agamma, Adaphostin, Adarotene, AdXanthromy lestat sodium hydrate, Sofinicline, Solabegron hydrochlo cin A, Aerothricin 1, Aerothricin 16, Aerothricin 41, Aero ride, Solpecainol hydrochloride, Soraprazan, Sotalol hydro thricin 45, Aerothricin 50, Aerothricin 55, Ajulemic acid, chloride, Sparfloxacin, Spermine dialdehyde, Spirapril, Alchemix, Aldifen, alpha-Mangostin, alpha-Methylepineph Spiroquinazoline, Squalamine lactate, Streptomycin, Stress rine, alpha-Methylnorepinephrine, Alpha-Peltatin, Altromy inl -A, Sumanirole maleate, Suprofenac 1, Suprofenac 2. cin A, Altromycin B. Altromycin C. Altromycin D. Altromy Suprofenac 3, Suronacrine maleate, Tafamidis meglumine, cins, Alvimopan hydrate, Alvocidib hydrochloride, Tafenoquine Succinate, Talarozole, Talibegron, Talibegron Amamistatin A, Amamistatin B, Amarogentin, Amelubant, hydrochloride, Talniflumate, Talotrexin, Taltobulin, Talu Amidox, Aminocandin, Amodiaquine, Amoxicillin trihy US 2016/00821 23 A1 Mar. 24, 2016

drate, Amrubicin Hydrochloride, Amurensin H. Anguillospo 722, Ecteinascidin 729, Ecteinascidin 736, Ecteinascidin ral, Anidulafungin, Ankinomycin, Annamycin, Annulin C, 745, Ecteinascidin 757, Ecteinascidin 770, Ecteinascidin Antimycin A11, Antimycin A12, Antimycin A13, Antimycin 875, Edotecarin, Edotreotide yttrium, Eflucimibe, Eflumast, A14, Antimycin A15, Antimycin A16, Apicularen A, Apicu Elansolid C1, Eldacimibe, Ellagic acid-4-gallate, Elliptinium laren B, Apigenin, Apomine, Apomorphine hydrochloride, acetate, Elsibucol, Eltrombopag olamine, Emodin, Enaza Arbidol, Arbutamine hydrochloride, Arformoterol tartrate, drem, Enofelast, Entacapone, ent-Estriol, Epidoxoform, Epi Artepillin C, Arzoxifene hydrochloride, Aspoxicillin, Atal gallocatechin-3-gallate, Epirubicin hydrochloride, Eplivan aphillidine, Atalaphillinine, Atraric acid, AVorelin, serin, Eplivanserin fumarate, Eplivanserin mesilate, Axitirome, AZaresveratrol, AZatoxin, AZepinostatin, Baica Epocarbazolin A, Epocarbazolin B, Eprotirome, Eptazocine lein, Baicalin, Balhimycin, Balsalazide disodium, Banox hydrobromide, Erabulenol A, Erabulenol B, Eremomycin, antrone, Bazedoxifene acetate, Bazedoxifene hydrochloride, Estetrol, Estradiol, Estriol, Etalocib sodium, Etamsylate, Bedoradrine sulfate, Benadrostin, Benanomicin A, Benano Ethinylestradiol, Ethyl gallate, Etoposide, Eurotinone. Eux micin B, Benastatin A, Benastatin B, Benastatin C, Benasta anthone, Evernimicin, Exifone, EZetimibe, Fadolmidine tin D, Benzbromarone, Berefrine, Berupipam maleate, beta hydrochloride, Feglymycin, Fenoldopam mesilate, Fenoterol Mangostin, Biemnidin, Biochanin A, Bioxalomycin alpha 1. hydrobromide, Fidaxomicin, Fidexaban, Fluostatin A. Flu Bioxalomycin alpha2, Bismuth subsalicylate, Bisphenol, ostatin B, Foetidine 1, Foetidine 2, Folipastatin, Formobactin, Bix, Bizelesin, Bogorol A, Brandisianin A, Brandisianin B, Formoterol fumarate, Fosopamine, Frederine, Fulvestrant, Brandisianin C, Brasilicardin A, Brevifolin carboxylic acid, Furaquinocin A, Furaquinocin B, Fusacandin A, Fusacandin Breynin A, Breynin B. Bromotopsentin, Buflomedil pyridox B. Fusidienol, Galactomycin I, Galactomycin II, Galarubicin alphosphate, Buprenorphine hydrochloride, Buserelin hydrochloride, Galocitabine, Gambogic acid, gamma-Man acetate. Butein, Buteranol, Butorphan, Butorphanol tartrate, gostin, gamma-Tocotrienol, Ganirelix, Ganirelix acetate, Calebin A, Calocoumarin A, Caloporoside D, Caloporoside Garvalone C. Garveatin E, Garveatin F. Genistein-7-phos E. Caloporoside F, Calphostin A, Calphostin B, Calphostin C, phate, Gigantol, Gilvusmycin, Glucopiericidinol A1, Glu Calphostin D. Calphostin I, Capillarisin, CapsaZepine, Car copiericidinol A2, Gludopa, Glycothiohexide alpha, Goser bazomadurin A, Carbazomadurin B, Carbetocin, Carbidopa, elin, Granaticin B. Griseusin C, Hatomarubigin A, Carmoterol hydrochloride, Caspofungin acetate, Cassigalol Hatomarubigin B. Hatomarubigin C, Hatomarubigin D, A, Cefetecol, CefoperaZone sodium, Ce?piramide Sodium, Hayumicin A, Hayumicin B. Hayumicin C1, Hayumicin C2, Cefprozil, Cefprozil monohydrate, Cetrorelix Acetate, Cha Hayumicin D. Helicquinomycin, Helvecardin A, Helvecardin etoatrosin A, Chafuroside, Chloroorienticin A, Chloroorien B, Hericenal A, Hericenal B, Hericenal C, Hidrosmin, His ticin B, Chondramide A, Chondramide B, Chondramide C, trelin, Histrelin acetate, Hongoquercin A, Hongoquercin B, Cinnatriacetin A, Cinnatriacetin B, cis-6-Shogaol, Citpress Honokiol diepoxide, Honokiol diepoxide, Human angio ine I, Citreamicin-Alpha, Citreamicin-eta, Citrusinine-I, tensin II, Hydromorphone methiodide, Hymenistatin 1, Clausenamine A, Combretastatin A-1, Combretastatin A-2, Hypeptin, Hypericin, Hyperoside, Icariin, Idarubicin hydro Combretastatin A-3, Combretastatin B-1, Combretastatin chloride, Idronoxil, Ifenprodil, Imidazoacridinone, Incyclin B-2, Combretastatin B-3, Combretastatin B-4, Combretasta ide, Indacaterol, Indanocine, Integracin A, Integracin B, Inte tin D-1, Combretastatin D-2, Complestatin, Coniferol Alco gracin C, Integramycin, Integrastatin A, Integrastatin B, hol, Conophylline, Corynecandin, Cosalane, Crisamicin C, Intoplicine, Iodochlorhydroxyquin, Iododiflunisal, Iodoru Crobenetine, Crobenetine hydrochloride, Curtisian A. Cur bidazone (p), Iolopride (123I), Ioxipride, Iralukast, Iralukast tisian B, Curtisian D, Cyanidin Chloride Monohydrate, Sodium, Irciniastatin A, Irciniastatin B, Isalmadol, Isoba Cyclocommunol, Cycloproparadicicol, Cyclotheonamide A, Vachalcone, Isodoxorubicin, Iso-iantheran A, Isoliquiritige Cyclothialidine, Cyrtominetin, Cytogenin, Cytosporone B. nin, Isomolpan Hydrochloride, Isoquine, Isovanihuperzine Cytotrienin I, Cytotrienin II, Dactylocycline A, Dactylocy A, Jadomycin B, Jasplakinolide, Kadsuphilin C, Kaitocepha cline B. Dalargin, Dalbavancin, Damunacantal, Daphnodorin lin, Kampanol A, Kampanol B, Kanglemycin A, Kapurimy A, Daphnodorin B. Daphnodorin C ((-)-enantiomer), Dar cin A1, Kapurimycin A3, Kapurimycin A3. Kehokorin D, bufelone, Darbufelone mesilate, Daunorubicin, Dau Kehokorin E. Kigamicin A, Kigamicin B. Kigamicin C, richromenic acid, Davidigenin, Deacetyl moxisylyte hydro Kigamicin D. Kigamicin E. Kigamicinone, Kistamicin A, chloride, Decaplanin, Decyl gallate, Deferasirox, Klainetin A, Klainetin B, Kodaistatin A, Kodaistatin B, Dehydrozingerone, Delphinidin, Denopamine, Deoxymu Kodaistatin C, Kodaistatin D. Korupensamine A, Korupen lundocandin, Dersalazine, Desacetylravidomycin N-oxide, samine B. Korupensamine C, Korupensamine D. Kosinosta Desglugastrin tromethamine. Deslorelin, Desmopressin tin, Labetalol hydrochloride, Laccaridione A, Lactonamycin, acetate, Desvenlafaxine Succinate, Dexanabinol, Dextror Lactosylphenyltrolox, Ladirubicin, Lamellarin alpha 20-sul phan, Dexylosylbenanomycin A, D-Fluviabactin, Diaza fate Sodium salt, Lamifiban, Lanreotide acetate, LaSofox philonic acid, Diazepinomicin, Dieckol, Diflunisal, Dihy ifene, LaSofoxifene tartrate, Latamoxef sodium, L-Chicoric drexidine, Dihydroavenanthramide D, Dihydrogranaticin B, acid, L-Dopamide, Lecirelin, LedaZerol, Leuprolide acetate, Dihydrohonokiol B, Dihydroraloxifene, Dilevalol, Dilevalol Leurubicin, Levalbuterol hydrochloride, Levodopa, hydrochloride, Dinapsoline, Dinoxyline, Dioncoquinone A, Levodopa 3-O-glucoside, Levodopa 4-O-glucoside, Levor Dioncoquinone B. Dipotassium gossypolate, Dobutamine phanol tartrate, L-Fluviabactin, Lipiarmycin B3, Lipiarmy hydrochloride, Dobutamine Phosphate, Dopexamine, cin B4, Liquiritin apioside, Lithospermic acid B magnesium Dopexamine hydrochloride, Dosmalfate, Doxorubicin salt, Lobatamide C, Lobatamide F, Loloatin B, Luminacin D, Hydrochloride, Doxorubicin, Morpholinyl, DoxoTam 12, Luteolin, Macrocarpin A, Macrocarpin B. Makaluvamine D. Doxycycline hyclate, Dronabinol, Droxidopa, Duocarmycin Makaluvamine E. Malonoben, Maltolyl p-coumarate, Man B1, Duocarmycin B2, Duocarmycin C1, Duocarmycin C2, nopeptimycin beta, Manzamine F, Marinopyrrole A, Marme Dutomycin, Dynemicin A, Dynemicin C, Econazole Sul lin, Masoprocol, Mastprom, Matteuorienate A. Matteuo fosalicylate, Ecopipam, Ecteinascidin 1560, Ecteinascidin rienate B. Matteuorienate C, Medicarpin, Melevodopa US 2016/00821 23 A1 Mar. 24, 2016 52 hydrochloride, Mellein, Meluadrine, Meluadrine tartrate, anoside B, Rhododaurichromanic acid A, Rifabutin, Rifala Memno-peptide A, Meptazinol hydrochloride, Mesalazine, zil, Rifamexil, Rifampicin, Rifapentine, Rifaximin, Rimot Metaraminol, Methanobactin, Methyl gallate, Methyldopa, erol hydrobromide, Riodoxol, Rohitukine, Rotigaptide, Methylmaltrexone bromide, Metirosine, Micacocidin A, Rotigotine, Roxindole Mesilate, Ruboxyl, Rufigallol, Rumy Micacocidin B. Micafungin sodium, Michellamine B, Mide cin 1, Rumycin 2, Russuphelin A, Sabarubicin hydrochloride, planin, Mimopezil, Minocycline hydrochloride, Miprox Saintopin, Saintopin E. Sakyomicin A, Sakyomicin E. Sala ifene, Mitoxantrone hydrochloride, MivaZerol, Modecainide, Zopyridazin, Salbutamol nitrate, Salbutamol sulfate, Salca Mollugin, Monohydroxyethylrutoside. Morphine Glucu prozic acid sodium salt, SalicylaZobenzoic acid, Salicylihala ronide, Morphine hydrochloride, Morphine sulfate, Moxife mide A, Salicylihalamide B, Saliphenylhalamide, tin hydrogen maleate, Mumbaistatin, Mureidomycin A, Salmaterol, Salmeterol Xinafoate, Saloxin, Salvianolic acid Mureidomycin B. Mureidomycin C, Mureidomycin D, L. Sampatrilat, Sanglifehrin A, Sanglifehrin B, Sanglifehrin Mureidomycin E, Mureidomycin F. Mureidomycins, Myco C, Sanglifehrin D. Saptomycin D. Sapurimycin, Saricandin, phenolate Mofetil, Mycophenolic acid sodium salt, Myrci Secoisolariciresinol diglucoside, Seglitide, Semorphone acitrin I, Myrciacitrin II, Myrciaphenone B. Myriceric acid A. hydrochloride, Shishijimicin A, Shishijimicin B, Shishijimi Mytolbilin, Mytolbilin acid, Mytolbilin acid methyl ester, cin C, Sibenadet hydrochloride, Silychristin, Sinomenine, Mytolbillinol, Naamidine A, Nabilone, N-Acetylcolchinol, Sivifene, Siwenmycin, Sootepenseone, Spinorphin, Spino Nafarelin acetate, Nalbuphine hydrochloride, Nalfurafine sulfate A, Spinosulfate B, Spiroximicin, Stachybocin A, hydrochloride, N-Allylsecoboldine, Nalmefene, Naloxone Stachybocin B, Stachybocin C, Stachybotrin C, Stachybotry hydrochloride, Naltrexone hydrochloride, Naltrindole, Nap dial, Staplabin, Sterenin A, Sterenin C, Sterenin D. Strepto samycin A, Napsamycin B, Napsamycin C, Napsamycin D, pyrrole. Succinobucol, Sulfasalazine, Sulphazocine, Susali Nardeterol, N-Cyclopentyl-tazopsine, Nebicapone, Nelfi mod, Symbioimine, Syriacusin A, Syriacusin B, Syriacusin navir mesilate, Nemorubicin, Neparensinol A, Neparensinol C, Tageflar, Taiwanhomoflavone A, TAP-doxorubicin, Tap B, Neparensinol C, Nerfilin I, Nicanartine, Nitecapone, entadol hydrochloride, Taramanon A, Tazofelone, Tazopsine, Nocardione A, Nocathiacin I, Nocathiacin III, Nocathiacin Tebufelone, Technetium Tc 99m depreotide, Teicoplanin IV, NO-Mesalamine, Nordamunacantal, Nostocyclopeptide A2-1, Teicoplanin-A2-2, Teicoplanin-A2-3, Teicoplanin-A2 M1. Nothramicin, N-tert butyl isoquine, Obelmycin H, 3, Teicoplanin-A2-5, Telavancin hydrochloride, Temoporfin, Ochromycinone, Octyl gallate, Odapipam acetate, O-Dem Teniposide, Tenuifoliside A, Tenuifoliside B, Tenuifoliside ethylchlorothricin, O-Demethylmurrayafoline A, Oenothein C, Terbutaline sulfate, Terprenin, Tetracycline hydrochloride, B, Okicenone, Olanzapine pamoate, Olcegepant, Olsalazine Tetragalloylquinic acid, Tetrahydrocurcumin, Tetrahydro Sodium, Onjixanthone I. Onjixanthone II, Oolonghomobis echinocandin B, Tetrahydroswertianolin, Thenorphine, flavan A, Oolonghomobisflavan C, Orciprenaline sulphate, Theophylline rutoside. Thiazinotrienomycin B. Thiazinot Orienticin A, Orienticin B, Orienticin C, Orienticin D, Orita rienomycin F. Thiazinotrienomycin G. Thielavin G. Thielo vancin, Orniplabin, Orthosomycin A, Orthosomycin B, cin B3, Thymopentin, Tigecycline, Tipelukast, Tocotrienol, Orthosomycin C, Orthosomycin D, Orthosomycin E, Ortho Tokaramide A, Tolcapone, Tolterodine Tartrate, Topotecan somycin F. Orthosomycin G, Orthosomycin H, Osutidine, Acetate, Topotecane Hydrochloride, Topsentine B1, Trabect Oximidine III, Oxymetazoline hydrochloride, Oxymorp edin, trans-Resveratrol, Traxoprodil, Traxoprodil mesylate, hazole dihydrochloride, Oxymorphone hydrochloride, Trimidox, Triphendiol, Troglitazone, Tubastrine, Tubulysin Oxyphenarsine, Ozarelix, Paeciloquinine A, Paeciloquinine A, Tubulysin B, Tubulysin C, Tucaresol, Tyropeptin A10. D. Paeciloquinone B, Paeciloquinone D. Pancratistatin-3,4- Tyropeptin A6, Tyropeptin A9, Tyroservatide, Tyrphostin 47. cyclic phosphate Sodium salt, Pannorin, Papuamide A, Pap Uncarinic acid A, Uncarinic acid B, Uncialamycin, Valrubi uamide B, Papuamide C. Papuamide D, Paracetamol, cin, Vancomycin hydrochloride, Veinamitol, Venorphin, Ver Parvisporin B. PEG-Vancomycin, Penicillide, Pentazocine ticillatine, Vexibinol, Vialinin B, Vinaxanthone, W Peptide, hydrochloride, Pepticinnamin E, Phaffiaol, Phakellistatin 7. Wiedendiol A, Wiedendiol B, Woodorien, Xamoterol Fuma Phakellistatin 8, Phakellistatin 9, Phenochalasin A, Phento rate, Xanthoangelol E., Xanthofulvin, Xanthomegnin, Xipa lamine mesilate, Phlorofucofuroeckol, Phomopsichalasin, mide, Yatakemycin, Zelandopam hydrochloride, Zorubicin Phthalascidin, Physostigmine salicylate, Piceatannol, Pido hydrochloride. benzone, Pinocembrin, Pipendoxifene, Pirarubicin, Pitts 0698 Suitable small molecule drugs comprising a burgh Compound B, Platencin, Platensimycin, Pluraflavin A, hydroxyl functional group are, for example, (-)-(2R*.3R*, Pluraflavin B, Pluraflavin E, Pneumocandin A0, Pneumocan 11bS*)-Dihydrotetrabenazine, (-)-(2R*,3S*,11bR*)-Dihy din B0, Pneumocandin B0 2-phosphate, Pneumocandin D0, drotetrabenazine, (-)-2-(2-Bromohexadecanoyl)paclitaxel, Polyestradiol phosphate, Polyketomycin, Popolohuanone E. (-)-4',5'-Didemethoxypicropodophyllin, (-)-4'-Demethox Pradimicin A, Pradimicin B, Pradimicin D, Pradimicin E, ypicropodophyllin, (-)-9-Dehydrogalanthaminium bromide, Pradimicin FA-1, Pradimicin FA-2, Pradimicin FL, Pradimi (-)-Calicheamicinone, (-)-Cicloprolol, (-)-cis-Resorcylide, cin FS ((+)-enantiomer), Pradimicin L. Pradimicin Q. (-)-Indocarbazostatin B, (-)-Kendomycin, (-)-Kolavenol, Pradimicin S, Pradimicin T1, Pradimicin T2, Prinaberel, (-)-Salmeterol, (-)-Subersic acid, (+)-(2R*.3R*.11bS*)-Di Probucol, Procaterol Hydrochloride Hemihydrate, Propofol, hydrotetrabenazine, (+)-(2R*,3S*,11bR*)-Dihydrotetra Propyl gallate, Protocatechuic acid, Protocatechuicaldehyde, benazine, (+)-(S)-Hydroxychloroquine, (+)-23.24-Dihydro Pseudohypericin, Purpuromycin, Pyrindamycin A. Pyrinda discodermolide, (+)-Almuheptolide A, (+)-alpha-Viniferin, mycin B, Quercetin-3-O-methyl ether, Quinagolide hydro (+)-AZacalanolide A, (+)-Dihydrocalanolide A, (+)-Etor chloride, Quinobene, rac-Apogossypolone, Rac-Tolterodine, phine, (+)-IndocarbaZostatin, (+)-Isamoltan, (+)-SCH Raloxifene hydrochloride, Ramoplanin A1, Ramoplanin A2, 351448, (+)-Sotalol, (E)-p-Coumaroylquinic acid, (R)- Ramoplanin A3. Ramorelix, Ravidomycin N-oxide, Raw Almokalant, (R)-Dixyrazine dihydrochloride, (R)-Gossypol, sonol, Reblastatin, Reproterol hydrochloride, Resobene, (R)-Sulfinosine, (S)-(+)-Curcuphenol, (S)-Almokalant, (S)- Resorthiomycin, Retaspimycin hydrochloride, Rhodiocy Methylmaltrexone bromide, (S)-Oxiracetam, (S)-Sulfinosine, US 2016/00821 23 A1 Mar. 24, 2016

(Z)-Indenaprost, 8-Gingerol, Arg(Me)9 MS-10, D-Tyr1, Alemcinal, Alfacalcidol, Alisamycin, Aliskiren fumarate, Arg(Me)9 MS-10, D-Tyr1AzaGly7. Arg(Me)9 MS-10, Alkasar-18, Allixin, Almokalant, Alogliptin benzoate, alpha D-Tyr1 MS-10, N-MeIle4-cyclosporin, psiCH2NH C-Galactosylceramide, alpha-Galactosylceramide, alpha Tpg4Vancomycin aglycon, Trp19 MS-10, 111 In-Pentet Galactosylceramide-BODIPY, alpha-Lactosylceramide, reotide, 11-Hydroxyepothilone D, 11-Keto-Beta-Boswellic alpha-Mangostin, alpha-Methylepinephrine, alpha-Methyl Acid, 13-Deoxyadriamycin hydrochloride, 14alpha-Lipoyl norepinephrine, Alpha-Peltatin, alpha-Pyrone I, Alprafenone andrographolide, 14beta-Hydroxydocetaxel-1,14-acetonide, hydrochloride, Alprenolol hydrochloride, Alprostadil, 14beta-Hydroxytaxotere, 14-Demethylmycoticin A, 14-Hy Altemicidin, Altorhyrtin C. Altromycin A. Altromycin B, droxyclarithromycin, 14-Isobutanoylandrographolide, Altromycin C. Altromycin D. Altromycins, Alvespimycin 14-Methoxymetopon, 14-Phenylpropoxymetopon, 14-Piv hydrochloride, Alvimopanhydrate, Alvocidib hydrochloride, aloylandrographolide, 15-Methylepothilone B, 16-Methy Amamistatin A, Amamistatin B, Amarogentin, AmbroXol loxazolomycin, 17-Aminogeldanamycin, 17beta-Hydroxy nitrate, Amdoxovir, Amelometasone, Amelubant, Ami begron wortmannin, 18, 19-Dehydrobuprenorphine hydrochloride, hydrochloride, Amidox, Amikacin, Aminocandin, Amlex 18-Hydroxycoronaridine, 19-O-Demethylscytophycin C, anox, Ammocidin A, Amodiaquine, Amosulalol Hydrochlo 19-O-Methylgeldanamycin, 1 alpha,25-Dihydroxyvitamin ride. Amoxicillin trihydrate, Amphidinolide E, Amphidino D3-23.26-lactone, 1alpha-Hydroxyvitamin D4, 1-Oxorapa lide T1, Amphinidin A, Amphotericin B, Amprenavir, mycin, 2.12-Dimethyleurotinone, 21-Aminoepothilone B. Amrubicin Hydrochloride, Amurensin H, Amycolamicin, 22-Ene-25-oxavitamin D, 22-Oxacalcitriol, 24(S)-Ocotillol, Amycomycin, Anandamide, Andenallene, ANDREA-1, 24-Deoxyascomycin, 25-Anhydrocimigenol-3-O-beta-D- Androstanolone, Anguillosporal, Anguinomycin C, Angui Xylopyranoside, 26-Fluoroepothilone, 2-Aminoaristeromy nomycin D, Anidulafungin, Ankinomycin, Annamycin, cin, 2-Aminoneplanocin A. 2'-Hydroxymatteucinol, 2-Meth Annocherimolin, Annulin C, Antheliatin, Antide, Antide-1. oxyestradiol, 2-Methyleurotinone, 2'-Palmitoylpaclitaxel, Antide-2, Antide-3, Antiflammin-1, Antiflammin-3, Antimy 3,5-Dicaffeoylquinic acid, 3,7a-Diepialexine, 36-Dihy cin A11, Antimycin A12, Antimycin A13, Antimycin A14, droisorolliniastatin 1,3-Allyl farnesol, 3-Bromodiosmetine, Antimycin A15, Antimycin A16, Apadenoson, Apalcillin 3-Bromodiosmine, 3-Chlorodiosmetine, 3-Chlorodiosmine, Sodium, Apaziquone, Aphidicolin, Aphidicolin Glycinate, 3-Deazaadenosine, 3-Epimaxacalcitol, 4,6-diene-Cer, 4,7,8- Apicularen A, Apicularen B, Apigenin, Aplaviroc hydrochlo Trihydroxyisoflavone, 41-Demethylhomooligomycin B, ride, Apomine, Apomorphine hydrochloride, Apricitabine, 44-Homooligomycin B, 4-Aminosalicylic acid, 4-Chlo Aragusterol A, Aragusterol C, Aranorosin, Aranorosinol A, rophenylthio-DADMe-immucillin-A, 4-Demethyl Aranorosinol B, Aranose, Arbekacin, Arbekacin sulfate, epothilone B, 4-Demethylpenclomedine, 4'-Ethynylstavu Arbidol, Arborcandin A, Arborcandin B, Arborcandin C, dine, 4-Hydroxyatomoxetine, 4"-Hydroxymevastatin Arborcandin D, Arborcandin E, Arborcandin F, Arbutamine lactone, 4-Iodopropofol, 5(R)-Hydroxytriptolide, 5,4'-Diepi hydrochloride, Archazolid A, Archazolid B, Arformoterol arbekacin, 5,6-Dehydroascomycin, 5'-Epiequisetin, 5-Eth tartrate, Argiotoxin-636, Arimoclomol maleate, Arisostatin ylthioribose, 5-Iodofredericamycin A, 5-N-Acetyl-15balpha A, Arisugacin A, Arotinolol hydrochloride, Artepillin C, hydroxyardeemin, 5-Phenylthioacyclouridine, Artilide fumarate, Arundifungin, Arzoxifene hydrochloride, 5-Thiaepothilone, 5Z-7-OxoZeaenol, 6alpha-7-Epipacli Ascosteroside, Asiatic acid, Asiaticoside, Asimadoline, taxel, 6alpha-FluorourSodeoxycholic acid, 6-Carboxygen Asperlicin B, Asperlicin E, ASpoxicillin, Assamicin I, Assa istein, 6'-Homoneplanocin A, 6-Hydroxyscytophycin B, 6-O- micin II, Astromicin Sulfate, Atalaphillidine, Atalaphillinine, mPEG4-Nalbupine, 6-O-mPEG5-Nalbuphine, 7,7a Atazanavir Sulfate, Atenolol, Atigliflozin, Atorvastatin, Ator Diepialexine, 7-Chlorokynurenic acid, 7-Deoxytaxol. vastatin calcium, Atorvastatin-Aliskiren, Atosiban, Atova 7-Methylcapillarisin, 8(R)-Fluoroidarubicin hydrochloride, quone, Atraric acid, Atrinositol, Auristatin E, Aurothioglu 8'9"-Dehydroascochlorin, 8-Carboxy-iso-iantheran A, cose, Australifungin, Australine, Avicenol A, Avicequinone 8-Paradol, 8-Prenylapigenin, 8-Prenylmaringenin, 9,11-De A, Avicin D, Avicin G, AVorelin, Axitirome, AZacitidine, hydrocortexolone 17alpha-butyrate, 9.9-Dihydrotaxol. AZaresveratrol, AZaromycin SC, AZatoxin, AZelastine 9-18FFluoropropyl-(+)-dihydrotetrabenazine, 99mTc-c embonate, AZepinostatin, Azithromycin, Azithromycin Cop (RGDfK*)2HYNIC, 9-Aminocamptothecin, 9-Hydroxyc per Complex, Bactobolin, Bafilomycin A1, Bafilomycin C1, risamicin A, 9-Hydroxyrisperidone, A-42867 pseudoagly Baicalein, Baicalin, Balhimycin, Balofloxacin, Balofloxacin cone, Abacavir Succinate, Abacavir Sulfate, Abaperidone dihydrate, Balsalazide disodium, Bambuterol, Banox hydrochloride, Abarelix, Abietaquinone methide, Abirater antrone, Baogongteng A, Barixibat, Barusiban, BaZedox one, Acacetin, Acadesine, Acarbose, Acaterin, Acebutolol ifene acetate, Bazedoxifene hydrochloride, Becatecarin, hydrochloride, Acemannan, Aceneuramic acid sodium salt, Beciparcil. Beclometasone dipropionate, Becocalcidiol. Aciclovir, Aclarubicin, Acolbifene hydrochloride, Acotia Bedoradrine sulfate. Befloxatone. Befunolol hydrochloride, mide hydrochloride hydrate, Acrovestone, Actinoplanone A, Begacestat, Belactin B, Belotecan hydrochloride, Benadros Actinoplanone B. Aculeacin Agamma, Acyline, Adamanty1 tin, Benanomicin A, Benanomicin B. Benastatin A, Benasta globotriaosylceramide, Adaphostin, Adaprolol maleate, tin B, Benastatin C, Benastatin D. Benexate cyclodextrin, Adaprolol Oxalate, Adarotene, Adecypenol, Adelmidrol, Bengazole A, Bengazole B, Benzbromarone, Beraprost Ademetionine tosylate Sulfate, Adenophostin A, Adenophos sodium, Berefrine, Berupipam maleate, Bervastatin, Besi tin B, Adenosine, Adlupulon, AdXanthromycin A, Aerothri floxacin hydrochloride, Beta-Boswellic Acid, beta-Mangos cin 1, Aerothricin 41, Aerothricin 45, Aerothricin 5, Aerothri tin, Betamethasone butyrate propionate, Betamethasone cin 50, Aerothricin 55, Afeletecan hydrochloride, Agelasphin dipropionate, Beta-Sialosylcholesterol Sodium Salt, Betax 517. Agelasphin 564, Aglaiastatin A, Aglaiastatin B, Aju olol hydrochloride, Bevantolol hydrochloride, Biapenem, lemic acid, Albaconazole, Albifylline, Albitiazolium bro Biemnidin, Bimatoprost, Bimoclomol, Bimoclomol 1-oxide, mide, Albocycline K3, Alchemix, Alclometasone dipropi Bimosiamose, Binfloxacin, Binodenoson, Biochanin A, onate, Alcuronium chloride, Aldecalmycin, Aldifen, Bioxalomycin alpha 1, Bioxalomycin alpha2, Bipranol US 2016/00821 23 A1 Mar. 24, 2016 54 hydrochloride, Bisabosqual B, Bisabosqual D, Bismuth sub din, Cosalane, Cositecan, Costatolide, Coumamidine salicylate, Bisoprolol fumarate, Bisphenol, Bitolterol mesy Gammal, Coumamidine Gamma2, Crassicauline A, Crell late, Bix, Bizelesin, Bleomycin A2 sulfate, Bogorol A, Bohe astatin A, Crisamicin C, Crisinatol mesilate, Crobenetine, mine, Boholmycin, Bolinaquinone, Borrellidin, Bosentan, Crobenetine hydrochloride, Cromakalim, Crossoptine A, Brandisianin A, Brandisianin B, Brandisianin C, Brasilicar Crossoptine B, Curtisian A. Curtisian B. Curtisian D. Curvu din A, Brasilinolide A, Brasilinolide B, Brecanavir, Breflate, larol, Cyanidin Chloride Monohydrate, Cyclamenol, Cycla Brevifolin carboxylic acid, Breynin A, Breynin B. Brivanib, indelate, Cyclipostin A, Cyclocommunol, Cyclohexanediol. Brivudine, Bromotopsentin, Bryostatin 1, Bryostatin 10, Bry Cyclomarin A, Cyclooctatin, Cycloplatam, Cyclopro ostatin 11, Bryostatin 12, Bryostatin 13, Bryostatin9, Budes paradicicol, Cyclosporin A, Cyclosporin J. Cyclotheonamide onide, Buflomedil pyridoxalphosphate, Bungeolic acid, A, Cyclothialidine, Cygalovir, Cypemycin, Cyrtominetin, Buprenorphine hydrochloride, Buserelin acetate. Butalactin, Cystocin, Cystothiazole C, Cystothiazole D, Cystothiazole F. Butein, Buteranol, Butixocort, Butofilolol, Butorphan, Cytallene, Cytarabine, Cytaramycin, Cytoblastin, Cytocha Butorphanol tartrate, Byssochlamysol, Cabazitaxel, Cabin 1, lasin B, Cytochlor, Cytogenin, Cytosporic acid, Cytosporone Cadralazine, Cadrofloxacin hydrochloride, Caffeine citrate, B, Cytostatin, Cytotrienin I, Cytotrienin II, Cytotrienin III, Calanolide A, Calanolide B, Calbistrin A, Calbistrin B, Cal Cytotrienin IV, Cytoxazone, DACH-Pt(II)-bis-ascorbate, bistrin C, Calbistrin D. Calcipotriol, Calcitriol, Calcium-like Dacinostat, Dactimicin, Dactylfungin A, Dactylfungin B, peptide 1, Calebin A, Calocoumarin A, Caloporoside B, Dactylocycline A, Dactylocycline B, Dactylorhin B, Caloporoside C, Caloporoside D, Caloporoside E. Caloporo DADMe-Immucillin-G, DADMe-Immucillin-H, Dalargin, side F, Calphostin A, Calphostin B, Calphostin C, Calphostin Dalbavancin, Dalfopristin mesilate, Dalvastatin, Damu D. Calphostin I, Calteridol calcium, Cambrescidin 800, Cam nacantal, Danofloxacin, Dapagliflozin, Daphnodorin A, brescidin 816, Cambrescidin 830, Cambrescidin 844, Cam Daphnodorin B. Daphnodorin C ((-)-enantiomer), Daprop iglibose, Campestanol ascorbyl phosphate, Canadensol, terin dihydrochloride, Darbufelone, Darbufelone mesilate, Canagliflozin, Candelalide B, Candelalide C, Cangrelor tet Darunavir, Dasantafil, Dasatinib, Daunorubicin, Dau rasodium, Canventol, Capadenoson, Capecitabine, Capillari richromenic acid, Davidigenin, Davunetide, Deacetyl moxi sin, CapraZamycin A, CapraZamycin B, CapraZamycin C, Sylyte hydrochloride, Decahydromoenomycin A, Decapla CapraZamycin E. CapraZamycin F. Capridine beta, Cap nin, Decarestrictine C, Decarestrictine D, Decatromicin A, Sazepine, Carabersat, Carbazomadurin A, Carbazomadurin Decatromicin B. Decitabine, Decursinol, Decyl gallate, B, Carbetocin, Carbidopa, Carbovir, Caribaeoside, Caris Deferasirox, Deferiprone, Deflazacort, Deforolimus, bamate, Carmoterol hydrochloride, Carpesterol, Carqui Degarelix acetate, Dehydelone, Dehydrodolastatin-13, nostatin A, Carsatirin, Carteolol hydrochloride, Carteramine Dehydrozingerone, Delafloxacin, Delaminomycin A, A, Carvastatin, Carvedilol, Caspofungin acetate, Cassigalol Delaminomycin B. Delaminomycin C, Delimotecan Sodium, A, Castanospermine, CefbuperaZone sodium, Cefcanel, Delphinidin, delta-Tocopherol glucoside, Deltibant, Deme Cefetecol, Cefonicid sodium, Cefoperazone sodium, Cefos thimmunomycin, Demethomycin, Demethylallosamidin, elis sulfate, Ce?piramide sodium, Cefprozil, Cefprozil mono Demethylasterriquinone B-1, Denopamine, Denufosol tetra hydrate, Celgosivir, Celikalim, Celiprolol hydrochloride, Sodium, Deoxyenterocin, Deoxylaidlomycin, Deoxymulun Cephalostatin 1, Cephalostatin 2, Cephalostatin 3, Cepha docandin, Deoxynoirimycin, Deoxyspergualin Hydrochlo lostatin 4, Cephalostatin 7, Cephalostatin 8, Cephalostatin 9. ride, Deprodone propionate, Dersalazine, Ceramidastin, Cerebroside A, Cerebroside B, Cerebroside C, Desacetyleleutherobin, Desacetylravidomycin N-oxide, Cerebroside D, Cerivastatin sodium, Ceruletide diethy Desacetylvinblastinehydrazide, Desacetylvinblastinehy lamine, Cetefloxacin, Cethromycin, Cetrorelix Acetate, drazide/folate conjugate, Desbutylbenflumetol, Desbutylha Chackol, Chaetoatrosin A, Chafuroside, Chenodeoxycholic lofantrine hydrochloride, Desferri-danoxamine, Desferri acid, Chetocin, Chinoin-169, Chloptosin, Chlorazicomycin, nordanoxamine, Desferri-salmycin A, Desferri-salmycin B, Chlorofusin, Chlorogentisylquinone, Chloroorienticin A, Desferri-salmycin C, Desferri-salmycin D. Desglugastrin Chloroorienticin B, Cholerae Autoinducer-1, Choline alfos tromethamine, Desisobutyrylciclesonide, Deslorelin, Desm cerate, Chondramide A, Chondramide B, Chondramide C, ethyleleutherobin, Desmin-370, Desmopressin acetate, Des Ciclesonide, Cicletanine, Cidofovir, Cimaterol, oxyepothilone B. Desoxyepothilone F. Desoxylaulimalide, Cimetropium bromide, Cinatrin A, Cinatrin B, Cinatrin C1, DeSVenlafaxine Succinate, Dexamethasone, Dexamethasone Cinatrin C2, Cinnabaramide A, Cinnatriacetin A, Cinnatri beloxil, Dexamethasone cipecilate, Dexamethasone Palmi acetin B, Cinolazepam, Ciprofloxacin hydrochloride, tate, Dexamethasone sodium phosphate, Dexanabinol, Dex Ciprokiren, cis-6-Shogaol, Citicoline, Citpressine I, Cit elvucitabine, Dextrorphan, Dexylosylbenanomycin A, reamicin-Alpha, Citreamicin-eta, Citropeptin, Citrullimy D-Fluviabactin, DHA-paclitaxel, Diadenosine tetraphos cine A, Citrusinine-I, Cladribine, Clarithromycin, Clause phate, Diazaphilonic acid, Diazepinomicin, Dicoumarol, namine A, Clavaric acid, Clavarinone, Clavulanate Dictyostatin 1, Didemnin X, Didemnin Y. Dideoxyinosine, potassium, ClaZosentan, Clevudine, Clindamycin hydrochlo Dieckol, Diepoxin-sigma, Diflomotecan, Diflunisal, Diga ride, Clitocine, Clobenoside, Clofarabine, Clopithepin, Clo lactosyldiacylglycerol, Digoxin, Diheteropeptin, Dihydrexi ranolol hydrochloride, Cocositol, Colabomycin A, Cole dine, Dihydroavenanthramide D, Dihydrocostatolide, Dihy neuramide, Coleophomone B, Colestimide, Colforsin, droeponemycin, Dihydrogranaticin B. Dihydroheptaprenol, Colforsindaproate hydrochloride, Colletoic acid, Colupulon, Dihydrohonokiol B, Dihydroisosteviol, Dihydroraloxifene, Combretastatin A-1, Combretastatin A-2, Combretastatin Dilevalol, Dilevalol hydrochloride, Dilmapimod, A-3, Combretastatin B-1, Combretastatin B-2, Combretasta Dimelamol, Dimethandrolone, Dimethylcurcumin, tin B-3, Combretastatin B-4, Combretastatin D-1, Combret di-mPEG5-Atazanavir, Dinaphine, Dinapsoline, Dinoxyline, astatin D-2, Complestatin, Conagenin, Coniferol Alcohol, Dioncoquinone A, Dioncoquinone B, Dioxolane thymine Coniosetin, Conocurvone, Conophylline, Contignasterol, nucleoside, Dipivefrine hydrochloride, Dipotassium gossy Contulakin G, Cortexolone 17alpha-propionate, Corynecan polate, Dipyridamole, Dipyridamole beta-cyclodextrin com US 2016/00821 23 A1 Mar. 24, 2016

plex, Dicquafosol tetrasodium, Dirithromycin, Discodermide, ide, Fluoroindolocarbazole A, Fluoroindolocarbazole B, Flu Discodermide acetate, Disermolide, Disodium cromproxate, oroindolocarbazole C, Fluoroneplanocin A. Fluostatin A, Disodium lettusate, Disorazol E1, Dobutamine hydrochlo Fluostatin B, Flupentixol hydrochloride, Fluphenazine ride, Dobutamine Phosphate, Docetaxel, Docosanol, Docosyl hydrochloride, Flurithromycin, Fluticasone furoate, Flutica cidofovir, Dofequidar fumarate, Dolastatin 13, Dopexamine, sone propionate, Fluvastatin sodium, Fluvirucin B2, Foeti Dopexamine hydrochloride, Doqualast, Doramectin, dine 1, Foetidine 2, Folinic acid, Folipastatin, Fondaparinux Doranidazole, Doretinel, Doripenem, DorrigocinA, Dorrigo Sodium, Formamicin, Formestane, Formobactin, Formosyn cin B, Dosmalfate, Dovitinib Lactate, Doxefazepam, Doxer A, Formoterol fumarate, Forodesine hydrochloride, Foso calciferol, Doxifluridine, Doxorubicin Hydrochloride, Doxo pamine, Fosteabine Sodium hydrate, Frederine, Fucoxanthin, rubicin, Morpholinyl, DoxoTam 12, Doxycycline hyclate, Fudosteine, Fuladectin component A3, Fuladectin compo Dridocainide, Dronabinol, Droxidopa, Droximavir, DTPA nent A4, Fulvestrant, Fumagalone, Furaquinocin A, adenosylcobalamin, Duocarmycin B1, Duocarmycin B2, Furaquinocin B, Fusacandin A, Fusacandin B, Fuscoside B, Duocarmycin C1, Duocarmycin C2, Duramycin, Dutomycin, Fusidate silver, Fusidienol, Gaboxadol, Gabusectin, Gabu Dynemicin A, Dynemicin C. Ecdysterone, Ecenofloxacin sectin methyl ester, Gadobutrol, Gadocoletic acid trisodium hydrochloride, Ecomustine, Econazole Sulfosalicylate, salt, Gadomelitol, Gadoterate meglumine, Gadoteridol. Ecopipam, Ecraprost, Ecteinascidin 1560, Ecteinascidin 722, Galactomycin I, Galactomycin II, Galactosyllactose, Gala Ecteinascidin 729, Ecteinascidin 736, Ecteinascidin 745, Ect mustine hydrochloride, Galantamine hydrobromide, Galaru einascidin 757, Ecteinascidin 770, Ecteinascidin 875, Edot bicin hydrochloride, Galocitabine, Gambogic acid, gamma ecarin, Edotreotide yttrium, Efepristin, Eflucimibe, Eflumast, Mangostin, gamma-Tocotrienol, Ganciclovir, Ganciclovir Eicosylcidofovir, Elacytarabine, Elansolid C1, Eldacimibe, elaidic acid, Ganciclovir monophosphate, Ganciclovir Eldecalcitol, Eleutherobin, Eleutheroside B, Eliprodil, Sodium, Ganefromycin Alpha, Ganefromycin Beta, Ganglio Elisapterosin B, Ellagic acid-4-gallate, Elliptinium acetate, side GM1, Ganirelix, Ganirelix acetate, Ganoderic acid X, Elocalcitol, Elomotecan hydrochloride, Elsibucol, Garenoxacin mesilate, Garomefrine hydrochloride, Garval Eltanolone, Eltrombopag olamine, Elvitegravir, Elvucitab one C, Garveatin E, Garveatin F. Gatifloxacin, Gemcitabine, ine, Emakalim, Embelin, Emestrin C, Emodin, Emtricitab Gemcitabine elaidate, Gemeprost, Gemifloxacin mesilate, ine, Enalkiren, EnaZadrem, Enfumafungin, Englerin A, Enig Genipin, Genistein-7-phosphate, Gigantol, Gilatide, Gilvus mol, Enkastin (D), Enkastin AD, Enkastin AE, Enkastin ID, mycin, Gimestat, Girodazole, Glaucocalyxin A, Gle Enkastin IE, Enkastin VD, Enkastin VE, Enocitabine, manserin, Glenvastatin, Glidobactin PF-1, Glucarolactam Enofelast, Enoloxone, Enoxacin, Enprostil, Enrasentan, potassium, Glucolanomycin, Glucolipsin A, Glucolipsin B, Enrofloxacin, Entacapone, Entecavir, ent-Estriol, Eperezolid, Glucopiericidinol A1, Glucopiericidinol A2, Glucosamine Eperezolid N-oxide, Epervudine, Epicochlioquinone A, Epi sulfate, Gludopa, Glufosfamide, Glycopin, Glycothiohexide doxoform, Epigallocatechin-3-gallate, Epirubicin hydro alpha, Glycyrrhizinic acid, Gomphostenin, Goodyeroside A, chloride, Epispongiadiol, Eplivanserin, Eplivanserin fuma Goodyeroside B, Goralatide, Goserelin, Granaticin B. Gre rate, Eplivanserin mesilate, Epocarbazolin A, Epocarbazolin pafloxacin hydrochloride, Griseusin C, Halistatin 1, Halista B, Epofolate, Eponemycin, Epoprostenol Sodium, tin 2, Halistatin 3, Halobetasol propionate, Halofantrine Epothilone A, Epothilone AN-oxide, Epothilone BN-oxide, hydrochloride, Halofuginone hydrobromide, Halometasone, Epothilone E. Epoxomicin, Epoxy vibsanin B, Eprotirome, Halopredone Acetate, Halovir A. Halovir B. Halovir C. Eptaloprost, Eptastatin Sodium, Eptastigmine Tartrate, Epta Halovir D. Halovir E. Halxazone, Haperforine B1, Zocine hydrobromide, Erabulenol A, Erabulenol B, Erec Hatomamicin, Hatomarubigin A, Hatomarubigin B, tumin A, Eremomycin, Eremophylene A, Eribulin mesilate, Hatomarubigin C, Hatomarubigin D. Hattalin, Hayumicin A, Eriocalyxin B, Eritoran tetrasodium, Ersentilide, Ersentilide Hayumicin B, Hayumicin C1, Hayumicin C2, Hayumicin D, hydrochloride, Ertapenem sodium, Eryloside A, Eryloside F. Hederacolchiside E. Heliquinomycin, Helvecardin A, Helve Erythritol, Erythrodiol, Erythromycin, Erythromycin Acis cardin B, Heptaminol AMP Amidate, Hericenal A. Hericenal trate, Erythromycin Salnacedin, Erythromycin stinoprate, B, Hericenal C, Hexadecyl cidofovir, Hexadecyloxypropyl Esafloxacin Hydrochloride, Esculeogenin A, Esculeoside A, cidofovir, Hexafluorocalcitriol, Hidrosmin, Himastatin, His Esmolol hydrochloride, Espatropate hydrate, Esperatrucin, trelin, Histrelin acetate, Hongoquercin A, Hongoquercin B, Estetrol, Estradiol, Estradiol acetate, Estren, Estriol, Etalocib Honokiol diepoxide, Human angiotensin II, Hyaluronate sodium, Etamsylate, Ethanolamine, Ethinylestradiol, Ethyl Sodium, Hydrocortisone Aceponate, Hydromorphone gallate, Ethylthio-DADMe-immucillin-A, Ethynylcytidine, methiodide, Hydrostatin A. Hydroxyakalone, Hydroxychlo Etiprednol diclo acetate, Etoposide, Etoposide phosphate roquine Sulfate, Hydroxymycotrienin A, Hydroxymycotrie disodium salt, Eugenodilol, Eugenosedin A, Euphodendroi nin B, Hydroxyphoslactomycin B, Hydroxyzine hydrochlo din D, Eurotinone, Euxanthone, Evernimicin, Everolimus, ride, Hymenistatin 1, Hypeptin, Hypericin, Hyperoside, Exatecan mesilate, Exifone, EZetimibe, EZetimibe glucu Hypocholamide, Hypocholaride, Ibutilide fumarate, Icariin, ronide, Fadolmidine hydrochloride, Faerieflungin A, Faerief Icatibant acetate, Idarubicin hydrochloride, Idebenone, ungin B. Fandofloxacin hydrochloride, Faropenem medox Idremcinal, Idronoxil, Ifenprodil, Ilatreotide, Iliparcil, omil, Faropenem sodium, Fasobegron hydrochloride, Ilonidap, Iloprost, Imidazoacridinone, Imipenem, Immun Fattiviracin A1, Favipiravir, Febradinol, Febuprol, Feglymy osine, Implitapide, Incyclinide, Indacaterol, Indianaprost (S), cin, Fenoldopam mesilate, Fenoterol hydrobromide, Ferpifo Indanocine, Indinavir Sulfate, Indomethacin-Simvastatin, sate sodium, Ferulinolol, Fesoterodine fumarate, Fexofena Indynaprost, Ingenolmebutate, Inophyllum B, Inophyllum P. dine hydrochloride, Fidaxomicin, Fidexaban, Filibu vir, Inosiplex, Integracide A, Integracide B, IntegracinA, Integra Fimbrigal P. Finafloxacin hydrochloride, Fingolimod hydro cin B, Integracin C, Integramycin, Integrastatin A, Integrasta chloride, Finrozole, Fleroxacin, Flomoxef Sodium, Flopris tin B, Intoplicine, Iobitridol, Iodixanol, Iodochlorhydrox tin, Floxuridine, Fludarabine phosphate, Fludelone, ycuin, Iododiflunisal, Iodorubidazone (p). Iofratol, Iohexol. Fludeoxyglucose (18F), Flunisolide, Flunoprost, Fluocinon Iolopride (123I), Iomeprol, Iopamidol, Iopentol, Iopromide, US 2016/00821 23 A1 Mar. 24, 2016 56

Iotriside, Iotrol, Ioversol, Ioxilan, Ioxipride, Ipratropium bro alicin B. Megovalicin C, Megovalicin D. Megovalicin G, mide, Iralukast, Iralukast Sodium, Irciniastatin A, Irciniasta Megovalicin H, Melevodopa hydrochloride, Mellein, tin B, Irinotecan hydrochloride, Irofulven, Isalmadol, Isepa Meloxicam, Meluadrine, Meluadrine tartrate, Memno-pep micin Sulfate, Isobavachalcone, Isodoxorubicin, tide A, Mepindolol sulfate, Mepindolol transdermal patch, Isoeleutherobin A, Isofagomine tartrate, Isofloxythepin, Iso Meptazinol hydrochloride, Meropenem, Mesalazine, Met homohalichondrin B, Iso-iantheran A, Isoliquiritigenin, Iso araminol, Metesind glucuronate, Methanobactin, Meth molpan Hydrochloride, Isoquine, Isosorbide 5-mononitrate, oxatone, Methscopolamine bromide, Methyl bestatin, Isospongiadiol, Isovanihuperzine A, Isoxazoledehydelone, Methyl gallate, Methyldopa, Methylmaltrexone bromide, Isoxazolefludelone, Itavastatin calcium, Itrocinonide, Ixa Methylpredniso lone, Methylprednisolone aceponate, Meth bepilone, Jadomycin B, Janthinomycin A, Janthinomycin B, ylpredniso lone suleptanate, Methylthio-DADMe-immucil Janthinomycin C, Jasplakinolide, Jorumycin, Kadsuphilin C, lin-A, Methysergide maleate, Metildigoxin, Metipranolol, Kahalalide F, Kaitocephalin, Kampanol A, Kampanol B, Metirosine, Metoprolol Fumarate, Metoprolol succinate, Kanamycin, Kanglemycin A, Kansuinin B, kappa-Conotoxin Metoprolol tartrate, Metrifonate, Metronidazole, Micacoci PVIIA, Kapurimycin A1, Kapurimycin A3, Karalicin, Kar din A, Micacocidin B, Micafungin sodium, Michellamine B. namicin B1, Katanosin A, Katanosin B. Kehokorin D, MichigaZone, Microbisporicin A2, Microcolin A, Microno Kehokorin E. Khafrefungin, Kifunensine, Kigamicin A, micin Sulfate, Midecamycin acetate, Mideplanin, Miglitol, Kigamicin B. Kigamicin C, Kigamicin D. Kigamicin E, Miglustat, Milataxel, Milbemycin alpha-9, Milrinone Lac Kigamicinone, Kijimicin, Kinsenoside, Kistamicin A, tate, Mimopezil, Minerval, Minocycline hydrochloride, Klainetin A, Klainetin B, Kobifuranone B, Kobin, Kodaista Miporamicin, Mipragoside, Miproxifene, Mirabegron, tin A, Kodaistatin B, Kodaistatin C, Kodaistatin D. Korupen Mirodenafil hydrochloride, Misakinolide, Misoprostol, samine A, Korupensamine B, Korupensamine C. Korupen Mitemcinal fumarate, Mitoxantrone hydrochloride, Mivaz samine D. Kosinostatin, Kuehneromycin A, Kurasoin B, erol, Mizoribine, Modecainide, Modithromycin, Moenomy Kynostatin-227, Kynostatin-272, Labedipinedilol A, Labe cin A chloride bismuth salt, Mollugin, Mometasone furoate, dipinedilol B, Labetalol hydrochloride, Labradimil, Laccar Momordin Ic, Monamidocin, Monlicin A, Monogalactosyl idione A, Lactonamycin, Lactosylphenyl trolox, Ladirubicin, diacylglycerol, Monohydroxyethylrutoside, Monophospho Lagatide, Laherradurin, Lamellarin alpha 20-sulfate sodium ryl lipid A. Montelukast sodium, Morphine Glucuronide, salt, Lamifiban, Lamivudine, Landiolol, Lanreotide acetate, Morphine hydrochloride, Morphine sulfate, Motexafin gado Lanthiopeptin, Larotaxel dihydrate, Lasinavir, Lasofoxifene, linium, Motexafin lutetium, Moxidectin, Moxifetin hydrogen Lasofoxifene tartrate, Lasonolide A, Latamoxef sodium, maleate, Moxifloxacin hydrochloride, Mozenavir mesilate, Latanoprost, Latrunculin S. Lavanduquinocin, L-Chicoric Multiforisin A, Mumbaistatin, Mupirocin, Muraminomicin acid, L-Dopamide, Lecirelin, LedaZerol, Leinamycin, A, Muraminomicin B, Muraminomicin C, Muraminomicin Lemuteporphin, Lenapenem hydrochloride, Lenapenem D, Muraminomicin E1, Muraminomicin E2, Muraminomicin hydrochloride hydrate, Leptofuranin A, Leptofuranin B. Ler F. Muraminomicin G, Muraminomicin H, Muraminomicin I, sivirine, Lestaurtinib, Leuprolide acetate, Leurubicin, Leus Muraminomicin Z1, Muraminomicin Z2, Muraminomicin troducsin A, LeuStroducsin B. Leustroducsin C. Leustroduc Z3, Muraminomicin Z4, Muramyl dipeptide C. Mureidomy sin H. Levalbuterol hydrochloride, Levobetaxolol cinA, Mureidomycin B. Mureidomycin C, Mureidomycin D, hydrochloride, Levobunolol hydrochloride, Levodopa, Mureidomycin E, Mureidomycin F. Mureidomycins, Myca Levodopa 3-O-glucoside, Levodopa 4-O-glucoside, Levo lamide A, Mycestericin E. Mycolactone A, Mycolactone B. dropropizine, Levofloxacin, Levonadifloxacin arginine salt, Mycophenolate Mofetil, Mycophenolic acid sodium salt, Levonebivolol, Levorphanol tartrate, Lexacalcitol, L-Fluvia Myrciacitrin I, Myrciacitrin II, Myrciaphenone B. Myriceric bactin, L-Histidinol, Liblomycin, Licorice-Saponin C2, acid A. Mytolbilin, Mytolbilin acid, Mytolbilin acid methyl Lificiguat, Limaprost alfadex, Linaprazan, Linopristin, Lipi ester, Mytolbillinol, N4-Hexadecyl-dC-AZT, N-9-Oxadecyl armycin B3, Lipiarmycin B4, Liquiritin apioside, Lisofyl 6-methyl-DGJ, Naamidine A, Nabilone, N-Acetylcolchinol, line, Lithospermic acid B magnesium salt, Lobatamide C. N-Acetylsperamycin A1, N-Acetylsperamycin A1B, N-Ace Lobatamide F, Lobophorin A, Lobophorin B, Lobucavir, tylsperamycin A2, Nadifloxacin, Nadolol, Nafarelin acetate, Lodenafil. Lodenosine, Loloatin B, Lomefloxacinhydrochlo Naftopidil, Nafuredin, Nafuredin-gamma, Nagstatin, Nalbu ride, Lometrexol, Longestin, Lopinavir, Lorazepam, phine hydrochloride, Nalfurafine hydrochloride, N-Al Lorimetazepam, Lornoxicam, Losartan, Losartan potassium, lylsecoboldine, Nalmefene, Naloxone hydrochloride, Naltr Losigamone, Loteprednoletabonate, Lovastatin, Loxoribine, exone hydrochloride, Naltrindole, Namitecan, Napsamycin L-threitol ceramide, L-threo-C6-pyridinium-ceramide-bro A, Napsamycin B, Napsamycin C, Napsamycin D. Narde mide, Lubeluzole, Lumefantrine, Luminacin D. Lupulone, terol, Naroparcil, Navuridine, N-Cyclopentyl-tazopsine, Lurtotecan, Luteolin, Lu-Tex bis(gluconate), Lysobactin, Nebicapone, Nebivolol, Nectrisine, Neldazosin, Nelfinavir Mabuterol hydrochloride, Macquarimycin B. Macrocarpin mesilate, Nelivaptan, Nelzarabine, Nemifitide ditriflutate, A. Macrocarpin B. Macrolactine M, Madecassic acid, Made Nemonoxacin, Nemorubicin, Neocimicigenoside A, Neo cassoside, Makaluvamine D, Makaluvamine E. Malonoben, cimicigenoside B, Neolaulimalide, Neomycin B-arginine Maltolyl p-coumarate, Manitimus, Mannopeptimycin alpha, conjugate, Neomycin-acridine, Nepadutant, Neparensinol A, Mannopeptimycin beta, Mannopeptimycin delta, Mannopep Neparensinol B, Neparensinol C, Nerfilin I, Neristatin 1, timycin epsilon, Mannopeptimycin gamma, Manoalide, Nesbuvir, Netilmicin sulfate, Netivudine, Neu5Ac2en, Manumycin A, Manumycin B. Manumycin C. Manumycin E, Ngercheumicin A, Ngercheumicin B, N-hexacosanol, Nica Manumycin F. Manumycin G. Manzamine F, Marbofloxacin, nartine, Nifekalant hydrochloride, Nileprost beta-cyclodex Maribavir, Marimastat, Marinopyrrole A, Marmelin, trin clathrate, Nipradolol, Nitecapone, Nitropravastatin, Maslinic acid, Masoprocol, Mastprom, Matteuorienate A, N-Nonyl-deoxygalactojirimycin, Nocardione A, No.cathiacin Matteuorienate B, Matteuorienate C, Mazokalim, Medi I, No.cathiacin II, Nocathiacin III, No.cathiacin IV, N-Octyl carpin, Mefloquine hydrochloride, Megovalicin A, Megov beta-valienamine, NO-hydrocortisone, Noladin ether, NO US 2016/00821 23 A1 Mar. 24, 2016 57

Mesalamine, Nooglutil, Noraristeromycin, Nordamunacan phate, Polyketomycin, Polymer bound human leukocyte tal, Norfloxacin, Norfloxacin succinil, Nortopixantrone elastase inhibitor, Ponalrestat, Popolohuanone E. Posacona hydrochloride, Nostocyclopeptide M1, Nothramicin, Zole, PosiZolid, Potassium embelate, Pradimicin A, Pradimi NO-Ursodeoxycholic acid, N-Retinoyl-D-glucosamine, cin B, Pradimicin D, Pradimicin E, Pradimicin FA-1, N-tert butyl isoquine, Nubiotic 2, Nutlin-2, Obelmycin H, Pradimicin FA-2, Pradimicin FL, Pradimicin FS ((+)-enanti Oberadillol, Oberadilol Monoethyl Maleate, Obeticholic acid, omer), Pradimicin L. Pradimicin Q, Pradimicin S. Pradimicin Ochromycinone, Ocimumoside A, Ocimumoside B, Octa T1, Pradimicin T2, Pradofloxacin, Prasterone, Prednicarbate, cosamicin A, Octacosamicin B, Octreotide Acetate, Octyl Prednisolone, Prednisolone acetate, Prednisolone farnesy gallate, Odapipam acetate, O-Demethylchlorothricin, late, Prednisone, Prefolic A, Premafloxacin, Premafloxacin O-Demethylmurrayafoline A, Odiparcil, Oenothein B, hydrochloride, Preussin, Prinaberel, Prisotinol, Pristinamy Ofloxacin, Okicenone, Olamufloxacin, Olamufloxacin mesi cin IA, Pristinamycin HA, Proamipide, Probestin, Probucol, late, Olanzapine pamoate, Olcegepant, Oleanolic acid, Ole Procaterol Hydrochloride Hemihydrate, Prolylmeridamycin, oyl-L-Valinol amide, Olsalazine sodium, Omaciclovir, Propafenone hydrochloride, Propeptin T. Propofol, Propra Ombrabulin, Ombrabulin hydrochloride. Onjixanthone I, nolol hydrochloride, Propyl gallate, Prostanit, Prostatin, Onjixanthone II, Onnamide A, Oolonghomobisflavan A, Prostratin, Protocatechuic acid, Protocatechuic aldehyde, Oolonghomobisflavan C, OPC-17083, Opiorphin, Proxodolol, Prulifloxacin, Prulifloxacin Hydrochloride, Pru Opipramol hydrochloride, Orbifloxacin, Orciprenaline sul lifloxacin Mesylate, Pseudoephedrine hydrochloride, phate, Orienticin A, Orienticin B, Orienticin C, Orienticin D, Pseudohypericin, Pseudomycin A", Pseudomycin B", Pur Oritavancin, Orniplabin, Ornoprostil, Ortataxel, Orthosomy puromycin, Purvalanol A. Pycnanthuquinone A. Pycnanthu cin A, Orthosomycin B, Orthosomycin C, Orthosomycin D, quinone B, Pyloricidin B, Pyridavone, Pyrindamycin A, Orthosomycin E, Orthosomycin F. Orthosomycin G, Ortho Pyrindamycin B, Pyripyropene A, Pyripyropene B, Pyripy somycin H, Ospemifene, Osutidine, Oxaspirol A, Oxaspirol ropene C, Pyripyropene D. Pyrrolosporin A, Quartromicin B, Oxazepam, Oxazofurin, Oxeclosporin, Oximidine III, A1, Quartromicin A2, Quartromicin A3. Quartromicin D1, Oxiracetam, Oxitropium bromide, Oxolide, Oxprenolol Quartromicin D2, Quartromicin D3, Quercetin-3-O-methyl hydrochloride, Oxymetazoline hydrochloride, Oxymethacyl, ether, Quetiapine fumarate, Quinagolide hydrochloride, Qui Oxymorphazole dihydrochloride, Oxymorphone hydrochlo nidine, Quinobene, Quinoxapeptin C. Quinupristin Mesilate, ride, Oxynor, Oxyphenarsine, Ozarelix, Ozenoxacin, Pachas rac-Apogossypolone, Rac-Tolterodine, Rafabegron, Ralox trissamine, Pachymedusa dacnicolor Tryptophyllin-1, Paci ifene hydrochloride, Raltitrexed, Raluridine, Rameswaralide, forgine, Paclitaxel, Paclitaxel ceribate, Paecilaminol, Ramoplanin A1, Ramoplanin A2, Ramoplanin A3. Ramo Paeciloquinine A, Paeciloquinine D. Paeciloquinone B. relix, Ranimustine, Ranolazine, Rapamycin, Ravidomycin Paeciloquinone D, Pafenolol, Palau'amine, Paldimycin B, N-oxide, Rawsonol, Razupenem, Rebamipide bismuth cit Palinavir, Palmidrol, Pamapimod, Pamaqueside, Pancratista rate tetramethyledamine, Reblastatin, Regadenoson, tin disodium phosphate, Pancratistatin-3,4-cyclic phosphate Remikiren mesilate, Remiprostol, Remogliflozin etabonate, Sodium salt, Panipenem, Pannorin, Pantethine, Papuamide A, Repandiol, Reproterol hydrochloride, Resobene, Resorthio Papuamide B, Papuamide C, Papuamide D, Paquinimod, mycin, Retapamulin, Retaspimycin hydrochloride, Revatro Paracetamol, Parasin I, Paricalcitol, Parodilol Hemifumarate, pate, Reveromycin A. Rhodiocyanoside A, Rhodiocyanoside Paromomycin, Parvisporin B, Patellazole A, Patellazole B. B. Rhododaurichromanic acid A. Rhodostreptomycin A, Patellazole C, Patupilone, Paulomycin, Paulomycin A2, Pau Rhodostreptomycin B. Ribavirin, Ribavirin eicosenate cis, lomycin B, Paulomycin C, Paulomycin D. Paulomycin E, Ribavirin eicosenate trans, Ribavirin elaidate, Ribavirinole Paulomycin F. PaZufloxacin, PaZufloxacin mesilate, Pefloxa ate, Rifabutin, Rifalazil, Rifamexil, Rifampicin, Rifapentine, cin, PEG40000-Paclitaxel, PEG5000-Paclitaxel, PEG-conju Rifaximin, Rilmakalim hemihydrate, Rimexo lone, Rimot gated camptothecin, PEG-Vancomycin, Pelitrexol, Peloru erol hydrobromide, Riodoxol, Ritipenem acoxil, Ritonavir, side A, Penasterol, Penbutolol sulfate, Penciclovir, Rivastigmine tartrate, Rivenprost, Rocagloic acid, Rocuro Penicillide, Pentazocine hydrochloride, Pentostatin, Peplo nium bromide, Rofleponide, Rofleponide palmitate, Rohituk mycin, Pepticinnamin E. Peramivir, Percyduinnin, Periciaz ine, Rokitamycin, Rolliniastatin 1, Romurtide, Roquinimex, ine, Perillyl alcohol, Perphenazine, Persin, Petrosaspongi Rosaprostol sodium, Roscovitine, Roselipin 1A, Roselipin olide M. PG-camptothecin, Phaffiaol, Phakellistatin 7. 1B, Roselipin2A, Roselipin2B, Rostafuroxine, Rosuvastatin Phakellistatin 8, Phakellistatin9, Phaseolinone, Phenochala calcium, Rosuvastatin Sodium, Rotigaptide, Rotigotine, sin A, Phenprocoumon, Phentolamine mesilate, Philinopside Roxatidine bismuth citrate, Roxindole Mesilate, Roxithro A, Phlorofucofuroeckol, Phomactin A, Phomactin B, Pho mycin, Rubiginone A1, Rubiginone A2, Rubiginone B1, moidride A, Phomopsichalasin, Phorboxazole A, Phorbox Rubiginone C1, Rubitecan, Ruboxyl, Rufigallol, Rufloxacin azole B. Phospholine, Phthalascidin, Physostigmine salicy Gluconate, Rufloxacin hydrochloride, Rumycin 1, Rumycin late, Piceatannol, Picumeterol fumarate, Pidobenzone, 2, Russuphelin A, Sabarubicin hydrochloride, Safingol, Sain Pimecrolimus, Pimilprost, Pindolol, Pinitol, Pinocembrin, topin, Saintopin E, Saishin N. Sakyomicin A, Sakyomicin E, Pipendoxifene, Pipotiazine, Pirarubicin, Pirbuterol hydro Salazopyridazin, Salbostatin, Salbutamol nitrate, Salbutamol chloride, Pirfenoxone, Pirodomast, Pironetin, Piroxicam, Sulfate, Salcaprozic acid sodium salt, Salicylazobenzoic acid, Pittsburgh Compound B, Pladienolide A, Pladienolide B, Pla Salicylihalamide A, Salicylihalamide B, Salinamide A, Sali dienolide C, Pladienolide D, Pladienolide E. Plantagoside, nosporamide A, Saliphenylhalamide, Salmaterol, Salmeterol Platencin, Platensimycin, Plaunotol, Plevitrexed, Plitidepsin, Xinafoate, Saloxin, Salvianolic acid L. Samaderine X, Sam Pluraflavin A, Pluraflavin B, Pluraflavin E, Plusbacin A1, patrilat, Sanfetrinem, Sanfetrinem cilexetil, Sanfetrinem Plusbacin A2, Plusbacin A3, Plusbacin A4, Plusbacin B1, sodium, Sanglifehrin A, Sanglifehrin B, Sanglifehrin C, San Plusbacin B2, Plusbacin B3, Plusbacin B4, Pneumocandin glifehrin D. Sapacitabine, Saptomycin D. Sapurimycin, A0, Pneumocandin B0, Pneumocandin B0 2-phosphate, Saquinavir, Saquinavir mesilate, Sarcophytol A, Sarcophytol Pneumocandin D0, Podophyllotoxin, Polyestradiol phos B, Saricandin, Saussureamine D. Saussureamine E. SaZeti US 2016/00821 23 A1 Mar. 24, 2016

dine-A, Scopinast fumarate, Scopolamine, Scyphostatin, Thiazohalostatin, Thielavin G, Thielocin B3, Thiofedrine, Secalciferol, Secobatzelline A, Secobatzelline B, Secoisola Thiomarinol, Thiomarinol B, Thiomarinol C, Thiomarinol D, riciresinol diglucoside, Securioside A, Securioside B, Seg Thiomarinol E. Thiomarinol F. Thioviridamide. Thioxamy litide, Selamectin, Selank, Selodenoson, Semagacestat, Sem cin, Thrazarine, Thymallene, Thymectacin, Thymopentin, duramicin, Semorphone hydrochloride, Seocalcitol, Tidembersat, Tienoxolol hydrochloride, Tigecycline, Til Seprilose, Sergliflozin etabonate, Serofendic acid, Sessilo isolol hydrochloride, Timolol hemihydrate, Timolol maleate, side, Setamycin, Setazindol, Shepherdin, Shishijimicin A, Tipelukast, Tipranavir, Tiqueside, Tisocalcitate, Tixocortol Shishijimicin B, Shishijimicin C, Sialosylcholesterol-Alpha buryrate propionate, Toborinone, Tobramycin, Tocotrienol, Sodium Salt, Sibanomicin, Sibenadet hydrochloride, Sibis Tokaramide A, Tolcapone, Toloxatone, Tolterodine Tartrate, koside, Sildenafil citrate, Silodosin, Siltenzepine, Silychris Tolvaptan, Tolytoxin, Tomatine, Tomeglovir, Tonabersat, tin, Simotaxel, Simvastatin, Sinomenine, Sitafloxacin Topixantrone hydrochloride, Topotecan Acetate, Topotecane hydrate, Sitostanol ascorbyl phosphate, Sivifene, Siwenmy Hydrochloride, Topovale, Topsentine B1, Torcitabine, Tor cin, Sizofiran, Smilagenin, Socorromycin, Sodium cro eZolid, Tosedostat, Tosufloxacin, Tosufloxacin Tosilate, Tra moglycate, Sodium oxybate, Solabegron hydrochloride, bectedin, Tradecamide, trans-Resveratrol, Trantinterol Solpecainol hydrochloride, Sonedenoson, Sootepenseone, hydrochloride, Travoprost, Traxoprodil, Traxoprodil mesy Soraprazan, Sorbicillactone A, Sorivudine, so-Simvastatin late, Trecadrine, Trecetilide fumarate, Treprostinil diethano 6-one, Sotalol hydrochloride, Sparfloxacin, Sparoxomycin lamine, Treprostinil Sodium, Triamcinolone acetonide, Tri A1, Sparoxomycin A2, Sperabillin A, Sperabillin B. Spera amcinolone hexacetonide, Trichodimerol, Trichomycin A, billin C, Sperabillin D. Sphingofungin F, Spinorphin, Spino Trichostatin D, Triciferol, Triciribine, Triciribine phosphate, sulfate A, Spinosulfate B, Spirocardin A, Spirocardin B, Trifluridine, Trilostane, Trimegestone, Trimidox, Trimopros Spiroximicin, Spiruchostatin A, Spiruchostatin B, Spisu til, Triphendiol, Tripterin, Triptolide, Troglitazone, Trova losine, Spongiadiol, Spongistatin 1, Spongistatin 3, Spong floxacin,Trovafloxacinhydrate,Trovafloxacinhydrochloride istatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7. mesylate, Trovafloxacin mesilate, Troxacitabine, Tsukuba Spongistatin 8, Spongistatin 9. Sporeamicin A, Sporeamicin mycin A, Tubastrine, Tubelactomicin A, Tuberactomycin B, B, Squalamine lactate, Squalestatin I, Stachybocin A, Stachy Tuberactomycin D, Tuberactomycin E. Tubingensin B, Tubu bocin B, Stachybocin C, Stachybotrin C, Stachybotrydial, lysin A, Tubulysin B, Tubulysin C, Tucaresol, Tuftsin, Tulath Staplabin, Starrhizin, Stavudine, Stelleramacrin A, Stellera romycin A, Tulathromycin B, Tulobuterol hydrochloride, macrin B, Sterenin A, Sterenin C, Sterenin D. Streptomycin, Turbostatin 1, Turbostatin 2, Turbostatin 3, Turbostatin 4, Streptopyrrole, Styloguanidine, Suberosenol A. Succinobu Tyropeptin A10, Tyropeptin A6, Tyropeptin A9, Tyroser col, Sugammadex sodium, Sulfasalazine, Sulfinosine, Sulfir Vatide, Tyrphostin 47, Ubenimex, Ukrain, Ulifloxacin, cin C, Sulopenem, Sulopenemetzadroxil, Sulphazocine, Sul Uncarinic acid A, Uncarinic acid B. Uncialamycin, Unopro phoquinovosyldiacylglycerol, Sulprostone, Sulukast, stone, Unoprostone isopropyl ester, Ursodeoxycholic acid, Sunflower trypsin inhibitor-1, Suplatast tosilate, Suronacrine Ustilipid A, Ustilipid B, Ustilipid C, Uvalol, Vadimezan, Val maleate, Susalimod, Swiftiapregnene, Symbioimine, Synad ganciclovir hydrochloride, Valnemulin, Valonomycin A, enol, Synguanol, Syriacusin A, Syriacusin B, Syriacusin C, Valopicitabine, Valrubicin, Vancomycin hydrochloride, Van Syzygiol, Tacalcitol, Tacapenem pivoxil, Taccalonolide E. coresmycin, Vanidipinedilol, Vaninolol, Variapeptin, Vebu Tacrolimus, Tafluprost, Tageflar, Taiwanhomoflavone A, floxacin, Veinamitol, Velnacrine Maleate, Velusetrag, Venor Takanawaene A, Takanawaene B, Takanawaene C, Tali phin, Vermisporin, Vernakalant hydrochloride, Verticillatine, begron, Talibegron hydrochloride, Talnetant, Tamandarin A, Vexibinol, Vialinin B, Vicenistatin, Vinaxanthone, Vindesine, Tamandarin B, Tamolarizine Hydrochloride, Tanespimycin, Vinfosiltine sulfate, Vinleucinol, Vinylamycin, Vicquidacin, TAP-doxorubicin, Tapentadol hydrochloride, Taramanon A, Viramidine Hydrochloride, Viranamycin-A, Viranamycin-B, Tasquinimod, Taurohyodeoxycholic acid, Tautomycin, Tax Viscosin, Vitilevuamide, Voclosporin, Voglibose, Volin uyunnanine, TaZofelone, Tazopsine, Tebipenem, Tebipenem anserin, Volpristin, Voreloxin, W Peptide, Wiedendiol A, cilexetyl, Tebipenem pivoxil, Tebufelone, Tecadenoson, Wiedendiol B, Woodorien, Xamoterol Fumarate, Xanthoan Technetium Tc 99m depreotide, Teicoplanin-A2-1, Teicopla gelol E., Xanthofulvin, Xanthomegnin, XenoVulene A, Xipa nin-A2-2. Teicoplanin-A2-3, Teicoplanin-A2-5. Telavancin mide, Xylocydine, Yatakemycin, Yohimbine, Zabofloxacin hydrochloride, Telbivudine, Telinavir, Telithromycin, Tema hydrochloride, Zahavin B, Zalcitabine, Zampanolide, Zan floxacin hydrochloride, Temazepam, Temoporfin, Tempol, amivir, Zankiren, Zaragozic acid D3, Zelandopam hydro chloride, Z-Eleutherobin, Zenarestat, Zidovudine, Zilascorb Temsirolimus, Temurtide, Tenidap, Teniposide, Tenoxicam, (2H), Zilpaterol, Zonampanel, Zorubicin hydrochloride, Tenuifoliside A, Tenuifoliside B, Tenuifoliside C, Tenuifoli ZoSuquidar trihydrochloride, Zotarolimus, ZoticaSone propi side D, Terbutaline sulfate, Terestigmine tartrate, Terfena onate, Zuclopenthixol hydrochloride. dine, Teriflunomide, Terlakiren, Ternatin, Terprenin, Ter reulactone A, Terreulactone B, Terreulactone C, 0699 Terreulactone D, Tertatolol hydrochloride, Tesetaxel, Test Suitable Small molecule drugs comprising a car osterone glucoside, Tetracosylcidofovir, Tetracycline hydro boxyl functional group are, for example, (-)-Subersic acid, chloride, Tetrafibricin, Tetragalloylquinic acid, Tetrahydro (+)-Deoxoartelinic acid, (+)-Hemipalmitoylcarnitinium, (+)- cortisol, Tetrahydrocurcumin, Tetrahydroechinocandin B, Indobufen, (+)-SCH-351448, (E)-p-Coumaroylquinic acid, TetrahydroSwertianolin, Tetrahydroxyquinone, Tetromycin (Z)-Indenaprost, 111 In-DTPA-Pro1,Tyr4 bombesin, 90Y A, Tetromycin B, Tetronothiodin, Texenomycin A, Tezacit DOTAGA-substance P. psiCH2NHITpg4Vancomycin abine, Tezosentan, Tezosentan disodium, Thenorphine, aglycon, 111 In-Pentetreotide, 11-Keto-Beta-Boswellic Acid, Theopederin D, Theoperidin E. Theophylline rutoside. Ther 15-Methoxypinusolidic acid, 1-Methyl-D-tryptophan, 3.5- mozymocidin, Thiamet-G, Thiamphenicol. Thiarubrine E. Dicaffeoylquinic acid, 3-MATIDA, 3-O-Acetyloleanolic Thiarubrine F. Thiarubrine G. Thiarubrine H, Thiazinotrieno acid, 4-Aminosalicylic acid, 6alpha-FluorourSodeoxycholic mycin B. Thiazinotrienomycin F. Thiazinotrienomycin G, acid, 6-Carboxygenistein, 7-Chlorokynurenic acid, 8-Car boxy-iso-iantheran A, 99mTc-c(RGDfK*)2HYNIC, US 2016/00821 23 A1 Mar. 24, 2016 59

A-42867 pseudoaglycone, Aceclofenac, Acemetacin, Ace gin, Dalbavancin, Danegaptide hydrochloride, Danofloxacin, neuramic acid sodium salt, Acetyl-11-Keto-Beta-Boswellic Darinaparsin, Darusentan, Daurichromenic acid, Davu Acid, Acetyl-Beta-Boswellic Acid, Acetylcysteine, Achimil netide, Decahydromoenomycin A, Decaplanin, Decatromi lic Acids, Acipimox, AcitaZanolast, Acrivastine, Actarit, Ada cin A, Decatromicin B. Deferasirox, Delafloxacin, Delapril palene, Adarotene, Ademetionine tosylate Sulfate, AdXan Hydrochloride, Deltibant, Deoxylaidlomycin, Deoxynega thromycin A, Ajulemic acid, Alacepril, Aladapcin, mycin, Dersalazine, Desacetylvinblastinehydrazide/folate Aleglitazar, Alitretinoin, Alminoprofen, Alogliptin benzoate, conjugate, Desferri-danoxamine, Desferri-nordanoxamine, alpha-Linolenic acid, alpha-Lipoic acid, alpha-Methyltryp Desglugastrin tromethamine, Desmin-370, Dexibuprofen, tophan, Alprostadil. Altemicidin, Alutacenoic acid B, Alvi Dexibuprofen lysine, Dexketoprofen, Dexketoprofen cho mopan hydrate, Amiglumide, Amineptine, Aminocaproic line, Dexketoprofen D.L-lysine, Dexketoprofen lysine, acid, Aminolevulinic acid hydrochloride, Amlexanox, Dexketoprofen meglumine, Dexketoprofen trometamol. Amoxicillin trihydrate, Amphotericin B, Amsilarotene, Dexloxiglumide, Dexpemedolac, dextro-Ciprofibrate, Dexy Anakinra, Antiflammin-1, Antiflammin-2, Antiflammin-3, losylbenanomycin A, Diacerein, Diazaphilonic acid, Di-Cal Apalcillin Sodium, Aplaviroc hydrochloride, Argatroban ciphor, Difenoxin, Diflunisal, Dihydroavenanthramide D, monohydrate, Argimesna, Artelinate, Artepillin C, Artesu Dihydrogranaticin B, Dihydroisosteviol, Dihydrolipoic acid, nate, Arundifungin, Ascosteroside, Asiatic acid, Aspirin, Disalazine, Disila-bexarotene, Disodium cromproxate, Diso Aspoxicillin, Assamicin I. Assamicin II, Ataluren, Atorvasta dium lettusate, Doqualast, Doripenem, Dormitroban, Dorri tin, Atorvastatin calcium, Atrasentan, AZaromycin SC, AZe gocin A, Dorrigocin B, Droxidopa, DTPA-adenosylcobal laic Acid, AZepinostatin, AZilsartan, AZOxybacilin, AZtre amin, Duramycin, Dynemicin A, Ecabet Sodium, onam, Aztreonam L-lysine, AZumamide E. Baclofen, Ecenofloxacin hydrochloride, Econazole Sulfosalicylate, Bafilomycin C1, Baicalin, Balhimycin, Balofloxacin, Balof Edetic acid, Edotreotide yttrium, Efletirizine, Eflornithine loxacin dihydrate, Balsalazide disodium, Bamirastine hydrochloride, Eglumetadhydrate, Elansolid C1, Elarofiban, hydrate, Belactosin A, Belactosin C, Benanomicin A, Bena Elastatinal B, Elastatinal C, Elsibucol, Eltrombopagolamine, nomicin B, Benastatin A, Benastatin B, Benazepril hydro Elvitegravir, Emricasan, Enalapril maleate, Enalapril nitrate, chloride, Benthocyanin A, Bepotastine besilate, Beraprost Enalaprilat, Enfumafungin, Enkastin (D), Enkastin AD, sodium, Besifloxacin hydrochloride, Beta-Boswellic Acid, Enkastin AE, Enkastin ID, Enkastin IE, Enkastin VD, Enkas beta-Hydroxy beta-methylbutyrate, Betamipron, Beta-Sialo tin VE, Enoloxone, Enoxacin, Enrasentan, Enrofloxacin, sylcholesterol Sodium Salt, Bevirimat, Bexarotene, Bezafi Epalrestat, Epidioxymanadic acid A, Epidioxymanadic acid brate, Biapenem, Bilastine, Bimosiamose, Bindarit, Bin B, Epithalon, Epofolate, Epoprostenol sodium, Epostatin, floxacin, Biphenyl-indanone A, Boc-Belactosin A, Epristeride, Eprosartan mesilate, Eprotirome, Eptaloprost, Borrellidin, Brasilicardin A, Brasilinolide A, Bremelanotide, Eptastatin Sodium, Eptastigmine Tartrate, Eptifibatide, Brevifolin carboxylic acid, Bucillamine, Bumetanide, Bun Erdosteine, Eremomycin, Ertapenem sodium, Ertiprotafib, geolic acid, Buprenorphine hemiadipate, Buprenorphine Eryloside F. Esafloxacin Hydrochloride, Esonarimod, Val-carbamate, Butibufen, Butoctamide hemisuccinate, Etacrynic acid, Etalocib sodium, Etodolac, Etretin, Eva ButyZamide, Cabin 1, Cadrofloxacin hydrochloride, Calbis tanepag, Evernimicin, Exisulind, EZetimibe glucuronide, trin A, Calbistrin B, Calbistrin C, Calbistrin D, Calcium-like Fandofloxacin hydrochloride, Faranoxi, Farglitazar, Faro peptide 1, Calcium-like peptide 2, Caloporoside B, Caloporo penem Sodium, Fasobegron hydrochloride, FebuXostat, Feg side C, Caloporoside D, Caloporoside E. Caloporoside F. lymycin, Felbinac, Felbinac Lysine Salt, Fenbufen, Fex Calpinactam, Calteridol calcium, Camprofen, Candesartan, ofenadine hydrochloride, Fidexaban, Finafloxacin Candoxatril, Candoxatrilat, Canfosfamide hydrochloride, hydrochloride, Fleroxacin, Flobufen, Flomoxef Sodium, Canrenoate potassium, CapraZamycin A, CapraZamycin B, Flunoprost, Flunoxaprofen, Flurbiprofen, Fluvastatin CapraZamycin C, CapraZamycin E. CapraZamycin F. Capto Sodium, Folinic acid, Fondaparinux sodium, Fosfosal, pril, Carbidopa, Carmoxirole hydrochloride, Carprofen, Fradafiban, Frusemide, Fudosteine. Furprofen, G1 peptide, Cefaclor, Cefalexin monohydrate, Cefbuperazone sodium, Gabadur, Gabapentin, Gabapentin enacarbil, Gabusectin, Cefcanel, Cefdaloxime, Cefdinir, Cefetecol, Cefixime, Cef Gadobenic acid dimeglumine salt, Gadobutrol, Gadocoletic matilenhydrochloride hydrate, Cefnmenoxime hydrochloride, acid trisodium salt, Gadodenterate, Gadomelitol, Gadopen Cefninox sodium, Cefodizime, Cefonicid sodium, Cefopera tetate dimeglumine, Gadoterate meglumine, Gadoteridol. Zone sodium, Cefoselis sulfate, Cefotiam hydrochloride, Gambogic acid, Gamendazole, Gamma-Linolenic Acid, Cefoxitin, Ce?pimizole sodium, Ce?piramide sodium, Cef Ganefromycin Alpha, Ganefromycin Beta, Ganglioside prozil, Cefprozil monohydrate, Ceftaroline fosamil acetate, GM1, Ganoderic acid X, Garenoxacin mesilate, Gastrazole, Ceftazidime, Ceftibuten, Ceftobiprole, Cefuroxime, Cer Gatifloxacin, Gemfibrozil, Gemifloxacin mesilate, Gemopat anapril, Cerivastatin sodium, Ceruletide diethylamine, Cet rilat, Gilatide, Gimatecan, Giripladib, Glaspimod, Glucaro efloxacin, Cetirizine hydrochloride, Chenodeoxycholic acid, lactam potassium, Gludopa, Glutathione Monoethyl Ester, Chinoin-169, Chlorambucil, Chloroorienticin A, Chloroori Glutathione Monoisopropyl Ester, Glycine-proline-Mel enticin B, Choline fenofibrate, Choline thioctate, Chrolacto phalan, Glycopin, Glycyrrhizinic acid, Golotimod, Goody mycin, Cilastatin Sodium, CilaZapril, Cilengitide, Cilomilast, eroside B. Goralatide, Grepafloxacin hydrochloride, GS-143, Ciluprevir, Cinaciguat, Cinalukast, Cinatrin A, Cinatrin B, Haterumadioxin A, Haterumadioxin B, Helvecardin A, Cinatrin C1, Cinatrin C2, Cinatrin C3, Cinnatriacetin A, Cin Helvecardin B, Heptelidic acid chlorohydrin, Hericenal A. natriacetin B, Ciprofibrate, Ciprofloxacin hydrochloride, Cir Hericenal B, Hericenal C. Homoindanomycin, Hongoquer cinamide, Cispentacin, Citrullimycine A, Clavaric acid, Cla cin A, Hongoquercin B. Human angiotensin II, Hyaluronate Vulanate potassium, Clinofibrate, Clopidogrel Sulfate, Sodium, Hydrostatin A, Ibuprofen, Icatibant acetate, Icofun Colletoic acid, Complestatin, Conagenin, Cosalane, Creatine gipen, Idrapril, Ifetroban, Ilepatril, Iloprost, Imidapril, Imi phosphate, Cyclocreatine, Cycloplatam, Cyclothialidine, dapril hydrochloride, Imiglitazar, Imipenem, Indianaprost Cytomodulin, Cytosporic acid, Dabigatran, Daglutril, Dalar (S), Indanomycin, Indeglitazar, Indobufen, Indole-3-propi US 2016/00821 23 A1 Mar. 24, 2016 60 onic acid, Indometacin, Indomethacintrometamol, Indoxam, bamate, Oxynor, OZagrel hydrochloride, Ozenoxacin, Pac Indynaprost, Inogatran, Inosiplex, Iododiflunisal, Iodofiltic timibe, Padoporfin, Paeciloquinone B, Paeciloquinone D. acid-123.I. IodoStearic Acid, Iralukast, Iralukast Sodium, Paldimycin B, Palovarotene, Panipenem, Parasin I, Parinaric Isalsteine, Isobongkrekic acid, Isotretinoin, Itavastatin cal acid, Paulomycin, Paulomycin A2, Paulomycin B, Paulomy cium, Itriglumide, Kaitocephalin, Kanglemycin A, Kapuri cin C, Paulomycin D. Paulomycin E, Paulomycin F. PaZu mycin A1, Kapurimycin A3. Ketoprofen, Ketoprofen lysine, floxacin, PaZufloxacin mesilate, Pefloxacin, PEG-vancomy Ketorolac, Ketorolac tromethamine, Khafrefungin, Kijimi cin, Pelagiomicin C, Peliglitazar, Pelitrexol, Pelretin, cin, Kistamicin A, L-4-Oxalysine, Labradimil, Lamectacin, Penasterol, Penicillamine, Peramivir, Perindopril, PG-camp Lamifiban, Lanthiopeptin, Lapaquistat acetate, LaraZotide tothecin, Phomallenic acid C, Phomoidride A, Phomoidride acetate, Laropiprant, Latamoxef sodium, L-Chicoric acid, B. Phosphinic cyclocreatine, Phosphosalsalate, Physostig Lenapenem hydrochloride, Lenapenem hydrochloride mine salicylate, Pibaxizine, Pidotimod, Piraxostat, Piret hydrate, Levocabastine hydrochloride, Levocetirizine dihy anide, Pirfenoxone, Pirprofen, Pivagabine, Pixantrone male drochloride, levo-Ciprofibrate, Levodopa, Levodopa 3-O- ate, Plakotenin, Platencin, Platensimycin, Plevitrexed, glucoside, Levodopa 4-O-glucoside, Levofloxacin, Pluraflavin E, Plusbacin A1, Plusbacin A2, Plusbacin A3, Levonadifloxacin arginine salt, L-Homothiocitrulline, Plusbacin A4, Plusbacin B1, Plusbacin B2, Plusbacin B3, Licofelone, Licorice-Saponin C2, Lidorestat, Limaprostalfa Plusbacin B4, Polyalthidin, Pomisartan, Ponalrestat, Poststa dex, Limazocic, Linoleic acid 18:2W6-cis, 9-cis, Linotroban, tin, PPI17-24, Pradimicin A, Pradimicin B, Pradimicin D, Lintitript, Lipohexin, Lisinopril, Lithium Succinate, Lithos Pradimicin E, Pradimicin FA-1, Pradimicin FA-2, Pradimicin permic acid B magnesium salt, Loloatin B, Lomefloxacin FL, Pradimicin FS ((+)-enantiomer), Pradimicin L. Pradimi hydrochloride, Lometrexol, Longestin, Lonidamine, Lora cin Q, Pradimicin S. Pradimicin T1, Pradimicin T2, Pradof carbef hydrate, Lorglumide, Lotrafiban, Loxiglumide, loxacin, Pralatrexate, Pranoprofen, Prefolic A. Pregabalin, L-Simexonyl homocysteine, L-Thiocitrulline, Lubiprostone, Premafloxacin, Premafloxacin hydrochloride, Prezatide cop Lumiracoxib, Lu-TeX bis(gluconate), Lysinated-betulonic per acetate, Proamipide, Probenecid, Probestin, Procysteine, acid, Lysine acetylsalicylate, Macrocarpin B. Madecassic Proglumide, Propagermanium, Propofol hemisuccinate, acid, Maracenin A1, Maracenin A2, Maracenin B1, Marace Prostatin, Prostratin succinate, Protocatechuic acid, Proto nin B2, Maracenin C1, Maracenin C2, Maracenin D1, porphyrin IX gallium(III) complex, Prulifloxacin, Prulifloxa Maracenin D2, Marbofloxacin, Maslinic acid, Matristatin cin Hydrochloride, Prulifloxacin Mesylate, Pseudomycin A', A1, Matristatin A2, Matteuorienate A, Matteuorienate B, Pseudomycin B, Pycnanthuquinone A. Pycnanthuquinone B. Matteuorienate C, Mebrofenin, Meclinertant, Mefenamic Pyloricidin B, Pyridazomycin, Pyrrolosporin A, Quiflapon acid, Melagatran, Memno-peptide A, Meptazinol-Val-car Sodium, Quinapril hydrochloride, Quinlukast, Rafabegron, bamate, Meropenem, Mersacidin, Mesalazine, Metesind glu Ragaglitazar, Raltitrexed, Ramatroban, Ramipril, Raxofelast, curonate, Methanobactin, Methotrexate, Methoxatin, Meth RaZupenem, Rebamipide bismuth citrate tetramethyl yldopa, Methylenolactocin, Methylhomoindanomycin, edamine, Rebamipide bismuth L-tartrate tetramethyl Metiapril, Metirosine, Micacocidin A, Micacocidin B, edamine, Repaglinide, Resobene, Reveromycin A, Midafotel, Midoriamin, Milrinone Lactate, Minerval, Mipi Rhododaurichromanic acid A. Ridogrel, Robenacoxib, Roca troban, Mispyric acid, Mixanpril, Moenomycin A chloride gloic acid, Rolafagrel, Romazarit, Romurtide, Rosaprostol bismuth salt, Moexipril hydrochloride, Moexiprilat, Mof Sodium, Rosuvastatin calcium, Rosuvastatin Sodium, eZolac, Momordin Ic, Monamidocin, Monoethanolamine Rufloxacin Gluconate, Rufloxacin hydrochloride, Rumycin oleate, Montelukast sodium, Morphine Glucuronide, Moxi 1. Rumycin 2, Salazopyridazin, Salcaprozic acid sodium salt, floxacin hydrochloride, Mumbaistatin, Mupirocin, Muragli Salicylazobenzoic acid, S-Allylmercaptocaptopril, Salm tazar, Muraminomicin A, Muraminomicin B. Muraminomi isteine, Salvianolic acid L. Samixogrel, Sampatrilat, San cin C, Muraminomicin D, Muraminomicin E1, fetrinem, Sanfetrinem sodium, Sapurimycin, Sarpogrelate Muraminomicin E2, Muraminomicin F. Muraminomicin G, hydrochloride, Saussureamine A, Saussureamine B, Saus Muraminomicin H, Muraminomicin I, Muraminomicin Z1, Sureamine C. Saussureamine D. Saussureamine E. Scabro Muraminomicin Z2, Muraminomicin Z3, Muraminomicin nine G. Scopadulcic acid B, Securioside A, Securioside B, Z4, Mureidomycin A, Mureidomycin B. Mureidomycin C, Selank, Semduramicin, Seocalcitol, Seratrodast, Serofendic Mureidomycin D, Mureidomycin E, Mureidomycin F. Mure acid, Sessiloside. Shepherdin, Sialosylcholesterol-Alpha idomycins, Mycaperoxide A, Mycaperoxide B, Mycestericin Sodium Salt, Sitafloxacin hydrate, S-Nitrosocaptopril, S-Ni E. Mycophenolic acid sodium salt, Myriceric acid A. Mytol trosoglutathione, Sodelglitazar, Sodium cromoglycate, bilin acid, Nadifloxacin, Nafagrel hydrochloride, Nafagrel Sodium oxybate, Sofalcone, Solabegron hydrochloride, Sor hydrochloride hemihydrate, Nagstatin, Napirimus, Napsa bicillactone A, Sparfloxacin, Sphingofungin F. Spinorphin, gatran, Napsamycin A, Napsamycin B, Napsamycin C, Nap Spirapril, Spiriprostil, Spiroglumide, Spiroximicin, Squal samycin D. Nateglinide, Naveglitazar, Nebostinel, Nemon estatin I, Stachybocin A, Stachybocin B, Stachybocin C, Sta oxacin, Neu5Ac2en, Niacin, Niglizin, Nileprost beta plabin, Starrhizin, Sterenin D. Subtilopentadecanoic acid, cyclodextrin clathrate, Nooglutil, Norfloxacin, Norfloxacin Succinobucol, Sufotidine bismuth citrate, Sugammadex Succinil, Obeticholic acid, Octacosamicin A, Octacosamicin Sodium, SulfaSalazine, Sulindac, Sulopenem, Sulukast, Sun B, O-Demethylchlorothricin, Ofloxacin, Olamufloxacin, flower trypsin inhibitor-1, Susalimod, Tafamidis meglumine, Olamufloxacin mesilate, Olanzapine pamoate, Oleanolic Tageflar, Talaglumetad hydrochloride, Talibegron, Tali acid, Olmesartan, Olopatadine Hydrochloride, Olsalazine begron hydrochloride, Talopterin, Taltobulin, Tamibarotene, sodium, Omapatrilat, Onnamide A, OPC-17083, Opiorphin, Tanogitran, Tanomastat, TAP-doxorubicin, Tarenflurbil, Orbifloxacin, Oreganic acid, Orienticin A. Orienticin B, Ori Targinine, Tazarotenic Acid, Tebipenem, Teicoplanin-A2-1, enticin C, Orienticin D. Oritavancin, Orniplabin, Oseltamivir Teicoplanin-A2-2, Teicoplanin-A2-3, Teicoplanin-A2-5. carboxylate, Ovothiol A, Ovothiol B, Ovothiol C, Oxaprozin, Telavancin hydrochloride, Telmesteine, Telmisartan, Tema Oxeglitazar, Oxiglutatione sodium, Oxymorphone-Val-car floxacin hydrochloride, Temocapril hydrochloride, US 2016/00821 23 A1 Mar. 24, 2016

Temurtide, Tenosal, Terbogrel, Terestigmine tartrate, Terikal cines, interleukines (1 alfa, 1 beta, 2, 3, 4, 6, 10, 11, 12), IL-1 ant fumarate, Tesaglitazar, Tetomilast, Tetradecylselenoace receptor antagonist (rhIL-1 ra), insulins, interferons (alfa 2a, tic acid, Tetrafibricin, Tetragalloylquinic acid, Tetrahydro alfa 2b, alfa 2c, beta 1a, beta 1b, gamma 1a, gamma 1b). echinocandin B, Tetronothiodin, TeZampanel, keratinocyte growth factor (KGF), lactase, leuprolide, Thermozymocidin, Thiazohalostatin, Thielavin G. Thielocin, levothyroxine, luteinizing hormone, lyme vaccine, natriuretic Thielocin B3. Thio foscarnet, Thioxamycin, Thrazarine, Thy peptide, pancrelipase, papain, parathyroid hormone, PDGF, mic humoral factor gamma-2, Thymopentin, Tiagabine pepsin, phospholipase-activating protein (PLAP), platelet hydrochloride, Tibenelast, Ticolubant, Tilarginine hydro activating factor alcetylhydrolase (PAF-AH), prolactin, pro chloride, Tiliquinatine, Timodepressin, Tipelukast, Tiplasi tein C, Octreotide, secretin, sermorelin, Superoxide dismutase (SOD). Somatropins (growth hormone). Somatostatin, Strep nin, Tirofiban hydrochloride, Tisartan, Tolfenamic acid, Tol tokinase, Sucrase, tetanus toxin fragment, tilactase, throm metin, Tolrestatin, Tomopenem, ToSufloxacin, ToSufloxacin bins, thymosin, thyroid stimulating hormone, thyrothropin, Tosilate, Trandolapril, Trandolaprilat, Tranexamic acid, Tra transforming growth factors, tumor necrosis factor (TNF). nilast, Treprostinil diethanolamine, Treprostinil sodium, Tre TNF receptor-IgG Fc, tissue plasminogen activator (tPA), tinoin, Triacetylshikimic acid, Trichomycin A, Triflusal, Tri transferrin, TSH, urate oxidase, and urokinase. mexautide, Trimoprostil, Tripterin, Tropesin, Trovafloxacin, 0703. In a preferred embodiment the drug is an antibody, Trovafloxacin hydrate, Trovafloxacin hydrochloride mesy Such as a monoclonal or polyclonal antibody or a fragment or late, Trovafloxacin mesilate, Tubelactomicin A, Tuberacto fusion thereof. Preferred antibody fragments are selected mycin D, Tuberactomycin E. Tubulysin A, Tubulysin B, from the group consisting of Fab (fragment, antigen-bind Tubulysin C, Tucaresol, Tuftsin, Turbinaric acid, Tyroser ing), F(ab) fragments. Fc (fragment, crystallizable), pFc' Vatide, Ubenimex, Ulifloxacin, Uncarinic acid A, Uncarinic fragment, Fv (fragment, variable), ScPv (single-chain vari acid B, Unoprostone, Ursodeoxycholic acid, Ursolic acid able fragment), di-scFv/diabodies, bi-specific T-cell engager, phosphate, Utibapril, Utibaprilat, Vadimezan, Valonomycin CDRS (complementarity determining regions), single-do A. Valproate Semisodium, Valproic acid, Valsartan, Vanco main antibodies (sdABS/Nanobodies), heavy chains (C., 8, 6. mycin hydrochloride, Varespladib, Vebufloxacin, Vedapro Y, u) or heavy chain fragments, light chains (W, 0) or light fen, Veliflapon, Verlukast, Vinaxanthone, Vicquidacin, Virana chain fragments, VH fragments (variable region of the heavy mycin-A, Viscosin, Vitilevuamide, Voreloxin, W Peptide, chain), VL fragments (variable region of the light chain), Xanthofulvin, Zabicipril Hydrochloride, Zabiciprilat Hydro VHH fragments and VNAR fragments. chloride, Zabofloxacin hydrochloride, Zaltoprofen, Zan 0704. In another preferred embodiment the protein drug is amivir, Zaragozic acid D3, Zenarestat, Zofenoprilat, Zofeno preferably a protein drug that modulates the activity of one or prilat arginine, Zolasartan, Zonampanel. more of the biological target(s) selected from the group con 0700 Suitable small molecule drugs comprising a phos sisting of basic fibroblast growth factors (bFGF), acidic fibro phate functional group are, for example, Adenophostin A, blast growth factors (aFGF), transforming growth factors Adenophostin B, Atrinositol, Buflomedil pyridoxalphos alpha (TGFa), transforming growth factors beta (TGFB), phate, Cytostatin, Fludarabine phosphate, Fosfluconazole, platelet-derived growth factor (PDGF), angiogenin, platelet FoSfonochlorin, Fosfosal, Fosopamine, Fosquidone, Fos derived endothelial cell growth factor (PD-ECGF), interleu tamatinib, Ganciclovir monophosphate, Genistein-7-phos kin-1 (IL-1) interleukin-8 (IL-8), interleukin-12, vascular phate, Hydroxyphoslactomycin B. Leustroducsin A, Leustro endothelial growth factor (VEGF), angiopoietin-I, Del-I, fol ducsin B. LeuStroducsin C. Leustroducsin H. Mangafodipir listatin, granulocyte colony-stimulating factor (G-CSF), trisodium, Menadiol sodium diphosphate, Miproxifene phos hepatocyte growth factor (HGF), leptin, midkine, placental phate, Monophosphoryl lipid A. Phospholine, Phosphosal growth factor, pleiotrophin (PTN), progranulin, proliferin, salate, Pneumocandin B02-phosphate, Tafluposide, Tricirib tumor necrosis factor-alpha (TNF-alpha), angioarrestin, ine phosphate, Ursolic acid phosphate. angiostatin (plasminogen fragment), antiangiogenic anti 0701 Suitable small molecule drugs comprising a thiol thrombin III, cartilage-derived inhibitor (CDI), CDS9 functional group are, for example, Acetylcysteine, Antileuki complement fragment, endostatin (collagen XVIII frag nate, Argimesna, Bucillamine, ButiXocort, Captopril, Dihy ment), fibronectin fragment, gro-beta, heparinases, heparin drolipoic acid, Gemopatrilat, Glutathione monoethyl ester, hexasaccharide fragment, human chorionic gonadotropin Glutathione monoisopropyl ester, Midoriamin, Omapatrilat, (hCG), interferon alpha/beta/gamma, interferon inducible Ovothiol A, Ovothiol B, Ovothiol C, Penicillamine, Rebim protein (IP-IO), kringle S (plasminogen fragment), metallo astat, Shepherdin, Zofenoprilat, Zofenoprilat arginine. proteinase inhibitors (TIMPs), 2-methoxyestradiol, placental 0702. In one embodiment the drug is a protein or peptide ribonuclease inhibitor, plasminogen activator inhibitor, plate drug. Preferably, such protein or peptide drug is selected from let factor-4 (PF4), prolactin 16 kD fragment, proliferin-re the group consisting of ACTH, adenosine deaminase, agalsi lated protein (PRP), retinoids, tetrahydrocortisol-S, thrombo dase, albumin, alfa-1 antitrypsin (AAT), alfa-1 proteinase spondin-I (TSP-I), Vasculostatin, and vasostatin (calreticulin inhibitor (API), alglucosidase, alteplase, anistreplase, ancrod fragment), prostaglandin, growth hormone, insulin-like serine protease, antibodies (monoclonal or polyclonal and growth factor-I (IGF-I), sphingosine-1-phosphate, factor D, fragments or fusions), antithrombin III, antitrypsins, aproti RTP801, inhibitors of complement, including C1, C3 and C5, nin, asparaginases, biphalin, bone-morphogenic proteins, C. adrenergic agonist, mTOR, ciliary neurotrophic factor calcitonin (salmon), collagenase, DNase, endorphins, enfu (CNTF), brain-derived neurotrophic factor (BDNF), glial virtide, enkephalins, erythropoietins, factor VIIa, factor VIII, cell-derived neurotrophic factor (GDNF), lens epithelium factor VIIIa, factor IX, fibrinolysin, fusion proteins, follicle derived growth factor (LEDGF), rod-derived cone viability stimulating hormones, granulocyte colony stimulating factor factor (RdCVF), and pigment epithelium-derived factor (G-CSF), galactosidase, glucagon, glucagon-like peptides (PEDF). like GLP-1, glucocerebrosidase, granulocyte macrophage 0705. If the drug is an affinity scaffold protein it is prefer colony stimulating factor (GM-CSF), chorionic gonadotro ably selected from the group consisting of shark-derived pin (hCG), hemoglobins, hepatitis B vaccines, hirudin, hyalu affinity scaffold proteins, Kunitz domain-derived affinity ronidases, idurnonidase, immune globulins, influenza vac scaffold proteins, centyrin-derived affinity scaffold proteins, US 2016/00821 23 A1 Mar. 24, 2016 62 ubiquitin-derived affinity scaffold proteins, lipocalin-derived poly(acrylamides), poly(alkyloxy) polymers, poly(amides), affinity scaffold proteins, ankyrin-derived affinity scaffold poly(amidoamines), poly(amino acids), poly(anhydrides), proteins, versabodies (disulfide-rich affinity scaffold pro poly(aspartamides), poly(butyric acids), poly(glycolic teins), fibronectin-derived affinity scaffold proteins, cam acids), polybutylene terephthalates, poly(caprolactones), eloid-derived antibody fragments and affinity scaffold pro poly(carbonates), poly(cyanoacrylates), poly(dimethylacry teins, llama-derived antibody fragments and affinity scaffold lamides), poly(esters), poly(ethylenes), poly(ethylenegly proteins, transferrin-derived affinity scaffold proteins, and cols), poly(ethylene oxides), poly(ethyl phosphates), poly squash-type protease inhibitors with cysteine-knot scaffold (ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl derived affinity scaffold proteins. acrylates), poly(hydroxyethyloxazolines), poly(hy droxymethacrylates), poly(hydroxypropylmethacryla Tag Moiety mides), poly(hydroxypropyl methacrylates), poly(hydrox ypropyloxazolines), poly(imino carbonates), poly(lactic 0706. In one embodiment, the tag moiety T is a small acids), poly(lactic-co-glycolic acids), poly(methacryla molecule. mides), poly(methacrylates), poly(methyloxazolines), poly 0707 Preferably, T is W: Cso alkyl: Clso alkenyl; or (organophosphaZenes), poly(ortho esters), poly(oxazolines), Clso alkynyl, which W. Clso alkyl, Clso alkenyl; and Clso polypropylene glycols), poly(siloxanes), poly(urethanes), alkynyl are optionally substituted with one or more R', poly(vinyl alcohols), poly(vinyl amines), poly(Vinylmethyl which are the same or different and which Clso alkyl: Clso ethers), poly(Vinylpyrrolidones), silicones, celluloses, car alkenyl; and C-so alkynyl are optionally interrupted by one or bomethyl celluloses, hydroxypropyl methylcelluloses, more group(s) selected from the group consisting of W. chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, man nans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate based polymers, Xylan, and copolymers thereof. O. : N(R)C(O)N(R) ; and OC(O)N(R'R''); 0718 Preferably, T is a polymer with a molecular weight 0708 wherein ranging from 0.5 to 50 kDa, more preferably from 0.5 to 40 (0709 R. R. R” are independently of each other H: kDa, even more preferably from 1 to 30, even more preferably W. Clso alkyl, Clso alkenyl; or Clso alkynyl, wherein from 1 to 20 kDa and most preferably from 2 to 15 kDa. W. Clso alkyl, C2-so alkenyl; and C2-so alkynyl are 0719. In a preferred embodiment T is a PEG-based poly optionally substituted with one or more R', which are mer comprising at least 70% PEG or a hyaluronic acid-based the same or different and wherein Clso alkyl, C-so polymer comprising at least 70% hyaluronic acid. More pref alkenyl; and Clso alkynyl are optionally interrupted by erably, T is a PEG-based polymer comprising at least 70% one or more group(s) selected from the group consisting PEG, even more preferably comprising at least 80% PEG and most preferably comprising at least 90% PEG. 0720 Preferred moieties T are a linear or branched PEG based polymer with a molecular weight ranging from 0.5 to 50 kDa and Co alkyl wherein said Co alkyl is optionally interrupted with by one or more group(s) selected from the group consisting of W. —C(O)C)— —O—; —C(O)—; C(O)N(R) : S(O)N(R) : S(O)N(R) :- S(O) nyl; Co cycloalkyl, 4 to 7 membered heterocyclyl; or ;-S(O)–: N(R)S(O)N(R') :-S : N(R)-; 8- to 11-membered heterobicyclyl, wherein W is option OC(O)R’: N(R)C(O) : N(R)S(O) : N(R)S ally substituted with one or more R', which are the (O) ; N(R)C(O)C : N(R)C(O)N(R) ; and same or different; OC(O)N(RR): 0711) R' is halogen; CN; oxo (=O); COOR: OR; 0721 wherein C(O)R'?: C(O)N(R'R'2); S(O)N(R'R'2); S(O)N 0722) R. R. Rare independently of each other H: (R'R'2); S(O).R'?: S(O)R'?: N(R')S(O)N W. Clso alkyl, C2-soalkenyl; or C2-so alkynyl. (R2R12); SR2. N(R2R12); NO; oCO32, 0723. It is especially advantageous if T is a polymer, in N(R)C(O)R12; N(R'2)S(O).R'2'; N(R)S(O)R'2'; particular a PEG-based polymer, in case the drug is not water N(R')C(O)OR'2'; N(R')C(O)N(R'R'2); OC(O)N soluble or has only limited water-solubility. The polymeric (R'R''); or Calkyl, wherein Calkyl is optionally moiety increases the solubility of the biologically active moi substituted with one or more halogen, which are the ety which may result in higher conjugation yields in process same or different; step (d). 0712 R'', R''", R', R'', R'' are independently of each other H; or Calkyl, wherein C alkyl is option Other Aspects ally substituted with one or more halogen, which are the 0724. The present invention further relates to a hydrogel same or different. linked prodrug releasing a tag moiety-biologically active 0713. In one embodiment R. R. R” may be indepen moiety conjugate obtainable by a process of the present dently of each other H. invention. 0714) In one embodiment R' is C, alkyl. 0725 Preferably, the hydrogel is obtainable by a process 0715. In one embodiment W is phenyl. wherein process step (d) is selected from (d-i), (d-ii), (d-iii) or 0716 Preferably, T is a linear, branched, or dendritic poly (d-iv). C. 0726. In another preferred embodiment the hydrogel is 0717. In another embodiment the tag moiety T is a poly obtainable by a process wherein step (d) is selected from mer which comprises one or more polymer(s) selected from (d-V), (d-vi), (d-vii) or (d-viii). the group consisting of polypeptides, 2-methacryloyl-oxy 0727. Another aspect of the present invention is a pharma ethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), ceutical composition comprising the prodrug of the present US 2016/00821 23 A1 Mar. 24, 2016 invention or a pharmaceutical salt thereof together with a 0740 Human growth hormone releasing factor fragment pharmaceutically acceptable excipient. 1-29 with a C-terminally added cysteine amide (GRF (1-29)- 0728. In one embodiment the release of the tag moiety Cys; sequence: H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser biologically active moiety conjugate from the hydrogel Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu linked prodrugs of the present invention occurs with a half Leu-Gln-Asp-Ile-Met-Ser-Arg-Cys-NH) e.g. synthesized life ranging from 1 hour to twelve months, e.g. from 6 hours by Fmoc-strategy can be obtained from any custom peptide to twelve months, from twelve hours to eleven months, from synthesis Supplier, Such as, for example, Peptide Specialty one day to ten months, from three days to nine months, from Laboratories GmbH, Heidelberg, Germany. six days to nine months, from one week to nine months, from two weeks to seven months, from three weeks to eight 0741. All other chemicals were from Sigma-ALDRICH months, from four weeks to eight months, from six weeks to Chemie GmbH. Taufkirchen, Germany. seven months, from eight weeks to seven months, from ten weeks to six months, from twelve weeks to six months or Methods: from sixteen weeks to five months. 0729. Yet another aspect of the present invention is a hydrogel-linked prodrug releasing a tag moiety-biologically Fmoc Deprotection: active moiety conjugate of the present invention or a pharma ceutical composition comprising the hydrogel-linked pro 0742 For Fmoc protecting-group removal, the resin was drugs releasing a tag moiety-biologically active moiety con agitated with 2/2/96 (v/v/v) piperidine/DBU/DMF (two jugate of the present invention for use as a medicament. times, 10 min each) and washed with DMF (ten times). 0730 Yet another aspect of the present invention is a method of treating, controlling, delaying or preventing in a mammalian patient, preferably in a human, in need of the RP-HPLC Purification: treatment of one or more conditions comprising administer ing to said patient a therapeutically effective amount of the 0743 RP-HPLC was done on a 100x20 mm or 100x40 hydrogel-linked prodrugs releasing a tag moiety-biologically mm C18 ReproSil-Pur 300 ODS-35um column (Dr. Maisch, active moiety conjugate of the present invention or the phar Ammerbuch, Germany) connected to a Waters 600 HPLC maceutical composition comprising the hydrogel-linked pro System and Waters 2487 Absorbance detector unless other drugs releasing a tag moiety-biologically active moiety con wise stated. Linear gradients of solution A (0.1% TFA in jugate of the present invention or a pharmaceutically HO) and solution B (0.1% TFA in acetonitrile) were used. acceptable salt thereof. HPLC fractions containing product were pooled and lyo philized. EXAMPLES Materials and Methods Flash Chromatography: 0731. Amino 4-arm PEG 5 kDa was obtained from Jen 0744 Flash chromatography purifications were per Kem Technology, Beijing, P. R. China. CithrolTM DPHS was formed on an Isolera One system from Biotage AB, Sweden, obtained from Croda International Pic, Cowick Hall, United using Biotage KP-Silsilica cartridges and n-heptane, ethyl Kingdom. cis-1,4-cyclohexanedicaboxylic acid was obtained acetate, and methanol as eluents. Products were detected at from TCI EUROPE N.V., Boerenveldseweg 6-Haven 1063, 2070 Zwijndrecht, Belgium. 254 nm. For products showing no absorbance above 240 nm 0732 Isopropylmalonic acid was obtained from ABCR fractions were screened by LC/MS. GmbH & Co. KG, 76.187 Karlsruhe, Germany. 0745. For hydrogel beads, syringes equipped with poly 0733 N-(3-maleimidopropionyl)-39-amino-4,7,10,13, ethylene frits were used as reaction vessels or for washing 16, 19.22,25,28.31,34.37-dodecaoxa-nonatriacontanoic acid steps. pentafluorophenyl ester (Mal-NH-PEG12-PFE) was 0746. Analytical ultra-performance LC (UPLC) was per obtained from Biomatrik Inc., Jiaxing, P. R. China. formed on a Waters Acquity system equipped with a Waters 0734 N-(3-maleimidopropionyl)-21-amino-4,7,10,13, BEH300 C18 column (2.1x50 mm, 1.7 um particle size) 16, 19-hexaoxa-heneicosanoic acid NHS ester (Mal-PEG6 coupled to a LTO Orbitrap Discovery mass spectrometer NHS) and t-boc-Amido-dPEG 12-alcohol was obtained from from Thermo Scientific. Celares GmbH, Berlin, Germany. 0735. 6-(S-Tritylmercapto)hexanoic acid was purchased 0747. HPLC-Electrospray ionization mass spectrometry from Polypeptide, Strasbourg, France. (HPLC-ESI-MS) was performed on a Waters Acquity UPLC 0736) 15-Tritylthio-4,7,10,13-tetraoxa-pentadecanoic with an Acquity PDA detector equipped with a Waters acid (Trt-S-PEG4-COOH) is obtained from Iris Biotech ACQUITY UPLC BEH300 C18 RP column (2.1x50 mm, GmbH, Marktredwitz, Germany. 300 A, 1.7 um, flow: 0.25 mL/min: solvent A: UP-HO--0. 0737. Oxyma pure, Fmoc-L-Asp(OtBu)-OH and Fmoc 04% TFA, solvent B: UP-Acetonitrile+0.05% TFA) and L-Asp(OBn)-OH were purchased from Merck Biosciences coupled to a Thermo LTQ Orbitrap Discovery high resolu GmbH. Schwalbach/Ts. Germany. tion/high accuracy mass spectrometer or a Waters ZQ 4000 0738 (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl 4-nitro ESI mass spectrometer. phenyl carbonate was purchased from Chemzon Scientific 0748 MS of PEG products showed a series of Inc., Lachine, QC, Canada. (CH2CH2O), moieties due to polydispersity of PEG starting (0739) ()-Maleimido-O-methoxy-PEG 750 Da was materials. For easier interpretation only one single represen obtained from Rapp Polymere, Tubingen, Germany tative m/z signal is given in the examples. US 2016/00821 23 A1 Mar. 24, 2016 64

Example 1 Synthesis of Backbone Reagent 1g 0749

is O NH NH2

's O C H HN N NH2 O N N

N-1-on- rO H O

N H HN NH2

O

in N 28 NH2

0750 Backbone reagent 1 g was synthesized from amino drous), EDC.HCl (1.15g, 6.00 mmol), HOBt.HO (0.96g, 4-arm PEG5000 la according to following scheme: 6.25 mmol), and collidine (5.20 mL, 40 mmol) were added. The reaction mixture was stirred for 30 min at RT. 0752. The reaction mixture was diluted with 1200 mL of Boc-Lys(Boc)-OH DCM and washed with 600 mL of 0.1 NHSO (2x), brine EDC, HOBt (1x), 0.1 MNaOH (2x), and 1/1 (v/v) brine/water (4x). Aque DMSO, Collidine ous layers were reextracted with 500 mL of DCM. Organic PEG1250-NH) - > phases were dried over NaSO filtered and evaporated to la give 6.3 g of crude product 1b as colorless oil. Compound 1b HC Dioxane, MeOH was purified by RP-HPLC. PEG1250-Lys(Boc) He (0753. Yield: 3.85 g (59%) colorless glassy product 1b. 1b Boc-Lys(Boc)-OH (0754 MS: m/z 1294.4-M+5H (calculated=1294.6). PEG125OK-Lys(NH) —- 0755 Compound 1c was obtained by stirring of 3.40 g of compound 1b (0.521 mmol) in 5 mL of methanol and 9 mL of 4N HCl in dioxane at RT for 15 min. Volatiles were removed HC Dioxane, MeOH PEG1250- LysLys2(Boc)44 Hip in vacuo. The product was used in the next step without further purification. Boc-Lys(Boc)-OH (0756 MS: m/z 1151.9-M+5M (calculated=1152.0). PEG1250-LysLys(NH) - > 0757. For synthesis of compound 1d, 3.26 g of compound 1c (0.54 mmol) were dissolved in 15 mL of DMSO (anhy HC Dioxane, MeOH drous). 2.99 g, Boc-Lys(Boc)-OH (8.64 mmol) in 15 mL PEG1250- LysLys-Lys4(Boc)84 -> DMSO (anhydrous), 1.55 g EDC.HCl (8.1 mmol), 1.24 g HOBt. HO (8.1 mmol), and 5.62 mL of collidine (43 mmol) were added. The reaction mixture was stirred for 30 min at RT. 0758 Reaction mixture was diluted with 800 mL DCM and washed with 400 mL of 0.1 NHSO (2x), brine (1x), 0.1 0751. For synthesis of compound 1b, amino 4-arm MNaOH (2x), and 1/1 (v/v) brine/water (4x). Aqueous layers PEG5000 1a (MW ca. 5200 g/mol, 5.20 g, 1.00 mmol, HCl were reextracted with 800 mL of DCM. Organic phases were salt) was dissolved in 20 mL of DMSO (anhydrous). Boc-Lys dried over NaSO filtered and evaporated to give a glassy (Boc)-OH (2.17 g. 6.25 mmol) in 5 mL of DMSO (anhy crude product. US 2016/00821 23 A1 Mar. 24, 2016

(0759 Product was dissolved in DCM and precipitated filtration through a glass filter and washed with 200 mL of with cooled (-18 C.) diethylether. This procedure was cold MTBE. The product was dried in vacuo for 16 h. repeated twice and the precipitate was dried in vacuo. (0776. Yield: 38.9 g (86%) 1c as a white powder 0760. Yield: 4.01 g (89%) colorless glassy product 1d. which was used in the next step without further purification. 0777 MS: m/z 960.1=M+6HI* (calculated=960.2). 0761. MS: m/z 1405.4=M+6H" (calculated=1405.4). 0778 For synthesis of compound 1d, boc-Lys(boc)-OSu 0762 Compound 1e was obtained by stirring a solution of (16.7g, 37.7 mmol) and DIPEA (13.1 mL, 75.4 mmol) were compound 1d (3.96 g., 0.47 mmol) in 7 mL of methanol and 20 added to a Suspension of 1c from the previous step (19.0 g, mL of 4 NHCl in dioxane at RT for 15 min. Volatiles were 3.14 mmol) in 80 ml 2-propanol at 45° C. and the mixture was removed in vacuo. The product was used in the next step stirred for 30 min at 45° C. Subsequently, n-propylamine without further purification. MS: m/z,969.6—M+7H7 (cal (1.56 mL, 18.9 mmol) was added. After 5 min the solution culated=969.7). was precipitated with 600 mL of cold MTBE and centrifuged 0763 For the synthesis of compound 1 f, compound 1e (3000 min', 1 min) The precipitate was dried in vacuo for 1 (3.55g, 0.48 mmol) was dissolved in 20 mL of DMSO (anhy hand dissolved in 400 mL THF.200 mL of diethylether were drous). Boc-Lys(Boc)-OH (5.32g, 15.4 mmol) in 18.8 mL of added and the product was cooled to -30°C. for 16 h without DMSO (anhydrous), EDC HCl (2.76g, 14.4 mmol), HOBt. stirring. The Suspension was filtered through a glass filter and H2O (2.20 g, 14.4 mmol), and 10.0 mL of collidine (76.8 washed with 300 mL cold MTBE. The product was dried in mmol) were added. The reaction mixture was stirred for 60 vacuo for 16 h. min at RT. (0779 Yield: 21.0 g (80%) 1d as a white solid 0764. The reaction mixture was diluted with 800 mL of DCM and washed with 400 mL of 0.1 NHSO (2x), brine 0780 MS: m/z 1405.4=M+6H" (calculated=1405.4). (1x), 0.1 MNaOH (2x), and 1/1 (v/v) brine/water (4x). Aque 0781 Compound 1e was obtained by dissolving com ous layers were reextracted with 800 mL of DCM. Organic pound 1d from the previous step (15.6g, 1.86 mmol) in 3 N phases were dried over NaSO filtered and evaporated to HCl in methanol (81 mL. 243 mmol) and stirring for 90 min give crude product if as colorless oil. at 40°C. 200 ml, of MeOH and 700 mL of iPrOH were added 0765 Product was dissolved in DCM and precipitated and the mixture was stored for 2 hat -30°C. For complete with cooled (-18°C.) diethylther. This step was repeated ness of crystallization, 100 mL of MTBE were added and the twice and the precipitate was dried in vacuo. suspension was stored at -30°C. overnight. 250 mL of cold 0766. Yield: 4.72 g (82%) colourless glassy product if MTBE were added, the suspension was shaken for 1 min and which was used in the next step without further purification. filtered through a glass filter and washed with 100 mL of cold 0767 MS: m/z 1505.3=M+8H (calculated=1505.4). MTBE. The product was dried in vacuo. 0768 Backbone reagent 1 g was obtained by stirring a 0782. Yield: 13.2 g (96%) leas a white powder solution of compound if (MW ca. 12035 g/mol, 4.72 g, 0.39 mmol) in 20 mL of methanol and 40 mL of 4N HCl in dioxane 0783 MS: m/z 679.1=M+10H' (calculated=679.1). at RT for 30 min. Volatiles were removed in vacuo. 0784. For the synthesis of compound 1f, boc-Lys(boc)- 0769 Yield: 3.91 g (100%), glassy product backbone OSu (11.9 g, 26.8 mmol) and DIPEA (9.34 mL, 53.6 mmol) reagent 1g. were added to a suspension of 1e from the previous step. (8.22 (0770 MS: m/z 977.2=M+9H (calculated=977.4). g, 1.12 mmol) in 165 ml 2-propanol at 45° C. and the mixture was stirred for 30 min. Subsequently, n-propylamine (1.47 Alternative Synthetic Route for 1g mL, 17.9 mmol) was added. After 5 min the solution was cooled to -18°C. for 2 h, then 165 mL of cold MTBE were 0771 For synthesis of compound 1b, to a suspension of added, the Suspension was shaken for 1 min and filtered 4-Arm-PEG5000 tetraamine (1a) (50.0 g, 10.0 mmol) in 250 through a glass filter. Subsequently, the filter cake was mL of iPrOH (anhydrous), boc-Lys(boc)-OSu (26.6 g. 60.0 washed with 4x200 mL of cold MTBEAiPrOH 4:1 and 1x200 mmol) and DIPEA (20.9 mL, 120mmol) were added at 45° C. and the mixture was stirred for 30 min. mL of cold MTBE. The product was dried in vacuo for 16 h. 0772 Subsequently, n-propylamine (2.48 mL, 30.0 0785. Yield: 12.8 g., MW (90%) if as a pale yellow lumpy mmol) was added. After 5 min the solution was diluted with solid 1000 mL of MTBE and stored overnight at -20°C. without 0786 MS: m/z 1505.3=M+8H (calculated=1505.4). stirring. Approximately 500 mL of the supernatant were 0787 Backbone reagent 1 g was obtained by dissolving decanted and discarded. 300 mL of cold MTBE (nominal 4ArmPEG5kDa(-LysLys-Lys (boc)) (1f) (15.5 g, 1.29 -20°C.) were added and after 1 min shaking the product was mmol) in 30 mL of MeOH and cooling to 0°C. 4 NHCl in collected by filtration througha (Por. 3) filter and washed with dioxane (120 mL, 480 mmol, cooled to 0°C.) was added 500 mL of cold MTBE. The product was dried in vacuo for 16 within 3 min and the ice bath was removed. After 20 min, 3 N h. HCl in methanol (200 mL, 600 mmol, cooled to 0°C.) was (0773. Yield: 65.6 g (74%) 1b as a white lumpy solid added within 15 minand the solution was stirred for 10 minat 0774 MS: m/z 937.4=M+7H7" (calculated=937.6). room temperature. The product solution was precipitated 0775 Compound 1c was obtained by stirring of com with 480 mL of cold MTBE and centrifuged at 3000 rpm for pound 1b from the previous step (48.8 g., 7.44 mmol) in 156 1 min. The precipitate was dried in vacuo for 1 h and redis mL of 2-propanol at 40°C. A mixture of 196 mL of 2-pro solved in 90 mL of MeCH, precipitated with 240 ml, of cold panol and 78.3 mL of acetylchloride was added under stirring MTBE and the suspension was centrifuged at 3000 rpm for 1 within 1-2 min. The solution was stirred at 40°C. for 30 min min. The product 1 g was dried in vacuo. and cooled to -30°C. overnight without stirring. 100 mL of cold MTBE were added, the suspension was shaken for 1 min 0788 Yield: 11.5 g (89%) as pale yellow flakes. and cooled for 1 h at -30°C. The product was collected by 0789 MS: m/z 1104.9-M+8H (calculated=1104.9). US 2016/00821 23 A1 Mar. 24, 2016 66

Example 2 Synthesis of Crosslinker Reagent 2d 0790 Crosslinker reagent 2d was prepared from adipic acid mono benzyl ester (English, Arthur R. et al., Journal of Medicinal Chemistry, 1990, 33(1), 344-347) and PEG2000 according to the following scheme:

2 O O -- On-OS-1NOH OH 2a in M 45 O DCC, DMAP, DCM

O O

O O 1--N-1NO O

O O 2b s Pol/C, EtOHAcOEt O O

HO O1--N-1N O OH

O O

2C pe. NHS, DCM O O O

N-O O 1-S-1N O O-N

O O O

0791) A solution of PEG 2000 (2a) (11.0 g, 5.5 mmol) and 0794. In a 500 mL glass autoclave PEG2000-bis-adipic benzyl adipate half-ester (4.8 g. 20.6 mmol) in DCM (90.0 acid-bis-benzyl ester 2b (13.3 g, 5.5 mmol) was dissolved in mL) was cooled to 0°C. Dicyclohexylcarbodiimide (4.47 g. ethyl acetate (180 mL) and 10% Palladium on charcoal (0.4 g) was added. The solution was hydrogenated at 6 bar, 40° C. 21.7 mmol) was added followed by a catalytic amount of until consumption of hydrogen had ceased (5-12h). Catalyst DMAP (5 mg) and the solution was stirred and allowed to was removed by filtration through a pad of CeliteR) and the reach room temperature overnight (12 h). The flask was Solvent was evaporated in vacuo. stored at +4°C. for 5h. The solid was filtered and the solvent 0795 Yield: 12.3 g (quantitative) 2c as yellowish oil. The completely removed by distillation in vacuo. The residue was product was used without further purification in the next step. dissolved in 1000 mL 1/l (v/v) diethyl ether?ethyl acetate and 0796 MS: m/z 753.1=M+3H]" (calculated=753.2) stored at RT for 2 hours while a small amount of a flaky solid 0797. A solution of PEG2000-bis-adipic acid halfester 2c was formed. The solid was removed by filtration through a (9.43 g, 4.18 mmol), N-hydroxysuccinimide (1.92 g, 16.7 pad of Celite(R). The solution was stored in a tightly closed mmol) and dicyclohexylcarbodiimide (3.44 g. 16.7 mmol) in flaskat -30°C. in the freezer for 12 huntil crystallisation was 75 ml, of DCM (anhydrous) was stirred over night at room complete. The crystalline product was filtered through a glass temperature. The reaction mixture was cooled to 0°C. and frit and washed with cooled diethyl ether (-30°C.). The filter precipitate was filtered off. DCM was evaporated and the cake was dried in vacuo. residue was recrystallized from THF. 0798 Yield: 8.73 g (85%) crosslinker reagent 2d as color 0792 Yield: 11.6 g (86%) 2b as a colorless solid. The less solid. product was used without further purification in the next step. 0799 MS: m/z 817.8=M+3H (calculated=817.9 0793 MS: m/z. 813.1=M+3M" (calculated=813.3) g/mol). US 2016/00821 23 A1 Mar. 24, 2016 67

Synthesis of 2e 0800 ------e in a 45

0801) 2e was synthesized as described for 2d except for the Example 4 use of glutaric acid instead of adipic acid MS: m/z. 764.4= M+3H (calculated=764.5). Preparation of Maleimide Functionalized Hydrogel Suspension 4 and Determination of Maleimide Example 3 Substitution (0806) Hydrogel 3 was pre-washed with 99/1 (v/v) DMSO/ Preparation of hydrogel beads 3 containing free DIPEA, washed with DMSO and incubated for 45 min with a amino groups solution of Mal-PEG6-NHS (2.0 eq relative to theoretical 0802. A solution of 1200 mg. 1g and 3840 mg2e in 28.6 amount of amino groups on hydrogel) in DMSO. Hydrogel mL DMSO was added to a solution of 425 mg Arlacel P135 were washed five times with DMSO and five times with pH (Croda International Plc) in 100 mL heptane. The mixture 3.0 succinate (20 mM, 1 mM EDTA, 0.01% Tween-20). The was stirred at 650 rpm with a propeller stirrer for 10minat 25° sample was washed three times with pH 6.0 sodium phos C. to form a suspension in a 250 ml reactor equipped with phate (50 mM, 50 mMethanolamine, 0.01% Tween-20) and baffles. 4.3 mLTMEDA was added to effect polymerization. incubated in the same buffer for 1 hat RT. Thenhydrogel was After 2 h, the stirrer speed was reduced to 400 rpm and the washed five times with pH 3.0 sodium succinate (20 mM, 1 mixture was stirred for additional 16 h. 6.6 mL of acetic acid mM EDTA, 0.01% Tween-20) and kept in that buffer to yield were added and then after 10 min 50 mL of water and 50 mL maleimide functionalized hydrogel 4 in suspension. of Saturated aqueous sodium chloride solution were added. (0807 For determination of maleimide content, an aliquot After 5 min, the stirrer was stopped and the aqueous phase of hydrogel 4 was washed three times with water and ethanol was drained. each. The aliquot was dried under reduced pressure and the 0803 For bead size fractionation, the water-hydrogel sus weight of hydrogel in the aliquot was determined. Another pension was wet-sieved on 75, 50, 40, 32 and 20 um mesh aliquot of hydrogel 4 was reacted with excess mercaptoetha steel sieves. Bead fractions that were retained on the 32, 40, nol (in 50 mM sodium phosphate buffer, 30 min at RT), and and 50 Lim sieves were pooled and washed 3 times with water, mercaptoethanol consumption was detected by Ellman test 10 times with ethanol and dried for 16 hat 0.1 mbar to give 3 (Ellman, G. L. et al., Biochem. Pharmacol., 1961, 7, 88-95). as a white powder. A maleimide content of 0.10-0.15 mmol/g dried hydrogel 0804 Amino group content of hydrogel was determined was calculated. by coupling of a fmoc-amino acid to the free amino groups of the hydrogel and subsequent fmoc-determination as Example 5 described by Gude, M.J. Ryfetal. (2002) Letters in Peptide Science 9(4): 203-206. Synthesis of Linker Reagent 5c 0805. The amino group content of 3 was determined to be (0808 Linker reagent 5c was synthesized according to the between 0.11 and 0.16 mmol/g. following scheme:

O O

FinocNsusOH INulls2 N 1N1 NHBoc SE Sl H OtBu OtBu US 2016/00821 23 A1 Mar. 24, 2016 68

-continued SAc

O O SAc insul 1- Modmoc S. O Nulls, 1-N-NH2

OH Sc

Synthesis of 5a hexyl-4-tert-butyl-L-aspartoyl)-ethylenediamine (0.65 g, (0809 Fmoc-L-Asp(OtBu)-OH (1.00g, 2.43 mmol) was 1.30 mmol. 73% over 2 steps) as white solid. dissolved with DCC (0.70 g, 3.33 mmol) in DCM (25 mL, 0814 MS: m/z. 504.27-M+H", (calculated=504.28). anhydrous, mol. sieve). Oxyma pure (0.51 g, 3.58 mmol) and collidine (0.50 mL, 3.58 mmol) were added in one portion 0815 N-boc-N'-(N-6-Acetylthiohexyl-4-tert-butyl-L- and a solution of N-Boc-ethylenediamine (0.41 g, 2.56 mmol) aspartoyl)-ethylenediamine (0.60 g, 1.18 mmol) was dis in DCM (15 mL, anhydrous, mol. sieve) was added slowly. solved in TFA (5 mL) and TES(0.13 mL) and water (0.13 mL) After stirring the mixture for 90 min at RT the formed pre were added. The mixture was stirred for 30 min at RT. TFA cipitate was filtered off and the filtrate washed with 0.1 M was removed in a stream of N, and crude 5b dissolved in HC1. The aqueous layer was extracted with DCM (2x) and the HO/ACN 1:1 and purified by RP-HPLC. combined organic fractions were washed with sat. aqueous 0816 Yield: 0.39 g, 0.85 mmol (TFA salt), 72%. NaHCOs (3x) and brine (1x), dried over NaSO filtered and concentrated in vacuo. The crude solid was purified by flash 0817 MS: m/z 348.25-M+H", (calculated=348.16). chromatography. The intermediate N-boc-N" (N-fmoc-4- tert.-butyl-L-aspartoyl)-ethylenediamine was obtained as a Synthesis of 5c white solid (0.98g, 1.77 mmol, 73%). 0810 MS: m/z 554.29–M+H", (calculated=554.29). 0818 5b (TFA salt, 0.38g, 0.80 mmol) was dissolved in 0811 N-boc-N'-(N-fmoc-4-tert.-butyl-L-aspartoyl)- DMF (5 mL, anhydrous, mol. sieve) and Modmoc-ONp ((5- ethylenediamine (0.98 g, 1.77 mmol) was dissolved in THF methyl-2-oxo-1,3-dioxol-4-yl)-methyl 4-nitrophenyl car (15 mL), DBU (0.31 mL) was added and the solution was bonate, 0.26g, 0.88 mmol) and DIPEA (0.28 mL, 1.6 mmol) stirred for 12 min at RT. The reaction was quenched with were added. The resulting suspension was diluted with DCM AcOH (0.5 ml), concentrated in vacuo and the residue puri (5 mL, anhydrous, mol. sieve) and stirred for 3 hat RT. More fied by flash chromatography to give 5a (0.61 g, 1.77 mmol. DIPEA (0.28 mL 1.6 mmol) was added and stirring continued 73% over 2 steps) as a white solid. for 2 h. DCM was concentrated in vacuo. The residue was 0812 MS: m/z 332.38=M+H", (calculated=332.22). purified by RP-HPLC to give Modmoc-N'-(N-6-acetylthio hexyl-L-aspartyl)-ethylenediamine (0.31 g, 0.62 mmol. 77%) Synthesis of 5b as a colorless oil. 0813 6-Acetylthiohexanoic acid (0.37 g, 1.95 mmol) was 0819 MS: m/z. 504.16—M+H", (calculated=504.17). dissolved in DCM (19.5 mL, anhydrous, mol. sieve) and Oxyma pure (0.35 g, 2.48 mmol) and DCC (0.40 g, 1.95 0820 Modmoc-N" (N-6-acetylthiohexyl-L-aspartyl)- mmol) added in one portion. The solution was stirred for 30 ethylene-diamine (150 mg, 0.30 mmol) was dissolved in min at RT, filtered, and the filtrate added to a solution of 5a DCM (17.5 mL, anhydrous, mol. sieve) and NHS (41 mg, (0.61 g, 1.77 mmol) in DCM (10.5, mL anhydrous, mol. 0.36 mmol), DCC (74 mg. 0.36 mmol) and DMAP (4 mg. 0.03 mmol) were added in one portion. The reaction was sieve). DIPEA (0.46 mL, 2.66 mmol) was added to the solu stirred for 1 h at RT and the resulting suspension filtered. The tion and the reaction stirred for 2 hat RT. The solution was precipitate was washed with a small amount of DCM and the washed with 0.1 MHSO (2x), sat. aqueous NaHCO (2x) combined filtrates were concentrated in vacuo. 5c was puri and brine. The organic layer was dried over NaSO filtered fied by RP-HPLC to give after lyophilization a colorless oil and concentrated in vacuo. The crude material was purified by (144 mg., 0.24 mmol, 80%). MS: m/z. 601.18—M+H", (cal flash chromatography to give N-boc-N'-(N-6-acetylthio culated=601.18). US 2016/00821 23 A1 Mar. 24, 2016 69

Example 6 purified by flash chromatography to give 6b (3.19 g, 4.15 mmol, 83%) as off white solid. MS:m/z. 768.35—M+H+, Synthesis of Linker Reagent 6e (calculated=768.35). 0821 Linker reagent 6e was synthesized according to the 0824) To a solution of 6b (8.59 g, 11.19 mmol) in THF (98 following scheme: mL) DBU (2 mL) was added. The solution was stirred for 12 Boc1 N N-1SN1 Tmob N-Fmoc

H N Tmob

Boc1 n-n- OB

OB 6c

0822. To a solution of N-Boc-ethylenediamine (2.08 g. min at RT, and the solvent was concentrated in vacuo. Flash 12.98 mmol) and NaCNBH (775 mg, 12.33 mmol) in MeOH chromatography afforded 4.89 g 6c (8.96 mmol. 80%). MS: (20 mL, anhydrous) a solution of 2,4,6-trimethoxybenzalde m/Z 546.28-M+1-1+... (calculated=546.28). hyde (2.29 g, 11.68 mmol) in 40 mL anhydrous MeOH/DCM 1/1 (v/v) was added over 2 h via syringe pump. The mixture 0825 6-Tritylmercaptohexanoic acid (2.04 g. 5.22 mmol) was stirred at RT for 90 min, acidified with 0.4 M HCl (60 was dissolved in DCM (20 mL, anhydrous, mol. sieve) and mL) and stirred further 15 min. The reaction mixture was DCC (1.08 g. 5.22 mmol) and Oxyma pure (94.5 mg. 6.65 extracted with ethyl acetate (5x). The combined organic mmol) were added. After 30 min, 6c (2.59 g, 4.75 mmol) and phases were washed with saturated NaHCO and brine and DIPEA (1.24 mL, 7.12 mmol) were added. The reaction dried over NaSO Solvents were removed in vacuo and the mixture was stirred for 22 hat RT. The mixture was extracted residue was dried in high vacuum (<0.1 mbar). Crude N-Boc with 1 N HSO (2x), sat. NaHCO, (2x) and brine. The N'-Tmob-ethylenediamine 6a was used in the next reaction organic phase was dried over Na2SO, concentrated in vacuo step without further purification. Yield: 3.70 g (10.87 mmol. and 6d was purified by flash chromatography. Yield: 4.10 g 84%) of a colorless solid. MS: m/z. 341.21=M+H+, (calcu (4.47 mmol, 94%). MS: m/z. 940.12=M+Na+, (calcu lated=341.21). lated=940.43). 0823. A solution of 6a (1.7g, 4.99 mmol) in DCM (40 ml, anhydrous, mol. sieve) was added to a solution of DCC (1.34 0826. To a solution of 6d (4.10 g, 4.47 mmol) in i-PrOH g, 6.50 mmol). Oxyma pure (995 mg, 7.00 mmol), Fmoc-L- (60 mL), water (20 mL) and LiOH (322 mg, 13.41 mmol) was Asp(OBn)-OH (2.22 g, 4.98 mmol) and collidine (1.24 mL, added and the reaction mixture was stirred for 1 h at RT. 9.53 mmol) in DCM (40 ml, anhydrous, mol. sieve). The Toluene (300 mL) was added and the organic phase was with reaction mixture was stirred for 3 hat RT. The precipitate was 0.1 NHCl and with brine. The organic phase was dried over filtered off and the filtrate was washed with 0.1 M HCl, sat. NaSO filtrated and concentrated in vacuo. 6e was purified NaHCO and brine. Organic phase was dried over NaSO by flash chromatography. Yield: 3.53 g (4.26 mmol. 95%). and solvents were removed in vacuo. The crude material was MS: m/z. 827.93-M+H+, (calculated=828.39). US 2016/00821 23 A1 Mar. 24, 2016 70

Example 7 Synthesis of Linker Reagent 7c 0827. Linker reagent 7c was synthesized according to the following scheme:

H H Boc1 N N-1 n1 Tmob Boc1 N n-1\1 Tmob H Trt N O n-n-n-n- O N1-1-1-sh O O O O

OH OH 6e 7a.

H HN N Tmob 2 N-1NNH Boc1 N-1SN1

AC AC O N1-n-n- O N1-N-N- O O O O O O HNN-1N HN

O O 3. 7c 7b

0828 Linker reagent 6e (420 mg, 0.508 mmol) was dis Example 8 solved in HFIP (9 mL), and acetic acid (0.5 mL) and TES (0.5 mL) were added. The reaction was stirred for 15 minat RT an Synthesis of Linker Maleimide Reagent 8d volatiles were removed in vacuo. 7a was isolated by RP HPLC to give a white substance after lyophilization (216 mg, 0831 Linker maleimide reagent 8d was synthesized 0.369 mmol. 73%). MS: m/z 608.26–M+Na", (calcu according to the following scheme: lated=608.26). 0829. To a solution of 7a (216 mg, 0.369 mmol) in DCM (15 ml, anhydous, mol. sieve) was added triethylamine (257 OH ul, 1.845 mmol), DMAP (45 mg, 0.037 mmol) and acetic boc1 N-non anhydride (140 ul, 1.476 mmol). Reaction mixture was stirred for 40 min. Reaction was quenched with sat. NaHCOs (30 mL) and extracted with DCM (2x). Combined organics were O dried over MgSO and concentrated in vacuo. Residue was O dissolved in DCM (15 mL, anhydrous, mol. sieve). PyBOP boc -N1-nuO 3 OH (384 mg. 0.738 mmol), DIPEA (257 ul, 1.476 mmol) and a O solution of aminoethylmaleimide (TFA salt, 188 mg, 0.738 8a. mmol) in DMF (2 mL) were added. Mixture was stirred for 40 min. Reaction was quenched with acetic acid. Volatiles were removed in vacuo. 7b was purified by RP-HPLC to give a O white substance after lyophilization (154 mg. 0.205 mmol. 56%). MS: m/z. 772.32=M+Nal", (calculated=772.32). HN-n O) 1n 3 OH 0830) 7b (154 mg., 0.205 mmol) was dissolved in 16.2 mL O of a mixture of HFIP/water/TES/TFA 39/1/1/3.3 (v/v/v/v) 8b and stirred for 90 minat RT. Volatiles were removed in vacuo and 7c was purified by RP-HPLC to give a white substance after lyophilization (48 mg, 50%). MS: m/z 470.21=M+H", (calculated=470.21). US 2016/00821 23 A1 Mar. 24, 2016 71

-continued -continued O O 7 O H O N N O Maleimide-PEG: \ 1n 1 N-1- O n-n O 3 OH O O O 8c n^ 16

0838 A solution of co-maleimido-O-methoxy-PEG 750 O O Da (2.25 mg 3 umol) in 0.5 mL PBS buffer containing 0.01% Tween20 is added to a solution of 7 mg GRF (1-29)-Cys in 0.5 mL PBS buffer. The mixture is incubated for 30 min at RT. 9 O n-nO N-nohn- O ^-so O is purified by SEC (Akta Purifier System equipped with a SD75 GL10/300 column, GE Healthcare, running buffer: pH 8d 7.4 PBS containing 0.01% Tween20, flow rate 0.75 ml/min). Example 10 0832 To a solution oft-boc-Amido-dPEG 12-alcohol (1 mmol) in DCM (10 mL, anhydrous, mol. sieve) is added Preparation of linker-GRF(1-29)-Cys-PEG 10b adipic anhydride (2 mmol), DIPEA (4 mmol) and DMAP 0839 Linker-GRF(1-29)-Cys-PEG 10b is prepared from (0.05 mmol). Volatiles are removed in vacuo, the residue is GRF (1-29)-Cys-PEG 9 by amidation reaction with linker dissolved in ACN/water, acidified with acetic acid and 8a is reagent 5c according to the following scheme: purified by RP HPLC. Product containing fractions are pooled and lyophilized. HN-GRF(1-29)-Cys-S-PEG 0833 8a (1 mmol) is dissolved in 10 mL HFIP/TFA 9/1 (v/v) and stirred at RT until complete removal of the boc 9 protecting group. Volatiles are removed in a stream of nitro Sc gen and residue is dissolved in ACN/water and 8b is purified by RPHPLC. Product containing fractions are pooled and lyophilized. 0834 8b (1 mmol) is dissolved in 10 mL ACN/water 9/1 NH (v/v). A solution of 3-(Maleimido)propionic acid N-hydrox y succinimide ester (1 mmol) in ACN (5 mL) is added and the pH is adjusted to pH 6-7.5 by adding 0.1 M phosphate buffer N-GRF(1-29). Cys-s-PEG pH 7.4. After conversion, 8c is purified by RPHPLC. Product SAc NH containing fractions are pooled and lyophilized. 0835 8c (1 mmol) is dissolved in 10 mL DCM (anhy Modmoc drous, mol. sieve). DCC (2 mmol) and HOSu (2 mmol) is N added. After conversion, Volatiles are removed in vacuo and 10a 8d is purified by RP 0836 HPLC. Product containing fractions are pooled and lyophilized.

Example 9 NH Preparation of GRF(1-29)-Cys-PEG 9 N-GRF(1-29)-Cys-s-PEG 0837 GRF(1-29)-Cys-PEG9 is prepared by PEGylation SH NH of GRF(1-29)-Cys via its reactive thiol group according to the following scheme: HN

HN-GRF(1-29)-Cys-SH -- Maleimide-PEG

0840. The reaction scheme depicts an amidation reaction on the N-terminus of the GRF-peptide. It is understood that HN-GRF(1-29)-Cys-S-PEG the amidation reaction can take place at any of the free amino 9 groups of GRF (1-29)-Cys-PEG (i.e. amino terminus or Lys side chains). US 2016/00821 23 A1 Mar. 24, 2016 72

0841 6 mg of Linker reagent 5c is dissolved in 100 uL Example 11 DMSO to yield a concentration of 100 mM. 1 molar equiva lent of linker reagent 5c relative to the amount of GRF(1-29)- Preparation of GRF(1-29)-Cys-linker 11b Cys-PEG is added to a solution of 9 mg GRF(1-29)-Cys-PEG 9 in 2 mL pH 7.4 PBS containing 0.01% Tween20. The reaction is mixed carefully and incubated for 5 min at room 0843 GRF (1-29)-Cys-linker with aminoethyl tag 11b is temperature. Subsequently, further molar equivalents of prepared by reaction with linker reagent 7c according to the linker reagent 5c are added to the Solution in 1 molar equiva following scheme:

GRF (1-29)-Cys-SH s

HN n1n NH

AC O ~~~~ O O O 1N1 NH GRF (1-29)-Cys-S

O 11a

HN N-1NNH O ~~~ O O O

N 1N-NH GRF (1-29)-Cys-S

11b

lent steps and after addition of each equivalent the reaction 0844. A solution of 0.8 mg GRF(1-29)-Cys in 0.2 mL 10 mixture is incubated for 5 min at room temperature, until an mM Citrat pH 6.5, 140 mM NaCl, 0.5 mM EDTA, 0.1% approx. 2/1 mixture (as determined by MS) of unmodified 9 Tween 80 is mixed with linker reagent 7c (4.7 ul of a 100 mM and the protected linker monoconjugate 10a is obtained. solution in DMSO). After 10 min incubation, 10 Jul 2-mer 0842. The pH of the reaction mixture is adjusted to pH 6.5 captoethanol solution (4.7 Jul 2-mercaptoethanol in 1 mL by addition of 1 M sodium citrate, pH 5.0. 0.5 M NH-OH water) is added and incubated for further 15 min. (NH-OH hydrochloride dissolved in 10 mM sodium citrate, 140 mM sodium chloride, 5 mM NaEDTA, adjusted to pH 0845 For removal of acetyl protecting group, 22 Jul of 0.5 6.5 with NaOH) is added to a final concentration of 45 mM M NH-OH (NH-OH hydrochloride dissolved in 10 mM and the deprotection reaction is incubated at room tempera sodium citrate, 140 mM sodium chloride, 5 mM NaEDTA, ture for 4 h yielding the linker-GRF (1-29)-Cys-PEG conju adjusted to pH 6.5 with NaOH) is added. Mixture is incubated gate 10b. The mixture of GRF(1-29)-Cys-PEG 9 and linker for 3 hat RT. 11b is purified/buffer exchanged by SEC (Akta GRF (1-29)-Cys-PEG conjugate 10b is buffer exchanged to Purifier System equipped with a SD75 GL10/300 column, GE pH 7.4 PBS containing 0.01% Tween and the overall concen Healthcare, running buffer: pH 7.4 PBS containing 0.01% tration of the two species is adjusted to 1 mg/mL. The content Tween20, flow rate 0.75 ml/min). Solution is concentrated to of 10b in the mixture is determined by ESI-MS. 300 ul by ultrafiltration.

US 2016/00821 23 A1 Mar. 24, 2016 74

0849 Backbone reagent 12g was synthesized from amino mixture was stirred for 15 min. Then, additional 1.9-bis-boc 4-arm PEG5000 12b according to the following scheme: 1.5.9-triazanonane (0.49 g, 1.5 mmol) was added. After com plete dissolution, the solvent was evaporated at room tem perature. PFP carbonate, DIPEA, DCM; 1.9-bis-boc-15.9-triazanonane 0858. The residue was dissolved in 35 mL iPrCH at 40°C. G125OEP-NH) He and diluted with 200 mL MTBE. The product was precipi HC in MeOH tated over night at -20°C. The precipitate was collected by PEG1250-TAN(Boc) -e- filtration through a glass filter Por. 3, and washed with 200 mL 12b of cooled MTBE (0°C.). The product was dried in vacuo over PFP carbonate, DIPEA, DCM; night to give 12d as a white solid. 1.9-bis-boc-1.59-triazanonane PEG1250-TAN(NH2)24 - -> 0859 Yield 11.6 g (90%) white solid 12d. 12c 0860 MS: m/z 1248.08–IM+7H7" (calculated=1248. HC in MeOH 27). PEG1250-TAN-TAN(Boc) - - 0861) For synthesis of compound 12e, the boc-protected 12d compound 12d (11.4g, 1.31 mmol) was dissolved in 40 mL of PFP carbonate, DIPEA, DCM; 3 M HCl in MeOH and stirred for 20 min at 45° C., then for 1.9-bis-boc-15.9-triazanonane 10 minat35° C. For precipitation, 10 mL MeOH and 200 mL PEG1250-TAN-TAN2(NH3)4] -e- of MTBE were added and the mixture was stored for 16 hat 12e -20°C. The precipitate was collected by filtration through a HC in Dioxane, MeOH glass filter Por. 3 and washed with 200 mL of cooled MTBE PEG1250-TAN-TAN-TAN (Boc) (0° C.). The product was dried in vacuo over night to give 12f white powder 12e. PEG1250-TAN-TAN-TAN (NH)s) 0862 Yield 7.60 g (75%) white powder 12e (HCl salt). 12g 0863 MS: m/z 891.96–M+8H (calculated=892.13). 0864 For synthesis of compound 12f, compound 12e 0850. For synthesis of compound 12b, amino 4-arm (7.56 g. 0.980 mmol, HCl salt) and bis(pentafluorophenyl) PEG5000 (MW ca. 5350 g/mol, 10.7g, 2.00 mmol, HCl salt) carbonate (9.27g, 23.0 mmol) were dissolved in 250 mL of and bis(pentafluorophenyl)carbonate (4.73 g, 12.0 mmol) DCM (anhydrous) and DIPEA (6.08g, 47.0 mmol, 8.19 mL) were dissolved in 43 mL of DCM (anhydrous) and DIPEA was added at 35° C. After 10 min, 1.9-bis-boc-1.5.9-triaza (3.10g, 24.0 mmol. 4.18 mL) was added at room temperature. nonane (5.30 g, 16.0 mmol) was added and the mixture was After 10 min, 1.9-bis-boc-1.5.9-triazanonane (5.30 g, 16.0 stirred for 15 min. Then additional 1.9-bis-boc-15.9-triaza mmol) was added and the mixture was stirred for 15 min. nonane (0.33 g, 1.0 mmol) was added. After complete disso Then additional 1.9-bis-boc-1.5.9-triazanonane (0.33 g, 1.0 lution, the solvent was evaporated at room temperature. mmol) was added. After complete dissolution, the reaction 0865. The residue was dissolved in 250 mL iPrOH at 60° mixture was filtered and the solvent was evaporated at room C. and diluted with 1350 mL MTBE. The product was pre temperature. cipitated over night at -20°C. The precipitate was collected 0851. The residue was dissolved in 40 mL iPrOH and by filtration through a glass filter Por. 3, and washed with 400 diluted with 320 mL MTBE. The product was precipitated mL of cooled MTBE (0°C.). The product was dried in vacuo over night at -20°C. The precipitate was collected by filtra over night to give 12f as a glassy Solid. tion through a glass filter Por. 3, and washed with 200 mL of cooled MTBE (0° C.). The product was dried in vacuo over 0866. Yield 11.1 g (83%) glassy solid 12f. night. 0867. MS: m/z 1312.01=IM+10H (calculated=1312. 0852. Yield 11.1 g (83%) white solid 12b. 21). 0853 MS: m/z. 1112.86–M+6H" (calculated=1113. 0868 For synthesis of backbone reagent 12g, the boc 04). protected compound 12f(7.84g, 0.610 mmol) was dissolved 0854 For synthesis of compound 12c, the boc-protected in 16 mL of MeOH at 37° C. and 55 mL of a precooled compound 12b (11.1 g, 1.66 mmol) was dissolved in 40 mL of solution of 4 M HCl (4°C.) in dioxane was added at room 3 M HCl in MeOH and stirred for 20 min at 45° C., then for temperature. The mixture was stirred without cooling for 20 10 min at 55° C. For precipitation, 10 mL MeOH and 200 mL min. After 20 min, 110 mL of 3M HCl in MeOH was added. of MTBE were added and the mixture was stored for 16 hat The solution was partitioned in 24 Falcon tubes (50 mL) and -20°C. The precipitate was collected by filtration through a precipitated with by adding 40 mL cold MTBE (-20°C.) to glass filter Por. 3 and washed with 200 mL of cooled MTBE each Falcon tube. After centrifugation at 3214 rcf for 1 min, (0° C.). The product was dried in vacuo over night. the Supernatant was decanted and the glassy Solid was dis 0855. Yield 9.14 g (89%) white powder 12c (HCl salt). solved in 5 mL MeoH per Falcon tube and precipitated by 0856. MS: m/z 979.45=M+6HI* (calculated=979.55). adding 40 mL cold MTBE (-20° C.) to each Falcon tube 0857 For synthesis of compound 12d, compound 12c again. The Supernatant was discarded and the remaining Solid (9.06 g, 1.47 mmol, HCl salt) and bis(pentafluorophenyl) was dried in vacuo over night. carbonate (6.95 g, 17.6 mmol) were dissolved in 50 mL of DCM (anhydrous) and DIPEA (4.56 g., 35.3 mmol, 6.15 mL) 0869. Yield 5.74 g (87%) white glassy solid 12g (HCl was added at room temperature. After 10 min, 1.9-bis-boc-1, salt). 5.9-triazanonane (7.80 g, 23.5 mmol) was added and the 0870 MS: m/z 965.46-M+10H'(calculated=965.45). US 2016/00821 23 A1 Mar. 24, 2016 75

Example 13 and mixture was stirred at room temperature overnight. The resulting Suspension was cooled to 0°C. and the Solid was Synthesis of Crosslinker Reagents 13d, 13.g. 13k, filtered off. The solvent was evaporated in vacuo. and 13o 0876. The residue was dissolved in 65 mL dichlo 0871 Crosslinker reagent 13e was prepared from azelaic romethane and diluted with 308 mL MTBE at room tempera acid monobenzyl ester and PEG10000 according to the fol ture. The mixture was stored over night at -20°C. The pre lowing scheme: cipitate was collected by filtration through a glass filter Por. 3,

O O

O --~~ OH -- to-ha- pi -n OH

13a pcc. DMAP, DCM

13b s Pd/C, MeOAc O O O O

HO ---7 O 1n--npi O ---7 OH 13c St. DIPEA, DCM O O O O O O N s-s-s 1nu--npi O ---1 no N O O 13

0872 For the synthesis of azelaic acid monobenzyl ester and washed with 250 mL of cooled MTBE (-20° C.). The 13a, a mixture of azelaic acid (37.6 g. 200 mmol), benzyl product was dried in vacuo over night. alcohol (21.6 g. 200 mmol), p-toluenesulfonic acid (0.80 g, 0877. Yield 40.8 g. (97%) white powder 13b. 4.2 mmol), and 240 mL toluene was refluxed for 7 h in a 0878 MS: m/z835.50-M+14HI''' (calculated=835.56). Dean-Stark apparatus. After cooling down, the solvent was 0879 For synthesis of compound 13c, compound 13b evaporated and 300 mL sat. aqueous NaHCO solution were (40.6 g. 3.86 mmol) was dissolved in methylacetate (250 mL) added. This mixture was extracted with 3x200 mL MTBE. and 203 mg of palladium on charcoal was added. Under a The combined organic phases were dried over NaSO and hydrogen atmosphere of ambient pressure, the mixture was the solvent was evaporated. The product was purified on stirred overnight at room temperature. The reaction mixture 2x340 g silica using ethyl acetate?heptane (10:90->25:75) as was filtered through a pad of celite and the filtrate was evapo eluent. The eluent was evaporated and the residue was dried in rated and dried in vacuo over night. vacuo over night. 0880. Yield 37.2 g (93%) glassy solid 13c. 0873. Yield 25.8 g (46%) colorless oil 13a. 0881. MS: m/z 882.53-M+13H]''' (calculated=882.51). 0874) MS: m/z 279.16=M+H" (calculated=279.16). 0882. For synthesis of compound 13d, compound 13c 0875 For synthesis of compound 13b, azelaic acid (32.0 g, 3.10 mmol) and TSTU (3.73 g, 12.4 mmol) were monobenzyl ester 13a (3.90 g, 14.0 mmol) and PEG 10000 dissolved in 150 mL dichloromethane at room temperature. (40.0 g, 4.00 mmol) were dissolved in 64 mL dichlo Then DIPEA (1.60 g, 12.4 mmol) was added and the mixture romethane and cooled with an ice bath. A solution of DCC was stirred for 1 h. The resulting suspension was filtered and (2.89 g, 14.0 mmol) and DMAP (0.024g, 0.020 mmol) in 32 the filtrate was diluted with 170 mL dichloromethane, washed mL dichloromethane was added. The ice bath was removed with 140 mL of a solution of 750 g water/197 g NaC1/3 g US 2016/00821 23 A1 Mar. 24, 2016 76

NaOH. The organic phase was dried over MgSO and the resulting Suspension was cooled to 0°C. and the Solid was Solvent was evaporated in vacuo. filtered off. The solvent was evaporated in vacuo. 0883. The residue was dissolved in 200 mL toluene, 0888. The residue was dissolved in 70 mL dichlo diluted with 180 mL MTBE at room temperature and stored romethane and diluted with 300 mL MTBE at room tempera over night at -20°C. The precipitate was collected by filtra ture. The mixture was stored over night at -20°C. The pre tion through a glass filter Por. 3, and washed with 100 mL of cipitate was collected by filtration through a glass filter Por. 3, cooled MTBE (-20°C.). The product was dried in vacuo over and washed with 500 mL of cooled MTBE (-20° C.). The night. product was dried in vacuo over night. 0884 Yield 28.8 g (88%) white powder 13d. 0889 Yield: 41.2 g (95%) white powder 13e. 0885 MS: m/z 795.47=M+15H'(calculated=795.54). 0890 MS: m/z 833.75-M+8H (calculated=833.74). 0886 Crosslinker reagent 13g was prepared from azelaic 0891. For synthesis of compound 13f, compound 13e acid monobenzyl ester and PEG6000 according to the follow (41.2g, 6.32 mmol) was dissolved in methylacetate (238 mL) ing scheme: and ethanol (40 mL), then 400 mg of palladium on charcoal

O O

O --~~ OH + HO -ha-u-npi OH - 135

13a

DCC, DMAP, DCM

13e

H2, Pd/C, MeOAc

HO ---... O 1N-"Nunpi O ... O

TSTU, DIPEA, DCM

O O O O O O

n N O ---... O 1N-"N-pi O O1 N O 7 O 13g

0887. For synthesis of compound 13e, azelaic acid was added. Under a hydrogen atmosphere of ambient pres monobenzyl ester 13a (6.50g, 23.3 mmol) and PEG 6000 Sure, the mixture was stirred overnight at room temperature. (40.0 g. 6.67 mmol) were dissolved in 140 mL dichlo The reaction mixture was filtered through a pad of celite and romethane and cooled with an ice bath. A solution of DCC the filtrate was evaporated and dried in vacuo over night. (4.81 g, 23.3 mmol) and DMAP (0.040 g, 0.33 mmol) in 40 mL dichloromethane was added. The ice bath was removed (0892 Yield 38.4 g (96%) glassy solid 13f. and mixture was stirred at room temperature overnight. The 0893 MS: m/z 750.46-M+9H (calculated=750.56). US 2016/00821 23 A1 Mar. 24, 2016 77

0894 For synthesis of compound 13.g., compound 13f 0899 For the synthesis of isopropylmalonic acid (38.2g, 6.02 mmol) and TSTU (7.25 g, mmol) were dissolved monobenzyl ester rac-13h, isopropylmalonic acid (35.0 g, in 130 mL dichloromethane at room temperature. Then 239 mmol), benzyl alcohol (23.3 g 216 mmol) and DMAP DIPEA (3.11 g, 24.1 mmol) was added and the mixture was (1.46g, 12.0 mmol) were dissolved in 100 mL acetonitrile. stirred for 1 h. The resulting suspension was filtered, the Mixture was cooled to 0°C. with an ice bath. A solution of filtrate was diluted with 100 mL dichloromethane and washed DCC (49.4g, 239 mmol) in 150 mL acetonitrile was added with 200 mL of a solution of 750 g water/197 g NaCl/3 g within 15 min at 0°C. The ice bath was removed and the NaOH. The organic phase was dried over MgSO and the reaction mixture was stirred over night at room temperature, Solvent was evaporated in vacuo. then the solid was filtered off. The filtrate was evaporated at 0895. The residue was dissolved in 210 mL toluene, diluted with 430 mL MTBE at room temperature and stored 40° C. in vacuo and the residue was dissolved in 300 mL over night at -20°C. The precipitate was collected by filtra MTBE. This solution was extracted with 2x300 mL sat. aque tion through a glass filter Por. 3, and washed with 450 mL of ous NaHCO Solution, then the combined aqueous phases cooled MTBE (-20°C.). The product was dried in vacuo over were acidified to pH=1-3 using 6 N hydrochloric acid. The night. resulting emulsion was extracted with 2x300 mL MTBE and (0896. Yield 35.8 g (91%) white powder 13.g. the solvent was evaporated. The combined organic phases 0897 MS: m/z 857.51=M+8H (calculated=857.51). were washed with 200 mL sat. aqueous NaCl and dried over 0898 Crosslinker reagent 13k was prepared from isopro MgSO. The product was purified on 340 g silica using ethyl pylmalonic acid monobenzyl ester and PEG10000 according acetate?heptane (10:90->20:80) as eluent. The eluent was to the following scheme: evaporated and the residue was dried in vacuo over night.

O OH -- to-ha- pi -n.OH in N 226

rac-13h DCC, DMAP, DCM th rac-13i

H2, Pd/C, MeOAc

HO 1N-'s--

TSTU, DIPEA, DCM US 2016/00821 23 A1 Mar. 24, 2016

0900 Yield: 9.62 g (17%) colorless oil rac-13h. overnight at room temperature. The reaction mixture was 0901 MS: m/z 237.11=M+H (calculated=237.11). filtered through a pad of celite and the filtrate was evaporated 0902 For synthesis of compound 13i, isopropylmalonic and dried in vacuo over night. acid monobenzyl ester rac-13h (94.5 mg. 4.00 mmol) and (0908. Yield: 3.25 g (98%) glassy solid 13. PEG 10000 (10.0 g, 4.00 mmol) were dissolved in 20 mL (0909 MS: m/z 731.25-M+16H" (calculated=731.25). dichloromethane and cooled with an ice bath. A solution of 0910 For synthesis of compound 13k, compound 13 DCC (825 mg, 4.00 mmol) and DMAP (6 mg, 0.05 mmol) in (3.10 g, 0.302 mmol) and TSTU (0.364g, 1.21 mmol) were 10 mL dichloromethane was added. The ice bath was dissolved in 15 mL dichloromethane at room temperature. removed and mixture was stirred at room temperature over Then DIPEA (0.156g, 1.21 mmol) was added and the mixture night. The resulting Suspension was cooled to 0°C. and the was stirred for 45 min. The resulting suspension was filtered solid was filtered off. The solvent was evaporated in vacuo. and the filtrate was washed with 2x10 mL of a 0.5 M phos 0903. The residue was dissolved in 20 mL dichlo phate buffer pH=6.5. The organic phase was dried over romethane and diluted with 150 mL MTBE at room tempera MgSO and the solvent was evaporated in vacuo. The residue ture. The mixture was stored over night at -20°C. The pre was dissolved in 20 mL toluene, diluted with 10 mL MTBE at cipitate was collected by filtration through a glass filter Por. 3, room temperature and stored over night at -20°C. The pre and washed with 500 mL of cooled MTBE (-20°C.). cipitate was collected by filtration through a glass filter Por. 3, 0904. The product was dried in vacuo over night. and washed with 250 mL of cooled MTBE (-20° C.). The (0905 Yield: 9.63 g (92%) white powder 13i. product was dried in vacuo over night. 0906 MS: m/z. 742.50-M+16H" (calculated=742.51). (0911. Yield: 2.66 g (84%) white powder 13k. 0907 For synthesis of compound 13, compound 13i (3.38 0912 MS: m/z. 743.37=M+16H" (calculated=743.38). g, 0.323 mmol) was dissolved in methyl acetate (100 mL) and 0913 Crosslinker reagent rac-13o was prepared from cis 105 mg of palladium on charcoal was added. Under a hydro 1,4-cyclohexanedicarboxylic acid and PEG10000 according gen atmosphere of ambient pressure, the mixture was stirred to the following scheme:

OH 1N- -n in M 226

rac-13 DCC, DMAP, DCM

O t

rac-13m

H2, Pd/C, MeOAc

O O

sh-'--O pi O HO OH

O rac-13n

TSTU, DIPEA, DCM US 2016/00821 23 A1 Mar. 24, 2016 79

-continued O O

O O1N--n pi O O -' 'n O O O O rac-13o

0914 For the synthesis of cis-1,4-cyclohexanedicarboxy and the filtrate was washed with 2x10 mL of a 0.5 M phos lic acid monobenzyl ester rac-131, cis-1,4-cyclohexanedicar phate buffer pH=6.5. The organic phase was dried over boxylic acid (20.0 g, 116 mmol), benzyl alcohol (11.3 g, 105 MgSO and the solvent was evaporated in vacuo. mmol) and DMAP (710 mg, 5.81 mmol) were dissolved in 0925. The residue was dissolved in 50 mL toluene, diluted 200 mL THF. Mixture was cooled to 0°C. with an ice bath. A with 25 mL MTBE at room temperature and stored over night solution of DCC (49.4g, 239 mmol) in 100 mL THF was at -20°C. The precipitate was collected by filtration through added within 15 min at 0°C. The ice bath was removed and a glass filter Por. 3, and washed with 400 mL of cooled MTBE the reaction mixture was stirred over night at room tempera (-20°C.). The product was dried in vacuo over night. ture, then the solid was filtered off. The filtrate was evaporated 0926 Yield: 7.62 g (84%) white powder 13O. at 40° C. and the residue was dissolved in 300 mL MTBE. 0927. MS: m/z 702.60–M+16H" (calculated=702.59). This solution was extracted with 2x300 mL sat. aqueous NaHCO solution, then the combined aqueous phases were Example 14 acidified to pH=1-3 using 6 N hydrochloric acid. The result 0928 Preparation of hydrogel beads 14a, 14b, 14c, and ing emulsion was extracted with 2x300 mL MTBE and the 14d containing free amino groups. In a cylindrical 250 mL Solvent was evaporated. The combined organic phases were reactor with bottom outlet, diameter 60 mm, equipped with washed with 200 mL sat. aqueous NaCl and dried over baffles, an emulsion of 218 mg CithrolTM DPHS in 100 mL MgSO. The product was purified on 340 g silica using ethyl undecane was stirred with an isojet stirrer, diameter 50 mm at acetate?heptane (10:90->20:80) as eluent. The eluent was 580 rpm, at ambient temperature. A solution of 250 mg 12a evaporated and the colorless oily residue crystallized during and 2205 mg 13d in 22.1 g DMSO was added and stirred for drying in vacuo over night. 10 min at RT to form a suspension. 1.1 mL TMEDA were (0915 Yield: 4.82 g (16%) colorless crystals rac-131. added to effect polymerization. The mixture was stirred for 16 (0916 MS: m/z 263.13-M+H" (calculated=263.13). h. 1.7 mL of acetic acid were added and then after 10 min 100 0917 For synthesis of compound 13m, cis-1,4-cyclohex mL of a 15 wt % solution of sodium chloride in water was anedicarboxylic acid monobenzyl ester rac-21 (2.10 g, 8.00 added. After 10 min, the stirrer was stopped and phases were mmol) and PEG 10000 (20.0g, 10.0 mmol) were dissolved in allowed to separate. After 2 h the aqueous phase containing 50 mL dichloromethane and cooled with an ice bath. A solu the hydrogel was drained. tion of DCC (1.65 g, 8.00 mmol) and DMAP (0.012 g, 0.10 0929. For bead size fractionation, the water-hydrogel sus mmol) in 25 mL dichloromethane was added. The ice bath pension was diluted with 40 mL ethanol and wet-sieved on was removed and mixture was stirred at room temperature 125, 100, 75, 63, 50, 40, and 32 um steel sieves using a Retsch overnight. The resulting Suspension was cooled to 0°C. and AS200 control sieving machine for 15 min. Sieving ampli the solid was filtered off. The solvent was evaporated in tude was 1.5 mm, waterflow 300 mL/min. Bead fractions that WaClO. were retained on the 63 and 75 um sieves were pooled and (0918. The residue was dissolved in 55 mL dichlo washed 3 times with 0.1% AcOH, 10 times with ethanol and romethane and diluted with 300 mL MTBE at room tempera dried for 16 h at 0.1 mbar to give 670 mg of 14a as a white ture. The mixture was stored over night at -20°C. The pre powder. cipitate was collected by filtration through a glass filter Por. 3, 0930 Amino group content of the hydrogel was deter and washed with 250 mL of cooled MTBE (-20° C.). The mined to be 0.145 mmol/gby conjugation of a fmoc-amino product was dried in vacuo over night. acid to the free amino groups on the hydrogel and Subsequent (0919. Yield: 18.2 g (87%) white powder 13m. fmoc-determination. 0920 MS: m/z. 745.76–M+16H (calculated=745.77). 0931. 14b was prepared as described for 14a except for the 0921 For synthesis of compound 13n, compound 13m use of 350 mg 12a, 2548 mg 13.g. 26.1 g DMSO, 257 mg (9.00 g, 0.857 mmol) was dissolved in methyl acetate (100 CithrolTM DPHS, 1.5 mL TMEDA, and 2.4 mL acetic acid, mL) and 157 mg of palladium on charcoal was added. Under yielding 550 mg 14b as a white powder, free amino groups a hydrogen atmosphere of ambient pressure, the mixture was 0.120 mmol/g. stirred overnight at room temperature. The reaction mixture 0932) 14c was prepared as described for 14a except for the was filtered through a pad of celite and the filtrate was evapo use of 250 mg 12a, 3019 mg rac-13k, 32.7 g DMSO, 290 mg rated and dried in vacuo over night. CithrolTM DPHS, 1.1 mL ml TMEDA, and 1.7 mL acetic acid, 0922 Yield: 8.83g (100%) glassy solid 13n. yielding 770 mg 13c as a white powder, free amino groups 0923 MS: m/z. 734.50-M+16H (calculated=734.50). 0.126 mmol/g. 0924 For synthesis of compound 13o, compound 13n 0933) 14d was prepared as described for 14a except for the (8.92 g, 0.864 mmol) and TSTU (1.04 g., 3.64 mmol) were use of 250 mg 12a, 2258 mg rac-13o, 22.6 g DMSO, 222 mg dissolved in 35 mL dichloromethane at room temperature. CithrolTM DPHS, 1.1 mL ml TMEDA, and 1.7 mL acetic acid, Then DIPEA (0.447g, 3.46 mmol) was added and the mixture yielding 186 mg 14d as a white powder, free amino groups was stirred for 45 min. The resulting suspension was filtered 0.153 mmol/g. US 2016/00821 23 A1 Mar. 24, 2016 80

Example 15 Example 16 Preparation of Maleimide Functionalized Hydrogel Preparation of Linker Maleimide Functionalized Beads 15 Hydrogel Beads 16 0934, 259.3 mg of dry hydrogel beads 14a was incubated 0935 259.3 mg of dry hydrogel beads 14a are incubated for 15 min in 10 mL 1% n-propylamine in NMP and subse for 15 min in 10 mL 1% n-propylamine in NMP and subse quently washed five times with NMP and two times with 2% quently washed five times with NMP and two times with 2% DIPEA in NMP 171 mg of Mal-NH-PEG12-PFE was dis DIPEA in NMP 169 mg of linker maleimide reagent 8d is solved in 1 mL NMP and added to the washed hydrogel beads dissolved in 1 mL NMP and added to the washed hydrogel 14a. The hydrogel Suspension was incubated for 2 hat room beads 14a. The hydrogel suspension is incubated for 2 hat temperature. Resulting maleimide functionalized hydrogel room temperature. Resulting maleimide functionalized beads 15 were washed five times each with NMP 20 mM hydrogel beads 16 are washed five times each with NMP 20 succinate, 1 mM NaFDTA, 0.01% Tween20, pH 3.0, water, mM succinate, 1 mM NaEDTA, 0.01% Tween20, pH 3.0, and with 0.1% acetic acid, 0.01% Tween20. water, and with 0.1% acetic acid, 0.01% Tween20.

O O 7 O N O N Hydrogel N- N-1-on- 3 O1 H2N O O O O 8d 14a | O / O H N N O

N- N-1-1N- 3 N-HydrogelH O O O 16

Example 17 Synthesis of Transient hydrogel-linker-GRF(1-29)-Cys-PEG Prodrug 17 0936) 1.5 mg of linker-GRF(1-29)-Cys-PEG 10b in pH 7.4 PBS containing 0.01% Tween20 are added to 5 mg of maleimide functionalized hydrogel beads 15 and incubated overnight at room temperature yielding transient hydrogel linker-GRF-(1-29)-Cys-PEG prodrug 17. Hydrogelbeads are washed several times with pH 7.4 PBS containing 0.01% Tween2O.

NH

HS hydrogel-N N-GRF(-29). Cys-s-PEG NH

HN 15 1Ob US 2016/00821 23 A1 Mar. 24, 2016

-continued O

NH O O S O N-GRF(1-29)-Cys-S-PEG hydrogel-N H NH

HN 17

Example 18 Synthesis of Transient GRF (1-29)-Cys-Linker-Hydrogel Prodrug 18 0937 1.5 mg of GRF(1-29)-Cys-linker with aminoethyl tag 11b in pH 7.4 PBS containing 0.01% Tween 20 are added to 5 mg of maleimide functionalized hydrogel beads 15 and incubated overnight at room temperature yielding transient GRF (1-29)-Cys-linker-hydrogel prodrug 18. Hydrogel beads are washed several times with pH 7.4 PBS containing 0.01% Tween20.

HN N-1NN H O N

O O ~~~ N-hydrogelydrog O O

N 1N-NH O GRF(1-29)-Cys-S

O 11b 15

HN N-1NNH H N O ~~~ O N-hydrogel O O 1N1 NH O GRF(1-29)-Cys-S

O 18 US 2016/00821 23 A1 Mar. 24, 2016 82

Example 19 Synthesis of Transient GRF(1-29)-Cys-PEG-linker-hydrogel Prodrug 19 0938 1.5 mg of GRF(1-29)-Cys in pH 7.4 PBS containing 0.01% Tween20 are added to 5 mg of maleimide functional ized hydrogel beads 16 and incubated overnight at room temperature yielding transient GRF(1-29)-Cys-PEG-linker hydrogel prodrug 19. Hydrogel beads are washed several times with pH 7.4 PBS containing 0.01% Tween20.

O O GRF(1-29)-Cys-SH 7 H N N O

N- N-1-1N- 3 N-HydrogelH O O O 16

O O GRF(1-29)-Cys-S H N N O

N- N-1-1N- 3 N-HydrogelH O O O 19

Example 20 aforementioned buffer. The suspension is incubated at 37°C. The buffer of the suspension is exchanged after different time In Vitro Release Kinetics—Determination of In Vitro intervals and analyzed by HPLC-SEC at 220 nm. Peaks cor Half-Life responding to the respective liberated tagged GRF (1-29)-Cys (see scheme below) are integrated and the total of liberated 0939 GRF(1-29)-Cys-hydrogel prodrugs 17, 18 and 19 tagged GRF(1-29)-Cys is plotted against total incubation respectively are washed five times with pH 7.4 PBS buffer time. Curve fitting software is applied to determine first-order containing 0.01% Tween20, and suspended in 1 mL of the cleavage rates.

17 pH 7.4 incubation

NH

hydrogel-N HN-Cys-GRF(1-29)-S-PEG N

HN US 2016/00821 23 A1 Mar. 24, 2016 83

-continued 18 t 7.4 incubation

O O H NH HN N 1N1 2 12 n1n GRF (1-29)-Cys-S N ~~~ O N-hydrogel O

O 19

7.4 incubation

O O GRF(1-29)-Cys-S N N- N- O1-N- HO 3 N-hydrogeliny 9. O O O

ABBREVIATIONS O969 MeOAc methyl acetate MeOH methanol 0940 Ac acetyl 0970) 0941 ACN acetonitrile 0971 Mmt 4-methoxytrityl 0942 AcOHacetic acid 0972 Modmoc (5-methyl-2-oxo-1,3-dioxol-4-yl)-methy 0943 AcOEt ethyl acetate loxycarbonyl 0944 Asp aspartate 0973 MS mass spectrum/mass spectrometry 0945 Bn benzyl 0974 MTBE methyl tert-butyl ether 0946 Boc t-butyloxycarbonyl 0975 MW molecular mass 0947 DBU 1,3-diazabicyclo5.4.0]undecene 0976 NHS N-hydroxy succinimide 0948 DCC N,N-dicyclohexylcarbodiimid 0977. Oxyma Pure ethyl 2-cyano-2-(hydroxyimino)ac 0949 DCM dichloromethane etate 0950 DIPEA diisopropylethylamine 0978 PEG poly(ethylene glycol) 0951 DMAP dimethylamino-pyridine 0979 PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino 0952 DMF N,N-dimethylformamide phosphonium hexafluorophosphate 0953 DMSO dimethylsulfoxide 0980 RP-HPLC reversed-phase high performance liquid 0954 DTT DL dithiotreitol chromatography 0955 EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodi 0981 rpm rounds per minute imid 0982 RT room temperature 0956 EDTA ethylenediaminetetraacetic acid 0983 SEC size exclusion chromatography 0957) eq Stoichiometric equivalent 0984 tEu tert-butyl 0958 EtOH ethanol 0985 TAN 15.9-triazanonane 0959 Fmoc 9-fluorenylmethoxycarbonyl 0986 TCEP tris(2-carboxyethyl)phosphine hydrochlo 0960| HFIP 1,1,1,3,3,3-hexafluoroisopropanol ride 0961 HPLC high performance liquid chromatography 0987 TES triethylsilane 0962 HOBt N-hydroxybenzotriazole 0988 TFA trifluoroacetic acid 0963 iPrOH 2-propanol 0989 THF tetrahydrofurane 0964 LCMS mass spectrometry-coupled liquid chroma 0990 TMEDANN,N',N'-tetramethylethylene diamine tography 0991 Tmob 2,4,6-trimethoxybenzyl 0965. Mal 3-maleimido propyl 0992 Trt triphenylmethyl, trityl 0966 Mal-NH-PEG12-PFE N-(3-maleimidopropionyl)- 0993 TSTU O-(N-succinimidyl)-N,N,N',N'-tetram 39-amino-4,7,10,13,16,19,22.25.28.31,34.37-dodecaoxa ethyluronium tetrafluoroborate nonatriacontanoic acid pentafluorophenyl ester 0994 UPLC ultra performance liquid chromatography 0967 Mal-PEG6-NHS N-(3-maleimidopropionyl)-21 0995 V volume amino-4,7,10,13,16,19-hexaoxa-heneicosanoic acid NHS 1. A process for the preparation of a hydrogel-linked pro ester drug releasing a tag moiety-biologically active moiety con 0968 Me methyl jugate comprising the steps of US 2016/00821 23 A1 Mar. 24, 2016

(a) providing a mixture comprising in a weight ratio of the at least one backbone reagent to (a-i) at least one backbone reagent, wherein the at least one the at least one crosslinker reagent ranging from 1:99 to backbone reagent has a molecular weight ranging from 99:1 and wherein the molar ratio of A" to functionalend 1 to 100 kDa, and comprises at least three functional groups is >1; groups A", wherein each A' is an amine ( NH or (b) polymerizing the mixture of step (a) to a hydrogel; —NH ), hydroxyl ( OH), carboxyl ( COOH) or (c) optionally covalently conjugating a spacer reagent of activated carboxyl ( COY", wherein Y is selected formula (VI) from formulas (fi) to (f-vi): AXISP2-AX2 (VI), wherein SP is Clso alkyl, Clso alkenyl or Clso alkynyl, which (f-i) Clso alkyl, C-soalkenyl and Clso alkynyl is option ally interrupted by one or more group(s) selected from the group consisting of —NH , —N(C. alkyl)-. —O— —S, —C(O)— —C(O)NH, —C(O)N(C. alkyl)-, —O—C(O)— —S(O)— —S(O). , 4- to 7-membered heterocyclyl phenyl and naphthyl; (f-ii) A' is a functional group for reaction with A' of the hydrogel; and A' is a functional group; to A" of the hydrogel from step (b); and (d) covalently conjugating (d-i) a reversible prodrug linker reagent to A' or A' of the hydrogel of step (b) or (c), respectively, resulting in a reversible prodrug linker moiety conjugated to the (f-iii) hydrogel of step (b) or (c), followed by covalent con jugation of a drug to said reversible prodrug linker moiety resulting in a reversible prodrug linker moi ety-biologically active moiety conjugate conjugated to the hydrogel of step (b) or (c), followed by covalent conjugation of a tag reagent to the biologically active moiety resulting in a reversible prodrug linker moi (fiv) ety-biologically active moiety-tag moiety conjugate conjugated to the hydrogel of step (b) or (c); or (d-ii) a reversible prodrug linker reagent to A' or A* of the hydrogel of step (b) or (c), respectively, resulting in a reversible prodrug linker moiety conjugated to the hydrogel of step (b) or (c), followed by covalent con jugation of a biologically active moiety-tag moiety conjugate reagent to said reversible prodrug linker moiety through a functional group of the biologically active moiety resulting in a reversible prodrug linker moiety-biologically active moiety-tag moiety conju gate conjugated to the hydrogel of step (b) or (c); or (d-iii) a reversible prodrug linker moiety-biologically active moiety conjugate reagent to A" or A' of the hydrogel of step (b) or (c), respectively, through a (f-vi) functional group of the reversible prodrug linker moi ety, followed by covalent conjugation of a tag reagent to said biologically active moiety; or (d-iv) a reversible prodrug linker moiety-biologically active moiety-tag moiety conjugate reagent to A" or A° of the hydrogel of step (b) or (c), respectively, wherein through a functional group of the reversible prodrug linker moiety; or the dashed lines indicate attachment to the rest of the (d-v) a reversible prodrug linker reagent to A' or A* of molecule, the hydrogel of step (b) or (c), respectively, resulting b is 1, 2, 3 or 4 in a reversible prodrug linker moiety conjugated to the hydrogel of step (b) or (c), followed by covalent con X is C1, Br, I, or F); jugation of a tag reagent to said reversible prodrug (a-ii) at least one crosslinker reagent, wherein the at least linker moiety resulting in a reversible prodrug linker one crosslinker reagent has a molecular weight ranging moiety-tag moiety conjugate conjugated to the hydro from 0.2 to 40 kDa and comprises at least two functional gel of step (b) or (c), followed by covalent conjugation end groups selected from the group consisting of acti of a drug to said tag moiety resulting in a reversible vated ester groups, activated carbamate groups, acti prodrug linker moiety-tag moiety-biologically active vated carbonate groups, activated thiocarbonate groups moiety conjugate conjugated to the hydrogel of step and amine groups: (b) or (c); or US 2016/00821 23 A1 Mar. 24, 2016 85

(d-vi) a reversible prodrug linker reagent to A' or A' of -continued the hydrogel of step (b) or (c), respectively, resulting in a reversible prodrug linker moiety conjugated to the hydrogel of step (b) or (c), followed by covalent con jugation of a tag moiety-biologically active moiety conjugate reagent to said reversible prodrug linker moiety through a functional group of the tag moiety; (d-vii) a reversible prodrug linker moiety-tag moiety conjugate reagent to A" or A of the hydrogel of step (b) or (c), respectively, through a functional group of the reversible prodrug linker moiety, followed by covalent conjugation of a drug to said tag moiety; or (d-viii) a reversible prodrug linker moiety-tag moiety biologically active moiety conjugate reagent to A" or A° of the hydrogel of step (b) or (c), respectively, through a functional group of the reversible prodrug linker moiety; RI wherein the linkage between the reversible prodrug linker moiety and the biologically active moiety in the O prodrug according to (d-i), (d-ii), (d-iii) and (d-iv) and -HS and the linkage between the reversible prodrug linker N moiety and the tag moiety in the prodrug according to (d-V), (d-vi), (d-vii) and (d-viii) is reversible. O y 2. The process of claim 1, wherein the at least one back bone reagent is selected from the group consisting of O (i) a compound of formula (I) B(-(A'),-(SP).2-A-P-A’-Hyp), (I), --N wherein B is a branching core, O S--, SP' is a spacer moiety selected from the group consisting of C1-alkyl, C2-alkenyl and C2-alkynyl, P is a PEG-based polymeric chain comprising at least 80% PEG, preferably at least 85% PEG, more preferably at wherein R' and R'' are independently of each other H or least 90% PEG and most preferably at least 95% PEG, C- alkyl, Hyp' is a moiety comprising an amine (-NH2 and/or —NH-) or a polyamine comprising at least two amines (ii) a compound of formula (II) ( NH and/or NH ), Hyp?-A-P-A-Hyp (II), X is an integer from 3 to 16, x1, x2 are independently of each other 0 or 1, provided that wherein X1 is 0, if X2 is 0, A'. A", A are independently of each other selected from P is defined as above in the compound of formula (I), the group consisting of Hyp, Hypare independently of each otherapolyamine comprising at least two amines (—NH and/or —NH ), and A and A are independently selected from the group consisting of

O O

--O---, ---O--, --S-S-H, -NEN--,

O RI O O -HC-N-H, -HN-C-H , --O-C-H, ---0-- US 2016/00821 23 A1 Mar. 24, 2016 86

-continued -continued O RI O O || | || -HC-N-H, -HN-C-H , --O-C-H, --C-O--, : : I O i ------k ------.R1 S ------. k R1 R1a O S --N-C-O--, -- -c--- s k RI Rila O O --O-C-N-H, ----0-- 1 i R1 R O O -HS and —-o-c--- s N R1 O a - O -HS and

6 y --N O O S--, --N

wherein:- R'1 and R''lca are--- independently: of each other H or O S--, C- alkyl, (iii) a compound of formula (III) P-AHyp? (III) wherein R' and R'' are independently of each H or C. alkyl: wherein and P' is a PEG-based polymeric chain comprising at least 80% (iv) a compound of formula (IV), PEG, preferably at least 85% PEG, more preferably at T-AG-Hyp (IV), least 90% PEG and most preferably at least 95% PEG, wherein Hyp4 is a polyamine comprising at least three amines Hyp is a polyamine comprising at least three amines ( NH and/or NH), and ( NH and/or —NH), and A is selected from the group consisting of A is selected from the group consisting of

--O-H-, --S-H-, --O-H-, --S-H-,

--N-H, ----, --N-H, ----, US 2016/00821 23 A1 Mar. 24, 2016 87

-continued wherein O O p1 is an integer from 1 to 5, preferably p1 is 4, and --O--- s ---O-- s the dashed line indicates attachment to A if the backbone reagent is of formula (I) and to A or A* if the backbone reagent is of formula (II); a moiety of formula (e-ii)

(e-ii)

wherein p2, p3 and p4 are identical or different and each is inde pendently of the others an integer from 1 to 5, preferably RI p2, p3 and p4 are 4, and O the dashed line indicates attachment to A if the backbone -HS and reagent is of formula (I), to A or A* if the backbone reagent is of formula (II), to A if the backbone is of N formula (III) and to A if the backbone reagent is of O X formula (IV); a moiety of formula (e-iii) O

--N (e-iii) O O

O S--, N p6 NH2

2 NH2 wherein R' and R'' are independently of each other H or C- alkyl, and 's-p7 NH2 T' is selected from the group consisting of Clso alkyl, O O

C2-soalkenyl and C2-so alkynyl, which Clso alkyl, C2-so alkenyl and Clso alkynyl are optionally interrupted by one or more group(s) selected from the group consisting N H NH, H H N N NH2 bered heterocyclyl phenyl and naphthyl. p10 p11 3. The process of claim 2, wherein Hyp', Hyp, Hyp, Hyp, and Hypare selected from the group consisting of O O a moiety of formula (e-i) wherein p5 to p11 are identical or different and each is indepen (e-i) dently of the others an integer from 1 to 5, preferably p5 NH2 to p11 are 4, and the dashed line indicates attachment to A if the backbone reagent is of formula (I), to A or A* if the backbone reagent is of formula (II), to A if the backbone reagent is of formula (III) and to A if the backbone reagent is of formula (IV); US 2016/00821 23 A1 Mar. 24, 2016 88

a moiety of formula (e-iv) a moiety of formula (e-vi) (e-v) NH2

(e-iv) , Nr NH

wherein p29 and p30 are identical or different and each is indepen dently of the other an integer from 2 to 5, preferably p29 and p30 are 3, and the dashed line indicates attachment to A if the backbone reagent is of formula (I), to A or A* if the backbone reagent is of formula (II), to A if the backbone reagent is of formula (III) and to A if the backbone reagent is of formula (IV); a moiety of formula (e-vii) (e-vii) NH2 H 1. N N NH2 13 N-56 O 1. NH2 , N N NH2

w O wherein p12 to p26 are identical or different and each is indepen wherein dently of the others an integer from 1 to 5, preferably p12 p31 to p36 are identical or different and each is indepen dently of the others an integer from 2 to 5, preferably p31 to p26 are 4, and to p36 are 3, and the dashed line indicates attachment to A if the backbone the dashed line indicates attachment to A if the backbone reagent is of formula (I), to A or A if the backbone reagent is of formula (I), to A or A* if the backbone reagent is of formula (II), to A if the backbone reagent reagent is of formula (II), to A if the backbone reagent is of formula (III) and to A if the backbone reagent is of is of formula (III) and to A if the backbone reagent is of formula (IV); formula (IV); a moiety of formula (e-V) a moiety of formula (e-viii) (e-viii) NH2 (e-v) ra. 138 r N Y1.NH 2 O 1.NH2 N N NH2 p.28 NH 137 Y1 Y1. O O NH2 wherein 1. p27 and p28 are identical or different and each is indepen N NH2 dently of the other an integer from 1 to 5, preferably p27 145 Y1. and p28 are 4, O NH2 q is an integer from 1 to 8, preferably q is 2 or 6 and most preferably 1 is 6, and , N N N1. NH the dashed line indicates attachment to A if the backbone ', w Y1. Y1. Y16, 2 reagent is of formula (I), to A or A if the backbone reagent is of formula (II), to A if the is of formula (III) w O O and to A if the backbone reagent is of formula (IV); US 2016/00821 23 A1 Mar. 24, 2016

wherein 4. The process of claim 2 or 3, wherein the branching core p37 to p50 are identical or different and each is indepen B is selected from the group consisting of: dently of the others an integer from 2 to 5, preferably p37 to p50 are 3, and the dashed line indicates attachment to A if the backbone (a-i) reagent is of formula (I), to A or A if the backbone reagent is of formula (II), to A if the is of formula (III) and to A if the backbone reagent is of formula (IV); and a moiety of formula (e-ix):

(e-ix) (a-ii) NH

H 1. 2 N 153 O 1. (a-iii) N. N. N. NH2 ar Y-1. N16sp O O 1. N NH 2 2. n16. (a-iv) O NH2 149 H H H arN N -6N N Sn1.N N Y1. O O O N 1. 9 H (a-v) ar N1, O 1.NH2 N. N. N. N. NH2 2. N1. N1, (a-vi) O O 1.NH2 3. N12, O NH2 1. (a-vii) -X,' N Y2Y N -1. N -1. N N16 NH2 O O O

(a-viii) wherein p51 to p80 are identical or different and each is indepen dently of the others an integer from 2 to 5, preferably p51 to p80 are 3, and the dashed line indicates attachment to A if the backbone reagent is of formula (I), to A or A if the backbone reagent is of formula (II), to A if the backbone is of (a-ix) formula (III) and to A if the backbone reagent is of formula (IV); and wherein the moieties (e-i) to (e-V) may at each chiral center be in either R- or S-configuration, preferably, all chiral centers of a moiety (e-i) to (e-V) are in the same configu ration.

US 2016/00821 23 A1 Mar. 24, 2016

-continued 6. The process of any one of claims 2 to 5, wherein P is of (a-Xxiii) formula (c-i):

(c-i)

wherein in ranges from 6 to 900, more preferably n ranges wherein from 20 to 700 and most preferably n ranges from 20 to dashed lines indicate attachment to A" or, if x1 and x2 are 250. both 0, to A', 7. The process of any one of claims 2 to 6, wherein the t is 1 or 2; preferably t is 1, moiety -A-Hyp' is v is 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13 or 14; preferably, V is 2, 3, 4, 5, 6; more preferably, V is 2, 4 or 6; most preferably, V is 2. 5. The process of any one of claims 2 to 4, wherein A' is ' H O >

O H N HN NH2

NH2 O

NH2 NH2 O --> H N N NH2 H NH 2 O HN NH2

O 4

wherein in ranges from 10 to 40, preferably from 10 to 30, more preferably from 10 to 20. 9. The process of any one of claims 1 to 8, wherein the crosslinker reagent is a compound of formula (V-II):

(Vb) O O Y D D2 D3 D Y2 * -3 o1 No *6 8

O R1 R1a R22 R22 R33 R3a3 R.4 R.4a O 2 S 7 sl ra. s2 US 2016/00821 23 A1 Mar. 24, 2016 92

wherein -continued D', D., D and D are identical or different and each is (f-v) independently of the others O, NR, S or CRR"; R. R. R. R. R. R. R. R., R and Rare identical or different and each is independently of the others Hor C, alkyl: optionally, one or more of the pair(s) R'/R". R2/R2, R/R,R/R,R/R,R/R,R/R2, and R/ R“form a chemical bond or are joined together with the atom to which they are attached to form a C-8 cycloalkyl or to form a ring A or are joined together with the atom to which they are attached to form a 4- to 7-membered (f-vi) heterocyclyl or 8- to 11-membered heterobicyclyl or adamantyl; --X A is phenyl, naphthyl, indenyl, indanyl or tetralinyl: P’ is wherein the dashed lines indicate attachment to the rest of the molecule; b is 1, 2, 3 or 4: X is C1, Br, I, or F. m ranges from 5 to 920, preferably from 5 to 460 and more 10. The process of any one of claims 1 to 9, wherein A' is preferably from 40 to 230; an amine and A' is CISO. , R' (C=O) , I-, Br—, Cl-, SCN CN O—C=N-, Y'-(C=O) , Y r1, r2, r7, r8 are independently 0 or 1; (C=O) NH-, or Y'-(C=O) O : r3, ré are independently 0, 1, 2, 3, or 4: wherein r4, rS are independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R" is H. C. alkyl, C-6 alkenyl, C2-6 alkynyl, Cs-s s1, s2 are independently 1, 2, 3, 4, 5 or 6: cycloalkyl, 4- to 7-membered heterocyclyl, 8- to Y',Y are identical or different and each is independently 11-membered heterobicyclyl phenyl, naphthyl, inde of the other selected from formulas (fi) to (f-vi): nyl, indanyl, or tetralinyl; and Y' is selected from formulas (f-i) to (f-vi):

(f-i) (f-i)

NO, (f-iii) (f-iii) NO , -o

NO, (fiv) (f-iv) , O Fb.

N US 2016/00821 23 A1 Mar. 24, 2016

-continued X is C1, Br, I or F: (f-v) Ar is phenyl, naphthyl, indenyl, indanyl, or tetralinyl; and R", R", R'' are independently of each other H, C, alkyl, Coalkenyl, C-alkynyl, C.s cycloalkyl, 4- to 7-mem bered heterocyclyl, 8- to 11-membered heterobicyclyl, O F phenyl, naphthyl, indenyl, indanyl, or tetralinyl. 12. The process of any one of claims 1 to 11, wherein step (d) is (d-iv) and preferably comprises the step of covalently F F and conjugating a reversible prodrug linker moiety-biologically F active moiety-tag moiety conjugate reagent of formula (XIII) (f-vi) A-L-A-D-A*-T (XIII), wherein --X L is a reversible prodrug linker moiety; D is a biologically active moiety; and T is a tag moiety; wherein A is a functional group selected from the group consist the dashed lines indicate attachment to the rest of the mol ing of —SH, -NH2, —SeH, -maleimide, —C=CH, ecule, N, CR'—CR'R'', (C-X) R', OH, b is 1, 2, 3 or 4, X is C1, Br, I, or F. Sn(R)(R')(R'), Ar B(OH)(OH), Ar X, 11. The process of any one of claims 1 to 10, wherein A' is selected from the group consisting of-maleimide. —SH, NH, -SeH, N, -C=CH, CR'—CR'R'', -OH, -(CH=X) R', -(C=O)—S R', -(C=O) H, NH NH, -O-NH. -Ar X. —Ar Sn(R')(R') (R'), Ar B(OH)(OH), Br, I,

O '', Xi, --S-F, W || , O O O

N X----H a--, F w

F | | s

, and

wherein dashed lines indicate attachment to L.; X is O, S, or NH, X is OH, - NR'R'', SH, or - SeH; R", R', R'' are independently of each other H. C. alkyl, C2-alkenyl, C2-alkynyl, Css cycloalkyl, 4- to with optional protecting groups; 7-membered heterocyclyl, 8- to 11-membered hetero wherein bicyclyl phenyl, naphthyl, indenyl, indanyl, or dashed lines indicate attachment to SP'; tetralinyl: X is O, S, or NH, Ar is phenyl, naphthyl, indenyl, indanyl, or tetralinyl, X is OH, - NR'R'', SH, or - SeH, and US 2016/00821 23 A1 Mar. 24, 2016 94

Y' is selected from formulas (fi) to (f-vi): -continued : l : l (f-i) Y& N > X, >1 A. H w H -1\O O, N : l '', : l A w H and O (f-ii) Y&: S l N >1, F H w

wherein the dashed lines marked with an asterisk indicate attach O NO, ment to L; and (f-iii) the unmarked dashed lines indicate attachment to D; NO A' is a linkage selected from the group consisting of , -0. : :

NO, (fiv) : : O Fb, '', 21 4. N s: -HS O (f-v)

O F and

F F

F (f-vi) --X

wherein the dashed lines indicate attachment to the rest of the molecule, b is 1, 2, 3 or 4, wherein X is C1, Br, I, or F, the dashed lines marked with an asterisk indicate attach ment to D; and A is a linkage selected from the group consisting of the unmarked dashed lines indicate attachment to T. to A" of step (b) or to A' of step (c), wherein A reacts with A' or A, respectively. 13. The process of claim 12, wherein A' is selected from the group consisting of

US 2016/00821 23 A1 Mar. 24, 2016

-continued -continued (f-iii) NO

and

NO, (f-iv) ' Fb. w O

wherein the dashed lines marked with an asterisk indicate attach N ment to L., and the unmarked dashed lines indicate attachment to D. 14. The process of any one of claims 1 to 11, wherein step (d) is (d-vii) and preferably comprises the steps of O F (i) covalently conjugating a reversible prodrug linker moi ety-tag moiety conjugate reagent of formula (XVII) Ax3-L-A-T-A-9 (XVII); F F and

wherein F L., T and Aare defined as in claim 12: (f-vi) A' is selected from the group consisting of-maleimide,

wherein the dashed lines indicate attachment to the rest of the molecule; b is 1, 2, 3 or 4: X is C1, Br, I, or F: A' is selected from the group consisting of

wherein w O s A. O O dashed lines indicate attachment to T; and Y' is selected from formulas (fi) to (f-vi): * l ', : l F H w F H w : l : l w w H and * l y H w

wherein O the dashed lines marked with an asterisk indicate attach ment to L; and the unmarked dashed lines indicate attachment to T. NO, to A' of step (b) or to A' of step (c), wherein A reacts with A' or A', respectively; and US 2016/00821 23 A1 Mar. 24, 2016 96

(ii) covalently conjugating a drug of formula (VIIIa) 16. The process of any one of claims 1 to 15, wherein the biologically moiety is a small molecule biologically active A*-D (VIIIa), moiety, a peptide biologically active moiety, a protein bio wherein logically active moiety or an oligonucleotide biologically D is a biologically active moiety; and active moiety. A is a functional group of the drug and is selected from 17. The process of any one of claims 1 to 16, wherein the the group consisting of carboxylic acid, amine, thiol, tag moiety is W. Clso alkyl, C2-so alkenyl; or C2-so alkynyl, Sulfonic acid, carbonate, carbamate, hydroxyl, alde which W. Clso alkyl: Clso alkenyl; and 2-50 alkynyl are hyde, ketone, hydrazine, isocyanate, isothiocyanate, optionally substituted with one or more R', which are the phosphoric acid, phosphonic acid, haloacetyl, alkyl same or different and which Clso alkyl: Clso alkenyl; and halides, acryloyl, aryl fluorides, hydroxylamine, dis Clso alkynyl are optionally interrupted by one or more group ulfides, vinyl Sulfone, vinylketone, diaZoalkanes, dia (s) selected from the group consisting of W. —C(O)O—: Zoacetyls, oxirane, and aziridine; to the conjugate of step (i) wherein Areacts with A'. 15. The process of any one of claims 1 to 11, wherein step (d) is (d-viii) and preferably comprises the step of covalently conjugating a reversible prodrug linker moiety-tag moiety biologically active moiety conjugate reagent of formula wherein (XVIII) R. R. Rare independently of each other H. W. Clso A*-L-A-T-A-D (XVIII), alkyl, Clso alkenyl; or Clso alkynyl, which W. Clso alkyl, C2-so alkenyl; and C2-so alkynyl are optionally wherein substituted with one or more R', which are the same or L.T., D and A are defined as in claim 12: different and which Clso alkyl, C2-soalkenyl; and C2-so A is defined as in claim 14: alkynyl are optionally interrupted by one or more group A' is a linkage selected from the group consisting of (s) selected from the group consisting of W. —C(O)O—: -O-; C(O)–: –C(O)N(R') : —S(O)N (R')–: S(O)N(R')–: S(O) ; –S(O); N(R')S(O)N(R') ; – S : N(R') ; OC (O)R'': N(R')C(O) :- N(R')S(O) :- N(R') S(O) : N(R')C(O)C : N(R')C(O)N(R') : and OC(O)N(R'R''); W is selected from the group consisting of phenyl; naph thyl; indenyl; indanyl; tetralinyl; Co cycloalkyl; 4 to 7 membered heterocyclyl; and 8- to 11-membered hetero bicyclyl, wherein Wis optionally substituted with one or more R', which are the same or different; R" is halogen; CN; oxo (=O); COOR: OR: C(O)R': C(O)N(R'R'2); S(O)N(R'R'2); S(O)N(R'R'2); S(Q).R. S(O)R2; N(R'2)S(O)N(R2R12); SR; N(R'R'2); NOOC(O)R'?:N(R)C(O)R'2'; N(R) S(O).R2; N(R'2)S(O)R12; N(R2)C(O)OR'2'; O NRFSC(O)N(RR?). OC(O)N(R'R''); or C. O w O & , alkyl, which Calkyl is optionally substituted with one w w w or more halogen, which are the same or different; : w 31w is w >1w s w N , w O R'', R''", R. R''", R'' are independently selected from w H w w w w the group consisting of H; and C alkyl, wherein C. O w p O w alkyl is optionally Substituted with one or more halogen, which are the same or different. No N1 , NN N1 , 18. The process of any one of claims 1 to 17, wherein the H w A. H H V tag moiety is a polymer with a molecular weight ranging from O O * , : 0.5 to 50 kDa. A. 19. A hydrogel-linked prodrug releasing a tag moiety-bio A. A. YxP A. Y&p logically active moiety conjugate obtainable by a process of N A. O A ? s A. and any one of claims 1 to 18. F F O 20. The prodrug of claim 19, wherein process step (d) is : ', A. & selected from (d-i), (d-ii), (d-iii) or (d-iv). A. w 21. The prodrug of claim 19, wherein process step (d) is S&f N O >1, F H w selected from (d-V), (d-vi), (d-vii) or (d-viii). 22. A pharmaceutical composition comprising the prodrug of any one of claims 19 to 21 or a pharmaceutical salt thereof wherein together with a pharmaceutically acceptable excipient. the dashed lines marked with an asterisk indicate attach ment to D; and 23. The prodrug of any one of claims 19 to 21 or the the unmarked dashed lines indicate attachment to T; pharmaceutical composition of claim 22 for use as a medica to A" of step (b) or to A' of step (c), wherein Areacts with ment. A' or A, respectively.