AU2020203321A1

AU2020203321A1 - Modulators of pharmacokinetic properties of therapeutics

Info

Publication number: AU2020203321A1
Application number: AU2020203321A
Authority: AU
Inventors: Manoj C. Desai; Allen Y. Hong; Hon C. Hui; Hongtao Liu; Vivian W. Randall; Lianhong Xu
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2007-02-23
Filing date: 2020-05-21
Publication date: 2020-06-11
Also published as: AU2017203502A1; AU2015204378B2; AU2015204378A1; AU2018232947A1

Abstract

The present application provides for a compound of Formula IV, R1 0 A L3 R5 R- YGN N X-R9 0 R2 R3 L3 0 'A Formula IV or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.

Description

MODULATORS OF PHARMACOKINETIC PROPERTIES OF THERAPEUTICS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Australian Patent Application No. 2018232947, the entire content of which is incorporated herein by reference.

FIELD OF THE INVENTION

This application relates generally to compounds and pharmaceutical compositions which modify, e.g., improve, the pharmacokinetics of a co-administered drug, and methods of modifying, e.g., improving, the pharmacokinetics of a drug by co-administration of the compounds with the drug.

BACKGROUND OF THE INVENTION

Oxidative metabolism by cytochrome P450 enzymes is one of the primary mechanisms of drug metabolism. It can be difficult to maintain therapeutically effective blood plasma levels of drugs which are rapidly metabolized by cytochrome P450 enzymes. Accordingly, the blood plasma levels of drugs which are susceptible to cytochrome P450 enzyme degradation can be maintained or enhanced by co-administrah'on of cytochrome P450 inhibitors, thereby improving the pharmacokinetics of the drug.

While certain drugs are known to inhibit cytochrome P450 enzymes, more and/or improved inhibitors for cytochrome P450 monooxygenase are desirable. Particularly, it would be desirable to have cytochrome P450 monooxygenase inhibitors which do not have appreciable biological activity other than cytochrome P450 inhibition. Such inhibitors can be useful for minimizing undesirable biological activity, e.g,, side effects. In addition, it would be desirable to have P450 monooxygenase inhibitors that lack significant or have a reduced level of protease inhibitor activity. Such inhibitors could be useful for enhancing the effectiveness of antiretroviral drugs, while minimizing the possibility of eliciting viral resistance, especially against protease inhibitors,

SUMMARY OF THE INVENTION

One aspect of the present application is directed to compounds and pharmaceutical compositions which modify, e.g., improve, the pharmacokinetics of a co-administered drug, e.g., by inhibiting cytochrome P450 monooxygenase.

In one embodiment, tire present application provides for compounds having a structure according to Formula IV,

or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein, each L³ is independently an alkylene or substituted alkylene;

each A is independently an aryl or substituted aryl;

X is heterocyclylalkyl;

2020203321 21 May 2020

Y is heterocyclylalkyl or alkyl;

G¹ and G² are independently CH or N, with the proviso that G^] and G² are different;

G' is -NR⁷- or -O-;

R', R³, R⁵, and R⁷ are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyb

R² is independently selected from the group consisting of substituted alkyl, alkoxyalkyl, hydroxyalkyl, trialkylsil oxy alkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -aIkylene-N(R^fi)-C(O)alkyl, -alkylene-NR^f’-C(O)-N(R^i,)2, -alkylene-NR^C^N-RQ-NiR’k, -alkyleneC(=N-R^l’)-N(Rⁱ')2, -alkylcne-C(O)-OH, -alkylene-C(O)-Oalkyl, and -alkyleneC(O)-N(R‘>;

R^s and R’ are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, and -CN;

each R^l! is independently selected from the group consisting of H, alkyl, and substituted alkyl;

R^h is selected from the group consisting of H, alkyl, substituted alkyl, CN, and S(Ch)-alkyI; and each R^l is independently selected from the group consisting of H, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, ~S(Ch)-alkyI, -S(Ch)-aryl, and substituted -S(O:)-aryl.

In another embodiment, the present application provides for a pharmaceutical composition comprising a compound of Formula 1, and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present application provides for a pharmaceutical composition comprising a compound of Formula 1, at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or exipient.

In another embodiment, the present application provides for a method for improving the pharmacokinetics of a drug, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

In another embodiment, the present application provides for a method for inhibiting cytochrome P450 monooxygenase in a patient comprising administering to a patient in need thereof an amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase.

In another embodiment, the present application provides for a method for treating a viral infection, e.g., HIV, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are metabolized by cytochrome P450 monooxygenase, and are suitable For treating a viral infection, e.g, HIV.

Ln another embodiment, the present application provides for a combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional active agent which is metabolized by cytochrome P450 m onoox y gen a se.

2020203321 21 May 2020

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the invention to those claims. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

All documents cited herein are each incorporated by reference in their entirety for all purposes,

Definitions

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.

As used herein, a compound of tine invention or a compound of formula (1) means a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or stereoisomer thereof, or a physiologically functional derivative thereof. Similarly, with respect to isolatable intermediates, the phrase a compound of formula (number) means a compound of that formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.

Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e, CiCx: alkyl), 1 to '10 carbon atoms (/>., G-Cio alkyl), or 1 to 6 carbon atoms (i.e., Ci-C>

2020203321 21 May 2020 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CEL·), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CHfCHs)’), 1-butyl (n-Bu, n-butyl, -CHzClUCHzCHs), 2-methyl-lpropyl G-Bu, i-butyl, -CHCHfCH?)/), 2-butyl (s-Bu, s-butyl, -CHiCHaJCHzCHs), 2methyl-2-propyl (t-Bu, t-butyl, -CfCHsJs), 1-pentyl (npentyl, -CH2CH2CH2CH2CH3), 2-pentyl (<H(CH₃)CH2CH2CH3), 3-pentyl (-CHfCHiCHs)?), 2-methyl-2-butyl (-CfCH^CHjCHs), 3-methyl-2-butyl (-CH(CH₃)CH(CHj)2), 3-methyl-1-butyl (-CH/CH/CHtCHj)/), 2-methyl-I-butyl (-CH3CH(CH;0CH₃CHx), 1-hexyl (-CHiCI-hCEKH/CH/CEb), 2-hexyl (-CH(CH₃)CH2CH₂CH<H3), 3-hexyl (-CH(CH2CH3)(CI^CH₂CH.₃)), 2-methyl-2pentyl (-CiCFL^CH/CH/CH/), 3-methyI-2-pentyl (-CH(CH₃)CH(CHj)CH2CH₅), 4methyl-2-pentyl (-CH(CH3)CH₂CH(CH3)₃), 3-methyl-3-pentyl (-qCH^CHiCHrM 2-methyl-3-pentyl (-CHfCHzCH^CI-liClL·):), 2,3-dimethyl-2-butyl (-C(CH3):CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CHs)C(CH·^ and octyl (-(CH:)7CH3).

Alkoxy means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atomsfi.e., C1-C12 alkoxy), or 1 to 6 carbon atoms(i.c, C1-C0 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-0-0¾ or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-O-C(CH3)₃ or -O'Bu) and the like.

I laloalkyl is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., Cj-Czc haloalkyl), 1 to 12 carbon atomsfi.e., Ci-Cu haloalkyl), or 1 to 6 carbon atoms(i.e., Ci-G alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CFs, -CHF?, -CFH?., -CFkCH, and the like.

Alkenyl is a hydrocarbon containing normal, secondary', tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp- double bond. For example, an alkenyl group car have 2 to 20 carbon atoms (i.e., C:-G:rf alkenyl), 2 to 12 carbon atoms (i.e., C?-Ci? alkenyl), or 2 to 6 carbon atoms (i.e., GQ alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CHi), allyl (-CHiOLCH?), cyclopentenyl (-C5H7), and 5hexenyl (-CH2CH2CH2CH2CH-CH2).

Alkynyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., Ci-Czc alkynyl), 2 to 12 carbon atoms (i.e., C2-C12 alkyne,), or 2 to 6 carbon atoms (i.e., CiCt> alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C=CH), propargyl (-CH’CsCH), and the like.

Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH?-), 1,1-ethyl (-CIT(CHs)-), 1,2-ethyl (-CH2CH2-), 1,1propyl (-CH(CI-hClL)-), 1,2-propyI (-CHCHiCFL·)-), 1,3-propyl (-CH2CH2CH2-), 1,4butyl (-CH2CH2CH2CH2-), and the like.

Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by fire removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, and alkenylene group can have 1 to 20 carbon atoms, 1 to 10

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PCT/US2008/054788 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not Limited to, 1,2-ethylene (-CH-CH-),

Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but arc not limited to, acetylene (-CAC-), propargyl (-CH:C=C-), and 4-pentynyl (-CFhCHiCHzC^a-l-).

“ Amino means an -ΝΉ2 or a -NR2 group in which the R groups are independently H, alkyl, haloalkyl, hydroxylalkyl, carbocyclyl (substituted or unsubstituted, including saturated or partially unsaturated cycloalkyl and aryl groups), hctcrocyclyj (substituted or unsubstituted, including saturated or unsaturated hetcrocycloalkyl and heteroaryl groups), arylalkyl (substituted or unsubstituted) or arylalkyl (substituted or unsubstituted) groups. Non-Limiting examples of amino groups include -NH2, -NH(alkyl), NH(haloalkyl), -NH(carbocyclyl), -NH(hcterocyclyl), N(alkyl):, -N(carbocyclyl)2, -N(heterocyclyl)2, -N(alkyl)(carbocyclyl), -N(alkyl)(hetero cyclyl), -N(carbocyclyl)(heterocyclyl), etc., wherein alkyl, carbocyclyl, and heterocyclyl can be substituted or unsubstituted and as defined and described herein. Substituted or protected amino means an aminoalkyl as described and defined herein in which a H of the amino group is replaced with e.g., acyl groups, for example conventional amine protecting groups such as Q-Fluorenylmetltyl carbamate (Fmoc), f-Butyl carbamate (Boc), Benzyl carbamate (Cbz), acetyl, tri fluor acetyl, -C(O)-amino, phthalimidyl, triphenyhnethyl, p-ToIuenesulfonyl (Tosyl), methylsulfonyl (mesyl), etc.

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PCT/US2008/054788

Aminoalkyl means an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, is replaced with an amino radical as defined and described herein. Non-limiting examples of aminoalkyl include -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2\Th, -CH2CH2CH2CH2-NH2, -CH₂CH(CH3)-NH2, -CH2CH₂CH(CH3)-NH2, -ch> NH(CH3), <H₂CH2-NH(CH3), -CHiCHaCHa-NHiCHa), -CHOLCHaCHN’H(CH₃), -CH2CH(CH3)-NH(CHs), -CH2CH2CH(CH₃)-NH(CH₃), -CH2N(CH₃)2, -CH2CH2-N(CH2.)-, -CH₃CH2CH.2-N(CH3)2, -CH2CH2CH2CH2N(CH₃)_3/ -CThCH(Cl-h)-N(Cl 1-)2, -CH2CH2CH(CHs)-N(Chb,)2,-Cl hNHfCHsCHs), -CHsCHz-NHfCH-CHs), -CH2CH2CH2NH(CH2CH₃), -akClkClbCH.-NIRCThCHs), -CH2CH(CH3)-NH(CH2CH3)_z -CH2C H2CH(CH3)-NH(CH2O-b), -CH2-N(CH<Fb)2, -CHnCI-b-NfCHzCHa)?, -CH2CH2CH2NiCHzCHi):, -CkL<ROLCH2-N(CH2CH₃)2, -CH^CHtChbl-NtCHiCI-L.):, -CH2CH2C H(CH₃)-N(CH2CH₃)2, etc. Substituted or protected aminoalkyl means an aminoalkyl as described and defined herein in which the H of the amino group is replaced with e.g., acyl groups, for example conventional amine protecting groups such as 9-riuorenylmethyl carbamate (Fmoc), /-Butyl carbamate (Boc), Benzyl carbamate (Cbz), acetyl, -C(O)-amino, triflu ora cetyl, phthalimidyl, triphenyl methyl, p-Toluen esulfonyl (Tosyl), mcthylsulfonyl (mesyl), etc.

Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Typical ary] groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and tire like.

Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, is

2020203321 21 May 2020 replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, 2-naphtl‘iophenylethan-l-yl and the like. The arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

“ Arylalkcnyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, but also an .sp² carbon atom, is replaced with an aryl radical. The ary! portion of the aryl alkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein. The arylalkenyl group can comprise 6 to 20 carbon atoms, e.g., the alkenyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

Arylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, but also an sp carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein. Ihe arylalkynyl group can comprise 6 to 20 carbon atoms, e.g., the alkynyl moiety is 1 to 6 carbon atoms and tire aryl moiety is 6 to 14 carbon atoms.

The term substituted in reference to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, substituted alkyl, substituted alkylene, substituted aryl, substituted arylalkyl, substituted heterocyclyl, and substituted carbocyclyl means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical

2020203321 21 May 2020 substituents include, but arc not limited to, -X, -R, -O, =O, -OR, -SR, -S , -NR;, -NR3, =NR, -CXs, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO;, =N;, -Ns, NHC(=O)R, -NHS(=O)2R, -C(=O)R, -C(=O)NRR -S(=O);O-, -S(=0):OH, -S(=O);R, OS(=O):OR, -S(=O):NR, -S(=O)R, -OP(=O)(OR)z, -P(0)(OR);, -P(=O)(O ):, -P(=O)(OH)z, -P(O)(OR)(O ), -C(=O)R, -C(=O)OR, -C(=O)X, -C(S)R, -C(O)OR, -C(O)O , -C(S)OR, -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, -C(=NR)NRR, where each X is independently a halogen: F, Cl, Br, or I; and each R is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting group or prodrug moiety. Alkylene, alkenylene, and a Iky ny lone groups may also be similarly substituted. When the number of carbon atoms is designated for a substituted group, the number of carbon atoms refers to the group, not the substituent (unless otherwise indicated). For example, a Cm substituted alkyl refers to a Cm alkyl, which can be substituted with groups having more the, e.g., 4 carbon atoms.

The term prodrug as used herein refers to any compound that when administered to a biological system generates the drag substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and other moietics of tlie compounds of Formula I should be selected in order to provide a compiound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of Formula I which have such stability are contemplated as falling within the scope of the present invention.

Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, Ο, N, or S. For example, if the carbon atom of the alkyl group which is attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting hcteroalkyl groups arc, respectively, an alkoxy group (e.g., -OCHz, etc.), an amine (e.g., -NHCHb, -N(CHi)z, etc.), or a thioalkyl group (e.g., -SCH?). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroaikyl groups are, respectively, an alkyl ether (e.g., -CFbCHz-O-CHs, etc.), an alkyl amine (e.g., -CHzNHCH-, -CHzNfCHs):, etc.), or a thioalkyl ether (e.g^-CHz-S-CHa). If a terminal carbon atom of die alkyl group is replaced with a heteroatom (e.g.. Ο, N, or S), the resulting heteroaikyl groups are, respectively, a hydroxyalkyl group (e.g., -CH2CH2-OI I), an ami noalkyl group (e.g., -CT-LNHz), or an alkyl thiol group (e.g., -CH2CH2-SH). A heteroaikyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A Ci-C^ heteroaikyl group means a heteroaikyl group having '1 to 6 carbon atoms.

Heterocycle or heterocyclyl as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13,14, 16,19, and 28; and /. Ani. Chem. Soo. (1960) 82:5566. In one specific embodiment of the invention heterocycle includes a carbocycle as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. Ο, N, or S), The terms heterocycle or heterocyclyl includes saturated rings (i.e., heterocycloalkyls), partially unsaturated rings, and aromatic rings (i.e., hetero aroma tic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups. A non-limiting example of a carbonyl substituted heterocyclyl is:

o _VNL,NH ^x ΪΓ o

Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophcnyl, sulfur oxidized tetrahydro thio phenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinol inyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrroiidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinollnyl, octahydroisoquinohnyl, azocmyl, triazinyl, 6H-1,2,5thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazmyl, indolizinyl, isoindolyl, 3H-indolyl, 1Hindazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxaliny], quinazolinyl, cinnoliiiyl, ptcridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyt phcnanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, pheno thia ziiiyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, im id azolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indo liny I, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, arid bis-te trail yd rofur any 1:

By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3,4, 5, or 6 of a

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PCT/US2008/054788 py rid azine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyr azine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2,4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1,3, 4, 5, 6, 7, or 8 of an isoquinolinc. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3pyrroline, imidazole, imid azolidine, 2-i mid azo line, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoIine, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholino, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include I-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety). Typical heterocyclyl alkyl groups include, but are not limited to hcterocyclylCH2-, heterocyclyl-CH(CHs)-, heterocyclyl-CHzCTL·-, 2-(heterocyclyI)ethan-l-yl, and the like, wherein the heterocyclyl portion includes any of the heterocyclyl groups described above, including those described in Principles of Modem Heterocyclic Chemistry. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by

2020203321 21 May 2020 means of a carbon-carbon bond ora carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclylalky] group comprises 2 to 20 carbon atoms, e.g., the alkyl portion of the heterocyclylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 1 to 14 carbon atoms. Examples of heterocyclylalkyls include by way of example and not limitation 5membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmcthyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperid in ylm ethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidyhnethyl, pyrazinylmethyl, etc.

Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, but also a sp- carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene- moiety). The heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described m Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein. One skilled In tire art will also understand that the heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclylalkenyl group comprises 3 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is Ί to 14 carbon atoms.

Hcterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkynylene- moiety). The heterocyclyl portion of the heterocyclyl

2020203321 21 May 2020 alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The hctcrocydylalkynyl group comprises 3 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclylalkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 1 to 14 carbon atoms.

Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen. Nonlimiting examples of heteroaryl rings include all of those listed in the definition of heterocyclyl, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, puriny], furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc,

Carbocycle or carbocyclyl refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic caxbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings. Nonlimiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopcntyl, 1-cyclopent-1-enyl, l-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclo hexyl, 1-cyclohex-1-enyl, l-cyclohex-2-enyl, Ί-cyclohex-3-enyl, and phenyl.

Non-limiting examples of bicyclo carbocycles includes naphthyl.

Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein. The aryl groups may be bonded to a carbon atom of the heteroalkyl group, oi' to a heteroatom of the heteroalkyl group, provided that tire resulting arylheteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group can have the general formulae -alkyleneO-aryl, -alkyleno-O-alkyIone-ary 1, -alkylene-NH-aryl, -alkykmc-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, airy of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.

Heteroarylalkyr refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein. Non-limiting examples of heteroaryl alkyl include -CHz-pyridinyl, -CHz-pyrrolyl, -CHi-oxazolyl, -CHz-indolyl, -CHz-isoindoi yl, -CHz-purinyi, -CHz-furanyl, -CHi-thienyl, -CHz-benzofuranyl, -CHz-benzothio phenyl, -CHz-carb azolyl, -CHz-imid azolyl, -CHz-thiazolyl, -CH?-isoxazolyl, -CHz-p yrazolyl, -CH z-isothi azolyl, -CTb-quinolyl, -CHz-isoquinoIyl, -CH--pyridazyl, -CH z-pyrimidyl, -CHz-pyrazyl, -CH(CHz)-pyridinyl, -CH(CH3)-pyrrolyl, -CH(CHs)-ox azolyl, -CH(CH₃)-indoIyl, -CH(CH₃)-isoindolyI, -CH(CH₃)-purinyl, -CH(CH_s)-fura nyl, -CH(CH?)-thienyl, -CH(CHj)-benzofuranyl, -CH(CFLi)-benzothiophenyI, -CH( CHp-carbazolyl, -CHfCHjj-iinidazolyl, -CH (CHa)-thiazolyl, -CH (CH?)-isox azolyl, -CH(CH3)-pyrazolyl, -CH(CH3)~isothiazolyl, -CH (CHa)-quinolyl, -CH(CHj)-isoqui nolyl, -CH(CI-h)-pyridazyl, -CH(ClT.)-pyrimidyl, -CI l(Cl-h)-pyrazyl, etc.

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The term optionally substituted in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted aryl group) refers to a moiety having 0/1,2, or more substituents.

Ac means acetyl (-C(O)CFh).

AqO means acetic anhydride.

DCM means dichloromethane (CH’Ch).

DIBAL means diisobutylaluminum hydride.

DMAP means dimethylaminopyridine.

EDC means 1 -(3-Dime thy lami no pro pyl)-3-e thy 1 carbodiimide.

Et means ethyl.

EtOAc means ethylacctatc.

HOBt means N-hydroxybenzotriazoIe.

Me means methyl (-CEb).

MeOH means methanol.

MeCN means acetonitrile.

Pr means propyl.

i-Pr means isopropyl (-CH(CFb):).

i-PrOl l means isopropanol.

rt means room temperature.

TFA means trifluoroacetic acid.

THF means tetr a hydro furan.

The term chiral refers to molecules which have the property of nonsuperimposability of the mirror image partner, while the term achiral refers to molecules which are superimposable on their mirror image partner.

Tire term stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

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Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

Enantiomers refer to two stereoisomers of a compound which are nonsuperimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral ccntcr(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with () or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer mav also be referred to as an enantiomer, and a mixture of such J isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

Protecting Groups

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In the context of the present invention, protecting groups include prodrug moieties and chemical protecting groups.

Protecting groups arc available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and tire nature of the chemical protecting group PG will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis, Tire PG groups do not need to be, and generally are not, tire same if the compound is substituted with multiple PG. Ln general, PG will be used to protect functional groups such as carboxyl hydroxyl, thio, or amino groups and to thus prevent side reactions ot to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.

Various functional groups of the compounds of the invention maybe protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) include ether- or estcrforming groups. Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.

A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts (John

Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9) (Greene). See also Kocienski, Philip ].; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2,11'ydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below'. Such groups include by way of example and not limitation, esters, amides, hydrazides, and tire like.

Ether- and Ester-forming protecting groups

Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bls-amidates; (2) carboxyl ester-forming groups, and (3) sulphur esteriorming groups, such as sulphonate, sulfate, and sulfinate.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g., C·¹ or H³) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no anti-infective activity of their own.

Compounds of Formula I

In one embodiment, the present application provides compounds according to Formula I,

Formula I or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein,

L·¹ is selected from the group consisting of ~C(R⁶)z-, -C(O)-, -SfCh)-, -_\^T(R⁷)-C(O)-, and -O-C(O)-;

L² is a covalent bond, -CfR⁶)?- or -C(O)-;

each L·¹ is independently a covalent bond, an alkylene, or substituted alkydene;

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each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl, with the proviso that when A is H, p is 0;

7) and Z^: are each independently Ό- or -N(R⁷)-;

Y and X are independently selected from the group consisting of heterocyclyl and heterocyclylalkyl;

each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R¹, R¹, and R⁵ are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;

each R- is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxy alkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)-OH, alkylene-C(O)-Oalkyl, -alkylene-C(O)amino, -alkylene-C(O)-alkyl;

R·¹ and R⁶ are independently selected from the group consisting of I I, alkyl, substituted alkyl, and heteroalkyl;

each R⁷ is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl;

and R are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and -CN;

m is 1 or 2;

2020203321 21 May 2020 n is 0 or 1; and each p is independently 0 or 1.

In another embodiment of the compounds of Formula I, n is 1.

In another embodiment of the compounds of Formula I, n is 0.

In another embodiment of the compounds of Formula 1, n is I and 1/ is CH(R⁶)-, wherein R'· is selected from the group consisting of fl, alkyl, substituted alkyl, and hctcroalkyl.

In another embodiment of the compounds of Formula I, n is 1 and L~ is CHj-,

In another embodiment of tire compounds of Formula I, n is 1 and L² is C(O)-.

In another embodiment of the compounds of Formula I, n is 1 and Y is heterocyclylalkyl.

In another embodiment of the compounds of Formula I, n is 1 and Y-R^s is CFb-isubstituted heteroaryl).

In another embodiment of the compounds of Formula I, n is 1 and Y-R⁸ is

In another embodiment of the compounds of Formula I, n is I and Y-R* is

wherein R^w is alkyl, for example 2-propyl.

In another embodiment of tire compounds of Formula I, n is 1 and X is heterocydylalkyl.

In another embodiment of the compounds of Formula Ϊ, n is 1 and X is CI h-heteroarvl.

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In another embodiment of the compounds of Formula I, n is 1 and X-R“ is s'W.

In another embodiment of the compounds of Formula I, n is 1 and X-R⁵ is

In another embodiment of tire compounds of Formula I, n is 1 and Z¹ is NW·

In another embodiment of the compounds of Formula 1, n is I and Z¹ is N(alkyl)- or -Nfcarbocyclyl)-.

In another embodiment of the compounds of Formula I, n is 1 and Z¹ is N(CHa)- or -N(cy ciop ropy 1)-.

In another embodiment of the compounds of Formula I, n is 1 and Z¹ is ΝΉ-.

In another embodiment of the compounds of Formula I, n is 1 and each A is independently aryl or substituted aryl.

In another embodiment of the compounds of Formula I, n is I and each A is phenyl.

In another embodiment of the compounds of Formula I, n is 1 and each A is phenyl and each p is t).

In another embodiment of the compounds of Formula I, n is 1 and R- is H, alkyl, substituted alkyl, or heteroalkyl.

In another embodiment of tire compounds of Formula I, n is 1 and R² is 2propyl, methyl, -CFF-O-benzyl, -CH(CH₃)(O-t-Bu), or -CH(CH3>(OH).

In another embodiment of the compounds of Formula I, L¹ is -C(O)-; each A is independently ary 1, substituted aryl, alkyl, or substituted alkyl;

R¹ is H or alkyl;

2020203321 21 May 2020 each R² is independently H, alkyl, substituted alkyl, or heteroalkyl;

R\ R⁴, R⁵, and R¹’ are each H;

each R⁷ is independently H, alkyl, or carbocyclyl;

R^H is H or alkyl;

R^Q is H;

X and Y are both heterocyclylalkyl;

Z^: is -O-; and p is 0.

In another embodiment of the compounds of Formula I, each A is phenyl;

R¹ is H or -CHi;

each R² is H, methyl, ethyl, 2-propyl, -CFb-O-benzyl, -CH(CFb)-OH, or -CH(CH0(O-t-Bu);

each R⁷ is H, methyl or cyclopropyl;

R^s is H or 2-propyl;

X is

R³; and

Yis

In another embodiment, the compounds of Formula 1 have the following general Formula IA:

Formula ΙΑ.

In another embodiment of the compounds of Formula ΙΑ, Z' is -N(R⁷)-. In a particular embodiment, R⁷ is H. In another particular embodiment, R⁷ is alkyl, for example any of the alkyl groups disclosed herein. In another particular embodiment, R⁷ is heteroalkyl, for example any of the heteroalkyl groups disclosed herein. In another particular embodiment, R⁷ is substituted or ursubstituted carbocyclyl, wherein for example, said carbocyclyl is any of the carbocyclyl groups disclosed herein. In another particular embodiment, R⁷ is substituted or unsubstituted heterocyclyb wherein for example, said hetcrocyclyl is any of the heterocyclyl groups disclosed herein.

In another embodiment of the compounds of Formula I A, Z¹ is -O-.

In another embodiment of the compounds of Formula 1A, L² is -C(R⁶)’-, xvherein each R¹’ is H.

In another embodiment of the compounds of Formula 1A, L^? is -CfR⁶)?-, wherein each R* is independently'· H or alkyl, and said alkyl includes any alkyl disclosed herein.

in another embodiment of the compounds of Formula I A, L·² is -C(R⁶)>, wherein one R^e is H and the other R^ is alkyl, wherein said alkyl includes any alkyl disclosed herein.

In another embodiment of the compounds of Formula I A, m is 1 and R² is H.

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In another embodiment of the compounds of Formula IA, m is 1 and R² is alkyl, wherein said alley] includes any alkyl disclosed herein.

In another embodiment of the compounds of Formula I A, m is 1 and R* is ipropyi.

hi another embodiment of the compounds of Formula I A, m is 1 and R² is ibutyl.

In another embodiment of the compounds of Formula LA, m is 1 and R² is ethyl.

In another embodiment of the compounds of Formula I A, m is 1 and R² is methyl.

In another embodiment of the compounds of Formula IA, m is 2 and each R² is independently selected from H and alkyl.

hr another embodiment of the compounds of Formula I A, m is 2 and each R² is H.

In another embodiment, the compounds of Formula I have the following general Formula IB:

Formula IB.

In another embodiment of the compounds of Formula IB, Z¹ is -N(R⁷)-. In a particular embodiment, R⁷ is FL In another particular embodiment, R⁷ is alkyl, for example any of the alkyl groups disclosed herein. In another particular embodiment, R⁷ is heteroalkyl, for example any of the heteroalkyl groups disclosed herein. In another particular embodiment, R⁷ is substituted or

2020203321 21 May 2020 unsubstituted carbocyclyl, wherein for example, said carbocyclyl is any of the carbocyclyl groups disclosed herein. In another particular embodiment, R⁷ is substituted or unsubstituted heterocydyl, wherein for example, said heterocydyl is any of the heterocydyl groups disclosed herein.

In another embodiment of the compounds of Formula IB, Z⁷ is -O-.

In another embodiment of the compounds of Formula IB, L^: is -C(R^f’)2-, wherein each R is H.

In another embodiment of the compounds of Formula IB, L² is -C(R^ft)z-, wherein each R'¹ is independently I I or alkyl, and said alkyl indudes any alkyl disclosed herein.

In another embodiment of the compounds of Formula IB, L² is -CfR⁶):-, wherein one R⁶ is H and the other R⁶ is alkyl, wherein said alkyl includes any alkyl disclosed herein.

In another embodiment of the compounds of Formula IB, R^s and R⁹ are both H.

In another embodiment of the compounds of Formula IB, R^s and R¹⁷ are independently selected from H and alkyl, wherein said alkyl includes any alkyl disdosed herein.

In another embodiment, the compounds of Formula I have one of the following structures:

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HN

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including stereoisomers or mixtures of stereoisomers thereof. One skilled in the art will recognize that stereoisomers or mixtures of stereoisomers of the compounds of the present application include enantiomers, diastereomers, and other stereoisomers. For example, for:

as well as mixtures of two or more of these stereoisomers.

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In still another embodiment of the compounds of Formula I, L¹ is -CfR⁰)?-, C(O)-, -5(0:)-, -N(R⁷)-C(O)-, or -O-C(O)-. When L¹ is -C(R^ft>, each R⁶ is independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substituted alkyl, and heteroalkyl are as defined and exemplified herein. Non-limiting examples of-QR⁶):- include CH2-, -CH(alkyl)-, -CH(substituted alkyl)-, -CH(heteroalkyl)-, -C(alkyl):-, -C(substituted alkyl):-, -C(heteroalkyl)2-, -C(alkyl)(substituted alkyl)-, -C(heteroalkyl)(substituted alkyl)-, and -C(alkyl)(heteroalkyl)-, wherein alkyl, substituted alkyl, and heteroalkyl are as defined and exemplified herein. When L¹ is -N(R⁷)-C(O)-, R⁷ is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are as defined and exemplified herein.

In still another embodiment of the compounds of Formula I, L² is -C(R^S)2or -C(O)-. When L^: is -C(RQ:-, each R^b is independently selected from H, alkyl, substituted alkyl or heteroalkyl, where each alkyl, substituted alkyl, or heteroalkyl can include any of the alkyl, substituted alkyl, or heteroalkyl groups defined or disclosed herein. Non-limiting examples of -C(R⁶)?- include CH:-, -CH(CHa)-, -CH(-CH2CHs)-, -CH(-CHCH<I-b)-, <Η(<Η(ΟΙ:φ)- -CH(CH2CH2CH2CH3)-, -CH(-CI-hCI I(CIL):)-, -CH(-CH(CH₃)CILCH3)-, -CH(CfCHsJs)-, -C(CH₃)2- -CH(OCIU)-, -CH(CH:OH)-, -CH(CH2CH:OH)-, etc.

In still another embodiment of the compounds of Formula 1, each I? is independently a covalent bond, an alkylene or substituted alkylene. When any I? is an allcylene, non-limiting examples of alkylene includes any of the alkylenes defined or disclosed herein. When any L⁵ is a substituted alkylene, non-limiting examples of substituted alkylene includes any of the substituted alkylenes defined

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In still another embodiment of the compounds of Formula I, each L·³ is the same, i.e., each L³ is the same alkylene or substituted alkylene group.

In still another embodiment of the compounds of Formula I, each L? is different, i.e., one L^7, is an alkylene and the other L³ is a substituted alkylene, one L·’ is an alkylene and the other L? is a different alkylene, or one L⁷ is a substituted alkylene, and the other L³ is a different substituted alkylene.

In still another embodiment of the compounds of Formula I, each L⁴ is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-O-, and -NH-. When L⁴ is alkylene, said alkylene includes any alkylene defined or exemplified herein. When L⁴ is substituted alkylene, said substituent includes any alkylene defined or exemplified herein, substituted by one or more substituents as defined herein.

In still another embodiment of the compounds of Formula I, both L⁴ groups are the same, i.e. both L⁴ groups are a covalent bond, both are -O-, both arc -CH2-O-, (wherein the CFL· group is attached to either the A moiety or the Ar moiety of Formula I), both are a substituted or unsubstituted alkylene, or both are -ΝΉ-.

In still another embodiment of the compounds of Formula I, cadi I? is different. For example, one L⁴ is a covalent bond and the other L⁴ is -O-, one L⁴ is a covalent bond and the other L? is -CH2-O- (wherein the CH: group is attached to either the A moiety or the Ar moiety of Formula 1), one L⁴ is a covalent bond and the other L⁴ is —NH-, one L⁴ is a -O- and the other L⁴ is -CH2-O- (wherein the

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CH? group is attached to either the A moiety or the Ar moiety of Formula I), one L⁴ is -O- and the other L⁴ is -NH-, one L⁴ is -CHc-O- (wherein the CH? group is attached to either the A moiety or the Ar moiety of Formula I) and the other 1? is -NH-, one L4 is a covalent bond and the other L⁴ is a substituted or unsubstituted alkylene, one L⁴ is a substituted alkylene and the other L⁴ is a unsubstituted alkylene, one L⁴ is a substituted or unsubstituted alkene and the other L⁴ is -O-, one 1_⁴ is a substituted or unsubstituted alkylene and the other L‘ is -CH2-O- (wherein the CH? group is attached to either the A moiety or the Ar moiety of Formula I), or one L⁴ is substituted or unsubstituted alkylene and the other L⁴ is -NH-.

In still another embodiment of the compounds of Formula I, each A is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl, with the proviso that when A is H, p is 0. When any A is alkyl, said alkyl includes any alkyl defined or exemplified herein. When any A is substituted alkyl, said alkyl includes any alkyl defined or exemplified herein substituted with, one or more of any substituent defined or exemplified herein. When any A is aryl, said aryl includes any aryl defined or exemplified herein. When any A is substituted aryl, said aryl includes any aryl defined or exemplified herein substituted with one or more of any substituent defined or exemplified herein. When any A is heterocyclyl, said heterocyclyl includes any heterocyclyl defined or exemplified herein. When any A is substituted heterocyclyl, said heterocyclyl is any heterocyclyl defined or exemplified herein substituted with one or more of any substituent defined or exemplified herein.

In still another embodiment of the compounds of Formula I, each A is H and each p is 0.

In still another embodiment of the compounds of Formula I, each A is substituted or unsubstituted alkyl, wherein alkyl is any alkyl defined or

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PCT/US2008/054788 exemplified herein, and, when present, the substituents on said alkyl include one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, each A is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein. In a particular embodiment, A is phenyl.

In still another embodiment of the compounds of Formula 1, each A is substituted or unsubstituted heterocyclyl, wherein heterocyclyl is any heterocyclyl defined or exemplified herein, and, when present, the substituents on said heterocyclyl include one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, one A is H and the other A is substituted or unsubstituted alky], wherein alkyl is any alkyl defined or exemplified herein, and, when present, the substituent on said alley! includes one or more of any substituent defined or exemplified herein.

In still another embodiment of the compounds of Formula 1, one A is H and the other A is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and the substituents on said aryl are any substituents defined and exemplified herein. In a particular embodiment, one A is phenyl.

In still another embodiment of the compounds of Formula I, one A is H and the other A is substituted or unsubstituted heterocyclyl, wherein heterocyclyl is any heterocyclyl defined or exemplified herein, and, when present, the substituents on said heterocyclyl include one or more of any substituent defined or exemplified herein.

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In still another embodiment of the compounds of Formula I, one A is substituted or un substituted alkyl, and the other A is substituted or unsubslituted aryl, wherein alkyl and aryl are any alkyl or aryl defined or exemplified herein, and, when present, the substituents on said alkyl or aryl include one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula 1, one A is substituted or unsubstituted alkyl, and the other A is substituted or unsubslituted heterocyclyl, wherein alkyl and heterocyclyl are any alkyl or heterocyclyl defined or exemplified herein, and, when present, the substituents on said alkyl or heterocyclyl include one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, one A is substituted or unsubstituted aryl, and the other A is substituted or unsubstituted heterocyclyl, wherein aryl and heterocyclyl are any aryl or heterocyclyl defined or exemplified herein, and, when present, the substituents on said aryl or heterocyclyl include one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z¹ is -O- or X(R⁷)-. When Z¹ is -N(R⁷)-, R⁷ is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl, substituted alkyl, heleroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z² is -O- or N(R⁷)-. When 72 is -N(R⁷)-, R⁷ is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl,

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PCT/US2008/054788 wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z^! and Z² are the same, e.g., Z^l and Z² are both -O-, or Z¹ and Z² are both -N(R⁷)-, where R⁷ is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z- and Z² are different, e.g. Z^! is -O- and Z² is -N(R⁷)-, Z¹ is -N(R⁷)- and Z² is -0-, or Ζ^Ί and Z/ are both -N(R⁷)- but in Z¹ the R⁷ is different from the R⁷ in Z². When either Z¹ of Zis -N(R⁷)-, R⁷ is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyd, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or exemplified herein.

In still another embodiment of tiro compounds of Formula I, Y is heterocyclyl or heterocyclylalkyl, wherein heterocyclyl and heterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined or exemplified herein. ]n a particular embodiment, Y is heterocyclylalkyl, e.g. thiazolylmethyl (-CHi-thiazolyl).

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In still another embodiment of the compounds of Formula I, X is heterocyclyl or heterocyclylalkyl, wherein heterocyclyl and heterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined or exemplified herein. In a particular embodiment, X is heterocyclylalkyl, e.g. thiazolyl methyl.

In still another embodiment of the compounds of Formula I, X and Y are different, e.g., X and Y are different heterocyclyls, X and Y are different heterocyclylalkyls, X is heterocyclyl and Y is heterocyclylalkyl, or X is heterocyclylalkyl and Y is heterocyclyl, wherein heterocyclyl and heterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, X and Y are the same. In a particular embodiment both X and Y are heterocyclylalkyl, e.g. thiazolylmethyl.

In still another embodiment of tire compounds of Formula I, each Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein the aryl or heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, the substituents on the aryl or heteroaryl include one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, each Ar is the same, e.g., each Ar is an aryl such as phenyl.

In still another embodiment of the compounds of Formula I, each Ar is different, e.g. one Ar is a substituted or unsubstituted aryl and the other Ar is a substituted or unsubstituted heteroaryl, each Ar is a different substituted or unsubstituted aryl, or each Ar is a different substituted or unsubstituted heteroaryl, wherein aiyl and heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, the substituents on the aryl or heteroaryl include one or more of any substituents defined or exemplified herein.

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In still another embodiment of the compounds of Formula 1, R¹, R³, and R⁵are each independently H, alkyl, or substituted alkyl, wherein alkyl and substituted alkyl include any of the alkyl or substituted alkyls defined or disclosed herein.

In still another embodiment of the compounds of Formula 1, R¹, R³, and R⁵are each the same. In a particular embodiment R¹, R¹, and R⁵ are each H. in another particular embodiment R¹, R³, and R³ are each alkyl, e.g. one of the alkyl groups defined or disclosed herein.

In still another embodiment of the compounds of Formula I, R¹, R³, and R^r’ are each different.

In still another embodiment of the compounds of Formula 1, one of R', R³, and R is different from the other two groups.

In still another embodiment of the compounds of Formula I, n and m are both 1, and each R² is independently FI, alkyl, substituted alkyl, arylheteroalkyl, arylalkyl, or heterocydylalkyl, wherein alkyl, substituted alkyl, arylheteroalkyl, aryl alky], or heterocydylalkyl is any alkyl, substituted alkyl, arylheteroalkyl, aryl alkyl, or heterocydylalkyl defined or disclosed herein.

In still another embodiment of the compounds of Formula I, n and m are both 1, and R² is H.

In still another embodiment of the compounds of Formula L, n is 1, m is 2, and R² is H.

In still another embodiment of the compounds of Formula I, n and m are both 1, and at least one R² is alkyl. In a particular embodiment at least one R² is methyl. In another particular embodiment at least one R² is ethyl. In another particular embodiment at least one R² is i-propyl. In another particular embodiment at least one R² is t-butyl, hi another particular embodiment, one R² is H, and the other R² is methyl. In another particular embodiment, one R^; is H, and

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PCT/US 2008/054788 the other R² is ethyl· In another particular embodiment one R² is H, and the other R² is i-propyl. In another particular embodiment, one R² is H, and the other R² is t-butyl.

In still another embodiment of the compounds of Formula I, n and m are both 1, and R² is substituted alkyl. In a particular embodiment at least one R² is CH(CH₃)OH or -CH(CH’.)O(t-Bu)

In still another embodiment of the compounds of Formula I, n and m are both 1, find at least one R² is arylheteroalkyl. In particular embodiment n and m are both 1, and at least one R^: is selected from the group consisting of H, methyl, ethyl, benzyl-O-CH:-, i-propyl, -CH(CFb)OBn, -CJ-I>CH(CH_S)-OtBu, -CH(CH₃)OH, -CI-hOH, -CFbOtBu, -CH2CH2NH2, -CH2CH2NH-P (where P is a protecting group such as Boc, Ac, methanesulfonyl, etc.), -CH?CHf-m or pholine, -CH£(O)OH, -CH2C(O)OtBu, and -CH2C(O)-N1FL·

In still another embodiment of the compounds of Formula I, n and m are both 1, and at least one R² is arylheteroalkyl. In particular embodiment n and m are both I, one R^: is H and one R² is selected from the group consisting of H, methyl, ethyl, benzyl-O-CH2-, i-propyl, -CH(CHQOBn, -CH:CH(CH₃)-OtBu, -CH(CFb)OH, -CH2OH, -ChkOtBu, -CH2CH2NH2, -CH2CH2NH-P (where P is a protecting group such as Boc, Ac, methanesulfonyl, etc.), -CHsCHi-morphoIine, -CttC(O)OH, -CH£(O)OtBu, and -CH₂C(O)-NH2.

In still another embodiment of the compounds of Formula I, R- is H, alkyl, substituted alkyl, and hetcroalkyl· wherein alkyl, substituted alkyl, and heteroalkyl are any alkyl, substituted alkyl, or hcteroalkyl defined or disclosed herein. A particular embodiment, R⁴ is H.

In still another embodiment of the compounds of Formula I, R^& is H, alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substituted alkyl, and

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PCT/US2008/054788 hcteroalky] arc any alkyl, substituted alkyl, or heteroalkyl defined or disclosed herein. A particular embodiment, R^& is H.

In still another embodiment of the compounds of Formula I, R^s and R- are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and -CN, wherein when R^s or R are alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl, said alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl arc any such groups defined or disclosed herein.

In still another embodiment of the compounds of Formula I, R^B and R^q are the same. In a particular embodiment R^s and R^u are both H.

In still another embodiment of the compounds of Formula I, R* and R·' are different. In a particular· embodiment R^s is alkyl and is H. in another particular embodiment, R^s is i-propyl and R¹' is H.

In yet another embodiment of the compounds of Formula I, at least one of the -lJ-A-(lJ-Ar)_r moieties is an -alkylene-aryI group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted or the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -U-A-iU-ArJp moieties is an -alkylene-aryl-alkylene-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -I?-A-(L^l-Ar)_P moieties is an -alkylene-ary]-alkylene-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and

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2020203321 21 May 2020 he ternary! moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl, and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L’-A-(L⁴-Ar)p moieties is an -alkylene-heteroaryl-alkylene-heteroaryl group, wherein said alkylene and heteroaryl moieties are any alkylene and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -1,^?’-A-(L⁴-Ar)p moieties is an -alkylene-heteroaryl-alkylene-aryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl, and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(U-Ar)_P moieties is an -alkylene-ary]-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the “LAA-(L⁴-Ar)_P moieties is an -alkylene-aryl-O-ary] group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula 1, at least one of the -L³-A-(1?-Ar)p moieties is an -aikylene-aryl-CFh-O-aryl group, wherein said □ σ

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In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(L⁴-Ar)_P moieties is an -alkylene-aryl-OCHs-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L^J-A-(L⁴-Ar)_P moieties is an -alkylcnc-aryl-NH-aryl group, wherein said alkylene and ary] moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L'-A-(L⁴-Ar)p moieties is an -alkylene-aryl-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryk and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula 1, at least one of the -IAA-(L⁴-Ar)p moieties is an -alkylene-aryl-O-heterocycIyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L^?'-A-(L⁴-Ar)_r moieties is an -alkylene-aryLCHj-O-heLerocyclyl group,

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PCT/US2008/054788 wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein,

In yet another embodiment of the compounds of Formula I, at least one of the 4ΛΑ-(ΙΛΑτ)_Ρ moieties is an -a Iky lene-aryI-OCH:i-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties arc any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -I/-A-(L⁴-Ar)p moieties is an -alkylene-aryl-NH-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(L⁴-Ar)p moieties is an -alkylene-heterocyclyl-aryl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-CL'-Ar)p moieties is an -alkylcnc-hetcrocyclyl-O-aryl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene

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PCT/US 2008/054788 and/or aryl and/or heterocydyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -[?-A-(L⁴-Ar)_P moieties is an -alkylene-heterocydyl-CFb-O-aryl group, wherein said alkylene, aryl, and heterocydyl moieties are any alkylene, aryl, and heterocydyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocydyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of tire - V-A-fL’-ArJp moieties is an -alkylene-heterocydyl-OCFb-aryl group, wherein said alkylene, aryl, and heterocydyl moieties are any alkylene, aryl, and heterocydyl moieties defined or exemplified herein, optionally substituted on tire alkylene and/or aryl and/or heterocydyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -1ΛΑ-(Ε⁴-Αγ)ρ moieties is an -alkylcnc-hctcrocyclyl-NH-ary] group, wherein said alkylene, aryl, and heterocydyl moieties are any alkylene, aryl, and heterocydyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocydyl with one or more of any substituents defined or exemplified herein.

hr yet another embodiment of the compounds of Formula I, at least one of the -IAA-(L⁴-Ar)_P moieties is an -alkylene-heterocydyl-heterocyclyl group, wherein said alkylene, aryl, and heterocydyl moieties arc any alkylene, aryl, and heterocydyl moieties defined or exemplified herein., optionally substituted on tire alkylene and/or aryl and/or heterocydyl with one or more of any substituents defined or exemplified herein.

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In yet another embodiment of the compounds of Formula I, at least one of the -L^:3-A-(L⁴-Ar)_P moieties is an -alkylene-heterocycIyl-O-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

hr yet another embodiment of the compounds of Formula 1, at least one of the -L³-A-(L⁴-Ar)p moieties is an -alkylene-heterocyclyl-Q h-O-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(L’-Ar)p moieties is an -alkylene-heterocyclyl-OCH:-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L^:i-A-(L⁴-Ar)p moieties is an -alkylene-heterocyclyl-NH-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(L⁴-Ar)_P moieties is an-alkylene-aryl-heteroaryl group, wherein said alkylene, and, and heteroaryl moieties are any alkylene, aryl, and hetero aryl

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PCT/US2008/054788 moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L?-A-(L^J-Ar)p moieties is an -alkylene-aryl-O-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(L⁴-Ar)_P moieties is an -alkylene-aryl-CHi-O-hctcroaryl group, wherein said alkylene, aryl, and hetcroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or he ternary] with one or more of any substituents defined or exemplified herein.

In yet another embodiment of tire compounds of Formula I, at least one of the -Ι?-Α-(ΙΛΑγ)ρ moieties is an -alkylene-aryl-OCH2-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -1?-A-(I?-Ar)_? moieties is an -alkylene-aryl-NH-heteroaryl group, wherein said alkylene, aryl, and hetero a nd moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

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In yet another embodiment of the compounds of Formula I, at least one of the -L'-A-(L--Ar)_P moieties is an -alkylene-heteroaryl-aryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more oi any substituents defined or exemplified herein.

In yet another embodiment of tire compounds of Formula Ϊ, at least one of the -ΙΛΑ-(ΙΑ-Αγ)ρ moieties is an -alkylene-hcteroaryl-O-aryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on tire alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of tire compounds of Formula I, at least one of the -L⁵-A-(L⁴-Ar)p moieties is an -alkylene-heteroaryl-Chb-O-aryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L?-A-(L⁴-Ar)_? moieties is an -alkylene-heteroaryl-OCHz-aryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -I?-A-(L⁴-Ar)_r moieties is an -aikylene-heteroaryl-NH-aryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryk and heteroaryl

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PCT/US 2008/054788 moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -1ΛΑ-(Ι?-Αγ)ρ moieties is an -alkylene-heterocyclyl-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(I?-Ar)p moieties is an -alkylone-hetorocyclyl-O-hetcroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -ΙΛΑ-(ΙΛΑι)ρ moieties is an -alkylene-heterocyclyl-CFk-O-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, ary4, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -U-A-(L^J-Ar)p moieties is an -alkylene-heteroaiyl-OCFb-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

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In yet another embodiment of the compounds of Formula I, at least one of the -L³-A-(L⁴-Ar)p moieties is an -alkylene-heteroaryl-NH-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one of the -L^:’-A-(L⁴-Ar)p moieties is an alkyl group.

In yet another embodiment of the compounds of Formula I, both of the -L³-A-(L⁴-Ar)p moieties are alkyl groups, wherein the alkyl groups are the same or different.

In yet another embodiment of the compounds of Formula I, both -L?-A(L*'-Ar)p moieties are -CH:-phenyl and X and Y are both -CH?-heterocyclyI.

In yet another embodiment of the compounds of Formula 1, both 4?-A(L⁴-Ar)p moieties are - CH:-phenyl and Y is -CH:-heterocyclyl.

In yet another embodiment of the compounds of Formula I, both -ΙΛΑ(L⁴-Ar)p moieties are -CH:-phenyl and X is -Cl b-hcterocyclyl.

In yet another embodiment of the compounds of Formula 1, both -ΙΛΑ(IAAr)p moieties are -CFb-phenyl and Y is -CH:-thiazolyl.

In yet another embodiment of the compounds of Formula J, both -L³-A(L⁴-Ar)p moieties are -CHs-phenyl and X is -CHi-thiazolyl.

In yet another embodiment of the compounds of Formula I, both -L--A(L⁴-Ar)_P moieties are -CH:-phenyl and X and Y are both -CH:-thiazolyl.

]n yet another embodiment of the compounds of Formula I, both -L³-A(L⁴-Ar)_P moieties are -CH?-phenyl, X and Y are both -CH:-thiazoIyl, and n and m are both 1.

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Tn yet another embodiment of the compounds of Formula I, both -1ΛΑ(L⁴-Ar)p moieties are -CH:-phenyl, X and Y are both -CH:-thiazolyl, n and m are both 1, and at least one R- is a Ci-G- alkyl.

In yet another embodiment of the compounds of Formula Ϊ, both -L-'-A(L⁴-Ar)_p moieties are -CHz-phenyl, X and Y are both -CH:-thiazolyl, n and m are both 1, and at least one R- is a Ci-Cf. hydroxyalkyl.

In yet another embodiment of the compounds of Formula I, both -L³-A(L’-Ar)p moieties are -CH:-phenyl, X and Y are bo tin -CH:-thiazolyl, n and m are both 1, and at least one R² is a C:-Cjo alkoxyalkyl.

In yet another embodiment of the compounds of Formula I, both -ΙΛΑ(I?-Ar)_r moieties are -CH’-phenyl, X and Y are both -CH:-thiazolyl, n and m are both 1, and at least one R² is a Cr-Cn arylalkyl oxy alkyl.

hi yet another embodiment of the compounds of Formula I, both -U-A(L⁴-Ar)_r moieties are -CH:-phenyl, X and Y are both -CH:-thiazolyl, n and m are both 1, and at least one R² is a Ci-Ci. aminoalkyl.

]n yet another embodiment of the compounds of Formula 1, both -ΙΛΛ(L⁴-Ar)p moieties are -CFL-phenyl, X and Y are both -CH:-thiazolyl, n and m are both 1, and at least one R² is a Ci-Ca aminoalkyl substituted on the nitrogen with an amine protecting group selected from acyl, alkylsulfonyl, arylsulfonyl, hctcrocydylacyl, and benzyl.

In yet another embodiment of the compounds of Formula 1, both -L³-A(L.⁴-Ar)_P moieties are -CFk-phenyl, X and Y are both -CI L-thiazolyl, n and m are both 1, and at least one R² is a substituted or unsubstituted heterocyclylalkyl.

In yet another embodiment of the compounds of Formula I, both -L³-A(L⁴-Ar)p moieties are — CHs-phenyl, X and Y are both -CH:-thiazolvl, n and m are both 1, and L² is - CH:-.

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In yet another embodiment of die compounds of Formula I, at least one -L³-A-(L⁴-Ar)_P moiety is-CHr-phenyl-CJ-b-phenyl.

In yet another embodiment of the compounds of Formula I, at least one -I ?-A-(I_⁴-Ar)p moiety is-CHi- heteroaryl-CH:~phenyI.

In yet another embodiment of fire compounds of Formula I, at least one -L³-A-(L^L’-Ar)_P moiety is-CHz-phenyl-CFh-heteroaryl.

In yet another embodiment of the compounds of Formula 1, at least one -L³-A-(L⁴-Ar)p moiety is-CH:- heteroaiyl-CHi-heteroaiyl.

In yet another embodiment of die compounds of Formula I, X and Y are both heterocyclylalkyl.

In yet another embodiment of the compounds of Formula I, X and Y are both heteroarylalkyl.

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, and both -ΣΛΑ-(1?-Αγ)_ρ groups are substituted or unsubstituted benzyl.

In another embodiment of the compounds of Formula L, L' is -C(O)-, R⁴ is FI, both -L³-A-(L⁴-Ar)_f. groups are substituted or unsubstituted benzyl, and L- isCFL·-.

In another embodiment of the compounds of Formula I, L’ is -C(O)-, R¹ is II, both -L³-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L^: is -CFL·-, and m and n are both 1.

In another embodiment of the compounds of Form Lila I, L¹ is -C(O)-, R⁴ is FI, both -LA-A-(L⁴-Ar)p groups are substituted or unsubstituted benzyl, L? is -Chhin and n are both 1, and R' is H.

In another embodiment of the compounds of Formula 1, L' is -C(O)-, R⁴ is H, both -L³-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L² is -CH:-, m and n are both I, R' is H, and Z¹ is -N(alkyl)-.

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In another embodiment of the compounds of Formula I, IJ is -C(O)-, R⁴ is H, both -L³-A-(L⁴~Ar)p groups are substituted or unsubstituted benzyl, L^: is -CH?-, m and n are both 1, R¹ is H, and Z¹ is -N(CHj)-.

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L³-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L² is -CH:-, m and n are both 1, R¹ is Η, Z' is -N(alkyl)-, and Z² is -O-.

In another embodiment of the compounds of Formula I, L' is -C(O)-, R⁴ is H, both -L^?-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L² is -CH:-, m and n are both 1, R¹ is Η, Z· is -N(CFL·)-, and 73 is -O-.

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L~-A-(L⁴-Aijp groups are substituted or unsubstituted benzyl, L² is -CFF-, m and n are both 1, R¹ is Η, Z¹ is -N (alkyl)-, 73 is -O-, and Y is substituted or unsubstituted -CH:-4-thiazole.

In another embodiment of the compounds of Formula 1, L¹ is -C(O)-, R⁴ is H, both -L³-A-(l?-Ar)_P groups are substituted or unsubstituted benzyl, L- is -CH?-, m and n are both I, R¹ is Fl, Z¹ is -N(alkyl)-, 73 is -O-, and R^s-Y is -CFb-(2-alky^rI-4thi azole).

In another embodiment of the compounds of Formula I, L’ is -C(O)-, R⁴ is H, both -L³-A-(L⁴-Ar)p groups arc substituted or unsubstituted benzyl, L² is -CH?-, m and n are both 1, R¹ is H, 72 is -N(H)-, Z² is --O-, and R'-Y is -CH2-(2-iPr-4thi azole).

In another embodiment of the compounds of Formula I, L’¹ is -C(O)-, R⁴ is H, both -L/-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, U is -CH:-, m and n are both 1, R¹ is Η, Z¹ is -N(alkyl)-, Z² is -Ο-, Y is substituted or unsubstituted -CFb-4-thiazole, and X is substituted or unsubstituted -CHs-5thiazole.

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In another embodiment of the compounds of Formula I, IJ is -C(O)-, R⁴ is H, both -1?-Α-(ΙΛΑΐ')_Ρ groups are substituted or unsubstituted benzyl, L² is -CH2-, m and n are both 1, R¹ is Η, Z¹ is -N(alkyl)-, 7- is -Ο-, Y is substituted or unsubstituted -CH2-4-thiazole, and X is unsubstituted -CH2-5-thiazole.

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L³-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L² is -CH?-, m and n are both 1, R¹ is Η, Z¹ is -N(H)-, Z² is -0-, R^s-Y is -CHz-(2-ΐΓι-4-thiazole), and X is unsubstituted -CH?-5-thiazole.

In another embodiment of the compounds of Formula I, each R² is independently H or hydroxyalkyl.

In another embodiment of the compounds of Formula I, each R² is independently H or heterocydylalkyl.

In another embodiment of the compounds of Formula I, each R² is independently 14 or -CFh-heterocyclyl, wherein said heterocycJyl is a 5- or 6membered ring having at least one ring nitrogen atom.

In another embodiment of the compounds of Formula I, each R² is independently H or-CFb-heterocydyl, wherein said heterocycJyl is a 6membered ring having at least one ring nitrogen atom.

In another embodiment of the compounds of Formula I, each R² is independently 11 or -CFL-hctcrocydyl, wherein said heterocyclyl is a 6membered ring having at least one ring nitrogen atom, where the -CH?- moiety’ thereof is bonded to the ring nitrogen atom.

In another embodiment of the compounds of Formula I, each R² is independently H or -CFb-heterocyclyL wherein said heterocyclyl is selected from the group consisting of piperadyl, piperazyl, and morpholinyl.

In another embodiment of the compounds of Formula I, each R² is independently FI or -CFL-heterocydyl, wherein said heterocyclyl is selected from

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Elie group consisting of piperad yl, piperazyl, and morpholinyl, and the -CHimoiety thereof is bonded to a ring nitrogen atom of the heterocyclyl.

in another embodiment of the compounds of Formula I, each R² is independently H or aminoalkyl.

In another embodiment of the compounds of Formula I, each R² is independently H or aminoalkyl substituted with an amine protecting group selected from the group consisting of acetyl, alkylsulfonyl, Boc, Cbz, and Fmoc.

In another embodiment of the compounds of Formula I, each R⁷ is independently H or ethylacetamide (-CH2CFhNHC(O)CH’).

In another embodiment of tire compounds of Formula I, U is -C(O)-, R⁴ is H, both -U-A-('L⁴-Ar)p groups are substituted or unsubstituted benzyl, 1.² is -CH2-, m and n are both 1, R^! is Η, Z¹ is -N(H)-, Z² is -O-, R^b-Y is -CI B-(2-iPr-4-thiazole), X is wisubsrituted -CH^-S-thiazolc, and R² is independently H or hydroxyalkyl.

In another embodiment of tire compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L?-A-(L¹-Ar)p groups are substituted or unsubstituted benzyl, L² is -Cl h-, m and n are both 1, R¹ is Η, Z¹ is -N(I-l)-, Z² is -O-, R^h-Y is -CH?-(2-iPr-4-thiazole), X is unsubstituted -CH?-5-thiazole, and one R² is H and the other R² is hydroxy alkyl.

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L³-A-(L⁴-Ar)p groups are substituted or unsubstituted benzyl, L² is -CH?-, m and n are both Ί, R¹ is Η, Z¹ is -N(H)-, Z² is -O-, R^H-Y is -C H 2-(2-1 Pr-4~thiazole), X is unsubstituted -CFb-5-thiazole, and one R² is H and the other R² is hydroxymethyl.

In another embodiment of the compounds of Formula 1, L¹ is -C(O)-, R⁴ is H, both -l?-A-(L⁴-Ar)p groups are substituted or unsubstituted benzyl, L² is -CH’-, m and n are both 1, R' is Η, Z- is -N(H)-, Z² is -O-, R^fi-Y is -CH?-(2-iPr-4-thiazole), X is unsubstituted -CH2-5-thiazoIe, and each R² is independently H or-CH66

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PCT/US 2008/054788 hctcrocvclyl, wherein said heterocyclyl is a 5- or 6-membered ring having at least one ring nitrogen atom.

In another embodiment of the compounds of Formula I, L^[ is -C(O)-, I?⁴ is H, both -I?-A-(L⁴-Ar)_P groups are substituted or un substituted benzyl, L² is -CH?-, m and n are both 1, R¹ is Η, Z¹ is -N(H)-, Z² is -O-, R*-Y is -CH?-(2-iPr-4-thiazole), X is unsubstituted -CHs-o-thiazole, and each R² is independently H or ΑΞΗξheterocyclyl, wherein said heterocyclyl is selected from the group consisting of piperadyl, piperazyl, and morpholinyl, and the -CHj- moiety thereof is bonded to a ring nitrogen atom of the heterocyclyl

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L³-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L^! is -CFh-, in and n are both 1, R¹ is Η, Z' is -N(H)-, Z² is -O-, R^LY is -CI-b-^-iPM-thiazole), X is unsubstituted -CFt-a-thiazole, and one R² is H and the other R² is -CHzheterocyclyl, wherein said heterocyclyl is selected from the group consisting of piperadyl, piperazyl, and morpholinyl, and the -CH2- moiety thereof is bonded to a ring nitrogen atom of the heterocyclyl

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L?-A-(L⁴-Ar)p groups are substituted or unsubstituted benzyl, L² is -CH?-, m and π are both 1, R’ is H, Z^J is -N(H)-, Z² is -O-, R^s-Y is -CH2-(2-iPr-4-thiazole), X is unsubstituted -CH:-5-thiazole, and each R² is independently H or aminoalkyl substituted with an amine protecting group selected from the group consisting of acetyl, a Iky I sulfonyl, Boc, Cbz, and Fmoc.

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L<A-(L⁴-Ar)p groups are substituted or unsubstituted benzyl, L? is -CH:-, m and n are both 1, R’ is Η, Z¹ is Z² is -O-, IU-Y is -CH--(2-iPr-4-thiazole), X is unsubstituted -CH:-5-thiazole, and one R² is H and the other R² is aminoalkyl

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In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -L?-A-(L⁴-Ar)_P groups are substituted or unsubstituted benzyl, L- is -CH:-, m and n are both 1, R¹ is Η, Z¹ is -N(H)-, Z² is -O-, R^s-Y is -CJ-b-(2-iPr-4-thiazole), X is unsubstituted -CFb-S-thiazole, and one R² is H and the other R² is ethylacetamide (-CH?CH2NHC(O)CHa).

In another embodiment of the compounds of Formula I, L¹ is -C(O)-, R⁴ is H, both -Ι?-Α-(1?-Αγ)_γ groups are substituted or unsubstituted benzyl, L² is -CH?-, m and n are both 1, R¹ is Η, Z’ is -N(alkyl)-, Z² is -O-, and Y is substituted or unsubstituted -CH:-thiazole.

In still another embodiment, the compounds of Formula I, or pharmaceutically acceptable salts, solvates, esters, or stereoisomers thereof, have the structure shown in Formula ΠΑ:

Formula II A wherein Rⁿ and R^ln are each independently heterocyclyl or substituted heterocyclyl; and R¹², R¹³, R¹⁴, arid R¹⁵ are each independently H, -Ci -t alkyl or -Cm substituted alkyl.

In still another embodiment of the compounds of Formula HA, R¹³ is H, -Cji alkyl, -(CH2)caCR^,7R^iSOR^ir', -(CTL^CRd^NR^R²¹, -(CI-k):>-*CR^]7R¹⁸NR^l7C(O)NF'R³¹, -(CH:)mC(O)R²², -(CH?)i-3S(O)2R²² or -(CH:)m-R*; R¹⁴ and R¹⁵ are each independently FI, -Cm alkyl or aryl alkyl; R^1? and R^1S are each independently H or Ci j alkyl; R^ie is H, -Cm alkyl or arylalkyl; R²⁰ and R²¹ are each independently H, Cm alkyl, -C(O)Rⁱ⁷ or -S(O)?R'⁷; or R²⁰ and R-', taken together with the nitrogen atom to which they are attached, form an unsubstituted or substituted 5-6

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PCT/US2008/054788 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O; R²² is H, -C1-3 alkyl, -OR³'¹ or -NR-°R²¹; and R²³ is an unsubstituted or substituted 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O.

In still another embodiment of the compounds of Formula IIA, R‘³ is (CH2)c-3CR⁵⁷R^lsNR^?pR’’, -(CIh)n-3CR^irR'^sNR^,7C(O)-N^TR²ⁿR²’, or -(CHz/.-s-R²³ wherein R²ⁱ⁾ and R²¹ form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O or R²³ is an unsubstituted or substituted 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O, and tire 5-6 membered heterocyclyl ring is optionally substituted with a Ci-: alkyl.

In still another embodiment of the compounds of Formula IIA, R^l3is(CH2)ii-iCR’¹⁷R^]8OR¹‘’- In a particular embodiment, R^l3is a C1-2 hydroxyalkyl or a Ci 6 alkoxy a Iky I group.

In still another embodiment of the compounds of Formula IIA, R'-is(CHihsCR^R^NR^R²’- In a particular embodiment, R¹³ is a Chalkylene-NH: group, Chalkylenc-ΝΉΡ (wherein P is a protecting group such as Boc, Fmoc, Cbz, Ac, trifluoroacetyl, toluenesulfony group, benzyl, etc.), or Ci-;alky]ene-N(alkyl)’ group.

In still another embodiment of the compounds of Formula IIA, R¹³ is (CI-12)o-3CR^,7R^1!;N^TR^l7C(0)-NR^2l,R^2!. In a particular embodiment, R¹³ is a Ci-ialkylene-C(O)NH2 group or C- 4alkylcirc-C(O)N^r(aikyl)r group.

In still another embodiment of tire compounds of Formula IIA, R”, R’-, R^!3, R¹⁴, R¹³, and R^ih are each independently selected from the groups shown in the Table, below:

RH _R12 R13 RW R15 R16

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In still another embodiment of the compounds of Formula HA, R¹¹ is substituted or unsubstituted heterocyclyl, R¹² is alkyl, R¹³ is substituted or

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In still another embodiment of the compounds of Formula ΠΑ, R^1! is substituted heterocyclyl, R¹² is alkyl, Rⁱ³ is unsubstituted heterocyclylalkyl, R’⁴ and R^1S are both unsubstituted arylalkyl, and R^?i' is unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula II A, Rⁿ is substituted or unsubstituted heterocyclyl, R¹² is alkyl, R¹³ is hydroxyalkyl, R¹' and R¹³ arc each independently substituted or unsubstituted arylalkyl, and R^R is substituted or unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula I1A, K¹¹ is substituted heterocyclyl, R¹² is alkyl, R¹³ is hydroxyalkyl, R¹⁴ and R ^s are both unsubstituted arylalkyl, and R¹' is unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula II A, Rⁿ is substituted or unsubstituted heterocyclyl, R¹² is alkyl, R¹³ is protected or unprotected aminoalkyl, R¹⁴ and R¹³ are each independent!) substituted or unsubstituted arylalkyl, and R'° is substituted or unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ is substituted heterocyclyl, R‘² is alkyl, R¹³ is protected aminoalkyl, Rⁱ⁴ and R¹⁵ are both unsubstituted arylalkyl, and R’⁶ is unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula IIA, R'¹ is substituted heterocyclyl, R¹² is alkyl, R¹³ is acylated aminoalkyl, R¹⁴ and R¹⁵ are both unsubstituted arylalkyl, and R¹” is unsubstituted heterocyclyl.

In another embodiment, the compounds of Formula 1, or pharmaceutically acceptable salts, solvates, stereoisomers and/or esters thereof, have the following structure IIB:

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R^1(to and R^Wh are each independently H or -G-t alkyl; R¹² is H or -Cl h; R¹³ is H, -G^ alkyl, -(CHz^iCR^R^OR’⁹, -(CH2>3CR^,7R^lflNR²⁰RG -(CHsj^CR^R ^NR¹⁷C(O) NR²ⁿR²¹, -(CH2)i-3C(O)RG -(CHQ>jS(OkJG or -(CH₂)m-R²³; R^;4 and R¹⁵ are each independently H, -Cm alkyl or arylalkyl; R¹⁷ and R^1!:i are each independently H or Ci-3 alkyl; R¹⁹ is H, -Ci-j alkyl or arylalkyl; R²⁰ and R²¹ are each independently H, G-ί alkyl, -C(O)R^1? or -S(O)iR'⁷; or R^2D and R²¹, taken together with the nitrogen atom to which they are attached, form an un substituted or substituted 5-6 membered heterocyclyl ring containing Ί-2 hcteroatoms selected from the group consisting of N and O; R²² is H, -Ci-salkyl, -OR¹⁹ or -NR^2,,R²¹; and R²¹ is an unsubstituted or substituted 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O.

In still another embodiment of the compounds of Formula ΠΒ, R¹' is (CH^CR'T^NR^R²¹, -(CH2)_u-₃CR^R^iSNR⁵⁷C(O)-NR²⁰R²¹, or -(CHz)m-R²³ wherein R^2U and R²' form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O or R²-³ is an unsubstituted or substituted 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O, and the 5-6 membered heterocyclyl ring is optionally substituted with a G-zalkyL hr another embodiment, the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers and/or esters thereof, have the following structure 11C:

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Formula IIC wherein: R^’is H, -Ci^ alkyl, -(Clk^iCR'^OR¹⁹, -(CH2)B-<R¹⁷R^?8XR^2I’R% -(CH=> 3CR^1?R'^,SNR’⁷C(O) NR*^!R^2!, -(CH:)i-3C(O)R- or -(CHzJi-s-R-; Rⁱ⁷ and R^1S are each independently H or Co alkyl; R¹⁹ is H, -Cn alkyl or arylalkyl; R²⁰ and R²’¹ are each independently H, -Ci a alkyl, -C(O)R¹⁷ or -S(O)2R¹⁷; or R²° and R²¹, taken together with the nitrogen atom to which they are attached, form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O; R²² is H, -C-’alkyl, -OR¹⁹ or -NR^2f,R²¹; and R²'³ is a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O.

In still another embodiment of the compounds of Formula UC, R¹² is (CH^UR^R^NR^R²¹, -(CH2)<^CR¹⁷R^1HNR^l7C(O)-NR^2t)R²¹, or -(CHyto^R²⁷ wherein R²¹· and R²¹ form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O or R~^?· is an unsubstituted or substituted 5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected from the group consisting of N and O, and the 5-6 membered heterocyclyl ring is optionally substituted with a C1-2alkyl.

In still another embodiment of the compounds of Formula JIC, R^Ki is (CI-b)^3CR¹⁷R^lf!NR^2ilR²L In a particular embodiment, Rⁱ³ is a CMalkylene-NH: group, CUalkylene-NHP (wherein P is a protecting group such as Boc, Fmoc, Cbz,

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Ac, tri fluoroacetyl, toluenesulfony group, benzyl, etc.), or C 14a lkylene-N (alkyl): group.

In still another embodiment of the compounds of Formula IIC, R^;? is (CFkXjCR^R’^R^QOl-NR^R²¹. In a particular embodiment, R ³ is a CMa!kylene-C(O)NH: group or Cwalkylene-C(O)N(aIkyl)? group.

In still another embodiment of the compounds of Formula 1IC, R'³is CFhOH, -CHiCH2.NHC(O)CHj or

In another embodiment, the compounds of of the present invention, or pharmaceutically acceptable salts, solvates, stereoisomers and/or esters thereof, have the following structure IJD:

(L⁴-Ar)_p

X—R⁹ wherein,

L¹ is selected from the group consisting of -C(R⁶)>, -C(O)-, -5(0:)-, -N(R)-C(O)-, and -O-C(O)-;

each L^J is independently a covalent bond, an alkylene, or substituted alkylene;

each U is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, -O-, -CH2-O-, and -ΝΙΊ-;

each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,

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PCT/US2008/054788 with the proviso that when A is H, p is 0;

Z' and Z^: are each independently -O- or -N'(R⁷)ri

Y and X arc independently selected from the group consisting of heterocydyl and heterocyclylalkyl;

each Ar is independently selected from the group consisting of aryl, substituted and, heteroaryl, and substituted heteroaryl;

R¹, R’, and R⁵ am each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;

R¹ is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylhetcroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocydylalkyl, aminoalkyl, substituted aminoalkyl, ~alkylene-C(O)-OH, alkyl ene-C(O)-Oa Iky 1, -al kylene-C(O) amino, -alkylene-C(O)-alkyl;

R⁴ and R⁽’ are independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroaikyl;

each R⁷ is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroaikyl, carbocyclyl, substituted carbocyclyl, heterocydyl, and substituted heterocydyl;

R^fi and R⁹ are each one or more substituents independently selected from the group consisting of H, alkyk substituted alkyl, halogen, aryl, substituted aryl heterocydyl, substituted heterocydyl, and -CN; and each p is independently 0 or 1.

In another embodiment of the compounds of Formula IID, L¹ is

In another embodiment of the compounds of Formula IID, L¹ is -CH;-.

In another embodiment of tire compounds of Formula IID, each L? is alkylene.

In another embodiment of the compounds of Formula IID, each L¹ is -CH?-.

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In another embodiment of the compounds of Formula IID, each A is aryl or substituted aryl.

In another embodiment of the compounds of Formula HD, each A is phenyl or substituted phenyl.

In another embodiment of the compounds of Formula IID, X is heterocyclylalkyl.

In another embodiment of the compounds of Formula UD, X is thiazolyl methyl.

In another embodiment of the compounds of Formula I ID, Y is he terocycly lalky 1.

In another embodiment of the compounds of Formula IID, Y is thiazolyl methyl.

In another embodiment of the compounds of Formula IID, Z· is -N(R⁷)-.

In another embodiment of the compounds of Formula HD, Z¹ is -NH-.

In another embodiment of the compounds of Formula IID, Z¹ is -N(alkyl)-.

In another embodiment of tine compounds of Formula 11D, Z^: is -NfCFL·)-.

In another embodiment of the compounds of Formula IID, Z² is -O-.

In another embodiment of the compounds of Formula IID, Id is -C(R^f’k- and X and Y are heterocyclylalkyl.

In another embodiment of the compounds of Formula IID, Id is -CHz- and X and Y arc heterocyclylalkyl.

In another embodiment of the compounds of Formula IID, L’’ is -CH:- and

X and Y are thiazolylmethyl.

In another embodiment of the compounds of Formula IID, Id is -C(R^f,b- and Z¹ is -N(R⁷)-.

In another embodiment of the compounds of Formula IID, L’ is -CFL·- and

Z¹ is -MR')76

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In another embodiment of the compounds of Formula I1D, L^! is -CH:- and Z’ is -NH-.

In another embodiment of the compounds of Formula I ID, L^! is -CH:- and Z' is -N(alkyl)-.

In another embodiment of Lire compounds of Formula IID, L^! is -CH:- and Z’ is-N(Chh)-.

in another embodiment of the compounds of Formula IID, L¹ is -C(R^h)2- and Z² is -O-.

In another embodiment of the compounds of Formula IID, each L³ is alkylene and each A is aryl or substituted aryl.

In another embodiment of the compounds of Formula HD, each L^:’ is -CHzand each A is aryl or substituted aryl.

In another embodiment of the compounds of Formula IID, each L³-A is benzyl or substituted benzyl.

In another embodiment of the compounds of Formula IID, X and Y are heterocyclylalkyl and Z¹ is -N(R⁷)-.

In another embodiment of the compounds of Formula IID, X and Y arc thiazolylmethyl and Z¹ is -N(R⁷)-.

In another embodiment of the compounds of Formula IID, X and Y are thiazolylmcthyl and Z¹ is -N(alkyl)-.

In another embodiment of the compounds of Formula IID, X and Y are thiazolylmethyl and Z¹ is -N(CH?)-.

in another embodiment of the compounds of Formula IID, X and Y are thiazoly line thy 1 and 7J is -NH-.

In another embodiment of the compounds of Formula HD, X and Y are heterocyclylalkyl and Z^: is -O-.

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In another embodiment of the compounds of Formula IID, X and Y are thiazolylmethyl and Z² is -O-.

In another embodiment of the compounds of Formula HD, Z¹ is -N(R⁷)- and Z² is -O-.

In another embodiment of the compounds of Formula IID, Z^! is -N(alkyl)- and Z² is -O-.

In another embodiment of the compounds of Formula IID, Z is -N(CH₃)- and Z² is -O-.

hi another embodiment of the compounds of Formula IID, Z¹ is -NH- and Z² is -O-.

In another embodiment of the compounds of Formula IID, IJ is -C(R'^J):-, X and Y arc heterocyclylalkyl, and Z' is -N(R⁷)-.

In another embodiment of the compounds of Formula IID, L¹ is -CH2-, X and Y are heterocyclylalkyl, and Z¹ is -N(R⁷)-.

In another embodiment of the compounds of Formula IID, L¹ is -CH:-, X and Y are thiazolylmethyl, and Z¹ is -N(R⁷)-.

In another embodiment of the compounds of Formula TID, L^! is -CH2-, X and Y arc thiazolylmothyl, and Z- is -Xfalkyl)^-·

In another embodiment of the compounds of Formula HD, L¹ is -CH2-, X and Y are Lhiazolylmethyl, and Z¹ is -N(CFb)-.

In another embodiment of the compounds of Formula IID, L' is -CH:-, X and Y are thiazolyl methyl, and Z¹ is -NH-.

In another embodiment of the compounds of Formula IID, L¹ is -C(K^h)2-; X and Ύ are heterocyclylalkyl; and Z² is -O-.

In another embodiment of the compounds of Formula IID, L¹ is -CH?-; X and Y are heterocyclylalkyl; and Z² is -O-.

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In another embodiment of the compounds of Formula IID, L¹ is -CH:-; X and Y are thiazolylmethyl; and Z² is -O-.

In another embodiment of the compounds of Formula IID, L= is -QRQ:-; each L³ is alkylene; each A is aryl or substituted aryl; X and Y are heterocyclylalkyl; Z¹ is -N(R⁷)-; and Z-’ is -O-.

In another embodiment of the compounds of Formula IID, L^; is -CH:-; each ΙΛΑ is benzyl or substituted benzyl; X and Y are thiazolylmethyl; Z¹ is -N(CHs)-; and Z² is -O-.

In another embodiment of the compounds of Formula UD, L¹ is -CH:-; each L³-A is benzyl or substituted benzyl; Z' is -N(CH3)-; Z² is -O-; X is

In another embodiment, the compounds of of the present invention, or pharmaceutically acceptable salts, solvates, stereoisomers and/or esters thereof, have the following structure IV:

wherein, each L³ is independently an alkylene or substituted alkylene;

each A is independently an aryl or substituted aryl;

X is heterocyclylalkyl;

Y is heterocyclylalkyl or alkyl;

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G¹ and G² are independently CI I or N, with the proviso that G¹ and G² are different;

G² is -NR⁷- or -O-;

R^l, R³, R³, and R⁷ are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;

R² is independently selected from the group consisting of substituted alkyl, alkoxyalkyl, hydroxyalkyl, trialkylsiloxyalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-N(R^a)-C(O)alkyl, -alky!ene-NR^a-C(O)-N(Rⁿ)2, -alkylcne-NR*-C(H\I-R^b)-N(R^ah -alkyleneC(=\--RQ-N(R’)2, -alkylene-C(O)-OH, -alkylene~C(O)-Oalkyl, and -alkylencC(O)-N(R9R^B and R^r’ are each one or more substituents independently selected from the group consisting of H, alky], substituted alkyl, halogen, and -C.\;

each R·¹ is independently selected from tire group consisting of H, alkyl, and substituted alkyl;

R^b is selected horn the group consisting of H, alkyl, substituted alkyl, CN, and S(Oz)-alky]; and each R^f is independently selected from the group consisting of H, alkyl, substituted alkyl, heterocydyl, and -S(O2)-alkyl.

In some embodiments of the compounds of Formula IV, each L² is alkylene, for example any of those described herein, e.g, -CHz- and each A is phenyl. In a particular embodiment, both -L^J-A moieties are benzyl.

In some embodiments of the compounds of Formula IV, X and Y are both heteroaryl (for example, any heteroaryl described herein). In a particular embodiment, both X and Ύ are thiazolyl·

In some embodiments of the compounds of Formula IV, G¹ is CH, and G² is N. In a particular embodiment, G² is N and R¹ is H. In another particular

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In some embodiments of the compounds of Formula IV, R² is substituted or unsubstituted aminoalkyl. In a particular embodiment, R² is substituted or unsubstituted aminoalkyl, G² is N and R¹ is H, and both X and Y are thiazolyl. In another particular embodiment, R² is -CHiCHi-NHR/ wherein R^d is selected from the group consisting of H, haloalkyl, -C(O)-N(R^a)2, -C(=N-R^b‘)-N(R^a);, hydroxyalkyl, -C(N(R^a)2)=CH.X'O2, -C(O)-alkyl, G² is N and R¹ is H, and both X and Y are thiazolyl. In still another particular embodiment, R² is -CH2CH2-NHC(O)-alkyk

In specific embodiments, the compounds of Formula IV have the following structures:

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In other embodiments, the compounds of Formula IV have the following general formula:

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Heterocyclyl

wherein said

Heterocyclyl is substituted or unsubstituted. In a particular embodiment said Heterocyclyl is a substituted or unsubstituted heteroaryl, for example, and of the heteroaryls described herein. In other embodiments, said Heterocyclyl is a substituted or unsubstituted heterocycloalkyl, including any heterocycloalkyl described herein, hi a particular embodiment, tire heterocyclyl is unsubstituted morpholinyl. In a more specific particular embodiment, the heterocyclyl is unsubstituted morpholinyl and R^s is alkyl.

In other embodiments, the compounds of Formula IV have the following genera] formula:

In a particular embodiment of the compounds of the above general formula, X and Y arc. both heteroarylalkyl, ]n other specific embodiments, the compounds of Formula IV have the following structures:

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wherein Q is -OH or -N(R^d):. In a particular embodiment, Q is -OH. In another particular embodiment, Q is -N(R^a):. In yet another particular embodiment, Q is -NH-pyridyl, -NH-pyrrolyl, or -NH-S(O2)-alkyl. In other specific embodiments, the compounds of the above general formula have the foil oiving structures:

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OH

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Ln other embodiments, the compounds of Formula IV have the following general formula:

R^s

Ph

wherein M is substituted or unsubstituted alkyl. In particular embodiments, M is a substituted alkyl, for example hydroxyalkyl, substituted hydroxy alkyl, cyanoalkyl, substituted cyanoalkyl, and trialkylsiloxyalkyl. In other particular embodiments, tire compounds of the above general formula have the following structures:

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In still other embodiments, the compounds of Formula IV have the following general formula:

a compound ol the above general formula has the following structure:

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In still other embodiments of the compounds of Formula IV, Y is alkyl. In particular' embodiments, such compounds have the following general formula:

R^s-Y- is alkyl, for example any alkyl described herein. In a particular embodiment, R^H-Y- is methyl. Specific particular embodiments of the above general structure include tire following structures:

In still yet another embodiment, the compounds of Formula I are named below in tabular format (Table 6) as compounds of general Formula II:

X2

I

T-|-----Z-----T2

X1

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Formula IL

Compounds of general formula 11 are depicted as a core structure (Z) substituted with four moi eties ΤΙ, T2, XI and X2. The core structures Z are depicted in Table 1. The points of attachment of ΤΙ, T2, XI and X2 are indicated on each of the core structures depicted in Table 1. Tables 2-5, respectively, show the structures of the ΤΙ, T2, XI and X2 moieties. The point of attachment of the core structure Z is indicated in each of the structures of ΤΙ, T2, XI and X2. Each core structure Z in Table '1, and each substituent ΤΙ, T2, XI and X2 and Tables 2-5 is represented by a code comprising a letter and a number. Each structure of a compound of Formula II can be designated in tabular form by combining the code representing each structural moiety using the following syntax: Ζ.ΤΙ.Τ2.ΧΊ.X2. Thus, for example, Z1.T1A.T2B.X1A.X2A represents the following structure:

In the structures depicted in Tables 1-5, the term Aik means a substituted or unsubstituted alkyl, cycloalkyl, or alkylene group, wherein the terms alkyl, cycloalkyl, and alkylene are as defined herein. Aik means an alkyl or cycloalkyl group when depicted as monovalent, and an alkylene group when depicted as divalent. Het is a substituted or unsubstituted heterocyclyl or heterocyclylone group, wherein the term heterocyclyl is as defined herein, and the term heterocyclylene means a heterocyclyl group as defined herein, in which a hydrogen atom has been replaced by an open valence (in analogy to alkylene), thereby defining a divalent heterocyclyl. Het is a heterocyclyl when depicted as monovalent, and heterocyclylene when depicted as divalent. Ar is a substitute or unsubstituted aryl or arylene group, wherein tire term and is as

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2020203321 21 May 2020 defined herein, and the term arylene means an aryl group as defined herein, in which a hydrogen atom has been replaced by an open valence (in analogy to alkylene), thereby defining a divalent aryl. Ar is aryl when depicted as monovalent, and arylene when depicted as divalent. When substituted, Aik, Het, and Ar can be substituted with any of the substituents defined or exemplified herein. For example, substituents of Aik can include ether, halogen, -OH, amide, amine, etc., substituents of Het can include alkyl, aryl, carbonyl, -OH, halogen, and substituents of Ar can include alkyl, aryl, -OH, halogen, etc., with the proviso that the resulting structure is chemically reasonable, and would provide compounds which are sufficiently stable for formulation in a pharmaceutically acceptable composition. When a structure or substructure shown in the tables below contains more than one Aik, Het or Ar group, these groups are independently selected and can be the same or different. So, for example, each of the Aik groups of substructure T1A are independently selected and may be the same or different.

Table 1: Core Structures

Code Core Structure

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Code

Z4

Z5

Z6

Core Structure

Table 2; T1 Structures

Code

ΊΤΑ

TIB

TIC

T1D

ΤΊ Structure

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Table 3: T2 Structures

Code	T2 Structure
T2A	-O-Aik-Het
T2B	-NH-A Ik-Het
T2C	-N(Alk)-Alk-Het
T2D	-N(Alk)-Het

Table 4: XI Structures
Code	XI Structure
Χ1Λ	-Aik
X1B	-Alk-Ar
X1C	-Aik-Het
XID	-Aik-Ar- O- A1 k-Ar
XIE	-Alk-Ar-O-Alk-
	Het

Table 5; X2 Structures

Code	X2 Structure
X2A	-Aik
X2B	-Alk-Ar
X2C	-Aik-Het
X2D	-Alk-Ar-O-Alk-Ar
X2E	-A lk-Ar-Ο-Λ IkHet

Table 6: List of Compound Structures of Formula 11

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Z1.T1A.T2A.XIA.X2A, Z2.T1A.T2A.X1A.X2A, Z3.T1A.T2A.X1A.X2A, Z4.T1A.T2A.X1A.X2A, Z5.T1A.T2A.X1A.X2A, Ζ6.ΤΊ A.T2A.X1 A.X2A, Z1.T1B.T2A_X1A.X2A, Z2.T1B.T2A.X1 A.X2A, Ζ3.ΤΊΒ.Τ2Α.Χ1 A.X2A, Z4.T1B.T2A.X1 A.X2A, Z5.T1B.T2A.X1A.X2A, Z6.T1B.T2A.X1A.X2A, Z1.T1C.T2A.X1A.X2A, Z2.T1C.T2A.X1A.X2A, Z3.T1C.T2A.X1A.X2A, Z4.T1C.T2A.X1A.X2A, Z5.T1C.T2A.X1 A.X2A, Z6.T1C.T2A.X1A.X2A, Z1.T1D.T2A.X1A.X2A, Z2.T1D.T2A.X1 A.X2A, Z3.T1D.T2A.X1A.X2A, Z4.T1D.T2A.X1A.X2A, Z5.T1D.T2A.X1 A.X2A, Z6.T1D.T2A.X1A.X2A, Z1.T1 A.T2B.X1 A.X2A, Z2.T1A.T2B.X1A.X2A, Z3_T1A.T2B.X1A.X2A, Z4.T1A.T2B.X1A.X2A, Z5.T1A.T2B.X1A.X2A, Z6.T1 A.T2B.X1 A.X2A, ZI.T1B.T2B.X1A.X2A, Z2.T1B.T2B.X1A.X2A, Z3.T1B.T2B.X1 A.X2A, Z4.T1B.T2B.X1 A.X2A, Z5_T1B.T2B.X1A.X2A, Z6.T1B.T2B.X1A.X2A, Z1.T1CT2B.X1A.X2A, Z2.T1C.T2B.X1A.X2A, Z3.T1C.T2B.X1A.X2A, Z4.T1C.T2B.X1A.X2A, Z5.T1C.T2B.X1A.X2A, Z6.T1C.T2B.X1 A.X2A, Z1.T1D.T2B.X1A.X2A, Z2.T1D.T2B.X1A.X2A, Z3.T1D.T2B.X1A.X2A, Z4.T1D.T2B.XJ A.X2A, Z5.T1D.T2B.X1A.X2A, Z6.T1D.T2B.X1A.X2A, Z1.T1A.T2C.X1A.X2A, Z2.T1A.T2C.X1 A.X2A, Z3.T1 A.T2C.X1 A.X2A, Z4.T1A.T2C.X1A.X2A, Z5.T1A.T2C.X1A.X2A, Z6.TlAfr2C.XlA.X2A, Z1.T1B.T2C.X1A.X2A, Z2.T1B.T2C.X1A.X2A, Z3.T1B.T2C.X1A.X2A, Z4.T1B.T2C.XIA.X2A, Z5.T1B.T2C.X1A.X2A, Z6.TIB.T2C.X1A.X2A, Z1.T1C.T2C.X1A.X2A, Z2.T1C.T2C.X'1 A.X2A, Z3.T1C.T2C.X1A.X2A, Z4.T1C.T2C.X1 A.X2A, Z5.T1C.T2C.X1 A.X2A, Z6.T1C.T2C.X1A.X2A,

Z1.T1D.T2C.X1A.X2A, Z2.T1D.T2C.X1A.X2A, Z3.T1D.T2C.X1A.X2A, Z4.T1D.T2C.X1A.X2A, Z5.T1D.T2C.X1A.X2A, Ζ6.ΤΊ D.T2C.X1 A.X2A, Z1.T1A.T2D.X1A.X2A, Z2.T1 A.T2D.X1A.X2A, Z3.TIA.T2D.X1A.X2A, Z4.T1A.T2D.X1A.X2A, Z5.T1A.T2D.X1A.X2A, Z6.T1A.T2D.X1A.X2A,

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Z1.T1B.T2D.X1A.X2A, Z2.T1B.T2D.X1A.X2A, Z3.T1B.T2D.X1A.X2A,

Z4.T1B.T2D.X1A.X2A, Z5.T1B.T2D.XIA.X2A, Z6.T1B.T2D.X1A.X2A,

Z1.T1C.T2D.X1A.X2A, Z2.T1C.T2D.X1 Λ.Χ2Α, Z3.T1C.T2D.X1A.X2A,

Z4.T1C.12D.X1 A.X2 A, Z5.T1C.T2D.X1A.X2A, Z6.T1C.T2D.X1A.X2A,

Z1 .TID.T2D.X1A.X2A, Z2.T1D.T2D.X1A.X2A, Z3.T1D.T2D.X1A.X2A,

Z4.T1D.T2D.X1 A.X2A, Z5.T1D.T2D.X1A.X2A, Z6.T1D.T2D.X1A.X2A,

Z1.T1A.T2A.X1B.X2A, Z2.T1A.T2A.X1B.X2A, Z3.T1A.T2A.X1B.X2A,

Z4.T1 A.T2A.X1B.X2A, Z5.T1A.T2A.X1B.X2A, Ζ6.Τ1Α.Τ2Α.Χ1Β.Χ2Λ,

Z1.T1B.T2A.X1B.X2A, Z2.T1B.T2A.X1B.X2A, Ζ3.ΤΊΒ.Τ2Λ.Χ1Β.Χ2Α,

Z4.T1B.T2A.X1B.X2A, Z5.T1B.T2A.X1B.X2A, Z6.T1B.T2A.X1B.X2A,

Z1.T1C.T2A.X1B.X2A, Z2.T1C.T2A.X1B.X2A, Z3.T1C.T2A.X1B.X2A,

Z4.T1C.T2A.X1B.X2A, Z5.TIC.T2A.X1B.X2A, Z6.T1C.T2A.X1B.X2A,

Z1.T1D.T2A.X1B.X2A, Z2.T1D.T2A.X1B.X2A, Z3.T1D.T2A.X1B.X2A,

Z4.T1D.T2A.X1B.X2A, Z5.T1D.T2A.X1 B.X2A, Z6.T1D.T2A.X1B.X2A,

Z1.T1A.T2B.X1B.X2A, Z2.T1 A.T2B.X1B.X2A, Z3.T1A.T2B.X1B.X2A,

Z4.T1A.T2B.X1B.X2A, Z5.TJΛ.Τ2Β.Χ1Β.Χ2Α, Z6.T1 A.T2B.X1B.X2A,

Ζ1.Τ1Β.Τ2Β.ΧΊΒ.Χ2Α, Ζ2.ΤΊΒ.Τ2Β.Χ1Β.Χ2Α, Ζ3.ΤΊΒ.Τ2Β.Χ1Β.Χ2Α,

Ζ4.ΊΊΒ.Τ2Β.Χ1Β.Χ2Α, Z5.T1B.T2B.X1B.X2A, Ζ6.Τ1Β.Τ2Β.ΧΊΒ.Χ2Α,

Z1.T1C.T2B.X1B.X2A, Z2.T1CT2B.X1B.X2A, Z3.T1C.T2B.XiB.X2A,

Z4.T1C.T2B.X1B.X2A, Z5.T1CT2B.X1B.X2A, Z6.T1C.T2B.X1B.X2A,

Z1.T1D.T2B.X1B.X2A, Z2.T1D.T2B.X1B.X2A, Z3.T1D.T2B.X1B.X2A,

Z4.T1D.T2B.X1B.X2A, Z5.T1D.T2B.X1B.X2A, Z6.T1D.T2B.X1B.X2A,

Z1.T1A.T2C.X1B.X2A, Z2.T1A.T2C.X1B.X2A, Z3.T1 A.T2C.X1B.X2A,

Z4.T1A.T2C.X1B.X2A, Z5.T1 A.T2C.X1 B.X2A, Z6.T1A.T2C.X1B.X2A,

Z1.T1B.T2C.X1B.X2A, Z2.T1B.T2C.X1B.X2A, Z3.T1B.T2C.X1B.X2A,

Z4.T1B.T2C.X1B.X2A, Z5.T1B.T2C.X1B.X2A, Z6.T1 B.T2C.X1B.X2A,

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Z1.T1C.T2C.X1B.X2A, Z2.TlC.r2C.XlB.X2A, Z3.T1C.T2C.XIB.X2A,

Z4.T1C.T2C.X1B.X2A, Z5.T1C.T2C.X1B.X2A, Z6.T1C.T2C.X1B.X2A,

ΖΊ T1D.T2C.X1B.X2A, Z2.T1D.T2C.X1B.X2A, Z3.T1 D.T2C.X1 B.X2A,

Z4.T1D.T2C.X1B.X2A, Z5T1D.T2C.X1B.X2A, Z6.T1D.T2C.X1B.X2A,

Z1T1AT2D.X1B.X2A, Z2.T1A.T2D.X1B.X2A, Z3.T1A.T2D.X1B.X2A,

Z4T1AT2D.X1B.X2A, Z5.T1A.T2D.X1B.X2A, Ζ6.Π A.T2D.X1B.X2A, Z1 ,T1 B.T2D.XIB.X2A, Z2.T1B.T2D.X1B.X2A, Z3.T1 B.T2D.X1 B.X2A, Z4T1B.T2D.X1B.X2A, Z5.T1B.T2D.X1B.X2A, Z6.T1B.T2D.X1B.X2A,

Z1.T1C.T2D.X1B.X2A, Z2.T1C.T2D.X1B.X2A, Z3.T1C.T2D.X1B.X2A,

Z4.T1C.T2D.X1B.X2A, Z5.T1C.T2D.X1B.X2A, Z6.T1C.T2D.X1B.X2A,

Z1.T1D.T2D.X1B.X2A, Z2.T1D.T2D.X1B.X2A, Z3T1D.T2D.X1B.X2A,

Z4.T1D.T2D.X1B.X2A, Z5.T1 D.T2D.X1 B.X2A, Z6.T1D.T2D.X1B.X2A,

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Z1.T1C.T2A.X1CX2A, Z2T1C.T2A.X1C.X2A, Z3.T1C.T2A.XIC.X2A,

Z4.T1C.T2A.X1C.X2A, Z5.T1C.T2A.X1C.X2A, Z6.T1C.T2A.X1C.X2A,

Z1.T1D.T2A.X1C.X2A, Z2.T1DT2A.X1C.X2A, Z3.T1D.T2A.X1CX2A,

Z4.T1D.T2A.X1C.X2A, Z5.T1D.T2A.X1C.X2A, Z6.T1D.T2A.X1C.X2A,

Z1.T1A.T2B.X1C.X2A, Z2.T1A.T2B.X1C.X2A, Ζ3.ΤΊ A.T2B.X1C.X2A,

Z4.T1A.T2B.X1C.X2A, Z5.T1A.T2B.X1C.X2A, Z6.T1A.T2B.X1C.X2A,

Z1T1B.T2B.X1C.X2A, Z2.T1B.T2B.X1C.X2A, Z3.T1B.T2B.X1C.X2A,

Z4.T1B.T2B.X1C.X2A, Z5.T1B.T2B.X1C.X2A, Z6.T1B.T2B.X1C.X2A,

Z1.T1C.T2B.X1C.X2A, Z2.T1C.T2B.X1C.X2A, Z3.T1C.T2B.X1C.X2A,

Z4.T1C.T2B.X1C.X2A,Z5.T1C.T2B.X1C.X2A, Z6.T1CT2B.X1C.X2A,

102

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Z1.T1D.T2B.X1CX2A, Z2.T1D.T2B.X1CX2A, Z3.T1D.T2B.X1C.X2A,

Z4.T1D.T2B.X1C.X2A, Z5.T1D.T2B.X1C.X2A, Z6.T1D.T2B.X1C.X2A,

Z1.T1A.T2CX1CX2A, Z2.T1A.T2C.X1C.X2A, Z3T1A.T2C.X1C.X2A,

Z4.T1A.T2C.X1C.X2A, Z5.T1A.T2C.X1C.X2A, Z6.T1 A.T2CX1C.X2A,

Z1.T1B.T2C.X1C.X2A, Z2.T1B.T2C.X1C.X2A, Z3.T1B.T2CX1C.X2A,

Z4.T1B.T2C.X1C.X2A, Z5.T1B.T2CX1C.X2A, Z6.T1B.T2C.X1C.X2A,

Z1.T1C.T2C.X1C.X2A, Z2.T1CT2C.X1C.X2A, Z3.T1CT2CX1CX2A,

Z4.T1C.T2C.X1C.X2A, Z5.T1CT2CX1CX2A, Z6.T1C.T2C.X1C.X2A,

Z1.T1D.T2CX1CX2A, Z2.T1D.T2C.X1C.X2A, Z3.T1D.T2CX1CX2A,

Z4.T1D.T2C.X1C.X2A, Z5.T1D.T2C.X1C.X2A, Z6.T1D.T2C.X1C.X2A,

Z1.TTA.T2D.X1C.X2A, Z2.1TA.T2D.X1C.X2A, Z3.T1A.T2D.X1C.X2A,

Z4.T1A.T2D.X1C.X2A, Z5.T1A.T2D.X1C.X2A, Z6.T1 A.T2D.X1C.X2A,

Z1.T1B.T2D.X1C.X2A, Z2.T1B.T2D.X1CX2A, Z3. ITB.T2D.X1C.X2A,

Z4.T1B.T2D.X1C.X2A, Z5.T1B.T2D.X1CX2A, Z6.T1B.T2D.X1C.X2A,

Z1.T1C.T2D.X1C.X2A, Z2.T1C.T2D.X1C.X2A, Z3.T1C.T2D.X1C.X2A,

Z4.T1C.T2D.X1C.X2A, Z5.T1C.T2D.X1C.X2A, Z6.T1CT2D.X1C.X2A,

Z1.T1D.T2D.X1C.X2A, Z2.T1D.T2D.X1CX2A, Z3.TTD.T2D.X1C.X2A,

Z4.T1D.T2D.X1C.X2A, Z5.T1D.T2D.X1C.X2A, Z6.T1D.T2D.X1CX2A,

Z1.T1A.T2A.X1D.X2A, Z2.T1A.T2A.X1D.X2A, Z3.T1A.T2A.X1D.X2A,

Z4.T1A.T2A.X1D.X2A, Z5.T1A.T2A.X1D.X2A, Z6.T1A.T2A.X1D.X2A,

Z1.T1B.T2A.X1D.X2A, Z2.T1B.T2A.X1D.X2A, Z3.T1B.T2A.X1D.X2A,

Z4.T1B.T2A.X1D.X2A, Z5.T1B.T2A.X1D.X2A, Z6.T1B.T2A.X1D.X2A,

Z1.T1C.T2A.X1D.X2A, Z2.T1CT2A.X1D.X2A, Z3.T1CT2A.X1D.X2A,

Z4.T1C.T2A.X1D.X2A, Z5.T1C.T2A.X1D.X2A, Z6.T1C.T2A.XTD.X2A,

Z1.T1D.T2A.X1D.X2A, Z2.T1D.T2A.X1D.X2A, Z3.T1D.T2A.X1D.X2A,

Z4.T1D.T2A.X1D.X2A, Z5.T1D.T2A.X1D.X2A, Z6.T1D.T2A.X1D.X2A,

103

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Z1.T1A.T2B.X1D.X2A, Z2.T1A.T2B.X1D.X2A, Z3.T1A.T2B.X1D.X2A, Z4.T1A.T2B.X1D.X2A, Ζ5.ΤΊ A.T2B.X1D.X2A, Z6-T1A.T2B.X1D.X2A, Z1.T1B.T2B.X1D.X2A, Z2.T1B.T2B.X1D.X2A, Z3.T1B.T2B.X1D.X2A, Z4.T1B.T2B.X1D.X2A, Z5T1B.T2B.X1D.X2A, Z6.T1B.T2B.X1D.X2A, Z1.T1C.T2B.X1D.X2A, Z2.TIC.T2B.X1D.X2A, Z3.TIC.T2B.X1D.X2A, Z4.T1C.T2B.X1D.X2A, Z5.T1C.T2B.X1D.X2A, Z6.T1C.T2B.X1D.X2A, ΖΊ ,ΤΊ D.T2B.X1 D.X2A, Ζ2. Π DT2B.X1 D.X2A, Ζ3.ΤΊ D.T2B.X1 D.X2Α, Z4.T1D.T2B.X1D.X2A, Z5.T1D.T2B.X1D.X2A, Z6.T1D.T2B.X1 D.X2A, ZI.T1A.T2C.X1D.X2A, Z2.T1A.T2GX1D.X2A, Z3.T1A.T2GX1D.X2A, Ζ4.ΤΊ A.T2C.X1D.X2A, Z5.T1A.T2GX1D.X2A, Z6.TIA.T2C.X1D.X2A, Ζ1.Τ1 B.T2GX1D.X2 Α, Ζ2.ΤΊ B.T2C.X1D.X2A, Ζ3.ΤΊ B.T2C.X1 D.X2A, Z4.T1B.T2C.X1D.X2A, Z5.T1B.T2C.X1D.X2A, Z6.T1B.T2C.X1D.X2A, Z1.T1C.T2C.X1D.X2A, Z2.T1C.T2C.X1D.X2A, Z3.T1C.T2C.X1D.X2A, Z4.T1C.T2C.X1D.X2A, Z5.T1C.T2C.X1D.X2A, Z6.T1C.T2C.X1D.X2A, Z1.ITD.T2C.X1D.X2A, Z2.T1D.T2C.X1D.X2A, Z3.T1D.T2C.X1D.X2A, Z4.T1D.T2C.X1D.X2A, Z5.T1D.T2C.X1D.X2A, Z6.T1D.T2C.X1D.X2A, Z1.T1A.T2D.X1D.X2A, Z2.T1A.T2D.X1D.X2A, Ζ3.Τ1 A.T2D.XID.X2A, Z4.T1A.T2D.X1D.X2A, Z5.T1A.T2D.X1D.X2A, Ζ6.ΤΊ A.T2D.X1D.X2A,

ZI. T1B.T2D.X1D.X2A, Z2.T1B.T2D.X1D.X2A, Z3.T1B.T2D.X1D.X2A, Z4.T1B.T2D.X1D.X2A, Z5.T1B.T2D.X1D.X2A, Z6.T1B.T2D.X1D.X2A,

ZJ. T1C.T2D.X1D.X2A, Z2.T1C.T2D.X1 D.X2A, Ζ3.ΤΊ C.T2D.X1 D.X2A, Z4.T1C.T2D.X1D.X2A, Z5.T1C.T2D.X1D.X2A, Z6.ITC.T2D.X1D.X2A, Z1.TID.T2D.X1D.X2A, Z2.T1D.T2D.X1D.X2A, Z3.T1D.T2D.X1D.X2A, Z4.T1D.T2D.X1D.X2A, Ζ-5. riD.T2D.XlD.X2A, Z6.T1D.T2D.X1D.X2A, Ζ1.Τ1Α.Τ2Α.ΧΊΕΧ2Α, Ζ2.Τ1Α.Τ2Α.Χ1Ε.Χ2Α, Ζ3.Τ1Α.Τ2Α.Χ1Ε.Χ2Α, Ζ4.Τ1Α.Τ2Α.Χ1Ε.Χ2Α, Ζ5.Τ1Α.Τ2Α.Χ1Ε.Χ2Α, Ζ6.Τ1Α.Τ2Α.Χ1Ε.Χ2Α,

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Z4.T1C.T2A.X1 E.X2A, Z5.HC.T2A.X1E.X2A, Z6.T1C.T2A.X1E.X2A,

Z1.T1D.T2A.X1E.X2A, Z2.T1D.T2A.X1E.X2A, Z3.T1D.T2A.X1E.X2A,

Z4.T1D.T2A.X1E.X2A, Z5.T1D.T2A.X1E.X2A, Z6.T1D.T2A.X1E.X2A,

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Z4.T1 A.T2B.X1E.X2A, Z5.T1 A.T2B.X1E.X2A, Z6.T1 A.T2B.X1E.X2A,

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Z4.T1B.T2B.X1E.X2A, Z5.T1B.T2B.X1E.X2A, Z6.T1B.T2B.X1E.X2A,

Z1.T1C.T2B.X1E.X2A, Z2.T1C.T2B.X1E.X2A, Z3.T1C.T2B.X1E.X2A,

Z4.T1C.T2B.X1 E.X2A, Z5.HC.T2B.X1 E.X2A, Z6.T1C.T2B.X1E.X2A,

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Z4.T1D.T2B.X1E.X2A, Z5.T1D.T2B.X1E.X2A, Z6.T1D.T2B.X1E.X2A,

Z1.T1A.T2C.X1E.X2A, Ζ2.ΤΊ A.T2C.X1E.X2A, Ζ3.ΤΊ A.T2C.X1E.X2A,

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Z4.T1B.T2C.X1E.X2A, Z5.T1B.T2C.X1E.X2A, Z6.T1B.T2C.X1E.X2A,

Z1.HC.T2C.XI E.X2A, Z2.T1C.T2C.X1E.X2A, Z3.T1C.T2C.X1E.X2A,

Z4T1C.T2C.X1E.X2A, Z5.T1CT2C.X1E.X2A, Z6.T1C.T2C.X1E.X2A,

Z1.T1D.T2C.X1E.X2A, Z2.HD.T2C.X1E.X2A, Z3.TW.T2C.X1E.X2A,

Z4.T1 D.T2C.X1 E.X2A, Z5.T] D.T2C.X1 E.X2A, Ζ6.ΤΊ D.T2C.X1 E.X2A,

Z1.T1A.T2D.X1E.X2A, Z2.T1A.T2D.X1E.X2A, Z3.T1A.T2D.X1E.X2A,

Z4.T1A.T2D.X1E.X2A, Z5.T1 A.T2D.X1E.X2A, Z6.T1A.T2D.X1E.X2A,

Z1.HB.T2D.X1E.X2A, Z2.HB.T2D.X1E.X2A, Z3.HB.T2D.X1E.X2A,

Z4.T1B.T2D.X1E.X2A, Z5.T1B.T2D.X1E.X2A, Z6.HB.T2D.X1E.X2A,

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Z1T1C.T2D.X1E.X2A, Z2.T1CT2D.X1E.X2A, Z3.T1C.T2D.X1E.X2A,

Z4.T1C.T2D.X1E.X2A, Z5.T1C.T2D.X1E.X2A, Z6.T1C.T2D.X1E.X2A,

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Z4.T1D.T2D.X1E.X2A, Z5.T1D.T2D.X1E.X2A, Z6.T1D.T2D.X1E.X2A,

Z1.T1A.T2A.X1A.X2B, Z2.T1A.T2A.X1 A.X2B, Z3.T1 A.T2A.X1A.X2B,

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Z4.T1B.T2B.X1A.X2B, Ζ5.ΏΒ.Τ2Β.ΧΊ A.X2B, Z6.T1B.T2B.X1A.X2B,

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Z4.T1D.T2B.X1A.X2B, Z5.T1D.T2B.X1A.X2B, Z6.T1D.T2B.X1A.X2B,

Z1.T1A.T2C.X1A.X2B, Z2.T1A.T2C.X1A.X2B, Z3.T1A.T2C.X1A.X2B,

Z4.T1A.T2C.X1A.X2B, Z5.T1A.T2C.X1 A.X2B, Z6.T1A.T2C.X1A.X2B,

ZET1B.T2C.X1A.X2B, Z2.T1B.T2C.X1A.X2B, Z3.T1B.T2C.X1A.X2B,

Z4.T1B.T2C.X1A.X2B, Z5.T1B.T2CX1A.X2B, Z6.T1B.T2C.X1A.X2B,

Z1.T1C.T2C.X1A.X2B, Z2.T1C.T2C.X1 A.X2B, Z3.T1C.T2C.X1A.X2B,

Z4.T1C.T2C.X1 A.X2B, Z5.T1C.T2C.X1 A.X2B, Z6.T1C.T2C.X1A.X2B,

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Z1.T1D.T2C.X1A.X2B, Z2.T1D.T2C.X1 A.X2B, Z3.TTD.T2C.X1 A.X2B,

Z4.T1D.T2C.X1A.X2B, Z5.T1D.T2CX1A.X2B, Z6.T1D.T2C.X1A.X2B,

Z1.T1A.T2D.X1A.X2B, Z2.T1A.T2D.XIA.X2B, Z3.T1A.T2D.X1A.X2B,

Z4.T1A.T2D.X1A.X2B, Z5.T1A.T2D.XIA.X2B, Z6.T1A.T2D.X1 A.X2B,

Z1.T1B.T2D.X1A.X2B, Z2.T1B.T2D.X1 A.X2B, Z3.T1B.T2D.X1 A.X2B,

Z.4.T1 B.T2D.X1A.X2B, Z5.T1 B.T2D.X1 A.X2B, Z6.T1B.T2D.X1 A.X2B,

Z1.T1C.T2D.X1A.X2B, Z2.T1C.T2D.X1A.X2B, Z3.T1C.T2D.X1A.X2B,

Z4.T1C.T2D.X1A.X2B, Z5.T1C.T2D.X1A.X2B, Z6.T1C.T2D.X1A.X2B,

Z1.T1D.T2D.X1A.X2B, Z2.T1D.T2D.X1 A.X2B, Ζ3.ΤΊ D.T2D.X1 A.X2B,

Z4.T1D.T2D.X1A.X2B, Z5.T1D.T2D.X1A.X2B, Z6.T1D.T2D.X1A.X2B,

Z1 .T1A.T2A.X1B.X2B, Z2.T1A.T2A.X1B.X2B, Z3.T1A.T2A.X1B.X2B,

Z4.T1A.T2A.X1B.X2B, Z5.T1A.T2A.X1B.X2B, Z6.T1A.T2A.X1B.X2B,

Z1.T1B.T2A.X1B.X2B, Ζ2.ΤΊΒ.Τ2Α.ΧΊΒ.Χ2Β, Ζ3.ΤΊΒ.Τ2Α.Χ1Β.Χ2Β,

Ζ4.Τ1Β.Τ2Α.ΧΊΒ.Χ2Β, Ζ5.ΤΊΒ.Τ2Α.Χ1Β.Χ2Β, Z6.T1B.T2A.X1B.X2B,

Z1.T1C.T2A.X1B.X2B, Z2.T1C.T2A.X1B.X2B, Z3.T1C.T2A.X1B.X2B,

Z4.T1C.T2A.X1B.X2B, Z5.T1C.T2A.X1B.X2B, Z6.T1C.T2A.X1B.X2B,

ΖΊ ,T1 D.T2A.X1B.X2B, Z2.T1D.T2A.X1B.X2B, Z3.T1D.T2A.X1B.X2B,

Z4.T1D.T2A.X1B.X2B, Z5.T1D.T2A.X1 B.X2B, Z6.T1D.T2A.X1B.X2B.

Z1.T1A.T2B.X1B.X2B, Ζ2.Τ1Α.Τ2Β.ΧΊΒ.Χ2Β, Z3.T1A.T2B.X1B.X2B,

Ζ4.ΤΊΑ.Τ2Β.Χ1Β.Χ2Β, Z5.T1A.T2B.X1B.X2B, Z6.T1A.T2B.X1B.X2B,

Z1.T1B.T2B.X1B.X2B, Ζ2.Τ1Β.Τ2Β.ΧΊΒ.Χ2Β, Z3.T1B.T2B.X1B.X2B,

Z4.T1B.T2B.X1B.X2B, Z5.T1B.T2B.X1B.X2B, Z6.T1B.T2B.X1B.X2B,

Z1.T1C.T2B.X1B.X2B, Z2.T1C.T2B.X1B.X2B, Z3.T1CT2B.X1B.X2B,

Z4.T1C.T2B.X1B.X2B, Z5.T1C.T2B.X1B.X2B, Z6.T1C.T2B.X1B.X2B,

Z1.T1D.T2B.X1B.X2B, Z2.T1D.T2B.X1B.X2B, Z3.T1D.T2B.X1B.X2B,

Z4.T1D.T2B.X1B.X2B, Z5.T1 D.T2B.X1B.X2B, Z6.T1D.T2B.X1 B.X2B,

107

WO 2008/103949

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2020203321 21 May 2020

Z1.T1AT2C.X1B.X2B, Z2.T1 AT2C.X1B.X2B, Z3T1AT2C.X1B.X2B,

Z4T1AT2C.X1B.X2B, Z5.T1 A.T2C.X1B.X2B, Z6T1AT2C.X1B.X2B,

ZL'nB.T2C.XlB.X2B, Z2.T1BT2C.X1B.X2B, Z3T1BT2C.X1B.X2B,

Z4T1B.T2CX1B.X2B, Z5.T1B.T2C.X1B.X2B, Z6.T1BT2C.X1B.X2B,

Z1 T1CT2C.X1B.X2B, Z2.T1C.T2C.X1 B.X2B, Ζ3.ΤΊC.T2C.X1 B.X2B,

Z4.T1C.T2C.X1B.X2B, Z5.T1C.T2CX1B.X2B, Z6.T1CT2C.X1B.X2B,

ZLT1D.r2C.XlB.X2B, Z2.T1D.T2C.X1B.X2B, Z3.T1D.T2C.X1B.X2B,

Z4.T1D.T2C.X1B.X2B, Z5.T1D.T2C.X1B.X2B, Z6T1DT2C.X1B.X2B,

Z1.T1A.T2D.X1B.X2B, Z2T1AT2D.X1B.X2B, Z3.T1A.T2D.X1B.X2B,

Z4T1A.T2D.X113.X2B, Z5T1A.T2D.X1B.X2B, Z6.T1A.T2D.X1B.X2B,

Z1T1B.T2D.X1B.X2B, Z2T1BT2D.X1B.X2B, Z3T1BT2D.X1B.X2B,

Z4T1BT2D.X1B.X2B, Z5T1B.T2D.X1B.X2B, Z6T1B.T2D.X1B.X2B,

Z1.T1CT2D.X1B.X2B, Z2T1CT2D.X1B.X2B, Z3.T1CT2D.X1B.X2B,

Z4.T1CT2D.X1B.X2B, Z5T1CT2D.X1B.X2B, Z6.T1C.T2D.X1B.X2B,

Z1T1DT2D.X1B.X2B, Z2.T1DT2D.X1B.X2B, Z3.T1D.T2D.X1B.X2B,

Z4T1DT2D.X1B.X2B, Z5T1DT2D.X1B.X2B, Z6T1DT2D.X1B.X2B,

Z1.T1 AT2A.X1C.X2B, Z2T1A.T2A.X1C.X2B, Z3T1A.T2A.X1C.X2B,

Z4T1AT2A.X1C.X2B, Z5.T1AT2A.X1CX2B, Z6T1AT2A.X1C.X2B,

Z1T1BT2A.X1C.X2B, Z2.T1BT2A.X1C.X2B, Z3TlB.f2A.XlC.X2B,

Ζ4.ΤΊ B.T2A.X1C.X2B, Z5T1BT2A.X1C.X2B, Z6T1B.T2A.X1C.X2B,

Z1.T1C.T2A.X1C.X2B, Z2.T1CT2A.X1C.X2B, Z3.T1C.T2A JK1C.X2B,

Z4T1CT2A.X1C.X2B, Z5.T1CT2A.X1C.X2B, Z6T1C.T2A.X1C.X2B,

Z1T1DT2A.X1C.X2B, Z2.T1DT2A.X1C.X2B, Z3.T1DT2A.X1C.X2B,

Z4TTDT2A.XIC.X2B, Z5.T1D.T2A.X1C.X2B, Z6T1D.T2A.X1C.X2B,

Z1T1AT2B.X1C.X2B, Z2.T1AT2B.X1C.X2B, Z3.T1AT2B.X1C.X2B,

Z4T1A.T2B.X1C.X2B, Z5T1A.T2B.X1C.X2B, Z6T1A.T2B.X1C.X2B,

108

WO 2008/103949

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2020203321 21 May 2020

Z1.T1B.T2B.X1C.X2B, Z2.TJB.T2B.X1C.X2B, Z3.T1B.T2B.XJ C.X2B,

Z4.T1B.T2B.X1C.X2B, Z5.T1B.T2B.X1C.X2B, Z6.T1B.T2B.X1C.X2B,

Z1.T1C.T2B.X1C.X2B, Z2.T1C.T2B.X1C.X2B, Z3.T1C.T2B.X1C.X2B,

Z4.T1C.T2B.X1C.X2B, Z5.T1C.T2B.X1C.X2B, Z6.T1C.T2B.X1C.X2B,

Z1.T1D.T2B.X1C.X2B, Z2.T1D.T2B.X1C.X2B, Z3.T1D.T2B.X1C.X2B,

Z4.T1D.T2B.X1C.X2B, Z5.T1D.T2B.X1CX2B, Z6.TTD.T2B.X1C.X2B,

Z1.T1A.T2C.X1C.X2B, Z2.T1A.T2C.X1C.X2B, Z3.T1A.T2C.X1C.X2B,

Z4.TIA.T2C.X1C.X2B, Z5.T1A.T2C.X1C.X2B, Z6.T1A.T2C.X1C.X2B,

Z1.T1B.T2C.X1C.X2B, Z2.T1B.T2C.X1C.X2B, Z3.T1B.T2C.X1C.X2B,

Z4.T1B.T2C.X1.C.X2B, Z5.T1B.T2C.X1C.X2B, Z6.T1B.T2C.X1C.X2B,

Z1.T1C.T2C.X1C.X2B, Z2.T1C.T2C.X1C.X2B, Z3.T1C.T2C.X1C.X2B,

Z4.T1C.T2C.X1C.X2B, Z5.T1C.T2C.X1C.X2B, Z6.T1C.T2C.X1C.X2B,

Z1.T1D.T2C.X1C.X2B, Z2.T1D.T2C.X1C.X2B, Z3.T1 D.T2C.X1C.X2B,

Z4.T1D.T2C.X1C.X2B, Z5.T1D.T2C.X1C.X2B, Z6.T1D.T2C.X1C.X2B,

Z1.T1A.T2D.X1C.X2B, Z2.T1A.T2D.X1C.X2B, Z3.T1A.T2D.X1C.X2B,

Z4.T1A.T2D.X1C.X2B, Z5.T1A.T2D.X1C.X2B, Z6.T1A.T2D.X1C.X2B,

Z1.T1B.T2D.X1C.X2B, Z2.T1B.T2D.X1C.X2B, Z3.T1B.T2D.X1C.X2B,

Z4.T1B.T2D.X1C.X2B, Z5.T1B.T2D.X1C.X2B, Z6.T1B.T2D.X1C.X2B,

Z1.T1C.T2D.X1C.X2B, Z2.T1C.T2D.X1C.X2B, Z3.T1C.T2D.X1C.X2B,

Z4.T1C.T2D.X1C.X2B, Z5.T1C.T2D.X1C.X2B, Z6.T1C.T2D.X1C.X2B,

Z1.T1D.T2D.X1C.X2B, Z2.T1D.T2D.X1C.X2B, Z3.T1D.T2D.X1C.X2B,

Z4.T1D.T2D.X1C.X2B, Z5.T1D.T2D.X1C.X2B, Z6.T1D.T2D.X1C.X2B,

Z1.T1A.T2A.X1D.X2B, Z2.T1A.T2A.X1D.X2B, Z3.T1A.T2A.X1D.X2B,

Z4.T1A.T2A.XID.X2B, Z5.T1A.T2A.X1D.X2B, Z6.T1A.T2A.X1D.X2B,

Z1.T1B.T2A.X1D.X2B, Z2.T1B.T2A.X1D.X2B, Z3.T1B.T2A.X1D.X2B,

Z4.T1B.T2A.X1D.X2B, Z5.T1B.T2A.X ID.X2B, Z6.TiB.T2A.XlD.X2B,

109

WO 2008/103949

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Z1 .T1C.T2A.X1D.X2B, Z2.T1C.T2A.X1D.X2B, Z3.T1C.T2A.X JD.X2B,

Z4.T1C.T2A.X1D.X2B, Z5.T1C.T2A.X1D.X2B, Z6.T1C.T2A.X1D.X2B,

Z1.T1D.T2A.X1D.X2B, Z2.T1D.T2A.X1D.X2B, Z3.T1D.T2A.X1D.X2B,

Z4.T1D.T2A.X1D.X2B, Z5.T1D.T2A.X1 D.X2B, Z6.T1D.T2A.X1D.X2B,

Z1.T1A.T2B.X1D.X2B, Z2.T1A.T2B.X1D.X2B, Z3.T1 A.T2B.X1D.X2B,

Z4.T1A.T2B.X1D.X2B, Z5.T1A.T2B.X1D.X2B, Z6.T1A.T2B.X1D.X2B,

ZI.T1B.T2B.X1D.X2B, Z2.T1B.T2B.X1D.X2B, Z3.TIB.T2B.X1D.X2B,

Z4.T1B.T2B.X1D.X2B, Z5.T1B.T2B.X1D.X2B, Z6.T1B.T2B.X1D.X2B,

ΖΊ .T1C.T2B.X1 D.X2B, Ζ2.ΤΊ C.T2B.X1 D.X2B, Ζ3.Γ1 GT2B.X1 D.X2B,

Z4.T1C.T2B.X1D.X2B, Z5.T1C.T2B.X1D.X2B, Z6.T1GT2B.X1D.X2B,

Z1.T1D.T2B.X1D.X2B, Z2.T1D.T2B.X1D.X2B, Z3.T1D.T2B.X1D.X2B,

Z4.T1D.T2B.X1D.X2B, Z5.T1D.T2B.X1D.X2B, Z6.nD.T2B.XlD.X2B,

Z1.T1A.T2C.X1D.X2B, Z2.T1A.T2C.X1D.X2B, Z3.T1A.T2C.X1D.X2B,

Z4.T1A.T2C.X1D.X2B, Z5.T1A.T2C.X1D.X2B, Z6.T1A.T2C.X1D.X2B,

Z1.T1B.T2C.X1D.X2B, Z2.T1B.T2C.X1D.X2B, Z3.T1B.T2C.X1D.X2B,

Z4.T1B.T2C.X1D.X2B, Z5.T1B.T2C.X1D.X2B, Z6.T1 B. r2C.XlD.X2B,

Z1.T1C.T2C.X1D.X2B, Z2.T1C.T2C.X1D.X2B, Z3.T1C.T2C.X1D.X2B,

Z4.T1C.T2C.X1D.X2B, Z5.T1C.T2C.X1D.X2B, Ζ6.ΤΊC.T2C.X1D.X2B,

Z1.T3D.T2C.X1D.X2B, Z2.T1D.T2C.X1D.X2B, Z3.T1D.T2C.X1D.X2B,

Z4.T1D2T2C.X1D.X2B, Z5.T1D.T2C.X1D.X2B, Z6.T1D.T2C.X1D.X2B,

Z1.T1A.T2D.X1D.X2B, Z2.T1A.T2D.X1D.X2B, Z3.T1A.T2D.X1D.X2B,

Z4.T1A.T2D.X1D.X2B, Z5.T1A.T2D.X1 D.X2B, Z6.T1A.T2D.X1D.X2B,

Z1.T1B.T2D.X1D.X2B, Z2.T1B.T2D.X1D.X2B, Z3.T1B.T2D.X1D.X2B,

Z4.T1B.T2D.X1D.X2B, Z5.T1B.T2D.X1D.X2B, Z6.T1B.T2D.X1D.X2B,

Z1.T1C.T2D.X1D.X2B, Z2.T1C.T2D.X1D.X2B, Z3.T1C.T2D.X1D.X2B,

Z4.T1 C.T2D.X1 D.X2B, Z5.T1C.T2D.X1D.X2B, Z6.T1C.T2D.X1 D.X2B,

110

WO 2008/103949

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Z1.T1D.T2D.X1D.X2B, Z2.T1D.T2D.X1D.X2B, Z3.T1D.T2D.X1D.X2B,

Z4.T1D.T2D.X1D.X2B, Z5.T1D.T2D.X1D.X2B, Z6.T1D.T2D.X1D.X2B,

Z1.T1A.T2A.X1E.X2B, Z2.T1A.T2A.X1E.X2B, Z3.T1A.T2A.X1E.X2B,

Z4.T1A.T2A.X1 E.X2B, Z5.T1 A.T2A.X1E.X2B, Z6.T1 Α.Τ2Α.ΧΊΕ.Χ2Β,

ZLT1B.T2A.X1E.X2B, Z2.T1B.T2A.X1E.X2B, Z3.T1B.T2A.X1E.X2B,

Z4.T1B.T2A.X1E.X2B, Z5.T1B.T2A.X1E.X2B, Z6.T1B.T2A.X1E.X2B,

Z1.T1C.T2A.X1E.X2B, Z2.T1C.T2A.X1 E.X2B, Z3.T1C.T2A.X1 E.X2B,

Z4.T1C.T2A.X1 E.X2B, Ζ5.ΤΊ C.T2A.X1E.X2B, Z6.T1C.T2A.X1E.X2B,

Z1.T1D.T2A.X1E.X2B, Z2.T1D.T2A.X1E.X2B, Z3.T1D.T2A.X1E.X2B,

Z4.T1D.T2A.X1E.X2B, Z5.T1D.T2A.X1E.X2B, Z6.T1D.T2A.X1E.X2B,

ZI.T1A.T2B.X1E.X2B, Z2.T1 A.T2B.X1E.X2B, Ζ3.Γ1 A.T2B.X1E.X2B,

Ζ4.ΠΑ.Τ2Β.Χ1Ε.Χ2Β, Z5.T1A.T2B.X1E.X2B, Z6.T1A.T2B.X1E.X2B,

Z1.T1B.T2B.X1E.X2B, Z2.T1B.T2B.X1E.X2B, Z3.T1B.T2B.X1E.X2B,

Z4.T1B.T2B.X1E.X2B, Ζ5.Τ1Β.Τ2Β.ΧΊΕ.Χ2Β, Ζ6.ΤΊΒ.Τ2Β.Χ1Ε.Χ2Β,

Z1.T1C.T2B.X1E.X2B, Z2.T1C.T2B.X1E.X2B, Z3.T1C.T2B.X1 E.X2B,

Z4.1TC:r2B.XlE.X2B, Z5.T1C.T2B.XIE.X2B, Z6.T1C.T2B.X1E.X2B,

Z1.T1D.T2B.X1E.X2B, Z2.T1D.T2B.X1E.X2B, Z3.T1D.T2B.X1E.X2B,

Z4.T1 D.T2B.X1 E.X2B, Z5.T1D.T2B.X1E.X2B, Z6.T1D.T2B.X1E.X2B,

ZLT1A.T2C.X1E.X2B, Z2.T1A.T2C.X1E.X2B, Z3.T1A.T2C.X1E.X2B,

Z4.T1A.T2C.X1E.X2B, Z5.T1A.T2C.X1E.X2B, Z6.T1A.T2CXIE.X2B,

ZI.T1B.T2C.X1E.X2B, Ζ2/ΠΒ.Τ2ΟΧ1Ε.Χ2Β, Z3.T1B.T2C.X1E.X2B,

Z4.'nB.^rJ'2C.XlE.X2B_r Z5.T1B.T2C.X1E.X2B, Z6.T1B.T2C.X1E.X2B,

Zl.riC.T2C.XlE.X2B, Z2.T1C.T2CX1E.X2B, Z3.T1C.T2C.X1 E.X2B,

Z4.T1C.T2C.X J E.X2B, Z5.T1C.T2C.X1E.X2B, Z6.T1C.T2C.X1E.X2B,

Z1.T1D.T2C.X1E.X2B, Z2.T1D.T2C.X1E.X2B, Z3.T1D.T2C.X1E.X2B,

Z4.T1D.T2C.X1E.X2B, Z5.T1D.T2C.X1E.X2B, Z6.T1D.T2C.X1E.X2B,

111

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112

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Z1.T1C.T2B.X1B.X2C, Z2.T1C.T2B.X1B.X2C, Z3.T1C.T2B.X1B.X2C,

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Z4.T1C.T2A.X1C.X2C, Z5.TJC.T2A.X1C.X2C, Z6.TTCT2A.X1C.X2C,

114

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Z1.T1D.T2A.X1C.X2C, Z2.T1D.T2A.X1C.X2C, Z3.T1D.T2A.X1C.X2C,

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Z4.T1D.T2D.X1C.X2C, Z5.T1D.T2D.X1C.X2C, Z6.T1D.T2D.X1C.X2C,

115

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2020203321 21 May 2020

Z1.T1A.T2A.X1D.X2C, Z2.T1 A.T2A.X1D.X2C, Z3.T1A.T2A.X1D.X2C,

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Z1.T1D.T2C.X1D.X2C, Z2.T1D.T2C.X1D.X2C, Z3.T1D.T2C.X1D.X2C,

Z4.T1D.T2C.X1D.X2C, Z5.T1D.T2C.X1D.X2C, Z6.T1D.T2C.X1D.X2C,

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Z4.T1 A.T2D.X1D.X2C, Z5.T1A.T2D.X1D.X2C, Z6.T1A.T2D.X1D.X2C,

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Z1.TTB.T2D.X1D.X2C, Z2.T1B.T2D.XJD.X2C, Z3.T1B.T2D.X1D.X2C,

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Z1.T1B.T2A.X1E.X2C, Z2.T1B.T2A.X1E.X2C, Z3.T1B.T2A.X1E.X2C,

Z4.T1B.T2A.X1E.X2C, Z5.T1 B.T2A.X1E.X2C, Z6.T1B.T2A.X1E.X2C,

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Z4.T1C.T2A.X1E.X2C, Z5.T1C.T2A.X1E.X2C, Z6.ITC.T2A.X1E.X2C,

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Z1.T1C.T2B.X1E.X2C, Z2.T1CT2B.X1E.X2C, Z3.T1C.T2B.X1E.X2C,

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Z1.T1D.T2B.X1E.X2C, Z2.T1D.T2B.X1E.X2C, Z3.T1 D.T2B.X1E.X2C,

Z4.T1D.T2B.X1E.X2C, Z5.T1D.T2B.X1E.X2C, Z6.T1D.T2B.X1E.X2C,

Z1.T1A.T2C.X1E.X2C, Z2.T1A.T2C.X1E.X2C, Z3.T1A.T2C.X1 E.X2C,

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Z4.T1B.T2C.XIE.X2C, Z5.T1B.T2C.X1E.X2C, Z6.T1B.T2CX1E.X2C,

117

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Z1.T1A.T2D.X1E.X2C, Z2.T1A.T2D.X1E.X2C, Z3.T1 A.T2D.X1E.X2C,

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Z4.T1D.T2D.X1E.X2C, Z5.T1D.T2D.X1E.X2C, Z6.T1D.T2D.X1E.X2C,

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Z4.T1C.T2A.X1A.X2D, Z5.T1C.T2A.X1A.X2D, Z6.T1GT2A.X1A.X2D,

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Z4JHC.T2B.X1 A.X2D, Z5.T1C.T2B.X1A.X2D, Z6.T1C.T2B.X1 A.X2D,

118

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Z4T1AT2C.X1A.X2D, Z5J1A.T2C.X1A.X2D, Z6T1A.T2C.X1A.X2D,

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Z4T1B.T2D.X1A.X2D, Z5.T1BT2D.X1 A.X2D, Z6T1BT2D.X1A.X2D,

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Z4.T1C.T2D.X1A.X2D, Z5.T1CT2D.X1A.X2D, Z6T1C.T2D.X1A.X2D,

Z1T1DT2D.X1A.X2D, Z2.T1D.T2D.X1 A.X2D, Z3.T1DT2D.X1A.X2D,

Z4.T1D.T2D.X1 A.X2D, Z5.T1D.T2D.X1A.X2D, Z6.T1DT2D.X1A.X2D,

Z1.T1AT2A.X1B.X2D, Z2.T1A.T2A.X1B.X2D, Z3.T1AT2A.X1B.X2D,

Z4.T1A.T2A.X1B.X2D, Z5T1A.T2A.X1B.X2D, Z6T1 AT2A.X1B.X2D,

Z1.T1BT2A.X1B.X2D, Z2T1BT2A.X1B.X2D, Z3.T1BT2A.X1B.X2D,

Z4T1BT2A.X1B.X2D, Z5.T1B.T2A.X1B.X2D, Z6T1B.T2A.X1B.X2D,

Z1TTCT21A.X1B.X2D, Z2T1C.T2A.X1B.X2D, 73.T1C.T2A.X1B.X2D,

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Z4T1D.T2A.X1B.X2D, Z5T1D.T2A.X1B.X2D, Z6T1DT2A.X1B.X2D,

119

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Z1.T1A.T2B.X1B.X2D, Z2.T1A.T2B.X1B.X2D, Z3.T1A.T2B.XIB.X2D,

Z4.T1A.T2B.X1B.X2D, Z5.T1A.T2B.X1B.X2D, Z6.T1A.T2B.X1B.X2D,

Z1.TTB.T2B.X1B.X2D, Z2.T1B.T2B.X1B.X2D, Z3.T1B.T2B.X1B.X2D,

Z4.T1B.T2B.X1B.X2D, Z5.T1B.T2B.X1B.X2D, Z6.T1B.T2B.X1B.X2D,

Z1.T1C.T2B.X1B.X2D, Z2.T1C.T2B.X1B.X2D, Z3.T1C.T2B.X1B.X2D,

Z4.T1C.T2B.X1B.X2D, Z5.T1C.T2B.X1B.X2D, Z6.T1C.T2B.X1B.X2D,

Z1.T1D.T2B.X1B.X2D, Z2.T1D.T2B.X1B.X2D, Z3.T1D.T2B.X1B.X2D,

Z4.T1D.T2B.X1B.X2D, Z5.T1D.T2B.X1B.X2D, Z6.TTD.T2B.X1B.X2D,

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Z4.T1A.T2C.X1B.X2D, Z5.T1A.T2C.X1B.X2D, ZS.T1A.T2C.X1B.X2D,

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Z4.T1B.T2C.X1B.X2D, Z5.T1B.T2C.X1B.X2D, Z6.T1B.T2C.X1B.X2D,

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Z4.T1C.T2C.X1B.X2D, Z5.T1C.T2C.X1B.X2D, Z6.T1C.T2C.X1B.X2D,

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Z1.T1B.T2D.X1B.X2D, Z2.T1B.T2D.XIB.X2D, Z3.T1B.T2D.X1B.X2D,

Z4.T1B.T2D.X1B.X2D, Z5.T1B.T2D.X1B.X2D, Z6.T1B.T2D.X1B.X2D,

Z1.T1C.T2D.X1B.X2D, Z2.T1C.T2D.X1 B.X2D, Z3.T1C.T2D.X1B.X2D,

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Z4.TID.T2D.X1B.X2D, Z5.T1D.T2D.X1 B.X2D, Z6.T1D.T2D.X1B.X2D,

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Z4.T1A.T2A.XIC.X2D, Z5.T1A.T2A.X1C.X2D, Z6.T1A.T2A.X1C.X2D,

120

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Z1.T1B.T2A.X1C.X2D, Z2.T1B.T2A.X1C.X2D, Z3.T1B.T2A.X1C.X2D,

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Z4.T1B.T2B.X1C.X2D, Z5.T1B.T2B.X1CX2D, Z6.T1B.T2B.X1C.X2D,

Z1.T1C.T2B.X1C.X2D, Z2.T1C.T2B.X1C.X2D, Z3.T1C.T2B.X1C.X2D,

Z4.T1C.T2B.X1C.X2D, Z5.T1C.T2B.X1C.X2D, Z6.T1C.T2B.X1C.X2D,

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Z4.T1C.T2C.X1C.X2D, Z5.T1C.T2C.X1C.X2D, Z6.T1C.T2C.X1C.X2D,

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Z4.T1A.T2D.X1C.X2D, Z5.T1A.T2D.X1C.X2D, Z6.T1A.T2D.X1C.X2D,

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Z4.T1B.T2D.X1C.X2D, Z5.T1B.T2D.X1C.X2D, Z6.T1B.T2D.X1C.X2D,

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Z1.T1C.T2D.X1C.X2D, Z2.T1C.T2D.X1C.X2D, Z3.T1C.T2D.X1C.X2D,

Z4.T1C.T2D.X1C.X2D, Z5.T1C.T2D.X1 C.X2D, Z6.T1CT2D.X1C.X2D,

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Z4.T1D.T2D.X1C.X2D, Z5.T1D.T2D.X1C.X2D, Z6.T1D.T2D.X1C.X2D,

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Ζ4.ΤΊ A.T2A.X1D.X2D, Z5.T1A.T2A.X1D.X2D, Z6.T1A.T2A.X1D.X2D,

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Z4.T1D.T2A.X1D.X2D, Ζ5.ΤΊ D.T2A.X1D.X2D, Z6.T1D.T2A.X1D.X2D,

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Z4.T1A.T2B.X1D.X2D, Z5.T1A.T2B.X1D.X2D, Z6.T1 A.T2B.X1D.X2D,

Z1.T1B.T2B.X1D.X2D, Z2.T1B.T2B.X1D.X2D, Z3.T1B.T2B.X1D.X2D,

Z4.T1B.T2B.X1D.X2D, Z5.T1B.T2B.X1D.X2D, Z6.T1B.T2B.X1D.X2D,

Z1.T1C.T2B.X1D.X2D, Z2.T1C.T2B.X1D.X2D, Z3.T1C.T2B.X1D.X2D,

Z4.T1C.T2B.X1D.X2D, Z5.T1C.T2B.X1D.X2D, Z6.T1C.T2B.X1D.X2D,

ZTT1D.T2B.X1D.X2D, Z2.T1D.T2B.X1D.X2D, Z3.T1D.T2B.X1D.X2D,

Z4.T1D.T2B.X1D.X2D, Z5.T1D.T2B.X1D.X2D, Z6.T1D.T2B.X1D.X2D,

Z1.T1A.T2C.X1D.X2D, Z2.T1 A.T2C.X1 D.X2D, Z3.T1A.T2C.X1D.X2D,

Z4.T1A.T2C.X1D.X2D, Z5.T1 A.T2C.X1D.X2D, Z6.T1A.T2C.X1D.X2D,

Z1.T1B.T2C.X1D.X2D, Z2.T1B.T2C.X1D.X2D, Z3.T1B.T2C.X1D.X2D,

Z4.T1B.T2C.X1D.X2D, Z5.T1 B.T2C.X1D.X2D, Z6.T1B.T2C.X1D.X2D,

Z1.T1C.T2C.X1D.X2D, Z2.T1C.T2C.X1D.X2D, Z3.T1C.T2C.X1D.X2D,

Z4.T1C.T2C.X1D.X2D, Z5.T1C.T2C.X1D.X2D, Z6.T1C.T2C.X1 D.X2D,

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Z1.T1D.T2C.X1D.X2D, Z2.T1D.T2C.X1D.X2D, Z3.T1D.T2C.X1D.X2D,

Z4.T1D.T2C.X1D.X2D, Z5.T1D.T2C.X1D.X2D, Z6.T1 D.T2C.X1D.X2D,

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Z4.T1B.T2D.X1D.X2D, Z5.T1B.T2D.X1D.X2D, Z6.T1B.T2D.X1D.X2D,

Z1 .T1C.T2D.X1D.X2D, Z2.T1C.T2D.X1 D.X2D, Z3.T1 C.T2D.X1 D.X2D,

Z4.T1C.T2D.X1D.X2D, Z5.T1C.T2D.X1D.X2D, Z6.T1CT2D.X1D.X2D,

Z1.T1D.T2D.X1D.X2D, Z2.T1D.T2D.X1D.X2D, Z3.T1D.T2D.X1D.X2D,

Z4.T1D.T2D.X1D.X2D, Z5.T1D.T2D.X1D.X2D, Z6.T1D.T2D.X1D.X2D, Z1 .TIA.T2A.X1 E.X2D, Ζ2.Τ1Α.Τ2Α.ΧΊ E.X2D, Z3.TJ Λ.Τ2Α.Χ1 E.X2D,

Z4.T1A.T2A.X1E.X2D, Z5.T1A.T2A.X1E.X2D, Z6.T1A.T2A.X1E.X2D, Z1.T1B.T2A.X1E.X2D, Z2.T1B.T2A.X1E.X2D, Z3.T1B.T2A.X1E.X2D,

Z4.T1B.T2A.X1E.X2D, Z5.T1 B.T2A.X1E.X2D, Z6.T1B.T2A.X1E.X2D,

Z1.T1C.T2A.X1E.X2D, Z2.T1C.T2A.X1E.X2D, Z3.T1C.T2A.X1E.X2D,

Z4.T1C.T2A.X1E.X2D, Z5.T1C.T2A.X1E.X2D, Z6.T1C.T2A.X1E.X2D,

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Z4.T1D.T2A.X1E.X2D, Z5.T1D.T2A.X1E.X2D, Z6.T1D.T2A.X1E.X2D,

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Z1.T1B.T2B.X1E.X2D, Z2.T1B.T2B.X1E.X2D, Z3.T1B.Γ2Β.Χ1 E.X2D,

Z4.T1B.T2B.X1E.X2D, Z5.T1B.T2B.X1E.X2D, Z6.T1B.T2B.X1E.X2D,

Z1.T1C.T2B.X1 E.X2D, Z2.T1C.T2B.X1E.X2D, Z3.T1C.T2B.X1E.X2D,

Z4.T1C.T2B.X1E.X2D, Z5.T1C.T2B.X1E.X2D, Z6.T1CT2B.X1E.X2D,

Z1.T1D.T2B.X1E.X2D, Z2.T1D.T2B.X1E.X2D, Z3.T1D.T2B.X1E.X2D,

Z4.T1D.T2B.X1E.X2D, Z5.T1D.T2B.X1E.X2D, Z6.T1D.T2B.X1E.X2D,

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Z1.T1AT2C.X1E.X2D, Z2.T1 A.T2C.X1E.X2D, Z3.T1A.T2C.X1E.X2D, Z4T1A.T2C.X1E.X2D, Z5.T1A.T2C.X1E.X2D, Z6.T1 AT2C.X1E.X2D, Z1T1B.T2C.X1E.X2D, Z2.T1B.T2C.X1E.X2D, Z3.T1B.T2C.X1E.X2D, Z4.T1BT2C.X1E.X2D, Z5.T1B.T2C.X1E.X2D, Z6.T1BT2C.X1E.X2D,

Z1.T1C.T2C.X1E.X2D, Z2.T1C.T2C.X1E.X2D, Z3T1CT2C.X1E.X2D, Z4T1CT2C.X1E.X2D, Z5T1CT2C.X1E.X2D, Z6T1CT2C.X1E.X2D,

Z1T1DT2C.X1E.X2D, Z2.T1D.T2C.X1E.X2D, Z3.T1D.T2C.X1E.X2D, Z4.TJDT2C.X1E.X2D, Z5.T1DT2C.X1E.X2D, Z6.T1D.T2C.X1E.X2D, Z1.T1AT2D.X1E.X2D, Z2T1A.T2D.X1E.X2D, Z3T1AT2D.X1E.X2D, Z4.T1AT2D.XIE.X2D, Z5.T1A.T2D.X1E.X2D, Z6.T1A.T2D.X1E.X2D, Z1T1B.T2D.X1E.X2D, Z2.T1B.T2D.X1E.X2D, Z3.T1B.T2D.X1E.X2D,

Z4T1BT2D.X1E.X2D, Z5T1B.T2D.X1E.X2D, Z6.T1BT2D.X1E.X2D, Z1T1CT2D.X1E.X2D, Z2.T1C.T2D.XIE.X2D, Z3.T1CT2D.X1E.X2D,

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Z4.T1BT2A.X1A.X2E, Z5.T1B.T2A.X1A.X2E, Z6T1BT2A.X1A.X2E, Z1T1CT2A.X1A.X2E, Z2T1C.T2A.X1A.X2E, Z3T1CT2A.X1A.X2E,

Z4.T1C.T2A.X1A.X2E, Z5.T1C.T2A.X1 A.X2E, Z6T1C.T2A.X1A.X2E, Z1.T1DT2A.X1A.X2E, Z2T1D.T2A.X1A.X2E, Z3.T1D.T2A.X1 A.X2E, Z4T1DT2A.X1A.X2E, Z5.T1DT2A.X1A.X2E, Z6.T1DT2A.X1A.X2E, ΖΊ.Τ1 A.T2B.X1A.X2E, Z2T1A.T2B.X1 A.X2E, Z3T1AT2B.X1A.X2E, Z4.T1AT2B.X1A.X2E, Z5.T1 A.T2B.X1A.X2E, Z6.T1 A.T2B.X1 A.X2E,

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Zl.nB.T2B.XlA.X2E, Z2.T1B.T2B.X1A.X2E, Z3T1B.T2B.X1A.X2E, Z4.T1BT2B.X1A.X2E, Z5.T1B.T2B.X1A.X2E, Z6.T1B.T2B.X1A.X2E, Z1.T1CT2B.X1A.X2E, Z2.T1CT2B.X1A.X2E, Z3.T1CT2B.X1A.X2E, Z4.T1CT2B.X1A.X2E, Z5T1C.T2B.X1A.X2E, Z6.T1C.T2B.X1 A.X2E, Z1.T1DT2B.X1 A.X2E, Z2.T1D.T2B.X1A.X2E, Z3.T1D.T2B.X1A.X2E, Z4.HD.T2B.X1A.X2E, Z5.T1D.T2B.X1A.X2E, Z0.T1D.T2B.X1A.X2E, Z1.T1A.T2C.X1A.X2E, Z2T1A.T2CX1A.X2E, Z3T1A.T2CX1A.X2E, Z4.T1A.T2C.X1A.X2E, Z5.T1A.T2CX1A.X2E, Z6.T1A.T2CX1 A.X2E,

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ZTT1C.T2A.X1B.X2E, Z2.T1C.T2A.X1B.X2E, Z3.T1C.T2A.X1B.X2E,

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Z4.T1D.T2C.X1B.X2E, Z5.T1D.T2C.X1B.X2E, Z6.T1 D.T2C.X1B.X2E,

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Z4.T1A.T2D.X1B.X2E, Z5.T1A.T2D.X1B.X2E, Z6.T1A.T2D.X1B.X2E,

Z1.T1B.T2D.X1B.X2E, Z2.T1B.T2D.X1B.X2E, Z3.T1B.T2D.XIB.X2E,

Z4.T1B.T2D.X1B.X2E, Z5.T1B.T2D.X1B.X2E, Z6.T1B.T2D.X1B.X2E,

Z1.T1C.T2D.X1B.X2E, Z2.T1C.T2D.X1B.X2E, Z3.T1C.T2D.X1B.X2E,

Z4.T1C.T2D.X1B.X2E, Z5.T1C.T2D.X1B.X2E, Z6.T1C.T2D.X1B.X2E,

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Z1 JTD.T2D.X1B.X2E, Z2JTD.T2D.X1B.X2E, Z3.T1D.T2D.X1B.X2E, Z4JTD.T2D.X1B.X2E, Z5.T1DT2D.X1B.X2E, Z6.T1D.T2D.X1B.X2E, Z1.T1A.T2A.X1C.X2E, Z2.T1A.T2A.X1C.X2E, Z3.T1A.T2A.X1C.X2E, Z4.T1 A.T2A.X1C.X2E, Z5.T1A.T2A.X1C.X2E, Z6 J1A.T2A.X1C.X2E, Z1.T1B.T2A.X1C.X2E, Z2.T1B.T2A.X1C.X2E, Z3.T1B.T2A.X1C.X2E, Z4T1B.T2A.X1C.X2E, Z5.T1B.T2A.X1C.X2E, Z6T1BT2A.X1C.X2E, Z1T1CT2A.X1C.X2E, Z2.T1C.T2A.X1C.X2E, Z3T1CT2A.X1C.X2E, Z4.T1C T2A.X1C.X2E, Z5.T1CT2A.X1C.X2E, Z6.T1CT2A.X1C.X2E, Z1.T1DT2A.X1C.X2E, Z2.T1D.T2A.X1C.X2E, Z3.T1D.T2A.X1C.X2E, Z4T1DT2A.X1C.X2E, Z5.T1D.T2A.X1C.X2E, Z6JTD.T2A.X1C.X2E, Z1.T1A T2B.X1C.X2E, Z2T1A.T2B.X1C.X2E, Z3.T1A.T2B.X1C.X2E, Ζ4.ΤΊ A.T2B.X1C.X2E, Z5JTA.T2B.X1C.X2E, Z6.T1A.T2B.X1C.X2E, Z1.T1B J2B.X1C.X2E, Z2.T1B.T2B.X1C.X2E, Z3.T1B.T2B.X1C.X2E, Z4.T1B.T2B.X1C.X2E, Z5JTB.T2B.X1C.X2E, Z6JTB.T2B.X1C.X2E, Z1.TIC.T2B.X1C.X2E, Z2.T1C.T2B.X JC.X2E, Z3.T1C.T2B.X1C.X2E, Z4.T1C.T2B.X1C.X2E, Z5.T1C.T2B.X1C.X2E, Z6 J1C J2B.X1C.X2E, Z1.T1D.T2B.X1C.X2E, Z2.T1D J2B.X1C.X2E, Z3.T1D J2B.X1C.X2E, Z4.T1D.T2B.X1C.X2E, Z5.T1D J2B.X1C.X2E, Z6.T1D.T2B.X1C.X2E, Z1.T1A.T2C.X1C.X2E, Z2.T1 AJ2C.X1C.X2E, Z3.T1A.T2C.X1C.X2E, Z4.T1A.T2C.X1C.X2E, Z5 J1A.T2C.X1C.X2E, Z6.T1 A.T2C.X1C.X2E, Z1.T1BT2C.X1C.X2E, Z2.T1B.T2C.X1C.X2E, Z3.T1B.T2C.X1C.X2E, Z4.T1BJ2C.X1C.X2E, Z5.T1B.T2C.X1C.X2E, Z6.T1BT2C.X1C.X2E, Z1.TTCT2CX1C.X2E, Z2.T1C.T2C.X1C.X2E, Z3.T1C.T2C.X1C.X2E, Z4.T1C.T2C.X1C.X2E, Z5.T1C.T2C.X1C.X2E, Z6.T1C.T2C.X1C.X2E, Z1 JTD.T2C.X1C.X2E, Z2.T1DT2C.X1C.X2E, Z3.T1D.T2C.X1C.X2E, Z4.T1D.T2C.X1C.X2E, Z5TTD.T2C.X1C.X2E, Z6.T1D.T2C.X1C.X2E,

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Z1T1AT2D.X1C.X2E, Z2.T1A.T2D.X1C.X2E, Z3.T1AT2D.X1C.X2E, Z4.T1AT2D.X1C.X2E, Z5.T1 A.T2D.X1C.X2E, Z6.T1 A.T2D.X1C.X2E, Z1.T1B.T2D.X1C.X2E, Z2.T1B.T2D.X1C.X2E, Z3T1BT2D.X1C.X2E, Z4T1B.T2D.X1C.X2E, Z5T1BT2D.X1C.X2E, Z6.T1B.T2D.X1C.X2E, Z1.T1C.T2D.X1C.X2E, Z2T1C.T2D.X1C.X2E, Z3T1C.T2D.X1C.X2E, Z4T1C.T2D.X1C.X2E, Z5T1C.T2D.X1C.X2E, Z6T1CT2D.X1C.X2E, ΖΪT1 DT2D.X1C.X2E, Z2.T1 D.T2D.X1C.X2E, Z3.T1D.T2D.X1 C.X2E, Z4T1D.T2D.X1C.X2E, Z5.T1D.T2D.X1C.X2E, Z6.T1D.T2D.X1C.X2E, Z1T1AT2A.X1D.X2E, Z2T1AT2A.X1D.X2E, Z3.T1AT2A.X1D.X2E, Z4.T1AT2A.X1D.X2E, Z5.T1 A.T2A.X1D.X2E, Z6.T1 AT2A.X1D.X2E, ΖΊ T1 B.T2A.X1D.X2E, Z2T1 BT2A.X1D.X2E, Ζ3.ΤΊ B.T2A.X1 D.X2E, Z4.T1B.T2A.X1D.X2E, Z5.T1B.T2A.X1D.X2E, Z6.T1BT2A.X1D.X2E, Z1.T1C.T2A.X1D.X2E, Z2.T1C.T2A.X1D.X2E, Z3.T1C.T2A.X1D.X2E, Z4.T1C.T2A.X1D.X2E, Z5.T1C.T2A.X1 D.X2E, Z6.T1C.T2A.X1D.X2E, Z1.T1D.T2A.X1D.X2E, Z2.T1DT2A.X1D.X2E, Z3T1DT2A.XTD.X2E, Z4T1DT2A.X1D.X2E, Z5T1D.T2A.X1D.X2E, Z6T1D.T2A.X1D.X2E, Z1T1 A.T2B.X1D.X2E, Z2.T1 A.T2B.X1 D.X2E, Z3T1 AT2B.X1D.X2E, Z4.T1A.T2B.X1D.X2E, Z5.T1A.T2B.X1D.X2E, Z6T1AT2B.X1D.X2E, Z1T1B.T2B.X1D.X2E, Z2T1BT2B.X1D.X2E, Z3T1BT2B.X1D.X2E, Z4T1BT2B.X1D.X2E, Ζ5ΤΊΒΤ2Β.ΧΊΟ.Χ2Ε, Ζ6. ΠΒ.Τ2Β.Χ1Ο.Χ2Ε, ZJT1CT2B.X1D.X2E, Z2.T1C.T2B.X1D.X2E, Z3T1CT2B.X1D.X2E,

Z4T1CT2B.X1D.X2E, Z5T1CT2B.X1D.X2E, Z6T1CT2B.X1D.X2E, Z1T1D.T2B.X1D.X2E, Z2T1DT2B.X1D.X2E, Z3.T1DT2B.X1D.X2E, Z4T1DT2B.X1D.X2E, Z5.T1DT2B.X1D.X2E, Z6T1DT2B.X1D.X2E, Z1.T1A.T2C.X1D.X2E, Z2.T1A.T2C.X1D.X2E, Z3T1A.T2C.X1D.X2E, Z4T1 A.T2C.X1D.X2E, Z5T1AT2C.X1D.X2E, Z6T1AT2C.X1D.X2E,

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Z1.T1B.T2C.X1D.X2E, Z2.T1B.T2C.X1D.X2E, Z3.T1B.T2C.X1D.X2E, Z4.HB.T2C.X1D.X2E, Z5.T1B.T2C.X1D.X2E, Z6.T1B.T2C.X1D.X2E, Z1.T1CT2C.XID.X2E, Z2.T1C.T2C.X1D.X2E, Z3.T1C.T2C.X1D.X2E, Z4.HC.T2C.X1D.X2E, Z5.HC.T2C.XID.X2E, Z6.T1C.T2C.X1D.X2E, Z1.T1D.T2C.X1D.X2E, Z2.HD.T2C.X1D.X2E, Z3.T1D.T2C.X1D.X2E, Z4.T1D.T2C.X1D.X2E, Z5.T1D.T2C.X1D.X2E, Z6.T1D.T2C.X1D.X2E, Z1.HA.T2D .XI D.X2E, Z2.T1A.T2D.X1D.X2E, Z3.T1A.T2D.X1D.X2E, Z4.TTA.T2D .XI D.X2E, Z5.T1 A.T2D.X1D.X2E, Z6.T1A.T2D.X1D.X2E, Z1.T1B.T2D.X1D.X2E, Z2.TTB.T2D.X1D.X2E, Z3.T1B.T2D.X1D.X2E, Z4.T1B.T2D.X1D.X2E, Z5.T1B.T2D.X1D.X2E, Z6.T1B.T2D.X1D.X2E, Z1.T1C.T2D.X1D.X2E, Z2.HC.T2D.X1D.X2E, Z3.T1C.T2D.X1D.X2E, Z4.T1C.T2D.X1D.X2E, Z5.HC.T2D.X1D.X2E, Z6.T1C.T2D.X1D.X2E, Z1.T1D.T2D.X1D.X2E, Z2.T1D.T2D.X1D.X2E, Z3.T1D.T2D.X1D.X2E, Z4.T1D.T2D.X1D.X2E, Z5.HD.T2D.X1 D.X2E, Z6.HD.T2D.X1D.X2E, Z1.T1A.T2A.X1E.X2E, Z2.T1A.T2A.X1E.X2E, Z3.HA.T2A.X1E.X2E, Z4.TTA.T2A.X1E.X2E_/Z5.T1A.T2A.X1E.X2E, Z6.T1 A.T2A.X1E.X2E, Z1.T1B.T2A.X1E.X2E, Z2.T1B.T2A.X1E.X2E, Z3.T1B.T2A.X1E.X2E, Z4.T1B.T2A.X1E.X2E, Z5.T1B.T2A.X1E.X2E, Ζ6.Τ1Β.Τ2Α.ΧΊΕ.Χ2Ε, Z1.T1C.T2A.X1E.X2E, Z2.T1C.T2A.X1E.X2E, Z3.HC.T2A.X1E.X2E, Z4.T1C.T2A.X1 E.X2E, Z5.T1C.T2A.X1E.X2E, Z6.T1C.T2A.X1E.X2E, Z1.HD.T2A.X1E.X2E, Z2.T1D.T2A.X1E.X2E, Z3.HD.T2A.X1E.X2E, Z4.T1D.T2A.X1E.X2E, Z5.HD.T2A.X1E.X2E, Z6.HD.T2A.X1E.X2E, Z1.T1A.T2B.X1E.X2E, Ζ2.ΠΑ.Τ2Β.Χ1Ε.Χ2Ε, Ζ3.ΊΤΑ.Τ2Β.Χ1Ε.Χ2Ε, Z4.T1A.T2B.X1E.X2E, Z5.T1A.T2B.X1E.X2E, Z6.T1A.T2B.X1E.X2E, Ζ1.ΠΒ.Τ2Β.Χ1Ε.Χ2Ε, Z2.T1B.T2B.X1E.X2E, Z3.T1B.T2B.X1E.X2E, Z4.T1B.T2B.X1E.X2E, Z5.T1B.T2B.X1E.X2E, Z6.T1B.T2B.X1E.X2E,

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Z1.T1C.T2B.X1E.X2E, Z2.T1C.T2B.X1E.X2E, Z3.T1C.T2B.X1E.X2E,

Z4.T1C.T2B.X1E.X2E, Z5.T1C.T2B.X1E.X2E, Z6.T1C.T2B.X1E.X2E,

Z1.T1D.T2B.X1E.X2E, Z2.T1D.T2B.X1E.X2E, Z3.T1D.T2B.X1E.X2E,

Z4.T1D.T2B.X1E.X2E, Z5.T1D.T2B.X1E.X2E, Z6.T1D.T2B.X1E.X2E,

Z'I.T1A.T2C.X1E.X2E, Z2.T1A.T2C.X1E.X2E, Z3.T1A.T2C.X1E.X2E,

Z4.T1A.T2C.X1E.X2E, Z5.T1A.T2C.X1E.X2E, Z6.T1A.T2C.X1E.X2E,

Z1.T1B.T2C.X1E.X2E, Z2.T1B.T2C.X1E.X2E, Z3.T1B.T2C.X1E.X2E,

Z4.T1B.T2C.X1E.X2E, Z5.T1B.T2C.X1E.X2E, Z6.T1B.T2C.X1E.X2E,

Z1.T1C.T2C.X1E.X2E, Z2.T1C.T2C.X1E.X2E, Z3.T1C.T2C.X1E.X2E,

Z4.T1C.T2C.X1E.X2E, Z5.T1C.T2C.X1E.X2E, Z6.T1C.T2C.X1E.X2E,

Z1.T1D.T2C.X1E.X2E, Z2.T1D.T2C.X1E.X2E, Z3.T1D.T2C.X1E.X2E,

Z4.T1D.T2CX1E.X2E, Z5.T1D.T2C.X1E.X2E, Z6.T1D.T2C.X1E.X2E,

Z1.T1A.T2D.X1E.X2E, Z2.T1A.T2D.X1E.X2E, Z3.T1A.T2D.X1E.X2E,

Z4.T1A.T2D.X1E.X2E, Z5.T1A.T2D.X1E.X2E, Ζ6.ΤΊ A.T2D.X1 E.X2E,

Z1.T1B.T2D.X1E.X2E, Z2.T1B.T2D.X1E.X2E, Z3.T1B.T2D.X1E.X2E,

Z4.T1B.T2D.X1E.X2E, Z5.T1B.T2D.X1E.X2E, Z6.T1B.T2D.X1E.X2E,

ZLT1C.T2D.X1E.X2E, Z2.T1C.T2D.X1E.X2E, Z3.T1C.T2D.X J E.X2E,

Z4.T1C.T2D.X1E.X2E, Z5.T1C.T2D.X1E.X2E, Z6.T1C.T2D.X1E.X2E,

Z1.T1D.T2D.X1E.X2E, Z2.T1D.T2D.X1E.X2E, Z3.T1D.T2D.X1E.X2E,

Z4.T1D.T2D.X1E.X2E, Z5.T1D.T2D.X1E.X2E, and Z6.T1D.T2D.X1E.X2E.

In still another embodiment, selected compounds of Formula J are named below in tabular format (Table 12) as compounds of general Formula III (below):

2------1------3

Formula Ill

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Table 7: 1 Structures

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Table 8: 2 Structures

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Table 9: 3 Structures

Code	3 Structure
3a	-O-C Hi-(S-thiazolyl)
3b	-O-CH:-(3-pyridyl)

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Code	3 Structure
3c	-NH-CHz-(5-thiazolyl)
3d	-NH-CHz-(3-pyridyI)
3e	-N(CHs)-CHs-<5- thiazolyl)
3f	-NiCHsLCHs-O-pyridyl)
3g	-\(CH9-(5-thiazolyl)
3h	-N(CHs)-(3-pyiidyl)

Table 10: 4 Structures

Code	4” Structure
4a	n-propyl
4b	i-butyl
4c	-CHz-cyclohexy I
4d	-CHi-phenyl
	-C H e th oxy ph en y 1)
4f	-CH2-(3-fluoro phenyl)
4g	-CHz-( 4-pyridyl)
411	-C Hz-(3-py ii dy 1)
4i	-CtC-tl-pyridyl)
	- C H zCHi- (4-mo rp ho 1 i n yl)
4k	<Ί1

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Table 11: 5 Structures

Code	5 Structure
5a	n-propyl
5b	i-butyl
5c	- CH 2-cy clo h e xy 1
5d	-CHi-pheoy!
5e	- CH 4-meth oxy p hen y 1)
5f	-C H 2-(3 -fluo ro phe nyl)
5g	-CH;-(4-pyridyl)
5h	-CHz-O-pyridyl)

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Code	5 Structure
5i	-CH?-(2-pyridyl)
5)	-CH2C H : (4-m orph ol i n yl)
5k
51
5m
5n	^N
5o

Table 12: List of Compound Structures of Formula JI la. 2a.3a.4a.5a., lb.2a.3a.4a.5a., lf.2a.3a.4a.5a., lh.2a.3a.4a.5a., lj.2a.3a.4a.5a., lp.2a.3a.4a.5a., 1 a.2b.3a.4a.5a., lb.2b.3a.4a.5a., lf.2b.3a.4a.5a., lh.2b.3a.4a.5a., lj.2b.3a.4a.5a., ]p.2b.3a.4a,5a., la.2e.3a.4a.5a., lb.2e.3a.4a.5a., lL2e.3a.4a.5a., Jh.2e.3a.4a.5a., lj.2e.3a.4a.5a., lp.2e.3a.4a.5a., la.2f.3a.4a.5a., lb.2f.3a.4a.5a., Jf.2L3a.4a.5a., lh.2f.3a.4a.5a., lj.2L3a.4a.5a., lp.2f.3a.4a.5a., la.2i.3a.4a.5a., lb. 2i.3a.4a.5a., lf.2i.3a.4a.5a., lh.2i.3a.4a.5a., lj.2i.3a.4a.5a., lp.2i.3a.4a.5a., la.2m.3a.4a.5a., lb.2m.3a.4a.5a., lf.2m.3a.4a.5a., lh.2m.3a.4a.5a., lj.2m.3a.4a.5a., lp.2m.3a.4a.5a., la.2o.3a.4a.5a., lb.2o.3a.4a.5a., lf.2o.3a.4a.5a„ lh.2o.3a.4a.5a., lj.2o.3a.4a.5a., lp.2o.3a.4a.5a., la.2u.3a.4a.5a., lb.2u.3a.4a.5a,, lf.2u.3a.4a.5a., lh,2u.3a.4a.5a., lj.2u.3a.4a.5a., lp.2u,3a,4a.5a., la.2y.3a.4a.5a., lb.2y.3a.4a.5a.,

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2020203321 21 May 2020 lf.2y.3a.4a.5a., lh.2y.3a.4a.5a., lj.2y.3a.4a.5a., lp.2y.3a.4a.5a., la.2a.3b.4a.5a„ lb.2a.3b.4a.5a., lL2a.3b.4a.5a., lh.2a.3b.4a.5a., lj.2a.3b.4a.5a., lp.2a.3b.4a.5a., la. 2b.3b.4a.5a., lb.2b.3b.4a.5a., If.2b.3b.4a.5a., lh.2b.3b.4a.5a., lj.2b.3b.4a.5a., lp.2b.3b.4a.5a., la.2e.3b.4a.5a», lb.2c.3b.4a.5a., lf.2c.3b.4a.5a., 1h.2e.3b.4a.5a., lj.2e.3b.4a.5a., lp.2e.3b.4a.5a., la.2L3b.4a,5a., lb.2L3b.4a.5a., lf.2L3b.4a.5a., lh.2f.3b.4a.5a., 1j.2L3b.4a.5a., lp.2L3b.4a.5a„ la.2i.3b.4a.5a., lb.2i.3b.4a.5a., lf.2i.3b.4a.5a., lh.2i.3b.4a.5a., lj.2i.3b.4a.5a., lp.2i,3b.4a.5a., la.2m.3b.4a.5a., lb. 2m.3b.4a.5a., lL2m.3b.4a. 5a., Ih. 2m .3b.4a. 5 a., lj.2m.3b.4a.5a., 1p.2m.3b.4a.5a., la.2o.3b.4a.5a., lb.2o.3b.4a.5a., lf.2o.3b.4a.5a., lh.2o.3b.4a.5a., lj.2o.3b.4a.5a., lp,2o.3b.4a.5a., la.2u.3b.4a.5a., lb.2u.3b.4a.5a., lf.2u.3b.4a.5a., lh.2u.3b.4a.5a., lj.2u.3b.4a.5a., lp.2u.3b.4a.5a., la.2y.3b.4a.5a., lb.2y.3b.4a.5a., lf.2y.3b.4a.5a., lh.2y.3b.4a.5a., lj.2y.3b.4a.5a., lp.2y.3b.4a.5a., la.2a.3c.4a.5a., lb.2a.3c.4a.5a., lf.2a.3e.4a.5a., lh.2a,3e.4a.5a., lj.2a.3e.4a.5a., lp.2a.3e.4a.5a., la.2b.3e.4a.5a.,

b.2b.3e.4a.5a., lf.2b.3e.4a.5a., 1h.2b.3e.4a.5a., lj.2b.3c.4a.5a., Ip.2b.3e.4a.5a., la.2e.3e.4a.5a., lb.2e.3e.4a.5a., lf.2e.3e.4a.5a., lh.2e.3e.4a.5a., lj.2e.3e.4a.5a., lp.2e.3e.4a.5a., la.2L3e.4a.5a., lb.2L3e.4a.5a., lf.2L3c.4a.5a., Ih.2L3c.4a.5a., lj.2f.3e.4a.5a,, lp.2I.3e.4a.5a,, la.2i.3e.4a.5a., lb.2i.3e.4a.5a., lL2i.3e.4a.5a., lh.2i.3e.4a.5a., lj.2i.3e.4a.5a., lp.2i.3e.4a.5a., la.2m.3e.4a.5a., lb.2m.3e.4a.5a., lL2m.3e.4a.5a., lh.2in.3e.4a.5a., lj.2m.3e.4a.5a., lp.2m.3e.4a.5a., la.2o.3e.4a.5a., 1 b.2o.3e.4a.5a., lL2o.3c.4a.5a., lh.2o.3c.4a.5a., lj.2o.3e.4a.5a., lp.2o.3c.4a.5a., la. 2u.3e.4a.5a., lb,2u.3e.4a.5a., lf.2u.3e.4a.5a., lh.2u.3e.4a.5a., lj.2u.3e.4a.5a„ 1p.2u.3e.4a.5a., la.2y.3c.4a.5a., lb.2y.3e.4a.5a., lf.2y.3e.4a.5a., lh.2y.3c.4a.5a., lj.2y.3e.4a.5a., lp.2y.3e.4a,5a„ la.2a.3g.4a.5a., lb-2a.3g.4a.5a., 1 L2a.3g.4a.5a., lh.2a.3g.4a.5a., lj.2a.3g.4a.5a., lp.2a.3g.4a.5a., la.2b.3g.4a.5a., lb.2b.3g,4a.5a., lf.2b.3g.4a.5a», lh.2b.3g,4a.5a., lj.2b.3g.4a.5a., lp.2b.3g.4a.5a., la.2e.3g.4a.5a., lb. 2c.3g.4a.5a., lL2e.3g.4a.5a., lh.2e.3g.4a.5a., lj.2e.3g.4a.5a., lp.2e.3g.4a.5a„ la. 2f.3g.4a.5a., lb.2f.3g.4a.5a., lL2L3g.4a.5a., lh.2L3g.4a.5a., lj.2f.3g.4a.5a., lp.2f.3g.4a.5a., la.2L3g.4a.5a., lb.2i.3g.4a.5a., lf.2i.3g.4a.5a., lh.2L3g.4a.5a,,

Ij.2i.3g.4a.5a., lp.2i.3g,4a.5a., la.2m.3g.4a.5a., lb.2m.3g.4a.5a., If.2m.3g.4a.5a., lh.2m.3g.4a.5a., lj.2m.3g.4a.5a., lp.2m.3g.4a.5a., la.2o.3g.4a.5a., lb.2o,3g.4a.5a„ lf.2o.3g.4a.5a., lh.2o.3g.4a.5a., lj.2o.3g.4a.5a., lp.2o.3g.4a.5a., la.2u.3g.4a.5a., lb. 2u.3g.4a.5a., lf.2u.3g.4a.5a., lh.2u.3g.4a.5a., lj.2u.3g.4a.5a., lp.2u.3g.4a.5a., la. 2y.3g.4a.5a., lb.2y.3g.4a.5a., lf.2y.3g.4a.5a., lh.2y.3g.4a.5a., lj.2y.3g.4a.5a., lp.2y.3g.4a.5a., la.2a.3a.4d.5a., lb.2a.3a.4d.5a., lf.2a.3a.4d.5a., lh.2a.3a.4d.5a», 1j.2a.3a.4d.5a., lp.2a.3a.4d.5a., la.2b.3a.4d.5a., lb.2b.3a.4d.5a., lf.2b.3a.4d.5a., lh,2b.3a.4d.5a., lj.2b.3a.4d.5a., Ip.2b.3a.4d.5a., 1a.2e.3a.4d.5a., 1b.2e.3a.4d.5a., lL2e.3a.4d.5a., lh.2e.3a.4d.5a., lj.2e.3a.4d.5a., lp.2e.3a.4d.5a., la.2f.3a.4d.5a., lb. 2L3a.4d.5a„ lf.2L3a.4d .5a., lh.2L3a.4d.5a., lj.2L3a.4d.5a., lp.2L3a.4d,5a., la.2i.3a.4d.5a., lb.2i.3a.4d.5a„ lf.2i.3a.4d.5a., lh.2i.3a.4d.5a., lj.2i.3a.4d.5a„ lp.2i.3a.4d.5a., la.2ni.3a.4d.5a., lb.2m.3a.4d.5a., 1f.2m.3a.4d.5a., lh.2rn.3a.4d.5a., lj.2m.3a.4d.5a., lp.2m.3a.4d.5a., la.2o.3a.4d.5a., lb.2o.3a.4d.5a., lL2o.3a.4d.5a,,

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2020203321 21 May 2020 lh.2o.3a.4d.5a., lj.2o.3a.4d.5a., lp.2o.3a.4d.oa., la.2u.3a.4d.5a., lb.2u.3a.4d.5a,, lf.2u.3a.4d.5a., lh.2u3a.4d.5a„ lj.2u.3a.4d.5a., lp,2u.3a.4d.5a., la.2y.3a.4d.5a., lb.2y.3a.4d.5a., lf.2y.3a.4d.5a., lh.2y.3a.4d.5a., lj.2y.3a.4d.5a., lp.2y.3a.4d.5a., la. 2a.3b.4d.5a., Ib.2a3b.4d.5a., lf.2a.3b.4d.5a., lh.2a.3b,4d.5a., lj.2a.3b.4d.5a., lp.2a.3b.4d.5a„ la.2b.3b.4d.5a„ lb.2b.3b.4d.5a., lf.2b.3b.4d.5a., lh.2b.3b.4d.5a., lj.2b.3b.4d.5a„ lp.2b.3b.4d.5a., la.2e.3b.4d.5a., lb.2e.3b.4d.5a., lf.2e.3b.4d.5a., lh.2e.3b.4d.5a., lj.2e.3b.4d.5a., lp.2e.3b.4d.5a., la.2f.3b.4d.5a„ lb.2L3b.4d.5a., lf.2f.3b.4d,5a„ lh.2f.3b.4d.5a., lj.2f.3b.4d.5a., lp.2f.3b.4d.5a., la.2i.3b.4d.5a., lb. 2i.3b.4d.5a., lf.2i.3b.4d.5a., lh.2i.3b.4d.5a., lj.2i.3b.4d.5a., lp.2i.3b.4d.5a., la. 2m.3b.4d ,5a,, lb.2m.3b.4d.5a., lf.2m.3b.4d.5a., lh.2m.3b.4d.5a., lj.2m.3b.4d.5a., lp.2m.3b.4d.5a., la.2o.3b.4d.5a„ lb.2o.3b.4d.5a., lf.2o.3b.4d.5a., lh.2o.3b.4d.5a., lj.2o.3b.4d.5a., lp.2o.3b.4d.5a., la.2u,3b.4d.5a., lb.2u.3b.4d.5a,, lf.2u.3b.4d.5a., lh.2u,3b.4d.5a., Ij.2u3b.4d.5a., lp.2u.3b.4d.5a., la.2y.3b.4d.5a., lb.2y.3b.4d.5a., If.2y3b.4d.5a„ lh.2y.3b.4d.5a„ lj.2y.3b.4d ,5a., lp.2y.3b.4d.5a„ la.2a.3e.4d.5a., lb. 2a3c.4d.5a., If.2a3e.4d.5a., lh.2a.3e.4d.5a., Ij.2a.3e.4d5a., lp.2a.3e.4d.5a., la. 2b3e.4d.5a., Ib.2b3e.4d.5a., lf.2b.3e.4d.5a., lh.2b.3e.4d.5a., Ij.2b3e.4d.5a., lp.2b.3e.4d.5a., Ia.2e3e.4d.5a., lb.2e.3e.4d.5a., lf.2c.3e.4d.5a., Ih.2e3e.4d5a., Ij.2e3e.4d.5a., Ip.2e3e.4d.5a., Ia.2f3e.4d.5a„ lb.2f.3e.4d,5a., lf.2f.3e.4d.5a., 1h.213e.4d.5a., lj.2f.3e.4d.5a., Ip.2f3e.4d.5a., la.2i.3e.4d.5a., lb.2i.3e.4d.5a., If.2i3e.4d.5a., 1h.2i3e.4d.5a., lj.2i.3e.4d.5a., lp.2i.3e.4d.5a., la.2m.3e.4d.5a., lb. 2m3e.4d.5a., lf.2m.3e.4d.5a., 1h.2m.3e.4d.5a., lj.2m.3e.4d.5a., lp.2m.3e.4d,5a., la. 2o.3e.4d.5a., Ib.2o3e.4d,5a., lf,2o.3e.4d.5a., Ih.2o3e.4d.5a., lj.2o.3e.4d.5a„ lp.2o3e.4d.5a,, la.2u.3e.4d.5a., lb.2u.3e.4d.5a., lf.2u.3e.4d.5a., lh.2u.3e.4d.5a., Ij.2u3e.4d.5a., lp.2u.3e.4d.5a., Ia.2y3e.4d.5a., lb.2y.3e.4d.5a., lf.2y.3e.4d.5a., Ih.2y3e.4d. 5a., lj.2y.3e.4d.5a., 1 p.2y.3e.4d.5a., la.2a.3g.4d.5a., lb.2a.3g.4d.5a., 'Jf.2a.3g.4d.5a., Ih.2a3g.4d.5a., lj.2a.3g.4d.5a., lp.2a.3g.4d.5a., la.2b.3g.4d.5a., lb. 2b3g.4d.5a., If.2b3g.4d.5a., Ih.2b.3g.4d.5a., lj,2b.3g.4d,5a., lp.2b.3g.4d.5a,, la. 2e.3g.4d.5a., lb.2e.3g.4d.5a., If.2e3g.4d.5a., lh.2e.3g.4d.5a., lj.2e.3g.4d.5a., lp.2e.3g.4d.5a., la.2f.3g.4d.5a., lb.2f.3g.4d.5a., lf.2f.3g.4d.5a., lh.2f.3g.4d.5a., lj.2f.3g.4d.5a., lp.2f.3g.4d.5a., la.2i.3g.4d.5a., lb.2i.3g.4d.5a., lf.2i.3g.4d.5a., lh,2i.3g.4d.5a., lj.2i.3g.4d.5a., Ip.2i3g.4d.5a., la.2m.3g.4d.5a., lb.2m.3g.4d.5a., lf.2m.3g.4d.5a., lh.2m.3g.4d.5a., Ij.2m3g.4d.5a., lp.2m.3g.4d.5a., Ia.2o3g.4d.5a., lb. 2o.3g.4d.5a., lf.2o.3g.4d.5a., lh.2o.3g,4d.5a., lj.2o.3g.4d.5a., lp.2o.3g.4d.5a., la. 2u.3g.4d.5a., lb.2u.3g.4d.5a,, lf.2u.3g.4d.5a., lh.2u.3g.4d.5a., Ij.2u3g.4d.5a., lp,2u.3g.4d.5a., la.2y.3g.4d.5a., lb.2y.3g.4d.5a., If.2y3g.4d.5a., lh.2y.3g.4d.5a., Ij.2y3g.4d.5a,, lp.2y.3g.4d.5a., la.2a.3a.4f,5a., lb.2a.3a.4f.5a., If.2a3a.4f.5a., Ih.2a3a.4f.5a., Ij.2a3a.4f.5a., lp.2a.3a.4f.5a., la.2b.3a.4f.5a., lb.2b.3a.4L5a., lf.2b.3a.4f.5a., lh.2b.3a.4f.5a., Ij.2b3a.4f.5a., lp.2b.3a.4f.5a., la.2e.3a.4f.5a., lb. 2c.3a.4f.5a., lf.2e.3a.4f.5a., lh.2e.3a.4f.5a., lj.2e.3a.4f.5a., lp.2e.3a.4f.5a., la.2f.3a.4f.5a., lb.2f.3a.4f.5a., If.2f3a.4f.5a., Ih.2f3a.4f.5a., lj.2f.3a.4f.5a., lp.2L3a.4f.5a., la.2i.3a.4f.5a., lb.2i.3a.4f.5a., lf.2i.3a.4f.5a., Ih.2i3a.4f,5a.,

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2020203321 21 May 2020 lj.2i.3a.4f.5a., lp.2i.3a.4f.5a_, la.2m.3a.4f.5a_, lb.2m.3a.4f.5a_, lf.2m.3a.4f.5a_, lh.2m.3a.4f.5a., lj.2m.3a.4f.5a., lp.2m.3a.4f.5a., la.2o.3a.4f.5a_, lb.2o.3a.4f.5a., lf.2o.3a.4f.5a., lh.2o.3a.4f.5a., 1j.2o.3a.4f.5a., lp.2o.3a.4f.5a., la.2u.3a.4f.5a., lb.2u.3a.4f.5a., lf.2u.3a.4f.5a., lh.2u.3a.4f.5a., lj.2u.3a.4f.5a., lp,2u,3a.4f.5a., la. 2y.3a.4f.5a., lb.2y.3a.4f.5a., lf.2y.3a.4f.5a., lh.2y.3a.4f.5a., lj.2y.3a.4f.5a., lp.2y.3a.4f.5a., la.2a.3b.4f.5a., lb.2a.3b.4f.5a., lf.2a.3b.4f.5a_, lh.2a_3b.4f.5a., Ij.2a.3b.4f.5a„ lp.2a.3b.4f.5a., la.2b.3b.4f.5a., lb.2b.3b.4f.5a., lf.2b.3b.4f.5a., lh.2b.3b.4f.5a., lj.2b.3b.4f.5a_, Ip.2b.3b.4f.5a., la.2e.3b.4f.5a., lb.2e.3b.4f.5a., lf.2e.3b.4f.5a., lh.2e.3b.4f.5a_, lj.2e.3b.4f.5a., lp.2e.3b.4f.5a., la.2f.3b.4f.5a„ lb. 2f.3b.4f.5a., lf.2f.3b.4f.5a., lh.2f.3b.4f.5a., lj.2f.3b.4f.5a., lp.2f.3b.4f.5a., la. 2i.3b.4f.5a., lb.2i.3b.4f.5a., lf.2i.3b.4f.5a., lh.2i.3b.4f.5a„ lj.2i.3b.4f.5a., lp.2i.3b.4f.5a., la.2m.3b.4f.5a_, lb.2m.3b.4f.5a., lf.2m.3b.4f.5a., lh.2m.3b.4f.5a_, lj.2m.3b.4f.5a_, lp.2m.3b.4f.5a., la.2o.3b.4f.5a., lb.2o.3b.4f.5a., lf.2o.3b.4f.5a., lh.2o.3b.4f.5a., lj.2o.3b.4f.5a., lp.2o.3b.4f.5a., la.2u.3b.4f.5a„ lb.2u.3b.4f.5a_, lf.2u.3b_4f.5a., lh.2u.3b.4f.5a_, lj.2u.3b.4f.5a_, lp.2u.3b.4f.5a., la.2y.3b.4f.5a_, lb. 2y.3b.4f.5a., lf.2y.3b.4f.5a_, lh.2y.3b.4f.5a., lj.2y.3b.4f.5a., lp.2y.3b.4f.5a., la. 2a.3e.4f.5a., lb.2a.3e.4f.5a., lf.2a.3e.4f.5a., lh.2a.3e.4f.5a., lj.2a.3e.4f.5a„ lp.2a.3e.4f.5a., 1a.2b.3e.4f.5a., lb.2b.3e.4f.5a., lf.2b.3e.4f.5a., lh.2b,3e.4f,5a., lj.2b.3e.4f.5a., lp.2b.3e.4f.5a., 'la.2e.3e.4f.5a., lb.2e.3e.4f.5a., lf.2e.3e.4f.5a., lh.2e.3e.4f.5a., lj.2e.3e.4f.5a., lp.2e,3e,4f.5a., la.2f.3e.4f.5a., lb.2f.3e.4f.5a., lf.2L3e.4f.5a„ lh.2f.3e.4f.5a., lj.2f.3e.4f.5a_, lp.2f.3e.4f.5a_, la.2i.3e.4f.5a., lb. 2i.3e.4f.5a., lf.2i.3e.4f.5a., lh.2i.3e.4f.5a_, lj.2i.3e.4f.5a., lp.2i.3e.4f.5a., la. 2m.3e.4f.5a., lb.2m.3e.4f.5a., lf.2m.3e.4f.5a., lh.2m.3e.4f.5a., lj.2m.3e.4f.5a., lp.2m.3e.4f,5a., la.2o.3e.4f.5a., lb.2o.3e.4f.5a., lf.2o.3e.4f.5a., lh.2o.3e.4f.5a., lj.2o.3e.4f.5a_, lp.2o.3e.4f.5a., la.2u.3e.4f.5a_, lb.2u.3e.4f.5a., lf.2u.3e.4f.5a., lh.2u.3e.4f.5a_, lj.2u.3e.4f.5a., 1p.2u.3e.4f.5a_, la.2y.3e.4f.5a., 'fb.2y.3e.4f.5a., 1f.2y.3e.4f.5a., lh.2y.3e.4f.5a., lj.2y.3e.4f.5a., lp.2y.3e_r4f.5a., la.2a.3g.4f.5a„ lb. 2a.3g.4f.5a., lf.2a.3g.4f.5a., lh.2a.3g.4f.5a., lj.2a.3g.4f,5a., lp.2a.3g.4f.5a_, la. 2b.3g.4f.5a_, lb.2b.3g,4f.5a., If.2b.3g.4f.5a., lh.2b.3g.4f.5a., lj.2b.3g.4f.5a., lp.2b.3g.4f.5a., la.2e.3g.4f.5a., lb.2c.3g.4f.5a., lf.2c.3g.4f.5a., lh.2e.3g.4f.5a_, lj.2e.3g.4f.5a., lp.2e,3g.4f.5a., la.2f.3g.4f.5a., lb.2f.3g.4f.5a., lf.2f.3g.4f.5a_, lh.2f.3g.4f.5a_, lj.2f.3g_4f.5a., lp.2f.3g.4f.5a„ 'la.2i.3g.4f.5a., lb.2i.3g.4f.5a., lf.2i.3g.4f.5a., lh.2i.3g.4f.5a., lj.2i.3g.4f.5a„ lp.2i.3g.4f.5a_, la.2m.3g.4f.5a., lb, 2m.3g.4f.5a., lf_2in.3g.4f.5a., lh.2m.3g,4f.5a., lj.2m.3g.4f.5a., lp.2m.3g.4f.5a., la. 2o.3g.4f.5a., lb.2o.3g,4f.5a., lf.2o.3g.4f_5a., 1h.2o.3g.4f_5a., lj.2o.3g.4f.5a_, lp.2o.3g.4f.5a_, la.2u.3g.4f.5a_, lb.2u.3g.4f.5a., lf.2u.3g.4f.5a_, lh.2u.3g.4f.5a., 'lj.2u.3g.4f.5a., lp.2u.3g.4f.5a., la.2y.3g.4f.5a., lb.2y.3g.4f.5a., lf.2y.3g.4f.5a., 1h.2y.3g.4f.5a., 1j.2y.3g.4f.5a., lp.2y.3g.4f.5a., la.2a.3a.4g.5a., lb.2a.3a.4g.5a., lf.2a.3a.4g.5a., lh.2a.3a.4g.5a., lj.2a.3a.4g.5a_, lp.2a.3a.4g.5a., la.2b.3a.4g.5a„ lb. 2b.3a.4g.5a., lf.2b.3a.4g.5a., lh.2b.3a.4g.5a., lj,2b.3a.4g.5a., lp.2b.3a.4g.5a., la.2e.3a.4g.5a_, lb.2e.3a.4g.5a., lf_2e.3a.4g.5a_, lh.2e.3a.4g.5a., lj.2e.3a.4g.5a_,

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Ip.2c.3a.4g.5a., la.2f.3a.4g.5a., lb.2f.3a.4g.5a., lf.2f.3a.4g.5a., lh.2f.3a.4g.5a., lj.2f.3a.4g.5a., lp.2f.3a.4g.5a., la.2i.3a.4g.5a., lb.2i.3a,4g.5a., lf.2i.3a.4g.5a., lh.2i.3a.4g.5a., lj.2i.3a.4g.5a., lp.2i.3a.4g.5a., la.2m.3a.4g.5a., lb.2m.3a.4g.5a., lf.2m.3a.4g.5a_, lh.2m.3a.4g.5a., lj.2m.3a.4g.5a., lp.2m.3a.4g.5a., la.2o.3a.4g.5a., lb.2o.3a.4g.5a., lf.2o.3a.4g.5a., lh.2o.3a.4g.5a., lj.2o.3a.4g.5a., lp.2o.3a.4g.5a., la. 2u.3a.4g.5a., lb.2u.3a.4g.5a., lf.2u,3a.4g.5a., Ih.2u.3a.4g.5a,, lj,2u.3a.4g.5a., lp.2u.3a,4g.5a., la.2y.3a.4g.5a„ lb.2y.3a.4g,5a„ lf,2y.3a.4g.5a., lh.2y.3a.4g.5a., lj,2y.3a,4g.5a., lp.2y.3a.4g.5a., la.2a.3b.4g.5a., lb.2a.3b.4g.5a., lf.2a.3b.4g.5a., lh,2a.3b.4g.5a., lj.2a.3b.4g.5a., Ip.2a.3b.4g.5a., la.2b.3b.4g.5a., 1b.2b.3b.4g.5a., lf.2b.3b.4g.5a., lh.2b.3b.4g.5a., lj.2b.3b.4g.5a., lp.2b.3b.4g.5a,, la.2e.3b.4g.5a., lb. 2e.3b.4g.5a., lf.2e.3b.4g,5a., lh.2e.3b.4g.5a., lj.2e.3b.4g.5a., lp.2e.3b.4g.5a., la. 2f.3b.4g.5a., lb.2f.3b.4g.5a., lf.2f.3b.4g.5a., lh.2f.3b.4g.5a., lj.2f.3b.4g,5a., lp.2f.3b.4g.5a., la.2i.3b.4g.5a,, lb.2i,3b,4g.5a., lf.2i.3b.4g.5a., lh.2i.3b.4g.5a., lj.2i.3b.4g.5a., lp.2i.3b.4g.5a., la.2m.3b.4g.5a., lb.2m.3b.4g.5a., lf.2m.3b.4g.5a., lh.2m.3b.4g.5a., lj.2m.3b.4g.5a., lp.2m.3b.4g.5a., la.2o.3b.4g.5a., Ib.2o.3b.4g.5a., lf.2o.3b.4g.5a., lh.2o.3b.4g.5a., lj.2o.3b.4g.5a., lp.2o.3b.4g.5a., la.2u,3b.4g.5a„ lb. 2u.3b.4g.5a., lf.2u.3b.4g.5a., lh.2u.3b.4g.5a., lj.2u.3b.4g.5a., lp.2u.3b.4g.5a., la. 2y.3b.4g.5a., lb.2y.3b.4g.5a., lf.2y.3b.4g.5a., lh.2y.3b.4g.5a., lj.2y.3b.4g.5a., lp.2y.3b.4g.5a., la.2a.3e.4g.5a., lb.2a.3e.4g.5a., lf.2a.3e.4g.5a., lh.2a.3c.4g.5a., lj.2a.3e.4g.5a., lp.2a.3e.4g.5a., la.2b.3e.4g.5a., lb.2b.3e.4g.5a., lf.2b.3e.4g.5a., lh.2b.3e.4g.5a., lj.2b.3e.4g.5a,, lp.2b.3e.4g.5a., la,2e.3e,4g.5a., lb.2e.3e.4g.5a., lf.2e.3e.4g,5a., lh.2e.3e,4g.5a., lj.2e.3e.4g.5a., lp.2e.3e.4g.5a., la.2f.3e.4g.5a., lb. 2f.3e.4g.5a., lf.2f.3e.4g.5a., lh.2f.3e.4g.5a., lj.2f.3e.4g,5a„ lp,2f,3e.4g.5a., la. 2i.3e.4g.5a., lb.2i.3e.4g.5a., lf.2i.3e.4g.5a., lh.2i.3e.4g.5a., lj.2i.3e.4g.5a., lp.2i,3e.4g.5a., la.2m.3e.4g.5a., lb.2m.3e.4g.5a., lf,2m.3e,4g.5a., lh.2m.3e.4g.5a., lj.2m.3e.4g.5a„ lp.2m.3e.4g.5a., la.2o.3e.4g.5a., lb.2o.3e.4g.5a,, If.2o.3e.4g.5a., lh.2o.3e.4g.5a., lj.2o.3e.4g.5a., lp.2o.3e.4g.5a., la.2u.3e.4g.5a., lb.2u.3e.4g.5a., lf.2u.3e.4g.5a., lh.2u.3e.4g.5a,, lj.2u.3e.4g.5a., lp.2u.3e.4g.5a., la.2y.3e.4g.5a„ lb. 2y.3e.4g.5a., lf,2y.3e,4g.5a., lh.2y.3e.4g.5a., lj.2y.3e.4g.5a., lp.2y.3e.4g.5a., la. 2a.3g.4g.5a., lb.2a.3g.4g.5a., lf.2a.3g.4g.5a., lh.2a.3g.4g.5a., lj.2a.3g.4g.5a., lp.2a.3g.4g.5a., la.2b.3g.4g.5a., lb.2b.3g.4g.5a., lf.2b.3g.4g.5a., lh.2b.3g.4g.5a., lj.2b.3g.4g.5a., Jp.2b.3g.4g.5a., la.2e.3g.4g.5a., lb.2e.3g.4g.5a., lf.2e.3g.4g.5a., lh.2e.3g.4g.5a., lj.2e.3g.4g.5a„ lp.2e.3g.4g.5a., la.2f.3g.4g.5a., Ib.2f3g.4g.5a_, If. 2f. 3g.4g. 5a., lh.2f.3g.4g.5a., lj.2f.3g.4g.5a., lp.2f.3g.4g.5a., 1 a.2i.3g.4g.5a., lb. 2i.3g.4g.5a., lf.2i.3g.4g.5a., lh.2i.3g.4g.5a., lj.2i.3g.4g.5a., 1p.2i.3g.4g.5a., la. 2m.3g.4g.5a., lb.2m.3g.4g.5a., 'Jf.2m.3g.4g.5a., lh.2m.3g.4g.5a,, lj.2m.3g.4g.5a., lp.2m.3g.4g.5a., la.2o.3g.4g.5a., lb.2o.3g.4g.5a., lf.2o.3g.4g.5a., lh.2o.3g.4g.5a., lj.2o.3g.4g.5a., lp.2o.3g.4g.5a., la.2u.3g.4g.5a., lb.2u.3g.4g.5a., lf.2u.3g.4g.5a., lh.2u.3g.4g.5a., lj.2u.3g.4g.5a., lp.2u.3g.4g.5a., la.2y.3g.4g.5a., lb.2y.3g.4g.5a., lf.2y.3g.4g.5a., lh.2y.3g.4g.5a., lj.2y.3g.4g.5a., lp.2y.3g.4g.5a., la.2a.3a.4h.5a„ lb. 2a.3a.4h.5a., lf.2a.3a.4h.5a., lh.2a.3a.4h.5a., lj.2a.3a.4h.5a., lp.2a.3a.4h.5a.,

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2020203321 21 May 2020 la. 2b.3a.4h.5a., lb.2b.3a.4h.5a., lf.2b.3a.4h.5a., lh.2b.3a.4h.5a., lj.2b.3a.4h.5a., lp.2b.3a.4h.5a., la.2e.3a.4h.5a., lb.2e.3a.41i.5a., lf.2e.3a.4h.5a., lh.2e.3a.4h.5a., lj.2e.3a.4h.5a., lp.2e.3a.4h.5a., 1 a.2f.3a.4h.5a., lb.2f.3a.4h.5a„ lf.2f.3a.4jr.5a., lh.2f.3a.4h.5a., lj.2f.3a.4h.5a., lp.2f.3a.4h.5a., la.2i.3a.4h.5a., lb,2i.3a.4h.5a., lf.2i.3a.4h.5a., lh.2i.3a.4h.5a., lj.2i.3a.4h.5a., lp_2i.3a.4h.5a., la.2m.3a.4h.5a., lb. 2m.3a.4h.5a., lf.2m.3a.4h.5a., lh.2m.3a.4h.5a., lj.2m.3a.4h.5a., Ip.2m.3a.4h.5a,, la. 2o.3a.4h.5a„ lb.2o.3a.4h.5a., lf.2o.3a.4h.5a., lh.2o.3a.4h.5a., lj.2o.3a.4h.5a., lp.2o.3a.4h.5a., la.2u.3a.4h.5a., lb.2u.3a.4h.5a., lf.2u.3a.4h.5a., lh.2u.3a.4h.5a., lj.2u.3a.4h.5a., lp.2u.3a.4h.5a., la.2y.3a.4h.5a., lb.2y.3a.4h.5a., lf.2y.3a.4h.5a., lh.2y.3a.4h.5a., lj.2y.3a.4h.5a,, lp.2y.3a.4h.5a., la.2a.3b,4h.5a., lb.2a.3b.4h.5a., lf.2a.3b.4h.5a„ lh.2a.3b.4h.5a., 1j.2a.3b.4h.5a., lp.2a.3b.4h.5a„ la.2b.3b.4h.5a., lb. 2b.3b.4h.5a., lf.2b.3b.4h.5a., lh.2b.3b.4h.5a., lj.2b.3b.4h.5a., lp.2b.3b.4h.5a., la. 2e.3b.4b.5a„ lb.2e.3b.4h.5a., lf.2e.3b.4h.5a., lh.2e.3b.4h.5a., lj.2e.3b.4h.5a., lp.2e.3b.4h.5a., la.2f.3b.4h,5a„ Ib.2f.3b.4h.5a., lf.2f.3b.4h.5a., lh.2f.3b.4h.5a., lj.2f.3b.4h.5a., lp.2f.3b.4h.5a, la.2i.3b.4h.5a., lb.2i.3b.4h.5a., lf.2i.3b.4h.5a., lh.2i.3b.4h.5a., lj.2i.3b.4h.5a., lp.2i.3b.41i.5a., la.2m.3b.4h.5a., lb.2m.3b.41i.5a., lf.2m.3b.4h.5a., lh.2m.3b.4h.5a_v lj.2m.3b.4h.5a,, lp.2m.3b.4h.5a., la.2o.3b.4h.5a., lb. 2o,3b.4h.5a., lf.2o.3b,4h.5a., lh.2o.3b.4h,5a., lj.2o.3b.4h.5a,, lp.2o.3b.4h.5a., la. 2u.3b.4h.5a., lb.2u.3b.4h.5a., If.2u.3b.4h.5a„ lh.2u.3b.4h.5a., lj.2u.3b.4h.5a„ lp.2u.3b.4h.5a., la.2y.3b.4h.5a., lb.2y.3b.4h.5a., lf.2y,3b.4h.5a., lh.2y.3b.4h.5a., 1j.2y.3b.4h.5a., lp.2y.3b.4li.5a., la.2a.3c.4h.5a., lb.2a.3c.4h.5a., If.2a.3c.4h.5a., lh.2a.3e.4h.5a., lj.2a.3e.4h.5a., lp.2a.3e.4h.5a., la.2b.3e.4h.5a., lb.2b.3e.4h.5a., lf.2b.3e.4h.5a., lh.2b.3e.4h.5a., lj.2b.3e.4h.5a., Ip.2b.3e.4h.5a., la.2e.3e.4h.5a., lb. 2e.3e.4h.5a., lf.2e.3e.4h.5a., lh.2e.3e.4h.5a., lj.2e.3e.4h.5a., lp.2e.3e.4h.5a., la. 2f.3e.4h.5a., lb.2f.3e.4h.5a., If.2f.3e.4h.5a., lh.2f.3e.4h.5a., lj.2f.3e.4h.5a., lp.2f.3e.4h.5a., Ia.2i.3e,4h5a., lb.2i.3e.4h.5a., lf.2i.3e.4h.5a., lh.2i.3e.4h.5a., lj.21.3e.4h.5a., Ip.2i.3c.4h.5a., la.2m.3e.4h.5a., lb.2m.3e.4h.5a., lf.2m.3e.41i.5a., 1h.2m.3e.4h.5a., lj.2m.3e.4h.5a., lp.2m.3c.4h.5a., 1 a.2o.3c.4h.5a., 1b.2o.3e.4h.5a., lf.2o.3e.4h.5a., lh.2o.3e.4h.5a., lj.2o.3e.4h.5a., lp,2o.3e.4h.5a., la.2u.3e.4h.5a., lb. 2u.3e.4h.5a., lf.2u.3e.4h.5a., lh.2u.3c.4h.5a., lj.2u.3e.4h.5a., lp.2u.3e.4h.5a., la. 2y.3e.4h.5a., lb.2y.3e.4h.5a., lf.2y.3e.4h.5a., lh.2y.3e.4h.5a., lj.2y.3e.4h.5a., lp.2y.3e.4h.5a., la.2a.3g.4h.5a., lb.2a.3g.4h.5a., lf.2a.3g.4h.5a„ lh.2a.3g.4h.5a., lj.2a.3g.4h_.5a., lp.2a.3g.4h.5a„ la.2b.3g.4h.5a., lb.2b.3g.4h.5a., lf.2b.3g.4h.5a„ lh.2b.3g.4h.5a., lj.2b.3g.4h.5a., lp.2b.3g.4h.5a., la.2e.3g,4h.5a., lb.2e.3g.4h.5a., lf.2e.3g.4h.5a., lh,2e.3g.4h.5a„ lj,2e.3g.4h.5a., lp.2e.3g.4h,5a., 1a.2f.3g.4h.5a., lb. 2f.3g.4h.5a., lf.2f.3g.4h.5a„ lh.2f.3g.4h.5a., lj.2f.3g.4h.5a., lp.2f.3g.4h.5a., 1 a.21.3g.411.5a., lb.2i.3g.4h.5a„ lf.2i.3g.4h.5a., lh.2i.3g.4h.5a., lj.2i.3g.4h.5a., lp.2i.3g.4h.5a., la,2m.3g.4h.5a., lb.2m.3g.4h,5a., lf.2m.3g.4h.5a., lh.2m.3g,4h,5a., lj.2m.3g.4h.5a., lp.2m.3g.4h.5a., la.2o.3g.4h.5a., lb.2o.3g.4h.5a., lf.2o.3g.4h.5a., lh.2o.3g.4h.5a., lj.2o.3g.4h.5a., lp.2o.3g.4h.5a,, la.2u.3g.4h.5a., lb.2u.3g.4h.5a., lf.2u.3g.4h.5a., lh.2u.3g.4h.5a., lj.2u.3g.4h.5a., lp.2u_.3g.4h.5a., la.2y.3g.4h.5a.,

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2020203321 21 May 2020 lb.2y.3g.4h.5a., lf.2y.3g.4h.5a., lh.2y.3g.4h.5a., lj.2y.3g.4h.5a., lp.2y.3g.4h.5a., la. 2a.3a.4i.5a., lb.2a,3a.4i.5a., lf.2a.3a.4i.5a., Ih.2a.3a.4i.5a., li.2a.3a.4i.5a., lp.2a.3a.4i.5a., la.2b.3a.4i.5a., lb.2b.3a.4i.5a., lf.2b.3a.4i.5a., lh.2b.3a.4L5a., lj.2b.3a.4i.5a., lp.2b.3a.4i.5a., la.2e.3a.4i.5a., lb.2e.3a.4i.5a., lf.2e.3a.4i.5a., 1h.2e.3a.4i.5a., lj.2e.3a.4i.5a., lp.2e.3a.4i.5a., la.2f.3a.4i.5a., lb.2f.3a.4i.5a., lf.2f.3a.4i.5a., lh.2f.3a.4i.5a., lj.2f.3a.4i.5a., lp.2f.3a.4L5a., la.2i.3a.4i.5a., lb. 2i.3a.4i.5a., lf,2i.3a.4i.5a., Ih.2i.3a.4i.5a., lj.2L3a.4i.5a., lp.2i.3a.4i.5a., la. 2m.3a.4i.5a., lb.2m.3a.4i.5a., lf.2m.3a.4i.5a., lh.2m.3a.4i.5a., lj.2m.3a.4i.5a., lp.2m.3a.4i.5a., la.2o.3a.4i.5a., lb.2o.3a.4i.5a., lf.2o.3a.4i.5a., lh.2o.3a.4i.5a., lj.2o.3a.4i.5a„ lp.2o.3a.4i.5a., la.2u.3a.4i.5a., lb.2u.3a.4i..5a., lf.2u.3a.4i.5a., lh.2u.3a.4i.5a., lj.2u.3a.4i.5a., lp.2u.3a.4i.5a., la.2y.3a.4i.5a., 'lb.2y.3a.4i.5a., lf.2y.3a.4i.5a., lh.2y.3a.4i.5a., lj.2y.3a.4i.5a., lp.2y.3a.4i.5a., la.2a.3b.4i.5a., lb. 2a.3b.4i.5a., lf.2a.3b.4i.5a., lh.2a.3b.4i.5a., lj.2a.3b.4i.5a., lp.2a.3b.4i.5a., la. 2b.3b.4i.5a., lb.2b.3b.4i.5a., lf.2b.3b.4i.5a., lh.2b.3b.4i.5a., lj.2b.3b,4i.5a,, lp.2b.3b.4i.5a., la.2e.3b.4i.5a., lb.2e.3b.4i.5a., lf.2e.3b.4i.5a., lh.2e.3b.4i.5a., lj.2e.3b.4i.5a., lp.2e.3b.4i.5a„ la.2f.3b.4i.5a„ lb.2f.3b.4i.5a., lf.2f.3b.4i.5a., lh.2f.3b.4i.5a., lj.2f.3b.4i.5a., lp.2f.3b.4i.5a., la.2i.3b.4i.5a., lb.2i.3b.4i.5a., lf.2i.3b.4i.5a., lh.2i.3b.4i.5a., lj.2i.3b.4i.5a., lp.2i.3b.4i.5a., la.2m.3b.41.5a., lb. 2m.3b.4i.5a., lf.2m.3b.4i.5a., lh.2in.3b.4i.5a., lj.2m.3b.4i.5a., lp.2m.3b.4i.5a., la. 2o.3b.4i.5a., lb.2o.3b.4i.5a., lf.2o.3b.4i.5a., lh.2o.3b.4i.5a., lj.2o.3b.4i.5a., lp.2o.3b.4i.5a., la.2u.3b.4i.5a., lb.2u.3b.4i.5a., lf.2u.3b.4i.5a., lh.2u.3b.4i.5a., lj.2u.3b.4i.5a., lp.2u.3b.4i.5a., la.2y.3b.4i.5a„ lb.2y.3b.4i.5a., lf.2y.3b.4i.5a., lh.2v.3b.4i.5a., lj.2y.3b.4i.5a,, lp.2y.3b.4i.5a., la.2a.3e.4i.5a.., lb.2a.3e.4i.5a., lf.2a.3e.4i.5a., lh.2a.3e.4i.5a., lj.2a.3e.4i.5a., lp.2a.3e.4i.5a., la.2b.3e.4i.5a., lb. 2b.3e.4i.5a., lf.2b.3e.4i.5a., lh.2b.3e.4i.5a., lj.2b.3e.4i.5a., lp.2b.3e.4i.5a., 1 a.2e.3e.4i.5a., lb.2e,3e.4i.5a., lf.2e.3e.4i.5a., lh.2e.3e.4i.5a., lj.2c.3e.4i.5a., lp.2e.3e.4i.5a„ la.2f.3e.4i.5a., lb.2f.3e.4i.5a., lf.2f.3e.4i.5a., lh.2f.3e.4i.5a„ 1j.2f.3c.4i.5a., lp.2f.3e.4i.5a., la.2i.3e.4i.5a., lb.2i.3e.4i.5a,, lf.2i.3e.4i.5a„ lh.2i.3e.4i.5a., lj.2i.3e.4i.5a., lp.2i.3e.4i.5a., la.2m.3e.4i.5a., lb.2m.3e,4i.5a., lf.2m.3e.4i.5a., lh.2m.3e.4i.5a., lj.2m.3e.4i.5a., lp.2m.3c.4i.5a., la.2o.3e.4i.5a., lb.2o.3e.4i.5a., lf.2o.3e.4i.5a>, lh.2o.3e.4i,5a., lj.2o.3e.4i.5a., lp.2o.3e.4i.5a., la. 2u.3c.4i.5a., lb.2u.3e.4L5a., lf.2u.3e.4i.5a., lh.2u.3e.4i.5a., lj.2u.3e.4i.5a., lp.2u.3e.4i.5a., la.2y.3e.4i.5a., lb.2y.3e.4i.5a., lf.2y.3e.4i.5a., lh.2y.3e.4L5a., lj.2y.3e.4i.5a., lp.2y.3e.4i.5a., la.2a.3g.4i.5a., 1 b.2a.3g.4i.5a., lf.2a.3g.4i.5a., lh.2a.3g,4i.5a., lj.2a.3g.4i.5a., lp.2a.3g.4i.5a., Ja.2b.3g.4i.5a., lb.2b.3g.4i.5a., lf.2b.3g.4i.5a., lh.2b.3g.4i.5a., lj.2b.3g.4i.5a., lp.2b.3g.4i.5a., la.2e.3g.4i.5a., lb. 2e.3g.4i.5a., lf.2e.3g.4i.5a., lh.2e.3g.4i.5a., lj.2e.3g.4i.5a., lp.2e.3g.4i.5a., la.2f.3g.4i.5a., lb.2f.3g.4i.5a., lf.2f.3g.4i.5a., lh.2f.3g.4i.5a., lj.2f.3g.4i.5a., lp,2f.3g.4i.5a._r la.2i.3g.4i.5a., lb.2i.3g.4i.5a., lf.2i.3g.4i.5a., lh.2i.3g.4i.5a., lj.2i.3g.4i.5a,, lp.2i.3g.4i,5a., la.2m.3g.4i.5a., lb.2m,3g.4i.5a., lf.2m.3g.4i.5a., lh.2m.3g.4i.5a., lj.2m.3g.4i.5a., lp.2m.3g.4i.5a., la.2o,3g.4i.5a., lb.2o.3g.4i.5a.,

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2020203321 21 May 2020 lf.2o.3g.4i.5a., lh_2o.3g.4i.5a., lj.2o.3g.4i.5a., lp.2o.3g.4i.5a., la.2u.3g.4i.5a., lb.2u.3g.4i.5a,, lf.2u.3g,4i.5a., lh.2u.3g.4i.5a., lj.2u.3g.4i.5a., lp.2u.3g.4i.5a., la. 2y.3g.4i.5a., lb.2y.3g.4i.5a., lf.2y.3g.4i.5a., lh.2y.3g.4i.5a., lj.2y.3g.4i.5a., lp.2y.3g.4i.5a., la.2a.3a.4a.5d., lb.2a.3a.4a.5d., lf.2a.3a.4a,5d., lh.2a.3a.4a.5d., lj.2a.3a.4a.5d., lp.2a.3a.4a.5d„ la.2b.3a.4a.5d., lb.2b.3a.4a.5d., lf.2b.3a.4a.5d., lh.2b.3a.4a.5d., lj.2b.3a.4a.5d., lp.2b.3a.4a.5d,, la.2e.3a.4a.5d„ lb.2e.3a.4a.5d., lf.2e.3a.4a.5d., lh.2e.3a.4a.5d„ lj.2e.3a.4a.5d., lp.2e.3a.4a.5d„ la.2f.3a.4a.5d., lb. 2f.3a.4a.5d., lf.2f.3a.4a.5d., lh.2f.3a,4a.5d., lj.2f.3a.4a.5d., lp.2f.3a.4a.5d,, la. 2i.3a.4a.5d., lb.2i.3a.4a.5d., lf.2i.3a.4a.5d., lh.2i.3a.4a.5d., lj.2i.3a.4a.5d., lp.2i.3a.4a.5d., la.2m.3a.4a.5d., lb.2m.3a.4a.5d., lf.2m.3a.4a.5d., lh.2m.3a.4a.5d., lj.2m.3a.4a.5d., lp.2m.3a.4a.5d., la.2o.3a.4a.5d., lb.2o.3a.4a.5d„ lf.2o.3a.4a.5d., lh.2o.3a.4a.5d., lj.2o.3a.4a.5d., lp.2o.3a.4a.5d., la.2u.3a.4a.5d., lb.2u.3a.4a.5d., lf.2u.3a.4a.5d., lh.2u.3a.4a.5d., lj.2u.3a.4a.5d., lp.2u.3a.4a.5d„ la.2y.3a.4a.5d., lb. 2y.3a.4a.5d., lji.2y.3a.4a.5d_v lh.2y.3a.4a.5d., lj.2y.3a.4a.5d., lp.2y.3a.4a.5d., la. 2a.3b.4a.5d., lb.2a.3b.4a.5d., lf.2a.3b.4a.5d., lh.2a.3b.4a.5d., lj.2a.3b.4a.5d., lp.2a.3b.4a.5d., la.2b.3b.4a.5d., lb.2b.3b,4a.5d„ lf.2b.3b.4a,5d., 1h.2b.3b,4a.5d., lj.2b.3b.4a.5d., J p.2b .3b.4a.5 d., la.2c.3b.4a.5d., lb.2c.3b.4a.5d., lf.2e.3b.4a.5d., lh,2e.3b.4a.5d., lj.2e.3b,4a.5d., lp.2e.3b.4a.5d., la.2f.3b.4a.5d., lb.2f.3b.4a.5d., lf.2f.3b.4a.5d., lh.2f.3b.4a.5d., lj,2f.3b.4a.5d„ lp.2f.3b.4a.5d., la.2i.3b.4a.5d., lb. 2i.3b.4a.5d., lf.2i.3b.4a.5d., lh.2i.3b.4a.5d., lj.2i.3b.4a.5d., lp.2i.3b.4a.5d., la. 2m.3b.4a.5d., lb.2m.3b.4a.5d., lf.2m.3b.4a.5d., lh.2m,3b.4a.5d., lj.2m.3b.4a.5d., lp.2m.3b.4a.5d., la.2o.3b.4a.5d., lb.2o.3b.4a.5d., lf.2o.3b.4a.5d., lh.2o.3b.4a.5d., lj.2o.3b.4a.5d., lp.2o.3b.4a.5d., la.2u.3b.4a.5d,, lb.2u.3b.4a.5d., lf.2u.3b.4a.5d., lh.2u.3b,4a.5d., lj.2u.3b.4a.5d., lp.2u.3b.4a.5d., la.2y.3b.4a.5d., lb.2y.3b.4a.5d., lf.2y.3b.4a.5d., lh.2y.3b,4a.5d., lj.2y.3b.4a.5d., lp.2y.3b.4a.5d., la.2a.3e.4a.5d., lb. 2a.3e.4a.5d., lf.2a.3e.4a.5d., lh.2a.3e.4a.5d., lj.2a.3e.4a.5d., lp.2a.3e.4a.5d., la. 2b.3c.4a.5d., lb.2b.3e.4a.5d., lf.2b.3e.4a.5d., lh.2b.3e.4a.5d., lj.2b.3e.4a.5d., lp.2b.3e.4a.5d., la.2e.3e.4a.5d., lb.2c.3c.4a.5d., lf.2c.3e.4a.5d., lh.2e.3e.4a.5d„ lj.2e.3e.4a.5d., lp.2e.3e.4a.5d., la.2f.3e.4a.5d., lb.2f.3e.4a.5d., lf.2f,3e.4a.5d., lh.2f,3e.4a.5d„ lj.2f.3e.4a.5d., lp.2f.3e.4a.5d„ la.2i.3e.4a.5d., lb.2i,3e.4a.5d., lf.2i.3e.4a.5d., lh.2i.3e.4a.5d., lj.2i.3e.4a.5d., lp.2i.3e.4a.5d., la.2m.3e.4a.5d., lb. 2m.3e.4a.5d., lf.2m.3c.4a.5d., lh.2m.3e.4a.5d., lj.2m.3e.4a.5d., lp.2m.3e.4a.5d., la. 2o.3e.4a.5d., lb.2o.3e.4a.5d., lf.2o.3e.4a.5d., lh.2o.3c.4a.5d., lj.2o.3e.4a.5d., lp.2o.3e.4a.5d., la.2u.3e.4a.5d., lb.2u.3e.4a.5d., lf.2u.3e.4a.5d., lh.2u.3e.4a.5d., lj.2u.3e.4a.5d., lp.2u.3e.4a.5d., la.2y.3e.4a.5d., lb.2y.3e.4a.5d., lf.2y.3e.4a.5d., lh.2y.3c.4a.5d., lj.2y.3e.4a.5d., lp.2y.3e.4a.5d., la.2a.3g.4a.5d., lb.2a.3g.4a.5d., lf.2a.3g.4a.5d., lh.2a.3g.4a.5d., lj.2a.3g.4a.5d., lp.2a.3g.4a.5d., la.2b.3g.4a.5d., lb. 2b.3g.4a.5d., lf.2b.3g.4a.5d., lh.2b.3g.4a.5d., lj.2b.3g.4a.5d., lp.2b.3g.4a.5d., la.2e.3g.4a.5d,, lb.2e.3g.4a.5d., lf.2e.3g.4a.5d., lh.2e.3g.4a.5d., lj.2e.3g.4a.5d., lp.2e.3g.4a.5d., la.2f.3g.4a.5d., lb.2f.3g.4a.5d., lf.2f.3g.4a.5d., lh.2f.3g.4a.5d., lj.2f.3g.4a.5d., lp.2f.3g.4a.5d., la.2i.3g.4a.5d., lb.2i.3g.4a.5d., lf.2i.3g.4a.5d.,

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2020203321 21 May 2020

1h.2i.3g.4a.5d., lj.2i.3g.4a.5d., lp.2i.3g.4a.5d., la.2m.3g.4a.5d., lb.2m.3g.4a.5d., lf.2m.3g.4a.5d., lh.2m.3g.4a.5d., lj.2m.3g.4a.5d., lp.2m.3g.4a.5d., la.2o.3g.4a.5d., lb.2o.3g.4a.5d., lf.2o.3g.4a.5d., lh.2o.3g.4a.5d., lj.2o.3g.4a.5d., lp.2o.3g.4a.5d., la. 2u.3g.4a.5d., lb.2u.3g.4a.5d., lf.2u.3g.4a.5d., lh.2u.3g.4a.5d., lj.2u.3g.4a.5d., 1p.2u.3g.4a.5d., la.2y.3g.4a.5d., lb.2y.3g.4a.5d., lf.2y.3g.4a.5d., lh.2y.3g.4a.5d., lj.2y.3g.4a.5d., lp.2y.3g.4a.5d., la.2a.3a.4d.5d., lb.2a.3a.4d.5d., lf.2a.3a.4d.5d., lh.2a.3a.4d.5d., lj.2a.3a.4d.5d., lp.2a.3a.4d.5d., la.2b.3a.4d.5d., lb.2b.3a.4d.5d., lf.2b.3a.4d.5d., lh.2b.3a.4d.5d., lj.2b.3a.4d.5d., lp.2b.3a.4d.5d., la.2e.3a.4d.5d., lb. 2c.3a.4d.5d., lf.2e.3a.4d.5d., lh.2e.3a.4d.5d., lj.2e.3a.4d.5d„ lp.2e.3a.4d.5d., la. 2f.3a.4d.5d., lb.2f.3a.4d.5d., lf.2f.3a.4d.5d., lh.2f.3a.4d.5d., lj.2f.3a.4d.5d., lp.2f.3a.4d.5d., la.2i.3a.4d.5d., lb.2i.3a.4d.5d., 1f.2i.3a.4d.5d., lh.2i.3a.4d.5d., lj.2i.3a.4d.5d., lp.2i.3a.4d.5d., la.2m.3a.4d,5d., lb.2m.3a.4d.5d., lf.2m.3a.4d.5d., lh.2m.3a.4d.5d., lj.2m.3a.4d.5d., lp.2m.3a.4d.5d-, Ia.2o.3a.4d.5d., lb.2o.3a.4d.5d., lf.2o.3a.4d.5d., lh.2o.3a.4d.5d_, lj.2o.3a.4d.5d., lp.2o.3a.4d.5d., la.2u.3a.4d.5d., lb. 2u.3a.4d.5d., lf.2Li.3a.4d.5d., lh.2u.3a.4d,5d., lj.2u.3a.4d.5d_, lp.2u.3a.4d.5d., la. 2y.3a.4d.5d., lb.2y,3a ,4d.5d., lf.2y.3a.4d.5d., lh.2y.3a.4d.5d., lj.2y.3a.4d.5d., Jp.2y.3a.4d.5d., la.2a.3b.4d.5d., lb.2a.3b.4d.5d., lf.2a.3b.4d.5d,, lh.2a.3b.4d.5d., lj.2a.3b.4d.5d., lp.2a.3b.4d.5d., 1a.2b.3b.4d.5d., lb.2b,3b.4d.5d., lf.2b.3b.4d.5d., lh.2b.3b.4d.5d., lj.2b.3b.4d.5d., lp.2b.3b.4d.5d., la.2e.3b.4d.5d., lb.2c.3b.4d.5d., lf.2e.3b.4d.5d„ lh.2e.3b.4d.5d„ lj.2e.3b.4d.5d., lp.2e.3b.4d.5d., la.2f.3b.4d.5d., lb. 2f.3b.4d.5d., lf.2f.3b.4d.5d„ lh.2f.3b.4d.5d., lj.2f.3b.4d.5d., lp.2f.3b.4d.5d., la. 2i.3b.4d.5d., lb.2i_3b.4d.5d., lf.2i.3b.4d.5d., lh.2i.3b.4d.5d., lj.2i,3b.4d.5d, lp.2i.3b.4d.5d., la.2m.3b.4d.5d., lb.2in.3b.4d.5d., lf.2m.3b.4d.5d., lh.2m.3b.4d.5d., lj.2m.3b.4d.5d., lp.2m.3b.4d.5d., la.2o.3b.4d.5d., lb.2o.3b.4d.5d., lf.2o.3b.4d.5d., lh.2o.3b.4d.5d., lj.2o.3b.4d.5d., lp.2o.3b.4d.5d,, la.2u.3b.4d.5d., lb.2u.3b.4d.5d., lf.2u_3b.4d.5d., lh.2u.3b.4d.5d., lj.2u.3b.4d.5d., lp.2u.3b.4d.5d„ la.2y.3b.4d.5d„ lb. 2y.3b.4d.5d„ lf.2y.3b.4d.5d„ lh.2y.3b.4d.5d., li-2y.3b.4d.5d., lp.2y.3b.4d.5d., la. 2a.3e.4d.5d., lb.2a.3e.4d.5d., lf.2a.3e.4d.5d„ lh.2a.3e.4d.5d., lj.2a.3e,4d.5d., lp.2a.3e.4d.5d., la.2b.3e.4d.5d., lb.2b.3e.4d.5d., lf.2b.3e.4d.5d., lh.2b.3e.4d.5d_, lj.2b.3e.4d.5d., lp.2b.3e.4d.5d., la.2e.3e.4d.5d., lb.2e.3e.4d.5d_, lf.2c.3c.4d.5d_, lh.2e.3e.4d.5d„ lj,2e.3e.4d.5d., lp.2e.3e.4d.5d_, la.2f.3e.4d.5d., lb.2f.3e.4d.5d, lf.2f.3c.4d.5d., lh.2f.3e.4d.5d., lj.2f.3e.4d.5d_, lp.2f.3e,4d.5d., la.2L3e.4d.5d., lb. 2i.3e.4d,5d., lf.2i.3e.4d.5d., lh.2i.3e.4d.5d., lj.2i.3e.4d.5d., lp.2L3e,4d.5d., la. 2m.3e.4d.5d., lb,2m.3e.4d,5d„ lf.2m.3e.4d.5d_, lh.2m.3e.4d.5d., lj.2m.3c.4d.5d_, lp.2m.3e.4d.5d., la.2o.3e.4d.5d„ lb.2o.3e.4d.5d., lf.2o.3e.4d.5d„ lh.2o.3e.4d.5d., lj.2o.3e.4d.5d., lp.2o,3e.4d.5d., la.2u,3e.4d.5d., lb.2u.3e.4d.5d., lf.2u.3e.4d.5d., lh.2u.3e.4d.5d., lj.2u.3c.4d.5d., lp.2u.3e.4d.5d., la.2y.3e.4d.5d., lb.2y.3e.4d.5d„ lf.2y.3e.4d.5d., lh.2y.3e.4d.5d., lj.2y.3c.4d.5d., lp.2y.3e.4d.5d., la.2a.3g.4d.5d., lb. 2a.3g.4d.5d., lf.2a.3g.4d.5d„ lh.2a.3g.4d.5d., lj.2a.3g,4d.5d., lp.2a.3g.4d.5d., la.2b.3g.4d.5d„ lb.2b.3g.4d.5d_, lf.2b.3g.4d.5d„ lh.2b.3g.4d.5d„ lj.2b.3g.4d.5d_, lp.2b.3g.4d,5d., la.2e.3g.4d.5d., lb.2e.3g.4d.5d., lf.2e.3g.4d.5d., lh.2e.3g.4d.5d.,

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2020203321 21 May 2020 lj.2e.3g.4d.5d., lp.2e.3g.4d.5d., la.2f.3g.4d.5d., lb.2f.3g.4d.5d., lf.2f.3g.4d.5d„ lh.2f.3g.4d.5d„ lj.21.3g.4d.5d„ lp.2f.3g.4d.5d., la.2i.3g.4d.5d., lb.2i.3g.4d.5d„ lf.2i.3g.4d.5d., lh.2i.3g.4d.5d., 1j.2i.3g.4d.5d., lp.2i.3g.4d.5d., la.2m.3g.4d.5d., lb.2m.3g.4d.5d., lf.2m.3g.4d.5d., lh.2m.3g.4d.5d., lj.2m.3g.4d.5d._rlp.2m.3g.4d.5d., la.2o.3g.4d.5d., lb.2o.3g.4d.5d., lf.2o.3g.4d.5d., 1 h.2o.3g.4d.5d., lj.2o.3g.4d.5d., lp.2o.3g.4d.5d., la.2u.3g.4d.5d., lb.2u.3g.4d.5d., lf.2u.3g,4d.5d., lh.2u.3g.4d.5d., lj_2u.3g.4d.5d., lp.2u.3g.4d.5d„ la.2y.3g.4d.5d., lb.2y.3g.4d.5d„ lf.2y.3g.4d.5d., lh.2y.3g.4d.5d., lj.2y.3g.4d,5d., lp.2y.3g.4d.5d., la.2a.3a.4f.5d., lb.2a.3a.4f.5d., lf.2a.3a.4f.5d., lh.2a.3a.4f.5d., lj.2a.3a.4f.5d., Ip.2a.3a.4f.5d., la. 2b.3a.4f.5d., lb.2b.3a.4f.5d„ lf.2b.3a.4f.5d„ Ih.2b.3a.4f.5d., lj.2b.3a.4f.5d., lp.2b.3a.4f.5d„ la.2e.3a.4f.5d., lb.2e.3a.4f.5d., If.2e.3a.4f.5d., lh.2e.3a.4f.5d., lj.2e.3a.4f.5d., lp.2e.3a.4f.5d., la.2f.3a.4f,5d., lb.2f.3a.4f.5d., lf.2f.3a.4f.5d., lh.2f.3a.4f.5d., lj.2f.3a.4f.5d., lp.2f.3a.4f.5d., la.2i.3a.4f.5d., 1b.2i.3a.4f.5d„ lf.2i.3a.4f.5d., lh.2i.3a.4f.5d., lj.2i.3a.4f.5d., lp,2i.3a.4f.5d„ la.2m.3a.4f.5d., lb. 2m.3a.4f.5d., lf.2m.3a.4f.5d„ lh.2m.3a.4f.5d., lj.2m.3a.4f.5d., lp.2m.3a.4f.5d., la. 2o.3a.4f.5d„ lb.2o.3a.4f.5d., lf.2o.3a.4f.5d., lh.2o.3a.4f.5d., lj.2o.3a.4f.5d., lp.2o.3a.4f.5d., la.2u.3a.4f.5d., lb.2u.3a.4f.5d., lf.2u.3a.4f.5d., lh.2u.3a.4f.5d., lj.2u.3a.4f.5d., lp.2u.3a.4f.5d., la.2y.3a.4f.5d., lb.2y.3a.4f.5d., lf.2y.3a.4f.5d., lh.2y.3a.4f.5d„ lj.2y.3a.4f.5d„ lp.2y.3a.4f.5d., la.2a.3b.4f.5d., lb.2a.3b.4f.5d., lf.2a.3b.4f.5d., lh.2a.3b.4f.5d„ ]j.2a.3b.4f.5d„ lp.2a.3b.4f.5d., la.2b.3b.4f.5d„ lb. 2b.3b.4f.5d., lf.2b.3b.4f.5d., lh.2b.3b.4f.5d„ lj.2b.3b.4f.5d„ lp.2b.3b.4f.5d., la. 2e.3b.4f.5d., lb.2e.3b.4f.5d„ lf.2e.3b.4f.5d., lh.2e.3b.4f.5d„ lj.2e.3b.4f.5d„ lp.2e.3b.4f.5d., la.2f.3b.4f.5d., lb.2f.3b.4f.5d., lf.2f.3b.4f.5d., lh.2f.3b.4f.5d., lj.2f.3b.4f.5d., Ip.2f.3b.4f5d., la.2i.3b.4f.5d., lb.2i.3b.4f.5d., lf.2i.3b.4f.5d., lh.2i.3b,4f.5d., lj.2i.3b.4f.5d., lp.2i.3b.4f.5d., la.2m.3b.4f.5d., lb.2m.3b.4f.5d„ lf.2m.3b.4f.5d„ lh.2m.3b.4f.5d., lj.2m.3b.4f.5d„ lp.2m.3b.4f.5d., 1a.2o.3b.4f.5d., lb. 2o.3b.4f.5d„ lf.2o.3b.4f.5d„ lh.2o.3b.4f.5d„ lj.2o.3b.4f.5d., lp.2o.3b.4f.5d., 1 a.2u.3b.4f.5d., lb.2u.3b.4f.5d., lf.2u.3b.4f.5d._z lh.2u.3b.4f.5d., lj.2u.3b.4f.5d., lp.2u.3b.4f.5d., la.2y.3b.4f.5d., lb.2y.3b.4f.5d., lf.2y.3b.4f.5d., lh,2y,3b.4f.5d„ lj.2y.3b.4f.5d., lp.2y.3b.4f.5d„ la.2a.3e.4f.5d., lb.2a.3e.4f.5d„ lf.2a.3e.4f.5d„ lh.2a.3e.4f.5d., lj.2a.3e.4f.5d., lp.2a.3e.4f.5d., la.2b.3e.4f.5d., lb.2b.3e.4f.5d., lf.2b.3c.4f.5d., lh.2b.3e.4f.5d., lj.2b.3e.4f.5d., lp.2b.3e.4f.5d„ la.2e.3e.4f.5d., lb.2e.3e.4f.5d., lf.2e.3e.4f.5d., lh.2e.3e.4f.5d„ lj.2e.3e.4f.5d„ lp.2e.3e.4f.5d., la. 2f.3e.4f.5d., lb.2f.3e.4f.5d., lf.2f.3e.4f.5d„ lh.2f.3e.4f.5d., lj.2f.3e.4f.5d., lp.2f.3e.4f.5d., la.2i.3e.4f.5d., lb.2i.3e.4f.5d., 1 f,2i.3e.4f.5d., 1h.2i.3e,4f.5d., lj.2i,3e.4f.5d., lp.2i.3e.4f.5d., la.2m.3e.4f.5d., lb.2m.3e.4f.5d., lf.2m.3e.4f.5d., lh.2m.3e.4f.5d., lj.2m.3e.4f.5d., lp.2m.3e.4f.5d., la.2o.3e.4f.5d., lb.2o.3e.4f.5d., lf.2o.3e.4f.5d., lh.2o.3e.4f.5d,, lj.2o.3e,4f.5d., lp.2o.3e.4f.5d., la.2u.3e.4f.5d., lb. 2u.3e.4f.5d., lf.2u.3e.4f.5d., lh.2u.3e.4f.5d., lj.2u.3e.4f.5d., lp.2u.3e.4f.5d., la.2y.3e.4f.5d., lb.2y.3e.4f.5d., lf.2y.3e.4f.5d., lh.2y.3e.4f.5d., lj.2y.3e.4f.5d., lp.2y.3e.4f.5d., la.2a.3g.4f.5d., lb.2a.3g.4f.5d., 'lf.2a.3g.4f.5d., lh.2a.3g.4f.5d.,

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2020203321 21 May 2020 jj.2a.3g.4f.5d., lp.2a.3g.4f.5d.., la.2b.3g.4f.5d., lb.2b.3g.4L5d., lf.2b.3g.4L5d., lh.2b.3g.4f.5d., 1j.2b.3g.4f.5d., lp.2b.3g.4f.5d., la.2e.3g.4f.5d., lb.2e.3g.4f.5d., lf.2e.3g.4f.5d., lh.2e.3g.4f.5d., lj.2e.3g.4f.5d., lp.2e.3g.4f.5d., Ia.2f.3g.4L5d., lb.2f.3g.4f.5d., lf.2f.3g.4f.5d„ lh.2f.3g.4f.5d„ lj.2f.3g.4f.5d., lp.2f.3g.4f.5d, la. 2i.3g.4f.5d., lb.2i.3g.4f.5d„ lf.2i.3g.4L5d„ lh.2i.3g.4f.5d., lj.2i.3g.4L5d., lp.2i.3g.4f.5d., 1a.2m.3g.4f.5d., lb.2m.3g.4f.5d., lf.2rn.3g.4L5d., lh.2m.3g.4f.5d., 1j.2m.3g.4f.5d., lp.2m.3g.4f.5d., 1a.2o.3g.4f.5d., lb.2o.3g.4f.5d., lf.2o.3g.4f.5d., lh.2o.3g.4L5d., lj.2o.3g.4f.5d., lp.2o.3g.4f.5d., la.2u.3g.4f.5d., Ib.2u.3g.4L5d., 1f.2u.3g.4f.5d., lh.2u.3g.4f.5d., 'lj.2u.3g.4f.5d., lp.2u.3g.4f.5d., la.2y.3g.4f.5d., lb. 2y.3g.4f.5d., lf.2y.3g.4f.5d., lh.2y.3g.4L5d., lj.2y.3g.4L5d., lp.2y.3g.4f.5d., la. 2a,3a.4g.5d., lb.2a.3a.4g.5d., lf.2a.3a.4g.5d., lh.2a.3a.4g.5d., lj.2a.3a.4g.5d., lp.2a.3a.4g.5d., la.2b.3a.4g.5d., lb.2b.3a.4g.5d., lf.2b.3a.4g.5d., lh.2b.3a.4g.5d., lj.2b.3a.4g.5d., lp.2b.3a.4g.5d., la.2e.3a.4g.5d., lb.2e.3a.4g.5d., lf.2e.3a.4g.5d., lh.2e.3a.4g.5d., lj.2c.3a.4g.5d., lp.2e.3a.4g.5d„ la.2L3a.4g.5d., lb.2f.3a.4g.5d,, lf.2f.3a.4g.5d., lh.2f.3a,4g.5d., 1j.2L3a.4g.5d., lp.2L3a.4g.5d., la.2i.3a.4g.5d., lb. 2i.3a.4g.5d., lf.2i.3a.4g.5d„ lh.2i.3a.4g.5d., lj.2i.3a.4g.5d., lp,2i.3a.4g.5d„

a.2m.3a.4g.5d., lb.2m.3a.4g.5d., lf.2m.3a.4g.5d., lh.2m.3a.4g.5d., lj.2m.3a.4g.5d., lp.2m.3a.4g.5d., la.2o.3a.4g.5d., lb.2o.3a.4g.5d., lf.2o.3a.4g.5d., lh.2o.3a.4g.5d., lj.2o.3a.4g.5d., lp.2o.3a.4g.5d., la.2u.3a.4g.5d., lb.2u.3a.4g.5d., lL2u.3a.4g.5d., lh.2u.3a.4g.5d., lj.2u.3a.4g.5d., lp.2u.3a.4g.5d., la.2y.3a.4g.5d., lb.2y.3a.4g.5d., lf.2y.3a.4g.5d., lh.2y.3a.4g.5d., lj.2y.3a.4g.5d., lp.2y.3a.4g.5d., la.2a.3b.4g.5d., lb.2a.3b.4g.5d., lf.2a.3b.4g.5d., lh.2a.3b.4g.5d., lj.2a.3b.4g.5d., lp.2a.3b.4g.5d„ la. 2b.3b.4g.5d„ lb.2b.3b.4g.5d., lf.2b.3b.4g.5d„ lh.2b.3b.4g.5d., lj.2b.3b.4g.5d., lp.2b.3b.4g.5d., la.2e.3b.4g.5d., lb.2e.3b.4g.5d., lf.2e.3b.4g.5d., lh.2e.3b. 4g.5d., lj.2e.3b.4g.5d., lp.2e.3b.4g.5d., la.2L3b.4g.5d_, lb.2L3b.4g.5d., lL2f.3b.4g.5d., lh-2L3b.4g.5d., lj.2f.3b.4g.5d., lp.2f.3b,4g.5d., la.2i.3b.4g.5d., lb.2i.3b.4g.5d., lL2i.3b.4g.5d., lh.2i.3b.4g.5d., lj.2i,3b.4g.5d., lp.2i.3b.4g.5d., la.2m.3b.4g.5d., lb. 2m.3b.4g.5d., lf.2m.3b.4g.5d., lh.2m.3b.4g.5d., lj.2m.3b.4g.5d., lp.2m.3b.4g.5d., la. 2o.3b.4g.5d., lb.2o.3b.4g.5d., lf.2o.3b.4g.5d., lh.2o.3b.4g.5d., lj.2o.3b.4g.5d., lp.2o.3b.4g.5d., la.2u.3b.4g.5d., lb.2u.3b.4g.5d., lf.2u.3b.4g.5d., lh.2u.3b.4g.5d., lj.2u.3b.4g.5d., lp.2u.3b.4g.5d., la.2y.3b.4g.5d., lb.2y.3b.4g.5d., lf.2y.3b.4g.5d., lh.2y.3b.4g.5d„ lj.2y.3b.4g.5d., lp.2y.3b.4g.5d„ la.2a.3e.4g.5d., 1b.2a.3c.4g.5d., lf.2a.3e.4g.5d., lh.2a.3e.4g.5d., lj.2a.3e.4g.5d., lp.2a.3e.4g.5d., la.2b.3e.4g.5d., lb. 2b.3e.4g.5d., lf.2b.3e.4g.5d„ lh.2b.3e.4g.5d„ lj.2b.3e.4g.5d., lp.2b.3e.4g.5d_, la. 2e.3e.4g.5d., lb.2e.3e.4g.5d„ lf.2e.3e.4g.5d., lh.2e.3e.4g.5d., lj.2e.3e.4g.5d., lp.2e.3e.4g.5d., la.2L3e.4g.5d., lb.2f.3e.4g.5d., lf.2f.3e.4g.5d., lh.2L3e.4g.5d., lj.2f.3e.4g.5d., lp.2L3e.4g.5d., la.2i.3e.4g.5d., lb.2i.3e.4g.5d., lf.2i.3e.4g.5d., lh.2i.3e.4g.5d., lj.2i.3e.4g.5d., lp.2i.3e.4g.5d„ la.2m.3e.4g.5d., lb.2m.3e.4g.5d., lf.2m.3e.4g.5d., lh.2m.3e.4g.5d., 1j.2m,3e.4g.5d., lp.2m.3e.4g.5d., la.2o.3e.4g.5d., lb. 2o.3e.4g.5d., lL2o.3e.4g.5d., lh.2o.3e.4g.5d., 1j.2o.3c.4g.5d., lp.2o.3e.4g.5d., la.2u.3e.4g.5d„ lb.2u.3e.4g.5d., lf.2u.3e.4g.5d., lh.2u.3e.4g.5d., lj.2u.3c.4g.5d.,

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2020203321 21 May 2020 lp.2u.3e.4g.5d., la.2y.3e.4g.5d., lb.2y.3e.4g.5d., lf.2y.3c.4g.5d., lh.2y.3e.4g.5d., lj.2y.3e.4g.5d., lp.2y.3e.4g.5d., la.2a.3g.4g.5d., lb.2a.3g.4g.5d., lf.2a.3g.4g.5d., lh.2a.3g.4g.5d., lj.2a.3g.4g.5d., lp.2a.3g.4g.5d., la.2b.3g.4g.5d., lb.2b.3g.4g.5d., lf.2b.3g.4g.5d., lh.2b.3g.4g.5d., Ij.2b.3g.4g.5d., lp.2b.3g.4g.5d., la.2e.3g.4g.5d., lb.2e.3g.4g.5d., lf.2e.3g.4g.5d., lh.2e.3g.4g.5d., lj.2e,3g.4g.5d., 1p.2e.3g.4g.5d., la. 2f.3g.4g.5d., lb.2f.3g.4g.5d., lf.2f.3g.4g.5d„ lh.2f.3g.4g.5d., lj.2f.3g.4g.5d„ lp.2f.3g.4g.5d., 1 a.2i.3g.4g.5d., lb.2i.3g.4g.5d., lf.2i.3g.4g.5d., lh.2i.3g.4g.5d., lj.2i.3g.4g.5d., lp.2i.3g.4g.5d., la.2m.3g.4g.5d,, lb.2m.3g.4g.5d., lf.2m.3g.4g.5d„ lh.2m.3g.4g.5d., lj.2m.3g.4g.5d., lp.2m.3g.4g.5d., la.2o.3g.4g.5d., lb.2o.3g.4g.5d., lf.2o.3g.4g.5d., lh.2o.3g.4g.5d., lj.2o.3g.4g.5d., lp.2o.3g.4g.5d., la.2u.3g.4g.5d., lb. 2u.3g.4g.5d., lf.2u.3g.4g.5d., lh.2u.3g.4g.5d., lj.2u.3g.4g.5d., lp.2u.3g.4g.5d., la. 2y.3g.4g.5d., lb,2y.3g.4g.5d., lf.2y.3g.4g.5d., lh.2y.3g.4g.5d., lj.2y.3g.4g.5d., 1p.2y.3g.4g.5d., la.2a.3a.4h.5d„ lb.2a.3a.4h.5d„ lf.2a.3a.4h.5d„ lh.2a.3a.4h.5d., lj.2a.3a.4h.5d., lp.2a.3a.4K5d., la.2b.3a.4h.5d., lb.2b.3a.4h.5d., lf.2b.3a.4h.5d., 'Jh.2b.3a.4h.5d., lj.2b.3a.4h.5d., lp.2b.3a.4h.5d., la.2e.3a.4h.5d., lb.2e.3a.4h.5d., lf.2e.3a.4h.5d., lh.2e.3a.4h.5d., lj.2e.3a.4h.5d., lp.2e.3a.4h.5d„ la.2f.3a.4h.5d., lb. 2f.3a.4h.5d., lf.2f.3a.4K5d., lh.2f.3a.4h.5d., lj.2f.3a.4h.5d., lp,2f.3a.4h.5d., la. 2i.3a.4h.5d., lb.2i.3a.4h.5d., lf.2i.3a.4h.5d., lh.2i.3a.4h.5d., lj.2i.3a.4h.5d„ 1p.2i.3a.4h.5d., la.2m.3a.4h.5d,, lb.2m.3a.4h.5d., 'Jf.2m.3a.4K5d., 'lh.2m.3a.4h.5d., lj.2m.3a.4h.5d„ lp.2m.3a.41T.5d., la.2o.3a.4K5d., lb,2o.3a.4K5d., lf.2o.3a.4K5d., lh.2o.3a.4h.5d., lj.2o.3a.4K5d., lp.2o.3a.4h.5d_v la.2u.3a.41T.5d., lb.2u.3a.4h.5d., lf.2u.3a.4h.5d., lh.2u.3a.4h.5d., lj.2u.3a.4h.5d„ lp.2u.3a.4h.5d., la.2y.3a.4K5d., lb. 2y.3a.4h.5d., lf.2y.3a.41T.5d., lh.2y.3a.4h.5d., lj.2y.3a.4h.5d., lp.2y.3a.4h.5d., la. 2a.3b.4h.5d., lb.2a.3b.4K5d-, lf,2a.3b.4h.5d„ lh.2a.3b.4K5d., lj.2a.3b.41T.5d., lp.2a.3b.4h.5d., la.2b.3b.4h.5d., lb.2b.3b.4h.5d., lf.2b.3b.4K5d., lh.2b.3b.4h.5d., lj.2b.3b.4K5d., lp.2b.3b.4K5d., la.2e.3b.4K5d., 1b.2e.3b.4K5d., lf.2e.3b.4h.5d., lh.2e.3b.4h.5d., lj.2e.3b.4h.5d., lp.2e.3b.4h.5d., la.2f.3b.4h.5d., lb.2f.3b.4h.5d., lf.2f.3b.4K5d., lh.2f.3b.4K5d., lj.2f.3K4h.5d., lp.2f.3b.4K5d., la.2i.3b.4K5d., lb. 2i.3b.4K5d., li.2i.3b.4K5d., lh.2i.3b.4h.5d., lj.2i.3b.4h.5d., lp.2i.3b.4h.5d., la. 2m.3b.4h.5d., lb.2m.3b.4h.5d., 1f.2m.3b.4h.5d., 1h.2m.3b.4K5d., lj.2m,3b.4h.5d., lp.2m.3b.4K5d., la.2o.3b.4h.5d., lb.2o.3b.41T.5d., lf.2o.3b.4h.5d„ lh.2o.3b.4K5d., lj.2o.3b.4h.5d., lp.2o.3b.4h.5d., la.2u.3b.4h.5d., lb.2u.3b.4h.5d., lf.2u.3b.4K5d., lh.2u.3b.4h.5d., lj.2u.3b.4h.5d., lp.2u.3b.4h.5d., la.2y.3b.4h.5d., lb.2y.3b.4h.5d., lf.2y.3b,4h.5d., lh.2y,3b.4h.5d., lj.2y.3b.4h.5d., lp.2y.3K4h.5d., la.2a.3e.4h.5d., lb. 2a.3e,4K5d., lf.2a.3e.4h.5d., lh.2a.3e.4K5d., lj.2a.3e.4h.5d., lp.2a.3e.4K5d., la. 2b.3e.4h.5d., lb.2b.3e.4h.5d., lf.2b.3e.4K5d., lh.2b.3e.4K5d., lj.2b.3e.4K5d., lp.2b.3e.4K5d., la.2e,3e.4h.5d., lb.2e.3e.4h.5d., lf.2e.3e.4h.5d„ lh.2e.3e.4h.5d., lj.2e.3e.4K5d., lp.2e.3e.4K5d., la.2f.3e.4K5d., lb.2f.3c.4K5d., lf.2f.3e.4h.5d., 1h.2f.3e.4h.5d„ 1j.2f.3e.4h.5d„ lp.2f.3e.4K5d., 1a.2i.3e.4K5d., lb.2i.3e.4h.5d., lf.2i.3e.4h.5d., lh.2L3e.4K5d., lj.2i.3e.4h.5d., lp.2i.3e.4h.5d., la.2m.3e.4h.5d., lb. 2m.3e.4h.5d., lf.2m.3e.4h.5d„ lh.2m.3e.4h.5d., lj.2m.3e.4h.5d., lp.2m.3e.4h.5d.,

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2020203321 21 May 2020 la. 2o.3e.4h.5d., lb.2o.3e.4h.5d., lf.2o.3e.4h.5d., 1h.2o.3e.4h.5d„ lj.2o.3e.4h.5d., lp.2o.3e.4h.5d., Ja.2u.3e.4h.5d., 1 b.2u.3e.4h.5d„ l£2u.3e.4h.5d„ lh.2u.3e.4h.5d, lj.2u.3c.4h.5d., lp.2u.3e.4h.5d., la.2y.3e.4h.5d., lb.2y.3e.4h.5d„ lf.2y.3e.4J7.5d., lh.2y.3e.4h.5d., lj.2y.3e.4K5d., Ip.2y.3e.4h.5d., la.2a.3g.4h.5d., lb.2a.3g.41r.5d., 1f.2a.3g.4h.5d., lh.2a.3g.4h.5d., lj.2a.3g.4h.5d., lp.2a.3g.4h.5d., la.2b.3g.4h.5d., lb. 2b.3g.4h.5d„ lf.2b.3g.4h.5d., lh.2b.3g.4h.5d., lj.2b.3g.4h.5d„ lp.2b.3g.4h.5d., la. 2c.3g.4h.5d., lb.2e.3g.4h.5d., lf.2e.3g.4h.5d., lh.2e.3g.4K5d., lj.2e.3g.4h.5d., lp.2e.3g.4h,5d., la.2f.3g.4h.5d., lb.2f.3g.4h.5d., lf.2f.3g.4h.5d., lh.2f.3g.417.5d., lj.2f.3g.4h.5d., lp.2f.3g.4h.5d., la,2i.3g.4h.5d., lb.2i.3g.4h.5d., lf.2i.3g.4h.5d., lh.2i.3g.4h.5d., lj.2i.3g.4h.5d., 1 p.2i.3g.4K5d., la.2m.3g.4h.5d., lb.2m.3g.41i.5d., lf.2m.3g.4h.5d., lh.2m.3g.4h.5d., lj.2m.3g.4h.5d., lp.2m.3g.4h.5d., la.2o.3g.4h.5d., lb. 2o.3g.4h.5d., 1f.2o.3g.4h.5d., 1 h.2o.3g.4h.5d., lj.2o.3g.4h.5d., lp.2o.3g.4h.5d., la. 2u.3g.4h.5d., lb.2u.3g.4h.5d., lf.2u.3g.4K5d., lh.2u.3g.4h.5d., 1j.2u.3g.4h.5d., lp.2u.3g.4K5d., la.2y.3g.4h.5d., lb.2y.3g.4K5d., lf.2y.3g.4h.5d., lh.2y.3g.417.5d., lj.2y.3g.4h.5d., lp.2y.3g.4h.5d., la.2a.3a.4i.5d., lb.2a.3a.4i.5d., lf.2a.3a.4i.5d., Ih.2a.3a.4i.5d., lj.2a.3a.4i.5d., lp.2a.3a.4i.5d., la.2b.3a.4i.5d., lb.2b.3a.4i.5d., lf.2b.3a,4i.5d., lh.2b.3a.4i.5d., lj.2b.3a.4i,5d., lp.2b.3a.4i.5d., la.2e.3a.4i.5d., lb. 2e.3a.4i.5d., lf.2e.3a.4i.5d., lh.2e.3a.4i.5d., lj.2e.3a.4i.5d., lp.2e.3a.4i.5d., la. 2f.3a.4i.5d„ lb.2f.3a.4i.5d„ lf.2f.3a.4i.5d., lh.2f.3a.4i.5d., 1 j.2f.3a.4i.5d., lp.2f.3a.4i.5d-, la.2i.3a.4i.5d., lb.2i.3a.4i.5d., lf.2i.3a.4i.5d., lh.2i.3a.4i.5d., lj.2i.3a.4i.5d., lp.2i.3a.4i.5d., la.2m.3a.4i.5d., 1b.2m.3a.4i.5d., lf.2m.3a.4i.5d., lh.2m.3a.4i.5d., lj.2m.3a.4i.5d., lp.2m.3a.4i.5d., la.2o.3a.4i.5d., lb.2o.3a.4i.5d., lf.2o.3a.4i.5d., lh.2o.3a.4i.5d., 1j.2o.3a.4L5d., lp.2o.3a.4i.5d., la.2u.3a.4i.5d., lb. 2u.3a.4i.5d., lf.2u.3a.4i.5d., lh.2u.3a.4i.5d., lj.2u.3a.4i.5d., Ip.2u.3a.4i.5d., la. 2y.3a.4i.5d., lb.2y.3a.4i.5d„ lf,2y.3a.4i.5d., lh.2y.3a.4i.5d., lj.2y.3a.4i.5d., lp.2y.3a.4i.5d., la.2a.3b.4i.5d., lb.2a.3b.4i.5d., lf.2a.3b.4i.5d-, lh.2a.3b.4i.5d., lj.2a.3b.4i.5d., lp.2a.3b.4L5d., la.2b.3b.4i.5d., lb.2b.3b.4i.5d., lf.2b.3b.4i.5d., lh.2b.3b.4i.5d., lj.2K3K4i.5d., lp,2b.3b.4i.5d., la.2e.3b.4i.5d„ lb.2e.3b.4i.5d., lf.2e.3b.4.i.5d., Ih.2e.3b.4i.5d., lj.2e.3b.4i.5d., lp.2e.3b.4i.5d„ la.2f.3b.4i.5d., lb. 2f.3b.4i.5d., lf.2f.3b.4i.5d., lh.2f.3b.4i.5d., lj.2f.3b.4i.5d., lp.2f.3b.4i.5d., la. 2i.3b.4i.5d., lb.2i.3b.4i.5d., lf.2i.3b.4i.5d., lh.2i.3b.4i.5d., 1 j.2i.3b.4i.5d., lp.2i.3b.4i.5d., la.2m.3b.4i.5d., lb.2m.3K4i.5d., lf.2in.3b.4i.5d., lh.2m.3b.4i.5d., lj,2m.3b.4i.5d., lp.2m.3b.4i.5d., la.2o.3b.4i.5d,, lb.2o.3b.4i.5d., If.2o.3b.4i.5d., lh.2o.3b.4i.5d., Ij.2o.3b.4i.5d„ lp.2o.3b.4i.5d., la.2u.3b.4i.5d., lb.2u.3b.4i.5d., lf.2u.3b.4i.5d., lh.2u.3b.4i.5d., lj.2u.3b.4i.5d., lp.2u.3b.4i.5d., la,2y.3b.4i.5d,, lb. 2y.3b.4i.5d., lf.2y.3b.4i.5d., lh.2y.3b.4i.5d., lj.2y.3b.4i.5d., lp.2y.3b.4i.5d., la.2a.3e.4L5d., lb.2a.3e.4i.5d., lf.2a.3e.4i.5d., lh.2a.3e.4i.5d., lj.2a.3e.4i.5d., lp,2a.3e.4i.5d„ la.2b.3e.4i.5d., Ib.2b.3e.4i.5d„ lf.2b.3e.4i.5d., lh.2b.3e.4i.5d„ lj.2b.3e.4i.5d., lp.2b.3e.4i.5d., la.2e.3e.4i.5d., lb.2e.3e.4i.5d., lf.2e.3e.4i.5d., lh.2e.3e.4i.5d., lj.2e.3e.4i.5d., lp.2c.3e,4i.5d., la.2f.3e.4i.5d., lb.2f.3e.4i.5d., lf.2f.3e.4i.5d., lh.2f.3e.4i.5d., lj.2f.3e.4i.5d., lp.2f.3e.4i.5d., la.2i.3c.4i.5d.,

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2020203321 21 May 2020 lb.2L3e.4i.5d., 1 f.2i.3e.4i.5d., lh.2i.3e.4i.5d., lj.2i.3e.4i.5d., lp.2i.3e.4i.5d., la. 2m.3e.4i.5d., 117.2m.3e.4i.5d., 1f.2m.3e.4i.5d., lh.2m.3e.4i.5d., lj.2m.3e.4i.5d., lp.2m.3e.4i.5d., la.2o.3e.4i.5d„ lb.2o.3e.4i.5d., lf.2o.3e.4i.5d., lh.2o.3e.4i.5d., lj.2o.3e.4i.5d., lp.2o.3e.4i.5d., la.2u.3e.4i.5d., lb.2u.3e.4i.5d., lf.2u.3e.4i.5d., lh.2u.3e.4i.5d., 1j.2u.3c.4i.5d., lp.2u.3e.4i.5d., la.2y.3e.4i.5d., lb.2y.3e.4i.5d., lf.2y.3e.4i.5d., lh.2y.3e.4i.5d., lj.2y.3e.4i.5d., lp.2y.3e.4i.5d., la.2a.3g.4i.5d., lb. 2a.3g.4i.5d., lf.2a.3g.4i.5d., lh.2a.3g.4i.5d., lj.2a.3g.4i.5d., lp.2a.3g.4i.5d., la. 2b.3g.4i.5d., lb.2b.3g.4i.5d, lf.2b.3g.4i.5d, lh.2b.3g.4i.5d., lj.2b.3g.4i.5d., lp.2b.3g.4i.5d., la.2e.3g.4i.5d., lb.2e.3g.4i.5d., lf.2e.3g.4i.5d., lh.2e.3g.4i.5d., lj.2e.3g.4i.5d., lp.2e.3g.4i.5d., la.2f.3g.4i.5d., lb.2f.3g.4i.5d., lf.2L3g.4i.5d., lh.2f.3g.4i.5d., lj.2f.3g.4i.5d„ lp.2f.3g.4i.5d., la.2i.3g.4i.5d., lb.2i.3g.4i.5d., f,2i.3g.4i.5d., lh.2i.3g.4i.5d., lj.2i,3g.4i.5d., lp.2i.3g.4i.5d., la.2m.3g.4i.5d., lb, 2m,3g.4i.5d., lf.2ni.3g.4i.5d., lh.2m.3g.4i.5d., lj.2m.3g.4i.5d., lp.2m.3g.4i.5d., la. 2o.3g.4i.5d., lb.2o.3g.4i.5d., lf.2o.3g.4i.5d., lh.2o.3g.4i.5d., lj.2o.3g.4i.5d., lp.2o.3g.4i.5d., la.2u.3g.4i.5d., lb.2u.3g.4i.5d„ lf.2u.3g.4i.5d., lh.2u.3g.4i.5d., lj.2u.3g.4i.5d., lp.2u.3g.4i.5d., la.2y.3g.4i.5d., lb.2y.3g.4i.5d., lL2y.3g.4i.5d., lh.2y.3g.4i.5d., lj.2y.3g.4i.5d., lp.2y.3g.4i.5d., la.2a.3a.4a.5f,, lb.2a.3a.4a.5f., lf.2a.3a.4a.5f., Ih.2a.3a.4a.5f, lj.2a.3a.4a.5f, lp.2a.3a.4a.5f., la.2b.3a.4a.5f., lb. 2b.3a.4a.5f., lf.2b.3a.4a.5f, Ih.2b.3a.4a.5f, lj.2b.3a.4a.5L, lp.2b.3a.4a.5f, la. 2e.3a.4a.5f., lb.2e.3a.4a.5f, lf.2e.3a.4a.5f, lh.2e.3a.4a.5f, lj.2e.3a.4a.5f, lp.2e.3a.4a.5f, la.2f.3a.4a.5f, lb.2f.3a.4a.5f, lf.2f.3a.4a.5f., lh.2f.3a.4a.5f, lj.2f.3a.4a.5f, lp.2f. 3a.4a.5f, la.2i.3a.4a.5f, lb.2i.3a.4a.5f, If.2i.3a.4a.5f, lh.2i.3a.4a.5f, lj.2i.3a.4a.5f, lp.2i.3a.4a.5f, la.2m.3a.4a.5f, lb.2m.3a.4a.5f, lf.2m.3a.4a.5f, lh.2m.3a.4a.5f., lj.2m.3a.4a .51., lp.2m.3a,4a.5f, la.2o.3a.4a.5f, lb. 2o.3a.4a.5f, lf.2o.3a.4a.5f, lh.2o.3a.4a.5f, lj.2o.3a.4a.5f, lp.2o.3a.4a.5f, la. 2u.3a.4a.5f, lb.2u.3a.4a.5f, lf.2u.3a.4a.5f, lh.2u.3a.4a.5f, lj.2u.3a.4a.5f, lp.2u.3a.4a.5f, la.2y.3a.4a.5f, lb.2y.3a.4a.5f, lf.2y.3a.4a.5f, lh.2y.3a.4a.5f, lj.2y.3a.4a.5f, lp.2y.3a.4a.5f, la.2a.3b.4a.5f, lb.2a.3b.4a.5f, lf2a.3b.4a.5f, lh.2a.3b.4a.5f, lj.2a.3b.4a.5f, lp.2a.3b.4a.5f, la.2b.3b.4a.5f, lb.2b.3b.4a.5f, lf2b.3b.4a.5f, lh.2b.3b.4a.5f, lj.2b.3b.4a.5f, lp.2b-3b.4a.5f., la.2c.3b.4a.5f., lb. 2c.3b.4a.5f, lf.2e.3b.4a.5f, lh.2e.3b.4a.5f, lj.2e.3b.4a.5f, lp.2e.3b.4a.5f, la. 2f.3b.4a.5f, lb.2f3b.4a.5f, If 2f3b.4a.5f, lh.2f.3b.4a.5f, 1j.2L3b.4a.5f., lp.2f.3b.4a.5f, la.2i.3b.4a.5f, lb.2i.3b.4a.5f, lf.2i.3b.4a.5f, lh.2i.3b.4a.5f, lj.2i.3b.4a.5f, lp.2i.3b.4a.5f, la.2m.3b.4a.5f, lb.2m.3b.4a.5f, lf.2m.3b.4a.5f, lh.2m.3b.4a.5L, lj.2m.3b.4a.5f, lp.2m.3b.4a,5f, la.2o.3b.4a.5h, lb.2o.3b.4a.5f, lf.2o.3b.4a.5f., lh.2o.3b.4a.5f, lj.2o.3b.4a.5f, lp.2o.3b.4a.5f, la.2u.3b.4a,5f., lb. 2u.3b.4a.5f, 1f.2u.3b.4a.5f, lh.2u.3b.4a.5f, lj.2u.3b.4a.5f, lp.2u.3b.4a.5f, la.2y.3b.4a.5f, lb.2y.3b.4a.5f, lf.2y.3b.4a.5f, lh.2y.3b.4a.5f, lj.2y.3b.4a.5f., lp.2y.3b.4a.5f, la.2a.3e.4a.5f., lb.2a.3e.4a.5f, lf.2a.3e.4a.5L, 117.2a.3e.4a.5f., lj.2a.3c.4a.5f, lp.2a.3e.4a.5f, la.2b.3e.4a.5f, lb.2b.3e.4a.5f, lf.2b.3e.4a.5f, lh.2b.3e.4a.5f, lj.2b.3c.4a.5f., lp.2b.3e.4a.5f, la.2e.3e.4a.5f, lb.2e.3e.4a.5f,

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2020203321 21 May 2020 lf2e.3e.4a.5f, lh.2e.3e.4a.5f, lj.2e.3e.4a.5f, lp.2e.3e.4a.5f, la.2f3e.4a.5f., lb.2f.3o.4a.5f, lf.2f.3e.4a.5f, lh.2f.3e.4a.5f, lj.2f.3e.4a.5f, lp.2f.3e.4a.5f, la. 2i.3e.4a.5f, lb.2i.3e.4a.5f, lf.2i.3c.4a.5f, lh.2i.3e.4a.5f, lj.2i.3e.4a.5f, lp.2L3e.4a.5f, la.2ni.3e.4a.5f, lb.2m.3e.4a.5f, lf.2m.3e.4a.5h, lh.2m.3e.4a.5f, lj.2m.3e.4a.5f, lp.2m,3e.4a.5fi, la.2o.3e.4a.5f, lb.2o.3e.4a.5f., lf.2o.3e.4a.5f, 1h.2o.3c.4a.5f, lj.2o.3e.4a.5f, lp.2o.3e.4a.5f, la.2u.3e.4a.5f, lb.2u.3e.4a.5f, lf.2u.3e.4a.5f, lh.2u.3e.4a.5f, lj.2u.3c.4a.5f, lp.2u.3e.4a.5f, la.2y.3e.4a.5f, lb. 2y.3e.4a.5f., lf.2y.3e.4a.5f, lh.2y.3e.4a.5h, lj.2y.3e.4a.5f,, lp.2y.3e.4a.5f„ la. 2a.3g.4a.5f, lb.2a.3g.4a.5f, lf.2a.3g.4a.5f., lh.2a.3g.4a.5f., lj.2a.3g.4a.5f., lp.2a.3g.4a.5f, 1 a.2b.3g.4a.5f., lb.2b.3g.4a.5f, lf.2b.3g.4a.5f, lh.2b.3g.4a.5f, lj.2b.3g.4a.5f, lp.2b.3g.4a.5f, la.2e_.3g.4a.5f, lb.2c.3g.4a.5f, lf.2e.3g.4a.5f, lh.2e.3g.4a.5f, lj.2e.3g.4a.5f, lp.2e.3g.4a.5f, la.2f.3g.4a.5f, lb.2f3g.4a.5f., lf.2f.3g.4a.5f, 1h.2f.3g.4a.5f, lj.2f.3g.4a.5f, lp.2f.3g.4a.5f., Ia.2i.3g.4a.5f., lb. 2i.3g.4a.5f, lf.2i.3g.4a.5f, lh.2i.3g.4a.5f, lj.2i.3g.4a.5f, lp.2i.3g.4a.5h, la. 2m.3g.4a.5h, 1b.2m.3g.4a.5f., lf.2m.3g.4a.5f, lh.2m.3g.4a.5f, lj.2m.3g.4a.5f., lp.2m.3g.4a.5f., la.2o.3g.4a.5f, lb.2o.3g.4a.5f, lf,2o.3g.4a.5f., lh.2o.3g.4a.5f, lj.2o.3g.4a.5f, lp.2o.3g.4a.5f, la.2u.3g.4a.5f., lb.2u.3g.4a.5f, lf.2u.3g.4a.5f,, 1h.2u.3g.4a.5f, lj,2u.3g.4a.5f., lp.2u.3g.4a.5f., la.2y.3g.4a.5f., lb.2y.3g.4a.5f, lf.2y.3g.4a.5f, lh.2y.3g.4a.5f., lj,2y.3g.4a.5f., lp.2y.3g.4a.5f., la.2a.3a.4d.5f., lb. 2a.3a.4d.5f, lf.2a.3a.4d.5f., lh.2a.3a.4d.5f, lj.2a.3a.4d.5f, lp.2a.3a.4ri.5f, la. 2b.3a.4d.5f, 1b.2b.3a.4d.5f, lf.2b.3a.4d.5f., lh.2b.3a.4d.5f., lj.2b.3a.4d.5f, lp.2b.3a.4d.5f., la.2e.3a.4d.5f, lb.2e.3a.4d.5f, lf.2c.3a.4d.5f., lh.2c.3a.4d.5f., lj.2e.3a.4d.5f, lp.2e.3a.4d.5f, la.2f.3a.4d.5f., lb.2f.3a.4d.5f., lf,2f. 3a.4d.5f, lh.2f.3a.4d.5f, lj.2f.3a.4d.5f., lp.2f.3a.4d.5f, la.2i.3a.4d.5f, lb.2i.3a.4d.5f, lf.2i.3a.4d.5f, lh.2i.3a.4d.5f., lj.2i.3a.4d.5f, lp.2i.3a.4d.5f., la.2m.3a.4d.5f, lb. 2m.3a,4d.5f,, lf.2m.3a.4d.5f., lh.2m.3a.4d.5f., lj.2m.3a.4d.5f., lp.2m.3a.4d.5f., la. 2o.3a.4d.5f, lb.2o.3a.4d.5f, lf.2o.3a.4d.5f, lh.2o.3a.4d.5f, lj.2o.3a.4d.5f., lp.2o.3a.4d.5f, la.2u.3a.4d.5f, lb.2u.3a.4d.5f., lf.2u.3a.4d.5f, lh.2u.3a,4d.5f, lj.2u.3a.4d.5f., lp.2u.3a.4d.5f, la.2y.3a.4d.5f, lb.2y.3a.4d.5f, lf.2y.3a.4d.5f, lh.2y.3a.4d.5f, lj.2y.3a.4d.5f, lp.2y.3a.4d.5f., la.2a.3b.4d.5f, lb.2a.3b.4d.5f, lf.2a.3b.4d.5f, lh.2a.3b.4d.5f, lj.2a.3b.4d.5f, lp.2a.3b.4d.5f., la.2b.3b.4d.5f, lb. 2b.3b.4d.5f, lf.2b.3b.4d.5f, lh.2b.3b.4d.5f, lj.2b.3b.4d.5f, lp.2b.3b.4d.5f, la. 2c.3b.4d.5f, lb.2e.3b.4d.5f, lf.2e.3b.4d.5f, lh.2e.3b.4d.5f, lj.2e.3b.4d.5f, lp.2e.3b.4d.5f, la.2f.3b.4d.5f, lb.2f3b.4d.5f, lf.2f3b.4d.5f, lh.2f.3b.4d.5f, lj.2f.3b.4d.5f, Ip.2f3b.4d.5f, la.2i.3b.4d.5f., lb.2i.3b.4d.5f, lf.2i.3b.4d.5f, lh.2i.3b.4d.5f, lj.2i.3b.4d.5f, lp.2i.3b.4d.5f, la.2m.3b.4d.5f, lb.2m.3b.4d.5f, lf.2m.3b.4d.5f, lh.2ni.3b.4d.5f., lj.2m.3b.4d.5f, lp.2m.3b.4d.5f, la.2o.3b.4d.5h, lb. 2o.3b.4d.5f, lf.2o.3b.4d.5f, lh.2o.3b.4d.5f, lj.2o.3b.4d.5f, lp.2o.3b.4d.5f, la.2u.3b.4d.5f, lb.2u.3b.4d.5f, lf.2u.3b.4d.5f, lh.2u.3b.4d.5f., lj.2u.3b.4d.5f., lp.2u.3b.4d.5f, la.2y.3b.4d.5f, lb.2y.3b.4d.5f, lf.2y.3b.4d.5f, lh.2y.3b.4d.5f, lj.2y.3b.4d.5f., lp.2y.3b.4d.5f, la.2a.3e.4d.5f, lb.2a.3e.4d.5f, lf2a.3e.4d.5f,

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2020203321 21 May 2020 lh.2a.3e.4d.5f, lj.2a.3e.4d.5f, lp.2a.3e.4d.5f, la.2b.3e.4d.5f, lb.2b.3e.4d.5f, lf.2b.3c.4d.5f, lh.2b.3e.4d.5f, lj.2b.3e.4d.5f, lp.2b.3e.4d.5f, la.2e.3e.4d.5f, lb.2e.3e.4d.5f, lf.2e.3e.4d.5f, lh.2e.3e.4d.5f, lj.2e.3e.4d.5f, lp.2c.3c,4d.5f., la. 2E3e.4d.5f, lb.2f.3e.4d.5f, lf.2f.3e.4d.5f, lh.2f3e.4d.5f, lj.2f.3e.4d.5f, lp.2f.3e.4d.5f, la.2i.3e.4d.5f, 'lb.2i.3e.4d.5f., If2i.3e.4d.5f., lh.2i.3e.4d.5f, lj.2i.3e.4d.5f, lp.2i.3e.4d.5f, la.2m.3e.4d.5f, lb.2m.3e.4d.5f, lf.2m.3e.4d,5f, lh.2m.3e.4d.5f, lj.2m.3c.4d.5f., lp.2m.3e.4d.5f, la.2o.3e.4d.5f, lb.2o.3e.4d.5f, lf.2o.3e.4d,5f, lh.2o.3e.4d.5f, lj.2o.3e.4d.5f, lp.2o.3e.4d.5f, la.2u.3e.4d.5f, lb. 2u.3e.4d.5f, lf2u.3e.4d.5f, lh.2u.3e.4d.5f, lj.2u.3e.4d.5f, lp.2u.3e.4d.5f, la. 2y.3c.4d.5f, lb.2y.3e.4d.5f, lf2y.3e.4d.5f, lh.2y.3e.4d.5f, lj.2y.3e.4d.5f, lp.2y.3e.4d.5f, la.2a.3g.4d.5f, lb.2a.3g.4d.5f, If.2a.3g.4d.5f, lh.2a.3g.4d.5f, lj.2a.3g.4d.5f., lp.2a.3g.4d.5f, la.2b.3g.4d.5f, Ib.2b.3g.4d.5f, lf,2b.3g.4d.5h, lh.2b.3g.4d.5f, lj.2b.3g.4d.5f, lp.2b.3g.4d.5f, la.2e.3g.4d.5f, lb.2e.3g.4d.5f, 'lf2e.3g.4d.5f, lh.2e.3g.4d.5f, lj.2e.3g.4d.5f, lp.2e.3g.4d.5f, la.2f.3g.4d.5f, lb. 2f3g.4d.5f, If2f3g.4d.5f, lh.2f3g.4d.5f, lj.2f.3g.4d.5f, lp.2f.3g.4d.5f, la. 2i.3g.4d.5f, lb.2i.3g.4d.5f, lf.2i.3g.4d.5f, lh.2i.3g.4d.5f, 1 j.2i.3g.4d.5f., lp,2i.3g.4d.5f, la.2m.3g.4d.5f, lb.2m.3g.4d.5f, lf2m.3g.4d.5f, lh.2m.3g.4d.5f, 1j.2m.3g.4d.5f, lp.2m.3g.4d.5f, la.2o.3g.4d.5f, lb.2o.3g.4d.5f, lf.2o.3g.4d.5f, lh.2o,3g.4d.5f, lj.2o.3g.4d.5f, Jp.2o.3g.4d.5f, la.2u.3g.4d.5f, lb.2u.3g.4d.5f, lf.2u.3g.4d.5f, lh.2u.3g.4d.5f, lj.2u.3g.4d.5f, 1p.2u.3g.4d.5f, la.2y.3g.4d.5f, lb. 2y.3g.4d.5f, If.2y.3g.4d.5f, lh.2y.3g.4d.5f, lj.2y.3g.4d.5f, lp.2y.3g.4d.5f, la. 2a.3a.4f.5f, lb.2a.3a.4f.5f, lf.2a.3a.4f.5f, lh.2a.3a.4f5f, 1j.2a.3a.4f5f, lp.2a.3a.4f.5f, la.2b.3a.4f.5f., lb.2b.3a.4f 5f, 1 f.2b.3a.4f.51., lh.2b.3a.4f.5f., lj.2b.3a.4f.5f, lp.2b.3a.4f5f, la.2e.3a.4f.5f, lb.2e.3a.4f.5f, lf.2e.3a.4f.5E, lh.2c.3a.4f.5f, lj.2e.3a.4E5f, lp.2e.3a.4f.5f, la.2f.3a.4f.5f, Ib.2f3a.4f5f, lf.2f.3a.4f.5f, lh.2f.3a.4f5f, 'Jj.2f3a.4f5f, ip.2f3a.4f5E, la.2i.3a.4f5f, lb. 2i.3a.4f5f, lf.2i.3a.4f.5f., Ih.2i.3a.4f5f, lj.2i.3a.4f.5f, lp.2i.3a.4f.5f, la. 2m.3a.4f.5f, lb.2m.3a.4f5f, lf2m.3a.4f.5f, lh.2m.3a.4f.5f., lj.2m.3a.4f.5f, lp.2m.3a.4f.5f, la.2o.3a.4f.5f, lb.2o.3a.4f 5f., lf.2o.3a.4f.5f, lh.2o.3a.4f.5f, lj.2o.3a.4f.5f, lp.2o.3a.4f.5E, la.2u.3a.4f.5f, lb.2u.3a.4f.5f, lf.2u.3a.4f.5f, lh.2u.3a.4f.5f., lj.2u.3a.4f.5f, lp.2u.3a.4f.5E, la.2y.3a.4E5E, lb.2y.3a.4E5E, lE2y.3a.4f.5f, lh.2y.3a.4f5f., Ij.2y.3a.4f5f, 1 p.2y.3a.4f.51., la.2a.3b.4f5f, lb. 2a.3b.4f.5f., lf2a.3b.4f.5f., lh.2a.3b.4f.5f, 1j.2a.3b.4f5f, 1 p.2a.3b.4f5f, la. 2b.3b.4E5f, lb.2b.3b.4f.5f, If 2b.3b.4f.5f, lh.2b.3b.4f.5f, lj.2b.3b.4f5f, lp.2b.3b.4f.5f, la.2e.3b.4f.5f, lb.2e.3b.4f5f, lf.2e.3b.4f.5f, lh.2c.3b.4f5f, lj.2e.3b.4f.5f, lp.2e.3b.4f.5f, la.2f3b.4f.5f, lb.2f.3b.4f.5f, lf.2f.3b.4f5f, lh.2f.3b.4f,5f, lj.2f.3b.4f.5f, lp.2f.3b.4f.5f, la.2i.3b.4f.5f, lb.2i.3b.4f.5f, lf.2i.3b.4f.5f, lh.2i.3b.4f.5f, lj.2i.3b.4f.5f, lp.2i.3b.4E5f, la.2m.3b.4f5f, lb. 2m_.3b.4f 5f, 1f2m.3b.4f.5f, lh.2m.3b.4f.5f, lj.2m.3b.4f.5f, lp.2m.3b.4f.5f, Ia.2o.3b.4f5f, lb.2o.3b.4f,5f, lf.2o.3b.4f5f, lh.2o.3b.4f5f, 1j.2o,3b.4f.5f, lp.2o.3b.4E5f, la.2u.3b.4E5f, lb.2u.3b.4f.5f, lf.2u.3b.4f.5f, lh.2u.3b.4E5f,

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2020203321 21 May 2020 li-2u.3b.4f.5f., lp.2u.3b.4f.5f., la.2y.3b.4f.5f, lb.2y.3b.4f.5f, lf.2y.3b.4f.5f, lh.2y.3b.4f.5f, 'lj.2y.3b.4f.5f, lp.2y.3b.4f.5f, la.2a.3e.4f.5f, lb.2a.3e.4f.5f, lf.2a.3c.4f.5f, lh.2a.3e.4f.5f, lj.2a.3e.4f.5f, lp.2a.3e.4f.5f, la.2b.3e.4f.5f„ lb.2b.3e.4f.5f, lf.2b.3e.4f.5f, lh.2b.3e.4f.5f, lj.2b.3e.4f.5f, lp.2b.3e.4f.5f, la. 2e.3e.4f.5f, lb.2e.3e.4f.5f, lf.2e.3e.4f.5f, lh.2e.3e.4f.5f, lj.2e.3e.4f.5f, lp.2e.3e.4f.5f, la.2f.3e.4f.5f, lb.2f.3e.4f.5f, lf.2f.3e.4f.5f, lh.2f.3e.4f.5f, lj.2f.3e.4f.5f, lp.2f.3e.4f.5f., la.2i.3e.4f.5f, lb.2i.3e.4f.5f, lf.2i.3e.4f.5f, lh.2i.3e.4f.5f, lj.2i.3c.4f.5f, lp.2i.3e.4f.5f, la.2m.3e.4f.5f, lb.2m.3e.4f.5f, lf.2m.3e.4f.5f, lh.2m.3e.4f.5f, lj.2m.3e.4f.5f, lp.2m.3e.4f.5f, la.2o.3c.4f.5f, lb. 2o.3e.4f.5f, lf.2o.3e.4f.5f, lh.2o.3e.4f.5f, lj.2o.3e.4L5f, lp.2o.3e.4f.5f, la. 2u.3c.4f.5f, lb.2u.3e.4f.5f, lf.2u.3e.4f.5f, lh.2u.3e.4f.5f, lj.2u.3e.4f.5f, lp.2u.3e.4f.5f, 1 a.2y.3e.4f.5f, 1b.2y.3e.4f.5f, lf.2y.3e.4f.5f, lh.2y.3e.4f.5f, lj.2y.3e.4f.5f, lp.2y.3e.4f.5f, la.2a.3g.4f.5f, lb.2a.3g.4f.5f, lf.2a.3g.4f.5f, lh.2a.3g.4f.5f, lj.2a.3g.4f.5f, lp.2a.3g.4f.5f, la.2b.3g.4f.5f, lb.2b.3g.4f.5f, lf.2b.3g.4f.5f, lh.2b.3g,4f.5f, lj.2b.3g.4f.5f, lp.2b.3g.4f.5f, la.2e.3g.4f.5f, lb. 2e.3g.4f.5f, 1f.2e.3g.4f.5f, lh.2c.3g.4f.5f, lj.2e.3g.4f.5f, lp.2e.3g.4f.5f, la. 2f.3g.4f.5f, lb.2f.3g.4f.5f, lf.2f.3g.4f.5f„ lh.2f.3g.4f.5f, lj.2f.3g.4f.5f, lp.2f.3g.4f,5f, la.2i.3g.4f.5f, lb.2i.3g.4f.5f, lf.2i.3g.4f.5f, lh.2i.3g.4f.5f,

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PCT/US2008/054788

2020203321 21 May 2020 lp.2m.3b.4g.5f., la.2o.3b.4g.5f, lb.2o.3b.4g.5f., lf.2o.3b.4g.5f., lh.2o.3b.4g.5f., lj.2o.3b.4g.5f, lp.2o.3b.4g.5f., la.2u.3b.4g.5f, lb.2u.3b.4g.5f., lf.2u.3b.4g.5f, lh.2u.3b.4g.5f, lj.2u.3b.4g.5f., lp.2u.3b.4g.5L, la.2y.3b.4g.5f., lb.2y.3b.4g,5f., lf.2y.3b.4g.5f, lh.2y.3b.4g.5f, lj.2y.3b.4g.5f., lp.2y.3b.4g.5f, la.2a.3e.4g.5f., lb.2a.3e.4g.5f„ lf.2a.3e.4g.5f, lh.2a.3e.4g.5f., lj.2a.3e.4g.5f., lp.2a.3e.4g.5f., Ja.2b.3e.4g.5f, lb.2b.3e.4g.5f., lf.2b.3e.4g.5f, lh.2b.3e.4g.5f., lj.2b.3e.4g.5f., lp.2b.3e.4g.5f., la.2e,3e.4g.5f,, lb.2e.3e.4g.5f., lf.2e.3e»4g.5f„ lh.2e.3e.4g.5E, lj.2e.3e.4g.5f., lp.2e.3e.4g.5f., la.2f.3e.4g.5f., lb.2f.3e.4g.5f., lf.2f.3e.4g.5f, lh.2f.3e.4g.5f., lj.2f.3e.4g.5f, lp.2f.3e.4g.5f., la.2i.3e.4g.5f., lb.2i.3e.4g.5f., lf.2i.3e.4g.5f., lh.2L3e.4g.5L, lj.2i.3e.4g.5f., lp.2L3e.4g.5f, la.2m.3e.4g.5f., lb.2m.3e.4g.5f., lf.2m,3e,4g.5f,, lh,2m.3e.4g.5f., lj.2m.3e.4g.5f., lp.2m.3e.4g.5f., la. 2o.3e.4g.5f., lb.2o.3e.4g.5f., lf.2o.3e.4g.5f., lh.2o.3e.4g.5f., lj.2o.3e.4g.5f., lp.2o.3e.4g.5f, la.2u.3e.4g.5f, lb.2u.3e.4g.5f., lf.2u.3e.4g.5f, lh.2u.3e.4g.5f., 'lj.2u.3e.4g.5f., lp.2u.3e.4g.5f., la.2y.3e.4g.5f., lb,2y.3e.4g.5f., If2y.3e.4g.5f., lh.2y,3e.4g.5f, 1j.2y.3e.4g.5f., lp.2y.3e.4g.5f., la.2a.3g.4g.5f., lb.2a.3g.4g.5f., lf.2a.3g.4g.5f, lh.2a.3g.4g.5f, lj.2a.3g.4g.5f., lp.2a.3g.4g.5f, la.2b.3g.4g.5f„ lb. 2b.3g.4g.5f, lf.2b.3g.4g.5f„ Ih. 2b.3 g.4g.5L, 1j.2b.3g.4g.5f, 1p.2b.3g.4g.5f., la. 2e.3g.4g.5f., lb.2e.3g.4g.5f», lf.2e.3g.4g.5f., lh.2e.3g.4g.5f», lj.2e.3g.4g.5f, lp.2e.3g.4g.5f, la.2L3g.4g.5f, lb.2f.3g.4g.5f„ lf.2f.3g.4g.5f., lh.2f.3g.4g.5f, 1 j.2f.3g.4g.5f., lp.2f.3g.4g.5f„ la.2i.3g.4g.5f., lb.2i.3g.4g.5f., lf.2i.3g.4g.5f., lh.2i.3g.4g.5f., lj.2i.3g.4g.5f», lp.2i.3g.4g.5f., 1 a.2m.3g.4g.5f., lb.2m.3g.4g.5f., lf.2m.3g.4g.5f., lh.2m.3g.4g.5f, lj.2m.3g.4g.5f., lp.2m.3g.4g.5f., la.2o.3g.4g.5f, lb. 2o.3g.4g.5f., lf.2o.3g.4g.5f., 'lh.2o.3g.4g.5f., lj.2o.3g,4g.5f., lp.2o.3g.4g.5f., la. 2u.3g.4g.5f., lb.2u.3g.4g.5f„ If. 2u.3g.4g.5f, 1h.2u.3g.4g.5f, lj.2u.3g.4g.5f, lp.2u.3g.4g.5f., la.2y.3g.4g.5f», lb.2y.3g.4g.5f., If.2y.3g.4g.5f, lh.2y.3g.4g.5f, lj.2y.3g.4g.5f, lp.2y.3g.4g.5f», la.2a.3a.4h.5L, lb.2a,3a.4h.5f., lf.2a.3a.4h.5f», lh.2a.3a.4h.5f., lj.2a.3a.4h.5f„ lp.2a.3a.4h.5f, la.2b.3a.4h.5f, lb.2b.3a.4h.5f, lf.2b.3a.4h.5f, lh.2b.3a.4h.5f, lj.2b.3a.4h.5L, lp.2b.3a.4h.5f., la.2e.3a.4h.5f, lb. 2e.3a.4h.5f, 'lf.2e.3a.4h.5f., lh.2e.3a.4h.5f, lj.2e.3a.4h.5f, lp.2e.3a.4h.5f, la. 2f.3a.4h5f, lb.2f.3a.4h5f, lf.2f.3a.4h.5f, lh.2f.3a.4h.5f, lj.2f.3a.4h.5f, lp.2f3a.41t.5f, la.2i.3a.4h.5f, lb.2i.3a.4h.5f, If.2i.3a.4h.5f, lh.2i.3a.4h.5f, lj.2L3a.4h.5f, lp.2L3a.4h.5f, 1a.2m.3a.4h.5f, lb.2m.3a.4h.5f, lf.2m.3a.4h.5f, lh.2m.3a.4h.5f, lj.2m.3a.41i.5f., lp.2m.3a.4h.5f, la.2o.3a.4h.5f, lb.2o.3a.4h.5f, If2o.3a.4h.5f, lh.2o.3a.4h.5f, lj.2o.3a.4h.5f., lp.2o.3a.4h.5L, la.2u.3a.4h.5f, lb. 2u.3a.4Ji.5f, lf.2u.3a.4h.5f, lh.2u.3a.4h.5f., lj.2u.3a.4h.5f, lp.2u.3a.4h.5f, la. 2y.3a.41i.5f, lb.2y.3a.4h.5f, lf.2y.3a.4h.5f, lh.2y.3a.4h5f., lj.2y.3a.4h.5f, lp.2y.3a.4h.5f., la.2a.3b.4h.5f, lb.2a.3b.4h.5f, lf2a.3b.4h.5f, lh.2a.3b.4h.5f, lj.2a.3b.4h.5f, lp.2a.3b.4h.5f, la.2b.3b.4h.5f, lb.2b.3b.4h.5f, lf.2b.3b.4h.5f, lh.2b.3b.4h.5f, lj.2b.3b.4h.5f, 1p.2b.3b.4h.5f, la.2e.3b.4h.5f., lb.2e.3b.4h.5L, lf.2e.3b.4h.5f, lh.2e.3b.4h.5L, lj.2e.3b.4Ji.5f, lp.2e.3b.4h.5f, la.2L3b.4h.5f., lb. 2f3b.4h.5f, lf.2L3b.4h.5f, lh.2L3b.4h.5f, lj.2L3b.4h.5f, lp.2f.3b.4h.5f,

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2020203321 21 May 2020 la. 2i.3b.4h.5f, lb.2i.3b.4h,5f, lf.2L3b.4h.5f, lh.2L3b.4h.5f, lj.2L3b.4h.5f, lp.2i.3b.4h.5f., la.2m.3b.4h.5f, 1 b.2m.3b.4h.5f., lf.2m.3b.4h.5f, Jh.2m.3b.4h.5f., lj.2m.3b.4h.5f, lp.2m.3b.4h.5f, la.2o.3b.4h.5f, lb.2o.3b.4h.5f, lf.2o.3b.4h.5f, lh.2o.3b.4h.5f, lj.2o.3b.4h.5f, lp.2o,3b.4h.5f, 1a.2u.3b.4h.5f, lb.2u.3b.4h.5f, lf.2u.3b.4h.5f, 1h.2u.3b.4h.5f, lj.2u.3b.4h.5f, 'lp.2u.3b.4h.5f, la.2y.3b.4h.5f, lb. 2y.3b.4h.5f, If 2y.3b.4h.5f, lh.2y.3b.417.5f, lj.2y.3b.4h.5f, lp.2y.3b.4h.5f, la. 2a.3e.4h.5f, lb.2a.3e.4h.5f, l£2a.3e.4h.5f, lh.2a.3e.4h.5f, lj.2a.3e.4h.5f, lp.2a.3e.4h.5f, la.2b.3e.4h.5f, lb.2b.3e.4h.5f, lf2b.3e.4h.5f., lh.2b.3e.4h.5f, lj.2b.3e.4h.5f, lp.2b.3e.4h.5f, la.2e.3e.4h.5f, lb.2e.3e.4h.5f, lf.2e.3e.4h.5f, lh.2e.3e.4h.5f, lj.2e.3e.4h.5f, 1p.2e.3e.4h.5f, la.2f.3e.4h.5f, lb.2f3e.4h.5f, lf.2f.3e.4h.5f., lh.2f.3e.4h.5f, lj.2f.3e.4h.5f, lp.2f.3e.4h.5f, la.2L3e.4h.5f, lb. 2L3e.4h.5f, lf.2L3e.4h.5f, lh.2L3e.4h.5f, lj.2i.3e.4h.5f, lp.2L3e.4h.5f, la. 2m.3c.4h.5f, lb.2m.3e.4h.5f, lf2m.3e.4h.5f, lh.2m.3e.4h.5f, lj.2m.3e.4h.5f, lp.2m.3e.4h.5f, la.2o.3e.4h.5f, lb.2o.3e.4h.5f, lf2o.3e.4h.5f, lh.2o.3e.4h.5f, lj.2o.3e.4h.5f, lp.2o.3e.4h.5f, la.2Li.3e.4h.5f., lb.2u.3e.4h.5f, lf.2u.3e.4h.5f, lh.2u.3e.4h.5f, lj.2u.3e.4h.5f, lp.2u.3e.4h.5f, la.2y.3e.4h.5f, lb.2y.3e.4h.5f, lf2y.3e.4h.5f, lh.2y.3c.4h.5f, lj.2y.3c.4h.5f, lp.2y.3e.4h.5f, la.2a.3g.4h.5f, lb. 2a.3g.4h.5f, lf.2a.3g.4h.5f, lh.2a.3g.4h.5f, lj.2a.3g.4h.5f, lp.2a.3g.41i.5f., la. 2b.3g.4h.5f, lb.2b.3g.4h.5f, lf.2b.3g.4h.5f, lh.2b.3g.4h.5f, lj.2b.3g.4h.5f, lp.2b.3g.4h.5f, la.2e.3g.4h.5f, lb.2e.3g.4h.5f, lf.2e.3g.4h.5f, lh.2e.3g.4h.5f, lj.2e.3g.4h.5f, lp.2e.3g.4h.5f, la.2f.3g.4h.5f, lb.2f.3g.4h.5f, lf.2f.3g.41i.5f., Ih.2f3g.4h.5f, lj.2f.3g.4h,5f, lp.2f.3g.4h.5f, la.2i.3g.4h.5f, lb.2L3g.4h.5f, lf.2L3g.4h.5f, lh.2L3g.4h.5f, lj.2i.3g.4h.5f, lp.2L3g.4h.5f, la.2m.3g.4h.5f, lb. 2m.3g.4h.5f, lf.2m.3g.4h.5f., lh.2m.3g.4h.5f, lj.2m.3g.4h.5f, lp.2m.3g.4h.5f, la. 2o.3g.4h.5f, lb.2o.3g.4h.5f, lf2o.3g.4h.5f, lh.2o.3g.4h.5f, lj.2o.3g.4h.5f, lp.2o.3g.41i.5f, 1a.2u.3g.4h.5f, lb.2u.3g.4h.5f, lf2u.3g.4h.5f, lh.2u.3g.4h.5f, lj.2u.3g.4h.5f, lp.2u.3g.41i.5f, la.2y.3g.4h.5f, lb.2y.3g.4h.5f, lf.2y.3g.4h.5f, 1h.2y.3g.4h.5f, lj.2y.3g.4h.5f, lp.2y.3g.4h.5f, la.2a.3a.4L5f, lb.2a.3a.4i.5f, lf2a.3a.4i.5f, lh.2a.3a.4i.5f, lj.2a.3a.4L5f, lp.2a.3a.4i.5f, la.2b.3a.4i.5f, lb. 2b.3a.4i.5f, lf.2b.3a.4L5f, lh.2b.3a.4i.5f, lj.2b.3a.4L5£, lp.2b.3a.4i.5f, la. 2e.3a.4L5f, lb.2e.3a.4i.5f, lf2e.3a.4L5f, lh.2e.3a,4i.5f, lj.2e.3a.4L5f, lp.2c.3a.4i.5f, la.2f.3a.4L5f, lb.2f.3a.4i.5f, If 2f3a.4i.5f, lh.2f.3a.4i.5f, lj.2f.3a.4L5E, lp.2f.3a.4L5f, la.2i.3a.4i.5f, 1b.2i.3a.4i.5f, 1 f2i.3a.4i.5f, lh.2i.3a.4i.5f, lj.2i.3a.4i.5f., lp.2i.3a.4i.5f, la.2m.3a.4i,5f, lb.2m.3a.4L5f, lf.2m.3a.4i.5f, lh.2m.3a.4L5f, lj.2m.3a.4i.5f, lp.2m.3a.4i.5f, la.2o.3a.4L5f, lb. 2o.3a.4i.5f, lf.2o.3a.4L5f, lh.2o.3a.4i.5f, lj.2o.3a.4L5f, lp.2o.3a.4L5f, 1a.2u.3a.4i.5f., lb.2u.3a.4L5f, l£2u.3a.4L5f, lh.2u.3a.4L5f, lj.2u.3a.4i.5f, lp.2u.3a.4L5f, la.2y.3a.4L5f, lb.2y.3a.4i.5f, lf.2y.3a.4i.5f, lh.2y.3a.4L5f, lj.2y.3a.4i.5f, lp.2y.3a.4i.5f, la.2a.3b.4L5f, lb.2a.3b.4i.5f, lf.2a.3b.4i.5f, lh.2a.3b.4i.5f, lj.2a.3b.4i.5f, lp.2a.3b.4i.5f, la.2b.3b.4L5f, lb.2b.3b.4L5f, lf.2b.3b.4L5f, lh.2b.3b.4L5f, lj.2b.3b.4i.5f, lp.2b.3b.4L5f, la.2e.3b.4i.5f,

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2020203321 21 May 2020 lb.2e.3b.4i.5f., l£2e.3b.4L5£, lh.2e.3b.4i.5£, lj.2e.3b.4i.5f., lp.2e.3b.4i.5E, la. 2£3b.4L5£, Jb.2f.3b.4i.5f., lf.2f.3b.4i.5E, lh.2f.3b.4i.5f„ lj.2f.3b.4i.5£, lp.2£3b.4i.5£, la.2i.3b.4i.5E, lb.2i.3b.4i.5E, l£2i.3b.4i.5E, lh.2i.3b.4i.5£, lj.2i.3b.4i.5E, lp.2i.3b.4i.5E, la.2m.3b.4i.5E, lb.2m.3b.4i.5E, lf.2m.3b.4i.5f., lh.2m.3b.4i.5E, lj.2m.3b.4i.5E, lp.2m.3b.4i.5E, la.2o.3b.4L5E, lb.2o.3b.4i.5E, lf.2ct.3b.4i.5E, lh.2o.3b.4i.5E, lj.2o.3b.4i.5E, lp.2o.3b.4i.5E, la.2u.3b.4i.5E, lb. 2u.3b.4i.5£, lf.2u.3b.4i.5f., lh.2u.3b.4i.5£, lj.2u.3b.4i.5E, lp.2u.3b.4i.5£, la. 2y.3b.4i.5E, lb.2y.3b.4i.5E, lf.2y.3b.4i.5£, lh.2y.3b.4i.5E, lj.2y.3b.4i.5L, lp.2y.3b.4i.5E, la.2a.3e.4i.5E, lb.2a.3e.4i.5E, lf.2a.3e.4i.5E, lh.2a.3e.4i.5E, lj.2a.3e.4L5E, lp.2a.3e.4i.5E, la.2b.3e.4i.5E, lb.2b.3e.4i.5E, lf.2b.3e.4i.5E, lh.2b.3e.4i.5£, lj.2b.3e.4i.5£, lp.2b.3c.4L5£, Ia.2c.3e.4i.5£, lb.2c.3e.4i.5f., l£2e.3e.4i.5£, lh.2e.3e.4i,5f., lj.2e.3e,4i.5£, lp.2e.3e.4i,5£, la.2£3e.4i.5£, lb. 2f.3e.4i.5E, lf.2£3e.4i.5£, lh.2£3e.4i.5£, lj.2£3e.4i.5£, lp.2£3e.4i.5£, la.2L3e.4i.5E, lb.2i.3e.4i.5£, l£2i.3e.4L5£, lh.2i.3e.4i.5E, lj.2i.3e.4i.5£, lp.2i.3e.4L5£, la.2m.3e.4i.5£, lb.2m.3e.4i.5£, l£2m.3e.4i.5£, lh.2m.3c.4i.5£, 1j.2m.3e.4L5f., 1p.2m.3e.4i.5£, la.2o.3e.4L5f., lb.2o.3e.4i.5£, lf.2o.3e.4i.5£, lh.2o.3e.4i.5£, lj.2o.3e.4i.5£, lp.2o.3e.4i.5£, la.2u.3e.4i.5£, lb.2u.3e.4L5E, lf.2u.3e.4i.5£, lh.2u.3e.4i.5£, lj.2u.3e.4i.5E, lp.2u.3e.4i.5£, la.2y.3e.4L5E, lb.2y.3e.4L5£, l£2y.3e.4L5£, lh.2y.3e.4i.5£, lj.2y.3e.4i.5£, lp.2y.3e.4i.5£, la.2a.3g.4i.5£, lb-2a.3g.4i.5E, lf.2a.3g.4i.5E, lh.2a.3g.4L5f., lj.2a.3g.4i.5f., lp,2a.3g.4i.5£, la. 2b.3g.4i.5£, lb.2b.3g.4i.5E, lf.2b.3g.4i.5E, lh.2b.3g.4L5£, lj.2b.3g.4i.5£, lp.2b.3g.4i.5£, la.2e.3g.4i.5f., lb.2e.3g.4i.5f., lf.2e.3g.4i.5£, lh.2e.3g.4i.5£, lj.2e.3g.4i.5E, lp.2e.3g.4i.5£, la.2£3g.4i.5£, lb.2f.3g.4L5f., l£2£3g.4L5£, lh.2£3g.4L5£, lj.2f.3g.4i.5£, lp.2f.3g.4i.5£, la.2i.3g.4i.5£, lb.2L3g.4L5E, lf.2i.3g.4i.5E, lh.2i.3g.4i.5f., lj.2i.3g.4i.5E, lp.2i.3g.4i.5f., la.2m.3g.4L5£, lb, 2m.3g.4L5£, lf.2m.3g.4i.5£, lh.2m.3g.4i.5£, lj.2m.3g.4i.5£, lp.2m.3g.4i.5£, la. 2o.3g.4i.5£, 1b.2o.3g.4i.5£, l£2o.3g.4L5£, lh.2o.3g,4i.5£, lj.2o.3g.4i.5E, lp.2o.3g.4i.5E, la.2u.3g.4i.5£, lb.2u.3g.4i.5E, If.2u.3g.4i.5f., lh.2u.3g.4i.5E, lj.2u.3g.4i.5f,, lp.2u,3g.4i.5£, la.2y.3g.4i.5£, lb.2y.3g.4L5£, l£2y.3g.4i.5£, lh.2y.3g.4i.5£, lj.2y.3g.4i.5£, lp.2y.3g.4i.5£, la.2a.3a.4a.5g., lb.2a.3a.4a.5g., l£2a.3a.4a.5g., lh.2a.3a.4a.5g., lj.2a.3a.4a.5g., lp.2a.3a.4a.5g., la.2b.3a.4a.5g., lb. 2b.3a.4a.5g., lf.2b.3a.4a.5g., lh.2b.3a.4a.5g., lj.2b.3a.4a.5g., lp.2b.3a.4a.5g., 1 a.2e.3a.4a.5g., lb.2e.3a.4a.5g., l£2e.3a.4a.5g., lh.2e.3a.4a.5g., lj.2e.3a.4a.5g., lp.2e.3a.4a.5g., la.2E3a.4a.5g., lb.2E3a.4a.5g., lf.2£3a.4a.5g., lh.2£3a.4a.5g., lj.2E3a.4a.5g., lp.2f.3a.4a.5g., 1a.2i.3a.4a.5g., lb.2i.3a.4a,5g., 1E2i.3a.4a.5g., lh.2i.3a.4a.5g., lj.2i.3a,4a.5g., lp.2L3a.4a.5g., la.2m.3a.4a.5g., lb.2m.3a.4a.5g., lf.2m.3a.4a.5g., lh.2ni.3a.4a.5g., lj.2m.3a.4a.5g., lp.2m.3a.4a.5g., la.2o.3a.4a.5g., lb.2o.3a.4a.5g., l£2o.3a.4a.5g., lh.2o.3a.4a.5g., lj.2o.3a.4a.5g., lp.2o.3a.4a.5g., la.2u.3a.4a.5g., lb.2u.3a.4a.5g., lf.2u.3a.4a.5g., lh.2u.3a.4a.5g., lj.2u.3a.4a.5g., lp.2u.3a.4a.5g., 1a.2y.3a.4a,5g., lb,2y.3a.4a.5g., l£2y.3a.4a.5g., lh.2y.3a.4a.5g., lj.2y.3a,4a.5g., lp.2y.3a.4a.5g., la.2a.3b.4a.5g., lb.2a.3b.4a.5g., lf.2a.3b.4a.5g.,

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2020203321 21 May 2020 lh.2a.3b.4a.5g., lj.2a.3b.4a.5g., lp.2a.3b.4a.5g., la.2b.3b.4a.5g., lb.2b.3b.4a.5g., lf.2b.3b.4a.5g., Ih.2b.3b.4a,5g., 1j.2b.3b.4a.5g., Ip.2b.3b.4a.5g., la.2c.3b.4a.5g., lb.2e.3b.4a.5g., lf.2e.3b.4a.5g„ lh.2e.3b.4a.5g», lj.2e.3b.4a.5g., lp.2e.3b.4a.5g., la. 2f.3b.4a.5g., lb.2f.3b.4a.5g., lf.2f.3b.4a.5g., lh.2f.3b.4a.5g., lj.2f.3b.4a.5g., 1p.2f.3b.4a.5g., la.2i.3b.4a.5g., lb.2i.3b.4a.5g., lf.2i.3b.4a.5g., lh.2i.3b.4a.5g., lj.2i.3b.4a.5g„ lp.2i.3b.4a.5g., la.2m.3b.4a.5g., lb.2m.3b.4a.5g., 1f.2m.3b.4a.5g„ lh.2m.3b.4a.5g., lj.2m.3b.4a.5g,, lp.2m.3b.4a.5g., la.2o.3b.4a,5g., lb.2o,3b.4a.5g., lf.2o.3b.4a.5g., lh.2o.3b.4a.5g., lj.2o.3b.4a.5g., lp.2o.3b.4a.5g., la.2u.3b.4a.5g., lb. 2u.3b.4a.5g., lf.2u.3b.4a.5g„ 1 h.2u.3b.4a.5g., lj.2u.3b.4a.5g., lp.2u.3b.4a,5g„ la. 2y.3b.4a.5g., lb.2y.3b.4a.5g„ lf.2y.3b.4a.5g., lh.2y.3b.4a.5g., lj.2y.3b.4a.5g., lp.2y.3b.4a.5g., la.2a.3e.4a.5g., lb.2a.3e.4a.5g., lf.2a.3e.4a.5g., lh.2a.3e.4a.5g., lj.2a.3c.4a.5g., lp.2a.3e.4a.5g», la.2b.3e.4a.5g., lb.2b.3e.4a.5g., lf.2b.3e.4a.5g., lh.2b.3e.4a.5g., Ij. 2b .3c.4a.5g., lp.2b.3e.4a.5g., la.2e.3e.4a.5g., lb.2e.3e.4a.5g., lf.2e.3e.4a.5g., lh.2e.3e.4a.5g., lj.2e.3e.4a.5g., lp.2e.3c.4a.5g„ la.2f.3c.4a.5g., lb. 2f.3e.4a.5g.,lf.2f.3e.4a.5g., lh.2f.3e.4a.5g., lj.2f.3e.4a.5g., lp.2f.3e.4a.5g., la. 2i.3e.4a.5g., lb.2i.3e.4a.5g., lf.2i.3e.4a.5g., lh.2i.3e.4a.5g., lj.2i.3e.4a.5g., lp.2i.3e.4a.5g., la.2m.3c.4a.5g., lb.2m.3e.4a.5g., lf.2m.3e.4a.5g., lh.2m.3e.4a.5g», lj.2m.3e.4a.5g., lp.2m.3e.4a.5g., la.2o.3e.4a.5g., lb.2o.3c.4a.5g., lf.2o.3c.4a.5g., lh.2o.3e.4a.5g., lj.2o.3e.4a.5g., lp.2o.3e.4a.5g., la.2u.3e.4a.5g., Ib.2u.3e.4a.5g., lf.2u.3e.4a,5g., lh.2u.3e.4a.5g„ lj.2u.3e.4a.5g., lp.2u.3e.4a.5g., la.2y.3e.4a.5g., lb. 2y.3e.4a.5g., lf.2y.3e.4a.5g., lh.2y.3e.4a.5g., lj.2y.3e.4a,5g., lp.2y.3e.4a.5g., la.2a.3g.4a.5g., lb.2a.3g.4a.5g., lf.2a.3g.4a.5g., lh.2a.3g.4a.5g., lj.2a.3g.4a.5g., lp.2a.3g.4a.5g., la.2b.3g.4a.5g., lb.2b.3g.4a.5g., lf.2b.3g.4a.5g., lh.2b.3g.4a.5g., lj.2b.3g.4a.5g., lp.2b.3g.4a.5g., la.2e.3g.4a.5g., lb.2e.3g.4a.5g., lf.2e.3g.4a.5g., lh.2e.3g.4a.5g», lj.2e.3g.4a.5g., lp.2e,3g.4a.5g., 1a.2f.3g.4a.5g., lb.2f.3g.4a.5g., lf.2f.3g.4a.5g., lh.2f.3g.4a.5g., lj.2f.3g.4a,5g., lp.2f.3g.4a.5g., la.2i.3g.4a.5g., lb .2i.3g .4a. 5g., lf.2L3g.4a.5g., lh.2i,3g.4a.5g., lj.2i.3g.4a.5g., lp.2i.3g.4a.5g., la. 2m.3g.4a.5g., lb.2m .3g.4a. 5g., If.2m.3g.4a.5g., lh.2m.3g.4a.5g., lj.2m.3g.4a.5g., lp.2m.3g,4a.5g., la.2o.3g.4a.5g., lb.2o.3g.4a.5g., lf.2o.3g.4a,5g., lh.2o.3g.4a.5g., lj.2o.3g.4a.5g., lp.2o.3g.4a.5g., la.2u.3g.4a.5g., lb.2u.3g,4a.5g„ lf.2u.3g.4a.5g., lh.2u.3g,4a.5g., lj.2u,3g.4a.5g., lp.2u.3g.4a.5g., la.2y.3g.4a.5g., lb.2y.3g.4a.5g., lf.2y.3g.4a.5g., lh.2y.3g.4a.5g., lj.2y.3g.4a.5g., lp.2y.3g.4a.5g., la.2a.3a.4d.5g., lb. 2a.3a.4d.5g., lf.2a.3a.4d.5g», lh.2a.3a.4d.5g., lj.2a.3a.4d.5g., lp.2a.3a.4d.5g., la. 2b.3a.4d.5g., lb.2b.3a.4d.5g., lf.2b.3a.4d.5g., lh.2b.3a.4d.5g., lj.2b.3a.4d.5g., lp.2b.3a.4d,5g., la.2e.3a.4d.5g., lb.2e.3a.4d.5g., lf.2e.3a.4d.5g», lh.2e.3a.4d.5g», lj.2e.3a.4d.5g., lp.2e.3a.4d.5g., la.2f.3a.4d.5g„ lb.2f.3a.4d.5g., lf.2f.3a.4d.5g», lh.2f.3a.4d.5g», lj.2f.3a.4d.5g., lp.2f.3a.4d.5g., la.2i.3a.4d.5g., lb,2i.3a.4d,5g., lf.2i.3a.4d.5g., lh.2i,3a.4d.5g., lj.2i.3a.4d.5g», lp.2i.3a.4d.5g., la.2m.3a.4d.5g., lb. 2m.3a.4d.5g., lf.2m.3a.4d.5g., lh,2m.3a.4d.5g., lj.2m.3a.4d.5g., lp.2m.3a.4d.5g., la.2o,3a.4d.5g., lb.2o.3a.4:d,5g., lf.2o.3a.4d.5g., lh.2o.3a.4d.5g., lj.2o.3a.4d.5g., lp.2o.3a.4d.5g., la.2u.3a.4d.5g., lb.2u.3a.4d.5g., lf.2u.3a.4d.5g., lh.2u.3a.4d.5g.,

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2020203321 21 May 2020 lj.2u.3a.4d.5g., lp.2u.3a.4d.5g., la.2y.3a.4d.5g., lb.2y.3a.4d.5g., lf.2y.3a.4d.5g., lh.2y.3a.4d.5g„ lj.2y.3a.4d.5g., lp.2y.3a.4d.5g., la.2a.3b.4d.5g., lb.2a.3b.4d.5g., lf.2a.3b.4d.5g., lh.2a.3b.4d.5g., lj.2a.3b.4d.5g., lp.2a.3b.4d.5g., la.2b.3b.4d.5g., lb.2b.3b.4d.5g„ lf.2b.3b.4d.5g., lh.2b.3b.4d.5g., lj.2b.3b.4d.5g., lp.2b.3b.4d.5g., la. 2e.3b.4d.5g., 1b.2c.3b.4d.5g., lf.2e.3b.4d.5g., lh.2e.3b.4d.5g., lj.2e.3b.4d.5g., lp.2e.3b.4d.5g., la.2f.3b.4d.5g., lb.2f.3b.4d.5g., lf.2f.3b.4d.5g., lh.2f.3b.4d.5g., lj.2f.3b.4d.5g., lp.2f.3b.4d.5g., la.2i.3b.4d.5g., lb.2i.3b.4d.5g_, 1f.2i.3b.4d.5g., lh.2i.3b.4d.5g., lj.2i.3b.4d.5g., lp.2i.3b.4d.5g., la.2m.3b.4d.5g., lb.2m.3b.4d.5g., lf.2m.3b.4d.5g., lh.2m.3b.4d.5g., lj.2ni.3b.4d.5g., lp.2m.3b.4d.5g., la.2o.3b.4d.5g., lb. 2o.3b.4d.5g., lf,2o,3b,4d.5g., lh.2o.3b.4d.5g., lj.2o.3b.4d.5g., lp.2o.3b.4d.5g., la_2u.3b.4d.5 g., lb.2u.3b.4d.5g., lf.2u.3b.4d.5g., lh.2u.3b.4d.5g., lj.2u.3b.4d.5g., lp.2u.3b.4d.5g., la.2y.3b.4d.5g., lb.2y.3b.4d.5g., lf.2y.3b.4d.5g., lh.2y.3b.4d.5g., lj.2y.3b.4d.5g., lp.2y.3b.4d.5g., la.2a.3e.4d.5g., lb.2a.3e.4d.5g., lf.2a,3e.4d.5g., lh_2a.3e.4d.5g., lj.2a.3e.4d.5g., lp.2a.3e.4d.5g., la.2b.3e.4d.5g., lb.2b.3e.4d.5g., lf.2b.3e.4d.5g., lh.2b.3e.4d.5g., lj.2b.3e.4d.5g., lp.2b.3e.4d.5g_, la.2e.3e.4d.5g., lb.2e.3e.4d.5g_, lf.2e.3e.4d.5g_, lh.2e.3c.4d.5g., lj.2e.3e.4d.5g., lp.2e.3e.4d.5g., la. 2f.3e.4d.5g_, lb.2f.3e.4d.5g., lf.2f.3e.4d.5g., lh.2f.3e.4d.5g., lj.2f.3e.4d.5g_, lp.2f.3e.4d.5g., la.2i.3e.4d.5g., lb.2i.3e.4d.5g., lf.2i.3e.4d.5g., lh.2i.3e.4d.5g„ lj.2i.3e.4d.5g., lp.2i.3e.4d.5g„ la.2m.3e.4d.5g., lb.2m.3e.4d,5g., lf.2m.3c.4d.5g., lh.2m.3e.4d.5g., lj.2m.3e.4d.5g_, lp.2m.3e.4d.5g., la.2o.3e.4d.5g., lb.2o.3e.4d.5g., lf.2o.3e.4d.5g., lh.2o.3e.4d.5g., lj.2o.3e.4d.5g., lp.2o.3e.4d.5g_, la.2u.3e.4d.5g., lb. 2u.3e.4d,5g., lf.2u.3e.4d.5g., lh.2u.3e.4d.5g., lj.2u.3e.4d.5g., lp.2u.3e.4d.5g., la. 2y.3e.4d.5g., lb.2y.3e.4d.5g., lf.2y.3e.4d.5g., lh.2y.3e.4d.5g., lj.2y.3e.4d.5g., lp.2y.3e.4d.5g., la.2a.3g.4d.5g., lb.2a.3g,4d.5g._r lf.2a.3g.4d.5g_, lh.2a.3g.4d.5g„ 1j.2a.3g.4d.5g., lp.2a.3g.4d.5g„ la.2b.3g.4d.5g., 'lb.2b.3g.4d.5g., lf.2b.3g.4d.5g., lh.2b.3g.4d.5g., lj.2b.3g.4d.5g., lp.2b.3g.4d.5g_, la.2e.3g.4d.5g., lb.2e.3g.4d.5g., lf.2c.3g.4d.5g., lh.2e.3g.4d.5g., lj.2e.3g.4d.5g., lp.2e.3g.4d.5g., Ia.2f.3g.4d.5g., lb. 2f.3g.4d.5g., lf.2f.3g.4d.5g., lh.2f.3g.4d.5g„ lj.2f.3g.4d.5g., lp.2f,3g.4d_5g., la. 2i.3g,4d.5g., lb.2i.3g.4d.5g., lf.2i.3g.4d.5g_, lh.2i.3g.4d.5g_, lj.2i.3g.4d.5g., lp.2i.3g.4d.5g., la.2m.3g.4d.5g., lb.2m.3g.4d.5g., lf.2m.3g.4d.5g., Ih.2m.3g.4d.5g., lj.2m.3g.4d.5g., lp.2m.3g.4d.5g_, la.2o.3g.4d.5g„ lb.2o.3g.4d.5g., lf.2o.3g.4d.5g., lh.2o.3g.4d.5g., lj.2o.3g.4d.5g., lp.2o.3g.4d.5g., la.2u.3g.4d.5g., lb.2u.3g.4d.5g., lf.2u.3g.4d.5g., lh.2u.3g.4d.5g_, lj.2u._3g.4d.5g., lp.2u.3g.4d.5g_, la.2y.3g.4d.5g_, lb. 2y.3g.4d.5g., lf.2y.3g.4d.5g_, lh.2y.3g.4d.5g., lj.2y.3g.4d.5g., 'Ip.2y.3g.4d.5g., la. 2a.3a.4f.5g., lb.2a.3a.4f.5g., lf.2a.3a.4f.5g„ lh.2a.3a.4f.5g„ lj.2a.3a.4f.5g., 1p.2a.3a.4f.5g., la.2b.3a.4f.5g., lb.2b.3a.4f.5g,, lf.2b.3a.4f.5g., lh.2b.3a.4f.5g., lj.2b.3a.4f.5g_, 1p.2b.3a.4f.5g., la.2e.3a.4f.5g., lb.2e.3a.4f.5g_, lf.2e.3a.4f.5g_, lh.2e.3a.4f.5g., lj.2e,3a.4f.5g„ lp.2e.3a.4f.5g., la.2f.3a_4f.5g., lb.2f.3a.4f.5g., lf.2f.3a.4f.5g., lh.2f.3a,4f.5g., lj.2f.3a.4f_5g., lp.2f,3a.4f.5g., la.2i.3a.4f.5g., lb. 2i.3a.4f.5g., lf.2i.3a.4f.5g., lh.2i.3a.4f.5g., lj.2i.3a.4f.5g„ lp.2i.3a.4f.5g., la.2m.3a.4f.5g., lb.2m.3a.4f.5g., lf.2m.3a.4f.5g., lh.2m,3a.4f.5g., lj_2m.3a.4f.5g.,

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2020203321 21 May 2020 lp.2m.3a.4f.5g., la.2o.3a.4f.5g., lb.2cL3a.4f.5g., lf.2o.3a.4f.5g., lh.2o.3a.4f.5g., lj.2o.3a.4f.5g., lp.2o.3a.4f.5g., la.2u.3a.4f.5g., lb.2u.3a.4f.5g., lf.2u.3a.4f.5g., lh.2u.3a.4f.5g», lj.2u.3a.4f.5g., lp.2u.3a.4f.5g., la.2y.3a.4f.5g., lb.2y.3a.4f.5g., lf.2y.3a.4f.5g., lh.2y.3a.4f.5g., lj.2y.3a.4f.5g., lp.2y.3a.4f.5g., la.2a.3b.4f.5g., lb.2a.3b.4f.5g„ lf.2a.3b.4f.5g., lh.2a.3b.4f.5g., lj.2a.3b.4f.5g., lp.2a.3b.4f.5g„ la. 2b.3b.4f.5g., lb.2b.3b.4f.5g., lf.2b.3b.4f.5g., lh.2b.3b.4f.5g., lj.2b.3b.4f.5g., lp.2b.3b.4f.5g., la.2c.3b.4f.5g., lb.2e.3b.4f.5g., lf.2e.3b.4f.5g., lh.2e.3b.4f.5g., Ij.2e.3b.4f.5g., lp.2e.3b.4f.5g., la.2f.3b.4f.5g., lb.2f.3b.4f.5g„ lf.2f.3b.4f.5g., lh.2f.3b.4f.5g., lj.2f.3b.4f.5g„ lp.2f.3b.4f.5g„ 1 a.2i.3b.4f.5g., lb.2i.3b.4f.5g„ lf.2i.3b.4f.5g., lh.2i.3b.4f.5g., lj.2i.3b.4f.5g„ lp.2i.3b.4f.5g., la.2m.3b.4f.5g., lb. 2m.3b.4f.5g., lf.2m.3b.4f.5g., lh.2m.3b.4f.5g., lj.2m.3b.4f.5g., lp.2m.3b.4f.5g., la. 2o.3b.4f.5g., lb.2o.3b.4f.5g., lf.2o.3b.4f.5g., lh.2o.3b.4f.5g., lj.2o.3b.4f.5g., lp.2o.3b.4f.5g., la.2u.3b.4f.5g., lb.2u.3b.4f.5g., lf.2u.3b.4f.5g., lh.2u.3b.4f.5g., lj.2u.3b.4f.5g., lp.2u.3b.4f.5g., la.2y.3b.4f.5g., lb.2y.3b.4f.5g., lf.2y.3b.4f.5g., lh.2y.3b.4f.5g., lj'.2y.3b.4f.5g., lp,2y.3b,4f.5g., la.2a.3e.4f.5g., lb.2a.3e.4f.5g., lf.2a.3e.4f.5g., lh.2a.3e.4f.5g., lj.2a.3e.4f.5g., lp.2a.3e.4f.5g., la.2b.3e.4f.5g., lb. 2b.3e.4f.5g., lf.2b.3e.4f.5g., lh.2b.3e.4f.5g., lj.2b.3c.4f.5g., lp.2b.3e.4f.5g„ la. 2c.3c.4f.5g., lb.2e.3e.4f.5g., lf.2e.3e.4f.5g., lh.2e.3e.4f.5g., lj.2e.3e.4f.5g., 1p.2e.3e.4f.5g., la.2f.3e.4f.5g., lb.2f.3e.4f,5g., lf.2f.3e.4f.5g., lh.2t.3e.4f.5g., lj.2f.3e.4f.5g., lp.2f.3e.4f.5g,, 1 a.2i.3e.4f.5g., lb.2i.3e.4f.5g., lf.2i.3e.4f.5g., lh.2i.3e.4f.5g., lj,2i.3e.4f.5g„ lp,2i.3e.4f.5g., la.2m.3e.4f.5g., lb.2m.3e.4f.5g., lf.2m.3e.4f.5g., lh.2m.3e.4f.5g., lj.2m.3e.4f.5g., lp,2m.3e.4f.5g., la.2o.3e.4f.5g., lb. 2o.3e.4f.5g., lf.2o.3e.4f.5g„ lh.2o.3c.4f.5g., lj.2o.3e.4f.5g., lp.2o.3e.4f.5g., la. 2u.3e.4f.5g., lb.2u.3e.4f.5g., lf.2u.3e.4f.5g., lh.2u.3e.4f.5g., lj.2u.3c.4f.5g., lp.2u.3c.4f.5g., la.2y.3e.4f.5g., lb.2y.3e.4f.5g., lf.2y.3e.4f.5g., lh.2y.3e.4f.5g., lj.2y.3e.4f.5g„ lp.2y.3c.4f.5g., la.2a.3g,4f.5g., lb.2a.3g.4f.5g., lf.2a.3g.4f.5g., lh.2a.3g.4f.5g., lj.2a.3g.4f.5g., lp.2a.3g.4f.5g., la.2b.3g.4f.5g., lb.2b.3g.4f.5g., lE2b.3g.4f.5g., lh.2b.3g.4f.5g., lj.2b,3g.4f.5g., lp.2b.3g.4f.5g., la.2e.3g.4f.5g., lb. 2e.3g.4f.5g., lf.2e.3g.4f.5g., lh.2e.3g.4f.5g., lj.2e.3g.4f.5g., lp.2e.3g.4f.5g., la. 2f.3g.4f.5g., lb.2f.3g.4f.5g., lf.2f.3g.4f.5g., lh.2f.3g.4f.5g., lj.2f.3g.4f.5g., lp.2f.3g.4f.5g., la.2i.3g.4f.5g., lb.2i.3g.4f.5g., lf.2i.3g.4f.5g., lh.2i.3g.4f.5g., lj.2i.3g.4f.5g., lp.2i.3g.4f.5g., la.2m.3g.4f.5g., lb.2m.3g.4f.5g., lf.2m.3g.4f.5g., lh.2m.3g.4f.5g., lj.2m.3g.4f.5g., lp.2m.3g.4f.5g., la.2o.3g.4f.5g., lb.2o.3g.4f.5g., lfllo.3g.4f.5g., lh.2o.3g.4f.5g., lj.2o.3g.4f.5g., lp.2o.3g.4f.5g., la.2u.3g.4f.5g., lb. 2u.3g.4f.5g., lf.2u.3g.4f.5g., lh.2u.3g.4f.5g„ lj.2u.3g.4f.5g., lp.2u.3g.4f.5g„ la. 2y.3g.4f.5g., lb.2y.3g,4f.5g., lf.2y.3g.4f.5g., lh.2y.3g.4f.5g., lj.2y.3g.4f.5g-, lp.2y.3g.4f.5g., la.2a.3a.4g.5g., lb.2a.3a.4g.5g., lf.2a.3a.4g,5g., lh.2a.3a.4g.5g., lj.2a.3a.4g.5g., lp.2a.3a.4g,5g., la.2b.3a.4g.5g., lb.2b,3a.4g.5g., lf.2b.3a.4g.5g., lh.2b.3a.4g.5g., lj.2b.3a.4g.5g., lp.2b.3a.4g.5g», la.2e.3a.4g.5g., lb.2e.3a.4g.5g., lf.2e.3a.4g.5g., lh.2e.3a.4g.5g., lj.2e.3a.4g.5g., lp.2e.3a.4g.5g,, la.2f.3a.4g.5g., lb. 2f.3a.4g.5g., lf.2f.3a.4g.5g., lh.2f.3a.4g.5g., lj.2f.3a.4g.5g., lp.2f.3a.4g.5g„

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2020203321 21 May 2020 la. 2L3a.4g.5g., lb.2L3a.4g.5g., lf.2i.3a.4g.5g., lh.2i.3a.4g.5g., lj.2i.3a.4g.5g., lp.2i.3a.4g.5g., la.2m.3a.4g.5g_, lb.2m.3a.4g.5g., lf.2m.3a.4g.5g., lh.2m.3a.4g.5g., lj.2m.3a.4g.5g., lp.2m.3a.4g.5g., la.2o.3a.4g.5g., lb.2o.3a.4g.5g_, lf.2o.3a.4g.5g., lh.2o.3a.4g.5g., lj.2o.3a.4g.5g., lp.2o.3a.4g.5g., la.2u.3a.4g.5g_, lb.2u.3a.4g.5g., lf.2u.3a.4g.5g_, lh.2u.3a.4g.5g., lj.2u.3a.4g.5g_, lp.2u.3a.4g.5g_, la.2y.3a.4g.5g., lb. 2y.3a.4g.5g., lf.2y.3a.4g.5g., lh.2y.3a.4g.5g., lj.2y.3a.4g.5g., lp.2y.3a.4g.5g., la. 2a.3b.4g.5g., lb.2a.3b.4g.5g., lf.2a.3b.4g.5g., lh.2a.3b.4g.5g., lj.2a.3b.4g.5g., lp.2a.3b.4g,5g., la.2b.3b.4g.5g., lb.2b.3b.4g.5g., lf.2b.3b.4g.5g., lh.2b.3b.4g.5g., lj.2b.3b.4g.5g_, lp.2b.3b.4g.5g., la.2e.3b.4g.5g., lb.2e.3b.4g.5g., If.2e.3b.4g.5g., lh.2e.3b_4g,5g,, lj.2e.3b.4g.5g., lp.2e.3b,4g.5g., la.2f.3b.4g.5g., lb.2f.3b.4g.5g., lf.2f.3b.4g.5g., lh.2f.3b.4g.5g., lj.2f.3b.4g.5g., lp.2f.3b.4g.5g., la.2i.3b.4g.5g., lb. 2L3b.4g.5g., lf.2L3b.4g.5g., lh.2i.3b.4g.5g., lj.2i.3b.4g.5g., lp.2L3b.4g.5g., la. 2m.3b.4g.5g., lb.2m.3b.4g.5g., lf.2m.3b.4g,5g., lh.2m.3b,4g.5g., lj.2m.3b.4g.5g., lp.2m.3b.4g.5g., la.2o.3b.4g.5g., lb.2o.3b.4g.5g., lf.2o.3b.4g.5g., lh.2o.3b.4g.5g., lj.2o.3b.4g.5g_, lp.2o.3b.4g,5g., la.2u.3b.4g.5g., lb.2u.3b.4g.5g., lf.2u.3b.4g.5g_, lh.2u.3b.4g.5g., lj.2u.3b.4g.5g_, lp.2u.3b.4g.5g_, la.2y.3b.4g.5g., lb.2y.3b.4g.5g., lf.2y.3b.4g.5g., lh.2y.3b.4g.5g., lj.2y.3b.4g.5g., lp.2y.3b.4g.5g_, la.2a.3e.4g.5g,, lb. 2a.3e.4g.5g., lf.2a.3e.4g.5g_, lh.2a.3e.4g.5g., lj.2a.3e.4g.5g_, lp.2a.3e.4g.5g., la. 2b.3e.4g.5g., lb.2b.3e.4g.5g., lf.2b.3e.4g,5g., lh.2b.3e.4g.5g_, lj.2b,3e.4g,5g_, lp_2b.3e.4g.5g., la.2e.3e.4g.5g., lb.2e.3e.4g.5g., 1 f.2e.3e.4g.5g., lh.2c.3e.4g.5g_, lj.2e.3e.4g.5g_, lp.2e.3e.4g.5g_, la.2f.3e.4g.5g„ lb.2f.3e.4g,5g., lf.2f.3e.4g.5g., lh.2f.3e.4g.5g., lj.2f.3e.4g.5g., lp.2f.3c.4g.5g., 'la.2L3c.4g.5g., lb.2i.3e.4g.5g., lf.2L3e.4g.5g., lh.2i.3e.4g,5g., lj.2i.3e.4g.5g., lp.2i.3e,4g.5g„ la.2m.3e.4g,5g., lb. 2m.3e.4g.5g_, lf.2m.3e.4g.5g., lh.2m.3e.4g.5g., lj,2m.3e.4g.5g., lp.2m.3e.4g.5g_, la. 2o.3e.4g.5g., lb.2o.3e.4g.5g_, lf.2o.3e.4g.5g_, lh.2o.3e.4g.5g_, lj.2o.3e.4g.5g„ lp.2o_t3e.4g.5g., la.2u.3c.4g.5g., lb.2u.3e.4g.5g_, lf.2ii.3e.4g.5g., lh.2u.3e.4g.5g., lj.2u.3e.4g.5g., lp.2u.3e.4g.5g., la.2y.3e.4g.5g., lb.2y.3e.4g.5g., lf.2y.3e.4g.5g_, lh.2y.3e.4g.5g., lj.2y.3e.4g.5g., Ip.2y.3e.4g.5g_, la.2a.3g.4g.5g_, lb,2a.3g_4g.5g„ lf.2a.3g.4g.5g„ lh.2a.3g.4g.5g_, lj.2a.3g.4g.5g_, lp.2a.3g.4g.5g., 1a.2b.3g.4g.5g_, lb. 2b.3g.4g.5g., lf.2b.3g.4g.5g., lh.2b.3g.4g.5g., lj.2b,3g.4g.5g., lp.2b.3g.4g.5g_, la. 2e.3g,4g.5g., lb.2e.3g.4g.5g_, lf.2e.3g.4g.5g_, lli.2e.3g.4g.5g., lj.2e.3g.4g.5g_, lp.2e.3g.4g.5g., la.2f.3g.4g.5g„ lb.2f.3g.4g.5g_, lf.2f.3g.4g.5g., lh.2f.3g.4g.5g., lj.2f.3g.4g_5g_, lp.2f.3g.4g.5g_, la.2i.3g.4g.5g., lb.2i.3g.4g.5g„ lf.2i.3g.4g.5g„ lh.2i.3g.4g.5g_, lj.2i.3g.4g.5g_, lp.2i.3g.4g.5g_, la.2m.3g.4g.5g_, lb.2m.3g.4g.5g„ lf.2m,3g.4g.5g., lh.2m.3g.4g.5g_, lj.2m.3g.4g.5g„ lp.2m.3g.4g.5g., la.2o.3g.4g.5g., lb. 2o.3g.4g.5g., lf.2o.3g.4g.5g_, lh.2o.3g.4g.5g_, lj.2o.3g.4g.5g., lp.2o.3g,4g,5g., la.2u.3g.4g.5g., lb.2u.3g.4g.5g_, lf.2u.3g.4g.5g., lh.2u_3g.4g.5g_, lj.2u,3g.4g.5g., lp.2u.3g.4g.5g„ la.2y.3g.4g.5g_, lb.2y.3g.4g.5g_, lf.2y.3g.4g.5g_, lh.2y.3g.4g.5g_, lj.2y.3g.4g.5g., lp.2y.3g.4g.5g_, la.2a.3a.4h.5g., lb.2a.3a.4h.5g., lf.2a.3a.4h.5g., lh.2a.3a.4h.5g., lj.2a.3a.4h.5g., lp.2a.3a.4h.5g_, la.2b.3a.4h.5g., lb.2b.3a.4h.5g., lf.2b.3a.4h.5g_, lh.2b.3a.4h.5g., lj.2b.3a.4h.5g., lp.2b.3a.4h,5g., la.2e.3a.4h.5g.,

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2020203321 21 May 2020 lb.2e.3a.4h.5g., lf.2e.3a.4h.5g., lh.2e.3a.41i.5g., lj.2e.3a.4h.5g., lp.2e.3a.4h.5g., la. 2f.3a.4h.5g., lb.2f.3a.41i.5g„ 1 f.2f.3a.4h.5g, 'Ih.2f.3a.4h.5g., lj.2f.3a.4h.5g., lp.2f.3a.4h.5g,, la.2i.3a.4h.5g., lb.2i.3a.4h.5g., lf.2i.3a.4h.5g., lh.2i.3a.4h.5g., lj.2L3a.4h.5g., lp.2i.3a.41i.5g., la.2m.3a.4h.5g., lb.2-m.3a.4h.5g., lf.2m.3a.4h.5g., lh.2m.3a,4h.5g., lj.2m.3a.4h.5g., lp.2m.3a.4h.5g., la.2o.3a.4h.5g., lb.2o.3a.4h.5g., lf.2o.3a.4h.5g., lh.2o.3a.4h.5g., lj.2o.3a.4h.5g., lp.2o.3a.4h.5g„ la.2u.3a.4h.5g., lb. 2u.3a.4h.5g., lf.2u.3a.4h.5g., lh.2u.3a.4Ji.5g., lj.2u.3a.4h.5g„ lp.2u.3a.4h.5g., la. 2y.3a.4h.5g., lb.2y.3a.4Ji.5g., lf.2y.3a.4h.5g., lh.2y.3a.4h.5g., lj.2y.3a.4h.5g., lp.2y.3a.4h.5g., la.2a.3b.4h.5g., lb.2a.3b.4h.5g., lf.2a.3b.4h.5g., lh.2a.3b.4h.5g., lj.2a.3b.4h.5g., lp.2a.3b,4h.5g., la.2b.3b.4h.5g., lb.2b.3b.4h.5g., lf.2b.3b.4h.5g., lh.2b.3b.4h.5g., lj.2b.3b.4h.5g., lp.2b.3b.4h.5g., la.2e.3b.4h.5g., lb.2e.3b.4h.5g., lf.2e.3b.4h.5g., lh.2e.3b.4h.5g., lj,2e.3b.4h.5g„ lp.2e.3b.4h.5g., 1a.2f.3b.4h.5g., lb. 2f.3b.4h.5g., 1f.2f.3b.4h.5g., lh.2f.3b.4h.5g., lj.2f.3b.4h.5g., lp.2f.3b.4h.5g„ la. 2i.3b.4h.5g., lb.2i.3b.4h.5g., lf.2i.3b.4h.5g., lh.2i.3b.4h.5g., lj.2i.3b.4h.5g., lp.2i,3b.4h.5g., 'Ia.2m.3b.4h.5g., lb,2m.3b.411.5g., lf.2m.3b.4h.5g., lh.2m.3b.4h.5g., lj.2m.3b.4h.5g., lp.2m.3b.4h.5g., la.2o.3b.4h.5g., lb.2o.3h.4h.5g., lf.2o.3b.4h.5g., lh.2o.3b.4h.5g., lj.2o-3b.4h.5g., lp.2o.3b.4h.5g., la.2u.3h.4h.5g., lb.2u.3b.411.5g., lf.2u.3b.4h.5g., lh.2u.3b.4h.5g., lj.2u.3b.4h.5g., lp.2u.3b.4h.5g., la.2y.3b.4h.5g., lb. 2y.3b.4h.5g., lf.2y.3b.4h.5g., lh.2y.3b.4h.5g., lj.2y.3b.4h.5g., lp.2y.3b.4h.5g., la. 2a.3e.4h.5g., lb.2a.3e.4h.5g., 1f.2a.3e.4h.5g., Jh.2a.3e.4h.5g., Jj.2a.3e.4h.5g., Jp.2a.3e.4h.5g., la.2b.3e.4h.5g., lb.2b.3e.4h.5g., lf.2b.3e.4h.5g., lh.2b.3e.4h.5g., lj.2b.3e.41i.5g., lp.2b,3e,4h.5g., la.2e.3e.4h.5g., lb.2e.3e.41i.5g., lf.2e.3e.4h.5g., lh.2e.3c.4h.5g., lj.2o.3e.4h.5g., lp.2e.3e.4h.5g„ la,2f.3e.4h.5g., lb.2f.3e.4h.5g., lf.2f,3e.4h.5g., lh.2f.3e.4h.5g., lj.2f.3c.4h.5g„ lp.2f.3e.4h.5g., la.2i.3e.4h.5g., lb. 2i.3e.4h.5g., lf.2i.3e.4h.5g., lh.2i.3e.4h.5g,, lj.2i.3e.4h.5g., lp.2i.3e.4h.5g., la. 2m.3e.4h.5g., lb,2m.3e.4h.5g., lf.2m.3e.4h.5g., lh.2m.3e.4h.5g., lj.2m.3e.4h.5g., 'Jp.2m.3e.4h.5g., la.2o.3e.4h.5g., lb.2o.3e.4h.5g., lf.2o.3e.4h.5g., Ih.2o.3e.4h.5g., lj,2o.3e.4h,5g., 1p.2o.3c.4h.5g., la.2u.3e.4h.5g., lb.2u.3e.4h.5g., lf.2u.3e.4h.5g., lli.2u.3e.4h.5g., lj.2u.3e.4h.5g., lp.2u.3e.4h.5g., la.2y.3e.4h.5g., lb.2y.3c.4h.5g., lf.2y.3e.4h.5g., lh.2y.3e.4h.5g., lj.2y.3e.4h.5g., lp.2y.3e.4h.5g., la.2a.3g.4h,5g., lb. 2a.3g.4h.5g., lf.2a.3g.4h.5g., lh.2a.3g.41i.5g., lj.2a.3g.4h.5g., lp.2a.3g.4h.5g., la. 2b.3g.4h.5g., 1 b.2b.3g.4h.5g., lf.2b.3g.4h.5g., lh.2b.3g.4h.5g., lj.2b.3g.4h.5g., lp.2b.3g.4h.5g., la.2e.3g.4h.5g., lb.2e.3g.4h.5g., lf.2e.3g.4h.5g., lh.2c.3g.4h.5g., lj.2e.3g.4h.5g., lp.2e.3g.4h.5g., la.2f.3g,4h.5g., lb.2f.3g.4h.5g., lf.2f.3g.4h.5g., lh.2f.3g.4h.5g., Ij.2f.3g.4h,5g., 'Ip.2f.3g.4h.5g., la.2i.3g.4h.5g., lb.2i.3g.4h.5g., lf.2i.3g.4h.5g., lh.2i.3g.4h.5g., lj.2i.3g.4h.5g., lp.2i.3g.4h.5g., la.2m,3g.4h.5g., lb. 2m.3g.4h.5g., lf.2m.3g.4h.5g., lh.2m.3g.4h.5g., lj.2m.3g.4h.5g., lp.2m.3g.4h.5g., la.2o.3g.4h.5g., lb.2o.3g.4h.5g., lf.2o.3g.4h.5g., lh.2o.3g.4h.5g., lj.2o.3g.4h.5g., lp.2o.3g.4h.5g., la.2u.3g.4h.5g., lb.2u.3g.4h.5g., lf.2u.3g.4h.5g., lh.2u.3g.4h.5g., lj.2u.3g.4h.5g., lp.2u.3g.4h.5g., la.2y.3g.4h.5g., lb.2y.3g.4h.5g., lf.2y.3g.4h.5g., lh.2y.3g.4h.5g., lj.2y.3g.4h.5g., lp.2y.3g.4h.5g., la.2a.3a.4i.5g., lb.2a.3a.4i.5g.,

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2020203321 21 May 2020 lf.2a.3a.4L5g., lh.2a.3a.4i.5g., lj.2a.3a.4i.5g., lp.2a.3a.4i.5g., la.2b.3a.4i.5g., lb.2b.3a.4L5g., lf.2b.3a.4i.5g., lh.2b.3a.4i.5g., lj.2b.3a.4i.5g„ lp.2b.3a.4i.5g., la. 2e.3a.4i.5g., lb.2e.3a.4i.5g., lf.2e.3a.4i.5g., lh.2e.3a.4i.5g., lj.2e.3a.4L5g., lp.2e.3a.4i.5g., la.2f.3a.4i.5g., lb.2f.3a.4i.5g., lf.2f.3a.4L5g., lh.2f.3a.4L5g., lj.2f,3a.4i.5g., lp.2f.3a.4L5g., la.2i.3a.4i.5g., lb.2i.3a.4i.5g., lf.2L3a.4L5g., lh.2i.3a.4L5g., lj.2L3a.4i.5g., lp.2i.3a.4L5g., la.2m.3a.4i.5g., lb.2m.3a.4i.5g., lf.2m.3a.4i.5g., lh.2m.3a.4i.5g., lj.2m.3a.4L5g., lp.2m.3a.4L5g., la.2o.3a.4L5g., lb. 2o.3a.4i.5g., lf.2o.3a.4L5g., lh.2o.3a.4i.5g., lj.2o.3a.4L5g., lp.2o.3a.4i.5g., la. 2u.3a.4i.5g., lb.2u.3a.4i.5g., lf.2u.3a.4i.5g., lh.2u.3a.4i.5g., lj.2u.3a.4L5g., lp.2u.3a.4L5g., la,2y.3a.4i.5g., lb.2y.3a.4L5g., lf.2y,3a.4i.5g., lh.2y.3a.4i.5g., lj.2y.3a.4i.5g., lp.2y.3a.4L5g., la.2a.3b.4L5g., lb.2a.3b.4i.5g., lf.2a.3b.4i.5g., lh.2a.3b.4i.5g., lj.2a.3b,4L5g., lp.2a.3b.4L5g„ la.2b.3b.4L5g., lb.2b.3b.4i.5g., lf.2b.3b.4i.5g., lh.2b.3b.4i.5g., lj.2b.3b.4i.5g., lp.2b.3b.4L5g., la.2e.3b.4i.5g., lb. 2e.3b.4i.5g., lf.2e.3b.4i.5g., lh.2e.3b.4i.5g., lj.2e.3b.4L5g., lp.2e.3b.4i.5g., la. 2f.3b.4i.5g., lb.2f.3b.4i.5g., lf.2f.3b.4i.5g., lh.2f.3b.4L5g., Ij.2f.3b.4L5g., lp.2f.3b.4i.5g., la.2i.3b.4i.5g„ lb.2L3b.4L5g., lf.2i.3b.4i.5g., lh.2L3b.4i.5g., lj.2i.3b.4i.5g., lp.2i.3b.4i.5g., la.2m.3b.4i.5g., Ib.2m.3b.4i.5g., lf.2m.3b.4L5g., lh.2m.3b.4i.5g., lj.2m.3b.4i.5g., lp.2m.3b.4i.5g., la.2o.3b.4i.5g., lb.2o.3b.4i.5g., lf.2o.3b.4i.5g., lh.2o.3b.4L5g., lj.2o.3b.4i.5g., lp.2o.3b.4i.5g., la.2u.3b.4L5g., lb. 2u.3b.4i.5g,, lf.2u.3b.4L5g., lh.2u.3b.4i.5g., 1 j.2ti.3b.4i.5g., lp.2u.3b.4i.5g., la. 2y.3b.4i.5g., lb.2y.3b.4L5g., lf.2y.3b.4L5g., lh.2y.3b.4L5g., lj.2y.3b.4i.5g., lp.2y.3b.4i.5g„ la.2a.3e.4i.5g., lb.2a.3e.4L5g., lf.2a.3c.4i.5g., lh.2a.3e.4i.5g., lj.2a,3e.4i.5g., lp.2a.3e.4i.5g., la.2b.3e.4i.5g., lb.2b.3e.4i.5g., lf.2b.3e.4L5g., lh.2b.3e.4L5g., lj.2b.3e.4i .5g., Ip.2b3e.4i.5g., la.2e.3e.4i.5g., lb.2e.3e.4L5g., lf.2e.3e.4i.5g., lh.2c3e.4L5g., lj.2e.3e.4i.5g., lp.2e.3e.4i.5g., la.2f.3e.4i.5g., lb. 2f.3e.4i.5g., lf.2f.3e.4L5g., 1h.2f.3e.4L5g., lj.2f.3e.4L5g., lp.2f.3e.4L5g., la. 2i.3e.4i.5g., lb.2L3e.4L5g., If.2i.3e.4i.5g., lh.2i.3e.4i.5g., lj.2i.3c.4i.5g., lp.2L3e.4i.5g., la.2m.3e.4i.5g., lb.2m.3e.4i.5g,, lf.2m.3e.4i,5g., lh.2m.3e.4L5g., 1j.2m.3e.4L 5g., lp.2m.3e.4i.5g., la.2o.3e.4L5g., lb.2o.3e.4i.5g., lf.2o.3e.4i.5g,, lh.2o.3e.4i.5g., lj.2o.3e.4L5g., lp.2o.3c.4i.5g., la.2u.3e.4L5g., lb.2u.3e.4L5g., lf.2u.3c.4L5g., lh.2u.3e.4i.5g., lj.2u.3e.4i,5g., lp.2u.3c.4L5g., la.2y.3e.4i.5g., lb. 2y.3e.4i.5g., lf.2y.3e.4i,5g., lh.2y.3e.4i.5g., lj.2y.3e.4L5g., lp.2y.3e.4i.5g„ la. 2a.3g.4i.5g., lb.2a.3g.4i.5g., lf.2a.3g.4i.5g., lh.2a.3g.4i.5g., lj.2a.3g.4i.5g., lp.2a.3g.4i.5g., la.2b.3g.4i.5g., lb.2b.3g.4i.5g., lf.2b.3g.4i.5g., lh.2b.3g.4i.5g., lj.2b.3g.4L5g., lp.2b.3g.4L5g., la.2e.3g.4i.5g., lb.2e.3g.4i.5g., lf.2e.3g.4L5g., lh.2e.3g.4i.5g., lj.2e.3g.4i.5g„ lp.2e.3g.4i.5g., la.2f.3g.4i.5g., lb.2f.3g.4L5g., lf.2f.3g.4i.5g., lh.2f.3g.4i.5g., lj.2f.3g.4L5g., lp.2f.3g.4i.5g., la.2i.3g.4i.5g., lb. 2i.3g.4i.5g., lf.2i.3g.4L5g., lh.2L3g.4i.5g., 1 j.2i.3g.4i.5g., lp.2i.3g.4i.5g., la.2m.3g.4i.5g., lb.2m.3g.4L5g., lf.2m.3g.4i.5g., lh.2m.3g.4L5g., lj.2m.3g.4i,5g., lp.2m.3g.4i.5g., la.2o.3g.4i.5g., lb.2o.3g.4i.5g., lf.2o.3g.4L5g., lh.2o.3g.4i.5g., lj.2o.3g.4L5g., lp.2o.3g.4i.5g., la.2u.3g.4i.5g., lb.2u.3g.4i.5g., 1 f.2u.3g.4i.5g.,

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2020203321 21 May 2020 lh.2u.3g.4i.5g., lj.2u.3g.4i.5g., lp.2u.3g.4i.5g., la.2y.3g.4i.5g„ lb.2y.3g.4i.5g., If2y.3g.4i.5g., lh.2y.3g.4L5g., lj.2y.3g.4L5g., lp.2y.3g.4i.5g., la.2a.3a.4a.5h., lb.2a.3a.4a.5h., lf.2a.3a.4a.5h,, lh.2a.3a.4a.5h., 1j.2a.3a.4a.5h., lp.2a.3a.4a,5h., la. 2b.3a_4a.5h., lb_2b.3a_4a.5h., If2b.3a.4a.5h., lh.2b.3a.4a.5h., lj.2b.3a.4a.5h., lp.2b.3a.4a.5h., la.2e.3a.4a.5h., lb,2e.3a.4a.5h., lf.2e.3a.4a.5h., lh.2e.3a.4a.5h., lj.2e.3a.4a.5h., lp.2e.3a.4a.5h., la.2f.3a.4a.5h., lb.2f.3a.4a,5h., lf.2f.3a.4a.5h., lh.2f.3a.4a.5h., lj.2f.3a.4a.5h., lp.2f.3a.4a.5h., la.2i.3a.4a.5h_, lb.2i.3a.4a.5h., lf.2i.3a.4a.5h_, lh.2i.3a.4a.5h_, lj.2i.3a.4a.5h_, lp.2i.3a.4a.5h_, la.2m.3a.4a.5h., lb. 2m.3a.4a.5h., If 2m. 3a.4a. 5h., lh.2in.3a.4a.5h., lj.2m.3a.4a.5h„ lp.2m.3a.4a.5h., la. 2o.3a.4a.511., lb.2o.3a.4a.5h., lf.2o.3a.4a.5h_, lh.2o.3a.4a.5h., lj.2o.3a.4a.5h., lp.2o.3a.4a.5h., la.2u.3a.4a.5h., lb.2u.3a.4a.5h., If. 2u.3a.4a.5h., lh.2Li.3a.4a.5h., lj.2u.3a.4a.5h., lp.2u.3a.4a.5h_, la.2y.3a.4a.5h., lb.2y.3a.4a.5h., If2y.3a.4a.5h., lh.2y.3a_4a.5h., lj.2y.3a.4a.5h., lp.2y.3a.4a.5h_, la.2a.3b.4a.5h., lb.2a.3b.4a.5h., If2a.3b.4a.5h_, lh.2a.3b.4a_5h„ lj.2a.3b.4a.5h_, lp.2a.3b.4a.5h_, la.2b.3b.4a.5h„ lb. 2b.3b.4a.5h_, lf2b.3b.4a.5h_, lh.2b,3b.4a.5h., lj.2b.3b.4a.5h., lp.2b.3b.4a.5h_, la. 2e.3b.4a.5h., 1b.2c.3b.4a.5h., lf.2e.3b.4a.5h., lh.2e.3b.4a.5h., lj.2e.3b.4a.5h., lp.2e.3b.4a.5h_, la.2f.3b.4a.5h., Ib.2f3b.4a.5h., 1f2f.3b.4a.5h., lh.2f.3b.4a.5h., lj.2f.3b.4a.5h_, lp.2L3b.4a.5h_, la.2i.3b.4a.5h_, lb.2i.3b.4a.5h., lf.2i.3b.4a.5h., lh.2i.3b.4a.5h., lj.2i.3b.4a.5h., lp.2i.3b.4a.5h., la.2m.3b.4a.5h., lb.2m.3b.4a.5h., lf.2m.3b.4a,5h., lh.2m.3b.4a.5h.., lj.2m.3b.4a.5h., lp,2m.3b.4a.5h., la.2o.3b.4a.5h., lb. 2o.3b.4a.5h., lf.2o.3b.4a.5h., lh.2o.3b.4a.5h., lj.2o.3b.4a.5h., lp.2o.3b.4a.5h., la. 2u.3b.4a.5h., lb.2Lt.3b.4a.5h., lf.2u.3b.4a,5h„ lh.2u.3b.4a.5h., lj.2u.3b.4a.5h., lp,2u.3b.4a.5h., la.2y.3b.4a.5h., lb.2y.3b.4a.5h., lf.2y.3b.4a.5h., lh.2y.3b.4a.5h., lj.2y.3b.4a.5h_, lp.2y.3b.4a.5h_, la.2a.3e.4a.5h_, lb.2a.3e.4a.5h., lf.2a.3c.4a.5h., lh.2a.3e.4a.5h., lj.2a.3e.4a.5h., lp.2a.3e.4a.5h., la.2b.3e.4a.5h., lb.2b.3e.4a.5h., lf.2b.3e.4a.5h., lh.2b.3e.4a.5h., lj.2b_3e.4a.5h., lp.2b.3e.4a.5h_, la.2e.3e.4a.5h_, lb. 2e.3e.4a.5h., 1 f.2e.3c.4a.5h., lh.2e.3e.4a.5h., lj.2e.3e.4a.5h., lp.2e.3e.4a.5h., la. 2f.3e.4a.5h_, lb.2f,3e.4a.5h., lf.2f.3e.4a.5h., Ih.2f3e.4a.5h., 1j.2f.3e.4a.5h., lp.2f.3e.4a.5h., la.2i.3e.4a.5h., lb.2i.3e.4a.5h,, lf.2i.3e.4a.5h., lh.2i.3e.4a.5h., lj.2i.3e.4a.5h., lp.2i.3e.4a.5h., la.2m.3e.4a.5h., lb.2m.3e.4a.5h., If.2m.3e.4a.5h.,

h.2m.3e.4a.5h., lj.2m.3e.4a.5h., lp.2m.3e.4a.5h., la.2o.3e.4a.5h„ lb.2o.3e.4a,5b., lf.2o.3e.4a.5h., lh.2o.3e.4a.5h., lj.2o.3e.4a.5h., 'lp.2o.3e.4a.5h., la.2u.3e.4a.5h., lb. 2u.3e.4a.5h., If.2u.3e.4a.5h_, lh.2u.3e.4a.5h., lj.2u.3e.4a.5h„ Ip.2u.3e.4a.5h., la. 2y.3e.4a.5h., lb.2y.3e.4a.5h., lf.2y.3e.4a.5h., lh.2y.3e.4a.5h„ lj.2y.3e.4a.5h., lp.2y.3c.4a.5h., la.2a.3g.4a.5h., lb.2a.3g.4a.5h., If. 2a.3g.4a.5h., lh.2a.3g.4a.5h., lj.2a.3g.4a.5h., lp.2a.3g.4a.5h., la.2b.3g.4a.5h_, lb.2b.3g.4a.5h., lf.2b.3g.4a.5h., lh.2b.3g.4a.5h„ lj.2b.3g.4a.5h., lp.2b.3g.4a.5h., la.2e.3g.4a.5h., 1b.2e.3g.4a.5h., lf.2e.3g.4a.5h., lh.2e.3g.4a.511., Ij.2e.3g.4a.5h., lp.2e.3g.4a.5h., la.2f.3g.4a.5h., lb. 2f.3g.4a.5h., lf.2f.3g.4a.5h., lh.2f.3g.4a.5h_, lj.2f.3g.4a.511., lp.2f.3g.4a.5h„ la.2i,3g.4a.5h., lb.2i.3g.4a.5h., lf.2i.3g.4a.5h., lh.2i.3g.4a.5h., lj.2i.3g.4a.5h., lp,2i.3g.4a.5h., la.2m.3g.4a.5h., lb.2m.3g.4a.5h., If.2m.3g.4a.5h., lh.2m.3g.4a.5h.,

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Jj.2m.3g.4a.5h., lp.2m.3g.4a.5h., la.2o.3g.4a.5h., lb.2o.3g.4a.5h., lf.2o.3g.4a.5h., lh.2o.3g.4a.5h., lj.2o.3g.4a.5h., lp.2o.3g.4a.5h„ la.2u.3g.4a.5h., lb.2u.3g.4a.5h., lf.2u.3g.4a.5h., lh.2u.3g.4a.5h., lj.2u.3g.4a.5h., lp.2u.3g.4a.5h., la.2y.3g.4a.5h., lb.2y.3g.4a.5h., lf.2y.3g.4a.5h., lh.2y.3g.4a.5h., lj.2y.3g.4a,5h., lp.2y.3g.4a.5h., la. 2a.3a.4d.5h., lb.2a.3a.4d.5h., lf.2a,3a.4d.5h„ lh.2a.3a.4d.5h., lj.2a.3a.4d.5h., lp.2a.3a.4d.5h., la.2b.3a.4d.5h., lb.2b.3a.4d.5h., lf.2b.3a.4d.5h., lh.2b.3a.4d.5h., 1j.2b.3a.4d.5h_, 1p.2b.3a.4d.5h., la.2e.3a.4d.5h_, lb.2o.3a.4d.5h., lf.2e.3a.4d.5h., lh.2e.3a.4d.5h., lj.2e.3a.4d.5h., lp.2e.3a.4d.5h., la.2f.3a.4d.5h., lb.2f.3a.4d.5h., If.2f.3a.4d.5h., lh.2f.3a.4d.5h., lj.2f.3a.4d.5h., lp.2f.3a.4d.5h„ la.2i.3a.4d.5h., lb. 2i.3a.4d.5h., lf.2i.3a.4d.5h., lh.2i.3a.4d.5h., lj.2i.3a.4d.5h., lp.2i.3a.4d.5h., la. 2m.3a.4d.5h., 1b.2m.3a.4d.5h., lf.2m.3a.4d.5h., lh.2m.3a.4d.5h,, lj.2m.3a.4d.5h., lp.2m.3a.4d.5h., la.2o.3a.4d.5h,, lb.2o.3a.4d.5h,, lf.2o.3a.4d.5h., lh.2o.3a.4d.5h., lj.2o.3a.4d.5h., lp.2o.3a.4d.5h., la.2u.3a.4d.5h., lb.2u.3a.4d.5h., lf.2u.3a.4d.5h_, lh.2u.3a.4d.5h., lj.2u.3a.4d.5h., lp.2u.3a.4d.5h., la.2y.3a.4d.5h., lb.2y.3a.4d.5h,,

f.2y.3a.4d.5h., lh.2y.3a.4d.5h., lj.2y.3a.4d.5h., lp.2y.3a.4d .511., la.2a.3b.4d.5h., lb. 2a.3b.4d.5h., lf.2a.3b.4d.5h., lh.2a.3b.4d.5h., lj.2a.3b.4d.5h„ lp.2a.3b.4d.5h., la. 2b.3b.4d.5h., lb.2b.3b.4d.5h., lf.2b.3b.4d.5h., lh.2b.3b.4d.5h., lj_2b.3b.4d.5h., lp.2b.3b.4d.5h„ la.2e.3b.4d.5h., lb.2e.3b.4d.5h., lf.2e.3b.4d.5h„ lh.2e.3b.4d.5h., lj.2e.3b.4d.5h., lp.2e.3b.4d.5h., la.2f.3b.4d.5h„ lb.2f.3b.4d.5h., lf.2f.3b.4d.511., lh.2f.3b.4d.5h., lj.2f.3b.4d.5h., lp,2f.3b.4d.5h., la.2i.3b.4d.5h., lb.2i.3b.4d.5h., lf.2i.3b.4d.5h., lh.2i.3b.4d.5h„ lj.2i.3b.4d.5h., lp.2i.3b.4d.5h., la.2m.3b.4d.5h., lb. 2m.3b.4d.5h., lf.2m.3b.4d.5h., lh.2m.3b.4d.5h„ lj.2m.3b.4d.5h., lp.2m.3b.4d.5h„ la.2o.3b.4d.5h., lb.2o.3b.4d.5h., lf.2o.3b.4d.5h., lh.2o.3b.4d.5h„ lj.2o.3b.4d.5h., lp.2o.3b.4d.5h., la.2u.3b.4d.5h., lb.2u.3b.4d.5h., lf,2u.3b.4d.5h., lh.2u.3b.4d.5h., lj.2u.3b.4d.5h., lp.2u.3b.4d.5h., la.2y.3b.4d.5h., lb.2y.3b.4d.5h., lf.2y.3b.4d.5h., lh.2y.3b.4d.5h., 1 j.2y.3 b.4d .511., 1p.2y.3b.4d.5b., la.2a,3e.4d.5h., lb.2a.3e.4d.5h., lf.2a.3e.4d.5h., lh.2a.3e.4d.5h., lj.2a.3e.4d.5h., lp.2a.3e.4d.5h., la. 2b.3e.4d.5h., lb.2b.3e.4d.5h., lf.2b.3e.4d.511., lh.2b.3e.4d.5h., lj.2b.3e.4d.5h., lp.2b.3e.4d.5h., la.2e.3e.4d.5h., lb.2e.3e.4d.5h_, lf.2e.3e.4d.5h., lh.2e.3e.4d.5h., Jj.2e.3c.4d.5h., lp.2e.3c.4d.5h., Ia.2f.3c.4d.5h., lb.2f.3c.4d.5h., lf.2f.3e.4d.5h., lh.2f.3e.4d.5h., lj.2f.3e.4d.5h., lp.2f.3e.4d.5h., la.2i.3e.4d.5h., lb.2i.3e.4d.5h., lf.2i.3e.4d.5b., lh.2i.3e.4d.5h., lj.2i.3e.4d.5h., lp.2i.3e.4d.5h., la.2m.3e.4d.5h., lb. 2m.3e.4d.5h., If.2m.3e.4d.511., lh.2m.3e.4d.5h., lj.2m.3e.4d.5h., lp.2m.3e.4d.5h., la.2o.3e.4d.5h., lb.2o.3e.4d.5h., lf.2o.3e.4d.5h., lh.2o.3e.4d.5h., lj.2o.3e.4d.5h., lp.2o.3e.4d.5h„ la.2u.3e.4d.5h_, 1b.2u.3e.4d.5h., lf.2u.3e.4d.5h., lh.2u.3e.4d.5h., lj.2u.3e.4d.5h., lp.2u.3e.4d.5h., la.2y.3e_4d.5h., Ib.2y.3e.4d.5h., lf.2y.3e.4d.5h., lli.2y.3e.4d.5h., lj.2y.3e.4d.5h., lp.2y.3e.4d.5h., la.2a.3g.4d.5h_, lb.2a,3g.4d.5h., lf.2a.3g.4d.5h., lh.2a.3g.4d.5h., lj.2a.3g.4d.5h., lp.2a.3g.4d.5h., la.2b.3g.4d.5h.,

b.2b.3g.4d.5h., 1f.2b.3g.4d.5h„ lh.2b.3g.4d.5h., lj.2b.3g.4d.5h„ lp.2b.3g.4d.5h., la.2e.3g.4d.5h., 1 b,2e.3g.4d.5h,, lf.2e.3g.4d,5h., lh.2e.3g.4d.5h., lj.2e.3g.4d.5h., lp.2e.3g.4d.5h., la.2f.3g.4d.5h., lb.2f.3g.4d.5h„ lf.2f.3g.4d.5h., 1h.2f.3g.4d.5h.,

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2020203321 21 May 2020 lj.2L3g.4d.5h., lp.2L3g,4d.5h., la.2i.3g.4d.5h., lb.2i.3g.4d.5h., lf.2i.3g.4d.5h., lh.2i.3g.4d.5h., lj.2i.3g.4d.5h., lp.2i.3g.4d.5h., la.2m.3g.4d.5h., lb.2m.3g.4d.5h., lf.2m.3g.4d.5h., lh.2m.3g.4d.5h., lj.2m.3g.4d.5h., lp.2m.3g.4d.5h., la,2o.3g.4d.5h„ lb.2o.3g.4d.5h., lf.2o.3g.4d.5h,, lh.2o.3g.4d.5h_v lj.2o.3g.4d.5h., lp,2o.3g.4d,5h., la. 2tL.3g.4d.5h., 1b.2u.3g.4d.5h., lf.2u.3g.4d.5h., lh.2ti.3g.4d.5h., lj.2u.3g.4d.5h., lp.2u.3g.4d.5h., la.2y,3g.4d.5h., lb.2y.3g.4d.5h., lf.2y.3g.4d.5h., lh.2y.3g.4d.5h,, lj.2y.3g.4d.5h_, lp.2y.3g.4d.5h„ la.2a.3a.4f.5h., lb.2a.3a.4f.5h„ lf.2a.3a.4f.5h., lh.2a.3a.4f.5h., lj.2a.3a.4f,5h., lp.2a.3a.4f.5h,, la.2b.3a.4f.5h., lb.2b.3a.4f.5h„ lf_2b.3a.4L5h., Jh.2b.3a.4f.5h., lj.2b.3a.4f.5h„ lp.2b.3a.4f.5h., la.2c.3a.4f.5h., lb. 2e.3a.4f.5h., Jf.2e.3a.4f.5h., lh.2e.3a.4L5h„ lj.2e.3a.4f.5h., lp.2e.3a.4f.5h„ la. 2L3a.4f.5h, lb.2f.3a.4f.5h, lf.2f.3a.4f.5h„ lh.2f.3a.4L5h, lj.2f.3a.4f.5h., lp.2f.3a.4f.5h., la.2i.3a.4f.5h., lb.2i.3a.4f.5h., lL2i.3a.4L5h, lh.2i,3a.4f.5h., 1j.2i.3a.4f.5h., lp.2L3a.4f.5h., la.2m.3a.4f.5h., lb.2m.3a.4f.5h., lf.2m.3a.4f.5h., lh.2m.3a.4f.5h., lj.2m.3a.4f.5h., lp.2m.3a.4f.5h., la.2o.3a.4f.5h., lb.2o.3a.4f.5h, lf.2o.3a.4L5h., lh.2o.3a.4f.5h, lj.2o.3a.4L5h, lp.2o.3a.4f.5h, la.2u.3a.4L5h., lb. 2u.3a.4L5h., lf.2u.3a.4f.5h, lh.2u.3a.4f.5h., lj.2u.3a.4L5h., lp.2u.3a.4L5h, la. 2y.3a.4L5h., 1b.2y.3a.4f.5h,, lf.2y.3a.4f.5h., lh.2y.3a.4f.5h, lj.2y.3a.4L5h., lp.2y.3a,4f.5h, la.2a.3b.4f.5h., lb.2a.3b.4L5h., lf.2a.3b.4f.5h, lh.2a.3b,4f.5h„ lj.2a.3b.4f.5h_, lp.2a.3b.4f.5h, la.2b.3b_4f.5h_, lb.2b.3b.4f.5h, lf.2b.3b.4f.5h, lh.2b.3b.4f.5h, lj.2b.3b.4L5h, lp.2b.3b.4L5h., 1 a.2e.3b.4f.5h„ lb.2e.3b.4L5h., 1f.2e.3b.4f.5h_, lh.2c.3b.4f.5h, lj.2c.3b.4f.5h, lp.2e.3b.4L5h., la.2f.3b.4f.5h„ lb. 2f.3b.4f.5h„ lf.2f.3b.4L5h„ lh.2f.3b,4f.5h, lj.2L3b.4f,5h, lp.2L3b.4f.5h., la. 2i.3b.4L5h., lb.2i.3b.4f.5h, lf.2i.3b.4f.5h, lh.2i.3b.4f.5h, lj.2i.3b.4f.5h, lp.2i.3b.4f.5h,, la.2m.3b.4f.5h, lb.2m.3b.4L5h., lf.2m.3b.4f 5h, lh.2m.3b.4f.5h., lj.2m.3b.4f.5h., lp.2m.3b.4L5h„ la.2o.3b.4L5h, lb.2o.3b.4L5h., lL2o.3b.4f.5h., lh.2o.3b.4f.5h„ lj.2o.3b.4L5h., lp.2o.3b.4L5h., la.2u.3b.4L5h., lb.2u.3b.4L5h, lf.2u.3b.4f.5h, lh.2u,3b.4f.5h, lj,2u.3b.4f.5h., lp.2u.3b.4f.5h., la.2y.3b.4L5h., lb, 2y.3b.4f,5h,, Jf.2y.3b.4f.5h., Jh.2y.3b.4f.5h., lj.2y.3b.4f.5h., lp.2y.3b.4L5h., la. 2a.3e.4L5h., lb.2a.3e.4f.5h., lf.2a.3e.4f.5h., lh.2a.3e.4L5h., lj.2a.3e.4f.5h., lp.2a.3e.4f.5h., la.2b.3e.4f.5h., 1b.2b.3e.4f.5h„ lf.2b.3e.4f.5h„ lh.2b.3e.4L5h., lj.2b.3e.4L5h., lp.2b.3e.4f.5h., la.2e.3e.4L5h., lb.2e.3e.4L5h., lf.2e.3e.4L5h., 1h.2e.3e.4f.5h., Jj.2e.3c.4f.5h., J p.2c.3e.4f.5h., la.2L3c.4f.5h., lb.2L3e.4f.5h., lf.2f.3e.4f.5h., lh.2f.3e.4f.5h., lj.2f.3e.4L5h., lp.2f.3e.4f.5h., la.2i.3e.4L5h., lb. 2i.3e.4L5h., lL2i.3e.4f.5h,, lh.2i.3e.4L5h., lj.2i.3e.4f.5h., lp.2L3e.4L5h., la. 2m.3e.4f.5h_, lb.2m.3e,4f.5h„ lf.2m.3e.4f.5h., lh.2m.3e.4L5h., lj.2m.3e.4L5h., lp.2m.3c.4f.5h., la.2o.3e.4L5h., lb.2o.3e.4L5h., lf.2o.3e.4f.5h., lh.2o.3e.4L5h., Jj.2o.3e.4f.5h., lp.2o.3e.4f.5h., 1a.2u.3e.4L5h., 1 b.2u.3c.4f.5h., lf.2u.3e.4L5h., lh.2u.3e.4f5h., lj.2u.3e.4f.5h., lp.2u.3e.4L5h., la.2y.3e.4L5h,, lb.2y.3e.4L5h., lL2y.3e.4L5h., lh.2y.3e.4L5h., lj.2y.3e.4f.5h., lp.2y.3e.4f.5h., la.2a.3g.4L5h., lb. 2a.3g.4f.5h., lf.2a.3g.4L5h., lh.2a.3g.4f.5h., lj.2a.3g.4f.5h., lp.2a.3g.4f.5h., la.2b.3g.4f.5h., lb.2b.3g.4L5h., lf.2b.3g.4L5h., lh.2b.3g.4f.5h., lj.2b.3g.4L5h.,

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Jp.2b.3g.4f5h., la.2c.3g.4f.5h., lb.2e.3g.4f.5h., If2e.3g.4f.5h., lh.2e.3g.4f.5h_, lj.2e.3g.4f.5h., lp.2e.3g.4f.5h., la.2f.3g.4f.5h., lb.2f.3g.4f.5h., lf.2f,3g.4f.5h., lh. 2f.3g.4f.5h., 1 j.2f.3g.4f.5h., lp.2f.3g.4f.5h., la.2i.3g.4f.5h., lb.2i.3g.4f.5h., li. 2i.3g.4f.5h., lh.2i.3g.4f.5h., lj.2i.3g.4f.5h., lp.2i.3g.4f.5h., la.2m.3g.4f.5h„ lb.2m.3g.4f.5h., lf.2m.3g.4f.5h., lh.2m.3g.4f.5h., lj.2m.3g.4f.5h., lp.2m.3g.4f.5h., la. 2o.3g.4f.5h., lb.2o.3g.4f.5h., lf.2o.3g.4f.5h„ lh.2o.3g.4f.5h., lf.2o.3g.4f.5h., lp.2o.3g.4f 5h., la.2u.3g.4f.5h., lb.2u.3g.4f.5h., lf.2u.3g,4f.5h., lh.2u.3g.4f.5h„ lj. 2u.3g.4f.5h., lp.2u.3g.4f 5h., la.2y.3g.4f.5h., Ib.2y.3g.4f5h., lf.2y.3g.4f.5h., Jh.2y.3g.4f5h., Ij.2y.3g.4f.5h., Ip.2y.3g.4h5h., la.2a.3a.4g.5h., lb.2a.3a.4g.5h., lf.2a.3a.4g.5h., lh.2a.3a.4g.5h., 1j.2a.3a.4g.5h., lp.2a.3a.4g.5h., la.2b.3a.4g.5h., lb. 2b.3a.4g.5h., lf.2b.3a.4g.5h., lh.2b.3a.4g.5h., lj.2b.3a.4g.5h., lp.2b.3a.4g.5h., la. 2e.3a.4g.5h., lb.2e.3a.4g.5h., 1f.2e.3a.4g.5h., lh.2e.3a.4g.5h., lj.2e.3a.4g.5h., lp.2e.3a.4g.5h., la.2f.3a.4g.5h., lb.2f.3a.4g.5h., lf.2f.3a.4g.5h., lh.2f.3a.4g.5h., lj.2f.3a.4g.5h., lp.2f.3a.4g.5h., 1a.2i.3a.4g.5h., lb.2i.3a.4g.5h., lf.2i.3a.4g.5h., lh.2i.3a.4g.5h., lj.2i.3a.4g.5h„ lp.2i.3a.4g.5h,, la.2m.3a,4g.5h., lb,2m.3a,4g.5h., lf.2m.3a.4g.5h., lh.2m.3a.4g.5h., lj.2m.3a.4g.5h., lp.2m.3a.4g.5h., la.2o.3a.4g,5h., lb. 2o.3a.4g.5h., Ih2o.3a.4g.5h., lh.2o.3a.4g.5h., lj.2o.3a.4g.5h., lp.2o.3a.4g.5h., la. 2u.3a.4g.5h., lb.2u.3a.4g.5h., lf.2u.3a.4g.5h., lh.2u.3a.4g.5h., lj.2u.3a.4g.5h., lp.2u.3a.4g,5h., la.2y.3a.4g.5h., lb.2y.3a.4g.5h., lf.2y.3a.4g.5h., lb.2y.3a.4g.5h., lj.2y.3a.4g.5h., lp.2y.3a.4g.5h., la.2a.3b.4g.5h., lb.2a.3b.4g.5h„ lf2a.3b.4g.5h„ lh.2a.3b.4g.5h., lj.2a.3b.4g.5h., lp.2a.3b.4g.5h., la.2b.3b.4g.5h., lb.2b.3b.4g.5h., lf.2b.3b.4g.5h., lh.2b.3b.4g.5h., lj.2b.3b.4g.5h., lp.2b.3b.4g.5h., la.2e.3b.4g.5h., lb. 2e.3b.4g.5h., lf.2e.3b.4g.5h., lh.2e.3b.4g,5h., lj.2e.3b.4g.5h„ lp.2e.3b.4g.5h., la. 2f.3b.4g.5h., Ib.2h3b.4g.5h., If2f.3b.4g.5h„ lh.2f.3b.4g.5h„ lj.2f.3b.4g.5h„ lp.2f.3b.4g.5h., la.2i.3b.4g.5h., lb.2i.3b.4g.5h„ lf.2i.3b.4g.5h., lh.2i.3b.4g.5h., l].2i.3b-4g.5h., lp.2i.3b.4g.5h., la.2m.3b.4g.5h., lb.2m.3b.4g.5h., lf.2m.3b.4g.5h., lh,2m.3b.4g.5h., lj.2m.3b.4g.5h., lp.2m.3b.4g.5h., la.2o.3b.4g.5h., lb.2o.3b.4g.5h., lf.2o.3b.4g.5h., J h.2o.3b.4g.5h., lj.2o.3b.4g.5h., lp.2o.3b.4g.5h., la.2u.3b.4g.5h., lb. 2u.3b.4g.5h., lf.2u.3b.4g.5h., lh.2u.3b.4g.5h., lj.2u.3b.4g.5h., lp.2u.3b.4g.5h., la. 2y.3b.4g.5h., lb.2y.3b.4g.5h., lf.2y.3b.4g.5h., lh.2y.3b.4g.5h., lj.2y.3b.4g.5h., lp.2y.3b.4g.5h., Ia.2a.3e.4g,5h., lb.2a.3e.4g.5h., lf.2a.3e.4g.5h., lh.2a.3e.4g.5h., Jj.2a.3e.4g.5h., lp.2a.3e.4g.5h., la.2b.3e.4g.5h., lb.2b.3e.4g.5h., lf.2b.3e.4g.5h., lh.2b.3e.4g.5h., lj.2b.3e.4g.5h., lp.2b.3c.4g.5h., la.2c.3e.4g.5h., lb.2c.3c.4g.5h., lf.2e.3e.4g.5h., lh.2e.3e.4g.5h., 1j,2e.3e.4g.5h., lp.2e.3e.4g.5h., la.2f.3e.4g.5h., lb. 2f.3e.4g.5h., lf.2f.3e.4g.5h., lh.2f.3c.4g.5h., lj.2f.3e.4g.5h., Ip.2f3e.4g.5h,, la. 2i.3e.4g.5h., lb.2i.3e.4g.5h., lf.2i.3e.4g.5h., lh.2i.3e.4g.5h., lj.2i.3e.4g.5h., lp.2i.3e.4g.5h., la.2m.3e.4g.5h., lb.2m.3e.4g.5h., lf.2m.3e.4g.5h., lh.2m,3e.4g.5h., lj.2m.3e.4g.5h., lp.2m.3e.4g.5h,, la.2o.3e.4g.5h., lb.2o.3e.4g.5h., lf.2o.3c.4g.5h., lh,2o.3e.4g.5h., lj.2o.3e.4g.5h., lp.2o.3e.4g.5h., la.2u.3e.4g.5h., lb.2u.3e,4g.5h., lf.2u.3e.4g.5h., lh.2u.3e.4g.5h., lj.2u.3e.4g.5h., lp.2u.3e.4g.5h., la.2y.3e.4g.5h., lb. 2y.3c.4g.5h., lf.2y.3e.4g.5h., lh.2y.3e.4g.5h., lj.2y.3e.4g.5h., lp.2y.3e.4g.5h.,

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2020203321 21 May 2020 la. 2a.3g.4g.5h,, lb.2a.3g.4g.5h., lf.2a.3g.4g.5K, lK2a.3g.4g.5K, lj.2a.3g.4g.5h„ lp.2a.3g.4g.5h., la.2b.3g.4g.5h., 1b.2b.3g.4g.5h., lf.2b.3g.4g.5h., lh.2b.3g.4g,5h., lj.2b.3g.4g.5K, lp.2b.3g.4g.5K, la.2e.3g.4g.5K, lb.2e.3g.4g.5K, lf.2e.3g.4g.5K, lh.2e.3g.4g.5h„ lj.2e.3g.4g.5K, lp.2e.3g.4g.5K, la.2f.3g.4g.5K, lK2f.3g.4g.5K, lf.2f.3g.4g.5K, lh.2f.3g.4g.5h., lj.2f.3g.4g.5K, lp.2f.3g.4g.5K, la.2i.3g.4g.5h, lb. 2i.3g.4g.5K, lf.2i.3g.4g.5K, lK2i.3g.4g.5K, lj.2i.3g.4g.5K, lp.2i.3g.4g.5K, la. 2m.3g.4g.5K, lb.2m.3g.4g.5K, lf.2m.3g.4g.5K, lK2m.3g.4g.5K, lj.2m.3g.4g.5K, lp.2m.3g.4g.5K, la.2o.3g.4g.5K, lb.2o.3g.4g.5K, lf.2o.3g.4g.5K, lK2o,3g.4g.5K, lj.2o.3g.4g.5h., lp.2o.3g.4g.5K, la.2u.3g.4g.5K, lb.2u.3g.4g.5K, lf.2u.3g.4g.5K, lh.2u.3g.4g.5K, lj.2u.3g.4g.5h., lp.2u.3g.4g.5K, la.2y.3g.4g.5K, lb.2y.3g.4g.5K, If.2y.3g.4g,5K, lh.2y.3g.4g.5K, lj.2y.3g.4g,5K, 1p.2y.3g.4g.5K, la.2a.3a.4K5K, lb. 2a.3a.4K5K, lf.2a.3a.4h.5h., lh.2a.3a.4h.5K, lj.2a.3a.4h.5K, lp.2a.3a.4K5K, la. 2b.3a.4K5K, lb.2b.3a.4K5K, lf.2b.3a.417.5h., lh.2b.3a.4h.5h., lj.2b.3a.4K5K, lp.2b.3a.4K5K, la.2e.3a.417.5h., lb.2e.3a.4K5K, lf.2e.3a.4l7.5h., lh.2e.3a.4K5K, lj.2e.3a.4h.5K, lp.2e.3a.4K5K, la.2f.3a.4K5K, lb.2f.3a.4K5K, lf.2f.3a.4h.5h., lh.2f.3a.4K5K, lj.2f.3a.4l7.5h., lp.2f.3a.4K5K, la.2i.3a.4K5K, lb.2i.3a.4K5K, lf.2i.3a.4K5K, lh.2i.3a.4K5K, lj.2i.3a.4K5K, lp.2i.3a.4h.5K, la.2m.3a.4K5K, lb. 2m.3a.4K5K, lf.2m.3a.4K5K, lh.2m.3a.4K5K, lj.2m.3a.4K5K, lp.2m.3a.4h.5h., la. 2o.3a.4h.5h., lb.2o.3a.417.5K, lf.2o.3a.4K5K, lh.2o.3a.4h.5K, lj.2o.3a.417.5K, lp.2o.3a.4K5K, la.2u.3a.4K5K, lb.2u.3a.4h.5K, lf.2u.3a.4K5K, lh.2u.3a.4K5K, lj.2u.3a.4h.5l7., 1p.2u.3a.4K5K, la.2y.3a.4K5K, lb.2y.3a.4h.5K, lf.2y.3a.4h.5K, lh.2y.3a.4K5K, lj.2y.3a.4K5K, lp.2y.3a.4K5K, la.2a.3b.4K5K, lb.2a.3b.4K5K, lf.2a.3b.4h.5K, lh.2a.3b.4h.5h., lj.2a.3b.4h.5K, lp.2a.3b.4K5K, la.2b.3b.4K5K, lb. 2b.3b.4K5K, lf.2b.3b.4K5K, lh.2b.3b.4h.5K, lj.2b.3b.4h.5h., lp.2b.3b.4K5K, la. 2e.3b.4h.5h., lb.2e.3b.4h.5K, lf.2e.3b.4K5K, lK2e.3b.4K5K, lj.2e.3b.417.517., lp.2e.3b.4h.5h., la.2f.3b.4K5K, lb.2f.3b.4K5K, 1f.2f.3b.4K5K, lh.2f.3b.4h.5K, lj.2f.3b.4h.5K, lp.2f.3b.4K5K, la.2i.3b.4h.5K, lb.2i.3b.4K5K, lf.2i.3b.4K5K, Ih.2i.3b.4h.5K, lj.2i.3b.4K5K, lp.2i.3b.417.5h., 1a.2m.3b.4K5K, lb.2m.3b.4h.5h„ lf.2m.3b.4l7.5h., lh.2m.3b.417.5h., lj.2m.3b.4K5K, lp.2m.3b.417.5h., la.2o.3b.4K5K, lb. 2o.3b.4K5K, lf.2o.3b.4h.5K, lh.2o.3b.4K5K, lj.2o.3b.4h.5h., lp.2o.3b.4K5K, la. 2u.3b.4h.5h., lb.2u,3K4h.5K, lf.2u.3b.4K5K, lh.2u.3b.4K5K, lj.2u.3b.4K5K, lp.2u.3b.4K5K, la.2y.3b.4K5K, lb.2y.3b.4h.5K, 1 f.2y.3b.4h.5h., lh.2y.3b.4h.5K, lj.2y.3b.4h.5h., lp.2y.3b.4K5K, la.2a.3e.4K5K, lb.2a.3e,4h.5h„ lf.2a.3e.4K5K, JK2a.3e.4K5K, lj.2a.3e.4K5K, lp.2a.3e.4h.5K, la.2b.3e.4K5K, lb.2K3e.4h.5K, lf.2b.3e.4K5K, lh.2K3e.4h.5K, lj.2b.3e.4h.5h., lp.2b.3e.4h.5K, la.2e.3e.4h.5K, lb. 2e.3e.4h.5h., lf.2e.3e.4h.5K, lh.2e.3e.4h.5h., lj.2e.3e.4h.5K, lp.2e.3e.4h.5K, la.2f.3e.4K5K, lb.2f.3e.4K5K, lf.2f.3e.4K5K, lh.2f.3e.4K5h., lj.2f.3c.4K5K, Jp.2f.3c.4K5K, la.2i.3e.4K5K, lb.2i.3e.4K5K, lf.2L3e.4K5K, lh.2L3e.4K5K, lj.2i.3e.4K5K, 1p.2i.3c.4K5K, la.2m.3e.4K5K, lb.2m.3e.4K5K, lL2m.3e.4K5K, Jh.2m.3e.4h.5h., lj.2m.3e.4K5K, lp.2ni.3e.4K5K, la.2o.3e.4K5K, lb.2o.3e.4h.5K, lf.2o.3e.4K5K, lh.2o.3e.4K5K, lj.2o.3e.4K5K, lp.2o.3c.4h.5K, la.2u.3e.4K5K,

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2020203321 21 May 2020 lb.2u.3e.4h.5h, lf_2u.3e.4h.5h, lh.2u.3e.4h.5h., lj.2u.3e.4h.5h„ lp.2u.3e.4h.5h, la. 2y.3e.4h.5K, lb.2y.3e.4h.5K, lf.2y.3e.4h.5h, lh.2y.3e.4h.5h„ lj.2y.3e.4K5h, lp.2y.3e.4h.5h., la.2a.3g.4h.5h., lb.2a.3g.4h.5h., lf.2a.3g.4h.5h, lh.2a.3g.4h.5h., lj.2a.3g.4h.5h, lp.2a.3g.4h.5h, la.2b.3g.4h.5h, lb.2b.3g.4h.5h, lf.2b.3g.4K5h, 'lh.2b.3g.4K5K, lj.2b.3g.4h.5K, lp.2b.3g.4h.5K, la.2e.3g.4h.5K, lb.2e.3g.4K5K, lf.2e.3g.4h.5K, lK2e.3g.4K5K, lj.2e.3g.4K5K, lp.2e.3g.4K5h, la.2f.3g.4K5K, lb. 2f.3g.4h.5K, lf.2f.3g.4K5h, lh.2f.3g.4h.5h„ lj.2f.3g.4h.5K, lp.2f.3g.4h.5K, la. 2i.3g.4K5K, lb.2i.3g.4h.5h, lL2i.3g.4h.5h., lh.2i.3g.4K5K, lj.2i.3g.4K5h., lp.2i.3g.4h.5h., la.2m.3g.4h.5K, lb.2m.3g.4h.5K, lf.2m.3g.4h.5K, lh.2m,3g.4h.5h,, lj.2in.3g.4h.5h, lp.2m.3g.4h.5h_, 1a.2o.3g.4K5K, lb.2o.3g.4h.5K, 1 f.2o.3g,4h.5h, lh.2o.3g.4h.5K, lj.2o.3g.4h.5K, lp.2o.3g.4K5h., la.2u.3g.4h.5K, lb.2u.3g.4K5K, lf.2u.3g.4h.5K, lh.2u.3g.4h.5K, 1j.2u.3g.4h.5h., lp.2u.3g.4K5h, la.2y.3g.4h.5K, lb. 2y.3g.4K5K, 'lf.2y.3g.4h.5K, lh.2y.3g.4h.5h., lj.2y.3g.4K5K, lp.2y.3g.4K5K, la. 2a.3a.4i.5K, lb.2a.3a.4i.5h., lf.2a.3a.4i.5h, lh.2a.3a.4L5h, lj.2a.3a.4i.5h., lp.2a.3a.4i.5K, la.2b.3a.4i.5K, lb.2b.3a.4i.5K, lf.2b.3a.4i.5K, lh.2b.3a.4i.5K, lj.2b.3a.4L5h., lp.2b.3a.4i.5K, la.2e.3a.4i.5h_, lb.2e.3a.4i.5h., lf.2e.3a.4i.5K, lh.2e.3a.4i.5K, lj.2e.3a.4i.5h., lp.2e.3a.4i.5K, la.2f.3a.4i.5K, lb.2f.3a.4i.5h„ lf.2f.3a.4i.5K, lK2f.3a.4i.5h„ lj.2f.3a.4i.5h, lp.2f.3a.4L5K, la.2i.3a.4i.5K, lb. 2i.3a.4L5h, lf.2i.3a.4i.5K, lh.2i.3a.4i.5h, lj.2i.3a.4i.5h, lp.2i.3a.4i.5h, la. 2m.3a.4i.5K, 1b.2m.3a.4i.5h, 1f.2m.3a.4i.5h, lh.2m.3a.4i.5h, lj.2m.3a.4i.5h, lp.2m.3a.4i.5h, la.2o.3a_4i.5h, lb.2o.3a.4i.5h, lf.2o.3a.4i.5h, lh.2o.3a.4i.5h, 1j.2o.3a.4i.5h, 1p.2o.3a.4i.5h, la.2u.3a.4i.5h, lb.2u.3a.4i.5h., 1f.2u.3a.4i.5h, lh.2u.3a.4i.5K, lj.2u.3a.4i.5h, lp.2u.3a,4i.5h, la.2y,3a.4i,5h, lb,2y.3a,4i.5h, lf.2y.3a.4i.5K, lh.2y.3a.4i.5K, lj.2y.3a.4i.5h, lp.2y.3a.4i.5K, la.2a.3b.4i.5K, lb. 2a.3b.4i.5h, lf.2a.3b.4i.5h, lh.2a.3b.4i.5h, lj.2a.3b.4i.5h, lp.2a.3b.4i.5h, la. 2b.3b.4i.5h, lb.2b.3b.4i.5h, lf.2b.3b.4i.5K, lh.2b.3b.4i.5h, lj.2b.3b.4i.5h, lp.2b.3b.4i.5h„ la.2e.3b.4i.5h, lb.2e.3b.4i.5h, lf.2e.3b.4i.5h, lh.2e.3b.4i.5h, 'lj.2e.3b.4i.5K, lp.2e.3b.4i.5K, la.2f.3b.4L5K, lb.2f.3b.4i.5h, lf.2f.3b.4i.5K, lh.2f.3b.4i.5K, lj.2f.3b.4i.5h, lp.2f.3b.4i.5K, la.2i.3b.4i.5h, lb.2i.3b.4i.5K, lf.2i.3b.4i.5h, lh.2i.3b.4i.5h, lj.2i.3b.4i.5h, lp.2i.3b.4i.5h, la.2m.3b.4i.5h, lb. 2m,3b.4i.5h, lf.2m.3b.4i.5h, lh.2m.3b.4i.5h, lj.2m.3b.4i.5h, 1p.2m.3b.4i.5h, la. 2o.3b.4i.5h, lb.2o.3b.4L5h, lf.2o.3b.4i.5h, lh.2o.3b.4i.5h, lj.2o.3b_4i.5h, lp.2o,3b.4i.5h, la.2u.3b.4i.5h, 1b.2u.3b.4i.5h, lf.2u.3b.4i.5h, lh.2u.3b.4i.5h, lj.2u.3b.4i.5h, lp.2u.3b.4i.5h, la.2y.3b.4i.5h, lb.2y.3b.4i.5h, lf.2y.3b.4i.5K, lh.2y.3b.4i.5h, lj_2y.3b.4i.5h, lp.2y.3b.4i.5h, la.2a.3e.4i.5h, Jb.2a.3e.4i.5h„ lf.2a.3e.4i.5h, lh.2a.3e.4i.5h, lj.2a.3e.4i.5h, lp.2a.3e.4i.5h, la.2b.3e.4i.5h, lb. 2b.3c.4i.5h, 'lf.2b.3e.4i.5K, lh.2b.3c.4L5h, lj.2b.3e.4i.5K, 1p.2b.3e.4i.5h, la.2e.3e.4i.5h, lb.2e,3e.4i.5h, lf.2e.3e,4i.5h, lh.2e.3e.4i.5h, lj.2e,3e,4i.5h, lp.2e.3e.4i.5h, la.2f.3o.4i.5h, lb.2f.3e.4i.5h, lf.2f.3e.4i.5h, lh.2f.3c.4i.5K, lj.2f.3e.4i.5h, lp.2f.3e.4i.5h, la.2i.3e.4i.5h, lb.2i.3e.4i.5K, 1 f.2i.3e.4i.5h, lh.2i.3e.4i.5h, lj.2i.3e.4i.5h,, lp.2i.3e.4i.5K, la.2m.3e.4i.5h, lb.2m.3e.4i.5K,

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PCT/US 2008/054788 lf.2m.3c.4i.5h., lh.2m.3e.4i.5h_, lj.2m.3e.4i.5h., lp.2m.3e.4i.5h., la.2o.3e.4L5K, lb.2o.3e.4i.5h., lf.2o.3e.4i.5K, lh.2o.3c.4i.5h., lj.2o.3e.4L5K, lp.2o.3e.4L5h., la. 2u.3e.4i.5h., Ib.2u.3e.4i.5h., lf.2u.3e.4i.5h_, lh.2u.3e.4i.5h_, lj.2u.3c.4i.5h_, lp.2u.3e.4i.5h., la.2y.3e.4L5K, lb.2y.3e.4i.5h., lf.2y.3e.4i.5h., lh.2y.3e.4i.5h., lj.2y.3e.4i.5h_, 1 p.2y.3e.4i.5h., la.2a.3g.4i.5h., lb.2a,3g.4i.5h., 1 f _2a.3g.4L5h., lb. 2a.3g.4i.5h., lj.2a.3g.4i.5h., lp.2a.3g.4i.5h., la.2b.3g.4i.5h., lb.2b.3g.4i.5h., lf.2b.3g.4i.5h., lh.2b.3g.4i.5h., lj.2b.3g.4i.5h., 1p,2b.3g.4i.5h., 1a.2e.3g.4i.5h., lb.2e.3g.4i.5h., lf.2e.3g.4i.5K, lh.2e.3g.4i.5h,, lj,2e.3g.4i.5h., lp.2e.3g.4i.5h., la.2f.3g.4i.5h., lb.2f.3g.4i.5h., lf.2f.3g.4i.5h., lh.2f.3g.4i.5h., lj.2f.3g.4i.5h., lp.2f.3g.4i.5h., la.2i.3g.4i.5h., lb.2i.3g.4i.5h., lf.2i.3g.4i.5h., lh.2i.3g.4i.5h., lj.2i.3g.4L5K, lp.2i.3g.4i.5K, la.2m.3g.4i.5h., lb.2m.3g.4i.5h., lf.2m.3g.4L5K, lh.2m.3g.4i.5h,, lj.2m.3g.4i.5h., lp.2m.3g.4i.5h., la.2o.3g.4i.5h_, lb.2o.3g.4i.5h., lf.2o.3g.4i.5h., lh.2o.3g.4i.5h., lj.2o.3g.4i.5h., lp.2o.3g.4i.5h., la.2u.3g.4L5K, lb.2u.3g.4i.5h., lf.2u.3g.4i.5h., 1 h.2u.3g.4L5h_, lj.2u.3g.4i.5h., lp.2u.3g.4i.5h., la. 2y.3g.4i.5h_, lK2y.3g.4L5K, lf.2y.3g.4i.5K, lh.2y.3g.4L5K, 1j.2y.3g.4i.5K, lp.2y.3g.4i.5K, la.2a.3a.4a.5i., 1b.2a.3a.4a.5i., lf.2a.3a.4a.5i., lh.2a.3a.4a.5i„ lj.2a.3a.4a.5i., lp.2a.3a.4a.5i., la.2b.3a.4a.5i., lb.2b.3a.4a.5i., 1f.2b.3a.4a.5L, lh.2b.3a.4a.5i., lj.2b.3a.4a.5i., Ip.2b.3a.4a.5i., la.2e.3a.4a.5i., lb.2e.3a.4a.5i., lf.2e.3a.4a.5L, lh.2e.3a.4a.5L, lj.2e.3a.4a.5i., lp.2e.3a.4a.5i., la.2f.3a.4a.5i., lb. 2f.3a.4a.5i., lf.2f.3a.4a.5i., lh.2f.3a.4a.5L, lj.2f.3a.4a.5L, lp.2f.3a.4a.5i., 1 a.2L3 a. 4a.5i., lb.2i.3a.4a.5i_, lf.2i.3a.4a.5i., lh.2i.3a.4a.5i., lj.2i.3a.4a.5L, lp.2i.3a.4a.5i., la.2m.3a.4a.5i., lb.2m.3a.4a.5i., lf.2m.3a.4a.5i., lh.2m.3a.4a.5i., lj.2m.3a.4a.5i., lp.2m.3a.4a.5i., la.2o.3a.4a.5i., 'lb.2o.3a.4a.5L, lf.2o.3a.4a.5i_, lK2o.3a.4a.5i., lj.2o.3a.4a.5i., lp.2o.3a.4a.5L, la.2u.3a.4a.5L, lb.2u.3a.4a.5i., lf.2u.3a.4a.5i., lh.2u.3a.4a.5i., lj.2u.3a.4a.5i., lp.2u.3a.4a.5L, la.2y.3a.4a.5L, lb.2y.3a.4a.5i., lf.2y.3a.4a.5t, lh.2y.3a.4a.5L, lj.2y.3a.4a.5i., lp.2y.3a.4a.5t, la. 2a.3b.4a.5t, lb.2a.3b.4a.5t, lf.2a.3b.4a.5i., lh.2a.3b.4a.5L, lj.2a.3b.4a.5t,

p.2a.3b.4a.5L, la.2b.3b.4a.5t, lb.2b.3b.4a.5t, lf.2b.3b.4a.5t, lh.2b.3b.4a.5t, lj.2b.3b.4a.5t, lp.2b.3b.4a.5t, la.2e.3b.4a.5i., lb.2e.3b.4a.5t, lf.2e.3b.4a.5t, lh.2e.3K4a.5t, lj.2e.3b.4a.5t, lp.2e.3b.4a.5t, la.2f.3b.4a.5t, lb.2f.3b.4a.5t, lf.2f.3b.4a.5i., lh.2f.3b.4a.5t, lj.2f.3b.4a.5t, lp.2f.3b.4a.5t, la.2L3b.4a.5L, lb. 2i.3b.4a.5t, lf.'2i.3b.4a.5i., lh.2i.3b.4a.5t, lj.2L3b.4a.5t, lp.2L3b.4a.5L,

a.2m.3b.4a.5i., lb.2m.3b.4a.5L, lf.2m.3b.4a.5L, lh.2m.3b.4a.5L, lj.2m.3b.4a.5L, lp.2m.3b,4a.5L, la.2o.3b.4a.5L, lb.2o.3b.4a.5L, 1f.2o.3b.4a.5L, lh.2o.3b.4a.5L, Ij.2o.3b.4a.5L, 1p.2o.3b.4a,5L, la.2u.3b.4a.5L, lb.2u.3b.4a.5L, lf.2u.3b.4a.5i_, lh.2u.3b.4a.5L, lj.2u.3b.4a.5L, lp.2u.3b.4a.5L, la.2y.3b.4a.5L, lb.2y,3b.4a.5L, lf.2y.3b_4a.5i., lh.2y.3b.4a.5L, lj.2y.3b.4a.5L, lp.2y.3b.4a.5t, la.2a.3e.4a.5i., lb.2a.3e.4a.5L, lf.2a.3e.4a.5L, lK2a.3c.4a.5L, lj.2a.3e.4a.5L, lp.2a.3e.4a.5L, la.2b.3e.4a.5L, lb.2b.3e.4a.5L, lf.2b.3e.4a.5L, lh.2b.3e.4a.5L, lj.2b.3e.4a.5i., lp.2b.3e.4a.5L, la.2e.3e.4a.5L, lb.2e.3e.4a.5L, lf.2e.3e.4a.5L, lh.2e.3e.4a.5L, 1j.2e.3e.4a.5L, lp.2e.3e.4a.5i., la.2f,3e.4a.5L, 1b.2f.3e,4a.5L, lf.2f.3e,4a.5i.,

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2020203321 21 May 2020 lh.2f.3e.4a.5i., lj.2f.3e.4a.5i., lp.2f.3e.4a.5i., la.2i.3e.4a.5i., lb.2L3e.4a.5L, lf.2i.3e.4a.5i., lh.2i.3e.4a.5i., lj.2i.3e.4a.5i., 1p.2i.3c.4a.5i., la.2m.3e.4a.5L, lb.2m.3e.4a,5i., lf.2m.3e.4a.5i., lh.2m.3e.4a.5L, lj.2m.3e.4a.5i., lp.2m.3e.4a,5i., la. 2o.3e.4a.5i., 1 b.2o.3e.4a.5L, lf,2o.3e.4a,5i., lh.2o.3e.4a.5i., lj.2o.3e.4a.5i„ lp.2o.3e.4a.5i., la.2u.3e.4a.5i., lb.2u.3e.4a.5i., lf.2u.3e.4a.5i., lh.2u.3e.4a.5i., lj.2u.3e.4a.5i., lp.2u.3e.4a.5i., la.2y.3e,4a.5L, lb.2y.3e.4a.5i., lf.2y.3e.4a.5L, lh.2y.3e.4a.5L, lj.2y.3e.4a.5i., lp.2y.3e.4a.5L, la.2a.3g.4a.5L, lb.2a.3g.4a .51., lf.2a.3g.4a.5i., lh.2a.3g.4a.5i., lj.2a.3g.4a.5i., lp.2a.3g.4a.5i., la.2b.3g.4a.5i., lb. 2b.3g.4a.5i., lf.2b.3g.4a.5i., 1h.2b.3g.4a.5i., lj,2b.3g.4a.5i., lp.2b.3g.4a.5i., la. 2e.3g.4a.5i., lb.2e.3g.4a.5i., lf.2e.3g.4a.5i., lh.2c.3g.4a.5i., lj.2e.3g.4a.5i., lp.2e.3g.4a.5L, la.2f.3g.4a.5i., lb.2f.3g.4a.5i., lf.2f.3g.4a,5i., lh.2f.3g.4a.5i., 1 j.2f.3g.4a.5L, 1p.2f.3g.4a.5L, la.2i.3g.4a.5i., lb.2i.3g.4a.5i., lf.2L3g.4a.5L, lh.2L3g.4a.5L, lj.2i.3g.4a.5i., lp.2L3g.4a.5i., la.2m.3g.4a.5L, lb.2m.3g.4a.5i., lf.2m.3g.4a.5L, lh.2m.3g.4a.5L, lj.2m.3g.4a.5L, lp.2m.3g.4a.5L, la.2o.3g.4a.5L, lb. 2o.3g.4a.5L, lf.2o.3g.4a.5L, lh.2o.3g.4a.5L, lj.2u.3g.4a.5i., 1p.2o.3g.4a.5i., la. 2u.3g.4a.5i., lb.2u.3g.4a.5L, lf.2u.3g.4a.5L, lh.2u.3g.4a.5i., lj.2u.3g.4a.5L, lp.2u.3g.4a.5L, la.2y.3g.4a.5L, lb.2y.3g.4a.5L, lf.2y.3g.4a.5L, lh.2y.3g.4a.5L, lj.2y.3g.4a.5L, lp.2y.3g.4a.5L, la.2a.3a.4d.5i., 1b.2a.3a.4d.5L, lf.2a.3a.4d.5L, lh.2a.3a.4d.5L, lj.2a.3a.4d.5L, lp.2a.3a.4d.5L, la.2b.3a.4d.5L, lb.2b.3a.4d.5L, 1f.2b.3a.4d.5L, lh.2b.3a.4d.5L, lj.2b.3a.4d.5L, lp.2b.3a.4d.5L, la.2e.3a.4d.5L, lb. 2e.3a.4d.5L, lf.2e.3a.4d.5L, lh.2e.3a.4d.5L, lj.2e.3a.4d.5L, lp.2e.3a.4d.5L, la. 2f.3a.4d.5L, lb.2f.3a.4d.5L, lf.2f.3a.4d.5L, lh.2f.3a.4d.5L, lj.2f.3a.4d.5i„ lp.2f.3a,4d.5i., la.2L3a.4d.5L, lb.2i.3a.4d.5L, lf.2L3a.4d.5L, lh.2L3a.4d.5L, lj.2i.3a.4d.5i., lp.2i.3a.4d.5i., la.2m.3a.4d.5L, lb.2m.3a.4d.5L, lf.2m.3a,4d.5i., lh.2m.3a.4il.5L, lj.2m.3a.4d.5i., lp.2m.3a.4d.5L, la.2o.3a.4d.5L, lb.2o.3a.4d.5L, 'if.2o.3a.4d.5i., lh.2o.3a.4d.5i», lj.2o.3a.4d.5L, lp.2o.3a.4d.5L, la.2u.3a.4d.5L, lb. 2u.3a.4d.5i., lf.2u.3a.4d.5L, lh.2u.3a.4d.5i., lj.2u.3a.4d.5L, lp.2u.3a.4d.5L, la. 2y.3a.4d.5L, lb.2y.3a.4d.5L, 1 f.2y.3a.4d.5L, lh.2y.3a.4d.5L, lj.2y.3a.4d.5L, lp.2y.3a.4d.5L, la.2a.3b.4d.5i., lb.2a.3b.4d.5i., lf.2a.3b.4d.5L, lh.2a.3b.4d.5i., lj.2a.3b.4d.5L, lp.2a.3b.4d.5L, la.2b.3b.4d.5i., lb.2b.3b.4d.5L, lf.2b.3b.4d.5L, lh.2b.3b.4d.5i., lj.2b.3b.4d.5i., lp.2b.3b.4d.5L, la.2c.3b.4d.5L, lb.2e.3b.4d.51., lf.2e.3b.4d.5L, lh.2e.3b.4d.5L, lj.2e.3b.4d.5L, lp.2e.3b.4d.5L, la.2f.3b.4d.5i., lb. 2f.3b.4d.5L, lf.2f.3b.4d.51., lh.2f.3b.4d.5L, 1 j.2f.3b.4d.5i., lp.2f.3b,4d.5i„ la. 2i.3b.4d.5i„ lb.2i.3b.4d.51., lf.2L3b.4d.5L, lh.2i.3b.4d.5L, lj.2L3b.4d.5L, lp.2i.3b.4d.5i., la.2m.3b.4d.5i., lb.2m.3b.4d.5i., lf.2iTL.3b.4d.5i., lh.2m.3b.4d.5L, lj.2m.3b.4d.5i., lp.2m.3b.4d.5L, la.2o.3b.4d.5L, lb.2o.3b.4d.5L, lf.2o.3b.4d.5i., lh.2o.3b.4d.5L, lj.2o.3b.4d.5L, lp.2o.3b.4d.5L, la.2u.3b.4d.5i., lb.2u.3b.4d.5L, lf.2u.3b.4d.5L, lh.2u.3b.4d.51., lj.2u.3b.4d.5i., lp.2u.3b.4d.5L, la.2y.3b.4d.5L, lb. 2y.3b.4d.5L, lf.2y.3b.4d.5L, lh.2y.3b.4d.5L, lj.2y.3b.4d.5L, lp.2y.3b.4d.5L, la.2a.3e.4d,5L, lb.2a.3e.4d.5L, lf.2a.3e.4d.5i., lh.2a.3e.4d.5i., lj.2a.3e.4d.5L,

Ip.2a.3e.4d.5L, la.2b.3e.4d.5L, lb.2b.3e.4d.5L, lf.2b.3e.4d.5L, lh.2b.3e.4d.5L,

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2020203321 21 May 2020 lj.2b.3e.4d.5i, lp,2b.3e.4d.5i, la.2e.3e.4d.5i., lb.2e.3e,4d.oi, lf.2e.3e.4d.5i, lh.2e.3e.4d.5i, lj.2e.3e.4d.5i,, lp.2e.3e.4d.5i., la.2f.3e.4d.5i, lb.2f.3e.4d.5i„ lf.2f.3e.4d.5i., lh.2f3c.4d.5L, lj.2f.3e.4d.5L, lp,2f.3e.4d.5i, la.2i.3e.4d.5i., lb.2i.3e.4d.5i., If.2i3e.4d.5i, lh.2L3e.4d.5i-, 1j.2i.3e.4d.5i., 1p.2i.3c.4d.5i, la. 2m,3e.4d.5i„ lb.2m.3e.4d.5i, lf2m.3c.4d.5i., Ih.2m3e.4d.5i„ lj.2m3e.4d.5L, lp.2m.3e.4d.5i., la.2o.3e.4d.5i., lb.2o.3e.4d.5i., lf.2o.3e.4d.5i, lh.2o.3e.4d.5i., Ij.2o3e.4d.5i, 1p.2o.3c.4d.5i, la.2u.3e.4d.5i, lb.2u.3e.4d.5i, lf.2u.3e.4d.5i, lh.2u.3e.4d.5i, lj.2u.3e.4d.5i., lp.2u.3e.4d.5i., la.2y.3c.4d.5i, lb.2y.3e.4d.5i., lf.2y.3e.4d.5i., lh.2y3e.4d.5i, lj.2y.3e.4d.5i, Ip.2y3e.4d.5i, la.2a.3g.4d.5i, lb. 2a.3g.4d.5i., lf.2a.3g.4d,5i, lh.2a.3g.4d.5i, lj.2a.3g.4d.5i., lp.2a.3g.4d.5i, la. 2b.3g.4d.5i-, 1b.2b.3g.4d.5i., lf.2b.3g.4d.5L, lh.2b.3g.4d.5i., Ij.2b3g.4d.5i, lp.2b.3g.4d.5i., la.2e.3g.4d.5L, lb.2e.3g.4d.5i., lf.2e.3g.4d.5i, lh.2c.3g.4d.5L, lj.2e-3g.4d.5i., lp.2e.3g.4d.5i, la.2f.3g.4d.5i, lb.2L3g.4d.5i., lf.2f.3g.4d.5L, lh.2f.3g.4d.5i., lj.2f.3g.4d.5L, lp.2f.3g.4d.5i, la.2i.3g.4d.5i., lb.2L3g.4d.5i„ lf.2i.3g.4d.5i., lh.2i.3g.4d.5i., lj.2i,3g.4d.5i., lp.2i.3g.4d.5i., la.2m.3g.4d.5i, lb. 2m.3g.4d.5i., lf2m.3g,4d.5i., lh.2m.3g.4d.5i., lj.2m.3g.4d.5L, lp.2m.3g.4d.5i., la. 2o3g.4d.5i., lb.2o.3g.4d.5i„ lf.2o.3g.4d.5i., lh.2o.3g.4d.5i, lj.2o.3g.4d.5i., Ip.2o3g.4d.5i., la.2u.3g.4d.5i., Ib.2u3g.4d.5i., lf.2u.3g.4d.5i., Ili.2u3g.4d.5i., Ij.2u3g.4d.5i, lp.2u.3g.4d.5i., la.2y.3g.4d.5i, lb.2y.3g.4d.5i, If.2y3g.4d.5i, lh.2y.3g.4d.5i., Ij.2y3g.4d.5i., Ip.2y3g.4d.5i., la.2a.3a.4f.5i, lb.2a.3a.4f.5i., If.2a3a.4f.51., lh.2a.3a.4f.5i., Ij.2a3a.4f.5i„ lp.2a.3a.4f,5i, la.2b.3a.4f.5i, lb. 2b.3a.4f.5i., lf.2b.3a.4f.5i, 1 h.2b.3a.4f.5L, lj.2b.3a.4f.5i, lp.2b.3a.4f.5L, la. 2e.3a.4f.5i„ lb.2e3a.4f.5i, lf.2e3a.4f.5L, Ih.2e.3a.4f.5i., lj.2e.3a.4f.5L, lp.2e.3a.4f.5i., la.2f.3a.4f.5L, lb.2f.3a.4f.5L, lf.2f.3a.4f.5L, lh.2f3a.4f.5i, lj.2f3a.4f.5L, lp.2f3a.4f.5i, la.2i.3a.4f.5L, lb.2i3a.4f.5i, lf.2i3a.4f.5i, lh.2i3a.4f.5i., lj.2L3a.4f.5i, lp.2L3a.4f.5L, la.2m3a.4f.5L, lb.2m.3a.4f.5i, lf.2m3a.4f.5i, lh.2m.3a.4f.5L, lj.2in.3a.4f.5i, lp.2m.3a.4f.5i, la.2o3a.4f.5i„ lb. 2o3a.4f.5i, 1f.2o.3a.4f.5i, lh.2o.3a,4f.5L, lj.2o3a.4f.5L, lp.2o.3a.4f.5L, la. 2u.3a.4f.5i, lb.2u.3a.4f.5i, lf.2u.3a.4f.5i, lh.2u.3a.4f.5i, lj.2u.3a.4f.5i, lp.2u.3a.4f.5i, la.2y.3a.4f.5i, lb.2y3a.4f.5i, lf.2y3a.4f.5i, lh.2y.3a.4f.5L, lj.2y.3a.4f.5i, lp.2y.3a.4f.5L, 1a.2a3b.4f.5i, lb.2a.3b.4f.5i, lf,2a.3b.4f.5i, lh.2a3b.4f.51, lj.2a.3b.4f.5L, lp.2a3b.4f.5L, la.2b3b.4f.5i, lb.2b.3b.4f.5i, lf.2b.3b.4f.5i, lh.2b.3b.4f.5i, lj.2b.3b.4f.5i„ lp.2b.3b.4f.5i, la.2e.3b.4f.5L, lb. 2c3b.4f.5L, lf.2c.3b.4f.5i, lh.2e.3b.4f.5i, lj.2e3b.4f.5L, lp.2e.3b.4f.5i, la. 2f.3b.4f.5i, Ib.2f3b.4f.5i, 1 f.2f.3b,4f.5i, lh.2f.3b.4f.5L, lj.2f.3b.4f.5L, lp.2f.3b.4f.5L, la.2L3b.4f.5i, lb.2i.3b.4f.5i, lf.2i3b.4f.5i., Ih.2i3b.4f.5i, lj.2i3b.4f.5i, lp.2i.3b.4f.5i, la.2m.3b.4f.5L, lb.2m3b.4f.5i, lf.2m.3b.4f.5i, lh.2m.3b.4f.5i, lj.2m.3b.4f.5i, lp.2m.3b.4f.5i, la.2o.3b.4f.5i, lb.2o.3b.4f.5i, lf.2o.3b.4f.5i, 1h.2o3b.4f.5i, lj.2o.3b.4f.5i, lp.2o3b.4f.5i, la.2u.3b.4f.5i, lb. 2u.3b.4f.5i, lf.2u.3b.4f.5i, lh.2u.3b.4f.5i, lj.2u.3b.4f.5i, lp.2u.3b.4f.5L, la.2y.3b.4f.5i, lb.2y.3b.4f.5i, lf.2y.3b.4f.5L, lh.2y.3b.4f.5i, lj.2y3b.4f.5i.

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j.2i.3b.4g.5i, lp.2i.3b.4g.5i, la.2m.3b.4g.5i, lb.2m.3b.4g.5i, lf.2m.3b.4g.5i, lh,2m.3b.4g.5i, lj.2m.3b.4g.5i, 1p.2m.3b.4g.5i, la.2o.3b.4g.5i, lb.2o.3b.4g.5i, lf.2o.3b.4g.5i, lh.2o.3b.4g.5i, lj.2o.3b.4g.5i, lp.2o.3b.4g.5i, la.2u.3b.4g.5i.

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2020203321 21 May 2020 lb.2u.3b.4g.5i., l£2u.3b,4g.5i., lh.2u.3b.4g.5i., lj.2u.3b.4g.5i., lp.2u.3b.4g.5i., la.2y.3b.4g.5i., lb.2y.3b.4g.5L, l£2y.3b.4g.5L, lh.2y.3b.4g.5L, lj.2y.3b.4g.5L, lp.2y.3b.4g.5i., la.2a.3e.4g.5i., 1b.2a.3c.4g.5L, lf.2a.3e.4g.5L, lh.2a.3e.4g.5L, lj.2a.3e,4g.5i., lp.2a.3e.4g.5i., la.2b.3e.4g,5i., 1b.2b.3c.4g.5i., lf.2b.3e.4g.5i., lh2b.3c.4g.5L, lj.2b.3e.4g.5i., lp.2b.3e.4g.5i., la.2e.3e.4g.5i., lb.2e.3e.4g.5i., lf.2e.3e.4g.5i., lh.2e.3e.4g.5L, lj.2e.3e.4g.5i„ lp.2e.3e.4g.5L, la.2f.3e.4g.5L, 1 b.2f.3e.4g.5L, lf.2f.3e.4g.5L, lh.2f.3c.4g.5i., lj.2E3e.4g.5L, lp.2f.3e.4g.5L, la. 2i.3e.4g.5i., lb.2i.3e.4g.5L, l£2L3e.4g.5L, lh.2i.3e.4g.5i., lj.2L3e.4g.5L, lp.2L3e.4g.5L, la.2m.3e.4g.5L, lb.2m.3e.4g.5L, lf.2m.3e.4g.5L, lh.2m.3e.4g.5L, lj.2m.3e.4g.5L, lp.2m.3c.4g.5L, la.2o.3e.4g.5L, lb.2o.3e.4g.5L, lf.2o.3e.4g.5L, lh.2o.3e.4g.5L, lj.2o.3e.4g.5L, lp.2o.3c.4g.5L, la.2u.3e.4g.5L, lb.2u.3e.4g.5L, lf.2u.3e.4g.5L, lh.2u.3e.4g.5i., lj.2u.3e.4g.5L, lp.2u.3c.4g.5L, la.2y.3e.4g.5i., lb. 2y.3c.4g.5L, lf.2y.3e.4g.5L, lh.2y.3e.4g.5L, lj.2y.3e.4g.5L, lp.2y.3e.4g.5L, la. 2a.3g.4g.5L, 1b.2a.3g.4g.5L, l£2a.3g.4g.5i., lh.2a.3g.4g.5L, lj.2a.3g.4g.5L, lp.2a.3g.4g.5i„ la.2b.3g.4g.5i., lb.2b.3g.4g.5L, lf.2b.3g.4g.5i., lh.2b.3g.4g.5i., lj.2b.3g.4g.5L, lp.2b.3g.4g.5L, la.2e.3g.4g.5L, 1b-2e.3g.4g.5i., lf.2e.3g.4g.5L, lh.2c.3g.4g.5L, lj.2e.3g.4g.5L, lp.2e.3g.4g.5L, la.2£3g.4g.5L, lb.2f.3g.4g.5L, l£2£3g.4g.5L, lh.2E3g.4g.5L, lj.2f.3g.4g.5L, lp.2f.3g.4g.5i., la.2L3g.4g.5L, lb. 2L3g.4g.5L, lf.2i.3g.4g.5L, lh.2L3g.4g.5L, lj.2L3g.4g.5L, lp.2i.3g.4g.5L, la. 2m.3g.4g.5i., lb.2m.3g.4g.5L, l£2m.3g.4g.5i., lh.2m.3g.4g.5L, lj.2m.3g.4g.5L, lp.2m.3g.4g.5L, la.2o.3g.4g.5L, lb.2o.3g.4g.5L, lf.2o.3g.4g.5L, lh.2o.3g.4g.5L, lj.2o.3g.4g.5L, lp.2o.3g.4g.5L, la.2ti.3g.4g.5L, 1b.2u.3g.4g.5i., lf.2u.3g.4g.5i., lh.2u.3g.4g.5i„ lj.2u.3g.4g.5i., lp.2u.3g.4g.5L, la.2y.3g.4g.5L, lb.2y.3g.4g.5L, lf.2y.3g.4g.5i., lh.2y.3g.4g.5L, lj.2y.3g.4g.5i., lp.2y.3g.4g.5i., la.2a.3a.4h,5L, lb. 2a.3a.4h.5L, lf.2a.3a.4h.5L, lh.2a.3a.4h.5i., lj.2a.3a.4fi.5i., lp.2a.3a.4h.5L, la. 2b.3a-4h.5i., lb.2b.3a.4h.5i., l£2b.3a.4h.5i., lh.2b.3a.4h.5L, lj.2b.3a.4h.5i., lp.2b.3a.4h.5i., la.2e.3a.4h.5L, lb.2e.3a.4h.5i„ lf.2e.3a.4h.5i., lh.2e.3a.4h.5i., 1j.2e.3a.4h.5i., lp.2e.3a.41t.5i., la.2E3a.4h.5i., lb.2f.3a.4h.5L, lf.2f.3a.4h.5L, lh.2f.3a.4h.5L, lj.2f.3a.4h.5L, lp.2£3a.4h.5L, la.2L3a.4h.5L, lb.2i.3a.4h.5i., lf.2L3a.4h.5L, lh.2i.3a.4h.5L, lj.2L3a.4h.5L, lp.2i.3a.4h.5L, la.2rn.3a.4h.5L, lb. 2ni.3a.4h.5L, lf.2m.3a.4h.5i., lh.2m.3a.4h.5L, lj.2m.3a.4h.5L, lp.2m.3a.4h.5L, la. 2o.3a.4h.5i., lb.2o.3a.4h.5L, lf.2o.3a.4h.5L, lh.2o.3a.4h.5L, lj.2o.3a.4h.5i., lp.2o.3a.4h.5i,, la.2u.3a.4h.5L, lb.2u.3a.4h.5i., lf.2u.3a.4h.5L, lh.2u.3a.4h.5i., lj.2u.3a.4h.5L, lp.2u.3a.4h.5L, la.2y.3a.4h.5L, lb,2y.3a.4h.5L, lf.2y.3a.4h.5L, lh.2y.3a.4h.5i., lj.2y.3a.4h.5i., lp,2y.3a.4h.5L, la.2a.3b.4h.5i., lb.2a.3b.4h.5L, lf.2a.3b.4h.5i„ lh.2a.3b.4h.5L, lj.2a.3b.4h.5L, lp.2a.3b.4h.5L, 1a.2b.3b.4h.5L, lb. 2b.3b.4h.5L, lf.2b.3b.4h.5L, lh.2b.3b.4h.5L, lj.2b.3b.4h.5L, lp.2b.3b.41i.5i., la.2e.3b.4h.5L, 1b.2e.3b.4h.5L, l£2e.3b.4h.5L, lh.2e.3b.4h.5i., lj.2e.3b,4h.5L, lp.2e.3b.4h.5L, la.2f.3b.4h.5i., lb.2f.3b.4h.5i., lf.2f.3b.4h.5L, lh.2f.3b.4h.5L, lj.2£3b.4Ii.5i., 1p.2f.3b.4h.5L, la.2L3b.4h.5L, lb.2i.3b.4h.5i., 1 E2L3b.4h.5L, lh.2i.3b.4h.5L, lj.2i.3b.4h.5L, lp.2i.3b.4h.5L, la.2m.3b.4h.5L, 1b.2m.3b.4h.5i.,

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2020203321 21 May 2020

If 2m.3b.4h.5i, lh.2m.3b.4h.5i, lj.2m.3b.4h.oi, lp.2m.3b.4h.5i, la.2o.3b.4h.5i, lb.2o3b.4h.5i, lf.2o3b.4h.5i, lli.2o.3b.4h.5i, lj.2o.3b.4h.5i, lp.2o.3b.4h.5i, la. 2u.3b.4h.5i, lb.2u.3b.4h.5i, lf.2u.3b.4h.5i, lh.2u.3b.4h.5i, lj.2u.3b.4h.5i, 1p.2u.3b.4h.5i, 'la.2y.3b.4h.5i, lb.2y.3b.4h.5i, lf2y.3b.4h.5i, lh.2y.3b.4h.5i, lj.2y.3b.4h.5i, lp.2y.3b.4h.5i, la.2a.3e.4h.5i, 1b.2a3e.4h.5i, lf.2a.3e.4h.5i, lh.2a.3e.4h.5i, lj.2a.3e.4h.5i, lp.2a.3e.4h.5i, la.2b.3e.4h.5i, lb.2b.3e.4h.5L, lf.2b.3e.4h.5i, lh.2b.3e.4h.5i, lj.2b.3e.4h.5i, lp.2b.3e.4h.5i, la.2e.3e.4h.5i, lb. 2e.3e.4h.5i, lf.2e.3e.4h.5i, lh.2e.3e.4h.5i, lj.2e.3e.4h.oi, lp.2e.3e.4h.5i, la. 2L3e.4h.5i, lb.2f3e.4h.5i, lf.2f.3e.4h.5i, lh.2f.3e.4h.5i, lj.2f3e.4h.5i, lp.2f.3e.4h.5i, la.2L3e.4h.5i, lb.2i.3e.4h.5i.,. lf.2i.3e.4h.5i, lh.2i.3e.4h.5i, lj.2i.3e.4h.5L, lp.2i.3e.4h.5i, la.2m.3e.4h.5i, lb.2m.3e.4h.5i., If 2m.3e.4h.5L, lh.2m.3c.4h.5i, lj.2m.3e.4h.5i, lp.2m.3e.4h.5i„ la.2o.3e.4h,5i, 1b.2o.3e.4h.5i, lf2o.3e.4h.5i, lh.2o.3e.4h.5i, lj.2o.3c.4h.5i, lp.2o.3c.4h.5i, la.2u.3e.4h.5i, lb. 2u.3e.4h.5i, lf.2u.3e.4h.5i, lh.2u.3e.4h.5i, lj.2u.3e.4h.5i, lp.2u.3e.4h.5i, la. 2y.3e.4h.5i, lb.2y.3e.4h.5i, lf.2y.3e.4h.5i, lh.2y.3e.4h.5i, lj.2y.3e.4h.5i, 1p.2y.3c.4h.oi, la.2a.3g.4h.5i, lb.2a.3g.4h.5i, If.2a.3g.4h.5i, lh.2a.3g.4h.5i, lj.2a.3g.4h.5i, lp.2a.3g.4h.5i, la.2b.3g.4h.5i, lb.2b.3g.4h.5i, lf.2b.3g.4h.5i, lh.2b.3g.4h.5i., lj.2b.3g.4h.oi, lp.2b.3g.4h.5i, la.2e.3g.4h,5i, lb.2e.3g.4h.5i, lf2e.3g.4h.5i, lh.2e.3g.4h.5i, lj.2e.3g.4h.5i, lp.2e.3g.4h.5i, la.2f.3g.4h.5i, lb. 2f.3g.4h.oi, If2f3g.4h.5i., lh.2f.3g.4h.5i, lj.2f3g.4h.5i, lp.2f.3g.4h.5i, la. 2i.3g.4h.5i, lb.2i.3g.4h.5i, lf.2i.3g.4h.5i, lh.2i.3g.4h.5i, lj.2i.3g.4h.5i, lp.2i.3g.4h.5i, la.2m.3g.4h.5i, lb.2m.3g.4h.5i, lf.2m.3g.4h.5i, lh.2m.3g.4h.5i, lj.2m.3g.4h.5i, lp.2m.3g.4h,5i, la.2o.3g.4h.5i, lb.2o.3g.4Ji.5i, lf.2o.3g.41i.5i., lh.2o.3g.4h.5i, lj.2o.3g.4h.5i, lp.2o.3g.4h.5i, la.2u.3g.4h.5i, lb.2u.3g.4h.5i, If2u3g.4h.5i, lh.2u.3g.4h.5i, lj.2u.3g.4h.5i, lp.2u.3g.4h.5i, la.2y.3g.4h.5i, lb. 2y.3g.4h.5i., lf.2y.3g.4h.5i, lh.2y.3g.4h.5i, lj.2y.3g.4h.5i, lp.2y.3g.4h.5i, la. 2a.3a.4i.5i, lb.2a.3a.4i.5i, lf2a.3a.4i.5i, lh.2a.3a.4i.5i, lj.2a.3a.4i.5i, lp.2a.3a.4i.5i, la.2b.3a.4i.5i, lb.2b.3a.4i.5i, lf.2b.3a.4i.5i, lh.2b.3a.4i.5i, lj.2b.3a.4i.5i, lp.2b.3a.4L5i, la.2e.3a.4i.5i, lb.2e.3a.4i.5i. If 2e.3a.4i.5i, lh.2e.3a.4i.5i, 1j.2e.3a.4i.5i, lp.2e.3a.4L5i, la.2f.3a.4i.5i, lb.2f3a.4i.5i, lf.2f3a.4L5i, lh.2f.3a.4i.5i, lj.2f.3a.4i.5i, lp.2f3a.4i.5i, la.2i.3a.4i.5i, lb, 2i.3a.4i.5i, lf2L3a.4i.5i, lh.2i.3a.4i.5i, lj.2i.3a.4i.5i, lp.2i.3a.4i.5i, la. 2m.3a.4L5i, lb.2m.3a.4i.5i, lf.2m.3a.4i.5i, lh.2m3a.4i.5i, lj.2m3a.4t.5i, lp.2m.3a.4i.5i, la.2o.3a.4i.5i„ lb.2o.3a.4i.5i, lf.2o3a.4i.5i, lh.2o.3a,4i.5i, lj.2o.3a.4i.5i, lp.2o.3a.4i.5i, la.2u.3a.4i.5i, lb.2u.3a.4i.5i, lf.2u.3a.4i.5i, lh.2u3a.4i.5i, lj.2u,3a.4i.5i, lp.2u.3a.4i.5i, la.2y.3a.4i.5i, lb.2y.3a.4i.5i, lf.2y.3a.4i.5i, lh.2y3a.4J.5i, Jj.2y3a.4i.5i, lp.2y.3a.4i.5i, la.2a.3b.4i.5i, lb. 2a.3b.4i.5i, If.2a.3b.4i.5i, lh.2a.3b.4i.5i, lj.2a.3b.4i.5i, lp.2a.3b.4i.5i, la.2b.3b.4i.5i, lb.2b3b,4i.5i, lf.2b.3b.4i.5i, lh.2b.3b.4i.5i, lj.2b.3b.4i.5i, lp.2b.3b.4i.5i, la.2e.3b.4i.5i, lb.2e.3b.4i.5i, lf2e.3b,4i.5i, lh.2e3b.4i.5i, lj.2e.3b.4i.5i, lp.2c.3b.4i.5i, la.2L3b.4i.5i, lb.2f.3b.4i.5i, lf.2f.3b.4i.5i.

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PCT/US 2008/054788 lh.2f.3b.4i.5i., lj.2f.3b.4i.5i., lp.2f.3b.4i.5L, la.2i.3b.4L5L, lb.2i.3b.4i.5i., 1 f.2i.3b.4i.5i., lh.2i.3b.4i.5i., lj.2i.3b.4i.5L, lp.2i.3b.4i.5i., la.2m.3b.4i.5i., lb.2m.3b.4i.5i., lf.2m.3b.4L5L, Ih.2m.3b.4L5i., lj.2m.3b.4i.5i., lp.2m.3b.4L5L, la. 2o.3b.4i.5i., lb.2o.3b.4i.5i., If.2o3b.4i.5i., lh.2o.3b.4i.5L, lj.2o.3b.4i.5i., lp.2o.3b.4L5L, la.2u.3b.4i.5i., lb.2u.3b.4i.5i., lf.2u.3b.4i.5L, lh.2u.3b.4i.5i., lj.2u.3b.4L5L, lp.2u.3b.4i.5i., la.2y.3b.4i.5i., lb.2y.3b.4L5L, lf.2y.3b.4L5L, lh.2y.3b.4i.5i., lj.2y.3b.4i.5i., lp.2y.3b.4i.5i., la.2a.3e.4L5L, lb.2a.3e.4i.5i., lf.2a.3e.4i.5i., 1 h.2a.3e.4i.5L, lj.2a.3e.4L5L, lp.2a.3e,4i.5L, la.2b.3e.4L5L, lb. 2b.3e.4i.5i., lf.2b.3e.4i.5i., lh.2b.3e.4i.5i., lj.2b.3e.4L5i., lp.2b.3e.4i.5L, la. 2e.3e.4L5L, lb.2c.3c.4L5L, lf.2e.3e.4L5L, lh.2e.3e.4L5L, lj.2e.3e.4L5L, lp.2e.3e.4L5L, la.2f.3e.4i.5L, lb.2f.3e.4L5L, 1f.2f.3e.4i.5L, lh.2f.3c.4i.5i., lj.2f.3e.4L5L, lp.2f.3e.4i.5L, la.2L3e.4L5L, lb.2L3e.4L5L, If.2i.3e,4i.5L, Ih.2i.3e.4L-5L, lj.2L3e.4i.5i., lp.2L3e.4L5L, la.2m.3e.4L5L, lb.2m.3e.4i.5L, lf.2m.3e.4L5i., lh.2m.3e.4i.5i., lj.2m.3c.4i.5L, lp.2m.3e.4L5L, la.2o.3e.4i.5L, lb.2o.3e.4i.5L, lf.2o.3e.4i.5i-, lh.2o.3e.4L5L, lj.2o.3e.4L5i., lp.2o.3e.4i.5L, la.2u.3e.4L5L, lb. 2u.3e.4L5L, lf.2u.3e.4L5L, lh.2u.3e.4L5L, lj.2u.3e.4i.5L, lp.2u.3e.4L5L, la. 2y.3e.4i.5L, lb.2y.3e.4L5L, lf.2y.3e.4L5L, lh.2y.3e.4L5i., 1j,2y.3e.4L5L, lp.2y.3e.4i.5L, la.2a.3g.4i,5L, lb.2a.3g.4i.5L, lf.2a.3g.4L5L, lh.2a.3g.4L5L, lj.2a.3g.4i.5i., lp.2a.3g.4L5L, la.2b.3g.4L5L, lb.2b.3g.4L5L, lf.2b.3g.4i.5L, lh.2b.3g.4L5L, lj.2b.3g.4i,5i., lp.2b.3g.4i.5i., la.2e.3g.4L5L, lb.2e.3g.4L5L, lf.2e.3g.4L5L, lh.2e.3g.4L5L, lj.2e.3g.4L5L, lp.2e.3g.4L5L, la.2f.3g.4L5L, lb. 2f.3g.4i.5i., lf.2f.3g.4i.5L, lh.2f.3g.4L5L, lj.2f.3g.4i.5i., lp.2f.3g.4L5i., la. 2L3g.4L5L, lb,2L3g.4i.5L, lf.2L3g.4i.5L, lh.2i.3g.4L5L, lj,2L3g.4i.5L, lp.2L3g.4L5L, la.2m.3g.4L5L, lb.2m.3g.4L5L, lf.2m.3g.4i.5i., lh.2m.3g.4L5L, lj.2m.3g.4i.5L, lp.2m.3g.4L5L, la.2o.3g.4L5L, lb.2o.3g.4L5L, lf.2o.3g.4L5L, lh.2o.3g.4i.5i., lj.2o.3g.4i.5i., lp.2o.3g.4L5L, la.2u.3g.4L5L, 'lb.2u.3g.4i.5i., lf.2u.3g.4i.5i., lh.2u.3g.4i.5L, lj.2u.3g.4i.5L, lp.2u.3g.4L5L, la.2y.3g.4i.5L, lb. 2y.3g.4L5L, lf.2y.3g.4L5L, lh.2y.3g.4i.5L, lj.2y.3g.4L5L, and lp.2y.3g.4i.5L.

In still yet another embodiment, the compound of the present invention has an inhibition activity against F450 ata level equal to or better than the inhibition activity of a compound as represented by an ICso of less than about 2000 nM, less than about 1500 nM, less than about 1000 nM, less than about 900 nM, less than about 800 n_M, less than about 700 nM, less than about 650 nM, less than about 600 n.M, less than about 550 nM, less than about 500 nM, less than about 400 nM, less than about 350 nM, less than about 300 nM, less than about 250 nM, less than about 200 nM, less than about 100 nM, or less than about 50 nM.

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In still yet another embodiment, the compound of the present invention has an inhibition activity·’ against an isozyme of P450, e.g., 3A in a range represented by ICsj from about 2000 nM to about 100 nM, from about 1000 nM to about 100 nM, from about 900 nM to about 200 nM, from about 800 nM to about 300 nM, from about 700 nM to about 200 nM, from about 600 nM to about 200 nM, from about 500 nM to about 200 nM, from about 700 nM to about 300 nM, from about 600 nM to about 300 nM, from about 700 nM to about 400 nM, from about 600 nM to about 400 nM, from about 400 nM to about 100 nM, from about 300 nM to about 100 nM, or from about 600 nM to about 150 nM.

In still yet another embodiment, the compound of the present invention has an inhibition activity against P450 at a level equal to or better than the inhibition activity of a compound as represented by an ICsn of less than about 2000 nM, less than about 1500 nM, less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 650 nM, less than about 600 nM, less than about 550 nM, less than about 500 nM, less than about 400 nM, less than about 350 nM, less than about 300 nM, less than about 250 nM, less than about 200 nM, less than about 100 nM, or less than about 50 nM, provided that such compound also does not substantially exhibit biological activities other than its inhibition activity against P450. For example, the compound of the present invention can have a reduced or not significant activity of protease inhibition, including without any limitation a level of protease inhibition as represented by HIV ECw of greater than about 1000 nM, greater than about 900 nM, greater than about 800 nM, greater than about 700 nM, greater than about 600 nM, greater than about 500 nM, greater than about 400 nM, greater than about 300 nM, greater than about 200 nM, greater than about 100 nM, greater than about 50 nM, greater than about 40 nM, greater than about 30 nM, greater than about 20

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PCT/US2008/054788 nM, greater than about WnM, greater than about 5 nM, or greater than about 1 nM.

In yet another embodiment, die compound of the present invention has an inhibition activity specifically against one or more isozymes of P450 including without limitation 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, and 3A4, 5, 7, etc.

in yet another embodiment, the compound of the present invention has an inhibition activity specifically against an isozyme of F450 that is involved in metabolizing anti-viral drugs, e.y„ indinavir, nelfinavir, ritonavir, saquinavir etc.

In still yet another embodiment, the compound of the present invention has an inhibition activity specifically against one or more isozymes of P450, but not the other(s). For example, the compound of the present invention can have an inhibition activity specifically against P450 3A, but a reduced, insubstantial, or minimum inhibition activity against another isozyme of P450, e.y., P450 2C9.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1985), herein incorporated by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxy alkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.

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While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical form illations. The formulations of the invention, both for veterinary and for human use, comprise at least one active ingredient, e.g. a compound of the present invention, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Scitmces (Mack Publishing Co., Easton, Pa.), herein incorporated by reference in its entirety. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-inwater liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or

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PCT/US2008/054788 granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.

For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingrcdicnt(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredieni(s) in a range between 0.1% and 207(1 in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-inwater cream base.

If desired, the aqueous phase of the ueam base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. 'The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through tire skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emu 1 gent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably,

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PCT/US2008/054788 a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage bom tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol di ester of coconut fa tty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for ora] use may be

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PCT/US2008/054788 prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing die active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or aiginic acid; binding agents, such as cellulose, microcrystal line cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the in vend on contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a

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PCT/US2008/054788 condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycctanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cety] alcohol. Sweetening agents, such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the in ven bon suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above, Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as

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PCT/US2008/054788 sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleatc. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxlc parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Ln addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materia] to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately '1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For

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PCT/US 2008/054788 example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ug of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient, The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth washes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 pm (including particle sizes in a range between 0.1 and 500 um in increments such as 0.5 pm, 1 pm, 30 pm, 35 pm, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of infections as described herein.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing

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PCT/US2008/054788 in addition to the active ingredient such carriers as are known in tire art to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

The formulations arc presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of die kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients provided by the present invention the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The invention further provides veterinary compositions comprising at least one active ingredient, e.g., a compound of the present invention together with a veterinary carrier.

Velerinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

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Compounds of die in ven don can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, die invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.

The effective dose of an active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophy tactically (lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. The effective dose can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 tng/kg body weight per day. More typically, from about 0.01 to about 5 mg/kg body weight per day. More typically, from about 0.05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, or between 5 mg and 500 mg, and may take the form of single or multiple doses.

In yet another embodiment, the present application discloses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and a pharmaceutically acceptable carrier or cxipient.

In yet another embodiment, the present application discloses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or exipient.

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According to the present invention, the therapeutic agent used in combination with tire compound of the present invention can be any agent having a therapeutic effect when used in combination with the compound of the present invention. For example, the therapeutic agent used in combination with the compound of the present invention can be any agent that is accessible to oxidative metabolism by cytochrome P450 enzymes, especially cytochrome P450 monooxygenase, e.g., 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2ΕΊ, 3A4,5,7, etc.

In another example, the therapeutic agent used in combination with the compound of the present invention can be any anti-viral agent, e.g., anti-FUV, antiHCV, etc., anti-bacterial agent, anti-fungal agent, immuno-modulator, e.g., immunosuppressant, anti-neopl a Stic agent, chemotherapeutic agent, agents useful for treating cardiovascular conditions, neurological conditions, etc.

In yet another example, the therapeutic agent used in combination with the compound of the present invention can be any proton pump inhibitor, antiepileptics, NSAID, oral hypoglycemic agent, angiotensin II, sulfonyl ureas, beta blocker, antidepressant, antipsychotics, or anesthetics, or a combination thereof.

In yet another example, the therapeutic agent used in combination with the compound of the present invention can be any 1) macrolide antibiotics, e.g., clarithromycin, erythromycin, telithromycin, 2) an ti-ar rhythmics, e.g., quinidine=>3-OH, 3) benzodiazepines, e.g., alprazolam, diazepam=>3OH, midazolam, triazolam, 4) immune modulators, e.g., cyclosporine, tacrolimus (FK506), 5) HIV antivirals, e.g., indinavir, nelfinavir, ritonavir, saquinavir, 6) prokinetic, e.g,, cisapride, 7) antihistamines, t’.y., astemizole, chlorpheniramine, terfenidine, 8) calcium channel blockers, e.g., amlodipine, diltiazem, felodtpine, lercani dipine, nifedipine, nisoldipine, nitrendipine, verapamil, 9) HMG Co A reductase inhibitors, e.g., atorvastatin, cerivastatin, lovastatin, simvastatin, or 10) steroid 6beta-011, e.g., estradiol, hydrocortisone, progesterone, testosterone.

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In still yet another example, the therapeutic agent used in combination with the compound of the present invention can be any alfentanyl, aprepitant, aripiprazole, buspirone, cafergot, caffeine, TMU, cilostazol, cocaine, codeine- Ndemethylation, dapsone, dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl, finasteride, gleevcc, haloperidol, irinotecan, LA AM, lidocaine, methadone, natcglinidc, ondansetron, pimozide, propranolol, quetiapine, quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, or zolpidem or a combination thereof.

In one embodiment, the present application discloses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nu clcos ide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, non-nucleoside inhibitors of HCV, CCR5 inhibitors, and combinations thereof, and a pharmaceutically acceptable carrier or exipient.

ha another embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent selected from Hue group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brccanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC681, DPC-684, GW640385X, DG17, PPL-100, DG35, AG 1859, capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) ealanoiide A, etravirine, GW5634, DPC-U83, DPC-961, DPC-963, MIV-150, TMC-120, TMC-278 (rilpivirene),

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BILR355 BS, VRX 840773, UK-453061, RDEA806, zidovudine, emtricitabine, didanosinc, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MTV-210, Racivir (±-FTC), D-d4FC, phosphazide, fozivudine tidoxil, apricitibine AVX754, amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), tenofovir disoproxil fumarate, adefovir dipivoxil, GS-9131, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurin tricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-8708I2, L-870810, MK-0518 (raltegravir), elvitegravir, BMS-538158, GSK364735C, BMS-707035, MK2048, BA 011, enfuvirtide, sifuvirtide, FB006M, TR1-1144, AMD-070, SP01A, B.MS488043, BlockAide/CR, immunitin, benzimidazole derivatives, benzo-1,2,4thiadiazine derivatives, phenylalanine derivatives, aplaviroc, vicriviroc, and maraviroc, cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629 (N,N-dimethyIglycy]-N-^2-hydroxy-3^(((4-mothoxyphcnyl)sulphonyI)(2methylpropyl)amino)-l -(phonylmethyl)propyl)-3-methyl-L-valinamide), KNI272, CGP 53437, CGP 57813 and U-103017 and a pharmaceutically acceptable carrier or exipient.

In still another embodiment, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with two or three additional therapeutic agents. For example, a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, is combined with two or three additional therapeutic agents selected from

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PCT/US2008/054788 the classes of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and HIV integrase inhibitors. The two or three additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents. The compounds of the present invention in such ternary or quaternary combinations can include any of the compounds of Formula I disclosed herein, for example a compounds of Formula IIA-D or Formula IV. In a particular embodiment, the pharmaceutical compositions of the present invention comprises a compound of Formula IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, combined with two or three additional therapeutic agents selected from the classes of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and HIV integrase inhibitors. In a still more particular embodiment, the pharmaceutical composition of the present in ven Hon comprises Example P, S, or X, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with two or three additional therapeutic agents selected from the classes of HTV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and HIV integrase inhibitors. For example, such combinations can comprise Example P, 5, or X, or a pharmaceutically acceptable salt, solvate, and/or ester thereof in combination with two or three additional therapeutic agents selected from the group consisting of tenofovir disoproxll fumarate, GS-913'1, emtricitabine, elvitegravir, efavrenz, atazanavir, darunavir, raltegravir, and rilpivirine (or pharmaceutically acceptable salts, solvates, and/or esters thereof).

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Specific embodiments of ternaiy combinations comprise, for example, Example P/tenofovir disoproxil fumarate/GS-9131, Example P/tenofovir disoproxil fumarate/emtricitabine, Example P/tenofovir disoproxil fumarate/clvitegravir, Example P/tenofovir disoproxil fumarate/efavrenz, Example P/tenofovir disoproxil fumaratc/atazanavir, Example P/tenofovir disoproxil fumarato/darunavir, Example P/tenofovir disoproxil fumarate/raltegravir, Example P/tenofovir disoproxil fumarate/rilpivirine. Example P/GS-9131/emtricitabine, Example P/GS-9131/elvitegravir, Example P/GS-9131/efavrenz, Example P/GS~9131/atazanavir, Example P/GS9131/darunavir, Example P/GS-9131/raltegravir, Example P/GS-9131/rilpivirine, Example Ρ/emtricitabine/elvitegravir, Example P/emtricitabine/cfavrcnz, Example P/emtricitabine/atazanavir, Example P/emtricitabine/darunavir, Example P/emtricitabine/raltegravir, Example P/emtricitabine/rilpivirine, Example P/elvitegravir/efavrcnz, Example P/elvitegravir/atazanavir, Example P/elvitegravir/darunavir, Example P/elvitegravir/raltegravir, Example P/elvitegravir/rilpivirine, Example P/efavrenz/atazanavir, Example P/efavrenz/darunavir, Example P/efavrenz/raltegravir, Example P/efavrenz/rilpivirine, Example P/atazanavir/darunavir, Example P/atazanavir/raltegravir, Example P/atazanavir/rilpivirine, Example P/darunavir/raltegravir, Example P/darunavir/rilpivirine, Example P/raltegravir/rilpivirine, Example S/tenofovir disoproxil fumaratc/GS-9131, Example S/tenofovir disoproxil fumarate/emtricitabine, Example S/tenofovir disoproxil fumarate/elvitegravir, Example S/tenofovir disoproxil fumarate/efavrenz, Example S/tenofovir disoproxil fumarate/atazanavir. Example S/tenofovir disoproxil fumarate/darunavir, Example S/tenofovir disoproxil fumarate/raltegravir, Example S/tenofovir disoproxil fumarate/rilpivirine, Example S/GS-9131/emtricitabine, Example S/GS-9131/elvitcgravir, Example

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S/GS-9131/efavrenz, Example S/GS-9131/ataz.anavir, Example S/GS9131/darunavir, Example S/GS-9131/raltegravir, Example S/GS-9131/rilpivirine, Example S/emtricitabine/elvitegravir, Example S/emtricitabine/efavrenz, Example S/emtricitabine/atazanavir, Example S/em tricitabin e/darunavir, Example S/emtricitabine/raltegravir, Example S/em trici tabine/rilpivirinc, Example S/elvifegravir/efavrenz, Example S/elvitegravir/atazanavir, Example S/elvitegravir/darunavir, Example S/elvitegravir/raltegravir, Example S/elvitegravir/rilpivirine, Example S/efavrenz/atazanavir, Example S/efavrenz/darunavir, Example S/efavrenz/raltegravir, Example S/efavrenz/rilpivirine, Example S/atazanavir/darunavir, Example S/atazanavir/raltegravir, Example S/atazanavir/rilpivirine, Example S/darunavir/raltegravir, Example S/darunavir/rilpivirine, Example S/raltegravir/rilpivirine, Example X/tenofovir disoproxil Fumarate/GS-9131, Example X/tenofovir disoproxil fumarate/emtricitabine, Example X/tenofovir disoproxil fumarate/elvitegravir, Example X/tenofovir disoproxil fumarate/efavrenz, Example X/tenofovir disoproxil fumarate/atazanavir, Example X/tenofovir disoproxil fumarate/darunavir, Example X/tenofovir disoproxil fumarate/raltegravir, Example X/tenofovir disoproxil fumarate/rilpivirine, Example X/GS-9131/emtricitabine, Example X/GS-9131/elvitegravir, Example X/GS-9131/efavrenz, Example X/GS-9131/atazanavir, Example X/GS9131/darunavir, Example X/GS-9131/raltegravir, Example X/GS-9131/rilpivirine, Example X/emtricitabine/elvitegravir, Example X/emtricitabine/efavrcnz, Example X/emtricitabine/atazanavir, Example X/cmtricitabme/darLinavir, Example X/emtricitabinc/raltegravir, Example X/emtricitabine/rilpivirine, Example X/elvitegravir/efavrenz, Example X/elvitegravir/atazanavir, Example X/elvitegravir/darunavir, Example X/elvitegravir/raltegravir, Example X/elvitegravir/rilpivirine, Example X/efavrenz/atazanavir, Example

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X/cfavrenz/darunavir, Example X/efavrenz/raltegravir, Example X/efavrenz/rilpivirine, Example X/atazanavir/darunavir, Example X/atazanavir/raltegravir, Example X/atazanavir/rilpivirine, Example X/darunavir/raltegravir, Example X/darunavir/rilpivirine, and Example X/raltegravir/rilpivirine (including pharmaceutically acceptable salts, solvates, and/or esters of any of the above).

Specific embodiments of quaternary combinations comprise, for example, Example P/tenofovir disoproxil fumarate/GS-9131/emtricitabine, Example P/tenofovir disoproxil fumarate/GS-9131/elvitegravir, Example P/tenofovir disoproxil fumarate/GS-9131/efavreriz, Example P/tenofovir disoproxil fumarate/GS-9131/atazanavir, Example P/tenofovir disoproxil fumarate/GS9131/darunavir, Example P/tenofovir disoproxil fumarate/GS-9131/raltegravir, Example P/tenofovir disoproxil fumarate/GS-9131/rilpxvirine, Example P/tenofovir disoproxil fumarate/emtricitabine/clvitegravir, Example P/tenofovir disoproxil fumarate/emtridtabine/efavrenz, Example P/tenoiovir disoproxil fumarate/em tricitabine/atazanavir, Example P/tenofovir disoproxil fumarate/emtricitabme/darunavir, Example P/tenofovir disoproxil fumarate/emtricitabine/raltegravir, Example P/tenofovir disoproxil fumaratc/emtricitabine/rilpivirine, Example P/tenofovir disoproxil fumarate/elvitegravir/efavrenz, Example P/tenofovir disoproxil fumarate/elvitegravir/atazanavir, Example P/tenofovir disoproxil fumarate/elvitegravir/darunavir, Example P/tenofovir disoproxil fumarate/elvitegravir/raltegravir, Example P/tenofovir disoproxil fumarate/elvitegravir/rilpivirine, Example P/tcnofovir disoproxil fumarate/efavrcnz/atazanavir, Example P/tenofovir disoproxil fumarate/efavrenz/darunavir, Example P/tenofovir disoproxil fumarate/efavrenz/raltegravir, Example P/tenofovir disoproxil

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PCT/US2008/054788 fumarate/efavrcnz/rilpivirine, Example P/tenofovir disoproxil Fumarate/atazanavir/darunavir, Example P/tenofovir disoproxil fumarate/atazanavir/raltegravir, Example P/tenofovir disoproxil fuinarate/atazanavir/rilpivirine, Example P/tenofovir disoproxil fumarate/danmavir/raltegravLT, Example P/tenofovir disoproxil fumarate/daronavir/rilpivirine, Example P/tenofovir disoproxil fumarate/raltegravir/rilpi virinc, Example P/GS-9131/emtricitabine/elvitegra vir,

Example P/GS-9131/emtricitabine/efavrenz, Example P/GS9131/emtricitabinc/atazanavir, Example P/GS-9131/emtricitabine/darunavir, Example P/GS-9131/emtricitabine/raltegravir, ExampleP/GS9131/emtricitabine/rilpivirme, Example P/GS-9131/elvitegravir/efavrenz, Example P/GS-9131/elvitegravir/atazanavir, Example P/GS-9131 /elvitcgravir/darunavir, Example P/GS-9131/elvitegravir/raltegravir, Example P/GS913'1/elvitegravir/riIprvirine, Example P/GS-9131/efavrenz/atazanavir, Example

P/GS-9131/efavrenz/darunavir, Example P/GS-9131/efavrenz/raltcgravir, Example P/GS-9131/efavrenz/rilpivirine, Example P/GS-9131 /atazanavir/darunavir, Example P/GS-9131/atazanavii7raltcg,ravii·, Example P/GS9131/atazanavir/rilpivirinc, Example P/GS-9131/darunavir/raltegravir, Example P/GS-913I/darunavir/rilpivirine, Example P/GS-9131/raItegravir/rilpivirine, Example P/emtricitabine/elvitegravir/efavrenz, Example

P/cmtricitabine/elvitegravir/atazanavir, Example P/emtricitabine/elvitegravir/darunavir, Example P/emtricitabine/elvitegravir/raltegravir, Example P/emtricitabine/elvitegravir/rilpivirine, Example P/emtricitabinc/cfavrcnz/atazanavir, Example P/em tri ci tabin e/efavrenz/daruna vir, Example P/emtricitabine/efavrenz/raltegravir, Example

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P/emtricitabine/efavrenz/rilpivirine, Example P/emtricitabine/atazanavir/darunavir, Example P/em trici Labin e/atazanavir/ral tegravir, Example P/em tri ci tabine/atazana vir/rilpivirine, Example P/em tri ci ta bin e/d ar unavir/r al tegravir, Example P/em tricitab ine/darunavir/rilpivirine, Example P/em trici tab ine/raltegr a vir/rilpivirine, Example P/elvitegravir/efavrenz/atazanavir, Example P/elvitcgravir/efavrenz/darunavir, Example P/elvitegravir/efavrenz/raltegravir, Example

P/elvitegravir/efavrenz/rilpivirine, Example P/elvitegravir/atazanavir/darunavir, Example P/elvitegravir/atazanavir/raltegravir, Example

P/elvitegravir/atazana vir/rilpivirine, Example P/elvitegravir/darunavir/raltegravir, Example P/elvitegravir/darun a vir/rilpivirine, Example P/elvitegravir/raltegravir/rilpivirine, Example P/efavrenz/atazanavir/darunavir, Example P/efavTcnz/atazanavir/r al tegravir, Example P/cfavrcnz/atazana vir/rilpivirine, Example

P/efavrenz/darunavir/raltegravir, Example P/efavrenz/darunavir/rilpivirine, Example P/efavrenz/raltegr a vir/rilpivirine, Example

P/atazanavir/darunavir/raltegravir, Example P/atazanavir/darunavir/rilpivirine, Example P/darunavir/raltegravir/rilpivirine, Example S/tenofovir disoproxil fumarate/GS-9131/emtricitabine, Example S/tenofovir disoproxil fumarate/GS9131/elvitegravir, Example S/tcnofovir disoproxil fumaratc/GS-9131/efavrenz, Example S/tenofovir disoproxil fmnarate/GS-9131/atazanavir, Example S/tenofovir disoproxil fumarate/GS-9131/darunavir, Example S/tenofovir disoproxil fum arate/GS-9131/ra I tegravir, Example S/tenofovir disoproxil fumarate/GS-9131/rilpivirine, Example S/tenofovir disoproxil fumarate/emtricitabine/elvitegravir, Example S/tenofovir disoproxil

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PCT/US2008/054788 fumarate/emtricitabine/efavrenz, Example S/tenofovir disoproxil fu mar ate/cmtricitabine/atazan a vir, Example S/tenofovir disoproxil fumaratc/emtricitabine/darunavir, Example S/tenofovir disoproxil fumarate/emtricitabine/raltegravir, Example S/tenofovir disoproxil fumarate/emtricitabine/rilpivirine, Example S/tenofovir disoproxil fumarate/elvitegravir/efavrenz, Example S/tenofovir disoproxil fumarate/elvitegravir/atazanavir, Example S/tenofovir disoproxil fumarate/elvitegravir/darunavir, Example S/tenofovir disoproxil fumarate/elvitegravir/raltegravir, Example S/tenofovir disoproxil fumaratc/elvitcgravir/rilpivirine, Example S/tenofovir disoproxil fumarate/efavrenz/atazanavir, Example S/tenofovir disoproxil fumarate/efavrenz/darunavir, Example S/tenofovir disoproxil fumarate/efavrenz/raltegravir, Example S/tenofovir disoproxil fumarate/efavrenz/rilpivirine, Example S/ienofovir disoproxil fumarate/atazanavir/darunavir, Example S/tenofovir disoproxil fumarate/atazanavir/raltegravir, Example S/tcnofovir disoproxil fumarate/atazanavir/rilpivirine, Example S/tenofovir disoproxil fumarate/darunavir/raltegravir, Example S/tenofovir disoproxil fumarate/danmavir/rilpivirme, Example S/tenofovir disoproxil fumarate/raltcgravir/rilpivirine, Example S/GS-9131/emtricitabine/clvitegravir, Example S/GS-9131/emtricitabine/efavrenz, Example S/GS9131/emtricitabine/atazanavir, Example S/GS-9131 /cmtricitabine/darunavir, Example S/GS-9131/emtricitabine/raltegravir, Example S/GS9131/emtricitabine/rilpivirine, Example S/GS-9131/elvitegravir/efavrenz, Example S/GS-9131/elvitegravir/atazanavir, Example S/GS-9131/elvitegravir/darunavir, Example S/GS-9131/clvitegravir/raItegravir, Example S/GS9131/el vitegravir/rilpivirine, Example S/GS-9131/efavrenz/atazanavir, Example

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S/GS-913l/efavrenz/dai'unavir_/ Example S/GS-9131/efavrenz/raltegravir, Example

S/GS-9131/efavrenz/rilpivirine, Example S/GS-9131/atazanavir/darunaviT,

Example S/GS-9131/atazanavir/raltegravir, Example S/GS9131/atazanavir/rilpivirine, Example S/GS-9131/damnavir/raltegravir, Example

S/GS-913'1 /darunavir/rilpivirine, Example S/GS-9131/raItegra^dr/riIpivirine,

Example S/emtricitabine/elvitegravir/efavrenz, Example

S/emtricitabine/elvitegravir/atazanavir, Example

S/em tri ci tabin e/elvitogravrr/darunavir, Example

S/emtricitabine/elvitegravir/raltegravir, Example

S/emtricitabine/elvitegravir/rilpivirine, Example

S/emtricitabine/efavrenz/atazanavir, Example

S/emtricitabine/efavrenz/darunavir, Example

S/emtricitabine/efavrenz/raltegravir, Example

S/emtricitabine/efavrenz/rilpivirinc, Example

S/emtricitabine/atazanavir/darunavir, Example

S/emtricitabine/atazanavir/raltegravir, Example

S/emlricitabme/atazanavir/rilpivirine, Example

S/em trici tabine/darunavir/raltegravir, Example

S/em trici tabme/damnavir/rilpivirine, Example

S/emti'icitabine/raltegravir/rilpivirine, Example

S/clvitegravir/efavrenz/atazanavir, Example S/elvitegravir/cfavrenz/darimavir,

Example S/elvitegravir/efawenz/raltegravir, Example

S/elvitegravir/efavrenz/rilpivirine, Example S/elvitegravir/atazanavir/darunavir,

Example S/elvitegravir/atazanavir/raltegravir, Example

S/elvitegravir/atazanavir/rilpivirine, Example

S/elvitcgravir/darunavir/raltegravir, Example S/elvitegravir/danmavir/rilpivirme,

Example S/ehdtegravir/raltegravir/rilpivirine, Example

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S/efavrenz/atazanavir/darunavir, Example S/efavrenz/atazanavir/raltegravir, Example S/efavrenz/atazanavir/rilpivirine, Example

S/efavrenz/darunavir/raltegravir, Example S/efavrenz/darunavir/rilpivirine, Example S/efavrenz/raltegravir/rilpivirine, Example

S/atazanavir/darunavir/raltegravir, Example S/atazanavrr/darunavir/rilpivirine, Example S/darunavir/raltegravir/rilpivirine, Example X/tenofovir disoproxil fumarate/GS-9131/emtricitabine, Example X/tcnofovir disoproxil fumarate/GS9131/elvitegravir, Example X/tcnofovir disoproxil fumaratc/GS-9131/cfavrcnz, Example X/tenofovir disoproxil fumarate/GS-9131/atazanavir, Example X/tenofovir disoproxil fumarate/GS-9131/darunavir, Example X/tenofovir disoproxil fumarate/GS-9131/raltegravir, Example X/tenofovir disoproxil fumarate/GS-9131/rilpivirine, Example X/tenofovir disoproxil fuinarate/emtricitabine/elvitegravir, Example X/tenofovir disoproxil fumarate/em trici tabine/ef a vrenz, Example X/tenofovir disoproxil fumarate/emtricitabinc/atazanavir, Example X/tcnofovir disoproxil fumarate/emtricitabine/darunavir, Example X/tenofovir disoproxil fum arate/em tri ci tabin e/raltegr a vir, Example X/tenofovir disoproxil fumarate/emtricitabine/rilpivirine, Example X/tcnofovir disoproxil fumarate/clvitegravir/efavrenz, Example X/tenofovir disoproxil fumarate/elvitegravir/atazanavir, Example X/tenofovir disoproxil fumarate/elvitegravir/darunavir, Example X/tenofovir disoproxil fumarate/elvitegravir/raltegravir, Example X/tenofovir disoproxil fLEmarate/elvitegravir/rilpivirine, Example X/tenofovir disoproxil fumarate/efavrenz/atazanavir, Example X/tenofovir disoproxil fumarate/ofavrenz/darunavir, Example X/tenofovir disoproxil fumarate/efavrenz/raltegravir, Example X/tenofovir disoproxil fumarate/efavrenz/rilpivirine, Example X/tenofovir disoproxil

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X/emtricitabine/elvitegravir/atazanavir, Example X/emti'icitabine/elvitcgravir/dai'Linavir, Example X/cmtricitabine/elvitegravir/raltegravir, Example X/emtricitabine/elvitegravir/rilpiviTine, Example X/emtricitabine/cfavrcnz/atazanavir, Example X/emtricitabine/efavrenz/darunavir, Example X/emtricitabine/efavrenz/raltegravir, Example X/emtricitabine/efavrenz/rilpivirine, Example

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X/emtricitabine/atazanavir/darunavir, Example X/emtricitabine/atazanavir/raltegravir, Example X/emtricitabine/atazanavir/rilpivirine, Example

X/emtricitabine/darunavir/raltegravir, Example X/emtricitabine/darunavir/rilpivirine, Example

X/cm trici tabin c/r altegravir/ rilpivirine, Ex ample

X/elvitegravir/efavrenz/atazanavir, Example X/elvitegravir/efavrenz/darunavir, Example X/elvitegravir/efavrenz/raltegravir, Example

X/elvitegravir/efavrenz/nlpivirine, Example X/elvitegravir/atazanavir/darunavir, Example X/elvitegravir/atazanavir/raltegravir, Example

X/elvitegravir/atazanavir/rilpivirine, Example

X/elvitegravir/darunavir/r altegravir, Example

X/elvitegravir/darunavir/rilpivirinc, Example

X/elvitegravir/raltegravir/rilpivirine, Example X/efavrenz/atazanavir/darunavii·, Example X/efavrenz/atazanavir/raltegravir, Example

X/efavrenz/atazanavir/rilpivirine, Example X/efavrenz/darnnavir/raltegravir, Example X/efavrenz/darunavir/rilpivirine, Example

X/efavrenz/raltegravir/rilpivirine, Example X/atazanavir/darunavir/raltegravir, Example X/atazanavir/darunavir/rilpivirine, and Example

X/darunavir/raltegravir/rilpivirine (including pharmaceutically acceptable salts, solvates, and/or esters of any of the above).

In yet another embodiment, the present application provides a combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof; and

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b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp!20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, and combinations thereof.

Routes of Administration

One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intra thecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bi oa vail able and can be dosed orally.

Combination Therapy

In one embodiment, the compounds of the present invention can be used alone, e.g., for inhibiting cytochrome P450 monooxygenase. In another embodiment, the compounds of the present invention are used in combination with other active therapeutic ingredients or agents. Preferably, the other active therapeutic ingredients or agents are metabolized or accessible to the oxidative metabolism by cytochrome P450 enzymes, e.g., monooxygenase enzymes such as 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, 3A4,5,7, etc.

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Combinations of the compounds of the present invention are typically selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-p roper ties of the combination. For example, when treating an infection (e.g., HIV or HCV), the compositions of the invention are combined with antiinfective agents (such as those described herein).

In one embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more anti-viral agents, e.g., anti-HIV, anti-HCV, etc., anti-bacterial agents, anti-fungal agents, immuno-modulators, e.g., immunosuppressant, anti-neoplastic agents, chemotherapeutic agents, agents useful for treating cardiovascular conditions, neurological conditions, etc.

In another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more proton pump inhibitors, anti-epileptics, NSAIDs, oral hypoglycemic agents, angiotensin II, sulfonylureas, beta blockers, antidepressants, antipsychotics, or anesthetics, or a combination thereof.

In yet another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more 1) macrolide antibiotics, e.g., clarithromycin, erythromycin, telithromycin, 2) anti-arrhvthmics, e.g,, quiridme=>3-OH, 3) benzodiazepines, e.g._r alprazolam, diazepam=>3OI I, midazolam, triazolam, 4) immune modulators, e.g., cyclosporine, tacrolimus (FK506), 5) HIV antivirals, e.g., indinavir, nelfinavir, ritonavir, saquinavir, 6) prokinetic, e.g., cisapride, 7) antihistamines, e.g., astemizole, chlorpheniramine, terfenidine, 8) calcium channel blockers, e.g., amlodipine, diltiazem, felodiplne, lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil, 9) HMG Co A reductase inhibitors, ay.,

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In still yet another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more compounds selected from the group consisting of alfentanyl, aprepitant, aripiprazole, buspirone, cafcrgot, caffeine=>TMU, cilostazol, cocaine, codeine- N-demethylation, dapsone, dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol, irinotecan, LA AM, lidocaine, methadone, nateglinide, odanestron, pimozide, propranolol, quetiapine, quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine, zaleplon, arid zolpidem or a combination thereof.

In still yet another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp!20 inhibitors, CCR5 inhibitors, and other drugs for treating HIV, interferons, ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inliibitors of HCV, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

More specifically, one or more compounds of tire present invention may be combined with one or more compounds selected from the group consisting of 1) amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DM P-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684,

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GW640385X, DG17, GS-8374, PPL-100, DG35, and AG 1859, 2) a HIV nonnucleoside inhibitor of reverse transcriptase, e.g·, capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC083, DPC-961, DPC-963, MTV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VEX 840773, UK-453061, and RDEA806, 3) a HIV nucleoside inhibitor of reverse transcriptase, e.g., zidovudine, cmtricitabme, did anosine, stavudine, zalcitabine, lam ivu dine, abacavir, amdoxovir, elvudtabine, a Io vu dine, M1V-210, racivir(±-FTC), D-d4FC, cmtricitabme, phosphazide, fozivudine tidoxil, apricitibine (AVX754), GS-7340, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), 4) a HIV nucleotide inhibitor of reverse transcriptase, e.g, tenofovir disoproxil fumarate and adefovir dipivoxil, 5) a HIV integrase inhibitor, e.g., curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurin tricarb oxy lie acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyr ph ostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L870810, MK-0518 (raltegravir), elvitegravir, BMS-538158, GSK364735C, BMS707035, MK-2048, and BA 011, 6) a gp41 inhibitor, e.g., enfuvirtide, sifuvirtide, FB006M, and TRI-1144, 7) a CXCR4 inhibitor, e.g., AMD-070, 8) an entry inhibitor, e.g, SP01 A, 9) a gpl20 inhibitor, e.g, BMS-488043 or BlockAide/ CR, 10) a G6PD and NADH-oxidase inhibitor, e.g., immunitin, 11) a CCR5 inhibitor, e.g, aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004,12) other drugs for treating HIV, e.g,, BAS-100, SPI-452, REP 9, SPOT A, TNX-355, DES6, ODN-93, ODN-H2, VGV-1, PAM57 (bevirimat), Ampligen, HRG214, Cvtolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040), 13) an interferon, e.g, pegylated rIFN-alpha 2b, pegylated rIFN-alpha

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2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, albuferon, locteron, Aibuferon, Rebif, Oral interferon alpha, IFNalpha~2b XL, Λ VI005, PEG-Infergen, and Pegylated IFN-beta, 14) a ribavirin analog, e.g., rebetol, copegus, viramidine (taribavirin), 15) a NS5b polymerase inhibitor, e.g., NM-283, valopicitabine, R1626, PSL6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433, 16) Λ NS3 protease inhibitor, e.g., SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191,17) an alpha-glucosidase 1 inhibitor, e.g., MX-3253 (celgosivir), UT-231B, 18) hepatoprotectants, e.g., 1DN-6556, ME 3738, LB-84451, and MitoQ, 19) a non-nucleoside inhibitor of HCV, e.g., benzimidazole derivatives, benzo1,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, GS-9190, and A689; and 20) other drugs for treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-4Q1 (virostat), PYNH7 (altirex), KPE02003002, actilon (CPG-10101), KRN7000, civacir, Gl-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

It is also contemplated that the compounds of the present invention can be used with any other active therapeutic agent or ingredient which is appreciably metabolized by cytochrome P450 monooxygenase enzymes, e.g, cytochrome P450 monooxygenase 3A, thereby reducing the amount or rate at which the other active therapeutic agent or ingredient is metabolized, whereby the pharmacokinetics of the other active therapeutic agent or ingredient is improved. Such improvements can include elevating the blood plasma levels of the other therapeutic agent or ingredient or maintaining a more therapeutically effective blood plasma level of the other therapeutic active agent or ingredient -- compared to blood plasma

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It is also possible to combine any compound of the invention with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. Tine combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents arc both present in the body of the patient.

Co-administration includes administration of unit dosages of the compounds of the in vention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes bv administration of a unit dose of one or more other active J therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the in vention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to

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The combination therapy may provide synergy” and synergistic effect, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) coformulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g,, in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

In yet another embodiment, the present application provides a method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with said drug, a therapeutically effective amount of a combination comprising said drug and a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

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In yet another embodiment the present application provides a method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase 3A, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutical!y acceptable salt, solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method for increasing blood plasma levels of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method for increasing blood plasma levels of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with said drug, a therapeutically effective amount of a combination comprising said drug and a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method for increasing blood plasma levels of a drug which is metabolized by cytochrome P450 monooxygenase 3A, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method for increasing blood plasma levels of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and wherein

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In yet another embodiment, the present application provides a method for inhibiting cytochrome P450 monooxygenase in a patient comprising administering to a patient in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase.

In yet another embodiment, the present application provides a method for inhibiting cytochrome P450 monooxygenase 3A in a patient comprising administering to a patient in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase 3A.

In yet another embodiment, the present application provides a method for inhibiting cytochrome P450 monooxygenase comprising contacting cytochrome P450 monooxygenase wi tin an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase.

In yet another embodiment, the present application provides a method for inhibiting cytochrome P450 monooxygenase 3A comprising contacting cytochrome P450 monooxygenase 3A with an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase 3A.

In yet another embodiment, the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic

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PCT/US2008/054788 agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.

Ln yet another embodiment, the present application provides a method for treating an HIV infection comprising administering to a pa tient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TX4C-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG 1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100, DG35, AG 1859, capra virine, emi virine, delaviridine, efavirenz, nevirapine, (+) calanolide Λ, etravirinc, GW5634, DPC4J83, DPC-961, DPC-963, M1V-150, 'EMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773,, UK-453061, RDEA806, zidovudine, emtiicitabine, did anosine, stavudine, zalcitabine, lamivudine, abaca vir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, fosalvudine tidoxil (formerly HDP 99.0003), tenofovir disoproxil fumarate, adefovir dipivoxil, curcumin, derivatives of curcumin, chi cor ic acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurin tricarboxylic acid, derivatives of aurin tri carboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, L-870810, MK-0518 (raltegravir), elvitegravir, BMS-538158, G5K364735C, BMS-707035, MK-2048, and BA 011,

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PCT/US 2008/054788 enfuvirtide, sifuvirtide, FB006M, and TRJ-1144, AMD-070, an entry inhibitor, SP01A, BMS-488043, BIockAidc/ CR, a G6PD and N ADH-oxidase inhibitor, immunitin, aplaviroc, vicriviroc, maraviroc, maraviroc, PRO-140, INCB15050, PF232798 (Pfizer), CCR5mAbOO4, BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, A LG 889, and PA-1050040 (PA-040).

In yet another embodiment, the present application provides a method for treating an HCV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen τ actimmune, IFN-omega with DUR OS, locteron, albuferon, rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and pegylated IFN-beta, rebetol, copegus, viramidine (taribavirin), NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, GSK625433, SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, ITMN-191, MX-3253 (cclgosivir), UT-231B, IDN-6556, ME 3738, LB-84451, MitoQ, benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, A-689, zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-I7 (aitirex), KPE02003002, actilon (CPG-I0W1), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, N1M.811, DEBI0-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

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In still yet another embodiment, the present application provides for the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, for the preparation of a medicament for inhibiting cytochrome P450 monooxygenase in a patientIn still yet another embodiment, the present application provides for the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, for the preparation of a medicament for treating an HIV infection.

In still yet another embodiment, the present application provides for the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, for the preparation of a medicament for increasing blood plasma levels of the drug which is metabolized by cytochrome P450 monooxygenase.

In still yet another embodiment, the present application provides for the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, for the preparation of a medicament for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 mon ooxy gen ase.

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Examples

Preparation of Example A

Scheme 1

Example A

Compound 2

To a solution of Compound 1 (ritonavir) (1.8 g, 2.5 mmol) in 1,2di chloroethane (15 mL) was added l,r-thiocarbonyldiimidazole (890 mg, 5.0 mmol). The mixture was heated at 75°C for 6 hours and cooled to 25°C. Evaporation under reduced pressure gave a white solid. Purification by flash column chromatography (stationary phase: silica gel; eluent: EtOAc) gave Compound 2 (1.6 g). m/z: 831.1 (M+H)'.

Example A

To the refluxing solution of tributyltin hydride (0.78 mL, 2.9 mmol) in toluene (130 mL) was added a solution of Compound 2 (1.6 g, 1.9 mmol) and 2,2'azobisisobutyronitrile (31 mg, 0.19 mmol) in toluene (30 mL) over 30 minutes.

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The mixture was heated at 115^eC for 6 hours and cooled to 25°C. Toluene was removed under reduced pressure. Purification by flash column chromatography (stationary phase; silica gel; eluent; hexane/EtOAc = 1/10) gave Example A (560 mg), m/z: 705.2 (M+H)⁺. Ή-NMR (CDCb) δ 8.79 (1 H, s), 7.82 (1 H, s), 7.26-7.05 (10 H, m), 6.98 (1 H, s), 6.28 (1 H, m), 6.03 (1 H, m), 5.27 (1 H, m), 5.23 (2 H, s), 4.45-4.22 (2 H, m), 4.17 (1 H, m), 3.98 (1 H, m), 3.75 (1 H, m), 3.25 (1 H, m), 2.91 (3 H, s), 2.67 (4 H, m), 2.36 (1 H, m), 1.6-1.2 (10 H, m), 0.85 (6 H, m).

Preparation of Example B

Scheme 2

Example B

To a solution of Compound 1 (ritonavir) (98 mg, 0.136 mmol) in dichloromethane (4 mL) was added Dess-Martin periodinane (61 mg, 0,143 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was then partitioned between dichloromethane and brine, the dichloromethane layer was separated, dried and evaporated to dryness. Purification with CombiFlash® (stationary phase: silica gel; eluent: 40-80% EtOAc/l loxanc gradient) gave Example B as a white solid. Example B was further purified by trituration with MeOH/hexane to give 83 mg of a white solid, m/z: 719 (M+H) .

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Preparation of Example C

Scheme 3

HCI

I. cyclopropylamine, MeCN, rt

Compound 3

Compound 3 was prepared according to the procedures of T. Med. Chem. 1998, 41, 602, herein incorporated by reference in its entirety⁷ for all purposes. Compound 4

A flask was charged with cyclopropylamine (8.2 mL, 117.8 mmol) at room temperature. A solution of Compound 3 (1 g, 4.71 mmol) in MeCN (8.5 mL) was added dropwise over 5 min. to produce a clear yellow solution that was allowed to stand at room temperature overnight. Volatiles were removed in vac.uo, and the resulting residue was purified via silica gel chromatography (gradient elution, 0 to 50% EtOAc/hexane) to afford 0.65 g (70%) of 4 as a yellow liquid (EC/MS m/z 197 (M+H)⁺; 218 (M+NaJQ.

Scheme 4

II. rt.DCM; III. 1M LiOH,THF/H₂O

Compound 5

Compound 5 was purchased from Aldrich or alternatively prepared according to the procedures of f. Org. Chem. 1994, 59, 1937, herein incorporated by reference in its entirety for all purposes.

Compound 6

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To a solution of Compound 4 in DCM (3 mL) at room temperature was added 5 (0.Ί mL, 0.695 mmol). The resulting clear solution was allowed to stand at room temperature for 2 h. The solvent was removed in vacuo, and the residue was chromatographed directly using silica gel chromatography (gradient elution, 0 to 50% EtOAc/hexane) to produce 0.218 g (89%) of 6 (LC/MS m/z 354 (M+H)’; 729 (2M + Na) ) as a colorless glass.

Compound 7

Compound 6 was taken up in THF (5 mL) at room temperature, and LiOH (1 M in FLO) was added. The resulting reaction mixture was then stirred vigorously for 1.5 h. The reaction mixture was acidified with 1 M HO to a pH of 3 (monitored using pH test strips). The acidified reaction mixture was then extracted several times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na^SCfi, and concentrated in vacuo to produce 0.20 g (quantitative yield) of 7 (LC/MS m/z 340 (M+H)*) as a colorless film. This material was used without further purification.

Scheme 5

Example C

IV. EDC, HOBt, DIPEA, THF

Example C

Compounds 7 (0Ό34 g, 0.100 mmol) and 8, (0.034 g, 0,083 mmol) were diluted in THF (2 mL) at room temperature. To die resulting solution were added /V,A'-di isopropyl ethyl amine (0.022 mL, 0.125 mmol), EDC (0.018 mL, 0.099 mmol) and HOBt (0.013 g, 0.099 mmol). The solution was then allowed to stand overnight at room temperature. The solvent was removed in vacuo and die residue was taken up in MeCN (0.5 mL) and passed through an Acrodisc LC13

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PVDF filter (0.45 uM) prior to purification by preparatory HPLC to afford 0.043 g (71 %) of Example C as a fluffy white solid. (’H-NMR (300 MHz, CDCb) δ 8.79 (s, 1H); 7.82 (s, 1H); 7.27-7.02 (m, 10 H); 6.81 (s, IH); 5.97 (br d, / = 8.7 Hz, IH); 5.76 (br d, / = 7.2 Hz, 1H); 5.21 (dt, / = 7.5,12.6 Hz, 2H); 5.02, br d, J = 8.4 Hz, IH); 4.58 (s, 2H); 4.16 (m, IH); 3.99 (br t, J = 6.6 Hz, IH); 3.79 (m, IH); 3.27 (pent, J = 6.6 Hz, IH); 2.85-2.50 (m, 3H); 2.23 (m, IH); 1.82 (br s, 2H); 1.60-1.22 (m, 4H); 1.36 (d, ] = 6.6 Hz, 6H); 0.91 (d, ] = 6.6 Hz, 3H); 0.90-0.7 (m, 4H); 0.80 (d, J = 6.6 Hz, 3H); 1.C/MS m/z 731 (M⁺)).

Preparation of Examples D-3

Scheme 6

a: R = H b: R = CH₃ c: R= CH₂CH₃ d: R = CH₂OHn e; R = CH(O-t-Bu)CH₃ f: R = CH(OH)CH₃

f. Et₃N/DMAP/THF/65 °C; Jf. CH₂CI₂/25 °C; III.

a. NaOH/diaxane/HjO;

b. HCl

Compound 9

Compound 9 was prepared according to the procedures of I. Med. Chem.

1998, 41, 602.

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Compound 10

The structures of Compound 10 were prepared according to the procedures of I- Med. Chem. 1998, 41, 602.

Compound 11

The structures of Compound 11 were purchased from Aldrich or prepared according to the procedures of L Org. Chem. 1994, 59,1937. Compound 12

Method 1: To a solution of Compound 9 (0.8 mmol) in THE (2 mL) was added a carbamate of Compound 10 (0.6 mmol), followed by DMAP (16 mg) and triethylamine (0.25 mL). The resulting mixture was heated at 70^aC for two hours and diluted with EtOAc. The organic phase was separated, and washed sequentially with saturated aqueous N’aiCOi, water, and brine, then concentrated under reduced pressure. Purification of tire residue by flash column chromatography (silica gel, 1/1 --1/3 hexanes/EtOAc gradient) gave compounds of Structure 12.

Method 2: To a solution of Compound 9 (2.4 mmol) in CEECh (2 mL) was added an isocyanate of Compound 11 (2 mmol). The resulting mixture was stirred for 4 hours and concentrated. Purification of the residue by flash column chromatography (silica gel, hexane/EtOAc 1/1 - 1/3) gave structures of Compound 12.

Compound 13

To a solution of structures of Compound 12 (1.8 mmol) in dioxane (8 mL) and water (8 mL) was added sodium hydroxide (3.6 mmol). The resulting reaction mixture was stirred for ] hour and acidified with E1CI in dioxane (3.6 mmol). Tire reaction mixture was extracted with EtOAc and the organic phase was dried with anhydrous MgSO«. Concentration of the dried organic phase gave structures of Compound 13.

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1. Et₃N/DCM

Compound 16

To a solution of Compound 15 (obtained commercially from Molekula) (17 mmol) in DCM (40 mL) was added Compound 14 (19 mmol), followed by triethyl amine (26 mmol). The resulting reaction mixture was stirred for 12 hour and concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed sequentially writh saturated aqueous NaiCCh, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes/EtOAc = 1/1) gave Compound 16 (4.7 g).

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Scheme 8

Examples:

D: R = H

E: R = CH₃

F: R = CH₂CH₃

G: R = CH₂OBn

H: R = CH(O-t-Bu)CH₃

I: R = CH(OH)CH₃

I. a. n-BuLIA78 C; b.i-Bu₂Al(OMe); II. a. Ac₂O/pyridine; b. Na-Hg/MeOH/THF; ill. Na/NHJ-33 C;

IV. a. H_?/10%Pd/C: b. TFA/DCM; V. 16/Et₃N; VI. acid of structure 13/EDC/HOBt

Compound 17

Compound 17 was prepared according to the procedures of Tetrahedron 1997, 53, 4769, herein incorporated by reference in its entirety for all purposes. Compound 18

Compound 18 was prepared according to the procedures of I. Org. Chem. 1987, 52, 3759, herein incorporated by reference in its entirety for all purposes.

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Compound 19

A suspension of Compound 18 (7.4 mmol) in THF (200 mL) was heated under reflux until a clear solution was obtained. The solution was cooled to -78'C and n-butyllithium (14.8 mmol) was added drop wise to provide a solution of the dianion of sulfone 18.

To a D1BAL-H solution (7.8 mmol) at 0°C was added a solution of MeOH (7.8 mmol) in THF (5 mL). The mixture was stirred for 5 minutes and cooled to 78^r)C. A solution of Compound 17 (6.6 mmol) in THF (5 mL) was added to the above DIBAL-H/MeOH solution, and the resulting reaction mixture was stirred for another 5 minutes. The resulting solution of aldehyde complexes was transferred to solution of the dianion of sulfone 18. The resulting mixture was stirred at-78°C for 30 minutes, quenched with an aqueous solution of NHiCl, and warmed to 25°C. The mixture was then extracted with EtOAc, and concentrated to give Compound 19 as a mixture of diastereomers, (m/z 737.3 (M+Na)⁺. Example 20

To a solution of Compound 19 in DCM (20 mL) was added Aa»0 (1.5 mL), followed by pyridine (3 mL). The resulting mixture was stirred for 12 hours and concentrated. The concentrate was dissolved in MeOH (30 mL) and cooled to 0°C. NaJ-LPO- (4.9 g) was added to the solution, followed by⁷ freshly prepared Na-I Ig (6%, 6 g), The resulting mixture was warmed to 25°C and stirred for 12 hours. Water (50 mL) was then added, and the mixture was filtered and concentrated. The concentrate was diluted with EtOAc and washed with brine. The organic phase was concentrated. Purification by flash column chromatography (silica gel, eluent: hexanes/EtOAc = 10/1) gave Compound 20 (1.4 g).

Compound 21

To liquid ammonia (25 mL) at -33°C was added a solution of Compound 20 (1.4 g) in THF (2.5 mL). Sodium was slowly added until the blue color of the

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Compound 22

A mixture of Compound 21 (1.15 g) and 10%Pd/C (160 mg) in MeOH (20 mL) was hydrogenated for 12 hours. CELITE was added and the resulting mixture was stirred for 5 minutes. The mixture was then filtered and concentrated to give an intermediate (1 g). The intermediate (700 mg) w'as dissolved in DCM (20 mL) and TFA (4 mL), and the resulting mixture was stirred for 4 hours, then concentrated under reduced pressure. The concentrated mixture was diluted with EtOAc, and washed sequentially with saturated aqueous Na?CO3, water, and brine. Concentration of the washed EtOAc mixture gave Compound 22 (420 mg).

Compound 8

To a solution of Compound 22 (1.57 mmol) in CHsCN (16 mL) was added Compound 16 (1.57 mmol), followed by diisopropylethylamine (3.14 mmol). The resulting mixture w^ras stirred for 12 hours. The mixture was then diluted with EtOAc, and washed sequentially with saturated aqueous Na’COs, water and brine. Purification by reverse-phase HPLC (Phenomenex Synergi® Cornb-HTS column, eluent: 25% -100% CHsCN in water) gave Compound 8 (460 mg). Example D

To the solution of Compound 13a (R= H; 0.08 mmol) and Compound 8 (0.06 mmol) in THF (1 mL) were added HOBt (15 mg), EDC (26 mg), and disopropylethylamine (0.25 mL). The mixture was stirred for 12 hours and

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2020203321 21 May 2020 concentrated. Purification by reverse phase HPl.C (Phenomenex Synergi® CombH IS column, eluent: 25% -100% CHjCN in water) gave Example D (27 mg), m/z 663.1 (M+H)⁺. Ή-NMR (CDCh) b 8.79 (1 H, s), 7.83 (1 H, s), 7.25-7.04 (10 H, m), 6.98 (1 H, s), 6.25 (1 H, m), 5.25 (3 H, m), 4.40 (2 H, s), 4.12 (1 H, m), 3.8 (3 H, m), 3.22 (1 H, m), 2.95 (3 H, s), 2.70 (4 H, m), 1.60 (4 H, m), 1.26 (6 11, d, J = 7 Hz). Example E

Example E was prepared following the procedure for Example D (30 mg), except that Compound 13b was used instead of Compound 13a. m/z 677.1 (M+Hy.

Example F

Compound F was prepared following the procedure for Example D (40 mg), except that Compound 13c was used instead of Compound 13a. m/z 691.2 (M+H)\ ’H-NMR (CDCh) b 8.80 (1 H, s), 7.83 (1 H, s), 7.25-7.06 (10 H, m), 6.98 (1 H, s), 6.35 (1 H, m), 6.23 (1 H, m), 5,24 (2 H, s), 5.12 (1 H, m), 4.34 (2 H, s), 4.10 (2 H, m), 3.78 (I H, m), 3.23 (1 H, m), 2.90 (3 H, s), 2.68 (4 H, m), 1.90 (2 H, m), 1.7-1.4 (4 H, m), 1.36 (6 H, d, J = 7.0 Hz), 0.90 (3 H, t, J = 7.3 Hz) Example G

Example G was prepared following the procedure for Example D (84 mg), except that Compound 13d was used instead of Compound 13a. m/z 783.2 (M+H)-.

Example H

Example H was prepared following the procedure for Example D (90 mg), except that Compound 13e was used instead of Compound 13a. m/z 763.2 (Mi-H)\ Example I

Example H (24 mg) was dissolved in TFA (2 mL) and lhe mixture was stirred for 12 hours, then concentrated. Purification by reverse phase HPLC

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PCT/US2008/054788 (Phenomenex Synergi® Comb-HTS column, eluent: 25% - 100% CHaCN in water) gave Example I (14 mg), m/z 707.2 (M+H)\ Ή-NMR (CDCb) 6 8.82 (1 H, s), 7.85 (1 H, s), 7.26-7.04 (10 H, m), 7.0 (1 H, s), 5.25 (2 H, s), 4.86 (1 H, m), 4.56 (1 H, m), 4.37 (2 H, m), 4.13 (1 H, m), 4.06 (1 H, m), 3.86 (1 H, m), 3.32 (1 H, m), 2.99 (3 H, s), 2.8-2.6 (4 H m), 1.6-1.4 (4 H, m), 1.37 (6 H, m), 1.15 (3 H, m).

Preparation of Example 1

Scheme 9

i. EDC/HOBt

Example 1

Compound 23 was prepared following tire procedure for Compound 13, with the exception that methyl 3-isocyanatopropionate was used instead of Compound 11.

Example J was prepared following the procedure for Example D (37 mg), except that Compound 23 was used instead of Compound 13a. m/z 677.2 (M+H)\

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Preparation of Example K

Scheme 10

1. NaNj/DMF; II. PPh₃/H₂O; III. a. CI₃COCOOCCI₃; b. HCI-NH₂CHiPrCO₂Et;

IV. a. NaOH; b. HCI; V. EDC/HOBt/compound 8

Example K

Compound 3a

Compound 5a was prepared following the literature procedure of Synthesis 823,1976, herein incorporated by reference in its entirety for all purposes.

Compound 3b

To the solution of Compound 3a (700 mg, 3.9 mmol) in THF (10 mL) was added water (69 pL, 3.9 mmol), followed by tri phenylphosphine (1.06 g, 4.0 mmol). 'The mixture was stirred for 12 hours. Solvents were removed and the mixture was dried to give Compound 3b, which, was used for next step without further purification.

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Compound 3c

To a solution of triphosgene (110 mg, 0.37 mmol) in CH?CL· (2 mL) at 0^aC was added a solution of Compound 3b (1 mmol) and iPrNEtz (0.38 mL, 2.2 mmol) in CH2CI2 (3.5 mL) over 30 minutes period. The mixture was stirred for 30 minutes, and a solution of amino N-methyl leucine methyl ester HC1 salt (182 mg, 1 mmol) and iPrNEtz (0.34 mL, 2.2 mmol) in CH2CI2 (2 mL) was added. The mixture was stirred for 12 hours, and diluted with EtOAc. Tire solution was washed with sat. Na^COa (2x), water (2x), and brine, and dried over NaiSO-i. Concentration and purification with silica gel flash column gave Compound 5c (300 mg).

Compound 3d

Compound 3d was prepared following the procedure for Compound 13, with the exception that Compound 3c was used instead of Compound 12. Example K

Example K was prepared following the procedure for Example D (7 mg), except that Compound 3d was used instead of Compound 13a. m/z 705.2 (M+H)’. Ή-NMR (CDCb) ft 8.8 (1 El, m), 7.86 (1 H, s), 7.26-6.8 (11 H, m), 6.10 (1 H, m), 5.55.10 (4 H, m), 4.46 (2 H, m), 4.2-3.75 (3 H, m), 3.25 (1 H, m), 2.82/2.4 (3 H), 2.8-2.5 (4 H, m), 2.17 (1 H, m), 1.7-1.2 (10 H, m), 0.8 (6 H, m).

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Preparation of Example L

Scheme 11

I o

Example L

I. Et₃N

Example L

To a solution of Compound 22 (1.57 mmol) in CLbCN (16 mL) was added Compound 16 (3.14 mmol), fohowed by triethylamine (471 mmol). The resulting mixture was stirred for 12 hours. The reaction mixture was diluted with EtOAc and washed sequentially with saturated aqueous Na^COs, water, and brine. The solvent was removed under reduced pressure. Purification of the residue by flash column chromatography (silica gel, eluent: hexanes/EtOAc= 1/1) gave Example L (460 mg), m/z 551.2 (M+H)\ ^]H-NMR (CDCh) & 8.81 (2 H, s), 7.85 (2 H, s), 7.26-7.0 (10 H, m), 5.24 (4 H, s), 4.50 (2 H, m), 3.87 (2 H, m), 2.73 (4 H, m), 1,4-1.2 (4 H, m).

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Alternate Prepciration of Compound 22

Scheme 12

Ph

NHCbz

^Ph ^Ph

I) : I» T

---. CbzHN^^_NHCbz----. ^H=^N-<^NH₂Ph^ Ph^

22

I. TCDVTHF/65 °C; II. P(OEth/160 °C; III. 10%Pd/C/i-PrOH/EtOAc

Compound 25

Compound 25 was prepared following the literature procedure described in L Org. Chem. 1996, 61, 444 (herein incorporated by reference in its entirety), except that the L-isomer was prepared instead of the D-isomer.

Compound 26

A mixture of Compound 25 (7.4 g) and l,l'-thiocarbonyldiimidaxole (4.5 g) in THF (260 mL) was heated at 65°C for 54 hours. Solvent was removed from the mixture under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc = 1/1) gave Compound 26 (7,33 g).

Compound 27

The mixture of Compound 26 (7,3 g) and tri ethyl phosphite (100 mL) was heated at 160^uC for 4 hours. Excess reagents were removed under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc = 3/1) gave Compound 27 (5 g). Compound 22

A mixture of Compound 27 (250 mg) in i-PrOH/EtOAc (5mL/5mL) was hydrogenated for 14 hours in the presence of 10%Pd/C (75 mg), CELITE was

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The skilled practitioner will recognize that the procedure outlined in Scheme 12 can be used to prepare a variety of 1,4-substi luted 1,4-diamines analogous to Compound 22. For example, an amine-protected 2,3-dihydroxy-l,4diamine analogous to Compound 25 can be prepared:

(L<Ar)_p

(L⁴-Ar)_p

Analogs of Compound 25 wherein L³, A, Ar, and P are as defined herein, and protecting group P is any amine protecting group described in described in Protective Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9), which is herein incorporated by reference in its entirety for all purposes. The analogs of Compound 25 can then be transformed, according to the methods outlined in Scheme 12, to form analogs of Compound 26:

{C-Ar)p

Analogs of Compound 26;

analogs of Compound 27;

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Analogs of Compound 27; and analogs of Compound 22:

(L⁴'Ar)_p

,.A L³ ^H2NV''''^x'^nh₂ /L³ r

(L⁴-Ar)_p .Analogs of Compound 22.

Preparation of Examples M and Nl

Scheme 13

I. a. LiOH, THF/H₂O, 25 °C; b. HCl

Compound 29

Compound 28 was prepared using a procedure similar to that used to prepare Compound 6 (described in Scheme 4) except that Compound 9 was used instead of Compound 4.

To a solution of Compound 28 (0.757 g, 2.31 mmol) in THF (9 mL) at room temperature was added freshly prepared IM LiOH (4.6 mL, 4.6 mmol). After 1.5 h, 1 M HCl (7 mL, 7 mmol) was added and the reaction mixture extracted thoroughly with EtOAc (5 X 15mL). The combined organic layers were dried over

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Scheme 14 h₂n

ΌΗ

Bn'

Boc

N_ ‘OH

Boc H

Bn , Ph Q ,O Γ

Ph'

NHBoc

111

Ph

Boc OH r

I c N g_r NHBoc so₂Ph

BocHN.

Ph

VI

IV

Bn

NHBoc

VII

Boc

H₂N

Ph

NHBoc

Boc

Bn

Ph

NHBoc

Ph

NH₂· 2TFA ³⁷

j. a. PhCHO, MeOH; b. NaBH^; c. Boc₂O, THF/H₂O. I!. Pyr-SO_3l Et₃N, DMSO 0 ’C. III. zj-BuLi, MeOAI(/-Bu)₂, THF, -73 °C. IV, a. Ac₂O, pyr, CH₂CI₂, b. 6% Na/Hg, Na₂HPO^, MeOH, V, H₂, 10% Pd/C, MeOH. VI. Na/NH₃, THF,-35 °C. VII. 20%TFA/DCM.

Compound 30

Compound 30 was purchased from Aldrich Chemical Co., and used without further purification.

Compound 31

To a solution of Compound 30 (8.25 g, 80 mmol) in MeOH (50 mL), was added benzaldehyde (8.1 mL, 80 mmol) and the resulting solution was allowed to stir at room temperature. After 2 h, the reaction mixture was cooled to 0°C and NaBHj (3.33 g, 88 mmol) was added in portions. After allowing the reaction mixture to warm to room temperature over 2 h, glacial acetic acid (2 mL) was added. The resulting viscous solution was concentrated in vacuo. EtOAc and H?O (50 mL each) were added and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated NaHCOs, brine, and

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Compound 32

Compound 31 (5.95 g, 20.3 mmol) and EbN (9.9 mL, 71 mmol) were diluted in DMSO (65 mL) and allowed to age at room temperature for 30 min before cooling to 0°C. Pyridme*SCh was added in one portion and the reaction mixture was maintained at 5°C to prevent freezing. After 45 min, the reaction mixture was poured into icewater and extracted with EtOAc. The combined organic layers were washed with saturated NaHCOs, H2O, and dried over anhydrous MgSOi prior to concentration in vacuo (bath temperature 25 ^fJC) to produce 4.39 g (74%) of Compound 32 as a clear, yellow colored oil that was used without further purification. Ή-NMR (CDCL, 300 MHz) 6 (major rotamer) 9.36 (br s, IH); 5.01 (d, ] = 15 Hz, IH); 4.12 (d, / = 15 Hz, HI); 3.45 (m, IH); 2.04-1.88 (m, 1H); 1.80-1.58 (m, 1H); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, / = 7.2 Hz, 3H), (minor rotamer) 9.46 (br s, IH); 4.71 (d, / = 15 Hz, IH); 4.20 (d, } = 15 Hz, IH); 3.78 (m, IH); 2.04-1.88 (m, IH); 1.80-1.58 (m, IH); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, J = 7.2 Hz, 3H) Compound 34

A suspension of Compound 33 (6.23 g, 16.6 mmol) in THF (500 mL) was heated under reflux until a homogeneous solution was obtained. The solution was cooled to -78°C and 1.6M Ji-BuLi (19.7 mL, 31.5 mmol) was introduced to produce a clear yellow solution. Meanwhile, DIBAL-OMe was prepared by

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PCT/US2008/054788 dilution of DIBAL-H (IM in hexanes, 18.1 mL, 18.1 mmol) in THF (8 mL) and cooling to (PC prior to addition of MeOH (0.73 mL, 18.1 mmol). This solution was allowed to age while Compound 32 (4.39 g, 15.1 mmol) was diluted in THF (15 mL) and cooled to -78°C. The DIBAL-OMe solution was cannulated to the solution of Compound 32 and allowed to age for 5 min prior to cannulation to the sulfur di an ion solution. The resulting clear yellow solution was allowed to age at -78^i?C for Ih. The reaction was quenched by addition of saturated NH-iCl (100 mL) at -78^CC and allowed to warm to room temperature. Water was added until all precipitated solids were dissolved and the layers separated. The THF layer was concentrated in vacuo while the aqueous layer was extracted with EtOAc. The recombined organic layers were washed with brine, and the resulting emulsion was heated with solid NaOH until homogeneous bilayers resulted. The aqueous layer was extracted with EtOAc and the combined organics dried over anhydrous NasSO*. Concentration in vacuo produced 9.57 g (95%) of Compound 34 as an amorphous white solid (LC/MS w/z: 689.3 (M+Na)Q that was used in the following procedures without further purification.

Compound 35

Crude Compound 34 was suspended in CH2CI2 (65 mL) followed by addition of pyridine (6.7 mL, 83 mmol) and acetic anhydride (3.5 mL, 36.5 mmol). Hie resulting solution was allowed to age at room temperature overnight. MeOH (6 mL) was added and after 10 min, the reach on was poured into brine, Addition of water produced a bi layer that was separated and the aqueous phase was repeatedly extracted with CLLCL. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to produce 8.95 g (88%) of a white solid that was immediately taken up in MeOH (100 mL). NasHPOi (11.4 g, 80.3 mmol) was added and the resulting slurry was cooled to (J°C prior to addition of Na-Hg (6%, 14.5 g, 37.8 mmol) in portions. After aging at room temperature

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Compound 36

Compound 35 ¢1.73 g, 3.4 mmol) was diluted in MeOH (7.5 mL) and 10% Pd/C (0.36 g, 0.34 mmol) was added. The atmosphere was replaced with a H: balloon and the reaction mixture allowed to age at room temperature. After 2 h, the reaction mixture was filtered through a pad of celite, the filtrate was washed several times with MeOH, and the combined organic layers were concentrated in vacuo to afford 1.45 g (83%) of Compound 36 as a colorless oil (LC/MS ni/z: 533.2 (M+Na)’) that was used in the following procedures without further purification. Compound 37

Compound 36 (0.528 g, 1.03 mmol) was diluted in THF (3 mL) and added to liquefied ammonia (approx. 20 ml.) at -35°C. Small pieces of Na were added until a blue color persisted. After 1.5 h, solid NHxCI was added in portions until the remaining Na was destroyed and the ammonia was allowed to escape at ambient temperature. Water and EtOAc (20 mL each) were added, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na^SOx and concentrated in vacuo to afford 0.395 g (91%) of Compound 37 as an amorphous white solid that was used without further purification in the following procedures (LC/MS m/z: 421.1 (M+H)~; 443.2 (M+Na)⁺).

Compound 38

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Compound 37 (0.362 g, 0.861 mmol) was diluted in CFLCb (3.2 mL).

Trifluoroacctic acid (0.8 mL) was added and the clear solution was allowed to age overnight. Following concentration in vacuo, the residue was azeotroped with toluene several times to remove residual TFA. 0.382 g (99%) of the bistrifluoroacetate salt of Compound 38 was collected as a colorless oil that was used without further purification (LC/M5 m/z: 221.1(Μ+Η)9·

Scheme 15

i. carbonate 16, DIPEA, MeCN; II acid 29, EDC, HOBt, DIPEA, THF

Compounds 39 and 40

Compound 38 (0.382 g, 0.852 mmol) w^ras diluted m MeCN (10 mL) and Ν,Ν-dusopropylethylamine (0.60 mL, 3.41 mmol) was added, followed by a solution of Compound 16 in MeCN (1.5 mL). The clear, yellow solution was allowed to age at room temperature for 4h and the volatiles were removed in vacuo. The residue was taken up in a 3/1 CHCb/IPA (v/v, 13 mL) and treated with saturated Na?COj (3 mL). The resulting suspension was diluted w’ith H;O (3 ml.,), and the aqueous phase thoroughly extracted W'ith 3/1 CHCb/IPA. The combined organic layers were dried over a 3/2 (w/w) mixture of anhydrous NazSO-i/anhydrous NasCOs and concentrated in vacuo. Chromatography on SiCh (0-20% MeOH/CH-Cb) afforded 0.043 g (14%) of Compound 39 as a colorless film

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Example M

A flask was charged with Compound 39 (0.048 g, 0,133 mmol) and Compound 29 was added as a 0.2 M solution in THF (0.8 mL, 0.160 mmol). THE (1 mL) was added, followed by DTPEA (0.026 mL, 0.Ί45 mmol), HOBt (0.022 g, 0.160 mmol) and finally EDC (0.028 mL, 0.160 mmol). The clear, colorless solution was allowed to age overnight. Volatiles were removed in vacuo and the residue chromatographed on SiO: (0-20% MeOH/CHsCh). Fractions containing the desired compound were concentrated in vacuo and submitted to preparatory LC/MS purification to afford 0.018 g (20%) of Example M as a colorless film LC/MS m/z: 657.2 (M+H)⁺; ⁵H-NMR (CDCh, 300 MHz) δ 8.95 (s, 1H); 7.88 (br s, 111); 7.27-7.04 (m, 5H); 7.04 (s, 1H); 6.60-6.20 (m, 2H); 5.22 (m, 2H); 5.12 (d, ] = 9.3 Hz, 1H); 4.50 (m, 2H); 4.01 (br s, 1H); 3.83 (m, 2H); 3.38 (m, 1H); 3.10-2.94 (m, 3H); 2.74 (m, 2H); 2,23 (m, 111); 1.64-1.15 (m, 8H); 1.40 (d, J = 6.9Hz, 6H); 0.96 (m, 6H); 0.83 (t, ] = 6.9 Hz, 3H). Example N

Example N was prepared using procedures similar to those used to prepare Example M, using the following reagents: Compound 40 (0.055 g, 0.152 mmol); Compound 29 (0.92 mL of 0.2 M THF solution, 0.183 mmol); THF (1 mL); DIPEA (0.040 mL, 0.228 mmol); HOBt (0.025 g, 0.182 mmol); EDC (0,032 mL, 0.182 mmol). 0.087 g (87%) of Example N was isolated as a colorless film (LC/MS m/z: 657.2 (M+H)⁺; Ή-NMR CDC13, 300 MHz) δ 8.84 (s, 1H); 7.86 (s, 1H); 7.27-7.04 (m, 5H); 7.04 (s, 1H); 6.28 (br s, 1I I); 6.12 (br s, 1H); 5.25 (m, 2H); 5.11 (d, J = 9.0 Hz, 1H); 4.62-4.32 (m, 2H); 4.19 (m, 1H); 4.01 (br s, 1H); 3.53 (m, 1H); 3.10-2.90 (m, 3H); 2.72 (d, ] - 6.0 Hz, 2H); 2.29 (m, 1H); 1.65-1.18 (m, 8H); 1.39 (d, / = 6.9 Hz, 6H); 1.00-0.78 (m, 9H).

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Preparation of Examples Q and P

Scheme 16

I. TCDI/THF/65 °C; II. P(OEt)₃/160 °C; III. H_?.10% Pd/C

Compound 41

Compound 41 was prepared following the procedure described in J. Org.

Chem. 1996,67,444-450.

Compound 42

A mixture of Compound 41 (1.73 g, 3 mmol) and 1,1'thiocarbonyldiimidazole (1.14 g, 6.1 mmol) in THF (60 mL) was heated at 65^CC for 72 hours. Solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and washed successively with IN HCl, water, and brine, and dried over MgSO*. Purification by flash column chromatography (silica gel, hexanes/EtOAc = 1./1) gave Compound 42 (980 mg), m/z: 611 . J (M+H)⁺.

Compound 43

A mixture of Compound 42 (980 mg) and triethyl phosphite (10 mL) was

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Compound 44

A mixture of Compound 43 (580 mg) in i-PrOH/EtOAc (12 mL/12 mL) was hydrogenated under high pressure (100 psi) for 24 hours in the presence of 10%Pd/C (200 mg). Celite was added and the mixture was stirred for 5 minutes. Filtration and evaporation gave Compound 44 (285 mg), m/z: 269.1 (M+H)\

The skilled practitioner will recognize that the procedure outlined in Scheme 16 can be used to prepare a variety of 1,4-substituted 1,4-dia mines analogous to Compound 44. For example, an a mine-protected 2,3-dihydroxy-l,4diamine analogous to Compound 41 can be prepared:

(L⁴-A% OH L³'^A , L³ OH (L^-Ar)_p

Analogs of Compound 41 wherein L³, A, Ar, and P are as defined herein, and protecting group P is any amine protecting group described in described in Protective Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9). The analogs of Compound 41 can then be transformed, according to the methods outlined in Scheme 16, to form analogs of Compound 42:

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Analogs of Compound 42;

analogs of Compound 43:

(L^'ArJp

(C-Ar)_p

Analogs of Compound 43; and analogs of Compound 44:

(L⁴-Ar)_p

A³(L⁴-Ar)_p

Analogs of Compound 44, if will also be recognized that stereochemical configurations other than those shown (i.e., enantiomers or diasteriomers) can be prepared by the selection of analogs of Compound 41 having the appropriate stereochemical configuration at the chiral centers.

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Scheme 17

Compound 46

To the solution of Compound 45 (950 mg, 3.5 mmol) in CHsCN (36 ml.) at U°C was added Compound 16 (892 mg, 3.2 mmol), followed by diisopropylethyl amine (1.2 ml., 7 mmol). The mixture was stirred for 12 hours at 25^OC. Tire mixture was diluted with EtOAc, and washed successively with saturated NaaCOs, water, and brine. Purification by flash column chromatography (silica gel, 100% EtOAc to ClLCh/McOH = 4/1) gave Compound 46 (770 mg), m/z: 410.1 (M+H)*.

The skilled practitioner will recognize that the procedure outlined in Scheme 17 can be used to prepare a variety of compounds analogous to Compound 46. For example, 1,4-di amines analogous to Compound 44 can be prepared as discussed above:

(L⁴-Ar)_p

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Analogs of Compound 44.

The analogs of Compound 44 can then be reacted with analogs of

Compound 16:

Analogs of Compound 16, (wherein Z², X, and R are as defined herein) to form analogs of Compound

46:

(L⁴-Ar)_p nh z²-x-r^! (L^d-Ar)_p

It will also be recognized that stereochemical configurations other than those shown (i.e, enantiomers or diasteriomers) can be prepared by the selection of analogs of Compound 44 having the appropriate stereochemical configuration at tire chiral centers.

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Scheme 18

I, CH₂CI₂/25 °C; II. a. NaOH/dioxane/H₂0; b. HCI: Ilf. amine 46/EDC/HOBt;

IV. a. TEA; b. NaOH

Compound 47

Compound 47 is commercially available from TCI.

Compound 48

To a solution of Compound 9 (500 mg, 3 mmol) in CHjCL (3 mL) was added Compound 47 (500 mg, 2.5 mmol). Tire mixture was stirred for 14 hours. Purification by flash column chromatography (hexanes/EtOAc = 1/1.5) gave Compound 48 (242 mg), m/z: 372.1 (M+H)·*.

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Compound 49

To a solution of Compound 48 (240 mg, 0.65 mmol) in dioxane (4 mL) and water (4 mL) was added sodium hydroxide (40 mg, 1 mmol). The mixture was stirred for 1 hour and acidified with 4 N HC1 in dioxane (0.25 mL, 1 mmol). The mixture was extracted with EtOAc and organic phase was dried with MgSOi. Concentration gave Compound 49 (200 mg), m/z: 356.2 (M-H)\

Example O

To a solution of corresponding acid 49 (30 mg, 0.08 mmol) and Compound 46 (22 mg, 0.05 mmol) in THF (1 mL) were added HOBt (15 mg, 0.11 mmol), EDC (20 pL, 0.11 mmol), and disopropylethylamine (0.2 mL). The mixture was stirred for '12 hours and concentrated. Purification by flash column chromatography (hexane s/EtO Ac = 1/5 to 0/100) gave Example O (17 mg), m/z: 749.3 (M+H)\

Example P

To Example O (17 mg) was added TFA (2 mL). The mixture was stirred for 3 hours and concentrated. The mixture was diluted with THF (2 mL) and 1.0 X NaOH solution was added until pH 11. The mixture was stirred for 10 minutes, and extracted with EtOAc. The organic phase was washed with water and brine. Purification by Rash column chromatography (EtOAc) gave Example P (12 mg). ⁵H-XMR (CDCh) & 8.76 (1 H, s), 7.79 (1 H, s), 7.25-6.9 (11 H, m), 6.51 (1 H, broad), 5.42 (1 H, m), 5.18 (2 H, m), 4.42 (2 H, m), 4.22 (1 H, m), 4.10 (1 H, m), 3.95 (1 H, m), 3.79 (1 H, m). 3.58 (1 H, m), 3.23 (1 H, m), 2.93 (3 H, s), 2.9-2.5 (4 H, m), 1.6-1.2 ( 10 H, m); m/z: 693.2 (M+H)’.

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Preparation of Examples O, R, and S

Scheme 19

I. CDI, DIPEA, CH₂CI₂; II. LiOH, THF/H₂O;

III. Cmpd. B, DIPEA, EDC, HOBt, THF;

IV. a. HCI/di oxane; b. Na_zCO_a; V. (BrCH₂CH₂hO. NaHCO₃, DMF

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Compound 50

Compound 50 is commercially available from Chem Impex International, and used without further purification.

Compound 51

Compound 50 (7.0 g, 26.0 mmol) was dissolved in Cf-bCL (330 mL) and 1,1carbonyldii mid azoic (4.22 g, 26.0 mmol) was added, followed by i-PnNEt (19 mL, 104 mmol). The solution was stirred at 25°C for 12 hours. Compound 9 (4.44 g, 26.0 mmol) was dissolved in 20 mL of CH:Cb and added to the reaction mixture. The solution was stirred at 25'C for 7 hours. The solvent was removed in vacuo and the residue was diluted with ethyl acetate and washed with water and brine. The organic layers were dried (NasSCf), filtered, and evaporated. Purification by Combiflash® (stationary phase: silica gel; eluent: 66-100% EtOAc/Hexane gradient) gave Compound 51 (7.34 g). m/z; 429.0 (M+H)'.

Compound 52

Compound 51 (7.34 g, 17.13 mmol) was dissolved in THF (90 mL) and IM aqueous LiOH (35 mL) was added. The mixture was stirred at 25°C for 0.5 hour. The reaction was quenched with IM HC1 (51 mL) and the mixture was adjusted to pH 2. The mixture was extracted with ethyl acetate. The organic layers were dried over Na:SCC, filtered, and evaporated to provide Compound 52 (7.00 g). The recovered Compound 52 was used in the next step without further purification, m/z: 415.0 (M+H)\

The skilled practitioner will recognize that the procedure outlined in Scheme 19 can be used to prepare a variety of compounds analogous to

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Compounds 51 and 52. For example, amines analogous to Compound 9 can be reacted with the appropriate amino ester analogous to Compound 50;

R²

R^b-Y-NH ₊ HN'^>f^0Me

R⁷ R¹ O

Cmpd 9 Analog Cmpd 50 Analog, to form compounds analogous to Compound 51, which are further reacted to form compounds analogous to Compound 52:

Cmpd 51 Analogs Cmpd 52 Analogswherein R¹, R-, R⁷, R- and Y are as defined herein.

It will also be recognized that stereochemical configurations other than those shown (i.e., enantiomers or diasteriomers) can be prepared by the selection of analogs of Compound 50 having the appropriate stereochemical configuration at the chiral center.

Example O

Compound 52 (2.57 g, 6.21 mmol) was dissolved in THF (67 mL).

Compound 8 (2.10 g, 5.13 mmol) was added, followed by HOBt (1.04 g, 7.70 mmol), i-PnNEt ¢3.67 ml.., 20.52 mmol), and EDC (1.82 mL, 10.26 mmol). The mixture was stirred at 25°C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed sequentially with saturated aqueous Na^CCb, water, and brine. The organic phase was dried over Na?SOi, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel; eluent: 5% iPrOFI/CH’Ch) gave Example Q (3.02 g). m/z,: 806.2 (M+J1)\

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Example R

Example Q (3.02 g, 3.74 mmol) was suspended in 4.0 N HCl/dioxane solution (30 mL) and stirred at 25°C for 3 hours. Solvent was removed under reduced pressure and Et:O was poured into the reaction mixture. The resulting suspension was stirred vigorously for 1.5 hours. The solid was allowed to settle and the ether layer was decanted. Washing of the precipitate with EbO was repeated two more times. The product was dried in vacuo to afford a white solid (3.18 g, quantitative yield). Saturated aqueous Na^CCh solution was added to above solid (3.18 g) with stirring until solid disappeared. The aqueous solution was extracted with ethyl acetate. The organic phases were dried over Na^SOi, filtered, and evaporated to afford Example Rasa yellow foam (2.44g, 81%). Tire recovered Example R was used without further purification in the next step, m/z: 706.1 (M+H)L

Example S

Method I:

Example R (1,00g, 1.42 mmol) was dissolved in DMF (20 mL) and bromoethyl ether (196 pL, 1.56 mmol) was added drop wise, followed by NaHCCh (0.239 g, 2.84 mmol). The reach on mixture was stirred at 25 °C for 2 hours. The solution was heated to 65°C and stirred for Ί2 hours. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed sequentially with water and brine. The organic phase was dried over Na:SCh filtered, and evaporated. Purification by reverse-phase HPLC (Phenomenex Synergi® Comb-HTS column, eluent: 5-95% CHsCN/water) gave Compound 70 (580 mg, 53%). ^]H NMR (CDCh) b 8.98 (s, 1H); 7.90 (s, 1H); 7.75 (m, 1H); 7.40-7.00 (m, I1H), 6.55 (br s, IB); 5.58 (m, 1H); 5.28, 5.19 (d_AB, J=14 Hz, 2H); 4.70-4.37 (m,

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3H); 3.99 (m, 5H); 376 (br s, 1H); 3.65-3.30 (m, 3H); 2.97 (m, 5H); 2.90-2.60 (m, 6H);

2.28 (br s, 1H); 1.91 (br s, 1H); 1.60-1.30 (m, 10H). m/z: 776.2 (M+Hy

Method II:

Scheme 20

HO' 'OH

I. Nal0₄, h₂o

Compound 54

Compound 54 was prepared following the procedure described in I. Med. Chem, 1993. 36, 1384 (herein incorporated by reference in its entirety for all purposes).

To solution of Compound 53 (0.550 g, 5.28 mmol) (Sigma-Aldrich) in H?O (8.8 mL) at 0°C was added bJalO (1.016 g, 4.75 mmol). The mixture was allowed to slowly warm to 25^aC and stirred for 12 hours. Solid NaHCCh was added to the reaction mixture until pH 7. CHCls (16 mL) was added and the mixture was allowed to stir for 5 minutes. The mixture was filtered and the solid was washed with CHCh (6 mL). The combined HzO/CHCL solution was used directly in the next step without further purification.

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Scheme 21

I. NaBH₃CN/CH₃CN/H₂O

Example S

To a solution of Example R (70 mg, 0.1 mmol) in CLLCN (5 mL) was added sodium cyanoborohydride (50 mg) in water (5 mL). To the above mixture was added a solution of dialdchyde Compound 54 (0.6 mmol) in CHCb/H?O) (4ml/1 mL). The mixture was stirred for 12 hours, and basified with saturated NazCOs solution. The mixture was extracted with EtOAc, and organic phase was washed with water and brine, and dried over NazSOi. Purification hy reverse-phase HPLC (Phenomencx Synergi® Comb-HTS column) gave Example S (57 mg),

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Method Hi

Scheme 22

I. TFA, CH₂CI₂; II. Cmpd 54, NaBH₃CN, H₂O/CH₃CN; III. LiOH, THF/H₂O; IV. amine Cmpd 8, DIPEA, EDC, HOBt, THF

Compound 55

Compound 51 (0.28 g, 0.66 mmol) was dissolved in CH?CI: (4 mL) and TFA (1 mL) was added dropwise. The reaction was allowed to stir at 25^UC for 1 hour. The solvent was removed under reduced pressure to afford Compound 55 (0.39 g). m/z: 329.0 (M+H)··.

Compound 56

To a solution of Compound 55 (0.39 g., 0.89 mmol) in CHjCX’ (45 mL) was added NaBHsCN (0.45 g, 7.12 mmol) arid IhO (45 mL). A solution of Compound 54 (0.55 g, 5.34 mmol) in CHCWFLO (40 mL) was added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was made basic with saturated aqueous

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Na^COs and extracted sequentially with ethyl acetate and dichloromethane. The combined organic layers were washed sequentially with H:O and brine, dried over NasSCh, filtered, and evaporated. Purification by Combiflash® (stationary phase: silica gel; eluent: 0-10% MtOH/CH:Ch gradient) gave Compound 56 (0.17 g). m/z: 399.1 (M+H)⁺.

Compound 57

Compound 56 (377 mg, 0.95 mmol) was dissolved in THF (4 mL) and IM aqueous LiOH (1.90 mL) was added. The mixture was stirred at25°C for 1 hour. The reaction was neutralized with 1M HCl. THF was removed under reduced pressure and the aqueous solution was lyophilized to afford Compound 57 (365 mg). The material was used directly in the next step without further purification, m/z: 385.1 (M+H)'.

Example S

Example S (185 mg, 57%) was prepared following the same procedure as for Example Q, except that Compound 57 (160 mg, 0.42 mmol) was used instead of Compound 52. mass m/z: 776.2 (M+H)'.

The skilled practitioner will recognize that the procedure outlined in Scheme 22 can be used to prepare a variety of compounds analogous to Compounds 55-57:

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Cmpd 56 Analogs

Cmpd 57 Analogs

I. TFA, CH₂CI₂; 11. Ex. R, NaBH₃CN, H₂O/CH₃CN; 111. LiOH, THF/H₂O wherein. R⁷, R^s and Y are as defined herein.

It will also be recognized that stereochemical configurations other than those shown (i.e., enantiomers or diasteriomers) can be prepared by the selection of analogs of Compound 51 having the appropriate stereochemical configuration at the chiral center.

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Method IV

!. a. NaOH/H2O; b. BnBr; II. SO3/pyridine; Hi. morphoiine/NaBH(OAc)3; IV. a. NaOH; b. HCl

Compound 59

To a solution of Compound 122 (33 g, 112 mmol) (see Scheme 69) in ethanol (366 mL) at 0°C was added a solution of sodium hydroxide (4.7 g, 117 mmol) in water (62 mL). The mixture was stirred for one hour at 25°C, and solvents were removed under reduced pressure. The mix hire was coevaporated with ethanol (3x400 mL), and dried at 60°C for two hours under high vacuum to give a white solid. To the solution of above solid in DMF (180 mL) was added benzyl bromide (16.2 mL, 136 mmol). The mixture was stirred for 16 hours under darkness, and was quenched with water (300 mL). The mixture was extracted with EtOAc (4x300 mL). The combined organic phase was washed with water (5x) and brine, and dried over NazSCh. Concentration gave Compound 59 (48 g), which was used in the next step without further purification.

Compound 60

A mixture of Compound 59 (33 g, 74 mmol) in DMSO (225 mL) and EhN (36 mL) was stirred for 30 minutes. Tire mixture was cooled to 0-10^;:C, SO₃pyridine (45 g) was added, and the stirring was continued for 60 minutes. Ice (300

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g) was added, and the mixture was stirred for 30 minutes. EtOAc (300 mL) was added and sat. Na?CCh was added until pH was 9~10. The organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (2x300ml). The combined organic phases were washed with sat Na^CO? (2x), water (3x), and brine. The mixture was dried over NazSOx and concentrated to give Compound 60 (32 g), which was used directly in next step without further purification.

Compound 61

To a solution of Compound 60 (32 g) in CHaCN (325 mL) was added morpholine (12.9 ml., 148 mmol), with a water bath around the reaction vessel, followed by HOAc (8.9 mL, 148 mmol), and NaBH(OAc)s (47 g, 222 mmol). The mixture was stirred for 12 hours. CH?CN was removed under reduced pressure, and the mixture was diluted with EtOAc (300 mL). Sat. NasCCh was added until the pH was 9-10, The organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (2x300 mL). The combined organic phases were washed with sat Na:COs (2x), water (lx), and brine (lx). The mixture was dried over Na^SCL The resulting residue was concentrated and purified by silica gel column chromatography (EtOAc to DCM/iPrOH =10/1) to give Compound 61 (30 g).

Compound 57

To a solution of Compound 61 (26.5 g, 56 mmol) in ethanol (160 mL) at 0°C was added a solution of sodium hydroxide (2.5 g, 62 mmol) in water (30 mL). The mixture was stirred for one hour at 25°C, and solvents were removed under reduced pressure. The mixture was diluted with water (200 mL), and was washed with CELCh (6x100 mL). The water phase was acidified with 12 N HC1 (5.2 mL), and was dried under reduced pressure to give Compound 57 (22 g).

Example S

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Com pound 57 was converted to Example S using the procedure described in Method III, above.

Preparation of Compounds T and U

Scheme 24

Compounds: Ex. T: X=NHAc Ex. U:X=NHMs

Va. CH3COCI, DIPEA, CH₂C1₂; Vb. CH₃COOH, DIPEA, EDC, HOBt, THF; VI. MsCI, DIPEA, CH_zCI₂;

Example T Method I

The hydrochloride salt of Example R (100 mg, 0.13 mmol) was suspended in Cl’LCb (2 mL) and dissolved by ad di Hon of iPrzNEt (69 pL). Acetyl chloride (11 pL) was added dropwise and the mixture was allowed to stir at 25°C for 4 hours. The solvent was removed in vacuo. Purification of the residue by flash column chromatography (stationary phase: silica gel; eluent: 8% iPrOH/Cl hCL) gave Example T (39 mg, 40%). m/z: 748.2 (M+H)'. Ή NMR (CDCE) & 8.85 (s, 1H); 7.87 (s, TH); 7.73 (s, 1H); 7.40-7.00 (m, 13H); 6.45 (br s, 1H); 5.70 (m, 1H); 532, 5.22 (Gah, 7=13 Hz, 2H); 4.51 (s, 2H); 4.20-3.90 (m, 4H); 3.78 (m, 1H); 3.38 (m, 211); 3.20-2.50 (m, 8H); 1.95 (s, 4H); 1.82 (m, 2H); 1.41 (m, 6H).

Method II

Saturated aqueous NazCOs solution was added to the hydrochloride salt of Example R (3.18 g, 3.46 mmol) while stirring until the solid disappeared. The

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Example R (300 mg, 0.43 mmol) was dissolved in THF (5.5 mL). Acetic acid (37 pL, 0.64 mmol) was added, followed by HOBt (85 mg, 0.64 mmol), iPnNEt (304 pL, 1.70 mmol), and EDC (151 pL, 0.85 mmol). The reaction mixture was allowed to stir at 25°C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed sequentially with saturated aqueous Na:CQj, water, and brine. The organic phase was dried over Na:SO.», filtered, and evaporated. Purification by Combiflash® (stationary phase: silica gel; eluent: 10% MeOH/CHzCh) gave Example T (249 mg, 77%). m/z: 748.2 (M+H)*.

Example U

Example R (100 mg, 0.13 mmol) was suspended in CHzCL (2 mL) and dissolved by addition of iPrzNEt (69 pL). Methanesulfonyl chloride (12 pL) was added drop wise and the mixture was allowed to stir at 25°C for 4 hours, lhe solvent was removed in vacuo. Purification of the residue by flash column chromatography (stationary phase: silica gel; eluent: 8% iPrOH/CHzCL) gave Example U (55 mg, 54%). m/z: 784.2 (M+H)'. Ή NMR (CDCb) b 8.90 (s, 1H); 7.88 (s, 1H); 7.40-7.00 (m, 12H); 6.54 (br s, 1H); 6.19 (br s, 1H); 5.25 (s, 2H); 4.53 (s, 2H); 4.38 (m, 1H); 4.12 (m, 1H); 3.79 (m, 1H); 3.79 (m, HI); 3.48 (m, 1H); 2.99 (s, 3H); 2.90 (m, 3H); 2.73 (m, 6H); 2.00 (m, 1H); 1.79 (m, 1H); 1.60-1.18 (m, 10H).

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Preparation of Examples V, W, X and Y

Scheme 25

NHBoc

Illa or lllb,

IV

I. Cmpd. 46, DIPEA, EDC, HOBt, THF;

II. HCi/dioxane; Illa. CH₃COCI, DIPEA, CH_zCI₂; lllb. CH₃COOH, DIPEA, EDC, HOBt, THF; IV. MsCI, DIPEA, CH₂CI₂

Compounds:

Ex. X; X=NHAc

Ex. Y: X=NHMs

Example V

Example V (692 mg) was prepared following the same procedure used for preparing Example Q, except that Compound 46 was used instead of Compound 8. m/z: 806.2 (M+H)⁺.

Example W

Example W (770 mg, quantitative yield) was prepared following the same procedure for Example R except that Example V was used instead of Example Q.

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2020203321 21 May 2020 m/z: 706.2 (M+H)¹. Ή NMR (CDOD) b 9.86 (s, 114); 8.23 (s, 114); 7.66 (s, 1H); 7.407.00 (m, 10H); 5.29, 547 (cU, /=13 Hz, 2H); 4.80-4.60 (m, 2H); 4.18 (s, 2H); 4.26 (m, 2H); 3.67 (br s, 1H); 3.55 (m, 2H); 3.03 (m, 3H); 2.90-2.60 (in, 8H); 2.53 (s, 2H); 2.001.80 (m, 214); 1.85-1.30 (m, 10H).

Example X

Method I

Example X (107 mg, 55%) was prepared following tire Method 1 procedure for Example T except that Example W was used instead of Example R. m/z: 748.2 (M+14)’. 44 NMR (CDCE) & 8.80 (s, 1H); 7.85 (s, 114); 7.40 (m, 1H); 7.38-7.00 (m, 10H), 6.94 (s, 1H); 6.30 (m, 2H); 5.75 (m, 1H); 5.30, 5.23 (Jab, J=13 Hz, 2H); 4.54, 4.46 (dxB, /=8 Hz, 2H); 4.20-3,90 (m, 2H); 3,74 (br s, 1H); 3.46 (br s, 1H); 3.28 (m, 1H); 2.98 (s, 314); 2.83 (ni, 3H); 2.72 (m, 1H); 2.62 (m, 1H); 2.05-Ί .20 (m, 1514). Method II

Example X (205 mg, 65%) was prepared following the Method II procedure for Example T except that Example W was used instead of Example R. m/z: 748.2 (M+H)⁺.

Example Y

Example Y (106 mg, 50%) was prepared following the same procedure for Example U, except that Example W was used instead of Example R. m/z: 784.2 (M+H)¹. Ή NMR (CDCE) b 8.81 (s, 114); 7.85 (s, 1H); 7.40-7.05 (m, 10H), 6.98 (s, 1H); 6,22 (br s, 114); 5.78 (s, 114); 5.25 (m, 4H); 4.29 (m, 2H); 4.33 (br s, 1H); 4.12 (br s, 1H); 3.77 (br s, 1H); 3.10 (br s, 1H); 2.98 (s, 3H); 2,90 (s, 3H); 2.73 (m, 614); 2.001.20 (m, 12H),

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Preparation of Examples Z-AD

Scheme 26

I. DIPEA, CH₃CN; II. HCI/dioxane, EtOAc; III. acid 29, DIPEA, EDC, HOBt, THF

Compound 62

Tert-butyl 2-aminoethylcarbamatc (62) is commercially available from Aldrich, and was used without further purification.

Compound 63

To a solution of Compound 62 (2.0 mmol) in CLbCN (15 mL) was added Compound 16 (L82 mmol), followed by the addition of N,Ndi isopropyl ethyl amine (0.61 mL). The mixture -was stirred at25°C for 12 hours. J'he solvent was removed in vacuo, and the residue was diluted with ethyl acetate and washed sequentially with saturated aqueous Na:CCh, water, and brine. The organic layers were dried with NajSOi, filtered, and evaporated. Purification by Com biflash® (stationary phase: silica gel; eluent: 25-100% EtOAc/hexane gradient) gave Compound 63. m/z: 301.9 (M+H)⁺.

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Compound 64

To a solution of Compound 63 (1.05 mmol) in EtOAc (3 mL) was added 4N HCl/dioxane solution (1,1 mL), The mixture was allowed to stir at 25^:C for 12 hours. The solvent was removed under reduced pressure, and Compound 64 was obtained as a white powder. This material was used in the next step without further purification, m/z: 216.0 (M+H)L Example Z

Compound 64 (70 mg, 0,29 mmol) was dissolved in THF (2.2 mL).

Compound 29 (91 mg, 0.29 mmol) was added to the reaction flask as a 1.0M solution in THF, followed by HOBt (59 mg, 0.44 mmol), N,Ν'di isopropylethylamine (207 pL, LI6 mmol), and EDC (103 pL, 0.58 mmol). The reaction was allowed to stir for 12 hours at 25°C and concentrated under reduced pressure. The residue was diluted with EtOAc and washed sequentially with saturated aqueous NazCOi, water, and brine. The organic layers were dried with XazSOc filtered, and evaporated. Purification by Combiflash® (stationary phase: silica gel; eluent: 0-10% MeOH/CHzCL gradient) gave Example Z (54 mg, 38%). m/z: 497.1 (M+H)¹. Ή XMR (CDCh) b 8.78 (s, 1H); 7.83 (s, 1H); 6.99 (s, 1H); 6.80 (br s, 1H); 6.22 (br s, 1H); 5.87 (hr s, 1H); 5.25 (s, 2H); 4.43 (s, 2H); 3.97 (m, 1H); 3.34 (m, 4H); 2.95 (s, 3H); 2,22 (m, 2H); 1.38 (d, /=7 Hz, 6H); 0.97 (d, /=7 Hz, 6H).

Example A A

Example A A was prepared following the procedures for steps Τ-Π1 (Scheme 20) for Example Z, with tire exception that tert-butyl 3aminopropylcarbamate was used instead of tert-butyl 2-aminoethyIcarbamate (Compound 62). After Combiflash® purification, 38 mg (34%) of Example A A was obtained, m/z: 511.1 (M+H)’. Ή NMR (CDCh) & 8.78 (s, 1H); 7.84 (s, 1H); 6.96 (s, 2H); 6.17 (br s, 1H); 5.80 (m, 1H); 5,26 (m, 2H); 4.44 (s, 2H); 4.09 (m, 1H); 3.40-3.10

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Example AB

Example AB was prepared following the procedures for steps 1-1II (Scheme 20) for Example Z, with the exception that tert-butyl 1-piperazinecarboxylate was used instead of tert-butyl 2-aminoethylcarbamate (Compound 62). After Combiflash® purification, 64 mg (45%) of Example AB was obtained, m/z: 523.1 (M+H)⁺. Ί-Ι NMR (CDCh) b 8.82 (s, HI); 7.89 (s, IH); 6.96 (s, IH); 5.93 (br s, IH); 5.35 (s, 2H); 4.62 (m, IH); 4.50 (m, 2H); 3.80-3.40 (m, 8H); 3.34 (m, IH); 3.00 (s, 3H); 1.97 (m, IH); 1.40 (d, >7 Hz, 6H); 0.96, 0.93 (d, /=7 Hz, 6H).

Example AC

Example AC was prepared following the procedures for steps 1-ΙΠ (Scheme 20) for Example Z, with the exception that tert-butyl 4-amino-lpiperidinecarboxylate was used instead of tert-butyl 2-aminoethylcarbamate (Compound 62). After Combiflash® purification, 60 mg (44%) of Example AC was obtained, m/z: 537.1 (M+H)⁺. Ή NMR (CDCb) & 8.82 (s, IH); 7.87 (s, IH); 6.97 (s, IH); 5.82 (br s, IH); 5.30 (m, 3H); 4.80-4.40 (m, 5H); 4.03 (m, IH); 3.72 (br s, IH); 3.34 (m, IH); 3.18 (m, IH); 3.01 (s, 3H); 2.79 (m, IH); 2.20-1.90 (m, 4H); 1.40 (d, /=7 Hz, 6H); 0.97, 0.90 (d, /=7 Hz, 6H).

Example AD

Example AD was prepared following the procedures Mil for Example Z, with the exception that tert-butyl 4-piperidinylcarbamate was used instead of tertbutyl 2-aminoethylcarbamate (Compound 62). After Combiflash® purification, 49 mg (36%) of Example AD was obtained, m/z: 537.1 (M+H)*. Ή NMR (CDCh) b 8.82 (s, IH); 7.87 (s, IH); 7.01 (s, IH); 6.33 (br s, IH); 6.11 (br s, 1H); 5.32 (s, 2H); 4.47 (s, 2H); 4.20-3.80 (m, 4H); 3.35 (m, IH); 3.10-2.80 (m, 6H); 2.21 (m, 2H); 1.90 (m, 2H); 1.40 (d, /=7 Hz, 6H); 0.97 (d, /=7 Hz, 6H).

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Preparation of Examples AE-AG

Scheme 27

I. CDI, DIPEA, CH₂CI₂; 11. NaOH, THF/H_ZO; III. Cmpd. 8, DIPEA, EDC, HOBt, THF; IV. neat TFA; V. (Boc)_zO, NH₄HCO₃, pyridine, dioxane, DMF

Compound 65

Compound 65 is commercially available from Chem Impex International, and was used without further purification.

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Compound 66

Compound 65 (956 mg, 4.0 mmol) was dissolved in CH?Ch (45 mL) and 1,1-carbonyldiimidiazole (648 mg, 4.0 mmol) was added, followed by i-PrzNEt (2.8 mL, 16 mmol). The solution was stirred at 25°C for 12 hours. Compound 9 (679 mg, 4.0 mmol) was dissolved in CHzCIz (5 mL) and added to the reaction. The mixture was allowed to stir for 5 hours. Then, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and filtered through celite. The ethyl acetate was then removed in vacuo. Purification by flash column chromatography (stationary phase: silica gel; eluent: EtOAc) gave Compound 66 (841 mg), m/z: 400.0 (M+H)'.

Compound 67

Compound 66 (841 mg, 2.11 mmol) was dissolved in THF (9 mL) and 2N aqueous NaOH was added. The solution was stirred at 25°C foi‘ 2 hours. The reaction was adjusted to pH 2 with IN HQ, The mixture was extracted with ethyl acetate, dried over Na^SO, filtered, and evaporated. Compound 67 (772mg) was used directly in die next step without further purification, m/z: 386.0 (M+H)*. Example AE

Compound 67 (569 mg, 1.48 mmol) was dissolved in THF (17 mL). Compound 8 (970 mg, 2.37 mmol) was added, followed by HOBt (300 mg, 2.22 mmol), i-Pr^NEt (1.06 mL, 5.92 mmol), and EDC (0.52 mL, 2.96 mmol). The mixture was stirred at 25°C for 36 hours. The solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate and washed sequentially with saturated aqueous NazCOa, water, and brine. The organic phase was dried over NazSCh, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel; eluent: 8% iPrOJI/CHzCE) gave Example AE (3.02 g). m/z: T772. (M+H)'.

Example AF

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Example AE (100 mg, 0.13 mmol) was dissolved in neat TFA (3 mL). The mixture was stirred at 25°C for 2 hours. The solvent was removed under reduced pressure. Purification by reverse-phase HPLC (Phenomenex Synergi® Comb-HTS column, eluent: 5-95% CH3CN/H2O gradient) gave Example AF (20 mg, 21%). m/z: 721.2 (M+H)\ Ή NMR (CDCh) & 8.92 (s, 1H); 7.91 (s, 1H); 7.40-7.00 (m, 11 Fl); 6.41 (br s, 1H); 6.12 (br s, 1 FI); 5.40-5.00 (m, 3H); 4.70-4.50 (m, 3H); 4.05 (br s, 1H); 3.81 (br s, 1H); 3.51 (br s, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H); 1.41 (d, (=7 Hz, 10H). Example AG

Example AF (70 mg, 0.10 mmol) was dissolved in dioxane (0.5 ml_). DMF (83 pL), pyridine (25 pL, 0.29 mmol), di-/erf-butyldicarbonate (27 mg, 0.13 mmol), and ammonium bicarbonate (15 mg, 0.19 mmol) were added. The mixture was stirred at25°C for 48 hours, then diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over NazSCE, filtered, and evaporated. Purification by reverse-phase HPLC (Phenomenex Synergi® Comb-HTS column, eluent: 5-95% CHsCN/H:O gradient) gave Example AG (35 mg, 50%). Ή NMR (CDCh) b 8.80 (s, 1H); 7.84 (s, 1H); 7.40-7.00 (m, 10H); 7.08 (s, 1H); 6.83 (m, 1H); 6.65 (m, 1H); 5.40-5.10 (m, 4H); 4.60-4.40 (m, 3H); 4.06 (m, 1H); 3.79 (m, 1H); 3.36 (m, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H); 2.45 (m, 1H); 1.70-1.20 (m, 10H).

Preparation of Compounds 68 and 69

Scheme 28

68: R=methyl

69: R=cyciopropyl

I. a. MsCI, TEA, CH₃CN; b. MeNH₂/H₂O; c. cyclopropyl amine

Compound 15

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Compound 15 is commercially available from Molekula, and was used without further purification. Compound 68

Compound 15 (6.81 g, 59.1 mmol) was dissolved in CTLCN (340 mL) and methanesulfonyl chloride (7.03 mL, 65.1 mmol) was added, followed by triethylamine (9.03 mL, 65.1 mmol). After the mixture was stirred for 20 min, 40% wt. methylamine/water (516 mL) was added to the reaction mixture. The solution was stirred for 12 hours at 25°C. Solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaaCCh and CHaClz. The organic phase was separated, dried over XaaSCh, filtered, and evaporated. Purification by flash chromatography (stationary phase: silica gel; eluent: 0-10% MeOH/CHzCb gradient) gave Compound 68 (5.07 g). m/z: 128.9 (M+H)’. Compound 69 Compound 15 (10.0 g, 80 mmol) was dissolved in CHsCN (500 mL) and methanesulfonyl chloride (7.0 mL, 88 mmol) was added, followed by triethylamine (12.3 mL, 88 mmol). After the mixture was stirred for 2h, cyclopropylamine (140 mL, 2000 mmol) in CHsCN (500 mL) was added to the reaction mixture. The solution was stirred for 36 hours at 25°C. Solvent was removed under reduced pressure and the slurry was partitioned between saturated aqueous NaaCCh and 3:1 CHaCh:i-PrOH. The organic phase was separated, dried over NaaSO, filtered, and evaporated. Compound 69 (12.81 g) was used in the next step without further purification, m/z: 155.0 (M+H)\ Preparation of Examples AM and Al Scheme 29

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I. DIPEA, CH₂CI₂; 11. LiOH, THF/H₂O;

III. Cmpd. 8, HOBt, EDC, DIPEA, THF;

IV. a. neat TFA; b. NaOH, THF, H₂O

Compound 70

Compound 68 (1.00 g, 7.80 mmol) was dissolved in THF (25 mL) and Compound lOe (2.51 g, 7.09 mmol) was added, followed by N,Ndimethaminopyridine (200 mg, 1.63 mmol), and triethylamine (4.34 mL, 31.2 mmol). The mixture was allowed to stir at 60 ^DC for 6 hours. Solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed sequentially with saturated aqueous NaiCCh, HzO, and brine. The organic layer was dried over Na?SC>4, filtered, and evaporated. The resulting residue was purified by Combiflash® (stationary phase: silica gel; eluent: 20-100% EtOAc/Hexane gradient) to give Compound 70 (2.14 g). m/z: 343.9 (M+H) .

Compound 71

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Compound 70 (2.14 g, 6.23 mmol) was dissolved in THF (25 mL) and IM aqueous LiOH (12.5 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction was quenched with 1M HC1 (15 mL) and the mixture was adjusted to pH 2. The mixture was extracted with ethyl acetate. The organic layers were dried over NazSOt, filtered, and evaporated to provide Compound 71 (1.96 g), This material was used in the next step without further purification, m/z: 330,0 (M+H)'.

Example AH

Compound 71 (43 mg, 0.Ί3 mmol) was dissolved in THF (1.5 mL). Compound 8 (50 mg, 0.12 mmol) was added, followed by HOBt (24 mg, 0.18 mmol), iPrzNEt (86 pL, 0.48 mmol), and EDC (42 pL, 0.24 mmol). The mixture was stirred at 25°C for 12 hours. The solvent was removed under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed sequentially with saturated aqueous NazCO.i, water, and brine. Tire organic phase was dried over NazSOj, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel; eluent: 1-10% MeOH/CHzCL gradient) gave Example AH (66 mg), m/z: 721.2 (M+H)¹.

Compound Al

Example AH (66 mg, 0.09 mmol) was dissolved in TFA and allowed to stir at 25 °C for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with THF (3 mL) and 2N aqueous NaOH was added until pH 12. The mixture was allowed to stir for 20 min and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried over NazSO^, filtered, and evaporated. Purification by flash chromatography (stationary phase: silica gel; eluent: 0-20% i-PrOH/CHzCh gradient) gave Example Al (71 mg, 97%). m/z: 665.2 (M+H)‘. Ή NMR (CDCh) δ 8.84 (s, 1H); 8.80 (s, 1H); 7.85 (s, 1H); 7.79 (s, 1H); 7.40-7.00 (m, 1 OH); 6.69 (m, 1H); 5.34 (m, 1H); 5.24 (s, 2H); 4.86 (m, 2H); 4.73,

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4.59 (cU, /=16 Hz, 2H); 4.30 (s, 1H); 4.15 (m, 2H); 3.86 (br s, 1H); 2.88 (s, 3H); 2.85

2.60 (m, 4H); 2.01 (s, 1H); '1.58 (s, 2H); 1.44 (s, 2H); 1.09 (d, J= 6 Hz, 3H).

Preparation of Examples AJ and AK

Scheme 30

6B 47

I. DIPEA, CH₂CI₃; II. LiOH, THF/H₂O;

III. Cmpd. 8, HOBt, EDC, DIPEA, THF;

IV. a. neat TFA; b. NaOH, THF, H₂O

Compound 47

Compound 47 is commercially available from TCI America, and was used without further purification.

Compound 72

Compound 72 was prepared following procedure for Compound 48 (Method II), except that Compound 68 was used instead of Compound 9. Compound 73

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Compound 73 was prepared following procedure for Compound 49, except that Compound 72 was used instead of Compound 48.

Example Al

Example A J (70 mg) was prepared following the same procedure used to prepare Example AH, with the exception that Compound 73 (41 mg, 0.13 mmol) was used instead of Compound 71. m/z: 707.2 (M+H)*.

Example AK

Example AK (43 mg, 67%) was prepared following the same procedure used to prepare Example Al, with the exception that Example AJ (70 mg, 0.10 mmol) was used instead of Example AH. m/z: 651.2 (M+H)⁺. Ή NMR (CDCls) & 8.83 (s, 211); 7.84 (s, 111); 7.79 (s, 1H); 7.40-7.00 (m, 10H); 6.65 (br s, 1H); 5.47 (br s, 1H); 5.24 (s, 2H); 4.90 (m, 1H); 4.82-4.50 (m, 2H); 4.30-4.00 (m, 311); 3.84 (br s, 1H); 3.49 (m, 1H); 2.87 (s, 3H); 2.75 (br s, 5H); 1.60-1.20 (m, 4H).

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Preparation of Examples AL and AM

Scheme 31

I. DIPEA, CH₂C!₂; II. LiOH, THF/H₂O;

III. Cmpd. 8, HOBt, EDC, DIPEA, THF;

IV. a. neat TFA; b. NaOH, THF, H₂O

Compound 74

Compound 69 (1.56 g, 10.1 mmol) was dissolved in CH2CI2 (10 mL).

Compound 47 (1.7 g, 8.5 mmol) in CH2CI2 (20 mL) was added, followed by iPr:NEt (3.02 mL, 16.9 mmol). The reaction was stirred at 25 °C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed sequentially with water and brine, dried over NasSCk, filtered, and evaporated. Purification by Combiflash® (stationary phase: silica gel; eluent: 50-100% EtOAc/hexane gradient) gave Compound 74 (2.92 g). m/z: 356.0 (M+H)-,

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Compound 75

Compound 74 (0.97 mmol) was taken up in THF (3 mL) and treated with freshly prepared 1M LiOH (2 mmol) and stirred vigorously for 1 h. The reaction was quenched with IM HC1 (2.5 mmol) and extracted with EtOAc (3 X 15 mL). The combined or games were washed with brine (25 mL), dried over anhydrous NaiSChand concentrated in vacuo to produce 0.331 g (quant) of Compound 75 as a colorless film ( m/z 342.0 (M+H)’).

Example AL

Example AL (2.20 g) was prepared following the same procedure used to prepare Example AH, with the exception that Compound 75 (2.00 g, 4.88 mmol) was used instead of Compound 71. m/z: 733.2 (M+H)’. Example AM

Example AM (1.88 g, 92%) was prepared following the same procedure used to prepare Example Al, with the exception that Example AL (2.20 g, 3.01 mmol) was used instead of Example AH. m/z: 677.2 (M+H)⁺. Ή NMR (CDCh) b 8.79 (s, 1H); 8.72 (s, 1H); 7.82 (s, 1H); 7.77 (s, 1H); 7.40-7.00 (m, 10H); 6.59 (m, 1H); 6.31 (m, 1H); 5.23 (s, 2H); 5.00 (m, 1H); 4.72, 4.60 (cLif, /=15 Hz, 2H); 4.18 (s, 2H); 4.03 (m, IB); 3.84 (br s, 1H); 3.48 (m, 1H); 2.85-2.60 (m, 4H); 2.37 (br s, 2H); 1.58 (s, 2H); 1.41 (s, 2H); 0.93 (m, 2H); 0.76 (in, 2H).

Scheme 32

76: Ri = H, R₂ = CH₃77: R-ι = H, R₂ = CH₂CH₃

78: R₁ = H, R₂ = CH₃79: R-t = H, R₂ = CH₂CH₃

I. compound 16, DIPEA, MeCN

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Compound 76

Compound 76 (rnJz 117.0 (M+H)* of diamine) was prepared using a procedure similar to that used to prepare Compound 22 (described in Scheme 12) except that CBZ-L-alininol was used instead of CBZ-L-phenylalininoI and Step III was performed with 1 M HCl added. Compound 77

Compound 77 (m/z 145.0 (M+H)’ of diamine) was prepared using a procedure similar to that used to prepare Compound 76 except that (S)-(-s)-2-CBZamino-1-butanol was used instead of CBZ-L-alininol. Compound 78

Compound 76 (7,93 mmol) is added to a solution of NaOH (16.7 mmol) in HaO (5 mL) that is cooled to 0 °C and diluted with MeCN (40 mL). DIPEA is added (2.1 mL, 11.9 mmol). Compound 16 (7.9 mmol) is taken up in MeCN (40 mL) and added to the reaction solution drop wise via an addition funnel over 1 h. The resulting solution is allowed to warm to room temperature overnight. The solvent is removed in vacuo and the residue taken up in 3/1 CHCh/IPA (50 mL). The resulting solution is washed with sat. Na^CO? (50 mL) and water is added until the aqueous layer is homogeneous. The aqueous layer is extracted with 3/1 CHCb/IPA (3 X 25 mL). The combmed organics are washed with saturated NkuCOi (50 mL), water (50 mL) and brine (50 mL) and arc dried over anhydrous NaiSCh. The solvent is removed in vacuo and the residue purified by column chromatography on SiCh (100% EtOAc, then 0 to 20% MeOH/DCM) to produce 0.63 g (31%) of 78 as an off-white solid, (m/z 258.0 (M f-H)⁴). Compound 79

Compound 79 (m/z 286.1 (M+H)+) w^ras prepared following the procedure for Compound 78 except that Compound 77 was used instead of Compound 76.

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Scheme 33

I. Cmpd. 79, HOBt, EDC, DIPEA, THF;

II. a. neat TFA; b. NaOH, THF, H₂O

Example AN

Example AN (68 mg) was prepared following the same procedure used to prepare Example AH, with the exceptions that Compound 49 (68 mg, 0.19 mmol) was used instead of Compound 71, and Compound 79 (50 mg, 0.18 mmol) was used instead of Compound 8. m/z: 625.2 (AI+H)\ Example AO

Example AO (66 mg, 76%) was prepared following the same procedure used to prepare Example Al, with the exception that Example AN (43 mg, 0.13 mmol) was used instead of Example AH. m/z: 569.2 (M+H). Ή NMR (CDCb) h 8.85 (s, IH); 7.89 (s, 1H); 7.08 (s, IH); 6.81 (m, IH); 5.29 (s, 2H); 4.87 (m, IH); 4.63, 4.48 (cUb, /=16 Hz, 2H); 4.31 (m, IH); 4.11 (m, IH); 3.76 (m, 2H); 3.44 (m, 2H); 3.02 (m, 4H); 1.60-1.20 (m, 14H); 1.00-0.70 (m, 6H).

Preparation of Examples AP and AO

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Scheme 34

I. LiOH, THF/HjO; fl. Cmpd. 79, HOBt, EDC, DIPEA, THF;

III. a. neat TFA; b. NaOH, THF, H₂O

Compound 13c

Compound 13e (1.39 g) was prepared following the same procedure used to prepare Compound 71, with the exception that Compound 12e (1.53 g, 3.97 mmol) was used instead of Compound 70 m/z: 372.0 (M+H)'.

Example AP

Example AP (87 mg) was prepared following the same procedure used to prepare Example AH, with the exception that Compound 13e (71 mg, 0.19 mmol) was used instead of Compound 71, and Compound 79 (50 mg, 0.18 mmol) was used instead of Compound 8. m/z: 639.2 (M+H)“.

Compound AO

Example AQ (61 mg, 76%) was prepared following the same procedure used to prepare Example Al, with the exception that Example AP (87 mg, 0.14

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3.52 (br s, 1H); 3.35 (br s, 1H); 3.01 (m, 3H); 2.07 (br s, 1H); 1.60-1.10 (m, 17H); 1.00

0.70 (m, 6H).

Preparation of Example AR

I. GDI, DIPEA, CH₂CI₂; U. LiOH, THF/H₂O;

III. Cmpd. 46, DIPEA, EDC, HOBt, THF

Compound 80

Compound 80 is commercially available from Chem Impex International, and was used without further purification.

Compound 81

Compound 80 (2,0 g, 11.0 mmol) was dissolved in CHzCL (170 mL) and 1,1carbonyldiimidazole (1.78 g, 11.0 mmol) was added, followed by iPnXEt (7.83 mL, 43.8 mmol). Hie solution was allowed to stir at 25°C for 12 hours. Compound

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PCT/US2008/054788 (1.86 g, 11.0 mmol J was dissolved in 20 mL of CFLCLand added to the reaction mixture. The solution was stirred at 25°C for 12 hours. The solvent was removed in vacuo and the residue was diluted with ethyl acetate and washed water and brine. The organic layers were dried over Na=SOi, filtered, and evaporated. Purification by Combiflash® (stationary phase: silica gel; eluent: 66-100% EtOAc/Hexane gradient) gave Compound 81 (0.252 mg), m/z: 343.0 (M+H)'. Compound 82

Compound 82 (0.252 g, 0.74 mmol) was dissolved in THF (4mL) and IM aqueous LiOH (1.48 mL) was added, The mixture was stirred at 25°C for 3 hours. The reaction was quenched with IM HC1 (2 mL) and the mixture was adjusted to pH 2. The mixture was extracted with ethyl acetate. The organic layers were dried over Na^SO, filtered, and evaporated to afford Compound 82 (0.18 g). This material was used in the next step without further purification, m/z: 329.1 (M+H)’. Example AR

Compound 82 (182 mg, 0.55 mmol) was dissolved in THF (7.15 mL).

Compound 46 (225 mg, 0.55 mmol) was added, followed by HOBt (112 mg, 0.83 mmol), iPnNEt (393 pL, 2.20 mmol), and EDC ¢194 pL, 1.10 mmol). The mixture was stirred at 25°C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted elhy 1 acetate and washed sequentially with saturated aqueous Na?COj, water, and brine. The organic phase was dried over Na2SCh, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel; eluent: 5-10% MeOH/CPLCL gradient) gave Example AR (208 mg, 53%). m/z: 720.2 (M+H)\ Ή NMR (CDCb) b 8,80 (s, 1H); 7.84 (s, 1H); 7.40-7.00 (m, 10H); 6.97 (s, 1H); 6.83 (m, 1H); 6.65 (br s, 1H); 5.99 (m, 1H); 5.40-5.10 (m, 4H); 4.52 (m, 3H); 4.06 (m, 1H); 3.79 (m, 1H); 3.34 (m, 1H); 2.97 (s, 3H); 2.902.60 (m, 5H); 2.50-2.40 (br s, 1H); 1.80-1.20 (m, 10H).

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Preparation of Example AS

Scheme 36

AS

I. DIPEA, CH₂CI₂; tl. LiOH, THF/H₂O; III. Cmpd. 8, HOBt, EDC, DIPEA, THF

Compound 85a

Compound 85a was prepared following the same procedure as Compound 4, except that 4-chloromethylthiazole (purchased from TCI America) was used instead of Compound 3, and methylamine was used instead of isopropylamine. Compound 83

To compound 85a (0.40 g, 3.12 mmol) in CII2CI2 (9 mL) was added N,Ndiisopropylethylamine (1.04 ml, 5.85 mmol), followed by Compound 5 (280 uL, 1.95 mmol). The reaction mixture was stirred for 3.5 hours at 25 °C. Solvent was removed under reduced pressure. Purification by Combiflash® (stationary phase: silica gel; eluent: 90-100% EtOAc/Hexane gradient) gave Compound 83 (0.51 g). m/z: 286.0 (Μ+Η)*.

Compound 84

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Compound 83 (0.51 g, 1.77 mmol) was dissolved in THF (10 mL) and IM aqueous LiOH (3.54 mL) was added. The mixture was stirred at 25°C for 2 hours. Fhe reaction was quenched with IM HC1 (4.8 mL) and the mixture was adjusted to pH 2. The mixture was extracted with ethyl acetate. The organic layers were dried over NanSO*, filtered, and evaporated to afford Compound 84 (0.430 g). This material was used in the next step without further purification, m/z: 272.0 (M+H)*.

Example AS

Compound 84 (150 mg, 0.55 mmol) was dissolved in THF (7.15 mL).

Compound 8 (225 mg, 0.55 mmol) was added, followed by HOBt (112 mg, 0.83 mmol), iPriNEt (393 pL, 2.20 mmol), and EDC (198 μL, 1.11 mmol). The mixture was stirred at 25°C for 12 hours. The solvent was removed under reduced pressure. The residue was diluted ethyl acetate and washed sequentially with saturated aqueous NasCOj, water, and brine. The organic phase was dried over Na^SO^, filtered, and evaporated. Purification by flash column chromatography (stationary phase: silica gel; eluent: 7% i-PrOH/CELCL) gave Example AS (219 mg, 60%). m/z: 663.1 (M+H)⁺. Ή NMR (CDCL) & 8.87 (s, 1H); 8.76 (s, 1H); 7.84 (s, 1H); 7.40-7.00 (m, 10H); 6.22 (br s, 1H); 5.73 (br s, TH); 5.22 (m, 2H); 4.50 (m, 2H); 4.16 (br s, 1H); 4.05 (br s, 1H); 3.75 (m, 1H); 2.93 (s, 3H); 2.90-2.60 (m, 5H); 2.90 (m, 1H); 2.3Ί (m, 1H); 1.60-1.30 (m, 4H); 1.00-0.80 (m, 6H).

Preparation of Example AT

Scheme 37

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I. DIPEA, CH₂CI₂; IL LiOH, THF/H₂O;

111. Cmpd 8, HOBt, EDC, DIPEA, THF

Compound 87

Compound 87 (386 mg) was prepared from Compound 86 following the same procedure used to prepare Compound 7 from Compound 6, except that Compound 68 was used was used instead of Compound 4. m/z 286.0 (M+H)'

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Preparation of Example AU

Scheme 38

AU

I. DIPEA, CH₂C1₂; II. LiOH, THF/H₂O; III. Cmpd. 8, HOBt, EDC, DIPEA, THF

Compound 85b

Compound 85b was prepared following the same procedure as Compound 4, except that4-chloromethylthiazolc (obtained from TCI America) was used instead of Compound 3.

Compound 88

Compound 88 (341 mg) was prepared following the same procedure used to prepare Compound 83, with tire exception that Compound 85b (300 mg, 1.95 mmol) was used instead of Compound 85a. m/z: 312.0 (M+H)‘.

Compound 89

Compound 89 (341 mg) was prepared following the same procedure for 84, with the exception that Compound 88 (293 mg, 0.99 mmol) was used instead of Compound 83. m/z: 298.0 (M+H)\ Example AU

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Example AU (226 mg, 64%) was prepared following the same procedure used to prepare Example AS, with the exception that Compound 89 (150 mg, 0.51 mmol) was used instead of Compound 84. m/z: 689.1 (M+H)\ ’HNMR (CDCh) 6 8.87 (s, 1H); 8.74 (s, 1H); 7.83 (s, 1H); 7.40-7.00 (m, 10H); 6.21 (m, 1H); 5.73 (m, 1H); 5.29 (m, 1H); 5.17 (m, 2H); 4.88 (d, /=16 Hz, 1H); 4.47 (d, /=16 Hz, 1H); 4.18 (m, 1H); 3.75 (br s, 1H); 2.90-2.60 (m, 6H); 2.51 (br s, 1H); 2.31 (m, 1H); 1.60-1.30 (m. 4H); 1.00-0.80 (m, 10H).

Preparation of Example AV

Scheme 39

I. DIPEA, CH₂CI₂; II. LiOH, THF/H₂O;

III. Cmpd. 8. HOBt, EDC, DIPEA, THF

Compound 90

Compound 90 (190 mg) was prepared following the procedure used to prepare Compound 4, except that 4-(chloromethyl)-2-methyI thiazole was used instead of Compound 3. m/z 141.1 (M-H)

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Compound 91

Compound 91 (400 mg) was prepared following the same procedure used to prepare Compound 6 except that Compound 90 was used instead of Compound 4. m/z 300.0 (M+H)'

Compound 92

Compound 92 (188 mg) was prepared following the same procedure as Compound 7 except that Compound 91 was used instead of Compound 6. m/z 284.0 (M-H)Example AV

Example AV (107 mg) was prepared following the procedure used to prepare Example C, except Compound 92 was used instead of Compound 7. TI NMR (CDCb) b 8.76 (s, 111), 7.78 (s, Ί.Η.), 7.27-7.07 (m, 10H), 6.93 (s, ΊΗ), 6.25 (m, 2H), 5.39 (m, 1H), 5.19 (m, 2H),4.37-4.32(m, 2H),4.06 (m, 1H), 3.81 (br s, 1H), 2.83 (m, 4H), 2.65 (br s, 7H), 2.28-2.22 (m, 1H), 1.51-1.37 (m, 4H), 0.82 (m, 6 H): m/z 677.2 (M+Hf

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Prepara Hon of Example AW

Scheme 40

l.SOCyMeOH; II.DIPEA,CH₂CI₂; III.LiOH,THF/H₂O;

IV. Cmpd 8, HOBt, EDC, IPEA.THF

Compound 93

Compound 93 is commercially available from TCI, and was used without further purification.

Compound 94

To a solution of Compound 93 (500 mg, 3.76 mmol) in methanol (20 mL) was added thionyl chloride (0.5 mL, 6.6 mmol) dropwisc. The mixture was stirred at 60 ^BC for 20 minutes, and concentrated in vacuo to gave Compound 94, Compound 95

To a stirred solution of Compound 94 (3.7 mmol) and diisopropylcthylaminc (1.4 mL, 8,3 mmol) in dichloro methane (50 mL) was added CDI (609 mg, 3.7 mmol). The mixture was stirred for 12 hours. Compound 9 was added, and the mixture was stirred for 12 additional hours. Concentration and purification by flash column chromatography (0-100%: EtOAc/hexane) gave Compound 95 (100 mg), m/z 344.3 (ΜΑΗ)⁴

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Compound 96

Compound 96 (39 mg) was prepared following the same procedure used to prepare Compound 7 except that Compound 95 was used instead of Compound 6. m/z 328.3 (M-H)

Example AW

Example AW (107 mg) was prepared following the procedure for Example C, except that Compound 96 was used instead of Compound 7. Ή NMR (CDCh) h 8.79 (s, 1H), 7.82 (s, 1H), 7.27-7.09 (m, 10H), 6.95 (s, 1H), 6.23 (m, 1H), 6.14 (s, 1H), 5.22 (s, 3H), 4.45 (m, 2 H), 4.35-4.0 (m, 3 H), 3.8 (m, 1 H), 3.6 (m, 1 H), 3.25 (s, 3H), 3.21 (m, 2H), 2.95 (s, 3 H), 2.8-2.6 (m, 4 H), 2.0-1.4 (m, 4 H), 1.25 (m, 4 H), 1.05 (m,4H): m/z 721.3 (M+H)‘

Preparation of Examples AX and AY

Scheme 41

I

I. DMSO. Et₃N, S0₃ pyridine:

II. NaBH(OAc)₃, AcOH, Methylamlne/MeOH

Example AX

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To a solution of Example I (650 mg, 1.00 mmol) in DMSO (3.5 mL) was added triethylamine (0.5 mL). The mixture was stirred for 30 minutes. Pyridine SCh was added to the mixture at 5C then stirred for 60 minutes. The mixture was poured on to ice-water, then stirred for 30 minutes. The mixture was diluted with EtOAc and washed with water, sat. NaHCCh, and brine. Concentration gave Example AX. m/z 705.2 (M+H)^h

Example AY

To a stirred solution of Example AX (70 mg, 0.099 mmol) and methylamine (1.5 mL, 2M) in MeOH (1.5 mL) was added AcOH (119 mg, 1.99 mmol). The mixture was stirred for 2 hours. NaBH(OAc)s (94 mg) was added, and the mixture was stirred for 2 hours. Concentration and purification by prep. HPLC gave Example AY (30 mg). ^JH NMR (CDCh) b 8.79 (s, 1H), 7.82 (s, 1H), 7.27-7.09 (m, 10H), 6.95 (s, 1H), 6.23 (m, 1H), 6.14 (s, 1H), 5.22 (s, 2 H), 4.45 (m, 1 H), 4.35-4.0 (m, 4 H), 3.8 (m, 1 H), 3.6 (m, 1 H), 3.21 (m, 1 H), 2.95 (s, 3 H), 2.93 (s, 3H), 2,8-2.6 (m, 4 H), 2.0-1.4 (m, 4 H), 1.25 (m, 4 H), 1.05 (m, 4H): m/z 720.3 (M+H)

Preparation of Example AZ

I. HOBt, EDC, DIPEA, THF

Example AZ

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Compound AZ (61 mg) was prepared following the procedure for Example C, except that Compound 87 was used instead of Compound 7 and Compound 79 was used instead of Compound 8. Ή NMR (CDCb) δ 8.77 (s, 1H), 8.72 (s, 1H), 7.78 (s, 1 Η), 7.71 (s, 1H), 6.23 (d, 1H), 5.28-5.24 (m, 2H), 4.85 (d, 1H), 4.71-4.57 (m, 2H), 4.08-4.03 (m, 1H), 3.78 (br s, 1H), 3.51 (br s, 1H), 2.87 (s, 3H), 2.33 (br s, 1H), 2.13-2.06 (m, 1H), 1.49-1.33 (m, 8H), 0.93-0.80 (m, 12 H): m/z 539.2 (M+H)^;Preparation of Examples BA and BB

Scheme 43

t, a. CDI/iPr₂NEt; b. Compound 9; 11.a. NaQH/THF/H₂O; b. HCf;

111. Cmpd 8/EDC/HOBt, IPEA, THF; IV. Et₃SiH, TFA

Compound 97

Compound 97 is commercially available from TCI, and was used as received.

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Compound 98

To a stirred solution of Compound 97 (1 g, 2.2 mmol) and diisopropylethylamine (1.6 mL, 8.9 mmol) in dichlorome thane (26 mL) was added GDI (362 mg, 2.2 mmol). Tine mixture was stirred for 12 hours. Compound 9 was added, and the mixture was stirred for 12 additional hours. Concentration and purification by flash column chromatography (0-8%: MeOH/DCM) gave Compound 98 (1.2 g). m/z 608.1 (M+H)' Compound 99

Compound 99 (1.2 g) was prepared following the same procedure used to prepare Compound 67, with tine exception that Compound 98 was used instead of Compound 66. m/z 592.2 (M-H)· Example BA

Example BA (111 mg) was prepared following the procedure used to prepare Example C, except that Compound 99 was used instead of Compound 7. m/z 986.1 (M+H)'

Example BB

To a stirred solution of Example BA (111 mg, 0.113 mmol) and TFA (1.4 mL) was added EbSiH (0.1 mL). The mixture was stirred for 60 minutes, then concentrated and partitioned with EtOAc and sat. NaHCO.n, followed by extraction with EtOAc (2X) and drying over NazSOj. Concentration and purification by flash column chromatography (0-15%: MeOH/DCM) gave Example BB (50 mg).

Ή-NMR (CDCL) b 8.75 (s, 1 H), 7.79 (s, 1 H), 7.42 (s, 1 H), 7.22-7.12 (m, 9H), 6.996.96 (m, 2H), 6.86 (s, IH), 6.71 (m, 2H), 5.51 (br s, 1 H), 5.17 (m, 2H), 4.57-4,52 (m, 1 H), 4.39-4.35 (m, 2 H), 4.07 (m, 1 H), 3.74 (br s 1 H), 3.28-3.19 (τη, 111,), 3.09-2.76 (m, 6 H), 3.65-2.58 (m, 3 Η), 1.49 (m, 2 H), 1.36-1.20 (m, 8 H); m/z 743.2 (M+H)⁺Preparation of Example BC

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Scheme 44

BC

I. HOBt, EDC, DIPEA, THF, Cmpd 29

Example BC

Example BC (95 mg) was prepared following the procedure used to prepare Example C, except that Compound 29 was used instead of Compound 7, and Compound 78 was used instead of Compound 8. H NMR (CDCb) i> 8.75 (s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 6.28 (d, 1H), 6.18 (m, 1H), 5.26-5.21 (m, 3H), 4.47-4.30 (m, 2H), 4.11-4,00 (m, 1H), 3.91 (br s, 1H), 3.59 (br s, 1H), 3.28 (m, 1H), 2.97-2.90 (m, 3H), 2.26-2.19 (m, 1H), 1.39-1.24 (m, 1 OH), 1.09-1.01 (m, 6 H), 0.94-0.86 (m, 6 H): m/z 553.1 (M+H)’

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Preparation of Examples BP and BE

Scheme 45

12e

13e

1. LiOH, THF/H_ZO; II. Cmpd. 78, HOBt, EDC, DIPEA, THF; HI. a. neat TFA; b. NaOH, THF, H_ZO

Example BD

Example BD (148 mg) was prepared following the procedure used to prepare Example C, except that Compound 13e was used instead of Compound 7, and Compound 78 was used instead of amine 8. m/z 611.1 (M+H) Example BE

Example BD (148 mg, 0.242 mmol) was dissolved in TFA (3 mL) and allowed to stir at 25 ^DC for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with THF (3 mL) and 2N aqueous NaOH was added until pH 10. The mixture w⁷as allowed to stir for 20 min and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried over NazSOi, filtered, and evaporated. Purification by flash chromatography

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Preparation of Example BF

Scheme 46

BF

1. LiOH, THF/H₂O; II. Cmpd. 8, HOBt, EDC, DIPEA, THF

Compound 100

Compound 100 was prepared using the same method used to prepare Compound 122, except that Compound 9 was replaced with Compound 68 (see Scheme 70).

Compound 101

Compound 100 (108 mg, 0.423 mmol) was dissolved in THF (2 mL), then 847 pl of 1 M LiOH/HiO was added. After stirring overnight, 843 pl of 1 N HC1 was added. Concentration gave Compound 101.

Ex^imple BF

Example BF (24 mg) was prepared following the procedure used to prepare Example C, except that Compound 101 was used instead of Compound 7.

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H NMR (CDCh) & 8.77 (s, ΊΗ), 8.73 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.27-7.10 (m, 10H), 6.55-6.52 (d, 1H), 5.84 (d, 1 H), 5.21-5.19 (m, 3 H), 4.77-4.53 (τη, 2H), 4.39 (br s, 1 H), 4.11-3.99 (m, 2 H), 3.81 (br s, 1H), 3.58 (m, 2 H), 2.86 (s, 3 H), 2.81-1.72 (m, 5H), 2.04 (m, 1 H), 1.85 (m, 1 H), 1.66-1.37 (m, 6 H): m/z 665.2 (M+H)' Preparation of Example BG

Scheme 47

I. Ethyltrifluoroacetate, Mel, Cs₂CO₃. THF

Example BG

Example R (102 mg, 0.137 mmol) was dissolved in THF (2 mL), then 2 mL of ethyltrifluoroactate was added. Then 1.3 eq of Mel and excess Cs?COj were added. After stirring for 1 day, the mixture was partitioned with EtOAc and sat. NazCOs, extracted with EtOAc (2X), and dried over NYcSOj. Purification by flash chromatography (0-20% McOH/CFLCE) gave Example BG (6.5 mg). Ή NMR (CD.-OD) b 9.94 (s, 1I-I), 8.27 (s, 1H), 7.73 (s, 1H), 7.30-7.10 (m, 10H), 5.29, 5.17 (d 2H), 4.72 (s, 3H), 4.29 (m, 1H), 4.15 (br s, 1H), 3.83 (br s, 1H), 3.61 (m, 2H), 3.07 (s, 3H), 2.93 (m, 2H), 2.82-2,70 (τη, 4H), 2.68-2.58 (m, 2H), 2.42 (s, 3H), 2.05 (m, 2H), 1,70-1.40 (m, 10H). m/z: 720.2 (M+H)\

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Preparation of Example BH

Scheme 48

I. amine 59, HOBt, EDC, DiPEA, THF

Example BH

Example BH (78 mg) was prepared following the procedure used to prepare Example C, except that Compound 87 was used instead of Compound 7, and Compound 46 was used instead of Compound 8. Ή NMR (CDCh) & 8.73 (s, 1H), 8.68 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.18-7.09 (m, 10H), 6.26 (m, 1H), 5.76 (m, 1H), 5.22-5.18 (m, 4H), 4.71-4.65 (d, ΊΗ), 4.46-4.40 (d, 1 H), 4.11-4.04 (m, 2H), 3.81 (br s, ΊΗ), 3.14 (br s, HI), 2.83 (s, 3H), 2.76-2.52 (m, 4H), 1.88 (m, 1H), 1.51-1.37 (m, 2H), 0.73-0.69 (m, 6 H) m/z 663.2 (M+H)^r

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Preparation of Examples BI and BI

I. Cmpd. 46/EDC/HOBt, IPEA, THF: II. Et₃SIH, TFA

Example BI

Example BI (1.78 g) was prepared following the procedure used to prepare Example C, except that Compound 99 was used instead of Compound 7, and Compound 46 was used instead of Compound 8. m/z 986.1 (M+H)’ Example BI

Example BJ (728 mg) was prepared following the procedure used to prepare Example BB, except that Example BI was used instead of Example BA. H-NMR (CDCI3) δ 8.75 (s, 1 H), 7.79 (s, 1 H), 7.42 (s, 1 H), 7.22-7.12 (m, 9H), 6.996.96 (m, 2H), 6.86 (s, 1H), 6.71 (m, 211), 5.51 (br s, 1 H), 5.17 (m, 2H), 4.57-4.52 (m, 1 H), 4.39-4.35 (m, 2 H), 4.07 (m, 1 H), 3.74 (br s 1 H), 3.28-3.19 (m, 1H,), 3.09-2.76 (m, 6 H), 3.65-2.58 (m, 3 H), 1.49 (m, 2 H), 1.36-1.20 (m, 8 II); m/z 743.2 (M+H)¹

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Preparation of Compounds 104-115

Scheme 50

102 103 104

I. a. GDI, DIPEA, MeCN; b. Cmpd. 9, MeCN. !l. 1M LiOH, THF.

Compound 102

Compound 102 is commercially available from Aldrich Chemical Co., and was used without further purification. Compound 103

Compound. 102 (5.5 mmol) was suspended in MeCN (55 mL) and DIPEA (8.25 mmol) was added. Carbonyl diimidazolc (5.5 mmol) was diluted in MeCN (20 mL) and the solution added slowly to the reaction mixture over 45 min. The resulting mixture was allowed to age overnight. Compound 9 (5.5 mmol) was diluted in MeCN (10 mL) and treated with DIPEA (8.25 mmol) before being added to the reaction mixture, which was then allowed to age overnight. The volatiles were removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with IM HC1 (50 mL). The layers were separated and the aqueous layer extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with sat. NaZZOsuntil the pH of the washes was - pH 8. A brine wash (30 mL) was followed by drying over anhydrous MgSO+. Following concentration in vacuo, the residue was purified on S1O2 (0-65% EtCAc/hox) to provide 0.340 g (20%) of Compound 103 as an amorphous white solid (m/z 314.0 (M+H)⁺). Compound 104

Compound 103 (1.1 mmol) was diluted in THF (5 mL) and treated with freshly prepared 1M LiOH (2.2 mmol). The biphasic reaction was stirred vigorously for 2 h before being quenched with IM HC1 (3 mmol). The reaction

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Scheme 51

I. HC1. MeOH; It. a. GDI, DIPEA, MeCN; b. Cmpd. 9, MeCN. III. 1M LiOH, THF.

Compound 105

Compound 105 is commercially available from Aldrich Chemical Co,, and was used without further purification.

Compound 106

Racemic Compound 105 (12.2 mmol) was diluted in MeOH (100 mL).

HCl/dioxane solution (4M, 25 mmol) was added and the solution was refluxed overnight. Volatiles were removed in vacuo to produce 2.60 g (97%) of Compound 106 as a racemic mixture. The foamy white solid w’as used without further purification (m/z 147.0 (M+H)⁺).

Compound 107

Compound 106 (5 mmol) was diluted in MeCN (65 mL) and treated with DIPEA (25 mmol). The resulting solution was added slowly via addition funnel

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Compound 108

Compound 107 (1.05 mmol) was taken up in THF (5 mL) and treated with freshly prepared IM LiOH solution (2.1 mmol). The solution was stirred vigorously for 2 h and quenched with ΊΜ HCl (2.1 mmol). The volatiles were removed in vacuo, and the resulting oil was azeotroped with toluene until a quantitative yield of racemic Compound 108 was produced as an amorphous white solid that was used without further purification (m/z 329.1 (M+H)⁺).

Scheme 52

I. p-O₂NC₆H₄O(CO)CI, NMM, DCM, 0 °C to rt; II. Cmpd. 9, Et₃N, DMAP, THF, 70 °C; III. 1M LiOH, THF

Compound 109

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Compound 109 is commercially available from Ba diem, and was used as received.

Compound 110

Compound 109 (4.1 mmol) was diluted in DCM (5 mL) and treated with Nmethylmorpholine (8.2 mmol). This solution was added slowly to a DCM (5 mL) solution of 4-nitrophenyl chloroformate (4.1 mmol) at 0 °C. The reaction was then allowed to warm to room temperature overnight. The volatiles were removed in vacuo and the residue was taken up in EtOAc and sat, NajCOs. The aqueous layer was extracted with EtOAc (3 X 10 mL) and the combined organics were washed with brine (30 mL) prior to being dried over anhydrous NazSO-i. Following concentration in vacuo, the residue was purified by column chromatography on SiCh (0-25% EtOAc/Hex) to produce 0.75 g (51%) of Compound 110 as an amorphous white solid (m/z 354.8 (M+H)’).

Compound 111

Compound 110 (1.1 mmol) was diluted in THF (.3.5 mL), Compound 9 (L4 mmol) was diluted in THF (3 mL), treated with ELN (2.8 mmol) and transferred to the reaction solution, DMAP (0.11 mmol) was added and the reaction was heated to 70 C for 2 h. After cooling to room temperature, EtOAc (10 mL) and sat. Na?COi were added. The aqueous phase was extracted with EtOAc (3 X 10 mL) and the combined organics were washed with saturated NasCOs, FLO, and brine (15 mL each). After drying over anhydrous MgSO^, volatiles were removed in vacuo and the residue was purified by column chromatography on SiOz (0-50% EA/hex) to produce 0.346 g (82%) of Compound 111 (m/z 386.0 (M+H)’), Compound 112

Compound 111 (0.88 mmol) was taken up in THF (4 mL) and treated with freshly prepared IM LiOH (1.8 mmol). The reaction mixture was stirred vigorously for 1,5 h and quenched with IM HCI (2,5 mmol). The reaction mixture

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Scheme 53

NHBoc NHBoc NHBoc

Fmoc^ Jx^OH —¹ ► Fmoc.. Λ .OMe '* ► _{u M}A^OMe N If N jf ^H2^N Π ^H O ^H 0 O

113 114 115

I. TMSCHN₂, THRMeOH; II. piperidine, DMF

Compound 113

Compound 113 is commercially available from Chem-lmpex, and was used without further purification.

Compound 114

Compound 113 (3.2 mmol) was diluted in THF (15 mL). TMSCHN? (3.2 mmol) was added slowly, followed by MeOH (5 mL). The solution rapidly became colorless, and heavy evolution of gas was observed. After aging overnight, tire volatiles were removed in vacuo and the residue purified by column chromatography on SiCh (0-50% EtOAc/hex) to produce 0.805 g (52%) of Compound 114 (m/z 505.2 (M-Na)’).

Compound 115

Compound 114 (1.7 mmol) was diluted in DMF (4 mL) and piperidine (1 mL) was added. After 30 min, the volatiles were removed in vacuo and the residue was purified by column chromatography on S1O2 (0-5% MeOH/DCM) to provide 0.414 (94%) of Compound 115 as an amorphous white solid (m/z 261.0 (M+H)⁴).

Preparation of Example BK

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Scheme 54

I. Cmpd. 29/EDC/HOBt/DIPEA/THF.

Compound BK

Compound 79 (0.70 mmol) and Compound 29 (0.91 mmol) were combined in THF (7 mL). HOBt (0.91 mmol), DIPEA (1,05 mmol) and EDC (0.91 mmol) were added consecutively at room temperature and the reaction was allowed to age overnight. The volatiles were removed in vacuo and the residue taken up in 3/1 Cl lCl.i/IPA and sat. NazCCh (15 mL each). The aqueous layer was extracted with 3/1 CHCL/IPA (3 X 10 mL) and the combined organics were washed with sat. NazCOz, water, and brine (15 mL each). Following drying over anhydrous MgSO, the volatiles were removed in vacuo and the residue was purified by column chromatography on SiCh (0-10% MeOH/DCM) to produce 8.5 mg (2%) of Compound BK m/z 581.2 (M+H)⁺; Td-NMR (CDCb, 300 MHz): 8.91 (s, 1H); 7,89 (s, 1H); 7.15 (s, 1H); 6.52-6.0 (br m, 2H); 5.26 (s, 2H); 5.18 (br d, J = 8.1 Hz, 1H); 4.55 (s, 2H); 4.06 (br s, 1H); 3.79 (br s, 1H); 3,48 (m, 2H); 3.09 (s, 3H, minor rotamer); 3.01 (s, 3H, major rotamer); 2.34 (m, 1H); 1.60-1.30 (m, 8H); 1.42 (d, J = 6.9 Hz, 6H); 0.98 (t, I = 7.2 Hz, 611); 0.86 (m, 6H).

Preparation of Example BL

Scheme 55

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O

I. Cmpd. 8/EDC/HOBVDIPEA/THF.

Example BL

Example BL was prepared in a similar fashion to Example BK using Compound 104 (0.26 mmol) and Compound 8 (0,29 mmol) to produce 0.087 g (64%) of Example BL as an amorphous white solid m/z 691.3 (M+H)’; Ή-NMR (CDCh, 300 MHz): 8.82 (s, 1H); 7.82 (s, 1H); 7.30-7.10 (m, 11H); 7.06 (s, 1H); 6.54 (d, J = 9.6 Hz, 1H); 5.89 (d, / = 8.4 Hz, 1H); 5.22 (s, 1H); 5.07 (m, 1H); 4.45 (AB d, J = 16.5 Hz, 1H); 4.37 (AB d, ] = 15.6 Hz, 1H); 4.07 (m, 1 H); 3.68 (m, 1H); 3.40 (m, 1H); 3.06 (s, 3H, minor rotamer); 2.89 (s, 3H, major rotamer); 2.90-2.54 (m, 4H); 1.601.25 (m, 16H).

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Preparation of Example BMa and BMb

Scheme 56

BMa and BMb

I. Cmpd. 8/EDC/HOBt/DIPEA/THF.

Examples BMa and BMb

Examples BMa and BMb were prepared in a similar fashion to Compound BK using racemic Compound 108 (0.36 mmol) and Compound 8 (0.28 mmol). The enantiomeric products were separated by preparatory HPLC (Chiralcel OD-H (250 X 4.6 mm, 70:30 Heptane/IPA, 30 min) to produce 0.008 g (4%) of enantiomer BMa (HPLC Rr= 11.71 min) m/z 720.3 (M+H)*; Ή-NMR (CDCb, 300 MHz): 8.73 (s, 1H); 7.78 (s, 1H); 7.41 (br s, 1H); 7.30-7.00 (m, 11H); 6.94 (s, 1H); 5.40 (br s, 1H);

5.18 (br s, 2H); 4.56 (AB d, / = 15 Hz, 1H); 4.48 (AB d, J = 16 Hz, 1H); 4.39 (br s, 1H); 4.05 (br s, 1H); 3.73 (br s, 1H); 3.25 (s, 3H, minor rotamer); 3.23 (m, 1H); 2.98 (s, 3H, major rotamer); 2.82-2.30 (m, 10H); 1.60-1.20 (m, 6H); 1.32 (d, /=7 Hz, 6H) and 0.010 g (5%) of enantiomer BMb (HPLC Rt= 15.41 min). (m/z 720.3 (M+H)*; ΉNMR (CDCh, 300 MHz): 8.78 (s, 1H); 7.83 (s, 1H); 7.38 (br d, / = 8 Hz, 1H); 7.307.7.05 (m, 11H); 7.02 (s, 1H); 5.52 (d, / = 9 Hz, 1H); 5.25 (AB d, J = 13 Hz, 1H); 5,21 (AB d, / = 13 Hz, 1H); 4.85-4.62 (m, 2H); 4.44 (d, (= 16 Hz, 1H); 3.99 (br s, 1H); 3,78

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2.77 (s, 6H); 2.86-2.60 (m, 4H); 1.6-1.3 (m, 6H); 1.35 (d, / = 7 Hz, 6H).

Preparation of Examples BN and BO

Scheme 57

BN (R = LBu) ► BO (R = H)

I. Cmpd. 8/EDC/HOBt/DIPEA/THF; II. TFA, 1M NaOH.

Example BN

Example BN was prepared in a similar fashion to Example BK using Compound 112 (0.78 mmol) and Compound 8 (0.60 mmol) to produce 0.227 g (50%) of Compound BN as colorless film. (fn/z 763.3 (M-r-Hj¹).

Example BO

Example BO was prepared in a similar fashion to Example AM using Example BN (0.29 mmol) to produce 0.149 g (72%) of Example BO as an amorphous white solid, (m/z 707.3 (M+H)⁺; Ή-NMR (CDCh, 300 MHz): 8.82 (s, 1H); 7.84 (s, IH); 7.26-7.03 (m, 11H); 6.99 (s, IH); 6.69 (d, / = 9.6, IH); 6.42 (br s, 1H); 5.47 (br d, / = 8.7 Hz, IH); 5.27 (AB d, / = 13 Hz, IH); 5.22 (AB d, / = 13 Hz, IH); 4.55 (AB d, J = 16 Hz, IH); 4.43 (AB d, J = 16 EL·, IH); 4.18 (m, IH); 4.00 (m,

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21-1); 3.72 (br s, 1H); 2.25 (m, 1H); 2.99 (s, 3H); 2.84-2.60 (m, 3H); 2.54-2.42 (m, 1H);

1.64-1.12 (m, 4H); 1.37 (d, ) = 7 Hz, 6H); 1.11 (d J = 6 Hz, 3H).

Preparation of Examples BP-BR

Scheme 58

NHBoc

^l,IL*-BR(R₁ = R₂ = CH₃)

I. Cmpd. 78/EDC/HOBVDIPEA/THF; IL 4M HCI/dioxane; III. HCHO, NaHB(OAc)₃, MeOH

Example BP

Example BP was prepared in a similar fashion to Example BK using Compound 52 (0.22 mmol) and Compound 78 (0.20 mmol) to produce 0.091 g (71¹½) of Example BP as colorless film {m/z 654.2 (M+H)^T).

Example BQ

Example BP (0.14 mmol) was treated with4MHCl in dioxane (2 mL) to produce a white precipitate within 5 min. The solvents were removed, and the solid was taken up in MeOH. Concentration in vacuo afforded 0.083 g (99%) of the HC1 salt of Example BQ as a colorless film (m/z 554.1 (M+H)^-; ¹H-NMR (CEhOD, 300 MHz): 10.03 (s, 1H); 8.41 (s, 1H); 7.81 (s, 1H); 5.48 (s, 2H, minor rotamcr); 5.35 (s, 2H, major rotamcr); 4.74 (s, 2H); 4.34 (br s, 1H); 3.90 (br s, 1H); 3.78-3.54 (m,

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2H); 3.20-2.98 (m, 5H); 2.20 (br s, IH); 2.07 (br s, IH); 1.60-1.4 (m, 10H); 1.12 (m, 6H).

Example BR

Example BQ (0.11 mmol) was taken up in MeOH (1.5 mL). Formaldehyde (37% in H:0,13.4 mmol) was added and aged 10 min. NaHB(OAc)3 (0.324 mmol) was added, and the reaction mixhire was allowed to age at room temperature overnight. More formaldehyde (13.4 mmol) and NaHB(OAc).i (0.324 mmol) were added and allowed to age an additional 6 h at room temperature. The solvents were removed in vacuo and the product was isolated by preparatory HPLC to produce 0.058 g (77%) of the TFA salt of Example BR as an amorphous solid, m/z 582.3 (M+II)3 Ή-NMR (CDrOD, 300 MHz): 9.07 (s, 1H); 7.91 (s, 1H); 7.25 (s, IH); 5.47 (s, 2H, minor rotamer); 5.28 (s, 2H, major rotamer); 4.59 (AB d, J = 16 Hz, IH); 4.53 (AB dJ = 16 Hz, IH); 4.31 (dd, J = 9.2, 5 Hz, IH); 3.88 (m, IH); 3.59 (m, IH); 3.32 (m, IH); 3.20 (m, 2H); 2.98 (&, 3H); 2.89 (br s, 6H); 2.23 (m, IH); 2.00 (m, IH); 1.44 (m, 4H); 1.37 (d, J - 7 Hz, 6H); 1.10 (m, 6H).

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Preparation of Examples BS and BT

Scheme 59

BS (R = f-Bu) _BT (_R = _H)

I. Cmpd. 8/EDC/HO0t/DIPEA/THF; II. TFA, 1M NaOH.

Compound 116

Compound 116 was prepared in a similar fashion to Compound 75 using Compound 4 (0.76 mmol) and Compound 47 (0.64 mmol) to produce 0.218 g (90%) of Compound 116 as a foamy white solid (ffl/z 384.1 (M-iH)⁺).

Example BS

Example BS was prepared in a similar fashion to Example BK using Compound 116 (0.28 mmol) and Compound 8 (0.25 mmol) to produce 0.139 g (72%) of Example BS as a colorless film (wi/z 775.3 (M+H)Q.

Example BT

Example BT was prepared in a similar fashion to Example AM using Example BS (0.18 mmol) to produce 0.080 g (62%) of Example BT as an amorphous white solid, m/z 719.3 (M+H)'; Ή-NMR (CDCE, 300 MHz): 8.79 (s, 1H); 7,82 (s, 1H); 7.27-7.0 (m, 10H); 6.98-6.82 (m, 1H); 6.85 (s, 1H); 6.44 (br s, 1H); 5.30 (s, 2H, minor retainer); 5.22 (s, 211, major rotamcr); 5.04 (br s, 1H); 4,62 (AB d.

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J = 15 Hz, 1H); 4,54 (AB d, / = 15 Hz, 1H); 4.27 (br s, 1H); 4.11 (br s, 1H); 3.97 (br d, / = 10 Hz, 1H); 3.82, br s, 1H); 3.57 (br s, 1H); 3,40-3.10 (m, 2H); 2.80-2.60 (m, 4H); 2.55 (m, 1H); 1.54 (οι, 2H); 1.46-1.30 (m, 2H); 1.35 (d, / = 7 Hz, 6H); 0.94-0.72 (m, 4H).

Preparation of Examples BU and BV

Scheme 60

BU(R = f-Bu) -¹¹·- BV(R = H)

I. Cmpd. 8/EDC/HOBt/DIPEA/THF: IL TFA, 1M NaOH.

Compound 117

Compound 117 was prepared in a similar fashion to Compound 13d except that Compound 4 (1.5 mmol) and the L-enantiomer of Compound lOd (1.15 mmol) were used to ultimately produce 0.328 g (88%) of Compound 190 as a foamy white solid (m/z 398.1 (M+H)').

Example BU

Example BU was prepared in a similar fashion to Example AL using Compound 117 (0.33 mmol) and Compound 8 (0.30 mmol) to produce 0.196 g (84%) of Example BU as an amorphous white solid (m/z 789.3 (M+H)').

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Example BV

Example BV was prepared in a similar fashion to Example AM using Example BL¹ (0.29 mmol) to produce 0.140 g (77%) of Example BV as an amorphous white solid, m/z 733.3 (M+H)⁺; Ή-NMR (CDCb, 300 MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 10H); 6.70-6.10 (m, 1H); 6.86 (s, 1H); 6.20 (br dj = 7 Hz, 1H); 5.24 (s, 2H); 4.81 (br d J = 7 Hz, 1H); 4.82 (s, 2H); 4.34 (br dJ = 7 Hz, 1H); 4.16 (br s, 1H); 4.07 (br d, J - 6 Hz, 1H); 3.86 (br s, 1H); 3.38 (br s, IH); 2.69 (m, 6H); 1.62-1.50 (in, 2H); 1.50-1.34 (m, 2H); 1.38 (m, 6H); 1.13 (d, / = 6 Hz, 3H); 0.98-0.76 (m, 4H).

Preparation of Examples BW and BX

Scheme 61

BW (R = t-Bu} 2!^ ex (R = H)

I Cmpd. 75/EDC/HOBt/DIPEA/THF; II. TFA, 1M NaOH.

Example BW

Example BW was prepared in a similar fashion to Example BK using Compound 75 (0.27 mmol) and Compound 46 (0.24 mmol) to provide 0.154 g (86%) of Example BW as an amorphous white solid (m/z 733.3 (M+H)').

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Example BX

Example BX was prepared in a similar fashion to Example AM using Example BW (0.21 mmol) to provide 0.091 g (98%) of the TFA salt of Example BX as an amorphous white solid, m/z 677.5 (M+H)⁺; Ή-NMR (CDCh, 300 MHz): 8.83 (s, 1EI); 8.77 (s, 1H); 7.84 (s, 1H); 7.77 (s, 1H); 7.27-7.00 (m, 10H); 6.62 (d, J = 9 Hz, 1H); 6.44 (d, / = 6 Hz, 1H); 5.35 (d, J = 10 Hz, 1H); 5.24 (s, 2H); 4.69 (AB dj = 15 Hz, 1H); 4.62 (AB d, J = 16 Hz, 1H); 4.14 (hr m, 2H); 3.96-3.78 (m, 2H); 3.51 (dd, J = 11, 4.5 Hz, 1H); 3.38 (br s, 1H); 2.82-2.58 (m, 4H); 2.41 (τη, 1H); 1.70-1,24 (m, 4H); 1.200.88 (m, 2H); 0.88-0.54 (m, 2H).

Preparation of Examples BY and BZ

Scheme 62

NHBoc

I. Cmpd. 8/EDC/HOBt/DIPEA/THF; II. 4M HCI/dioxane.

Compound 118

Compound 118 was prepared in a similar fashion to Compound 104 except that Compound 115 (0.40 mmol) was used instead of Compound 102, which was

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Example BY was prepared in a similar fashion to Example BM using Compound 118 (0.17 mmol) and Compound 8 (0.15 mmol) to produce 0.079 g (62%) of Example BY as an amorphous white solid (miz 834.3 (M+H)^F). Example BZ

Example BZ was prepared in a similar fashion to Example BQ using Example BY (0.095 mmol) to provide 0.082 g (99%) of tire HCI salt of Example BZ as an amorphous white solid mfz 734.2 (M+H)⁺; Ή-NMR (DMSO-cG 300 MHz): 8.08 (s, 1H); 7.86 (br m, 3H); 7.58 (d, / = 9 Hz, 1H); 7.25-7.00 (m, 11H); 6.32 (br s, Ί H); 5.16 (s, 2H); 4.99 (br in, 4H); 4.48 (AB d, / = 15 Hz, 1H); 4.43 (AB d J = 15 Hz, 1H); 4,02 (m, 1H); 3.89 (nr, 1H); 3.63 (nr, 1H); 3.22 (hep, / = 7 Hz, 1H); 2.87 (s, 3H); 2.76-2.56 (m, 4H); 1.58-1.15 (nr, 10H); 1.29 (d, / = 7 Hz, 6H).

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Preparation of Example CA

Scheme 63

I. 4-morpholinecarbonyl chloride, DIPEA, DCM.

Example CA

Example R (0.11 mmol) was diluted in DCM (1 mL) and treated with 4morpholinecarbonyl chloride (0.13 mmol) and DIPEA (0.16 mmol). After 2 h, volatiles were removed in vacuo and the residue was purified by column chromatography on SiCE (0-20% MeOH/DCM) to afford 0.068 g (76%) of Example CA as an amorphous w^rhite solid m/z 819.1 (M+H)‘; Ή-NMR (CDCE, 300 MHz): 8.82 (s, 1H); 7.85 (s, 1H); 7.27-7.07 (m, 12H); 6.94 (s, 1H); 6.26 (br s, 1H); 5.73 (d, ] = 8 Hz, 1H); 5.28 (AB d, J = 13 Hz, 1H); 5.22 (AB dj = 13 Hz, 1H); 4.50 (AB d, / = 16 Hz, 1H); 4.44 (AB d, /= 16 Hz, 1H); 4.17 (m, 1H); 3.98 (br s, 1H) 3.76 (br s, 1H); 3.68 (br s, 1H); 3.60 (m, 4H); 3.40 (m, 2H), 3.32 (m, 4H); 2.97 (s, 3H); 2.87 (dd, / = 13, 5 Hz, 2H); 2.73, (m, 2H); 2.57 (m, 2H); 1.79 (m, 2H); L60-J .20 (m, 6H); 1.37 (d, / = 7 Hz, 6H).

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Preparation of Compound CB

Scheme 64

I. morpholine, EDC, HOBt, THF.

Example CB

Example AE (0.15 mmol) was diluted in THF (1 mL) and treated with morpholine (0.61 mmol), HOBt (0.18 mmol) and finally EDC (0,18 mmol). The reaction mixture was allowed to age overnight. The reaction mixture was then diluted in EtOAc and sat. NazCOs. The aqueous layer was extracted with EtOAc and tire combined organic layers were washed with brine, dried over anhydrous MgSQj and concentrated in vacuo. The resulting residue was purified via preparatory HPLC to provide 0.024 g (20%) of Example CB as an amorphous white solid. m!z 790.4 (M+H)'; Ή-NMR (CDCb, 300 MHz): 8.81 (s, 1H); 7.84 (s, IH); 7.27-7.10 (m, 1014); 6.96 (s, IH); 6.78 (d, / = 8 Hz, 1H); 6.67 (s, IH); 5.36 (d, / = 9 Hz, IH); 5.27 (AB dj = 13 Hz, 1H); 5.20 (AB dj= 13 Hz, IH); 4.59 (s, IH); 4.51 (s, 2H); 4.02 (m, IH); 3.80-3.30 (m, 10H); 2.98 (s, 3H); 2.90-2.45 (m, 6H); 1.52 (m, 2H); 1.39 (d, / = 7 Hz, 6H); 1.32 (m, 2H).

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Preparation of Compound CC

I. N-methyl pi perazine, EDC, HOBt, DIPEA,THF.

Example CC

Example CC was prepared in a similar fashion to Example CB except that N-methylpiperazine (0.16 mmol) was reacted with Compound AF (0.10 mmol) instead of morpholine and DIPEA (0.19 mmol) was added to produce 0.009 g (11%) of Example CC as an amorphous white solid mil 803.4 (M+H)*; ’H-NMR (CDCh, 300 MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, I1H); 6.91 (s, 1H); 6.78 (m, 2H); 5.27 (AB dj = 13 Hz, 1H); 5.21 (AB d, / = 13 Hz, 1H); 4.59 (m, 1H); 4.49 (AB d J = 16 Hz, 4.44 (AB d, / = 16 Hz, 1H); 4.01 (m, 1H); 3.90-3.40 (m, 4H); 3.27 (hep, /=7 Hz, 1H); 3.10-2.90 (m, 1H); 2.97 (s, 3H); 2.90-2.30 (m, 1111); 1.60-1.25 (m, 6H); 1.37 (d,/ = 7Hz, 6H).

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Preparation of Example CD

Scheme 66

Example CD

To a solution of Example R (30.5 mg, 0.043 mmol) in methanol (1.5 mL) was added formaldehyde (1 mL, 37% in H?O). After stirring for 10 minutes, NaBH(OAc)? (49 mg, 0.23 mmol) was added and the resulting mixture was stirred for 10 h. The reaction was monitored with LC/MS. When LC/MS indicated the absence of starting material Example R, the reaction mixture was evaporated to dryness, and filtered through a cotton plug. The crude product was then purified through CombiTlash (10% MeOH/CHzCE) to give 29.7 mg of Example CD ΉNMR (CDCb, 500 MHz): 8.78 (s, IH); 7.83 (s, IH); 7.12-7.22 (m, 10H); 6.85 (s, IH); 5.83 (d, IH, J = 8.5 Hz ), 5.23 (Bae, 2H, J = 13.1 Hz); 4.49 (d_A3, 2H, J = 16.5 Hz); 4.29 (m, IH); 4.15 (m, IH); 3.75 (m, IH); 3.30 (m, IH); 2.93 (s, 3H); 2.87 (dd, IH,]I= 5.5 Hz, J2 = 13.5 Hz); 2.72 (m, 2H); 2,66 (dd, Jl= 7.3 Hz, J2 = 13.3 Hz), 2.47 (br s, 1H), 2.36 (br s, IH), 2.23 (s, 6H), 1.91 (m, 2H), 1.56 (m, 2H), 1.40 (m, 2H), 1.40 (d, 6H, J = 6.8 Hz), m/z 734 (M+H)’; 756 (M+Na)-;

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Preparation of Example CE

Scheme 67

I.EDC, HOBt, iPr₂NEt, THF II. a. HCl;/dioxane; b. GDI, iPr₂NEt, Compound 9, CH₂CI₂Compound 119

Compound 119 is commercially available from Aldrich, and was used as received.

Compound 120

A mixture of Compound 119 (200 mg, 0.91 mmol), Compound 8 (373.7 mg, 0,91 mmol), EDC (212 mg, 1.37 mmol), HOBt (160.3 mg, 1.19 mmol) and iPrzNEt (794.7 pL, 4.56 mmol) in THF was stirred for 10 h at room temperature. Ihe mixture was then evaporated to a small volume and purified by CombiFlash (eluted with 1 to 10 % MeOH/CHzCE). The fractions containing the target Compounds were collected and re-purified by CombiFlash (40-100% EtOAc/hexanes) to give 449 mg of Compound 120 as oil. (mlz 611.0 (M+H)^f), Example CE

Compound 120 (449 mg, 0.74mmol) was treated withHCI/dioxane (3 mL). The resulting mixture was evaporated to dryness and lyophilized to provide 373.6 mg of a white solid.

To a solution of the above white compound (52.5 mg, 0.096 mmol) in CHzCL (10 mL) was added Compound 9 (19.8 mg, 0.096 mmol), CDI (15.6 mg,

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0.096 mmol) followed by iPnNEt (33.4 pL, 0.192 mmol). The mixture was stirred for 20 h before it was evaporated to dryness. The mixture was added CHzClz, then filtered through a cotton plug. The filtrate was evaporated to dryness and purified with CombiFlash. The fractions with Example CE was collected and repurified on theTLC to give 15.1 mg of Example CE. Ή-N'MR (CDCh, 300 MHz): 8.79 (s, 1H); 7.82 (s, 1H); 7.09-7.27 (m, 10H), 6.94 (s, 1H); 6.25 (d, 2H, J = 8.7 Hz);

5.23 (s, 2H); 5.17 (br s, 1H); 4.43 (d_A3, 2H, J = 16.5 Hz); 4.29 (m, 1H); 4.13 (m, 1H),

3.76 (m, 2H); 3.48 (m, 1H); 3.29 (s, 3H); 3.25 (m, 1H), 2.94 (s, 3H), 2.65-2.82 (m, 4H), 1.75 (m, 2H), 1.54 (m, 2H), 1.39 (d, 5H, J = 6.9 Hz), m/z 707 (M+H)*; 729 (M+Na)*.

Preparation of Example CF

Scheme 68

Example CF

Example CF was prepared using the same method as Example CE, except that Compound 9 was replaced with Compound 68. Ή-NMR (CDCh, 300 MHz): 8.79 (s, 1H); 8.74 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H); 7.12-7.27 (m, 10H); 6.15 (d, 1H, J = 8.7 Hz), 5.39 (d, 1H, J = 6.8 Hz); 5.21 (s, 2H), 5.06 (d, J = 9.1 Hz, 1H); 4.64 (Jab, 2H, J = 15.5 Hz); 4.28 (m,lH); 4.134 (τη,1Η), 3.79 (m, 1H), 3.70 (m, 1H); 3.34 (m, 1H); 3.28 (s, 3H); 2.87 (s, 314); 2.72 (m, 4H); 1.57 (m, 2H); 1.50 (m, 2H). (m/z 665.2 (M+H)*; 687.3 (M+Na)⁺.

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Preparation of Compound CG

Scheme 69

I. a. GDI, DIPEA, MeCN; b. compound 9, MeCN. II. 1M LiOH, THF.

III. EDCI, HOBt, iPr2NEt, compound 8

Compound 121

Compound 121 is commercially available from Aldrich, and was used as received.

Compound 122

To a suspension of Compound 121 (2.05 g, 11 .3 mmol) in CH2CI2 (40 mL) was added. iPnNEt ¢5.87 mL, 33.9 mmol) followed by CD1 (1.86 g, 11.3 mmol). The resulting mixture was stirred at room temperature for 6 h, then Compound 9 (2.33g, Π.3 mmol) was added. The resulting mixture was stirred for another 10 h before it was evaporated to dryness. The mixture was re-dissolved in CHiCband the solid was removed by filtration. The filtrate was evaporated to dryness and purified by Combi Flash (eluted with 20-80% EtOAc/hexanes) to give 3.2 g of Compound 207 as a pale yellow oil. m/z 298.0 (M+H)L Compound 123

To a solution of Compound 122 (3.2g, 10.8 mmol) in THF (100 mL) was added freshly prepared IM LiOH (10.8 mmol). The biphasic reaction was stirred

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Example CG

Example CG was prepared following the same procedure for Example C instead that Compound 123 was used instead of Compound 7. Ή-NMR (CDCb, 500 MHz): 8.80 (s, 1H); 7.83 (s, 1H), 7.11-7.26 (m, 10H), 6.96 (s, 1H); 7.12-7.27 (m, 101 I); 6.52 (br s, 1H), 6.40 (br s, 1H), 5.23 (s, 2H), 5.20 (m, 1H), 4.44 (d,w, 2H, J = 15.5 Hz), 4.39 (m, 1H), 4.11 (m, 1H), 3.80 (m, 1 H), 3.61 (m, 2H), 3.28 (sep, 1H, J = 7.0 Hz); 2,94 (s, 3H), 2.79 (dd, 1H, JI = 6.1 Hz, J2= 13.4 Hz); 2.71 (m, 3H), 1.93 (in, 1H), 1.71 (m, 1H), 1.54 (m, 1H), 1.38 (d, 6H, J = 7.0 Hz) 1.37 (m, ΊΗ). (: )'; m!z 707.3 (M+Hh), 729.2 (M+Na)\ Preparation of Compound 100

Scheme 70

121 100

I. a. CDI, DIPEA, MeCN;

Compound 100 was prepared using the same method used to prepare Compound 122, except that Compound 9 was replaced with Compound 68.

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Preparation of Example CH

Scheme 71

I. EDCI/HOBt/iPr₂NEt/THF; II. HCHO/NaBH(OAc)₃/HOAc/CH₃CN;

III. Cmpd. l6/iPr₂NEt/CH₃CN

Compounds 124 and 125

To a solution of Compound 29 (135 mg, 0.43 mmol) and Compound 22 (116 mg, 0,43 mmol) in THF (5 mL) were added HOBt (70 mg, 0.52 mmol), EDC (94 uL, 0.52 mmol), and diisopropylethylamine (150 pL, 0.83 mmol). The mixture was

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PCT/US2008/054788 stirred for 12 hours and concentrated. Purification by reverse HZPLC gave Compound 124 (70 mg) and Compound 125 (120 mg). Compound 124: ’H-NMR (CDCh) b 7.2-7.1 (10 H, m), 7.0 (2 H, s), 6.45 (2 H, m), 6.15(2 H, m), 4.45 (4 H, s), 4.1 (2 H, m), 3.96 (2 H, m), 3.3 (2 H, m), 2.98 (6 H, s), 2.7 (4 H, m), 2.1 (2 H, m), 1.6-1.3 (16 H, m), 0.90 (12 H, m). m/z 859.3 (M+H)’; Compound 125: m/z 564.3 (M+H)Compound 126

To a solution of Compound 125 (120 mg, 0.21 mmol) in CH.iCN (1 mL) was added 37% formaldehyde solution (17 pL, 0.23 mmol), followed by HO Ac (24 pl, 0.42 mmol). The mixture was stirred for 2 hours, and NaBH(OAc)s (140 mg, 0.63 mmol) was added. The mixture was stirred for 2 additional hours and diluted with EtOAc. The organic phase was washed with saturated NaiCO? solution, water, and brine, and dried over NazSOi. Concentration gave Compound 126, which was used in the next step without further purification, m/z 578.3 (M+H)’ Example CH

Example CH (26 mg) was prepared following the procedure used to prepare Example L, except that Compound 126 was used instead of Compound 22. Ή-NMR (CDC13) b 8.91 (1 H, m), 7.82 (1 H, m), 7.2-7.0 (11 H, m), 6.4 (1 H, m), 6.2 (1 H, m), 5.23-5.05 (2 H, m), 4.44 (2 H, s), 4.44 (1 11, m), 4.2 (1 PI, m), 3.95 (1 H, m), 3.32 (1 H, m), 2.98 (3 H, s), 2.8-2.5 (7 H, m), 2.15 (1 H, m), 1.7-1.2 (10 H, m), 0.88 (6H, m). m/z 719.3 (M+H)’

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Preparation of Example CI

Scheme 72

I. HCHO/N3BH(OAc)₃/HOAc/CH₃CN; II. Cmpd. 29/EDCI/HOBt/iPr₂NEt/THF

Compound 127

Compound 127 (110 mg) was prepared following the procedure used to prepare Compound 126, except that Compound 8 was used instead of Compound 125. m/z 424.4 (M+H)^r

Example CI

Example Cl (7 mg) was prepared following the procedure used to prepare Example C, except that Compounds 127 and 29 were used instead of Compounds 8 and 7. Ή-XMR (CDC13) & 9.0 (1 H, s), 8.92 (1 H, s), 7.4-7.0 (11 14, m), 5.25 (2 H, m), 4.6-4.0 (5 H, m), 3.4 (1 H, m), 3.1-2.6 (10 H, m), 1.9 (1 H, m), 1.8 (10 H, m), 0.9 (6 H, m); m/z 719.2 (M+H)*

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Preparation of Compound CT

Scheme 73

I. a. TFA/CH₂CI₂: b. Na₂CO₃, II. Cmpd. 16/iPr₂NEt/CH₃CN:

III. Cmpd. 29/EDCl/HOBt/iPr₂NEt/THF

Compound 128

To a solution of Compound 21 (100 mg) in dichloromethane (5 mL) was added TFA (1 mL). The mixture was stirred for 3 hours, and excess reagents were evaporated. The oil was diluted with EtOAc, and then was washed with saturated NasCCh solution (2x), water (2x), and brine, and dried over Na^SCh. Concentration gave Compound 128 (46 mg), m/z 267.1 (M+Hp Compound 129

Compound 129 (44 mg) was prepared following the procedure for Compound 8, except that Compound 128 was used instead of Compound 22. m/z 408.10 (M+H)⁺

Example CT

Example CJ (55 mg) was prepared following the procedure for Example C, except that Compounds 129 and 29 were used instead of Compounds 8 and 7.¹ Pl

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NMR (CDC13) δ 8,81 (1 H, s), 7.85 (1 H, s), 7.2-7.0 (11 H, m), 6.4 (1 H, m), 6.12 (1 H, m), 5.44 (2 H, m), 5.26 (2 H, s), 4,85 (1 H, m), 4.70 (1 H, m), 4.4 (3 H, m), 4.06 (1 H, m), 3.25 (1 H, m), 2.98 (3 H, s), 2.78 (4 H, m), 2.21 (1 H, m), 1.38 (6 H, m), 0.88 (6 H, m); m/z 703.2 (M+H)’

Preparation of Compounds CK and CL

Scheme 74

I. Cmpd B/EDC/HOBt; II. a. TFA; b. NaOH/THF

Example CK

Example CK (88 mg) was prepared following the procedure used to prepare Example C, except that Compound 49 was used instead of Compound 7. m/z 749,2 (M+H)' Example CL

A mixture of Example CK (85 mg) and TFA (5 mL) was stirred for 3 hours. Excess TFA was evaporated and the mixture was dried under high vacuum. The

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Concentration and purification by flash column chromatography (EtOAc) gave

Example CL (66 mg). Ή-NMR (CDC13) b 8.81 (1 H, s), 7.84 (1 H, s), 7.30-6.96 (11

H, m), 5.22 (2 H, s), 4.90 (1 H, m), 4.45 (I H, m), 4.35-4.0 (4 H, m), 3.8 (1 H, m), 3.6 (1 H, m), 3.21 (1 H, m), 2.95 (3 H, s), 2.8-2.6 (4 I ], m), 2.0-1,4 (4 H, m), 1.25 (6H, m).

m/z 693.2 (M+H)\

Preparation of Example CM

I. SOCI₂/MeOH; II. a. CDI/iPr₂NEt; b. Cmpd. 9; IILa. NaOH/THF/H₂O; b. HCi;

IV. Cmpd. 8/EDC/HOBt:

Compound 130

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Compound 130 is commercially available from (TCI), and was used as received.

Compound 131

To the solution of Compound 130 (510 mg, 3 mmol) in methanol (12 mL) at 0 °C was added thionyl chloride (0.5 mL, 6.6 mmol), dropwise. The mixture was stirred at 0 ^L’C for 30 minutes and brought to reflux for 3 hours. Concentration gave Compound 131 as a white solid.

Compound 132

To a stirred solution of Compound 131 (3 mmol) and di isopropylethyl amine (2 mL, 12 mmol) in di chloromethane (35 mL) was added CDI (486 mg, 3 mmol). The mixture was stirred for 12 hours. Compound 9 was added, and the mixture was stirred for 12 additional hours. Concentration and purification by flash column chromatography (CHiCL/iPrOH = 10/1) gave Compound 132 (414 mg), m/z 380.0 (M+H)’

Compound 133

Compound 133 was prepared following the procedure for Compound 67, except that Compound 132 was used instead of Compound 66. m/z 364.0(M-H) Example CM

Example CM (600 mg) was prepared following the procedure for Example C, except Compound 133 was used instead of Compound 7. ’H-NMR (CDCL3) b 9.18 (1 H, s), 8.35 (1 H, s), 7.95 (1 H, s), 7.6 (1 hl, m), 7.3-7.0 (11 H, m), 5.22 (2I I, m), 4.70 (1 H, m), 4.50 (2 H, m), 4.05 (1 El, m), 3.86 (3 H, s), 3.80 (2 H, m), 3.55 (1 H, m), 3.10 (1 H, m), 2.90 (3 H, s), 2.70 (4 H, in), 1.45 (10 H, m); m/z 757.3 (M+H)’

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Preparation of Examples Ο, P, CN, and CO

Scheme 76

CN R = Me

P R = H

CO R = Me

I. Cmpd. 16/iPr2NEt; II. Cmpd. 13d or Cmpd. 49/EDC/HOBt; 111. a. TFA; tr NaOHTHF

Example O

Example O (17 mg) was prepared following the procedure for· Example C, except Compounds 46 and 49 were used instead of Compounds 8 and 7. m/z 749.3 (M+H)’

Example CN

Example CN (22 mg) was prepared following the procedure used to prepare Example C, except Compounds 46 and 13e were used instead of Compounds 8 and 7. m/z 763.2 (M+I~iy Example P

Example P (12 mg) was prepared following the procedure used to prepare Example CL, except Example O was used instead of Example CK. Ή-NMR (CDCL?) b 8.76 (1 H, s), 7.79 (1 H, s), 7.257.9 (11 H, m), 6.51 (1 H, broad), 5.42 (1 II,

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m), 5.18 (2 H, m), 4.42 (2 H, m), 4.22 (1 H, m), 4.10 (1 H, m), 3.95 (1 H, m), 3.79 (1 H, m), 3.58 (1 H, m), 3.23 (1 H, m), 2.93 (3 H, s), 2.9-2,5 (4 H, m), 1.6-1.2 (10 H, m); m/z: 693.2 (M+H)\

Compound CO

Example CO (13 mg) was prepared following the procedure used to prepare Example CL, except Example CN was used instead of Compound CIG Ή-NMR (CDCL) δ 8.85 (1H, m), 7.88 (1 H, m), 7.3-7.0 (11 H, m), 6.55 (1 H, m), 6.24 (1 H, m), 5.45 (1 H, m), 5.23 (2 H, m), 4.6 (2 H, m), 4.2 (1 H, m), 4.0 (2 11, m), 3.7 (1 H, m), 3.5 (1 14, m), 3.02 (3 H, s), 2.70 (4 H, m), 1.6-1.0 (13 H, m); m/z: 707.3 (M+-H)*. Preparation of Examples CP-CS

Scheme 77

I. Cmpd. 16/iPr_zNEt; II. Cmpd. 13d or 49/EDC/HOBt; 111. a. TFA; b. NaOH/THF

Compound 134

Compound 134 was prepared using procedure described for Compound

76, except that CBZ-D-alaninol was used instead of CBZ-L-alaninol. ' 1

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2020203321 21 May 2020

Compound 135

Compound 135 was prepared following the procedure used to prepare Compound 8, except Compound 134 was used instead of Compound 22, Example CP

Example CP (12 mg) was prepared following the procedure used to prepare Example C, except Compounds 135 and 49 were used instead of Compounds 8 and Ί, m/z 597,2 (M+H)\ Example CO

Example CQ (11 mg) was prepared following the procedure used to prepare Example C, except Compounds 135 and 13d were used instead of Compounds 8 and 7. m/z 611,2 (M+H)'.

Example CR

Example CR (7 mg) was prepared following the procedure used to prepare Example P, except that Example CP was used instead of Example O . Ή-NMR (CDCh) b 8.82 (1 H, s), 7.88 (1 H, s), 7.02 (1 H, s), 6.92 (1 H, m), 5.28 (2 H, s), 5.10 (1 H, m), 4.5 (2 H, in), 4.15 (2 H, m), 3.88 (1 H, m), 3.8-3.5 (2 H, m), 3.35 (1 H, m), 3.0 (3 H, s), 1.5-1.0 (16 H, m); m/z: 541.1 (M+H)'.

Example C5

Example CS (8 mg) was prepared following the procedure used to prepare Example CO, except that Example CQ was used instead of Example CN. ΉNMR (CDCh) b 8.83 (1 H, s), 7.88 (1 H, s), 6.98 (1 H, s), 6.81 (1 H, m), 6.58 (1 H, m), 5.28 (2 14, s), 5.18 (1 11, m), 4.4M.3 (2 11, m), 4.03 (1 H, m), 3.85 (1 H, m), 3.58 (2 H, m), 3.3 (1 H, m), 2.99 (3 H, s), 1.5-0.98 (19 H, in); m/z: 555.2 (M+H)⁺.

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Preparation of Examples CT-CV

Scheme 78

R ,^χ-·\ _ HN /^X~\ ____!1 nh₂ nh

136 137 ^R

138

CT X = CH₂CH₂;R = H

CU X = CH₂CH₂; R= Bn CV X = CH₂; R = Bn

L PhCH0/NaBH₄; II. Cmpd 16/iPr₂NEt; II. Cmpd 13d/EDC/HOBt;

Compound 136

Compounds 136a-c are commercially available (Sigma-Aid rich). Compound 137

To a solution of Compound 136 (20 mmol) in methanol (25 mL) was added benzaldehyde (40 mmol) dropwisc. The mixture was stirred for 2 hours and was cooled to 0 ^QC. Sodium borohydride (44 mmol) was added in portions. The mixture was warmed to 25 °C and stirred for 2 hours. Acetic acid (10 mL) was added and the mixture was stirred for 10 minutes. Methanol was removed and the mixture was partitioned between EtOAc and 3 N NaOH solution. The organic layer was separated and water phase was extracted with EtOAc (2x). Tire combined organic layers was washed with water, brine., and dried over NaiSOi. Concentration gave Compound 137.

Compound. 138

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Compound 138 was prepared following the procedure used to prepare Compound 8, except that Compound 137 was used instead of Compound 22. Example CT

Example CT (70 mg) was prepared following the procedure used to prepare Example C, except that Compounds 29 and 138a was used instead of Compounds 7 and 8. .¹H-NMR (CDCh) b 8.79 (Ί H, s), 7.86 (1 H, s), 6.97 (1 H, s), 6.49 (Ί H, m), 6.15 (1 Id, m), 5.28 (2 Id, s), 5.20 (1 Id, m), 4.44 (2 Id, m), 4.05 (I H, m), 3.25 (5 H, m), 3.0 (3 H, s), 2.24 (I H, m), 1.8-1.45 (4 H, m), 1.38 (6 I I, m), 0.97 (6 H, m); m/z; 525.2 (M+H)¹.

Example CD

Example CU (140 mg) was prepared following the procedure used to prepare Example C, except that Compounds 29 and 138b was used instead of Compounds 7 and 8. Ή-NMR (CDCh) b 8.78 (1 H, s), 7.85 (1 H, m), 7,4-7.05 (10 H, m), 6.93 (1 H, s), 5.90 (1 I I, m), 5.35 (2 H, s), 4.9-4.6 (2 H, m), 4.6-4.4 (4 H, m), 4.2 (1 H, m), 3.4-3.05 (5 H, m), 3.0 (3 H, s), 2.0 (1 H, m), 1.8-1.3 (10 H, m), 0.90 (6 H, m); m/z: 705.2 (M+H)’.

Exam I e CV

Example CV (145 mg) was prepared following the procedure used to prepare Example C, except that Compounds 29 and 138c was used instead of Compounds 7 and 8. Ή-NMR (CDCh) b 8.76 (1 H, m), 7.86 (1 H, m), 7.4-7.02 (10 H, m), 6.97 (1 H, m), 5.75 (1 H, m), 5.38 (2 H, m), 4.95-4.3 (6 H, m), 4.15 (1 H, m), 3.4-3.0 (5 H, m),, 3.0 (3 H, s). 2.2-1,6 (3 H, m), 1.4 (6 H, m), 0.88 (6 H, m); m/z; 691.2(M+H)⁺.

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Preparation of Example CW

CW

Example CW could be prepared, e.g. by reacting Compound 8 with a compound having the following structure:

where LG is a leaving group such as a halogen. Such compounds could be prepared by one-carbon degradation of the corresponding carboxylic acid or ester (e.g., Compounds 28 or 29) by known methods such as the Hunsdieker reaction or the Kochi reaction or similar methods.

Preparation of Example CX

Scheme 79

I. a.TMSNCO/iPrjNEt/THF; b. MeOH Example R

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Example R (hydrochloride salt) was synthesized following the procedure described in WO 2008/010921 A2 (herein incorporated by reference in its entirety for all purposes) or as described above.

Example CX

To a suspension of Example R (hydrochloride salt) (150 mg, 0.2 mmol) in THF (2 mL) was added diisopropylethylamine (70 ·!, 0.4 mmol). The mixture was stirred until a clear solution was obtained. To this solution was added trimethylsilyl isocyanate (30 ·!, 0.22 mmol) dropwise, and the mixture was stirred for 12 hours. The solvent was removed and the mixture was coevaporated twice w^rith 5 mL of MeOH. Purification with preparative thin layer chromatography (preparative TLC) gave Example CX (86 mg), m/z: 749.2 (M+H)⁺. ^JH NMR (CD_?OD) δ 8.99 (s, 1H): 7.83 (s, 1H); 7.72 (m, 1H); 7.30-7.00 (m, 11H); 5.22 (s, 2H); 4.54 (s, 2H); 4.19 (s, TH); 4.07 (m, 1H); 3.75 (m, 1H); 3.28 (m, 1H); 3.30-2.90 (m, 2H); 2.97 (s, 3H); 2.71 (m, 4H); 1.79 (m, 2H); 1.50 (m, 4H); 1.38 (d, 6H, /=7 Hz). Preparation of Example CY

Scheme 80

I. diformylhydrazine/ pyridine/Et₃N/TMSCI/100 C

Example CY

To a solution of Example R (hydrochloride salt) (269 mg, 0.36 mmol) in pyridine (3 mL) was added diformylhydrazine (95 mg, 1.1 mmol), followed by

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2020203321 21 May 2020 chlorotrimethylsilane (2.7 mL) and tri ethyl amine (0.34 mL). The mixture was heated at 100 °C for 14 hours, and solvents were removed. The mixture was quenched with water, and extracted three times with EtOAc. The organic layer was dried over Na,SO₄ and concentrated to give a white solid. Purification by I-IPLC and preparative TLC (5% MeOH in di chloromethane.) gave Example CY (5 mg), m/z: 758.3 (M+H)'. Ή NMR (CD OD) ¢5 8.98 (s, IH); 8.50 (s, 2H); 7.83 (s, IH); 7.30-7.00 (m, 11H); 5.21 (s, 2H); 4.54 (m, 2H); 4.11 (m, 4H); 3.76 (m, IH); 3.28 (m, IH); 2.95 (s, 3H); 2.69 (m, 4H); 2.04 (m, 2H); 1.70-1.20 (m, 10H).

Preparation of Example CZ

Scheme 81

I. Methyl A-bromobutyrate/NaHCOa/DMF/SO C

Example CZ

To a suspension of Example R (hydrochloride salt) (200 mg, 0.27 mmol) and sodium bicarbonate (92 mg, 1.1 mmol) in DMF (2 mL) was added a solution of methyl 4-bromobutyrate (74 ·], 0.54 mmol) in DMF (1 mL). Hie mixture was heated at 65 °C for 20 hours and the solvent was removed under reduced pressure. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed three times with water, twice with sodium carbonate solution, and once with brine, and dried over Na₂SO.. Concentration followed by

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PCT/US2008/054788 purification using HPLC gave Example CZ as a white solid (23 mg), m/z: 774.3 (M+H)\ ¹H NMR (CD₃OD) ft 8.99 (s, 1H); 7.84 (s, 1H); 7.30-7.00 (m, UH); 5.22 (s, 2H); 4.55 (m, 2H); 4.09 (m, 2H); 3.90-3,60 (m, 1H); 3.55-3.10 (m, 5H); 2.98 (s, 3H); 2.71 (m, 4H); 2.37 (m, 2H); 2.04 (m, 2H); 1.81 (m, 2H); 1.70-1.20 (m, 10H).

Preparation of Example DA

Scheme 82

i. 2,5-dimethoxyTHF/NaOAc/HOAc/125 C

Example DA

To a suspension of Example R (hydrochloride salt) (250 mg, 0.34 mmol) in acetic acid (0.73 mL) was added sodium acetate (153 mg, 1.9 mmol), fallowed by 2,5-dimethoxyTHF (44 ·!, 0.34 mmol). The mixture was heated at 125 ^CC for 90 minutes, and the solvent was removed under reduced pressure. Ore residue was quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed sequentially with saturated NaHCO₃ solution, water, and brine, and dried over Na,SO₄. Concentration and purification by HPLC gave a white solid, which was further purified by preparative TLC to give Example DA (25 mg), m/z: 756.3 (M+H)’. Ή NMR (CD_:,OD) ft 8.96 (s, IH); 7.82 (s, 1H); 7.30-7.00 (m, 11H); 6.62 (s, 2H); 6.02 (s, 2H); 5.20 (s, 2H); 4.51 (s, 2H); 4.20-3.95

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PCT/US2008/054788 (m, 2H); 3.88 (m, 2H); 3.75 (m, 1H); 3.26 (m, 1H); 2.93 (s, 3H); 2.70 (m, 4H); 2.01 (m, 2H); 1.70-1.20 (m, 1 OH).

Preparation of Example DB

Scheme 83

1. NH₃-H2O/formaldehyde/glyoxal/n-PrOH/80 C

Example DB

To Example R (220 mg, 0.34 mmol) in propanol (1.9 mL) was added aqueous ammonia (39 mg, 0.34 mmol, 28-30%). The mixture was stirred for 5 minutes. To the above mixture was added a solution of glyoxal (53 mg, 0.37 mmol, 40%wt) and formaldehyde (30 mg, 0.37 mmol, 37%wt) in propanol (3.7 mL) dr op wise. The mixture was heated at 80 °C for 5 hours. The solvent was removed under reduced pressure, and tire residue was diluted with EtOAc. The organic layer was washed with water and brine, and dried over Na^SO,. Concentration of the organic layer and purification by HPLC gave Example DB as a white powder (101 mg), m/z: 757.3 (M+H). Ή NMR (CD.OD) δ 8.97 (s, 1H); 7.82 (s, 1H); 7.60 (s, 1H); 7.30-7.00 (m, 12H); 6.96 (s, 1H); 5.20 (s, 2H); 4.53 (m, 2H); 4.20-3.90 (m, 4H); 3.76 (m, 1H); 3.28 (m, 1H); 2.95 (s, 3H); 2.70 (m, 4H); 2.02 (m, 2H); 1.70-1.20 (m, 10H).

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Preparation of Example DC

Scheme 84

i. a. succinic anhydride/CH₂Cl2; b. Ac₂O/NaOAc Example DC

To a solution of Example R (220 mg, 0.34 mmol) in di chloromethane (1.5 mL) was added succinic anhydride (41 mg, 0.41 mmol). The mixture was heated at 45 ^OC for 12 hours. The solvent was removed and a white solid was dried under high vacuum. To this solid was added sodium acetate (10 mg, 0.12 mmol), followed by acetic anhydride (1.5 mL). Tire mixture was heated at 85 °C for 1 hour, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc, and was washed sequentially with water, saturated NaHCO,, water, and brine, and dried over Na.,SO₄. Concentration gave Example DC (190 mg), m/z: 788.2 (M+II)\ Ή NMR (CD,OD) δ 8.99 (s, 1H); 7.84 (s, 1H); 7.30-7.00 (m, 11H); 5.22 (s, 2H); 4.70-4.40 (m, 2H); 4.20-3.90 (m, 2H); 3.75 (m, 1H); 3.54 (m. 1H); 3.42 (m, 1H); 3.28 (m, 1H); 2.98 (s, 3H); 2.67 (m, 8H); 2.00 (m, II I); 1.81 (m, II J); 1.70-1.20 (m, 10H).

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Preparation of Example DD

Scheme 85

I. CF₃CH₂OSO₂CCI₃/NaHCO₃/DMF

Example DD

To a solution of Example R (220 mg, 0.34 mmol) in DMF (3 mL) was added sodium carbonate (100 mg), followed by 2,2,2-trifluoroethyl Lrichloromethancsulfonate (112 »1,0.68 mmol). The mixture was stirred for 3 days and the solvent was removed under reduced pressure. The residue was diluted with EtOAc. The organic layer was sequentially washed twice with saturated sodium carbonate solution, once with water, and once with brine, and dried over Na,SO₄. Concentration and purification by flash column chromatography (9% MeOH in dichloromethane) gave Example DD (109 mg), m/z: 788.2 (M+H)⁺. ‘H NMR (CD.OD) b 8.98 (s, IH); 7.82 (s, IH); 7.62 (d, IH, [=9 Hz); 7.30-7.00 (m, 11H); 6.85 (d, IH, /=9 Hz); 5.20 (m, 2H); 4.54 (s, 2H); 4.23 (m, Ί H); 4.11 (m, IH); 3.77 (m, IH); 3.31 (m, 2H); 3.12 (q, 2H, /=10 Hz); 2.95 (m, 3H); 3.80-2.50 (m, 6H); 1.77 (m, 2H); 1.70-1.20 (m, 10H). ”F NMR (CD.OD) · -73.28 (t, IH, /=10 Hz).

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Preparation of Example DE

Scheme 86

I. a. (MeS)₂C=NCN/EtOH; b. MeNH₂/EtOH

Example DE

To a clear solution of dimethyl N-cyanodithio iminocarb onate (50 mg, 0.34 mmol) in ethanol (0.5 mL) was added slowly a solution of Example R (220 mg, 0.34 mmol) in ethanol (2.5 mL·). The mixture was stirred for 12 hours. To the above mixture was added a solution of methylamine in EtOH (1.6 mL, 33%wt). The mixture was stirred for 6 hours, and solvents were removed under reduced pressure. Purification by HPLC gave Example DE (92 mg), m/z: 787.3 (M+H)⁺. Tri NMR (CDpD) b 8.98 (s, 1H); 7.83 (s, 1H); 7.30-7.00 (m, 11H); 5.21 (s, 211); 4.51 (s, 2H); 4.18 (m, 1H); 4.09 (m, 1H); 3.77 (m, 1H); 3.28 (m, 2H); 3.16 (m, 1.H); 2.97 (s, 3H); 2.80 (s, 3H); 2.715 (m, 4H); 1.84 (m, HI); 1.70 (m, 1H); 1.65-1.20 (m, 10H).

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Preparation of Examples DF-DG

Scheme 87

I. BrCH₂CH₂OH/Na₂CO₃/DMF/70 C; It. CDI/DMAP/THF/70 C

Example DF

To a solution of Example R (220 mg, 0.34 mmol) in DMF (1 mL) was added sodium carbonate (72 mg, 0.68 mmol), followed by a solution of 2-bromoethanol (24 ·!, 0.34 mmol) in DMF (0.4 mL). The mixture was heated at 70 °C for 12 hours. Concentration under high vacuum gave Example DF. m/z: 750.2 Example DG

To a suspension of Example DF (0.34 mmol) in THF (3.4 mL) w· as added carbonyldiimidazole (CDI) (83 mg, 0.51 mmol), followed by DMAP (4 mg). The mixture was heated at 70 ³C for 3 hours, and the solvent was removed. The residue was diluted with EtOAc, and was washed with water and brine, and

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PCT/US 2008/054788 dried over Na₂SO„. Concentration and purification with preparative TLC gave Example DG (83 mg), m/z: 776.2 (M+H)⁴. *H NMR (CQOD) & 8.98 (s, 1H); 7.83 (s, 1H); 7.67 (m, 1H); 7.30-7.00 (m, 11H); 6.87 (m, 1H); 6.49 (m, 1H); 5.21 (s, 2H); 4.704.40 (m, 2H); 4.34 (t, 2H, /=8 Hz); 4.18 (m, 1H); 4.06 (m, 1H); 3.76 (m, 1H); 3.60 (t, 2H, /=8 Hz); 3.24 (m, 3H); 2.97 (s, 3H); 2.71 (m, 4H); 1.86 (m, 2H); 1.70-1.20 (m, 10H).

Preparation of Example PH

Scheme 88

I. diformyl hydrazine/ pyridine/EtsN/TMSCI/IOQ C

Example W

Example W was synthesized following the procedure described in W02008/010921 A2, and as described above in Scheme 25.

Example DH

Example DH (100 mg) was prepared following the procedure used to prepare example CY, except that Example W was used instead of Example R. H NMR (CD.OD): h 8.97 (s, 1H), 8.40 (s, 2H), 7.81 (s, 1H), 7.15 (m, 10H), 5.20 (s, 2H), 4.54 (m, 211), 4.20 (m, 1H), 4.07 (m, 1H), 3.87 (m, 3H), 3.24 (m, 1H), 2.95 (s, 3H), 2.85 (m, 1H), 2.60 (m, 3H), 1.81 (m, 2H), 1.604.43 (m, 4H), 1.33 (d, J=7.2 Hz, 6H). Mass Spectrum (πι/e): (M+H)' 758.2, (M-H)' 755.9.

Preparation of Example DI

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Scheme 89

1. Methyl Abromabutyrate/NaHCOj/DMF/eO C Example DI

Example DI (28 mg) was prepared following the procedure used to prepare Example CZ, except that compound W (160 mg) was used instead of Example R. m/z: 774.2 (M+H)’. Ή NMR (CD₃OD) δ 8.97 (1 H, s), 7,81 (1 H, s), 7.24-7.02 (11 H, m), 5.20 (2 H, s), 4.54 (2 H, m), 4.18 (1 H, m), 4.0 (1 H, m), 3,75 (1 H, m), 3.20 (4 H, m), 3.01 (1 H, m), 2.99 (3 H, s), 2.8-2.5 (4 H, m), 2.38 (2 H, m), 2.04 (2 I I, m), 1.62-1.40 (6 H, m), 1.31 (6 H, m).

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Preparation of Example DI

Scheme 90

I. NH₃-H₂O/formaldehyde/glyoxal/n-PrOH/80 C Example DI

Example DJ (44 mg) was prepared following the procedure used to prepare Example DB, except that Example W (160 mg) was used instead of Example R. m/z: 757.3 (M+H)’. Ή NMR (CD,OD) f) 8.97 (1 H, s), 7.83 (1 11, s), 7.50 (1 H, s), 7.25-7Ό4 (11 H, m), 6.99-6.96 (2 H, m), 5.20 (2 H, s), 4.52 (2 H, m), 4.20 (1 H, m), 4.03 (1 H, m), 3.78 (3 H, m), 3.22 (1 H, m), 2.95 (3 H, s), 2.9-2.4 (4 H, m), 1.8 (2 Η, m), 1.7-1,4 (4 H, m), 1.31 (6 H, m).

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Preparation of Examples DK-DL

Scheme 91

I. BrCH₂CH₂OH/Na₂CO₃/DMF/70 C; II. CDI/DMAP/THF/70 C

Example DK

Example DK was prepared following the procedure used to prepare Example DF, except that Example W (160 mg) was used instead of Example R. Example DL

Example DL (28 mg) was prepared following the procedure used to prepare Example DG, except that Example DK was used instead of Example DF. m/z: 776.2 (M+H)\ Ή NMR (CD.OD) & 8.97 (1 H, s), 7.81 (1 H, s), 7.25-7.05 (Π H, m), 5.20 (2 H, s), 4.55 (2 H, m), 4.31 (2 H, m), 4.2-4.0 (2 H, m), 375 (1 H, m), 3.44 (2 H, m), 3.3-3.0 (3 H, m), 2.98 (3 H, s), 2.8-2.4 (4 H, m), 17-1.4 (6 H, m), 1.32 (6 H, m). Preparation of Examples DM(a-c)

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Scheme 92

139a

139b

139c

140b

140c

DM(b)

DM(c)

in ^139a

140a

138a

DM(a)

138b in ^139b140b

DM(b)

138c in 139c

140c

DM(c)

I. EDC/HOBl/DIPEA/THF; 11. HCI/diaxane; III. a. CDI/DIPEA; b. empd 9/DIPEA

Compound 8

Compound 8 was synthesized following the procedure described in W02008/010921 A2, and as described above.

Compounds 138a/138b/138c

Compounds 138a, 138b, and 138c were obtained from Aldrich.

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Compound 139a

To a solution of acid 138a (266 mg, 1.0 mmol) and amine 8 (409 mg, 1.0 mmol) in THF (10 mL) were added HOBt (203 mg, 1.5 mmol), EDC (294 “1, 2.0 mmol), and diisopropylethylamine (0.835 mL, 4.0 mmol). The mixture was stirred for 12 hours and the solvents were removed. The residue was diluted with EtOAc. The organic phase was washed three times with saturated NJa.,CO, solution, twice with water, and once with brine, and dried over Na,SO₄. Concentration and purification by flash column chromatography (0%-10% MeOH in dichloromethane) gave Compound 139a ¢509 mg), m/z: 658.1 (M+H)⁺. Compound 139b

Compound 139b (543 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 138b was used instead of Compound 138a. m/z: 658.1 (M+H)\ Compound 139c

Compound 139c (587 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 138c was used instead of Compound 138a. m/z; 658.2 (M+H)⁺. Compound 140a

To Compound 139a (500 mg) was added 10 mL of HC1/dioxane solution (4N, 40 mmol). The mixture was stirred for 1 hour, and the solvents were removed. The residue was diluted with diethyl ether, and stirred for 1 hour. The diethyl ether layer was decanted. The solid was washed with diethyl ether (2x) and dried under vacuum. The resulting Compound 140a was a brown powder (520 mg), m/z: 558.3 (M+H)’. Compound 140b

Compound 140b (476 mg) was prepared following the procedure used to prepare Compound 140a, except that Compound 139b was used instead of Compound 139a. m/z: 558.2 (M+H)¹.

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Compound 140c

Compound 140c (536 mg) was prepared following the procedure used to prepare Compound 140a, except that Compound 139c was used instead of Compound 139a. m/z; 558.3 (M+H)'. Compound 9

Compound 9 was synthesized following the procedure described in W020D8/010921 A2. Example DM (a)

To the stirred solution of Compound 140a (520 mg, 0.75 mmol) and diisopropy] ethylamine (0.52 mL, 3.0 mmol) in di chloromethane (6 mL) was added CDI (122 mg, 0.75 mmol). The mixture was stirred, for 12 hours. To this mixture was added a solution of Compound 9 (128 mg, 0.75 mmol) in di chloromethane (2 mL), and the mixture was stirred for 5 additional hours. The solvents wore removed, and the residue was diluted with EtOAc. The organic layer was washed twice with water and once with brine, and dried over Na,SO₄. Concentration and purification by HPLC gave Example DM(a) (270 mg), m/ z; 754.3 (M+H)^T. ‘H NMR (CD.OD) b 8.97 (s, 111); 8.41 (m, 111); 7.82 (s, 111); 7.70 (m, 2H); 7.30-7.00 (m, 11H); 6.99 (s, 1H); 5.21 (s, 2H); 4.56 (m, 1H); 4.48 (s, 2H); 4.02 (m, 1H); 3.72 (m, 1H); 3.28 (m, 1H); 3.15-2.90 (m, 2H); 2.93 (s, 3H); 2.68 (m, 4H); 1.60-1.30 (m, 10H). Example DM(b)

Example DM(b) (36 mg) was prepared following the procedure used to prepare Example DM(a), except that Compound 140b was used histead of Compound 140a. m/z: 754.3 (M+H)⁺. ^JH NMR (CD,OD) & 8.97 (s, 1H); 8.38 (m, 2H); 7.83 (s, 111); 7.68 (m, 1H); 7.33 (m, 111); 7.30-7.00 (m, 10H); 6.96 (s, 1H); 5.21 (s, 2H); 4.45 (m, 3H); 4.01 (m, 1H): 3.72 (m, 1.H); 3.28 (m, 1H); 3.15-2.90 (m, 2H); 2.90 (s, 3H); 2.68 (m, 4H); 1.60-1.30 (m, 10H). Example DM(c)

Example DM(c) (283 mg) was prepared following the procedure used to prepare Example DM(a), except that Compound 140c was used instead of Compound 140a. m/z: 754.3 (M+H)2 Ή NMR (CD^OD) δ 8.97 (s, 1H); 8.39 (d, 211,

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M Hz); 7.82 (s, 1H); 7.27 (d, 2H, >6 Hz); 7.30-7.00 (m, 10H); 6.94 (s, 1H); 5.21 (s, 2H); 4.53 (m, 1H); 4.45 (s, 2H); 4.03 (m, 1H); 3.74 (m, 1H); 3.32 (m, 1H); 3.10-2.90 (m, 2H); 2.90 (s, 3H); 2.72 (m, 4H); 1.60-1.30 (m, 10H).

Preparation of Example DN

Scheme 93

I. SOCI₂'MeOH; II. a. CDI/iPr₂NEt; b. cmpd 9; lll.a. NaOH/THF/H₂O; b. HCI;

IV. cmpd 8/EDC/HOBt;

Compound 141

Compound 141 was obtained from TCI.

Compound 142

To a solution of Compound 141 (1.0 g, 6.4 mmol) in methanol (20 mL) at 0 °C was added thionyl chloride (1.0 mL, 14.2 mmol) dropwise. The mixture was stirred at 0 °C for 30 minutes and brought to reflux for 3 hours. Concentration gave Compound 142 as a white solid.

Compound 143

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Compound 143 (1.68 g) was prepared following the procedure used to prepare Example DM(a), except that Compound 142 was used instead of Compound 140a. m/z: 366.0 (M+H)⁺.

Compound 144

To a solution of Compound 143 (1.68 g, 4.8 mmol) in MeOH/H,O (20 mL/20 mL) at 0 °C was added sodium hydroxide (229 mg, 5.74 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. Hydrochloric acid in dioxane (1.5 mL, 4N,6 mmol) was added, and the mixture was evaporated and dried under high vacuum. Compound 144 was obtained as a white solid (1.8 g).

Example DN

Example DN (260 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 144 was used instead of Compound 138a. m/z: 743.2 (M+H)'. ‘H NMR (CDCIJ & 8.78 (1 H, s), 7.81 (1 H, s), 7.44 (1 H, s), 7.39 (1 H, s), 7.3-7.0 (10 H, m), 6.95 (2 H, m), 6.7 (1 H, br), 6.2 (1 H, m), 5.3 (1 H, m), 5.2 (2 H, m), 4.5M.2 (5 H, m), 4.1 (1 H, m), 3.70 (1 H, m), 3.22 (1 H, m), 2.96 (3 H, s), 2.8-2.5 (4 H, m), 1.5-1.2 (10 H, m).

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Preparation, of Example DO

Scheme 94

I. EDC/HOBt;

Compound 46

Compound 46 was synthesized following the procedure described in W02008/010921 A2, Example DO

Example DO (215 mg) was prepared following the procedure used to prepare Compound 139a, except that Compounds 144 and 46 were used instead of Compounds 8 and 138a, m/z: 743.2 (M+H)^k. Ή NMR (CD^OD) & 8.97 (s, 1H); 7.82 (s, 1 FI); 7.45 (s, 1H); 7.30-7.00 (m, 13H); 6.19 (s, 1H); 5.20 (s, 2H); 4.60-4.40 (m, 2H); 4.21 (in, 2H); 4.09 (m, 1H); 3.25 (m, 1H); 2.93 (s, 3H); 2.90-2.50 (m, 5H); 1.701.20 (m, 10H).

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Preparation of Examples DP-DT

Scheme 95

OH

DS DT

I. RNH₂/EDC/HOBt;

Example AF

Example AF was synthesized following the procedure described in W02008/010921 A2, and as described above in Scheme 27.

Exiimpie DP

Example DP (23 mg) was prepared following the procedure used to prepare Compound 139a, except that Example AF and 2-aminopyridine were used instead of Compounds 8 and 138a. m/z: 797.2 (M+H)’. Ή NMR (DMSO-d₆) b 10.45 (1H, s), 9.06 (1 H, s), 8.31 (1 FI, m), 8.04 (1 H, m), 7.85 (1 H, m), 7.75 (1 H, m), 7.55 (1 H, m); 7.2-7.0 (13 H, m), 6.54 (1 H, m), 5.12 (2 H, s), 4.52 (1 H, m), 4.43 (2 H, s), 3.93 (1 H, m), 3.58 (1 H, m), 3.17 (1 H, m), 2.85 (3 H, s), 2.8-2.4 (6 H, m), 1.36 (4 Fl, m), 1.25 (6 H, m).

Example DQ

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Example DQ (32 mg) was prepared following the procedure used to prepare Compound 139a, except that Example AF and 3-aminopyridine were used instead of Compounds 8 and 138a. m/z; 797.2 (M+H)*. H NMR (DMSO-d6) b 10.39 (IH, s), 9.06 (1 H, s), 8.88 (1 11, s), 8.36 (1 H, m), 8.18 (1 H, m), 7.85 (1 H, s), 7.54 (2 H, m), 7.2-7.0 (12 H, m), 6.60 (1 H, m), 5.14 (2 H, s), 4.55 (1 H, m), 4.45 (2 H, s), 4.0-3.5 (2 H, m), 3.19 (1 H, m), 2.86 (3 H, s), 2.8-2.4 (6 H, m), 1.37 (4 H, m), 1.26 (6 H, m). Example DR

Example DR (30 mg) was prepared following the procedure used to prepare Compound I39a, except that Example AF and 4-amino pyridine were used instead of Compounds 8 and 138a. m/z; 797.3 (M+H)'. Ή NMR (DMSO-d6) b 11.24 (1 H, s), 9.05 (1 H, s), 8.61 (2 H, d, J = 6.3 Hz), 7.96 (2 H, d, J = 6.3 Hz), 7.84 (1 H, s), 7.58 (1 H, m), 7.2-7.0 (12 H, m), 6.65 (1 H, m), 5.14 (2 H, s), 4.6 (1 H, m), 4.46 (2 H, s), 3.9 (1 H, m), 3.4 (1 H, m), 3.20 (1 Fl, m), 2.87 (3 II, s), 2.7-2.4 (6 Ii, m), 1.37 (4H, m), 1.25 (6H,m).

Example DS

Example DS (50 mg) was prepared following the procedure used to prepare Compound 139a, except that Example AF and 1-aminopyrrolidine were used instead of Compounds 8 and 138a. m/z: 789.2 (M- 11) . FI NMR (DMSO-d6) ft 9.06 (1 H, s), 8.63 (1 H, s), 8.26 (1 H, s), 7.85 (1 H, s), 7.55 (1 H, m), 7.35 (1 H, m), 7.2-7.0 (10 H, m); 6,40 (1 H, m), 5.15 (2 H, s), 4.55-4.30 (3 H, m), 3.85 (1 H, m), 3.63 (1 H, m), 3.4-3.1 (5 H, m), 2.86 (3 H, s), 2.8-2.4 (6 H, m), 1.66 (4 H, m), 1.4-1.2 (10 H, m).

Example DT

Example DT (50 mg) was prepared following the procedure used to prepare Compound 139a, except that Example AF and methanesulfonamide were used instead of Compounds 8 and 138a. m/z: 798.2 (M+H)¹. ^lH NMR (DMSO-d6) b 11.65 (1 H, s), 9.10 (1 1I, s), 7.88 (1 H, s), 7.50 (1 H, m), 7.2-7.0 (12 H, m), 6.6 (1 H, m), 5.15 (2 H, s), 4.5-4,4 (3 H, m), 4.0-3.4 (2 H, m), 3.20 (1 H, m), 3.15 (3 H, s), 2.85 (3 H, s), 2.7-2.4 (6 H, m), 1.4-1.2 (10 H, m).

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Preparation of Examples DU(a-c)

Scheme 96

. 146c 'ⁿ 147c

DU(c)

I. TMSI/EtOH/DCM; II. amino alcohol/DCM; 111. a. NaOH/THF/H₂O; b. HCI;

IV. empd 8/EDC/HOBt/DIPEA/DMF

Compound 122

Compound 122 was synthesized following the procedure described in W02008/010921 A2, and as described above in Scheme 69.

Compound 145

To a solution of Compound 122 (1.0 g, 4 mmol) in dichloromethane (5 mL) was added ethyl alcohol (1.5 mL, 25.6 mmol), followed by iodotrimcthylsilane (2 mL, 14.3 mmol). The mixture was stirred for 6 hours and the mixture was used directly for the next step, m/z: 453.9 (M+H)'.

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Compound 146a

To a solution of Compound 1.45 (1 mmol) in dichloromethane (2 mL) was added a solution of (R)-3-hydroxypyrrolidine (435 mg, 5 mmol) in dichloromethane (1 mL). The mixture was stirred for 12 hours and the solvents were removed under reduced pressure. Purification by flash column chromatography (0-20% MeOH in dichloromethane) gave Compound 146a (230 mg), m/z: 413.1 (M+H)⁺.

Compound 146b

Compound 146b (200 mg) was prepared following the procedure used to prepare Compound 146a, except that compound (S)-3-hydroxypyrrolidine was used instead of compound (R)-3-hydroxypyrrolidine. m/z: 413.1 (M+H)¹. Compound 146c

Compound 146c (380 mg) was prepared following the procedure used to prepare Compound 146a, except that compound 4-hydroxypiperidine was used instead of compound (R)-3-hydroxypyrrolidine. m/z: 427.1 (M+H)'. Compound 147a

Compound 147a (250 mg) was prepared following the procedure used to prepare Compound 144, except that Compound 146a was used instead of Compound 143.

Compound 147b

Compound 147b (210 mg) was prepared following the procedure used to prepare Compound 144, except that Compound 146b was used instead of Compound 143.

Compound 147c

Compound 147c (400 mg) was prepared following the procedure used to prepare Compound 144, except that Compound 146c was used instead of Compound 143.

Example DU(a)

Example DU(a) (250 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 147a was used instead of

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Compound 138a. m/z; 776.3 (M+H) . Ή NMR (CD..OD) δ 8.97 (1 H, s), 7.81 (1 H, s), 7.25-7.05 (11 H, m), 5.19 (2 H, m), 4.54 (2 H, m), 4.25 (1 H, m), 4.2-4.1 (2 H, m), 3.75 (1 H, m), 3.22 (1 H, m), 2.94 (3 H, s), 2.8-2.7 (6 H, m), 2.5-2.3 (4 H, m), 2.1-1.8 (2 H, m), 1.7-1.4 (6 H, m), 1.37 (6 H, m).

Example DU(b)

Example DU(b) (Z53 mg) was prepared following the procedure used to prepare Compound 139a, except that compound 147b was used instead of Compound 138a. m/z: 776.3 (M+H)⁺. Ή NMR (CD3OD) δ 8.97 (1 H, s), 7.81 (1 H, s), 7.22-7.05 (11 H, m), 5.18 (2 H, m), 4.5 (2 H, m), 4.25 (1 H, m), 4.2-4.1 (2 H, m), 3.78 (1 H, m), 3.25 (1 H, m), 2.95 (3 H, s), 2.8-2.6 (6 H, m), 2.6-2.3 (4 H, m), 2.1 -1.8 (2 H, m), 1.8-1.4 (6 H, m), 1.37 (6 H, m).

Example DU(c)

Example DU(c) (450 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 147c was used instead of Compound 138a. m/z: 790.3 (M+H)^h. Ή NMR (CD3OD) & 8.97 (1 ί I, s), 7.81 (1 H, s), 7.25-7.05 (11 H, m), 5.20 (2 H, m), 4.54 (2 H, m), 4.2-4.0 (2 H, m), 3.75 (1 H, m), 3.58 (1 H, m), 3.25 (1 H, m), 2.97 (3 H, s), 2.8-2,6 (6 H, m), 2.25 (2 H, m), 2.08 (2 H, m), 1.9-1.6 (4 H, m), 1.6-1.4 (6 H, m), 1.38 (6 H, m).

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Preparation of Example DV

Scheme 97

OH

I· SO₃-pyridlne/Et₃N/DMSO

Example DV

A mixture of Example DU(c) (230 mg, 0.29 mmol) and triethylamine (0.14 mL) in DMSO (1 mL) was stirred at 25 °C for 30 minutes, and then was cooled to 5-10 ^CC. Sulfur trioxide pyridine complex (0.17 g) was added to above reaction mixture and the mixture was stirred for 1 hour at 5-10 °C. The mixture was poured into ice water, and stirred for 20 minutes, and was extracted with EtOAc. The organic phase was washed twice with water, twice with saturated NJaHCO._;solution, twice with water, and once with brine, and dried over Concentration and purification by flash column chromatography (0-20% MeOH in dichloro methane) gave Example DV (67 mg), m/z: 788.3 (M+H). ^lH NMR (CDClj b 8.78 (1 H, s), 7.81 (1 H, s), 73-7.1 (W H, m), 6.90 (1 H, s), 6.5 (1 H, br), 5.35 (1 H, m), 5.22 (2 H, s), 4,4-4.0 (4 H, m), 3.78 (1 H, m), 3.23 (1 H, m), 2.93 (3 H, s), 2.8-2.5 ( 8 H, m), 2.4-2.2 (6 H, m), 2.0-1.4 (6 H, m), 1.32 (6 H, m).

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Preparation of Example DW

Scheme 98

I. SO₃-pyridine/Et₃N/DMS0

Example DW

Example DW (78 mg) was prepared following the procedure used to prepare Example DV, except that Example DU(a) was used instead of Example DU(c). m/z: 774.3 (M+H)’. Ή NMR (CDC1J b 8.78 (1 H, s), 7.82 (1 H, s), 7.3-7.0 (10 H, m), 6.89 (1 H, s), 6.55 (1 H, br), 5.40 (1 H, m), 5.21 (2 H, s), 4.54.2 (3 H, m), 4.15 (1 H, τη), 3.78 (1 H, m), 3.23 (1 H, m), 3.1-2.9 (4 H, m), 2.9 (3 H, s), 2.8-2.5 (6 H, m), 2.40 (2 H, m), 1.90 (2 11, m), 1.55 (2 H, m), 1.38 (8 H, m).

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Preparation of Examples DX(a-f)

Scheme 99

O

R ^OBn ¹¹

R

Ac . 148a

R = [ J ^ln 149a

N DX{a) uvw 1 . 148d

R = I J ^In 149d DX(d)

SO₂Et _R rA , 1«»

J in 149b ^t< DX(b)

ΛΛΛ/

I b148e in 149e

N DX(e)

DX{a)

DX(b)

DX(c)

DX(d)

DX(e)

DX(f)

OF-,

148c in 149c

DX(c)

ΚΑΛΛΓ

F a_F 148f in 149f

N DX(f)

I. amine/NaBH(OAc)₃/AcOH/CH₃CN; II. a. NaOH/EtOH/H₂O; b. HCl;

III.compound 8/EDC/HOBt/DIPEA

Compound 60

Compound 60 was synthesized following the procedure described in WO2008/010921 A2, and as described above in Scheme 23.

Compound 148a

To a solution of Compound 60 (800 nig, 2 mmol) in CH₃CN (8 mL) was added a solution of l-acetylpiperazinc (512 mg, 4 mmol) in CH,CN (1 mL),

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Compound 148b (530 mg) was prepared following the procedure used to prepare Compound 148a, except that l-ethylsulfonylpiper azine was used instead of 1-acetylpiperazine, m/z: 566.1 (M+H)/ Compound 148c

Compound 148c (384 mg) was prepared following the procedure used to prepare Compound 148a, except that 4-tri fluor omethylpi peri dine was used instead of 1-acetylpiperazine. m/z: 541.2 (M+H)’.

Compound 148d

Compound 148d (342 mg) was prepared following the procedure used to prepare Compound 148a, except that 4, 4-dif]uoropiperidine was used instead of l-acetylpiperazine. m/z: 509.1 (M+LI)'.

Compound 148e

Compound 148e (320 mg) was prepared following the procedure used io prepare Compound 148a, except that 4-fliioropiperidine was used instead oflacetylpip era zine, m/z: 491.1 (M+H)*.

Compound 148f

Compound 148f (389 mg) was prepared following the procedure used to prepare Compound 148a, except that 3,3-difluoropiperidme was used instead of 1-acetylpiperazine. m/z: 509.1 (M+H)*.

Example 149a

To a solution of Compound 148a (250 mg, 0.48 mmol) in ethyl alcohol (3 mL) was added 1.0 N sodium hydroxide solution (0.53 mL, 0,53 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. 4.0 N Hydrochloric acid in dioxane (0.13 mL, 0.52 mmol) was added,

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2020203321 21 May 2020 and the mixture was evaporated. Coevaporation with DMF (2x100 mL) gave Compound 149a, which was used without further purification in the next step. Example 149b

Compound 149b was prepared following the procedure used to prepare Compound 149a, except that Compound 148b was used instead of Compound 148a.

Example 149c

Compound 149c was prepared following the procedure used to prepare Compound 149a, except that Compound 148c was used instead of Compound 148a,

Example 149d

Compound 149d was prepared following the procedure used to prepare Compound 149a, except that Compound 148d w*as used instead of Compound 148a.

Example 149e

Compound 149e was prepared following the procedure used to prepare Compound 149a, except that Compound 148e was used instead of Compound 148a.

Example 149f

Compound 149f was prepared following the procedure used to prepare Compound 149a, except that Compound 148f was used instead of Compound 148a.

Example DX(a)

Example DX(a) (90 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 149a was used instead of Compound 138a. m/z: 817.3 (M+H)'. Ή NMR (CDC1.) · 8.78 (1 H, s), 7.81 (1 H, s), 7.3-7.0 (10 H, m), 6,90 (1 H, s), 6,40 (1 H, m), 5.40 (1 H, m), 5.22 (2 H, s), 4.6-4.3 (2 H, m), 4.3-4.1 (2 H, m), 3.78 (1 H, m), 3.5-3.2 (5 H, m), 2.92 (3 H, s), 2.9-2.6 (4 H, m), 2.4-2.2 (6 H, m), 2.07 (3 H, s), 1.9 (2 H, m), 1.6-1.3 (10 H, m).

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Example DX(b)

Example DX(b) (150 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 149b was used instead of Compound 138a. m/z: 867.3 (M+H)\ Ή NMR (CDCL_?) · 8.78 (1 H, s), 7.81 (1 H, s), 7.3-7.0 (10 H, m), 6.92 (1 H, s), 6.4 (1 H, br), 5.35 (1 H, br), 5.2 (2 H, s), 4.6-4.0 (4 H, m), 3.78 (1 H, m), 3.3-3.1 (5 H, m), 2.92 (5 H, m), 2.8-2.6 (4 El, m), 2.5-2.2 (6 H, m), 1.90 (2 H, in), 1.6-1.3 (13 H, m).

Example DX(c)

Example DX(c) (427 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 149c was used instead of Compound 138a. m/z: 842.2 (M+H)'. Ή NMR (CDC1J · 8.77 (1 H, s), 7.80 (1 H, s), 7.3-7.0 (10 H, m), 6.88 (1 H, s), 6.40 (1 H, br), 5.50 (1 H, br), 5.20 (2 H, m), 4.7-4.3 (2 H, m), 4.18 (2 H, m), 3.75 (1 H, m), 3.23 (1 H, m), 3.05-2.8 (4 II, m), 2.8-2.6 (4 H, m), 2.25 (2 H, m), 2.0-1.65 (6 II, m), 1.6-1.2 (14 I I, m).

Example DX(d)

Example DX(d) (390 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 149d was used instead of Compound 138a. m/z: 810.2 (M+H). Ή NMR (CDCL) · 8.78 (1 H, s), 7.81 (1 H, s), 7.4-7.0 (10 H, m), 6.89 (1 H, s), 6.40 (1 H, br), 5.40 (1 H, br), 5.22 (2 H, m), 4.6-4.3 (2 11, m), 4.22 (2 H, m), 3.78 (1 H, m), 3.24 (1 H, m), 3.0-2.6 (7 H, m), 2.5 -2.2 (6 H, in), 2.0-1.7 (6 H, m), 1.6-1.2 (10 H, m).

Example DX(e)

Example DX(e) (160 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 149e was used instead of Compound 138a. m/z: 792.3 (M+H)’. Ή NMR (CDC1J · 8.77 (1 H, s), 7.81 (1 H, s), 7.3-7.0 (10 H, m), 6.87 (1 H, s), 6.45 (1 H, br), 5.55 (1 H, br), 5.20 (2 H, m), 4.9-4.3 (3 H, m), 4.3-4.1 (2 H, m), 375 (1 H, m), 3.25 (1 H, m), 3.1-2.8 (5 H, m), 2.8-2.6 (4 11, m), 2.6-2.1 (6 H, in), 2.0-1.4 (8 H, m), 1.37 (6 H, m).

Example DX(f)

Example DX(f) (480 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 149f was used instead of

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Compound 138a. m/z: 810.2 (M+H)⁺. Ή NMR fCDCl,) - 8.77 (I H, s), 7.80 (1 H, s), 7.3-7.0 (10 H, m), 6.93 (1 H, br), 6.84 (1 H, s), 6.40 (1 H, br), 5.50 (1 II, br), 5.20 (2 H, m), 4.5-4.3 (2 H, m), 4.3-4.I (2 H, m), 3.75 (1 H, m), 3.24 (I H, in), 3.05-2.8 (5 H, m), 2.8-2.6 (4 H, m), 2.5-2.2 (6 H, m), 2.0-1.75 (4 H, m), 1.7-1.37 (10 H, m).

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Preparation of Example DY

Scheme 100

156

1. Boc₂0/THF; ILNaOMe/MeOH: 111 SO₃-pyridine/DMSO/Et₃N;

IV. thiomQrpholine/NaBH(OAc)₃/HOAc; V. 4-methylmorpholine N-oxide/OsO^ V). HCI; VII, a. CDI; b. cmpd 9; VIII. a. NaOH; b. HCI;

IX. EDC/HOBi/cmpd B

Compound 150

Compound 150 was obtained from Aldrich.

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Compound 151

To a suspension of Compound 150 (25 g, 137 mmol) in THF (400 mL) was added tricthylamine (21 mL, 151 mmol), followed by Boc_;O (31.5 g, 144 mmol). The mixture was stirred for 48 hours, and the solvents were removed. The residue was diluted with EtOAc, and washed twice with saturated sodium carbonate solution, once with water, and once with brine, and dried over Na,SO₄, Concentration gave Compound 151 (25 g).

Compound 152

To a solution of Compound 151 (2.0 g, 10 mmol) in MeOFl (20 mL) at 0 C was added 4.4 N sodium methoxide solution in methanol (0.46 mL, 2 mmol). The mixture was stirred for 45 minutes, and quenched with saturated NH.C1 solution. The solvent was evaporated, and the residue was diluted with EtOAc. The organic phase -was washed with saturated NH^Cl solution, water, and brine, and dried over Na,SO^. Concentration gave Compound 152 (2.6 g).

Compound 153

Compound 153 (1.9 g) was prepared following the procedure used to prepare Example DV, except that Compound 152 was used instead of Example DU(c).

Compound 154

Compound 154 (1.65 g) was prepared following the procedure used to prepare Compound 148a, except that Compound 153 and 4-thiomorpholine were used instead of Compound 60 andl-acetylpiperazine.

Compound 155

To a solution of Compound 154 (1.55 g, 4.86 mmol) in acetone/water (270 mL/70 mL) was added 4-methyImorpholine N-oxide (1.25 g, 10 mmol), followed by OsOj/tBuOH solution (6.8 mL, 2.5%). The mixture was stirred for 12 hours and the solvents were removed under reduced pressure. Purification by flash column chromatography (60-100% EtAOc in hexanes) gave Compound 155 (1.44 g)Compound 156

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Compound 156 was prepared following the procedure used to prepare Compound 140a, except that Compound 155 was used instead of Compound 139a.

Compound 157

Compound 157 (660 mg) was prepared following the procedure used to prepare Example DM (a), except that Compound 156 was used instead of Compound 140a. m/z; 447.0 (M+H)'.

Compound 158

Compound 158 was prepared following the procedure used to prepare Compound 144, except that Compound 157 was used instead of Compound 143. m/z: 433.1 (M+H)⁺.

Example DY

Example DY (350 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 158 was used instead of Compound 138a. m/z: 824.2 (M+H)\ 'HNMR (CDC1,) · 8.80 (1 H, s), 7.82 (1 H, s), 7.2-7.0 (10 H, m), 6.96 (1 H, s), 6.71 (1 H, br), 6.4 (1 H, br), 5,21 (2 H, m), 5.15 (1 H, br), 4.5-4.1 (4 H, m), 3.80 (1 H, m), 3.22 (1 H, m), 3.0-2.8 (11 H, m), 2.8-.2.6 (4 H, m), 2.47 (2 H, m), 2.0-1.7 (2 H, m), 1.6-1.3 (Ί 0 H, m).

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Preparation of Examples DZ-EA

Scheme 101

I. NaCN/(NH₄)₂CO₃/EtOH/H₂O/90 C; II, EDC/HOBVcmpd 8

Compounds 159/160

To a solution of Compound 60 (1.6 mmol) in EtOH/H,O (1.6 inL/1.6 mL) was added ammonium carbonate (600 mg, 6.4 mmol), followed by sodium cyanide (158 mg). The mixture was heated at 90 °C for 16 hours and cooled to 25 °C. 1 N hydrochloric acid was added until pH - 3-4. The residue was diluted with EtOAc, and washed with water and brine. The organic phase was dried over

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Na,SO. and concentrated to give Compounds 159 and 160, which were used without Further purification in the next step.

Examples DZ/EA

Examples DZ (80 mg) and ΈΑ (60 mg) were prepared following the procedure used to prepare Compound 139a, except that Compounds 159 and 160 were used instead of Compound 138a. Example DZ: m/z: 732.3 (M+H)^h. Ί 1 NMR (CDC1.) · 8.75 (1 H, m), 7.80 (1 H, m), 7.3-7.0 (10 H, m), 6.95 (1 H, m), 6.8 (Ί H, br), 6.40 (1 H, br), 5.8 (1 H, br), 5.20 (2 H, m), 4.40 (2 H, m), 4.2-3.8 ( 3 H, m), 3.78 (1 H, m), 3.23 (1 H, m), 2.95 (3 H, m), 2.8-2.3 (6 H, m), 1.6-1.3 (10 H, m). Example EA: m/z: 775.2 (M+H)\ Ή NMR (CDCQ · 8.81 (1 H, s), 8.02 (1 H, br), 7.9 (1 H, s), 7.85 (1 H, br), 7.3-7.0 (11 H, m), 6.3 (1 H, br), 5.4-5.1 (3 H, m), 4.6-4.3 (2 H, m), 4.2-3.8 (2

H, m), 3.8-3.4 (1 H, m), 3.3 (1 H, m), 3.1-2.9 (3 H, m), 2.8-2.4 (4 H, m), 2.15 (2 H, m),

I. 7-1.2 (10 ΙΊ, m).

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Preparation of Example EB

Scheme 102

I. morpholine/Na8H(OAc)₃/HOAc; II. HCI; III. a. GDI; b. cmpd 3b; IV. a. NaOH; b. HCi;

V. EDC/HOBt/cmpd 8

Compound 161

Compound 161 (11g) was prepared following the procedure used to prepare Compound 148a, except that Compounds 153 and morpholine were used instead of Compounds 60 and 1-acetyl piperazine. m/z: 303.0 (M+H)⁺. Compound 162

Compound 162 (10.4 g) was prepared following the procedure used to prepare Compound 140a, except that Compound 161 w^Tas used instead of Compound 139a. m/z: 203,1 (M+H)⁺.

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Example 3b

Compound 3b was synthesized following the procedure described in W02008/010921 A2, and as described above in Scheme 10.

Example 163

Compound 163 (540 mg) was prepared following the procedure used to propan' Example DM(a), except that Compounds 162 and 36 were used instead of Compounds 140a and 9. m/z: 385.1 (M+H)*.

Example 164

Compound 164 (780 mg) was prepared following tire procedure used to prepare Compound 144, except that Compound 163 was used instead of Compound 143. m/z: 371.0 (M+H)’.

Example EB

Example EB (210 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 164 was used instead of Compound 138a. m/z: 762.2 (M+H)’. Td MMR (DMSO-d6) · 9.06 (1 H, s), 7.85 (1 H, s), 7.7 (1 H, br), 7.2-7.0 (12 H, m), 6.55 (1 H, br), 6.20 (1 H, br), 5.18 (2 H, s), 4.23 (2 H, m), 4.15 -3.8 (2 H, m), 3.65 (1 H, m), 3.55 (4 H, m), 3.2 (1 H, m), 2.7-2.4 (6 H, m), 2.3-2.0 (6 H, m), 1.54.2 (10 H, m).

Preparation of Compound 166

Scheme 103

1. NaOH/HaO; II, bis(4-nitrophenyl) carbonste/EtaN

Compound 3

Compound 3 was synthesized following the procedure described in WO2008/010921 A2.

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Compound 165

To a suspension of Compound 3 (2.65 g, 12.5 mmol) in water (10 mL) was added sodium hydroxide (1,5 g, 38 mmol). The mixture was heated at 90 °C for 12 hours and cooled to 25 °C. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over N’a,SO_r Purification by flash column chromatography (50% EtOAc in hexanes) gave Compound 165 (810 mg). Compound 166

To a solution of Compound 165 ¢810 mg, 5.2 mmol) in DCM (12 mL) was added bis(4-nitrophenyl) carbonate (1.73 g, 5.7 mmol), followed by triethylamine (1.1 mL, 7.8 mmol). The mixture was stirred for 14 hours, and the solvents were removed. The residue was diluted with EtOAc, and washed twice with saturated sodium carbonate, followed by water, and then brine, and was dried over Na-SCE. Concentration and purification by flash column chromatography (20% EtOAc in hexanes) gave Compound 166 (1.4 g).

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Preparation of Example EC

168

I. a. NaOH; b. HCI; V. EDC/HOBt/cmpd 8; III. a. HCI; b. NaOH;

IV. cmpd 166/iPr2NEt

Compound 167

Compound 167 was prepared following the procedure used to prepare

Compound 144, except that Compound 161 was used instead of Compound 143.

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Compound 168

Compound 168 (1.2 g) was prepared following the procedure used to prepare Compound 139a, except that Compound 167 was used instead of Compound 138a. m/z: 680.3 (M+H)*. Compound 169

To a solution of Compound 168 (1.2 g, 1.8 mmol) in MeOH (10 mL) was added 4 N hydrochloric acid (4.4 mL, 17.6 mmol). The mixture was stirred for 6 hours, and the solvents were removed. The residue was basified with 2 N sodium hydroxide solution (pH — 11), and extracted with EtOAc. Hie organic layer was washed with brine and dried over Na_;SO_r Concentration gave Compound 169 (1.0 g) Example EC

To a solution of Compound 169 (116 mg, 0.2 mmol) in CH.CN (2 mL) was added Compound 166 (71 mg, 0.22 mmol), followed by triethylaminc (71 »L, 0.4 mmol). Tire mixture was stirred for 48 hours, and was diluted with EtOAc. The organic layer was washed with saturated sodium carbonate solution, water, and brine, was dried over Na,SO_r Purification by flash column chromatography (ΟΙ 5% iPrOII in DCM) gave compound 1073 (130 mg), m/z: 763.3 (M+H)⁺. Ή NMR (CDC1,) · 8.75 (1 H, s), 7.78 (1 H, s), 7.67 (1 H, br), 7.3-7.0 (11 H, m), 6.22 (1

H, m), 5.24 (2 H, s), 5.16 (2 H, s), 5.10 (1 H, br), 4.28-4.10 (2 H, m), 3.8 (1 H, m), 3.6 (4 H, m), 3.32 (1 H, m), 2.9-2.6 (4 H, m), 2.4-2.1 (6 H, m), 1.8 (2 H, m), 1.6 (2 H, m),

I. 4 (8 H, m).

Preparation of Compound 173

Scheme 105

OH OH

170 VI 172 173

Compound 170

Compound 170 was obtained from Aldrich.

Compound 171

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Hydrogen sulfide gas was passed through a solution of Compound 170 (1.8 mL, 20 mmol) in pyridine (100 mL) and triethylamine (4.4 mL) for 5 hours. The solution was purged with nitrogen for 10 minutes, and the solvents were removed. The residue was coevaporated three times with 10 mL of ethyl alcohol. Purification by flash column chromatography (10% iPrOH in DCM) gave Compound 171 (2.0 g).

Compound 172

To a solution of Compound 171 (2 g, 17 mmol) in acetone (30 mL) was added 1,3-dichloroacetone (2.1 g, 17 mmol), followed by MgSO₄ ¢2.0 g, 17 mmol). The mixture was refluxed for 12 hours and cooled to 25 ^DC. The mixture was filtered. Concentration gave Compound 172. m/z: 19L9 (M+H)'.

Compound 173

To a solution of 40% methylamine in water (36 mL) was added a solution of Compound 172 (17 mmol) in water (10 mL). The mixture was stirred for 1 hour, and concentrated under reduced pressure, Purification by flash column chromatography (10% MeOH in DCM) gave Compound 173. m/z: 187Ό (M+H)^T.

Preparation of Compound 177

Scheme 106

(. a. NaOH/EtOH/H₂O; b. BnBr/DMF; II. SO₃-pyridine;

111. morpholine/NaBH(Oac)₃/HOAc; IV, HCI

Compound 174

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To a solution of Compound 151 (10.5 g, 50 mmol) in ethyl alcohol (160 mL) was added sodium hydroxide solution (2.1 g, 52.5 mmol, 30 mL). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. The residue was coevaporated three times with 200 ml, of ethyl alcohol. The white solid was dried at 60 °C for 2 hours under high vacuum. To this solid was added DMF (80 mL), followed by benzyl bromide (7.3 mL, 61 mmol). The mixture was stirred for 12 hours in darkness and diluted with EtOAc. The organic phase was washed five times with water followed once with brine, and was then dried over Na,SO₄. Concentration gave Compound 174 (15 g).

Compound 175

Compound 175 was prepared following the procedure used to prepare Example DV, except that Compound 1.74 was used instead of Example DU(c). Compound 176

Compound 176 was prepared following the procedure used to prepare Compound 148a, except that Compound 175 and morpholine were used instead of Compound 60 and 1-acetylpiperazine.

Compound 177

Compound 177 (3.4 g) was prepared following the procedure used to prepare example 140a, except that Compound 176 was used instead of Compound 139a. m/z; 279.1 (M+H)\ Preparation of Example ED

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Scheme 107

I. a. CDI/DIPEA; b. crnpd 173; II. a. NaOH; b. HCI; III. cmpd 8/EDC/HOBt

Compound 178

Compound 178 (300 mg) was prepared following the procedure used to prepare Example DM(a) except that Compounds 173 and 177 were used instead of Compounds 140a and 9. m/z: 491.3 (M+H)*.

Compound 179

Compound 179 was prepared following the procedure used to prepare Compound 149a, except that Compound 178 was used instead of Compound 148a.

Example ED

Example ED (370 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 179 was used instead of Compound 138a. m/z: 792.3 (M+H)^h. Ή NMR (CD₃OD) · 8.98 (1 H, s), 7.83 (1 H, s), 7.20-7.08 (11 H, m), 5.20 (2 H, m), 4.55 (2 H, m), 4.3-4.0 (4 H, m), 3.75 (3 H, m),

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3.4 (2 H, m), 3.2-3.0 (4 H, m), 2.99 (3 H, s), 2.70 (4 H, m), 2.1-1.8 (2 H, m), 1.7-1.4 (10 H, m).

Preparation of Example EE

Scheme 108

I. cmpd 9/EDC/HOBt; 11. a. NaH/DMF; b. 2-morpholineethylbramide;

III. a. TFA/DCM; b. NaOH; IV. a. triphosgene/DIPEA; b. cmpd 8/DIPEA

Compound 180

Compound 180 was obtained from Aldrich.

Compound 181

Compound 181 (1.6 g) was prepared following the procedure used to prepare Compound 139a, except that Compounds 180 and 9 were used instead of Compounds 8 and 138a. m/z: 327.9 (M+H)'.

Compound 182

To a suspension of sodium hydride (52 mg, 60%, 1.3 mmol) in DMF (4 ml_) was added a solution of Compound 181 (327 mg, 1 mmol) in DMF (1 mL). The mixture was stirred for 90 minutes, and a solution of 2-inorpholineethyl bromide (212 mg, 1.1 mmol) in DMF (1 mL) was added drop wise. The mixture was stirred for 12 hours, and quenched with water. The aqueous phase was extracted three

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Compound 183

Compound 183 (175 mg) was prepared following the procedure used to prepare Compound 169, except that Compound 182 was used instead of Compound 168. m/z: 341.2 (M+H)’. Example EE

To a solution of triphosgene (56 mg, 0.19 mmol) in DCM (1 mL) at 0 °C was added □ solution of Compound 8 (210 mg, 0.51 mmol) and DIPEA (194 *1) in DCM (1.8 mL). The mixture was stirred for 30 minutes, and a solution of Compound 183 (175 mg, 0.51 mmol) and DIPEA (194 · 1) in DCM (1 mL) was added. The mixture was warmed to 25 °C and stirred for 12 hours. The mixture was diluted with EtOAc, and washed twice with saturated sodium carbonate, once with water, and once with brine, and was dried over Na, SO.. The dried organic phases were concentrated and purified by flash column chromatography (15% iPrOH in DCM) gave Example EE (150 mg), m/z: 776.3 (M+H)'. Ή NMR (CD.OD) · 8.97 (1 H, s), 7.82 (1 H, s), 7.25-7.05 (Π H, m), 5.21 (2 H, s), 4.6 (2 H, m), 4,3-4.1 (2 H, m), 3.95 (1 H, m), 3.75 (1 H, s), 3.47 (4 H, m), 3.3 (5 H, m), 3.06/2.94 (3 H, s), 2.7 (4 H, m), 2.30 (4 H, m), 1.6-1.2 (10 H, m).

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Preparation of Examples EE-EH

Scheme 109

NHBcc

CIH-H₃N

OMe

184

O

OMe

NHBoc

186

185

EF

EH

1. a. CDI/DiPEA; b. MeNH₂; ll.a. NaOH/THF/H₂O; b. HCI;

lll.cmpd 8/EDC/HOBVDIPEA: IV. a. TFA/DCM; b. NaOH;

V. NaBH(OAc)₃/HOAc

Compound 184

Compound 184 was obtained from Aldrich.

Compound 185

Compound 185 (291 mg) was prepared following the procedure used to prepare Example DM(a), except that Compound 184 and methylamine were used instead of Compounds 140a and 9. m/z: 289.9 (Μ+Η)\ Compound 186

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Compound 186 was prepared following the procedure used to prepare Compound 144, except that Compound 185 was used instead of Compound 143. m/z: 275.9 (M+H)\ Example EF

Example EF (102 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 186 was used instead of Compound 138a. m/z: 667.1 (M+H)'.

Example EG

Example EG (144 mg) was prepared following the procedure used to prepare Compound 169, except that Example EF was used instead of Compound 168 m/z: 567.2 (M+H)’.

Compound 54

Compound 54 was synthesized following the procedure described in WO2008/010921 A2.

Example EH

Example EH (25 mg) was prepared following the procedure used to prepare Compound 148a, except that Example EG and Compound 54 were used instead of Compound 60 and 1-acetylpiperazine, m/z: 637.3 (M+H)’. Ή NMR (CDC1₃) · 9.00 (br s, IH); 7.94 (br s, IH); 7.72 (br s, IH); 7.40-7.00 (m, 10H); 5.49 (m, IH); 5.25 (s, 2H); 4.47 (m, IH); 4.30 (m, IH); 4.02 (br s, IH); 3.65 (m, 2H); 3.41 (m, 2H); 2.76 (m, 9H); 2.25-1.70 (m, 4H); 1.70-1.40 (m, 6H).

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Preparation of Example EI-ET

I. a. CDI/DIPEA; b. cmpd 9; II. a. NaOH/EtOH; b. BnBr/DMF; III. SO3-pyridlne/Et₃N; IV. morpholine/NaBH(OAc)_3/AcOH/CH₃CN; V. a. Ν30Η/Εί0Η/Η_Ξ0: b. HCI; IV.cmpd 8/EDC/HOBt/DlPEA; VII. chiral column separation

Compound 187

Compound 187 was obtained from Aldrich.

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Compound 188

Compound 188 (897 mg) was prepared following the procedure used to prepare Example DM(a), except that Compound 187 was used instead of Compound 140a. m/z: 298.0 (M+H)¹.

Compound 189

Compound 189 (1.24 g) was prepared following the procedure used to prepare Compound 174, except that Compound 188 was used instead of Compound 151. m/z: 406.1 (M+H)'.

Compound 190

Compound 190 (712 mg) was prepared following the procedure used to prepare Example DV, except that Compound 189 was used instead of Example DU(c). m/z: 40.4.0 (M+H)“.

Compound 191

Compound 191 (384 mg) was prepared following the procedure used to prepare Compound 148a, except that Compound 190 and morpholine were used instead of Compound 60 and 1-acetyl piperazine, m/z: 475.1 (M+Hf.

Compound 192

Compound 192 (900 mg) was prepared following the procedure used to prepare Compound 149a, except that Compound 191 was used instead of Compound 148a. m/z: 385.0 (Ms-H)‘.

Example El

Example El (151 mg) was prepared following the procedure used to prepare Compound 139a, except that Compound 192 was used instead of Compound 138a. m/z: 776.2 (M+H)¹. Ή NMR (CD,OD) · 8.97 (1 H, s), 7.82 (1 H, s), 7.3-7.1 (11 H, m), 5.2 (2 H, s), 4.5 (2 H, m), 4.18 (2 H, m), 3.78 (1 H, m), 3.59 (4 H, m), 3.23 (1 H, m), 2.97 (3 H, s), 2.8-2.5 (4 H, m), 2.5-2.1 (6 H, m), 1.9-1.6 (2 H, m), 1.6-1.3 (10 H, m).

Example El

Example El was purified with HPLC (chiral cel OD-H column by Chiral Technologies Inc, heptane/iPrOH = 70/30) to give Example EJ. m/z: 776.2 (M+H)\ Ή NMR (CDCL) · 8.9S (s, IH); 7.90 (s, IH); 775 (m, IH); 7.40-7.00 (m,

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15H), 6.55 (br s, 1H); 5.92 (br s, 1H); 7.75 (d, 1H); 5.28,5.19 (d_A3, J=14 Hz, 2H); 4.704.37 (m, 3H); 3.99 (m, 5H); 3.76 (br s, 1H); 3.65-3.30 (m, 3H); 2.97 (m, 5H); 2.90-2.60 (m, 7H); 2.28 (br s, 2H); 1.91 (br s, 2H); 1.6-1.3 (m, Ί 2H).

Preparation of Example EK

Scheme 111

I. UA1H4, THF; [I. PCI5, toluene; III. MeNHjin MeOH;

IV.a. CDI/DIPEA; b. cmpd 169

Compound 193

Compound 193 was synthesized following the procedure from J, Med.

Chem, 41(4), 1998, 602-617 (herein incorporated by reference in its entirety for all purposes).

Compound 194

Compound 193 (1.4 g, 7 mmol) was dissolved in anhydrous THF (7 ml.) and added dropwise over 1 hour into a 1 M LiAlH. solution in THF stirring at 0 C under nitrogen gas. Tire reaction mixture was then allowed to warm to room temperature and stirred for 1 hour, at which time HPLC showed that reaction was

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Compound 195

Compound 194 (1 g, 6.37 mmol) was dissolved in anhydrous toluene (6 mL). To the resulting solution was added PCI, (1.3 g, 6.37 mmol). After the reaction mixture was stirred for 1 hour, the reaction was complete. Solid sodium bicarbonate was added to the reaction mixture, which was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, followed by saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield Compound 195 (0.91 g, 81%).

Compound 196

Compound 195 (0.91 g, 5.2 mmol) was dissolved in 2 M methylamine in methanol (15 mL). The reaction mixture was stirred for 15 hours, then concentrated under reduced pressure. The resulting oil was dissolved in dilute aqueous HC1 solution to give a solution with a pH of 2. The solution was then washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Compound 196 (0.6 g, 56%).

Example EK

Example EK (14 mg) was prepared following the procedure used to prepare Example DM(a), except that Compounds 169 and 196 were used instead of Compounds 140a and 9. Ή NMR (CD,OD): · 8.98 (s, IH), 7.82 (s, IH), 7.55 (s, IH), 7.19 (m, 1011), 5.21 (m, 2H),4.68 (τη,2H),4.20 (m, 111), 4.15 (m, IH), 3.79 (τη, 1H), 3.64 (m, 414), 3.25 (m, 114), 2.98 (s, 314), 2.73 (m, 4H), 2.23-2.40 (m, 6H), 1.901.70 (m, 2H), 1.51 (m, 4H), 1.36 (d, )=6.9 Hz, 6H). Mass Spectrum (m/c): (M+H)’ 776.3, (M-H)' 773.9

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Preparation of Example EL

Scheme 112

I. a. 1,1-bis(methylthio)-2-nitroethylerie/DMF; b. MeNHs/MeOH Example EL

Example W (71 mg, 0.1 mmol) and l,l-bis(methylthio)-2-nitroethylcne (17 mg, 0.1 mmol) was dissolved in anhydrous DMF (2 ml.). The resulting mixture was stirred at room temperature for 90 minutes, followed by another 16 hours at 40 ‘C. An additional 10% of l,l-bis(methyltluo)-2-nitroethylene was added and the mixture was stirred at 60 ^C'C for 8 hours, A solution of 2 M methylamine in methanol (1.2 mL, 2.4 mmol) was added and the mixture was stirred for 3 hours at room temperature. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. Tire organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel column chromatography (3-10% McOFl in DCM). Final purification with C₁₅-reverse phase prep HPLC gave Example EL (55 mg, 68%). Ή NMR (CD,OD): · 8.97 (s, 1H), 7.81 (s, ΊΗ), 7.16 (m, I0H), 6.66 (s, 1H), 5.20 (s, 2H), 4.54 (m, 2H), 4.17 (m, 2H), 3.80 (m, 1H), 3.35 (s, 3H), 3.23 (m, 1H),

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3.00-2.80 (m, 9H), 2.63 (τη, 3H), 1.60-1.43 (m, 6H), 1.33 (d, J =7.2 Hz, 6H). Mass

Spectrum (m/e): (M+H)' 806.3, (M-H)' 804.1.

Preparation of Examples EM-EN

Scheme 113

I. TMS-l/EtOH; II. KCN/DMSO; III. NaOH/H₂O/EtOH; IV. EDC,/HOBt/TEA/THF;

V.a. HCi/MeOH; b. H₂NSO₂NH₂

Compound 197

Compound 122 (460 mg, 1.5 mmol) was dissolved in anhydrous ΕΧΞΜ. To the resulting solution was added EtOH (540 *L, 9.28 mmol), followed by TMS-I (663 ·Ε, 4.6 mmol) dropwise. The mixture was stirred for 2 hours at room temperature. Additional TMS-I (200 *L) was added and the mixture was stirred for 1 hour. Hie reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOH and concentrated under reduced pressure. The

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2020203321 21 May 2020 residue was again dissolved in another portion of EtOH. The resulting oil was dissolved in anhydrous DMSO (5 mL). KCN was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. Tire organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with flash silica gel column chromatography (EtOAc). The product (260 mg, 0.74 mmol) was dissolved in EtOH and stirred in an ice bath. NaOH (33 mg, 0.82 mmol) was dissolved in water and added to the EtOH solution in portions. The reaction mixture was acidified with 10% citric acid to a pH of 2-3 and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting Compound 197 (228 mg, 47%) was used in the next step without further purification.

Example EM

Compound 197 (228 mg, 0.7 mmol) was dissolved in anhydrous THF (5 mL). EDC (202 mg, 1,05 mmol) and HOBl (162 mg, 1.05 mmol) were added to the solution and the resulting mixture was stirred for 30 minutes. Compound 8 (214 mg, 0.7 mmol) was added to the reaction mixture along with anhydrous DMF (3 mL) and TEA (294 »L, 2.11 mmol). The mixture was stirred for 90 minutes, then diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue w^ras purified with flash silica gel column chromatography (0-10% MeOH in DCM). Final purification with Q_s-reverse phase prep HPLC gave Example EM (29'lmg, 58%). 'HNMR (CD₃OD): · 8.97 (s, 1H), 7.83 (s, 1H), 7.17 (m, 10H), 5.22 (s, 2H), 4.53 (s, 2H), 4.23 (m, 1H), 4,06 (m, 1H), 3.77 (m, 1H), 3.27 (m, 1H), 2.96 (s, 3H), 2.72 (m, 4H), 2.37 (m, 2H), 1.88 (m, 2H), 1.52 (m, 4H), 1.38 (d, J =7.2 Hz, 6H). Mass Spectrum (m/e): (M+H) 716.2, (M-H) 713.9.

Example EN

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Example EM (120 mg, 0.168 mmol) was dissolved in anhydrous MeOH (5 mL) and concentrated under reduced pressure. This process was repeated twice with fresh portions of MeOH. The residue was dissolved in MeOH (5 mL) and stirred in an ice bath under nitrogen gas. HC1 gas was bubbled into the MeOH solution for 5-10 minutes to saturate the solution. The reaction vessel was sealed and the reaction mixture ivas stirred at 0 C for 8 hours. The reaction mixture was then concentrated under reduced pressure at room temperature. The residue was dissolved in EtOAc and washed twice with 10% aqueous sodium carbonate solution, followed by saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 2-methoxy ethanol (5 mL). Sutfamide (161 mg, 1.68 mmol) was added to the solution, which was stirred at 80 °C for 8 hours and then at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Hie residue was dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate solution, followed by saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified with flash silica gel column chromatography (0-10% MeOH in DCM). Final purification with C_1B-reverse phase prep HPLC gave Example EN (16 mg, 12%). ‘FI NMR (CD.OD): · 8.98 (s, 1H), 7.83 (s, 1H), 7.67 (m, 1H), 7.16 (m, 10H), 6.82 (m, 1H), 5.21 (s, 2H), 4.53 (m, 2H), 4.15 (m, 2H), 3.77 (m, 1H), 3.28 (m, 1H), 2.96 (s, 3H), 2.68 (m, 4H), 2.21 (m, 2H), 1.88 (m, 2H), 1.45 (m, 4H), 1.35 (d, J=7.2 Hz, 6H). Mass Spectrum (m/e): (M+H)’ 812.1, (M-H)' 810.0.

Preparation of Example EQ

Scheme 114

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I. a. cmpd 169/CDI/DIPEA; b. cmpd 68

Compound 68

Compound 68 was synthesized following the procedure described in VV02008 / 010921 A2.

Example EQ

Example EO (39 mg) was prepared following the procedure used to prepare Example DM(a), except that Compounds 68 and 169 were used instead of Compounds 140a and 9. Ή NMR (CD^OD): · 8.98 (s, 1H), 8.93 (s, 1H), 7.82 (s, 2H), 7.19 (m, 10H), 5.21 (s, 2H), 4.60 (m, 2H), 4.20 (m, 1H), 4.10 (m, 1H), 3.77 (m, 111), 3.64 (m, 4H), 2.93 (s, 3H), 2.74 (m, 4H), 2.38-2.28 (m, 6H), 1.84-1.70 (m, 2H), 1.50 (m, 4H). Mass Spectrum (m/e): (M+H)’ 734.3, (M-H)’ 731.9

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Preparation of Example EP-EQ

Scheme 115

200

IV

EP

EQ

I. cmpd 46/EDC/HOBt/D!PEA; If HCI/dioxane: III, TBSCI/pyrrdine;

IV. a. CDI/DIPEA; b.cmpd 68; V. HCI/dioxane

Compound 198

Compound 198 was obtained from Aldrich.

Compound 199

Compound 198 (205 mg, 1 mmol) was mixed with Compound 46 (446 mg, 1 mmol) and HOBt (230 mg, 1.5 mmol) in anhydrous DMF (5 mL). EDC (230mg, 1.2 mmol) was then added. The resulting mixture was stirred for 30 minutes. DIPEA (348 »L, 2 mmol) was added. The mixture was stirred for 2 hours, then diluted with EtOAc, washed sequentially with saturated aqueous sodium

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PCT/US2008/054788 bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified with flash silica gel column chromatography (0-100% EtOAc in DCM) to give Compound 199 (345 mg, 58%). Compound 200

Compound 199 (345 mg, 0.58 mmol) was dissolved in a small amount of MeOH. A solution of 4 N HCl in dioxane (5 mL) was added. The resulting mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in anhydrous DCM (10 mL). Pyridine (163 Έ, 2 mmol) and t-butyldimethylsilyl chloride (166 mg, 1.1 mmol) were added. Tire resulting mixture was stirred for 15 hours. More pyridine (163 •L) and TBS-C1 (60 mg) were added. The resulting mixture was stirred for another 24 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, The crude material was purified by flash silica gel column chromatography (0-5% MeOH in DCM) to give Compound 200 (248 mg, 69%), Example EP

Example EP was prepared following the procedure used to prepare Example DM(a), except that Compounds 200 and 68 were used instead of Compounds 140a and 9. Example EQ

To Example EP was added 4 N HCl in dioxane (4 mL). The mixture was stirred for 1 hour and tire solvent was evaporated. The residue was diluted with EtOAc, and washed sequentially with saturated aqueous sodium carbonate, water, and brine. The organic layer was dried over NaSO₄, then concentrated.

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The residue was purified by flash column chromatography (10% iPrOl i in DCM) to give Example EQ (35 mg). Ή NMR (CD_?OD): 5 8.97 (s, 1H), 8.89 (s, 1H), 7.S1 (s, 2] I), 7.70 (m, 1H), 7.19 (m, 10H), 6.92 (m, 1H), 5.20 (s, 2H), 4.73 (m, 2H), 4.22 (m, 1H), 4.13 (m,1H), 3.78 (m, HI), 3.56 (d, >5.4Hz, 2H), 3.31 (m, 1H), 2.94 (s, 3H), 2.67 (m, 4H), 1.45 (m, 4H). Mass Spectrum (m/e); (M+H/ 651.2, (M-I I) 648.8.

ICsa Determinations for Human Liver Cytochrome P450

Materials and General Methods

Pooled (n > 15 donors) human hepatic microsomal fraction was obtained from BD-Gentest (Woburn, MA) who also supplied hydroxy-terfenadine, 4'hydroxy diclofenac and NADPH regenerating system. Ritonavir was prepared from commercial Norvir® oral solution (Abbott Laboratories, Abbott Park, IL). Other reagents were from Sigma-Aldrich (St. Louis, MO) and included terfenadine, fexofenadine, BRL 15572, diclofenac and mefenamic acid.

Incubations were performed in duplicate in 50 mM potassium phosphate buffer, pH 7.4 with NADPH regenerating system used as described by the manufacturer. The final microsomal protein concentrations had previously been determined to be within the linear range for activity and resulted in less than 20% consumption of substrate over the course of the incubation. The final substrate concentrations used were equal to the apparent Km values for the activities determined under the same conditions. Inhibitors were dissolved in DMSO, and the final concentration of DMSO, from both substrate and inhibitor vehicles, was 1% (v/v). Incubations were performed at 37^CC with shaking and were initiated by addition of substrate. Aliquots were then removed at 0, 7 and 15 minutes. Samples were quenched by treatment with an acetonitrile, formic acid, w^rater (94.8%/0.2%/5%, v/v/v) mixhire containing internal standard. Precipitated protein

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PCT/US2008/054788 was removed by centrifugation at 3000 rpm for 10 min and aliquots of the supernatant were then subjected to LC-MS analysis.

The LC-MS system consisted of a Waters Acquity UPLC, w'ith a binary solvent manager and a refrigerated (8C) sample organizer and sample manager, interfaced to a Micromass Quattio Premier tandem mass spectrometer operating in clcctrospray ionization mode. The column was a Waters Acquity UPLC BEl I Cis 2.1 x 50 mm, 1.7 urn pore size. Mobile phases consisted of mixtures of acetonitrile, formic acid and w^Tater, the composition for mobile phase A being l%/0.2%/98.8% (v/v/v) and that for mobile phase B being 94.8%/0.2%/5% (v/v/v). I'he injection volumes were 5 pL and the flow rate was 0.8 mL/min, Concentrations of metabolites were determined by reference to standard curves generated with authentic analytes under the same conditions as the incubations.

IC’P values (the concentration of inhibitor reducing CYP3A activity by 50%) were calculated by non-linear regression using GraphPad Prism 4,0 software and a sigmoidal model.

CYP3A Inhibition Assay

The potencies of the compounds as inhibitors of human hepatic cytochromes P450 of the CYP3A subfamily (particularly CYP3A4) were assessed using terfenadine oxidase, a well-characterized CYP3A-sclcctive activity described in Ling, K.-H.J., et al Drug Metab. Dispos. 23, 631-636, (1995) and JurimaRomet, et al Drug Mctab. Dispos. 22, 849-857, (1994). The final concentrations of microsomal protein and terfenadine substrate were 0.25 mg/mL and 3 μΜ, respectively. Metabolic reactions were terminated by treatment with seven volumes of quench solution containing 0.1 μΜ BRL 15572 as internal standard. A further 8 volumes of water were added before centrifugation and aliquots of tine supernatant were removed for analysis.

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For LC-MS analysis chromatographic elution was achieved by a series of linear gradients starting at 20% B and holding for 0,1 minutes, then increasing to 80% Β over 1.5 minutes, holding for 0.4 minutes and then returning to the starting conditions for 0.05 min. The system was allowed to re-equilibrate for at least 0.25 minutes prior to the next injection. Hie mass spectrometer was operated in positive ion mode and the following precursor ([M+H] )/product ion pairs were monitored and quantified using MassLynx 4.0 (SP4, 525) software: hydroxyterfenadine 488.7/452,4, fexofenadine 502.7/466.4 and BRL 15572 407.5/209,1. Tcrfenadinc oxidase activity was determined from the sum of hydroxyterfenadine and carboxy-terfenadine (fexofenadine) metabolites.

CYP2C9 Inhibition Assay

The potencies of the compounds as inhibitors of human hepatic CYP2C9 were assessed using diclofenac 4'-hydroxylase, an activity specific for this enzyme, as described in Leeman, T., ct al Life. Sci. 52, 29-34, (1992). The final concentrations of microsomal protein and diclofenac substrate were 0.08 mg/mL and 4 μΜ, respectively. Metabolic reactions were terminated by treatment with three volumes of quench solution containing 1 μΜ mcfenamic acid as internal standard. After centrifugation a further 4 volumes of water were added. Aliquots of the supernatant wore then subjected to LC-MS analysis.

For LC-MS anti lysis chromatographic elution was achieved by a series of linear gradients starting at 20% B and holding for 0.3 minutes, then increasing to 99% B over 1.2 minutes, holding for 0.5 minutes and then returning to the starting conditions for 0,25 min. The system was allowed to re-equilibrate for at least 0.25 minutes prior to the next injection. Tire mass spectrometer was operated in negative ion mode and the following precursor ([M-H])/product ion pairs were monitored and quantified: 4'-hy dr oxy -diclofenac 312.4/294.2 and mefenamic acid 242.4/224.2.

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Biological Assays Used for the Characterization of HIV Protease Inhibitors

HIV-l Protease Enzyme Assay (Ki)

The assay is based on the fluorimetric detection of synthetic hexapeptide substrate cleavage by HIV-1 protease in a defined reaction buffer as initially described by M.V. Toth and G.R.Marshall, lot. I. Peptide Protein Res. 36, 544 (1990) (herein incorporated by reference in its entirety for all purposes).

The assay employed (2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Plie-Gln-Arg as the substrate and recombinant HIV-1 protease expressed in E.Coli as the enzyme. Both of the reagents were supplied by Bachem California, Inc. (Torrance, CA; Cat. no. H-2992). The buffer for this reaction was 100 mM ammonium acetate, pH 5.3, 1 M sodium chloride, 1 mM ethylendiaminetetraacetic acid, 1 mM dithio threitol, and 10% dime thy Isulf oxide.

To determine the inhibition constant Ki, a series of solutions were prepared containing identical amount of the enzyme (1 to 2.5 nM) and the inhibitor to be tested at different concentrations in the reaction buffer. The solutions were subsequently transferred into a white 96-well plate (190 μΐ each) and preincubated for 15 min at 37 °C Tine substrate was solublized in 100% dimethyl sulfoxide at a concentration of SOO μΜ and 10 ul of 800 μΜ substrate was added into each well to reach a final substrate concentration of 40 μΜ. The real-time reaction kinetics was measured at 37 °C using a Gemini 96-well plate fluorimeter (Molecular Devices, Sunnyvale, CA) at λ(Εχ) = 330 nm and λ(Εηι) = 420 nm. Initial velocities of the reactions with different inhibitor concentrations were determined and the Ki value (in picomolar concentration units) was calculated by using EnzFitter program (Biosoft, Cambridge, U.K.) according to an algorithm for tight-binding competitive inhibition described by Ermolieff J., Lin X., and Tang J., Biochemistry 36, 12364 (1997).

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HIV-1 Protease Enzyme Assay (1C50)

As for the Ki assay, above, the ICso assay is based on the fluorimerrxc detection of synthetic hexapeptide substrate cleavage by H1V-I protease in a defined reaction buffer as initially described by M.V. Toth and G.R.Marshall, Int. L Peptide Protein Res. 36, 544 (1990),

The assay employed (2-aminobenzoyl)Thr-Ilc-Nle-(p-nitro)Phe-Gln-Arg as the substrate and recombinant HIV-1 protease expressed in E.Coli as the enzyme. Both of the reagents were supplied by Bachem California, Inc. (Torrance, CA; Cat nos. H-2992 and H-9040, respectively). The buffer for this reaction was 100 mM ammonium acetate, pH 5.5, 1 M sodium chloride, 1 mM ethylendiaminetetraacetic acid, and 1 mM dithio threitol, and 10% dime th vlsulf oxide.

To determine the IC50 value, 170 μL of reaction buffer was transferred into the wells of a white 96-weIl microliter plate. A scries of 3-fold dilutions in DMSO of the inhibitor to be tested was prepared, and 10 pL of the resulting dilutions was transferred into the wells of the microtiter plate. 10 pL· of a 20-50 nM enzyme stock solution in reaction buffer was added to each well of the 96-wcll plate to provide a final enzyme concentration of 1-2.5 tlM. The plates were then preincubated for 10 minutes at 37%? The substrate was solublized in 100% dimethylsulfoxide at a concentration of 400 pM and 10 pl of the 400 pM substrate was added into each well to reach a firval substrate concentration of 20 pM. The real-Lime reaction kinetics were measured using a Gemini 96-well plate fluorimeter (Molecular Devices, Sunnyvale, CA) at Λ(Εχ) 330 nm and A(Em) = 420 nm. Initial velocities of the reactions with different inhibitor concentrations were determined and the ICx> value (in nanomolar concentration units) was calculated by using GraphPad Prism ™ software to fit nonlinear regression curves, Anti-HlV-l Cell Culture Assay (EC50)

The assay is based on quantification of the HIV-l-associated cvtopathic

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PCT/US2008/054788 effect by a colorimetric detection of the viability of virus-infected cells in the presence or absence of tested inhibitors. HlV-l-induced cell death was determined using a metabolic substrate 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)2H-tetrazolium-5-carboxanilide (XTT) which is converted only by intact cells into a product with specific absorption characteristics as described by Weislow OS, Kiser R, Fine DL, Bader J, Shoemaker RH and Boyd MR, 1. Natl. Cancer Inst· 81, 577 (1989) (herein incorporated by reference in its entirety for all purposes).

MT2 cells (N1H AIDS reagent program, Cat # 237) maintained in RPMI1640 medium supplemented with 5% fetal bovine serum and antibiotics w^rere infected with the wild-type HIV-1 strain 1I1B (Advanced Biotechnologies, Columbia, MD) for 3 hours at 37 °C using the virus inoculum corresponding to a multiplicity of infection equal to 0.01. The infected cells in culture media were distributed into a 96-well plate (20,000 cells in 100 μΐ/well), and incubated in the presence of a set of solutions containing 5-fold serial dilutions of the tested inhibitor (100 μΐ/well) for 5 days at 37 °C. Samples with untreated infected and untreated mock-infected control cells were also distributed to the 96-well plate and incubated under the same conditions.

To determine the antiviral activity of the tested inhibitors, a substrate XTT solution (6 mL per assay plate) at a concentration of 2 mg/mL in a phosphatebuffered saline pH 7.4 was heated in water-bath for 5 min at 55 °C before 50 μΐ of N-methylphenazonium methasulfate (5 gg/'mL) was added per 6 mL of XTT solution. After removing 100 μΐ media from each well on the assay plate, 100 μΐ of the XTT substrate solution was added to each well. The cells and the XTT solution were incubated at 37 °C for 45 to 60 min in a CO: incubator. To inactivate the virus, 20 μΐ of 2% Triton X-100 was added to each well. Viability, as determined by the amount of XTT metabolites produced, was quantified spectrophotometrically by the absorbance at 450 nm (with subtraction of the

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PCT/US2008/054788 background absorbance at 650 nm). Data from the assay was expressed as the percentage absorbance relative to untreated control and the fifty percent effective concentration (ECw) was calculated as the concentration of compound that effected an increase in the percentage of XTT metabolite production in infected, compound treated cells to 50% of that produced by uninfected, compound-free cells.

Anti-HIV-1 Cell Culture Assay (EQn) in presence of 40% Human Serum or Human Serum Proteins

This assay is almost identical to the Anti-HIV-1 Cell Culture Assay described above, except that the infection was made in the presence or absence of 40% human serum (Type AB Male Cambrex 14-498E) or human serum proteins (Human «-acid Glycoprotein, Sigma G-9885; Human Serum Albumin, Sigma Al653, 96-99%) at physiological concentration. The HIV-1-induced cell death was determined as described above, except that the infected cells distributed in the 96well plate were incubated in 80% Human Serum (2X concentration) or in 2 mg/mL Human «-acid Glycoprotein + 70 mg/mL HSA (2X concentration) rather than in culture media.

Cytotoxicity Cell Culture Assay (CCso)

The assay is based on the evaluation of cytotoxic effect of tested compounds using a metabolic substrate 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium5-carboxanilide (XTT) as described by Weislow OS, Kiser R, Pine DL, Bader J, Shoemaker RH and Boyd MR, J. Natl. Cancer Inst. 81, 577 (1989). This assay is almost identical to the previous assay described (Anti-HIV-1 Cell Culture Assay), except that the cells were not infected. The compound induced cell death (or growth reduction) was determined as previously described.

MT-2 cells maintained in RPMI-1640 medium supplemented with 5% fetal bovine serum and antibiotics were distributed into a 96-well plate (20,000 cells in 100

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PCT/US 2008/054788 μΐ./well) and incubated in the presence or absence of 5-fold serial dilutions of the tested inhibitor (100 μΐ/well) for 5 days at 37 °C. Controls included untreated infected cells and infected cells protected by 1 μΜ of P4405 (Podophyllotoxin, Sigma Cat # P4405).

To determine cytotoxicity, an XTT solution (6 mL per assay plate) at a concentration of 2 mg/mL m phosphate-buffered saline pH 7.4 was heated in the dark in a water-bath for 5 min at 55 ^QC before 50 ul of N-methylphenazonium methasulfate (5 pg/mL) was added per 6 mL of XTT solution. After removing 100 μΕ media fro tn each well on the assay plate, 100 μΕ of the ΧΊΤ substrate solution was added to each well. The cells and the XTT solution were incubated at 37 °C for 45 to 60 min in a CO: incubator. To inactivate the idrus, 20 μΐ of 2% Triton X100 was added to each well. Viability, as determined by the amount of XTT metabolites produced, is quantified spectrophotometrically by the absorbance at 450 nm (with subtraction of the background absorbance at 650 run). Data from the assay is expressed as the percentage absorbance relative to untreated control, and the fifty percent cytotoxicity concentration (EOi) was calculated as the concentration of compound that effected an increase in the percentage of cell growth in compound treated cells to 50% of the cell growth provided by uninfected, compound-free cells.

Experimental data based on representative Examples A-EQ demonstrate that the compounds of Formula (IV) of the present invention can have a CYP450 3A4 inhibition activity in a range represented by an I Cm from about 100 nM to about 4700 nM, and a CYP450 2C9 inhibition activity in a range represented by an ICw from about 100 nM to about 10,000 nM.

Experimental data based on representative Examples A-EQ demonstrate that the compounds of Formula (IV) of the present invention can have a protease

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C:\Interwoven\NRPortbl\DCC\RBR\17725109_].docx-17/09/2018 inhibition activity in a range represented by HIV EC₅₀ from about 140 nM to greater than about 30000 nM.

Experimental data based on representative Examples P, S, and T have a CYP450 3A4 inhibition activity in a range represented by an IC₅₀ from about 80- 150 nM, a CYP450 2C9 inhibition activity in a range represented by an IC₅₀ from about 1000-10,000 nM, and a protease inhibition activity in a range represented by HIV EC₅₀greater than about 30,000 nM.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: A compound of formula IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein, each L3 is independently an alkylene or substituted alkylene; each A is independently an aryl or substituted aryl; X is heterocyclylalkyl; Y is heterocyclylalkyl or alkyl; G1 and G2 are independently CH or N, with the proviso that G' and G2 are different; G3 is-NR7- or-O-; R1, R3, Rs, and R7 are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; R2 is independently selected from the group consisting of substituted alkyl, alkoxyalkyl, hydroxyalkyl, trialkylsiloxyalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-N(Ra)-C(O)alkyl, -alkylene-NRa-C(O)-N(Ra)2, -alkylene-NRa-C(=N-Rb)-N(Ra)2, -alkyleneC(=N-Rb)-N(Ra>, -alkylene-C(0)-OH, -alky!ene-C(O)-Oalkyl, and -alkyleneC(O)-N(R<>; R8 and R9 are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, and -CN; each Ra is independently selected from the group consisting of H, alkyl, and substituted alkyl; 402 WO 2008/103949 PCT/US2008/054788 Rb is selected from the group consisting of H, alkyl, substituted alkyl, CN, and S(O2)-aIkyl; and each Rc is independently selected from the group consisting of H, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, -S(Ch)-alkyl, -S(Ch)aryl, and substituted -S(Ch)-aryI.

(1) said HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(1) said HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(1) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, lFNalpha-2b XL, AVI-005, PEG-lnfergen, and Pegylated IFNbeta;

(1) said HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-lOO, DG35, and AG 1859;

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PCT/US2008/054788 (2) said HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, TMC-278 (rilpivirene), BILR 355 BS, VRX 840773, UK-453061, and RDEA806;
(2) said HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806;

(2) said HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806;

(2) said ribavirin analogs are selected from the group consisting of rebetol, copegus, and viramidine (taribavirin);

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PCT/US2008/054788 (3) said NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PS1-6130 (R1656), HCV-796, BILB 1941, XTL2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;

2. The compound of claim 1, having the following formula:

wherein R^d is selected from the group consisting of H, haloalkyl, -C(O)-N(R^;1)2, C(=N-R^b)-N(R^a)2, hydroxy alkyl, -C(N(R^a)₂)=CHNO2, -C(O)-alkyI.
(3) said HIV nucleoside inhibitors of reverse transcriptase are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alov udine, MIV-210, radvir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003),;

(3) said HIV nucleoside inhibitors of reverse transcriptase are selected from tiie group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (+-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003),;

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PCT/US2008/054788 (4) said HIV nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir disoproxil fumarate, GS-9131, and adefovir dipivoxil;

(3) said HIV nucleoside inhibitors of reverse transcriptase are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, M.IV-210, racivir (±-FTC), D-d4FC, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003);

3. The compound of claim 1, having the following formula:
(4) said HIV nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir disoproxil fumarate, GS-9131, and adefovir dipivoxil;

(4) said NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ΓΓΜΝ191;

(4) said HIV nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir disoproxil fumarate, GS-9131, and adefovir dipivoxil;

4. The compound of claim 3, wherein said Heterocyclyl is a substituted or unsubstituted heteroaryl.
(5) said HIV integrase inhibitors are selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5

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PCT/US2008/054788 dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurin tricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic add phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L870810, MK-0518 (raltegravir), elvitegravir, BMS-538158, GSK364735C, BMS707035, MK-2048, and BA Oil;

(5) said HIV integrase inhibitors are selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L870810, MK-0518 (raltegravir), elvitegravir, BMS-538158, GSK364735C, BMS707035, MK-2048, and BA Oil;

(5) said alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;

(5) said HIV integrase inhibitors are selected from the group consisting of curcumin, derivatives of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, L-870810, MK-0518 (raltegravir), elvitegravir, BMS538158, GSK364735C, BMS-707035, MK-2048, and BA Oil;

5. The compound of claim 4, wherein said heteroaryl is selected from the group consisting of triazolyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, and imidazolidin-dionyl.

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(6) said gp41 inhibitor are selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;

(6) said gp41 inhibitor are selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;

(6) said hepatoprotectants are selected from the group consisting of IDN6556, ME 3738, LB-84451, and MitoQ;

(6) said gp41 inhibitor are selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;

6. The compound of claim 3, wherein said Heterocyclyl is a substituted or unsubstituted heterocycloalkyl.
(7) said CXCR4 inhibitor is AMD-070;

(7) said CXCR4 inhibitor is AMD-070;

(7) said non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and (8) said other drugs for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL6865, ANA 971, NOV-205, tarvadn, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

32. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and a pharmaceutically acceptable carrier or exipient.

33. The pharmaceutical composition of claim 32, further comprising at least one additional therapeutic agent metabolized by cytochrome P450.

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34. The pharmaceutical composition of claim 33, wherein the at least one additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, alphaglucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, other drugs for treating HCV, and combinations thereof.

35. The pharmaceutical composition of claim 34, wherein:

(7) said CXCR4 inhibitor is AMD-070;

7. The compound of claim 6, wherein said heterocycloalkyl is selected from the group consisting of pyrrolidinonyl, pyrrolidine-dionyl, oxazolidinonyl, pyrrolidinyl, piperidinyl, piperidinonyl, piperazinyl, thiomorpholinyl, and morpholinyl.
(8) said entry inhibitor is SP01 A;

(8) said entry inhibitor is SP01A;

(8) said entry inhibitor is SP01 A;

8. The compound of claim 7, wherein said heterocycloalky I is morpholinyl.
(9) said gpl20 inhibitor is BMS-488043 or BlockAide/ CR;

(9) said gpl20 inhibitor is BMS-488043 or Block Aide/ CR;

(9) said gp!20 inhibitor is BMS-488043 or BlockAide/ CR;

9. The compound of claim 1, having the following formula:

Q

wherein Q is -OH or -N(R^a)2.
(10) said G6PD and NADH-oxidase inhibitor is immunitin;

(10) said G6PD and NADH-oxidase inhibitor is immunitin;

(10) said G6PD and NADH-oxidase inhibitor is immimitin;

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PCT/US2008/054788 (11) said CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;

10. The compound of claim 9, wherein Q is -OH.
(11) said CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAbOO4;

(11) said CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;

11. The compound of claim 9, wherein Q is -NHR^a, and R^a is substituted or unsubstituted heterocyclyl or sulfonylalkyl.
(12) said other drugs for treating HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040);

(12) said other drugs for treating HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040);

(12) said other drugs for treating HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040).

30. A method for treating an HCV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of interferons, ribavirin, analogs, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, or mixtures thereof.

31. The method of claim 30, wherein:

12. The compound of claim 1, having the following formula:

wherein M is substituted alkyl.

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(13) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DL1ROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFNbeta;

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(13) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus

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IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFNbeta;

13. The compound of claim 12, wherein said substituted alkyl is selected from hydroxyalkyl, substituted hydroxyalkyl, cyanoalkyl, substituted cyanoalkyl, and trialkylsiloxyalkyl.
(14) said ribavirin analogs are selected from the group consisting of rebetol, copegus, and viramidine (taribavirin);

(14) said ribavirin analogs are selected from the group consisting of rebetol, copegus, and viramidine (taribavirin);

14. The compound of claim 1, having the following formula:

lb. The compound of claim 1, having the following formula:
(15) said NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;

(15) said NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PS1-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;
(16) said NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN191;

(16) said NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN191;

16. The compound of claim 15, wherein R⁸ is H.
(17) said alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;

(17) said alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;

17. The compound of claim lb, wherein R² is aminoalkyl or heterocyclylalkyl.
(18) said hepatoprotectants are selected from the group consisting of IDNI6556, ME 3738, LB-84451, and MitoQ;

(18) said hepatoprotectants are selected from the group consisting of IDN6556, ME 3738, LB-84451, and MitoQ;

(19) said non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and (20) said other drags for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

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36. A new pharmaceutical composition or use for the preparation of a medicament, comprising a compound of claim 1.

37. A compound of claim 1 as a therapeutic substance.

38. The use of a compound of claim 1 for tire manufacture of a medicament for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase, increasing the blood plasma level of a drug which is metabolized by cytochrome P450 monooxygenase, inhibiting cytochrome P450 monooxygenase, treating an HIV infection, or treating an HCV infection in a patient.

39. The use of claim 38, wherein said drug which is metabolized by cytochrome P450 monooxygenase is an HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, an interferon, ribavirin analog, NS3 protease inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, non-nucleoside inhibitor of HCV, and other drugs for treating HCV, or mixtures thereof.

40. Tire use of claim 39, wherein said medicament is a combination of a compound of claim 1 and one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HTV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH

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41. The use of claim 40, wherein:

18. The compound of claim 1, selected from the group consisting of:

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NHAc

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OH

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OH

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19. A compound which is:

or a pharmaceutically acceptable salt, ester, and/or solvate thereof.

20. A compound which is

or a pharmaceutically acceptable salt, ester, and/or solvate thereof.

21. A compound which is

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22. A method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with said drug, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

23. The method of claim 22 wherein said administering comprises administering a therapeutically effective amount of a combination comprising said drug and the compound of Formula IV or a pharmaceutically acceptable salt, solvate, and/or ester of the compound of Formula IV.

24. The method of claim 22, wherein the drug metabolized by cytochrome P450 is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, capsid polymerization inhibitors, other drugs for treating HIV, an interferon, ribavirin analog, NS3 protease inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, non-nucleoside inhibitor of HCV, NS5a inhibitors, NS5b polymerase inhibitors, other drugs for treating HCV, or mixtures thereof.

25. The method of claim 23, wherein the drug and the compound or pharmaceutically acceptable salt, solvate, and/or ester thereof of claim 1 is administered as a single composition to the patient.

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26. The method of claim 22, wherein said improving is increasing blood plasma levels of the drug which is metabolized by cytochrome P450 monooxygenase.

27. A method for inhibiting cytochrome P450 monooxygenase in a patientcomprising administering to a patient in need thereof an amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase.

28. A method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HTV nucleotide inhibitors of reverse transcriptase, HFV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.

29. The method of claim 28, wherein:
(19) said non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and (20) said other drugs for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).