SA515361045B1 - Tripeptide epoxy ketone protease inhibitors - Google Patents

Abstract

Provided herein are tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of diseases including inflammation and neurodegenerative disease.

Description

— \ — Tripeptide epoxy ketone protease inhibitors FULL DESCRIPTION BACKGROUND This disclosure relates to inhibitors of oS su) tripeptide epoxy ketone protease including methods of their action and use. in eukaryotes; Proteolysis results predominantly through the ubiquitin-0 pathway in which proteins targeted for destruction are bound to a polypeptide ubiquitin amino acid 0 207100 7. Once targeted; The ubiquitin-treated proteins act as FSS for the 26S proteasome, which is a multicatalytic protease; which cleaves proteins into short 65 peptides by affecting their three main activities (dal) of proteases. While Ve has a general function in intracellular protein homeostasis, proteasomal degradation also plays an important role in many processes Jie the presence of a class | major histocompatibility complex (MHC) histocompatibility complex programmed cell death class | antigen presentation ¢ WAN growth regulation NF-KB activation Alge processing “antigen” and transmission of inflammatory signals 5 Proteasome 205 is a multi-stimulatory protease complex with a cylindrical shape 7060 kDa consists of YA subunit formed in four rings In yeast and other eukaryotic cells VO JRE all subunits of different outer rings 1 JE subunits 8 different inner rings Functioning of subunits as binding sites for regulatory complexes 195 (08700) and 115 (PA28) as well as a physical barrier to the endogenous proteolytic compartment formed Yo by two rings of Bly subunits

Accordingly; inside living cells; The proteasome is thought to exist as Particle 265 (Proteasome 265). In in vivo experiments it has been shown that inactivation of 205, which is a form of the proteasome, can be easily corrected to inactivate P265. Cleavage of the amino-terminal conjugate sequences of the 8 subunits during particle formation exposes the subunits. The camino-terminal threonine structures that act as nucleophilic catalytic factors.Accordingly, the subunits responsible for the catalytic activity in the proteasome possess a nucleophilic amine-terminal residue »and these subunits belong to the family N-terminal nucleophile hydrolases -No (Ntn) (where the affinity for the end-terminal unit is shail! For example “Thr (Ser (Cys (JE)) and other penicillin moieties 6 Penicillin 6 acylase (another nucleophile JB). This family includes eg 0

PRPP Glutamine (PVA) penicillin V acylase PGA acylase glutamine PRPP | and the bacterial glycosylasparaginase (GAT) amidotransferase that is widely expressed in Bde dll a. In addition to the 686 units of interferon induction ALE B have three Lay subunits (LY), vertebrates olay

BL BS replaces the natural analogues Ally (MECLI 5 (LMP2 (LMP7) / - 101678000 10, respectively; accordingly; the catalytic activities of the proteasome are modified. Through the use of BT different peptide substrates; the main catalytic activities have been identified Proteases for real cell proteosomes: chymotrypsin-like activity (CT-L) that cleaves after large hydrophobic residues; 10/0510 like activity | 0 (1-1) ); Branched-chain amino acid rangshat (SNAAP) which cleaves after small neutral amino acids. It is shown that the activities of the major proteasome Yoo proteases are led by various catalytic sites; due to inhibitors; mutations identified in

— ¢ — 8 subunits Interferon-7 exchange that induces B subunits modulates these activities to several degrees. US Application No. 70097/90597485 relates to classes of molecules known as peptide—ps peptide epoxides 6006065 and peptide a and m-aziridine 8210101085. It is understood that parent molecules © bind effectively, irreversibly and selectively to nucleophilic hydrolases of the N-terminal nucleophile (Ntn) hydrolases and can specifically inhibit the activities of enzymes that have multiple catalytic activity 5. The request relates to 0097/949597. with inhibitors that preferentially inhibit the activity of the immunoproteasome over the activity of the structural proteasome 0 in certain models; The invention relates to the treatment of diseases related to immunity; Comprising the administration of the compound of the invention. in certain models; The invention relates to the treatment of cancer diseases involving the administration of the compound of the invention. Novel formulations and methods for preparation and formulation of the proteasome inhibitor(s) will be useful. GENERAL DESCRIPTION OF THE INVENTION Vo The present invention is intended to provide elie proteosome inhibitors that maintain and increase immunoproteosome selectivity despite increasing other desired properties; In particular solubility. There are two forms of the kasproteasome, the constitutive proteasome and the immune proteasome. Although most tissues express the structural proteasome; Only cells of the immune system (such as T cells and call cells) express the immune proteosome Ye. Ala) to that; The highly expressed immune proteosome becomes at sites of inflammation in patients with autoimmune disorders. And therefore; Selective inhibition of the proteasome immune system can regulate immune responses in multiple clinically relevant ways. For example, selective proteasome inhibitors can block the production of several inflammatory cytokines that have also been targeted by approved biological therapies, including

El, 17-A, and 23-A. In addition, selective inhibition of the IL-6 5 TNF-q immunoproteasome could prevent the function of known autoproliferating T-cell subsets, 151 and 1517 cells, but simultaneously improve the number of regulatory T-cells and T-cell subsets. which are usually non-functional in chronic inflammation. And therefore; In autoimmune disorders, an immunoproteasome to target the immune proteosome oo has great therapeutic potential. For example; A proteasome inhibitor of autoimmune disorders that produces a potentially non-inflammatory effect PR-957 (also known as 5K ONX 0914 selective known) results in symptomatic improvement and disease alleviation in animal models of lupus and multiple sclerosis. There is a need for the development of inflammatory bowel disease and rheumatoid arthritis. There is a need for immunoproteasome inhibitors with enhanced efficacy, greater selectivity, and/or solubility potential. Or (A): (X) Compounds with the general formula 1 M 3 0 R? 0 are available here.

TT px 1 the RN bal N 1 Rehr N 00 0 R2 RE o Ris or 1 © R © nat), 0 )( ye with replacement groups as discussed in detail below. OR Two pharmaceutically acceptable diluents carrier dla sale A pharmaceutical composition that includes Wal is available here or a pharmaceutically acceptable salt thereof. clin A compound such as “diseases” is available. Neurodegenerative diseases include inflammatory disease 10118101181000 and neurodegenerative disease - 0 specifically described rheumatoid, including but not limited to rheumatoid arthritis.

Crohn's and Crohn's disease » multiple sclerosis; lupus arthritis

disease accordingly; Here is a method for treating that disease or disorder in a patient; The method comprises the administration of a therapeutically effective amount of a compound or combination as provided herein to produce a therapeutic effect. unless indicated otherwise; All technical and practical expressions used herein shall have the same meanings as are generally understood by the person of ordinary skill in the art to which this disclosure belongs. Methods and materials are described here for use in the present disclosure; Lag can use other appropriate methods and materials known in the art. be material; roads; The examples are illustrative only and are not intended to be limiting. All publications » and patent applications are included; patents «sequences»; Database Entries” and other references are mentioned here for reference 0 in full. In case of conflict" it will JF on the Jal description including the definitions. Other features and benefits will be evident from the detailed AEN descriptions and forms and claims. Description 1 for detail: Definitions 1 For the expressions 'eg 'JE' and the grammatical equivalents of 'without limitation' is understood to be applied unless otherwise clearly stated. As used herein the expression 'about' is meant to indicate variations of the result of an empirical Tadd. It is understood that all measurements shown here are modified by the expression 'about'; Whether the expression is used explicitly or not unless otherwise indicated. As used here, the singular indefinite forms of 'knowledge' and 'knowledge' 0 include plural references unless the context expressly states otherwise. As used herein, chemical structures containing one or more stereocenters indicated by dashed bonds and in bold (ie, my cnn) are intended to denote the absolute stereochemical features of the stereocenter(s) present in the chemical structure. As used here, links denoted by a simple line icon do not

—y— to holographic existence. unless otherwise indicated; The chemical structures that include one or more stereocenters and are illustrated here without the absolute or relative chemical characteristics are possible stereoisomers (JB die lo) of the compound pall all Gea and mixtures thereof. Structures with a thick line (enantiomers, single diastereomers or as a dash and at least one additional simple line; include single enantiomeric series 0 from all possible diastereomers. Single enantiomeric series

Contrast of racemic mixtures can be accomplished by any of several methods known in the art. An illustrative sale method involves fractional recrystallization using a polar decomposition acid which is Waa active (Jus organic acid of a salt. Suitable degrading agents 0 for sale methods) Fractional crystallization; For example; are optically active acids »; Like the pictures, no, tartaric acid ¢ Diacetyltartaric acid 8660 diacetyltartaric ¢ dibenzoyltartaric acid Mandelicacid malic acid lactic acid; Or multiple camphorsulfonic acids, Vo, Jie, Camphorsulfonic acid. Other solvates suitable for fractional crystallization methods include stereo-pure forms of methylbenzylamine (eg die 5 Really, or stereo_pure no018516600081108); . Jud—Y glycinol 16100/AA9ala0060 “_norephedrine ¢ ephedrine—N » ephedrine methylephedrine; cyclohexylamine gd gh -¥ 1 1 cyclohexylethylamine cyclohexane

diaminocyclohexane » and the like. Contrast of racemic mixtures can also be accomplished by eluating on a Lome column with a decomposing agent (si gh JED due Jl) Wan ba benzoyl. dss glycine (dinitrobenzoylphenylglycine). Appropriate eluting solvent formulations can be determined

Yo by an expert in the art.

—A— Compounds provided here can also include all similar types of atoms resulting in intermediate compounds or final compounds. Similar species include those having the same number of atoms. Includes species similar to hydrogen (atomic JE but having different mass numbers. For example, deuterium; tritium; Syntax used herein is to include all stereoisomers; All compounds can exist; chemically acceptable salts terminated with other substances such as water, solvates, hydrates, and solvents (eg, hydrates 0 products) to saturated or unsubstituted hydrocarbon groups; “yalkyl” indicates The expression '/a-#© alkyl includes straight-chain alkyl groups and branched-chain alkyl groups that have * to no carbon atoms in the chain. For example, alkyl refers to alkyl groups with number of carbon atoms) Also, subgroups (on 1 to 1 carbon atom). The range includes all J (ie; no carbon atoms). The expressions 1 eo cf FY 1 FF om) Y= JB allowed Ve aliphatic pathways to unsaturated or not yalkynyl and C2-y yalkenyl groups. have the same length and potential substitution as the alkyl compounds described above, but contain at least one double or triple bond, respectively. To an alkyl group with a ©0779 oxygen attached to it. Includes alkoxy ethoxy ethoxy methoxy illustration alkoxy alkoxy groups Yo is "ether" and the like. The tert-butoxy ether is 1 propoxy two hydrocarbons attached to oxygen. Accordingly, the alkyl substituent group that makes the alkoxy or its like is an alkyl ether.

q —_ _ denotes 'a-*© alkoxyalkyl J)" yalkoxyalkyl Cx-y alkyl group; as previously defined;" and has a de ganas substituted with an alkoxy e.g. Cl-6 “alkoxy alkyl” denotes a 6-01 alkyl group substituted with an alkoxy group, thus forming ether ju The expression “/a-”*© denotes aralkyl yaralkyl " to a /a-*© alkyl group; as previously defined © and substituted with an aryl group as JE The expression "61-6 (duly) as used herein denotes a 6-61 alkyl group have an aryl group substituted. The terms 'amine' and 'amino0' are known in the art and denote both the substituent amine R p £ —N, Ed and salts thereof; Fie half It can be represented by the general formula: R R + or R ¢ where each R ie gana over Baa represents hydrogen “alkyl-3alkenyl-3”—(CH2)b—T

A nitrogen atom plus the nitrogen atom be of which they are R or two of the 7 0 groups to which they are attached complete a heterocyclic having a number of atoms of ; to 8 in the ring structure; N ; heterocycle cycloalkenyl; aryl cycloalkyl; Cycloalkyl Jia

heterocyclyl or polycyclyl ala0la0la00 ; 5 is a zero or an integer from 1 to 48. In certain embodiments; The amine group is basic; This means that the image has been added

onl is greater than 7.00. In some embodiments; pKa denotes a proton having a 1 and an “amino” moiety that is covalently bonded to a nitrogen atom with or without a substituent. It has a carbonyl substituent in domain Bicarbonyl 'amido sud' ' amide aud' both expressions are known

0 to the amine and includes a moiety that can be represented by the general formula: Ww . in some embodiments; Amides will not include amide compounds; which may not be fixed.

0 The term aryl as used herein includes single-ring aromatic groups having 0, 76-, and -atoms with or without substitution and in which each atom of the ring is a carbon. The term "aryl" also includes multiple ring systems having two or more rings in which he is

"yam two or more carbon atoms shared with two adjacent rings where at least one of the rings is aromatic" for example; Other rings can be cycloalkyls cycloalkynyls + cycloalkenyls cycloalkyls + cycloalkyls ; and/or heteroaryls Jo (dy compounds); cycloalkynyls « benzene aryls Aryl groups include benzene Jheterocyclyls heterocycle © ; what aniline; Aniline phenol “phenanthrene ulus; naphthalene Jie” halogen similar. in some embodiments; The aryl ring can have a fluorine substitution with a halogen of the form Je carbocyclyl and a carbocycle The term denotes a carbon ring with or without a substitution and which is 17-non-aromatic with the number of atoms ?- to dala used here to 0 in which every atom in the ring is a carbon The ring can be completely saturated or it can have one or more unsaturated bonds so that the ring remains non-aromatic. Includes The terms "carbon ring" and "carbon cyclic" are also multiple ring systems which have two or more rings in which one or more carbon atoms are shared with two adjacent rings in which at least one of the rings is a carbon ring; For example; Other Vo rings can be cycloalkyl compounds; cycloalkyl compounds; cycloalkynyl compounds; aryl compounds; heterocyclic; and/or a heterogeneous cyclel. Carbocyclyl dif compounds include; cyclopentyl; Cyclopropyl except 0M7010010©; Cyclopentyl Carbocyclyls cyclohexylmethyl ¢ cyclohexyl ; Cyclohexyl cyclopentenyl and;- methylcyclohexyl ala*©00a0/AA/A0061. Examples of polycyclic carbocyclines include bicyclo[2,2,1]heptanyl, spiro[7-;] heptanyl, Jala [1-7-7] cyclo GL .adamantyl and adamantyl » norbornyl » spiro 2.4]heptanyl as used herein denotes a ring with the number of atoms? includes -17 to polycyclic systems with two or more rings in which a carbon atom is Unf _the term "cycloalkyl" vo

-11- One or more co-rings with two adjacent rings where at least one of the rings is a cycloalkyl ring. The term "cycloalkenyl " as used herein denotes a dala with or without ae -17 JY atoms substituted in which each atom in the ring is a carbon. The ring includes one or more unsaturated bonds such that the ring remains non-aromatic. The term JEL “alkenyl” nd includes multiple ring systems with two or more rings in which one or more carbon atoms are shared with two adjacent rings and where at least one of the rings is a cycloalkyl ring. The expression 'carbonyl' is known in the domain and includes hashes containing the group 0-0; 0 0

X to + where J Afr a is that which is represented by the formula (JB for example 0 hydrogen is hydrogen R and represents csulfur or sulfur oxygen is a bond or represents oxygen an alkyl hydrogen; Alkenyl or RT or a pharmaceutically acceptable salt; represents —(CH2)b—T (Jus (Jill 0) where 0 and 1 are as defined above. Where L is oxygen “—(CH2)b—T is oxygen X from hydrogen; the formula represents an "ester". When He is 4 and is not "a or . carboxylic acid is hydrogen"; the formula represents "a carboxylic acid R and is 1 over Defined syntax Js Oxy The expression “not-*© aralkyl heterocyclic” denotes a group

C16 “(JB) prefixes; has a hetero-aryl group substituted. For example, hetero-aralkyl”; as used herein denotes a 6-6-alkyl group with a hetero-aryl group substituted. 0 The term “aryl heterocyclic” includes aromatic structures with number of atoms from 0 to 7 with or without casa (eg JB rings with ©- to - atoms; in which the ring structures include one to four heteroatoms. The term "heteroaryl aryl" also includes polycyclic systems which have two or more rings and in which two or more carbon atoms are shared with two adjacent rings and where at least one of the rings is an aromatic heterocyclic ring; eg

-117- The other rings could be cycloalkyl compounds; Cycloalkenyls; (JB) cycloalkynyls; aryl compounds; heteroaryl aryl compounds; and/or cyclyl compounds other than pyrrole 07016la 0 furan (Jha) congener. Includes heteroaryl aryl groups; e.g. thiazoles oxazole imidazole thiophene thiophene ¢ furan pyrazine pyridine pyrazole triazole © thiazole and the like In some embodiments it is possible that the pyrimidine; nitrogen Heterocyclic atoms include nitrogen (JR). For example sulfur and sulfur » phosphorus phosphorus oxygen | 0 The expression 'heterocycle' or 'heterocyclic group' refers to cyclic structures non-atoms; for example, rings of -01 aromatic with or without substituents and with ?*- to whose ring structures include one to four non-atoms homogeneous. oY to Fal The ring can be completely saturated (eg; The heterocyclic cycloalkyl) or the lo cycl can have one or more unsaturated bonds such that the ring remains non-aromatic (V (heterocyclic cycloalkyl). The term 'heterocycle' or 'heterocyclic group (JE') also includes multiple ring systems having one or more rings and in which two or more carbon atoms are shared with adjacent rings where at least one of the rings is Other rings can be JED heterocycles; for example, cycloalkyl compounds; cycloalkyl compounds; cycloalkynyl compounds; aryl compounds; heterocyclic Ye compounds; and/or non-cyclyl compounds Non-dy cyclyl groups include piperazine pyrrolidine eg piperidine piperidine ulate lactones morpholine morpholine lactones “pyrrolidine” and the like.

Q1 The expression “/a-*© yhydroxyalkyl” refers to a group “(JI Cx-y as defined 0” Bl in which a hydroxy group is substituted. For example, “01-6” denotes "hydroxyalkyl" to a 6-61 alkyl group substituted with a hydroxy group. The term thioether (fi)oF denotes an alkyl group; as defined above; it has a sulfur moiety attached to it. In some embodiments, the "thioether" is represented by - -8- alkyl. The fi) groups of the annotations include methylthio sf ¢ ethylthio " and the like. The expression “substituted” refers to moieties having substituent groups that substitute hydrogens on one or more non-hydrogen atoms of the molecule. The term “substituted” or “substituted by” will be understood to imply that such substitution Ey is of the permitted valency has for the atom or 0 substituent group” and the substitution is caused in a stable compound, for example, which She Jill WEE is not subjected to by rearrangement; cyclization, GRY etc. As used herein is meant by Substitute” to include all permitted substitution groups of organic compounds. in a comprehensive aspect; Permissible substituent groups include substituent groups for organic compounds that are cyclic and acyclic; branched and unbranched; 1 carbonaceous and heterocyclic; Aromatic and non-aromatic. Allowed substitution groups can be one or more similar or different suitable organic compounds. Gaal the purposes of this disclosure; Heteroatoms such as nitrogen can have hydrogen substituent groups and/or other substituent groups allowed from the organic compounds described here that achieve valences of heteroatoms. Substitution groups' can include 0 - eg; alkyl alkenyl; alkynyl; halogen hydroxyl; carbonyl (as carboxyl; ester; thio 101065161 ji.) alkoxycarbonyl “formyl 0” or “(acyl Jel) thiocarbonyl ( such as thioester; thioacetate or thioformate (alkoxyl thioformate; phosphoryl “Yo phosphate”; phosphonate; phosphinate; amine

1- amido sad « amino; amidine imine Cyano Nitro ii « cyano ¢ Azido 22100 « sulfhydryl » alkylthio; sulfate sulfonate sulfamoyl « sulfonamido ¢ sulfonyl sulfonyl ; carbocyelyl (eg; cycloalkyl; cycloalkyl); a non-homocyclic cyclase (eg, a heterocyclic alkyl cyclo); aralkil; aralkyl is heterocyclic; or an aromatic moiety (ie, an aryl) or a heteroaromatic moiety (ie, a heteroaryl). sled owners in the field will understand that substituent moieties on the hydrocarbon chain can themselves be le substituents; If appropriate. in some embodiments; oS The replacement group is halogen; Like Laie's, Wfluorine has a 0 chemical functional group that has more than one substitution group; Substitution groups can be bonded to the same carbon atom or to two or more different carbon atoms. A chemical functional group that has a substitution itself can include one or more substituent groups. in some embodiments; The compounds presented herein or their salts are largely isolated or purified. By the expression 'largely isolated' it is meant that the compound is partially or largely separated from the Vo medium in which it was formed or exposed. Partial dismissal may include; For example JB is a composition rich in compounds presented here. The class can largely include compositions containing at least about +965; at least about BT at least Ye ds at least about 60# at least about 96960 at least about 9695; at least about PY or on JE about 9694 wt vehicles; or salt thereof. Methods for isolating compounds and their Ye salts are routine in the field. The term 'preventive or curative' treatment is known in the art and includes administration to the host of one or more formulations subject of the invention. If the composition subject of the invention is administered prior to clinical manifestation of an undesirable disease condition (eg JB disease or other undesirable condition in the host animal) then the treatment is prophylactic (i.e., protects the host against development of the disease condition undesirable Yo desirable); while if the composition subject of the invention is given after the appearance of the condition

a J \ _

Unwanted pathology The treatment is curative; (ie; scheduled to be curtailed; or

mitigation; fixation of an existing unwanted condition or its side effects).

The term "proteasome" as used herein is meant to include proteasomes

Immunoproteasome and formative. In some embodiments, the detection compound is significantly inhibited

o Preferred immune proteasome.

The expression “1208 as used herein refers to the immunogenic proteasome 208

The term "0205" as used herein denotes constitutive proteasome 205.

As used herein, “RES” is intended to describe a compound that inhibits or reduces the activity of an enzyme or an enzyme

system of enzymes or receptors; or another drug target (eg, inhibition of 0-lysoprotease cleavage of the standard fluorogenic peptide substrates Jie Mexenil (Leu-Leu—Val-Tyr—-AMC-

(Z-Leu-Leu-Glu-AMC , Boc-Leu-Leu—-Arg—AMC) Inhibition of different catalytic activities

to the proteasome 205). An inhibitor can act with competitive inhibition; or non-competitive; or not competitive. maybe

to bind an inhibitor reversibly or non-reversibly and thus; The expression includes compounds that are lethal substrates of

the enzyme. An inhibitor can modify one or more sites on or near the active site of the enzyme; 05 or can cause a conformational change in the AT site on the enzyme. The expression inhibitory is used extensively

More broadly here than in scientific articles for Wadd to include other classes of pharmacologically useful agents

or therapeutically; Jie catalysts; antagonistic agents; Catalysts"; common factors; and the like.

Ald A “therapeutic” of a compound in relation to the method of treatment subject to the invention; denotes an amount of

The compound(s) in a preparation where; When administered as part of a required dosage regimen (to a patient eg yo; human) satisfactorily attenuates or improves ALA presentation; or slow down ly cases

Satisfying Gy of Accepted Criteria Us) for the disorder or condition being treated or

cosmetic purpose For example; with a reasonable risk/benefit rate that can be applied to any treatment

As used herein the expression 'treat' or 'treat' includes the opposite of; or reduce »; or suppression of symptoms and clinical signs; the underlying pathogen of a disease state in a way that improves or stabilizes compounds 0 in one aspect; The list provides a compound with the formula (©); or a pharmaceutically acceptable salt of which: 2 Hy iP 1 1 R* Ny x 00 0 hum km) 4 0” nm b n R® 9 1 where: each of 177 and 7 independently is yellow 1 or 7 and 00 + SFY =n ; m is zero or 1; Sle q Yo for zero oo) 31 a is chosen from the set of (CR5R6 Tekla —NH— (N(C=0)OR7 “(C=0)—0 y” SO and 502; E is “CR7 JN) RT is selected from the set consisting of (H 1-6 alkyl; C2-6 alkyl; REN C2-6 1 63-6 cycloalkyl; and cycloalkyl has ae = F atoms where in RT is optionally substituted with one or more The substituent groups chosen from the group consisting of halo ORT ¢(C=O)N(R7)2 5 «CN (N(R7)2 7 R2) are 61-2 alkylene6©-- or —G(C=0), where © is chosen from the group consisting of an aryl, heteroaryl, and pyridinone, provided that Laie is R2 0 being CH2 phenyl In vinyl, one or more combinations are substituted

for \ _ substitutions that are chosen from the group consisting of (Jil 01-3 “sila (ORT 00]3;” CN ((C=O)N(R7)2 SO2R7 and 50210(87)2; R3 is chosen from the group of 7-63 cycloalkyls” 7-63 cycloalkyls; a heterocyclic alkyl having atomic number VF and a heterocycle alkyl having atoms number 7-7; where © is in 3 optionally substituted with one or Most of the substituent groups chosen from the group consisting of Cl-3 «O(C=O)N(R7)2 (N(R7)2 SR7 087 =O »la 6alkyl;4 are JH 61 3-alkyl R65 5 each independently selected from the group consisting of OH (H halo; (Jif 01-3 0 and 0]3; or forming ke R65 RS plus the carbon atom that associated with 1 C=0 or r ¢ where WwW is 0 or NR7 ¢ and r is Y 1 ¢ or 7 ¢ and each RT is independently an expression for JH 61-6 alkyl In some embodiments 77 is a 0 In many embodiments the 0 is a f in some embodiments m is a 1 In some embodiments the 0 is is BLY in some embodiments; © is .1 in some embodiments; © Ble is about zero. in an embodiment; n+m is XY in many embodiments; n+m is ?. in many incarnations; Ble NEM is about 4. In some embodiments; m is yellow and in many incarnations”; m is 00 in some embodiments; 0 is zero. in some embodiments “9 is .1 in many embodiments”; 0 is 7.

m \ _ in some embodiments; m is zero and NEM is 4. In many embodiments it is; M is 1 and NEM is 4. In many embodiments it is; M is zero and 07+00 is ?. In many incarnations it is; m is 1 and 70+00 is LF in some embodiments; where m is zero and NM is © for ?. in some embodiments; M is 1 and NAM is ?. in ax embodiments; K is .CR5R6 in some embodiments; R6 R5 each independently is (CH3 (F (OH H) or 011260013; or forms R5 and 6 ke - plus the carbon to which they are bonded 0-6 or OTF where © is .1 eg. K is chosen from (CH(OH) (1A6113()0) “CH(Cl) (CF2 (CH2 (”C=O 7] . COH(CH3); (C— (CH(CF3) 0 in some cases”); K is -CH(OH) in many embodiments; Ma is (NRT) and is RT is “CH2CH3 H or .CH3 for example.” Jal may include NCH3 K or NCH2CH3 in some embodiments; sje K is of N(C=0)ORT7 (on For example, “(N(C=0)OCH3) § N(C=0)OH —NH—(C=0)—5; 50; or 502. In many embodiments” is ple K of 0. V0 in some embodiments; BE is NN in al embodiments and p is a CRT eg CH (Jd) or C(CH3) in . Many embodiments; BE is NO or CH in some cases; 5 sje is N or CH and se K is 0; CH2 or .CH(OH ) fg by K~) in some embodiments; ge OR) is the combination of:

0 0 a m 7 but ha N ~~ ‘ 0 0 0 0 0 6 0

EHO0

N N 2 JENS Gl 1-01 « Cl ' ' 0 ' 0 mah no DB :

N

0 Dp Hamh 1 0 ¢ 0 + 0 ¢ 0 ¢ FsC « F 0 OR LOT By ¢ 0 ¢ 0 0 ¢ HO 0 ¢ 0

Me HO HQ Q HO

M

Oa 4 A 2 but not Ta 0 3 0 3 0 3 0 3 0 5

Me 5 HO N 2 N Me 0 SIT 0 the 0 / ¢ HO ¢ 0 [4 0 0 ¢ 2

N

SY ap. Me and ¢ HN. 0 0 + shake Et : o OL 0 Lh 9 in different cases; is selected

HO 0 or Ta ov 0 .HO 6 and 0 ' 0 is 3-61 alkyl; RL is 6-1kyl or RT in some embodiments; For example, “CH2CH3” or “CH2CN” CH(OH)CH3 “CF3 (CH20H (CH3 (is)

RI in various embodiments; is .CH2CN; CH20H (CH3) 1 can be selected from “Ji

=” \ — Sle for “CH2=CH2CH Jie (Just C2-6 or C2-6 alkyl). Ex. CH2C=CH. in some embodiments; ple RI for 6-63 cycloalkyl eg “cyclopropyl” cyclobutyl “cyclopentyl” or cyclohexyl in various embodiments; RI© is a heterocyclic alkyl with 1 7 atoms; eg oxetanyl Vi tetrahydrofuranyl or piperadinyl . In some embodiments the 42 is a 2-01 alkylene heterocyclic aryl eg Jy ) -©112 (Ji) heterocyclic. in multiple incarnations; 42 is 2-61 alkylpyridinone. in multiple incarnations; R2 is Cl-2 alkylene-aryl. in ax 0 embodiments; R2 is 112©-aryl. in some cases; 42 are selected from the group consisting of: O07 through O07 MeO F 3 0 « MeO « 0 OH oT 3 \ kJ MeO,S of pn jog W MeO ' ' H “ToS” ¥ oa of or NC ' 0 1605 " 05 ' M and B Q B Q 0 A HN.

OR N 3 0 3 © N « MeN © 3 Ss Your friendly ory JOY «HO Node ' N '

H rr H or Me Or H BOS ¢ Et « Me ¢ HO « MeO

MeO ¥ ye H BOR Me Tr Me or ¢ OMe «HO « MeO «HO

OMe OH HO Be MeO 9©“ “RE” “HO” MeO ' OH ' OH 577 0 “All that you are” MeO 2 1 J ¢ N 0 D 0 0 OH or or or or MeO Or « MeO » FCO « MeO.S ¢ NF©

N

J Hayy yr OY 3 3 | 2 3 NA ¢ Z 2 «F 7

MeYYNr. 0 2 3 ¢ Me” N 2 from the group consisting of: RZ in various embodiments; is selected

Oh

“Lee Sun” ea [4 ¢ HO ¢ MeO ¢ MeO

H H M H

9 2 ~~ DOR “OY BOR . Et «Me. HO «MeO 11

MeO for 104 OY NON Me JO ¢ OMe ‘ HO ‘ MeO ‘ HO

OMe OH HO Be MeO ©“ and [Sans . HO and MeO ¢ OH ¢ OH “MeO” MeO in some cases; 42 is

Oh

OY jon: .Me or “MeO” of the group consisting of: RZ in various embodiments; © 0 OF BEAM SOR

N N 4

H ¢ H « O ¢ ¢ H [4 H ¢ H ¥ ¢

SO H (J LI and 07-0 « H

son

> . H from the group consisting of: R2 In some embodiments 10 is selected

N

Ham OY “Wi w [4 N 7 [4 Z [4 N %] 4 F [4 F 7 A JT L ~d Moi Bhan P F]

tucked in in some cases; RZ is chosen from the group consisting of: OY Ng Bq oY FsCO « MeO F ' J ' or . IGANG Ran GANG id nor see) HaNO2S MeO,S OH or ow IT or Me NF . © MeN MeO,S 0 0 oie “m” “© OOF ° , 00, 00 In various embodiments R3 is eg 7-63 Cyclo JS Cyclopropyl Cyclobutyl Cyclobutyl Cyclopentyl; or Cyclohexyl. In some embodiments, the 7-03 cycloalkyl is substitutable with at least one substituent group chosen from the group consisting of NH2(CO)O 5 012 (Me (F (OH)). cases; R3 is 0 is cyclopentenyl or cyclohexyl. In several embodiments the 43 is 63-7 cyclo Jie (Jaf) cyclopentenyl or cyclohexyl. In some of these embodiments it is 03-7 Cycloalkenyls substitutable with at least one substituent group chosen from the group consisting of Me;OH in various embodiments; 43 is a heterocycloalkyl with 7-7 atoms”; for example (JE tetrohydrofuranyl tetrohydrofuranyl ; tetra Vo hydro tetrahydropyranyl (ulus + pyrrolindinyl + or pyrrolidinyl 01000A07/00. In some embodiments; 43 is a heterocycloalkyl with ccd 7-" eg" Di Hydro Piranha l dihydropyranyl or dihydrofuranyl .dihydrofuranyl

an. 1 1 1 1 1 inf “¢ “a,” “nn, a rn “a,” “on, af LOS kk m [=o N N H ¢ H « Me 1 ¢. F HO ¢ ' 1 0 1 8 mm mm 0 00 = L 3 0 NH; > Me d NH «¢ » 00 o 0 0 In some cases, R3 is “an intentional reparation of o from 3 d 1 or 2 . In some cal R3 is 3d or 2 and 9 is 0 or 3 or 9 is a in some embodiments; 44 is 3-01 alkyl; Jie is methyl or ethyl. in multiple incarnations; RE is AH in some cases; REA is methyl. RA is J, specifier presenting compound 8,KY of dye X includes 0, + » as then described in « R1 1 0 as then described by ¢ R2 as then described by ¢ R3 As then ¢ R4 as then described. In some illustrative embodiments: 77 and 7 are independently ?; m is 1;0 is; K is 08586 or ©0; E is for 8 or CRT, Rl is (CH2OH (CH3) or CH2CN (CH(OH)CH3) or oxytaniyl; 2 is MeO OH 3 HO HO : W 7 4 MeO ' MeO or Me ¢ R3 is

_ \ AG 2 is RE, tH is RS, is methyl; be RA or; be +

H is RT 0; It is of: (X) in some embodiments; A compound is chosen according to the formula

HO. oy o H Pls @N 0 Fx “hep Ee 3 0” ‘ 0”

CNG

CXLES 7

N Ton © 0: “N Ton 0 H © H ©

ONT N Yb N oJ © H o 0 L A >

N Ton for you ©: " 6 0 0 0 0

ONY ro o J o H 5 0

O.L

F oN

Hof H 0 ©.) N Ybb N 1 0 & o

N N

0 0 0 0 ONY (oJ) o 0 60 0-0 6 0

HofH0

N Py N 0 0

IS 0 " 0 Yap «NH A Pi »

N N H © M ©

IS ©: H SE OY N B N SL

Oo.

A & i , ml N N 0 iS 0 H SE NY N b N SL oJ) o H n 0 0

Oh

0 0 0 >

N N 0 0

Hoo Hoo 1N

ONY o oJ o " 50 ¢ ¢ 0 > 7 0 H © 0 0 0 0 0 1 SPP \

HJ H Hol HJ : 0” : 6 0=8=0

O.L

Hof H 0 H 0 H 0 without sacrifice N NY N oJ o " o| his 6 Ho 0 ¢ ¢ 9 b 0 >

N N N ybb 0 0 Lys 3 ' 0

0 H 0 0 0 0 0 0 0 H 0 H 0 0 0 0 0 0 0 > 0 0

H H

0 0 0 N N

H

N N o 0 0 0 0 0 ¢ 0” ‘ 0 4 0 oJ m 0 °o| oJ o 0 0 0 F ' HN ' F 7 > 1 A 0 ml N N 0 0 0 0 0 tah " §& H © i 0 l 0 H 0 0 ¢ 0 [3

Oh

\

N—¢© OH oY 09 ho © 0 0 0

H 6 lo) 0 0 6 0 ' 0 ' cL

N

0 0 lo) 0 oY 0 0 :

H J H § Ho for 0

Vv ¢ 0 ¢ 0 0 > 0 0 oy wm 1 i LQ ~~

N A N N N E N 1 N a N N " 2“ 0 OU 0 "N 5 ' 0” ‘ oN Ow

H 0 & 0 H 0 1 0

N N ug 0 " o| O 0 0 0

F

[3 [3

_ Ad «=

ONG oO.

F. NY oy N N >) 0 " 5 0. LO H J 5

Fr [3 [3 0

N

NH,

ONY a CNTY Ton oJ © 0 o| oJ o 0 0 [3 [3 b W 0 0 0 0 0 H 0 7 0 6 N N N b 1 N 0 0 o) " n 6 od ' 9 _NH, k' 0 0 0 0 m A N m 1 i 1 i

N N ONY a

H H

0 0 0 oJ o " 0 ' 0

0 0 0 0 lo) HO 0

HN N N L N

H 0 H 0 H o H 0 0 HO ¢ 0” ¢ ol

Oh

0 0-7 ~ 0 0 H © H 0 o o

Ay N y 1 0 " n o| ] ybb oJ) o 0 0 [3 [3]

Oh

(ONG lo) ; lo) 0 0 : 0 x 0

J fo) 0 fo " 6 0

Oh

0

HO

; fo) Y o lo): lo) 0 73 00 6 6 6 fo) HO 6 0”

_— \ since OL WEP ml LAA CT OY }= HN 0 0 0 0 0 0 =N N=\ NH NH (no wind (oJ) 6 0 0 oJ) © 0 0 ¢ ¢ OH 0 (ONG 0 HO N N N ybb N ONY SE: oJ o 1 " 8 ¢ ¢ FE F y © 0 0 H © O 0 0 or N A N N or N N N 0 HO 0 HO © 0 6 “0

_ except 0 (9 0 0 0 8 0 0 0

HO M 9 © ' p: 4 0

NH

N N N N

B: © for you o) 6 jon fo) H ©

Ho Ho 0”

Oo.

HO

Ty 5 | Ta ll

VY NY SONY LN oJ o " 0 "oo Ae!

Ho:: 0

Oh

O.L

CEs | O.L.)

H H for oJ) 6 0 0 0 .

F

<r

0-5 0 0 0

H on fly | TEL or.

N N H J H 0 'm H §

HO No. 13 0” 3 H (ONG

HO Q Ho 0 0

H©VE N

N N

N N a H N H_o 0 H © . HO ¢ 0 ne “NH 0 th 0 0 1 0 0 0

N

N N NY ro 60 0 o 0 0 0

HO

' 0 ' 0 [oN ~

H © nH © H i 1 i

N N

NY YBB ©© YBB 1 1 oJ) 6 0 0 0 0 3 [3 [3 F]

H as 0 Nd 5 HO 0 hee 007 H HO 0 0 0 0 0 ' 0 ' x 0 0 0 ' 0 0 0 _N 0 0 0 0 '0 ' 0 OH Ng n m 0 oY fo) Se N N N N GY oJ) © " 0 0" 0 No H ' H o N¢Zo lo) lo) 0 AF HALF N N CY CYT overt HO o 0 0 0 NS ~N 13 '

!and N=\ NH HO HO 0 6 0 0 Ts bug | & b Ae n I H SE H o” 3 3 (ON 0 Hof H 0 Hof H 0 N N NYY N N 22 0 n " oJ 6 Ho o| oJ) o ¢ ¢ OH Hof Hf 0-5 fo) 0 0 YY N SPIE \ oJ) a, 0 0 8 H 0 NH m 3 3 0 6 0 0 6 H 1 0 0 0 Ds 666: a a © 2 m gon 0 £8 O ot '0'

Oh

Oh

1 A "0 1 A 1

N N N N

SAAS SE Seas SE [3 [3

HO 0 0-5 0 H © 0 5 0 0 fo

SEE Ts dent ANN © nol nol ' 0” ¢ 0”

Oh

09

Ho Hof 1 for 1

N N N N

JY Th SL UTA IL [3 [3 oO a Nod

HQ & 0 1 0 7 0 Ku 7 Alorat [3 [3

0-ou

Ho 9 H O 0 0

SRLS N money: oJ) 6 Ho 6 ig 3 H m 5

HO

[3 [3

TN NH

H H 0 Hof H 0

SRLS N AN N oJ o " o| oJ o " n 0 [3 [3 0 6 9 & :

HQ 0 0 & 0 B N H H

N N N N rT SL 06 l [3 [3 hy © HO gravel 0 hoo 0

SRS N PAP N oJ o “ 0 Ho H_o 1 1 0”

_ «= _N 0-1 0- >

A ed o 0 LH 38

N N N N

SEARS SLIRSR AEOL

= [3 [3 0

ONG2N

Hof Hf Hof > 0

N ro N N ro N

N N N N

66 ROR: 6 ry [3 [3 %]

HO©0

YY A

H N N oS 0 1 for you I H SE [3 [3 9

N05

N A N L N AKMO A RR OL [3 [3

Oh oh

0" fo) hoo 0 0 fo) 0 0

N cel. N se Ng N cel. N “m 96 0 0 0 0” . H,N . HoN oN and yO ° oY o hy © 0 on LAK N nA N 8 9 § " § H © ¢ 0 3 [4 0” of it. Wana or an acceptable salt of the group consisting of: (X) of the formula Ga, in some illustrative embodiments; Compound © is selected

Oh

0-

HO

H 0 H 0 0 H 0 0 It only takes: 0 0 0 0 HO 0 0”

0 oY fo) on 0 0 oY lo) Pe 0

NA N 1 NOL N y

H Qe for H © Ho ' 0 ' 0

ON ON

HO

A 1 inl N N N N . © N ISL Yours Eee SE [3 [3

Oh

ONGOL

HO

N N N N

SANE SL SANS SE

[3 [3] [3

ON

HO y © aq 0 oy and hy © 0 2 N 8 N b N x _ N A N A N Se oJ o© Ho 0 H l n

HO

1 1 0

Oh

H © H 9 9 "0 o 6 b AA N oJ o Ho 0 " n Ho

HO

1 1 0

Oh

CN

N i Pi Hof & 0

N N N N

60 L jean Se 0 0 0 0 0 0 0

HO

3 [3 [3

ON py 0 6 6 fo)

NZ

[3 of the group consisting of: (X) in some illustrative embodiments; A compound is selected according to the formula ©

Oh

Oo.

HO

Yep (fo) Se) 0 fo) N 6 jon N N

H H §

HO 0 ¢ 0 0 0 fo) OH 5 0 0 fo)

AR TH " TAR Lx ° 96 6 6 6 0 0”

Oo Oo.

H © H 0 H "8 0 R mys N © N oJ o H 5 ol oJ oJ " M 0

Oh

ONG Oo. 0

N N N N

SANE 1s SANE SE ¢ ¢

O.L

HO

H 0 7 0 oY 0 0 0 The Ln A AN N oJ o© Ho 0 "n "

HO

' 0

Oh

H 9 H © 0-5 J 0 0 an AA N oJ mouth Ho 0 H n n Ho

HO

' 0

—¢0—

Oh

Oo.

A 1 7 ِ 0

N N B 1

JET SL STE r= 3 [3 [3

Oo.

N N

N ~~ [3 or a pharmaceutically acceptable salt thereof. Of the group consisting of: (X) of the formula By eg; Compound can be selected

ONG

HO OH

0 0 0 0 0 0 (NY eed Ch JA v se oJ 9.” o 0 “og AL © 3 ¢ 0 fo)

Oh

ONGOL

N N N N

6 SE © Gs [3 [3

O.L

HO oY 9 0 0 0 HO

ATA Ts Lahis Seed mo ASL © oJ o Hoo 0 ‘ o’ ‘

Oo.

HO HO oy and Te 0 y © gy © _ N A N 1 N Ts H N 8 N B N od "og Ao oJ M 0 0 ' 0

Oh

O.L

0 0

H 0 9 0 H H b N a quantitative N

N all" lee 0 H og oJ) © " n 0 ¢ ¢

Oh

ONG

PPG: HA i

N N N N op Lys 017 5b yum ¢ 3 ¢ or a pharmaceutically acceptable salt thereof. 0 Stereochemical: USE (X) of the formula By od all of yall is in y © R2 y ©

TL el 0+0 m 0 o_ 6 20

Loon RS a

in many incarnations; A compound is chosen according to the formula (X) from: HO, Ne hy © ' 0 m d f 0 0 0 mcl Sia ils SSUES Ho Ho Ao Ao C-1002 C-1001 SN 0 0 0 0 Ie Th or 12 H 1 2 y SE A 0 1 7[ 1 0-3 0-4 oO.

ON LHS M L and NA NJ.

CNTY YON : "8 1 CNY 8 oJ o © o : Zo :© . 8 7 C-1005 0-6 F oO _ 0 HQ H © Hof H 0 ALES, and the \ N "M LK 5" M LK C-1008 C-1007 ed) 1

Ho © H © 0 0

RA AR, 1 1 - N m. It has 4 and 0 ST IvY rs

C-1010 C-1009

PT o

N Pi & N A } L NA. N ae . LAMMA DM C-1012 C-1011 NH IN Ho H © B go N NA NA. INFN NA,

TINY S| OTUYNT YR

C-1014 C-1013 0 fed Hof H © H © H © N NI, l, RNY ABA bus C-1016 C-1015

Oh

(ONGON

H© H© H 9 H©

N ANF NH N NA NH

EXTEN Y 7 | EYE TK

J©

C-1018 C-1017 fo) 4 oY 0 0 o oY 0 0 o nA RL 4 (AA 7

Hol: HJ "8 lm 9: L

C-1020 C-1019

Oo.

H H H /

NA N 5 N NAS, and 7 CY | ja aa af ' pO

C-1022 C-1021 Ddan Oo. H H © H H

ANE NA NN NA

6m 1 1 why a !a INL YS

C-1024 C-1023

ONG

0 a 0 0 for you : H 0 8 pas

H H

A NA Nh. ad yours © = Moo 5 0 ' J C-1025

C-1026 0 mia m fed , 9 : f , © 0 0 0 : N A “hey 1 l 1 l

N ~~ °N . 2 Baba Ablat Maya: TJ

C-1028 C-1027

Oo. Wind Ie bitter, otherwise Daba harm Alb 11 to 0 0 « pO

C-1030 C-1029 0 = m Ds 1 : m Ds 0 ~__N “sy, Oo. ~__N ay, 6660 YY LH)

-E 1- food) 1

Ho © H © 0 0 L L 1

N 20: as 2 I don't know] 1 '" REAR ee 2 8 Z XT |. =e

C-1034 C-1033

Oo.

ISAC rrb Ww ~ N 2 N N l

SY 20 7 N 20: and {J NT iH © yours : Ho 5 0 ai ng

C-1036 C-1035

ONG

Ay A, | A LAK Ds 3 8 AA 2 oJ o = Mo 2 0 EE 6 of JO

C-1038 C-1037

Oh

N © OH oY o 0 0 0 0 on IAA b Ay b 6 m laz oJ o # MH 5 : Lo ' a. ' of

Hog C-1040 C-1039 od N fo) © , and : oO 0 0 0 "0 Hog Hog Ndel" Hol 3. Hog Ho H J = H § C-1042 C-1041 0 oY lo) 0 fo) o AL LAA | Pl : i prb CYT OY YY a, ¢ a ' C-1044 C-1043 Ow 0 H © HO HQ 0 1 Mullah 1 PNP F o ° o : lo a o = o : Lo C-1046 C-1045 ON ou m © y © m ]| $ Ho : and 1 in N ; No. N N A N N ERT 5 of 5 © Hoo 12 “Why C-1048 C-1047

Arg ZN i NH, Ho 9 H © Hof H @ A .N NA NA.

N NA 1 iY : ] for you A SRS 1 C-1050 C-1049 Q ya 01 o 6 0 0 for NJ mapla 0 2 , :20 5 YA 0 the af 0 C-1052 C-1051 nor fed ; 0 0 nm : © 24 0 , oA NSS | Fr LH 0 801 :]1 y a OW z C-1054 C-1053 0 0 = 0 0 0 = 0 7 z i) 2 ne CY 0 0 7 NY 9.0 RON 0 , C-1056 C-1055

84 + 0 = 0 0 ~ oN or,

IBS SBS ANOS ESQ: 2-0 NT : D HO" TL 0 0

RON

C-1058 C-1057 0-0 0

H H “_N 2

ONY N dissolved N fixed fixed: N I

RO o Hl 112 0

C-1060 C-1059

Oh oh

ONG Oo. 0 0 0 0 0 0 TARA AE Arena "Nl: Lo 5 Ho: Lo

C-1062 C-1061 0 for 2 of N Nr B N I Tt N 0 : N I

HO" 0 TL o) TL ' 0' ' 0

C-1064 C-1063

Coon

Oh

(ONG © 0 © OO 0 l 1 lm 0 and lk : Hg i 5 1 i : 5

C-1066 C-1065 0 = 0 0 0 = 0 0

LAN Ds TON 1H 7 2 <7] NT IHS 0 1 M tn! ' pO. ' pO

C-1068 C-1067 —=N=

NH NH

Ho ¢ H @ Ho 0 H 0

NA NH Yale NJ.

N "ON as N 40 Thief Shae 5 L A [1] TR

C-1070 C-1069

OH 0 0 (ONG

OO H H © 0 0 Lay' NA. N N 1 TH 6-4 © 1N 5 L 0 7 0 5

C-1072 C-1071

-g3 F JP 0 : 7 0 for © A N “a, reply” © N 4 : TNT 8601© 0 1 0 1 C-1074 C-1073 0 0 = - - °N i “USN iY . IH § m [ NY PHS Ho~( for 0" pO | ,© C-1078 0-7 p H 5 0 but H 5 0 1 N... “uy N...” hy rl Ory ey ) Shake HOY HO HO HO “0 ' ”0 ' C-1080 C-1079

H 0 NH oY 0 hw © 0 L L Bo on AR, N Hg H_0 Gad 4 HO oJ o ° o : Lo af ' 0 1 C-1082 C-1081 ONG 0 mal 0 0 m oy N A N A N Ds “ty 2 N 8 N EN N Hs 0 _na Ho HAO oJ o # HH o : 5 TL 2 of plus C-1084 C-1083 OH ONG 0 . 0 0-5 Ln _N AAA “un, ho 9 H © OS AN oe !l : ] 8” Tr oJ o = MH o i Lo C-1086 C-1085 berl | and : 0 oF | = 0 rd “NJ “i, ~_N : bin dhs dh HO TL HO TL o” 0 ' C-1088 C-1087

Hama - 0 0 nm = 9 HO HQ 0 © NI “ur, LA : WN NJ.

NY n “o : 5 HO” yy “0 3 7 [ ¢ C-1090 C-1089 M SNH M ML 1 H 5 NAL - N NA Nh : Hoses SiN ARA RES pO ¢ af ¢ C-1092 C-1091 Oo SB A Gs Rh N ON A, oJ o 4 0" 6 : 5 Ae ~~ 0 lb emtnbm at H © = 8 oJ o ° Nag 0 3 C- 1094 | « F C-1093 0 . and L. Bakri > “ N NJ.

N N N N Ah, ,, CTY | OTN TS C-1096 C-1095

—04— 2 pearl na pearl : N NA N 'ty JU - N ml 20

N 41 “ISN B” 07 md for “RO ¢ pO

C-1098 C-1097

Oh

O.L

WED: b l

N God oa ~ WAN 2 0 1] 5 SRD ESQ: 6 of [4 pO

C-1100 C-1099

Ho ool 2 0 0 0 0

H© H O NN AA -

N N | N N

FY 5 b "oo eo = 0 0 m ¢ ¢ H

C-1102 C-1101

HO

_ N A N 1 N Ts 2 of N 8 N BD 0 1 pO 1 yk 0-4 0-3

_ h «=

SN! B 4 © > and 0 4 © & 0

N A os “a [ a N A

N God's God 2 Ae, L 8 1 5 06 "M 0 LK 5

C-1106 C-1105 0 0 0 0 0 0 © A N A N A N’ Roy N NA is 7

H 0 5 H 0 NY z N 8 8 rr oJ o A o : Lo ‘ oo ‘ of

C-1108 C-1107 0 OH 6 OL 0

Bi food PUES

N NH, N NJ,

N ~~ - ab ya N ~~ N and b oY Ys | Baya bhabhi

C-1110 C-1109 9 nm: 9 0 of N 8 N with N “a, o 0 0 2 “oo AN © fH HO TL ©8601, ab 0”

HO “oo” OL 0 0 C-1111

C-1112

Oh

Oh

H © H © Ho 9 fed 0

N N_ J, N No J,

SR 5 Mall Pal 0 above

C-1114 C-1113

HO 0 oy and Ho 9 0 025 6 0 0

A EL A >

H Og H.o " § 2 H 0 ' 0 C-1116 C-1115

Oh

Ox for Ie 9 LL R

ISR for you sab rah CNT YR wo o ° o : lo 8

C-1118 C-1117 0 , A 0 fed 0 PN 1 0 NA NJ. N NSN Ne

UTR TINT IR

C-1120 C-1119

0-8 o and b 0 1A

N : N hn, N . N21! Any

YY HO and 0 0-2 0-1 NH A Ho 9 H © Hof H 0 N NA NH N NA NA. M" 1: [Lm A 1]: ] TR 0-4 0-23 0 6 9 B 0 and L 1 fetid T 1 Tahim N 3 N Y 8 8 bar CYTES C-1126 C-1125 0 3 >< 0 05 0 0 0

Ay m ab nA AA “uy oJ o = HH o : lo Ho 2H. 0 c a,

C-1128 0-7

M OH oH 6 B 1 NY 61 : y N Non Nh TR NO 1 Lamaz 51 oJ C-1130 C-1129 Oo. BBE on B 77 (CNTY © Ns 5 Ope o 5 N 7 °N a a) Hoo © 5: Yours C-1132| « I C-1131 OL OL H H 0 Ho H 1 N x, B N 8 N N x, 2 N 81 N H N o : Lo| oJ JN 0 : to 0 for F YY F CY C-1134 C-1133 OH Oo. Hof H © Hof H© R N NA NH N SRY " o 5 5 6 0 : Yours C-1136 C-1135

0 0 | Ng oY m hy © 0 0 ae be 20 A ab 0 © 0 oJ o = PH o : lo ' 0” ‘ of

C-1138 C-1137 _N Ow

S¥ed AEs

N NI, N NH.

YT Y YE OY NY YK oJ o : o : a oJ o 6 : '4o a 2 m C-1140 C-1139

SN

H©&s 6

NL NJ, ZN

OY : N 1 ig 8 o 8 a 5

H H

Mr AN He oJ o = 0" 56 : Lo

C-1142] « of

C-1141 (ONG 0 gio. o 5 0

H H H Ho

N NA NH N ANN NA

: LA [AM] PES

C-1144 C-1143

M?- 0 6 B (Pe) HO,, 0 M Pit § B Ham H Foes Ye 8 N N 2 N 3 N OL: 7 2 Bar C-1146 C-1145 Mia OH | oY 0 0 0 0 7 fed! L rad ran" l 3 CNTY YON lm 0 Holo: oJ) o 3 o : lo .9 0 1 “0 ' C-1148 C-1147 OH OH oY 0 0 0 0 oy 0 0 EL be passed Aa lem 9 : for " H a, H J a, ' 0 ' C-1150 C-1149 Al Hy N TL 5 0 timeout 0 ' and C-1152

-??- Or acceptable salt Gara from it. in some illustrative embodiments; The list presents a compound selected from the group of C-: “C-1057” “C-1056” “C-1022” “C-1018” 1009 0-1072 0-1082 0-1083 C- 5-1144 C-1138 “C-1135” C-1129 “C-1118” C-1117 0-6 1150” or a pharmaceutically acceptable salt thereof. For example JE The disclosure provides a compound selected from the group consisting of: C- “C-1009 “C-1118 “C-1117 “C-1116 .-1082 .-1083 “C-1022 +68 0 -1129 C-1144 (C-1135 5 ¢ 1150 or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure presents a tripeptide epoxyketone compound having the structure chosen from: oY 0 hy © 0 H 0 0 _ N NA NT 0 Ts 0 Hoc on AAA N Ho H_o

Ho for o ® o” ZF 0 0 0 0] or tell us as NOLEN N N H |! 1 | n Ho | © yz ' 0

0

O.L

HO oY 0 0 0 We see Ts

CNTY Ybb H 5 L 0 H © 8 _ [3 [3

No

HO

0 0 0 0 N Yb and Ataina 7:

H 0 H 0 0 (7 0 0) 0 0 H 0 0 Na N NA N SPs or 0 Ho

N_ 0 0 o ¢ 0 .

0 H 0 0 0 H 0 0 m N A N N ct N A N N 0 H 56 Ho " n Ho ' 0” ' 0” i A N pl N OL Le - 7 and N N 0 XO o [3 = N [3

OH o Y 0 Te o fo) Me 0

N N N

Ay N 7 ry 0 0 N 0 lo) ‘ 0 0

ONG oJ 0 0 0 oY lo) Se 0 y! (nN

Ho H N ©

0-5 0 hy © 0 Rt Dql L N \ H OH QL Ho J

H 5 for P 0 od ‘ 0 lo) fo) o F C AA Ts oy is LO 0

OG ENNIS SY

H H o 5 5 0 [4 0 oY o ho © 0 0

LUN 20a 0 6 o) 0 9 0 ° ‘ o’ N S

HO oY 0 00 0 0 H © o | Son A : y N Tx L 1 Hol Ho J 0 H 5 Ho 0 0 :

_ 7 «= 0 Pe 0 0 H 0 0 N A N N

N A, N N Ho Ho

H 5 H 5 HO 0 ¢ 0 0 hy © 0 0 0 0 0

N A N N tah N N

H H

HO H 0 H 0 0 0 6 0 [4 0 Lawa "0

DS tle] sails 1 N 1 N or N N N

H H

06

HO 0 0 0 OD

Oh

O.L

Pe One 0

NY N OH

H oJ) 6 0 0 0 n N N N N 8 N oJ © 0 0

00 7 0 4 0

N N fo 0 0 0 N yep © yul A for you "m RARE 0 " n Hoo ' ~o 0 oY 0 hy © 0 0 0 0 (NN A N please @ NA N A N x : 0:0

Ho Hoo

HO OH

HO 0

Oh

0 OH 0 0 0 0 for

JA ~o OH [4 [4 oo” 0 0 0 A 2 >

H N N

Sater IU l 11 0 fo) HN os bos [3 © © [3

HO

F oY 0 hy © 0 oN © H 0 o | Non A 30

N A N A N b" H 0 H 0 0 0 F - 0 tooth 0 H,N ~N oY 0 y © 0 y fo) yh 0 0 on JAA N

SWE YC

6 6 m 0

0 0 0 b" fig - from SS SUE PE 0 0 0

H § & - 5

SEAS LIZ 2 1 1 Z SASS ISL

RON oY lo) 0 0

Bi & AER Ne:

N N N N 0 0 © To pe 0

HO

0 0 hy © 0 I am he A, a

H0 H0

0-5 lo) Hy © 0 _ N NA N A N N 0 0 H 0 0 mo AAO on JAA 1

H 5 Ho ' 0' H 0 [3

OCH; 0 0 0 0 0 H 0 0 NA NJ N N N ory \ To NA°

No 0 n for P 0 0 < p 3 [3 [3 0 0-4 0 0 0 0] N N

Ho Hoo 0 [3] or a pharmaceutically acceptable salt thereof. The disclosure presents a compound (epoxyketone tripeptide having the structure to be chosen (JB) as:

—Vo- oY 0 0 0 oY 0 0 0

OL Fs OI Cool H to 0 J Ho Lm 0 .: L

C-1154 C-1153 0 0-5 0 ™ 0 0 0 0 0 0 Na N A N 8 N tc 0 bm N A N Sol 7

H EH : 0 0 " e <_N_o a, ©

C-1156 C-1155

HO0

Og 07 0 0 0 0 0 0 Let us be 0 for me

H for : H did not H for : H [

RGN QS

C-1158 C-1157

0

ON

Ho 9 H oY gt 0 0 B Gx ALA HE

N ON N N 5 R 0 : 1" 5 N L N J

Cr is C-1160 C-1159

Ho nN oy m 0 0 Ho $ b wey yinh ody

Ho for 9 m: l oJ o = H 56 75 a, of

C-1162 C-1161

AN

0 lo) 0 0 a o | LAL ar 0 RS N b N bal N “te, H 0 = H 0 for “O° RGN ‘ o” .

C-1164 C-1163

0 0 lo) 0 0 0

H

Cm N A N Tah 7 B N A N Fs 'ry

Hog:. 2 [ N Ho l = H

C-1166 C-1165 0 0 0 0 0 0

H H

Ny 1 Ra 0 HAA cold 0 H L 2 H J J HL : 0 L C-1168 C-1167 0 0 0 0 0 0 ~All for JS SN Fs —N H i: H — N H 58 0 8 6 6 Mega Mega

C-1170 C-1169 oY m Hy © 0 0 1 LT) j CETL a 7 TINT ~N H oO = H 0 a : 0 >" :

C-1172 C-1171

OH OH oY oN 0 0 7 0 0 0 © Bard 1 No © LL Bard A

H 7 z H 7 H 7 8 H 7 To

C-1174 C-1173

ON

Ho © no 9 oY 0 0 0 2 N 1 N a N Gs _ N B 1 TB H A 1 2 H 6 Ho 0 0 To KAO ©

C-1176 C-1175

O.L

0-5 0 0 0 0 ny AA 4 ? [ L 8 N ~~ °N 7

H H 0 © Yours ©: 5 H 0 8 0

C-1178 C-11717 3 oY 0 H © 0 1 A N Cold 1 o , 0 °

H 0 H 0 So N A N NA N Answer it H 5 z H 7 0 Time it out

2 7 0 0 0

NL LN Fs 3 "8 lm 0 : no

Hof, i 0 TL

Ny : 2 0 ) 0 = 0

C-1182 C-1181 0

HO

0 0 1 0 M D F 0 0 © A N N EN N “ry, A N L 1 N BAL N B H o = H o H 0 = H 0

XL 0 has 0

C-1184 C-1183 0 E H Ps OL NA 4 0 - 0 0

N©:401:7:H

H I H N 2

HO" of © AON ©. N © b 8 0 fo) lo) 0 ° C" pO

C-1186 C-1185

_ A «= 9 >: nm 9 0 0 : H 0 0 8 JU N A N B 27 ©6001 1 ml ne YT O° 0 fo) P

TL 5 ' 0

C-1188 C-1187

J Fs ~ NJ “a, = 0-7 7 Refer to the

HO TL NY No P 0 0 0 A 0 Maya C-1190 C-1189

HN

HO

0 0 0 0 © AA Ary

N: No.: 9 A 9 0 - Jalak 8 p) p) 6 ©

H : 0 “HO” © 0 0 AE C-1192 C-1191

OH 0 oN OH

PN L L L

N N_ J, N N_

N oY thief N thief: and M: No, no

Oh

OH oy oo HQ 0 Ho 0 7 0 ss NA A Fs N N bal N N A, : o ° 1 0 lk 0 : 0 8 5 her of

C-1196 C-1195 0 Q H © 0 oY 0 0 0

OL Fs rent H R = H 3 H ;: for H m wo 0 “0 BOW

C-1198 C-1197

Oh

to OH ~

N N N 0 0 0 1 0 o for you 0 1 1 m on AAR, and H : H for VE So OH

C-1200 C-1199

0” 0” m for Bi

N0 N0

N 2H N 241: L: H BAC Sl: H BAS Mohsem Mohss

C-1202 C-1201

HO

3 oY wow 0 and <5 o 0 0

NOLIN A Hs

H 0 E H 7 1 H 0 5 H 7 Lma TL 0” F 0

C-1204 C-1203 0 oN HoN og Ie 0 D Wow o Hy © 0 on HAR 7 Lal Lal Lal 7

H Oo =: H 0 H o : H 0 a, a,

C-1206 C-1205

H H,N._ _O for 0 o 6 0 << F 0 and H on A AN on IA RL 1 H for :1 HJ " ;: for H J

RGN RGN

C-1208 C-1207 03 — 0 0 Bi 5 Bi 2 N N , N N 777 N Steel N Cut

CYAN YR A 1 M YA

C-1210 C-1209 0-5 0 0 0 0 oY 0 0 o on AAA AY, on IA RL Ye ‎H o 8 H o H 0 5 H o

RGN RGN

C-1212 C-1211 OL ON L 1 L 1 5 ] L N N_ J, N N_ J, N 1 H N "> N FOR GOD LIT 2 5 257 kg ,

H oy 9 H § oo 0 0

ALANA TAL Iw ml H 7 2 H 7 H I 3 H J 0 a,

C-1216 C-1215 0-5 0 0 0 oY 0 0 0

AL RN Fs Nn A Fs

H H H H

Qo 6 96 lo) o” 0

C-1218 C-1217

OCH oY lo) 3 e 0 oY 0 0 0 l 1 BA A AL MR $ B

H o 8 H 7 H 0 > H 7

C-1220 C-1219

— A c ~ a 0 0 0 0 H no lm 7 2 Ln f 0

H; for H § N NSN a TL Nn H ; L H J 2 0d 0 0 "8 yea 3 3 3

C-1222 C-1221 M 0 Hof 0

LAR 7 Ra o 8 o pO

C-1211 or a pharmaceutically acceptable salt thereof. tripeptide epoxy The detection provides a tripeptide epoxyketone compound (Ua AT in an aspect to be chosen from: ketone having NH A LA | or fo fo) fo ) 0

N N H

H5hoo

7 fo) 1 Ts d 11 "NAAN 1 0 a b j a a oY 0 H Ts nah ha N N N 00 b 0 0 z a or i 3 oY 6 Ho © 0 0 0 0 0 (UN AA N L L © P N Ts o “oo Ho J H J

sh

and, or a pharmaceutically acceptable salt thereof. For example; The detection provides a tripeptide epoxy ketone complex to be selected from: L NH AAR 0-7 0 0 0

H H / H o o = H o : 5 on AR and 3 − H for 8 : no

C-1225 C-1224

OL oY fo) ho 0 ° AF uy Sed F 0 710 0 his 5 =: H LAE 0

C-1227 C-1226

SN

O.L

Ranp PPE by dof own for 8 AN N cll SERRA

SNe)

oy 0 Nala tag LL sp | et LCE

AAAS | SS eye

H J : H [ oJ o 0 : = O of

Eng

C-1231 C-1230 They are this 0 0 oY o 0 0 Altaina Aaa Ll

H o 3 H 6 H 7 s H 0

To

C-1233 C-1232 oy 0 y © 0 a N A N N 1s oY 0 H 0 0 " for : on no on AANA

H 7 b fo) E 3 3 3

C-1235 C-1234 or a pharmaceutically acceptable salt thereof. In another aspect, a compound having a structure according to the formula (!); Or a pharmaceutically acceptable salt thereof:

A q — 7 c oO R® x 1 a m q r qim R? rg O 15 0 (1) B is non-existent; Lo is 0-0; © each independently M is non-existent or 12-61 alkyl ; is © non-existent; is X is 0; RI is selected from ~C1-6 “alkyl hydrogen -8; C1-6 hydroxyalkyl” and 61-6 alkoxyalky ; is selected R2 from D D D D N.

Pe > b 0 + 5 . Designed by SX %N © D+ >“ Ye 2 | & ' ra lm ' Sv ' IN ' JO ' ge ' D 24 4 5 a = SEAN + N, b Di

¢ SA ¢ R F : 0 R ; hydroxy butoxy butoxy - temethoxy where Na is selected from hydrogen; methoxy and trifluoromethyl; Trifluoromethyl cyano cyano “halogen” hydroxy is 0 other than benzyl, where 2 is benzyl Laie, provided that it is (Jf 61-4

Ve hydrogen R3 is selected from a heterocyclyl a- and a tcarbocyclyl carbocyclyl R4 is ¢tN(RS)L-Q-R6

q “= — Ble RS is about hydrogen; RO is chosen from a heterocyclyl M-cyclyl and carbocyclyl a/a; 47a and 48 are hydrogens; And R15 is selected from hydrogen; Jl Cl-6 and 6- Cl are hydroxyalkyl. © Based on Se old Compound representation pall By (!) b: H o m o 0 At wam lb oO” g (IA) H O in some embodiments; R15 is selected from ethyl Ja) methyl hydroxymethyl and 7-hydroxyethyl Ji} D LC.

in some embodiments; 42 is > &; No selection is made of methoxy

methoxy 0 “hydroxy” trifluromethyl and 61-4 alkyl. in some embodiments; RE is a cyclel other than M—heterocyclic; in other incarnations; She RE stands for M—carbocyclyl

0 hy " " In ax embodiments, R is chosen from the set of: 0 0 and 2 N m 2 but ja but Oo 0 0 0 0 0 0 HO 0 R 5

or OY HRS

« Cl © ' 0 0 0 Yo

0 F 1 0 2 L' no Chon 6 eT hig 0 0 ' 0 + 0 + 0 (FC "32 0 throttle or Tp ' 0 ' 0 0 ' HO 0 ' 0 0

HO H 2 HO

Me

Ty Yana «Op Bla 0 0 0 1 0

Me

HO N Me.

N

Yen age OE 0 0 0 1 0

N ~~: 0 % N 2

OT is welcome. Me and + HN for 0 «HO fo) of the group consisting of: R2 in some embodiments; is selected

H BOR H ROR JOR JOM

'MeO' ¢ HO 4 MeO

Me rr H POS H BOR M OY ¢ HO ‘ Et ‘ Me ‘ HO

MeO MeO or RA H OY BOR ' OH ' OMe . HO «MeO

OMe OH HO 5S 2 Ba Aw Kham

Cr and 6HO ' MeO ' OH 1 0

R3 is a carbocyclyl-. in many incarnations; R3 in some embodiments; It is a carbocyclic-/a and is only 01-12 alkyl. in some embodiments; be Sle

q \ — — R3 is a Jil -0012 carbon; Whereas, a carbocyclyl is selected from the group consisting of: “nn, “an, hid “rn oh intentionally hid give 8 8 3 qO le 0 Ie Ie nt 0 Van,” “an, 0 “hn, 0 nd” an, Me | 7 p [ | )) Me ' « HO . F ¢ “F ‘ ‘ ¢ O° ( ) NH oo . in some embodiments; R3 is -0112; where carbo is an, rum lm cyclyl is ©0 or 0. The compounds provided herein can be synthesized using conventional techniques with readily available starting materials. in general; The compounds available here are traditionally obtained through standard synthesis methods in organic chemistry. (For example, JB) the compounds provided herein can be prepared using the methods described herein or using the synthetic methods described in US Patent No. The compounds disclosed herein are inhibitors of the immunoproteasome |0(a).In some cases, a compound as disclosed herein inhibits the iP subunits Sa LMPT7 (Sa LMPT7) by inhibiting LMPT activity. by at least 9001” 96700 on J 9670 on (JB 96460 on (Ji +9659 at least) 96760 on (JS 9670 at least) or at least 9680; as measured in a unit experiment

sub-hh of the proteasome as described below in the examples. One or more additional IP subunits can be inhibited by a compound as detected as cla as LMP2 bl (MECL-1 02; 8.055 many embodiments; compound as detected aie here 7 is inhibited and one or both of LMP2 and 1-a1/50. The compounds disclosed herein can decrease cytokine activity or gene expression” eg one or more of 2-a; JIFN-fB 5 ( TNFa (IL-6 (MHC-I) accordingly; available here are methods whereby a compound as disclosed die herein inhibits the genetic expression or activity of one or more of 16-1-A2 9600 As; IFN -B (TNFa “6 at least” 96710 at least (JN 9630) at (JN 96460 at least (JAY 9656) at least 967660; at least 9670; or at least 860; at 0 As measured in an experiment as described below in ARN the biological consequences of proteasome inhibition are manifold Proteasome inhibition has been proposed as prevention and/or treatment for many of the diseases involved, including but not limited to neurotoxic diseases Alzheimer's / degenerative Alzheimer's 's; Cases of localized blood ischemic conditions “inflammation”; Yo autoimmune diseases (HIV auto-immune; organ graft rejection; septic shock; inhibition of canal presentation) decreasing viral gene expression ¢ cases parasitic infections 0831351116 cases associated with acids acidosis ¢ macular degeneration; 4.4 pulmonary conditions “muscle wasting diseases” 0 fibrotic diseases; bone and hair growth diseases accordingly; provide formulas for specific proteasome compounds; Such as the class of molecules of epoxy ketone, a means of administering the drug to a patient and treating these conditions. The proteasome modulates NFB, which in turn modulates genes involved in the immune and inflammatory response. For example, NF-iB is required for genetic expression of the immunoglobulin 8 light chain of the gene “x immunoglobulin light chain” and receptor 2-aa. chain gene; class qi cytokine genes for the major histocompatibility complex gene; a number of cytokine genes encoding 6-a; cell colony-stimulating factor (IL-2 for example; but not limited to) encoding

Palombellaet al., )] no “granulocyte colony-stimulating factor” accordingly; Methods for influencing the level of expression are available here (Cell (1994) 78:773-5

OSA or any other preexisting proteins IFN=B (TNFa 6H) MHC-I (IL-2) Evidence for less than 0 Each method involves giving a patient a therapeutically effective amount of a compound or combination disclosed here. Ja Also provided herein is a method for treating an autoimmune disease in a patient and involves administration of a therapeutic amount of the compound described herein. The expression ''autoimmune disease' as used herein is from and directed against an individual's own tissues. Examples of diseases include Li is a disease or disorder 0 Skin diseases Jie for example but not limited to Inflammatory responses LSA Inflammatory responses involved ¢ (inflammatory skin eg; allergic dermatitis Je) Psoriasis ; Skin Crohn's disease Jie) Systemic scleroderma and sclerosis; inflammatory bowel disease responses Ulcerative colitis “Crohn's disease yo adult respiratory distress syndrome shortness of breath meningitis encephalitis dermatitis dermatitis ¢(ARDS) colitis glomerulonephritis color uveitis; encephalitis eczema such as eczema allergic conditions; allergic conditions glomerulonephritis and other conditions including T cell infiltration and inflammatory responses; asthma and leukocyte 0; chronic atherosclerosis; atherosclerosis; lupus rheumatoid arthritis; rheumatoid arthritis adhesion deficiency diabetes mellitus (SLE) systemic lupus erythematosus systemic erythematosus ¢ (insulin) (eg type or insulin-dependent diabetes mellitus; inflammation Reynaud's syndrome Raynaud's syndrome ¢ multiple sclerosis ©

E40 autoimmune thyroiditis; allergic encephalomyelitis; Sjorgen's syndrome; juvenile onset diabetes; de lid responses associated with acute and delayed hypersensitivity elicited by cytokines and T lymphocytes typical of tuberculosis; sarcoidosis; polymyositis; granulomatosis and vasculitis; pernicious anemia (Addison's disease 8001500'5); diseases involving WIA leukemia; An inflammatory disorder of the central nervous system ¢ (CNS) nervous system

multi-organ syndrome; Hemolytic anemia (including, but not limited to, cryoglobinemia or Coombs ¢ (positive anemia) myasthenia gravis; diseases resulting from an anti-antibody complex Antibody complex APs anti-glomerular basement membrane disease Antiphospholipid antiphospholipid syndrome Allergic neuritis ¢ Vo Graves' disease '578765 Myasthenia gravis Lambert-Eaton syndrome Lambert-Eaton myasthenic syndrome; pemphigoid bullous; pemphigus pemphigus; autoimmune polyendocrinopathies; July 5 disease; stiff-man syndrome; disease 568666 [1; giant cell arteritis; immune complex nephritis; immune complex nephritis 0; Dae) Kidney (gM) Multiple nephropathies (IgM) adi immune thrombocytopenic purpura (ITP) immune thrombocytopenic purpura or deficiency thrombocytopenia;

Autoimmune .autoimmune thrombocytopenia examines the immune system for eng-infected autonomous cells that have undergone oncogenic transformation or present unusual peptides on their surface. YO intracellular protease degradation generates small peptides for presentation to T lymphocytes to induce immune responses triggered by class | to

MHC accordingly; Provided herein is a method for using a compound or formulation presented herein as an immunomodulatory agent to inhibit or modulate antigen presentation into a cell; It involves exposing the cell (or giving a patient) the compound described here. Certain embodiments include a method for treating graft- or transplant-related diseases; Jie (graft-dla host disease) or graft-versus-host disease (GVD) in a patient; © and includes the administration of a therapeutically effective amount of the compound described herein. The term “graft” as used herein refers to biological material derived from a donor for transplantation into a recipient. Grafts contain such a variety of materials, for example; isolated cells WIA Jie islet; Tissue Jie (glo Las of newborns; bone marrow; cells producing blood components; ocular tissue; Jie corneal tissue; organs Jie skin; heart heart; liver liver; spleen spleen; and tubular organs (eg, intestines, blood vessels, or esophagus). Tube organs can be used to replace damaged parts of the esophagus, blood vessels; or bile duct. Skin grafts can be used not only for burns; But Lad as a lining for damaged intestines or to close specific defects Jie hiatal hernia. The bait is derived from any chemical source; includes human; Either from 1 cadavers or living donors. in some cases; The donor and recipient are the same person. in some embodiments; The graft is bone marrow or an organ such as a heart and the graft donor and host are matched for HLA class 11 antigens. Inhibition of the Wal proteasome has been associated with inhibition of NF-KB activation and stabilization of p53 levels accordingly; The formulations presented here can be used to inhibit NF-kB activation and stabilize Yo 053 levels in cell culture. Since NF-kB is a Gy regulator of inflammation, it has potential for therapeutic intervention. Anti-inflammatory Accordingly, the formulations presented herein can be useful in the treatment of conditions associated with inflammation, including, but not limited to, COPD, psoriasis ¢ asthma, bronchitis, rheumatoid arthritis 38 + and cystic fibrosis

—qy—

The compositions disclosed can be used in the treatment of conditions that are directly caused by the proteolytic function of the proteasome Jie muscle loss; or result directly from proteins that are processed by the proteasome such as 7-168No. The proteasome is involved in the rapid removal and post-mutational processing of Sh proteins (eg; enzymes) involved in cellular modification (eg 0;50 cells; gene transcription; metabolic pathways); intercellular communication; and immune response (eg; presentation of an antigen). Specific examples include which are discussed below

amyloid protein B and proteins Jie All) cyclin complexes and transcription factor NF-KB in some embodiments; The combination provided here is useful in treating diseases and conditions of neurological degeneration; Which includes, but is not limited to, stroke; local anemia damage to the Y nervous system; neurological trauma (Jo) eg; traumatic brain damage; spinal cord injury; traumatic damage to the nervous system); Multiple Sclerosis; and other immune-mediated neuropathies (eg, Guillain-Barre syndrome and its variants; acute motor axonal neuropathy as ¢; acute inflammatory demyelinating polyneuropathy). ; Fisher Syndrome 1; AIDS/HIV; dementia complex; diabetic neuropathy; Parkinson's disease; Huntington's disease; Bacterial meningitis, parasitic, fungal, viral meningitis, encephalitis, vascular dementia, and multi-infarct dementia. Lewy body dementia Frontal lobe dementia such as Pick's disease Subcortical dementia 5 such as Huntington's or progressive supranuclear palsy supranuclear palsy focal cortical atrophy syndromes Such as primary retention, “primary aphasia,” “metabolic-toxic dementia (Jis) dementias, chronic hypothyroidism, or insufficiency” (B12).

-8M4- and dementia due to infection (such as syphilis or chronic meningitis). Alzheimer's disease is characterized by extracellular deposition of BAP-amyloid protein in aging platelets and cerebral vessels. BAP is a peptide fragment 9 to EY© acid derived from β-producing amyloid protein (APP) Define at least three isoforms of APP (e Voy (an) and YY of amino acids).

BAP The processing of the abnormal protein by the proteasome is thought to contribute to the abundance of BAP in the Alzheimer's brain. The rat APP processing enzyme contains about ten different 0 subunits (YY) kDa-7? kDa). The Yo subunit kDa comprises an N-terminus sequence of “X-GIn-Asn—-Pro—Met-X-Thr-Gly-Thr-Ser which corresponds to the B subunit of large pain Kojima, 5. et al., Fed.

Eur.

Biochem. ( al 304:57-60 )1992( ,.506)._APP-processing enzyme cleaves at the GIn15 bond——6!); in the presence of a calcium ion; The enzyme also cleaves at the Aspl--1/161-1 bond 10 and the Aspl--Ala2 bond to release the extracellular domain BAP. A method for treating Alzheimer's disease is presented here. Involves giving a patient a therapeutically effective amount of a disclosed formulation. This treatment includes decreasing the rate of BAP processing, decreasing the rate of BAP plaque formation, decreasing the rate of BAP generation, and decreasing clinical signs of Alzheimer's disease. 0 Methods for treating wasting and muscle wasting diseases are also presented here.The proteasome degrades many proteins as retinal cells mature and WAN fibroblasts grow in WIA deprived of insulin or serum;the rate of proteolysis approaches double.Inhibition of the proteasome leads to Decreased proteolysis, thus reducing both muscle protein loss and nitrogen load on the kidneys and liver Proteasome inhibitors Peptide proteasome (eg compound or YO combination presented herein) are sade for the treatment of Jie cancer cancer; disease of injury

chronic infectious diseases; fever muscle disuse (atrophy) and denervation; nerve injury 0 fasting; renal failure associated with acidosis alll ¢ kidney disease and liver failure -hepatic failure © see for example » (Goldberg US Patent No. OYE YT – the contents of which are incorporated herein by reference. Treatment modalities include: decreasing the rate of myoproteolysis in a cell; decreasing the rate of proteolysis within a cell; decreasing the rate of degradation of 53m protein in a cell; and inhibiting the growth of 053-related cancers. Each of these modalities involves cell contact (intracellular or extracellular). (JB muscle in a patient) with an amount of Aad from a pharmaceutical formulation disclosed herein to decrease the rate of muscle proteolysis in the cell; decrease the rate of proteolysis within the cell; and/or reduce the rate of proteolysis of 053 in In some embodiments,” the method involves administration to a patient of a therapeutically effective amount of a pharmaceutical formulation disclosed herein. Ble fibrosis is the result of persistent and excessive formation of scar tissue resulting from hyperproliferative growth of Vo-fibroblasts and associated with activation of the TOF signaling pathway Fibrosis involves excessive deposition of extracellular mold and can occur within virtually any tissue or tissue across multiple different tissues. naturally; The level of an intracellular signaling protein (Smad) that activates transcription of target genes during stimulation of 16-8 is regulated by activation of the proteasome. However; Jame degradation of 16-8 signaling components has been observed in cancers and other hyperproliferative conditions. A JBL certain embodiments; Ye is presented as a method for the treatment of hyperproliferative conditions such as diabetic retinopathy; macular degeneration; diabetic nephropathy; glomerulosclerosis; IgA nephropathy; cirrhosis; sll atresia; biliary atresia; congestive heart failure « scleroderma; Radiation-induced fibrosis “lung fibrosis” (idiopathic pulmonary fibrosis “Yo” collagen vascular disease ¢ sarcoidosis “

Naam extrinsic and external lung disorders ¢ interstitial lung diseases Interstitial lung diseases Treatment of burn victims is often hampered by fibrosis; Thus; (lung disorders in some embodiments a compound presented herein may be administered by topical or systemic administration to treat the postoperative wound by disfiguring scars; which may be prevented from Ble) burns. Mostly associated with inhibition of fibrosis. Accordingly; in certain embodiments; A method for preventing or reducing scarring is presented. Here, Rel can be a member of the protein family (NF-KB processed by the proteasome is AT, a protein of transcription-activating proteins into two groups. The first group requires the processing of the state of Rel by dividing the kDa family). 001 kDa) and 0852 (7-2L; 011 (NF=xBI) p50 for protein” includes (c-Rel) Rel (RelA) for protein” and includes 65m Alla The second group requires processing of the 0 of homo- and hetero-dimers by members of the 3S family forming Se and 888). For example; It is a 050-065 hetero-dimer. After phosphorylation (NF-KB (Rel), the two proteins are degraded and processed, respectively, to produce LOSS KB and add ubiquitin to active as it moves from the cytoplasm to the nucleus. 0105 is processed with added ubiquitin NF-KB forming .( Palombella et al., Cell (1994) 78:773-785) sli by proteasomes Vo

active HMG is a stereospecific enhancer complex with transcriptional coactivators and; For example, NF-kB is selective for a specific gene. Shy (7); including the expression of genes involved in the immune and inflammatory response; and mitotic events. NF-KB upregulates a gene required for the expression of an immunoglobulin light chain © gene; NF-kB for example; be

Glia is a 0-chain gene; A major histocompatibility complex class A gene and an IL-2 receptor 00

IFN = 5 6-aa; granulocyte colony stimulating factor; 11-2 JB encodes cytokines; For example, some embodiments include methods of either dFN-B (TNFa IL-6 (MHC-I) or any of the dFN-B (TNFa) IL-6 (MHC-I) to influence the level of gene expression of the IL-6 state (Palombellaetal., Cell (1994) 78:773-785).2 Each method involves giving a patient a therapeutically effective amount of (AY) The aforementioned proteins, including 050, are fast mediators, Ly, a composition disclosed here, complexes, Yo a.

to acute inflammatory responses and immune responses) and Maniatis, T., Cell. Thanos,

80:529-532 (1995). Lad NF-kB is involved in the transcriptional expression of WAY adhesion genes encoding E-selectin, P-selectin. Collins, T., Lab.

Invest. (1993) 68:499- ( VCAM-1 © 508). in some embodiments; A method for inhibiting cell adhesion (eg, cell adhesion induced by CAM ¢ E-selectin, P-selectin or VCAM-1 including cell contact with an Aled amount of a pharmaceutical formulation disclosed here) is presented. In some embodiments, a method for inhibiting cell adhesion (eg, selectin-induced cell adhesion (CAM) or VCAM-1) is presented involving administration to a patient of a therapeutically effective amount of a pharmaceutical formulation that has been

0 disclosed here. Local anemia and reperfusion lead to hypoxia; And it is Alla, which causes a deficiency of oxygen reaching the tissues of the body. This condition causes excessive degradation of 12-86 and thus leads to activation of NF-kB. It has been shown that the severity of hypoxic injury can be reduced by administration of a proteasome inhibitor. Accordingly; A method for treating an ischemic condition or reperfusion injury is presented here

VO involves giving a patient in need (dalled) a therapeutically effective amount of a compound presented here. Examples of such illnesses or injuries include; without limitation to acute coronary syndrome (umbilical plaques (lI all cerebral occlusal arterial disease; peripheral arterial; vascular occlusion); atherosclerosis (coronary sclerosis; coronary artery disease); infarction; heart failure; Inflammation (uly Sal) myocardial hypertrophy; stenosis; restenosis.

0 NF-KB is also specifically associated with HIV enhancer/enhancer when compared to Nef of 01306239; The HIV-regulatory protein Nef differs from 00114 by two amino acids in the region that controls protein kinase binding. The protein kinase is thought to transmit 1168| phosphorylation signals which catalyzes degradation of 8 through the ubiquitin-proteasome pathway. After decay, NF-kB is released into the nucleus, thus improving HIV transcription (J., Science, (1995) 267:960, 000860)._ A method is presented here.

1-7

To inhibit or reduce HIV infection in pape and a method to reduce the level of transgenic expression of a gene

viral; Each method involves giving the patient a therapeutically effective amount of a formulation disclosed here. Viral infections contribute to the condition of many diseases. The heart conditions Jie Jie persistent myocarditis and dilated cardiomyopathy have been linked to coxsackievirus © beta?. In the cases of microgroup analyzes of the overall set of genetic factors being compared in rat hearts; Specific proteasome subunits were systematically increased in cdl hearts) which progressed to chronic myocarditis (by Szalay et al, Am (Pathol 168:1542-52, 2006). Ubiquitin - proteasome in

The viral entry step where the virus is released from the endosome into the cytosol. Ye The mouse hepatitis virus (MHV) belongs to the family of coronaviruses; Which also includes the severe acute respiratory syndrome (SARS) coronavirus. Yu and Lai (J Virol) 2005, 79:644-648 explained that treatment of MHV-infected cells with a proteasome inhibitor in reducing viral replication; associated with a reduced viral titer compared to untreated cells. At the same time, the human hepatitis B virus (HBV) 1 virus, a member of the virus family 1608008711086, requires virally encoded envelope proteins for propagation. Inhibition of the proteasomal degradation pathway causes a significant reduction in the amount of secreted envelope proteins (Simsek et al, J Virol, 719:12914-12920). In addition to HBV, Lay may use other hepatitis viruses (ea) df and e) the ubiquitin-proteasome degradation pathway for secretion; Genesis and generate 0 diseases. Based on that; in specific embodiments; There is no way to treat a viral infection; Jie SARS hepatitis co of co d cas comprising cell contact with an active amount of compound which is detected as Us in some embodiments; A method for treating viral infections is provided; SARS Jie or hepatitis A; C d cas and it includes giving the patient an amount

therapeutically more effective than the compound ade is disclosed here.

A 1 Excessive production of lipopolysaccharide (LPS) induced cytokines (Gud Sele 11050 Jie) is considered to be a factor in processes associated with septic stroke. Furthermore, it is accepted as dele that the first step in cell activation by LPS is the binding of LPS to specific membrane receptors. The ded© and m units of proteasome complex 205© have been identified as LPS-binding proteins, suggesting the possibility that Gar LPS-induced signal transduction could be therapeutic Lb in the treatment or prevention of sepsis (Qureshi (2003)171: , N. et al., J.

Immun. 1515-5). Based on that; in specific embodiments; The constructs as provided herein for inhibition 11170 can be used to prevent and/or treat septic stroke. Intracellular proteases generate small peptides for presentation to T lymphocytes to induce MHC class A-induced immune responses. The immune system detects virally infected autonomous cells that have undergone oncogenic transformation. One embodiment is a method to inhibit antigen presentation into a cell; It involves exposing the cell to the composition described here. in some embodiments; The cell is contacted with an effective amount of a compound or formulation provided herein to inhibit the presentation of the antigen into the cell. Another embodiment is a method of suppressing a patient's immune system (eg (JE Vo suppression of transplant rejection; allergy; asthma); this involves administering to the patient a therapeutically active dose of a formulation described herein. Wal may use the formulations presented here in the treatment of diseases Autoimmunity Jie lupus Rheumatoid arthritis Multiple sclerosis Inflammatory bowel diseases such as Irritable colitis and Crohn's disease Another embodiment is a method to modify a set of antigenic peptides produced by the proteasome 01 or other 1000 with polystimulatory activity. For example (JB) if the PGPH activity of the 205 proteasome were selectively inhibited, different degenerate antigenic peptides would be produced by the proteasome and presented in MHC molecules on the cell surfaces of Yau by either producing and presenting them without Any enzyme inhibition or eg with selective inhibition of the chymotrypsin-like activity of the proteasome.

ru

JS-specific proteasome inhibitors impede the degradation and processing of ubiquitin-expressed NF=kB both outside and in vivo. Wal proteasome inhibitors block 19-6 degradation and activation Palombella, et al. Cell (1994) 78:773-785; and Traenckner, et al.) NF-kB EMBO J. (1994) 13:5433-5441, .21). in some embodiments; A method for inhibition of 0 degradation (IkB-a) involving cell contact with a formulation is described herein. In some embodiments, a cell is contacted with an effective amount of the formulation to inhibit 6©-168. An additional method is to reduce the intracellular content of NF-kB In dla a muscle, organ, or patient, Aa involves contact of a muscle, organ, or patient with a formulation described herein. In some embodiments, a cell is contacted with an effective amount of the formulation to reduce the cellular content of NFB in a cell. 0 Other eukaryotic transcription factors requiring proteolytic manipulation include generic transcription factor (TFIA) HSV accessory protein 1/016 (family cell factor); virus-inducible IFN regulatory factor ? protein; and binding protein 1 of a membrane-bound sterol regulatory element. Further provided here is a method for influencing true cyclin-dependent cell cycles; 1 involving exposing a cell (extracellular or intracellular) to a composition disclosed herein. Cyclin factors are proteins involved in the control in the cell cycle The proteasome is involved in the degradation of cyclins Examples of cyclins include mitotic cyclin factors cyclin factors 61 and cycline b. Cyclin degradation enables the cell to exit one stage of a cell cycle (eg, mitosis) and enter another (eg, mitosis). It is believed that all cyclin factors bind to protein-0 kinase or associated kinase enzymes. Hay) targets for protease degradation are localized to amino acid 42-RAALGNISEN-50 (destroyer box). There is evidence that cyclin converts to a form exposed to ubiquitin ligase and that a cyclin-specific ligase is activated during mitosis (79:13-21 (1994) (A., Cell, 0160080078). Proteasome inhibition inhibits cyclin degradation; thus inhibiting cell proliferation; For example; In cancer diseases Kumatori et al., Proc. Natl. Acad. Sci. USA (1990) (cyclin-related) Yo

-1.8- Here is provided a method for treating a proliferative disease in a patient (eg; 67:7071-5). psoriasis; or restenosis); It involves administration to a patient of a therapeutically effective amount of a combination Here is a method for treating cyclin-related inflammation in a patient; Wal is disclosed here. It is available from a formulation described here. ladle and involves giving the patient an effective dose

In another embodiment, the compositions disclosed are useful in the treatment of parasitic infections; Jie Infections caused by protozoan parasites. The proteasome of these fungi is mainly involved in cell differentiation and transcriptional activities (Paugam et al., 2003, Trends Parasitol. 55-9:(19)2). Furthermore it; Entamoeba species have been shown to lose their cystic ability upon exposure to proteasome inhibitors (Gonzales, et al., Arch.

Med.

Res. 1997, 28, Spec

No: 139-140 | 0 4. Such embodiments; formulations disclosed herein are useful in the treatment of parasitic infections in humans caused by a selected protozoan of the species Plasmodium (including Plasmodium falciparum; Plasmodium vivax). vivax; Plasmodium malariae and Plasmodium ovale (ally 'ovale' cause malaria); Protozoa species

38a) including Trypanosoma cruzi, which causes Chagas disease

Chagas' disease Vo + and Protozoan brucei which cause sleeping sickness (AA) Leishmania species (including Leishmania amazonesis 'Leishmania donovani'; Leishmania infantum 'Leishmania mexicana' etc); Dial Pneumocystis carinii (a protozoan known to cause rheumatoid arthritis in HIV and other immunosuppressed patients” (immunosuppressed)

Entamoeba histolytica zeal a 45534) « Toxoplasma gondii Toxoplasma larvae 00 Giardia lamblia Ala. and Giazdia « Entamoeba invadens zy: 53) ' in specific embodiments; The disclosed formulations are useful in the treatment of parasitic infections in animals and livestock caused by protozoan parasites selected from P. neurocystis; and follicles afl Lal) type cryptic hair Echinococcus granulosa; dle)

0 h —_ \ _ neuron. Other compounds useful as proteasome inhibitors in the treatment of parasitic diseases are described in ISPM AN 4¢ and are included here for reference. in specific embodiments; The detected constructs reversibly inhibit proteasome activity in the parasite. It has been shown that this non-reversible inhibition induces inactivation of the enzyme without 0 dephosphorylation in red blood cells and white blood cells. in specific embodiments; The long half-life may provide extended treatment protection against repeated exposures to parasites. in specific embodiments; The pee half-life of blood cells can provide extended chemoprevention protection against future infection. Prokaryotic cells include the eukaryotic proteasome 205 equivalent. Although the 0 subunit composition of prokaryotic 205 is simpler than that of eukaryotic cells; They include the ability to hydrolyze peptide bonds in a similar way. For example (JE) nucleophilic attacks on peptide bonds occur within the threonine residue at the end rather than the 8 subunits. In some embodiments a method for treating prokaryotic infections is provided and involves administering to a patient a therapeutically effective amount of a compound or combination provided here Vo prokaryotic infections caused by mycobacteria (such as tuberculosis, leprosy, Buruli ulcers, or Archaea) can include Inhibitors that bind to proteasome 205 have also been shown to induce bone formation in cultures of bone and organs. Given systemically (hill), specific proteasome inhibitors increased bone volume and rates of bone formation above 9676 (Garrett, I. oR. etal., J.

Clean.

Invest. (2003) 111: 1771-2 accordingly suggest that Al0_ubiquitin-proteasomes regulate osteoblast differentiation and bone formation. Subsequently; The combinations disclosed could be useful in treating and/or preventing diseases associated with bone loss; Jie Osteoporosis osteoporosis Here is a method for treating a chosen autoimmune disease or condition; the condition associated with the implanted graft or organ; neurodegenerative disease; Alla is associated with fibrosis; poverty-related cases

l-1 topical blood; infection (viral; parasitic or prokaryotic); diseases associated with bone loss; Including given compound as provided here. Bone tissue is a source of lias for factors that have the potential to stimulate bone WIA. Accordingly, bone tissue extracts not only contain structural proteins that are responsible for maintaining the structural cohesion of bone; But they are also Ble about bioactive bone growth factors that can stimulate bone cells to multiply. Among these other factors is the described “Base” family of proteins called bone morphogenetic proteins (BMPs) “All growth factors have effects on other types of LNA as well as bone cells”; including (1992) Hardy, M.

H., et al., Trans Genet 0 8:55-61 describes evidence that bone-forming proteins (BMPs) are genetically differentially expressed in hair follicles during development. Harris, 5. E., etal., J Bone Miner Res (1994) 9:855-863 describe the effects of TGF-B on hl expression of BMP-2 and other substances in bone cells. Expression (hs) of 81/0-2 occurs in hair follicles during maturation and after 558 cell proliferation 144Y (Hardy, et al above). Depending on the ld Vo compounds available here can also be useful in stimulating the growth of hair follicles. Available here (Lad) a method for treating a storage disorder in the lysosome by administering a compound as detected Gs ade Lysosome storage disorders are a group of diseases resulting from abnormal metabolism of multiple substrates, including glycosphingolipids glycogen mucopolysaccharides 0 “and glycoproteins Metabolism of high molecular weight exogenous and endogenous compounds occurs naturally in lysosomes; the process is naturally regulated in a step-by-step process by degrading enzymes. Consequently, it can inhibit deficient activity in one of the enzymes (lead) leading to the accumulation of specific substrates. It has also been shown that inhibition of the proteasome can improve the function of specific substrates in patients with lysosomal storage disorder (Y.

Shimada et al.

Biochem.

Biophys

“VW Commun. (2011) 415(2):274-8(485).The majority of these diseases can be classified clinically into subtypes: 1) onset in infants; (Y prefix in juvenile; or 9) or prefix late. Sale Infant primers are the most severe and typically have no residual enzyme activity. Sale late starters are the mildest ones with low or detectable residual enzyme activity. 0 The risk of Bald pictures in juveniles is between Infants and Sabies. Non-exhaustive examples of these diseases include: Pompe disease; Gaucher disease; Fabry disease; gangliosidosis; GMI-gangliosidosis; Tay-Sachs disease; Sandhoff disease; Niemann-Pick disease Krabbe disease, Farber disease; Jia sald white (JAE) on Metachromatic leukodystrophy “hla-Scheie disease Hurler—Scheie disease Hunter disease” Sanfilippo disease “Sanfilippo disease” B Sanfilippo disease Sanfilippo disease C disease Manfilippo disease D Sanfilippo A Morquio disease VO B Morquio disease Maroteaux-Lamy disease Sly disease ¢ ca - mannosidosis Gajsild mannosidosis - 8 413 fucosidosis; sialidosis and jis-Kanzaki disease. Accordingly; One embodiment of the treatment of Bohm's disease is; It involves giving the patient a therapeutically effective 0 dose of a formulation available here. Lad a constructs disclosed herein as diagnostic agents (eg in diagnostic kits for use in clinical laboratories) for screening proteins (eg enzymes; transcription factors) that have been processed by the enzymes Ntn hydrolases; containing the proteasome. The disclosed constructs are also useful as search reagents to specifically bind the 'Yo subunit 20/1/81' or '-chain' to inhibit the associated proteolytic activities on

0 q —_ \ _ eg; The activity (specific inhibitors) of other subunits of the proteasome can be determined. The majority of cellular proteins undergo proteolytic processing during maturation or activation. The enzyme inhibitors disclosed here can be used to determine if a cellular process is regulated; evolutionary or physiological or output by the proteolytic activity of a specific enzyme hydrolase 1400. © (gaa) These methods guarantee obtaining an organism; healthy cell preparation; or a cell extract; exposing the organism; cell preparation or cell extract of a formulation disclosed herein; exposing the exposed organism to the compound; cell preparation; or cell extract for reference; and monitor the process or output. The high selectivity of the compounds disclosed here allows rapid and precise removal or inclusion of Ntn Yo (eg JE 3) proteasome (20S) in a specific evolutionary or physiological PEPE process. Pharmaceutical formulations and administration 3 include the methods presented in the application. The present manufacture and use of pharmaceutical compositions; lly includes one or more of the compounds submitted in the present application. It also includes the pharmaceutical composition itself. In some embodiments, the compounds presented in the present application may be formulated Bde as described in US Patent No. 1 77797117 and the US application with serial number CIV EAYANY, each of which is included in the present application for reference in their entirety. Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. The term “Jedd pharmaceutically” is used here to refer to such crosslinked compounds; sally formulations and/or dosage forms which are within the range of sound medical judgment; and which are suitable for use in contact with tissues of human organisms and animals without excessive toxicity; or irritation; or allergic response; or any problems or complications (gal). In proportion to the reasonable rate of interest A/ Danger. The term 'pharmaceutically acceptable carrier' as used herein means 'sale, formulation, or 'sale' pharmaceutically acceptable carrier Jie liquid, solid filler, diluent, excipient, solvent, or encapsulated material.

-111- For use in the present application the term 'pharmaceutically acceptable carrier' includes buffer solution; FER and sterile water for injection; solvents; dispersing media; coatings; antibacterial and antifungal agents; isosurfactants and absorption retarders; etc. and the like; compatible with Pharmaceutical Administration. Each carrier must be 'acceptable' in terms of its compatibility with other components of the formulation and not be harmful to the patient. Sugars (1) de Wana Examples of some substances include Starch (Y) Jie starch used as acceptable carriers; sucrose as lactose 1801058, glucose 91106056, sucrose 635 is not substituted; (7) cellulose By — cyclodextrin wheat, potato starch, cyclodextran sodium carboxymethyl and its derivatives, such as sodium carboxymethyl cellulose |0 (¢); cellulose acetate; cellulose acetate; ethyl cellulose; (0) sprouted barley such as cocoa butter and waxes for suppositories; (4) oils excipients excipients (A); oil Peanut, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil Jie (11); propylene glycol; glycol compounds such as propylene glycol (01) and soybean oil; Vo sorbitol and sorbitol; Polyhydroxyl esters (VV) ¢ polyethylene glycol polyethylene glycol mannitol (V¢) ¢ agar (VY); ethyl laurate ethyl oleate Jie oleate and aluminum hydroxide Magnesium hydroxide Buffering agents such as magnesium hydroxide Free water (V1); alginic acid Alginic acid (Yo) aluminum hydroxide 0 (VA) “isotonic saline isotonic salt (VV) pyrogen—free water pyrogen solutions (01) ethyl alcohol (J) (V4) Ringer's solution ju}, solution Other compatible non-toxic materials Used in formulas (YY) tphosphate regulated pharmaceutical grade phosphate. in certain embodiments; The pharmaceutical compositions presented in the present application shall be non-inducing when administered to the patient. Shall have thermogenics; That is, it does not induce great elevations in the degree of Yo

-111-

The expression 'pharmaceutical acceptable salt' refers to the addition salts of a non-toxic organic acid pis, lad organic from a compound presented in the present application. These salts may be prepared on site during the final isolation and purification of a compound presented in the present application, or by a compound-by-compound reaction in the form of the free base thereof with a suitable organic or inorganic acid, and isolate the salt thus formed. nitrate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate Tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate lactobionate; lauryl sulphonate salts; and amino acid salts, amino a cid” and the like. (See, for example, Berge et al. (1977) 'Pharmaceutical Salts', J.

(. Pharm.

Sci. 66: 1-19 VO in some embodiments; The compound presented in the present application can contain one or more acidic functional groups and thus be able to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “Blane Acceptable Salts” in such cases refers to the inorganic and organic non-toxic gawd salts of the compound presented in the present application. Thus, these salts can be prepared on site during the separation and final purification of the compound; or by reacting the purified compound separately as the free acid formed using a suitable base; Jie hydroxide or carbonate or bicarbonate of a pharmaceutically acceptable metal cation cation 016181 with ammonia or with a pharmaceutically acceptable primary, secondary or tertiary amine. Clarifying salts include alkaline or alkaline earth | alkaline earth contains salts of lithium, sodium, yo, potassium, calcium, magnesium, aluminum

-11"-

Ls aluminum is the same. The annotating organic amines useful for forming base addition salts include ethylamine or diethylamine

or slo-ethylenediamine or ethanolamine or diethanolamine or piperazine and the like (see, for example, Berge

© et al. above). There can be wetting agents, emulsifiers, lubricants such as sodium lauryl sulfate and magnesium stearate als » magnesium stearate coloring agents and release agents ©63856©! Coating agents, sweetening agents, and materials

0 Flavoring agents, perfuming agents, and preservatives

Preservatives and antioxidants 4 formulations.

Examples of acceptable Wana antioxidants include: (1) the water-soluble antioxidants Jie ascorbic acid; cysteine hydrochloride and sodium bisulfate Meta Bay Sodium Sulphate

sodium metabisulfite 10 ; sodium sulfite and the like; (7) Oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) butylated hydroxyanisole Js gully, butylated hydroxytoluene (BHT), and lecithin; Jus) propyl gallate, alpha-tocopherol and the like; Wii (7)

0 | metal chelating agents; such as citric acid; And ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The pharmaceutical composition may also include auxiliaries such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the influence of living organisms can be ensured by

© | The inclusion of several antibacterial and antifungal agents; For example, JE

-7?1- paraben » and chlorobutanol; Phenol, sorbic acid, and the like. It may also be required that stress modulating agents Jie sugars and the like be included in the formulations. in addition to; Prolonged absorption of the injectable formulation is possible by the inclusion of absorption delaying agents such as aluminum monostearate and .gelatin in some cases; to prolong the effect of one or more of the compounds presented in the present application; It is desirable to slow down the absorption of the compound from subcutaneous or by intramuscular injection. For example (JE) Delayed absorption of a compound administered by non-intestinal route can be achieved by dissolving or suspending the compound in a carrier oil. Ve The formulations described here can be administered in a variety of forms depending on the disorder being treated and the age of and patient condition and body weight as well known in the art. For example (JE) when formulations are administered orally; they may be formulated as tablets, capsules, pills, powders, or syrups; and, in relation to parenteral administration, Non-enteric; these formulations may be formulated in parenteral forms (intravenously, intramuscularly, subcutaneously Yo) or as an infusion formulation or as suppositories. Formulation of these formulations in the form of eye drops or in the form of eye ointments These formulations may be prepared using conventional methods in combination with the methods given in the present document If desired the active ingredient may be mixed using any conventional additive sale or excipients (Jie binder, dispersing agent, or sald) no Lubricants, softeners, dissolving agent, suspending agent, emulsifying agent or coating agent. Acceptable formulations for oral administration may be in the form of capsules (eg, gelatin capsules); rivets, pills, tablets, lozenges (using a flavor base which is usually sucrose, gum arabic or gum tragacanth) or powders; or granules; or as a solution or suspension in aqueous or non-liquid (Sle, oil-in-water or water-in-oil emulsion; or in the form of an elixir or syrup; or in the form of pastilles (using an inert Jie mold)

-115- and/or in the form of (and acacia and sucrose gum; or sucrose, glycerin, and glycerin, and those quantities include previously determined quantities of cell mouthwash and the like in the form of Ung The formulation hadi The compound presented in the present application may be administered in the form of a large dose ingredient; a slurry; or in the form of a paste. Oral formulations generally include edible. carrier dla sale or inert diluent ©

Pharmacologically compatible agents may be included; and/or adjuvants as part of the oral formulation. in solid dosage forms for oral administration (capsules; pallets; lozenges or powders, granules, and the like); The active ingredient is mixed with one or more pharmaceutically acceptable carriers (sodium citrate or dicalcium phosphate) and/or any of the following: (i) fillers or materials Extension Jie starch, cyclodextrins, lactose, sucrose, glucose, mannitol and/or silicic acid; (7)_ binders “Jie binders” for example; carboxymethyl carboxymethylcellulose or alginate compounds 310173165 and gelatin or polyvinyl pyrrolidone; sucrose 0 and/or polystyrene (1) acacia ¢ humectants such as glycerol; (4) dispersing agents Jie agar-agar; calcium carbonate or potato or tapioca starch or alginic acid or silicate

Certain and sodium carbonate; (©) sala Jase of solution such as paraffin; (1) adsorption accelerators Jie (V) tquaternary ammonium Ye wetting agents such as; for example JB acetyl alcohol and Glycerol monostearate (A) glycerol monostearate Absorbents such as kaolin and bentonite clay ¢ (4) Lubricants Jie Talc, calcium stearate, magnesium stearate, rigid polyethylene, sodium lauryl sulfate sodium lauryl sulfate, and mixtures thereof, and (10) YO lubricating agents such as amyloid silicon dioxide (VV) » colloidal silicon dioxide agents

p-11 (VY) tcoloring flavoring agents such as mint; Methyl salicylate or orange flavor. and in the case of capsules, tablets, and pills; Pharmaceutical compositions may include buffer solutions. Similar solid compositions of the same type that are used as fillers in capsules of method and hard gelatin can be used using whey excipients as lactose © or pulp sugars as well as high molecular weight polyethylene glycols and the like that. A tablet may be prepared by pressing or molding and optionally with one or more additional ingredients. Tablets for compression may be prepared using a binder (eg gelatin, hydroxypropylmethyl cellulose (cellulose 0), lubricant, inert diluent, sale preservative, or sale solvent (eg ; sodium glycolate starch or cross-linked carboxymethyl cellulose), surfactant or dispersing agent. The molded tablets may be prepared by molding in a device suitable for a powder molding mixture which is moistened with an inert liquid diluent. Other solid dosage forms such as lozenges, capsules, pills Vo and granules in a form calculated by points or may be prepared with Jie wrappers or wrappers Mucous wrappers and other packagings known in the field of pharmaceutical formulation They may also be formulated to provide slow release or Controlled release of the active ingredient in them using, for example, hydroxypropyl methyl cellulose in various ratios to provide the desired release form or use of other polymeric templates; liposomes and/or microspheres.0 Can be sterilized that mod; For example; By filtering through a filter containing bacteria or including sterilizing agents in order to form sterile solid formulations which can be dissolved in sterile water or other sterile injectable media immediately prior to use. Such formulations may optionally include non-absorbing agents and may be formulated such that they release only the active ingredient(s) or an amie form at a particular sda of the gastrointestinal tract and specifically Yo in a delayed manner. Examples of formulations that are included include polymeric materials and composites

-111- Waxy. The active ingredient can be in a precisely formulated form if appropriate with one or more of the excipients described above. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, and Syrups and elixirs. In addition; The active ingredient or ejection dosage forms may include the inert diluents being used oo, liquefaction agents and al substances for example; water or any solvent Jad) generally in isopropyl alcohol and isopropyl alcohol ethyl alcohol Ji) Jie emulsification benzyl and benzyl alcohol ethyl acetate and ethyl carbonate Ji) and carbonate —-Y D “propylene glycol ALA 5602, propylene glycol benzoate, benzyl benzoate 8160001; oils (particularly cottonseed oil, oats, butylene glycol, milled Ve butylene glycol, other seeds, olive oil, castor oil, sesame oils), glycerol compounds, poly(ethylene glycol, esters) tetrahydrofuryl alcohol, tetrahydrofuryl alcohol, and mixtures thereof. sorbitan from sorbitan fatty acid esters in addition; inert diluents and formulations that can be taken of wetting agents, emulsifiers, suspensions, and sweeteners Oral Jie may include Vo adjuvants and Vo agents In addition to the active compound(s), suspensions may include suspension agents such as ethoxylated isostearyl alcohols, isocetearyl alcohols (Jha) and polyoxyethylene esters. sorbitol Li) ethoxy-polyoxy-treated aluminum hydroxide lies microcrystalline cellulose raw sorbitan and microcrystalline cellulose 0 and gum 8981-81 Oak als bentonite bulk aluminum metahydroxide Pharmaceutical compositions suitable for parenteral administration by non-enteric route include one or more compounds in combination with one or more compounds and with one or more pharmaceutically acceptable sterile solutions or

-/A11- Non-aqueous solutions, dispersions, suspensions, emulsions or sterile powders which may be dissolved in ALE sterile solutions for injection or dispersions prior to use; which may include antioxidants, buffers, bacterial states and solutes which can render the formulation isotonic with the blood of the intended recipient or with a suspension or thickening agents Examples include suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions presented in the present application; water for injection (eg, sterile water for injection); bacteria-inhibiting water; ethanol » polyhydroxyl (such as glycerol; propylene glycol and polyethylene glycol; liquid polyethylene glycol and the like); sterile buffer solution (eg citrate buffer solution) 0 and suitable mixtures of finishes and vegetable oils; Fie olive oil; injectable organic esters; as ethyl oleate” 5 Cremophor EL™ (BASF, Parsippany, NJ). In all cases, the formula must be sterile and fluid to an extent that is easy to inject. adequate liquidity can be maintained; For example (JB) by using a coating layer of Jie lecithin, by maintaining the required particle size in the case of dispersants and by using 0 surfactants, and the composition must be stable in conditions Manufacturing and storage must be preserved against contamination caused by microorganisms such as bacteria and fungi.Protection from the effect of microorganisms can be achieved by means of antibacterial and antifungal agents, such as JED, parabens, chlorobutanol; phenol, ascorbic acid 86010 0, thimerosal, etc. In HES cases it would be better to include sill agents, for example, sugars; polyalcohols such as mannitol; sorbitol; Sodium chloride in the compound Prolonged absorption can be achieved from injectable compounds that contain the agent that delays absorption, for example aluminum monostearate and gelatin.

-11 A- Sterile injection solutions can be prepared by combining the active compound in the required amount in a solvent, as required. followed by filter sterilization. lef is suitable with one or a combination of the components mentioned and in general; The dispersion is made by incorporating the active compound into a sterile medium which contains an alkaline dispersion medium and other required components of those listed above. and in the case of sterile powders, sterile solutions for injection; The preferred methods of preparation are freeze-drying (lyophilization); day© which yields a powder of the active ingredient plus any additional ingredient required from a sterile, previously filtered solution. For microencapsulation or ALE size adaptable stock images were prepared For injection by preparing polylactide- nano templates of composite in biodegradable polymers such as polylactide-polyglycolide 00O79O700108. Depending on the drug-to-polymer ratio and the nature of the polymer; is done specifically | 0 The use of a polymer and the rate of decomposition of the drug is controlled. Examples of other biodegradable polymers and poly(anhydrides) (011065/A80)/A001TM poly(orthoesters) include poly(ortho esters) via drug retention in lipid particles or in emulsions (cial) also for the preparation of formulations Ally nanoemulsions or microemulsions compatible with body tissue. VO for inhalation; The compounds can be ingested by aerosol spraying from a pressure vessel or dispenser containing, for example, an appropriate amount for the propellant; Gas such as carbon dioxide or aerosols. These mentioned methods include what is described in US Patent No. Intranasal administration; As described in; Bee In addition; be +8. Hamajima et al., Clin.

Immunol.

Immunopathol., 88(2), 205-10 (1998) 0 Liposomes and microencapsulations or nanoencapsulations (eg as described in US Patent No. 149777975; which is listed in Jia) may also be used. current demand in its entirety); Biodegradable nanoparticle delivery systems may also be used (eg, as described in US Patent No.

-?411- The systemic administration of the therapeutic compound as described here may also be through the skin or through the mucous membrane. Dosage forms for surface or transdermal administration of the compound provided herein include powders; courtyards; ointments; pastes; creams; palliatives; jellies solutions; Patches and inhalants. Active ingredients can be mixed under aseptic conditions with Jala Acceptable Wana and with any of the preservatives; organizations; or motives required. For percutaneous or epidermal administration, the formulation is used until permeated by appropriate skin penetration. And those penetrating materials are generally known in the field; These include, for example (JU) for mucosal administration; The active compounds in ointments, paints, gels, or creams generally known in the art Ointments, pastes, creams, and jellies may, in addition to one or more of the compounds presented in the present application, include excipients such as animal and vegetable fats, oils, and waxes Paraffin materials, starch or tragacanth gum, cellulose derivatives, polyethylene Yo glycol compounds, silicone compounds, bentonites, cyclic acid (0 silicic) and talc (zinc oxide hij) or mixtures Of which. Powders and cll materials in addition to the compound presented in the present application may include excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder Polyamide powder or mixtures of these materials. Spray materials may additionally include ordinary propellants Jie chlorofluorohydrocarbons and non-volatile substituted hydrocarbons such as butane and propane 0200810©8. The compound presented in the present application can be administered via aerosol. This can be accomplished from Yo by preparing an aqueous aerosol and a liposome or solid particle preparation to be included in

119. example; Fluorocarbon propellant (Jo) formula. A non-aqueous suspension may be used in some embodiments Sonic aerosols are preferred because they (fluorocarbon +) reduce the shear factor and can result in decomposition of the compound. Normally, an aqueous aerosol is manufactured by formulating the aqueous solution or suspension of agent with pharmaceutically acceptable carriers and stabilizers The carriers and stabilizers with © requirements vary with specific formulations but typically include reducing agents

PLURONIC® “(polysorbates sorbates Js) TWEEN®) non-ionic lecithin surfactant; and lysine sorbitan esters and sorbitan esters » poloxamers (poloxamers) and acceptable co-solvents o ((polyethoxylates) CREMOPHOR® ¢ serum albumin Jie polyethylene glycol and benign proteins Jie Pharmaceutical 0 « lecithin; Sugar alcohols Transdermal patches have the additional advantage of providing controlled delivery of the compound presented in the present application to the body Dosage forms may be manufactured by decomposition or dispersion of agent Vo in a suitable medium. Absorption enhancers increase the reflux of the compound through the skin.The rate of this reflux can be controlled by either providing a membrane that controls the range or dispersing the compound in a polymer matrix or gel.Pharmaceutical formulations can be prepared as retention suppositories or enemas for administration rectally and/or To give vaginally. The formulations presented as Suppository 0 may be prepared by mixing one or more of the compounds presented in the present application with one or more suitable non-irritant excipients or carriers; It includes, for example, cocoa butter and room poly but it is Sha (ethylene glycol) and its waxy load or salicylate which is solid at effective temperature in the rectum or Jalal) is liquid at body temperature and therefore; Fusion can take place in the vaginal vacuole and release the active agent. Formulations suitable for vaginal administration also include YO

-111- on pessaries, tampons, creams, jellies, pastes, foams or spray formulations comprising such carriers as are known in the art to be suitable. Compounds lea in one embodiment; Therapeutic compounds are prepared with carriers that will provide a rated release mode; Which includes therapeutic fie systems against their rapid elimination from the body;

Jie microencapsulation and implant. Biodegradable and biodegradable polymers can be used oo ethylene vinyl acetate; polyanhydrides; polyglycol acid; collagen; Polo ortho ester and urea lactic acid. Such compositions may be prepared using standard techniques or may be

Way) for example »from Alza Company and Nova Pharmaceutical Company. Clads may be obtained using liposomal suspensions (containing liposomes that target selected cells with monoclonal antibodies to antigens) as pharmaceutically acceptable carriers. This may be prepared 0 as described in patent (J) known to those experienced in the field; for example, which is included in the present application for reference in its entirety. US No. 407748111 Giving preparations of one or more of the compounds provided (Ka described above; WG in the present application by mouth; by non-enteric injection; or by topical or formulations suitable for the route of administration. JE can be administered intrarectally. They may be given as 1 given as tablets or capsules by injection or inhalation or as an eyewash, ointment, suppository or infusion agent or may be given as a topical lotion or ointment and may be given into the rectum By suppository. In some Buk incarnations, administration is by mouth. By injection had the phrases “non-intestinal parenteral administration” and “non-intestinal Yo” have also been used This refers to modes of administration other than topical administration, which is by injection normally and includes, but is not limited to, intravenous, intramuscular, arterial, or subcutaneous administration. inside the sheath, inside the case, inside the orbit, inside the heart, inside the skin, inside the peritoneum, inside the trachea, under the skin, under the epidermis, or inside

-111- Joint, subcapsular, subarachnoid, intramedullary, intrasternal injection, or infusion. “Peripheral administration” Jal The expressions mean “systemic administration”; Giving that pervades the body “peripheral administration” as it was used here to give a bonding compound, drug or any other substance through that directly within the central nervous system so that it enters the patient’s systems and thus 5 undergoes metabolism and other processes and this is done by subcutaneous administration; For example, the compound presented in the present application may be administered to human patients and other organisms for the purpose of treatment using any appropriate route of administration including oral administration, administration by spray, rectal application, or inside the vagina or JB) nasal passage; or for example topical intravitreal sacy J or s administration by non-enteric injection or administration or in the form of powders, ointments or drops including buccal or sublingual administration. Regardless of which compound presented in the present application may be used in the liad (consideration of the route of administration) an appropriate liquefied form and/or the pharmaceutical formulations contained in the present document are formulated in using traditional methods known to those skilled in the art. In an embodiment of Wana Acceptable Dosage Forms 1 the pharmaceutical composition shall be an oral solution or an injectable solution by non-AT structure before administration. And in sale) in a lyophilized formulation, Al can be enteric. It is an embodiment. solid; This formulation may also include tablets, capsules, or powders for sale Image The actual dose levels of the active ingredients can vary in the pharmaceutical formulations presented in the present document in order to obtain the amount of active ingredient that is effective to achieve the response 0 treatment required for a particular patient; A given formulation and route of administration without being toxic The concentration of the compound presented in the present application in the pharmaceutically acceptable mixture will vary depending on several factors which include the dose of the compound to be administered; and pharmacokinetic properties of

ARAL

The compound(s) used and route of administration. in some embodiments; Compositions may be provided w/v of the PV ome compound (comprising between) the Sle presented in the present document in solution and among other materials for parenteral administration other than the lin disclosed 50 mg/kg body weight to about 0.09 enteric Typical dose ranges vary from about 1 to 1 day and are administered in -1 divided doses Each divided dose may include the same compounds © or on other compounds of the invention.Doses are effective in an amount dependent upon the general health of the patient, formulation, and route of administration of the compound (Aad) factors including (compounds) chosen.Dosage forms or formulations may be prepared Which contain a compound as described in the document in a balance of non-toxic carrier. 96 001 to 96 1.005 current in the range of 0 The methods of preparation of these compositions are known to those with experience in the art. The expected formulations may contain the active ingredient. In one embodiment it is 0-790 and in another it is Zeon-21. Although doses will vary based on symptoms; And the age and body weight of the patient.” the nature and severity of the disorder to be treated or prevented; Method of administration and form of the drug mg of the compound for an adult patient from Tenn to -109 in general; Daily doses of -5 This may be given in a single dose or in divided doses. The quantity of the active ingredient that can produce a single dose form will be that amount of the compound that produces the effect of Alda Sale combining it with my treatment. The pharmaceutical composition may be administered once or it may be divided into a number of doses Small to be eaten at intervals of time. It is accepted that the exact dose and duration of treatment is a function of disease treatment, which can be determined empirically using known test protocols or by inference from in vivo or laboratory test data. It should be noted that the degree of concentration and doses may also vary according to the seriousness of the condition to mitigate it. It should also be understood

Gay that each specific patient has therapeutic regimens for doses that are adjusted over time to the person's need and the medical opinion of the person who supervises the use of these combinations, and that the ranges of Yo

-16- The concentrations mentioned in the present document are examples only and are not intended to limit the range or use of the formulations to be protected. The exact time of administration and/or amount of formulation will depend on the outcome on activity and kinetics. Wal in a given patient and dalled) relates to the effective lod efficacy the pharmacology and bioavailability of a given compound and the physiological status of the patient (which includes 0 age, sex, type of disease, stage, general physical condition, response to a given dose, type medication) and route of administration; etc. However; The previous approach can be used as a basis for micro-tunnel treatment. For example; Determine the preferred time and/or the preferred amount of administration that does not require more than the usual experimental procedures consisting of monitoring the patient and adjusting the dose and/or time.” Pharmaceutical compounds may be placed in a container; Administration. A combination therapy is also provided whereby one or more other therapeutic agents are administered together with a compound or pharmaceutical composition comprising the compound presented in the present application. Such combination therapy may be accomplished by administering a dose at the same time; or sequentially or separately from stand-alone treatment components Non-exclusive examples of combination treatments include those included in the international application 1 and included in the present application by reference in their entirety. 0101/1 48744 in certain embodiments; uniformly with one or more other JE inhibitor (see eg sulin) (clade), each of which is listed here by reference in its entirety.) Examples include cAVAAVEY 5 27778 marizomib; Carfilzomib (see “Additional Proteasome Inhibitors” MLNOTO8 to “Bortezomib” 0 US Patent No. 67 751976); and those compounds disclosed in JE (U.S. Pat. No. 7768976557 and USP. No. 77191887) each of which are incorporated herein as Gil for reference in their entirety. In certain embodiments; a pharmaceutical composition is given and oY-0 co-localized with a cytokine Cytokines include, but are not limited to, interferon-

—yyo-— and 17 and granulocytes; mononuclear cells, stimulating factor 01, 8-1, and interleukins Bs

TGF=B 5 Ramh-11th-and-say “(GM-CSF) colonies in certain embodiments; The pharmaceutical formulation mentioned herein is administered uniformly with a steroid. Appropriate steroids may include: without limitation; on “alclometasone sulin Kl”; amcinonide algestone s chlorprednisone ¢ budesonide budesonide betamethasone; clocortolone; clobetasol ¢ chloroprednisone cortisone cortisone corticosterone + cloprednol; Dezoned06500106; deoxymetazone deflazacort; cortivazol 0; diflorasone; flurazone A; Dexamethasone 6 Fuprednate 010010600816 ¢ Enoxolone GLA+. diflucortolone diflucortolone flumethasone + flucloronide fluozacort + “fluzacort” enoxolone 10001001006 fluocinolone acetonide ¢ flunisolide flumethasone ¢ flumethasone ¢ 1110001110 butyl; butylfluocinonide; fluocinonide acetonide Yo fluperolone; fluorometholone acetate; Fluorometholone Fluprednisolone 1. 10060010606 acetate flupredinidine acetate fluticasone fluticasone propionate » flurandrenolide flurandrenolide » fluprednisolone; halcinonide propionate ¢ formocortal Formocortal ¢ propionate hydrocortisone » halometasone » halobetasol propionate 0 ; _mazipridone loteprednol etabonate ¢ methyl hydrocortisone + meprednisone meprednisone « medrysone + mazipredone ; paramethasone mometasone furoate; methylprednisolone furoate prednisolone prednisolone Prednisolone prednicarbate ¢ paramethasone « diethylaminoacetate sud 7-diethyl acetate © prednisolone Prednisolone Yo

-1?1-

Prednisolone sodium phosphate ¢ Remixolone

rimexolone ¢ prednival ;_prednylidene ¢ texocortol

triamcinolone fluocinolone ¢ triamcinolone triamcinolone ¢ tixocortol

acetonide ¢ triamcinolone benetonide; or triamcinolone hexa

© triamcinolone hexacetonide; salts and/or derivatives thereof.

in some embodiments; The pharmaceutical composition mentioned herein is administered uniformly with a therapeutic agent

immune. Appropriate immunotherapeutic agents may include; For example, but not limited to

MDR modifiers (verapamil; valspordar; biricodar;

tariquidar; laniquidar; cyclosporine; thalidomide | 0; lenalidomide “((REVLIMID®) lenalidomide pomalidomide

And monoclonal antibodies A0100001002. It could be antibodies

Monoclonal either shee or combination such as rituximab ¢ tositumomab

0” alemtuzumab “alemtuzumab epratuzumab + ibritumumab tiuxetan

gemtuzumab ozogamicin ¢ ibritumomab tiuxetan erlotinib ¢ erlotinib ¢ cetuximab ¢ bevacizumab bevacizumab 1

trastuzumab and transtuzumab

Other embodiments: It must be understood that while the disclosure is read in relation to the description

detail it; The previous description is intended to clarify and not limit the scope of disclosure; which is specified

by the scope of the ancillary safeguards. side interference; the benefits; and other modifications within the scope of Yo the following claims.

Examples

general experimental methods

Magnetic resonance (NMR) spectra were recorded at 5080 MHz for TH giving offsets.

chemical (8) in sia per million form for the lower domain of tetra die silane;

-1/- Spectrophotometer (Hz) SS in (J ad) internal standard” and coupling constants were used to confirm the mass of the compounds by ionizing the compounds to generate charged particles or mass (MS) fragments (Collision El molecules and measuring their mass-to-charge ratios (01/2). As an ionization method, electrophoresis was used). -N-((R)=1-(((S)-1-(((S)-3—(Cyclopent-1-en-1-yl)-1-((R)-2- methyloxir—an -2-yl)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl)- 1-oxopropan—-2-yljamin—- 0)—1-oxopropan-2-yl)-4-hydroxy—4 - methylcyclohexanecarboxamide (C-1087) 1. Hy, PdIC

H-D-Ala-OBn 2. H4-MeO-Phe-OBn

HO HATU HO H 0 HATU Baum COOH 5 9" >: Nm 9 1. Hy, PIC o - 0 AAA 1 PH 0

YY : 080 2. HATU, DIPEA PARCH - 9 > H 0 = H 0

OMe TFA 0 Ho a, LAOA 0 Ve 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5—0.54 mg added (mmol) (Voy ¢HATU) b]pyridinium 3-0610 hexafluorophosphate mL; 1,14 cane 760) to a solution of acid (se 54 mM in (Use 0.14 mM; Yo0) (R)-benzyl 2—aminopropanoate 1 Aggie (/01;©mL) was heated at 0° dimethylformamide dimethylformamide to ambient temperature and stirred for 6.5 h Water was added ad Reaction mixture (EtOAc) ethyl acetate left mL (The resulting mixture was extracted using ethyl acetate (01)

-1 YA-brine mL) and Brine 001) organic layers collected with water Jue (Fx mL 0 anhydrous sodium sulfate mL); drying over sodium anhydrous sulfate 001 (silica gel) and concentration. Purified (R)-benzyl 2—((1r, for ) :Y = EtOAc [petroleum ether (ji) mg; YY +) 4r)-4- hydroxy—4-methylcyclohexanecarboxamido)propanoate o A yellowish-white solid. sale (Toll) as 9601: to a solution of (R)-benzyl 2—((1r, 4r)-4-hydroxy—-4 (ml) methylcyclohexane carboxamido (ml) palladium (Ve mol) was added in Je 0.01 mg; YY) propanoate The mixture was stirred under an atmosphere of (9600 v 01 PAC). palladium carbon. atmosphere) at ambient temperature for ¥ hours. 1 (hydrogen atmosphere) the mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure to obtain the color; used in Age mg; quantitative) as a solid (YT) on the acid Views Next step without further purification. mmol) to 5.06 “lll Ve) DIPEA 5 mmol) 0.7 mg; HATU £04” 1 methoxy added =) Y = f(5)-benzyl = amino (Use 0.145 mg TF) solution of acid (salt (S)-benzyl 2—-amino-3—( 4-methoxyphenyl) propanoate Phenyl) propanoate

DMF mmol) in 100 mg; YYY (HCI) hydrochloric 8610 HCl to ambient temperature lad Celsius. The dap reaction mixture (mL) was left at zero Vv (mL) and the resulting mixture was extracted using Yo) hour. Water was added 1.5 sad and stirred 0 ml) and Brian 001 (?). The combined organic layers were washed with 01 x milliliter water (mL); drying over anhydrous sodium sulfate and concentration. The residue was purified by 001 to obtain (Y:1 = EtOAc) flash chromatography column on silica gel (petroleum ether/acid:

-4?1- (S)—2—((R)-2—((1r,4r)—4-hydroxy—4-methylcyclohexanecarboxamido) «axe YY0) propanamid-o)-3-(4 -methoxyphenyl)propanoic acid 76617 yield) in the form of a white-yellow solid. to a solution of : (S)—2—((R)-2—((1r,4r)—4-hydroxy—-4-methylcyclohexanecarboxamido) (aa YY 0) propanamid- 0)-3—( 4-methoxyphenyl)propanoic acid © 14 mmol) in (THE 10 milliliters) 0/0 Vo) mg added; .)9600 The mixture was stirred under an atmosphere of hydrogen (1 atmosphere) at ambient temperature for 1 hour. The mixture was filtered through a bed of silite and the filtrate was concentrated under reduced pressure to give the compound (R= 2—((1r,4R)—4-hydroxy—4-methylcyclohexanecarboxamido)propanoic acid (710 mg; quantitative) as a colorless solid; it was used in the next step without further purification. Yo A) HATU added mg; AY + mmol) 5 oY) DIPEA milliliters; 0.01 mmol) to a solution of (R)=2—((1r,4R)—-4-hydroxy—4- 101( methylcyclohexanecarboxamido) propanoic acid mg; 14 Ak mol) (S)-2-amino-3~-(cyclopent-1-en—-1-yl)-1-((R)-2-methyloxiran-2-, 01 150(yl)propan—1- o-ne mg; 164 mmol) DMF (1 milliliter) at zero degrees Celsius. The reaction mixture was left to warm to ambient temperature and stirred for 1.5 hours. Water (Yo) was added (mL) and the resulting mixture was extracted with EtOAC (04 mL) (Vx). Combined organic layers were washed with water (001 mL) and Bryan (01 mL); drying over Vo sulfate. anhydrous sodium and the concentrate.The residue was purified by column chromatography on silica gel (EtOAC) to obtain -2-(4))-1-(Al7E-07/6100601-1-80-1)-3-(5). ))-1-(5))-1-g(a))-l-(4 1) ‎methyloxi— ran-2-yl)-1-oxopropan-2-ylj)amino)-3— (4-methoxyphenyl)- 1-oxopropan—2-yl)ami- no)-1-oxopropan-2-yl)—4-hydroxy-4-

_ \ Ad «= _mg; 9677 yield) as a solid (Y1+)methylcyclohexanecarboxamide white to yellowish colour. (CDCI3)): 5 7.16 (d, J = 8.4 Hz, 2H), 111 dichloroform NMR (300 MHz, 6.83 (m, 1H) ), 6.82 (d, J = 8.4 Hz, 2H), 6.35 (m, 1H), 6.16 (m, 1H), 5.32 (m, 1H), 4.56 (m, 2H), 4.36 (m, 1H), 3.78 (s, 3H), 3.29 (m, 1H), 2.98 E0 (m, 2H), 2.89 (m, 1H), 2.26 (m, 1H), 2.05 (m, 5H), 1.86-1.78 (m, 6H ), 1.48 (d, J = 6.3 Hz, 3H), 1.43 (m, 2H), 1.26 (m, 4H), 1.23 (s, 3H), 0.87 (m, 3H).

Detected A[Na+M] 0167 “C32H45N307 of MS (El) (1s,4S)-N-((R)-1-(((S)-1—-(((S)-3) —(cyclopent-1-en-1-yl)-1-((R)-2—- 1. methyloxi— ran-2-yl)-1-oxopropan-2-ylj)amino)-3—(4- methoxyphenyl)-1-oxopropan—2-yl)ami-no)-1-oxopropan-2-yl)—4-hydroxy-4- : methylcyclohexanecarboxamide 1H NMR (300 MHz, CDCI3): 6 7.16 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 4

Hz, 2H), 6.60 (d, J = 7.2 Hz, 1H), 6.16 (d, J = 7.2 Hz, 2H), 5.30 (m, 10 1H), 4.56 (m, 2H), 4.36 (m, 1H) , 3.79 (s, 3H), 3.28 (d, J = 5.1 Hz, 1H), 2.99 (m, 2H), 2.89 (m, 1H), 2.26 (m, 2H), 2.18-2.15 (m, 6H), 1.85- 1.64 (m, 9H), 1.47 (d, J = 6.3 Hz, 3H), 1.27- 1.24 (m, 6H).

A[Na+M] 0167 detected “C32H45N307 of MS (El)

Y Example Yo (S)-N-((S)-3-(Cyclohex-1-en-1-yl)~-1—((R)-2-methyloxiran-2-yl)-1- oxopropan —-— 2-yN)-2—((S)-3-hydroxy-2—(2- morpholinoacetamido)propanamido)-3—(3-hydroxy—- 4-

-11- methoxyphenyl)propanamide (C- 1109) o on 1. TFA 1. TFA 0 2. A 0000

BocHN H ove 2. Boo L-Ser sono Keone HATU —_— _ Sixty 0 = _— =

LS Ma Obn 080

Oh

OH oY they 0 oN o the ron LAR Lr except A NAoye I'm not NYY

H 5 0 Maya CL, OH

Obn

Oh

HATU, DIPEA 0" 0 H © 0 by ALN

H § 2 H §

TFA 0 Yamaya (HD OH 06 mL) to a solution of Yo ¢TFA) Trifluoroacetic acid (S)—-methyl 3—(3—(benzyloxy)-4-methoxyphenyl)- was added. 2—((tert- from © mmol) in 0.1 g dichloro; 0,0 +) butoxycarbonyl) amino)propanoate at 0 °C with stirring. (ill 00 ¢“CH2CI2) dichloromethane was soaked for 1 hour and then concentrated to dryness. The residue was agitated 1 time to obtain TRA (mL per fraction) to remove residues of Yo) EtOAC azeotropically three times with (S)-methyl 2-amino-3—(3—(benzyloxy) -4- Crude compound 0 of. TFA as salt methoxyphenyl)propanoate (S)-methyl -4-(/0*7un5602)-3)-2-30100-3 all dissolved compound (mL) followed by DMF (04 mmol) in VY (TFA (methoxyphenyl salt) propanoate

-1©7- mmol (YAY can TAY) HATU (mmol); VY can 7,497) Addition of ©80-a-serine to Bad at 0°C with stirring. A mixture was left The reaction (01 lille (H0a0 Yoo) milliliters) and water You) hours. 0/56p 1 ambient temperature was added and stirred for (vx mL 001 (EtOAC using Sl mL) and the two layers were separated. Phase extraction 7 mL 3); and drying over sulfate 0000) and the combined organic phases were washed with Brain©; the concentration. The residue was purified by anhydrous sodium sulfate silica gel on a silica gel flash column chromatography (S) column. )-methyl 3-)3- (methanol) :70 = (MeOH) [CH2CI2) (benzyloxy)-4-methoxyphenyl)-2-((S)-2~((tert-butoxycarbonyl) )amino)- g » 9677 toll). ¢,¢) 3- ~hydroxypropanamido)propanoate 0

(01 mL) TFA was added to a solution of (S)-methyl 3—(3—(benzyloxy)-4- methoxyphenyl)-2—((S)-2-((tert-butoxycarbonyl)amino )-3- - hydroxypropanamido)propanoate )¢,£ g; AY mL (Js in 0012012 (+0 mL) at 0°C with stirring. The mixture was stirred for 1 hour and thereafter concentrated to the degree of dryness. The residue was azeotropic three times with EtOAC (01 milliliters per fraction) to remove the TFA residue to yield the crude compound (S)—methyl 2—((S)-2-amino—

3-hydroxypropanamido)-3-(3—(benzyloxy)-4-methoxyphenyl)pro-

6 as its TFA salt. The crude compound (S)—methyl 2—((S)-2-amino-3-hydroxypropanamido)—3— (3—(benzyloxy)-4-methoxyphenyl)pro— 0800816 | 0 (AY salt (TFA mmol) in DMF (o+) mL) followed by addition of F=morpholinoacetic acid AY can VT mmol); HATU (0.0 g; 11.1 mmol) DIPEA 5 (0.4 milliliters) at 0°C with stirring. The reaction mixture, Bad, was left to ambient temperature and stirred for ? hours. EtOAC (Yoo) mL) and water (Yeu mL) were added and the two layers were separated. Yo the aqueous phase was extracted with 100 mL EtOAC (Fx) and the organic phases were washed

The 1 was collected using Brain (Yeo) X 0 mL, drying over anhydrous sodium sulfate, and concentration. The remaining sald) was purified by flash chromatography column on silica gel (1:01:01 = CH2CI2/EtOAc/MeOH) to yield: (S)—methyl 3—(3—(benzyloxy)-4-methoxyphenyl )-2—((S)-3-hydroxy-2- aa ¥,4) (2-morpho linoacetamido)propanamido)propanoate © 9617 toll). (S)—methyl 3-(3-(benzyloxy)-4-methoxyphenyl)-2—((S)-3- V,+) hydroxy-2-(2-morpho linoacetamido)propanamido)propanoate was treated g 4 mmol) using a solution of lithium H20- lithium hydroxide (++¢ mg; 01 mmol) in water/THE (00 milliliters/Yo milliliters) for ¥ hour. THF 001 was removed and the aqueous phase was then acidified to pH = 1p using HCI 2 1 followed by concentration to dehydration to obtain the corresponding acid. The acid was dissolved in MeOH (Yo) mL) and 1 (Pd/C g; 90600) was added. The mixture was stirred under 1 (atmospheric) hydrogen at ambient overnight and then filtered through a layer of silite. The filtrate was concentrated under reduced pressure to give: (S)-2-((S)-3-hydroxy—2—(2-morpholinoacetamido)propanamido)-3—-(3—- 10) ©Y +) hydroxy—4- -methoxyphenyl)propanoic acid total 90764 yield) as a colorless solid. oY) HATU added mg; V,0 mmol) DIPEA (0.8 mL) to a solution of (S)—2—(((S)—-3-hydroxy-2—(2-morpholinoacetamido)propanamido)—3—( 3—YO) hydroxy—4-methoxyphenyl)propanoic acid ~~ Y. mg; 1 mmol) and-2-(5)amino-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan—1- 1 (TFA zk) one mmol) in DMF (YO) milliliters) at 0 °C with stirring. The reaction mixture ad was left to ambient temperature and stirred sad ? hours. EtOAc (01 mL) and water (Veo mL) were added and the two layers separated. The aqueous phase was extracted using

1©4-

X milliliter (Yoo) and the combined organic phases were washed with Brain (1 x milliliter) (01) remaining EtOAc by sald column, drying over anhydrous sodium sulfate and concentration. The oY was purified to yield (7:01:01 = CH2CI2/EtOAc/MeOH) fluorescence chromatography on silica gel: (S)-N-((S)-3—(cyclohex-1) -en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1- e oxopropan-— —2-yl)=2~((S)~3-hydroxy-2 —(2-morpholinoacetamido) «ax YY +) propanamido)-3—(3-hydroxy— —4-methoxyphenyl)propanamide yield). 658 1H NMR (300 MHz, DMSO-d6): & 8.74 (s, 1H) ), 8.22 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.78 (m, 1H), 6.73 (d, J = 8.4 Hz, 1H), 0 6.63 (s, 1H), 6.54 (m, 1H), 5.39 (m, 1H), 5.03 (m, 1H), 4.40-4.60 (m, 2H), 4.30 (m, 1H), 3.71 (s, 3H), 3.60 (m , 4H), 3.50 (m, 2H), 3.22 (m, 1H), 2.80-3.10 (m, 3H), 2.40 (m, 3H), 2.20 (m, 2H), 1.90-2.10 (m, 4H), 1.50-1.70 (m, 4H), 1.37 (s, 3H), 1.00-1.30 (m, 3H).

A(MH) 117,7 detected “C31H44N409 IMS (El)vo The following compounds were synthesized in a similar way: (S)-N=((S)-3-cyclopentyl-1-((R)-2- methyloxiran—-2-yl)-1-oxopropan—2- yh-3— (4-methoxyphenyl)-2-((R)-2—(2~-(tetrahydro-2H-pyran—4- yl)acetamido) propanam-ido)propanamide (C-1011): 1H NMR (300 MHz, CDCI3): § 7.12 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.7 0)

Hz, 2H), 6.58 (d, J = 7.8 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.23 (d, J = 7.5 Hz, 1H), 4.62 (m, 1H), 4.47 ( m, 1H), 4.37 (m, 1H), 3.94 (m, 2H), 3.80 (s, 3H), 3.36 (m, 2H), 3.29 (d, J = 5.1 Hz, 1H), 3.00 (m, 2H ), 2.90

10E (d, J = 4.8 Hz, 1H), 2.15 (m, 2H), 2.07 (m, 1H), 1.51 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H), 1.06-1.83 ( m, 15H). +(MH) 07,5 detected «C31H45N307 1 MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1 -oxopropan—2- yh-3— (4-methoxyphenyl)-2-((S)-2-(2-(tetrahydro-2H-pyran-4-© yl)acetamido)propanam-ido)propanamide (C-1010) ): 1H NMR (CDCI3, 300 MHz): § 7.11 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7

Hz, 2H), 6.75 (d, J = 6.6 Hz, 2H), 6.38-6.43 (m, 1H), 6.20-6.27 (m, 1H), 4.62-4.65 (m, 1H), 4.47-4.53 (m, 2H), 3.92-3.98 (m, 2H), 3.79 (s, 3H), 3.41 (t, J = 8.7 Hz, 2H), 3.23 (d, J = 4.8 Hz, 1H), 2.95-3.03 (m, 0 2H), 2.90 (d, J = 4.8 Hz, 1H), 2.06-2.13 (m, 2H), 1.53-1.92 (m, 11H), 1.52 (s, 3H), 1.39 (d, J = 7.5 Hz, 3H ), 1.03-1.36 (m, 4H).

A+(MH) ovY,y detected «C31H45N307 1 MS (El) Example ? (S)-N-((S)-3-(Cyclohex-1-en-1-yl)-1~(( R)-2-methyloxiran-2-yl)-1- 0m oxopropan—— 2-yh)=2~((S)-3-hydroxy—-2-(2-morpholinoacetamido) propanamido)—-3-( 4-(methyls— ulfonyl)phenyl)propanamide (C-1110)

-1035-

OH oY © 0 1 S

H0

HATU

AA N HN A N A N " § = H §

SO,Me

TFA05

LANE

1 10 m 0 “06 HATU added (00 mg; VT millimoles) V, Yo) DIPEA milliliters) to a solution of

YYo) (S)-3-hydroxy-2—(2-morpholinoacetamido)propanoic acid (S)-2-amino-N-((S)-3—(cyclohex-1-en-1-yl) -1- f (ds mM +, AY mg” (((R)-2-methyloxiran—-2-yl)- —1-oxopropan-2-yl)-3-(4-© AA) (methylsulfonyl)phenyl)propanamide, + mmol) in (Yo) DMF (mL) at 0 °C with stirring. The reaction mixture, Bad, was left to ambient temperature and stirred for ? hours. EtOAC (001 milliliters) and water (001 milliliters) were added and the two layers were separated. The aqueous phase was extracted with EtOAC (04 mL L(Y) x 0. The combined organic phases were washed with Brain Yoo) mL (VX), dried over anhydrous sodium sulfate, and concentrate. The residue was daw. by ame bial ae on silica gel (5(-01-))5(-3-) on dpasll (+,¥ :01 :01 = CH2CI2/EtOAc/MeOH) (cyclohex—1-en- 1-yl)-1-((R)-2-methyloxiran—-2-yl)-1-oxopropan— -2- yl)=2—((S)-3-hydroxy—2—(2-morpholinoacetamido) (propanamido)-3—(4- 90725 toll total). 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.46 (d,

1 lam

J - 7.8 Hz, 2H), 5.40 (m, 1H), 5.05 (m, 1H), 4.45-4.70 (m, 2H), 4.30 (m, 1H), 3.57 (m, 4H), 3.50 (m, 2H ), 3.22 (m, 1H), 3.20 (s, 3H), 3.10 (m, 1H), 2.80-3.00 (m, 4H), 2.40 (m, 2H), 2.20 (m, 2H), 1.90-2.10 ( m, 4H), 1.50-1.70 (m, 3H), 1.37 (s, 3H), 1.00-1.30 (m, 3H).

A(MH) £4, discovered «C31H44N409S IMS (El)© The following compounds were synthesized in a similar way: (1 r,4R)-N—-((R)-1-((((S)~1) -(((S)—-3—cyclopentyl-1—((R)—-2-methyloxiran— -(Al-2 —1-oxopropan-2-yl)amino)-3-(3-hydroxy- 4-methoxyphenyl)-1-oxopropan-2-yljam-ino)-1-oxopropan-2-yl)-4-hydroxycyclohexane carboxamide 00 1H NMR (400 MHz, CDCI3 & 8.70 (s, 1H), 8.20 (d, J) = 7.0 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.55 (dd, J = 8.2, 2.0 Hz, 1H), 4.52 (d, J = 4.5 Hz, 1H), 4.47 — 4.34 (m, 1H), 4.34 — 4.21 (m, 1H), 4.15 (p, J = 7.1,7.1,7.0, 7.0 Hz, 1H), 3.70 (s, 3H), 3.28 (td, J = 10.7, 10.6, 5.3 Hz, 0 1H), 3.21 (d, J = 5.3 Hz, 1H), 3.00 (d, J = 5.3 Hz, 1H), 2.87 (dd, J = 13.8, 3.7 Hz, 1H), 2.04 (ddt, J = 11.9, 8.4, 3.4, 3.4 Hz, 1H), 1.96 - 1.84 (m, 1H), 1.84 — 1.43 (m, 13H), 1.40 (s, 3H), 1.23 (s, 2H), 1.15 - 0.99 (m, 4H), 0.95 (d, J = 7.0 Hz, 3H).

A(MH) oAA, . Detected “C31H45N308 L 05 (EI) 0 (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R)-2-methyloxiran-2) -yl)-1- oxopropa— n—2-yl)-3—(3-hydroxy—4-methoxyphenyl)-2—((S)-2-(2- morpholinoacetamido)prop— anamido)propanamide (C-1085) ):

-1 h 1H NMR (400 MHz, CDCI3) 7.50 (d, J = 7.7 Hz, 1H), 6.83 - 6.63 (m, 4H), 6.16 (d, J = 7.0 Hz, 1H), 5.34 (s, 1H), 4.58 (ddd, J = 8.6, 7.1, 4.7

Hz, 1H), 4.51 (9, J = 6.9, 6.9, 6.9 Hz, 1H), 4.43 (9, J = 7.2, 7.2, 7.1 Hz, 1H), 3.86 (s, 3H), 3.81 — 3.65 (m, 4H), 3.27 (d, J = 4.9 Hz, 1H), 3.18 (ad, J = 7.5, 7.4, 7.4, 4.4 Hz, 1H), 3.02 (s, 2H), 2.97 — 2.86 (m, 3H), © 2.59 - 2.44 (m, 4H), 2.30 - 2.21 (m, 3H), 2.18 (t, J = 7.4, 7.4 Hz, 2H), 1.83 (dt, J = 13.6, 6.9, 6.9 Hz, 2H), -1.70 1.66 (m, 2H), 1.44 (d, J = 6.6

Hz, 3H), 1.36 (d, J = 7.1 Hz, 3H).

A+(MH) oY, detected «C30H42N408 1 MS (El) (1 r4R)-N-((R)-1-(((S)-1-(((S)-3—(cyclopent-1) -en-1-y)-1-((R)-2- 1.methylox-iran—2-yl)~1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan —-2-yljam-ino)-3-hydroxy—1-oxopropan—2-yl)-4- hydroxycyclohexanecarboxamide (C-1092): 1H NMR (400 MHz, CDCI3) § 7.13 (d, J = 8.8 Hz, 2H ), 6.98 (d, J = 7.7

Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 7.0 Hz, 1H), 6.21 (d, J = 10 7.3 Hz, 1H), 5.32 (s, 1H), 4.65 - 4.46 (m, 2H), 4.35 (dd, J = 7.2, 4.6, 3.1 Hz, 1H), 4.02 (dd, J = 11.4, 3.0 Hz, 1H), 3.78 (s, 3H), 3.70 — 3.49 (m , 2H), 3.26 (d, J = 5.3 Hz, 1H), 2.99 (dd, J = 6.7, 3.4 Hz, 2H), 2.89 (d, J = 4.9 Hz, 1H), 2.48 (dd, J = 15.0, 6.5 Hz, 1H), 2.29 - 1.97 (m, 9H), 1.96 — 1.37 (m, 9H), 1.33-1.24 (m, 3H). 0

A(MH) AT, + detected «C31H43N308 for MS (El) (S)-N=((S)-3—(cyclohex-1-en-1-yl)-1-((R) -2-methyloxiran—-2-yl)-1- oxopropan-— —2-yl)=3—(4—(methylsulfonyl)phenyl)-2—((S)-2—(2- morpholinoacetamido)propan— amido )propanamide (C-1126):

-10384- 1H NMR (300 MHz, DMSO-d6): 6 8.33 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H) , 7.73 (d, J = 7.8 Hz, 1H), 7.46 (d,

J - 7.8 Hz, 2H), 5.40 (m, 1H), 4.45-4.70 (m, 2H), 4.25 (m, 1H), 3.56 (m, 4H), 3.10-3.2 (m, 4H), 3.00-3.10 (m, 2H), 2.80-3.00 (m, 3H), 2.40 (m, 4H), 2.20 (m, 1H), 1.80-2.10 (m, 5H), 1.50-1.70 (m, 3H), 1.38 (s , © 3H), 1.13 (d, J = 6.9 Hz, 3H). (MH) 7,7 Detected «C31H44N408S of MS (El) (18,38)-N—((R)-1-(((S)~1-(((S)—-3— cyclopentyl-1-((R)-2-methyloxiran— 2-yl)—= 1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- 2-yl)amino)-1 -oxop-ropan-2-yl)-3-hydroxycyclopentanecarboxamide 0 (C-1076): 1H NMR (300 MHz, DMSO-d6): § 10.96 (5, 1H), 8.31 (d, J = 7.2 Hz, 1H) , 8.03 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.35 (m, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 4.40 (m, 1H), 4.26 (m, 2H), 3.49 (m, 4H), 3.17 (d, J = 5.1 Hz, 1H), 3.02 10 (m , 3H), 2.79 (m, 3H), 2.29 (m, 4H), 1.99 (m, 1H), 1.72 (m, 2H), 1.65 (m, 4H), 1.50 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H). (MH) oAY, ¢ detected (C31H43N506 for MS (El) (1 rdR)=-N-((R)-1-(((S)-1-(((S)-3—( cyclopent-3-en-1-yl)-1-((R)-2~ methylox-iran—-2-yl)-1-oxopropan—-2-yl)amino)-3—(4-methoxyphenyl)- 0 1-oxopropan—-2-yljam-ino)—1-oxopropan—-2-yl)-4- hydroxycyclohexanecarboxamide (C-1074): 1H NMR (500 MHz, CDCI3) § 7.15 - 7.00 (m, 2H), 6.85 - 6.76 (m, 2H), 6.58 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.12 (d, J = 7.0 Hz,

-1 «= 1H), 5.64 (ddd, J = 7.6, 5.9, 3.9 Hz, 2H), 4.60 (q, J = 6.6, 6.6, 6.6 Hz, 1H), 4.51 (ddd, J = 9.8, 8.1, 3.5 Hz, 1H), 4.34 (p, J = 7.0, 7.0, 7.0, 7.0

Hz, 1H), 3.77 (s, 3H), 3.59 (tt, J = 10.6, 10.6, 4.9, 4.9 Hz, 1H), 3.26 (d,

J - 5.0 Hz, 1H), 3.05 (dd, J = 14.1, 6.7 Hz, 1H), 2.95 (dd, J = 14.1, 6.4

Hz, 1H), 2.89 (d, J = 5.0 Hz, 1H), 2.44 (dd, J = 11.9, 7.0 Hz, 2H), 2.34 E0 - 1.93 (m, 6H), 1.93 — 1.78 (m, 3H) , 1.78 - 1.59 (m, 3H), 1.55 - 0 (m, 6H), 1.27 (d, J = 7.0 Hz, 4H).

A(MH) ov. + Detected “C31H43N307 for MS (El) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R)-2-methyloxiran-2) -yl)-1- oxopropa-— n-2-yl)-3-(4—(methylsulfonyl)phenyl)-2—((S)-2-(2- 0 morpholinoacetamido)propa— namido)propanamide (C- 1125): 1H NMR (300 MHz, DMSO-d6): 6 8.40 (d, J = 7.5 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H) , 7.75 (d, J = 7.2 Hz, 1H), 7.48 (d,

J - 7.8 Hz, 2H), 5.41 (m, 1H), 4.45-4.70 (m, 2H), 4.25 (m, 1H), 3.56 (m, 4H), 3.20 (s, 3H), 3.00-3.10 (m , 2H), 2.80-3.00 (m, 4H), 2.40 (m, 0 4H), 2.10-2.30 (m, 4H), 1.70-1.90 (m, 2H), 1.39 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H). (MH) YAY detected “C30H42N408S of MS (El) (1R,38)-N—((R)-1-(((S)-1-(((S)-3-cyclopentyl-1) -((R)-2-methyloxiran— 2-yl)—— 1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan—- 00 2-yl)amino)-1- oxop-ropan-2-yl)-3-hydroxycyclopentanecarboxamide : (C-1078) 1H NMR (300 MHz, DMSO-d6): 6 8.23 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 8.4 Hz) , 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.78 (d,

-151-

J = 8.4 Hz, 2H), 4.45 (m, 2H), 4.30 (m, 1H), 4.10-4.20 (m, 2H), 3.69 (s, 3H), 3.20 (m, 1H), 2.90-3.10 (m , 2H), 2.80 (m, 1H), 2.60 (m, 1H), 1.40-2.00 (m, 13H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 0.95 (d, J = 6.9

Hz, 3H).

Detected A(MH) o0A,Y «C30H43N307 IMS (El)© (1R,3R)=N—((R)-1-(((S)~1-(((S)—-3—cyclopentyl) -1—((R)-2-methyloxiran— 2-yl)—= 1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- 2-yl)amino)-1- oxop-ropan-2-yl)-3-hydroxycyclopentanecarboxamide : (C-1077) 1H NMR (300 MHz, DMSO-d6): 6 8.26 (d, J = 6.3 Hz, 1H), 8.04 (d, J = 0 8.1 Hz, 1H), 7.93 (d,J = 7.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.78 (d,

J = 8.4 Hz, 2H), 4.75 (m, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.69 (s, 3H), 3.20 (m, 1H), 2.90-3.10 (m, 2H), 2.50-2.70 (m, 2H), 1.40-2.00 (m, 13H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 0.95 (d,

J - 6.9 Hz, 3H). 0

Detected A(MH) 028.7 “C30H43N307 for MS (El) (18,3R)=N—((R)-1-(((S)-1-(((S)-3-cyclopentyl- 1-(((R)-2-methyloxiran— 2-yl)—= 1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- 2-yl)amino)-1-oxop - ropan-2-yl)-3-hydroxycyclopentanecarboxamide : (C-1075) 0 1H NMR (300 MHz, DMSO-d6): 6 8.24 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 8.7 Hz) , 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.78 (d,

J = 8.4 Hz, 2H), 4.45 (m, 2H), 4.30 (m, 1H), 4.10-4.20 (m, 2H), 3.70 (s, 3H), 3.20 (m, 1H), 2.90-3.10 (m , 2H), 2.80 (m, 1H), 2.60 (m, 1H),

-1?7- 1.40-2.00 (m, 13H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 0.95 (d, J = 6.9

Hz, 3H). +(MH) detected 58.7 «C30H43N307 1 MS (El) (1 rdR)=-N-((R)=1-(((S)-1-(((S)-3—(cyclopent-1) -en-1-yl)-1-((R)-2- methylox— iran—2-yl)—1-oxopropan-2-yljamino)-3-(4-© (methylsulfonyl)phenyl)-1-oxopropa — n—2-yl)amino)-1-oxopropan-2-yl)- 4-hydroxycyclohexanecarboxamide (C-1096): 1H NMR (300 MHz, DMSO-d6): 6 8.35 (d, J = 6.9 Hz, 1H ), 8.08 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 5.42 (m, 1H), 4.40-4.70 (m , 3H), 4.15 (m, 1H), 3.30-3.60 (m, 2H), 3.20 (s.3H), 0 3.15 (m, 1H), 3.00 (m, 1H), 2.80 (m, 1H), 2.40 (m, 1H), 2.20-2.40 (m, 5H), 2.05 (m, 2H), 1.70-1.90 (m, 4H), 1.60 (m, 2H), 1.38 (s, 3H), 1.00- 1.30 (m , 4H), 0.90 (d, J = 7.2 Hz, 3H).

Detected A(MH) 18.4 “C31H43N308S for MS (El) ¢ Jie Vo (1r,4R)-N—((R)-1-(((S)~1-(((S) —-3—(Cyclopent-1-en-1-yl)-1-(((R)-2- methyloxir—an-2-yl)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl) - 1-oxopropan—-2-yljamin—- 0)—1-oxopropan-2-yl)-4-hydroxy-1- methylcyclohexanecarboxamide (C-1111)

-16©- oo fos

HATU, DIPEA OY I NINEB TL

Eee 0.01 cane £YY (HATU) mmol) V,£A) DIPEA mL) was added to a solution of (S)—2—((R)-2—aminopropanamido)-N—(( S)-3—(cyclopent-1-en-1-yl)-1- (((R)—2-me- thyloxiran—2-yl)—1-oxopropan-2-yl)-3—(4 - methoxyphenyl)propanamide 0 (salt (TFA) 10 mg A® , + m(Js and trans—4—YY) hydroxy—1-methylcyclohexane carboxylic acid mg; AY , + mL (Use in 01 mL DMF) at 0 °C with stirring. The reaction mixture was left to warm to ambient temperature and stirred for 1 h. 01 (EtOAC) 01 mL water and Veo were added The two layers were separated and the aqueous phase was extracted with 04 mL EtOAC (Fx Jue the combined organic phases were prepared using Brain oF x lle Yoo) and dried over anhydrous sodium sulfate; focus. The residue was purified by a gel flash chromatography column: to obtain (+) :01 :0 = CH2CI2Z/EtOAC/MeOH) silica 1)rdR-N-((R)=1-((((S) )~1-(((S)-3—(cyclopent-1-en-1-yh)-1-(((R)-2- methyloxiran— —2-yl)—1-oxopropan-2-ylj)amino )-3—(4-methoxyphenyl)- 1-oxopropan-2-yljamino)- —1-oxopropan-2-yl)-4-hydroxy-1- 101 (Yor) methylcyclohexanecarboxamide mg" 9071 toll). (d, J = 6.6 Hz, 1H), 7.96 (d, J = 8.33 h) 1H NMR (300 MHz, DMSO-d6): Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H ), 7.10 (d, J = 8.4 Hz, 2H), 6.78 (d, 8.4 J = 8.4 Hz, 2H), 5.40 (s, 1H), 4.40-4.60 (m, 2H), 4.20 (m, 1H ), 3.69 (s, 3H), 3.20-3.60 (m, 2H), 3.22 (m, 1H), 2.90-3.10 (m, 2H), 2.40-2.60 0

-1562- (m, 2H), 2.10-2.30 (m, 5H), 2.05 (m, 2H), 1.75 (m, 2H), 1.55 (m, 2H), 1.23 (s, 3H), 1.00-1.30 ( m, 5H), 0.96 (d, J = 6.9 Hz, 3H).

A(MH) oA, Y detected (C32H45N307 for MS (El) The following compounds were synthesized in a similar way: (R)=-N=((R)-1—(((S)-1- (((S)-3-cyclopentyl-1—((R)-2-methyloxiran-2—- © yl)~1-ox~- opropan-2-yljamino)-3-(4-methoxyphenyl)-1- oxopropan-2-yl)amino)-1-oxopropa-n-2-yl)-5-oxopyrrolidine-3-carboxamide (C- : 1067) 1H NMR (300 MHz, DMSO-d6): &8.23 (d, J = 6.9 Hz, 1H), 8.14 (m, 2H), 7.54 (br s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 0 4.31 (m , 1H), 4.29 (m, 1H), 4.21 (m, 1H), 3.70 (s, 3H), 3.21 (m, 3H), 3.02 (m, 2H), 2.60 (m, 1H), 2.22 (d, J = 8.1 Hz, 2H), 2.02 (m, 1H), 1.73 (m, 2H), 1.57 (m, 2H), 1.48 (m, 4H), 1.41 (s, 3H), 1.13 (m, 2H), 0.95 (d,

J = 7.2 Hz, 3H). ~[M-H) 555.7 Detected (C29H40N4O07 IMS (EI) 10 (S)-N—-((R)-1-(((S)—-1-(((S)—-3—cyclopentyl) -1—(((R)—-2-methyloxiran—2- yl)~1-ox~-opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1 -oxopropa-n-2-yl)-5-oxopyrrolidine-3-carboxamide (C- : 1068) 1H NMR (300 MHz, DMSO-d6): &8.27 (d, J = 7.5 Hz, 1H), 8.15 (m) , 0 2H), 7.57 (br s, 1H), 7.12 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 4.32 (m, 1H), 4.30 (m, 1H) , 4.21 (m, 1H), 3.71 (s, 3H), 3.23 (m, 3H), 3.02 (m, 2H), 2.60 (m, 1H), 2.22 (m, 2H), 2.02 (m, 1H), 1.73 (m, 2H),

-1j 1.57 (m, 2H), 1.48 (m, 4H),1.42 (s, 3H), 1.13 (m, 3H), 0.95 (d, J = - 2

Hz, 3H). ~(MH) oov,¥ Detected (C29H40N407 of MS (El)

N-((R)-1-(((S)~1-(((S)—-3—cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-

OXOpro— pan—2-yl)amino)-3—(4-methoxyphenyl)-1-oxopropan-2- 0 yl)amino)—1-oxopropan—-2-- yl)cyclopentanecarboxamide (C-1021): 1H NMR (300 MHz, DMSO-d6): 6 8.23 (d, J = 6.3 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 4.8 Hz, 2H), 6.76 (d,

J = 8.4 Hz, 2H), 4.41 (m, 1H), 4.27 (m, 1H), 4.13 (m, 1H), 3.68 (s, 3H), 3.00 (m, 2H), 2.96 (m, 2H), 2.54 (m, 2H), 1.90 (m, 1H), 1.72 (m, 4H), 0 1.54 (m, 10H), 1.39 (s, 3H), 1.07 (m, 3H), 0.93 (d, J = 6.9 Hz, 3H). ~(MH)of. ¢ Detected (C30H43N306 1 MS (El) (S)-N—-((R)-1-(((S)—-1-(((S)—-3—cyclopentyl-1—((R) )—-2-methyloxiran—2- yl)~1-ox~- opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)-1-oxopropa— n-2 -yl)tetrahydrofuran-3-carboxamide (C-1037) 0 1H NMR (300 MHz, DMSO-d6): 6 8.23 (d, J = 6.9 Hz, 1H), 8.08-8.12 (m, 2H), 7.12 (d , J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.58 (m, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 3.81 (m, 1H), 3.70 (s, 3H), 3.65 (m, 1H), 3.55 (m.1H), 3.22 (d, J = 4.8 Hz, 1H), 2.90-3.10 (m, 3H), 2.50- 2.70 (m, 2H), 1.80-2.00 (m, 3H), 1.50-1.80 (m, 7H), 1.42 (s, 3H), 0 1.00-1.30 (m, 3H), 0.96 (d, J = 6.6 Hz, 3H).

-157- ~(MH) 0 47,7 Detected (C29H41N30O7 for MS (El) (S)-N—-((R)-1-(((S)—-1-(((S) )—-3—cyclopentyl-1—((R)—-2-methyloxiran—2- yl)~1-ox~-opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)-1-oxopropa- n-2-yljtetrahydro-2H-pyran-3-carboxamide 1H NMR (300 MHz, DMSO-d6): 6 8.25 (d, J = 7.2 Hz, 1H), 7.90-8.10 E (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.45 (m, 1H), 4.30 (m, 1H), 4.18 (m, 1H), 3.80 (m, 2H), 3.71 (s, 3H), 3.20-3.40 (m, 3H), 2.90-3.10 (m, 2H), 2.65 (m, 1H), 2.40 (m, 1H), 1.90 (m, 1H), 1.50-1.85 (m, 10H), 1.41 (s, 3H), 1.00-1.30 (m, 2H), 0.95 (d, J = 6.6

Hz, 3H). 01 ~(MH) 005.7 Detected “C30H43N307 of MS (El) (R)=N=((R)=1—(((S)-1-(((S)-3-cyclopentyl) -1—(((R)-2-methyloxiran—2- yl)~1-ox~-opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)—1- oxopropa—n—2-yl)tetrahydro—2H-pyran—3—-carboxamide (C- : 1052) yo 1H NMR (300 MHz, DMSO-d6): 6 8.23 (d, J = 7.2 Hz, 1H), 7.90 -8.10 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.45 (m, 1H), 4.30 (m, 1H), 4.18 (m, 1H), 3.80 (m 1H), 3.71 (s, 3H), 3.20-3.30 (m, 3H), 2.90-3.10 (m, 2H), 2.65 (m, 1H), 2.40 (m, 1H), 1.90 ( m, 1H), 1.50-1.85 (m, 11H), 1.41 (s, 3H), 1.00-1.30 (m, 2H), 0.97 (d, J=6.6 00

Hz, 3H).). ~(MH) 005.7 Detected «C30H43N307 of MS (El)

A a (1s,45)-N-((R)=1-(((S)~1-(((S)-3—(cyclopent-1-en-1-yh-1-((R) -2- methyloxi—ran-2-yl)-1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan—2-yl)ami-no)-1-oxopropan—2- yl)-4- hydroxycyclohexanecarboxamide (C-1056): 1H NMR (400 MHz, CDCI3) § 7.20 — 7.04 (m, 2H), 6.90 — 6.68 (m, 3H), © 6.32 (d, J - 7.1 Hz, 1H) ), 6.21 (d, J = 7.1 Hz, 1H), 5.32 (s, 1H), 4.57 (q,

J = 17.0, 6.6, 6.6 Hz, 2H), 4.43 (p, J = 7.0, 7.0, 6.9, 6.9 Hz, 1H), 3.93 (s, 1H), 3.78 (s, 3H), 3.28 (d, J = 4.9 Hz, 1H), 2.98 (p, J = 7.3, 7.3, 7.2, 7.2 Hz, 2H), 2.88 (d, J = 5.0 Hz, 1H), 2.49 (d, J = 14.1 Hz, 1H), 2.21 ( ddd, J = 21.9, 13.1, 7.9 Hz, 6H), 2.02 - 1.70 (m, 7H), 1.70 - 1.52 (m, 0 4H), 1.48 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H ).

A(MH) ov. + Detected “C31H43N307 of MS (El)

N-((R)-1-(((S)~1-(((S)—-3—(cyclopent-1-en-1-yl)-1-((R)-2- methyloxiran—2 -yl-)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yl)amino)—1-ox-opropan-2-yljoxetane-3—-carboxamide 10: ( C-1055) 1H NMR (400 MHz, CDCI3) § 7.22 - 7.08 (m, 2H), 6.92 — 6.74 (m, 2H), 6.58 (d, J = 7.7 Hz, 1H), 6.25 (d, J = 6.9 Hz, 1H), 6.17 (d, J = 7.0 Hz, 1H), 5.31 (s, 1H), 4.91 — 4.66 (m, 4H), 4.55 (q, J = 7.6, 7.6, 6.8 Hz, 2H), 4.40 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 1H), 3.79 (s, 4H), 3.26 (d, J = 0 5.0 Hz, 1H), 3.08 - 2.93 (m, 2H), 2.93 - 2.81 ( m, 1H), 2.49 (dd, J = 14.1, 2.7 Hz, 1H), 2.24-2.18 (m, 5H), 1.92 - 1.70 (m, 2H), 1.49 (s, 3H), 1.28 (d, J = 7.0Hz, 3H).

A(MH) oYA, + detected “C28H3T7N3O7 of MS (El)

-1 m (1 rdR)=-N-((R)-1-(((S)-1-(((S)-3—(cyclopent-1-en-1-yl)-1 -((R)-2~ methylox-iran—2-yl)~1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan—-2-yljam-ino)—1- oxopropan—-2-yl)-4- hydroxycyclohexanecarboxamide (C-1057): 1H NMR (400 MHz, CDCI3) § 7.19 - 7.09 (m, 2H), 6.88 — 6.71 (m, 2H), © 6.53 (d, J = 7.7 Hz, 1H), 6.10 (dd, J = 12.8, 7.0 Hz, 2H), 5.30 (s, 1H), 4.54 (td, J = 7.9, 6.8, 3.4 Hz, 2H), 4.36 (p, J = 7.0, 7.0, 7.0, 7.0 Hz, 1H), 3.78 (s, 3H), 3.61 (td, J = 10.8, 10.7, 5.5 Hz, 1H), 3.28 (d, J = 5.0

Hz, 1H), 2.97 (qd, J = 14.1, 14.0, 14.0, 6.7 Hz, 2H), 2.89 (d, J = 5.0

Hz, 1H), 2.45 (s, 1H), 2.36 — 2.20 (m, 3H), 2.19 - 2.10 (m, 2H), 2.04 0 (dt, J = 11.7, 3.4, 3.4 Hz, 3H), 1.95 - 1.69 (m, 4H), 1.58 - 1.36 (m, 6H), 1.26 (d, J = 7.0 Hz, 4H).

A(MH) ov. + Detected “C31H43N307 of MS (El) (S)-N—-((R)-1-(((S)—-1-(((S)—-3—cyclopentyl-1—( (R)—-2-methyloxiran—2- yl)~1-ox~-opropan-2-yljamino)-3—(4-methoxyphenyl)-1-oxopropan-2—- 01 yl)amino)-1-oxopropa -n-2-yl)-6-oxopiperidine-3—-carboxamide (C- : 1059) 1H NMR (300 MHz, DMSO-d6): 6 8.25 (d, J = 7.5 Hz, 1H), 8.06-8.12 ( m, 2H), 7.43 (s, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.45 (m, 1H), 4.30 (m, 1H), 4.18 (m, 1H), 3.71 (s, 3H), 3.10-3.30 (m, 0 3H), 2.90-3.10 (m, 2H), 2.50-2.70 (m, 2H), 2.10 (m, 2H), 1.50 -1.85 (m, 9H), 1.41 (s, 3H), 1.00-1.30 (m, 4H), 0.95 (d, J = 6.6 Hz, 3H).

A(MH) oby, + detected «C30H42N407 of MS (El)

-1?4- ‎ (R)=N=((R)=1—(((S)-1-(((S)-3-cyclopentyl-1—((R)-2-methyloxiran—2- yl)~1-ox~-opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)-1-oxopropa-n-2-yl)-6-oxopiperidine-3 —-carboxamide (C- 1H NMR (300 MHz, CDCI3): & 7.40 (m, 1H), 7.33 (m, 2H), 6.92- 1058) 6.86 (m, 3H), 6.40 (d, J = 7.2 Hz, 1H), 4.91 (m, 1H), 4.68 (m, 1H), © 4.47-4.43 (m, 2H), 4.40 (m, 1H), 3.81 (s, 3H), 3.74-3.72 (m, 4H), 3.25(d, J = 4.8 Hz, 1H), 2.99 (m, 1H), 2.91(d, J = 4.8 Hz, 1H), 2.51 (m, 4H), 1.74-1.63 (m, 4H), 1.61 (m , 5H), 1.53(s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.28- 1.20 (m, 3H).

Detected A(MH) 084.7 «C30H44N408 IMS (EI) 0 (1r,4R)-N—((R)-1-(((S)—-1—(((S)—-3-cyclopentyl- 1-(((R)-2-methyloxiran— 2-yl)—= 1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- 2-yl)amino)-1-oxop ~— ropan-2-yl)-4-hydroxycyclohexanecarboxamide (C1064): 1H NMR (400 MHz, CDCI3) 8.22 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 8.7 1

Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.26 - 7.00 (m, 2H), 6.96 — 6.69 (m, 2H), 4.50 (d, J = 3.7 Hz, 1H), 4.43 (td , J = 10.1, 9.5, 3.9 Hz, 1H), 4.29 (a,J=17.2,7.2,77.2 Hz, 1H), 4.24 - 4.07 (m, 1H), 3.28 (s, 1H), 3.21 (s, 1H ), 3.00 (d, J = 5.3 Hz, 1H), 2.95 (dd, J = 13.8, 3.8 Hz, 1H), 2.60 (dd,

J = 13.9, 10.2 Hz, 1H), 2.07 (s, 1H), 1.84 - 1.77 (m, 2H), 1.76 — 1.43 0 (m, 8H), 1.40 (s, 3H), 1.36 — 1.21 (m, 2H ), 1.21 - 1.00 (m, 4H), 0.94 (d, J = 7.1 Hz, 3H).

A(MH) ovy,¥ Detected «C31H45N307 of MS (El)

-1m8 (R)=N=((R)=1-(((S)-1-(((S)-3—(cyclopent-1-en-1-yl)-1-( (R)-2- ‎methyloxiran—- 2-yl)—1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yljamino)—— 1-oxopropan—2- yl)—1-methylpiperidine-3- carboxamide (C-1099): 1H NMR (300 MHz, DMSO-d6): § 8.28 (d, J = 7.2 Hz, 1H), 8.02 (m, 0 2H), 7.12 ( d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 5.42 (m, 1H), 4.62 (m, 1H), 4.48 (m, 1H), 4.18 (m, 1H), 3.71 (s, 3H), 3.22 (d, J = 4

Hz, 1H), 2.99 (d, J = 5.4 Hz, 1H), 2.91 (m, 1H), 2.62 (m, 3H), 2.51 (m, 2H), 2.37 (m, 4H), 2.10 (d, J = 5.4 Hz, 3H), 1.89-1.78 (m, 4H), 1.83 (m, 2H), 1.44 (s, 3H), 1.38 (m, 2H), 0.96 (d, J = 7.2 Hz, 3H). 0

A(MH) 014, ¢ detected “C31H44N406 of MS (El)

N-((R)-1-(((S)~1-(((S)—-3—(cyclopent-1-en-1-yl)-1-((R)-2- methyloxiran—2 -yl-)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yljamino)—1-ox-opropan-2-yl)—1-methylpiperidine-4- carboxamide ( C-1098: yo 1H NMR (300 MHz, DMSO-d6): 6 8.27 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.2 Hz , 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.77 (d,

J = 8.7 Hz, 2H), 5.41 (m, 1H), 4.62 (m, 2H), 4.19 (m, 1H), 3.70 (s, 3H), 3.22 (d, J = 5.1 Hz, 1H), 2.99 ( d, J = 5.4 Hz, 1H), 2.91 (m, 1H), 2.62 (m, 2H), 2.59 (m, 1H), 2.50 (m, 2H), 2.21 (m, 4H), 1.94 (m, 3H ), 1.85 0 (m, 3H), 1.77 (m, 4H), 1.51 (s, 3H), 1.38 (m, 2H), 0.94 (d, J = 6.9 Hz, (MH) 74.7 detected « C31H44N406 for MS (El) 3H) (1s,48)-N-((R)=1-(((S)~1-(((S)-3—(cyclohex-1-en-1- yl)-1-((R)-2- methyloxir—an-2-yl)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl)-

-1H-1-oxopropan—-2-yljamin—- 0)-1-oxopropan—2-yl)-4- hydroxycyclohexanecarboxamide (C-1097) 1H NMR (400 MHz, CDCI3): 7.18-7.16 (m, 2H) ), 6.85-8.82 (m, 2H), 6.85-6.56 (m, 2H), 6.58-6.56 (d, 1H), 6.06-6.02 (m, 2H), 5.27 (s, 1H), 4.53-4.51 (m , 2H), 4.40-4.36 (m, 1H), 3.95-3.91 (m, 1H), 3.78 (s, 3H), © 3.31-3.30 (m, 1H), 3.01-2.88 (m, 3H), 2.41- 2.32 (m, 1H), 2.25-2.18 (m, 1H), 1.98-1.44 (m, 19H), 1.29 (m 3H).

A(MH) 084,0. Detected “C32H45N307 of MS (El) (28)-2—-((2S)-2~(2—(6—oxa-3-azabicyclo[3.].1]heptan-3- yl) acetamido)propana- mido)-N—((S)-3—-cyclopentyl-1-((R)-2- 0 methyloxiran-2-yl)-1-oxopropan-2-yl)-3- -)4 - methoxyphenyl)propanamide (C-1229) 1H NMR (400 MHz, DMSO-d6): 8.31-8.05 (m, 4H), 7.74-7.72 (m, 1H), 7.12-7.10 (m, 2H), 6.80-6.77 (m, 2H), 4.49-4.22 (m, 5H), 3.70 (s 3H), 3.66-3.58 (m, 4H), 3.32 (s, 3H), 3.19-3.10 (m, 4H), 3.04-2.90 ( m, 3H), 0 2.778-2.60 (m, 2H), 2.22-2.21 (m, 1H), 1.90-1.42 (m, 4H), 1.41 (s, 3H), 1.16-1.14 (d, 3H).

A(MH) oAo, + detected «C31H44N407 of MS (El) (1s,45)-N-((R)=1-(((S)~1-(((S)-3— (cyclopent-1-en-1-yh-1-((R)-2- methyloxi— ran-2-yl)-1-oxopropan—-2-yl)amino)-3—(4-methoxyphenyl)- 0 1-oxopropan—2-yl)ami-no)-1-oxopropan-2-yl)—4-hydroxy—-1- methylcyclohexanecarboxamide (C-1112)

-1 o Y-— 1H NMR (300 MHz, DMSO-d6): 6 8.30 (d, J = 6.9 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 7.2 Hz , 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.78 (d,

J = 8.4 Hz, 2H), 5.40 (s, 1H), 4.40-4.60 (m, 2H), 4.37 (m, 1H), 4.20 (m, 1H), 3.69 (s, 3H), 3.45 (m, 1H ), 3.22 (m, 1H), 2.90-3.10 (m, 2H), 2.40-2.60 (m, 4H), 2.15-2.30 (m, 5H), 1.75-1.85 (m, 2H), 1.40-1.70 © ( m, 6H), 1.38 (s, 3H), 1.00-1.30 (m, 2H), 0.96 (d, J = 6.9 Hz, 3H). ~(MH) 087.1 Detected «C32H45N307 of MS (El) o Jia (S)-N-((S)-3—(Cyclopent-1-en-1-yl)~1~(( R)-2-methyloxiran-2-yl)-1- oxopropan— —2-yl)-2—((S)-2—(2-morpholinoacetamido)propanamido)-4- 0 phenylbutanamide (C-1128) 0 0 La o age 5 o

Oy_-OBn0H

J HATU, NMM aA AR, Lao 7 _ 7 #7?.7xxx? H 5 RT H 3

TFA A

0

H,N 0 mmol) to a mixture of ,00” g; 0.0 (95) Methylmorpholine was added (1-methylmorpholine mmol); (2-001000100808180100(01:003006 8610 in mmol) 7.17 g 011 (TFA (salt) (S)-benzyl 2—-amino—4-phenylbutanoate Yo) at 0° ( Ab ov mol) in dichloromethane Ale 7.97 aa (HATU, 1 h. 1 was added up to ambient temperature and stirred for a period of 1 ad. The reaction mixture was left

Shake 1 water (04 mL) and the resulting mixture was extracted with dichloromethane (ov) mL AF x organic extracts collected; drying over anhydrous sodium sulfate; focus. The remaining sald) was purified by flash chromatography column on silica gel (dichloromethane / methanol 1:001 = methanol to 1:01) to yield (5)benzyl 2 -((S)—2—-(2-morpholinoacetamido)propanamido)-4- © aa +, 4) phenylbutanoate 9671 yield). (S)-benzyl 2—((S)-2-(2-morpholinoacetamido)propanamido)—-4— 017 can »,17( phenylbutanoate mmol) was hydrogenated in the presence of Pd/C ) 1 + g) in 10 (mL) methanol 1 sad hour at ambient temperature. The 0/90 was separated by filtration and the 0/filtrate was concentrated to yield the corresponding acid. The acid was dissolved in dichloromethane (Yo) and treated with -2-801700-3-(5) (cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2). -yl)propan—-1-o— ne v 80 0 (sub V, FY mmol) 5 0.47 aa + HATU (070 mmol). =N methylmorpholine (+07 g) added; 5.7 mmol) to the solution at 0 °C. The reaction mixture, Bal 1, was left to ambient temperature and stirred for 1 hour. Water (00 mL) was added and the resulting mixture extracted with dichloromethane (04) (FX ible). The organic extracts were collected; drying over anhydrous sodium sulfate; and concentration. The residue was purified by flash chromatography column on silica gel (dichloro methane/methanol = 001:1 to TLC 1 0 preparative to obtain -1-(EL-01/0100601-1-80-1)-3-(5))-L1-(5) ((R)—2-methyloxiran-2-yl)-1-oxopropa- n-2-yh-2-((S)-2-(2- 0 Y 40) morpholinoacetamido)propanamido)-4-phenylbutanamide 97677 mg 1H NMR (300 MHz, DMSO-d6): 6 8.22 (d, J = 6.9 Hz, 1H), 8.13 (d, J = Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.28 (m, 2H), 7.17 (m, 3H), 5.41 7.5 (m, 1H), 4.49 (m, 1H), 4.37 (m, 2H), 4.28 (m, 1H), 3.58 ( m, 4H), 3.22 veo

-1 o ¢— (d, J = 5.1 Hz, 1H), 2.97 (m, 1H), 2.92 (m, 2H), 2.43 (m, 4H), 2.24 (m, 5H), 1.83 (m, 4H) , 1.37 (s, 3H), 1.23 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H). +(MH) 000.71 Detected “C30H42N406 for MS (El) The following compounds were synthesized in a similar way: (S)-N—((S)—-3-cyclopentyl-1—((R) -oxiran-2-yl)-1-oxopropan-2-yl)-3— © (3,4-dim- ethoxyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C- 1071) 1H NMR (300 MHz, DMSO-d6): 6 8.49 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 6.71-6.86 (m, 3H), 4.53 (m, 1H), 4.28 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.55 (m, 4H), 2.62-3.03 (m, 0 6H), 2.37 (m, 4H), 1.40-1.97 (m, 9H), 1.24 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H). —(MH) C30H44N408 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1 -oxopropan—2- yh)=3—- (4—(methylsulfonyl)phenyl)-2-(((S)-2-(2-morpholinoacetamido) 0 1H NMR (300 MHz, DMSO- : propanamido)pro— panamide ( C-1027) d6): 6 8.38 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 4.60 (m, 1H), 4.20-4.40 (m, 2H), 3.60 (m, 4H), 3.44 (m.1H), 3.18 ( s, 3H), 3.10- 3.20 (m, 2H), 2.80-3.00 (m, 3H), 2.40 (m, 4H), 1.40-2.00 (m, 7H), 0 1.40 (s, 3H), 1.16 (d , J = 6.6 Hz, 3H). (MH) 7011 Detected “C30H44N408S for MS (El)

-1 mg (S)-N=((S)-3-cyclopentyl-1-(((R)-2-methyloxiran—-2-yl)-1-oxopropan—2- yh-3— ( 3—(methylsulfonyl)phenyl)-2—((S)-2-(2- morpholinoacetamido)propanamido)pro— panamide 1H NMR (300 MHz, DMSO-d6): 6 8.42 (d, J = 7.5 Hz, 1H) , 8.15 (d, J = 8.1 Hz, 1H), 7.70-7.90 (m, 3H), 7.50-7.60 (m, 2H), 4.60 (m, 1H), © 4.20-4.40 (m, 2H), 3.60 ( m, 4H), 3.44 (m.1H), 3.18 (s, 3H), 3.10-3.20 (m, 2H), 2.80-3.00 (m, 3H), 2.40 (m, 4H), 1.40-2.00 (m, 7H), 1.40 (s, 3H), 1.16 (d, J = 6.6 Hz, 3H).(MH) 7011 Detected “C30H44N408S for MS (El)(S)—-3—(4-cyanophenyl) -N—((S)-3-cyclopentyl-1—((R)-2-methyloxiran-2- 1.yh-1— oxopropan-2-yl)-2-((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1050): 1H NMR (300 MHz, DMSO-d6): 6 8.35 (d, J = 6.9 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.75 (br s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.8

Hz, 2H), 4.61 (m, 1H), 4.26 (m, 2H), 3.56 (m, 4H), 3.17 (d, J = 5.1 Hz, 1H 0), 2.73-3.10 (m, 5H), 2.37 ( m, 4H), 1.42-2.03 (m, 11H), 1.42 (s, 3H), 0.86 (d, J = 6.6 Hz, 3H). ~(MH) 277,0 Detected «C30H41N506 1 MS (El) 4=((S)-3~(((S)—3—cyclopentyl-1—((R)-2-methyloxiran-2-yl) )-1- oxopropan-2-yl- Jamino)—2—((S)-2—(2-morpholinoacetamido) 0 propanamido)-3-oxopropyl)benzamide (C-1049): 1H NMR (300 MHz, DMSO- d6): 6 8.34 (d, J = 6.9 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.90 (br s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 ( m, 1H),

EE

7.29 (m, 1H), 7.28 (d, J = 7.8 Hz, 2H), 4.62 (m, 1H), 4.28 (m, 2H), 3.55 (m, 4H), 3.18 (d, J = 5.1 Hz, 1H ), 2.71-3.06 (m, 5H), 2.35 (m, 4H), 1.42-1.89 (m, 11H), 1.42 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H). —(MH)oA¢,¢ detected (C30H43N507 for MS (El) (S)-N—((S)-3-cyclopentyl-1—((R)-2-methyloxiran—2-yl) -1-oxopropan-2-©yh-2—- ((S)—2-(2-morpholinoacetamido)propanamido)-3—(4- 1H NMR (300 MHz, DMSO- : sulfamoylphenyl)propanamid—e (C- (1054) d6): 6 8.37 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.1 Hz , 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.29 (br s, 2H), 4.56 (m, 1H), 4.27 (m, 2H), 3.56 (m, 4H), 3.16 (d, J = 5.4 Hz, 0 1H), 2.74-3.11 (m, 5H), 2.38 (m, 4H), 1.42-1.91 (m, 11H), 1.42 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H (MH) YY, ¥ Detected “C29H43N508S for MS (El) (S)-N-((S)-3—(Cyclohex-1-en-1-yl)-1-((R) )-2-methyloxiran-2- : 1 Ex. yl)—1-oxopropan—- 2-yl)-3—-(4-methoxyphenyl)-2—((S)-2-(2- 0 morpholinoacetamido) )—-2—(oxetan-3-yl)-acetamido)propanamide (C- 1138)

o 7 _ \ _ oid EAE fo) 1. Hy, RC a) Zim oe Bu LS 2. DheD%u < Pe i ls 3 Chin" Fone DheHNT TDM mmm" imo May SOF Color . o I He, POE i hai 4 J : aw "ey _— + polar. ye EN 8 1 13 LON oN UF No b and oy 1 b b i 3 : 0 17 1 I 0 a Ba 3 and 7 1 se on 0 J 1 5 i ~ 1 koi from emt ba = mf Lo b 3 Ha 0 aa 161,759 ¢ DBU) added 1,8-Diazabicycloundec—7- ene 40 mM (Uso by distillation into a solution of N-benzyloxy carbonyl-(phosphono glycine can YY.) trimethylester) 000 mmol) and ?7-one oxetan-3-one 5.1 (©g; Ve mmol) in methylene chloride (Yo +) methylene chloride mL) at ambient temperature under 812. The reaction mixture was stirred for $A hour at ambient temperature. The solvent was removed and the residue was dissolved in EtOAc (0 0 mL).The resulting solution was Jue with 965 KHSO4 aqueous Yoo) mL ¢ (Y x 1811003 saturated aqueous Yoo) mL x Y ( ¢ and Brian ) Y 010 milliliters t 1 x ( 4 [ respectively . Then the organic phase was dried over 0 anhydrous sodium sulfate and concentrate. The residue was purified by flash chromatography column on silica gel (hexane/1:0 = EtOAc) to yield methyl 2-(benzyloxycarbonylamino)-2-YY,0)(0xetan-3-ylidene)acetate g ; 9014 toll). Then add 700 Pd/C (29.6 g) to a solution of

mH -1 V+, +) methyl 2—(benzyloxycarbonylamino)-2—(oxetan—-3-ylidene)acetate g; 77 mmol) in 001 (MeOH) milliliters. The suspension was stirred under hydrogen atmosphere at ambient temperature for 11 hours. The catalyst was separated by filtration and washed with 0.01 (mL) MeOH. The filtrate and wash were combined, followed by the addition of: benzyloxycarbonyl N-succinimide ° (N002-05; can 50001 mmol) and tri(Ji)amine #01 ¢lik (15.7 mmol). The reaction mixture was stirred for VY h at ambient temperature and then concentrated. The residue was purified by flash chromatography column on silica gel (hexane (Vv :0 = EtOAc / Hexane to yield -2 methyl 9641 aa £,Y) (benzyloxycarbonylamino)-2—(oxetan-3-yl) acetate (Vs) as a yellow solid. A solution of LIOH (1590 mg; 77.0 mmol) in water (Vo (mL)) was added to a solution of ¥,0)methyl 2—(benzyloxycarbonylamino)-2—(oxetan—3-yl)acetate g 5.0 Ak mol) in tetrahydrofuran ov (¢THF) tetrahydrofuran mL) at 0 °C with stirring. The reaction mixture was stirred for VY h for 1 hour and then acidified with 7 p 1 101 aqueous to pH = 7. Most of the solvent was removed and the resulting mixture was extracted with EtOAC (04 mL L(Y) x phases were washed organic matter collected with Brain (21 mL “1”); drying over anhydrous sodium sulfate and concentration to obtain the corresponding acid (0.7 g); It was used directly without further purification. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)—4-methylmorpholinium p Ae 11 aa 4,4 <DMTMM)chloride mol) and no-methylmorpholine were added -NO (YOY ) methylmorpholine g 71 mmol) to a solution of acid (0.0 g Av mmol) wa-; - methoxylphenylalanine (methyl ester hydrochloride) + ¥ , g; AY mmol) in methylene chloride (0116 milliliters) at 0 °C with stirring. The suspension was stirred for 1 hour at ambient temperature Yo and then washed with 965 aqueous KHSO4 (01 x 1 milliliters);

o q — \ — saturated aqueous NaHCO3 (001 milliliters oF x and Braine) 00 milliliters x 1), respectively. The organic phase was dried over anhydrous sodium sulfate and the concentrate. then purify the residue, dad gs, by a flash chromatography column on silica gel (hexane/) 1 iF = EtOAC to obtain a mixture of stereoisomers (1.0 g); They were then separated by a preparative polarized HPLC to yield (S)-methyl 2—(((S)-2-(benzyloxycarbonylamino)-2—(oxetan-3- YY) yl)acetamido)-3— (4-methoxyp— henyl)propanoate g » 90677 yield) as a colorless solid. 0.1;9600( Pd/C g) was added to a solution of -2-(5))-2 (S)—methyl (benzyloxycarbonylamino)—2—(oxetan—3-yl)acetamido) -3-(4-methoxyp— Tv +) henyl)propanoate 0 ca. 0.01 mmol) in Ve (MeOH) milliliters). The suspension was stirred under hydrogen atmosphere at ambient temperature for 1 hour. The catalyst was separated by filtration and washed with (01 mL MeOH). The filtrate, wash products and concentrate were combined to dryness. The residue was dissolved in methylene chloride (+0 mL) followed by addition of VO—Y morpholinoacetic acid (0150 mg; 0.01 mmol); HATU (0004 mg; 0.460 mmol) “lle .,701 (DIPEA 10; mmol) at zero dap. The reaction mixture was left to warm to ambient temperature and stirred for 6.5 hours. Saturated aqueous NaHCO3 Yo (mL) was added and the two phases were separated. The Sl phase was extracted using (Yo) CH2CI2 mL “7). The combined organic phases were washed with Brain (Yo)Ye mL oT x, dried over anhydrous sodium sulfate, and concentrate. The residue was purified by a flash chromatography column on silica gel (1:* 0. = CH2CI2/MeOH) to obtain: (S)-methyl 3—(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)— YAY) 2—(oxetan—-3- yl)acetamido)propanoate compound (DEA byproduct).

-?11- A solution of YA cane Yo (LIOH) LIOH mmol) in water (01 milliliters) was added to a solution of (S)—methyl 3—(4-methoxyphenyl)-2-((S) -2~(2-morpholinoacetamido)-2- YE +) (OXxetan—3-yl) acetamido)propanoate mg"; YT, + mmol) in The (Vo) milliliters) at 0 °C with stirring. The reaction mixture was stirred for ? hours and then © acidification using ? p 101 aqueous to pH = ©. The mixture was concentrated to dryness to yield the corresponding acid YO (mg); It was used directly without further purification. Ave cane HATU (YY) + mmol) DIPEA (0+ mL) was added to a solution of 760 mg YOu acid (Js F-0106-1-80-1/A26)-2 -81100-3-(5)yl)=1-((R)-2-methyloxiran—-2-yl)propan—-1-on-© (A TFA salt + mmol) Y in DMF (Yo) milliliters) at 0 °C with stirring. The ad suspension was left to ambient temperature and stirred for 1 hour. The mixture was diluted with EtOAC (01 mL) and then washed with 965 401504 aqueous (04) NaHCO3 ((¥ x saturated aqueous) + 0 mL “oF” and Bryan (04 mL “) 1, respectively. The organic phase was dried over anhydrous sodium sulfate and the concentrate. The residue was purified by a gel flash chromatography column (Kili:1:01 = CH2CI2Z/EtOAc/MeOH). 1 0,+( to get (S)-N—((S)-3- (cyclohex—1-en-1-yl)-1-((R)-2-methyloxiran—-2- yl)-1-oxopropan— -2- yl)=3—(4-methoxyphenyl)-2—((S)-2~(2-morpholinoacetamido)-2- VY) (Oxetan-3-yl - Jacetamido)propanamide mg; 079 yield 2-step) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 6 8.28 (d, J = 7.5 Hz, 1H), 8.16 (d, J = 00 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H) , 7.10 (d, J = 7.2 Hz, 2H), 6.78 (d, 7.2 J = 7.2 Hz, 2H), 5.38 (m, 1H), 4.62 (m, 1H), 4.40-4.60 (m, 4H) , -4.20 (m, 2H), 3.70 (s, 3H), 3.54 (m, 4H), 3.20 (m, 1H), 2.90-3.10 (m, 4.40 4H), 2.75 (m, 1H) , 2.20-2.50 (m, 6H), 1.80-2.10 (m, 5H), 1.50-1.70 (m, 4H), 1.37 (s, 3H). Yo

-111-

A(MH) 7,7 Detected “C33H46N408 for MS (El) 1 Example -06180E2-0081-(6A))-1-(EL-0/01009601-1-980-1)- 3-(5))-1-(3))-haze) Al-2 (-1-0- xopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- 2-yl)-2—(2-morpholino- acetamido)pent-4-ynamide (C-1139) © i SLY, ae with 0 8 8

A, 7 mkl LAT NA Bock A Aon Mu'a Nri Sen hi i

SNe

TFA | . 8 Acid?- Morcholine acetic acid

HATU, which wa 3 b Hasman: ; LH Px RN aS z [a]

CA I rE fs mm CTA IR TYE IS RRO

G Tea I Si Cae

Hab 7

O

(S)-2-(tert—=) to a solution of (dso Ae 1 aa VY) HATU (S)-benzyl mmol) and ¥,A g” +,7) butoxycarbonylamino were added ) pent-4-ynoic acid mmol) 7.1 g; Then add. YEP in milliliters (at zero degrees Al) in dichloromethane A (mmol) and the reaction mixture was left to warm to ambient temperature and stirred for 0.11 milliliters) and the resulting mixture was extracted using dichloromethane Yo) an hour. Water was added (1), then the organic extracts (4) were collected and dried over sodium sulfate. (7 X milliliters Y 0 ) remaining by flash chromatography column on anhydrous silica gel; focus. (S)-benzyl 2-))5(-2-)1611- was purified to yield (1:* to 1:0 = EtOAc petroleum/10 butoxycarbonylamino)pent—4-ynamido)— 3—(4-methoxy phenyl)propanoate Colorless solid. sale yield) as %AY (aa VY)

-7?1- (S)—-Benzyl 2—((S)-2—(tert-butoxycarbonylamino)pent-4-ynamido)— 1( 3—(4-methoxy phenyl)propanoate) dissolved g; 7.1 mmol) in dichloromethane (01 milliliters) and treated with TRA (V0 milliliters) for 1 hour at ambient temperature. The solvent was removed and the residue was added to a solution of ?-morpholinoacetic acid (0.77 g; 7.7 AL mol) 5 (0.1 HATU g; 7.6 mmol) in dichloromethane Yo ) milliliters). Added——N methylmorpholine (TY) mL; 5.7 mmol) at zero degrees Celsius. The reaction mixture was left to simmer to ambient temperature and stirred for 1 hour. Water (Yo) was added in milliliters) and the resulting mixture was extracted using dichloromethane (Yo) milliliters (7). organic extracts collected; drying over anhydrous sodium sulfate; focus. The residue A (dad gs) was purified by a flash chromatography column on silica gel (J) chloro[ole methanol = 1 iY to 1:001 to yield (S)-Benzyl 3—(4). -methoxyphenyl)-2—((S)-2-(2- ‎morpholinoacetamido)pent-4-ynamido)propanoate (8," g 90614 yield) as a colorless solid.

A solution of (S)-benzyl 3-(4-methoxyphenyl)-2—((S)-2-(2—- morpholinoacetamido)pent-4-ynamido)propanoate yo (8,"g") was treated 0.1 mmol) in water/THE (© milliliters/? milliliters) using (+,VYV) LIOH-H20 g; 7.1 mmol) for 1 hour at ambient temperature. The mixture was neutralized to a pH of -7 using

HC is an aqueous concentrate and then concentrated under vacuum to dryness. The remaining sald) was added to a mixture of (S)-2-amino-3~—(cyclopent-1-en—1-yl)-1- (((R)=2-methyloxiran—-2- yl)propan—1-o0— ne 0 (0 9 g 01 mmol) HATU (17 g; 1117 mmol) in dichloromethane (Yo) milliliters). L-1-methylmorpholine (EY) 0.0 mL added; Ale 4.0 mol) at 0 °C the reaction mixture ad was left to ambient temperature and stirred for 1 hour. Water was added (Vo) mL) and the resulting mixture was extracted with dichloromethane (FO) mL (FX) The organic extraction products were collected; Yo, drying over anhydrous sodium sulfate, and concentration.Then the residue was purified (dad gs) Chromatography column

-11- To obtain (1 Av to 1 Yen = flash on silica gel (dichloromethane/methanol (S)-N=((S)-1-(((S)—3-) cyclopent-1-en-1-yl)-1-(((R)-2-methyloxiran-2- yl)=1-- oxopropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2 - mg” 9614 toll). ), 8.09 (d,J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.78 (d,

J = 8.4 Hz, 2H), 5.40 (m, 1H), 4.49 (m, 3H), 3.70 (s, 3H), 3.57 (m, 4H), 3.18 (d, J = 5.1 Hz, 1H), 2.99 ( d, J = 5.1 Hz, 1H), 2.84 (m, 2H), 2.63 (m, 2H), 2.41 (m, 6H), 2.23 (m, 6H), 1.80 (m, 2H), 1.38 (s, 3H) ).

A(MH) ©1578 finder «C32H42N407 IMS (EI) 0 The following compounds were synthesized in a similar way: (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran) -2-yl)~1-oxopropan-— (a-10180-2) --3- ( al-2 -2-))5(-2-)2- morpholinoacetamido)propanamido)propanamide )0-1013 (: .sup.1H NMR (300 MHz, CDCl.sub.3): Vo 1H NMR (300 MHz, CDCI3): 6 7.60 (brs, 1H), 7.32 (m, 1H), 6.80 (d, 1H), 6.50 (d, 1H), 6.28 (m, 1H), 6.12 (d, J = 3.3 Hz, 1H), 4.72 (m, 1H), 4.46 (m, 2H), 3.78 (m, 4H), 3.67 (m , 1H), 3.26 (d, J = 4.8 Hz, 1H), 3.16-3.06 (m, 4H), 2.57 (m, 1H), 1.74 (m, 4H), 1.73-1.64 (m, 10H), 1.55 ( d, 3H), 1.48-0.92 (m, 3H).

A(MH) oY, ¢ for 02711401407 detected MS (El)

N-((R)-1-(((S)~1-(((S)—-3—cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1- oxopro— pan- 2-yljamino)-3—(4—(methylsulfonyl)phenyl)-1-oxopropan—2-

A yl)amino)—1-oxo- propan-2-yl)tetrahydro—2H-pyran—4-carboxamide (C- 1051): 1H NMR (300 MHz, DMSO-d6): 6 8.32 (d, J = 6.3 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.47 (d,

J = 8.1 Hz, 2H), 4.65 (m, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 3.40 (m, 2H), E 3.30 (m, 2H), 3.18 (s , 3H), 3.15 (m, 1H), 3.08 (m, 1H), 2.82 (m, 1H), 2.40 (m, 1H), 1.95 (m, 1H), 1.40-1.80 (m, 12H), 1.42 ( s, 3H), 1.00- 1.30 (m, 2H), 0.94 (d, J = 6.9 Hz, 3H). ~(MH) 0160.20 Detected «C30H43N308S 1 MS (El) (1 r,4R)-N-((R)-1-(((2S,3R)-1—(((S)-3) —(cyclopent-1-en—-1-yl)-1-((R)- 0 2-meth— yloxiran-2-yl)—-1-oxopropan-2-yljamino)-3-hydroxy—3—( 4- methoxyphenyl)-1-oxo- propan-2-yljamino)—]1-oxopropan-2-yl)-4- hydroxycyclohexanecarboxamide (C-1080): 1H NMR (400 MHz, CDCI3) 7.94 (dd, J = 13.9, 7.1 Hz, 2H), 7.73 (d, J = 9.0 Hz, 1H), 7.24 (s, 2H), 6.94 — 6.68 (m, 2H), 5.53 (s, 1H), 5.41 (s, 10 1H), 5.02 (s, 1H), 4.56 (9, J = 7.7, 71.7, 7.7 Hz, 1H), 4.30 (dd, J = 9.0, 2.8 Hz, 1H), 4.23 (p, J = 7.0, 7.0, 7.0, 7.0 Hz, 1H), 3.71 (s, 3H), 3.21 (d, J = 5.2 Hz, 1H), 2.96 (d, J = 5.2 Hz, 1H), 2.50 (tt, J = 3.3, 3.3, 1.7 , 1.7 Hz, 3H), 2.44 (dd, J = 14.5, 5.6 Hz, 1H), 2.38 - 2.12 (m, 5H), 2.12 - 2.01 (m, 1H), 1.80 (d, J = 7.2 Hz, 4H) , 1.73 - 1.59 (m, 2H), 1.44 - 0 1.24 (m, 4H), 1.09 (d, J = 13.2 Hz, 2H), 0.98 (d, J = 7.1 Hz, 3H).—(MH) detected 584.7 “C31H43N308 for MS (El) (1r,4R)-N-((R)-1-(((2S,3R)-1—((((S)-3—cyclopentyl-1—((( R)-2-methyloxiran—-2—— yl)-1-o xopropan—2-yljamino)-3-hydroxy-3—(4-

-119- methoxyphenyl)—-1-oxopropan-2-yl- )amino)—]1-oxopropan-2-yl)-4- hydroxycyclohexanecarboxamide (C-1079): 1H NMR (400 MHz, CDCI3) § 7.97 (d , J = 6.3 Hz, 1H), 7.93 (d, J = 7.1

Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.92 - 4 (m, 2H), 5.54 (d, J = 4.7 Hz, 1H), 5.08 (dd, J = 4.5, 2.5 Hz, 1H), 4.54 e (d, J = 4.5 Hz, 1H), 4.33 (ddd, J = 10.2, 7.2, 3.9 Hz, 1H), 4.30 — 4.18 (m, 2H), 3.70 (s, 3H), 3.29 (dd, J = 9.8, 5.2 Hz, 2H), 2.99 (d, J = 5.3

Hz, 1H), 2.05 (tt, J = 11.8, 11.8, 3.4, 3.4 Hz, 1H), 1.98 - 1.89 (m, 1H), 1.87 - 1.43 (m, 13H), 1.39 (s, 3H), 1.37 - 1.22 (m, 2H), 1.22 - 0 (m, 2H), 0.96 (d, J = 7.0 Hz, 3H). 0

A(MH) detected 085.7 «C31H45N308 of MS (El) (S)-N—=((S)=1-(((S)—-3—cyclopentyl-1-((R)-2) -methyloxiran-2-yl)-1- oxopropan—- 2-yljamino)-3—(4-methoxyphenyl)—-1-oxopropan-2-yl)-2- (2—-morpholinoacetamido— )butanamide (C-1106 ): 1H NMR (300 MHz, CDCI3): § 7.51 (brs, 1H), 7.11 (d, J = 8.4 Hz, 2H), 0 6.79 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 6.9 Hz, 1H), 6.27 (d, J = 6.9 Hz, 1H), 4.61 (m, 1H), 4.52 (m, 1H), 4.28 (m, 1H), 3.77 (s, 3H), 3.72 (m, 4H), 3.24 (d, J = 4.8 Hz, 1H), 2.85-3.07 (m, 5H), 2.50 (m, 4H), 1.51 (s, 3H), 0.83-1.95 (m, 16H).+(MH) ) Av, (C31H46N407 1 MS (EI) 0 (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1-oxopropan—2- yh )=2——((S)—-2-cyclopropyl-2—(2-morpholinoacetamido acetamido)—3—(4- methoxyphenyl)— propanamide (C-1107):

-115- 1H NMR (300 MHz, CDCI3): 6 7.72 (br s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 3.6 Hz, 1H), 6.31 (d, J = 3.6 Hz, 1H), 4.46-4.67 (m, 2H), 3.77 (s, 3H), 3.75 (m, 5H), 3.25 (d, J = 4.8 Hz , 1H), 2.85-3.16 (m, 5H), 2.54 (m, 4H), 1.57 (s, 3H), 0.39-1.83 (m, 16H). 0 +(MH) 244, 0321461407 1 MS (EI)

A Example (S)-N-((S)-3—(Cyclopent-1-en-1-yl)~1~((R)-2-methyloxiran-2-yl)-1- oxopropan -— —2-yl)=3—-(2-methoxypyridin—4-yl)-2-((S)-2-(2- morpholinoacetamido)propanami-do)propanamide (C-1141) 01 OMe OMe mm Zn, Pda(dba), SN TFA > N a | “ZN S-Phos Ao pe LC COOMe LAOA BocHN COOMe TAN or HATU ° oY 0 0 1. LIOH oY 0 0 nA RL 3 = HAT nA RL, H 0 z AQ 0 -——— H 0 E 4 b 0 TFA Li OMe HN OMe 6 dry DMF (Yo) was added to zinc dust EY, can Y,YA) zinc dust mmol) in a flame-dried round flask under N2 was added -16:1)-2 (R)-Methyl T,A0) butoxycarbonylamino)—-3-iodopropanoate g; 1111 mmol) followed by a stimulated Yo of iodine (Ye can Y, 1) iodine mmol). Then the mixture was stirred at ambient temperature for 1.5 hours. £AY) Pd2(dba)3 mg added; 0,100 ms (Js 5-0005

-1197/- 4-1000 -2- methoxypyridine -Y- mmol) and -bromo Ye g; £YV) Te mmol degree). The reaction mixture was heated to 110 g; YL 0)methoxypyridine

Yeo ) EtOAc ambient temperature. Then add an hour and then refrigerate to Toad YEP x milliliters Yoo (ml). the organic phase was separated; Washing with Yoo water (mL) and water L, drying over anhydrous sodium sulfate, and concentration. Then, the substance 1 and Bryan (.7 ml) 0 2 was purified to obtain 1) ?: = EtOAc remaining by a flash chromatography column on a silica gel (hexane / (S)—-methyl 2-(tert-butoxycarbonylamino) )-3—(2-methoxypyridin-4- on yield). 9077 aa 1, 4( yl)propanoate TFA (0 mL) was added to a solution of: (S)—-methyl 2- (tert-butoxycarbonylamino)-3-(2-methoxypyridin—4- Yu ‎VY, €)yl)propanoate g; V,Y mmol) in 01 (CH2CI2 milliliters) at 0°C with stirring. The mixture was stirred for 1 hour and then concentrated to dryness. The residue was azeotropic three times with 540/86 01 (mL per fraction) to remove the TFA residue to yield the crude Sal(S)-methyl 2-amino-3-(2-methoxypyridin—4- yl)propanoate 1 as its TFA salt. The crude compound (S)-methyl 2-amino-3—(2-methoxypyridin—-4- yl)propanoate (V,Y (TFA ms) salt (Js) was dissolved in (01) DMF milliliter). (1) DIPEA (1 mL) at 0 °C with stirring. The 0 |Bad reaction mixture was left to ambient temperature and stirred for 1 hour. EtOAc (A) (mL) and 5 Ma were added (A milliliters) As the separation of the two layers. Then the aqueous phase was extracted using EtOAc (vv) mL (1x) and the combined organic phases were washed using Brain (brine) mL * 7 (¢) and drying over anhydrous sodium sulfate and concentration. Then the residue was purified by dad gs by a flash chromatography column on a silica gel (1:01 = CH2CI2Z/MeOH) to obtain -(5)

1-18 methyl 3-(2-methoxypyridin—4-yl)-2—((S)-2-(2- toll). % EA (xa V,0) morpholinoacetamido)propanamido)pro— panoate (S )-methyl 3—(2-methoxypyridin-4-yl)-2-((S)-2-(2- morpholinoacetamido)propanamido)pro— panoate (1.5 g, 48% yield). (5(- methyl 3—-(2-methoxypyridin-4-yl)-2—((S)-2-(2-© mmol) 0.01 mg; Av +) morpholinoacetamido)propanamido) pro— panoate collected 7.80 mL (YY) H20- lithium hydroxide using a solution of lithium hydroxide and acidified THE min. ve was removed in milliliters) for 10 ml/10 (THF fold) mol) in 101 aqueous p. The resulting mixture was concentrated to 1 pH aqueous phase to 1 Om-?-; Without further purification, Hale was used without further purification. Dehydration to obtain the corresponding acid was used 0 (5)-2-80100-3- and the compound (All Yo) DMF was added The acid was dissolved in (cyclopent-1 -en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan—-1-o— ne mL) at zero 1 (DIPEA mmol) 7.56 can VY ) HATU mmol) Ye 0) * surrounding and stirring for Shall up to Bud degrees Celsius with stirring. The reaction mixture was left and the two layers were separated. EtOAc (001 idle) and water (001 h) were added. Vo Jue organic phases were added and EtOAC (Fx mL v0) was extracted from the aqueous phase using a Brain pool (04 mL). 7 3); drying over anhydrous sodium sulfate; focus. The remainder was obtained by flash chromatography column on a melica gel (sald das) to obtain (1:01:01 = CH2CI2 /EtOAC/MeOH) (S)-N-((S)-3—(cyclopent-1). -en-1-yl)~1-((R)-2-methyloxiran-2-yl)-1- 0 oxopropa— n-2-yl)-3—(2-methoxypyridin-4-yl)-2- ((S)-2-(2- yield %Y4 mg” YY'+) morpholinoacetamido)propanam-— ido)propanamide in two steps).

-114- 1H NMR (300 MHz, :(50-06AA0 6 8.38 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 6.84 (d,

J = 8.1 Hz, 1H), 6.35 (s, 1H), 5.77 (m, 1H), 4.50-4.70 (m, 2H), 4.25 (m, 1H), 3.80 (s, 3H), 3.57 (m, 4H ), 3.20 (m, 1H), 3.05 (m, 1H), 2.80- 3.00 (m, 3H), 2.70 (m, 1H), 2.37 (m, 4H), 2.10-2.30 (m, 5H), 1.80 ( m, © 1H), 1.39 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H).

The detected A(MH) ovY,Y “C29H4INSOT of MS (El) The following compounds were synthesized in a similar way: (S)-N=((S)-3-cyclopentyl-1-((R)-2) -methyloxiran—2-yl)-1-oxopropan—2- yh-3—- (1H-indol=5-yl)-2~((S)~-2~(2-morpholinoacetamido) 0 propanamido) propanamide (C-1123) 1H NMR (300 MHz, DMSO-d6): 6 10.96 (brs, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.35 (m, 1H),7.22 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 4.40 (m, 1H), 4.26 (m, 2H), 3.49 (m, 4H), 3.17 (d,J = 5.1 Hz, 1H), 3.02 0 (m, 3H), 2.79 (m, 3H), 2.29 (m , 4H), 1.99 (m, 1H), 1.72 (m, 2H), 1.65 (m, 4H), 1.50 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H).

Detected A(MH) 087,4 «C31H43N506 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl) -1-oxopropan—2- yh-3—- (1H-indol-6-yl)-2~((S)~-2~(2-morpholinoacetamido)0 propanamido)propanamide (C-1124): 1H NMR ( 300 MHz, DMSO-d6): § 10.97 (brs, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 6.9 Hz, 1H ), 7.36 (d, J = 7.8

_ \ 7 «=

Hz, 1H), 7.25 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H), 6.34 (s, 1H), 4.34 (m, 1H), 4.26 (m, 2H), 3.49 (m, 4H ), 3.17 (d, J = 5.4 Hz, 1H), 3.09 (m, 1H), 3.04 (m, 1H), 2.98 (m, 1H), 2.84 (m, 3H), 2.29 (m, 4H), 1.90 (m, 1H), 1.71 (m, 2H), 1.65 (m, 4H), 1.50 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H). (MH) oAY,¢ detected “C31H43N506 1LC- 1/05 © (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1 -oxopropan—2- yl)=3- (2-fluoro—4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)pro— panamide (C-1008): 1H NMR (300 MHz) , DMSO-d6): 6 8.10 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.06 (m, 1H), 6.83 (m,1H), 6.61 0 (m, 1H), 4.55 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.80 (s, 3H), 3.60 (m, 4H), 3.19 (m.1H), 3.01 (m, 1H), 2.80-3.00 (m, 3H), 2.75 (m, 1H), 2.40 (m, 4H), 1.95 (m, 1H), 1.50-1.85 (m, 7H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H).

Detected A(MH)oa, ¥ “C30H43FN4O07 IMS (El) 10 (S)—3—(benzofuran-5-yl)-N—((S)-3—-cyclopentyl-1—((R)-) 2-methyloxiran— 2-yl)— 1-oxopropan-2-yl)-2-((S)-2~(2-morpholinoacetamido) propanamido)propanamide (C-1007): 1H NMR (300 MHz, DMSO-d6) ): 6 8.35 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H) , 7.40- 0 7.50 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.87 (m, 1H), 4.39 (m, 1H), 4.28 (m, 1H), 4.28 (m, 1H) , 3.50 (m, 4H), 3.20 (m.1H), 3.10 (m, 1H), 3.01 (m, 1H), 2.80-3.00 (m, 3H), 2.29 (m, 4H), 1.95 (m, 1H) ), 1.50-1.85 (m, 7H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H).

A

A(MH) discovered 087.7 «C31H42N407 of MS (El)

S)-3—(benzold[1,3]dioxol-5-yl)-N-((S)-3-cyclopentyl-1-((R)-2- methyloxir— an-2-yl)-1 -oxopropan-2-yl)-2-((S)-2—-(2- morpholinoacetamido) propanamido)pro— panamide (C-1012): 1H NMR (300 MHz, DMSO-d6): 6 8.30 (d, J = 7.2 Hz, 1H), 8.02 (d,J = E 8.7 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 6.75-6.79 (m, 2H), 6.65 (m, 5H ), 5.95 (s, 2H), 4.48 (m, 1H), 4.29 (m, 1H), 4.28 (m, 1H), 3.60 (m, 4H), 3.57 (s, 2H), 3.18 (m. 1H) , 3.05 (m, 1H), 2.90 (m, 2H), 2.75 (m, 1H), 2.40 (m, 4H), 1.95 (m, 1H), 1.50-1.85 (m, 4H), 1.40 (s, 3H) ), 1.00-1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H). 0

A(MH) AY, 1 detected «C30H42N408 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl) -1-oxopropan—2- yh-3—- (1H=indol-3-yl)-2~((S)~2~(2-morpholinoacetamido) propanamido)propanamide (C-1014): 1H NMR (300 MHz) , DMSO-d6): 6 10.84 (brs, 1H), 8.30 (d, J = 7.2 Hz, 0 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H) , 7.57 (d, J = 7.5

Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.95-7.15 (m, 3H), 4.55 (m, 1H), 4.20-4.40 (m, 2H), 3.60 (m, 4H), 3.10 -3.20 (m, 2H), 2.80-3.00 (m, 4H), 2.40 (m, 4H), 1.95 (m, 1H), 1.50-1.85 (m, 7H), 1.40 (s, 3H), 1.00- 1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H). 0

Detected A(MH) 087.7 “C31H43N506 for MS (El) (S)—3—(benzofuran-3-yl)-N—((S)-3—-cyclopentyl-1—((R)-) 2-methyloxiran— 2-yl)— 1-oxopropan-2-yl)-2-((S)-2~(2-morpholinoacetamido)

AR propanamido)propanamide (C-1015):1H NMR (300 MHz, DMSO-d6): 8.20 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.60-7.70 (m , 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.20-7.30 (m, 2H), 4.65 (m, 1H), 4.20-4.40 (m, 2H), 3.55 (m, 4H), 3.16 ( m.1H), 2.95-3.10 (m, 2H), 2.90 (m, 2H), 2.40 (m, 4H), 1.95 (m, 1H), 1.50-1.85 (m, 7H), 1.40 (s, 3H) , 1.00-1.20 E (m, 2H), 1.26 (d, J = 6.6 Hz, 3H).

Detected A(MH) 0AY,0 «C31H42N407 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl) -1-oxopropan—2- yh-2—- ((S)—2-(2-morpholinoacetamido)propanamido)-3—(4- (trifluoromethoxy)phenyl)p— ropanamide (C-1084): 0 1H NMR ( 300 MHz, DMSO-d6: 6 8.34 (d, J = 6.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.74 (d,J = 7.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.22 (d,

J = 8.1 Hz, 2H), 4.56 (m, 1H), 4.30 (m, 2H), 3.56 (m, 4H), 3.17 (d, J = 5.1 Hz, 1H), 2.65-3.03 (m, 5H), 2.37 (m, 4H), 1.41-2.01 (m, 11H), 1.41 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H). 0

Detected A(MH) 71,7 «C30H41F3N407 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl) -1-oxopropan—2-yl)—2--((S)-2-(2-morpholinoacetamido)propanamido)-3—(2-oxoindolin- 5-yl)propanamid—- e (C-1081): 1H NMR (300 MHz, DMSO-d6): 6 10.31 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H 00), 8.06 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 6.90-7.10 (m, 2H), 6.65 (m, 1H), 4.50 (m, 1H), 4.20-4.40 (m, 2H), 3.60 (m, 4H), 3.18 (m, 1H) , 3.05 (m, 1H), 2.80-3.00 (m, 5H), 2.60 (m, 1H), 2.30-2.50 (m, 4H), 1.50-1.95 (m, 7TH), 1.40 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H).

A

—(MH) 047.7 Detected “C31H43N507 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1 -oxopropan—2- yh-2—- ((S)—2—(2-morpholinoacetamido)propanamido)-3—(2-oxo- 1,2,3,4-tetrahydroquin— olin-6-yl)propanamide ( C-1086): 1H NMR (300 MHz, DMSO-d6): 6 10.02 (s, 1H), 8.32 (d, J = 7.2 Hz, E0 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 6.90-7.00 (m, 2H), 6.68 (m, 1H), 4.48 (m, 1H), 4.20-4.30 (m, 2H), 3.56 (m, 4H) , 3.18 (m, 1H), 3.05 (m, 1H), 2.80-3.00 (m, 5H), 2.60 (m, 1H), 2.30-2.50 (m, 6H), 1.50-1.95 (m, 7H), 1.40 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H).

Detected A(MH) 111 «C32H45N507 IMS (El)0 (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1-oxopropan —2- yl)-3——(1,1-dioxido-3,4-dihydro-2H-benzole][1,2]thiazin-6-yl)-2—((S)~- 2—(2 -morphol-inoacetamido)propanamido)propanamide (C-1091): 1H NMR (300 MHz, DMSO-d6): 6 8.40 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.78 (d,J = 7.8 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.39 (m, 0 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H) , 4.63 (m, 1H), 4.30 (m, 2H), 3.58 (m, 6H), 3.17 (d, J = 5.1 Hz, 1H), 2.97 (m, 2H), 2.89 (m, 4H), 2.75 ( m, 1H), 2.39 (m, 4H), 1.42-1.92 (m, 10H), 1.42 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H).

Detected A(MH) 48.257 “C31H45N508S for MS (El) 0 (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R)- 2-methyloxiran-2-yl)-1-oxopropa-n-2-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((S)—2 —(2-morpholinoa— cetamido)propanamido)propanamide (C-1147):

-1/64- 1H NMR (300 MHz, DMSO-d6): 6 8.37 (d, J = 6.9 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.27 (d, J = 9.3 Hz, 1H), 6.25 (d, J = 9.0 Hz, 1H), 5.40 (m, 1H), 4.47 (m, 2H), 4.32 ( m, 1H), 3.56 (m, 4H), 3.20 (d, J = 5.1 Hz, 1H), 2.99 (d, J = 5.7 Hz, 1H), 2.90 (m, 2H), 2.66 (m, 1H), 2.38 (m, 7TH), 2.23 (m, 5H), 1.79 (m, 2H), 1.38 E0 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 0.84 (m, 2H). (MH) lah 291411507 1 MS (EI) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R)-2-methyloxiran-2- yl)-1- oxopropa-— n—2-yl)-3-(6-methoxypyridin-3-yl)-2—((S)-2-(2- morpholinoacetamido)propanam-ido)propanamide (C-1140 ): A 1H NMR (300 MHz, DMSO-d6): 6 8.36 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.40 (m, 1H), 4.51 (m, 2H), 4.27 (m, 1H), 3.79 (s, 3H), 3.55 (m, 4H), 3.18 (d, J = 5.1 Hz, 1H), 2.99 (m, 1H), 2.86 (m, 3H), 2.65 (m, 1H), 2.37 (m, 4H), 2.24 (m, 6H), 1.79 (m, 2H), 1.38 10 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H).

A(MH) ovy,¥ detected (C29H41N507 for MS (El) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R) -2-methyloxiran-2-yl)-1-oxopropa-n-2-yl)-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((S)= 2-(2-morpholinoa— cetamido)propanamido)propanamide (C-1137): 90 1H NMR (300 MHz, DMSO-d6): 6 38.35 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 6.0 Hz, 1H), 6.18 (s, 1H), 6.11 (d, J = 7.2 Hz, 1H), 5.40 ( s, 1H), 4.51 (m, 2H), 4.27 (m, 1H), 3.58 (m, 4H), 3.35 (s, 3H), 3.18 (d, J = 4.8 Hz, 1H), 2.97 (d, J = 6.9

AG 7\_

Hz, 1H), 2.90 (m, 2H), 2.76 (m, 1H), 2.39 (m, 4H), 2.23 (m, 5H), 1.80 (m, 2H), 1.38 (s, 3H), 1.16 (d , J = 6.9 Hz, 3H).

A(MH) ov), 4 detected “C29H4INSOT for MS (El) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R) )-2-methyloxiran-2-yl)-1-oxopropa— n-2-yl)-3-(4-ethyl-3-hydroxyphenyl)-2—((S$)-2-(2-© morpholinoacetamido) propan—amido)propanamide (C-1136) 1H NMR (300 MHz, DMSO-d6): & 9.07 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 7.8

Hz, 1H), 6.62 (s, 1H), 6.56 (d, J = 7.8 Hz, 1H), 5.40 (s, 1H), 4.51 (m, 2H), 4.28 (m, 1H), 3.57 (m, 4H) ), 3.18 (d, J = 4.8 Hz, 1H), 2.98 (d, J= 0 5.1 Hz, 1H), 2.91 (m, 2H), 2.88 (m, 1H), 2.47 (m, 2H), 2.38 ( m, 4H), 2.24 (m, 5H), 1.79 (m, 2H), 1.38 (s, 3H), 1.16 (d, J = 6.3 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H).

Detected A(MH) 08474 “C31H44N407 of MS (El)

S)-N~—((S)-3—(cyclopent-1-en-1-yl)-1-(((R)-2-methyloxiran-2-yl)-1- 1m oxopropa— n—2 -yl)-3—(4-hydroxy—-3-methylphenyl)-2—((S)-2-(2- morpholinoacetamido)propa— namido)propanamide (C-1131): 1H NMR (300 MHz, DMSO- d6): & 9.03 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 6.86 (s , 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.39 (s, 1H), 4.35 0 (m, 1H), 4.28 (m, 1H), 4.06 (m, 1H), 3.55 (m, 4H), 3.18 (d, J = 5.1 Hz, 1H), 2.97 (d, J = 4.8 Hz, 1H), 2.91 (m, 3H), 2.36 (m, 4H ), 2.21 (m, 5H), 2.03 (s, 3H), 1.76 (m, 2H), 1.38 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H).

-1716-

A(MH) ov. A discovered 03011421407 1 MS (El)

S)-N—((S)-3-cyclopentyl-1-((R)—-2-methyloxiran—2-yl)—1—-oxopropan—2- yh-3— (3—hydroxyphenyl)-2 ((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1114): 1H NMR (300 MHz, DMSO-d6): § 9.21 (s, 1H), 8.30 (d, J = 7.2 Hz, ‏ E 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 6.99 (m, 1H), 6.50-6.70 (m, 2H), 4.50 (m, 1H), 4.15-4.30 (m, 2H), 3.60 (m, 4H), 3.16 (m, 1H), 3.00 (m, 1H), 2.80-3.00 (m, 3H), 2.70 (m, 1H), 2.30 (m, 4H), 1.41-2.00 (m, 9H), 1.41 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H).

Detected A(MH) 004,Y (C29H42N407 IMS (EI) 0 (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1 -oxopropan—2- yh-3— (4-hydroxyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1113): 1H NMR (300 MHz, DMSO-d6): & 9.17 (s, 1H), 8.29 (d, J = 6.6 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 0

Hz, 2H), 6.60 (d, J = 8.1 Hz, 2H), 4.45 (m, 1H), 4.28 (m, 2H), 4.22 (m, 1H), 3.57 (m, 4H), 3.17 (d, J = 8.4 Hz, 1H), 2.86 (d, J = 5.4 Hz, 1H), 2.63 (m, 3H), 2.60 (m, 1H), 2.38 (m, 4H), 1.72 (m, 1H), 1.70 (m , 2H), 1.66 (m, 6H), 1.41 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H).

A(MH) o04,Y detected (C29H42N407 IMS (EI) 0 (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1 -oxopropan—2- yl)—-2-— ((S)-2—(2-morpholinoacetamido)propanamido)-3—(2-oxo0-3,4- dihydro—-2H-benzo[e-][1] ,3]oxazin-6-yl)propanamide (C-1108):

-1 for 1H NMR (300 MHz, DMSO-d6): 6 8.36 (d, J = 6.3 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.04 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 4.50 (m, 1H), 4.35 (s, 2H), 4.30 (m, 2H), 3.55 (m, 4H), 3.17 (d, J = 4.5 Hz, 1H), 2.70-3.06 (m, 4H), 2.63 (m, 1H), 2.36 ( m, 4H), 1.31-2.02 (m, 11H), 1.48 (s, 3H), 1.15 AH (d, J = 6.3 Hz, 3H).

A+[Na+M] 17.0 detected “C31H43N508 for MS (El)

S)-3~-(1H-benzo[d]imidazol-5-yl)-N—((S)-3-cyclopentyl-1-((R)-2- methyloxir— an-2-yl)-1 -oxopropan-2-yl)-2-((S)-2—-(2- morpholinoacetamido)propanamido)pro— panamide (C-1069): 0 1H NMR (300 MHz, DMSO-d6): & 8.33 (m , 1H), 8.32 (d, J = 6.9 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.42 (m , 2H), 7.07 (d, J = 8.4 Hz, 1H),4.57 (m, 1H), 4.25 (m, 2H), 3.50 (m, 4H), 3.18 (d, J = 4.5 Hz, 1H), 2.71 -3.15 (m, 5H), 2.31 (m, 4H), 1.41-2.03 (m, 11H), 1.40 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H). 10

Detected A(MH) 087,4 «C30H42N606 for MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl) -1-oxopropan—2- yh-3—- (1H-indazol-5-yl)-2—((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1070): 1H NMR (300 MHz) , DMSO-d6): 6 12.94 (s, 1H), 8.35 (m, 1H), 8.10 (d, 00

J = 8.7 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.62 (m, 1H), 4.30 (m, 2H), 3.49 (m, 4H), 2.70-3.25 (m, 6H), 2.26 (m, 4H), 1.41-1.93 (m , 10H), 1.40 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H).

-1 1/8

A(MH) 087,4 detected (C30H42N606 for MS (El) (1 r,4R)-N—((R)-1-(((S)-3—(1H-benzo[d]) imidazol-5-yl)-1—(((S)-3— cyclopenty— I-1-(((R)-2-methyloxiran—2-yl)-1-oxopropan—-2-yl)amino)- 1 -oxopropan—2-yl)ami- no)-1-oxopropan—2-yl)-4- hydroxycyclohexanecarboxamide (C-1105): E0 1H NMR (300 MHz, CDCI3): 6 12.47 (br 5, 1H), 8.29 (d, J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 7.42 (m, 2H), 7.06 (d, J = 6.9 Hz, 1H), 4.52 (m, 2H), 4.27 (m, 1H), 4.15 (m, 1H), 2.69-3.27 (m, 6H), 0.91-2.03 (m, 19H) , 1.41 (s, 3H), 0.87 (d, - for 9 Hz, 3H).Yo +(MH) AY, YY 311143506 1 MS (EI) (1r,4R)-N—((R)-1 -(((S)—-3—(4—cyanophenyl)-1—(((S)-3-cyclopentyl-1- ((R)—2—m- ethyloxiran—2-yl)—1—-oxopropan —2-yl)jamino)—1—oxopropan—2- yl)amino)-1-oxopro— pan-2-yl)-4-hydroxycyclohexanecarboxamide (C- 1103): yo 1H NMR (300 MHz, DMSO-d6) : 6 8.29 (d, J = 6.9 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.39 (d,

J = 8.1 Hz, 2H), 4.53 (m, 2H), 4.30 (m, 1H), 4.11 (m, 1H), 3.30 (m, 1H), 3.22 (d, J = 4.8 Hz, 1H), 3.10 ( m, 1H), 3.02 (d, J = 5.1 Hz, 1H), 2.80 (m, 1H), 1.83 (m, 1H), 1.79 (m, 1H), 1.73 (m, 3H), 1.53 (m, 4H) ), 1.48 0 (m, 4H), 1.37 (s, 3H), 1.33 (m, 3H), 1.25 (m, 4H), 0.91 (d, J = 6.9 Hz, 3H).

A(MH) ov, ¥ detected «C31H42N406 1 MS (El)

-11O4- (S)-N=((S)-3-cyclopentyl-1-(((R)-2-methyloxiran—-2-yl)-1-oxopropan—2- yl)=3—=(2 ,2-dioxido-3,4-dihydro-1H-benzo[c][1,2]thiazin-6-yl)-2—((S)~- 2—(2-morphol- inoacetamido)propanamido)propanamide ( C-1102): 1H NMR (300 MHz, DMSO-d6): 6 10.00 (s, 1H), 8.33 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.80 ( m, 1H), 6.90-7.10 (m, 2H), 6.62 (d, ©

J = 8.1 Hz, 1H), 4.50 (m, 1H), 4.20-4.30 (m, 2H), 3.60 (m, 4H), 3.20- 3.30 (m, 4H), 3.10 (m, 1H), 3.00 (m , 1H), 2.80-3.00 (m, 3H), 2.70 (m, 1H), 2.30 (m, 4H), 1.41-2.00 (m, 9H), 1.41 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H).

A(MH) 48.5 detected “C31H45N508S for MS (Ely 0

N—((S)-3-cyclopentyl-1—((R)-2-methyloxiran—2-yl)—1-oxopropan—2-yl)—- 2-))5(- —2—(2- morpholinoacetamido)propanamido)-3—(2-oxo-2,4- dihydro-1H-benzo[d][1,-3]oxazin—-6-yl)propanamide (C-1101): 1H NMR (300 MHz, DMSO-d6: 6 10.14 (brs, 1H), 8.40 (d, J = 6.9 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 8.1 0 m

Hz, 1H), 7.02 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.21 (s, 2H), 4.43 (m, 1H), 4.29 (m, 2H), 3.55 (m, 4H ), 3.16 (d, J = 4.8 Hz, 1H), 2.61-3.06 (m, 5H), 2.36 (m, 4H), 1.41-1.97 (m, 11H), 1.41 (s, 3H), 1.16 (d, J = 6.6 Hz, 3H).

A(MH) 1 ¢,A detected “C31H43N508 of 05 (El). (S)-3—(benzo[d][1,3]dioxol-5-yl)-N—((S)-3—cyclopentyl-1—((R)—oxiran—-2- -(except ‎ —1-oxopropan—2-yl)-2—((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1060):

_ \ A «= 1H NMR (300 MHz, CDCI3): § 7.51 (d, J = 4.5 Hz, 2H), 6.81 (d, J = 6.6

Hz, 1H), 6.76-6.64 (m, 3H), 6.46 (d, J = 6.6 Hz, 1H), 5.94 (s, 2H), 4.57-4.42 (m, 3H), 3.79 (s, 3H), 3.51 (m, 1H), 3.13 (m, 2H), 3.01- 2.99 (m, 4H), 2.37 (m, 4H), 1.76 (m, 5H), 1.69-1.53 (m, 6H), 1.39 (d , J - 6.9 Hz, 3H). © (+MH) ov¥,¢ detected (C29H40N408 of MS (El) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2- yl)-1-oxopropan—2- yh-3— (3—hydroxy-4-methoxyphenyl)-2-((S)-2—-(2- morpholinoacetamido)propanamido)pr— opanamide (C-1018): 1H NMR (300 MHz, DMSO-d6): & 8.73 (s, 1H), 8.26 (d, J = 7.2 Hz, 0 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 8.4

Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 6.60-6.58 (m, 1H), 4.49-4.43 (m, 1H), 4.35-4.20 (m, 2H), 3.72 (s, 3H) , 3.68-3.60 (m, 4H), 3.22-3.18 (m.1H), 3.01-2.80 (m, 4H), 2.65-2.58 (m, 1H), 2.45—2.34 (m, 4H), 1.91- 1.81 ( m, 1H), 1.85-1.50 (m, 7H), 1.40 (s, 3H), 1.20-1.00 (m, 2H), 1.26 0 (d, J = 6.6 Hz, 3H). (+MH) 0.084 Detected “C30H44N408 for MS (El) Example ? (S)-N-((S)-3—((1R,3r,5S)-Bicyclo[3.1.0]hexan -3-yl)-1—-((R)-2- methyloxiran—2- —yl)—1-oxopropan—2-yl)-3-(4-methoxyphenyl)-2—((S)- 0 2 -(2-morpholinoacetamido— )propanamido)propanamide (C-1095)

-81 m1- OD and Asn 2 2 lo} AA AAAS and win oy QL, Malakala? (All 0) TFA was added to a solution of tert-butyl ((R)-3-((1R,3r,58)-bicyclo[3.1.0]hexan-3-yl)-1~( (R)-2-methyloxiran-2-yl)-— 1 -oxopropan- (YY +) 2-yl)carbamate mg; 111 mmol) in 112012 VT (milliliter) at 0° © stirred. The mixture was stirred for 1 hour and concentrated to dryness. The residue was azeotropic three times with EtOAC (0 mL per fraction) to remove the TFA residue to yield -2-(4))-1-(Al610[3.1.0[0880-3-7C16-(55, -114,3))-2-301110-3-(5) 0080-1-6 (Al-2- methyloxiran— (quantitative) as TFA salt thereof. (S)—2- is dissolved Amino-3—((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-1-((R)-2- methyloxiran— —2-yl)propan—1-one 01 (TFA salt) in Yo)DMF mL) and (S)-3—(4-methoxyphenyl)-2—((S)-2—(2- morpholinoacetamido)propanamido)propa acid was added — noic acid (170 mg” 101 mM YY 0) HATU (Us mg; 0.80 mmol) (all), 2A) DIPEA at 0°Lge with stirring. The reaction mixture, Bad, was left to ambient temperature and stirred for ? hours. 1 001 EtOAc (100 milliliters) and water (001 milliliters) were added and the two layers separated. The Ald phase was extracted with EtOAC (04 mL) (Fx). The combined organics were washed with Brain Yoo) x 7 mL and dried over anhydrous sodium sulfate; focus. The residue was purified by flash chromatography column on silica gel (1:01:0 = CH2CI2Z/EtOAC/MeOH) to yield (S)-N—((S)-3-((1R,3r, 5S)-bicyclo[3.1.0]hexan-3-yl)-1- (((R)-2-methyloxiran—— 2-yl)—1-oxopropan—-2-yl)-3—-(4 -methoxyphenyl)- 0 Yo.) 2—((S)-2-(2-morpholinoacetamid— o)propanamido)propanamide mg; 9654 toll).

-187- 1H NMR (300 MHz, :(50-06AA0 6 8.25 (d, J = 6.9 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.75 (d,J = 7.5 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.80 (d,

J = 8.4 Hz, 2H), 4.45 (m, 1H), 4.20-4.40 (m, 2H), 3.71 (s, 3H), 3.56 (m, 4H), 3.15 (m, 1H), 3.05 (m, 1H ), 2.80-3.00 (m, 3H), 2.65 (m, 1H), 2.35 (m, 4H), 1.70-1.80 (m, 2H), 1.40-1.60 (m, 3H), 1.42 (s, 3H), © 1.10-1.30 (m, 3H), 1.16 (d, J = 6.9 Hz, 3H).

The detected A(MH)oAo,y “C31H44N407 of MS (El) The following compounds were synthesized in a similar way:

S)-N-((S)-3-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-1-((R)-2- methyloxiran—- 2-yl) —1-oxopropan—2-yl)-3-(4-methoxyphenyl)-2—((S)- 0 2-(2-morpholinoacetamid- o)propanamido)propanamide (C-1094): 1H NMR (300 MHz, DMSO-d6): 6 8.25 (d, J = 6.9 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.75 (d,J = 7.5 Hz, 1H), 7.13 (d, J = 8.4 Hz , 2H), 6.80 (d,

J = 8.4 Hz, 2H), 4.45 (m, 1H), 4.20-4.40 (m, 2H), 3.71 (s, 3H), 3.56 (m, 4H), 3.15 (m, 1H), 3.05 (m, 1H ), 2.80-3.00 (m, 3H), 2.65 (m, 1H), 0 2.35 (m, 4H), 1.70-1.80 (m, 2H), 1.40-1.60 (m, 3H), 1.42 (s, 3H) , 1.10-1.30 (m, 3H), 1.16 (d, J = 6.9 Hz, 3H).

A(MH) oAo,Y detected “C31H44N407 for LC-MS

S)-N—((S)-3—((1r,4S)—4-hydroxycyclohexyl)-1—(((R)-2-methyloxiran—2- yh-1-- oxopropan—2-yl)-3 —(4-methoxyphenyl)-2—((S)-2-(2- 00 morpholinoacetamido)propan—amido)propanamide (C-1002): 1H NMR (400 MHz, CDCI3) § 7.44 (d, J = 7.3 Hz , 1H), 7.10 (d, J = 8.6

Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 7.5 Hz, 1H), 6.29 (d, J =

1 m 8.0 Hz, 1H), 4.54 (q, J = 7.2, 7.1, 7.1 Hz, 2H), 4.41 (p, J = 7.6, 71.6, 7.4, 7.4 Hz, 1H), 3.84 — 3.64 (m , 8H), 3.63 - 3.45 (m, 1H), 3.23 (d, J = 4.9 Hz, 1H), 3.11 - 2.79 (m, 5H), 2.64 — 2.43 (m, 4H), 2.01 - 1.83 (m, 5H ), 1.64 (dt, J = 12.8, 2.9, 2.9 Hz, 1H), 1.55 - 1.46 (m, 3H), 1.36 (d, J = 8.0 Hz, 3H), 1.32 - 1.12 (m, 4H), 1.07 - 0.91 (m, 2H). © [(+MH) 107,4 detected (C31H4G6N4O8 for MS (El) (S)-N-((S)-3—((1s,4R)-4-hydroxycyclohexyl)-1—(( R)-2-methyloxiran—-2- yh-1— oxopropan—-2-yl)-3-(4-methoxyphenyl)-2-((S)-2—(2- morpholinoacetamido)propan—amido)propanamide ( C-1001): 1H NMR (400 MHz, CDCI3) § 7.43 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.6 0

Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 7.5 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 4.65 — 4.49 (m, 2H), 4.42 (p, J = 7.2, 7.2, 7.2, 7.2 Hz, 1H), 3.77 (s, 3H), 3.69 (t, J = 4.5, 4.5 Hz, 4H), 3.23 (d, J = 5.0 Hz, 1H) , 3.07 - 2.81 (m, 5H), 2.45 (d, J = 7.5 Hz, 4H), 1.87 - 1.61 (m, 4H), 1.50-1.12 (m, 15H). 0 [(+MH) 107,4 detected (C31H4G6N4O8 for MS (El) (S)-N=((S)-3-cyclopropyl-1~-((R)~-2-methyloxiran-2) -yl)-1-oxopropan- -3-(Al-2 (4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)propanamide (C-10006): 1H NMR (400) MHz, CDCI3) § 7.43 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 8.5 0

Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 7.4 Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), 4.64 — 4.49 (m, 2H), 4.49 - 4.34 (m, 1H), 3.77 (s, 3H), 3.70 (t, J = 4.5, 4.5 Hz, 4H), 3.23 (d, J = 5.0 Hz, 1H), 2.98 (dd, J = 13.6, 7.0 Hz, 3H), 2.89 (dd, J = 10.7, 5.7 Hz, 2H), 2.52-2.39 (m, 4H),

—VAE-

1.58 - 1.45 (m, 4H), 1.36 (d, J = 11.1 Hz, 3H), 1.24 - 1.12 (m, 1H),

0.56 (s, 1H), 0.05- -0.07 (m, 3H).

+(MH) discovered ogo, 028014011407 1 MS (El)

(S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1-oxopropan—2-

yh-3—- (4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)© propanamido)propanamide (C-1005):

1H NMR (400 MHz, CDCI3) 6 7.42 (d, J = 7.5 Hz, 1H), 7.16 - 7.05 (m,

2H), 6.87 - 6.75 (m, 2H), 6.64 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 7.9 Hz,

1H), 4.64 - 4.34 (m, 3H), 3.77 (s, 3H), 3.70 (t, J = 4.6, 4.6 Hz, 4H), 3.24 (d, J = 5.0 Hz, 1H), 3.07 - 2.79 (m , 5H), 2.54 — 2.35 (m, 4H), 0

1.77-1.43 (m, 12H), 1.36 (d, J = 7.1 Hz, 3H), 1.11 (s, 1H), 0.96 (s,

1H).

—(MH) 599.7 detected «C30H44N407 1 MS (El)

(S)-N—((S)—-3-cyclobutyl-1—((R)-2-methyloxiran—-2-yl)-1-oxopropan—2- yh=3—(- 4-methoxyphenyl)- 2—((S)-2-(2-0 morpholinoacetamido)propanamido)propanamide (C-1004):

1H NMR (400 MHz, CDCI3) § 7.45 (d, J = 7.6 Hz, 1H), 7.18 - 7.07 (m,

2H), 6.87 - 6.76 (m, 2H), 6.69 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 7.8 Hz,

1H), 4.53 (9, J = 7.0, 7.0, 7.0 Hz, 1H), 4.46 — 4.31 (m, 2H), 3.78 (s, 3H), 3.71 (t, J = 4.6, 4.6 Hz, 4H), 3.20 (d, J = 5.0 Hz, 1H), 3.09 - 2.80 0

(m, 5H), 2.59 — 2.39 (m, 4H), 2.32 - 2.07 (m, 3H), 2.06 - 1.89 (m, 2H),

1.89 - 1.71 (m, 2H), 1.69-1.59 (m, 1H), 1.58 — 1.41 (m, 4H), 1.37 (d, J

= 7.1 Hz, 3H).

_ \ A AG (0/1)5 54,1+. Detected “C29H42N407 of MS (EI) (5)-3-)4-0081 (E-01080-2E2-081-) © a))-1-(5)) -no- (the darkest wad -1-0*»0- 3-))5(-16- trahydrofuran—2-yl)propan-2-yl)-2- ((S)-2-(2- morpholinoacetamido)propanamid-o)propanamide (C-1016): 1H NMR (300 MHz, CDCI3): § 7.42 (m, 1H), 7.17 (d, J = 8.7 Hz, 2H ), E 6.95 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 7.8 Hz, 1H), 4.61 (m, 1H), 4.59 (m, 1H), 4.45 (m, 1H), 3.81 (s, 3H), 3.79-3.72 (m, 6H), 3.25 (d, J = 5.1 Hz, 1H), 3.00 (m, 3H), 2.91 ( d, J = 5.1 Hz, 1H), 2.53 (m, 4H), 2.01 (m, 2H), 1.85-1.64 (m, 5H), 1.55 (s, 3H), 1.38 (d, J =6.9 Hz, 3H ), 1.15 (d, J = 6.0 Hz, 1H). 0 +(MH)ovo,0 detected «C29H42N408 for MS (El) (S)—3~—(4-methoxyphenyl)-N—((S)-1—~((R)-2-) methyloxhan-2-yl)-1-oxo-3-((R)-te-trahydrofuran—2-yl)propan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamid-o )propanamide (C-1017): 1H NMR (300 MHz, CDCI3): § 7.42 (m, 1H), 7.15 (m, 3H), 6.82 (d, J - H01 8.7 Hz, 2H), 6.60 (m, 1H), 4.62-4.60 (m, 2H), 4.44 (m, 1H), 3.80 (m, 1H), 3.79 (s, 3H), 3.79-3.72 (m, 6H), 3.32 (d, J = 4.8 Hz , 1H), 3.05- 2.89 (m, 5H), 2.52-2.49 (m, 4H), 1.91-1.81 (m, 6H), 1.53 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H).

A(MH) ove,v detected (C29H42N408 of 05 (EI) 0 (S)-N=((S)-3—(cyclohex-1-en-1-yl)-1-((R) )-2-methyloxiran—-2-yl)-1- oxopropan-— —2-yl)-3-(4-methoxyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamido)pro— panamide (C-1019):

-181- 1H NMR (300 MHz, DMSO-d6): 6 8.25 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H) , 7.11 (m, 2H), 6.78 (m, 2H), 4.81 (m, 1H), 5.40 (s, 1H), 4.52 (m, 2H), 4.21 (m, 1H), 3.71 (s, 1H), 3.33 (m, 4H), 3.20 (m, 1H), 2.98 (m, 1H), 2.95 (m, 2H), 2.50 (m, 1H), 2.36 (m, 4H), 2.20 (m, 1H), 1.99 (m, 6H), 1.54 (m, 4H), 1.37 (s, 3H), 1.16 (m, © 3H).

Detected A(MH)oAo,¢ “C31H44N407 for MS (El) (S)-N-((S)-3—(3,6—dihydro-2H-pyran-4-yl)-1- ((R)-2-methyloxiran-2-yl)-1-ox-opropan-2-yl)-3-(4-methoxyphenyl)-2-((S)-2—-(2- morpholinoacetamido)propanam- ido)propanamide (C-1020): 01 1H NMR (300 MHz, CDCI3): 6 7.17 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7

Hz, 2H), 6.81 (m, 1H), 6.14 (m, 1H), 5.37 (s, 1H), 4.56 (m, 2H), 4.34 (m, 1H), 4.06 (m, 2H), 3.80 (s) , 3H), 3.79-3.72 (m, 4H), 3.29 (d, J = 4.8

Hz, 1H), 3.01-2.93 (m, 5H), 2.51 (m, 4H), 2.04 (m, 2H), 1.68 (m, 3H), 1.52 (s, 3H), 1.37 (d, J = 6.9 Hz , 3H). 0

Detected A(MH) C30H42N408 of MS (El) (S)—-N—((S)-3—((S)-3,3—difluorocyclopentyl)-1—((R)- 2-methyloxiran-2- yh-1— oxopropan—-2-yl)-3-(4-methoxyphenyl)-2-((S)-2—(2- morpholinoacetamido)propan—amido)propanamide (C-1033) : 1H NMR (300 MHz, CDCI3): § 7.47 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.4 00

Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 4.56 (m, 1H), 4.42 ( m, 2H), 3.79 (s, 3H), 3.75 (m, 4H), 3.22 (d, J = 4.8 Hz, 1H), 2.91-3.10 (m, 5H), 2.51 (m, 4H), 1.69-2.38 (m, 9H), 1.52 (s, 3H), 1.36 (d, J = 5.7 Hz, 3H).

-1 - L

A(MH) 01 5.4 for 0301142210407; Detected MS (El) (S)-N—((S)-3-((R)-3,3-difluorocyclopentyl)-1-((R)-2-methyloxiran—-2- yh-1— oxopropan —-2-yl)-3-(4-methoxyphenyl)-2-((S)-2—(2- morpholinoacetamido)propan—amido)propanamide (C-1034): 1H NMR (300 MHz, CDCI3): § 7.45 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 8.4©

Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 7.8 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 4.55 (m, 1H), 4.40 ( m, 2H), 3.79 (s, 3H), 3.73 (m, 4H), 3.23 (d, J = 5.1 Hz, 1H), 2.87-3.13 (m, 5H), 2.50 (m, 4H), 1.62-2.18 (m, 9H), 1.52 (s, 3H), 1.39 (d, J = 5.7 Hz, 3H).

Detected A(MH) 01,4 “C30H42F2N407 IMS (Ely 0 (2S)—-3—(4-methoxyphenyl)-N—((2S)-3—(1-methyl-2—oxopyrrolidin-3-yl) )- 1-((R)- —2-methyloxiran—2-yl)—1-oxopropan-2-yl)-2-((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1040) : 1H NMR (300 MHz, CDCI3): § 8.50 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1

Hz, 1H), 7.10 (m, 2H), 6.77 (m, 2H), 4.74 (m, 1H), 4.50 (m, 1H), 4.32 10 (m, 1H), 4.13 (m, 1H), 3.76 ( s, 3H), 3.74-3.68 (m, 4H), 3.60 (m, 3H), 3.35 (m, 1H), 3.35-3.04 (m, 4H), 3.00-2.85 (m, 2H), 2.80 (m, 3H), 2.47 (m, 4H), 2.45-2.06 (m, 1H), 1.57-1.60 (m, 2H), 1.58 (s, 3H), 1.42 (d, J = 6.9 Hz, 3H).

Detected A(MH) 00.1 “C30H43N5S08 L 05 (EI) 0 (28)-3—(4-methoxyphenyl)-N—((25)-1—-((R)-2-methyloxiran) -2-yl)-1- 0*0-3-)5-0- xopyrrolidin—-3-yl)propan-2-yl)-2—((S)-2-(2- morpholinoacetamido) propanamido)propanamide (C-1035):

-1 AA- 1H NMR (300 MHz, CDCI3): § 8.07 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1

Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.77 (m, 2H), 4.74 (m, 2H), 4.47 (m, 2H), 3.76 (s, 3H), 3.71-3.68 (m, 4H), 3.33 (m, 3H), 3.06 (m, 1H), 2.92 (m, 3H), 2.47 (m, 4H), 2.40 (m, 4H) , 1.80 (m, 2H), 1.52 (s, 3H), 1.38 (d, J = 6.9 Hz, 3H). ©

A(MH) detected rum (C29H41N508 of MS (El) (1r,3R)-N—((R)-1-(((S)—-1—-(((S)—-3) -cyclopentyl-1-((R)-2-methyloxiran— 2-yl)—= 1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- 2-yl)amino)- 1-oxop~-ropan-2-yl)-3-hydroxycyclobutanecarboxamide (C1041): 10 1H NMR (300 MHz, DMSO-d6): 67.11 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.68-6.85 (m, 2H), 6.45-6.70 (m, 1H), 4.65-4.75 (m, 2H), 6.42 (m, 2H), 5.88 (m, 1H), 5.10 (s, 2H), 4.80-4.83 (m, 1H), 4.63-4.66 (m, 1H), 4.48-4.53 (m, 2H), 4.30-4.40 (m, 1H), 3.80 (s, 3H), 3.32 (d, J = 5.1 Hz, 1H), 3.11 (dd, J = 4.2, 13.8 Hz, 1H), 2.89-2.99 (m, 2H), 0 2.48-2.54 (m, 4H), 2.14-2.22 (m, 2H), 1.40-1.80 (m, 3H), 1.44 (s, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.08-1.20 (m, 1H).

A(MH) of 4,7 detected (C29H41N30O7 for MS (El) (S)—3~—(4-methoxyphenyl)-N—((S)~-1—((R)~2- methyloxiran-2-yl)~1-oxo- 3-(2-oxo- pyrrolidin—1-yl)propan-2-yl)-2—((S)-2-(2-00 morpholinoacetamido)propanamido)propanamide ( C-1042):

IH NMR (300 MHz, DMSO-d6): & 7.65 (m, 1H), 7.30-7.60 (m, 2H), 7.05-7.15 (m, 2H), 6.70-6.85 (m, 3H), 4.40-4.70 ( m, 3H), 3.78 (s, 3H), 3.60-3.75 (m, 4H), 3.30-3.60 (m, 3H), 3.15 (m, 1H), 2.80-3.00 (m,

-1 4m 4H), 2.30-2.60 (m, 6H), 1.80-2.10 (m, 3H), 1.39 (s, 3H), 1.20-1.30 (m, 3H). (+ (MH) detected 0.4 (C29H41IN5SO08 of MS (EI)

A(MH)o AA, 4 detected «C29H41N508 for MS (El) (S)—-3—(4-methoxyphenyl)-N-((S)-3—-(2-methylcyclopent-1-) en-1-yl)-1-© ((R)—2-m-— ethyloxiran—2-yl)—1-oxopropan-2-yl)-2-((S)-2-(2- morpholinoacetamido) propanamido)propanamide (C-1044): 1H NMR (300 MHz, CD30D): 6 8.31 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.78 (d,

J = 8.7 Hz, 2H), 4.28-4.54 (m, 2H), 4.22-4.30 (m, 1H), 3.71 (s, 3H), 0 3.56 (brs, 4H), 3.18 (d, J = 5.1 Hz, 1H) , 1.57 (s, 3H), 1.39 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H).

Detected A(MH) oAo,¢ “C31H44N407 of MS (El) (1r,4R)-N—((R)-1-(((S)—-1-(((S)—3) —(3,3—difluorocyclobutyl)-1-((R)-2- 1 methyl-oxiran—2-yl)-1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan —2-yl)- amino)—1-oxopropan-2-yl)—4- hydroxycyclohexanecarboxamide (C-1073): 1H NMR (400 MHz, CDCI3) 8.25 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 8.6

Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.19 - 7.02 (m, 2H), 6.87 - 6.63 (m, 0 2H), 4.50 (d, J = 4.5 Hz, 1H), 4.41 ( ddd, J = 10.2, 8.7, 3.9 Hz, 1H), 4.30 - 4.20 (m, 1H), 4.13 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 1H), 4.08 — 3.95 (m, 1H), 3.69 (s, 3H), 3.26 (s, 1H), 3.21 (d, J = 5.1 Hz, 1H), 3.03 (d, J

-1 q «= = 5.2 Hz, 1H), 2.94 (dd, J = 13.8, 3.8 Hz, 1H), 2.77 - 2.56 (m, 3H), 2.10 = 1.99 (m, 1H), 1.62 (s, SH) , 1.41 (s, 2H), 1.14 - 1.00 (m, 2H), 0.95 (d, J = 7.1 Hz, 2H).

A(MH) oa 4, detected «C30H41F2N307 of MS (El) (1r,4R)-N-((R)=1-(((S)-1-(((S)-3— (cyclopent-1-en-1-y)-1-((R)-2- e methyloxi— ran—2-yl)—1-oxopropan-2-yljamino)-3—(3-hydroxy- 4- methoxyphenyl)—-1-oxopropa—- n-2-yljamino)—]1-oxopropan-2-yl)-4- hydroxycyclohexanecarboxamide (C-1065): 1H NMR (300 MHz, DMSO-d6): 6 8.70 (br s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 00 8.1Hz, 1H), 6.62 (m, 1H), 6.55 (d, J = 8.1Hz, 1H), 5.40 (brs, 1H), 4.51 (d, J = 4.5 Hz, 2H), 4.30 (m, 1H) , 4.18 (m, 1H), 3.70 (s, 3H), 3.28 (m, 1H), 3.16 (d, J = 5.4 Hz, 1H), 2.98 (d, J = 5.4 Hz, 1H), 2.70 (m, 1H), 2.62 (m, 2H), 2.48 (m, 2H), 2.24 (m, 3H), 1.94 (m, 1H), 1.80 (m, 4H), 1.63 (m, 2H), 1.37 (s, 3H) ), 1.32 (m, 2H), 1.28 (m, 2H), 0.95 (d, J = 7.2 0

Hz, 3H).

Detected A(MH) 085.7 «C31H43N308 of MS (El) (S)-N=((S)-3—(cyclopent-3-en-1-yl)~1-((R)-2) -methyloxiran-2-yl)-1-oxopropa-— n-2-yl)-3-(4-methoxyphenyl)-2—-((S)-2-(2- morpholinoacetamido)propanamido)pr— opanamide (C -1066): Y.1H NMR (300 MHz, DMSO-d6): 6 8.36 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.8 Hz , 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.80 (d,

J = 8.4 Hz, 2H), 5.68 (m, 2H), 4.50 (m, 1H), 4.20-4.40 (m, 2H), 3.75 (s, 3H), 3.70 (m, 4H), 3.15 (m, 1H ), 3.05 (m, 1H), 2.80-3.00 (m, 3H),

-11- 2.65 (m, 1H), 2.35 (m, 4H), 1.90-2.10 (m, 2H), 1.60 (m, 1H), 1.50 (m, 1H), 1.42 (s, 3H), 1.14 (d , J = 6.9 Hz, 3H).

A(MH)ovy,1¢ detected «C30H42N407 1 MS (El)

A(MH) ov, ¥ detected «C30H42N407 of MS (El) (1r,4R)-N—((R)=1-(((S)-1-(((S)-3— (cyclohex-1-en-1-yh-1—-((R)-2-© methyloxir—an-2-yl)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl)- 1- oxopropan—-2-yljamin—- 0)-1-oxopropan—2-yl)-4- hydroxycyclohexanecarboxamide (C-1089): .sup.1H NMR (300 MHz,

DMSO-d.sub.6): 1H NMR (300 MHz, DMSO-d6): & 8.26 (m, 1H), 7.79 (d, J = 6.9 Hz, 0 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.4

Hz, 2H), 5.41 (m, 1H), 4.53 (m, 2H), 4.40 (m, 1H), 4.08 (m, 1H), 3.70 (s, 3H), 3.34 (m, 2H), 3.25 (m , 2H), 2.93 (m, 2H), 2.10 (m, 1H), 1.99- 1.80 (m, 8H), 1.66-1.46 (m, 3H), 1.37 (d, J = 6.9 Hz, 3H), 1.29 ( m, 2H), 1.14 (m, 2H), 0.94 (d, J = 6.9 Hz, 3H). 0

A(MH) 064,4 detected (C32H45N307 of MS (El) (1r,4R)-N—((R)-1—(((S)—1—(((S)—3- cyclobutyl-1—((R)—-2-methyloxiran—-2- yl)~1- —oxopropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)-1 -oxopr-opan-2-yl)-4-hydroxycyclohexanecarboxamide (C— 1090): |0 1H NMR (300 MHz, CDCI3): 6 7.11 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 0

Hz, 2H), 6.76 (m, 1H), 6.52 (m, 1H), 6.33 (m, 1H), 4.44 (m, 1H), 4.39 (m, 2H), 3.79 (s, 3H), 3.56 (m , 1H), 3.23 (d, J = 5.1 Hz, 1H), 2.99 (m,

-17- 2H), 2.88 (m, 1H), 2.08 (m, 1H), 2.06-2.02 (m, 4H), 1.99-1.77 (m, 8H), 1.65 (m, 2H), 1.64 (m, 5H) ), 1.27 (m, 5H).

Detected A(MH)oo AY «C30H43N30O7 of MS (El) (S)-N-((S)-3-((1R,5S,6s)-bicyclo[3.1.0]hexan-6- yl)-1—((R)-2- methyloxhan—2- —yl)—1-oxopropan—2-yl)-3—(4-methoxyphenyl)-2—((S)- © 2—(2- morpholinoacetamido- ) propanamido)propanamide (C-1143): 1H NMR (300 MHz, DMSO-d6): 6 8.37 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.72 ( d,J = 7.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.78 (d,

J = 8.7 Hz, 2H), 4.64 (m, 1H), 4.37 (m, 1H), 4.26 (m, 1H), 3.70 (s, 3H), 3.56 (m, 4H), 3.23 (d, J = 4.8 Hz, 1H), 2.94 (m, 1H), 2.90 (m, 3H), 2.86 0 (m, 1H), 2.36 (m, 4H), 1.99 (m, 3H), 1.80 (m, 4H), 1.34 ( m, 3H), 1.30- 1.28 (m, 3H), 1.16 (d, J = 5.1 Hz, 3H), 1.13 (m, 1H). +(MH) Detected 47,D58 «C31H44N407 I MS (EI) (S)-N—((S)-3-(3,3-difluorocyclobutyl)-1-(((R)-2-methyloxiran-2) -yl)-1-oxopr-opan-2-yl)-3—-(4-methoxyphenyl)-2-((S)-2-(2- 0 morpholinoacetamido)propanamido— )propanamide (C-1093): 1H NMR (400 MHz, CDCI3) 8.24 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.17 - 6.99 (m, 2H), 6.86 — 6.70 (m, 2H), 5.41 (s, 1H), 4.52 (s, 3H), 4.47 - 4.35 (m, 3H), 4.18 (p, J = 7.2, 7.2, 7.0, 7.0 Hz, 1H), 3.71 (s, 3H), 3.62 (pd, J = 6.6, 00 6.6, 6.6, 6.6, 3.9 Hz, 2H), 3.22 (d, J = 5.3 Hz, 1H ), 3.14 (qd, J = 7.4, 7.3, 7.3, 4.3 Hz, 2H), 3.02 — 2.95 (m, 1H), 2.97 — 2.88 (m, 1H), 2.88 - 2.72 (m, 1H), 2.59 (dd , J = 13.9, 10.3 Hz, 1H), 2.42 (dd, J = 14.1, 4.7

-18»-

Hz, 1H), 2.34 - 2.11 (m, 2H), 1.90 — 1.70 (m, 2H), 1.38 (s, 3H), 0.92 (d, J = 7.1 Hz, 3H).

A(MH) Detected 08, 47 «C29H40F2N407 1 MS (EI) (S)—3~—(4-methoxyphenyl)-N—((S)~-1—((R)~2-methyloxiran-2) -yl)~1-oxo- 3-((R)-t- etrahydrofuran-3-yl)propan-2-yl)-2—((S)-2-(2- 0 morpholinoacetamido) propanamido)propanamide (C -1026): 1H NMR (300 MHz, DMSO-d6): 6 8.36 (d, J = 7.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.75 (d,J = 7.5 Hz, 1H ), 7.13 (d, J = 8.4 Hz, 2H), 6.80 (d,

J = 8.4 Hz, 2H), 4.50 (m, 1H), 4.20-4.30 (m, 2H), 3.75 (m, 4H), 3.60- 3.70 (m, 5H), 3.30 (m, 1H), 3.15 (m , 1H), 3.00 (m, 1H), 2.80-3.00 (m, 0 3H), 2.70 (m, 1H), 2.35 (m, 4H), 2.20 (m, 1H), 2.00 (m, 1H), 1.70 (m, 1H), 1.50-1.70 (m, 2H), 1.42 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H). +(MH)ovo,0 detected «C29H42N408 of MS (El) (S)-N-((S)-3—((1R,5S,6r)-bicyclo[3.1.0]hexan-6 -yl)-1-((R)-2- methyloxiran—- 2-yl)—1-oxopropan—2-yl)-3—(4-methoxyphenyl)-2—((S)- H2—( 2-morpholinoacetamid— (e propanamido)propanamide (C-1142): 1H NMR (300 MHz, CDCI3): § 7.65 (brs, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.80 (m, 3H), 6.36 (m, 1H), 4.56 (m, 2H), 4.43 (m, 1H), 3.78 (s, 3H), 3.75 (m, 4H), 3.21(d, J = 4.8 Hz, 1H), 3.06-2.94 (m, 4H), 2.88 (d, J = 4.8 Hz, 1H), 2.57 (m, 4H), 1.69-1.41 (m, 4H), 1.41 (m, 3H), 1.36 (d, J 00 = 7.2 Hz, 3H), 1.28 (m, 1H), 1.20 (m, 1H), 0.96 (m, 1H), 0.95 (m, 1H), 0.88 (m, 2H), 0.37 (m, 1H).

A(MH) oAo,¥ Detected «C31H44N407 of MS (El)

-146- (S)—3~—(4-methoxyphenyl)-N—((S)~-1—((R)~2-methyloxiran-2-yl)~1-oxo- 3-))5( -1- etrahydrofuran—3-yl\propan-2-yl)-2-((S)-2-(2- morpholinoacetamido)propanami-do) propanamide (C-1025): 1H NMR (300 MHz, DMSO-d6) ): 6 8.45 (d, J = 6.9 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H) , 6.80 (d, ©

J = 8.4 Hz, 2H), 4.45 (m, 1H), 4.20-4.30 (m, 2H), 3.80 (m, 2H), 3.75 (s, 3H), 3.60-3.70 (m, 6H), 3.10-3.30 (m, 3H), 3.05 (m, 1H), 2.80-3.00 (m, 3H), 2.75 (m, 1H), 2.35 (m, 4H), 2.20 (m, 1H), 1.95 (m, 1H), 1.50- 1.70 (m, 1H), 1.42 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H).

A(MH) ove, 4 detected (C29H42N408 IMS (EI) 0 (2S)—-3—(4-methoxyphenyl)-N—((2S)-3—(3-methylcyclopent-1-en—1- yl)- 1-((R)-2- —methyloxiran—2-yl)-1-oxopropan-2-yl)-2-((S)-2—-(2- morpholinoacetamido) propanamido)propanamide (C- 1122): 1H NMR (300 MHz, DMSO-d6): & 8.35 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 0

Hz, 2H), 5.31 (m, 1H), 4.50-4.60 (m, 2H), 4.25 (m, 1H), 3.70 (s, 3H), 3.50 (m, 4H), 3.18 (m, 1H), 2.95 (m, 1H), 2.80-2.90 (m, 3H), 2.65 (m, 1H), 2.35 (m, 4H), 1.70-2.10 (m, 4H), 1.38 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H), 0.39 (m, 3H).

A(MH)oo, Y detected (C31H44N407 IMS (EI) 0 (S)-N—((S)—-3-cyclohexyl-1—((R)—-2-methyloxiran—-2-yl) -1-oxopropan—2- yh=3—(- 4-methoxyphenyl)-2-((S)-2—-(2- morpholinoacetamido)propanamido)propanamide (C-1003):

—y40- 1H NMR (400 MHz, CDCI3) 6 7.42 (d, J = 8.0 Hz, 1H), 7.19 - 7.01 (m, 2H), 6.90 - 6.77 (m, 2H), 6.63 (d, J = 7.8 Hz , 1H), 6.17 (d, J = 7.5 Hz, 1H), 4.66 — 4.47 (m, 2H), 4.41 (p, J = 7.1, 7.1, 6.8, 6.8 Hz, 1H), 3.78 (s, 3H), 3.70 (t, J = 4.6, 4.6 Hz, 4H), 3.26 (d, J = 5.0 Hz, 1H), 3.11 - 2.93 (m, 3H), 2.93 - 2.80 (m, 2H), 2.60 — 2.35 (m, 4H), 1.84 - 1.51 (m, © 11H), 1.30 - 1.00 (m, 6H), 1.02 - 0.75 (m, 2H). (tM) oAv, 4 detected «C31H46N407 l 1/15 (EI) (S)-N=((S)-3-cyclopentyl-1—((R)-oxiran-2-yl)-1 -oxopropan-2-yl)-3- (4-metho- xyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamido)propanamide (C-1030): 01 1H NMR (300 MHz, CDCI3) : § 7.40 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.61 (m, 1H), 4.49 (m, 1H), 4.42 (m, 1H), 3.79 (s, 3H), 3.74 (m, 4H), 3.51 (m, 1H), 3.13 -3.10 (m, 4H), 3.08-3.03 (m, 2H), 2.50 (m, 4H), 1.74 (m, 2H), 1.63 (m, 1H), 1.53 (m, 2H), 1.34 (d, J = 8.4 Hz, 3H), 1.27 0 (m, 3H), 0.85-1.16 (m, 3H). (+MH) 00d, A detected (C29H42N407 for MS (El) (S)-N-((S)-3—(cyclopent-1-en-1-yl)~1-((R) -oxiran-2-yl)-1- oxopropan-2-yl)—- 3—(4-methoxyphenyl)-2—((S)-2-(2- morpholinoacetamido)propanamido)propanamid— e (C1038): Y 1H NMR (300 MHz, CDCI3): § 7.40 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.1 Hz , 1H), 6.47 (d, J = 8.1 Hz, 1H), 5.37 (m, 1H), 4.58 (m, 1H), 4.53 (m, 1H), 4.42 (m, 1H), 3.80 (s, 3H) , 3.74 (m, 4H), 3.51 (m, 1H), 3.13-3.10 (m, 4H), 3.08-3.03 (m, 1H),

-11- 2.58 (m, 4H), 2.35-2.19 (m, 5H), 1.87 (m, 2H), 1.37 (d, J = 8.4 Hz, 3H). (+MH) cov, ¥ l 02911401407 Discovered MS (El) 01 Example (S)—-3-Cyano-N—((S)-1-(((S)-3—(cyclopent-) 1-en-1-yl)-1-((R)-2- © methyloxiran—2- —yl)—1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan— 2-yl)-2—(2-mo-rpholinoacetamido)propanamide (C-1135)

TFA 0°

Ay z cn

AON BPE

CN OMe BocHN NN

I = 0 = H 0

BocHN” “COOH, Nami DIEA, DMF TL

ome

CN oY m 0 1. TFA, DCM H 0 on AA LHR, b 2.0 0 0 - 0 l matt

HATU, DIEA, OMe

dmf

mL 7.8 mL 3), DIEA v0) 5 mmol) VY 0 can 1, YY) HATU Then (S)—2-amino-N-((S)-3—) was added (cyclopent—1- mol) to a solution at 0°C of Vo en—1-yl)-1-(((R)-2-methyloxiran-2-yl)~-1-- oxopropan-2-yl) -3—(4- mL).Yo)DMF mmol) in 110 (TFA (methoxyphenyl)propanamide salt) The reaction mixture was left to warm to ambient temperature and stirred for ? hours. Added

EtOAc in milliliters). The aqueous layer was extracted using 100 (mL) water (EtOAC 001).

-1/- mL” 3); Yoo) The organic phases combined with Brain Jue were L(Y x mL 04) and dried over anhydrous sodium sulfate; focus. The residue was purified by tert-butyl chromatography (5)-3- to yield (1:Y = hexane [EtOAC) flashing on cyano-1-((((S)-1) silica gel -(((S)-3-(cyclopent-1-en—-1-yl)-1-(((R)-2-methyl oxiran-2-yl)—1-oxopropan-2-yl)Jamino)- 3—-(4-methoxyphenyl)-1- © 7648 mg 04 )OXopropan—2-yl- Jamino)-1-oxopropan-2-yl)carbamate tert-butyl ((S)-3—-cyano-1 —(((S)-1—(((S)-3—(cyclopent-1-en—) to a solution of Ela2-008-(4))-1-g(Ella-1oxiran—- 2-yl)-1-oxopropan—2-yljamino)-3—(4- methoxyphenyl)-1-oxopropan-2-yl- Jamino)-]1-oxopropan—-2- 00° TFA (mL) added 01) DCM (mmol) in 0.1 g; 0.0 (1 yl)carbamate min at ambient temperature and then concentrated to 115 mL). The reaction mixture was stirred for (S)—2-amino-3-cyano-N—((S)-1-(((S)-3—(cyclopent—) dehydration to obtain 1-en—-1- yl)-1—~((R)-2-methy-loxiran—2-yl)-1-oxopropan—-2-yl)amino)- 3-(4-methoxyphenyl)-1-oxopropan-2-yl- Jpropanamide yo from it; used directly without further purification. TFA mg; quantitative (as salt) 00 ml; 7.8 mL (0.75 mmol) and Ghana (0.6 can +,1)) HATU Then (S)-2-amino-3-cyano-N—((S)-) was added 1- mol) to a solution at 0°C of (((S)—3—(cyclopent-1-en-1-yl)-1-((R)-2-methy-loxiran—2-yl) -1- oxopropan—-2-yl)amino)-3—(4-methoxyphenyl)-1-oxopropan-2-yl- 0 morpholinoacetic acid —Y (mmol) and (V)propanamide acid (mL) ) with flipping. The reaction mixture was left to warm (DMF (Yo) mmol) in 0.01 mg; (1601 mL) and water (EtOAC 001) until ambient temperature and stirred for ? hours. x mL was added 0 (1 mL EtOAC). The two layers were separated and the aqueous phase was extracted using 001 (and drying over (VX mL You) the combined organic phases using Brian Jue YO 7).

1-8 sodium anhydrous sulfate; focus. The residue was purified by flash chromatography column to yield -(5))-1-(5))-L3-01800-1-(5 (¥ :1 = hexane [EtOAC) silica gel ‎ 3—(cyclopent-1-en—1-yl)-1—(((R)-2-methyloxiran— 2-yl)—-1-oxopropan— 2-yl)amino)-3-(4-methoxyphenyl) -1-oxopropan-2-yl)-2—(2-m-toll). %Y0 (ans ¥) +) orpholinoacetamido)propanamide © 1H NMR (300 MHz, DMSO-d6): 6 8.44 (d, J = 6.6 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.78 (d,

J = 8.4 Hz, 2H), 5.40 (s, 1H), 4.60-4.35 (m, 3H), 3.70 (s, 3H), 3.62- 3.57 (m, 4H), 3.18 (m, 1H), 3.05-2.80 (m, 3H), 2.65 (m, 1H), 2.50- 2.10 (m, 10H), 1.90-1.70 (m, 2H), 1.37 (s, 3H). 0

Detected A(MH) 047.7 “C31H41NSO7 of MS(EI) The following compounds were synthesized in a similar way:

N-((R)-1-(((S)-1-(((S)-3—(cyclopent-1-en-1-yl)-1-((R)-2- methyloxiran—2- yl-)-1-oxopropan-2-yljamino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yljamino)-]1-ox-opropan-2-yh-2- eo oxaspiro[3,3]heptane- 6-carboxamide (C-1063): 1H NMR (400MHz,

CDCI3) 6 8.24 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.17 - 6.99 ( m, 2H), 6.86 — 6.70 (m, 2H), 5.41 (s, 1H), 4.52 (s, 3H), 4.47 — 4.35 (m, 3H), 4.18 (p, J = 7.2, 7.2, 7.0, 7.0 Hz, 1H), 3.71 (s, 3H), 3.62 (pd, J = 6.6, 6.6, 6.6, 6.6, 3.9 Hz, 0 2H), 3.22 (d, J = 5.3 Hz, 1H), 3.14 (qd, J = 7.4, 7.3, 7.3, 4.3 Hz, 2H), 3.02 - 2.95 (m, 1H), 2.97 - 2.88 (m, 1H), 2.88 — 2.72 (m, 1H), 2.59 (dd, J = 13.9, 10.3 Hz , 1H), 2.42 (dd, J = 14.1, 4.7 Hz, 1H), 2.34 -

-14- 2.11 (m, 4H), 1.90 - 1.70 (m, 2H), 1.38 (s, 3H), 0.92 (d, J = 7.1 Hz, 3H).

A+(MH) 271A, + detected “C31H41IN3O7 of MS(El)

N=((S)~1-(((S)-3—(cyclopent-1-en-1-yl)-1-((R)~-2-methyloxiran-2-yl)- 1-oxop- ropan—2-yljamino)-3—(4-methoxyphenyl)—-1-oxopropan-2-yl)- H-3,3,3-trifluoro-2- (2-morpholinoacetamido)propanamide (C-1134): .sup.1H NMR (300 MHz, DMSO-d.sub.6): 1H NMR (300 MHz, DMSO-d6): § 8.95 (m, 1H), 8.52 (m, 1H), 8.24 (m, 1H) , 8.05 (m, 1H), 7.15 (m, 2H), 6.78 (dd, J = 7.2 Hz, 2H), 5.20-5.50 (m, 2H), 4.40-4.60 (m, 2H), 3.70 (s, 3H ), 3.60 (m, 4H), 3.18 (m, 1H), 0 2.80-3.10 (m, 3H), 2.65 (m, 1H), 2.30-2.50 (m, 5H), 2.10-2.30 (m, 4H) , 2.00 (m, 1H), 1.70-1.90 (m, 2H), 1.38 (s, 3H).

Detected A+(MH) Yo, A «C30H39F3N407 for MS (El) (R)=N=((S)-1-(((S)-3—(cyclopent-1-en-1-yl) )~1~((R)-2-methyloxiran—2- yl)~1-- oxopropan-2-yljamino)-3—(4-methoxyphenyl)-1-oxopropan-2—- 01 yl)=3,3 ,3-trifluor- 0—2-(2-morpholinoacetamido)propanamide (C-1132): 1H NMR (300 MHz, DMSO-d6): § 8.95 (m, 1H), 8.52 (m, 1H), 8.24 (m , 1H), 8.05 (m, 1H), 7.15 (m, 2H), 6.78 (2d, J = 7.2 Hz, 2H), 5.20-5.50 (m, 2H), 4.40-4.60 (m, 2H), 3.70 ( s, 3H), 3.60 (m, 4H), 3.18 (m, 1H), 2.80-3.10 (m, 3H), 2.65 (m, 1H), 2.30-2.50 (m, 5H), 2.10-2.30 (m, Y. 4H), 2.00 (m, 1H), 1.70-1.90 (m, 2H), 1.38 (s, 3H).

A(MH) 7 7 detected (C30H39F3N407 1 LC-MS 11) Example

_ \ a= (S)-N-((S)-3—(Cyclopent-1-en-1-yl)~1~((R)-2-methyloxiran-2-yl)-1- oxopropan-— —2-yl)-3-(4-methoxyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamido)pro- panamide (C-1009) 2 fu ? SHO pi A Bool Ada Seto] gp Se Nm 2 Hammh Mortholin Aesthetic -* Ro La Ana HATS DIEA, 8 Depth 01 1 08 ' HRTY, Sot We Trass Elia M Bahn, © A 0 - 4 Answer A n.p. Hy Fai : 8 1 a > shout alt 03 > 3 3 b ali hd and hasi 83 £3 sat b THE 8 £3 3 b 0 mag massage 4 we b TRA Hat HD

N Ben Ah 9! +

ATL, DIBA, DUP PL. 1 NA AL Nef

SE A 3 lac Na [5] @ ke mL 1701 (5.7? mL; DIEA 5 mmol) 0.1 g; 14.7) HATU thereafter © ? 07 mL VV) alanine to a solution at 0°C of ©80-a-alanine (Use

L-4-MeO-alanine benzyl ester p-toluenesulfonate dud -MeO-¢-L ales (Use ? mmol) in 4.0 g; V0, +) phenylalanine benzyl ester p-toluenesulfonate to ambient temperature and stirred lad milliliters) with stirring. The reaction mixture (Yoo) DMF was left for 1 hour. The mixture was then concentrated and the residue was purified by a VY flash chromatography column of duration 0 to yield -2-(5))-2 O58602-(5)1:¥ = EtOAc on a silica gel (hexane/ ((tert-butoxycarbonyl)amino)propanamido)-3—(4-methoxyphenyl)prop— yield). DAA (xa VY,V) anoate (S)-benzyl 2-((S)—2—(((( tert- then stir a solution of butoxycarbonyl)amino)propanamido)-3—(4-methoxyphenyl)prop- anoate yo

-1.?- can 79.0(17.1 ms (Use in ¥ p from You) HCI-EtOAC mL) 1 sad hour at ambient shall dag. The mixture was concentrated and the residue was washed with (jbl V+.) petroleum ether to obtain -2-(5))-2 (S)-benzyl aminopropanamido)-3—(4-methoxyphenyl)propanoate As salt HCl © (quantitative); They were used directly in the next step without further purification.

to a solution of (S)-benzyl 2-((S)-2-aminopropanamido)-3—-(4- methoxyphenyl)propanoate (salt can 70.1 (HCI 07.5 mmol) in DMF (Yoo) milliliters) at 0 °C HBTU (8 can Yo 8007 mmol) and [AY aa 1081] (01,0 mmol) were added. The mixture was stirred for ¾ minutes after which –Y Vomorpholinoacetic acid (0 aa AV ,07 mmol) DIEA (£7.0 ml 7014 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 min. Then saturated aqueous NaHCO3 Yoo (mL) was added and the resulting mixture was extracted with (0/6) Yoo (mL) (YX) The combined extracts were washed with Braine (£14 mL); drying over anhydrous sodium sulfate; focus. The residue was purified by flash chromatography column on silica gel (heptane 10) to [EtOAc heptane = ¥: (Y) to obtain (S)-benzyl 3-(4-methoxyphenyl)-2—- YY, ())5(-2-)2- morpholinoacetamido)propanamido)propanoate 76/895 g

yield) as a colorless solid. A mixture of (S)-benzyl 3-(4-methoxyphenyl)-2—((S)-2-(2- morpholinoacetamido)propanamido)propanoate ) + 9.0 g was stirred; 014 mmol (0.1%) (0) Pd/C, XY.g) in THE (00 milliliters) under hydrogen for 1 hour. The mixture was filtered and concentrated to obtain 3-(4-methoxyphenyl)-2-E5802-(5)Y,Y) ((S)—2-(2-morpholinoacetamido)propanamido)propanoate g 7644

yield) as a colorless solid. (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.24 6): (50-06AA0 1H NMR (300 MHz, Hz, 1H), 7.13 (m, 2H), 6.82 (m , 2H), 4.35 (m, 2H), 3.71 (s, 3H), Yo 7.8

-Y 0 Y-— 3.63-3.56 (m, 4H), 2.99-2.65 (m, 4H), 2.41-2.38 (m, 4H), 1.20 (d, J = 6.9 Hz, 3H). [(+MH) va ¢,0 detected (C19H2TN3O6 for MS (El): to a solution of (S)—3—(4-methoxyphenyl)-2—((S)-2-(2) -morpholinoacetamido) o (S)-2-amino-3-5 mg; crude) Ao.) propanamido)propa— noic acid (salt (cyclopent-1-en—1-yl)-1—) (R)-2-methyloxiran—2-yl)propan—1-o- ne mg; HATU (YAY) mL) added 01 (DCM mmol) in +, TA vg; 001 ( TFA

DIEA Mall). The mixture was cooled to 0 °C and based with Je +, Vo min and Te to pH = 8. The reaction mixture was stirred at ambient temperature for 0 and (YX mL Yo) DCM was milliliters). The resulting mixture was extracted using (000) adding water salad collection of extraction products, drying over anhydrous sodium sulfate, and concentration. Then, purifying the remaining EtOAc = 1: by flash chromatography column on silica gel (petroleum ether/) to obtain on ( YY . = methanol /DCM then AEE (S)-N=((S)-3—(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran) —-2-yl)-1- yo oxopropa— n—2-yl)-3—(4-methoxyphenyl)-2—((S)-2-(2- on (VA mg”; VY +) morpholinoacetamido)propanamido)pr— opanamide colorless solid. sale as 1H NMR (300 MHz, CDCI3): 67.29 (br. s, 1H), 7.16 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 7.2 Hz, 1H), 6.10 (d, J = 7.2 Hz, 0 1H), 5.33 (s, 1H), 4.56-4.44 (m, 2H), 3.80 (s, 3H), 3.75-3.73 (m, 4H), 3.29 (d, J = 4.8 Hz, 1H), 3.00-2.91 (m, 5H), 2.53-2.47 (m, 5H), 2.27 - 2.16 (m, 5H), 1.90-1.81 (m, 1H), 1.73 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H).

A(MH)ov), ¢ detected (C30H42N407 of MS (El)

-Y 0 ".- The following compounds were synthesized in a similar way: (S)-N=((S)-3—(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran) —-2-yl)-1- oxopropan-— (-1,1)-2)-2-(5))-2-(ala-2- ‎dioxidothiomorpholino)acetamido)propanamido)-3—(4- - methoxyphenyl)propanamide (C-1127): o 1H NMR (300 MHz, DMSO-d6): 6 8.25 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.87 ( d, J = 6.9 Hz, 1H), 7.10 (d, J = 6.3 Hz, 2H), 6.78 (d,

J = 6.3 Hz, 2H), 5.38 (m, 1H), 4.50 (m, 2H), 4.28 (m, 1H), 3.70 (s, 3H), 3.18 (m, 1H), 2.99-3.15 (m, 5H ), 2.81-2.97 (m, 6H), 2.62 (m, 1H), 2.23 (m, 1H), 1.83-2.11 (m, 6H), 1.42-1.63 (m, 4H), 1.36 (s, 3H), 1.16 0 (d, J = 4.8 Hz, 3H).

Detected A(MH) 77.7 «C31H44N408S for MS (El) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R) -2-methyloxiran-2-yl)-1- oxopropa—- n—2-yl)-2-((S)-2-(2—(1,1-dioxidothiomorpholino)acetamido) propanamido)-3—(4 - —-methoxyphenyl)propanamide (C-1115): yo 1H NMR (300 MHz, DMSO-d6): 6 8.31 (d, J = 6.9 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.88 (d,J = 7.5 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.79 (d,

J = 8.1 Hz, 2H), 5.40 (s, 1H), 4.49 (m, 2H), 4.29 (m, 1H), 3.70 (s, 3H), 2.68-3.23 (m, 10H), 1.81-2.72 (m , 4H), 2.24 (m, 4H), 2.21 (m, 1H), 1.97 (m, 1H), 1.79 (m, 2H), 1.37 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H) . 0

Detected A(MH) 19.7 «C30H42N408S for MS (El) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R) -2-methyloxiran-2-yl)-1- oxopropa-— n—2-yl)-2—((S)-2-(2-(4-hydroxy—4-methylpiperidin—1-

-Y 0 ¢— yl)acetamido)propanamid— o0)-3—(4-methoxyphenyl)propanamide (C- 1121): 1H NMR (300 MHz, DMSO-d6): 6 8.30 (d, J = 6.9 Hz, 1H ), 8.10 (d, J = 8.1 Hz, 1H), 7.70 (d,J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.79 (d,

J = 8.4 Hz, 2H), 5.40 (br s, 1H), 4.51 (m, 2H), 4.27 (m, 1H), 4.13 (m, © 1H), 3.70 (s, 3H), 3.50 (m, 1H ), 3.18 (d, J = 5.1 Hz, 1H), 2.98 (d, J = 5.1 Hz, 1H), 2.84 (m, 3H), 2.64 (m, 1H), 2.37 (m, 4H), 2.24 (m , 4H), 1.77 (m, 2H), 1.45 (m, 4H), 1.43 (s, 3H), 1.17 (m, 4H), 1.14 (d, J = 6.6

Hz, 3H). ~(MH) oav,o Detected (C32H46N407 IMS (EI) 0 (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R)-2) -methyloxiran-2-yl)-1-oxopropa-n—-2-yl)-3-(4-methoxyphenyl)-2-((S)-2-(2-(3-oxopiperazin- 1-yl)acetamido )pro— panamido)propanamide (C-1120): 1H NMR (300 MHz, DMSO-d6): 6 8.31 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.80 ( m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.7 Hz, 10 2H), 5.40 (m, 1H), 4.49 (m, 2H), 4.27 (m, 1H) , 3.70 (s, 3H), 3.18 (d, J = 5.1 Hz, 1H), 3.13 (m, 2H), 2.73-3.09 (m, 6H), 2.65 (m, 1H), 2.56 (m, 2H), 2.37 (m, 1H), 2.23 (m, 5H), 1.79 (m, 2H), 1.40 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H).

A(MH) oA¢,¢ detected (C30H41INSO7 IMS (EI) 0 4=((S)-3~(((S)—3—cyclopentyl-1—((R)-2-methyloxiran-2- yl)-1-oxopropan-2-yl- Jamino)-2—((S)-2~(2-morpholinoacetamido) propanamido)-3-oxopropyl)pyridine 1-oxide (C-1119):

-Y mg 1H NMR (300 MHz, :(50-06AA0 6 8.43 (d, J = 6.9 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 6.6 Hz, 2H), 7.78 (d, J = 7.5 Hz, 1H), 7.23 (d,

J = 6.9 Hz, 2H), 4.61 (m, 1H), 4.28 (m, 2H), 3.57 (m, 4H), 3.03 (m, 2H), 3.00 (m, 2H), 2.97 (m, 3H), 2.39 (m, 4H), 1.75 (m, 1H), 1.69 (m, 2H), 1.65 (m, 6H), 1.49 (d, J = 5.1 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H ). ©

Detected A(MH) 050.7 “C28H4INSOT for MS (El) (S)-N=((S)-3—(cyclohex-1-en-1-yl)-1-((R)-2) -methyloxiran—-2-yl)-1- oxopropan-— —2-yl)=2~((S)~3-hydroxy-2—(2-morpholinoacetamido) propanamido)-3—(4-methoxy— phenyl) propanamide (C-1104): 1H NMR (300 MHz, CDCI3): § 7.88 (m, 1H), 7.16 (d, J = 8.9 Hz, 2H), 0 6.94 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.18 (d, J = 6.6 Hz, 1H), 5.28 (br 5, 1H), 4.56 (m, 2H), 4.50 (m, 1H), 4.02 (m, 1H ), 3.78 (s, 3H), 3.74-3.71 (m, 4H), 3.62 (m, 2H), 3.29 (d, J = 4.8 Hz, 1H), 3.03- 2.97 (m, 4H), 2.50 (m, 4H), 2.34 (m, 2H), 1.89 (m, 5H), 1.60 (m, 3H), 1.53 (s, 3H). 0

Detected A(MH) Tey, A “C31H44N408 of MS (El) 11 Example (2S,3R)-N—((S)-3-Cyclopentyl-1-((R)-2-) methyloxiran-2-yl)-1- ‎oxopropan—2-yl)— —3-hydroxy-3—(4-methoxyphenyl)-2-((S)-2-(2-

_ \ 0 - morpholinoacetamido)propanamido- )propanamide (C-1022) oY m MeO 0 oY 0 gy © o 600 nA AR 080

HATU, DIEA, DMF Go

HN” ~COOBn

OMe oY M Te TFA | ,

Hy, Pd/C nA AR OH HN —_— Qo - =

THF HATU, DIEA, DMF

OMe oY m 0 ° on AAR 0 :

H qq H §

OMe mM 105.0 ALL YN) DIEA mmol) 8.976 ca ¥, 8) HATU Then (28,3R)-benzyl 2—amino-3-hydroxy-3- mol) was added to A solution at 0 pH of (mmol)(-2)-2-(5) 1,597 «aa, 01(4-methoxyphenyl)propanoate ©

Yo) DMF in (Js mL 0.497 g 1.71) morpholinoacetamido)propanoic acid h. 1 sad was concentrated in milliliters). The reaction mixture was left to warm to ambient temperature and the remaining (P/A) was stirred by a flash chromatography column on silica gel (salted) the mixture was purified and (28,3R)-benzyl 3-hydroxy-3—-(4) was purified - to get (Y :1 to 1 ?: = EtOAc methoxyphenyl)-2-((S)-2-(2-morpholino 0 acetamido)propanamido)propanoate ( ; 0.1 g;7004 yield) as a colorless solid.to a solution of (2S,3R)-benzyl 3-hydroxy—-3—(4-methoxyphenyl)-2—((S)-2- Y, +) (2-morpholino acetamido)propanamido)propanoate g” 5.6 mmol) Yo in The (£4 ml) PAJC (000 mg 9600) was added. The mixture was stirred under atmosphere

—¥.y— atmospheric) at ambient temperature overnight and then filtered through a layer of V) hydrogen celite. The filtrate was concentrated under reduced pressure and the residue was washed with (28,3R)-3-hydroxy—3-(4-methoxyphenyl)— - mL) to yield EtOAc (20 = 01(((S). )—2~(2-morpholinoacetamido)pro— panamido)propanoic acid yield) as a colorless solid. %YA g; © 1H NMR (300 MHz, DMSO-d6): 6 8.08 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 5.10~ 5.07 (m, 1H), 4.41-4.39 (m, 2H), 3.71 (s, 3H), 3.56-3.55 (m, 4H), 2.97-2.73 (m, 2H), 2.38-2.35 (m, 4H), 1.16 (d, J = 6.9 Hz, 3H).

Detected A(MH) 5001.17 “C19H2TN3OT IMS (EI) 0 10 mM; DIEA (+7 mmol) 4,850 can (84, HATU) After that (28.3R) was added )-3-hydroxy-3—(4-C of dap into a solution at zero (ds methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)pro-mmol) and (5 )-"-amino-7-cyclo 5.00 g; (YR) dine to ambient temperature and stirred for bad (ml). The reaction mixture was left (DMF) vv (min.) The mixture was concentrated and the residue was purified by a flash chromatography column on silica gel: to obtain (EtOAc) To 1 ?: = EtOAc ((eths petroleum/(2S,3R)-N—((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1) - oxopropan—2-yl- )-3-hydroxy-3-(4-methoxyphenyl)-2—((S)-2—-(2- 00 toll) 906711 aa), £0) morpholinoacetamido)propanamid— o)propanamide as a colorless solid. 1H NMR (300 MHz, CDCI3): 6 7.40 (d, J = 5.7 Hz, 1H), 7.32-7.22 (m, 2H), 7.06-6.99 (m, 2H) ), 6.82 (d, J = 8.7 Hz, 2H), 5.26-5.21 (m, 1H),

-Y 0 m 4.68-4.60 (m, 2H), 4.58-4.39 (m, 2H), 4.01-3.85 (m, 1H), 3.81 (s, 3H), 3.74-3.72 (m, 4H), 3.25 (d, J = 4.8 Hz, 1H), 2.99-2.85 (m, 2H), 2.53~ 2.39 (m, 4H), 1.74-1.61 (m, 8H), 1.53 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.28-1.20 (m, 3H).

A(MH) oA, ¥ Detected «C30H44N408 1 MS(El)© The following compounds were synthesized in a similar way: (2S,3R)-N—((S)—-3~(cyclohex-1-en— 1-yl)-1~((R)-2-methyloxiran-2-yl)- 1-oxopr-opan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2—-((S )-2-(2- morpholinoacetamido)p— ropanamido)propanamide (C-1082): 1H NMR (300 MHz, CDCI3): § 7.43-7.40 (m, 1H), 7.27-7.25 (m, 2H), 0 7.00 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 4.8 Hz, 1H), 6.83-6.81 (m, 2H), 5.45-5.44 (m, 1H), 5.21-5.20 (m, 1H), 4.61-4.58 (m, 2H), 4.46-4.38 (m, 1H), 3.77 (s, 3H), 3.72-3.66 (m, 4H), 3.26 (d, J = 4.8 Hz, 1H), 2.91-2.89 ( m, 3H), 2.60-2.32 (m, 4H), 2.07- 1.95 (m, 4H), 1.69-1.40 (s, TH), 1.31 (d, J = 6.9 Hz, 3H). 0

Detected A(MH) 00017 “C31H44N408 of MS(EI) (2S,3R)-N—((S)-3~(cyclopent-1-en-1-yl)-1—((R) -2-methyloxiran-2-yl)- 1-oxop~- ropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2—-((S)-2-(2- morpholinoacetamido)— propanamido)propanamide (C-1083): 1H NMR (300 MHz, CDCI3): § 7.43 (d, J = 7.5 Hz, 1H), 7.29-7.23 (m, 02H), 7.01 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.7

Hz, 2H), 5.48-5.46 (m, 1H), 5.25-5.22 (m, 1H), 4.63-4.60 (m, 2H), 4.50-4.42 (m, 1H), 3.80 (s, 3H), -3.70 3.66 (m, 4H), 3.28 (d, J = 1

_ \ 0 q —_

Hz, 1H), 2.99-2.92 (m, 3H), 2.62-2.22 (m, 10H), 1.89-1.84 (m, 2H), 1.54 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H) .

A(MH) oY, check out “C30H42N408 for MS(EI) 11 Example (2S,3R)-N—((S)-3-(Cyclohex-1-en-1-yl)~1 -((R)-2-methyloxiran-2-yl)- 1-0*0010- pan—2-yl)-3-hydroxy-2-((S)-3-hydroxy-2—- (2- morpholinoacetamido)propanamido) —-3—(4-methoxyphenyl)propanamide (C-1116) ?- morpholine acetic acid ¢ OM Pa a yum Dea a Aa a en, A Po, 4H. BEC, THE a a 3 mm a - i Cay BC, THE mo 0 1 NE N— 2101-50 HO Waziat- << 31 8 mr - b 28 5 4 : J Dua TLD Brother J OY 2 5 9 0 AAR LNG NJ 1 LIENS NA BAGCH Ugg, D 7 D HATU, DIES, DME ]| Foe Tum 0 was compacted after which HATU (180 mg) was added; 1.001 mmol (DIEA) +49 mL; 5.7 mmol) to a solution at 0 °C of (28,3R)-benzyl 2—amino-3-hydroxy-3- (4-methoxyphenyl) propanoate (salt (Use Ak 0,1 cane) £VY HCI f-806 1.41 cane 790 ( Ser-OH mmol) in DMF (A) milliliters). The reaction mixture was left to warm to ambient temperature and stirred for 70 minutes. The mixture was concentrated and the remaining VO was purified by a flash chromatography column on a petroleum jelly (A) Kha petroleum/EtOAc = ?: 1 twice to obtain (28,3R)-benzyl 2—-amino—- 3-hydroxy-3—(4- ‎methoxyphenyl)propanoate )1£7 mg; 90957 toll) as a colorless solid.

YY a— (2S,3R)-benzyl 2-))5(- mL) A solution of 10 p;0) HCI-EtOAc was added to 2~((tert-butoxycarbonyl)amino)— 3-hydroxypropanamido)-3-hydroxy-3—(- mL). Substance 900 was washed and the mixture was stirred at ambient temperature for the remaining (2S,3R)-benzyl 2-))5(-2-) with diethyl ether (0 mL) to obtain © amino-3-hydroxypropanamido )-3-hydroxy-3—(4-sale mg; 76/85 yield) as VE (HCI (methoxyphenyl salt)propanoate colorless solid. mL; £.0 mL + YA) DIEA 5 mmol) 0.74 mg; 049) HATU Then (2S,3R)-benzyl 2—((S)-2-amino-3- mol) was added to solution at zero Dimeric degree of Vo (hydroxypropanamido salt)-3-hydroxy-3-(4-methoxyphenyl)propano- ate morpholinoacetic acid —Y mmol) and acid 111 974; mg (HC to Bad in milliliters). The reaction mixture (DMF (A) mmol) was left in 1.1" cav (VY) min. The mixture was concentrated and the residue was washed with Te sad at ambient temperature and stirring (28,3R)-benzyl 3 as substance Colorless solid. YE) (28,3R)-benzyl 3-hydroxy-2—((S)-3-hydroxy-2-(2-) to a solution of morpholinoacetamido)propanamido)-3-(4-met - hoxyphenyl)propanoate (%V + mg; 001 (Pd/C mL) THE (Yo) mol) was added in (eo, TAC (aaa TER) Ye atmosphere) at ambient temperature overnight and then 1) The mixture was stirred under hydrogen atmosphere by (28,3R)-3-hydroxy—filtration through a bed of silite. The filtrate was concentrated to obtain 2—((S)-3-hydroxy—2-( 2-morpholinoacetamido)propanamido)-- 3-(4-mg; 7047 yield) in the form of a colorless 111(methoxyphenyl)propanoic acid solid. Yo

-?11-‎ milliliters; 5.88 mM DIEA (5 mmol) YoY 0.1 mg; 0TY) HATU Then (28,3R)-3-hydroxy—2—((S)-3-hydroxy) was added — mol) to a solution at 0°C of 2—(2-morpholinoacetamido)propanamido)—- 3-)4- and -2-(5) (Js 0.18 mM; 50 +) methoxyphenyl)propanoic acid amino-3-(cyclohex—1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-©mL). A mixture of 01 (DMF mmol) in 0.08 mg; YE (TFA zk) -00 © was left up to ambient temperature and stirred for ¼ min. The mixture was concentrated and the remaining (Bad reaction: 01 to 1 ier = DCM/MeOH) was purified by a silica gel flash chromatography column twice to obtain -2-(4))-1-(E) -61008-1-80-1/a6)-3-(5))-no- (4a25,3) )1 methyloxiran—2-yl)—-1-oxopr-opan—2-yl)-3 hydroxy-2—((S)-3-hydroxy- 0 2—(2-morpholinoacetamido)propanamido- -3-)4- dae mg; 9051 yield) as a solid © ++) methoxyphenyl)propanamide Colour. 1H NMR (300 MHz, DMSO-d6): 67.97 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.80 (d, 0

J = 8.7 Hz, 2H), 5.61 (d, J = 4.5 Hz, 1H), 5.40-5.38 (m, 1H), 5.23-5.21 (m, 1H), 5.04-5.02 (m, 1H), 4.62-4.51 (m, 1H), 4.45-4.35 (m, 2H), 3.71 (s, 3H), 3.68-3.41 (m, 6H), 3.33 (s, 1H), 3.21 (d, J = 5.1 Hz, 1H), 2.97-2.80 (m, 3H), 2.39-2.21 (m, 4H), 2.11-1.71 (m, 4H), 1.56-1.40 (m, 4H), 1.26 (s, 3H), 1.28-1.22 (m, 1H) ). 0

A(MH) 11, 4 detected “C31H44N409 for MS(EI) The following compounds were synthesized in a similar way: (2S,3R)-N—((S)-3~(cyclopent-1-en-1) -yl)-1—((R)-2-methyloxiran-2-yl)- 1-oxop-— ropan—2-yl)-3-hydroxy-2—((S)-3-hydroxy-2 —(2-

-?117- morpholinoacetamido )propanamid- 0)—-3—(4-methoxyphenyl)propanamide (C-1144): 1H NMR (300 MHz, DMSO-d6): 6 8.03 (d, J = 7.2 Hz, 1H) , 7.92 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H), 6.81 (d,

J = 8.7 Hz, 2H), 5.63 (d, J = 4.5 Hz, 1H), 5.41 (s, 1H), 5.25 (m, 1H), 0 5.04 (m, 1H), 4.41 (m, 1H), 4.37 (m, 2H), 4.30 (m, 2H), 3.71 (s, 3H), 3.67 (m, 1H), 3.55 (m, 4H), 3.35 (m, 1H), 3.20 (d, J = 5.4 Hz, 1H), 2.97 (m, 2H), 2.89 (m, 1H), 2.39 (m, 4H), 2.25 (m, 4H), 1.82 (m, 2H), 1.36 (s, 3H).

Detected A(MH) Tv, YA “C30H42N409 IMS (El) 0 (2S,38)-N—((S)-3-cyclopentyl-1—((R)-2-methyloxiran-2-yl)- 1- oxopropan—2-yl- )—3—hydroxy—-3-(4-methoxyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamid-o)propanamide (C-1023): 1H NMR (300 MHz, CDCI3): 6 7.40 (m, 1H), 7.33 (m, 2H), 6.92-6.86 (m, 3H), 6.40 (d, J = 7.2 Hz, 1H), 4.91 (m, 1H), 4.68 (m, 1H), 4.47- 10 4.43 (m, 2H), 4.40 (m, 1H), 3.81 (s, 3H), 3.74-3.72 (m, 4H), 3.25 (d, J = 4.8 Hz, 1H ), 2.99 (m, 1H), 2.91(d, J = 4.8 Hz, 1H), 2.51 (m, 4H), 1.74-1.63 (m, 4H), 1.61 (m, 5H), 1.53(s, 3H) , 1.33 (d, J = 6.9 Hz, 3H), 1.28- 1.20 (m, 3H).

A(MH) Detected 084.7 “C30H44N408 L 05 (EI) 0 ye Example (S)-N-((S)-3-Cyclopentyl-1—((R)-2-methyloxiran-2) -yl)-1-oxopropan- ‏-)-3-(El-2 3-hydroxy-4-methylphenyl)-2—((S)-2-(2-

Add morpholinoacetamido)propanamido)prop- anamide (C-1117) 9 LN et gg LOR NY - 0: 8 NTC 1 1 0 5 A Pr LN - PEL Ca mols oe 0 ri b YT Ove A L - HATU, DIEA [7] a Ey i A I H R A DMF M 00 HRT s Lo . ONO a SN MA LOH, THE 1. H { Lud A M [a Ho, PAC, MeOH 2 .wd bd - “N sa b > note a a bar oy Ho : 1 8 a 4 HATE THES, DMF 1 = .3 mM hd N OH Na TFA A 1 2-amino-3-(3—(benzyloxy)—-4- all frame 008-(5) dissolved methylphenyl)propanoate (DMF salt (Js Jk Y,0 (TFA )© mL) and © added (S)-2—-(2-morpholinoacetamido)propanoic acid) 1.70 g 0.1 mV,8Y) HATU (Use g; 7.71 mmol); 0.1 (DIEA mL) at 0°Lge with stirring. The reaction mixture was left to warm to ambient temperature and stirred for ? hours. EtOAc (ald 001) and water (001 mL) were added. The aqueous phase was extracted with EtOAc (vv) mL x 7 (mL) and the combined organic phases were washed with brine (ov) mL * (V0 0). drying over anhydrous sodium sulfate, and concentration. 4-methylphenyl)-2—((S)-2-(2-morpholinoacetamido) ),Y) propanamido)propanoate g” 90,697 toll). (S)-Methyl 3-(3—(benzyloxy)-4-methylphenyl)-2—((S)-2-(2- morpholinoacetamido) propanamido)propanoate Yo (, g; 7,4) was treated ‎Ae mol)

-641?- using a solution of lithium hydroxide (You) H20-mg; A Y, mmol) in water/THF 10 (milliliter/01 milliliter) 70 sad minutes. THE was removed and the aqueous phase was acidified to —V=pH ; using 1 p HCL and then concentrate to dryness to obtain -3)-3-(5) (benzyloxy)-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido)prop - anamido)propanoic acid ©; Bale was used without further purification. m Dissolve the crude compound (S)-3—(3—(benzyloxy)-4-methylphenyl)-2—((S)-2-(2— morpholinoacet-amido)propanamido)propanoic acid in 01) MeOH (mL) and then add YN (Pd/C 0.1 g). Then the suspension was stirred in Ja hydrogen atmosphere at ambient temperature for 11 hours. The 0/50 was separated by filtration and washing with MeOH (0 mL). The filtrate, washes and concentrate were combined to dryness. (S)-3-(3-Hydroxy—-4-methylphenyl)-2-((S)-2-(2- morpholinoacetamido)propanam- ido)propanoic acid was dissolved in DMF (mL) ) and added (S)—2-amino-3-cyclopentyl-1-((R)~2-methyloxiran—2-yl)propan-1- 6 h (TFA 80 + g; 0, 1 mL HATU (Je)10 + g; 0.5 mmol) DIEA 1 (*, .mL) at 0 °C with stirring. The reaction mixture, Bad, was left to ambient temperature and stirred for 1 sad hours. EtOAC (001 mL) and Yoo water (mL) were added and the two layers were separated. The aqueous phase was extracted with (Yo)EtOAc mL (Fx) and the combined organic phases were washed with Brain (04 oF x lil) and dried over anhydrous sodium sulfate; focus. The remaining sald) was purified by flash chromatography column on silica gel (1:01:0 = DCM/EtOAC/MeOH) 0 to yield: (S)-N=((S)-3-cyclopentyl-1 -((R)-2-methyloxiran-2-yl)~1-oxopropan-—‏ (3—hydroxy—-4-methylphenyl)-2—((S)-2-(2- --3- (L-2 Yoo)morpholinoacetamido)propanamido)propanamide mg; 97011 three-step yield).

—Yyo-— 1H NMR (300 MHz, DMSO-d6): & 9.06 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.75 (d , J = 7.5 Hz, 1H), 6.89 (d, J = 7.8

Hz, 1H), 6.61 (s, 1H), 6.53 (d, J = 7.2 Hz, 1H), 4.51-4.39 (m, 1H), 4.30-4.15 (m, 2H), 3.69-3.61 (m, 4H) , 3.17 (d, J = 5.4 Hz, 1H), 3.00 (d, J = 5.1 Hz, 1H), 2.90-2.81 (m, 3H), 2.42-2.30 (m, 4H), 2.04 (s, © 3H) , 1.91-1.42 (m, TH), 1.41 (s, 3H), 1.30-1.02 (m, 6H).

The following compounds were synthesized in a similar way: (S)-N=((S)-3-cyclopentyl-1-((R)-2) -methyloxiran—-2-yl)-1-oxopropan—2- yl)-3—- (3,4-dihydroxyphenyl)-2—-((S)-2—-(2- 0 morpholinoacetamido) propanamido)propanam-ide (C-1039): 1H NMR (300 MHz, DMSO-d6): 6 8.69 (s, 1H), 8.63 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H) , 8.01 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 6.3 Hz, 1H), 6.55- 6.65 (m, 2H), 6.45 (m, 1H), 4.45 (m, 1H), -4.20 4.40 (m, 2H), 3.60 (m, 4H), 3.18 (m.1H), 3.05 (m, 1H), 2.90 (m, 2H), 2.80 (m, 1H), 2.40 (m, 0 4H), 1.95 (m, 1H), 1.50-1.85 (m, 7H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H). (MH) over, . Detected (C29H42N4087 for MS(EI)

N-((R)-1-(((S)~1-(((S)—-3—cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-

OXOpro— pan—-2-yl)amino)-3—(3-hydroxy-4-methoxyphenyl)-1- 0 oxopropan—2-yljamino)-1-ox— opropan—-2-yljtetrahydro-2H-pyran-4 - carboxamide (C-1061): 1H NMR (300 MHz, DMSO-d6): 6 8.77 (br s, 1H), 8.22 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H) ), 7.93 (d, J = 6.9 Hz, 1H), 6.75 (d, J = 8.4

11-

Hz, 1H), 6.64 (s, 1H), 6.57 (d, J = 8.1 Hz, 1H), 4.39 (m, 1H), 4.27 (m, 1H), 4.18 (m 1H), 3.82 (s, 3H) , 3.22-3.43 (m, 3H), 3.01 (d, J = 5.4 Hz, 1H), 2.88 (m, 1H), 2.51 (m, 1H), 2.40 (s, 2H), 1.41 (s, 3H), 1.13-1.98 (m, 15H), 0.99 (d, J = 6.9 Hz, 3H).

A(MH) ove, ¢ detected (C30H43N308 IMS (EI) ©

N-((R)-1-(((S)~1-(((S)—-3—(cyclopent-1-en-1-yl)-1-((R)-2- methyloxiran—2 -yl- )—1—oxopropan-2-yljamino)-3—(3-hydroxy—4- methoxyphenyl)-1-oxopropan-2-yl)a-mino)—1-oxopropan-2- yhtetrahydro-2H-pyran -4-carboxamide 1H NMR (300 MHz, DMSO-d6): § 8.70 (s, 1H), 8.24 (d, J = 7.2 Hz, 0 1H), 8.01 (d, J - 7.2 Hz, 1H), 7.87 ( d, J = 7.5 Hz, 1H), 7.12 (d, J = 8.4

Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.63 (m, 1H), 6.58 (d, J = 8.7 Hz, 1H), 5.42 (s, 1H), 4.52 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 3.81 (m, 2H), 3.71 (s, 3H), 3.31-3.23 (m, 3H), 3.00 (m, 1H), 2.94 (m, 1H) , 2.50 (m, 2H), 2.24 (m, 4H), 1.83 (m, 2H), 1.80 (m, 4H), 1.38 (s, 3H), 0.97 (d, 0

J = 6.9 Hz, 3H).

Detected A(MH) 077,4 «C28H41IN3O7 for MS (El) (S)-N=((S)-3—(cyclopent-1-en-1-yl)~1-((R) -2-methyloxiran-2-yl)-1- oxopropa— n—2-yl)-3—(3-hydroxy—4-methylphenyl)-2—((S)-2-(2- morpholinoacetamido)propa— namido ) propanamide (C-1129): Yep. 1H NMR (300 MHz, DMSO-d6): & 9.08 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 7.8

Hz, 1H), 6.61 (s, 1H), 6.53 (d, J = 7.2 Hz, 1H), 5.76-5.74 (m, 1H), 4.50-4.40 (m, 2H), 4.29-4.21 (m, 1H) , 3.57-3.54 (m, 4H), 3.35 (s, 1H),

-?11/- 3.19 (d, J - 5.1 Hz, 1H), 3.00-2.72 (m, 5H), 2.58-2.10 (m, 10H), 1.79- 1.39 (m, 2H), 1.39 (s, 3H ), 1.15 (d, J = 6.9 Hz, 3H).

A(MH) 00/7. . Detected “C30H42N407 for MS(EI) (S)-N=((S)-3—(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran—-2) -yl)-1- oxopropan-— —2-yl)-3—(3-hydroxy—-4-methylphenyl)-2—-((S)-2—-(2-© morpholinoacetamido)propan—amido)propanamide (C-1130): 1H NMR (300 MHz, DMSO-d6): & 9.08 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 7.8

Hz, 1H), 6.61 (s, 1H), 6.53 (d, J = 7.2 Hz, 1H), 5.77 (m, 1H), 4.40-4.50 (m, 2H), 4.25 (m, 1H), 3.55 (m , 4H), 3.19 (m, 1H), 3.00 (m, 1H), 2.80- 0 3.00 (m, 3H), 2.70 (m, 1H), 2.30 (m, 4H), 2.20 (m, 1H), 1.80 -2.10 (m, 5H), 1.50-1.70 (m, 4H), 1.37 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H).

Detected A(MH) oA, Yo «C31H44N407 of 1/15 (EI) (S)-N-((S)-3—(Cyclopent-1-en—1-yl)-1—((( R)-2-methyloxiran-2-: Yo Ex. yl)—1-oxopropan-— —2-yN)-2—((S)-2-(2—(4-hydroxypiperidin-1- 10 yl) )acetamido)propanamido)-3—(4-me~ thoxyphenyl)propanamide (C- 1118)

H 0 A 0 XL">. 0 M 0”> 0 OMe HAA A - 5

NH HATU, NMM, DCM ROW

HO. 1. Ha, Pd/C, MeOH TAA, [ f 2. HATU, DCM, NMM H 0 : B 0 8 TFA 0

HoN0

0C1?- to a solution of can +, 83) 2—(4-hydroxypiperidin—1-yl)acetic acid 7.1 mmol) and (S)-benzyl 2—((S)—2— (-aminopropanamido)—3—(4- methoxyphenyl)propanoate (salt (HCI 57 g; 7.1 mmol) in dichloromethane (Vo) mL) at 0°C (1,000) was added HATU g; 7.4 mmol) follows © that for 1-methylmorpholine (1.00 Ale 04 μmol). The lad reaction mixture was left to ambient temperature and stirred for 1 hour. water (Yo) mL) was added and the resulting mixture was extracted with dichloromethane (Yo) mL “). 1) The organic extracts were collected; drying over anhydrous sodium sulfate; focus. The residue was purified by flash chromatography column on silica gel (petroleum ether/dichloromethane = 1 0 to 1 : 1) to yield (S)-benzyl 2—((S)-2-(2— (4-hydroxypiperidin-1- 0 V,V) yl)acetamido)propanamido)-3—(4-methoxyp— henyl)propanoate g %AY yield) as a colorless solid. A mixture of: (S)-benzyl 2-((S)—2—(2—(4-hydroxypiperidin—1- yl)acetamido)propanamido)-3—(4-methoxyp— henyl)propanoate yo was hydrogenated )+ ,+ g 0 mmol) Pd/C, ) ),+ g) in methanol (Yo) in milliliters) for 1 hour at ambient shall degrees. 0/20 was separated by filtration and the filtrate was concentrated. The residue was dissolved in dichloromethane (Yo) (mL) followed by the addition of -2-80100-3-(5) ne -10030-1-0m (A8-2-7 in frame 2-008- (a)) -1-(EL-0100601-1-80-1No6) (Yeo salt (TFA Yo g; 0.17 mmol) 5 HATU) 80 g; 0.1 mmol). N-methylmorpholine (A VA can 2,7) Methylmorpholine mol) was added to the solution at 0° Aggie The reaction mixture ad was left to ambient temperature and stirred for 1 hour. (Lille Yo) el) dl) and the resulting mixture was extracted with (Y +) dichloromethane mL (VX). The organic extracts were collected; drying over YO anhydrous sodium sulfate. and concentrate.The residue was purified

-?1- dichloromethane by flash chromatography column on silica gel ((5(-11-))5(-dichloromethane) prepared for TLC, (80:1 to 0010:1 = methanol) Methanol 3—(cyclopent-1-en—1-yl)-1—(((R)-2-methyloxiran—2-yl)- 1-oxopropan— 2-y1)=2-((S)—2 -(2—(4-hydroxypiperidin—1 -yl)acetamido)propanami- do)- mg; 9077 toll). , 1H), 7.71 (br.s, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4

Hz, 2H), 5.40 (s, 1H), 4.58 (br.s, 1H), 4.52-4.41 (m, 2H), 4.32-4.26 (m, 1H), 3.70 (s, 3H), 3.49-3.35 ( m, 1H), 3.34 (s, 1H), 3.18 (d, J = 5.1

Hz, 1H), 2.98 (d, J = 5.1 Hz, 1H), 2.92-2.72 (m, 3H), 2.63-2.35 (m, 0 5H), 2.29-1.91 (m, 7TH), 1.85-1.70 (m , 4H), 1.38 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H). +(MH) Detected 585.7 “C31H44N407 for MS(EI) The following compounds were synthesized in a similar way: (S)-N—((S)-3-cyclopentyl-1—-((R)-2) -methyloxiran—2-yl)-1-oxopropan-2- 1 Hazala 2 -- ((8)-2-(2-(3,3—difluoropyrrolidin—1-yl)acetamido)propanamido)— 3—( 4-methoxy— phenyl)propanamide (C-1048): 1H NMR (300 MHz, CDCI3): § 8.27 (d, J = 6.9 Hz, 1H), 7.97 (d, J = 7.2

Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.1 Hz, 2H), 4.30 (m, 1H), 4.27 ( m, 1H), 3.71 (s, 3H), 3.17 (d, J = 5.1 0

Hz, 1H), 3.10 (m, 2H), 2.90 (m, 2H), 2.77 (m, 2H), 2.70 (m, 2H), 2.23 (m, 2H), 1.85 (m, 2H), 1.61-1.49 (m, 7TH), 1.45 (s, 3H), 1.15 (d, J = 6.9

Hz, 3H).

A(MH) 047.4 Detected «C30H42F2N406 for MS(EI)

-Y\«= (S)-N=((S)-3-cyclopentyl-1-(((R)-2-methyloxiran—-2-yl)-1-oxopropan—2- yl)=3—~ ( 4-methoxyphenyl)-2—~((S)-2—(2~(4—(trifluoromethyl)piperidin—1- yl)acetamido—- )propanamido)propanamide (C-1047): 1H NMR (300 MHz, CDCI3) ): § 7.13 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.4

Hz, 2H), 6.75 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 4.60 (m, © 1H), 4.58 (m, 1H), 4.51 (m, 1H) , 3.94 (s, 2H), 3.79 (s, 3H), 3.27 (d, J = 4.8 Hz, 1H), 3.00 (m, 3H), 2.97 (m, 4H), 2.18 (m, 3H), 2.18 ( m, 3H), 1.90 (m, 3H), 1.72-1.68 (m, 5H), 1.52 (m, 3H), 1.39 (d, J = 6.9 Hz, 3H), 1.44-1.27 (m, 3H).

A(MH) 174, L 03211457311406 discovered MS(El) 0 (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl)-1- oxopropan—2- yl)-2-— ((8)-2-(2-(4,4—difluoropiperidin—1-yl)acetamido)propanamido)- 3—(4-methoxyp— henyl)propanamide (C-1046 ): 1H NMR (300 MHz, CDCI3): § 7.13 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.4

Hz, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 4.59 (m, 10 1H), 4.57 (m, 1H), 4.48 (m, 1H) , 3.79 (s, 3H), 3.25 (d, J = 5.1 Hz, 1H), 3.04-2.91 (m, 3H), 2.90 (m, 2H), 2.63-2.59 (m, 4H), 2.02 (m, 4H ), 1.98 (m, 1H), 1.70 (m, 4H), 1.64 (m, 3H), 1.52 (m, 5H), 1.37 (d, J = 6.9

Hz, 3H), 1.27 (m, 1H), 1.25 (m, 1H).

Detected A(MH) 010.4 “C31H44F2N406 for MS(EI) 0 (S)=2-((S)—2—-(2-(4-chloropiperidin—1-yl)acetamido)propanamido) -N- ))5(-3-6- yclopentyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan—2-yl)—- 3—(4-methoxypheny— l)propanamide (C-1045):

-?71- 1H NMR (300 MHz, CDCI3): 6 7.13 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.4

Hz, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 4.59 (m, 1H), 4.57 (m, 1H), 4.48 (m, 1H), 4.13 (m, 1H), 3.78 (s, 3H), 3.26 (d, J = 5.1 Hz, 1H), 3.02-2.97 (m, 3H), 2.90 (m, 2H), 2.73 (m, 2H), 2.42 (m, 2H), 2.09 (m, 2H), 1.92 (m, 4H), 1.87 (m, 4H), 1.73 (m, 4H), 1.52 (m, H03H), 1.41 (d, J = 6.9 Hz, 3H), 1.38 (m, 1H), 1.36 (m, 1H).

Detected A(MH) 005.4 “C31H45CIN4O6 for MS(EI) (S)-N=((S)-3-cyclopentyl-1-((R)-2-methyloxiran—-2-yl) -1-oxopropan—2- Hazala 2 -- ((8)-2-(2-(3,3—difluoropiperidin—1-yl)acetamido)propanamido)- 3-(4-methoxyp— henyl)propanamide ( C-1043: Yu 1H NMR (300 MHz, CDCI3): § 7.13 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.4

Hz, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 4.60 (m, 1H), 4.58 (m, 1H), 4.39 (m, 1H), 3.94 (s, 2H), 3.79 (s, 3H), 3.27 (d, J = 4.8 Hz, 1H), 3.00 (m, 4H), 2.90 (m, 2H), 2.88 (m, 2H), 2.50 (m , 2H), 1.94 (m, 2H), 1.89 (m, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.51 (s, 3H), 0 1.37 (d, J = 6.9 Hz, 3H ), 1.36-1.27 (m, 4H).

Detected A(MH) 4,000 “C31H44F2N406 for MS(EI) (R)=N=((R)=1—(((S)-1-(((S)-3-cyclopentyl- 1—(((R)-2-methyloxiran—2- yl)~1-ox~- opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)-1-oxopropa — n—-2-yl)tetrahydrofuran-3-carboxamide (C-1036): 0 1H NMR (300 MHz, DMSO-d6): 6 8.23 (d, J = 6.9 Hz, 1H), 8.07-8.11 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.55 (m, 1H), 4.33 (m, 1H), 4.20 (m, 1H), 3.80 ( m, 1H), 3.75 (s, 3H), 3.55-3.75 (m, 2H), 3.22 (d, J = 4.8 Hz, 1H), 2.90-3.10 (m, 3H), 2.65 (m, 1H),

—YYY- 1.80-2.05 (m, 3H), 1.50-1.80 (m, 7TH), 1.42 (s, 3H), 1.00-1.30 (m, 2H), 0.96 (d, J = 6.6 Hz, 3H).

A(MH) 0 44.0 Detected «C29H41N3OT for MS(EI)

N-((R)-1-(((S)~1-(((S)—-3—cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-

OXOpro— pan—2-yl)amino)-3—(4-methoxyphenyl)-1-oxopropan-2- 0 yl)amino)—1-oxopropan—2—- yl)tetrahydro—2H-pyran—4-carboxamide ( C- 1028: 1H NMR (300 MHz, CDCI3): 6 7.11 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 4

Hz, 2H), 6.65 (m, 1H), 6.52 (m, 1H), 6.29 (m, 1H), 4.64 (m, 1H), 4.52 (m, 1H), 4.40 (m, 1H), 4.03 (d , J = 3.3 Hz, 1H), 3.99 (d, J = 2.7 Hz, 1H 0), 3.80 (s, 3H), 3.40 (m, 2H), 3.28 (d, J = 5.1 Hz, 1H), 3.04 ( m, 2H), 2.89 (m, 1H), 2.42 (m, 1H), 1.80-1.75 (m, 6H), 1.68 (m, 4H), 1.55 (m, 5H), 1.30 (d, J = 6.9 Hz , 3H), 1.20 (m, 2H), 1.06 (m, 1H).

A(MH) 028,16 detected «C30H43N307 of MS (El)

N=((R)-1-(((S)-1-(((S)-3-cyclopentyl-1—((R)-2-methyloxiran-2-yl)-1-1m)

OXOpro— pan—-2-yl)amino)-3—(4-methoxyphenyl)-1-oxopropan—2- yl)amino)-1-oxopropan-2-- yl)-3-oxocyclobutanecarboxamide (C- 1029): 1H NMR (300 MHz, CDCI3): § 7.12 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.7

Hz, 2H), 6.49 (m, 3H), 4.66 (m, 1H), 4.52 (m, 1H), 4.40 (m, 1H), 3.81 0 (s, 3H), 3.45-3.43 (m, 3H), 3.30-2.92 (m, 5H), 2.92 (m, 2H), 1.98 (m, 4H), 1.74 (m, 6H), 1.33 (d, J = 6.6 Hz, 3H), 1.30 (m, 2H), 1.26 (m, 1H).

A(MH) 0 47.6 Detected (C29H39N3OT for MS (El)

—Yyy- (S)-N—-((R)-1-(((S)—-1-(((S)—-3—cyclopentyl-1—((R)—-2-methyloxiran—2 -yl)~1-ox~- opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)-1-oxopropa— n—-2-yl)tetrahydrofuran-2- carboxamide (C-1031): 1H NMR (300 MHz, DMSO-d6): 6 8.33 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.57 (d,J = 7.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, J0

J = 8.4 Hz, 2H), 4.50 (m, 1H), 4.15-4.40 (m, 3H), 3.70-3.90 (m, 2H), 3.71 (s, 3H), 3.20 (d, J = 5.1 Hz, 1H ), 2.90-3.10 (m, 2H), 2.65 (m, 1H), 2.10 (m, 1H), 1.50-1.90 (m, 10H), 1.41 (s, 3H), 1.00-1.30 (m, 4H), 0.99 (d, J = 6.6 Hz, 3H).

A(MH) © 4 4,0 Detected (C29H41IN3OT7 IMS(El) 0 (R)=N=((R)=1—(((S)-1-(((S)-3-cyclopentyl- 1—(((R)-2-methyloxiran—2- yl)~1-ox~- opropan-2-yljamino)-3-(4-methoxyphenyl)-1-oxopropan-2- yl)amino)—1-oxopropa — n—2-yl)tetrahydrofuran—2 carboxamide (C-1032): 1H NMR (300 MHz, DMSO-d6): 6 8.33 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.60 (d,J = 7.5 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.79 (d, 0

J = 8.4 Hz, 2H), 4.50 (m, 1H), 4.15-4.40 (m, 3H), 3.70-3.90 (m, 2H), 3.71 (s, 3H), 3.20 (d, J = 5.1 Hz, 1H ), 2.90-3.10 (m, 2H), 2.65 (m, 1H), 2.10 (m, 1H), 1.50-1.90 (m, 10H), 1.41 (s, 3H), 1.00-1.30 (m, 4H), 0.99 (d, J = 6.6 Hz, 3H).

A(MH) © 4 4.0 Discovered (C29H41IN3OT7 IMS(El) 0 11 Example)

—YYi- (28,3R)=N—((S)-1—(((S)-3—(Cyclohex-1-en-1-yl)-1-((R)-2- methyloxiran—2 -yl)-— 1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yl)-3-hydroxy—-2-- (2-morpholinoacetamido)butanamide (C- 1148) pe fede 1 14 >. Asthik Amal ERE 5 ny Mother JERE SENT EDIT EAM 1 ALA M A A

HN SOM and dab hi m 00 1. Ha, PAC

THAT AH

A - oo NE LASP TER { NE Asn on Um 0 Amik ee A A A Tn Bose ye JE ry

Ii A a "0 1 b l (correctly correct lo } mol) to a solution of ?-morpholinoacetic acid (Ae You) g; HATU (2S,3R) was added -methyl 2—amino— mmol) aa V8 3 morpholinoacetic acid mmol) in dichloro YA g; dap ie ae (lll Yi) fe to Bad mmol) and the reaction mixture was left for 0.8 an 0.1) Methylmorpholine AD hr. The mixture was concentrated and the residue was purified by column 1 temperature Surrounding and stirring for methanol/dichloromethane scintillation chromatography on silica gel (dichloromethane (28,3R)-methyl 3-hydroxy-2- to obtain 1:110 to 1:001 = methanol) yield). VV 0 g (Yo)morpholinoacetamido)butanoate h at 1 g; 7.6 mmol) for LIOH-H20 (VY mL/©mL) using concentrate and then HOE at ambient temperature. The mixture was neutralized to a pH of -7 using T.T Concentrate to the point of dryness

E11" The residue was added to a solution of 4 -060-068-080 (TFA zk) d g VY mM YT can (0.1 HATU (Use mmol) in dichloromethane Yo ) milliliters). The mixture and the remaining © were purified by a flash chromatography column on a silica gel (dichloromethane/methanol = +: 1 to 1:01) to obtain: (S)-benzyl 2-((28,3R) -3-hydroxy-2-(2- morpholinoacetamido)butanamido)-3-(4-methoxyphe— nyl)propanoate )+0 g; 9677 yield).0 solution of (S)-benzyl 2- ((28,3R)-3-hydroxy-2-(2- morpholinoacetamido)butanamido)-3-(4-methoxyphe— nyl)propanoate (0.0 g; 01 mmol) in 01 methanol (mL) was stirred under a hydrogen atmosphere in the presence of Pd/C (+ g) for 1 hour at ambient temperature. The 0/20 was filtered and the filtrate was concentrated to dryness. residue to a mixture of tert-butyl ((S)-3—(cyclohex—-1-en—1- carbamat e -(EL-1-0*0010080-2-(EL-060180-2 EL2-00281-(4A))-1-(ELA (0.1 aa 77 salt (TFA mmol)) 5 HATU ) 87+ g; 01 millimoles) in 01 DCM (milliliter). —N methylmorpholine (£7 + 0, mmol fille) was added to the solution at 0°C. The reaction mixture ad was left to ambient temperature and stirred for 1 hour. Water (Yo) was added (mL) and the resulting mixture was extracted with (Vo) EtOAC (mL) (Fx) Organic extracts were collected; drying over anhydrous sodium sulfate Sly The residue was purified by flash chromatography column on silica gel ( Dichloromethane/methanol - 1 to 1 : 071 to get (28,3R)=N—((S)-1-(((S)—-3—(cyclohex—-1-) en—1-yl)-1-((R)-2-methyloxiran—2-yl)~ —1-oxopropan-2-yljamino)-3

(4-methoxyphenyl)—1-oxopropan-2-yl)-3-hydroxy-2- -)2- (YV+) morpholinoacetamido)butanamide 9548 mg yield). 1H NMR (300 MHz, DMSO-d6): 6 8.28 (d, J = 7.2 Hz, 1H), 7.93 (d, J = Hz, 1H), 7.63 (d, J = 4.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.76 (d, 8.4 E J = 8.4 Hz, 2H), 5.77 (s, 1H), 5.40 (m, 1H), 5.02 (d, J = 5.1 Hz , 1H) (m, 2H), 4.19 (m, 1H), 3.95 (m, 1H), 3.70 (s, 3H), 3.55 (m, 4H), 4.51 (d, J = 5.1 Hz, 1H), 2.95 m, 2H), 2.89 (m, 2H), 2.65 (m, 1H), 2.39 3.21 (m, 3H), 2.23 (m, 1H), 1.78-2.09 (m, 5H), 1.56 (m, 4H), 1.37 (s, 3H), (d, J = 6.0 Hz, 3H).0.95 A+(MH) 117 32114601408 1 MS (EI) 0 The following compounds were synthesized in a similar way: (28,38)-N—((S)-1-(((S)-3—(cyclohex-1-en-1-yl)-1-((R)-2- methyloxiran—2- yl)—- —1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yl)-3-hydroxy-2- —(2-morpholinoacetamido)butanamide (C-1150): yo 1H NMR (300 MHz, DMSO-d6): 6 8.21 (d, J = 6.9 Hz, 1H), 8.10 (d, J = Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, 8.4 J = 8.4 Hz, 2H), 5.76 (s, 1H), 5.39 (m, 1H), 4.99 (d, J = 4.5 Hz, 1H), (m, 2H), 4.25 (m, 1H), 3. 79 (m, 1H), 3.70 (s, 3H), 3.54 (m, 4H), 4.50 (d, J = 5.1 Hz, 1H), 2.89 (m, 4H), 2.64 (m, 1H), 2.37 (m, 3H), 2.21 0 3.21 (m, 1H), 2.03 (m, 5H), 1.56 (m, 4H), 1.37 (s, 3H), 0.97 (d, J = 6.3 Hz, 3H MS (El) of “C32H46N408 detected A(MH) hve, Y.”

—YYy- (28,38)-N—((S)-1-(((S)-3—(cyclohex-1-en-1-yl)-1-((R)-2- methyloxiran—2 -yl)—- —1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yl)-3-hydroxy-2 —(2-morpholinoacetamido)butanamide (C-1149) ): 1H NMR (300 MHz, DMSO-d6): 6 8.21 (d, J = 6.9 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.7 Hz , 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d,

J = 8.4 Hz, 2H), 5.39 (m, 1H), 4.99 (d, J = 4.5 Hz, 1H), 4.50 (m, 2H), 4.25 (m, 1H), 3.79 (m, 1H), 3.70 ( s, 3H), 3.54 (m, 4H), 3.21 (d, J = 5.1

Hz, 1H), 2.89 (m, 4H), 2.64 (m, 1H), 2.37 (m, 4H), 2.21 (m, 1H), 2.03 (m, 5H), 1.56 (m, 4H), 1.37 (s) , 3H), 0.97 (d, J = 6.3 Hz, 3H). 0

A(MH) hve, Y detected “C32H46N408 for MS (El) synthesis procedure--fragments

VY Example tert—Butyl ((28)-3-(3—-methylcyclopent-1-en-1-yl)-1-((R)-2- methyloxiran-2-y- |)~1- oxopropan-2-yl)carbamate yo a” $a, WoO© : or iy Ba 0 @ A Hy 3

Eye Hho == Or =r 1 85 Mutaqarqah (M2 by 3 A) Abkhala and Hay Taq yo Yaqo JN - 7 Mq Als 1. Mart Algha 1: ey L 3 oro t 7 1-1 for b

SEAN Mahsis Shit Melb 1 REE oo 1 Boo" a's a Jomt COOH 8

—YYA-

A mixture of (TV) methyl 2--oxocyclopentanecarboxylate g was heated; EY , + mol); VY) K2CO3 g 0.08 mol) 5 0.08 can 11970 ( Mel mol) in acetone (00 * milliliters) under the return of VY sad h. The mixture was cooled to ambient temperature and then concentrated. The residue was dissolved in EtOAC (Avo mL) and the resulting solution washed with saturated aqueous ©NaHCO3 (004 mL (Fx and Brian Yoo) x 1 mL); drying over anhydrous sodium sulfate; concentration to the point of dehydration. The residue was purified by distillation to yield the DAY aa (1,0 methyl 1-methyl-2-oxocyclopentanecarboxylate yield). “xa 1), +) methyl 1-methyl-2-oxocyclopentanecarboxylate 1 mol) was added dropwise to a freshly prepared solution of (Use +,YA) NaOMe in 1 (MeOH L) at 0° ambient temperature. The solution was heated under reflux for ? hours and then focus. The residue was dissolved in 1 toluene (1 L toluene) and the resulting solution was heated under reflux for ½ hours. The mixture was cooled to ambient temperature; washing with saturated aqueous NaHCO3 (044 mL (FX and Brian Vou) 7 mL 1); drying over anhydrous sodium sulfate; concentration to the point of dehydration. The residue was purified by distillation to obtain -3 methyl

V4, +) methyl-2-oxocyclopentanecarboxylate yo g 9014 yield). (Use 710 aa 4,94) NaBH4 was added in parts to a solution of methyl ?-methyl-?-oxocyclopentane carboxylate (£7,000 g; 177 mol) in MeOH (mL) at 0 °C The reaction mixture (Bad) was left to ambient temperature and stirred for ½ hours The reaction was quenched with saturated aqueous NHACT (ovr (mL) and the resulting mixture (0) was extracted with (You) EtOAc (mL) x #).The combined organic phases were washed with 7 mL brine oY and dried over anhydrous sodium sulfate; concentrate to obtain methyl

Y¢,+) 2-hydroxy-3-methylcyclopentanecarboxylate g). Et3N (95 µmol ),¥ mol) 5 (Y,09) DMAP g added; 7011 mmol) was then reduced to a solution of ¥v,o)methyl 2-hydroxy-3-methylcyclopentanecarboxylate YO (1.71 mol) in Av (CH2CI2 mL) at 0°C. It was then added

1.85 “plik (10.7 MsCl) mol) by distillation over 1 Jae h. The reaction mixture was stirred at zero degrees Lge for 1 hour and then left to warm to ambient temperature and stirred for hours. Water (00ml) was added and the two layers were separated. The organic layer was washed with 1 aqueous HCI (p; Yeo mL x ¥ (¢ 1801003 saturated aqueous Yoo) mL oF x and Bryan Yeu) 0 mL x 1); straight. The organic solution was dried over LLY sodium sulfate and the concentrate to dryness.

The remaining sald was dissolved in 112012 Te (mL) and cooled to 0 °C. A solution of «jill ©, (DBU 77, + mol) was added in 112012 (001 milliliters) by droplet. The reaction mixture was left to warm to ambient temperature and stirred overnight. Yoo water (ald Ve) was added and the two layers were separated. Jue organic layer was quenched with 1) Sl HOE p; Yeu mL NaHCO3 (YX saturated aqueous 00) 7 mL of VX and Bryan (Ye) x 1 milliliters), respectively. The organic solution was dried over AY sodium sulfate and concentrated to dryness. The residue was distilled purified to give methyl 3—methylcyclopent—]1-enecarboxylate ‏

(aa 15.7(9077 yield in three steps).15 LIAIHA suspension of VE) 15 g refrigerated; 0900 mol) in The Yeo (milliliter) to zero degrees in Jb nitrogen. A solution of methyl 3-methylcyclopent—1- 1011686 g was added; Ak 171 mol) in (Yo) THE milliliter) by distillation. The reaction mixture was left to ambient shall and stirred for ½ hours. The reaction was quenched with water (7.4 mL); 9695 aqueous NaOH (7.4 milliliters) and water (77.7 milliliters) Yo carefully. The resulting mixture was filtered and washed with THF (100 mL L (V x filtrate and wash products, SE, were combined to Glial to yield crude compound -3)

YA) methylcyclopent-1-en—1-yl)methanol g) in the form of oil. A) Phosphorous tribromide m AY ¢ pile mmol) was added to a solution of (YA,0)(3-methylcyclopent-1-en—1-yl)methanol g 111 mL ( Je YO in [Yoo (20 milliliters) at -01°C with stirring. The mixture was cooled until warm

Is day the ambient temperature and stirring for a period of ? hours. The reaction was quenched using 100 (mL) ice-water. the organic phase was separated; washing with saturated aqueous 1811003 (001 milliliters * ) and Bryan (1 700 milliliters); drying over anhydrous sodium sulfate; and concentration to dryness to obtain the corresponding bromide (4.0 5 g). © Potassium tert-butoxide added (11.9 g; 09 mol) in parts to a solution of 017 aa 759.7( diethyl 2-acetamidomalonate mol) in (bile Veo) DMF although the temperature was kept below 10°C. After the addition is completed; Bad Glad) was stirred 1.5 hours at 01°C and bromide (0) (p>YE,) was added by drop. The reaction mixture was stirred for 10 hours at ambient temperature and 00 water was added. (000 milliliters). The resulting mixture was extracted using 6/10 (000001) milliliters L (Y x Jue). The combined organic phases were extracted using saturated aqueous NaHCO3 (044) (Y x lll 965 aqueous KHSO4 044) mL oF x and Bryan Ye) mL x 1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography column on silica gel (hexanes/compounds 10/6 = 1:01 to get Diethyl 2-acetamido-2-((3—-methylcyclopent-]1-enyl)methyl)malonate yo PTY can YEE yield). Diethyl 2-acetamido-2—-((3-methylcyclopent-1- 021006) (a©0(a0© (4,;7) (se ©0011 cpa) mL) was dissolved in Yoo ethanol) and added 1 NaOH (aqueous all Yeu) 6.7 mol). The solution was heated under reflux Asad Yo for hours and then cooled to ambient temperature. The organic solvent was removed and the remaining AW solution was washed with diethyl ether (00 mL (Vox) and acidification with 1 p-Sl hydrochloric acid to pH = ?. The resulting mixture was extracted using (Yoo) EtOAc x 1 mL) and the combined organic phases were washed with Brain Yo) mL o() X and dried over anhydrous sodium sulfate; concentrate to dryness.

The residue was suspended in water (00 mL) and NaOH (Mani 1(p) was added dropwise to adjust to pH = 7.5. The mixture was stirred for Te min at TV °C and then filtered. L—L acylase (1.5 g) was added to the filtrate and the mixture was stirred for fv hr at vv°C. The mixture was cooled to ambient temperature and purified with ion exchange resin 001 #7277 (©g) to yield the corresponding +- L-amino acid gud.

A-amino acid was dissolved in water and acetone (1:0 000) and the solution was made basic with 1 p aqueous NaOH to pH = 8. 800620 (+ YY, g) was added; 1 mmol) and the reaction mixture was stirred for VY h at dap ambient temperature. The organic solvent was removed and the remaining (Ald) solution was washed with Ji (Yoo) ethyl ether (mL x Ve) and acidified with 1 p Sk Hydrochloric acid to pH = ?. The resulting mixture was extracted with Yoo (EtOAC x 1 milliliters). The combined organic phases were washed with Brain 100 (mL * 1); dried over anhydrous sodium sulfate; concentration to obtain (2S)-2—(tert-Butoxycarbonylamino)-3—(3- (aa £,A) methylcyclopent-1-enyl)propanoic acid 9017 yield); been used

1 directly without further filtering. Triethylamine (VY) (Ji) lle 5.7 mmol) was added to a suspension of dimethylhydroxylamine hydrochloride (exercise a 49.7 mM (ds and ( 2S)-2—(tert-butoxycarbonylamino)-3-(3- aa 7,1( methylcyclopent-1-enyl)propanoic acid 5.7 mmol) in methylene dichloride 01 ) at 0 °C followed by the addition of EDCI CAN 1.45 (9.7 mmol).The reaction mixture was stirred overnight at ambient temperature and water (Yo) was added (mL). The organic layer was separated and washed with 965 aqueous KHSO4 (mL x 9); saturated aqueous NaHCO3 (04 milliliters oF x and Braine ov) milliliters x 1), respectively. The organic phase was dried over anhydrous sodium sulfate and the concentrate. The remaining material was purified

1 +) = 1:01 EtOAc by a flash chromatography column on silica gel (hexane compounds/corresponding ad Weinreb to obtain fresh isopropenyl lene in ml) and a solution of (04) THF was added. The amide was dissolved in distillation at 0 °C with stirring. THF was stirred in (Use lle VO) magnesium bromide aqueous NHACH reaction mixture at 0 °C for © hours and then quenched with © TAM (Fx 001 mL (EtOAC mL) The resulting mixture was extracted using saturated (001 fv x 001 mL) aqueous KHSO4 965 organic layers combined with Jue respectively. (1 x ©); and Brian (00) Milliliters x milliliters 001 (saturated aqueous NaHCO3 dad gs) Drying the organic phase over anhydrous sodium sulfate and concentration. Then purifying the residue to obtain EtOAc = 1:01 by a flash chromatography column on silica gel (hexane compounds). / 0 yield). - At (ill 00) DMF mmol) in TY can 7.1 (the enone) °C and water (?00 milliliters) was added. -01 hour was done at 1 the reaction mixture was stirred For the organic layers Jue (Fx 001 mL) (0/6) the resulting mixture was extracted using 1 (001) aqueous saturated 21811003 ¢ (¥ x mL) 001 aqueous KHSO4 965 bundled with respectively. The organic phase was dried over sulfate (1 “001 milliliter) and Brian 7 x 7 milliliter flash chromatography column on anhydrous sodium dail gs gel and concentrate. Then the residue was purified: to obtain 1) 10 = EtOAC silica (hexane compounds/ tert-butyl (2S)-3—(3-methylcyclopent-1-enyl)-1-((R)-2-methyloxiran- 0 yield). 90900 cu, 1( -1-0*000080-(except-2 —2-ylcarbamate tert-butyl (28)-3—(3-methylcyclopent-1-enyl)-1—-((R)-2- Done) Synthesize by a similar method starting from methyloxiran-2-yl)—1-oxopropan— E-2- 88068

Add (S)—2~((tert-butoxycarbonyl)amino)-3-(cyclopent-3-en—-]1-yl)propanoic .acid Example tert-Butyl ((S)-1 —((R)-2-methyloxiran-2-yl)-1-oxo-3—((R)- : YA ‎tetrahydrofuran—3- —yl)propan-2-yl)carbamate and tert-Butyl )5 (-1-))(- 2-methyloxiran-2-yl)—-1-oxo-3—((S)-tetrahydrofuran-3-yl) propan-2- 0ylcarbamate NiBo 1 ACHHCH(CODE, 2.5/55 S) Mal Dy P-BUK 3 . If we have 7 a SENS pr OCH Monaro and 1 limited SS license 11 + a7 a < and again oe! NHAg TTT Yd Ae hd + hd MB PRE SA UPS L A CY THD hep asain i NeBior to NMSoo KMBos 2 TT Polarized Wali | v > JEW ae The 3 BonHN hi ~~ Bark a 0 A mixture of Lala (aa 0+) Raney and tetrahydrofuran-3—carbaldehyde 001g was stirred 01 (Sle 969 0 mol) under 0 pH at ambient temperature for VY h. The catalyst was separated by filtration and washed with Yo water (mL). The filtrate and wash products were combined, and the solvent was removed by azeotropic treatment with toluene. The residue was distilled to give I hydro-7-furanmethanol tetrahydro-3—furanmethanol (£0 g) on Bas colorless oil.

-4 pm?

Triethylamine (VY) mL was added; 98 mL (Use to a solution of UE hydro-7-furan

Methanol (AI g + AA mmol) in methylene chloride (Yoo mL) at zero degrees YEP

followed by adding methanesulfonyl chloride (018 aa VY,Y) methanesulfonyl chloride

mol) by distillation. The reaction mixture was stirred at 0 °C for 1 hour and then left to load

Even dap ambient temperature and stir overnight. Aqueous hydrochloric acid 1 (p;

0 ml) and the two layers were separated. The organic layer was washed with 1 P HCl

aqueous ijk Sodium bicarbonate oY x 001 ml ( Sk Hydrochloric acid)

sSodium bicarbonate saturates 001 (7 milliliters); and Bryan 1 (5 milliliters x 1), respectively. 0. of tetrahydro-?-furan methanol.

The mesylate was dissolved in acetone (1 L) and sodium iodide was added

sodium iodide (1.5; g; 1.7 mol). The suspension was heated under reflux overnight. It was completed

Cool the mixture to ambient temperature and filter. The filter paste was washed with cold acetone

) 1 milliliter). The filtrate, wash products and concentrate were collected. 100 (mL) Vo ethyl ether was added to the residue and the resulting precipitate was separated by filtration and washing with 100 (mL) ethyl ether X

The filtrate and wash products were concentrated and the residue was distilled to obtain 7?-(iodo

Methyl)tetrahydrofuran (VV) 3—(iodomethyljtetrahydrofuran g; 76955 yield)

In the form of Cu yellow.

The remainder of the synthesis was carried out in a manner similar to that of tert-butyl (28)-3-(3-methylcyclopent— 1-enyl)~1-((R)-2-methyloxiran-2-yl)-1-oxopropan— -2-ylcarbamate 0

The ash stereochemical formation was done by X-ray crystal formation analysis.

ya example

tert—Butyl ((S)—1-((R)-2-methyloxiran—2-yl)—1-oxo-3—((R)-

tetrahydrofuran-2- -yl)propan-2-yl)carbamate and tert-butyl ((S)-1-

E0+? (((R)—2-methyloxiran—2-yl)—1-oxo-3—((S)-tetrahydrofuran—2-yl)propan— - 2-yl)carbamate Co i abhorrent and complete 1 For ID ewow amet © TY lon m1 AHH Koo Ten J coos sce 1 and shook "to the power of 0 sa A FE m2 IE Tr PY EO TT oe A A AL idl 9 l | | NE D iD BocHN J 8H A 0 0 The synthesis was carried out in a manner similar to that of tert-Butyl ((S)-1-((R)-2-methyloxiran—2-m and 81580816 RAL -2- yl)-1-oxo-3~((R)-tetrahydrofuran-3-yl)propan- tert—Butyl (S)—-1-((R)—2—methyloxiran—-2- yl)—1-oxo0-3—((S)~- ‎tetrahydrofuran-3-yl) propan-2-ylcarbamate and the reduction of (5(- ‎tert-Butyl 3—(furan-2-yl) -1-(methoxy(methyl)amino)—1-oxopropan-2-yl LScarbamate follows: A solution of (S)-tert-Butyl 3—(furan-2-yh-1- AT) (methoxy(methyl)amino)—1-oxopropan—2-yl carbamate | 0 g; YAS mol) in v)ethyl acetate (Ji) .€ mL) Pd/C ) added ¥ 0 , g;(Vr) The mixture was stirred under 1 hydrogen atmosphere (atmospheric) at Av °C overnight and then cooled to room temperature. The mixture was filtered through a layer of silite and allowed to cool. The filtrate was aliquoted under reduced pressure to yield -1-(800100(a/a08106/)0810)-1(S)-tert-Butyl m At)oxo-3-—(tetrahydrofuran-2-yl )propan-2-ylcarbama- te g76576

1 1- toll) in the form of a viscous oil; They were used in the next step without further purification. The stereochemical formation was confirmed by X-ray crystal composition analysis. Example tert-Butyl ((S)-3-((1R,5S,6r)-bicyclo[3.1.0]hexan—-6-yl)-1-((R)— : 01 2-methyloxi- ran-2-yl)-1-oxopropan-2-yl)carbamate H H NaOMe * mb * m-CPBA p Cen 0 solution > H H OMeNHCbz MeO-P— H H Ha, PO, Cy ooo generation oO COOMe H 31 H 4 NHCbz 3, NHCbz ,3 Hy, Pd/C .1 pec H COOH 1. L-Acylase H 2 a 2. 8000 XL _~__COOH (CD 2 Bay — H 0 3 NHBoc H 0 Li H 0 cm MeNHOMe @ + 0 Y Ben Kim 5 Vl | 211 H NHBoc H NHBoc NaClO 0 BocHN fo} 0 to a solution of norbornadiene (Yo, v) norbornadiene g; #01 mmol) in CH2CI2 (£44 milliliters) (Use (Ale 018) was collected in portions over 1 hour at 0 °C) (YY,)) M-CPBA dil) The reaction mixture was stirred for 1.8 hours at ambient temperature and then filtered.The filtrate was washed with 965 mL aqueous cold NaHCO3 (Yoo)

AA a milliliters); drying over anhydrous sodium sulfate; and concentrate to obtain Yoo) and cold water in the form of clear oil. (1S,5R,6R)-bicyclo[3.1.0]hex-2-ene—6-carbaldehyde in methanol (18,5R,6R) )-bicyclo[3.1.0]hex-2-ene—6—carbaldehyde (mmol) was withdrawn. The mixture was heated under Yo) g; 8.15 (NaOMe mL) and Yoo) was added for 1 h and then cooled to ambient temperature. The mixture was diluted with YE reflux for 0. The combined organic layers were washed with (7 x 120 mL) Yoo water and extracted with 120 mL); drying over anhydrous sodium sulfate and concentration. 001 (ml) and Brian (001) were done with water - 86/10. The residue was documented by a flash chromatography column on silica gel (petroleum ether/

Y,V)trans-bicyclo[3.1.0]hex-2-ene-6—-carbaldehyde to obtain 0 (0:1 c 9677 two-step yield) as a light yellow oil. 0 g 8 ,0 )trans-bicyclo[3.1.0]hex-2-ene—6-carbaldehyde A mixture of methyl 2—(benzyloxycarbonylamino)-2-bl) was stirred; C. 144 mol) YY, ) (dimethoxyphosphoryl)acetate h. The mixture is decanted 1 mL sad (at ambient temperature DCM (Yoo mmol) in 001 mL DOM (mL) and then extracted using 151 V (1401 L saturated water) Vo (Y x 001 mL saturated aqueous NHACH The combined organic layers were washed with (mL VX); dried over anhydrous sodium sulfate; and concentrate. The residue 001 (and Brian) 1 was purified to 4;: 1:01 = EtOAc by scintigraphy column on silica gel (petroleum ether/methyl 2—(benzyloxycarbonylamino)—-3—(trans— for two-step yield) on 7648 aa V, +) bicyclo[ 3.1.0]hex-2-en—6-yl)acrylate 0 in the form of a colorless oil. methyl 2—(benzyloxycarbonylamino)-3—(trans— solution of J

Yoo) mmol) in TY an 001(bicyclo[3.1.0]hex-2—-en—6-yl)acrylate 1 h. 1 g). The mixture was stirred under a hydrogen atmosphere for 102 milliliters (oA) was added, the mixture was filtered through a layer of celite and then concentrated to obtain the crude compound Yo

delete

2-(benzyloxycarbonylamino)-3—(trans-bicyclo[3.1.0]hexan-6-yl)

propanoate Halk was used without further purification.

to a solution of the crude compound ‎methyl 2-(benzyloxycarbonylamino)-3—(trans—

001(bicyclo[3,1,0]lhexan-6-yl)propanoate g; A YY, mol) in methanol Yer (0 mL) was added by 0.1;9600 (Pd/C g). The mixture was stirred under hydrogen atmosphere

for VY hours. The mixture was filtered through a layer of silite and then concentrated. The article has been cleaned

residual by flash chromatography column on silica gel (petroleum ether/81086 - 1:00 to

;: HPLC 5) Preparatory to obtain the corresponding amine (+ aa 9694 two-step outcome)

In the form of a colorless oil.

Et3N (mL) containing DCM (Yo) in (Use 7.87 aa 57 mL) to a solution of amine 0 mol) by distillation at Abe 7.17 aa (AcCl (7.17 mol) was done. Add Ale 7,00 “slide +47) 1 hour at 0 degrees 1 minute. The reaction mixture was stirred for 0 over an Augie cycle (0 degrees milliliters). The resulting mixture was extracted using (Yo) hydrate and saturated aqueous 81811003 (71 ml) was added and the combined organic layers were concentrated to obtain acetyl-amide (DCM 10).

V0 (c.9094 toll) as a colorless oil. To a mixture of acetyl-amide (10 g 7.17 mmol) in THE (Yo) water was added (Ye) mL) lithium hydroxide (4.1 g); (Me VET Mall). The reaction mixture was stirred at ambient temperature for +0.0 h and diluted with water (00 ml). The solution was washed with 1 0 ETOAC (mL) and the aqueous phase was adjusted to a pH of -1 with

0 101 aqueous Yo) milliliters). The resulting precipitate was collected by filtration and dried under vacuum to yield 8660-7 acetamido—3-(trans-bicyclo[3.1.0]hexan-6-yl)propanoic ) 0,+ g; %A yield) as a yellow solid. A mixture of acetamido—3—(trans-bicyclo[3.1.0]hexan—-6-yl)propanoic—Y Av) acid vol. 5,660 mmol) in water (0 mL) was adjusted to pH = Ao using

1+4°C and YA aqueous. The mixture was filtered and the filtrate was heated to NaOH (1 mg). The mixture was stirred for; § an hour and then the filtration. The resulting mixture was adjusted (001) by adding 1- acylase to the resulting mixture Jue and Al HCl 1 p. The filtrate was adjusted to pH = 71-? using EtOAc (1 Xj 01) using 3 Dr. M

The methylcellulose is adjusted to pH -=A and a solution of 802620 (T0A) mg) is added; 0 mmol) in 01 (milliliter) acetone. The reaction mixture was stirred at ambient temperature overnight and the acetone was removed. The resulting mixture was adjusted to pH = $F and then extracted with Yo) EtOAc (mL Fx) The combined extract was concentrated to give S)-3-(trans-bicyclo[3.]1.0] acid hexan—6-yl)-2-(tert-).

%YA (xa), ¢) butoxycarbonylamino)propan—oic acid 0 (two-step yield) as colorless oil. The remainder of the synthesis was hin done according to the procedure for tert-butyl (28)-3-(3-methylcyclopent—1- .enyl)-1-((R)-2-methyloxiran-2-yl)-1- oxopropan- —2-ylcarbamate Ex 71 tert—Butyl ((5)-3—((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-1-(((R) -2—- 0 methyloxi— ran-2-yl)-1-oxopropan-2-yl)carbamate

=« ¢ \ — LiAIH, 0 TsCl 0 Nal©.0 OH OTs | see AcNHCH(CO,Et), ~ 1. L-Acylase t-BuOK NaOH ~ 2. Boc,0 EtOOC NES OF AcHN COOH 0 Ra Toa Mel, K,CO3 2 CHaly, 2 BocHN™ “COOH BocHN™ “COOMe come ow 1. CICO,Et, NMM \ OD 2. CHNHOCH, Una Boc,0 DO BocHN A coome BocHN Loon OLA Oo 5 A BrMg aw NaClO LD 0 —_— O —_ BocHN Lo BocHN 0 BocHN LX Pr Noo 0 Refrigerated suspension of ‎ Yo 8) LIAIHA g; 1.54 mol) in THE (veo) milliliters) to 0 degression under nitrogen.nitrogen a solution of cyclopent-3—enecarboxylic FT cpa 0+ mol (in 001) was added THE milliliters) by drip. AY) the cooling bath was completed and the reaction mixture was warmed to 50 °C and stirred for ? hour. The mixture was cooled to 0°C again and YE water (mL) was added by careful droplet. The resulting mixture was acidified with ele HCI diluted to a hydrate number = 1-1 and then extracted with Yeo (EtOAc) 1 x 1 mL. The organics were collected; washing with 48k NaHCO3 saturated Yoo (YX bile and Brian Yoo mL); drying over anhydrous sodium sulfate; And the concentration to obtain 0 on cyclopent-3-enylmethanol on daa light yellow oil (76 g d / 96 yield).

To a solution of cyclopent-?-enylmethanol (Use + VY con VV) in (0.0 DCM L) triethylamine V (009 mL) was added. The mixture was cooled to 0 °C and (aa 174.4 (TsCl 0.94 mol) was added in 1.5 h parts. Then DMAP (1077 can £8 mol) was added and left The reaction mixture was heated to ambient temperature and stirred under nitrogen overnight. Saturated aqueous NaHCO3 (0.1 L) was added and the two phases were separated. The aqueous phase was extracted using DOM (000 mL). organic matter collected; washing with NHACH saturated water 01 (L) and Bryan 01 (L); drying over anhydrous sodium sulfate and concentration to obtain 4-cyclopent-3--enylmethyl methylbenzenesulfonate as brown oil (aa VVE) 90698 yield); They were used in the next step without further purification. To a solution of 11 4) cyclopent-3-enylmethyl 4-methylbenzenesulfonate g (Je +0190 in 7.1 (L) acetone) 11 (Nal g 7.17 mol) was added. The reaction mixture was stirred at 71 °C overnight and then cooled to ambient temperature.(A Ye)eld was added and the mixture was extracted with 1 (L x 7 DCM).The YO products were collected extraction, drying over anhydrous sodium sulfate, and concentration. ) 7687 Example YY 00 Synthesized (S)-3—((1R,3r,5S)-bicyclo[3.1.0]hexan—-3-yl)-2—((tert-) butoxycarbonyl)amino— )propanoic acid was synthesized from (1R,3r,5S)- 3—(iodomethyl)bicyclo[3.1.0]hexane in a manner similar to the synthesis of (2S)-2—(tert— butoxycarbonylamino) -3-(tetrahydrofuran-3-yl)propanoic acid

A

(S)-3-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-2—((tert—) into a solution of

DMF mmol) in 09.8 «aa £, +) butoxycarbonyl)amino- )propanoic acid g; 77.5 mmol). The mixture was stirred at 7 °C (K2CO3 mL) and VY (mol) was added. The mixture of (Ale YALA (?7 g; Mel) was stirred for 1 hour followed by the addition of 1.5 ambient temperature for 1 mL. The resulting mixture was extracted using Yoo) overnight reaction and water was added o milliliters); Yoo) organic matter collected; washing with L(Y “mL Yeo) MTBE brain: drying over anhydrous sodium sulfate; and concentration to obtain (S)—-methyl 2—(tert-butoxycarbonylamino)-3—(cyclopent-3- viscous oil; used in step As g; 40% yield) on £4)enyl)propanoate following without further purification. Ye (S)-methyl 2—(tert-butoxycarbonylamino)-3—(cyclopent-3-) into a solution of 001 mL at 0 °C (DCM mmol) in AAT can Y,TA) enyl)propanoate mol) by distillation. The mixture was stirred Ale VAT lille 18.7 M; 1 (©1220 C) was added

DCM mmol) in 771.6”lll (?,15) 001212 min and a solution of Vo was added for 1 (51220 AT mL) rapidly. The reaction mixture was stirred for © minutes and a portion of 1 ?(1 mM YT, 1 mL ?7.15 (mL CH2I2; 5.75 mL; 9.75 mmol) followed by a solution of 1 mL) again. The reaction mixture was left to warm to ambient temperature (VY DCM mol) in 1) aqueous HOI and stirred overnight. The mixture was cooled to 0 °C again and

NaHCO3 p) to modify 1AM-1. The two phases were separated, and the cationic phase was converted to alkaline using milliliters (7). The materials were pooled (Ye) DCM into 11AM-9-8 and then extracted using SLY. : membership; drying over anhydrous sodium sulfate; concentration to obtain (S)-methyl 2-amino-3—((1R,3r,5S)-bicyclo[3.1.0]hexan—-3-yl)propanoate) as a viscous oil; It was used in the next step without further % 90 aa), 0% purification

110 (S)-Methyl 2-amino-3-((1R,3r,5S)-bicyclo[3.1.0]hexan-3—- dissolved

Boc20 mL) and THF (Yo) (mmol) were added in g AE; 0.5 4(yl)propanoate mmol). The reaction mixture was stirred at ambient temperature for ? 0111 hours cpa X,Y)

Sl) and then focus. The residue was purified by flash chromatography column on silica gel: to obtain 1) iY. = EtOAc petroleum/ © (S)-methyl 3-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-2—(tert- as oil in color 097 «xa Y ,Y) butoxycarbonylamino) propanoate 5) A g% yield but bonylami t is light yellow. (S)—methyl 3—((1R,3r,5S)-bicyclo[3.1.0]hexan—3-yl) -2-(tert-) into a solution of

Av) THE [ell mol) in 1111 g; Y,) 0) butoxycarbonylamino) propanoate | 0 g; The reaction mixture was stirred at ambient temperature for 854 hours, the organic phase was separated, and the methyl phase L(Y x 04 mL) EtOAc was acidified using DCM to pH = 71-?4. The resulting mixture was extracted with Ak HCL using: organic matter and the concentration combined to obtain (Fx mL Yeo) No (S)-3—((1R,3r,5S)-bicyclo[3.1.0 [hexan-3-yl)-2~(tert-g; quantitative) as viscous oil Y,Y) butoxycarbonylamino) propanoic acid was used in the next step without further purification. (S)-3-( (1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-2—(tert= to a solution of in (de dl 1.85 g; Y,Y) butoxycarbonylamino) propanoic acid 00 ethyl chloroformate (Ji) at zero degree of adhesion (1:1 pli 1) THF/DCM allll 0.58 NMM was added, followed by the addition of dss 1.717 mll V (Yo)chloroformate, mmol) by distillation.The reaction mixture was stirred at 0 °C under nitrogen 0.71 (A) h (solution 1 for)

to a solution of N,O-dimethylhydroxylamine (0.79 salt (HCI g; AL 06.7 mol) in DCM (£4 mL) at 0 °C was Add TEA (Y.07 mL 15,500 mmol) by droplet. That mixture was transferred to a flask fal with solution LA The resulting mixture faa was left to rise to ambient temperature and stirred for 1 hour. Water (00 milliliters) was added and the two layers were separated. The organic layer was washed using water (50 mL); drying over anhydrous sodium sulfate and concentration. The residue was purified by flash chromatography column on silica gel (petroleum ether/1086 = 1:01 to 1 52) to yield tert-butyl (S)-3-((1R,3r,5S)-bicyclo [3.1.0]hexan-3-yl)-1- (methoxy(methyl)amino)-1-ox-opropan-2-ylcarbamate )+ ¥ g PAY

Yo product) in the form of a colorless oil. to a solution of -1-(EL-101/010]3.1.0[6*80-3-(14,3,55))-3-(5) tert-butyl (methoxy(methyl)amino) —1-ox—opropan-2-ylcarbamate )+ ,¥ g; 4.7 mmol) in anhydrous THF (£4 mL) to a freshly prepared amount of prop-1-yn-?-ylmagnesium bromide FALE) mmol £1 mL in (THF) was added at 0°C by distillation 1 The reaction mixture was stirred at 0°C for 1 hour and then quenched with saturated aqueous ammonium chloride (100 milliliters). The resulting mixture was extracted with EtOAc 04 mL (Y x) organic phases were collected; drying over anhydrous sodium sulfate and concentration. The residue was purified by flash chromatography column on silica gel A) petroleum/ 1:001 = EtOAc to 0:1* .to obtain -1-(5) tert-butyl ((1R,3r,5S)-bicyclo[3.1.0]hexan-3~-yl)-4-methyl-3-oxopent-4-en -2-ylc- 0

1.1 (1686 g; 9079 yield) as a colorless oil. A solution of tert-butyl (S)-1-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)—4-«aa ,1( methyl-3-oxopent) was cooled -4-en-2-ylc— arbamate 8.5 mmol) in DMF (YY) milliliters) to Yoo Augie and bleach (Ale 01.9 cll AY) mol added; YO (% active species) by distillation under nitrogen. The reaction mixture was warmed to 0 °C

— \ ¢ h. Water (04 mL) was added and the resulting mixture extracted using 1 and stirring for x mL ov) The organic phases were collected; washing with Brain L(Y x 04 mL) EtOAC and drying over anhydrous sodium sulfate; focus. The residue was purified by oY tert- column to obtain (1:001 = EtOAc petroleum/AY) scintillation chromatography on silica gel butyl ((S)=3—((1R,3r,5S)- bicyclo[3.1.0]hexan-3-yl)-1-((R)-2- H 7644 xa +,Yo)methyloxiran-2-yl)-- 1-oxopropan-2-yl)carbamate yield) as viscous oil. 1H NMR (CDCI3, 300 MHz): § 4.84 (d, J = 8.4 Hz, 1H), 4.20 (t, J = 9.0)

Hz, 1H), 3.26 (t, J = 5.1 Hz, 1H), 2.88 (t, J = 5.1 Hz, 1H), 1.96 (dd, J = 12.0, 6.0 Hz, 1H), 1.85 (dd, J = 12.0 , 6.6 Hz, 1H), 1.56-1.64 (m, 3H), 0 1.51 (s, 3H), 1.46 (s, 9H), 1.41-1.52 (m, 2H), 1.30-1.37 (m, 2H), 0.23 - 0.30 (m, 1H), 0.13-0.18 (m, 1H). Confirmation of the stereochemical formation 5. Detected +[Na+M] 777,7 ("C17H27NO4 of MS (El)) by X-ray crystal formation analysis.

YY Example Vo tert—Butyl ((S)—3—(2-methylcyclopent-1-en-1-yl)-1-(((R)-2- methyloxiran—2-yl- )—1-oxopropan- 2-yl)carbamate

LDA 9 0 HCI | PhN(OTf), 2 a1/6/u00 > 0 NE o | — = 0 — TO 0 1 ren come Zn, Pd(dppf)Cl, LIOH 1 . A 2. CICO,Et Pe MgBr | MeNHOMe 06 8606140 BA 0 0 wo 0 BocHN lo}

To a suspension of ethyl-7-oxocyclopentanecarboxylate: Y+,Y) ethyl 2-oxocyclopentanecarboxylate g; o¥,A) K2CO3 5 (Use 100 g; Ya., + mol) in acetone (84 mL) then add Mel (¥1.4 g; 8 mol) at ambient temperature. The reaction mixture was stirred for 900 minutes at ambient temperature and then heated under reflux for 1 hour. The acetone was removed under reduced pressure and Yeo diethyl ether (mL) was added to the residue. The resulting mixture was stirred for 11 minutes and filtered. The filtrate was concentrated under reduced pressure followed by distillation under vacuum

to obtain :ethyl 1-methyl-2-oxocyclopentanecarboxylate (Y +0) 001 g; 9/767 toll). A mixture of 0 +) ethyl 1-methyl-2-oxocyclopentanecarboxylate g was heated; 00 mol) in HCl (0 mL concentration) under reflux for ? hours. The mixture was cooled to ambient temperature and then extracted with (Yor) DCM mL (Fx) The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure

—YiV-

to obtain Y = methylcyclopentanone (xa 4,0) 2-methylcyclopentanone 76860 to a solution of =F methylcyclopentanone (09.0 g; (se 0.701 in (lille ovo) THF) LDA solution (? 0.101 lille Yo Fp mol) was added at -78 °C. The mixture was stirred 11 32d© h at YA at urethra followed by addition of a solution of N= 1770 aa Yo (phenyltriflimide mol) in THF (Yo, milliliters) at YA= urethra through a cannula. The reaction mixture was left to warm to ambient temperature and stirred for 17 dele. The reaction was quenched with NaOH 9601 aqueous Yeo (mL) and the resulting mixture was extracted with diethyl ether Yao (mL) L (Y x mL). Washing of the collected organic phases using Braine and drying over anhydrous sodium sulfate 'and concentration, then purification of the crude oil by dad gs by flash chromatography column on silica gel (Joi A) to obtain 2-methylcyclopent-1-

xa) + £) en—]-yltrifluoromethanesulfonate 96974 yield). To a suspension of 1081 aa powder (ZN 11.7 mmol) in freshly distilled DMF (+ Y milliliters) trimethylsilyl chloride (1 0.17 milliliters aqueous) was added under atmosphere ND Suspension 1 was stirred vigorously for YO min. The resulting dilute organic supernatant was removed with a syringe. Zn Laud) was washed with (01 mL x 7) DMF. To a suspension of Zn-activated powder in freshly distilled DMF (+0 mL) A-3-1000-(E0:6/6815010I-1611)-No methyl 416 (8, g; 01 mmol) at zero degrees Celsius. The mixture was stirred for © minutes and the cooling bath was removed. The mixture was stirred for 1 yo min at ambient temperature. The gray supernatant Ye was transferred by a syringe into a dry beaker under N2 and the remaining zinc metal was washed with DMF.

01 (mL) is followed by transfusion (solution M). to a solution of A,1 +) 2-methylcyclopent—1-en—1-yl trifluoromethanesulfonate g; 0 TV, mmol) in DMF (YA) milliliters) 1,Y) Cl2(dppf)Pd g added; 1.0 mmol). The resulting brown solution was stirred at ambient temperature for 010 sad minutes. Yo was added to solution A at zero Aan and the reaction mixture was left to ambient temperature

(YtA- in milliliters) and EtOAC (0: Yoo) was filtered (1 h). The mixture was poured into water/11 and stirred for 11 minutes. The resulting suspension was passed through a layer of celite. The two phases were separated and the aqueous phase was extracted using x mL Yoo) The collected organic materials were washed using water (VY x mL Vou) EtOAc salad mL) 4, drying over anhydrous sodium sulfate, and concentration. Then purify Yeo (and Brian (Y

The remaining EtOAC was obtained by flash chromatography column on silica gel (petroleum ether to petroleum ether/5 to obtain -2)-3-(80100(!10:0:0/681501n-1611))-2 08-(5) ) 1 : = g; (S)-methyl 2—((tert-butoxycarbonyl)amino)-3—-(2— - to a solution of 0 mol) in 0.174 aa 78.0( methylcyclopent-1-en—-1-yl) propanoate 0 mol) 75 cpa Vo (8) LIOH-H20 mL) was added 11 mL/Yo) MeOH/H20 hr at 0 °C and then 1 Bad at 0 °C. The aqueous reaction mixture (4,0 p) was stirred. The organic solvent in HOE was removed with /-17 - adjusted to an aqueous pH NaOH with = 01 under pressure reduced and the resulting mixture was adjusted to pH and adjustment to pH (Y x milliliters of EtOAc (Yoo p). The solution was washed with +0) Vo

Vou) EtOAC p). The resulting mixture was extracted with Sle HOI (+,0) using 6-7 = 001 (mL) and Bryan 001 (and the combined extracts were washed with water (Vx mL YY) mL); drying over anhydrous sodium sulfate; And the concentration to obtain the corresponding acid yield) in the form of a pale yellow oil. ‎ 0 bicyclo[3.1.0]hexan-3-yl)-1~(((R)-2-methyloxiran-2-yl)-— 1 -oxopropan- .2-yl)carbamate

-1:4?- Example vé¢ tert-Butyl ((S)—-1—((R)-2-methyloxiran—-2-yl)—1-oxo-3—(2-oxopyrrolidin— 1-yl)— propan-2-yl)carbamate O Mel, .1 NaH .2 0 0 61611212000 0 a 3. LiOH HN on — SAP I A NHBoc H NHBoc oN ON Ares Q 0 0 1 9 NHBoG and with NHBoc 0 NaCIO OD 0 = BocHN 0 © added ¢—chlorobutanoyl chloride AT can 1,1( Chlorobutanoyl chloride mmol) to a solution of YA aa L-Dap-Boc (17.0 mmol) in dioxane (001 mL) and 1096 2182003 aqueous VAY (mL) at 0 deg by distillation. The reaction mixture was stirred at 0 dap C for 1 hour after which Bad was left to come to ambient temperature and stirred overnight. The mixture was acidified with 1 p aqueous hydrochloric acid to pH - ? and extraction using Yau (EtOAC milliliters x 3). The combined organic phases were washed with 1 mL aqueous hydrochloric acid (Vx and Bryan Yoo) mL x 1); dried over anhydrous sodium sulfate; concentration to obtain (S)—2-(tert= butoxycarbonylamino)-3-(4-chlorobutanamido)propanoic acid ) 2.0 g; 54 outcome); Bale was used without further purification. Vo" (1.0 K2CO3 g; 0 Ale mol) is added to a solution of:

C81 (S)—2~(tert-butoxycarbonylamino)-3-(4-chlorobutanamido)propanoic 0 ) acid g 74.0 mmol) in Yao ) acetonitrile mL) followed by the addition of methyliodine methyliodine (0.7 g); 1? mmol). The suspension was heated at 10-81 °C for ; hours. After the mixture has been cooled to ambient temperature; It was filtered and the filter cake was washed with acetonitrile (04 mL). The filtrate, wash products and concentrate were combined to dryness. The residue was purified by flash column chromatography on silica gel (hexane/EtOAC = ?:1) to obtain the corresponding ester. The ester was dissolved in DMF (001 mL) and NaH (9660 suspension) was added; 1 h and then left to cool to ambient temperature and stirred overnight The reaction was quenched with ice-water (000 mL) and the resulting mixture extracted with EtOAc (vou) mL (Fx) The combined organic phases were washed with 01811603 saturated aqueous (040 milliliters (Vx 1p HC Aqueous 00h) milliliters x ?); and Bryan Yeu) milliliters x 1), respectively. The organic phase was dried over anhydrous sodium sulfate and the concentrate. The residue was purified by Vo chromatography column and flashed on silica gel (hexane/0/6a = 1:1 to obtain methyl ester (a 1,0 ester 90517 yield) in the form of oil. A methyl ester (1.0 g; YY mmol) was dissolved in (Yo) MeOH (mL) and a solution of (Ae AE aa (7.1 LIOH mol) in water (Vo) mL) at 0 °C was added Aggie with a flip. The reaction mixture was stirred for ? hours and then acidification with 1 p aqueous HCE to pH Yo = ©. The mill mixture was concentrated to obtain -6:1)-2-(5) butoxycarbonylamino)-3—(2-oxopyrrolidin—1-yl)propanoic acid (,5 g; 677 yield); Hale was used without further purification. The remainder of the synthesis was carried out according to the special procedure tert-butyl (25)-3-(3-methylcyclopent-1- 068 a-2- enyl)-1-((R)-2-methyloxiran—2-yl)- 1-oxopropan-

o \ —_ \ _ Example Yo tert-Butyl ((2S)—-1-(((R)—-2-methyloxiran—2-yl)—-1-oxo-3—(2—oxopyrrolidin - 3-yl-) propan-2-yl)carbamate LIHMDS lo} MeOOC 1 0 BrCH,CN HOON oe Hy, Pd/C pe MS100 NHBoc NC NHBoc NH, Laoi hg 0 © 2 Bui 9 0 o 0 9 NYY YF ~~ WOT ~ NYY owe NHBoc NHBoc NHBoc = NH 9 0 for 0 © to a solution of aa 0.1 (OMe- (OMe)Boc-Glu 77.1 mmol) in THF (ov) milliliters) was added dropwise with a solution of YoY can 71, (LIHMDS) in THF (You) milliliters) at YAS Cryogenic degree under nitrogen atmosphere. The mixture was stirred at YA = RT for 1.5 hours and bromoacetonitrile 11 (bromoacetonitrile G 018 mmol) was added by distillation over 1 hour although the temperature was kept below Vim Aggie degree 0 The reaction mixture was stirred at +/- °C for 1 hour and quenched with pre-cooled methanol (Vo mL) in one batch. The mixture was stirred for 10 minutes and then treated with a precooled solution of acetic acid (9 milliliters) in THE (10 milliliters). The mixture was stirred for 10 minutes and poured into Brian Yoo (mL). The resulting mixture was extracted with (Ye) EtOAc mL (Y x) and the combined extract was dried over anhydrous 1 sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography column on silica gel (heptane compounds). 1 : 1 = EtOAc [ heptanes to get -(25)

o \ — \ — dimethyl 2—((tert-butoxycarbonyl)amino)—-4-(cyanomethyl)pentanedioate 10 ) g; 9/6106 toll) on Cu Lua in light brown. to a solution of (2S)-dimethyl ~~ 2—((tert-butoxycarbonyl)amino)-4- YY, A;100 mg( (cyanomethyl)pentanedioate mmol) in AcOH (7 50 mL) and then Add Pd/C 9600 (,1g) and then stir the mixture in Ja atmosphere H2 2 MPa for ¥ hours. The mixture was filtered through a bed of silite and the filtrate was evaporated under reduced pressure. The residue was treated with MTBE and evaporated again to yield -(45) dimethyl 2—(2-aminoethyl)-4—((tert-butoxycarbonyl)amino)pentanedioate (crude) as a light pink solid. 0 to a solution of (4S)—dimethyl 2—(2-aminoethyl)-4—(((tert- butoxycarbonyl)amino)pentanedioate (crude) in Yo)THF mL) Et3N was added Y 4) milliliters. The reaction mixture was stirred at 60 °C overnight and subsequently cooled to ambient temperature. Water (00 mL) was added and the resulting mixture extracted with methylene chloride (Yeo mL Y X). Collecting the organic layers; drying over anhydrous 1 sodium sulfate; concentrating under reduced pressure. The residue was purified. By scintillation chromatography column on silica gel (heptane/6/10 = 1:1 to obtain -1611)-2 (2S)-methyl butoxycarbonyl)amino)-3—(2-oxopyrolidin—- 3-yl)propanoate (0.0 g 7618 2-step yield) as a light brown oil to a solution of (28)-methyl 2—((tert-butoxycarbonyl)amino)-3-(2—- 90 0016 (E-0007/0011010-3 (0.0 g; 19 mmol) in methanol (04 mL) water added (Yo) mL) lithium hydroxide (0.1 g; YA mmol). The mixture was stirred at ambient temperature for 1 hour. The solution was diluted with water (04 mL) and washed with EtOAC (00 mL). The aqueous phase was adjusted to pH = ? Using 1 what was done SAL the mixture using © 101 then X a ; p HCl aqueous and the resulting mixture was prepared with M A EtOAc

o — \ — “). The organic phases were collected; dried over anhydrous sodium sulfate; concentrated to obtain the corresponding acid 1.5 (g; quantitative) as yellow oil. A mixture of dimethylhydroxylamine hydrochloride was cooled dimethylhydroxylamine 1 3 hydrochloride g 11.7 mmol); acid 1 g 7 mmol); 11.17 aa 7.7 4 (EDCI© mmol) and 1081 11.17 can (V,0A) mmol) in DMF (Vo mL) to 0 °C and triethylamine (©0,mL 77.3 mmol) was added. The reaction mixture was stirred at ambient temperature for VO min. Saturated aqueous sodium bicarbonate (04 mL) was added. The resulting mixture was extracted with EtOAC (04 mL 1x). The combined extracts were dried over anhydrous sodium sulfate and concentrated under 0 reduced pressure. sald) was obtained by a flash chromatography column on silica gel A) petroleum/1:01 = EtOAc to obtain: tert-butyl ((2S)-1—-(methoxy(methyl)amino)-1- oxo—-3—(2-oxopyrrolidin- ,Y) 3-yl) propan-2-yl)carbamate g; 9657 yield) as yellow oil.Y,0) n-Bu added Li is a molar of YAY in millimeters; 1.9 mmol) by distillation into a solution of iso-propenylbromide (0.8 Abe AY can mol) in Vo, 1 (THE milliliter) at YA = Asie degree and the mixture was stirred at YAS degrees Celsius for 10 minutes. A solution of: tert-butyl ((2S)-1—-(methoxy(methyl)amino)-1-oxo—-3—(2-oxopyrrolidin- V,0A cane © +) 3-yl) was added. propan-2-yl)carbamate mL (Use in THF (0.4 mL) by distillation. The reaction mixture was stirred at YA °C for ? hours and then leave it to warm up to 00 ambient temperature and stir for VY hours. 10 (mL) saturated aqueous NHACH was added and the resulting mixture extracted with 6/10 ov mL (Y x) The combined extracts were washed with Braine; dried over anhydrous sodium sulfate; and concentrated. Purify the residue by a flash chromatography column on silica gel (petroleum fil/)1:01 = EtOAc to obtain

and 1" on tert-butyl ((2S)-4-methyl-3-oxo-1-(2-oxopyrrolidin-3-yl)pent-4- (aan 001( en-2-yl)carbamate 9647 yield) as yellow oil. to a solution of tert-butyl ((2S)-4-methyl-3-oxo-1-(2-oxopyrrolidin=3— 001( YI)pent—4-en—2 -yl)carbamate mg; 711 mmol) in 01 (mL) methanol © at 0 C was added 0.4 cpa (1.0 1202 96700 mmol) followed by Ala) benzonitrile (70 © Ale 5.001 cane mol) Ae 5.0 “lll AY) DIPEA mol The reaction mixture was stirred for hours at ambient temperature and then diluted with water (Yo) mL. Extracted The resulting mixture was using mL EtOAc x 7 ov. The combined extracts were jue Brain, dried over anhydrous sodium sulfate, and concentrated.Vo residue was purified by flash chromatography column on silica gel (heptane / :Y = EtOAc )1 to get -2-)-1-00-3-(l-2- 061:30 th-2-0081-(6a))-1-(5)) tert- butyl ‎oxopyrrolidin-3-yl) propan—2-yl)carbamate (40 mg 9648 yield) as yellow oil Ex. 76 tert—Butyl ((28)—-3—(1-methyl-2—o xopyrrolidin-3-yl)-1-((R)-2- 0 methyloxiran—2- -yl)~1-oxopropan-2-yl)carbamate

— 00 \ _ 0 OMe 006" ROM Wim 9 LIHMDS 0 DL 2 wooo ~ A, BrCH,CN oO on NHBoc NC NHBoc NH, HCHO Q Laoa .1 Br MeOOC : l 1 9. iia sah sg SN buti wn me wo TY NHBoc NHBoc NHMe NMe 8 0 for 0 tert-butyl ((S)-synthesis was performed 3—(((R)-1-methyl-2-oxopyrrolidin-3-yl)-1- (((R)-2-methyloxiran—2-yl)—-1-- oxopropan-2-yljcarbamate similarly tert-butyl . ((S)-1-((R)-2-methyloxiran—2-yl)-1-oxo-3—(-2- lal .oxopyrrolidin—3-yl) propan-2- yl)carbamate© The crude compound S)-dimethyl ~~ 2-(2-aminoethyl)-4—((tert-¢) butoxycarbonyl)amino)pentanedioate ) 0.0 g YO, m mol) in (001 mL) methanol and 96460 formaldehyde VE aa 0.,1(formaldehyde mmol) (p > + A) Pd/C 0 was added The mixture was stirred under Yo) H2 psi) A sad hours at ambient temperature. The mixture was filtered through a bed of silite and the filtrate was evaporated under reduced pressure to yield: (28)-dimethyl 2—((tert-butoxycarbonyl) amino)—4—(2- (methylamino)ethyl)pentane dioate (0.4 g; crude) on Baa dark brown oil.

— \ o a —

YV Example (S)—-2-Amino-3—((S)-3,3-difluorocyclopentyl)-1—((R)-2-methyloxiran—-2- yl)pro— pan—1 -one and (S)-2-amino-3—((R)-3,3-difluorocyclopentyl)-1- ((R)—=2-methyloxiran-2-yl)pr— opan-1-one

Bi. i 0 0 Hawn TINIAN “ BOC 3 1

Fi Fit, O oy Zn, Pelpleal; ha 2. ier © ha f= py mm Al SE for ald on 1 1

“Rub Matt Boot” pF Fo 1 3 m Basar LIER m 7 EN Ma As 2 05 h ALR

LE LN

Boch LA Boch 3 0 0 b "5 i. 25 m hot

Ie 5 SC, TRON rs on Hy SiC, Ter ye Yip: Ne £3

PG Chapter B | Canny EY indications

HE fe 0 1 ert “Aseel: Ih Ky Poti, TOM HR i 1 Ng 0 a 0: fe

Chip “YX ~] oh : od lo } Triphenylphosphine (se EA aa YY) 100106 A mixture of iodine (1+) acetonitrile mol) was stirred in acetonitrile 970 aa 18 (triphenylphosphine = F-0; 1 hour at ambient temperature Then cyclopentane-1,3-dione (TAY) cyclopentane-1,3-dione 001 was added (for _mol) and triethylamine 5400 aa (TAY) and the reaction mixture was stirred overnight at ‎ (Jeo, 8A «all TTY] triethylamine 0 °C. The mixture was cooled to ambient temperature and concentrated. The residue was purified by 1:* to 1:01 = EtOAc flash chromatography column on silica gel (petroleum ether/

—Yoy—

On 7'-iodocyclopent-7-enone 07)3-iodocyclopent-2-enone Gm 7617

yield) as a colorless solid. A solution of (R)y-methyl 2—(tert-butoxycarbonylamino)-3—- 10000 «aa YY,4)iodopropanoate mol) in DMF (Yo) mL) was added to a mixture of Zn 1.0090 aa (19.5 © mol) and iodine (50 g); YT mmol) in DMF (YO) milliliters) in Jb nitrogen protected. The mixture was stirred for 1 hour at ambient temperature. then adding a solution of =F iodocyclopent-?- enone (Y+,A) 3-iodocyclopent-2-enone g; 0 mol) in Pd2(dba)3 «( slik 0+) DMF (7.7 g; 0.¥ mS—Phos 5 (Js) 7.1 g; 0.0 m (Use sequentially. The reaction mixture was stirred overnight at 00 °C. Done

0 The mixture was cooled to ambient temperature and water (100 milliliters) was added. The resulting mixture was extracted using (Yo) EtOAC (1 mL) x 1. The combined organic extract was dried as anhydrous sodium sulfate and concentrate. The remaining sald was purified by flash chromatography column on silica gel petroleum (fu)/1:# = EtOAc to ?:(1) to yield -16:1)-2 (S)—methyl VY) butoxycarbonylamino)-3-(3-oxocyclopent-]1-enyl)propanoate g;

15 9660 yield) is a pale yellow oil. A solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3— Ale 0,7 can YY, +) oxocyclopent-1-enyl)propanoate mol) was hydrogenated in Yoo methanol mL) in the presence of (aa V0) Pd/C overnight at ambient temperature. The Pd/C was separated by filtration and the filtrate was concentrated to give a colorless oil (YY g).

0 The crude compound cyclopentanone (YY, +) cyclopentanone is dissolved g; YV,Y mmol) in 001 dichloromethane ( dichloromethane milliliters) and DAST (, g, 701 mol) was added. The reaction mixture was stirred for 7 days at ambient temperature and then decanted in saturated aqueous sodium bicarbonate (100 milliliters). The two layers were separated and the aqueous layer was extracted with 100 dichloromethane (7 milliliters 1). The organic extracts were collected;

Yo and drying over anhydrous sodium sulfate; focus. The remaining material was purified by column chromatography

mH-0 flashed on silica gel Jf) petroleum/1 iV = EtOAc to 1:01 to obtain -(25) methyl 2—(tert-butoxycarbonylamino)-3—(3, 3- (aa Vo) difluorocyclopentyl)propanoate 90617 yield) in the form of a pale yellow oil. © 1.159 aa 1,7( LIOH-H20 mol) was added to a mixture of (2S)-methyl 2—(tert— Yo, +) butoxycarbonylamino)-3—-(3,3—difluorocyclopentyl )propanoate g; Ake £AA mol) in water/THF (00 milliliters/ 00 milliliters). The reaction mixture was stirred for 1 hour at ambient temperature. (THE All) and the remaining solution, Sl, was acidified to pH = 5-4 with aqueous KHSO4 90010. The resulting mixture was extracted with 001 mL EtOAc (FX). Organic extracts were collected; drying over anhydrous sodium sulfate; concentration to obtain the corresponding acid (paVET) as pale yellow oil; Bile was used. Without further purification the crude acid VET (together EAA mmol) was dissolved in dichloromethane Yoo (mL) and N-methylmorpholine (£,37 con $A con mmol) was added ). The solution was cooled to 0 °C NO and isobutyl carbonochloridate (1.70 g; 4 _mmol) was added dropwise. The mixture was stirred for 1 hour at 0 °C followed by the addition of a mixture of no-0-dimethylhydroxylamine HCI salt (5.77 g; “© mmol) and triethylamine (7,17 SLL 00.1 mmol) in dichloromethane (Yo) milliliters). The reaction mixture was stirred for 1 hour at ambient temperature. Mixture 0 is poured into water (you milliliters) and the two phases are separated. The aqueous phase was extracted with 100 mL EtOAC (Fx organic phases were collected; drying over anhydrous sodium sulfate; concentrate. sald) was purified by flash chromatography column on Sha (petroleum ether/ether) gel 1:01 = EtOAc to (Vee to obtain the corresponding add Weinreb) 11.1 (g) as colorless oil.

o q —_ \_ Weinreb amide (0 VY, c. 77.7 mmol) was dissolved in THE (001 mL) and a solution of prop-1-yn-?-ylmagnesium bromide was added prop—1-en-2-ylmagnesium Y Ao) bromide g 0 mol) in Yeo ( THF milliliters) at zero an an ion. Then the reaction mixture was stirred for 1 hour at zero degrees Celsius, and then ? A clock at Shall 0 degree ambient. The mixture was decanted in 96010 aqueous nitric acid (Yor) mL) and the resulting mixture was extracted using [0/6] 00101 mL (FX) The organic extracts were collected; drying over anhydrous sodium sulfate  and concentration. Then purification residue dail gs a flash chromatography column on silica gel (petroleum ether/1oY = EtOAc to 1:1) to obtain: tert-butyl (2R)-1-(3,3-difluorocyclopentyl)- 4-methyl-3-oxopent-4-en- 2-yl 080580316 0 (£.0 g; %Y4 three-step yield). Aqueous NaCIO (0096; 70.1 γ 94.7 mmol) was added dropwise to a solution of: tert-Butyl (2R)-1—(3,3—difluorocyclopentyl)-4-methyl-3 -oxopent-4-en- 2-yl carbamate )+ 0.0 g; 105.8 mmol) in DMF (Yo) milliliters) at 0-5 °C although the internal temperature was kept below -01 °C. The reaction mixture was stirred for 1 7 hours at 0 °C and then overnight at ambient temperature. The mixture is decanted in water (01 milliliters) and the resulting mixture extracted with (You) EtOAC milliliters (Fx) organic extraction product collection; drying over anhydrous sodium sulfate; concentration 0 and then purification of the residue by flash chromatography column on silica gel (Jil) petroleum/:1 = EtOAc 1 to 1:01 to obtain: tert-butyl (28)-3—(3,3-difluorocyclopentyl)-1-(( R)-2-methyloxiran-2— - 0 propan-2-ylcarbamate 1-0"*0-sal )0,¥ (aa 5448 yield). (VV) TFA added g; 0.15 mmol) to a solution of -3,3)-3-(25) tert-butyl difluorocyclopentyl)-1-((R)-2-methyloxiran-2-yl)-1-oxo propan-2-

IRV

milliliters). A mixture of 01 (mmol) in dichloromethane V,0 g;(Y,0)ylcarbamate was stirred for ¥ hour at ambient temperature and then concentrated to obtain the amine (quantitative). 1(?) dioxane dioxane - 4 11 in (Use mV,0 TFA) amine (salt) dissolved at A=0 and then neutralized with saturated aqueous sodium bicarbonate to pH mol) and the reaction mixture was stirred for Ae 9.0 cpa 7.7 (4 052-05 Ais pg © x 04 milliliters) EtOAC was added for hours at ambient temperature. The mixture was extracted using The organic extracts were collected; drying over anhydrous sodium sulfate; and concentration. The residue was purified by flash chromatography column on silica gel (petroleum ether/) to obtain a mixture of stereoisomers (7). ,4 g 9639 yield); 3-difluorocyclopentyl)-1-((R)-2-methyloxiran—-2- benzyl (S)-3-((R)-3,3— and (a ),))yl)-1-oxo propan-2-ylcarbamate difluorocyclopentyl)-1-((R)- 2-methyloxiran-2-yl)-1-oxo propan-2-g); respectively. +,V) ylcarbamate

Benzyl (S)—-3-((S)—3,3—difluorocyclopentyl)-1-(((R)-2-) then hydrogenated 5 mg; + 989 mM Yo +) methyloxiran—2-yl) —1-- oxo propan-2-ylcarbamate mg; 000+ mmol) in V0 (8) p-TSOH-H20, (aa +,)) Pd/C in the presence of (Use). The 0/0 was separated by filtration and then done 0-9 hours. At 1 methanol (1 mL) for (5(-2-20100-3-))5(-3,3-) concentrate the filtrate to dryness to obtain (-1-((R) & difluorocyclopentyl) (S)-2-amino-3((R)-3,3-difluorocyclopentyl)-1-((R)- 2-: It was synthesized in a similar way. Methyloxiran-2-yl)pro— 0880-1-6

11-

YA Example tert-Butyl ((S)-3—((1r,4S)-4-((4-methoxybenzyl)oxy)cyclohexyl)-1-((R)- 2-me- thyloxiran-2- yl)-1-oxopropan-2-yl)carbamate

OH OH MeO CCl, .. Who do I give to: 22 1 PPTS NH B BocHN jo Pro cong? DCM eS

OPMB OPMB

NaOH (aq) for CDI, DCM, DIEA 11 Nee

MeOH and with OF MeNHOMe-HCI EE THF 6 l © 0i PMBO, 1. NaOCl, DMF 1.

Sun A Re

BocHN BocHN 0 6 (S)-methyl 2—((tert-butoxycarbonyl)amino)-3—-(4- A mixture of ©acetic was hydrogenated in 1.0 mmol); acetic acid 09.0( hydroxyphenyl)propanoate g; 0.7 9( platinum oxide mol); and platinum oxide Ae 0.09 microliters?” (71 0

Parr milliliters) in a shaking jar YY 7 isopropanol mmol) in 8.17 isopropanol from celite daha h. Then the mixture was filtered through 1 MPa for EY time using hydrogen to obtain (EtOAC 1:1/hexane compounds) and concentration. Purification was done by chromatography column 0 which was recrystallized from (aa YY) 015/0805 isomers mixture of cis/trans isomers cis alcohol (S)-methyl 2—((tert-butoxycarbonyl)amino)- to obtain EtOAC (purity) 9050 960 g; (17,) 3—((1s,4R)—-4-hydroxycyclohexyl)propanoate trans alcohol (S)-methyl 2-))6:1- (cll la sak in the form of butoxycarbonyl)amino)-3—((( 1r,4S)-4-hydroxycyclohexyl)propanoate yo (S)—methyl 2—((tert— clear oil and overreducing Jeo (s& 9085 967 mg; 1,8)

-7+?- “aa 001,7 ( butoxycarbonyl)amino)-3—-cyclohexylpropanoate 9607). The enriched isomer was used in the following reaction without further purification. A solution of -(1,45))-3-(800100(Al4/681501H1Na1611-5))-2 (S)-methyl YO, +) 4-hydroxycyclohexyl)propanoate g was added; 17.0 mmol) in dichloromethane (All You)© at 0°C was added =f a methoxy—benzyl ester of BYYY trichloro-acetimidic acid —acetimidic acid can YA, 4) 95.7 mM (Use and 0015 (17, c. 1.70 mmol). The reaction mixture Ga was left to dap ambient temperature over YE h Dichloromethane (Yor mL) was added and the organic layers were washed with sodium bicarbonate (saturated); water; Brian; 0 drying over sodium sulfate” and filtration; focus. Purified by chromatography to yield (S)-methyl ~~ 2-((tert-butoxycarbonyl)amino)-3—((1r,4S)-4-((4- YY, +) methoxybenzyl)oxy (cyclohe— xyl)propanoate g; (AY as colorless oil. 1H NMR (300 MHz, CDCI3) 6 7.26 (d, J = 8.7 Hz, 1H), 6.87 ) J = 8.7 Hz, 1H), 4.88 (d, J = 8.1 Hz, 1H), 4.47 (s, 2H), 4.33 (m, 1H), 3.80 (s, 0 3H), 3.75 (s, 3H), 3.26 (m, 1H), 2.08 (m, 2H) , 1.90 (m, 2H), 1.74-1.15 (m, SH), 1.43 (s, 9H), 0.89 (m, 2H). “C23H35NO6 1 MS (El) detected 444.7 F[ Na+M] to a solution of (S)—methyl 2—((tert-butoxycarbonyl)amino)—-3—((1r,48)-4—((4- V0, +) methoxybenzyl) oxy)cyclohe— xyl)propanoate 00 g; 5,71? mmol) in Yo. (MeOH (mL) at 0 °C to which NaOH (aqueous; 1 M 7.0 No 70.7 “plik” mmol) was added. The mixture was stirred at ambient temperature for ; hours. after Al is the solvent; The residue was diluted with dichloromethane (Yoo) mL) and the solution adjusted with (1 M HOI) to pH YY The organic layer was washed with water

+1

and Brian; drying over sodium sulfate; rad ily and focus. Purified by column chromatography to give (S)—2—((tert-butoxycarbonyl)amino)-3—((1r,45)-4—((4-)

.)76/87 g YY,0) methoxybenzyl)oxy)cyc— lohexyl)propanoic acid (S)—2—((tert-butoxycarbonyl)amino)-3—((1r,45)-4—(( 4- A solution of (J mmol) 111 aa VY, 0) methoxybenzyl)oxy)cyc— lohexyl)propanoic acid ° carbonyl mL) at zero pH was added carbonyl diimidazole (Yor) DCM in 0.8 for Aggie mmol) and the mixture was stirred at zero degrees 50850 aa, 2A) diimidazole hydrochloride oad hydroxyl die solution was added. J) hr. RLA 1 (DIEA mmol) 14 g 0.44) dimethylhydroxylamine hydrochloride hr. 01 sad to ambient temperature and agitation Bad C; 11.4 mmol). The mixture was cooled (0 celal) sodium bicarbonate (saturated); HCL p oY The organic layer was washed with water; Brian; Drying over sodium sulfate. organic layers have been aggregated; filtration and focus. tert-butyl ((S)-1-(methoxy(methyl)amino)- was purified by column chromatography to yield 3—((1r,4S)-4~((4-methoxybenzyl)oxy)cyclohex— 1Hazala -00010680-2-

(%7¢ g; AQ)yl)carbamate yo tert-butyl ((S)—1-(methoxy(methyl)amino)-3—((1r,48)-4—((4—) into solution of 5 (methoxybenzyl)oxy)cyclohex—yl)—1-oxopropan-2-yljcarbamate propynylmagnesium bromide —Y Alm) (pall of) THE in (Use Ake) 04 ml mol) by distillation 99, ible 111 mol (0.0) propenylmagnesium bromide °C for 7 days, then left to warm up to Yoo °C for an hour. The mixture was stirred at 1 over 0 saturated water 1011401 hours further and then decanted at 1 ambient temperature. The mixture was stirred for 1 ml) and the mixture was adjusted (Yoo) EtOAC for 1 hour. 1 sad mL) was added and stirred £04) the organic layer was washed with water Y = p) to pH 1) HCI using and purified by GS and Bryan column; Drying over sodium sulfate. The solution was filtered” tert-butyl ))5(-1-))1,45(-4-))4- to obtain Kha Sa Yo chromatography

methoxybenzyl)oxy)cyclohexyl)-4-methyl-3-oxopent-4-- en-2- V, 8) yl)carbamate g (PAY) to a solution of tert-butyl ((S) -1-((1r,4S)-4—((4- methoxybenzyl)oxy)cyclohexyl)-4-methyl-3-oxopent-4-- en-2-yl) carbamate 2 ) 6 g 1/7 mmol" is 0.1 equivalent) in YY. (DMF in milliliters) .101 die °C NaOCI (967 w/w 7.7 milliliters; 4.4 mmol) was added at a rate to maintain an internal temperature below < -01°C. The mixture was stirred at 0 °C for 1 h and then diluted with EtOAc (Vou (mL) and (You) water (mL); extraction with Jue (XY) EtOAc organic layers using water and brine; drying over Ye sodium sulfate; filtering; and focus. The remaining raw material was then purified by chromatography to obtain tert-butyl ((S)=3—((1 r4S)-4-((4- methoxybenzyl)oxy)cyclohexyl)-1-((R)-2 -methyloxiran— —2-yh-1- ax Y,1Y) oxopropan—-2-yl)carbamate (£%) 1H NMR (300 MHz, CDCI3) § 7.27 (d, J = 6.9 Hz, 1H ), 6.87 (d, J = 6.9 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H), 4.47 (s, 2H), 4.31 (m, 1H), 3.79 (s, 0 3H ), 3.27 - 3.25 (m, 2H), 2.88 (d, J = 5.1 Hz, 1H), 2.11 - 1.84 (m, 3H), (m, 2H), 1.51 (s, 3H), 1.48 (s , 9H), 1.50 — 0.98 (m, 6H). 1.65 = 1.72 “C25H3TNOG 1 MS (El) Detected 4707 A[Na+M] Ex. 3-cyclohexyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan— 0 2-yl)- carbamate

-¥10— isobutylchloroformate, MeNHOMe HCI, TEA, DCM, Je Or NMM | BrMg BocHN BocHN N-ome THF 0 0 NaOCl, DMF 0 no BocHN BocHN 0 0 to a solution of dimethylhydroxylamine “aa,54( aa) hydrochloride 500 mmol ) in DCM (04 milliliters) at zero degrees date (0,000 milliliters (£Y) triamine (Ji) 491.9 mmol) was added. In a separate beaker -(5) V+, +)2—((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid o g was cooled; 4 mmol) in DCM (00 mL) THF (5 ov) mL) to zero pH and isobutylchloroformate (lll £,AY) isobutylchloroformate 1.5 ? mmol) followed by 0.5-11-methylmorpholine ( methylmorpholine 1.4 Ale mol). After 1 hour, it was added to the dimethylhydroxylamine mixture. 0 The combined mixture, Bad, was left at ambient temperature for 16 ae hours. During this period, it was quenched with Ma 6 and washed with sodium bicarbonate. (saturated) ¢, extraction with EtOAc (XY), washing with Braine, drying with sodium sulfate; filtering; focus. Then, (S)-tert-Butyl (3-cyclohexyl-1-(methoxy(methyl)amino)-1- VY, Y) oxopropan-2-yl)carbamate g) was obtained in the form of a colorless oil. Move it to the next stage 1 without further purification. MS (EI) of “C1I6H30N204 detected +[M-Boc] 711,1 to (S)-tert-butyl (3—cyclohexyl-1-(methoxy(methyl)amino)—1-oxopropan — VY,Y) 2-yl)carbamate g; YA mmol) in THE (Yoo) milliliters) at 0 °C isopropenylmagnesium bromide was added

VY, Y) milliliters of a solution of 1.5 p in methyl THF = 1.0107 mol) by distillation. After stirring at 0°C for 7 hours, the mixture was quenched with heptane/citric acid (1:1). The product was extracted with EtOAC (77); washed with brine; dried with sodium sulfate; filtered; and concentrated. Grind the crude product with cold (0°C) methanol © to obtain (S)-tert-butyl (1-cyclohexyl-4-methyl-3-oxopent-4-en-2-yl)carbamate )0, 1 g; £9) as a colorless crystalline solid. MS (El) for 01711290103; detected +[M-Boc] 1093.7 to (S)-tert-butyl (1-cyclohexyl-4- methyl-3-oxopent-4-en-2-6 (ala (5.771 g YAY mmol) in DMF at -01° Lge fll £V,1 added) 018001 0 of 909.5 fos by weight of solution; YY mmol).NaOC was added at a rate to maintain an internal temperature of < -01°C. After completion of the addition, the reaction mixture was transferred to an ice bath and stirred for An additional 1 hour was then diluted with water (EtOAc) and extracted with EtOAC (77); washing with brine; drying with sodium sulfate; filtration; concentration. Then purification by column chromatography 9:1 heptane/(EtOAc). Vo to obtain tert-butyl ((S)-3—-cyclohexyl-1-((R)-2-methyloxiran-2-yl)-1- aa YA) OXopropan-2-yl)carbamate (70%) as a colorless, amorphous solid. MS (El) 1 0171129104 detected (=MH) 00117 The following compounds were synthesized in a similar way: tert-butyl ((S)—3-cyclopropyl-1 ~((R)-2-methyloxiran-2-yl)-1- 0 ‎oxopropan—2-yljcarbamate tert-bu tyl ((S)-3-cyclobutyl-1-((R)-2- ‎methyloxiran—2-yl)-1-oxopropan-2-yljcarbamate .

—Y1v- 01 Example tert—Butyl ((S)—3—cyclopentyl-1—((R)—oxiran-2-yl)-1-oxopropan—2- yl)carbama- te tN } } 3 Boel , MEL, &

A Aol, Me Lk 0088 . A, MO hd EA TE NE and Hob Hus | and house 3 d ihe

Sig Ni MOH IRIN AA a 0084 1

A 1 “1” Ode article 0

THC, EN A Hag, ! 1 Hash a on OGM Lamb RMB 1 1 L 1 Les P Sc > Wear A Yasa Karha In, 15-5 L 1 Tlmah and 0 DMF Mmq | b[‎ ust

LOH, 0 2 Mp, POC, 0 chloroforms ha Ny PRA, THEDICM; aaaa as I wa bio ad yom [PE 1 s Joe IB. SHR JeDRMMe HOLL Na NHB Se SHBG BUS, TEA ~~. sve =,

Pian J Poa < ; gs is isotropic las 1 to Asan L GY “yr THF Boe 7 ke BME 5 8 in a round bottom flask was heated to 0 °C and acetylcholine (illo) was added £00) 5 mol methanol was cooled by distillation. After the addition is completed; 1.77 “lll 00)acetyl chloride dirulac 075 gm Vo) H-Ser-OH was stirred for minutes and 01 sad was added to the mixture at ambient temperature for an hour and then 1 for a period of de The degree of Av mol) is divided into three parts. The reaction mixture was heated to (S)—methyl 2-2800100-3- concentration. The residue was added under vacuum to obtain (quantitatively) a colorless solid; hydroxypropanoate hydrochloride | 0 to be used in the next step without further purification. (S)-methyl 2-amino-3-hydroxypropanoate The crude compound was suspended in milliliters) and to that mixture was added triethyl (DCM mol) (Yo) in + ,Y 4) hydrochloride

—Y1A- at zero degrees Celsius. Boc20 (Use 171 aa TA) 5 (Use 1,257 amines (79 mL; cooled) and the reaction mixture was stirred at ambient temperature overnight and then ales removed mL). The filtrate was diluted using the remaining MTBE (Yeo) by flash chromatography column on silica gel sald) reduced pressure. (S)-methyl 2—((tert-butoxycarbonyl)amino)-3 was purified to yield © yield) as colorless oil. 9094 (aa 01 ( hydroxypropanoate g; 50860 mol) YTV ) triphenylphosphine A mixture of triphenylphosphine (mL) was cooled to zero pH (001 DCM mol) in 50 g; YE) imidazole and imidazole h. (Use 50 gm VYV) iodide was added in small portions for cooling, and the mixture was stirred for 6.5 hours. After re-cooling the mixture to 0° ales AN) 0 (S)—methyl 2—((tert-butoxycarbonyl)amino)-3— quenched; A solution of mL) was added by drop. After Yer) DCM in (se “YY g; VY) hydroxypropanoate up to ambient temperature and stirring for Bad addition; The cooling bath was removed and the mixture was cooled

MTBE hours. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. 5 was added to the residue and the mixture was filtered to remove triphenylphosphine oxide (Gillke £00) Vo. The filtrate was concentrated and the residue was purified by a Ltriphenylphosphine oxide (R)-methyl 2-((tert-) column For Kha flash chromatography on gel yield) as 90614 aa VE, +) butoxycarbonyl)amino)-3-iodopropanoate a colorless solid. In the procedure cyclopent-1-en—1-yl The synthesis of trifluoromethanesulfonate 0 tert-Butyl ((S)-3—(cyclopent-1-en-1-yl)-1—((R)-2-methyloxiran— specific 2-yl)-1 is described. TMSCI-oxopropan-2-yl-Jcarbamate (TMSCI £7 mL) DMF (00 mol) in 0.60 g; VYY) was added to a suspension of zinc mL) by droplet. The mixture was stirred at ambient temperature for 0° minutes. The fluid was drained (milliliter). The upper clearant (DMF 000077) was resuspended and the remaining material was washed with Yo

The resulting solid in Yeo DME (mL) and the mixture was cooled to 0 °C. A solution of (R)-methyl 2—((tert-butoxycarbonyl)amino)-3-iodopropanoate (01 g; 1.771 mol) in Yeo (DMF) was added. The mixture was stirred at 0 °C under nitrogen for 10 minutes. The upper clear was drained off and added dropwise to a solution of cyclopent-1-en-1-yl trifluoromethanesulfonate o (+4 g) (Uso YY CI2(dppf)Pd )3,¥ g; £,V mmol) in DMF (00 milliliters). after addition; The reaction mixture was stirred at 500 °C under nitrogen overnight and then cooled to ambient temperature. Braine ove (mL) was added and the resulting mixture extracted with MTBE (5000 XY) mL). organic layers have been aggregated; washing with brine; focus. The remaining 0 was purified by a flash chromatography column on silica gel A) petroleum/0/6p-1:001 to _)1 0 to obtain (S)-methyl 2—((tert-) butoxycarbonyl)amino)-3—- (cyclopent-]1-en—1-yl)propanoate as viscous oil (17 g; 9677 yield).

to a solution of (S)—methyl 2—((tert-butoxycarbonyl)amino)-3—(cyclopent-1- en—1-yl)propanoate (17 g; YY + mol) in water Ave/methanol 7 mL: 1)Vo added lithium hydroxide 19.7 (lithium hydroxide hydrate g" 5760© mol). The reaction mixture was stirred at ambient temperature overnight and then concentrated to remove most of the methanol. The residue was Jue with DOM (£00 mL) and the Sl phase was acidified with HOI diluted to pH = 4-7 . The resulting mixture was extracted using DCM (ills Tou xY) the organic layers were combined and the concentration was combined to give -1611))-2-(5) butoxycarbonyl)amino)-3—-(cyclopent-1-en-1- yl)propanoic acid 90 (71©) g

59 outcome) on AAA viscous oil; They were used in the next step without further purification. to a solution of (S)—2-((tert-butoxycarbonyl)amino)-3—(cyclopent-1-en—-1- yl)propanoic acid )01 g YY + mol) in ove) Jolie (tr) YY) Pd/C added

gm mua in ad lwa ~- & £ g; vo YY mol + 0% (then stirred the mixture in Ja hydrogen atmosphere (1 atm) at ambient temperature Yo overnight and then filtered through a layer of celite. The filtrate was concentrated in Jb

IVI

(S)—2-((tert-butoxycarbonyl)amino)-3—- Squeeze & lower to get g; 96959 toll) in the form of viscous oil; 00) cyclopentylpropanoic acid was used in the next step without further purification. to a beaker filled with -3-(810100(E10/6810017Na1611-5))-2-(5) cyclopentylpropanoic acid °C (00.4 g); 70 mmol) Av + (THE/DCM) 1:1 “bile” was added. The solution was cooled to 0 °C and ethyl chloroformate (©;?) was added. milliliters Yov mmol) YA, 3 NMM milliliters Yov mmol) by distillation thereafter. after addition; The mixture was stirred at 0 °C under nitrogen for 1 els to an AY beaker filled with die gh -© WN hydroxylamine YOY «an 5,0 ( HCI dimethylhydroxylamine | 0 mmol) DCM (g++ milliliters) added. The mixture was cooled to 0°C and TEA (YAY) mL was added; 7748 mmol). The resulting mixture was transferred to the previous reaction beaker. The bad reaction mixture was left to ambient temperature and stirred overnight. Then the reaction was quenched with ove water (mL) and the two phases were separated. The organic phase was washed with water (04 mL); drying over anhydrous VO sodium sulfate; and concentration to obtain (S)-tert-butyl (3-cyclopentyl-1- da le (methoxy(methyl)amino)—1-oxopropan-2-yljcarbamate colorless oil aa Tr) 90957 yield); They were used in the next step without further purification. to a solution of (S)-tert-butyl (3—cyclopentyl-1—(methoxy(methyl)amino)-1- 880136 (E-0:40010680-2 (dss Ak AY an Y,0) in (Yo) THE in milliliters) Ye was added (Y1,Y) vinylmagnesium bromide in milliliters 77.7 mol) at 0 °C by distillation. After the addition is completed; The reaction mixture was stirred at 0 °C for 7 h and then quenched with saturated aqueous ammonium chloride (Vo (mL). The resulting mixture was extracted with ETOAC (77 0 mL). organic layers have been aggregated; drying over anhydrous sodium sulfate; focus. The residue, Yo, was purified by a flash chromatography column on petroleum jelly (Jil/10/6 = 1:001) to obtain

-1/?- on (S)-tert-butyl (1-cyclopentyl-3-oxopent-4-en-2-yl)carbamate as yellow oil (AOE) mg 9674 yield). A solution of (S)-tert-butyl (1-cyclopentyl-3-oxopent-4-en-2- 816 only (Ao mg; ?10 mmol) in Vo) DMF was cooled ) to Veo © and a bleaching solution (4.00 mL A 1.8 mol; A) was added. 9601 active species) by distillation under nitrogen. The reaction mixture was warmed to 0°C and stirred for 0.5 hours. Water (Vo) was added (mL) and the mixture extracted with EtOAC (xY) 00 mL). The organic phases 4 were collected, washed with Brain (OXY mL) ¢, dried over anhydrous sodium sulfate, concentration 0, then purified the residue by a flash chromatography column on a silica gel (Ad) petroleum (1): A+ = EtOAc 0 to obtain tert-butyl ((S)-3-cyclopentyl-1-((R)-oxiran— 2-yl)—1-oxopropan-2-yl)carbamate as viscous oil V0) mg ; contaminated with some impurities; 9647 yield) on dia yellow oil. Example tert-Butyl ((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2- : Y methyloxiran—2-yl)—1-oxop— ropan— 2- yl)carbamate yo 3 a OMe ah emq 4 Zn, 15-4 oO "m EO RAO - 1 and nan ps [ Dhai A _ Ng EY es OMe See THE HO MeOH od NMBag THE, DOM 5 [ran AL ~~ Mas PEN 0 mb TY

—YVY-

to a solution of cyclopentanone (00 g; 1176 mol) in (A 0,) DCM 182003 (10 Cm) 94860 (Jee) was added and the mixture was cooled to Yeo degree Aggie ddl Trifluoromethanesulfonic anhydrous YYV) Trifluoromethanesulfonic anhydride (YY eo plik, + mol) by distillation. After addition, the ales were removed, cooled, and the reaction mixture was stirred at ambient temperature overnight. GC-MS analysis indicated that the reaction was incomplete and the reaction was added. Trifluoromethanesulfonic anhydrous additional 1.70 "lille TF (mol). The reaction mixture, gal sad, was stirred for 4 hours and then quenched with water (800 mL). The aqueous phase was extracted using Yeo DCM (mL). organic matter collected; washing with brine; And focus to get ‎le Michaelou .| Pentenyl trichloromethanesulfonate cyclopentenyltrifluoromethanesulfonate 00 in the form of viscous oil (Vr) gm 7677

outcome); They were used in the next step without further purification. to a suspension of zinc (VYY) ZINC g; 0.560 mol) in DMF (00 mL) TMSCI (£7 mL) was added dropwise. The mixture was stirred at ambient temperature for 0° minutes. The upper clear liquid was removed and the residue was Jue with DMF (Yo) mL (VY x sale) 1 The resulting solid was suspended in DME (Yo) mL) and the mixture was cooled to 0 °C resting place A solution of (R)y-methyl ~~ 2—((tert-butoxycarbonyl)amino)-3—- iodopropanoate (?10 g; 1771 mol) in Yoo) DMF mL was added ). The mixture was stirred at zero Ryde degrees under nitrogen for 10 minutes. The upper clear liquid was removed and added to a solution of trifluoromethanesulfonate E-02(0/0100601-1-80-1 g FaYo mol) 5 CI2(dppf)Pd (7.5 g; lb, Y mmol) in DMF (000 mL) by distillation. after addition; The reaction mixture was stirred at 0 5 °C under nitrogen overnight and then cooled to −da ambient temperature. Bryan (044 mL) was added and the resulting mixture extracted with Yeo (MTBE mL x ?). organic matter collected; washing with brine; focus. The remaining sol) was purified by flash chromatography column on silica gel (A) petroleum/EtOAc =

Bank 1: to )1 :500 to obtain (S)-Methyl 2-(tert-butoxycarbonylamino)-3—cyclopentenylpropanoate as viscous oil (aa NY) 9677 yield). 1H NMR (300 MHz, CDCI3): 6 5.48 (br s, 1H), 4.97 (d, J = 6.6 Hz, 1H), (m, 1H), 3.74 (s, 3H), 2.46-2.63 ( m, 2H), 2.23-2.34 (m, 4H), 4.40-4.43 (m, 2H), 1.45 (s, 9H). © 1.82-1.93 to a solution of (S)-methyl 2—(tert-butoxycarbonylamino)-3- cyclopentenylpropanoate (17 g (Use +, YY) in water/methanol (000 mL): 7 1) Lithium hydroxide hydrate (arctgy 510 mol) was added. The reaction mixture was stirred at ambient Shall °C overnight and thereafter the concentration AY Vo most of the methanol. The remaining sald) was washed with DOM (£00 mL) and the SW phase was acidified with HOI diluted to pH = -7; The resulting mixture was extracted using DCM (Yoo) milliliters (FX). The organic layers were combined and concentrated to obtain -1611)-2-(5) “xa 07) Butoxycarbonylamino)-3-cyclopentenylpropanoic acid 76550 yield) in the form of oil. sticky; They were used in the next step without further purification. 1H NMR (300 MHz, CDCI3): 6 10.47 (br. 5, 1H), 5.52 (br. s, 1H), 4.98 10 (d, J = 8.1 Hz, 1H), 4.40-4.44 (m, 1H), 2.50-2.70 (m, 2H), 2.25-2.34 (m, 4H), 1.79-1.93 (m, 2H), 1.45 (s, 9H). into a beaker filled with (S)—2 ~(tert-Butoxycarbonylamino)-3- 70 can 00,4) cyclopentenylpropanoic acid mmol) THF/DCM (Ave) 0 10 mL was added (1:1). The solution was cooled to 0°C. Celsius and the addition of ethyl chloroformate (© ;? milliliters Yov mmol) Yov ¢ sills YA, 3 NMM mmol) by distillation thereafter. after addition; The mixture was stirred at 0 °C under nitrogen for 1 hour. To the other beaker filled with a ©-dimethylhydroxylamine (Ak YoV (aa Yo) HCI dimethylhydroxylamine mol) (g++) DCM was added.

1/6

milliliters). The mixture was cooled to 0°C and YYA (mmol slike YAY) TEA was added. The resulting mixture was transferred to the previous reaction beaker. The reaction mixture, Bad, was left to ambient temperature and stirred overnight. The mixture was quenched with water (5000 milliliters) and the organic phase was washed with water (00© milliliters); drying over anhydrous sodium sulfate; and focus © to obtain (S)—tert-butyl (3—(cyclopent-1-en-1-yl)-1- (methoxy(methyl)amino)—1-oxopropan-2-yl)carbamate on da pure oil

color (can Te) 9697 toll ; They were used in the next step without further purification. to a solution of (S)—tert-butyl (3—(cyclopent-1-en-1-yl)-1- AY) (methoxy(methyl)amino)—1-oxopropan-2-yl)carbamate g; 171 mol) Ye in 001( THE milliliters) Ala) a freshly prepared amount of prop—1-en-2-ylmagnesium 0.1 ill 47,056 mol) was done at zero degrees Biology by distillation. After the addition is completed; The reaction mixture was stirred at 0 °C for 1 h, then quenched with saturated aqueous ammonium chloride (0 vv) 0 mL. The resulting mixture was extracted with EtOAc (£44 x 7 mL). The organic phases were grouped; drying over anhydrous 15 sodium sulfate; focus. The residue was purified by a flash chromatography column on silica gel (Jl) petroleum/1:001 = EtOAc to obtain (1-(cyclopent-1-en-1-Al1111-5-(5)). yl)-4-methyl-3—oxopent-4-en-2-yl)carbamate as colorless oil

aa 9.7 (96507 toll). A solution of (S)-tert-butyl (1-(cyclopent-1-en—1-yl)-4-methyl-3- can 0 ) oxopent-4-en-2-yl)carbamate Ye was cooled. 75.1 mmol) in YA (DMF mL) to yom acidity and bleach was added (08.0 mL 7017 mmol; + (%) by distillation under nitrogen. The reaction mixture was warmed to 0 °C and stirred for 1.0 h. Water (Yoo) was added (mL) and the mixture was extracted with EtOAC (001 mL x “). The organic phases were collected, washed with Brain (700 mL 7 7), dried over YO sodium lamate sulfate, and concentrated.

Ag 7 \ _ silica gel to obtain tert-butyl ((S)-3—(cyclopent-1-en-1-yl)-1-((R)-2- methyloxiran—2-yl)—- 1-oxopropan—-2-yl- 1636 as viscous oil (0.1% oY can yield). 1H NMR (300 MHz, CDCI3): 6 4.62 (s, 1 H), 4.91 (d, J = 7.5 Hz, 1 H), 4.44-4.37 (m, 1H), 3.29 (d, J = 4.8 Hz , 1H), 2.89 (d, J = 4.8 Hz, 1H), © 2.56-2.52 (m, 1H), 2.29-2.26 (m, 5H), 1.92-1.82 (m, 2H), 1.51 (s, 3H) ), 1.41 (s, 9H). The following compound was synthesized in a similar way: tert-butyl ((S)-3—(cyclohex-1-en-1-yl)-1~((R)-2-methyloxiran-2-yl)-1- oxopropan -2-yl)-carbamate 0 1H NMR (300 MHz, CDCI3): 5.46 (s, 1H), 4.87 (d, J = 7.5 Hz, 1H), 4.45-4.38 (m, 1H), 3.31 (d, J = 5.1 Hz, 1H), 2.90 (d, J = 5.1 Hz, 1H), 2.44-2.38 (m, 1H), 2.01-1.90 (m, 5H), 1.64-1.48 (m, 4H ), 1.48 (s, 3H), 1.42 (s, 9H). 1 Ex 10 tert—Butyl ((S)—3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1- oxopropan-2-yl- carbamate 0 0 0

TY H,, Pd/C (TL MeONHMe LO

NHBoc - NHBoc - 66

NHBoc Meat NaOCl - _— 0

NHBoc BocHN 0 to a solution of (S)—2~(tert-butoxycarbonylamino)-3-cyclopentenylpropanoic 0 g Y 9 Pd/C mL) and then adding Cun (mol) in YY methanol (aa ° 7) acid Yo

—YVi- atmospheric) at ambient temperature throughout (1 mol; +) %). The mixture was stirred under hydrogen atmosphere overnight and then filtered through a bed of silite. The filtrate was concentrated under reduced pressure (S)—2~(tert-butoxycarbonylamino)—-3-cyclopentylpropanoicacid (for yield) as viscous oil; It was used in the next step without further 90997 aa 00) tert-butyl ((S)-3-cyclopentyl-1-((R)-2- remainder of the dn synthesis. Purification: Done by © tert- method Similar to the synthesis of methyloxiran—2-yl)—1-oxopropan-2-yl)carbamate butyl ((S)-3-(cyclopent-1-en-1-yl)-1—((R)-2-methyloxiran- 2-yl)-1-.oxopropan-2-yl-carbamate 1H NMR (300 MHz, CDCI3): § 4.90 (m, 1H), 4.30 (m, 1H), 3.30 (d, J = 5.0 Hz, 1H) , 2.90 (d, J = 5.0 Hz, 1H), 1.57 (s, 3H), 1.51 (s, 9H), 1.95- 0 1.20 (m, 11H). tert-Butyl ((S)-3—(3, 3-difluorocyclobutyl)-1-((R)-2- : vv Jb methyloxiran-2-yl)-1-o- xopropan-—2-yljcarbamate nN 8 : 3 + f EF tH PAC a, SRM :

A 2 BART M 2 Riis Ch 27 a plo > o

Ty No ww Ae Ps 3 Aal Jjah 1 0 A ad Sng 3 © hs Tw =e 5 Help Ps 4 Bry MG 1 pont 5 1 4

Aree SA (2

N.E. Seon

Seem

Born” L L’ E TT Ninh © x ey 4 Tamu B 0 Fook PY 3 h

FCI Le

Boch AA. B, oxocyclobutanecarboxylic cyclobutane carboxylic SY, then stirred a mixture of acid

—YVy- 77 aa mol (£0) €) benzyl bromide mol (benzyl bromide) 177 aa YO (mL) overnight at DMF (Yo mol) in 0.44 vol T0 , Y) and potassium carbonate (mL). Yoo) ambient temperature. The mixture was separated by filtration and the filtrate was decanted in water Extraction products were collected (FX mL Yeo) BtOAC The resulting mixture was extracted using organic; drying over anhydrous sodium sulfate; focus. The residue was purified by column 5 to obtain (1:01 to 1:001 = 81086) fluorescence chromatography on silica gel (petroleum ether/yield. 96/4 aa YA) to benzyl ester. DAST (44 g) The benzyl ester was dissolved in dichloromethane (000 milliliters) and 96010 mol was added. The reaction mixture was stirred overnight at ambient temperature. The solution was poured into aqueous sodium bicarbonate fizzled with ice (£00 milliliters). The organic layer was separated and the Ye (FX mL Veo) chloromethane (gla) chloromethane layer was extracted using anhydrous sodium sulfate and concentrate. The residue was purified by column chromatography to obtain 1) 300 (J) Yee = 81088 flash on silica gel (petroleum ether/yield). 9011 g; YA) benzyl 061050180668006/A3,3-011100100 117 Gp YA) benzyl 3,3-difluorocyclobutanecarboxylate A mixture of Vo is hydrogenated at ambient temperature. 1 mL (for 151 minutes) was filtered in methanol (aa ©) and 0/0 (Use 0/0) separated by filtration and the filtrate was concentrated. The residue was dissolved in dichloromethane (Use ©7560 can To,A) DMAP (mL) and cool down to 0°C (Yoo mol) sequentially. EDCI (+) E+ aa ¥1.9 mol) and 11460 cua (14.7 Meldrum mL) were added and the reaction mixture was stirred overnight at ambient temperature. Water was added 0 products were collected (FX mL Tao) The resulting mixture was extracted using dichloromethane organic extraction; drying over anhydrous sodium sulfate; focus. The residue was purified to = 1:001 by flash chromatography column on silica gel (5-(3,3—difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3—dichloromethane/methanol) to obtain (0:1 toll). 9674 aa Yi) 010*806-4,6-010068 | ©

—YVA- 5-(3,3—difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3- A solution of apo (mL) to (Ye) THE mmol) cooled in oV,Y aa Vo, +) dioxane-4,6-dione © mol). The mixture was stirred for +, TY g; TA) acetic 8050 mol and acetic acid (mol) was added over 101 g; (1,0) sodium borohydride min and sodium borohydride was added h at 0 adjika degree and then pour into the water 1 batches. The reaction mixture was stirred for (Vx mL Yeo) (0/6 mL). The resulting mixture was extracted using chilled Yoo organic extract pooling; drying over anhydrous sodium sulfate; focus. The residue was purified by flash chromatography column on silica gel (dichloromethane/methanol).

5-((3,3—difluorocyclobutyl)methyl)-2,2—- to obtain 0:1 to 0:1 g 9607 yield). AY) 1,3-010808-4, 6-68-F01018 i 5-((3,3—difluorocyclobutyl)methyl)-2,2—-dimethyl-1,3- A solution of benzyl alcohol mmol) and benzyl alcohol YAY g heated Vyee ) dioxane—4,6—dione mL) at 48-90 °C overnight. The toluene was removed and 10 (mL) in toluene 10 the residue was purified by flash chromatography column on silica gel (dichloromethane/methanol which has been hydrogenated in benzyl ester to yield benzyl ester) 1:0 to 1 Yee = hour at ambient temperature. Presence: 1 milliliter) for Yo (g) was soaked in 1 (0/00) methanol by filtration and the filtrate was concentrated to obtain Pd/C separation g; 9677 yield). ¥ ,V) 2—((3,3-difluorocyclobutyl)methyl)malonic acid 2-))3,3- by distillation into a solution of (AL 0.,1( Bromine ddl) mmol ) in diethyl 11,8 aa 1,Y) difluorocyclobutyl)methyl)malonic acid 00 The mixture was stirred for 0 Sls (ml) keeping the solution when returning 0) diethyl ether ether (0) minutes and water was added (0) milliliters) keeping the mixture for return. The organic layer was separated 0 . and focus

—Yva-

Shall °C for ¥ h and then cooling to 1660 °C the residue was heated at and the resulting mixture was washed (Alle 04) ambient. Saturated aqueous sodium bicarbonate was added. The aqueous layer was acidified to a pH of - (1 x mL Yo) EtOAc using saturated aqueous EtOAC (04 x mL) and then extracted using KHSO4. Using the organic extracts were collected; drying over anhydrous sodium sulfate; and concentrate to obtain (g. YY) a yellow oil (001) isopropyl alcohol. A solution of yellow oil was treated in isopropyl alcohol overnight at ambient temperature. The solvent was removed and NH3 was autoclaved in Presence of (ile g Y,+1) PhCH2COCI mL) followed by the addition of Yo (dissolving the residue in acetonitrile mmol) and triethylamine (09.09 mL 77.7 mmol). The reaction mixture was stirred = 1,9 0 for 7 hours. Water (04 mL) was added and the resulting mixture was acidified to pH Extraction products were collected (FOX chloromethane) 00 mL (gla; extraction using organic; drying over anhydrous sodium sulfate and concentration. Substance was purified remaining by column She = 1:01 to 1:001 (dichloromethane/methanol) 3-(3,3-difluorocyclobutyl)-2-(2-phenylacetamido)propanoic gel to obtain on Vo yield .96460 aa), ¢) acid 3—(3,3—difluorocyclobutyl)-2-(2-) then stirred a mixture of g)01 (PGA mmol) and coenzyme 7 “aa 0.4 ( phenylacetamido)propanoic acid (milliliter) with a pH of -9-8 for ? days at 77°C. The enzyme 1) was separated in water by filtration and the filtrate was acidified to a pH of -4. The resulting mixture was washed with Ys (Y x 01 mL) EtOAc

Yo) in acetone/water (se). The aqueous layer was treated with 80020 (4.07 g; 7.1 ms for © hours at ambient temperature. A = mL) was removed at pH 10 mL/acetone and the aqueous solution was acidified to pH = 4. The mixture was extracted using combined organic extracts; and drying over sulfate (FX 04 mL) EtOAc Yo

CY A= sodium anhydrous and concentrate. The residue was purified by a gel flash chromatography column (S)—2-(tert— to yield 1:01 to 1:001 = silica (dichloromethane/methanol g), 5 ( butoxycarbonylamino)-3-(3,3-difluorocyclobutyl)propanoic acid yield). 7 : isopropylchloroformate (10+g) added; 5.8 mmol) by distillation to a solution of 5 (S)—2~(tert-butoxycarbonylamino)-3—(3,3-difluorocyclobutyl)propanoic mmol) in 5.0 g di; ,£ mmol) and N-methylmorpholine (4.0 g; ), (Y) acid h at 0 degrees 1 mL) at 0 degrees Celsius. The mixture was stirred for 71 (chloromethane 5.1 mM; 0.0) HCI-HCI followed by the addition of a mixture of No-0-dimethylhydroxylamine mL). (Yo) mmol) in dichloromethane 5.0 and diethylamine (0.14 mL) (Use 0 01) aqueous HOI 965 ambient temperature and pour in day The reaction mixture was stirred overnight at EtOAC products (7 x 00 milliliters) were collected. The resulting mixture was extracted using organic extraction; washing with saturated sodium bicarbonate (101 mL); And drying over the remaining by flash chromatography column on sald) sodium anhydrous sulfate and concentrate. Purified: to yield 1:01) to 1:001 = .silica gel (dichloromethane/methanol 1 (S)-tert-Butyl 3—-(3,3—difluorocyclobutyl)-1 -(methoxy(methyl)amino)-1- yield).%AY g; ,Y) oxo propan—2-ylcarbamate (S)—tert-Butyl 3—(3,3—difluorocyclobutyl)-1 - 11 g ml 0 ( (methoxy(methyl)amino)—1-oxo propan-2-ylcarbamate ml) was dissolved and then cooled to 0°C. Prop-1- Yen-(Yo) THE mol) was added in Ys h at 1 mol) by distillation and the reaction mixture was stirred for a period of (V£,93 lle) ylmagnesium bromide -" ambient temperature The mixture was decanted in ice water (00 mL) and extracted using combined organic extracts; drying over L(V x 10 mL) sodium sulfate anhydrous EtOAc sodium sulfate and concentrate. The residue was purified by a gel flash chromatography column ,

-1M ?- silica A) petroleum/ 1:0010 = EtOAc to 1:001) to get -1 (S)-tert-Butyl (3,3—difluorocyclobutyl) -4- methyl-3-oxopent-4-en-2-ylcarbamate (in g; 9677 yield). A solution of (S)-tert-Butyl 1-(3,3-difluorocyclobutyl)-4-methyl-3—oxopent-4-en-2-ylcarbamate ° ) was cooled to 7.1 mL mol) in DMF (0 mL) to 0 °C and add 9000 aqueous NaCIO solution (560, 0176 mL (se) keeping the internal temperature below © °C. The reaction mixture was stirred for 1 hour at 0 °C and poured into saturated aqueous sodium bicarbonate (04 milliliters). The resulting mixture was extracted with EtOAC (04 mL L(V) x organic extracts collected; 0 washing with Braine (001 mL) oF X drying over anhydrous sodium sulfate; concentration. The residue was purified by scintillation chromatography column on silica gel (petroleum ether/ 56086 - 1 < 0 to 1 ) :* 00 to obtain tert-butyl ((5)-3-(3,3-difluorocyclobutyl)-1 (((R)-2-methyloxiran—2-yl)—1-oxopropan-2- -yl)carbamate )+ )0 mg 7 yield). (d, J = 8.7 Hz, 1H), 4.25 (m, 1H), 0 5.02 e 1H NMR (300 MHz, CDCI3): (d, J = 4.5 Hz, 1H), 2.93 (d, J = 4.8 Hz, 1H), 2.73 (m, 2H), 2.25 3.23 (m, 3H), 1.92 (m, 1H), 1.55 (m, 1H), 1.54 (s, 3H), 1.43 (s, 9H). : tert-Butyl ((S)-3-((1R,5S,6s)-bicyclo[3.1.0]hexan-6-yl)-1-:((R)~2-methyloxi- ran- 2-yl)-1-oxopropan-2-yljcarbamate 90

—YAY- May I forgive you

H fi an AA 8 MaliH H

Fa ry pe + A Fa ~ TN B ala "ML Ce AT MSN CAS NE' 3 3 % MHP 0 Ty RHE

LTES wn 2 Rel x a l 3 LOH vid 2 yrw then lghssm eH 0 rrr iE HN l w autelss 7 a 8 ha 4 NHR od a: m na a A 2 heat ny Ale ra 0 ~ LE a NaC SEN

Ca —— ayy — Ls

M BHBOS i? NHS Bont ¥ g; mol); 0.00 g; 5.5 mL (VY) DBU 5 mol) 19.4 aa) +, +) (dimethoxyphosphoryl)acetate h. The mixture is poured into 1 mL (at ambient temperature for DCM mol) (Vor) in ©

DCM (Veo) in milliliters) and the resulting mixture was extracted using Vor (140 l - saturated water mL) 001 saturated aqueous NHAC. The organic layers collected using Jue (Vx mL - saturated aqueous salad) were 4 and drying over anhydrous sodium sulfate and concentration. Then purify A) and Brain (Y x) to the remaining EtOAc = 1:01 by flash chromatography column on silica gel (petroleum/methyl 3-(cis-bicyclo[3.1. 0]hex-2-en-6-yl)-2—(tert— to obtain 1:¢ 0 yield) as colorless oil. 9677 (aa 0,7) butoxycarbonylamino)acrylate methyl 3— (cis— g; 78.5 mmol) in parts to a mixture of 0.00 0( NaBH4 bicyclo[3.1.0]hex-2-en-6-yl)-2~(tert-butoxycarbonylamino) added acrylate mmol) in 19.8 g methanol; 6H2O-NICI2 (VAL) 5 mmol) 15.8 g; (0 lb.8) min and then decanting 11 ml) at 0 Celsius. The reaction mixture was stirred for 1 Vee

Yoo) DCM in milliliters). The resulting mixture was extracted using (001 in 1140 l saturated aqueous mL) 001) saturated aqueous NHAC collected organic layers using Jue Tum (Vx mL).

—YAY- (1) * and Bryan (001 milliliters); drying over anhydrous sodium sulfate and concentration. The residue was purified by flash chromatography column on silica gel (petroleum ether/1:01 = EtOAc to: HPLC 4)1 preparatively to obtain - (Ala-0[78*80-6.615- 5101/010]3.1)-3 methyl %YY aa), +) 2—(tert-butoxycarbonylamino)propa—- noate) as colorless oil. has been implemented. Remaining synthesis a, for special procedure tert-butyl (S)-3—(trans— bicyclo[3.1.0]hexan-6-yl)-1-((R)-2-methyloxiran-2-yl )~1-oxop- 10080- .2-ylcarbamate vo Example :(S)-Methyl 2-amino-3~(1H-indol-5-yl)propanoate Yu ‎je CbzHN” ~COOMe , wa PPh

NH m" Zn, Pdy(dba), H

RES. 8 S-Phos H,, Pd/C CbzHN™ “COOMe” OMe HN OMe 0 6 A mixture of triphenylphosphine (YY,Y) g; 8860 mol) imidazole (cpa, 0 mol) imidazole (84 mol) in DCM (001 milliliters) to zero pH and iodide (77.1 g) was added (Use AS) in small portions over 0.5 hours After AY Vo cooling bath the mixture was stirred for 6.5 hours After sale the mixture was cooled to 0°C a solution of aa 05.1 Cbz-L-Ser-OMe 09 was added , + mol) in 001 DCM (mL) by distillation. after adding; The cooling bath was removed and the Bad mixture was cooled to ambient temperature by stirring for 1.5 hours. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (40 mL) was added to the residue and the mixture was filtered to remove triphenylphosphoine 0 oxide. The filtrate was concentrated and the residue was purified by a flash-gel chromatography column

-06M ?- silica (petroleum ether/ 1 00 = EtOAc to 1:01) to obtain -2 (R)y-methyl VY,Y)(benzyloxycarbonylamino)-3-iodopropanoate g 9601 yield) in the form of a colorless solid. to a suspension of zinc (07 Y, g; YALA mmol) in DMF (Yo) mL) was added, followed by the addition of a solution of (©)-methyl 7-(benzyloxycarbonylamino)-?-iodopropanoate (4,760; 11 μmol) in DMF (Yo) milliliters). The mixture was stirred at ambient temperature for ¾ minutes and heated at TO ºC for 50 minutes. Thereafter a solution of ©—bromo-11-indole (15.5 aa ov) mmol) in DMF (Vo) milliliters); 3 (Use Ak 1717 aa ,71) and 5-0005 (75 g; 110 mmol) were added. The reaction mixture was stirred at 0 °C under nitrogen overnight and then cooled to Ambient temperature Braine 000 (5 mL) was added and the resulting mixture extracted with EtOAC (70 mL (FX organics collected; washing with Tb Braine) mL) and concentrate. by scintillation chromatography column on silica gel (AY) petroleum/EtOAc = 1:01 to 1 zo to obtain (S)-methyl 2—(benzyloxycarbonylamino)-3— (IH-indol -5-yl)propanoate yo as viscous oil (aa VYY) 9060 yield). to a solution of (S)-methyl 2-(benzyloxycarbonylamino)-3—(1H-indol-5- VOY V)yl)propanoate g LV mmol) in methanol (79 mL) and then add Pd /C 001 PNY (mg). Then the mixture was stirred under hydrogen atmosphere at ambient temperature for 1 hour and then filtered through a layer of silite. & concentrate the filtrate to obtain 2-amino-3—(1H-indol-5-08-(5),A)yl)propanoate g %AA yield) as sale green solid Light; It was used directly without further purification.

C A \ — Ex. 76 (S)-Methyl ~~ 2—amino-3—(3—(benzyloxy)-4-methylphenyl)propanoate 8 BocHN™ "0006 OBn BnBr 20, 9 KoCO3 cr S-Phos 6 Br 080 DMF ies Br OH BocHN™~ 006 OBn TFA DCM HN" ~COOMe to a solution of 5-bromo-2-methylphenol (0.4 pYY mmol) in acetonitrile (pli 00) 0 was added K2CO3 (4, Abe VY aa mol) followed by benzyl bromide YY aa 0,0 ) mL bromide (Use) The suspension was heated at 5-10 °C for 10-10 hours and then cooled to ambient temperature. The mixture was filtered and the filter cake was washed with acetonitrile (Yo) (mL). The filtrate, wash products and concentrate were combined to dryness. The residue was purified by flash chromatography column on silica gel (hexane/EtOAc = 1 )1 0 to yield (S)—methyl 3—(3—(benzyloxy)-4-methylphenyl)-2-(tert). - butoxycarbonylamino) propanoate (0.5 g/qm) as oil. Dry DMF (01 milliliters) was added to zinc dust 018 aa Vv (mmol) in a flame-dried flask at 2 to 8. R)-methyl 2—(tert-butoxycarbonylamino)-) 4,Y) 3-iodopropanoate g added; YA mmol) and a catalyst amount of iodine (97 g; 1 mVo mol). The mixture was stirred at ambient temperature for 0.5 hours; 1) aa 5-0005 (Js Ak 0.10 aa 1,4(3 4.6 mmol)-2-(benzyloxy)-4-bromo—1-methylbenzene (1,0 g) was then added. 770 mmol).The reaction mixture was stirred at 10°C for 7 h and then cooled to ambient temperature.Can (EtOAc mL) and Ma (Cun s mL) were added and the organic phase separated; washing with Yeo water (Yo Xx mL) and Brian (Yeo X 1 mL) and drying over anhydrous sodium sulfate

—YA- residue by flash chromatography column on silica gel (hexane/sald) and concentrate. (S)-methyl 3-(3—-(benzyloxy)-4-) was purified on 1:01 - EtOAc 7677 g; £,+) methylphenyl)-2—((tert-butoxycarbonyl) (amino)propanoate (S)—methyl mL) to a solution of -4-(/a*0l5602)-3)-3 0) TFA added © 0#0g 01(methylphenyl)-2- ((tert-butoxycarbonyl)amino)propanoate 1 milliliter) at 0°C with stirring. The mixture was stirred for 10 DCM (mmol) in

EtOAc for 1 hour and then concentrate to dryness. The residue was azeotropic treated with (S)—methyl 2—amino—3— and obtained the crude product TFA to remove residue (Fx 01 mL) from it. TFA in the form of salt (3—( benzyloxy)-4-methylphenyl)propanoate |

PN COOH Mel A CoOMe or Lo PN COOMe

ET Loe CT Tree ESR (4-1)(3-Br) (4-SO,Me) (3-SO,Me)

K2CO3 mmol) to a suspension of YO g; 7,1 lodomethane (iodomethane 0 g; © iodophenylalanine mmol) and ©80-a-? - Iodophenylalanine, Yo aa, 5 (for an Aggie degree fv, milliliter). The reaction mixture was heated at ou (mmol) in acetone for 105 hours. The mixture was cooled to ambient temperature and then filtered. The filter cake 0 was washed with acetone (00 mL) and the filtrate and wash products were combined. The solvent was removed and the residue was purified (1:01 = EtOAc) by flash chromatography column on silica gel (hexane/0-iodophenylalanline methyl ji.) —¢-L-Boc to obtain a yield ) as a colorless solid.‎ 70957 aa (5,; ester

—YAV-

Boc-L-3-bromophenylalanline methyl ester was prepared from ©1-80-? - Iodophenyl Boc—L-3-bromophenylalanine alleline methyl ester. A mixture of ©800-a-?-bromophenylalanine methyl ester (7.0 g; © mmol) was heated;

Cul (mmol) 1 mg; 000(50000 methanesulfinate sodium methanesulfinate © 01 sodium methane sulfinate (DMSO) in 1 mg; 47) The mixture shall be cooled to UN2 hr under VY sad mL (at 960 °C mL). The resulting mixture was extracted with ambient Foo and then diluted with 1 pH aqueous water. The combined organic phases were washed with “(FY x mL 001 (EtOAc 0 X mM Cu) and Bryan 10 X mL Yoo) saturated aqueous NaHCO3 oY X mL Yoo) Ye, respectively. The organic solution was dried 38 anhydrous sodium sulfate; focus. The substance was purified to obtain the remaining 1) Y = EtOAC: by flash chromatography column on silica gel (hexane/methylsulfonylphenylalanline methyl ester abil methylsulfonylphenyl —¢-L-Boc on yield) on Colorless solid body. 90017 aa 1,1( methyl ester) sulfonylphenylalanylene methyl ester was prepared in a similar way. Jie 806-a-2-1

YA Example 6-Bromo-3,4-dihydro—1H-benzo[c][1,2]thiazine 2,2-dioxide

OH 0 > -. MsCl CX o MnO, 0 o and Ce

NH, NH-§— NH-§— of 0 0

Li/NH, Nes Br — (Le — Clk mL; Y+,Y) methane sulfonyl chloride A solution of methanesulfonyl chloride 0 mL) is added dropwise to a solution of (7-amino 001 (chloroform mol) in chloroform + VY

Yoo) mol) in pyridine 107 g; 059.01 ((2-aminophenyl)methanol) methanol

—YAA-

milliliters) and chloroform (104 milliliters) under nitrogen over 1 hour at 0°C. The reaction mixture was stirred for 11 hours at ambient temperature and then washed with (V) HCl; You milliliters (YX) organic phase was dried over anhydrous 0.504 and concentrate. The residue was purified by flash chromatography column on silica gel (JEtOAc) (hexane = :1) to obtain N-[2- VY, +) (hydroxymethyl)phenyljmethanesulfonamide g; 97007 toll) in the form of

yellow oil. Junie dioxide (9685; 45.0 157 con mol) was added to a solution of N-[2- VY, +) (hydroxymethyl)phenylmethanesulfonamide g; Ae To mol) in di 0 chloromethane (mL) at ambient Shall degree under nitrogen. The reaction mixture was stirred for 11 hours and then filtered through a layer of celite. The layer was washed with dichloromethane/methanol (1:1) and the combined organic matter was concentrated to yield N-(2= aa 011( Formylphenyl)methanesulfonamide 9074 yield) as a solid.

yellow coloured. Vo carbonate added (VA, +) Cesium carbonate, gin g; 00 mmol) and benzyl bromide (de Me oo «gli 7,7) benzyl bromide to a solution of N-(2-formylphenyl)methanesulfonamide ) 0.00 g 7.1 mmol) in acetonitrile YY ) milliliters). The reaction mixture was heated at 01 °C for 11 Bad hours and then cooled to ambient temperature. The mixture was diluted with Yeo (EtOAC (mL)) and filtered. The Yo filter cake was washed with 6/10 Yoo (mL) and the combined organics were concentrated. The remaining sala was purified by flash chromatography column on silica gel (EtOAc) (hexane-1:©) to yield 1-benzyl-1H-benzo[c][1,2]2,2-thiazine dioxide (1.0 g);

%AY yield) as a colorless oil. Freshly polished lithium foil (0,174 con mol) was added to a solution of 1-benzyl-1H- YE xa (7,0) benzo[c][1,2]thiazine 2,2-dioxide Yo mM Mall) at 01 ( THE

—YAS- mL) at £0°C with stirring (Yo) liquid NH3 (5 mL) EtOH (VY) mL/g). Water was added (NHACH 10 hr. The reaction was quenched using 1.5 mL aqueous phase extraction As powder). Then the two layers were separated by Yoo (EtOAc mL) Yeo) The combined organic phases were washed with Brain (Fx 01 mL) EtOAc using and dried over anhydrous sodium sulfate; the concentration. The residue was purified (Vx 0) Yeo (0) milliliters to obtain 1:4 = hexane [EtOAC) by column scintillation chromatography on silica gel yield (967 4 an V,0) 3,4-dihydro-1H-benzol. [c][1,2]thiazine 2,2-dioxide 3,4-dihydro—1H- was added to a solution of (Use te AY aa V0) NBS (ml) DMF (1 °) mL mol) in AY g 0 °) benzolc[1,2]thiazine 2,2 dioxide mL) Yoo) The reaction mixture was stirred overnight at ambient temperature followed by the addition of water 0

EtOAc in milliliters). The two layers were separated and the aqueous phase was extracted using 001 (EtOAc 3); x milliliter Yoo) the combined organic phases using Brian Jue 7 x lll 001 column chromatography (dail gs remaining salad). Drying over anhydrous sodium sulfate 4 and concentration. Then purify 6-bromo-3,4- to obtain (Y:1 = hexane [EtOAC) flashing on silica gel yield). 9679 aa, 7( dihydro—1H-benzo[c] [1,2]thiazine 2,2-dioxide 10 va Example (R)-Methyl 2—(((tert—-butoxycarbonyl)amino)-3—(2-(2,4-dimethoxybenzyl)- 1,1 -d- ioxido—3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)propanoate 1. CISO3H Poa 2. MeO.OMe 1. LiBH

Jo aw JJ 0 NH 2. DEAD, PPh,

Br CoMe MS 5AAA 0

AL

CO,Me 9 0 OMe I 9 8 OMe Todd Miss Name

Br OMe 806011017 OMe

—Y4.— mmol) by distillation into AY can Yo) Methyl 2—(3-bromophenyl)acetate (mL) was added at zero degrees Celsius. The reaction mixture was stirred overnight at CISO3H (14 mL) slowly and the mixture was extracted (100 mL ambient temperature. The solution was poured into ice-water 7 7 mL). organic extracts collected; drying (001) (0/6 of the yield) using anhydrous sodium persulfate; concentration (©mL) and cooling to zero (001 (g) in dichloromethane (Yo) the resulting red oil was dissolved 2) 0.746 mol (and add YY) in Celsius. triethylamine dap g; 1.0 mmol) slowly. The mixture was stirred 11.7 (dimethoxyphenyl)methanamine (mL) and Yoo) for 1 hour at ambient temperature. The mixture is poured into water for 1 reaction and then the products are collected X 000 milliliters Yeo) Extraction of the resulting mixture using dichloromethane Yeo organic extraction; drying over anhydrous sodium sulfate; focus. The residue (1) to ?: 1:01 = EtOAc was purified by a flash chromatography column on silica gel (petroleum ether/methyl 2-(5-bromo-2-(N-(2,4-)) to obtain 9016 gm toll). Vo was added g; [THE in (se mL) 17 h at ambient temperature and then pour into ice-water 1 Stir the reaction mixture for (Vx 001 mL (6/10 mL) collected The resulting mixture was extracted with 100 (mL); drying over sulfate (You) organic extract; washing with 0 brine.

sodium anhydrous; and concentration to obtain the corresponding alcohol (0,005 can £,V mmol). Alcohol (AL 7.7 can V8 mol) and DEAD (1.0 g; 6.5 mmol) were dissolved in THF (50 mL) followed by the addition of 00503 (1.1 g; 1, 0 mmol) in batches. The reaction mixture was stirred overnight at ambient temperature. The solvent was removed and the residue was purified by a Yo column flash chromatography on silica gel (Ji/1 Vo = EtOAc to 1 zo) to obtain

6-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine),Y)1,1-dioxide g; 96951 yield) in the form of a yellow solid. iodine (1+ aa 87 mmol) was added to a mixture of R)-methyl 2—(tert-) ,01( butoxycarbonylamino)-3—iodopropanoate g; 7.54 te mol) and your weight can be ,170 (0 9.75 mmol) in DMF (Yo) milliliters). The mixture was stirred for 10 minutes and an AT fraction of iodine 1.47 CAN ©11 (mmol) was added. The mixture was stirred for another 1 hour. 6-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydro-2H- 0,7 4(benzo[e][1,2]thiazine 1,1-dioxide g) was added; ¥,Yo m Pd2(dba)3 «(Js can 6 A) a 0 mmol) RY can 6 Yo ) S-Phos mmol). Then the reaction mixture was stirred at 00 degrees for a period of time; hours and then refrigerate to ambient temperature. The mixture was filtered and the filtrate was decanted into water (0 milliliters). The resulting mixture was extracted using 100 mL EtOAC (L(V Xx) organic extracts were collected; drying over anhydrous sodium sulfate ¢ and concentration. Then the residue was purified by dail gs by a flash chromatography column on a petroleum silica gel Ji / 1 Vo = EtOAc to ?: )1 to get -2 (R)-methyl (((tert-butoxycarbonyl)amino)-3—(2—(2,4-dimethoxybenzyl)-1, 1 -dioxido— 10 ‎—dihydro-2H-benzo[e][1,2]thiazin-6-yl)propanoate (0.8 g, 46% -3,4 ‎can +, A) yield) 9647 yield ) in the form of a yellow oil. Example 560 (S)—-4-(3-(Benzyloxy)-2—((tert-butoxycarbonyl)amino)-3- oxopropyl)pyridine 1 -oxide 90 BnBr 0-2 .1 p.O. m-CPBA 2.b BocHN™ “COOH BocHN™ 0080

Bromomethylbenzene added (470 mg; 5.14 Ale mol) by distillation to a mixture of (S)-2-(tert-butoxycarbonylamino)-3—(pyridin-4- aa 0.01(yl)propanoic acid 7.76 mmol ) and 7 (052003.0 g; 7.21 mmol) in DMF (Yo) milliliters) at ambient temperature. The reaction mixture was stirred at 0° ambient temperature for 1.5 hours and poured into water (ov milliliters).

The resulting mixture was extracted with [0/6] (00 mL) 1 x and the organics were washed

pooled using water (+©mL) and Brine (+©mL); and drying over anhydrous sodium sulfate

focus. The remaining sald) was purified by flash chromatography column on Sha (petroleum ether/) gel.

1 :*. = EtOAC to obtain the corresponding aa 0.1 benzyl ester (9674 yield) as 0 oil.

To a solution of benzyl ester 0.01 (g; 7.8 mmol) in 112012 Yo (mL) was added

07-0088 (7, g; 5.6 mmol) at 0°C. The reaction mixture was stirred at

Ambient temperature overnight and pour in water (+0 (ile).

The resulting mixture was extracted using 112012 (00 milliliters “7”). Jue Organic Layers 1_Collected using Saturated Water 1182503 (01 milliliters) and Bryan (001 milliliters); And drying over

anhydrous sodium sulfate; focus.

The residue was purified by a flash chromatography column on silica gel [DOM) methanol = 0 5:

(S)—-4-(3-(Benzyloxy)-2—(tert-butoxycarbonylamino)-3—- to get )1

001( oxopropyl)pyridine 1-06 mg;%AT yield) as a colorless solid 0.

+6 Example 1: (2S,3R)-benzyl 2—amino-3-hydroxy-3-(4-methoxyphenyl) propanoate p tay ay ro ben + da FORE NS hd Naw ll haj RN Tune Dj Bass A Xs 0 1 Yee BORG Groups Ee EAS, EN I Re fie 1 AA, ow RT peer LT enone oe ERR he © TEAL DUR EAS 3 MERE, WR, on Aon Bak Loom A solution of glycine (£0 g) was stirred; 0510 mol) and anisaldehyde (YYY) g; 0 0.500 mol) in 0.5*(L) ethanol at ambient temperature and KOH (AY,V) g added; 0 mol). The reaction mixture was stirred overnight at ambient temperature. The mixture was concentrated under vacuum and was mostly ethanol. The remaining salad was dissolved in water (Ave milliliters) and the solution was adjusted to pH = 0 using ; p. 101 watery. The resulting mixture was Jue spiked with EtOAC (Yoo x milliliters ?) to remove any impurities. The aqueous layer was concentrated to a volume of 5-0000 milliliters. Yo The mixture was filtered and the filter cake was thoroughly washed with Yoo (mL) water (Fx) and dried to yield Y4) 2-amino-3-hydroxy-3—(4-methoxyphenyl)propanoic acid g; %YY toll; threo - (on Lua a colorless solid. Thionyl chloride (19 mmol VY, YT) was added by distillation to methanol (You) milliliters) at 0 °C followed by the addition of 2 —amino—3-hydroxy—-3—(4- ‎Yo, +) methoxyphenyl)propanoic acid yo g; 111 Mall). The reaction mixture was stirred at ambient temperature for 1 hour and heated under reflux for ? hours. The mixture was cooled to ambient temperature and then concentrated to dryness. The remaining material was purified by

Scaling column chromatography on silica gel (DCM) methanol = 1) Te to obtain (2S,3R)-methyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (aa Yo, V ) 9654 toll; Therio -) on La colorless oil. Then again separation dad gs polarization preparative HPLC to obtain (28,3R)-methyl 2—amino-3-hydroxy-3—- 2 080016 (Ex4-0061000/060)( 0,1 g; 9640 toll). To Y. THF (ml) was added (28,3R)-methyl 2-amino-3-hydroxy—-3—(4-100(methoxyphenyl)propanoate g; 4.44 mmol) This is followed by 80620 0.13 ( Je 5.77 can mol). The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated to obtain the crude compound (28,3R)-2—(tert-butoxycarbonylamino)-3-) 0,4 54( hydroxy-3-(4). -methoxyphenyl)propano- ate 10 g; quantitative) as a colorless solid. A mixture of (28,3R)-2—(tert-butoxycarbonylamino)-3—hydroxy—3—(4— Ak £,£¢ «an 0,4 4( methoxyphenyl)propano- ate mol) was stirred YA+) LIOH-H20, mg; 1.17 mmol) in MeOH/THF (0? milliliters” 1 sad) 1 : 1 hour at 1 ambient temperature. EtOAc (water (Vo) mL/00 mL) was added and the two phases were separated. The aqueous phase was washed with EtOAC (Yo) mL (Vx) then acidified with HOI diluted to pH = *#. The resulting mixture was extracted with EtOAC (00 mL L(Y x) Organics were collected drying over anhydrous sodium sulfate and concentration to obtain (2S, 3R)-2- (tert-butoxycarbonylamino)-3-hydroxy-3—(4-methoxyphenyl)propano- ic )an acid Yo g 9665 yield ) on Lua is a colorless solid. Benzyl bromide added (£80g; 75.7 mmol) by distillation to a mixture of (2S,3R)=2- (tert-butoxycarbonylamino)-3-hydroxy-3—(4-methoxyphenyl)propano- ic acid )+ +,£ g; 1.4 mmol) 5 Cs2C03 (£.74 g) 1.5 mmol) in DMF (AV) milliliters) at 0°C. The reaction mixture bad was left to ambient temperature Yo and stirred for 1 hour. Water was added (Av) milliliters) and the resulting mixture was extracted using

—Y4o-

Yoo) the combined extracts were washed with water L (Y x 001 mL ( EtOAc salad mL) 4 , dried over anhydrous sodium sulfate 4 , and concentration. Then purified A ( mL) and Bryan to 1:01 = residual EtOAc by flash chromatography column on silica gel (petroleum ether/(2S,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3- to obtain 1) ;: g; 97017 yield) as (hydroxy-3-(4-methoxyphenyl)propanoate 2), a colorless solid. (28,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3— -(4- to mL)?01(DCM mmol) in Y.0 g; Y, +) methoxyphenyl)propanoate min Vo was diluted and the mixture was stirred at 0° resting place After (all Yo) TRA addition in ml) and 001 (saturated aqueous NaHCO3 ml) was separated. (Veo) DCM was added using 0 and the materials were dried (V x 001 ml) DCM two layers. The aqueous layer was extracted using (2S,3R)—organic collected over anhydrous sodium sulfate and concentrate to obtain the compound Crude g; 1,7 ( benzyl 2-amino-3-hydroxy-3—-(4-methoxyphenyl) propanoate quantitatively) as oil; used directly in the next step without further purification. ¢Y Example Vo (28,38)-2—((tert-Butoxycarbonyl)amino)-3-hydroxy—-3—(4- methoxyphenyl)propan- oic acid i HG da 0 8 ye Ls ty NG J al ENP NEE iy n 01 3 > 1 out l — 1 = fe m for "Man".

ALD gp Se + m ya AIBN the SY R oA ka J we ST

Sa khai pr 6 m jal ah oy d ravers) sir + Dad LL EEA Le se wi A] meen nou AF

Hoos “Ne Sook oan

Saturated aqueous potassium carbonate (1,900 mL) and 4-methoxybenzoyl chloride (A) methoxybenzoyl chloride (A) 757 mmol) was added to a solution of glycine methyl ester (Yo (0) g; YY millimoles) in THF (001 milliliters) at zero degrees Celsius. The reaction mixture was stirred for ? hours at zero degrees (Age) and then pour in water (Vee milliliters). The resulting mixture was extracted using Yeo) mL (V x) The combined extract was dried over anhydrous sodium sulfate and concentrate to yield methyl 7-(?-methoxybenzamido)acetate (7,7; BAT con

toll) as a colorless solid; It was used directly without further purification. £1,Y) Methyl 2—(4-methoxybenzamido)acetate g dissolved; YoY mmol) in 0 Vou acetonitrile milliliters). Di~tert-butyl dicarbonate 0117 aa 15.416 mmol (DMAP 01.01 g; YY mmol) was added. The reaction mixture was stirred overnight at ambient temperature and then concentrated. The remaining sal) was purified by flash chromatography column on silica gel (petroleum ether/)100 = EtOAC to yield methyl 2—(N~(tert-butoxycarbonyl)-4-methoxybenzamido)acetate) 07 VO total 9697 toll) in the form of a colorless solid. DMPU (1.75 ? milliliters; Yoo mmol) (5 1) LIHMDS molar of solution; You milliliters; You mL (Use) was added to a solution of methyl 2—( N-(tert-butoxycarbonyl)-4-methoxybenzamido)acetate (YY, 0) g; The reaction mixture was stirred for 1.5 hours at YA = °C and quenched with saturated aqueous NHACH (Vor Ye mL). The resulting mixture was extracted with (You) EtOAc (mL) (Fx (Fx) the combined extraction products were extracted using water (Too (mL) and Brian (Yoo) (mL); drying over sodium lamate sulfate; focus. Jue residue was done with petroleum ether/mL EtOAC (Yoo); )1 0 and drying to yield methyl 2—(tert-butoxycarbonylamino)-3—(4- xa YY) methoxyphenyl)-3-oxopropanoate 9070 yield) as a colorless Yo solid. HCI-EtOAC (1 p) was added from the solution; Yoo milliliters) to a solution of

methyl 2~-(tert-butoxycarbonylamino)—-3—(4-methoxyphenyl)-3- OXOpropanoate (04.4 g” 00 Y mL (Use in Yoo) EtOAC mL) at The degree of the surrounding shall with permutation. The Je lal mixture was stirred for 90 minutes and then concentrated to dryness. The residue was washed with 1mL Yoo petroleum ether (VY x) and dried to yield methyl 2—amino-3-(4-methoxyphenyl)-3-oxopropanoate 2 salt (HCl d?

g; DAA outcome). to a solution of methyl 2—amino-3-(4-methoxyphenyl)-3-oxopropanoate 117 aa 75.5 (mmol) Ae £3 “fille oV,¥) Et3N mol) in (001) DCM (mL) at 0 °C was added dropwise (1",9 (ACI g; VTE mmol). The reaction mixture was stirred at 0 °C for 56 min and then quenched with Ove water. The resulting mixture was extracted with DOM (Yo) mL (YX) and the combined organic layers were dried over anhydrous sodium sulfate and concentrate. The residue was washed with petroleum ether/EtOAC (1001:1) To : YY, )methyl 2—-acetamido-3~-(4-methoxyphenyl)-3-oxopropanoate g 9011 1 toll) as a colorless solid. A solution of : methyl 2-acetamido was cooled -3—(4-methoxyphenyl)-3— AO,Y can YY ,Y)oxopropanoate mmol) in methanol (Ov mL) to 0 °C and AV) NaBH4 was added mg; 75.7 mmol) in batches. The reaction mixture was stirred for 1 hour at 0 °C and then quenched with water (1 L). The resulting mixture was extracted with (0/6) Yoo milliliters (FX) organic extract collected; drying over anhydrous sodium sulfate and concentration. The residue was washed with petroleum ether/100 milliliters EtOAC (10:1) to yield: 2—acetamido-3-hydroxy—3-(4-methoxyphenyl) propanoate (VY 08, g). 9654 yield; image-Erythro >9695) as a colorless solid.

—YaA- to a solution of : methyl ~~ 2-acetamido-3-hydroxy-3—(4- (aa) ¥,0) methoxyphenyl)propanoate 5.5 mL (Use in Yoo methanol (ml) a solution of lithium hydroxide (70, 0101 con mL) was added in water 001 (ml). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated To remove © the organic solvent, the residue: (2-acetamido-3-hydroxy—-3—(4- methoxyphenyl)propanoic acid” was used in solution (SW) directly in the next step. Solution 2 was adjusted —acetamido-3-hydroxy—3-(4-methoxyphenyl)propanoic acid aqueous 0.1 (mL) to pH = 8.5 using 1 M aqueous NaOH and the mixture was filtered. YA °C followed by the addition of –—L acylase 0.1 ( 0 g acylase). The mixture was stirred at FA °C for 7 days and then filtered. To the filtrate 0 was added; - gla xane (You) (mL) and 80020 (1.1 g; 00 mmol). The reaction mixture was stirred overnight at Pad ambient and then concentrated. The remaining Solid) was purified by scintillation chromatography column on silica gel (petroleum ether/ 1:01 = EtOAc to (V2) to obtain (28,3S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4- yl)propanoic acid yo -0080/A*016100 Y,A) g; 90187 toll on three steps). Example 5-Bromo—-1-methylpyridin-2(1H)-one : gy 1. HCI

Re 2. NaH, Mel “TL

N” “OMe NO mM OF, Y g; 001 (5-Bromo—1-methylpyridin-2(1H)-one) an aqueous solution (04 mL) was returned for © hours. The solution was cooled to ©°C HCl in +p (Use sodium sodium hydroxide solution 70710 Eq. to pH = 1.0 using 0 aqueous. The resulting precipitate was collected by filtration and drying to yield ©-bromopyridine 56 g; 96951 toll) as substance A,0) S-bromopyridin—-2(1H)-one —(1H)Y-g 11.0 mL Y, vv) 3-8 00©:+00000/11010-2(111)-00 Colorless solid. Added

-4?4?- mol) in parts to a mixture of sodium hydride (VY +) sodium hydride g; 77.5 mmol) in 001 (THE milliliters) at zero degrees Celsius. The mixture was stirred for 1 hour at 0 °C followed by the addition of iodomethane (AY) iodomethane g; 07.5 mmol). The reaction mixture ad was left to ambient temperature and stirred overnight. The reaction was quenched with (Y) water (mL) and then concentrated. The residue was suspended in water (00 mL) and the resulting mixture was extracted using 0 mL EtOAc (0 mL) vox, then collecting the organic extraction products ¢, drying over anhydrous sodium sulfate 4, and concentrating. Then washing the residue with petroleum Jl Yo) mL) and drying to yield 5-bromo-1-methylpyridin-2(1H)-one 1.97 (c 9679 yield) as a yellow solid. 0 Ex 44 : (R)-2-((1R,3S)-3-Hydroxycyclopentanecarboxamido)propanoic acid and (R)-2-((1S,3R)-3-hydroxycyclopentanecarboxamido)propanoic acid Because of Lm 1 Bri M 08 Tess HO I 2 the Ky ,— ef patka oases 1 AH 777 Luim 7 W ( CA Ci = e x as b © the “ | Hall with a gel column 1. By, PEC ga + L 1 Eien Dj-Wonq 2 Wah Mels 1 Aqw 2 Maqsada A Momomaz #rrr : fod a IPE mde 1 NT a Lee lv (rina, +53 NE.

SE p Rn ol by "ROR the > oh chapter b HOLD ; 0 Rel 7 preparatory g “Ee 8 akh aam and ris : od 1 2 om “EOOR b 9 etc. fen M Hy, POC Bbh 0

L YOO aa 75.1 (K2CO3 mmol) was added to a solution of cyclopent-?-ene carboxylic acid 001 g; YYA m(ds) in acetonitrile ) + © .mL) followed by the addition of benzyl bromide (70 aa YLT) mmol). The reaction mixture was stirred for 11 hours at ambient temperature. The mixture was filtered and washed with Yoo acetonitrile (mL). The filtrate, wash products and concentrate were combined to dryness. The remaining sald was purified by flash chromatography column on a Sh (hexane/)1:01 = EtOAC to yield benzyl cyclopent-3-enecarboxylate (Y1,0) SL. g” 9614 toll) in the form of oil.

Vo) THE mmol) in £Y.7 g; 5.80 (pinene) A solution of (-)-0-pinene 0

(V,0 «¢ V+) Me2S- borane (mL) to 0 °C and a solution of borane (mmol) was added. The mixture was stirred for; hours at 0 °C and benzyl Vo was added in milliliters g; ¥,0) benzyl cyclopent-3-enecarboxylate cyclopent-7-ene carboxylate mmol). The reaction mixture was left to warm to ambient temperature and stirred overnight. The VY Vo mixture was cooled to 0°C again and quenched with water (¥ mL (5 mL NaOH aqueous Yo oT) mL). After that, 97670 hydrogen peroxide (Yo) was added dropwise. The mixture was stirred for 1 hour at 0 °C and diluted with water (Yo) milliliters) and EtOAc (00 milliliters). The two layers were separated and the Sl phase was extracted using 510/6 (04 mL) (YF x 7 mL) and the combined organic phases were washed with Yoo Bryan (Ye x 7 mL) and dried over anhydrous sodium sulfate; concentrate. The residue was purified by a silica gel flash chromatography column [EtOAC (hexane = 1:4;) to yield benzyl %YY aa), 4 (3-hydroxycyclopentanecarboxylate yield). A solution of TBSCI (0.0V) g was added; 50 mmol) in THE (0 mL) by distillation into a solution of “an 001( benzyl 3-hydroxycyclopentanecarboxylate +,£0 mM YO mol) and imidazole (T,¢) imidazole g; 00 mmol) in Yeo (DMF) milliliters) at

ambient temperature. The reaction mixture was stirred for ? hours and Yoo water was added (milliliter). The resulting mixture was extracted with Yeu (EtOAC x 7 milliliters). The combined organic extracts were washed with 965 001504 aqueous 001 (001 mL) NaHCO3 (v x saturated aqueous 001 (001 mL oF X) and Braine (001 mL x 1); respectively. They were dried © Organic solution over anhydrous sodium sulfate; concentrate to dryness The residue was purified by a flash chromatography column on silica gel [EtOAC) hexane = (1:01) to obtain benzyl (V0,Y)3—) tert-butyldimethylsilyloxy)cyclopentanecarboxylate g; quantitative) as oil. (Ve) Pd/C ,5 g) was added to a solution of 3-benzyl (V0,Y) hydroxycyclopentanecarboxylate 001 g; £0.0 mmol) in 001 ( THE milliliters). The suspension was stirred under hydrogen atmosphere at ambient temperature for ½ hours. PA/C was separated by filtration and washing with (le 01) THF. The filtrate, wash products and concentrate were combined to dryness to obtain the corresponding acid. The acid was dissolved at £0.0 mM (Js) and 8-080L-1-0 Voy g; Salt (HCl £0.0 mVo mol) in DMF (Yo) milliliters). HATU (Y1,0) can 7.0 mmol) DIPEA Ale 1187 pil (17 mol) at 0 °C with stirring was added. The reaction mixture was left to warm to ambient temperature and stirred for ? hours. 0 has been added. +) EtOAC (ml) and water (004 ml). The two layers were separated and the aqueous phase was extracted with EtOAC (ov) mL x (YF) The combined organic phases were washed with You (You) mL oF x and dried over Ye anhydrous sodium sulfate and concentrate. The residue was purified by flash chromatography column on silica gel [EtOAC) hexane = 1:1( to yield (R)-benzyl 2-(3-(tert- 0"),1( butyldimethylsilyloxy)cyclopentanecarboxamido ) propanoate g; 96971 toll). Then separate:

Al (R)-Benzyl 2—(3—(tert-butyldimethylsilyloxy)cyclopentanecarboxamido) 056 by flash chromatography column on silica gel EtOAc) hexane = (Vr:1) to obtain cis—(R)-benzyl 2—(3—(tert- butyldimethylsilyloxy)cyclopentanecarboxamido) propanoate (8, g) and trans—(R)—-benzyl 2-(3—-(tert- 0) «(p> +, A (butyldimethylsilyloxy)cyclopentanecarboxamido)propanoate, respectively.

A solution of tetrabutylammonium fluoride (5,1 >« 11 mmol) in THE (Yo) mL) was added dropwise to a solution of 2-cis—(R)-benzyl ¥ ,0)(3~(tert-butyldimethylisilyloxy)cyclopentanecarboxamido) propanoate 10 g; AT mmol) in 01 (THE milliliters) at 0 °C with stirring. The Je laa mixture was left to Sa ambient temperature and stirred for VY h. (001 mL) water was added and the resulting mixture was extracted with (Veo) CH2CI2 mL (V x) The extraction and washing products were combined with 965 aqueous KHSO4 (001 mL NaHCO3) x 1 aqueous saturated Vo 001 (mL oF X and Brian ALI 001(7 1); respectively. The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by a flash-gel chromatography column Silica [EtOAC)hexane = (Y:1 to obtain -(4)-015 benzyl-3-hydroxycyclopentanecarboxamido)propanoate (1 g 761776 yield). Then prepare trans—(R)—-benzyl 2 -((1S,3R)-3-

hydroxycyclopentanecarboxamido)propanoate 00 in a similar way. 1;9000 (Pd/C g) was added to a solution of -3-(14,35))-2 (R)-benzyl 00 +) hydroxycyclopentanecarboxamido)propanoate mg; 117 mmol) in (ALLY) MeOH the suspension was stirred under hydrogen atmosphere at ambient temperature for 1 hour. 0/20 was separated by filtration and washing with MeOH (0 mL). The Yo filtrate, wash, and dry concentrate were combined to give =3-(38)(R)-2-(IR).

0 ".- since hydroxycyclopentanecarboxamido)propanoic acid (£04 mg; quantitative). & obtain (R)-2—((1S,3R)-3~ hydroxycyclopentanecarboxamido)propanoic acid in a similar way. Example ¢ (R)-2—((1R,3R)-3-Hydroxycyclopentanecarboxamido)propanoic acid o : p-NO,PhCOOH .1 _ PPh, DIAD 1 : : 1 000" 7L N“”>coosn 2. LiOH HO ( B ot diisopropyl azodicarboxylate ¢DIAD) 07 + mL. 7.75 Je mol) was added dropwise to a solution of -2 E5602-(4) VV pas 004) ((1R,38)-3-hydroxycyclopentanecarboxamido)propanoate

mmol) triphenylphosphoene (iva mg 11 mmol) and ¢-nitrobenzoic acid 9 A 7.01 pas mmol) in dry THE (Vo) milliliters) over 1.5 hours at 0-9 degrees in the shade of 2 to 8. The mixture was stirred for 1 hour at 0-9 deg C after which it was left at Bad Sa at ambient temperature and stirred for 116 sad hours. EtOAC (04 mL) and water (0 mL) were added and the two layers separated. The ddl layer was extracted using (Yo) EtOAC x mL

7 x aqueous (04 mL KHSO4 965) and the combined organic layers were washed with 1 Vo (?1 mL “1”); respectively. Yo) dried 7); Brian x saturated (04 ml) 43 NaHCO3 organic solution over anhydrous sodium sulfate and concentrate to dryness. The residue was purified to obtain (Y: = 1) by a flash chromatography column on silica gel (10/6]/hexane vol. 907197 yield) as a yellow solid. ©01 (Ester)

0 mg solution of LIOH (YAS) is added; 5.80 mmol) in water (0 mL) to a solution of the ester 5©01 (combined Ak 0.01 mol) in (blk 01) MeOH at 0 °C. The reaction mixture was stirred for 1 h and then acidified with 1 p Sk HCE to pH = ?. The organic solvent was removed and the resulting mixture was extracted with EtOAC/THF

0 _ since Yo 0: (mL L(Y x) washing the combined organic phases using water yo) mL (Fx and Bryan 1 (7 mL) 1); drying over sodium sulfate anhydrous; and concentrate to obtain (R)-2-((1R,3R)-3-hydroxycyclopentanecarboxamido)propanoic acid lal You ) mg; 966 yield) ¢ and use in the next step without further purification. © Example ¢1 (S)—-6—Oxopiperidine-3—carboxylic acid on RUC, NalO, ye Hel ye N 0 N 0 ™N Boc Boc H A solution of NalO4 was added ) 0.7 g; YT mmol) in water Yo (mL) 5 V¢ (RUCI3 mg) to a solution of ean 0,*( Boc—(R)-piperidine-3-carboxylic acid 1.6 mL Ve mol) in EtOAC (V0 milliliters). The reaction mixture was stirred overnight at ambient temperature. The two layers were separated and the aqueous phase was extracted using EtOAC (ml EtOAC (ov) mL (Fx Jue). The combined organic phases were eluted with Brain (04 oF x lil) and dried over anhydrous sodium sulfate; focus. The remaining sald) was purified by a flash chromatography column on silica gel (1:01 = CH2CI2/MeOH) to yield (S)—1-(tert-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid. yo (790 mg; 0649 yield) as a pale yellow solid. A solution of HCI in dioxane (1 mol 01 mL) was added to a solution of 001((S)—1~(tert-butoxycarbonyl)-6—oxopiperidine-3-carboxylic acid mg; 0 mmol) in dioxane (© milliliters) at 0 °C with stirring. The reaction mixture was stirred for ; hours and concentrate to the point of dehydration. The remaining solid) was azeotropicly treated three times with 01 (MeOH mL per fraction) to yield (S)—-6—oxopiperidine=3—001 (8500/1 acid mg; quantitative) as sale is a colorless solid. (R)=6—oxopiperidine—3—carboxylic acid was prepared in a similar way.

mg eg gy (S)-Tetrahydro-2H-pyran-3-carboxylic acid and (R)-tetrahydro-2H- pyran—3—carboxylic acid 0 Absorbent FB B 4 Maf One 1 a {Ly CRON 2.903 B00, ETH . 0 Son ig polarization separation 3 oy saf > 0 TTT | Nau[Los A 0 : Ni Na L 0 oR he ee Ruin My, PAC {Bbh lo} then cooling Yoxalyl chloride milliliters; YY, + mmol) to zero degrees and added ?; 4-Dihydro-211-pyran (ilk YA) 3,4-dihydro-2H-pyrane « YY, + mol) by distillation. The lad solution was left to ambient temperature and stirred for 1 dele. An excess amount of oxalyl chloride was removed under vacuum and the remaining 0 was heated at 081°C for 1.5 hours. . The mixture was cooled to ambient temperature and decanted in 960 1182003 aqueous cold 001 (mL). The resulting solution was washed with methylene chloride (04 mL) VX and then acidified with + p JHC pH LY = the mixture was extracted with methylene chloride (04 mL) Fx and the combined organic phases were dried over sodium sulfate Anhydrous and concentrated to obtain 3,4=dihydro-2H- pyran—5-carboxylic acid yo (5.1 g; 9077 yield); used directly without further purification. Pd/C (0090) added ?(p> to a solution of 3,4-dihydro-2H-pyran-5- carboxylic acid (1/1 g; 00 mmol) in 001 (MeOH) was done. The suspension was stirred in Ja atmosphere of hydrogen in MPa at $v degree YEP for 10 hours.

The catalyst was filtered and washed with MeOH (00 mL). The filtrate, wash products and concentrate were combined to dryness to obtain the crude product. The crude product was dissolved in Yeo acetonitrile (mL) and then benzyl bromide (4 9 g) was added; oA mmol) (aa 18 ) K2CO3 VTA mmol). The resulting suspension was heated at 10–5 °C for ; hours and then 0 cooling to dap ambient temperature. The mixture was filtered and the filter cake was washed with acetonitrile (00 milliliters). The filtrate, wash products and concentrate were combined to dryness. The residue was purified by flash chromatography column on silica gel (hexane/:1 = EtOAc)_ to yield a mixture of (V, g) of (S)-benzyl tetrahydro-2H-pyran-3 carboxylate and (R)-benzyl tetrahydro—-2H-pyran-3-carboxylate ¢ 0 were separated by a polarized preparative HPLC to yield (S)-benzyltetrahydro-2H-pyran—90117 «xa Y,V) 3—carboxylate toll) ; (R)-benzyl tetrahydro-2H-pyran—3- Y, +) carboxylate g; 90,176 toll); respectively. 1;90600 (Pd/C g) was added to a solution of tetrahydro-2H-pyran-3-5612-(5)VY)carboxylate g; © mmol) in 1/6011,01 (milliliter). The suspension was stirred under VO atmosphere of hydrogen at ambient temperature for 1 hour. The catalyst was separated by filtration and washed with MeOH (0 mL). The filtrate, wash products and concentration to dryness were combined to yield (S)-tetrahydro-2H-pyran-3-carboxylic acid (7+ g 7657 yield). (R)-Tetrahydro—-2H-pyran—3—carboxylic acid was prepared by 0 method. Example: (S)-Tetrahydrofuran—3-carboxylic acid in SF OF 0 0 nt Eh 3 | 10 i Li J" A . “a LIOH, Hoh TH 5 > b zo ht TR | 0 1 ° 10 NH Ph 9 Ld 7 pr

0 7 _ as YY ¢EDCI) 1-Ethyl-3—(3—-dimethylaminopropyl)carbodiimide mg added; 0 mmol) DMAP (011 mg; 0.60 mmol) to a solution of (R)-4-benzyl-oxazolidin-2-one (77? 0.50 mg) mL tetrahydrofuran—3—carboxylic (Js Yeo )acid mg; no mmol) in CH2CI2 (90 mL) an die ambient temperature. Then stir the reaction mixture for a period of ? hours at ambient temperature and Yo water (mL) was added. The two layers were separated, and the aqueous phase was extracted using (Yo)CH2CI2 mL (Vx). Washing the combined organic phases with Brain (04) (Fx lil), drying over anhydrous sodium sulfate, and concentration. The remaining sald) was purified by a flash chromatography column on silica gel RY-4-benzyl-3-((S)- J Y + . = CH2CI2/EtOAC No (R) VY) tetrahydrofuran—3-carbonyl)oxazolidin-2-one | 0 mg 9676 toll). H202 (88 + 90760 7.0 mmol) was added dropwise to a solution of -4-(”)Yo)benzyl-3—((S)-tetrahydrofuran—-3-carbonyl)oxazolidin-2 -one mg; +40 mmol) in (01 milliliters) at 0°C with stirring over #0 hours. The mixture was stirred for 10 minutes and a solution of (At) LIOH-H20 mg VO 0.1 mmol) in water (v0 milliliters) was added by droplet. The reaction mixture was stirred for ? hours at zero degrees and then agitation with 2182503 saturated water (01 milliliters). The organic solvent was removed and the remaining aqueous solution was washed with 0112012 Yo) milliliters (Vx) and acidified with 1 p HCL to pH = 7. The solution was concentrated to dryness to obtain the crude acid (5)- tetrahydrofuran-? ‎: 2-(3-Oxopiperazin—1-yl)acetic acid ‎TEA, 8601000817 0 1 0 Pd/C, nor 2. HN 0 αLT HN A NH NOLS

0 where triethylamine £.0F (mL 7050 mmol) was added dropwise to a solution of piperazine - "- 0106820-2-006 0106820-2-006 0.1 (g; 01 mmol) and benzyl benzyl bromoacetate (1.7 g; 01 mmol) in dichloromethane (Yo) milliliters) at 0 °C. The reaction mixture ad was left to ambient temperature and stirred for 1 h. Water (Ye) was added (mL) and the resulting mixture was extracted with dichloromethane (Yo) mL (Fx) Organic extracts were collected; drying over anhydrous sodium sulfate and concentration. The residue was purified by column chromatography Illuminated on silica gel (dichloromethane/methanol - Y Yeo to 1 on (for Sis) benzyl) 05 g 9616 yield) as a colorless solid sale; subjected to hydrolysis pH in the presence of (Y) Pd/C, + g) in methanol (01 mL Ye) for 1 hour at ambient temperature to obtain 2-(3-oxopiperazin— aa +, 8) 1 -yl)acetic acid 9647 toll).

Ow example 2-(4-Hydroxy—-4-methylpiperidin—1-yl)acetic acid

Moab 1. TFA eMgBr 2. BrCH,CO,Bn ope LEER 10 ©

Obn

Hy, Pd/C SQ o

naon

(Yo) THE mmol) in 5.0 g; V0) piperidine-4-one “N-Boc A solution of Vo is dissolved in mol; 7.7 milliliters; (7.8 MeMgBrr milliliters) and then cooling to -<560°C. Even temperature liad minutes were added. The reaction mixture (10 mmol) was left slowly over 0 h NHAC. The mixture was cooled to 0°C and 1 mixture was added and stirred for 1 hour

Jue milliliters). (001 saturates (0/86) 00 milliliters). The resulting mixture was extracted using the organic substrate using water (00 mL) and Bryan (00 mL); Drying over sodium sulfate Ye

0 q —_ as anhydrous; and concentrate to obtain tert-butyl 4-hydroxy—-4-methylpiperidine—1- 018006 g 9697 yield) in the form of yellow oil. TFA (1,_mL) was added to a solution of tert-butyl 4-hydroxy-4- 01( methylpiperidine—]1—carboxylate g; £,Y mmol) in 0112012) 0 mL ) © at zero degrees Augie with flipping. The reaction mixture was stirred for 1 hour and then concentrated to dryness. The residue was azeotropic three times with EtOAC (? milliliter per fraction) to remove the TRA residue to obtain the amino compound aa 01 (quantitative) as TFA salt thereof. CAN 1,9 K2CO3 (00 mmol) was added to a solution of TRA salt (Y,00) g 16.6 mL (Use) and benzyl 2-bromoacetate (0 4.7 g (184 mm 0 mol) in DMF (10 milliliters). The reaction mixture was stirred at ambient temperature for 2 hours and then poured into water (Yeo milliliters). Then the resulting mixture was extracted using 71 mL EtOAc (Fx) and the combined organic layers were washed with water (0 mL) and concentrated. The residue was purified by a flash chromatography column on a silica gel (10+1 = DCM/MeOH) to obtain (Ye). g 6 + 96186 yield) on CuLua yellow.Vo to a solution of benzyl 2—(4-hydroxy-4-methylpiperidin—-1-yl)acetate ) p mg y, mmol ) in methanol (a milliliter) then Yeo (%Y (%Y) Pd/C mg) was added and the mixture was stirred under hydrogen atmosphere at ambient temperature for 1 h. The mixture was filtered through a bed of celite and the filtrate was concentrated To obtain 2—(4-hydroxy-4- Yoo) methylpiperidin—1-yl)acetic acid mg; quantitative) as a solid dae color Ye, Hale was used without further of purification. Example oy (S)-4,5,6,7-Tetrahydro-1H-indazole-5-carboxylic acid and (R)-4,5,6,7- tetrahydro—1H-indazole-5- carboxylic acid

From this i [JINR EN 3 bl Li \ STEMS Eon FRO, Mele i 5 eee EDT = RE SA NT Ns he see CL, Cry CL je H H A S 00 Psi Ma , BS 1 ] Sed A 1 1 B B Yok | Separation = HERS 0 y polarized ed MN why just sold MeO Ney 1 except 1 1 M + a solution of ethyl 4-oxocyclohexanecarboxylate (0 g » 79 mol) was heated In (blk YVo) DMF-DMA at 110°C VY sad hour. The mixture was concentrated and hydrazine hydrate (0.47 aa YY,0 mol) hydrazine in © dei (Voor) mL) was heated under reflux overnight. Most of the ethanol was removed and the remaining mixture was treated with water (£00mL). The resulting mixture was extracted with EtOAc (£40 mL) and the combined organic layers were washed with Brain (£00 mL) and concentrate. The residue was purified by flash chromatography column on silica gel (1 Ve = DCM/MeOH) to obtain the crude compound (YA) ethyl 4,5,6,7—tetrahydro—1H-indazole-5-carboxylate (g) 0 as a colorless solid. To a solution of 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate only 81 (0.01 g 05 mmol) in methanol (01 mL) water (01) was added mL) and lithium hydroxide (YAY) lithium hydroxide hydrate mg; 5,960 mmol). The reaction mixture was stirred at ambient temperature overnight and then concentrated to remove most of the methanol. 1 The remaining mixture was acidified with an aqueous HOE diluted to a pH of - ; And then focus. The residue was added under vacuum to obtain the corresponding acid (an VV 96717 yield) as a colorless solid s; Hale was used without further purification.

-11 mmol) in YY mmol) and 5002 (*,7 g; 1 mL) under reflux for Ye) methanol and thereafter concentrate. The residue was purified by a flash chromatography column on silica gel yield (in the form of %00 aa V0) to obtain the crude product (1:01 = DCM/MeOH) polarized preparatively to obtain HPLC light yellow solid ; They were then separated by © g) 0 ,( (R)—-methyl 4,5,6,7-tetrahydro—1H-indazole-5-carboxylate on (+,Y) ( R)-methyl 4,5,6,7-tetrahydro—1H-indazole-5-carboxylate, respectively. (S)-methyl 4,5,6,7-tetrahydro-1H-indazole-5- carboxylate to a solution of (100 mL) and (100 mL) water then adding water (1 mmol) in methanol (Cana 8 Yo) mg; 0.0 mmol) at YE) lithium hydroxide hydrate lithium hydroxide hydrate 1 hour and then 1 0°C. The reaction mixture was stirred at ambient temperature for a dilution to a Sle HOI number of concentration to remove most of the methanol. The remaining mixture was acidified with (5)- pH = , and then concentrated. The residue was added under vacuum to give 96481 yield (780) mg 4,5,6,7-tetrahydro—-1H-indazole -5-carboxylic acid yo

R)— as a colorless solid; It was used directly without further purification. was created

HAS (edna) was counted and then proceeded without 2 in a similar way. Example (S)—2-( methyl 4,5,6,7-tetrahydro—1H-indazole—5-carboxylate oy) 2-Morpholinoacetamido)propanoic acid 2 H-L-Ala-OBn 3 0 0 DMTMM, NMM, Wa Pd

NPL DMF, DCM on coon

OH ’ H MeOH oy M ~ N A N Loon

H.A.K

©17- ¢ Alle 7,5? (NMM) mol) and 1-methylmorpholine +, YVT can ¥1,)) DMTMM added from 7-morpholinoacetic acid Age dap Zero Ne to a solution of (de Te wa-alanine benzyl hydro ester (Use g; 748 mL Yo, +) morpholinoacetic acid

DMF mol) in FAR REFER Yo,v) alanine benzyl ester hydrochloride shall chloride; hours at SAD (milliliter). The reaction mixture DCM (001 mL) (Yoo) was stirred into the residue. (0 00) ambient then concentrate. 6/10] (000 mL) and water were added. Yoo XY EtOAC ) the two resulting layers were separated and the aqueous phase extracted using mL); and drying over sulfate (XY¥ 00). The collected organic layers were washed using Brain flash chromatography column on the gel of the remaining dad gs salad anhydrous day sodium ¢ and concentrate. Then purify (S)-benzyl 2-)2- ?)_ to obtain:001 = DCM/MeOH) Milica 0 yield. 9169+ xa YY, morpholinoacetamido)propanoate (S)-benzyl 2-)2-g) then add a solution of ov HV. ) Pd/C to (001 mmol) MeOH in 0.19 g” Y +, (morpholinoacetamido)propanoate mL). The mixture was stirred under hydrogen atmosphere at ambient temperature for ; hours; then milliliters). The filtrate, wash products and concentrate (MEOH) Yoo were combined, filtered and rinsed with 1 mL 001 xY) EtOAC to dryness to yield the crude product which was washed with (S)—2-(2-morpholinoacetamido)propanoic and drying under vacuum to obtain a yield) in the form of a white-yellow solid. %AT aa VY, A) acid 1H NMR (300 MHz, DMSO-d6): 6 7.95 (m, 1H), 4.25 ( m, 1H), 3.70 (m, 4H), 3.08 (d, J = 15.4 Hz, 2H), 2.40-2.55 (m, 4H), 1.30 (d, J = 6.6 Hz, 0 3H).

Example R)-1-(2,4-Dimethoxybenzyl)-5-oxopyrrolidine—3—carboxylicacid : oY and (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid

Add COOH NNTP i a J WES WW oh 3 HOC Aron 88 MeOH | FO on poor :800 & 07 T oy A 31 1 Sn : Hs EIB 0 Polarization separation a hE | COME COOH DME : py LOH oy i — 3 — = ot BR and Lone We solder 8 to a solution of VY, v)itaconicacid eli SG g; 001 mmol) in toluene (ov) mL) a solution of oF-dimethoxybenzylamine 015.1 aa (17.54 mmol) in toluene (00 mL) was added and The reaction mixture was stirred for ~Vohr under reflux. The mixture was cooled to ambient temperature and then concentrated under pressure then reduced. then treat the residue with a Di (Ja) (Yoo) milliliters) and then collect the resulting precipitate by filtration; and washing with Di(EtOAC 5 fi) Ji) and drying to yield (1,01(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid g 76171 yield) as a colorless solid. 50012 (1.8 g) is added; 08 mmol) by distillation into methanol (40 mL) followed by addition of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (0.4 g YA mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 1 hour and then heated under reflux for 1 hour. The mixture was cooled to ambient temperature and concentrated. The remaining (sal) was purified by flash chromatography column on silica gel (Sl) 0 petroleum/1:+1 = EtOAc to ¥:1)_ to yield -2,4)-1 methyl dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (a mixture of two chameleons” £7, aa 9681 toll) as colorless oil. The isomers were separated by preparative HPLC

duvet cpa 1,77) LIOH *,7 added? Ae mol) to a solution of -2,4)-1 (R)y-methyl 01 aa ,1( dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate mmol) at 117/1120:1 ( 0 56 milliliters) at 0 °C and the reaction mixture was stirred for 1 hour. The THE was removed and the remaining dihydrogen solution was washed with gla ethyl ether (ov) milliliters x .)1 © The aqueous phase was adjusted to pH = © using ? p Al HCl and the resulting mixture was extracted with DCM (£4 milliliters “1). The combined extraction products were washed with water (Yeo X milliliters) and brine (Yeo X 1 milliliters) ) and drying over anhydrous sodium sulfate and concentration to obtain the compound (R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine— aa Y,VT)3-carboxylic acid 906/8 yield) in the form of sale Colorless solid. 0 Prepared (S)—1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine—3-carboxylic acid eg ot (1r,4r)-4-Hydroxy—1-methylcyclohexanecarboxylic acid .1 NaBH or 2. TBSCI or “LDA, Mel TBSO 0 HOAc S .1 = LOH © 2. © HO” Yo “1850 aa VY,Y) NaBH4 added 74 mol) on shal to a solution of 4-ethyl oxocyclohexanecarboxylate (©7.0 g; 171 mol) in Yoo ethanol (mL) at 0°C over a period of 1.5 hours with flipping. The suspension was stirred overnight at ambient temperature and then inactivated with 1 p001 (SHC mL). The solvent was removed

—Y¥yo-— milliliters). The remaining CH2CI2 (000) solution was washed in sald) pressure reduced and Jha dissolved

Vx mL Yeo) and Bryan (Fx mL Yeo) saturated aqueous NaHCO3 using msl) and drying over anhydrous sodium sulfate; concentration to the point of dehydration to obtain the corresponding alcohol (mol). 14596 total (0.4 mL) and imidazole DMF (Yo) was added. The alcohol was dissolved in (© mL) by distillation and THE mol (Yo) was dissolved at 700 cpa (08.8) Adding a solution of (1850 milliliters (V) h. VY water was added and the reaction mixture was stirred at ambient temperature for “7 milliliters”). The extracts were washed with ETOAC (Vou) and the resulting mixture was extracted using Saturated aqueous 21811003 ¢(¥ x mL Yo +) aqueous organic KHSO4 965 collected using 1” mL; respectively. The organic solution was dried over Yon) and Bryan oF X mL © 0 (10) sodium sulfate anhydrous and concentrated to dryness. The residue was purified by column chromatography, 1:16- (4-ethyl) to obtain 1:00 = hexane [EtOAC) and flashing on silica gel. Yield of 9054 aa (0.; butyldimethylsilyloxy)cyclohexanecarboxylate two steps) in the form of oil. mmol) by distillation into a solution of 15.4 ml 7.71 molar of solution (LDA) Vo. added

V¢ g £0) ethyl 4—(tert-butyldimethylsilyloxy)cyclohexanecarboxylate from 1 °C with stirring. The mixture was stirred for YAS (mL) at Vo) THE mmol) in mmol) by distillation. The reaction mixture was stirred 15.4 con 7.70 (h followed by the addition of iodomethane to ambient temperature and stirred Bad °C for +0, h and then left at YA- at mL) and extracted resulting mixture Yeo) overnight. The reaction was quenched with water, the combined organic phases were washed with Bryan (7 x ml You) CH2CI2 and dried over anhydrous sodium sulfate and concentrate. The residue (1 x 044 mL) was purified to yield 1:001 = 10/6 by flash chromatography column on silica gel (hexane/trans—ethyl 4-(tert-butyldimethylsilyloxy)— 1-methylcyclohexanecarboxylate yield) in the form of oil.‎ 9000 aa YT) Yo

1 - Then add acetic acid (+ 0.7 milliliters) by distillation to a solution of trans-ethyl 468668606 FA No. 1 1-008 - (for thunder anra calt 41008 ga-1611)-4 (1) g 00 mmol) in THE (Vo) milliliters) at ambient temperature. The reaction mixture was heated at 0 °C for ? hours. The mixture was concentrated and then diluted with water (Veo© milliliters). The resulting mixture was extracted with CH2CI2 (04 mL Jue (Vx) extracts combined using 1811003 saturated aqueous 1 (5 mL) Vx and Bryan (1001 mL X); drying over sodium sulfate The alcohol was treated with a solution of V+ (H20- lithium hydroxide YO cana mmol) in water/THF (01 milliliters/4 milliliters) for Fe min. THF Ye was removed and the aqueous solution was acidified to pH = 4-7 using 1 p Al HCL The resulting mixture was concentrated to dryness to obtain the crude compound trans—4-hydroxy—-1- Yo +) methylcyclohexanecarboxylic acid mg; 9017 toll); Srila was used without further purification. Example oo (1r,4r)—-4-Hydroxy—4-methylcyclohexanecarboxylic acid yo Fn | A eT . . Chapter 3. + B avai Q T™ ho Tm Lk 1 ed L CCR Aceon Hc *"<-_bboadjuice> to a solution of ethyl 4-oxocyclohexanecarboxylate (8 g 775 mmol) ) in diethyl ether (Av) mL) was added Mel (7.6 mL; se 1 in diethyl ether) at -01°C under nitrogen atmosphere. The mixture was stirred The interaction at Te

and degrees Celsius for Fo min. Saturated aqueous NHAC (04 mL) was added and the resulting mixture was extracted using (100 mL EtOAc “* ?). The combined organic layers were Jue prepared using Brain Vou (mL) and water (10 mL); drying over anhydrous sodium sulfate; focus. The remaining sala was purified by flash chromatography column on silica gel (A) petroleum/EtOAc = (©01:1) to yield V,A) ethyl 4-hydroxy-4-methylcyclohexanecarboxylate 9641 aa yield) in the form of oil.

1.5 can +,0A) NaOH mM (Use) was added to a solution of ethyl 4-hydroxy—4- 1 A) methylcyclohexanecarboxylate (g GLY mmol) in ethanol/Ye) H20 milliliters/11 milliliters) at 0°C and the reaction mixture was stirred at 0°C for

11 0 hours. The mixture was concentrated to obtain the corresponding acid in the form of its sodium salt. Benzyl bromide TT (g 09 mmol) was added to a suspension of acid (sodium salt) in DMF (40 mL). The reaction mixture was stirred at ambient temperature for 1 hour and water (Ver milliliters) was added. The resulting mixture was extracted with 01 EtOAC (7 x 1 milliliters). The combined organic layers were washed with Brain (You) mL and No (Vou) water (mL); drying over anhydrous sodium sulfate; focus. The residue was purified by flash chromatography column on silica gel (petroleum ether/510/86 = £1 1 to ;:1) to yield (5869 mg; 071 yield) and cis-benzyl 4-hydroxy -4-

VEA)methylcyclohexanecarboxylate mg 97071 toll); respectively. To a solution of (1r,4)-benzyl 4-hydroxy-4-methylcyclohexanecarboxylate (00d) 0 0 aggregate 0.06 mmol) in THE (Yo) milliliter) 0/60 (00 mg) was added ; .)9601 The mixture was stirred in Jb hydrogen atmosphere (1 atmosphere) at ambient temperature for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure to give Y1+)(1r,4)-benzyl 4-hydroxy—4-methylcyclohexanecarboxylate mg; 7 outcome) as a colorless solid; They were used in the next step without further ado

1 M (1s,4s)-4-hydroxy—4-methylcyclohexanecarboxylic acid from purification. 57 examples (1s,4s)-4-Hydroxy—1-methylcyclohexanecarboxylic acid 1. HOAc 3 2. p-NO,PhCOOH 0 dom 1- EtONa © _-_| 18 to whom 200 2 LioH © 7850 “HO”

ON o Then add acetic acid (Y) milliliters) by distillation to a solution of (1r,4r)—ethyl 4—((tert— Y, +) butyldimethylsilyl)oxy)—1-methylcyclohexanecarboxylate g” 1 mmol) in THF (10 milliliters) at ambient temperature. The reaction mixture was heated at 5 0 °C for ? hours. The mixture was concentrated and Yeo water (mL) was added. The resulting mixture >0 was extracted with CH2CI2 (00 mL) (VX) and the combined extract was washed with saturated aqueous NaHCO3 (04 mL) (Fx) and Bryan (001 mL x 1); drying over anhydrous sodium sulfate ¢ and concentration Then purification of the remaining salad dad gs flash chromatography column on silica gel (hexane/0/6pa = ©: 1) to obtain the corresponding alcohol 1,aa (90684 yield) as oil (Joe Ale 1000 g; VY mmol); acid? - Nitrobenzoic o, f aa 0.1 (the alcohol is dissolved in Vo milliliters). The mixture was cooled to 0 (£0 mmol) in 8.01 can?,11 (triphenylphosphine) by distillation over 8.0 can 1.74 (1.74 DIAD) and N2 was added. 0° C under shade and then Adie left it for 1 hour at 0° 1 hour. The reaction mixture was stirred for 1.5 milliliters (EtOAC) 001 h. 11 leds were added Until the ambient temperature and stirring for a period of yo and water (5 A milliliters) As the two layers separated. Then, the aqueous layer was extracted using EtOAc (a ml x 7). The collected organic layers were washed with 100 ml Bryan VX, dried over anhydrous sodium sulfate, and the concentration. Then, the residue was purified by a flash chromatography column. on

and 1 silica gel (hexane/)1:0 = EtOAc to obtain cis—4-(ethoxycarbonyl)-4- aa), Y)methylcyclohexyl 4-0106 9017 yield). 4-nitrobenzoate was added to a freshly prepared solution of NaOEt (10:0/6810010)-4-kah (AY.)cane 7,560 mmol) to a freshly prepared solution of NaOEt (1,5 mM). (Js) in 0 (?1 mL) EtOH at 0 °C. The mixture was stirred for T hours at ambient temperature and then concentrated. The residue was purified by flash chromatography column on silica gel (hexane / EtOAc = ?:1)_ to obtain (Is,4s)-ethyl 4-hydroxy-1- +r )methylcyclohexanecarboxylate ¢ mg; 9614 yield). The 4-hydroxy—1-methylcyclohexanecarboxylate Al1©-(15,45) was treated with a solution of lithium hydroxide (AR) H20-mg; 1 A, millimoles) in water/THF (a milliliters/4 milliliters) ve sad a minute. The was removed and the aqueous solution was acidified to pH = =F using 1 p JHC The mixture was concentrated to dryness to yield the crude compound cis—4-hydroxy—1-methylcyclohexanecarboxylic acid (quantitative ); It was used directly without further purification. Vo eg ov 2—(4-Hydroxypiperidin—1-yl)acetic acid NaBH THF, 1 Cap 2. 110 Sled gh HG ™ o DOM, TEA My KD NBS Hg, PRC, MeOH 4. Sodium borohydride (0,¥) g added; 09 mol) in parts to a solution of V0) tert-butyl 4-oxopiperidine—]-carboxylate g; Yo mmol) in Vou) 0/11/8011 0 milliliters/ 01 milliliters) at -01°C. The reaction mixture was stirred for 71 minutes. Then extract

The resulting mixture was used with EOAC (00© mL (FX) and the combined extract was dried over anhydrous sodium sulfate and concentrate to give tert-butyl 4-hydroxypiperidine-1- aa 11, 806 9049 yield). 4-hydroxypiperidine—1-carboxylate alan1611-8 with a solution of 1 p[HCl 0 dioxane (01 mL) and the mixture was left to settle for 10 minutes at ambient temperature. To piperidin-;- ol piperidin—4-ol (5.0 g salt (HCI; quantitative). To piperidin-;- ol (HC salt 5.0 g) a solution of benzyl = F bromoacetate 0.05 (benzyl 2-bromoacetate g; 15.7 mmol) in dichloromethane (Yoo) mL). The mixture was cooled to 0 °C and triethylamine (YY) milliliters (Yer 0 00 mol) was added. The reaction mixture was left to warm to ambient temperature and stirred for 1 hour. Water (01 milliliters) was added and the resulting mixture was extracted with 0 (001 milliliters) dichloromethane (0) x then combined with the organic extraction products; drying over anhydrous sodium sulfate and concentration. The residue was purified by column chromatography Illumination on silica gel (dichloromethane/methanol = 1:01 to 1:01) to obtain benzyl 2—(4-hydroxypiperidin—0 | 8681816g(E-1 001 xa AY) Yield). for 1 hour at ambient temperature. The Pd/C was separated by filtration and the filtrate was concentrated to dryness to yield 2-(4-hydroxypiperidin—1-yl)acetic acid (1, g 9694 yield). Yo Example SA 2—(3,3-Difluoropiperidin—1-yl)acetic acid, 2-(4,4-difluoropiperidin—1-yl)acetic acid, 2-(3,3-difluoropyrrolidin —1-yl)acetic acid, 2-(4- (trifluoromethyl)piperidin—1-yl)acetic acid, and 2—(4—-chloropiperidin—1-ylh)acetic acid

©71- 5 ag H a@ “COOH

NH Lee COOH

F F

F 1. BrCH, COOBnN F

EtsN 2. Hy, Pd/C rN H CN “COOH

F F

for H for “COOH

FaC FaC

Lr Jee

Cl cl difluoroF = 3 mL 4.77 mmol) to a solution of (TT + triethylamine mol) and benzyl "-bromo Ae (7.117 mg; 000) HCI was added 3,3—difluoropiperidine (Vo) in methylene chloride (Use mg; 7.77 mM VAY) benzyl 2-bromoacetate acetate mL). The reaction mixture was stirred at ambient temperature for ¥ h The mixture was washed sequentially with aqueous sodium hydroxide and water The organic layer was concentrated and substance 1 was purified with EtOAC: Y = 1) by flash chromatography column on silica gel (hexane/2) —(3,3—difluoropiperidin-1-yl)acetic acid from benzyl ester on benzyl ester mg; 9057 yield) as yellow oil. $A)¢AT) 2-(3,3-difluoropiperidin -1-yl)acetic acid to a solution of benzyl ester of 0 mg) then 6 011 (Pd/C mL) and then add Yo (mg; practical mmol) in methanol h. Chapter 1 Stirring the suspension under hydrogen atmosphere at ambient temperature for mL. The filtrate and wash products (©) MEOH were collected by filtration and washed with isl 2—(3,3—difluoropiperi din—1-yl)acetic acid and concentrate to dryness to obtain 1 (YAY) 9690 yield) as a sale solid yellow-green; $d was used without further filtering.

The following compounds were not similarly synthesized: 2—(4,4—difluoropiperidin—1-yl)acetic acid, 2—-(3,3—difluoropymolidin—1-yl)acetic acid, 2—(4—( trifluoromethyl)piperidin— 1-yl)acetic acid, 2—(4-chloropiperidin—1-yl)acetic acid Example 59 M -3-(1638)-2-(8))-2-(8) ‎ Hydroxycyclobutanecarboxamido)propanamido)—3—(4-me- thoxyphenyl)propanoic acid TFA .1 H 0 2. HATU, DIPEA 0 : H 0 : o=>—coMH TTY os NaBH Mumabamo family o = -— © Oo = TL TL HO,C— )—NO, 0 SH 0 oe rt 92 DIAD, PPh, for p holt " 0 of 08 i adduct HO 0 TL P 0 oo © , : 9 LiOH on HO" 0 TL ~~ 0 0 to a solution of (S)-benzyl 2-(( R)-2—((tert- butoxycarbonyl)amino)propanamido)—-3—(4-methoxy phenyl)propanoate can VY) 7.1 mmol) in DCM (Vo) mL) was added TFA (? milliliters). The mixture was stirred at ambient temperature for 1.5 h and then concentrated to dryness into crude amine (TFA salt).

RA

mL) and ?-exocyclobutane acid 01 (DCM) was added in TFA the amine (salt) was suspended

HATU 5 mmol (7.11 g) (+71) 3-0xocyclobutanecarboxylic acid (carboxylic acid) to DIPEA (mmol). The mixture was cooled to 0 °C followed by the addition of 0.47 C (0.0 9 min) and the reaction mixture was stirred at ambient temperature for A = pH Addition of water (00 milliliters) . The organic layer was dried over anhydrous sodium sulfate and the concentrate. © - 56086 The residue was purified by flash chromatography column on silica gel (petroleum ether/(S)-benzyl 3—(4-methoxyphenyl)-2—((R)-2-(3-) to obtain 1:1 to 70 g 687 L +,44)oxocyclobutanecarboxamido(propanamido)pro— panoate two-step yield) as a colorless solid. (S)-benzyl ~~ 3—-(4-methoxyphenyl )-2—-((R)-2-(3—- from dss to 0 ms V,Y g” +,44) oxocyclobutanecarboxamido)propanamido)pro— panoate g; ¢,£ mmol) on three +, (VY) 188114 mL) Yo (mol) was added in ethanol min. After the addition is completed; The reaction mixture was stirred at 71 °C over an hour and then quenched with saturated aqueous ammonium chloride (00 mL). ambient 1 for 50 DCM The ethanol is removed under reduced pressure and the residue is extracted Using Ve organic matter was collected, dried over anhydrous sodium sulfate, and concentrated. (YX mL:01-residue was purified by flash chromatography column on silica gel (/001/(S)-Ethyl methanol) 2-((R)-2-((1s,3S)-3~ for (0 hydroxycyclobutanecarboxamido)propanamido)-3—(4-metho- ‎Xyphenyl)propanoate 0)4.1 g; 7017 yield ) as a colorless solid. to a solution of (S)—ethyl 2-((R)-2—((1s,3S5)-3~ hydroxycyclobutanecarboxamido) propanamido)-3-(4-metho- TY) Xyphenyl)propanoate , + g; 0.0 mmol); acid? -Nitrobenzoic (07+ g); 3 mL (Use thiphenylphosphoene con + AA) 3.4 mmol) in (Yo) THE milliliters of Yo added Abe 7.77 all 170 (DIAD mol). The reaction mixture was stirred under nitrogen

© for 7 days and inactivation with NaHCO3 saturated water (04 mL). The resulting mixture was extracted with [0/6] (04 mL) Vx and the organics collected; dried over anhydrous sodium sulfate ¢ and concentrated. Then the remaining salad was purified by flash chromatography column on silica gel to obtain S (S). )—ethyl 3—(4-methoxyphenyl)-2—((R)-2—((1r,3R)-3-0H ‎(4-nitrophenoxy)cyclobutane carboxamido)propanamido)propanoate ) ,+24 g; 96977 yield) as a colorless solid. to a solution of (S)—ethyl 3—(4-methoxyphenyl)-2—((R)-2—((1r,3R)-3-(4- nitrophenoxy)cyclobutane carboxamido)propanamido)propanoate ) 0.24 + g 1 mmol) in (Vo) CH3OH/H20 mL ?: 1) LIOH-H20 (£ ,+g) added; (Jee JA 7,9) The reaction mixture was stirred at ambient temperature for 1 h and then concentrated. Water (00 mL) was added to the remaining sald and the resulting mixture was washed with DCM (04 mL). .) 1 x the aqueous phase was acidified with Sk HCI diluted to pH = '-; and then washed again with DCM (04 milliliters x 7). The aqueous phase was concentrated under vacuum to obtain the crude compound (S)=2-((R)=2-((1r.3R)-3— hydroxycyclobutanecarboxamido)propanamido)-3—(4-m- 101 aa +, £7) ethoxyphenyl)propanoic acid 906/4 yield) as a colorless solid; They were used for the next step without further purification. Te JB (S)—2—((tert-Butoxycarbonyl)amino)—-3-cyanopropanoic acid 7.4 - acetone (oo DOC, BocHN “COOH Leda BooHN™ “COOH)

quilt added a solution of dicyclohexylcarbodiimide yal (AY DCC) g; 4 mmol) in acetone (Yoo mL) by distillation of a suspension of 00-asparagine (9.7 g; £4 mL (Use in pyridine) (04 mL) at 0°C under nitrogen. The reaction mixture was stirred at ambient temperature for ? hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloro Ole (00© mL) and the solution was Jue with 1 p 101 aqueous Yo (mL (FV x Bryan Yoo) mL); drying over sodium anhydrous cll; and concentration to obtain -16:1)-2-(5) aa 0,0) butoxycarbonylamino)-3-cyanopropanoic acid 90607 yield); It was used directly without further purification. 0 . Example 1:2—((tert-Butoxycarbonyl)amino)-3,3,3-trifluoropropanoic acid FC PH 5 TFAA CFs 000 yen 0 0 HN ap * Fey + con — Coan? OF OEt 0 0 NaBH, or Lae 6 cba OE 1776 mmol) in dichloromethane (1 L) benzyl carbamate (Y1,71 g) was added. Vo reaction mixture was stirred at ambient temperature for YE h and the resulting precipitate was collected by filtration and dried under vacuum to give ethyl 2—(benzyloxycarbonylamino)-3,3,3— DAY x a £4, 4) trifluoro-2-hydroxypropanoate toll); It was used directly without further purification. To a solution of ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2- p hydroxypropanoate (9.0; YOY «aa mmol) in diethyl ether Yoo) mL) was

© Distillation addition of 17/8 (5.3 ?VTA (aa mmol) at 0 °C followed by distillational addition of pyridine (771.5 g; Use Ale TYTN at 0 °Adie) The reaction mixture was left to warm to ambient temperature and stirred for 7 h.The mixture was filtered and the filtrate was concentrated to give 3,3-1111110100106800316, 3-(171100L030/068+500E5612)-2 ethyl (0.4 g; 9697 yield); was used Sale without further purification to a solution of ethyl 2—-(benzyloxycarbonylimino)-3,3,3~trifluoropropanoate VEAL an 45.0(dee in diethyl ether Yoo) milliliters (Ala) sodium borohydride YAY (aa) 117 mM (Use) was divided in portions at 0 °C. The reaction mixture, Ba, was left at ambient temperature and stirred for 176 h. The reaction was quenched with water (Vor > mL) carefully and the organic layer was separated. The aqueous layer was extracted with 100 mL EtOAc (FX organic layers were collected; washing with Brain x ALLY eo) 7); drying over anhydrous sodium sulfate and concentration. The residue was purified by a flash chromatography column on silica gel ([EtOAc) petroleum (A) = 1:4) to yield 1.2-ethyl (benzyloxycarbonylamino)-3,3,3-trifluoropropanoate g 7668 05 toll).A suspension of ethyl ~~ 2-(benzyloxycarbonylamino)-3,3,3-Jtrifluoropropanoate 08 g 114 mmol) was returned in 1 p HCI mani) Yeu mL ) for T hours. The mixture was cooled to ambient Shall Point and then concentrated under reduced pressure. remaining sald) was suspended in acetonitrile (100 mL) and triethylamine (£97.97 Yo) mL was added; Abe FT mol) and di-tert-butyl dicarbonate YA can 7.9 mmol). The pale yellow solution was stirred at ambient temperature overnight and then diluted with dichloromethane (£4 mL). The resulting solution was washed with 1 P 1101 Aqueous 001 (mL and Brian Yoo (mL); drying over anhydrous sodium sulfate and concentration. The remaining sald) was washed with 100 (mL) petroleum ether to yield -2

—yYy- %Vo g ¥, + )(tert-Butoxycarbonylamino)-3,3,3-trifluoropropanoic acid Colorless solid.

TY Example (S)-3-(3,4-Bis(benzyloxy)phenyl)-2-((S)-2-(2- morpholinoacetamido)propanami- do)propanoic acid ° 1. TFA 2. oY 0 "0, 1. Boc,0 - 2. BnBr, 00 HATU

H,N™ "COOH BocHN™ 0080 ~ LitN 0 0 0 LiOH N AA

AAA RE, SS I A 00 << 2 for OBn OBn 086

Yeo ) mL) and acetone You ) mmol) in water Cu (aa 1011 ) Dopa-— L then suspension 802620 A= aqueous was added to adjust the pH NaOH p 1 mL) An hour was added at ambient temperature. VY sad (mmol) and the reaction mixture was stirred (01.5 cpa) and after (Vx 001 mL (using ethyl ether Ald) the organic solvent was removed The combined organic phases were washed (VY x mL You) EtOAc (the resulting mixture was washed with 1 mL of EtOAc), dried over anhydrous sodium sulfate, and concentrated to obtain (001) using Bryan g. ; quantitative); was used directly for the next step without further 15.1 dopa (-L-Boc) upon purification. Yo 001 (dopa mmol) into a solution of 806-a-You g; 70.,1) K2CO3 has been added

YYY “g YY,” (mL) followed by the addition of benzyl bromide Yoo (mmol) in acetonitrile YY (gm C) for hours and then cooling to Tomo (mmol). The suspension was heated at (0*) ambient temperature. The mixture was filtered and the filter cake was washed with acetonitrile

hum + milliliters). The filtrate, wash products and concentrate were combined to dryness. The residue was purified by flash chromatography column on silica gel (hexane/6/10 = 1:0) to yield (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-(tert). - (aa) 0,Y) butoxycarbonylamino)propanoate (toll 0 768). “(LkY)TFA was added to a solution of -4,)-3 (S)-benzyl bis(benzyloxy)phenyl)-2—(tert-butoxycarbonylamino)propanoate )1,4 g 1 mmol) in 112012 (0 mL) at 0 °C with stirring. The mixture was stirred for 1 hour and concentrated to dryness. The remaining sald was azeotropic three times with 510/86 (0 mL per part) To remove the TRA residue and the amine was obtained as a 0 salt case TFA Hal was used without further purification.HATU (9, g; 1.5 mmol) and no-methyl were added morpholine (1.0 Ale 15 μmol) to a solution of an amine salt (do le ©, TFA f-2)-2-(8) Avo) morpholinoacetamido)propanoic acid total 7.71 mL mol) in methylene chloride (00 milliliters) (01 milliliters DMF) at 0 °C with stirring. The suspension was stirred 1 for 1 hour at ambient temperature and then concentrated. The residue was purified by column Scalp chromatography on silica gel (methylene chloride/methanol = 1:1) to obtain -(5) benzyl 3—-(3,4-bis(benzyloxy)phenyl)-2—((S)-2-( 2-morpholinoacetamido) can , V+)propanamido)propanoate (%AY) as sale is a colorless solid. A solution of LIOH (79 mg; 1,6 (Me mol) in water (1 mL) was added to a solution of (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)-2 —((S)-2-(2— 0 0.17 can), V) morpholinoacetamido) propanamido)propanoate mmol) in Yo) MeOH mL) at 0 °C with stirring. The reaction mixture was stirred for ? hours and then acidify with 1 p of SL HO to pH = ?. The resulting mixture was concentrated and the residue transferred without further purification.

-4+ Ex. 7 (S)-2-Amino-N—((S)-3—(cyclopent-1-en-1-yl)~1—((R)-2-methyloxiran— 2-yl )~1-0- xopropan-2-yl)-3—(4-methoxyphenyl)propanamide Salt :TFA Boon + TFA Ios 1.HATU,DEA DMF © © Ios Sel FN J 2. TFA, DCM Ay J © to (S)—2~((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic 0. 1 0 g” T,YA m(S)-2-amino-3~—(cyclopent-1-en-1-yl)-1- 5 (Js V, 2A) ((R) —-2-methyloxiran—2-yl)propan-]1-o- ne g; 74 _mmol) in DMF (01 milliliters) at 0°C HATU (0.0 0 (8.776 mmol) was added, followed by DIEA (0.44 milliliters Ake YY, mol) and stirred mixture for Vo min then quenching 0 with NaHCO3 (saturated aqueous); extraction with 0/6] (XY) and washing with Brain; And drying using sodium sulfate, crab lly and concentrate. Purified by column chromatography 1:1([pla 0/6p)_ compounds to yield -3-(5))-1-(5)) tert-butyl (cyclopent-1-en- 1-yl)-1—-((R)-2-methyloxiran-2-yl)—1-oxopro— pan—2- ‎Y,1Y)yl)amino)-3—(4-methoxyphenyl)-1 -oxopropan-2-yl)carbamate g (%AY | 0) as colorless oil. MS(EI) for “C26H36N206 detected 577.7 A(MH) to tert-butyl ((S)~1-(((S)—-3—(cyclopent-1-en-1-y)-1-((R)-2- ‎pan-2-yljamino)-3-(4 -methoxyphenyl)—- -1-00010 - ( E-20-2 sold out EF1 06 81686 (E-1-00010080-2 )44,+ 7.1 aa mmol) DCM added) 0 0 milliliters) TRA (0 milliliters). The mixture was left to settle at ambient temperature for 1 min and then concentrated to give the crude compound (S)—2-amino-N-((S)-3—(cyclopent-1-en-1-)

f yh)=1-((R)—-2-methyloxiran-2-yl)-1—- oxopropan-2-yl)-3—(4-methoxyphenyl)propanamide (quantitative) and transport without further purification. MS(EI) of “C21H28N204 Detected 77,7 A(MH) S)-2-amino—-N—((S)-3-cyclohexenyl-1—(((R)) synthesized -2-methyloxiran—-2— 0e 1002030106 (a/81m (ala00i5el0061)-4)-3- ( al-2 - yl)-1-oxopropan— in an example way 4 (S)—2 —((S)—2-Aminopropanamido)-N—((S)-3—(cyclopent-1-en-1-yl)-1- ((R)—2-met- hyloxiran—2-yl )—1-oxopropan-2-yl)-3—(4-methoxyphenyl)propanamide 00 (salt: (TFA) 0 lo) TFA H © 0 0 mL HATU, DIEA, DMF 1. TFA, DCM 5 = H 3 .2 0 2 TL.

RON to (S)—2-amino-N-((S)-3—(cyclopent-1-en-1-yl)-1-((R)-2- methyloxiran—-2-yl )- —1-oxopropan-2-yl)-3—(4- methoxyphenyl)propanamide (can 0.01 salt (TFA 5.77 mmol) and -2-(5)Avo) ( (tert-butoxycarbonyl)amino)propanoic acid yo mg; 5.77 mmol) in DMF (01 milliliters) at 0 °C HATU (1.42 g) added; 5.11 mmol) is followed by €,7Y) DIEA in milliliters. 75.6 mmol) and the mixture was stirred for 1 min and then quenched with 1811003 (saturated aqueous); extraction with ¢(XY) EtOAC, Braine Washing, Sodium Sulfate Drying and Filtration; focus. Purified by 1:1 column chromatography (hexane/(EtOAc) to yield -3-(5))-1-(5))-1-(5)) tert-butyl

Elf (cyclopent-1-en-1-yl)-1—((R)-2-methyloxiran-2-yl)—— 1 -oxopropan—2-yl)amino)-3-(4-methoxyphenyl )-1-oxopropan-2-yljamino)-1-oxop- (%AE aa Vd E)ropan—2-yl)carbamate in the form of a colorless oil. MS(EI) for 02914111307 detected 4,7 4 0 A(MH) © to tert-butyl ((S)-1-(((S)-1-(((S)-3— (cyclopent-1-en-1-y)-1-((R)-2- ‎methyloxiran—2-yl)-— 1-oxopropan-2-ylj)amino)-3—(4-methoxyphenyl)- 1-oxopropan-2-yljamino)-1-oxop~- ropan-2-yljcarbamate (4¢,) g; 7.08 mmol) (01 DCM) (01 milliliters) TRA was added. The mixture was left to stabilize at ambient temperature for 1 min and then concentrated to give the crude compound tert-butyl (((S)=1=(((S)—1-(((S)-3—(cyclopent)) -1-en-1-yl)-1-((R)-2-methyloxiran- 0 ,1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan- -_ (E-2 ropan-2-yl)carbamate -1-0«*»00-(2-7(800100 (quantitative)) was transferred without further purification. MS(EI) of “C24H33N305” detected 44,7 A(MH) Yeo Ex M (S)—-3-Hydroxy—-2—(2-morpholinoacetamido)propanoic acid H-Ser-OBn .1 HATU OH 2 (H,Pac OT) © 1 M oy COOH nOL HATU (Y0,Y) g; 16.0 mmol (Yo) DIPEA mL) was added to a solution of "-morpholino acid" acetic 00.0 can A, vv) mmol) W-serine benzyl ester 0 (1.17 salt (HCI 55.0 mmol) in 7/00 Vou) mL) at 0 °C with stirring. The reaction mixture lad was left at ambient temperature and stirred for A hours. EtOAc (ible 04) and water (040 mL) were added and the two layers were separated.

Add the aqueous phase extraction with EtOAC (Yoo) mL (Fx) and the combined organic phases were washed with Yeo (Bryan) X 0 mL, dried over anhydrous sodium sulfate, and concentrated. The remaining sald was purified by flash chromatography column on silica gel (CH2CI2Z/MeOH) = 1 0 to yield the benzyl ester DEY aa AY (yield). © 6/00 TV (9600 mmol) was added to a solution of the YO can AY ester (mmol) in THF AY (5 milliliters (Yo) H20 milliliters). The mixture was stirred under 1 hydrogen atmosphere (atmospheric) at ambient shall degree overnight and then filtered through a layer of silite. The filtrate was concentrated in Jhb pressurized & reduced to obtain (S)-3-hydroxy-2-(2- aa 0,0) morpholinoacetamido)propanoic acid 90/88 yield) as substance 0 Colorless solid. Example 76 (S)—2-amino-1—((R)-2-methyloxiran—2-yl)-3-phenylpropan—1- one salt of TFA _ was prepared using the methods described. In the following_reference: International Application 2 and the contents of which are included here for reference. 1 Further synthesis procedures eg TY (S)—-3-cyclopropyl-N—((S)-1-((R)~2-methyloxiran—2-yl)-1-oxo-3~ phenylpropan—— 2-yN-2-((S)-2-(2- morpholinoacetamido)propanamido)propanamide :(C-1224) 0

Love the (J TEAS HH rs a a n 5 Boer.

THE 9 Bae dou A Owner M: 880 EA ST Lee 8 1 Surveyor 5 . NF Soy Rr Eo Ne NN A 504 a 3 L 1 2 £3 TEA DEM —_—_ 0 Lo HAT, DIES, THROUGH DIES SSAT i 4 = A b NN FS !2 ? tv editor § ] bo : w 8 UN KR 1 Pe TEA, TON Hood DIE Noms WP Tal Takh 3 Y 0 Noms & 83 for 3 Noms £2 WF Avi No? - Oise acid LR i N ( » m 0 s hill oN 0 I l lg] 81 [l HAT, THEA, Log Hamir i to 5 a 0 le 8 a © fre rete " SE AL hv to Te +)(S)—2—-amino-3—cyclopropylpropanoic acid mg; 5.19 mmol) in THF (? milliliters) and water (? milliliters) was added ) Y,¥ +) K2CO3 g; 131 mmol) and di-tert-butyldicarbonate (0.71 di-tert-butyl dicarbonate g; 1.017 mmol). The mixture was concentrated, washed with iethyl ether, then acidified with citric acid to a pH of ~y, then extracted with Xx 9 DCM (and dried with Sodium sulfate, filtration, and concentration. Color moved to next stage 0 without further refinement. MS (El) for 01111190104 detected 1.1 7 (0/1 1+).

F to (S)—2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid CAN), Y) 8¢,£ mmol) -0:01:80-2un2-00810- was added (4))-2-2100-1-(5)yl)-3-phenylpropan—1-one salt (YE) TFA , 1 g 4.44 mmol YoY) HATU g; 0.77 mmol); 01 DMF (milliliter). The mixture was cooled to 0 °C and 2.1 (DIEA©5 mL; 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate Ji (77); drying with sodium sulfate; and filtering. focus. Purified by column chromatography 9670-1(ethyl acetate/heptane) to yield tert-butyl ((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran— 2-yl)~1-oxo-3-phenylprop- an-2-yl)amino)-1-oxopropan-2- \. (%VY aa, YY)yl)carbamate as sale Colorless solid. MS (El)l (C23H32N205) detected 27,7 [(+MH) to tert-butyl ((S)-3-cyclopropyl-1-(((S)-1-((R) )-2-methyloxiran-2-yl)- 1-oxo-3-phenylprop- an-2-yl)amino)-1-oxopropan-2-yl)carbamate 0.59 cane 117 (1 mL) (Use DCM (Y,0) milliliters) TRA (0,¥ milliliters) added. The mixture was left to settle at pall ambient for yo min before being concentrated to yield -2-(5)amino-3-cyclopropyl-N—((S)-1-((R)-2-methyloxiran— 2-yl)-1-oxo-3~ phen— ylpropan—-2-yl)propanamide salt T0Y) TFA mg; quantitative) in the form of yellow oil that was transferred to the next stage without further purification. (C20H24F3N204 1 05 (EI) 0 detected [AM=TFA] 117 to (S)—2-amino-3-cyclopropyl-N—((S)-1-((R)-2-methyloxiran- 2-yl)-1- henylpropan-2-yl)propanamide -0406-3-0 salt (T0V) TFA mg; 0.99 mmol) (S)-2~((tert-butoxycarbonyl)amino)propanoic acid )14 CAN 7.18 mmol) was added; 0.0 (HATU g; 7.17 mmol); and DMF (0 milliliters). been cooled

The mixture was reduced to 0 °C and Ale 1.77 all 0.11 (DIEA mol) was added. The reaction mixture was stirred at ambient hall temperature for ∼1 min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (XY) and drying with sodium sulfate; filtering; focus. Purified by column chromatography ( = 968 ethyl acetate/heptane) to yield tert-butyl ((S)—1-(((S)-3—cyclopropyl-1-(((S)-1-((R) )-2- methyloxiran—2-yl)~1-oxo-3~-ph—- enylpropan-2-yljamino)—1-oxopropan— YAY) 2-yl)amino)-1-oxopropan-2 -yl)carbamate mg; %£9) as sale as a colorless solid. MS (El) l 026113701306 detected ¢AA,¢ (0/1+). 0 to tert-butyl ((S)-1 -(((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran— 2-yl)~1-oxo-3-ph- enylpropan-2-yl) (amino)-1-oxopropan-2-yljamino)- YY aaa YA) 1-0xopropan-2-yl)carbamate,+ mmol) DCM (0,¥) Y,0) added TRA milliliters). The mixture was left to stabilize at ambient temperature for 700 s. min before being concentrated to obtain (S)—2~((S)—2-aminopropanamido)-3-cyclopropyl-N— (((S)~1-( (R)-2-methyloxiran— —2-yl)-1-oxo-3-phenylpropan-2- 0 yl)propanamide salt (YVY) TFA mg; quantitative) in the form of a yellow oil that has been alas passed to the next stage without further purification. Discovered reg ‎AIM=TFA] to -2-(4))-1-(5))-to 1!- um 10 from to 6--3- (2-3100010030810190-(5))-2 -(5) ran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide free frame 08 TFA salt (YYV) 0 mg YY + mmol) acid was added? - morpholinoacetic 0.576 cane YY) acid m DMF (Js (Ma 0.14 cane 177( HATU (se )£ mL). The mixture was cooled to 0 °C and DIEA) TA was added , + milliliters; 7.1 mmol). The reaction mixture was stirred at ambient temperature for 700 min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (77); drying with Yo sodium sulfate; and filtering. focus. Purified by column chromatography (3: [DCM 1 acetate

Add 9000-01 + Ji) methanol) to get (S)—3~-cyclopropyl-N—((S)-1-((R)-2- -2)-2-(5) )-2-(Al-2-7- methyloxiran-2-yl)~1-oxo-3-phenylpropan- YY +) morpholinoacetamido)propanamido)propanamide mg; 96/0) as a colorless solid. (d, J - 7.6 Hz, 1H), 7.32 - 7.22 (m, © 7.54 h) 1H NMR (400 MHz, CDCI3): 3H), 7.16 = 7.14 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 4.86 — 4.81 (m, 1H), 4.43 (q, J = 6.8 Hz, 2H), 4.34 (dd, J = 14.4 , Hz, 1H), 3.74 - 3.72 (m, 4H), 3.30 (d, J = 4.8 Hz, 1H), 3.14 (dd, J 6.8 Hz, 1H), 3.04 (d, J = 4.8 Hz , 2H), 2.92 (d, J = 4.8 Hz, 1H), 5.2 = ,14.0 (dd, J = 14.0, 7.8 Hz, 1H), 2.54 - 2.52 (m, 4H), 1.56 (t, J = 6.8 0 2.83 Hz, 2H), 1.50 (s, 3H), 1.35 (d, J = 7.2 Hz, 3H), 0.41 - 0.36 (m, 2H), MS (El) 0.05 - 0.00 (m, 2H). 1-ox0—-3- : TA ‎—(2-morpholinoacetamido)propanamido)—‏ -2-(5))-2- (0-2-7 1902 A.D. Uncle ‎3—(pyridin—2-yl)propanamide (C-1505) 0 a) TEA QO ENO00C BMAP TER BOK HL Mn, Mali pow, he 2 YEA, BO SEN 3 iD i 734 solve and 0 { DISS, ACK i o rea HCH convergence, no, Aco i Bost A on L8 for 67 “6 LCH 7#7 SLN/TA 5 B Wala A K K K K K E E + E E E E E E E E E E E E Ros? HTL, HOBL DEA, H 11893 2.285 a AY o 0 PN o em 0 8 n fof Be awe eye CAAA AR morpholine acetic acid 2 > ¥ 1 01 collocated 3 times HET a he N° = 1 N wg ay »

add to (S)—2~((tert-butoxycarbonyl)amino)-3—(pyridin—2-yl)propanoic acid 0.0 0) g; 7.77 mmol) in DCM (Vo mL) was added TEA (0.9974 mL Ale 0.7 l mol) YY) DMAP conjugated (Ae 1.1848 mol) and cooled The reaction mixture brought to zero ad libitum 5 4.51 "lll Ye (BnCOCI mmol) was added via an addition funnel over the course of ©71 min. Bad mixture was cooled to ambient temperature overnight at which point quenching was done with sodium bicarbonate (saturated); extraction with ethyl acetate (XY) and drying with sulfate (aid gaa and filtration; concentration. purification dad gs column chromatography ) + 905 acetate [Jdhexane + )% m)_ to obtain (S)- benzyl 2—((tert- butoxycarbonyl)amino)-3—(pyridin—2-yl)propanoate ( 80 g” 7647) in 10 as a light brown solid. MS (EI) for “C20H24N204 detected +[M-Boc] Yov,v to (S)-benzyl 2—((tert-butoxycarbonyl)amino)-3—(pyridin-2-yl) propanoate (0.517 can be 1.004 mmol) added (Y) DCM (mL) followed by Y (TFA (mL)). The reaction mixture was left to settle for 1 hour at which time it was concentrated to obtain the 5602-(5) 2-amino—3—(pyridin-2-yl)propanoate 10 TFA salt (quantity yield) in the form of oil yellow. MS (El) L017116301203 detected 0.7 A[M-TFA] to (S)-2—((tert-butoxycarbonyl)amino)propanoic acid (£40 mg 7 mmol) ADD 100300816 (EL-11010-2L/A0)-2-800100-3 (S)-benzyl 0 .,87 aa salt (TFA 7.77 mmol); [1081 AY] mg; 7,517 mmol); HBTU (75, C 7.517 mol Ae); 01 (ACN milliliters). The mixture was cooled to zero degrees Asie and 0.45 (DIEA mL; Me AAA mol) was added. The reaction mixture was stirred at ambient temperature for 6? minutes then | to quench with (saturated) sodium bicarbonate 3 and to extract with a ethyl acetate (77); drying with sodium sulfate; filtering; and focus to get

Add the crude compound -61))-2-(5))-2 (S)-benzyl ebutoxycarbonyl)amino)propanamido)-3—(pyridin-2-yl)propano- ate as a colorless solid ) £7,+g) transferred to the next stage without further purification. MS (El)l (C23H29N305 detected ¢YA,¥ (0/01+).© to (S)-benzyl 2—((S)-2—((tert-butoxycarbonyl)amino) propanamido)-3- (pyridin—2-yl)propano— ate ) ,874+ g; V0 A mmol) in 01,117 (mL) 0/0 (0096; 550 mg) was added and a hydrogen atmosphere (in color) was added. after ; The reaction was filtered through celite and concentrated to obtain (S)—-3—-(4-methoxyphenyl)-2-(2- methyl-2—-(2-morpholinoacetamido)propanamido)— propanoic acid )+ Tn (Ne g) as sale is a colorless solid. MS (EI) L 01612311305 detected (HM) 17,7 to (S)—3-(4-methoxyphenyl)-2-(2-methyl-2-(2-»01) morpholinoacetamido ) propanamido)propanoic g” + ,+ mmol) (S)—2-amino-1—((R)-2-methyloxiran—-2-yl)-3-phenylpropan—1- YVA) was added ) TFA = k one yo mg 1.970 mmol); 1081 1995 (mg; 0.57 mmol); 006A) HBTU combined 0.47 mmol) DMF (? milliliters). The mixture was cooled to 0 °C and Abe VTA lille (DIEA (70 Y mol) was added). The reaction mixture was stirred at ambient temperature for ∼o min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (77); drying with sodium sulfate; filtering; focus. Yo was purified by column chromatography (9610-0 ethyl acetate/heptane) to yield -(5)) tert-butyl 1-(((S)~1-(((S)~1-) ((S)-2-methyloxiran-2-yl)—1-oxo-3-phenylpropan- ‎2-y- l)amino)—1-oxo-3—(pyridin—2-yl)propan-2- yl)amino)—1-oxopropan— YY 0) 2-yl)carbama- te mg; 710%) as a colorless, amorphous solid. MS (EI) of (C28H36N406, #075 (+M) detected

o to ‎tert-butyl ((S)—-1-(((S)-1-(((S)-1—-((S)—2-methyloxiran—-2-yl)-1-oxo- 3—phenylpropan—-2-y- lyamino)—1-oxo-3—(pyridin—-2-yl)propan-2- YY 0) yl)amino)-1-oxopropan-2-yl) carbama-te mg; 2000 mmol) DCM (£mL) was added, followed by Y (TRA mL). The reaction mixture was left to settle for ? © h at that time was concentrated to obtain -(2-300100010080810100-(5))-2-(5) N=((S)~1-((S)—-2-methyloxiran-2-yl)- 1-oxo-3- —phenylpropan-2-yl)-3- (pyridin—2-yl)propanamide TFA salt in the form of yellow oil was transferred to the next stage without further purification. MS (El) of (C25H28F3N405 Detected 175.7 A[M-TFA] 0 to (S)—2-((S)—2-aminopropanamido)-N—((S) ~1-((S)-2-methyloxiran-2—-‏ ‎Yl)=1-ox— o-3-phenylpropan-2-yl)-3-(pyridin-2-yl)propanamide salt of Ale . ,100 (putative mol TFA) morpholinoacetic acid (VV) mg was added; 001 mmol); 1081 Ae 977 aan 11 (Mall); HBTU (15? pan 9717 mmol) and DMF (? milliliters). The mixture was cooled to 0 °C and DIEA (1,797 milliliters; Ne 1D1, ?mmol) was added. The reaction mixture was stirred at ambient temperature for 1 min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (7*); drying with sodium sulfate; filtering, and focus. Purified by column chromatography (3: JDCM 1 acetate Ji + 9019-6 _methanol) to yield -2-(4))-1-(5))-11-r(5)methyloxiran-2 -yl)-1-oxo-3-phenylpropan-2-yl)-2—((S)—- 2-)2- 171( morpholinoacetamido)propanamido)-3—(pyridin-2-yl)propanamide ~ ~ 0 (%YY) (pas as sale is a colorless solid. 1H NMR (400 MHz, CDCI3) § 8.39 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.89 (d , J = 6.7 Hz, 2H), 7.60 (ddt, J = 7.7, 5.6, 1.8, 1.8 Hz, 2H), 7.25 - (m, 5H), 7.09 — 6.99 (m, 2H), 4.88 — 4.65 ( m, 2H), 4.47 (p, J = 7.09 Hz, 1H), 3.88 — 3.61 (m, 4H), 3.34 — 3.23 (m, 2H), Yo 7.0 ,71.0 ,7.1 ,71.1

- «= 3.14 (dd, J = 15.2, 6.3 Hz, 1H), 3.08 - 2.94 (m, 3H), 2.88 (d, J = 5.0

Hz, 1H), 2.76 (dd, J = 14.1, 7.9 Hz, 1H), 2.66 - 2.42 (m, 4H), 1.45 (s, 3H), 1.35 (d, J = 7.1 Hz, 3H). (+MH) 557,4 Detected (C29H3TN506 for MS (El) The following compound was synthesized in a similar way: (S)—3~—(4-methoxyphenyl)-N—((S)~-1— ((R)~2-methyloxiran-2-yl)~1-oxo- 3—phenylp- ropan-2-yl-2-(2-(2- morpholinoacetamido)acetamido)propanamide (C-1153) 1H NMR (400 MHz, CDCI3) § 7.66 (t, J = 5.8, 5.8 Hz, 1H), 7.26 — 7.19 (m, 3H), 7.07 (s, 2H), 7.00 (s, 2H), 6.86 — 6.76 (m, 2H), 6.54 (s, 1H), 0 (d, J =7.4 Hz, 1H), 4.71 (td, J = 7.8, 7.7, 4.9 Hz, 1H), 4.50 (9, J = 6.19 Hz, 1H), 3.86 (dd, J = 5.7, 4.0 Hz, 2H), 3.78 (s, 3H), 3.76 6.8 , 6.9 , 6.9 (m, 4H), 3.24 (d, J = 5.0 Hz, 1H), 3.07 (dd, J = 14.0, 4.9 Hz, 3.67 - 1H), 2.99 (d, J = 2.9 Hz, 2H), 2.95 (d, J = 6.3 Hz, 1H), 2.93 - 2.83 (m, 2H), 2.68 (dd, J = 14.0, 8.3 Hz, 1H), 2.60 — 2.43 (m, 4H), 1.48 (s, 3H). Detected C30H38N407 of MS (El) 19 Example (S)—-3—(3,4-dimethoxyphenyl)-N—((S)-1-((R)-2-methyloxiran-2) -yl)-1- ‎oxo—3-phe- nylpropan—2-yl)-2—((S)-2-(2-

morpholinoacetamido)propanamido)propanamide (C-1160) TFA 0 'TFA 0 .1 0 0 : except I HN.2 ROB 800011 A 5 0 Lb —_ HATU, DIEA, DMF CL ,2 cm 1 _O 2. TFA, DCM 0 Synthesis performed tert-butyl ((S)-3-(3,4-dimethoxyphenyl)-1—(((S)-1-((S)-2-) methyloxiran—2-yl)~1-oxo-3~-- phenylpropan-2-yljamino)-1-oxopropan—2-yl)carbamate 2 in a manner similar to the synthesis of (S)—3~-cyclopropyl-N —((S)-1-((R)-2- ‏ -2)-2-(5))-2-(Al-2-7- ‎methyloxiran-2-yl)~1-oxo-3-phenylpropan - .morpholinoacetamido)propanamido)propanamide . Lycem morpholine acetic acid 1. HO 1 One 05: HETU, DIBA, DS 1 1 8 ! HN Ye NNR AOR 0 84 1 moiety KOM, 2 .0 to (S)—methyl 2—aminopropanoate HCI salt (0) ,4 g »; 5,8? mmol) in DMF (YO) 0 mL) at 0 °C to which morpholinoacetic acid was added (0.99 ± 75.48 mmol); 1081 can V, VE) (07.7 mmol); oY, Y can YY) HBTU mmol); This is followed by DIEA (, 7 0.067 ill mol). The mixture was left to stir for ∼V min at which time it was quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (XY) and drying with sodium sulfate; filtering; and concentrate to obtain -2)-2 (S)-methyl morpholinoacetamido)propanoate yo (quantitative yield) as a colorless solid sale. MS (El) for “C10HI8N204 Detected [(+MH) 7011

EAL

The crude compound (S)—methyl 2—(2-morpholinoacetamido)propanoate was dissolved in methanol (Vv)mL)Yo)KOH mL of solution 1P; 070 mmol). The reaction mixture was stirred for ? hours then focus; dissolution in methanol; and filtering. The filtrate was concentrated

AY A)potassium (S)-2-(2-morpholinoacetamido)propanoate (for © vol. 9657 on 1 step) as a colorless oil. MS (EI) for 091115/401204; Detected [AIM=K] 11,7 they “TFA HNL 5 lm 0 : B 1 0 9 0 0 0 HATY, DIEA, (AAR 2 mL I H J _— H oo = 0 0 0 (S)-2-amino-3-(3,4-dimethoxyphenyl)-N-((S)-1-((S)-2- to

TFA (methyloxiran-2-yl)- —1-oxo-3-phenylpropan-2-yl)propanamide potassium (5(-2-)2- mL) (DMF (mmol)) was added in 0.54 mg; YAE) 0 ¢Ve)morpholinoacetamido)propanoate mg 0.85 mmol HATU minus 1.85 cans mmol); V, oY) DIEA milliliters; 1.16 mmol). The mixture was left to stir for 1 min at this point then quenched with 0 (saturated) sodium bicarbonate, extracted with ethyl (XY) acetate, and dried with sodium sulfate; cad illy and focus. Purified by VO column chromatography (©: [DCM 1 ethyl acetate + 9610-0 methanol) followed by pulverization of ethyl acetate/heptane (1:1) to obtain (S)—3 -(3,4-dimethoxyphenyl)-N—((S)-1-(((S)~ ‎2-methyloxiran-2-yl)-1-oxo-3-ph-enylpropan-2-yl)-2 -((R)-2-(2- YYY) morpholinoacetamido)propanamido)propanamide mg; 4 97067) as a colorless, amorphous solid.

S 1H NMR (400 MHz, CDCI3) 7.41 (d, J = 7.7 Hz, 1H), 7.26 - 7.20 (m, 2H), 6.99 (dd, J = 7.5, 1.8 Hz, 2H), 6.86 — 6.68 (m, 3H), 6.64 (d, J = 7.3 Hz, 1H), 6.16 (d, J = 7.0 Hz, 1H), 4.78 — 4.64 (m, 1H), 4.48 (q, J = 7.1, 7.1, 7.0 Hz, 1H), 4.42 — 4.28 (m, 1H), 3.86 (d, J = 4.0 Hz, 6H), 3.69 (t, J = 4.6, 4.6 Hz, 4H), 3.27 (d, J = 5.0 Hz, 1H ), 3.08 (dd, J = © 14.0, 4.9 Hz, 1H), 3.02 - 2.79 (m, 5H), 2.64 (dd, J = 14.0, 8.3 Hz, 1H), 2.45 (9, J = 4.0, 3.9, 3.9 Hz, 4H), 1.49 (s, 2H), 1.30 (d, J = 7.1 Hz, 3H). (FMH) 11117 Detected “C32H42N408 for MS (El) The following compound is synthesized in a similar way: (S)—3—(4—(dimethylamino)phenyl)-N—((S)-1-(( R)-2-methyloxiran—-2-yl)- —phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido) -1-0*»0-3 propanamido) propanamid- e (C-1161) (d, J = 8.8 Hz, 1H), 7.25 - 7.20 (m, 7.45 E 1H NMR (400 MHz, CDCI3) 3H), 7.06 (d, J = 8.7 Hz, 2H), 7.03 - 6.91 (m, 2H), 6.67 — 6.60 (m, 2H), 0 (d, J = 7.6 Hz, 1H), 6.16 (d, J = 7.0 Hz, 1H), 4.71 (ddd, J = 8.1, 6.52 7.2, 4.9 Hz, 1H), 4.45 (q, J = 6.9, 6.9, 6.9 Hz, 1H), 4.43 - 4.31 (m, 1H), 3.82 — 3.63 (m, 4H ), 3.28 (d, J = 5.0 Hz, 1H), 3.15 - 3.02 (m, 1H), 3.02 — 2.88 (m, 9H), 2.83 (dd, J = 14.1, 7.0 Hz, 2H), 2.66 (dd, J = 14.0, 8.2 Hz, 1H), 2.57 - 2.37 (m, 4H), 1.49 (s, 3H), 1.29 (d, J - 7.0 000

Hz, 3H). (+MH) 04 4,7 Detected «C32H43N506 for MS (El) (S)—3—(4—(dimethylamino)phenyl)-N—((S)-1-((R)-2) -methyloxiran—-2-yl)—- 1-0*»0-3- —phenylpropan-2-yl)-2—((S)-2-(2-

—YiE— morpholinoacetamido)propanamido) ~~ propanamid—- e (C-1161)

Q

0 ?- Irumu-2 Fluoropyridine Boon Balal BocHN NE FFP, 28 OME H GB 3 _— A SR,

Sy0i

No op g; 1) (R)-benzyl 2—((tert-butoxycarbonyl)amino)-3—-iodopropanoate to mL) and DMF ¥,0) mg; 0.80 mmol) ZINC (Too) ZINC mol) and Zn (ALY, EY) were added at ambient temperature, then N2 was added min under Fe sad stirring the mixture (© mmol). The mixture was stirred at ambient temperature for 1.7 47 mg; (VY VO 0) 4 then diluted with water and ethyl acetate; an additional hour N2 extraction under fA using ethyl acetate (77); drying with sodium sulfate; filtering; And the concentration to obtain Al-5602-(5) 2—((tert-butoxycarbonyl)amino)-3—(5-fluoropyridin-2-) on orange-colored oil that was transferred to phase Ba in g; quantitative yield) on 0.01 ( yl)propanoate 01 followed without further purification. (+MH) 75.7 detected “C20H23FN204 for MS (EI) (S)-3—(5-fluoropyridin-2-yl) -N—((S)-1-((R)-2-) The rest of the synthesis of methyloxiran-2-yl)-1-oxo-3-p- henylpropan-2-yl)-2-((S) was carried out. (-2-(2- (5)- in a manner similar to (A) morpholinoacetamido) propanamido) propanamide yo

N—((S)-3-cyclohexyl-1—((R)-2-methyloxiran—2-yl)-1-oxopropan—2-yl)—- 3-)- 4-methoxyphenyl)-2-(( S)-2—-(2-(¢)morpholinoacetamido)propanamido)propanamide 1H NMR (400 MHz, DMSO-d6) E 8.49 - 8.37 (m, 2H), 8.11 (d, J = 8.5

Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.58 (td, J = 8.8, 8.8, 3.0 Hz, 1H), 0 7.40 - 7.08 (m, 6H), 4.66 (td, J = 9.0 , 8.7, 5.0 Hz, 1H), 4.54 (ddd, J = 9.3, 7.4, 4.2 Hz, 1H), 4.28 — 4.14 (m, 1H), 3.65 — 3.48 (m, 4H), 3.19

They are (d, J - 5.1 Hz, 1H), 3.09 (dd, J = 13.9, 4.8 Hz, 1H), 3.00 (d, J = 5.1 Hz, 1H), 2.98 - 2.79 (m, 4H), 2.70 (dd , J = 13.9, 9.3 Hz, 1H), 2.44 — 2.28 (m, 4H), 1.36 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H). (MH) 08.1 Detected (C29H36F506 for MS (El) (S)-N-((S)-3-(4-hydroxyphenyl)-1-((R)-2-methyloxiran-2- yl)-1-©oxopropan—2-y— )-3-(4-methoxyphenyl)-2-((S)-2-(2- morpholinoacetamido)propanamido)propana— mide (C-1162) was synthesized by following methods Used in the synthesis of 0-1003.1H NMR (400 MHz,) § 7.43 (d, J = 7.1 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.91 - 6.83 (m, 2H), 6.83 — 6.75 (m , 2H), 6.75 - 6.66 (m, 2H), 6.57 (d, 0

J = 7.7 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 4.70 (dt, J = 7.8, 4.1, 4.1 Hz, 1H), 4.48 (9, J = 7.2, 7.2, 7.1 Hz, 1H ), 4.38 (p, J = 7.0, 7.0, 6.9, 6.9

Hz, 1H), 3.77 (s, 3H), 3.69 (t, J = 4.6, 4.6 Hz, 4H), 3.22 (d, J = 4.9 Hz, 1H), 3.03 (dd, J = 14.4, 5.0 Hz, 1H ), 2.99 — 2.82 (m, 5H), 2.58 (dd, J = 14.1, 8.3 Hz, 1H), 2.54 - 2.38 (m, 4H), 1.51 (s, 3H), 1.30 (d, J = 7.1 1

Hz, 3H). (+MH) 049,7 Detected “C31H40N408 of MS (El) 71 Example (S)—-3-hydroxy—N—((S)-3-(4-methoxyphenyl)-1-( ((S)-1-((R)-2- methyloxiran—2-y- )—~1-oxo-3-phenylpropan-2-yl)amino)—-1-oxopropan— 0 2-yl)-2 —(2-morpholinoaceta—mido)propanamide (C-1159)

EA

Obn

OH o sony b °

BocHN owe HATU, DIEA, "we N “Howe LiOH, THF, H,0 , I:

TL. TL, o8n 0 a oBn . H 0 wesw TRA ona 0 son A 0 3 oy 0 = H 0

TL HATU, TL

OMe DIEA, DMF OMe oY and TFA, DCM, tt TFA: oe 0 0 NUNN LAO N A N —_— o = H o HATU,

TL DIEA, DMF

OMe with 0 on o 5 Ha, PAIC, 0 on o 5 Ha

SINT emih oO = 0 TL

OMe OMe (S)—3~—(benzyloxy)-2—((tert-butoxycarbonyl)amino)propanoic acid to acid

HATU (mL) at 0 °C (DMF 01 mol) was added in Abe 7.79 g; V0 (0 mmol). The mixture was stirred for a period of © minutes to dissolve the solids at this time 7,727 can VEY) (S)—-methyl 2—((tert-butoxycarbonylj)amino)-3-(4-©

V,vY) DIEA g; 7.74 mmol) and +, V+ A) methoxyphenyl)propanoate was added min then 70 sad at ambient temperature (J lal) mmol). 0700 mL mixture was stirred; (XY) quench with sodium bicarbonate (saturated); extraction with ethyl acetate (5)- and drying with sodium sulfate; filtration; concentration to obtain the crude compound methyl 2—((S)-3—(benzyloxy)-2—((tert-0)

—YEv- butoxycarbonyl)amino)propanamido)-3-(4-meth— oxyphenyl)propanoate in the form of a yellow oil that was transferred to the next stage without further purification. (M-Boc)? C26H34N207 to MS (El) (S)—-methyl 2—((S)—3—(benzyloxy)-2—(((tert- to butoxycarbonyl)amino) propanamido)-3-(4- methoxyphenyl(propanoate© mmol putative) aqueous lithium hydroxide (0 milliliters of a solution of 7 p) TTY) hours was added and then diluted with ethyl acetate ©sad and methanol (0 milliliters). The acidification reaction mixture was stirred with citric acid; extraction (71(Ji)); washing with coldly acetate and drying with sodium sulfate; filtering; and concentration (oly) and washing with (S)—2—((S)—-3—(benzyloxy)-2—((tert-) to obtain 0-butoxycarbonyl)amino)propanamido acid -3—(4-- methoxyphenyl)propanoic as a yellowish-white amorphous solid. (MH) 597.1 Detected (C25H32N207 for MS (El) (S)—2—((S) )—-3—(benzyloxy)-2—((tert- to butoxycarbonyl)amino)propanamido)-3- (4-methoxyphenyl)propanoic acid 0 mL) DMF (01 mmol) in 7 ,87 can (20) HATU 5 mmol (assumed) ¥, ¥9) At zero degrees Celsius -3-(ex-0:61:30-2 except2-0081-(4))-2 was added -2100-1-(5) © Mall). The mixture was stirred for (AL 7,417 cpa), 00) TFA phenylpropan salt—[1-one mmol). 1,848 “ill YL EY) DIEA minutes were stirred to dissolve the solids and the reaction mixture was added at the same temperature for 10 minutes, then quenched with 0 sodium bicarbonate and dried with sodium sulfate; (XY) (saturated ); and extraction using tert-butyl ethyl acetate ((S)-3—(benzyloxy)-1-) and concentration to obtain the crude compound, mali jill (((S)—3—(4-methoxyphenyl)-1—((((((S) )-1-((R)-2-methyloxi- ran-2-yl)-1- oxo—3-phenylpropan—2-yljamino)—1-oxopropan-2-yljamino)—1-oxopr-

M + opan-2-yl)carbamate (quantitative) in the form of yellow oil that was transferred to the next stage without further purification. MS (El) for 0371145013056 detected 130,4 (MH) to tert-butyl ((S)-3—(benzyloxy)—-1-(((S)-3—-(4-methoxyphenyl) )-1-(((S)- 1-(((R)—2-methyloxi— ran-2-yl)-1-oxo-3-phenylpropan-2-yljamino)-1- Y (4¢)oxopropan-2-yljamino)-1-oxopr-opan-2-yljcarbamate putative mmol) (01 mL) DCM (01 mL) (TRA) was added. The reaction mixture was stirred for 10 minutes. min at ambient temperature at which time it was concentrated and transported without further purification.” C32H3TN306 1 MS (El) detected stagnant (1-a). 0 to (S)—2-amino-3—(benzyloxy )-N—((S)-3-(4-methoxyphenyl)-1-(((S)- 1-((R)—2-— methyloxiran—2-yl)-1-oxo-3- phenylpropan—-2-yljamino)-1- Jk 7,14( TFA = k oxopropan-2-yl)propa— namide mole putative) =F morpholinoacetic acid (cane TEY) added 4.476 mmol ); VAT) HATU g; 5.51 mmol); 5 DMF (0 milliliters). The mixture was cooled to 0 °C and DIEA (+ ¥ Yo ), mL Abe 17.8 mol) was added. The reaction mixture was stirred at ambient temperature for Vo min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (XY) and drying with sodium sulfate; filtering; and focus. Then purification by 9 chromatography column: 1/DCM ethyl acetate + 9600-0 methanol) to obtain -(5))-L1-(/A0NO56102)-3-(5) 3—(4 -methoxyphenyl)-1—(((S)-1-((R)-2-methyloxira—n-2-yl)-1-oxo0-3- phenylpropan—-2-yljamino)—1-oxopropan- 2-yl)-2—(2-morpholino— 0 ‎acetamido)propanamide ) 174 mg; %YA on © steps) as a colorless, amorphous solid.

(+0/11) TAY, ¢ detected (C38H46N408 for MS (El) (S)—3—(benzyloxy)-N—((S)-3-(4-methoxyphenyl)-1-) ((S)-1-((R)-2-) to methylox-iran-2-yl)-1-oxo-3-phenylpropan-2-yljamino)—1-oxopropan-— micro EA mg; YY)2-yl)-2~(2-morphol- inoacetamido)propanamide mg). The reaction mixture was stirred in 5000 PAC (9600; 9600 mL) Yo) mol) methanol was added © h at 560 °C before being cooled to VT in hydrogen atmosphere (in color) for JB acetate Ethyl [DCM 1:() ambient and filtrate through celite. Purified by column chromatography (S)-3-hydroxy-N—(($)-3—-(4-) to obtain (dss 000-60 + methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-- yl)-1-oxo-3- phenylpropan—-2-yljamino)-1-oxopropan-2-yl) -2—(2-morpholinoacet- 00) as a colorless, amorphous solid. (EY mg; VY 4)amido)propanamide 1H NMR (400 MHz,) 7.89 (d, J = 7.7 Hz , 1H), 7.26 - 7.19 (m, 3H), 7.10-7.06 (m, 2H), 7.01-6.96 (m, 2H), 6.82-6.79 (m, 2H), 6.73 (d, J = 8.0 Hz 1H) , 6.50 (d, J = 7.8 Hz, 1H), 4.80 (td, J = 7.7, 7.7, 5.4 Hz, 1H), 4.64 — 4.48 (m, 1H), 4.45 — 4.31 (m, 1H), 3.92 (dd , J = 11.0, 3.9 Hz, 0 1H), 3.79-3.74 (m, 5H), 3.73 - 3.67 (m, 3H), 3.54 (dd, J = 11.0, 6.7

Hz, 1H), 3.27 (d, J = 4.9 Hz, 1H), 3.15 - 2.84 (m, 6H), 2.72 (dd, J = 14.0, 7.8 Hz, 1H), 2.55 - 2.39 (m, 4H), 1.48 (s, 3H). (+MH) oav,) detected (C31H40N408 of MS (El) vy eg Yo (28,38)-3-hydroxy-N—((S)-3—(4-methoxyphenyl)-1 -(((S)-1-((R)-2- methyloxiran— —2-yl)—1-oxo-3-phenylpropan-2-yljamino)—1-oxopropan— 2-yl)-2—(( 3-morpholino—prop—1-en-2-yl)amino)butanamide (C-1174)

c! a! HOB, HBTU, 0 0 0 yalp 8001401 DIEA, DMF, rt 0 + prab 800001 a! L TFA" HoN 8 le 1 le oMe OMe WOH 0 nam 0 0 N 0 1 yap 1 TFA DCM t | Han Ay aa, BocHN TL l 0 = ROW OMe oY o NLR WOH HATU, TFA, DCM , rt mJ NL \ © | Dita DMF H fo) > = 0 to (S)—2—((tert) acid -butoxycarbonyl)amino)-3-(4- 0.1( methoxyphenyl)propanoic acid g; Ak TYV,9 mol) in DMF (V+) milliliters) © at 0 °C £ can be added AY) HOBt 77.7 mmol) 5 HBTU (18.1 g; 7 mmol) The mixture was stirred for ½ minutes to dissolve the solids at this time -2-(5)((tert-butoxycarbonyl) )amino)-3—-(4-methoxyphenyl)propanoic acid TFA salt (V4, Y) g; 9 TY, mmol) added 1.001 lille VY, (8 DIEA mol) The reaction mixture was stirred at ambient temperature for 1V min and then quenched with 0 (saturated) sodium bicarbonate, extracted with ethyl (XY) acetate, dried with sodium sulfate, filtered, and concentrated. 1(0 -0 966 ethyl acetate/heptane) to get tert-butyl ((S)=3—(4-methoxyphenyl)-1-(((S)-1-((R)-2-)

e methyloxiran—2-yl)~1-oxo-3~-phen- ylpropan-2-yljamino)-1-oxopropan—VY, £) 2-yl)carbamate g; (%AY) as sale is a colorless crystalline solid. MS (El) L 027113411206 detected 587.7 (0/11+). To tert-butyl ((S)-3—(-4) methoxyphenyl)-1-(((S)-1-((R)-2- ‎methyloxiran—2-yl)-1-oxo-3-phen- ylpropan-2-yl)amino)—1-oxopropan— - © 36 (Ala-2 (0.11 mmol) then add DCM (°mL) TFA (°mL). The reaction mixture was stirred for 10 min at ambient temperature at which time it was concentrated and transferred without further purification. (S)—2-amino-3—(4-methoxyphenyl)-N— (((S)~1-(((R)—-2-methyloxiran—-2-yl)—1-oxo—) transferred - 3—-phenylpropan-2- yl)propanamide 0 salt of TFA directly to the next step (quantitative yield). MS (El)l (C22H26N204 Detected 7877 (0/11+). to (2S,3S)-2~((tert-butoxycarbonyl)amino)-3-hydroxybutanoic acid (57; mg; 7.17 mmol) in 01 (DMF) at 0 °C (HATU (aaa ATO) 7.76 mmol) was added. The mixture was stirred for ½ minutes to dissolve the solids at this period M0 (S)—2-amino-3-(4-methoxyphenyl)-N-((S)-1—-((R)-2-methyloxiran-2) - —oxo-3-phenylpropan-2-yl)propanamide -1- (except salt Ae Y,+V) mol TFA assumed) and DIEA (0.70 mL) was added (A 001.75 mol). tert-butyl ((2S,3S)-3-hydroxy—1—(((S)-3-(4- ‎methoxyphenyl)—1—(((S)-1-((R)-2-methyloxi) -ran-2-yl)—1-oxo-3- phenylpropan—2-yl)amino)—1—-oxopropan—2-yl)amino)—-1-oxobu— tan-2-yl) carbamate in the form of a yellow oil that was transferred to the next stage without further purification.

Blame to -(5))))-1- ( 4-006110:0/0080)-3-(5))-1-no000no-3-(25,35)) tert-butyl 1-( (R)—2-methyloxi— ran—-2-yl)-1-oxo-3-phenylpropan—-2-yljamino)-1- Y,+V)oxopropan-2-yljamino)-1-oxobu- assumed tan-2-yl)carbamate mmol) DCM (0,¥ milliliter) TFA (0,¥ milliliter) added. The reaction mixture was stirred for ∼Vomin at ambient temperature at which time it was concentrated and the crude compound -2-(25,35) amino—3-hydroxy—N—((S)-3—-) was transferred 4-methoxyphenyl)-1—-(((S)-1-((R)-2-met- hyloxiran-2-yl)-1-oxo-3-phenylpropan—-2-yljamino)—1— -oxopropan—2- yl)butanami- de TFA salt without further purification.

to (28,3S)-2-amino-3-hydroxy-N—((S)-3—(4-methoxyphenyl)-1-(((S)- 1-((R)-2- - methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1- 0 (+,YV) TFA = k oxopropan-2-yl)butan-amide mmol putative) done addition of Y morpholinoacetic acid (£4.0 771 cane mM YT) HATU (Use G 771 mmol); 1 (DMF in milliliters). The aps mixture was reduced to 0 °C and DIEA (1797, mM Abe 0.004 mol) was added. The reaction mixture was stirred at ambient temperature for ³ min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (XY) and drying with sodium sulfate; filtering; focus. Purified by column chromatography [DCM 1:©(ethyl acetate + 9610-0 methanol) to obtain (25,35)=3~hydroxy—-N- (((S)~3—(4) -methoxyphenyl)-1-(((S)-1-((R)-2-methyloxira— n-2-yl)-1- ‎oxo—3-phenylpropan—2-yl)amino)-]1- oxopropan-2-yl)-2-(2-morpholino-

Av)acetamido)butanamide 0 mg; (%7TY as a colorless solid. 1H NMR (400 MHz, DMSO-d6): 6 8.40 (d, J = 7.6 Hz, 1H), 8.10 (d, J = Hz, 1H) ), 7.62 (d, J = 8.8 Hz, 1H), 7.32-7.21 (m, 4 H), 7.09 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 4.57-7.6 (m, 1H), 4.31-4.23 (m, 1H), 4.26-4.22 (m, 1H), 3.77-3.74 (m, 4.56 1H), 3.69 (s, 3H), 3.34-3.30 (m, 4H), 3.19-3.18 (m, 1H), 2.99-2.84 (m, Yo

o — since 6H), 2.72-2.64 (m, 2H), 2.40-2.33 (m, 4H), 1.34 (s, 3H), 0.95 (d, J = Hz, 3H). 6.4 MS (El) of “C32H42N408 Detected [(+MH)1116) Example VY AH Synthesis of (R)=N—((S)-1-(((S)-3-(4) -methoxyphenyl)-1-(((S)-1-((R)-2- ‎methyloxiran—2-yl-)—1-oxo-3-phenylpropan-2-yljamino)—1-oxopropan-— 2-yl)amino)-]1-oxopropan-2-y- l)jtetrahydrofuran-2-carboxamide (C- )1166 HOBY, HBTU, 0 0 9 yalp 860001 DIEA, DMF, rt 0 + AP 800001 TFA* HoN _— inl : 6 Ma M & ° A H 0 0 0 sonny hy 1 er TFA, DCM, rt - Ay y 6 ~ _ for 8 TL OMe OMe & 3 3 OH 0 H 0 60 0 } DIEA, DMF Ey z 5 TFA, DCM, rt | Ta Ay ial — 0 OU © = | — RON OMe 0 to (S)—2—((tert-butoxycarbonyl)amino)-3-(4- V+, +) methoxyphenyl)propanoic acid g; Ak YV.9 mol) in 01 (DMF) at 0 °C added ∼4.81 (11081 77.7 mmol) nor 181 (18.1 g); YY millimoles). The mixture was stirred for a period of minutes to the dissolved solids at this period - (5)

yoh 2-amino—-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan—]1-one salt TFA V4, Y) g; 9 TY, mmol) and 1.001 lille VY, (8 DIEA mol) added. The reaction mixture was stirred at ambient temperature for 70 min and then quenched with sodium bicarbonate (saturated); extraction with ethyl acetate (XY) and drying with sodium sulfate; © and nomination; focus. Purified by 0-1(961 ethyl acetate/heptane) column chromatography to yield tert-butyl ((S)—3—(4-methoxyphenyl)-1-(((S)-1-(((R)) -2- methyloxiran—2-yl)~1-oxo-3~-phen- ylpropan-2-yljamino)-1-oxopropan— VY, £) 2-yl)carbamate g; (%AY) as sale is a colorless crystalline solid.

(+0/11) 587,7 L 027113411206 Detected MS (El) tert-butyl ((S)-3-(4-methoxyphenyl)-1-(((S)-1-(((R)-) 2-methyloxiran— to 0 (2-yl)-1-oxo-3-phen- ylpropan-2-yljamino)—-1-oxopropan—2-°) TFA (°) TFA (milliliter) (°) DCM (mmol) Addition of 0.11 g (0 yl)carbamate min at ambient temperature at that time (V0 ml). The reaction mixture was stirred for (S)—2-amino-3—(4-methoxyphenyl)-N— to concentrate and transfer without further purification. Transfer ((S)~1-((R)—-2-methyloxiran—-2-yl)—1-oxo—- 3—-phenylpropan-2—- 01

yl)propanamide the salt of TFA directly to the next step (quantitative yield).

(.)+0/11( 7877) Detected (C22H26N204 for MS (El) (S)—-2—-amino-3—(4-methoxyphenyl)-N—((S)-1-(( R)-2-methyloxiran— to 0.10 mM ( TFA -1-0-(a-2-salt xo-3-phenylpropan-2-yl)propanamide mg YAY) (S)- 2—(((tert-butoxycarbonyl)amino)propanoic mol) Yo acid added mL). The mixture cooled DMF (V) 5 mol); Ae £,YY g; HATU (87 mM) mol), 54 mmol). A mixture of 0007 mL DIEA (32.5 4) was stirred to 0 °C and the reaction was added at ambient temperature for 70 min, then quenched with sodium bicarbonate and dried with sodium sulfate; (XY) (saturated ), and extraction with ethyl acetate

e and filtering; focus. Purified by column ld 9680-0( ChE ethyl/heptane tert-butyl ((S)-1-(((S)-3—-(4-methoxyphenyl)-1-) to yield (heptane (( (S)~1—((R)—2-methyloxiran—2-yl)—1-ox— o-3-phenylpropan-2- yl)amino)-1-oxopropan-2-yljamino)—1-oxopropan- 2-yljcarb— amate (AY) 0 mg;(%AY) as a colorless solid. (+0/1) ¢AA,¢ for 026113701306 detected MS (El) tert-butyl ( (S)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2- to methyloxiran—2-yl)~1- ox- o-3-phenylpropan-2-yljamino)—1-oxopropan— ‎cane V4 +) 2-yl)amino)-]1-oxopropan-2-yl)carb— amate 417 mmol) 0 Add DCM (¥ milliliters) Y) TFA milliliters). The reaction mixture s.d. was stirred for 10 min at ambient temperature at which time it was concentrated and transferred to the crude compound -2-(5))-2-(5)aminopropanamido)—-3—(4-methoxyphenyl)-N— ((S)-1-((R)-2-methyl- oxiran-2-yl)—1-oxo-3-phenylpropan-2-yl)propanamide salt of TFA for next stage without further purification. .)+0/11( 977 Detected 02711317301307 IMS (El) 0 (S)—2-((S)—2-aminopropanamido)-3-(4-methoxyphenyl)-N—(((S)-1) - to (((R)~2-met- hyloxiran—2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide (R)-tetrahydrofuran—-2-mol putative) mixture was added of (Jd +8 mmol) acid; 0.494 mg HATU (1 mmol) (AY); 0.494 mg carboxylic acid (ov) mL; DIEA (YoY) + mL). The mixture was cooled to 0 °C and ¥ (DMF, 0 min) was added and then quenched (11 mmol). The reaction mixture was stirred at ambient temperature for 7 using sodium bicarbonate (saturated); extraction with ethyl acetate (7*); And drying

JDCM 1:©(using sodium sulfate” and filtration. Concentration. Purified by column chromatography ) to obtain -4)-3-(5))-1-(5))-l-b( (dsl) 9000-1 + Jd acetate

1e,methoxyphenyl)-1-(((S)-1-(((R)-2-methyloxiran-2-yl- (-1-0*0-3- phenylpropan—2-yl)amino)—1 —-oxopropan—2-yl)amino)—1—oxopropan—2-y—- (VY) I)tetrahydrofuran-2-carboxamide (%0V) aggregated as a colorless amorphous solid. e = 1H NMR (400 MHz, DMSO-d6): 6 8.46 (d, J = 7.6 Hz, 1H), 7.93 (d, J Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.31 - 7.20 (m, 5H), 7.08 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.59 - 4.54 (m, 1H), 4.48 — 4.42 8.4 (m , 1H), 4.21 - 4.16 (m, 2H), 3.80 — 3.69 (m, 5H), 3.18 (d, J = 5.2 Hz, 1H), 2.98 (d, J = 6.4 Hz, 1H), 2.95 — 2.86 (m, 2H), 2.73 - 2.59 (m, 2H), (m, 1H), 1.80 - 1.66 (m, 3H), 1.11 (d, J = 7.2 Hz, 3H).0 1.99 - 2.05 MS (El) for (C30H37N3O7 Detected 057.7 (+MH) Distinguish (S)-N—=((S)=1-(((S)~3—(4-methoxyphenyl) )-1-(((S)-1-((R)-2- ‎methyloxiran—2-yl-)—1-oxo-3-phenylpropan-2-yljamino)—1-oxopropan-— 2 -yl)amino)-]1-oxopropan-2-y- l)jtetrahydrofuran-2-carboxamide (C- yo ) 1167 1H NMR (400 MHz, DMSO-d6): 6 8.46 (d, J = 7.2 Hz, 1H), 8.00 ( d, J = Hz, 1H), 7.59 (d,J = 7.6 Hz, 1H), 7.31 - 7.20 (m, 5H), 7.08 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.58 - 4.56 (m, 1H), 4.51 — 4.42 8.4 (m, 1H), 4.22 — 4.15 (m, 2H), 3.84 — 3.67 (m, 5H), 3.18 (d , J = 5.2 Hz, 1H), 2.99 (d, J = 5.2 Hz, 1H), 2.95 = 2.87 (m, 2H), 2.72 - 2.62 (m, 2H), 0 (m, 1H), 1.78 - 1.74 (m, 3H), 1.09 (d, J = 7.2 Hz, 3H). —=((S)-1-(((S)-3—(4-methoxyphenyl)-1-(((S)-1-((R)-2- ‎methyloxiran—2-yl)~1 -- oxo-3-phenylpropan-2-yljamino)—1-oxopropan-—

c + 2-yl)amino)-]1-oxopropan-2-yl)-1- -methylazetidine-3-carboxamide (C-1172) 1H NMR (400 MHz, DMSO-d6)6 8.57 ( d, J = 7.6 Hz, 1H), 8.40 (d, J = Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 7.31 - 7.10 (m, 5H), 6.84 (d, J = 8.4 Hz, 1H), 4.59 — 4.48 (m, 2H), 3.94 - 3.91 (m, 1H), 3.72 (s, 3H), © 8.8 (m, 1H), 3.03 - 2.95 (m, 2H) ), 2.85 - 2.82 (m, 6H), 2.73 - 3.02 = 3.20 (m, 1H), 2.46 — 2.36 (m, 1H), 1.38 (s, 3H), 1.24 (d, J = 6.8 Hz, 2.67 3H). ELISA “proteasome constitutive/immunoproteasome pA” (ProCISE) subunit enzyme-linked immunosorbent assay 1 for quantitative assessment of subunit-specific activity as described by Glu. In Parlati F, Lee SJ, M, et al.

Blood (2009) 114:3439-7 no 2 sle._The test compounds were serially diluted in DMSO at a concentration of 0.001 and then diluted to 1 0 in a surfactant Sle buffer. The assay was processed from a human lymphoblastic leukemia sala cell line. (MOLT-4) for 1 hour at YO entrapped with a compound at a final YO concentration LIX, then the treated cell lysates were incubated using an active site binding probe to the biotinylated proteasome for 1 time. hour at YO degree Aggie After that, the solubilization product was denatured in guanidine hydrochloride “and the subunits attached to the probe were separated using sepharose beads conjugated with Lstreptavidin 5 Using probes with subunits single (eg

Meh + Example » 5 MECL-1 (LMP2 (LMP7) subunit-specific primary antibodies; followed by HRP-conjugated secondary antibodies. A Biles fluorescent substrate was used to generate an HRP-binding signal that was detected The fluorescence signal was normalized for protein content, and the percentage activity was then calculated for comparison samples treated with DMSO to generate 1050 curves. Proteasome chymotrypsin; caspase-like; trypsin-like of many of the compounds presented here using AMC-Tyr-Val-Leu-Leu-succinyl (AMC-Tyr-Val-Leu-Leu-V+) 2-—Leu-Leu (V+) AMC-Glu 0 µmol/L) and 8026-Na-OnH/-NL (01 µmol/L); respectively; with purified human proteasome 205 (ct oY) and 0.4 nmol/l, respectively) or cell lysis product 117-29 (175; 75 and YO, + µg protein/mL, respectively). The buffer solution for the experiment was formed from the solution [JeYo]TE idl mol/L Tris (its pH

SDS 960.07 with or without (205) (cell lysis product) [EDTA mol/L Ak,*) 0

AMC Reactions were initiated by addition of enzyme or degradation product and monitored for product information Vo at ©[27] with a plate-based spectofluorometer (Tecan) af 050 determined based on reaction rate measured between 10 and 75 minutes.Demo, 5. D. et al., Cancer Res. 2007, 67, 6383-6391 See also.

o q — since it is a compound content of 1 | Composite Content 1 | Capability content 1 content dele] 1 solubility del solubility hour Hu hour of Hu number of product of Hu number of Hu of product of | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | 5 (micro E (micro olin E LMP7| oly E g/mL LMP7 g/mL MOLT (|MOLT4 | MOLT4 liter)) 4: IC50 :|IC50 : 4 IC50 IC50 S|sb) (4 molar) | amolar) (nanomolar) molar) C- C- 1001 1154 C- C- 1002 1155 C- C- 1003 1156 C- C- 1004 1158 C- C- 1005 1159

.© Content Complex 1 | Composite Content 1 | Capability content 1 content dele] 1 solubility del solubility hour Hu hour of Hu number of product of Hu number of Hu of product of | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | 5 (micro E (micro olin E p LMP7|oly |g/mL LMP7 g/mL MOLT MOLT (|MOLT4 | MOLT4 liter)) 4: IC50 :|IC50 : 4 IC50 IC50 S|sb) (nanomolar) |molar) (nanomolar) molar) C- C- 1007 1161 C- C- 1008 1162 C- C- 1009 1163 C- C- 1010 1164 C- C- 1111 1165

-1©- Compound Content 1 | Composite Content 1 | Capability content 1 content dele] 1 solubility del solubility hour Hu hour of Hu number of product of Hu number of Hu of product of | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | 5 (micro E (micro olin E p LMP7|oly |g/mL LMP7 g/mL MOLT MOLT (|MOLT4 | MOLT4 liter)) 4: IC50 :|IC50 : 4 IC50 IC50 S|sb) (4 molar) | amol) (nanomolar) molar) C- C- 1112 1166 C- C- 1113 1167 C- C- 1114 1168 C- C- 1115 1170 C- C- 1116 1171

-7?+ Compound Content 1 | Composite Content 1 | Capability content 1 content dele] 1 solubility del solubility hour Hu hour of Hu number of product of Hu number of Hu of product of | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | 5 (micro E (micro olin E p LMP7|oly |g/mL LMP7 g/mL MOLT MOLT (|MOLT4 | MOLT4 liter)) 4: IC50 :|IC50 : 4 IC50 IC50 S|sb) (4 molar) | amol) (nanomolar) molar) C- C- 1118 1173 C- C- 1119 1174 C- C- 1120 1175 C- C- 1121 1176 C- C- 1122 1177

A compound content 1 | Composite Content 1 | Capability content 1 content dele] 1 solubility del solubility hour Hu hour of Hu number of product of Hu number of Hu of product of | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | 5 (micro E (micro olin E p LMP7|oly |g/mL LMP7 g/mL MOLT MOLT (|MOLT4 | MOLT4 liter)) 4: IC50 :|IC50 : 4 IC50 IC50 S|sb) (4 molar) | amol) (nanomolar) molar) C- C- 1123 1178 C- C- 1124 1179 C- C- 1125 1180 C- C- 1127 1181 C- C- 1128 1183

1 content compound | Composite Content 1 | Capability content 1 content dele] 1 solubility del solubility hour Hu hour of Hu number of product of Hu number of Hu of product of | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | 5 (micro E (micro olin E p LMP7|oly |g/mL LMP7 g/mL MOLT MOLT (|MOLT4 | MOLT4 liter)) 4: IC50 :|IC50 : 4 IC50 IC50 S|sb) (4 molar) | amolar) (nanomolar) molar) C- C- 1130 1185 C- C- 1131 1186 C- C- 1132 1187 C- C- 1133 1188 C- C- 1135 1189

© compound content 1 | ability compound content 1 | susceptibility content 1 content dele] 1 solubility del solubility hour Hu hour of product Hu number of product Hu number of product Hu to product | hydrolysis dissolution hid liquid dissolved solute 5 i.e. to 005 ani vy ProCIS i) E | 5 (micro E (micro olin E p LMP7| oly |g LMP7 mg/mL MOLT MOLT (|MOLT4 | MOLT4 IL) 4: IC50 :|IC50 : 4 IC50 IC50 S| sb) (4 molar) | molar) (nano molar) molar) C- C- 1136 1190 C- C- 1137 1191 C- C- 1138 1124 C- C- 1139 1125 C- C- 1140 1126

-1?+- a compound content 1 | Composite Content 1 | Ability Content 1 Content 1 | hour to dissolve hour to dissolve hour hour Hu hour Hu number output Hu number output Hu number output | Hydrogen melting Hydrogen melting head rugged melting 5 i.e. l 005 I vy (ProCIS i) E | ProCIS (micro E (micro lin E oly E | 11057 g/mL LMPT g/mL MOLT4 | MOLT4 liter) MOLT 4: IC50 :| IC50 : 4 IC50 (Nano (Nano IC50 (Secomolar) | Amylar) (Nanomolar) Molar) C- C- 1142 1128 C- C- 1144 1129 C- 1153 ee VY Y [ ] The results for the selected compounds are shown in the following table: Hours of hours J

LLVY LLVY c20S | : i20S Hu es (5 billion) | IC50 (nanomolar)

father-in-law ?-

++1 and -

-Except ©

Claims (1)

+ Elements of protection (20): A compound of formula -1 CASES Se M and 7 are independently hash 1 rt + p0h Pt J FY © is a zero or a 1; 0 is ha 1 or ?; —NH— (N(C=0O)OR7 (NRT 04546) is selected from the set of K ((C=0)— 0 5 50 and 502; “CR7 JN is E C2-6alkynyl (Al60” (L02-68)); “3-6000” and cycloalkyl Jif has ax atoms =F where it is in RI An optional substitution with one or more substitution groups chosen from the constituent group ¢ (C=O)N(RT)2 «CN (N(R7)2 SRT Bakhan (halo la) R2 is Cl-2alkylene—G or —G(C=0); where © is chosen from 1 the aryl group consisting of a caryl aryl heteroaryl ; and pyridinone Provided that when sie R2 is about CH2 phenyl “phenyl” the phenyl is substituted with one or more substituent groups to be chosen from the group made up of (ORT) halo “CN ((C=O)N(R7)2 50247 0013 « C1-36alkyl « halo 5020(47)2; « C3-Tcycloalkenyl « C3-7cycloalkyl is selected from the group of R3 carbons 7-7; cycloalkyl non-axe with heterocycloalkyl cycloalkyl heterocyclic Yo A heterocycloalkyl homologue has a 7-7 carbon atoms where it is in the 3+ optionally substituent with one or more replacement groups chosen from the group made up of halo ¢ Cl-6alkyl and O(C=0O)N(R7)2 «N(R7)2 SRT Wei Rakan R4 is H or C1-3alkyl ; A halo halo (OH H) each selected separately from the group formed by R65 RS plus the carbon atom to which they bond 3[ke and 0] or form 45 and 46 Cl-3alkyl 7 A or ?; and “1 is 1 and NRT is © or sie W where CTF or 0-0 ¢ C 1 —6al kyl or and H is For dss 3) gaa R7 of which each or a pharmaceutically acceptable salt is formed. 13 0 13 0 13 0 13 0 13 0 0 13 5 0 h HO ory o ' 0 ' 0 ke : tb OY l l 6 l fo) 0 0 ' 0 ¢ F3C ¢ F ¢ Cl 0 0 0 'ORUNOR EE. 0 ¢ 0 Me I 0 HO N Me-,, 5 N Me 0 It HO [4 0 [4 0 [4 0] [4 0 2 N 0 Lm] ey . Me Lay 6 and 0 Ola he hye K : 2 *- Compound according to claim 1 or oF where go nO is chosen Group consisting of: HO 0 NY 5 %, N ISR: OY Oo + 0 + 0 mo HO © ;- compound according to any of the claims 1 to oF where le RL is about 61-3 alkyl or selected from the containing group of . CH2CN ; CH(OH)CH3 « CH20H(CH3 =o) compound according to any of the claims 1 through cf where R2 is 0112-aryl heteroaryl or aryl J j—CH2 Ve 7- Compound By of any of the claims from 1 to 00 where 2 is chosen from the group oor or containing: 0 ¢ MeO F Re J: J OH Hm Crs ~ : © æ $ ¢ mna ¢ Nes ¢ ¢ N ¢ 9 core 0 wos «NC '0 605 108 N lemme TTT of N '8 05 Yo 8 J LTT OY oy Or 75 N ' Me;N ' FCO 0 ' ,0 ' Fill in Pod IT LT M Ih A O25. PN HO ' 0 0 H ' H ¢ HO OY JOH HO sf HO ' MeO ' 5 ¢ original to 'pray' on MeO ¢ HO ¢ Et 'Me ¢ HO MeO MeO HO ¢ 0 ) > oY OH ' OH ' OMe «HO ' OMe OH oa “© “© * © HN co NF HO MeO 5 OH 0” n “Hg” Me “+ E (F3CO 605 ' 1h “MeO 7 0 Ami Had P Ham Hen” NA ¢ 2 “F 2 “MeO ¢ 2 | ¢ Me. 0 SJD 77 ‘No. Me’ 6 and 2 0. 0 7- Compound Ey for any of the claims from 1 to 0 where 2 is chosen from group OH HO ory PY or containing: MeO MeO MeO and BOS Me. No 4- The compound according to any of the claims 1 to of where R3 is: cyclopropyl ; cyclobutyl cyclopentyl or cyclohexyl cyclopentenyl cyclohexenyl tetrohydrofuranyl tetrahydropyranyl ; © pyrrolindinyl + pyrrolidinonyl ; gh dihydropyranyl or dihydrofuranyl “ or A Ne is chosen from the group containing 9 3 9 6 . 4- The compound Gy of claimant 1 with the formula: L-al-ab-his KA o rR 0 0 RS 0 \ K is Of CH(OH); se E is for N or 087 ; A +1 is 01120110113 “CH(OH)CH3 or CH2CN ; Vo is R25 OH HO oY Per “or “MeO” MeO “MeO BOA Me Y. Bala 2 ar and 3 + is an or . -0 Compound fy of claim 9 having a structural formula chosen from the group containing: ON ONG A 1 A & i N N N N SE 0177 of SEAS [a] 3 4 OH ON Oo.N N N SEARS SLISRAAS SL 3[ 3] Oo. HO 0 0 0 0 N the la 01 1 wa rest oJ) © H SE H § H J 0 ' ' OL HO 0 09 hm 5 yO 6 o N (AA AN N live bar oJ) © Ho 0 Qo 0 od ' ' Hallam OH NG Zab La Illa Alh SE MARRS 49 © H 1 6 5 H 1 D Hs 0 OL Ae 0 CH Cx Seas 1 + ae Ds N " 0 0 N N HO © £4 ° 0 3 8 ONG Tna Na Mt © 0 0 8 H N WE 0 N " o._/ %o oO 0 5 z 3[ 0 OH 1 - 2 0 N SWS N Ts 2 H 0 H 0 _ N en N 1 HO 0 1 077 z 02 OH : ~ IGP: Pi Nai FERAL SLESR THY o) 6 d 3[ [a]. Nor OH OH H 0 & 1 & N ro N H H N N N N ET UE Shas r= [3 [3 oO. OH N N N N SEPL oe SANE for N a [3 [3 Ng (ONG HO N N N N SASS eg SAPS Lys [3 [3 OH OH oY 0 fo) 0 oY lo) 0 0 © AL 1 or a AL 1 or M9 0 0 0 0 +F 0 or a pharmaceutically acceptable salt thereof. 5 having a structural formula chosen from group containing 01 the compound of claim -11 contains: = “6 ?- OH Te N Ho 1 1 N as SE oy oo H N 0 HO 0 © o” 3 oY 0 OH y SEPuSIt IN: All JASE TAR Lk I IAT 8 N 6 6 z o” ' 0 Oo Hof H © 8 N 1 i Bar SARE py: Pi 07 kb HO 0 4[ OH 1 HO od i rest N N Pi SAAS YY SERSRRAET 0 z 4[ Oo b Jo ] fo) 0 and a SE _ N A ee 0 bib YY N H i 0 0 H 4 HO 0 ee x 0 ' Um OH HQ H © ON 3° Hf 0 N N # lal N rsi oJ o " 60 "og A © 6 : : OH Oo. Ho © H 0 0 0 H H N i 2 5 a a r o BOR nol n " oJ o 3 3 3 Oo. Hof H 0 ONY N N 0 " 2 L " or a pharmaceutically acceptable salt thereof. 0 ?1- Compound By of claim 01 having a structural formula chosen from the group containing: Oo. Tuo 0 a )9 0 Ww IY N N NOL N N i o " Ae you HO HO 0 ' 3 OH Oh. Oo. Hof H © H 0 H © NY N SRLS N 0 n " 6 his o n " oJ o + ON HO 0 0 0 N N ONY N "n " 5 oJ o " 0 HO : 0- + 0- HO HO SUBS N N ONY N "” n Hoo has o " 0 HO ' 0” OH ON & 0 0 0 0 H H H H N N Ee NY a wo 0 " o oJ © 0 0 3 3 OH Oo. 0 0 0 oO© 0 0 0 NZ 3 3 3 or a pharmaceutically acceptable salt thereof. 0 JOY salt to 1 pharmaceutical composition comprising the compound according to any of the claims from -1 . Pharmaceuticalally acceptable diluent or diluted carrier sales Pharmaceuticalally acceptable terminator 01 of protectant Gy or formulation 11 to 1 of any of the claims of By VEY compound and includes immunoproteasome of a cell For use to inhibit the immunoproteasome of a cell Ges infected the cell with the compound or LSE effectively to inhibit the eld proteasome in the cell Immunoproteasome in the cell .V0 = the compound or combination for use pursuant to claim 06 where Ladi the compound © (LMPT7)B5i and also optionally inhibits one or both of 80102 and 1501-1 . The validity period of this patent is twenty years from the date of filing the application, provided that the annual financial fee is paid for the patent and that it is not invalid or forfeited for violating any of the provisions of the patent system, layout designs of integrated circuits, plant varieties, and industrial designs, or its executive regulations issued by King Abdulaziz City for Science and Technology; Saudi Patent Office P.O. Box TAT Riyadh 57??11 ¢ Kingdom of Saudi Arabia Email: Patents @kacst.edu.sa