NZ711715B2 - 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. 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 CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit ofUS. Provisional Application Nos. 61/941,798 (filed February 19, 2014), 61/883,798 (filed on September 27, 2013), 61/856,847 (filed on July 22,2013), 61/847,780 (filed on July 18,2013), 61/786,086 (filed on March 14,2013), 61/883,843 (filed on September 27, 2013), and ,608 (filed on March 14, 2013), each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE ION Field of the Invention This disclosure relates to tide epoxy ketone protease inhibitors including methods ofmaking and using the same.

Description of Related Technology In eukaryotes, protein ation is predominately mediated through the ubiquitin pathway in which proteins targeted for destruction are ligated to the 76 amino acid polypeptide ubiquitin. Once targeted, ubiquitinated proteins then serve as substrates for the 26S proteasome, a atalytic protease, which s proteins into short peptides through the action of its three major proteolytic activities. While having a general function in intracellular protein turnover, proteasome-mediated degradation also plays a key role in many processes such as major histocompatibility complex (MHC) class I antigen presentation, apoptosis, cell grth regulation, NF-KB activation, antigen sing, and uction of pro-inflammatory signals.

The 20S proteasome is a 700 kDa cylindrical-shaped multicatalytic protease complex comprised of 28 subunits organized into four rings. In yeast and other eukaryotes, 7 different or subunits form the outer rings and 7 different [3 subunits comprise the inner rings.

The 0L subunits serve as g sites for the 19S (PA700) and 11S (PA28) regulatory complexes, as well as a physical barrier for the inner proteolytic r formed by the two B subunit rings. Thus, in vivo, the proteasome is believed to exist as a 26S particle (“the 26S proteasome”). In vivo ments have shown that inhibition of the 20S form of the proteasome can be y correlated to inhibition of 26S proteasome. Cleavage of amino- terminal prosequences of [3 subunits during particle formation expose amino—terminal threonine residues, which serve as the catalytic nucleophiles. The subunits responsible for catalytic activity in proteasomes thus possess an amino terminal nucleophilic residue, and these ts belong to the family of N-terminal nucleophile (Ntn) hydrolases (where the nucleophilic N-terminal residue is, for example, Cys, Ser, Thr, and other philic moieties). This family includes, for example, penicillin G acylase (PGA), penicillin V acylase (PVA), glutamine PRPP amidotransferase (GAT), and bacterial glycosylasparaginase. In addition to the ubiquitously expressed β subunits, higher vertebrates also possess three interferon-y-inducible β subunits (LMP7, LMP2 and MECL1), which replace their normal counterparts, B5, Bl and B7 tively, thus altering the catalytic activities of the some. Through the use of different peptide ates, three major proteolytic activities have been defined for the eukaryote 20S proteasome: chymotrypsin-like ty (CT-L), which cleaves after large hydrophobic residues; trypsin-like activity (T-L), which cleaves after basic residues; and peptidylglutamyl peptide hydrolyzing activity (PGPH), which cleaves after acidic residues. Two additional less characterized activities have also been ed to the proteasome: BrAAP activity, which cleaves after branched-chain amino acids; and SNAAP activity, which cleaves after small neutral amino acids. The major proteasome proteolytic activities appear to be buted by different catalytic sites, since inhibitors, point mutations in β subunits and the ge of γ interferon-inducing β subunits alter these activities to various degrees.

New compositions and methods for preparing and formulating proteasome inhibitor(s) would be useful.

SUMMARY OF THE INVENTION [0005a] According to a first aspect, the invention relates to a compound of Formula (X): wherein: m and n each ndently are 0, 1 or 2, and m + n = 2, 3, or 4; p is 0 or 1; q is 0, 1, or 2; K is ed from the group consisting of CR5R6, NR7, N(C=O)OR7, —NH—(C=O)—, O, S, SO, and SO2; E is N or CR7; R1 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, and 3-6 membered heterocycloalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of halo, OR7, SR7, N(R7)2, CN, and (C=O)N(R7)2; R2 is C1-2alkylene—G or (C=O)—G; wherein G is selected from the group consisting of aryl, heteroaryl, and pyridinone, with the proviso that when R2 is nyl, the phenyl is tuted with one or more substituents selected from the group consisting of OR7, halo, C1-3alkyl, OCF3, SO2R7, (C=O)N(R7)2, CN, and SO2N(R7)2, or R2 is selected from the group consisting of , , , , , , , , , , , , , , , , and R3 is selected from the group consisting of C3-7cycloalkyl, C3-7cycloalkenyl, a 3-7 ed heterocycloalkyl, and a 3-7 ed heterocycloalkenyl, wherein R3 is optionally substituted with one or more substituents selected from the group consisting of halo, =O, OR7, SR7, N(R7)2, O(C=O)N(R7)2, and C1-6alkyl; R4 is H or C1-3alkyl; R5 and R6 are each independently selected from the group ting of H, OH, halo, C1-3alkyl, and CF3, or R5 and R6 together with the carbon to which they are attached form C=O or , wherein W is O or NR7, and r is 1, 2 or 3; and each R7 is independently H or C1-6alkyl, or a pharmaceutically acceptable salt thereof. [0005b] According to a second aspect, the invention relates to a pharmaceutical composition comprising the compound of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. [0005c] According to a third aspect, the invention relates to use of a compound of the invention or the composition of the invention in the cture of a medicament for inhibiting immunoproteasome in the cell. [0005d] According to a fourth , the invention relates to use of a compound of the invention or the composition of the invention in the manufacture of a medicament for the treatment of an immune-related disease. [0005e] According to a fifth aspect, the invention relates to use of a nd of the invention or the composition of the ion in the manufacture of a medicament for the treatment of inflammation. [0005f] According to a sixth aspect, the invention relates to use of a compound of the invention or the composition of the invention in the manufacture of a medicament for treating an infection. [0005g] According to a h , the invention relates to use of a compound of the invention or the ition of the invention in the manufacture of a medicament for treating a neurodegenerative disease.

Provided herein are nds of general formula (X) or (I): with substituents defined as discussed in detail below.

Also provided herein is a ceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound provided herein, or a ceutically acceptable salt thereof.

The compounds can compositions provided herein are useful in the treatment of diseases or disorders, such inflammation and neurodegenerative disease. Specifically contemplated diseases include, but are not limited to, rheumatoid arthritis, lupus, multiple 2b followed by page 3 sis, and Crohn’s disease. Accordingly, provided herein is a method of treating such a disease or disorder in a patient, the method sing administering a eutically effective amount of a compound or composition as provided herein to cause a therapeutic effect.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their ty. In case of conflict, the present specification, including definitions, will control.

Other features and ages of the disclosure will be apparent from the ing detailed description and figures, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION Definitions For the terms “for example” and “such as” and grammatical equivalences thereof, the phrase “and t limitation” is understood to follow unless explicitly stated otherwise.

As used herein, the term ” is meant to account for variations due to experimental error.

All ements reported herein are understood to be modified by the term “about,” r or not the term is explicitly used, unless explicitly stated ise. As used herein, the singular forms “ )9 (C a an,” and “the” include plural referents unless the context clearly dictates otherwise.

As used herein, chemical structures which contain one or more stereocenters ed with dashed and bold bonds (i.e., ----n and —— ) are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used herein, bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise indicated to the contrary, chemical structures that include one or more centers which are illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (e.g., diastereomers, enantiomers) and mixtures thereof Structures with a single bold or dashed line, and at least one additional simple line, encompass a single enantiomeric series of all possible diastereomers.

Resolution of c mixtures of compounds can be carried out by any of numerous methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable ing agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, oyltartaric acid, mandelic acid, malic acid, lactic acid, or the s optically active camphorsulfonic acids such as camphorsulfonic acid. Other resolving agents suitable for fractional llization methods include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N—methylephedrine, exylethylamine, 1,2- diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). le n solvent compositions can be determined by one skilled in the art. nds provided herein can also include all isotopes of atoms ing in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include hydrogen, tritium, and deuterium.

The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and es of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates).

The term “Cx_yalkyl” refers to tuted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that n from x to y carbons in the chain. For example, C1_7alkyl refers to an alkyl groups having a number of carbon atoms encompassing the entire range (i.e., l to 7 carbon atoms), as well as all subgroups (e.g., 1-6, 2-7, 1-5, 3-6, 1,2, 3, 4, 5,6, and 7 carbon atoms). The terms “C2_yalkenyl” and “C2_yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

The term “alkoxy” refers to an alkyl group having an oxygen attached thereto.

Representative alkoxy groups include methoxy, ethoxy, y, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or les an alkoxy.

The term, “Cx_yalkoxyalkyl” refers to a Cx_yalkyl group, as previously defined, substituted with an alkoxy group. For example, the term “C1_6a1koxyalkyl” refers to a C1_ 6alkyl group substituted with an alkoxy group, thereby forming an ether.

The term, “Cx_yaralkyl” refers to a Cx_yalkyl group, as previously , substituted with an aryl group. For example, the term “C1_6aralkyl”, as used , refers to a C1_6alkyl group substituted with an aryl group.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts f, e.g., a moiety that can be represented by the general 8 3+ _N —[}]—R formulae: R or R where each R group independently represents a en, an alkyl, an alkenyl, —(CH2)b—T, or two of the R groups taken together with the N atom to which they are attached te a heterocycle having from 4 to 8 atoms in the ring structure; T represents an aryl, a cycloalkyl, a cycloalkenyl, a cyclyl or a polycyclyl; and b is zero or an r from 1 to 8. In certain embodiments, an amino group is basic, meaning its protonated form has a pKa above 7.00. In some embodiments, the terms “amine” and “amino” refer to a moiety that is covalently bonded to a unsubstituted or substituted nitrogen atom.

The terms “amide” and “amido” are art-recognized as an amino-substituted KAN), yl and include a moiety that can be represented by the general formula: «Jw . In some embodiments, the amide will not include imides, which may be unstable.

The term “aryl” as used herein includes 5-, 6-, and 7-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. The term “aryl” also includes polycyclic ring s having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. In some embodiments, an aryl ring can be substituted with a halogen, such as fluorine.

The terms “carbocycle” and “carbocyclyl”, as used herein, refer to a 3— to 7- membered non-aromatic substituted or unsubstituted ring in which each atom of the ring is carbon. The ring may be completely saturated or may have one or more unsaturated bonds such that the ring remains non-aromatic. The terms “carbocycle” and cyclyl” also include polycyclic ring systems having two or more cyclic rings in which one or more carbons are common to two adjoining rings wherein at least one of the rings is carbocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. yclyls include cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexylmethyl, and 4-methy1cyclohexyl. Examples of polycyclic yclyls include bicyclo[2.2.l]heptanyl, spiro[2.4]heptanyl, norbomyl, and tyl.

The term “cycloalkyl” as used herein refers to a 3- to 7—membered saturated substituted or unsubstituted ring in which each atom of the ring is carbon. The term “cycloalkyl” also includes polycyclic ring systems having two or more cyclic rings in which one or more carbon atoms are common to two adjoining rings n at least one of the rings is a cycloalkyl.

The term “cycloalkenyl” as used herein refers to a 3- to 7-membered substituted or unsubstituted ring in which each atom of the ring is carbon. The ring has one or more unsaturated bonds such that the ring remains non-aromatic. The term “cycloalkenyl” also includes polycyclic ring s having two or more cyclic rings in which one or more carbon atoms are common to two adjoining rings wherein at least one of the rings is a lkenyl.

The term “carbonyl” is art—recognized and es moieties containing a C=O )Lx’R group, such as, for example, those represented by the general formulae: 01' X R' wherein X is a bond or represents an oxygen or a sulfiir, and R represents a hydrogen, an alkyl, an alkenyl, —(CH2)b—T or a pharmaceutically acceptable salt, R’ ents a hydrogen, an alkyl, an alkenyl or —(CH2)b—T, where m and T are as defined above. Where X is an oxygen and R or R’ is not hydrogen, the formula represents an “ester”.

Where X is an oxygen and R is a hydrogen, the formula ents a “carboxylic acid”.

The term, “Cx_yheteroaralkyl” refers to a Cx_yalkyl group, as previously defined, substituted with a heteroaryl group. For example, the term “C1_6heteroaralkyl”, as used herein, refers to a C1_6alkyl group substituted with a heteroaryl group.

The term “heteroaryl” includes substituted or unsubstituted ic 5— to 7- membered ring structures, for example, 5- to 6-membered rings, whose ring structures include one to four heteroatoms. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e. g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.

Heteroaryl groups include, for example, pyrrole, furan, thiophene, ole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. In some embodiments, a heteroaryl ring can be substituted with a halogen, such as fluorine.

The term oatom” as used herein means an atom of any element other than carbon or hydrogen. For example, heteroatoms include nitrogen, oxygen, phosphorus, and sulfur.

The term “heterocyclyl” or “heterocyclic group” refers to substituted or unsubstituted non-aromatic 3- to lO-membered ring ures, for example, 3- to 7- membered rings, whose ring structures include one to four heteroatoms. The ring may be completely ted (e.g., heterocycloalkyl) or may have one or more unsaturated bonds such that the ring remains non—aromatic (e.g., heterocycloalkenyl). The term “heterocyclyl” or “heterocyclic group” also includes clic ring systems having one or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for e, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term, “Cx_yhydroxyalkyl” refers to a Cx_yalkyl group, as previously defined, substituted with a hydroxy group. For example, the term ydroxyalkyl” refers to a C1_ 6alkyl group substituted with a hydroxy group.

The term “thioether” refers to an alkyl group, as d above, having a sulfiir moiety ed thereto. In some embodiments, the “thioether” is represented by —S— alkyl. entative her groups include methylthio, ethylthio, and the like. 2014/026987 The term ituted,” refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the tuent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the sible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and omatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have en substituents and/or any permissible substituents of organic nds described herein which satisfy the es of the heteroatoms. Substituents can include, for example, an alkyl, alkenyl, alkynyl, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an ester, a thioester, an carbonyl, a formyl, or an acyl), a rbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a oryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a carbocyclyl (e. g., cycloalkyl, lkenyl), a heterocyclyl (e. g., heterocycloalkyl), an aralkyl, a heteroaralkyl, or an aromatic (i.e., aryl) or aromatic (i.e., heteroaryl) moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. In some embodiments, the substituent is a halogen, such as fluorine. When a chemical functional group includes more than one tuent, the substituents can be bound to the same carbon atom or to two or more different carbon atoms. A substituted chemical functional group can itself include one or more substituents.

In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated or purified. By “substantially isolated” is meant that the compound is at least partially or substantially ted from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can e compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds, or salt f. Methods for isolating compounds and their salts are routine in the art.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If the subject composition is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if the subject composition is administered after manifestation of the ed condition, the treatment is therapeutic, (i.e., it is intended to diminish, rate, or stabilize the ng unwanted condition or side effects thereof).

The term “proteasome” as used herein is meant to include immuno- and constitutive proteasomes. In some embodiments, a compound of the disclosure preferentially inhibits the immunoproteasome.

The term “i208” as used herein refers to the 208 immunoproteasome.

The term “0208” as used herein refers to the constitutive ZOS proteasome.

As used herein, the term itor” is meant to be a compound that blocks or reduces an activity of an enzyme or system of enzymes, receptors, or other pharmacological target (for example, inhibition of lytic cleavage of rd fluorogenic peptide substrates such as succinyl-Leu-Leu-Val-Tyr-AMC, Boc-Leu-Leu-Arg-AMC and Z-Leu- Leu-Glu-AMC, inhibition of various catalytic activities of the 208 proteasome). An inhibitor can act with itive, uncompetitive, or noncompetitive inhibition. An tor can bind reversibly or irreversibly, and therefore, the term es compounds that are suicide substrates of an enzyme. An inhibitor can modify one or more sites on or near the active site of the enzyme, or it can cause a conformational change ere on the enzyme. The term inhibitor is used more broadly herein than scientific literature so as to also encompass other classes of pharmacologically or therapeutically useful agents, such as agonists, antagonists, stimulants, co-factors, and the like.

A “therapeutically effective amount” of a compound with respect to the subject method of treatment, refers to an amount of the compound(s) in a preparation which, when stered as part of a desired dosage regimen (to a patient, e.g., a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.

As used herein, the term “treating” or “treatment” includes reversing, reducing, or arresting the ms, al signs, and underlying pathology of a condition in manner to improve or stabilize a patient's condition.

Compounds In one aspect, the disclosure provides a compound having a structure of Formula (X), or a pharmaceutically acceptable salt f: gggwlfiQuiet“firm wherein: m and n each independently are 0, l or 2, and m + n = 2, 3, or 4; p is 0 or 1; q is 0, l, or 2; K is selected from the group ting of CR5R6, NR7, N(C=O)OR7, —NH— (C=O)—, O, S, SO, and SOZ; E is N or CR7; R1 is ed from the group consisting of H, C1_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl, and 3-6 membered heterocycloalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of halo, 0R7, SR7, , CN, and (C=O)N(R7)2; R2 is C1_2alkylene—G or (C=O)—G; wherein G is selected from the group consisting of aryl, heteroaryl, and pyridinone, with the proviso that when R2 is Cnghenyl, the phenyl is tuted with one or more substituents selected from the group consisting of 0R7, halo, C1_3alky1, OCF3, SOZR7, (C=O)N(R7)2, CN, and sozN(R7)2; R3 is selected from the group consisting of C3_7cycloalkyl, C3_7cycloalkenyl, a 3-7 ed heterocycloalkyl, and a 3-7 membered heterocycloalkenyl, wherein R3 is optionally substituted with one or more substituents selected from the group consisting of halo, =0, 0R7, SR7, N(R7)2, O(C=O)N(R7)2, and C1_6alkyl; R4 is H or C1_3alkyl; R5 and R6 are each independently selected from the group consisting of H, OH, halo, WO 52134 C1_3 alkyl, and CF3, or R5 and R6 together with the carbon to which they are 5111 attached form C=O or r n W is O or NR7, and r is , 1, 2 or 3; and each R7 is independently H or C1_6alkyl.

In some embodiments, m is 0. In various embodiments, m is 1. In some embodiments, m is 2.

In some ments, n is 2. In some embodiments, n is 1. In some embodiments, nis 0.

In some embodiments, m + n is 2. In various embodiments, m + n is 3. In various ments, m + n is 4.

In some ments, p is 0, and in s embodiments, p is 1.

In some embodiments, q is 0. In some embodiments, q is 1. In various embodiments, q is 2.

In some embodiments, p is 0 and m + n is 4. In various embodiments p is 1 and m + n is 4. In various embodiments, p is 0 and m + n is 3. In various embodiments, p is 1 and m + n is 3. In some embodiments, p is 0 and m+ n is 2. In some embodiments, p is 1 and m +nis2.

In some embodiments, K is CR5R6. In some of these embodiments, R5 and R6 are each independently H, OH, F, CH3, or CH2CH3, or R5 and R6 together with the carbon to which they are attached from C=O or (ID—4i, where r is 1. For example, K is selected from |—_? CH(OH), C(CH3)(OH), C=O, CH2, CF2, CH(Cl), CH(CFg), C and COH(CH3). In some cases, K is CH(OH). In various embodiments, K is NR7, and R7 is H, CH2CH3, or CH3. For example, K can include NCH3 or NCH2CH3. In some embodiments, K is N(C=O)OR7 (e. g., N(C=O)OH or N(C=O)OCH3), —NH—(C=O)—, S, SO, or 802. In various embodiments, K is O.

In some embodiments, E is N. In other embodiments, E is CR7, such as, for e, CH or C(CH3). In various embodiments, E is N or CH. In some cases, E is N or CH and K is 0, CH2, or CH(OH).

K(IE/E 44%};) In some exemplary embodiments, “ is selected from the group consisting of: O O O N “a E 0Y3“ EYE OWE {DYE Utffifimfi £3F N/\fl/”a *2, N “2 NW3 F O FcfifigrN a UTE fiugfi a QY“ 3 O O O O , , 9 , 9 O HO mm om‘1 3 SR6, HN Q67, '4”ng o o 0, CKEY OW KJY‘ [40032Me\ OQIwanmeIHN\) and Me %(m PE; 0%2&6???- Lj\g/ various cases, ” is selected from HOOH?“ ONEO 0 and HO , .

In some embodiments, R1 is C1_6alky1 or R1 is C1_3alkyl, such as, CH3, CHZOH, CF3, CH(OH)CH3, CH2CN, or CH2CH3. For example, R1 can be ed from CH3, CHgOH and CHZCN. In s embodiments, R1 is C2_6alkenyl, such as CHZCH=CH2; or C2_6alkynyl, such as CH2CECH. In some embodiments, R1 is C3_6cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In various ments, R1 is a 3-6 membered heterocycloalkyl, such as, for example, oxetanyl, tetrahydrofuranyl, or piperadinyl.

In some embodiments, R2 is C1_2alkylene-heteroaryl, such as, for example, CH2- heteroaryl. In various embodiments, R2 is C1_2alkylene—pyridinone. In various embodiments, R2 is C1_2alkylene-aryl. In some embodiments, R2 is yl. In some cases, R2 is ed from the group consisting of: “Aw/(DAM?,mm(go/(:63 <O:©/\;,EC>—\ Mimi?loci Merry; Monger" HZNYJKGA; Nc/Qflf HZNOZS/Oflf (”DAN. 3" ”VWMOON MD“ WWiA/Qfl0W9 i ON HOE)”,HZDA“ mgMo 5 Mo 3MZU:M:DHN HOD/\ OH O 0 MeOfig”, MeOZS/©)\Hi Eco/gag”, Meo/[>)k£y LTNUN cm: N: MZD/Tf . In various embodiments, R2 is selected from the group consisting of: ”We? weno:HO MeO H “Newe 3 HO A; EDITHUN” WVN”it? (iHO OH OMe eO/(jfl(if i D/XHJ ,and HO/Ejflg.

In some cases, R2 is M90 “0 N‘ MeO”GUN omMeO or Me , , . In various embodiments, R2 is O “"1! selected from the group consisting of: O O , 5 QB? HUN CCFN3 N « £0“ @er N N N N ‘N H H H H H ’ 9 a a H H 2 o o and H . 2 In some embodlments, R . . . . 1s selected from the group con31st1ng of: 0g\ 3‘ 01 and 0 ”N . In some cases, R2 is selected from the group consisting of: ©/\f‘, QNE, mom‘s, F300/©Afig, NCOAF, WC? not not fit M8028 HzNOZS M6028 Me/N / / MezN O O , , , 9 O o F300 0*“ ,and M60 .

In various ments, R3 is C3.7cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the C3_7cycloalkyl is substituted with at least one substituent selected from the group consisting of OH, F, Me, NH2, and O(CO)NH2. In some cases, R3 is cyclopentyl or cyclohexyl. In various embodiments, R3 is C3_7cycloalkenyl, such as cyclopentenyl or cyclohexenyl. In some of these ments, the C3_7cycloalkenyl is substituted with at least one substituent selected from the group consisting of OH and Me. In various embodiments, R3 is a 3-7 membered heterocycloalkyl, such as, for example, ydrofuranyl, tetrahydropyranyl, pyrrolindinyl, or pyrrolidinonyl. In some embodiments, R3 is a 3-7 membered heterocycloalkenyl, such as, for example, dihydropyranyl or dihydrofuranyl. For example, R3 can be selected from the NW JVVVWVVMV E? (5,»???$56 (5 0 g group consisting of: 9 9 9 9 “uh, o N 0 H G0 N Me NH NH2 EEO In some cases, , , , 2, OYOE ,and W W "‘44, “a", W W R3is 6, 6 ,or i d E: ,or i . Insomecases,R3is , andqis00rl,or qis l.

In some embodiments, R4 is C1_3alky1, such as methyl or ethyl. In various embodiments, R4 is H. In some case, R4 is methyl. ‘fiaEWE qu) O Specifically contemplated is a compound of Formula X ing " described in paragraph [0053], R1 as described in paragraph [0054], R2 as described in paragraph [0055], R3 as described in paragraph [0056], and R4 as described in paragraph In some exemplary embodiments: m and n are each independently 2; p is l; q is l; Kis CR5R6 orO' E isN or CR7- R1 is CH3, CHZOH CH(OH)CH3 CHZCN, or yl' R2 is MeODA:MH(:qu6092:: mmmgor Me , , ; R4 is methyl; R5 is H; R6 is OH; and R7 is H.

In some embodiments, a nd of Formula (X) is selected from: Q 0:27 o O NW N D Cd 43:0 12 H 0 O o o o o O O O O (\NWNWANH H Cd H 0 o o O O rkNH H Cd H 0 o o O O (\N/firNfikNH H Cd H 0 o o WO 52134 I \ O 0 Cd H 0 o 0 WO 52134 od 2=82:3: 53%N 0 o O O o o o n H H N O O H H O o o O/ 0/ o o o O O H H H N pN fin #NJWW/NH H o o 0d O O O O\ O\ 4:I2 ZI 03L2 (\N N 0 0 od 0 o O o o 0 H H Q H o o O 2014/026987 \ O R0IZ0:2;ZI O 0 O O O/ O O T1 21 I N TI 20:? I2 H 0 O O O 2014/026987 O o I I I/\N N N N H Cd(\NWNVLN H 0 o o \\ / O O O O O H H O N\H\N N H H H u 0 o o o o 9 9 0\\ ,NH2 o o 0 HO H0 H NNNN N N Odo H oH HO o o 0 O O O O O O N H N N HN N N H H H H O O O O HO 0 0/ 0/ 0'\O O\ O O O O O H H H H N N |/\N N N N {Ln O O O WO 52134 o o o o o o H n H 0 o o o O O O O O H o H H O O O O O O O O I/\N/\n/ \HLN N N od O:(j)\H H 0 o o HN NH NH O L O O 0 H H H (OI/I \fik”N N phi/\fl/N o o {)— O O O O\ 0\ o o 0 o H H H H N N FNW {Lu H Cd 0 O 0 0 o o 2014/026987 0 RN 0 O O a“ O O HO HO o o o o H H N N O o o H0 0H0 0 fi“ 0 o o o ULH H H N N N o O HO HO Oil/WC? VLHN o o o/fi o o 0 0H0 ng LWH 0 u H NW $uIf} 0 0 O oOdeNJYHo o o o 0 H H o 0F odpNWHWANH0 o okFF 2014/026987 0/} o o 0 l\/N\)LNJ\WH O O O N ZI H H o O IZJfif IZ o 0 N o km“ 0 o O H H N N N N HO H 0 o o (REP “ N o o o o |/\N N H N N 0d H H 0 o o o 0 o\ o\ O O H H O 0 H H |/\N N 0Q H 0 O 0 p od N\HLNH 0 o o \\S\\/ H H N N N N N H H H o o o O O 9 0 Ho 0 \N N N O HO HO o 0/, O O/\bNANJWHfiEiflHo o O ZI 4&0 ZI 3 I2 H o 0 O O N)»; ZI \”‘0 (I) O O O O O O O u ’ (j 3:010Z 0:84 o 0 HO I2 I2 o %H O O O / O\ 0 O O ZI ZI H H 3Z:2 LgmI2 (\N/\fl/N N O O od H 0 o o O/fi O O o o O H H H 0 0(\ /\[OEONJAN O O 0&0, \\S\g o o o 0% N n O 0 H0 O (9/7?N N N N NfiLN H o 0 f/jll/ Ho 0 Q\ HO o o o 0:8ONOLNJNN0 O O o/fi N ONOLNJNNH H H H H O O OHO O O/ 0/, O O H H |/\N/\n/ ” N O O O O OWka”0 o o :5{II} 0\ / ZI10 21 9%NiON N 3 I2 O O OJ 0 O o O O (\N/\n/N\flJ\NH H od H 0 o 0 Go \ 0“ / ,cn 3‘2; o/ O 0 H H ZI10 ZI WANH @Nj/HX :2 I2 0 O o o og/fi' gN¢LNJYNo o o H H 2=82:3: o o Cd Gd 0 o 0 0 OH O\ O O O H 0 rkNH H H N (\N/\”,N N 0d H 0 o o 0Q 0F FH o o O I O O O 0*)”n n H H N N o 0d(\N/fil/NVLNH0 o o N/ o o 0 {3 0 pwfifiLN H Cd H 0 o o O\ o O 0 (\NWNH H Cd H 0 o 0 O ZI#0 ZI 32 I2 od 0 0 o contra]? \ O HO 0 o O O H H LNgHo o o “sf Ill 0 Ho I/ o O o 0 pNWHfLN H H od H 0 0 Cd(\N/YHWANH0 o 0 o/figNmLNjngOHo OH o 0/} o o o N gNoLNj/YH N H H H H o o 0H0 o o/ o/ H2N HZNTO o/fibNdLNfiNo o o o o o H 0/} N K/NdLNJWrNH N H H H H o o o o 0/ ,and 0/ or a pharmaceutically acceptable salt thereof.

In some exemplary embodiments, a compound of Formula (X) is selected from the group ting of: O O O O H O 0*” HW H N N N O O O O O Cd 0 0 Cd 0 o o/fiK/NQLNJWrHo o o o H H (\N/\n/N\RLN0H0]? OHO 0 Cd H 0 o o O/\| OHO O O K/NdLN H O H H |/\N/\n/NW)LN OHo 0 0d H$0N O/ m H H O H $0N O O oodo mand O O H H (\N/WN N od H 0/ o o or a pharmaceutically acceptable salt thereof.

For example, a compound of a (X) can be selected from the group consisting Gig“OH O O 0H0 O H H N N N N H H (\NW fifi o 0 Ho 0Q oHO o o O\ O\ {DEN N N N H H o o oil/Er o o OHO O O H H /\| O 013%” N bNa o o O HO1%} §O\ O N O HO NJ’L I2 n o 0 O NWKSCK 0\ o 0 WVLN0 Ho HOJ3 1?“ O o 0 O N ZI I2ECG o 0 f:2Q o o o ,and , or a pharmaceutically acceptable salt thereof.

In various embodiments, a nd of Formula (X) has a stereochemical (F‘E 0"ngN configuration: “(kn/:13%? In various embodiments, a compound of Formula (X) is selected from: WO 52134 C-1001 C-1002 C-1004 C-1006 C—1010 WO 52134 0Qp“:ngng HQZ03 C-1011 C-1012 I \ H 9 O ol/\N /\([)l/ N N\/l|,, o 5 _ Ag, WO 52134 C 1021 C 1022 N N H H C-1023 C-1024 H N C 1025 C 1026 C-1028 C-1029 C-1030 0-1033 C1034 O 0 O E O O /N\)LNH H H NQIHK O \ILN/\n/N\.)J\NH= i H 5 H o o - o o o 0 0%)” U HN 0/ C-1035 C-1036 WO 52134 WO 52134 ; H o o d [10/ 0-1051 0-1052 O\\,NH2 0-1056 0 g o o H ('1 g o o N/\n/N\.)I\N- - H I \\ N/\n/ EJLNN /, ’ HN ' H a H H : H o O O O I; 0 o/ I;0/ , , C—1057 C-1058 o o C—1060 2014/026987 OH OH O\ O\ OOWerkNO o OOWerLNO 0 H H H H H H o o NQL/K NQLK o o o o C-1061 C-1062 WO 52134 o o H H .,,l N NQL n/ H a K O O E O C-1071 C-1072 O E 0%H2 N\/k Ho‘“ 0-1075 C-1076 ii U1 0 o 3 o o m-‘ Nmo ' "1,, N HO" O‘\\IJ\N/H]/H N 1 : :H H 1 H o o O 0/ : ‘o/ , , 0-1077 C-1078 ;I ;I I2 10:? I2 0 I2 10:? I2 IQ O IQ O 0-1079 O o N N 0H0 0 C-1082 2014/026987 00” o 0%oF C-1084 O/fi O gN¢LNJWH¢LNHO o H o N .

H 1 C-1090 oHO\_ o o 2014/026987 o 0 H UL 1 nj NdLH Ndl’m K\N/\n/ 0/:[31/ E u : K 3 fl 0 o - o 0 0 _ Ag ‘5 Pg 53 F 0-1094 C-1101 C-1102 2014/026987 C-1106 O/fi O o O gN¢LNJYHgLNH a H 0 C-1108 098/ N N N Hi of A520; N Hj ; 2 K o o 0-1110 0 - O O 2014/026987 0399” i“92% C-1114 {5gm 2::23:0 i H o o 110/ C-1115 WO 52134 WO 52134 HN NHO H$::¢F NH F F C-1138 C-1142 C-1 1 51 or a pharmaceutically acceptable salt thereof.

In some exemplary embodiments, the disclosure provides a compound selected from the group consisting of: C-1009, C-1018, C-1022, C-1056, C-1057, , C-1082, C-1083, , C-1117, C-1118, C-1129, C-1135, C-1138, C-1144, and C-1150, or a ceutically acceptable salt thereof.

For example, the disclosure provides a compound selected from the group consisting of: C-1009, C-1018, C-1022, , C-1083, C-1116, C-1117, C-1118, C-1129, C-1135, C-1144, and C-1150, or a aceutically acceptable salt thereof.

In another aspect, the disclosure provides a tripeptide epoxy ketone compound having a structure selected from: “MW {Ell Civil)I; <35, 0/} HO 0 o o o o H H K/N\)L k“ N N N\fiLN ,1] HO 1H 0gNuNJYHo 0 O 0 H H o o WO 52134 o o N N N N H H H H O O N\ O O 0/ 0/ o o o o o o O N H N N N N H H 0 H H o o o o 0/ 0/ o o o o o o 0/ l/N 3%anO O O O O O O n @994 N OVLN H H H H /N O O 0/} o o o 0 $0 g $HJYH H N N N M NW WANN o o o 9 9 WO 52134 o o ‘NN N N N HHO HO Ho Ho O/ / o/fi o NJWrN o o 0/}K/N\)LN/HVN0 0 o K/N H N N H H H H o o o o 0/ 0/ O/ O O O O O O O H H H O O O N N Odo / o 0, HO O O O N N N N N N HO HO 0 Ho Ho / 0/ o o O o NJ\n/N o o H N N N N H H H H o 0 o o 0/ 0/ 2014/026987 O O o O O H o 0% H O O fiflNEO O 0/ 0/, HO H2N O O 0 O 013er O O OVLNH“ N N N H H H H o 0 o o 0/ 0/ 0/ OH OH O\ o o O o 001%H H N N H H N N 001‘N o #LNH o o O O FNWN%NH H 0/W 0 O o N RVLNKW“ N 0d H 0 0 O H H o o WO 52134 2014/026987 H2N o H oK/N\)Ln/ngo 0 O (0Z)3:0 0 O H 2:: I2 IZ 0:8; I2 O O \ \ O 0 \ oA O O o o ZI#0 ZI ZI#0 ZI Q I2 :22 I2 0 O Q 3% O O 0QQLN%(“o o 0 o 0/W H N K/NdLNwaN N H H H H o o o o 0/}gN¢LNJWHo o o 0/} o O o N N H H gN¢LNngH H 0H0 0 0O 0 o/ 0/ or a pharmaceutically acceptable salt thereof.

For e, the disclosure provides a tripeptide epoxy ketone compound selected from the group consisting of: C-1153 C-1154 WO 52134 WO 52134 C-1175 C-1176 WO 52134 HN\)L H N |,, WO 52134 0-1195 C-1196 WO 52134 C-1199 C-1200 2014/026987 C-1208 C QO 0% C-1210 C-1212 ZI .....g:o :2 12{IQ§—O/O C O OR C-1214 2014/026987 C-121 1 or a pharmaceutically acceptable salt thereof.

In yet another aspect, the disclosure provides a tripeptide epoxy ketone compound selected from: OJWMELX QWVyNH o H o O o o o o 0/} H H H K/NQLN N N N F/A\N /A\H/ N F N H H H F o 0 QWWEJJK 0/}WW2:o 0 o ,N\V/fl\H/i\H:N\I:f\H0 High 0/}L\v/N\V/fl\H/i\W/N\iii3::1\nij\o o o s\ a ©01ng (outfield; 0 ,and or a pharmaceutically acceptable salt thereof.

For example, the disclosure provides a tripeptide epoxy ketone compound selected from: WO 52134 C-1234 or a pharmaceutically acceptable salt thereof.

In still another aspect, provided herein is a compound having a structure of a (I), or a pharmaceutically acceptable salt thereof: wherein: B is absent; L is C=O; each M is independently absent or is C1_12alkyl; Q is absent; X is O; R1 is selected from hydrogen, -C1_6alkyl—B, C1_6hydroxyalkyl, and koxyalky; R2 is selected from D D D D /,:'/,3J),:\/\ NAA |N~x ~/.~N 344D | | DES awe/,5”, \ D E\N S'/\ S -_1/ D if} . and 31%“ . 3 9 wherein D is selected from en, methoxy, t—butoxy, hydroxy, halogen, cyano, trifluoromethyl, and C1_4alkyl, with the proviso that when R2 is benzyl, D is other than hydrogen; R3 is selected from yclylM- and carbocyclyl; R4 is N(R5)L-Q-R6; R5 is hydrogen; R6 is selected from heterocyclylM— and carbocyclylM—; R7 and R8 are hydrogen; and R15 is selected from hydrogen, ky1, and C1_6hydroxyalkyl.

Therefore, a compound of Formula (I) can be represented as: o R1 H o R3 | O ' ' R15 o R2 H 0 (IA).

In some embodiments, R15 is selected from hydrogen, , ethyl, hydroxymethyl, and 2-hydroxyethyl. 9’5\/®/ In some embodiments, R2 is and D is selected from methoxy, hydroxy, trifluromethyl, and C1_4alkyl.

In some embodiments, R6 is heterocyclylM—, and in other embodiments, R6 is carbocyclylM—.

In some ments, R61]??? is selected from the group consisting of: O O O WiAO/Io/OF N ‘777. ‘4, N 5“ ”W15 70% O ,FF 0, F O 0% UT», of, OY (DY,0 F30 o o o o O HO Hom 50m$71 3“ HN \BQWER Um}, '4'“ng O O O 9 9 3 5 QW€%R%OfiC% 0-073 OW‘ ,th O ,andHOQW‘?Me In some embodiments, R2 is selected from the group consisting of: OW if““0 t‘ ”0U; e0 HO UMeO , , , , CoefmémowroH MeO HO “0UWE?”HOD/\ (if if OH OMe eO/Ejfl”’5 if 3‘ HO and ©/\ , , .

In some embodiments, R3 is carbocycly1-. In various embodiments, R3 is yclylM— and M is C1_12a1ky1. In some embodiments, R3 is carbocyclleH2-, Where the w, “M E§ (5 w a“ 6 carbocycyl is ed from the group consisting of: , , 5, Er , , F HO F 9 9 9 9 9 9 9 9 ' 9 “44, Me, f 0Y0 ,M9 In some embodiments, R3 is carbocycleH2-, NH2 , NHZ, and . wherein the carbocycyl is 6 d or Em) , , .

The compounds provided herein can be synthesized using conventional techniques using readily available starting materials. In general, the compounds provided herein are conveniently ed via standard organic chemistry synthesis s. For e, the compounds provided herein may be prepared using the methods described herein or using the synthetic methods described in US. Patent Nos. 7,232,818; 7,417,042; 7,687,456; 7,691,852; and 8,088,741, each of which is orated by reference in its entirety.

Methods ofUse The compounds disclosed herein can be inhibitors of immunoproteasome (iP). In some cases, a compound as disclosed herein ts the iP subunit LMP7. LMP7 activity can be inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%, as measured in a proteasome subunit assay as described below in the es. One or more additional iP subunits can be inhibited by a compound as disclosed , such as LMP2, MECL-l, Bl, [32, and [35. In various embodiments, a compound disclosed herein inhibits LMP7 and one or both of LMP2 and MECL—l. The compounds disclosed herein can reduce cytokine activity or expression, e.g., one or more of IL-2, MHC-I, IL-6, TNFOL, and IFN—B. Thus, provided are s wherein a compound as disclosed herein inhibits expression or activity of one or more of IL—2, MHC-I, IL-6, TNFOL, and IFN-B by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%, as measured in an assay as described below in the examples.

The biological consequences of proteasome inhibition are numerous. Proteasome inhibition has been suggested as a prevention and/or treatment of a multitude of diseases including, but not limited to, neurotoxic/degenerative diseases, Alzheimer's, ischemic conditions, inflammation, auto-immune diseases, HIV, organ graft rejection, septic shock, inhibition of antigen presentation, sing viral gene expression, parasitic ions, conditions associated with acidosis, macular degeneration, pulmonary conditions, muscle wasting diseases, fibrotic diseases, and bone and hair growth diseases. ore, pharmaceutical ations for proteasome-specific compounds, such as the epoxy ketone class of molecules, e a means of administering a drug to a patient and treating these conditions.

WO 52134 The proteasome regulates NF-KB, which in turn regulates genes involved in the immune and inflammatory response. For example, NF-KB is required for the expression of the immunoglobulin light chain K gene, the IL-2 receptor (x-chain gene, the class I major histocompatibility complex gene, and a number of cytokine genes encoding, for example, IL- 2, IL-6, granulocyte colony-stimulating factor, and IFN—B (Palombella et al., Cell (1994) 78:773-785). Thus, provided herein are methods of affecting the level of expression of IL-2, MHC—I, IL-6, TNFu, IFN—B or any of the other previously-mentioned proteins, each method comprising administering to a patient a eutically effective amount of a compound or composition disclosed .

Also provided herein is a method of treating an autoimmune disease in a patient sing administering a therapeutically effective amount of the compound described . An “autoimmune disease” as used herein is a disease or disorder arising from and directed against an individual’s own tissues. Examples of autoimmune diseases include, but are not limited to, inflammatory responses such as inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; responses associated with inflammatory bowel e (such as Crohn’s disease and ulcerative s); respiratory distress syndrome (including adult respiratory distress syndrome(ARDS)); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; ic conditions such as eczema and asthma and other conditions involving ration of T cells and c inflammatory responses; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE); diabetes mellitus (e.g., Type I diabetes mellitus or insulin dependent diabetes mellitus); multiple sclerosis; Reynaud’s me; autoimmune ditis; allergic encephalomyelitis; Sjorgen’s syndrome; juvenile onset diabetes; and immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes typically found in tuberculosis, dosis, polymyositis, granulomatosis and vasculitis; pernicious anemia on’s e); diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder; multiple organ injury syndrome; hemolytic anemia (including, but not limited to cryoglobinemia or Coombs positive anemia); myasthenia gravis; antigen—antibody x mediated diseases; anti-glomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; ’ disease; Lambert-Eaton myasthenic syndrome; pemphigoid bullous; pemphigus; autoimmune polyendocrinopathies; Reiter’s disease; stiff-man me; Beheet disease; giant cell arteritis; immune complex tis; IgA nephropathy; IgM polyneuropathies; immune thrombocytopenic purpura (ITP) or autoimmune thrombocytopenia.

The immune system screens for autologous cells that are virally infected, have one oncogenic transformation or present unfamiliar peptides on their surface.

Intracellular proteolysis generate small peptides for presentation to T-lymphocytes to induce MHC class I-mediated immune responses. Thus, provided herein is a method ofusing a compound or composition ed herein as an immunomodulatory agent for ting or altering antigen presentation in a cell, comprising exposing the cell (or administering to a patient) to the compound bed herein. Specific ments include a method of treating graft or transplant-related diseases, such as graft-versus—host disease or host versus- graft disease in a patient, comprising administering a therapeutically effective amount of the compound described herein. The term “graft” as used herein refers to ical material derived from a donor for transplantation into a recipient. Grafts include such diverse material as, for example, isolated cells such as islet cells; tissue such as the amniotic membrane of a n; bone marrow; hematopoietic precursor cells; ocular tissue, such as corneal tissue; and organs such as skin, heart, liver, spleen, pancreas, thyroid lobe, lung, , and tubular organs (e. g., intestine, blood vessels, or esophagus). The tubular organs can be used to e damaged ns of esophagus, blood vessels, or bile duct. The skin grafts can be used not only for burns, but also as a dressing to d intestine or to close certain defects such as agmatic hernia. The graft is derived from any mammalian source, including human, whether from cadavers or living donors. In some cases, the donor and recipient is the same patient. In some embodiments, the graft is bone marrow or an organ such as heart and the donor of the graft and the host are matched for HLA class II antigens.

Proteasome inhibition has also been associated with tion ofNF-KB activation and stabilization of p53 . Thus, compositions provided herein may also be used to inhibit NF-KB activation, and stabilize p53 levels in cell culture. Since NF-KB is a key regulator of inflammation, it is an attractive target for anti-inflammatory therapeutic intervention. Thus, compositions provided herein may be useful for the treatment of conditions associated with inflammation, including, but not d to COPD, psoriasis, asthma, bronchitis, emphysema, and cystic fibrosis.

The disclosed itions can be used to treat conditions mediated directly by the proteolytic fianction of the proteasome such as muscle wasting, or mediated indirectly via proteins which are processed by the proteasome such as NF-KB. The proteasome participates in the rapid elimination and post-translational processing of proteins (e.g., enzymes) involved in cellular regulation (e.g., cell cycle, gene transcription, and metabolic pathways), intercellular communication, and the immune response (e.g., antigen presentation). Specific examples discussed below include B—amyloid protein and regulatory ns such as cyclins and transcription factor NF-KB.

In some embodiments, a composition provided herein is useful for the treatment of neurodegenerative diseases and conditions, including, but not limited to, stroke, ischemic damage to the nervous system, neural trauma (e.g., sive brain damage, spinal cord injury, and traumatic damage to the s system), multiple sclerosis, and other immune— mediated neuropathies (e.g., in-Barre me and its ts, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, and Fisher Syndrome), HIV/AIDS dementia complex, y, diabetic neuropathy, Parkinson’s disease, Huntington’s disease, bacterial, tic, fungal, and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe ia such as Pick’s disease, subcortical ias (such as Huntington or progressive supranuclear palsy), focal cortical atrophy syndromes (such as primary aphasia), metabolic-toxic ias (such as chronic hypothyroidism or B12 deficiency), and dementias caused by infections (such as syphilis or chronic meningitis).

Alzheimer’s e is characterized by extracellular deposits of B-amyloid protein (B-AP) in senile plaques and cerebral vessels. B-AP is a peptide fragment of 39 to 42 amino acids derived from an amyloid n sor (APP). At least three isoforms ofAPP are known (695, 751, and 770 amino acids). Alternative splicing ofmRNA generates the isoforms; normal processing affects a portion of the B-AP sequence, thereby preventing the generation of B-AP. It is believed that abnormal protein processing by the proteasome contributes to the abundance of B-AP in the Alzheimer brain. The APP—processing enzyme in rats contains about ten different subunits (22 kDa-32 kDa). The 25 kDa subunit has an N- terminal sequence of X—Gln-Asn-Pro-Met-X-Thr-Gly-Thr—Ser, which is identical to the B— subunit of human ain a, S. et al., Fed. Eur. Biochem. Soc., (1992) 304:57-60).

The APP-processing enzyme cleaves at the Glnl 5--Lys16 bond; in the presence of calcium ion, the enzyme also cleaves at the Met-l--Aspl bond, and the Ala2 bonds to release the extracellular domain of B-AP.

Therefore, provided herein is a method of treating Alzheimer’s disease, including administering to a patient a therapeutically effective amount of a composition disclosed herein. Such treatment includes reducing the rate of B-AP processing, reducing the rate of [3- AP plaque formation, reducing the rate of B-AP generation, and ng the al signs of mer’s disease.

Also ed herein are methods of treating cachexia and muscle-wasting diseases. The proteasome degrades many proteins in maturing reticulocytes and growing fibroblasts. In cells deprived of insulin or serum, the rate of proteolysis nearly doubles.

Inhibiting the proteasome s proteolysis, thereby reducing both muscle protein loss and the nitrogenous load on kidneys or liver. Peptide proteasome inhibitors (e.g., a compound or composition provided herein) are useful for treating conditions such as cancer, chronic ious diseases, fever, muscle disuse (atrophy) and denervation, nerve injury, g, renal failure associated with acidosis, kidney disease, and hepatic failure. See, e.g., Goldberg, US. Pat. No. 5,340,736, which is incorporated herein by reference in its entirety. Methods of treatment include: reducing the rate of muscle protein degradation in a cell; reducing the rate of intracellular n degradation; reducing the rate of degradation ofp53 protein in a cell; and inhibiting the growth of p53-related cancers. Each of these methods es contacting a cell (in vivo or in vitro, e. g., a muscle in a patient) with an effective amount of a pharmaceutical composition disclosed herein to reduce the rate of muscle protein degradation in the cell; reduce the rate of ellular protein degradation in the cell; and/or reduce the rate of degradation ofp53 protein in the cell. In some embodiments, the methods include administering to a t a therapeutically effective amount of a pharmaceutical composition disclosed herein.

Fibrosis is the excessive and persistent formation of scar tissue resulting from the hyperproliferative grth of fibroblasts and is associated with activation of the TGF-B ing y. Fibrosis involves extensive deposition of extracellular matrix and can occur within virtually any tissue or across several different tissues. Normally, the level of intracellular signaling protein (Smad) that activates transcription of target genes upon TGF-B stimulation is regulated by proteasome activity. However, accelerated degradation of the TGF-B signaling components has been observed in cancers and other hyperproliferative conditions. Thus, in certain embodiments, a method for treating hyperproliferative conditions such as diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA pathy, cirrhosis, y atresia, congestive heart failure, scleroderma, radiation- induced fibrosis, and lung fibrosis (idiopathic pulmonary fibrosis, collagen vascular disease, sarcoidosis, interstitial lung es, and extrinsic lung disorders) is provided. The treatment of burn victims is often hampered by fibrosis, thus, in some embodiments a compound provided herein may be administered by topical or systemic administration to treat burns.

Wound e following surgery is often associated with disfiguring scars, which may be prevented by inhibition of fibrosis. Thus, in certain ments, a method for the prevention or reduction of scarring is provided herein.

Another protein processed by the proteasome is NF-KB, a member of the Rel protein family. The Rel family of transcriptional activator proteins can be divided into two groups. The first group requires proteolytic processing, and includes p50 (NF-KBI, 105 kDa) and p52 (NF-K2, 100 kDa). The second group does not require proteolytic processing, and includes p65 (RelA, Rel ), and RelB). Both homo- and heterodimers can be formed by Rel family members; NF-1<B, for example, is a p5 0-p65 heterodimer. After phosphorylation and ubiquitination of IKB and p105, the two proteins are degraded and processed, respectively, to produce active NF-KB which translocates from the cytoplasm to the nucleus. tinated p105 is also processed by purified proteasomes (Palombella et al., Cell (1994) 78:773-785). Active NF-KB forms a stereospecific enhancer complex with other transcriptional activators and, e. g., HMG I(Y), inducing selective expression of a particular gene.

NF-KB regulates genes involved in the immune and inflammatory response, and mitotic events. For example, NF-KB is required for the expression of the immunoglobulin light chain K gene, the IL-2 receptor u-chain gene, the class I major histocompatibility x gene, and a number of ne genes encoding, for example, IL-2, IL-6, granulocyte colony-stimulating factor, and IFN-B (Palombella et al., Cell (1994) -785).

Some embodiments include methods of affecting the level of expression of IL-2, MHC-I, IL- 6, TNFor, IFN—B, or any of the other usly-mentioned proteins, each method including administering to a patient a therapeutically effective amount of a composition disclosed herein. Complexes including p50 are rapid mediators of acute inflammatory and immune ses (Thanos, D. and Maniatis, T., Cell (1995) 80:529-532).

NF-KB also participates in the expression of the cell adhesion genes that encode E- selectin, P-selectin, ICAM, and VCAM-l (Collins, T., Lab. Invest. (1993) 68:499-508). In some embodiments, a method for ting cell adhesion (e.g., cell adhesion mediated by E- in, P-selectin, ICAM, or VCAM-l) is provided, including contacting a cell with an ive amount of a pharmaceutical composition disclosed . In some embodiments, a method for ting cell adhesion (e.g., cell adhesion mediated by E-selectin, P-selectin, ICAM, or VCAM-l) is provided, including administering to a patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

Ischemia and reperfiision injury results in a, a condition in which there is a deficiency of oxygen reaching the tissues of the body. This condition causes increased degradation of IK-Bd, thereby resulting in the activation ofNF-KB. It has been demonstrated that the severity of injury resulting in hypoxia can be reduced with the administration of a proteasome inhibitor. Thus, provided herein is a method of treating an ischemic condition or reperfusion injury comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound provided herein. Examples of such ions or injuries include, but are not limited to, acute ry syndrome (vulnerable plaques), arterial ive disease (cardiac, cerebral, eral arterial, and vascular occlusions), sclerosis (coronary sclerosis, coronary artery disease), infarctions, heart failure, pancreatitis, myocardial rophy, stenosis, and restenosis.

NF-KB also binds specifically to the HIV-enhancer/promoter. When ed to the Nef of mac239, the HIV regulatory protein Nef of pbj l4 differs by two amino acids in the region which controls n kinase binding. It is believed that the protein kinase signals the phosphorylation of IKB, ring IKB degradation h the tin-proteasome pathway. After degradation, NF-KB is released into the nucleus, thus enhancing the transcription of HIV (Cohen, J ., Science, (1995) 267:960). Provided herein is a method for inhibiting or reducing HIV infection in a patient, and a method for decreasing the level of viral gene sion, each method including stering to the patient a therapeutically effective amount of a ition disclosed herein.

Viral infections contribute to the pathology ofmany diseases. Heart conditions such as ongoing myocarditis and dilated cardiomyopathy have been linked to the kievirus B3. In a comparative whole-genome microarray analyses of infected mouse hearts, specific proteasome subunits were uniformly up-regulated in hearts of mice which developed chronic myocarditis (Szalay et al, Am J Pathol 168:1542-52, 2006). Some Viruses utilize the ubiquitin-proteasome system in the viral entry step where the virus is released from the endosome into the cytosol. The mouse hepatitis virus (MHV) belongs to the Coronaviridae family, which also includes the severe acute respiratory syndrome (SARS) coronvirus. Yu and Lai (J Viral 79:644-648, 2005) demonstrated that treatment of cells infected with MHV with a proteasome inhibitor resulted in a decrease in viral replication, correlating with reduced viral titer as compared to that of untreated cells. The human hepatitis B Virus (HBV), a member of the Hepadnaviridae Virus family, likewise requires Virally encoded envelop proteins to propagate. Inhibiting the proteasome degradation pathway causes a significant ion in the amount of secreted envelope proteins k et al, J Viral 79:12914-12920, 2005). In addition to HBV, other hepatitis Viruses (A, C, D and B) may also utilize the ubiquitin-proteasome ation pathway for ion, morphogenesis and pathogenesis. Accordingly, in certain embodiments, a method for treating Viral infection, such as SARS or hepatitis A, B, C, D and E, is provided comprising contacting a cell with an effective amount of the compound disclosed herein. In some embodiments, a method for treating Viral infection, such as SARS or hepatitis A, B, C, D and E, is ed comprising administering to a patient a therapeutically effective amount of the compound disclosed herein. oduction of lipopolysaccharide (LPS)-induced nes such as TNFu is considered to be central to the processes associated with septic shock. Furthermore, it is generally accepted that the first step in the activation of cells by LPS is the binding of LPS to specific membrane receptors. The 0L- and B-subunits of the 208 some complex have been identified as LPS—binding proteins, suggesting that the LPS-induced signal transduction may be an ant therapeutic target in the treatment or prevention of sepsis (Qureshi, N. et al., J. Immun. (2003) 171: 1515—1525). Therefore, in certain embodiments, compositions as provided herein may be used for the inhibition of TNth to prevent and/or treat septic shock.

Intracellular proteolysis generates small es for presentation to T-lymphocytes to induce MHC class I-mediated immune responses. The immune system screens for autologous cells that are Virally infected or have undergone nic transformation. One embodiment is a method for inhibiting antigen presentation in a cell, including exposing the cell to a composition bed herein. In some embodiments, the cell is contacted with an effective amount of a compound or composition provided herein to inhibit antigen presentation in the cell. A fiirther embodiment is a method for suppressing the immune system of a patient (e.g., inhibiting transplant rejection, y, asthma), including stering to the patient a therapeutically effective amount of a composition described herein. Compositions ed herein can also be used to treat autoimmune diseases such as lupus, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. r embodiment is a method for altering the repertoire of antigenic peptides produced by the proteasome or other Ntn with multicatalytic ty. For example, if the PGPH activity of 208 proteasome is selectively inhibited, a different set of antigenic peptides will be produced by the proteasome and presented in MHC molecules on the surfaces of cells than would be produced and presented either without any enzyme inhibition, or with, for example, selective inhibition of chymotrypsin-like ty of the some.

Certain proteasome inhibitors block both degradation and processing of ubiquitinated NF-KB in Vitro and in viva. Proteasome inhibitors also block IKB—(x degradation and NF-KB activation (Palombella, et al. Cell (1994) 78:773-785; and kner, et al., EMBO J. (1994) 13:5433-5441). In some ments, a method for inhibiting IKB-(x degradation is provided, including contacting a cell with a composition described herein. In some embodiments, a cell is contacted with an effective amount of the composition to inhibit IKB-a degradation. A further embodiment is a method for reducing the cellular content of NF-KB in a cell, muscle, organ, or patient, including contacting the cell, muscle, organ, or patient with a composition described herein. In some embodiments, a cell is ted with an ive amount of the composition to reduce the cellular t ofNF-KB in a cell.

Other otic transcription s that require proteolytic processing include the general transcription factor TFIIA, herpes simplex Virus VP16 accessory protein (host cell factor), inducible IFN regulatory factor 2 protein, and the membrane-bound sterol regulatory element-binding protein 1. r provided herein are methods for affecting cyclin-dependent eukaryotic cell cycles, including exposing a cell (in Vitro or in Vivo) to a composition disclosed herein.

Cyclins are proteins involved in cell cycle control. The proteasome participates in the ation of cyclins. Examples of cyclins include mitotic cyclins, G1 cyclins, and cyclin B. Degradation of cyclins enables a cell to exit one cell cycle stage (e. g., mitosis) and enter another (e.g., division). It is believed all cyclins are ated with p34cdc2 protein kinase or related kinases. The proteolysis targeting signal is localized to amino acids 42— RAALGNISEN—SO (destruction box). There is evidence that cyclin is converted to a form vulnerable to a ubiquitin ligase or that a cyclin-specific ligase is activated during mitosis (Ciechanover, A., Cell, (1994) 79: . Inhibition of the proteasome inhibits cyclin degradation, and therefore inhibits cell eration, for example, in cyclin-related cancers (Kumatori et al., Proc. Natl. Acad. Sci. USA (1990) 87:7071-7075). Provided herein is a method for treating a proliferative disease in a patient (e.g., , psoriasis, or restenosis), ing administering to the patient a therapeutically effective amount of a composition sed herein. Also provided herein is a method for treating cyclin-related inflammation in a patient, including administering to a patient a therapeutically effective amount of a composition described herein.

In another ment, the disclosed compositions are useful for the treatment of a parasitic ion, such as ions caused by protozoan parasites. The proteasome of these parasites is considered to be involved ily in cell entiation and ation activities (Paugam eta1., Trends tol. 2003, 19(2): . Furthermore, entamoeba s have been shown to lose encystation capacity when exposed to proteasome inhibitors (Gonzales, et al., Arch. Med. Res. 1997, 28, Spec No: 139-140). In certain such embodiments, the disclosed compositions are useful for the treatment of parasitic infections in humans caused by a protozoan parasite selected from Plasmodium sps. (including P. falciparum, P. vivax, P. malariae, and P. ovale, which cause malaria), Trypanosoma sps. (including T. cruzi, which causes Chagas’ e, and T. brucei which causes African sleeping sickness), Leishmania sps. (including L. amazonesis, L. donovani, L. infantum, L. mexicana, etc.), Pneumocystis carinii (a protozoan known to cause pneumonia in AIDS and other immunosuppressed patients), Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens, and Giardia lamblia. In certain embodiments, the disclosed compositions are usefial for the ent of parasitic infections in animals and ock caused by a protozoan parasite selected from Plasmodium hermani, Cryptosporidium sps., Echinococcus granulosus, Eimeria tenella, ystis neurona, and Neurospora crassa. Other compounds useful as proteasome inhibitors in the treatment of tic diseases are described in W0 98/10779, which is incorporated herein in its entirety.

In certain embodiments, the disclosed compositions inhibit proteasome activity irreversibly in a parasite. Such irreversible inhibition has been shown to induce wn in enzyme activity without recovery in red blood cells and white blood cells. In certain such embodiments, the long half-life of blood cells may provide prolonged protection with regard to therapy against recurring exposures to parasites. In certain embodiments, the long half-life of blood cells may provide prolonged protection with regard to chemoprophylaxis against future infection.

] Prokaryotes have what is equivalent to the eukaryote 20S proteasome particle.

Albeit, the subunit composition of the prokaryote 20S particle is simpler than that of eukaryotes, it has the ability to hydrolyze e bonds in a similar manner. For example, the nucleophilic attack on the peptide bond occurs through the threonine residue on the N- us of the B-subunits. In some embodiments, a method of treating prokaryotic 2014/026987 infections is provided, comprising administering to a patient a therapeutically effective amount of a compound or composition provided herein. Prokaryotic infections may include diseases caused by either mycobacteria (such as tuberculosis, leprosy or Buruli Ulcer) or archaebacteria.

It has also been demonstrated that inhibitors that bind to the 208 proteasome stimulate bone formation in bone organ cultures. Furthermore, when such inhibitors have been administered systemically to mice, certain proteasome inhibitors increased bone volume and bone ion rates over 70% (Garrett, I. R. et al., J. Clin. Invest. (2003) 111: 1771- 1782), therefore suggesting that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation. Therefore, the disclosed compositions may be useful in the treatment and/or prevention of diseases associated with bone loss, such as orosis.

] Provided herein is a method for treating a disease or condition selected from autoimmune disease, graft or transplant-related condition, neurodegenerative disease, fibrotic-associated condition, ic—related conditions, infection (viral, parasitic or prokaryotic), and diseases associated with bone loss, comprising administering a compound as provided herein.

Bone tissue is an excellent source for s which have the capacity for stimulating bone cells. Thus, ts of bovine bone tissue contain not only ural proteins which are responsible for maintaining the structural integrity of bone, but also biologically active bone grth factors which can stimulate bone cells to proliferate. Among these latter factors are a recently described family of proteins called bone morphogenetic proteins (BMPs). All of these growth factors have effects on other types of cells, as well as on bone cells, including Hardy, M. H., et al., Trans Genet (1992) 1 bes evidence that bone morphogenetic proteins (BMPs), are differentially expressed in hair follicles during development. Harris, S. E., et al., JBone Miner Res (1994) 9:855—863 describes the effects of TGF-B on expression of BMP-2 and other substances in bone cells. BMP-2 expression in mature follicles also occurs during maturation and after the period of cell proliferation , et al. (1992, supra). Thus, compounds provided herein may also be usefiil for hair follicle growth stimulation.

Also provided herein is a method for treating a lysosomal e disorder by administration of a compound as disclosed herein. Lysosomal storage disorders are a group of diseases resulting from the al metabolism of various substrates, including glycosphingolipids, glycogen, mucopolysaccharides, and glycoproteins. The metabolism of exo- and nous high molecular weight compounds normally occurs in the lysosomes, and the process is normally regulated in a stepwise process by degradation s. ore, a nt activity in one enzyme may impair the process, resulting in an accumulation of particular substrates. It has been shown that inhibition of the proteasome can improve the function of certain substrates in patients suffering from a lysosomal storage disorder (Y. Shimada et al. Biochem. Biophys. Res. Commun. (2011) 415(2):274—8). Most of these es can be clinically classified into subtypes: i) infantile-onset; ii) juvenile-onset; or iii) late-onset. The infantile—onset forms are often the most severe usually with no residual enzyme activity. The later-onset forms are often milder with low, but often detectable residual enzyme activity. The severity of the juvenile-onset forms are in between the infantile-onset and late-onset forms. miting examples of such disorders include: Pompe disease, Gaucher disease, Fabry disease, GMl-gangliosidosis, Tay-Sachs disease, Sandhoff e, Niemann-Pick disease, Krabbe disease, Farber disease, Metachromatic leukodystrophy, Hurler-Scheie e, Hunter e, Sanfilippo disease A, Sanfilippo e B, Sanfilippo disease C, Sanfilippo e D, Morquio disease A, Morquio disease B, Maroteaux-Lamy disease, Sly disease, a-mannosidosis, B-mannosidosis, fucosidosis, sialidosis, and Schindler-Kanzaki e. One embodiment, therefore, is a method of treating Pompe e, including administering to a patient a therapeutically effective amount of a composition provided herein.

The disclosed compositions are also useful as stic agents (e. g., in diagnostic kits or for use in clinical laboratories) for screening for proteins (e.g., enzymes, transcription factors) processed by Ntn ases, including the proteasome. The disclosed compositions are also useful as research reagents for specifically binding the X/MBl subunit or a-chain and inhibiting the proteolytic activities associated with it. For example, the activity of (and specific inhibitors or) other subunits of the proteasome can be determined.

Most cellular proteins are subject to proteolytic processing during maturation or activation. Enzyme tors disclosed herein can be used to determine whether a ar, developmental, or physiological process or output is regulated by the proteolytic activity of a particular Ntn hydrolase. One such method includes obtaining an organism, an intact cell preparation, or a cell extract; exposing the organism, cell preparation, or cell extract to a composition disclosed herein; exposing the compound-exposed organism, cell preparation, or cell extract to a signal; and monitoring the process or . The high selectivity of the compounds disclosed herein permits rapid and accurate elimination or implication of the Ntn (for example, the 208 proteasome) in a given cellular, pmental, or physiological process . ceutical Compositions and Administration The methods provided herein include the manufacture and use of pharmaceutical compositions, which include one or more of the compounds provided herein. Also included are the pharmaceutical compositions themselves. In some embodiments, the compounds provided herein can be formulated as described in US Patent No. 7,737,112 and US.

Application Serial No. 13/614,829, each of which is incorporated herein by reference in its ty. Pharmaceutical compositions typically include a pharmaceutically acceptable carrier.

The phrase “pharmaceutically acceptable” is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical nt, suitable for use in contact with the tissues of human beings and animals without ive toxicity, irritation, ic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically able carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein the language “pharmaceutically acceptable carrier” includes buffer, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers e: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted B- extrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) ed tragacanth; (5) malt; (6) gelatin; (7) talc; (8) ents, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as ene glycol; (l l) polyols, such as glycerin, ol, mannitol, and polyethylene ; (12) esters, such as ethyl oleate and ethyl e; (l3) agar; (l4) ing agents, such as ium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer‘s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible nces employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions provided herein are non- pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

The term “pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid addition salts of a compound provided herein. These salts can be prepared in situ during the final isolation and purification of a compound ed herein, or by separately reacting the compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts e the hydrobromide, hloride, sulfate, bisulfate, phosphate, nitrate, e, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, te, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19.) In some embodiments, a compound provided herein may contain one or more acidic functional groups and, thus, is capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically able salts” in these instances refers to the relatively non-toxic nic and c base addition salts of a compound provided herein. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the d compound in its free acid form with a le base, such as the hydroxide, carbonate, or bicarbonate of a ceutically acceptable metal , with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, ium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and ium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated yanisole (BHA), butylated ytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid , sorbitol, tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition may also contain adjuvants such as preservatives, g agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifiangal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include tonicity-adjusting agents, such as sugars and the like into the compositions. In addition, prolonged absorption of the inj ectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of one or more compounds provided herein, it is ble to slow the absorption of the compound from subcutaneous or uscular injection. For example, delayed absorption of a parenterally administered compound can be accomplished by dissolving or suspending the compound in an oil vehicle.

Compositions prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the t, as is well known in the art. For example, where the compositions are to be administered orally, they may be ated as tablets, es, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections venous, intramuscular, or subcutaneous), drop infusion preparations, or suppositories. For application by the ophthalmic mucous membrane route, they may be formulated as eye drops or eye ointments. These ations can be prepared by conventional means in conjunction with the s described , and, if desired, the active ingredient may be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, or a g agent.

Formulations suitable for oral stration may be in the form of capsules (e.g., gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), s, troches, granules, or as a solution or a suspension in an aqueous or non-aqueous , or as an -water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes, and the like, each containing a predetermined amount of a compound provided herein as an active ingredient. A composition may also be administered as a bolus, electuary, or paste. Oral compositions lly include an inert diluent or an edible carrier.

] Pharmaceutically compatible binding agents, and/or nt materials can be included as part of an oral composition. In solid dosage forms for oral stration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient can be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, saccharin, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, microcrystalline cellulose, gum tragacanth, alginates, gelatin, polyvinyl idone, e, and/or acacia; (3) humectants, such as glycerol; (4) egrating agents, such as agar—agar, calcium ate, potato, corn, or a , alginic acid, Primogel, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, Sterotes, solid polyethylene glycols, sodium lauryl e, and mixtures thereof; (10) a glidant, such as dal silicon dioxide; (1 l) coloring agents; and (12) a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

In the case of capsules, s, and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of a powdered compound ned with an inert liquid diluent.

Tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled e of the active ingredient n using, for example, hydroxypropylmethyl cellulose in varying proportions to e the desired e profile, other polymer matrices, liposomes, microspheres, and/or nanoparticles. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating izing agents in the form of sterile solid compositions which can be ved in sterile water, or some other sterile inj ectable medium immediately before use. These itions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ient can also be in micro-encapsulated form, if riate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration include ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl te, ene , l,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, hylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compound(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and an esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Pharmaceutical compositions suitable for parenteral administration can include one or more compounds provided herein in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile s which may be reconstituted into sterile inj ectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended ent or suspending or thickening agents.

Examples of le aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions ed herein include water for injection (e.g., sterile water for injection), bacteriostatic water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol such as liquid polyethylene glycol, and the like), sterile buffer (such as citrate buffer), and suitable mixtures thereof, vegetable oils, such as olive oil, injectable organic esters, such as ethyl , and Cremophor ELTM (BASF, Parsippany, NJ). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The composition should be stable under the conditions of manufacture and storage and must be preserved t the inating action of microorganisms such as bacteria and fimgi. Prevention of the action of microorganisms can be ed by various antibacterial and ngal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include ic agents, for example, sugars, cohols such as mannitol, sorbitol, and sodium chloride in the ition. ged absorption of the inj ectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum earate and gelatin.

Sterile inj ectable solutions can be prepared by orating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the ation of sterile injectable solutions, the methods of preparation are freeze-drying (lyophilization), which yields a powder of the active ingredient plus any additional desired ingredient from a usly sterile-filtered solution thereof.

Injectable depot forms can be made by forming microencapsule or nanoencapsule matrices of a compound provided herein in biodegradable polymers such as polylactide- polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug e can be controlled. es of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot inj ectable formulations are also ed by entrapping the drug in liposomes,microemulsions or ulsions, which are compatible with body tissue.

] For stration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, e. g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in US. Patent No. 6,468,798. Additionally, intranasal delivery can be accomplished, as described in, inter alia, Hamajima et al., Clin. Immunol. pathol., 88(2), 205-10 (1998). Liposomes (e.g., as described in US. Patent No. 6,472,375, which is incorporated herein by reference in its entirety), microencapsulation and nanoencapsulation can also be used. Biodegradable targetable article delivery systems or biodegradable targetable nanoparticle delivery systems can also be used (e. g., as bed in US. Patent No. 6,471,996, which is orated herein by reference in its entirety).

Systemic administration of a therapeutic compound as described herein can also be by transmucosal or ermal means. Dosage forms for the topical or transdermal administration of a compound provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active component may be mixed under sterile conditions with a ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be ted are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.

Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The ointments, pastes, , and gels may contain, in addition to one or more compounds ed herein, excipients, such as animal and vegetable fats, oils, waxes, paraffins, , tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound provided herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

A compound ed herein can be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing a compound or composition provided herein. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which can result in ation of the compound.

Ordinarily, an aqueous aerosol can be made by formulating an aqueous solution or suspension of the agent er with conventional pharmaceutically able carriers and stabilizers. The carriers and izers vary with the requirements of the particular composition, but typically include nonionic surfactants (TWEEN® (polysorbates), PLURONIC® (poloxamers), sorbitan esters, lecithin, CREMOPHOR® (polyethoxylates)), ceutically acceptable co-solvents such as polyethylene glycol, innocuous proteins like serum albumin, an esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols lly are prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of a compound provided herein to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be lled by either providing a rate lling ne or dispersing the compound in a polymer matrix or gel.

The pharmaceutical compositions can also be prepared in the form of itories or retention enemas for rectal and/or vaginal delivery. ations presented as a suppository can be prepared by mixing one or more compounds ed herein with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, glycerides, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent. Formulations which are le for vaginal stration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

In one embodiment, the therapeutic nds are prepared with carriers that will t the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and ncapsulated delivery systems.

Biodegradable, biocompatible polymers can be used, such as ethylene Vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard ques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to ed cells with monoclonal antibodies to cellular antigens) can also be used as ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US. Patent No. 4,522,811, which is incorporated herein by reference in its entirety.

As described above, the preparations of one or more compounds provided herein may be given orally, parenterally, topically, or ly. They are, of course, given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, nt, suppository, on; topically by lotion or nt; and ly by suppositories. In some embodiments, administration is oral.

The phrases teral administration” and istered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion.

The phrases “systemic administration33 ECadministered systemically3) “ , , peripheral administration”, and istered peripherally” as used herein mean the administration of a ligand, drug, or other material via route other than ly into the central nervous system, such that it enters the patient’s system and thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

A compound provided herein may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally, and topically, as by powders, ointments or drops, including buccally and sublingually. Regardless of the route of administration ed, a compound provided herein, which may be used in a suitable hydrated form, and/or the pharmaceutical itions provided herein, is formulated into a pharmaceutically acceptable dosage form by conventional methods known to those of skill in the art. In another embodiment, the pharmaceutical composition is an oral solution or a parenteral solution. Another embodiment is a -dried preparation that can be reconstituted prior to administration. As a solid, this formulation may also include tablets, capsules or powders.

Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The concentration of a compound provided herein in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. In some embodiments, the compositions provided herein can be provided in an aqueous solution containing about 01-10% w/V of a compound disclosed herein, among other substances, for parenteral administration. l dose ranges can include from about 0.01 to about 50 mg/kg of body weight per day, given in 1-4 divided doses. Each divided dose may n the same or different compounds. The dosage will be a eutically effective amount depending on several s including the overall health of a patient, and the formulation and route of administration of the selected compound(s).

Dosage forms or compositions containing a compound as bed herein in the range of 0.005% to 100% with the balance made up from non-toxic r may be prepared.

Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001%-100% active ient, in one embodiment 01-95%, in another embodiment 75-85%. Although the dosage will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dosage of from 0.01 to 2000 mg of the nd is recommended for an adult human patient, and this may be administered in a single dose or in divided doses. The amount of active ingredient which can be ed with a carrier material to produce a single dosage 2014/026987 form will generally be that amount of the compound which produces a therapeutic effect.

The ceutical ition may be stered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being d and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be ed over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

The precise time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a ular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc. However, the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the patient and adjusting the dosage and/or timing.

The ceutical compositions can be included in a container, pack, or dispenser together with instructions for stration.

Also provided herein is a conjoint therapy wherein one or more other therapeutic agents are administered with a compound or a pharmaceutical composition comprising a compound provided herein. Such conjoint treatment may be achieved by way of the simultaneous, sequential, or te dosing of the individual components of the treatment.

Non-limiting examples of conjoint therapies e those provided in , which is incorporated herein in its ty.

In certain embodiments, a composition ed herein is conjointly administered with one or more other proteasome inhibitor(s) (see, e.g., US. Patent Nos. 7,232,818 and 8,088,741, each of which is incorporated herein by nce in its entirety). Additional 2014/026987 examples of proteasome inhibitors include bortezomib, MLN9708, marizomib, carfilzomib (see, e. g., US. Patent No. 7,417,042), and those compounds disclosed in US. Patent No. 7,687,456 and US. Patent No. 7,691,852, each of which is incorporated herein by reference in its entirety.

In certain embodiments, a pharmaceutical composition as provided herein is ntly stered with a cytokine. nes e, but are not limited to, Interferon- y, -()t, and -B, Interleukins 1-8, 10 and 12, Granulocyte Monocyte Colony—Stimulating factor (GM-CSF), TNF-u and -B, and TGF-B.

In certain embodiments, a ceutical composition provided herein is conjointly administered with a d. Suitable steroids may e, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, sone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, ednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone fiJroate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and/or derivatives thereof.

In some embodiments, a pharmaceutical composition provided herein is conjointly administered with an immunotherapeutic agent. Suitable immunotherapeutic agents may include, but are not d to, MDR modulators (e.g., verapamil, valspordar, biricodar, tariquidar, laniquidar), cyclosporine, thalidomide, lenalidomide MID®), pomalidomide, and onal antibodies. The monoclonal antibodies can be either naked or conjugated such as rituximab, tositumomab, alemtuzumab, epratuzumab, ibritumomab tiuxetan, gemtuzumab ozogamicin, bevacizumab, mab, erlotinib, and trastuzumab.

Other ments It is to be understood that while the disclosure is read in conjunction with the detailed description thereof, the foregoing ption is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

EXAMPLES l Experimental Methods Nuclear Magnetic Resonance (NMR) spectra were recorded at 400 MHz for 1H.

Chemical shifts (5) are given in ppm downfield from tetramethylsilane, an internal rd, and coupling constants (J—Values) are in hertz (Hz). Mass spectrometry (MS) was used to confirm the mass of the compounds by ionizing the compounds to generate charged molecules or molecule fragments and measuring their mass-to-charge ratios (m/z). As the ionization method, EI (electron impact) ionization was used. tic Procedures—Tripeptide Epoxy Ketone Compounds Example 1 [00 1 61] (lr,4R)-N—((R)- l -(((S)- l -(((S)—3 -(Cyclopent—l -enyl)- l 2-methyloxiran—2- yl)—l -oxopropanyl)amino)(4-methoxyphenyl)- l -oxopropanyl)amino)— 1 -oxopropan- 2-yl)-4—hydroxymethylcyclohexanecarboxamide 7): 1. H2 Pd/C H-D—Ala-OBn 2 HMeO-Phe-OBn Ho:\l- : HATU HO" HATU COOH OH%OBn—> _©)LN:\H/H_$03“ 1. H2, Pd/C o o 2 HATU,D|PEA o 3 . I HNEW/“\ANOa H 1-[Bis(dimethylamino)methylene]-1H—l,2,3—triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU; 751 mg, 1.98 mmol) and N,N—Diisopropylethylamine (DIPEA; 1.15 mL, 6.58 mmol) were added to a solution of the acid (260 mg, 1.64 mmol) and (R)- benzyl 2-aminopropanoate (355 mg, 1.98 mmol) in dimethylformamide (DMF; 5 mL) at 0 °C. The reaction e was allowed to warm to ambient temperature and stirred for 0.5 h.

Water (20 mL) was added and the resulting mixture was extracted with ethyl acetate (EtOAc; 50 mL><3). The ed organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 2:3) to afford (R)- benzyl 2-((Ir, 4r)—4-hydroxymethylcyclohexanecarboxamido)propanoate (320 mg, 61% yield) as an off-white solid.

To a on of nzyl 2—((1r, 4r)—4-hydroxy-4— methylcyclohexanecarboxamido)propanoate (320 mg, 1.0 mmol) in THF (10 mL) was added palladium on carbon (Pd/C; 30 mg, 10%). The mixture was stirred under en atmosphere (1 atm) at ambient temperature for 2 h. The mixture was d through a pad of Celite and the filtrate was concentrated under reduced pressure to afford the ponding acid (230 mg, quantitative) as a colorless solid, which was used in the next step without r purification.

] HATU (458 mg, 1.2 mmol) and DIPEA (0.70 mL, 4.0 mmol) were added to a solution of the acid (230 mg, 1.645 mmol) and (S)-benzyl 2-amino(4-methoxyphenyl) propanoate (hydrochloric acid (HCl) salt, 323 mg, 1.0 mmol) in DMF (7 mL) at 0 °C. The on mixture was allowed to warm to ambient temperature and stirred for 0.5 h. Water (20 mL) was added and the resulting mixture was extracted with EtOAc (50 . The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 1:2) to afford (S)((R)—2-((Ir,4r)—4- hydroxymethylcyclohexanecarboxamido)propanamido)(4-methoxyphenyl)propanoic acid (315 mg, 63% yield) as an off-white solid.

To a solution of (S)((R)((Ir,4r)—4-hydroxy methylcyclohexanecarboxamido)propanamido)—3—(4-methoxyphenyl)propanoic acid (315 mg, 0.64 mmol) in THF (10 mL) was added Pd/C (30 mg, 10%). The mixture was stirred under hydrogen atmosphere (1 atm) at ambient temperature for 2 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford compound (R)((1r,4R)-4—hydroxy—4-methylcyclohexanecarboxamido)propanoic acid (260 mg, quantitative) as a colorless solid, which was used in the next step without further purification.

HATU (308 mg, 0.81 mmol) and DIPEA (0.2 mL, 1.15 mmol) were added to a solution of (R)((1r,4R)hydroxymethylcyclohexanecarboxamido)propanoic acid (260 mg, 0.64 mmol) and (S)amino(cyclopentenyl)((R)methyloxiran yl)propanone (190 mg, 0.64 mmol) in DMF (6 mL) at 0 CC. The reaction mixture was allowed to warm to ambient temperature and stirred for 0.5 h. Water (20 mL) was added and the resulting mixture was extracted with EtOAc (50 mL><3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column tography on silica gel (EtOAc) to afford )-N-((R)(((S)—1-(((S)(cyclopentenyl)((R) methyloxiran—2-yl)-l opanyl)amino)-3—(4-methoxyphenyl)— 1 -oxopropan—2- yl)amino)oxopropanyl)hydroxymethylcyclohexanecarboxamide (260 mg, 63% yield) as an off—white solid. 1H NMR (300 MHz, deuterated form (CDC13)): 8 7.16 (d, J = 8.4 Hz, 2H), 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 (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). MS (EI) for C32H45N3O7, found 606.3 [M+Na]+. [00 1 67] (ls,4S)-N—((R)—l-(((S)—1-(((S)-3 -(cyclopent-1—enyl)((R)—2-methyloxiran—2- yl)-1 -oxopropanyl)amino)(4-methoxyphenyl)oxopropanyl)amino)— 1 -oxopropan- 2-yl)-4—hydroxymethylcyclohexanecarboxamide (C-1088): 1H NMR (300 MHZ, CDC13)C 5 7.16 (d, J: 8.7 Hz, 2H), 6.82 (d, J: 8.4 Hz, 2H), 6.60 (d, J: 7.2 Hz, 1H), 6.16 (d, J: 7.2 Hz, 2H), 5.30 (m, 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). MS (EI) for C32H45N3O7, found 606.3 [M+Na]+.

Example 2 [00 1 68] ((S)-3 -(Cyclohexenyl)((R)methyloxiranyl)-1 -oxopropan—2- yl)-2—((S)-3 -hydroxy-2—(2-morpholinoacetamido)propanamido)—3 —(3-hydroxy-4— methoxyphenyl)propanamide (C-1 109): 1. TFA O OH 2. (\NACOOH BOCHNQLOMe 1 TFA O - H O 2. Boc—L—Ser BocHNngdkOMe _ HATU HATU ; 5 —> o OBn OOMe 0/W OH 0/} o OHH 0 o K/NQK #HdLOMe ;: H3311“:. K/NdLn/[fNVkOH = o [ :i ; OMe HATU,D|PEA Ofi O O K/NdL IZ 0:31wLNL goH TFA O E 1 H2N OH Trifluoroacetic acid (TFA; 25 mL) was added to a on of (S)-methyl 3—(3- (benzyloxy)methoxyphenyl)((tert-butoxycarbonyl)amino)propanoate (5.00 g, 12.0 mmol) in romethane (CH2C12; 50 mL) at 0 CC with stirring. The mixture was d for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (20 mL for each portion) to remove residual TFA to afford crude compound (S)-methyl 2-amino- 3-(3-(benzyloxy)methoxyphenyl)propanoate as its TFA salt.

Crude (S)-methyl 2-amino(3-(benzyloxy)—4-methoxyphenyl)propanoate (TFA salt, 12 mmol) was dissolved in DMF (50 mL) followed by addition of Boc-L-serine (2.47 g, 12 mmol), HATU (6.87 g, 18.1 mmol) and DIPEA (10 mL) at 0 CC with ng. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (200 mL) and water (200 mL) was added and two layers were ted. The aqueous phase was extracted with EtOAc (100 mL><3) and the combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CHZClz/methanol (MeOH) = 20: 1) to afford thyl 3-(3-(benzyloxy)methoxyphenyl)((S)((tert- butoxycarbonyl)amino)hydroxypropanamido)propanoate (4.4 g, 73% yield).

TFA (20 mL) was added to a solution of (S)—methyl 3-(3-(benzyloxy)—4- yphenyl)((S)((tert—butoxycarbonyl)amino)—3-hydroxypropanamido)propanoate (4.4 g, 8.7 mmol) in CH2C12 (50 mL) at 0 CC with stirring. The mixture was stirred for l h and then concentrated to s. The residue was azeotroped three times with EtOAc (20 mL for each portion) to remove residual TFA to afford crude (S)—methyl 2-((S)—2—amino—3- hydroxypropanamido)—3-(3-(benzyloxy)methoxyphenyl)propanoate as its TFA salt.

Crude (S)-methy1 2—((S)-2—aminohydroxypropanamido)—3-(3-(benzyloxy)—4- methoxyphenyl)propanoate (TFA salt, 8.7 mmol) was dissolved in DMF (50 mL) ed by addition of 2-morpholinoacetic acid (1.3 g, 8.7 mmol), HATU (5.0 g, 13.1 mmol) and DIPEA (5.0 mL) at 0 0C with stirring. The reaction mixture was d to warm to ambient temperature and stirred for 3 h. EtOAc (200 mL) and water (200 mL) was added and two layers were separated. The s phase was extracted with EtOAc (100 mL><3) and the combined c phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was d by flash column chromatography on silica gel (CHzClg/EtOAc/MeOH = 20: 10: l) to afford (S)-methyl 3-(3-(benzyloxy) methoxyphenyl)((S)hydroxy(2-morpho linoacetamido)propanamido)propanoate (2.9 g, 62% yield).

(S)-methyl 3-(3 -(benzyloxy)methoxyphenyl)((S)—3-hydroxy(2-morpho linoacetamido)propanamido)propanoate (1.0 g, 1.9 mmol) was treated with a solution of lithium hydroxide-H20 (400 mg, 10 mmol) in water/THF (50 mL/20 mL) for 2 h. THF was removed and the aqueous phase was acidified to pH = 3—4 with 1N HCl followed by concentration to dryness to afford the corresponding acid.

The acid was dissolved in MeOH (20 mL) and Pd/C (l g, 10%) was added. The mixture was stirred under hydrogen atmosphere (1 atm) at t temperature overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford (S)((S)hydroxy(2-morpholinoacetamido)propanamido)-3—(3-hydroxy methoxypheny1)propanoic acid (520 mg, 64% yield) as a colorless solid.

HATU (570 mg, 1.5 mmol) and DIPEA (1.48 mL) were added to a solution of (S)- 2-((S)hydroxy(2-morpholinoacetamido)propanamido)(3-hydroxy methoxyphenyl)propanoic acid (425 mg, 1 mmol) and (S)amino(cyclohexen-l-yl)-l - ((R)methyloxiranyl)propan-l-one (TFA salt, 1 mmol) in DMF (20 mL) at 0 CC with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (50 mLX3) and the combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (CH2C12/EtOAc/MeOH = : 1020.2) to afford (S)-N-((S)—3 -(cyclohexenyl)((R)-2—methyloxiranyl) oxopropan-2—yl)((S)hydroxy(2-morpholinoacetamido)propanamido)—3—(3-hydroxy methoxyphenyl)propanamide (220 mg, 35% yield). 1H NMR (300 MHZ, DMSO—d6): 5 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), 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). MS (EI) for C31H44N4Oo, found 617.3 (MH)+.

The ing compounds were synthesized in a similar manner: (S)—N—((S)-3 —cyclopentyl- 1 2-methyloxiranyl)—1-oxopropan-2—yl)—3 -(4— methoxyphenyl)((R)—2-(2-(tetrahydro-2H-pyran tamido)propanamido)propanamide (C-1011): 1H NMR (300 MHZ, CDC13): 5 7.12 (d, J = 8.4 HZ, 2H), 6.83 (d, J: 8.7 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 (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), .83 (m, 15H). MS (ET) for C31H45N307, found 572.5 (MH)+.

(S)-N-((S)-3 -cyclopentyl-1—((R)methyloxiranyl)—1-oxopropanyl)—3 -(4- methoxyphenyl)—2-((S)—2-(2-(tetrahydro—2H-pyran yl)acetamido)propanamido)propanamide (C-1010): 1H NMR (CDClg, 300 MHZ): 8 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), .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, 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).

MS (EI) for N307, found 572.3 (MH)+.

Example 3 (S)—N—((S)-3 -(Cyclohexenyl)((R)methyloxiranyl)-1 -oxopropan yl)((S)-3 -hydroxy(2-morpholinoacetamido)propanamido)-3 -(4- (methylsulfonyl)phenyl)propanamide (C-1 1 1 0): OK/jN\jJ:N/ECOOH OL::l\,l\ O /[%rH\,JkNO 0 HATU : H O O SOzMe TFA O itN\/J\N O a H SOZMG HATU (502 mg, 1.3 mmol) and DIPEA (1.35 mL) were added to a solution of (S)- 3-hydroxy(2-morpholinoacetamido)propanoic acid (225 mg, 0.97 mmol) and (S)amino- (cyclohex-1 -eny1)((R)methyloxiranyl)oxopropanyl)—3-(4- (methylsulfonyl)phenyl)propanamide (0.88 mmol) in DMF (20 mL) at 0 CC with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (50 mLX3). The combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate and trated. The residue was purified by flash column tography on silica gel (CHzClz/EtOAc/MeOH = 20: 10:02) to afford (S)-N-((S)-3 ohexen-1—yl)((R)methyloxiranyl)—1-oxopropan-2—yl)- 2-((S)hydroxy(2-morpholinoacetamido)propanamido)—3-(4- (methylsulfonyl)phenyl)propanamide (200 mg, 35% . 1H NMR (300 MHZ, DMSO—d6): 8 8.33 (d, J: 7.2 Hz, 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, 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). MS (EI) for C31H44N409S, found 649.0 (MH)+.

The following compounds were synthesized in a similar manner: [00 1 82] (1r,4R)-N-((R)(((S)(((S)-3 -cyclopentyl((R)rnethyloxirany1) oxopropan-Z-y1)arnino)-3 droxymethoxyphenyl)ox0propan—2-y1)amino) 0x0propany1)hydroxycyc10hexanecarboxarnide (C-1072): ) 1H NMR (400 MHz, CDC13 6 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, .1: 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, 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). MS (EI) for C31H45N308, found 588.0 (MH)+.

(S)-N-((S)-3 -(cyclopent-1 -enyl)((R)methyloxirany1)-1 opan y1)-3 -(3-hydr0xyrneth0xypheny1)-2—((S)(2- morpholinoacetamido)propanamido)pr0panamide (C-1085): 1H NMR (400 MHz, CDC13) 5 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 (q, J: 6.9, 6.9, 6.9 Hz, 1H), 4.43 (q, .1: 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 (qd, 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). MS (EI) for C30H42N40g, found 587.0 (MH)+. [00 1 84] (1r,4R)-N—((R)-1—(((S)-1—(((S)-3 -(cyclopent—1-en-1—y1)((R)rnethy10xiran y1)-1 -oxopropany1)arnino)(4-rneth0xypheny1)0x0pr0pany1)amino)—3—hydr0xy oxopropan-Z-y1)hydroxycyclohexanecarboxamide (C-1092): 1H NMR (400 MHz, CDC13) 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: 7.3 Hz, 1H), 5.32 (s, 1H), 4.65 — 4.46 (m, 2H), 4.35 (ddd, 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: .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). MS (EI) for C31H43N308, found 586.0 (MH)+. [00 1 85] (S)-N-((S)—3 -(cycloheX-1—eny1)—1-((R)—2-methy10xiran-2—y1)oxopropan y1)-3 -(4-(methylsulfony1)pheny1)((S)(2- morpholinoacetamid0)propanamido)pr0panamide (C-1126): 1H NMR (300 MHz, 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, 2014/026987 4H), 310—32 (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). MS (EI) for C31H44N4OgS, found 633.3 (MH)+. [00 1 86] (15,3S)-N—((R)—1-(((S)—1-(((S)—3 -cyclopentyl((R)methy10xirany1) oxopropan-Z-y1)arnino)-3 -(4-meth0xypheny1)-1 —0X0pr0panyl)amino)— 1 -0X0pr0pan-2—y1)- 3-hydroxycyclopentanecarboxamide (C-1076): 1H NMR (300 MHz, DMSO-d6): 8 10.96 (br s, 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 (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). MS (EI) for C31H43N506, found 582.4 (MH)+. (1r,4R)-N—((R)(((S)(((S)—3-(cyc10penteny1)((R)—2-rnethy10xiran—2- y1)-1 opany1)amino)(4-rnethoxypheny1)0xopropany1)amino)— 1 —0X0propan- 2-y1)-4—hydr0xycyclohexanecarboxamide (C-l074): 1H NMR (500 MHZ, CDC13) 5 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, 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, .1 = 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 — 1.93 (m, 6H), 1.93 — 1.78 (m, 3H), 1.78 — 1.59 (m, 3H), 1.55 — 1.40 (m, 6H), 1.27 (d, J= 7.0 Hz, 4H).MS (E1) for C31H43N307, found 5700 (MH)+. [00 1 88] (S)-N-((S)—3 -(cyc10pent-1 -eny1)((R)-2—methy10x1ran-2—y1)-1 -0X0propan—2- y1)(4-(methylsulfony1)pheny1)((S)—2-(2- morpholinoacetamido)propanamido)propanamide (C-1125): 1H NMR (300 MHz, DMSO-d6): 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, 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). MS (EI) for N408S, found 618.7 (MH)+. (1R,3 S)-N-((R)—1-(((S)(((S)cyclopenty1—1-((R)rnethy10xiran-2—y1)-1 - pan-Z—y1)arnino)-3 -(4-methoxypheny1)ox0propanyl)amino)— 1 -0X0propany1)- 3-hydroxycyclopentanecarboxamide (C-1078): 1H NMR (300 MHz, DMSO-d6): 5 8 .23 (d, J = 6.9 Hz, 1H), 8.04 (d, .1: 8.4 Hz, 1H), 7.92 (d, .1: 6.9 Hz, 1H), 7.10 (d, .1: 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), 3.69 (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). MS (EI) for C30H43N307, found 558.2 (MH)+.

] )-N-((R)(((S)(((S)cyclopenty1—1-((R)—2-rnethy10xiranyl)—1- oxopropan-Z—yl)arnino)-3 -(4-methoxyphenyl)ox0propanyl)arnino)-1 -0X0propany1)- 3-hydroxycyclopentanecarboxamide (C-1077): 1H NMR (300 MHz, 6): 5 8.26 (d, J = 6.3 Hz, 1H), 8.04 (d, J: 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). MS (EI) for C30H43N307, found 558.2 (MH)+. (1S,3R)-N—((R)—1-(((S)—1-(((S)cyclopentyl((R)—2-methyloxiran—2-y1) oxopropany1)arnino)—3 -(4-methoxyphenyl)-1 —0x0pr0panyl)amino)— 1 -0X0pr0pan-2—yl)- 3-hydroxycyclopentanecarboxamide (C-1075): 1H NMR (300 MHz, DMSO-d6): 8 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), 1.40-2.00 (m, 13H), 1.40 (s, 3H), 1.00-1.20 (m, 2H), 0.95 (d, J: 6.9 Hz, 3H). MS (EI) for C30H43N307, found 558.3 (MH)+. [00 1 92] (1r,4R)-N—((R)(((.S')(((S)—3 -(cyclopent—1-enyl)((R)rnethyloxiran y1)-1 -0xopropany1)amin0)-3—(4-(rnethylsulfony1)phenyl)-1 -0x0propany1)amino)— 1 — pany1)hydroxycyclohexanecarboxamide (C-1096): 1H NMR (300 MHZ, DMSO- d6): 5 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), 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).

MS (EI) for C31H43N308S, found 618.4 (MH)+.

Example 4 [00 1 93] (1r,4R)-N—((R)(((S)(((S)—3 opent—1-eny1)((R)rnethyloxiran y1)-1 —oxopropan—2-yl)amino)-3—(4-methoxyphenyl)-1 -0xopropan—2-yl)amino)-1—oxopropan— 2-y1)hydroxymethylcyclohexanecarboxamide (C-1 1 1 1): Ho‘“OCOOH o 5 o : H O HATU, DIPEA ? /\fl/N\)J\ N . N H ' —> 2 H O O HO‘" TFA g . e “ZN/HfN ; N HATU (472 mg, 1.20 mmol) and DIPEA (1.48 mL) were added to a on of (S)((R)aminopropanamido)-N-((S)(cyclopenten-1 -yl)((R)methyloxiran yl)oxopropanyl)—3-(4-methoxyphenyl)propanamide (TFA salt, 460 mg, 0.85 mmol) and trans—4-hydroxy—1-methylcyclohexanecarboxylic acid (131 mg, 0.83 mmol) in DMF (20 mL) at 0 °C with stirring. The reaction e was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (200 mLX3), dried over anhydrous sodium sulfate, and concentrated. The residue was d by flash column chromatography on silica gel (CHzClz/EtOAc/MeOH = 20:10:0.1) to afford (1r,4R)-N-((R)(((S)-1—(((S)(cyclopent en-l -yl)((R)—2-methyloxiran—2-yl)-1 —oxopropanyl)amino)—3 -(4-methoxyphenyl)— 1 — oxopropanyl)amino)-1 -oxopropanyl)hydroxy-1 lcyclohexanecarboxamide (150 mg, 30% yield). 1H NMR (300 MHz, DMSO-dg): 5 8.33 (d, J: 6.6 Hz, 1H), 7.96 (d, J: 8.4 Hz, 1H), 7.38 (d, J: 7.2 Hz, 1H), 7.10 (d, J: 8.4 Hz, 2H), 6.78 (d, J: 8.4 Hz, 2H), 5.40 (s, 1H), 4.40-4.60 (m, 2H), 4.20 (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 (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). MS (EI) for C32H45N307, found 584.2 (MH)+.

The following compounds were synthesized in a r manner: [00 1 96] (R)-N-((R)—1-(((S)(((S)cyclopenty1—1-((R)—2-methyloxiran-2—yl) oxopropanyl)amino)-3 -(4-methoxyphenyl)oxopropany1)amino)—1 -oxopropanyl)- -oxopyrrolidinecarboxamide (C-1067): 1H NMR (300 MHz, DMSO-d6): 8 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), 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, 2014/026987 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). MS (EI) for C29H40N4O7, found 555.2 (M-H]'. [00 1 97] (S)—N-((R)—1-(((S)—1—(((S)-3—cyclopenty1—1-((R)rnethyloxirany1)—1- oxopropan-Z—y1)arnino)-3 -(4-methoxypheny1)oxopropanyl)arnino)— 1 -oxopropany1)- -oxopyrrolidinecarboxarnide (C-1068): 1H NMR (300 MHz, DMSO—dé): 8 8.27 (d, J = 7.5 Hz, 1H), 8.15 (rn, 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), 1.57 (m, 2H), 1.48 (m, 42 (s, 3H), 1.13 (m, 3H), 0.95 (d, J: 7.2 Hz, 3H). MS (EI) for C29H40N4O7, found 557.3 (MH)‘. [00 1 98] —1-(((S)—1-(((S)—3 -cyclopenty1—1-((R)rnethyloxirany1)oxopropan y1)amino)-3 -(4-1nethoxypheny1)- 1 opan—2-y1)amino)oxopropan y1)cyclopentanecarboxarnide (C-1021): 1H NMR (300 MHz, DMSO-d6): 5 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), 1.54 (m, 10H), 1.39 (s, 3H), 1.07 (m, 3H), 0.93 (d, J: 6.9 Hz, 3H). MS (EI) for C30H43N306, found 540.4 (MH)'.

(S)—N-((R)—1-(((S)—1-(((S)-3—cyclopenty1—1-((R)rnethyloxirany1)—1- oxopropan-2—y1)arnino)-3 -(4-methoxypheny1)oxopropanyl)amino)— 1 -oxopropan y1)tetrahydrofuran-3 -carboxamide (C-1037): 1H NMR (300 MHz, DMSO-d6): 8 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), 1.00—1.30 (m, 3H), 0.96 (d, J: 6.6 Hz, 3H). MS (EI) for C29H41N307, found 542.2 (MH)'.

(S)-N-((R)—1-(((S)—1-(((S)—3—cyclopenty1—1—((R)rnethyloxirany1) oxopropany1)arnino)-3 -(4-methoxypheny1)oxopropanyl)arnino)— 1 -oxopropan y1)tetrahydro-2H-pyrancarboxamide (C-1053): 1H NMR (300 MHz, 6): 5 8.25 (d, J: 7.2 Hz, 1H), 7.90-8.10 (rn, 2H), 7.12 (d, J: 8.4 Hz, 2H), 6.79 (d, J: 8.4 Hz, 2H), 4.45 (m, 1H),4.30(1n, 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). MS (EI) for C30H43N307, found 556.3 (MH)'.

(R)-N-((R)(((S)(((S)cyclopentyl-1 -((R)rnethyloxirany1) oxopropany1)arnin0)-3 -(4-meth0xypheny1)-1 -oxopr0panyl)amino)0X0pr0pan y1)tetrahydro-2H-pyrancarb0xamide (C-1052): 1H NMR (300 MHZ, DMSO'd6): 8 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 HZ, 3H). ). MS (EI) for N307, found 556.3 (MH)‘. (15,4S)-N-((R)—1-(((S)(((S)—3 -(cyclopent-1—eny1)—1-((R)—2-rnethy10xiran—2— y1)-1 opany1)amino)(4-rneth0xypheny1)0x0pr0pany1)amino)— 1 -oxopropan- 2-y1)—4—hydroxycyclohexanecarboxamide 6): 1H NMR (400 MHZ, CDC13) 5 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= 7.0, 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, 4H), 1.48 (s, 3H), 1.26 (d, J: 7.0 HZ, 3H). MS (EI) for C31H43N307, found 5700 (MH)+.

N—((R)—1-(((S)(((S)—3-(cyclopent-1—eny1)—1-((R)—2-methy10xiran—2-y1)-1— oxopropany1)arnino)-3 -(4-Ineth0xypheny1)-1 -oxopr0panyl)amino)ox0propan y1)0xetanecarboxamide (C-1055): 1H NMR (400 MHZ, CDC13) 5 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: 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: 7.0 HZ, 3H). MS (EI) for C28H37N307, found 528.0 (MH)+. ] (1r,4R)-N-((R)(((S)(((S)-3 -(cyc10penteny1)((R)rnethy10xiran y1)-1 —oxopropan—2-yl)amino)-3—(4-methoxypheny1)-1 -0xopropan—2-yl)amino)-1—oxopropan- 2-y1)hydroxycyclohexanecarboxamide (C-1057): 1H NMR (400 MHZ, CDC13) 5 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), .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 (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). MS (EI) for C31H43N307, found 570.0 (MH)+.

(S)—N-((R)—1 -(((S)(((S)cyc10penty1—1-((R)rnethy10xirany1)—1 - oxopropan-Z-y1)arnino)-3 -(4-methoxyphenyl)0xopropanyl)amino)- 1 opany1)- 6-ox0piperidinecarboxarnide (C-1059): 1H NMR (300 MHz, DMSO—d6): 8 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, 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). MS (EI) for C30H42N4O7, found 571.0 (MHY.

(R)-N-((R)—1-(((S)(((S)cyc10penty1—1-((R)rnethy10xirany1)—1- oxopropan-Z-y1)amino)—3 -(4-methoxyphenyl)-1—oxopropanyl)amino)—1—oxopropan-2—y1)- 6-0X0piperidinecarboxarnide (C-1058): 1H NMR (300 MHz, CDC13): 8 7.40 (m, 1H), 7.33 (m, 2H), .86 (m, 3H), 6.40 (d, J= 7.2 Hz, 1H), 4.91 (m, 1H), 4.68 (m, 1H), .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). MS (EI) for C30H44N40g, found 589.3 (MH)+. (1r,4R)-N-((R)(((S)(((S)-3 -cyclopentyl- 1 2-rnethyloxirany1)— 1 - oxopropan-Z-y1)amino)—3 -(4-methoxyphenyl)- 1 —oxopropanyl)amino)— 1 -oxopropan-2—y1)- 4-hydroxycyclohexanecarboxamide (C-1064): 1H NMR (400 MHz, CDC13) 5 8.22 (d, J = 7.0 Hz, 1H), 7.95 (d, J: 8.7 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 (q, J: 7.2, 7.2, 7.2 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 (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). MS (EI) for C31H45N307, found 572.3 (MH)+.

(R)-N-((R)—1-(((S)(((S)(cyclopenteny1)((R)methyloxirany1) oxopropan-Z-y1)amino)—3 -(4-methoxyphenyl)-1—oxopropanyl)amino)—1—oxopropan-2—y1)- 1-rnethy1piperidinecarb0xamide (C-1099): 1H NMR (300 MHZ, DMSO-d6): 8 8.28 (d, J = 7.2 Hz, 1H), 8.02 (m, 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, 3 H), 3.22 (d, J: 5.4 Hz, 1H), 2.99 (d, J: .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).

MS (EI) for C31H44N4O6, found 569.4 (MH)+, N—((R)—1-(((S)(((S)-3 -(cyclopent—1—eny1)—1-((R)—2-rnethy10xiran—2-y1)-1— oxopropany1)arnin0)-3 -(4-methoxypheny1)-1 -oxopr0panyl)arnino)0X0propany1)- 1-rnethy1piperidineCarboxamide (C-1098): 1H NMR (300 MHz, DMSO-dg): 5 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 (m, 3H), 1.77 (m, 4H), 1.51 (s, 3H), 1.38 (m, 2H), 0.94 (d, J = 6.9 Hz, 3H). MS (ED for C31H44N406, found 569.3 (MH)+. (18,4S)-N-((R)(((S)(((.S')(cyc10heXeny1)((R)—2-rnethy10xiran—2- y1)-1 —oxopropan—2-yl)amino)-3—(4-methoxypheny1)0xopropan—2-yl)amino)-1—oxopropan— 2-y1)hydr0xycyclohexanecarboxamide (C-1097): 1H NMR (400 MHz, : 7.18-7.16 (m, 2H), 6.85-8.82 (m, 2H), .56 (m, 2H), 6.58-6.56 (d, 1H), .02 (m, 2H), 5.27 (s, 1H), 4.53-4.51 (m, 2H), 4.40-4.36 (m, 1H), .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). MS (EI) for C32H45N307, found 584.0 (MH)+. [0021 1] (2S)((2S)(2-(6-oxaazabicyclo[3.1.1]heptan—3- y1)acetamido)propanamido)—N—((S)cyclopenty1—1-((R)—2-methy10xiran—2-y1)-1—oxopr0pan- 2-y1)—3-(4-rnethoxypheny1)propanarnide (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), .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), 2.78-2.60 (m, 2H), 2.22-2.21 (m, 1H), 1.90-1.42 (m, 4H), 1.41 (s, 3H), .14 (d, 3H). MS (EI) for C31H44N4O7, found 585.0 (MH)+. [002 1 2] (13,4S)-N-((R)(((.S')(((S)-3 -(cyc10pentenyl)((R)rnethy10xiran y1)-1 -0xopr0panyl)amino)-3—(4-rneth0xypheny1)0x0pr0pan—2-y1)amino)—1—0xopropan- 2-y1)hydroxymethy1cyclohexanecarboxamide (C-1112): 1H NMR (300 MHz, DMSO- d6): 8 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). MS (EI) for C32H45N307, found 582.1 (MH)'.

Example 5 (S)-N—((S)—3 -(Cyclopenteny1)((R)rnethyloxirany1)ox0pr0pan y1)((S)(2-morpholinoacetarnido)propanamido)—4-phenylbutanamide (C-1128): twinge. j/ GOV? Mo HATU,NMM ”Jfif OBn .H2N O 0/} o o 1.H2,Pd/C K/NdLNJm/N¢LN’ é :0 2.HATU,NMM H 5 H o o N-Methylmorpholine (1.09 g, 10.8 mmol) was added to a mixture of (S)(2— morpholinoacetamido)propanoic acid (0.58 g, 2.7 mmol), (S)-benzyl 2-amino phenylbutanoate (TFA salt, 1.03 g, 2.7 mmol) and HATU (1.13 g, 2.97 mmol) in dichloromethane (50 mL) at 0 OC. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (50 mL) was added and the ing mixture was extracted with dichloromethane (50 mL>< 3). The organic extracts were combined, dried over anhydrous sodium sulfate, and trated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 10:1) to afford (S)- benzyl 2-((S)(2-morpholinoacetamido)propanamido)—4-phenylbutanoate (0.9 g, 71% yield).

(S)-Benzyl2-((S)(2-morpholinoacetamido)propanamido)—4-pheny1butanoate (0.62 g, 1.3 mmol) was hydrogenated in the presence of Pd/C (0.1 g) in methanol (20 mL) for l h at ambient temperature. Pd/C was filtered off and the filtrate was concentrated to afford the corresponding acid.

The acid was dissolved in dichloromethane (30 mL) and d with amino(cyclopenten-l-yl)—l-((R)methyloxiranyl)propan-l-one (0.450 g, l .3 3 mmol) and HATU (0.560 g, 1.46 mmol). N—Methylmorpholine (0.53 g, 5.2 mmol) was added to the on at 0 °C. The on mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (50 mL) was added and the resulting mixture was extracted with dichloromethane (50 . The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography WO 52134 on silica gel (dichloromethane/methanol = 100:1 to 20:1) and prep-TLC to afford (S)-N-((S)— 3 -(cyclopent-l-enyl)((R)methyloxiranyl)-1 opanyl)((S)(2- morpholinoacetamido)propanamido)phenylbutanamide (195 mg, 26% yield). 1H NMR (300 MHz, DMSO-dg): 5 8.22 (d, J= 6.9 Hz, 1H), 8.13 (d, J= 7.5 Hz, 1H), 7.87 (d, J= 7.5 Hz, 1H), 7.28 (m, 2H), 7.17 (m, 3H), 5.41 (m, 1H), 4.49 (m, 1H), 4.37 (m, 2H), 4.28 (m, 1H), 3.58 (m, 4H), 3.22 (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). MS (EI) for C30H42N4O6, found 555.6 (MH)+.

The following compounds were synthesized in a similar manner: (S)—N-((S)-3 -cyclopentyl((R)-oxiranyl)—1-oxopropanyl)-3 -(3 ,4- dimethoxyphenyl)((S)(2-morpholinoacetamido)propanamido)propanamide (C-107 l): 1H NMR (300 MHz, DMSO'd6): 5 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, 6H), 2.37 (m, 4H), 1.40-1.97 (m, 9H), 1.24 (s, 3H), 1.16 (d, J: 6.9 Hz, 3H). MS (EI) for C30H44N40g, found 587.3 (MH)'.

(S)-N-((S)—3 -cyclopentyl((R)—2-methyloxiran-2—yl)oxopropanyl)—3 -(4- (methylsulfonyl)phenyl)—2-((S)(2-morpholinoacetamido)propanamido)propanamide (C- 1027): 1H NMR (300 MHz, DMSO-d6): 5 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), 1.40 (s, 3H), 1.16 (d, J: 6.6 Hz, 3H). MS (EI) for C30H44N408S, found 621.3 (MH)+.

(S)-N-((S)-3 -cyclopentyl((R)methyloxiranyl)oxopropanyl)—3 -(3- lsulfonyl)phenyl)—2-((S)(2-morpholinoacetamido)propanamido)propanamide (C- 1024): 1H NMR (300 MHz, DMSO-d6): 5 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), .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). MS (EI) for C30H44N4OgS, found 621.3 (MH)+.

(S)-3 -(4-cyanophenyl)-N-((.S')—3 -cyclopentyl((R)methyloxiranyl)— 1 - oxopropanyl)—2-((S)—2—(2-morpholinoacetamido)propanamido)propanamide (C-1050): 1H NMR (300 MHz, DMSO-d6): 8 8.35 (d, J: 6.9 Hz, 1H), 8.15 (d, J: 8.1Hz, 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), 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). MS (EI) for C30H41N506, found 566.5 (MH)'. —3 -(((S)—3 -cyclopenty1—1-((R)methy10xirany1)—1-oxopropan y1)amino)((S)—2-(2-morph0linoacetamido)propanamido)oxopropyl)benzamide (C- 1049): 1H NMR (300 MHz, DMSO-dg): 5 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), 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). MS (EI) for N507, found 584.4 (MH)'.

(S)—N-((S)-3 -cyclopenty1—1-((R)rnethy10xirany1)0X0propan-2—y1)((S) (2-morpholinoacetamido)propanamido)(4-su1famoylpheny1)propanamide (C-1054): 1H NMR (300 MHz, DMSO-dg): 5 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, 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). MS (EI) for C29H43N508S, found 622.3 (MH)+.

Example 6 (S)-N—((S)—3 -(CycloheXeny1)((R)methy10xirany1)—1-0xopropan y1)-3 -(4-methoxypheny1)((S)—2-(2-m0rph0linoacetamido)(oxetan-3 — y1)acetamido)propanamide (C-1 138): oxetanone O 1. H2, Pd/C O foye DBU 2. Cbz-OSu CszN P’L | —’ M de CszN COOMe CszN COOMe 1' H2’ Pd/C 1. LiOH o 2. Coupling with 2 O/fi H-Phe(4-OMe)-OMe ' NVCOOH NHi 3. Separation by HATU Chiral HPLC CbZHN O'V'e —> O _ E 10/ 0/fi 0 O 1.L'OH o o o K/N\)J\N HQLOMe 2. HIATU ()de HJLN H 5 —’ o H E H [1 / o I)o O 0/ 1,8—Diazabicycloundecene (DBU; 16.25 g, 95 mmol) was added dropwise to a solution ofN—benzyloxy carbonyl-(phosphono glycine hylester) (23.0 g, 70.0 mmol) and oxetanone (5.0 g, 70 mmol) in methylene chloride (200 mL) at ambient temperature under N2. The reaction mixture was stirred for 48 h at ambient temperature. The solvent was removed and the e was dissolved in EtOAc (500 mL). The resulting solution was washed with 5% aqueous KHSO4 (300 mL><2), ted aqueous NaHC03 (300 mL><3), and brine (200 mL>< 1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The e was purified by flash column chromatography on silica gel (Hexane/EtOAc = 5:1) to afford methyl 2-(benzyloxycarbonylamino)(oxetan ylidene)acetate (13.5 g, 69% yield).

Pd/C (10%, 5.0 g) was added to a on of methyl 2- (benzyloxycarbonylamino)—2-(oxetan-3—ylidene)acetate (10.0 g, 36 mmol) in MeOH (100 mL). The suspension was stirred under en atmosphere at ambient temperature for 12 h.

The catalyst was filtered off and washed with MeOH (100 mL). The filtrate and washings WO 52134 were combined followed by addition of benzyloxycarbonyl N—succinimide Su; 10.0 g, 40 mmol) and triethylamine (15.2 mL, 108 mmol). The reaction mixture was stirred for 12 h at ambient temperature and then concentrated. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 5: 1) to afford methyl 2- (benzyloxycarbonylamino)(oxetanyl)acetate(4.3 g, 41% yield) as a yellow solid.

] A solution of LiOH (650 mg, 27.0 mmol) in water (10 mL) was added to a on methyl 2-(benzyloxycarbonylamino)-2—(oxetan—3-yl)acetate (2.5 g, 9.0 mmol) in tetrahydrofuran (THF; 50 mL) at 0°C with stirring. The reaction e was stirred for 12 h and then acidified with 2 N aqueous HCl to pH=3. Most of the solvent was removed and the remaining mixture was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (50 mL>< 1), dried over anhydrous sodium sulfate and concentrated to afford the corresponding acid (2.0 g), which was used directly without further purification. 4—(4,6-Dimethoxy—1,3,5-triazinyl)methylmorpholinium chloride (DMTMM; 4.4 g, 16 mmol) and N—methylmorpholine (3.2 g, 32 mmol) were added to a solution of the acid (2.0 g, 8.0 mmol) and Lmethoxylpheny1alanine methyl ester hydrochloride (2.0 g, 8.2 mmol) in methylene chloride (100 mL) at 0 °C with stirring. The sion was stirred for 1 h at ambient ature and then washed with 5% aqueous KHSO4 (100 mL><2), saturated aqueous NaHC03 (100 mL><3), and brine (50 mL><1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel e/EtOAc = 3: 1) to afford a mixture of two diastereomers (2.5 g), which was fiarther separated by chiral prep-HPLC to give (S)-methyl 2- ((S)—2-(benzyloxycarbonylamino)—2-(oxetan-3—yl)acetamido)(4- methoxyphenyl)propanoate (1.1 g, 26% yield) as a colorless solid.

Pd/C (10%, 1.0 g) was added to a solution of (S)-methyl 2-((S) (benzyloxycarbonylamino)(oxetan-3—yl)acetamido)-3—(4- methoxyphenyl)propanoate (600 mg, 1.30 mmol) in MeOH (10 mL). The suspension was stirred under hydrogen atmosphere at ambient temperature for 2 h. The catalyst was filtered off and washed with MeOH (10 mL). The e and washings were combined and concentrated to s.

The residue was dissolved in ene chloride (50 mL) followed by addition of 2-morpholinoacetic acid (190 mg, 1.30 mmol), HATU (550 mg, 1.40 mmol) and DIPEA (0.70 mL, 410 mmol) at 0 CC. The reaction mixture was d to warm to ambient temperature and stirred for 0.5 h. Saturated aqueous NaHC03 (20 mL) was added and two phases were separated. The aqueous phase was extracted with CH2C12 (20 mL><3). The combined organic phases were washed with brine (20 mL><3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (CH2C12MeOH = 50:1) to afford (S)-methyl ethoxyphenyl)—2-((S)—2—(2- linoacetamido)—2-(oxetan yl) ido)propanoate (280 mg, 48% yield).

A solution of LiOH (70 mg, 2.8 mmol) in water (10 mL) was added to a solution of (S)—methyl 3—(4-methoxyphenyl)((S)—2-(2—morpholinoacetamido)-2—(oxetan—3- yl)acetamido)propanoate (340 mg, 0.760 mmol) in THF (10 mL) at 0 °C with stirring. The reaction mixture was d for 3 h and then acidified with 2N aqueous HCl to pH=3. The mixture was concentrated to dryness to afford the corresponding acid (350 mg), which was used directly without further purification.

HATU (320 mg, 0.800 mmol) and DIPEA (0.5 mL) were added to a solution of the acid (350 mg, 0.760 mmol) and (S)amino(cyclohex-l-en-l-yl)-l-((R)—2- methyloxiran—2-yl)propan-l-one (TFA salt, 0.8 mmol) in DMF (20 mL) at 0 CC with stirring.

The suspension was allowed to warm to t temperature and stirred for l h. The mixture was diluted with EtOAc (100 mL) and then washed with 5% aqueous KHSO4 (50 mL><3), saturated aqueous NaHC03 (50 mL>< 3), and brine (50 mL>< 1) respectively. The organic phase was dried over anhydrous sodium sulfate and trated. The residue was purified by flash column chromatography on silica gel (CHzClz/EtOAc/MeOH = 20: 1005) to afford (S)-N- ((S)(cyclohexenyl)-l 2-methyloxiran-2—yl)- l -oxopropan—2-yl)-3 —(4- methoxyphenyl)((S)(2-morpholinoacetamido)(oxetanyl)acetamido)propanamide (120 mg, 25% yield over two steps) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8 8.28 (d, J=7.5 Hz, 1H), 8.16 (d, J: 7.2 Hz, 1H), 7.90 (d, J: 7.8 Hz, 1H), 7.10 (d, J: 7.2 Hz, 2H), 6.78 (d, J: 7.2 Hz, 2H), 5.38 (m, 1H), 4.62 (m, 1H), 4.40-4.60 (m, 4H), 4.20-4.40 (m, 2H), 3.70 (s, 3H), 3.54 (m, 4H), 3.20 (m, 1H), 2.90-3.10 (m, 4H), 2.75 (m, 1H), 2.20-2.50 (m, 6H), .10 (m, 5H), 1.50-1.70 (m, 4H), 1.37 (s, 3H). MS (EI) for C33H46N4Og, found 627.2 (MHY.

Example 7 (S)-N—((S)— l -(((S)(Cyclopentenyl)— l -((R)-2—methyloxiranyl)- l - oxopropanyl)amino)-3 -(4-methoxyphenyl)- 1 —oxopropanyl)(2- morpholinoacetamido)pentynamide (C-1 139): MeO H a””2 W —.HATU,NMM BocHN N\)J\OBn 2 OH .

NHBoc 1. TFA 2. holinoacetic acid HATU NMM ONbNdQfirH$N0% 1.LiOH o 2.HATU ON 0% o H = H K/NdQW/H\.)J\OBDH = TFA O OMe OMe ] HATU (1.2 g, 3.1 mmol) was added to a solution of (S)—2-(tert- butoxycarbonylamino) pent-4—ynoic acid (0.6 g, 2.8 mmol) and (S)-benzyl 2-amino(4— yphenyl) propanoate (HCl salt, 1.0 g, 3.1 mmol) in dichloromethane (20 mL) at 0 oC.

N—Methylmorpholine (1.20 mL, 11.3 mmol) was added and the reaction mixture was allowed to warm to t ature and stirred for 1 h. Water (20 mL) was added and the resulting mixture was extracted with dichloromethane (20 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10:1 to 5:1) to afford (S)-benzyl 2-((S)(tert—butoxycarbonylamino)pentynamido)—3 -(4-methoxy )propanoate (1.1 g, 81% yield) as a colorless solid.

] (S)—Benzyl 2—((S)-2—(tert-butoxycarbonylamino)pent—4—ynamido)(4—methoxy phenyl)propanoate (1.1 g, 2.3 mmol) was dissolved in dichloromethane (10 mL) and treated with TFA (1.5 mL) for 1 h at ambient temperature. The t was removed and the residue was added to a solution of 2-morpholinoacetic acid (0.33 g, 2.3 mmol) and HATU (1.0 g, 2.6 mmol) in dichloromethane (20 mL). N—Methylmorpholine (0.63 mL, 5.7 mmol) was added at 0 CC. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h.

Water (20 mL) was added and the resulting mixture was extracted with dichloromethane (20 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 200:1 to 100: 1) to afford (S)-Benzyl 3-(4—methoxyphenyl)—2- ((S)(2-morpholinoacetamido)pent ynamido)propanoate (0.8 g, 69% yield) as a colorless 2014/026987 solid.

A on of nzyl 3-(4-methoxyphenyl)((S)—2-(2- morpho1inoacetamido)pent o)propanoate (0.8 g, 1.6 mmol) in water/THF (5 mL/3 mL) was treated with LiOH-HQO (0.13 g, 3.1 mmol) for 1 h at ambient temperature. The mixture was neutralized to pH=7 with concentrated aqueous HCl and then concentrated under vacuum to dryness.

] The residue was added to a mixture of (S)amino(cyclopentenyl) ((R)methyloxirany1)propanone (0.50 g, 1.6 mmol) and HATU (0.66 g, 1.7 mmol) in dichloromethane (20 mL). N—Methylmorpholine (0.43 mL, 4.0 mmol) was added at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (30 mL) was added and the resulting mixture was extracted with dichloromethane (30 mL><3).

The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated.

The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 200:1 to 80: 1) to afford (S)-N-((S)—1-(((S)—3-(cyclopent-1 -en y1)-1 —((R)methyloxiranyl)oxopropanyl)amino)(4-methoxyphenyl) oxopropanyl)(2-morpholinoacetamido)pentynamide (130 mg, 14% . 1H NMR (300 MHz, DMSO-d6): 8 8.35 (d, J: 7.2 Hz, 1H), 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). MS (EI) for C32H42N4O7, found 595.28 (MH)+.

The following compounds were synthesized in a similar manner: (S)-N-((S)-3 -cyclopentyl((R)methyloxiranyl)oxopropanyl)—3 -(furan- 2-y1)((S)-2—(2-morpho1inoacetamido)propanamido)propanamide (C-1013): 1H NMR (300 MHz, CDCl3): 5 7.60 (br s, 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). MS (EI) for C27H40N4O7, found 533.4 (MH)+.

N—((R)—1-(((S)(((S)cyclopentyl((R)methyloxiranyl)oxopropan yl)amino)(4—(methylsulfonyl)phenyl)—1-oxopropan-2—yl)amino)oxopropan—2— yl)tetrahydro-2H-pyrancarboxamide (C-1051): 1H NMR (300 MHZ, DMSO-d6): 5 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, .1: 8.1 Hz, 2H), 4.65 (m, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 3.40 (m, 2H), 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, .1: 6.9 Hz, 3H). MS (EI) for C30H43N308S, found 606.0 (MH)'.

)-N-((R)(((2S,3R)—1-(((S)-3—(cyclopenten—1-y1)-1—((R) methyloxiran—Z-y1)- 1 —0X0pr0panyl)amino)hydr0xy(4-meth0xyphenyl)-1 -oxopropan- 2-yl)amin0)-1—0xopropany1)—4-hydr0xycyclohexanecarboxamide 0): 1H NMR (400 MHz, CDC13)5 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, 1H), 5.02 (S, 1H), 4.56 (q, .1: 7.7, 7.7, 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, .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 — 1.24 (m, 4H), 1.09 (d, J: 13.2 Hz, 2H), 0.98 (d, J: 7.1 Hz, 3H). MS (EI) for C31H43N308, found 584.3 (MH)'. (1r,4R)-N-((R)(((2S ,3R)—1-(((S)—3-cyc10penty1—1-((R)methyloxiranyl)-1 - oxopropan-Z-y1)amino)—3 -hydroxy(4—methoxypheny1)— 1 -ox0propan-2—yl)amino) 0x0propany1)hydroxycyc10hexanecarboxamide (C-1079): 1H NMR (400 MHz, CDC13) 7.97 (d, J: 6.3 Hz, 1H), 7.93 (d, J: 7.1Hz, 1H), 7.85 (d, J: 9.1 Hz, 1H), 7.24 (d, J: 8.7 Hz, 2H), 6.92 — 6.74 (m, 2H), 5.54 (d, J: 4.7 Hz, 1H), 5.08 (dd, J: 4.5, 2.5 Hz, 1H), 4.54 (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 — 1.00 (m, 2H), 0.96 (d, J: 7.0 Hz, 3H).MS (EI) for C31H45N308, found 586.3 (MH)+.

(S)-N-((S)-1 cyc10penty1—1 -((R)methy10xirany1)—1-0X0propan yl)amino)-3 -(4—methoxypheny1)— 1 -ox0propan-2—y1)—2-(2—morpholinoacetamido)butanamide (C-1106): 1H NMR (300 MHz, CDC13): 5 7.51 (br s, 1H), 7.11 (d, J: 8.4 Hz, 2H), 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). MS (EI) for C31H46N4O7, 587.7 (MH)+.

(S)—N-((S)-3 penty1—1-((R)methyloxiranyl)—1-0x0propan-2—y1)—2-((S)—2- cyc10propy1—2-(2-rnorpholinoacetamido)acetamido)(4-meth0xyphenyl)propanamide (C- 1107): 1H NMR (300 MHz,CDC13): 5 7.72 (br s, 1H), 7.12 (d, J: 8.7 Hz, 2H), 6.80 (d, J: WO 52134 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). MS (EI) for C32H46N4O7, 599.1 (MH)+.

Example 8 (S)—N—((S)—3 —(Cyclopent-1 -en—1-yl)—1—((R)-2—methyloxiran-2—y1)—1-oxopropan—2- yl)—3 -(2-methoxypyridinyl)—2-((S)—2-(2-morpholinoacetamido)propanamido)propanamide (C-1 14 1): BocHN ICOOMe OMe Zn a)3 \ N 8Phos \N \ / BrflOMe BOCHN COOMB COOMe o o K/NJNJWrOH 0.30.444480444444 Dry DMF (30 mL) was added to zinc dust (2.78 g, 42.6 mmol) in a flame dried bottom flask under N2. (R)-Methyl 2-(tert-butoxycarbonylamino)—3-iodopropanoate (3.85 g, 11.7 mmol) was added followed by a catalytic amount of iodine (1.06 g, 0.10 mmol). The mixture was stirred at ambient temperature for 0.5 h. Pd2(dba)3 (487 mg, 0.050 mmol), S- Phos (437 g, 0.100 mmol) and 4-bromomethoxypyridine (2.00 g, 10.6 mmol) were added.

The reaction mixture was heated at 60 °C for 6 h and then cooled to ambient temperature.

EtOAc (200 mL) and water (200 mL) were added. The c phase was separated, washed with water (300 mL><3) and brine (300 mL><1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel e/EtOAc = 2: 1) to afford (S)-methyl 2-(tert—butoxycarbonylamino)-3 -(2- methoxypyridinyl)propanoate (2.4 g, 73% yield).

TFA (5 mL) was added to a solution of (S)-methyl 2-(tert—butoxycarbonylamino)— 3-(2-methoxypyridinyl)propanoate (2.4 g, 7.7 mmol) in CH2C12 (10 mL) at 0 °C with ng. The e was stirred for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (10 mL for each portion) to remove residual TFA to afford crude (S)-methyl 2-amino(2-methoxypyridinyl)propanoate as its TFA salt.

The crude (S)-methyl 2-amino(2-methoxypyridinyl)propanoate (TFA salt, 7.7 mmol) was dissolved in DMF (10 mL). (S)—2—(2-morpholinoacetamido)propanoic acid (1.7 g, 7.7 mmol), HATU (4.40 g, 11.6 mmol) and DIPEA (1 mL) were added at 0 CC with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (30 mLX3) and the combined organic phases were washed with brine (50 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CHgClz/MeOH = 20: 1) to afford (S)-methyl 3-(2—methoxypyridin—4-yl)-2—((S)(2- morpholinoacetamido)propanamido)propanoate (1.5 g, 48% . thy13-(2-methoxypyridinyl)—2-((S)—2-(2- morpholinoacetamido)propanamido)propanoate (800 mg, 2.00 mmol) was treated with a solution of lithium hydroxide-H20 (329 mg, 7.80 mmol) in water/THF (10 mL/10 mL) for 30 min. THF was removed and the aqueous phase was acidified to pH=3 -4 with 1N s HCl. The resulting e was trated to dryness to afford the corresponding acid, which was used ly without fiarther purification.

The acid was dissolved in DMF (20 mL) and compound (S)—2-amino (cyclopent-l-en-l-yl)—1—((R)-2—methyloxiran-2—yl)propan-l-one (2.00 mmol), HATU (1.12 g, 2.90 mmol) and DIPEA (1 mL) were added at 0 0C with stirring. The reaction mixture was d to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (30 mL><3) and the combined organic phases were washed with brine (50 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CHZClz/EtOAc/MeOH = 20: 10: 1) to afford (S)—N-((S)—3- (cyclopent- l -en-l -yl)-l -((R)-2—methyloxiran-2—yl)- l -oxopropanyl)—3—(2-methoxypyridin- 4-yl)—2-((S)—2-(2-morpholinoacetamido)propanamido)propanamide (330 mg, 29% yield over two steps). 1H NMR (300 MHZ, DMSO-d6): 8 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), .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). MS (EI) for C29H41N507, found 572.2 (MH)+.

] The following compounds were synthesized in a similar manner: (S)—N-((S)-3 —cyclopentyl((R)methyloxiranyl)—1-oxopropan-2—yl)—3-(1H— indoly1)((S)(2-morpholinoacetamido)propanan1ido)propanamide (C-1123): 1H NMR (300 MHz, DMSO-dg): 5 10.96 (br s, 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 (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). MS (EI) for C31H43N506, found 582.4 (MH)+.

(S)—N-((S)—3 —cyclopentyl-1—((R)methyloxiranyl)—1-oxopropan-2—yl)(1H- indol—6-y1)((S)(2-morpholinoacetamido)propanan1ido)propanamide 4): 1H NMR (300 MHZ, DMSO-dg): 5 10.97 (br s, 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 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). LC- MS for C31H43N506, found 582.4 (MH)+.

(S)—N-((S)-3 —cyclopentyl((R)methyloxiranyl)—1-oxopropan-2—yl)—3 -(2— fluoron1ethoxyphenyl)((S)—2-(2-morpholinoacetamido)propanamido)propanamide (C- 1008): 1H NMR (300 MHz, DMSO-d6): 5 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 (n1,1H), 6.61 (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), .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). MS (EI) for C30H43FN4O7, found 591.3 (MH)+.

(S)—3 -(benzofuran-5—yl)-N-((S)—3 -cyclopentyl((R)—2-n1ethyloxiran—2-yl) oxopropan-Z-yl)((S)(2-morpholinoacetamido)propanamido)propanamide 7): 1H NMR (300 MHz, DMSO-ds): 8 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), 7.40-7.50 (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). MS (EI) for C31H42N4O7, found 583.3 (MH)+.

(S)-3 -(benzo[d][1 ,3]di0X01—5 -y1)-N-((S)-3 -cyc10penty1—1 -((R)rnethy10xiran y1)-1 -0xopropanyl)((S)(2-rnorpholinoacetamid0)propanamido)propanamide (C- 1012): 1H NMR (300 MHz, DMSO-dg): 8 8.30 (d, J: 7.2 Hz, 1H), 8.02 (d, J: 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). MS (EI) for C30H42N4Og, found 587.6 (MHY.

((S)-3 -cyc10penty1— 1 -((R)methy10xiranyl)— 1 -ox0pr0pany1)—3 -(1H- indol—3—y1)((S)(2—morpholinoacetamido)propanamido)pr0panamide (C-1014): 1H NMR (300 MHz, DMSO-d6): 8 10.84 (br s, 1H), 8.30 (d, J: 7.2 Hz, 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). MS (EI) for C31H43N506, found 582.3 (MH)+.

(S)-3 -(benzofurany1)-N-((S)—3 -cyc10penty1— 1 2-rnethy10xiran—2-y1) oxopropan-Z-y1)((S)—2-(2-morpholinoacetamido)propanamido)propanamide (C-1015): 1H NMR (300 MHz, 6): 8 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 (m, 2H), 1.26 (d, J= 6.6 Hz, 3H). MS (EI) for C31H42N4O7, found 583.5 (MH)+.

(S)-N-((S)—3 -cyc10penty1— 1 —((R)methy10xiranyl)— 1 -0X0propany1)((.S') (2-morph01inoacetamido)propanamido)—3-(4-(trifluoromethoxy)phenyl)propanamide (C- -1H NMR (300 MHz, DMSO-d6): 5 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), .01 (m, 11H), 1.41 (s, 3H), 1.13 (d, J= 6.9 Hz, 3H). MS (EI) for C30H41F3N4O7, found 627.3 (MH)+.

(S)-N-((S)—3 -cyc10penty1—1—((R)methy10xiranyl)—1-0x0propany1)—2-((S)—2- (2-rn0rpholinoacetarnido)propanamid0)—3-(2-oxoindolin—5-y1)pr0panamide (C-1081): 1H NMR (300 MHZ, DMSO-d6): 8 10.31 (s, 1H), 8.32 (d, J: 7.2 Hz, 1H), 8.06 (d, J: 8.4 Hz, 1H), 7.75 (d, J: 7.8 Hz, 1H), .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), .95 (m, 7H), 1.40 (s, 3H), 1.26 (d, J: 6.6 Hz, 3H). MS (EI) for C31H43N507, found 596.3 (MH)'. [0026 1] (S)-N-((S)—3 -cyc10penty1—1—((R)methy10xiranyl)—1-0x0propany1)—2-((S)—2- (2-rn0rph0linoacetarnido)propanarnido)—3 -(2-ox0-1 ,2,3 rahydroquin01in yl)pr0panarnide (C-1086): 1H NMR (300 MHZ, DMSO-d6): 5 10.02 (s, 1H), 8.32 (d, J: 7.2 HZ, 1H), 8.03 (d, J: 8.4 HZ, 1H), 7.75 (d, J: 7.8 HZ, 1H), .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), .95 (m, 7H), 1.40 (S, 3H), 1.26 (d, J: 6.6 HZ, 3H). MS (EI) for C32H45N507, found 612.7 (MH)+.

] (S)-N-((S)—3 -cyc10penty1— 1 —((R)methy10xiranyl)— 1 -ox0propan—2-y1)—3 -(1 ,1- dioxido-3 ,4-dihydr0-2H-benzo[e][1,2]thiaZin-6—y1)((S)(2- morpholinoacetamid0)propanamido)pr0panamide (C-1091): 1H NMR (300 MHZ, DMSO-d6): 8 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, 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). MS (EI) for C31H45N5088, found 648.52 (MH)+.

(S)—N-((S)-3 -(cyc10pent-1 -eny1)((R)methy10xirany1)-1 -oxopr0pan—2- y1)-3 —(1-rnethy1—6-ox0-1,6-dihydr0pyridin-3 -y1)((S)—2-(2- morpholinoacetamido)propanamido)pr0panarnide (C-1147): 1H NMR (300 MHZ, DMSO-dé): 8 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, 7H), 2.23 (m, 5H), 1.79 (m, 2H), 1.38 (s, 3H), 1.16 (d, J: 6.9 HZ, 3H), 0.84 (m, 2H). MS (EI) for C29H41N507, 572.3 (MH)+.

(S)-N-((S)—3 -(cyc10pant-1 —eny1)((R)methy10xiran-2—yl)-1 -0x0pr0pan—2- y1)-3 -(6-methoxypyridiny1)—2-((S)—2—(2-rn0rpho1in0acetarnido)propanamido)propanamide (C-1140): 1H NMR (300 MHZ, DMSO-d6): 5 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), .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 (s, 3H), 1.14 (d, J: 6.9 Hz, 3H). MS (EI) for C29H41N507, found 572.3 (MH)+.

(S)-N-((S)—3 -(cyclopant-1 —eny1)((R)methy10xiran-2—y1)-1 -0x0pr0pan—2- y1)-3 -(1-rnethy1—2-0X0—1,2-dihydr0pyridiny1)((S)(2- morpholinoacetamido)propanamido)propanamide (C-1137): 1H NMR (300 MHz, 6): 8.35 (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 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). MS (EI) for C29H41N507, found 571.9 (MH)+.

(S)—N-((S)-3 -(cyclopent-1 -eny1)((R)methyloxirany1)-1 -oxopr0pan—2- y1)-3 —(4-ethy1hydroxypheny1)((S)—2-(2- morpholinoacetamid0)propanamido)propanarnide (C-1136): 1H NMR (300 MHZ, DMSO-d6): 8 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: 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). MS (EI) for C31H44N4O7, found 584.9 (MH)+.

(S)-N-((S)—3 -(cyclopent-1 —eny1)((R)methy10xiran-2—y1)-1 opan—2- y1)-3 -(4-hydr0xyrnethy1pheny1)((S)(2- morpholinoacetamido)propanamido)propanamide (C-1131): 1H NMR (300 MHz, DMSO-d6): 8 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: 8.1Hz, 1H), 5.39 (s, 1H), 4.35 (m, 1H), 4.28 (m, 1H), 4.06 (m, 1H), 3.55 (m, 4H), 3.18 (d, J: 5.1Hz, 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). MS (EI) for C30H42N407, found 570.8 (MHY.

] (S)—N-((S)-3 penty1— 1 -((R)rnethy10xiranyl)— 1 -ox0pr0pan-2—y1)—3 -(3- hydroxyphenyl)((S)(2-m0rpholinoacetamido)propanamido)propanamide (C-1 1 14): 1H NMR (300 MHz, DMSO-d6): 5 9.21 (s, 1H), 8.30 (d, J: 7.2 Hz, 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). MS (EI) for C29H42N4O7, found 559.2 (MH)+.

(S)—N-((S)-3 -cyclopenty1((R)methyloxiranyl)0X0propany1)-3 -(4- ypheny1)((S)(2-morpholinoacetamido)propanamido)propanamide (C-1 1 13): 1H NMR (300 MHz, DMSO-d6): 8 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 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). MS (EI) for C29H42N4O7, found 559.2 (MH)+.

(S)-N-((S)-3 -cyc10penty1—1-((R)methy10xiranyl)—1-0X0propany1)((.S') (2-morpholinoacetamido)propanamido)—3 o—3 ,4-dihydro-2H—benzo[e][1,3]oxazin-6— y1)pr0panarnide (C-1108): 1H NMR (300 MHz, DMSO-d6): 5 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 (d, J: 6.3 Hz, 3H). MS (EI) for C31H43N508, found 636.0 [M+Na]+.

(S)-3 -(1H-benz0[d]imidazol-5 -y1)-N-((S)-3 -cyclopenty1—1-((R)methyloxiran y1)-1 —oxopropanyl)—2—((S)-2—(2-morpholinoacetamido)propanamido)propanamide (C- 1069): 1H NMR (300 MHz, DMSO-d6): 5 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). MS (EI) for C30H42N6O6, found 583.4 (MH)+.

(S)-N-((S)—3 -cyclopenty1—1—((R)methyloxiranyl)0x0propany1)—3-(1H- indazoly1)-2—((S)-2—(2-rn0rph0linoacetamido)propanamid0)pr0panamide (C-1070): 1H NMR (300 MHz, 6): 8 12.94 (s, 1H), 8.35 (m, 1H), 8.10 (d, 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). MS (EI) for C30H42N606, found 583.4 (MH)+. (1r,4R)-N—((R)(((S)(1H-benzo[d]imidazoly1)(((S)—3-cyclopenty1—1— ((R)—2-methy10xiranyl)0xopr0panyl)amino)0X0pr0panyl)amino)- 1 opan- 2-y1)hydr0xycyclohexanecarboxamide (C-1105): 1H NMR (300 MHZ, CDC13): 5 12.47 (br s, 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- 2014/026987 3.27 (m, 6H), 0.91—2.03 (m, 19H), 1.41 (s, 3H), 0.87 (d, .1: 6.9 Hz, 3H). MS (EI) for C31H43N506, 582.22 (MH)+.

)-N—((R)(((S)-3 -(4—cyanopheny1)-1—(((S)-3 -cyclopenty1—1-((R)—2- methyloxirany1)-1 -0X0propany1)amino)0X0propanyl)amino)- 1 opan-2—y1) hydroxycyclohexanecarboxamide 3): 1H NMR (300 MHz, DMSO'd6): 5 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 (m, 4H), 1.37 (s, 3H), 1.33 (m, 3H), 1.25 (m, 4H), 0.91 (d, J = 6.9 Hz, 3H). MS (EI) for C31H42N4O6, found 567.3 (MH)+.

(S)-N-((S)—3 -cyc10penty1— 1 —((R)methy10xiranyl)— 1 -ox0propan—2-y1)—3 -(2,2- d10xid0-3 ydro-1H-benzo[c][1,2]thiazin-6—y1)((S)—2-(2- morpholinoacetamido)propanamido)propanamide (C-1102): 1H NMR (300 MHz, DMSO-d6): 8 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). MS (EI) for C31H45N508S, found 648.5 (MH)+.

N-((S)-3 penty1—1 -((R)—2-rnethy10xiran—2-y1)—1-0x0propany1)—2-((S)(2- morpholinoacetamido)propanam1do)—3-(2-0x0-2,4-dihydr0- 1 H-benzo [d] [ 1 ,3]oxazin y1)pr0panarnide(C-1101): 1H NMR (300 MHz, DMSO—d6): 5 10.14 (br S, 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: 8.1Hz, 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). MS (EI) for C31H43N508, found 614.8 (MH)+.

(S)—3 -(benzo[d][1,3]d10x01-5 -y1)-N-((S)-3 -cyc10penty1—1 -((R)-oxirany1) oxopropany1)((S)(2-morph011noacetamido)propanamid0)propanamide (C-1060): 1H NMR (300 MHz, CDC13): 8 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, 2 H), 4.57-4.42 (m, 3H), 3.79 (s, 3H), 3.51 (m, 1H), 3.13 (m, 2 H), 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). MS (EI) for C29H40N4Og, found 5734 (MH+).

(S)-N-((S)-3 -cyclopentyl((R)rnethyloxiranyl)oxopropany1)-3 -(3- hydroxymethoxyphenyl)((S)(2-morpholinoacetamido)propanamido)propanamide (C-1018): 1H NMR (300 MHz, 6): 8 8.73 (s, 1H), 8.26 (d, J: 7.2 Hz, 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 (d, J: 6.6 Hz, 3H). MS (EI) for C30H44N4Og, found 589.7 (MH+).

Example 9 (S)-N—((S)—3-((1R,3r,5 S)—Bicyclo[3. l .0]hexan-3 -yl)— l -((R)—2—methyloxiranyl)- 1-oxopropanyl)(4-methoxyphenyl)((S)(2- morpholinoacetamido)propanamido)propanamide (C-1095): 1. TFA OMks 2. HATU ..O”? O/fi O o \‘ O RNQLNJYNJNW BocHN MJWVNE/KOHo o H i H H o o = @0Me o : OMe TFA (5 mL) was added to solution of tert—butyl ((R)—3-((1R,3r,5 S)- bicyclo[3. 1 .0]hexanyl)((R)methyloxiranyl)—l-oxopropanyl)carbamate (3 10 mg, 1.1 mmol) in CH2C12 (16 mL) at 0 CC with stirring. The e was d for 1 h and concentrated to dryness. The residue was azeotroped three times with EtOAc (5 mL for each portion) to remove residual TFA to afford (S)amino((1R,3r,5S)—bicyclo[3.1.0]hexan yl)—1-((R)methyloxiranyl)propanone (quantitative) as its TFA salt.

(S)Amino-3 -((1R,3r,5 S)-bicyclo[3 . 1 .0]hexanyl)((R)—2-methyloxiran yl)propan-l-one (TFA salt) was dissolved in DMF (20 mL) and (4—methoxyphenyl) ((S)(2-morpholinoacetamido)propanamido)propanoic acid (670 mg, 1.70 mmol), HATU (710 mg, 1.80 mmol) and DIPEA (1.48 mL) were added at 0 °C with stirring. The reaction mixture was allowed to warm to ambient temperature and d for 3 h. EtOAc (100 mL) and water (100 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (50 mLX3). The combined organics were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The e was purified by flash column chromatography on silica gel (CH2Clz/EtOAC/MCOH = 20: 10:0. 1) to afford (S)- N-((S)-3 -((1R,3r,5 S)-bicyclo [3. 1 .0]hexan-3 -yl)((R)methyloxiranyl)oxopropan yl)-3 -(4-methoxyphenyl)((S)—2-(2-morpholinoacetamido)propanamido)propanamide (350 mg, 54% yield). 1H NMR (300 MHz, DMSO—dg): 5 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). MS (E1) for C31H44N4O7, found 585.1 (MH)+.

The following compounds were sized in a similar manner: (S)—N-((S)((1R,3s,5 S)—bicyclo[3 .1 .0]hexanyl)-1 -((R)methyloxiranyl) oxopropan-2—yl)(4—methoxypheny1)—2-((S)—2-(2- morpholinoacetamido)propanamido)propanamide (C-1094): 1H NMR (300 MHZ, DMSO-d6): 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), .40 (m, 2H), 3.71 (s, 3H), 3.56 (m, 4H), 3.15 (m, 1H), 3.05 (m, 1H), .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). LC—MS for C31H44N4O7, found 585.1 (MH)+.

(S)-N-((S)—3 -((1r,4S)hydroxycyclohexy1)-1 -((R)methyloxiran—2-yl) oxopropanyl)(4-methoxyphenyl)—2-((S)-2—(2- linoacetamido)propanamido)propanamide (C-1002): 1H NMR (400 MHz, CDC13) 8 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: 8.0 Hz, 1H), 4.54 (q, .1: 7.2, 7.1, 7.1 Hz, 2H), 4.41 (p, .1: 7.6, 7.6, 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, .1: 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). MS (EI) for N4Og, found 603.4 (MH+).

(S)-N-((S)—3 -((1s,4R)hydroxycyclohexy1)—1-((R)—2-methyloxiran—2-yl)-1 - oxopropanyl)(4-methoxyphenyl)—2-((S)-2—(2- morpholinoacetamido)propanamido)propanamide (C-1001): 1H NMR (400 MHz, CDC13) 8 7.43 (d, J: 7.5 Hz, 1H), 7.10 (d, J: 8.6 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, .1: 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). MS (EI) for C31H46N4Og, found 603.4 (MH+).

(S)—N-((S)-3 -cyc10pr0py1((R)methy10xiranyl)ox0propan-2—y1)-3 -(4- methoxypheny1)((S)(2-morpholinoacetamido)pr0panarnido)propanamide (C-1006): 1H NMR (400 MHz, CDC13) 5 7.43 (d, J: 7.7 Hz, 1H), 7.13 (d, J: 8.5 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), 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).MS (E1) for C28H40N4O7, 545.0 found (MHY.

(S)-N-((S)—3 -cyc10penty1— 1 —((R)methy10xiranyl)— 1 -ox0propan—2-y1)—3 -(4- methoxypheny1)((S)(2-m0rph01in0acetamido)propanarnid0)propanamide (C-1005): 1H NMR (400 MHz, CDC13) 8 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), 1.77-1.43 (m, 12H), 1.36 (d, J: 7.1 Hz, 3H), 1.11 (s, 1H), 0.96 (s, 1H).MS (EI) for C30H44N4O7, found 571.3 (MH)'.

(S)-N-((S)—3 -cyclobuty1—1 2-methy10xirany1)—1-0X0pr0pany1)-3 -(4- ypheny1)((S)(2-m0rph01in0acetamido)propanarnido)propanamide (C—1004): 1H NMR (400 MHz, CDC13 ) 5 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 (q, 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 (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). MS (EI) for N4O7, found 559.1(MH)+.

(S)—3 -(4-rneth0xypheny1)-N—((S)((R)rnethy10xirany1)-1 -0X0-3 -((S)- tetrahydromranyl)propany1)((S)(2- morpholinoacetamido)propanamido)pr0panarnide (C-1016): 1H NMR (300 MHZ, CDC13): 5 7.42 (m, 1H), 7.17 (d, J: 8.7 Hz, 2H), 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). MS WO 52134 (E1) for C29H42N4Og, found 575.5 (MH)+.

(S)-3 -(4-methoxypheny1)-N-((S)((R)methy10xirany1)-1 -0X0—3-((R)- tetrahydrofidrany1)propan-2—y1)((S)(2- morpholinoacetamido)propanamido)pr0panamide (C-1017): 1H NMR (300 MHz, CDC13): 5 7.42 (m, 1H), 7.15 (m, 3H), 6.82 (d, J: 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). MS (EI) for C29H42N4Og, found 575.7 (MH)+. [0029 l] (S)-N-((S)—3 -(cycloheX-1—eny1)—1-((R)—2-rnethy10xiran-2—y1)oxopropan y1)-3 -(4-rnethoxypheny1)((S)(2-morph01inoacetamido)propanamido)propanamide (C- 1019): 1H NMR (300 MHz, DMSO-d6): 5 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). MS (EI) for C31H44N4O7, found 585.4 (MH)+.

(S)-N-((S)—3 -(3,6—dihydro—2H-pyranyl)((R)—2-rnethyloxiran-2—yl) oxopropany1)(4-methoxypheny1)—2-((S)(2- morpholinoacetamido)propanamido)pr0panamide (C-1020): 1H NMR (300 MHz, CDC13): 5 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). MS (EI) for N4Og, found 587.7 (MH)+.

((S)-3 -((S)-3 ,3 -difluorocyclopentyl)((R)methy10xiranyl) oxopropany1)(4-methoxypheny1)—2-((S)(2- morpholinoacetamido)propanamido)propanamide (C-1033): 1H NMR (300 MHz, CDC13): 5 7.47 (d, J: 7.5 Hz, 1H), 7.10 (d, J: 8.4 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), .38 (m, 9H), 1.52 (s, 3H), 1.36 (d, J = 5.7 Hz, 3H). MS (EI) for C30H42F2N4O7, found 609.4 (MH)+.

(S)—N—((S)-3—((R)-3,3—diflu0rocyclopentyl)-1 —((R)methyloxirany1)— 1 - oxopropany1)(4-methoxypheny1)—2-((S)(2- morpholinoacetamido)propanamido)propanamide 4): 1H NMR (300 MHz, CDC13): 5 2014/026987 7.45 (d, .1: 7.2 Hz, 1H), 7.10 (d, .1: 8.4 Hz, 2H), 6.81 (d, .1: 8.7 Hz, 2H), 6.69 (d, .1: 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, .1: 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). MS (EI) for C30H42F2N4O7, found 609.4 (MH)+.

] (ZS)(4-methoxypheny1)-N-((2S)(1-rnethy1—2-ox0pyrrolidiny1)((R)—2- oxirany1)-1 -0Xopropany1)—2-((S)(2-morph011noacetarnido) propanamid0)propanamide (C-1040): 1H NMR (300 MHZ, CDC13)2 8 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 (m, 1H), 4.13 (m, 1H), 3.76 (s, 3H), .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). MS (EI) for C30H43N508, found 603.0 (MH)+.

(ZS)(4-methoxypheny1)-N-((2S)((R)-2—methyloxiran-2—y1)0x0(5- oxopyrrolidiny1)propany1)((S)—2-(2-m0rpholinoacetamido) propanamido)propanamide (C—1035): 1H NMR (300 MHZ, CDC13): 5 8.07 (d, J = 8.1 HZ, 1H), 7.56 (d, J: 8.1HZ, 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). MS (EI) for C29H41N508, found 588.6 (MH)+. (1r,3R)-N—((R)(((S)(((S)—3 -cyclopenty1—1 -((R)rnethy10xirany1)— 1 - oxopropan-Z—yl)amino)-3 -(4-methoxyphenyl)ox0propanyl)amino)— 1 -0xopropany1)- 3-hydroxycyclobutanecarboxamide (C—1041): 1H NMR (300 MHZ, DMSO-d6): 5 7.11 (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), 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). MS (EI) for C29H41N307, found 544.3 (MH)+.

(S)—3 -(4-rneth0xypheny1)-N—((S)((R)rnethy10xirany1)—1 -0X0-3 -(2- oxopyrrolidin-l -y1)propany1)((S)(2-m0rpholinoacetamido) propanamido)propanamide (C—1042): 1H NMR (300 MHZ, DMSO-dg): 5 7.65 (m, 1H), 7.30- 7.60 (m, 2H), .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, 4H), 2.30—2.60 (m, 6H), 1.80- 2.10 (m, 3H), 1.39 (s, 3H), .30 (m, 3H). MS (E1) for C29H41N508, found 588.4 (MH)+.

). MS (E1) for C29H41N508, found 588.4(MH)+.

(S)—3 -(4-rneth0xypheny1)-N—((S)-3 -(2-rnethy1cyclopenten-1 -y1)((R) methyloxirany1)-1 -0Xopropany1)—2-((S)(2-rnorpholinoacetarnido) propanamid0)propanamide (C—1044): 1H NMR (300 MHZ, I 5 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), 3.56 (br s, 4H), 3.18 (d, J: .1 HZ, 1H), 2.82-2.98 (m, 4H), 2.64-2.67 (m, 1H), 2.35-2.45 (m, 5H), 2.13-2.26 (m, 5H), 1.71 (t, J: 7.2 HZ, 1H), 1.57 (S, 3H), 1.39 (s, 3H), 1.16 (d, J: 6.9 HZ, 3H). MS (EI) for C31H44N4O7, found 585.4 (MH)+. (1r,4R)-N—((R)(((S)(((S)—3 -(3 ,3-difluorocyc10buty1)-1 -((R)methy10xiran y1)-1 -ox0propany1)amino)(4-rnethoxypheny1)0xopropany1)amino)—1—0X0propan- 2-y1)—4-hydroxycyclohexanecarboxamide (C-1073): 1H NMR (400 MHZ, CDC13) 5 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, 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: 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, 5H), 1.41 (s, 2H), 1.14 — 1.00 (m, 2H), 0.95 (d, J: 7.1 HZ, 2H). MS (E1) for F2N307, found 594.0 (MH)+. [0030 l] (1r,4R)-N—((R)(((S)(((S)—3 -(cyclopent—1-eny1)((R)rnethy10xiran y1)-1 -0xopropany1)amino)-3—(3-hydr0xymethoxypheny1)-1 -oxopropany1)arnino)— 1 - 0x0propany1)hydroxycyclohexanecarboxamide (C-1065): 1H NMR (300 MHZ, DMSO- d6): 8 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= 8.1HZ, 1H), 6.62 (m, 1H), 6.55 (d, J: 8.1HZ, 1H), 5.40 (br s, 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 HZ, 3H). MS (E1) for C31H43N308, found 586.3 (MH)+.

(S)-N-((S)—3 -(cyc10pent-3 -eny1)((R)-2—methy10xiran-2—y1)-1 -ox0propan—2- y1)-3 thoxypheny1)((S)—2-(2-m0rpholin0acetamido)propanamido)propanamide (C- 1066): 1H NMR (300 MHZ, DMSO-d6): 8 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 2014/026987 (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), 2.65 (m, 1H), 2.35 (m, 4H), .10 (m, 2H), 1.60 (m, 1H), 1.50 (m, 1H), 1.42 (s, 3H), 1.14 (d, J: 6.9 HZ, 3H). MS (EI) for C30H42N4O7, found 571.64 (MH)+. MS (EI) for C30H42N4O7, found 571.3 (MH)+, (1r,4R)-N-((R)(((S)(((S)—3-(cyclohex-1—enyl)—1-((R)—2-rnethy10xiran—2- y1)-1 -0X0propany1)amino)(4-rnethoxypheny1)0xopr0pany1)amino)oxopropan- 2-y1)—4—hydroxycyclohexanecarboxamide (C-l089): 1H NMR (300 MHZ, DMSO—dg): 5 8.26 (m, 1H), 7.79 (d, J: 6.9 HZ, 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 (111,2H), 3.25 (111,2H), 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). MS (EI) for C32H45N307, found 584.4 (MH)+, (1r,4R)-N-((R)(((5)(((S)-3 -cyclobuty1—1-((R)methy10xirany1) oxopropan-Z-y1)arnino)—3 -(4-meth0xypheny1)-1 —0x0pr0panyl)amino)— 1 0pan-2—y1)- 4-hydroxycyclohexanecarboxamide (C-1090): 1H NMR (300 MHZ, CDClg): 5 7.11 (d, J = 8.4 HZ, 2H), 6.82 (d, J: 9.0 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, 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). MS (EI) for C30H43N307, found 558.3 (MH)+.

(S)-N-((S)((1R,SS,6S)-bicyclo[3.1 .0]hexany1)((R)methy10xiran-2—y1) 0x0propany1)(4-meth0xypheny1)—2-((S)-2—(2-rnorpholinoacetarnido) propanamido)propanamide (C-1143): 1H NMR (300 MHZ, DMSO-d6): 8 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 (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). MS (EI) for C31H44N4O7, found 585.43 (MH)+.

] (S)-N-((S)—3 -(3 ,3 -difluorocyclobutyl)((R)—2-methy10xiran—2-y1)—1—0x0propan- 2-y1)—3-(4-methoxypheny1)-2—((S)(2-m0rph011noacetamido)propanamido)propanamide (C- 1093): 1H NMR (400 MHZ, CDC13) 8 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 WO 52134 (pd, .1: 6.6, 6.6, 6.6, 6.6, 3.9 Hz, 2H), 3.22 (d, J: 5.3 Hz, 1H), 3.14 (qd, .1: 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, .3 Hz, 1H), 2.42 (dd, .1: 14.1, 4.7 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). MS (EI) for C29H40F2N4O7, found 585.43 (MH)+.

(S)—3 -(4-methoxypheny1)—N—((S)((R)methy10xiranyl)— 1 -0x0—3 -((R)- tetrahydrofidrany1)propany1)((S)(2-morpholinoacetamido )propanamido)propanamide 6): 1H NMR (300 MHZ, DMSO-ds): 5 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, 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). MS (EI) for C29H42N4Og, found 575.5 (MH)+.

(S)-N-((S)—3-((1R,5S,6r)-bicyc10[3. 1 .0]hexany1)—1-((R)methy10x1rany1)- 1-0x0propan-2—y1)(4—meth0xypheny1)((S)—2-(2-morpholin0acetamido) propanamido)propanamide (C-1142): 1H NMR (300 MHZ, CDC13): 5 7.65 (br s, 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: 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). MS (EI) for N4O7, found 585.3 (MH)+.

(S)—3 -(4-rneth0xypheny1)-N—((S)((R)rnethy10xirany1)—1 -0X0-3 —((S)- tetrahydrofidrany1)propany1)((S)(2-morpholinoacetamido)propanamido) propanamide (C-1025): 1H NMR (300 MHZ, DMSO-ds): 5 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), .70 (m, 1H), 1.42 (s, 3H), 1.16 (d, J= 6.9 HZ, 3H). MS (EI) for C29H42N40g, found 575.4 (MH)+. [003 1 0] (2S)—3-(4-meth0xypheny1)—N-((2S)—3 -(3-methylcyclopent-1—eny1)((R) methyloxiran—Z-y1)-1 -0xopropany1)—2-((S)-2—(2-rn0rph011noacetamido) propanamido)propanamide (C-1122): 1H NMR (300 MHZ, DMSO-d6): 8 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 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, .1: 6.9 Hz, 3H), 0.39 (m, 3H). MS (EI) for C31H44N4O7, found 585.2 (MH)+. [003 1 1] (S)-N-((S)—3 -cyc10hexy1— 1 2-methyloxirany1)-1 -ox0propan-2—y1)-3 -(4- methoxyphenyl)((S)—2-(2-m0rpholin0acetamido)propanarnido)propanamide (C-1003): 1H NMR (400 MHz, CDC13) 5 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). MS (EI) for C31H46N4O7, found 587.4 (M+). [003 1 2] (S)-N-((S)—3 -cyc10penty1—1—((R)-oxirany1)—1-0x0propany1)-3 -(4- methoxyphenyl)((S)(2-m0rpholin0acetamido)propanarnid0)propanamide (C-1030): 1H NMR (300 MHZ, CD03) 5 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), .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 (m, 3H), 0.85-1.16 (m, 3H). MS (EI) for C29H42N4O7, found 559.8 (MH+). [003 13] (S)-N-((S)—3 -(cyclopent-1 -eny1)((R)-oxiranyl)0xopropany1)-3 -(4- methoxyphenyl)((S)(2-m0rpholin0acetamido)propanarnido)propanamide (C-1038): 1H NMR (300 MHZ, CDC13)2 5 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), 2.58 (m, 4H), .19 (m, 5H), 1.87 (m, 2H), 1.37 (d, J: 8.4 Hz, 3H). MS (EI) for C29H40N4O7, found 557.3 (MH+).

Example 10 (S)—3 -Cyan0-N—((S)—1-(((S)—3 -(cyclopenteny1)-1—((R)-2—methyloxiran-2—y1)- 1-0x0propan—2-yl)amino)(4-methoxyphenyl)0xopropany1)(2- morpholinoacetamido)propanamide (C— 1 135): HZNQkN o CN Um BocHN/gf EJLN r = H o o BocHN COOH HATU,D|EA,DMF UOMe 1. TFA, DCM mi #Hi 0 2_ o/fi o M i M O O N \JLOH HATU, DIEA, Sequentially HATU (1.21 g, 3.20 mmol) and DIEA (1.35 mL, 7.8 mmol) were added to a 0 OC solution of (S)(tert—butoxycarbonylamino)—3-cyanopropanoic acid and (S)- o-N-((S)—3-(cyclopent- 1 —enyl)— 1 -((R)—2-methyloxiran—2-yl)-1 -oxopropanyl)—3 -(4- yphenyl)propanamide (TFA salt, 2.1 mmol) in DMF (20 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The s layer was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/ hexane = 1:2) to afford tert-butyl —cyano(((S)-1—(((S)(cyclopent-l-en— 1 -yl)-l -((R)-2—methyl oxiranyl)oxopropanyl)amino)(4-methoxyphenyl) oxopropanyl) -l-oxopropan—2-yl)carbamate (590 mg, 45% yield).

To a solution of tert—butyl ((S)cyano(((S)-l-(((S)—3 -(cyclopent-1—eny1)—1- ((R)methyl oxiranyl)— 1 -oxopropanyl)amino)(4-methoxyphenyl)oxopropan yl) amino)oxopropan—2-yl)carbamate (0.59 g, 1.0 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred for 15 min at ambient temperature then concentrated to dryness to afford (S)aminocyano-N-((S)-l -(((S)(cyclopent-l -enyl)- l -((R) methyloxiranyl)-l -oxopropanyl)amino)(4-methoxyphenyl)— 1 -oxopropan yl)propanamide (650 mg, quant.) as its TFA salt, which was used directly t further purification.

Sequentially HATU (0.61 g, 1.6 mmol) and DIEA (1.35 mL, 7.8 mmol) were added to a 0 °C solution of (S)—2-aminocyano-N-((S)—1-(((S)—3-(cyclopentenyl) ((R)—2-methyloxiranyl)oxopropanyl)amino)—3—(4-methoxyphenyl)— 1 -oxopropan yl)propanamide (1 mmol) and 2-morpholinoacetic acid (160 mg, 1.10 mmol) in DMF (20 mL) with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and trated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1 :2) to afford cyano-N-((S)—1-(((S)(cyclopentenyl)((R) oxiranyl)-l -oxopropanyl)amino)(4-methoxyphenyl)—1-oxopropanyl)(2- morpholinoacetamido)propanamide (210 mg, 35% . 1H NMR (300 MHz, DMSO—d6): 5 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). MS(EI) for C31H41N507, found 596.3 (MH)+.

The following compounds were synthesized in a similar manner: N-((R)— l -(((S)- l -3 opent-l-enyl)((R)methyloxiran—2-yl)-1— oxopropan-2—yl)amino)-3 -(4-methoxyphenyl)oxopropanyl)amino)— l -oxopropanyl)- 2-oxaspiro[3.3]heptanecarboxamide (C-1063): 1H NMR (400 MHZ, CDCl3) 8 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, 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 — 2.11 (m, 4H), 1.90 — 1.70 (m, 2H), 1.38 (s, 3H), 0.92 (d, J= 7.1 Hz, 3H). MS(EI) for C31H41N307 , found 568.0 (MH)+.

N-((S)— l -(((S)—3 -(cyclopent—1-en-1—yl)((R)methyloxiranyl)—1-oxopropan- 2-yl)amino)-3—(4-methoxyphenyl)oxopropan—2-yl)—3 ,3 ,3 -trifluoro(2- morpholinoacetamido)propanamide (C-1134): 1H NMR (300 MHZ, DMSO-d6): 8 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- WO 52134 .50 (m, 2H), 4.40-4.60 (rn, 2H), 3.70 (s, 3H), 3.60 (111, 4H), 3.18 (111, 1H), 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). MS (EI) for C30H39F3N4O7, found 625.8 (MH)+. [0032 1] (R)-N-((S)—1-(((S)—3-(cyc10penteny1)—1-((R)-2—methyloxirany1) oxopropan-Z-yl)arnino)-3 -(4-meth0xypheny1)-1 0pany1)-3 ,3 ,3 -triflu0r0—2-(2- morpholinoacetamid0)propanarnide (C-1132): 1H NMR (300 MHZ, DMSO-d6): 8 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- .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), .50 (m, 5H), 2.10—2.30 (m, 4H), 2.00 (m, 1H), 1.70—1.90 (m, 2H), 1.38 (s, 3H). LC-MS for C30H39F3N4O7, found 625.7 (MH)+.

Example 11 (S)—N—((S)—3 —(Cyclopenter1y1)—1—((R)-2—methyloxiran-2—yl)—1-0xopropan—2- y1)-3 —(4-rneth0xypheny1)((S)(2-rnorpholinoacetarnido)pr0panamido)propanarnide (C- 1 009): 0 Hi 1. HCI H2N\_)J\OBn Boc—L-AIa-OH N 2. 2-morpholinoacetic acid BocHN OBn HATU, DIEA, DMF i HBTU, DIEA, DMF o —, I) / o/ O OprNJYHgtOBnO O OON O O H910, O _ \ THF : OMe TFA H2N 0 oQQLNJWVHdeo o HATU, DIEA, DMF —> H i H O ' O Sequentially HATU (19.3 g, 51.0 mmol) and DIEA (29.6 mL, 170 mmol) were added to a 0 °C solution of Boc-L-alanine (7.70 g, 40.7 mmol) and LMeO-phenylalanine benzyl ester p-toluenesulfonate salt (15.0 g, 34.0 mmol) in DMF (200 mL) with stirring. The on mixture was allowed to warm to ambient temperature and stirred for 12 h. The mixture was then concentrated and the e was purified by flash column chromatography on silica gel (hexane/EtOAc = 3:1) to afford (S)-benzyl 2-((S)((tert- butoxycarbonyl)amino)propanamido)—3 -(4-methoxyphenyl)propanoate (13.7 g, 88% yield).

A solution of (S)-benzyl ((tert-butoxycarbonyl)amino)propanamido)—3- (4-methoxyphenyl)propanoate (29.0 g, 63.6 mmol) in 3 N HCl—EtOAc (150 mL) was d for 1 h at ambient temperature. The mixture was concentrated and the residue was washed with petroleum ether (100 mL) to afford (S)-benzyl 2-((S)aminopropanamido)—3-(4- methoxyphenyl)propanoate as an HCl salt (quant), which was used directly in the next step without further purification.

To a solution of (S)-benzyl 2-((S)-2—aminopropanamido)—3-(4- methoxyphenyl)propanoate (HCl salt, 21.0 g, 53.5 mmol) in DMF (200 mL) at 0 °C was added HBTU (30.4 g, 80.3 mmol) and HOBt (10.8 g, 80.3 mmol). The mixture was stirred for 5 min then 2-morpholinoacetic acid (8.15 g, 56.2 mmol) and DIEA (46.5 mL, 214 mmol) were added. The reaction mixture was stirred at ambient temperature for 30 min. Saturated s NaHC03 (200 mL) was then added and the resulting mixture was extracted with EtOAc (300 mL ><2). The ed extracts were washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated. ation of the residue by flash column chromatography on silica gel (heptane to EtOAc/heptane = 3:2) afforded (S)-benzyl 3-(4- methoxyphenyl)((S)(2—morpholinoacetamido)propanamido)propanoate (23.0 g, 89% yield) as a colorless solid.

A mixture of (S)-benzyl 3-(4-methoxyphenyl)((S)(2- morpholinoacetamido)propanamido)propanoate (5.00 g, 10.4 mmol) and Pd/C (10%, 1.0 g) in THF (50 mL) was stirred under a hydrogen atmosphere for 2 h. The mixture was filtered and concentrated to afford (S)—3—(4-methoxyphenyl)((S)(2— morpholinoacetamido)propanamido)propanoic acid (3.3 g, 94% yield) as a ess solid. 1H NMR (300 MHz, s): 5 8.24 (d, J= 8.1 Hz, 1H), 7.76 (d, J= 7.8 Hz, 1H), 7.13 (rn, 2H), 6.82 (m, 2H), 4.35 (m, 2H), 3.71 (s, 3H), 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). MS (EI) for C19H27N306, found 394.5 (MH+).

To a solution of (S)—3-(4-methoxyphenyl)-2—((S)—2-(2— morpholinoacetamido)propanamido)propanoic acid (850 mg, crude) and (S)amino (cyclopenten—1 -yl)—1—((R)-2—methyloxiran-2—yl)propanone (TFA salt, 200 mg, 0.680 mmol) in DCM (10 mL) was added HATU (283 mg, 0.750 mmol). The mixture was cooled to 0 °C and basified with DIEA to pH=8. The reaction mixture was stirred at ambient temperature for 30 min and water (30 mL) was added. The resulting mixture was ted with DCM (30 mL><2) and the extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column tography on silica gel (petroleum ether/EtOAc = 2:1 to 1:2, then DCM/methanol = 70:1) to afford (S)-N-((S)—3- (cyclopenten-1 -yl)((R)-2—methyloxiran-2—yl)oxopropan—2-yl)—3—(4-methoxyphenyl)- 2-((S)(2-morpholinoacetamido)propanamido)propanamide (170 mg, 18%) as a ess solid. 1H NMR (300 MHZ, CDClg): 57.29 (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, 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). MS (EI) for C30H42N4O7, found 571.4 (MH)+.

The following compounds were sized in a similar manner: (S)-N-((S)-3 -(cyclohexenyl)((R)methyloxiranyl)-1 -oxopropanyl)- 2-((S)—2—(2-(1 ,1—dioxidothiomorpholino)acetamido)propanamido)—3 -(4- methoxyphenyl)propanamide (C-1127): 1H NMR (300 MHZ, DMSO-d6): 5 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), .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 (d, J: 4.8 HZ, 3H). MS (EI) for C31H44N4OgS, found 633.2 (MH)+.

(S)—N-((S)-3 —(cyclopent-l -en— 1 -yl)- l —((R)-2—methyloxiranyl)-1 -oxopropan—2— yl)-2—((S)(2-(1 , 1 -dioxidothiomorpholino)acetamido)propanamido)-3—(4- methoxyphenyl)propanamide (C-1115): 1H NMR (300 MHZ, DMSO-dg): 5 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). MS (EI) for C30H42N4OgS, found 619.2 (MH)+.

((S)—3 -(cyclopentenyl)-1—((R)-2—methyloxiran-2—yl)—1-oxopropan—2- yl)((S)(2-(4-hydroxymethylpiperidin-1 -yl)acetamido)propanamido)-3 -(4- methoxyphenyl)propanamide (C-1121): 1H NMR (300 MHZ, DMSO-d6): 5 8.30 (d, J = 6.9 Hz, 1H), 8.10 (d, .1: 8.1 Hz, 1H), 7.70 (d, .1: 7.2 Hz, 1H), 7.11 (d, .1: 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, .1: 5.1 Hz, 1H), 2.98 (d, .1: 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). MS (EI) for C32H46N407, found 597.5 (MH)'.

(S)-N-((S)—3 -(cyc10pent-1 -eny1)((R)-2—methy10xiran-2—y1)-1 -oxopropan—2- y1)-3 —(4-methoxypheny1)((S)—2-(2-(3—0x0piperazin- 1 — y1)acetarnido)propanamido)propanarnide (C-1120): 1H NMR (300 MHz, DMSO-d6): 5 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, 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). MS (EI) for N507, found 584.4 (MH)+. —3 -(((S)—3 -cyclopentyl—1-((R)-2—methy10xiran-2—y1)—1-0x0propan y1)amin0)((S)—2-(2—m0rpholin0acetamido)propanamid0)oxopropyl)pyridine 1-0X1de (C- 1119): 1H NMR (300 MHz, DMSO-d6): 5 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). MS (EI) for C28H41N507, found 560.2 (MH)+.

(S)—N-((S)-3 -(cyclohexen— 1 -y1)- 1 —((R)methy10xirany1)-1 -0x0propany1)- 2-((S)hydroxy(2-m0rph011n0acetamido)propanamido)—3-(4- methoxypheny1)propanamide (C-1104): 1H NMR (300 MHZ, : 8 7.88 (m, 1H), 7.16 (d, J: 8.9 Hz, 2H), 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 s, 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). MS (ED for C31H44N408, found 601.8 (MH)+.

Example 12 (2S,3R)—N—((S)Cyc10penty1—1-((R)rnethy10xirany1)oxopropanyl)-3 - hydroxy—3-(4—methoxyphenyl)—2—((S)-2—(2-morpholinoacetamido)propanamido)propanamide (C- 1 022): 0/0K/N\)J\N/LCOOH0 o M60 QQL a“,o 0 OH M OBn HATU, DIEA, DMF HO HZN COOBn Oi O TFA 0 H H N2 H2, Pd/C ” OH —> O — THF H0 HATU, DIEA, DMF LNJWrNMo o H N120 H H 0H0 o tially HATU (3.41 g, 8.96 mmol) and DIEA (2.60 mL, 15.0 mmol) were added to a 0 OC solution of (2S, 3R)-benzyl 2-aminohydroxy(4-methoxyphenyl) propanoate (2.30 g, 7.47 mmol) and (S)—2-(2-morpholinoacetamido)propanoic acid (1.61 g, 7.47 mmol) in DMF (35 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 2:1 to 1:2) to afford (2S,3R)—benzyl 3-hydroxy—3—(4-rnethoxyphenyl)((S)(2-rnorpholino acetamido)propanamido)propanoate (2.04 g, 54% yield) as a colorless solid.

To a solution of (2S,3R)-benzyl 3-hydroxy(4-methoxyphenyl)—2-((S)(2— morpholino acetamido)propanamido)propanoate (2.0 g, 4.0 mmol) in THF (40 mL) was added Pd/C (500 mg, 10%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of celite. The filtrate was trated under reduced pressure and the e was washed with EtOAc (10 mL) to afford (2S,3R)hydroxy(4-methoxyphenyl)((S)—2-(2- morpholinoacetamido)propanamido)propanoic acid (1.30 g, 78% yield) as a ess solid. 1H NMR (300 MHz, DMSO-dg): 5 8.08 (d, J= 8.7 Hz, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.27 (d, .1: 8.4 Hz, 2H), 6.81 (d, .1: 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). MS (EI) for C19H27N307, found 410.2 (MH)+. tially HATU (1.84 g, 4.80 mmol) and DIEA (0.63 mL, 20 mmol) were added to a 0 °C solution of (25,3R)—3 -hydroxy—3 -(4-methoxyphenyl)—2-((S)(2— morpholinoacetamido)propanamido)propanoic acid (1.65 g, 4.00 mmol) and (S)amino cyclopentyl-l—((R)methyloxiranyl)propan—l-one (1.2 g, 4.0 mmol) in DMF (30 mL).

The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min.

The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 2:1 to EtOAc) to afford (2S,3R)-N-((S)—3-cyclopentyl- 1-((R)methyloxirany1)oxopropanyl)hydroxy(4-methoxyphenyl)((S)(2- morpholinoacetamido)propanamido)propanamide (1.45 g, 61% yield) as a colorless solid. 1H NMR (300 MHZ, CDC13)I 8 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), 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), .20 (m, 3H).

MS(EI) for C30H44N4Og, found 589.3 (MH)+.

The following compounds were synthesized in a similar manner: (ZS,3R)-N-((S)—3 -(cyclohex—l -en-1—yl)— l -((R)methyloxiranyl)-l -oxopropan- 2-yl)—3-hydroxy—3-(4-methoxyphenyl)—2-((S)(2- morpholinoacetamido)propanamido)propanamide 2): 1H NMR (300 MHZ, : 5 .40 (m, 1H), 7.27-7.25 (m, 2H), 7.00 (d, J: 8.7 HZ, 1H), 6.84 (d, J: 4.8 HZ, 1H), .81 (m, 2H), 5.45—5.44 (m, 1H), 5.21-5.20 (m, 1H), .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), .89 (m, 3H), 2.60-2.32 (m, 4H), 2.07— 1.95 (m, 4H), 1.69-1.40 (s, 7H), 1.31 (d, J: 6.9 HZ, 3H). MS(EI) for C31H44N4Og, found 601.3 (MH)+. [0034 l] (2S,3R)-N—((S)(cyclopentenyl)((R)methyloxirany1)—1-oxopropan- 2-yl)hydroxy(4-methoxyphenyl)—2-((S)-2—(2- morpholinoacetamido)propanamido)propanamide (C-1083): 1H NMR (300 MHZ, CDCl3)I 5 7.43 (d, J: 7.5 HZ, 1H), 7.29-7.23 (m, 2H), 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: 5.1 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, .1: 6.9 Hz, 3H). MS(EI) for C30H42N40g, found 587.4 (MHY. e 13 (2S,3R)—N—((S)(Cyclohex-l -en-1—yl)- l 2-methyloxiranyl)-1 -oxopropan- 2-yl)—3 —hydroxy—2-((S)—3 —hydroxy(2—morpholinoacetamido)propanamido)-3 -(4— methoxyphenyl)propanamide (C-1 1 1 6): 1. Boc—Ser—OH HATU DMF 1. 2-morpholinoacetic HO,“ —>H2NDIEA acid HATU DIEA DMF 2 HCI-EtOAc 2. H2 Pd/C THF H2N COOBn LwfiélNJ’L O ONJDLHLWfiMLgi HATU DIEA DMF Sequentially HATU (645 mg, 1.706mmol) and DIEA (0.99 mL, 5.7 mmol) were added to a 0 °C solution of (2S,3R)—benzyl 2—amino—3-hydroxy(4—methoxyphenyl)propanoate (HCl salt, 477 mg, 1.41 mmol) and Boc-Ser-OH (290 mg, 1.41 mmol) in DMF (8 mL). The on mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 2:1) twice to afford (25,3R)—benzyl 2—((S)—2-((tert— butoxycarbonyl)amino)hydroxypropanamido)—3-hydroxy(4-methoxyphenyl)propanoate (646 mg, 93% yield) as a colorless solid.

To HCl-EtOAc (5 N, 10 mL) was added a solution of (2S,3R)—benzyl 2—((S) ((tert—butoxycarbonyl)amino)—3-hydroxypropanamido)—3-hydroxy(4- yphenyl)propanoate (646 mg, 1.32 mmol) in DCM (10 mL). The mixture was d at ambient temperature for 30 min and then concentrated. The residue was washed with diethyl ether (5 mL) to afford (2S,3R)-benzyl —2-amino-3—hydroxypropanamido)—3— hydroxy(4-methoxypheny1)propanoate (HCl salt, 474 mg, 85% yield) as a colorless solid.

Sequentially HATU (509 mg, 1.34 mmol) and DIEA (0.78 mL, 4.5 mmol) were added to a 0 °C solution of (ZS,3R)-benzyl 2-((S)aminohydroxypropanamido) hydroxy—3-(4-methoxyphenyl)propanoate (HCl salt, 474 mg, 1.12 mmol) and 2- morpholinoacetic acid (162 mg, 1.12 mmol) in DMF (8 mL). The reaction mixture was allowed to warm to ambient temperature and d for 30 min. The mixture was concentrated and the residue was washed with EtOAc to afford (2S,3R)-benzyl 3-hydroxy ((S)—3-hydroxy(2—morpholinoacetamido)propanamido)—3-(4-methoxyphenyl)propanoate (349 mg, 67% yield) as a colorless solid.

To a solution of (2S,3R)-benzyl 3-hydroxy((S)hydroxy(2- morpholinoacetamido)propanamido)-3—(4-methoxyphenyl)propanoate (349 mg, 0.680 mmol) in THF (20 mL) was added Pd/C (100 mg, 10%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight then filtered through a pad of celite.

The filtrate was concentrated to afford )-3 -hydroxy((S)hydroxy(2- linoacetamido)propanarnido)—3-(4-rnethoxyphenyl)propanoic acid (121 mg, 42% yield) as a colorless solid.

Sequentially HATU (537 mg, 1.41 mmol) and DIEA (1.02 mL, 5.88 mmol) were added to a 0 °C solution of (25,3R)—3 -hydroxy—2—((S)hydroxy—2-(2- morpholinoacetamido)propanamido)—3-(4-methoxyphenyl)propanoic acid (500 mg, 1.18 mmol) and (S)—2-amino—3-(cyclohex-l—enyl)—l -((R)-2—methyloxiran-2—yl)propanone (TFA salt, 364 mg, 1.18 mmol) in DMF (10 mL). The reaction mixture was allowed to warm to ambient ature and d for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (DCM/MeOH = 50:1 to 30: 1) twice to afford (2S,3R)-N-((S)—3-(cyclohex-1—enyl)—1-((R)—2-methyloxiranyl) oxopropanyl)hydroxy((S)hydroxy(2-morpholinoacetamido)propanamido)—3-(4- methoxyphenyl)propanamide (500 mg, 57% yield) as a colorless solid. 1H NMR (300 MHz, 6): 8 7.97 (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, J: 8.7 Hz, 2H), 5.61 (d, J: 4.5 Hz, 1H), 5.40-5.38 (m, 1H), .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). MS(EI) for C31H44N409, found 617.4 (MH)+.

The following nds were synthesized in a similar manner: (25,3R)-N-((S)(cyclopent—1-en-1—yl)((R)methyloxiranyl)-1—oxopropan- 2-yl)-3 -hydroxy((S)—3 -hydroxy(2-morpholinoacetamido)propanamido)-3 -(4- yphenyl)propanamide (C-1144): 1H NMR (300 MHZ, DMSO-d6): 5 8.03 (d, J = 7.2 Hz, 1H), 7.92 (d, .1: 8.7 Hz, 1H), 7.74 (d, .1: 7.8 Hz, 1H), 7.25 (d, .1: 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), 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). MS (EI) for C30H42N409, found 603.28 (MH)+. (2S,3S)-N-((S)—3 -cyclopenty1— 1 -((R)rnethyloxiranyl)-1 opanyl)-3 - hydroxy(4—meth0xyphenyl)—2-((S)-2—(2-m0rpholin0acetarnido)propanamido)propanamide (C-1023): 1H NMR (300 MHz, CDC13): 8 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—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). MS (EI) for C30H44N4Og, found 589.3 (MH)+.

Example 14 (S)-N-((S)-3 -Cyclopenty1—1-((R)methyloxiranyl)ox0propany1)-3 -(3 - hydroxyrnethylpheny1)((S)(2-morpholinoacetamido)pr0panamido)propanarnide (C- 1 1 1 7): 0/} o OBn K/NdeJ]OH OOwkO N |EA fi/Rf 0M9 o _ HZN COOIVIe $1 $167511??? ‘3J1 J51“J1 o o o 3. HATU, DIEA, DMF m TFA OH Crude (S)-methyl 2—arnino(3-(benzyloxy)—4-rnethylphenyl)propanoate (TFA salt, 2.5 mmol) was dissolved in DMF (5 mL) and (S)—2-(2-m0rpholin0acetamido)propanoic acid (0.65 g, 3.0 mmol), HATU (1.43 g, 3.70 mmol), and DIEA (1.0 mL) were added at 0 0C with ng. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The s phase was extracted with EtOAc (30 mL><3) and the combined c phases were washed with brine (50 mLX3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 20: 1) to afford (S)-Methyl 3-(3- (benzyloxy)-4—methylphenyl)((S)-2—(2-morpholinoacetamido) propanamido)propanoate (1.2 g, 96% yield).

(S)—Methyl 3—(3 -(benzyloxy)—4-methylphenyl)—2-((S)—2—(2-morpholinoacetamido) amido)propanoate (1.2 g, 2.4 mmol) was treated with a solution of lithium hydroxide- H20 (300 mg, 7.2 mmol) in water/THF (10 mL/10 mL) for 30 min. The THF was removed and the aqueous phase was acidified to pH=3 -4 with 1 N HCl and then concentrated to s to afford (S)(3-(benzyloxy)—4-methylphenyl)—2-((S)(2- morpholinoacetamido)propanamido)propanoic acid, which was used directly without r purification.

The crude (S)(3—(benzyloxy)—4-methylphenyl)—2-((S)(2— morpholinoacetamido)propanamido)propanoic acid was ved in MeOH (20 mL) and Pd/C (10%, 1.0 g) was added. The suspension was stirred under a hydrogen atmosphere at ambient temperature for 12 h. The Pd/C was filtered off and washed with MeOH (5 mL). The e and washings were combined and concentrated to dryness.

(S)—3-(3-Hydroxy-4—methylphenyl)((S)-2—(2- morpholinoacetamido)propanamido)propanoic acid was dissolved in DMF (5 mL) and (S) amino—3-cyclopentyl-1—((R)-2—methyloxiranyl)propan—1-one (TFA salt, 0.40 g, 1.3 mmol), HATU (0.65 g, 1.9 mmol) and DIEA (0.5 mL) were added at 0 0C with stirring. The reaction mixture was d to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (30 mL><3) and the combined organic phases were washed with brine (50 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/EtOAc/MeOH = 20: 10: 1) to afford (S)- N-((S)—3 -cyclopentyl-1 -((R)methyloxiranyl)oxopropan—2-yl)—3 -(3-hydroxy methylphenyl)—2-((S)—2-(2-morpholinoacetamido)propanamido)propanamide (150 mg, 11% yield over three steps). 1H NMR (300 MHz, DMSO-d6): 8 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, .1: 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, .1 = 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), .42 (m, 7H), 1.41 (s, 3H), 1.30—1.02 (m, 6H). MS(EI) for C30H44N4O7, found 573.3 (MH)+.

The following compounds were synthesized in a similar manner: (S)—N-((S)-3 -cyclopentyl((R)n1ethyloxiranyl)—1-oxopropanyl)—3 -(3 ,4- dihydroxyphenyl)((S)(2-morpholinoacetamido)propanamido)propanamide (C-1039): 1H NMR (300 MHz, DMSO-a’6): 5 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, 4H), 1.95 (m, 1H), .85 (m, 7H), 1.40 (s, 3H), .20 (m, 2H), 1.26 (d, J: 6.6 Hz, 3H). MS(EI) for C29H42N4Og7, found 575.0 (MH)+.

N-((R)-l -(((S)— l —3 -cyclopentyl((R)rnethyloxiranyl)oxopropan yl)amino)-3 -(3-hydroxymethoxyphenyl)-1 -oxopropanyl)amino)— 1 -oxopropan yl)tetrahydro-2H-pyrancarboxarnide (C-1061): 1H NMR (300 MHZ, DMSO-d6): 5 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 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). MS (EI) for C30H43N308, found 574.4 (MH)+.

] N—((R)—1-(((S)—1-(((S)—3-(cyclopent-1—enyl)—1-((R)—2-methyloxiran—2—yl)-1— oxopropan-Z-yl)arnino)-3 -(3-hydroxyrnethoxyphenyl)oxopropanyl)arnino) oxopropan-Z-yl)tetrahydro-2H-pyrancarboxamide (C-1062): 1H NMR (300 MHZ, DMSO- d6): 5 8.70 (s, 1H), 8.24 (d, J: 7.2 Hz, 1H), 8.01 (d, J: 7.2 Hz, 1H), 7.87 (d, J: 7.5 Hz, 1H), 7.12 (d,.]= 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, J: 6.9 Hz, 3H). MS (EI) for C28H41N307, found 532.4 (MH)+.

(S)-N-((S)(cyclopent-l -enyl)((R)-2—methyloxiranyl)-1 -oxopropan—2- yl)—3—(3—hydroxymethylphenyl)((S)—2-(2-morpholinoacetamido)propanamido) propanamide (C-1129): 1H NMR (300 MHz, DMSO-d6): 5 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), 2014/026987 6.53 (d, .1: 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), 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, .1: 6.9 Hz, 3H). MS(EI) for C30H42N4O7, found 572.0 (MH)+.

(S)—N-((S)-3 —(cyclohexen— 1 -y1)- 1 —((R)methyloxiranyl)-1 -oxopropan-2—yl)- 3-(3-hydroxymethylphenyl)((S)(2-morpholinoacetamido)propanamido)propanamide (C-1130): 1H NMR (300 MHZ, DMSO—d6): 8 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), 2.80-3.00 (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). MS (EI) for C31H44N4O7, found 586.25 (MH)+.

Example 15 (S)-N-((S)-3 -(Cyclopentenyl)((R)methyloxiranyl)oxopropan y1)((S)(2-(4-hydroxypiperidinyl)acetamido)propanamido)-3 -(4- yphenyl)propanamide (C-1 1 1 8): HO N - o H a NdkOH o HATU NMM DCM HOU\)\1. H2 Pd/C MeOH 2. HATU DCM NMM NJWVNEJOLN I g0 "\©\OOMe TFA O To a solution of 2-(4-hydroxypiperidinyl)acetic acid (0.41 g, 2.6 mmol) and (S)-benzy1 2-((S)aminopropanamido)—3-(4-methoxyphenyl)propanoate (HC1 salt, 0.93 g, 2.6 mmol) in dichloromethane (30 mL) at 0 °C was added HATU (1.1 g, 2.9 mmol) followed by N—methylmorpholine (1.05 g, 10.4 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (30 mL) was added and the resulting mixture was ted with dichloromethane (30 mL><3). The c extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The e was purified by flash column chromatography on silica gel (petroleum ether/dichloromethane = 5:1 to 1:1) to afford (S)- benzyl 2-((S)(2-(4-hydroxypiperidiny1)acetamido)propanamido)(4- methoxyphenyl)propanoate (1.1 g, 87% yield) as a colorless solid.

A mixture of (S)-benzyl 2-((S)(2-(4-hydroxypiperidin yl)acetamido)propanamido)-3—(4-methoxyphenyl)propanoate (0.50 g, 1.0 mmol) and Pd/C (0.1 g) in methanol (20 mL) was hydrogenated for 1 h at ambient temperature. The Pd/C was filtered off and the filtrate was trated.

] The residue was dissolved in dichloromethane (20 mL) followed by on of (S)—2-amino(cyclopentenyl)((R)methyloxiran-2—yl)propanone (TFA salt, 0.300 g, 1.02 mmol) and HATU (0.40 g, 1.0 mmol). N—Methylmorpholine (0.36 g, 3.8 mmol) was added to the solution at 0 OC. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (20 mL) was added and the resulting mixture was extracted with dichloromethane (20 mLX 3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 200:1 to 80:1) and preparative TLC to afford (S)-N—((S)(cyclopent—1—enyl)—1-((R)—2-methyloxiran—2-y1)-1—oxopropan- 2-yl)—2-((S)(2-(4-hydroxypiperidin-1 -yl)acetamido)propanamido)—3 -(4- methoxyphenyl)propanamide (151 mg, 26% yield). 1H NMR (300 MHZ, DMSO-d6): 8 8.30 (d, J: 7.2 Hz, 1H), 8.09 (d, J: 8.1 Hz, 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), .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: 5.1Hz, 1H), 2.92—2.72 (m, 3H), 2.63-2.35 (m, 5H), 2.29-1.91 (m, 7H), 1.85—1.70 (m, 4H), 1.38 (s, 3H), 1.14 (d, J: 6.9 Hz, 3H). MS(EI) for C31H44N4O7, found 585.2 (MH)+.

] The following compounds were synthesized in similar manner: ] (S)-N-((S)—3 -cyclopentyl-1—((R)methyloxiran-2—yl)—1-oxopropan—2-yl)—2—((S)—2- (2-(3 ,3 ropyrrolidinyl)acetamido)propanamido)—3 -(4-methoxyphenyl)propanamide 8): 1H NMR (300 MHz, CDC13): 5 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 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, 7H), 1.45 (s, 3H), 1.15 (d, J: 6.9 Hz, 3H). MS(EI) for C30H42F2N4O6, found 593.4 (MH)+.

(S)-N-((S)-3 -cyclopenty1((R)methyloxiranyl)oxopropany1)-3 -(4- methoxypheny1)((S)(2-(4-(triflu0r0rnethyl)piperidin y1)acetamid0)propanamido)propanamide (C-1047): 1H NMR (300 MHZ, CDC13): 5 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: 8.1HZ,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), .27 (m, 3H). MS(EI) for C32H45F3N4O6, found 639.0 (MH)+.

(S)-N-((S)-3 -cyc10penty1—1-((R)methy10xiranyl)—1-0X0propany1)((.S') (2-(4,4—difluoropiperidin— 1 -y1)acetamido)propanamido)—3—(4-methoxyphenyl)propanamide (C-1046): 1H NMR (300 MHZ, : 5 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, 1H), 4.57 (m, 1H), 4.48 (m, 1H), 3.79 (s, 3H), 3.25 (d, J: 5.1 HZ, 1H), .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). MS(EI) for C31H44F2N4O6, found 607.4 (MH)+.

(S)((S)—2-(2-(4-ch10ropiperidiny1)acetamido)propanamido)-N-((S)-3 - cyclopentyl- 1 —((R)methy10xirany1)— 1 -ox0propan-2—y1)—3 -(4— methoxyphenyl)propanarnide (C-1045): 1H NMR (300 MHZ, CDC13): 5 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, 3H), 1.41 (d, J: 6.9 HZ, 3H), 1.38 (m, 1H), 1.36 (m, 1H).

MS(EI) for C1N4O6, found 605.4 (MH)+.

(S)—N-((S)-3 —cyclopenty1— 1 -((R)methy10xiranyl)—1-0x0pr0pan-2—y1)—2-((S)—2- (2-(3 ,3 -difluoropiperidiny1)acetarnido)propanamido)—3-(4-Inethoxypheny1)propanamide (C-1043): 1H NMR (300 MHZ, CDC13)I 5 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), 1.37 (d, J = 6.9 HZ, 3H), 1.36-1.27 (m, 4H). MS(EI) for C31H44F2N4O6, found 607.4 (MH)+.

(R)—N-((R)—1-(((S)-1—(((S)-3—cyc10penty1—1-((R)rnethy10xiranyl)—1- oxopropan-2—y1)arnino)-3 -(4-methoxypheny1)ox0pr0panyl)amino)— 1 -oxopropan yl)tetrahydrofuran-3 -carboxamide (C-1036): 1H NMR (300 MHZ, DMSO-dg): 8 8 .23 (d, J = 6.9 Hz, 1H), 8.07-8.11 (m, 2H), 7.12 (d, .1: 8.4 Hz, 2H), 6.79 (d, .1: 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), 1.80-2.05 (m, 3H), 1.50-1.80 (m, 7H), 1.42 (s, 3H), 1.00-1.30 (m, 2H), 0.96 (d, J= 6.6 Hz, 3H). MS(EI) for C29H41N307, found 544.0 (MH)+.

N—((R)—1-(((S)(((S)-3 -cyclopentyl((R)—2-methyloxirany1)0x0pr0pan n0)-3 -(4—methoxypheny1)— 1 -0X0pr0pan-2—y1)amino)0xopr0pan—2-y1)tetrahydro—2H- pyrancarb0xamide 8): 1H NMR (300 MHZ, CDC13): 8 7.11 (d, J: 8.7 Hz, 2H), 6.83 (d, J: 8.4 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), 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). MS (EI) for N307, found 5586 (MH)+.

N—((R)—1-(((S)(((S)-3 -cyclopentyl—1-((R)-2—methy10xiran-2—y1)0xopr0pan y1)amin0)(4-meth0xypheny1)0x0propany1)arnino)oxopropany1) 0x0cyclobutanecarboxamide (C-1029): 1H NMR (300 MHz, CDC13): 8 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 (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). MS (EI) for C29H39N307, found 542.6 (MH)+.

] (S)—N-((R)—1-(((S)-1—(((S)-3—cyc10penty1—1-((R)rnethy10xirany1)—1- oxopropan-Z—y1)arnino)-3 -(4-methoxypheny1)ox0propanyl)amin0)oxopropan y1)tetrahydrofurancarboxamide (C-1031): 1H NMR (300 MHZ, DMSO'dé): 8 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, 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: 5.1Hz, 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), LOO-1.30 (m, 4H), 0.99 (d, J= 6.6 Hz, 3H). MS(EI) for C29H41N3O7, found 544.0 (MH)+.

((R)—1-(((S)(((S)cyc10penty1—1-((R)methy10xirany1) oxopropan-Z-y1)arnino)-3 -(4-meth0xypheny1)-1 —0X0pr0panyl)amino)— 1 -ox0pr0pan-2— y1)tetrahydrofurancarb0xam1de (C-1032): 1H NMR (300 MHz, DMSO-d6): 8 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, .1: 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, .1: 6.6 Hz, 3H). MS(EI) for C29H41N307, found 5440 (MH)+.

Example 16 (2S,3R)—N—((S)(((S)-3 -(Cyclohexenyl)((R)methyloxiranyl) oxopropanyl)amino)-3 -(4-methoxyphenyl)oxopropanyl)hydroxy(2- linoacetamido)butanamide (C-1 148): 1 LiOH j:OH 2-morpholinoacetic acid 2. Phe-OBn HATU MdLOOHI HATU H2N COOMe 7 1. H2, Pd/C 2. HATU o/\ o OHH o TFA O o/fi o OHH o K/NJLN N\.)J\0Bn o HZN K/NdLN H - o H a H o ON\_)J\N D. I): HATU (7.66 g, 20.1 mmol) was added to a solution of 2-rnorpholinoacetic acid (2.44 g, 16.8 mmol) and (2S,3R)—methyl 2-aminohydroxybutanoate hydrochloride (2.84 g, 16.8 mmol) in romethane (20 mL) at 0 CC. N—Methylmorpholine (5.1 g, 50.4 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (dichloromethane/methano1 = 100:1 to 60:1) to afford (2S,3R)- methyl 3-hydroxy(2-morpholinoacetamido)butanoate (2.1 g, 48% yield).

A solution of (2S,3R)-methyl 3-hydroxy(2-morpholinoacetamido)butanoate (0.35 g, 1.3 mmol) in water/THF (5 mL/3 mL) was treated with LiOH-HZO (0.11 g, 2.6 mmol) for 1 h at ambient temperature. The mixture was neutralized to pH=7 with concentrated HCl and then concentrated to dryness.

The residue was added to a on of 4-MeO-Phe-0Bn (TFA salt, 0.52 g, 1.3 mmol) and HATU (1.0 g, 2.6 mmol) in dichloromethane (20 mL). N—Methylmorpholine (0.63 mL, 5.7 mmol) was added at 0 OC and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (dichloromethane/ methanol = 50:1 to 10: 1) to afford (S)-benzyl 2-((2S,3R)—3-hydroxy(2—morpholinoacetamido)butanamido)—3-(4- methoxyphenyl)propanoate (0.5 g, 72% yield).

A solution of (S)-benzy1 2-((2S,3R)hydroxy(2- morpholinoacetamido)butanamido)(4— methoxyphenyl)propanoate (0.5 g, 1.0 mmol) in methanol (10 mL) was stirred under hydrogen atmosphere in the presence of Pd/C (0.1 g) for 1 h at ambient temperature. Pd/C was filtered off and the filtrate was concentrated to dryness.

The e was added to a mixture of compound tert-butyl ((S)—3 -(cyclohex—1-en- 1-yl)((R)methyloxiran-2—yl)oxopropanyl)carbamate (TFA salt, 0.32 g, 1.0 mmol) and HATU (0.46 g, 1.2 mmol) in DCM (20 mL). N—Methyl morpholine (0.43 mL, 4.0 mmol) was added to the solution at 0 OC. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (30 mL) was added and the resulting mixture was extracted with EtOAc (30 mL><3). The c extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel oromethane/ methanol = 200:1 to 120: 1) to afford (28,3R)-N-((S)—1-(((S) (cyclohexenyl)-1 -((R)methyloxiranyl)oxopropanyl)amino)-3 -(4- methoxyphenyl)oxopropanyl)-3 xy(2-morpholinoacetamido)butanamide (270 mg, 45% yield). 1H NMR (300 MHz, 6): 5 8.28 (d, J= 7.2 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.63 (d, J: 4.8 Hz, 1H), 7.09 (d, J: 8.4 Hz, 2H), 6.76 (d, J: 8.4 Hz, 2H), 5.77 (s, 1H), 5.40 (m, 1H), 5.02 (d, J: 5.1 Hz, 1H) 4.51 (m, 2H), 4.19 (m, 1H), 3.95 (m, 1H), 3.70 (s, 3H), 3.55 (m, 4H), 3.21 (d, J: 5.1 Hz, 1H), 2.95 m, 2H), 2.89 (m, 2H), 2.65 (m, 1H), 2.39 (m, 3H), 2.23 (m, 1H), 1.78-2.09 (m, 5H), 1.56 (m, 4H), 1.37 (s, 3H), 0.95 (d, J: 6.0 Hz, 3H). MS (EI) for N4Og, 616.2 (MH)+.

The following nds were synthesized in a similar manner: (2S,3S)-N—((S)—1-(((S)—3 -(cyclohexen-1—yl)—1-((R)methyloxiranyl) panyl)amino)-3 -(4-methoxyphenyl)-1 -oxopropanyl)hydroxy(2- morpholinoacetamido)butanamide (C-1150): 1H NMR (300 MHZ, DMSO-d6): 5 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), 5.76 (s, 1H), 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, 3H), 2.21 (m, 1H), 2.03 (m, 5H), 1.56 (m, 4H), 1.37 (s, 3H), 0.97 (d, .1 = 6.3 Hz, 3H). MS (EI) for C32H46N408, found 615.2 (MH)+. (2S,3S)-N—((S)—1-(((S)—3 -(cyclohexenyl)((R)—2-methyloxiran—2-yl) oxopropan-2—yl)amino)-3 -(4-methoxyphenyl)oxopropanyl)hydroxy(2- morpholinoacetamido)butanamide (C-1149): 1H NMR (300 MHZ, DMSO-dé): 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). MS (EI) for C32H46N4Og, found 615.2 (MH)+.

Synthetic Procedures—Fragments Example 17 tert—Butyl 3 -(3 -methylcyclopent—1-enyl)—1-((R)methyloxiranyl)-1 -oxopropan- 2-y1)carbamate: O/ 1. MeONa <0 700:0 Mel, K2003 0 2. reflux NaBH4 0 weOko \OCiO 1. PBr3 1_ M301 0 2. HCH(COZEt)2 L1AM 2. DBU KOBu COOEt W'cooaNHAc 1. MeNHOMe EDCI 1. NaOH K 2. L-acylase 2_ 3ng 3- B0620 3. NaCIO ’ o BocHN BocHN COOH 0 A mixture of methyl 2-oxocyclopentanecarboxylate (67 g, 0.47 mol), K2C03 (163 g, 1.18 mol) and Mel (167 g, 1.18 mol) in acetone (500 mL) was heated under reflux for 12 h.

The mixture was cooled to ambient ature and then trated. The residue was dissolved in EtOAc (800 mL) and the resulting solution was washed with saturated aqueous NaHC03 (500 mL><3) and brine (300 mL><1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl l-methyl oxocyclopentanecarboxylate (60.5 g, 82% yield).

Methyl l-methyloxocyclopentanecarboxylate (61.0 g, 0.39 mol) was added dropwise to a freshly prepared solution ofNaOMe (0.78 mol) in MeOH (l L) at ambient temperature. The solution was heated under reflux for 3 h and then concentrated. The residue was dissolved in toluene (l L) and the resulting solution was heated under reflux for 5 h. The mixture was cooled to ambient ature, washed with saturated s NaHCOg (500 mL><3) and brine (300 mL>< 1), dried over anhydrous sodium sulfate, and concentrated to dryness. The e was purified by distillation to afford methyl 3-methyl—2- oxocyclopentanecarboxylate (39.0 g, 64% yield).

NaBH4 (9.98 g, 0.260 mol) was added in portions to a solution of methyl 3- methyloxocyclopentanecarboxylate (41.2 g, 0.26 mol) in MeOH (250 mL) at 0 CC. The reaction mixture was allowed to warm to ambient temperature and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl (500 mL) and the resulting mixture was extracted with EtOAc (250 mL><5). The ed organic phases were washed with brine (500 mL><2), dried over anhydrous sodium sulfate, and concentrated to afford methyl 2- hydroxymethylcyclopentanecarboxylate (34.0 g).

Et3N (295 mL, 2.1 mol) and DMAP (2.59 g, 21.2 mmol) were added sequentially to a solution of methyl oxymethylcyclopentanecarboxylate (33.5 g, 0.21 mol) in CH2C12 (800 mL) at 0 oC. Then MsCl (65.6 mL, 0.85 mol) was added dropwise over 1 h. The reaction mixture was stirred at 0 CC for l h and then allowed to warm to ambient temperature and stirred for 8 h. Water (500 mL) was added and the two layers were separated. The organic layer was washed with aqueous HCl (IN, 200 mL><3), saturated aqueous NaHC03 (200 mL><3), and brine (300 mL>< 1), respectively. The organic solution was dried over anhydrous sodium sulfate and trated to dryness.

The residue was dissolved in CH2C12 (600 mL) and cooled to 0 0C. A on of DBU (53.2 mL, 0.36 mol) in CH2C12 (100 mL) was added dropwise. The reaction e was allowed to warm to ambient temperature and stirred overnight. Water (200 mL) was added and the two layers were separated. The organic layer was washed with s HCl (IN, 200 mL><3), saturated aqueous NaHC03 (200 mL><3), and brine (300 mL>< 1), tively. The organic solution was dried over anhydrous sodium e and concentrated to dryness. The residue was purified by distillation to afford methyl 3-methylcyclopent-1— enecarboxylate (15.3 g, 38% yield over three steps).

A suspension of LiAlH4 (7.4 g, 190 mol) in THF (100 mL) was cooled to 0 CC under nitrogen. A on of methyl 3—methylcyclopentenecarboxylate (26.0 g, 170 mmol) in THF (100 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and d for 5 h. The reaction was quenched with water (7.4 mL), % aqueous NaOH (7.4 mL) and water (22.2 mL) carefiilly. The resulting mixture was filtered and washed with THF (100 mL>< 3). The filtrate and washings were ed and concentrated to dryness to afford crude (3-methylcyclopentenyl)methanol (18.6 g) as an oil. orous tribromide (8mL, 83 mmol) was added to a solution of (3- methylcyclopent-l-enyl)methanol (18.5 g, 165 mmol) in Eth (300 mL) at —10 0C with stirring. The mixture was allowed to warm to ambient ature and stirred for 3 h. The on was quenched with ice-water (100 mL). The organic phase was separated, washed with saturated aqueous NaHC03 (100 mL><3) and brine (100 mL><1), dried over anhydrous sodium sulfate, and concentrated to dryness to afford the corresponding bromide (24.0 g).

Potassium tert—butoxide (16.9 g, 0.15 mol) was added in portions to a solution of diethyl 2-acetamidomalonate (25.3 g, 0.12 mol) in DMF (100 mL) while maintaining the temperature below 10 0C. After the addition was complete, the suspension was stirred for 0.5 h at 10 CC and the bromide (24.0 g) was added dropwise. The reaction mixture was stirred for h at ambient temperature and water (500 mL) was added. The resulting mixture was extracted with EtOAc (500 mL><3). The e organic phases were washed with saturated aqueous NaHC03 (500 mL><3), 5% aqueous KHSO4 (500 mL><3), and brine (300 mL><1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc = 10: 1) to afford diethyl 2-acetamido-2—((3-methylcyclopent-1— enyl)methyl)malonate (34.4 g, 67% yield).

Diethyl 2—acetamido((3-methy1cyclopentenyl)methyl)malonate (34.4 g, 0.110 mol) was dissolved in l (200 mL) and 1N aqueous NaOH (200 mL, 0.2 mol) was added. The on was heated under reflux for 8 h and then cooled to t temperature.

The organic solvent was removed and the remaining s solution was washed with ethyl ether (50 mL><3) and acidified with 2N s hydrochloric acid to pH=3. The resulting mixture was extracted with EtOAc (200 mL><6) and the combined organic phases were washed with brine (200 mL>< 1), dried over anhydrous sodium sulfate, and concentrated to dryness.

The residue was suspended in water (500 mL) and aqueous NaOH (1N) was added dropwise to adjust to pH=7.5. The e was stirred for 30 min at 37 OC and then filtered.

L-Acylase (5.0 g) was added to the filtrate and the mixture was stirred for 40 h at 37 CC. The mixture was cooled to ambient temperature and purified by change resin (732#, 100 g) to afford the corresponding L-amino acid.

] L-Amino acid was dissolved in water and acetone (1:1, 200 mL) and the solution was basified with 2N aqueous NaOH to pH=8. BoczO (22.0 g, 0.1 mmol) was added and the reaction mixture was stirred for 12 h at ambient temperature. The organic solvent was d and the remaining aqueous solution was washed with ethyl ether (200 mL><3) and acidified with 2N aqueous hydrochloric acid to pH=3. The resulting mixture was extracted with EtOAc (200 mL><6). The combined organic phases were washed with brine (100 mLX 1), dried over anhydrous sodium sulfate, and concentrated to afford (2S)—2-(tert- Butoxycarbonylamino)—3-(3-methylcyclopent-l-enyl)propanoic acid (4.8 g, 16% yield), which was used directly without further purification.

] Triethylamine (1.3 mL, 9.7 mmol) was added to a suspension of dimethylhydroxyl amine hydrochloride (1.86 g, 9.7 mmol) and (ZS)(tert-butoxycarbonylamino)—3-(3- methylcyclopent-l-enyl)propanoic acid (2.6 g, 9.7 mmol) in methylene dichloride (50 mL) at 0 °C followed by addition of EDCI (1.86 g, 9.7 mmol). The reaction mixture was stirred overnight at ambient temperature and water (30 mL) was added. The c layer was separated and washed with 5% aqueous KHSO4 (30 mLX3), saturated aqueous NaHC03 (50 mL><3), and brine (50 mL>< 1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (hexanes/ EtOAc = 10:1) to afford the corresponding Weinreb amide.

] The amide was dissolved in THF (50 mL) and a freshly prepared solution of isopropenylmagnesium bromide (75 mmol) in THF was added dropwise at 0 °C with stirring.

The reaction e was stirred at 0 °C for 5 h and then quenched with saturated aqueous NH4Cl (100 mL). The ing mixture was extracted with EtOAc (100 . The combined c layers were washed with 5% s KHSO4 (100 mL><3), saturated aqueous NaHC03 (100 mL><3), and brine (50 mL>< 1), respectively. The organic phase was dried over anhydrous sodium sulfate and trated. The residue was purified by flash column chromatography on silica gel (hexanes/ EtOAc = 10: 1) to afford the corresponding enone (2.1 g, 69% yield).

Aqueous NaClO (10%, 16.3 mL, 22 mmol) was added dropwise to a solution of the enone (2.1 g, 6.7 mmol) in DMF (50 mL) at -10 °C with stirring. The reaction mixture was stirred for 2 h at -10 CC and water (300 mL) was added. The resulting e was ted with EtOAc (100 mLX3). The ed organic layers were washed with 5% aqueous KHSO4 (100 mL><3), saturated aqueous NaHC03 (100 mL><3), and brine (100 mL>< 1) respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column tography on silica gel (hexanes/EtOAc = 5: 1) to afford tert-butyl (2S)—3 -(3 -methylcyclopentenyl)((R) methyloxiranyl)—1- oxopropanylcarbamate (1.1 g, 50% yield). tert—Butyl ((R)-3 -(cyclopent—3 -en-1—yl)—1-((R)methyloxiranyl)-1 -oxopropan- 2-yl)carbamate was synthesized in a similar manner ng from (S)((tertbutoxycarbonyl )amino)(cyclopent-3—enyl)propanoic acid.

Example 18 ] tert—Butyl ((S)((R)—2-methyloxiranyl)—l -oxo((R)-tetrahydrofuran-3 - yl)propanyl)carbamate and tert—Butyl (S)((R)methyloxiranyl)-1 -oxo—3 -((S)- tetrahydrofiaranyl) propanylcarbamate: 1. H2, Ni 2. MsCI AcNHCH(COOEt)2 (0‘ 3. Nal t—BuOK COOEt CH0 0V. —, MargoEt 0 1. L--acylase H EDCI NaOH mCOO—> 2. BoczO COOH MeNHOMe NHAc 0 NHBoc \N’0\ 1. 2\MgBr 0 o“ o 2. Separation NHBoc NHBoc O NHBoc by chiral HPLC NaCIO NaClO O O BocHN BocHN A mixture of Raney Ni (50 g) and tetrahydrofurancarbaldehyde (100 g, 50% aqueous, 1.0 mol) was stirred under hydrogen atmosphere at ambient temperature for 12 h.

The catalyst was filtered off and washed with water (20 mL). The filtrate and washings were ed and the solvent was removed by azeotroping with toluene. The residue was led to afford tetrahydro-3—fi1ranmethanol (45 g) as a colorless oil.

Triethylamine (13.7 mL, 98 mmol) was added to a solution of tetrahydro furanmethanol (10.0 g, 98 mmol) in methylene chloride (100 mL) at 0 °C followed by addition of methanesulfonyl chloride (12.3 g, 108 mmol) dropwise. The reaction e was stirred at 0 °C for 1 h and then allowed to warm to ambient temperature and stirred overnight.

Aqueous hydrochloric acid (IN, 100 mL) was added and the two layers were separated. The organic layer was washed with 1N aqueous hydrochloric acid (100 mL><2), saturated aqueous sodium bicarbonate (100 mL><3), and brine (50 mL>< 1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude te of tetrahydro- 3-fi1ranmethanol.

The mesylate was dissolved in acetone (1 L) and sodium iodide (45.0 g, 0.3 mol) was added. The suspension was heated under reflux overnight. The e was cooled to t temperature and filtered. The filtration cake was washed with cold acetone (50 mL).

The filtrate and gs were combined and concentrated. Ethyl ether (100 mL) was added to the residue and the resulting precipitate was filtered off and washed with ethyl ether (100 mL><2). The filtrate and washings were concentrated and the e was distilled to afford 3- (iodomethyl)tetrahydrofuran (20.1 g, 95% yield) as a yellow oil.

The remainder of the synthesis was carried out in a similar manner to the sis of tert—butyl (25)-3 -(3—methylcyclopent—1-enyl)—1-((R)-2—methyloxiran-2—yl) oxopropan-Z- ylcarbamate.

The stereochemical configuration was confirmed by x-ray crystallographic analysis.

Example 19 tert-Butyl ((S)((R)methyloxirany1)((R)-tetrahydrofuran yl)propany1)carbamate and tert-butyl ((S)((R)methyloxirany1)—1-oxo—3 -((S)- tetrahydrofiaran-Z-y1)propan—2—yl)carbamate: 1. AcNHCH(C02Et)2 O \ tert—BuOK O 1. L-Acylase O \ \ \ 2. NaOH fi2. BoczO MeNHOMe \ \ \ CI BOCHN AcHN COOH BocHN COOH /N‘OMe H2, Pd/C l O CO 0 A O \“' separation MgBr O + ‘— o O O BocHN BocHN BocHN BocHN/g0 /N‘0Me NaClOk ‘ NaClO \“'CO O O BocHN BocHN O O The synthesis was carried out in a similar manner to tert—Butyl ((S)-l-((R)methyloxiran yl)-1 —oxo((R)—tetrahydrofuran-3 -yl)propan-2—yl)carbamate and tert-Butyl (S)—1—((R)-2— methyloxiranyl)-l -oxo((S)—tetrahydrofi1ranyl) propanylcarbamate and the reduction of (S)-tert-Butyl 3 -(furanyl)(methoxy(methy1)amino)— 1 -oxopropanyl ate was carried out as follows: To a solution of (S)-tert—Butyl 3-(fi1ranyl)—l-(methoxy(methyl)amino)—l- oxopropan-Z-yl carbamate (8.6 g, 28.9 mol) in ethyl acetate (400 mL) was added Pd/C (2.0 g, %). The mixture was stirred under hydrogen atmosphere (1 atm) at 80°C ght and then cooled to room temperature. The mixture was filtered h a pad of Celite and the filtrate was concentrated under reduced pressure to afford rt—Butyl l- (methoxy(methyl)amino)oxo—3-(tetrahydrofuranyl)propan— 2-y1carbamate (8.4 g, 96% yield) as a Viscous oil, which was used in the next step without further purification.

The stereochemical configuration was confirmed by x-ray crystallographic analysis.

Example 20 tert—Butyl ((S)—3 -((1R,SS,6r)-bicyclo[3 . l .0]hexan-6—yl)- l 2-methyloxiran yl)-l -oxopropanyl)carbamate: dl—’m—CPBA H 0040—.NaOMe : ” ., ., ’CHO OMeNHCbz MeO- IF':—( 0 000““ H'YCOOMe H21Pt02 —’ :,YCOOMeH ‘zH NHCbz NHCbZ 1 H2 Pd/C 2 ACC' 1. L-Acylase 3. LiOH <:>‘\\(COOH—>2 30020 fl‘\\rCOOHH NHAC NHBoc MeNHOMe <>$93~ \ —» <> NHBoc NHBoc NaCIO O BocHN To a solution of norbomadiene (10.0 g, 108 mmol) in CH2C12 (400 mL) was added m-CPBA (22.1 g, 108 mmol) in portions over 1 h at 0 °C. The reaction mixture was stirred for 1.5 h at ambient temperature and then filtered. The filtrate was washed with cold 5% s NaHC03 (200 mL) and cold water (200 mL), dried over anhydrous sodium sulfate, and trated to afford (1 S,5R,6R)-bicyclo[3.l.0]hexenecarbaldehyde as a clear oil. [0041 l] (1 R)—bicyclo[3. 1 .0]Hexenecarbaldehyde was taken up in ol (150 mL) and NaOMe (8.15 g, 151 mmol) was added. The mixture was heated under reflux for 24 h and then cooled to ambient temperature. The mixture was diluted with water and extracted with EtzO (200 mL><2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel leum ether/EtOAc = 10: 1) to afford trans-bicyclo[3. 1 .0]hexene—6-carbaldehyde (2.7 g, 23% yield over two steps) as a light yellow oil.

A mixture of trans-bicyclo[3. 1 .0]hexenecarba1dehyde (5.0 g, 6.3mmol), methyl 2-(benzyloxycarbonylamino)—2- (dimethoxyphosphoryl)acetate (23.0 g, 69.4 mol) and DBU (11.0 g, 69.4 mmol) in DCM (150 mL) was stirred at ambient temperature for 1 h. The mixture was poured into saturated aqueous NH4C1 (150 mL) and then extracted with DCM (100 mL><2). The combined organic layers were washed with saturated aqueous NH4Cl (100 mL><2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel leum ether/EtOAc = : 1 to 4: 1) to afford methyl 2-(benzyloxycarbonylamino)—3-(trans-bicyclo[3.1.0]heXen- crylate (7.0 g, 48% yield over two steps) as a colorless oil.

To a solution of methyl 2-(benzyloxycarbonylamino)(trans-bicyclo[3.1.0]hex- 2-en-6—yl)acrylate (10.0 g, 33 mmol) in methanol (200 mL) was added PtOz (0.8 g). The mixture was stirred under hydrogen atmosphere for 2 h. The mixture was filtered through a pad of Celite and then concentrated to afford crude methyl 2-(benzyloxycarbonylamino) (trans-bicyclo[3.l.0]hexanyl) propanoate, which was used directly without fiirther purification.

] To a solution of crude methyl 2-(benzyloxycarbonylamino)-3 —(trans— bicyclo[3.1.0]hexanyl) propanoate (10.0 g, 31.0 mmol) in methanol (300 mL) was added Pd/C (10%, 1.0 g). The mixture was stirred under hydrogen here for 12 h. The mixture was filtered through a pad of Celite and then concentrated. The residue was purified by flash column chromatography on silica gel (petroleum EtOAc = 20: 1 to 4:1) and prep-HPLC to afford the corresponding amine (0.9 g, 9% yield over two steps) as a colorless oil.

To a solution of amine (0.52 g,2.82 mmol ) in DCM (20 mL) containing Eth (0.96 mL, 7.06 mmol) was added AcCl (0.3 g, 3.67 mmol) dropwise at 0 °C over 30 min. The reaction mixture was stirred for l h at 0 oC and ted aqueous NaHC03 (20 mL) was added. The resulting mixture was extracted with DCM (20 mL) and the combined organic layers were concentrated to afford -amide (0.6 g, 94% yield) as a colorless oil.

To a mixture of acetyl-amide (0.60 g, 2.67 mmol ) in THF (20 mL) and water (20 mL) was added lithium hydroxide (0.6 g, 14.6 mmol). The reaction mixture was stirred at ambient ature for 0.5 h and d with water (50 mL). The solution was washed with EtOAc (50 mL) and the aqueous phase was adjusted to pH=4 with 2N s HCl (20 mL).

The resulting precipitate was collected by filtration and dried under vacuum to afford 2— acetamido(trans-bicyclo[3.1.0]hexanyl)propanoic acid (0.5 g, 89% yield) as a yellow solid.

A mixture of 2-acetamido(trans-bicyclo[3.1.0]hexanyl)propanoic acid (850 mg, 4.00 mmol) in water (5 mL) was adjusted to pH= 8.5 with 1M aqueous NaOH. The mixture was filtered and the filtrate was heated to 38 °C and L-acylase (100 mg) was added.

The mixture was stirred for 24 h and then filtrated. The filtrate was adjusted to pH= 2—3 with 1N aqueous HCl and the resulting mixture was washed with EtOAc (20 mLXZ).

The s layer was adjusted to pH=8-9 and a solution of BoczO (658 mg, 3.0 mmol) in acetone (10 mL) was added. The on mixture was stirred at ambient temperature overnight and acetone was removed. The remaining mixture was adjusted to pH=3-4 and then extracted with EtOAc (20 mLX2). The combined extracts were concentrated to afford (S)-3—(trans-bicyclo[3. l .0]hexanyl)—2—(tert—butoxycarbonylamino)propanoic acid (1.14 g, 28% yield over two steps) as a colorless oil.

The remainder of the synthesis was carried out according to the procedure for tert- butyl (2S)—3 -(3 -methylcyclopent- l -enyl)- l -((R)—2-methyloxiran—2-yl)-l — oxopropan ylcarbamate.

Example 21 tert-Butyl -((1R,3r,5 S)-bicyclo[3. l .0]hexan-3 -yl)- l 2-methyloxiran yl)-l —oxopropan-2—yl)carbamate: O UA'H4 [>4 —» TsCI Nal —» m —» OH OH OTs I AcNHCH(C02Et)2 1. L-Acylase t-BUOK NaOH 2. BOC2O —. —D —’ EtOOC NHRQOEt ACHN COOH Mel, K2003 IO CHZIZ, EtZZn “O. —* 1“ BocHN COOH BOCHN COOMe H2N COOMe "1.5 "15 1. ClCOzEt, NMM 80020 LiOH O 2. CH2NHOCH3 BocHN l COOMe BocHN COOH CII L5 CII I5 OI| |‘L BngJ\ NaCIO —’ —> o BOCHN o BOCHN BocHN A suspension of LiAlH4 (20.4 g, 0.54 mol) in THF (700 mL) was cooled to 0 °C under nitrogen. A solution of cyclopent-3 rboxy1ic acid (40.0 g, 0.36 mol) in THF (100 mL) was added se. The cooling bath was removed and the reaction e was warmed to 40 oC and stirred for 2 h. The mixture was cooled to 0 CC again and water (24 mL) was added dropwise carefially. The resulting mixture was acidified with dilute aqueous HCl to pH=2-3 and then extracted with EtOAc (300 mL><2). The organics were combined, washed with saturated aqueous NaHCO3 (300 mL><2) and brine (300 mL), dried over anhydrous sodium sulfate, and trated to afford cyclopenteny1methanol as a light yellow oil (300 g, 85% yield).

To a on of cyclopent-3—eny1methanol (71 g, 0.72 mol) in DCM (2.0 L) was added triethylamine (151 mL, 1.09 mol). The mixture was cooled to 0 °C and TsCl (179.4 g, 0.94 mol) was added in portions over 1.5 h. Then DMAP (4.4 g, 0.036 mol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred under nitrogen overnight. Saturated aqueous NaHC03 (1.0 L) was added and the two phases were separated.

The aqueous phase was extracted with DCM (500 mL). The organics were combined, washed with saturated aqueous NH4C1 (1.0 L) and brine (1.0 L), dried over ous sodium sulfate and concentrated to afford cyclopentenylmethyl 4-methylbenzenesulfonate as a brown oil (174 g, 95% yield), which was used in the next step without flirther purification.

To a solution of cyclopent-3—enylmethyl 4-methylbenzenesulfonate (174 g, 0.690 mol) in acetone (2.0 L) was added NaI (311 g, 2.07 mol). The reaction mixture was d at 70 °C overnight and then cooled to ambient temperature. Water (2.0 L) was added and the mixture was extracted with DCM (1 LX2). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether) to afford 4-(iodomethyl)cyclopent-l-ene as a light yellow oil (119 g, 82% yield).

Example 22 ] (S)((1R,3r,5S)—bicyclo[3.1.0]hexanyl)—2-((tert- butoxycarbonyl)amino)propanoic acid was synthesized from (1R,3r,5S) (iodomethyl)bicyclo[3.1.0]hexane in a r manner to the synthesis of (2S)—2—(tert— butoxycarbonylamino)—3 -(tetrahydrofuran-3—y1)propanoic acid To a solution of (S)—3-((1R,3r,5S)—bicyclo[3.l.0]hexanyl)—2-((tert— butoxycarbonyl)amino)propanoic acid (4.0 g, 15.8 mmol) in DMF (120 mL) was added K2C03 (3.3 g, 23.5 mmol). The mixture was stirred at ambient temperature for 0.5 h followed by addition ofMel (2.7 g, 18.8 mmol). The reaction mixture was stirred overnight and water (200 mL) was added. The ing mixture was extracted with MTBE (200 mL><2). The organics were combined, washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-methyl 2-(tert-butoxycarbonylamino)-3 opent enyl)propanoate (4.0 g, 95% yield) as a viscous oil, which was used in the next step without further purification.

To a solution of thyl 2-(tert-butoxycarbonylamino)—3-(cyclopent enyl)propanoate (2.38 g, 8.86 mmol) in DCM (100 mL) at 0 °C was added Et2Zn (1 M, 18.6 mL, 18.6 mmol) dropwise. The mixture was stirred for 15 min and a solution of CH212 (2.15 mL, 26.6 mmol) in DCM (13 mL) was added rapidly. The reaction mixture was d for 5 min and another portion of Etgzn (1 M, 9.75 mL, 9.75 mmol) was added ed by a solution of CH212 (2.15 mL, 26.6 mmol) in DCM (13 mL) again. The reaction mixture was allowed to warm to t temperature and stirred overnight. The mixture was cooled to 0 OC again and aqueous HCl (1 N) was added to adjust pH=1. Two phases were separated and the aqueous phase was d with s NaHCO3 to pH=8-9 and then extracted with DCM (30 mL><3). The organics were combined, dried over anhydrous sodium sulfate, and concentrated to afford (S)-methyl o-3—((1R,3r,5S)—bicyclo[3.1.0]hexan—3- yl)propanoate (1.54 g, 95% yield) as a Viscous oil, which was used in the next step without further purification.

(S)—Methyl 2-amino—3-((1R,3r,5S)-bicyclo[3.1.0]hexanyl)propanoate (1.54 g, 8.4 mmol) was dissolved in THF (25 mL) and BoczO (2.20 g, 10.1 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h and then concentrated. The residue was purified by flash column chromatography on silica gel leum ether/EtOAc = : 1) to afford (S)-rnethyl 3-((1R,3r,SS)-bicyclo[3.1.0]hexanyl)(tert- butoxycarbonylamino) propanoate (2.3 g, 96% yield) as a light yellow oil.

To a solution of (S)-methyl ,3r,5S)—bicyclo[3.1.0]hexanyl)—2-(tert— butoxycarbonylamino) propanoate (3.15 g, 11.1 mol) in water/THF (80 mL, 1:1) was added lithium hydroxide hydrate (1.40 g, 33.4 mol). The reaction mixture was stirred at ambient ature for 2 h and then washed with EtOAc (50 mL><2). The organic phase was discarded and the aqueous phase was acidified with aqueous HCl to pH=3 -4. The resulting mixture was extracted with DCM (100 mL><2) and the organics were combined and concentrated to afford (S)((1R,3r,5S)—bicyclo[3.1.0]hexanyl)—2-(tert— butoxycarbonylamino) propanoic acid (3.2 g, quantitative) as a Viscous oil that was used in the next step t further purification.

To a solution of (S)((1R,3r,5S)—bicyclo[3.1.0]hexanyl)—2-(tert- butoxycarbonylamino) propanoic acid (3.2 g, 11.89 mmol) in THF/DCM (50 mL, 1:1) at 0 0C was added ethyl chloroformate (1.35 mL, 14.27 mmol) followed by addition ofNMM (1.58 mL, 14.27 mmol) dropwise. The reaction mixture was stirred at 0 °C under nitrogen for 1 h ion A).

To a solution of N,0-dimethylhydroxylamine (HCl salt, 1.39 g, 14.3 mmol) in DCM (40 mL) at 0 CC was added TEA (2.16 mL, 15.50 mmol) dropwise. This mixture was transferred into the flask charged with solution A. The resulting mixture was allowed to warm to ambient temperature and d for 2 h. Water (50 mL) was added and two layers were separated. The organic layer was washed with water (50 mL), dried over anhydrous sodium e and trated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10:1 to 5:1) to afford tert—butyl (S)((1R,3r,5S)— bicyclo[3.1.0]hexanyl)(methoxy(methyl)amino)— l-oxopropanylcarbamate (3.0 g, 87% yield) as a colorless oil.

To a solution of tert—butyl (S)—3-((1R,3r,5S)—bicyclo[3.1.0]hexanyl)—1- (methoxy(methyl)amino)- 1-oxopropan—2-ylcarbamate (3.0 g, 9.6 mmol) in anhydrous THF (40 mL) was added freshly prepared propenylmagnesium bromide (38.4 mmol, 40 mL in THF) at 0 °C se. The reaction mixture was stirred at 0 °C for 2 h and then quenched with ted aqueous ammonium chloride (100 mL). The resulting mixture was extracted with EtOAc (50 mL><2) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was d by flash column chromatography on silica gel leum ether/EtOAc = 100:1 to 50: 1) to afford tert-butyl (S)((1R,3r,53)- bicyclo[3.1.0]hexan-3—yl)—4-methyloxopenten- 2-ylcarbamate (1.1 g, 39% yield) as a colorless oil.

A solution of tert—butyl (S)-1—((1R,3r,5S)—bicyclo[3.1.0]hexan—3-yl)—4—methyl—3- tenylcarbamate (1.6 g, 5.5 mmol) in DMF (27 mL) was cooled to -20 oC and bleach (8.30 mL, 10.9 mmol, 10% active spice) was added dropwise under nitrogen. The reaction e was warmed to 0 OC and stirred for 2 h. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (50 mL><2). The organic phases were combined, washed with brine (50 mL><2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel leum ether/EtOAc = 100: 1) to afford tert—butyl ((S)—3-((1R,3r,5S)—bicyclo[3.1.0]hexanyl)—1-((R)-2— methyloxiranyl)-l-oxopropanyl)carbamate (0.75 g, 44% yield) as a Viscous oil. 1H NMR(CDC13, 300 MHz): 8 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: 5.1Hz, 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), 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). MS (EI) for C17H27NO4, found 332.2 [M+Na]+. The stereochemical configuration was confirmed by x-ray crystallographic analysis.

Example 23 tert—Butyl ((S)—3 -(2-methylcyclopentenyl)((R)methyloxiranyl)—1- oxopropanyl)carbamate: O O LDA OEt KZCO3/Mel OEt HCI f)2 O —> —> O —>TfO BocHN 002Me Zn, f)C|2 1. LiOH 2\MgBr 2. CICOZEt MeNHOMe BocHN BocHN BocHN COZMe NaCIO BocHN To a suspension of ethyl yclopentanecarboxylate (20.3 g, 0.130 mol) and K2C03 (53.8 g, 0.390 mol) in acetone (90 mL) was added Mel (36.9 g, 0.250 mol) at ambient temperature. The reaction mixture was stirred for 30 min at ambient temperature and then heated under reflux for l h. Acetone was removed under reduced pressure and diethyl ether (200 mL) was added to the residue. The ing mixture was stirred for 15 min and filtered.

The filtrate was concentrated under reduced pressure followed by distillation under vacuum to afford ethyl 1-methyloxocyclopentanecarboxylate (20.5 g, 92% .

A mixture of ethyl l-methyl—2-oxocyclopentanecarboxylate (20.0 g, 0.120 mol) in HCl (concentrated, 150 mL) was heated under reflux for 3 h. The mixture was cooled to ambient temperature and then ted with DCM (150 mL><3). The ed organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-methylcyclopentanone (9.5 g, 80% yield) as a colorless oil.

To a solution of 2-methylcyclopentanone (59.5 g, 0.610 mol) in THF (500 mL) was added LDA solution (2N, 303 mL, 0.610 mol) at -78 °C. The mixture was stirred for 16 h at -78 OC followed by addition of a solution of N—phenyltriflimide (260 g, 0.730 mol) in THF (150 mL) at -78 oC Via cannula. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction was quenched with 10% aqueous NaOH (200 mL) and the resulting mixture was extracted with diethyl ether (300 mLX3). The combined c phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude oil was purified by flash column chromatography on silica gel (petroleum ether) to afford ylcyclopent-l-enyl trifluoromethanesulfonate (104 g, 74% yield).

To a sion of Zn powder (11.7 g, 180 mmol) in freshly distilled DMF (20 mL) was added trimethylsilyl chloride (5.0 mL, 0.2 eq.) under N2 here. The suspension was d vigorously for 35 min. The resulting pale orange supernatant was removed Via a syringe. The ted Zn was washed with DMF (20 mLX2). To a suspension of the activated Zn powder in y distilled DMF (50 mL) was added methyl N—(tert— butoxycarbonyl)-3 -iodo-L-alaninate (9.8 g, 30 mmol) at 0 CC. The mixture was stirred for 5 min and the cooling bath was d. The mixture was stirred for 20 min at ambient temperature. The grayish supernatant was transferred Via a syringe into a dry flask under N2 and the remaining zinc metal was washed with DMF (10 mL) followed by the transfer (solution A).

] To a solution of 2-methylcyclopent-l-enyl trifluoromethanesulfonate (8.60 g, 37.5 mmol) in DMF (18 mL) was added Pd(dppf)C12 (1.2 g, 1.5 mmol). The resulting brown solution was stirred at ambient temperature for 20 min. The solution A was added at 0 °C and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was poured into water/EtOAc (1 :1, 300 mL) and the resulting suspension was filtered through a pad of Celite. The two phases were separated and the aqueous phase was ted with EtOAc (150 mL><2). The combined organics were washed with water (200 mL><2) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/EtOAc = 9: 1) to afford (S)-methyl rt—butoxycarbonyl)amino)(2- cyclopent-l-en-l-yl) propanoate (5.9 g, 68% yield) as a pale yellow oil.

To a solution of (S)-methyl 2-((tert—butoxycarbonyl)amino)(2-methylcyclopent- l-en-l-yl) propanoate (35.0 g, 0.124 mol) in MeOH/HzO (250 mL/125 mL) was added LiOH-HZO (10.4 g, 0.25 mol) at 0 CC. The reaction mixture was stirred for 1 h at 0 CC and then was adjusted to pH=7-8 with aqueous HCl (0.5 N). The organic solvent was removed under reduced pressure and the remaining mixture was adjusted to pH=10 with aqueous NaOH (0.5 N). The solution was washed with EtOAc (150 mL><2) and adjusted to pH=3-4 with aqueous HCl (0.5 N). The resulting mixture was extracted with EtOAc (150 mL><3) and the combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium e, and concentrated to afford the corresponding acid (32 g, 96% yield) as a pale yellow oil.

The remainder of the synthesis was carried out according to the procedure for tert- butyl ((S)-3 -((1R,3r,5 S)-bicyclo [3. 1 .0]hexanyl)—l-((R)methyloxiranyl)—1-oxopropan- 2-yl)carbamate.

Example 24 [0044 l] tert—Butyl ((S)- l 2-methyloxiranyl)—l -oxo(2-oxopyrrolidin- l -yl)propan- 2-yl)carbamate: 1. Mel K2003 O CICHZNCHZgé-IZCOCI 2. NaH HZNfiALOH —. QM”$0,,82 3 3. LiOH NHBOC NHBOC &¢ EDCI A 0 MeNHOMe MQBF NHBocH —> @/\l\/’L éN o NHBoc NHBoc NaCIO 23 —>BocHN/géQO 4-Chlorobutanoyl de (12.1 g, 86 mmol) was added to a on of Boc-L- Dap (16.0 g, 78 mmol) in dioxane (160 mL) and 10% s Na2C03 (180 mL) at 0 °C dropwise. The reaction mixture was stirred at 0 0C for l h and then allowed to warm to ambient temperature and stirred overnight. The mixture was acidified with 1N s hydrochloric acid to pH=3 and extracted with EtOAc (300 mL><3). The combined organic phases were washed with 1N aqueous hydrochloric acid (300 mL>< 3) and brine (300 mL><1), dried over anhydrous sodium e, and concentrated to afford (S)(tert- butoxycarbonylamino)—3 -(4—chlorobutanamido)propanoic acid (15.5 g, 64% yield), which was used directly without fiarther purification.

K2C03 (7.0 g, 51 mmol) was added to a solution of (S)(tert— butoxycarbonylamino)—3 -(4-chlorobutanamido)propanoic acid (10.0 g, 34.0 mmol) in acetonitrile (100 mL) followed by addition of methyl iodine (5.6 g, 41 mmol). The suspension was heated at 50-60 °C for 4 h. After the mixture was cooled to ambient temperature, it was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and gs were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 2: 1) to afford the ponding ester.

The ester was dissolved in DMF (100 mL) and NaH (60% suspension, 1.1 g, 45 mmol) was added at 0 oC. The reaction mixture was stirred at 0 0C for 1 h and then allowed to warm to ambient temperature and stirred overnight. The reaction was ed with ice— water (500 mL) and the resulting mixture was extracted with EtOAc (300 mL><3). The combined organic phases were washed with saturated aqueous NaHCO3 (500 mLX3), 1N s HCl (500 mL><3), and brine (300 mL>< 1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 1:1) to afford the methyl ester (6.0 g, 57% yield) as an oil.

The methyl ester (60 g, 21 mmol) was dissolved in MeOH (20 mL) and a solution of LiOH (2.0 g, 84 mmol) in water (10 mL) was added at 0 CC with stirring. The reaction mixture was stirred for 3 h and then acidified with 2 N s HCl to pH=3. The resulting mixture was concentrated to afford (S)—2-(tert-butoxycarbonylamino)—3-(2-oxopyrrolidin yl)propanoic acid (4.1 g, 72% yield), which was used ly t fiirther purification.

The remainder of the synthesis was carried out according to the procedure for tert- butyl (2S)—3 -(3 -methylcyclopentenyl)((R)methyloxiranyl) oxopropan ylcarbamate.

Example 25 tert—Butyl ((2S)— 1 -((R)methyloxirany1)(2-oxopyrrolidin-3 - yl)propanyl)carbamate: o LiHMDS o M6000 MeOOC BrCHch MeOOC H2. Pd/C OMe OMe OMe# NHBoc NHBoc NHBoc Et3N fi/Br 1. LiOH O O O O O O 2. HNMe(OMe) BuLi , .—o ‘— \ HN HN T HN 0M6 NHBOC NHBoc NHBoc Hzozl BocHN To a solution of u(OMe)—OMe (20.0 g., 72.6 mmol) in THF (50 mL) was added dropwise a solution of LiHMDS (26.3 g, 157 mmol) in THF (250 mL) at -78 0C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1.5 h and bromoacetonitrile (13.0 g, 108 mmol) was added se over 1 h while maintaining the temperature below -70 OC.

The reaction mixture was stirred at -78 °C for 2 h and quenched with oled methanol (10 mL) in one portion. The mixture was stirred for 10 min and then d with a pre-cooled solution of acetic acid (9 mL) in THF (60 mL). The mixture was stirred for 10 min and poured into brine (200 mL). The resulting mixture was extracted with EtOAc (300 mL><2) and the combined extracts were dried over anhydrous sodium sulfate and concentrated under d pressure. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc = 1:1) to afford (2S)-dimethyl 2-((tert—butoxycarbonyl)amino)—4- (cyanomethyl)pentanedioate (16.0 g, 70% yield) as a light brown oil.

To a solution of (2S)-dimethyl 2-((tert—butoxycarbonyl)amino) (cyanomethyl)pentanedioate (10.0 g, 31.8 mmol) in AcOH (240 mL) was added 10% Pd/C (2.0 g) and the mixture was stirred under H2 atmosphere (70 psi) for 3 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced re. The residue was treated with MTBE and evaporated again to afford (4S)-dimethyl 2-(2- aminoethyl)—4-((tert—butoxycarbonyl)amino)pentanedioate (crude) as a light pink solid.

] To a solution of (4S)-dimethyl 2-(2-aminoethyl)((tert— butoxycarbonyl)amino)pentanedioate (crude) in THF (20 mL) was added Et3N (20 mL). The reaction mixture was stirred at 60 CC overnight and then cooled to ambient temperature.

Water (50 mL) was added and the resulting mixture was extracted with methylene chloride (100 . The organic layers were combined, dried over ous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc = 1:1) to afford (2S)-methyl 2-((tert— butoxycarbonyl)amino)(2-oxopyrrolidinyl)propanoate (5.5 g, 60% yield over two steps) as a light brown oil.

To a solution of (2S)-methyl 2-((tert—butoxycarbonyl)amino)—3-(2-oxopyrrolidin- 3-yl)propanoate (5.5 g, 19 mmol) in methanol (50 mL) and water (25 mL) was added lithium hydroxide (1.6 g, 38 mmol). The mixture was stirred at ambient temperature for l h. The solution was diluted with water (50 mL) and washed with EtOAc (50 mL). The aqueous phase was adjusted to pH=2 with 0.1 N aqueous HCl and the resulting mixture was extracted with EtOAc (100 mL><2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the corresponding acid (5.1 g, quantitative) as a yellow oil.

A mixture of dimethylhydroxylamine hydrochloride (1.14 g, 11.7 mmol), the acid (2.12 g, 7.80 mmol), EDCI (2.24 g, 11.7 mmol) and HOBt (1.58 g, 11.7 mmol) in DMF (10 mL) was cooled to 0 °C and triethylamine (3.0 mL, 23.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min and saturated aqueous sodium bicarbonate (50 mL) was added. The resulting mixture was ted with EtOAc (50 mL><2).

The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20: 1) to afford tert—butyl ((2S)—l-(methoxy(methyl)amino)-1—oxo- 3-(2-oxopyrrolidinyl) propanyl)carbamate (1.3 g, 53% yield) as a yellow oil. n-BuLi (2.5 M, 3.17 mL, 7.9 mmol) was added dropwise to a solution of isopropenyl bromide (0.9 g, 8.3 mmol) in THF (15.0 mL) at -78 CC and the mixture was d at -78 °C for 30 min. A solution of tert—butyl ((ZS)-l-(methoxy(methyl)amino)-l-oxo- 3-(2—oxopyrrolidinyl) yl)carbamate (500 mg, 1.58 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was stirred at -78 0C for 3 h and then allowed to warm to t temperature and stirred for 12 h. ted aqueous NH4C1 (50 mL) was added and the resulting mixture was ted with EtOAc (50 . The combined extracts were washed with brine, dried over anhydrous sodium e, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to afford tert-butyl ((2S)methyl-3 -oxo(2-oxopyrrolidin-3 -yl)penteny1)carbamate (200 mg, 42% yield) as a yellow oil.

To a solution of tert—butyl ((2S)methyloxo-l-(2-oxopyrrolidinyl)pent enyl)carbamate (200 mg, 0.67 mmol) in methanol (10 mL) at 0 °C was added 30% H202 (l .5 g, 1.4 mmol) followed by addition of benzonitrile (520 mg, 5.00 mmol) and DIPEA (0.87 mL, 5.0 mmol). The on mixture was d for 8 h at t temperature and then diluted with water (25 mL). The resulting mixture was extracted with EtOAc (50 mL><2).

The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc = 2:1) to afford utyl ((S)((R)rnethyloxiranyl)oxo( oxopyrrolidin—3-yl) propanyl)carbamate (95 mg, 45% yield) as a yellow oil.

Example 26 utyl ((2S)-3 -( 1 -methyloxopyrrolidin-3 -y1)((R)methyloxiranyl)-l- oxopropanyl)carbamate: LiHMDS o M6000 MeOOC\/\H(J:O|V|e 0M6 BrCHZCN MeOOC H Pd/C OMez—_ NHBOC NHBOC NHBoc NC NH2 HCHO Br 1.Et3N meOOC o o \l/ 2 “OH o o OMe Bu“ 3. HNMe(OMe) NHBoc ‘ ,O\<— MeN MeN T NHMB NHBoc NHBoc H202 l BocHN The synthesis of tert-butyl ((S)((R)-l-methyl-2—oxopyrrolidin-3—yl)-l-((R) methyloxiranyl)-l -oxopropanyl)carbamate was carried out in a r manner to tertbutyl ((S)-l-((R)methyloxiranyl)—1-oxo(oxopyrrolidin-3 -yl) propan—2- yl)carbamate.

The crude (4S)-dimethyl 2—(2-aminoethyl)((tert- butoxycarbonyl)amino)pentanedioate (5.00 g, 15.7 mmol) was dissolved in methanol (100 mL) and 40% formaldehyde (1.0 g, 14 mmol) and Pd/C (0.8 g) were added. The mixture was stirred under H2 atmosphere (20 psi) for 8 h at ambient temperature. The mixture was filtered h a pad of Celite and the filtrate was ated under reduced pressure to afford (2S)- dimethyl 2-((tert-butoxycarbonyl)amino)(2-(methylamino)ethyl)pentane dioate (5.0 g, crude) as a dark brown oil.

Example 27 (S)—2-Amino-3 -((S)—3 ,3 -difluorocyclopentyl)—l -((R)methyloxiran-2—yl)propanone and (S)—2-amino-3 3 ,3 -difluorocyclopentyl)—1 -((R)methyloxiranyl)propan- l - 0116: BocHNlCOOMeI1 I 1 H2 Pd/C of—>PPh3I2 Zn, a)3 2_ DAST BOCHN COOMe BOCHN COOMe 1 LiOH 2 MeNH(0Me) 3 3ng 1 TFA NaCIO 2. Cbz-OSu BocHN BocHN CszN H2 Pd/C,TsOH O —’ CszN Separation by. 0 chiral HPLC —> F [BF F H2 Pd/C, TSOH 0“ 6F . \\\.

CszNW A mixture of iodine (121 g, 0.480 mol) and triphenylphosphine (135 g, 0.520 mol) WO 52134 2014/026987 in acetonitrile (600 mL) was stirred for 2 h at ambient temperature. Then cyclopentane-l ,3- dione (39.2 g, 0.400 mol) and triethylamine (66.1 mL, 0.480 mol) were added. The reaction mixture was stirred overnight at 100 CC. The mixture was cooled to ambient temperature and concentrated. The residue was purified by flash column tography on silica gel (petroleum ether/EtOAc = 20:1 to 5:1) to afford 3-iodocyclopentenone (56 g, 67% yield) as a colorless solid.

A solution of (R)-methyl 2-(tert—butoxycarbonylamino)iodopropanoate (32.9 g, 0.100 mol) in DMF (20 mL) was added to a e ofZn (19.5 g, 0.300 mol) and iodine (6.6 g, 26 mmol) in DMF (30 mL) under nitrogen protection. The mixture was stirred for 1 h at ambient temperature. Then a solution of 3-iodocyclopentenone (20.8 g, 0.100 mol) in DMF (50 mL), Pd2(dba)3 (2.3 g, 2.5 mmol) and S-Phos (2.1 g, 5.0 mmol) were added successively. The reaction mixture was stirred overnight at 50 °C. The mixture was cooled to t temperature and water (100 mL) was added. The resulting mixture was extracted with EtOAc (150 mL><3). The combined c extracts were dried over anhydrous sodium sulfate and trated. The e was purified by flash column tography on silica gel (petroleum ether/EtOAc = 5:1 to 2:1) to afford (S)-methyl 2—(tert—butoxycarbonylamino)- 3-(3—oxocyclopent-l-enyl)propanoate (17 g, 60% yield) as a pale yellow oil.

A solution of (S)-methyl 2-(tert-butoxycarbonylamino)(3-oxocyclopent enyl)propanoate (23.0 g, 81.2 mmol) in methanol (100 mL) was hydrogenated in the presence of Pd/C (3.0 g) overnight at ambient temperature. Pd/C was filtered off and the filtrate was concentrated to give a colorless oil (22.0 g).

The crude cyclopentanone (22.0 g, 77.2 mmol) was ved in dichloromethane (100 mL) and DAST (37.3 g, 0.230 mol) was added. The reaction mixture was stirred for 2 d at ambient ature and then poured into saturated aqueous sodium bicarbonate (100 mL).

The two layers were separated and the aqueous layer was ted with dichloromethane (100 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1 to 10:1) to afford (2S)-methyl 2-(tert—butoxycarbonylamino)- 3-(3,3-difluorocyclopentyl)propanoate (15 g, 63% yield) as a pale yellow oil.

LiOH—HgO (6.2 g, 0.15 mol) was added to a mixture of (2S)-methyl 2—(tert- butoxycarbonylamino)-3 -(3,3-difluorocyclopentyl)propanoate (15.0 g, 48.8 mmol) in water/THF (50 mL/50 mL). The reaction mixture was stirred for l h at ambient temperature.

THF was removed and the remaining aqueous solution was acidified to pH=4-5 with 10% aqueous KHSO4. The resulting mixture was extracted with EtOAc (100 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated to afford the ponding acid (14.3 g) as a pale yellow oil, which was used directly without further purification.

The crude acid (14.3 g, 48.8 mmol) was ved in dichloromethane (100 mL) and N—methylmorpholine (4.93 g, 48.8 mmol) was added. The solution was cooled to 0 °C and isobutyl ochloridate (6.70 g, 48.8 mmol) was added dropwise. The mixture was stirred for 1 h at 0 °C followed by addition of a mixture of N,O—dimethylhydroxyl amine HCl salt (5.23 g, 53.7 mmol) and triethylamine (7.67 mL, 55.2 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 1 h at ambient temperature. The mixture was poured into water (150 mL) and the two phases were separated. The aqueous phase was extracted with EtOAc (100 mLX3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1 to 10: 1) to afford the corresponding Weinreb amide (11.0 g) as a colorless oil.

The Weinreb amide (11.0 g, 32.7 mmol) was dissolved in THF (100 mL) and a solution of propenylmagnesium bromide (28.5 g, 0.200 mol) in THF (100 mL) was added at 0 CC. The reaction mixture was stirred for 2 h at 0 CC and then 2 h at ambient temperature. The mixture was poured into 10% aqueous nitric acid (150 mL) and the resulting mixture was extracted with EtOAc (200 mL><3). The organic extracts were combined, dried over ous sodium sulfate, and concentrated. The residue was d by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1 to 10: 1) to afford utyl (2R)— 1 -(3 ,3 -difluorocyclopentyl)methyl-3 -oxopent—4-enyl ate (4.5 g, 29% yield over three . s NaClO (10%, 70.6 g, 94.6 mmol) was added dropwise to a solution of tert-Butyl (2R)(3,3-difluorocyclopentyl)methy1oxopentenyl ate (5.00 g, .8 mmol) in DMF (20 mL) at -20 CC while maintaining the internal temperature below -10 °C. The reaction mixture was stirred for 2 h at 0 CC and then overnight at ambient temperature. The mixture was poured into water (100 mL) and the resulting mixture was extracted with EtOAc (150 mLX3). The organic extracts were combined, dried over anhydrous sodium sulfate, and trated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1 to 10: 1) to afford tert-butyl (2S)—3-(3 ,3 -difluorocyclopentyl)((R)methyloxiranyl)—1-oxo propany1carbamate (2.5 g, 48% .

TFA (1.71 g, 15.0 mmol) was added to a solution of tert—butyl (2S)—3—(3,3- difluorocyclopentyl)—1-((R)methyloxiran-2—yl)oxo propanylcarbamate (2.5 g, 7.5 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 2 h at ambient temperature and then concentrated to afford the amine (quantitative).

The amine (TFA salt, 7.5 mmol) was dissolved in 1,4-dioxane (30 mL) and then neutralized with saturated aqueous sodium bicarbonate to pH=8 at 0 oC. Cbz-OSu (2.24 g, 9.0 mmol) was added and the reaction mixture was stirred for 3 h at ambient temperature.

The mixture was extracted with EtOAc (50 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The e was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 30:1 to 10: 1) to afford a mixture of diastereomers (2.4 g, 69% yield), which was further separated by chiral prep- HPLC to afford pure benzyl (S)—3-((S)—3,3-difluorocyclopentyl)—1-((R)-2—methyloxiran-2—yl)- 1-oxo propan—2-ylcarbamate (1.1 g) and benzyl ((R)—3,3-difluorocyclopentyl)((R) methyloxiran—2—yl)oxo propanylcarbamate (0.7 g), tively.

Benzyl (S)—3-((S)—3,3-difluorocyclopentyl)-1 -((R)methyloxiranyl)oxo propany1carbamate (200 mg, 0.550 mmol) was hydrogenated in the presence of Pd/C (0.1 g) and p-TsOH-HZO (104 mg, 0.550 mmol) in methanol (6 mL) for 1 h at 0-5 c’C. Pd/C was filtered off and then the filtrate was trated to dryness to e (S)—2-amino((S)— 3 ,3 -difluorocyclopentyl)((R)methyloxiran—2-yl)propanone which was used immediately.

] (S)amino-3 -((R)-3 ,3 -difluorocyclopentyl)((R)methyloxiranyl)propan- 1-one was synthesized in a similar manner.

Example 28 tert—Butyl ((S)-3 -((1r,4S)-4—((4-methoxybenzyl)oxy)cyclohexyl)((R)—2- methyloxiranyl)-1 -oxopropanyl)carbamate: O OH Me04©—\ CCI3 OPMB PtOQ’ H2 “ NH 0’ —> PPTS I PrOH._ BOCHN BOCHN/Lfo DCM 0Me BocHN/Rhonae OPMB opt/IE3)L NaOH (aq) “"0, CDI. DCM, DIEA w.O MgBr MeOH BocHNJfifo'i —> L]? —.

'V'eNHO'V'e-HC' THF 0 /N\ PMBO0,, PMBO NaOCI, DMF I U,l/ BocHN BocHN O 0 A mixture of (S)-methyl rt—butoxycarbonyl)amino)(4— yphenyl)propanoate (15.0 g, 64.0 mmol), acetic acid (322 uL, 5.59 mmol), and um oxide (1.29 g, 5.66 mmol) in isopropanol (322 mL) in a Parr shaker jar was hydrogenated with hydrogen (60 psi) for 2 h. The e was filtered h a pad of Celite and concentrated. Purification by column chromatography (1 :1 hexanes/EtOAc) provided a mixture of cis/trans isomers (33.0 g) that was recrystallized from EtOAc to provide -cz's alcohol thyl 2—((tert-butoxycarbonyl)amino)-3—(( 1 s,4R)—4- hydroxycyclohexyl)propanoate (1.93 g, 10%, 90% purity) as a colorless solid, -trans alcohol (S)-methyl 2—((tert-butoxycarbonyl)amino)—3-((1r,4S)—4-hydroxycyclohexyl)propanoate (1 .4 1 mg, 7%, 85% purity) as clear oil, and over-reduced (S)—methyl 2-((tert— butoxycarbonyl)amino)—3-cyclohexylpropanoate (10.3 g, 56%). The enriched isomer was used in the subsequent reaction without further purification.

A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)—3-((1r,4S) hydroxycyclohexyl)propanoate (20.0 g, 66.5 mmol) in dichloromethane (200 mL) at 0 0C was added 2,2,2-trichloro-acetimidic acid 4-methoxy-benzyl ester (28.0 g, 99.7 mmol) and PPTS (1.67 g, 6.65 mmol). The reaction mixture was allowed to warm to ambient temperature over 24 h. Dichloromethane (200 mL) was added and the organic layers were washed with sodium bicarbonate (sat), water, brine, and dried over sodium sulfate, filtered, and concentrated.

Purification by column chromatography provided thyl 2—((tert-butoxycarbonyl)amino)- 3-((1r,4S)((4-rnethoxybenzyl)oxy)cyclohexyl)propanoate (23.0 g, 82%) as a colorless oil. 1H NMR (300 MHz,CDC13)5 7.26 (d, J = 8.7 Hz, 1H), 6.87 (d, J: 8.7 Hz, 1H), 4.88 (d, J: 8.1 Hz, 1H), 4.47 (s, 2H), 4.33 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.26 (m, 1H), 2.08 (m, 2H), 1.90 (m, 2H), 1.74—1.15 (m, 5H), 1.43 (s, 9H), 0.89 (m, 2H). MS (EI) for C23H35N06, found 444.2 [M+Na]+.

To a solution of (S)—methyl 2—((tert-butoxycarbonyl)amino)-3—((1r,4S)—4-((4- methoxybenzyl)oxy)cyclohexyl)propanoate (15.0 g, 35.6 mmol) in MeOH (150 mL) at 0 0C was added NaOH (aq, 1 M, 71.2 mL, 71.2 mmol). The mixture was stirred at ambient temperature for 4 h. After removal of the solvent, the residue was diluted with dichloromethane (200 mL) and the on was adjusted with HCl (1M) to pH 2-3. The organic layer was washed with water and brine, dried over sodium sulfate, d, and concentrated. Purification by column chromatography provided (S)((tert— butoxycarbonyl)amino)((1r,4S)—4-((4-methoxybenzyl)oxy)cyclohexyl)propanoic acid (12.5 g, 86%).

To a solution of (S)—2-((tert—butoxycarbonyl)amino)—3—((1r,4S)—4-((4- methoxybenzyl)oxy)cyclohexyl)propanoic acid (12.5 g, 30.7 mmol) in DCM (150 mL) at 0 0C was added carbonyl diimidazole (6.48 g, 40.0 mmol) and the mixture was stirred at 0 0C for 0.5 h. To the solution was added ylhydroxylamine hydrochloride (5.99 g, 61.4 mmol) and DIEA (7.90 g, 61.4 mmol). The mixture was allowed to warm to ambient temperature and stirred for 20 h. The organic layer was washed with water, 0.2 N HCl, sodium bicarbonate (sat), water, brine, and dried over sodium sulfate. The c layers were combined, filtered, and concentrated. Purification by column chromatography provided tert-butyl ((5)1 -(methoxy(methyl)amino)-3 -((l r,4S)((4-methoxybenzyl)oxy)cyclohexyl)- 1-oxopropan-2—yl)carbamate (8.9 g, 64%).

To a solution of utyl -(methoxy(methyl)amino)—3-((1r,4S)—4-((4- methoxybenzyl)oxy)cyclohexyl)oxopropanyl)carbarnate (8.9 g, 19.8 mmol) in THF (50 mL) was added 2-propenylmagnesium bromide (0.5 M, 118 mL, 59.3 mmol) dropwise over 1 h. The mixture was stirred at —20 °C for 2 d then allowed to warm to ambient temperature.

The mixture was stirred for an additional 2 h then poured into saturated s NH4Cl (400 mL) and stirred for 1 h. EtOAc (200 mL) was added and the mixture was ed with HCl (6 N) to pH 2-3. The organic layer was washed with water and brine, and dried over sodium sulfate. The solution was filtered, concentrated, and purified by silica gel column chromatography to provide tert—butyl ((S)- 1 4S)—4-((4-methoxybenzyl)oxy)cyclohexyl)- yl-3 -oxopentenyl)carbamate (7.4 g, 87%).

To a solution of tert—butyl ((S)((1r,4S)((4-methoxybenzyl)oxy)cyclohexyl)- 4-methyl-3 -oxopentenyl)carbamate (7.40 g, 17.2 mmol, 1.0 eq) in DMF (130 mL) at - 0C was added NaOCl (6% w/w, 42.6 mL, 34.4 mmol) at a rate to maintain an internal temperature below 5 -10 0C. The mixture was stirred at 0 0C for 7 h then diluted with EtOAc (150 mL) and water (150 mL), and extracted with EtOAc (2X). The organic layers were washed with water and brine, dried over sodium e, filtered, and concentrated. The crude residue was purified by column chromatography to provide tert—butyl ((S)—3-((1r,4S)((4— methoxybenzyl)oxy)cyclohexyl)((R)methyloxiranyl)oxopropany1)carbamate (3.12 g, 41%).1H NMR (300 MHz, CDC13)8 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, 3H), 3.27 — 3.25 (m, 2H), 2.88 (d, J = 5.1 Hz, 1H), 2.11 — 1.84 (m, 3H), 1.72 — 1.65 (m, 2H), 1.51 (s, 3H), 1.48 (s, 9H), 1.50 — 0.98 (m, 6H). MS (EI) for C25H37NO6, found 470.2 [M+Na]+.

Example 29 tert—Butyl ((S)-3 hexyl((R)—2-methyloxiranyl)oxopropan yl)carbamate: isobutylchloroformate MeNHOMeHCI TEA DCM L NMM | Bng BOCHN BOCHN N‘OMe ' I NaOCI, DMF BocHN BocHN ] To a solution of dimethylhydroxylamine hydrochloride (3.98 g, 40.6 mmol) in DCM (50 mL) at 0 °C was added triethylamine (5.43 mL, 41.9 mmol). In a separate flask (S)- rt—butoxycarbonyl)amino)—3-cyclohexylpropanoic acid (10.0 g, 36.9 mmol) in DCM (50 mL) and THF (50 mL) was cooled to 0 oC and isobutylchloroformate (4.83 mL, 36.9 mmol) was added followed by N-methylmorpholine (4.06 mL, 36.9 mmol). After 1 h it was added to the dimethylhydroxylamine mixture. The combined mixture was allowed to warm to ambient temperature over 16 h at which time it was quenched with water, washed with sodium bicarbonate (sat.), extracted with EtOAc (2 X), washed with brine, dried with sodium sulfate, filtered, and concentrated. (S)-tert-Butyl (3-cyclohexyl(methoxy(methyl)amino) oxopropanyl)carbamate (12.2 g) was provided as a ess oil that was carried forward without further purification. MS (EI) for C16H30N204, found 215.3 ]+.

To rt—butyl (3—cyclohexyl(methoxy(methyl)amino)-1 —oxopropan yl)carbamate (12.2 g, 38.9 mmol) in THF (150 mL) at 0 0C was added isopropenylmagnesium bromide (71.2 mL of a 1.5 N solution in methyl—THF, 0.107 mol) dropwise. After stirring at 0 °C for 2 h the mixture was quenched with heptane/citric acid (1:1). The product was extracted with EtOAc (2X), washed with brine, dried with sodium sulfate, filtered, and concentrated. The crude product was triturated from cold (0 oC) methanol to provide rt-buty1 (1-cyclohexy1methy1-3 ntenyl)carbamate (5.36 g, 49%) as a ess crystalline solid. MS (EI) for C17H29N03, found 196.2 ]+.

To (S)—tert—butyl (1-cyclohexylmethyl-3—oxopent—4-enyl)carbamate (5.36 g, 18.1 mmol) in DMF at -10 0C was added NaOCl (47.1 mL of a 9.5% w/w solution, 36.2 mmol). Addition ofNaOCl was performed at a rate to maintain an internal temperature of S - °C. After the on was complete the reaction mixture was transferred to an ice bath and stirred for an additional 2 h at which time it was diluted with water and EtOAc, extracted with EtOAc (2 ><), washed with brine, dried with sodium sulfate, filtered, and trated.

Purification by column chromatography (3 :1 heptane/EtOAc) provided tert-butyl ((S) cyclohexyl-l-((R)methyloxiran-2—yl)oxopropan—2-y1)carbamate (3.68 g, 65%) as a colorless ous solid. MS (EI) for C17H29NO4, found 310.2 (MH').

The following compounds were synthesized in a similar manner: tert-butyl ((S)-3 -cyclopropyl((R)methyloxiranyl)-1 -oxopropan yl)carbamate tert—butyl ((S)—3 -cyclobutyl((R)methyloxiranyl)oxopropan yl)carbamate Example 30 tert—Butyl ((S)-3 -cyclopentyl((R)-oxiran—2-yl)-1—oxopropanyl)carbamate: O O BocZO, NEt3, O AcCl, MeOH DCM HO OH —’ HO OMe — ’ HO OMe NH2 NH2 HCI NHBoc Iz, PPh3, O _ ' | OMe NHBoc TfZO, Nach3, I OMe 0:0 DCM NHBoc —> OTf —> we Zn, TMS-Cl Pd(dppf)C|2, DMF NHBOC ethyl LiOH H20, H2: Pd/C, MeOH O chloroformate.

MeOH NMM, THFIDCM; OH —’ OH —’ MeONHMe HCI, NHBoc NHBoc DCM, TEA /\MgBr BocHN BocHN ol (450 mL) in a bottom flask was cooled to 0 oC and acetyl chloride (55 mL, 0.77 mol) was added dropwise. After completion of the on, the mixture was stirred at ambient temperature for 10 min and H-Ser-OH (30 g, 0.29 mol) was added in three portions. The reaction mixture was heated at 80 °C for 2 h and then concentrated. The e was dried under vacuum to afford (S)-methyl 2-amino hydroxypropanoate hydrochloride (quantitative) as a ess solid, which was used in the next step without further purification.

The crude (S)-methyl 2-aminohydroxypropanoate hydrochloride (0.29 mol) was suspended in DCM (200 mL) and to this mixture was added triethylamine (79 mL, 0.57 mol) and B0020 (68 g, 0.31 mol) at 0 CC. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight and then diluted with MTBE (300 mL).

The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford thyl 2— ((tert—butoxycarbonyl)amino)—3-hydroxypropanoate (60 g, 94% yield) as a colorless oil.

A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50 mol) in DCM (600 mL) was cooled to 0 oC and iodide (127 g, 0.50 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h.

WO 52134 After the mixture was re-cooled to 0 °C, a solution of (S)-methyl 2-((tert- butoxycarbonyl)amino)hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was d to remove triphenylphosphine oxide. The filtrate was concentrated and the e was purified by flash column chromatography on silica gel to afford (R)-methyl 2-((tert-butoxycarbonyl)amino)iodopropanoate (74.0 g, 68% yield) as a colorless solid.

The synthesis of cyclopent-l-en-l-yl trifluoromethanesulfonate was described in the procedure for tert-Butyl ((S)-3 -(cyclopentenyl)((R)methyloxirany1)—1- oxopropanyl)carbamate ] To a suspension of zinc (123 g, 1.90 mol) in DMF (500 mL) was added TMSCl (46 mL) dropwise. The mixture was stirred at ambient temperature for 45 min. The upper clear liquid was drained out and the residue was washed with DMF (2x200 mL). The resulting solid was re-suspended in DMF (200 mL) and the e was cooled to 0 °C. A solution of (R)-methyl 2-((tert—butoxycarbonyl)amino)iodopropanoate (104 g, 0.320 mol) in DMF (300 mL) was added. The mixture was stirred at 0 °C under nitrogen for 20 min. The upper clear liquid was drained out and added dropwise to a solution of cyclopent-l-en-l—yl romethanesulfonate (90 g, 0.37 mol) and Pd(dppf)C12 (3.9 g, 4.7 mmol) in DMF (500 mL). After addition, the reaction mixture was stirred at 50 CC under nitrogen overnight then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with MTBE (3 X300 mL). The organic layers were ed, washed with brine, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 100:1 to 40:1) to afford (S)-methyl rt— butoxycarbonyl)amino)—3-(cyclopentenyl)propanoate as a viscous oil (62 g, 72% .

To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)(cyclopenten yl)propanoate (62 g, 0.23 mol) in water/methanol (900 mL, 2:1) was added lithium hydroxide hydrate (19.3 g, 0.460 mol). The on mixture was stirred at ambient temperature overnight and then concentrated to remove most of the methanol. The residue was washed with DCM (400 mL) and the aqueous phase was acidified with dilute HCl to pH=3 -4. The resulting mixture was extracted with DCM (3 X300 mL). The organic layers were ed and concentrated to afford (S)((tert—butoxycarbonyl)amino)-3 -(cyclopenten yl)propanoic acid (56 g, 95% yield) as Viscous oil, which was used in the next step t further purification.

To a solution of (S)—2-((tert—butoxycarbonyl)amino)—3 -(cyclopent-l-en-l - yl)propanoic acid (56 g, 0.22 mol) in methanol (500 mL) was added Pd/C (23 g, 0.022 mol, %). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of celite. The e was concentrated under reduced pressure to afford (S)—2—((tert-butoxycarbonyl)amino)-3—cyclopentylpropanoic acid (55 g, 97% yield) as Viscous oil, which was used in the next step t further purification.

To a flask charged with compound (S)((tert-butoxycarbonyl)amino)—3- cyclopentylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The solution was cooled to 0 oC and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4 mL, 257 mmol) was added dropwise tially. After addition, the mixture was d at 0 0C under nitrogen for l h. To the other flask charged with N,O—dimethylhydroxylamine HCl (25.0 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0 °C and TEA (38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction flask. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was then quenched with water (500 mL) and the two phases were separated. The organic phase was washed with water (500 mL), dried over anhydrous sodium sulfate, and trated to afford (S)-tert—butyl (3 -cyclopentyl-l-(methoxy(methyl)amino)— l-oxopropanyl)carbamate as colorless oil (60 g, 93% , which was used in the next step without r purification.

To a on of (S)-tert-butyl (3-cyclopentyl-l-(methoxy(methyl)amino) oxopropanyl)carbamate (2.5 g, 8.3 mmol) in THF (35 mL) was added Vinylmagnesium bromide (16.7 mL, 33.3 mol) at 0 oC dropwise. After completion of the addition, the reaction mixture was stirred at 0 0C for 2 h and then quenched with saturated aqueous ammonium chloride (30 mL). The resulting mixture was extracted with EtOAc (2X40 mL). The c layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 100:1) to afford (S)-tert—butyl (l -cyclopentyl-3 -oxopentenyl)carbamate as a yellow oil (854 mg, 38% yield).

] A solution of (S)-tert-butyl (l-cyclopentyloxopentenyl)carbamate (854 mg, 3.20 mmol) in DMF (70 mL) was cooled to -20 °C and a bleach solution (9.50 mL, 12.8 mmol, 10% active spice) was added dropwise under nitrogen. The reaction mixture was warmed to 0 °C and stirred for 1.5 h. Water (70 mL) was added and the e was extracted with EtOAc (2X50 mL). The organic phases were combined, washed with brine (2X50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 80: 1) to afford tert- butyl ((S)cyclopentyl((R)-oxiranyl)—1-oxopropanyl)carbamate as a viscous oil (390 mg, contaminated with some ties, 43% yield) as a yellow oil.

Example 31 tert—Butyl ((S)—3 -(cyclopenten- 1 —y1)((R)methyloxiranyl)—1-oxopropan- 2-yl)carbamate: l/YkOMe NHBoc 2'" TMS'C' Tf20 NaZCO3 0 0:0 ’ . on f)CI2 DCM DMF NHBOEMEI lVleONHMe HCI, —>Wwethylchloroformate LiOH NMM N,o\ 2“MgBr H20 MeOH NHBoc THF DCM NHBotI: THF W?NaOCI O NHBoc BocHN To a solution of entanone (55 g, 0.66 mol) in DCM (1.3 L) was added Na2C03 (104 g, 0.980 mol) and the mixture was cooled to -20 OC. Trifluoromethanesulfonic anhydride (121 mL, 0.720 mol) was added dropwise. After the on, the cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight. GC-MS analysis showed the reaction was not complete and additional romethane sulfonic anhydride (33 mL, 0.20 mol) was added. The reaction mixture was stirred for another 4 h then quenched with water (800 mL). The aqueous phase was extracted with DCM (300 mL).

The organics were combined, washed with brine, and concentrated to afford cyclopentenyltrifluoromethanesulfonate as viscous oil (104 g, 73% , which was used in the next step without fiirther purification.

To a suspension of zinc (123 g, 1.90 mol) in DMF (500 mL) was added TMSCl (46 mL) dropwise. The mixture was d at ambient temperature for 45 min. The upper clear liquid was removed and the residue was washed with DMF (200 mL><2). The resulting solid was re-suspended in DMF (200 mL) and the mixture was cooled to 0 0C. A solution of (R)-methyl rt—butoxycarbonyl)amino)-3—iodopropanoate (104 g, 0.320 mol) in DMF (300 mL) was added. The mixture was stirred at 0 0C under nitrogen for 20 min. The upper clear liquid was removed and added to a solution of cyclopent-l -enyl trifluoromethanesulfonate (90 g, 0.37 mol) and Pd(dppf)C12 (3.9 g, 4.7 mmol) in DMF (500 mL) dropwise. After addition, the reaction mixture was stirred at 50 °C under nitrogen overnight then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with MTBE (300 mL><3). The organics were combined, washed with brine, and concentrated. The residue was purified by flash column chromatography on silica gel leum ether/EtOAc = 100:1 to 40: 1) to afford thyl 2-(tert- butoxycarbonylamino)-3 -cyclopentenylpropanoate as viscous oil (62 g, 72% . 1H NMR (300 MHz, 2 8 5.48 (br s, 1H), 4.97 (d, J: 6.6 Hz, 1H), .43 (m, 1H), 3.74 (s, 3H), 2.46-2.63 (m, 2H), 2.23-2.34 (m, 4H), .93 (m, 2H), 1.45 (s, 9H).

To a solution of (S)—methyl 2-(tert-butoxycarbonylamino) cyclopentenylpropanoate (62 g, 0.23 mol) in water/methanol (900 mL, 2: 1) was added lithium hydroxide hydrate (19.3 g, 0.460 mol). The on mixture was stirred at ambient temperature overnight and then concentrated to remove the majority ofmethanol. The residue was washed with DCM (400 mL) and the aqueous phase was acidified with diluted HCl to pH=3-4. The resulting mixture was extracted with DCM (300 mL ><3). The organic layers were combined and concentrated to afford (S)(tert-Butoxycarbonylamino) cyclopentenylpropanoic acid (56 g, 95% yield) as viscous oil, which was used in the next step without further purification. 1H NMR (300 MHz, CDC13): 8 10.47 (br. s, 1H), 5.52 (br. s, 1H), 4.98 (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).

] To a flask charged with (S)—2—(tert-Butoxycarbonylamino)-3— cyclopentenylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The solution was cooled to 0 °C and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4 mL, 257 mmol) were added se sequentially. After addition, the mixture was stirred at 0 °C under nitrogen for 1 h. To the other flask charged with N,O-dimethylhydroxylamine HCl (25 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0 °C and TEA (38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction flask. The reaction mixture was allowed to warm to t temperature and stirred overnight. The mixture was quenched with water (500 mL) and the organic phase was washed with water (500 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-terI-butyl (3-(cyclopent- 1 —enyl)—1 -(methoxy(methyl)amino)oxopropan yl)carbamate as ess oil (60 g, 93% yield), which was used in the next step without further purification.

To a solution of (S)—tert-butyl (3-(cyclopent-1—enyl) (methoxy(methyl)amino)oxopropanyl)carbamate (81 g, 0.27 mol) in THF (600 mL) was added freshly prepared prop—1-en-2—ylmagnesium bromide (96.0 mL, 1.08 mol) at 0 OC dropwise. After completion ofthe addition, the reaction mixture was stirred at 0 0C for 2 h then quenched with saturated aqueous ammonium chloride (500 mL). The resulting mixture was extracted with EtOAc (400 . The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was d by flash column chromatography on silica gel (petroleum ether/EtOAc = 100: 1) to afford (S)-tert—butyl (1- pent-l-en-l-yl)methyloxopentenyl)carbamate as ess oil (39.3 g, 52% yield).

A solution of (S)-tert-butyl (1-(cyclopentenyl)methyloxopenten bamate (10.0 g, 35.6 mmol) in DMF (180 mL) was cooled to -20 °C and bleach (54.0 mL, 71.2 mmol, 10%) was added dropwise under nitrogen. The reaction mixture was warmed to 0 °C and stirred for 1.5 h. Water (200 mL) was added and the mixture was extracted with EtOAc (200 mL><2). The c phases were ed, washed with brine (200 mL><2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel to afford utyl ((S)-3—(cyclopenten—1-yl)((R)- 2-methyloxiranyl)—l-oxopropanyl)carbamate as Viscous oil (5.6 g, 53% yield). 1H NMR (300 MHz,CDC13): 8 4.62 (s, l H), 4.91 (d, J: 7.5 Hz, 1 H), .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 manner: tert—butyl ((S)-3 -(cyclohex—1-enyl)((R)methyloxiranyl)—1—oxopropan- 2-yl)carbamate 1H NMR (300 MHz, CDCl3)Z 6 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: 5.1Hz, 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).

Example 32 tert—Butyl ((S)—3 -cyclopentyl- l -((R)methyloxiranyl)— l -oxopropan yl)carbamate: O/fOH O H2 Pd/C MeONHMe NHBoc NHBocH III/O\ NHBoc AMQBF WNaOCI NHBoc BocHN To a solution of (S)(tert-butoxycarbonylamino)—3O-cyclopentenylpropanoic acid (56 g, 0.22 mol) in methanol (500 mL) was added Pd/C (23 g, 0.022 mol, 10%). The mixture was stirred under a en atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of . The filtrate was concentrated under reduced re to afford (S)—2- (tert—butoxycarbonylamino)-3—cyclopentylpropanoic acid (55 g, 97% yield) as Viscous oil, which was used in the next step without further purification.

The remainder of the synthesis of tert-butyl ((S)-3 -cyclopentyl-l-((R)—2- methyloxiranyl)-l -oxopropanyl)carbamate was carried out in a similar manner to the synthesis of tert—butyl ((S)-3 -(cyclopent-l -en- 1 —yl)- l 2-methyloxiranyl)— l - oxopropanyl)carbamate. 1H NMR (300 MHz, CDC13): 8 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), 1.95-1.20 (m, 11H).

Example 33 ] tert—Butyl ((S)—3 -(3 ,3 -difluorocyclobutyl)- l -((R)-2—methyloxiran-2—yl) oxopropanyl)carbamate: 1 BnBr 1- H2 Pd/C ¢2H NaBH4 2. DAST 2. Meldrum'sacid HOAc COZBn 1. Brz 2. Heat F F F F 3. NH3 1. PGA 1' BnOH 2_ H2] pd/C 4. PhCHZCOCI 2. B0020 —> O —> NHCOBn coOH F F F F H HCI JLMgBr BocHN 0 o BocHN BocHN /N‘O/ NaCIO BocHN A mixture of yclobutanecarboxylic acid (25 g, 0.22 mol), benzyl bromide (45.14 g, 0.26 mol) and potassium carbonate (60.7 g, 0.44 mol) in DMF (200 mL) was stirred overnight at ambient temperature. The e was filtered off and the filtrate was poured into water (200 mL). The resulting mixture was extracted with EtOAc (200 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and trated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 100:1 to 20:1) to afford benzyl ester (38 g, 84% yield).

The benzyl ester was dissolved in dichloromethane (500 mL) and DAST (90 g, 0.56 mol) was added. The reaction mixture was stirred overnight at t temperature. The solution was poured into ice-cooled 10% aqueous sodium bicarbonate (400 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (300 mL><3).

The organics were combined, dried over ous sodium sulfate and trated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 200:1 to 50: 1) to afford benzyl 3,3-difluorocyclobutanecarboxylate (28 g, 67% yield).

A mixture of benzyl 3,3-difluorocyclobutanecarboxylate (28 g, 0.12 mol) and Pd/C (5 g) in methanol (150 mL) was hydrogenated for 2 h at ambient ature. Pd/C was filtered off and the filtrate was concentrated. The residue was dissolved in dichloromethane (200 mL) and cooled to 0 oC. DMAP (30.8 g, 0.250 mol), Meldrum’s acid (19.6 g, 0.140 mol) and EDCI (26.9 g, 0.140 mol) were added successively. The reaction mixture was stirred overnight at ambient temperature. Water (200 mL) was added and the ing mixture was extracted with dichloromethane (300 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 20: 1) to afford 5-(3,3-difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (24 g, 74% yield).

] A solution of 5-(3,3—difluorocyclobutanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6- dione (15.0 g, 57.3 mmol) in THF (200 mL) was cooled to -5 °C and acetic acid (38 g, 0.63 mol) was added. The mixture was stirred for 5 min and sodium borohydride (6.5 g, 0.17 mol) was added in portions. The reaction mixture was stirred for 2 h at -5 CC and then poured into ice water (200 mL). The resulting mixture was extracted with EtOAc (300 mL><3). The c extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 30: 1) to afford 5-((3,3-difluorocyclobutyl)methyl)— methyl-1,3-dioxane-4,6—dione (8.2 g, 58% yield).

A solution of 5-((3,3—difluorocyclobutyl)methyl)—2,2—dimethyl—1,3-dioxane-4,6— dione (7.00 g, 28.2 mmol) and benzyl alcohol (10 mL) in e (10 mL) was heated at 80- 90 °C overnight. Toluene was removed and the residue was purified by flash column chromatography on silica gel oromethane/methanol = 100:1 to 10:1) to afford the benzyl ester, which was hydrogenated in the presence of Pd/C (1 g) in methanol (30 mL) for 1 h at ambient temperature. Pd/C was filtered off and the filtrate was concentrated to afford 2-((3,3-difluorocyclobutyl)methyl)malonic acid (3.7 g, 63% .

Bromine (1.0 mL) was added dropwise to a on of 2-((3,3- difluorocyclobutyl)methyl)malonic acid (3.7 g, 17.8 mmol) in diethyl ether (50 mL) while keeping the solution ng slightly. The mixture was stirred for 10 min and water (5 mL) was added while keeping the mixture refluxing. The organic layer was separated and concentrated.

The residue was heated at 140 0C for 2 h and then cooled to t temperature.

Saturated aqueous sodium bicarbonate (50 mL) was added and the resulting mixture was washed with EtOAc (30 mL><2). The aqueous layer was acidified to pH=4 with saturated aqueous KHSO4 and then extracted with EtOAc (50 mLX3). The organic extracts were combined, dried over anhydrous sodium e, and concentrated to afford a yellow oil (2.7 A solution of the yellow oil in isopropyl alcohol (100 mL) was aved in the presence ofNH3 overnight at ambient temperature. The solvent was removed and the residue was dissolved in itrile (20 mL) followed by addition of PhCH2COCl (2.06 g, 13.3 mmol) and triethylamine (3.09 mL, 22.2 mmol). The reaction mixture was stirred for 6 h.

Water (50 mL) was added and the resulting mixture was acidified to pH=4 and extracted with romethane (50 mL><3). The c extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 10: 1) to afford 3-(3,3— difluorocyclobutyl)(2-phenylacetamido)propanoic acid (1.4 g, 40% yield).

A mixture of 3-(3,3-difluorocyclobutyl)—2-(2-phenylacetamido)propanoic acid (1.4 g, 4.7 mmol) and PGA enzyme (1.0 g) in water (20 mL) with pH-8—9 was stirred for 3 d at 36 OC. Enzyme was filtered off and the filtrate was acidified to pH=4. The resulting mixture was washed with EtOAc (50 .

The aqueous layer was treated with BoczO (0.56 g, 2.6 mmol) in acetone/water (20 mL/20 mL) with pH—8 for 5 h at ambient temperature. Acetone was removed and the aqueous solution was acidified to pH=4. The mixture was extracted with EtOAc (50 mL><3).

The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated.

The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 10: 1) to afford (S)(tert-butoxycarbonylamino)—3- (3,3-difluorocyclobutyl)propanoic acid (0.4 g, 62% yield). ] pyl chloroformate (0.65 g, 4.8 mmol) was added dropwise to a solution of (S)(tert-butoxycarbonylamino)(3,3-difluorocyclobutyl)propanoic acid (1.2 g, 4.3 mmol) and N—methylmorpholine (0.5 g, 5.0 mmol) in dichloromethane (20 mL) at 0 CC. The mixture was stirred for 1 h at 0 °C followed by addition of a mixture of N,0-dimethylhydroxylamine- HCl (0.5 g, 5.1 mmol) and triethylamine (0.69 mL, 5.0 mmol) in dichloromethane (20 mL).

The reaction mixture was stirred ght at ambient temperature and poured into 5% aqueous HCl (50 mL). The resulting mixture was ted with EtOAc (50 mL><3). The organic extracts were combined, washed with saturated sodium bicarbonate (150 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 10:1) to afford (S)-tert- Butyl 3 —(3 ,3 -difluorocyclobutyl)— 1 -(methoxy(methyl)amino)- 1 —oxo propanylcarbamate (1.2 g, 87% yield). [005 1 8] (S)-Zert-Butyl 3 -(3 ,3 -difluorocyclobutyl)- 1 —(methoxy(methyl)amino)— 1 -oxo propanylcarbamate (1.2 g, 3.7 mmol) was dissolved in THF (20 mL) and then cooled to 0 oC. Propenylmagnesium bromide (14.9 mmol) was added dropwise and the on mixture was stirred for 1 h at ambient temperature. The mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum EtOAc = 200:1 to 100:1) to afford (S)-tert- Butyl -difluorocyclobutyl)—4-methyloxopent-4—enylcarbamate (0.8 g, 72% yield).

] A solution of (S)-tert-butyl -difluorocyclobutyl)methyloxopenten- 2-ylcarbamate (0.80 g, 2.6 mmol) in DMF (20 mL) was cooled to 0 °C and 10% aqueous NaClO solution (7.90 mL, 10.6 mmol) was added while g the internal temperature below 5°C. The reaction mixture was stirred for 1 h at 0 oC and poured into saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with EtOAc (50 mL>< 3). The organic extracts were combined, washed with brine (100 mL><2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 200:1 to 50:1) to afford tert-butyl ((S)(3 ,3 -difluorocyclobutyl)((R)methyloxiranyl)-1 -oxopropanyl)carbamate (510 mg, 62% yield). 1H NMR (300 MHz, CDClg): 5 5.02 (d, J: 8.7 Hz, 1H), 4.25 (m, 1H), 3.23 (d, J= 4.5 Hz, 1H), 2.93 (d, J= 4.8 Hz, 1H), 2.73 (m, 2H), 2.25 (m, 3H), 1.92 (m, 1H), 1.55 (m, 1H), 1.54 (s, 3H), 1.43 (s, 9H). MS (EI) for C15H23F2NO4, found 358.14 [M+K]+.

Example 34 tert-Butyl ((S)((1R,5 bicyclo[3.1.0]hexanyl)((R)methyloxiran yl)-1 -oxopropanyl)carbamate: 2014/026987 QMeNHBoc H IVIeO_I'3'—<coom H NQBH“ l" ’ 0 e “ CHO COOMe NICI2 -‘ COOMe —> \ fl "’H 'uH II'H T—I ’H NHBOC T—I NHBOC 1.TFA 1. L-Acylase 2. AcCI 1., fl 3. LiOH : 2- 30020 COOH .~ MeNHOMe COOH : , ’H T—I NHAc T—l NHBoc :14 0 Li? 1.. 0 A7 - -‘ NaClO . N’O\ ”H —> —> a I O H NHBoc a BocHN H NHBoc ] A mixture of cis-bicyclo[3.1 .0]hexenecarbaldehyde (6.00 g, 55.5 mmol), methyl 2-(tert-butoxycarbonylamino)— 2-(dirnethoxyphosphoryl)acetate (10.0 g, 69.4 mol) and DBU (130 g, 85.5 mmol) in DCM (150 mL) was stirred at ambient temperature for 1 h.

The e was poured into saturated aqueous NH4C1 (150 mL) and the resulting e was extracted with DCM (100 mL><2). The combined organic layers were washed with saturated aqueous NH4C1 (100 mL><2) and brine (100 mL), dried over ous sodium sulfate, and concentrated. The residue was d by flash column chromatography on silica gel (petroleum ether/EtOAc = 10: 1 to 4: 1) to afford methyl 3-(cz‘s-bicyclo[3. l .0]hexen yl)—2-(tert-butoxycarbonylamino)acrylate (5.6 g, 36% yield) as a colorless oil.

NaBH4 (3.00 g, 78.5 mmol) was added in portions to a mixture of methyl 3-(cz's- bicyclo[3.1.0]hex-2—eny1)—2-(tert-butoxycarbonylamino)acrylate (4.40 g, 15.8 mmol) and NiC12—6H20 (3.80 g, 15.8 mmol) in methanol (100 mL) at 0 CC. The reaction e was stirred for 15 min and then poured into saturated aqueous NH4Cl (100 mL). The resulting mixture was extracted with DCM (100 mL><2). The combined organic layers were washed with saturated aqueous NH4C1 (100 mLX2) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10: l to 4:1) and prep-HPLC to afford methyl 3-(cz‘s- bicyclo[3. l .0]hexan-6—yl)(tert-butoxycarbonylamino)propanoate (1.0 g, 22% yield) as a colorless oil.

The remainder of the synthesis was carried out according to the procedure for tert- WO 52134 butyl (S)—3 -(trans-bicyclo [3 - oxopropan . 1 .0]hexanyl)-1 -((R)methyloxirany1)— 1 ylcarbamate.

Example 35 (S)-Methy1 2-amino(1H-indolyl)propanoate: CszN COOIVIe l2» PPh3j Zn, Pd2(dba)3 12 Br ' <15 S-Phos H2, Pd/C + I § —» N CszN COOMe OMe OMe H CszN H2N 0 0 A mixture of triphenylphosphine (23.3 g, 0.890 mol) and imidazole (6.0 g, 0.89 mol) in DCM (100 mL) was cooled to 0 oC and iodide (22.6 g, 0.890 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0 °C, a solution of Cbz-L—Ser—OMe 15.0 g, 0.590 mol) in DCM (100 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the e and the e was filtered to remove triphenylphosphine oxide.

The e was concentrated and the e was purified by flash column tography on silica gel (petroleum ether/EtOAc = 50:1 to 10: 1) to afford thyl 2- (benzyloxycarbonylamino)iodopropanoate (12.3 g, 57% yield) as a colorless solid.

To a suspension of zinc (2.53 g, 38.8 mmol) in DMF (20 mL) was added 12 (1.10 g, 4.15 mol) followed by addition of a solution of (R)-methyl 2—(benzyloxycarbonylamino) iodopropanoate (4.70 g, 13.0 mmol) in DMF (20 mL). The mixture was stirred at ambient temperature for 5 min and heated at 35 °C for 40 min. Then a solution of 5-bromo-1H—indole (3.00 g, 15.5 mmol) in DMF (10 mL), a)3 (0.25 g, 0.27 mmol) and S-Phos (0.25 g, 0.60 mmol) were added. The reaction mixture was stirred at 50 °C under nitrogen overnight and then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with EtOAc (200 rnL><3). The organics were combined, washed with brine (300 mL) and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10:1 to 5:1) to afford (S)-methyl 2— 2014/026987 loxycarbonylamino)(lH-indolyl)propanoate as a Viscous oil (3.27 g, 60% yield).

To a solution of (S)-methyl 2-(benzyloxycarbonylamino)(lH—indol panoate (3.27 g, 9.39 mmol) in methanol (30 mL) was added Pd/C (10%, 200 mg). The mixture was stirred under hydrogen atmosphere at ambient temperature for l h and then filtered through a pad of Celite. The e was concentrated to afford (S)-methyl 2-amino (lH—indolyl)propanoate (l .8 g, 88% yield) as a light green solid, which was used directly without further purification.

Example 36 (S)-Methyl 2-amino(3-(benzyloxy)methylphenyl)propanoate: BocHN COOMe OBn BnBr Zn, Pd2(dba)3 /©\/ K2CO3 /©\/ S—Phos Br OH ACCN Br OBn DMF BocHN COOMe HZN COOMe To a solution of 5-bromomethylphenol (5.0 g, 27 mmol) in acetonitrile (50 mL) was added K2C03 (4.4 g, 32 mmol) followed by benzyl bromide (5.5 g, 32 mmol). The suspension was heated at 50-60 0C for 4 h then cooled to ambient temperature. The mixture was filtered and the ion cake was washed with acetonitrile (20 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 6:1) to afford (S)—methyl 3-(3- (benzyloxy)methylphenyl)(tert-butoxycarbonylamino) propanoate (7.5 g, quant.) as an oil.

] Dry DMF (100 mL) was added to zinc dust (7.00 g, 108 mmol) in a flame dried flask under N2. (R)-methyl 2-(tert-butoxycarbonylamino)—3-iodopropanoate (9.7 g, 29 mmol) and a catalytic amount of iodine (0.7 g, 2 mmol) were added. The mixture was stirred at ambient temperature for 0.5 h, then a)3 (1.9 g, 2.0 mmol), S-Phos (l .6 g, 4.0 mmol) and 2-(benzyloxy)—4-bromo-l-methylbenzene (7.40 g, 27.0 mmol) were added. The reaction mixture was stirred at 60 °C for 6 h then cooled to ambient temperature. EtOAc (500 mL) and water (500 mL) were added and the organic phase was separated, washed with water (300 mL><3) and brine (300 mL><1), dried over anhydrous sodium sulfate, and trated.

The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = : 1) to afford (S)-methyl 3-(3-(benzyloxy)methylphenyl)-2—((tert- butoxycarbonyl)amino)propanoate (4.0 g, 37% yield).

To TFA (5 mL) was added to a solution of (S)-methyl 3-(3-(benzyloxy) methylphenyl)((tert—butoxycarbonyl)amino)propanoate (1.0 g, 2.5 mmol) in DCM (10 mL) at 0 °C with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped with EtOAc (10 mL><3) to remove residual TFA and afford crude (S)- methyl 2-amino—3-(3-(benzyloxy)methylphenyl)propanoate as its TFA salt.

Example 37 Boc-Lmethylsulfonylphenylalanline methyl ester and Boc-L methylsulfonylphenylalanline methyl ester: MeSOzNa COOH Mel COOMe COOMe \ \ Cul,L-Pro \ X—i —’XL— —> ' MeOZS+ / NHBoc / NHBoc / NHBoc (4-|)(3-Br) (4—SOzMe) (3-SOzMe) thane (3.6 g, 25 mmol) was added to a sion of K2C03 (3.5 g, 25 mmol) and Boc-Liodophenylalanine (5 g, 12.5 mmol) in acetone (50 mL). The reaction mixture was heated at 40 °C for 12 h. The mixture was cooled to ambient temperature and then filtered. The filtration cake was washed with acetone (50 mL) and the e and washings were combined. The solvent was removed and the residue was purified by flash column tography on silica gel (Hexane/EtOAc = 10: 1) to afford 4- iodophenylalanline methyl ester (4.9 g, 93% yield) as a colorless solid.

Boc—Lbromophenylalanline methyl ester was prepared from Boc-L—3- bromophenylalanine following the same procedure for Boc-Liodophenylalanline methyl ester.

A mixture of Boc-Lbromophenylalanline methyl ester (2.0 g, 5 mmol), sodium methanesulfinate (600 mg, 6 mmol), CuI (96 mg, 0.5 mmol) and ine (115 mg, 1 mmol) in DMSO (30 mL) was heated at 90 CC for 12 h under N2. The mixture was cooled to ambient temperature and then diluted with water (300 mL). The resulting mixture was extracted with EtOAc (100 mL><3). The ed organic phases were washed with 1N aqueous HCl (100 , saturated aqueous NaHC03 (100 mL><3), and brine (50 mL><1), respectively. The organic solution was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 2: 1) to afford Boc- Lmethylsulfonylphenylalanline methyl ester (1.1 g, 62% yield) as a colorless solid. Boc-L- 3-methylsulfonylphenylalanline methyl ester was ed in a similar manner. e 38 6-Bromo-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide: OH 0 \ | BnBr 40 OH MsCI MnOz 032003 IS¢ II II NHz NH-fi— [)2 A solution of methane sulfonyl chloride (10.2 ml, 0.13 mol) in chloroform (100 mL) was added dropwise to a solution of (2-aminophenyl)methanol (15.0 g, 0.12 mol) in ne (100 mL) and chloroform (150 mL) under nitrogen over 1 h at 0°C. The reaction mixture was stirred for 12 h at ambient temperature and then washed with hydrochloric acid (2N, 200 m1><2). The organic phase was dried over anhydrous MgSO4 and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:3) to afford hydroxymethyl)phenyl]methanesulfonamide (13.0 g, 53% yield) as a yellow oil.

] Manganese dioxide (85%, 45.0 g, 0.52 mol) was added to a solution ofN—[2- (hydroxymethyl)phenyl]methanesulfonamide (13.0 g, 65 mmol) in dichloromethane (200 mL) at ambient temperature under nitrogen. The reaction mixture was stirred for 12 h and then filtered through a pad of Celite. The pad was washed with dichloromethane/methanol (1:1) and the combined organics were concentrated to afford N—(2- Formylpheny1)methanesulfonamide (10.1 g, 78% yield) as a yellow solid.

Cesium carbonate (18.0 g, 55 mmol) and benzyl bromide (6.6 mL, 55 mmol) were added to a solution of N—(2-forrnylphenyl)methanesulfonamide (5.50 g, 27.6 mmol) in acetonitrile (120 mL). The reaction mixture was heated at 60 °C for 16 h and then cooled to ambient ature. The mixture was diluted with EtOAc (200 mL) and filtered. The filtration cake was washed with EtOAc (200 mL) and the ed organics were concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:5) to afford yl-lH—benzo[c][l,2]thiazine 2,2-dioxide (6.5 g, 87% yield) as a colorless oil.

Freshly polished lithium flakes (2.0 g, 0.28 mol) were added to a solution of 1- benzyl-lH—benzo[c][1,2]thiazine 2,2-dioxide (6.5 g, 24 mmol) in THF (120 mL)/EtOH (12 mL) and liquid NH3 (150 mL) at -40 °C with stirring over 0.5 h. The reaction was quenched with NH4C1 powder (10 g). Water (200 mL) and EtOAc (200 mL) were added. The two layers were separated and the aqueous phase was extracted with EtOAc (100 mL><3). The combined c phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:4) to afford 3,4-dihydro-1H—benzo[c][1,2]thiazine 2,2-dioxide (1.5 g, 34% yield).

] NBS (1.5 g, 8.2 mmol) was added to a solution of 3,4-dihydro-1H- benzo[c][l,2]thiazine 2,2-dioxide (1.5 g, 8.2 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature followed by addition of water (200 mL) and EtOAc (100 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (100 mL><3). The combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel /hexane = 1:3) to afford 6—bromo-3,4-dihydro- 1H—benzo[c][1,2]thiazine 2,2-dioxide (1.7 g, 79% yield).

Example 39 ] (R)—Methyl 2-((tert—butoxycarbonyl)amino)(2-(2,4-dimethoxybenzyl)-1 l - , dioxido-3 ydro-2H—benzo[e] [ 1 ,2]thiazinyl)propanoate: 1. CISO3H 2_ MeOflOMe “em/0M9 1. LiBH4 ”2” O“ 2. DEAD, PPh3 COZMe—> s’ —> Br \\ COzMe 0\\ no OMe /( mfi O“ [9 OMe BocHN COOMe Br OMe BocHOj/(D/MCESJq/fiN "I, OMe Methyl romophenyl)acetate (20 g, 87 mmol) was added dropwise to CISO3H (60 mL) at 0 °C. The reaction mixture was d overnight at ambient temperature.

The solution was poured into ice-water (100 mL) slowly and the resulting mixture was 2014/026987 extracted with EtOAc (100 mL><3). The c extracts were combined, dried over ous sodium sulfate, and concentrated.

The resulting red oil (20 g) was dissolved in dichloromethane (100 mL) and cooled to 0 °C. Triethylamine (33.1 mL, 0.240 mol) and (2,4-dimethoxyphenyl)methanamine (11.2 g, 66.0 mmol) were added slowly. The reaction e was stirred for 2 h at ambient temperature. The mixture was poured into water (100 mL) and the resulting mixture was extracted with dichloromethane (100 mL>< 3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 1021 to 3:1) to afford methyl 2-(5— 2-(N-(2,4-dimethoxybenzy1)sulfamoy1)pheny1)acetate (5.3 g, 14% yield).

LiBH4 (1.02 g, 46.4 mmol) was added in portions to a solution of methyl 2-(5- bromo(N-(2,4-dimethoxybenzy1)sulfamoyl)phenyl)acetate (5.30 g, 11.6 mmol) in THF/methanol (100 mL/20 mL) at 0 CC. The reaction mixture was stirred for 1 h at ambient temperature and then poured into ice-water (100 mL). The resulting mixture was extracted with EtOAc (100 mL><3). The organic extracts were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give the corresponding alcohol (4.70 g, 10.9 mmol).

The l (1.4 g, 3.3 mmol) and DEAD (1.1 g, 6.5 mmol) were dissolved in THF (50 mL) followed by addition of PPh3 (1.6 g, 6.5 mmol) in portions. The reaction mixture was d ght at ambient temperature. The solvent was removed and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = :1 to 5: 1) to afford 6-bromo—2-(2,4-dimethoxybenzyl)—3,4-dihydro-2H— benzo[e][1,2]thiazine 1,1-dioxide (1.3 g, 91% yield) as a yellow solid.

Iodine (0.11 g, 0.43 mmol) was added to a mixture of (R)-methy1 2-(tert- butoxycarbonylamino)—3 -iodopropanoate (1.30 g, 3.58 mmol) and zinc (0.620 g, 9.75 mmol) in DMF (30 mL). The mixture was stirred for 10 min and another portion of iodine (0.11 g, 0.43 mmol) was added. The mixture was stirred for r 1 h. 6-Bromo(2,4- oxybenzy1)-3,4—dihydro—2H—benzo[e][1,2]thiazine 1,1-dioxide (1.34 g, 3.25 mmol), Pd2(dba)3 (0.08 g, 0.09 mmol) and S-Phos (0.070 g, 0.17 mmol) were added. The reaction e was stirred at 50 CC for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtrate was poured into water (50 mL). The resulting mixture was extracted with EtOAc (100 mL><3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 15:1 to 3:1) to afford (R)-methyl 2-((tert- butoxycarbonyl)amino)(2-(2,4-dimethoxybenzyl)-l , l - dioxido-3 ,4-dihydro-2H— benzo[e][l,2]thiazinyl)propanoate (0.8 g, 46% yield) as a yellow oil.

Example 40 (S)(3-(Benzyloxy)((tert—butoxycarbonyl)amino)oxopropyl)pyridine 1- oxide: N/ 1.BnBr 013/ l 2. m—CPBA | \ \ BocHN COOH BocHN COOBn Bromomethylbenzene (965 mg, 5.64 mmol) was added dropwise to a mixture of (tert-butoxycarbonylamino)—3-(pyridin—4-yl)propanoic acid (1.00 g, 3.76 mmol) and CszC03(l .23 g, 3.76 mmol) in DMF (20 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1.5 h and poured into water (50 mL). The resulting mixture was extracted with EtOAc (50 ml><2) and the combined cs were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 50:1) to afford the corresponding benzyl ester (1.0 g, 74% yield) as an oil.

To a solution of the benzyl ester (1.0 g, 2.8 mmol) in CH2C12 (20 mL) was added m-CPBA (1.2 g, 5.6 mmol) at 0 CC. The on mixture was stirred at t temperature overnight and poured into water (50 mL). The resulting mixture was extracted with CH2C12 (50 ml><3). The ed organic layers were washed with saturated aqueous Na2S03 (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/ methanol = 50: l) to afford (3-(Benzyloxy)(tert-butoxycarbonylamino)oxopropyl)pyridine l-oxide (900 mg, 86% yield) as a colorless solid.

Example 41 ] (ZS,3R)-Benzyl 2-amino-3—hydroxy(4-methoxyphenyl)propanoate: O HZNACOOH OMe OMe 0%.. fl, SOCI MeOH Ho. 2v_, Ho.

MeO H000 ”’NHz MeOOC "’NHz OMe OMe Chiral HPLC — HOTQ/ M» HO:|/©/ 1. BnBr, CszcosY DMF 2. LiOH, MeOH, MeOOC ’NH2 2. TFA, DCM THF HOOC "’NHBoc MeOOf” H2N COOBn A solution of glycine (45 g, 0.60 mol) and anisaldehyde (122 g, 0.900 mol) in ethanol (1.5 L) was stirred at t temperature and KOH (82.7 g, 1.47 mol) was added.

The reaction mixture was stirred overnight at ambient temperature. The mixture was concentrated under vacuum the majority of l. The residue was dissolved in water (800 mL) and the on was adjusted to pH=5 with 4 N aqueous HCl. The resulting mixture was washed with EtOAc (200 mL><2) to remove any impurities. The aqueous layer was concentrated to a volume of ~400 mL. The mixture was filtered and the filtration cake was washed thoroughly with water (100 mL><2) and dried to afford 2-amino—3-hydroxy(4- methoxyphenyl)propanoic acid (29 g, 23% yield, ) as a colorless solid.

Thionyl chloride (12.3 mL, 169 mmol) was added dropwise to methanol (250 mL) at 0 °C followed by addition of 2-aminohydroxy(4-methoxyphenyl)propanoic acid (25.0 g, 118 mol). The reaction mixture was d at ambient temperature for 1 h and heated under reflux for 3 h. The mixture was cooled to ambient ature and then concentrated to dryness. The residue was d by flash column chromatography on silica gel (DCM/methanol = 60:1) to afford (2S,3R)—methyl 2-aminohydroxy(4- methoxyphenyl)propanoate (15.7 g, 59% yield, thre0-) as a colorless oil. Further separation by chiral preparative HPLC afforded (2S,3R)—methyl 2-aminohydroxy(4- methoxyphenyl)propanoate (7.0 g, 45% yield).

To THF (20 mL) was added )—methyl 2-amino—3-hydroxy(4— methoxyphenyl)propanoate (1.00 g, 4.44 mmol) ed by BoczO (1.16 g, 5.33 mmol). The reaction mixture was stirred for 1 h at ambient temperature then concentrated to afford crude (2S,3R)—2-(tert-butoxycarbonylamino)hydroxy(4—methoxyphenyl)propanoate (1.44 g, quant.) as a colorless solid.

A mixture of (2S,3R)—2-(tert-butoxycarbonylamino)—3-hydroxy(4- methoxyphenyl)propanoate (1.44 g, 4.44 mmol) and LiOH-HZO (280 mg, 6.66 mmol) in HF (30 mL, 1:1) was stirred for l h at ambient temperature. EtOAc/water (30 mL/50 mL) was added and the two phases were separated. The aqueous phase was washed with EtOAc (30 mL><2) then acidified with dilute HCl to pH=5. The resulting mixture was ted with EtOAc (50 mL><2). The organics were combined, dried over anhydrous sodium sulfate, and concentrated to afford (2S,3R)—2-(tert-butoxycarbonylamino)hydroxy(4- yphenyl)propanoic acid (0.90 g, 65% yield) as a colorless solid.

Benzyl bromide (4.40 g, 25.7 mmol) was added dropwise to a mixture of (ZS,3R)- 2-(tert-butoxycarbony1amino)hydroxy(4-methoxyphenyl)propanoic acid (4.00 g, 12.9 mmol) and CszC03 (4.20 g, 12.9 mmol) in DMF (80 mL) at 0 OC. The reaction mixture was allowed to warm to ambient temperature and stirred for l h. Water (80 mL) was added and the resulting mixture was extracted with EtOAc (100 . The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum EtOAc = 10:1 to 4:1) to afford )-benzyl 2-((tert— butoxycarbonyl)amino)hydroxy(4-methoxyphenyl)propanoate (3.7 g, 66% yield) as a colorless solid.

To (2S,3R)—benzyl 2-((tert—butoxycarbonyl)amino)hydroxy(4- methoxyphenyl)propanoate (3.0 g, 7.5 mmol) in DCM (30 mL) was added TFA (15 mL) and the mixture was stirred at 0 CC. After 30 min it was diluted with DCM (100 mL). Saturated aqueous NaHC03 (100 mL) was added and the two layers were ted. The aqueous layer were extracted with DCM (100 mL><2) and the combined organics were dried over anhydrous sodium sulfate and concentrated to afford crude (2S, 3R)-benzyl ohydroxy—3-(4- methoxyphenyl)propanoate (2.3 g, quant.) as an oil, which was used directly in the next step without further purification.

Example 42 (2S,3 S)((tert—Butoxycarbonyl)amino)-3 -hydroxy-3 -(4- methoxyphenyl)propanoic acid: O H—GIy—OMe O O K2003 BOCQO, DMAP OMe c1 —» N/firOMe—»H N/\n/Bee 0 0 MeO MeO MeO OMe OMe DMPU 1_ HCI OMe LiHMDS 0 2. AcCI 0 NaBH4 —> —> HO ome ome BocHN AcHN MeOOC NHAc O O OMe (racemic) 1. L-acy/ase LiOH 2. Boc20 HO —> —> ”000 ”HA0 BocHN COOH (racemic) ] Saturated aqueous potassium carbonate (190 mL) and 4-methoxybenzoyl de (60.8 g, 358 mmol) were added to a solution of glycine methyl ester (30.0 g, 239 mmol) in THF (100 mL) at 0 °C. The reaction mixture was stirred for 3 h at 0 °C and then poured into water (100 mL). The resulting mixture was extracted with EtOAc (200 ml><2). The combined extracts were dried over ous sodium sulfate and concentrated to afford methyl 2-(4- methoxybenzamido)acetate (46.2 g, 86% yield) as a colorless solid, which was used ly without further ation.

Methyl 2-(4-methoxybenzamido)acetate (46.2 g, 207 mmol) was dissolved in acetonitrile (150 mL). Di-tert-butyl dicarbonate (69.0 g, 207 mmol) and DMAP (3.0 g, 21 mmol) were added. The reaction mixture was stirred overnight at ambient ature and then concentrated. The residue was purified by flash column chromatographic on silica gel (petroleum ether/EtOAc = 50:1) to afford methyl 2-(N—(tert—butoxycarbonyl)-4— methoxybenzamido)acetate (56 g, 92% yield) as a colorless solid.

DMPU (25.0 mL, 205 mmol) and LiHMDS (lM solution, 250 mL, 250 mmol) were added to a solution of methyl 2—(N-(tert—butoxycarbonyl)methoxybenzamido)acetate (33.0 g, 102 mmol) in THF (200 mL) at -78 CC. The reaction mixture was stirred for 1.5 h at - 78 °C and quenched with saturated aqueous NH4Cl (300 mL). The resulting e was extracted with EtOAc (250 mL><3). The combined extracts were washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium e, and concentrated. The residue was washed with petroleum ether/EtOAc (200 mL, 20:1) and dried to afford methyl 2—(tert- butoxycarbonylamino)-3 -(4-methoxyphenyl)oxopropanoate (23 g, 70% yield) as a colorless solid.

HCl-EtOAc (6N solution, 200 mL) was added to a solution of methyl 2-(tert- butoxycarbonylamino)—3 -(4-methoxyphenyl)oxopropanoate (50.0 g, 155 mmol) in EtOAc (300 mL) at ambient temperature with stirring. The reaction mixture was stirred for 30 min and then concentrated to dryness. The residue was washed with petroleum ether (200 mL><3) and dried to afford methyl o(4-methoxyphenyl)oxopropanoate (HCl salt, 35.5 g, 88% .

] To a solution of methyl 2-amino(4-methoxyphenyl)—3-oxopropanoate (35.5 g, 137 mmol) and Et3N (57.2 mL, 411 mmol) in DCM (120 mL) at 0 CC was added AcCl (12.9 g, 164 mmol) se. The reaction mixture was stirred at 0 °C for 40 min and then quenched with water (500 mL). The resulting mixture was extracted with DCM (300 mLX2) and the ed organic layers were dried over anhydrous sodium sulfate and concentrated.

The residue was washed with petroleum ether/EtOAc (300 mL, 100: 1) to methyl 2- acetamido-3 ethoxyphenyl)oxopropanoate (22.0 g, 61% yield) as a colorless solid.

A solution of methyl 2-acetamido-3—(4-methoxyphenyl)oxopropanoate (22.7 g, 85.7 mmol) in methanol (500 mL) was cooled to 0 °C and NaBH4 (976 mg, 25.7 mmol) was added in portions. The reaction e was stirred for 1 h at 0 OC and then quenched with water (1 L). The resulting mixture was extracted with EtOAc (300 ml><3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The e was washed with petroleum ether/EtOAc (100 mL, 10:1) to afford methyl 2-acetamido hydroxy(4-methoxyphenyl)propanoate (13.5 g, 59% yield, erythro- form >95%) as a colorless solid.

To a solution of methyl 2-acetamidohydroxy(4-methoxyphenyl)propanoate (13.5 g, 50.5 mmol) in methanol (200 mL) was added a solution of lithium hydroxide hydrate (4.20 g, 101 mmol) in water (100 mL). The reaction mixture was stirred at ambient temperature for 1 h and then concentrated to remove the organic solvent. The residue (2— acetamido-3 -hydroxy(4-methoxyphenyl)propanoic acid, in aqueous solution) was used ly in the next step.

Aqueous 2—acetamidohydroxy(4-methoxyphenyl)propanoic acid solution (100 mL) was adjusted to pH=8.5 with 2M s NaOH and the mixture was filtered. The filtrate was heated to 38 CC followed by addition ofL-acylase (2.0 g). The mixture was stirred at 38 0C for 2 d and then filtered.

] To the filtrate were added 1,4—dioxane (200 mL) and B0020 (13.1 g, 60 mmol).

The reaction mixture was stirred overnight at ambient temperature and then concentrated.

The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1 to 5:1) to afford (2S,3S)—2—(tert—butoxycarbonylamino)hydroxy(4- methoxyphenyl)propanoic acid (2.8 g, 18% yield over three steps).

Example 43 5-Bromomethylpyridin-2(1H)—one: 1. HCI mm 2. NaH, Mel Br —> l N/ OMe N 0 ] A solution of omethoxypyridine (10.0 g, 53.2 mmol) in 6N aqueous HCl (50 mL) was refluxed for 5 h. The solution was cooled to 5 oC and neutralized to pH=6.5 with 20% aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration and dried to afford 5-bromopyridin-2(1H)—one (8.5 g, 91% yield) as a colorless solid. 5-Bromopyridin-2(1H)—one (2.00 g, 11.5 mmol) was added in portions to a mixture of sodium e (1.10 g, 27.5 mmol) in THF (100 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C followed by addition of thane (8.20 g, 57.5 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with water (2 mL) and then concentrated. The residue was suspended in water (50 mL) and the resulting mixture was extracted with EtOAc (50 mL><3). The organic extracts were ed, dried over anhydrous sodium sulfate, and concentrated. The residue was washed with eum ether (30 mL) and dried to afford 5-bromomethylpyridin-2(1H)— one (1.7 g, 79% yield) as a yellow solid.

Example 44 (R)((1R,3S)—3-Hydroxycyclopentanecarboxamido)propanoic acid and (R) ((1S,3R)—3-hydroxycyclopentanecarboxamido)propanoic acid: WO 52134 Bn Br 1. (-)-(|pc)2BH D—COOH —>ch03 2. H202 COOBn —> Ucoosn TBSCI < R=TBS ‘3‘NACOOBn| HO,“ 1. H2, PdlC O 1. Separation by 2. H-D-AIa-OBn /?\ silica gel column HATU (ma'or +/_) J ’ T880 [11' COOBn 2. TBAF OJ“NACOOBn| HOTOI O = (minor, +l-) HOMO” LnACOOR IOLNA R=Bn Separation by H2! Pd/C HOII.O“‘N COOBn chiral prep-HPLC R—H_ H2 PdlC<<R=Bn K2C03 (35.0 g, 255 mmol) was added to a on of cyclopentenecarboxylic acid (20.0 g, 178 mmol) in acetonitrile (500 mL) followed by addition of benzyl e (36.6 g, 214 mmol). The on mixture was stirred for 12 h at ambient temperature. The mixture was filtered and washed with acetonitrile (200 mL). The filtrate and washings were combined and trated to dryness. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 10:1) to afford benzyl cyclopent enecarboxylate (26.5 g, 74% yield) as an oil.

A solution of (-)-(x-pinene (5.80 g, 42.6 mmol) in THF (10 mL) was cooled to 0 °C and a solution of borane-Megs (ION, 1.5 mL, 15 mmol) was added. The mixture was d for 4 h at 0 OC and benzyl cyclopentenecarboxylate (3.5 g, 17 mmol) was added.

The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was cooled to 0 OC again and quenched with water (2 mL) and aqueous NaOH (3N, mL). Then 30% hydrogen peroxide (20 mL) was added dropwise. The mixture was stirred for l h at 0 OC and diluted with water (20 mL) and EtOAc (50 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:4) to afford benzyl oxycyclopentanecarboxylate (1.4 g, 37% yield).

] A solution of TBSCl (7.5 g, 50 mmol) in THF (50 mL) was added dropwise to a solution of benzyl oxycyclopentanecarboxylate (10.0 g, 45.0 mmol) and imidazole (3.4 g, 50 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred for 3 h and water (300 mL) was added. The resulting mixture was extracted with EtOAc (200 mL><3). The combined organic extracts were washed with 5% aqueous KHSO4 (100 mL><3), saturated aqueous NaHC03 (100 mL><3), and brine (100 mL>< 1), respectively. The organic solution was dried over ous sodium sulfate, and concentrated to dryness. The e was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:20) to afford benzyl 3-(tert-butyldimethylsilyloxy)cyclopentanecarboxylate (15.2 g, quantitative) as an oil.

Pd/C (10%, 5.0 g) was added to a solution of benzyl 3-(tert- butyldimethylsilyloxy)cyclopentanecarboxylate (15.2 g, 45.5 mmol) in THF (100 mL). The suspension was stirred under hydrogen atmosphere at ambient temperature for 5 h. Pd/C was filtered off and washed with THF (50 mL). The filtrate and washings were combined and concentrated to dryness to afford the corresponding acid.

The acid (45.5 mmol) and a-OBn (10.0 g, HCl salt, 45.5 mmol) were dissolved in DMF (100 mL). HATU (26.5 g, 73.0 mmol) and DIPEA (16.2 mL, 118 mmol) were added at 0 °C with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (500 mL) and water (500 mL) was added. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate and trated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:6) to afford (R)-benzyl tert— butyldimethylsilyloxy)cyclopentanecarboxamido) propanoate (13.1 g, 71% yield).

(R)-Benzyl tert—butyldimethylsilyloxy)cyclopentanecarboxamido) oate was separated by flash column chromatography on silica gel (EtOAc/hexane = 1:10) to afford cis-(R)—benzyl 2—(3-(tert—butyldimethylsilyloxy)cyclopentanecarboxamido) propanoate (3.5 g) and trans-(R)—benzyl 2-(3 -(tert- butyldimethylsilyloxy)cyclopentanecarboxamido) propanoate (0.8 g), respectively.

] A on of tetrabutylammonium fluoride (4.6 g, 17 mmol) in THF (20 mL) was added dropwise to a on of compound cis-(R)-benzyl 2-(3 -(tert- imethylsilyloxy)cyclopentanecarboxamido) propanoate (3.5 g, 8.6 mmol) in THF (10 mL) at 0 °C with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 12 h. Water (100 mL) was added and the resulting mixture was extracted with CH2C12 (100 mL><3). The extracts were combined and washed with 5% aqueous KHSO4 (100 mL><3), saturated aqueous NaHC03 (100 mL><3), and brine (100 mL>< 1), respectively. The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:2) to afford )—benzylhydroxycyclopentanecarboxamido)propanoate (1.9 g, 76% yield).

The trans- (R)—benzyl 2—((1S,3R)hydroxycyclopentanecarboxamido)propanoate was ed in a similar manner.

Pd/C (10%, 1 g) was added to a solution of compound (R)—benzyl 2-((1R,3S) hydroxycyclopentanecarboxamido)propanoate (500 mg, 1.7 mmol) in MeOH (20 mL). The suspension was stirred under hydrogen here at ambient temperature for 2 h. Pd/C was filtered off and washed with MeOH (5 mL). The filtrate and washings were combined and concentrated to dryness to afford (R)((1R,3S)—3- ycyclopentanecarboxamido)propanoic acid (450 mg, quantitative). (R)-2—((1S,3R)—3- hydroxycyclopentanecarboxamido)propanoic acid was obtained in a similar manner.

Example 45 (R)—2-((1R,3R)—3-Hydroxycyclopentanecarboxamido)propanoic acid: 1. p—NOZPhCOOH 0 _ 2 o .JL PPh DIAD 3 3‘ ' HON-O" HACOOBn 2.LiOH .JL H00” ”ACOOH Diisopropyl azodicarboxylate (DIAD; 0.53 mL, 2.75 mmol) was added dropwise to a solution of (R)-benzyl 2-((IR,3S)-3—hydroxycyclopentanecarboxamido)propanoate (500 mg, 1.70 mmol), triphenylphosphine (676 mg, 2.60 mmol) and 4-nitrobenzoic acid (373 mg, 2.20 mmol) in dry THF (15 mL) over 0.5 h at 0—5°C under N2. The mixture was stirred for 1 h at 0-5 CC and then allowed to warm to ambient temperature and stirred for 16 h. EtOAc (50 mL) and water (50 mL) was added and the two layers were separated. The aqueous layer was ted with EtOAc (30 mL><3) and the combined organic layers were washed with 5% aqueous KHSO4 (50 mL><3), saturated aqueous NaHCO3 (50 mL><3), and brine (30 mL><1), respectively. The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The e was purified by flash column chromatography on silica gel (EtOAc/hexane = 1:2) to afford the ester (510 mg, 67% yield) as a yellow solid.

A solution of LiOH (185 mg, 4.80 mmol) in water (5 mL) was added to a solution of the ester (510 mg, 1.20 mmol) in MeOH (10 mL) at 0 °C. The reaction mixture was stirred for 3 h and then acidified with 2 N aqueous HCl to pH=3. The organic solvent was removed and the remaining mixture was extracted with EtOAc/THF (1:1, 20 mL><3), The combined organic phases were washed with water (20 mL><3) and brine (20 mL>< 1), dried over anhydrous sodium sulfate, and concentrated to afford crude (R)—2—((1R,3R)—3- hydroxycyclopentanecarboxamido)propanoic acid (350 mg, 80% , which was used in the next step t further purification. e 46 (S)—6-Oxopiperidine-3 -carboxylic acid: 0“COOH\ \COOH \COOH RuCI3, NaIO4 J HCI Q —> —> N O N O N Boc Boc H A solution 4 (5.6 g, 26 mmol) in water (30 mL) and RuC13 (14 mg) were added to a solution of Boc-(R)-piperidinecarboxylic acid (1.5 g, 6.6 mmol) in EtOAc (30 mL). The reaction mixture was stirred overnight at ambient temperature. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL><3). The combined organic phases were washed with brine (50 , dried over anhydrous sodium sulfate, and trated. The residue was d by flash column chromatography on silica gel (CH2ClQ/MGOH = 20:1) to afford (S)(tert-butoxycarbonyl)oxopiperidinecarboxylic acid (790 mg, 49% yield) as a pale yellow solid.

A solution of HCl in dioxane (6M, 10 mL) was added to a solution of (S)-l-(tert— butoxycarbonyl)—6-oxopiperidinecarboxylic acid (700 mg, 2.90 mmol) in dioxane (5 mL) at 0 °C with stirring. The reaction mixture was stirred for 4 h and concentrated to dryness.

The residue was azeotroped three times with MeOH (10 mL for each portion) to afford (S) oxopiperidine—3-carboxylic acid (600 mg, quantitative) as a colorless solid. (R) eridinecarboxylic acid was made in similar manner.

Example 47 (S)-Tetrahydro-2H-pyrancarboxylic acid and (R)-tetrahydro-2H-pyran carboxylic acid: 1. H2, Pd/C (COCI)2 2. BnBr, K2CO3 OK/j reflux H 3. Chiral separation Oxalyl chloride (20 mL, 0.22 mmol) was cooled to 0 °C and 3,4-dihydro-2H— pyrane (28 mL, 0.33 mol) was added dropwise. The solution was d to warm to ambient temperature and stirred for 2 h. An excess of oxalyl chloride was removed under vacuum and the e was heated at 120 0C for 0.5 h. The mixture was cooled to ambient temperature and poured into cold 10% aqueous Na2C03 (100 mL). The resulting solution was washed with methylene chloride (50 mL><3) and then acidified with 6 N HCl to pH=3. The mixture was extracted with methylene chloride (50 rnL><3) and the combined c phases were dried over anhydrous sodium sulfate and concentrated to afford 3,4-dihydro-2H—pyran carboxylic acid (9.1 g, 32% yield), which was used directly without further purification.

Pd/C (10%, 3 g) was added to a solution of 3,4-dihydro-2H-pyrancarboxy1ic acid (7.0 g, 55 mmol) in MeOH (100 mL). The suspension was stirred under hydrogen atmosphere (100 psi) at 40 °C for 10 h. The catalyst was filtered off and washed with MeOH (50 mL). The filtrate and washings were combined and concentrated to dryness to afford crude product. The crude t was dissolved in acetonitrile (200 mL) and benzyl bromide (9.9 g, 58 mmol) and K2C03 (19.0 g, 138 mmol) were added. The resulting suspension was heated at 50-60 °C for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 20: 1) to afford a mixture (7.1 g) of (S)- benzyl tetrahydro-2H—pyran-3—carboxylate and (R)-benzyl tetrahydro- 2H—pyran carboxylate, which was separated by chiral prep-HPLC to afford (S)-benzyl tetrahydro-2H- 3-carboxylate (2.1 g, 17% yield) and nzyl tetrahydro- 2H—pyran-3—carboxylate (2.0 g, 16% yield), respectively.

Pd/C (10%, 1 g) was added to a solution of (S)-benzy1 tetrahydro-2H—pyran carboxylate (1.1 g, 5 mmol) in MeOH (10 mL). The suspension was stirred under hydrogen atmosphere at ambient temperature for 2 h. The catalyst was filtered off and washed with MeOH (5 mL). The filtrate and washings were combined and concentrated to dryness to afford trahydro-2H—pyrancarboxylic acid (0.6 g, 92% yield). (R)-Tetrahydro-2H— pyran—3-carboxylic acid was made in a similar manner.

Example 48 trahydrofuran-3 -carboxylic acid: COOH O 1 ' EDC DMAP’ % , . COOH 2. Separation >\N "' LIOH, H202 9 Qx/J —————————_.

O "I, [‘3 4 pl 0 0 NH 1-Ethy1(3-dimethylaminopropyl)carbodiirnide (EDCI; 362 mg, 1.90 mmol) and DMAP (202 mg, 1.90 mmol) were added to a solution of (R)benzyl-oxazolidinone (333 mg, 1.90 mmol) and tetrahydrofuran—3- carboxylic acid (200 mg, 1.70 mmol) in CH2C12 (20 mL) at ambient temperature. The reaction mixture was stirred for 3 h at ambient temperature and water (20 mL) was added. The two layers were separated and the aqueous phase was extracted with CH2C12 (20 mL><3). The ed organic phases were washed with brine (50 mL>< 3), dried over anhydrous sodium sulfate and concentrated. The e was d by flash column chromatography on silica gel (CHQClz/EtOAC = 100:2) to afford (R)benzyl- -tetrahydrofurancarbonyl)oxazolidinone (120 mg, 25% yield).

H202 (0.44 mL, 30%, 7.0 mmol) was added dropwise to a solution of (R) benzyl((S)-tetrahydrofurancarbonyl)oxazolidin-2—one (250 mg, 0.900 mmol) in THF (10 mL) at 0 CC with stirring over 0.5 h. The mixture was stirred for 10 min and a solution of LiOH—HZO (84 mg, 2.0 mmol) in water (0.5 mL) was added dropwise. The reaction e was stirred for 3 h at 0 OC and then quenched with saturated aqueous Na2803 (10 mL). The organic solvent was removed and the residual aqueous solution was washed with CH2C12 (20 mL><3) and acidified with 1N HCl to pH=3. The solution was trated to dryness to afford crude (.S')—tetrahydrofurancarboxylic acid (100 mg, quantitative), which was used directly t further purification.

Example 49 2-(3-Oxopiperaziny1)acetic acid: 1. TEA, BrCHZCOOBn 0 O 2. H2, Pd/C HN HN K/NH K/NQOKOH Triethylamine (4.13 mL, 30.0 mmol) was added dropwise to a solution of piperazinone (1.0 g, 10 mmol) and benzyl bromoacetate (2.3 g, 10 mmol) in romethane (20 mL) at 0 OC. The reaction e was allowed to warm to ambient temperature and stirred for 2 h. Water (20 mL) was added and the resulting mixture was extracted with dichloromethane (20 mLX 3). The c ts were combined, dried over anhydrous sodium sulfate and trated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 50:1) to afford the benzyl ester (1.5 g, 60% yield) as a colorless solid, which was subjected to hydrogenolysis in the presence of Pd/C (0.2 g) in methanol (10 mL) for 1 h at ambient ature to afford 2- (3-oxopiperazin—1-yl)acetic acid (0.4 g, 42% yield).

Example 50 2-(4-Hydroxy—4-methylpiperidinyl)acetic acid: 1. TFA MeMgBr 2. BrCH co Bn H2, Pd/C H030 0 A solution of N—Boc-piperidinone (1.0 g, 5.0 mmol) was dissolved in THF (20 mL) and then cooled to -40 °C. MeMgBr (2.8 M, 7.2 mL, 20 mmol) was added slowly over min. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was cooled to 0 °C and saturated aqueous NH4C1 (50 mL) was added. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 4-hydroxymethylpiperidine—1-carboxylate (1.0 g, 92% yield) as a yellow oil.

TFA (3.0 mL) was added to a solution of tert—butyl 4—hydroxy piperidine-l-carboxylate (1.0 g, 4.7 mmol) in CH2C12 (5 mL) at 0 0C with stirring. The reaction mixture was stirred for 1 h and then concentrated to s. The e was azeotroped three times with EtOAc (3 mL for each portion) to remove al TFA to afford compound the amine (1.0 g, quantitative) as its TFA salt.

K2C03 (6.9 g, 50 mmol) was added to a solution of the TFA salt (2.50 g, 16.6 mmol) and benzyl 2—bromoacetate (4.30 g, 18.8 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and then pound into water (300 mL). The resulting mixture was extracted with EtOAc (300 mL><3) and the combined organic layers were washed with water (400 mL) and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 50:1) to afford (3.0 g, 68% yield) as a yellow oil.

To a solution of compound benzyl ydroxymethylpiperidinyl)acetate (400 mg, 1.61 mmol) in methanol (10 mL) was added Pd/C (10%, 100 mg) and the mixture was stirred under hydrogen atmosphere at ambient temperature for 1 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to afford 2-(4-hydroxy methylpiperidin-l-yl)acetic acid (250 mg, quantitative) as a colorless solid, which was used directly t further purification.

Example 51 (S)—4,5,6,7—Tetrahydro-lH-indazole—S-carboxylic acid and (R)-4,5,6,7-tetrahydrolH-indazole-S-carboxylic acid: o DMF-DMA; O 1. LiOH O NH2NH2 2. SOCIZ, MeOH EtO —>E ot | \,N —> | \,N N N O H H Separation by MeO \ chiral HPLC I N A solution of ethyl 4—oxocyclohexanecarboxylate (50 g, 0.29 mol) in DMF-DMA (275 mL) was heated at 110 °C for 12 h. The mixture was concentrated and ine hydrate (73.5 g, 1.47 mol) in ethanol (1000 mL) was heated under reflux overnight. Most of ethanol was removed and the remaining mixture was treated with water (400 mL). The resulting mixture was extracted with EtOAc (400 m1><2). The combined organic layers were washed with brine (400 mL) and concentrated. The residue was d by flash column chromatography on silica gel (DCM/MeOH = 30: 1) to afford crude ethyl 7-tetrahydro- 1H—indazolecarboxylate (18 g) as a colorless solid.

To a solution of ethyl 4,5,6,7-tetrahydro-1H—indazolecarboxylate (3.00 g, 15.5 mmol) in methanol (10 mL) was added water (10 mL) and lithium hydroxide hydrate (780 mg, 5.90 mmol). The reaction mixture was stirred at ambient temperature overnight and then concentrated to remove most of methanol. The remaining mixture was acidified with diluted aqueous HCl to pH=4 and then concentrated. The residue was dried under vacuum to afford the corresponding acid (1.7 g, 66% yield) as a colorless solid, which was used directly without r purification.

A mixture of the acid (1.7 g, 10 mmol) and SOC12 (2.5 g, 21 mmol) in methanol (20 mL) was heated under reflux for 2 h. The e was cooled to ambient temperature and then concentrated. The residue was purified by flash column tography on silica gel (DCM/MeOH = 30: 1) to afford the crude product (1.0 g, 55% yield) as a light yellow solid, which was further separated by preparative chiral-HPLC to afford (S)-methyl 7- tetrahydro-1H-indazolecarboxylate (0.2 g) and (R)-methy1 4,5,6,7-tetrahydro-1H-indazole- -carboxylate (0.2), respectively.

To a solution of thyl 4,5,6,7-tetrahydro-1H—indazolecarboxylate (500 mg, 2.80 mmol) in methanol (20 mL) were added water (10 mL) and lithium hydroxide hydrate (234 mg, 5.57 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated to remove most of methanol. The remaining mixture was acidified with diluted aqueous HCl to pH=4 and then concentrated. The residue was dried under vacuum to afford (S)-4,5,6,7-tetrahydro-1H-indazolecarboxylic acid (380 mg, 81% yield) as a colorless solid, which was used ly without fiarther purification. (R)- methyl 4,5,6,7—tetrahydro-1H-indazole—5-carboxylate was synthesized in a similar manner.

Example 52 (S)(2-Morpholinoacetamido)propanoic acid: H-L-AIa-OBn fi O/fi O o o DMTMM, NMM /L H2' Pd/C K/NdkOH DMF, DCM K/N\)J\l:l COOBn V OK//WN\)OL|l:l|/LCOOH To DMTMM (76.1 g, 0.276 mol) and N—methylmorpholine (NMM; 32.9 mL, 0.300 mol) was added to a 0 °C solution of holinoacetic acid (20.0 g, 0.138 mmol) and L-alanine benzyl ester hydrochloride (35.7 g, 0.166 mol) in DMF (100 mL) and DCM (200 mL). The on mixture was d for 4 h at ambient temperature then concentrated.

EtOAc (500 mL) and water (500 mL) was added to the residue. The resulting two layers were separated and the aqueous phase was extracted with EtOAc (3 X300 mL). The combined organic layers were washed with brine (3 X500 mL), dried over ous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 100:3) to afford (S)-benzyl orpholinoacetamido)propanoate (21.1 g, 50% yield).

To Pd/C (10%, 5.0 g) was added a solution of (S)-benzyl 2-(2- morpholinoacetamido)propanoate (20.0 g, 69.0 mmol) in MeOH (200 mL). The mixture was stirred under a hydrogen atmosphere at ambient temperature for 4 h, then it was filtered and rinsed with MeOH (200 mL). The filtrate and washings were combined and concentrated to dryness to afford crude t which was washed with EtOAc (2X 100 mL) and dried under vacuum to afford (S)(2-morpholinoacetamido)propanoic acid (12.8 g, 86% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): 5 7.95 (m, 1H), 4.25 (m, 1H), 3.70 (m, 4H), 3.08 (d, .1: 15.4 Hz, 2H), 2.40—2.55 (m, 4H), 1.30 (d, J: 6.6 Hz, 3H).

Example 53 (R)—1-(2,4-Dimethoxybenzyl)oxopyrrolidine-3 -carboxylic acid and (2,4- dimethoxybenzy1)oxopyrrolidinecarboxylic acid: COOH “W’j{:LMeO OMe HOOC\)LCOOH SOCb,MeOHl figf_§poome COOH 0 O N N COOMe 6MB | chiral separtion N §00Me §OOH DMB gifi) ‘ o o N N DMB 6MB To a solution of itaconic acid (13.0 g, 100 mmol) in toluene (50 ml) was added a solution of 2,4-dimethoxybenzy1amine (17.54 g, 105.0 mmol) in toluene (50 mL) and the reaction mixture was stirred for 15 h under reflux. The mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was treated with diethyl ether (100 mL) and the resulting precipitate was ted by filtration, washed with diethyl ether and EtOAc and dried to afford 1-(2,4-dimethoxybenzy1)-5—oxopyrrolidine carboxylic acid (20.0 g, 71% yield) as a colorless solid.

SOC12 (6.4 g, 54 mmol) was added se to methanol (40 mL) followed by addition of 1-(2,4-dimethoxybenzy1)—5-oxopyrrolidinecarboxy1ic acid (5.0 g, 18 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h and then heated under reflux for 7 h. The mixture was cooled to ambient temperature and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 6:1 to 2: 1) to afford methyl l-(2,4-dimethoxybenzy1)—5 rrolidinecarboxy1ate (a mixture of two enantiomers, 4.3 g, 81% yield) as a colorless oil. The two enantiomers were separated by chiral prep-HPLC.

] LiOH (1.36 g, 32.5 mmol) was added to a on of (R)-methyl 1-(2,4- dimethoxybenzy1)oxopyrrolidine-3—carboxy1ate (3.18 g, 10.9 mmol) in THF/HQO (1:1, 40 mL) at 0 CC and the reaction mixture was d for 1 h. THF was removed and the remaining aqueous solution was washed with diethyl ether (50 mL><2). The aqueous phase was adjusted to pH=5 with 3 N aqueous HCl and the ing mixture was extracted with DCM (40 m1><3). The combined extracts were washed with water (100 mLX3) and brine (100 mL><1), dried over anhydrous sodium sulfate and concentrated to afford nd (R) (2,4-dimethoxybenzyl)—5-oxopyrrolidinecarboxylic acid (2.76 g, 88% yield) as a colorless solid. (S)(2,4-dimethoxybenzyl)oxopyrrolidinecarboxylic acid was prepared using the same method.

Example 54 (1r,4r)Hydroxymethylcyclohexanecarboxylic acid: 1.NaBH4 Q0003 2. TBSCI UCOOEt LDA, Mel o TBSO ‘3‘ 1. HOAc OCOOEt 2. LiOH COOH TBso‘“ Ho“ : NaBH4 (12.7 g, 0.34 mol) was added in portions to a solution of ethyl 4- oxocyclohexanecarboxylate (52.0 g, 0.31 mol) in ethanol (300 mL) at 0 °C over a period of 0.5 h with stirring. The suspension was stirred overnight at ambient temperature and then quenched with 1N aqueous HCl (100 mL). The solvent was removed under reduced re and the residue was dissolved in CH2C12 (500 mL). The resulting solution was washed with ted aqueous NaHCO3 (300 mL><3) and brine (300 mL><1), dried over anhydrous sodium sulfate, and concentrated to dryness to give the corresponding alcohol.

The alcohol was dissolved in DMF (300 mL) and imidazole (51.4 g, 0.450 mol) was added. A solution of TBSCl (54.4 g, 0.360 mol) in THF (100 mL) was added dropwise and the reaction e was stirred at ambient temperature for 12 h. Water (300 mL) was added and the resulting mixture was extracted with EtOAc (300 mL><2). The combined organic extracts were washed with 5% s KHSO4 (300 mL><3), saturated aqueous NaHC03 (300 mL><3), and brine (300 mL><1), respectively. The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was d by flash column chromatography on silica gel (EtOAc/ Hexane = 1:30) to afford ethyl 4-(tert— butyldimethylsilyloxy)cyclohexanecarboxylate (48.0 g, 54% yield over two steps) as an oil.

LDA (2M solution, 7.70 mL, 15.4 mmol) was added dropwise to a solution of ethyl 4-(tert—butyldimethylsilyloxy)cyclohexanecarboxylate (4.0 g, 14 mmol) in THF (30 mL) at -78 °C with ng. The mixture was stirred for 1 h followed by addition of thane (2.20 g, 15.4 mmol) se. The on mixture was stirred at -78 CC for 0.5 h and then allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with water (200 mL) and the resulting mixture was extracted with CH2C12 (200 . The combined organic phases were washed with brine (500 mLX 1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 100: 1) to afford trans-ethyl 4-(tert— butyldimethylsilyloxy)—1-methylcyclohexanecarboxylate (2.3 g, 60% yield) as an oil.

Acetic acid (2.0 mL) was added dropwise to a on of trans-ethyl 4-(tert- butyldimethylsilyloxy)methylcyclohexanecarboxylate (2.0 g, 7.0 mmol) in THF (10 mL) at ambient temperature. The reaction mixture was heated at 50 °C for 3 h. The mixture was concentrated and then diluted with water (100 mL). The resulting mixture was extracted with CH2C12 (50 mL><3). The combined extracts were washed with saturated aqueous NaHC03 (50 mL><3) and brine (100 mL>< 1), dried over anhydrous sodium sulfate, and trated to afford the alcohol.

The l was treated with a solution of lithium hydroxide-H20 (100 mg, 25 mmol) in water/THF (10 mL/4 mL) for 30 min. THF was removed and the aqueous solution was acidified to pH=3-4 with 1N aqueous HCl. The resulting mixture was concentrated to dryness to afford crude transhydroxy—1-methylcyclohexanecarboxylic acid (150 mg, 13% yield), which was used directly without fithher purification.

Example 55 (1r,4r)Hydroxymethylcyclohexanecarboxylic acid: 1. NaOH HmCOOBn 2. BnBr 3. Separation 0003 coca COOBn H2, Pd/C —, Hob COOH To a solution of ethyl 4-oxocyclohexanecarboxylate (4.00 g, 23.5 mmol) in diethyl ether (80 mL) was added MeLi (37.6 mL, 1M in diethyl ether) at -60 CC under nitrogen atmosphere. The reaction mixture was stirred at -60 °C for 30 min. Saturated aqueous NH4C1 (50 rnL) was added and the resulting mixture was extracted with EtOAc (100 mL><2). The combined organic layers were washed with brine (150 mL) and water (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10: 1) to afford ethyl 4—hydroxy cyclohexanecarboxylate (1.8 g, 41% yield) as an oil.

NaOH (0.58 g, 14.5 mmol) was added to a solution of ethyl 4-hydroxy methylcyclohexanecarboxylate (1.8 g, 9.7 mmol) in ethanol/H20 (30 mL/15 mL) at 0 °C and the reaction mixture was stirred at 0 CC for 12 h. The mixture was concentrated to afford the corresponding acid as its sodium salt.

Benzyl bromide (3.3 g, 19 mmol) was added to a suspension of the acid (sodium salt) in DMF (40 mL). The reaction mixture was stirred at t temperature for l h and water (100 mL) was added. The resulting e was extracted with EtOAc (100 mL><2).

The combined c layers were washed with brine (150 mL) and water (150 rnL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 6:1 to 4:1) to afford (507 mg, 21% yield) and cis-benzyl 4-hydroxymethylcyclohexanecarboxylate (748 mg, 31% yield), respectively.

To a solution of )—benzyl 4-hydroxymethylcyclohexanecarboxylate (500 mg, 2.00 mmol) in THF (20 mL) was added Pd/C (50 mg, 10%). The mixture was stirred under a hydrogen here (1 atm) at ambient temperature for 2 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford (lr,4r)—4-hydroxymethylcyclohexanecarboxylic acid (260 mg, 82% yield) as a colorless solid, which was used in the next step without further purification. (1 s,4s)—4- hydroxymethylcyclohexanecarboxylic acid was synthesized in a r manner.

Example 56 )Hydroxy-1 —methylcyclohexanecarboxylic acid: 1 HOAC 2 p-NOzPhCOOH 1. EitONa ‘. .UCOOEt TBso“ Ho‘“ Acetic acid (2 mL) was added dropwise to a solution of (lr,4r)-ethyl 4-((tert- butyldirnethylsilyl)oxy)-l-methylcyclohexanecarboxylate (2.0 g, 7 mmol) in THF (10 mL) at ambient temperature. The reaction e was heated at 50 CC for 3 h. The mixture was concentrated and water (100 mL) was added. The resulting e was extracted with CH2C12 (50 mL><3) and the combined extracts were washed with saturated aqueous NaHC03 (50 mLX3) and brine (100 mLX 1), dried over anhydrous sodium sulfate, and concentrated.

The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 3:1) to afford the ponding alcohol (1.1 g, 84% yield) as an oil.

The l (1.0 g, 5.4 mmol), 4-nitrobenzoic acid (1.2 g, 7.0 mmol) and triphenylphosphine (2.11 g, 8.10 mmol) were dissolved in THF (40 mL). The mixture was cooled to 0 °C under N2 and DIAD (1.74 g, 8.60 mmol) was added dropwise over 0.5 h. The on mixture was stirred for l h at 0 CC and then allowed to warm to ambient temperature and stirred for 16 h. EtOAc (100 mL) and water (100 mL) were added and two layers were separated. The aqueous layer was extracted with EtOAc (100 mL><3). The combined organic layers were washed with brine (100 mLX 1), dried over anhydrous sodium sulfate and trated. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 5:1) to afford cis(ethoxycarbonyl)—4-methylcyclohexyl 4-nitrobenzoate (1.2 g, 66% . cis(Ethoxycarbonyl)methylcyclohexyl obenzoate (970 mg, 2.90 mmol) was added to a freshly prepared solution ofNaOEt (14.5 mmol) in EtOH (40 mL) at 0 °C.

The mixture was stirred for 6 h at ambient temperature and then concentrated. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 3: 1) to afford (ls,4s)—ethyl 4—hydroxy-l-methylcyclohexanecarboxylate (400 mg, 74% yield). (ls,4s)-Ethyl 4-hydroxy-l-methylcyclohexanecarboxylate was treated with a solution of lithium hydroxide-H20 (361 mg, 8.6 mmol) in water/THF (10 mL/4 mL) for 30 min. THF was removed and the aqueous solution was acidified to pH=3-4 with 1N HCl. The mixture was concentrated to dryness to afford crude nd cz'Shydroxy methylcyclohexanecarboxylic acid (quantitative), which was used directly without further cation.

Example 57 2-(4-Hydroxypiperidin-l-yl)acetic acid: 1. NaBH4, THF, MeOH of) 2. HCI-dioxane H00 0 NBOC 3. BrCHZCOOBn, DCM, TEA NQLOH 4. H2, Pd/C, MeOH Sodium borohydride (5.7 g, 0.15 mol) was added in portions to a solution of tert- butyl 4-oxopiperidine—1-carboxylate (15 g, 75 mmol) in THF/MeOH (150 mL/30 mL) at -10 oC. The reaction mixture was stirred for 30 min at -10 °C and then poured into ice-water (300 mL). The resulting mixture was extracted with EtOAc (300 mLX3) and the ed extracts were dried over anhydrous sodium sulfate and concentrated to afford tert-butyl 4— hydroxypiperidine-l-carboxylate (13.2 g, 87% yield). tert-Butyl 4-hydroxypiperidine-l-carboxylate was treated a 6 N HCl/dioxane solution (20 mL) and the mixture was allowed to stand for 20 min at ambient temperature.

The solvent was removed to afford piperidinol (HCl salt, 9.0 g, ).

To piperidin—4-ol (HCl salt, 9.0 g) was added a solution of benzyl 2-bromoacetate (15.0 g, 65.7 mmol) in romethane (100 mL). The e was cooled to 0 oC and triethylamine (27.6 mL, 0.200 mol) was added. The reaction mixture was d to warm to t temperature and stirred for 2 h. Water (100 mL) was added and the resulting mixture was extracted with dichloromethane (100 mL><3). The c extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 20:1 to 10: 1) to afford benzyl 2- (4-hydroxypiperidin-1—yl)acetate (8.3 g, 51% yield).

] A mixture of benzyl 2-(4-hydroxypiperidinyl)acetate (1.0 g, 4.0 mmol) and Pd/C (0.1 g) in methanol (20 mL) was hydrogenated for 1 h at ambient temperature. The Pd/C was filtered off and the filtrate was concentrated to dryness to afford 2-(4- hydroxypiperidin-l-yl)acetic acid (0.6 g, 94% yield).

Example 58 2-(3 ,3 -Difluoropiperidinyl)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-yl)acetic acid: F F FUH FUACOOH NH NACOOH F F F 1. BrCHZCOOBn F Et3N 2. H2, Pd/C OH OACOOH F3C F3C C CI Triethylamine (0.660 mL, 4.76 mmol) was added to a solution of 3,3— difluoropiperidine-HCl (500 mg, 3.17 mmol) and benzyl 2-bromoacetate (763 mg, 3.33 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was washed with l N aqueous sodium ide and water, successively. The organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (Hexane/EtOAc = 25: l) to afford benzyl ester of2-(3,3- difluoropiperidiny1)acetic acid (486 mg, 56% yield) as a yellow oil.

To a solution of benzyl ester of 2-(3,3 ropiperidin-l-yl)acetic acid (486 mg, 0.850 mmol) in methanol (20 mL) was added Pd/C (10%, 100 mg). The suspension was stirred under hydrogen here at ambient temperature for l h. The catalyst was filtered off and washed with MeOH (5 mL). The filtrate and washings were combined and concentrated to dryness to afford 2-(3,3—difluoropiperidin—l-yl)acetic acid (292 mg, 90% yield) as a greenish yellow solid, which was used directly without further purification.

The ing compounds were synthesized in a r : 2-(4,4- difluoropiperidin- l -yl)acetic acid, 2-(3,3-difluoropyrrolidin- l -yl)acetic acid, 2-(4- (trifluoromethyl)piperidin- l -yl)acetic acid, 2-(4-chloropiperidin-l-yl)acetic acid Example 59 (S)—2-((R)(( l 3-Hydroxycyclobutanecarboxamido)propanamido)—3 -(4- methoxyphenyl)propanoic acid: 1. TFA 2. HATU, DIPEA O E O O H E H BocHN/I\n’N\,)k0I3n O=<>—C02H ”WNgkOBn NaBH4 2 _ O O o \©\O/ : ‘o/ HOzC—Q—NOZ ON 0 2 Hi = $03 MHAWN DIAD PPh3 HO 0 O E 0 —’ .MLN/YH\)J\OHH Ho‘ 0 \© To a solution of (S)-benzyl ((tert—butoxycarbonyl)amino)propanamido)—3-(4- methoxy phenyl)propanoate (1.2 g, 2.6 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at ambient temperature for 0.5 h and then concentrated to dryness to the crude amine (TFA salt).

To the amine (TFA salt) was suspended in DCM (20 mL) and 3- oxocyclobutanecarboxylic acid (0.36 g, 3.15 mmol) and HATU (1.09 g, 1.43 mmol) were added. The mixture was cooled to 0 °C ed by addition of DIPEA to pH=8. The reaction mixture was stirred at ambient temperature for 30 min and water (50 mL) was added. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel leum ether/EtOAc = 2:1 to 1:1) to afford nzyl 3-(4-methoxyphenyl)((R)—2-(3- oxocyclobutanecarboxamido)propanamido)propanoate (0.99 g, 83% yield over two steps) as a colorless solid.

To a solution of (S)-benzyl 3-(4-methoxyphenyl)—2-((R)(3- oxocyclobutanecarboxamido)propanamido)propanoate (0.99 g, 2.2 mmol) in ethanol (20 mL) was added NaBH4 (0.17 g, 4.4 mmol) in three portions over 20 min. After te addition, the reaction mixture was stirred at ambient temperature for 2 h and then quenched with saturated aqueous ammonium chloride (50 mL). Ethanol was removed under reduced pressure and the residue was extracted with DCM (50 mL><2). The cs were combined, dried over ous sodium sulfate, and concentrated. The e was purified by flash column chromatography on silica gel (DCM/methanol = 10:1) to afford (S)-Ethyl 2-((R)—2- ((ls,3S)hydroxycyclobutanecarboxamido)propanamido)(4-methoxyphenyl)propanoate (0.62 g, 63% yield) as a colorless solid.

To a solution of (S)-ethyl 2-((R)—2-((ls,3S)—3- hydroxycyclobutanecarboxamido)propanamido)—3- (4-methoxyphenyl)propanoate (0.62 g, 1.6 mmol), 4-nitrobenzoic acid (0.53 g, 3.2 mmol) and triphenylphosphine (0.88 g, 3.4 mmol) in THF (20 mL) was added DIAD (0.660 mL, 3.36 mmol). The reaction mixture was stirred under nitrogen for 2 d and quenched with saturated aqueous NaHC03 (50 mL). The resulting mixture was extracted with EtOAc (50 mLXZ) and the organics were ed, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel to afford (S)-ethyl 3-(4—methoxyphenyl)—2-((R)((lr,3R)(4- nitrophenoxy)cyclobutane carboxamido)propanamido)propanoate (0.59 g, 73% yield) as a colorless solid.

To a solution of (S)—ethyl ethoxyphenyl)((R)—2-((1r,3R)—3-(4— nitrophenoxy)cyclobutane carboxamido)propanamido)propanoate (0.59 g, 1.1 mmol) in CH3OH/H20 (15 mL, 2:1) was added LiOH—HgO (0.14 g, 3.3 mmol). The reaction mixture was stirred at t temperature for l h and then concentrated. Water (50 mL) was added to the residue and the resulting e was washed with DCM (50 mL><2). The s phase was acidified with diluted aqueous HCl to pH=3-4 and then washed again with DCM (50 mLX2). The aqueous phase was trated under vacuum to afford crude (S)((R)—2- (( l r,3R)—3 -hydroxycyclobutanecarboxamido)propanamido)—3 -(4- methoxyphenyl)propanoic acid (0.46 g, 84% yield) as a colorless solid, which was used for the next step without further purification.

Example 60 (S)((tert—Butoxycarbonyl)amino)—3-cyanopropanoic acid: CONHZ CN DCC, acetone BocHN COOH pyridine BocHN COOH A solution of dicyclohexylcarbodiimide (DCC, 8.3 g, 40 mmol) in acetone (100 ml) was added dropwise a suspension of Boc-asparagine (9.3 g, 40 mmol) in pyridine (50 mL) at 0 CC under nitrogen. The reaction mixture was stirred at ambient temperature for 3 h.

The mixture was filtered and the filtrate was concentrated. The residue was ved in dichloromethane (400 mL) and the solution was washed with 2 N aqueous HCl (20 mL><3) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S) butoxycarbonylamino)-3—cyanopropanoic acid (5.5 g, 56% yield), which was used directly without further purification.

Example 61 2-((tert—Butoxycarbonyl)amino)—3,3,3-trifluoropropanoic acid: 0 0 CF3 JK DOM F30 OH TFAA OEt O H2N O + F3C _> t —’ CbZNN CbZHN 0 CB 0 JNaBH4 1. 6N HCI 2. Boc20 CF3 OH OEt BocHN ‘— CszNW o 0 To a solution of ethyl 3,3,3—trifluoro—2-oxopropanoate (30 g, 176 mmol) in romethane (1 L) was added benzyl carbamate (26.6 g). The reaction mixture was d at ambient temperature for 24 h and the resulting precipitate was ted by filtration and dried under vacuum to afford ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro hydroxypropanoate (49.0 g, 87% yield), which was used directly without further purification.

To a on of ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2— hydroxypropanoate (49.0 g, 153 mmol) in diethyl ether (350 mL) was added dropwise TFAA (35.3 g, 168 mol) at 0 oC followed by addition of pyridine dropwise (26.5 g, 336 mmol) at 0 CC. The reaction mixture was allowed to warm to ambient temperature and stirred for 6 h.

The mixture was d and the filtrate was concentrated to afford ethyl 2- (benzyloxycarbonylimino)-3,3,3-trifluoropropanoate (45.0 g, 97% yield), which was used directly without further purification.

To a solution of ethyl 2-(benzyloxycarbonylimino)-3,3,3-trifluoropropanoate (45.0 g, 1485 mmol) in diethyl ether (300 mL) was added sodium borohydride (11.3 g 297 mmol) in portions at 0 CC. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction was quenched with water (100 mL) lly and the organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL><3). The organic layers were combined, washed with brine (200 mL><2), dried over anhydrous sodium sulfate and concentrated. The e was purified by flash column chromatography on silica gel (EtOAc/petroleum ether = 1:9) to afford ethyl 2-(benzyloxycarbonylamino)-3,3,3- trifluoropropanoate (22.0 g, 48% yield).

A suspension of ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoropropanoate (5.0 g, 16.4 mmol) in 6N aqueous HCl (200 mL) was refluxed for 6 h. The mixture was cooled to ambient temperature and then concentrated under reduced pressure.

The residue was suspended in acetonitrile (100 mL) and triethylamine (4.96 mL, 36 mmol) and di-tert—butyl dicarbonate (3.9 g, 18 mmol) were added. The pale yellow solution was stirred at t temperature overnight and then diluted with romethane (400 mL). The resulting on was washed with 1N aqueous HCl (100 mL) and brine (200 mL), dried over anhydrous sodium sulfate and concentrated. The residue was washed with petroleum ether (100 mL) to afford 2-(tert—Butoxycarbonylamino)—3,3,3—trifluoropropanoic acid (3.0 g, 75% yield) as a colorless solid.

Example 62 (S)—3-(3,4-Bis(benzyloxy)phenyl)((S)(2- linoacetamido)propanamido)propanoic acid: 1. TFA 2. o 0 OH OBn 1% 1 1.8000 N COOH HO 2 BnO H 2. BnBr, cho3 HATU H2N COOH BocHN COOBn o/fi o o O O O LiOH N N N OBn a ; o H : o UOBn L-Dopa (10.0 g, 50 mmol) was ded in water (100 mL) and acetone (100 mL) and 2N aqueous NaOH was added to adjust pH=8. BOC2O (10.5 g, 50 mmol) was added and the reaction mixture was stirred for 12 h at ambient temperature. The c solvent was removed. The aqueous solution was washed with ethyl ether (100 mL><3) and then acidified with 2N aqueous hydrochloric acid to pH=3. The resulting mixture was extracted with EtOAc (200 mL><3). The combined organic phases were washed with brine (100 mL>< 1), dried over anhydrous sodium sulfate, and concentrated to afford Boc-L-dopa (15.1 g, quantitative), which was used ly for the next step without further purification.

K2C03 (21.0 g, 150 mmol) was added to a solution of Boc-L—dopa (10.0 g, 33 mmol) in acetonitrile (100 mL) followed by addition of benzyl bromide (21.0 g, 123 mmol).

The suspension was heated at 50-60 °C for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and washings were ed and concentrated to dryness. The residue was purified by flash column chromatography on silica gel e/EtOAc = 20: 1) to afford (S)-benzyl 3-(3,4- bis(benzyloxy)pheny1)(tert-butoxycarbonylamino)propanoate (15.3 g, yield 80%).

TFA (2 mL) was added to a solution of (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)— 2-(tert—butoxycarbonylamino)propanoate (1.9 g, 3.1 mmol) in CH2C12 (5 mL) at 0 0C with stirring. The mixture was stirred for 1 h and trated to dryness. The e was azeotroped three times with EtOAc (5 mL for each portion) to remove residual TFA and the amine was obtained as its TFA salt, which was used directly without further ation.

HATU (1.9 g, 5.1 mmol) and N—methylmorpholine (1.5 g, 15 mmol) were added to a solution of amine (TFA salt, 3.4 mmol) and (S)-2—(2-morpholinoacetamido)propanoic acid (800 mg, 3.70 mmol) in methylene chloride (20 mL) and DMF (10 mL) at 0 CC with stirring. The suspension was stirred for 1 h at ambient ature and then concentrated.

The e was d by flash column chromatography on silica gel (methylene chloride/methanol = 20: 1) to afford (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)—2-((S)(2- morpholinoacetamido) propanamido)propanoate (1.70 g, yield 82%) as a colorless solid.

A solution of LiOH (279 mg, 6.6 mmol) in water (6 mL) was added to a solution of (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)((S)(2-morpholinoacetamido) propanamido)propanoate (1.1 g, 1.66 mmol) in MeOH (30 mL) at 0 CC with stirring. The reaction mixture was stirred for 3 h and then acidified with 2 N aqueous HCl to pH=3. The resulting e was concentrated and the residue was carried forward without further purification.

Example 63 (S)—2-Amino-N—((S)—3-(cyclopent- 1 —enyl)— 1 -((R)methyloxiranyl) oxopropanyl)(4-methoxyphenyl)propanamide TFA salt: BocHN\_)J\OH TFA o 1 HATU DIEA DMF \©\ 2. TFA, DCM 32'qu OMe \©\0Me To (S)—2-((tert—butoxycarbonyl)amino)(4-methoxypheny1)propanoic acid (2.00 g, 6.78 mmol) and (S)—2—amino—3-(cyclopent-1—eny1)—1-((R)-2—methyloxiran-2—yl)propan- 1-one (1.98 g, 6.78 mmol) in DMF (10 mL) at 0 °C was added HATU (3.00 g, 8.36 mmol) followed by DIEA (5.90 mL, 33.9 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2X), washed with brine, dried with sodium sulfate, filtered, and trated. Purification by column chromatography (1 :1 hexanes/EtOAc) provided tert-butyl ((S)(((S)—3 -(cyclopenteny1)((R) methyloxiran-Z-yl)-1 -oxopropanyl)amino)(4-methoxyphenyl)—1-oxopropan yl)carbamate (2.62 g, 82%) as a colorless oil. MS(EI) for C26H36N206, found 473.3 (MH)+.

To tert-butyl ((S)—1-(((S)—3 -(cyclopenten-1 -yl)((R)methyloxirany1)-1 - oxopropanyl)amino)—3 thoxyphenyl)-1—oxopropany1)carbamate (0.99 g, 2.1 mmol) was added DCM (5 mL) and TFA (5 mL). The mixture was allowed to stand at ambient ature for 30 min then it was concentrated to provide crude (S)-2—amino-N— -(cyclopentenyl)((R)methyloxiranyl)oxopropanyl)-3 -(4- methoxypheny1)propanamide (quant.) and carried forward without fiarther purification.

MS(EI) for C21H28N204, found 373.2 (MH)+.

(S)amino-N-((S)—3-cyclohexeny1((R)methyloxiranyl)oxopropan yl)-3 -(4-(methylsulfonyl)phenyl)propanamide was synthesized in a r manner.

Example 64 (S)((S)—2-Aminopropanamido)-N—((S)-3—(cyclopenten-1 -yl)-1—((R) methyloxiran—2-yl)-1 -oxopropanyl)—3-(4-methoxyphenyl)propanamide (TFA salt): BocHNJW(OH TFA dc]: O O TFA 1HATU DIEA DMF H o HZN i , N —" ; H2N N$N =. H: H o 2.TFA,DCM i o o OMe \©\OMe [0066 1] To (S)—2—amino-N—((S)—3—(cyclopent-l -enyl)((R)methyloxiranyl)—1- panyl)(4-methoxyphenyl)propanamide (TFA salt, 2.00 g, 4.26 mmol) and (S) ((tert—butoxycarbonyl)amino)propanoic acid (805 mg, 4.26 mmol) in DMF (10 mL) at 0 0C was added HATU (1.94 g, 5.11 mmol) followed by DIEA (4.37 mL, 25.6 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat, aq.), extracted with EtOAc (2 X), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1 :1 hexanes/EtOAc) provided tert—butyl ((S)(((S)(((S)—3— (cyclopenten—1 -yl)—1—((R)-2—methyloxiran-2—yl)oxopropan—2-yl)amino)—3 -(4— methoxyphenyl)oxopropan—2-yl)amino)oxopropanyl)carbamate (1.94 g, 84%) as a colorless oil. MS(EI) for C29H41N307, found 544.3 (MH)+.

To tert-butyl ((S)—1—(((S)—1-(((S)—3 opent-l -en-l-yl)((R)methyloxiran yl)-1 -oxopropanyl)amino)(4-methoxyphenyl)oxopropanyl)amino)— 1 opan- 2-yl)carbamate (1.94 g, 2.18 mmol) was added DCM (10 mL) and TFA (10 mL). The mixture was allowed to stand at ambient temperature for 30 min then it was concentrated to provide crude tert—butyl ((S)—1—(((S)-1 -(((S)-3 -(cyclopent—1-en-1—yl)—1-((R)methyloxiran yl)— 1 opanyl)amino)(4-methoxyphenyl)oxopropanyl)amino)— 1 -oxopropan- arbamate (quant) which was carried forward without r purification. MS(EI) for C24H33N305, found 444.2 (MH)+.

Example 65 (S)—3-Hydroxy(2—morpholinoacetamido)propanoic acid: 1.H-Ser-0Bn HATU 0/\, o 2. H2, PdlC 0/} o I K/N\)J\0H K/NQL” COOH HATU (25.2 g, 66.0 mmol) and DIPEA (20 mL) were added to a solution of 2- morpholinoacetic acid (8.00 g, 55.0 mmol) and L-serine benzyl ester (HCl salt, 12.7 g, 55.0 mmol) in DMF (150 mL) at 0 0C with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 8 h. EtOAc (500 mL) and water (500 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (300 mL><3) and the combined organic phases were washed with brine (200 mL><3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column tography on silica gel (CH2C12/1VIeOH = 20: 1) to afford the benzyl ester (8.1 g, 47% yield).

Pd/C (3 g, 10%) was added to a solution of ester (8.1 g, 25 mmol) in THF (80 mL) and H20 (20 mL). The mixture was stirred under en atmosphere (1 atm) at ambient temperature overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford (S)hydroxy(2-morpholinoacetamido)propanoic acid (5.5 g, 85% yield) as a colorless solid.

Example 66 ] (S)amino- l -((R)methyloxiranyl)phenylpropanone TFA salt was prepared using methods bed in the following reference: WO2007/149512A2, which is incorporated herein by reference in its entirety.

Additional Synthetic Procedures Example 67 ] (S)—3 -cyclopropyl-N—((S)- l -((R)methyloxirany1)- l -phenylpropan—2- yl)-2—((S)(2-morpholinoacetamido)propanamido)propanamide (C-1224): TFA HZN O B002OTHF o HZNQLOH 1 , HATU DIEA H20,K2CO3 BocHN\)J\OH DMF —> BOCHNEJiN BocHN/'\[(OH TFA, DCM O _ HATU, DIEA, TFA HzNJN —. DMF E H —> BocHN/RfN_NEELN I Cog—> o TFA DCM H o TFA- HZNJWV A” linoacetic acid 0 O O HATU, DIEA, Mnukflgfi O —p O ‘\ O To (S)—2-aminocyclopropylpropanoic acid (600 mg, 4.65 mmol) in THF (3 mL) and water (3 mL) was added K2C03 (2.20 g, 16.0 mmol) and di—tert-butyl dicarbonate (1.31 g, 6.03 mmol). After stirring at t temperature for 12 h the mixture was concentrated and washed with diethyl ether. The aqueous layer was acidified with citric acid to pH ~3 then extracted with DCM (3 X), dried with sodium sulfate, filtered, and concentrated. The crude (S)((tert-butoxycarbonyl)amino)cyclopropy1propanoic acid (1.13 g, quant.) was provided as a colorless oil that was carried forward without further purification. MS (EI) for C11H19NO4, found 230.1 (MH+) To ((tert—butoxycarbonyl)amino)cyclopropylpropanoic acid (1.02 g, 4.44 mmol) was added (S)amino((R)methyloxiranyl)phenylpropanone TFA salt (1.34 g, 4.44 mmol), HATU (2.02 g, 5.33 mmol), and DMF (10 mL). The e was cooled to 0 °C and DIEA (3.09 mL, 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column tography (0-70% ethyl acetate/heptane) provided tert-butyl ((S) cyclopropyl(((S)((R)methyloxirany1)-1 -oxo—3-phenylpropan—2-y1)amino) oxopropanyl)carbamate (1.33 g, 72%) as a colorless solid. MS (EI) for C23H32N205, found 417.3 (MH+).

To tert-butyl ((S)—3-cyclopropyl-1 -(((S)-1 -((R)methyloxiranyl)—1-oxo phenylpropan—2—y1)amino)—1-oxopropan—2-yl)carbamate (663 mg, 1.59 mmol) was added DCM (2.5 mL) and TFA (2.5 mL). The mixture was allowed to stand at ambient temperature for 30 min before it was concentrated to provide (S)amino-3—cyclopropy1—N—((S)—1-((R)—2- methyloxirany1)oxopheny1propany1)propanamide TFA salt (657 mg, quant.) as a yellow oil that was carried forward without fiirther purification. MS (EI) for C20H24F3N204, found 317.2 [M-TFA]+.

To (S)—2-aminocyclopropyl-N—((S)((R)methyloxiranyl)—1-oxo-3 - phenylpropan—2-y1)propanamide TFA salt (657 mg, 1.59 mmol) was added (S)-2—((tert- butoxycarbonyl)amino)propanoic acid (601 mg, 3.18 mmol), HATU (1.40 g, 3.67 mmol), and DMF (5 mL). The mixture was cooled to 0 °C and DIEA (1.11 mL, 6.36 mmol) was added.

The reaction mixture was d at ambient temperature for 30 min then quenched with sodium bicarbonate (sat), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-80% ethyl acetate/heptane) ed tert—butyl ((S)(((S)cyclopropyl(((S)((R) oxirany1)-1 -oxopheny1propany1)amino)— 1 -oxopropany1)amino)— 1 - oxopropanyl)carbamate (380 mg, 49%) as a colorless solid. MS (EI) for C26H37N306, found 488.4 (MH+).

To tert-butyl ((S)—1-(((S)—3—cyclopropyl-1 -(((S)— 1 -((R)methyloxiranyl)-1 - phenylpropan-2—y1)amino)— 1 -oxopropan—2—yl)amino)oxopropan—2-yl)carbamate (380 mg, 0.779 mmol) was added DCM (2.5 mL) and TFA (2.5 mL). The mixture was allowed to stand at ambient ature for 30 min before it was concentrated to provide (S)- 2-((S)aminopropanamido)—3-cyclopropy1-N-((S)((R)methyloxirany1)—1-oxo phenylpropan—2-y1)propanamide TFA salt (377 mg, quant.) as a yellow oil that was d forward without r purification. MS (EI) for C23H29F3N305, found 388.3 [M-TFA]+.

To (S)—2-((S)—2-aminopropanamido)—3-cyclopropyl-N-((S)((R)methyloxiran- 2-yl)—1—oxo-3—phenylpropan-2—y1)propanamide TFA salt (377 mg, 0.779 mmol) was added 2- linoacetic acid (226 mg, 1.56 mmol), HATU (622 mg, 1.64 mmol), and DMF (4 mL).

The mixture was cooled to 0 °C and DIEA (0.68 mL, 3.9 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2 X), dried with sodium e, filtered, and concentrated. Purification by column tography (3 :1 DCM/ethyl acetate + 0-10% methanol) provided (S)cyclopropyl-N—((S)—1-((R)methyloxiran-2—yl)—1-oxo-3 - phenylpropan—2-y1)((S)—2-(2—morpholinoacetamido)propanamido)propanamide (320 mg, 80%) as a colorless solid. 1H NMR (400 MHz, CDC13)I 5 7.54 (d, J: 7.6 Hz, 1H), 7.32 — 7.22 (m, 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, .1: 6.8 Hz, 2H), 4.34 (dd, J: 14.4, 6.8 Hz, 1H), 3.74 — 3.72 (m, 4H), 3.30 (d, J: 4.8 Hz, 1H), 3.14 (dd, J: 14.0, 5.2 Hz, 1H), 3.04 (d, J: 4.8 Hz, 2H), 2.92 (d, J: 4.8 Hz, 1H), 2.83 (dd, J: 14.0, 7.8 Hz, 1H), 2.54 — 2.52 (m, 4H), 1.56 (t, J: 6.8 Hz, 2H), 1.50 (S, 3H), 1.35 (d, J: 7.2 Hz, 3H), 0.41 — 0.36 (m, 2H), 0.05 — 0.00 (m, 2H). MS (EI) for C27H38N4O6, found 515.4 (MH+).

Example 68 (S)—N-((S)-1—((R)-2—methyloxiran-2—yl)-1 -oxo—3 -pheny1propan—2-y1)-2—((S)-2—(2- morpholinoacetamido)propanamido)—3-(pyridiny1)propanamide (C-1505): o ~TFA O BOCHN\/U\OH 1. BnOCOCI, DMAP, TEA, DCM H2N\;)J\OBn ‘ 2. TFA, DCM \ | N / 1. HOBt, HBTU, DIEA, ACN 0 Hdk 'TFA O 0C P _ 2 \COZH J\n/N 5 0 0 \(j —>N / 2. Pd/C(10%), hydrogen, HBTU HOBt DIEA THF ' ' ' BocHNJfif \KUWH I go 1.TFA O 0 O H o H 2. morphollnoaoetlcaCId,. . .

: K/NQLNJfifoflm O Y‘j O H 5 H HOBt, HBTU, DIEA, O )6 O N/ N/ To (S)—2-((tert—butoxycarbonyl)amino)(pyridiny1)propanoic acid (1.00 g, 3.76 mmol) in DCM (10 mL) was added TEA (0.974 mL, 7.52 mmol) and DMAP (23 mg, 0.188 mmol) and the reaction mixture was cooled to 0 OC and BnCOCl (635 mL, 4.51 mmol) was added Via an addition funnel over 20 min. The mixture was d to warm to ambient temperature ght at which time it was quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2 X), dried with sodium sulfate, filtered, and concentrated.

Purification by column chromatography (0-50% ethyl acetate/hexanes + 1% TBA) provided (S)-benzyl 2—((Zert-butoxycarbonyl)amino)—3—(pyridin—2-yl)propanoate (0.558 g, 42%) as a light brown solid. MS (EI) for C20H24N204, found 257.2 [M-Boc]+.

To (S)-benzyl rt—butoxycarbonyl)amino)(pyridinyl)propanoate (0.558 g, 1.57 mmol) was added DCM (2 mL) followed by TFA (2 mL). The reaction mixture was allowed to stand for 1 h at which time it was concentrated to provide (S)-benzyl 2-amino (pyridiny1)propanoate TFA salt (quant. yield) as a yellow oil. MS (EI) for C17H16F3N203, found 2572 [M-TFA]+.

To (S)—2-((tert—butoxycarbonyl)amino)propanoic acid (495 mg, 2.62 mmol) was added (S)-benzyl 2-amino(pyridin-2—yl)propanoate TFA salt (0.82 g, 2.22 mmol), HOBt (482 mg, 3.57 mmol), HBTU (1.35 g, 3.57 mmol), and ACN (10 mL). The mixture was cooled to 0 °C and DIEA (1.46 mL, 8.88 mmol) was added. The reaction mixture was stirred at t temperature for 30 min then ed with sodium bicarbonate (sat.), extracted with ethyl acetate (2 X), dried with sodium sulfate, d, and concentrated to provided crude (S)-benzyl 2-((S)((tert-butoxycarbonyl)amino)propanamido)(pyridin yl)propanoate as a colorless solid (0.46 g) that was carried forward without further purification. MS (EI) for C23H29N305, found 428.3 (MHl).

To nzyl 2-((S)—2-((tert—butoxycarbonyl)amino)propanamido)(pyridin yl)propanoate (0.460 g, 1.08 mmol) in THF (10 mL) was added Pd/C (10%, 500 mg) and a hydrogen atmosphere was established (ballon). After 4 h the reaction was filtered through Celite and trated to provide (S)—3 thoxyphenyl)—2-(2—methyl—2-(2- morpholinoacetamido)propanamido)propanoic acid (0.310 g) as a colorless solid. MS (EI) for C16H23N305, found 337.2 (M).

To (S)(4—methoxyphenyl)(2-methyl(2-morpholinoacetamido) propanamido)propanoic acid (0.310 g, 0.920 mmol) was added (S)amino((R)—2- methyloxiran—2-yl)-3 -phenylpropanone TFA salt (278 mg, 0.920 mmol), HOBt (199 mg, 1.47 mmol), HBTU (558 mg, 1.47 mmol) and DMF (3 mL). The mixture was cooled to 0 oC and DIEA (0.607 mL, 3.68 mmol) was added. The reaction mixture was stirred at ambient 2014/026987 temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (50- 1 00% ethyl acetate/heptane) provided tert—butyl ((S)(((S)(((S)- l - ((S)methyloxiranyl)—1—oxophenylpropanyl)amino)—1-oxo(pyridinyl)propan- 2-yl)amino)-1—oxopropanyl)carbamate (315 mg, 65%) as a colorless amorphous solid. MS (EI) for C28H36N4O6, found 525.3 (M+).

To tert-butyl ((S)-1—(((S)—1—(((S)((S)—2-methyloxiranyl)—1-oxo-3— phenylpropanyl)amino)oxo(pyridinyl)propanyl)amino)oxopropan yl)carbamate (315 mg, 0.600 mmol) was added DCM (4 mL) followed by TFA (2 mL). The reaction e was allowed to stand for 2 h at which time it was trated to provide (S)((S)aminopropanarnido)-N—((S)((S)rnethyloxirany1)oxopheny1propan- 2-yl)(pyridinyl)propanamide TFA salt as a yellow oil that was carried forward without further purification. MS (EI) for F3N405, found 425.3 [M-TFA]+.

To (S)((S)—2-aminopropanamido)—N-((S)-1—((S)-2—methyloxiran-2—yl)oxo—3 - phenylpropanyl)—3-(pyridiny1)propanamide TFA salt (0.601 mmol assumed) was added morpholinoacetic acid (174 mg, 1.20 mmol), HOBt (130 mg, 0.962 mmol), HBTU (365 mg, 0.962 mmol) and DMF (3 mL). The mixture was cooled to 0 °C and DIEA (0.627 mL, 3.61 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate + 0-15% methanol) provided (S)-N-((S)—1-((R)methyloxiranyl)oxo phenylpropanyl)—2-((S)(2-morpholinoacetamido)propanamido)-3 din yl)propanamide (121 mg, 37%) as a colorless solid. 1H NMR (400 MHz, CDCl3) 5 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 — 7.09 (m, 5H), 7.09 — 6.99 (m, 2H), 4.88 — 4.65 (m, 2H), 4.47 (p, J: 7.1, 7.1, 7.0, 7.0 Hz, 1H), 3.88 — 3.61 (m, 4H), 3.34 — 3.23 (m, 2H), 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). MS (EI) for N506, found 552.4 (MHl).

The following compound was synthesized in a similar manner: (S)—3 -(4-methoxyphenyl)-N—((S)((R)methyloxiranyl)— 1 — phenylpropanyl)—2—(2-(2-morpholinoacetamido)acetamido)propanamide (C- l 1 53): 1H NMR (400 MHz, CDC13) 5 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), 6.19 (d, .1: 7.4 Hz, 1H), 4.71 (td, J: 7.8, 7.7, 4.9 Hz, 1H), 4.50 (q, J: 6.9, 6.9, 6.8 Hz, 1H), 3.86 (dd, J= 5.7, 4.0 Hz, 2H), 3.78 (s, 3H), 3.76 — 3.67 (m, 4H), 3.24 (d, .1: 5.0 Hz, 1H), 3.07 (dd, .1: 14.0, 4.9 Hz, 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). MS (EI) for N4O7, found 567.4 (MH+).

Example 69 (S)-3 -(3,4-dimethoxyphenyl)-N—((S)((R)methyloxiranyl)oxo-3 - phenylpropan—2-y1)((S)(2-morpholinoacetamido)propanamido)propanamide (C- 1 160): O ‘THF/I: O 'TFA o BOCHN\_)J\OH 2 o O N O/ HATU, DIEA, DMF 00/ o 2. TFA, DCM / /0 The synthesis of tert-butyl ((S)(3,4-dimethoxyphenyl)(((S)((S)—2- methyloxiran—2-y1)-1 -oxophenylpropanyl)amino)—1-oxopropany1)carbamate was carried out in a similar manner as in the synthesis of (S)cyclopropyl—N—((S)((R) methyloxiran—2—yl)-1 -phenylpropanyl)—2-((S)—2—(2- morpholinoacetamido)propanamido)propanamide. 1. morpholinoacetic acid, ' 0 HCIHZNJwr OMe HOBt, HBTU, DIEA, DMF ON K/Nde — + O 2. KOH, MeOH, rt H To (S)—methyl 2-aminopropanoate HCl salt (5.0 g, 35.8 mmol) in DMF (30 mL) at 0 0C was added morpholinoacetic acid (5.19 g, 35.8 mmol), HOBt (7.74 g, 57.3 mmol), HBTU (21.7 g, 57.3 mmol), followed by DIEA (24.9 mL, 0.143 mol). The mixture was allowed to stir for 15 min at which time it was quenched with sodium onate (sat.), extracted with ethyl acetate (2 X), dried with sodium sulfate, filtered, and concentrated to provide (S)-methy1 2-(2-morpho1inoacetamido)propanoate (quant. yield) as a colorless solid.

MS (EI) for C10H18N204, found 231.2 (MH+).

Crude (S)-methyl 2—(2-morpholinoacetamido)propanoate was dissolved in methanol (10 mL) and KOH (20 mL of a 1N on, 0.020 mmol). The reaction mixture was stirred for 3 h then trated, dissolved in methanol, and filtered. The filtrate was concentrated to provide ium (S)(2-morpholinoacetamido)propanoate (8.38 g, 92% over 2 steps) as a colorless oil. MS (EI) for C9H15KN204, found 217.2 [M'K]+.

'TFA o H2N\_)LN o a H o o 0/H O OVLNJYO-g emhwmH O O ' o o.0 To (S)amino-3 -(3 ,4-dimethoxyphenyl)-N—((S)((S)methyloxiranyl)— 1 - oxo—3-phenylpropanyl)propanamide TFA salt (784 mg, 1.54 mmol) in DMF (5 mL) was added potassium (S)-2—(2-morpholinoacetamido)propanoate (470 mg, 1.85 mmol), HATU (702 mg, 1.85 mmol), DIEA (1.02 mL, 6.16 mmol). The mixture was allowed to stir for 15 min at which time it was quenched with sodium bicarbonate (sat), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3 :1 DCM/ethyl acetate + 0-10% methanol) followed by trituration from ethyl acetate/heptane (1 :1) provided (S)(3,4-dimethoxyphenyl)-N-((5)—1-((S)—2- methyloxiran—2—yl)-1 -phenylpropanyl)—2-((R)—2—(2- morpholinoacetamido)propanamido)propanamide (322 mg, 34%) as a colorless ous solid. 1H NMR (400 MHz, CDClg) 5 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, .1: 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 (q, J: 4.0, 3.9, 3.9 Hz, 4H), 1.49 (s, 2H), 1.30 (d, J: 7.1 Hz, 3H). MS (EI) for C32H42N4Og, found 611.3 (MH+).

The following compound was synthesized in a similar manner: [0069 l] (S)-3 -(4-(dimethylamino)phenyl)-N-((S)-1—((R)methyloxiranyl)—1-oxo—3- phenylpropan—2-yl)((S)(2-morpholinoacetamido)propanamido)propanamide (C- 1 16 1): 1H NMR (400 MHz, CDC13) 8 7.45 (d, .1: 8.8 Hz, 1H), 7.25 — 7.20 (m, 3H), 7.06 (d, J: 8.7 Hz, 2H), 7.03 — 6.91 (m, 2H), 6.67 — 6.60 (m, 2H), 6.52 (d, J: 7.6 Hz, 1H), 6.16 (d, .1: 7.0 Hz, 1H), 4.71 (ddd, J: 8.1, 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, .1: 14.1, 7.0 Hz, 2H), 2.66 (dd, .1: 14.0, 8.2 Hz, 1H), 2.57 — 2.37 (m, 4H), 1.49 (s, 3H), 1.29 (d, J: 7.0 Hz, 3H). MS (EI) for C32H43N506, found 594.3 (MH+).

(S)—3 -(5 -f1uoropyridiny1)—N-((S)-1—((R)-2—methyloxiran-2—yl)oxo—3 - phenylpropany1)((S)(2-morpholinoacetamido)propanamido)propanamide (C- 1 154): O . .

BocHN\/U\O|3n 2-bromo—5-fluoropyrldIne, BocHN Pd(PPh3)4, Zno, DMF \i/lkOBn K \ I N‘ / To (R)-benzy1 2-((tert-butoxycarbonyl)amino)iodopropanoate (1 g, 2.47 mmol) and zinc (355 mg, 5.45 mmol) was added DMF (2.5 mL) and mixture was stirred for 30 min under N2 at ambient temperature then Pd(PPh3)4 (175 mg, 0.247 mmol) was added. The e was stirred at ambient temperature for an additional 48 h under N2 then diluted with water and ethyl acetate, extracted with ethyl acetate (2 X), dried with sodium sulfate, filtered, and concentrated to e (S)-benzyl 2-((tert—butoxycarbonyl)amino)—3-(5 -fluoropyridin panoate (1.108 g, quant. yield) as an orange oil that was carried d without further purification. MS (EI) for C20H23FN204, found 375.2 (MH+).

The der of the synthesis of (S)—3-(5-fluoropyridinyl)-N—((S)-1—((R)-2— methyloxiranyl)-1 -oxopheny1propany1)((S)(2- morpholinoacetamido)propanamido)propanamide (8) was carried out in a similar manner as (S)-N-((S)cyclohexyl((R)methyloxiranyl)oxopropanyl)—3 -(4- methoxyphenyl)((S)(2—morpholinoacetamido)propanamido)propanamide (4). 1H NMR (400 MHz, DMSO-d6) 8 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), 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 (d, J = 5.1 Hz, 1H), 3.09 (dd, J: 13.9, 4.8 Hz, 1H), 3.00 (d, J: 5.1Hz, 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).

MS (EI) for cnggéFsoé, found 568.1 (MH+).

(S)-N-((S)(4-hydroxyphenyl)-l-((R)—2-methyloxirany1)oxopropany1)- 3-(4-rnethoxyphenyl)((S)(2-rnorpholinoacetarnido)propanamido)propanamide (C- 1 1 62): Synthesized following methods used in the synthesis of C-1003. 1H NMR (400 MHz, ) 5 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, 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 (q, .1: 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 Hz, 3H).MS (EI) for C31H40N4Og, found 597.3 (MH+).

Example 70 (S)—3 -hydroxy-N—((S)-3 -(4—rnethoxyphenyl)—1-(((S)((R)—2-rnethyloxiranyl)- 1-oxo—3-phenylpropan—2-yl)amino)- 1 opan—2-yl)—2—(2- morpholinoacetamido)propanarnide (C- 1 1 59): BMW/(YOH OBn BocHN\gLOMe HATU D'OEA BocHN/ngNfiOMe LiOH THF H20 DMF rt BocHN/RfNNE/(lDLOH O TFA' HZN OBocHN/gffiNgLu O HATU, OMe DIEA, DMF 0;“ TFA, DCM, rt TFA' gr o K/N\)J\OH ' H2N o o HATU \O , DIEA, DMF ®$Ngn$NOBn H ,Pd/C, 0 O O O O 2 O O Ll\/N\)J\N H\)kN O H a H H o =. o o H: o : OMe OMe To (S)(benzyloxy)—2-((tert-butoxycarbonyl)amino)propanoic acid (1.00 g, 3.39 mmol) in DMF (10 mL) at 0 °C was added HATU (1.42 g, 3.73 mmol). The mixture was stirred for 5 min to ve the solids at which time (S)—methyl 2-((tert- butoxycarbonyl)amino)(4-methoxyphenyl)propanoate (0.708 g, 3.39 mmol) and DIEA (1.77 mL, 10.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat), extracted with ethyl acetate (2 X), dried with sodium sulfate, filtered, and concentrated to provide crude (S)—methyl 2-((S) (benzyloxy)((tert-butoxycarbonyl)amino)propanamido)(4-methoxyphenyl)propanoate as a yellow oil that was carried forward without further purification. MS (EI) for N207, found 387.1 ).

To crude thyl 2-((S)(benzyloxy)((tert-butoxycarbonyl)amino) propanamido)—3 -(4-methoxyphenyl)propanoate (3 .39 mmol assumed) was added aqueous lithium hydroxide (5 mL of a 2 N solution) and methanol (5 mL). The reaction mixture was stirred for 5 h then diluted with ethyl e and water, washed with ethyl acetate (1 X), acidified with citric acid, extracted with DCM, washed with brine, dried with sodium sulfate, filtered, and concentrated to provide (S)—2-((S)—3-(benzyloxy)((tert-butoxycarbonyl) propanamido)(4-methoxyphenyl)propanoic acid as an amorphous off-white solid.

MS (EI) fOI' C25H32N207, found 471.1 (MH).

] To (S)((S)(benzyloxy)((tert-butoxycarbonyl)amino)propanamido)-3—(4- methoxyphenyl)propanoic acid (3.39 mmol assumed) and HATU (1.45 g, 3.82 mmol) in DMF (10 mL) at 0 CC was added (S)amino((R)methyloxiranyl)—3-phenylpropan- l-one TFA salt (1.05 g, 3.47 mmol). The mixture was d for 5 min to ved the solids and and DIEA (2.41 mL, 13.88 mmol) was added. The reaction mixture was stirred at this temperature for 15 min then quenched with sodium onate (sat.), extracted with ethyl acetate (2X), dried with sodium sulfate, d, and concentrated to provide crude tert-butyl ((S)—3-(benzyloxy)-1—(((S)—3-(4-methoxyphenyl)—1-(((S)-1 -((R)methyloxiran—2-yl)-1—oxophenylpropanyl)amino)-1 —oxopropanyl)amino)—l -oxopropanyl)carbamate (quant.) as a yellow oil that was carried forward without further purification. MS (EI) for C37H45N308, found 660.4 (MH+).

To tert-butyl ((S)(benzyloxy)(((S)-3 -(4-methoxypheny1)(((S)((R)—2- methyloxirany1)-1 —oxophenylpropan-2—yl)amino)— 1 -oxopropanyl)amino)— 1 - oxopropanyl)carbamate (2.94 mmol assumed) was added DCM (10 mL) and TFA (10 mL). The reaction e was stirred for 30 min at ambient temperature at which time it was trated and carried forward without fiarther purification. MS (EI) for C32H37N306, found 559.7 (M-TFA).

To amino(benzyloxy)-N-((S)—3-(4-methoxyphenyl)—l—(((S)—1—((R)-2— methyloxiranyl)-1 -oxophenylpropany1)amino)oxopropanyl)propanamide TFA salt (2.94 mmol assumed) was added 2-morpholinoacetic acid (647 mg, 4.46 mmol), HATU (1.86 g, 4.91 mmol), and DMF (5 mL). The mixture was cooled to 0 CC and DIEA (3.10 mL, 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then ed with sodium bicarbonate (sat.), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3 :1 DCM/ethyl acetate + 0—10% methanol) provided (S)(benzyloxy)-N—((S)—3-(4— methoxyphenyl)(((S)((R)methyloxiranyl)oxophenylpropan-2—yl)amino)-1 - oxopropany1)(2-morpholinoacetamido)propanamide (660 mg, 28% over 5 steps) as an amorphous colorless solid. MS (EI) for C38H46N40g, found 687.4 (MH+).

To (S)(benzyloxy)—N—((S)(4-methoxypheny1)—1-(((S)-1—((R)—2-methyloxiran- 2-yl)—1-oxophenylpropanyl)amino)oxopropan—2-yl)—2—(2- morpholinoacetamido)propanamide (330 mg, 0.480 umol) was added methanol (20 mL) and Pd/C (10%, 500 mg). The on mixture was stirred under a hydrogen atmosphere (balloon) for 16 h at 40 0C before it was cooled to ambient temperature and filtered through Celite. Purification by column tography (3 :1 DCM/ethyl acetate + 0-10% methanol) provided (S)-3—hydroxy—N—((S)—3 —(4-methoxypheny1)—1—(((S)—1-((R)methyloxiranyl)—1- oxophenylpropany1)amino)—1-oxopropan—2-y1)—2-(2- morpholinoacetamido)propanamide (119 mg, 42%) as a colorless amorphous solid. 1H NMR (400 MHz, ) 8 7.89 (d, J: 7.7 Hz, 1H), 7.26 — 7.19 (m, 3H), .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, 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). MS (EI) for C31H40N4Og, found 597.1 (MH1).

Example 71 (2S,3 S)—3 -hydroxy—N-((S)(4-methoxypheny1)—1-(((S)((R)methyloxiran yl)-1 —oxo-3 -phenylpropanyl)amino)-1 -oxopropanyl)((3-morpholinopropen yl)amino)butanamide (C- 1 1 74): BOCHNEJKOH HOBt HBTU + O DIEA DMF rt TFA HN' 2 CL 0 OMe BocHN\E)\:E>\N\©\0Me BOCHN\OH ‘OH H o HATU DITEA NQL TFA H N N 2 jLN TFA DCM DMF rt OHBocHNjfif 5 rt H —’ r13... —’°o:. o o K/NQKOH H HATU, TFA> DCM: rt jfirNJL DIEA, DMF —> —> OHOZMO To (S)—2-((tert—butoxycarbonyl)amino)(4-methoxyphenyl)propanoic acid (10.0 g, 33.9 mmol) in DMF (10 mL) at 0 CC was added HOBt (4.81 g, 37.3 mmol) and HBTU (14.1 g, 37.3 mmol). The e was stirred for 5 min to the dissolve solids at which time (S)-2—amino-1—((R)methyloxiranyl)phenylpropanone TFA salt (10.2 g, 33 .9 mmol) and DIEA (17.4 mL, 0.101 mol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-60% ethyl acetate/heptane) provided tert-butyl ((S)-3 —(4- methoxyphenyl)(((S)— 1 -((R)methyloxiran-2—yl)oxo-3 -phenylpropanyl)amino)—1 - oxopropan-Z-yl)carbamate (13.4 g, 82%) as an colorless ous solid. MS (ED for C27H34N206, found 483.3 (MH+).

To utyl ((S)—3-(4-methoxyphenyl)—1-(((S)((R)—2-methyloxiranyl)—l- oxo-3—phenylpropan-2—yl)amino)—1-oxopropan—2-yl)carbamate (1.00 g, 2.07 mmol) was added DCM (5 mL) and TFA (5 mL). The reaction mixture was stirred for 15 min at ambient ature at which time it was concentrated and carried forward without further purification. (S)amino(4-methoxyphenyl)-N-((S)((R)methyloxiranyl)-1 -oxo phenylpropan—2-yl)propanamide TFA salt was immediately carried forward into the subsequent step . yield). MS (EI) for C22H26N204, found 383.2 (MH+).

] To (2S,3S)—2-((tert—butoxycarbonyl)amino)hydroxybutanoic acid (453 mg, 2.07 mmol) in DMF (10 mL) at 0 °C was added HATU (865 mg, 2.28 mmol). The mixture was stirred for 5 min to dissolve the solids at which time (S)—2-amino—3-(4-methoxyphenyl)-N— ((S)((R)methyloxiranyl)oxophenylpropanyl)propanamide TFA salt (2.07 mmol assumed) and DIEA (1.71 mL, 10.35 mmol) was added. The reaction e was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2 X), dried with sodium e, filtered, and concentrated to provide crude tert—butyl ((2S,3 S)—3 -hydroxy(((S)-3 -(4-methoxyphenyl)(((S)((R) methyloxiranyl)-1 —oxophenylpropan-2—yl)amino)—1 -oxopropanyl)amino)— 1 - oxobutanyl)carbamate as a yellow oil that was d forward without further purification.

To tert-butyl ((2S ,3 S)-3 -hydroxy(((S)-3 thoxyphenyl)(((S)((R) methyloxiran—2—yl)-1 -oxophenylpropanyl)amino)—1 —oxopropanyl)amino)— 1 - oxobutanyl)carbamate (2.07 mmol assumed) was added DCM (2.5 mL) and TFA (2.5 mL). The reaction mixture was d for 15 min at ambient temperature at which time it was concentrated and crude (2S,3S)aminohydroxy-N-((S)(4-methoxypheny1)(((S)-1 - ((R)—2-methyloxiranyl)oxophenylpropanyl)amino)oxopropanyl)butanamide TFA salt was carried forward without further purification.

To (2S,3S)—2-aminohydroxy-N-((S)—3-(4-methoxypheny1)(((S)—1-((R) methyloxiran—2—yl)-1 -oxophenylpropanyl)amino)—1-oxopropanyl)butanamide TFA salt (0.207 mmol assumed) was added 2-morpholinoacetic acid (48.0 mg, 0.331 mmol), HATU (0.126 g, 0.331 mmol), and DMF (1 mL). The mixture was cooled to 0 °C and DIEA (0.177 mL, 0.104 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then ed with sodium bicarbonate (sat), extracted with ethyl e (2 X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate + 0-10% methanol) provided (2S,3S)hydroxy—N—((S)—3-(4- methoxyphenyl)(((S)((R)methyloxiranyl)-1—oxophenylpropanyl)amino)-1 - oxopropany1)(2-morpholinoacetamido)butanamide (80 mg, 63%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): 8 8.40 (d, J: 7.6 Hz, 1H), 8.10 (d, J: 8.0 Hz, 1H), 7.62 (d, J: 8.8 Hz, 1H), 7.32-7.21 (m, 4 H), 7.09 (d, J: 7.6 Hz, 1H), 6.75 (d, J: 8.4 Hz, 1H), 5.02 (d, .1: 4.8 Hz, 1H), .56 (m, 1H), 4.31—4.23 (m, 1H), 4.26-4.22 (m, 1H), 3.77—3.74 (m, 1H), 3.69 (s, 3H), 3.34-3.30 (m, 4H), 3.19-3.18 (m, 1H), 2.99-2.84 (m, 6H), 2.72-2.64 (m, 2H), 2.40—2.33 (m, 4H), 1.34 (s, 3H), 0.95 (d, J: 6.4 Hz, 3H). MS (EI) for C32H42N4Og, found 611.6 (MH+).

Example 72 Synthesis of (R)-N-((S)(((S)-3 thoxyphenyl)—1-(((S)((R) methyloxiran-Z-yl)-1 -oxopheny1propanyl)amino)-1 -oxopropanyl)amino) oxopropanyl)tetrahydrofi1rancarboxamide (C-1 166) HOBt, HBTU, o JLOH o + o DIEA, DMF, rt BocHN\_)J\N ( é : TFA' H2N a H I) o OMe OMe BocHNJfif HATU DIOEA TFA' H N2 BocHNaf TFA DCM DMF rt rt \EjiN ONEJOL \©\0Me $300M TFA HATU TFA DCM rt ON\:J\©\N DIEA DMF \©\OMe OI—lgjbllUOMe To (S)((tert—butoxycarbonyl)amino)(4-methoxyphenyl)propanoic acid (10.0 g, 33.9 mmol) in DMF (10 mL) at 0 °C was added HOBt (4.81 g, 37.3 mmol) and HBTU ((14.1 g, 37.3 mmol). The mixture was stirred for 5 min to the dissolve solids at which time (S)-2—amino- l —((R)methyloxiranyl)—3-phenylpropan— 1 -one TFA salt (10.2 g, 33 .9 mmol) and DIEA (17.4 mL, 0.101 mol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat), extracted with ethyl acetate (2X), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-60% ethyl acetate/heptane) provided tert-butyl ((S)-3 -(4- methoxyphenyl)- l -(((S)- l 2-methyloxiran—2-yl)- l —oxo-3 -phenylpropanyl)amino)-l - oxopropan-Z-yl)carbamate (13.4 g, 82%) as an colorless amorphous solid. MS (ED for C27H34N206, found 483.3 (MH+). [007 13] To tert-butyl ((S)—3-(4-methoxyphenyl)—1-(((S)((R)methyloxiranyl)—1- oxo-3—phenylpropan-2—yl)amino)oxopropan—2-yl)carbamate (1.00 g, 2.07 mmol) was added DCM (5 mL) and TFA (5 mL). The reaction mixture was stirred for 15 min at ambient temperature at which time it was concentrated and carried forward t further purification. (S)amino(4—methoxyphenyl)—N-((S)((R)methyloxiranyl)-1 -oxo phenylpropan—2—yl)propanamide TFA salt was immediately carried forward into the subsequent step (quant. yield). MS (EI) for C22H26N204, found 383.2 (MH+). [007 14] To (S)amino-3—(4-methoxyphenyl)—N—((S)— 1 -((R)—2-methyloxiran—2-yl)- 1 —oxo- 3-phenylpropanyl)propanamide TFA salt (2.07 mmol) was added (S)—2-((tert— butoxycarbonyl)amino)propanoic acid (782 mg, 4.14 mmol), HATU (1.82 g, 4.77 mmol), and DMF (7 mL). The mixture was cooled to 0 OC and DIEA (3.54 mL, 20.7 mmol) was added.

The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat), extracted with ethyl acetate (28), dried with sodium sulfate, filtered, and concentrated. ation by column chromatography (0-80% ethyl acetate/heptane) provided tert—butyl ((S)—1-(((S)—3 -(4-methoxyphenyl)-1—(((S)-1—((R) methyloxiranyl)-1 -oxophenylpropanyl)amino)oxopropanyl)amino)— 1 - oxopropan-Z-yl)carbamate (897 mg, 89%) as a colorless solid. MS (EI) for N306, found 488.4 (MH+). [007 1 5] To Zert-butyl ((S)—1-(((S)—3 thoxyphenyl)(((S)-1 -((R)methyloxiran yl)-1 -oxo-3 -phenylpropanyl)amino)—1 -oxopropanyl)amino)oxopropan-2— yl)carbamate (190 mg, 0.412 mmol) was added DCM (2 mL) and TFA (2 mL). The reaction mixture was stirred for 15 min at ambient temperature at which time it was trated and crude ((S)aminopropanamido)—3-(4-methoxyphenyl)-N—((S)((R)methyloxiran- 2-yl)—1—oxo-3—phenylpropan-2—yl)propanamide TFA salt was carried forward without further purification. MS (EI) for C27H31F3N307, found 470.3 (MH+).

To (S)((S)aminopropanamido)—3-(4-methoxyphenyl)-N—((S)—1—((R) methyloxiranyl)oxophenylpropanyl)propanamide (0.412 mmol d) was added a mixture of (R)-tetrahydrofurancarboxylic acid (57 mg, 0.494 mmol), HATU (187 mg, 0.494 mmol), and DMF (3 mL). The mixture was cooled to 0 CC and DIEA (0.352 mL, 2.06 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 min then quenched with sodium onate (sat), extracted with ethyl acetate (2X), dried with sodium sulfate, d, and concentrated. Purification by column tography (3 :1 hyl acetate + 0-10% methanol) provided (R)-N-((S)(((S)(4-methoxyphenyl) (((S)((R)methyloxiranyl)— 1 -oxo-3 -phenylpropanyl)amino)-1—oxopropan y1)amino)oxopropany1)tetrahydrofurancarboxamide (130 mg, 57%) as a colorless amorphous solid. 1H NMR (400 MHz, DMSO-d6): 5 8.46 (d, J: 7.6 Hz, 1H), 7.93 (d, J: 8.0 Hz, 1H), 7.54 (d, J: 8.0 Hz, 1H), 7.31 — 7.20 (m, 5H), 7.08 (d, J: 8.4 Hz, 1H), 6.77 (d, J: 8.4 Hz, 1H), 4.59 — 4.54 (m, 1H), 4.48 — 4.42 (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), 2.05 — 1.99 (m, 1H), 1.80 — 1.66 (m, 3H), 1.11 (d, J: 7.2 Hz, 3H). MS (EI) for C30H37N307, found 552.3 (MH*).

Characterization of (S)-N-((S)(((S)-3 -(4-methoxyphenyl)(((S)((R) oxiranyl)-1 -oxophenylpropany1)amino)— 1 -oxopropanyl)amino)— 1 - oxopropan-2—yl)tetrahydrofi1rancarboxamide (C-1 167) 1H NMR (400 MHz, 6): 8 8.46 (d, J: 7.2 Hz, 1H), 8.00 (d, J: 8.4 Hz, 1H), 7.59 (d, J: 7.6 Hz, 1H),7.31— 7.20 (m, 5H), 7.08 (d, .1: 8.4 Hz, 1H), 6.77 (d, .1: 8.8 Hz, 1H), 4.58 — 4.56 (m, 1H), 4.51 — 4.42 (m, 1H), 4.22 — 4.15 (m, 2H), 3.84 — 3.67 (m, 5H), 3.18 (d, .1: 5.2 Hz, 1H), 2.99 (d, .1: 5.2 Hz, 1H), 2.95 — 2.87 (m, 2H), 2.72 — 2.62 (m, 2H), 2.08 — 2.05 (m, 1H), 1.78 — 1.74 (m, 3H), 1.09 (d, J: 7.2 Hz, 3H). MS (EI) for C30H37N307, found 552.3 (MH+).

Characterization of N—((S)—1-(((S)-3—(4-methoxyphenyl)(((S)((R) methyloxiran—2-yl)oxophenylpropanyl)amino)— 1 -oxopropanyl)amino)— 1 - oxopropan-2—yl)methylazetidine-3—carboxamide (C-1 172) 1H NMR (400 MHz, DMSO-d6) 8 8.57 (d, J: 7.6 Hz, 1H), 8.40 (d, J: 8.4 Hz, 1H), 7.53 (d, J: 6.4 Hz, 1H), 7.31 — 7.10 (m, 5H), 6.84 (d, J: 8.8 Hz, 1H), 4.59 — 4.48 (m, 2H), 3.94 — 3.91 (m, 1H), 3.72 (s, 3H), 3.20 — 3.02 (m, 1H), 3.03 — 2.95 (m, 2H), 2.85 — 2.82 (m, 6H), 2.73 — 2.67 (m, 1H), 2.46 — 2.36 (m, 1H), 1.38 (s, 3H), 1.24 (d, J: 6.8 Hz, 3H). MS (EI) for C30H38N4O6, found 550.6 (M).

Assays Example 73 - Proteasome active-site ELISA An ELISA-based technique, the proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay, was utilized for quantitative ment of subunit-specific activity, as previously described in Parlati F, Lee S], Aujay M, 2014/026987 et al. Blood (2009) 114:3439-3447. Test compounds were serially diluted in DMSO at 100K concentration, then diluted to 10X in aqueous hypotonic lysis buffer. Lysate from the human acute lymphoblastic leukemia cell line, MOLT—4, was treated for 1 hour at 25°C with nd at a final 1X concentration. d cell lysate was then incubated with a biotinylated proteasome active—site binding probe for 2 hours at 25°C. Following, lysate was denatured in guanidine hydrochloride, and subunits bound to probe were isolated with streptavidin-conjugated sepharose beads. Individual subunits (e. g., [35, LMP7, LMP2, MECL—l) were probed with subunit-specific primary antibodies, followed by HRP- conjugated secondary antibodies. A chemiluminescent substrate was used to generate signal associated with HRP binding, which was detected on a plate reader. Luminescent signal was normalized to n content, then, t activity calculated relative to DMSO—treated controls to generate IC50 curves. s for select compounds provided herein are shown in the ing table: ProCISE Solubility ProCISE ProCISE Solubility ProCISE LMP7 pH 7 betas LMP7 pH 7 betas MOLT4 (pg/mL) MOLT4 MOLT4 (ug/mL) MOLT4 lysate Hu lysalt: H“ lysate Hu lysate Hu 1h 1h 1h CONT: CONT: CONT: CONT: ICso (11M) ICso (nM) ICso (11M) ICso (11M) NT NT 6110.5 NT NT 1669.6 NT NT NT C-1096 867.54 25.2 916.6 2565 NT NT 7833.2 NT NT 7310.5 4571-7 4091.2 mm 3408-7 21455 32665 56947 9602 1999 _NT NT 47309 38245 83803 NT NT 10724 11136 _NT NT 3785-2 C-lll4—NT NT 792.9 38662 C-lllS NT NT 495.8 W0 52134 ProCISE Solubility ProCISE ProCISE Solubility ProCISE LMP7 pH 7 betas LMP7 pH7 betas MOLT4 (Hg/mL) MOLT4 MOLT4 (pg/mL) MOLT4 lysate Hu lysate Hu lysate Hu lysate Hu 1h 1h 1h 1h CONT: CONT: CONT: CONT: ICso (nM) IC50 (11M IC50(nM) IC50 (nM) _C-1024 NT NT 4762.55 8225.7 _C-1025 NT NT > 10 1564.2 _C-1027 1045.6 165.41 5750.9 6257.4 _C-1028 807.08 52.61 214.9 10558.7 _C-1029 3790.84 303.09 822.5 8002.4 _C-1030 496.51 11.25 220.1 286.9 1 a a 462 1825.6 _C-1032 a a 251.4 \‘T \IT 1465.7 _C-1033 a a 3211.9 56.5 _C-1034 a a 2780.2 566.21 97.63 7717.2 a a > 10 7275.7 _C-1036 a 277.3 15177 _C-1037 /. a 1326 \‘T \IT 1367.6 _C-1038 NiH 00O N \1 9.07 230.5 1757.6 _C-1039 a 7014.8 1138.4 _C-1040 .7aagaaaaea a 12339.3 \‘T \IT 1700.8 _C-1041 2535.15 4; DJ 9.53 1826.7 158.9 _C-1042 a 8775.5 182.5 _C-1043 a 79.2 1864.4 4 a 1899.6 54.4 a 50.2 > 10000 _C-1046 9°NDJ 37.88 151.9 23505 _C-1047 .4 172.1 24.1 _C-1048 [7 a 152.9 >10000 _C-1049 796.47 53.49 3510.1 9011.2 _C-1050 764.71 15.86 1277.5 2341.3 _C-1051 705.31 90.8 702 >10000 _C-1052 511.92 101.3 705.6 3273 _C-1053 4543.31 269.9 647.6 1909.3 _C-1054 805.42 131.37 2859.6 2090.4 _C-1055 7147.69 953.3 1296.5 NT _C-1056 17.44 2.72 298.1 3033.3 _C-1057 2550.39 34.02 491.3 1914.7 _C-1058 NT .4 3009.8 1527.7 _C-1059 NT a 6005.3 2114.5 _C-1060 422.61 12.37 1375.3 1273.6 _C-1061 978.49 70.76 2052.5 NT NT 2460.5 _C-1062 388.46 38.39 139.8 2667.6 _C-1063 443.45 90.69 1310.35 2146.1 _C-1064 4050.97 60.5 NT 535.8 _C-1065 1482.63 34.635 2662.6 790.5 _C-1066 335.37 47.12 3196.85 212.7 _C-1067 NT NT 4592.5 1681.9 ProCISE Solubility 05w:a. ProCISE ProCISE Solubility ProCISE LMP7 pH 7 betas LMP7 pH 7 betas MOLT4 (pg/mL) MOLT4 MOLT4 (ug/mL) M0LT4 lysate Hu lysate Hu lysate Hu lysate Hu 1h 1h 1h 1h CONT.

CONT: CONT: CONT: 1C5" (“1“) 1C50 (nM) IC50 (HM) IC50 (11M _C-1068 4409.5 C-1172 1902.9 _C-1069 3541.65 C-1173 113.82 28.91 2343.7 _C-1070 2140.35 C-1174 149.53 22.93 1781.5 _C-1071 4295.55 C-1175 440.95 107.14 2476.1 _c—1072 4742.65 C-1176 1890.6 _C-1073 2175.85 C-1178 3835.17 510.43 1189.7 _C—1074 1153 C-1179 525.81 119.31 1299 _C-1075 1647.3 C-1180 312.21 1380.2 _C-1076 1041.1 C-1181 120.38 13.54 937.6 _C-1077 1536 C-1183 101.4 17.14 4537.9 _01078 873 C-1184 63.9 19.5 2732.1 9 2050.7 C-1185 283.17 30.35 150.5 _C—1080 NT C-1186 781.81 23.2 240 1 2759.7 C-1187 43.41 10.5 130.4 _C-1082 6130.4 C-1188 185.07 29.23 12.1 _C—1083 7072.1 C-1189 476.27 58.55 22.7 _C-1084 125.3 C-1190 204.98 16.78 456.6 _C-1085 8193.5 C-1191 678.01 24.71 4245.5 _C-1086 NT 3864.7 0124 NT NT 257.1 _C-1087 1745.09 5989 1126.5 C-1225 204.8 49.52 3446.9 _01088 1414.6 3821.8 9 984.9 C-1227 1976.35 _01090 979.1 682.3 _01091 230.5 3623.1 _C-1092 3068.2 NT — Not Tested Example 74 — 20S Proteasome Assays Proteasome chymotrypsin-like, caspase-like, and trypsin-like activities for various compounds provided herein were determined using succinyl-Leu-Leu-Val-Tyr-AMC (10 Amol/L), Z-Leu-Leu-Glu-AMC (10 Amol/L), and Boc—Leu-Arg—Arg-AMC (50 ), respectively, with d human 20S proteasome (2, 4, and 8.0 nmol/L, respectively) or HT- 29 cell lysate (0.125, 0.25, and 0.25 Ag protein/mL, respectively). Assay buffer consisted of TE buffer [20 mmol/L Tris (pH 8.0), 0.5 mmol/L EDTA] with (20S) or without (cell lysate) 0.03% SDS. Reactions were ted by enzyme or lysate addition and monitored for AMC t formation at 27jC with a plate-based spectofluorometer (Tecan). ICso values were determined based on the reaction velocity ed between 60 and 75 min. See also Demo, S. D. et al., Cancer Res. 2007, 67, 6383—6391.

Results for select nds provided herein are shown in the following table: LLVY LLVY i208 Hu 6205 Hu Compound meow meow: ICso(nM) ICso(nM)

Claims (94)

WHAT IS CLAIMED IS:

1. A compound of Formula (X): wherein: m and n each independently are 0, 1 or 2, and m + n = 2, 3, or 4; p is 0 or 1; q is 0, 1, or 2; K is selected from the group consisting of CR5R6, NR7, N(C=O)OR7, —NH—(C=O)—, O, S, SO, and SO2; E is N or CR7; R1 is selected from the group consisting of H, C1-6alkyl, kenyl, C2-6alkynyl, C3-6cycloalkyl, and 3-6 membered heterocycloalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of halo, OR7, SR7, , CN, and (C=O)N(R7)2; R2 is C1-2alkylene—G or (C=O)—G; wherein G is selected from the group consisting of aryl, heteroaryl, and pyridinone, with the o that when R2 is CH2phenyl, the phenyl is tuted with one or more substituents selected from the group consisting of OR7, halo, C1-3alkyl, OCF3, SO2R7, (C=O)N(R7)2, CN, and SO2N(R7)2, or R2 is selected from the group consisting of , , , , , , , , , , , , , , , , and R3 is selected from the group consisting of C3-7cycloalkyl, C3-7cycloalkenyl, a 3-7 membered cycloalkyl, and a 3-7 membered heterocycloalkenyl, wherein R3 is optionally substituted with one or more substituents selected from the group consisting of halo, =O, OR7, SR7, N(R7)2, O(C=O)N(R7)2, and C1-6alkyl; R4 is H or kyl; R5 and R6 are each independently selected from the group consisting of H, OH, halo, C1-3alkyl, and CF3, or R5 and R6 together with the carbon to which they are ed form C=O or , wherein W is O or NR7, and r is 1, 2 or 3; and each R7 is independently H or kyl, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein m is 0.

3. The compound of claim 1, wherein m is 1.

4. The compound of claim 1, wherein m is 2.

5. The compound of any one of claims 1 to 4, wherein n is 2.

6. The nd of claim 1, 3, or 4, wherein n is 1.

7. The compound of claim 1 or 4, wherein n is 0.

8. The compound of any one of claim 1 to 7, wherein p is 0.

9. The compound of any one of claim 1 to 7, wherein p is 1.

10. The compound of any one of claim 1 to 9, wherein q is 0.

11. The compound of any one of claim 1 to 9, wherein q is 1.

12. The compound of any one of claim 1 to 9, wherein q is 2.

13. The compound of any one of claims 1 to 12, wherein K is CR5R6.

14. The compound of claim 13, n K is selected from the group consisting of CH(OH), C(CH3)(OH), C=O, CH2, CF2, CH(Cl), CH(CF3), , and COH(CH3).

15. The compound of any one of claims 1 to 12, wherein K is NR7.

16. The compound of claim 15, wherein K is NCH3 or NCH2CH3.

17. The compound of any one of claims 1 to 12, wherein K is OR7, —NH—(C=O)—, S, SO, or SO2.

18. The compound of any one of claims 1 to 12, wherein K is O.

19. The nd of any one of claims 1 to 18, wherein E is N.

20. The compound of any one of claims 1 to 18, wherein E is CR7.

21. The compound of claim 20, wherein E is CH or C(CH3).

22. The compound of any one of claims 1 to 21, wherein is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , and .

23. The compound of any one of claims 1 to 22, wherein is selected from the group consisting of: , , , and .

24. The compound of any one of claims 1 to 23, wherein R1 is C1-6alkyl.

25. The compound of claim 24, wherein R1 is C1-3alkyl.

26. The compound of any one of claims 1 to 23, wherein R1 is CH3, CH2OH, CF3, CH(OH)CH3, CH2CN, or CH2CH3.

27. The compound of claim 26, wherein R1 is CH3, CH2OH, CH(OH)CH3, or CH2CN.

28. The nd of any one of claims 1 to 23, wherein R1 is C2-6alkenyl or C2-6alkynyl.

29. The compound of claim 28, wherein R1 is CH2CCH.

30. The compound of any one of claims 1 to 23, wherein R1 is cloalkyl.

31. The compound of claim 30, wherein R1 is cyclopropyl, utyl, cyclopentyl, or cyclohexyl.

32. The compound of any one of claims 1 to 23, wherein R1 is a 3-6 membered heterocycloalkyl.

33. The compound of claim 32, n R1 is an oxetanyl, tetrahydrofuranyl, or piperadinyl.

34. The compound of any one of claims 1 to 33, wherein R2 is C1-2alkyleneheteroaryl.

35. The compound of claim 34, wherein R2 is CH2-heteroaryl.

36. The nd of any one of claims 1 to 33, wherein R2 is C1-2alkylenepyridinone.

37. The compound of any one of claims 1 to 33, wherein R2 is C1-2alkylene-aryl.

38. The compound of claim 37, wherein R2 is CH2-aryl.

39. The compound of any one of claims 1 to 37, wherein R2 is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and

40. The nd of any one of claims 1 to 33, wherein R2 is selected from the group consisting of: , , , , , , , , , , , , , , , and .

41. The compound of claim 40, wherein R2 is selected from the group consisting , , , and .

42. The compound of any one of claims 1 to 33, wherein R2 is selected from the group consisting of , , , , , , , , , , , , and .

43. The compound of any one of claims 1 to 33, wherein R2 is ed from the group consisting of: , , , , , , , and .

44. The compound of any one of claims 1 to 33, wherein R2 is selected from the group consisting of: , , , , , , , , , , , , , and .

45. The compound of any one of claims 1 to 44, wherein R3 is C3-7cycloalkyl.

46. The compound of claim 45, wherein the C3-7cycloalkyl is substituted with at least one substituent selected from the group consisting of OH, F, Me, NH2, and O(CO)NH2.

47. The compound of claim 45, wherein R3 is cyclopropyl, cyclobutyl, cyclopentyl, or exyl.

48. The nd of claim 47, wherein R3 is cyclopentyl or cyclohexyl.

49. The compound of any one of claims 1 to 44, wherein R3 is C3-7cycloalkenyl.

50. The compound of claim 49, wherein the C3-7cycloalkenyl is substituted with at least one substituent selected from the group consisting of OH and Me.

51. The compound of claim 49, wherein R3 is cyclopentenyl or cyclohexenyl.

52. The compound of any one of claims 1 to 44, wherein R3 is a 3-7 membered cycloalkyl.

53. The compound of claim 52, wherein R3 is tetrohydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or pyrrolidinonyl.

54. The compound of any one of claims 1 to 44, wherein R3 is a 3-7 membered heterocycloalkenyl.

55. The nd of claim 54, wherein R3 is a dihydropyranyl or dihydrofuranyl.

56. The compound of any one of claims 1 to 44, wherein R3 is ed from the group consisting of: , , , , , , , , , , , , , . , , , , , , , , , , , and .

57. The compound of any one of claims 1 to 44, wherein R3 is selected from the group consisting of , , and .

58. The compound of any one of claims 1 to 57, wherein R4 is C1-3alkyl.

59. The nd of claim 58, wherein R4 is methyl.

60. The compound of any one of claims 1 to 57, wherein R4 is H.

61. The compound of claim 1, wherein: m and n are each independently 2; p is 1; q is 1; K is CR5R6 or O; E is N or CR7; R1 is CH3, CH2OH, CH(OH)CH3, or CH2CN; R2 is , , , or ; R3 is , , or ; R4 is methyl; R5 is H; R6 is OH; and, R7 is H.

62. The compound of claim 1 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically acceptable salt thereof.

63. The compound of claim 62 having a ure selected from the group consisting of: , , , , , , , , , , , , , , , and or a ceutically acceptable salt thereof.

64. The compound of claim 62 having a structure selected from the group consisting of: , , , , , , , , , , , and or a pharmaceutically acceptable salt thereof.

65. The compound of any one of claims 1 to 64, wherein the compound has a stereochemical uration:

66. The compound of claim 1 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically able salt thereof.

67. The nd of claim 66 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , and , or a pharmaceutically acceptable salt thereof.

68. The nd of claim 67 having a structure selected from the group consisting of: , , , , , , , , , , , and , or a pharmaceutically acceptable salt thereof.

69. A pharmaceutical composition comprising the compound of any one of claims 1 to 68, or pharmaceutically acceptable salt f, and a pharmaceutically acceptable carrier or diluent.

70. Use of a compound of any one of claims 1 to 68 or the composition of claim 69 in the manufacture of a medicament for inhibiting immunoproteasome in the cell.

71. The use of claim 70, wherein the medicament inhibits β5i (LMP7).

72. The use of claim 71, wherein the ment further inhibits one or both of LMP2 and .

73. The use of any one of claims 70 to 72, wherein the medicament is formulated for administration orally, parenterally, via injection, via inhalation, transdermally, or transmucosally.

74. The use of any one of claims 70 to 73, wherein the subject suffers from an autoimmune disease.

75. The use of claim 74, wherein the autoimmune disease is psoriasis, dermatitis, systemic scleroderma, sis, Crohn’s disease, ulcerative colitis; respiratory distress me, meningitis; encephalitis; uveitis; colitis; glomerulonephritis; eczema, , chronic mation; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE); diabetes mellitus; multiple sclerosis; Reynaud’s syndrome; autoimmune thyroiditis; allergic alomyelitis; n’s syndrome; juvenile onset diabetes; tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia (Addison’s disease); diseases involving leukocyte diapedesis; central nervous system (CNS) inflammatory disorder; le organ injury me; hemolytic anemia; myasthenia gravis; antigen-antibody complex mediated es; anti-glomerular basement membrane disease; ospholipid syndrome; allergic neuritis; Graves’ disease; Lambert-Eaton myasthenic syndrome; pemphigoid bullous; pemphigus; autoimmune polyendocrinopathies; Reiter’s disease; stiff-man syndrome; Behcet disease; giant cell arteritis; immune complex nephritis; IgA pathy; IgM polyneuropathies; or autoimmune thrombocytopenia (ITP).

76. Use of a compound of any one of claims 1 to 68 or the composition of claim 69 in the manufacture of a medicament for the treatment of an immune-related disease.

77. The use of claim 76, wherein the immune-related disease is rheumatoid arthritis, lupus, inflammatory bowel disease, multiple sis, or Crohn’s disease.

78. Use of a compound of any one of claims 1 to 68 or the composition of claim 69 in the cture of a medicament for the treatment of inflammation.

79. Use of a nd of any one of claims 1 to 68 or the composition of claim 69 in the manufacture of a medicament for treating an infection.

80. Use of a compound of any one of claims 1 to 68 or the composition of claim 69 in the manufacture of a medicament for treating a neurodegenerative disease.

81. The use of claim 80, n the neurodegenerative disease is multiple sclerosis.

82. The use of claim 74, wherein the autoimmune e is SLE, polymyositis, hemolytic anemia, or ITP.

83. The use of claim 74, wherein the autoimmune disease is rheumatoid arthritis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus (SLE), multiple sclerosis, ischemia, restenosis, stenosis, pancreatitis, fibrosis, autoimmune nephritis, graftversus-host disease, autoimmune thyroiditis, or myasthenia gravis.

84. The compound of claim 1 having a structure of or a pharmaceutically acceptable salt thereof.

85. The compound of claim 1 having a structure of or a pharmaceutically able salt f.

86. The compound of claim 1 having a structure of or a pharmaceutically able salt thereof.

87. The compound of claim 1 having a structure of or a pharmaceutically acceptable salt thereof.

88. The compound of claim 1 having a structure of or a pharmaceutically acceptable salt thereof.

89. The compound of claim 1 having a structure of or a pharmaceutically able salt f.

90. The compound of claim 1 having a structure of or a pharmaceutically acceptable salt thereof.

91. The compound of claim 1 having a structure of or a pharmaceutically acceptable salt thereof.

92. The compound according to any one of claims 1 to 68 or 84 to 91, substantially as herein described with reference to any one or more of the examples but ing comparative es.

93. The pharmaceutical composition according to claim 69, substantially as herein described with reference to any one or more of the es but excluding comparative examples.

94. The use according to any one of claims 70 to 83, substantially as herein described with reference to any one or more of the examples but excluding comparative examples.