WO2012054510A1

WO2012054510A1 - Oxadiazole compounds which inhibit beta-secretase activity and methods of use thereof

Info

Publication number: WO2012054510A1
Application number: PCT/US2011/056747
Authority: WO
Inventors: Geoffrey M. Bilcer; Thippeswamy Devasamudram; John C. Lilly; Sudha V. Ankala; Nikolai V. Moskalev; Chunfeng Liu; Makoto Inoue; Shimpei Kawakami; Ryosuke Munakata; Toshihiro Hamajima
Original assignee: Astellas Pharma Inc; CoMentis Inc
Current assignee: Astellas Pharma Inc; CoMentis Inc
Priority date: 2010-10-19
Filing date: 2011-10-18
Publication date: 2012-04-26
Anticipated expiration: 2013-04-19
Also published as: TW201300380A

Abstract

The invention provides novel beta-secretase inhibitors and methods for their including methods of treating Alzheimer's disease.

Description

OXADIAZOLE COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY

AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of United States Provisional Application No. 61/394,680, filed on October 19, 2010, the content of which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Alzheimer's disease is a progressive mental deterioration in a human resulting, inter alia, in loss of memory, confusion and disorientation. Alzheimer's disease accounts for the majority of senile dementias and is a leading cause of death in adults (Anderson, R. N., Natl. Vital Stat. Rep. 49:1-87 (2001), the teachings of which are incorporated herein in their entirety). Histologically, the brain of persons afflicted with Alzheimer's disease is

characterized by a distortion of the intracellular neurofibrils and the presence of senile plaques composed of granular or filamentous argentophilic masses with an amyloid protein core, largely due to the accumulation of β-amyloid protein (Αβ) in the brain. Αβ

accumulation plays a role in the pathogenesis and progression of the disease (Selkoe, D.J., Nature 399: 23-31 (1999)) and is a proteolytic fragment of amyloid precursor protein (APP). APP is cleaved initially by β-secretase followed by γ-secretase to generate Αβ (Lin, X., et al., Proc. Natl. Acad. Sci. USA 97:1456-1460 (2000); De Strapper, B., et al, Nature 391:381-390 (1998)). Inhibitors of β-secretase are described in US 7,214,715; US 7,504,420; US

2007/0032470; WO 2002/02520; WO 2002/02505; WO 2002/02512; WO 2002/02518; WO 2003/040096; WO 2003/050073; WO 2003/072535; WO 2004/043916; WO 2004/050619; WO 2004/080376; WO 2005/030709; WO 2005/103020; WO 2006/034296; WO

2006/110668; WO 2009/015369; WO 2009/042694; Stachel, S.J., J. Med. Chem. 47, 6447- 6450 (2004); Stachel, S.J., Bioorg. Med. Chem. Lett. 16, 641-644 (2006); and Varghese, J., Curr. Top. Med. Chem. 6: 569-578 (2006).

[0003] There is a need to develop effective compounds and methods for the treatment of Alzheimer's disease. The present invention fulfills these and other needs.

BRIEF SUMMARY OF THE INVENTION

[0004] Disclosed are novel beta-secretase inhibitors and methods for their use, including methods of treating Alzheimer's disease. In one aspect, the invent provides a compound of the formula (I):

wherein

R 1 is A1 -L1 - or taken together with R 2 and the nitrogen to which they are

attached form a 5- or 6-membered heterocycloalkyl ring substituted with A¹-!.¹-, R^6A and R^6B;

R² is hydrogen, -N(R⁸)R⁹, -S(0)₂Rⁿ, -C(0)R¹², or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or taken together with R¹ and the nitrogen to which they are attached form a 5- or 6-membered heterocycloalkyl ring substituted with A^L¹-, R^6A and R^6B;

A¹ is an optionally substituted heteroaryl;

L¹ is a bond, -N(R¹⁷)-, -S-,, -S(O)-,, -S(0)₂-, or an optionally substituted

alkylene;

R^6A and R^6B are independently hydrogen, halogen, -OH, -N0₂, -N(R⁸)R⁹, - OR¹⁰,

-SH, -SR¹¹, -S(0)Rⁿ, -S(0)₂Rⁿ, -C(0)R¹², or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR¹⁰, - alkyl-N(R 8 )R 9 , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;

A is an optionally substituted moiety selected from cycloalkylene,

heterocycloalkylene, arylene and heteroarylene;

X 1¹ and X 2" are independently N or CH;

R³ is hydrogen, -N(R⁸)R⁹, -S(0)₂Rⁿ, -C(0)R¹², or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R⁵ is hydrogen, or an optionally substituted moiety selected from alkyl,

cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; R is an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR¹⁰, -alkyl-N(R⁸)R⁹, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl, or taken together with R and the carbon to which they are attached form a cycloalkyl ring substituted with R⁴-L⁴-;

R^7B is R⁴-L⁴- or taken together with R^7A and the carbon to which they are attached form a cycloalkyl ring substituted with R⁴-L⁴-;

R⁴ is hydrogen, halogen, -OH, -N0₂, -N(R⁸)R⁹, -OR¹⁰, -SH, -SR¹¹, -S(0)Rⁿ, -

11 12

S(0)₂R¹¹, -C(0)R", or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR¹⁰, -alkyl-N(R⁸)R⁹, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;

L⁴ is a bond or an optionally substituted alkylene;

8 13 14

R° is independently hydrogen, -C(0)R , -S(0)₂R , or an optionally

substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R⁹ is independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R¹⁰ is independently -C(0)R¹³, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R¹¹ is independently an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, wherein if attached to S(0)₂, R¹¹ can also be -NR¹⁵R¹⁶;

R¹² and R¹³ are each independently hydrogen, -N(R¹⁸)R¹⁹, -OR¹⁹, or an

optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; R¹⁴ is independently hydrogen, -N(R¹⁸)R¹⁹, or an optionally substituted

moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and

R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

provided that when R 3 and R 5 are both hydrogen, one of R 7^,A^rt. and R 7^,B^D is methyl and the other is benzyl, each X 1 and X2 is N, A 2 is 5-substituted-l,3- phenylene and R 1 is taken together with R 2 and the nitrogen to which they are attached to form a 5-membered heterocycloalkyl ring, the 5-membered heterocycloalkyl ring formed by taking R 1 together with R 2 and the nitrogen to which they are attached is a moiety other than a 2-substituted-pyrrolidinyl substituted with 5-chlorofuran-2-yl, 5-methylfuran-2-yl, 3-pyridyl or 5-bromo- 3-pyridyl;

or a pharmaceutically acceptable salt or solvate thereof.

[0006] In one embodiment, the β-secretase inhibitor compound includes any one, any combination, or all of the compounds of Example 2 and/or Table 1 ; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound has a memapsin 2 Kj of less than about 300 nM. In some embodiments, the compound has an apparent memapsin 2 K; of less than about 300 nM as measured by inhibition of memapsin 2 catalytic activity toward the fluorogenic substrate FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2). In some embodiments, the compound is capable of inhibiting cellular Αβ production with an IC50 of less than about 1.5 μΜ, or less than about 500 nM. In some embodiments, the compound has a memapsin 1 K; and/or cathepsin D K; of greater than about 300 nM. In some embodiments, the compound has an apparent memapsin 1 Kj and/or apparent cathepsin D Kj of greater than about 300 nM, as measured by the substrate peptide MCA- GKPILFFRLK(DNP)-dR (SEQ ID NO.: 1). In some embodiments, the compound has a CYP 3 A Kj of greater than about 1 μΜ, or greater than 5 μΜ, or greater than 10 μΜ, as determined by the metabolism of midazolam. In some embodiments, the compound is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity. In some embodiments, the compound is capable of selectively reducing memapsin 2 catalytic activity relative to cathepsin D catalytic activity. In some embodiments, the compound is capable of selectively reducing memapsin 2 catalytic activity relative to CYP3A catalytic activity. In some of these embodiments, the relative reduction is greater than about 5-fold. In other embodiments, the reduction is greater than about 10-fold. In another embodiment, the β-secretase inhibitor compound (a) has a memapsin 2 Kj of less than about 750 nM (or less than about any one of 500 nM, 300nM, 250 nM, 100 nM, 50 nM, or 10 nM); (b) is capable of inhibiting cellular Αβ production with an IC₅₀ of less than about 1.5 μΜ (or less than about any one of 1 μΜ, 500 nM, 250 nM, 100 nM, 40 nM, or 10 nM); (c) is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity by greater than about 5-fold (or greater than about 10-fold, or about 100-fold), and/or (d) is capable of selectively reducing memapsin 2 catalytic activity relative to CYP3A catalytic activity by greater than about 5-fold (or greater than about 10-fold, or about 100- fold). In some embodiments, the compound has a hepatic intrinsic clearance in liver microsomes of less than about 700 mL/min/kg, or less than about 400 mL/min/kg, as measured by LC/MS/MS. In some embodiments, the compound has an AUC more than 50 hr-ng/ml, or more than 500 hr-ng/ml, as measured in rats after an oral dose of 10 mg/kg of the drug is administered.

[0007] In another aspect, is provided any one of the β-secretase inhibitor compounds is present in substantially pure form.

[0008] In another aspect, provided are formulations comprising any one of the β-secretase inhibitor compounds described herein and a carrier (e.g., a pharmaceutically acceptable carrier). In some embodiments, the formulation is suitable for administration to an individual.

[0009] In another aspect, provided are formulations comprising an effective amount of any one of the β-secretase inhibitor compounds described herein and a carrier (e.g., a

pharmaceutically acceptable carrier).

[0010] In another aspect, provided are pharmaceutical formulations comprising a β- secretase inhibitor compound or a β-secretase inhibitor compound in combination with a pharmaceutically acceptable carrier.

[0011] In another aspect, provided are methods of treating Alzheimer's disease in an individual in need thereof, comprising administering to the individual an effective amount of any one of the β-secretase inhibitor compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve),

(Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table

1), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the individual has one or more symptoms of Alzheimer's disease. In some embodiments, the individual has been diagnosed with Alzheimer's disease.

[0012] In another aspect is provided methods of treating of a condition mediated by memapsin 2 catalytic activity, comprising administering to the individual an effective amount of any one of the β-secretase inhibitor compounds described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the individual has one or more symptoms of the condition mediated by memapsin 2 catalytic activity. In some embodiments, the individual has been diagnosed with condition mediated by memapsin 2 catalytic activity.

[0013] In another aspect is provided methods of reducing memapsin 2 catalytic activity, comprising contacting memapsin 2 with an effective amount of any one of the β-secretase inhibitor compounds described herein. In some variations, the memapsin 2 beta-secretase is contacted in a cell. In some embodiments, the cell is contacted in vivo. In some

embodiments, the cell is contacted in vitro.

[0014] In another aspect is provided methods of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity, comprising contacting memapsin 2 with an effective amount of any one of the β-secretase inhibitor compounds described herein in the presence of memapsin 1.

[0015] In another aspect is provided methods of selectively reducing memapsin 2 catalytic activity relative to cathepsin D catalytic activity, comprising contacting memapsin 2 with an effective amount of any one of the β-secretase inhibitor compounds described herein in the presence of cathepsin D.

[0016] In another aspect is provided methods of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity and cathepsin D catalytic activity, comprising contacting memapsin 2 with an effective amount of any one of the β-secretase inhibitor compounds described herein in the presence of memapsin 1 and cathepsin D.

[0017] In another aspect is provided methods of selectively reducing memapsin 2 catalytic activity relative to CYP3A4 catalytic activity, comprising contacting memapsin 2 with an effective amount of any one of the β-secretase inhibitor compounds described herein in the presence of CYP3A4.

[0018] In another aspect is provided methods of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity, cathepsin D catalytic activity, and CYP3A4 catalytic activity, comprising contacting memapsin 2 with an effective amount of any one of the β-secretase inhibitor compounds described herein in the presence of memapsin 1, cathepsin D, and CYP3A4.

[0019] In another aspect is provided methods of treating Glaucoma in an individual in need thereof, comprising administering to the individual an effective amount of any one of the β- secretase inhibitor compounds described herein. In some embodiments, the individual has one or more symptoms of glaucoma. In some embodiments, the individual has been diagnosed with Glaucoma.

[0020] In another aspect is provided any one of the β-secretase inhibitor compounds described herein or a pharmaceutically acceptable salt or solvate thereof for use as a medicament. Also provided is any one of the β-secretase inhibitor compounds described herein or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of Glaucoma in an individual in need thereof.

[0021] Another aspect is provided the use of any one of the β-secretase inhibitor compounds described herein or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of a condition mediated by memapsin 2 catalytic activity. In another aspect is provided the use of one or more of the β- secretase inhibitor compounds described herein or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of a condition mediated by memapsin 2 catalytic activity. In some variations, the condition is Alzheimer's disease.

[0022] In another aspect is provided kits for the treatment or prevention in an individual with Alzheimer's disease, comprising any one of the β-secretase inhibitor compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging. In some embodiments, the kit comprises a formulation of any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging.

[0023] In another aspect is provided kits for the treatment or prevention in an individual of a condition mediated by memapsin 2 catalytic activity, comprising any one of the β-secretase inhibitor compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging. In some embodiments, the kit comprises a formulation of any one of the compounds described herein or a pharmaceutically acceptable salt or solvate thereof; and packaging.

[0024] In another aspect, the β-secretase inhibitor compounds can be employed in methods to mediate memapsin 2 activity, e.g., decrease memapsin 2 activity, decrease hydrolysis of a β-secretase site of a memapsin 2 substrate, and/or decrease the accumulation of β-amyloid protein relative to the amount of memapsin 2 activity, hydrolysis of a β-secretase site, and accumulation of β-amyloid protein, respectively, in the absence of the β-secretase inhibitor.

[0025] In another aspect, the β-secretase inhibitor compounds can be employed in the treatment of diseases or conditions associated with β-secretase activity, hydrolysis of a β- secretase site of a β-amyloid precursor protein, and/or β-amyloid protein accumulation. Typically, a mammal is treated for the disease or condition. In an exemplary embodiment, the disease is Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The invention provides, inter alia, compositions of beta-secretase inhibitors and methods for their use, e.g. methods of treating Alzheimer's disease.

[0027] Abbreviations and Definitions

[0028] The abbreviations used herein have their conventional meaning within the chemical and biological arts, unless otherwise specified.

[0029] Nomenclature of some compounds described herein (e.g., some compounds described in Example 2 and Table 1) may be identified using IUPAC or other naming conventions including ChemDraw Ultra Version 12.0, available from CambridgeSoft®.

[0030] Where substituent groups are specified by their conventional chemical formula, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH₂O- is equivalent to -OCH₂-.

[0031] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched hydrocarbon chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Q-Qo means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,

(cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n- octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl,

1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-). [0032] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH₂CH₂CH₂CH₂-.

Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. In some embodiments, an alkyl group will have from 1 to 6 carbon atoms. In some embodiments, the alkylene groups are methylene and methylmethylene.

[0033] The term "cycloalkyl" by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions of "alkyl." Additionally, cycloalkyl may contain multiple rings, but excludes aryl and heteroaryl groups. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, norbornyl, and the like. The term "cycloalkylene" by itself or as part of another substituent means a divalent radical derived from a cycloalkyl, as exemplified, but not limited, by -cyclohexyl-.

[0034] The term "heterocycloalkyl," by itself or in combination with other terms, represents a stable saturated or unsaturated cyclic hydrocarbon radical containing of at least one carbon atom and at least one annular heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S and Si may be placed at any interior position of the heterocycloalkyl group or at the position at which the heterocycloalkyl group is attached to the remainder of the molecule. Additionally, heterocycloalkyl may contain multiple rings, but excludes aryl and heteroaryl groups.

Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2- yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2- piperazinyl, and the like. The term "heterocycloalkylene" by itself or as part of another substituent means a divalent radical derived from a heterocycloalkyl, as exemplified, but not

[0035] The term "cycloalkyl-alkyl" and "heterocycloalkyl-alkyl" designates an alkyl- substituted cycloalkyl group and alkyl-substituted heterocycloalkyl, respectively, where the alkyl portion is attached to the parent structure. Non-limiting examples include cyclopropyl- ethyl, cyclobutyl-propyl, cyclopentyl-hexyl, cyclohexyl-isopropyl, 1-cyclohexenyl-propyl, 3- cyclohexenyl-t-butyl, cycloheptyl-heptyl, norbornyl-methyl, 1-piperidinyl-ethyl, 4- morpholinyl-propyl, 3-morpholinyl-t-butyl, tetrahydrofuran-2-yl-hexyl, tetrahydrofuran-3-yl- isopropyl, and the like. Cyclo alkyl- alkyl and heterocycloalkyl-alkyl also include substituents in which a carbon atom of the alkyl group (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., cyclopropoxymethyl, 2-piperidinyloxy-t-butyl, and the like).

[0036] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent. Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocycloalkyl rings.

Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four annular heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule at an annular carbon or annular heteroatom. Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocycloalkyl rings. Non-limiting examples of heteroaryl groups are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2- quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for substituted aryl and heteroaryl ring systems are described below.

[0037] The term "arylene" and "heteroarylene" means a divalent radical derived from an aryl and heteroaryl, respectively. Each of the two valencies of arylene and heteroarylene may be located at any portion of the ring (e.g.,

and

Non-limiting examples of arylene include phenylene, biphenylene, naphthylene, and the like. Examples of heteroarylene groups include, but are not limited to, pyridinylene, oxazolylene, thioazolylene, pyrazolylene, pyranylene, imidazolylene, and furanylene.

[0038] The term "aralkyl" designates an alkyl- substituted aryl group, where the alkyl portion is attached to the parent structure. Examples are benzyl, phenethyl, phenylvinyl, phenylallyl, pyridylmethyl, and the like. "Heteroaralkyl" designates a heteroaryl moiety attached to the parent structure via an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl, and the like. Aralkyl and heteroaralkyl also include substituents in which a carbon atom of the alkyl group (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like).

[0039] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" is mean to include, but not be limited to,

trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0040] The term "substituted" refers to the replacement of one or more hydrogen atoms of a moiety with a monovalent or divalent radical. "Optionally substituted" indicates that the moiety may be substituted or unsubstituted. A moiety lacking the terms "optionally substituted" and "substituted" is intended an unsubstituted moiety (e.g., "phenyl" is intended an unsubstituted phenyl unless indicated as a substituted phenyl or an optionally substituted phenyl).

[0041] The terms, "pharmaceutically effective amount," "therapeutically effective amount," "effective amount," and cognates of these terms, as used herein refer to an amount that results in a desired pharmacological and/or physiological effect for a specified condition (e.g., disease, disorder, etc.) or one or more of its symptoms and/or to completely or partially prevent the occurrence of the condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition. In reference to conditions mediated by memapsin 2 beta-secretase, a

pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause antagonism of memapsin 2 beta-secretase. In reference to glaucoma, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, decrease intraocular pressure; and/or halt, reverse, and/or diminish the loss of retinal ganglion cells (RGCs). In certain embodiments, the

pharmaceutically effective amount is sufficient to prevent the condition, as in being administered to an individual prophylactically.

[0042] The "pharmaceutically effective amount" or "therapeutically effective amount" will vary depending on the composition being administered, the condition being

treated/prevented, the severity of the condition being treated or prevented, the age and relative health of the individual, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors appreciated by the skilled artisan in view of the teaching provided herein.

[0043] A "pharmaceutically suitable carrier" or "pharmaceutically acceptable carrier," as used herein refers to pharmaceutical excipients, for example, pharmaceutically,

physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the extract.

[0044] When used with respect to methods of treatment/prevention and the use of the compounds and compositions thereof described herein, an individual "in need thereof may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.).

[0045] In some variations, the individual has been identified as having one or more of the conditions described herein. Identification of the conditions as described herein by a skilled physician is routine in the art and may also be suspected by the individual or others, for example, due to loss of memory in the case of Alzheimer's, exhibiting the symptoms of schizophrenia, etc., and due to a decrease and/or loss of contrast sensitivity or vision in the case of Glaucoma.

[0046] In some embodiments, the individual has been identified as susceptible to one or more of the conditions as described herein. The susceptibility of an individual may be based on any one or more of a number of risk factors and/or diagnostic approaches appreciated by the skilled artisan, including, but not limited to, genetic profiling, family history, medical history (e.g., appearance of related conditions), lifestyle or habits.

[0047] In some embodiments, the individual is a mammal, including, but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate. In some embodiments, the mammal is a primate. In some embodiments, the primate is a human. In some embodiments, the individual is human, including adults, children and premature infants. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non-human primate such as chimpanzees and other apes and monkey species. In some embodiments, the mammal is a farm animal such as cattle, horses, sheep, goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "individual" does not denote a particular age or sex. [0048] "Pharmaceutically acceptable salts" are those salts which retain the biological activity and which can be administered as drugs or pharmaceuticals to and individual (e.g., a human).

[0049] As used herein, "isomer" includes all stereoisomers of the compounds referred to in the formulas herein, including enantiomers, diastereomers, as well as all conformers, rotomers, and tautomers.

[0050] "Amyloid precursor protein," or "APP," as used herein, refers to a β-amyloid precursor comprising a β-secretase site.

[0051] "Memapsin-2," as used herein, refers to proteins identified by National Center for Biotechnology Information ("NCBI") accession number NP_036236 (sometimes referred to as "β-site APP-cleaving enzyme 1 " or "BACE-1 " or generically as "β-secretase" or "beta- secretase"), including homologs, isoforms and subdomains thereof that retain proteolytic activity. Sequence identities of active memapsin 2 proteins and protein fragments (and nucleic acid coding sequences thereof) have been previously disclosed and discussed in detail in U.S. Application No. 20040121947, and International Application No. PCT/US02/34324 (Publication No. WO 03/039454), which are herein incorporated by reference for all purposes in their entirety.

[0052] "Memapsin- 1," as used herein, refers to proteins identified by National Center for Biotechnology Information ("NCBI") accession number NP_036237 (sometimes referred to as "β-site APP-cleaving enzyme 2" or "BACE-2") and/or those previously disclosed and discussed in detail in see U.S. Patent Application Publication No. 20040121947, and

International Application No. PCT/US02/34324 (Publication No. WO 03/039454), incorporated by reference herein in their entirety for all purposes, including homologs, isoforms and subdomains thereof that retain proteolytic activity.

[0053] "Cathepsin D," as used herein, refers to proteins identified by National Center for Biotechnology Information ("NCBI"), for example accession number NP_599161, and/or proteins identified by Enzyme Commission number EC3.4.23.5, including that from any species, homologs, isoforms, and subdomains thereof that retain proteolytic activity.

[0054] A "β-secretase site" is an amino acid sequence that is cleaved by an active memapsin 2 or active fragment thereof. Specific β-secretase sites have also been previously set forth and discussed in detail in U.S. Application No. 20040121947, and International Application No. PCT/US02/34324 (Publication No. WO 03/039454), which are herein incorporated by reference for all purposes in their entirety, and include the Swedish mutation sequence, and the native β-amyloid precursor protein cleavage sequence. Thus, β-secretase inhibitors may be tested for their ability to decrease the hydrolysis of the β-secretase site of a substrate, such as the β-amyloid precursor protein, compounds of β-amyloid precursor protein, or fragments of β-amyloid precursor protein.

[0055] A "beta-secretase inhibitor" (i.e. β-secretase inhibitor) refers to a compound capable of reducing the proteolytic activity of memapsin-2 relative to the activity in the absence of inhibitor.

[0056] "Cytochrome P450 3A4" or "CYP3A4," as used herein refers to proteins identified by Genbank Sequence Accession Number: AF280107; HGNC:2637; Enzyme ID: 1.1.1.161, e.g., which can be found in the product 7<¾V¾roCYP™M-class™ Human Liver Microsomes from Celsis.

[0057] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0058] The terms "a" or "an," as used in herein means one or more. /. β-Secretase Inhibitors

[0059] In one aspect, is provided compounds that mediate {e.g., inhibit) the catalytic activity of the β-secretase enzyme (memapsin 2). These compounds may be referred to herein as "β-secretase inhibitor compounds," or "memapsin 2 β-secretase inhibitors." In this aspect, the compounds have the formula (I):

wherei

Pv² is hydrogen, -N(R⁸)R⁹, -S(0)₂Rⁿ, -C(0)R¹², or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or taken together with R and the nitrogen to which they are attached form a 5- or 6-membered heterocycloalkyl ring substituted with A^L¹-, R^6A and R^6B; A¹ is an optionally substituted heteroaryl;

L¹ is a bond, -N(R¹⁷)-, -S-_,, -S(O)-_,, -S(0)₂-_, or an optionally substituted

alkylene;

A is an optionally substituted moiety selected from cycloalkylene,

heterocycloalkylene, arylene and heteroarylene;

X 1¹ and X 2" are independently N or CH;

R⁵ is hydrogen, or an optionally substituted moiety selected from alkyl,

cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;

R^7A is an optionally substituted moiety selected from alkyl, cycloalkyl,

cycloalkyl-alkyl, -alkyl-OR¹⁰, -alkyl-N(R⁸)R⁹, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl, or taken together with R and the carbon to which they are attached form a cycloalkyl ring substituted with R⁴-L⁴-;

11 12

L⁴ is a bond or an optionally substituted alkylene; 8 13 14

R° is independently hydrogen, -C(0)R , -S(0)₂R , or an optionally

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R¹⁴ is independently hydrogen, -N(R¹⁸)R¹⁹, or an optionally substituted

provided that when R 3 and R 5 are both hydrogen, one of R 7^,A^rt. and R 7^,B^D is methyl and the other is benzyl, each X 1 and X2 is N, A 2 is 5-substituted-l,3- phenylene and R 1 is taken together with R 2 and the nitrogen to which they are attached to form a 5-membered heterocycloalkyl ring, the 5-membered heterocycloalkyl ring formed by taking R 1 together with R 2 and the nitrogen to which they are attached is a moiety other than a 2-substituted-pyrrolidinyl substituted with 5-chlorofuran-2-yl, 5-methylfuran-2-yl, 3-pyridyl or 5-bromo- 3-pyridyl; or a pharmaceutically acceptable salt or solvate thereof.

[0060] The substituents on an optionally substituted moiety of formula (I) (e.g., substituents on any optionally substituted alkyl, cycloalkyl, cycloalkyl-alkyl,

heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and/or heteroaralkyl) may be one, two, three, or more groups selected from, but not limited to, hydroxyl, nitro, amino (e.g., -NH₂ or dialkyl amino), imino, cyano, halo (such as F, CI, Br, I), haloalkyl (such as -CCI₃ or -CF₃), thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,

methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, alkoxy, alkoxy- alkyl, alkylcarbonyl, alkylcarbonyloxy (-OCOR), aminocarbonyl, arylcarbonyl,

aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl (-NHCOOR- or -OCONHR-), urea (-NHCONHR-), aryl and the like, where R is any suitable group, e.g., alkyl or alkylene. In some embodiments, the optionally substituted moiety is optionally substituted only with select radicals, as described herein. In some embodiments, the above groups (e.g., alkyl groups) are optionally substituted with, for example, alkyl (e.g., methyl or ethyl), haloalkyl (e.g., -CCI₃, -CH₂CHC1₂ or -CF₃), cycloalkyl (e.g., -C₃H₅, -C₄H₇, -C₅H₉), amino (e.g., -NH₂ or dialkyl amino), alkoxy (e.g., methoxy), heterocycloalkyl (e.g., as morpholine, piperazine, piperidine, azetidine), hydroxyl, and/or heteroaryl (e.g., oxazolyl). In some embodiments, a substituent group is itself optionally substituted. In some embodiments, a substituent group is not itself substituted. The group substituted onto the substitution group can be, for example, carboxyl, halo, nitro, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, aminocarbonyl, -SR, thioamido, - SO₃H, -S0₂R or cycloalkyl, where R is any suitable group, e.g., a hydrogen or alkyl.

[0061] In some of these embodiments, A¹ is an optionally substituted 5 to 7 membered heteroaryl (e.g., wherein the heteroaryl is attached to Li at the 1, 2, 3, 4, or 5 position and/or wherein the heteroaryl is substituted at the 1, 2, 3, 4, and/or 5 position(s)). In other embodiments, A¹ is an optionally substituted 5-membered heteroaryl (e.g., wherein the heteroaryl is attached to Li at the 1, 2, 3, 4, or 5 position and/or wherein the heteroaryl is substituted at the 1, 2, 3, 4, and/or 5 position(s)).

[0062] In some of these embodiments, A¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno- pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, pyrazinyl, pyrrolinyl, indolyl, and benzodiazepinyl.

[0063] In some of these embodiments, A¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, pyrazinyl, pyrrolinyl, indolyl, and benzodiazepinyl.

[0064] In some of these embodiments, A¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thiophenyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl,

benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, pyrazinyl, pyrrolinyl, indolyl, and benzodiazepinyl.

[0065] In some of these embodiments, A¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thiophenyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, pyrazinyl, pyrrolinyl, indolyl, and benzodiazepinyl.

[0066] In some of these embodiments, A¹ is an optionally substituted moiety selected from the group consisting of thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiophenyl, pyridyl, pyrimidyl, oxadiazolyl, and pyranyl.

[0067] In some of these embodiments, A¹ is an optionally substituted moiety selected from the group consisting of thiazolyl (e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl), oxazolyl (e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4-substituted)oxazolyl or a 4-(2-substituted)oxazolyl), imidazolyl, pyrazolyl, isoxazolyl, pyrimidyl, oxadiazolyl and pyranyl. In some embodiments, A¹ is an optionally substituted moiety selected from the group consisting of thiazolyl (e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4- substituted)thiazolyl or a 4-(2-substituted)thiazolyl), oxadiazolyl, and oxazolyl (e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4- substituted)oxazolyl or a 4-(2-substituted)oxazolyl). In some embodiments, A¹ is an optionally substituted thiazolyl (e.g., an optionally substituted 2-thiazolyl or a an optionally substituted 4-thiazolyl, such as a 2-(4-substituted)thiazolyl or a 4-(2-substituted)thiazolyl). In some embodiments, A¹ is an optionally substituted oxazolyl (e.g., an optionally substituted 2- oxazolyl or an optionally substituted 4-oxazolyl, such as a 2-(4-substituted)oxazolyl or a 4- (2-substituted)oxazolyl). In some embodiments, A¹ is an optionally substituted oxadiazolyl. In some embodiments, A¹ is an optionally substituted imidazolyl. In some embodiments, A¹ is an optionally substituted pyrazolyl. In some embodiments, A¹ is an optionally substituted isoxazolyl. In some embodiments, A¹ is an optionally substituted pyrimidyl. In some embodiments, A¹ is an optionally substituted 2-thiazolyl. In some embodiments, A¹ is an optionally substituted 2-oxazoyl.

[0068] In some of these embodiments, A¹ is an optionally substituted thiophenyl (e.g., an optionally substituted 2-thiophenyl). In some of these embodiments, A¹ is an optionally substituted pyridyl (e.g., an optionally substituted 2-pyridyl, an optionally substituted 3- pyridyl or an optionally substituted 4-pyridyl, such as 6-methylpyridin-3-yl, 6-methylpyridin-

2- yl and 4-pyridyl). In some of these embodiments, A¹ is an optionally substituted pyrazinyl (e.g., an optionally substituted 2-pyrazinyl). In some of these embodiments, A¹ is an optionally substituted oxadiazolyl (e.g., an optionally substituted 1,2,4- oxadiazolyl or an optionally substituted 1,2,3-oxadiazolyl, such as 3-methyl-l,2,4-oxadiazol-5-yl). In some of these embodiments, A¹ is an optionally substituted pyrazolyl (e.g., an optionally substituted

3- pyrazolyl, an optionally substituted 4-pyrazolyl or an optionally substituted 5-pyrazolyl, such as l-methylpyrazol-3-yl, l-methylpyrazol-4-yl, l,3-dimethylpyrazol-5-yl, 1- methylpyrazol-5-yl, and l,5-dimethylpyrazol-4-yl). In some of these embodiments, A¹ is an optionally substituted oxazolyl (e.g., an optionally substituted 2-oxazolyl or an optionally substituted 4-oxazolyl, such as 2-methyloxazol-4-yl and 2,5-dimethyloxazol-4-yl). In some of these embodiments, A¹ is an optionally substituted thiazolyl (e.g., an optionally substituted 2-thiazolyl or an optionally substituted 4-thiazolyl, such as thiazol-2-yl, 4-methylthiazol-2-yl,

4- ethylthiazol-2-yl, 4-bromothiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4- (methoxymethyl)thiazol-2-yl, 4,5-dimethylthiazol-2-yl, and 2-methylthiazol-4-yl).

[0069] In some embodiments, R¹ is taken together with R² and the nitrogen to which they are attached to form a 5-membered heterocycloalkyl ring and A¹ is an optionally substituted 5 to 7 membered heteroaryl other than an optionally substituted furanyl and an optionally substituted pyridyl. In some of these embodiments, A¹ is an optionally substituted 5- membered heteroaryl other than a substituted or unsubstituted furanyl. In some of these embodiments, A¹ is an optionally substituted 5-membered heteroaryl other than a substituted furanyl. In some of these embodiments, A¹ is an optionally substituted 5-membered heteroaryl other than a 5-substituted furan-2-yl. In some of these embodiments, A¹ is an optionally substituted 5-membered heteroaryl other than 5-chlorofuran-2-yl and 5- methylfuran-2-yl. In some of these embodiments, A¹ is an optionally substituted 6- membered heteroaryl other than a substituted or unsubstituted pyridyl. In some of these embodiments, A¹ is an optionally substituted 6-membered heteroaryl other than an

unsubstituted pyridyl. In some of these embodiments, A¹ is an optionally substituted 6- membered heteroaryl other than a substituted pyridyl. In some of these embodiments, A¹ is an optionally substituted 6-membered heteroaryl other than a substituted 3-pyridyl. In some of these embodiments, A¹ is an optionally substituted 6-membered heteroaryl other than 3- pyridyl and 5-bromo-3-pyridyl.

[0070] The substituents on an optionally substituted A¹ of formula (I) may be one, two, three, or more groups selected from, but not limited to, hydroxyl, nitro, amino, imino, cyano, halo, haloalkyl, thiol, thioalkyl, sulfonyl, thioamido, amidino, oxo, oxamidino,

methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, cycloalkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, aryl, heteroaryl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl, and urea.

[0071] In some embodiments, substituents on an optionally substituted A¹ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, OCHF₂). In some embodiments, A¹ (e.g., thiazolyl) is substituted with alkyl, such as methyl (e.g., at the 1, 2, 3, or 4 position of A¹). In some of these embodiments, the alkyl (e.g., methyl) is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F).

[0072] In some of these embodiments, L¹ is a bond or an optionally substituted alkylene.

1 17

In other embodiments, L is -N(R )-, -S-, -S(O)-, -S(0)₂-, or an optionally substituted alkylene. In other embodiments, L¹ is -N(R¹⁷)-, -S-, -S(O)- or -S(0)₂-. In other

1 17 1

embodiments, L is -N(R )-. In other embodiments, L is -S-, -S(O)- or -S(0)₂-. In other embodiments, L is a bond. In other embodiments, L is an optionally substituted alkylene. In other embodiments, L¹ is an optionally substituted Ci-C₆ alkylene. In other embodiments, L¹ is an optionally substituted methylene. In other embodiments, L¹ is a Ci-C₆ alkylene (e.g., methylene or methylmethylene). In other embodiments, L¹ is a branched Ci-C₆ alkylene (e.g., methylmethylene). In other embodiments, L¹ is methylene. In other embodiments, L¹ is methylmethylene.

[0073] In some embodiments, substituents on an optionally substituted L¹ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, OCHF₂).

[0074] In some of these embodiments, the compound has the formula (II):

or a pharmaceutically acceptable salt or solvate thereof; wherein A 1, A2, L 1, X 1, X2, R 2, R 3,

R 5^J, R 7 A , and R 7B are as defined for Formula (I) and any variations thereof.

[0075] In some of these embodiments, R² is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl. In some embodiments, R 2 is hydrogen or an optionally substituted alkyl. In some embodiments, R 2 is hydrogen or an optionally substituted Ci-C₆ alkyl. In some embodiments, R is hydrogen. In some embodiments, R 2 is an optionally substituted Ci-C₆ alkyl. In some embodiments, R 2 is an optionally substituted Ci-C₃ alkyl. In some embodiments, R is an optionally substituted

C₃-C₆ cycloalkyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is methyl.

[0076] In some of these embodiments, R² is hydrogen, an optionally substituted Ci-C₆ alkyl, or an optionally substituted C₃-C₆ cycloalkyl. In some embodiments, R is an optionally substituted Ci-C₆ alkyl, such as methyl, ethyl, 2-fluoroethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl). In some embodiments, R is an optionally substituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0077] In some embodiments, substituents on an optionally substituted R² may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), CrC₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl) or CrC₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, -OCHF₂). In some embodiments, substituents on an optionally substituted R are selected from methyl and cyclopropyl.

[0078] In some embodiments, the compound has the formula (III):

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

W is -CH₂- , -0-_,, -N(R¹⁷)-, -S- , -S(O)-_,, or -S(0)₂-_, or where W is -CH- or -N-_, and is substituted with R^6A or R^6B, or where W is -C-, and is substituted with R^6A and R^6B; m is 1 or 2; and

A¹, A², L¹, X¹, X², R², R³, R⁵, R^6A, R^6B, R^7A, R^7B, and R¹⁷ are as defined above in the discussion of Formula (I).

[0079] In some variations of the formula (III), W is -0-. In some variations, W is -S-, -

17

S(O)-, or -S(0)₂. In some variations, W is -S-. In some variations, W is -N(R )-. In some variations, W is -N(R^6A)- or -N(R^6B)-. In some variations, W is -CH₂-. In some variations, W is -CH(R^6A)- or -CH(R^6B)-. In some variations, W is -C(R^6A)(R^6B)-. In some variations, m is 1. In some variations, m is 2. In some variations, W is -O- and m is 1. In some variations, W is -S- and m is 1.

[0080] In some embodiments, the compound has the formula (Ilia):

or a pharmaceutically acceptable salt or solvate thereof; wherein A 1, A2, L 1, X 1, X2, R 2, R 3, R⁵, R^6A, R^6B, R^7A, and R^7B are as defined above in the discussion of Formula (I).

[0081] In some embodiments, the A^L¹- moiety is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:

, such as or

[0082] In some of these embodiments, L¹ is a bond, and A¹ is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:

[0 In some em o ments, t e - - mo ety s substituted on the pyrrolidine heterocycloalkyl ring according to the formula:

[0084] In some embodiments, L¹ is a bond, and A¹ is substituted on the pyrrolidine heterocycloalkyl ring according to the formula:

[0085] In some embodiments, L¹ is a bond, and A¹, R^6A and R^6B are substituted pyrrolidine heterocycloalkyl ring according to the formula:

[0086] In some embodiments, the A^L¹- moiety, R^6A and R^6B are substituted on the

pyrrolidine heterocycloalkyl ring according to the formula herein

and R may be substituted on different carbon atoms,

or

substituted on the same carbon atom, e.g.

[0087] In some embodiments, R^6A and R^6B are independently hydrogen,

halogen, -OH, -N(R⁸)R⁹, -OR¹⁰, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R^6A is hydrogen, or an optionally substituted moiety selected from aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R^6A is hydrogen, halogen (e.g., F or CI), an optionally substituted alkyl (e.g., haloalkyl), or an optionally substituted -OR (e.g., an optionally substituted -O-alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, or halogenated variants thereof). In some

embodiments, R^6A is hydrogen, F, an optionally substituted (Ci-C4)alkyl (e.g., methyl, ethyl, propyl, butyl, -CF₃, -CHF₂, -CH₂F), an optionally substituted -0-(C_rC₄)alkyl (e.g., -0-(C C₄)alkyl, such as methoxy, ethoxy, propoxy, or isopropoxy, substituted with 1, 2, or 3 fluoro groups, such as -OCH₂F, -OCHF₂). In some embodiments, R^6A is hydrogen or halogen. In some embodiments, R^6A is halogen, e.g. fluoro. In some embodiments, R^6A is hydrogen. In

6B

some variations of these embodiments, R is hydrogen. In some variations of these

6B

embodiments, R is an optionally substituted alkyl. In some variations of these

embodiments, R^6B is a halogen (e.g. fluoro). In some particular variations, R^6A and R^6B are independently halogen. In some particular variations, each R^6A and R^6B is fluoro.

[0088] In some embodiments, the compound is of the formula I, II, III, IV, V, VI or any variations thereof, where A is an optionally substituted arylene or an optionally substituted heteroarylene. In some embodiments, A is an optionally substituted moiety selected from the group consisting of phenylene, pyridinylene, oxazolylene, thioazolylene, pyrazolylene, pyranylene, imidazolylene, and furanylene. In some variations, A is an arylene bearing at least two substituents and the two substituents may be taken together to form another heterocycle that is fused to the arylene, e.g. chromanylene or dihydrobenzofuranylene. In some variations, A is an optionally substituted pyridonylene.

[0089] In some of these embodiments, A² has the formula:

wherein 2 3

If and V are independently a bond or an optionally substituted Q-C5 alkylene;

20 21 22 24 25

R , R , and are independently hydrogen, halogen, -N(R )R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl,

heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and

heteroaralkyl; and

Y is -N= or -C(R²³)=, wherein R²³ is hydrogen, halogen, -N0₂, -N(R²⁴)R²⁵, -

OR²⁶, -SR²⁷, -S(0)R²⁷, -S(0)₂R²⁷, or -C(0)R²⁸, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

R²⁴ and R²⁵ are independently hydrogen, -C(0)R²⁹, or -S(0)₂R³⁰, or an

wherein

29 31 32 33

R is independently hydrogen, -N(R )R , or -OR , an optionally

wherein

31 32 33

R , R , and R^JJ are independently hydrogen, or an optionally

substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

30

R is an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R²⁶ is hydrogen, or an optionally substituted moiety selected from alkyl,

cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

27 34 35

R" is -N(R^J")R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; wherein

34 35

and R^JJ are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

28 36 37 38

IT⁵ is -OR , -N(R^{J ,})R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl- alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

36 37 38

R , R , and R are each independently hydrogen, or an optionally

substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

In some of these embodiments, A² has the formula:

wherein

2 3

If and V are independently a bond or an optionally substituted C₁-C5

alkylene;

20 21 22 24 25

R , R , and R^{^} are independently hydrogen, halogen, -N(R )R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

23 24 25 each R is independently hydrogen, halogen, cyano, -NO₂, -N(R )R , -OR²⁶, -SR²⁷, -S(0)R²⁷, -S(0)₂R²⁷, or -C(0)R²⁸, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

Y is -N= or -C(R²³)=;

wherein

R²⁴ and R²⁵ are each independently hydrogen, -C(0)R²⁹, or -S(0)₂R³°, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

R 29 is independently hydrogen, -N(R 31 )R 32 , or -OR 33 , an optionally

wherein

R 31 , R 32 , and R 3^J3^J are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

R 30 is independently an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

R²⁶ is independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

27 is independently -N(R 3^J4")R 35 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl,

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

R 3^J4" and R 3^J5^J are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl,

heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and R is independently -OR , -N(R )R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

R 36 , R 37 , and R 38 are each independently hydrogen, or an optionally

In other of these embodiments, A has the formula:

wherein R , R , and R are defined herein.

[0092] In other of these embodiments, A² has the formula:

wherein R 20 , R 21 , and R 22 are as defined herein.

[0093] In some of these embodiments, A² has the formula:

wherein R 23 is as defined herein. [0094] In other of these embodiments, A has the formula:

wherein R²⁰, R²¹, and R²² are as defined herein.

[0095] In some of these embodiments, Y is -C(R )=. In other embodiments, Y is -N=

[0096] In some of these embodiments, A² has the formula.

90 1

wherein R , R , and R ^" are as defined herein.

[0097] In other of these embodiments, A² has the formula:

wherein R²⁰, R²¹, and R²² are as defined herein.

[0098] In other of these embodiments, A^" has the formula:

wherein R , R , and R are as defined herein.

[0099] In other of these embodiments, A² has the formula:

wherein R and R are as defined herein.

[0100] In some of these embodiments, A² has the formula:

wherein R is as defined herein.

[0101] In some of these embodiments, A² has the formula:

wherein R is as defined herein.

23 24 25

[0102] In some embodiments, R is hydrogen, halogen, cyano, -N0₂, -N(R )R , -OR²⁶, -SR²⁷, -S(0)R²⁷, -S(0)₂R²⁷, or -C(0)R²⁸, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R 23 is halogen, cyano, or-N0₂. In some embodiments, R is halogen (e.g., F, CI, Br or I). In some embodiments, R is

23

cyano. In some embodiments, R is -N0₂.

23 24 25 24 25

[0103] In some embodiments, R is -N(R )R where each R and R is independently hydrogen, an optionally substituted CrC₆ alkyl (e.g., methyl, ethyl and 2-methoxyethyl), or -C(0)R where R is hydrogen, an optionally substituted CrC₆ alkyl (e.g., methyl). In

23 23

some embodiments, R is -NH₂. In some embodiments, R" is -NH(CH₂CH₃). In some

23 23

embodiments, R" is -NH(CH₂CH₂OCH₃). In some embodiments, R is - N(CH₃)(CH₂CH₂OCH₃). In some embodiments, R²³ is -N(CH₃)C(0)CH₃.

23 26 26

[0104] In some embodiments, R is -OR . In some embodiments, R is hydrogen or an optionally substituted Ci-C₆ alkyl. In some embodiments, R²⁶ is unsubstituted Ci-C₆ alkyl (e.g., methyl) or substituted Ci-C₆ alkyl (e.g., Ci-C₆ alkyl substituted with one or more halogen atoms, such as fluoromethyl, difluromethyl, trifluoromethyl, 2-fluoroethyl and 2,2,2-

23 23

trifluoroethyl). In some embodiments, R is -OH. In some embodiments, R is -OCH₃. In

23 23

some embodiments, R is -OCH₂CH₃. In some embodiments, R is -OCHF₂. In some

23

embodiments, R is -OCF₃.

23 · 28 · 28

[0105] In some embodiments, R ^J is -C(0)R . In some embodiments, R is an optionally substituted CrC₆ alkyl (e.g., methyl) or an optionally substituted CrC₆ alkyl. In some

28 36 36

embodiments, R is -OR where R is hydrogen or an optionally substituted CrC₆ alkyl

28 37 38 37 38

(e.g., methyl or ethyl). In some embodiments, R is -N(R )R where each R and R is independently hydrogen or an optionally substituted Ci-C₆ alkyl (e.g., methyl and ethyl). In

23 23

some embodiments, R is -C(0)OH. In some embodiments, R is -C(0)OCH₂CH₃. In

23 23

some embodiments, R is -C(0)NH₂. In some embodiments, R is -C(0)NHCH₃. In some embodiments, R²³ is -C(0)N(CH₃)₂.

[0106] In some embodiments, R²³ is hydrogen, an optionally substituted Ci-C₆ alkyl or an

23

optionally substituted C₃-C₆ cycloalkyl. In some embodiments, R is unsubstituted CrC₆ alkyl (e.g., methyl) or substituted CrC₆ alkyl (e.g., CrC₆ alkyl substituted with one or more halogen atoms, such as fluoromethyl, difluromethyl, trifluoromethyl, 1-fluoroethyl, 2-

23 fluoroethyl, 1,1-difluoroethyl and 2,2,2-trifluoroethyl). In some embodiments, R is an optionally substituted C₃-C₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0107] In some of these embodiments, R²³ is hydrogen, halogen, -N(R²⁴)R²⁵, -OR²⁶, -SR²⁷, -S(0)R²⁷, -S(0)₂R²⁷, -C(0)R²⁸, or an optionally substituted heterocycloalkyl. In other

23 24 25

embodiments, R is hydrogen, -N(R )R (e.g., -N(alkyl)alkylsulfonamido, such as N- methyl-methanesulfonamido), or an optionally substituted heterocycloalkyl (e.g., an

23

optionally substituted cyclic sulfonamido). In other embodiments, R is hydrogen

24 25

or -N(R )R (e.g., -N(alkyl)alkylsulfonamido, such as N-methyl-methanesulfonamido). In

23 23 24 25

other embodiments, R is hydrogen. In other embodiments, R is -N(R )R

(e.g., -N(alkyl)alkylsulfonamido, such as N-methyl-methanesulfonamido) or an optionally

23

substituted heterocycloalkyl (e.g., a cyclic sulfonamido). In other embodiments, R

24 25

is -N(R )R (e.g., -N(alkyl)alkylsulfonamido, such as N-methyl-methanesulfonamido). In

23

other embodiments R is an optionally substituted heterocycloalkyl (e.g., an optionally

substituted cyclic sulfon

23

some embodiments, R

some embodiments, R is

. In other embodiments, R is -OR . In other embodiments, R²³ is -SR²⁷, -S(0)R²⁷, or -S(0)₂R²⁷. In other embodiments, R²³ is -C(0)R²⁸.

23

In some embodiments, R is hydrogen, an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl,

23

heteroaryl, and heteroaralkyl. In some embodiments, R is an optionally substituted moiety

23

selected from alkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, R is an

23

optionally substituted alkyl. In some embodiments, R is an optionally substituted Ci-C₆

23 23

alkyl. In some embodiments, R is methyl. In some embodiments, R is an optionally

23

substituted cycloalkyl. In some embodiments, R is an optionally substituted

23

heterocycloalkyl. In some embodiments, R is an optionally substituted moiety selected from cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl,

23

23 selected from aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R is an

23 optionally substituted moiety selected from aryl and heteroaryl. In some embodiments, R is

23

an optionally substituted aryl. In some embodiments, R is an optionally substituted heteroaryl. [0108] In some embodiments, R²³ is an optionally substituted heterocycloalkyl. In some embodiments, R 23 is an optionally substituted pyrrolidinyl (e.g., 1 -pyrrolidinyl or an oxo-

substituted pyrrolidinyl such as Ί~ν- and -w]/w^> ) j_{n some} embodiment ²³ is an

optionally substituted oxazolidinyl (e.g., an oxo-substituted oxazolidinyl such as

).

In some embodiments, R is an optionally substituted oxadiazolinyl (e.g., an oxo-substituted

oxadiazolinyl such as

). In some embodiments, R is an optionally substituted

piperidinyl (e.g., 1-piperidinyl or an oxo-substituted piperidinyl suc

[0109] In some embodiments, R²³ is an optionally substituted moiety selected from pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidyl, pyranyl, pyrazinyl, pyrrolyl and furanyl. In some embodiments, R 23 is an optionally substituted moiety selected from thiazolyl, oxadiazolyl, oxazolyl, imidazolyl, pyrrolyl and pyrazinyl. In some embodiments, R 23 is an optionally substituted phenyl. In some embodiments, R 23 is an optionally substituted pyridyl. In some embodiments, R 23 is an optionally substituted thiazolyl. In some embodiments, R 23 is an optionally substituted oxazolyl. In some embodiments, R 23 is an optionally substituted oxadiazolyl. In some embodiments, R 23 is an optionally substituted imidazolyl. In some embodiments, R 23 is an optionally substituted pyrazolyl. In some embodiments, R 23 is an optionally substituted isoxazolyl. In some embodiments, R 23 is an optionally substituted pyrimidyl. In some embodiments, R 23 is an optionally substituted pyrazinyl. In some embodiments, R 23 is an optionally substituted pyranyl. In some embodiments, R 23 is an optionally substituted furanyl.

In some embodiments, R 23 is an optionally substituted 2-thiazolyl. In some embodiments,

R 23 is an optionally substituted 2-oxazoyl. In some embodiments, R 23 is an optionally substituted 5-oxazoyl.

[0110] In some embodiments, R is an optionally substituted aryl or an optionally substituted heteroaryl. In some embodiments, R 23 is an optionally substituted phenyl (e.g phenyl, 2-methoxyphenyl, 3-methoxylphenyl or 2-cyanophenyl). In some embodiments, R 23 is an optionally substituted furanyl (e.g., 2-furanyl or 3-furanyl). In some embodiments, R is an optionally substituted thiophenyl (e.g., 2-thiophenyl or 3-thiophenyl). In some

23

embodiments, R is an optionally substituted pyrrolyl (e.g., 1-pyrrolyl or l-methylpyrrol-2-

23

yl). In some embodiments, R is an optionally substituted oxazolyl (e.g., 2-oxazolyl or 5-

23

oxazolyl). In some embodiments, R is an optionally substituted isoxazolyl (e.g., 3-

23

isoxazolyl or 5-isoxazolyl). In some embodiments, R is an optionally substituted thiazolyl (e.g., 2-thiazolyl, 2-methylthiazol-4-yl or 4,5-dimethylthiazol-2-yl). In some embodiments,

23

R is an optionally substituted pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1- methylpyrazol-3-yl, l-methylpyrazol-4-yl or l-methylpyrazol-5-yl). In some embodiments,

23

R is an optionally substituted imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl or 1-

23

methylimidazol-2-yl). In some embodiments, R is an optionally substituted oxadiazolyl

23

(e.g., l,3,4-oxadiazol-2-yl or 5-methyl-l,3,4-oxadiazol-2-yl). In some embodiments, R is an optionally substituted triazolyl (e.g., 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl or 1,2,5-triazol-l-

23

yl). In some embodiments, R is an optionally substituted pyridyl (e.g., 2-pyridyl, 3-pyridyl

23

or 4-pyridyl). In some embodiments, R is an optionally substituted pyrimidyl (e.g., 5-

23

pyrimidyl). In some embodiments, R is an optionally substituted pyrazinyl (e.g., 2- pyrazinyl).

[0111] The substituents on an optionally substituted R²³ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, nitro, amino, imino, cyano, halo, haloalkyl, thiol, thioalkyl, sulfonyl, thioamido, amidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, cycloalkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, aryl, heteroaryl, arylcarbonyl,

aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl, and urea.

[0112] In some embodiments, substituents on an optionally substituted R²³ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, OCHF₂).

[0113] In some embodiments, A² has the formula:

where I 2, L 3^J, R 20 , R 21 , and 22 are as defined herein.

[0114] In some embodiments, L² is an optionally substituted C₂-C₅ alkylene and L³ is a bond. In one variation, L 2 is an optionally substituted 3

C₂-C₄ alkylene and L is a bond. In another variation, L 2 is an optionally substituted ethylene and L 3 is a bond. In another variation, L 2 is an optionally substituted propylene and L 3 is a bond. In another variation, L 2 is an optionally substituted butylene and L 3 is a bond. In one variation, L 2 is a C₂-C₄ alkylene and L 3 is a bond. In another variation, L 2 is ethylene, propylene or butylene and L 3 is a bond.

In another variation, L 2 is propylene and L 3 is a bond. In another variation, L 2 is butylene and L is a bond.

[0115] In some embodiments, L2 is an optionally substituted C1-C4 alkylene and L3 is an optionally substituted methylene. In one variation, L2 is an optionally substituted C2-C4 alkylene and L3 is an optionally substituted methylene. In another variation, L2 is an optionally substituted ethylene and L3 is an optionally substituted methylene. In another variation, L2 is an optionally substituted propylene and L3 is an optionally substituted methylene. In one variation, L2 is a C1-C3 alkylene and L3 is methylene. In another variation, L2 is methylene or ethylene and L3 is methylene. In a specific variation, each L2 and L3 is methylene.

[0116] In some embodiments, L² is an optionally substituted C₁-C3 alkylene and L³ is an optionally substituted ethylene. In some variations, L is an optionally substituted methylene or ethylene and L 3 is an optionally substituted propylene. In some variations, L 2 is an optionally substituted methylene and L is an optionally substituted butylene.

[0117] In some embodiments, L² is a bond and L³ is an optionally substituted C₂-C₅ alkylene. In one variation, L 2 is a bond and L 3 is an optionally substituted C₂-C₄ alkylene. In another variation, L 2 is a bond and L 3 is an optionally substituted ethylene. In another variation, L 2 is a bond and L 3 is an optionally substituted propylene. In another variation, L 2 is a bond and L is an optionally substituted butylene.

[0118] In some embodiments, A² has the formula:

where R and R are as defined herein.

[0119] In some embodiments, A² has the formula:

where R and R are as defined herein. In one variation, each R and R is hydrogen.

[0120] In some embodiments, A² has the formula:

where R and R are as defined herein.

[0121] In some embodiments, A² has the formula:

[0122] In some of these embodiments, R 20 , R 21 , and R 22 are independently hydrogen, or an optionally substituted Ci-Cio alkyl. In some embodiments, R 20 , R 21 , and R 22 are

independently hydrogen, or an optionally substituted Ci-C₆ alkyl. In some embodiments, at least one of R 20 , R 21 , and R 2^{^}2 is hydrogen. In some embodiments, R 20 , R 21 , and R 22 are hydrogen.

[0123] In some of these embodiments, R²² is hydrogen. In some embodiments, R²² is hydrogen; and R 20 or R 21 , where applicable, is hydrogen or an optionally substituted Ci-C₆ alkyl. In some embodiments, R 22 is hydrogen; and R 20 and R 21 , where applicable, is hydrogen or methyl. In some embodiments, R 22 is hydrogen and R 20 or R 21 , where applicable, is methyl. In some embodiments, at least on of R 20 , R 21 , or R 2^{^}2 is -N(R 2"4")R 25. In some embodiments, R 20 or R 21 , where applicable, is -N(R 24 )R 25. In some embodiments, R 22 is -N(R²⁴)R²⁵.

[0124] In some of these embodiments, R²⁴ and R²⁵ are independently hydrogen, or an optionally substituted moiety selected from alkyl and heteroalkyl. In some embodiments, R 24 and R 25 are independently hydrogen, or an optionally substituted alkyl. In some

embodiments, at least one of R 24 and R 25 is hydrogen. In some embodiments, wherein R 24 and

R 25 are hydrogen. In some embodi ·ments, at least one of R 2"4" and 25 is an optionally substituted alkyl. In some embodiments, R 24 and R 25 are independently an optionally substituted alkyl. In some embodiments, at least one of R and R is methyl. In some embodiments, R 24 and R 25 are independently hydrogen, an optionally substituted

alkyl, -C(0)R²⁹, or -S(0)₂R³°. In some embodiments, one of R²⁴ and R²⁵ is -C(0)R²⁹ or -S(0)₂R 3^J0. In some embodiments, one of 24 and 25 is -C(0)R 29. In some embodiments, one of R²⁴ and R²⁵ is -S(0)₂R³°.

[0125] In some of these embodiments, R²⁹ is independently hydrogen, an optionally substituted alkyl, -N(R 3^J1¹)R 32 , or -OR 3^J3. In some embodiments, R 29 is independently hydrogen, or an optionally substituted alkyl. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted alkyl. In some embodiments, R is methyl. In some embodiments, R 29 is independently -N(R 31 )R 32 , or -OR 33. In some embodiments, R 29 is -N(R³¹)R³². In some embodiments, R²⁹ is -OR³³.

[0126] In some of these embodiments, R 31 , R 32 , and R 33 are independently hydrogen, or an optionally substituted alkyl.

[0127] In some embodiments, R³⁰ is an optionally substituted alkyl. In some embodiments, R³⁰ is methyl.

[0128] In some of these embodiments, A² has the formula:

where R is halogen (e.g., F, CI, Br or I) or an optionally substituted alkoxy (e.g., methoxy or trifluoromethoxy).

[0129] In some embodimen ² has the formula:

where each R is independently hydrogen or an optionally substituted alkyl. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted alkyl. In some embodiments, R is an optionally substituted Ci-C₆ alkyl (e.g., methyl or ethyl).

[0130] In some embodiments, A² has the formula:

where each R is independently halogen or an optionally substituted alkyl. In some embodiments, R⁴⁰ is halogen (e.g., F, CI, Br or I). In some embodiments, R⁴⁰ is or an optionally substituted alkoxy (e.g., methoxy or trifluoromethoxy).

[0131] In some embodiments, the compound is of the formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII),

1 2

(IX), (X) or any variations thereof, where X and X are independently N or CH. In some

1 2 1 embodiments, X is N. In some embodiments, X is N. In some embodiments, each X and

2 1 2

X s N. In some embodiments, X is CH. In some embodiments, X is CH. In some

1 2 1 2

embodiments, each X and X is CH. In some embodiments, X is N and X is CH. In some

1 2

embodiments, X is CH and X is N.

[0132] In some embodiments, the compound is of the formula I, II, III, IV or any variations thereof, where R³ is hydrogen, -N(R⁸)R⁹, -S(0)₂R^U, -C(0)R¹², or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl- alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R is hydrogen. In some embodiments, R³ is -N(R⁸)R⁹, -S(0)₂Rⁿ, -C(0)R¹². In some embodiments, R³ is an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl,

heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

[0133] In some of these embodiments, R³ is hydrogen, -C(0)^£Bu, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In some embodiments, R is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl. In some embodiments, R is hydrogen or an optionally substituted alkyl. In some embodiments, R is hydrogen or an optionally substituted Ci-C₆ alkyl. In some

3 3

embodiments, R is hydrogen. In some embodiments, R is an optionally substituted Ci-C₆

3 3 t

alkyl. In some embodiments, R is methyl. In some embodiments, R is -C(O) Bu.

[0134] In some embodiments, substituents on an optionally substituted R³ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropy) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, OCHF₂). [0135] In some embodiments, the compound is of the formula I, II, III, IV or any variations thereof, where R⁵ is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. In some embodiments, R⁵ is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl. In some embodiments, R⁵ is hydrogen, or an optionally substituted alkyl. In some embodiments, R⁵ is hydrogen, or an optionally substituted Ci-C₆ alkyl. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is an optionally substituted Ci-C₆ alkyl. In some embodiments, R⁵ is a Q- C₆ alkyl. In some embodiments, R⁵ is an optionally substituted C₁-C₃ alkyl. In some embodiments, R⁵ is a C₁-C₃ alkyl. In some embodiments, R⁵ is methyl.

[0136] In some embodiments, substituents on an optionally substituted R⁵ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropy) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, -OCHF₂).

[0137] In some embodiments, the compound is of the formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, where R^7A is an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR¹⁰, -alkyl-N(R⁸)R⁹, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. In some embodiments, R^7A is an optionally substituted moiety selected from alkyl, cycloalkyl and cycloalkyl-alkyl. In some embodiments, R^7A is an optionally substituted alkyl. In some embodiments, R^7A is an optionally substituted Ci-C₆ alkyl. In some embodiments, R^7A is methyl.

[0138] In some embodiments, R^7A is an optionally substituted moiety selected from -alkyl- OR¹⁰ and -alkyl-N(R⁸)R⁹. In some embodiments, R is an optionally substituted -alkyl- OR¹⁰. In some embodiments, R^7A is -CH₂OCH₃.

[0139] In some embodiments, R^7A is an optionally substituted moiety selected from heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. In some embodiments, R^7A is an optionally substituted aralkyl. In some embodiments, R^7A is optionally substituted -alkylene-phenyl (e.g. benzyl or 3-phenylpropyl).

[0140] In some embodiments, R^7A is an optionally substituted moiety selected from phenyl, pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzoisazolyl, dimethylhydantoin, pyrazinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, indolyl, diazepinyl, azepinyl, thiepinyl, piperidinyl, and oxepinyl. In some embodiments, R^7A is an optionally substituted moiety selected from pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidyl, pyrazinyl and furanyl. In some embodiments, R^7A is an optionally substituted moiety selected from pyridyl and imidazolyl (e.g. l-methylimidazol-2-yl).

[0141] In some embodiments, substituents on an optionally substituted R^7A may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropy) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, -OCHF₂).

[0142] In some embodiments, the compound is of the formula I, II, III, IV or any variations thereof, where R^7A is taken together with R⁵ to form an optionally substituted propylene. In some embodiments, R^7A is taken together with R⁵ to form an unsubstituted propylene. In some embodiments, R^7A is taken together with R⁵ to form an propylene optionally substituted with one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropy) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, -OCHF₂).

[0143] In some embodiments, the compound is of the formula I, II, III or any variations thereof, where R^7B is R⁴-L⁴- or taken together with R^7A and the carbon to which they are attached form a cycloalkyl ring substituted with R⁴-L⁴-.

[0144] In some of these embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is an optionally substituted moiety selected from alkyl and heteroalkyl. In some embodiments, R⁴ is an optionally substituted moiety selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, R⁴ is an optionally substituted moiety selected from cycloalkyl and heterocycloalkyl. In some embodiments, R⁴ is an optionally substituted moiety selected from aryl and heteroaryl. In some embodiments, R⁴ is an optionally substituted aryl (e.g., phenyl, 4-fluorophenyl, 3,5-difluorophenyl or 3-fluorophenyl). In some embodiments, R⁴ is an optionally substituted heteroaryl. In some embodiments, R⁴ is phenyl, optionally substituted with one or more halogens. In some embodiments, R⁴ is phenyl, 4- fluorophenyl, 3,5-difluorophenyl, or 3 -fluorophenyl. In some embodiments, R⁴ is phenyl or 4-fluorophenyl. In some embodiments, R⁴ is phenyl. In some embodiments, R⁴ is 3,5- difluorophenyl. In some embodiments, R⁴ is 4-fluorophenyl. In some embodiments, R⁴ is 3- fluorophenyl.

[0145] In some embodiments, substituents on an optionally substituted R⁴ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropy) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, -OCHF₂).

[0146] In some of these embodiments, L⁴ is a bond, or an optionally substituted alkylene. In some embodiments, L⁴ is a bond. In some embodiments, L⁴ is an optionally substituted alkylene. In some embodiments, L⁴ is an optionally substituted Ci-C₆ alkylene. In some embodiments, L⁴ is a Ci-C₆ alkylene. In some embodiments, L⁴ is methylene (e.g., when L⁴- R⁴ is (e.g., -CH₂-phenyl or -CH₂-difluorophenyl).

[0147] In some embodiments, substituents on an optionally substituted L⁴ may be one, two, three, or more groups selected from, but not limited to, hydroxyl, halo (such as F, CI, Br, I), Ci-C₆ alkyl (e.g., methyl, ethyl, propyl, isopropy) or Ci-C₆ alkoxy (methoxy, ethoxy, propoxy, isopropoxy, wherein each Ci-C₆ alkyl and Ci-C₆ alkoxy is optionally substituted with 1-3 halogens (e.g., -CF₃, -CHF₂, -CH₂F, -OCH₂F, -OCHF₂).

[0148] In some of these embodiments, the compound has the formula (IV):

2 4 1 2 1 2 3 or a pharmaceutically acceptable salt or solvate thereof, wherein A , L , X , X , R , R , R , R⁴, R⁵, and R^7A are as defined for Formula (I) and any variations thereof.

[0149] In some of these embodiments, the compound has the formula (IVa):

or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2, 3 or 4, and A 2 , L 4 , X¹, X², R¹, R², R³, R⁴, R⁵, R^7A and R^7B are as defined for Formula (I) and any variations thereof. In some of these embodiments, the compound has the formula (IVa-1):

In some of these embodiments, the compound has the formula (IVa-2):

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0150] In some embodiments, the compound has the formula (V)

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, A², X¹, X², R^6A, R^6B, R^7A and R^7B are as defined for Formula (I) and any variations thereof. In some embodiments, R^6A is hydrogen. In some embodiments, R^6A is halogen (e.g. fluoro). In some embodiments, R^6B is hydrogen. In some embodiments, R 6B is halogen (e.g. fluoro). In some embodiments, both R^6A and R^6B are hydrogen. In some embodiments, both R^6A and R^6B are fluoro. In some embodiments, A¹ is optionally substituted thiazolyl (e.g. 4-methylthiazol-2-yl or 4- (fluoromethyl)thiazol-2-yl). In some embodiments, A¹ is optionally substituted oxazolyl (e.g.

4-methyloxazol-2-yl). In some embodiments, X 1 is N. In some embodiments, X 2 is N. In some embodiments, both X 1 and X2 are N. In some embodiments, X 1 is N and X2 is CH. In some embodiments, X 1 is CH and X2 is N. In some embodiments, both X 1 and X2 are CH. In some embodiments, R^7A is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In some embodiments, R 7 A is methyl. In some embodiments, R 7B is optionally substituted -alkylene-phenyl (e.g. benzyl or 4-fluorobenzyl).

[0151] In some embodiments, the compound has the formula (Va):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, A², X¹, X², R^6A, R^6B, R and R 7B are as defined for Formula (V).

[0152] In some embodiments, the compound has the formula (Vb):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, A², L⁴, X¹, X², R⁴, R^6A, R^6B and R^7A are as defined for Formula (I) and any variations thereof. In some embodiments, A¹, A², L⁴, X¹, X², R^6A, R^6B and R^7A are as defined for Formula (V). In some embodiments, L⁴ is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4-fluorophenyl). In some embodiments, A¹ is optionally substituted thiazolyl and R⁴ is optionally substituted phenyl. In some embodiments, A¹ is 4-methylthiazol-2-yl, 4- (fluoromethyl)thiazol-2-yl or 4-methyloxazol-2-yl and R⁴ is phenyl or 4-fluorophenyl.

[0153] In some embodiments, the compound has the formula (Vc):

or a pharmaceutically acceptable salt or solvate thereof, wherein A 1, A2, L 4, X 1, X2, Y, R 4, R^6A, R^6B, R^7A, R²⁰, R²¹ and R²² are as defined for Formula (I). In some embodiments, A¹, A², L⁴, X¹, X², Y, R⁴, R^6A, R^6B, R^7A, R²⁰, R²¹ and R²² are as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described. In some embodiments, A¹, L⁴, X¹, X², R⁴, R^6A, R^6B and R^7A are as defined for

Formula (V). In some embodiments, each X 1 and X2 is N. In some embodiments, one of X 1 and X 2 is N and the other is CH. In some embodiments, R 7 A is Ci-C₆ alkyl (e.g., methyl). In some embodiments, R^6A and R^6B are independently hydrogen or fluoro. In some

embodiments, one of R^6A and R^6B is hydrogen and the other is fluoro. In some embodiments, each R^6A and R^6B is hydrogen. In some embodiments, each R^6A and R^6B is fluoro. In some embodiments, L⁴ is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4-fluorophenyl). In some embodiments, A¹ is optionally substituted thiazolyl and R⁴ is optionally substituted phenyl. In some embodiments, A¹ is 2-methylthiazol-4-yl, 4- methylthiazol-2-yl, 4-ethylthiazol-2-yl, 4-cyclopropylthiazol-2-yl, , 4-(fluoromethyl)thiazol- 2-yl 4-(methoxymethyl)thiazol-2-yl, 4,5-dimethylthiazol-2-yl or 4-methyloxazol-2-yl and R⁴ is phenyl or 4-fluorophenyl. In some embodiments, R 23 is as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described.

[0154] In some embodiments, the compound has the formula (Vd):

[0155] In some embodiments, the compound has the formula (Ve):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, L⁴, X¹, X², R⁴, R^6A, R^6B, R^7A and R²³ are as defined for Formula (I). In some embodiments, A¹, L⁴, X¹, X², R⁴, R^6A,

R 6B , R V^ and R 23 are as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described. In some embodiments, A¹, L⁴, X¹, X², R⁴, R^6A, R^6B and R^7A are as defined for Formula (V). In some embodiments, each X¹ and

X 2 s N. In some embodiments, one of X 1¹ and X2" is N and the other is CH. In some embodiments, R^7A is Ci-C₆ alkyl (e.g., methyl). In some embodiments, R^6A and R^6B are independently hydrogen or fluoro. In some embodiments, one of R^6A and R^6B is hydrogen and the other is fluoro. In some embodiments, each R^6A and R^6B is hydrogen. In some embodiments, each R^6A and R^6B is fluoro. In some embodiments, L⁴ is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4-f uorophenyl). In some embodiments, A¹ is optionally substituted thiazolyl and R⁴ is optionally substituted phenyl. In some embodiments, A¹ is 2-methylthiazol-4-yl, 4-methylthiazol-2-yl, 4-ethylthiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4-(fluoromethyl)thiazol-2-yl 4-(methoxymethyl)thiazol-2-yl, 4,5- dimethylthiazol-2-yl or 4-methyloxazol-2-yl and R⁴ is phenyl or 4-fluorophenyl. In some embodiments, R 23 is as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described.

[0156] In some embodiments, the compound has the formula (Vf):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, L⁴, X¹, X², R⁴, R^6A, R^6B and R^7A are as defined for Formula (I), Y is N or CH, R⁴⁰ is halogen or optionally substituted alkoxy. In some embodiments, Y is CH. In some embodiments, Y is N. In some

embodiments, R⁴⁰ is optionally substituted Ci-C₆ alkoxy (e.g., methoxy). In some

embodiments, R⁴⁰ is halogen (e.g., F, CI, Br or I). In some embodiments, R⁴⁰ is fluoro. In some embodiments, R⁴⁰ is chloro. In some embodiments, A¹, L⁴, X¹, X², R⁴, R^6A, R^6B and R^7A are as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described. In some embodiments, A¹, L⁴, X¹, X², R⁴, R^6A, R^6B and R^7A are as defined for Formula (V). In some embodiments, each X¹ and X² is N. In some embodiments, one of X¹ and X² is N and the other is CH. In some embodiments, R is Ci-C₆ alkyl (e.g., methyl). In some embodiments, R^6A and R^6B are independently hydrogen or fluoro. In some embodiments, one of R^6A and R^6B is hydrogen and the other is fluoro. In some embodiments, each R^6A and R^6B is hydrogen. In some embodiments, each R^6A and R^6B is fluoro. In some embodiments, L⁴ is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4-fluorophenyl). In some embodiments, A¹ is optionally substituted thiazolyl and R⁴ is optionally substituted phenyl. In some embodiments, A¹ is 2- methylthiazol-4-yl, 4-methylthiazol-2-yl, 4-ethylthiazol-2-yl, 4-cyclopropylthiazol-2-yl, , 4- (fluoromethyl)thiazol-2-yl 4-(methoxymethyl)thiazol-2-yl, 4,5-dimethylthiazol-2-yl or 4- methyloxazol-2-yl and R⁴ is phenyl or 4-fluorophenyl. [0157] In some embodiments, the compound has the formula (VI):

or a pharmaceutically acceptable salt or solvate thereof, wherein A 1, A2, L 1, X 1, X 2, R 2, R 7A and R 7B are as defined for Formula (I) and any variations thereof. In some embodiments, A 1 is optionally substituted thiazolyl (e.g. 4-methylthiazol-2-yl or 4-(fluoromethyl)thiazol-2-yl). In some embodiments, A¹ is optionally substituted oxazolyl (e.g. 4-methyloxazol-2-yl). In some embodiments, L 1 is methylene. In some embodiments, R 2 is H or optionally substituted alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is optionally substituted alkyl (e.g. methyl). In some embodiments, R is optionally substituted cycloalkyl (e.g.

cyclopropyl or cyclopentyl). In some embodiments, X 1 is N. In some embodiments, X 2 is N.

In some embodiments, both X 1 and X2 are N. In some embodiments, X 1 is N and X2 is CH.

In some embodiments, X 1 is CH and X2 is N. In some embodiments, both X 1 and X2 are CH. In some embodiments, R^7A is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In some embodiments, R 7 A is methyl. In some embodiments, R 7B is optionally substituted -alkylene-phenyl (e.g. benzyl or 4-fluorobenzyl).

[0158] In some embodiments, the compound has the formula (Via):

or a pharmaceutically acceptable salt or solvate thereof, wherein A 1, A 2, L1, L4, X 1, X 2, R2, R4 and R^7A are as defined for Formula (I) and any variations thereof. In some embodiments, A¹,

A 2", V 1, r 2 and R 7" A¹ are as defined for Formula (VI). In some embodiments, L 4 is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4- fluorophenyl). In some embodiments, A¹ is optionally substituted thiazolyl and R⁴ is optionally substituted phenyl. In some embodiments, A¹ is 4-methylthiazol-2-yl, 4- (fluoromethyl)thiazol-2-yl or 4-methyloxazol-2-yl and R⁴ is phenyl or 4-fluorophenyl.

[0159] In some embodiments, the compound has the formula (VII):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, L¹, L⁴, X¹, X², Y, R², R⁴,

R 7A , R 20 , R 21 and R 2^{^}2 are as defined for Formula (I) and any variations thereof. In some embodiments, A¹, L¹, L⁴, X¹, X², R², R⁴ and R^7A are as defined for Formula (VI) or (Via). In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R 20 is hydrogen. In some embodiments, R 22 is hydrogen. In some embodiments, R 20 and R 22 are both hydrogen. In some embodiments, R 21 is hydrogen.

[0160] In some embodiments, the compound has the formula (VIII):

[0161] In some embodiments, the compound has the formula (IX):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, L¹, L⁴, X¹, X², R², R⁴,

R 7'A^{^}. and R 2"3 are as defined for Formula (I). In some embodiments, A 1 , L 1 , 174, X 1¹, X 2", R 2", R 4", R and R are as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described. In some embodiments, A¹, L¹, L⁴, X¹, X², R², R⁴ and R^7A are as defined for Formula (VI) or (Via). In some embodiments, each X¹ and

X 2 s N. In some embodiments, one of X 1¹ and X2" is N and the other is CH. In some embodiments, R^7A is Ci-C₆ alkyl (e.g., methyl). In some embodiments, L⁴ is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4-fluorophenyl). In some embodiments, A¹ is optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted thiophenyl, optionally substituted oxadiazolyl, optionally substituted pyridyl or optionally substituted pyrazinyl. In some embodiments, L¹ is optionally substituted Ci-C₆ alkylene (e.g., methylene or

methylmethylene). In some embodiments, A¹ is 2-methyloxazol-4-yl and 2,5- dimethyloxazol-4-yl). In some embodiments, A¹ is thiozol-2-yl, 4-methylthiazol-2-yl, 4- ethylthiazol-2-yl, 4-bromothiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4-(methoxymethyl)thiazol- 2-yl, 4,5-dimethylthiazol-2-yl, and 2-methylthiazol-4-yl). In some embodiments, A¹ is 2- thiophenyl. In some embodiments, A¹ is 3-methyl-l,2,4-oxadiazol-5-yl. In some

embodiments, A¹ is l-methylpyrazol-3-yl, l-methylpyrazol-4-yl, l,3-dimethylpyrazol-5-yl, l-methylpyrazol-5-yl, and l,5-dimethylpyrazol-4-yl). In some embodiments, A¹ is 6- methylpyridin-3-yl, 6-methylpyridin-2-yl or 4-pyridyl. In some embodiments, A¹ is 2- pyrazinyl. In some embodiments, R is hydrogen, an optionally substituted Ci-C₆ alkyl, or an optionally substituted C3-C6 cycloalkyl. In some embodiments, R is hydrogen. In some embodiments, R is methyl, ethyl, 2-fluroethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl or tert-butyl. In some embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 23 is as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described.

[0162] In some embodiments, the compound has the formula (X):

or a pharmaceutically acceptable salt or solvate thereof, wherein A¹, L¹, L⁴, X¹, X², R², R⁴ and R^7A are as defined for Formula (I), Y is N or CH, R⁴⁰ is halogen or optionally substituted alkoxy. In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R⁴⁰ is optionally substituted Ci-C₆ alkoxy (e.g., methoxy). In some embodiments, R is halogen (e.g., F, CI, Br or I). In some embodiments, R is fluoro. In some embodiments, R⁴⁰ is chloro. In some embodiments, A¹, L¹, L⁴, X¹, X², R², R⁴ and R^7A are as described for any applicable variations of formula (I) detailed herein as if each and every variation is individually described. In some embodiments, A¹, L¹, L⁴, X¹, X², R², R⁴ and R^7A are as defined for Formula (VI) or (Via). In some embodiments, each X¹ and X² is

1 2 ·

N. In some embodiments, one of X¹ and X" is N and the other is CH. In some embodiments, R^7A is Ci-Ce alkyl (e.g., methyl). In some embodiments, L⁴ is methylene. In some embodiments, R⁴ is substituted or unsubstituted aryl (e.g. phenyl or 4-fluorophenyl). In some embodiments, L¹ is optionally substituted Ci-C₆ alkylene (e.g., methylene or

methylmethylene). In some embodiments, A¹ is optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted thiophenyl, optionally substituted oxadiazolyl, optionally substituted pyridyl or optionally substituted pyrazinyl. In some embodiments, A¹ is 2-methyloxazol-4-yl and 2,5-dimethyloxazol-4-yl). In some embodiments, A¹ is thiozol-2-yl, 4-methylthiazol-2-yl, 4-ethylthiazol-2-yl, 4- bromothiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4-(methoxymethyl)thiazol-2-yl, 4,5- dimethylthiazol-2-yl, and 2-methylthiazol-4-yl). In some embodiments, A¹ is 2-thiophenyl. In some embodiments, A¹ is 3-methyl-l,2,4-oxadiazol-5-yl. In some embodiments, A¹ is 1- methylpyrazol-3-yl, l-methylpyrazol-4-yl, l,3-dimethylpyrazol-5-yl, l-methylpyrazol-5-yl, and l,5-dimethylpyrazol-4-yl). In some embodiments, A¹ is 6-methylpyridin-3-yl, 6- methylpyridin-2-yl or 4-pyridyl. In some embodiments, A¹ is 2-pyrazinyl. In some embodiments, R is hydrogen, an optionally substituted Ci-C₆ alkyl, or an optionally

2

substituted C3-C6 cycloalkyl. In some embodiments, R is hydrogen. In some embodiments, R is methyl, ethyl, 2-fluroethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0163] In some embodiments, provided are any one, any combination, or all of the compounds of Table 1. In some embodiments, provided are any one, any combination, or all of the compounds detailed in Example 2, such a compound of Examples 2.1 to 2.213, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) is in substantially pure form. Unless otherwise stated, "substantially pure" intends a preparation of the compound that contains no more than 15 % impurity, wherein the impurity intends compounds other than the indicated inhibitor compound, but does not include other forms of the inhibitor compound (e.g., different salt form or a different stereoisomer, conformer, rotamer, or tautomer of the compound depicted). In one variation, a preparation of substantially pure compound is provided wherein the preparation contains no more than 25 % impurity, or no more than 20 % impurity, or no more than 10 % impurity, or no more than 5 % impurity, or no more than 3 % impurity, or no more than 1 % impurity, or no more than 0.5 % impurity. In some embodiments, the compound is present with no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1 % of the total amount of compound in a different stereochemical form (e.g., when the an S,S compound no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the total R,R; S,R; and R,S form is present).

[0165] The compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) and methods of using the same, unless otherwise stated, include all solvate and/or hydrate forms. In some embodiments, the compounds described herein can exist in unsolvated forms as well as solvated forms (i.e., solvates). The compounds may also include hydrated forms (i.e., hydrates).

[0166] The compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1), as well as methods of using the same, unless otherwise stated, include all salt forms of the compounds. The compounds also include all non-salt forms of any salt of a compound described herein, as well as other salts of any salt of a compound described herein. In some embodiments, the salts of the compounds are pharmaceutically acceptable salts. The desired salt of a basic functional group of a compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. The desired salt of an acidic functional group of a compound can be prepared by methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, bismuth salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, trimethylamine, and triethylamine salts. Examples of inorganic salts of base compounds include, but are not limited to, hydrochloride and hydrobromide salts. Examples of organic salts of base compounds include, but are not limited to, tartrate, citrate, maleate, fumarate, and succinate. In some embodiments, the compounds in the salt form of hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. In some embodiments, the compounds described herein exist as a citrate salt (e.g., mono citrate, hydrogen citrate, or dihydrogen citrate) and/or a mesylate salt (e.g., dimesylate). These salts may be prepared by methods known to those skilled in the art.

[0167] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0168] In addition to salt forms, also provided are compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the desired compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). Additionally, prodrugs can be converted to the compounds described herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds described herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0169] Metabolites of the compounds are also embraced. Metebolites may include primary metabolites and/or secondary metabolites. However, metabolites of substances which occur naturally in subjects are excluded from the claimed compounds.

[0170] Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotomers, and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer. A compound containing multiple chiral carbon atoms is intended to embrace all enantiomers and diastereomers (including (R,R), (S,S), (R,S), and (R,S) isomers). When a compound is explicitly indicated in a particular stereochemical arrangement (e.g., 2S,3R), the compound may, in other embodiments, be described in another specific stereochemical arrangement (e.g., 2R,3S) and/or a mixture of stereochemical arrangements.

[0171] A composition may contain the compound as mixtures of such stereoisomers, where the mixture may be enantiomers (e.g., S,S and R,R) or diastereomers (e.g., S,S and R,S or S,R) in equal or unequal amounts. A composition may contain the compound as a mixture of 2 or 3 or 4 such stereoisomers in any ratio of stereoisomers.

[0172] The compounds herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 (¹⁴C). All isotopic variations or isotopologues of the compounds herein, whether radioactive or not, are contemplated.

[0173] Included in all uses of the compounds disclosed herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1), is any or all of the stereochemical, enantiomeric, diastereomeric, conformational, rotomeric, tautomeric, isotopic, solvate, hydrate, salt, and pharmaceutically acceptable salts of the compounds as described.

//. General Synthetic Methods

[0174] The compounds herein are synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing the compounds herein are both readily apparent and accessible to those of skill in the relevant art in light of the teachings described herein. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds herein. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds herein.

[0175] The oxadiazole compounds describe herein may be synthesized according to Scheme I. In one alternative, carboxylic acid A is converted to acyl hydazide C, which is coupled with carboxylic acid B to form intermediate E. In another alternative, carboxylic acid B is converted to acyl hydazide D, which is coupled with carboxylic acid A to form intermediate E. Intermediate E is treated with a dehydrating agent such as Burgess' Reagent to form the oxadiazole compound F. Appropriate protection groups are used when necessary in any of the reaction steps. Scheme 1

F

[0176] Scheme 2 shows an exemplary synthesis of an oxadiazole compound described herein according to Scheme 1. Coupling of acid A' with acyl hydrazide D' affords intermediate E', which undergoes cyclization to form oxadiazole F. Deprotection of F gives β-secretase inhibitor compound G'.

Scheme 2

[0177] An exemplary systhesis of an oxazole compound is shown in Scheme 3. Scheme 3

[0178] An oxazole compound of formula (I) where Xi is CH and X₂ is N may be synthesized following the exemplary Scheme 4.

Scheme 4

[0179] A furan compound of formula (I) where both Xi and X₂ are CH may be synthesized following the exemplary Scheme 5a or 5b. Scheme 5a

Scheme 5b

[0180] Compounds of formula (I) - (VIII) or any variations thereof may be synthesized following Scheme 1, 2 or 3 using appropriate stating materials, either available from commercial sources or synthesized following literature procedures or procedures described in Examples herein.

Beta-Secretase Inhibitor Activity

[0181] To develop useful β-secretase inhibitors, candidate inhibitors capable of selectively mediating, e.g., decreasing, memapsin 2 catalytic activity may be identified in vitro and subsequently tested for their ability to reduce the production of Αβ. The activity of the inhibitor compounds can be assayed utilizing methods known in the art and/or those methods presented herein. [0182] Compounds that decrease memapsin 2 catalytic activity may be identified and tested using biologically active memapsin 2, either recombinant or naturally occurring. Memapsin 2 can be found in native cells, isolated in vitro, or co-expressed or expressed in a cell.

Measuring the reduction in the memapsin 2 catalytic activity in the presence of an inhibitor relative to the activity in the absence of the inhibitor may be performed using a variety of methods known in the art.

[0183] For example, the compounds may be tested for their ability to cause a detectable decrease in hydrolysis of a β-secretase site of a peptide in the presence of memapsin 2. These data can be expressed, for example, as Kj, Kj apparent, Vi/V₀, or percentage inhibition. Kj is the inhibition equilibrium constant which indicates the ability of compounds to inhibit a given enzyme (such as memapsin 2, memapsin 1, and/or cathepsin D). Numerically lower K; values indicate a higher affinity of the compounds herein for the enzyme. The Kj value is independent of the substrate concentration, and converted from Kj apparent.

[0184] K; apparent is determined in the presence of substrate according to established techniques (see, for example, Bieth, J., Bayer-Symposium V: Proteinase Inhibitors, pp. 463- 469, Springer- Verlag, Berlin (1994)). The standard error for the Kj apparent is the error from the nonlinear regression of the V V₀ data measured at different concentrations of the compounds herein (e.g., between about 10 nM to about 1000 nM) employing well-known techniques (see, for example, Bieth, J., Bayer-Symposium V: Proteinase Inhibitors, pp. 463- 469, Springer- Verlag, Berlin (1994), Ermolieff, J., et al, Biochemistry 59:12450-12456 (2000), the teachings of which are incorporated herein by reference in their entirety). Vj/V₀ depicts the ratio of initial conversion velocities of a substrate (Ermolieff, et al., Biochemistry 40:12450-12456 (2000)) by an enzyme in the absence (V₀) or presence (Vj) of an inhibitor. A Vj/V_o value of 1.0 indicates that a compound does not inhibit the enzyme at the

concentration tested. A V V₀ value less than 1.0 indicates that a compound herein inhibits enzyme activity.

[0185] In some embodiments, the compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) are capable of reducing memapsin 2 beta-secretase activity. In some embodiments, the compounds have a memapsin 2 beta-secretase K; and/or K; apparent (e.g., using any inhibitory assay described herein) of less than about any one of 10 μΜ, 5 μΜ, 1 μΜ, or less than about any one of 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM; or from about 1 to 5, 1 to 10, 1 to 100, 1 to 300, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM. In some embodiments, the compounds have a memapsin 2 beta- secretase K; and/or K; apparent (e.g., using any inhibitory assay described herein) of less than about 300, 301 to 500, or greater than 501 nM.

[0186] Once compounds are identified that are capable of mediating, e.g., reducing, the hydrolysis of a β-secretase site of a peptide in the presence of memapsin 2, the compounds may be further tested for their ability to selectively inhibit memapsin 2 relative to other enzymes. Typically, the other enzyme is a peptide hydrolase, such as memapsin 1 or cathepsin D; or from another family of interest, such as Cytochrome P450 3A4 (CYP3A4). Compounds that decrease cathepsin D catalytic activity or memapsin 1 catalytic activity are tested using biologically active enzyme, either recombinant or naturally occurring. Cathepsin D or memapsin 1 catalytic activity can be found in native cells, isolated in vitro, or co- expressed or expressed in a cell. Inhibition by a compound described herein is measured using standard in vitro or in vivo assays such as those well known in the art or as otherwise described herein.

[0187] For example, selectivity of a compound may be measured by determining the extent to which memapsin 2 hydrolyzes a substrate peptide compared to the extent to which the same compound inhibits memapsin 1 and/or cathepsin D cleaving of a substrate peptide in the presence of the compound. Exemplary substrate peptides that are useful in determining the activity of memapsin 2 and or memapsin 1 include APP and derivatives thereof, such as FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2) (Bachem Americas, Torrance, CA).

Exemplary substrate peptides that are useful in determining the activity of cathepsin D include, for example, peptides which include the sequence MCA-GKPILFFRLK(DNP)-dR (SEQ ID NO.: 1). These substrate peptides can be synthesized using known peptide synthesis methods, e.g., solid-phase peptide synthesis (e.g., FMOC amino acid coupling etc.). These data can be expressed, for example, as Ki, K; apparent, Vi/Vo, or percentage inhibition and depict the inhibition of a compound for memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity. For example, if the Kj of a reaction between an inhibitor compound herein and memapsin 1 or cathepsin D is 1000 and the K; of a reaction between an inhibitor compound herein and memapsin 2 is 100, the inhibitor compound inhibits the β- secretase activity of memapsin 2 with ten-fold selectivity over memapsin 1 or cathepsin D. [0188] The compounds described herein may be capable of selectively inhibiting memapsin 2 over Cytochrome P450 3A4 (CYP3A4). CYP3A4 plays an important role in the

metabolism of xenobiotics. Inhibition of CYP3A4 can lead to unwanted drug-drug interactions by modulating the metabolism of other therapeutics. Many patients, particularly those patients in advanced age seeking treatment for conditions such as Alzheimer's disease, are prescribed multiple therapeutics for various conditions, wherein drug-drug interactions caused by inhibition of CYPAA4 would be highly undesirable. Accordingly, the ability to selectively inhibit memapsin 2 over CYP3A4 (e.g., not effect or minimally effect CYP3A4) may aid in decreasing unwanted drug-drug interacations leading to decreased toxicity and increased effectiveness of beta-secretase inhibitors. Some compounds described herein have been shown to exhibit strikingly selective inhibition of memapsin 2 in the presence of Cytochrome P450 3A4.

[0189] In some embodiments, the compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) are capable of selectively reducing memapsin 2 relative to memapsin 1, cathepsin D and/or CYP3A4. In some embodiments, the compounds are capable of selectively reducing memapsin 2 relative to memapsin 1, cathepsin D, and/or CYP3A4 with greater than about 2- fold selectivity, or greater than about any one of 3, 5, 7, 10, 25, 50, 75, 100, 300, 200, 500, 750, 1000, 2000, 5000, or 10000-fold selectivity. In some embodiments, the compounds have a memapsin 2 beta-secretase K; and/or K; apparent (e.g., using any inhibitory assay described herein) of less than about 10 μΜ, 5 μΜ, 1 μΜ, or less than about any one of 750, 500, 400, 300, 250, 200, 100, 75, 50, 25, 10, 5, 2, or 1 nM, or from about any of 1 to 5, 1 to 10, 1 to 100, 1 to 250, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 250 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM; and have a memapsin 1 and/or cathepsin D K; and/or K; apparent of more than about 10 μΜ, 5 μΜ, 1 μΜ, or more than about any one of 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or from about any of 1 to 5, 1 to 10, 1 to 100, 1 to 300, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM. In some embodiments, the compounds have a memapsin 2 beta-secretase Kj and/or Kj apparent (e.g., using any inhibitory assay described herein) of less than about 10 μΜ, 5 μΜ, 1 μΜ, or less than about any one of 750, 500, 400, 300, 250, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or from about any of 1 to 5, 1 to 10, 1 to 100, 1 to 250, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 250 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM; and have a CYP3A4 K_; and/or K_; apparent of more than about 100 μΜ, 50μΜ, 25 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, or more than about any one of 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or from about any of 1 to 5, 1 to 10, 1 to 100, 1 to 300, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM.

[0190] Compounds demonstrating the ability to cause a detectable decrease in hydrolysis of a β-secretase site of a peptide in the presence of memapsin 2 (or, in addition, selectivity of action toward memapsin 2), may be tested in cell models or animal models for their ability to cause a detectable decrease in the amount or production of β-amyloid protein (Αβ). For example, isosteric inhibitors of memapsin 2 have been tested for their ability to decrease Αβ production in cultured cells (see U.S. Patent Application Publication No. 20040121947, International Application No. PCT/US02/34324 (Publication No. WO 03/039454), and International Application No. PCT/US06/13342 (Publication No. WO 06/110668, the contents of which are hereby incorporated by reference)). Briefly, inhibitors may be added to a culture of cells (e.g., human embryonic kidney (HEK293) cells, HeLa cells, Chinese hamster ovary cells, or neuroblastoma line SK-N-BE(2)) stably transfected if needed with a nucleic acid constructs that encode human APP and, if needed, a nucleic acid construct encoding human memapsin 2. Immunoprecipitation of Αβ followed by SDS-gel

electrophoresis allows detection and quantitation of the amount of Αβ produced in the presence and absence of inhibitor.

[0191] In addition to cell cultures, animal models may be used to test inhibitors of memapsin 2 for their ability to decrease Αβ production. For example, an animal (e.g., rat) may be administered an inhibitor orally or intravenously. The plasma may then be collected and Αβ levels determined by capture ELISA (BioSource International, Camarillo, CA).

[0192] In some embodiments, the compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) are capable of reducing cellular Αβ production. In some embodiments, the compounds are capable of reducing cellular Αβ production with a IC₅₀ (e.g., using an Αβ inhibitory assay described herein) of less than about 10 μΜ, 5 μΜ, 1 μΜ, or less than about 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or from about 1 to 5, 1 to 10, 1 to 100, 1 to 300, 1 to 500, 1 to 1000, 100 to 500, 200 to 500, 300 to 500, 100 to 750, 200 to 750, 300 to 750, 400 to 750, 500 to 750, 100 to 1000, 250 to 1000, 500 to 1000, or 750 to 1000 nM. In some embodiments, the compounds are capable of reducing cellular Αβ production with a IC50 (e.g., using an Αβ inhibitory assay described herein) of less than 1 μΜ, between 1 and 5 μΜ, or greater than 5 μΜ.

[0193] The presence of inhibitors in organs of animal models or within cellular

compartments may be ascertained using a fluorescent tag conjugated to the inhibitor and visualization via confocal microscopy (see U.S. Patent Application Publication No.

20040121947, and International Application No. PCT/US02/34324 (Publication No. WO 03/039454), the contents of which are hereby incorporated by reference in their entirities).

[0194] The sample obtained from the mammal can be a fluid sample, such as a plasma or serum sample; or can be a tissue sample or extract, such as a brain biopsy. The amount of β- amyloid protein or a decrease in the production of β-amyloid protein can be measured using standard techniques (e.g., western blotting and ELISA assays).

[0195] Further examples of assays for identifying memapsin 2^-secretase inhibitors are set forth in the Examples section below. Other methods for assaying the activity of memapsin 2, memapsin 1, cathepsin D, and CYP3A4 and the activity of agents that decrease the activity of these enzymes are known in the art. The selection of appropriate assay methods is well within the capabilities of those of skill in the art, particularly in view of the teaching provided herein.

IV. Formulations

[0196] In another aspect, provided are formulations (e.g., pharmaceutical formulations) comprising a memapsin 2 β-secretase inhibitor compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) with a carrier, such as a pharmaceutically acceptable carrier. The formulations may include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. The memapsin 2 β-secretase inhibitor included in the formulation may be covalently attached to a carrier moiety. Alternatively, the memapsin 2 β-secretase inhibitor included in the formulation is not covalently linked to a carrier moiety.

[0197] Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which preferably do not deleteriously react with the intended compound of use.

[0198] The compounds described herein can be administered alone or can be

coadministered to the individual. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances related to the treatment of a specified condition (e.g., to reduce metabolic degradation).

[0199] The β-secretase inhibitors described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Thus, the compounds herein can be administered by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds herein can be administered transdermally. Compounds herein may also be administered locally (e.g., ocular administration such as topical eye drops or ointment). It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the inhibitor compounds described herein.

Accordingly, also provided are pharmaceutical formulations comprising a pharmaceutically acceptable carrier or excipient and one or more inhibitor compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1).

[0200] For preparing pharmaceutical formulations from the compounds described herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substance, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. [0201] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0202] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium

carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term

"preparation" is intended to include the formulation of the active compound with

encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0203] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed

homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0204] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0205] When parenteral application is needed or desired, particularly suitable admixtures for the compounds herein are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampules are convenient unit dosages. The compounds herein can also be incorporated into liposomes or administered via transdermal pumps or patches.

Pharmaceutical admixtures suitable for use herein are well-known to those of skill in the art and are described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference. [0206] Ocular administration preparations (e.g., in use of glaucoma treatment) include, but are not limited to, formulations in saline, optionally with additional carriers, stabalizers, etc. know to those of skill in the art.

[0207] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0208] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0209] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0210] Also provided are unit dosage forms comprising the formulations described herein. These unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed. For example, the pharmaceutical formulation (e.g., a dosage or unit dosage form of a pharmaceutical formulation) may include (i) an in inhibitor (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) and (ii) a pharmaceutically acceptable carrier. In some embodiments, the formulation also includes one or more other compounds (or pharmaceutically acceptable salts thereof). In various variations, the amount of inhibitor compound in the formulation is included in any of the following ranges: about 5 to about 50 mg, about 20 to about 50 mg, about 50 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg. In some embodiments, the amount of compound in the formulation (e.g., a dosage or unit dosage form containing any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg, of the compound.

[0211] Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; cyclodextrin; polyoxyl 35 castor oil; or other agents known to those skilled in the art. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.

[0212] Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, combinations of the foregoing, and other agents known to those skilled in the art. Such agents are typically employed at a level between about 0.01% and about 2% by weight. Determination of acceptable amounts of any of the above adjuvants is readily ascertained by one skilled in the art.

[0213] The formulations described may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841 ; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

A. Effective Dosages

[0214] Pharmaceutical formulations described include formulations wherein the active ingredient (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) is contained in an effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat Alzheimer's disease, such compositions will contain an amount of active ingredient effective to achieve the desired result {e.g., decreasing β- secretase activity or β-amyloid production). Determination of an effective amount of a compound herein is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0215] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, including a disease that results in increased activity of memapsin 2 or increased accumulation of β-amyloid protein, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated {e.g., Alzheimer's disease), kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein. Adjustment and manipulation of established dosages {e.g., frequency and duration) are well within the ability of those skilled in the art.

[0216] For any compound described herein, the effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of reducing the activity of memapsin 2 activity, as measured using the methods described herein or known in the art.

[0217] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring memapsin 2 inhibition and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan, particularly in view of the teaching provided herein.

[0218] Dosages may be varied depending upon the requirements of the individual and the compound being employed. The dose administered to an individual, should be sufficient to affect a beneficial therapeutic response in the individual over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects.

Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. In one embodiment, the dosage range is 0.001% to 10% w/v. In another embodiment, the dosage range is 0.1% to 5% w/v.

[0219] Additional examples of dosages which can be used are an effective amount within the dosage range of about 0.1 g/kg to about 300 mg/kg, or within about 1.0 g/kg to about 40 mg/kg body weight, or within about 1.0 g/kg to about 20 mg/kg body weight, or within about 1.0 g/kg to about 10 mg/kg body weight, or within about 10.0 μg/kg to about 10 mg/kg body weight, or within about 100 μg/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight. Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg body weight. Compounds herein may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.

[0220] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular individual. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, individual body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

B. Kits

[0221] Also provided are kits for administration of the compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1, formulations, and dosage forms thereof).

[0222] In certain embodiments the kits may include a dosage amount of at least one formulation as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the formulation. Kits may also comprise a means for the delivery of the formulation thereof.

[0223] The kits may include other pharmaceutical agents for use in conjunction with the one or more compounds described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). In some variations, the pharmaceutical agent(s) may be one or more anti-psychotic drugs. These agents may be provided in a separate form, or mixed with the compounds described herein, provided such mixing does not reduce the effectiveness of either the pharmaceutical agent or compound described herein and is compatible with the route of administration. Similarly the kits may include additional agents for adjunctive therapy or other agents known to the skilled artisan as effective in the treatment or prevention of the conditions described herein.

[0224] The kits may optionally include appropriate instructions for preparation and administration of the composition, side effects of the composition, and any other relevant information. The instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, optical disc or directions to internet-based instructions.

[0225] In another aspect, provided are kits for treating an individual who suffers from or is susceptible to the conditions described herein, comprising a first container comprising a dosage amount of a formulation as disclosed herein, and instructions for use. The container may be any of those known in the art and appropriate for storage and delivery of intravenous formulation. In certain embodiments the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for preparation of the

composition to be administered to the individual.

[0226] Kits may also be provided that contain sufficient dosages of the inhibitor (including formulation thereof) as disclosed herein to provide effective treatment for an individual for an extended period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more. [0227] Kits may also include multiple doses of the compound and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.

[0228] The kits may include the compounds as described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) packaged in either a unit dosage form or in a multi-use form. The kits may also include multiple units of the unit dose form. In certain embodiments, provided are the compound described herein in a unit dose form. In other embodiments the compositions may be provided in a multi-dose form (e.g., a blister pack, etc.).

C. Toxicity

[0229] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD₅₀ (the amount of compound lethal in 50% of the population) and ED₅₀ (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g., Fingl et al, In: THE PHARMACOLOGICAL BASIS OF

THERAPEUTICS, Ch.l, p.l, 1975. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the individual's condition and the particular method in which the compound is used.

V. Methods of Reducing the Activity of Memapsin 2 Beta-Secretase

[0230] In another aspect, the β-secretase inhibitor compounds herein can be employed in methods to decrease memapsin 2 activity, decrease hydrolysis of a β-secretase site of a memapsin 2 substrate, and/or decrease the accumulation of β-amyloid protein relative to the amount of memapsin 2 activity, hydrolysis of a β-secretase site, and accumulation of β- amyloid protein, respectively, in the absence of the β-secretase inhibitor.

[0231] In an exemplary embodiment, a method of reducing memapsin 2 activity is provided. The method includes contacting a memapsin 2 with a β-secretase inhibitor compound herein. The memapsin 2 may be contacted in any appropriate environment (e.g., in vitro, in vivo). The memapsin 2 activity is decreased relative to the amount of activity in the absence of β-secretase inhibitor.

[0232] In another exemplary embodiment, a method is provided of selectively mediating (e.g., reducing) memapsin 2 activity using an inhibitor described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). Selective reduction of the activity of memapsin 2 means that memapsin 2 is not only reduced relative to its activity in the absence of inhibitor, but is reduced to a greater extent as compared to the reduction in activity due to inhibitor action against another enzyme, such as a peptide hydrolase (e.g., cathepsin D, memapsin 1) and/or Cytochrome P450 3A4. For example, as described above, the reduction in activity of an enzyme may be expressed in terms of the inhibitory constant (K_;). Where an inhibitor selectively reduces the activity of memapsin 2, the K; of the reaction between an inhibitor compound described herein and memapsin 2 is less than the Kj of the reaction between an inhibitor compound herein and another peptide hydrolase and/or Cytochrome P450 3A4.

[0233] In some embodiments, the K; of the reaction between an inhibitor compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) and memapsin 2 is less than the Kj of the reaction between an inhibitor compound and another peptide hydrolase (e.g., cathepsin D, memapsin 1). In some related embodiments, the inhibitor selectively reduces the activity of memapsin 2 as compared to memapsin 1. In other related embodiments, the inhibitor selectively reduces the activity of memapsin 2 as compared to cathepsin D. In some embodiments, the Kj of the reaction between an inhibitor compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) and memapsin 2 is less than the Kj of the reaction between an inhibitor compound and Cytochrome P450 3A4. In an exemplary embodiment, the K; of the reaction between an inhibitor compound herein and memapsin 2 is at least 2 times less than the K; of the reaction between an inhibitor compound herein and another peptide hydrolase and/or Cytochrome P450 3A4. In another exemplary embodiment, the Kj of the reaction between an inhibitor compound herein and memapsin 2 is at least 3, 5, 7, 10, 25, 50, 75, 100, 300, 200, 500, 750, 1000, 2000, 5000, or 10000 times less than the K; of the reaction between an inhibitor compound herein and another peptide hydrolase and/or Cytochrome P450 3A4.

[0234] Thus, provided are methods of selectively reducing the activity of memapsin 2. The methods include contacting a memapsin 2 with a β-secretase inhibitor compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). In a related embodiment, the method includes contacting the memapsin 2 with a β-secretase inhibitor in the presence of memapsin 1. In an alternative related embodiment, the method includes contacting the memapsin 2 with a β-secretase inhibitor in the presence of cathepsin D. In yet another related embodiment, the method includes contacting the memapsin 2 with a β-secretase inhibitor in the presence of cathepsin D and memapsin 1. In yet another embodiment, the method includes contacting the memapsin 2 with a β-secretase inhibitor in the presence of Cytochrome P450 3A4. In still another related embodiment, the method includes contacting the memapsin 2 with a β-secretase inhibitor in the presence of cathepsin D, memapsin 1, and Cytochrome P450 3A4.

[0235] In some embodiments, the activity of memapsin-2 β-secretase may be determined by measuring the hydrolysis of a β-secretase site of a β-secretase substrate. Thus, described are methods of decreasing the hydrolysis of a β-secretase site of a β-secretase substrate by contacting a memapsin 2 with a β-secretase inhibitor compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). In some embodiments, the hydrolysis of a β-secretase site is decreased relative the amount of hydrolysis in the absence of the inhibitor. In other embodiments, the hydrolysis is selectively reduced as compared to hydrolysis by memapsin 1 and/or cathepsin D. Thus, a method of selectively decreasing hydrolysis of a β-secretase site of a β-amyloid precursor protein relative to memapsin 1 and/or cathepsin D in a sample is provided. The method includes contacting a memapsin 2 with a β-secretase inhibitor compound.

[0236] In another embodiment, provided are methods of decreasing the amount of β- amyloid protein in a sample by contacting the memapsin 2 with an inhibitor compound (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). The amount of β-amyloid protein in a sample is decreased relative the amount of β-amyloid protein in the sample in the absence of the inhibitor. Thus, the accumulation of β-amyloid protein is thereby decreased.

[0237] Memapsin 2 may be contacted in any suitable environment or any suitable sample. For example, memapsin 2 may be contacted in vitro, within a cell, or within a mammal.

Typically, in vitro solutions are selected such that the components do not substantially interfere with the enzymatic activity of memapsin 2 (e.g., aqueous solutions). In some embodiments, the in vitro solution includes a biological sample, such as a mammalian sample. Exemplary mammalian samples include plasma or serum samples and tissue samples or extracts, such as a brain biopsy. Any appropriate cell or cellular sample may be selected in which to contact the memapsin 2 with the inhibitor. The cell may contain endogenous memapsin 2 or recombinant memapsin 2 as previously described (see U.S. Patent Application Publication No. 20040121947 (the contents of which are hereby incorporated by reference), and International Application No. PCT/US02/34324 (Publication No. WO 03/039454)). Exemplary cells include human embryonic kidney (HEK293) cells, HeLa cells, Chinese hamster ovary cells, or neuroblastoma cell line SK-N-BE(2) (ATCC number CRL- 2271), Hela cells, 293 cells. In an exemplary embodiment, the compounds herein are administered to a mammal to inhibit the hydrolysis of a β-secretase site of a β-amyloid precursor protein (e.g., a mouse, rat or human).

VI. Methods of Treating Alzheimer's Disease

[0238] In another aspect, the β-secretase inhibitor compounds herein can be employed in the treatment of diseases or conditions associated with and/or mediated by β-secretase activity, hydrolysis of a β-secretase site of a β-amyloid precursor protein, and/or β-amyloid protein accumulation. Typically, a mammal is treated for the disease or condition. In an exemplary embodiment, the disease is Alzheimer's disease.

[0239] Thus, in some embodiments, provided are methods of treating Alzheimer's disease in a mammal comprising the step of administering to the mammal in need thereof an effective amount of a β-secretase inhibitor (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). In some embodiments, the individual has one or more symptoms of Alzheimer's disease. In some embodiments, the individual has been diagnosed with Alzheimer's disease. The mammals treated with the inhibitors may be human primates, nonhuman primates or non-human mammals (e.g., rodents, canines). In one embodiment, the mammal is administered a compound herein that reduces β-secretase activity (inhibits memapsin 1 and memapsin 2 activity). In another embodiment, the mammal is administered a compound that selectively reduces memapsin 2 activity. In a related embodiment, the compound has minimal or no effect on reducing memapsin 1 activity. Therefore, also provided is a method of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a β-secretase inhibitor compound. In an exemplary embodiment, the β-secretase inhibitor compound is part of a pharmaceutical formulation, as described above.

[0240] The inhibitor compounds herein can be employed in the treatment of diseases or conditions in an individual associated with β-secretase activity (e.g., memapsin 2 activity), which can halt, reverse or diminish the progression of the disease or condition, in particular Alzheimer's disease. In some embodiments, the individual has one or more symptoms of the disease or condition associated with β-secretase activity. In some embodiments, the individual has been diagnosed with disease or condition associated with β-secretase activity. In addition to compounds that decrease memapsin 2 activity, compounds that selectively reduce memapsin 2 activity are useful to treat diseases or conditions or biological processes associated with memapsin 2 activity rather than diseases or conditions or biological processes associated with both memapsin 2 activity and another peptide hydrolase (such as cathepsin D or memapsin 1).

[0241] For example, both memapsin 1 and memapsin 2 cleave amyloid precursor protein (APP) at a β-secretase site to form β-amyloid protein (also referred to herein as Αβ or β-amyloid protein). Thus, both memapsin 1 and memapsin 2 have β-secretase activity (Hussain, I., et ah, J. Biol. Chem. 276:23322-23328 (2001)). However, the β-secretase activity of memapsin 1 is significantly less than the β-secretase activity of memapsin 2 (Hussain, I., et ah, J. Biol. Chem. 276:23322-23328 (2001)). Memapsin 2 is localized in the brain, and pancreas, and other tissues (Lin, X., et ah, Proc. Natl. Acad Sci. USA 97:1456- 1460 (2000)) and memapsin 1 is localized preferentially in placentae (Lin, X., et ah, Proc. Natl. Acad Sci. USA 97:1456-1460 (2000)). Alzheimer's disease is associated with the accumulation of Αβ in the brain as a result of cleaving of APP by β-secretase (also referred to herein as memapsin 2, ASP2 and BACE). Thus, methods employing the compounds which selectively inhibit memapsin 2 activity relative to memapsin 1 activity may be important in the treatment of memapsin 2-related diseases, such as Alzheimer's disease. Selective inhibition of memapsin 2 activity makes the compounds herein suitable drug candidates for use in the treatment of Alzheimer's disease.

VII. Methods of Treating Glaucoma

[0242] In another aspect, the β-secretase inhibitor compounds herein can be employed in the treatment of diseases associated with vision loss (e.g., glaucoma). In some embodiments, provided are methods of treating glaucoma (e.g. closed-angle glaucoma and open-angle glaucoma) in an individual comprising the step of administering to the individual in need thereof an effective amount of the β-secretase inhibitors herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1). In an exemplary embodiment, the β-secretase inhibitor compound is part of a

pharmaceutical formulation, as described above.

[0243] In some aspects, the inhibitor compounds herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) can be employed in the treatment of diseases or conditions associated with β-secretase activity, which can halt, reverse or diminish the progression of glaucoma (e.g. closed-angle glaucoma and open- angle glaucoma). In some embodiments, the inhibitor compounds herein can be used to halt, reverse or diminish the loss of retinal ganglion cells (RGCs). In other

embodiments, compounds herein (e.g., any compound of formula I, II, III, or any variations thereof, Example 2 and/or Table 1) are employed to improve or decrease intraocular pressure (IOP).

[0244] Compounds desribed herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) may be used to treat glaucoma by one of several known routes of administration, including, but not limited to, orally (e.g., in tablet or capsule form), parenterally (e.g., injected into the anterior chamber, intravenous, intramuscular, or subcutaneous), or locally (e.g., topical eye drops or ointment). Compounds herein may also be formulated for sustained release during glaucoma treatment.

[0245] Additional embodiments for treating glaucoma with compounds herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) are described by adapting one or more of the methods in Guo, et. al. Proc. Natl. Acad. Sci., 14, 13444-13449 (2007); Yamamoto, et. al., Neuroscience Letters, 370, 61- 64 (2004); and/or Urcola et. al., Exp. Eye Research, 83, 429-437 (2006). The content of these applications are hereby incorporated by reference in its entireties.

A. Methods of Administering Beta-Secretase Inhibitors to the CNS

[0246] The inhibitor compounds of herein {e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1) may be administered to the CNS through either invasive or non-invasive methods. Non-invasive methods of administration include those methods that do not require the use of a mechanical or physical means to breach the integrity of the blood-brain barrier. Typically, non-invasive methods include the use of immunoliposomes, blood-brain barrier disruption (BBBD), or the olfactory pathway.

[0247] Immunoliposomes are liposomes with antibodies or antibody fragments that bind to receptors or transporters expressed on brain capillary endothelial cells attached to the surface of the liposome. An exemplary immunoliposome combines polymer (e.g., PEGylation) technology with that of chimeric peptide technology. For example, the β-secretase inhibitor may be packaged into a unilamellar lipid vesicle containing a PEG²⁰⁰⁰ derivative that contains a reactive groups at one end, for attachment to a complementary reactive group of an antibody or fragment thereof. Complementary reactive groups are well known in the art and, include, fro example, amine and activated carboxylic acids, thiols and maleimides, and the like (Ambikanandan et al., J. Pharm Pharmaceut Sci 6(2):252-273 (2003); Huwyler et al., Proc. Natl. Acad. Sci. USA, 93:14164-14169 (1996); and Huwyler et al., J Pharmcol Exp Ther. 282:1541-1546 (1997); and U.S. Pat. No. 6,372,250, all of which are herein

incorporated by reference for all purposes in their entirety).

[0248] Blood-brain barrier disruption is a temporal loss of the integrity of the tight junctions between endothelial cells that comprise the blood brain barrier. Typically, the compound is administered via systemic or intercarotid injection in conjuction with transient blood-brain barrier disruption (BBBD). Exemplary agents useful for inducing BBBD include solvents such as dimethyl sulfoxide (DMSO); ethanol (EtOH); metals (e.g., aluminum); X- irradiation; induction of pathological conditions (e.g., hypertension, hypercapnia, hypoxia, or ischemia); anti-neoplastic agents (e.g., VP-16, cisplatin, hydroxyurea, flurouracil and etoposide); or concurrent systemic administration of the convulsant drug metrazol and the anti-convulsant drug pentobarbital (Ambikanandan et al., J. Pharm Pharmaceut Sci 6(2):252- 273 (2003)); vasoactive leukotrienes (Black et al., J Neurosurg, 81(5):745-751 (1994)); intracarotid infusion of bradykinin, histamine, or the synthetic bradykinin compound RMP-7 (Miller et al., Science 297:1116-1118 (2002), Matsukado, et al., Neurosurgery 39:125-133 (1996), Abbott, et al., Mol Med Today 2:106-113 (1996), Emerich et al., Clin Pharmacokinet 40:105-123 (2001)); hyaluronidase (U.S. Patent Application Publication No. 20030215432, Kreil, et al. Protein Sci., 4(9):1666-1669 (1995)); and intercarotid injection of inert hypertonic solutions such as mannitol, or arabinose (Neuwelt, E.A., et al., in Neuwelt EA (ed), Implications of the Blood Brain Barrier and its Manipulation: Clinical Aspects. Vol. 2, Plenum Press, New York, (1989), Neuwelt, et al., J Nucl Med, 35:1831-1841 (1994), Neuwelt et al., Pediatr Neurosurg 21:16-22 (1994), Kroll et al., Neurosurg, 42:1083-1099 (1998), Rapoport, Cell Mol Neurobiol 20:217-230 (2000), and Doran et al., Neurosurg 36:965-970, (1995)).

[0249] Olfactory pathway administration is the intranasal delivery of the compound to the olfactory nerves in the upper third of the nasal passages. After intranasal delivery, the compound is transported back along the sensory olfactory neurons to yield significant concentrations in the cerebral spinal fluid (CSF) and olfactory bulb (Thorne et al., Brain Res, 692(l-2):278-282 (1995); Thorne et al., Clin Pharmacokinet 40:907-946 (2001); Ilium, Drug Discov Today 7:1184-1189 (2002); U.S. Pat. 6,180,603; U.S. Pat. 6,313,093; and U.S. Patent Application Publication No. 20030215398).

[0250] Invasive methods of administration are those methods that involve a physical breach of the blood-brain barrier typically through a mechanical or physical means to introduce the compound into the CSF, or directly into the parenchyma of the brain. Typically, invasive methods of administration may include injection or surgical implantation of the compound.

[0251] In injection methods, a needle is used to physically breach the BBB and deliver the compound directly into the CSF. Exemplary injection methods include intraventricular, intrathecal, or intralumbar routes of administration and may also involve infusion of the compound through a reservoir external to the body (Krewson et al., Brain Res 680:196-206 (1995); Harbaugh et al., Neurosurg. 23(6):693-698 (1988); Huang et al, J Neurooncol 45:9- 17 (1999); Bobo et al. Proc Natl Acad Sci USA 91 :2076-2082 (1994); Kroll et al., Neurosurg. 38(4): 746-752 (1996)). [0252] In surgical implantation methods, the compound is placed directly into the parenchyma of the brain. Exemplary surgical implantation methods may include

incorporation of the compound into a polyanhydride wafer placed directly into the interstitium of the brain (Bremet al., Sci Med 3(4): 1-11 (1996); Brem et al., J Control Release 74:63-67 (2001)).

VIII. Crystallized Complexes

[0253] In another aspect, is provided a crystallized complex containing a memapsin 2 protein and a beta-secretase inhibitor herein. Memapsin 2 proteins useful in forming co- crystals with isostere compounds (e.g., memapsin 2 protein fragments, transmembrane proteins, etc.) have been previously discussed in detail (see U.S. Patent Application

Publication No. 20040121947, and International Application No. PCT/US02/34324

(Publication No. WO 03/039454)). These memapsin 2 proteins are equally useful in forming crystallized complexes with beta-secretase inhibitors described herein (e.g., any compound of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (Via), (VII), (VIII), (IX), (X) or any variations thereof, Example 2 and/or Table 1).

[0254] The crystallized complex may be formed employing techniques described in U.S. Patent Application Publication No. 20040121947, and International Application No.

PCT/US02/34324 (Publication No. WO 03/039454). Briefly, a nucleic acid construct encoding the memapsin 2 protein is generated, and the protein is expressed in a host cell, such as a mammalian host cell (e.g., Hela cell, 293 cell) or a bacterial host cell (e.g., E. coli), the protein is then purified and crystallized with a compound or compounds herein. The diffraction resolution limit of the crystallized protein can be determined, for example, by x- ray diffraction or neutron diffraction techniques.

[0255] In an exemplary embodiment, the crystallized protein may have an x-ray diffraction resolution limit not greater than about 4.0 angstroms. The crystallized protein may also have an x-ray diffraction resolution limit not greater than about 4.0 angstroms, about 3.5 angstroms, about 3.0 angstroms, about 2.5 angstroms, about 2.0 angstroms, about 1.5 angstroms, about 1.0 angstroms, or about 0.5 angstroms. In some embodiments, the crystallized protein may also have an x-ray diffraction resolution limit not greater than about 2 angstroms. The diffraction resolution limit of the crystallized protein can be determined employing standard x-ray diffraction techniques. [0256] The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described, or portions thereof, it being recognized that various modifications are possible. Moreover, any one or more features of any embodiment described herein may be combined with any one or more other features of any other embodiment described herein, without departing from the envisioned scope. For example, the features of the β-secretase inhibitors described herein are equally applicable to the methods of treating disease states and/or the pharmaceutical formulations described herein. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

IX. Examples

Example 1: Preparation of Selected Beta-Secretase Inhibitors and Precursor Compounds

[0257] The described synthesis of Beta-Secretase inhibitors and precursor compounds is related to WO 2006/110668, filed on 4/10/2006 and entitled "Compounds Which Inhibit Beta-Secretase Activity and Methods of Use Thereof," the content of which is incorporated herein by reference in its entirety, and particularly with respect to the synthetic methods described therein, e.g., paragraphs 150-153 and paragraphs 215-285; and United States Provisional Patent Application No. 60/952,198, filed on 07/26/2007 and entitled

"Compounds Which Inhibit Beta-Secretase Activity and Methods of Use Thereof," the content of which is incorporated herein by reference in its entirety, and particularly with respect to the synthetic methods described therein, e.g., paragraphs 83-86 and paragraphs 161-354.

[0258] The precursor compounds synthesized below are useful in the methods of making compounds provided herein. Using the guidance provided, (for example, in the Exemplary Syntheses of Scheme 1) one skilled in the art will immediately recognize that the exemplified synthesis of the below precursor compounds may be modified using well known techniques and the teaching provided herein to arrive at a wide variety of inhibitor compounds (e.g., compounds of Example 2). Certain starting materials described, and some precursor compounds not described, may be commercially available and purchased from, for example, Sigma- Aldrich, Alfa Aesar, or Ryan Scientific.

[0259] NMR spectra were collected on a comercially available NMR spectrometer such as a Varian Mercury model VX-300 NMR spectrometer or other comercially available NMR spectrometers. NMR solvents were purchased from commercial sources such as Cambrige Isotope Laboratories and other commercial sources. Chemical shifts are reported in ppm and coupling constants (J) are reported in Hertz. In addition, characterization of some

compounds was performed using standard LCMS instrumentation.

[0260] Solvents used in the synthesis of inhibitor compounds were purchased from commercial sources including, but not limited to, Aldrich, VWR, and EMD. Typically, solvents were ACS Reagent Grade or higher, and used without further purification.

Example 1.1: Synthesis of amine building blocks.

Example 1.1.1: (4-methylthiazol-2-yl)methanamine

[0261] Methylthiazole (1.0 g, 10.1 mmol) in tetrahydrofuran (THF) at - 78 °C was treated with n-BuLi (1.6 M, 7.56 mL) for 30 min, dimethylformamide (DMF) (1.4 mL, 18.2 mmol) was added dropwise. The resulting reaction mixture was warmed to r.t. After the starting material disappeared (by TLC), the reaction mixture was recooled to 0 °C and lithium aluminum hydride (LAH) (0.69 g, 18.5 mmol) was added. The mixture was warmed to r.t. and stirred for 1 h, the reaction was quenched with aqueous NH₄C1, diluted with ethyl acetate (EtOAc). The organic solution was separated, extracted twice with EtOAc, dried with Na₂S0₄, and concentrated. The residue was purified with flash chromatography to give the corresponding alcohol as a light yellow oil. 1H-NMR: (300 MHz, CDC1₃), δ: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).

[0262] Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with mesyl chloride (0.42 mL, 5.4 mmol) and triethyl ethylamine at 0 °C in dichloromethane. The resulting mixture was stirred for 20 minutes followed by quenching with aqueous NH₄C1. Evaporation of the solvent from the organic layer and flash chromatography of the residue afforded the corresponding mesylate as an oil. The mesylate (0.25g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours followed by cooling and washing with aqueous NH₄C1. Evaporation of the solvent from the organic layer resulted in the corresponding azide. The azide (0.14g, 0.91mmol) was dissolved in ethyl acetate, Pd(OH)₂ (0.07g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through Celite. Evaporation of the solvent and flash chromatography of the residue afforded the desired methylthiazole methylamine as a yellow oil. 1H-NMR: (300 MHz, CDC1₃), δ: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).

[0263] Using an alternative synthetic route, NaBH₄ (0.75 g, 19.9 mmol, 1.3 eq) was added to a stirred solution of 4-methylthiazole-2-carbaldehyde (Aldrich, 1.7 ml, 2.0 g, 15.3 mmol, 1 eq) in 30 ml anhydrous MeOH at 0 °C. After 45 min the solvent was removed in vacuo. The residue was diluted with saturated aqueous NH4C1 and extracted with EtOAc (x3). The combined organics were washed with brine (xl) and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded (4-methylthiazol-2-yl)methanol in quantitative yield.

[0264] Diphenylphosphoryl azide (DPPA) (1.2 eq) and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of (4-methylthiazol-2-yl)methanol (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo.

Purification via flash chromatography yielded2-(azidomethyl)-4-methylthiazole.

[0265] 2-(azidomethyl)-4-methylthiazole was dissolved in 5 ml MeOH. Pd(OH)₂ (20% by wt. on carbon) was added and the mixture was stirred vigorously under H₂ overnight. The mixture was filtered through Celite, and the filter cake rinsed with MeOH. The solvent was removed in vacuo yielding(4-methylthiazol-2-yl)methanamine.

Exam le 1.1.2

[0266] Ti(0'PR)₄ (1.3 eq) was added with stirring to MeNH₂ (2.0 M in MeOH, 3 eq) at 0 °C under Ar. After 15 min. the aldehyde (Aldrich, 1 eq) was added, and the solution was stirred for 2-3 h. The NaBH₄ (1.4 eq) was added in batches, and the reaction was stirred at 0° C to room temperature overnight. The MeOH was removed via rotary evaporation. The residue was diluted with water/CH₂Cl_2; and a white ppt formed. The mixture was filtered through Celite, and the layers were separated. The aqueous layer was extracted with CH₂C1₂ (x3) and the combined organics were dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via column

chromatography yielded the product (80-85%). Example 1.1.3

[0267] To a stirred solution of N-Boc-2-aminoacetonitrile (3.0g, 19.21 mmol) in a 4:1 mixture of EtOH and water (25mL) were added NaOH (860mg, 21.5mmol) and

hydroxylamine hydrochloride 9 1.44g, 20.7mmol) and the reaction was stirred for 30h. All the solvent was evaporated under reduced pressure. The solid was dissolved in water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried on Na₂S0₄ and concentrated to provide 1.8g of (Z)-tert-butyl 2-amino-2-(hydroxyimino)ethylcarbamate.

[0268] To a stirred solution of (Z)-tert-butyl 2-amino-2-(hydroxyimino)ethylcarbamate (945mg, 5 mmol) and EtOAc (2.0mL, 20.0 mmol) in EtOH (lOOmL) was added a solution of NaOEt in EtOH (13mL, 50.0mmol) and refluxed for 6h. The reaction mixture was cooled and all the solvent was evaporated under reduced pressure. The residue was dissolved in water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried on Na₂S0₄ and concentrated to provide l.Og of tert-butyl (5-methyl-l,2,4-oxadiazol-3- yl)methylcarbamate.

[0269] tert-Butyl (5-methyl-l,2,4-oxadiazol-3-yl)methylcarbamate was converted into (5- methyl-l,2,4-oxadiazol-3-yl)methanamine using standard deprotection protocol of Boc group with TFA.

Example 1.1.4: N -meth l- l-(pyrazin-2-yl)methanamine

1.4.1 1.4.2 1.4.3

[0270] A solution of 1.4.1 (3.0 g, 32 mmol) in CHC1₃( 100 mL) was heated to reflux and solid Trichloro isocyanuric acid (3.11 g, 13.4 mmol) was added in 4 portions in 1 hour and the reaction was refluxed overnight. The reaction mixture was filtered through celite and washed with IN NaOH, dried and concentrated. The crude 1.4.2 (3.0g) was taken to the next step without purification.

[0271] To an aq. solution of MeNH₂ (25 mL, 40% in water) was added neat 1.4.2 and stirred for 2h. Excess MeNH₂ was removed on rota-vapour, extracted with chloroform, dried and concentrated to give N-methyl-l-(pyrazin-2-yl)methanamine (1.8 g). Example 1.1.5: N -methyl- l-(2-methylthiazol-4-yl)methanamine

1.5.1 1.5.2

[0272] To a solution of thioacetamide (5.0 g, 70 mmol) in EtOH( 50 mL) was added 1,3- dicholroparopanone (8.5 g, 70 mmol) and the mixture was refluxed for 5.5h. Solvent was evaporated. The residue was dissolved in water and adjusted to pH ~ 8 with addition of solid NaHC0₃. The mixture was extracted with ether, dried and concentrated. The crude 1.5.1 (6.0g) was taken to the next step without purification.

[0273] To an aq. solution of MeNH₂ (25 mL, 40% in water) was added neat 1.5.1 and stirred for 2h. Excess MeNH₂ was removed on a rota-vapour, extracted with chloroform, and dried. The residue was acidified to pH~l and extracted with CHC1₃. The aq. layer was adjusted to pH ~ 8 with addition of solid NaHC0₃ and extracted with CHC1₃ to give N- methyl-l-(2-methylthiazol-4-yl)methanamine (2.5 g).

Example 1.1.6: N-methyl-l-(2-methyloxazol-4-yl)methanamine

I

1.6.3

[0274] To a solution of acetamide (5.0 g, 85.0 mmoles) and 1,3-dichloro acetone (10.7 g, 85.0 mmoles) in acetone (lOOmL) were added NaHC0₃ (7.2 g, 85.0 mmoles) and MgS0₄ (13.65 g, 113 mmoles) and reflxed for 60h. The reaction mixture was filtered through Celite and concentrated, and chromatographed on silica gel (80% ether/ 20% pentane) to yield 20 % of 1.6.1.

[0275] A solution of 1.6.1 (2.56 g, 17.2 mmoles) in 1,2-dichloroethane (10 mL) was added to a solution of thionyl chloride (1.5 mL, 20.6 mmoles) in 1,2-dichloroethane (40 mL) at 0°C. The solution was heated at 70 °C for 15-20 min, cooled to room temperature and concentrated. The residue was dissolved in water and brought to pH~8 with solid NaHC0₃ and extracted with ether, dried, concentrated to yield 88 % of crude 1.6.2, which was not purified.

[0276] To an aq. solution of MeNH₂ (25 mL, 40% in water) was added neat 1.6.2 and stirred for 2h. Excess MeNH₂ was removed on rota-vapour, extracted with chloroform, dried and concentrated to give N-methyl-l-(2-methyloxazol-4-yl)methanamine in quantitative yield.

-tert-butyl (l-(4-methylthiazol-2-yl)ethyl)carbamate

1.7.1 1.7.2 1.7.3

[0277] To a solution of 1.7.1 (1.38 g, 7.34 mmoles) in 1, 2-DME (35 mL) was added Lawesson's reagent (1.55 g, 3.82 mmoles) and stirred for 4h. All solvent was evaporated, and diluted with 100 mL of saturated NaHC0₃ and extracted with ether (2 X 200 mL). The combined organic layers are dried over anhydrous Na₂S0₄ and concentrated. The residue was chromatographed on silica gel (35% ethyl acetate/ 75% hexane) to yield 1.5 g of 1.7.2.

[0278] A mixture of Boc-D-alanine-thioamide (1.5 g, 7.35 mmoles), chloroacetone (0.65 mL, 8.18 mmoles) and calcium carbonate (l.Og, 10.22mmoles) were refluxed in ethanol (25mL) for 4h. The reaction was cooled to room temperature and quenched with 20mL of saturated aq. NaHC0₃ solution. Ethanol was evaporated under reduced pressure and extracted with ethyl acetate (2 x 30mL). The combined organic layers was dried over Na₂S0₄ and concentrated. The residue was chromatographed on silica gel (20% ethyl acetate/ 80% hexane) to yield 600 mg of (R)-tert-butyl (l-(4-methylthiazol-2-yl)ethyl)carbamate.

Example 1.1.8: N-meth l-l-(5-methylthiazol-2-yl)methanamine

1.8.1 1 8.2 1 -8.3

[0279] To a solution of BuLi (1.6 M in hexanes, 12.6 mL, 20.2 mmoles) in 25mL of diethyl ether at -78°C, was added a solution of 5-methyl thiazole 1.8.1 (2.0g, 20.2 mmoles) in ether (6mL), drop-wise and stirred at -78°C for 1.5h. Then a solution of DMF (2.33mL, 30.3 mmoles in ether (5 mL) was added at once and the reaction mixture was allowed to warm to RT and stirred overnight. Some ice was added to the reaction mixture and 4N HCl was added slowly. This was taken up in a separating funnel, 30mL of ether was added, and the mixture shaken. The organic layer was discarded. The aqueous layer was brought to pH~7.5 with solid NaHC0₃ and extracted with ether twice. The ether layer was dried over Na₂S0₄ and concentrated and the crude product 1.8.2 (1.6g) was carried over to the next-step without purification.

[0280] Ti (0'Pr)4 (1.3 eq) was added with stirring to MeNH₂ (2.0 M in MeOH, 3 eq) under Ar. After 5 min. the aldehyde 1.8.2 (1 eq) was added, and the solution was stirred for 1-2 h. The reaction was cooled to 0° C and the NaBH₄ (1.3 eq) was added. The solution was stirred at 0° C to RT overnight. After quenching the reaction with water the mixture was filtered through Celite to remove the white ppt. MeOH was removed in vacuo. The residue was diluted with EtOAc. The resulting solution was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganic material was filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded the pure product N-methyl-l-(5-methylthiazol-2-yl)methanamine in 80 % yield.

Example 1.1.9: tert-butyl methyl((4-methyloxazol-2-yl)methyl)carbamate

1.9.4 1.9.5 1.9.6

[0281] To a solution of L-Serine methyl ester hydrochloride (4.76 g, 30.54 mmoles), in

CH₂C1₂ (150mL) at 0°C, were added Et₃N ( 4.65 mL, 33.59 mmoles), Boc-D-Glycine (5.35 g, 30.54 mmoles), and DCC (6.92 g, 33.59 mmoles) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (80% ethyl acetate/ 30% chloroform) to yield 7.5 g of 1.9.1.

[0282] Deoxo-flour (5.51 mL , 29.89 mmoles) was added drop-wise to a solution of 1.9.1 (7.5 g, 27.17 mmoles) in CH₂CI₂ (200 mL) at -20°C. The solution was stirred for 30 min and BrCCl₃ (9.65 mL, 97.8 mmoles) was added drop-wise. The reaction was stirred at 2-3 °C, for 8h., quenched with Satd. Aq. NaHC0₃ solution and extracted with ethyl actetate. The organic layer was concentrated and chromatographed on silica gel (30% ethyl acetate/ 70% hexanes) to yield 2.95 g of 1.9.2.

[0283] To a solution of 1.9.2 (2.95 g, 11.5 mmoles) in THF (25 mL) at 0°C, was added LiBH₄ (17.2 mL, 2.0M in THF, 34.5 mmoles ) followed by EtOH (3.4 mL, 57.5 mmoles). The reaction was allowed to warm to room temperature and stirred for 3h. Ethyl acetate (l lmL) was added drop-wise and stirred for 30 min. The reaction was cooled to 0°C and 17 mL of IN HC1 was added drop- wise and diluted with 30 mL of water. It was then extracted with ethyl acetate, dried on Na₂S0₄, concentrated, and chromatographed on silica gel (3% MeOH / 97% chlorofrom) to yield 1.54 g of 1.9.3.

[0284] To a solution of TPP (3.54 g, 13.51 mmoles) in CH₂C1₂ ( 30 mL), was added I₂ (3.43 g, 13.51 mmoles), and stirred for 10 min. Imidazole (920 mg, 13.51 mmoles) was added and stirred for another 10 min and then a solution of 1.9.3 (1.54 g, 6.75 mmoles), in CH₂C1₂ (40 mL), was added. After 2h, the reaction mixture was washed successively with satd. aq. NaHC0₃, aq. Na₂S₂0₃, dried on Na₂S0₄ and concentrated under low pressure. The residue was chromatographed on silica gel (25% ethyl acetate/ 75% hexanes) to yield 1.81g of 1.9.4.

[0285] To a solution of 1.9.4 (1.81g, 5.34 mmoles) in HMPA (30 mL), was added

NaCNBH₃ (1.34 g, 21.36 mmoles). The reaction was stirred for 4h and poured into ice-cold water and extracted with hexanes. The organic layer was dried on Na₂S0₄, concentrated, and chromatographed on silica gel (10% ethyl acetate/ 90% hexanes) to yield 580 mg of 1.9.5.

[0286] To a stirred solution of 1.9.5 (380 mg, 1.78 mmol) in THF ( 8 mL ) at 0 °C, wered added 60 % NaH (86 mg, 2.14 mmol) and Mel (0.22 mL, 3.56 mmol). The reation was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with Na₂S₂0_3; brine, and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 175 mg of product tert-butyl methyl((4-methyloxazol-2-yl)methyl)carbamate.

Example 1.1.10: l-( 2,5-dimethyloxazol-4-yl ) -N-methylmethanamine

[0287] Ti(0^,PR)₄ (1. 08 mL, 3.69 mmoles) was added with stirring to MeNH₂ ( 4.3 mL, 2.0 M in MeOH, 8.5 mmoles ) at 0 °C under Ar. After 15 min the aldehyde ( 360 mg, 2. 83 mmoles) was added, and the reaction was stirred for 2-3 h. NaBH₄ (139 mg, 3.69 mmoles) was added in batches, and the reaction was stirred at 0° C to RT overnight. The solvent was removed via rotary evaporation. The residue was diluted with water/CH₂Cl₂. A white ppt formed and was removed via filtration through Celite. The layers were separated. The aqueous layer was extracted with CH₂C1₂ (x3) and the combined organics were dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation to give 300 mg of l-(2,5-dimethyloxazol-4-yl)-N-methylmethanamine.

Exam le 1.1.11: (3-methyl-l,2,4-oxadiazol-5-yl)methanamine

1.11.1 1.11.2 1.11.3

[0288] To a stirred solution of acetonitrile (5mL, 95 mmol) in a 4:1 mixture of EtOH and water (180mL) were added NaOH (4.26g, 107 mmol) and hydroxylamine hydrochloride ( 7.1g, 0.1 mmol) and the reaction was refluxed for 24h. It was then concentrated under reduced pressure. The white solid was dissolved in 150 mL of absolute EtOH and filtered to remove the inorganic salts. Concentration of the filtrate gave a crude white solid, which was recrystalized form isopropanol to obtain 3.2 g of 1.11.1.

[0289] To a stirred suspension of molecular sieves (3A°) in anhydrous THF (200mL) was added 1.11.1 (900mg, 10.0 mmol) and stirred for 15 min. NaH (1.3g, 32.0 mmol) wad added and the reaction was stirred for 45 min. Then Glycine methyl ester (1.89g, 10 mmol) was added and the reaction was refluxed overnight, cooled, filtered over celite and concentrated. The residue was dissolved in CH₂C1₂, washed with water, dried on Na₂S0₄ and concentrated. The residue was purified by column chromatography (40% EtOAc in hexanes) to provide 460 mg of 1.11.2. [0290] 1.11.2 was converted into (3-methyl-l,2,4-oxadiazol-5-yl)methanamine standard deprotection protocol of a Boc group with TFA.

Exampl

[0291] To a solution of 4-Methylthioazole-2-aldehyde (3.217 g, 25.296 mmol) in THF (100 mL) at room temperature was added t-butylamine (5.55 g, 75.89 mmol) and stirred at this temperature for overnight. The NaB(OAc)₃H (10.73 g, 50.593 mmol) was then added to the reaction in portions slowly, the resulting mixture was stirred for 16 hrs, diluted with EtOAc and washed with aqueous sodium bicarbonate, saturated aqueous sodium chloride, separated, dried (sodium sulfate) and concentrated to give the product as an oil which was purified with flash chromatography to produce the amine as an oil (3.9 g, 84%).

Example 1.1.13

[0292] Example 1.1.4 was synthesized using the same procedure as Example 1.1.2. 2- aminoethanol was purchased from Aldrich.

Exampl -((4-methylthiazol-2-yl)methyl)ethanamine

[0293] Ti(0'PR)₄ (Commercial source: sigma- aldrich) (2.9 g, 10.22 mmol) was added with stirring to EtNH₂(Commercial source: sigma- aldrich) (2.0 M in MeOH, 12 ml, 23.6 mmol) under Ar. After 5 min. the aldehyde ,4-methylthiazole-2-carbaldehyde (1.0 g, 7.86 mmol) (Commercial source: sigma- aldrich) was added, and the solution was stirred for 2 h. The reaction was cooled to 0° C and the NaBH₄ (418 mg, 11.0 mmol) was added. The solution was stirred at 0° C to RT overnight. After quenching the reaction with water the mixture was filtered through celite to remove the white precipitate. Then MeOH was removed in vacuo. The residue was diluted with EtOAc. The resulting solution was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded the pure N-((4-methylthiazol-2-yl)methyl)ethanamine in 50% yield.

Example 1.1.15: Synthesis of 1 -(3 -fluoropyridin-2-yl)-N-methylmethanamine

[0294] Ti(0'PR)₄ (Commercial source: sigma-aldrich) (2.95 g, 10.4 mmol) was added with stirring to MeNH₂(Commercial source: sigma-aldrich) (2.0 M in MeOH, 12 ml, 23.7 mmol) under Ar. After 5 min. the aldehyde, 3-fluoropicolinaldehyde (1.0 g, 7.99 mmol)

(Commercial source: sigma-aldrich) was added, and the solution was stirred for 2 h. The reaction was cooled to 0° C and the NaBH₄ (395 mg, 10.4 mmol) was added. The solution was stirred at 0° C to RT overnight. After quenching the reaction with water the mixture was filtered through celite to remove the white precipitate. Then MeOH was removed in vacuo. The residue was diluted with EtOAc. The resulting solution was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded the pure l-(3-fluoropyridin-2-yl)-N-methylmethanamine in 67% yield.

Example 1.1.16: Synthesis of N-methyl-1 -(4-(trifluoromethyl)thiazol-2-yl)methanamine

[0295] To the thioamide, 2-amino-2-thioxoethyl pivalate (3.0 g, 17.02 mmol) (Commercial source: Acros organics) in ethanol (10 ml), 3-bromo-l,l,l-trifluoropropan-2-one (3.23 g, 17.02 mmol) (Commercial source: Apollo scientific) was added and heated at 60°C for 24h. Then reaction mixture was cooled, DBU (2.59g, 17.02 mmol) was added and stirred at rt for 2d. Then volatiles were removed in vacuum, reaction mixture was partitioned between ethyl acetate and water. Organic layer was dried, evaporated and column purified to yield (4- (trifluoromethyl)thiazol-2-yl)methanol in 30% yield. [0296] To the alcohol, (4-(trifluoromethyl)thiazol-2-yl)methanol (245 mg, 1.34 mmol) in DCM (10 ml) at 0°C, DMP (681 mg, 1.61 mmol) was added. Reaction was allowed to come to rt and stirred for 3h. Then saturated sodium bicarbonate, hypo mixture was added and stirred for 10 min. Then reaction mixture was further diluted with DCM and product was extracted into DCM. Volatiles were removed under vacuum and the resulting aldehyde, 4- (trifluoromethyl) thiazole-2-carbaldehyde was carried to the next step without further purification.

[0297] Ti(0'PR)₄ (Commercial source: sigma-aldrich) (495 mg, 1.74 mmol) was added with stirring to MeNH₂(Commercial source: sigma-aldrich) (2.0 M in MeOH, 2 ml, 4.02 mmol) under Ar. After 5 min. the aldehyde, 4-(trifluoromethyl)thiazole-2-carbaldehyde (245 mg, 1.34 mmol) was added, and the solution was stirred for 2 h. The reaction was cooled to 0° C and the NaBH₄ (66 mg, 1.742 mmol) was added. The solution was stirred at 0° C to RT overnight. After quenching the reaction with water the mixture was filtered through celite to remove the white precipitate. Then MeOH was removed in vacuo. The residue was diluted with EtOAc. The resulting solution was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded the pure N-methyl-l-(4- (trifluoromethyl)thiazol-2-yl)methanamine in 37% yield overall for 2 steps.

Example 1.2: Synthesis of cyclic amine building blocks.

Example 1.2.1: (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole

[0298] To a solution of the commercially available (R)-l-(benzyloxycarbonyl)pyrrolidine- 2-carboxylic acid (Synthetech, 9.97g, 40.0 mmoles) in 1, 4-dioxane (60mL) was added pyridine (2mL), di-tert-butyl dicarbonate ((Boc)₂0) ( 11.35mL, 52 mmoles) and NH₄HCO₃ ( 3.98g, 50.4 mmoles) and stirred for 12h. All solvent was evaporated, diluted with EtOAc and washed with water, 5% H₂S0₄ and brine. The organic layer was dried over anhydrous Na₂S0₄ and concentrated. (R)-benzyl 2-carbamoylpyrrolidine-l-carboxylate was generated in quantitative yield and used in the following step without further purification.

[0299] To a solution of (R)-benzyl 2-carbamoylpyrrolidine-l-carboxylate (9.97g, 40.0 mmoles) in 1,2-dimethoxyethane (1,2-DME or DME) (2000mL) was added Lawesson's reagent (8.9g, 0.55 mmoles) and stirred for 4h. All solvent was evaporated, diluted with lOOmL of saturated NaHC0₃ and extracted with ether (2x200mL). The combined organic layers was dried over anhydrous Na₂S0₄ and concentrated. Crude (R)-benzyl 2- carbamothioylpyrrolidine-l-carboxylate was carried on to the next step without further purification.

[0300] To a solution of (R)-benzyl 2-carbamothioylpyrrolidine-l-carboxylate (~ 40 mmoles) in EtOH ( 120mL) was added chloroacetone (4.7 mL, 60 mmoles) and heated at 75 °C for 6h.The reaction was cooled to room temperature and poured into 100 mL of saturated aq. NaHC0₃ solution. Ethanol was evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (2x200mL). The combined organic layers was dried over Na₂S0₄ and concentrated. The residue was chromatographed on silica gel (35% ethyl acetate/ 80% hexane) to generate (R)-benzyl 2-(4-methylthiazol-2-yl)pyrrolidine-l-carboxylate in 86% yield after three steps.

[0301] HBr in AcOH (60mL) was added to (R)-benzyl 2-(4-methylthiazol-2-yl)pyrrolidine-

1- carboxylate (neat) at room temperature. After lh, ether (150 mL) was added slowly with vigorous strring. Stirring was continued for 10 min and allowed to settle for 5-10 min. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colourless. The semi-solid was dissolved in water (50 mL) and brought to P ~8 with IN LiOH and extracted with 5% MeOH/95% CHC1₃ (3xl00mL) to yield 4.0 g of (R)-4-methyl-

2- (pyrrolidin-2-yl)thiazole.

Example 1.2.2: (R)-4-methyl-2-(pyrrolidin-2-yl)oxazole

[0302] To a solution of L-Serine methyl ester hydrochloride (Aldrich, 5.0 g, 32.0 mmoles), in CH₂C1₂ (150 mL) at 0 °C, were added Et₃N (4.88 mL, 35.2 mmoles), Cbz-D-Proline (8.01 g, 32.0 mmoles) and Ν,Ν'-dicyclohexylcarbodiimide (DCC) (7.26 g, 35.2 mmoles) sequentially. The reaction was allowed to warm to room temperature and stirred overnight.

All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and

chromatographed on silica gel (70% ethyl acetate/ 30% chloroform) to yield 8.5g of (R)- benzyl 2-((S)-3-hydroxy-l-methoxy-l-oxopropan-2-ylcarbamoyl)pyrrolidine-l-carboxylate.

[0303] Deoxo-flour (4.5 mL , 24.16 mmoles) was added drop-wise to a solution of (R)- benzyl 2-((S)-3-hydroxy- 1 -methoxy- 1 -oxopropan-2-ylcarbamoyl)pyrrolidine- 1 -carboxylate

(8.5g, 22.0 mmoles) in CH₂C1₂ (150mL) at -20°C. The solution was stirred for 30 min and BrCCl₃ (7.8 mL, 79.0 mmoles) was added drop-wise followed by DBU (11.8mL, 79 mmoles). The reaction was stirred at 2-3 °C, for 10h., quenched with satd. aq. NaHC0₃ solution and extracted with ethyl actetate. The organic layer was concentrated and

chromatographed on silica gel (10% ethyl acetate/ 90% chloroform) to yield 6.95 of (R)- methyl 2-(l-(benzyloxycarbonyl)pyrrolidin-2-yl)oxazole-4-carboxylate.

[0304] To a solution of (R)-methyl 2-(l-(benzyloxycarbonyl)pyrrolidin-2-yl)oxazole-4- carboxylate (6.95g, 21.1 mmoles) in THF (50mL) at 0°C, was added LiBH₄ (32 mL, 2.0M in THF, 63.2 mmoles ). The reaction was allowed to warm to room temperature and stirred for 3h. Ethyl acetate (25mL) was added drop-wise and stirred for 30 min. The reaction was cooled to 0°C and 50 mL of IN HC1 was added drop- wise and diluted with 100 mL of water. It was then extracted with ethyl acetate, dried on Na₂S0₄, concentrated, and chromatographed on silica gel (3% MeOH / 97% chloroform) to yield 4.1g of (R)-benzyl 2-(4- (hydroxymethyl)oxazol-2-yl)pyrrolidine- 1 -carboxylate.

[0305] To a solution of (R)-benzyl 2-(4-(hydroxymethyl)oxazol-2-yl)pyrrolidine-l- carboxylate (l.lg, 3.64 mmoles) in HMPA (18mL), was added

methyltriphenoxyphosphonium iodide (3.29g, 7.28mmoles) and stirred for 30min.Then NaCNBH₃ was added and the reaction was heated at 50 °C for 3h and poured into lOOmL of ice-cold water and extracted with ether( 2X100mL). The organic layer was dried on Na₂S0₄, concentrated, and chromatographed on silica gel (50% ethyl acetate/ 50% hexanes) to yield 180mg of (R)-benzyl 2-(4-methyloxazol-2-yl)pyrrolidine-l -carboxylate.

[0306] HBr in AcOH (60mL) was added to (R)-benzyl 2-(4-methyloxazol-2-yl)pyrrolidine-

1 - carboxylate (neat) at room temperature. After lh, ether (20mL) was added slowly with vigorous strring. Stirring was continued for 10 min and allowed to settle for 5-10 min. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colourless. The semi-solid was dissolved in water (50 mL) and brought to pH ~8 with IN LiOH and extracted with 5% MeoH/95% CHC1₃ (3X100 mL) to yield 55 mg of (R)-4-methyl-

2- (pyrrolidin-2-yl)oxazole. Example 1.2.3: 2-((2R,4S)-4-fluoropyrrolidin-2-yl)-4-methylthiazole

[0307] To the alcohol 2.3.1 (5.0 g, 20.38 mmol) in dichloromethane (DCM) (50 ml) at - 78°C, deoxofluor (Commercial source: sigma-aldrich) was added. Then the reaction mixture was allowed to come to room temperature (rt) and stirred at rt for 12h. Then the reaction mixture was quenched with saturated aq sodium carbonate solution at 0°C, warmed to rt. Then the reaction mixture was extracted with ethyl acetate. Organic layer was washed with water, brine and dried. Crude residue was column chromatographed to obtain 3.05 g of the ester 2.3.2.

[0308] To the ester 2.3.2 (3.05, 12.33 mmol) in MeOH (20 ml), THF (20 ml), aq sodium hydroxide (986 mg, 24.66 mmol) was added. After 2h, volatiles were removed in vacuum. Aqueous layer's pH was adjusted to about 3 with concentrated HC1, and reaction mixture was extracted with MeOH/CHCl₃ (1:9). Combined organic layers were washed with brine, dried and concentrated to yield 2.8 g of the acid 2.3.3.

[0309] To the acid 2.3.3 (2.07 g, 8.87 mmol) in dioxane (20 ml) pyridine (Commercial Source: sigma-aldrich) (1 ml), (Boc)₂0 (Commercial source: sigma-aldrich) (2.52 g, 11.53 mmol), followed by sodium bicarbonate (882 mg, 11.2 mmol). Reaction mixture was stirred overnight at rt , then volatiles were removed in vacuum. Then reaction mixture was partitioned between chloroform and water. Organic layer was dried and evaporated to obtain the amide 2.3.4 in quantitative yield.

[0310] La wesson's reagent (Commercial source: sigma-aldrich) (1.98 g, 4.90 mmol) was added to the amide 2.3.4 (2.07 g, 8.91 mmol) in DME (Commercial source: sigma-aldrich) (30 ml) and the reaction mixture was stirred overnight at rt. Then volatiles were removed in vacuum and the reaction mixture was partitioned between ether and water. Ether layer was concentrated and column purified to obtain 1.74 g of the thioamide 2.3.5. [0311] To the thioamide 2.3.5 (1.7 g, 6.85 mmol) in ethanol (20 ml), calcium carbonate (2.06 g, 20.55 mmol) was added, followed by chloroacetone (Commercial source: sigma- aldrich) (955 mg, 10.27 mmol). After heating at 70°C for 5h, volatiles were removed in vacuum. Reaction mixture was filtered and partitioned between water and ether. Organic layer was dried and evaporated. To the crude residue 4N HCl/dioxane (Commercial source: sigma-aldrich) (4 ml) was added and stirred at rt for 3h. Then volatiles were removed in vacuum and reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. Oragnaic layer was dried, evaporated and column purified to yield 900mg of the proline 2.3.6.

Example 1.2.4: (R)-2-(4,4-difluoropyrrolidin-2-yl)-4-methylthiazole

BOC₂0

Py,

NH4HCO3

[0312] To an ice-cold solution of 4-(R)-hydroxyl-2-(R)-hydroxymethylpyrrolidine- lcarboxylic acid tert-butyl ester (9.81 g, 40.93 mmol) in DMSO (50 mL) was added

triethylamine (16.2 mL, 163.73 mmol) and sulfurtrioxide-pyridine complex (12.73 g, 81.87 mmol). The resulting mixture was stirred 30 min, warmed to room temperature and stirred 30 min, diluted with diethyl ether and washed with 5% aqueous citric acid, saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated to give the title compound as an oil which was purified with flash chromatography to produce the ketone (7.5 g). 1H NMR (300 MHz, CDCI3), δ: 4.818-4.673 (m, 1 H), 3.903 (s, 1 H), 3.871(s, 1 H), 3.749 (s, 3 H), 3.003- 2.862 (m, 1 H), 2.605-2.542 (m, 1 H), 1.468, 1.445 (s, 9 H).

[0313] To a solution of 4-oxopyrrolidine-N-l,2-(R)-dicarboxylic acid 1 -tert-butyl ester 2- methyl ester (7.5 g, 35.76 mmol) in dichloromethane (80 mL) at -78°C was added Deoxo- Fluor (17 mL, 1.07 mol). The resulting mixture was stirred and warmed to room temperature for overnight, then was cooled in ice bath diluted with chloroform and quenched with saturated sodium bicarbonate solution. Warmed to room temperature, separated and dried (magnesium sulfate), concentrated and purified with silica gel chromatography to give the compound as an oil (6.47 g). 1H NMR (300 MHz, CDC1₃), δ: 4.568-4.422 (m, 1 H), 3.894- 3.725 (m, 2 H), 3.767(s, 3 H), 2.798-2.601 (m, 1 H), 2.553-2.385 (m, 1 H), 1.470, 1.422 (s, 9 H).

[0314] To the ester (6.2 g, 23.37 mmol) in THF (60 ml), aq sodium hydroxide (8 ML of 1 M solution, 15 ML of water, 32 mmol) was added. After 3 h, volatiles were removed in vacuum. Aqueous layer was adjusted to about PH = 3 with 3 M HC1 solution, and reaction mixture was extracted with ethyl acetate three times. Combined organic layers were washed with brine, dried and concentrated to yield a white solid (5.55 g), which was used for the next step without further purification and identification.

[0315] To the crude acid (5.55 g, 22.08 mmol) in dioxane (50 ml) were added pyridine (Commercial source: Sigma- Aldrich) (1.25 ml), (Boc)₂0 (Commercial source: Sigma- Aldrich) (6.75 g, 30.92 mmol), followed by ammonium bicarbonate (2.36 g, 29.82 mmol). The resulting reaction mixture was stirred overnight at rt, then volatiles were removed in vacuum. Then reaction mixture was dissolved in ethyl acetate, washed with aqueous diluted HC1 (1 M), sodium bicarbonate and brine. Organic layer was dried and evaporated to obtain the amide in quantitative yield 5.6 g), which was used for the next step without further purification and identification.

[0316] Lawesson's reagent (Commercial source: Sigma- Aldrich) (5.41 g, 13.37 mmol) was added to the amide (5.6 g, 22.28 mmol) in DME (Commercial source: Sigma-Aldrich) (100 ml) and the reaction mixture was stirred overnight at rt. Then volatiles were removed in vacuum and the reaction mixture was partitioned between ether and water. Ether layer was concentrated and column purified to obtain 4.6 g of thioamide.

[0317] To the thioamide (4.6 g, 17.21 mmol) in ethanol (50 ml) was added chloroacetone (Commercial source: sigma- aldrich) (2.3 g, 25.81 mmol). After heating at 75 °C for 5h, volatiles were removed in vacuum. Reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate. Organic layer was dried and evaporated. To the crude residue 4N HCl/dioxane (Commercial source: Sigma-Aldrich) (10 ml) was added and stirred at rt for 3h. Then volatiles were removed in vacuum and reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. Organic layer was dried and evaporated to yield 1.2 g of the desired product amine. 1H NMR (300 MHz, CDC1₃), δ: 6.818 (s, 1 H), 4.733 (t, / = 7.8 Hz, 1 H), 3.345-3.301 (m, 2 H), 2.861-2.710 (m, 1 H), 2.596-2.413 (m, 1 H), 2.420 (s, 3 H).

Ex (R)-2-(piperidin-2-yl)-4-methylthiazole

2-5.7 2.5.8 2.5.9

[0318] Methyl thiazole-piperidine ligand 2.5.9 was prepared following the same procedure as in the preparation of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole starting from the

commercially available R-N-Boc-2-piperidine 2.5.7 (Aldrich) carboxylic acid to obtain 2.5.8 which was deprotected using standard TFA conditions to obtain 2.5.9.

Example 1.2.6: 2-(5-methylfuran-2-yl)pyrrolidine

[0319] 2-(5-methylfuran-2-yl)pyrrolidine was purchased from ACB Blocks.

Exam -4-methyl-2-(pyrrolidin-2-yl)thiazole

2.7.5 2.7.4

[0320] To a solution of 2.7.1 (9.97g, 40.0 mmoles) in 1, 4-dioxane (60mL) were added pyridine (2mL), (Boc)₂0 (11.35mL, 52 mmoles) and NH₄HC0₃ ( 3.98g, 50.4 mmoles) and stirred for 12h. All solvent was evaporated, diluted with EtOAc and washed with water, 5% H₂S0₄ and brine. The organic layer was dried over anhydrous Na₂S0₄ and concentrated. The crude yield of 2.7.2 was quantitative. This was not purified.

[0321] To a solution of 2.7.2 (9.97g, 40.0 mmoles) in 1, 2-DME (2000mL) was added Lawesson' s reagent (8.9g, 0.55 mmoles) and stirred for 4h. All solvent was evaporated, and diluted with lOOmL of saturated NaHC0₃ and extracted with ether (2 x 200mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated. The crude 2.7.3 was carried on to the next step.

[0322] To a solution of 2.7.3 (~ 40 mmoles) in EtOH (120mL) was added chloroacetone (4.7 mL, 60 mmoles) and heated at 75°C for 6h.The reaction was cooled to room temperature and poured into 100 mL of saturated aq. NaHC0₃ solution. Ethanol was evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (2 x 200mL). The combined organic layers were dried over Na₂S0₄ and concentrated. The residue was chromatographed on silica gel (35% ethyl acetate/ 80% hexane) to yield 86% of 2.7.4 after three steps.

[0323] HBr in AcOH (60mL) was added to 2.7.4 (neat) at room temperature. After lh, ether (150mL) was added slowly with vigorous strring. Stirring was continued for 10 min and allowed to settle for 5-10 min. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colourless. The semi-solid was dissolved in water (50 mL) and brought to pH~8 with IN LiOH and extracted with 5% MeoH/95% CHC1₃ (3 x lOOmL) to obtain 4.0g of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole.

Example 1.2.8: 2-((2R,4S)-4-fluoropyrrolidin-2-yl)-4-methylthiazole

[0324] 2-((2R,4S)-4-fluoropyrrolidin-2-yl)-4-methylthiazole was synthesized using the procedure described in Example 1.2.7.

Example 1.2.9: (R)-4-(4-methylthiazol-2-yl)oxazolidine

[0325] To a solution of commercially available D-Serine hydrochloride 2.9.1(3.0g, 24.8 mmoles) in H₂0 (8 mL) at room temperature, was added 37% solution of formaldehyde

(817mg, 27.3 mmoles) and stirred for 24h. Then NH₂OH.HCl (172 mg, 2.48 mmoles), NaOH

(50mL, 2N, 100 mmoles), acetone (50mL), and (Boc)₂0 (6.27 mL, 27.28 mmoles) were added and stirred for 12h. The reaction mixture was extracted with ether. The aqueous layer was acidified to pH~3.5 with IN HC1 and then extracted with 5% MeOH/95% CHC1₃ (3 x lOOmL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to yield 2.49g of crude 2.9.2.

[0326] 2.9.2 was converted into (R)-4-(4-methylthiazol-2-yl)oxazolidine using the procedure described in Example 1.2.7.

Example 1

[0327] tert-Butyl (2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidine-l-carboxylate: To a stirred solution of tert-butyl (2R)-2-carbamothioylpyrrolidine-l-carboxylate (200 mg, 0.868 mmol) in EtOH (8 ml) were added 2-bromo-l-cyclopropylethanone (315 mg, 1.74 mmol) and CaC0₃ (261 mg, 2.61 mmol) at rt and the mixture was stirred at 80 degree for 5 min.

Volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 0 to 66%) to give tert-butyl (2R)-2-(4-cyclopropyl-l,3-thiazol-2- yl)pyrrolidine-l-carboxylate (230 mg, 90% yield) as a colorless oil. MS (ESI) m/z: 295

[M+H]⁺.

[0328] 4-Cyclopropyl-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole: A solution of tert-butyl (2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidine-l-carboxylate (230 mg, 0.781 mmol) and TFA (1 ml) in CH₂CI₂ (2 ml) was left at rt for 2 hours and volatiles were evaporated to give a crude, which was dissolved in CHC1₃. This mixture was washed with satd. NaHC0₃ aq., dried over MgS0₄ and evaporated to give a crude of 4-cyclopropyl-2-[(2R)-pyrrolidin-2-yl]- 1,3-thiazole (120 mg, 79% yield) as a free form, which was used for the next reaction without further purification. MS (ESI) m/z: 195 [M+H]⁺.

Example 1

[0329] tert-Butyl (2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidine-l-carboxylate: The desired compound was synthesized from tert-butyl (2R)-2-carbamothioylpyrrolidine-l- carboxylate (220 mg, 0.955 mmol) in a similar manner to Example 1.2.10. (228 mg, 85% yield) MS (ESI) m/z: 283 [M+H]⁺.

[0330] 4-Ethyl-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole: The desired compound was synthesized from tert-butyl (2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidine-l -carboxylate (228 mg, 0.807 mmol) in a similar manner to Example 1.2.10. (103 mg, 70% yield) MS (ESI) m/z: 183 [M+H]⁺.

Example 1.2.12

[0331] tert-Butyl (2R)-2-[4-(chloromethyl)-l,3-thiazol-2-yl]pyrrolidine-l-carboxylate:

The desired compound was synthesized from tert-butyl (2R)-2-carbamothioylpyrrolidine-l- carboxylate (200 mg, 0.868 mmol) in a similar manner to Example 1.2.10. (262 mg, >99% yield) MS (ESI) m/z: 303 [M+H]⁺.

Exampl

[0332] tert-Butyl (2R)-2-[4-(methoxymethyl)-l,3-thiazol-2-yl]pyrrolidine-l- carboxylate: To a stirred solution of tert-butyl (2R)-2-[4-(chloromethyl)-l,3-thiazol-2- yl]pyrrolidine-l -carboxylate (262 mg, 0.865 mmol) in MeOH (5 ml) was added K₂CO₃ (598 mg, 4.33 mmol) at rt and the mixture was stirred at 70 degree for 3 hours. The starting molecule was completely consumed in 3 hours and volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 0 to 66%) to give tert- butyl (2R)-2-[4-(methoxymethyl)-l,3-thiazol-2-yl]pyrrolidine-l-carboxylate (64 mg, 25% yield). MS (ESI) m/z: 299 [M+H]⁺.

[0333] 4-(Methoxymethyl)-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole trifluoroacetate (1:1):

To a stirred solution of tert-butyl (2R)-2-[4-(methoxymethyl)-l,3-thiazol-2-yl]pyrrolidine-l- carboxylate (64 mg, 0.219 mmol) in CH₂CI₂ (2 ml) was added TFA (1 ml) at rt and the mixture was left at rt for 2 hours. Volatiles were evaporated to give a crude of 4- (methoxymethyl)-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole trifluoroacetate (1:1) which was used for the next reaction without further purification. MS (ESI) m/z: 199 [M+H]⁺.

Example 1.3: Synthesis of isophthalate building blocks.

Example 1.3.1

[0334] To a stirred solution of dimethyl 5-aminoisophthalate (Aldrich, 2.09 g, 10 mmol) in dichloromethane (30 mL), pyridine (2.43 mL, 30 mmol) was added at room temperature. At 0 °C, methanesulfonyl chloride (0.86 mL, 11 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and ethyl acetate (50 mL) was added. The resulting white precipitate was filtered and washed with hexanes to give dimethyl 5-(methylsulfonamido)isophthalate in 95% (2.715 g) yield as a white solid.

[0335] To a stirred suspension of NaH (0.24 g, 10 mmol, 60% in oil dispersion) in 10 mL of DMF was added dimethyl 5-(methylsulfonamido)isophthalate (1.435 g, 5 mmol) followed by iodomethane (0.62 mL, 10 mmol) at room temperature. After 5 h, the reaction was quenched by H₂0 (25 mL). Then the reaction mixture was extracted with EtOAc, further washed with H₂0 to remove excess of DMF, dried over anhydrous Na₂S0₄ and concentrated. The crude product thus obtained was washed with hexanes to give dimethyl 5-(N- methylmethylsulfonamido)isophthalate as a white solid in 91% (1.37 g) yield.

[0336] Dimethyl 5-(N-methylmethylsulfonamido)isophthalate (0.842 g, 2.8 mmol) was dissolved in THF:MeOH (1:1) (8 mL) and H₂0 (3 mL). Solid NaOH (0.112 g, 2.8 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. Saturated NaHC0₃ (10 mL) was added to the reaction mixture and extracted with toluene (to remove <10% unreacted starting material). The aqueous solution was acidified with dilute HC1 (10%), extracted with EtOAc, and dried over anhydrous Na₂S0_4. The solvent was evaporated and dried under reduced pressure to give 3- (methoxycarbonyl)-5-(N-methylmethylsulfonamido)benzoic acid as a white solid (75%, 0.598 g), which was used without further purification. Example 1.3.2

3.2.10 3.2.11

[0337] A solution of the starting material (1.0 g, 4.78 mmol, 1 eq) in anhydrous CH₂CI₂ (10 ml) was cooled to -78 °C. Tf₂0 (0.88 ml, 1.48 g, 5.26 mmol, 1.1 eq was added dropwise with stirring. The reaction was stirred at -78 °C to room temperature overnight. The reaction was quenched with saturated aqueous NaHC0₃ and diluted with EtOAc. The layers were separated. The organic layer was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation.

Purification via flash chromatography on silica gel yielded 0.8979 g (2.63 mmol, 55%) of

3.2.10.

[0338] A stirred solution of 3.2.10 (0.6013 g, 1.76 mmol, 1 eq) in anhydrous DMF (5 ml) was treated with Mel (0.22 ml, 0.5 g, 3.52 mmol, 2 eq). The resulting solution was protected from light and cooled to 0 °C. NaH (60% dispersion in oil, 0.1057 g, 2.64 mmol, 1.5 eq) was added and the reaction was stirred at 0 °C to room temperature overnight. The reaction was quenched with saturated aqueous NaHC0₃ and the resulting mixture diluted with

EtOAc/H₂0. The layers were separated. The organic layer was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.5693 g (1.60 mmol, 91%) of 3.2.11.

Example 1.3.3

[0339] To dimethyl 5-bromoisophthalate (Matrix Scientific, 617 mg, 2.26 mmol) in toluene (10 ml), 2-tributylstannyl pyrazine (lg, 2.71 mmol) was added followed by Pd(PPh₃)₄ (102 mg, 0.09 mmol). Then reaction mixture was refluxed for 22h. Then the reaction mixture was filtered through celite and volatiles were removed under vacuum. Crude residue was column chromatographed (50% ethylacetate/50 % Hexanes) to obtain 455 mg of dimethyl 5-(pyrazin- 2-yl)isophthalate as a pale yellow solid.

Example 1.3.4

[0340] 2,5-dimethoxytetrahydrofuran (0.74 ml, 0.76 g, 5.74 mmol, 1.2 eq) was added to a stirred suspension of dimethyl 5-aminoisophthalate (Aldrich, 1.0 g, 4.78 mmol, 1 eq) in 7 ml acetic acid under Ar. The mixture was heated to reflux at 135 °C. After 45 min the reaction was cooled to RT, and the solvent was removed in vacuo. The residue was stirred in saturated aqueous NaHC0₃/EtOAc overnight. The layers were separated. The organic layer was washed with saturated aqueous NaHC0₃ (xl), water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo.

Purification via flash chromatography yielded 1.00 g (4.6 mmol, 80% yield) of dimethyl 5- (lH-pyrrol-l-yl)isophthalate.

Example 1.3.5

[0341] CH₂0 (aq, 37%) (3.2 ml, 3.49g, 43.0 mmol, 6 eq) was added to a stirred solution of dimethyl 5-aminoisophthalate (1.5 g, 7.17 mmol, 1 eq) in CH₃CN (50 ml) at 0 °C. After 15 min NaBH₃CN (1.09 g, 16.49 mmol, 2.3 eq) was added. The reaction was adjusted to pH ~ 7 with HOAc. Stir at 0 °C to RT overnight. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NaHC0₃. The layers were separated. The organic layer was washed with water (x3), brine(xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 1.62 g (6.83 mmol, 95% yield) of dimethyl 5- (dimethylamino)isophthalate. Example 1.3.6

[0342] The diester (1.00 g, 4.78 mmol, 1 eq) and glyoxal trimer · 2H₂0 (1.004 g, 4.78 mmol, 1 eq) were stirred in 6 ml EtOH overnight. NH₄C1 (0.5114 g, 9.56 mmol, 2 eq) was added. After 15 min aqueous formaldehyde (37%, 0.71 ml, 0.78 g, 9.56 mmol, 2 eq) was added and the mixture was heated to reflux at 90 °C. After 1 h the reaction was cooled to room temperature. After the dropwise addition of H₃PO₄ (85%, 0.65 ml, 1.1 g, 9.56 mmol, 2 eq) the reaction was heated to reflux at 95 °C. After 6 h the reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was stirred in CHCI₃ and the mixture was filtered through cotton to remove any insoluble material. Purification via flash chromatography yielded 0.7329 g (2.82 mmol, 59% yield) of the product.

Example 1.3.7

[0343] A solution of (NH₄)₂Ce(N0₃)6 (7.6 g, 12.6 mmol, 2 eq) in water (16 ml) was added dropwise to a stirred solution of the diester (1.6 g, 6.3 mmol, 1 eq) in HO Ac (16 ml). The reaction was heated to 70 °C. After 90 min the reaction was cooled to room temperature. The reaction was diluted with water and extracted with EtO Ac (xl). The organic layer was washed with saturated aqueous NaHC0₃ (x4), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off and the solvent was removed in vacuo yielding 1.3 g (5.19 mmol, 82% yield) of the product.

[0344] NH₃ (2.0 M in MeOH, 4.8 ml, 9.6 mmol, 8 eq) was added to a flask charged with the diester (0.300 g, 1.2 mmol, 1 eq) and glyoxal trimer · 2H₂0 (0.252 g, 1.2 mmol, leq) at 0 °C under Ar. The reaction was stirred at 0 °C to room temperature overnight. The solvent was removed in vacuo. The residue was stirred in EtO Ac and filtered through cotton to remove any insoluble material. Purification via flash chromatography yielded 0.1293 g (0.45 mmol, 37% yield) of the product. Example 1.3.8

[0345] To a stirred solution of the aldehyde (529 mg, 2.1 mmol) and p- toluenesulfonylmethyl isocyanide (483 mg, 2.5 mmol) in DME (15 mL) and MeOH (15 mL) was added K₂CO₃. The resulting mixture was heated to reflux for 4 h and cooled to room temperature. The solvent was removed and the residue was dissolved in EtOAc and H₂0. The layers were separated and the aqueous layer was extracted with EtOAc (2 x20 mL). The combined organic layer was washed with brine, dried with Na₂S0₄ and concentrated under reduced pressure to provide 9 (103 mg, 19%). 1H NMR (CDC1₃) δ 8.63 (s, 1H), 8.49 (s, 2H), 8.00 (s, 1H), 7.54 (s, 1H), 4.00 (s, 6H).

Exam le 1.3.9

[0346] One drop of Et₃N (catalytic) was added to a stirred solution of 4-chlorobutanoic acid (.029 ml, 0.35 g, 2.87 mmol 1.2 eq) in SOCl₂ (2 ml, 3.27 g, 27.5 mmol, 11.5 eq) and the mixture was heated to 80 °C. After 1.5 h the reaction was cooled to room temperature, and the solvent was removed in vacuo. The flask was evacuated and back-filled with Ar (x3). The residue was dissolved in 2 ml anhydrous CH₂C1₂. The resulting solution was added dropwise to a stirred suspension of dimethyl 5-aminoisophthalate in 8 ml anhydrous CH₂C1₂. After 1 h Et₃N (1 ml, 0.73 g, 7.17 mmol, 3 eq) was added. After 2h the solvent was removed in vacuo, and the resulting residue was dissolved EtOAc. The organic layer was washed with saturated aqueous NaHC0₃ (x2), water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.6353 g (2.0 mmol, 85% yield) of dimethyl 5-(4- chlorobutanamido)isophthalate.

[0347] A solution of dimethyl 5-(4-chlorobutanamido)isophthalate (0.635 g, 2.02 mmol, 1 eq) dissolved in 5 ml anhydrous DMF was added dropwise to a stirred suspension of NaH (60% dispersion in oil, 0.101 g, 2.53 mmol, 1.25 eq) in 2 ml anhydrous DMF at 0 °C under Ar. The reaction was stirred at 0 °C to room temperature overnight. After stirring overnight the reaction was heated to 100 °C for 19 h. After cooling to room temperature the reaction was poured into ice-water to quench. The mixture was extracted with EtOAc (xl). The organic layer was washed with water (x4), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash

chromatography yielded 0.3487 g (1.26 mmol, 62% yield) of dimethyl 5-(2-oxopyrrolidin-l- yl)isophthalate.

Example 1.3.10

[0348] A mixture of 5.0 g (32.2 mmol) of citrazinic acid (Aldrich), 3.9 g (35.6 mmol) of Me₄NCl, and 9 mL of POCl₃ was stirred with gradual heating to 130 °C under a CaCl₂ drying tube for about 16h. MeOH (100 mL) was added with ice bath cooling; after 1 h, solid NaHC0₃ was added to pH = 8. Water was added, and the aqueous layer was extracted with EtOAc (2x). The combined extracts were washed with brine (100 mL), dried over Na₂S0₄, filtered, and concentrated. Purification by flash silica gel chromatography (10%

EtOAc/hexanes) pro the dichloride as a pink solid in 64% yield.

[0349] To a stirring solution of (7.33 mmol) of the methyl ester in 25 mL of MeOH and 5 mL of THF at 0 °C was added (21.7 mmol) of NaBH₄. After 2 h the ice bath was removed and stirring was continued with warming to r.t. and after a further 15 min. 1.06 g of NaBH₄ was added. After another 15 min., the solution was concentrated, and EtOAc was added. The pH was adjusted to 7 with IN HC1, and the layers were separated. The aqueous layer was extracted with EtOAc (2x), and the combined extracts were washed with brine (50 mL), dried over Na₂S0₄, filtered, and concentrated. Purification by flash silica gel

chromatography yielded the crude alcohol.

[0350] A mixture of crude alcohol in 7 mL of (CH₃)₂NH (40 wt % solution in H₂0) was stirred at r.t. for 45 min. The temperature was increased to 50 °C, and the solution was stirred at 50 °C for about 24 h. Ethyl acetate and H₂0 (15 mL) were added, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na₂S0₄, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) provided 1.01 g of the Ν,Ν-dimethylaminopyridine with some impurity (unreacted starting material).

[0351] To a stirring solution of the Ν,Ν-dimethylaminopyridine in 7 mL of pyridine was added 1.2 mL of Ac₂0. After the solution was stirred for 12 h, the solution was concentrated, and saturated NaHC0₃ solution was added to pH = 7. The aqueous layer was extracted with EtOAc, and the organic layer was washed with H₂0 (15 mL) and brine (15 mL), dried over Na₂S0₄, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided the acetate as a yellow oil with some impurity.

[0352] To a solution of 1.17 g (5.10 mmol) of the acetate in 10 mL of DMF (degassed) was added 488 mg (4.16 mmol) of Zn(CN)₂ and 519 mg (0.449 mmol) of Pd(PPh₃)₄. The mixture was stirred at 80 °C and more Pd(PPh₃)₄ was added in the following quanitities at various intervals in a period of 10 h: 486 mg (50 min.), 708 mg (3 h), 657 mg (6 h). The temperature was increased to 100 °C and stirring was continued for about 11 h. Ethyl acetate and 50 mL of 10% NH₄OH solution were added. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine. The aqueous layer (brine) was extracted with EtOAc, and the combined extracts were dried over Na₂S0₄, filtered, and concentrated.

Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 284 mg of the cyanide as a pale yellow solid.

[0353] To a stirring solution of 364 mg (1.66 mmol) of the acetate in 7 mL of MeOH was added 365 mg (2.64 mmol) of K₂C0₃. After 1 h, the mixture was filtered through Celite with MeOH and EtOAc. More EtOAc and H₂0 (30 mL) were added; the aqueous layer was extracted with EtOAc (4x). The combined extracts were washed with brine (50 mL), dried over Na₂S0₄, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) provided 253 mg of the pale yellow solid in 86% yield.

[0354] A mixture of 440 mg of the cyanide in 3 mL of concentrated H₂S0₄ and 1.8 mL of H₂0 was stirred at 135 °C for 12 h. The temperature was decreased to 95 °C, 6 mL of MeOH was added, and the solution was stirred at 95 °C for 1 h. The solution was added to ice with H₂0 and EtOAc. Solid NaHC0₃ and sat. NaHC0₃ solution were added to a pH=8. The aqueous layer was extracted with EtOAc (2x). The combined extracts washed with brine (40 mL), dried over Na₂S0₄, filtered and concentrated to give the methyl ester which was used without further purification.

[0355] A mixture of 250 mg (1.19 mmol) of the alcohol and 1.12 g (12.8 mmol) of Mn0₂ in 10 mL of CH₂C1₂ was stirred at 50 °C. To the mixture was added more Mn0₂ in the following quanitities at various intervals in a period of 75 min.: 674 mg (15 min.), 788 mg (15 min.), 924 mg (10 min.), 675 mg (15 min.), 690 mg (15 min.). The mixture was filtered through Celite with EtOAc and MeOH and concentrated. The acid was used in the next reaction without further purification.

Example 1.3.11

[0356] KMNO₄ (19.15 g, 121.2 mmol, 6.6 eq) followed by the anisole (Aldrich, 2.6 ml, 2.5 g, 18.36 mmol, 1 eq) were added to a stirred solution of KOH (3.30 g, 58.74 mmol, 3.2 eq) in 98 ml of water. The reaction was heated to 80 °C. After 3 h the reaction was cooled to room temperature. The mixture was filtered through Celite. The solution was adjusted to pH ~ 7 with concentrated HC1 and again the mixture was filtered through Celite. The solution was adjusted to pH = 2-3 with concentrated HC1 and extracted with EtOAc (x2). The combined organics were washed with brine (xl) and dried over Na₂S0₄. The inorganics were filtered off and the solvent was removed via rotary evaporation yielding 1.552 g (7.91 mmol, 43% yield) of the product.

[0357] SOCl₂ (1.85 ml, 3.03 g, 25.5 mmol, 10 eq) was added dropwise with stirring to a solution of the diacid (0.500 g, 2.55 mmol, 1 eq) in 10 ml anhydrous MeOH at 0 °C under Ar. The reaction was stirred at 0 °C to room temperature overnight. The solvent was removed via rotary evaporation and the residue dissolved in EtOAc. The solution was washed with saturated aqueous NaHC0₃ (x2), water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off and the solvent was removed via rotary evaporation yielding 0.6785 g (3.01 mmol, 118% yield) of the product with some impurities.

[0358] BBr₃ (1.0M in CH₂C1₂, 7.53 ml, 7.53 mmol, 2.5 eq) was added dropwise to a stirred solution of the anisole (0.6785 g, 3.01 mmol, 1 eq) in anhydrous CH₂C1₂ (4 ml) at 0 °C under Ar. After 30 min the reaction was warmed to room temperature. After 2 h the reaction was quenched anhydrous MeOH (1 ml) and stirred overnight. The solvent was removed via rotary evaporation and the residue dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHC0₃ (x2), water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification via flash chromatogr of the product.

[0359] Benzyl bromide (0.34 ml, 0.49 g, 2.89 mmol, 1.5 eq) was added to a stirred suspension of the phenol (0.4045 g, 1.92 mmol, 1 eq) and K₂C0₃ (0.5317 g, 3.85 mmol, 2 eq) in anhydrous DMF (2 ml) under Ar. After 48 h the reaction was diluted with Et₂0. The mixture was washed with water (x4), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification via flash chromatography yielded 0.5207 g (1.73 mmol, 90% yield) of the product.

Example 1.3.12

3.12.12 3.12.13

[0360] To a solution of dimethyl 5-iodoisophthalate 3.12.12 (Commercial source: Matrix Scientific) (2 g, 6.25 mmol) in 15 mL THF was added 2-cyano-phenyl zinc bromide

(Commercial source: sigma-aldrich), (15 mL, 7.5 mmol, 0.5 M THF) and

tetrakis(triphenylphosphine) palladium (Commercial source: sigma-aldrich), (71 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 2 h. The precipitated solid was filtered, the filtrate was diluted with MeOH to provide after filtration a second crop for a total of 1.2 g of dimethyl 5-(2-cyanophenyl)isophthalate 3.12.13. Example 1.3.13

3.13.14 3.13.15

[0361] To a mixture of the bromo compound 3.13.14 (2.1g, 8.0 mmol) (Commercial source: Matrix Scientific), l-Methyl-4-pyrazoelboronic acid pinacol ester (2.0 g, 9.61 mmol) (Commercial source: sigma-aldrich)and K₂ CO₃ (3.32 g, 24.0 mmol) (Commercial source: sigma-aldrich) in 40 ml of dioxane and 16 ml of water dichloro [1,1 '-bis

(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (653 mg, 0.80 mmol) (Commercial source: sigma-aldrich) was added. The reaction mixture was heated at 80°C for 6h, then concentrated in vacuo. The residue was purified by flash column chromatography with 70% ethyl acetate/30 % Hexanes to obtain 1.3 g of 3.13.15 as a brown solid.

Example 1.3.14

3.14.16 3.14.17

[0362] To the iodo compound (commercial source: Matrix Scientific) 3.14.16 (800 mg, 2.5 mmol) in THF (20 ml), 2-pyridine boronic acid N-phenyldiethanol amine ester (commercial source: Aldrich) (1.8 g, 6.6 mmol), K₂CO₃ (912 mg, 6.6 mmol), triphenyl phosphine (173 mg, 0.66 mmol) were added followed by Pd(OAc)₂ and cuprous iodide (251 mg, 1.32 mmol). After refluxing for 24h, reaction mixture was filtered through a pad of celite. Residual solvent was evaporated on a rotavap under reduced pressure and the crude was dissolved in ethyl acetate. Insoluble material was filtered off and the remaining residue was evaporated to dryness and column purified (60%ethylacetate/40% hexanes) to yield 400 mg of 3.14.17 as yellow solid.

I l l Example 1.3.15

3.15.18 3.15.19 3.15.20

[0363] To the acid 3.15.18 (3.0 g, 11.28 mmol) in DCM (30 ml), 1-hydroxybenzotriazole (HOBT) (1.83 g, 13.54 mmol) and l-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDCI or EDC) (3.03 g, 15.79 mmol) were added. After stirring for lh at rt, reaction mixture was cooled and acetyl hydrazide (commercial source: Sigma- Aldrich) (834 mg, 11.28 mmol) was added followed by DIPEA (0.5 ml). After stirring at rt for 16h, DCM was removed in vacuum. EtOAc was added to the crude followed by saturated aqueous sodium bicarbonate solution. White precipitate formed. The precipitate was filtered, washed with water and dried thoroughly to yield the hydrzide 3.15.19.

[0364] To the hydrazide (1.3 g, 4.03 mmol), POCl₃ (commercial source: Sigma- Aldrich) (40 ml) was added and heated at 100°C for 5h. Then reaction mixture was cooled, POCI₃ removed in vacuum. Crude was dissolved in ethyl acetate, washed with water, aq NaHC0₃, brine and dried. Crude residue was column chromatographed to yield 600mg of oxadiazole 3.15.20.

Example 1.3.16

3.16.23 3.16.24

[0365] To the oxazole 3.16.21 (226 mg, 3.28 mmol) in THF (10 ml) at -78°C, n-BuLi (2.4 ml, 3.79 mmol) was added. After 0.5h, ZnCl₂ (21 ml, 10.33 mmol) was added. After stirring at -78 °C for 0.5h, then at 0°C for lh, iodo-isophthalic acid 3.16.22 (lg, 3.12 mmol) was added followed by Pd(PPh₃)₄ (191 mg, 0.16 mmol). Then the reaction mixture was refluxed for 2.5 h. The reaction mixture was cooled, diluted with water and extracted with

ethylacetate. Organic layer was dried with anhydrous sodium sulfate and the volatiles were removed on a rotavap under reduced pressure. Then crude residue was column chromatographed to obtain the diester 3.16.23 as a pale yellow solid in 50% yield.

[0366] 1 N NaOH (0.9 eq) was added to a stirred solution of the diester 3.16.23 in 1:3 MeOH/THF. After stirring overnight the solvent was removed via rotary evaporation, and the residue was diluted with saturated aqueous NaHC0₃. The mixture was extracted with EtOAc (x2). The aqueous layer was adjusted to pH ~ 3 with concentrated HC1, and extract with EtOAc (x3). The appropriate organics were combined, washed with water (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation yielding the product in 75% yield of 3.16.24.

Example 1.

3.17.26

[0367] To the iodo compound 3.17.25 (commercial source: Matrix scientific) in 1,4- dioxane (10 ml), pyridine 3-boronoic acid, sodium carbonate (2M aqueous solution) and Pd(PPh₃)₄ was added and heated at 90°C for 4h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (60%ethylacetate/40% hexanes) to yield 450 mg of 3.17.26 as pale yellow solid.

Example 1.3.18

[0368] The ester was synthesized in a manner similar to that of Example 1.3.16.

Saponification was carried out in a manner similar to that for Example 1.4.4.

[0369] Synthesis of Example 1.3.18 was carried out according to the procedure of Example 1.3.16 above. Example 1.3.19: Synthesis of diethyl [1,1 '-biphenyl]-3,5-dicarboxylate

[0370] A mixture of Na₂C0₃ (776 mg, 7.32 mmol), Pd (OAc)₂ (4.5 mg, 0.02 mmol), aryl halide, diethyl 5-bromoisophthalate (lgm, 3.66 mmol), phenyl boronic acid (670 mg, 5.49 mmol) , distilled water (14 ml) and acetone (12 ml) was stirred at 35°C for 0.5h. Afterward, the reaction solution was extracted four times with diethyl ether (4X20 ml). The combined organic phase washed with brine, dried over sodium sulfate and then filtered. The solvent was removed under vacuum, and the crude diester , diethyl [l,l'-biphenyl]-3,5-dicarboxylate was taken to the next step without any further purification.

Example 1.3.20: Synthesis of dimethyl 5-(trifluoromethyl)isophthalate

[0371] A mixture of Methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (Commercial source: sigma-aldrich) (3.5 ml, 27.49 mmol), copper iodide (Commercial source: sigma-aldrich) (2.74 g, 14.37 mmol) and the iodo compound, dimethyl 5-iodoisophthalate (Commercial source: Matrix Scientific) (4.0 g, 12.5 mmol) in DMF (25 ml) was stirred under argon atmosphere for 6h at 70°C. The reaction was then cooled to room temperature. It was diluted with DCM, the solution washed with water, dried with Na₂S0₄, and concentrated to afford a syrup. The purification was done by column chromatography (10% ethylacetate/90 %

Hexanes) to give 1.5 g of pure diester, dimethyl 5-(trifluoromethyl)isophthalate as a white solid. Example 1.3.21: S nthesis of dimethyl 5-(N-methylsulfamoyl)isophthalate

[0372] To the diester, sodium 3,5-bis(methoxycarbonyl)benzenesulfinate (5g, 17.12 mmol) (Commercial source: sigma-aldrich), thionyl chloride (20 ml) was added followed by couple of drops of DMF. Reaction mixture was heated at 80°C for 20h. Volatiles were then removed under vacuum. Crude was washed with water, brine, dried and column purified to yield 5g of the dimethyl 5-(chlorosulfonyl)isophthalate.

[0373] To the sulfonyl chloride (l.Og, 3.47 mmol) in THF (10 ml), methyl amine (2.0M, 6 ml, 12.25 mmol) was added and stirred at rt for 3h. Then volatiles were removed, reaction mixture was diluted with ethyl acetate, washed with IN HC1, brine and dried. Crude residue was purified by column chromatography to give 700 mg of dimethyl 5-(N- methylsulfamoyl)isophthalate.

Example 1.3.22

[0374] tert-Butyl 2-chloro-6-methoxyisonicotinate: To a stirred solution of 2-chloro-6- methoxyisonicotinic acid (20 g, 106.6 mmol) and Boc₂0 (53.5 g, 245.2 mmol) in NMP (100 ml) was added DMAP (2.60 g, 21.3 mmol) at rt and the mixture was stirred at rt overnight. The starting molecule was completely consumed and the mixture was diluted with EtOAc and H₂0. The organic phase was separated and the aqueous layer was extracted with EtOAc (x3). The combined organic layer was washed with H₂0 (x3) and brine, dried over MgS0₄ and evaporated to give a crude product, which was briefly purified with column chromatography (EtOAc in hexane = 10%, Si0₂ 50 g) to give tert-butyl 2-chloro-6- methoxyisonicotinate (22.2 g, 85% yield) as a white solid. MS (ESI) m/z: 244 [M+H]⁺.

[0375] 4-tert-Butyl 2-methyl 6-methoxypyridine-2,4-dicarboxylate: To a stirred solution of tert-butyl 2-chloro-6-methoxyisonicotinate (22.2 g, 90.9 mmol) and Et₃N (41.2 ml, 296 mmol) in MeOH (240 ml) and DMSO (240 ml) were added Pd(OAc)₂ (2.20 g, 9.82 mmol) and dppf (5.44 g, 9.82 mmol) at rt. CO was bubbled in the mixture for 10 min and the mixture was stirred under CO atmosphere (balloon) at 80 degree overnight, at which the starting molecule was completely consumed. The mixture was filtered through a pad of Celite and the filtrate was evaporated to some extent (to remove MeOH). The residue of DMSO solution was diluted with EtOAc and H₂0. The organic layer was separated and the aqueous layer was extracted with EtOAc (x3). The combined organic layer was washed with H₂0 (x3) and brine, dried over MgS0₄ and evaporated to give a crude, which was briefly purified with column chromatography (EtOAc in hexane = 10 to 20%, Si0₂ 100 g) to give 4-tert-butyl 2- methyl 6-methoxypyridine-2,4-dicarboxylate (22.4 g, 92% yield) as a white solid. MS (ESI) m/z: 268.1 [M+H]⁺.

Example 1.3.2

[0376] 4-tert-Butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4-dicarboxylate: To a stirred solution of 4-tert-butyl 2-methyl 6-methoxypyridine-2,4-dicarboxylate (15.0 g, 56.1 mmol) in MeCN (150 ml) were added Nal (25.2 g, 168 mmol) and TMSC1 (21.3 ml, 168 mmol) at rt and the mixture was stirred for 18 hours at the same temperature under Ar atmosphere. The mixture was quenched with satd. NaHC0₃ aq. The organic layer was separated and the aqueous layer was extracted with EtOAc (x3). The combined organic layer was washed with satd. NaHC0₃ aq., and brine, dried over MgS0₄ and evaporated to give a crude, which was briefly purified with column chromatography (EtOAc in hexane = 20 to 100%) to give 4-tert- butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4-dicarboxylate (22.2 g, 85% yield) as a white solid. MS (ESI) m/z: 254 [M+H]⁺. Example 1.3.24

[0377] 6-(Methoxycarbonyl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid: To a stirred solution of 4-tert-butyl 2-methyl 6-methoxypyridine-2,4-dicarboxylate (5.0 g, 18.7 mmol) in MeCN (50 ml) were added Nal (8.41 g, 56.1 mmol) and TMSC1 (7.10 ml, 56.1 mmol) at rt and the mixture was stirred for 12 hours at the same temperature under Ar atmosphere. To this stirred mixture was added H₂0 (0.66 ml) at rt and the mixture was stirred for 30 min at 60 degree. The mixture was cooled to rt and it was quenched with H₂0 (100 ml). A precipitated solid was collected and it was washed with IPE (x3) and dried under reduced pressure to give 6-(methoxycarbonyl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid (3.68 g, >99% yield) as a pale brown solid. MS (ESI) m/z: 198 [M+H]⁺.

Example 1.3.

[0378] 4-tert-Butyl 2-methyl 6-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2,4- dicarboxylate: To a stirred solution of 4-te/t-butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4- dicarboxylate (2.0 g, 7.90 mmol) and z^'-Pr₂NEt (2.02 ml, 11.8 mmol) in CH₂C1₂ (80 ml) were added Tf₂0 (1.59 ml, 9.48 mmol) at 0 degrees drop by drop and the mixture was stirred at the same temperature for 1 hour. The starting molecule was completely consumed and it was quenched with satd. NaHC0₃ aq. The organic layer was separated and the aqueous layer was extracted with CHC1₃ (x3). The combined organic layer was washed with satd. NaHC0₃ aq. and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 0 to 20%) to give 4-tert-butyl 2-methyl 6- { [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate (2.68 g, 88% yield) as a white solid. MS (ESI) m/z: 386 [M+H]⁺. Example 1.3.

[0379] 4-tert-Butyl 2-methyl 6-cyclopropylpyridine-2,4-dicarboxylate: To a stirred solution of 4-tert-butyl 2-methyl 6-{ [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4- dicarboxylate (200 mg, 0.519 mmol) and cyclopropylboronic acid (89 mg, 1.04 mmol) in toluene (2.0 ml) were added Pd₂(dba)₃ (48 mg, 0.052 mmol), SPhos (85 mg, 0.21 mmol) and K₃P0₄ (331 mg, 1.56 mmol) at rt and the mixture was stirred at 100 degree for 1 hour. The starting molecule was completely consumed and it was evaporated to give a purple residue. This was purified with column chromatography (EtOAc in hexane = 0 to 80%) to give 4-tert- butyl 2-methyl 6-cyclopropylpyridine-2,4-dicarboxylate (36 mg, 25% yield) as a pale yellow oil. MS (ESI) m/z: 278 [M+H]⁺.

Example 1.

[0380] 4-tert-Butyl 2-methyl 6-(2-cyanophenyl)pyridine-2,4-dicarboxylate: The desired compound was synthesized from 4-te/t-butyl 2-methyl 6-

{ [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate (200 mg, 0.519 mmol) in a similar manner to Example 1.3.26. (35 mg, 20% yield) MS (ESI) m/z: 339 [M+H]⁺.

Example 1.3.2

[0381] 4-tert-Butyl 2-methyl 6-(l,3-oxazol-2-yl)pyridine-2,4-dicarboxylate: A solution of 1,3-oxazole (0.5 M THF solution, 15.6 ml, 7.79 mmol) was placed under reduced pressure for 30 min at -78 degree for the removal of dissolved 0₂ in THF. To this stirred oxazole/THF solution was added ra-BuLi (1.65 M hexane solution, 2.83 ml, 4.67 mmol) at -78 degree and the mixture was stirred at the same temperature for 30 min. ZnCl₂ (1.0 M THF solution, 4.67 ml, 4.67 mmol) was added to the mixture at the same temperature and the mixture was allowed to warm up at rt. To this stirred solution was added 4-tert-butyl 2-methyl 6- { [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate (300 mg, 0.779 mmol) and Pd(PPh₃)₄ (180 mg, 0.156 mmol) and the mixture was heated at 85 degree for 1 min. The starting molecule was completely consumed and it was quenched with MeOH and volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 20 to 100%) to give 4-tert-butyl 2-methyl 6-(l,3-oxazol-2-yl)pyridine-2,4- dicarboxylate (87 mg, 37% yield) as a yellow oil. MS (ESI) m/z: 305 [M+H]⁺.

Example 1.3.2

[0382] 4-tert-Butyl 2-methyl 6-[methyl(methylsulfonyl)amino]pyridine-2,4- dicarboxylate: To a stirred solution of 4-tert-butyl 2-methyl 6- { [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate (300 mg, 0.779 mmol),

CH₃S0₂NHCH₃ (170 mg, 1.56 mmol) and K₃P0₄ (496 mg, 2.34 mmol) in dioxane (3 ml) were added Pd₂(dba)₃ (143 mg, 0.156 mmol) and Xantphos (270 mg, 0.467 mmol) at rt and the mixture was stirred for 1 hour at 100 degree. Volatiles were evaporated and the mixture was purified with column chromatography (EtOAc in hexane = 0 to 80%) to give 4-tert-butyl 2-methyl 6-[methyl(methylsulfonyl)amino]pyridine-2,4-dicarboxylate (234 mg, 87% yield) as a colorless oil. MS (ESI) m/z: 345 [M+H]⁺.

Example 1.3.30

[0383] 4-tert-butyl 2-methyl 6-(2-oxopyrrolidin-l-yl)pyridine-2,4-dicarboxylate: To a solution of 4-tert-butyl 2-methyl 6-{ [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4- dicarboxylate (100 mg, 0.26 mmol) in toluene (3 ml), pyrrolidin-2-one (44mg, 0.52mmol), Cs₂C03 (127 mg, 0.39 mmol), xantphos (54 mg, 0.093 mmol) were added followed by Pd₂(dba)₃ (14 mg, 0.016 mmol). After refluxing for 1.5 hours, reaction mixture was purified using column chromatography (EtOAc / hexane = 1:1) to yield 76 mg (91% yield) of 4-tert- butyl 2-methyl 6-(2-oxopyrrolidin-l-yl)pyridine-2,4-dicarboxylate as a white solid. MS (ESI) m/z: 321 [M+H]⁺.

Example 1.3.31

[0384] 4-tert-butyl 2-methyl 6-(2-oxo-l,3-oxazolidin-3-yl)pyridine-2,4-dicarboxylate:

The desired compound was synthesized from 4-tert-butyl 2-methyl 6- { [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate in a similar manner to Example 1.3.30 (62 mg, 74% yield). MS (ESI) m/z: 323 [M+H]⁺.

Example 1.3.32

[0385] 4-tert-butyl 2-methyl 6-(2-methyl-5-oxopyrrolidin-l-yl)pyridine-2,4- dicarboxylate: The desired compound was synthesized from 4-tert-butyl 2-methyl 6- { [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate in a similar manner to Example 1.3.30 (72 mg, 83% yield). MS (ESI) m/z: 335 [M+H]⁺.

Example 1.3.33

[0386] 4-tert-butyl 2-methyl 6-(2-oxopiperidin-l-yl)pyridine-2,4-dicarboxylate: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-

{ [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylate in a similar manner to Example 1.3.30 (258 mg, 99% yield). MS (ESI) m/z: 335 [M+H]⁺. Example 1.3.34

[0387] 4-tert-butyl 2-methyl 6-(pyrrolidin-l-yl)pyridine-2,4-dicarboxylate: To a stirred solution of 4-tert-butyl 2-methyl 6-{ [(trifluoromethyl)sulfonyl]oxy}pyridine-2,4- dicarboxylate (119 mg, 0.309 mmol) in dioxane (1 mL) was added pyrrolidine (0.5 mL). After stirring for 30 minutes the reaction mixture was concentrated in vacuo and the residue was purified with silica-gel column chromatography (hexane/EtOAc = 95:5 to 80:20) to give 4-tert-butyl 2-methyl 6-(pyrrolidin-l-yl)pyridine-2,4-dicarboxylate as a yellow solid. (63 mg, 67% yield) MS (APCI/ESI) M/Z: 307 [M+H]⁺.

Example 1.3.35

[0388] 4-tert-butyl 2-methyl l-methyl-6-oxo-l,6-dihydropyridine-2,4-dicarboxylate:

To a solution of 4-tert-butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4-dicarboxylate (200 mg, 0.791 mmol) in DMF (4 mL) were added iodomethane (0.15 mL, 2.37 mmol) and potassium carbonate (218 mg, 1.58 mmol). After stirring forl4 hours at room temperature, the reaction mixture was concentrated in vacuo. The residue was purified with silica-gel column chromatography (hexane/EtOAc 95:5 to 0:100) to give 4-tert-butyl 2-methyl l-methyl-6-oxo- l,6-dihydropyridine-2,4-dicarboxylate as a colorless solid. (146 mg, 69% yield) MS (ESI) M/Z: 268 [M+H]⁺.

Example 1.3.36

[0389] 4-tert-butyl 2-methyl 6-(difluoromethoxy)pyridine-2,4-dicarboxylate: To a solution of 4-tert-butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4-dicarboxylate (55 mg, 0.217) in MeCN (1 mL) was added difluoro(fluorosulfonyl)acetic acid (0.027 mL, 0.26 mmol) and potassium carbonate (35 mg, 0.33 mmol). After stirring for 14 hours, the mixture was filtered with Celite and the filtrate was concentrated in vacuo to give crude 4-tert-butyl 2-methyl 6-

(difluoromethoxy)pyridine-2,4-dicarboxylate.

Example 1.4: Synthesis of isophthalamide intermediates.

Example 1.

[0390] 20% Pd(OH)₂/C (0.04 g, 40 wt %) was added to a stirred solution of the acid (0.1006 g, 0.24 mmol) in MeOH. The mixture was stirred under a H₂ (double balloon) overnight. The mixture was filtered through Celite and the solvent was removed via rotary evaporation yielding 0.0790 g (0.24 mmol, 100% yield) of the product.

Example 1.4.2

[0391] Et₃N (1 drop, catalytic) was added to a stirred suspension of mono-Methyl isophthalate (0.294 mmol, 1.0 eq) in 2 ml SOCl₂ under Ar. The mixture was heated to reflux at 90 °C for 2h. The reaction was cooled to RT, and the solvent was removed in vacuo. The residue was placed under an Ar atmosphere and dissolved in 2 ml anh CH₂C1₂. The resulting solution was treated with a solution of the amine (0.294 mmol, 1.0 eq) dissolved in 1 ml anh CH₂C1₂ under Ar. After stirring at RT for 30 min, the reaction was treated with ET₃N (0.294 mmol, 1 eq). After stirring at RT for 30 min, the reaction is poured into a seperatory funnel, washed with sat. NaHC0₃ (xl), water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were removed via filtration, and the solvent was removed in vacuo yielding the crude product in 93% yield. Example 1.4.3

[0392] To an ice-cold solution of 4-(R)-hydroxyl-2-(R)-hydroxymethylpyrrolidine-l- carboxylic acid tert-butyl ester (9.81 g, 40.93 mmol) in DMSO (50 mL) was added triethylamine (16.2 mL, 163.73 mmol) and sulfurtrioxide-pyridine complex (12.73 g, 81.87 mmol). The resulting mixture was stirred 30 min, warmed to room temperature and stirred 30 min, diluted with diethyl ether and washed with 5% aqueous citric acid, saturated aqueous sodium chloride, dried (sodium sulfate) and concentrated to give the title compound as an oil which was purified with flash chromatography to produce the ketone (7.5 g). ¹H NMR (300 MHz, CDCI3), δ: 4.818-4.673 (m, 1 H), 3.903 (s, 1 H), 3.871(s, 1 H), 3.749 (s, 3 H), 3.003- 2.862 (m, 1 H), 2.605-2.542 (m, 1 H), 1.468, 1.445 (s, 9 H).

[0393] To a solution of 4-oxopyrrolidine-N-l,2-(R)-dicarboxylic acid 1 -tert-butyl ester 2- methyl ester (7.5 g, 35.76 mmol) in dichloromethane (80 mL) at -78°C was added Deoxo- Fluor (17 mL, 1.07 mol). The resulting mixture was stirred and warmed to room temperature for overnight, then was cooled in ice bath diluted with chloroform and quenched with saturated sodium bicarbonate solution. Warmed to room temperature, separated and dried (magnesium sulfate), concentrated and purified with silica gel chromatography to give the compound as an oil (6.47 g). 1H NMR (300 MHz, CDC1₃), δ: 4.568-4.422 (m, 1 H), 3.894- 3.725 (m, 2 H), 3.767(s, 3 H), 2.798-2.601 (m, 1 H), 2.553-2.385 (m, 1 H), 1.470, 1.422 (s, 9 H).

[0394] To the ester (6.2 g, 23.37 mmol) in THF (60 ml), aq sodium hydroxide (8 ML of 1 M solution, 15 ML of water, 32 mmol) was added. After 3 h, volatiles were removed in vacuum. Aqueous layer was adjusted to about PH = 3 with 3 M HC1 solution, and reaction mixture was extracted with ethyl acetate three times. Combined organic layers were washed with brine, dried and concentrated to yield a white solid (5.55 g), which was used for the next step without further purification and identification.

[0395] To the crude acid (5.55 g, 22.08 mmol) in dioxane (50 ml) were added pyridine (Commercial source: sigma-aldrich) (1.25 ml), (Boc)₂0 (Commercial source: sigma-aldrich) (6.75 g, 30.92 mmol), followed by ammonium bicarbonate (2.36 g, 29.82 mmol). The resulting reaction mixture was stirred overnight at rt, then volatiles were removed in vacuum. Then reaction mixture was dissolved in ethyl acetate, washed with aqueous diluted HC1 (1 M), sodium bicarbonate and brine. Organic layer was dried and evaporated to obtain the amide in quantitative yield 5.6 g), which was used for the next step without further purification and identification.

[0396] Lawesson's reagent (Commercial source: sigma-aldrich) (5.41 g, 13.37 mmol) was added to the amide (5.6 g, 22.28 mmol) in DME (Commercial source: sigma-aldrich) (100 ml) and the reaction mixture was stirred overnight at rt. Then volatiles were removed in vacuum and the reaction mixture was partitioned between ether and water. Ether layer was concentrated and column purified to obtain 4.6 g of thioamide.

[0397] To the thioamide (4.6 g, 17.21 mmol) in ethanol (50 ml) was added chloroacetone (Commercial source: sigma-aldrich) (2.3 g, 25.81 mmol). After heating at 75 °C for 5h, volatiles were removed in vacuum. Reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate. Organic layer was dried and evaporated. To the crude residue 4N HCl/dioxane (Commercial source: sigma-aldrich) (10 ml) was added and stirred at rt for 3h. Then volatiles were removed in vacuum and reaction mixtute was patitioned between chloroform and aqueous sodium bicarbonate. Oragnaic layer was dried and evaporated to yield 1.2 g of the desired product amine. 1H NMR (300 MHz, CDC1₃), δ: 6.818 (s, 1 H), 4.733 (t, J= 7.8 Hz, 1 H), 3.345-3.301 (m, 2 H), 2.861-2.710 (m, 1 H), 2.596-2.413 (m, 1 H), 2.420 (s, 3 H). [0398] To a stirred solution of mono acid (726.2 mg, 2.94 mmol), amine (600 mg, 2.94 mmol) in DCM were added triethylamine (1.64 mL, excess), Py-BOP (1.68 g, 3.23 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Then aqueous saturated sodium bicarbonate was added and the reaction mixture was extracted with chloroform. The organic layers were dried over Na₂S0₄ and concentrated. The crude product thus obtained was purified by silica gel flash column chromatography to provide the corresponding amide (700 mg). 1H NMR (300 MHz, CDC1₃), δ: 8.817 (s, 1 H), 8.414 (s, 1 H), 8.286 (s, 1 H), 7.781(s, 1 H), 7.306 (m, 1 H), 6.879 (s, 1 H), 5.918 (m, 1 H), 4.159 (m, 1 H), 3.978 (s, 3 H), 3.878 (m, 1 H), 3.175 (m, 1 H), 2.948 (m, 1 H), 2.467 (s, 3 H).

[0399] The ester (700 mg, 1.62 mmol) was dissolved in THF:MeOH (1:1) (15:15 mL) and H₂0 (3 mL). Solid NaOH (194 mg, 4.845 mmol) was added and stirred at 50 °C for lhour. The reaction mixture was concentrated under reduced pressure. Saturated NaHC0₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove organic impurities). The aqueous reaction mixture was acidified with diluted HC1 (10%), extracted with EtOAc, dried over anhydrous Na₂S0₄. The solvent was evaporated and dried under reduced pressure to give the crude acid which can be used directly for next reaction.

Example 1.4.4

[0400] Dimethyl 5-(N-methylmethane-5-ylsulfonamido)isophthalate: To a stirred solution of dimethyl5-aminoisophthalate (2.09 g, 10 mmol) in dichloromethane (30 mL), pyridine

(2.43 mL, 30 mmol) was added at room temperature. At 0°C, methanesulfonyl chloride (0.86 mL, 11 mmol) was added and the resulting mixture was stirred at room temperature for overnight. Then the reaction mixture was concentrated under reduced pressure and ethyl acetate (50 mL) was added. The resulting white precipitate was filtered and washed with hexanes to give the sulfonamide in 95% (2.715 g) yield as a white solid. See Stachelet al., J. Med. Chem. 2004, 47, 6447-6450.

[0401] To a stirred suspension of NaH (0.24 g, 10 mmol, 60% in oil dispersion) in 10 mL of DMF was added the above sulfonamide (1.435 g, 5 mmol) followed by iodomethane (0.62 mL, 10 mmol) at room temperature. After 5 hours, the reaction was quenched by H₂0 (25 mL). Then the reaction mixture was extracted with EtOAc, further washed with H₂0 to remove excess of DMF, dried over anhydrous Na₂S0₄ and concentrated. The crude product thus obtained was washed with hexanes to give the diester as a white solid in 91 % (1.37 g) yield.

[0402] 3-(Methoxycarbonyl)-5-(N-methylmethan-5-ylsulfonamido )benzoic acid: The diester (0.842 g, 2.8 mmol) was dissolved in THF:MeOH (1:1) (8 mL) and H₂0 (3 mL). Solid NaOH (0.112 g, 2.8 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. Saturated NaHC0₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove <10% unreacted staring material). The aqueous solution was acidified with dil HCl (10%), extracted with EtOAc, dried over anhydrous Na₂S0₄. The solvent was evaporated and dried under reduced pressure to give the mono acid as a white solid (75%, 0.598 g) which was used for further reaction without purification.

[0403] To a stirred solution of mono acid (0.393 g, 1.37 mmol), amine (185 mg, 1.3 mmol) in DCM were added triethylamine (1 mL, excess), Py-BOP (784 mg, 1.507 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Then water was added and the reaction mixture was extracted with EtOAc. The organic layers were dried over Na₂S0₄ and concentrated. The crude product thus obtained was purified by silica gel flash column chromatography (2% MeOH in ethyl acetate) to provide the corresponding amide (0.510 g) which was dissolved in THF:MeOH (1:1) (15:15 mL) and H₂0 (2 mL). Solid NaOH (146 mg, 3.645 mmol) was added and stirred at 50 °C for lhour. The reaction mixture was concentrated under reduced pressure. Saturated NaHC0₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove organic impurities). The aqueous reaction mixture was acidified with diluted HCl (10%), extracted with EtOAc, dried over anhydrous Na₂S0₄. The solvent was evaporated and dried under reduced pressure to give the crude acid 2 which can be used directly for next reaction. Example 1.4.

[0404] The amine 4.5.27 was coupled to 4.5.28 using HOBT and EDCI according to the general procedure and the so obtained ester was saponified to yield acid 4.5.29.

Example 1.4.6

[0405] EDCI HC1 (0.372 g, 1.9 mmol, 1.3 eq) and HOBT H₂0 (0.202 g, 1.5 mmol, 1.0 eq) were added to a stirred solution of the acid 4.6.30 (0.37g, 1.5 mmol, 1 eq) in 8 ml anhydrous CH₂C1₂ at 0 °C under Ar. The resulting solution was treated with a solution of DIPEA (0.78 mL, 4.5 mmol, 3.0 eq) and the amine 4.6.31 (0.252, 1.5 mmol, 1.0 eq) in 2 ml anhydrous CH₂C1₂. The reaction was stirred at 0 °C to room temperature overnight. The solvent was removed via rotary evaporation. The residue was quenched with water, and the resulting mixture was extracted with EtOAc (xl). The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.8308 g (2.5 mmol, 65% yield) of the product 4.6.32.

[0406] IN LiOH (3.0 mL) was added to a stirred solution of the ester 4.6.32 (0.38 g, 2.5 mmol, 1 eq) in THF (3 ml) and. After stirring for 2 h, the medium was adjusted to pH ~ 3 with IN HC1 and extracted with 10% MeOH/ 90% EtOAc/ (x2). The organics were combined and dried over Na₂S0₄. The inorganics were filtered off, and the solvent removed via rotary evaporation yielding 0.28 g (76 % yield) of the product 4.6.33.

[0407] Acids 4.6.34 and 4.6.35 were synthesized similar to that of 4.6.33 starting with the appropriate commercially available isophthalic acid diesters.

Example 1.4.7

[0408] 3-Methoxycarbonyl-5-hydroxylmethylbenzoic acid: The diester (4.12 g, 16.33 mmol) was dissolved in THF:MeOH (1:1) (80 mL) and H₂0 (15.52 mL). Solid NaOH (0.62 g, 15.52 mmol) was added and stirred at 0°C and slowly warmed to room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. Saturated NaHC0₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove <10% unreacted staring material). The aqueous solution was acidified with dil HCl (10%), extracted with EtOAc, dried over anhydrous Na₂S0₄. The solvent was evaporated and dried under reduced pressure to give the mono acid as a white solid (3.32 g) which was used for further reaction without purification.

[0409] A solution of amine (1.62 g, 9.64 mmol) and acid (2.23 g, 10.6 mmol) in DCM (100 mL) were added diisopropylethylamine (6.7 mL, excess), HOBt (1.3 g, 9.64 mmol) and EDCI (2.4 g, 12.53 mmol). The resulting solution was stirred at room temperature for overnight. The reaction mixture was diluted with chloroform, washed with sodium

bicarbonate saturated aqueous solution and separated. The aqueous layer was extracted one more time with chloroform. The combined organic layers were concentrated to give a residue, which was purified with flash chromatography to produce the desired compound (2.2 g, 67%)). 1H NMR (300 MHz, CDC1₃), δ: 8.011 (m, 1.5 H), 7.876 (br, 0.5 H), 7.683 (m, 1 H), 6.749 (m, 1 H), 5.579 (m, 0.7 H), 5.061 (br, 0.3 H), 4.641 (br, 1.2 H), 4.525 (br, 0.8 H), 3.875 (m, 3 H), 3.692 (m, 1 H), 3.457 (m, 1 H), 2.345 (m, 5 H), 2.034 (m, 2 H).

[0410] Alcohol (2.1 g, 5.83 mmol) in dry DCM (60 mL) at -78 ^°C was added [Bis(2- methoxyethyl)amino] sulfur trifluoride (1.29 mL, 7.0 mmol) slowly and stirred at the same temperature for 2 hrs, then warmed to room temperature for overnight. The reaction was carefully quenched with aqueous saturated NaHC0₃, extracted with chloroform three times. The combined organic solvent was dried with anhydrous Na₂S0_4; removed in vacuum and the residue was purified by silica gel chromatography to afford monofluoride (1.6 g, 76%).1H NMR (CDC1₃) δ 8.211-7.784 (m, 2.7 H), 7.420 (s, 0.3 H), 6.778 (s, 1 H), 5.645-5.076 (m, 3 H), 3.929-3.741 (m, 4 H), 3.519 (m, 1 H), 2.428-2.325 (m, 5 H), 2.088-1.930 (m, 2 H).

[0411] The ester (1.53 g, 4.22 mmol) was dissolved in THF:MeOH (1:1) (20:20 mL) and H₂0 (6.5 mL). Solid NaOH (507 mg, 12.66 mmol) was added and stirred at 50 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The aqueous reaction mixture was acidified with diluted HC1 (10%), extracted with EtOAc, dried over anhydrous Na₂S0₄. The solvent was evaporated and dried under reduced pressure to give the crude acid (1.5 g, quantative yield) which can be used directly for next reaction without further purification and characterization.

Example 1.4.8: 2' -cyano-5-(2-(5-methylfuran-2-yl)pyrrolidine- 1 -carbonyl)-[ 1 , 1 ' -biphenyl] - 3-carboxylic acid

[0412] 2'-cyano-5-(2-(5-methylfuran-2-yl)pyrrolidine-l-carbonyl)-[l,l'-biphenyl]-3- carboxylic acid was synthesized following a similar experimental procedure as for Example 1.4.6.

Example 1.4.9: 3-(methyl((3-methyl-l,2,4-oxadiazol-5-yl)methyl)carbamoyl)benzoic acid

[0413] 3-(methyl((3-methyl- 1 ,2,4-oxadiazol-5-yl)methyl)carbamoyl)benzoic

synthesized following a similar experimental procedure as for Example 1.4.6.

Example 1.4.10

[0414] This compound was synthesized following a similar experimental procedure as for Example 1.4.7.

Example 1.4.11

[0415] This compound was synthesized following a similar experimental procedure as for Example 1.4.6.

Example 1.4.12

[0416] This compound was synthesized following a similar experimental procedure as for Example 1.4.6. Example 1.4.13

[0417] This compound was synthesized following a similar experimental procedure as for Example 1.4.6.

Exam le 1.4.14

[0418] DMP Oxidation: To a solution of alcohol (560 mg, 1.554 mmol) in DCM (60 mL), Dess-Martin periodinane (790.8 mg, 1.864 mmol) was added at rt. After 2 hrs' stirring, the mixture was poured into a mixture of aqueous 1 M Na₂S203 (30 mL) and aqueous saturated NaHC0₃ (30 mL), and it was extracted with DCM three times. The combined organic layers were concentrated in vacuum and the residue was purified by flash silica chromatography to give the product (530 mg). 1H NMR (CDC1₃) δ 10.094, 9.933 (s,s, 1 H), 8.592-7.908 (m, 3 H), 6.796 (s, 1 H), 5.661 (m, 0.65 H), 5.083 (m, 0.35 H), 3.969-3.743 (m, 4 H), 3.515 (m, 1 H), 2.429-2.308 (m, 5 H), 2.145-1.939 (m, 2 H).

[0419] To a solution of aldehyde (530 mg, 1.47 mmol) in CH₂C1₂ (50 mL) at -78°C was added [Bis(2-methoxyethyl)amino] sulfur trifluoride (0.46 mL, 2.49 mmol) slowly, then a couple drops of ethanol was added, and the mixture was stirred at same temperature for 2hr. The resulting mixture was warmed to room temperature and stirred overnight. The solution was slowly poured into saturated NaHC0₃, extracted with methylene chloride three times, dried (Na₂S0₄), filtered, and evaporated in vacuo. Flash chromatography on silica gel afforded the pure product (442 mg). 1H NMR (CDC1₃) δ 8.330-7.919 (m, 2.7 H), 7.528 (s, 0.3 H), 6.902-6.368 (m, 3 H), 5.638 (m, 0.7 H), 5.048 (m, 0.3 H), 3.946-3.746 (m, 4 H), 3.488 (m, 1 H), 2.412-2.312 (m, 5 H), 2.112-1.950 (m, 2 H).

[0420] To a solution of aldehyde (740 mg, 2.065 mmol) in THF (40 mL) at -78°C was added methyl magnesium bromide (3 M in ether, 0.69 mL), and the mixture was stirred at same temperature for 2hr. The resulting mixture was warmed to room temperature and stirred overnight. The solution was slowly poured into aqueous saturated NH₄C1, extracted with EtOAc three times, washed with brine, dried (Na₂S0₄), filtered, and evaporated in vacuo. Flash chromatography on silica gel afforded the pure product (720 mg).

[0421] The second alcohol was fluorinated with Deoxo-Fluro give the product (4.14.1).

[0422] The second alcohol was oxidized with DMP to give the product (4.14.2).

[0423] The ketone was fluorinated with Deoxo-Fluro give the product (4.14.3).

Example 1.4.15

[0424] The ketone (240 mg) was treated with Ν,Ν-dimethylformamide dimethyl acetal (5 mL, excess) at 100 °C for 17 hrs to give the crude product (170 mg), which was then treated with hydroxylamine hydrochloride (81.3 mg, 1.17 mmol) in ethanol (10 mL) at 90 °C overnight to give the crude product. Flash chromatography on silica gel afforded the pure product (50 mg). The intermediate was treated with hydrazine to give the pyrazole product. Exam le 1.4.16

3. NaOH

[0425] The aldehyde (610 mg, 1.702 mmol) in methanol (5 mL) was treated with hydroxylamine hydrochloride (130 mg, 1.872 mmol) and sodium acetate (237.3 mg, 2.8934 mmol) at room temperature overnight. The solvent was moved under vacuum, diluted with EtOAc, washed with saturated NH₄C1, aqueous saturated NaHC0₃, brine, dried (Na₂S0₄), filtered, and evaporated in vacuo to give the crude product, which was then treated with trimethylsilylacetylene (1 mL) and bleach (6.5 mL) in THF (6.5 mL) at room temperature overnight. The mixture was diluted with EtOAc, washed with aqueous saturated NaHC0₃, aqueous saturated NH₄C1, brine, dried (Na₂S0₄), filtered, and evaporated in vacuo. Flash chromatography on silica gel afforded the pure product (325 mg). [0426] The general hydrolysis procedure gave the corresponding acid, meanwhile the silyl group was removed.

Example 1.4.17

[0427] EDCI HC1 (0.3946 g, 2.1 mmol, 1.1 eq) and HOBT H₂0 (0.2789 g, 2.1 mmol, 1.1 eq) were added to a stirred solution of the acid (Aldrich, 0.500 g, 1.9 mmol, 1 eq) in anhydrous CH₂C1₂ (10 ml) at 0 °C under Ar. After 1 h the resulting solution was treated sequentially with the amine (0.3048 g, 1.9 mmol, 1 eq) and DIPEA (0.98 ml, 0.73 g, 5.6 mmol, 3 eq). The reaction was stirred at 0 °C to RT overnight. The reaction was quenched with water, and the volatiles were removed via rotary evaporation. The residue was partititioned between EtOAc/H₂0, and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed vai rotary evaporation. Purification via flash chromatography on silica gel yielded the diester in quantitative yield.

[0428] A solution of the diexter (0.8097 g, 1.9 mmol, 1 eq) in 2:1 THF/MeOH (5 ml) was cooled to 0 °C with stirring. IN NaOH (1.8 ml, 1.8 mmol 0.95 eq) was added dropwise. The reaction was stirred at 0 °C to room temperature overnight. The reaction was diluted with saturated aqueous NaHC0₃, and the volatiles were removed via rotary evaporation. The resulting mixture was diluted with water and extracted with CH₂C1₂ (x2). The aqueous layer was adjusted to pH ~ 2 with HC1 and extracted with EtOAc (x2). The combined EtOAc fractions were dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation to yield 0.6842 g (1.77 mmol, 95%) of the monoacid.

Example 1.4.1

[0429] A solution of alcohol (0.0955g, 0.24 mmol, 1 eq) in anhydrous DCM (4 ml) under Ar was cooled to -78 °C under Ar. The cooled solution was treated with Deoxo-Fluor (53 μΐ, 0.06 g, 0.29 mmol, 1.2 eq). The reaction was stirred at -78 °C to room temperature overnight. The reaction was diluted with saturated aqueous NaHC0₃, and the layers were separated. The organic layer was washed with water (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation.

Purification via flash chromatography yielded 0.0204 g (0.051 mmol, 21%) of the fluoro compound. Saponification was carried out in a manner similar to that for Example 1.4.4. Example 1.4.19

[0430] The synthesis was carried out in a manner similar to that for Example 1.4.6.

Example 1.4.20

[0431] The synthesis was carried out in a manner similar to that for Example 1.4.6.

Example 1.4.21

[0432] The synthesis was carried out in a manner similar to that for Example 1.4.6. Example 1.4.22

The synthesis was carried out in a manner similar to that for Example 1.4.6.

Example 1.4.23

[0433] The synthesis was carried out in a manner similar to that for Example 1.4.6.

Example 1.4.24

[0434] The ester was synthesized in a manner similar to that of 1.4.2 using the appropriate starting materials. Saponification was carried out in a manner similar to that for Example 1.4.4.

Example 1.4.25: Synthesis of (R)-5-(2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)-[l,l '- biphenyl]-3-carboxylic acid

[0435] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6.

Example 1.4.26: Synthesis of (R)-3-iodo-5-(2-(4-methylthiazol-2-yl)pyrrolidine-l- carbonyl)benzoic acid

[0436] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6. Example 1.4.27: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)-5- (trifluoromethyl)benzoic acid

[0437] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6.

Example 1.4.28: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-l -carbonyl)-5- nitrobenzoic acid

[0438] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6.

Example 1.4.29: Synthesis of 3-(methyl((4-methylthiazol-2-yl)methyl)carbamoyl)-5-(N- methylsulfamoyl)benzoic acid

[0439] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6.

Example 1.4.30: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-l -carbonyl)-5- (pyrazin-2-yl)benzoic acid

[0440] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6.

Example 1.4.31: Synthesis of 3-(ethyl((4-methylthiazol-2-yl)methyl)carbamoyl)-5-(oxazol-2- yl)benzoic acid

[0441] Ester formation followed by spaonification of the resulting ester was carried out in a manner similar to that depicted in Example 1.4.6. Example 1.4.32

[0442] Methyl 6-chloro-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate: A-tert- Butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4- dicarboxylate (6.4 g, 25.3 mmol) was dissolved in SOCl₂ (55 ml) and a catalytic amount of DMF (5 drops) was added. This mixture was stirred for 36 hours at 80 degree. Additional DMF (30 drops) was added and the mixture was stirred for 24 hours at 80 degree. SOCl₂ was evaporated to give a residue, which was azeotroped with toluene. The obtained residue was dissolved in CH₂C1₂ (64 ml) and Et₃N (7.05 ml, 50.5 mmol) and 4-methyl-2-[(2R)-pyrrolidin- 2-yl]-l,3-thiazole (5.02 g, 29.8 mmol) was added at rt. The mixture was stirred at the same temperature for 2 hours. The reaction was quenched with 1 M HC1 aq. and the organic layer was separated. The aqueous layer was extracted with CHC1₃ (x3) and the combined organic layer was washed with satd. NaHC0₃ aq. and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 30 to 100%) to give methyl 6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate (8.67 g, 94% yield) as a pale yellow oil. MS (ESI) m/z: 366[M+H]⁺.

Example 1.4.33

[0443] 3-(cyclopropyl((4-methylthiazol-2-yl)methyl)carbamoyl)-5-(oxazol-2-yl)benzoic acid: The desired compound was synthesized following a similar experimental procedure as for Example 1.4.2.

Example 1.4.34

[0444] The ester was synthesized in a manner similar to Example 1.4.6 using the appropriate starting materials. Saponification was carried out in a manner similar to that for Examplel.4.4.

Example 1.4.35

[0445] The ester was synthesized in a manner similar Example 1.4.6 using the appropriate starting materials. Saponification was carried out in a manner similar to that for

Examplel.4.4.

Example 1.5: Synthesis of acyl hydrazide intermediates.

Exam le 1.5.1

[0446] A stirred suspension of the acid (Aldrich, 0.5 g, 4.3 mmol, 1 eq) in anhydrous CH₂CI₂ (15 ml) under Ar was cooled to 0 °C. The reaction was treated with Et₃N (0.9 ml, 0.66 g, 6.5 mmol, 1.5 eq). After 5 min (Boc)₂0 (1.3 ml, 1.2 g, 5.6 mmol, 1.3 eq) was added dropwise. After 3 h the reaction was quenched by the addition of aqueous citric acid (5%, 15 ml). The layers were separated, and the organic layer was dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation.

Purification via flash chromatography on silica gel yielded 0.7386 g (3.4 mmol, 80%) of the protected acid. [0447] A solution of the acid (0.7386 g, 3.4 mmol, 1 eq) in anhydrous CH₂C1₂ (10 ml) under Ar was cooled to 0 °C with stirring. The solution was treated ΗΟΒΤ·Η₂0 (0.5559 g, 4.1 mmol, 1.2 eq) followed by EDCI-HCl (0.7209 g, 3.8 mmol, 1.1 eq) 30 min later. After lh anhydrous N₂H₄ (0.43 ml, 0.44 g, 13.2 mmol, 4 eq) was added followed by DIPEA (2.3 ml, 1.7 g, 13.2 mmol, 4 eq) 10 min later. The reaction was stirred at 0 °C to room temperature overnight. The reaction was quenched with water and diluted with saturated aqueous NaHC0₃. The layers were separated. The aqueous layer was extracted with CH₂C1₂ (x3). The combined organics were dried over Na2S04. The inorganics were filtered off, and the volatiles were removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.5616 g (2.4 mmol, 72%) of the hydrazide.

Example 1.5.2

[0448] To a solution of 5.2.36 (3.0g, 10.75 mmoles) in CH₃CN was added EDC (3.5g, 18.28 mmoles). After 5 min, anhydrous hydrazine was added and stirred overnight at room temperature. All the solvent was evaporated; the residue was quenched with satd.aq. NaHC0₃ and was extracted with EtOAc. The organic extract was washed with brine, dried, concentrated and purified on silica gel (3% MeOH/97% CHC1₃) to obtain 1.42g (45%) of 5.2.37.

Example 1.5.3: (R)-tert-butyl(3-(4-fluorophenyl)-l-hydrazinyl-2-methyl-l-oxopropan-2- yl)carbamate

[0449] To a solution of 5.3.1 (2.97 g, 10 mmoles) in CH₃CN was added EDC (3.25 g, 17 mmoles). After 5 min, anhydrous hydrazine (0.79 mL, 25 mmoles) was added and stirred overnight at room temperature. All the solvent was evaporated; the residue was quenched with satd.aq. NaHC0₃ and was extracted with EtOAc. The organic extract was washed with brine, dried, concentrated and purified on silica gel (3% MeOH/97% CHCI₃) to obtain 2.15 g of (R)-tert-butyl(3-(4-fluorophenyl)- 1 -hydrazinyl-2-methyl- 1 -oxopropan-2-yl)carbamate. Example 1.5.4.

9 Boc EDCI, HOBT, DIPEA _{H N} j» Boc

[0450] The hyd ^Hra^ozideo was sy—nthesized in a m—anner sim -ilar to that of Example 1.5.1 using the appropriate starting materials (Peptech).

Example 1.5.5: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-l -carbonyl)-5- (pyrazin-2-yl)benzohydrazide

[0451] To the acid,(R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)-5-(pyrazin-2- yl)benzoic acid (300mg, 0.76 mmol) in DCM (5 ml), HOBT (103 mg, 0.76mmol), EDCI (146 mg, 0.76 mmol) was added and stirred at rt for 2h. Then the resulting solution was added to the hydrazine hydrate (114 mg, 2.28 mmol) in DCM at -30°C. Reaction mixture was stirred at rt for 48h and then worked up and column purified to yield (R)-3-(2-(4-methylthiazol-2- yl)pyrrolidine-l-carbonyl)-5-(pyrazin-2-yl)benzohydrazide in 93% yield.

Example 1.6: Synthesis of advanced intermediates.

Example 1.6.1

[0452] A solution of the acid (0.1106 g, 0.33 mmol, 1 eq) in anhydrous CH₂C1₂ (5 ml) under Ar was cooled to 0 °C with stirring. The solution was treated ΗΟΒΤ·Η₂0 (0.0497 g,

0.37 mmol, 1.1 eq) followed by EDCI-HCl (0.0703 g, 0.37 mmol, 1.1 eq) 30 min later. After lh anhydrous N₂H₄ (0.042 ml, 0.043 g, 1.34 mmol, 4 eq) was added followed by DIPEA

(0.12 ml, 0.087 g, 0.67 mmol, 2 eq) 10 min later. The reaction was stirred at 0 °C to room temperature overnight. After stirring overnight the reaction was quenched with water and the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/ water and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.1223 g (0.36 mmol, 108%) of the slight crude hydrazide.

[0453] A solution of the acid (0.0935 g, 0.335 mmol, 1 eq) in anhydrous CH₂C1₂ (3 ml) under Ar was cooled to 0 °C with stirring. The solution was treated ΗΟΒΤ·Η₂0 (0.0542 g, 0.40 mmol, 1.2 eq) followed by EDCI HC1 (0.0703 g, 0.37 mmol, 1.1 eq) 30 min later. After lh the reaction was treated with a solution of the crude hydrazide (0.1223 g, 0.36 mmol, ~ 1 eq) in anhydrous CH₂C1₂ (2 ml). After 5 min DIPEA (0.22 ml, 0.17 g, 1.28 mmol, 4 eq) was added, and the reaction was stirred at 0 °C to room temperature overnight. The reaction was quenched with water and the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/ water and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.1507 g (0.25 mmol, 75%) of the product.

Example 1

[0454] A solution of the starting material (0.0641 g, 0.11 mmol, 1 eq) in anhydrous DMF (2 ml) under Ar was cooled to 0 °C with stirring. Mel (0.017 ml, 0.039 g, 0.27 mmol, 2.5 eq) was added, and the reaction was protected from light. NaH (60% dispersion in oil, 0.0065 g, 0.16 mmol, 1.5 eq) was added, and the reaction was stirred at 0 °C to room temperature overnight. The reaction was quenched with water and extracted with EtOAc (xl). The organic layer was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.0608 g (0.10 mmol, 92%) of the product. Example 1.6.3: (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-5-(oxazol-2-yl)benzoic acid

[0455] 6.3.1 and 6.3.2 were coupled using a standard coupling procedure involving HOBT, EDCI, and DIPEA in CH₂CI₂ and stirring overnight, resulting in 6.3.3 in 81% yield.

[0456] To a solution of 6.3.3 (3.51g, 6.72 mmoles) in dicholoroethane (25 mL) was added Burgess' reagent (3.6g, 15.43 mmoles) and refluxed for 5h. The reaction mix was then cooled to room temperature, diluted with CH₂CI₂ and washed successively with satd.aq. NaHC0₃ and brine, dried, concentrated and purified on silica gel (1% MeOH/99% CHC1₃) to obtain 3.1g of 6.3.4.

[0457] 6.3.4 was hydrolyzed using standard hydrolysis conditions using IN LiOH in THF for lh followed by acidic work-up to obtain (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)benzoic acid in quantitative yield. Example 1.6.4: (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-(4-fluorophenyl)propan-2-yl)- l,3,4-oxadiazol-2-yl)-5-(oxazol- -yl)benzoic acid

[0458] (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-(4-fluorophenyl)propan-2-yl)- 1,3,4- oxadiazol-2-yl)-5-(oxazol-2-yl)benzoic acid was synthesized using the same procedure as in Example 1.6.3.

Example 1.6.5: (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-5-(pyrazin-2-yl)benzoic acid

[0459] (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2- yl)-5-(pyrazin-2-yl)benzoic acid was synthesized using the same procedure as in Example 1.6.3. Example 1.6.6: (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-5-(pyridin-2-yl)benzoic acid

[0460] (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2- yl)-5-(pyridin-2-yl)benzoic acid was synthesized using the same procedure as in Example 1.6.3.

Example 1.6.7: (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-4-chlorobenzoic acid

6.7.4

6.7.3 6.7.2

[0461] To a solution of 5-bromo-2-chlorobenzoic acid (2 g, 8.49 mmol) and (R)-tert-butyl (l-hydrazinyl-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate (2.74 g, 9.34 mmol) in CH₂C1₂ (Volume: 50ml) was added HOBT (1.301 g, 8.49 mmol), EDC (1.954 g, 10.19 mmol) and DIPEA (4.45 ml, 25.5 mmol) and stirred overnight.The reaction mixture was diluted with CH₂C1₂ (Volume: 50ml) and washed with 0.1M HCl, sat NaHC0₃ and sat NaCl. The organic layer was dried on Na₂S0₄, filtered and concentrated.The residue was purified on combi-flash 0- 30% EtO Ac/70% hexane to obtain 2.5 g of (R)-tert-butyl (l-(2-(5-bromo- 2-chlorobenzoyl)hydrazinyl)-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate (6.7.1).

[0462] To a solution of (R)-tert-butyl (l-(2-(5-bromo-2-chlorobenzoyl)hydrazinyl)-2- methyl-l-oxo-3-phenylpropan-2-yl)carbamate (2.95 g, 5.78 mmol) in DCE (Volume: 75 ml) was added Burgess' reagent (3.44 g, 14.44 mmol), and refluxed for 4h. The reaction was cooled to room temperature, diluted with CH2CI2 (50 mL) and washed with sat NaHC0₃ and sat. NaCl. The organic layer was dried on Na₂S0₄, filtered and concentrated. The residue was purified on combi-flash 0- 30% EtO Ac/70% hexane to obtain 2.13 g of (R)-tert-butyl (2-(5- (5-bromo-2-chlorophenyl)-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (6.7.2).

[0463] A solution of (R)-tert-butyl (2-(5-(5-bromo-2-chlorophenyl)-l,3,4-oxadiazol-2-yl)-

1- phenylpropan-2-yl)carbamate (492.793 mg, 1.000 mmol) in Et₃N (Volume: 8mL) and MeOH (1.214 mL, 30.0 mmol) (both solvents degassed) in a vial, was purged with carbon monoxide for 2 min and palladium(II) acetate (22.45 mg, 0.100 mmol) (Aldrich Lot # 83697MJV), and XANTPHOS (116 mg, 0.200 mmol) (Aldrich Lot # MKBF8281V) were added and refluxed for 2hl5min. TLC shows -95% conversion.The reaction was filtered through a cotton plug and concentrated.The residue was purified on combi-flash 0- 40% EtO Ac/60% hexane to obtain 370 mg of (R)-methyl 3-(5-(2-((tert-butoxycarbonyl)amino)-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-chlorobenzoate (6.7.3).

[0464] To a solution of (R)-methyl 3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-

2- yl)-l,3,4-oxadiazol-2-yl)-4-chlorobenzoate (370 mg, 0.784 mmol) in THF (Volume: 5 ml) was added LiOH (1 ml, 0.784 mmol) and stirred for lh. TLC shows ~ 60% conversion. Continued stirring for 2h more. IN HC1 was added drop-wise to bring it to pH ~4. The mixture was diluted with EtO Ac and washed with brine, dried and concentrated to obtain 347 mg of (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)- 4-chlorobenzoic acid (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-4-chlorobenzoic acid. Exam le 1.6.8

[0465] The ester (216 mg) was treated with hydrazine (0.3 mL, excess) in ethanol under microwave conditions (140 °C, 28 min) to give the product (170 mg), which was treated with triethyl orthoformate (2 mL) in toluene under microwave conditions (170 °C, 15 min) to give the crude product (90 mg).

[0466] The hydazide product (170 mg ) in DCM (10 mL) was cooled with an ice bath, treated with phosgene (20% in toluene, 2 mL, excess) for 20 min, then warmed to room temperature and stirred one more hour. The solvent was moved under vacuum to give the crude product, which was diluted with EtOAc, washed with aqueous saturated NH₄C1, aqueous saturated NaHC0₃, brine, dried (Na₂S0₄), filtered, and evaporated in vacuo. Flash chromatography on silica gel afforded the pure product (100 mg). Example 1.6.9

[0467] The iodide (150 mg, 0.2147 mmol) and pyrazole (13.2 mg, 0.1923 mmol) were treated with Cu₂0 (8.25 mg, 0.0577 mmol) and CsC0₃ (125.3 mg, 0.385 mmol) in DMF (4 mL) under microwave condition (140 °C, 70 min) to give the product (30 mg). 1H NMR (300 MHz, CDC1₃+CD₃0D) δ 8.298 (m, 1 H), 8.119 (s, 1.2 H), 8.063 (m, 0.8 H), 7.782 (m, 2 H), 8.218 (m, 3 H), 7.042 (m, 2 H), 6.805 (s, 0.8 H), 6.757 (s, 0.2 H), 6.541 (s, 0.8 H), 6.480 (s, 0.2 H), 5.675 (m, 0.8 H), 5.213 (m, 0.2 H), 3.929 (m, 1 H), 3.845 (m, 1 H), 3.634 (m, 1 H), 3.266 (m, 1 H), 3.124 (m, 1 H), 2.446 (m, 3 H), 2.130 (m, 2 H), 1.974 (m, 2 H), 1.668 (s, 3 H).

Exam le 1.6.10

[0468] The iodide was treated with Zn(CN)₂ in DMF in the presence of palladium (0) to give the product.

Example 1.6.11

[0469] A solution of the starting material (0.4g, 1.4 mmol, 1 eq) in MeOH was purged with Ar to degas. Rh (5% on alumina, 0.4 g, 100% by wt) was added. The mixture was hydrogenated via a Parr shaker at 55 psi and 50 °C for 60h. After cooling to room

temperature the mixture was filtered through Celite. The volatiles were removed via rotary evaporation to yield 0.3502 g (88%) of the product.

Example 1.6.12: Synthesis of tert-butyl ((R)-2-(5-(3-(l-methyl-lH-imidazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-l,3,4-oxa

yl)carbamate

[0470] To the acid (400mg, 1.61 mmol) in DCM (10 ml), HOBT (261 mg, 1.93mmol), EDCI (433 mg, 2.26 mmol) was added and stirred at rt for 2h. Then to the resulting solution, hydrazide (612 mg, 2.09 mmol) was added. Reaction mixture was stirred at rt for 16h and then worked up and column purified to yield the hydrzide in 93% yield.

[0471] To the hydrazide (630 mg, 1.2 mmol) in 1,2 -DCE, burgess reagent (861 mg, 3.6 mmol)(commercial source: Alfa-Aesar) was added and the reaction mixture was heated at 60oC for 5h. Then reaction mixture was cooled, diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, water, brine and dried. Crude residue was column chromatographed to yield the product in 75% yield. [0472] The resulting ester was converted to acid using aqueous sodium hydroxide in a manner similar to depicted in Example 1.4.6.

[0473] To the acid (174mg, 0.35 mmol) in DCM (5 ml), HOBT (51 mg, 0.42mmol), EDCI (94 mg, 0.49 mmol) was added and stirred at rt for 2h. Then the amine, (R)-4-methyl-2- (pyrrolidin-2-yl)thiazole (59 mg, 0.35 mmol) and DIPEA (0.1 ml) was added to the reaction mixture and allowed to stir overnight and then worked up and column purified to yield the Boc compound in 30% yield.

Example 1.6.13

[0474] 2-Cyclopropyl-6-(methoxycarbonyl)isonicotinic acid: 4-te/t-Butyl 2-methyl 6- cyclopropylpyridine-2,4-dicarboxylate (236 mg, 0.85 mmol) was placed into a vessel to which TFA (4.9 ml) was added. The mixture was stirred at rt for 1 hour and volatiles were evaporated to give a crude of 2-cyclopropyl-6-(methoxycarbonyl)isonicotinic acid , which was immediately used for the next reaction without further purification.

[0475] Methyl 6-cyclopropyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate: To a stirred solution of 2-cyclopropyl-6- (methoxycarbonyl)isonicotinic acid (188 mg, 0.85 mmol), 4-methyl-2-[(2R)-pyrrolidin-2-yl]- 1,3-thiazole (172 mg, 1.02 mmol) and Et₃N (0.118 ml, 0.85 mmol) in CH₂C1₂ (5 ml) were added EDCI-HCl (196 mg, 1.02 mmol) and HOBt (138 mg, 1.02 mmol) at rt and the mixture was stirred at the same temperature overnight. The mixture was quenched with H₂0 and the organic layer was separated. The aqueous layer was extracted with CHC1₃ (x3) and the combined organic layer was washed with satd. NaHC0₃ aq. (x2), IN HCl aq. and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 0 to 66%) to give methyl 6-cyclopropyl-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate (245 mg, 78% yield) as a yellow oil. MS (ESI) m/z: 372 [M+H]⁺.

[0476] 6-Cyclopropyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carbohydrazide: To a stirred solution of methyl 6-cyclopropyl-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate (245 mg, 0.66 mmol) in EtOH was added NH₂NH₂-H₂0 (0.32 ml, 6.60 mmol) at rt and the mixture was stirred at 65 degree for 1 hour. The reaction cleanly proceeded and it was diluted with H₂0/EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc (x3). The combined organic layer was washed with H₂0 (x3) and brine, dried over MgS0₄ and evaporated to give a crude of 6-cyclopropyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carbohydrazide as a colorless oil, which was used for the next reaction without further purification.

[0477] tert-Butyl [(2R)-l-{2-[(6-cyclopropyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-2-methyl-l-oxo-3- phenylpropan-2-yl]carbamate: To a stirred solution of 6-cyclopropyl-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carbohydrazide (245 mg, 0.66 mmol) and N-(iert-butoxycarbonyl)-alpha-methyl-D-phenylalanine (221 mg, 0.79 mmol) in CH₂C1₂ (5 ml) were added EDCI-HCl (152 mg, 0.79 mmol) and HOBt (107 mg, 0.79 mmol) at rt and the mixture was stirred at the same temperature overnight. The mixture was quenched with H₂0 and the organic layer was separated. The aqueous layer was extracted with CHCI₃ (x3) and the combined organic layer was washed with satd. NaHC0₃ aq. (x2), 1 M HC1 aq. and brine, dried over MgS0₄ and evaporated to give a crude of tert-butyl [(2R)-1- {2-[(6-cyclopropyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin- 2-yl)carbonyl]hydrazino}-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate which was used for the next reaction without further purification. MS (ESI) m/z: 633[M+H]⁺. Example 1.6.14

[0478] 2-(2-Cyanophenyl)-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1):

The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(2- cyanophenyl)pyridine-2,4-dicarboxylate (95 mg, 0.281 mmol) in a similar manner to

Example 1.6.13. MS (ESI) m/z: 283 [M+H]⁺.

[0479] Methyl 6-(2-cyanophenyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate: The desired compound was synthesized from 2-(2- cyanophenyl)-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) (111 mg, 0.281 mmol) in a similar manner to Example 1.6.13. (121 mg, >99% yield) MS (ESI) m/z: 433

[M+H]⁺.

[0480] 6-(2-Cyanophenyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 6-(2-cyanophenyl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate (121 mg, 0.281 mmol) in a similar manner to Example 1.6.13. MS (ESI) m/z: 433 [M+H]⁺.

[0481] tert-Butyl [(2R)-l-(2-{[6-(2-cyanophenyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]carbonyl}hydrazino)-2-methyl-l-oxo-3- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 6-(2- cyanophenyl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2- carbohydrazide (121 mg, 0.281 mmol) in a similar manner to Example 1.6.13. MS (ESI) m/z:

694 [M+H]⁺. Example 1.6.15

[0482] 2-(Methoxycarbonyl)-6-(l,3-oxazol-2-yl)isonicotinic acid trifluoroacetate (1:1):

The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(l,3-oxazol-2- yl)pyridine-2,4-dicarboxylate (92 mg. 0.302 mmol) in a similar manner to Example 1.6.13. MS (ESI) m/z: 283 [M+H]⁺.

[0483] Methyl 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(l,3- oxazol-2-yl)pyridine-2-carboxylate: The desired compound was synthesized from 2- (methoxycarbonyl)-6-(l,3-oxazol-2-yl)isonicotinic acid trifluoroacetate (1:1) (109 mg 0.301 mmol) in a similar manner to Example 1.6.13. (114 mg, 95% yield) MS (ESI) m/z: 399

[M+H]⁺.

[0484] 4-{[(2R)-2-(4-Methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(l,3-oxazol-2- yl)pyridine-2-carbohydrazide. The desired compound was synthesized from methyl 4- { [(2R)-2-(4-methyl- 1 ,3 -thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-( 1 ,3-oxazol-2-yl)pyridine-2- carboxylate (114 mg, 0.286 mmol) in a similar manner to Example 1.6.13. MS (ESI) m/z: 433 [M+H]⁺.

[0485] tert-Butyl [(2R)-2-methyl-l-(2-{[4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]carbonyl}hydrazino)-l-oxo- 3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 4-{ [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-( 1 ,3-oxazol-2-yl)pyridine-2- carbohydrazide (110 mg, 0.251 mmol) in a similar manner to Example 1.6.13. MS (ESI) m/z: 660 [M+H]⁺. Example 1.6.16

[0486] 2-(Methoxycarbonyl)-6- [methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1:1): The desired compound was synthesized from 4-tert-butyl 2-methyl 6- [methyl(methylsulfonyl)amino]pyridine-2,4-dicarboxylate (234 mg, 0.679 mmol) in a similar manner to Example 1.6.13. (247 mg, 90% yield) MS (ESI) m/z: 289 [M+H]⁺.

[0487] Methyl 6-[methyl(methylsulfonyl)amino]-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate: The desired compound was synthesized from 2-(methoxycarbonyl)-6-[methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1:1) (186 mg, 0.462 mmol) in a similar manner to Example 1.6.13. (171 mg, 84% yield) MS (ESI) m/z: 439 [M+H]⁺.

[0488] N-[6-(Hydrazinocarbonyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl]-N-methylmethanesulfonamide: The desired compound was synthesized from methyl 6-[methyl(methylsulfonyl)amino]-4-{ [(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate (171 mg, 0.390 mmol) in a similar manner to Example 1.6.13. (156 mg, 91% yield) MS (ESI) m/z: 439 [M+H]⁺.

[0489] t^Butyl [(2R)-2-methyl-l-{2-[(6-[methyl(methylsulfonyl)amino]-4-{[(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-l- oxo-3-phenylpropan-2-yl] carbamate: The desired compound was synthesized from N-[6- (hydrazinocarbonyl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin- 2-yl]-N-methylmethanesulfonamide (156 mg. 0.356 mmol)in a similar manner to Example 1.6.13. MS (ESI) m/z: 701 [M+H]⁺. Example 1.6.17

[0490] 2-Methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1): The desired compound was synthesized from 4-ie/t-butyl 2-methyl 6-methoxypyridine-2,4- dicarboxylate (337 mg, 1.26 mmol) in a similar manner to Example 1.6.13. (370 mg, 90% yield) MS (ESI) m/z: 445 [2M+Na]⁺.

[0491] Methyl 6-methoxy-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate: The desired compound was synthesized from 2- methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) (370 mg, 1.14 mmol) in a similar manner to Example 1.6.13. (170 mg, 41% yield) MS (ESI) m/z: 362 [M+H]⁺.

[0492] 6-Methoxy-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 6-methoxy-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine- 2-carboxylate (170 mg, 0.470 mmol) in a similar manner to Example 1.6.13. MS (ESI) m/z: 362 [M+H]⁺.

[0493] tert-Butyl [(2R)-l-{2-[(6-methoxy-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-2-methyl-l-oxo-3- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 6-methoxy-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carbohydrazide (170 mg, 0.470 mmol) in a similar manner to Example 1.6.13. Example 1.6.18

[0494] 2-(Methoxycarbonyl)-6- [methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1:1): 4-tert-Butyl 2-methyl 6-[methyl(methylsulfonyl)amino]pyridine-2,4- dicarboxylate (234 mg, 0.679 mmol) was placed into a vessel to which TFA (4 ml) was added. The mixture was stirred at rt for 1 hour and volatiles were evaporated to give a crude of 2-(methoxycarbonyl)-6-[methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1 : 1), which was immediately used for the next reaction without further purification. MS (ESI) m/z: 289 [M+H]⁺.

[0495] Methyl 4-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl}hydrazino)carbonyl]-6-[methyl(methylsulfonyl)amino]pyridine-2- carboxylate: To a stirred solution of 2-(methoxycarbonyl)-6-

[methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1 : 1) (93 mg, 0.23 mmol) and z^'-Pr₂NEt (0.087 ml, 0.51 mmol) in CH₂C1₂ (5 ml) were added tert-butyl [(2R)-1- hydrazino-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate (81 mg, 0.28 mmol) and HATU (105 mg, 0.28 mmol) at rt and the mixture was stirred at the same temperature overnight. The mixture was quenched with H₂0 and the organic layer was separated. The aqueous layer was extracted with CHCI₃ (x3) and the combined organic layer was washed with aq. KHSO₄ (pH 4), NaHC0₃ aq. and brine, dried over MgS0₄ and evaporated to give a crude of methyl 4-[(2- { (2R)-2-[(ieri-butoxycarbonyl)amino]-2-methyl-3-phenylpropanoyl}hydrazino)carbonyl]-6- [methyl(methylsulfonyl)amino]pyridine-2-carboxylate, which was used for the next reaction without further purification. [0496] Methyl 4-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylate: Methyl 4-[(2- { (2R)-2- [(tert-butoxycarbonyl)amino] -2-methyl-3-phenylpropanoyl }hydrazino)carbonyl] -6- [methyl(methylsulfonyl)amino]pyridine-2-carboxylate (130 mg, 0.23 mmol) and Burgess reagent (164 mg, 0.69 mmol) were placed into a vessel for microwave reactions. This vessel was sealed and irradiated with microwave at 120 degree for 20 min. Volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 20 to 100%) to give methyl 4-(5-{(2R)-2-[(ieri-butoxycarbonyl)amino]-l- phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2- carboxylate (99 mg, 79% yield in 3 steps) as a pale yellow oil. MS (ESI) m/z: 546 [M+H]⁺. Example 1.6.19

[0497] tert-Butyl {(2R)-2-[5-(6-[methyl(methylsulfonyl)amino]-4-{[(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: The desired compound was synthesized from tert-butyX [(2R)-2-methyl-l-{2-[(6-[methyl(methylsulfonyl)amino]-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl)carbonyl]hydrazino } - 1 -oxo-3-phenylpropan-2-yl] (248 mg, 0.354 mmol) in a similar manner to Example 1.6.18. {I ll mg, 48% yield) MS (ESI) m/z: 682 [M+H]⁺.

Example 1.6.20

[0498] 4-(5-{(2R)-2-[(tert-Butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid: The desired compound was synthesized from methyl 4-(5-{(2R)-2-[(iert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- l,3,4-oxadiazol-2-yl)-6-oxo-l,6-dihydropyridine-2-carboxylate (406 mg, 0.893 mmol) in a similar manner to Example 1.7.56.

[0499] tert-Butyl {(2R)-2-[5-(6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-2-oxo-l,2-dihydropyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: The desired compound was synthesized from 4-(5-{(2R)-2-[(tert- butoxycarbonyl)amino] - 1 -phenylpropan-2-yl } - 1 ,3 ,4-oxadiazol-2-yl)-6-oxo- 1,6- dihydropyridine-2-carboxylic acid (393 mg, 0.892 mmol) in a similar manner to Example 1.7.56. (268 mg, 51% yield in 2 steps) MS (ESI) m/z: 591 [M+H]⁺.

Example 1.6.21

[0500] 6-Chloro-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylic acid: To a stirred solution of methyl 6-chloro-4-{ [(2R)- 2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate (3.21 g, 8.77 mmol) in THF (10 ml) was added 3 M NaOH aq. (8.77 ml, 26.3 mmol) at rt and the mixture was stirred at rt for 1 hour. The mixture was quenched with 6 M HC1 aq. (4.38 ml) and volatiles were evaporated to give a crude of 6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylic acid, which was used for the next reaction without further purification.

[0501] tert-Butyl [(2R)-l-{2-[(6-chloro-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-2-methyl-l-oxo-3- phenylpropan-2-yl]carbamate: To a stirred solution of 6-chloro-4-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylic acid (3.09 g, 8.77 mmol) and tert-butyl [(2R)-l-hydrazino-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate (2.70 g, 9.21 mmol) in CH₂C1₂ (50 ml) were added HATU (3.50 g, 9.21 mmol) and z-Pr₂NEt (1.58 ml, 9.21 mmol) at rt and the mixture was stirred at the same temperature overnight. The mixture was quenched with aqueous citric acid (pH 3) and the organic layer was separated. The aqueous layer was extracted with CHCI₃ (x3) and the combined organic layer was washed with aqueous citric acid (pH 3), satd. NaHC0₃ and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (NH- silica, EtOAc in hexane = 20 to 100% then MeOH in CHC1₃ = 0 to 20%) to give ierf-butyl [(2R)-l-{2-[(6-chloro-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2- yl)carbonyl]hydrazino}-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate (3.84 g, 70% yield) as a yellow oil. MS (ESI) m/z: 627 [M+H]⁺.

[0502] t^Butyl {(2R)-2-[5^6-chloro-4-{[(2R)-2^4-methyl-l,3-thiazol-2-yl)pyrrolidin- l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate: tert- Butyl [(2R)- 1 - { 2- [(6-chloro-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-2-methyl-l-oxo-3-phenylpropan-2- yl]carbamate (3.84 g, 6.12 mmol) and Burgess reagent (4.38 g, 18.4 mmol) were placed into a vessel for microwave reactions. This vessel was sealed and irradiated with microwave at 120 degree for 20 min. Volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 20 to 100%) to give tert-butyl {(2R)-2-[5-(6- chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)- 1,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (2.55 g, 68% yield) as a pale brown solid. MS (ESI) m/z: 609 [M+H]⁺.

Example 1.6.22

[0503] 2-Methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1): 4-tert- Butyl 2-methyl 6-methoxypyridine-2,4-dicarboxylate (400 mg, 1.49 mmol) was placed into a vessel, to which TFA (4 ml) was added at rt. The mixture was stirred at the same temperature for 1 hour and volatiles were evaporated to give a crude of 2-methoxy-6- (methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) as a white solid, which was used for the next reaction without further purification.

[0504] Methyl 4-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl}hydrazino)carbonyl]-6-methoxypyridine-2-carboxylate: To a stirred solution of 2-methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) (486 mg, 1.49 mmol) and z-Pr₂NEt (0.52 ml, 3.06 mmol) in CH₂C1₂ (10 ml) were added HATU (597 mg, 1.57 mmol) and tert-butyl [(2R)-l-hydrazino-2-methyl-l-oxo-3-phenylpropan-2- yl]carbamate (460 mg, 1.57 mmol) at rt and the mixture was stirred at the same temperature overnight. The mixture was quenched with H₂0 and the organic layer was separated. The aqueous layer was extracted with CHC1₃ (x3) and the combined organic layer was washed with satd. NaHC0₃ aq. (x2) and brine, dried over MgS0₄ and evaporated to give a crude of methyl 4-[(2-{ (2R)-2-[(iert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl}hydrazino)carbonyl]-6-methoxypyridine-2-carboxylate, which was used for the next reaction without further purification. MS (ESI) m/z: 487 [M+H]⁺.

[0505] Methyl 4-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-methoxypyridine-2-carboxylate: methyl 4-[(2-{ (2R)-2-[(iert- Butoxycarbonyl)amino]-2-methyl-3-phenylpropanoyl}hydrazino)carbonyl]-6- methoxypyridine-2-carboxylate (727 mg, 1.49 mmol) and Burgess reagent (1.07 g, 4.48 mmol) were placed into a vessel for microwave reactions. This vessel was sealed and irradiated with microwave at 120 degree for 20 min. Volatiles were evaporated to give a crude, which was briefly purified with column chromatography (EtOAc in hexane = 33%, Si0₂ 10 g) to give methyl 4-(5-{(2R)-2-[(iert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- l,3,4-oxadiazol-2-yl)-6-methoxypyridine-2-carboxylate containing some byproducts as a pale yellow oil. MS (ESI) m/z: 469 [M+H]⁺.

Example 1.6.23

[0506] 4-(5-{(2R)-2-[(tert-Butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2- yl trifluoromethanesulfonate: To a stirred solution of tert-butyl {(2R)-2-[5-(6-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2-dihydropyridin-4-yl)- 1,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (268 mg, 0.454 mmol) and z-Pr₂NEt (0.116 ml, 0.68 mmol) in CH₂C1₂ (5 ml) was added Tf₂0 (0.091 ml, 0.54 mmol) at 0 degree. The starting molecule was completely consumed in 1 hour and it was quenched with satd.

NaHC0₃ aq. The organic layer was separated and the aqueous layer was extracted with CHC1₃ (x2). The combined organic layer was washed with H₂0 and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (MeOH in CHC1₃ = 0 to 10%) to give 4-(5-{(2R)-2-[(ieri-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- 1 ,3,4-oxadiazol-2-yl)-6- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl}pyridin-2-yl trifluoromethanesulfonate (208 mg, 63% yield) as a colorless oil. MS (ESI) m/z: 723 [M+H]⁺.

Example 1.6.24

[0507] tert-butyl {(2R)-2-[5-(6-[acetyl(methyl)amino]-4-{[(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro- 4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.3.21 (126 mg, 79%).

Example 1.6.25

[0508] 2-(methoxycarbonyl)-6-(2-oxopyrrolidin-l-yl)isonicotinic acid: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(2-oxopyrrolidin-l-yl)pyridine-2,4- dicarboxylate in a similar manner to Example 1.6.13 (60 mg).

[0509] methyl 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopyrrolidin-l-yl)pyridine-2-carboxylate: The desired compound was synthesized from 2-(methoxycarbonyl)-6-(2-oxopyrrolidin-l-yl)isonicotinic acid in a similar manner to Example 1.6.13 (88 mg, 94% yield: 2 steps). MS (ESI) m/z: 415 [M+H]⁺.

[0510] 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopyrrolidin-l-yl)pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopyrrolidin-l-yl)pyridine-2-carboxylate in a similar manner to Example 1.6.13 (86 mg).

[0511] tert-butyl [(2R)-2-methyl-l-(2-{[4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxopyrrolidin-l-yl)pyridin-2-yl]carbonyl}hydrazino)- l-oxo-3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(2-oxopyrrolidin- 1 - yl)pyridine-2-carbohydrazide in a similar manner to Example 1.6.13 (58 mg, 41% yield: 2 steps). Example 1.6.26

[0512] 2-(methoxycarbonyl)-6-(2-oxo-l,3-oxazolidin-3-yl)isonicotinic acid: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(2-oxo-l,3-oxazolidin-3- yl)pyridine-2,4-dicarboxylate in a similar manner to Example 1.6.13 (51 mg).

[0513] methyl 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxo-l,3-oxazolidin-3-yl)pyridine-2-carboxylate: The desired compound was synthesized from 2-(methoxycarbonyl)-6-(2-oxo-l,3-oxazolidin-3-yl)isonicotinic acid in a similar manner to Example 1.6.13 (58 mg, 73% yield: 2 steps). MS (ESI) m/z: 417 [M+H]⁺.

[0514] 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxo-l,3- oxazolidin-3-yl)pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxo-l,3- oxazolidin-3-yl)pyridine-2-carboxylate in a similar manner to Example 1.6.13 (58 mg).

[0515] tert-butyl [(2R)-2-methyl-l-(2-{[4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2- yl]carbonyl}hydrazino)-l-oxo-3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxo-l,3-oxazolidin-3-yl)pyridine-2-carbohydrazide in a similar manner to Example 1.6.13 (28 mg, 30% yield: 2 steps). Example 1.6.27

[0516] 2-(methoxycarbonyl)-6-(2-methyl-5-oxopyrrolidin-l-yl)isonicotinic acid: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(2-methyl-5-oxopyrrolidin- l-yl)pyridine-2,4-dicarboxylate in a similar manner to Example 1.6.13 (58 mg).

[0517] methyl 6-(2-methyl-5-oxopyrrolidin-l-yl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate: The desired compound was synthesized from 2-(methoxycarbonyl)-6-(2-methyl-5-oxopyrrolidin-l-yl)isonicotinic acid in a similar manner to Example 1.6.13 (70 mg, 78% yield: 2 steps). MS (ESI) m/z: 429 [M+H]⁺.

[0518] 6-(2-methyl-5-oxopyrrolidin-l-yl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 6-(2-methyl-5-oxopyrrolidin-l-yl)-4-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate in a similar manner to Example 1.6.13 (70 mg).

[0519] tert-butyl [(2R)-2-methyl-l-(2-{[6-(2-methyl-5-oxopyrrolidin-l-yl)-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]carbonyl}hydrazino)-l- oxo-3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 6-(2- methyl-5-oxopyrrolidin-l-yl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carbohydrazide in a similar manner to Example 1.6.13 (112 mg, 99% yield: 2 steps). Example 1.6.28

[0520] 2-(methoxycarbonyl)-6-(2-oxopiperidin-l-yl)isonicotinic acid: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(2-oxopiperidin-l-yl)pyridine-2,4- dicarboxylate in a similar manner to Example 1.6.13 (211 mg).

[0521] methyl 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopiperidin-l-yl)pyridine-2-carboxylate: The desired compound was synthesized from 2- (methoxycarbonyl)-6-(2-oxopiperidin-l-yl)isonicotinic acid in a similar manner to Example 1.6.13 (124 mg, 38% yield: 2 steps). MS (ESI) m/z: 429 [M+H]⁺.

[0522] 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopiperidin-l-yl)pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopiperidin-l-yl)pyridine-2-carboxylate in a similar manner to Example 1.6.13 (120 mg).

[0523] tert-butyl [(2R)-2-methyl-l-(2-{[4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxopiperidin-l-yl)pyridin-2-yl]carbonyl}hydrazino)-l- oxo-3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(2-oxopiperidin- 1 - yl)pyridine-2-carbohydrazide in a similar manner to Example 1.6.13 (193 mg, 98% yield: 2 steps). Example 1.6.29

[0524] 2-(methoxycarbonyl)-6-(2-oxopyrrolidin-l-yl)isonicotinic acid: 4-tert-butyl 2- methyl 6-(2-oxopyrrolidin-l-yl)pyridine-2,4-dicarboxylate (228 mg, 0.71 mmol) was placed into a vessel to which TFA (3.3 ml, 43mmol) was added. The mixture was stirred at rt for 1 hour and evaporated azeotropically with toluene to give a crude of 2-(methoxycarbonyl)-6- (2-oxopyrrolidin-l-yl)isonicotinic acid (174 mg, 93%), which was immediately used for the next reaction without further purification.

[0525] 4-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl}hydrazino)carbonyl]-6-(2-oxopyrrolidin-l-yl)pyridine-2-carboxylic acid: To a solution of 2-(methoxycarbonyl)-6-(2-oxopyrrolidin-l-yl)isonicotinic acid (174 mg, 0.66 mmol) and tert-butyl [(2R)-l-hydrazino-2-methyl-l-oxo-3-phenylpropan-2- yl]carbamate (232 mg, 0.79 mmol) in DMF (3 ml) were added EDCI HC1 (164 mg, 0.86 mmol) and HOBt (89 mg, 0.66 mmol) at rt and the mixture was stirred at the same temperature overnight. 1M aq. NaOH and CHCI₃ were added to the mixture, and then the organic layer was separated. The aqueous layer was acidified with 1M aq. HCl and extracted with EtOH/CHCl₃(l:5 v/v) (x3) after adding brine. The combined organic layer was dried over MgS0₄ and evaporated to give a crude 4-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2- methyl-3-phenylpropanoyl }hydrazino)carbonyl] -6-(2-oxopyrrolidin- 1 -yl)pyridine-2- carboxylic acid (416 mg, >100% yield) as a colorless oil, which was used for the next reaction without further purification. [0526] tert-butyl [(2R)-2-methyl-l-{2-[2-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxopyrrolidin-l-yl)isonicotinoyl]hydrazino l-l-oxo-3- phenylpropan-2-yl]carbamate: To a solution of 4-[(2-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-methyl-3-phenylpropanoyl}hydrazino)carbonyl]-6-(2- oxopyrrolidin-l-yl)pyridine-2-carboxylic acid (416 mg, 0.79 mmol)and 4-methyl-2-[(2R)- pyrrolidin-2-yl]-l,3-thiazole (266 mg, 1.6 mmol) in DMF (4 ml) were added EDCI-HCl (303 mg, 1.6 mmol) and HOBt (107 mg, 0.79 mmol). After stirring at rt for 14 hours, the reaction mixture was treated with EtO Ac/water. The organic layer was dried over MgSCk and volatiles were removed under reduced pressure. Purification of the obtained residue via column chromatography (EtOH/CHCl₃ = 0:100 to 5:95) yielded 320 mg (60%) of tert-butyl [(2R)-2-methyl-l-{2-[2-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2- oxopyrrolidin-l-yl)isonicotinoyl]hydrazino}-l-oxo-3-phenylpropan-2-yl]carbamate as a slightly reddish oil.

[0527] tert-butyl [(2R)-2-{5-[2-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(2-oxopyrrolidin-l-yl)pyridin-4-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: To a stirred solution of tert-butyl [(2R)-2-methyl-l-{2-[2- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(2-oxopyrrolidin- 1 - yl)isonicotinoyl]hydrazino}-l-oxo-3-phenylpropan-2-yl]carbamate (320 mg, 0.47 mmol) in CH₂C1₂ (6 ml) were added CBr₄ (314 mg, 0.95 mmol), PPh₃ (248 mg, 0.95 mmol) and imidazole (64 mg, 0.95 mmol) and the mixture was stirred at rt for 2 hours. The mixture was evaporated and the obtained residue was purified with column chromatography (EtOH/CHCl₃ = 0:100 to 5:95) to give tert-butyl [(2R)-2-{5-[2-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(2-oxopyrrolidin-l-yl)pyridin-4-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl] carbamate as a colorless oil.

Example 1.6.30

[0528] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(lH-l,2,4-triazol-l-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: A suspension of tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl} carbamate (120 mg, 0.20 mmol), lH-l,2,4-triazole (68 mg, 0.99 mmol) and CS₂CO₃ (96 mg, 0.30 mmol) in NMP (2.4 ml) were placed into a vessel for microwave reactions. The vessel was sealed and irradiated with microwave at 150 °C for 10 min. After cooling, H₂0 was added and then the mixture was extracted with EtOAc. The organic layer was dried over MgS0₄ and concentrated under reduced pressure. The obtained residue was purified with column chromatography (EtOH / CHCI₃ = 0:100 to 5:95) to give tert-butyl [(2R)-2- { 5-[4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-( 1H- 1 ,2,4- triazol-l-yl)pyridin-2-yl]-l, 3, 4-oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate (32 mg, 25% yield) as a pale yellow solid.

Example 1.

[0529] tert-butyl [(2R)-2-{5-[6-(lH-imidazol-l-yl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-

4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- l-yl]carbonyl}pyridin-2-yl)- 1 ,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.6.30 (62 mg, 59% yield) as a pale yellow solid.

Example 1

[0530] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(lH-pyrazol-l-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl]carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro- 4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- l-yl]carbonyl}pyridin-2-yl)- 1 ,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.6.30 (144 mg, 91% yield) as a pale yellow oil.

Example 1.6.33

[0531] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(2H-l,2,3-triazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.6.30 (116 mg, 28% yield) as a colorless oil (more polar). MS (ESI) m/z: 642 [M+H]⁺

[0532] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(lH-l,2,3-triazol-l-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.6.30 (86 mg, 20% yield) as a colorless solid (less polar). MS (ESI) m/z: 642 [M+H]⁺.

Example 1.6.34

[0533] tert-butyl [(2R)-2-{5-[6-(l-methyl-lH-pyrazol-4-yl)-4-{[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: A suspension of tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl} carbamate (300 mg, 0.49 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (307 mg, 1.6 mmol), Pd₂(dba)₃ (113 mg, 0.25 mmol), SPhos (101 mg, 0.25 mmol) and K₃P0₄ (314 mg, 1.5 mmol) in toluene (3.0 ml) were placed into a vessel for microwave reactions. The vessel was sealed and irradiated with microwave at 130 °C for 30 min. After cooling, H₂0 and brine were added and then the mixture was extracted with CHC1₃. The organic layer was dried over MgS0₄ and concentrated under reduced pressure. The obtained residue was purified with column chromatography (NH-silica, EtOAc / hexane = 50:50 to 100:0) to give tert-butyl [(2R)-2-{5-[6-(l-methyl-lH-pyrazol-4-yl)-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol- 2-yl}-l-phenylpropan-2-yl] carbamate (212 mg, 66% yield) as a yellow oil. MS (ESI) m/z: 655 [M+H]⁺

Exampl

[0534] tert-butyl [(2R)-2-{5-[6-(l-methyl-lH-pyrazol-3-yl)-4-{[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.6.34 (320 mg, 99% yield) as a yellow oil. MS (ESI) m/z: 655 [M+H]⁺. Exampl

112 [0535] tert-butyl [(2R)-2-{5-[6-(l-methyl-lH-pyrazol-5-yl)-4-{[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate in a similar manner to Example 1.6.34 (356 mg, 100% yield) as a yellow oil. MS (ESI) m/z: 655 [M+H]⁺. Example 1.

[0536] tert-butyl [(2R)-2-{5-[4-{[(4-bromo-l,3-thiazol-2- yl)methyl](methyl)carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: To a stirred solution of 2-(5-{(2R)-2-[(tert- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid (160 mg, 0.33 mmol), z-Pr₂NEt (0.061 ml, 0.36 mmol) and l-(4-bromo- l,3-thiazol-2-yl)-N-methylmethanamine (74 mg, 0.36 mmol) in CH₂C1₂ (4.8 ml) was added HATU (136 mg, 0.36 mmol) at rt and the mixture was stirred at the same temperature for 2 hours. The mixture was quenched with H₂0 and was extracted with CHCI₃. The organic layer was washed with brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (EtOAc/hexane = 10:90 to 80:20) to give tert-butyl [(2R)-2-{5-[4-{ [(4-bromo-l,3-thiazol-2-yl)methyl](methyl)carbamoyl}-6-(l,3-oxazol-2- yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (204 mg, 92% yield) as a colorless oil. MS (ESI) m/z: 680, 682 [M+H]⁺.

Example 1.6.38

[0537] tert-butyl [(2R)-2-{5-[4-{methyl[(6-methylpyridin-3-yl)methyl]carbamoyl}-6- (l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l- phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2-yl)isonicotinic acid in a similar manner to Example 1.6.37 (86 mg, 69% yield) as a colorless oil. MS (ESI) m/z: 610 [M+H]⁺. Example

[0538] tert-butyl [(2R)-2-{5-[4-{[l-(l-methyl-lH-pyrazol-3-yl)ethyl]carbamoyl}-6-(l,3- oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l- phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2-yl)isonicotinic acid and 1-(1- methy-lH-pyrazol-3-yl) ethanamine in a similar manner to Example 1.6.37 (80 mg, 82% yield) as a white powder. MS (ESI) m/z: 599 [M+H]⁺

Example 1.6.4

[0539] tert-butyl [(2R)-2-{5-[4-{methyl[(6-methylpyridin-2-yl)methyl]carbamoyl}-6- (l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l- phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2-yl)isonicotinic acid in a similar manner to Example 1.6.37 (90 mg, 73% yield) as a colorless oil. MS (ESI) m/z: 610 [M+H]⁺. Example 1.6.4

[0540] tert-butyl [(2R)-2-(5-{4-[methyl(3-methylbenzyl)carbamoyl]-6-(l,3-oxazol-2- yl)pyridin-2-yl}-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l- phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2-yl)isonicotinic acid in a similar manner to Example 1.6.37 (90 mg, 91% yield) as a colorless oil. MS (ESI) m/z: 609 [M+H]⁺. Example 1.6.4

[0541] tert-butyl [(2R)-2-{5-[4-{methyl[(l-methyl-lH-pyrazol-4- yl)methyl]carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2- [(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid in a similar manner to Example 1.6.37 (114 mg, 94% yield) as a yellow oil.

Example 1.6.

[0542] tert-butyl [(2R)-2-{5-[4-{[(l,5-dimethyl-lH-pyrazol-4- yl)methyl](methyl)carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2- [(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid in a similar manner to Example 1.6.37 (110 mg, 88% yield) as a pale yellow oil.

Example 1.

[0543] tert-butyl [(2R)-2-{5-[4-{[(l,3-dimethyl-lH-pyrazol-5- yl)methyl](methyl)carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2- [(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid in a similar manner to Example 1.6.37 (118 mg, 95% yield) as a yellow oil. MS (ESI) m/z: 655 [M+H]⁺.

Example 1.6.45

[0544] methyl 6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine- 2-carboxylate: The desired compound was synthesized from 6-(methoxycarbonyl)pyridine- 2-carboxylic acid (237 mg, 1.31 mmol) in a similar manner to Example 1.6.13. (325 mg, 83% yield) MS (ESI) M/Z: 332 [M+H]⁺.

[0545] 6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2- carbohydrazide: The desired compound was synthesized from methyl 6-{ [(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate (322 mg, 0.973 mmol) in a similar manner to Example 1.6.13. (322 mg, 100% yield) MS (ESI) M/Z: 332 [M+H]⁺.

[0546] tert-butyl [(2R)-2-methyl-l-{2-[(6-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-l-oxo-3-phenylpropan-2- yl] carbamate: To a solution of N-(tert-butoxycarbonyl)-alpha-methyl-D-phenylalanine (183 mg, 0.656 mmol) in dichloromethane (5 mL) were added HATU (272 mg, 0.716 mmol) and diisopropylethylamine (0.13 mL, 0.72 mmol). After stirring for 30 minutes at room temperature, (198 mg, 0.597 mmol) was added. After stirring for 6 hours at room

temperature, the reaction mixture was diluted with ethyl acetate and washed consecutively with 0.2 M HCl-brine (1:1), sat. aq. NaHC0₃-brine-H₂0(l:l:l), brine. The oraganic layer was dried with anhydrous Na₂S0₄ and concentrated in vacuo to give tert-butyl [(2R)-2- methyl-l-{2-[(6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2- yl)carbonyl]hydrazino}-l-oxo-3-phenylpropan-2-yl]carbamate as a colorless amorphous. (324 mg, 92% yield) MS (ESI) M/Z: 593 [M+H]⁺.

Example 1.6.46

[0547] methyl 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine- 2-carboxylate: The desired compound was synthesized from methyl 4-{ [(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate [public] (200 mg, 1.19 mmol) in a similar manner to Example 1.6.13. (362 mg, 92% yield) MS (ESI) M/Z: 332

[M+H]⁺.

[0548] 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2- carbohydrazide: The desired compound was synthesized from methyl 4-{ [(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carboxylate (359 mg, 1.08 mmol) in a similar manner to Example 1.6.13. (244 mg, 68% yield) MS (ESI) M/Z: 332 [M+H]⁺.

[0549] tert-butyl [(2R)-2-methyl-l-{2-[(4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)carbonyl]hydrazino}-l-oxo-3-phenylpropan-2- yl]carbamate: The desired compound was synthesized from 4-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine-2-carbohydrazide (220 mg, 0.664 mmol) in a similar manner to Example 1.6.45. (378 mg, 96% yield) MS (ESI) M/Z: 593 [M+H]⁺. Example 1.6.47

[0550] 2-(methoxycarbonyl)-6-(pyrrolidin-l-yl)isonicotinic acid: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(pyrrolidin-l-yl)pyridine-2,4-dicarboxylate (63 mg, 0.21 mmol) in a similar manner to Example 1.6.13. (51 mg, 100% yield) MS (APCI/ESI) M/Z: 251 [M+H]⁺.

[0551] methyl 4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6- (pyrrolidin-l-yl)pyridine-2-carboxylate: The desired compound was synthesized from 2- (methoxycarbonyl)-6-(pyrrolidin-l-yl)isonicotinic acid (51 mg, 0.206 mmol) in a similar manner to Example 1.6.13. (62mg, 75% yield) MS (APCI/ESI) M/Z: 401 [M+H]⁺.

[0552] 4-{[(2R)-2^4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(pyrrolidin-l- yl)pyridine-2-carbohydrazide: The desired compound was synthesized from methyl 4- { [(2Pv)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(pyrrolidin- 1 -yl)pyridine-2- carboxylate (62 mg, 0.155 mmol) in a similar manner to Example 1.6.13. (62mg, 100% yield) MS (APCI/ESI) M/Z: 401 [M+H]⁺.

[0553] tert-butyl [(2R)-2-methyl-l-(2-{[4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-(pyrrolidin-l-yl)pyridin-2-yl]carbonyl}hydrazino)-l-oxo- 3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from 4-{ [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-(pyrrolidin- 1 -yl)pyridine-2- carbohydrazide in a similar manner to Example 1.6.45. (99 mg, 100% yield) MS (APCI/ESI) M/Z: 662 [M+H]⁺. Example 1.6.48

[0554] 6-(methoxycarbonyl)-l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylic acid:

The desired compound was synthesized from 4-tert-butyl 2-methyl l-methyl-6-oxo-l,6- dihydropyridine-2,4-dicarboxylate (146 mg, 0.546 mmol) in a similar manner to Example 1.6.13. (115 mg, 100% yield)

[0555] methyl l-methyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-oxo-l,6-dihydropyridine-2-carboxylate: The desired compound was synthesized from 6-(methoxycarbonyl)- 1 -methyl-2-oxo- 1 ,2-dihydropyridine-4-carboxylic acid (115 mg, 0.546 mmol) in a similar manner to Example 1.6.13. (166 mg, 84% yield) MS (ESI) M/Z: 362 [M+H]⁺.

[0556] l-methyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo- l,6-dihydropyridine-2-carbohydrazide: The desired compound was synthesized from methyl l-methyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6- dihydropyridine-2-carboxylate (148 mg, 0.409 mmol) in a similar manner to Example 1.6.13. (148 mg, 100% yield) MS (ESI) M/Z: 362 [M+H]⁺.

[0557] tert-butyl [(2R)-2-methyl-l-{2-[(l-methyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)carbonyl]hydrazino l-l-oxo- 3-phenylpropan-2-yl]carbamate: The desired compound was synthesized from l-methyl-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridine-2- carbohydrazide (164 mg, 0.464 mmol) in a similar manner to Example 1.6.45. (237 mg, 84% yield) MS (ESI) M/Z: 623 [M+H]⁺ Example 1.6.49

[0558] 2-(difluoromethoxy)-6-(methoxycarbonyl)isonicotinic acid: The desired compound was synthesized from 4-tert-butyl 2-methyl 6-(difluoromethoxy)pyridine-2,4- dicarboxylate (313 mg, 1.03 mmol) in a similar manner to Example 1.6.13. (255 mg, 100% yield) MS (ESI) M/Z: 248 [M+H]⁺.

[0559] methyl 6-(difluoromethoxy)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carboxylate: The desired compound was synthesized from 2- (difluoromethoxy)-6-(methoxycarbonyl)isonicotinic acid (255 mg, 1.03 mmol) in a similar manner to Example 1.6.13. (385 mg, 94% yield) MS (ESI) M/Z: 398 [M+H]⁺.

[0560] 6-(difluoromethoxy)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridine-2-carbohydrazide: The desired compound was synthesized from 6- (difluoromethoxy)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridine- 2-carboxylate (385 mg, 0.969 mmol) in a similar manner to Example 1.6.13. (385 mg, 100% yield) MS (ESI) M/Z: 398 [M+H]⁺.

[0561] tert-butyl [(2R)-l-(2-{[6-(difluoromethoxy)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]carbonyl}hydrazino)-2-methyl-l-oxo-3- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 6- (difluoromethoxy)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl jpyridine- 2-carbohydrazide (383 mg, 0.964 mmol) in a similar manner to Example 1.6.45. (634 mg, 100% yield) MS (ESI) M/Z: 659 [M+H]⁺. Example 1.6.50

[0562] 4-(tert-butoxycarbonyl)-l-methyl-6-oxo-l,6-dihydropyridine-2-carboxylic acid:

To a solution of 4-tert-butyl 2-methyl l-methyl-6-oxo-l,6-dihydropyridine-2,4-dicarboxylate (217 mg, 0.812 mmol) in methanol (10 mL) was added 1 M aq. NaOH (1.1 mL, 1.1 mmol). After stirring for 1 hour, 1M HC1 was added and brought to pH 5. The precipitate which formed was filtered off, washed with water, and dried in vacuo to give 4-(tert- butoxycarbonyl)-l-methyl-6-oxo-l,6-dihydropyridine-2-carboxylic acid as a colorless solid. (149 mg, 73% yield) MS (ESI) M/Z: 254 [M+H]⁺.

[0563] l-methyl-6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2-oxo- l,2-dihydropyridine-4-carboxylate: To a solution of 4-(tert-butoxycarbonyl)-l-methyl-6- oxo-l,6-dihydropyridine-2-carboxylic acid (143 mg, 0.565 mmol) in dichloromethane (5 mL) were added HOBt (76 mg, 0.565 mmol) and EDCI.HC1 (141 mg, 0.734 mmol). After stirring for 30 minutes, 4-methyl-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole (105 mg, 0.621 mmol) was added. After stirring for 5 hours, the reaction mixture was concentrated in vacuo and the residue was purified with silica-gel column chromatography (CHCls/MeOH =99:1 to 95:5) to give tert-butyl l-methyl-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2- oxo-l,2-dihydropyridine-4-carboxylate as a colorless oil. (228 mg, 100% yield) MS (ESI) M/Z: 404 [M+H]⁺.

[0564] l-methyl-6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2-oxo-

1.2- dihydropyridine-4-carboxylic acid: To a solution of l-methyl-6-{ [(2R)-2-(4-methyl-

1.3- thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -2-oxo- 1 ,2-dihydropyridine-4-carboxylate (228 mg, 0.565 mmol) in dichloromethane (0.5 mL) was added TFA (2 mL). The mixture was stirred for 2 hours and concentrated in vacuo to give l-methyl-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2-dihydropyridine-4-carboxylic acid as a colorless amorphous (196 mg, quant.) MS (ESI) M/Z: 348 [M+H]⁺. [0565] tert-butyl [(2R)-2-methyl-l-{2-[(l-methyl-6-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2-dihydropyridin-4-yl)carbonyl]hydrazino}-l-oxo- 3-phenylpropan-2-yl]carbamate: To a solution of l-methyl-6-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -2-oxo- 1 ,2-dihydropyridine-4-carboxylic acid (196 mmol, 0.565 mmol) in dichloromethane (5 mL) were added HOBt (76 mg, 0.565 mmol) and EDCI.HC1 (130 mg, 0.678 mmol). After stirring for 30 minutes, tert-butyl [(2R)-l-hydrazino- 2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate (182 mmol, 0.621 mmol) was added. After stirring for 6 hours the reaction mixture was diluted with EtOAc and washed consecutively with 0.2 M HCl-brine (1:1), sat. aq. NaHC0₃-brine-H₂0(l:l:l), brine to give crude tert-butyl [(2R)-2-methyl- 1 - { 2- [( 1 -methyl-6- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl } -2-oxo- 1 ,2-dihydropyridin-4-yl)carbonyl]hydrazino } - 1 -oxo-3-phenylpropan-2- yl]carbamate as a colorless amorphous. (212 mg, 60% yield) MS (ESI) M/Z: 623 [M+H]⁺. Example 1.6.51

[0566] 4-(tert-butoxycarbonyl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid: To a solution of 4-tert-butyl 2-methyl 6-oxo-l,6-dihydropyridine-2,4-dicarboxylate (320 mg, 1.26 mmol) in methanol (3 mL) was added 1M aq. NaOH (3.2 mL, 3.2 mmol). After stirring for 14 hours, 1M aq. HCl was added. The precipitate which formed was filtered off, washed with water, and dried in vacuo to give 4-(tert-butoxycarbonyl)-6-oxo-l,6-dihydropyridine-2- carboxylic acid as a colorless solid. (243 mg, 80% yield) MS (ESI) M/Z: 240 [M+H]⁺

[0567] tert-butyl 6-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl}hydrazino)carbonyl]-2-oxo-l,2-dihydropyridine-4-carboxylate: To a stirred solution of 4-(tert-butoxycarbonyl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid (241 mg, 1.01 mmol) were added HOBt (136 mg, 1.01 mmol) and EDCI.HC1 (232 mg, 1.21 mmol) and stirred for 30 minutes. Tert-butyl [(2R)-l-hydrazino-2-methyl-l-oxo-3- phenylpropan-2-yl]carbamate (325 mg, 1.11 mmol) was added and the reaction mixture was stirred for 16 hours. The mixtures was poured into H₂0 and extracted with chloroform and the organic layer was concentrated in vacuo. The residue was purified with silica-gel column chromatography (CHCl₃/MeOH = 99.5:0.5 to 95:5) to give tert-butyl 6-[(2-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-methyl-3-phenylpropanoyl}hydrazino)carbonyl] -2-oxo- 1,2- dihydropyridine-4-carboxylate as a colorless amorphous. (373 mg, 73% yield) MS (ESI) M/Z: 515 [M+H]⁺

[0568] tert-butyl 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- l,3,4-oxadiazol-2-yl)-2-oxo-l,2-dihydropyridine-4-carboxylate: To a stirred solution of tert-butyl 6-[(2-{ (2R)-2-[(tert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl }hydrazino)carbonyl] -2-oxo- 1 ,2-dihydropyridine-4-carboxylate were added triphenylphosphine (161 mg, 0.612 mmol), imidazole (42 mg, 0.61 mmol), and carbon tetrabromide (203 mg, 0.612 mmol). After stirred for 1.5 hours at room temperature the mixture was directly loaded and purified with silica-gel column chromatography

(hexane/EtOAc = 98:2 to 50:50) to give tert-butyl 6-(5-{(2R)-2-[(tert- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-2-oxo-l,2- dihydropyridine-4-carboxylate as a colorless amorphous. (93 mg, 92% yield) APC17ESI: 497 [M+H]⁺.

Example 1.6.52

[0569] 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid: To a solution of tert-butyl 6- (5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-2-oxo- l,2-dihydropyridine-4-carboxylate in MeOH (3 mL) were added H₂0 (1 mL) and potassium hydroxide (103 mg, 1.84 mmol). After stirred for 3 hours at 60 degC 1 M aq. HCl (2 mL) was added to the reaction mixture at 0 degC. The mixtrue was extracted with CHC1₃ and the organic layer was concentrated in vacuo to give 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]- 1 -phenylpropan-2-yl } - 1 ,3 ,4-oxadiazol-2-yl)-2-oxo- 1 ,2-dihydropyridine-4-carboxylic acid as a coloress solid. (73 mg, 99% yield) MS (ESI) M/Z: 441 [M+H]⁺.

[0570] tert-butyl {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: To a solution of 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan- 2-yl}-l,3,4-oxadiazol-2-yl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid in dichloromethane (3 mL) were added HOBt and EDCI.HC1. After stirred for 30 minutes at room temperature 4- methyl-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole (30 mg, 0.18 mmol) was added. After stirred for 1 day, the mixtures was concentrated in vacuo and the residue was purified with silica-gel column chromatography (CHCl₃/MeOH 99:1 to 90:10) to give tert-butyl {(2R)-2-[5-(4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2- yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate as a colorless solid. (72 mg, 76% yield) MS (ESI) M/Z: 591 [M+H]⁺.

Example 1.6.

[0571] tert-butyl [(2R)-2-{5-[l-(cyclopropylmethyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: To a solution of tert-butyl {(2R)-2-[5-(4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)-l,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (72 mg, 0.12 mmol) in MeCN (2 mL) was added cyclopropyl bromide (0.023 mL, 0.24 mmol), potassium carbonate (37 mg, 0.24 mmol), and tetra-n-butylammonium iodide (4.5 mmol, 0.012 mmol). After stirred for 7 hours at 60 degC the mixture was concentrated in vacuo and the residue was purified with silica-gel column chromatography (CHCl₃/MeOH = 99.5:0.5 to 90:10) to give tert-butyl [(2R)-2-{5-[l- (cyclopropylmethyl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo- l,6-dihydropyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate as a colorless amorphous. (29 mg, 37% yield) MS (APC17ESI) M/Z: 645 [M+H]⁺

Example 1.6.54

[0572] tert-butyl {(2R)-2-[5-(6-ethoxy-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin- l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate and tert-butyl {(2R)-2-[5-(l-ethyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(4-{ [(2R)- 2-(4-methyl-l,3-tmazol-2-yl)pyrrolidm

oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (150 mg, 0.254 mmol) in a similar manner to Example 1.6.53. (N-alkyl: 35 mg, 22% yield) MS (ESI) M/Z: 619 [M+H]⁺; (O-alkyl 107 mg, 68% yield) MS (ESI) M/Z: 619 [M+H]⁺

Example 1.6.55

[0573] 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin- 2-yl trifluoromethanesulfonate: To a solution of tert-butyl {(2R)-2-[5-(4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)- 1,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (100 mg, 0.169 mmol) in dichloromethane (2 mL) at 0 degC were added triflic anhydride (0.034 mL, 0.20 mmol) and

diisopropylethylamine (0.041 mL, 0.20 mmol). After stirred at the same temperature for 1 hour, saturated aq. NaHC0₃ was added. The mixture was extracted with CHC1₃ and the organic layer was concentrated in vacuo to give crude 6-(5-{ (2R)-2-[(tert- butoxycarbonyl)amino] - 1 -phenylpropan-2-yl } - 1 ,3 ,4-oxadiazol-2-yl)-4- { [(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl trifluoromethanesulfonate. MS (ESI) M/Z: 723 [M+H]⁺.

Exampl 1.6.56

[0574] tert-butyl {(2R)-2-[5-(6-[(2-methoxyethyl)amino]-4-{[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: To a solution of 6-(5-{(2R)-2-[(tert- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-4-{ [(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl trifluoromethanesulfonate (60 mg, 0.083 mmol) in acetonitrile (1 mL) was added 2-methoxyethylamine (0.036 mL, 0.42mmol). After stirred for 1 day, the mixture was poured into water and extracted with chloroform. The organic layer was concentrated in vacuo and the residue was purified with silica-gel chlomatography (EtOAc) to give tert-butyl {(2R)-2-[5-(6-[(2-methoxyethyl)amino]-4-{ [(2R)- 2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl }pyridin-2-yl)- 1 ,3 ,4-oxadiazol-2-yl] - 1 - phenylpropan-2-yl} carbamate as a pale yellow amorphous (30 mg, 56% yield). MS

(APCI/ESI) M/Z: 648 [M+H]⁺.

Exampl 1.6.57

[0575] tert-butyl {(2R)-2-[5-(6-[(2-methoxyethyl)(methyl)amino]-4-{[(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: The desired compound was synthesized from 6-(5-{ (2R)-2- [(tert-butoxycarbonyl)amino] - 1 -phenylpropan-2-yl } - 1 ,3,4-oxadiazol-2-yl)-4- { [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl trifluoromethanesulfonate (60 mg, 0.083 mmol) in a similar manner to Example 1.6.56. (52 mg, 95% yield) MS (APCI/ESI) M/Z: 662 [M+H]⁺.

Example 1.6.58

[0576] tert-butyl [(2R)-2-{5-[6-(ethylamino)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl]carbamate: To a solution of tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yljcarbamate (150 mg, 0.246mmol) was added ethylamine (80% yield in water; 0.1 mL, 1.2 mmol). After stirred for 4 hours under microwave irradiation at 130 degC in a sealed tube, the mixture was concentrated in vacuo and purifed by silica-gel chlomatography (CHCls/MeOH = 100:0 to 90:10) to give tert-butyl [(2R)-2-{5-[6-(ethylamino)-4-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl }pyridin-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -phenylpropan-2- yl]carbamate as a yellow amorphous (72 mg, 47%,). MS (APCI/ESI) M/Z: 618 [M+H]⁺. Example 1.6.59

[0577] methyl 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate: To a suspention of methyl 5-bromo-2-hydroxynicotinate (1.00 g, 4.31 mmol) in MeOH/DMF (10 + 10 mL) was added methyl iodide (0.81 mL, 13 mmol) and potassium carbonate (1.19 g, 8.62 mmol). After stirred for 14 hours at room temperature, the reaction mixture was diluted with ethyl acetate and the washed sequentially by H₂0-brine (1:1), H₂0-saturated aq.

NaHC0₃ (1:1), brine and dried with anhydrous Na₂S0₄, and concentrated in vacuo. The residue was purified with silicagel chlomatography (CHCl₃/MeOH 100:0 to 90:10) to give methyl 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate as a beige solid (745 mg, 70% yield). MS (ESI) M/Z: 246,248 [M+H]⁺.

[0578] 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carbohydrazide: To a stirred solution of methyl 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (649 mg, 2.64 mmol) in methanol (6 mL) was added hydrazine monohydrate (198 mg, 3.96 mmol) at room temperature. The mixture was stirred for 3 hours at the same temperature and poured into water. The precipitate which formed was filtered off, washed with water, and dried in vacuo to give 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carbohydrazide (649 mg, quant.) as a beige solid. MS (ESI) M/Z: 246,248 [M+H]⁺.

[0579] tert-butyl [(2R)-l-{2-[(5-bromo-l-methyl-2-oxo-l,2-dihydropyridin-3- yl)carbonyl]hydrazino}-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate: To a solution of N-(tert-butoxycarbonyl)-alpha-methyl-D-phenylalanine (734 mg, 2.63 mmol) in dichloromethane (16 mL) was added diisopropylethylamine (0.59 mL, 3.4 mmol) and HATU (1.10 g, 2.89 mmol). The mixture was stirred for 30 minutes and 5-bromo-l-methyl-2-oxo- l,2-dihydropyridine-3-carbohydrazide (647 mg, 2.63 mmol) were added. After stirred for 6 hours, the reaction mixture was diluted with ethyl acetate and the washed sequentially by H₂0-brine (1:1), H₂0-saturated aq. NaHC0₃ (1:1), brine and dried with anhydrous Na₂S0₄, dried and concentrated in vacuo to give crude tert-butyl [(2R)-l-{2-[(5-bromo-l-methyl-2- oxo-l,2-dihydropyridin-3-yl)carbonyl]hydrazino}-2-methyl-l-oxo-3-phenylpropan-2- yl]carbamate (1.33 g, quant.). MS (ESI) M/Z: 507,509 [M+H]⁺.

[0580] tert-butyl {(2R)-2-[5-(5-bromo-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-l,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate: To a sitred solution of tert-butyl [(2R)-1- { 2- [(5-bromo- 1 -methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)carbonyl]hydrazino } -2-methyl- 1 -oxo- 3-phenylpropan-2-yl]carbamate (1.33 g, 2.63 mmol) in dichloroethane (19 mL) was added Burgess reagent (1.88 g, 7.89 mmol) then sitrred under microwave irradiation for 20 min atl20 degC. The crude product was directly purified by silica-gel column chromatography (hexane/EtOAc = 90:10 to 50:50) to give tert-butyl {(2R)-2-[5-(5-bromo-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate as a beige amorphous (1.03 g, 80% yield). MS (ESI) M/Z: 489,491 [M+H]⁺.

Exampl

[0581] methyl 5-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate: To a stirred solution of tert-butyl {(2R)-2-[5-(5-bromo-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)-l,3,4-oxadiazol- 2-yl]-l-phenylpropan-2-yl}carbamate (589 mg, 1.20 mmol) in MeOH/DMSO were added palladium diacetate (135 mg, 0.602 mmol), l,l'-Bis(diphenylphosphino)ferrocene (333 mg, 0.602 mmol), and triethylamine (0.50 mL, 3.6 mmol) at rt and the mixture was stirred at 80 degree for 8 hours under CO atmosphere. The mixture was cooled to rt and it was filtered through a pad of Celite. The filtrate was evaporated and the resulting solution was extracted three times with EtOAc. The combined organic layer was washed with H₂0 (x3) and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with silica-gel column chromatography (CHCl₃/MeOH = 99:1 to 80:20) to give methyl 5-(5-{(2R)-2-[(tert- butoxycarbonyl)amino] - 1 -phenylpropan-2-yl } - 1 ,3 ,4-oxadiazol-2-yl)- 1 -methyl-6-oxo- 1,6- dihydropyridine-3-carboxylate as beige amorphous (564 mg, 100% yield). MS (ESI) M/Z: 469 [M+H]⁺. [0582] 5-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylic acid: To a stirred solution of methyl 5-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (564 mg, 1.20 mmol) in MeOH/THF (3:1) was added 1 M aqueous NaOH at rt and the mixture was stirred at the same temperature for 5 hours. The mixture was acidified with 1M HC1 aq. (1.57 ml) and concentrated in vacuo. The residue was suspended in CHCls/MeOH (5:1) and the preciptate was filtered off. The filtered solution was concentrated in vacuo to give crude 5-(5-{ (2R)-2- [(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-l-methyl-6-oxo- l,6-dihydropyridine-3-carboxylic acid as a beige amorphous (503 mg, 92% yield). MS (ESI) M/Z: 455 [M+H]⁺.

Example 1.6.61

[0583] tert-butyl {(2R)-2-[5-(l-methyl-5-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2-dihydropyridin-3-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: The desired compound was synthesized from 5-(5-{ (2R)-2- [(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-l-methyl-6-oxo- l,6-dihydropyridine-3-carboxylic acid (140 mg, 0.308 mmol) in a similar manner to Example 1.6.37. (175 mg, 94% yield).

E mple 1.6.62

[0584] tert-butyl 6-(hydrazinocarbonyl)-l-methyl-2-oxo-l,2-dihydropyridine-4- carboxylate: The desired compound was synthesized from 4-tert-butyl 2-methyl l-methyl-6- oxo-l,6-dihydropyridine-2,4-dicarboxylate (3.00 g, 11.2 mmol) in a similar manner to Example 1.6.59. (3.00 g, 100% yield) MS (ESI) M/Z: 268 [M+H]⁺.

[0585] tert-butyl 6-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-methyl-3- phenylpropanoyl}hydrazino)carbonyl]-l-methyl-2-oxo-l,2-dihydropyridine-4- carboxylate: The desired compound was synthesized from tert-butyl 6-(hydrazinocarbonyl)- l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylate (3.00 g, 11.2 mmol) in a similar manner to Example 1.6.59. (5.94 g, 100% yield).

[0586] tert-butyl 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- l,3,4-oxadiazol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylate: The desired compound was synthesized from tert-butyl 6-[(2-{(2R)-2-[(tert-butoxycarbonyl)amino]-2- methyl-3-phenylpropanoyl }hydrazino)carbonyl] - 1 -methyl-2-oxo- 1 ,2-dihydropyridine-4- carboxylate (5.94 g, 11.2 mmol) in a similar manner to Example 1.6.A47 Ex A60. (5.39 g, 94% yield) MS (ESI) M/Z: 511 [M+H]⁺.

Example 1.6.63

[0587] 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylic acid: The desired compound was synthesized from tert-butyl 6-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l- phenylpropan-2-yl } - 1 ,3 ,4-oxadiazol-2-yl)- 1 -methyl-2-oxo- 1 ,2-dihydropyridine-4-carboxylate (5.39 g, 10.6 mmol) in a similar manner to Example 1.6.52. (4.80 g, quant.) MS (ESI) M/Z: 455 [M+H]⁺. Exam le 1.6.64

Burgess' Reagent

1 ,2-dichloroethane, 95 °C

1 N NaOH, THF, r.t.

[0588] (R)-4-(5-(2-((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-5-fluoropicolinic acid: To a stirring mixture of 0.9672g (4.4 mmol) of 2- bromo-5-fluoroisonicotinic acid, 0.9458g (4.93 mmol) of EDCI, and 0.6748 g (4.994 mmol) of HOBt in 10 mL of CH₂C1₂ at r.t. was added 1.2988g (4.43 mmol) of (R)-tert-butyl (1- hydrazinyl-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate and 3.0 mL of DIPEA . After the mixture was stirred at r.t. for 15 h, H₂0 was added, and the aqueous layer was extracted with CHCI₃. The combined extracts were washed with water 2x and brine, dried over Na₂S0₄, filtered, and concentrated. Purification by flash silica gel chromatography ((50-60)% EtOAc/hexanes) provided 0.921 lg of (R)-tert-butyl-(l-(2-(2-bromo-5- fluoroisonicotinoyl)hydrazinyl)-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate (6.64.1)

[0589] A solution of 0.9211 g of (R)-tert-butyl-(l-(2-(2-bromo-5- fluoroisonicotinoyl)hydrazinyl)-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate and 1.1806 g (4.95 mmol) of Burgess reagent in 10 mL of CH2CICH2CI was stirred at 95 °C under Ar for 25 min. Sat. NaHC03 (25 mL) and CHCI3 were added, and the layers separated. The aqueous layer was extracted with CHCI3. The combined extracts were washed with brine, dried over Na2S04, filtered, and cone. Purification by flash silica gel chromatography ((40- 50)% EtOAc/hexanes) provided 0.8006 g of (R)-tert-butyl (2-(5-(2-bromo-5-fluoropyridin-4- yl)-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (6.64.2).

[0590] To a degassed solution of 0.8006 g (1.677 mmol) of (R)-tert-butyl (2-(5-(2-bromo- 5-fluoropyridin-4-yl)-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate and 0.1 mL (0.7174 mmol) of Et3N in 4 mL of DMF and 4 mL of EtOH (solution degassed by bubbling in Ar and evacuation and backfilling 3x) was added 0.1877 g (0.3385 mmol) of dppf and 0.1892 g (0.8427 mmol) of Pd(OAc)2 (evacuated and backfilled flask with Ar after each addition, 3x). The flask was evacuated and backfilled solution with CO once. The mixture stir was stirred under CO at 50 °C for ~ 3 h. Water (5 mL) and EtOAc were added, and the layers were separated. The org. layer was washed with brine, dried over Na2S04, filtered, and concentrated. Purification by flash silica gel chromatography (20% EtOAc/hexanes) provided 94 mg of (R)-ethyl 4-(5-(2-((tert-butoxycarbonyl)amino-l-phenylpropan-2-yl)- l,3,4-oxadiazol-2-yl)-5-fluoropicolinate (6.64.3).

[0591] To a stirring solution of 112.7 mg of (R)-ethyl 4-(5-(2-((tert- butoxycarbonyl)amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-fluoropicolinate in 5 mL of THF was added 1.5 mL of 1 N NaOH. The solution was stirred at r.t. for 19.5 h. Water and CH2CI2 were added, and the layers partly separated. The aqueous layer was extracted with CH2CI2. Partially sep. aqueous layer and added more ¾0 and CH2CI2; separated layers. The org. layer was washed with ¾0; IN HC1 and sat. NaHC03 were added to pH= 2. The aqueous layer was extracted with the extract of 10%MeOH/10%H2O/80%CHCl3 2x, dried over Na2S04, filtered, and cone, to provide (R)-4-(5-(2-((tert-butoxycarbonyl)amino)- l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-fluoropicolinic acid (6.64.4).

Exam le 1.6.65

6.65.3 6.65.5 [0592] (R)-4-(5-(2-(((tert-butoxycarbonyl)amino)-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-5-methoxypicolinic acid: To a stirring solution of 94 mg of (R)-ethyl 4-(5- (2-((tert-butoxycarbonyl)amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- fluoropicolinate in 2 mL of THF and 1 mL of MeOH was added 0.5 mL of 1 N NaOH. After 18 h, 1.0 mL of IN NaOH was added. (Solution warmed for ~ lh). The solution was stirred at 50 °C for 45 min. Water and CH2CI2 were added, ^and the layers separated but not completely. More ¾0 and CH2CI2 were added, and the layers separated. The org. layer was washed with H₂0. IN HC1 was added to pH= 2. The aqueous layer was extracted with the extract of 10%MeOH/10%H2O/80%CHCl3 3x. The combined extracts were dried over Na₂S0₄, filtered, and cone, to provide (R)-4-(5-(2-(((tert-butoxycarbonyl)amino)-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-methoxypicolinic acid (6.65.5).

Example 1.6.66

[0593] To a solution containing the acid, 5-bromo-2-fluorobenzoic acid (391 mg, 1.784 mmol)in DCM (3 ml), HOBT (328 mg, 2.141 mmol) and EDC (479 mg, 2.498 mmol)were added and the reaction mixture was stirred for lh at rt. After lh, reaction mixture was cooled to 0°C, and (R)-tert-butyl (3-(4-fluorophenyl)-l-hydrazinyl-2-methyl-l-oxopropan-2- yl)carbamate (500 mg, 1.606 mmol)was added in DCM (1 mL) along with DIPEA (0.935 ml, 5.35 mmol). The reaction mixture color was dark brown. After stirring overnight at rt, DCM was removed in vacuum. Then reaction mixture was diluted with ethyl acetate, and saturated aq sodium bicarbonate solution was added. After stirring for 10 mins at rt, aqueous layer was extracted with ethyl acetate (2X10 ml). Combined organic layers were washed with water, brine and dried. Crude residue was carried to the next step.

[0594] To the hydrazide (1.08 g, 2.11 mmol) in DCE (20 ml), Burgess reagent (1.26 g, 5.27 mmol) was added and refluxed for 3h at which time reaction color turned brown. Then reaction mixture was cooled, diluted with DCM, washed with aq sodium bicarbonate solution, water brine and dried. Crude residue was column chromatographed. (30%ethyl acetae/hexane). Product is a yellow syrup and was obtained in 67% yield.

[0595] To the bromo compound, (R)-tert-butyl (2-(5-(5-bromo-2-fluorophenyl)-l,3,4- oxadiazol-2-yl)-l-(4-fluorophenyl)propan-2-yl)carbamate (700 mg, 1.416 mmol) in dioxane (Ratio: 2.96, Volume: 8 ml) and Water (Ratio: 1.000, Volume: 2.7 ml), PALLADIUM(II) ACETATE (15.90 mg, 0.071 mmol) and XANTPHOS (82 mg, 0.142 mmol) ,Et₃N (1.974 ml, 14.16 mmol) were added and the reaction mixture was purged with carbon monoxide. Then reaction mixture (a yellow suspension) was heated to 75°C for 3h by which time the suspension is greyish green. Then reaction mixture was cooled, dioxane was removed in vacuum. Water was added and filtered. Water layer was basified and extracted with ethyl acetate. Aqueous layer was then acidified and extracted with 5%MeOH/Ethyl acetate.

Organic layer was dried and evaporated to yield 460mg of acid.

[0596] Resulting acid is converted to the final compound in a manner similar to that as in Example 1.7.1.

Example 1.6.67

[0597] To a solution containing the acid, 5-bromo-2,4-difluorobenzoic acid (1.5 g, 6.33 mmol)in DCM (10 ml), HOBT (1.163 g, 7.59 mmol) and EDC (1.699 g, 8.86 mmol)were added and the reaction mixture was stirred for lh at rt. After lh, reaction mixture was cooled to 0°C, and (R)-tert-butyl (l-hydrazinyl-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate (1.671 g, 5.70 mmol)was added in DCM (3mL) along with DIPEA (3.32 ml, 18.99 mmol). The reaction mixture color was dark brown. After stirring overnight at rt, DCM was removed in vacuum. Then reaction mixture was diluted with ethyl acetate, and saturated aq sodium bicarbonate solution was added. After stirring for 10 mins at rt, aqueous layer was extracted with ethyl acetate (2X10 ml). Combined organic layers were washed with water, brine and dried. Crude residue was carried to the next step.

[0598] To the hydrazide (500 mg , 1.06 mmol) in DCE (20 ml), Burgess reagent (629 mg , 2.64 mmol) was added and refluxed for 2h at which time reaction color turned dark brown. Then reaction mixture was cooled, diluted with DCM, washed with aqueous sodium bicarbonate solution, water, and brine and dried. Crude residue was column

chromatographed. (30%ethyl acetate/hexane). Product is a colorless foamy syrup and was obtained in 67% yield. [0599] To the bromo compound, (R)-tert-butyl (2-(5-(5-bromo-2,4-difluorophenyl)- 1,3,4- oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (1.0 g, 2.023 mmol) in dioxane and water, PALLADIUM(II) ACETATE (0.023 g, 0.101 mmol) and XANTPHOS (0.117 g, 0.202 mmol) ,Et₃N (2.82 ml, 20.23 mmol) were added and the reaction mixture was purged with carbon monoxide. Then reaction mixture was heated to 75°C for 4h. Then reaction mixture was cooled, water was added and filtered. Water layer was basified and extracted with ethyl acetate. Aqueous layer was then acidified and extracted with 5%MeOH/Ethyl acetate.

Organic layer was dried and evaporated to yield 360mg of acid. Organic layer also had some product along with some impurities. Partitioning the material obtained from organic layer between, aqueous( basic ) layer and 5%MeOH/ethyl acetate yielded 450 mg of acid.

[0600] Resulting acid is converted to the final compound in a manner similar to that as in Example 1.7.1.

Example 1.6.68

The final compound was prepared using similar procedure to that of Example

Example 1.7: Multi-step synthesis of oxadiazole inhibitors.

Example 1.7.1

[0602] 7.1.38 and 7.1.39 were coupled using standard coupling procedure involving HOBT, EDCI DIPEA in CH₂C1₂ and stirring overnight resulted in 7.1.40 in 81% yield.

[0603] To a solution of 7.1.40 (2.37g, 3.60 mmoles) in dicholoroethane (50 mL) was added Burgess' reagent (2.57g, 10.80 mmoles) and refluxed overnight (~ 16h). The reaction mix was then cooled to room temperature, diluted with CHC1₃ and washed successively with satd.aq. NaHC0₃ and brine, dried, concentrated and purified on silica gel (1% MeOH/99% CHC1₃) to obtain 2.12g (92%) of 7.1.41.

[0604] A solution of 7.1.41 (2.12g, 3.31 mmoles) in a mixture of 4N HCl in 1,4-dioxane ( 20mL) and 1.5N HCl in MeOH ( 5 mL) at 0 °C to RT was stirred for 45 min. TLC indicated the consumption of SM. All the solvent was evaporated; the residue was quenched with satd.aq. NaHC0₃ and was extracted with EtOAc. The organic extract was washed with brine, dried, concentrated and purified on basic alumina (1% MeOH/99% CHC1₃) to obtain 1.44g (80%) of compound 7.1.42. Example 1.7.2

[0605] To a solution of 7.2.43 (150 mg, 0.43 mmoles) in CH₃CN was added EDC

(commercial source: sigma-aldrich) (90 mg, 0.47 mmoles) and HOBT (commercial source: sigma-aldrich) (63 mg, 0.47 mmol). After lh, anhydrous hydrazine (commercial source: sigma-aldrich) (55 mg, 1.72 mmol) was added and stirred overnight at room temperature. All the solvent was evaporated; the residue was quenched with satd.aq. NaHC0₃ and was extracted with DCM. The organic extract was washed with brine, dried, concentrated and purified on silica gel to obtain 85 mg of 7.2.44.

[0606] To a solution of 7.2.44 (85 mg, 0.23 mmoles) in DCM (5 ml) was added EDC (commercial source: sigma-aldrich) (62 mg, 0.32 mmoles) and HOBT (commercial source: sigma-aldrich) (37 mg, 0.28 mmol). After lh, acid 7.2.45 (commercial source: Peptech) (64 mg, 0.23 mmol) was added and stirred overnight at room temperature. All the solvent was evaporated; the residue was quenched with satd.aq. NaHC0₃ and was extracted with ethyl acetate. The organic extract was washed with brine, dried, concentrated and purified on basic Alumina to obtain 78 mg of 7.2.46.

[0607] To a solution of 7.2.46 (78 mg, 0.12 mmoles) in dicholoroethane (5 mL) was added Burgess' reagent (89 mg, 0.36 mmoles) and refluxed for 6h. The reaction mix was then cooled to room temperature, diluted with CHC1₃ and washed successively with satd.aq. NaHC0₃ and brine, dried, concentrated and purified on silica gel (1% MeOH/99% CHC1₃) to obtain 55mg of 7.2.47.

[0608] A solution of 7.2.47 (55mg, 0.09 mmoles) in a mixture of 4N HC1 in 1,4-dioxane ( 4mL) and 1.5N HC1 in MeOH ( 5 mL) at 0 °C to RT was stirred for 3h. TLC indicated the consumption of SM. All the solvent was evaporated; the residue was quenched with satd.aq. NaHC0₃ and was extracted with EtOAc. The organic extract was washed with brine, dried, concentrated and purified on basic alumina (1% MeOH/99% CHC1₃) to obtain 32 mg of desired product 7.2.48.

Example

[0609] 7.3.49 and 7.3.50 were coupled using standard coupling procedure involving HOBT, EDCI DIPEA in CH₂C1₂ and stirring overnight resulted in 7.3.51 in 77% yield. Final compound 7.3.53 was synthesized from ligand 7.3.51 as depicted above.

Example 1.7.4

[0610] The bromide (1.0 ml, 1.44 g, 11.9 mmol, 1.25 eq) was added to a stirred suspension of 7.4.54 (Aldrich, 2.0 g, 9.5 mmol, 1 eq) and K₂C0₃ (2.959 g, 21.4 mmol, 2.25 eq) in anhydrous DMF (10 ml) under Ar. The mixture was heated to 60 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and filtered through cotton. The organic layer was washed with water (x4), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation.

Purification via flash chromatography on silica gel yielded 2.14 g (8.6 mmol, 90%) of 7.4.55.

[0611] A solution of 7.4.55 (1.04 g, 4.2 mmol, 1 eq) in diethylaniline (5 ml) was purged with Ar for 5 min to degas. The solution was heated to 195 °C with stirring. After 24 h the reaction was cooled to room temperature and diluted with Et₂0. The organic layer was washed with 1 N HC1 (x2), water (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation. Purification via flash chromatography on silica gel yielded the impure product. Recrystallization from CH₂Cl₂/hexane yielded 0.579 g (2.3 mmol, 56%) of 7.4.56. [0612] Anhydrous CH₃CN (10ml) was added to a flask charged with 7.4.56 (0.8369 g, 3.3 mmol, 1 eq) and Cu(OAc)₂ (0.7289 g, 4.0 mmol, 1.2 eq) under Ar. The flask was evacuated and back-filled with 02 (x3). Tetravinyltin (0.73 ml, 0.9 g, 4.0 mmol, 1.2 eq) was added with stirring. After stirring over the weekend the mixture was poured into aqueous NH₄OH (30%, 75 ml) with stirring. After 15 min the mixture was extracted with EtOAc (xl). The organic layer was washed with brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and volatiles were removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.7338 g (2.7 mmol, 80%) of the 7.4.57.

[0613] A solution of 7.4.57 (0.2521 g, 0.9 mmol, 1 eq) in anhydrous CH₂C1₂ (10 ml) was purged with Ar to degas (5 min). 2^nd generation Grubb's Catalyst (0.0772 g, 0.09 mmol, 10 mol %) was added with stirring. After stirring overnight the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.166 g (0.677 mmol, 74%) of 7.4.58.

[0614] A solution of 7.4.58 (0.166 g, 0.67 mmol, 1 eq) in MeOH (10 ml) was treated with 10% Pd/C (0.017 g, ca.10% by wt) and placed under H₂ (double balloon). After stirring vigorously overnight the mixture was filtered through Celite. The volatiles were removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.142 g (0.57 mmol, 85%) of 7.4.59.

[0615] A solution of 7.4.59 (0.142 g, 0.57 mmol, 1 eq) in 1 : 1 THF/MeOH (3 ml) was cooled to 0 °C with stirring. NaOH (1 N, 0.6 ml, 0.6 mmol, 1.05 eq) was added dropwise. After 4 h at temperature the reaction was allowed to warm gradually as it stirred overnight. The reaction was diluted with saturated aqueous NaHC0₃, and the volatiles were removed via rotary evaporation. The residue was diluted with water and extracted with 3:1 CH₂Cl₂/hexane (x2). The aqueous layer was adjusted to pH ~ 2 with 1 N HC1. The aqueous layer was extracted with 2% MeOH in CH₂C1₂ (x2). The appropriate organics were combined and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation yielding 0.088 g (0.37 mmol, 65%) of a mixture of 7.4.61 and 7.4.60 (-1:2)

[0616] A solution of 7.4.61 and 7.4.60 (0.079 g, 0.33 mmol, 1 eq) in anhydrous CH₂C1₂ (5 ml) under Ar was cooled to 0 °C with stirring. The cooled solution was treated with

EDCI HC1 (0.0703 g, 0.37 mmol, 1.1 eq) and ΗΟΒΤ·Η₂0 (0.0497 g, 0.37 mmol, 1.1 eq). After 1 h the reaction was treated sequentially with the hydrazide (0.0981 g, 0.33 mmol, 1 eq) and DIPEA (0.23 ml, 0.17 g, 1.3 mmol, 4 eq). The reaction was stirred at 0 °C to room temperature overnight. After quenching with water the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/ water and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation.

Purification via flash chromatography on silica gel yielded a small amount of 7.4.62 and 0.1256 g (0.25 mmol) of 7.4.63 with some impurity. Some mixed fractions were also collected.

[0617] Burgess' Reagent (0.1426 g, 0.61 mmol, 2.5 eq) was added to a stirred solution of 7.4.63 (0.1256 g, 0.25 mmol, 1 eq) in anhydrous 1,2-dichloroethane (5 ml) under Ar. The solution was heated to reflux overnight. After cooling to room temperature the reaction was diluted with CH₂C1₂. The organic layer was washed with saturated aqueous NaHC0₃ (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.0984 g (0.2 mmol, 80%) of 7.4.64.

[0618] NaOH (1 N, 0.25 ml, 0.25 mmol, 1.25 eq) was added to a stirred solution of 7.4.64 (0.0984 g, 2.0 mmol, 1 eq) in 1:1 THF/MeOH (3 ml). After stirring overnight the reaction was diluted with saturated aqueous NaHC0₃. The volatiles were removed via rotary evaporation. The residue was diluted with water and CH₂C1₂. The aqueous layer was adjusted to pH ~ 2 with 1 N HC1. The aqueous layer was extracted with CH₂C1₂ (x2). The organics were combined and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation yielding 0.0887 g (0.18 mmol, 92%) of 7.4.65.

[0619] A solution of 7.4.65 (0.0887 g, 0.18 mmol, 1 eq) in anhydrous CH₂C1₂ (5 ml) was cooled to 0 °C with stirring. The solution was treated with ΗΟΒΤ·Η₂0 (0.0275 g, 0.2 mmol, 1.1 eq) followed by EDCI HC1 (0.0389 g, 0.2 mmol, 1.1 eq) 30 min later. After 1 h the resulting solution was treated sequentially with the amine (0.0311 g, 0.18 mmol, 1 eq) and DIPEA (0.13 ml, 0.096 g, 0.74 mmol, 4 eq). The reaction was stirred at 0 °C to room temperature overnight. After quenching with water the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/ water and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary evaporation.

Purification via flash chromatography on silica gel yielded 0.0864 g, (0.14 mmol, 76%) of 7.4.66. Example 1.7.5

1. NaOH

2. Hydrazide, BOP

4. Burgess

3. HCI

[0620] Lawesson's reagent (Commercial source: sigma-aldrich) (11.33 g, 280 mmol) was added to the amide (10 g, 46.67 mmol) in DME (Commercial source: sigma-aldrich) (140 ml) and the reaction mixture was stirred overnight at rt. Then the reaction mixture was diluted with ethyl acetate/Hexanes, washed with aqueous sodium bicarbonate. The organic layer was separated, dried with anhydrous sodium sulfate, concentrated to obtain pale yellow solid thioamide (9.65 g), which was used directly for the next reaction without further purification and identification.

[0621] To the thioamide (9.65 g, 41.91 mmol) in ethanol (150 ml) was added ethyl bromopyruvate (7.9 mL, 62.86 mmol, Commercial source: sigma-aldrich). After heating at 75 °C for 5h, then resulting mixture was kept at room temperature for overnight. The volatiles were removed in vacuum. Reaction mixture was diluted with chloroform, washed with sodium bicarbonate. Organic layer was dried and evaporated to give a residue, which was purified through flash column to obtain the amine (6.65 g). 1H NMR (300 MHz, CDC1₃), δ: 8.063 (s, 1 H), 4.627 (m, 1 H), 4.397 (m, 2 H), 3.115 (m, 2 H), 2.354 (m, 1 H), 2.016 (m, 1 H), 1.852 (m, 2 H), 1.405 (m, 3 H).

[0622] To the amine (3.38 g, 14.91 mmol) in DCM (100 mL) at r.t, Boc₂0 (4.23 g, 19.39 mmol) was added, followed by pyridine (2.95 mL, 37.28 mmol). The resulting reaction mixture was stirred at r.t. overnight, then diluted with chloroform, washed with sodium bicarbonate. Organic layer was dried and evaporated to give a residue, which was purified through flash column to obtain the ester (4.0 g).

[0623] The ester (4 g, 12.25 mmol) in THF (50 mL) at 0 °C was added LiBH₄ (2.0 M solution in THF, 18.4 mL, 36.76 mmol) and stirred, slowly warmed to rt overnight. The reaction mixture was diluted with ethyl acetate, carefully quenched with 5 % aqueous citric acid. The organic layer was separated, dried and evaporated to yield product which was purified by flash column to give alcohol (2.1 g).

[0624] To a solution of alcohol (2.1 g, 7.38 mmol) in dichloromethane (60 mL) at -78°C was added Deoxo-Fluor (1.77 mL, 9.6 mmol). The resulting mixture was stirred and warmed to room temperature for overnight, then was cooled in ice bath diluted with chloroform and quenched with saturated sodium bicarbonate solution. The mixture was warmed to room temperature, separated and dried, concentrated and purified with silica gel chromatography to give the compound (1.1 g). 1H NMR (300 MHz, CDC1₃), δ: 7.239 (s, 1 H), 5.495 (s, 1 H), 5.337 (s, 1 H), 5.216 (m, 0.4 H), 5.099 (m, 0.6 H), 3.612-3.405 (m, 2 H), 2.274 (m, 2 H), 1.932 (m, 2 H), 1.468 (s, 4 H), 1.318 (s, 5 H).

[0625] To the fluoride (1.1 g, 3.84 mmol) in methanol (4.5 ml), 4 M HC1 in dioxane (9.6 mL) was added at rt. After 1.5 h, volatiles were removed in vacuum. The resulting solid was used directly for the next reaction without further purification. To a stirred solution of the salt (400 mg, 1.8 mmol), acid (443.8 mg, 1.8 mmol) in DCM (80 mL) were added PyBOP (1.03 g, 1.8 mmol), triethylamine (1 mL, excess) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Then aqueous saturated sodium bicarbonate was added and the reaction mixture was extracted with chloroform. The organic layers were dried over Na₂S0₄ and concentrated. The crude product thus obtained was purified by silica gel flash column chromatography to provide the corresponding amide (623 mg). 1H NMR (300 MHz, CDC1₃), δ: 8.762 (s, 1 H), 8.419 (s, 1 H), 8.295 (s, 1 H), 7.765 (s, 1 H), 7.273 (m, 2 H), 5.697- 5.150 (m, 3 H), 3.957 (s, 3 H), 3.783 (m, 1 H), 3.545 (m, 1 H), 2.431 (m, 2 H), 2.171-1.920 (m, 2 H). [0626] The ester (623 mg, 1.5 mmol) was dissolved in THF:MeOH (1:1) (15:15 mL) and H₂0 (2.3 mL). Solid NaOH (180 mg, 4.5 mmol) was added and stirred at 50 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. Saturated NaHC0₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove organic impurities). The aqueous reaction mixture was acidified with diluted HC1 (10%), extracted with EtOAc, dried over anhydrous Na₂S0₄. The solvent was evaporated and dried under reduced pressure to give the crude acid which can be used directly for next reaction.

Example 1.7.6

[0627] 3-[5-(l-Amino-2-phenylcyclohexyl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4- methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate: The mixture of 3-[5-(l-amino-2- phenylcyclohexyl)-l,3,4-oxadiazol-2-yl]benzoic acid (180mg, 0.5mmol), EDC (114 mg, 0.59 mmol), HOBt (80 mg, 0.59mmol), N-methyl-l-(4-methyl-l,3-thiazol-2-yl)methaneamine (85 mg, 0.59 mmol) in DMF (4 mL) was stirred for 4 h at ambient temperature. After dilution with EtOAc, the organic layer was washed with H₂0, sat. NaHC0₃ aq. and brine, dried over MgS0₄, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl₃:MeOH = 100:0-95:5) to give a free base (44 mg) as an amorphous solid, which was dissolved in EtOH and then oxalic acid (8 mg, 0.09 mmol) and trace Et₂0 were added. The resulting precipitate was collected by filtration, washed with Et₂0 and dried in vacuo to give 3-[5-(l-amino-2-phenylcyclohexyl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methyl-l,3- thiazol-2-yl)methyl]benzamide ethanedioate as a colorless solid (13 mg, 5%). MS (ESI) m/z: 488 [M + H]⁺.

[0628] 3-[5-(l-Amino-2-phenylcyclohexyl)-l,3,4-oxadiazol-2-yl]benzoic acid: To an ice- chilled solution of methyl 3-({2-[(l-amino-2- phenylcyclohexyl)carbonyl]hydrazino}carbonyl)benzoate (161 mg, 0.41 mmol) in CH₂C1₂ (2 mL) were added DBU (0.304 mL, 2.04 mmol) and 2-chloro-l,3-dimethylimidazolium chloride ( 206 mg, 1.22 mmol). The reaction mixture was allowed to warm to room temperature. After stirring overnight at ambient temperature, the mixture was partitioned between EtOAc and H₂0, the organic layer was washed with sat. NaHC0₃ aq. and brine, dried over MgS0₄ and concentrated in vacuo. The residue (100 mg) was dissolved in dioxane (1 mL) and ethylene glycol (lmL), CsOH.H₂0 (226 mg, 1.35 mmol) was added to the solution. The mixture was stirred for 2 h at 150°C. After cooling to ambient temperature, 1M aq. HC1 was added and then the mixture was extracted with EtOAc, washed with brine, dried over MgS0₄ and concentrated in vacuo to give 3-[5-(l-amino-2-phenylcyclohexyl)-l,3,4- oxadiazol-2-yl]benzoic acid (186 mg, 126%), which was used for the next step without further purification. MS (ESI) m/z: 364 [M + H]⁺.

[0629] Methyl 3-({2-[(l-Amino-2- phenylcyclohexyl)carbonyl]hydrazino}carbonyl)benzoate: A mixture of l-amino-2- phenylcyclohexanecarbohydrazide dihydrochloride (180 mg, 0.59 mmol), EDC (135 mg, 0.71 mmol), HOBt (95 mg, 0.71 mmol), Et₃N (0.180 mL, 1.29 mmol) and 3- (methoxycarbonyl)benzoic acid (106 mg, 0.59 mmol) in CH₂CI₂ (4 mL) was stirred for 4 h at ambient temperature. After dilution with EtOAc, the organic layer was washed with H₂0, sat. aq. NaHC0₃ and brine, dried over MgS0₄, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc = 100:0-50:50) to give methyl 3-({2- [(l-amino-2-phenylcyclohexyl)carbonyl]hydrazino}carbonyl)benzoate as an amorphous solid. MS (ESI) m/z: 396 [M + H]⁺.

[0630] l-Amino-2-phenylcyclohexanecarbohydrazide dihydrochloride: tert-Butyl 2-[(l- amino-2-phenylcyclohexyl)carbonyl]hydrazinecarboxylate (160 mg, 0.48 mmol) was dissolved in 4 M HCl/EtOAc. After stirring overnight, the mixture was evaporated to give 1- amino-2-phenylcyclohexanecarbohydrazide dihydrochloride as a colorless oil. MS (ESI) m/z: 234 [M + H]⁺.

[0631] tert-Butyl 2-[(l-amino-2-phenylcyclohexyl)carbonyl]hydrazinecarboxylate: A mixture of l-amino-2-phenylcyclohexanecarboxylic acid hydrochloride (500 mg, 1.96 mmol), EDC (450 mg, 2.35 mmol), HOBt (317 mg, 2.35 mmol) and tert-butyl

hydrazinecarboxylate (620 mg, 4.69 mmol) in DMF (10 mL) was stirred overnight at ambient temperature. After dilution with EtOAc, the organic layer was washed with H₂0 and brine, dried over MgS0₄, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc = 100:0-50:50) to give tert-butyl 2-[(l-amino-2- phenylcyclohexyl)carbonyl]hydrazinecarboxylate as a colorless solid (167 mg, 26%). MS (ESI) m/z: 334 [M + H]⁺.

Example 1.7.7

[0632] rel-3-{5-[(lR,2R)-l-Amino-2-phenylcyclopropyl]-l,3,4-oxadiazol-2-yl}-N- methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide 4-methylbenzenesulfonate: A mixture of tert-butyl rel-[(lR,2R)-l-{ [2-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2-phenylcyclopropyl]carbamate (55.6 mg, 0.099 mmol) and Burgess reagent (70.5 mg, 0.296 mmol) in dichloroethane (DCE) (1 mL) was stirred for 20 min at 130°C in a sealed tube under microwave irradiation. The mixture was partitioned between CHCI₃ and water. The organic layer was washed with satd. aq. NaHC0₃ and brine, dried over MgS0₄, silicagel and celite, filtered off, and the filtrate was evaporated. Silicagel column chromatography (CHCl₃-MeOH, a linear gradient of MeOH from 0 to 4%) afforded a colorless gum (MS (ESI) m/z: 568.10 [M + Na]⁺). The gum was dissolved in MeCN (1 mL), and to the solution was added p-toluenesulfonic acid monohydrate (56.3 mg). The mixture was stirred for 1 h at 50°C. The mixture was partitioned between CHC1₃ and satd. aq. NaHC0₃. The organic layer was washed with brine, dried over MgS0₄, filtered, and the filtrate was evaporated. The residue was dissolved in isopropyl alcohol (IP A), and to the solution was added p-toluenesulfonic acid monohydrate (18.8 mg). The solvent was evaporated off, and the residue was triturated in EtOAc to give 3- { 5- [( 1 R,2R)- 1 -amino-2-phenylcyclopropyl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [(4-methyl- l,3-thiazol-2-yl)methyl]benzamide 4-methylbenzenesulfonate (1:1) as a white powder, which was collected by filtration, washed with EtOAc and dried in vacuo (26.3 mg, 60.9%). MS (ESI) m/z: 446.2 [M + H]⁺.

[0633] tert-Butyl rel-[(lR,2R)-l-{[2-(3-{Methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2-phenylcyclopropyl]carbamate: A mixture of rel-(lR,2R)-l-[bis(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid (129 mg, 0.342 mmol), 3-(hydrazinocarbonyl)-N-methyl-N-[(4-methyl-l,3-thiazol-2- yl)methyl]benzamide (156 mg, 0.513 mmol), EDC (91.7 mg, 0.478 mmol) and HOBt (55.4 mg, 0.410 mmol) in DMF (2 mL) was stirred for 13 h at ambient temperature. The mixture was partitioned between EtOAc and water. The organic layer was washed with 1 N HC1, satd. aq. NaHC0₃, and brine, dried over MgS0₄, filtered, and the filtrate was evaporated. Silicagel column chromatography (CHCl₃-MeOH, a linear gradient of MeOH from 0 to 4%) afforded tert-butyl rel-[(lR,2R)-l-{ [2-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2-phenylcyclopropyl]carbamate (55.6 mg, 28.9%) as a colourless foam.

[0634] rel-(lR,2R)-l-[Bis(tert-butoxycarbonyl)amino]-2- phenylcyclopropanecarboxylic acid: To a solution of methyl rel-(lR,2R)-l-[bis(tert- butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylate (150 mg, 0.383 mmol) in MeOH- H₂0 (2:1, 1.5 mL) was added 85% KOH (126 mg, 1.92 mmol). The mixture was stirred for 1.5 h at ambient temperature and 2 h at 70°C. The mixture was washed with Et₂0 (two times), and acidified by adding 1 N HC1 (pH = 3). The residue was extracted with CHC1₃- MeOH (five times). The extract was dried over MgS0₄ and alumina, filtered, and the filtrate was evaporated to give rel-(lR,2R)-l-[bis(tert-butoxycarbonyl)amino]-2- phenylcyclopropanecarboxylic acid as a colorless gum (129 mg). MS (ESI) m/z: 686.15 [M + Na]⁺.

[0635] Methyl rel-(lR,2R)-l-[bis(tert-butoxycarbonyl)amino]-2- phenylcyclopropanecarboxylate: To a suspension of trimethylsulfoxonium iodide (350 mg, 1.59 mmol) in DMSO (1.5 mL) was added NaH (63.6 mg, 60% in oil, 63.6 mmol) at ambient temperature. After stirring for 1 h, to the mixture was added a solution of methyl 2-[bis(tert- butoxycarbonyl)amino]-3-phenylacrylate (300 mg, 0.795 mmol) in DMSO (1.5 mL). The mixture was stirred for 5 h at ambient temperature. The reaction was quenched by adding 10% citric acid. The mixture was partitioned between EtOAc and water. The organic layer was washed with water (two times) and brine, dried over MgS0₄, filtered, and the filtrate was evaporated. Silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 20%) afforded methyl rel-(lR,2R)-l-[bis(tert-butoxycarbonyl)amino]-2- phenylcyclopropanecarboxylate as a colourless oil (150 mg, 48.2%). MS (ESI) m/z: 414.05 [M + Na]⁺.

Example 1.7.8

[0636] rel-3-{5-[(lR,2S)-l-Amino-2-phenylcyclopropyl]-l,3,4-oxadiazol-2-yl}-N- methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide 4-methylbenzenesulfonate (1:1): The desired compound was synthesised from tert-butyl rel-[(lR,2S)-l-{ [2-(3- {methyl[(4-methyl-l,3-thiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2- phenylcyclopropyl] carbamate (283 mg) in a similar manner to Ex.1.7.7 (143 mg, 61.6%). MS (ESI) m/z: 446.2 [M + H]⁺.

[0637] tert-butyl rel-[(lR,2S)-l-{[2-(3-{Methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2-phenylcyclopropyl]carbamate:

The desired compound was synthesised from rel-(lR,2S)-l-[(tert-butoxycarbonyl)amino]-2- phenylcyclopropanecarboxylic acid (150 mg) in a similar manner to Ex. 1.7.7 (238 mg, 78.1%). MS (ESI) m/z: 564.20 [M + H]⁺.

[0638] rel-(lR,2S)-l-[(tert-Butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid: The desired compound was synthesised from ethyl rel-(lR,2S)-l-[(tert- butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylate (1.21 g) in a similar manner to Ex. 1.7.7 (892, 81.2%). MS (ESI) m/z: 300.11 [M + H]⁺. Example 1.7.9

[0639] 3-(5-(2-Amino-l-methoxy-3-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N- methyl-N-((4-methylthiazol-2-yl)methyl)benzamide oxalate: tert-Butyl 2-benzyl-3- methoxy- 1 - [2-(3- { methyl[(4-methylthiazol-2-yl)methyl]carbamoyl }benzoyl)hydrazinyl] - 1 - oxopropan-2-ylcarbamate (40 mg, 0.069 mmol) was treated with 4N HCl/EtOAc at ambient temperature for 1 h. The reaction mixture was evaporated and neutralized with sat. aq.

NaHC0₃, extracted with EtOAc, washed with brine, dried over MgS0₄, then evaporated off. The residue was dissolved in ether. To the solution was added oxalic acid (6.2 mg, 0.069 mmol), and the resulting solid was collected, washed with ether, then dried under vacuum to afford 3-[5-(2-amino-l-methoxy-3-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl]-N-methyl-N- [(4-methylthiazol-2-yl)methyl]benzamide oxalate as a white amorphous solid (30 mg, 76%). MS (ESI) m/z: 478.2 [M + H]⁺.

[0640] tert-Butyl l-methoxy-2-(5-(3-(methyl((4-methylthiazol-2- yl)methyl)carbamoyl)phenyl)-l,3,4-oxadiazol-2-yl)-3-phenylpropan-2-ylcarbamate: 2-

Benzyl-3-methoxy-l-[2-(3-{methyl[(4-methylthiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazinyl]-l-oxopropan-2-ylcarbamate (130 mg, 0.22 mmol) was dissolved in CH₂CI₂ (2.6 mL) then to the solution was added Burgess reagent (156 mg, 0.655 mmol). The mixture was heated under microwave conditions (130°C, 20 min) then the reaction was diluted with CHC1₃, washed with water and brine then dried over MgS0₄ and evaporated. The crude material was purified with silica gel column chromatography to afford tert-butyl l-methoxy-2-[5-(3-{methyl[(4-methylthiazol-2-yl)methyl]carbamoyl}phenyl)- l,3,4-oxadiazol-2-yl]-3-phenylpropan-2-ylcarbamate as a colorless oil (90 mg, 71%). MS (ESI) m/z: 600.2 [M + Na]⁺.

[0641] 2-Benzyl-3-methoxy-l-(2-(3-(methyl((4-methylthiazol-2- yl)methyl)carbamoyl)benzoyl)hydrazinyl)-l-oxopropan-2-ylcarbamate: To a solution of 2-benzyl-2-(tert-butoxycarbonylamino)-3-methoxypropanoic acid (180 mg, 0.58 mmol) in DMF (1.8 ml) was added 3-(hydrazinecarbonyl)-N-methyl-N-[(4-methylthiazol-2- yl)methyl]benzamide (212.5 mg, 0.7 mmol), EDC (134 mg, 0.7 mmol) and HOBt (78.6 mg, 0.58 mmol) then stirred at ambient temperature overnight. After adding water, the mixture was extracted with EtOAc, washed with brine then dried over MgS0₄. The crude material was purified with silica gel column chromatography to afford tert-butyl 2-benzyl-3-methoxy- 1 - [2-(3- { methyl[(4-methylthiazol-2-yl)methyl]carbamoyl }benzoyl)hydrazinyl] - 1 -oxopropan- 2-ylcarbamate as a colorless oil (130 mg, 38%). 1H-NMR (400 MHz, CDC1₃) δ: 10.00 (s, 1H), 8.98 (s, 1H), 8.01-7.90 (m, 2H), 7.66 (m, 1H), 7.5 (m, 1H), 7.31-7.17 (m, 5H), 6.89 (s, 1H), 5.33 (m, 1H), 5.0-4.6 (m, 2H), 3.97 (m, 1H), 3.67 (m ,1H), 3.51 (s, 3H), 3.50-3.33 (m, 2H), 3.12-2.85 (m, 2H), 2.45 (s, 3H), 1.48 (s, 9H).

[0642] 2-Benzyl-2-(tert-butoxycarbonylamino)-3-methoxypropanoic acid: To a solution of methyl 2-benzyl-2-(tert-butoxycarbonylamino)-3-methoxypropanoate (270 mg, 0.84 mmol) in MeOH (2.8 ml) was added 3N NaOH aq. (2.8 ml) then heated at 50°C until the reaction was complete. The MeOH was evaporated off and the aqueous solution was washed with ether, acidified with KHS0₄ aq., extracted with EtOAc, the organic phase was washed with brine, dried over MgS0₄ and evaporated to give 2-benzyl-2-(tert-butoxycarbonylamino)- 3-methoxypropanoic acid (200 mg, 77%). 1H-NMR (400 MHz, CDC1₃) δ: 7.30-7.10 (m, 4H), 5.36 (s, 1H), 3.98-3.70 (m, 1H), 3.5-3.17 (m, 4H), 2.04 (s, 2H), 1.48 (s, 9H).

[0643] Methyl 2-benzyl-2-(tert-butoxycarbonylamino)-3-methoxypropanoate: A mixture of methyl 2-benzyl-2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (270 mg, 0.87 mmol), methyl trifluoromethanesulfonate (573 mg, 3.5 mmol) and 2,6-di-tert-butyl-4- methylpyridine (789 mg, 3.8 mmol) in DCE (2.7 ml) was stirred at ambient temperature overnight. The solution was quenched with sat. aq. KHS0₄, extracted with EtOAc, washed with sat. aq. NaHC0₃, brine and dried over MgS0₄. Purification with silica gel column chromatography (0 to 30% EtOAc/hexane) gave methyl 2-benzyl-2-(tert- butoxycarbonylamino)-3-methoxypropanoate (200 mg, 71%) as a colorless oil. MS (ESI) m/z: 224.15 [M - Boc + 2H]⁺.

Example 1.7.10

[0644] (3-(5-(rel-(lS,2R)-l-Amino-2-phenylcyclobutyl)-l,3,4-oxadiazol-2-yl)-N-methyl- N-((4-methylthiazol-2-yl)methyl)benzamide) hydrochloride: tert-Butyl rel-(lS,2R)-l-[5- (3-{methyl[(4-methylthiazol-2-yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-2- phenylcyclobutylcarbamate (180 mg, 0.32 mmol) was treated with 4N HCl/EtOAc at ambient temperature for 3 h, then evaporated to dryness. The residue was washed with ether, and then dried under vacuum to afford 3-{5-[(lS,2R)-l-amino-2-phenylcyclobutyl]-l,3,4-oxadiazol-2- yl}-N-methyl-N-[(4-methylthiazol-2-yl)methyl]benzamide hydrochloride as a colorless amorphous solid. MS (ESI) m/z: 460.1 [M+ H]⁺.

[0645] tert-Butyl rel-(lS,2R)-l-(5-(3-(Methyl((4-methylthiazol-2- yl)methyl)carbamoyl)phenyl)-l,3,4-oxadiazol-2-yl)-2-phenylcyclobutylcarbamate: The desired compound was synthesized from tert-butyl (lS,2R)-l-[2-(3-{methyl[(4- methylthiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazinecarbonyl]-2- phenylcyclobutylcarbamate (230 mg, 0.4 mmol) in a similar manner to Ex. 1.7.9 (190 mg, 85%). MS (ESI) m/z: 560.15 [M+ H]⁺.

[0646] tert-Butyl rel-(lS,2R)-l-(2-(3-(Methyl((4-methylthiazol-2- yl)methyl)carbamoyl)benzoyl)hydrazinecarbonyl)-2-phenylcyclobutylcarbamate: To a solution of rel-(lS,2R)-l-(tert-butoxycarbonylamino)-2-phenylcyclobutanecarboxylic acid (200 mg, 0.69 mmol) in DMF (2 ml) was added 3-(hydrazinecarbonyl)-N-methyl-N-[(4- methylthiazol-2-yl)methyl]benzamide (313 mg, 1 mmol), EDC (197 mg, 1 mmol) and HOBt (93 mg, 0.69 mmol), then stirred at ambient temperature overnight. After adding water, the mixture was extracted with EtOAc, washed with brine then dried over MgS0₄. The crude material was purified with silica gel column chromatography to afford tert-butyl rel-(lS,2R)- 1 - [2-(3- { methyl[(4-methylthiazol-2-yl)methyl]carbamoyl }benzoyl)hydrazinecarbonyl] -2- phenylcyclobutylcarbamate as a colorless form (230 mg, 58%). MS (ESI) m/z: 578.15 [M+ H]⁺.

Example 1.7.11

[0647] 3-{5-[rel-(lR,2R)-l-Amino-2-phenylcyclobutyl]-l,3,4-oxadiazol-2-yl}-N-methyl- N-[(4-methylthiazol-2-yl)methyl]benzamide: The desired compound was synthesised from tert-butyl rel-(lR,2R)-l-[5-(3-{methyl[(4-methylthiazol-2-yl)methyl]carbamoyl}phenyl)- l,3,4-oxadiazol-2-yl]-2-phenylcyclobutylcarbamate (390 mg, 0.7 mmol) by a similar manner to Ex.1.7.10 (220 mg, 64%). MS (ESI) m/z: 460.1 [M+ H]⁺.

[0648] tert-butyl rel-(lR,2R)-l-[5-(3-{methyl[(4-methylthiazol-2- yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-2-phenylcyclobutylcarbamate: The desired compound was synthesized from tert-butyl rel-(lR,2R)-l-[2-(3-{methyl[(4- methylthiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazinecarbonyl]-2- phenylcyclobutylcarbamate (230 mg, 0.4 mmol) in a similar manner to Ex. 1.7.9 (390 mg, 81%). MS (ESI) m/z: 560.15 [M+ H]⁺.

[0649] tert-Butyl rel-(lR,2R)-l-(2-(3-(Methyl((4-methylthiazol-2- yl)methyl)carbamoyl)benzoyl)hydrazinecarbonyl)-2-phenylcyclobutylcarbamate : To a solution of rel-(lR,2R)-l-(tert-butoxycarbonylamino)-2-phenylcyclobutanecarboxylic acid (300 mg, 1 mmol) in DMF (3 ml) was added 3-(hydrazinecarbonyl)-N-methyl-N-[(4- methylthiazol-2-yl)methyl]benzamide (470 mg, 1.5 mmol), EDC (296 mmol, 1.5 mmol) and HOBt (139 mg, 1 mmol) then stirred at ambient temperature overnight. After adding water, the mixture was extracted with EtOAc, washed with brine then dried over MgS0₄. The crude material was purified with silica gel column chromatography to afford tert-butyl rel-(lR,2R)- 1 - [2-(3- { methyl[(4-methylthiazol-2-yl)methyl]carbamoyl }benzoyl)hydrazinecarbonyl] -2- phenylcyclobutylcarbamate as a colorless form (500 mg, 84%). MS (ESI) m/z: 578.15 [M+ H]⁺.

Example 1.7.12

[0650] 3-{5-[(4E)-2-Amino-l,5-diphenylpent-4-en-2-yl]-l,3,4-oxadiazol-2-yl}-N- methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1): To a stirred solution of 3-{5-[(4E)-2-amino-l,5-diphenylpent-4-en-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl- N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide (90 mg, 0.16 mmol) in Et₂0 was added oxalic acid (14 mg, 0.16 mmol). The precipitate which formed was filtered off, washed with Et₂0, and dried in vacuo to give 3-{5-[(4E)-2-amino-l,5-diphenylpent-4-en-2-yl]-l,3,4- oxadiazol-2-yl}-N-methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1) as a colorless solid (0.077 g, 75%). MS (ESI) m/z: 549 [M + H]⁺.

[0651] 3-{5-[(4E)-2-Amino-l,5-diphenylpent-4-en-2-yl]-l,3,4-oxadiazol-2-yl}-N- methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide: To tert-butyl {(4E)-2-[5-(3- {methyl[(4-methyl-l,3-thiazol-2-yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-l,5- diphenylpent-4-en-2-yl}carbamate (0.510 g, 1.21 mmol) was added 4M hydrogen chloride in dioxane (5 mL). After being stirred overnight, the reaction mixture was poured into sat. aq. NaHC0₃ and extracted with EtOAc. The organic layer was dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo to give the title compound as a colorless oil (481 mg, quant.). MS (APC17ESI) m/z: 550 [M + H]⁺.

[0652] tert-Butyl {(4E)-2-[5-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-l,5-diphenylpent-4-en-2- yl}carbamate: The title compound was synthesised from tert-butyl {(4E)-2-benzyl-l-[2-(3- {methyl[(4-methyl-l,3-thiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazino]-l-oxo-5- phenylpent-4-en-2-yl}carbamate (0.610 g) by a similar manner to Ex. 1.7.9 (0.510 g, 86%). MS (APC17ESI) m/z: m/z 648 [M - H]^~.

[0653] tert-Butyl {(4E)-2-benzyl-l-[2-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]-l-oxo-5-phenylpent-4-en-2-yl}carbamate: To a stirred solution of N-(tert-butoxycarbonyl)-alpha-[(2E)-3-phenylprop-2-en-l- yl] phenylalanine (0.370 g, 0.970 mmol) in CH₂C1₂ (5 mL), were added 0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.443 g, 1.17 mmol) and iPr₂NEt (0.24 mL, 1.36 mmol). The mixture was stirred for 15 minutes and 3- (hydrazinocarbonyl)-N-methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide (0.443 g, 1.46 mmol) was added. After being stirred overnight, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed successively with sat. aq. NaHC0₃ and brine, dried with anhydrous Na₂S0₄, and concentrated in vacuo to give tert- butyl { (4E)-2-benzyl- 1 - [2-(3 - { methyl[(4-methyl- 1 ,3-thiazol-2- yl)methyl] carbamoyl }benzoyl)hydrazino] - 1 -oxo-5-phenylpent-4-en-2-yl jcarbamate as a colorless oil (0.610 g, 94%). MS (APCI/ESI) m/z: 690 [M + Na]⁺.

[0654] N-(tert-Butoxycarbonyl)-alpha-[(2E)-3-phenylprop-2-en-l-yl]phenylalanine:

To a stireed solution of ethyl N-(tert-butoxycarbonyl)-alpha-[(2E)-3-phenylprop-2-en-l- yl]phenylalaninate (0.395 g, 0.965 mmol) in MeOH was added 3 M aq. NaOH (3.2 mL, 9.6 mmol). After being stirred for 3 days at 50°C, the reaction mixture was concentrated in vacuo. To the residue was added 1M aq. HCl and extracted with EtOAc. The organic layer was washed with brine, dried with anhydrous Na₂S0₄, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/hexane 0:100 to 100:0) to give N-(tert-butoxycarbonyl)-alpha-[(2E)-3-phenylprop-2-en-l-yl]phenylalanine (0.370 g, 100%) as a colorless solid. MS (APCI/ESI) m/z: 380 [M-H]^~.

[0655] Ethyl N-(tert-butoxycarbonyl)-alpha-[(2E)-3-phenylprop-2-en-l- yl]phenylalaninate: To a stirred solution of ethyl alpha-[(2E)-3-phenylprop-2-en-l- yl]phenylalaninate (0.750 g, 1.02 mmol) in dioxane (5 mL) was added Boc₂0 (0.635 g, 2.91 mmol). After being stirred for 1 day at 50°C, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/hexane 0:100 to 20:80) to give ethyl N-(tert-butoxycarbonyl)-alpha-[(2E)-3-phenylprop-2-en-l- yl]phenylalaninate as colorless oil (0.400 g, 40%). MS (ESI) m/z: 410 [M + H]⁺.

[0656] Ethyl alpha-[(2E)-3-phenylprop-2-en-l-yl]phenylalaninate: To a stirred solution of ethyl (E)-N-(4-chlorobenzylidene)-L-phenylalaninate (4.00 g, 12.7 mmol) in MeCN (100 mL) were added [(lE)-3-bromoprop-l-en-l-yl]benzene (3.12 g, 15.8 mmol), K₂C0₃ (4.38 g, 31.7 mmol), and tetrabutylammonium bromide (0.408 g, 1.27 mmol). After being stirred for 4 days under reflux, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed successively with water and brine. The organic layer was dried with anhydrous Na₂S0₄ and concentrated in vacuo. The residue was dissolved in THF (40 mL) and 1 M aq. HCl (40 mL) was added. After being stirred for 1 hour, the aqueous layer was washed with Et₂0, neutralized, and extracted with CH₂C1₂. The organic layer was dried with anhydrous Na₂S0₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/hexane 10:90 to 50:50) to give ethyl alpha-[(2E)-3-phenylprop-2-en-l-yl]phenylalaninate as a colorless oil (0.750 g, 19%). MS (APC17ESI) m/z: 310 [M+H]⁺.

Example 1.7.13

[0657] 3-[5-(2-Amino-l,5-diphenylpentan-2-yl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4- methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1): A solution of 3-{5-[(4E)- 2-amino- 1 ,5-diphenylpent-4-en-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [(4-methyl- 1,3- thiazol-2-yl)methyl]benzamide (0.100 g, 0.331 mmol) in EtOH (10 mL) was passed through the H-Cube (registered trademark) reactor (Pd/C CatCart; 1.0 mL/min; 1 atm H₂; room temperature). The eluted solution was concentrated in vacuo and purified by column chromatography on silica gel (MeOH/CHCl₃ 1:99 to 10:90). The residue was dissolved in Et₂0 and oxalic acid (0.016 g, 0.178 mmol) was added. The precipitate which formed was filtered off, washed with Et₂0, and dried in vacuo to give 3-[5-(2-Amino-l,5-diphenylpentan- 2-yl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1) as a colorless solid (0.072 g, 62%). MS (ESI) m/z: 552 [M - H]^~.

Example 1.7.14

[0658] 3-[5-(2-Amino-l,3-diphenylpropan-2-yl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4- methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1): To tert-butyl {2-[5-(3- {methyl[(4-methyl-l,3-thiazol-2-yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-l,3- diphenylpropan-2-yl}carbamate (0.240 g, 0.385 mmol) was added 4 M hydrogen chloride in dioxane (5 mL). After being stirred overnight, the reaction mixture was poured into sat. aq. NaHC0₃ and extracted with EtOAc. The organic layer was washed with brine, dried with anhydrous Na₂S0₄ and concentrated in vacuo. The residue was dissolved in Et₂0 and oxalic acid (0.035 g, 0.39 mmol) was added. The precipitate which formed was filtered off, washed with Et₂0, and dried in vacuo to give 3-[5-(2-amino-l,3-diphenylpropan-2-yl)-l,3,4- oxadiazol-2-yl] -N-methyl-N- [(4-methyl- l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1) as a colorless solid (0.180 g, 76%). MS (ESI) m/z: 524 [M + H]⁺.

[0659] tert-Butyl {2-[5-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-l,3-diphenylpropan-2-yl}carbamate:

The title compound was synthesised from tert-butyl {2-benzyl-l-[2-(3-{methyl[(4-methyl- l,3-thiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazino]-l-oxo-3-phenylpropan-2- yljcarbamate (0.254 mg) by a similar manner to Ex. 1.7.9 (0.241 g, 98%). MS (APC17ESI) m/z: 622 [M - H]^~. [0660] tert-Butyl {2-benzyl-l-[2-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]-l-oxo-3-phenylpropan-2-yl}carbamate: To a stireed solution of alpha-benzyl-N-(tert-butoxycarbonyl)phenylalanine (0.240 g, 0.675 mmol) in CH₂C1₂ (5 mL), were added HATU (0.333 g, 0.878 mmol) and iPr₂NEt (0.18 mL, 1.01 mmol). The reaction mixture was stirred for 15 minutes and 3-(hydrazinocarbonyl)-N- methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide (0.267 g, 0.877 mmol) was added. After being stirred overnight, the reaction mixture was poured into water, extracted with EtOAc and washed successively with sat. aq. NaHC0₃ and brine. The organic layer was dried with anhydrous Na₂S0₄ and concentrated in vacuo to give tert-butyl {2-benzyl-l-[2-(3- {methyl[(4-methyl-l,3-thiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazino]-l-oxo-3- phenylpropan-2-yl} carbamate as a pale yellow oil (0.254 g, 59%). MS (APCI/ESI) m/z: m/z 640 [M - H]^~.

Example 1.7.15

[0661] rel-3-{5-[(lR,2R)-l-Amino-2-phenylcyclopentyl]-l,3,4-oxadiazol-2-yl}-N- methyl-N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide ethanedioate (1:1): To tert-butyl rel-{(lR,2R)-l-[5-(3-{methyl[(4-methyl-l,3-thiazol-2-yl)methyl]carbamoyl}phenyl)-l,3,4- oxadiazol-2-yl]-2-phenylcyclopentyl} carbamate (0.214 g, 0.362 mmol) was added 4 M hydrogen chloride in dioxane (5 mL). After being stirred overnight, the reaction mixture was poured into sat. aq. NaHC0₃ and extracted with EtOAc. The organic layer was washed with brine, dried with anhydrous Na₂S0₄ and concentrated in vacuo. The residue was dissolved in Et₂0, and oxalic acid (0.033 g, 0.36 mmol) was added. The precipitate which formed was filtered off, washed with Et₂0, and dried in vacuo to give rel-3-{5-[(lR,2R)-l-Amino-2- phenylcyclopentyl] - 1 ,3,4-oxadiazol-2-yl } -N-methyl-N-[(4-methyl- 1 ,3-thiazol-2- yl)methyl]benzamide ethanedioate (1:1) as a beige solid (0.190 g, 93%). MS (ESI) m/z: 474 [M + H]⁺.

[0662] tert-Butyl rel-{(lR,2R)-l-[5-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}phenyl)-l,3,4-oxadiazol-2-yl]-2-phenylcyclopentyl}carbamate:

The title compound was synthesised from tert-butyl rel-[(lR,2R)-l-{ [2-(3-{ methyls- methyl- l,3-thiazol-2-yl)methyl]carbamoyl}benzoyl)hydrazm^

phenylcyclopentyl] carbamate (0.270 g) in a similar manner to Ex. 1.7.9 (0.214 g, 82%). MS (APCI/ESI) m/z: 4574 [M + H]⁺.

[0663] tert-Butyl rel-[(lR,2R)-l-{[2-(3-{methyl[(4-methyl-l,3-thiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2-phenylcyclopentyl]carbamate: To a stirred solution of rel-(lR,2R)-l-[(tert-butoxycarbonyl)amino]-2- phenylcyclopentanecarboxylic acid (0.150 g, 0.491 mmol) in CH₂CI₂ (3 mL), were added HATU (0.224 g, 0.589 mmol) and iPr₂NEt (0.13 mL, 0.74 mmol). The reaction mixture was stirred for 15 minutes and 3-(hydrazinocarbonyl)-N-methyl-N-[(4-methyl-l,3-thiazol-2- yl)methyl]benzamide (0.224 g, 0.687 mmol) was added. After being stirred overnight, the reaction mixture was poured into water, extracted with EtOAc and washed successively with sat. aq. NaHC0₃ and brine. The organic layer was dried with anhydrous Na₂S0₄ and concentrated in vacuo to give tert-butyl rel-[(lR,2R)-l-{ [2-(3-{methyl[(4-methyl-l,3-thiazol- 2-yl)methyl]carbamoyl}benzoyl)hydrazino]carbonyl}-2-phenylcyclopentyl]carbamate as a pale yellow oil (0.270 g, 93%). MS (APCI/ESI) m/z: 640 [M - H]^~.

[0664] rel-(lR,2R)-l-[(tert-Butoxycarbonyl)amino]-2-phenylcyclopentanecarboxylic acid: To a solution of ethyl isocyanoacetate (2.6 mL, 23.9 mmol) in MeCN (77 mL) was added K₂C0₃ (19.8 g, 144 mmol), Bu₄NHS0₄ (1.63 g, 4.79 mmol) and (1,4- dibromobutyl)benzene (6.99 g, 23.9 mmol). The mixture was heated at 80°C until all of the starting electrophile had been consumed. The reaction mixture was cooled and filtered through celite to remove insoluble solid. The solid material was washed with acetonitrile and the filtrate was evaporated. The residue was taken into ether and washed with water and brine and then dried over MgS0₄. The residue was purified with silica gel column chromatography (AcOEt/hexane = 0:100 to 30:70) to give a yellow oil (2.67 g) as a product.

[0665] To a solution of the product of the previous step in EtOH (50 mL) was added 12 M hydrogen chloride (0.91 mL, 11 mmol). The reaction mixture was stirred until complete consumption of the starting material was achieved. The reaction mixture was concentrated in vacuo, and the resulting solid was suspended in dichloroethane (110 mL) and triethylamine (2.3 mL, 16 mmol) was added. After 5 min, Boc₂0 (7.19 g, 32.9 mmol) was added. After being stirred at ambient temperature for 1 day, the reaction mixture was diluted with dichloroethane and washed successively with aq. KHS0₄, aq. NaHC0₃ and brine. The organic layer was dried over MgS0₄ and the solvent evaporated to yield a residue, which was purified by flash column chromatography to give the Boc-protected amine as a white solid (3.21 g).

[0666] To a solution of the product of the previous step in EtOH (32 mL) was added 6 M aq. NaOH (5.0 mL, 30 mmol). The reaction mixture was heated under reflux for 5 h. The mixture was cooled to room temperature and water (5 ml) was added. The aqueous layer was washed with dichloromethane, acidified with KHS0₄ aq, and then extracted with dichloromethane. The organic layer was concentrated in vacuo to give rel-(lR,2R)-l-[(tert- butoxycarbonyl)amino]-2-phenylcyclopentanecarboxylic acid as a colorless solid (1.49 g, 81%). MS (ESI) m/z:306 [M + H]⁺.

Example 1.7.16

[0667] A 100 ml round bottom flask was charged with methyl 5-iodo-2-methoxybenzoate (Aldrich, 0.5 g, 1.712 mmol) and a stir bar. A solution of THF/MeOH (7 ml: 3 ml) was added with stirring. The resulting solution was treated with NaOH (1M, 3.42 ml, 3.42 mmol). After stirring overnight, the solution was adjusted to pH = 1-2 with HC1 (~ 6M) and extracted with EtOAc (xl). The layers were separated. The organic layer was washed with water (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation yielding 5-iodo-2-methoxybenzoic acid (0.4599 g, 1.654 mmol, 97 % yield) as a white solid.

[0668] A 100 ml round bottom flask charged with 5-iodo-2-methoxybenzoic acid (0.4599 g, 1.654 mmol) and a stir bar was evacuated and back-filled with Ar (x3). Anhydrous DCM (10 mL) was added, and the solution was cooled to 0 °C with stirring. The solution was treated with EDCI-HCl (0.349 g, 1.819 mmol,) and HOBT H₂0 (0.279 g, 1.819 mmol). After 1 h (R)-tert-butyl (l-hydrazinyl-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate (0.461 g, 1.571 mmol) and DIPEA (0.867 ml, 4.96 mmol) were added sequentially. The reaction was stirred at 0 °C to room temperature overnight. After stirring overnight the volatiles were removed via rotary evaporation. The residue was partitioned between EtO Ac/water, and the layers were separated. The organic layer was washed with water (x2), brine (xl), and the volatiles were removed via rotary evaporation. Purification via flash chromatography eluting with EtOAc/hexanes yielded (R)-tert-butyl (l-(2-(5-iodo-2-methoxybenzoyl)hydrazinyl)-2- methyl-l-oxo-3-phenylpropan-2-yl)carbamate (0.7363 g, 1.331 mmol, 80 % yield).

[0669] A 10-20 ml microwave vial was charged with (R)-tert-butyl (l-(2-(5-iodo-2- methoxybenzoyl)hydrazinyl)-2-methyl-l-oxo-3-phenylpropan-2-yl)carbamate (0.7363 g, 1.331 mmol) and a stir bar. Burgess' reagent (0.951 g, 3.99 mmol) was added. The vial was sealed with a rubber septum (14/20) and evacuated and back-filled with Ar (x3). Anhydrous

I, 2-Dichloroethane (6 ml) was added. The vial was sealed with a cap, and the contents were shaken gently to dissolve. The resulting solution was irradiated at 120 °C for 12 min. After cooling to room temperature the solution was transferred to a round bottom flask, and the volatiles were removed via rotary evaporation. The residue was partitioned between EtO Ac and saturated aqueous NaHC03. The layers were separated. The organic layer was washed with water (x2) and brine (xl). The volatiles were removed via rotary evaporation.

Purification via flash chromatography eluting with EtOAc/hexanes yielded (R)-tert-butyl (2- (5-(5-iodo-2-methoxyphenyl)-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (0.6141 g, 1.147 mmol, 86 % yield) as a white foam.

[0670] A 100 ml round bottom flask was charged with (R)-tert-butyl (2-(5-(5-iodo-2- methoxyphenyl)-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (0.6141 g, 1.147 mmol), Pd(OAc)2 (0.013 g, 0.057 mmol), Xantphos (0.066 g, 0.115 mmol), and a stir bar. The flask was evacuated and back-filled with Ar (x3). Dioxane (6 ml) and water (2 ml) were combined and purged with Ar to degas, and the resulting solution was added to the flask. After stirring for 2-3 min, the resulting green-black solution was treated with Et3N (1.599 ml,

I I.47 mmol) which had been degassed via Ar purge. The flask was sealed with a septum which was then secured with electrical tape. The mixture was purged with CO with stirring for 3 min, and the reulting mixture was heated to 75 °C with stirring under CO. After stirring for 4 hours the brown solution was cooled to room temperature. The dioxane was removed via rotary evaporation. The residue was diluted with water and filtered through Celite. The filter pad was rinsed with dilute NaOH (pH ~ 9). The combined aqueous fractions were adjusted to pH = 4-5 with 3 N HC1, and a white ppt was formed. The mixture was extracted with EtO Ac (xl), and the layers were separated. The organic layer was washed with water (xl), brine (xl), and dried over Na2S04. The inorganics were filtered off, and the volatiles were removed via rotary evaporation yielding (R)-3-(5-(2-((tert-butoxycarbonyl)amino)-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-methoxybenzoic acid (0.5 g, 1.103 mmol, 96 % yield) as a white foam.

[0671] A 25 ml round bottom flask charged with (R)-3-(5-(2-((tert-butoxycarbonyl)amino)- l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-methoxybenzoic acid (0.040 g, 0.088 mmol) and a stir bar was evacuated and back-filled with Ar (x3). Anhydrous DCM (5 mL) was added, and the solution was cooled to 0 °C with stirring. The solution was treated with EDCI HC1 (0.019 g, 0.097 mmol) and HOBT H₂0 (0.015 g, 0.097 mmol). After 1 h l-(2,5- dimethyloxazol-4-yl)-N-methylmethanamine (0.012 g, 0.088 mmol) and DIPEA (0.046 ml, 0.265 mmol) were added sequentially. The reaction was stirred at 0 °C to room temperature overnight. After stirring overnight, the volatiles were removed via rotary evaporation. The residue was partitioned between EtO Ac/water, and the layers were separated. The organic layer was washed with water (x2), brine (xl), and the volatiles were removed via rotary evaporation. Purification via flash chromatograpy eluting with EtOAc/MeOH yielded (R)- tert-butyl (2-(5-(5-(((2,5-dimethyloxazol-4-yl)methyl)(methyl)carbamoyl)-2- methoxyphenyl)-l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (0.0393 g, 0.068 mmol, 77 % yield).

[0672] A 25 ml round bottom flask charged with (R)-tert-butyl (2-(5-(5-(((2,5- dimethyloxazol-4-yl)methyl)(methyl)carbamoyl)-2-methoxyphenyl)-l,3,4-oxadiazol-2-yl)-l- phenylpropan-2-yl)carbamate (0.0393 g, 0.068 mmol) and a stir bar was evacuted and backfilled with Ar (x3). Anhydrous DCM (0.5 mL) was added with stirring. The resulting solution was treated with TFA (0.5 mL, large excess). After 1 h the volatiles were removed via rotary evaporation. The residue was partitioned between saturated aqueous NaHC03 and EtO Ac. After stirring for several minutes the layers were separated. The organic layer was washed with water (xl), brine (xl), and dried over Na2S04. The inorganics were filtered off, and the volatiles were removed via rotary evaporation yielded (R)-3-(5-(2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-4-methoxy- N-methylbenzamide (0.0238 g, 0.050 mmol, 73.3 % yield) as a sticky whtie solid. Example 1.7.17

[0673] The compound was synthesized in a manner similar to that of Example 1.7.1. Example 1.7.18

[0674] The compound was synthesized in a manner similar to that of example 1.7.2.

Example 1.7.19

[0675] The compound was synthesized in a manner similar to that of example 1.7.2.

Example 1.7.20

[0676] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.21

[0677] IN NaOH (0.16 ml, 0.16 mmol, 1.5 eq) was added to a stirred solution of SM (0.071 g, 0.11 mmol, 1 eq). in THF/MeOH (1 ml:0.5 ml). After 3 h the volatiles were removed via rotary evaporation. IN HC1 was added to pH = 5-6 producing a white ppt. The mixture was extracted with EtOAc (xl), and the layers were separated. The organic layer was washed with water (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotarty evaporation to yield the acid (100%).

[0678] Final deprotection was carried out in a manner similar to that of Example 1.7.1. Example 1.7.22

[0679] EDCI HC1 (0.0161 g, 0.084 mmol, 1.1 eq) and HOBT H₂0 (0.0114 g, 0.084 mmol, 1.1 eq) were added to a stirred solution of the acid (0.0473 g, 0.077mmol, 1 eq) in anhydrous CH₂C1₂ (5 ml) at 0 °C. After 1 h MeNH₂ HCl (Aldrich, 0.0155g, 0.23 mmol, 3 eq) and DIPEA (0.07 ml, 0.05g, 0.38 mmol, 5 eq) were added sequentially. The reaction was stirred at 0°C to room temperature overnight. The reaction was quenched with water, and the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/H₂0, and the layers were separated. The organic layer was washed with water (x2), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed vai rotary evaporation. Purification via flash chromatography on silica gel yielded 0.0365 g (0.058 mmol, 75%) of the amide.

[0680] Final deprotection was carried out in a manner similar to that of Example 1.7.1. Example 1.7.23

[0681] The compound was synthesized in a manner similar to that of example 1.7.22. Example 1.7.24

[0682] The compound was synthesized in a manner similar to that of example 1.7.22. Example 1.7.25

[0683] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.26

[0684] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.27

[0685] The compound was synthesized in a manner similar to that of example 1.7.22. Example 1.7.28

[0686] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.29

[0687] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.3

[0688] A flask charged with the starting material (0.0402 g, 0.08 mmol, 1 eq), NaCN (0.0196 g, 0.4 mmol, 5 eq), and a stir bar was evacuated and back-filled with Ar (x3). Anhydrous DMSO (2.5 ml) was added, and the resulting mixture was heated to 180 °C with stirring. After 5 h the reaction was cooled to room temperature. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (x3), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation. Purification via flash chromatography yielded 0.0207 g (0.042 mmol, 53%) of the product.

Example 1.7.31

[0689] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.32

[0690] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.33

[0691] The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.34

[0692] The compound was synthesized in a manner similar to that of example 1.7.1.

Example 1.7

[0693] A flask charged with the starting material (0.0571 g, 0.082 mmol, 1 eq) and a stir bar was evacuated and back-filled with Ar (x3). Anhydrous DMC (0.5 ml) was added. The resulting solution was treated with HCl (4.0 M in 1,4-dioxane, 0.5 ml, large excess) with stirring. After 1 h the volatiles were removed via rotary evaporation. The residue was partitioned between with saturated aqueous NaHC03/EtOAc, and the layers were separated. The organic layer was washed with water (xl), brine (xl), and dried over Na₂S0₄. The inorganics were filtered off, and the volatiles were removed via rotary evaporation.

Purification via flash chromatography yielded 0.033g (0.061 mmol, 74%) of the product. Example 1.7.36

[0694] The compound was synthesized in a manner similar to that of example 1.7.17. Example 1.7.37

[0695] The compound was synthesized in a manner similar to that of example 1.7.17. Example 1.7.38

[0696] The compound was synthesized in a manner similar to that of example 1.7.17 starting with methyl 5-bromo-2-methoxynicotinate (Combi-Blocks).

Example 1.7.39

[0697] The compound was synthesized in a manner similar to that of example 1.7.17 starting with methyl 5-bromo-2-methoxynicotinate (Combi-Blocks).

Example 1.7.40

[0698] The compound was synthesized in a manner similar to that of example 1.7.17 starting with methyl 5-bromo-2-methoxynicotinate (Combi-Blocks).

Example 1.7.41

[0699] The compound was synthesized in a manner similar to that of example 1.7.17 starting with 5-bromo-2-(trifluoromethoxy)benzoic acid (Combi-Blocks). Example 1.7.42: Synthesis of (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)- 5-( 1 -meth l- lHimidazol-2- l hen l)((R)-2-( 4-meth lthiazol-2-yl)pyrrolidin-l-yl )methanone

[0700] Deprotection of the Boc protected compound using a procedure similar to the one depicted in Example 1.7.2 yielded the final product.

Example 1.7.43

[0701] The compound was synthesized in a manner similar to that as in Example 1.7.1, Example 1.7.44

[0702] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.45

[0703] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.46

[0704] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.47

[0705] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.48

[0706] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.49

[0707] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.50

[0708] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.7.51

[0709] tert-Butyl {(2R)-2-[5-(6-cyclopropyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: To a stirred solution of te/t-butyl [(2R)-l-{2-[(6-cyclopropyl-4-{ [(2R)-2-(4- methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl)carbonyl]hydrazino } -2- methyl-l-oxo-3-phenylpropan-2-yl]carbamate (417 mg, 0.66 mmol) in CH₂CI₂ (10 ml) were added CBr₄ (437 mg, 1.32 mmol), PPh₃ (346 mg, 1.32 mmol) and imidazole (89 mg, 1.32 mmol) at 0 degree and the mixture was stirred at rt for 2 hours. The starting molecule was completely consumed and volatiles were evaporated to give a crude product. This was purified with column chromatography (EtOAc in hexane = 0 to 100%) to give tert-butyX { (2R)-2- [5-(6-cyclopropyl-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate containing a significant amount of 0=PPh₃ as a white solid, which was used for the next reaction without further purification. MS (ESI) m/z: 615 [M+H]⁺.

[0710] (2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- cyclopropylpyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1): To a stirred solution of tert-butyl {(2R)-2-[5-(6-cyclopropyl-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol- 2-yl]-l-phenylpropan-2-yl} carbamate (405 mg, 0.66 mmol) in CH₂CI₂ (0.4 ml) was added TFA (0.8 ml) at rt and the mixture was stirred for 1 hour. Volatiles were evaporated and the residue was purified with column chromatography (NH- silica, EtOAc in hexane = 20 to 100%) to give the desired product as a free form. This was dissolved in EtOH (1 ml) and fumaric acid (1 eq. to the free form) was added. The mixture was stirred at rt for 1 hour and EtOH was evaporated to give a solid, which was collected, washed with IPE and dried under reduced pressure to give (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- cyclopropylpyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) (145 mg, 35% yield in 4 steps) as an off-white solid.

Example 1.7.52

[0711] tert-Butyl [(2R)-2-{5-[6-(2-cyanophenyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from tert-butyl [(2R)-l-(2-{ [6-(2- cyanophenyl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2- yl]carbonyl}hydrazino)-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate (194 mg, 0.281 mmol) in a similar manner to Example 1.7.51. MS (ESI) m/z: 676 [M+H]⁺.

[0712] 2-(6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)benzonitrile (2E)-but-2- enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[6-(2- cyanophenyl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]- 1, 3, 4-oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate (188 mg, 0.278 mmol) in a similar manner to Example 1.7.51. (50 mg, 26% yield in 6 steps).

Example 1.7.53

[0713] tert-Butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from tert-butyl [(2R)-2-methyl-l-(2- { [4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(l,3-oxazol-2- yl)pyridin-2-yl]carbonyl}hydrazino)-l-oxo-3-phenylpropan-2-yl]carbamate (160 mg, 0.250 mmol) in a similar manner to Example 1.7.50. (116 mg, 72% yield) MS (ESI) m/z: 642

[M+H]⁺.

[0714] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedioate (1:1) : The desired compound was synthesized from tert-buty\ [(2R)-2-{5-[4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-2- yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (116 mg. 0.180 mmol) in a similar manner to Example 1.7.50. (85 mg, 72% yield).

Example 1.7.54

[0715] tert-Butyl {(2R)-2-[5-(6-methoxy-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: The desired compound was synthesized from tert-buty\ [(2R)-l-{2-[(6- methoxy-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2- yl)carbonyl]hydrazino}-2-methyl-l-oxo-3-phenylpropan-2-yl]carbamate (292 mg, 0.469 mmol) in a similar manner to Example 1.7.50. (160 mg, 56% yield) MS (ESI) m/z: 605

[M+H]⁺.

[0716] (2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5- (6-methoxy-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)- l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (160 mg, 0.265 mmol) in a similar manner to Example 1.7.50. (120 mg, 73% yield). Exampl

id)

[0717] N-(6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N- methylmethanesulfonamide (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-[methyl(methylsulfonyl)amino]-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl} carbamate (117 mg, 0.172 mmol) in a similar manner to Example 1.7.50. (67 mg, 56% yield).

Example 1.7.56

[0718] 4-(5-{(2R)-2-[(tert-Butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid: To a stirred solution of methyl 4-(5-{ (2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylate (99 mg, 0.18 mmol) in THF (1.36 ml) was added 1 M NaOH aq. (1.36 ml) at rt and the mixture was stirred at rt for 1 hour. The reaction was quenched with 1 M HC1 aq. (1.36 ml) The mixture was evaporated to give a crude of 4-(5-{(2R)-2-[(ieri-butoxycarbonyl)amino]-l-phenylpropan-2- yl}-l,3,4-oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid as a white solid, which was used for the next reaction without further purification.

[0719] ter^Butyl {(2R)-2-[5-(2-[methyl(methylsulfonyl)amino]-6-{[(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: To a stirred solution of 4-(5-{(2R)-2-[(tert- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6- [methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid (96 mg, 0.18 mmol), z-Pr₂NEt (0.068 ml, 0.40 mmol) and 4-methyl-2-[(2R)-pyrrolidin-2-yl]-l,3-thiazole (36 mg, 0.22 mmol) in CH₂C1₂ (1 ml) was added HATU (82 mg, 0.22 mmol) at rt and the mixture was stirred at the same temperature overnight. The mixture was quenched with H₂0 and the organic layer was separated. The aqueous layer was extracted with CHC1₃ (x3) and the combined organic layer was washed with aq. KHSO₄ (pH 4), satd. NaHC0₃ aq and brine, dried over MgS0₄ and evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 20 to 80%) to give tert-butyl {(2R)-2-[5-(2- [methyl(methylsulfonyl)amino]-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (62 mg, 50% yield) as ayellow oil. MS (ESI) m/z: 682 [M+H]⁺.

[0720] N-(4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N- methylmethanesulfonamide (2E)-but-2-enedioate (1:1) : To a stirred solution of tert-butyl {(2R)-2-[5-(2-[methyl(methylsulfonyl)amino]-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yljcarbamate (62 mg, 0.090 mmol) in CH₂C1₂ (2 ml) was added TFA (4 ml) at rt and the mixture was stirred for 1 hour. Volatiles were evaporated and the residue was purified with column chromatography (NH-silica, EtOAc in hexane = 20 to 100%) to give the desired product as a free form. This was dissolved in EtOH (1 ml) and fumaric acid (1 eq. to the free form) was added. The mixture was stirred at rt for 1 hour and EtOH was evaporated to give a solid, which was collected, washed with IPE and dried under reduced pressure to give N-(4- {5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N-methylmethanesulfonamide (2E)-but- 2-enedioate (1:1) (25 mg, 40% yield) as an off-white solid.

Example 1.7.57

[0721] 4-(5-{(2R)-2-[(tert-Butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4- oxadiazol-2-yl)-6-methoxypyridine-2-carboxylic acid: The desired compound was synthesized from methyl 4-(5-{(2R)-2-[(ieri-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- l,3,4-oxadiazol-2-yl)-6-methoxypyridine-2-carboxylate (650 mg, 1.39 mmol) in a similar manner to Example 1.7.56. MS (ESI) m/z: 668 [M+H]⁺.

[0722] tert-Butyl {(2R)-2-[5-(2-methoxy-6-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: The desired compound was synthesized from 4-(5-{(2R)-2-[(iert- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-methoxypyridine-2- carboxylic acid (630 mg, 1.39 mmol) in a similar manner to Example 1.7.56. (677 mg, 81% yield) MS (ESI) m/z: 605 [M+H]⁺.

[0723] (4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-2-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5- (2-methoxy-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-4-yl)- l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (246 mg, 0.407 mmol) in a similar manner to Example 1.7.56. (125 mg, 50% yield). Example 1.7.58

)

[0724] tert-Butyl [(2R)-2-{5-[4-{[(2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from 2-(5-{(2R)-2-[(ieri- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid (120 mg, 0.244 mmol) in a similar manner to Example 1.7.56. (147 mg, 92% yield) MS (ESI) m/z: 657 [M+H]⁺.

[0725] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl][(2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4- { [(2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]- 1, 3, 4-oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate (147 mg, 0.244 mmol) in a similar manner to Example 1.7.56. (91 mg, 60% yield).

Example 1.7.59

[0726] tert-Butyl [(2R)-2-{5-[4-{[(2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from 2-(5-{(2R)-2-[(ieri- butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid (120 mg. 0.244 mmol) in a similar manner to Example 1.7.56. MS (ESI) m/z: 669 [M+H]⁺.

[0727] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl][(2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1 : 1) : The desired compound was synthesized from tert-butyl [(2R)-2- {5-[4-{ [(2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(l,3-oxazol-2- yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (163 mg, 0.244 mmol) in a similar manner to Example 1.7.56. (94 mg, 56% yield in 2 steps).

Example 1.7.60

d)

[0728] tert-Butyl [(2R)-2-{5-[4-({(2R)-2-[4-(methoxymethyl)-l,3-thiazol-2- yl]pyrrolidin-l-yl}carbonyl)-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from 2-(5-{(2R)-2- [(ieri-butoxycarbonyl)amino]-l-phenylpropan-2-yl}-l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2- yl)isonicotinic acid (100 ,mg. 0.203 mmol) in a similar manner to Example 1.7.56.

[0729] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl]{(2R)-2-[4-(methoxymethyl)-l,3-thiazol-2-yl]pyrrolidin-l- yl}methanone (2E)-but-2-enedioate (1 :1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4-({(2R)-2-[4-(methoxymethyl)-l,3-thiazol-2-yl]pyrrolidin-l- yl}carbonyl)-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl]carbamate (120 mg, 0.179 mmol) in a similar manner to Example 1.7.56. (12 mg, 10%

yield in 2 steps).

Example 1.7.61

[0730] tert-Butyl {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-2,3'-bipyridin-6-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate:

To a stirred solution of tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yljcarbamate (120 mg, 0.197 mmol) in toluene (1.5 ml) were added pyridin-3-ylboronic acid (73 mg, 0.59 mmol), Pd₂(dba)₃ (36 mg, 0.039 mmol) and SPhos (65 mg, 0.158 mol) at rt and the mixture was irradiated at 150 degree for 30 min. The starting molecule was completely consumed and volatiles were evaporated to give a crude product. This was purified with column chromatography (EtOAc in hexane = 20 to 100% then MeOH in CHC1₃ = 0 to 10%) to give ierf-butyl {(2R)-2-[5-(4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-2,3'-bipyridin-6-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (74 mg, 58% yield) as a colorless oil. MS (ESI) m/z: 652 [M+H]⁺.

[0731] (6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-2,3'-bipyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : To a stirred solution of tert-butyl {(2R)-2-[5-(4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-2,3'-bipyridin-6-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yljcarbamate (74 mg, 0.114 mmol) in CH₂C1₂ (2 ml) was added TFA (4 ml) at rt and the mixture was stirred for 1 hour. Volatiles were evaporated and the residue was purified with column chromatography (NH-silica, EtOAc in hexane = 20 to 100%) to give the desired product as a free form. This was dissolved in EtOH (1 ml) and fumaric acid (1 eq. to the free product) was added. The mixture was stirred at rt for 1 hour and EtOH was evaporated to give a solid, which was collected, washed with IPE and dried under reduced pressure to give (6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-2,3'-bipyridin-4-yl)[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) (50 mg, 66% yield) as an off-white solid.

Example 1.7.62

[0732] tert-Butyl {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-2,4'-bipyridin-6-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate:

The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl} carbamate (240 mg, 0.394 mmol) in a similar manner to Example 1.7.61. (124 mg, 48% yield) MS (ESI) m/z: 652 [M+H]⁺.

[0733] (6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-2,4'-bipyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5-(4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2,4'-bipyridin-6-yl)-l,3,4-oxadiazol-2-yl]- l-phenylpropan-2-yl} carbamate (124 mg, 0.190 mmol) in a similar manner to Example 1.7.61. (53 mg, 42% yield).

Example 1.7.63

[0734] tert-Butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(pyrimidin-5-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-

4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (200 mg, 0.328 mmol) in a similar manner to Example 1.7.61. (180 mg, 84% yield) MS (ESI) m/z: 597 [M-i-Bu+H]⁺.

[0735] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(pyrimidin-

5- yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(pyrimidin-5-yl)pyridin-2- yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (180 mg, 0.276 mmol) in a similar manner to Example 1.7.61. (104 mg, 47% yield).

Example 1.7.64

[0736] t^Butyl {(2R)-2-[5-(6-methyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4- methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl }pyridin-2-yl)- 1 ,3 ,4-oxadiazol-2-yl] - 1 - phenylpropan-2-yl} carbamate (150 mg, 0.246 mmol) in a similar manner to Example 1.7.61. (144 mg, 99% yield) MS (ESI) m/z: 589 [M-i-Bu+H]⁺.

[0737] (2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methylpyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5- (6-methyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)- l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (144 mg, 0.245 mmol) in a similar manner to Example 1.7.61. (54 mg, 37% yield).

Example 1.7.65

[0738] tert-Butyl [(2R)-2-{5-[6-(l,l-dioxido-l,2-thiazolidin-2-yl)-4-{[(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: To a stirred solution of tert-butyl {(2R)-2-[5-(6-chloro-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol- 2-yl]-l-phenylpropan-2-yl} carbamate (150 mg, 0.246 mmol) in dioxane (3 ml) were added 1,2-thiazolidine- 1,1 -dioxide (90 mg, 0.74 mmol), Pd₂(dba)₃ (113 mg, 0.12 mmol), Xantphos (214 mg, 0.37 mmol) and K₃P0₄ (157 mg, 0.74 mmol) at rt and the mixture was irradiated with microwave at 150 degree for 30 min. The starting molecule was completely consumed and volatiles were evaporated to give a crude, which was purified with column

chromatography (EtOAc in hexane = 20 to 100%) to give tert-butyl [(2R)-2-{5-[6-(l,l- dioxido-l,2-thiazolidin-2-yl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (144 mg, 84% yield) as a colorless oil. MS (ESI) m/z: 694 [M+H]⁺.

[0739] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,l-dioxido l,2 hiazolidin-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : To a stirred solution of tert-butyl [(2R)-2-{5-[6- (1,1 -dioxido- 1 ,2-thiazolidin-2-yl)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (144 mg, 0.208 mmol) in CH₂CI₂ (2 ml) was added TFA (4 ml) at rt and the mixture was stirred for 1 hour. Volatiles were evaporated and the residue was purified with column chromatography (NH-silica, EtOAc in hexane = 20 to 100%) to give the desired product as a free form. This was dissolved in EtOH (1 ml) and fumaric acid (1 eq. to the free amine) was added. The mixture was stirred at rt for 1 hour and EtOH was evaporated to give a solid, which was collected, washed with IPE and dried under reduced pressure to give [2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 , 1 -dioxido- 1 ,2-thiazolidin-2-yl)pyridin-4- yl] [(2R)-2-(4-methyl- 1 ,3 -thiazol-2-yl)pyrrolidin- 1 -yl] methanone (2E)-but-2-enedioate (1:1) (84 mg, 57% yield) as an off-white solid.

Example 1.7.66

[0740] tert-Butyl {(2R)-2-[5-(6-[(methylsulfonyl)amino]-4-{[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin- 2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (150 mg, 0.246 mmol) in a similar manner to Example 1.7.65. (112 mg, 68% yield) MS (ESI) m/z: 668 [M+H]⁺.

[0741] N-(6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)methanesulfonamide (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyX {(2R)- 2-[5-(6-[(methylsulfonyl)amino]-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (112 mg, 0.168 mmol) in a similar manner to Example 1.7.65. (51 mg, 45% yield).

[0742] tert-Butyl {(2R)-2-[5-(2-{[(2R)-2-(5-Bromo-4-methyl-l,3-thiazol-2-yl)pyrrolidin- l-yl]carbonyl}-6-methoxypyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: To a stirred solution of tert-butyl {(2R)-2-[5-(2-methoxy-6-{ [(2R)-2-(4- methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl }pyridin-4-yl)- 1 ,3 ,4-oxadiazol-2-yl] - 1 - phenylpropan-2-yl} carbamate in CC1₄ (1.32 ml) was added NBS (94 mg) at rt and the mixture was stirred at 70 degree for 1 hour. The starting molecule was completely consumed and volatiles were evaporated. This resulting crude was purified with column

chromatography (EtOAc in hexane = 0 to 66%) to give tert-butyl {(2R)-2-[5-(2-{ [(2R)-2-(5- bromo-4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-methoxypyridin-4-yl)- 1 ,3,4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (222 mg, 74% yield) as a colorless oil, which was immediately used for the next reaction.

[0743] tert-Butyl {(2R)-2-[5-(2-{[(2R)-2-(4,5-dimethyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-methoxypyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yl}carbamate: To a stirred solution of tert-butyl {(2R)-2-[5-(2-{ [(2R)-2-(5-bromo-4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-methoxypyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl} carbamate (111 mg, 0.162 mmol) in toluene (1.39 ml) were added trimethylboroxine (102 mg, 0.81 mmol), Pd₂(dba)₃ (74 mg, 0.081 mmol), SPhos (133 mg, 0.33 mmol) and K₃P0₄ (103 mg, 0.49 mmol) at rt and the mixture was stirred at 110 degree for 30 min. The starting molecule was completely consumed and volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 10 to 80%) to give ierf-butyl {(2R)-2-[5-(2-{ [(2R)-2-(4,5-dimethyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-methoxypyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (98 mg, 98% yield) as a colorless oil. MS (ESI) m/z: 620 [M+H]⁺

[0744] (4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-2-yl)[(2R)-2-(4,5-dimethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : To a stirred solution of tert-butyl {(2R)-2-[5-(2-{ [(2R)-2-(4,5- dimethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-methoxypyridin-4-yl)-l,3,4-oxadiazol- 2-yl]-l-phenylpropan-2-yl} carbamate (98 mg, 0.158 mmol) in CH₂C1₂ (2.7 ml) was added TFA (1.3 ml) at rt and the mixture was stirred for 1 hour. Volatiles were evaporated and the residue was purified with column chromatography (NH-silica, EtOAc in hexane = 20 to 80%) to give the product as a free form. This was dissolved in EtOH (1 ml) and fumaric acid (1 eq. to the free amine) was added. The mixture was stirred at rt for 1 hour and EtOH was

evaporated to give a solid, which was collected, washed with IPE and dried under reduced pressure to give (4-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-2-yl)[(2R)-2-(4,5-dimethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) (56 mg, 56% yield) as an off-white solid.

Example 1.7.68

(fumaric acid)

[0745] tert-Butyl [(2R)-2-{5-[2-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(l,3-oxazol-2-yl)pyridin-4-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: A solution of 1,3-oxazole (0.19 ml, 2.88 mmol) in THF (3 ml) was placed into a vessel and it was placed under reduced pressure for 30 min at -78 degree for the

removal of dissolved 0₂ in THF. To this stirred oxazole/THF solution was added ra-BuLi (1.6 M hexane solution, 1.08 ml, 1.72 mmol) at -78 degree and the mixture was stirred at the same temperature for 1 hour. ZnCl₂ (1.0 M THF solution, 1.72 ml, 1.72 mmol) was added to the mixture, which was allowed to warm up to 0 degree and stirred for 15 min at this degree To this stirred solution was added 4-(5-{(2R)-2-[(ieri-butoxycarbonyl)amino]-l-phenylpropan-2- yl}-l,3,4-oxadiazol-2-yl)-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl trifluoromethanesulfonate (208 mg, 0.288 mmol) in THF (0.5 ml, freshly opened, not degassed) and Pd(PPh₃)₄ (333 mg, 0.288 mmol) and the mixture was heated at 80 degree for 1 hour. The starting molecule was completely consumed and it was quenched with MeOH and volatiles were evaporated to give a crude, which was purified with column chromatography (EtOAc in hexane = 20 to 100%) to give tert-butyl [(2R)-2-{5-[2- { [(2R)-2-(4-methyl- 1 ,3 -thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-( 1 ,3-oxazol-2-yl)pyridin-4- yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate containing some byproducts, which was used for the next reaction without further purification.

[0746] [4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-2-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedoate (1:1) : To a stirred solution of tert-butyl [(2R)-2-{5-[2-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-( 1 ,3-oxazol-2-yl)pyridin-4-yl] - 1 ,3 ,4-oxadiazol-2- yl}-l-phenylpropan-2-yl]carbamate (184 mg, 0.287 mmol) in CH₂CI₂ (2 ml) was added TFA (1 ml) at rt and the mixture was stirred for 1 hour. Volatiles were evaporated and the residue was purified with column chromatography (NH-silica, EtOAc in hexane = 20 to 100%) to give the product as a free form. This was dissolved in EtOH (1 ml) and fumaric acid (1 eq. to the free amine) was added. The mixture was stirred at rt for 1 hour and EtOH was evaporated to give a solid, which was collected, washed with IPE and dried under reduced pressure to give [4-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol-2- yl)pyridin-2-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedoate (1:1) (97 mg, 51% yield) as an off-white solid.

Example 1.7.69

(fumaric acid)

[0747] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(2-oxopyrrolidin-l-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl

[(2R)-2-methyl- 1 -(2- { [4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-(2- oxopyrrolidin-l-yl)pyridin-2-yl]carbonyl}hydrazino)-l-oxo-3-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.51 (56 mg, 99%).

[0748] l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5- [4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(2-oxopyrrolidin- 1 - yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.51 (30 mg, 52% yield).

Example 1.7.70

(fumaric acid)

[0749] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(2-oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl

[(2R)-2-methyl- 1 -(2- { [4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-(2- oxo-l,3-oxazolidin-3-yl)pyridin-2-yl]carbonyl}hydrazino)-l-oxo-3-phenylpropan-2- yl]carbamate in a similar manner to Example 1.7.51 (27 mg, 99%).

[0750] 3-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3-oxazolidin-2-one (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- { 5-[4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-(2-oxo- 1 ,3- oxazolidin-3-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.51 (13 mg, 47% yield). Example 1.7.71

(fumaric acid)

[0751] tert-butyl [(2R)-2-{5-[6-(2-methyl-5-oxopyrrolidin-l-yl)-4-{[(2R)-2-(4-methyl- l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate: The desired compound was synthesized from tert-butyl

[(2R)-2-methyl- 1 -(2- { [6-(2-methyl-5-oxopyrrolidin- 1 -yl)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol- 2-yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl]carbonyl jhydrazino)- 1 -oxo-3-phenylpropan-2- yl]carbamate in a similar manner to Example 1.7.51 (86 mg, 79% yield). MS (ESI) m/z: 672 [M+H]⁺.

[0752] l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-5-methylpyrrolidin-2- one (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[6-(2-methyl-5-oxopyrrolidin-l-yl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] carbonyl }pyridin-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -phenylpropan-2- yl]carbamate in a similar manner to Example 1.7.A1 Ex A9 (15 mg, 26% yield).

Example 1.7.72

(fumaric acid)

[0753] tert-butyl [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(2-oxopiperidin-l-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan- 2-yl]carbamate: The desired compound was synthesized from tert-butyl [(2R)-2-methyl-l- (2- { [4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(2-oxopiperidin- 1 - yl)pyridin-2-yl]carbonyl}hydrazino)-l-oxo-3-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.51 (134 mg, 71% yield). MS (ESI) m/z: 672 [M+H]⁺.

[0754] l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3 hiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)piperidin-2-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5- [4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl } -6-(2-oxopiperidin- 1 - yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.51 (8.4 mg, 6.1% yield).

Example 1.7.73

[0755] N-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N-methylacetamW (2E)-but-2-enedioate (1:1) : To a solution of tert-butyl {(2R)-2-[5-(6- [acetyl(methyl)amino] -4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (126mg, 0.20 mmol) in CH₂C1₂ ( 0.7mL), TFA ( 1.5ml, 19mmol) was added at 0 °C, and the mixture was stirred for 3 hours at room temperature. All the solvent was evaporated azeotropically with toluene. The residue was purified using column chromatography (NH-silica,

EtOH/CHCl₃ = 1:99) to obtain 60 mg of the desired compound as a colorless oil. A solidification of the compound (60mg) with fumaric acid gave N-(6-{5-[(2R)-2-amino-l- phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin- l-yl]carbonyl}pyridin-2-yl)-N-methylacetamide (2E)-but-2-enedioate (1:1) (45mg, 35% yield) as a white powder. Example

[0756] l-(4-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-{[(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5- [2- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-(2-oxopyrrolidin- 1 - yl)pyridin-4-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (60 mg, 19% yield) as a white powder.

Example

[0757] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-l,2,4- triazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- { 5- [4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } - 6- ( 1 H- 1 ,2,4-triazol- 1 - yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (40 mg, 100% yield) as a white powder.

Example

[0758] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH- imidazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- {5-[6-(lH-imidazol-l-yl)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (21 mg, 34% yield) as a beige powder.

Example

[0759] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-pyrazol-

1- yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-

2- enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(lH-pyrazol-l-yl)pyridin-2- yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (74 mg, 50% yield) as a white powder.

Example 1

[0760] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(2H-l,2,3- triazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- {5-[4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(2H-l,2,3-triazol-2- yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (38 mg, 43% yield) as a white powder.

Example 1.7.79

[0761] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-l,2,3- triazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- {5-[4-{ [(2R)-2-(4-methyl ,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(lH ,2,3-triazol - yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (73 mg, 62% yield) as a beige powder.

Example

[0762] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l-methyl- lH-pyrazol-4-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- { 5 - [6-( 1 -methyl- lH-pyrazol-4-yl)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl] - 1 ,3,4-oxadiazol-2-yl } - 1 -phenylpropan-2- yl]carbamate in a similar manner to Example 1.7.73 (115 mg, 55% yield) as a pale yellow powder.

Example

[0763] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l-methyl- lH-pyrazol-5-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- { 5- [6-( 1 -methyl- lH-pyrazol-5-yl)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl] - 1 ,3,4-oxadiazol-2-yl } - 1 -phenylpropan-2- yl] carbamate in a similar manner to Example 1.7.73 (202 mg, 61% yield) as a white powder.

Example 1.7

[0764] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(4-bromo- l,3-thiazol-2-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2- enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4-{ [(4- bromo- 1 ,3-thiazol-2-yl)methyl] (methyl)carbamoyl } -6-( 1 ,3-oxazol-2-yl)pyridin-2-yl] -1,3,4- oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate in a similar manner to Example 1.7.73 (56 mg, 52% yield) as a white powder.

Example 1.

[0765] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(6- methylpyridin-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4-{methyl[(6- methylpyridin-3-yl)methyl]carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2- yl}-l-phenylpropan-2-yl] carbamate in a similar manner to Example 1.7.73 (56 mg, 52% yield) as a white powder. Example

[0766] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[l-(l-methyl- lH-pyrazol-3-yl)ethyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) :

The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4-{ [l-(l-methyl-lH- pyrazol-3-yl)ethyl]carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l- phenylpropan-2-yl]carbamate and l-(l-methy-lH-pyrazol-3-yl) ethanamine in a similar manner to Example 1.7.73 (64 mg, 77% yield) as a white powder.

Example 1.7.

[0767] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(6- methylpyridin-2-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4-{methyl[(6- methylpyridin-2-yl)methyl]carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]-l,3,4-oxadiazol-2- yl}-l-phenylpropan-2-yl] carbamate in a similar manner to Example 1.7.73 (75 mg, 85% yield) as a white powder.

Example 1

[0768] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(l- methyl-lH-pyrazol-4-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[4-{methyl[(l- methyl-lH-pyrazol-4-yl)methyl]carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-2-yl]- 1,3,4- oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate in a similar manner to Example 1.7.73 (89 mg, 76% yield) as a white powder.

Example 1.

[0769] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(l,5- dimethyl-lH^yrazol-4-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5- [4-{ [(l,5-dimethyl-lH-pyrazol-4-yl)methyl](methyl)carbamoyl}-6-(l,3-oxazol-2-yl)pyridin- 2-yl]-l, 3, 4-oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate in a similar manner to Example 1.7.73 (47 mg, 42% yield) as a white powder.

Example 1.

[0770] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(l,3- dimethyl-lH^yrazol-5-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-

[4-{ [(l,3-dimethyl-lH-pyrazol-5-yl)methyl](methyl)carbamoyl}-6-(l,3-oxazol-2-yl)pyridin-

2-yl]-l, 3, 4-oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate in a similar manner to Example

1.7.73 (97 mg, 80% yield) as a white powder. 1H NMR (400 MHz, DMSO-d₆) δ: 8.43 (0.7H, s), 8.42 (0.3H, s), 8.27 (0.7H, s), 8.25 (IH, s), 8.19 (0.3H, s), 7.57 (IH, s), 7.26-7.16 (3H, m),

7.11-7.05 (2H, m), 6.61 (2H, s), 6.14 (0.7H, s), 6.09 (0.3H, s), 4.74 (1.4H, s), 4.55 (0.6H, s), 3.78-3.50 (3H, m), 3.40 (2H, br.s), 3.15 (2H, s), 3.02 (0.9H, s), 2.90 (2.1H, s), 2.14-2.10 (3H, m), 1.50-1.49 (3H, m). MS (ESI) m/z: 513 [M+H]⁺.

Example 1.7.

[0771] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l-methyl- lH-pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone : To a solution of tert-butyl [(2R)-2-{5-[6-(l-methyl-lH-pyrazol-3-yl)-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol- 2-yl}-l-phenylpropan-2-yl] carbamate (310mg, 0.47 mmol) in CH₂CI₂ ( l.OmL) was added TFA ( 3.0ml, 39mmol) at 0 °C, and the mixture was stirred for 3 hours at room temperature. Volatiles were evaporated azeotropically with toluene. The residue was purified using column chromatography (NH-silica, EtOAc / hexane = 50:50 to 100:0) to give 210 mg of the desired compound as a pale yellow solid. A trituration of the solid in EtOH gave [2-{5-[(2R)- 2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 -methyl- 1 H-pyrazol-3-yl)pyridin-4- yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (96mg, 37% yield) as a white powder. 1H NMR (400 MHz, DMSO-d₆), δ: 8.11 (0.6H, d, J = 1.3 Hz), 8.02 (0.6H, d, J = 1.3 Hz), 7.89-7.88 (1.0H, m), 7.83 (0.4H, d, J = 2.1 Hz), 7.74 (0.4H, d, J = 0.4 Hz), 7.26- 7.04 (6H, m), 6.96 (0.6H, d, J = 2.2 Hz), 6.85 (0.4H, d, J = 2.2 Hz), 5.48 (0.6H, dd, J = 8.0, 4.1 Hz), 5.23-5.18 (0.4H, m), 3.97 (1.8H, s), 3.94 (1.2H, s), 3.76-3.54 (2H, m), 3.17-3.08 (2H, m), 2.46-1.93 (9H, m), 1.50 (1.8H, s), 1.48 (1.2H, s). MS (ESI) m/z: 555 [M+H]⁺.

Example 1.7.90

[0772] tert-butyl {(2R)-2-[5-(6-[(4-methoxybenzyl)amino]-4-{[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: A solution of tert-butyl {(2R)-2-[5-(6-chloro-4-{ [(2R)-2-(4- methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl }pyridin-2-yl)- 1 ,3 ,4-oxadiazol-2-yl] - 1 - phenylpropan-2-yl} carbamate (300 mg, 0.49 mmol) and l-(4-methoxyphenyl)methanamine (203 mg, 1.5 mmol) in NMP (1.5 ml) were placed into a vessel for microwave reactions. The vessel was sealed and irradiated with microwave at 140 °C for 30 min. After cooling, H₂0 and brine were added and then the mixture was extracted with CHC1₃. The organic layer was dried over MgS0₄ and concentrated under reduced pressure. The obtained residue was purified with column chromatography (NH-silica, EtOAc / hexane = 10:90 to 100:0) to give tert-butyl {(2R)-2-[5-(6-[(4-methoxybenzyl)amino]-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] carbonyl }pyridin-2-yl)- 1 ,3 ,4-oxadiazol-2-yl] - 1 -phenylpropan-2- yljcarbamate (76 mg, 22% yield) as a colorless oil. MS (ESI) m/z: 710 [M+H]⁺.

[0773] (2-amino-6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2- yl}pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : To a solution of tert-butyl {(2R)-2-[5-(6-[(4-methoxybenzyl)amino]-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl)- 1 ,3,4-oxadiazol- 2-yl]-l-phenylpropan-2-yl}carbamate (73 mg, 0.10 mmol) in TFA (1.6 ml) was added anisole (0.5 ml) and the mixture was stirred at 60 °C for 8 hours. After cooling, saturated aq.

NaHC0₃ and brine were added, and then the mixture was extracted with CHC1₃. The organic layer was dried over MgS0₄ and concentrated under reduced pressure. The residue was purified with column chromatography (NH-silica, EtOH / EtOAc / hexane = 0:50:50 to 5:95:0) to give the desired product (33mg) as a free form. A salt formation of the obtained white solid with fumaric acid gave (2-amino-6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]- l,3,4-oxadiazol-2-yl}pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) (35 mg, 56% yield in 2 steps) as a white powder. Example 1

(fumaric acid) [0774] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(l- methyl-lH-pyrazol-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : To a solution of 2-(5-{(2R)-2-[(tert-butoxycarbonyl)amino]-l-phenylpropan-2-yl}- l,3,4-oxadiazol-2-yl)-6-(l,3-oxazol-2-yl)isonicotinic acid (80 mg, 0.16 mmol) and N-methyl- l-(l-methyl-lH-pyrazol-3-yl)methanamine (31 mg, 0.24 mmol) in CH₂C1₂ (3.2 ml) were added EDCI HC1 (47 mg, 0.24 mmol) and HOBt (22 mg, 0.16 mmol) at rt and the mixture was stirred at the same temperature overnight. 0.1M aq. HC1 and CHC1₃ were added to the mixture and the organic layer was separated. The aqueous layer was extracted with CHCI_3. The combined organic layer was washed with saturated aq. NaHC0₃ and brine, dried over MgS0₄ and evaporated. The residue was purified with column chromatography (EtOAc / hexane = 50:50 to 100:0) to give colorless solid. To a solution of the obtained solid in CH₂C1₂ ( l.OmL) was added TFA ( 2.0m) at 0 °C, and the mixture was stirred for 3 hours at room temperature. Volatiles were evaporated azeotropically with toluene. The residue was purified using column chromatography (NH-silica, EtOAc / hexane = 20:80 to 100:0) to obtain 50 mg of the desired compound as a colorless oil. A solidification of the compound with fumaric acid gave 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [( 1 - methyl- lH-pyrazol-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) (28mg, 28% yield) as a white powder.

Example 1.7.92

[0775] tert-butyl rel-{(2R)-2-[5-(6-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate: The desired compound was synthesized from tert-butyl [(2R)-2-methyl-l-{2-[(6-{ [(2R)-2-(4- methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl)carbonyl]hydrazino } - 1 -oxo-3- phenylpropan-2-yl] carbamate (321 mg, 0.542 mmol) in a similar manner to Example 1.7.51. (270 mg, 87% yield) MS (ESI) M/Z: 575 [M+H]⁺.

[0776] (6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}pyridin-2- yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone 2-hydroxypropane- 1,2,3-tricarboxylate (1:1) : The desired compound was synthesized from tert-butyl rel- {(2R)-2-[5-(6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)- l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (267 mg, 0.464 mmol) in a similar manner to Example 1.7.51. (143 mg, 46% yield)

Example 1.7.93

[0777] tert-butyl rel-{(2R)-2-[5-(4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate: The desired compound was synthesized from tert-butyl [(2R)-2-methyl-l-{2-[(4-{ [(2R)-2-(4- methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl)carbonyl]hydrazino } - 1 -oxo-3- phenylpropan-2-yl] carbamate (375 mg, 0.633 mmol) in a similar manner to Example 1.7.51. (320 mg, 88% yield) MS (ESI) M/Z: 575 [M+H]⁺.

[0778] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}pyridin-4- yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone 2-hydroxypropane-

1.2.3- tricarboxylate (1:1) : The desired compound was synthesized from tert-butyl rel- {(2R)-2-[5-(4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-

1.3.4- oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (317 mg, 0.552 mmol) in a similar manner to Example 1.7.51. (299 mg, 82% yield)

Example 1.7.94

[0779] tert-butyl rel-[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-(pyrrolidin-l-yl)pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from tert-butyl [(2R)-2-methyl-l-(2- { [4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(pyrrolidin-l-yl)pyridin- 2-yl]carbonyl}hydrazino)-l-oxo-3-phenylpropan-2-yl]carbamate (99 mg, 0.15 mmol) in a similar manner to Example 1.7.51. (45 mg, 47% yield) MS (APCI/ESI) M/Z: 644 [M+H]⁺.

[0780] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(pyrrolidin- l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedioate (1:1) : The desired compound was synthesized from tert-butyl rel-[(2R)-2-{5-[4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-(pyrrolidin-l-yl)pyridin-2- yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2-yl]carbamate (45 mg, 0.070 mml) in a similar manner to Example 1.7.51. (35 mg, 76% yield)

Example 1.7.95

[0781] tert-butyl rel-{(2R)-2-[5-(l-methyl-4-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: The desired compound was synthesized from tert-butyl [(2R)-2-methyl-l-{2-[(l-methyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}-6-oxo-l,6-dihydropyridin-2-yl)carbonyl]hydrazino}-l-oxo-3-phenylpropan-2- yl]carbamate (235 mg, 0.377 mmol) in a similar manner to Example 1.7.51. (228 mg, 100% yield) MS (ESI) M/Z: 605 [M+H]⁺.

[0782] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-4- {[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl rel-{ (2R)-2- [5-( 1 -methyl-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-oxo- 1,6- dihydropyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (226 mg, 0.374 mmol) in a similar manner to Example 1.7.51. (211 mg, 91 mmol)

Example 1.7.96

[0783] tert-butyl rel-[(2R)-2-{5-[6-(difluoromethoxy)-4-{[(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl]-l,3,4-oxadiazol-2-yl}-l-phenylpropan-2- yl] carbamate: The desired compound was synthesized from (634 mg, 0.962 mmol) in a similar manner to Example 1.7.51. (480 mg, 78% yield) MS (ESI) M/Z: 641 [M+H]⁺. [0784] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- (difluoromethoxy)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl rel-[(2R)-2-{ 5- [6-(difluoromethoxy)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl]carbonyl }pyridin-2-yl] - 1 ,3,4-oxadiazol-2-yl } - 1 -phenylpropan-2- yl]carbamate (488 mg, 0.762 mmol) in a similar manner to Example 1.7.51. (386 mg, 77% yield)

Example 1.7.97

[0785] tert-butyl {(2R)-2-[5-(l-methyl-6-{[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2-dihydropyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l- phenylpropan-2-yl}carbamate: The desired compound was synthesized from (210 mg, 0.337 mmol) in a similar manner to Example 1.7.51. (86 mg, 42% yield) MS (ESI) M/Z: 605 [M+H]⁺.

[0786] 4-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-6- {[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5- (l-methyl-6-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2- dihydropyridin-4-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (86 mg, 0.14 mmol) in a similar manner to Example 1.7.51. (69 mg, 79% yield)

Example 1.7.98

[0787] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l- (cyclopropylmethyl)-4-{[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-{5-[l-(cyclopropylmethyl)-4-{ [(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin- 1 -yl] carbonyl } -6-oxo- 1 ,6-dihydropyridin-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - l-phenylpropan-2-yl]carbamate (55 mg, 0.085 mmol) in a similar manner to Example 1.7.73. (24 mg, 43% yield)

Example 1.7.99

[0788] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-ethyl-4- {[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5- (l-ethyl-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6- dihydropyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (35 mg, 0.057 mmol) in a similar manner to Example 1.7.73. (24 mg, 66% yield)

Example 1.7.100

[0789] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-ethoxypyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-ethoxy-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol- 2-yl]-l-phenylpropan-2-yl}carbamate (106 mg, 0.171 mmol) in a similar manner to Example 1.7.73. (90 mg, 83% yield)

Exam le 1.7.101

[0790] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-[(2- methoxyethyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-[(2-methoxyethyl)amino]-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yljcarbamate (24 mg, 0.036 mmol) in a similar manner to Example 1.7.73. (20 mg, 81% yield)

Exam le 1.7.102

[0791] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-[(2- methoxyethyl)(methyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-

1- yl]methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5-(6-[(2-methoxyethyl)(methyl)amino]-4-{ [(2R)-2-(4-methyl-l,3-thiazol-

2- yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2- yljcarbamate (52 mg, 0.079 mmol) in a similar manner to Example 1.7.73. (44mg, 82% yield)

Examp

fumaric acid

[0792] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- (ethylamino)pyridin-4-yl] [(2R) -2- (4-methyl- 1 ,3 -thiazol-2-yl)pyrrolidin- 1 -yl] methanone (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2- {5-[6-(ethylamino)-4-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin- 2-yl]-l, 3, 4-oxadiazol-2-yl}-l-phenylpropan-2-yl] carbamate (72 mg, 0.12 mmol) in a similar manner to Example 1.7.73. (33mg, 44% yield) Examp

[0793] 3-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-5- {[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)- but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5- (l-methyl-5-{ [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-2-oxo-l,2- dihydropyridin-3-yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (173 mg, 0.286 mmol) in a similar manner to Example 1.7.73. (93 mg, 52% yield)

Example 1.7.105

[0794] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{[(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)-but-2- enedioate (1:1) : The desired compound was synthesized from tert-butyl {(2R)-2-[5-(4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}-6-oxo-l,6-dihydropyridin-2- yl)-l,3,4-oxadiazol-2-yl]-l-phenylpropan-2-yl}carbamate (50 mg, 0.085 mmol) in a similar manner to Example 1.7.73. (39 mg, 77% yield)

Example 1.7.106

[0795] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl-2- oxo-N-(pyridin-3-ylmethyl)-l,2-dihydropyridine-4-carboxamide : To a solution of N- methyl-N-(3-pyridylmethyl)amine (6.1 mg, 0.05 mmol) and 6-(5-{ (2R)-2-[(tert- butoxycarbonyl)amino] - 1 -phenylpropan-2-yl } - 1 ,3 ,4-oxadiazol-2-yl)- 1 -methyl-2-oxo- 1 ,2- dihydropyridine-4-carboxylic acid (9.1 mg, 0.02 mmol) and HATU (7.6 mg, 0.02 mmol) in DMF (0.8 mL) was added diisopropylethylamine (30.8 uL, 0.18 mmol). The reaction mixture was stirred at rt overnight, and concentrated in vacuo. The residue was dissolved in chloroform (0.5 mL) and trifluoroacetic acid (0.5 mL). The solution was stirred at r.t. for 30 min. and concentrated in vacuo. The residue was directly purified by LC-MS (5% aqueous formic acid /MeOH ) to give 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2- yl } -N, 1 -dimethyl-2-oxo-N-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-4-carboxamide.

Example 1.7.107

[0796] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl- N-[(6-methylpyridin-2-yl)methyl]-2-oxo-l,2-dihydropyridine-4-carboxamide : The desired compound was synthesized from 6-methyl-2-picolylmethylamine (6.8 mg, 0.05 mmol) in a similar manner to Example 1.7.106.

Example 1.7.108

[0797] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-butyl-l- methyl-2-oxo-N-(pyridin-4-ylmethyl)-l,2-dihydropyridine-4-carboxamide : The desired compound was synthesized from N-(4-pyridinylmethyl)-l-butanamine hydrochloride (10.0 mg, 0.05 mmol) in a similar manner to Example 1.7.106.

Example 1.7.109

[0798] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-4-{[2- (3-methyl-l,2,4-oxadiazol-5-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one : The desired compound was synthesized from 3-methyl-5-(2-pyrrolidinyl)-l,2,4-oxadiazole (7.7 mg, 0.05 mmol) in a similar manner to Example 1.7.106.

Example 1.7.110

[0799] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-butyl-l- methyl-2-oxo-N-(pyridin-3-ylmethyl)-l,2-dihydropyridine-4-carboxamide : The desired compound was synthesized from N-(3-pyridinylmethyl)-l-butanamine (8.2 mg, 0.05 mmol) in a similar manner to Example 1.7.106.

Example 1.7.111

[0800] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl-2- oxo-N-(lH-pyrazol-5-ylmethyl)-l,2-dihydropyridine-4-carboxamide : The desired compound was synthesized from methyl-(2H-pyrazol-3-ylmethyl)-amine (5.6 mg, 0.05 mmol) in a similar manner to Example 1.7.106.

Example 1.7.112

[0801] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl-2- oxo-N-[l-(2-thienyl)ethyl]-l,2-dihydropyridine-4-carboxamide : The desired compound was synthesized from N- methyl- l-(2-thienyl)ethanamine hydrochloride (8.8 mg, 0.05 mmol) in a similar manner to Example 1.7.106.

Example 1.7.113

[0802] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(2,5- dimethyl-l,3-oxazol-4-yl)methyl]-N,l-dimethyl-2-oxo-l,2-dihydropyridine-4- carboxamide : The desired compound was synthesized from N-[(2,5-dimethyl-l,3-oxazol-4- yl)methyl]-N-methylamine (7.0 mg, 0.05 mmol) in a similar manner to Example 1.7.106. Example 1.7.114

[0803] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-(tert-butyl)-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide : The desired compound was synthesized in a similar manner to Example 1.4.11 and Example 1.7.1.

Example 1.7.115

[0804] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: The desired compound was synthesized in a similar manner to Example 1.4.11 and Example 1.7.1. In the final step, TFA was used instead of 4N HQ in dioxane.

Example 1.7.116

[0805] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (fluoromethyl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone: The desired compound was synthesized in a similar manner to Example 1.4.10 and Example 1.7.1.

Example 1.7.117

[0806] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl- N-((4-methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide : The desired compound was synthesized in a similar manner to Example 1.4.13 and Example 1.7.1. Example 1.7.118

[0807] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (difluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: The desired compound was synthesized in a similar manner to Example 1.4.14 and Example 1.7.1. Example 1.7.119

[0808] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclobutyl-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide : The desired compound was synthesized in a similar manner to Example 1.4.12 and Example 1.7.1.

Example 1.7.120

[0809] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l,3,4- oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.4.17, Example 1.7.1, and Example 1.6.8.

Example 1.7.121

[0810] 5-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-l,3,4-oxadiazol-2(3H)-one : The desired compound was synthesized in a similar manner to Example 1.4.17, Example 1.7.1, and Example 1.6.8.

Example 1.7.122

[0811] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l- fluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.4.14 and Example 1.7.1.

Example 1.7.123

[0812] l-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)ethanone : The desired compound was synthesized in a similar manner to Example 1.4.14 and Example 1.7.1.

Example 1.7.124

[0813] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrazol- l-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.6.9. Example 1.7.125

[0814] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(isoxazol-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.7.123 and Example 1.4.15. Example 1.7.126

[0815] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l,l- difluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.4.14 and Example 1.7.1. Example 1.7.127

[0816] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(isoxazol-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.4.16 and Example 1.7.1.

Example 1.7.128

[0817] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrazol- 3-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : The desired compound was synthesized in a similar manner to Example 1.7.123 and Example 1.4.15. Example 1.7.129

[0818] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzonitrile : The desired compound was synthesized in a similar manner to Example 1.6.10 and Example 1.7.44.

Example 1.7.130

[0819] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. :The final compound was prepared using similar procedure to that of Example 1.7.1.

Example 1.7.131

[0820] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- bromophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. : The compound was synthesized in a manner similar to that of Example 1.7.1.

Example 1.7.132

[0821] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- chlorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. :

The compound was synthesized in a manner similar to that of example 1.7.1. Example 1.7.133

[0822] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide : Starting from the commercially available chemical, following a similar procedure to Example 1.7.16 to make the compound.

Example 1.7.134

[0823] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4,5- difluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone : Starting from the commercially available chemical, following a similar method to Example 1.7.16 to make the compound.

Example 1.7.135

[0824] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone : To a solution containing the acid, 5-bromo-2-fluorobenzoic acid (391 mg, 1.784 mmol)in DCM (3 ml), HOBT (328 mg, 2.141 mmol) and EDC (479 mg, 2.498 mmol)were added and the reaction mixture was stirred for lh at rt. After lh, reaction mixture was cooled to 0°C, and (R)-tert- butyl (3-(4-fluorophenyl)-l-hydrazinyl-2-methyl-l-oxopropan-2-yl)carbamate (500 mg, 1.606 mmol)was added in DCM (1 mL) along with DIPEA (0.935 ml, 5.35 mmol). The reaction mixture color was dark brown. After stirring overnight at rt, DCM was removed in vacuum. Then reaction mixture was diluted with ethyl acetate, and saturated aq sodium bicarbonate solution was added. After stirring for 10 mins at rt, aqueous layer was extracted with ethyl acetate (2X10 ml). Combined organic layers were washed with water, brine and dried. Crude residue was carried to the next step.

[0825] To the hydrazide (1.08 g, 2.11 mmol) in DCE (20 ml), Burgess reagent (1.26 g, 5.27 mmol) was added and refluxed for 3h at which time reaction color turned brown. Then reaction mixture was cooled, diluted with DCM, washed with aq sodium bicarbonate solution, water brine and dried. Crude residue was column chromatographed. (30%ethyl acetae/hexane). Product is a yellow syrup and was obtained in 67% yield.

[0826] To the bromo compound, (R)-tert-butyl (2-(5-(5-bromo-2-fluorophenyl)-l,3,4- oxadiazol-2-yl)-l-(4-fluorophenyl)propan-2-yl)carbamate (700 mg, 1.416 mmol) in dioxane (Ratio: 2.96, Volume: 8 ml) and Water (Ratio: 1.000, Volume: 2.7 ml), PALLADIUM(II) ACETATE (15.90 mg, 0.071 mmol) and XANTPHOS (82 mg, 0.142 mmol) ,Et₃N (1.974 ml, 14.16 mmol) were added and the reaction mixture was purged with carbon monoxide. Then reaction mixture (a yellow suspension) was heated to 75°C for 3h by which time the suspension is greyish green. Then reaction mixture was cooled, dioxane was removed in vacuum. Water was added and filtered. Water layer was basified and extracted with ethyl acetate. Aqueous layer was then acidified and extracted with 5%MeOH/Ethyl acetate.

Organic layer was dried and evaporated to yield 460mg of acid.

[0827] Resulting acid is converted to the final compound in a manner similar to that as in Example 1.7.1.

Example 1.7.136

[0828] (R)-5-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-2,4-difluoro-N-methylbenzamide : To a solution containing acid, 5-bromo-2,4-difluorobenzoic acid (1.5 g, 6.33 mmol)in DCM (10 ml), HOBT (1.163 g, 7.59 mmol) and EDC (1.699 g, 8.86 mmol)were added and the reaction mixture was stirred for lh at rt. After lh, reaction mixture was cooled to 0°C, and (R)-tert-butyl (l-hydrazinyl-2- methyl-l-oxo-3-phenylpropan-2-yl)carbamate (1.671 g, 5.70 mmol)was added in DCM (3mL) along with DIPEA (3.32 ml, 18.99 mmol). The reaction mixture color was dark brown. After stirring overnight at rt, DCM was removed in vacuum. Then reaction mixture was diluted with ethyl acetate, and saturated aq sodium bicarbonate solution was added. After stirring for 10 mins at rt, aqueous layer was extracted with ethyl acetate (2X10 ml).

Combined organic layers were washed with water, brine and dried. Crude residue was carried to the next step.

[0829] To the hydrazide (500 mg , 1.06 mmol) in DCE (20 ml), Burgess reagent (629 mg , 2.64 mmol) was added and refluxed for 2h at which time reaction color turned dark brown. Then reaction mixture was cooled, diluted with DCM, washed with aqueous sodium bicarbonate solution, water, and brine and dried. Crude residue was column

chromatographed. (30%ethyl acetate/hexane). Product is a colorless foamy syrup and was obtained in 67% yield.

[0830] To the bromo compound, (R)-tert-butyl (2-(5-(5-bromo-2,4-difluorophenyl)- 1,3,4- oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate (1.0 g, 2.023 mmol) in dioxane and water, PALLADIUM(II) ACETATE (0.023 g, 0.101 mmol) and XANTPHOS (0.117 g, 0.202 mmol) ,Et₃N (2.82 ml, 20.23 mmol) were added and the reaction mixture was purged with carbon monoxide. Then reaction mixture was heated to 75°C for 4h. Then reaction mixture was cooled, water was added and filtered. Water layer was basified and extracted with ethyl acetate. Aqueous layer was then acidified and extracted with 5%MeOH/Ethyl acetate.

[0831] Resulting acid is converted to the final compound in a manner similar to that as in Example 1.7.1. Example 1.7.137

[0832] (R)-4-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-5-fluoro-N-methylpicolinamide : The compound was synthesized in a manner similar to that of example 1.8.2.

Example 1.7.138

[0833] (R)-4-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-5-methoxy-N-methylpicolinamide : The compound was synthesized in a manner similar to that of example 1.8.2.

Example 1.7.139

[0834] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide : Starting from the commercially available chemical, following a similar method to Example 1.7.16 to make the compound. Example 1.7.140

[0835] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-4,5- difluorophenyl)((S)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone : Starting from the commercially available chemical, following a similar method to Example 1.7.16 to make the compound.

Example 1.7.141

[0836] 5-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-3-methyl-l,3,4-oxadiazol-2(3H)-one :

The desired compound was synthesized in a similar manner to Example 1.4.17, Example 1.7.1, and Example 1.6.8.

Example 1.7.142

211

[0837] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yI)-2,4- difluorophenyI)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone:The final compound was prepared using similar procedure to that of Example 1.8.11.

[0838] Example 1.7.143

[0839]

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-(3- methylbenzyl)-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1 : 1)

The desired compound was synthesized from tert-butyl [(2R)-2-(5-{4-[methyl(3- methylbenzyl)carbamoyl]-6-(l,3-oxazol-2-yl)pyridin-2-yl}-l,3,4-oxadiazol-2-yl)-l- phenylpropan-2-yl]carbamate in a similar manner to Example 1.7.73 (58 mg, 65% yield) as a white powder. 1H NMR (400MHz, DMSO-d₆) δ: 8.44 (0.55H, s), 8.41 (0.45H, s), 8.28 (0.55H, s), 8.27 (0.55H, s), 8.24 (0.45H, s), 8.23 (0.45H, s), 7.57 (0.55H, s), 7.55 (0.45H, s), 7.32-7.01 (9H, m), 6.62 (2H, s), 4.69 (I.IH, s), 4.49 (0.9H, s), 3.40 (2H, br.s), 3.15 (I.IH, s), 3.12 (0.9H, s), 3.00 (1.35H, s), 2.88 (1.65H, s), 2.35 (1.65H, s), 2.27 (1.35H, s), 1.50 (1.65H, s), 1.48 (1.35H, s). MS (ESI) m/z: 509 [M+H]⁺.

Example 1.8: Synthesis of oxazole inhibitors.

Example 1.8.1

[0840] To a solution of 8.1.67 (3.5g, 19.53mmoles) in THF (50mL) at room temperature was added NaBH₄ (1.85g, 48.82mmoles) in one portion and cooled to 0 °C. Then I₂ (4.96g, 19.53mmoles) in THF (lOmL) was added over a period of 30 min and then refluxed for 40h. The reaction was cooled to 0 °C and quenched with slow addition of MeOH until the bubbling subsided. All the solvent was evaporated. The residue was dissolved in 15mL of 5N NaOH and refluxed for 2.5 h. It was then cooled to room temperature and extracted with CH₂CI₂ (4x20mL). Combined organic layers were dried on Na₂S0₄and concentrated. The crude 8.1.68(3.2g) was carried on to the next step.

[0841] (Boc)₂0 (4.66g, 21.33mmoles) in CH₂Cl₂(80mL) was added to a solution of 8.1.68 (3.2g, 19.39mmoles) in CH₂C1₂ (20mL) and 1M NaOH (lOOmL) and the reaction was stirred overnight. The layers were separated and the aqueous layer was extracted with CH₂CI₂. Combined organic layers were dried on Na₂S0₄and concentrated. The crude was purified on silica gel (40% EtO Ac/60% Hexanes) to yield 4.4g (85% for two steps) of 8.1.69.

[0842] To a solution of 8.1.69 (4.4g, 16.60mmoles) in CH₂C1₂-DMS0 (5:1, 85mL) was added Et3N (6.9 mL, 49.81mmoles) followed by S03.Py (6.6g, 41.51mmoles). After stirring overnight, the reaction mixture was diluted with ether and washed with 10% NaHS04, saturated NaHC03, brine, dried on Na₂S0₄and concentrated. The crude aldehyde 8.1.70 (4.1g, 94%) was used in the next step without purification.

[0843] To a solution of 8.1.70 (4.1g, 15.59 mmoles) in CH₃CN (60mL) at room

temperature was added water (25 drops) followed by trimethylsulfonium iodide (3.34g, 16.37 mmoles) and potassium hydroxide (2.19g, 38.97 mmoles). The reaction was stirred at in a sealed tube at 60 °C for 3h, diluted with ethylacetate and washed with water, brine dried on Na₂S0₄and concentrated. The crude was purified on silica gel (50% EtO Ac/50% Hexanes) to yield 900mg (21%) of 8.1.71.

[0844] A solution of 8.1.71 (4. lg, 15.59 mmoles) and NH₄OH (30 mL) in EtOH ( 30 mL) was stirred at 60 °C in a sealed tube for 16h. All the solvent was evaporated and purified on basic alumina (10% MeOH/90% CHC1₃) to yield 900mg (94%) of 8.1.72.

[0845] All starting materials and reagents were mixed up at r. t. in DCM then cooled to about zero in ice water bath and DIE A added and the mix was allowed warming to room overnight. Next morning TLC (MeOH/CHCl₃, 1:9) indicated clean reaction completed to show single spot of the product 8.1.73. After bicarbonate and water wash DCM was replaced with EtOAc and solution washed with 10% citric acid and then bicarbonate and dried over sodium sulfate. Yield 401 mg of 8.1.73 as foamy solid (82 %).

[0846] The above mix in 20 ml of dry DCM was stirred for 5 hours at room temperature (~ 21°C) then an aliquot was taken into 5 % NaOH and TLC (10 % MeOH in CHC1₃) showed a new spot just slightly up of that of s. m. Proton NMR indicated reaction completion. New group of signals in 4.5 - 4.8 ppm area (CH₂C=0) appeared. Nevertheless, 20 ml more DCM added (because of some solids presence) and the mix was stirred overnight. Next day 5% NaOH was added (20 ml) followed by sat. NH₄C1 and mix was stirred additional 1 h. Organic layer separated, washed with water and dried over Na₂S0₄. Solvent removed in rotor then 40 ml of toluene added and stripped in rotor to remove possible residual water. Yield of yellowish solid was 360 mg (>100% contained sole 20% of toluene by NMR). Estimated yield is 80% of 8.1.74 (single spot on TLC).

[0847] The ketone 8.1.74 was heated with ~ 9 g of poly phosphoric acid (PPA) at 100°C for 1 h in an opened 20 ml vial to let C0₂ and i-BuOH from Boc-decomposition out. Foaming was observed. Reaction progress was monitored by TLC (10% MeOH in CHC1₃). Starting material was gone by 20 min and de-Boc amine was detected instead in a sample treated with water then 20% NaOH and EtOAc. Temperature was set to 110°C and the reaction mixture (yellow) stirred at that temperature for 9 hours in closed vial. Dark brown reaction mixture was cooled to ca. 40°C, diluted with 20 ml of water then 28 g of 20% NaOH added to pH ~ 9 and yellow turbid mixture was extracted 2 x 20 ml of EtOAc and organic layer was dried with Na₂S0₄. After solvent removal in rotor 160 mg of yellow material was obtained (93 % crude). This was purified very well on 4 g CombiFlash silica gel column with 0 to 4 % MeOH in chloroform for 35 min to isolate 81 mg of pure product 8.1.75 (47 %) as slightly yellowish foamy solid. 1H NMR (CDC1₃) δ 8.74 and 8.62 (s, IH); 8.32 and 8.10 (s, 2H), 7.79 and 7.71 (s, IH); 7.22 (m, 4 H); 6.98 (m, 2H); 6.80 (m, 2H); 5.70 and 5.20 (t, IH); 3.75 (m, 2H); 3.10 (dd, 2H, / = 13.5 Hz); 2.45 (m, 4 H); 2.05 (m, 4 H); 1.71 (br. s 2H) and 1.53 (s, 3H). ESI MS: 540.20 (M + 1). Please note that central benzene ring protons appear as two signals of amide rotamers.

Example 1.8.2 : (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5- (oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide

[0848] 8.2.1 and 8.2.2 were coupled using standard coupling procedure involving HOBT, EDCI, DIPEA in CH₂CI₂ and stirring overnight to obtain 8.2.3 which was deprotected using 30% TFA in CH₂C1₂ for lh to obtain (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-N-methyl-5-(oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide. Example 1.8.3

[0849] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.4

[0850] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.5

[0851] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.6

[0853] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.8

[0854] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.9

[0855] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.10

[0856] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.11

[0857] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.12

[0858] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.13

[0859] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.14

[0861] The compound was synthesized in a similar fashion of example 1.8.2. Example 1.8.16

[0862] The compound was synthesized in a similar fashion of example 1.8.2 Example 1.8.17

[0863] The compound was synthesized in a similar fashion of example 1.8.2.

Example 1.8.18

[0864] The compound was synthesized in a similar fashion of example 1.8.2.

Example 1.8.19

[0865] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.8.20

[0866] The compound was synthesized in a manner similar to that as in Example 1.7.1. Example 1.8.21

[0867] To the iodide (lOOmg, 0.12 mmol) in toluene (9 ml), water (3 ml) (3:1 ratio), 3- Methoxyphenylboronic Acid (21 mg, 0.14 mmol) (commercial source: Sigma- Aldrich), K3P04 (commercial source: Sigma- Aldrich) (76 mg, 0.36 mmol) was added followed by palladium acetate (0.5 mg, 0.02 mmol) (commercial source: Sigma- Aldrich) and X-phos (2.3 mg, 0.04 mmol) (commercial source: Sigma- Aldrich). Then the reaction mixture was heated under reflux for 4h. Then reaction mixture was cooled, diluted with ether and filtered through celite. Filtrate was partitioned between ether and water. Organic layer was dried evaporated and column purified to yield 50 mg of the product.

[0868] Deprotection of the resulting Boc compound using a procedure similar to the one depicted in Example 1.7.2 yielded the final product.

Example 1.8.22

[0869] Following the above procedure, coupling of the iodo compound with with 2- Methoxyphenylboronic Acid (commercial source: Sigma- Aldrich) and deprotection of the resulting Boc compound using a procedure similar to the one depicted in Example 1.7.2 yielded the final product.

Example 1.8.23

[0870] Following the above procedure, coupling of the iodo compound with furan 2- boronic Acid (commercial source: Sigma- Aldrich) yielded the coupled product.

[0871] To the Boc compound (10 mg,0.016 mmolO in DCM (1ml), aqueous phosphoric acid (20 microlitres) was added and stirred at rt for 3h. Then reaction mixture was cooled, basified to PH8 with 50% aqueous sodium hydroxide solution. Then the aqueous solution was extracted with DCM. Organic layer was dried, evaporated and column purified to yield final product.

Example 1.8.24

[0872] To the iodide (lOOmg, 0.12 mmol) in dioxane (9 ml), water (3 ml) (3:1 ratio), furan3-lboromc Acid (16 mg, 0.14 mmol) (commercial source: Sigma-Aldrich), K₃PO₄ (commercial source: Sigma-Aldrich) (76 mg, 0.36 mmol) was added followed by palladium acetate (0.5 mg, 0.02 mmol) (commercial source: Sigma-Aldrich) and X-phos (2.3 mg, 0.04 mmol) (commercial source: Sigma-Aldrich). Then the reaction mixture was heated to 130° for 40 min under microwave conditions. . Then reaction mixture was cooled, diluted with ether and filtered through celite. Filtrate was partitioned between ether and water. Organic layer was dried evaporated and column purified to yield the coupled product. Deprotection of the resulting Boc compound using a procedure similar to the one depicted in Example 1.7.2 yielded the final product.

Example 1.8.25

[0873] Following the above procedure, coupling of the iodo compound with with pyrimidine 5-lboronic Acid(commercial source: Frontier Scientific) and deprotection of Boc group using 4N HCl using a procedure similar to Example 1.7.2 gave the final product. Example 1.8.26

[0874] Following the above procedure, coupling of the iodo compound with with pyridine 3-boronic Acid(commercial source: matrix Scientific) and deprotection of Boc group using 4N HCl using a procedure similar to Example 1.7.2 gave the final product.

Example 1.8.27

[0875] Following the above procedure, coupling of the iodo compound with pyridine 3- boronic Acid (commercial source: Combiphos catalysts) and deprotection of Boc group using 4NHC1 using a procedure similar to Example 1.7.2 gave the final product.

Example 1.8.28

[0876] Following the above procedure, coupling of the iodo compound with pyridine 3- boronic Acid(commercial source: Synthonix) and deprotection of Boc group Boc group using 4NHC1 using a procedure similar to Example 1.7.2 gave the final product.

Exam le 1.8.29

[0877] To the acid (150mg, 0.30 mmol) in DCM (5 ml), HOBT (49 mg, 0.36mmol), EDCI (81 mg, 0.42 mmol) was added and stirred at rt for 2h. Then the acid (150mg, 0.30 mmol) and DIPEA (0.1 ml) was added to the reaction mixture and allowed to stir overnight and then worked up and column purified to yield the coupled product in 78% yield.

[0878] Deprotection of the resulting Boc protected compound as in Example 1.7.2 gave final product. Example 1.8.30

[0879] The final compound was prepared using similar procedure to that of Example 1.8.9. Example 1.8.31

[0880] To a solution containing the acid, 2-fluoro-5-(methoxycarbonyl)benzoic acid (380 mg, 1.918 mmol)in DCM (3 ml), HOBT (352 mg, 2.301 mmol) and EDC (515 mg, 2.68 mmol)were added and the reaction mixture was stirred for lh at rt.After lh, reaction mixture was cooled to 0°C, and (R)-tert-butyl (l-hydrazinyl-2-methyl-l-oxo-3-phenylpropan-2- yl)carbamate (506 mg, 1.726 mmol)was added in DCM (1- niL) along with DIPEA (1.005 ml, 5.75 mmol). After stirring overnight at rt, DCM was removed in vacuum. Then reaction mixture was diluted with ethyl acetate and saturated aq sodium bicarbonate solution was added. After stirring for 10 mins at rt,aqeous layer was extracted with ethyl acetate (2X10 ml). Combined organic layers were washed with water, brine and dried. Crude residue was purified by column chromatography (100%hexane-100% ethyl acetate) to yield the hydrazide in 66% yield.

[0881] To the hydrazide (500 mg, 1.056 mmol) in DCE (10 ml), Burgess reagent (629 mg, 2.64 mmol) was added and refluxed for 4h at which time reaction colour turned brown, then reaction mixture was cooled, diluted with DCM, washed with aq sodium bicarbonate solution, water brine and dried. Crude residue was column chromatographed. (50%ethyl acetae/hexane). Product is a yellow syrup and was obtained in 62% yield.

[0882] To the ester, (R)-methyl 3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)- 4-fluorobenzoate (300 mg, 0.844 mmol) in MeOH (Ratio: 3.00, Volume: 3 ml) and Water (Ratio: 1.000, Volume: lmL) , sodiumhydroxide (101 mg, 2.53 mmol) was added and the reaction mixture was stirred for 4h at rt. then reaction mixture was acidfied and extracted with ethylacetate. Organic layer was dried and evaporated to yield the product acid in its pure form as tan colour solid.

[0883] Resulting acid is converted to the final compound in a manner similar to that as in Example 1.7.1.

Example 1.8.32

[0884] The final compound was prepared using similar procedure to that of Example 1.8.31.

Example 1.8.33

[0885] The final compound was prepared using similar procedure to that of Example 1.8.31.

Example 1.8.34

[0886] The final compound was prepared using similar procedure to that of Example 1.8.31.

Example 1.8.35

[0887] The final compound was prepared using similar procedure to that of Example 1.8.31.

Example 1.8.36

The final compound was prepared using similar procedure to that of Example

Example 1.9: Supplemental Compounds.

Example 1.9.1: 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((R)-l-(4- fluorophenyl)ethyl)-5-(N-methylmethylsulfonamido)benzamide

[0889] 1H NMR (300 MHz, CDC1₃) δ 8.40 (br s, 1H), 8.14 (br s, 1H), 8.05 (br s, 1H), 7.82 (d, / = 7.5 Hz, 1H), 7.42-7.38 (m, 2H), 7.30-7.20 (m, 3H) , 7.08-7.00 ( m, 4H) , 5.40-5.24 (1.0H), 3.40 ( s, 3H), 3.32 (d, J = U Hz, 1H), 3.12 (d, / = 14 Hz, 1H), 2.94 ( s, 3H), 2.39 ( s, 2H), 1.67 ( s, 3H), 1.61 (d, / = 6.9 Hz, 3H).

Example 1.9.2: (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl ) -N,N-dipropylbenzamide

[0890] 1H NMR (300 MHz, CDC1₃) δ 0.75-0.78 (m, 3H), 0.99-1.04 (m, 3H), 1.57-1.84 (m, 7H), 3.08-3.31 (m, 4H), 3.47-3.52 (m, 2H), 7.02-7.05 (m, 2H), 7.21-7.31 (m, 4H), 7.79 (s, 1H), 8.11 (t, 1H, J= 1.8 Hz), 8.20 (t, 1H, J= 1.5 Hz), 8.68 (t, 1H, J=1.5 Hz). Example 1.9.3: 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl ) -N-( (R)-l -phenylethyl)benzamide

[0891] 1H NMR (300 MHz, CDC1₃) δ 1.65-1.68 (m, 6H), 3.08-3.32 (m, 2H), 5.36-5.41 (m, 1H), 6.65 (d, 1H, J= 7.8 Hz), 7.02-7.27 9m, 2H), 7.21-7.44 (m, 8H), 7.80 (s, 1H), 8.52 (s, 1H), 8.59 (s, 1H), 8.76 (s, 1H).

Example 1.9.4: ((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)(3-(pyrazin-2-yl)-5-(5-((R)- pyrrolidin-2 -yl)-l, 3,4-oxadiazol-2 - l )phenyl )methanone

[0892] 1H NMR (300 MHz, CDC1₃) δ 9.15-9.10 (m, 1H), 8.86-8.35 (m, 5H), 8.10-7.77 (m, 2H), 6.81-6.76 (m, 1H), 5.72-5.66 (m, 0.6H), 5.30-5.18 (m, 0.3H), 3.93-3.73 (m, 2H), 3.64- 3.46 (m, 1H), 2.47-2.29 (m, 5H), 2.24-1.93 (m, 4H).

Example 1.9.5: ((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)(3-(pyrazin-2-yl)-5-(5-((S)- pyrrolidin-2 -yl)-l, 3,4-oxadiazol-2 - l )phenyl )methanone

[0893] 1H NMR (300 MHz, CDC1₃) δ 9.14 (m, 1H), 8.50-8.36 (m, 5H), 8.11-8.02 (m, 1H), 6.81-6.77 (m, 1H), 5.71-5.67 (m, 0.7H), 5.20-5.18 (m, 0.3H), 4.58 (broad s, 1H), 3.98-3.73 (m, 2H), 3.64-3.47 (m, 1H), 3.18-3.12 (m, 2H), 2.45-1.87 (m, 14H).

Example 1.9.6: 3'-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5'-(2-(5- methylfuran-2-yl)pyrrolidine-l-carbonyl)-[l,l '-biphenyl] -2-carbonitrile

"> 77 78

[0894] To a solution of dimethyl 5-iodoisophthalate 76 (Commercial source: Matrix Scientific) (2 g, 6.25 mmol) in 15 mL THF was added 2-cyano-phenyl zinc bromide

(Commercial source: Sigma- Aldrich), (15 mL, 7.5 mmol, 0.5 M THF) and

tetrakis(triphenylphosphine) palladium (Commercial source: Sigma- Aldrich), (71 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 2 h. The precipitated solid was filtered, was diluted with MeOH to provide after filtration a second crop for a total of 1.2 g (65 %) of dimethyl 5-(cyanophenyl)isophthalate 77 .

[0895] NaOH (155 mg, 3.86 mmol) was added to a stirred solution of the diester 77 (1.2 g, 4.07 mmol,) in 1:3:3 H₂0/MeOH/THF (25 ml). Reaction mixture was stirred overnight at room temperature. Volatiles were removed in vacuum and the residue is partitioned between ethyl acetate and saturated aqueous NaHC0₃. Reaction mixture was extracted with EtOAc .

Aqueous layer's P was adjusted to about 3 with concentrated HCl, and reaction mixture was extracted with 10% MeOH\90%CHCl₃ (x5). Combined organic layers were washed with brine, dried and concentrated to yield 0.9 g (79 %) of the mono acid 78.

[0896] To a solution of 2-(5-methyl-2-furyl)pyrrolidine 79 (Commercial source: ACB Blocks Ltd.) (54 mg, 0.36mmoles) and 78 (lOOmg, 0.36mmoles) in CH₂C1₂ (8 mL) was added HOBT (48 mg, 0.36 mmoles) and (EDC 82mg, 0.42 mmoles) followed by DIPEA (0.186 mL, 1.07 mmoles) and stirred over night at room temperature. All the solvent was evaporated; the residue was diluted with EtOAc and washed with 0.5 N HC1 and satd. aq. NaHC0₃. The organic layer was washed with brine, dried, concentrated and purified on silica gel (50% EtO Ac/50% hexanes) to obtain 120 mg (77%) of 80.

[0897] IN LiOH (1.0 mL) was added to a stirred solution of the ester 80 (120 mg, 0.28 mmol ) in THF (3 ml) and. After stirring for 1 h, the medium was adjusted to pH ~ 4 with IN HC1 and extracted EtOAc. The organics were combined and dried over Na₂S0₄. The inorganics were filtered off, and the solvent removed via rotary evaporation yielding 110 mg (94 % yield) of the 81. [0898] To a solution of 81 (60 mg, 0.14 mmoles) and 82 (42 mg, 0.14 mmoles) in CH₂C1₂ (8 mL) was added HOBT (19 mg, 0.14 mmol ), EDC (33 mg, 0.17 mmol) and DIPEA (0.075 mL, 0.43 mmoles) and stirred over night at room temperature. The solvent was removed via rotary evaporation. The residue was quenched with satd. aq. NaHC0₃ and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine and dried over Na₂S0₄. The inorganics were filtered off, and the solvent was removed via rotary

evaporation. Purification via flash chromatography on silica gel yielded 80 mg (82 %) of the product 83.

[0899] To a solution of 83 (80 mg, 0.12 mmoles) in dichloromethane (5 mL) was added Burgess' reagent (85 mg, 0.35 mmoles) and refluxed for 5h. The reaction mix was then cooled to room temperature, diluted with CHC1₃ and washed successively with satd. aq.

NaHC0₃ and brine, dried, concentrated and purified on silica gel (1% MeOH/99% CHC1₃) to obtain 60 mg (76%) of 84.

[0900] A solution of 84 (60 mg, 0.09 mmoles) in a mixture of 4N HC1 in 1,4-dioxane ( 3mL) and 1.5N HC1 in MeOH ( 1 mL) at 0 °C to RT was stirred for 45 min. TLC indicated the consumption of SM. All the solvent was evaporated; the residue was quenched with satd. aq. NaHC0₃ and was extracted with EtOAc. The organic extract was washed with brine, dried, concentrated and purified on silica gel (2% MeOH/98% CHC1₃) to obtain 30 mg (59%) of 85. 1H NMR (300 MHz, CDC1₃) 8.32-8.17 (m, 1H), 8.00-7.80 (m, 2H), 7.80-7.60 (m, 2H), 7.60-7.44 (m, 2H), 7.38-7.20 (m, 3H), 7.12-6.98 (m, 2H), 6.20 (s, 0.5H), 5.85 (s, 0.5H), 5.72 (s, 0.5H), 5.68 (s, 0.5H), 5.40 (s, 0.5H), 5.00 (s, 0.5H), 3.96-3.70 (m, 1H), 3.70-3.22 (m, 3H), 2.30-1.80 (m, 7H), 1.67-1.66 (two s, 3H).

Example 1.

[0901] 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-(3- methylbenzyl)-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : The desired compound was synthesized from tert-butyl [(2R)-2-(5-{4-[methyl(3- methylbenzyl)carbamoyl]-6-(l,3-oxazol-2-yl)pyridin-2-yl}-l,3,4-oxadiazol-2-yl)-l- phenylpropan-2-yl] carbamate in a similar manner to Example 1.7.73 (58 mg, 65% yield) as a white powder. 1H NMR (400 MHz, DMSO-d₆) δ 8.44 (0.55H, s), 8.41 (0.45H, s), 8.28 (0.55H, s), 8.27 (0.55H, s), 8.24 (0.45H, s), 8.23 (0.45H, s), 7.57 (0.55H, s), 7.55 (0.45H, s), 7.32-7.01 (9H, m), 6.62 (2H, s), 4.69 (I.IH, s), 4.49 (0.9H, s), 3.40 (2H, br.s), 3.15 (I.IH, s), 3.12 (0.9H, s), 3.00 (1.35H, s), 2.88 (1.65H, s), 2.35 (1.65H, s), 2.27 (1.35H, s), 1.50 (1.65H, s), 1.48 (1.35H, s). MS (ESI) m/z: 509 [M+H]⁺.

Example 2: Inhibitor Compounds

Example 2.1

[0902] tert-Butyl (2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)carbamoyl)phenyl)-l,3,4- oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate. 1H NMR (300 MHz, CDC1₃) δ 8.30-8.12 (m, 2H), 7.80-7.54 (m, 2H), 7.40-7.20 ( m, 3H) 7.18- 7.00 (m, 2H), 6.92 (br s, 1H), 5.02 (br s,2.2H), 4.78 (br s, 0.8H), 3.64-3.40 (m, 2H), 3.30-3.00 (m, 3H), 2.49 ( s, 3H), 1.76 ( br s 3H), 1.44 ( s, 9H).

Example 2.2

[0903] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.20-8.00 (m, 2H), 7.70-7.44 (m, 2H), 7.20-7.10 ( m, 3H) 7.00- 6.90 (m, 2H), 6.80 (br s, 1H), 4.92 (br s, 1.2H), 4.64 (br s, 0.8H), 3.24-2.90 (m, 5H), 2.39 ( s, 3H), 1.80 ( br s 2H), 1.58 ( s, 3H). Example 2.3

[0904] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(pyridin-3-yl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.88 (br s, IH), 8.72 (br s, IH), 8.38-7.80 ( m, 4H) 7.48 (s, IH), 7.36-7.20 (m, 3H), 7.12-7.00 (m, 2H), 6.98 (br s, IH), 5.04 (br s, 1.2H), 4.80 (br s, 0.8H), 3.40-3.06 (m, 5H), 2.50 ( s, 3H), 1.80 ( br s 2H), 1.71 ( s, 3H).

Example 2.4

[0905] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.80 (s, 0.6H), 8.68 (s, 0.4H), 8.42 (s, 0.6H), 8.38 (s, 0.6H), 8.14 (s, 0.4H), 8.04 (s, 0.4H), 7.82 (s, 0.6H), 7.78 (s, 0.4H), 7.39-7.19 (m, 4H), 7.12-7.00 (m, 2H), 6.83 (s, 0.6H), 6.78 (s, 0.4H), 5.76-5.70 (m, 0.6H), 5.22-5.18 (m, 0.4H), 4.02-3.84 (m, 2H), 3.70-3.58 (m, IH), 3.40-3.24 (m, IH), 3.20-3.06 (m, IH), 2.57-2.40 (m, 4H), 2.24-1.80 (m, 4H), 1.74-1.62 (two s, 3H). Example 2.5

[0906] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 8.76 (s, 0.6H), 8.60 (s, 0.4H), 8.42 (s, 0.6H), 8.36 (s, 0.6H), 8.02 (s, 0.4H), 8.00 (s, 0.4H), 7.82 (s, 0.6H), 7.78 (s, 0.4H), 7.39-7.19 (m, 5H), 7.04-6.96 (m, 2H), 5.40-5.32 (m, 0.6H), 4.94-4.84 (m, 0.4H), 4.00-3.80 (m, 2H), 3.64-3.54 (m, IH), 3.38-3.20 (m, IH), 3.18- 3.04 (m, IH), 2.43-2.04 (m, 4H), 2.04-1.70 (m, 4H), 1.67 ( s, 3H).

Example 2.6

[0907] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- methylphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 7.99-7.72 (m, 2H), 7.55 (s, IH), 7.29-7.19 (m, 4H), 7.05-7.00 (m, 2H), 6.80-6.77 (m, IH), 5.69-5.65 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.93-3.87 (m, IH), 3.81-3.74 (m, IH), 3.59-3.49 (m, IH), 3.30-3.21 (m, IH), 3.11-3.03 (m, IH), 2.47-2.26 (m, 8H), 2.24-2.03 (m, 3H), 2.00-1.74 (m, 3H), 1.65-1.59 (m, 3H).

Example 2.7

[0908] (3-methyl-5-(5-((R)-2-(methylamino)-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone 1H NMR (300 MHz, CDCI₃) δ 7.96-7.69 (m, 2H), 7.54 (s, IH), 7.29-7.16 (m, 4H), 7.02-7.00 (m, 2H), 6.80-6.76 (m, IH), 5.69-5.65 (m, 0.7H), 5.14-5.11 (m, 0.3H), 3.90-3.89 (m, IH), 3.80-3.72 (m, IH), 3.58-3.49 (m, IH), 3.19-3.16 (m, 2H), 2.46-2.25 (m, 10H), 2.21-2.04 (m, 3H), 1.99-1.90 (m, IH), 1.77 (m, 2H), 1.61-1.55 (m, 3H).

Example 2.8

[0909] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 7.99-7.72 (m, 2H), 7.55 (s, IH), 7.29-7.19 (m, 4H), 7.05-7.00 (m, 2H), 6.80-6.77 (m, IH), 5.69-5.65 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.93-3.87 (m, IH), 3.81-3.74 (m, IH), 3.59-3.49 (m, IH), 3.30- 3.21 (m, IH), 3.11-3.03 (m, IH), 2.47-2.26 (m, 5H), 2.24-2.03 (m, 3H), 1.65-1.59 (two s, 3H).

Example 2.9

[0910] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyrazin-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 9.13-8.56 (m, 4H), 8.41-8.04 (m, 2H), 7.29-7.21 (m, 3H), 7.04-7.02 (m, 2H), 6.80- 6.77 (m, IH), 5.71-5.67 (m, 0.6H), 5.20-5.18 (m, 0.3H), 3.97-3.81 (m, 2H), 3.65-3.57 (m, IH), 3.31-3.23 (m, IH), 3.12-3.05 (m, IH), 2.44-2.28 (m, 7H), 2.21-2.10 (m, 2H), 2.03-1.93 (m, 3H), 1.67-1.64 (m, 3H). Example 2.10

[0911] N-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)phenyl)-N-methylmethanesulfonamide. 1H NMR (300 MHz, CDC1₃) δ 8.12-7.52 (m, 3H), 7.31-7.21 (m, 4H), 7.04-7.01 (m, 2H), 6.79-6.72 (m, IH), 5.66-5.62 (m, 0.6H), 5.20-5.17 (m, 0.3H), 3.91-3.80 (m, IH), 3.63-3.55 (m, IH), 3.39- 3.20 (m, 4H), 3.10-3.03 (m, IH), 2.91-2.79 (m, 3H), 2.43-2.28 (m, 5H), 2.21-2.03 (m, 2H), 2.01-1.70 (m, 3H), 1.64-1.61 (m, 3H).

Example 2.11

[0912] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (fluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 8.20 (s, 0.6H), 8.06 (s, 0.6H), 8.00 (s, 0.4H), 7.90 (s, 0.4H), 7.78 (s, 0.6H), 7.40 (s, 0.4H), 7.29-7.19 (m, 3H), 7.05-6.90 (m, 2H), 6.80 (s, 0.6H), 6.78 (s, 0.4H), 5.69-5.60 (m, 0.6H), 5.57 (s, IH), 5.41 (s, IH), 5.19-5.08 (m, 0.4H), 3.98-3.84 (m, IH), 3.84- 3.74 (m, IH), 3.59-3.48 (m, IH), 3.30-3.18 (m, IH), 3.16-3.00 (m, IH), 2.47-2.06 (m, 5H), 2.24-1.80 (m, 3H), 1.72-1.60 (two s, 3H). Example 2.12

[0913] (3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- chlorophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.62-2.42 (m, 10H), 3.04-3.26 (m, 2H), 3.24-3.82 (m, 2H), 5.62-5.72 (m, IH), 6.80 (s, IH), 6.84-7.21 (m, 5H), 7.74 (s, IH), 8.02-8.18 (m, 2H).

Example 2.13

[0914] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 9.21-8.64 (m, 4H), 8.49-8.10 (m, 2H), 7.34-7.33 (m, IH), 7.08-6.88 (m, 5H), 5.76 (m, 0.6H), 5.28 (m, 0.3H), 4.02-3.93 (m, IH), 3.71-3.42 (m, IH), 3.36-3.28 (m, IH), 3.18-3.15 (m, IH), 2.51-2.45 (m, 3H), 2.36-1.83 (m, 5H), 1.73 (m, 3H).

Example 2.14

[0915] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((2R,4S)-4- fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.42 (s, 3H), 2.42 (s, 3H), 2.68-2.86 (m, 2H), 3.02-3.26 (m, IH), 3.61-4.14 (m, 3H), 5.28 (d, IH, J= 42 Hz), 5.62-5.72 (m, IH), 6.81 (s, IH), 7.01-7.06 (m, 2H), 7.21-7.28 (m, 3H), 7.51- 7.60 (m, IH), 7.72-7.74 (m, IH), 8.10-8.22 (m, 2H).

Example 2.15

[0916] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCls) δ 8.76 (s, 0.6H), 8.60 (s, 0.4H), 8.42 (s, 0.6H), 8.36 (s, 0.6H), 8.06 (s, 0.4H), 8.02 (s, 0.4H), 7.82 (s, 0.6H), 7.78 (s, 0.4H), 7.26 (s, 0.6H), 7.22 (s, 0.4H), 7.04-6.84 (m, 4H), 6.80 (s, 0.6H), 6.76 (s, 0.4H), 5.74-5.62 (m, 0.6H), 5.20-5.18 (m, 0.4H), 3.98-3.80 (m, 2H), 3.64-3.50 (m, IH), 3.30-3.16 (m, IH), 3.16-3.02 (m, IH), 2.50-2.30 (m, 4H), 2.24-1.80 (m, 4H), 1.64-1.62 (two s, 3H).

Example 2.16

[0917] l-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)pyrrolidin-2-one. 1H NMR (300 MHz, CDCI₃) δ 8.38-8.14 (m, 2H), 7.98-7.90 (m, IH), 7.28-7.15 (m, 4H), 7.04-7.02 (m, 2H), 6.78- 6.74 (m, IH), 5.69-5.65 (m, 0.6H), 5.23-5.21 (m, 0.3H), 3.99-3.50 (m, 4H), 3.29-3.21 (m, IH), 3.10-3.03 (m, IH), 2.70-2.59 (m, 2H), 2.44-2.08 (m, 8H), 2.03-1.88 (m, 3H), 1.64-1.61 (m, 3H). Example 2.17

[0918] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (dimethylamino)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 7.43-7.33 (m, 2H), 7.30-7.16 (m, 5H), 7.05-7.02 (m, 3H), 6.80-6.68 (m, IH), 5.69-5.65 (m, 0.6H), 5.20-5.17 (m, 0.4H), 4.15-3.74 (m, 2H), 3.62-3.54 (m, IH), 3.33- 3.21 (m, IH), 3.11-3.03 (m, 5H), 2.86 (s, 3H), 2.48-2.16 (m, 6H), 2.14-2.05 (m, 3H), 2.01- 1.73 (m, 3H), 1.68-1.60 (m, 3H).

Example 2.18

[0919] (4-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6- (dimethylamino)pyridin-2-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 7.65-7.61 (m, IH), 7.27-7.20 (m, 4H), 7.12 (m, IH), 7.02-6.99 (m, 2H), 6.76-6.68 (m, IH), 6.21-6.19 (m, 0.5H), 5.72-5.68 (m, 0.4H), 4.21-3.89 (m, 2H), 3.28-3.14 (m, 4H), 3.09-3.05 (m, IH), 2.91 (s, 3H), 2.43-2.31 (m, 5H), 2.17-1.75 (m, 5H), 1.63 (s, 3H).

Example 2.19

[0920] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- methoxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 7.76-7.51 (m, 2H), 7.28-7.20 (m, 4H), 7.03-6.91 (m, 2H), 6.78-6.76 (m, IH), 5.67-5.63 (m, 0.6H), 5.16-5.14 (m, 0.3H), 3.90-3.69 (m, 5H), 3.60-3.49 (m, IH), 3.28-3.19 (m, IH), 3.10-3.02 (m, IH), 2.43-2.28 (m, 5H), 2.22-1.90 (m, 5H), 1.64-1.61 (m, 3H).

Example 2.20

[0921] 3'-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5'-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)-[l,l'-biphenyl]-2-carbonitrile. 1H NMR (300 MHz, CDCls) δ 1.65 (s, 3H), 1.95-2.46 (m, 7H), 3.06-3.30 (m, IH), 3.60-3.75 (m, 2H), 3.90- 3.93 (m, IH), 5.66-5.70 (m, IH), 6.78 (s, IH), 7.02-7.05 (m, 2H), 7.19-7.26 (m, 4H), 7.54- 7.92 (m, 4H), 8.24-8.29 (m, 2H).

Example 2.21

[0922] (7-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)chroman-5-yl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 7.50-7.42 (m, 2H), 7.34-7.20 (m, 4H), 7.05-6.98 (m, 2H), 6.82-6.6.69 (m, IH), 5.66-5.63 (m, 0.6H), 5.04 (m, 0.3H), 4.29-4.12 (m, 2H), 3.95-3.86 (m, IH), 3.55-3.33 (m, IH), 3.28-3.20 (m, IH), 3.09-2.90 (m, 2H), 2.82-2.54 (m, IH), 2.44-2.29 (m, 5H), 2.23-1.73 (m, 7H), 1.64-1.62 (m, 3H). Example 2.22

[0923] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrrol-l- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.06-8.02 (m, 2H), 7.82-7.75 (m, IH), 7.37-7.18 (m, 5H), 7.05-6.95 (m, 3H), 6.81- 6.58 (m, IH), 6.41-6.34 (m, 2H), 5.70-5.65 (m, 0.5H), 5.19-5.17 (m, 0.4H), 3.94-3.77 (m, 2H), 3.64-3.56 (m, IH), 3.34-3.22 (m, IH), 3.12-3.06 (m, IH), 2.45-2.33 (m, 4H), 2.27-2.11 (m, 2H), 2.02-1.74 (m, 3H), 1.68-1.65 (m, 3H).

Example 2.23

[0924] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-2- hydroxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI3) δ 10.63-10.50 (m, IH), 7.79-7.54 (m, 2H), 7.28-7.21 (m, 4H), 7.10-6.69 (m, 4H), 5.73-5.69 (m, 0.5H), 5.21-5.19 (m, 0.4H), 3.95-3.90 (m, IH), 3.73-3.66 (m, IH), 3.55- 3.46 (m, IH), 3.31-3.25 (m, IH), 3.12-3.08 (m, IH), 2.47-2.17 (m, 5H), 2.12-1.60 (m, 3H). Example 2.24

[0925] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-N-((4-methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.182 (s, 1 H), 8.067 (d, / = 3.9 Hz, 1 H), 7.735 (d, / = 7.8 Hz, 1 H), 7.559 (t, / = 7.8, 15.6 Hz, 1 H), 7.024-6.861 (m, 5 H), 5.019 (s, 2 H), 3.232 (d, / = 13.5 Hz, 1 H), 3.056 (d, / = 13.5 Hz, 1 H), 2.928 (m, 1 H), 2.443 (s, 3 H), 1.625 (s, 3 H), 0.638 (m, 2 H), 0.528 (m, 2 H).

Example 2.25

[0926] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-4,4-difluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.738 (s, 1 H), 8.361 (s, 1 H), 8.276 (s, 1 H), 7.795 (s, 1 H), 7.7.219 (m, 3 H), 7.013 (m, 2 H), 6.872 (s, 1 H), 5.886 (br, 1 H), 4.173 (m, 1 H), 3.903 (m, 1 H), 3.272 (d, / = 13.5 Hz, 1 H), 3.086 (d, / = 13.5 Hz, 1 H), 2.945 (m, 2 H), 2.443 (s, 3 H), 1.655 (s, 3 H).

Example 2.26

[0927] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((4-methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.184 (s, 1 H), 8.068 (d, / = 7.8 Hz, 1 H), 7.756 (d, / = 7.8 Hz, 1 H), 7.557 (t, / = 7.8, 15.6 Hz, 1 H), 7.207 (m, 3 H), 7.027 (m, 2 H), 6.871 (s, 1 H), 5.029 (s, 2 H), 3.268 (d, / = 13.2 Hz, 1 H), 3.086 (d, / = 13.5 Hz, 1 H), 2.932 (m, 1 H), 2.451 (s, 3 H), 1.649 (s, 3 H), 0.675 (m, 2 H), 0.533 (m, 2 H). Example 2.27

[0928] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-(N- methylmethylsulfonamido)-N-((4-methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.056 (m, 2 H), 7.791(m, 1 H), 7.213 (m, 3 H), 7.002 (m, 2 H), 6.916 (m, 1 H), 4.973 (s, 1.4 H), 4.718 (s, 0.6 H), 3.390 (s, 3 H), 3.288-3.061 (m, 2 H), 3.105 (s, 3 H), 2.917 (s, 3 H), 2.448 (s, 3 H), 1.647 (s, 3 H).

Example 2.28

[0929] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 1.65 (s, 3H), 2.44 (s, 3H), 2.80-2.90 (m, 2H), 3.07-3.30 (m, 2H), 3.60- 4.08 (m, 3H), 5.30 (d, 1H, J= 48 Hz), 5.82-5.88 (m, 1H), 6.85 (s, 1H), 7.01-7.04 (m, 2H), 7.21-7.30 (m, 4H), 7.79 (s, 1H), 8.31 (s, 1H), 8.39 (s, 1H), 8.74 (s, 1H).

Example 2.29

[0930] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopentyl-N- ((4-methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.09-8.08 (m, 2H), 7.62-7.54 (m, 2H), 7.28-7.18 (m, 4H), 7.06-7.01 (m, 2H), 6.84 (m, IH), 4.90 (broad s, 2H), 4.12-4.10 (m, IH), 3.27 (d, IH), 3.09 (d, IH), 2.04-1.60 (m, 12H), 1.44 (m, 2H).

Example 2.30

[0931] (4-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.62(s, 3H), 1.95-2.46 (m, 7H), 3.07-3.61 (m, 3H), 5.62-5.64 (m, IH), 6.85 (s, IH), 7.01-7.14 (m, 2H), 7.21-7.38 (m, 3H), 7.60 (s, IH), 8.40 (s, IH), 8.86 (s, IH).

Example 2.31

[0932] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l-methyl-lH- pyrazol-4-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.65 (s, 3H), 1.84-2.20 (m, 4H), 2.44 (s, 3H), 3.01-3.36 (m, 2H), 3.54-3.92 (m, 5H), 5.62-5.65 (m, IH), 6.83 (s, IH), 7.01-7.04 (m, 2H), 7.18-7.22 (m, 2H), 7.48 (s, IH), 7.71-7.82 (m, 3H), 7.98 (s, IH), 8.14 (s, IH). Example 2.32

[0933] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-imidazol-l- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.16-7.97 (m, 2H), 7.78-7.72 (m, IH), 7.39-7.36 (m, IH), 7.31-7.20 (m, 5H), 7.06- 7.03 (m, 2H), 6.83 (m, H), 5.70-5.65 (m, 0.5H), 5.17-5.12 (m, 0.4H), 3.95-3.81 (m, 2H), 3.64-3.59 (m, IH), 3.35-3.23 (m, IH), 3.13-3.07 (m, IH), 2.46-2.28 (m, 4H), 2.23-2.08 (m, 2H), 2.05-1.72 (m, 4H), 1.69-1.66 (m, 3H).

Example 2.33

[0934] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 8.32-8.26 (m, IH), 8.01-7.91 (m, 2H), 7.62-7.53 (m, IH), 7.30-7.19 (m, 4H), 7.06- 7.03 (m, 2H), 6.82-6.79 (m, IH), 5.70-5.66 (m, 0.6H), 5.16-5.14 (m, 0.4H), 3.96-3.78 (m, 2H), 3.63-3.55 (m, IH), 3.31-3.23 (m, IH), 3.13-3.06 (m, IH), 2.45-2.30 (m, 4H), 2.22-2.11 (m, 2H), 2.05-1.82 (m, 3H), 1.68-1.65 (m, 3H). Example 2.34

[0935] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- methylphenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃+CD₃0D) δ 7.981 (s, 1 H), 7.914 (s, 1 H), 7.577 (s, 1 H), 7.229 (m, 3 H), 7.021 (m, 2 H), 6.841 (s, 1 H), 5.807 (m, 0.8 H), 5.329 (s, 0.2 H), 5.371 (s, 0.5 H), 5.196 (s, 0.5 H), 4.085-3.811 (m, 2 H), 3.300-3.072 (m, 2 H), 2.835 (m, 2 H), 2.465 (s, 3 H), 2.435 (s, 3 H), 1.659 (s, 3 H).

Example 2.35

[0936] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)pyridin-3-yl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.61(s, 3H), 1.82-2.47 (m, 7H), 3.06-3.32 (m, 3H), 3.51-3.92 (m, 3H), 5.62-5.64 (m, IH), 6.82 (s, IH), 6.88-7.10 (m, 2H), 7.21-7.38 (m, 3H), 8.42 (s, IH), 8.88 (s, IH), 9.30 (s, IH). Example 2.36

[0937] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-(fluoromethyl)thiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.729 (s, 1 H), 8.405 (s, 1 H), 8.329 (s, 1 H), 7.808 (s, 1 H), 7.744- 7.188 (m, 5 H), 7.038 (m, 2 H), 5.714-5.207 (m, 3 H), 3.868 (m, 1 H), 3.609 (m, 1 H), 3.27 (m, 1 H), 3.102 (m, 1 H), 2.457 (m, 2 H), 2.173 (m, 1 H), 1.999 (m, 1 H), 1.670 (s, 3 H). Example 2.37

[0938] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-imidazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI₃) δ 8.64-8.54 (m, IH), 8.34-7.90 (m, 2H), 7.39-7.17 (m, 4H), 7.06-7.01 (m, 4H), 6.77- 6.68 (m, IH), 5.66-5.59 (m, 0.7H), 5.26-5.24 (m, 0.2H), 3.89-3.81 (m, IH), 3.63-3.55 (m, IH), 3.45-3.22 (m, IH), 3.12-3.05 (m, IH), 2.61-2.26 (m, 5H), 2.19-1.92 (m, 3H), 1.63 (broad s, 3H).

Example 2.38

[0939] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)chroman-7-yl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 7.65-7.40 (m, IH), 7.33-7.19 (m, 4H), 7.05-6.88 (m, 2H), 6.78-6.75 (m, IH), 5.59-5.64 (m, 0.6H), 5.20- 5.18 (m, 0.3H), 4.24-4.17 (m, 2H), 3.88-3.73 (m, IH), 3.62-3.53 (m, IH), 3.29-3.06 (m, 3H), 2.44-2.17 (m, 4H), 2.14-1.70 (m, 6H), 1.64-1.61 (m, 3H).

Example 2.39

[0940] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (CDC1₃) δ 8.74 and 8.62 (s, IH); 8.32 and 8.10 (s, 2H), 7.79 and 7.71 (s, IH); 7.22 (m, 4 H); 6.98 (m, 2H); 6.80 (m, 2H);

5.70 and 5.20 (t, IH); 3.75 (m, 2H); 3.10 (dd, 2H, / = 13.5 Hz); 2.45 (m, 4 H); 2.05 (m, 4 H);

1.71 (br. s 2H) and 1.53 (s, 3H).

Example 2.40

[0941] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyridin-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.67 (s, 3H), 1.84-2.47 (m, 7H), 3.06-3.32 (m, 2H), 3.57-3.92 (m, 3H), 5.62-5.64 (m, IH), 6.81 (s, IH), 7.03-7.05 (m, 2H), 7.22-7.34 (m, 4H), 7.83-7.85 (m, 2H), 8.27 (s, IH), 8.40 (s, IH), 8.70-8.75 (m, 2H). Example 2.41

[0942] tert-butyl (2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)carbamoyl)phenyl)-l,3,4- oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate. 1H NMR (300 MHz, CDC1₃) δ 8.21-7.95 (m, 2H), 7.76-7.48 (m, IH), 7.28-7.19 (m, 3H), 7.05-7.02 (m, 2H), 7.02-6.75 (m, IH), 5.67- 5.63 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.94-3.76 (m, IH), 3.60-3.43 (m, 4H), 3.29-3.22 (m, IH), 3.12-3.05 (m, IH), 2.49-2.32 (m, 4H), 2.23-1.95 (m, 5H), 1.66-1.64 (m, 3H).

Example 2.42

[0943] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l-methyl-lH- pyrrol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.11-7.86 (m, 2H), 7.76-7.42 (m, IH), 7.27-7.22 (m, 4H), 7.05-7.02 (m, 2H), 6.80-6.72 (m, 2H), 6.34-6.17 (m, 2H), 5.71-5.66 (m, 0.6H), 5.22-5.20 (m, 0.3H), 3.96-3.57 (m, 4H), 3.30-3.22 (m, IH), 3.11-3.04 (m, IH), 2.47-2.31 (m, 4H), 2.24-1.93 (m, 3H), 1.77 (broad s, 3H), 1.66-1.63 (m, 3H).

Example 2.43

[0944] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. 1H NMR (300 MHz,

CDCI₃+CD₃OD) δ 8.707 (s, 1 H), 8.403 (s, 1 H), 8.301 (s, 1 H), 7.798 (s, 1 H), 7.303-7.199 (m, 4 H), 7.038 (m, 2 H), 6.882 (s, 1 H), 5.049 (s, 2 H), 3.319 (m, 1 H), 3.134 (m, 1 H), 3.011 (m, 1 H), 2.460 (s, 3 H), 1.674 (s, 1 H), 0.687 (m, 2 H), 0.561 (m, 2 H).

Example 2.44

[0945] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.64(s, 3H), 2.45 (s, 3H), 2.76-2.90 (m, 2H), 3.05-3.28 (m, 2H), 3.85-4.14 (m, 2H), 5.30 (d, IH, J= 51 Hz),5.83-5.88 (m, IH), 6.85-7.03 (m, 4H), 7.30 (s, 2H), 7.80 (s, IH), 8.34 (s, 1H0, 8.40 (s, IH), 8.74 (s, IH).

Example 2.45

[0946] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (pyrazin-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.66 (s, 3H), 2.45 (s, 3H0, 2.79-2.91 (m, 2H), 3.06-3.29 (m, 2H), 3.90-4.19 (m, 2H), 5.31 (d, IH, J= 51 Hz), 5.84-5.89 (m, IH), 6.86-7.7.05 (m, 7H), 8.33 (s, IH), 8.43 (s, IH), 8.61 (s, IH), 8.69 (s, IH), 8.76 (s, IH), 9.15 (s, IH). Example 2.46

[0947] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)piperidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.18-8.14 (m, 2H), 7.70-7.42 (m, 2H),7.32-7.14 (m, 3H), 7.10-6.90 (m, 2H), 6.87(s, IH), 6.30-6.18 (m, 0.6H), 5.20-5.02 (m, 0.4H), 3.70-2.60 (m, 4H), 2.44(s, 3H) 1.84(s, 3H), 1.64 (s, 3H), 2.08- 1.40 (m, 5H).

Example 2.47

[0948] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(5-methyl-l,3,4- oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 1.24 (s, 3H), 1.69 (s, 3H), 1.93-2.42 (m, 6H), 3.04-3.28 (m, 2H), 3.51- 3.56 (m, IH), 3.77-3.93 (m, 2H), 5.63-5.67 (m, IH), 6.74 (s, IH), 6.99-7.01 (m, 2H), 7.20- 7.25 (m, 3H), 8.20 (s, IH), 8.33 (s, IH), 8.47 (s, IH). Example 2.48

[0949] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-isopropyl-N-((4- methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.06-8.01 (m, 2H), 7.58-7.53 (m, 2H), 7.28-7.17 (m, 3H), 7.04-7.01 (m, 2H), 6.84 (s, IH), 4.92-4.45 (m, 2H), 4.07 (m, IH), 3.26 (d, IH), 3.08 (d, IH), 2.42 (s, 3H), 1.09 (s, 3H), 1.24-1.19 (m, 6H).

Example 2.49

[0950] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.80 (s, 0.8H), 8.72 (s, 0.2H), 8.38 (two s, 1.7H), 7.98 (s, 0.3H), 7.80 (s, IH), 7.34-7.20 (m, 4H), 7.00-6.92 (m, 2H), 6.82 (s, IH), 6.80 (s, IH), 5.92-5.82 (m, IH), 5.40 (br s , 0.5H), 5.20 (br s , 0.5H), 4.17-3.84 (m, 2H), 3.20-3.00 (m, 2H), 2.94-2.84 (m, IH), 2.84-2.78 (m, IH), 2.46 (s, 3H), 1.78 ( br s, 2H), 1.53 ( s, 3H).

Example 2.50

[0951] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((5- methyl-l,2,4-oxadiazol-3-yl)methyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.22-8.06 (m, 2H), 7.80-7.52 (m, 2H), 7.23-7.18 ( m, 3H) 7.04- 6.96 (m, 2H), 4.86 (br s, 1.2H), 4.56 (br s, 0.8H), 3.26-3.04 (m, 5H), 2.39 ( br s, 3H), 1.83 ( br s 2H), 1.64 ( s, 3H).

Example 2.51

[0952] (2-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6- (dimethylamino)pyridin-4-yl)((R)-2-(4-methylthiazo 1H NMR (300 MHz, CDC1₃) δ 7.32-7.16 (m, 5H), 7.10-7.02 (m, 2H), 6.83-6.77 (m, 2H), 5.65- 5.61 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.91-3.72 (m, 2H), 3.58-3.49 (m, 1H), 3.45-3.26 (m, 1H), 3.22-2.98 (m, 7H), 2.45-2.33 (m, 4H), 2.22-1.92 (m, 3H), 1.67-1.63 (m, 3H).

Example 2.52

[0953] 3-[5-(l-Amino-2-phenylcyclohexyl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methyl- 1 , 3 -thiazol-2-yl)methyl] benzamide .

Example 2.53

[0954] rel-3- { 5- [(1R,2R)- 1 -Amino-2-phenylcyclopropyl] - 1 ,3,4-oxadiazol-2-yl } -N-methyl- N- [(4-methyl- 1 , 3 -thiazol-2- yl)methyl] benzamide . Example 2.54

[0955] re/-3-{5-[(lR,2S)-l-Amino-2-phenylcyclopropyl]-l,3,4-oxadiazol-2-yl}-N-methyl- N- [(4-methyl- 1 , 3 -thiazol-2- yl)methyl] benzamide .

Example 2.55

[0956] 3-(5-(2-Amino-l-methoxy-3-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl- N- ((4-methylthiazol-2- yl)methyl)benzamide .

Example 2.56

[0957] 3-(5-(^/-(lS,2R)-l-Amino-2-phenylcyclobutyl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-

((4-methylthiazol-2-yl)methyl)benzamide.

Example 2.57

[0958] 3-(5-(re/-(lR,2R)-l-Amino-2-phenylcyclobutyl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-

((4-methylthiazol-2-yl)methyl)benzamide.

Example 2.58

[0959] 3- { 5 - [(4E)-2- Amino- 1 ,5-diphenylpent-4-en-2-yl] - 1 ,3,4-oxadiazol-2-yl } -N-methyl-

N-[(4-methyl-l,3-thiazol-2-yl)methyl]benzamide.

Example 2.59

[0960] 3-[5-(2-Amino-l,5-diphenylpentan-2-yl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4- methyl- 1 , 3 -thiazol-2- yl)methyl] benzamide .

Example 2.60

[0961] 3-[5-(2-Amino-l,3-diphenylpropan-2-yl)- l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4- methyl-l,3-thiazol-2-yl)methyl]benzamide. Example 2.61

[0962] rel-3-{ 5- [( 1 R,2R)- 1 - Amino-2-phenylcyclopentyl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl- N- [(4-methyl- 1 , 3 -thiazol-2- yl)methyl] benzamide .

Example 2.62

[0963] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-(oxazol- 2-yl)-N-(pyrazin-2-ylmethyl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.78 (s, IH), 8.72 (s, IH), 8.64-8.50 (m, 2H), 8.34 (s, IH), 8.12 (s, IH), 7.80 (s, IH), 7.30 (s, IH), 7.28-7.00 (m, 3H), 7.04-6.98 (m, 2H), 4.96 (s, 1.4 H), 4.68 (s, 0.6 H), 3.36-3.20 (m, IH), 3.36-3.02 (m, 4H), 1.67 (s, 3H).

Example 2.63

[0964] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((2- methylthiazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.70 (s, IH), 8.48-8.20 (m, 3H), 7.80 (m, IH), 7.32 (s, IH), 7.28-6.98 (m, 3H), 7.04-6.98 (m, 2H), 4.92 (s, IH), 4.54 (s, IH), 3.36-3.22 (m, IH), 3.20-3.02 (m, 4H), 2.78-2.72 (two s, 3H), 2.00 (br s, 2H), 1.67-1.66 (two s, 3H).

Example 2.64

[0965] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((2- methyloxazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.72 (s, IH), 8.48-8.18 (m, 3H), 7.80 (m, IH), 7.60, 7.60 (two s, IH), 7.32-7.00 (m, 3H), 7.06-7.00 (m, 2H), 4.60 (s, 1.2H), 4.38 (s, 0.8H), 3.35-3.24 (m, IH), 3.20-3.02 (m, 4H), 2.52-2.40 (two s, 3H), 1.80 (br s, 2H), 1.67 (s, 3H).

Example 2.65

[0966] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.72 (s, IH), 8.42-8.00 (m, 2H), 7.80 (s, IH), 7.36 (s, IH), 7.30-7.00 (m, 3H), 7.08-6.98 (m, 2H), 6.92 (s, IH), 5.00 (s, 1.3H), 4.78 (s, 0.7H), 3.37-3.22 (m, IH), 3.22-3.00 (m, 4H), 2.42 (s, 3H), 1.90 (br s, 2H), 1.66 (s, 3H). Example 2.66

[0967] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((R)-l-(4- methylthiazol-2-yl)ethyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.78 (s, IH), 8.62 (s, IH), 8.58 (s, IH), 7.80 (s, IH), 7.32-7.20 (m, 3H), 7.06-7.00 (m, 2H), 6.82 (s, IH), 5.64-5.58 (m, IH), 3.30 (d, J = 14.8 Hz, IH), 3.10 (d, J = 14.8 Hz, IH), 2.43 (s, 3H), 2.02 (br s, 2H), 1.74 (d, / = 7.2 Hz, 3H), 1.66 (s, 3H).

Example 2.67

[0968] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl- N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.70 (s, IH), 8.42-8.20 (m, 2H), 7.8 (s, IH), 7.32 (s, IH), 7.06-6.98 (m, 2H), 6.98-6.88 (m, 3H), 5.00 (s, 1.4H), 4.78 (s, 0.6H), 3.32-3.02 (m,5H), 2.43 (s, 3H), 1.80 (br s, 2H), 1.65 (s, 3H). Example 2.68

[0969] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((5- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.77 (s, IH), 8.40-8.00 (m, 2H), 7.80 (s, IH), 7.40 (s, IH) 7.32 (s, IH), 7.30-7.00 (m, 3H), 7.06-6.98 (m, 2H), 4.97 (s, 1.4H), 4.72 (s, 0.6H), 3.37-3.24 (m, IH), 3.20-3.00 (m, 4H), 2.44 (s, 3H), 1.90 (br s, 2H), 1.67 (s, 3H).

Example 2.69

[0970] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methyloxazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.76 (s, IH), 8.42-8.20 (m, 2H), 7.8 (s, IH), 7.40 (s, IH), 7.36 (s, IH), 7.30-7.20 (m, 3H), 7.08-6.98 (m, 2H), 4.82 (s, 1.3H), 4.56 (s, 0.7H), 3.36-3.24 (m,lH), 3.20-3.04 (m,4H), 2.2 (s, 3H), 1.80 (br s, 2H), 1.67 (s, 3H).

Example 2.70

[0971] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.70 (s, IH), 8.22 (s, IH), 8.18 (s, IH), 7.79 (s, IH), 7.31 (s, IH), 7.30-7.20 (m, 3H), 7.04-6.98 (m, 2H), 4.58 (s, 1.2H), 4.24 (s, 0.8H), 3.30 (d, J = 14.8 Hz, IH), 3.12 (d, J = 14.8 Hz, IH), 3.12 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 1.80 (br s, 2H), 1.67 (s, 3H).

Example 2.71

[0972] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-4-(4-methylthiazol-2-yl)oxazolidin-3-yl)methanone: 1H NMR (300 MHz, CDCI₃) δ 8.92 (s, IH), 8.82 (s, IH), 8.70 (s, IH), 7.82 (s, IH), 7.80 (d, / = 9Hz, IH), 7.33 (s, IH), 7.26-7.20 (m, 4H), 7.06-7.00 (m, 2H), 6.92 (s, IH), 5.8-5.72 (m, IH), 4.77 (d, / = 6.2 Hz, 2H), 3.36 (d, / = 14.8 Hz, IH), 3.16 (d, / = 14.8 Hz, IH), 2.46 (s, 3H), 1.82 (br s, 2H), 1.69 (s, 3H).

Example 2.72

[0973] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDCI₃) δ 8.88 (s, IH), 8.83 (s, IH), 8.00 (s, IH), 7.80 (s, IH), 7.32 (s, IH), 7.06-6.90 (m, 4H), 4.60 (s, 1.3H), 4. 24 (s, 0.7H), 3.28 (d, J = 14.8 Hz, IH), 3.08 (d, J = 14.8 Hz, IH), 3.12 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 1.84 (br s, 2H), 1.65 (s, 3H). Example 2.73

[0974] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyrazin-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 9.34-8.18 (m, 6H), 7.34-7.00 (m, 3H), 7.20-7.00 (m, 2H), 4.58 (s, 1.1H), 4. 26 (s, 0.9H), 3.32 (d, / = 14.8 Hz, IH), 3.10 (d, J = 14.8 Hz, IH), 3.14 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 1.68 ( s, 3H).

Example 2.74

[0975] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 9.18 (s, IH), 8.80-8.20 (m, 5H), 7.32-7.20 (m, 3H), 7.14-7.00 (m, 2H), 6.92 (s, IH), 5.00 (s, 1.2H), 4. 78 (s, 0.8H), 3.38-3.04 (m, 2H), 3.18 (s, 3H), 2.46 (s, 3H), 1.98 (s, 2H), 1.68 (s, 3H).

Example 2.75

[0976] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((3- methyl-l,2,4-oxadiazol-5-yl)methyl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.18-8.10 (m, 2H), 7.70-7.62 (m, IH), Ί .62-1.51 (m, IH), 7.28-7.00 (m, 3H), 7.04-7.00 (m, 2H) 4.97 (s, 1.4H), 4. 64 (s, 0.6H), 3.30 (d, / = 14.8 Hz, IH), 3.10 (d, / = 14.8 Hz, IH), 3.18 (s, 3H), 2.44 (s, 3H), 1.78 (s, 2H), 1.66 (s, 3H).

Example 2.76

[0977] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyridin-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 8.82-7.80 (m, 6H), 7.36-7.30 (m, IH), 7.30-7.00 (m, 3H), 7.20-6.98 (m, 2H), 4.58 (s, 1.3H), 4. 28 (s, 0.7H), 3.30 (d, / = 14.8 Hz, IH), 3.20-3.06 (m, 4H), 2.42 (s, 3H), 2.41 (s, 3H), 1.90 (br s, 2H), 1.67 (s, 3H).

Example 2.77

[0978] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-chloro-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methylbenzamide: [M+H] : 480.180.

Example 2.78

[0979] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- chlorophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: [M+H] : 508.157. Example 2.79

[0980] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- chlorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: [M+H] : 526.148.

Example 2.80

[0981] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-(tert-butyl)-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide : 1H NMR (300 MHz,

CDCI₃+CD₃OD) δ 8.626 (m, 1 H), 8.313 (m, 1 H), 8.223 (m, 1 H), 7.762 (s, 1 H), 7.281- 7.205 (m, 4 H), 7.023-6.991 (m, 2 H), 6.787 (s, 1 H), 4.801 (s, 2 H), 3.278 (d, J = 13.5 Hz, 1 H), 3.087 (d, J = 13.5 Hz, 1 H), 2.360 (s, 3 H), 1.859 (br, 2 H), 1.647 (s, 3 H), 1.565 (s, 9 H). Example 2.81

[0982] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((4-methylthiazol- 2-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.674 (s, 1 H), 8.628 (s, 1 H), 8.546 (s, 1 H), 7.731 (s, 1 H), 7.265-7.173 (m, 4 H), 6.995 (m, 2 H), 6.787 (s, 1 H), 4.888 (m, 2 H), 3.215 (d, / = 13.5 Hz, 1 H), 3.088 (d, / = 13.5 Hz, 1 H), 2.350 (s, 3 H), 1.623 (s, 3 H).

Example 2.82

[0983] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (fluoromethyl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃+CD₃0D) δ 8.068 (s, 1 H), 7.955 (s, 1 H), 7.725 (s, 1 H), 7.306- 7.145 (m, 5 H), 6.815 (s, 1 H), 5.742 (m, 1 H), 5.469 (s, 1 H), 5.322 (s, 2 H), 5.156 (s, 1 H), 4.006 (m, 1 H), 3.742 (m, 1 H), 3.271 (m, 2 H), 2.757 (m, 2 H), 2.409 (m, 3 H), 1.400 (s, 3 H).

Example 2.83

[0984] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((4-methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide : 1H NMR (300 MHz,

CDC1₃+CD₃0D) δ 9.126 (s, 1 H), 8.712-8.674 (m, 2 H), 8.597 (s, 1 H), 8.422 (s, 1 H), 8.296 (s, 1 H), 7.262-7.186 (m, 3 H), 7.023 (m, 2 H), 6.877 (s, 1 H), 5.049 (s, 2 H), 3.264 (d, / = 13.2 Hz, 1 H), 3.123 (d, / = 13.5 Hz, 1 H), 3.007 (m, 1 H), 2.453 (s, 3 H), 1.671 (s, 3 H), 0.673 (m, 2 H), 0.574 (m, 2 H). Example 2.84

[0985] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (difluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone: 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.313 (s, 0.56 H), 8.180 (s, 0.60 H), 8.082 (s, 0.44 H), 8.035 (s, 0.40 H), 7.802 (s, 0.65 H), 7.472 (s, 0.35 H), 7.216 (m, 3 H), 7.002 (m, 2 H), 6.757 (m, 1.45 H ), 6.552 (m, 0.55 H), 5.642 (m, 0.7 H), 5.074 (m, 0.3 H), 3.747 (m, 1 H), 3.524 (m, 1 H), 3.239 (m, 1 H), 3.087 (m, 1 H), 2.429 (s, 2 H), 2.295 (s, 1 H), 2.138 (m, 2 H), 1.983 (m, 2 H), 1.654 (s, 3 H).

Example 2.85

[0986] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclobutyl-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide : 1H NMR (300 MHz,

CDCI₃+CD₃OD) δ 8.733 (s, 1 H), 8.273 (s, 1 H), 8.196 (m, 1 H), 7.806 (s, 1 H), 7.321-7.228 (m, 4 H), 7.047 (m, 2 H), 6.859 (s, 1 H), 5.108 (s, 2 H), 4.283 (br, 1 H), 3.280 (d, J = 13.5 Hz, 1 H), 3.134 (d, / = 13.5 Hz, 1 H), 2.451 (s, 3 H), 2.318 (m, 2 H), 2.043 (m, 2 H), 1.672 (s, 5 H). Example 2.86

[0987] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l,3,4-oxadiazol- 2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 9.272 (br, 0.7 H), 8.871 (br, 0.3 H), 8.507 (s, 0.7 H), 8.403 (s, 0.3 H), 8.298 (s, 0.7 H), 8.294 (s, 0.7 H), 8.018 (s, 0.3 H), 7.908 (s, 0.3 H), 7.179 (m, 3 H), 6.978 (m, 2 H), 6.703 (s, 1 H ), 5.635 (m, 0.65 H), 5.162 (m, 0.35 H), 3.797 (m, 1 H), 3.535 (m, 1 H), 3.216 (m, 1 H), 3.086 (m, 1 H), 2.364 (s, 2 H), 2.268 (s, 1 H), 2.078 (m, 2 H), 1.950 (m, 2 H), 1.625 (s, 3 H).

Example 2.87

[0988] 5-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-l,3,4-oxadiazol-2(3H)-one : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.462 (s, 0.7 H), 8.361 (s, 0.3 H), 8.347 (s, 0.7 H), 8.205 (s, 0.7 H), 8.005 (s, 0.3 H), 7.844 (s, 0.3 H), 7.217 (m, 3 H), 7.019 (m, 2 H), 6.819 (s, 0.7 H ), 6.792 (s, 0.3 H), 5.657 (m, 0.65 H), 5.205 (m, 0.35 H), 3.927 (m, 1 H), 3.815 (m, 1 H), 3.564 (m, 1 H), 3.266 (m, 1 H), 3.112 (m, 1 H), 2.442 (s, 2 H), 2.391 (m, 1 H), 2.295 (s, 1 H), 2.161 (m, 2 H), 2.029 (m, 1 H), 1.675 (s, 2 H), 1.648 (s, 1 H). Example 2.88

[0989] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l- fluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.156 (s, 0.6 H), 8.032 (s, 0.6 H), 7.943 (s, 0.4 H), 7.888 (s, 0.4 H), 7.736 (s, 0.6 H), 7.352 (s, 0.4 H), 7.262 (m, 3 H), 7.007 (m, 2 H), 6.806 (m, 1 H ), 5.804 (m, 0.3 H), 5.644 (m, 1.05 H), 5.464 (m, 0.3 H), 5.102 (m, 0.35 H), 3.916 (m, 1 H), 3.793 (m, 1 H), 3.549 (m, 1 H), 3.256 (m, 1 H), 3.109 (m, 1 H), 2.442 (s, 2 H), 2.310 (m, 1 H), 2.111 (m, 2 H), 1.966 (m, 2 H), 1.661 (s, 3 H).

Example 2.89

[0990] l-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)ethanone : 1H NMR (300 MHz,

CDCI₃+CD₃OD) δ 8.608 (s, 0.65 H), 8.515 (s, 0.35 H), 8.417 (s, 0.65 H), 8.327 (s, 0.65 H), 8.162 (s, 0.35 H), 7.938 (s, 0.35 H), 7.221 (m, 3 H), 7.021 (s, 2 H), 6.806 (s, 1 H ), 5.664 (m, 0.65H), 5.107 (m, 0.35 H), 3.928 (m, 1 H), 3.847 (m, 1 H), 3.550 (m, 1 H), 3.261 (m, 1 H), 3.112 (m, 1 H), 2.697 (s, 2 H), 2.508 (s, 1 H), 2.442 (s, 3 H), 2.311 (s, 1 H), 2.141 (m, 2 H), 1.985 (m, 1 H), 1.659 (s, 3 H). Example 2.90

[0991] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrazol-l- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.298 (m, 1 H), 8.119 (s, 1.2 H), 8.063 (m, 0.8 H), 7.782 (m, 2 H), 8.218 (m, 3 H), 7.042 (m, 2 H), 6.805 (s, 0.8 H), 6.757 (s, 0.2 H), 6.541 (s, 0.8 H), 6.480 (s, 0.2 H), 5.675 (m, 0.8 H), 5.213 (m, 0.2 H), 3.929 (m, 1 H), 3.845 (m, 1 H), 3.634 (m, 1 H), 3.266 (m, 1 H), 3.124 (m, 1 H), 2.446 (m, 3 H), 2.130 (m, 2 H), 1.974 (m, 2 H), 1.668 (s, 3 H).

Example 2.91

[0992] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(isoxazol-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.449 (s, 0.7 H), 8.367 (s, 1 H), 8.309 (s, 0.3 H), 8.262 (s, 0.7 H), 8.160 (s, 0.7 H), 8.014 (s, 0.3 H), 7.755 (s, 0.3 H), 7.220 (m, 3 H), 7.024 (m, 2 H), 6.775 (m, 1.6 H), 6.500 (s, 0.4 H), 5.680 (m, 0.8 H), 5.159 (m, 0.2 H), 3.934 (m, 1 H), 3.820 (m, 1 H), 3.608 (m, 1 H), 3.258 (m, 1 H), 3.100 (m, 1 H), 2.445 (s, 2 H), 2.280 (s, 1 H), 2.158 (m, 2 H), 2.002 (m, 2 H), 1.669, 1.645 (m, 3 H). Example 2.92

[0993] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l,l- difluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.597 (s, 0.7 H), 8.507 (s, 0.3 H), 8.409 (s, 0.7 H), 8.313 (s, 0.7 H), 8.161 (s, 0.3 H), 7.932 (s, 0.3 H), 7.211 (m, 3 H), 7.029 (m, 2 H), 6.802, 6.775 (m, 1 H), 5.666 (m, 0.7 H), 5.115 (m, 0.3 H), 3.925 (m, 1 H), 3.833 (m, 1 H), 3.540 (m, 1 H), 3.251 (m,

1 H), 3.093 (m, 1 H), 2.691 (s, 2 H), 2.500 (s, 1 H), 2.440 (m, 2 H), 2.307 (m, 1 H), 2.130 (m,

2 H), 1.948 (m, 1 H), 1.658, 1.635 (m, 3 H).

Example 2.93

[0994] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(isoxazol-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.509 (m, 2 H), 8.297 (m, 0.7 H), 8.231 (s, 0.7 H), 8.024 (m, 0.3 H), 7.816 (br, 0.3 H), 7.198 (m, 3 H), 7.191 (m, 2 H), 6.812 (s, 1.3 H), 6.746 (s, 0.3 H), 6.594 (s, 0.4 H), 5.626 (m, 0.8 H), 5.177 (m, 0.2 H), 3.878 (m, 2 H), 3.604 (m, 1 H), 3.258 (m, 1 H), 3.102 (m, 1 H), 2.421 (m, 3 H), 2.124 (m, 2 H), 1.977 (m, 2 H), 1.651 (s, 3 H). Example 2.94

[0995] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrazol-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone : LC/MS RT: 6.23, m z 540.209.

Example 2.95

[0996] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzonitrile : LC/MS RT: 5.68, m z 499.184. Example 2.96

[0997] 5-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-3-methyl-l,3,4-oxadiazol-2(3H)-one : LC/MS RT: 5.63, m z 572.200.

Example 2.97

[0998] Ethyl 3-(5-((R)-2-amino-l-phenylpropan-2-yl)- 1,3, 4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzoate. 1H NMR (300 MHz, CDC1₃) δ 8.80- 8.60 (m, IH), 8.41-8.07 (m, 2H), 7.29-7.19 (m, 4H), 7.05-7.02 (m, 2H), 6.91-6.71 (m, IH), 5.70-5.66 (m, 0.6H), 5.13-5.11 (m, 0.3H), 4.49-4.34 (m, 2H), 3.99-3.77 (m, 2H), 3.59-3.51 (m, IH), 3.31-3.23 (m, IH), 3.12-3.05 (m, IH), 2.45-2.31 (m, 4H), 2.23-2.03 (m, 2H), 2.04- 1.85 (m, 4H), 1.67-1.64 (m, 3H), 1.46-1.36 (m, 3H).

Example 2.98

[0999] (3-(5-((R)-2-amino-l-cyclohexylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.80-8.60 (m, IH), 8.24-7.94 (m, 2H), 7.76-7.41 (m, 2H), 6.79-6.75 (m, IH), 5.69-5.65 (m, 0.7H), 5.17- 5.15 (m, 0.3H), 3.91-3.76 (m, 2H), 3.60-3.52 (m, IH), 2.48-2.26 (m, 4H), 2.22-1.70 (m, 8H), 1.62-1.49 (m, 7H), 1.42-1.32 (m, 2H), 1.27-0.81 (m, 5H). Example 2.99

[1000] (3-(5-((R)-2-amino-l-cyclohexylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.76-8.64 (m, IH), 8.41-8.04 (m, 2H), 7.81-7.74 (m, IH), 7.32-7.27 (m, IH), 6.81- 6.74 (m, IH), 5.71-5.67 (m, 0.7H), 5.20-5.18 (m, 0.3H), 3.97-3.75 (m, 2H), 3.65-3.56 (m, IH), 2.46-2.26 (m, 6H), 2.22-1.70 (m, 7H), 1.62-1.34 (m, 10H), 1.42-1.32 (m, 2H), 1.27-0.83 (m, 5H).

Example 2.100

[1001] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(thiazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI3) δ 8.63-8.60 (m, IH), 8.41-7.88 (m, 3H), 7.46-7.7.39 (m, IH), 7.27-7.20 (m, 3H), 7.20-7.03 (m, 2H), 6.81-6.74 (m, IH), 5.70-5.66 (m, 0.6H), 5.20-5.18 (m, 0.3H), 3.96-3.81 (m, 2H), 3.65-3.57 (m, IH), 3.31-3.23 (m, IH), 3.12-3.05 (m, IH), 2.45-2.27 (m, 4H), 2.20- 2.11 (m, 5H), 1.67-1.64 (m, 3H). Example 2.101

[1002] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-((R)-2- (4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.45-8.37 (m, IH), 8.32-7.81 (m, 2H), 7.28-7.20 (m, 4H), 7.04-7.02 (m, 2H), 6.79-6.76 (m, IH), 6.68-6.39 (m, IH), 5.67-5.63 (m, 0.7H), 5.17-5.15 (m, 0.3H), 3.93-3.78 (m, 2H), 3.59- 3.48 (m, IH), 3.29-3.21 (m, IH), 3.11-2.98 (m, 4H), 2.44-2.26 (m, 4H), 2.21-2.09 (m, 2H), 2.00-1.76 (m, 4H), 1.65-1.62 (m, 3H).

Example 2.102

[1003] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.54- 8.45 (m, IH), 8.37-7.89 (m, 2H), 7.29-7.19 (m, 4H), 7.04-7.01 (m, 2H), 6.91-6.77 (m, 2H), 6.13-6.5.80 (broad s, IH), 5.67-5.63 (m, 0.6H), 5.18-5.16 (m, 0.3H), 3.92-3.80 (m, 2H), 3.61- 3.53 (m, IH), 3.29-3.19 (m, IH), 3.17-3.05 (m, IH), 2.49-2.26 (m, 4H), 2.24-1.76 (m, 6H), 1.65-1.63 (m, 3H). Example 2.103

[1004] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N,N-dimethyl-5- ((R)-2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.25-7.98 (m, 2H), 7.78-7.51 (m, IH), 7.33-7.15 (m, 4H), 7.03-7.01 (m, 2H), 6.79- 6.74 (m, IH), 5.68-5.63 (m, 0.7H), 5.18-5.15 (m, 0.3H), 3.91-3.75 (m, 2H), 3.59-3.51 (m, IH), 3.29-2.91 (m, 8H), 2.44-2.26 (m, 4H), 2.23-1.92 (m, 3H), 1.90-1.70 (broad s, 3H), 1.65- 1.62 (m, 3H).

Example 2.104

[1005] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(thiazol-2-yl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.67- 8.62 (m, IH), 8.32-8.16 (m, 2H), 7.94-7.93 (m, IH), 7.44 (m, IH), 7.28-7.21 (m, 3H), 7.04- 7.02 (m, 2H), 6.92-6.88 (m, IH), 5.01 (broad s, 1.3H), 4.74 (broad s, 0.7H), 3.31-3.27 (m, IH), 3.19-3.08 (m, 4H), 2.46 (m, 3H), 2.10-1.80 (m, 2H), 1.67 (broad s, 3H). Example 2.105

[1006] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-(2-fluoroethyl)-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.73-8.72 (m, IH), 8.42-8.20 (m, 2H), 7.79 (s, IH), 7.33-7.32 (m, IH), 7.31-7.19 (m, 4H), 7.05-7.02 (m, 2H), 6.93-6.86 (m, IH), 5.09-4.82 (m, 4H), 3.98-3.70 (m, 2H), 3.31-3.27 (m, IH), 3.12-3.08 (m, 3H), 2.44 (broad s, 3H), 1.90-1.60 (m, 8H).

Example 2.106

[1007] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-ethyl-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 8.45- 8.37 (m, IH), 8.31-7.72 (m, 2H), 7.25-7.14 (m, 4H), 7.04-6.95 (m, 2H), 6.79-6.75 (m, IH), 6.65-6.34 (m, IH), 5.67-5.63 (m, 0.7H), 5.15-5.13 (m, 0.3H), 3.90-3.78 (m, 2H), 3.59-3.36 (m, 3H), 3.28-3.21 (m, IH), 3.11-3.04 (m, IH), 2.43-2.26 (m, 5H), 2.20-2.04 (m, 2H), 2.00- 1.89 (m, 3H), 1.64-1.62 (m, 3H), 1.27-1.24 (m, 3H). Example 2.107

[1008] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(thiazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.67-8.55 (m, IH), 8.35-7.94 (m, 3H), 7.47-7.46 (m, IH), 7.26-7.22 (m, 4H), 7.05-7.04 (m, 2H), 6.86-6.56 (m, IH), 5.89-5.84 (m, 0.8H), 5.53-5.23 (m, 1.2H), 4.15- 3.89 (m, 2H), 3.32-3.27 (m, IH), 3.13-3.08 (m, IH), 2.94-2.79 (m, 2H), 2.45-2.21 (m, 3H), 2.04-1.74 (m, 2H), 1.67 (broad s, 3H).

Example 2.108

[1009] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (thiazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.69-8.28 (m, IH), 8.35-7.94 (m, 3H), 7.48-7.46 (m, IH), 7.06-6.87 (m, 4H), 5.90-5.84 (m, 0.8H), 5.55-5.20 (m, 1.2H), 4.16-3.90 (m, 2H), 3.29-3.25 (m, IH), 3.11-3.06 (m, IH), 2.95-2.80 (m, 2H), 2.46-2.19 (m, 3H), 2.10-1.72 (m, 6H).

Example 2.109

[1010] 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzoic acid. 1H NMR (300 MHz, CDC1₃ + CD30D) δ 8.67-8.58 (m, IH), 8.35-7.98 (m, 2H), 7.26-7.17 (m, 5H), 6.98 (m, 2H), 6.76-6.69 (m, IH), 5.57 (m, 0.7H), 5.13 (m, 0.2H), 3.87-3.07 (m, 5H), 2.39-1.93 (m, 7H), 1.65-1.62 (m, 3H).

Example 2.110

[1011] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- hydroxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 7.66-7.45 (m, 2H), 7.39-7.15 (m, 4H), 7.03-6.90 (m, 2H), 6.80-6.75 (m, IH), 5.63- 5.59 (m, 0.7H), 5.23-5.21 (m, 0.3H), 3.92-3.73 (m, 2H), 3.58-3.56 (m, IH), 3.27-3.17 (m, IH), 3.10-3.02 (m, IH), 2.48-2.32 (m, 5H), 2.24-1.88 (m, 3H), 1.63-1.60 (m, 3H).

Example 2.111

[1012] (3-(5-((S)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((S)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.73-8.63 (m, IH), 8.41-8.03 (m, 2H), 7.81-7.74 (m, IH), 7.32-7.19 (m, 3H), 7.06- 7.03 (m, 2H), 6.82-6.74 (m, IH), 5.72-5.67 (m, 0.7H), 5.20-5.17 (m, 0.3H), 3.96-3.81 (m, 2H), 3.64-3.56 (m, IH), 3.32-3.24 (m, IH), 3.13-3.06 (m, IH), 2.45-2.41 (m, 4H), 2.27-2.11 (m, 2H), 2.03-1.64 (m, 6H). Example 2.112

[1013] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((S)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDC1₃) δ 8.71-8.61 (m, IH), 8.39-8.00 (m, 2H), 7.79-7.73 (m, IH), 7.30-7.20 (m, 3H), 7.01 (m, 2H), 6.79-6.72 (m, IH), 5.69-5.65 (m, 0.7H), 5.17-5.15 (m, 0.3H), 3.91-3.81 (m, 2H), 3.59-3.57 (m, IH), 3.30-3.22 (m, IH), 3.11-3.06 (m, IH), 2.44-2.41 (m, 4H), 2.25-1.91 (m, 5H), 1.65-1.62 (m, 3H).

Example 2.113

[1014] (3-(5-((S)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. 1H NMR (300 MHz, CDCI3) δ 8.72-8.61 (m, IH), 8.40-8.01 (m, 2H), 7.80-7.73 (m, IH), 7.31-7.17 (m, 3H), 7.05- 7.02 (m, 2H), 6.80-6.73 (m, IH), 5.70-5.66 (m, 0.7H), 5.18-5.16 (m, 0.3H), 3.94-3.79 (m, 2H), 3.62-3.49 (m, IH), 3.31-3.23 (m, IH), 3.12-3.05 (m, IH), 2.44-2.39 (m, 4H), 2.26-1.89 (m, 5H), 1.66-1.62 (m, 3H). Example 2.114

[1015] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(dimethylamino)- N-methyl-N-((4-methylthiazol-2-yl)methyl)benzamide. 1H NMR (300 MHz, CDC1₃) δ 7.36- 7.19 (m, 5H), 7.01 (m, 2H), 6.89 (m, IH), 4.98 (broad s, 1.1H), 4.73 (broad s, 0.9H), 3.28- 3.23 (m, IH), 3.14-3.00 (m, 10H), 2.44-2.41 (m, 3H), 2.08 (broad s, 2H), 1.64 (s, 3H).

Example 2.115

[1016] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(N- methylmethylsulfonamido)-N-((4-methylthiazol-2-yl)methyl)benzamide. [M+H]

Example 2.116

[1017] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4-methoxy-N-methylbenzamide. [M+H] = 476.2. Example 2.117

[1018] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- methoxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. [M+H] = 504.2. Example 2.118

[1019] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- methoxyphenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. [M+H] = 522.2.

Example 2.119

[1020] (R)-5-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-6-methoxy-N-methylnicotinamide. [M+H] = All2. Example 2.120

[1021] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-methoxypyridin- 3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. [M+H] = 505.2.

Example 2.121

[1022] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-methoxypyridin- 3-yl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. [M+H] = 523.2. Example 2.122

[1023] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-4-(trifluoromethoxy)benzamide. [M+H] Example 2.123

[1024] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l-methyl-lH- imidazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.60 (s, 3H), 1.78-2.42 (m, 7H), 3.16-3.38 (m, 2H), 3.58-3.86 (m, 5H), 5.64 (m, IH), 6.80 (s, IH), 6.86-7.38 (m, 7H), 8.40 (s, IH), 8.22 (s, IH), 8.40 (s, IH).

Example 2.124

[1025] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-[l,r-biphenyl]-3- yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.61 (s, 3H), 1.81-2.42 (m, 6H), 3.10-3.38 (m, 2H), 3.56-3.64 (m, IH), 3.81-3.98 (m, 2H), 5.63-5.76 (m, IH), 6.80-8.36 (m, 14H).

Example 2.125

[1026] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-3'-methoxy-[l,l'- biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDCI₃) δ 1.62 (s, 3H), 1.82-2.54 (m, 7H), 3.10-3.38 (m, 2H), 3.56-3.64 (m, 1H), 3.78-3.98 (m, 4H), 5.61-5.76 (m, 1H), 6.76-7.60 (m, 10H), 7.96 (s, 1H), 8.16-8.22 (m, 2H).

Example 2.126

[1027] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-2'-methoxy-[l,r- biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDCI₃) δ 1.61 (s, 3H), 1.83-2.42 (m, 7H), 3.0-3.24 (m, 2H), 3.61-3.96 (m, 5H), 5.61-5.72 (m, 1H), 6.81-7.42 (m, 10H), 7.98 (s, 1H), 8.18-8.22 (m, 2H).

Example 2.127

[1028] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(furan-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDCI₃) δ 1.61 (s, 3H), 1.82-2.41 (m, 6H), 3.10-3.24 (m, 2H), 3.41-3.98 (m, 3H), 5.61-5.65 (m, 1H), 6.80 (s, 1H), 6.88-7.24 (m, 8H) , 8.10-8.41 (m, 3H).

Example 2.128

[1029] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-iodophenyl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.63 (s, 3H), 1.96-2.13 (m, 3H), 2.13-2.45 (m, 3H), 3.04-3.25 (m, 2H), 3.29-3.56 (m, IH), 3.53-3.92 (m, 2H), 5.62-5.66 (m, IH), 6.81 (s, IH), 7.04-7.22 (m, 2H), 7.23-7.26 (m, 3H), 8.05 (s, IH), 8.08 (s, IH), 8.38 (s, IH).

Example 2.129

[1030] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-ethyl-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 1.61 (s, 3H), 2.40 (s, 3H), 3.10-3.46 (m, 4H), 5.0 (br s, 2H), 6.82-7.24 (m, 8H), 7.80 (s, IH), 8.18- 8.23 (m, IH), 8.76 (s, IH).

Example 2.130

[1031] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.60 (s, 3H), 1.82-2.42 (m, 6H), 3.20-3.84 (m, 5H), 5.61-5.72 (m, IH), 6.78-7.22 (m, 6H), 8.0-8.41 (m, 3H).

Example 2.131

[1032] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-nitrophenyl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.62 (s, 3H), 1.98-2.41 (m, 6H), 3.10-3.32 (m, 2H), 3.52-3.61 (m, IH), 3.98-4.02 (m, 2H), 5.61-5.66 (m, IH), 6.78-7.24 (m, 6H), 8.18-8.92 (m, 3H).

Example 2.132

[1033] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(furan-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.62 (s, 3H), 1.95-2.14 (m, 3H), 2.46 (s, 3H), 3.06-3.27 (m, 2H), 3.58-3.63 (m, IH), 3.79-3.96 (m, 2H), 5.69-5.71 (m, IH), 6.81-6.83 (m, 2H), 7.19 (br s, 2H), 7.23-7.28 (m, 2H), 7.46-7.63 (m, 2H), 7.81-7.86 (m, 2H), 8.11-8.16 (m, 2H).

Example 2.133

[1034] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyrimidin-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.63 (s, IH), 1.94-2.40 (m, 5H), 2.42-3.26 (m, 2H), 3.42-3.56 (m, IH), 3.58-3.92 (m, 2H), 5.66-5.70 (m, IH), 6.8 (s, IH), 7.02-7.21 (m, 2H), 7.22-7.26 (m, 4H), 7.43 (s, IH), 7.56-7.61 (m, IH), 7.75-7.77 (m, IH), 7.94-8.22 (m, 2H). Example 2.134

[1035] (3-(5-((R)-2-arnino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyridin-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.66 (s, 3H), 1.97-2.18 (m, 3H), 2.41 (s, 3H), 3.10-3.27 (m, 2H), 3.31-3.60 (m, IH), 3.64-3.95 (m, 2H), 5.67-5.71 (m, IH), 6.81 (s, IH), 7.03-7.05 (br s, 2H), 7.19-7.26 (m, 3H), 7.95-8.01 (m, 2H), 8.20-8.27 (m, 2H), 8.65-8.67 (m, 2H), 8.91 (s, IH).

Example 2.135

[1036] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-(N- methylsulfamoyl)-N-((4-methylthiazol-2-yl)methyl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 1.60 (s, 3H), 2.40 (s, 3H), 2.60-2.74 (m, 3H), 3.1-3.36 (m, 5H), 5.0 (br s, 2H), 6.92-7.22 (m, 7H), 8.18-8.52 (m, 2H).

Example 2.136

[1037] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(pyridin-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 1.66 (s, 3H), 2.39 (s, 3H), 3.07-3.31 (m, 5H), 5.0 (br s, 2H), 6.91-7.32 (m, 7H), 7.82 (s, 2H), 8.15- 8.21 (m, 2H), 8.68-8.72 (m, 2H).

Example 2.137

[1038] (3-(5-((R)-2-amino-l-(2-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.60 (s, 3H), 1.76-2.42 (m, 6H), 3.10-4.12 (m, 5H), 5.61-5.78 (m, IH), 6.79- 7.38 (m, 6H), 8.10-8.82 (m, 4H), 9.20 (s, IH).

Example 2.138

[1039] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(2-methylthiazol- 4-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1 1H NMR (300 MHz, CDCI₃) δ 1.60 (s, 3H), 1.81-2.41 (m, 6H), 2.78 (s, 3H), 3.0-3.36 (m, 2H), 3.52-4.02 (m, 3H), 5.62-5.74 (m, IH), 6.76-7.36 (m, 14H), 7.51 (s, IH), 8.18-8.28 (m, 2H), 8.60 (s, IH). Example 2.139

[1040] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(4,5- dimethylthiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: 1H NMR (300 MHz, CDC1₃) δ 1.60 (s, 3H), 2.01-2.42 (m, 6H), 3.10-3.32 (m, 2H), 3.58-3.62 (m, IH), 3.92-4.02 (m, 2H), 5.68-5.82 (m, IH), 6.72-7.31 (m, 7H), 8.20 (s, IH), 8.44-8.60 (m, IH).

Example 2.140

[1041] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((3-fluoropyridin- 2-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 1.6 (s, 3H), 3.10-3.38 (m, 5H), 4.70 (s, IH), 5.0 (s, IH), 7.0 (m, 2H), 7.20-7.31 (m, 6H), 7.80 (d, IH), 8.22-8.61 (m, 3H), 8.71 (s, IH).

Example 2.141

[1042] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-(oxazol- 2-yl)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)benzamide: 1H NMR (300 MHz, CDC1₃) δ 1.60 (s, 3H), 3.04-3.38 (m, 5H), 5.02 9s, 2H), 7.02-7.38 (m, 6H), 7.80-7.84 (m, 2H), 8.21- 8.39 (m, 2H), 8.76 (s, 1H).

Example 2.142

[1043] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-fluoro-N-methyl- N-((4-methylthiazol-2-yl)methyl)benzamide: m/z: M^÷: 466,169,

Example 2.143

[1044] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4-fluoro-N-methylbenzamide: m/z: M⁺: 464.207.

Example 2.144

[1045] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone: m/z: M

Example 2.145

[1046] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone: m/z: M Example 2.146

[1047] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4- fluorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone: m/z: M⁺: 510.174.

Example 2.147

[1048] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((2,5-dimethyloxazol-4-yl)methyl)-4-fluorobenzamide: m z: M⁺: 490.222.

Example 2.148

[1049] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- cyclopropylpyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) 1H NMR (400 MHz, CDC1₃) δ 7.84 (0.6H, s), 7.61 (0.4H, s), 7.61 (0.6H, s), 7.21 (4.0H, m), 7.06 (2.4H, m), 6.62 (2H, s), 5.46 (0.6H, dd, / = 4.1 Hz), 5.18 (0.4H, m), 3.60 (2H, m), 3.11 (2H, m), 2.40 (2H, m), 2.40 (1.8H, s), 2.22 (1.2H, s), 2.13 (1H, m), 1.97 (2H, m), 1.48 (3H, m), 1.05 (4H, m). MS (ESI) M/Z: 258.3 [M+2H]⁽²⁺⁾/2. Example 2.149

[1050] 2-(6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)benzonitrile (2E)-but-2- enedioate (1:1): 1H NMR (400 MHz, CDC1₃) δ 8.24 (0.6H, s), 8.22 (0.6H, s), 8.06 (1.8H, m), 7.90 (2H, m), 7.73 (IH, m), 7.20 (3.6H, m), 7.05 (2.4H, m), 6.62 (2H, s), 5.50 (0.6H, dd, / = 4.4 Hz), 5.33 (0.4H, m), 3.76 (1.2H, m), 3.61 (0.8H, m), 3.12 (2H, m), 2.41 (IH, m), 2.37 (1.8H, s), 2.16 (IH, m), 2.16 (1.2H, s), 2.01 (2H, m), 1.50 (3H, m) MS (ESI) M/Z: 288.8 [M+2H]⁽²⁺⁾/2.

Example 2.150

[1051] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol-2- yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 8.44 (0.6H, s), 8.40 (0.4H, s), 8.31 (0.6H, s), 8.26 (0.6H, s), 8.03 (0.4H, s), 8.01 (0.4H, s), 7.58 (0.6H, s), 7.53 (0.4H, s), 7.22 (3.6H, m), 7.07 (2.4H, m), 6.62 (2H, s), 5.50 (0.6H, dd, / = 4.0 Hz), 5.23 (0.4H, m), 3.67 (2H, m), 3.15 (2H, m), 2.41 (IH, m), 2.37 (1.8H, m), 2.16 (1.2H, m), 2.14 (IH, m), 1.99 (2H, m), 1.50 (3H, s) MS (ESI) M/Z: 271.8 [M+2H]⁽²⁺⁾/2. Example 2.151

[1052] (2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 7.71 (0.6H, s), 7.44 (0.4H, s), 7.19 (3.6H, m), 7.05 (3H, m), 6.62 (2H, s), 6.88 (0.4H, s), 5.44 (0.6H, dd, / = 4.0 Hz), 5.20 (0.4H, m), 4.00 (1.8H, s), 3.92 (1.2H, s), 3.60 (2H, m), 3.11 (2H, m), 2.42 (1H, m), 2.35 (1.8H, s), 2.20 (1.2H, s), 2.12 (1H, m), 1.97 (2H, m), 1.49 (3H, m)MS (ESI) M/Z: 505.3 [M+H]⁺.

Example 2.152

[1053] N-(6-{5-[(2R)-2-Amino-l-phenylpropan-2-ylH

methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbon

(2£)-but-2-enedioate (1: 1) : 1H NMR (400 MHz, CDC1₃) δ 7.89 (0.6H, s), 7.70 (0.6H, s), 7.61 (0.4H, s), 7.42 (0.4H, s), 7.20 (3.6H, m), 7.05 (2.4H, m), 6.61 (2H, s), 5.46 (0.6H, dd, / = 4.0 Hz), 5.21 (0.4H, m), 3.64 (2H, m), 3.43 (1.8H, s), 3.40 (1.2H, s), 3.33 (1.2H, s), 3.31 (1.8H, s), 3.11 (2H, m), 2.41 (1H, m), 2.34 (1.8H, s), 2.20 (1.2H, s), 2.13 (1H, m), 1.97 (2H, m), 1.48 (3H, m) MS (ESI) M/Z: 582.3 [M+H]⁺.

Example 2.153

[1054] N-(4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N-methylmethanesulfonam (2E)-but-2-enedioate (1: 1) : 1H NMR (400 MHz, CDC1₃) δ 8.07 (0.6H, s), 8.03 (0.6H, s), 7.97 (0.4H, s), 7.90 (0.4H, s), 7.20 (3H, m), 7.14 (0.4H, s), 7.04 (2.6H, m), 6.62 (2H, s), 5.92 (0.4H, m), 5.53 (0.6H, dd, / = 4.0 Hz), 4.01 (0.4H, m), 3.78 (1.6H, m), 3.45 (1.8H, s), 3.33 (1.2H, s), 3.13 (1.2H, s), 3.11 (1.8H, s), 3.12 (2H, m), 2.42 (IH, m), 2.35 (1.8H, s), 2.21 (1.2H, s), 2.05 (3H, m), 1.48 (3H, s) MS (ESI) M/Z: 582.3 [M+H]⁺.

Example 2.154

[1055] (4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-2-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 7.88 (0.5H, s), 7.81 (0.5H, s), 7.50 (0.5H, s), 7.36 (0.5H, s), 7.20 (3H, m), 7.14 (0.5H, s), 7.02 (2.5H, m), 6.62 (2H, s), 6.02 (0.5H, m), 5.52 (0.5H, dd, / = 4.0 Hz), 4.08 (0.5H, m), 4.01 (1.5H, s), 3.91 (0.5H, m), 3.78 (IH, m), 3.65 (1.5H, s), 3.11 (2H, m), 2.42 (IH, m), 2.34 (1.5H, m), 2.23 (1.5H, m), 2.06 (2H, m), 1.83 (IH, m), 1.48 (3H, m) MS (ESI) M/Z: 505.3 [M+H]⁺.

Example 2.155

[1056] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol-2- yl)pyridin-4-yl][(2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 8.45 (0.6H, s), 8.39 (0.4H, s), 8.31 (0.6H, s), 8.27 (0.6H, s), 8.02 (0.4H, s), 7.99 (0.4H, s), 7.58 (0.6H, s), 7.52 (0.4H, s), 7.21 (3.6H, m), 7.07 (2.4H, m), 6.62 (2H, s), 5.50 (0.6H, dd, / = 4.0 Hz), 5.26 (0.4H, m), 3.69 (2H, m), 3.15 (2H, m), 2.72 (1.2H, q, J = 7.4 Hz), 2.47 (IH, m), 2.40 (0.8H, m), 2.15 (IH, m), 1.99 (2H, m), 1.50 (3H, m), 1.24 (1.8H, t, / = 7.4 Hz), 0.99 (1.2H, t, J = 7.8 Hz) MS (ESI) M/Z: 556.4

[M+H]⁺.

Example 2.156

[1057] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol-2- yl)pyridin-4-yl][(2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but- 2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 8.44 (0.6H, s), 8.40 (0.4H, s), 8.31 (0.6H, s), 8.25 (0.6H, s), 8.00 (0.4H, s), 8.00 (0.4H, s), 7.59 (0.6H, s), 7.53 (0.4H, s), 7.21 (3.6H, m), 7.08 (2.4H, m), 6.62 (2H, s), 5.47 (0.6H, dd, / = 4.0 Hz), 5.24 (0.4H, m), 3.64 (2H, m), 3.15 (2H, m), 2.40 (0.6H, m), 2.07 (2H, m), 1.96 (2H, m), 1.82 (0.4H, m), 1.49 (3H, m), 0.90 (1.2H, m), 0.81 (1.2H, m), 0.70 (0.8H, m), 0.57 (0.4H, m), 0.46 (0.4H, m) MS (ESI) M/Z: 568 [M+H]⁺.

Example 2.157

[1058] [2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol-2- yl)pyridin-4-yl] { (2R)-2- [4-(methoxymethyl)- 1 ,3-thiazol-2-yl]pyrrolidin- 1 -yl jmethanone (2E)-but-2-enedioate (1: 1) : MS (ESI) m z: 572 [M+H]⁺. Example 2.158

[1059] (6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-2,3'-bipyridin-4- yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 9.43 (0.6H, s), 9.23 (0.4H, s), 8.74 (0.6H, dd, / = 2.7 Hz), 8.70 (0.4H, dd, / = 2.7 Hz), 8.60 (0.6H, dt, / = 8.0, 1.8 Hz), 8.42 (0.4H, dt, / = 8.0, 1.8 Hz), 8.37 (0.6H, s), 8.14 (0.6H, s), 8.05 (0.4H, s), 7.87 (0.4H, s), 7.59 (IH, m), 7.21 (3.6H, m), 7.07 (2.4H, m), 6.61 (2H, s), 5.50 (0.6H, dd, / = 4.0 Hz), 5.31 (0.4H, m), 3.77 (IH, m), 3.58 (IH, m), 3.15 (2H, m), 2.43 (IH, m), 2.38 (1.8H, s), 2.18 (IH, m), 2.15 (1.2H, s), 2.00 (2H, m), 1.52 (3H, m) MS (ESI) M/Z: 276.8 [M+2H]⁽²⁺⁾/2.

Example 2.159

[1060] (6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-2,4'-bipyridin-4- yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 8.80 (0.6H, s), 8.80 (0.6H, s), 8.78 (0.4H, s), 8.76 (0.4H, s), 8.42 (0.6H, s), 8.22 (0.6H, s), 8.21 (0.6H, s), 8.20 (0.6H, s), 8.10 (0.4H, s), 8.03 (0.4H, s), 8.02 (0.4H, s), 7.93 (0.4H, s), 7.23 (3.6H, m), 7.07 (2.4H, m), 6.62 (2H, s), 5.50 (0.6H, dd, / = 4.0 Hz), 5.29 (0.4H, m), 3.76 (IH, m), 3.58 (IH, m), 3.15 (2H, m), 2.44 (IH, m), 2.37 (1.8H, s), 2.17 (IH, m), 2.13 (1.2H, s), 2.01 (2H, m), 1.52 (3H, s) MS (ESI) M/Z: 276.8

[M+2H]⁽²⁺⁾/2. Example 2.160

[1061] [2-{5-[(2R)-2- Amino- l-phenylpropan-2-yl]- 1, 3,4-oxadiazol-2-yl}-6-(pyrimidin-5- yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 9.61 (1.2H, s), 9.44 (IH, s), 9.34 (0.8H, m), 8.47 (0.6H, s), 8.19 (0.6H, s), 8.15 (0.4H, s), 7.93 (0.4H, s), 7.21 (3.6H, m), 7.07 (2.4H, m), 6.62 (2H, s), 5.51 (0.6H, dd, / = 4.0 Hz), 5.33 (0.4H, m), 3.77 (1.2H, m), 3.58 (0.8H, m), 3.14 (2H, m), 2.44 (IH, m), 2.38 (1.8H, s), 2.20 (IH, m), 2.15 (1.2H, s), 1.99 (2H, m), 1.51 (3H, m) MS (ESI) M/Z: 277.3 [M+2H]⁽²⁺⁾/2.

Example 2.161

[1062] (2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-methylpyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 7.97 (0.7H, s), 7.71 (0.3H, s), 7.63 (0.7H, s), 7.21 (4H, m), 7.06 (2.3H, m), 6.62 (2H, s), 5.46 (0.7H, dd, / = 4.0 Hz), 5.20 (0.3H, m), 3.56 (2H, m), 3.11 (2H, m), 2.65 (2.1H, s), 2.51 (0.9H, s), 2.39 (IH, m), 2.37 (2.1H, s), 2.21 (0.9H, s), 2.15 (IH, m), 1.98 (2H, m), 1.47 (3H, m) MS (ESI) M/Z: 489.3 [M+H]⁺.

Example 2.162

[1063] [2- { 5 - [(2R)-2- Amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 , 1 -dioxido- l,2-thiazolidin-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 7.78 (0.7H, s), 7.53 (0.3H, s), 7.44 (0.7H, s), 7.21 (4H, m), 7.05 (2.3H, m), 6.61 (2H, s), 5.46 (0.7H, dd, / = 4.0 Hz), 5.17 (0.3H, m), 4.05 (1.4H, m), 3.92 (0.6H, m), 3.71 (2H, m), 3.56 (2H, m), 3.12 (2H, m), 2.43 (3H, m), 2.36 (2.1H, s), 2.22 (0.9H, s), 2.13 (1H, m), 1.98 (2H, m), 1.48 (3H, m) MS (ESI) M/Z: 594.4 [M+H]⁺.

Example 2.163

[1064] N-(6-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)methanesulfonamide (2E)-but- 2-enedioate (1:1) : MS (ESI) m/z: 285 [M+2H]⁽²⁺⁾/2.

Example 2.164

[1065] (4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- methoxypyridin-2-yl)[(2R)-2-(4,5-dimethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : MS (ESI) m/z: 260.3 [M+2H]⁽²⁺⁾/2.

Example 2.165

[1066] [4-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol-2- yl)pyridin-2-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedoate (1:1) : 1H NMR (400 MHz, CDC1₃) δ 8.67 (0.6H, s), 8.52 (0.4H, s), 8.45 (0.6H, s), 8.36 (0.4H, s), 8.34 (0.6H, s), 8.12 (0.4H, s), 7.60 (0.6H, s), 7.56 (0.4H, s), 7.23 (3H, m), 7.15 (0.6H, s), 7.06 (2.4H, m), 6.61 (2H, s), 6.03 (0.4H, m), 5.57 (0.6H, dd, / = 4.0 Hz), 4.15 (0.6H, m), 3.85 (1.4H, m), 3.13 (2H, m), 2.50 (1H, m), 2.37 (1.8H, s), 2.17 (1H, m), 2.15 (1.2H, s), 2.02 (2H, m), 1.48 (3H, s) MS (ESI) M/Z: 271.7 [M+2H]⁽²⁺⁾/2.

Example 2.166

[1067] l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.62 (0.7H, d, J = 1.0 Hz), 8.28 (0.3H, d, J = 1.0 Hz), 7.86 (0.7H, d, J = 1.0 Hz), 7.65-7.55 (1.3H, m), 7.26-7.15 (3H, m), 7.09-7.02 (2H, m), 6.62 (2H, s), 5.48 (0.7H, dd, J = 8.1, 4.1 Hz), 5.16-5.12 (0.3H, m), 4.10 (1.4H, t, J = 7.0 Hz), 4.05-3.99 (0.6H, m), 3.76-3.07 (6H, m), 2.68-1.90 (11H, m), 1.49 (2.1H, s), 1.48 (0.9H, s). MS (ESI) m z: 558 [M+H]⁺.

Example 2.167

[1068] 3-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3-oxazolidin-2-one (2E)- but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.39 (0.7H, d, J = 1.1 Hz), 8.07 (0.3H, d, J = 1.0 Hz), 7.86 (0.7H, d, J = 1.1 Hz), 7.66-7.52 (1.3H, m), 7.26-7.16 (3H, m), 7.09-7.01 (2H, m), 6.62 (2H, s), 5.48 (0.7H, dd, J = 8.1, 4.1 Hz), 5.16-5.13 (0.3H, m), 4.56- 4.46 (2H, m), 4.32-4.16 (2H, m), 3.76-3.06 (6H, m), 2.56-1.90 (7H, m), 1.50 (2.1H, s), 1.48 (0.9H, s). MS (ESI) m/z: 560 [M+H]⁺.

Example 2.168

[1069] l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-5-methylpyrrolidin-2-one (2E)-but-2-enedioate (1: 1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.55-8.52 (0.7H, m), 8.23-8.21 (0.15H, m), 8.13-8.10 (0.15H, m), 7.87-7.84 (0.7H, m), 7.63-7.61 (0.15H, m), 7.55-7.52 (0.15H, m), 7.24-7.15 (4H, m), 7.08-7.00 (2H, m), 6.61 (2H, s), 5.48 (0.7H, dd, I = 8.0, 4.1 Hz), 5.19-5.14 (0.3H, m), 4.85-4.70 (1H, m), 3.78-3.02 (6H, m), 3.89-1.70 (11H, m), 1.50 (2.1H, s), 1.49 (0.9H, s), 1.41-1.27 (3H, m). MS (ESI) m/z: 572 [M+H]⁺.

Example 2.169

[1070] l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)piperidin-2-one (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.11 (0.7H, d, J = 1.1 Hz), 7.91 (0.7H, d, J = 1.1 Hz), 7.80 (0.3H, d, J = 1.1 Hz), 7.60 (0.3H, d, J = 1.1 Hz), 7.25-7.15 (4H, m), 7.06-7.00 (2H, m), 6.62 (2H, s), 5.47 (0.7H, dd, J = 8.1, 4.0 Hz), 5.23-5.17 (0.3H, m), 4.04-3.05 (8H, m), 2.67-1.80 (13H, m), 1.49 (2.1H, s), 1.47 (0.9H, s). MS (ESI) m/z: 572 [M+H]⁺. Example 2.170

[1071] N-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N-methylacetamide (2E)-but- 2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 7.95 (0.65H, s), 7.94 (0.65H, s), 7.63 (0.35H, s), 7.61 (0.35H, s), 7.25-7.15 (4H, m), 7.09-7.00 (2H, m), 6.62 (2H, s), 5.47 (0.65H, dd, J = 8.1, 4.0 Hz), 5.28-5.22 (0.35H, m), 3.80-2.94 (9H, m), 2.67-1.90 (10H, m), 1.49 (1.95H, s), 1.48 (1.05H, s). MS (ESI) m/z: 546 [M+H]⁺.

Example 2.171

[1072] l-(4-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 9.04 (0.55H, d, J = 1.4 Hz), 8.91 (0.45H, d, J = 1.4 Hz), 8.00 (0.55H, d, J = 1.4 Hz), 7.92 (0.45H, d, J = 1.4 Hz), 7.26-7.01 (6H, m), 6.62 (2H, s), 5.94 (0.45H, dd, J = 7.4, 5.4 Hz), 5.54 (0.55H, dd, J = 7.9, 3.1 Hz), 4.15-3.02 (8H, m), 2.70-1.75 (11H, m), 1.49 (1.65H, s), 1.48 (1.35H, s). MS (ESI) m/z: 558 [M+H]⁺. Example 2.172

[1073] [2- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl }-6-(lH-l,2,4- triazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 9.52 (0.6H, s), 9.43 (0.4H, s), 8.43 (0.6H, s), 8.38 (0.4H, s), 8.18 (0.6H, d, J = 1.1 Hz), 8.08 (0.6H, s), 7.94-7.93 (0.4H, m), 7.85- 7.84 (0.4H, m), 7.26-7.18 (4H, m), 7.10-7.05 (2H, m), 6.62 (2H, s), 5.49 (0.6H, dd, J = 8.1, 4.0 Hz), 5.26-5.23 (0.4H, m), 3.78-3.00 (6H, m), 2.73-1.88 (7H, m), 1.53-1.48 (3H, m). MS (ESI) m/z: 542 [M+H]⁺.

Example 2.173

[1074] [2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 H-imidazol- l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.74 (0.55H, s), 8.56 (0.45H, s), 8.17-7.77 (3H, m), 7.27-7.15 (5H, m), 7.10-7.02 (2H, m), 6.62 (2H, s), 5.49 (0.55H, dd, J = 7.9, 3.9 Hz), 5.35-5.29 (0.45H, m), 3.82-3.05 (6H, m), 2.68-1.90 (7H, m), 1.53-1.45 (3H, m). MS (ESI) m/z: 541 [M+H]⁺.

Example 2.174

[1075] [2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 H-pyrazol- 1 - yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.73 (0.6H, d, J = 2.5 Hz), 8.64 (0.4H, d, J = 2.6 Hz), 8.13 (0.6H, m), 8.06 (0.6H, m), 7.95 (0.6H, m), 7.91-7.88 (0.8H, m), 7.80-7.78 (0.4H, m), 7.26-7.15 (4H, m), 7.10-7.03 (2H, m), 6.71 (0.6H, dd, J = 2.5, 1.7 Hz), 6.66 (0.4H, dd, J = 2.4, 1.8 Hz), 6.61 (2H, s), 5.49 (0.6H, dd, J = 8.0, 4.0 Hz), 5.26-5.22 (0.4H,

3.10 (6H, m), 2.70-1.86 (7H, m), 1.53-1.47 (3H, m). MS (ESI) m/z: 541 [M+H]⁺.

Example 2.175

[1076] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(2H-l,2,3- triazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.32 (1.2H, s), 8.26 (1.4H, s), 8.23 (0.6H, s), 8.00 (0.4H, s), 7.97 (0.4H, s), 7.26-7.18 (4H, m), 7.10-7.04 (2H, m), 6.62 (2H, s), 5.50 (0.6H, dd, J = 8.1, 4.0 Hz), 5.29-5.22 (0.4H, m), 3.79-3.57 (2H, m), 3.30 (2H, t, J = 7.0 Hz), 3.19-3.11 (2H, m), 2.70 (3H, s), 2.47-1.86 (4H, m), 1.51 (1.8H, s), 1.50 (1.2H, s). MS (ESI) m/z: 542 [M+H]⁺.

Example 2.176

[1077] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-l,2,3- triazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.98 (0.6H, d, J = 1.1 Hz), 8.89 (0.4H, d, J = 1.1 Hz), 8.36-7.97 (3H, m), 7.26-7.15 (4H, m), 7.10-7.03 (2H, m), 6.62 (2H, s),

5.50 (0.6H, dd, J = 8.1, 4.0 Hz), 5.29-5.26 (0.4H, m), 3.79-3.13 (6H, m), 2.70-1.86 (7H, m),

1.51 (1.8H, s), 1.50 (1.2H, s). MS (ESI) m/z: 542 [M+H]⁺. Example 2.177

[1078] [2- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 -methyl- 1 H- pyrazol-4-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1: 1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.50 (0.6H, s), 8.32 (0.4H, s), 8.20 (0.6H, s), 7.99 (0.4H, s), 7.96 (0.6H, d, J = 1.2 Hz), 7.90 (0.6H, d, J = 1.2 Hz), 7.28-7.02 (6.8H, m), 6.62 (2H, s), 5.49 (0.6H, dd, J = 8.0, 3.9 Hz), 5.30-5.24 (0.4H, m), 3.94 (1.8H, s), 3.92 (1.2H, s), 3.80-3.52 (2H, m), 3.40 (2H, br.s), 3.21-3.11 (2H, m), 2.48-1.85 (7H, m), 1.55-1.48 (3H, m). MS (ESI) m/z: 555 [M+H]⁺.

Example 2.178

[1079] [2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 -methyl- 1 H- pyrazol-5-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1: 1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.10 (0.6H, d, J = 1.1 Hz), 8.07 (0.6H, d, J = 1.0 Hz), 7.82 (0.4H, d, J = 1.0 Hz), 7.77 (0.4H, m), 7.57 (0.6H, d, J = 2.0 Hz), 7.53 (0.4H, d, J = 2.0 Hz), 7.26-7.16 (3.6H, m), 7.11 (0.6H, d, J = 2.0 Hz), 7.09-7.01 (2.4H, m), 6.81 (0.4H, d, J = 2.0 Hz), 6.62 (2H, s), 5.49 (0.6H, dd, J = 8.0, 3.8 Hz), 5.28-5.24 (0.4H, m), 4.24 (1.8H, s), 4.17 (1.2H, s), 3.80-3.08 (6H, m), 2.46-1.86 (7H, m), 1.53-1.46 (3H, m). MS (ESI) m/z: 555 [M+H]⁺. Example 2.179

[1080] 2- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N- [(4-bromo- 1,3- thiazol-2-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.44 (0.6H, s), 8.41 (0.4H, s), 8.27-8.23 (1.6H, m), 7.89 (0.6H, s), 7.85 (0.4H, s), 7.65-7.53 (3.4H, m), 7.25-7.17 (3H, m), 7.10-7.05 (2H, m), 6.62 (2H, s), 4.99 (1.2H, s), 4.85 (0.8H, s), 3.18-3.05 (5H, m), 1.51 (1.8H, s), 1.49 (1.2H, s). MS (ESI) m/z: 580,582 [M+H]⁺.

Example 2.180

[1081] 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [(6- methylpyridin-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : MS (ESI) m/z: 510 [M+H]⁺.

Example 2.181

[1082] 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N- [ 1 -( 1 -methyl- lH-pyrazol-3-yl)ethyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 9.51 (1H, d, J = 8.3 Hz), 8.73 (1H, d, J = 1.4 Hz), 8.69 (1H, d, J = 1.5 Hz), 8.44 (1H, d, J = 1.0 Hz), 7.61 (1H, d, J = 2.2 Hz), 7.58 (1H, d, J = 0.7 Hz), 7.25- 7.17 (3H, m), 7.09-7.06 (2H, m), 6.62 (2H, s), 6.22 (1H, d, J = 2.2 Hz), 5.29 (1H, qu), 3.81 (3H, s), 3.40 (2H, br.s), 3.17 (1H, d, J = 13.5 Hz), 3.15 (1H, d, J = 13.5 Hz), 1.55-1.50 (6H, m). MS (ESI) m/z: 499 [M+H]⁺.

Example 2.182

[1083] 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [(6- methylpyridin-2-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.49 (0.6H, d, J = 1.3 Hz), 8.44 (0.4H, m), 8.41 (0.6H, d, J = 1.3 Hz), 8.40 (0.6H, m), 8.34 (0.4H, d, J = 1.2 Hz), 8.31 (0.4H, d, J = 1.2 Hz), 7.73 (0.4H, t, J = 7.6 Hz), 7.67 (0.6H, t, J = 7.6 Hz), 7.58 (0.4H, s), 7.54 (0.6H, s), 7.26-7.02 (7H, m), 6.62 (2H, s), 4.78 (0.8H, s), 4.51 (1.2H, s), 3.30 (2H, br.s), 3.16 (0.8H, s), 3.13 (1.2H, s), 2.99 (1.2H, s), 2.96 (1.8H, s), 2.54 (1.8H, s), 2.52 (1.2H, s), 1.51 (1.2H, s), 1.48 (1.8H, s). MS (ESI) m/z: 510 [M+H]⁺.

Example 2.183

[1084] 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [( 1 - methyl-lH-pyrazol-4-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : MS (ESI) m/z: 499 [M+H]⁺. Example 2.184

[1085] 2- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N- [( 1 ,5-dimethyl- lH-pyrazol-4-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : MS (ESI) m/z: 513 [M+H]⁺.

Example 2.185

[1086] 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N- [( 1 ,3-dimethyl- lH-pyrazol-5-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.43 (0.7H, s), 8.42 (0.3H, s), 8.27 (0.7H, s), 8.25 (IH, s), 8.19 (0.3H, s), 7.57 (IH, s), 7.26-7.16 (3H, m), 7.11-7.05 (2H, m), 6.61 (2H, s), 6.14 (0.7H, s), 6.09 (0.3H, s), 4.74 (1.4H, s), 4.55 (0.6H, s), 3.78-3.50 (3H, m), 3.40 (2H, br.s), 3.15 (2H, s), 3.02 (0.9H, s), 2.90 (2.1H, s), 2.14-2.10 (3H, m), 1.50-1.49 (3H, m). MS (ESI) m/z: 513 [M+H]⁺.

Example 2.186

[1087] 2- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 -methyl- 1 H- pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone : 1H NMR (400 MHz, DMSO-d₆) δ 8.11 (0.6H, d, J = 1.3 Hz), 8.02 (0.6H, d, J = 1.3 Hz), 7.89- 7.88 (1.0H, m), 7.83 (0.4H, d, J = 2.1 Hz), 7.74 (0.4H, d, J = 0.4 Hz), 7.26-7.04 (6H, m), 6.96 (0.6H, d, J = 2.2 Hz), 6.85 (0.4H, d, J = 2.2 Hz), 5.48 (0.6H, dd, J = 8.0, 4.1 Hz), 5.23-5.18 (0.4H, m), 3.97 (1.8H, s), 3.94 (1.2H, s), 3.76-3.54 (2H, m), 3.17-3.08 (2H, m), 2.46-1.93 (9H, m), 1.50 (1.8H, s), 1.48 (1.2H, s). MS (ESI) m/z: 555 [M+H]⁺.

Example 2.187

[1088] (2-amino-6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } pyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 7.28-6.96 (8H, m), 6.73 (0.75H, s), 6.72 (0.75H, s), 6.62 (2H, s), 6.54 (0.25H, s), 6.45 (0.25H, s), 5.44 (0.75H, dd, J = 8.0, 4.2 Hz), 5.21-5.16 (0.25H, m), 3.76-3.00 (6H, m), 2.43-1.85 (7H, m), 1.47 (2.25H, s), 1.45 (0.75H, s). MS (ESI) m/z: 490 [M+H]⁺.

Example 2.188

[1089] 2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [( 1 - methyl-lH-pyrazol-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1) : 1H NMR (400 MHz, DMSO-d₆) δ 8.42 (1H, d, J = 3.7 Hz), 8.36 (0.6H, m), 8.32 (0.6H, m), 8.23 (0.4H, m), 8.21 (0.4H, m), 7.68 (0.4H, d, J = 2.0 Hz), 7.65 (0.6H, d, J = 2.0 Hz), 7.57-7.56 (1H, m), 7.25-7.17 (3H, m), 7.10-7.05 (2H, m), 6.62 (2H, s), 6.27 (0.4H, d, J = 2.1 Hz), 6.21 (0.6H, d, J = 2.1 Hz), 4.64 (0.8H, s), 4.38 (1.2H, s), 3.83 (1.2H, s), 3.81 (1.8H, s), 3.40 (2H, br.s), 3.17 (1H, d, J = 13.5 Hz), 3.15 (1H, d, J = 13.5 Hz), 3.01 (1.8H, s), 2.91 (1.2H, s), 1.51 (3H, s). MS (ESI) m/z: 499 [M+H]⁺.

Example 2.189

[1090] (6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}pyridin-2- yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone 2-hydroxypropane-l,2,3- tricarboxylate (1:1) : MS (ESI) M/Z: 475 [M+H]⁺.

Example 2.190

[1091] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}pyridin-4- yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone 2-hydroxypropane-l,2,3- tricarboxylate (1:1) : MS (ESI) M/Z: 475 [M+H]⁺.

Example 2.191

[1092] [2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-(pyrrolidin- 1 - yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2- enedioate (1:1) : MS (ESI) M/Z: 544 [M+H]⁺, 1H NMR (400 MHz, DMSO-d₆) δ 7.24-7.15 (4.6H, m), 7.06-7.02 (2.4H, m), 6.66 (0.6H, br s), 6.62 (2H, s), 6.30 (0.4H, br s), 5.43 (0.6H, dd, J = 3.9, 8.0 Hz), 5.18 (0.4H, m), 3.72-3.32 (6H, m), 3.23 (3H, br s), 3.15-3.06 (2H, m), 2.39-2.32 (1H, m), 2.36 (1.8H, s), 2.24 (1.2H, s), 2.12 (0.6H, m), 2.04-1.90 (6.4H, m), 1.49 (1.8H, s), 1.47 (1.2H, s). Example 2.192

[1093] 6- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -methyl-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)-but-2- enedioate (1:1) : MS (ESI) M/Z: 505 [M+H]⁺.

Example 2.193

[1094] [2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- (difluoromethoxy)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1: 1) : MS (ESI) M/Z: 541 [M+H]⁺.

Example 2.194

[1095] 4- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -methyl-6- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)-but-2- enedioate (1:1) : MS (ESI) M/Z: 505 [M+H]⁺. Example 2.195

[1096] 6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 - (cyclopropylmethyl)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yl]carbonyl jpyridin- 2(lH)-one (2E)-but-2-enedioate (1:1) : MS (ESI) M/Z: 545 [M+H]⁺.

Example 2.196

[1097] 6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -ethyl-4- { [(2R)- 2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)-but-2- enedioate (1:1) : MS (ESI) M/Z: 519 [M+H]⁺.

Example 2.197

[1098] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-ethoxypyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)-but-2-enedioate (1:1) : MS (ESI) M/Z: 519 [M+H]⁺, 1H NMR (400 MHz, DMSO-d₆) δ 7.69 (0.6H, s), 7.41 (0.4H, s), 7.17-7.24 (3.6H, m), 7.02-7.12 (3H, m), 6.84 (0.4H, s), 6.62 (2H, s), 5.43-5.46 (0.6H, m), 5.20-5.22 (0.4H, m), 4.45 (1.2H, q, J = 7.0 Hz), 4.35 (0.8H, q, J = 7.0 Hz), 3.49- 3.73 (2H, m), 3.34 (3H, br s), 3.06-3.15 (2H, m), 2.33-2.42 (1H, m), 2.36 (1.8H, s), 2.20 (1.2H, s), 2.11 (0.6H, m), 1.91-2.10 (2.4H, m), 1.49 (1.8H, s), 1.47 (1.2H, s), 1.39 (1.8H, t, J = 7.0 Hz), 1.33 (1.2H, t, J = 7.0 Hz). Example 2.198

[1099] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-[(2- methoxyethyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yl]methanone (2E)-but-2-enedioate (1:1) : MS (ESI) M/Z: 548 [M+H]⁺, 1H NMR (400 MHz, DMSO-d₆) δ 7.27-7.17 (5.3H, m), 7.10-6.97 (2.7H, m), 6.83 (0.7H, s), 6.62 (2H, s), 6.51 (0.3H, s), 5.43 (0.7H, dd, I = 4.1, 8.0 Hz), 5.18 (0.3H, m), 3.71-3.40 (6H, m), 3.32 (3H, br s), 3.30 (2.1H, s), 3.27 (0.9H, s), 3.14-3.04 (2H, m), 2.38 (IH, m), 2.36 (2.1H, s), 2.24 (0.9H, s), 2.09 (0.7H, m), 2.00-1.91 (2.3H, m), 1.48 (2.1H, s), 1.46 (0.9H, s).

Example 2.199

[1100] (2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-[(2- methoxyethyl) (methyl) amino] pyri^

yl]methanone (2E)-but-2-enedioate (1:1) : MS (ESI) M/Z: 562 [M+H]⁺, 1H NMR (400 MHz, DMSO-d₆) δ 7.23-7.13 (4.6H, m), 7.05-7.01 (2.4H, m), 6.87 (0.6H, s), 6.62 (2H, s), 6.53 (0.4H, s), 5.43 (0.6H, dd, J = 3.8, 7.0 Hz), 5.18 (0.4H, m), 3.80 (IH, m), 3.72-3.45 (5H, m), 3.40 (3H, br s), 3.27 (1.8H, s), 3.24 (1.2H, s), 3.13 (1.8H, s), 3.12-3.07 (2H, m), 2.95 (1.2H, s), 2.37 (IH, m), 2.36 (1.8H, s), 2.24 (1.2H, s), 2.13 (0.6H, m), 2.02-1.91 (2.4H, m), 1.49 (1.8H, s), 1.47 (1.2H, s). Example 2.200

[1101] [2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-

(ethylamino)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone (2E)- but-2-enedioate (1:1) : MS (ESI) M/Z: 518 [M+H]⁺, 1H NMR (400 MHz, DMSO-d₆) δ 7.24- 7.11 (5.3H, m), 7.05-6.98 (2.7H, m), 6.73 (0.7H, br s), 6.62 (2H, s), 6.40 (0.3H, br s), 5.43 (0.7H, dd, I = 4.1, 8.0 Hz), 5.18 (0.3H, m), 3.70-3.48 (2H, m), 3.40 (3H, br s), 3.35 (1.4H, m), 3.21-3.05 (2.6H, m), 2.38 (1H, m), 2.36 (2.1H, s), 2.24 (0.9H, s), 2.10 (0.7H, m), 2.03-1.89 (2.3H, m), 1.49 (2.1H, s), 1.47 (0.9H, s), 1.19 (2.1H, t, I = 7.2 Hz), 1.17 (0.9H, t, I = 7.2 Hz). Example 2.201

[1102] 3-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-5- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)-but-2- enedioate (1:1) : MS (ESI) M/Z: 505 [M+H]⁺.

Example 2.202

[1103] 6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -4- { [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one (2E)-but-2-enedioate (1:1) : MS (ESI) M/Z: 491 [M+H]⁺. Example 2.203

[1104] 6- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N, 1 -dimethyl-2- oxo-N-(pyridin-3-ylmethyl)-l,2-dihydropyridine-4-carboxamide : MS (ESI) m/z: 459

[M+H]⁺.

Example 2.204

[1105] 6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N, 1 -dimethyl-N- [(6-methylpyridin-2-yl)methyl]-2-oxo-l,2-dihydropyridine-4-carboxamide : MS (ESI) M/Z: 473 [M+H]⁺.

Example 2.205

[1106] 6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-butyl- 1 -methyl- 2-oxo-N-(pyridin-4-ylmethyl)-l,2-dihydropyridine-4-carboxamide : MS (ESI) m/z: 501 [M+H]⁺. Example 2.206

[1107] 6- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -methyl-4- { [2-(3- methyl-l,2,4-oxadiazol-5-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one : MS (ESI) m/z: 490 [M+H]⁺.

Example 2.207

[1108] 6- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-butyl- 1 -methyl- 2-oxo-N-(pyridin-3-ylmethyl)-l,2-dihydropyridine-4-carboxamide : MS (ESI) m/z: 501

[M+H]⁺.

Example 2.208

[1109] 6- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N, 1 -dimethyl-2- oxo-N-(lH-pyrazol-5-ylmethyl)-l,2-dihydropyridine-4-carboxamide : MS (ESI) m/z: 448 [M+H]⁺.

Example 2.209

[1110] 6- { 5 - [(2R)-2-amino - 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N, 1 -dimethyl-2- oxo-N-[l-(2-thienyl)ethyl]-l,2-dihydropyridine-4-carboxamide : MS (ESI) m/z: 478 [M+H]⁺. Example 2.210

[1111] 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(2,5-dimethyl- l,3-oxazol-4-yl)methyl]-N,l-dimethyl-2-oxo-l,2-dihydropyridine-4-carboxamide : MS (ESI) m/z: 477 [M+H]⁺.

Example 2.211

[1112] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. 1H NMR (300 MHz, CDCI₃+CD₃OD) δ 8.690 (s, 1 H), 8.397 (s, 1 H), 8.309 (s, 1 H), 7.787 (s, 1 H), 7.286 (m, 1 H), 7.039-6.868 (m, 5 H), 5.042 (s, 2 H), 3.270 (d, J = 13.5 Hz, 1 H), 3.093 (d, J = 13.5 Hz, 1 H), 2.990 (m, 1 H), 2.452 (s, 3 H), 1.905 (br, 2 H), 1.637 (s, 3 H), 0.666 (m, 2 H), 0.558 (m, 2 H).

Example 2.212

[1113] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- bromophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. : 1H NMR (300 MHz, CDCI3) δ 8.20-8.11 (m, 2H), 7.86 (m, IH), 7.33-7.21 (m, 4H), 7.03-7.01 (m, 2H), 6.81-6.79 (m, IH), 5.67-5.63 (m, 0.6H), 5.11 (m, 0.3H), 3.98-3.70 (m, 2H), 3.59-3.54 (m, IH), 3.29- 3.21 (m, IH), 3.11-3.07 (m, IH), 2.45-2.34 (m, 5H), 2.18-2.07 (m, 2H), 2.02-1.94 (m, 2H), 1.67-1.64 (m, 3H).

Example 2.213

[1114] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- chlorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone. : 1H NMR (300 MHz, CDC1₃) δ 8.01-7.93 (m, 2H), 7.73-7.72 (m, IH), 7.29-7.22 (m, 4H), 7.04- 7.01 (m, 2H), 6.85-6.84 (m, IH), 5.85-5.85 (m, IH), 5.54-5.23 (m, 2H), 4.06-3.63 (m, 4H), 3.29-3.24 (m, IH), 3.11-3.07 (m, IH), 290-2.76 (m, 2H), 2.44-2.29 (m, 3H), 2.00-1.74 (m, 2H), 1.67-1.64 (m, 3H).

Example 2.214

[1115] (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide : LC/MS RT: 7.30, m/z 482.201.

Example 2.215

[1116] (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4,5- difluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone : LC/MS RT: 7.08-7.45, m z 494.200.

Example 2.216

[1117] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone : m/z: M⁺: 494.200. Example 2.217

[1118] (R)-5-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-2,4-difluoro-N-methylbenzamide : m/z: M⁺: 482.201 . Example 2.218

[1119] (R)-4-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-5-fluoro-N-methylpicolinamide : (R)-4-(5-(2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-5-fluoro-N- methylpicolinamide. MS (ESI) RT 6.66, m/z: 465.204 [M+l]⁺.

Example 2.219

[1120] (R)-4-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-5-methoxy-N-methylpicolinamide : (R)-4-(5-(2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-5-methoxy- N-methylpicolinamide. MS (ESI) RT 6.57, m/z: 477.224 [M+l]⁺.

Example 2.220

[1121] (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide : LC/MS RT: 7.53, m/z 500.188.

Example 2.221

[1122] (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-4,5- difluorophenyl)((S)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone : LC/MS RT: 7.51, m z 512.189.

Example 2.222

[1123] (5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yi)-2,4- difluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyiToUdin-l-yl)methanone: m/z: M⁺:

494.200.

Example 3: Inhibition of Memapsin 2 Beta-Secretase Activity

Example 3.1

[1124] Potency of compounds were determined by measurement of their inhibition of memapsin 2 activity toward a fluorescent substrate. Kinetic inhibition experiments were performed using the procedure as described in Ermolieff, et al. (Biochemistry 39:12450- 12456 (2000), the teachings of which are incorporated hereby in their entirety). Briefly, assays were performed at pH 4, 37 °C, by pre-incubation of memapsin 2 enzyme with compound for 20 minutes. Activity measurements were initiated by addition of a fluorogenic substrate FS-2 (Bachem Americas, Torrance, CA) MCA-SEVNLDAEFK-DNP (SEQ ID NO.: 2). The substrate was derived from 10 amino acids of the human amyloid precursor protein (APP), with the Swedish variant amino acids at the beta-secretase cleavage site. The terminal amino acid was modified from arginine to lysine to facilitate derivatization with a functional group for detection by autofluorescence. The amino acid sequence of the "core" peptide of the substrate is SEVNLDAEFK (SEQ ID NO.: 3). The amino terminus was derivatized with (7-methoxycoumarin-4-yl)acetyl (MCA), and the epsilon amine of the lysine side chain of the terminal residue (K in sequence SEVNLDAEFK (SEQ ID NO.: 3)) was derivatized with 2,4-dinitrophenyl (DNP). Results are shown in Table 1 ("BACE1 Ki"). For example, the BACE1 Ki determined using this procedure for (7-(5-((R)-2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)chroman-5-yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin-l-yl)methanone is about 702 nM. In additional examples, 3'-(5-((R)-2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5'-(2-(5-methylfuran-2-yl)pyrrolidine-l-carbonyl)- [l,l'-biphenyl]-2-carbonitrile is about 1562 nM, 3'-(5-((R)-2-amino-l-phenylpropan-2-yl)- l,3,4-oxadiazol-2-yl)-5'-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)-[l,l'- biphenyl]-2-carbonitrile is about 201 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide is about 61 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyrazin-2-yl)benzamide is about 101 nM, (2-(5- ((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-(oxazol-2-yl)pyridin-4-yl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone fumarate is about 139 nM, (R)-3-(5-(2- amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4- yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide is about 25 nM, (2-(5-((R)-2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyridin-4-yl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone fumarate is about 124 nM, (R)-3-(5-(2- amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol- 2-yl)methyl)-5-(oxazol-2-yl)benzamide is about 29 nM, (R)-3-(5-(2-amino-l-phenylpropan- 2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2- yl)benzamide is about 30 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2- yl)-N-cyclopropyl-N-((2,5-dimethyloxazol-4-yl)methyl)-4-fluorobenzamide is about 18 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4- yl)methyl)-4,5-difluoro-N-methylbenzamide is about 63 nM, (3-(5-((R)-2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4- methylthiazol-2-yl)pyrrolidin-l-yl)methanone is about 101 nM, (R)-3-(5-(2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-((4-methylthiazol-2-yl)methyl)- 5-(oxazol-2-yl)benzamide is about 20 nM, (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone is about 63 nM, (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2- yl)-5-methylphenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone is about 438 nM, l-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)pyrrolidin-2-one is about 677 nM, and (3- (5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-methylphenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin-l-yl)methanone is about 473 nM.

Example 3.2

[1125] For measurement of memapsin 2 enzyme IC₅₀, assays were performed at pH 4.4, at room temperature, by pre-incubation of memapsin 2 enzyme with compound for 15 minutes. Fluorescence intensities were measured 60 minutes after addition of a fluorogenic substrate, MCA-SEVNLDAEFK-DNP (SEQ ID No:2) (M-2485, Bachem Americas, Torrance, CA). The values of IC₅₀ were calculated by SAS version 8.2.

Example 3.3

[1126] The values of IC₅₀ were measured as described in Example 3.2 except that calculation was conducted with Graphpad Prism version 5.

Example 3.4

[1127] BACE1 % inhibition was measured as described in Example 3.2, at 3μΜ inhibitor concentration.

TABLE 1: Compound Assay data.

BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki <400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++ >2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4- oxadiazol-2-yl)-5-(oxazol-2-

1-4 +++ +++ +++ yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4- oxadiazol-2-yl)-5-(oxazol-2-

1-5 +++ +++

yl)phenyl)((R)-2-(4- methyloxazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4- oxadiazol-2-yl)-5-

1-6 ++ ++

methylphenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-methyl-5-(5-((R)-2- (methylamino)- 1 -phenylpropan- 2-yl)-l,3,4-oxadiazol-2-

1-7 + N.I.

yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1-8 oxadiazol-2-yl)phenyl)((R)-2-(4- ++ ++

methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4- oxadiazol-2-yl)-5-(pyrazin-2-

1-9 +++ +++

yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

N-(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4-

++ +

10 methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)phenyl)-N- methylmethanesulfonamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ +++

11 (fluoromethyl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ ++

12 chlorophenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(pyrazin-2-

+++ +++

13 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)phenyl)((2R,4S)- ++ N.I.

14

4-f uoro-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+++ +++ ++ 15 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

l-(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- ++ ++

16

methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)phenyl)pyrrolidin-2-one

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ +++

17 (dimethylamino)phenyl)((R)-2-

(4-methylthiazol-2-yl)pyrrolidin- l-yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(4-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-6-

N.I.

18 (dimethylamino)pyridin-2- yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

++ ++

19 methoxyphenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

3'-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5'-((R)-2-(4- 1 1

20 methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)- [ 1 , 1 '-biphenyl] -2- carbonitrile

(7-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)chroman-5- ++ ++ +++ 21

yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(lH-pyrrol-l-

+++ ++

22 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-2-

+ N.I.

23 hydroxyphenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopropyl- +++ +++

24

N-((4-methylthiazol-2- yl)methyl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki <400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+++ +++

25 yl)phenyl)((R)-4,4-difluoro-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopropyl- +++ ++

26

N-((4-methylthiazol-2- yl)methyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-5-(N-

+++ N.I.

27 methylmethylsulfonamido)-N-

((4-methylthiazol-2- yl)methyl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+++ +++

28 yl)phenyl)((2R,4S)-4-fluoro-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopentyl-N- ++ N.I.

29

((4-methylthiazol-2- yl)methyl)benzamide

(4-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)pyridin-2-yl)((R)- ++ N.I.

30

2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - ( 1 -methyl- 1 H-

+++ +++

31 pyrazol-4-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - ( 1 H-imidazol-

++ ++

32 l-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-5-

+++ +++

33 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

++ ++

34 methylphenyl)((2R,4S)-4-fluoro- 2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)pyridin-3-yl)((R)- ++ N.I.

35

2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+++ +++

36 yl)phenyl)((R)-2-(4- (f uoromethyl)thiazol-2- yl)pyrrolidin- 1 -yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - ( 1 H-imidazol-

++ ++

37 2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)chroman-7- +++ +++

38

yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)oxazol-2-yl)-

1- 5-(oxazol-2-yl)phenyl)((R)-2-(4- ++ +++

39

methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(pyridin-2-

+++ +++

40 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

tert-butyl (2-(5-(3-(methyl((4- methylthiazol-2-

1- yl)methyl)carbamoyl)phenyl)- + +

41

1 ,3,4-oxadiazol-2-yl)- 1 - phenylpropan-2-yl)carbamate

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - ( 1 -methyl- 1 H-

+++ ++

42 pyrrol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopropyl-

+++ +++

43 N-((4-methylthiazol-2- yl)methyl)-5-(oxazol-2- yl)benzamide

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+++ 1

44 yl)phenyl)((2R,4S)-4-fluoro-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(pyrazin-2-

+++ +++

45 yl)phenyl)((2R,4S)-4-fluoro-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)phenyl)((R)-2-(4- ++ +

46

methylthiazol-2-yl)piperidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - (5 -methyl-

++ ++

47 l,3,4-oxadiazol-2-yl)phenyl)((R)- 2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-isopropyl-N- + N.I.

48

((4-methylthiazol-2- yl)methyl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)oxazol-2-yl)-

1- 5-(oxazol-2-yl)phenyl)((2R,4S)- ++ +++

49

4-f uoro-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((5- + N.I.

50

methyl- 1 ,2,4-oxadiazol-3- yl)methyl)benzamide

(2-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-6-

+++ +++

51 (dimethylamino)pyridin-4- yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

3-[5-(l-Amino-2- phenylcyclohexyl) -1,3,4-

1- oxadiazol-2-yl]-N-methyl-N-[(4-

52 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide

ethanedioate BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+ rel-3- { 5- [(1R,2R)- 1 - Amino-2- phenylcyclopropyl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-methyl-N- [(4-

+

53 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide 4- methylbenzenesulfonate

rel-3-{5-[(lR,2S)-l-Amino-2- phenylcyclopropyl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-methyl-N- [(4-

+

54 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide 4- methylbenzenesulfonate (1:1)

3-(5-(2-Amino-l-methoxy-3- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +

55

methylthiazol-2- yl)methyl)benzamide oxalate

(3-(5-(rel-(lS,2R)-l-Amino-2- phenylcyclobutyl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4-

+

56 methylthiazol-2- yl)methyl)benzamide)

hydrochloride

3-{5-[rel-(lR,2R)-l-Amino-2- phenylcyclobutyl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-methyl-N- [(4- +

57

methylthiazol-2- yl)methyl]benzamide

3-{5-[(4E)-2-Amino-l,5- diphenylpent-4-en-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-methyl-N- [(4-

+

58 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide

ethanedioate (1:1)

3-[5-(2-Amino-l,5- diphenylpentan-2- yl) - 1 , 3 ,4-

1- oxadiazol-2-yl] -N-methyl-N- [(4-

+

59 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide

ethanedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

3-[5-(2-Amino-l,3- diphenylpropan-2-yl)- 1 ,3 ,4-

1- oxadiazol-2-yl] -N-methyl-N- [(4-

+

60 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide

ethanedioate (1:1)

rel-3- { 5- [(1R,2R)- 1 - Amino-2- phenylcyclopentyl] - 1 ,3 ,4-

1- oxadiazol-2-yl } -N-methyl-N- [(4-

+

61 methyl- 1 ,3-thiazol-2- yl)methyl]benzamide

ethanedioate (1:1)

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -N-methyl- 5 - ++ +++

62

(oxazol-2-yl)-N-(pyrazin-2- ylmethyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((2- +++ +++

63

methylthiazol-4-yl)methyl)-5- (oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((2- +++ +++

64

methyloxazol-4-yl)methyl)-5- (oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +++ +++

65

methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((R)-l-(4- ++ +++

66

methylthiazol-2-yl)ethyl)-5- (oxazol-2-yl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(R)-3-(5-(2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +++ +++

67

methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((5- + ++

68

methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +++ +++

69

methyloxazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

70

dimethyloxazol-4-yl)methyl)-N- methyl-5-(oxazol-2-yl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+ N.I.

71 yl)phenyl)((R)-4-(4- methylthiazol-2-yl)oxazolidin-3- yl)methanone

(R)-3-(5-(2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

72

dimethyloxazol-4-yl)methyl)-N- methyl-5-(oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5-

+++ 1

73 dimethyloxazol-4-yl)methyl)-N- methyl-5-(pyrazin-2- yl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +++ +++

74

methylthiazol-2-yl)methyl)-5- (pyrazin-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((3- ++ +++

75

methyl- 1 ,2,4-oxadiazol-5- yl)methyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- 1 1

76 dimethyloxazol-4-yl)methyl)-N- methyl- 5 - (pyridin-2- yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-chloro-N-((2,5- +++ +++

77

dimethyloxazol-4-yl)methyl)-N- methylbenzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

+++ +++

78 chlorophenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

++ +++

79 chlorophenyl)((2R,4S)-4-fluoro- 2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-(tert-butyl)-N- ++ +++

80

((4-methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((4- ++ ++

81

methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+ N.I.

82 (fluoromethyl)phenyl)((2R,4S)-4- fluoro-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopropyl-

+++ +++

83 N-((4-methylthiazol-2- yl)methyl)-5-(pyrazin-2- yl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ +++

84 (dif uoromethyl)phenyl)((R)-2-

(4-methylthiazol-2-yl)pyrrolidin- l-yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclobutyl-N- +++ +++

85

((4-methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(l,3,4-

+++ N.I.

86 oxadiazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

5-(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4-

+++

87 methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)phenyl) -1,3,4- oxadiazol-2(3H)-one BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki <400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(l-

++ ++

88 fluoroethyl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

l-(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- +++ +

89

methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)phenyl)ethanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(lH-pyrazol-l-

+++ ++

90 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(isoxazol-5-

+ +++

91 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(l , 1 -

+++ ++

92 difluoroethyl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(isoxazol-3-

+++ +++

93 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(lH-pyrazol-3-

+++ +++

94 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- ++ ++

95

methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)benzonitrile

5-(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- 1 1

96 methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)phenyl)-3-methyl-l,3,4- oxadiazol-2(3H)-one

Ethyl 3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- +++ +++

97

methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)benzoate

(3-(5-((R)-2-amino-l- cyclohexylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)phenyl)((R)-2-(4- + +

98

methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- cyclohexylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

++ +++

99 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(thiazol-2-

+++ +++

100 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-5-((R)-

++ ++

101 2-(4-methylthiazol-2- yl)pyrrolidine-l- carbonyl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- ++ ++

102

methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)benzamide

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N,N-dimethyl-5-

+ N.I.

103 ((R)-2-(4-methylthiazol-2- yl)pyrrolidine-l- carbonyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +++ +++

104

methylthiazol-2-yl)methyl)-5- (thiazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-(2-

+++ +++

105 fluoroethyl)-N-((4-methylthiazol-

2-yl)methyl)-5-(oxazol-2- yl)benzamide

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-ethyl-5-((R)-2-

++ N.I.

106 (4-methylthiazol-2- yl)pyrrolidine-l- carbonyl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(thiazol-2-

+++ 1

107 yl)phenyl)((2R,4S)-4-fluoro-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(thiazol-2-

+++ 1

108 yl)phenyl)((2R,4S)-4-fluoro-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-((R)-2-(4- +++ N.I.

109

methylthiazol-2-yl)pyrrolidine- 1 - carbonyl)benzoic acid

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

++ +

110 hydroxyphenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((S)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+ +

111 yl)phenyl)((S)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

112 yl)phenyl)((S)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((S)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(oxazol-2-

+++ N.I.

113 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

114 (dimethylamino)-N-methyl-N-

((4-methylthiazol-2- yl)methyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(N- _ +| + |_ +

115 methylmethylsulfonamido)-N-

((4-methylthiazol-2- yl)methyl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

116

dimethyloxazol-4-yl)methyl)-4- methoxy-N-methylbenzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

+++ +++

117 methoxyphenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

++ ++

118 methoxyphenyl)((2R,4S)-4- fluoro-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-5-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

119

dimethyloxazol-4-yl)methyl)-6- methoxy-N-methylnicotinamide

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-6-

++ +++

120 methoxypyridin-3-yl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-6-

++ ++

121 methoxypyridin-3-yl)((2R,4S)-4- fluoro-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5-

++ +++

122 dimethyloxazol-4-yl)methyl)-N- methyl-4-

(trifluoromethoxy)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki <400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - ( 1 -methyl- 1 H-

+ ++

123 imidazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)- [ 1 , 1 '-biphenyl] -3- +++ +++

124

yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-3 '-methoxy- [ 1 , 1 '-

+++ +++

125 biphenyl] -3-yl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-2'-methoxy- [ 1 , 1 '-

+++ +++

126 biphenyl] -3-yl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(furan-2-

+++ +++

127 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ +++

128 iodophenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-ethyl-N-((4- +++ +++

129

methylthiazol-2-yl)methyl)-5- (oxazol-2-yl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ +++

130 (trifluoromethyl)phenyl)((R)-2-

(4-methylthiazol-2-yl)pyrrolidin- l-yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ ++

131 nitrophenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - (furan- 3 -

+++ ++

132 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - (pyrimidin- 5 -

++ +

133 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -5 - (pyridin- 3 -

++ +++

134 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-5-(N- _| | Γ_ τ

135 methylsulfamoyl)-N-((4- methylthiazol-2- yl)methyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-methyl-N-((4- +++ +++

136

methylthiazol-2-yl)methyl)-5- (pyridin-2-yl)benzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l-(2- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(pyrazin-2-

++ ++

137 yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(2-

138 methylthiazol-4-yl)phenyl)((R)-2-

(4-methylthiazol-2-yl)pyrrolidin- l-yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-(4,5-

139 dimethylthiazol-2-yl)phenyl)((R)- 2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((3- +++ +++

140

fluoropyridin-2-yl)methyl)-N- methyl-5-(oxazol-2-yl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl) -N-methyl- 5 -

++ +

141 (oxazol-2-yl)-N-((4- (trifluoromethyl)thiazol-2- yl)methyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-fluoro-N- +++ +++

142

methyl-N-((4-methylthiazol-2- yl)methyl)benzamide

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

143

dimethyloxazol-4-yl)methyl)-4- fluoro-N-methylbenzamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

+++ +++

144 fluorophenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

++

145 fluorophenyl)((R)-2-(4- methyloxazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

++ ++

146 fluorophenyl)((2R,4S)-4-fluoro- 2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopropyl- +++ +++

147

N-((2,5-dimethyloxazol-4- yl)methyl)-4-fluorobenzamide

(2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-

1- cyclopropylpyridin-4-yl)[(2R)-2- +++ +++ +++

148

(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

2-(6-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

+++ +++ +++

149 yl)pyrrolidin-l- yl]carbonyl}pyridin-2- yl)benzonitrile (2E)-but-2- enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

[2-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 ,3-oxazol-2-

1- yl)pyridin-4-yl] [(2R)-2-(4- +++ +++ +++

150

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

(2-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-

1- methoxypyridin-4-yl)[(2R)-2-(4- +++ +++ +++

151

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

N-(6- { 5- [(2R)-2- Amino- 1 - phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

++ ++ +++

152 yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-N- methylmethanesulfonamide (2E)- but-2-enedioate (1:1)

N-(4- { 5- [(2R)-2- Amino- 1 - phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-6-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

++ ++ +++

153 yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-N- methylmethanesulfonamide (2E)- but-2-enedioate (1:1)

(4-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-

1- methoxypyridin-2-yl)[(2R)-2-(4- ++ ++ +++

154

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

1- yl)pyridin-4-yl][(2R)-2-(4-ethyl- ++ ++ +++

155

1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]methanone (2E)-but-2- enedioate (1:1)

1- yl)pyridin-4-yl] [(2R)-2-(4- ++ ++

156

cyclopropyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

1- yl)pyridin-4-yl] { (2R)-2-[4- ++ ++

157

(methoxymethyl) -1,3 -thiazol-2- yl]pyrrolidin- 1 -yl } methanone

(2E)-but-2-enedioate (1:1)

(6-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl}-2,3'-bipyridin-4-

+++ +++ +++

158 yl)[(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

(6-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -2,4'-bipyridin-4-

+++ +++ +++

159 yl)[(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

[2-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-6-(pyrimidin-5-

1- yl)pyridin-4-yl] [(2R)-2-(4- +++ +++ +++

160

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki <400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ

Compound Structure

# 400-2000 '+++ '4-4-4- 500-2000 nM '++ 400-2000 1-5 μΜ nM '++ >2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(2-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-methylpyridin-

1- 4-yl)[(2R)-2-(4-methyl- 1,3- 161

thiazol-2-yl)pyrrolidin- 1 - yljmethanone (2E)-but-2- enedioate (1:1)

[2-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 , 1 -dioxido-

1- 1 ,2-thiazolidin-2-yl)pyridin-4- +4 +4 +4

162

yl][(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

N-(6- { 5- [(2R)-2- Amino- 1 - phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4- 1- methyl- l,3-thiazol-2-

4- 4- 163 yl)pyrrolidin-l- yl]carbonyl}pyridin-2- yl)methanesulfonamide (2E)-but- 2-enedioate (1:1)

(4-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-

1- methoxypyridin-2-yl)[(2R)-2- 4- 4- 164

(4,5-dimethyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

[4-{5-[(2R)-2-Amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 ,3-oxazol-2-

1- yl)pyridin-2-yl] [(2R)-2-(4- -4-4 -4-4 4-4-4

165

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedoate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki <400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++ >2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+ l-(6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

+++ +++ +++

166 yl)pyrrolidin-l- yl]carbonyl}pyridin-2- yl)pyrrolidin-2-one (2E)-but-2- enedioate (1:1)

3-(6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

+++ +++ +++

167 yl)pyrrolidin-l- yl]carbonyl }pyridin-2-yl)- 1,3- oxazolidin-2-one (2E)-but-2- enedioate (1:1)

1- (6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

++ ++ +++

168 yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-5- methylpyrrolidin-2-one (2E)-but-

2- enedioate (1:1)

l-(6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

++ ++ ++

169 yl)pyrrolidin-l- yl]carbonyl}pyridin-2- yl)piperidin-2-one (2E)-but-2- enedioate (1:1)

N-(6- { 5- [(2R)-2-amino- 1 - phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

++ ++ +++

170 yl)pyrrolidin-l- yl]carbonyl}pyridin-2-yl)-N- methylacetamide (2E)-but-2- enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+ l-(4-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-6-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2-

++ ++ +++

171 yl)pyrrolidin-l- yl]carbonyl}pyridin-2- yl)pyrrolidin-2-one (2E)-but-2- enedioate (1:1)

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 H- 1 ,2,4-

1- triazol- 1 -yl)pyridin-4-yl] [(2R)-2- ++ ++ +++

172

(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 H-imidazol-

1- l-yl)pyridin-4-yl] [(2R)-2-(4- +++ +++ +++

173

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 H-pyrazol- 1 -

1- yl)pyridin-4-yl] [(2R)-2-(4- +++ +++ +++

174

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-6-(2H- 1,2,3-

1- triazol-2-yl)pyridin-4-yl] [(2R)-2- +++ +++ +++

175

(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 H- 1 ,2,3-

1- triazol- 1 -yl)pyridin-4-yl] [(2R)-2- +++ +++ +++

176

(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-( 1 -methyl- 1 H-

1- pyrazol-4-yl)pyridin-4-yl][(2R)- +++ +++ +++

177

2-(4-methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

1- pyrazol-5-yl)pyridin-4-yl][(2R)- +++ ++

178

2-(4-methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -N- [(4-bromo-

1- l,3-thiazol-2-yl)methyl]-N- +++ +++

179

methyl-6-(l,3-oxazol-2- yl)isonicotinamide (2E)-but-2- enedioate (1:1)

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-methyl-N- [(6- 180 methylpyridin-3-yl)methyl] -6- (l,3-oxazol-2-yl)isonicotinamide

(2E)-but-2-enedioate (1:1)

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N- [ 1 -( 1 -methyl-

+ +

181 lH-pyrazol-3-yl)ethyl]-6-(l,3- oxazol-2-yl)isonicotinamide (2E)- but-2-enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-methyl-N- [(6-

++ ++

182 methylpyridin-2-yl)methyl] -6- (l,3-oxazol-2-yl)isonicotinamide

(2E)-but-2-enedioate (1:1)

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -N-methyl-N- [( 1 -

1- methyl- lH-pyrazol-4-yl)methyl]- + +

183

6-(l,3-oxazol-2- yl)isonicotinamide (2E)-but-2- enedioate (1:1)

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -N- [( 1 ,5-

1- dimethyl- lH-pyrazol-4- 184

yl)methyl]-N-methyl-6-(l,3- oxazol-2-yl)isonicotinamide (2E)- but-2-enedioate (1:1)

2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -N- [( 1 ,3-

1- dimethyl- lH-pyrazol-5- + +

185

(2-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-6-(l -methyl- 1H-

+++ +++ ++

186 pyrazol-3-yl)pyridin-4-yl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin- l-yl)methanone

(2-amino-6- { 5- [(2R)-2-amino- 1 - phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl}pyridin-4-

++ ++

187 yl)[(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

1- methyl- lH-pyrazol-3-yl)methyl]- ++ ++

188

6-(l,3-oxazol-2- yl)isonicotinamide (2E)-but-2- enedioate (1:1)

(6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}pyridin-2-

1- yl)[(2R)-2-(4-methyl-l,3-thiazol- + +

189

2-yl)pyrrolidin- 1 -yl] methanone 2- hydroxypropane- 1 ,2,3- tricarboxylate (1:1)

(2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}pyridin-4-

1- yl)[(2R)-2-(4-methyl-l,3-thiazol- ++ ++ +++

190

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-(pyrrolidin- 1 -

1- yl)pyridin-4-yl] [(2R)-2-(4- +++ +++ +++

191

methyl- 1 ,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } - 1 -methyl-4-

1-

{ [(2R)-2-(4-methyl- 1 ,3-thiazol-2- +++ +++ +++

192

yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

(2E)-but-2-enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-

1-

(dif uoromethoxy)pyridin-4- ++ ++ +++

193

yl][(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

4-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } - 1 -methyl-6-

1-

{ [(2R)-2-(4-methyl- 1 ,3-thiazol-2- ++

194

yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

(2E)-but-2-enedioate (1:1)

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } - 1 -

1- (cyclopropylmethyl)-4-{ [(2R)-2-

+++

195 (4-methyl-l,3-thiazol-2- yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

(2E)-but-2-enedioate (1:1)

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } - 1 -ethyl-4- { [(2R)-

1- 2-(4-methyl- 1 ,3-thiazol-2- + +

196

yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

(2E)-but-2-enedioate (1:1)

(2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-ethoxypyridin-

1- 4-yl)[(2R)-2-(4-methyl- 1,3- +++ +++ +++

197

thiazol-2-yl)pyrrolidin- 1 - yl]methanone (2E)-but-2- enedioate (1:1) BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6- [(2-

1- methoxyethyl)amino]pyridin-4- ++ ++ +++

198

yl)[(2R)-2-(4-methyl-l,3-thiazol- 2-yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

(2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6- [(2-

1- methoxyethyl)(methyl)amino]pyr

+++ +++ +++

199 idin-4-yl)[(2R)-2-(4-methyl-l,3- thiazol-2-yl)pyrrolidin- 1 - yl]methanone (2E)-but-2- enedioate (1:1)

[2-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -6-

1-

(ethylamino)pyridin-4-yl][(2R)-2- +++ +++ +++

200

(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yl] methanone

(2E)-but-2-enedioate (1:1)

3-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } - 1 -methyl-5-

1-

{ [(2R)-2-(4-methyl- 1 ,3-thiazol-2- ++

201

yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

(2E)-but-2-enedioate (1:1)

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl}-4-{ [(2R)-2-(4-

1- methyl- 1 ,3-thiazol-2- ++ ++

202

yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

(2E)-but-2-enedioate (1:1)

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N, 1 -dimethyl-2- &

203

oxo-N-(pyridin-3-ylmethyl)- 1 ,2- dihydropyridine-4-carboxamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N, 1 -dimethyl-N-

&

204 [(6-methylpyridin-2-yl)methyl] - 2-oxo- 1 ,2-dihydropyridine-4- carboxamide

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-butyl- 1 -

&

205 methyl-2-oxo-N-(pyridin-4- ylmethyl)- 1 ,2-dihydropyridine-4- carboxamide

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } - 1 -methyl-4- { [2-

&&

206 (3-methyl-l,2,4-oxadiazol-5- yl)pyrrolidin-l- yl]carbonyl}pyridin-2(lH)-one

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N-butyl- 1 -

&&

207 methyl-2-oxo-N-(pyridin-3- ylmethyl)- 1 ,2-dihydropyridine-4- carboxamide

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N, 1 -dimethyl-2-

&&

208 oxo-N-(lH-pyrazol-5-ylmethyl)- 1 ,2-dihydropyridine-4- carboxamide

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4-

1- oxadiazol-2-yl } -N, 1 -dimethyl-2- &&

209

oxo-N- [ 1 -(2-thienyl)ethyl] - 1 ,2- dihydropyridine-4-carboxamide BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

6-{5-[(2R)-2-amino-l- phenylpropan-2-yl] - 1 ,3,4- oxadiazol-2-yl } -N- [(2,5- +++

1- dimethyl- 1 ,3-oxazol-4-

210

yl)methyl] -N, 1 -dimethyl-2-oxo- &&&

1 ,2-dihydropyridine-4- carboxamide

(R)-3-(5-(2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-cyclopropyl-

+++ +++

211 N-((4-methylthiazol-2- yl)methyl)-5-(oxazol-2- yl)benzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ +++

212 bromophenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 - yl)methanone

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-5-

+++ N.I.

213 chlorophenyl)((2R,4S)-4-fluoro- 2-(4-methylthiazol-2- yl)pyrrolidin- 1 -yl)methanone

(R)-3-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

214

dimethyloxazol-4-yl)methyl)-4,5- difluoro-N-methylbenzamide

(3-(5-((R)-2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4,5-

+++ ++

215 difluorophenyl)((R)-2-(4- methyloxazol-2-yl)pyrrolidin- 1 - yl)methanone BACE1 BACE1 BACE1 Cathepsin

Ki * Enzyme Cellular D Ki

<400 nM IC₅₀ ** IC₅₀ <500 nM

Ref '+++ <400 nM <1 μΜ '+++

Compound Structure

# 400-2000 '+++ '+++ 500-2000 nM '++ 400-2000 1-5 μΜ nM '++

>2000 nM '++ '++ >2000nM nM '+ >2000nM '+ >5 μΜ '+ '+

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4-

+++ +++

216 fluorophenyl)((R)-2-(4- methyloxazol-2-yl)pyrrolidin- 1 - yl)methanone

(R)-5-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

217

dimethyloxazol-4-yl)methyl)-2,4- difluoro-N-methylbenzamide

(R)-4-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ ++

218

dimethyloxazol-4-yl)methyl)-5- fluoro-N-methylpicolinamide

(R)-4-(5-(2-amino-l- phenylpropan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

219

dimethyloxazol-4-yl)methyl)-5- methoxy-N-methylpicolinamide

(R)-3-(5-(2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-N-((2,5- +++ +++

220

dimethyloxazol-4-yl)methyl)-4,5- difluoro-N-methylbenzamide

(3-(5-((R)-2-amino-l-(4- fluorophenyl)propan-2-yl)- 1 ,3,4-

1- oxadiazol-2-yl)-4,5-

+++ ++

221 difluorophenyl)((S)-2-(4- methyloxazol-2-yl)pyrrolidin- 1 - yl)methanone

(5-(5-((R)-2-amino-l- phenylpropan-2- yl)- 1 ,3,4-

1- oxadiazol-2-yl)-2,4-

++ ++

222 difluorophen yl )( (R)-2-(4- methyloxazol-2-yl)pyrrolidin-l- yl)methanone

N.I. = no inhibition of Αβ observed using the cellular assay described in Example 5. * measured using assay conditions described in Example 3.1;

** Entries with plusses (+) without underlining were measured using assay conditions described in Example 3.2. Entries with plusses (+) and with underlining were measured using assay conditions described in Example 3.3. Entries with ampersands (&) were measuring using assay conditions described in Example 3.4, where & = % inhibition from 26-50%, && = % inhibition from 51-75%, and &&& = % inhibition from 76-100+%.

TABLE 2: Compound Assay data - Supplemental Compounds.

BACE1

BACE1 BACE1 Cathepsi

Enzyme

Ki Cellular n D Ki

<400 nM IC₅₀ ** <500 nM

<400 nM IC₅₀

Ref +++ <1 μΜ +++

Compound Structure '+++

# 400-2000 +++ 500-2000

400-2000

nM ++ 1-5 μΜ nM ++ nM '++

>2000 ++ >2000

>2000nM

nM + >5 μΜ + nM +

'+

(R)-2-(5-(2-amino-l-phenylpropan-

2-yl) - 1 ,3,4-oxadiazol-2-yl)-N-

2-7 methyl-N-(3-methylbenzyl)-6- ++ ++

(oxazol-2-yl)isonicotinamide

fumarate

N.I. = no inhibition of Αβ observed using the cellular assay described in Example 5.

** Entries with plusses (+) and with underlining were measured using assay conditions described in Example 3.3.

Example 4: Inhibition of Memapsin 1 Beta-Secretase Activity and Cathepsin D Activity

Inhibition of Memapsin 1 Activity

[1128] Recombinant memapsin 1 (R&D Systems) is assayed for activity and inhibition by compounds using the same procedure outlined in Example 3 above.

Inhibition of Cathepsin D Activity

[1129] A fluorogenic FRET peptide substrate for cathepsin D acvtivity (Mca-Gly-Lys-Pro-

Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2), catalog number M-2455, Bachem) (SEQ

ID NO.: 1) was dissolved at 75 μΜ in DMSO. Cathepsin D protein was obtained from rat liver homogenates. Briefly, rat livers were homogenized in PBS. The extract was acidified to pH 4 with 2 M sodium acetate, pH 4 and allowed to incubate at 4 °C overnight. Following addition of Triton X-100 to a final concentration of 1%, the extract was centrifuged at 25,000 xg and stirred overnight with pepstatin A immobilized on agarose beads (Sigma- Aldrich).

Following wash with sodium acetate/1% Triton X-100 pH 4, pepstatin-A-immobilized cathepsin D was eluted with an addition of 0.1 M Tris-HCl pH 8.5. Eluent was immediately adjusted to pH 5 with 2 M sodium acetate. Assay of cathepsin D activity vs. cathepsin D substrate was performed at pH 4, 37 °C, using the same assay procedure for Memapsin 2 activity and Ki outlined in Example 3 above, in presence and absence of compound. For example, the cathepsin D Ki determined using this procedure for (7-(5-((R)-2-amino-l- phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)chroman-5-yl)((R)-2-(4-methylthiazol-2- yl)pyrrolidin-l-yl)methanone is about 411 nM. Example 5: Cellular Αβ IC50 Determinations

Example 5.1

[1130] The potency of compounds against intracellular memapsin 2 activity was determined in a cellular assay of Αβ production. Compounds that successfully penetrate the cell membrane demonstrated their ability to inhibit intracellular memapsin 2 activity by blocking the production of Αβ detected following secretion into the culture medium. Human neuroblastoma cell line SK-N-BE(2) (ATCC number CRL-2271) was seeded in 96- well plates at 10,000 cells/well in complete medium [MEM+F12 (1:1 ratio) + 1% pen/strep + 10% fetal bovine serum] and incubated at 37 oC/5% C0₂ for 24h. Compounds are diluted to 50 μΜ in DMSO, then further diluted to a final concentration range of between 1 μΜ - 0.00002 μΜ into serum-limited culture medium [MEM+F12 (1:1 ratio) + 1% pen/strep + 5% fetal bovine serum] at a final DMSO concentration of 0.2%. Following a 24 hour incubation at 37 °C/5% C0₂, a portion (100 μΐ) of conditioned media was removed for analysis of Αβ₄₀ using a sandwich ELISA (Invitrogen). The amount of Αβ₄ο over the range of concentration of compounds, expressed relative to control incubations without compound, was fit to a 4- paramter IC50 model. Results are provided in Table 1 above ("Cellular ICso")- F°^r example, the cellular Αβ ICso determined using this procedure for (7-(5-((R)-2-amino-l-phenylpropan- 2-yl)-l,3,4-oxadiazol-2-yl)chroman-5-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone is about 1.5 μΜ. In additional examples, 3'-(5-((R)-2-amino-l-phenylpropan- 2-yl)-l,3,4-oxadiazol-2-yl)-5'-(2-(5-methylfuran-2-yl)pyrrolidine-l-carbonyl)-[l,l'- biphenyl]-2-carbonitrile showed no inhibition, 3'-(5-((R)-2-amino-l-phenylpropan-2-yl)- l,3,4-oxadiazol-2-yl)-5'-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)-[l,l'- biphenyl]-2-carbonitrile is about 432 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4- oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide is about 23 nM, (2-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-(oxazol-2- yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone fumarate is about 75 nM, (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide is about 40 nM, (2-(5- ((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-(l-methyl-lH-pyrazol-4- yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone fumarate is about 90 nM, (R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide is about 50 nM, (R)-3-(5-(2- amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2- yl)methyl)-5-(oxazol-2-yl)benzamide is about 56 nM, (R)-3-(5-(2-amino-l-phenylpropan-2- yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-((2,5-dimethyloxazol-4-yl)methyl)-4- fluorobenzamide is about 20 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol- 2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide is about 78 nM, (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone is about 21 nM, (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide is about 22 nM, and (3-(5-((R)-2- amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin-l-yl)methanone is about 30 nM.

Example 5.2

[1131] The potency of compounds against BACE1 activity was determined in a cellular assay of Abeta production. Human SK-N-BE(2) neuroblastoma cells were plated at 96,000 οεΙΙβΛνεΙΙ/ΙΟΟμΙ. in 96-well plates in RPMI1640/10%FBS/penicilin-strepromycin and cultured for 24 hours at 37°C, 5% C0₂. Test compounds were dissolved and diluted into Me₂SO and further diluted into RPMI1640 /5%FBS /penicilin-strepromycin (yielding a final Me₂SO concentration of 0.5%). The culture media in 96-well plates were replaced by 125 μΐ ννεΐΐ of the media containing test compounds. After incubation for 6 hours at 37°C, 5% C0₂, 50 \L media were transferred into a fresh 96-well plate and used for Abeta40 assay by an ELISA kit (#27718, Immuno-Biological Laboratories, Japan). Cell viability was measured after removal of 5Q \L media for the Abeta assay by CellTiter-Glo™ Luminescent Cell Viability Assay (#7571, Promega). CellTiter-Glo Substrate was dissolved into CellTiter-Glo Buffer and added to the plates in 75μίΛνε11. After 2 minutes shaking the plates, the whole sample was transferred into a white 96-well plate and luminescence was measured for ATP quantification as the cell viability. Abeta concentration measured by ELISA was normalized by the viability of the corresponding cells.

Example 6: Determination of CYP3A4 Inhibition

[1132] To evaluate the drug-drug interaction potential for compounds, the potency to inhibit the major metabolic cytochrome CYP450 isoform 3A4 is assessed. The inhibition constant K_; is determined for inhibition of the metabolism of midazolam, a CYP3A4 substrate. Assay Procedure

[1133] CYP3A4 Kj assays are performed following a recently published protocol with slight modifications (Di, L., Kerns, E.H., Li, S.Q., and Carter, G.T. (2007) Comparison of cytochrome P450 inhibition assays for drug discovery using human liver microsomes with LC-MS, rhCYP450 isozymes with fluorescence, and double cocktail with LC-MS.

International Journal of Pharmaceutics 335: 1-11). The P450 inhibition assay is performed in 96- well plates at 37.2 °C in a shaking incubator. The compounds are diluted from 5 mM stocks in 100% DMSO and incubated at seven final concentrations from 0.078 to 10 μΜ (0.1% DMSO in each final incubation), with human liver microsomes (HLM) at a final protein concentration of 0.1 mg/mL protein and a substrate (midazolam) concentration ranging from 1.25 to 10 mM.

[1134] The assay is standardized for both phosphate buffer (100 mM, pH 7.4) and the NADPH regenerating system (MgCl₂, 3.3 mM; G6P, 3.3 mM; G6PD, 1 U/ml; NADP+, 1.3 mM). Eight replicate control samples (0.1% DMSO, no compound) are prepared. Assays (200 L) are set up by mixing HLM+substrate stock, 10 mL of test article in 2% DMSO, and the substrate before initiating the reaction with the addition of the regenerating system mixture. Reactions are quenched following incubation for 20, 30 and 40 minutes as described following.

Reaction Quench and MS-Prep

[1135] After incubation for the specified time in a humidified shaking incubator, 20 mL of the reaction mixture is removed and the reactions are terminated by adding 200 μΐ_^ of cold acetonitrile. Samples are centrifuged at 1000 xg for 15 minutes in Solvinert filter plate. The receptor plate is dried via speed vacuum at 40 °C. The sample is reconstituted with a reconstitution buffer composed of 10% acetonitrile, 10% DMSO, 90% H20 with an internal standard added at a concentration of 100 ng/ml. MS-Analysis is completed using LC-MS/MS. Formation of l'-hydroxymidazolam is measured by monitoring a specific SRM (342>203) transition for the CYP3A4 metabolite.

Determination ofKi

[1136] Data are expressed as the quantity of midazolam metabolite relative to control incubations. Initial velocities are obtained by multiplying the relative quantity by the initial substrate concentration and dividing by the incubation duration. Data are transformed to inverse of initial velocity and expressed vs. inhibitor concentration [I] for determination of Kj by the Dixon method (Dixon, M. (1953) Biochemical Journal 55: 170-171) using where intercept is determined at multiple substrate concentrations.

Example 7: In Vivo Tests

Example 7.1 Abeta 40 reduction in rats

Formulation

[1137] Test compounds were prepared in a vehicle of 35% HPpCD in H₂0. The test compound was formulated the same day as oral dosing. Dose and concentration were based on the free base equivalent. Sonication was used where required to facilitate the formulation.

Test species

[1138] Male Sprague-Dawley rats (200-400 grams) were obtained from Taconic Farms (Hudson, NY) and were given approximately one week of acclimation. Prior to oral dosing, animals were fasted overnight; and food returned 2 hours post administration. Water was made available ad libitum throughout the study. Animals were visually inspected for health before being included into the study group, and were randomly assigned to the treatment and control groups to achieve similar group mean body weights. Dosing was performed in the morning. The dosing solution (dose volume < 10 ml/kg) was administered directly into the stomach using a 3-inch metallic rodent gavage needle. Control animals received oral administration of equivalent volume of the vehicle.

Sampling methods

[1139] Blood samples (volume -150 μΐ) were collected from the saphenous vein.

Alternatively, blood was sampled terminally by cardiocentesis (see Terminal Procedures below). Blood samples were collected into lithium-heparin tubes and placed on wet ice. Plasma was separated by centrifugation at 6,000 rpm (3,300 rcf) for 10 min at 4 °C and subsequently stored at -70 °C.

Terminal Procedures

[1140] At a fixed time post-dose (e.g., 3 h), animals were euthanized with excess of isoflurane. Blood was collected by cardiocentesis. CSF was carefully withdrawn from the cisterna magna using a 29 gauge needle after a quick dissection to expose the atlanto- occipital membrane. The CSF samples were centrifuged at 6000 rpm (3,300 rcf) for 10 min to confirm free of blood contamination and stored at -70 °C. Immediately following the CSF collection, brain hemispheres were harvested, dissected into segments (cortex, hippocampus, cerebellum), snap frozen in liquid nitrogen, and subsequently stored at -70 °C.

Extraction of Brain Abeta [1141] Fragments of brain hemispheres (-100 mg) or hippocampus (from 1 hemisphere) were weighed while frozen. A 10-fold volume (w:v) of 0.2% diethylamine (DEA) containing 50 mM NaCl (pH 10) was added, followed by a 100-fold dilution (v:v) of Protease Inhibitor Cocktail 1 (containing AEBSF, aprotinin, E-64 protease inhibitor, EDTA, and leupeptin; catalog number 539131, Calbiochem). Brains were homogenized by sonication for 35 seconds on ice (level 10 of XL-2000 Microson cell disruptor) in microcentrifuge tube.

Resulting homogenates were centrifuged at 14,000 xg for 30 min in a refrigerated benchtop centrifuge at 4 °C. Supernatants were collected and stored at -70 °C.

Determination ofAbeta

[1142] Abeta40 in brain homogenates, plasma, and CSF were analyzed by ELISA

(Human/Rat Abeta40 ELISA II, catalog number 294-64701, WAKO Chemicals, Inc., USA). Amount of Abeta40 reduction was determined by obtaining the mean concentration of Abeta40 from animals treated with test article divided by the mean Abeta40 from animals receiving vehicle alone (control group).

Example 7.2 Cognitive function in mice

Animals:

[1143] Tg2576 mice, hemizygous transgenic mice overexpressing human mutant APP (K670N/M671L) (Hsiao K, et al. Correlative memory deficits, Ab elevation, and amyloid plaques in transgenic mice. Science 1996;274:99-102) bred to normal C57BL6/SJL mice at the Charles River Japan (Atsugi, Japan). Studies were performed in Japan (including Tsukuba, Japan) using female Tg2576 mice and age-matched wild type (Wt) littermates. The mice were genotyped by PCR using DNA from tails.

Drug treatment:

[1144] A compound of the formula (I) was dissolved in distilled water and administered at a volume of 10 ml/kg orally. The compound of the formula (I) was administered 3 hours before the Y-maze or Morris water maze task in 6-month-old Tg2576.

Y-maze test (YM):

[1145] Working memory performance was examined by recording spontaneous alteration behavior in Y-maze test. Mice were placed at the end of one arm and the number of arm entries and alterations were counted for 8 minutes. Alteration was defined as entries into all three arms on consecutive occasions. Alteration rate (%) was calculated as follows:

Alteration rate (%) = (Alterations / Total entries - 2) x 100

Morris water maze task (MWM): [1146] Spatial memory was tested with the Morris water maze task, which consisted of three parts: visible platform training (day 1), hidden platform training (days 2-4), and probe trial (day 4). A circular pool (100 cm in diameter) was filled with opaque water at a temperature of 21 + 1°C, and a clear acrylic platform (9 cm in diameter) submerged 1.5 cm below the surface of the water was placed in the pool. The escape platform was kept in a constant position in the center of one of the four quadrants of the pool. During the visible platform training, the platform location was indicated by a marker rising above the water. In the first part of the test (visible), the ability of the mice to locate a visible platform was tested to exclude differences in vision and motivation with 4 trials. In the second part of the test (hidden), mice were trained to locate a hidden platform, each consisting of three consecutive trials (of 1 minute each) (designated H1-H3). When the mice found the platform, they were allowed to remain on it for 30 seconds. If the mice did not find the platform within 60 seconds, they were removed from the water and then placed on the platform for 30 seconds. In the third part of the test (probe), we examined whether the mice spent more time searching in the quadrant that used to contain the platform (target quadrant) than in the other quadrants of the pool (the platform was removed). This test was performed immediately after H6 and gave a putative measure for retention of spatial memory. Escape latency (the time to find the hidden platform) and time spent swimming in the target quadrant were recorded for each trial. The cumulative latencies of 3 days hidden platform trials were calculated in each treatment group.

Claims

1. A compound of the formula (I):

wherein

R 1 is A1 -L1 - or taken together with R 2 and the nitrogen to which they are

A¹ is an optionally substituted heteroaryl;

alkylene;

A is an optionally substituted moiety selected from cycloalkylene,

heterocycloalkylene, arylene and heteroarylene;

X 1 and X 2 are independently N or CH;

R³ is hydrogen, -N(R⁸)R⁹, -S(0)₂Rⁿ, -C(0)R¹², or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; R⁵ is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;

R^7A is an optionally substituted moiety selected from alkyl, cycloalkyl,

SCO^R 1¹1¹, -C(0)R 1^{^}2, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR¹⁰, -alkyl-N(R⁸)R⁹, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;

L⁴ is a bond or an optionally substituted alkylene;

8 13 14

R° is independently hydrogen, -C(0)R , -S(0)₂R , or an optionally

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and hetero aralkyl;

provided that when R³ and R⁵ are both hydrogen, one of R^7A and R^7B iS methyl and the other is benzyl, each X 1 and X2 is N, A 2 is 5-substituted-l,3- phenylene and R 1 is taken together with R 2 and the nitrogen to which they are attached to form a 5-membered heterocycloalkyl ring, the 5-membered heterocycloalkyl ring formed by taking R 1 together with R 2 and the nitrogen to which they are attached is a moiety other than a 2-substituted-pyrrolidinyl substituted with 5-chlorofuran-2-yl, 5-methylfuran-2-yl, 3-pyridyl or 5-bromo- 3-pyridyl;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein A¹ is an optionally substituted 5 to 7 membered heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 2, wherein A¹ is an optionally substituted 5-membered

heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3, wherein A¹ is an optionally substituted 5-membered

heteroaryl comprising at least one ring nitrogen; or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of any one of claim 1 or 2, wherein A¹ is an optionally substituted moiety selected form the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thiophenyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl,

benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, pyrazinyl, pyrrolinyl, indolyl, and benzodiazepinyl; or a

pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 5, wherein A is an optionally substituted moiety selected from the group consisting of thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiophenyl, pyridyl, pyrimidyl, oxadiazolyl, and pyranyl; or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of claim 5, wherein A¹ is an optionally substituted moiety selected from the group consisting thiazolyl, oxadiazolyl, and oxazolyl; or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 5, wherein A¹ is an optionally substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of claim 5, wherein A¹ is an optionally substituted oxazolyl; or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 5, wherein A¹ is an optionally substituted oxadiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 5, wherein A¹ is an optionally substituted imidazolyl; or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 5, wherein A¹ is an optionally substituted pyrazolyl; or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of claim 5, wherein A¹ is an optionally substituted isoxazolyl; or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 5, wherein A¹ is an optionally substituted thiophenyl; or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 5, wherein A¹ is an optionally substituted pyridyl; or a

pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 5, wherein A¹ is an optionally substituted pyrazinyl; or a pharmaceutically acceptable salt or solvate thereof.

17. The compound of claim 5, wherein A¹ is an optionally substituted pyrimidyl; or a pharmaceutically acceptable salt or solvate thereof.

18. The compound of claim 5, wherein A¹ is an optionally substituted 2-thiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 5, wherein A¹ is an optionally substituted 2-oxazoyl; or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of any one of claims 1-19, wherein L¹ is a bond, or an optionally substituted alkylene; or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of claim 20, wherein L is a bond; or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of claim 20, wherein L¹ is an optionally substituted alkylene; or a pharmaceutically acceptable salt or solvate thereof.

23. The compound of claim 20, wherein L¹ is an optionally substituted CrC₆ alkylene; or a pharmaceutically acceptable salt or solvate thereof.

24. The compound of claim 20, wherein L¹ is optionally substituted methylene; or a

pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 20, wherein L¹ is methylmethylene; or a pharmaceutically acceptable salt or solvate thereof.

26. The compound of claim 20, wherein L¹ is a Ci-C₆ alkylene; or a pharmaceutically acceptable salt or solvate thereof.

27. The compound of claim 20, wherein L¹ is methylene; or a pharmaceutically

acceptable salt or solvate thereof.

28. The compound of any one of claims 1-27, having the formula (II):

or a pharmaceutically acceptable salt or solvate thereof.

29. The compound of any one of claims 1 to 28, wherein R is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a

pharmaceutically acceptable salt or solvate thereof.

30. The compound of claim 29, wherein R is hydrogen, or an optionally substituted

moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

31. The compound of claim 29, wherein R is hydrogen or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

32. The compound of claim 29, wherein R is hydrogen or an optionally substituted Ci-C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

33. The compound of claim 29, wherein R is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

34. The compound of claim 29, wherein R is an optionally substituted CrC₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

35. The compound of claim 29, wherein R is an optionally substituted C1-C₃ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

36. The compound of claim 29, wherein R is 2-fluoroethyl; or a pharmaceutically

acceptable salt or solvate thereof.

37. The compound of claim 29, wherein R is an optionally substituted C₃-C6 cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

38. The compound of claim 29, wherein R is cyclopropyl; or a pharmaceutically

acceptable salt or solvate thereof.

39. The compound of claim 29, wherein R is cyclobutyl; or a pharmaceutically

acceptable salt or solvate thereof.

40. The compound of claim 29, wherein R is methyl; or a pharmaceutically acceptable salt or solvate thereof.

41. The compound of claim 29, wherein R is ethyl; or a pharmaceutically acceptable salt or solvate thereof.

42. The compound of claim 29, wherein R is butyl; or a pharmaceutically acceptable salt or solvate thereof.

43. The compound of any one of claims 1-27, having the formula (III):

wherein

W is -CH₂- , -O-,, -N(R¹⁷)-, -S- , -S(O)-,, or -S(0)₂-, or where W is -CH- or - and is substituted with R^6A or R^6B, or where W is -C-, and is substituted with R^6A and R^6B; and

m is 1 or 2;

or a pharmaceutically acceptable salt or solvate thereof.

44. The compound of claim 43, wherein W is -0-; or a pharmaceutically acceptable salt or solvate thereof.

45. The compound of claim 44, wherein m is 1; or a pharmaceutically acceptable salt or solvate thereof.

46. The compound of claim 43, wherein W is -S-_,, -S(O)-_,, or -S(0)₂; or a pharmaceutically acceptable salt or solvate thereof.

47. The compound of claim 43, wherein W is -S-; or a pharmaceutically acceptable salt or solvate thereof.

48. The compound of claim 47, wherein m is 1; or a pharmaceutically acceptable salt or solvate thereof.

49. The compound of claim 43, wherein W is -N(R 17 )-; or a pharmaceutically acceptable salt or solvate thereof.

50. The compound of claim 43, wherein W is -CH₂-; or a pharmaceutically acceptable salt or solvate thereof.

51. The compound of claim 50, wherein m is 1; or a pharmaceutically acceptable salt or solvate thereof.

52. The compound of claim 43, having the formula (Ilia):

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 52, wherein the A^L¹- moiety is substituted

pyrrolidine heterocycloalkyl ring according to the formula:

or a pharmaceutically acceptable salt or solvate thereof.

54. The compound of claim 53, wherein A¹ is an optionally substituted moiety selected form the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno-pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, pyrazinyl, pyrrolinyl, indolyl, and benzodiazepinyl; or a pharmaceutically acceptable salt or solvate thereof.

55. The compound of claim 53, wherein L¹ is a bond; A¹ is a substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

56. The compound of claim 55, wherein A¹ is 4-methylthiazol-2-yl; or a pharmaceutically acceptable salt or solvate thereof.

57. The compound of any one of claims 1 to 27 and 43 to 56, wherein R^6A and R^6B are independently hydrogen, halogen, -OH, -N(R⁸)R⁹, -OR¹⁰, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a

pharmaceutically acceptable salt or solvate thereof.

58. The compound of claim 57, wherein R 6B is hydrogen, or an optionally substituted moiety selected from aryl, aralkyl, heteroaryl, and heteroaralkyl; or a

pharmaceutically acceptable salt or solvate thereof.

59. The compound of claim 57, wherein R 6B is hydrogen, halogen, an optionally

substituted alkyl, or -OR¹⁰; or a pharmaceutically acceptable salt or solvate thereof.

60. The compound of claim 57, wherein R 6B is halogen; or a pharmaceutically acceptable salt or solvate thereof.

61. The compound of claim 60, wherein R 6B is fluoro; or a pharmaceutically acceptable salt or solvate thereof.

62. The compound of claim 57, wherein R^6B is hydrogen; or a pharmaceutically

acceptable salt or solvate thereof.

63. The compound of any of claims 58 to 62, wherein R^6A is hydrogen, halogen or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

64. The compound of any of claims 58 to 62, wherein R^6A is hydrogen or halogen; or a pharmaceutically acceptable salt or solvate thereof.

65. The compound of any of claims 58 to 62, wherein R^6A is hydrogen; or a

pharmaceutically acceptable salt or solvate thereof.

66. The compound of any of claims 58 to 62, wherein R^6A is halogen; or a

pharmaceutically acceptable salt or solvate thereof.

67. The compound of claim 66, wherein R^6A is fluoro; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 57, wherein each R and R is fluoro; or a pharmaceutically acceptable salt or solvate thereof.

The compound of any one of claims 1 to 27 and 52 to 68, wherein R^6A and R^6B are substituted on the pyrrolidine heterocycloalkyl ring according to the formula:

or a pharmaceutically acceptable salt or solvate thereof.

The compound of any one of claims 1 to 27 and 52 to 68, wherein R^6A and R^f substituted on the pyrrolidine heterocycloalkyl ring according to the formula:

or a pharmaceutically acceptable salt or solvate thereof.

71. The compound of any one of claims 1 to 70, wherein A is an optionally substituted arylene, an optionally substituted heteroarylene; or a pharmaceutically acceptable salt or solvate thereof.

72. The compound of claim 71, wherein A is an optionally substituted moiety selected from the group consisting of phenylene, pyridinylene, oxazolylene, thioazolylene, pyrazolylene, pyranylene, oxadiazolylene, imidazolylene, furanylene and

pyridonylene; or a pharmaceutically acceptable salt or solvate thereof.

73. The compoun

wherein

L 2 and L 3 are independently a bond or an optionally substituted C₁-C5

alkylene;

R 20 , R 21 , and R 22 are independently hydrogen, halogen, -N(R 24 )R 25 , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and hetero aralkyl;

each R 23 is independently hydrogen, halogen, cyano, -N0₂, -N(R 24 )R 25 , - OR²⁶, -SR²⁷, -S(0)R²⁷,

-S(0)₂R 27 , or 28

-C(0)R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl- alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

Y is -N= or -C(R²³)=;

wherein

R 29 is independently hydrogen, -N(R 31 )R 32 , or -OR 33 , an optionally

wherein

R 31 , R 32 , and R 3^J3^J are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl- alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and R is independently an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

R 3^J4" and R 3^J5^J are each independently hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and

28 36 37 38

R"° is independently -OR , -N(R^J')R , or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

wherein

R 36 , R 37 , and R 38 are each independently hydrogen, or an optionally

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 73, wherein A2 has the formula:

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 73, wherein A2 has the formula:

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 73, wherein A has the formula:

or a pharmaceutically acceptable salt or solvate thereof.

77. The compound of any one of claims 73 to 76, wherein Y is -C(R 23 )=; or a

pharmaceutically acceptable salt or solvate thereof.

78. The compound of any one of claims 73 to 76, wherein Y is -N=;-or a

pharmaceutically acceptable salt or solvate thereof.

79. The compound of any one of claims 73 to 77, wherein R 23 is hydrogen,

halogen, -N(R²⁴)R²⁵, -OR²⁶, -SR²⁷, -S(0)R²⁷, -S(0)₂R²⁷, -C(0)R²⁸, or an optionally substituted heterocycloalkyl;-or a pharmaceutically acceptable salt or solvate thereof.

80. The compound of claim 79, wherein R 23 is cyano or -N0₂, or a pharmaceutically acceptable salt or solvate thereof.

23 24 25

81. The compound of claim 79, wherein R is hydrogen, halogen, -N(R )R , or an optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

82. The compound of claim 81, wherein R 23 is halogen, or a pharmaceutically acceptable salt or solvate thereof.

83. The compound of claim 81, wherein R 23 is hydrogen

or a

pharmaceutically acceptable salt or solvate thereof.

84. The compound of claim 83, wherein R 23 is hydrogen; or a pharmaceutically

acceptable salt or solvate thereof.

85. The compound of claim 83, wherein R 23 is -N(R 24 )R 25 ; or a pharmaceutically

acceptable salt or solvate thereof.

86. The compound of claim 85, wherein R is -N(alkyl)alkylsulfonamido; or a pharmaceutically acceptable salt or solvate thereof.

87. The compound of claim 86, wherein R 23 is -N-methyl-methanesulfonamido; or a pharmaceutically acceptable salt or solvate thereof.

88. The compound of claim 79, wherein R²³ is -OR²⁶; or a pharmaceutically acceptable salt or solvate thereof.

89. The compound of claim 88, wherein R²⁶ is hydrogen or optionally substituted alkyl, or a pharmaceutically acceptable salt or solvate thereof.

90. The compound of claim 89, wherein R²⁶ is optionally substituted alkyl, or a

pharmaceutically acceptable salt or solvate thereof.

91. The compound of claim 90, wherein R²⁶ is difluromethyl or trifluoromethyl, or a pharmaceutically acceptable salt or solvate thereof.

92. The compound of claim 90, wherein R²⁶ is methyl or ethyl, or a pharmaceutically acceptable salt or solvate thereof.

93. The compound of claim 79, wherein R²³ is -SR²⁷, -S(0)R²⁷ or -S(0)₂R²⁷; or a

pharmaceutically acceptable salt or solvate thereof.

94. The compound of claim 79, wherein R 23 is -C(0)R 28 ; or a pharmaceutically

acceptable salt or solvate thereof.

95. The compound of claim 94, wherein R 28 is -OR 36 , or a pharmaceutically acceptable salt or solvate thereof.

96. The compound of claim 95, wherein R³⁶ is CrC₆ alkyl, or a pharmaceutically

acceptable salt or solvate thereof.

97. The compound of claim 94, wherein R 28 is -N(R 37 )R 38 , or a pharmaceutically

acceptable salt or solvate thereof.

98. The compound of claim 97, wherein each R 37 and R 38 is independently hydrogen or methyl, or a pharmaceutically acceptable salt or solvate thereof.

99. The compound of any one of claims 73 to 77, wherein R 23 is hydrogen, an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a

pharmaceutically acceptable salt or solvate thereof.

100. The compound of claim 99, wherein R 23 is an optionally substituted moiety selected from alkyl, cycloalkyl, and heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

101. The compound of claim 99, wherein R is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

102. The compound of claim 99, wherein 23

R is an optionally substituted Ci-C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

103. The compound of claim 99, wherein 23

R is CrC₆ alkyl substituted with one or more halogen; or a pharmaceutically acceptable salt or solvate thereof.

104. The compound of claim 103, wherein 23

R is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl and 2,2,2-trifluoroethyl; or a pharmaceutically acceptable salt or solvate thereof.

105. The compound of claim 99, wherein 23

R is methyl; or a pharmaceutically acceptable salt or solvate thereof.

106. The compound of claim 99, wherein 23

R is an optionally substituted cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

107. The compound of claim 106, wherein 23

R is cyclopropyl, or a pharmaceutically acceptable salt or solvate thereof.

108. The compound of claim 99, wherein 23

R is an optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

109. The compound of any one of claims 79, 81, 99, 100 or 108, wherein the optionally substituted heterocycloalkyl is an optionally substituted cyclic sulfonamido; or a pharmaceutically acceptable salt or solvate thereof.

110. The compound of claim 109, wherein the optionally substituted cyclic sulfonamido is

an optionally substituted

; or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 109, wherein R²³ is -_{v wn} ; or a pharmaceutically acceptable salt or solvate thereof.

112. The compound of claim 109, wherein R 23 is

; or a pharmaceutically acceptable salt or solvate thereof.

113. The compound of claim 109, wherein R 23 is optionally substituted pyrrolidinyl, or a pharmaceutically acceptable salt or solvate thereof.

114. The compound of claim 113, wherein R 23 is 2-oxopyrrolidin-l-yl, or a

pharmaceutically acceptable salt or solvate thereof.

115. The compound of claim 109, wherein R 23 is optionally substituted piperidinyl, or a pharmaceutically acceptable salt or solvate thereof.

116. The compound of claim 115, wherein R 23 is 2-oxopiperidin-l-yl, or a

pharmaceutically acceptable salt or solvate thereof.

117. The compound of claim 109, wherein R 23 is oxazolidinyl, or a pharmaceutically

acceptable salt or solvate thereof.

118. The compound of claim 117, wherein R 23 is 2-oxo-3-oxazolidinyl, or a

pharmaceutically acceptable salt or solvate thereof.

119. The compound of any one of claims 73 to 77, wherein R 23 is an optionally substituted moiety selected from cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl- alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.

120. The compound of claim 119, wherein R 23 is an optionally substituted moiety selected from aryl, aralkyl, heteroaryl, and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.

121. The compound of claim 119, wherein R 23 is an optionally substituted moiety selected from aryl and heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

122. The compound of claim 119, wherein R 23 is an optionally substituted aryl; or a

pharmaceutically acceptable salt or solvate thereof.

123. The compound of claim 119, wherein R 23 is an optionally substituted heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

124. The compound of claim 119, wherein R 23 is an optionally substituted moiety selected from pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, pyrimidyl, pyranyl, pyrazinyl, and furanyl; or a pharmaceutically acceptable salt or solvate thereof.

125. The compound of claim 124, wherein R is an optionally substituted moiety selected from thiazolyl, oxadiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl and pyrazinyl; or a pharmaceutically acceptable salt or solvate thereof.

126. The compound of claim 124, wherein R 23 is an optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof.

127. The compound of claim 124, wherein R 23 is an optionally substituted pyridyl; or a pharmaceutically acceptable salt or solvate thereof.

128. The compound of claim 124, wherein R 23 is an optionally substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

129. The compound of claim 124, wherein R 23 is an optionally substituted oxazolyl; or a pharmaceutically acceptable salt or solvate thereof.

130. The compound of claim 124, wherein R 23 is an optionally substituted oxadiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

131. The compound of claim 124, wherein R 23 is an optionally substituted imidazolyl; or a pharmaceutically acceptable salt or solvate thereof.

132. The compound of claim 124, wherein R 23 is an optionally substituted pyrazolyl; or a pharmaceutically acceptable salt or solvate thereof.

133. The compound of claim 124, wherein R 23 is an optionally substituted isoxazolyl; or a pharmaceutically acceptable salt or solvate thereof.

134. The compound of claim 124, wherein R 23 is an optionally substituted pyrimidyl; or a pharmaceutically acceptable salt or solvate thereof.

135. The compound of claim 124, wherein R 23 is an optionally substituted pyrazinyl; or a pharmaceutically acceptable salt or solvate thereof.

136. The compound of claim 124, wherein R 23 is an optionally substituted furanyl; or a pharmaceutically acceptable salt or solvate thereof.

137. The compound of claim 124, wherein R 23 is an optionally substituted triazolyl; or a pharmaceutically acceptable salt or solvate thereof.

138. The compound of claim 137, wherein R 23 is an optionally substituted 1,2,3-triazolyl; or a pharmaceutically acceptable salt or solvate thereof.

139. The compound of claim 137, wherein R 23 is an optionally substituted 1,2,4-triazolyl; or a pharmaceutically acceptable salt or solvate thereof.

140. The compound of claim 128, wherein R 23 is an optionally substituted 2-thiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

141. The compound of claim 129, wherein R is an optionally substituted 2-oxazoyl; or a pharmaceutically acceptable salt or solvate thereof.

142. The compound of claim 129, wherein R 23 is an optionally substituted 5-oxazoyl; or a pharmaceutically acceptable salt or solvate thereof.

143. The compound of claim 135, wherein R 23 is an optionally substituted 2-pyrazinyl; or a pharmaceutically acceptable salt or solvate thereof.

144. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein R 24 and R 25 are independently hydrogen, or an optionally substituted moiety selected from alkyl and heteroalkyl; or a pharmaceutically acceptable salt or solvate thereof.

145. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein R 24 and R 25 are independently hydrogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

146. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein at least one of

24 and 25 is hydro gen; or a pharmaceutically acceptable salt or solvate thereof.

147. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein R 24 and R 25 are hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

148. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein at least one of

24 and 25 is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

149. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein R 24 and R 25 are independently an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

150. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein at least one of

R 24 and R 25 is methyl; or a pharmaceutically acceptable salt or solvate thereof.

151. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein R 24 and R 25

29 30 are independently hydrogen, an optionally substituted alkyl, -C(0)R , or -S(0)₂R ; or a pharmaceutically acceptable salt or solvate thereof.

152. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein one of R 2"4" and

R 25 is -C(0)R 29 or -S(0)₂R 30 ; or a pharmaceutically acceptable salt or solvate thereof.

153. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein one of R 2"4" and

R 25 is -C(0)R 29 ; or a pharmaceutically acceptable salt or solvate thereof.

154. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein one of R 2"4" and

R 25 is -S(0)₂R 30 ; or a pharmaceutically acceptable salt or solvate thereof.

155. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

R 29 is independently hydrogen, an optionally substituted alkyl, -N(R 31 )R 32 , or -OR 33 ; or a pharmaceutically acceptable salt or solvate thereof.

156. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

9Q

R is independently hydrogen, or an optionally substituted alkyl; or a

pharmaceutically acceptable salt or solvate thereof.

157. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

9Q

R is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

158. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

9Q

R is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

159. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

9Q

R is methyl; or a pharmaceutically acceptable salt or solvate thereof.

160. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

R 29 is independently -N(R 31 )R 32 , or -OR 33 ; or a pharmaceutically acceptable salt or solvate thereof.

161. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

R 29 is -N(R 31 )R 32 ; or a pharmaceutically acceptable salt or solvate thereof.

162. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein

R 29 is -OR 33 ; or a pharmaceutically acceptable salt or solvate thereof.

163. The compound of any one of claims 73 to 77, 79 to 83, 85, 151 to 153, 155 and 160 to

162, wherein R 31 , R 32 , and R 33 are independently hydrogen, or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

164. The compound of any one of claims 73 to 77, 79 to 83, 85, 151, 152 and 154, wherein

R 30 is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

165. The compound of any one of claims 73 to 77, 79 to 83, 85, 151, 152 and 154, wherein

R 30 is methyl; or a pharmaceutically acceptable salt or solvate thereof.

166. The compound of claim 73, wherein A has the formula:

or a pharmaceutically acceptable salt or solvate thereof.

167. The compound of claim 166, wherein L is an optionally substituted C₂-C₅ alkylene; and L is a bond; or a pharmaceutically acceptable salt or solvate thereof.

168. The compound of claim 166, wherein L 2 is a bond; and L 3 is an optionally substituted C₂-C₅ alkylene; or a pharmaceutically acceptable salt or solvate thereof.

169. The compound of claim 166, wherein L 2 and L 3 are independently an optionally

substituted C₁-C₂ alkylene; or a pharmaceutically acceptable salt or solvate thereof.

170. The compound of claim 166, wherein L is an optionally substituted C₁-C₄ alkylene; and L is an optionally substituted methylene; or a pharmaceutically acceptable salt or solvate thereof.

171. The compound of claim 166, wherein L is an optionally substituted C₂-C₄ alkylene; and L is a bond or an optionally substituted methylene; or a pharmaceutically acceptable salt or solvate thereof.

172. The compound of any one of claims 73 to 171, wherein R 20 , R 21 , and R 22 are

independently hydrogen, or an optionally substituted C₁-C₁₀ alkyl; or a

pharmaceutically acceptable salt or solvate thereof.

173. The compound of any one of claims 73 to 171, wherein R 20 , R 21 , and R 22 are

independently hydrogen, or an optionally substituted Ci-C₆ alkyl; or a

pharmaceutically acceptable salt or solvate thereof.

174. The compound of any one of claims 73 to 171, wherein at least one of R 20 , R 21 , and

R 22 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

175. The compound of any one of claims 73 to 171, wherein R 20 , R 21 , and R 22 are

hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

176. The compound of any one of claims 73 to 171, wherein at least on of R 20 , R 21 and R 22 is -N(R 24 )R 25 ; or a pharmaceutically acceptable salt or solvate thereof.

177. The compound of any one of claims 73 to 171, wherein R 20 is -N(R 24 )R 25 ; or a

pharmaceutically acceptable salt or solvate thereof.

178. The compound of any one of claims 73 to 171, wherein R is -N(R )R ; or a pharmaceutically acceptable salt or solvate thereof.

179. The compound of any one of claims 73 to 171, wherein R is hydrogen; or a

pharmaceutically acceptable salt or solvate thereof.

180. The compound of any one of claims 73 to 171, wherein R²² is hydrogen and R ^u and

R 21 are independently hydrogen, or an optionally substituted Ci-C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

181. The compound of any one of claims 73 to 171, wherein R 22 is hydrogen and R 20 and

R 21 are independently hydrogen or methyl; or a pharmaceutically acceptable salt or solvate thereof.

182. The compound of any one of claims 73 to 171, wherein R 22 is hydrogen and one of

R 20 and R 21 is methyl; or a pharmaceutically acceptable salt or solvate thereof.

183. The compound of claim 166, wherein A is a moiety selected from the group

consisting of

, ,

or a pharmaceutically acceptable salt or solvate thereof.

184. The compound of claim 166, wherein A is a moiety of the formula

or a pharmaceutically acceptable salt or solvate thereof.

185. The compound of claim 183 or 184, wherein 20

R is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

186. The compound of claim 166, wherein A is a moiety selected from the group

consisting of

or a pharmaceutically acceptable salt or solvate thereof.

187. The compound of claim 166, wherein A is a moiety of the formula

armaceutically acceptable salt or solvate thereof.

188. The compound of claim 186 or 187, wherein R is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

189. The compound of any one of claims 73 to 188, wherein R 22 is hydrogen; or a

pharmaceutically acceptable salt or solvate thereof.

190. The compound of any one of claims 73 to 188, wherein R 22 is -N(R 24 )R 25 ; or a

pharmaceutically acceptable salt or solvate thereof.

191. The compound of cl

wherein each R is independently hydrogen or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

192. The compound of claim 191, wherein R³⁹ is hydrogen; or a pharmaceutically

acceptable salt or solvate thereof.

193. The compound of claim 191, wherein R is optionally substituted alkyl; or a

pharmaceutically acceptable salt or solvate thereof.

194. The compound of claim 191, wherein R is CrC₆ alkyl; or a pharmaceutically

acceptable salt or solvate thereof.

195. The compound of claim 194, wherein

is methyl or ethyl; or a pharmaceutically acceptable salt or solvate thereof.

196. The compound of any one of claims 1 to 195, wherein X¹ is N; or a pharmaceutically acceptable salt or solvate thereof.

197. The compound of any one of claims 1 to 195, wherein X is N; or a pharmaceutically acceptable salt or solvate thereof.

198. The compound of any one of claims 1 to 195, wherein both X 1 and X 2 are N; or a pharmaceutically acceptable salt or solvate thereof.

199. The compound of any one of claims 1 to 195, wherein both X 1 and X 2 are CH; or a pharmaceutically acceptable salt or solvate thereof.

200. The compound of any one of claims 1 to 195, wherein X 1 is N and X 2 is CH; or a pharmaceutically acceptable salt or solvate thereof.

201. The compound of any one of claims 1 to 195, wherein X 1 is CH and X 2 is N; or a pharmaceutically acceptable salt or solvate thereof.

202. The compound of any one of claims 1 to 201, wherein R³ is -N(R⁸)R⁹, -S(0)₂Rⁿ or -C(0)R 12 ; or a pharmaceutically acceptable salt or solvate thereof.

203. The compound of any one of claims 1 to 201, wherein R 3 is hydrogen, -C(O) t Bu, or an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

204. The compound of claim 202, wherein R 3 is -C(0)R 12 ; or a pharmaceutically

acceptable salt or solvate thereof.

205. The compound of claim 204, wherein R 12 is an optionally substituted CrC₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

206. The compound of any one of claims 1 to 201, wherein R³ is hydrogen, or an

optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.

207. The compound of claim 206, wherein R is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

208. The compound of claim 206, wherein R is hydrogen or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

209. The compound of claim 206, wherein R is hydrogen or an optionally substituted Ci- C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

210. The compound of claim 206, wherein R is hydrogen; or a pharmaceutically

acceptable salt or solvate thereof.

211. The compound of claim 206, wherein R is an optionally substituted Ci-C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

212. The compound of claim 206, wherein R is methyl; or a pharmaceutically acceptable salt or solvate thereof.

213. The compound of any one of claims 1 to 212, wherein R⁴ is hydrogen; or a

pharmaceutically acceptable salt or solvate thereof.

214. The compound of any one of claims 1 to 212, wherein R⁴ is an optionally substituted moiety selected from alkyl and heteroalkyl; or a pharmaceutically acceptable salt or solvate thereof.

215. The compound of any one of claims 1 to 212, wherein R⁴ is an optionally substituted moiety selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

216. The compound of claim 215, wherein R⁴ is an optionally substituted moiety selected from cycloalkyl and heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

217. The compound of claim 215, wherein R⁴ is an optionally substituted moiety selected from aryl and heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

218. The compound of claim 215, wherein R⁴ is an optionally substituted aryl; or a

pharmaceutically acceptable salt or solvate thereof.

219. The compound of claim 215, wherein R⁴ is an optionally substituted heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

220. The compound of claim 218, wherein R⁴ is phenyl; or a pharmaceutically acceptable salt or solvate thereof.

221. The compound of claim 218, wherein R⁴ is phenyl, optionally substituted with one or more halogens; or a pharmaceutically acceptable salt or solvate thereof.

222. The compound of claim 221, wherein R⁴ is 3,5-difluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.

223. The compound of claim 221, wherein R⁴ is 4-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.

224. The compound of claim 221, wherein R⁴ is 3 -fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.

225. The compound of any one of claims 1 to 224, wherein L⁴ is a bond, or an optionally substituted alkylene; or a pharmaceutically acceptable salt or solvate thereof.

226. The compound of claim 225, wherein L⁴ is a bond; or a pharmaceutically acceptable salt or solvate thereof.

227. The compound of claim 225, wherein L⁴ is an optionally substituted alkylene; or a pharmaceutically acceptable salt or solvate thereof.

228. The compound of claim 225, wherein L⁴ is an optionally substituted CrC₆ alkylene; or a pharmaceutically acceptable salt or solvate thereof.

229. The compound of claim 225, wherein L⁴ is a Ci-C₆ alkylene; or a pharmaceutically acceptable salt or solvate thereof.

230. The compound of claim 225, wherein L⁴ is methylene; or a pharmaceutically acceptable salt or solvate thereof.

231. The compound of any one of claims 1 to 230, wherein R⁵ is hydrogen, or an

232. The compound of claim 231, wherein R⁵ is hydrogen, or an optionally substituted moiety selected from alkyl, cycloalkyl, and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

233. The compound of claim 231, wherein R⁵ is hydrogen or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

234. The compound of claim 231, wherein R⁵ is hydrogen or an optionally substituted Cp C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

235. The compound of claim 231, wherein R⁵ hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

236. The compound of claim 231, wherein R⁵ is an optionally substituted Ci-C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

237. The compound of claim 231, wherein R⁵ is methyl; or a pharmaceutically acceptable salt or solvate thereof.

238. The compound of any one of claims 1-237, having the formula (IV):

or a pharmaceutically acceptable salt or solvate thereof.

239. The compound of claim 238, wherein R^7A is an optionally substituted moiety selected from alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR¹⁰, -alkyl-N(R⁸)R⁹,

heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.

240. The compound of claim 239, wherein R^7A is an optionally substituted moiety selected from alkyl, cycloalkyl and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

241. The compound of claim 239, wherein R is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof.

242. The compound of claim 239, wherein R^7A is an optionally substituted Ci-C₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof.

243. The compound of claim 239, wherein R^7A is methyl; or a pharmaceutically acceptable salt or solvate thereof.

244. The compound of claim 239, wherein R^7A is an optionally substituted moiety selected from -alkyl-OR¹⁰ and -alkyl-N(R⁸)R⁹; or a pharmaceutically acceptable salt or solvate thereof.

245. The compound of claim 239, wherein R^7A is an optionally substituted -alkyl-OR¹⁰; or a pharmaceutically acceptable salt or solvate thereof.

246. The compound of claim 245, wherein R^7A is -CH₂OCH₃; or a pharmaceutically

acceptable salt or solvate thereof.

247. The compound of claim 239, wherein R^7A is an optionally substituted moiety selected from heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; or a pharmaceutically acceptable salt or solvate thereof.

248. The compound of claim 239, wherein R^7A is an optionally substituted aralkyl; or a pharmaceutically acceptable salt or solvate thereof.

249. The compound of claim 239, wherein R^7A is an optionally substituted -alkylene- phenyl; or a pharmaceutically acceptable salt or solvate thereof.

250. The compound of claim 249, wherein R^7A is benzyl or 3-pheylpropyl; or a

pharmaceutically acceptable salt or solvate thereof.

251. The compound of claim 239, wherein R^7A is an optionally substituted moiety selected from phenyl, pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothieno- pyrazolyl, thianaphthenyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzisoxazolyl, dimethylhydantoin, pyrazinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, indolyl, diazepinyl, azepinyl, thiepinyl, piperidinyl, and oxepinyl; or a pharmaceutically acceptable salt or solvate thereof.

252. The compound of claim 239, wherein R^7A is an optionally substituted moiety selected from pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidyl, pyrazinyl and furanyl; or a pharmaceutically acceptable salt or solvate thereof.

253. The compound of claim 239, wherein R^7A is an optionally substituted moiety selected from pyridyl and imidazolyl; or a pharmaceutically acceptable salt or solvate thereof.

254. The compound of claim 1, wherein the compound is selected from the group

consisting of:

tert-Butyl (2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)carbamoyl)phenyl)- l,3,4-oxadiazol-2-yl)-l-phenylpropan-2-yl)carbamate;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(pyridin-3-yl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- methylphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-methyl-5-(5-((R)-2-(methylamino)-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyrazin-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

N-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-N-methylmethanesulfonamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- (fluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- chlorophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone; (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((2R,4S)- 4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

l-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)pyrrolidin-2-one;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- (dimethylamino)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(4-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-6- (dimethylamino)pyridin-2-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- methoxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

3'-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5'-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)-[ 1 , 1 '-biphenyl] -2-carbonitrile;

(7-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)chroman-5- yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrrol-l- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-2- hydroxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-N-((4-methylthiazol-2-yl)methyl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-4,4-difluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((4-methylthiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-(N- methylmethylsulfonamido)-N-((4-methylthiazol-2-yl)methyl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopentyl-N- ((4-methylthiazol-2-yl)methyl)benzamide; (4-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5-(l -methyl- 1H- pyrazol-4-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-imidazol-

1- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- methylphenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)pyridin-3-yl)((R)-

2- (4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-(fluoromethyl)thiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-imidazol- 2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)chroman-7- yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)- 2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyridin-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5-(l -methyl- 1H- pyrrol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(3-(5-((R)-2-amino-l-(4-f uorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone; (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (pyrazin-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4- methylthiazol-2-yl)piperidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(5-methyl- l,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-isopropyl-N- ((4-methylthiazol-2-yl)methyl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((5- methyl- 1 ,2,4-oxadiazol-3-yl)methyl)benzamide;

(2-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-6- (dimethylamino)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

3 - [5-( 1 - Amino-2-phenylcyclohexyl)- 1 ,3 ,4-oxadiazol-2-yl] -N-methyl-N- [(4- methyl- 1 , 3 -thiazol-2- yl)methyl] benzamide ;

rel-3- { 5- [( 1 R,2R)- 1 - Amino-2-phenylcyclopropyl] - 1 ,3 ,4-oxadiazol-2-yl } -N- methyl-N-[(4-methyl- 1 ,3-thiazol-2-yl)methyl]benzamide;

rel-3- { 5-[( 1R,2S)- 1 -Amino-2-phenylcyclopropyl] - 1 ,3,4-oxadiazol-2-yl } -N- methyl-N-[(4-methyl- 1 ,3-thiazol-2-yl)methyl]benzamide;

3-(5-(2- Amino- l-methoxy-3-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl- N- ((4-methylthiazol-2- yl)methyl)benzamide ;

3-(5-(rel-(lS,2R)-l-Amino-2-phenylcyclobutyl)-l,3,4-oxadiazol-2-yl)-N-methyl- N- ((4-methylthiazol-2- yl)methyl)benzamide ;

3-(5-(rel-(lR,2R)-l-Amino-2-phenylcyclobutyl)-l,3,4-oxadiazol-2-yl)-N-methyl- N- ((4-methylthiazol-2- yl)methyl)benzamide ;

3-{5-[(4E)-2-Amino-l,5-diphenylpent-4-en-2-yl]-l,3,4-oxadiazol-2-yl}-N- methyl-N-[(4-methyl- 1 ,3-thiazol-2-yl)methyl]benzamide;

3-[5-(2-Amino-l,5-diphenylpentan-2-yl)-l,3,4-oxadiazol-2-yl]-N-methyl-N-[(4- methyl- 1 , 3 -thiazol-2- yl)methyl] benzamide ;

3- [5-(2- Amino- 1 ,3-diphenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl] -N-methyl-N- [(4- methyl- 1 ,3-thiazol-2-yl)methyl]benzamide; rel-3- { 5-[( 1R,2R)- 1 - Amino-2-phenylcyclopentyl] - 1 ,3,4-oxadiazol-2-yl } -N- methyl-N-[(4-methyl- 1 ,3-thiazol-2-yl)methyl]benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5- (oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((2- methylthiazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((2- methyloxazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((R)-l-(4- methylthiazol-2-yl)ethyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N- methyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((5- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methyloxazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-4-(4-methylthiazol-2-yl)oxazolidin-3-yl)methanone;

(R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyrazin-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((3- methyl- 1 ,2,4-oxadiazol-5-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyridin-2-yl)benzamide; (R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-chloro-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methylbenzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- chlorophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- chlorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-(tert-butyl)-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- (fluoromethyl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((4-methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- (difluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclobutyl-N- ((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l,3,4- oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

5-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-l,3,4-oxadiazol-2(3H)-one;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5-(l - fluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

l-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)phenyl)ethanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrazol-l- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(isoxazol-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(l,l- difluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone; (3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(isoxazol-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(lH-pyrazol-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)benzonitrile;

5-(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine-l-carbonyl)phenyl)-3-methyl-l,3,4-oxadiazol-2(3H)- one;

Ethyl 3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)benzoate;

(3-(5-((R)-2-amino-l-cyclohexylpropan-2-yl)-l,3,4-oxadiazol-2-yl)phenyl)((R)-2- (4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(3-(5-((R)-2-amino-l-cyclohexylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(thiazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-((R)- 2-(4-methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)benzamide;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)benzamide;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N,N-dimethyl-5- ((R)-2-(4-methylthiazol-2-yl)pyrrolidine-l-carbonyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(thiazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-(2-fluoroethyl)- N- ((4-methylthiazol-2- yl)methyl) - 5 -(oxazol-2-yl)benzamide ;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-ethyl-5-((R)-2- (4-methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)benzamide;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(thiazol-2- yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone; (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (thiazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone;

3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-((R)-2-(4- methylthiazol-2-yl)pyrrolidine- 1 -carbonyl)benzoic acid;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- hydroxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((S)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((S)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((S)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((S)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (dimethylamino)-N-methyl-N-((4-methylthiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(N- methylmethylsulfonamido)-N-((4-methylthiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4-methoxy-N-methylbenzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- methoxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- methoxyphenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone;

(R)-5-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-6-methoxy-N-methylnicotinamide;

(5-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-6- methoxypyridin-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(5-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-6- methoxypyridin-3-yl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l- yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-N-methyl-4-(trifluoromethoxy)benzamide; (3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5-(l -methyl- 1H- imidazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-[l,l'-biphenyl]-3- yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin- 1 -yl)methanone;

(5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-3'-methoxy-[l,l'- biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-2'-methoxy-[l,l'- biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(furan-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- iodophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-ethyl-N-((4- methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- nitrophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(furan-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyrimidin-5- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(pyridin-3- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5-(N- methylsulfamoyl)-N-((4-methylthiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-N-((4- methylthiazol-2-yl)methyl)-5-(pyridin-2-yl)benzamide;

(3-(5-((R)-2-amino-l-(2-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(2- methylthiazol-4-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone; (3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5-(4,5- dimethylthiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((3- fluoropyridin-2-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-methyl-5- (oxazol-2-yl)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-4-fluoro-N- methyl-N-((4-methylthiazol-2-yl)methyl)benzamide;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4-fluoro-N-methylbenzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4- fluorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((2,5-dimethyloxazol-4-yl)methyl)-4-fluorobenzamide;

(2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- cyclopropylpyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

2-(6- { 5-[(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3,4-oxadiazol-2-yl } -4- { [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yljcarbonyl }pyridin-2-yl)benzonitrile;

[2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

(2- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- methoxypyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

N-(6- { 5-[(2R)-2-Amino- 1 -phenylpropan-2-yl] - 1 ,3,4-oxadiazol-2-yl } -4- { [(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N- methylmethanesulfonamide;

N-(4- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- { [(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-N- methylmethanesulfonamide; (4- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- methoxypyridin-2-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl][(2R)-2-(4-ethyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl][(2R)-2-(4-cyclopropyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l,3-oxazol- 2-yl)pyridin-4-yl] {(2R)-2-[4-(methoxymethyl)-l,3-thiazol-2-yl]pyrrolidin-l- yljmethanone;

(6- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -2,3'-bipyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

(6- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -2,4'-bipyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2-{5-[(2R)-2-Amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(pyrimidin-5- yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

(2- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- methylpyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 , 1 -dioxido- l,2-thiazolidin-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

N-(6- { 5-[(2R)-2-Amino- 1 -phenylpropan-2-yl] - 1 ,3,4-oxadiazol-2-yl } -4- { [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yljcarbonyl }pyridin-2- yl)methanesulfonamide;

(4- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- methoxypyridin-2-yl)[(2R)-2-(4,5-dimethyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

[4- { 5- [(2R)-2- Amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6-( 1 ,3 -oxazol- 2-yl)pyridin-2-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

1 -(6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -4- { [(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one;

3-(6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -4- { [(2R)-2- (4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2-yl)-l,3-oxazolidin-2- one; l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yljcarbonyl }pyridin-2-yl)-5-methylpyrrolidin- 2-one;

l-(6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yljcarbonyl }pyridin-2-yl)piperidin-2-one;

N-(6- { 5-[(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3,4-oxadiazol-2-yl } -4- { [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yljcarbonyl }pyridin-2-yl)-N- methylacetamide ;

1- (4-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-{ [(2R)-2- (4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 -yljcarbonyl }pyridin-2-yl)pyrrolidin-2-one;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-l,2,4- triazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-imidazol- l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-pyrazol- l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(2H-l,2,3- triazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(lH-l,2,3- triazol-l-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l-methyl- lH-pyrazol-4-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l-methyl- lH-pyrazol-5-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

2- {5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(4-bromo- l,3-thiazol-2-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide;

2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N-methyl-N- [(6- methylpyridin-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide; 2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[l-(l-methyl- lH-pyrazol-3-yl)ethyl]-6-(l,3-oxazol-2-yl)isonicotinamide;

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(6- methylpyridin-2-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide;

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(l- methyl-lH-pyrazol-4-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide;

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(l,5- dimethyl-lH-pyrazol-4-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide;

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(l,3- dimethyl-lH-pyrazol-5-yl)methyl]-N-methyl-6-(l,3-oxazol-2-yl)isonicotinamide;

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(l-methyl-lH- pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

(2-amino-6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}pyridin- 4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-methyl-N-[(l- methyl-lH-pyrazol-3-yl)methyl]-6-(l,3-oxazol-2-yl)isonicotinamide;

(6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl }pyridin-2- yl)[(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- l-yl]methanone;

(2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl }pyridin-4- yl)[(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- l-yl]methanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6-(pyrrolidin-l- yl)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- (difluoromethoxy)pyridin-4-yl] [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yljmethanone;

4- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 -methyl-6- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one;

6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } - 1 - (cyclopropylmethyl)-4- { [(2R)-2-(4-methyl- 1 ,3-thiazol-2-yl)pyrrolidin- 1 - yl]carbonyl}pyridin-2(lH)-one; 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-ethyl-4- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one;

(2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- ethoxypyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]methanone;

(2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- [(2- methoxyethyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

(2- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -6- [(2- methoxyethyl)(methyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-l,3-thiazol-2- yl)pyrrolidin- 1 -yljmethanone;

[2-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-6- (ethylamino)pyridin-4-yl][(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l- yljmethanone;

3-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-5- { [(2R)-2-(4-methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-4-{ [(2R)-2-(4- methyl-l,3-thiazol-2-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl-2- oxo-N-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-4-carboxamide;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl-N- [(6-methylpyridin-2-yl)methyl] -2-oxo- 1 ,2-dihydropyridine-4-carboxamide;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-butyl-l- methyl-2-oxo-N-(pyridin-4-ylmethyl)-l,2-dihydropyridine-4-carboxamide;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-l-methyl-4-{ [2- (3-methyl-l,2,4-oxadiazol-5-yl)pyrrolidin-l-yl]carbonyl}pyridin-2(lH)-one;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-butyl-l- methyl-2-oxo-N-(pyridin-3-ylmethyl)-l,2-dihydropyridine-4-carboxamide;

6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N,l-dimethyl-2- oxo-N-(lH-pyrazol-5-ylmethyl)-l,2-dihydropyridine-4-carboxamide;

6- { 5- [(2R)-2-amino- 1 -phenylpropan-2-yl] - 1 ,3 ,4-oxadiazol-2-yl } -N, 1 -dimethyl-2- oxo-N-[ 1 -(2-thienyl)ethyl] - 1 ,2-dihydropyridine-4-carboxamide; 6-{5-[(2R)-2-amino-l-phenylpropan-2-yl]-l,3,4-oxadiazol-2-yl}-N-[(2,5- dimethyl- 1 ,3-oxazol-4-yl)methyl] -N, 1 -dimethyl-2-oxo- 1 ,2-dihydropyridine-4- carboxamide;

(R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N- cyclopropyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- bromophenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-5- chlorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide;

(3-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-4,5- difluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone;

(3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-4- fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-5-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-2,4-difluoro-N-methylbenzamide;

(R)-4-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-5-fluoro-N-methylpicolinamide;

(R)-4-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-5-methoxy-N-methylpicolinamide;

(R)-3-(5-(2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-N-((2,5- dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide;

(3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-4,5- difluorophenyl)((S)-2-(4-methyloxazol-2-yl)pyrrolidin-l-yl)methanone; and

(5-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-2,4- diiluorophenyl)((R)-2-(4-melhyloxazol-2-yl)pyrrolidin- 1 -yl)methanone;

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 1, wherein the compound is selected from the group consisting of:

(3-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-5-(oxazol-2- yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone; (3-(5-((R)-2-amino-l-(4-fluorophenyl)propan-2-yl)-l,3,4-oxadiazol-2-yl)-5- (oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(2-(5-((R)-2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-6-(oxazol-2- yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(2-(5-((R)-2-amino- 1 -phenylpropan-2-yl)- 1 ,3,4-oxadiazol-2-yl)-6-(l -methyl- 1H- pyrazol-4-yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-l-yl)methanone;

(R)-3-(5-(2-amino-l-phenylpropan-2-yl)-l,3,4-oxadiazol-2-yl)-N-cyclopropyl-N- ((2,5-dimethyloxazol-4-yl)methyl)-4-fluorobenzamide; and

or a pharmaceutically acceptable salt or solvate thereof.

256. A compound of the formula (V):

wherein A¹, A², X¹, X², R^6A, R^6B, R^7A and R^7B are as defined in any one of the preceeding claims, where applicable;

or a pharmaceutically acceptable salt or solvate thereof.

257. The compound of claim 256, wherein the compound is of the formula (Va):

wherein L⁴ and R⁴ are as defined in any one of the preceeding claims, where applicable;

or a pharmaceutically acceptable salt or solvate thereof.

259. The compound of claim 258, wherein the compound is of the formula (Vc):

wherein Y, R , R and R are as defined in any one of claims 73 and 77 to 190, where applicable;

or a pharmaceutically acceptable salt or solvate thereof.

260. The compound of claim 258, wherein the compound is of the formula (Vd):

or a pharmaceutically acceptable salt or solvate thereof.

The compound of claim 258, wherein the compound is of the formula (Ve):

wherein R is as defined in any one of claims 73 and 79 to 165;

or a pharmaceutically acceptable salt or solvate thereof.

262. The compound of claim 258, wherein the compound is of the formula (Vf):

wherein Y is N or CH, and

R⁴⁰ is halo gen or optionally substituted alkoxy;

or a pharmaceutically acceptable salt or solvate thereof.

263. The compound of claim 262, wherein Y is CH, or a pharmaceutically acceptable salt or solvate thereof.

264. The compound of claim 262 or 263, wherein R⁴⁰ is optionally substituted methoxy, or a pharmaceutically acceptable salt or solvate thereof.

265. The compound of claim 262 or 263, wherein R⁴⁰ is halogen, or a pharmaceutically acceptable salt or solvate thereof.

266. The compound of claim 265, wherein R is fluoro or chloro, or a pharmaceutically acceptable salt or solvate thereof.

267. The compound of any one of claims 256 to 266, wherein R^6B is hydrogen; or a

pharmaceutically acceptable salt or solvate thereof.

268. The compound of any one of claims 256 to 266, wherein R^6B is halogen; or a

pharmaceutically acceptable salt or solvate thereof.

269. The compound of claim 268, wherein R 6B is fluoro; or a pharmaceutically acceptable salt or solvate thereof.

270. The compound of any one of claims 256 to 269, wherein R^6A is hydrogen; or a

pharmaceutically acceptable salt or solvate thereof.

271. The compound of any one of claims 256 to 269, wherein R^6A is halogen; or a

pharmaceutically acceptable salt or solvate thereof.

272. The compound of claim 271, wherein R^6A is fluoro; or a pharmaceutically acceptable salt or solvate thereof.

273. A compound of the formula (VI):

wherein A¹, A², X¹, X², L¹, R², R^7A and R^7B are as defined in any one of the preceeding claims, where applicable;

or a pharmaceutically acceptable salt or solvate thereof.

274. The compound of claim 273, wherein the compound is of the formula (Via):

or a pharmaceutically acceptable salt or solvate thereof.

275. The compound of claim 274, wherein the compound is of the formula (VII):

or a pharmaceutically acceptable salt or solvate thereof.

276. The compound of claim 274, wherein the compound is of the formula (VIII):

or a pharmaceutically acceptable salt or solvate thereof.

277. The compound of claim 274, wherein the compound is of the formula (IX):

wherein R is as defined in any one of claims 73 and 79 to 165;

or a pharmaceutically acceptable salt or solvate thereof.

278. The compound of claim 274, wherein the compound is of the formula (X):

wherein Y is N or CH, and R is halogen or optionally substituted alkoxy;

or a pharmaceutically acceptable salt or solvate thereof.

279. The compound of claim 278, wherein Y is CH, or a pharmaceutically acceptable salt or solvate thereof.

280. The compound of claim 278 or 279, wherein R⁴⁰ is halogen, or a pharmaceutically acceptable salt or solvate thereof.

281. The compound of claim 278 or 279, wherein R⁴⁰ is optionally substituted alkoxy, or a pharmaceutically acceptable salt or solvate thereof.

282. The compound of claim 281, wherein R⁴⁰ is trifluromethoxy, or a pharmaceutically acceptable salt or solvate thereof.

283. The compound of any one of claims 273 to 282, wherein L¹ is methylene; or a

pharmaceutically acceptable salt or solvate thereof.

284. The compound of any one of claims 256 to 283, wherein R^7A is substituted or

unsubstituted alkyl or substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt or solvate thereof.

285. The compound of claim 284, wherein R^7A is methyl; or a pharmaceutically acceptable salt or solvate thereof.

286. The compound of any one of claims 256 to 285, wherein L⁴ is methylene; or a

pharmaceutically acceptable salt or solvate thereof.

287. The compound of claim 286, wherein R⁴ is substituted or unsubstituted aryl; or a pharmaceutically acceptable salt or solvate thereof.

288. The compound of claim 287, wherein R⁴ is phenyl; or a pharmaceutically acceptable salt or solvate thereof.

289. The compound of claim 287, wherein R⁴ is 4-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.

290. The compound of any one of claims 256 to 289, wherein A¹ is optionally substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof.

291. The compound of claim 290, wherein A¹ is 4-methylthiazol-2-yl; or a

pharmaceutically acceptable salt or solvate thereof.

292. The compound of claim 290, wherein A¹ is 4-(fluoromethyl)thiazol-2-yl; or a

pharmaceutically acceptable salt or solvate thereof.

293. The compound of any one of claims 256 to 289, wherein A¹ is optionally substituted oxazolyl; or a pharmaceutically acceptable salt or solvate thereof.

294. The compound of claim 293, wherein A¹ is 4-methyloxazol-2-yl; or a pharmaceutically acceptable salt or solvate thereof.

295. The compound of any one of claims 256 to 266 and 267 to 285, wherein A¹ is

optionally substituted thiazolyl; and R⁴ is optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof.

296. The compound of claim 295, wherein A¹ is 4-methylthiazol-2-yl, 4- (fluoromethyl)thiazol-2-yl or 4-methyloxazol-2-yl; and R⁴ is phenyl or 4- fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof.

297. The compound of any one of claims 256 to 296, wherein X¹ is N; or a

pharmaceutically acceptable salt or solvate thereof.

298. The compound of claim 297, wherein X is N; or a pharmaceutically acceptable salt or solvate thereof.

299. The compound of claim 297, wherein X is CH; or a pharmaceutically acceptable salt or solvate thereof.

300. The compound of any one of claims 256 to 296, wherein X¹ is CH; or a

pharmaceutically acceptable salt or solvate thereof.

301. The compound of claim 300, wherein X is CH; or a pharmaceutically acceptable salt or solvate thereof.

302. The compound of claim 300, wherein X is N; or a pharmaceutically acceptable salt or solvate thereof.

303. The compound of any one of claims 1 to 302, wherein the compound has a memapsin 2 K; of less than about 300 nM; or a pharmaceutically acceptable salt or solvate thereof.

304. The compound of any one of claims 1 to 302, wherein the compound has an apparent memapsin 2 K_; of less than about 300 nM as measured by inhibition of memapsin 2 catalytic activity toward the fluorogenic substrate FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2); or a pharmaceutically acceptable salt or solvate thereof.

305. The compound of any one of claims 1 to 304, wherein the compound is capable of inhibiting cellular Αβ production with an IC₅₀ of less than about 500 nM; or a pharmaceutically acceptable salt or solvate thereof.

306. The compound of any one of claims 1 to 305, wherein the compound is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 306, wherein the compound is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity by greater than about 5-fold; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 307, wherein the compound is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity cathepsin D by greater than about 5-fold; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 308, wherein the compound (a) has a memapsin 2 K_; of less than about 300 nM; (b) is capable of inhibiting cellular Αβ production with an IC₅₀ of less than about 500 nM; and (c) is capable of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 or cathepsin D catalytic activity by greater than about 5-fold; or a pharmaceutically acceptable salt or solvate thereof.

The compound of any one of claims 1 to 309, wherein the compound is substantially pure; or a pharmaceutically acceptable salt or solvate thereof.

1. A formulation comprising a compound of any one of claims 1 to 309 or a

pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

A formulation comprising an effective amount of compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

A method of treating Alzheimer's disease in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof.

A method of treating of a condition mediated by memapsin 2 catalytic activity in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof.

A method of reducing memapsin 2 catalytic activity, the method comprising contacting memapsin 2 with an effective amount of a compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof.

The method of claim 315, wherein said memapsin 2 is contacted in a cell.

A method of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity, the method comprising contacting a memapsin 2 with an effective amount of a compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof in the presence of memapsin 1.

318. A method of selectively reducing memapsin 2 catalytic activity relative to cathepsin D catalytic activity, the method comprising contacting a memapsin 2 protein with a therapeutically effective amount of a compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof in the presence of cathepsin D.

319. A method of selectively reducing memapsin 2 catalytic activity relative to memapsin 1 catalytic activity and cathepsin D catalytic activity, the method comprising contacting memapsin 2 with a therapeutically effective amount of a compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof in the presence of memapsin 1 and cathepsin D.

320. A compound of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.

321. Use of one or more compounds of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of a condition mediated by memapsin 2 catalytic activity.

322. Use of one or more compounds of any one of claims 1 to 309 or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of a condition mediated by memapsin 2 catalytic activity.

323. Use as described in claim 321 or 322, wherein the condition is Alzheimer's disease.

324. A kit for the treatment or prevention in an individual with Alzheimer's disease,

comprising:

(a) a compound of any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvate thereof; and

(b) packaging.

325. A kit for the treatment or prevention in an individual of a condition mediated by

memapsin 2 catalytic activity, comprising:

(b) packaging.

326. A kit for the treatment or prevention in an individual with Alzheimer's disease,

comprising:

(a) a formulation of claim 321 or 322; and (b) packaging.

A kit for the treatment or prevention in an individual of a condition mediated by memapsin 2 catalytic activity, comprising:

(a) a formulation of claim 321 or 322; and

(b) packaging.